Selective synthesis and reactivity of indolizines · indolizines and nitrosocompounds”...

Selective synthesis and reactivity of indolizines

María José González Soria

https://www.ua.es/

http://www.eltallerdigital.com/es/index.html

Instituto de Síntesis Orgánica

Facultad de Ciencias

SELECTIVE SYNTHESIS AND REACTIVITY OF

INDOLIZINES

MARÍA JOSÉ GONZÁLEZ SORIA

Alicante, 26/07/2018

Manuscript submitted for a PhD in Organic Synthesis, University of Alicante

Mention of International PhD

Scientific advisor:

FRANCISCO ALONSO VALDÉS

Agradecimientos

Quiero agradecer en especial a Luis y a mi madre, a mis hermanas y hermanos y a

Juan por todo el apoyo recibido durante este tiempo.

Asimismo, agradezco a Francisco Alonso por su ayuda y por darme la oportunidad

de trabajar en su grupo de investigación, al Instituto de Síntesis Orgánica y a la

Generalitat Valenciana por el apoyo económico. También a mi familia orgánica,

Juani, Iris y Xavi, por estar siempre a mi lado cuando más lo he necesitado tanto en

lo profesional como en lo personal. A Nieves, Manu, María y Edgar, y a todos los

compañeros del laboratorio y, en general, a todos los miembros del Departamento de

Química Orgánica e Instituto de Síntesis Orgánica de la Universidad de Alicante,

muchas gracias por todo.

Y gracias a mi padre, sin su sacrificio no habría podido llegar hasta aquí.

Index

7

PROLOGUE 7

SUMMARY 11

GENERAL INTRODUCTION 15

A. Introduction to nanoparticles 17

A.1. Properties of metallic nanoparticles 17

A.2. Synthesis of metallic nanoparticles 18

A.3. Metallic nanoparticles in catalysis 21

A.4. Copper nanoparticles (CuNPs) 23

B. Introduction to indolizines 27

B.1. Structure and applications 27

B.2. Synthetic methods 29

GENERAL OBJECTIVES 37

CHAPTER I. Multicomponent synthesis of 1-

aminoindolizines

41

1. Introduction 43

1.1.1. Multicomponent reactions in heterocyclic

synthesis

43

1.1.2. Multicomponent synthesis of indolizines 44

2. Results and discussion 48

1.2.1. Previous study 48

1.2.2. Substrate scope 49

1.2.3. Reutilization of the catalyst 54

1.2.4. Comparison with commercial catalysts 54

1.2.5. Reaction mechanism 57

1.2.6. Biological activity 59

CHAPTER II. Catalytic hydrogenation of indolizines:

synthesis of indolizidines

65

1. Introduction 67


2.2.1. Optimization of the reaction 72

2.2.2. Reutilization of the catalysts 76

Index

8


2.2.4. Stereochemistry and mechanism 80

2.2.5. Debenzylation of indolizidines 82

2.2.6. Biological activity 86

CHAPTER III. Reactivity of indolizines: synthesis of dyes 87

1. Introduction 89



3.2.2. Structural analysis 100


3.2.4. Optical properties 110

3.2.5. Metal detection 115

CHAPTER IV. Reactivity of indolizines with

nitrosocompounds: synthesis of β-enaminones

and pyrroles

119

1. Introduction 121

4.1.1. β-Enaminones 121

4.1.2. Pyrroles 123

2. Results and disussion 127

4.2.1. Synthesis of β-enaminones 127

4.2.2. Selectivity in the synthesis of β-enaminones 133

4.2.3. Synthesis of pyrroles 135


Conclusions 157

Resumen

Conclusiones 161

Experimental part 165

General 167

Experimental part of chapter I 168

Experimental part of chapter II 187

Index

9

Experimental part of chapter III 199

Experimental part of chapter IV 210

Selected NMR spectra 229

Abbreviations 239

PROLOGUE

Prologue

13

Part of the results reported in this thesis have already been published:†

- “Synthetic and mechanistic studies on the solvent-dependent copper-

catalyzed formation of indolizines and chalcones” Albaladejo, M. J.; Gonzalez-Soria,

M. J.; Alonso, F. ACS Catalysis 2015, 5, 3446.

- “Synthesis of aminoindolizidines through the chemoselective and

diastereoselective catalytic hydrogenation of indolizines” Albaladejo, M. J.;

Gonzalez-Soria, M. J.; Alonso, F. J. Org. Chem. 2016, 81, 9707.

- “Catalyst-free remote-site C-H alkenylation: regio- and diastereoselective

synthesis of solvatochromic dyes” Albaladejo, M. J.; Gonzalez-Soria, M. J.; Alonso,

F. Green Chemistry 2018, 20, 701.

- “Substrate-controlled divergent synthesis of enaminones or pyrroles from

indolizines and nitrosocompounds” Gonzalez-Soria, M. J.; Alonso, F. Manuscript in

preparation.

† This research has been generously supported by the Spanish Ministerio de Economía y

Competitividad, the Generalitat Valenciana, the Instituto de Síntesis Orgánica and the University of

Alicante.

SUMMARY

Summary

17

SUMMARY

The present doctoral thesis report describes the synthesis and reactivity

of indolizines.

In chapter I, the multicomponent synthesis of 1-aminoindolizines is

presented using CuNPs/C as catalyst in dichloromethane. A reaction

mechanism is proposed based on the participation of propargylamines as

intermediates.

In chapter II, the catalytic hydrogenation of indolizines is studied,

introducing a new straightforward methodology to obtain indolizidines with a

high diastereoselectivity.

In chapter III, the reactivity of indolizines in acidic media is

investigated. A new series of indolizine dyes is reported, the optical and

structural properties of which are extensively studied.

In chapter IV, a new synthesis of β-enaminones and pyrroles is

developed from the metal-free reaction of indolizines with nitrosocompounds.

GENERAL

INTRODUCTION

General introduction

21

GENERAL INTRODUCTION

A. INTRODUCTION TO NANOPARTICLES

A.1. Properties of metallic nanoparticles

The particles with a size between 1 and 100 nm are considered

nanoparticles (NPs).1 The Greek word “nano” refers to the variation of a

property in a magnitude of 10–9

. The nanometer is the length unit equivalent to

one billionth of a meter (1 nm = 10–9

m). Commonly, it is a unit used to

measure the wavelength of ultraviolet and infrared radiation and visible light.

In order to give an idea about how small a nanometer is, different examples

can be compared: the diameter of human hair is between 10.000 and 50.000

nm, the viruses have a diameter of about 80 nm, and the molecule of fullerene

C60 has an icosahedron structure with a diameter of ca. 1 nm (Figure 1).

Figure 1. Comparison of the size of atoms, NPs and some other biological entities.

1a

The properties of metal nanoparticles (MNPs) differ from those of the

bulk solid. Changes in the physical form also result in changes in the optical,

electronic, magnetic and catalytic properties of the metal. A very peculiar

feature of MNPs is their high surface-to-volume ratio, what confers greater

chemical reactivity on them when compared with the equivalent bulk solid.

1 Reviews and monographs: (a) Gu, H.; Xu, K.; Xu, C.; Xu, B. Chem. Commun. 2006, 941. (b)

Nanoparticles: From Theory to Application, 2nd

Edn.; Schmid, G., Ed.; Wiley-VCH: Weinheim, 2010. (c)

Goesmann, H.; Feldmann, C. Angew. Chem. Int. Ed. 2010, 49, 1362. (d) Vollath, D. Nanomaterials: An

Introduction to Synthesis, Properties and Applications, 2nd Edn.; Wiley-VCH: Weinheim, 2013.

General Introduction

22

A.2. Synthesis of metallic nanoparticles

MNPs can be obtained through physical and chemical methods. Within

these two types of methods, different techniques can be mentioned as can be

seen in Scheme 1. It should be noted that the chemical methods are the most

used ones because of the simplicity to implement and, in addition, the higher

control of the size of the particle attained.2 The chemical reduction of salts of

transition metals is the most widely used method to generate MNPs in

suspension, commonly called metallic colloids.

Scheme 1. Classification of the methods of preparation of NPs.

Turkevich was the one who proposed a mechanism for the formation of

nanoclusters based on the nucleation, growth and agglomeration of metallic

2 Reviews and monographs: (a) Roucoux, A.; Schulz, J.; Patin, H. Chem. Rev. 2002, 102, 3757. (b)

Cushing, B. L.; Kolesnichenko, V. L.; O’Connor, C. J. Chem. Rev. 2004, 104, 3893. (c) Dahl, J. A.; Maddux,

B. L. S.; Hutchison, J. E. Chem. Rev. 2007, 107, 2228. (c) Inorganic Nanoparticles: Synthesis, Applications,

and Perspectives; Altavilla, C., Ciliberto, E., Eds.; CRC Press: London, 2010. (d) An, K.; Alayoglu, S.;

Somorjai, G. A. J. Colloid Interface Sci. 2012, 373, 1. (e) Xu, C.; De, S.; Balu, A. M.; Ojeda, M.; Luque, R.

Chem. Commun. 2015, 51, 6698.

Chemical

Methods

- Chemical reduction of metal salts

- Thermal, photochemical or sonochemical

decomposition

- Reduction and displacement of ligands from

organometallic compounds

- Microemulsion techniques

- Electrochemical reduction

- Microwaves

- Solvothermal methods

- Biologic methods

Physical

Methods

- Condensation of metal atomic vapors

- Laser ablation

- Pulse wire discharge (PWD)

- Mechanical grinding

-


23

atoms until the formation of the particle.3 This mechanism, which still remains

valid, is first based on the reduction of the metal salt to the corresponding

zero-valent metal atoms. Then, these metallic atoms act as centers of

nucleation, giving rise to clusters whose growth will continue as long as the

supply of atoms is maintained, thus forming the particle (Figure 2).

Figure 2. Mechanism for the formation of MNPs proposed by Turkevich.

NPs have a large surface area compared to their mass, which generates

an excess of free energy on their surface making them thermodynamically

unstable. Therefore, a crucial aspect in the formation of NPs is their

stabilization. Two NPs may be attracted to one another by van der Waals

forces and, in the absence of repulsive forces counteracting this attraction,

agglomeration may occur. There are different methods to counteract this

attraction. Depending on the type of protection used, the stabilization of

metallic NPs in solution can be classified in:4

a) Electrostatic: double layer of anions and cations is formed that

interacts with the surface of the metallic NP avoiding the agglomeration.

b) Steric: stabilization occurs by adsorption of molecules on the surface,

such as polymers, surfactants, dendrimers or ligands.

c) Electrosteric: a combination of the above two effects; the

nanoparticles can be stabilized in micelles or microemulsions.

d) Solvents: THF, THF/MeOH or long-chain alcohols.

3 (a) Turkevich, J.; Stevenson, P. C.; Hillier, J. Discuss. Faraday Soc. 1951, 11, 55. (b) Turkevich, J. Gold

Bull. 1985, 18, 86. (c) Review: Wu, Y.; Wang, D.; Li, Y. Chem. Soc. Rev. 2014, 43, 2112. 4 Metal Nanoclusters in Catalysis and Materials Science. The Issue of Size Control; Corain, B., Schmid, G.,

Toshima, N., Eds.; Elsevier: Amsterdam, 2008.


24

The synthesis of metal nanoparticles by chemical reduction of metal

salts can be carried out using different reducing agents. The most commonly

used reducing agents are oxidizable solvents (usually alcohols),5 H2,

6 CO,

7

hydrides,8 some salts such as sodium citrate or activated alkali metals, among

others.

The synthesis of MNPs based on the use of activated alkali metals has

been extensively developed in the last decade in our research group. Metal

lithium and an arene as an electron transfer agent are used in this

methodology, in which highly reactive metals commonly known as Rieke

metals are generated.9

The process involves a first electron transfer from the alkali metal to the

arene, generating a radical anion (Ar•–

). The radical anion can be further

reduced giving rise to a dianionic species (Ar2–

). Both, the anions and dianions

mentioned can act as electron transfer agents and reduce different metal salts

to generate nanoparticles of transition metals in low-valence state (Scheme 2).

Scheme 2. Generation of MNPs by reduction with the alkali metal-arene system.

A widely used electron carrier is 4,4'-di-tert-butylbiphenyl (DTBB),

because its radical anion is a very potent reducing agent (reduction potential:

5 Shiraishi, Y.; Arakawa, D.; Toshima, N. Eur. Phys. J. E: Soft Matter Biol. Phys. 2002, 8, 377.

6 Boutonnet, M.; Kizling, J.; Touroude, R.; Maire, G.; Stenius, P. Appl. Catal. 1986, 20, 163.

7 Kopple, K.; Meyerstein, D.; Meisel, D. J. Phys. Chem. 1980, 84, 870.

8 (a) Mayer, A. B. R.; Johnson, R. W.; Hausner, S. H.; Mark, J. E. J. Macromol. Sci., Pure Appl. Chem. 1999,

A36, 1427. (b) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.; Yeung, L. K. Acc. Chem. Res. 2001, 34, 181. 9 Reviews: (a) Rieke, R. D. Crit. Rev. Surf. Chem. 1991, 1, 131. (b) Rieke, R. D.; Hanson, M. V. Tetrahedron

1997, 53, 1925. (c) Rieke, R. D. Aldrichimica Acta 2000, 33, 52. (d) See, also: Schöttle, C.; Bockstaller, P.;

Popescu, R.; Gerthsen, D.; Feldmann, C. Angew. Chem. Int. Ed. 2015, 54, 9866.


25

E1/2 = –2.14 eV). In addition, it favors the transfer of electrons against other

possible secondary reactions (protonation or homocoupling of the arene), due

to the steric contribution of the two tert-butyl groups present in its structure.

This method has allowed to obtain MNPs, such as Ni,10

Cu,11

and Fe,12

with uniform size and high reactivity against different functional groups. An

advantage of this methodology is that the synthesis of MNPs occurs at ambient

temperature and in short reaction times, without the need for nucleating agents

or stabilizers.

A.3. Metallic nanoparticles in catalysis13

Transition metals represent a fundamental tool in organic synthesis,

since they are capable of promoting a large number of reactions, both in the

transformation of different functional groups and in the coupling reactions for

the formation of carbon-carbon bonds.14

However, many of these metals do

not exhibit a natural or spontaneous reactivity to organic molecules and, in

many cases, may not be due to the chemical properties inherent in the metal

but they are in an inadequate physical form. It is the case of metals with a low

surface area or with a surface deactivated by the existence of oxide films or

salts.

10

Reviews: (a) Alonso, F.; Yus, M. Chem. Soc. Rev. 2004, 33, 284. (b) Alonso, F.; Yus, M. Pure Appl.

Chem. 2008, 80, 1005. (c) Alonso, F.; Riente, P.; Yus, M. Acc. Chem. Res. 2011, 44, 379. (d) Yus, M.;

Alonso, F. e-EROS Encyclopedia of Reagents for Organic Synthesis [Online], 27 May 2014. 11

(a) Alonso, F.; Vitale, C.; Radivoy, G.; Yus, M. Synthesis 2003, 443. (b) Alonso, F.; Moglie, Y.; Radivoy,

G.; Vitale, C.; Yus, M. Appl. Catal. A: Gen. 2004, 271, 171. (c) Radivoy, G.; Alonso, F.; Moglie, Y.; Vitale,

C.; Yus, M. Tetrahedron 2005, 61, 3859. (d) Moglie, Y.; Mascaró, E.; Nador, F.; Vitale, C.; Radivoy, R.

Synth. Commun. 2008, 38, 3861. 12

(a) Alonso, F.; Moglie, Y.; Radivoy, G.; Vitale, C.; Yus, M. Tetrahedron 2006, 62, 2812. (b) Moglie, Y.;

Alonso, F.; Vitale, C.; Yus, M.; Radivoy, G. Appl. Catal. A: Gen. 2006, 313, 94. (c) Moglie, Y.; Radivoy, G.;

Vitale, C. Tetrahedron Lett. 2008, 49, 1828. 13

Monographs: (a) Nanoparticles and Catalysis; Astruc, D., Eds.; Wiley-VCH: Weinheim, 2008. (b)

Selective Nanocatalysts and Nanoscience: Concepts for Heterogeneous and Homogeneous Catalysis;

Zecchina, A.; Bordiga, S.; Groppo, E., Eds.; Wiley-VCH: Weinheim, 2011. (c) Nanocatalysis: Synthesis and

Applications; Polshettiwar, V., Asefa, T., Eds.; John Wiley & Sons: Hoboken (NJ), 2013. (d)

Nanomaterials in Catalysis; Serp, P.; Philippot K., Eds.; Wiley-VCH: Weinheim, 2013. 14

Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004.


26

These problems can be attenuated, or even eliminated, if metals are

subjected to any of the various activation techniques available. These

activation processes lead to the generation of what we know as activated

metals, which are characterized by a high reactivity and large surface area.15

Transition MNPs have emerged in recent years as a new family of

catalysts capable of efficiently promoting a wide variety of reactions of

interest in organic synthesis.16

In particular, MNPs are an important tool in

organic synthesis due to their high efficiency, selectivity and high capacity for

the transformation of functional groups. In addition, they meet in many cases

the requirements demanded for the so-called Green Catalysis,17

that is to say,

the synthesis of catalysts of low environmental impact, of easy preparation and

with the possibility of being reused without loss of the efficiency.

Metal NPs have been widely used as catalysts in different reactions of

hydrogenation, oxidation, hydrosilylation, amination, carbonylation,

cycloaddition and coupling (formation of C-C and C-heteroatom bonds),

among others. In addition, they have been defined as semi-heterogeneous

catalysts,18

i.e., they are at the interface between heterogeneous and

homogeneous catalysts.

15

Fürstner, A. Active Metals; VCH: Weinheim, 1996. 16

Reviews: (a) Corma, A.; García, H. Chem. Soc. Rev. 2008, 37, 2096. (b) Ranu, B. C.; Chattopadhyay, K.;

Adak, L.; Saha, A.; Bhadra, S.; Dey, R.; Saha, D. Pure Appl. Chem. 2009, 81, 2337. (c) Somorjai, G. A.; Li, Y.

Top. Catal. 2010, 53, 832. (d) Polshettiwar, V.; Luque, R.; Fihri, A.; Zhu, H.; Bouhara, M.; Basset, J.-M.

Chem. Rev. 2011, 111, 3036. (e) Balanta, A.; Godard, C.; Claver, C. Chem. Soc. Rev. 2011, 40, 4973. (f)

Cong, H.; Porco, Jr., J. A. ACS Catal. 2012, 2, 65. (g) Wu, L.; Zhang, Y.; Ji, Y.-G. Curr. Org. Chem. 2013, 17,

1288. (h) Wang, Y.; Xiao, Z.; Wu, L. Curr. Org. Chem. 2013, 17, 1325. (i) Geukens, I.; De Vos, D. E.

Langmuir 2013, 29, 3170. (j) For a special issue on nanocatalysis, see: Acc. Chem. Res. 2013, 46, issue nº

8. (k) Zaera, F. Chem. Soc. Rev. 2013, 42, 2746. 17

Reviews: (a) Kidwai, M. In Handbook of Green Chemistry; Anastas, P. T., Crabtree, R. H., Eds.; Wiley-

VCH: Weinheim, 2009, Vol. 2, pp. 81–92. (b) Yan, N.; Xiao, C.; Kou, Y. Coord. Chem. Rev. 2010, 254,

1179. (c) Polshettiwar, V.; Varma, R. S. Green Chem. 2010, 12, 743. (d) Gilbertson, L. M.; Zimmerman, J.

B.; Plata, D. L.; Hutchinson, J. E.; Anastas, P. T. Chem. Soc. Rev. 2015, 44, 5758. (e) Duan, H.; Wang, D.;

Li, Y. Chem. Soc. Rev. 2015, 44, 5778. 18

Reviews: (a) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198, 317. (b) Astruc, D.; Lu, F.;

Aranzaes, J. R. Angew. Chem. Int. Ed. 2005, 44, 7852. (c) Durán Pachón, L.; Rothenberg, G. Appl.

Organomet. Chem. 2008, 22, 288. (d) Narayanan, R.; Tabor, C. Top. Catal. 2008, 48, 60. (e) Shylesh, S.;

Schünemann, V.; Thiel, W. R. Angew. Chem. Int. Ed. 2010, 49, 3428.


27

However, most of the reactions mentioned above are catalyzed by noble

transition metals, such as Pd, Pt, Ru, Rh, Ir, etc. In general, these transition

metals have some disadvantages such as the high cost, the need for the use of

additives or ligands to avoid the agglomeration of the particles, as well as the

use of complex methods of synthesis of the catalysts.

The synthesis of less noble transition metal nanoparticles, such as Cu or

Fe, represents an interesting alternative in organic synthesis due to their low

cost and low or no environmental impact compared to other transition metals.

On the other hand, the immobilization of metallic nanoparticles on high

surface area inorganic supports allows a greater stability and dispersion of the

particles, as well as an advantage of the special activity and reuse of the

catalyst.19

A.4. Copper nanoparticles (CuNPs)20

In recent years, our research group has been especially interested in the

study of CuNPs catalysts. This metal was chosen because of its low cost and

easy availability, in addition to its properties, some due to its electronic

configuration of "noble" metal. A very important fact that can be highlighted

is its low toxicity compared to other transition metals; the oral toxicity in

humans (LDLO) is 100 mg/kg.21

In addition, copper is an essential nutrient

needed to prevent anemia and keep the skeletal, reproductive and nervous

systems healthy.

19

Reviews: (a) Sun, J.; Bao, X. Chem. Eur. J. 2008, 14, 7478. (b) White, R. J.; Luque, R.; Budarin, V. L.;

Clark, J. H.; Macquarrie, D. J. Chem. Soc. Rev. 2009, 38, 481. (c) Campelo, J. M.; Luna, D.; Luque, F.;

Marinas, J. M.; Romero, A. A. ChemSusChem 2009, 2, 18. (d) De Rogatis, L.; Cargnello, M.; Gombac, V.;

Lorenzut, B.; Montini, T.; Fornasiero, P. ChemSusChem 2010, 3, 24. (e) Cao, A.; Lu, R.; Veser, G. Phys.

Chem. Chem. Phys. 2010, 12, 13499. (f) Munnik, P.; de Jongh, P. E.; de Jong, K. P. Chem. Rev. 2015, 115,

6687. 20

Review on the synthesis and applications of CuNPs: Gawande, M. B.; Goswami, A.; Felpin, F.-X.; Asefa,

T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S. Chem. Rev. 2016, 116, 3722. 21

.Concise Encyclopedia of Chemical Technology, 5th Edn.; Kirk-Othmer, Ed.; John Wiley & Sons:

Hoboken, 2007; Vol. 1, pp. 672–685.


28

Different physical, chemical and biological techniques have been studied

for the synthesis of copper nanoparticles.20,22

According to the method chosen

for the synthesis of the nanoparticles, different oxidation states, sizes and

particle shapes will be achieved, which will confer some properties or other to

the nanoparticles.

The CuNPs used in the present work were prepared by reduction of

anhydrous CuCl2 with metal lithium powder and a catalytic amount of an

arene (DTBB), used as an electron carrier. The reaction was carried out in dry

tetrahydrofuran (THF) as a solvent, under an argon atmosphere and at room

temperature.

The generation of the CuNPs from the CuCl2-Li-DTBB system could be

described as shown in Scheme 3. First, the formation of the radical anion or

dianion takes place through an electron transfer from lithium to the arene,

which has an intense green coloration. Electron transfer from these species to a

receptor in the medium is a very quick process. In this case, the receptor is

CuCl2, which rapid reduction leads to the formation of CuNPs of spherical

morphology and a size of 1–5 nm, approximately.11d

This method has been

proved to be more convenient than the one originally developed by Rieke et

al., which involved the reduction of copper(I) iodide with potassium metal and

a catalytic amount of naphthalene (10 mol%) in 1,2-dimethoxyethane.23

In this

case, the required long stirring times (8-12 h at room temperature) led to a

grey-black granular solid suspended in a clear solution.

Once the CuNPs are formed, what can be determined visually since the

reaction mixture acquires a black coloration, they can be used in suspension or

supported on different inorganic materials.

22

Reviews: (a) Umer, A.; Naveed, S.; Ramzan, N.; Rafique, M. NANO 2012, 7, 1230005. (b) Benavente,

E.; Lozano, H.; González, G. Recent. Pat. Nanotechnol. 2013, 7, 108. 11

(d) Moglie, Y.; Mascaró, E.; Nador, F.; Vitale, C.; Radivoy, R. Synth. Commun. 2008, 38, 3861. 23

(a) Rieke, R. D.; Rhyne, L. D. J. Org. Chem. 1979, 44, 3445. (b) Rieke, R. D.; Sell, M. S.; Klein, W. R.;

Chen,T.; Brown, J. D.; Hanson, M. V. En Active Metals; Fürstner, A.; VCH: Weinheim, 1996; p. 33.


29

Scheme 3. Synthesis of CuNPs with the Li-arene system.

In the last years, our research group has developed several catalysts

based on the immobilization of CuNPs on different supports. Some of our

recent applications of supported CuNPs in organic synthesis follow:

Scheme 4. Cross-dehydrogenative coupling of amines and alkynes.

24

24

Alonso, F.; Arroyo, A.; Martín-García, I.; Moglie, Y. Adv. Synth. Catal. 2015, 357, 3549.


30

Scheme 5. Multicomponent synthesis of 1,2,3-triazoles (Click Chemistry).25

Scheme 6. Cross-coupling reactions.26

25

Alonso, F.; Moglie, Y.; Radivoy, G. Acc. Chem. Res. 2015, 48, 2516. 26

Mitrofanov, A. Y.; Murashkina, A. V.; Martín-García, I.; Alonso, F.; Beletskaya, I. P. Catal. Sci. Technol.

2017, 7, 4401.


31

B. INTRODUCTION TO INDOLIZINES

B.1. Structure and applications

Indolizines are fused bicyclic systems with a nitrogen atom in the bridge

linking the two rings (Figure 3). One of the cycles is an electron rich pyrrole

and the other one is a π-deficient pyridine. In general, these compounds are

light and air sensitive, and act as weak bases, having the simplest indolizines a

pKa of 3.94.27

They also tend to be protonated at C3 when the ring is

unsubstituted.

Figure 3. Common structure of indolizines.

The indolizine system is an important scaffold in natural product

synthesis.28

They also have a large variety of pharmacological activities,29

including anticancer, anti-inflammatory, antioxidant, antibacterial, antifungal,

anti-tubercular30

or analgesic activity, among others (Figure 4).

27

Armarego, W. L. F. J. Chem. Soc. 1964, 4226. 28

Bronner, S. M.; Im, G.-Y. J.; Garg, N. K. In Heterocycles in Natural Product Synthesis; Majumdar, K. C.,

Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp. 221–265. 29

Reviews: (a) Vemula, V. R.; Vurukonda, S.; Bairi, C. K. Int. J. Pharm. Sci. Rev. Res. 2011, 11, 159. (b)

Sing, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237. (c) Sharma, V.; Kumar, V. Med. Chem. Res.

2014, 23, 3593. (d) Sadowski, B.; Klajn, J.; Gryko, D. T. Org. Biomol. Chem. 2016, 14, 7804. 30

Gundersen, L-L.; Charnock, C.; Negussie, A.H.; Rise, F.; Teklu, S. Eur. J. Pharm. Sci. 2007, 30, 26.


32

Figure 4. Structure and biological activity of some indolizines.

Some indolizines have been reported to be HIV-1 viron infectivity factor

(VIF) inhibitors, with those derived from VEC-5 (VIF-ElonginC), with the

modification of the three substituents improving the inhibition activity (Fig.).31

Figure 5. Structure of VEC-5 and derivatives.

31

Huang, W.; Zuo, T.; Luo, X.; Jin, H.; Liu, Z.; Yang, Z.; Yu, X.; Zhang, L.; Zhang, L. Chem. Biol. Drug Des.

2013, 81, 730.


33

In the lasts years, new synthetic strategies have been developed not only

to obtain new biologically more active indolizines but also to exploit their

important fluorescence-related applications. For instance, some indolizines are

organic fluorophores with tunable emission wavelength covering the full range

of visible color, only by changing the substituents, which can be applied as

fluorescent probes (Figure 6).32

Figure 6. Structure of indolizines with fluorescent properties.

B.2. Synthetic methods

The two more common classical methods to obtain indolizines are the

Scholtz reaction33

and the Tshitschibabin34

reaction (Scheme 7) but, in the last

years, new methodologies have been developed in order to obtain a large

variety of different substitution patterns. Indolizines have been synthesized

following different methods,29b,d,35

which can be classified according to the

type of bond being formed during the synthesis of the indolizine, such as: one

C-N and other C-C bonds, two C-C bonds, or the transformation of a ring, for

example, the ring contraction of 4H-quinolizine. The indolizine syntheses can

32

(a) Kim,E.;Koh,M.; Lim, B.J.;Park, S.B. J. Am. Chem. Soc. 2011, 133, 6642. (b) Liu, B.; Wang, Z.; Wu, N.;

Li, M.; You, J.; Lan, J. Chem. Eur. J. 2012, 18, 1599. (c) Park, S.; Kwon, D. I.; Lee, J.; Kim, I. ACS Comb. Sci.

2015, 17, 459. 33

Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 1718. 34

Kostik, E. I.; Abiko, A.; Oku, A. J. Org. Chem. 2001, 66, 2618. 29

(b) Sing, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237. (d) Sadowski, B.; Klajn, J.; Gryko, D. T.

Org. Biomol. Chem. 2016, 14, 7804. 35

Shipman, M. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme: Stuttgart, 2001; Vol. 10, pp.

745–787.


34

be also classified by the type of the reaction, with the most common reactions

used being the condensation, 1,3-dipolar cycloaddition and 1,5-dipolar

cycloaddition, among others.36

Scheme 7. Classical methods for the synthesis of indolizines.

The synthetic principle of the 1,3-dipolar cycloaddition applied to the

synthesis of indolizines is advantageous with respect to the classical methods,

because of the use of more simple procedures; however, the substituents at the

positions 1, 2 and 3 are restricted to electron-withdrawing groups. There are

different types of starting materials for that reaction: the pyridinium ylides and

their derivatives are the most common ones (Scheme 8).37

36

(a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209. (b) Review: Cernaks, D. Chem. Heterocycl. Compd.

2016, 52, 524. (c) Sandeep, C.; Mohammed, A. K.; Attimarad, M.; Padmashali, B.; Kulkarni, R. S.;

Venugopala, R.; Odhav, B.; Katharigatta, N. V. J Basic Clin. Pharm. 2017, 8, 49. 37

(a) Yang, Y.; Kuang, C.; Jin, H.; Yang, Q. Synthesis 2011, 21, 3447. (b) Hu, H.; Feng, J.; Zhu, Y.; Gu, N.;

Kan, Y. RSC Adv. 2012, 2, 8637.


35

Scheme 8. 1,3-Dipolar cycloaddition-based synthesis of indolizines.

Some cyclization reactions forming a new C3-N4 bond to obtain

indolizines are carried out by iodine-mediated38

and transition-metal

catalyzed39

cycloisomerization of pyridines bearing alkynyl, propargyl, allenyl

or cyclopropenyl substituents at the 2 position (Scheme 9). Some methods

based on two-component intermolecular annulations catalyzed by copper have

also been reported (Scheme 10).40

38

(a) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48, 6863. (b) Kim, I.; Kim, S. G.; Kim,

J. Y.; Lee, G. H. Tetrahedron Lett. 2007, 48, 8976. 39

For reviews, see: (a) Majumdar, K. C.; Debnath, P.; De, N.; Roy, B. Curr. Org. Chem. 2011, 15, 1760. (b)

Dudnik, A. S.; Gevorgyan V. In Catalyzed Carbon-Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-

VCH: Weinheim, 2011, pp 317–410. (c) Wang, L.; Tang, Y. Eur. J. Org. Chem. 2017, 2207. (d) For a

leading reference, see: Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (e)

See also: Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783. (f) Li, Z.; Chernyak,

D.; Gevorgyan, V. Org. Lett. 2012, 14, 6056 and the references cited therein. (g) Zhang, C.; Zhang, H.;

Zhang, L.; Wen, T. B.; He, X.; Xia, H. Organometallics 2013, 32, 3738. 40

(a) Barluenga, J.; Lonzi, G.; Riesgo, L.; López, L. A.; Tomás, M. J. Am. Chem. Soc. 2010, 132, 13200. (b)

Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Org. Lett. 2012, 14, 957. (c) Hu, H.; Feng, J.; Zhu, Y.; Gu, N.; Kan, Y. RSC

Adv. 2012, 2, 8637. (d) Oh, K.H.; Kim, S.M.; Park, S.Y.; Park, J.K. Org. Lett. 2016, 18, 2204.


36

Scheme 9. Synthesis of indolizines by cycloisomerization.

Scheme 10. Synthesis of indolizines via intermolecular annulation.


37

Pyrroles can be also used as starting materials for the synthesis of

indolizines by formation of a C8-C9 bond. There are a few examples of this

type of synthesis because of the less number of commercially available

pyrroles, their lower oxidation potential and their less stability compared with

the pyridines. One example starting from a N-H free pyrrole and using a

cyclopentadiene-phosphine/Pd catalyst is the reaction of pyrroles with 1,4-

dibromo-1,3-dibutadienes.41

The use of allyl bromides to N-alkylate a 2-

formylpyrrole has been also reported (Scheme 11).42

Other routes, starting

from N-substituted pyrroles, include the transition-metal free one-pot synthesis

of fully-substituted pyridine-ring indolizines43

or the intramolecular

aromatization of dicarbonyl compounds (Scheme 12).44

Scheme 11. Synthesis of indolizines from N-H free pyrroles.

41

Hao, W.; Wang, H.; Ye, Q.; Zhang, W.-X.; Xi, Z. Org. Lett. 2015, 17, 5674. 42

Park, S.; Kim, I. Tetrahedron 2015, 71, 1982. 43

Kucukdisli, M.; Opatz, T. J. Org. Chem. 2013, 78, 6670. 44

Lee, J. H.; Kim, I. J. Org. Chem. 2013, 78, 1283.


38

Scheme 12. Synthesis of indolizines from N-substituted pyrroles.

The indolizines can act as nucleophiles, so that they rarely suffer

nucleophilic attacks. The C1 and C3 are the most preferred positions to react

with electrophiles because of the resonance stability of the pyridine ring as

show in Scheme 13. 45

Scheme 13. Resonance stability of indolizines.

The reactivity of the indolizines has not been studied as much as new

syntheses, though there are some typical reactions for this type of heterocycles

(Scheme 14).36,46

45

De Souza, C. R.; Gonçalves, A. C.; Amaral, M. F. Z. J.; Dos Santos, A. A.; Clososki, G. C. Targets

Heterocycl. Syst. 2016, 20, 365. 36

(a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209. (b) Review: Cernaks, D. Chem. Heterocycl. Compd.

2016, 52, 524. (c) Sandeep, C.; Mohammed, A. K.; Attimarad, M.; Padmashali, B.; Kulkarni, R. S.;

Venugopala, R.; Odhav, B.; Katharigatta, N. V. J Basic Clin. Pharm. 2017, 8, 49. 46

Elattar, K. M.; Youssef, I.; Fadda, A. A. Synth. Commun. 2016, 46, 719.


39

Scheme 14. Typical reactions of indolizines.

GENERAL OBJECTIVES

General objectives

43

Taking into account what aforementioned, the main objectives of this

thesis are:

1. To develop an efficient multicomponent synthesis of 1-

aminoindolizines based on the use of copper nanoparticles as the

catalyst.

2. To transform the indolizines into indolizidines by catalytic

hydrogenation.

3. To explore the reactivity of the indolizines in acid medium.

4. To study the reactivity of the indolizines against nitrosocompounds.

CHAPTER I

MULTICOMPONENT SYNTHESIS OF

1-AMINOINDOLIZINES

Chapter I. Multicomponent synthesis of 1-aminoindolizines

47

1. MULTICOMPONENT SYNTHESIS OF 1-AMINOINDOLIZINES

1.1. INTRODUCTION

1.1.1. Multicomponent reactions in heterocyclic synthesis

Multicomponent Reactions (MCRs) are those which involve three or

more starting materials to synthesize a product and all, or at least most of the

atoms, contribute to the final compound. MCRs offer many advantages

compared with the traditional methodologies, such as selectivity, efficiency,

time saving, atom-economy and simplicity. It should be also noted that one-

pot reactions only involve one synthetic procedure and one work-up procedure

compared with multi-step reactions, thus being a greener chemistry (less use

of solvents, energy consumption and waste). Another advantage is the easier

scale-up of this type of reactions; in that way, most of the new procedures can

be carried out on an industrial scale. These are some of the reasons whereby

MCRs have been very studied in the last years.47,48

The types of MCRs for the synthesis of heterocycles can be classified

according to the size of the new formed heterocycle or the number of

heteroatoms in the cycle.49

They can be also classified according to the type of

reaction being used to form the heterocycle.1c

On the other hand, the synthesis of nitrogen heterocycles can be

challenging50

due to the necessity of using protecting groups in many cases,

hence needing additional steps. Some of them are very important because are

present in many different drugs. Therefore, it is important to develop new

47

For general reviews, see: (a) Orru, R. V. A.; Ruijter, E. Synthesis of Heterocycles via Multicomponent

Reactions I and II. Top. Heterocycl. Chem.; Springer: Berlin, 2010; Vol. 25, pp. 231–288. (b) Dömling, A.;

Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (c) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K.

Chem. Rev. 2014, 114, 8323. 48

For reviews on MCRs using metals see: (a) Arndtsen, B. A. Chem. Eur. J. 2009, 15, 302. (b) Maji, P. K.;

Islam, R. U.; Bera, S. K. Heterocycles 2014, 89, 869. (c) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem.

Rev. 2015, 115, 1622. (d) Das, D. ChemistrySelect 2016, 1, 1959. 49

Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5, 2318. 50

Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Nat.

Chem. 2018, 10, 383.


48

strategies that enable the synthesis of rather inaccessible nitrogen-containing

heterocycles in a more efficient and environmentally friendly manner and with

a high compatibility with different functional groups in order to have a broad

scope.

1.1.2. Multicomponent synthesis of indolizines

One of the first multicomponent synthesis of indolizines was developed

starting from 2-propargylpyridines, aryl iodides, and CO, all of which are

incorporated into the final indolizine (Scheme 1.1).51

Scheme 1.1. Multicomponent synthesis of indolizines from 2-propargylpyridines.

Another palladium-catalyzed multicomponent synthesis of indolizines

has been reported by Liu and co-workers and consists on a three-component

cascade reaction of 2-(2-enynyl)pyridines with nucleophiles and allyl halides,

enabling the synthesis of densely functionalized indolizines using Pd as

catalyst in the presence of a base in MeCN (Scheme 1.2).52

Scheme 1.2. Synthesis of 1,2,3-substituted indolizines.

51

Li, Z.; Chernyak, D.; Gevorgyan, V. Org. Lett. 2012, 14, 6056. 52

Liu, R.-R.; Lu, C.-J.; Zhang, M.-D.; Gao, J.-R.; Jia, Y.-J. Chem. Eur. J. 2015, 21, 7057.


49

More recently, Liu and coworkers have developed a multicomponent

reaction using pyridines, methyl ketones and alkenoic acids in neat conditions

under an O2 atmosphere. This synthesis involves a cascade of processes

starting with a copper-catalyzed bromination of the methyl ketone, pyridine N-

alkylation, 1,3-dipolar cycloaddition of the pyridinium ylide with the alkenoic

acid, followed by an oxidative decarboxylation and dehydrogenative

aromatization of the primary cycloadduct (Scheme 1.3).53

Scheme 1.3. Synthesis of indolizines through a 1,3-dipolar cycloaddition.

Another example of multicomponent synthesis of indolizines through a

1,3-dipolar cycloaddition starts from pyridine derivatives, benzyl bromides

and electron-deficient alkenes or alkynes in the presence of a base and the

ionic liquid [OMIM]Br (Scheme 1.4).54

Scheme 1.4. Synthesis of indolizines through a 1,3-dipolar cycloaddition in an ionic

liquid.

Introducing an amino group in the skeleton of the indolizine opens many

possibilities for a further functionalization. In this context, the synthesis of 3-

aminoindolizines was developed via Pd/Cu-catalyzed sequential Sonogashira

cross-coupling/cycloisomerization55

or via a multistep sequence using

53

Wang, W.; Han, J.; Sun, J.; Liu, Y. J. Org. Chem. 2017, 82, 2835. 54

Zhang, X.; Lu, G.; Xu, Z.; Cai, C. ACS Sustainable Chem. Eng. 2017, 5, 9279. 55

Lange, P. P.; James, K. ACS Comb. Sci. 2012, 14, 570.


50

Hantzsch ester as a hydride transfer agent starting from

pyridinecarboxaldehydes and malononitrile (Scheme 1.5).56

Scheme 1.5. Two synthetic approaches to 3-aminoindolizines.

A new protocol emerged in order to synthesize 1-aminoindolizines in a

single-step reaction and high atom economy starting from 2-

pyridinecarbaldehyde derivatives, secondary amines and terminal alkynes

(Scheme 1.6). Indeed, Liu and Yan were the first to report that kind of

multicomponent synthesis using a gold catalyst.57

Other catalytic processes

with different metals such as silver,58

iron,59

copper60

and zinc61

were

described for the same purpose.

56

Li, L.; Chua, W. K. S. Tetrahedron Lett. 2011, 52, 1392. 57

Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. 58

Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, X.-W. J. Comb. Chem. 2010, 12, 696. 59

Patil, S. S.; Patil, S. V.; Bobade, V. D. Synlett 2011, 16, 2379. 60

(a) Dighe, S. U.; Hutait, S.; Batra, S. ACS Comb. Sci. 2012, 14, 665. (b) Pan, C.; Zou, J.; Zeng, R. Chin. J.

Chem. 2013, 31, 799. 61

Mishra, S.; Bagdi, A. K.; Ghosh, M.; Sinha, S.; Hajra, A. RSC Adv. 2014, 4, 6672.


51

Scheme 1.6. Multicomponent syntheses of 1-aminoindolizines.

More recently, several related methods have been developed to obtain

indolizines with the same substitution based on copper nanocatalysts, such as

CuNPs-decorated mesoporous ZSM-5 in DCM62

or CuI/CSP nanocomposites

in EG.63

A Copper Organic Framework decorated with CuNPs has been also

reported for the multicomponent synthesis of 1-aminoindolizines; in this case,

the catalyst could be recycled over 5 cycles without losing conversion.64

62

Sharma, B.; Satpati, B.; Srivastava, R. RSC Adv. 2016, 6, 87066. 63

Rajesh, U. C.; Purohit, G.; Rawat, D. S. ACS Sustainable Chem. Eng. 2015, 3, 2397. 64

Rani, P.; Siril, P. F.; Srivastava, R. Mol. Catal., 2017, 433, 100.


52

1.2. RESULTS AND DISCUSSION

1.2.1. Previous study

Recently, in our research group, the multicomponent synthesis of

indolizines and pyrrolo[1,2-a]quinolines has been effectively accomplished

from pyridine-2-carbaldehyde derivatives, secondary amines and alkynes

using CuNPs/C as catalyst in dichloromethane. Interestingly, the same

procedure, when applied in the absence of solvent using piperidine as the

secondary amine, has led to heterocyclic chalcones as major products and

exclusive E stereochemistry (Scheme 1.7).65

Scheme 1.7. Synthesis of indolizines and chalcones catalyzed by CuNPs/C.

In this chapter, we are going to focus, mainly, in the synthesis of 1-

aminoindolizines. For this reaction, the metal support, solvent and conditions

were previously optimized using pyridine-2-carbaldehyde (1a), piperidine (2a)

and phenylacetylene (3a) as model compounds;66

copper nanoparticles on

activated carbon (CuNPs/C) was found to be the catalyst of choice in

dichloromethane at 70 ºC.

65

Albaladejo, M. J.; Alonso, F.; Yus, M. Chem. Eur. J. 2013, 19, 5242. 66

Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por

Nanopartículas de Cobre Soportadas, Tesis Doctoral, Universidad de Alicante, 2014.


53

The copper-on-activated-carbon catalyst was previously characterized67

by different techniques. The copper content, 1.6 wt%, was determined by

Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Analysis by TEM

revealed the presence of spherical nanoparticles dispersed on the active carbon

with diameters of ca 4-8 nm (Figure 1.1). Energy-dispersive X-ray (EDX)

analysis on various regions confirmed the presence of copper, with energy

bands of 8.04, 8.90 keV (K lines) and 0.92 keV (L line). X-Ray Photoelectron

Spectroscopy (XPS) analysis showed two O (1s) peaks at 532.2 and 534.2 eV,

and three Cu (2p3/2) peaks at 934.1, 936.4, and 945.7 eV. From these results it

was inferred that the surface of the copper nanocatalyst was mainly oxidized

and it was a mixture of oxidized copper nanoparticles (Cu2O and CuO).

0

5

10

15

20

25

30

35

40

45

dis

trib

uti

on

(%

)

diameter (nm)diameter (nm)

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Figure 1.1. TEM image and size distribution of CuNPs/C.

1.2.2. Substrate scope

With the optimized conditions in hand, a wide range of indolizines was

synthesized in modest-to-high isolated yields using a low catalyst loading (0.5

mol%) (Table 1.1). Pyridine-2-carbaldehyde (1a) was successfully combined

with nine different secondary amines (Table 1.1, 2a–i) and five aryl acetylenes

containing electron-neutral, -withdrawing or -releasing substituents (Table 1.1,

3a–e). Aliphatic alkynes (Table 1.1, 3f and 3g) were found to be more

67 Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Adv. Synth. Catal. 2010, 352, 3208.


54

reluctant to react, leading to the expected indolizines (Table 1.1, 4agf and

4agg) in relatively lower yields (55% and 42%, respectively) due to partial

decomposition during chromatographic purification. In contrast, the alkyne

derived form phthalimide was obtained in a good yield (Table 1.1, 4agh).

Reactions with pyridine-2-carbaldehydes substituted at the 6 position

(1b–d) required prolonged heating, probably because of steric reasons (Table

1.2). Poor yield was noted for the 5-bromoindolizine 4bga due to the major

formation of the A3 coupling product. However, we could make use of this

result to prove the reaction mechanism (see below). Indolizines derived from

6-methylpyridine-2-carbaldehyde (1c) and dibenzylamine (2g) with different

electronic substituents in the aromatic alkyne were synthesized with moderate-

to-good yields (Table 1.2, 4cga–4cge). N-Methylaniline (1f) was also tested

with 6-methylpyridine-2-carbaldehyde, to form the expected indolizine in a

moderate yield (Table 1.2, 4cfa). The best yield was attained for the sulfone-

functionalized indolizine 4dga. The methodology was found to be also

effectual when applied to quinoline-2-carbaldehyde (1e), giving the

corresponding pyrrolo[1,2-a]quinolines 4eaa–ega in good-to-high isolated

yields (Table 1.2).

Our method was not as good for aliphatic alkynes, that is why we

decided to use a commercial catalyst which a good performance according to

the literature.14b

We tested CuI, in the absence of solvent and with a higher

metal loading (10 mol%), in the multicomponent synthesis of indolizines from

pyridine-2-carbaldehyde, secondary amines and aliphatic alkynes. Five

different amines were tested with 1-hexyne leading to the corresponding

indolizines in moderate-to-good yields (Table 1.3, 4aai, 4aci, 4adi, 4afi, and

4agi). The conversion was worse for shorter or longer aliphatic-chain alkynes

(Table 1.3, 4agj–4agm). Finally, 6-methylpyridine-2-carbaldehyde was tested

with dibenzylamine and 1-hexyne, giving the expected indolizine in good

conversion (85% by GC) but with a moderate isolated yield (Table 1.3, 4cgi).

Although the use of CuI generally increases the conversion for this type of

indolizines, the isolated yields are low or moderate because of the instability

of these indolizines in column chromatography and the additional work-up

required removing CuI from the reaction crude.


55

Table 1.1. Synthesis of 1,3-disubstituted indolizines catalyzed by CuNPs/C. a

a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C [20 mg, ca. 0.5 mol%,

determined from the Cu content (1.4 wt%) and the Cu2O/CuO area from XPS (ca. 1:1)], CH2Cl2 (1 mL),

70 ºC; reaction time and isolated yield in parentheses.


56

Table 1.2. Multicomponent synthesis of indolizines substituted at C5 catalyzed by

CuNPs/C. a

a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C (20 mg, ca. 0.5 mol%),

CH2Cl2 (1 mL), 70 ºC; reaction time and isolated yield in parentheses. b The propargylamine 6bfa (see

below) was the major product (72%).


57

Table 1.3. Multicomponent synthesis of indolizines catalyzed by CuI. a

a Reaction conditions: 1 (2 mmol), 2 (2 mmol), 3 (2 mmol), CuI (38.1 mg, 10 mol%), neat, 70 ºC;

reaction time and isolated yield in parentheses.


58

1.2.3. Reutilization of the catalyst

The CuNPs/C catalyst, which could be reused in other multicomponent

reactions, could not be efficiently recycled in this case (only 40% of

conversion was obtained in the second cycle). The possible poisoning of the

catalyst and the observed leaching of the metal could be the reasons that

account for this behavior. This fact is not so important because of the low

charge of copper used in the formation of the indolizines.

In the case of the synthesis of chalcones, 66

the catalyst could be recycled

in 4 cycles using low loading (0.13 mol%) with a decrease in the catalytic

activity (Scheme 1.8).

Scheme 1.8. Reutilization of the catalyst in the synthesis of the chalcone (E)-3-

phenyl-1-(pyridin-2-yl)prop-2-en-1-one (5aa) using 0.13 mol% CuNPs/C.

1.2.4. Comparison with commercial catalysts

In principle, any laboratory-made catalyst should be more efficient

than commercially available catalysts used for the same purpose. Otherwise, it

is difficult to economically justify the time, materials and human resources

employed during its preparation. Taking into account this premise, we

undertook a comparative study on the reactivity of CuNPs/C with that of some

commercial copper catalysts. The standard conditions were applied to the


59

model reaction of pyridine-2-carbaldehyde (1a), piperidine (2a) and

phenylacetylene (3a). As shown in Scheme 1.9, the best performance was

attained with CuNPs/C in terms of catalyst loading, reaction time and

conversion.

Scheme 1.9. Synthesis of indolizine 4aaa catalyzed by CuNPs/C and commercial

catalysts. Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), catalyst

(10 mol%, unless otherwise stated), CH2Cl2 (1 mL), 70 ºC. Conversion into 4aaa

determined by GC.


60

A similar study was done by comparing the catalytic activity of

CuNPs/C with that of the same commercial copper catalysts as above in the

synthesis of chalcones (Scheme 1.10). Chalcone 5aa was used as the model

target, which was obtained in less than 50% conversion in all cases with the

exception of CuI; moderate conversion was obtained with the latter, though

larger amount of this non-recyclable catalyst and longer reaction time than

with CuNPs/C were required. Moreover, an increase in the amount of CuI had

a detrimental effect on the conversion.

Scheme 1.10. Synthesis of chalcone 5aa catalyzed by CuNPs/C and commercial

catalysts. Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), Cu

catalyst (10 mol%), neat, 70 ºC. Conversion into 5aa was determined by GC.


61

1.2.5. Reaction mechanism

The kinetic profile for the synthesis of the indolizine 4aaa shows almost

a linear increase of the conversion within the first 3 h (up to 92%), being

nearly quantitative after 4 h (98%) (Figure 1.2). For this particular reaction,

TON and TOF of up to 200 and 65 h–1

, respectively, were recorded.

0

20

40

60

80

100

0 5 10 15 20

Co

nve

rsio

n (

%)

t (h) Figure 1.2. Plot showing the evolution of the synthesis of the indolizine 4aaa

catalyzed by CuNPs/C.

Based on our previous mechanistic studies on the aldehyde-amine-

alkyne coupling (A3 coupling), as well as on other methodologies, we can

propose a reaction mechanism for this multicomponent synthesis of

indolizines including: (a) CuNPs-mediated enhancement of the alkyne acidity

by coordination to the carbon-carbon triple bond, so that enables the formation

of the corresponding copper(I) acetylide; (b) addition of the latter to the in-situ

generated iminium ion derived from the aldehyde and the secondary amine; (c)

copper-promoted cycloisomerization of the resulting propargylamine (A3

product) through a 5-endo-dig and aromatization processes; and (d)

protonolysis of the intermediate copper indolizide (Scheme 1.11). The

participation of propargyl amines as indolizine precursors has been often

postulated10–14

but, to the best of our knowledge, never demonstrated. These

pyridinyl propargyl amines must be rather elusive intermediates, which once

generated in the reaction medium, rapidly cyclize to the corresponding

indolizines. It is noteworthy that tiny peaks attributable to propargylamines


62

were detected by GC-MS (the same m/z as that of indolizines) in some of the

reaction crudes derived from pyridine-2-carbaldehyde (1a). Notwithstanding

the limitations to isolate a pyridinyl propargylamine and transform it into the

corresponding indolizine, we turned our attention to the 6-substituted pyridine-

2-carbaldehyde derivatives.

Scheme 1.11. Reaction mechanism proposed for the three-component synthesis of

indolizines catalyzed by CuNPs/C.


63

The steric hindrance arisen between the 6-substituent of the pyridine and

the alkyne substituent prior to ring closure, could be a chance to isolate the

pursued propargylamine. We capitalized on the low indolizine conversion

recorded for some 6-bromopyridin-2-carbaldehyde derivatives and managed to

isolate propargylamine 6bga. Subsequent treatment of 6bga with CuNPs/C in

dichloromethane furnished the expected indolizine 4bga after prolonged

heating (Scheme 1.12). These results distinctly unveil that 2-pyridinyl

propargyl amines are the precursor intermediates of indolizines.

Scheme 1.12. Transformation of propargylamine 6bga into the indolizine 4bga.

1.2.6. Biological activity

Indolizines have diverse biological activities, as aforementioned in the

general introduction, that is why we decided to study the possible activity of

the new synthesized 1-aminoindolizines (indolizines 4a'-4h' were previously

synthesized in our research group66

but their biological activity had not been

assessed yet). Both, in-silico and in vitro screening, were performed through

the Lilly Open Innovation Drug Discovery (OIDD) program.68

There are four main therapeutic areas for testing the compounds:

Neuroscience, Endocrine/Cardiovascular, Oncology, and Neurodegeneration

and pain. Within these, the indolizines were tested in different target cell lines.

66

Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por

Nanopartículas de Cobre Soportadas, Tesis Doctoral, Universidad de Alicante, 2014. 68

https://openinnovation.lilly.com


64

Neuroscience

Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist: the

CGRP plays an important role in the patho-physiology of migraine. The

CGRP level has been reported to be elevated during a migraine attack.

m-Glu2R Receptor Allosteric Antagonist: glutamate is the major

excitatory neurotransmitter acting as G-protein coupled receptors. Antagonist

of glutamate receptors have been postulated to be useful in neurological and

psychiatric indications.


65

Nav1.7 Antagonist: Nav1.7 is a sodium ion channel involved in

generation, propagation and neurotransmitter release. Many nonselective

sodium channels inhibitors are used clinically as analgesics and anesthesics,

however, their efficacy is limited by their lack of selectivity over the other

sodium channel anti-targets. That is why selective Nav1.7 inhibitors may

provide a novel therapeutic approach to chronic pain of different etiologies

without significant safety side-effects.

Endocrine/Cardiovascular

GLP-1 Secretion: Glucagon-like peptide 1 is a potent anti-

hyperglycemic hormone which induces glucose-dependant insulin secretion

and supresses glucagon secretion. There are two assays where indolizines have

shown some activity.


66

PCSK9 Synthesis inhibition: the proprotein convertase subtilisin kesin

(PCSK) belongs to the proteinase K family, this plays a major role regulating

the cholesterol homeostasis. The PCSK9 regulates LDL level reducing its

accumulation.


67

RXFP1 Antagonist: relaxin is a reproductive hormone involved in the

remodelation of the tract during the pregnancy. Some clinical trials have been

reported to use relaxin as a treatment of scleroderma, fibromyalgia or

preeclampsia.

Oncology

SETD8 Inhibitor: SET domain containing lysine methyltransferase 8 is

an essential enzyme which catalysed the cell cycle stages. SETD8 interacts

directly with several proteins for the regulation of transcription, DNA

replication and DNA damage repair. The SETD8 depletion results in a large

scale chromatin decondensation/less compact chromatin in vivo, decreasing

the proliferation of carcinogenic cells.


68

K-Ras/Wnt Synthetic Lethal: most colorectal cancers are developed from

benign lesions, then an activating KRAS mutation is required for the

progression to colorectal cancer. The reason for the co-mutational requirement

is due to undefined interactions between the WNT and KRAS signalling

pathways. It is important to develop small molecules selectively lethal to

tumor cells that depend on this WNT-KRAS synergy.

Neurodegeneration and pain

Protein Translation Inhibition for Alzheimer’s disease (Tau): the

Alzheimer’s disease is characterized by the accumulation of amyloid plaques

and intracellular formation of neurofibrillary tangles, composed by Aβ protein

and tau protein respectively. A therapeutic strategy is the inhibition of those

proteins.

CHAPTER II

CATALYTIC HYDROGENATION OF

INDOLIZINES: SYNTHESIS OF

INDOLIZIDINES

Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines

71

2. CATALYTIC HYDROGENATION OF INDOLIZINES: SYNTHESIS

OF INDOLIZIDINES

2.1. INTRODUCTION

There is a general upsurge of interest in developing new strategies to

effectively obtain saturated N-heterocycles from readily accessible starting

materials. This demand is supported by the potential development of new

pharmaceuticals related to this type of heterocycles and their natural

abundance.69

Among them, indolizidine alkaloids are widespread in nature and

have attracted a great deal of attention because of their structural diversity and

varied biological activity.70

Indolizidine alkaloids are bicyclic compounds, which have one basic

nitrogen in their structure. Many of them present biological activity such as

fitotoxic, antibacterial, antifungal or neurological activities, and they can be

extracted from diverse natural sources: poisonous frogs, ants, fungi, plants,

etc.

Figure 2.1. Common structure of indolizidines.

For instance, indolizidine 167B was originally found as a trace

component in the skin secretions of a frog belonging to the genus

Dendrobates,71

whereas (+)-monomorine I was isolated from both Pharaoh’s

ant Monomorium pharaonis and from bufonid toads of the Melanopbryniscus

69

(a) Synthesis of Heterocycles via Metal-Catalyzed Reactions that Generate One or More Carbon-

Heteroatom Bonds; Top. Heterocycl. Chem.; Wolfe, J. P., Ed.; Springer-Verlag: Berlin, 2013; Vol. 32. (b)

Synopsis: Vo, C.-V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809. 70

Reviews: (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24,

191. (c) Michael, J. P. Beilstein J. Org. Chem. 2007, 3, No. 27, doi:10.1186/1860-5397-3-27. (d) Michael,

J. P. Nat. Prod. Rep. 2008, 25, 139. 71

Edwardsj, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188.


72

genus.72

(–)-Tashiromine was first isolated from the stems of Maackia

Tashiroi (Leguminosae),73

a bush from subtropical Asia, and later on from

leaves and seeds of the Poecilanthe74

genus and from Ethiopian Crotalaria

species.75

Swainsonine was first identified in the Australian legume Swainsona

canescens76

and, subsequently, as the toxin in Astragalus and Oxytropis

species that cause locoism in livestock.77

In contrast, the potential importance

of swainsonine in the therapy for cancer and immunology has been reported.78

(+)-Lentiginosine was first isolated from the leaves of Astragalus lentiginosus

in 1990,79

which is a potent glycosidase-inhibitor, also the synthetic (–)-

lentiginosine80

is so effectual against different cell lines. Indolizidines have

also played an important role in the synthesis of other natural products.81

Due

to the insignificant isolated amounts of these alkaloids from their natural

sources, new synthetic methods to obtain them have been developed.

72

(a) Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E. J.; Stein, F. Experientia 1973, 29, 530. (b)

Garrafo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.; Gross, E. G. J. Nat. Prod. 1993, 56, 357. 73

Ohmiya, S.; Kubo, H.; Otomasu, H.; Saito, K.; Murakoshi, I. Heterocycles 1990, 30, 537. 74

Greinwald, R.; Bachmann, P.; Lewis, G.; Witte, L.; Czygan, F.-C. Biochem. Syst. Ecol. 1995, 23, 547. 75

Asres, K.; Sporer, F.; Wink, M. Biochem. Syst. Ecol. 2004, 32, 915. 76

Collegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257. 77

Molyneux, R. J.; James, L. F. Science 1982, 216, 190. 78

Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oredipe, O. A.; Newton, S. A.; White,

S. L. Pharmacol. Ther. 1991, 50, 285. 79

Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D. Biochemistry 1990, 29, 1886. 80

Cordero, F. M.; Vurchio, C.; Brandi, A. J. Org. Chem. 2016, 81, 1661. 81

Bronner, S. M.; Im, G.-Y. J.; Garg, N. K. In Heterocycles in Natural Product Synthesis; Majumdar, K. C.,

Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp. 221–265.


73

Figure 2.2. Structure of some naturally-occuring indolizidines.

The synthetic strategies developed to construct the indolizidine skeleton

according to the substitution pattern pursued (Scheme 2.1),82

include: (a) the

use of pyrroles as building blocks,83

(b) from α-aminoacids via

stereocontrolled rhodium-catalyzed hydroformylation of N-allylpyrroles84

or

via a decarboxylative annulation with γ-nitroaldehydes,85

(c) based on

organosulfur and selenium chemistry (i.e., conjugate addition of nitrogen

nucleophiles containing ester or chloroalkyl substituents to acetylenic

sulfones, followed by base-mediated intramolecular alkylation or acylation),86

(d) by stereocontrolled cyclic nitrone cycloaddition,87

(e) by addition of

allylsilanes to N-acyliminium ions,88

(f) by stereoselective conjugate addition

reactions,89

(g) through radical azidation reactions,90

(h) through chiral

82

Pansare, S. V.; Thorat, R. G. In Targets in Heterocyclic Systems. Chemistry and Properties; Attanasi, O.

A.; Spinelli, D., Eds.; Società Chimica Italiana: Roma, 2013; Vol. 17, pp 57–86. 83

Review: Jefford, C. W. Curr. Org. Chem. 2000, 4, 205. 84

Review: Lazzaroni, R.; Settambolo, R. Chirality 2011, 23, 730. 85

Kang, Y.; Seidel, D. Org. Lett. 2016, 18, 4277. 86

Review: Back, T. G. Can. J. Chem. 2009, 87, 1657. 87

Review: Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15, 7808. 88

Review: Remuson, R. Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32. 89

Review: Toyooka, N.; Tsuneki, H.; Kobayashi, S.; Zhou, D.; Kawasaki, M.; Kimura, I.; Sasaoka, T.;

Nemoto, H. Curr. Chem. Biol. 2007, 1, 97. 90

Review: Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. Pure Appl. Chem. 2012, 84, 1633.


74

oxazolopiperidone lactams,91

(i) via enaminone intermediates,92

(j)

enantioselective Brönsted-acid catalyzed vinylogous Mannich reaction,93

or

(k) the sequential double addition to N-protected piperidine through the α-

lithio-derivatives followed by an intramolecular reductive amination.94

However, despite the synthesis of indolizidines by the reduction of indolizines

seems to be a direct approach, it has been barely documented and limited to

some isolated examples.95

Just a few reports describe the synthesis of

indolizidines by heterogeneous catalytic hydrogenation of the pyrrole ring of

5,6,7,8-tetrahydroindolizines.96

To the best of our knowledge, there is only one

systematic study on the synthesis of indolizidines by full hydrogenation of

indolizines, recently reported by Coelho et al.97

At any rate, partial reduction is

a common problem encountered, which together with a desirable higher

diastereoselectivity,98

make the selective hydrogenation of indolizines a

challenging objective.

91

Review: Escolano, C.; Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198. 92

Riley, D. L.; Michael, J. P.; de Koning, C. B. Beilstein J. Org. Chem. 2016, 12, 2609. 93

Abels, F.; Lindemann, C.; Koch, E.; Schneider, C. Org. Lett. 2012, 14, 5972. 94

Nebe, M. M.; Zinn, S.; Opatz, T. Org. Biomol. Chem. 2016, 14, 7084. 95

(a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (b) Chai, W.; Kwok,

A.; Wong, V.; Carruthers, N. I.; Wu, J. Synlett 2003, 13, 2086. (c) Zhang, L.; Li, X.; Liu, Y.; Zhang, D. Chem.

Commun. 2015, 51, 6633. 96

(a) Castaño, A. M.; Cuerva, J. M.; Echavarren, A. M. Tetrahedron Lett. 1994, 35, 7435. (b) Gracia, S.;

Jerpan, R.; Pellet-Rostaing, S.; Popowycz, F.; Lemaire, M. Tetrahedron Lett. 2010, 51, 6290. (c) Jiang, C.;

Frontier, A. J. Org. Lett. 2007, 9, 4939. (d) Ortega, N.; Tang, D.-T. D.; Urban, S.; Zhao, D.; Glorius, F.

Angew. Chem. Int. Ed. 2013, 52, 9500. 97

Teodoro, B. V. M.; Correia, J. T. M.; Coelho, F. J. Org. Chem. 2015, 80, 2529. 98

See, ref. 95a (79:12:9 dr), ref. 95b (3.67:1.00 dr), ref. 96a (2:2:1 dr), ref. 96b (85–88% de), ref. 96d

(91:5:2:1 dr).


75

Scheme 2.1. Different approaches to the synthesis of indolizidines.


76


2.2.1. Optimization of the reaction

First, the catalyst and reaction conditions were optimized for the

catalytic hydrogenation of indolizines. N,N-Dibenzyl-3-phenylindolizin-1-

amine (4aga) was chosen as the model substrate because its hydrogenation

was considered more challenging due to the presence of three carbon-nitrogen

bonds prone to undergo hydrogenolysis. In addition, the different

hydrogenation degree for the five and six- membered rings of the indolizine

nucleus made the desired transformation more difficult to achieve. In

principle, all reactions were carried out at room temperature with 10 mol% of

a platinum catalyst in different solvents or mixtures of solvents at various

hydrogen pressures (Table 2.1); MeOH-CH2Cl2 or MeOH-HOAc mixtures

favored solubilization of the starting indolizine with respect to the use of only

MeOH. As regards the use of PtO2 as catalyst (Table 2.1, entries 1–14), higher

pressure (3.7 atm) and shorter reaction time (2 h) increased the conversion into

the desired indolizidine 7aga, particularly in the presence of HOAc as solvent

(Table 2.1, entry 8); variable amounts of the mono-debenzylated indolizidine

8aga and a semihydrogenation product (at this stage postulated to be 10aga)

were also formed.

Longer reaction time (8 h) at the same pressure had a detrimental effect

on the conversion due to additional by-product formation (Table 2.1, compare

entries 8 and 9). The combination of HOAc with either MeOH or CH2Cl2 gave

quite good results but did not improve those reached with HOAc (Table 2.1,

entries 13 and 14). Then, we explored the behaviour of different platinum-

based supported catalysts. The highest conversions were achieved with Pt(5

wt%)/CaCO3 and Pt(5 wt%)/C (Table 2.1, entries 18 and 24, respectively), as

above, when pressure (3.7 atm) and short reactions time (3 h) were applied in

HOAc, with the concomitant formation of 8aga and 10aga. As in the case of

PtO2 (Table 2.1, entry 11), lower catalyst loading (5 mol%) in the supported

catalysts led to a decrease in the conversion though of a lower magnitude

compared to the former (Table 2.1, entries 19 and 25).


77

Table 2.1. Hydrogenation of indolizine 4aga using platinum catalysts.a

Entry Catalyst Solvent P (H2, atm) t (h) 7/8/9/10 (%)b

1 PtO2 MeOH-CH2Cl2c 1.0 72 47/-/-/-

2 PtO2 MeOH-CH2Cl2c 3.7 2 44/7/-/6

3 PtO2 EtOH 3.7 8 8/2/-/-

4 PtO2 CH2Cl2 3.7 2 8/-/-/-

5 PtO2 EtOAc 3.7 2 23/-/-/-

6 PtO2 EtOAc 3.7 9 26/-/-/-

7 PtO2 HOAc 1.0 24 39/-/-/-

8 PtO2 HOAc 3.7 2 65/2/-/21

9 PtO2 HOAc 3.7 8 26/10/-/5

10 PtO2 HOAc 5.1 1 48/-/-/-

11 PtO2d HOAc 3.7 2 40/-/-/12

12 PtO2 HOAc 1.0e 23 19/24/-/25

13 PtO2 MeOH-HOAcf 3.7 2 53/-/-/20

14 PtO2 CH2Cl2-HOAcf 3.7 2 65/13/-/10

15 Pt(1 wt%)/Al2O3 MeOH-CH2Cl2c 3.7 2 31/-/-/-

16 Pt(1 wt%)/Al2O3 HOAc 3.7 2 55/-/-/-

17 Pt(5 wt%)/Al2O3 HOAc 1.0e 20 -/-/-/-

18 Pt(5 wt%)/CaCO3 HOAc 3.7 3 62/14/-/14

19 Pt(5 wt%)/CaCO3d HOAc 3.7 3 57/7/-/30

20 Pt(5 wt%)/CaCO3 HOAc 1.0e 20 10/23/-/36

21 Pt(5 wt%)/SiO2 HOAc 3.7 3 -/-/-/-

22 Pt(10 wt%)/C MeOH-CH2Cl2c 3.7 4 24/-/-/-

23 Pt(10 wt%)/C HOAc 3.7 2 56/-/-/-

24 Pt(5 wt%)/C

HOAc 3.7 3 68/6/-/8

25 Pt(5 wt%)/Cd HOAc 3.7 3 52/7/-/15

26 Pt(5 wt%)/C HOAc 1.0e 23 16/19/-/9

27 Pt(5 wt%)/C HOAc 1.0e 7g 30/14/-/26

28 Pt(5 wt%)/C HOAc 1.0e 48g 22/46/-/-

29 Pt(5 wt%)/C MeOH-HOAcc 3.7 3 9/5/-/- a Reaction conditions: 4aga (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. b Conversion

determined by GC. c 3:1 v/v. d 5 mol%. e In balloon. f 1:1 v/v. g Reaction at 50 ºC.


78

Other metal catalysts were also tested with the aim to minimize by-

product formation (Table 2.2). Pd(10 wt%)/C provided a moderate conversion

into 7aga at ambient pressure and prolonged stirring in MeOH, together with a

substantial amount of mono-debenzylated 8aga (Table 2.2, entry 1); higher

hydrogen pressure shortened the reaction time but did not improve the

conversion (Table 2.2, entry 2). An interesting effect of the pressure was

noticed with Pd(20 wt%)/C in HOAc, leading to 8aga at 3.7 atm or 9aga at

ambient pressure with some selectivity (Table 2.2, entries 4 and 5).

Unfortunately, any possibility for directly transforming the starting indolizine

4aga into 8aga or 9aga by the choice of the pressure vanished because of the

low diastereoselectivity attained in both cases (Table 2.2, footnotes d and g).

This lack of diastereoselectivity was also manifested with the deployment of

Pd(5 wt%)/CaCO3 which, conversely, was highly chemoselective towards the

formation of 8aga (Table 2.2, entry 7). Other catalysts, either heterogeneous

[Pd(OH)2/C, Rh(5 wt%)/C and Ru(5 wt%)/C] or homogeneous

{[Rh(COD)Cl]2, [RuCl2(p-cymene)]2 and [Ir(COD)Cl]2}, and/or reaction

conditions furnished complex reaction mixtures (Table 2.2, entries 6, 8, 9 and

11), no product (Table 2.2, entries 12–14) or a certain amount of N-

benzylidene-3-phenylindolizin-1-amine, i.e., the imine of mono-debenzylated

8aga (Table 2.2, entries 3, 16 and 17).


79

Table 2.2. Hydrogenation of indolizine 4aga using other metal catalysts.a

Entry Catalyst Solvent

P (H2, atm) t (h) 7/8/9/10 (%)b

1 Pd(10 wt%)/C MeOH 1.0 48 64/19/-/-

2 Pd(10 wt%)/C MeOH 3.7 7 48/4/-/-

3 Pd(10 wt%)/C HOAc 3.7 2 -c

4 Pd(20 wt%)/C HOAc 3.7 3 -/92d/8/-

5 Pd(20 wt%)/C HOAc 1.0e

23 -/16f/64

g/-

6 Pd(5 wt%)/CaCO3 HOAc 3.7 3 -h

7 Pd(5 wt%)/CaCO3 HOAc 1.0e

20 -/81i/-/-

8 Pd(OH)2/C MeOH 1.0 22 -h

9 Pd(OH)2/C MeOH-CH2Cl2j

1.0 13 -h

10 Pd(OH)2/C MeOH-CH2Cl2j

3.7 6 -/27/-/-

11 Pd(OH)2/C MeOH-

CH2Cl2k 1.0 15 -

h

12 Rh(5 wt%)/C HOAc 1.0e

20 -

13 Rh(5 wt%)/C HOAc 3.7 3.5 -

14 Ru(5 wt%)/C HOAc 3.7 4 -

15 [Rh(COD)Cl]2 MeOH-CH2Cl2j

3.7 10 -l

16 [RuCl2(p-cymene)]2 i-PrOH 3.7 8 -m

17 [Ir(COD)Cl]2 HOAc 3.7 8 -n

a Reaction conditions: 4aga (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. b Conversion

determined by GC. c Monodebenzylated 4aga (25%) and its imine (35%). d 55:45 dr. e In balloon. f

62:38dr. g 64:19:17 dr. h Complex mixture. i 47:44:9 dr. j MeOH-CH2Cl2 (3:1 v/v). k MeOH-CH2Cl2 (1:1

v/v). l Unidentified product (29%). m Imine of monodebenzylated 4aga (12%). n Imine of

monodebenzylated 4aga (4%).

From this optimization study it can be concluded that PtO2 and Pt (5

wt%)/C are the best catalysts in terms of conversion and selectivity (Table 2.1,

entries 8 and 24, respectively).


80

2.2.2. Reutilization of the catalysts

Given the heterogeneous nature of both catalysts, they are potentially

recoverable and recyclable. PtO2 could be easily reused by decantation,

supernatant removal and catalyst washing in the same hydrogenation flask. In

contrast, further manipulation and centrifugation were required for Pt(5

wt%)/C. For comparative purposes, all recycling experiments were conducted

at 3.7 atm for 2 h (Figure 2.3). Catalyst reutilization was found to be more

efficient with PtO2 than with Pt(5 wt%)/C (60% versus 36% in the second

cycle). The catalytic activity of both catalysts decreased in subsequent cycles:

35 and 30% for PtO2 and <10% for Pt(5 wt%)/C, albeit better conversions

would be expected for longer reaction times. In addition to this, we also

observed that the catalytic performance of Pt(5 wt%)/C with substrates other

than 4aga was lower than with PtO2. In view of the aforementioned results, the

catalytic system of choice was that composed of PtO2 (10 mol%) in HOAc at

3.7 atm H2 (Table 2.1, entry 8).

0

10

20

30

40

50

60

70

1 2 3 4

Pt(IV) oxide Pt(5 wt%)/C

cycles

co

nvers

ion

(%)

Figure 2.3. Catalyst recycling experiments in the hydrogenation of 4aga (3.7 atm H2,

2 h).


81


In order to study the substrate scope, the optimized catalyst and

reaction conditions were applied to a variety of indolizines 4, derived from

pyridine-2-carbaldehyde (1a), secondary amines (2) and terminal alkynes (3),

producing the expected indolizidines 6 in modest-to-high yields and with high-

to-excellent diastereoselectivity (Table 2.3). The yield and diastereoselectivity

were found to be dependent on the substituents at the 1 and 3 positions, with

the amino group at the 1 position apparently exerting a stronger effect. For

instance, the indolizines derived from piperidine and arylacetylenes were

isolated in lower yields, with the lowest diastereoselectivity been recorded for

the phenylacetylene derivative (7aaa). The diastereomeric ratio was improved

when a para substituent was present in the arylacetylene-derived moiety while

at the same time maintaining the 1-piperidinyl group (Table 2.3, compare 7aaa

with 7aab and 7aac). Fortunately, purification by column chromatography

allowed the isolation of 7aaa and 7aab as single diastereoisomers. Better yield

and excellent diastereoselectivity were observed when changing the 1-

piperidinyl into a 1-morpholino group (Table 2.3, compare 7aaa with 7aba).

In general, the results with acyclic amines were better than those with the

cyclic counterparts concerning all, the yield, the diastereoselectivity and the

reaction time. The diastereoselectivity increased when increasing the steric

hindrance of the secondary amine (Table 2.3, compare 7ada and 7aea with

7aca and 7aga). The indolizidines derived from dibenzylamine followed a

similar trend to that of dibutylamine (7aca), being generally obtained in

relatively short hydrogenation reaction times and as single diastereoisomers

(Table 2.3, 7aga-7agf). This remarkable behavior was displayed irrespective

of the substituent at the 3 position of the indolizidine nucleus, including aryl

substituents with electron-neutral (Table 2.3, 7aga and 7agb), -releasing

(Table 2.3, 7agc) and -withdrawing groups (Table 2.3, 7agd and 7age), as well

as aliphatic substituents (Table 2.3, 7agf).


82

Table 2.3. Synthesis of the indolizidines 7.a

a Reaction conditions: 4 (0.5 mmol), PtO2 (10 mol%), HOAc (3 mL), H2 (3.7 atm), rt; reaction time and

isolated yield in parentheses; diastereomeric ratio in brackets determined by GC-MS from the reaction

crude. b Diastereomeric ratio after purification by column chromatography. c Reaction at 4.1 atm.


83

We endeavored to extend this method to more demanding indolizines

in order to validate its applicability. Such is the case of N,N-dibutyl-1-

phenylpyrrolo[1,2-a]quinolin-3-amine (4eca), a benzo-fused indolizine

coming from the coupling of quinoline-2-carbaldehyde (1e), dibutylamine (2c)

and phenylacetylene (3a). We also applied the same conditions to 1-phenyl-3-

(piperidin-1-yl)pyrrolo[1,2-a]quinoline (4eaa), but the chemoselectivity was

very low. It is worthy of note that the catalytic hydrogenation failed under the

standard pressure and that a slightly higher pressure was necessary to initiate

the reaction. Consequently, the latter was found to be more chemoselective at

lower than at higher conversions, with an increase of byproduct formation in

the second case. The scant yield of the expected hexahydropyrrolo[1,2-

a]quinolin-3-amine 7eca was compensated for the high diastereomeric ratio

reached; the presence of the fused benzene in the tricyclic indolizine core did

not vary the stereochemical outcome with respect to the bicyclic counterparts.

We went one step further by dealing with the hydrogenation of the

trisubstituted indolizine 4cga, the precursors of which were 6-methylpyridine-

2-carbaldehyde (1c), dibenzylamine (2g) and phenylacetylene (3a). In this

case, a short reaction time was more convenient to minimize byproduct

formation. It was gratifying to know that, though in modest isolated yield, the

four-stereocenter indolizidine 7cga could be obtained with very high

diastereoselectivity.


84

2.2.4. Stereochemistry and mechanism

First, the stereochemistry of the indolizidines 7 was proposed on the

basis of 2D-NMR experiments conducted for 7aba, 7aga, 7eca and 7bga

(Figure 2.4) and, later on, unequivocally established by X-ray crystallographic

analysis of compound 7aaa (Figure 2.5). In view of these data, the major

diastereoisomer obtained in the catalytic hydrogenation of the indolizines is

that resulting from the addition of hydrogen to the same face of the indolizine

nucleus.

Figure 2.4. Selected

1H-

1H correlations from NOESY experiments.


85

Figure 2.5. X-ray structure of compound 7aaa.

Finally, we wanted to know about the hydrogenation pathway and the

structure of any possible semihydrogenated intermediate. With this purpose in

mind, indolizine 4aaa was hydrogenated under the standard conditions but for

a shorter reaction time. These intermediates were found to be rather elusive

because of their minor formation and high tendency to over-hydrogenation.

Notwithstanding these added difficulties, we managed to isolate a certain

amount of the 5,6,7,8-tetrahydroindolizine 10aaa, which confirmed the

preferential hydrogenation of the six-membered ring of the indolizine nucleus.

Further hydrogenation of 10aaa gave rise to the fully reduced indolizidine

7aaa with the same stereoselectivity as above. These results lend weight to the

argument that the stereochemistry of the indolizidines is fixed in a second

stage, where all hydrogen atoms are delivered from the catalyst to the same

face of the pyrrole ring in 10aaa (Scheme 2.2).


86

Scheme 2.2. Sequential hydrogenation of the indolizine 4aaa and hydrogenation

model of 10aaa.

2.2.5. Debenzylation of indolizidines

Secondary amines are versatile nitrogenated compounds with multiple

applications in organic chemistry as, for example, as organocatalysts, as Lewis

bases (e.g., for the activation of electron-deficient olefins) or as building

scaffolds for multicomponent reactions, among many others. On the other

hand, in organic chemistry, it is desirable that the selective conversion of a

single starting material into two or more different products can be

accomplished by the selection of the catalyst. In this vein, attempts to directly

transform indolizine 4aga into the mono-benzylated secondary amine 8aga

were found to be successful in terms of conversion under palladium catalysis;

regretfully, the diastereoselectivity of these reactions was too low (Table 2.2,

entries 4 and 7, footnotes d and i). Then, we decided to take advantage of the

presence of two benzyl groups in the indolizidines 7aga-7agf and 7cga to

investigate the possibilities of effecting selective hydrogenolysis, leading to


87

secondary amines 8 or primary amines 9, through mono- and di-debenzylation

processes, respectively.

Taking into account the information in tables 2.1 and 2.2, four catalysts

were considered for this study, including platinum and palladium catalysts,

using indolizidine 7aga as the starting material (Table 2.4). As a general trend,

platinum catalysts provided the mono-debenzylated product 8aga whereas the

palladium catalyst favoured the full debenzylated product 9aga. A significant

effect of the hydrogen pressure was also discerned, with ambient pressure

resulting in higher conversions and less formation of side products. Prolonged

stirring was recommended in both cases because did not alter the high

selectivity attained with the platinum catalysts [Pt(5 wt%)/C and PtO2] (Table

3.4, entries 3 and 4) and guaranteed the full hydrogenolysis with Pd(20

wt%)/C (Table 2.4, compare entries 7 and 8).

Table 2.4. Optimization of the hydrogenolysis of 7aga. a

Entry Catalyst P

(H2, atm) t (h)

8aga/9aga

(%)b

1 Pt(5 wt%)/C 3.7 2 15/-

2 Pt(5 wt%)/C 3.7 6 31/-

3 Pt(5 wt%)/C 1.0c

22 61/-

4 PtO2 1.0c

17 83/-

5 Pt(5 wt%)/CaCO3 1.0c

16 59/-

6 Pd(20 wt%)/C 3.7

2 31/-

7 Pd(20 wt%)/C 1.0c

7 6/77

8 Pd(20 wt%)/C 1.0c

23 -/82 a Reaction conditions: 7aga (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL)

and H2 at rt. b Conversion determined by GC. c In balloon.


88

The optimized conditions were first applied to the selective mono-

debenzylation of some of the indolizidines 7aga-7agf. As representative

examples, indolizidines derived from aromatic alkynes of diverse electronic

nature (neutral, rich and deficient ones), as well as from aliphatic alkynes,

were converted into the monobenzylated counterparts 7 in moderate-to-high

yields (Table 2.5). Although both catalysts, PtO2 and Pt(5 wt%)/C selectively

catalyzed the mono-debenzylation reaction at ambient hydrogen pressure and

temperature, the yields were slightly higher when the former was utilized for

7aga and 7agc, and the latter for 7agd and 7agf.

Table 2.5. Mono-debenzylation of indolizidines 7.a

a Reaction conditions: 7 (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL) and H2 (1 atm) at rt;

isolated yield after purification by preparative TLC (hexane/EtOAc 6:4); conversions into 8

were in the range 82->99%); diastereomeric ratio determined by GC-MS from the reaction

crude. b Reaction catalyzed by PtO2. c Reaction catalyzed by Pt(5 wt%)/C.


89

When the same substrates, as above, were submitted to hydrogenolysis

catalyzed by Pd(20 wt%)/C at ambient hydrogen pressure and temperature, the

corresponding free amino indolizidines 8 were produced in high yields as a

result of a di-debenzylation process (Table 2.6). It is noteworthy that the

original stereochemical integrity of the indolizidines was unaffected during the

hydrogenolyses leading to the desired products as single diastereomers.

Table 2.6. Di-debenzylation of indolizidines 7.a

a Reaction conditions: 7 (0.3 mmol), Pd(20 wt%)/C (10 mol%), HOAc (3.0 mL) and

H2 (1 atm) at rt; conversions into 9 were in the range 73->99%. Compounds 9aga and

9agd were purified by preparative TLC (EtOAc). Compounds 9agc and 9agf did not

require any further purification. Diastereomeric ratio determined by GC-MS from the

reaction crude.


90

2.2.6. Biological activity

Endocrine/Cardiovascular

GLP-1 Secretion: Glucagon-like peptide 1 is a potent anti-

hyperglycemic hormone which induces glucose-dependant insulin secretion

and supresses glucagon secretion. There are two primary assays where

indolizines have activity.

CHAPTER III

REACTIVITY OF INDOLIZINES:

SYNTHESIS OF DYES

Chapter III. Reactivity of indolizines: synthesis of dyes

93

3. REACTIVITY OF INDOLIZINES: SYNTHESIS OF DYES

3.1. INTRODUCTION

There is a general upsurge of interest in developing more efficient and

sustainable processes for the alkenylation of aromatic and heteroaromatic

compounds based on C-H activation. Among them, the transition-metal free

cross-coupling of aryl halides with alkenes is praiseworthy but requires the

action of strong bases that curtail the substrate scope of the method.99

The

cross-dehydrogenative coupling (CDC) of arenes and alkenes (oxidative Heck-

type or Fujiwara-Moritani reaction) represents a much more advantageous and

resourceful strategy because skips the pre-installation of the halide on the

aromatic unit and produces hydrogen as the only byproduct (i.e., high atom

economy).100

At any rate, the presence of a noble transition metal is necessary,

normally accompanied by a stoichiometric oxidant under thermal treatment;

rhodium,101

ruthenium102

and, especially, palladium103

catalysts are the most

common metals in this field. The control of the regio- and stereoselectivity are

major issues in this type of reactions; the former is commonly addressed by

activation of HetCsp2-H bonds (e.g., NCsp2-H bonds) or by the introduction of a

directing group (e.g., ortho alkenylation). Remote site-selective Csp2-H

olefination is, yet, a much more challenging hot topic.104

99

Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219. 100

Reviews: (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744. (b) Wu, Y.; Wang, J.; Mao, F.;

Kwong, F. Y. Chem. Asian J. 2014, 9, 26. (c) Zhou, L.; Lu, W. Chem. Eur. J. 2014, 20, 634. (d) Kitamura, T.;

Fujiwara, Y. In From C-H to C-C Bonds. Cross-Dehydrogenative Coupling; Li, C.-J., Ed.; The Royal Society

of Chemistry: Cambridge (UK), 2015. 101

(a) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichim. Acta 2012, 45, 31. (b) Ye, B.; Cramer, N.

Acc. Chem. Res. 2015, 48, 1308. (c) Satoh, T.; Miura, M. In Catalytic Transformations via C-H Activation

1, Science of Synthesis; Thieme: Stuttgart, 2016; Chapter 1.1.6. 102

Arockiam, P. B.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 103

(a) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Doman, P. K.; Dong, V. M. In Catalytic

Transformations via C-H Activation 1, Science of Synthesis; Thieme: Stuttgart, 2016; Chapter 1.1.5. 104

(a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518. (b) Deng, Y.; Yu, J.-Q. Angew. Chem.

Int. Ed. 2015, 54, 888. (c) Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D. Angew. Chem. Int. Ed. 2015, 54, 8515.

(d) Zhang, Z.; Tanaka, K.; Yu, J.-Q. Nature 2017, 543, 538.


94

In recent years, the selective alkenylation of nitrogen heterocycles

making use of the CDC tool has been paid a great deal of attention;105

this

additional introduction of functionality can be ultimately used for further

synthetic purposes or to enhance the inherent biological activity of the

compounds. Pyridines,106

uracils,107

indole derivatives,108

imidazo[1,2-

a]pyridines109

and indolizines110

are some of the substrates successfully

subjected to this reaction (Scheme 3.1). However, the corresponding methods

implemented are far from being sustainable and green, and conditional on

close site-selective C-H activation. Furthermore, it seems rather unviable to

scale up the procedures from the economic (expensive catalysts), safety (high

temperatures in O2 atmosphere) and environmental point of view (use of non-

recommended solvents111

). Therefore, there is a justification to explore new

routes toward heterocycle alkenylation. Moreover, the alkenylation of

aromatic compounds by C-H activation also elongates the π-system, producing

conjugated organic materials with new and potential photophysical

characteristics (e.g., as organic electronic materials).112

105

Nakao, Y. In Catalytic Transformations via C-H Activation 1, Science of Synthesis; Thieme: Stuttgart,

2016; Chapter 1.2. 106

Wen, P.; Li, Y.; Zhou, K.; Ma, C.; Lan, X.; Ma, C.; Huang, G. Adv. Synth. Catal. 2012, 354, 2135. 107

(a) Huang, Y.; Song, F.; Wang, Z.; Xi, P.; Wu, N.; Wang, Z.; Lan, J.; You, J. Chem. Commun. 2012, 48,

2864. (b) Yu, Y.-Y.; Georg, G. I. Chem. Commun. 2013, 49, 3694. 108

(a) Zhang, L.-Q.; Yang, S.; Huang, X.; You, J.; Song, F. Chem. Commun. 2013, 49, 8830. (b) Yang, X.-F.;

Hu, X.-H; Feng, C.; Loh, T.-P. Chem. Commun. 2015, 51, 2532. (c) Kannaboina, P.; Kumar, K. A.; Das, P.

Org. Lett. 2016, 18, 900. (d) Gorsline, B. J.; Wang, L.; Ren, P.; Carrow, B. P. J. Am. Chem. Soc. 2017, 139,

9605. 109

(a) Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271. (b) Zhan, H.;

Zhao, L.; Li, N.; Chen, L.; Liu, J.; Liao, J.; Cao, H. RSC Adv. 2014, 4, 32013. 110

Hu, H.; Liu, Y.; Zhong, H.; Zhu, Y.; Wang, C.; Ji, M. Chem. Asian J. 2012, 7, 884. 111

Reviews: (a) Eastman, H. E.; Jamieson, C.; Watson, A. J. B. Aldrichim. Acta 2015, 48, 51. (b) Prat, D.;

Wells, A.; Hayler, J.; Sneddon, H.; McElroy, R.; Abou-Shehadad, S.; Dunne, P. J. Green Chem. 2016, 18,

288. 112

Review: Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem. Int. Ed. 2015, 54, 66.


95

Scheme 3.1. Transition-metal catalyzed alkenylation of some N-heterocycles.


96

On the other hand, natural dyes and pigments have been used for

millennia, mainly, as coloring agents.113

However, synthetic dyes show greater

stability, which has allowed to introduce new applications and open new

markets in such varied fields. Dyes derived from indolizines (Figure 3.1) have

been relatively poorly studied compared to the more common types of

triphenylmethane, azo compound, or anthraquinone (Figure 3.2).

Figure 3.1. Examples of indolizine dyes.

Figure 3.2. Classical types of dyes.

113

Handbook of Natural Colorants; Bechtold, T., Mussak, R., Eds.; John Wiley & Sons: Chichester (UK),

2009.


97

Organic dyes with a D-π-A configuration contain both electron-donating

(D) and electron-withdrawing groups (A) connected by a π-conjugated section;

alternatively, a D-A-π-A configuration can be molecularly designed where the

additional intercalated A is a heterocyclic component (Figure 3.3). The

particular light absorption of these compounds makes them ideal candidates

for chemosensors114

and dye-sensitized solar cells.115

The construction of the

alkenyl linker usually relies on a Wittig reaction, for which a proper

functionalization of the starting materials is required.

Figure 3.3. Dyes with D-π-A and D-A-π-A configurations.

Moreover, both the pyridinyl chalcone and indolizine systems are very

useful scaffolds in synthetic organic chemistry as well as in materials science.

In the latter respect, indolizine dyes have found practical applications as

materials in laser-based recording and reading devices, electrochromic

devices,116

thermography and fotothermography, optical filters,117

as well as

114

Selected reviews: (a) Zhou, Y.; Yoon, J. Chem. Soc. Rev. 2012, 41, 52. (b) Jung, H. S.; Chen, X.; Kim, J.

S.; Yoon, J. Chem. Soc. Rev. 2013, 42, 6019. (c) Uglov, A. N.; Bessmertnykh-Lemeune, A.; Guillard, R.;

Averin, A. D.; Beletskaya, I. P. Russ. Chem. Rev. 2014, 83, 196. 115

Reviews: (a) Ooyama, Y.; Harima, Y. Eur. J. Org. Chem. 2009, 2903. (b) Wu, Y.; Zhu, W. Chem. Soc.

Rev. 2013, 42, 2039. (c) Viewpoint: Kloo, L. Chem. Commun. 2013, 49, 6580. 116

Jung, Y.-S.; Jaung, J.-Y Dyes Pigments 2005, 65, 205. 117

Inagaki, Y.; Kubo T. (Fuji Photo Film Co., Ltd.). JP 03074471A, 1991; Chem. Abstr. 1991, 115, 138212.


98

photoelectric converters.118

. Within the most recent literature, several articles

covering the photophysical behavior (e.g., halochromism, fluorescence, etc.)

of indolizine119

and heterocyclic chalcone dyes120

have been reported (Figure

3.4). It is worth noting that the more specific 2-pyridinyl chalcones can

additionally behave as probes for sensing of metal ions by coordination

through the 2-pyridinylcarbonyl fragment.22b

Figure 3.4. Examples of indolizines and chalcones with photophysical properties.

As part of our interest in studying the reactivity of indolizines, we

explored their reactivity under acidic conditions, leading to indolizine dyes

through a singular remote alkenylation process.

118

Tanabe, J.; Shinkai, M.; Tsuchiya, M. (TDK Electronics Co., Ltd.). JP 2008101064A, 2008; Chem. Abstr.

2008, 148, 520703. 119

(a) Rotaru, A.; Druta, I.; Avram, E.; Danac, R. ARKIVOC 2009, xiii, 287. (b) Amaral, M. F. Z. J.;

Deliberto, L. A.; de Souza, C. R.; Naal, R. M. Z. G.; Naal, Z.; Clososki, G. C. Tetrahedron 2014, 70, 3249. (c)

Kim, E.; Lee, Y.; Lee, S.; Park, S. B. Acc. Chem. Res. 2015, 48, 538. (d) Song, Y. R.; Limb, C. V.; Kima, T. W.

Luminescence 2016, 31, 364. (e) Zhang, Y.; Garcia-Amorós, J.; Captain, B.; Raymo, F. M. J. Mater. Chem.

C 2016, 4, 2744. (f) Outlaw, V. K.; Zhou, J.; Bragg, A. E.; Townsend, C. A. RSC Adv. 2016, 6, 61249. 120

(a) Rurack, K.; Bricks, J. L.; Reck, G.; Radeglia, R.; Resch-Genger, U. J. Phys. Chem. A 2000, 104, 3087.

(b) Mashraqui, S. H.; Khan, T.; Sundaram, S.; Ghadigaonkar, S. Tetrahedron Lett. 2008, 49, 3739. (c) El-

Daly, S. A.; Gaber, M.; Al-Shihry, S. S.; El Sayed, Y. S. J. Photochem. Photobiol. A: Chem. 2008, 195, 89.

(d) Gaber, M.; El-Daly, S. A.; El-Sayed, Y. S. Y. J. Mol. Struct. 2009, 922, 51. (e) El-Sayed, Y. S. Opt. Laser

Technol. 2013, 45, 89. (f) El-Sayed, Y. S.; Gaber, M. Spectrochim. Acta, Part A 2015, 137, 423–431. (g)

Shinozaki, Y.; Arai, T. Heterocycles 2017, 95, 972.


99


The reactivity of indolizines in acidic medium was formerly optimized

for the indolizine 4aga,66

with the highest conversion to the corresponding dye

being obtained with HOAc at room temperature.


With the optimized conditions in hand, a wide range of dyes were

synthesized from different indolizines in low-to-high isolated yields (Table

3.1). We first studied the effect of the substitution on the 3-aryl group for a

series of 1-dibenzylamino indolizine derivatives. The presence of electron-

donating groups at the para position (4agb and 4agc) was found to be

somewhat beneficial with respect to the unsubstituted indolizine (4aga),

obtaining the corresponding dyes (11agb and 11agc) in good isolated yields.

For the existence of para electron-withdrawing groups, the opposite effect was

noted, with lower yields around 50% for 11agd and 11age. The substitution of

the 3-aryl group into a 3-alkyl substituent in 4 exerted a certain detrimental

effect (11agi). Next, we tested the influence of the amino substituents:

replacing a benzyl with a methyl group had a considerable decrease in the

yield (compare 11ada with 11aga). That decrease was more pronounced in the

case of N-methyl-N-phenethyl- (11aea), N-piperidinyl- (11aaa) or N,N-

dibutylamino (11aca) substituents; in the last two cases, the reaction was

especially slow. Dyes bearing a N-methyl-N-phenyl moiety could be also

synthesized, either containing the normal indolizine/pyridinyl (11afa) or the 5-

methylindolizine/6-methylpyridinyl (11cfa) nuclei, the second one in very

modest yield. Pleasantly, the yield was boosted above 70% when two strong

electron-donating groups (i.e., 4-methoxyphenyl) were bonded to nitrogen

(11aha). The methodology was also effective for the construction of chiral

dyes, such in the case of the (R)-N-benzyl-N-α-methyl)benzylamino derivative

66 Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por

Nanopartículas de Cobre Soportadas, Tesis doctoral, Universidad de Alicante, 2014.


100

Table 3.1. Transformation of indolizines 4 into dyes 11.a,b

a Reaction conditions: indolizine 4 (0.5 mmol) and HOAc (3 mL) at rt for the specified time; then sat.

NaHCO3 until neutralization. b Yield of the isolated product 11 based on 2 equiv. of 4. c NMR yield

based on 2 equiv. of 4.


101

11aia. It can be concluded that the existence of the 1-dibenzylamino and 3-

aryl groups is essential to obtain good yields.

Scale up is a hurdle generally encountered in organic synthesis, more

markedly in multi-step procedures and in catalysis, which often curtails the

transfer of laboratory basic research into the productive sector. In this vein, we

tried to adapt the preceding one-pot method to a multi-gram scale. For this

purpose, several parameters were readjusted: (a) 5 mol% CuI was used instead

of 0.5 mol% CuNPs/C; (b) CH2Cl2 was removed, making the reaction greener

under solvent-free conditions; (c) the neutralization step was executed with

NaOH solution instead of sat. NaHCO3 to avoid excessive bubbling; and (d)

the purification of the dye was accomplished by recrystallization in lieu of

column chromatography, with the former being always preferred by the

chemical industry. We must underline that the use of CuNPs/C is

advantageous because it enables an adequate metal separation from the

reaction medium by filtration; in contrast, with CuI, washing with ammonia

solution is suggested during the work-up for copper removal. Nevertheless, in

this manner, 187 mmol (20 g) of pyridine-2-carbaldehyde were converted to

40 g of the pure dye 11aga (Scheme 3.2). The yield achieved (72%) is

concordant with that of the small-scale synthesis and denotes a highly robust

and reproducible method.

Scheme 3.2. Multigram scale one-pot synthesis of the dye 11aga.


102

Attempts to prepare mixed dyes from two different indolizines by

varying either the 1-dialkylamino and/or the 3-aryl substituent were unfruitful.

The formation of the homoadducts was preferred to that of the heteroadducts

[Scheme 3.3, eq. (1) and (2)]. In the case of 4aga and 4agc, three spots were

observed by TLC, two of them corresponding to the homoadducts 11aga and

11agc [Scheme 3.3, eq. (2)]. The third one, after isolation by column

chromatography, showed a mixture of two heteroadduct dyes in a 1:1 ratio

(Figure 3.5), hence demonstrating a low reaction selectivity.

As a general trend, indolizine 4aga reacted faster as the nucleophilic

partner leading to the indolizine dye 10aga preferentially over others bearing

other 1-alkyl- or arylamino groups (Schemes 3.3 and 3.4).

Scheme 3.3. Some attempts to synthesize mixed dyes.


103

Figure 3.5.

1H NMR spectrum of a 1:1 mixture of 11AB and 11BA.

Scheme 3.4. Competing experiments in the synthesis of dyes.


104

3.2.2. Structural analysis

From the structural viewpoint, we were delighted to find out that the

resulting trisubstituted indolizine dyes 11 maintained the original structure of

the starting material 4, but had grown up selectively through the 7-position of

the indolizine nucleus by the incorporation of a heterocyclic chalcone

fragment from another indolizine molecule. In this sense, the dyes 11 can be

considered as indolizine-chalcone hybrids selectively bonded through a Csp2-

Csp2 bond. Certainly, this is a very singular Csp2-Csp2 bond formation with the

following salient features: (a) the conversion of 4 into 11 can be formally

considered as a remote-site C–H self-alkenylation reaction; (b) transition-

metal catalysis is dispensable; (c) contrary to the published alkenylation

strategies which result in quaternaryCsp2-tertiaryCsp2 bond formation, the more

challenging quaternaryCsp2-quaternaryCsp2 bonds are made now (i.e., with a

1,1-disubstituted alkenyl fragment); (d) it is worthwhile mentioning the

extraordinary selectivity achieved in this reaction, with the dyes 11 being

obtained with absolute control of both the regioselectivity and the

stereoselectivity. Thus, out of the ten potential isomers which can be drawn as

products (five possible regioisomers at the indolizine positions 2, 5, 6, 7, and

8, each as two possible Z/E diastereoisomers), only one was formed, the 7-

substituted E isomer.

The structure of the dyes 11 was unequivocally established by X-ray

crystallography of 11aga and 11agc (Figure 3.6). The X-ray plot of 11aga

brings into view a quasi-flat arrangement of the chalcone-indolizine backbone.

Conversely, the phenyl group at the β-position of the C=O (C15–C16) lays

near perpendicular to that backbone (C17–C16–C15–C22 torsion angle 80º) in

order to reduce the steric interaction of the ortho Hs with the C=O and the C5–

H. The phenyl ring on the indolizine nucleus also appears deviated from co-

planarity (C2–C1–C9–C14 torsion angle 31º) to prevent C2–H/C14–H and

C8–H/C10–H interactions. Finally, the carbonyl group and the C–N of the

pyridinyl group are exposed to view in an anti-periplanar conformation (O1–

C23–C24–N2) to minimize dipole-dipole interactions. The structural X-ray

patterns displayed by the dyes 11aga and 11agc were alike.


105

Figure 3.6. Plot showing the X-ray structure and atom numbering of the dyes 11aga

and 11agc.

Surprisingly, the response of the dyes in solution was very different from

that in the solid state: duplicity of some NMR signals was observed for all

compounds 11 except 11agi. For instance, compound 11aga exhibited a ca.

1:5 signal ratio in CDCl3 which was constant irrespective of the reaction

conditions or purification method (chromatography or recrystallization).

Apparently, compounds 11 exist as a mixture of two distinguishable rotamers

in solution; the fact that the above ratio varies with the NMR solvent used

would bolster this hypothesis (Table 3.2). In general, the major rotamer seems

to be more favored in the more polar solvents (Table 3.2, compare entry 2 with

5, 7 and 8); this fact entails important consequences in the optical performance

of the dyes (see below). The trend to signal coalescence and to equal the

population species, noticed by heating, is also typical of rotamers (Table 3.2,

entries 5 and 6).


106

Table 3.2. Chemical shifts and ratio of the two rotamers A (major) and B (minor).

pyridine-D5

C6D6

CDCl3

acetone-D6

DMSO-D6

r.t.

DMSO-D6

110 ºC

ethanol-

D6

CD3CN

Entry Solvent δA/δB (ppm) A/B εa

1 pyridine-D5 4.31/4.24 3.52:1 13.26

2 C6D6 4.21/4.05 3.65:1 2.28

3 CDCl3 4.19/4.15 4.97:1 4.81

4 acetone-D6 4.23/4.15 5.41:1 21.01

5 DMSO-D6 4.15/4.09 5.60:1 47.24

6 DMSO-D6 4.24/4.20b 3.00:1

b 47.24

7 ethanol-D6 4.16/4.10 6.00:1c 25.30

8 CD3CN 4.14/4.09 12.00:1c 36.64

a Dielectric constant. b Data obtained at 110 ºC. c Ratio estimated from other spectrum signals.

The coexistence of the two rotamers could be ascribed to the

circumstance that compounds 11 are push-pull highly conjugated systems,

possessing the electron-releasing and -withdrawing amino and acyl groups,

respectively. Therefore, resonant forms with a partial double bond connecting

the chalcone and indolizine nucleus could be drawn (Scheme 3.5a). The

restricted rotation around that bond would lead to two highly conjugated and

conformationally stable η-enaminoketones. NOESY experiments are in

agreement with the rotamer A being the major one which, in turn, coincides

with the structure of 11aga in the solid state (Scheme 3.5b). The conformation

suggested for rotamer B is more dubious, albeit it is evident that Hd' and Hk'

are far each other now (Scheme 3.5b).


107

Scheme 3.5. (a) Proposed structures for the rotamers A and B of 11aga in solution

and their resonant forms. (b) Selected NOEs.


108

In fact, these two protons experienced the most pronounced variation in

the chemical shift (ca. 0.40 and 0.55 ppm, respectively) with a displacement to

a higher field (Figure 3.7). Due to the relative spatial proximity of the β-

phenyl and Hk', the former might exert a shielding impact on the latter by

polarization and field effects.121

The calculated dipolar moments122

for the

rotamer A (3.17 D) and rotamer B (1.32 D) marry up with their abundance as a

function of the solvent polarity; i.e., the rotamer A prevails in polar solvents.

Figure 3.7. Partial assignment of the

1H NMR signals of 11aga (CDCl3). Letters with

a prime denote hydrogens of the minor rotamer.

We managed to get a 1H NMR spectrum of the pure rotamer A by

dissolving the solid 11aga in CDCl3 just before running the NMR experiment

(Figure 3.8). In-situ 1H NMR analysis of this sample at room temperature

disclosed that complete rotamer equilibration was attained after 2 h (Figure

3.9).

121

Anson, C. W.; Thamattoor, D. M. J. Org. Chem. 2012, 77, 1693. 122

The dipolar moments were determined by calculation with the PM3 semiempirical method: Stewart,

J. J. P. J. Comput. Chem. 1991, 12, 320.


109

Figure 3.8.

1H NMR spectrum of the pure rotamer A of dye 11aga (solid 11aga was

dissolved in CDCl3 just before running the NMR experiment).

Figure 3.9. In-situ

1H NMR analysis of the rotamer A of dye 11aga in CDCl3.


110

Rotamers were also observed for dyes of the 3-aryl-1-dibenzylamino

series (Table 3.3, entries 1–5 and 14): the presence of electron-withdrawing

groups at the para position of the phenyl group displaced the equilibrium

towards the rotamer A (Table 3.3, entries 4 and 5) and vice versa (Table 3.3,

entry 3). A quite homogeneous A/B ratio was measured for the N-alkylated

(non-benzylic) dyes 11ada–11aca (Table 3.3, entries 7–10). The most

pronounced effect in favor of the minor rotamer B was noted for the N-phenyl

substituted dyes 11aca and 11afa (Table 3.3, entries 11 and 12), probably due

to electron delocalization of the N lone pair though the phenyl ring. This effect

was of less magnitude in dye 11aha because the p-OMe groups work in the

opposite direction (Table 3.3, entry 13). Startlingly, the dye 11agi, bearing two

alkyl chains in the chalcone-indolizine skeleton, was held up to view as a

single set of NMR signals in solution; the broad signals plotted might be

linked to the existence of unresolved rotamers during the time-scale of the

Table 3.3. 1H NMR chemical shifts of dyes 11 and ratio of the two rotamers A

(major) and B (minor).

Entry Dye δA/δB (ppm)a A/B

1 11aga 6.86/6.35 83:17

2 11agb 6.84/6.34 83:17

3 11agc 6.81/6.34 78:22

4 11agd 6.90/6.36 91:9

5 11age 6.95/6.38 88:12

6 11agi 6.85b >99:1

7 11ada 6.93/6.38 83:17

8 11aea 6.86/6.38 81:19

9 11aaa 6.84/6.33 85:15

10 11aca 6.88/6.40 84:16

11 11afa 6.84/6.45 70:30

12 11cfa 2.62/2.58c 68:32

c

13 11aha 3.78/3.73d 79:21

d

14 11aia 6.97/6.41 86:14 a Chemical shift of Hk/Hk' unless otherwise stated.

b Only one rotamer was detected

by NMR. c

Ratio determined from the MeAr group. d Ratio determined from the

OMe group.


111

NMR experiment at room temperature. The larger conformational freedom of

the butyl group, compared to that of the phenyl group, could account for this

abnormality. As a general tendency, all the δB data for N-C-H were at higher

field than the δA counterparts.

3.2.3. Reaction mechanism

The dyes 11 are trisubstituted indolizines which keep the original

structure of the starting indolizine 4 but have selectively grown up through the

7-position. The reactivity at this position might be supported, in part, by the

deuteration studies by Engewald et al. to determine the exchange rate of the

indolizine hydrogens in D2O/dioxane at 50 ºC123

and in 0.02 M D2SO4/dioxane

at 200 ºC.124

These studies established the following relative order of reactivity

of the positions against electrophiles: 3 > 1 > > 2 > 7 ~ 5 > 6 > 8. In our case,

the positions 1 and 3 are already substituted and the position 2 is more

sterically encumbered than the position 7. Nevertheless, the amino group at the

position 1 seems to play a paramount role in this selectivity.

When the transformation of 4aga into 11aga was carried out following

the standard procedure but in CD3CO2D instead of CH3CO2H, no

incorporation of D was observed in 11aga; this result supports the activating

character of acetic acid and rules out any structural role. In-situ NMR analysis

of the reaction of 4aga with CD3CO2D in CDCl3 brought forth a major

depletion of the signal intensity for the indolizine hydrogen atoms (e.g., NC5-

H, ca. 8.2 ppm) and the benzylic methylene groups (NCH2, ca. 4.2 ppm). This

outcome could indicate a first deuteration/protonation stage involving the

nitrogen atoms. However, signals corresponding to the dye 11aga were not

present in the spectra. We observed that some dye 11aga was formed after

prolonged exposure of indolizine 4aga to HOAc but the reaction was much

slower compared to that subjected to posterior neutralization with sat.

NaHCO3, evidencing the necessity of water and/or base for the onward

progress of the reaction.

123

Engewald, W.; Mühlstädt, M.; Weiss, C. Tetrahedron 1971, 27, 4171. 124

Engewald, W.; Mühlstädt, M.; Weiss, C. Tetrahedron 1971, 27, 851.


112

Figure 3.10. In-situ

1H RMN analysis of indolizine 4aga in CDCl3 after the addition

of 20 equiv. of CD3CO2D.

On the basis of the above results, the following reaction mechanism was

put forward, exemplified for the substrate 4aga (Scheme 3.6): two molecules

of the indolizine 4aga are involved in the process, one acting as an

electrophile (after proper activation) and the other one as a nucleophile. On

one hand, it is our belief that 4aga possesses an enamine character and,

therefore, it might experience hydrolysis prior protonation to give the

corresponding ketone, with the concomitant loss of dibenzylamine (detected in

the reaction crude by GC/MS and 1H NMR). On the other hand, another

molecule of 4aga would act as a nucleophile through the dienamine subunit,

selectively reacting at its less hindered γ position (7 position of the indolizine

nucleus), by conjugate addition to an intermediate of the type 12. Ring

opening by C–N bond cleavage in 13 would furnish 14 which would,

eventually, undergo re-aromatization of the indolizine nucleus and oxidation

of the dihydropyridine ring, giving rise to the dye 11aga.

0 s

2 s

5 min

10 min

15 min

30 min

1 h

2 h

4 h

6 h


113

Scheme 3.6. Proposed reaction mechanism for the formation of the dyes 11.

We got some evidence on the formation of an intermediate of the type

13 by reacting indolizine 4aga with acetic acid, followed by acid evaporation

(in air). IR analysis of a sample, exposed to view the absence of acetic acid

[typical bands at 3500-2500 cm–1

(O-H); 1758 and 1714 cm–1

(C=O)] but the

presence of a peak at 1709 cm–1

, typical of a five-membered α,β-unsaturated

ketone [cyclopent-2-one, 1707 cm–1

(C=O)]. The stretching frequency of the

N-H bond in trisubstituted ammonium salts is manifested in the form of a

medium-intensity wide band of pronounced structure, with the maximum

interval being located at 2700-2250 cm–1

. We observed that type of shape in

the spectrum of the sample, but it is less conclusive due to its low intensity.


114

Unfortunately, dissolution of this sample for NMR analysis mainly gave

11aga [1662 cm–1

(C=O)].

The amino group can be considered as both a leaving (enamine hydrolysis)

and a nucleophilic group (dienamine), contributing largely to the optical and

structural properties of 11 in solution. It is noteworthy the relatively good

isolated yields recorded for a process which implies the reaction of a

nucleophile and an in-situ generated electrophile, both derived from the same

molecule. On the other hand, this process entails a change in the intrinsic

electronic properties of the indolizine nucleus because the pyridine ring (π-

deficient) acts as a nucleophile and the pyrrol (π-exceeding) ring as an

electrophile.

3.2.4. Optical properties

The heterocyclic chalcone moiety, selectively grafted to the 7-position of

the indolizines 4, notably enlarges the π-conjugation system of the indolizine

nucleus generating a new chromophoric assembly which confers dye attributes

to them. For instance, compound 11aga in the solid state exhibits a nice

reddish orange color that resembles that of Congo Red. In acetonitrile solution

(2 × 10–3

M), however, the pale yellow color of the starting indolizine 4aga

(λmax 340 nm), changes into reddish purple for the corresponding dye 11aga

(λmax 493 nm), a color similar to that of a young red wine (reach in

anthocyanins) (Figure 3.11).

Figure 3.11. The starting indolizine 4aga and the dye 11aga in acetonitrile solution

(2.0 × 10–3

M).


115

Analysis of the color of other dyes could be nicely rationalized as a

function of the substitution pattern. The following remarks could be made

taking dye 11aga as a reference compound with λmax = 493 nm: (a) the

influence of the p-substituent in the 3-aryl-1-dibenzylamino series of dyes is

scanty (Figure 3.12a), with a slight batochromic effect for those with electron-

donating substituents (Table 3.4, compare entries 1, 4 and 5 with 2 and 3); (b)

the contribution to color of the aryl units at the β-position of the carbonyl

group and 3-position of the indolizine seem to be negligible (Table 3.4,

compare entries 6, 7 and 14) (Figure 3.12b); (c) the batochromic shift for dyes

with a 1-alkylamino (non-benzylic) group was noticeable (Table 3.4, entries

8–10) (Figure 3.12c); (d) on the contrary, the 1-arylamino group lead to a

hypsochromic shift with the highest λ (Table 3.4, entries 11 and 12) (Figure

3.12d); (e) the highest λmax was recorded for the N,N-di-(4-

methoxyphenyl)amino derivative 11aha (Table 3.4, entry 13) (Figure 3.12d).

In summary, the chalcone-indolizine framework seems to be the chromophoric

component of the dyes, whereas the amino groups are auxochromic

components that modulate the color according as the electronic character of

their substituents.

Table 3.4. Vis radiation absorption data of dyes 11.

Entry Dye λmax (nm) (M–1

cm–1

)

1 11aga 493 7150

2 11agb 498 11450

3 11agc 504 6000

4 11agd 492 12400

5 11age 493 13850

6 11agi 486 13450

7 11ada 515 7100

8 11aea 522 9700

9 11aaa 521 15600

10 11aca 506 5350

11 11afa 480 26600

12 11cfa 482 23000

13 11aha 532 13400

14 11aia 486 20250


116

Figure 3.12. UV-Vis spectra for the different dyes 11.

A significant singularity of dyes 11 is that their color in the solid state

varies with their particle size. We briefly evaluated the influence of the

particle size on the color of 11aga by spectrophotometry and SEM. A

relatively wide maximum absorbance range of 420–520 nm was recorded for a

sample of crystalline 11aga (Figure 3.13). For a mortar ground sample, a

variation from reddish orange to almost black was observed; this result is

consonant with the decrease in the particle size observed by SEM and the

linear constant absorption in all the visible spectrum (Figure 3.14).

Figure 3.13. Color of dye 11aga in solid state, its TEM image and UV-Vis spectrum.

a) b)

c) d)


117

Figure 3.14. Dye 11aga after being ground in a mortar, its TEM image and UV-Vis

spectrum.

Another remarkable attribute to be highlighted is that the dyes 11 are

solvatochromic, that means that in solution they bring into view a different

color depending on the solvent utilized; different sheds of pink, violet, and

orange have been observed for 11aga (Table 3.5, Figure 3.15). A correlation

between the rotamer population, solvent polarity and visible absorbance can be

established: the proportion of the rotamer A generally increases with the

solvent polarity while the wavelength decreases. This hypsochromic (blue)

shift of λmax while increasing the solvent polarity is a clear case of negative

solvatochromism.

Table 3.5. Solvatochromic behavior of dye 11aga (2.0 × 10–5

M).

Entry Solvent λmax (nm) Abs Color

1 CHCl3 526 0.352 violet

2 hexane 520 0.072 light pinkish

3 EtOH 519 0.288 violet

4 CH2Cl2 511 0.350 purple

5 DMF 505 0.354 red

6 dioxane 504 0.297 pinkish

7 acetone 495 0.393 orange

8 MeCN 493 0.322 orange


118

Figure 3.15. Vis spectra and color of the dye 11aga in different solvents (2.0 × 10

–5

M).

In spite of the fact that the research on functional dyes is a very active

research field, its application as a practical technology is often hampered

because of reasons such as: (a) the expensive materials and catalysts required;

(b) the multi-step sequences that decrease the efficiency of the process

increasing the waste; (c) the non-green conditions and reaction media used; (d)

the experimental procedures are implemented at a laboratory scale but are

troublesome when scaled up. We took advantage of the optical characteristics

of dyes 11 to analyze their colouration power when injected into plastics. The

experiments were carried out at Colortech Química S.L. and IQAP

Masterbatch Group S.L. A preliminary examination revealed that migration of

the dye 11aga occurred in poly(vinyl chloride) (PVC) and polyamides but


119

high compatibility was found with polyolefins [e.g., polypropylene (PP) or

polystyrene (PS)]. Three plates were prepared (Figure 3.16): two with 11aga

and HIPS (high-impact polystyrene SB), with or without TiO2, and a third one

with 11aga and PP. The first conclusion is that the dye 11aga possesses a

strong colouration power at a very low concentration. We were delightfully

astonished to check that the solvatochromic character of the dye was also

demonstrated in plastic materials transparent to the visible radiation, such as

PS and PP. Indeed, three differently coloured plastic plates could be obtained

with a single dye. The effect was particularly dramatic when changing the

polymeric material from HIPS to PP.

Figure 3.16. Plates of 11aga injected into plastics: (a) 0.2 wt% 11aga + 0.5 wt%

TiO2 in HIPS (high-impact polystyrene SB); (b) 0.2 wt% 11aga in HIPS; (c) 0.05

wt% 11aga in PP (polypropylene).

3.2.5. Metal detection

In the lasts years, the photochemical properties of organic π-conjugated

molecules have been widely studied due to their interesting utility as

fluorescent probes or sensors.114

Developing new chemosensors for transition

metal ions or toxic anions has a huge importance for environmental and

biological applications. Recently, some examples of indolizines and chalcones

with some optical properties have been reported to be Cu(II)125

and pH126

sensors.

114

Selected reviews: (a) Zhou, Y.; Yoon, J. Chem. Soc. Rev. 2012, 41, 52. (b) Jung, H. S.; Chen, X.; Kim, J.

S.; Yoon, J. Chem. Soc. Rev. 2013, 42, 6019. (c) Uglov, A. N.; Bessmertnykh-Lemeune, A.; Guillard, R.;

Averin, A. D.; Beletskaya, I. P. Russ. Chem. Rev. 2014, 83, 196. 125

(a) Mashraqui, S. H.; Khan, T.; Sundaram, S.; Ghadigaonkar, S. Tetrahedron Lett. 2008, 49, 3739. (b)

Gaber, M.; El-Daly, S. A.; El-Sayed, Y. S. Y. J. Mol. Struct. 2009, 922, 51. (c) El-Sayed, Y. S.; Gaber, M.

Spectrochim. Acta Part A 2015, 137, 423.


120

In this context, the standard dye 11aga, with a chalcone and indolizine

moiety, was tested as a potential metal sensor with different metals in solution.

The dye was dissolved in a EtOH:H2O (8:2) solvent mixture (λmax 521 nm) at

10–5

M concentration. Then, the metal salt was added at 10–3

M concentration in

the same mixture of solvents and the absorbance was measured with a UV-Vis

spectrophotometer. Apparently, the dye did not form any complex with

alkaline and alkaline-earth metals (Table 3.6, entries 1-5) as no variation in the

absorbance was observed. Regarding transition metal ions, some of them did

not vary the solution color (Table 3.6, entries 6, 9, 13, 17 and 18), but a

significant change in the absorbance of the solution was observed in others

(Table 3.6, entries 7, 8, 10-12, 14-16, 19-20).

Table 3.6. Vis absorbance of a solution of the dye 11aga in the presence of different

metal ions.a

Entry Metal λmax

(nm)

Color

change Entry Metal

λmax

(nm)

Color

change

1 Li+ 521 No 12 Cu

+ 491 Yes

2 Na+ 521 No 13 Zn

2+ 521 No

3 K+ 521 No 14 Rh

2+ –

b Yes

4 Mg2+

521 No 15 Ir4+

–b Yes

5 Ca2+

521 No 16 Pd2+

535 Yes

6 Mn2+

521 No 17 Pt2+

521 No

7 Fe2+

504 Yes 18 Hg2+

521 No

8 Fe3+

–b Yes 19 Ag

+ 431 Yes

9 Co2+

521 No 20 Au3+

430 Yes

10 Ni2+

517 Yes 21 Al3+

430 Yes

11 Cu2+

428 Yes a A 1:1 mixture of dye 11aga (10–5M) and metal ion (10–3M) in EtOH:H2O (8:2). b No max was

observed.

126

(a) Zhang, Y.; Garcia-Amorós, J.; Captain B.; Raymo, F. M. J. Mat. Chem. 2016, 4, 2744. (b) Outlaw, V.

K.; Zhou, J.; Bragg, A. E.; Townsend, C. A. RSC Adv. 2016, 6, 61249.


121

The variation experienced by λmax can be explained in terms of

complexation of the metal ions to the pyridinoyl moiety as shown in Figure

3.17. However, no selectivity towards any particular ion was observed.

Figure 3.17. Proposed complexation model of dye 11aga to metal ions.

Some organic compounds with chromogenic properties have been

reported to be able to complex toxic anions in solution such as CN– 127

or NO2

in air.128

We also tested different anions under the same conditions as in the

case of the cations, but, unfortunately, no interaction anion-dye was observed.

Table 3.7. Vis absorbance of a solution of the dye 11aga in the presence of different

anions.a

Entry Anion λmax

(nm)

Color

change Entry Metal

λmax

(nm)

Color

change

1 Cl– 521 No 5 ClO

– 521 No

2 I– 521 No 6 IO3

– 521 No

3 AcO– 521 No 7 CN

– 521 No

4 SO42–

521 No 8 NO3– 521 No

a A 1:1 mixture of dye 11aga (10–5M) and anion (10–3M) in EtOH:H2O (8:2).

127

Gotor, R.; Costero, A. M.; Gil, S.; Parra, M.; Martínez-Máñez, R.; Sancenón, F.; Gaviña, P. Chem.

Commun. 2013, 49, 5669. 128

Juárez, L. A.; Costero, A. M.; Parra, M.; Gil, S.; Sancenón, F.; Martínez-Máñez, R. Chem. Commun.

2015, 51, 1725.

CHAPTER IV

REACTIVITY OF INDOLIZINES WITH

NITROSOCOMPOUNDS: SYNTHESIS

OF -ENAMINONES AND

PYRROLES.

Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-

enaminones and pyrroles

125

4. REACTIVITY OF INDOLIZINES WITH NITROSOCOMPOUNDS:

SYNTHESIS OF -ENAMINONES AND PYRROLES

4.1. INTRODUCTION

Continuing the study on the reactivity of indolizines, we explored the

reaction versus different electrophiles, focusing our attention on

nitrosocompounds. Interestingly, we found out that the course of the reaction

was driven by the aromatic or aliphatic nature of the substituent at the 3-

position of the indolizine ring.

Scheme 4.1. Synthesis of β-enaminones and pyrroles from indolizines and

nitrosocompounds.

4.1.1. β-Enaminones

Enaminones can be considered as push-pull olefins which merge the

nucleophilic character of the enamines with the electrophilic one of the

enones.129

The enaminone moiety can be found as part of the structure of

different natural products, such as the glucose-lowering (–)-multiflorin (I),130

and also of some synthetic compounds, such as the anticonvulsant II131

(with

129

Reviews: (a) Kuckländer, U. In The Chemistry of Enamines, Part 1; Rappoport, Z., Ed.; Wiley:

Chichester, 1994; Chapter 10. (b) Elassar, A.-Z. A.; El-Kahir, A. A. Tetrahedron 2003, 59, 8463. (c) Negri,

G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl. Chem. 2004, 41, 461. (d) Stanovnik, B.; Svete, J. Chem.

Rev. 2004, 104, 2433. (e) Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015, 51, 16437. (f)

Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015, 51, 16450. 130

Kubo, H.; Kobayashi, J.; Higashiyama, K.; Kamei, J.; Fujii, Y.; Ohmiya, S. Biol. Pharm. Bull. 2000, 23,

1114. 131

Scott, K. R.; Rankin, G. O.; Stables, J. P.; Alexander, M. S.; Edafiogho, I. O.; Farrar, V. A.; Kolen K. R.;

Moore, J. A.; Sims, L. D.; Tonnut, A. D. J. Med. Chem. 1996, 38, 4033.



126

comparable potency to that of diazepam) or the fluorinated quinolone

antibacterials (e.g., ciprofloxacin, III) (Figure 4.1).132

In addition, enaminones

are highly versatile scaffolds in heterocyclic chemistry133,134

and, particularly,

in the total synthesis of alkaloids.

Figure 4.1. Examples of natural and synthetic enaminones.

Different synthetic strategies have been developed to construct

enaminones, the most common ones being condensation reactions, addition

reactions, cleavage of heterocycles and acylation of enamines (Scheme

4.2).135,1a–c

Among them, the condensation of primary or secondary amines

with 1,3-dicarbonyl compounds is the most used methodology. However, the

less nucleophilic aromatic amines are more reluctant to react and azeotropic

removal of water is mandatory in order to shift the equilibrium towards the

enaminone. Some alternative procedures mostly based on transition-metal

catalysis have emerged in the last years,136

with those involving the

transmutation of heterocycles into enaminones being uncommon.136b

132

Kaushik, A.; Ogbaghebriel, A.; Sharma, A. AAA’s Quinolones & Fluoroquinolones: Man-made

Antibiotics; LAP Lambert: Düsseldorf, 2011. 133

Reviews: (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277. (b) Kuckländer, U. In The Chemistry of

Enamines, Part 1; Rappoport, Z. Ed.; Wiley: Chichester, 1994. (c) Kascheres, C. M. J. Braz. Chem. Soc.

2003, 14, 945. 134

Recent examples: (a) Zhang, Q.; Liu, X.; Xin, X.; Zhang, R.; Liang, Y.; Dong, D. Chem. Commun. 2014,

50, 15378. (b) Yan, R.; Li, X.; Yang, X.; Kang, X.; Xiang, L.; Huang, G. Chem. Commun. 2015, 51, 2573. (c)

Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034. (d) Wang, F.; Jin, L.; Kong, L.; Li, X. Org. Lett. 2017,

19, 1812. 135

Review: Ferraz, H. M. C.; Pereira, F. L. C. Quim. Nova 2004, 27, 89. 136

(a) Bhatte, K. D.; Tambade, P. J.; Dhake, K. P.; Bhanage, B. M. Catal. Commun. 2010, 11, 1233. (b)

Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512. (c) Miura, T.; Funakoshi, Y.; Morimoto, M.;



127

Scheme 4.2. Typical procedures for the synthesis of β-enaminones.

4.1.2. Pyrroles

The pyrrole ring can be found in numerous natural products (e.g.,

lamellarin O, IV)137

as well as in the small-molecule drug list of the FDA

Orange Book,138

albeit it is relatively less frequent in drugs. Nevertheless, the

Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17440. (d) Shi, L.; Xue, L.; Lang, R.; Xia, C.; Li, F.

ChemCatChem 2014, 6, 2560. (e) Xu, K.; Zhang, Z.; Qian, P.; Zha, Z.; Wang, Z. Chem. Commun. 2015, 51,

11108. 137

Huang, X.-C.; Xiao, X.; Zhang, Y.-K.; Talele, T. T.; Salim, A. A.; Chen, Z.-S.; Capon, R. J. Mar. Drugs

2014, 12, 3818. 138

Miniperspective: Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.



128

best-selling pharmaceutical within the recent past, atorvastatin (V, a

cholesterol-lowering agent), consists of a polysubstituted pyrrole ring. The

latter ring is represented in other best-selling drugs, such as sunitib (anticancer

agent),139

or in agrochemicals, such as the fungicides fenpiclonil (VI, Beret®)

and fludioxonil (Celest®).140

The N-arylated pyrroles VII141

and TDR37250

(VIII)142

have been identified as powerful substances for the treatment of

leishmaniasis and malaria, respectively (Figure 4.2).

Figure 4.2. Examples of biologically active pyrroles.

139

Review: Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442. 140

Lamberth, C. In Bioactive Heterocyclic Compound Classes: Agrochemicals; Lamberth, C., Dinges, J.,

Eds.; Wiley-VCH: Weinheim, 2012; Chapter 13. 141

Baiocco, P.; Poce, G.; Alfonso, S.; Cocozza, M.; Porretta, G. C.; Colotti, G.; Biava, M.; Moraca, F.;

Botta, M.; Yardley, V.; Fiorillo, A.; Lantella, A.; Malatesta, F.; Ilari, A. ChemMedChem 2013, 8, 1175. 142

Murugesan, D.; Mital, A.; Kaiser, M.; Shackleford, D. M.; Morizzi, J.; Katneni, K.; Campbell, M.;

Hudson, A.; Charman, S. A.; Yeates, C.; Gilbert, I. H. J. Med. Chem. 2013, 56, 2975.



129

Pyrroles are usually synthesized using the Hantzsch procedure,143

the

Knorr synthesis,144

and the Paal-Knorr synthesis (Scheme 4.3).

Scheme 4.3. Classical methods for the synthesis of pyrroles.

Multitude of efficient approaches to the synthesis of pyrroles have been

devised,145

mostly relying on transition-metal catalysis and multicomponent

reactions. Palladium,146

rhodium, gold and copper147

catalysts have been the

143

Wang, Y.; Jiang, C.-M.; Li, H.-L.; He, F.-S.; Luo, X.; Deng, W.-P.; J.Org. Chem. 2016, 81, 8653. 144

Li, T.; Yan, H.; Li, X.; Wang, C.; Wan, B. J.Org. Chem. 2016, 81, 12031. 145

Reviews: (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084.

(b) Yoshikai, N.; Wei, Y. Asian J. Org. Chem. 2013, 2, 466. (c) Estévez, V.; Villacampa, M.; Menéndez, J. C.

Chem. Soc. Rev. 2014, 43, 4633. (d) Vessally, S. RSC Adv. 2016, 6, 18619. (e) Anuradha, S.; Piplani, P. J.

Heterocycl. Chem. 2017, 54, 27. (f) Fujita, T.; Ichikawa, J. Heterocycles 2017, 95, 694. 146

Senadi, G. C.; Hu, W.-P.; Garkhedkar, A. M.; Boominathan, S. S. K.; Wang, J.-J. Chem. Commun. 2015,

51, 13795.



130

most applied transition metals for this purpose, not only in MCRs but in

intramolecular cyclizations148

or intermolecular annulations involving

alkynes149

or other substrates;150

organocatalyzed procedures are also

known.151

As occurred in the case of the enaminones, the transformation of

other heterocycles into pyrroles is barely documented.152

Due to the type of

starting materials normally deployed for pyrrole synthesis (such as enamino

amides,153

enamino esters or ketones154

), the majority of the products end with

a carboxylate/carbonyl moiety attached to the pyrrole ring.

147

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131

4.2 RESULTS AND DISCUSSION

4.2.1 Synthesis of β-enaminones

We first assessed the effect of the amino substituent at the 1-position of

the indolizine. For this purpose, indolizine 4 (derived from pyridine-2-

carbaldehyde, a secondary amine and phenylacetylene) and nitrosobenzene

(15a) were deployed as the model substrates and allowed to react at room

temperature in ethanol (Table 4.1, entries 1–5). The dibenzylamino substituted

indolizine 4aga gave the highest conversion (Table 4.1, entry 3). A range of

solvents was tested for this indolizine derivative, concluding that acetonitrile

was the best choice (Table 4.1, entry 7). The absence of solvent or presence of

CuNPs/C (utilized for the synthesis of the indolizines) were detrimental to the

conversion (Table 4.1, entries 6 and 13, respectively).

With the optimized conditions in hand (Table 4.1, entry 7), we tried and

expand the procedure to other substrates (Table 4.2). Nitrosobenzene (15a)

was combined with indolizines bearing all sort of substituents on the aryl ring

at the 3-position (R1), i.e., electron-neutral, electron-donating and electron-

withdrawing ones; the corresponding β-enaminones 16agaa–16agea were

formed in good isolated yields. The outcome for indolizines with additional

substitution was uneven. For instance, the 5-methyl-substituted indolizine

4cga performed much better that the (methylsulfonyl)phenyl counterpart

(4dga), which was more reluctant to react and required warming at 50 ºC for

improving the yield. The product for that indolizine brought into view two sets

of signals by NMR in the crude, what was attributed to the obtention of the

two possible β-enaminones in a ratio 1.5/1, being the major one the product

16dgaa. The procedure was also successfully applied to the more complex dye

of indolizine 11aga, furnishing the expected product 16agaa’ with a double

pyridinyl chalcone motif. Nitrosoarenes other than nitrosobenzene were also

tested (15b–15h); para-substituted representative examples with electron-

donating, electron-withdrawing and halogen groups gave rise the enaminones

16agab–16agae in moderate yields. Ortho-substituted nitrosobenzenes

behaved similarly (16agaf–16agah), though some by-product formation was



132

observed in the case of the cyano derivative 16agag. As an exception, a β-

alkyl-β-enaminone could be also synthesized (16agid), albeit only with the

presence of the strong electron-releasing dimethylaminophenyl group.

Table 4.1. Optimization of the enaminone synthesis.a

Entry R1 R

2 Solvent Conv. (%)

b

1 (CH2)5 EtOH 71

2 Bu

Bu EtOH 32

3 Bn Bn EtOH 80

4 Bn Me EtOH 76

5 Ph Me EtOH 49

6 Bn Bn -

25c

7 Bn Bn MeCN 90

8 Bn Bn THF 36

9 Bn Bn PhMe 49

10 Bn Bn CH2Cl2 42

11 Bn Bn H2O 15

12 Bn Bn CH3COCH3 24

13 Bn Bn MeCNd 45

a Reaction conditions: 4 (0.1 mmol), 15a (0.1 mmol), solvent (1 mL), rt,

overnight. b Conversion into 16agaa determined by GC. c Reaction at 50

ºC.d In the presence of CuNPs/C (5 mol%).



133

Table 4.2. Synthesis of the enaminones 16.a

a Reaction conditions: 4 (0.3 mmol), 15 (0.3 mmol), MeCN (1 mL), rt, overnight; isolated yield in

parentheses. b Reaction at 50 ºC.



134

The kinetic profile corresponding to the reaction of the indolizine 4aga

with nitrosobenzene (15a) displays the highest conversion variation in the

interval 4–8 h (Figure 4.3); the progress of the reaction is much slower at the

outset of the reaction and after 8 h.

Figure 4.3. Plot displaying the evolution of the synthesis of the enaminone 16agaa

from the indolizine 4aga and nitrosobenzene 15a.

We also attempted to reach the enaminone in one pot from the

commercial starting materials, pyridine-2-carbaldehyde (1a), dibenzylamine

(2g) and phenylacetylene (3a), without the need to isolate the intermediate

indolizine (Scheme 4.4); the moderate success of this approach could be due to

the interference of CuNPs/C in the second step of the sequence (see, Table 4.1,

entry 13). It was, however, gratifying to demonstrate that the enaminone

16agaa could be synthesized with equal efficiency at a gram scale (Scheme

4.5).



135

Scheme 4.4. One-pot synthesis of the enaminone 16agaa.

Scheme 4.5. Gram-scale synthesis of the enaminone 16agaa.

It is noteworthy that all the β-enaminones were obtained as single

stereoisomers. The Z stereochemistry was unequivocally assigned by X-ray

crystallographic analysis of enaminone 16agaa (Figure 4.4). The formation of

an intramolecular hydrogen bond with the participation of the oxygen carbonyl

group and the N–H of the arylamino moiety is a common feature to all the

enaminones, also observable by 1H NMR.



136

Figure 4.4. X-ray structure of the enaminone 16agaa.

Regarding the atom economy of this reaction, after completing the

reaction, we treated the crude with HClaq. in order to protonate the

dibenzylamine formed during the reaction; in this way, it could be extracted

from the organic phase into the aqueous phase. After the separation of the two

phases, the aqueous phase was treated with NaHCO3 until neutral pH, what

allowed to recover dibenzylamine in the organic phase.

The usefulness of the obtained enaminones as building blocks for

heterocyclic synthesis was exemplified by transforming 16agaa into the

pyridinyl-containing oxazole155

18, pyrazoles156

19 and 20, and indole157

21

(Scheme 4.6).

155

Domínguez, E.; Ibeas, E.; Martínez de Marigorta, E.; Palacios, J. K.; San Martín, R. J. Org. Chem. 1996,

61, 5435. 156

Kovács, S.; Novák, Z. Tetrahedron 2013, 69, 8987. 157

He, Z.; Liu, W.; Li, Z. Chem. Asian J. 2011, 6, 1340.



137

Scheme 4.6. Transformation of the enaminone 16agaa into different

heterocyclic compounds.

4.2.2. Selectivity in the synthesis of β-enaminones

As said in the introduction, -enaminones are readily accesible by the

condensation of primary or secondary amines with 1,3-dicarbonyl compounds;

this path is particularly effective for symmetrically substituted diketones.

However, for unsymmetrical substrates and when coordinating fragments are

present, other factors go into play which might condition both the conversion

and regioselectivity of the reaction. In this context and, in order to validate our

procedure, the unsymmetrical 1,3-dione 22 was synthesized and subjected to

some of the available literature methods for enaminone synthesis (Table 4.3).

For instance, Cu(OTf)2, which proved to be a good catalyst for the

condensation of acetylacetone with aniline (78% yield), completely failed in



138

the test reaction (Table 4.3, entry 1); this behavior could be explained in terms

of copper complexation with the pyridinylcarbonyl unit of 22.19

In contrast,

good conversion was attained with Yb(OTf)2 albeit towards the opposite

regioisomer 23 (Table 4.3, entry 2). The reaction was unproductive in the

absence of catalyst (Table 4.3, entries 3 and 4), whereas montmorillonite K-10

under ultrasounds18c

also formed the product 23 in moderate conversion (Table

4.3, entry 5). It is clear that the condensation route is not valid for the target

enaminone 16agaa because of the larger electrophilicity of the carbonyl

bonded to the pyridine ring and, therefore, this fact reinforces the utility of our

strategy.

Table 4.3. Reaction of the 1,3-dione 22 with aniline under different conditions.a

Entry Catalyst Conditions 16agaa, 23 (%)b

Ref.

1 Cu(OTf)2 (5 mol%) neat, rt, 16 h - 158

2 Yb(OTf)2 (5 mol%) neat, rt, 60 min 0, 85 158

3 - neat, 70 ºC, 16 h - 158

4 - H2O, rt, 16 h - 159

5 MK-10c

ultrasounds, 16 h 0, 65 160

a

1,3-Dione 22 (0.2 mmol), aniline (0.4 mmol). b

Conversion into 16agaa or 23

determined by GC. c Montmorillonite K-10 (60 mg).

158

Chen, J.; Yang, X.; Liu, M.; Wu, H.; Ding, J.; Su, W. Synth. Commun. 2009, 39, 4180. 159

Stefani, H. A.; Costa, I. M.; Silva, D. de O. Synthesis 2000, 1526. 160

Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante, M. E. F. Synthesis 1998, 1019.



139

4.2.3 Synthesis of pyrroles

Indolizine 4agi and nitrosobenzene (15a) were used as the model

substrates to optimize the reaction conditions (Table 4.4). Practically, every

organic solvent tested was adequate to accomplish this transformation,

providing conversions above 85% for 17agia (Table 4.4, entries 2–7). On the

contrary, the absence of solvent or presence of water had an adverse effect,

decreasing the conversion or impeding the reaction, respectively (Table 4.4,

entries 1 and 8). Ethanol was considered the solvent of choice because of

being a recommended solvent161

and achieving the highest conversion (Table

4.4, entry 2). To our delight, the reaction proceeded under ambient conditions

and, as occurred in the case of the β-enaminones, the presence of CuNPs/C

exerted a negative effect on the conversion (Table 4.4, entry 9).

These mild and green conditions were extended to an array of

indolizines and nitrosocompounds (Table 4.5). First, the amino group at the 1-

position of the indolizine was varied: the expected pyrroles were produced in

good-to-excellent isolated yields for dibenzyl, dialkyl, cyclic, alkylaryl and

alkylbenzyl amino groups (17agia–17adia). Pyrroles with a substituted

pyridine, different alkyl chain length or functionalized alkyl chain were also

accessible by this way but with relatively lower yields (17cgia–17agma), in

the latter case because of some by-product formation. Finally, the N-aryl

substituent could be modified by the choice of the nitrosoarene, recording

moderate-to-good yields for the N-arylated pyrroles. It is worthwhile

mentioning that product 17agif was an atropoisomeric chiral pyrrole, with the

free rotation through the C–N bond at room temperature being suppressed by

the ortho-tolyl substituent.

The reaction profile for the pyrrole synthesis notably differed from that

of the enaminone synthesis: a high conversion (80%) was reached after only 1

h at room temperature, continuing to completeness after 6 h (Figure 4.5).

161

Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, R.; Abou-Shehadad, S.; Dunne, P. J. Green Chem.

2016, 18, 288.



140

Table 4.4. Optimization of the pyrrole synthesis.a

Entry Solvent Conversion (%)b

1 neatc

57

2 EtOH

96

3 MeCN 93

4 THF 90

5 PhMe 95

6 CH2Cl2 91

7 CH3COCH3 85

8 H2Oc 0

9 EtOHd 59

a Reaction conditions: 4agi (0.1 mmol), 15a PhNO (0.1 mmol),

solvent (1.0 mL) at rt. b Conversion determined by GC. c Reaction

at 50°C. d CuNPs/C

Figure 4.5. Plot displaying the evolution of the synthesis of the pyrrole

17agia from the indolizine 4agi and nitrosobenzene 15a.



141

Table 4.5. Synthesis of the pyrroles 17.a

a Reaction conditions: 1 (0.3 mmol), ArNO (0.3 mmol), EtOH (1.0 mL), rt, overnight; isolated yield in

parentheses.



142

An effective one-pot synthesis of pyrrole 17agia was shown to be

plausible following a multicomponent synthesis of the indolizine and

nitrosocompound addition sequence (Scheme 4.7). CuI is recommended as

catalyst instead of CuNPs/C in order to improve the yield of the intermediate

3-alkylindolizine. Furthermore, the simplicity of the experimental operation

and satisfactory reproducibility allowed the gram scale synthesis of the pyrrol

17agia obtained by cristalization (Scheme 4.8).

Scheme 4.7. One-pot synthesis of the pyrrole 17agia.

Scheme 4.8. Gram-scale synthesis of the pyrrole 17agia.

The structure of the pyrroles 17 was confirmed by X-ray

crystallographic examination of the derivative 17agia (Figure 4.6). The

perpendicular arrangement of the N-phenyl group with respect to the pyrrole

ring accounts for the symmetry break when introducing an ortho-methyl group

and the consequent manifestation of atropoisomerism.



143

Figure 4.6. X-ray structure for the pyrrole 17agia.

4.2.4 Reaction mechanism

Different studies were carried out in order to know the reaction

mechanism for the formation of the two products, the β-enaminones and the

pyrroles.

First, a series of labelling experiments was carried out. The starting

indolizines were synthesized from pyridine-2-carbaldehyde, deuterated

dibenzylamine and deuterated terminal alkyne. Then, they were subjected to

the standard conditions showing a total loss of D in the β-enaminone 16agaa.

In contrast, most of the original D was maintained in the case of the pyrrole

17agia (Scheme 4.9).



144

Scheme 4.9. Deuterium-labelling experiments in the synthesis of the β-enaminone

16agaa and pyrrole 17agia.

Another experiment consisted in the synthesis of 16agaa in a mixture of

deuterated solvents, CD3CN:D2O (1:0.4), observing the incorporation of D

into the final product (by 1H NMR of the reaction crude) but mainly at the

nitrogen atom of the amine with an incorporation of 83%.

Scheme 4.10. Incorporation of deuterium into the β-enaminone 16agaa.

In order to prove any participation of radicals in the reaction mechanism,

radical traps were added under the standard reactions (Scheme 4.11), but they

did not alter the outcome of the processes as the final compounds were

obtained in good conversions and the radical traps were recovered unchanged.

Those results are in concordance with an ionic reaction pathway.



145

Scheme 4.11. Standard reactions carried out in the presence of radical traps.

In the case of β-enaminones, the reaction was performed under different

atmospheres. As it can be seen in Figure 4.7, neither the use molecular oxygen

nor an inert atmosphere (using dry MeCN) were beneficial for the reaction. In

contrast, the reaction was accelerated by under air or in the presence of water,

being almost complete after 2 h in the latter case.

Figure 4.7. Reaction profile for the synthesis of 16agaa under different atmospheres.



146

With those results in hand, the following reaction mechanism

(exemplified for indolizine 4aga) was proposed for the formation of the β-

enaminones 16 from indolizines 4 (Scheme 4.12). As mentioned in the general

introduction, the position 3 of the indolizine nucleus is activated toward

electrophiles; therefore, first, nitrosobenzene could act as an electrophile to

form a C-N bond at the 3 position. Ring opening involving the resonance of

the dibenzylamino group followed by intramolecular 5-exo-dig cyclization

would furnish a dihydroisoxazole intermediate. Alternatively, the

intramolecular cyclization might occur prior to the ring opening, but involving

in this case a less favorable 5-endo-dig process. Dibenzylamine elimination

followed by isoxazole ring opening would provide the corresponding β-

enaminone. The fact that water accelerates the reaction could be related to

water acting as a proton source, as two new N-H bonds are formed.

Scheme 4.12. Proposed mechanism for the formation of β-enaminones.



147

Comparing the structure of the starting indolizine with that of the final

pyrrole, it seems clear that the dibenzylamino substituent has migrated to the

vicinal carbon atom. Apparently, this substituent is lost during the reaction and

reincorporated again into the final structure. Indeed, when the reaction was

carried out in the presence of 3 eq. of an external secondary amine, such as N-

methylaniline, the corresponding amino substituent was integrated into the

pyrrole as also occurred with the dibenzylamino group, thus demonstrating

what postulated above (Scheme 4.13).

Scheme 4.13. Effect of the addition of an external amine in the synthesis of pyrroles.

Several reactions were also performed to explore the possibility of the

β-enaminone being the intermediate in the formation of the indolizines.

However, the reaction of the unique aliphatic β-enaminone we could obtain

(17agid) with dibenzylamine did not produce the expected pyrrole, either

under the standard conditions or higher reaction temperature (Scheme 4.14).

This behavior was somewhat expected as the precursor indolizine of 16agid

did not furnish the corresponding pyrrole at all.

Scheme 4.14. Reaction of the β-enaminone 16agid with dibenzylamine



148

Compound 25 was synthesized as a potential intermediate in the

formation of the pyrrole XXX by the addition of aniline to the ketoalkyne 24

in MeOH, followed by reaction with dibenzylamine. However, the reaction of

25 with nitrosobenzene did not provide the corresponding pyrrole (Scheme

4.15).

Scheme 4.15. Synthesis of 25 and its reaction with PhNO.

A retrosynthetic analysis of pyrrole 17agaa gave us two potential

precursors with their tautomeric forms (Scheme 4.16).

Scheme 4.16. Retrosynthetic analysis of pyrrole 17agaa.



149

In-situ NMR analysis of the reaction of indolizine 4agi with

nitrosobenzene (15a) at room temperature in CD3CN for 1 h revealed the

presence of significant signal at 188.8 ppm in the 13

C NMR spectrum (Figure

4.8). This signal could be attributed to a doubly conjugated carbonyl group,

which might be bonded to a pyridinyl unit at to a carbon-carbon double bond.

Figure 4.8.

13C NMR for the synthesis of 17agia at 10 min.

The reaction between 4agi and 15a was also analyzed by GC-MS and

HRMS/Q-TOF after 10 min. In both cases, the presence of a peak of m/z 278

was confirmed; this peak dimished in intensity with the reaction course and

disappeared after completion of the reaction, thus evidencing its role as a

reaction intermediate (Figure 4.9).



150

Figure 4.9. HRMS/Q-TOF and low resolution MS spectra of the intermediate in the

synthesis of the pyrrole 17agia.



151

Several structures match the m/z 278 and some of the fragmentations

observed (Figure 4.10). However, taking into account the disconnection in

Scheme 4.16, the structure C can be practically ruled out as the intermediate.

This is a very important finding as demonstrates that the nitrosocompound

fragment is incorporated first and the dibenzylamine second, prior to the ring

closure. A wide peak at longer reaction time (27.5 min) was observed by GC-

MS. Although the molecular ion could not be detected, the average

fragmentation points to structures which are the immediate precursors of the

pyrroles (Figure 4.11).

Figure 4.10. Structures and MS fragmentation proposed for the pyrrole synthesis

intermediates.

Figure 4.11. Structures and MS fragmentation proposed for the pyrrole precursors.

On the basis of the above results, a tentative reaction mechanism has

been proposed including two variants (Figure 4.12). We have considered in

both variants that the source of oxygen in the nitrosocompound, given that the

reaction takes place nicely in solvents of different nature except in water. In

variant (a), two equivalents of nitrosobenzene are involved, one providing the

carbonyl oxygen and the other one providing the PhN moiety. Although it is

true that the reaction is faster with two equivalents of PhNO, this route entails

the sacrifice of one equivalent of PhNO that is transformed into



152

phenylhydroxylamine or O-ethyl-N-phenylhydroxylamine, depending on

whether water of ethanol are involved in the process. In this way, the pyrrole

precursor does not coincide with any of the structures proposed in Figure 4.11.

Scheme 4.16. Reaction mechanism proposed for the synthesis of pyrrole 17agia from

compound 4agg and nitrosobenzene (15a).



153

In the variant (b) one equivalent of PhNO participates but requires intra-

or intermolecular delivery of the anilino moiety (PhN) to provide one of the

pyrrole precursors in Figure 4.11, which could undergo intramolecular

condensation to give the pyrrole.

We believe that more experimentation is needed in order to propose a

more accurate reaction mechanism for the synthesis of pyrroles. We can,

however, establish the sequence of the process in which similar intermediates

to those shown might be involved (Scheme 4.17).

Scheme 4.17. Proposed reaction sequence in the synthesis of pyrroles from

indolizines and nitrosocompounds.

CONCLUSIONS

Conclusions

157

CONCLUSIONS

The multicomponent synthesis of a series of new 1-aminoindolizines and

pyrrolo[1,2-a]quinolines has been effectively accomplished using CuNPs/C as

catalyst in dichloromethane at 70 ºC. The methodology has been applicable to

a variety of amines and alkynes, with the latter including aryl alkynes (bearing

electron-neutral, -releasing, and -withdrawing groups) as well as aliphatic

alkynes with moderate-to-high isolated yields. Our catalyst has been shown to

be superior to some commercially available copper catalysts. A reaction

mechanism has been proposed based on the evidence of the participation of

propargylamines.

The synthesis of indolizidines through the heterogeneous catalytic

hydrogenation of indolizines has been accomplished using PtO2 as catalyst in

acetic acid as solvent and a pressure of 3.7 atm. The indolizidines have been

obtained with high diastereoselectivity, also in the case of forming four

stereocenters. Experimental evidence supports the indolizine hydrogenation

occurring through the pyrrolic intermediate 5,6,7,8-tetrahydroindolizine.

Furthermore, this indolizidines have been mono or didebenzylated by the

choice of the catalyst.

A number of new organic compounds have been synthesized by treating

the indolizines in acidic medium. These products are well-defined D-A-π-A

reddish-to-deep violet dyes derived from the condensation of two molecules of

indolizine. The structure of the indolizine dyes has been established by X-ray

analysis in the solid state, but it splits into two rotamers in solution. A reaction

mechanism has been proposed in which the same indolizine acts as both a

nucleophile and an electrophile. A preliminary study on the optical features of

these dyes has revealed a particle-size dependent color, high coloration power

and solvatochromic character, also in plastic materials.

The reactivity of the indolizines with nitrosocompounds has been also

studied, giving two different products depending on the substituent at the three

position of the indolizine. β-Enaminones have been formed for aromatic

substituents in good-to-high isolated yields, with this method providing

opposite regiochemistry to that of the reported procedures. For aliphatic

Conclusions

158

substituents, tetrasubstituted pyrroles have been obtained in moderate-to-good

yields. Many different experiments have been carried out in order to

understand the pathways for the formation of β-enaminones and pyrroles.

RESUMEN

Resumen

161

RESUMEN

En la presente memoria se ha estudiado la síntesis multicomponente de

1-aminoindolizidinas y su reactividad.

En la introducción general se describe qué se considera una

nanopartícula y los diferentes medios que hay para sintetizarlas, además de los

métodos que se conocen para estabilizarlas. Se ha resaltado la importancia del

uso de nanopartículas metálicas en síntesis orgánica, destacando la

importancia de usar metales como el cobre, debido a su bajo coste y su baja

toxicidad frente a otros metales de transición como puede ser el caso del

platino, paladio, rutenio, rodio o iridio.

Nuestro grupo de investigación ha generado nanopartículas de cobre

mediante la reducción de cloruro de cobre (II) con litio metálico y DTBB, el

cual actúa como transportador de electrones. En el proceso tiene lugar una

transferencia electrónica del litio al areno, provocando la formación de un

anión radical y/o del dianión correspondiente, generando una suspensión verde

oscura. A continuación, se produce una transferencia electrónica por parte de

estas especies hacia la sal metálica. Esta transferencia, la cual es muy rápida,

provoca la reducción de la sal, y como consecuencia, la formación de

nanopartículas de cobre. La presencia de las nanopartículas hace que la

suspensión adquiera una coloración negra. Es en este momento en el que se

adiciona el soporte inorgánico a la mezcla, seguido de filtrado, lavado y

secado al aire para obtener el catalizador deseado, el cual, se usa en la síntesis

de derivados indolizidínicos.

También se introduce la estructura de indolizina, la cual se trata de un

biciclo de cinco y seis miembros, con un átomo de nitrógeno en el puente entre

ambos. Este tipo de estructuras han sido muy estudiadas debido a la

importancia de su actividad biológica. Se ha demostrado que las indolizinas

tienen diversas aplicaciones debido a su actividad anticancerígena,

antiinflamatoria, antioxidante, antibacteriana y antifúngica, entre otras. Cabe

destacar que en los últimos años se han desarrollado nuevas metodologías de

síntesis de indolizinas no solo por su importancia biológica, sino por sus

propiedades fotofísicas.

Resumen

162

Se ha incluido una revisión bibliográfica de las diferentes metodologías

clásicas que se usan para la síntesis de indolizinas como, por ejemplo, la

reacción de Tschitschibabin o la reacción de Scholtz. También se han descrito

otras síntesis de indolizinas a través de reacciones 1,3-dipolar o de

cicloisomerización de alquinos.

Las indolizinas pueden actuar como nucleófilos debido a la estabilidad

resonante que poseen dentro del anillo. Debido a la deslocalización electrónica

que poseen estas estructuras, las posiciones más reactivas son los carbonos

uno y tres. Sin embargo, a pesar de los numerosos estudios relacionados con la

síntesis de indolizinas, la reactividad de estos compuestos no se ha investigado

en profundidad, aunque hay descritos ejemplos de reacciones típicas como

nitración, acilación, etc.

Como se ha mencionado anteriormente, en nuestro grupo de

investigación se ha llevado a cabo la síntesis de indolizinas a través de una

reacción multicomponente. En el primer capítulo se describe en qué consiste

este tipo de reacciones y su uso para el desarrollo de nuevas metodologías para

la obtención de heterociclos; se comentan diversas síntesis multicomponentes

de indolizinas desarrolladas más recientemente. Considerando que la

introducción de un grupo amino en las estructuras de compuestos abre nuevas

funcionalizaciones dando lugar a una variedad más amplia de compuestos, se

presenta la síntesis multicomponente de 1-aminoindolizinas catalizada por

sales metálicas de oro, plata o hierro. En nuestro grupo de investigación se ha

logrado de manera efectiva la síntesis multicomponente de una serie de

indolizinas y pirrolo[1,2-a]quinolinas a partir de derivados de piridin-2-

carbaldehído, aminas secundarias y alquinos terminales usando NPsCu/C

como catalizador en diclorometano. Curiosamente, el mismo procedimiento,

cuando se aplica en ausencia de disolvente usando piperidina como amina

secundaria, ha conducido a chalconas heterocíclicas como productos

principales con rendimientos de moderados a buenos y estereoquímica E

exclusivamente (esta parte ha sido estudiada en detalle en una tesis anterior).

El catalizador ha sido caracterizado con anterioridad usando distintas técnicas

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para saber el contenido de Cu y el estado de oxidación de éste en el catalizador

de NPsCu/C.

La síntesis multicomponente de 1-aminoindolizinas se ha aplicado a una

gran variedad de aminas tanto alifáticas como bencílicas y aromáticas con

altos rendimientos (55-93%). También se han empleado alquinos de diferente

naturaleza electrónica, incluyendo alquinos aromáticos (con sustituyentes

electrónicamente neutros, electrón-atrayentes y electrón-donadores) y alquinos

alifáticos, aunque las indolizinas se obtienen con menores rendimientos (42-

77%). Además, se han probado piridin-2-carbaldehídos sustituidos en la

posición 6; cabe destacar el bajo rendimiento obtenido con el sustituyente de

bromo (20%), lo cual puede deberse a un mayor impedimento estérico. La

metodología ha aplicado a quinolin-2-carbaldehído obteniendo las pirrolo[1,2-

a]quinolinas con rendimientos de buenos a altos (66-92%). En los casos en los

que nuestro procedimiento no ha sido efectivo para la síntesis de indolizinas,

se ha probado un método alternativo, que consiste en el uso de CuI, en lugar

de nuestro catalizador, pero en este caso, en ausencia de disolvente. Se han

sintetizado varios ejemplos variando la amina de partida, la cadena alifática e

incluso con un metilo en la posición 6 del aldehído. Comparado con nuestro

método, se han obtenido las indolizinas con mayor conversión, aunque sigue

siendo baja y el rendimiento aislado, por consiguiente, también es bajo. Para la

obtención de indolizinas y chalconas se ha demostrado que el catalizador de

NPsCu/C es superior a un amplio número de catalizadores de cobre

comerciales, presentando la ventaja de poder reutilizarse en la síntesis de

chalconas durante cuatro ciclos con una leve disminución de la actividad

catalítica (conversión del 85-64%). En base a la pruebas mecanísticas

realizadas previamente en el grupo de investigación, se ha propuesto un

mecanismo de reacción para la formación de indolizinas, basado en la

concluyente evidencia experimental de la participación de aminas

propargílicas como intermedios: en primer lugar, la amina reacciona con el

aldehído formando la correspondiente sal de iminio, por otro lado, el

catalizador incrementa la acidez del protón del triple enlace del alquino,

formando un acetiluro de cobre. Ambos reaccionan formando la

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correspondiente amina propargílica; en este punto, se produce una ciclación y

posterior aromatización, obteniendo así la indolizina.

Finalmente, se expone la bioactividad que presentan estas estructuras,

comentando las líneas celulares en las cuales, algunas de ellas, han dado

actividad in-silico e in-vitro. Estas pruebas se llevaron a cabo a través del

programa Lilly Open Innovation Drug Discovery (OIDD).

En el segundo capítulo se ha desarrollado una nueva metodología para la

obtención de indolizidinas a partir de indolizinas. Existe un creciente interés

general en el desarrollo de nuevas estrategias para obtener de forma efectiva

N-heterociclos saturados a partir de materiales de partida fácilmente

accesibles. Esta demanda está respaldada por el desarrollo potencial de nuevos

productos farmacéuticos relacionados con este tipo de heterociclos y su

abundancia en compuestos naturales. Entre ellos, los alcaloides de indolizidina

han atraído una gran atención debido a su diversidad estructural y su variada

actividad biológica.

Los alcaloides indolizidínicos son compuestos bicíclicos que tienen un

nitrógeno básico en su estructura. Muchos de ellos presentan actividad

biológica del tipo fitotóxica, antibacteriana, antifúngica o neurológica, y se

pueden extraer de diversas fuentes de la naturaleza: hormigas, ranas

venenosas, hongos, plantas, etc. Se han desarrollado diferentes estrategias

sintéticas para construir el esqueleto de indolizidina según el patrón de

sustitución perseguido, pero sólo hay un estudio sistemático sobre la síntesis

de indolizidinas por hidrogenación completa de indolizinas, ya que la

reducción parcial es un problema común encontrado, que junto con una

diastereoselectividad deseable más alta, hacen que la hidrogenación selectiva

de indolizinas sea un objetivo desafiante.

Para conseguir la hidrogenación de indolizinas se ha hecho una

optimización exhaustiva, probando diferentes metales (aunque el más

estudiado ha sido el platino) y soportes, diferentes disolventes y distintas

presiones. Este estudio ha llevado a la conclusión de que el mejor catalizador

es el óxido de platino (IV), en ácido acético como disolvente y a una presión

de 3.7 atm (55 psi). Los catalizadores con mayor conversión (PtO2 y Pt/C) se

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han intentado reutilizar pero, desgraciadamente, tras el primer ciclo disminuyó

la conversión del producto deseado.

Estas condiciones óptimas de reacción se han aplicado a algunas

indolizinas ya descritas en el primer capítulo, obteniendo las correspondientes

indolizidinas con rendimientos de moderados a buenos. Se ha visto que el

rendimiento y la diastereoselectividad dependen de los sustituyentes en las

posiciones 1 y 3 de la indolizina, siendo el grupo amino en la posición 1 el

que, aparentemente, ejerce un efecto más fuerte. Las indolizinas derivadas de

piperidina y arilacetilenos se han aislado con rendimientos más bajos,

registrándose la diastereoselectividad más baja también en el crudo (92:8),

aunque tras la purificación aumentó esa diastereoselectividad (>99:1). Se ha

observado un mejor rendimiento y una excelente diastereoselectividad al

cambiar el 1-piperidinilo por un grupo 1-morfolino (68%, >99:1). La

diastereoselectividad ha aumentado al aumentar el impedimento estérico de la

amina secundaria. Las indolizidinas derivadas de dibencilamina se han

obtenido en tiempos de reacción de hidrogenación relativamente cortos y

como únicos diastereoisómeros. Este comportamiento se ha mostrado

independientemente del sustituyente que tuviera en la posición 3 la indolizina

de partida, incluidos los sustituyentes arilo con grupos electrónicamente

neutros, electrón-dadores y electrón-aceptores, y los sustituyentes alifáticos.

Las estructuras de este tipo de compuestos han sido comprobadas mediante

espectros 2D de RMN y por espectroscopía de rayos X, confirmando que

todos los sustituyentes se encuentran en la misma cara de la molécula. Se ha

podido aislar el intermedio, comprobando la secuencia de hidrogenación, la

cual comienza en el anillo de seis miembros y continúa con el de cinco.

El uso de dos catalizadores distintos para conseguir distintos compuestos

a partir del mismo producto de partida es muy interesante. En este sentido, se

ha estudiado la mono y doble desbencilación de las indolizidinas sintetizadas,

obteniendo estas estructuras con un grupo amina secundaria o primaria, la cual

podría funcionalizarse con posterioridad.

En el tercer capítulo, se expone la alquenilación C-H regio y

diastereoselectiva de indolizinas a través de una reacción sin metales en un

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medio ácido. El hecho más fascinante es la formación de enlaces Csp2-Csp2

utilizando un solo material de partida que sufre una autoalquilación para

formar una indolizina con una parte de chalcona, generando estructuras de alta

complejidad, las cuales se pueden emplear como colorantes. Los tintes

orgánicos con una configuración D-π-A contienen tanto grupos donadores de

electrones (D) como aceptores de electrones (A) conectados por una sección π

conjugada; alternativamente, una configuración D-A-π-A puede diseñarse

molecularmente donde la A intercalada adicionalmente es un componente

heterocíclico. Esta configuración permite aumentar la capacidad de absorción

de luz de estos compuestos haciéndolos candidatos ideales para ser empleados

como quimiosensores y ser aplicados en células solares sensibilizadas por

tintes. Se han obtenido hasta 14 tintes diferentes con rendimientos de bajos a

altos (23-83%). Las indolizinas sustituidas en la posición 3 con un grupo

aromático generan los correspondientes tintes con rendimientos buenos (50-

83%), disminuyendo el rendimiento aislado en el caso de tener un grupo

electrón-aceptor, ocurre lo mismo al poseer un grupo alifático en la misma

posición (54%). El mismo comportamiento se repite al cambiar la amina de

partida, observando que las aminas alifáticas reaccionan peor que las que

poseen una naturaleza electrónica diferente.

En este mismo capítulo, se ha descrito la reacción en dos pasos de un

tinte de indolizina a una escala de cuarenta gramos a partir de piridina-2-

carbaldehído, dibencilamina y fenilacetileno como materiales de partida. Para

esta escala, se ha decidido sustituir el catalizador, usando yoduro de cobre en

lugar de las nanopartículas de cobre, facilitando así la síntesis a escala

industrial. Además, de este modo se evita el uso de disolventes y la necesidad

de purificación de la indolizina. Seguidamente, se ha tratado el crudo con

ácido acético y a través de precipitación se ha obtenido el correspondiente

tinte, sin pérdida de rendimiento comparado con la menor escala. También se

ha intentado sintetizar tintes mixtos procedentes de dos indolizinas diferentes,

pero sin ningún resultado satisfactorio.

Los tintes muestran una única estructura en estado sólido pero en

cambio, se han observado dos estructuras estables en disolución (rotámeros),

de los cuales se ha hecho un estudio de resonancia magnética nuclear usando

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diferentes disolventes para ver la diferencia entre ellos. Este comportamiento

se ha repetido en todos los tintes, a excepción de uno de ellos, el cual posee

una cadena alifática en la posición 3 de la indolizina de partida. Se ha

propuesto un mecanismo de reacción basado en diferentes estudios realizados,

donde la indolizina tiene una doble funcionalidad actuando como nucleófila y

electrófila. En el primer paso la indolizina, en medio ácido, sufre una hidrólisis

para generar la correspondiente enamina, seguido por una adición Michael

debida al ataque de otra molécula de indolizina que favorece la apertura del

ciclo y, finalmente, se produce la rearomatización obteniendo el compuesto

deseado. Se ha hecho un extenso estudio de las propiedades ópticas de los

tintes, comparando las diferentes tonalidades de cada uno, la cual varía en

función de los sustituyentes que poseen. Los estudios preliminares sobre las

propiedades ópticas de los tintes han revelado que poseen propiedades

solvatocrómicas (es decir, se observan diferentes colores en solución para un

mismo tinte dependiendo de la polaridad del disolvente que se use). Además,

el color es dependiente del tamaño de partícula en estado sólido. Cuanto más

cristalina es la muestra, más grande es el tamaño de partícula, confiriendo al

sólido una tonalidad anaranjado-rojiza. Sin embargo, al disminuir el tamaño de

partícula, el color se vuelve más oscuro, pareciendo casi negro.

Sorprendentemente, el comportamiento solvatocrómico también se ha

mostrado tras injectar estos tintes a termoplásticos del tipo poliolefina

(poliestireno y polipropileno).

Debido a las propiedades ópticas de los tintes de indolizina, se ha

pensado que podrían utilizarse como detectores de metales, ya que hay varios

ejemplos donde los emplean para este fin. Debido a esto, se ha descrito el

estudio preliminar de la interacción del tinte de indolizina con varios cationes

metálicos, pudiendo observarse cambios de color en algunos casos pero sin

especial selectividad. Sin embargo, al probar diferentes aniones, no se ha

obtenido ninguna variación del color de la disolución.

En el cuarto capítulo, se estudia la reactividad nucleofílica de las

indolizinas frente a nitrosocompuestos como electrófilos. Esta reacción ha

resultado ser una útil herramienta sintética ya que se han obtenido distintos

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compuestos al cambiar los sustituyentes de las indolizinas. Estos compuestos

son β-enaminonas y pirroles, dependiendo de si el sustituyente en la posición 3

de la indolizina es un grupo aromático o alifático. La estructura de enaminona

se puede encontrar en diversos compuestos naturales o en compuestos

biológicamente activos. Existen varios métodos clásicos para la obtención de β

-enaminonas como son la reacción de condensación de aminas con

compuestos 1,3-dicarbonílicos, la reacción de adición a triples enlaces, la

apertura de heterociclos y la acilación de enaminas. En los últimos años se han

desarrollado nuevas metodologías que hacen uso de metales de transición para

catalizar estas reacciones. En el caso de los pirroles, éstos también son

compuestos que se encuentran formando parte de muchos medicamentos ya

comercializados, los cuales suelen sintetizarse comúnmente mediante la

síntesis de Hantzsch o la síntesis de Paal Knorr. Actualmente, se han

desarrollado numerosas metodologías efectivas para la síntesis de pirroles

polisustituidos usando metales de transición o la síntesis multicomponente.

En la reacción de indolizinas con nitrosocompuestos para la obtención

de β-enaminonas, se han optimizado las condiciones de reacción, estudiando,

en primer lugar, la mejor amina para su obtención seguida de la optimización

del disolvente. La mayor conversión se ha obtenido llevando a cabo la

reacción en acetonitrilo, sin el uso de metal y con la indolizina derivada de

dibencilamina a temperatura ambiente. Esta metodología se ha aplicado a

varias indolizinas sintetizadas en el primer capítulo, consiguiendo las

correspondientes β-enaminonas con rendimientos de moderados a buenos (35-

88%). Para las indolizinas con un grupo aromático sustituido en para, los

rendimientos obtenidos han sido altos (65-88%). Cabe destacar, que el menor

rendimiento se obtuvo para la indolizina con un grupo muy voluminoso en la

posición 5 de la indolizina debido, seguramente, al impedimento estérico que

ésta presenta. La metodología también ha sido efectiva empleando el tinte

derivado de indolizina con un buen rendimiento (64%). También se han

probado nitrosoderivados de diferente naturaleza electrónica y sustituidos

tanto en orto como en para, obteniendo los correspondientes compuestos con

rendimientos de moderados a buenos (40-74%). Sorprendentemente, se pudo

obtener la β-enaminona con una cadena alifática al usar la N,N-dimetil-4-

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nitrosoanilina (60%). Se ha podido escalar la reacción a 5 mmoles

consiguiendo el mismo rendimiento que a menor escala, obteniendo en este

caso el producto puro por precipitación. Se ha intentado llevar a cabo la

síntesis de β-enaminonas a través de la reacción multicomponente descrita en

el capítulo 1 en dos pasos en el mismo medio de reacción, es decir, generando

la correspondiente indolizina in situ, seguida de la adición del nitrosoderivado;

desgraciadamente la conversión ha sido menor. Para poder elucidar la

estereoquímica del compuesto se ha analizado la estructura por rayos X,

confirmando la estereoquímica Z, apoyado por la señal de resonancia

magnética nuclear de 1H que aparece a desplazamientos muy altos debido a la

formación de un enlace de hidrógeno entre el oxígeno carbonílico y el grupo

NH. También se han llevado a cabo algunas de las reacciones más comunes de

enaminonas, obteniendo los productos heterocíclicos deseados.

Después, se ha decidido estudiar la selectividad de nuestro método frente

a los métodos clásicos de obtención de β-enaminonas; para ello se ha

sintetizado un compuesto 1,3-dicarbonílico a partir de picolinato de etilo y

acetofenona. La mezcla de este compuesto y anilina se han sometido a las

condiciones de reacción descritas en la bibliografía. No todas las metodologías

descritas han funcionado, y en los casos que sí ha habido producto, se

comprobó que se obtiene mayormente el otro isómero. Por lo tanto, nuestra

metodología es selectiva y novedosa para obtener las β-enaminonas con esa

sustitución.

En segundo lugar, se ha optimizado la reacción para la obtención de

pirroles a partir de indolizinas con sustituyentes alifáticos en la posición 3. Se

ha observado que, en la mayoría de disolventes, se obtiene el pirrol con una

alta conversión, por lo que se decidió usar etanol, ya que es un disolvente

menos nocivo y más respetuoso con el medio ambiente. Al igual que en el

caso de la obtención de β-enaminonas, la reacción se ha llevado a cabo sin el

uso de ningún catalizador. Para comprobar que esta metodología es apta para

la síntesis de pirroles tetrasustituidos, las condiciones optimizadas de reacción

se han aplicado a diversas indolizinas obteniendo los correspondientes

compuestos finales con rendimientos de moderados a altos (33-96%). Todos

los pirroles obtenidos empleando diferentes aminas en la posición 1 de la

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indolizina se han obtenido con altos rendimientos (65-96%). Al tener un

sustituyente en la posición 6 de la indolizina, el rendimiento ha disminuido

considerablemente (33%). De igual manera, el rendimiento es menor cuando

se acorta o se alarga la cadena alifática (36-60%). En el caso de usar

nitrosocompuestos sustituidos en para o en orto, la conversión ha sido buena

(56-68%). En el perfil de reacción se puede apreciar cómo se obtiene una

conversión alta tan solo al cabo de una hora de reacción. Al igual que en el

caso de las β-enaminonas, se ha llevado a cabo la reacción a mayor escala,

obteniendo un buen rendimiento por precipitación del pirrol. En el caso de la

síntesis partiendo de piridin-2-carbaldehído, dibencilamina y 1-hexino, en

presencia de cobre y seguida de la adición de nitrosobenceno, se ha obtenido

una conversión buena, aunque es menor que aislando la indolizina

previamente. La estructura de los pirroles se ha confirmado por cristalografía

de rayos X.

El siguiente apartado del capítulo trata de explicar el mecanismo de la

reacción para la obtención de ambos compuestos. Para los dos casos, se han

sintetizado las indolizinas de partida deuteradas en la posición 2 y se han

sometido a las condiciones estándar de reacción, viendo que el deuterio se

pierde en el caso de las β-enaminonas, en cambio, se mantiene para la síntesis

de pirroles. La reacción de la β-enaminona en presencia de agua deuterada

demuestra que la incorporación de deuterio se produce en el protón

intercambiable del grupo NH.

Para verificar si hay presencia o no de radicales en el medio de reacción,

se han añadido trampas radicalarias en las reacciones estándar, pero los

compuestos finales se han obtenido con buena conversión, por lo que todo

indica que transcurre a través de un mecanismo iónico. Para el caso de las β-

enaminonas, se ha llevado a cabo la reacción bajo diferentes atmósferas, pero

se ha visto que la reacción bajo argón así como bajo oxígeno es mucho más

lenta. En cambio, la presencia de una cantidad catalítica de agua es beneficiosa

y aumenta la velocidad de reacción considerablemente. Considerando todos

los resultados obtenidos, se ha propuesto un mecanismo para la obtención de

β-enaminonas en el cual la indolizina actúa como nucleófilo reaccionando con

el nitrógeno del nitrosocompuesto, seguido de la pérdida de dibencilamina y

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siguiente ciclación dando una estructura intermedia de isooxazol, la cual se

abre y se protona dando lugar a la β-enaminona.

En el caso de la obtención de los pirroles se ha demostrado que se

produce una migración del sustituyente en la posición 1 a otro carbono en la

estructura final. Además, se ha intentado ver si la reacción procede de la

ciclación de la β-enaminona, usando la única enaminona alifática que se ha

obtenido, sin embargo, no se han obtenido resultados satisfactorios. Se ha

tratado de capturar el intermedio de la reacción usando hidracina,

hidroxilamina o el reactivo de Lawesson, pero ha sido imposible aislarlo. Se

ha realizado el seguimiento de la reacción por resonancia magnética y se ha

analizado por espectrometría de masas la reacción a los pocos minutos, antes

de la conversión completa. Con estos datos, se ha propuesto el que podría ser

el intermedio y el mecanismo de la reacción para obtener los pirroles.

CONCLUSIONES

Conclusiones

CONCLUSIONES

Se ha llevado a cabo la síntesis multicomponente de una serie de 1-

aminoindolizinas y pirrolo[1,2-a]quinolonas de manera efectiva a partir de

derivados de 2-piridincarbaldehído, aminas secundarias y alquinos terminales

utilizando CuNPs/C como catalizador en diclorometano a 70 ºC. La

metodología se ha aplicado a una variedad de aminas y alquinos, los últimos

incluyendo arilacetilenos así como alquilacetilenos, con rendimientos de

moderados a altos. Dicho catalizador ha demostrado ser superior a una serie de

catalizadores de cobre comerciales. Finalmente, se ha propuesto un

mecanismo de reacción basado en la probada participación de aminas

propargílicas como intermedios de reacción.

Se han sintetizado indolizidinas a través de la hidrogenación catalítica

heterogénea de indolizinas usando PtO2 como catalizador en ácido acético

como disolvente y a una presión de 3,7 atm. Las indolizidinas se han obtenido

con una elevada diastereoselectividad, incluso en el caso de poseer cuatro

estereocentros. Se ha demostrado experimentalmente que la hidrogenación de

la indolizina se produce a través del intermedio pirrólico 5,6,7,8-

tetrahidroindolizina. Además, estas indolizidinas se han podido mono- o di-

desbencilar usando un catalizador diferente.

Se ha sintetizado una nueva familia de compuestos orgánicos por

reacción de las indolizinas en medio ácido. Estos productos son tintes de

indolizina de color violeta-rojizos que tienen una estructura D-A-π-A bien

definida. La estructura de los tintes de indolizina se ha establecido mediante

análisis de rayos X en estado sólido, pero se pueden distinguir dos rotámeros

en disolución. Se ha propuesto un mecanismo de reacción en el que la propia

indolizina actúa como nucleófilo y electrófilo; en éste, una molécula sufre

hidrólisis en medio ácido y la adición Michael de la segunda molécula de

indolizina. Un estudio de las características ópticas de estos tintes ha revelado

un cambio de color dependiente del tamaño de partícula, un alto poder de

coloración y un carácter solvatocrómico (es decir, que el color de la disolución

del compuesto depende de la polaridad del disolvente usado), también en

materiales plásticos.

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176

Finalmente, se ha estudiado la reactividad de las indolizinas con

nitrosocompuestos, obteniendo dos productos diferentes según el sustituyente

en la posición tres de éstas. En el caso de poseer un sustituyente aromático se

obtienen β-enaminonas. Se ha realizado un estudio del alcance de esta

metodología cambiando los sustituyentes 1, 3 y 6 de las indolizinas y usando

compuestos nitrosoaromáticos con distintos sustituyentes en orto y para,

obteniendo las correspondientes β-enaminonas con rendimientos aislados de

moderados a buenos. El uso de esta metodología ha demostrado ser el más

apropiado para obtener ese tipo de regioisómero, comparado con las

metodologías clásicas de condensación de compuestos 1,3-dicarbonilos con

aminas que dan el regioisómero opuesto. Para sustituyentes alifáticos, se han

obtenido pirroles tetrasustituidos con rendimientos de moderados a buenos,

variando los cuatro sustituyentes en la estructura de pirrol. Se han llevado a

cabo varios experimentos para elucidar el mecanismo de reacción. Se ha

demostrado que proceden vía iónica, no radicalaria. La presencia de agua es

beneficiosa para la obtención de β-enaminonas, en cambio, una atmósfera de

oxígeno o de argón no lo son. Con todo ello, se ha propuesto un mecanismo

para la obtención de éstas en el que participa una estructura de isooxazol como

intermedio. En el caso de los pirroles, se ha demostrado que hay una

migración de la dibencilamina en la estructura. Tras varios experimentos,

enfocados en la obtención de un posible intermedio de reacción, se ha

propuesto la secuencia del mecanismo para la obtención de pirroles. En primer

lugar, se ha propuesto el ataque nucleófilo al nitrosocompuesto, abriendo la

estructura y perdiendo dibencilamina, formando así una cetona α,β-insaturada,

seguido del ataque de la dibencialamina y posterior ciclación para la obtención

del pirrol.

EXPERIMENTAL

PART

Experimental Part

179

EXPERIMENTAL PART

GENERAL

SOLVENTS AND REAGENTS

All the starting materials and other reagents were commercially

available of the best grade (Aldrich, Acros, Alfa Aesar, Fluorochem, Evonik)

and were used without further purification. THF was dried in a Sharlab PS-

400-3MD solvent purification system using an alumina column.

INSTRUMENTS AND CROMATOGRAPHY

Melting points were obtained with a Reichert Thermovar apparatus and

are uncorrected. NMR spectra were recorded on Bruker Avance 300 and 400

spectrometers (300 and 400 MHz for 1H NMR; 75 and 101 MHz for 13C

NMR); chemical shifts are given in (δ) parts per million and coupling

constants (J) in Hertz. Infrared analysis was performed with a Jasco 4100LE

(Pike MIRacle ATR) spectrophotometer; wavenumbers (υ) are given in cm–1.

Mass spectra (EI) were obtained at 70 eV on Agilent 5763 (GC) and Agilent

5973 (DIP) spectrometers; fragment ions in m/z with relative intensities (%) in

parentheses. HRMS analyses (EI) were also carried out at 70 eV on an Agilent

7200-QTOF spectrometer. Elemental analyses were performed on a Thermo

Finnigan Flash 1112 microanalyzer. The purity of volatile compounds and the

chromatographic analyses (GLC) were determined with an Agilent 6890N

instrument equipped with a flame ionization detector and an HP-5MS 30 m

capillary column (0.32 mm diameter, 0.25 µm film thickness), using nitrogen

(2 mL/min) as carrier gas, Tinjector = 270 ºC, Tcolumn = 60 ºC (3 min) and

60–270 ºC (15 ºC/min); retention times (tr) are given in min. Analytical thin-

layer chromatography (TLC) was carried out on ALUGRAM® Xtra SIL G

UV254 aluminium sheets. Column chromatography was performed using

silica gel 60 of 40–60 microns (hexane/EtOAc as eluent).X-ray data collection

was based on three -scan runs (starting = –34) at the values of = 0,

Experimental Part

180

120, 240 with the detector at 2 = –32. An additional run at = 0 of 100

frames was collected to improve redundancy. The diffraction frames were

integrated using the SAINT program and the integrated intensities were

corrected for Lorentz-polarization effects with SADABS.32

The purity of

volatile compounds and the chromatographic analyses (GLC) were determined

with a gas chromatograph equipped with a flame ionization detector and a 30

m capillary column (0.32 mm diameter, 0.25 m film thickness), using

nitrogen (2 mL/min) as carrier gas, Tinjector = 270 ºC, Tcolumn = 80 ºC (3 min)

and 80–270 ºC (20 ºC/min); retention times (tR) are given in min. Thin-layer

chromatography was carried out on TLC aluminium sheets covered with silica

gel. Column chromatography was performed using silica gel of 40–60 microns

(hexane/EtOAc as eluent). Preparative thin-layer chromatography was carried

on laboratory-made TLC glass plates with silica gel 60 PF254 (hexane/EtOAc).

Experimental Part

181

EXPERIMENTAL PART OF CHAPTER I

General procedure for the synthesis of indolizines catalyzed by CuNPs/C.

The aldehyde (1, 0.5 mmol), amine (2, 0.5 mmol), and alkyne (3, 0.5

mmol) were added to a reactor tube containing CuNPs/C (20 mg, ca. 0.5

mol%) and dichloromethane (1.0 mL). The reaction mixture was warmed to 70

ºC without the exclusion of air and monitored by TLC and/or GLC until total

or steady conversion of the starting materials. The solvent was removed under

vacuum; EtOAc (2 mL) was added to the resulting mixture followed by

filtration through Celite and washing with additional EtOAc (4 mL). The

reaction crude obtained after evaporation of the solvent was purified by

column chromatography (silica gel, hexane/EtOAc) or preparative TLC (silica

gel, hexane/EtOAc) to give the corresponding indolizine 4. Purification of the

5-substituted indolizines 4bga, 4cgc and 4dga was done by preparative TLC

(silica gel, hexane/EtOAc) with prior impregnation of the plate with Et3N in

order to minimize product decomposition. The reaction of 1b with 2g and 3a

furnished the corresponding propargylamine 5bga as the major product (72%).

General procedure for the synthesis of the indolizines catalyzed by CuI.

The aldehyde (1, 2 mmol), amine (2, 2 mmol), and alkyne (3, 2 mmol)

were added to a reactor tube containing CuI (38 mg, 10 mol%). The reaction

mixture was warmed to 70 ºC without the exclusion of air and monitored by

TLC and/or GLC until total or steady conversion of the starting materials.

EtOAc (2 mL) was added to the resulting mixture followed by filtration

through Celite and washing with additional EtOAc (4 mL). The reaction crude

obtained after evaporation of the solvent was purified by column

chromatography (silica gel, hexane/EtOAc) to give the corresponding

indolizines 4.

3-Phenyl-1-(piperidin-1-yl)indolizine (4aaa). Yellow oil; tr

18.51; Rf 0.38 (hexane/EtOAc, 9:1); IR (neat) υ 3055, 2927,

2848, 2789, 1597, 1509, 1425, 1301, 1014, 733, 697; 1H NMR

(400 MHz, C6D6) δ 1.38–1.51 (m, 2H; NCH2CH2CH2), 1.66–

Experimental Part

182

1.74 (m, 4H; 2 × NCH2CH2), 2.98 (t, J = 5.2, 4H; 2 × NCH2), 5.99–6.08 (m,

1H; ArH), 6.29–6.40 (m, 1H; ArH), 6.75 (s, 1H; ArH), 7.04–7.11 (m, 1H;

ArH), 7.14–7.24 (m, 2H; 2 × ArH), 7.33–7.41 (m, 2H; 2 × ArH), 7.55 (d, J =

9.2, 1H; ArH), 7.93 (d, J = 7.2, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ 24.9,

27.1, 55.7 (5 × CH2), 106.6, 111.0, 114.6, 118.5, 121.8, 126.8, 128.2, 129.2

(10 × ArCH), 122.8, 126.1, 132.1, 133.3 (4 × ArC); MS (70 eV) m/z (%) 277

(22) [M++1], 276 (100) [M

+], 234 (18), 233 (14), 220 (13), 219 (12), 207 (18),

206 (16), 78 (11); HRMS (EI) m/z calcd for C19H20N2 276.1626, found

276.1593.

4-(3-Phenylindolizin-1-yl)morpholine (4aba). Yellow oil; Rf

0.34 (hexane/EtOAc, 8:2); tr 18.68; IR (neat) υ 3060, 2951,

2851, 2811, 1509, 1426, 1301, 1259, 1112, 896, 734, 698; 1H

NMR (400 MHz, C6D6) δ 2.97 (t, J = 4.6, 4H; 2 × NCH2), 3.85

(t, J = 4.6, 4H; 2 × CH2O), 6.12–6.16 (m, 1H; ArH), 6.44 (ddd,

J = 9.0, J = 6.3 Hz, J = 0.9, 1H; ArH), 6.76 (s, 1H; ArH), 7.13–

7.23 (m, 1H; ArH), 7.25–7.32 (m, 2H; 2 × ArH), 7.45 (d, J = 7.2, 2H; 2 ×

ArH), 7.53 (dt, J = 9.0, J = 1.2, 1H; ArH), 8.01 (dd, J = 7.2, J = 0.9, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ 54.7 (2 × NCH2), 67.6 (2 × OCH2), 106.5,

111.1, 114.9, 118.2, 121.9, 127.0, 128.2, 129.2 (10 × ArCH), 123.0, 126.1,

130.6, 133.1 (4 × ArC); MS (70 eV) m/z (%) 279 (20) [M++1], 278 (100)

[M+], 221 (16), 220 (56), 219 (24), 192 (10), 96 (13), 78 (11); HRMS (EI) m/z

calcd for C18H18N2O 278.1419, found 278.1437.

N,N-Dibutyl-3-phenylindolizin-1-amine (4aca). Yellow oil;

Rf 0.80 (hexane/EtOAc, 8:2); tr 14.10; IR (neat) υ 3065, 3035,

2954, 2929, 2869, 2808, 1511, 1300, 1075, 770, 741, 722, 698; 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J = 7.2, 6H; 2 × CH3),

1.20–1.53 (m, 8H; 4 × CH2), 2.80–3.13 (t, J = 6.8, 4H; 2 × CH2), 6.31–6.43 (t,

J = 6.5, 1H; ArH), 6.45–6.59 (t, J = 7.5, 1H; ArH), 6.73 (s, 1H; ArH), 7.24–

7.32 (m, 1H; ArH), 7.34–7.50 (m, 3H; 3 × ArH), 7.51–7.61 (m, 2H; 2 × ArH),

8.17 (d, J = 7.2, 1H; ArH); 13

C NMR (75 MHz, CDCl3) δ 14.2 (2 × CH3), 20.7,

30.3, 56.9 (6 × CH2), 108.6, 110.7, 114.9, 118.2, 121.8, 126.8, 127.9, 129.0

Experimental Part

183

(10 × ArCH), 123.1, 128.1, 128.7, 132.9 (4 ×ArC); MS (70 eV) m/z (%) 321

(24) [M++1], 320 (100) [M

+], 278 (12), 277 (55), 263 (37), 235 (47), 221 (27),

220 (64), 219 (20), 194 (14), 193 (17), 192 (10), 105 (11); HRMS (EI) m/z

calcd for C22H28N2 320.2252, found 320.2280.

N-Benzyl-N-methyl-3-phenylindolizin-1-amine (4ada).

Yellow oil; Rf 0.60 (hexane/EtOAc, 8:2); tr 16.57; IR (neat)

ῦ 3060, 3030, 2932, 2784, 1598, 1510, 731, 696; 1H NMR

(400 MHz, C6D6) δ 3.08 (s, 3H; CH3), 4.49 (s, 2H; CH2),

6.39–6.45 (m, 1H; ArH), 7.72 (ddd, J = 9.2, 6.4, 0.8, 1H;

ArH), 7.45–7.63 (m, 7H; 7 × ArH), 7.72–7.78 (m, 2H; 2 × ArH), 7.80–7.86

(m, 2H; 2 × ArH), 7.97 (dt, J = 8.8, 1.2, 1H; ArH), 8.31 (dt, J = 7.2, 0.8 Hz,

1H; ArH); 13

C NMR (101 MHz, C6D6) δ 43.0 (CH3), 63.2 (CH2), 107.2, 111.0,

114.8, 118.4, 121.8, 126.9, 127.3, 128.2, 128.4, 128.6, 128.9, 129.1 (15 ×

ArCH), 122.9, 126.2, 131.1, 133.2, 140.0 (5 × ArC); MS (70 eV) m/z (%) 312

(34) [M+], 222 (17), 221 (100), 119 (35), 78 (17); HRMS (EI) m/z calcd for

C22H20N2 312.1626, found 312.1642.

N-Methyl-N-phenethyl-3-phenylindolizin-1-amine

(4aea). Brown oil; Rf 0.66 (hexane/EtOAc, 8:2); tr 17.43;

IR (neat) ῦ 3059, 3024, 2931, 2784, 1599, 1510, 1348,

1300, 1051, 771, 734, 696; 1H NMR (300 MHz, C6D6) δ

2.83 (s, 3H; CH3), 2.86–2.94 (m, 2H; CH2CH2N), 3.23–

3.37 (m, 2H; CH2CH2N), 6.04–6.15 (m, 1H; ArH), 6.41 (ddd, J = 9.0, 6.3, 1.0,

1H; ArH), 6.84 (s, 1H; ArH), 7.12–7.30 (m, 8H; 8 × ArH), 7.41–7.48 (m, 2H;

2 × ArH), 7.55 (dt, J = 9.0, 1.0, 1H; ArH), 8.00 (dt, J = 7.2, 1.0, 1H; ArH); 13

C

NMR (75 MHz, C6D6) δ 34.8 (CH2CH2N), 44.5 (CH3), 60.5 (CH2CH2N),

107.6, 111.0, 115.0, 118.5, 121.8, 126.2, 127.0, 128.2, 128.6, 129.1, 129.2 (15

× ArCH), 123.2, 127.4, 130.1, 133.2, 141.1 (5 × ArC); MS (70 eV) m/z (%)

326 (36) [M+], 236 (18), 235 (100), 221 (11), 220 (40), 219 (13), 194 (27), 78

(12); HRMS (EI) m/z calcd for C23H23N2 [M + H]+ 327.1861, found 327.1877.

Experimental Part

184

N-Methyl-N,3-diphenylindolizin-1-amine (4afa). Yellow

oil; tR 18.43; Rf 0.71 (hexane/EtOAc, 8:2); IR (neat) ῦ 3056,

3032, 2877, 2808, 1597, 1497, 1432, 1310, 1211, 1114, 1037,

741, 692; 1H NMR (400 MHz, CDCl3) δ 3.33 (s, 3H; CH3),

6.41 (br, 1H; ArH), 6.55 (br, 1H; ArH), 6.69–6.76 (m, 4H; 4 ×

ArH), 7.13–7.18 (m, 3H; 3 × ArH), 7.27–7.30 (m, 1H; ArH), 7.41–7.44 (m,

2H; 2 × ArH), 7.54–7.55 (m, 2H; 2 × ArH), 8.24 (br, 1H; ArH); 13

C NMR

(101 MHz, CDCl3) δ 40.8 (CH3), 111.0, 112.1, 113.1, 116.8, 117.6, 122.3,

127.2, 128.0, 129.0, 129.1 (15 × CH), 122.9, 123.8, 128.5, 132.3, 150.3 (5 ×

ArC); MS (GC) m/z 299 (M++1, 24), 298 (M

+, 100), 284 (19), 283 (85), 181

(55), 149 (14), 141 (13), 78 (31), 77 (47), 51 (16). HRMS (EI) m/z calcd for

C21H18N2 298.1470, found 298.1469.

N,N-Dibenzyl-3-phenylindolizin-1-amine (4aga). Yellow oil;

Rf 0.69 (hexane/EtOAc, 8:2); tr 26.44; IR (neat) ῦ 3055, 3025,

2927, 2829, 1598, 1509, 1239, 730, 695; 1H NMR (300 MHz,

C6D6) δ 4.26 (s, 4H; 2 × CH2), 6.01–6.12 (m, 1H; ArH), 6.42

(ddd, J = 9.0, 6.3, 0.6 Hz, 1H; ArH), 6.81 (s, 1H; ArH), 7.10–7.17 (m, 2H; 2 ×

ArH), 7.18–7.30 (m, 7H; 7 × ArH), 7.31–7.37 (m, 2H; 2 × ArH), 7.50 (d, J =

7.2, 4H; 4 × ArH), 7.65 (d, J = 9.0, 1H; ArH), 7.91 (d, J = 7.2, 1H; ArH); 13

C

NMR (75 MHz, C6D6) δ 59.5 (2 × CH2), 108.8, 110.9, 115.2, 118.2, 121.8,

126.9, 127.2, 128.2, 128.5, 128.9, 129.1 (20 × ArCH), 123.1, 127.5, 133.0,

140.0 (6 × ArC); MS (70 eV) m/z (%) 388 (30) [M+], 298 (24), 297 (100), 193

(21), 91 (43); HRMS (EI) m/z calcd for C28H24N2 388.1939, found 388.1964.

N,N-Bis(4-methoxyphenyl)-3-phenylindolizin-

1-amine (4aha). Yellow solid; Rf 0.38

(hexane/EtOAc, 8:2); m.p. 46.5–47.1 ºC; IR

(neat) ῦ 3058, 3027, 2963, 2867, 1593, 1495,

1432, 1299, 1231, 1114, 738, 695; 1H NMR

(400 MHz, C6D6) δ 3.34 (s, 6H; 2 × CH3), 5.98–

6.02 (m, 1H; ArH), 6.25 (dd, J = 9.0, 6.4 Hz,

1H; ArH), 6.76 (d, J = 9.0 Hz, 2H; 2 × ArH), 6.84 (s, 1H; ArH), 7.05–7.09 (m,

Experimental Part

185

1H; ArH), 7.14–7.20 (m, 7H; 7 × ArH), 7.23 (d, J = 9.0 Hz, 1H; ArH) 7.32–

7.34 (m, 2H; 2 × ArH), 7.97 (d, J = 7.2 Hz, 1H; ArH); 13

C NMR (101 MHz,

C6D6) δ 55.1 (2 × CH3), 111.2, 112.9, 114.9, 116.5, 118.5, 122.3, 123.1, 127.2,

128.2, 129.2 (14 × CH), 123.3, 124.3, 132.6, 143.0, 155.0 (6 × ArC); MS

(DIP) m/z 421 (M++1, 31), 420 (M

+, 100), 405 (17), 210 (16), 205 (13);

HRMS (EI) m/z calcd for C28H24N2O2 420.1838, found 420.1839.

(R)-N-Benzyl-3-phenyl-N-(1-phenylethyl)indolizin-1-

amine (4aia). Yellow oil; Rf 0.67 (hexane/EtOAc, 6:4); IR

(neat) ῦ 3060, 3025, 2971, 2817, 1599, 1509, 1492, 1450,

1346, 1301, 1239, 1073, 1027, 737, 695; 1H NMR (400

MHz, CDCl3) δ 1.34 (d, J = 6.7, 3H; CH3), 3.96–4.14 (m,

2H; CH2), 4.30 (br s, 1H), 6.33 (br s, 1H; ArH), 6.50 (br s, 1H; ArH), 6.66 (s,

1H; ArH), 7.06–7.10 (m, 1H; ArH), 7.15 (t, J = 7.4, 2H; ArH), 7.23–7.28 (m,

4H; 4 × ArH), 7.35 (t, J = 7.5, 2H; 2 × ArH), 7.41–7.50 (m, 7H; 7 × ArH),

8.13 (br s, 1H; ArH); 13

C NMR (101 MHz, CDCl3) δ 19.8 (CH3), 56.7 (CH2),

63.4 (CH), 110.6, 111.1, 115.4, 118.2, 121.7, 126.4, 126.8, 127.0, 127.9,

128.0, 128.3, 128.6, 128.9 (20 × ArCH), 122.9, 125.0, 130.1, 132.8, 140.5,

144.6 (6 × ArC); MS (GC) m/z 403 (M++1, 4), 402 (M

+, 12), 298 (24), 297

(100), 193 (19), 91 (22). HRMS (EI) m/z calcd for C29H26N2 402.2096, found

402.2100.

1-(Piperidin-1-yl)-3-(p-tolyl)indolizine (4aab). Yellow oil;


2930, 2848, 2779, 1520, 1427, 1343, 1300, 1110, 1014, 810,

736; 1H NMR (300 MHz, CDCl3) δ 1.52–1.65 (m, 2H;

NCH2CH2CH2), 1.75–1.88 (m, 4H; 2 × NCH2CH2), 2.39 (s,

3H; CH3), 3.04 (m, 4H; 2 × NCH2), 6.37 (t, J = 6.5, 1H; ArH),

6.66 (s, 1H; ArH), 7.25, 7.43 (AA’XX’ system, 4H; 4 × ArH),

7.50 (d, J = 8.4, 1H; ArH), 8.14 (d, J = 7.2, 1H; ArH); 13

C

NMR (75 MHz, CDCl3) δ 21.4 (CH3), 24.4, 26.4, 55.6 (5 × CH2), 105.5,

110.8, 118.2, 121.8, 127.9, 129.7 (9 × ArCH, ArC), 114.5, 122.6, 124.9, 136.7

(4 × ArC); MS (70 eV) m/z (%) 291 (24) [M++1], 290 (100) [M

+], 248 (17),

Experimental Part

186

247 (14), 234 (12), 233 (11), 221 (17), 220 (15); HRMS (EI) m/z calcd for

C20H22N2 290.1783, found 290.1778.

3-(4-Methoxyphenyl)-1-(piperidin-1-yl)indolizine (4aac).

Yellow oil; Rf 0.57 (hexane/EtOAc, 8:2); tr 17.31; IR (neat)

ῦ 3035, 2931, 2848, 2789, 1519, 1281, 1242, 1175, 1032,

834, 736, 723; 1H NMR (400 MHz, C6D6) δ 1.55 (quintet, J

= 5.9, 2H; NCH2CH2CH2), 1.80 (quintet, J = 5.6, 4H; 2 ×

NCH2CH2), 3.12 (t, J = 5.4, 4H; 2 × NCH2), 3.44 (s, 3H;

OCH3), 6.22–6.12 (m, 1H; ArH), 6.45 (ddd, J = 9.0, 6.3, 0.9

Hz, 1H; ArH), 6.86 (s, 1H; ArH), 6.91, 7.40 (AA’BB’

system, 4H; 4 ×ArH), 7.68 (dt, J = 9.0, 1.2, 1H; ArH), 8.01 (dt, J = 7.2, 0.8,

1H; ArH); 13

C NMR (101 MHz, C6D6) δ 24.9, 27.1, 55.8 (5 × CH2), 54.9

(OCH3), 106.2, 110.8, 114.2, 114.7, 118.5, 121.7, 129.8 (9 × ArCH), 122.7,

125.6, 125.8, 131.9, 159.2 (5 × ArC); MS (70 eV) m/z (%) 307 (23) [M++1],

306 (100) [M+], 264 (14), 263 (12), 237 (16), 236 (14), 235 (11); HRMS (EI)

m/z calcd for C20H22N2O 306.1732, found 306.1749.

1-(Piperidin-1-yl)-3-[4-(trifluoromethyl)phenyl]indolizine

(4aad). Yellow oil; Rf 0.57 (hexane/EtOAc, 8:2); tr 14.73; IR

(neat) ῦ 3060, 2934, 2852, 2792, 1611, 1320, 1162, 1106,

1064, 1014, 845, 778; 1H NMR (300 MHz, CDCl3) δ 1.52–

1.67 (m, 2H; CH2), 1.83 (br s, 4H; 2 × CH2), 3.05 (br s, 4H; 2

× CH2), 6.47 (t, J = 6.6, 1H; ArH), 6.62 (t, J = 6.6, 1H; ArH),

6.75 (s, 1H; ArH), 7.48–7.61 (m, 1H; ArH), 7.63–7.70 (m,

4H; 4 × ArH), 8.21 (d, J = 6.9, 1H; ArH); 13

C NMR (75

MHz, CDCl3) δ 24.3, 26.3, 55.5 (5 × CH2), 106.6, 111.7,

118.5, 121.6, 126.0, 126.1, 127.4 (9 × ArCH), 121.1, 122.6, 123.4, 126.2,

136.1 (5 × ArC), 126.1 (q, JC-F = 15; 2 × ArCH); MS (70 eV) m/z (%) 345 (23)

[M++1], 344 (100) [M

+], 302 (17), 301 (13), 288 (13), 287 (11), 275 (16), 274

(15); HRMS (EI) m/z calcd for C20H19F3N2 344.1500, found 344.1572.

Experimental Part

187

N,N-Dibenzyl-3-(p-tolyl)indolizin-1-amine (4agb). Yellow

oil; Rf 0.83 (hexane/EtOAc, 8:2); tr 30.68; IR (neat) ῦ 3060,

3030, 2912, 1523, 1452, 1345, 1300, 817, 735, 726; 1H NMR

(400 MHz, C6D6) δ 2.52 (s, 3H; CH3), 4.58 (s, 4H; 2 × CH2),

6.33–6.42 (m, 1H; ArH), 7.72 (dd, J = 8.4, 6.4, 1H; 1 × ArH),

7.37, 7.45 (AA’XX’ system, 4H; 4 × ArH), 7.51–7.57 (m, 5H;

5 × ArH), 7.60 (d, J = 8.0, 2H; 2 × ArH), 7.80 (d, J = 7.6, 4H;

4 × ArH), 7.95 (d, J = 9.2, 1H; ArH), 8.26 (d, J = 7.2, 2H; 2 × ArH); 13

C NMR

(101 MHz, C6D6) δ 21.2 (CH3), 60.0 (2 × CH2), 108.6, 110.8, 115.0, 118.2,

121.9, 127.1, 128.4, 128.5, 129.0, 129.8 (19 × ArCH), 123.2, 127.3, 130.2,

136.5, 140.0 (ArC); MS (70 eV) m/z (%) 403 (9) [M++1], 402 (29) [M

+], 312

(26), 311 (100), 310 (12), 207 (17), 91 (58); HRMS (EI) m/z calcd for

C29H26N2 402.2096, found 402.2070.

N,N-Dibenzyl-3-(4-methoxyphenyl)indolizin-1-amine

(4agc). Yellow solid; m.p. 90.9–92.4 ºC; Rf 0.63

(hexane/EtOAc, 8:2); tr 33.52; IR (neat) ῦ 3065, 3035, 3006,

2917, 2819, 1521, 1478, 1282, 1240, 1034, 836, 820, 754,

735, 694; 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H;

OCH3), 4.19 (br s, 4H; 2 × CH2), 6.06–6.83 (m, 3H; 3 ×

ArH), 6.96 (br s, 2H; 2 × ArH), 7.15–7.56 (m, 13H; 13 ×

ArH), 8.02 (s, 1H; ArH); 13

C NMR (101 MHz, CDCl3) δ 55.5 (CH3), 59.5 (2 ×

PhCH2), 107.9, 110.6, 114.4, 117.9, 121.6, 126.9, 128.2, 128.7, 129.4 (19 ×

ArCH), 122.5, 126.2, 128.0, 139.8, 158.7 (7 × ArC); MS (70 eV) m/z (%) 418

(29) [M+], 328 (25), 327 (100), 223 (15), 91 (76); elemental analysis calcd for

C29H26N2O: C 83.22, H 6.26, N 6.69, found: C 83.49, H 6.27, N 7.09.

N,N-Dibenzyl-3-[4-(trifluoromethyl)phenyl]indolizin-1-

amine (4agd). Yellow solid; m.p. 128.9–130.0 ºC; Rf 0.80

(hexane/EtOAc, 8:2); tr 23.86; IR (neat) ῦ 3065, 3025, 2927,

2819, 1613, 1321m 1165, 1105, 1065, 846, 754, 739, 727,

695; 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 4H; 2 × CH2),

6.41 (t, J = 6.8, 1H; ArH), 6.56 (t, J = 7.4, 1H; ArH), 6.70 (s,

Experimental Part

188

1H; ArH), 7.18–7.40 (m, 10H; 10 × ArH), 7.49–7.66 (m, 5H; 5 × ArH), 8.15

(d, J = 6.8, 1H; ArH); 13

C NMR (101 MHz, CDCl3) δ 59.5 (2 × PhCH2),

109.3, 111.5, 115.9, 118.2, 121.6, 125.9, 126.0, 127.0, 127.4, 128.3, 128.7 (19

× ArCH), 121.2, 128.0, 136.2, 139.5 (6 × ArC); MS (70 eV) m/z (%) 456 (25)

[M+], 366 (25), 365 (100), 261 (26), 91 (43); elemental analysis calcd for

C29H23F3N2: C 76.30, H 5.08, N 6.14, found: C 76.85, H 5.16, N 6.61.

Methyl 4-[1-(dibenzylamino)indolizin-3-yl]benzoate

(4age). Yellow solid; Rf 0.60 (hexane/EtOAc, 8:2); m.p.

133.8–136.2 ºC; IR (neat) ῦ 3027, 2942, 2922, 2847,

1718, 1601, 1514, 1433, 1283, 1178, 1108, 859, 754, 737,

696; 1H NMR (400 MHz, C6D6) δ 3.54 (s, 3H; CH3), 4.15

(s, 4H; 2 × CH2), 5.95–5.99 (m, 1H; ArH), 6.33 (ddd, J =

9.0, 6.4, 0.8 Hz, 1H; ArH), 6.69 (s, 1H; ArH), 7.03–7.07

(m, 2H; 2 × ArH), 7.13–7.18 (m, 6H; 6 × ArH), 7.38–7.39 (m, 4H; 4 × ArH),

7.52 (dt, J = 9.0, 1.1 Hz, 1H; ArH), 7.74 (d, J = 7.2 Hz, 1H; ArH), 8.12 (d, J =

8.5 Hz, 2H; 2 × ArH); 13

C NMR (101 MHz, C6D6) δ 51.6 (CH3), 59.9 (2 ×

CH2), 109.8, 111.5, 116.1, 118.2, 122.0, 127.1, 127.3, 128.5, 128.9, 130.5 (19

× CH), 122.1, 128.2, 128.7, 129.0, 138.1, 139.8 (7 × ArC), 166.5 (C=O); MS

(DIP) m/z 447 (M++1, 8), 446 (M

+, 25), 356 (25), 355 (100), 251 (15), 91 (39).

HRMS (EI) m/z calcd for C30H26N2O2 446.1994, found 446.1978.

N,N-Dibenzyl-3-decylindolizin-1-amine (4agf). Yellow oil;


2923, 2854, 1529, 1462, 1375, 1341, 1089, 742, 720; 1H NMR

(300 MHz, C6D6) δ 0.81–0.96 (m, 9H; 3 × CH3), 1.22–1.65

(m, 24H; 12 × CH2), 2.51 (t, J = 7.7, 2H; CCH2), 3.04 (t, J =

7.2, 4H; 2 × NCH2), 6.13–6.20 (m, 1H; ArH), 6.42 (ddd, J = 9.0, 6.3, 0.9, 1H;

ArH), 6.63 (s; 1H; ArH), 7.24 (d, J = 7.2, 1H; ArH), 7.68 (dt, J = 9.0, 1.2, 1H;

ArH); 13

C NMR (75 MHz, C6D6) δ 14.3, 14.4 (3 × CH3), 21.0, 23.1, 26.4,

27.7, 29.8, 29.9, 30.0, 30.1, 31.0, 32.4, 57.7 (15 × CH2), 106.6, 110.1, 113.7,

118.3, 121.3 (5 × ArCH), 122.4, 126.5, 128.2 (3 × ArC); MS (70 eV) m/z (%)

Experimental Part

189

385 (29) [M++1], 384 (100) [M

+], 341 (24), 327 (21), 299 (19), 257 (15), 157

(36), 130 (10); HRMS (EI) m/z calcd for C26H44N2 384.3504, found 384.3474.

N,N-dibenzyl-3-cyclohexylindolizin-1-amine (4agg). Yellow

solid; m.p. 112.5–113.9 ºC; Rf 0.80 (hexane/EtOAc, 8:2); tr

23.51; IR (neat) ῦ 3089, 3060, 3030, 2919, 2848, 1534, 1494,

1450, 1420, 1363, 1356, 1339, 746, 738, 728, 695; 1H NMR

(400 MHz, CDCl3) δ 1.21–1.48, 1.70–2.10, 2.60–2.84 (3m,

11H; 5 × CH2, CH), 4.13 (s, 4H; 2 × NCH2), 6.28–6.40, 7.06–

7.61 (2m, 15H; 15 × ArH); 13

C NMR (101 MHz, CDCl3) δ 26.5, 26.7, 31.9,

59.5 (7 × CH2), 35.3 (CH), 104.1, 109.7, 113.0, 117.9, 121.1, 126.7, 128.1,

128.8 (15 × ArCH), 125.0, 127.3, 139.9 (5 × ArC); MS (70 eV) m/z (%) 394

(22) [M+], 304 (23), 303 (100), 91 (36); elemental analysis calcd for C28H30N2:

C 85.24, H 7.66, N 7.10, found: C 84.85, H 7.64, N 6.84.

2-((1-(dibenzylamino)indolizin-3-

yl)methyl)isoindoline-1,3-dione (4agh). Yellow

solid; m.p. 112.5–113.9 ºC; Rf 0.33 (hexane/EtOAc,

8:2); IR (neat) ῦ 3023, 2930, 2830, 1765, 1710,1421,

1388, 1330, 1303, 1104, 933, 737, 670; 1H NMR (300

MHz, CDCl3) δ 4.11 (s, 4H; 2 CH2), 4.99 (s, 2H;

CH2), 6.42–6.52 (m, 2H; 2 × ArH), 6.82 (s, 1H; ArH), 7.11–7.24 (m, 6H; 6 ×

ArH), 7.32–7.34 (m, 4H; 4 × ArH), 7.38–7.42 (m, 1H; 1 × ArH), 7.61–7.65

(m, 2H; 2 × ArH), 7.75–7.81 (m, 2H; 2 × ArH), 7.49 (dt, J = 6.8, 1.2 Hz, 1H;

ArH); 13

C NMR (75 MHz, CDCl3) δ 33.0, 59.6 (3 × CH2), 110.7, 110.9, 115.0,

117.4, 122.6, 123.4, 126.8, 128.1, 128.7, 134.1 (19 × ArCH), 115.4, 126.7,

126.9, 132.2, 139.7, 168.3 (7 × ArC); MS (70 eV) m/z (%) 471 (M+, 22), 381

(27), 380 (100), 235 (10), 233 (24), 130 (21), 91 (22); HRMS (EI) m/z calcd

for C31H25N3O2 471.1947, found 471.1903.

N,N-Dibenzyl-5-bromo-3-phenylindolizin-1-amine (4bga).

Yellow oil; Rf 0.54 (hexane/EtOAc, 8:2); IR (neat) ῦ 3081,

Experimental Part

190

3060, 3029, 2957, 2923, 2852, 1600, 1494, 1453, 1279, 1208, 1028, 749, 697; 1H NMR [300 MHz, (CD3)2CO] δ 4.21 (s, 4H; 2 × CH2), 6.45 (dd, J = 8.8, 6.8,

1H; ArH), 6.75 (dd, J= 6.8, 1.1, 1H; ArH) 6.76 (s, 1H; ArH); 7.17 (t, J= 7.2,

2H; 2 × ArH), 7.26 (t, J = 7.2, 4H; 4 × ArH), 7.29–7.38 (m, 5H; 5 × ArH),

7.42 (d, J= 7.2, 4H; 4 × ArH), 7.65 (dd, J= 8.8, 1.1, 1H; ArH); 13

C NMR [75

MHz, (CD3)2CO] δ 60.4 (2 × CH2), 112.6, 114.8, 116.9, 118.0, 126.8, 127.3,

128.0, 128.6, 130.8 (19 × ArCH), 112.2, 125.7, 128.2, 129.9, 134.2, 139.4 (7 ×

ArC); MS (70 eV) m/z (%) 469 (5) [M++1,

81Br], 468 (15) [M

+,

81Br], 467 (5)

[M++ 1,

79Br], 466 (15) [M

+,

79Br], 378 (11.5), 377 (49), 376 (13), 375 (48),

191 (17), 91 (100), 44 (13); HRMS (EI) m/z calcd for C28H2379

BrN2 466.1045,

found 466.1042; calcd for C28H2381

BrN2 468.1024, found 468.1022.

N,N-Dibenzyl-5-methyl-3-phenylindolizin-1-amine (4cga):

yellow oil (247 mg, 61%); tR 29.11; Rf 0.73 (hexane/EtOAc,

8:2); IR (neat) ῦ 3079, 3066, 3027, 2925, 2827, 1599, 1492,

1472, 1451, 1292, 1070, 748, 696; 1H NMR (300 MHz,

CDCl3) δ 2.01(s, 3H), 4.17 (s, 4H), 6.13 (d, J = 6.5 Hz, 1H), 6.48 (dd, J = 8.8,

6.5 Hz, 1H), 6.55 (s, 1H), 7.14–7.29 (m, 11H), 7.37 (d, J = 7.0 Hz, 1H), 7.49

(d, J = 8.9 Hz, 1H); 13

C NMR (75 MHz, CDCl3) δ 23.0, 59.4, 111.4, 111.9,

114.7, 115.6, 126.7, 126.8, 127.0, 128.0, 128.6, 130.9, 123.5, 127.2, 134.0,

136.0, 139.6; MS (EI) m/z 402 (M+, 0.3), 311 (23), 310 (99), 309 (39), 295

(10), 281 (18), 221 (10), 209 (13), 208 (24), 207 (100), 191 (17), 91 (26);

HRMS (ESI) m/z: [M]+ Calcd for C29H26N2 402.2096; Found 402.2093.

N,N-Dibenzyl-5-methyl-3-(p-tolyl)indolizin-1-amine (4cgb).

Yellow oil; Rf 0.76 (hexane/EtOAc, 8:2); IR (neat) ῦ 3024,

2973, 2919, 2821, 2796, 1453, 1292, 1146, 1119, 1070, 820,

754, 739, 694; 1H NMR (400 MHz, C6D6) δ 3.27(s, 3H; CH3),

4.20 (s, 4H; 2 × CH2), 5.92 (d, J = 6.4 Hz, 1H; ArH), 6.44 (dd,

J= 8.9, 6.4, 1H; ArH) 6.62, 6.99 (system AA’XX’, J = 8.7 Hz,

4H, 4 × ArH), 6.66 (s, 1H; ArH); 7.05 (t, J= 7.4, 2H; 2 ×

ArH), 7.14 – 7.18 (m, 4H; 4 × ArH), 7.45 (d, J= 6.4 Hz, 4H; 4 × ArH), 7.69

(d, J= 8.9 Hz, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ 22.9, 54.8 (2 × CH3),

Experimental Part

191

60.2 (2 × CH2), 111.6, 112.3, 112.4, 115.1, 116.2, 127.1, 128.5, 128.9, 132.6

(18 × ArCH), 123.9, 127.3, 128.6, 128.8, 134.3, 140.2, 159.4 (8 × ArC); MS

(70 eV) m/z (%) 416 (M+, 25), 326 (25), 325 (100), 91 (68); HRMS (EI) m/z

calcd for C30H28N2 416.2252, found 416.2262.

N,N-Dibenzyl-3-(4-methoxyphenyl)-5-methylindolizin-1-

amine (4cgc). Yellow oil; Rf 0.68 (hexane/EtOAc, 8:2); IR

(neat) ῦ 3030, 3001, 2934, 2837, 1605, 1506, 1291, 1245,

1149, 1029, 832, 743, 699; 1H NMR (400 MHz, C6D6) δ

1.79 (s, 3H, CH3), 2.10 (s, 3H, CH3), 4.20 (s, 4H; 2 × CH2),

5.93 (d, J = 6.4 Hz, 1H; ArH), 6.45 (dd, J= 8.9, 6.4 Hz, 1H;

ArH) 6.67 (s, 1H; ArH); 6.84 (d, J= 7.8, 2H; 2 × ArH), 6.99

(d, J = 8.0 Hz, 2H; 2 × ArH), 7.06 (t, J = 7.3 Hz, 2H; 2 × ArH), 7.14 – 7.18

(m, 4H; 4 × ArH), 7.45 (d, J= 7.2 H, 2H; 2 × ArH), 7.70 (d, J = 8.9 Hz, 1H;

ArH); 13

C NMR (101 MHz, C6D6) δ 21.2, 23.0 (2 × CH3), 60.2 (2 × CH2),

111.7, 112.4, 115.2, 116.1, 127.1, 127.7, 128.5, 129.0, 131.3 (18 × ArCH),

124.1, 127.5, 128.9, 133.6, 134.3, 136.7, 140.2 (8 × ArC); MS (70 eV) m/z (%)

433 (M++1, 10), 432 (M

+, 28), 342 (25), 341 (100), 91 (79); HRMS (EI) m/z

calcd for C30H28N2O 432.2202, found 432.2204

N,N-Dibenzyl-5-methyl-3-[4-

(trifluoromethyl)phenyl]indolizin-1-amine (4cgd). Brown

oil; Rf 0.54 (hexane/EtOAc, 8:2); IR (neat) ῦ 3085, 3061,

3029, 2925, 2850, 2802, 1614, 1453, 1432, 1321, 1164,

1120, 1064, 846, 741, 696; 1H NMR [300 MHz, (CD3)2CO] δ

2.04 (s, 3H; CH3), 4.19 (s, 4H; 2 × CH2), 6.32 (d, J= 6.4 Hz,

1H; ArH), 6.62 (dd, J= 8.8, 6.6 Hz, 1H; ArH), 6.79 (s, 1H;

ArH), 7.14–7.79 (m, 15H; 15 × ArH); 13

C NMR [75 MHz, (CD3)2CO] δ 23.4

(CH3) 60.5 (2 × CH2), 113.3, 113.6, 116.3, 116.8, 127.6, 128.9, 129.4, 131.5

(16 × ArCH), 124.7 (q, 3JC-F =3.6 Hz; 2 × HCCCF3), 129.2 (q,

2JC-F = 27.0 Hz;

CCF3), 122.7, 128.4, 129.2, 130.6, 134.7, 140.5 (6 × ArC); MS (70 eV) m/z

(%) 471 (8) [M+], 470 (23) [M], 380 (25), 379 (100), 275 (8), 91 (59); HRMS

(EI) m/z calcd for C30H25F3N2 470.1970, found 470.1982.

Experimental Part

192

Methyl 4-(1-(dibenzylamino)-5-methylindolizin-3-

yl)benzoate (4cge). Yellow oil; Rf 0.52 (hexane/EtOAc,

8:2); IR (neat) ῦ 3060, 3026, 2949, 2925, 1718, 1603,

1518, 1433, 1273, 1101, 748, 697; 1H NMR (300 MHz,

C6D6) δ 2.06 (s, 3H; CH3), 3.93 (s, 3H; CH3), 4.18 (s, 4H;

2 × CH2), 6.24 (d, J= 6.5 Hz, 1H; ArH),6.57 (dd, J= 8.7,

6.5 Hz, 1H; ArH), 6.61 (s, 1H; ArH), 7.16 – 7.22 (m, 2H;

ArH), 7.24 – 7.29 (m, 4H; ArH), 7.34, 7.99 (AA’BB’ system, J= 8.5 Hz, 4H;

4 ×ArH), 7.35 – 7.38 (m, 4H; ArH), 7.51 (d, J= 8.5 Hz, 1H; ArH); 13

C NMR

(101 MHz, CDCl3) δ 23.5, 52.3 (2 × CH3) 59.5 (2 × CH2), 112.3, 112.9, 115.7,

115.8, 126.9, 128.2, 128.3, 128.7, 130.0 (18 × ArCH), 122.4, 128.0, 128.1,

129.4, 134.0, 139.6, 140.4, 167.2 (9 × ArC); MS (70 eV) m/z (%) 461 (M+ + 1,

7), 460 (M+ , 21), 370 (26), 369 (100), 91 (62); HRMS (EI) m/z calcd for

C31H28N2O2 460.2151, found 460.2160.

N,5-Dimethyl-N,3-diphenylindolizin-1-amine (1l). Yellow

oil; tR 18.99; Rf 0.72 (hexane/EtOAc, 8:2); IR (neat) ῦ 3054,

3023, 2923, 2808, 1597, 1496, 1477, 1293, 1110, 762, 747,

691; 1H NMR (400 MHz, C6D6) δ 1.84 (s, 3H; CH3), 3.17 (s,

3H; CH3), 5.93 (d, J = 6.5 Hz, 1H; ArH), 6.37 (dd, J = 8.9, 6.5

Hz, 1H; ArH), 6.64 (s, 1H; ArH), 6.78–6.81 (m, 1H; ArH), 6.87–6.89 (m, 2H;

2 × ArH), 7.03–7.07 (m, 3H; 2 × ArH), 7.14–7.23 (m, 5H; 5 × ArH); 13

C NMR

(101 MHz, C6D6) δ 22.9, 40.7 (2 × CH3), 112.7, 113.7, 115.3, 115.9, 116.9,

117.4, 127.2, 127.4, 129.3, 131.3 (14 × CH), 122.9, 125.1, 130.4, 134.9, 136.0,

150.9 (6 × ArC); MS (70 eV) m/z 313 (M++1, 24), 312 (M

+, 100), 311 (32),

298 (12), 297 (49), 235 (12), 204 (11), 195 (44), 156 (15), 148 (13), 102 (10),

92 (31), 77 (39), 65 (17). HRMS (EI) m/z calcd for C22H20N2 312.1626, found

312.1618.

N,N-Dibenzyl-5-[4-(methylsulfonyl)phenyl]-3-

phenylindolizin-1-amine (4dga). Dark orange oil; Rf 0.54

(hexane/EtOAc, 6:4); IR (neat) ῦ 3028, 2954, 2919, 2849,

Experimental Part

193

1453, 1314, 1149, 768, 754, 698; 1H NMR [300 MHz, (CD3)2CO] δ 2.99 (s,

3H, CH3), 4.27 (s, 4H, 2 × CH2), 6.55 (dd, J = 6.6, 1.3, 1H; ArH); 6.72–6.84

(m, 4H, 4 × ArH), 6.92–6.97 (m, 3H; ArH), 7.16–7.52 (m, 14H; 14 × ArH),

7.74 (dd, J = 8.9, 1.3 Hz, 1H; ArH); 13

C NMR [75 MHz, (CD3)2CO] δ 44.8

(CH3), 60.4 (2 × CH2), 111.9, 115.8, 116.9, 118.5, 126.6, 127.3, 127.7, 128.1,

128.9, 129.2, 129.4 (23 × ArCH), 125.1, 129.8, 130.0, 135.0, 135.3, 140.5,

140.6, 142.2 (9 × ArC); MS (70 eV) m/z (%) 542 [M+] (16), 452 (18), 451

(68), 355 (15), 91 (100), 44 (55); HRMS (EI) m/z calcd for C35H30N2O2S

542.2028, found 542.2002

1-Phenyl-3-(piperidin-1-yl)pyrrolo[1,2-a]quinoline

(4eaa). Yellow solid; m.p. 107.1–110.2 ºC; Rf 0.66

(hexane/EtOAc, 8:2); tr 20.37; IR (neat) ῦ 3050, 2920,

2853, 2794, 1491, 1448, 1375, 1319, 1123, 781, 746,

696; 1H NMR (300 MHz, CDCl3) δ 1.58 (quintet, J = 5.7, 2H; NCH2CH2CH2),

1.81 (quintet, J = 5.7, 4H; 2 × NCH2CH2), 3.04 (t, J = 5.3, 4H; 2 × NCH2),

6.52 (s, 1H; ArH), 8.85 (d, J = 9.3, 1H; ArH), 6.99–7.08 (m, 1H; ArH), 7.16

(td, J = 7.4, 1.2, 1H; ArH), 7.33–7.57 (m, 8H; 8 × ArH); 13

C NMR (75 MHz,

CDCl3) δ 24.4, 26.5, 55.6 (5 × CH2), 108.5, 116.7, 117.7, 117.9, 123.3, 126.1,

127.5, 128.3, 128.6, 129.2 (10 × ArCH), 123.9, 127.7, 134.2, 135.8 (ArC); MS

(70 eV) m/z (%) 327 (25) [M++1], 326 (100) [M

+], 325 (11), 284 (10), 283

(11), 269 (12), 241 (11), 128 (14), 121 (17); HRMS (EI) m/z calcd for

C23H22N2 326.1783, found 326.1784.

N,N-Dibutyl-1-phenylpyrrolo[1,2-a]quinolin-3-amine

(4eca). Yellow oil; Rf 0.74 (hexane/EtOAc, 8:2); tr

18.45; IR (neat) ῦ 3060, 2954, 2929, 2858, 2803, 1490,

1447, 1361, 1315, 1111, 792, 746, 701; 1H NMR (300

MHz, CDCl3) δ 0.87 (t, J = 7.2, 6H; 2 × CH3), 1.20–1.58 (m, 8H; 4 × CH2),

2.79–3.16 (m, 4H; 2 × CH2), 6.56 (s, 1H; ArH), 6.78–6.94 (d, J = 8.7, 1H;

ArH), 7.05 (dt, J = 7.2, 0.9, 1H; ArH), 7.15 (dt, J = 7.4, 0.9, 1H; ArH), 7.31–

7.62 (m, 8H; 8 × ArH); 13

C NMR (75 MHz, CDCl3) δ 14.2 (2 × CH3), 20.6,

30.4, 56.9 (6 × CH2), 110.9, 117.8, 123.2, 126.1, 127.5, 128.4, 128.6, 129.3

Experimental Part

194

(12 × ArCH), 116.9, 133.4, 134.3, 135.9 (ArC); MS (70 eV) m/z (%) 371 (29)

[M++1], 370 (100) [M

+], 328 (13), 327 (48), 313 (19), 285 (41), 271 (23), 270

(57), 269 (20), 244 (13), 243 (14), 242 (12), 241 (17), 155 (12), 142 (13), 128

(22); HRMS (EI) m/z calcd for C26H30N2 370.2409, found 370.2423.

N,N-Dibenzyl-1-phenylpyrrolo[1,2-a]quinolin-3-

amine (4ega). Orange oil; Rf 0.64 (hexane/EtOAc, 8:2);

IR (neat) ῦ 3059, 3026, 2922, 2827, 1558, 1492, 1450,

1360, 1317, 1071, 1027, 962, 906, 739, 695; 1H NMR

(400 MHz, C6D6) δ 4.29 (s, 4H; 2 × CH2), 6.66 (s, 1H; ArH), 6.78 (d, J = 9.3,

1H; ArH), 6.83 (m, 1H; ArH), 6.99 (t, J = 7.5, 1H; ArH), 7.16 – 7.23 (m, 5H;

ArH), 7.25 – 7.29 (m, 4H; ArH), 7.35 (dd, J = 7.8, 1.6, 1H; ArH), 7.39 (dd, J =

7.8, 1.2, 1H; ArH), 7.51 (d, J = 7.3, 4H; ArH), 7.59 (d, J = 8.5, 1H; ArH), 7.65

(d, J = 9.3, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ 59.9 (2 × CH2), 111.2,

117.4, 117.9, 118.0, 123.4, 126.4, 127.3, 127.6, 128.6, 128.7, 128.9, 129.6 (22

× ArCH), 126.1, 126.5, 131.1, 134.7, 136.2, 139.8(8 × ArC); MS (70 eV) m/z

(%) 439 (M++1, 9) 438 (M

+, 27), 348 (26), 347 (100), 243 (13), 91 (44);

HRMS (EI) m/z calcd for C32H26N2 438.2096, found 438.2097.

3-Butyl-1-(piperidin-1-yl)indolizine (4aai): yellow oil (383

mg, 75%); tR 13.20; Rf 0.68 (hexane/EtOAc, 8:2); IR (neat) ῦ

2930, 2855, 2786, 1625, 1533, 1425, 1314, 1091, 733, 716; 1H

NMR (400 MHz, C6D6) δ 0.85 (t, J = 7.4 Hz, 3H; CH3), 1.23 –

1.32 (m, 2H; CH2), 1.46 – 1.54 (m, 4H; CH2), 1.67 – 1.73 (m,

4H; CH2), 2.43 – 2.47 (m, 2H; CH2), 2.99 – 3.02 (m, 4H; CH2),

6.15 – 6.18 (m, 1H; ArH), 6.35 (dd, J = 8.9, 6.4 Hz, 1H; ArH),

6.50 (s, 1H; ArH), 7.21 (d, J = 7.1 Hz, 1H; ArH), 7.57 (d, J = 9.0 Hz, 1H;

ArH); 13

C NMR (101 MHz, C6D6) δ 14.2 (CH3), 23.0, 24.9, 25.9, 27.2, 29.8,

56.0 (8 × CH2), 104.3, 110.1, 112.7, 118.4, 121.1 (5 × ArCH), 121.6, 124.3,

130.5 (3 × ArC); MS (EI) m/z 257 (M+ +1, 17), 256 (M

+, 86) 254 (17), 214

(19), 213 (100), 211 (11), 157 (36), 131 (10), 130 (26), 105 (10), 78 (19);

HRMS (ESI) m/z: [M + H]+ Calcd for C17H24N2 256.1939; Found 256.1935.

Experimental Part

195

N,N,3-Tributylindolizin-1-amine (4aci): yellow oil (214 mg,

37%); tR 12.94; Rf 0.80 (hexane/EtOAc, 8:2); IR (neat) ῦ 2955,

2929, 2870, 1527, 1457, 1375, 1339, 1314, 1088, 805, 740,

719; 1H NMR (400 MHz, C6D6) δ 0.82 – 0.87 (m, 9H; CH3).

1.22 – 1.31 (m, 2H; CH2), 1.34 – 1.43 (m, 4H; CH2), 149 –

1.56 (m, 6H; CH2), 2.44 – 2.48 (m, 2H; CH2), 3.02 – 3.05 (m, 4H; CH2), 6.13

– 6.17 (m, 1H; ArH), 6.41 (ddd, J = 9.0, 6.3, 0.8 Hz, 1H; ArH), 6.59 (s, 1H;

ArH), 7.20 (d, J = 7.1 Hz, 1H; ArH), 7.67 (dt, J = 9.0, 1.2 Hz; 1H; ArH); 13

C

NMR (101 MHz, C6D6) δ 14.1, 14.4 (2 × CH3), 21.0, 23.0, 26.0, 29.8, 31.0,

57.8 (9 × CH2), 106.6, 110.0, 113.7, 118.2, 121.3 (5 × ArCH), 122.4, 126.5,

128.2 (3 × ArC); MS (EI) m/z 301 (M+ + 1, 14), 300 (M

+, 73), 258 (12), 257

(45), 243 (33), 215 (36), 201 (25), 200 (13), 199 (11), 186 (11), 183 (10), 171

(12), 157 (100), 156 (12), 143 (12), 130 (28), 105 (19), 78 (10), 57 (17);


N-Benzyl-3-butyl-N-methylindolizin-1-amine (4adi):


8:2); IR (neat) ῦ 3060, 3028, 2955, 2929, 2868, 1529, 1454,

1406, 1061, 948, 798, 733, 698; 1H NMR (400 MHz, C6D6) δ

0.95 (t, J = 7.3 Hz, 3H; CH3), 1.36 (dq, J = 14.6, 7.3 Hz, 2H;

CH2), 1.57 – 1.63 (m, 2H; CH2), 2.50 – 2.54 (m, 2H; CH2), 2.83 (s, 3H; CH3),

4.23 (s, 2H; CH2), 6.24 – 6.28 (m, 1H; ArH), 6.45 (ddd, J = 9.0, 6.3, 0.8 Hz,

1H; ArH), 6.56 (s, 1H; ArH), 7.19 – 7.23 (m, 1H; ArH), 7.27 – 7.32 (m, 3H;

ArH), 7.53 – 7.55 (m, 2H; ArH), 7.70 (dt, J = 9.0, 1.2 Hz, 1H; ArH); 13

C NMR

(101 MHz, C6D6) δ 14.1 (CH3), 22.9, 25.9, 29.7 (3 × CH2), 43.3 (CH3), 63.5

(CH2), 105.0, 110.1, 112.9, 118.3, 121.2, 127.2, 128.5, 128.9 (10 × ArCH),

121.7, 124.5, 129.4, 140.2 (4 × ArC); MS (EI) m/z 292 (M+, 28), 202 (13), 201

(100), 158 (11), 157 (28), 119 (19), 92 (17), 91 (48), 78 (15), 65 (16); HRMS

(ESI) m/z: [M + H]+ Calcd for C20H24N2 292.1939; Found 292.1939.

3-Butyl-N-methyl-N-phenylindolizin-1-amine (4afi):


8:2); IR (neat) ῦ 3019, 2952, 2927, 2860, 1595, 1556, 1497,

Experimental Part

196

1314, 1148, 1081, 950, 739, 692; 1H NMR (400 MHz, C6D6) δ 0.95 (t, J = 7.3

Hz, 3H; CH3), 1.31 – 1.41 (m, 2H; CH2), 1.55 – 1.62 (m, 2H; CH2), 2.51 –

2.55 (m, 2H; CH2), 3.27 (s, 3H; CH3), 6.23 – 6.27 (m, 1H; ArH), 6.40 – 6.44

(m, 1H; ArH), 6.52 (s, 1H; ArH), 6.89 (t, J = 7.2 Hz, 1H; ArH), 6.93 – 6.95

(m, 2H; ArH), 7.23 – 7.34 (m, 4H; ArH); 13

C NMR (75 MHz, C6D6) δ 14.1

(CH3), 22.9, 25.8, 29.6 (3 × CH2), 40.8 (CH3), 110.0, 110.3, 113.6, 115.1,

117.2, 117.7, 121.7, 129.2 (10 × ArCH), 122.1, 123.1, 127.3, 151.1 (4 × ArC);

MS (EI) m/z 279 (M+ + 1, 16), 278 (M+, 72), 263 (17), 236 (19), 235 (100),

220 (29), 181 (15), 117 (11), 77 (12); HRMS (ESI) m/z: [M + H]+ Calcd for

C19H22N2 278.1783; Found 278.1782.

N,N-Dibenzyl-3-butylindolizin-1-amine (4agi): yellow solid;

(736 mg, 69%); tR 21.76; Rf 0.76 (hexane/EtOAc, 8:2); m.p.

55.8–57.6 ºC; IR (neat) ῦ 3023, 2952, 2921, 2823, 2796, 1623,

1551, 1450, 1427, 1344, 1316, 1244, 1148, 1027, 1001, 978,

809, 727, 696; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 7.3

Hz, 3H; CH3), 1.34 (dq, J = 14.5, 7.3 Hz, 2H; CH2), 1.28–1.41 (m, 2H; CH2),

2.68 (t, J = 7.3 Hz, 2H; CH2), 4.15 (s, 4H; 2 × CH2), 6.35–6.42 (m, 3H; 3 ×

ArH), 7.14–7.26 (m, 6H; 6 × ArH), 7.33 (d, J = 7.2 Hz, 4H; 4 × ArH), 7.40 (d,

J = 8.3 Hz, 1H; ArH), 7.51 (d, J = 6.6 Hz, 1H; ArH); 13

C NMR (75 MHz,

CDCl3) δ 14.1 (CH3) 22.6, 25.7, 29.4, 59.6 (5 × CH2), 106.3, 109.8, 112.9,

117.7, 121.1, 126.8, 128.1, 128.8 (15 × CH), 121.8, 125.1, 126.5, 139.9 (5 ×

ArC); MS (GC) m/z 369 (M++1, 8), 368 (M

+, 31), 278 (23), 277 (100), 233

(20), 130 (13), 91 (19). HRMS (EI) m/z calcd for C26H28N2 368.2252, found

368.2257.

N,N-Dibenzyl-3-propylindolizin-1-amine (4agj): yellow

solid (184 mg, 26%); tR 19.49; Rf 0.76 (hexane/EtOAc, 8:2);

IR (neat) ῦ 3074, 3024, 2958, 2924, 2870, 2796, 1624, 1542,

1492, 1452, 1424, 1341, 1315, 1235, 1138, 1065, 989, 938,

797, 731, 694; 1H NMR (400 MHz, C6D6) δ 0.79 (t, J = 7.4

Hz, 3H; CH3), 1.39 – 1.49 (m, 2H; CH2), 2.25 (t, J = 7.5 Hz, 2H; CH2), 4.19

(s, 4H; 2 CH2), 6.07 – 6.11 (m, 1H; ArH), 6.34 (ddd, J = 9.0, 6.3, 0.7 Hz,

Experimental Part

197

1H; ArH), 6.38 (s, 1H; ArH), 7.03 – 7.06 (m, 3H; 3 × ArH), 7.12 – 7.16 (m,

4H; ArH), 7.40 (d, J = 7.4 Hz, 1H; 4 ArH), 7.54 (dt, J = 9.0, 1.1 Hz, 1H;

ArH); 13

C NMR (101 MHz, C6D6) δ 14.0 (CH3), 20.7, 28.0, 60.2 (4 × CH2),

106.7, 109.9, 113.4, 118.0, 121.2, 127.1, 128.4, 129.0 (15 × ArCH), 121.2,

125.8, 126.6, 140.2 (5 × ArC); MS (EI) m/z 354 (M+, 29), 263 (100), 233 (41),

157 (16), 130 (23), 92 (11), 91 (99), 78 (14), 65 (20); HRMS (ESI) m/z: [M +

H]+ Calcd for C25H26N2 354.2096; Found 354.2097.

N,N-Dibenzyl-3-hexylindolizin-1-amine (4agk): yellow solid

(277 mg, 35%); tR 25.67; Rf 0.81 (hexane/EtOAc, 8:2); IR

(neat) ῦ 3026, 2953, 2925, 2854, 2798, 2782, 1622, 1545,

1493, 1455, 1423, 1312, 1237, 1143, 1075, 940, 792, 730, 695; 1H NMR (400 MHz, C6D6) δ 0.89 (t, J = 7.1 Hz, 3H; CH3),

1.16 – 1.26 (m, 6H; 3 CH2), 1.45 – 1.49 (m, 2H; CH2), 2.32 (t, J =7.6 Hz,

2H; CH2), 4.20 (s, 4H; 2 CH2), 6.09 – 6.12 (m, 1H; ArH), 6.34 (ddd, J = 9.0,

6.3, 0.8 Hz, 1H; ArH), 6.42 (s, 1H; ArH), 7.03 – 7.09 (m, 1H; ArH), 7.09 (d, J

= 7.2, 1H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.39 – 7.41 (m, 4H; ArH), 7.55

(dt, J = 9.0, 1.1 Hz, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ 14.4 (CH3), 23.1,

26.1, 27.4, 29.5, 32.0, 60.2 (7 × CH2), 106.6, 110.0, 113.4, 118.0, 121.2,

127.1, 128.4, 129.0 (15 × ArCH), 121.9, 125.7, 126.7, 140.2 (5 × ArC); MS

(EI) m/z 396 (M+, 10), 306 (22), 305 (100), 233 (26), 130 (13), 106 (13), 105

(23), 91 (78), 78 (13), 77 (23), 62 (22), 51 (14); HRMS (ESI) m/z: [M + H]+

Calcd for C28H32N2 396.2565; Found 396.2564.

N,N-Dibenzyl-3-(4-chlorobutyl)indolizin-1-amine (4agl):

yellow oil (161 mg, 20%); Rf 0.68 (hexane/EtOAc, 8:2); IR

(neat) ῦ 3066, 3027, 2925, 2827, 1599, 1492, 1472, 1451,

1292, 1070, 748, 696; 1H NMR (400 MHz, C6D6) δ 1.31 –

1.38 (m, 4H; CH2), 2.14 (t, J = 7.0 Hz, 2H; CH2), 3.01 (t, J =

6.4 Hz, 2H; CH2), 4.18 (s, 4H; 2 CH2), 6.08 – 6.12 (m, 1H; ArH), 6.30 (s,

1H; ArH), 6.34 (ddd, J = 9.0, 6.3, 0.7 Hz, 1H; ArH), 6.99 (d, J = 7.1 Hz, 1H;

ArH), 7.03 – 7.07 (m, 1H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.38 – 7.40 (m,

4H; ArH), 7.54 (dt, J = 9.0, 1.1 Hz, 1H; ArH); 13

C NMR (101 MHz, C6D6) δ

Experimental Part

198

24.4, 25.0, 32.3, 44.6, 60.2 (6 × CH2), 106.9, 110.1, 113.5. 118.0, 121.2,

127.1, 128.4, 129.0 (15 × ArCH), 120.8, 125.9, 126.6, 140.1 (5 × ArC); MS

(EI) m/z 404 (M+, 8), 402 (22), 313 (35), 312 (23), 311 (100), 233 (25), 130

(18), 91 (35), 43 (19); HRMS (ESI) m/z: [M + H]+ Calcd for C26H27ClN2

402.1863; Found 402.1864.

4-(1-(Dibenzylamino)indolizin-3-yl)butanenitrile (4agm):

yellow solid, m.p. 133.2 – 135.8 (265 mg, 35%); Rf 0.42


1492, 1451, 1428, 1359, 1345, 1318, 1243, 1150, 979, 813,

732, 700; 1H NMR (400 MHz, C6D6) δ 1.09 – 1.16 (m, 2H;

CH2), 1.28 (t, J = 7.2 Hz, 2H; CH2), 2.13 (t, J = 7.2 Hz, 2H; CH2), 4.14 (s, 4H;

2 CH2), 6.04 – 6.07 (m, 1H; ArH), 6.19 (s, 1H; ArH), 6.30 – 6.34 (m, 1H;

ArH), 6.84 (d, J = 7.1 Hz, 1H; ArH), 7.03 – 7.05 (m, 2H; ArH), 7.11 – 7.16

(m, 4H; ArH), 7.37 (d, J = 7.1 Hz, 4H; ArH), 7.50 (dt, J = 9.0, 1.1 Hz, 1H;

ArH); 13

C NMR (101 MHz, C6D6) δ 15.9, 22.9, 24.3, 60.2 (5 × CH2), 107.4,

110.3, 113.8, 118.0, 121.0, 127.2, 128.4, 128.9 (15 × ArCH), 118.7, 119.2,

126.2, 126.5, 139.9 (6 × ArC); MS (EI) m/z 379 (M+, 29), 289 (22), 288 (100),

233 (17), 130 (21), 91 (26); HRMS (ESI) m/z: [M + H]+ Calcd for C26H25N3

379.2048; Found 379.2052.

N,N-Dibenzyl-3-butyl-5-methylindolizin-1-amine (4cgi):


8:2); IR (neat) ῦ 3064, 3025, 2956, 2930, 2870, 1538, 1452,

1428, 1359, 1029, 733, 698; 1H NMR (500 MHz, C6D6) δ 0.82

(t, J =7.4 Hz, 3H; CH3), 1.12 – 1.20 (m, 2H; CH2), 1.37 – 1.46

(m, 2H; CH2), 2.16 (s, 3H; CH3), 2.73 – 2.76 (m, 2H; CH2), 4.19 (s, 4H; 2

CH2), 5.83 (d, J = 6.4 Hz, 1H; ArH), 6.32 (dd, J = 8.9, 6.4 Hz, 1H; ArH), 6.41

(s, 1H; ArH), 7.03 – 7.06 (m, 2H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.42 – 7.43

(m, 4H; ArH), 7.57 (d, J = 8.9, 1H; ArH); 13

C NMR (126 MHz, C6D6) δ 14.2,

21.6 (2 CH3), 22.5, 29.7, 33.6, 60.2 (5 × CH2), 109.3, 112.2, 114.0, 116.2,

127.0, 128.4, 129.0 (14 × ArCH), 124.6, 126.5, 128.8, 133.8, 140.2 (6 × ArC);

MS (EI) m/z 382 (M+, 10), 292 (18), 291 (74), 106 (15), 92 (15), 91 (100), 77

Experimental Part

199

(14), 65 (16); HRMS (ESI) m/z: [M + H]+ Calcd for C27H30N2 382.2409;

Found 382.2404.

N,N-Dibenzyl-1-(6-bromopyridin-2-yl)-3-phenylprop-

2-yn-1-amine (5bga). Yellow solid; Rf 0.54

(hexane/EtOAc, 8:2); m.p. 92–96 ºC; IR (neat) ῦ 3081,

3060, 3024, 3002, 2926, 2893, 2840, 1597, 1579, 1552,

1121, 986, 795, 752, 732, 697, 687; 1H NMR (300 MHz,

CDCl3) δ 3.74, 3.85 (AB system, J = 13.5, 4H; 2 × CH2), 5.05 (s, 1H; NCH),

7.24–7.70 (m, 18H; 18 × ArH); 13

C NMR (75 MHz, CDCl3) δ 55.0 (2 × CH2),

58.1 (NCH), 84.3, 88.2 (C≡C), 121.5, 126.8, 127.1, 128.3, 128.8, 132.0, 138.5

(18 × ArCH), 123.1, 139.0, 141.5, 160.1 (5 × ArC); MS (70 eV) m/z (%)469

(5) [M++1,

81Br], 468 (17) [M

+,

81Br], 467 (5) [M

++1,

79Br], 466 (17) [M

+,

79Br], 375 (52), 295 (9), 191 (18), 91 (100); HRMS (EI) m/z calcd for

C28H2379

BrN2 466.1045, found 466.1039; calcd for C28H2381

BrN2 468.1024,

found 468.1028.

Experimental Part

200

EXPERIMENTAL PART OF CHAPTER II

General procedure for the hydrogenation of indolizines 4 catalyzed by

PtO2.

The indolizine 4 (0.5 mmol) was poured into the hydrogenation flask,

followed by the addition of PtO2 (11.4 mg, 10 mol%) and glacial HOAc (3

mL), with this mixture being subjected to hydrogenation at 3.74 atm (55 psi)

and ambient temperature. The reaction was monitored by TLC and/or GLC

until total or steady conversion of the starting material (see Table 3.1). The

catalyst was separated by filtration and the solvent was removed under

vacuum. Purification of the reaction crude by column chromatography (silica

gel, hexane/EtOAc) afforded the pure indolizidines 7 as single

diastereoisomers.

(1R*,3R

*,8aR

*)-3-Phenyl-1-(piperidin-1-

yl)octahydroindolizine (7aaa): yellow solid (83 mg, 58%); tR

12.62; Rf 0.40 (hexane/EtOAc, 4:6); mp 68.9–70.9 ºC (EtOH);

IR (neat) ῦ 3084, 3050, 3030, 2929, 2851, 2789, 2789, 1601,

1439, 1364, 1260, 1142, 1126, 1105, 863, 755, 698; 1H NMR

(400 MHz, CDCl3) δ 1.13–1.26, 1.34–1.66, 1.71–1.85, 1.98–

2.11, 2.29–2.40, 2.67–2.86, 3.11–3.32 (7m, 22H), 2.96 (t, J = 8.7 Hz, 1H),

7.19–7.25, 7.28–7.44 (2m, 5H); 13

C NMR (101 MHz, CDCl3) δ 24.7, 24.8,

25.6, 26.3, 26.6, 31.7, 51.7, 52.9, 65.3, 68.9, 70.2, 126.8, 127.4, 128.4, 143.8;

MS (EI) m/z 284 (M+, 9), 201 (13), 174 (10), 173 (76), 172 (100), 110 (44);


(1R*,3R

*,8aR

*)-1-(Piperidin-1-yl)-3-(p-

tolyl)octahydroindolizine (7aab): brown oil (52 mg, 35%); tR

13.14; Rf 0.40 (hexane/EtOAc, 1:1); IR (neat) ῦ 3046, 3009,

2927, 2851, 2786, 2747, 1512, 1439, 1260, 1143, 1126, 1105,

1036, 863, 813, 797, 735; 1H NMR (300 MHz, CDCl3) δ 1.15–

1.86 (m, 14H), 1.92–2.08 (m, 2H), 2.27–2.40 (m, 5H), 2.63–

2.86 (m, 3H), 2.92 (t, J = 8.7Hz, 1H), 3.16 (ddd, m, J = 9.0 Hz,

Experimental Part

201

7.4, 3.8, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H); 13

C NMR (75

MHz, CDCl3) δ 21.2, 24.8, 24.9, 25.6, 26.4, 26.6, 31.7, 51.8, 52.9, 65.4, 69.0,

70.0, 127.3, 129.1, 136.3, 140.9; MS (EI) m/z 298 (M+, 6), 215 (12), 188 (10),

187 (71), 186 (100), 110 (45); HRMS (ESI) m/z: [M + H]+ Calcd for C20H31N2

299.2487; Found 299.2500.

(1R*,3R

*,8aR

*)-3-(4-Methoxyphenyl)-1-(piperidin-1-

yl)octahydroindolizine (7aac): this compound was isolated

together with an inseparable impurity as a brown oil (71 mg,

aprox. 45%); tR 14.20; Rf 0.42 (hexane/EtOAc, 4:6); IR

(neat) ῦ 3060, 2991, 2930, 2852, 2785, 2749, 1611, 1509,

1439, 1300, 1242, 1179, 1170, 1143, 1126, 1101, 1036, 828,

798; Selected NMR data: 1H NMR (400 MHz, CDCl3) δ

1.06–1.91 (m, 15H), 1.94–2.09 (m, 2H), 2.26–2.49 (m, 2H),

2.73–2.81 (m, 2H), 2.91 (t, J = 8.7 Hz, 1H), 3.12–3.30 (m, 1H), 3.80 (s, 3H),

6.84–6.89 (m, 2H), 7.21–7.32 (m, 2H); 13

CNMR (101 MHz, CDCl3) δ 24.7,

24.8, 25.6, 26.2, 26.6, 31.7, 51.7, 52.8, 55.4, 65.2, 68.9, 69.7, 113.8, 128.4,

135.8, 158.6; MS (EI) m/z 314 (M+, 6), 231 (15), 204 (11), 203 (76), 202

(100), 110 (47); HRMS (ESI) m/z: [M + H]+ Calcd for C20H31N2O 315.2436;

Found 315.2435.

4-[(1R*,3R

*,8aR

*)-3-Phenyloctahydroindolizin-1-

yl]morpholine (7aba): yellow solid (97 mg, 68%); tR 12.69; Rf

0.34 (hexane/EtOAc, 8:2); mp 53.7–55.7 ºC (EtOH); IR (neat)

ῦ 3079, 3060, 3030, 2939, 2849, 2802, 2749, 1603, 1448, 1258,

1136, 1114, 998, 866, 755, 699; 1H NMR (300 MHz, CDCl3) δ

1.16–1.28, 1.34–1.38, 1.50–1.69, 1.71–1.88, 2.00–2.12, 2.31–

2.51, 2.73–2.91 (7m, 15H; 7 × CH2, CH), 2.30 (t, J = 8.7 Hz, 1H; CH), 3.06–

3.23 (m, 1H; CH), 3.66–3.77 (m, 4H; 2 × CH2), 7.21–7.36 (m, 5H; 5 × ArH); 13

C NMR (75 MHz, CDCl3) δ 24.6, 25.6, 26.7, 31.8, 51.1, 52.9, 67.4 (9 ×

CH2), 65.1, 68.9, 70.2 (3 × CH), 126.9, 127.3, 128.5 (5 × ArCH), 143.5 (ArC);

MS (EI) m/z 286 (M+, 3), 203 (14), 173 (71), 172 (100), 112 (41), 104 (10);

Experimental Part

202

Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78. Found: C, 75.88; H,

9.28; N 9.94.

(1R*,3R

*,8aR

*)-N,N-Dibutyl-3-phenyloctahydroindolizin-1-

amine (7aca): brown oil (108 mg, 66%); tR 12.74; Rf 0.54


2792, 1601, 1492, 1451, 1363, 1263, 1145, 1027, 976, 755,

741, 731, 696; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 6H), 1.14–

1.87, 2.01–2.15, 2.18–2.36, 2.75–2.86, (4m, 23H), 2.94 (t, J = 8.7 Hz, 1H),

3.29–3.45 (m, 1H), 7.19–7.25 (m, 1H), 7.28–7.38 (m, 4H); 13

C NMR (75

MHz, CDCl3) δ 14.4, 20.9, 25.0, 25.8, 27.1, 31.1, 34.1, 52.2, 52.8, 60.7, 69.5,

70.3, 126.8, 127.5, 128.4, 144.0; MS (EI) m/z 328 (M+, 4), 174 (10), 173 (84),

172 (100), 154 (40), 140 (10), 117 (10), 91 (11); HRMS (ESI) m/z: [M + H]+

Calcd for C22H37N2 329.2961; Found 329.2957.

(1R*,3R

*,8aR

*)-N-Benzyl-N-methyl-3-

phenyloctahydroindolizin-1-amine (7ada): brown oil; tR

14.14 (96 mg, 60%); Rf 0.57 (hexane/EtOAc, 8:2); IR (neat)

ῦ 3084, 3065, 3025, 2934, 2858, 2784, 1599, 1492, 1449,

1361, 1262, 1147, 1099, 1071, 1019, 867, 755, 731, 697; 1H

NMR (400 MHz, CDCl3) δ 1.14–1.27, 1.36–1.48, 1.49–1.61, 1.69–1.80, 1.81–

1.95, 2.10–2.19 (6m, 10H), 2.33 (s, 3H), 2.84 (d, J = 10.6 Hz, 1H), 3.02 (t, J =

8.7 Hz, 1H), 3.34–3.47 (d, m, J = 13.8 Hz, 2H), 4.10 (d, J = 13.8 Hz, 1H),

7.22–7.26, 7.28–7.40 (2m, 10H); 13

C NMR (101 MHz, CDCl3) δ 24.8, 25.5,

26.7, 32.1, 52.8, 59.0, 39.9, 63.1, 69.0, 70.1, 126.9, 127.0, 127.4, 128.4, 128.5,

128.9, 139.4, 143.5; MS (EI) m/z 320 (M+, 2), 237 (13), 173 (76), 172 (100),

146 (46), 91 (35); HRMS (ESI) m/z: [M + H]+ Calcd for C22H29N2 321.2335;

Found 321.2331.

(1R*,3R

*,8aR

*)-N-Methyl-N-phenethyl-3-

phenyloctahydroindolizin-1-amine (7aea): brown oil;

tR 15.50 (102 mg, 61%); Rf 0.66 (hexane/EtOAc, 4:6); IR

(neat) ῦ 3084, 3065, 3025, 2933, 2848, 2784, 2749, 1603,

Experimental Part

203

1493, 1451, 1362, 1262, 1144, 1100, 1029, 934, 867, 802, 755, 697; 1H NMR

(300 MHz, CDCl3) δ 1.19–1.89, 2.04–2.18 (2m, 10H), 2.42 (s, 3H), 2.44–2.63,

2.73–2.85, 2.94–3.11, 3.25–3.42 (4m, 7H), 7.15–7.36 (m, 10H); 13

C NMR

(101 MHz, CDCl3) δ 24.8, 25.7, 26.9, 32.8, 35.0, 52.8, 57.2, 40.1, 64.1, 69.2,

70.1, 125.9, 126.9, 127.4, 128.3, 128.4, 128.9, 141.1, 143.6; MS (EI) m/z 334

(M+, 1), 251 (11), 243 (39), 173 (70), 172 (100), 160 (42), 139 (10), 91 (11);


(1R*,3R

*,8aR

*)-N,N-Dibenzyl-3-

phenyloctahydroindolizin-1-amine (7aga): brown oil

(129 mg, 65%); tR 21.06; Rf 0.89 (hexane/EtOAc, 8:2);

IR ῦ 3060, 3025, 2936, 2852, 2792, 1601, 1492, 1451,

1363, 1263, 1145, 1027, 976, 755, 741, 731, 696; 1HNMR (300 MHz, CDCl3) δ 1.14–1.25 (m, 1H; Hf),

1.34–1.44 (m, 1H; He’), 1.46–1.59 (m, 2H; He, Hd’), 1.75–1.87 (m, 3H; Hb, Hf’,

Hg), 1.88–1.95 (m, 1H; Hg’), 1.99–2.08 (m, 1H; Hh), 2.08–2.19 (m, 1H; Hb’),

2.81 (d, J = 10.4 Hz, 1H; Hd), 2.98 (t, J = 8.8 Hz, 1H; Hc), 3.28 (d, J = 14.8

Hz, 2H; 2 × Hi), 3.36 (td, J = 8.8, 4.0 Hz, 1H; Ha), 4.20 (br s, 2H; 2 × Hi’),

7.19–7.27 (m, 3H; 3 × ArH), 7.28–7.40 (m, 8H; 8 × ArH), 7.41–7.51 (m, 4H;

4 × ArH); 13

C NMR (75 MHz, CDCl3) δ 24.8 (C-6), 25.6 (C-7), 27.0 (C-8),

32.4 (C-2), 52.9 (C-5), 56.1 (2 × C-9), 58.5 (C-1), 69.1 (C-8a), 70.2 (C-3),

126.7, 126.9, 127.4, 128.4, 128.5 (15 × ArCH), 140.8, 143.7 (3 × ArC); MS

(EI) m/z 396 (M+, 0.3), 306 (14), 305 (59), 222 (51), 174 (10), 173 (79), 172

(100), 117 (12), 91 (72); HRMS (ESI) m/z: [M + H]+ Calcd for C28H32N2

396.2565; Found 396.2585.

(1R*,3R

*,8aR

*)-N,N-Dibenzyl-3-(p-tolyl)octahydroindolizin-

1-amine (7agb): brown oil (119 mg, 58%); tR 22.80; Rf 0.86


2858, 2794, 2754, 1603, 1493, 1451, 1362, 1263, 1145, 813,

770, 740, 728, 696; 1H NMR (400 MHz, CDCl3) δ 1.14–1.56,

1.75–1.96, 1.99–2.16 (3 m, 10H), 2.35 (s, 3H), 2.80 (d, J =

10.6 Hz, 1H), 2.94 (t, J = 8.7 Hz, 1H), 3.28 (d, J = 14.5 Hz,

Experimental Part

204

2H), 3.31–3.40 (m, 1H), 4.19 (br s, 2H), 7.12–7.16, 7.19–7.25, 7.25–7.34,

7.41–7.53 (4m, 14H); 13

C NMR (101 MHz, CDCl3) δ 21.3, 24.8, 25.6, 27.0,

32.4, 52.9, 56.1, 58.5, 69.1, 69.9, 126.7, 127.3, 128.3, 128.5, 129.2, 136.5,

140.7, 140.8; MS (EI) m/z 410 (M+, 0.2), 320 (10), 319 (41), 236 (31), 222

(10), 188 (11), 187 (77), 186 (97), 131 (12), 118 (14), 117 (11), 106 (10), 105

(27), 91 (100); HRMS (ESI) m/z: [M + H]+ Calcd for C29H35N2 411.2800;

Found 411.2813.

(1R*,3R

*,8aR

*)-N,N-Dibenzyl-3-(4-

methoxyphenyl)octahydroindolizin-1-amine (7agc):

brown oil (183 mg, 86%); tR 31.39; Rf 0.26 (hexane/EtOAc,

8:2); IR (neat) ῦ 3060, 3025, 2934, 2851, 2832, 2791, 2752,

1610, 1509, 1242, 1170, 1145, 1101, 1036, 828, 740, 728,

697; 1H NMR (300 MHz, CDCl3) δ 1.11–1.55, 1.76–2.15

(2m, 10H), 2.79 (d, J = 10.4 Hz, 1H), 2.91 (t, J = 8.7 Hz,

1H), 3.20–3.43 (d, m, J= 14.4 Hz, 3H), 3.81 (s, 3H), 3.93–4.45 (m, 2H), 6.86–

6.92, 7.18–7.26, 7.28–7.36, 7.42–7.54 (4m, 14H); 13

C NMR (75 MHz, CDCl3)

δ 24.9, 25.6, 27.0, 32.3, 52.8, 56.1, 55.4, 58.4, 69.1, 69.6, 113.9, 126.7, 128.3,

128.4, 128.5, 135.7, 140.8, 158.7; MS (EI) m/z 426 (M+, 0.3), 343 (10), 336

(18), 335 (74), 252 (35), 222 (23), 204 (13), 203 (91), 202 (100), 134 (10), 121


Found 427.2763.

(1R*,3R

*,8aR

*)-N,N-Dibenzyl-3-[4-

(trifluoromethyl)phenyl]octahydroindolizin-1-amine

(7agd): beige solid (128 mg, 55%); tR 19.28; Rf 0.80

(hexane/EtOAc, 7:3); mp 141.6–144.4 ºC; IR (neat) ῦ 3079,

3060, 3030, 2937, 2853, 2792, 2754, 1617, 1322, 1161,

1121, 1102, 1066, 1018, 834, 739, 729, 697; 1H NMR (300

MHz, CDCl3) δ 1.13–1.64, 1.74–1.99, 2.05–2.22 (3m, 10H),

2.79 (d, J = 10.5 Hz, 1H), 3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4 Hz, 2H),

3.32–3.49 (m, 1H), 3.97–4.42 (m, 2H), 7.20–7.26, 7.29–7.36, 7.43–7.52, 7.58–

7.63 (4m, 14H); 13

CNMR (75 MHz, CDCl3) δ 24.7, 25.5, 27.0, 32.3, 52.9,

Experimental Part

205

56.0, 58.6, 69.1, 69.7, 125.5 (q, 3JC-F = 3.8), 126.8, 127.6, 128.4, 128.5, 140.5,

148.0; MS (EI) m/z 464 (M+, 0.1), 373 (39), 291 (10), 290 (54), 242 (11), 241

(78), 240 (100), 172 (11), 91 (82); Anal. Calcd for C29H31F3N2: C, 74.98; H,

6.73; N, 6.03. Found: C, 74.95; H, 6.75; N, 5.90.

Methyl 4-[(1R*,3R

*,8aR

*)-1-(dibenzylamino)octa-

hydroindolizin-3-yl)]benzoate (7age): white solid (216

mg, 95%); Rf 0.60 (hexane/EtOAc, 8:2); mp 144.5–147.6;

IR (neat) ῦ 3058, 2945, 2792, 1719, 1274, 1110, 1097,

769, 733, 697; 1H NMR (300 MHz, CDCl3) δ 1.16–1.61

(m, 4H), 1.76–1.95 (m, 4H), 2.04–2.19 (m, 2H), 2.79 (d, J

= 10.7 Hz, 1H), 3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4

Hz, 2H), 3.39 (td, J = 8.7, 3.9 Hz, 1H), 3.92 (s, 3H), 4.17 (br s, 2H), 7.23 (t, J

= 7.3 Hz, 2H), 7.32 (t, J = 7.5 Hz, 4H), 7.45 (m, 6H), 8.02 (m, 2H); 13

C NMR

(75 MHz, CDCl3) δ 24.6, 25.4, 26.8, 32.1, 52.0, 52.8, 55.8, 58.5, 69.0, 69.6,

126.6, 127.1, 128.2, 128.3, 129.8, 128.7, 140.4, 149.2, 167.1; MS (EI) m/z 454

(M+, 0.4), 364 (18), 363 (72), 281 (13), 280 (65), 232 (14), 231 (100), 230

(96), 222 (10), 216 (20), 91 (70); Anal. Calcd for C30H34N2O2: C, 79.26; H,

7.54; N, 6.16. Found: C, 78.80; H, 7.48; N, 6.11.

(1R*,3S

*,8aR

*)-N,N-Dibenzyl-3-decyloctahydroindolizin-1-

amine (7agf): brown oil (166 mg, 72%); tR 25.57; Rf 0.83

(hexane/EtOAc, 7:3); IR ῦ 3079, 3060, 3020, 2922, 2852,

2791, 2754, 1603, 1493, 1452, 1364, 1263, 1148, 1027, 981,

938, 771, 733, 696; 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J =

6.7 Hz, 3H), 1.07–1.45, 1.47–1.89 (2m, 29H), 3.08–3.16, 3.17–3.25 (2m, 2H),

3.29 (d, J = 14.6 Hz, 2H), 3.84–4.29 (m, 2H), 7.17–7.23, 7.26–7.33, 7.39–7.50

(3m, 10H); 13

CNMR (75 MHz, CDCl3) δ 14.3, 22.9, 25.1, 25.7, 26.8, 27.0,

28.0, 29.5, 29.8, 29.9, 30.3, 32.1, 32.8, 53.0, 56.1, 58.0, 65.6, 69.8, 126.6,

128.3, 128.4, 140.9; MS (EI) m/z 460 (M+, 0.4), 370 (20), 369 (71), 238 (18),

237 (100), 236 (50), 166 (12), 138 (12), 124 (42), 122 (18), 111 (17), 110 (51),

98 (11), 97 (21), 96 (13), 91 (72), 84 (12); Anal. Calcd for C32H48N2: C, 83.42;

H, 10.50; N, 6.08. Found: C, 83.81; H, 10.23; N, 5.73.

Experimental Part

206

(1R*,3R

*,8aR

*)-N,N-Dibutyl-1-phenyl-1,2,3,3a,4,5-

hexahydropyrrolo[1,2-a]quinolin-3-amine (7eca):

yellow oil (85 mg, 45%), tR 21.37; Rf

0.75(hexane/EtOAc, 9:1); IR (neat) ῦ 3021, 2957, 2921,

2856, 2816, 1598, 1491, 1455, 1320, 1097, 1079, 1029, 803, 751, 703; 1H

NMR (300 MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H; 2 CH3), 1.14–1.43 (m,

8H; 4 × CH2), 1.94 (ddd, J = 14.0, 6.5, 3.6 Hz, 1H; CH), 2.06–2.19 (m, 4H; 2

× CH2), 2.52–2.65 (m, 3H), 2.92–3.00 (m, 2H), 3.36–3.52 (m, 2H), 4.35 (dd, J

= 9.8, 6.5 Hz, 1H; CH), 6.14 (dd, J = 8.1, 0.9 Hz, 1H; ArH), 6.64 (td, J = 7.3,

1.1 Hz, 1H; ArH), 6.79 (td, J = 8.2, 1.7 Hz, 1H; ArH), 7.05 (dd, J = 7.4, 1.2

Hz, 1H; ArH), 7.17–7.29 (m, 5H; ArH); 13

C NMR (75 MHz, CDCl3) δ 14.2 (2

× CH3), 20.6, 24.5, 27.9, 30.3, 36.1, 51.8 (9 × CH2), 60.7, 63.2, 64.2 (3 × CH),

114.9, 117.9, 125.9, 126.3, 128.1, 128.3, 128.7 (9 × ArCH), 125.6, 144.0,

146.9 (3 × ArC); MS (EI) m/z 376 (M+, 18), 329 (9), 247 (11), 246 (12), 245

(20), 244 (30), 221 (55), 220 (100), 202 (20), 155 (11), 154 (72), 117 (25), 115

(12), 91 (11); HRMS (ESI) m/z: [M+] Calcd for C26H36N2 376.2878; Found

376.2889.

(1R*,3R

*,5R*,8aR

*)-N,N-Dibenzyl-5-methyl-3-

phenyloctahydroindolizin-1-amine (7cga): yellow oil (82

mg, 40%), tR 28.22; Rf 0.83 (hexane/EtOAc, 8:2); IR (neat) ῦ

3027, 2926, 2849, 2797, 1492, 1452, 1140, 993, 732, 697, 617; 1H NMR (300 MHz, CDCl3) δ 0.54 (d, J = 6.4 Hz, 3H), 1.18–1.44 (m, 5H),

1.72–1.95 (m, 5H), 2.14–2.25 (m, 2H), 3.21 (d, J = 14.2 Hz, 2H; CH2), 3.23 (t,

J = 4.4 Hz, 1H), 3.28 (ddd, J = 9.5, 7.9, 3.6 Hz, 1H), 4.23 (d, J = 14.2 Hz, 2H;

CH2), 7.18–7.25 (m, 3H; 3 × ArH), 7.29–7.34 (m, J = 7.5 Hz, 8H; 8 × ArH),

7.46 (d, J = 7.5 Hz, 4H; 4 × ArH); 13

C NMR (75 MHz, CDCl3) δ 23.3 (CH3),

25.3, 27.3, 34.2, 35.6 (4 × CH2), 55.9 (2 × CH2N), 58.5, 62.9, 69.8, 70.8 (4 ×

CH), 126.2, 126.6, 126.7, 128.1, 128.4 (15 × ArCH), 140.1, 148.0 (3 × ArC);

MS (EI) m/z 319 (73), 222 (49), 207 (20), 187 (64), 186 (89), 117 (14), 106

(10), 104 (12), 92 (11), 91 (100); HRMS (ESI) m/z: [M+] Calcd for C29H34N2

410.2722, [M – Bn]+ 319.2174; Found 319.2195.

Experimental Part

207

General procedure for the hydrogenolysis of indolizidines 7 to

monobenzylated indolizidines 8.

The indolizidine 7 (0.3 mmol) was poured into the hydrogenation flask,

followed by the addition of Pt(5 wt%)/C (117 mg, 10 mol%) or PtO2 (11.4 mg,

10 mol%) and glacial HOAc (3 mL), with this mixture being subjected to

hydrogenation at ca. 1 atm (balloon) and ambient temperature. The reaction

was monitored by TLC and/or GLC until total or steady conversion of the

starting material. The catalyst was separated by filtration and the glacial

HOAc was neutralized with 2M NaOH, followed by extraction with EtOAc,

drying of the organic phase with Na2SO4 and solvent evaporation under

vacuum. Purification of the reaction crude by preparative TLC (silica gel,

hexane/EtOAc 6:4) afforded the pure indolizidines 8 as single

diastereoisomers.

(1R*,3R

*,8aR

*)-N-Benzyl-3-phenyloctahydroindolizin-1-

amine (8aga): brown oil (63 mg, 68%); tR 15.38; Rf 0.44

(hexane/EtOAc, 3:7); IR (neat) ῦ 3029, 2935, 2851, 2789, 1603,

1492, 1451, 1145, 1117, 754, 731, 609; 1H NMR (300 MHz,

CDCl3) δ 1.15–1.31 (m, 1H), 1.38–1.86 (m, 8H), 2.06–2.15 (m,

1H), 2.43 (dt, J = 13.5, 8.0 Hz, 1H), 2.83, (d, J = 10.7 Hz, 1H), 3.07 (t, J = 8.4

Hz, 1H), 3.14 (ddd, J = 7.9, 6.1, 3.1 Hz, 1H), 3.68, 3.86 (AB system, J = 13.4

Hz, 2H), 7.20–7.37 (m, 10H); 13

C NMR (75 MHz, CDCl3) δ 24.4, 25.4, 26.4,

41.7, 51.4, 52.1, 57.5, 68.8, 69.9, 126.8, 126.9, 127.6, 128.1, 128.3, 140.7,

143.3; MS (70 eV) m/z (%) 306 (M+, 3), 223 (20), 197 (21), 196 (20), 173

(61), 172 (100), 168 (11), 132 (29), 91 (25); HRMS (EI) m/z: Calcd for

C21H26N2 306.2096; Found 306.2092.

Experimental Part

208

(1R*,3R

*,8aR

*)-N-Benzyl-3-(4-

methoxyphenyl)octahydroindolizin-1-amine (8agc):

brown oil; (73 mg, 72%); tR 18.52; Rf 0.13 (hexane/EtOAc,

6:4); IR (neat) ῦ 3060, 2951, 2851, 1509, 1426, 1301, 1259,

1112, 896, 734, 698; 1H NMR (300 MHz, CDCl3) δ 1.19–

1.92 (m, 9H), 2.02–2.13 (m, 1H), 2.41 (dt, J = 13.5, 8.0 Hz,

1H), 2.81 (d, J = 10.7 Hz, 1H), 3.02 (t, J = 8.4 Hz, 1H), 3.14

(ddd, J = 7.8, 6.1, 3.1 Hz, 1H), 3.69, 3.87 (AB system, J =

13.4 Hz, 2H), 3.80 (s, 3H), 6.86 (d, J = 8.4 Hz, 2H), 7.21–7.36 (m, 7H); 13

C

NMR (75 MHz, CDCl3) δ 24.3, 25.3, 26.3, 41.6, 51.4, 52.0, 55.2, 57.4, 68.8,

69.4, 113.7, 126.8, 128.1, 128.3, 128.7, 135.0, 140.6, 158.6; MS (70 eV) m/z

(%) 336 (M+, 2), 253 (21), 252 (10), 231 (10), 227 (39), 226 (13), 212 (17),

207 (13), 203 (58), 202 (100), 162 (34), 135 (12), 134 (20), 132 (39), 106 (16),

92 (10), 91 (66), 84 (12), 77 (14), 65 (10); HRMS (EI) m/z: Calcd for

C22H28N2O 336.2202; Found 336.2185.

(1R*,3R

*,8aR

*)-N-Benzyl-3-[4-

(trifluoromethyl)phenyl]octahydroindolizin-1-amine

(8agd): brown oil (73 mg, 65%); tR 15.06; Rf 0.48


2753, 1509, 1325, 1162, 1119, 1018, 837, 731, 697; 1H NMR

(300 MHz, CDCl3) δ 1.08–1.99 (m, 9H), 2.07–2.29 (m, 1H),

2.34–2.61 (m, 1H), 2.80 (d, J = 10.7 Hz, 1H), 3.08–3.21 (m,

2H), 3.67, 3.84 (AB system, J = 13.3 Hz, 2H), 7.20–7.35 (m,

5H), 7.47, 7.56 (AA’BB’system, J = 8.2 Hz, 4H); 13

C NMR (75 MHz, CDCl3)

δ 24.2, 25.3, 26.4, 41.8, 51.5, 52.1, 57.7, 68.7, 69.3, 124.3 (q, J = 271.8 Hz)

125.3 (q, J = 3.7 Hz), 126.8, 127.8, 128.1, 128.3, 129.1 (q, J = 32.2 Hz) 140.7,

147.9; MS (70 eV) m/z (%) 374 (M+, 2), 291 (8), 269 (11), 242 (10), 241 (62),

240 (100), 172 (11), 132 (20), 91 (38), 84 (27); HRMS (EI) m/z: Calcd for

C22H25F3N2 374.1970; Found 374.1967.

Experimental Part

209

(1R*,3R

*,8aR

*)-N-Benzyl-3-decyloctahydroindolizin-1-amine

(8agf): brown oil (90 mg, 81%); tR 19.19; Rf 0.20

(hexane/EtOAc, 3:7); IR (neat) ῦ 3029, 2922, 2852, 2817, 1566,

1454, 1145, 980, 743, 698; 1H NMR (300 MHz, CDCl3) δ 0.88

(t, J = 6.7 Hz, 3H), 1.09–1.40 (m, 20H), 1.43–2.04 (m, 9H), 2.2

(dt, J = 13.1, 7.8 Hz, 1H), 2.96–3.07 (m, 1H), 3.19 (d, J = 10.5

Hz, 1H), 3.65, 3.84 (AB system, J = 13.4 Hz, 2H), 7.17–7.35 (m, 5H); 13

C

NMR (75 MHz, CDCl3) δ 14.1, 22.7, 24.6, 25.2, 26.2, 26.6, 29.3, 29.6, 30.0,

31.9, 38.0, 51.6, 52.2, 56.9, 65.3, 69.4, 126.6, 128.1, 128.2, 140.7; MS (70 eV)

m/z (%) 370 (M+, 3), 261 (9), 238 (13), 237 (49), 236 (23), 229 (28), 135 (14),

134 (100), 132 (12), 124 (27), 111 (10), 110 (27), 97 (11), 91 (25); HRMS (EI)

m/z: Calcd for C25H42N2 370.3348; Found 370.3337.

General procedure for the hydrogenolysis of indolizidines 7 to

debenzylated indolizidines 9.

The indolizidine 7 (0.3 mmol) was poured into the hydrogenation flask,

followed by the addition of Pd(20 wt%)/C (16 mg, 10 mol%) and glacial

HOAc (3 mL), with this mixture being subjected to hydrogenation at ca. 1 atm

(balloon) and ambient temperature. The reaction was monitored by TLC

and/or GLC until total or steady conversion of the starting material. The

catalyst was separated by filtration and the glacial HOAc was neutralized with

2M NaOH, followed by extraction with EtOAc, drying of the organic phase

with Na2SO4 and solvent evaporation under vacuum. Compounds 9agc and

9agf did not require any further purification; compounds 9aga and 9agd were

purified by preparative TLC (EtOAc). In all cases, the pure indolizidines 7

were obtained as single diastereoisomers.

(1R*,3R

*,8aR

*)-3-Phenyloctahydroindolizin-1-amine (9aga):

yellow oil (55 mg, 85%); tR 11.11; Rf 0.20 (EtOAc/MeOH, 8:2);

IR (neat) ῦ 3038, 2932, 2854, 1555, 1455, 1388, 1311, 1145,

754, 698; 1H NMR (300 MHz, CDCl3) δ 1.21–1.62 (m, 6H),

1.63–1.88 (m, 3H), 2.02 (ddd, J = 7.5, 5.4, 2.7 Hz, 2H), 2.62 (ddd, J = 14.0,

8.8, 8.0 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 3.07 (t, J = 8.4 Hz, 1H), 3.27 (ddd,

Experimental Part

210

J = 7.7, 5.1, 2.4 Hz, 1H), 7.15–7.26 (m, 1H), 7.28–7.36 (m, 4H); 13

C NMR (75

MHz, CDCl3) δ 23.9, 25.2, 26.0, 43.9, 51.7, 52.3, 68.6, 69.4, 126.8, 127.4,

128.2, 143.2; MS (70 eV) m/z (%) 217 (M++1, 1), 216 (M

+, 8), 173 (51), 172

(100), 132 (8), 104 (7), 84 (15); HRMS (EI) m/z: Calcd for C14H20N2

216.1626, C14H17N [M+ – NH3] 199.1361; Found 199.1356.

(1R*,3R

*,8aR

*)-3-(4-Methoxyphenyl)octahydroindolizin-

1-amine (9agc): brown oil (57 mg, 77%); tR 12.59; Rf 0.17

(acetone); IR (neat) ῦ 2933, 2851, 1583, 1242, 1035, 828,

626; 1H NMR (300 MHz, CDCl3) δ 0.95–2.01 (m, 9H), 2.57

(dt, J = 13.9, 8.4 Hz, 1H), 2.73 (s, 2H), 2.8 (d, J = 10.8 Hz,

1H), 2.99 (t, J = 8.4 Hz, 1H), 3.27 (ddd, J = 7.9, 5.2, 2.5 Hz,

1H), 3.78 (s, 3H), 6.85, 7.24 (AA’XX’, J = 8.7 Hz, 4H); 13

C

NMR (75 MHz, CDCl3) δ 23.9, 25.2, 25.9, 43.7, 51.6, 52.1, 55.1, 68.6, 69.0,

113.6, 128.5, 134.9, 158.5; MS (70 eV) m/z (%) 247 (M++1, 3), 246 (M

+, 17),

203 (48), 202 (100), 162 (11), 134 (16), 132 (11), 84 (43); HRMS (EI) m/z:

Calcd for C15H22N2O 246.1732; Found 246.1723.

(1R*,3R

*,8aR

*)-3-[4-

(Trifluoromethyl)phenyl]octahydroindolizin-1-amine

(9agd): yellow oil (63 mg, 74%); tR 10.99; Rf 0.45

(EtOAc/MeOH, 8:2); IR (neat) ῦ 3024, 2939, 2851, 1553,

1457, 1322, 1162, 1117, 1066, 838; 1H NMR (300 MHz,

CDCl3) δ 1.29–1.60 (m, 4H), 1.73–1.89 (m, 3H), 2.12 (ddd, J

= 10.9, 4.9, 2.4 Hz, 1H), 2.60–2.83 (m, 5H), 3.19 (t, J = 8.5

Hz, 1H), 3.37–3.42 (m, 1H), 7.46, 7.57 (AA’XX’ system, J = 8.2 Hz, 4H); 13

C

NMR (75 MHz, CDCl3) δ 23.9, 25.2, 26.0, 44.2, 51.7, 52.5, 68.7, 68.9, 124.2

(q, J = 272.0 Hz), 125.3 (q, J = 3.6 Hz), 127.6, 129.0 (q, J = 32.0 Hz), 147.8;

MS (70 eV) m/z (%) 285 (M++1, 1), 284 (M

+, 5), 265 (7), 242 (8), 241 (62),

240 (100), 200 (6), 172 (9), 84 (12); HRMS (EI) m/z: Calcd for C15H19F3N2

284.1500, C15H16F3N [M+ – NH3] 267.1235; Found 267.1221.

Experimental Part

211

(1R*,3R

*,8aR

*)-3-Decyloctahydroindolizin-1-amine (9agf):

brown oil (77 mg, 92%); tR 15.44; Rf 0.20 (EtOAc/MeOH, 7:3);

IR (neat) ῦ 2921, 2851, 1560, 1467, 1458, 1387, 1147, 1121,

811, 721, 687; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.7

Hz, 3H), 1.06 (ddd, J = 13.6, 8.1, 2.7 Hz, 1H), 1.20–1.85 (m,

27H), 2.04–2.19 (m, 2H), 2.35 (dt, J = 13.6, 8.3 Hz, 1H), 3.12–3.20 (m, 2H); 13

C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 24.2, 25.2, 25.9, 26.4, 29.3, 29.6,

29.9, 31.9, 33.5, 40.2, 52.1, 51.8, 65.0, 69.5; MS (70 eV) m/z (%) 280 (M++1,

1), 279 (M+, 1), 237 (16), 236 (11), 140 (10), 139 (100), 124 (17), 122 (15),

110 (25), 96 (11); Anal. Calcd for C18H36N2: C, 77.08; H, 12.94; N, 9.99.

Found: C, 76.72; H, 12.65; N, 9.50.

Experimental Part

212

EXPERIMENTAL PART OF CHAPTER III

General procedure for the synthesis of the dyes 11 from indolizines 4.

A solution of the starting indolizine 4 (0.5 mmol) in glacial acetic acid

(3.0 mL) was stirred for 6–14 h at room temperature (see Table 2). The

resulting mixture was neutralized with a saturated solution of sodium

bicarbonate and extracted with ethyl acetate (3 10 mL). The organic phase

was washed with a saturated solution of sodium bicarbonate (3 20 mL),

followed by decantation and drying with anhydrous magnesium sulfate. The

reaction crude obtained after solvent evaporation was purified by column

chromatography (silica gel, hexane/ethyl acetate) or submitted to

recrystallization in absolute ethanol to give the corresponding indolizine dyes

11.

(E)-3-[1-(Dibenzylamino)-3-

phenylindolizin-7-yl]-3-phenyl-1-(pyridin-2-

yl)prop-2-en-1-one (11aga). Orange solid; Rf

0.66 (hexane/EtOAc, 6:4); m.p. 138.9–140.4

ºC (EtOH); IR (neat) ῦ 3104, 3084, 3055, 3025,

2995, 2833, 1662 (C=O), 1560, 1541, 1490,

1469, 1360, 1207, 1139, 1049, 1026, 993, 873,

799, 747, 738, 695, 682, 661, 618; NMR data

of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 4.15 (s, 4H; 2 × CH2),

6.55 (s, 1H; ArH), 6.87 (dd, J = 7.8, 1.8, 1H; ArH), 7.17–7.51 (m, 22H; 22 ×

ArH), 7.76 (td, J = 7.8, 1.8, 1H; ArH), 7.99 (d, J = 8.1, 1H; ArH), 8.04 (d, J =

7.8, 1H; ArH), 8.12 (s, 1H; CHCO), 8.68 (d, J = 4.8, 1H; ArH); selected NMR

data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 4.19 (s, 4H; 2 ×

CH2), 6.35 (dd, J = 7.5, 1.8 Hz, 1H; ArH), 8.65 (d, J = 4.7 Hz, 1H; ArH);

NMR data of the mixture of rotamers: 13

C NMR (101 MHz, CDCl3) δ 58.8,

58.9 (CH2), 107.9, 108.1, 109.3, 113.8, 115.8, 120.2, 120.3, 121.3, 122.1,

122.5, 122.7, 122.8, 126.3, 126.4, 126.8, 126.9, 127.2, 127.5, 127.8, 127.9,

128.1, 128.2, 128.3, 128.4, 128.9, 129.0, 129.1, 129.2, 129.6, 129.9, 136.9,

148.6, 148.8 (CH), 125.7, 126.0, 126.7, 131.8, 133.4, 139.0, 139.2, 139.4,

Experimental Part

213

142.4, 155.6, 155.8, 156.1, 157.5 (ArC), 188.7, 189.5 (CO); MS (DIP) m/z 596

(M++1, 24), 595 (M

+, 53), 505 (28), 504 (100), 399 (21), 398 (67), 397 (21),

383 (13), 237 (18), 91 (66). Elemental analysis calcd. for C42H33N3O: C 84.68,

H 5.58, N 7.05, found: C 84.92, H 5.58, N 7.19.

(E)-3-[1-(Dibenzylamino)-3-(p-

tolyl)indolizin-7-yl]-1-(pyridin-2-yl)-3-(p-

tolyl)prop-2-en-1-one (11agb). Orange solid;

Rf 0.34 (hexane/EtOAc, 8:2); m.p. 174.3–175.4

ºC (EtOH); IR (neat) ῦ 3100, 3060, 3026, 2962,

2922, 2826, 1661 (C=O), 1559, 1544, 1507,

1470, 1377, 1361, 1205, 1138, 1047, 1029,

993, 874, 811, 800, 776, 746, 732, 697; NMR

data of the major rotamer: 1H NMR (400

MHz, CDCl3) δ 2.39, 2.42 (2s, 6H; 2 × CH3), 4.17 (s, 4H; 2 × CH2), 6.50 (s,

1H; ArH), 6.84 (dd, J = 7.8, 1.2, 1H; ArH), 7.10–7.26 (m, 16H; 16 × ArH),

7.32–7.40 (m, 4H; 4 × ArH), 7.74 (td, J = 7.8, 1.2, 1H; ArH), 7.95–8.03 (m,

2H; 2 × ArH), 8.08 (s, 1H; CHCO), 8.68 (d, J = 4.8, 1H; ArH); selected NMR

data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 2.38, 2.40 (2s, 6H; 2

× CH3), 4.19 (s, 4H; 2 × CH2), 6.34 (dd, J = 7.5, 1.6 Hz, 1H; ArH), 6.51 (s,

1H; ArH), 8.12 (s, 1H; ArH), 8.64 (d, J = 4.2 Hz, 1H; ArH); NMR data of the

mixture of rotamers: 13

C NMR (101 MHz, CDCl3) δ 21.4, 21.5, 21.7 (CH3),

58.7, 58.9 (CH2), 107.5, 107.8, 109.4, 113.8, 115.6, 119.3, 120.2, 121.3, 122.1,

122.5, 122.6, 122.7, 126.2, 126.8, 126.9, 127.8, 127.9, 128.2, 128.3, 128.4,

128.9, 129.1, 129.6, 129.7, 129.8, 136.9, 139.9, 148.6, 148.7 (CH), 125.2,

126.0, 126.7, 133.4, 136.3, 137.5, 139.0, 139.2, 155.9, 156.6 (ArC), 188.6,

189.4 (CO); MS (DIP) m/z 624 (M++1, 24), 623 (M

+, 48), 533 (41), 532 (100),

427 (20), 426 (58), 425 (17), 412 (10), 411 (12), 251 (12), 91 (83). Elemental

analysis calcd. for C44H37N3O: C 84.72, H 5.98, N 6.74; found: C 84.61, H

6.02, N 6.61.

(E)-3-[1-(Dibenzylamino)-3-(4-

methoxyphenyl)indolizin-7-yl]-3-(4-

Experimental Part

214

methoxyphenyl)-1-(pyridin-2-yl)prop-2-en-1-one (11agc). Orange solid; Rf

0.43 (hexane/EtOAc, 6:4); m.p. 157.1–158.8 ºC (EtOH); IR (neat) ῦ 3084,

3065, 3025, 2995, 2927, 2829, 1654 (C=O), 1608, 1556, 1540, 1506, 1469,

1362, 1286, 1249, 1234, 1206, 1175, 1138, 1026, 832, 808, 778, 750, 731,

700; NMR data of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 3.84 (s,

6H; 2 × OCH3), 4.19 (s, 4H; 2 × CH2), 6.47 (s, 1H; ArH), 6.81 (dd, J = 7.7,

1.8, 1H; ArH), 6.90 (d, 2H; J = 8.8, 2 × ArH), 6.97 (d, 2H; J = 8.8, 2 × ArH),

7.14–7.26 (m, 12H; 12 × ArH), 7.35–7.46 (m, 4H; 4 × ArH), 7.75 (td, J = 7.7,

1.7, 1H; ArH), 8.00 (dd, J = 8.0, 0.8, 1H; ArH), 8.02 (dd, J = 8.0, 0.8, 1H;

ArH), 8.03 (s, 1H, CHCO), 8.67–8.69 (m, 1H; ArH); selected NMR data of the

minor rotamer: 1H NMR (400 MHz, CDCl3) δ 3.85 (s, CH3), 4.20 (CH2), 6.34

(dd, J = 7.5, 1.8 Hz; ArH), 8.65 (d, J = 4.7 Hz; ArH); NMR data of the mixture

of rotamers: 13

C NMR (101 MHz, CDCl3) δ 55.2, 55.5 (CH3), 58.7, 58.9

(CH2), 107.2, 107.5, 109.6, 113.5, 113.7, 113.8, 114.4, 114.5, 115.5, 118.2,

120.1, 122.3, 121.1, 122.1, 122.7, 126.2, 126.8, 126.9, 128.1, 128.2, 128.3,

128.4, 129.3, 129.5, 130.8, 131.4, 136.9, 148.6, 148.7 (CH), 124.3, 124.9,

125.8, 126.7, 131.3, 131.9, 133.4, 134.8, 139.0, 139.2, 155.9, 156.1, 156.4,

157.7, 158.9, 159.1, 159.5, 161.1 (ArC), 188.7, 189.1 (CO); MS (DIP) m/z 656

(M++1, 20), 655 (M

+, 42), 565 (41), 564 (100), 459 (13), 458 (37), 443 (19),

91 (100). Elemental analysis calcd. for C44H37N3O3: C 80.59, H 5.69, N 6.41;

found: C 80.14, H 5.68, N 6.43.

Experimental Part

215

(E)-3-{1-(Dibenzylamino)-3-[4-

(trifluoromethyl)phenyl]indolizin-7-yl}-1-

(pyridin-2-yl)-3-[4-(trifluoromethyl)-

phenyl]prop-2-en-1-one (11agd). Orange

solid; Rf 0.37 (hexane/EtOAc, 8:2); m.p.

198.4–200.0 ºC (EtOH); IR (neat) ῦ 3084,

3065, 3025, 2937, 2829, 1662 (C=O), 1614,

1562, 1512, 1321, 1208, 1164, 1119, 1105,

1065, 1026, 993, 846, 752, 743, 733, 697;

NMR data of the major rotamer: 1H NMR

(400 MHz, CDCl3) δ 4.18 (s, 4H; 2 × CH2), 6.59 (s, 1H; ArH), 6.90 (dd, J =

7.8, 2.0, 1H; ArH), 7.12–7.34 (m, 13H; 13 × ArH), 7.44 (ddd, J = 7.5, 4.8, 1.2,

1H; ArH), 7.58–7.72 (m, 6H; 6 × ArH), 7.80 (td, J = 7.7, 1.7, 1H; ArH), 7.98

(d, J = 7.8, 1H; ArH), 8.07 (d, J = 7.5, 1H; ArH), 8.18 (s, 1H; CHCO), 8.70–

8.72 (m, 1H; ArH); selected NMR data of the minor rotamer: 1H NMR (400

MHz, CDCl3) δ 4.23 (s, 4H, 2 × CH2), 6.36 (dd, J = 7.5, 1.8 Hz, 1H; ArH),

8.21 (s, 1H; ArH), 8.75 (d, J = 4.7 Hz, 1H; ArH); NMR data of the mixture of

rotamers: 13

C NMR (101 MHz, CDCl3) δ 58.6, 58.8 (CH2), 108.2, 109.6,

116.9, 121.4, 122.5, 122.6, 123.2, 123.3, 124.8, 126.7, 127.0, 127.2, 127.3,

127.7, 127.9, 128.1, 128.3, 128.5, 128.7, 128.9, 129.4, 129.9, 137.1, 137.3,

148.7, 149.1 (CH), 124.8, 125.8, 126.5, 134.2, 135.2, 138.7, 138.9, 143.3,

153.9, 155.4 (ArC), 125.2 (q, 3JC-F = 3.3 Hz; CHCCF3), 125.9 (q,

3JC-F = 3.7

Hz; CHCCF3), 126.2 (q, 3JC-F = 3.3; CHCCF3), 188.6, 189.3 (CO); MS (DIP)

m/z 732 (M++1, 20), 731 (M

+, 42), 641 (39), 640 (93), 535 (26), 534 (79), 533

(25), 519 (16), 363 (10), 306 (31), 106 (15), 91 (100), 78 (26). Elemental

analysis calcd. for C44H31F6N3O: C 72.22, H 4.27, N 5.74; found: C 72.13, H

4.49, N 5.62.

Experimental Part

216

Methyl (E)-4-{1-[1-

(dibenzylamino)-3-(4-

(methoxycarbonyl)phenyl) indolizin-7-

yl]-3-oxo-3-(pyridin-2-yl)prop-1-en-1-

yl}benzoate (11age). Dark solid; Rf 0.12

(hexane/EtOAc, 8:2); m.p. 130.5-133.8 ºC

(EtOH); IR (neat) ῦ 3053, 3030, 2999,

2949, 2876, 1713 (C=O), 1654 (C=O),

1537, 1272, 1101, 1031, 766, 694; NMR

data of the major rotamer: 1H NMR (300

MHz, CDCl3) δ 3.94 (s, 3H; CH3), 3.99 (s, 3H; CH3), 4.18 (s, 4H; 2 × CH2),

6.59 (s, 1H; ArH), 6.95 (dd, J = 7.8, 1.9 Hz, 1H; ArH), 7.12–7.28 (m, 10H,

ArH), 7.43 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H; ArH), 7.55 (d, J = 8.5 Hz, 2H, ArH),

7.79 (td, J = 7.7, 1.7 Hz, 1H; ArH), 7.98 (d, J = 7.8 Hz, 1H; ArH), 8.05 (d, J =

8.5 Hz, 2H; ArH), 8.04–8.14 (m, 5H; 5 × ArH), 8.13 (d, J = 8.0 Hz, 1H; ArH),

8.20 (s, 1H; ArH), 8.70 (dd, J = 4.7, 0.7 Hz, 1H; ArH); selected NMR data of

the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 3.93, 3.97 (2s, 6 H; 2 ×

CH3), 4.21 (s, 4H; 2 × CH2), 6.38 (dd, J = 7.5, 1.9 Hz, 1H; ArH), 6.63 (s, 1H;

ArH); NMR data of the mixture of rotamers: 13

C NMR (75 MHz, CDCl3) δ

52.1, 52.2 (CH3), 58.4, 58.8 (CH2), 108.6, 109.5, 116.3, 121.6, 122.5, 122.6,

126.5, 127.0, 127.1, 127.9, 128.2, 128.3, 128.4, 128.9, 129.6, 130.3, 130.4,

137.1, 148.7 (CH), 125.2, 125.9, 126.6, 129.4, 134.3, 136.0, 138.6, 144.6,

154.4, 155.4, 166.7, 167.0, 188.3 (ArC); MS (DIP) m/z 732 (M++1, 20), 731

(M+, 42), 641 (39), 640 (93), 535 (26), 534 (79), 533 (25), 519 (16), 363 (10),

306 (31), 106 (15), 91 (100), 78 (26). Elemental analysis calcd. for

C44H31F6N3O: C 72.22, H 4.27, N 5.74; found: C 72.13, H 4.49, N 5.62.

(E)-3-[3-Butyl-1-

(dibenzylamino)indolizin-7-yl]-1-(pyridin-

2-yl)hept-2-en-1-one (11agi). Purple

semisolid; Rf 0.38 (hexane/EtOAc, 8:2); IR

(neat) ῦ 3027, 2956, 2928, 2870, 1644

(C=O), 1560, 1535, 1494, 1452, 1348, 1214,

Experimental Part

217

1062, 995, 740, 696; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz, 3H;

CH3), 0.95 (t, J = 7.1 Hz, 3H; CH3), 1.25–1.69 (m, 8H; 4 × CH2), 2.71 (br s,

2H; CH2), 3.12 (br s, 2H; CH2), 4.30 (s, 4H; 2 × CH2), 6.31 (s, 1H; ArH), 6.85

(d, J = 7.4 Hz, 1H; ArH), 7.20–7.43 (m, 11H; ArH), 7.41 (ddd, J = 7.5, 4.8,

1.2 Hz, 1H; ArH), 7.78 (s, 1H; ArH), 7.83 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.00

(s, 1H; ArH), 8.14 (dd, J = 7.9, 0.9 Hz, 1H; ArH), 8.68 (ddd, J = 4.8, 1.7, 0.9

Hz, 1H; ArH); 13

C NMR (75 MHz, CDCl3) δ 13.9, 14.1 (CH3), 22.4, 23.3,

25.6, 29.3, 29.6, 32.5, 59.1 (CH2), 106.2, 108.3, 114.9, 118.2, 120.5, 122.3,

125.9, 126.9, 128.2, 136.8, 148.4 (CH), 124.2, 125.3, 139.2, 156.3, 160.4

(ArC), 189.1 (CO); MS (DIP) m/z 556 (M++1, 25), 555 (M

+, 59), 505 (40),

480 (18), 465 (37), 464 (100), 462 (10), 373 (27), 344 (10), 330 (27), 329 (1),

315 (19), 285 (16), 267 (36), 210 (20), 209 (12), 182 (12), 91 (67), 78 (17).

HRMS (EI) m/z calcd for C38H41N3O 555.3250, [M+–91] 464.2702, found

464.2688.

(E)-3-{1-[Benzyl(methyl)amino]-3-

phenylindolizin-7-yl}-3-phenyl-1-(pyridin-

2-yl)prop-2-en-1-one (11ada). Orange solid;

Rf 0.49 (hexane/EtOAc, 6:4); m.p. 125.6–

127.1 ºC (EtOH); IR (neat) ῦ 3084, 3055,

3025, 2986, 2946, 2808, 2779, 1661 (C=O), 1562, 1540, 1491, 1470, 1450,

1357, 1199, 1030, 770, 753, 697, 675; NMR data of the major rotamer: 1H

NMR (300 MHz, CDCl3) δ 2.67 (s, 3H; CH3), 4.04 (s, 2H; CH2), 6.56 (s, 1H;

ArH), 6.93 (dd, J = 7.8, 2.0, 1H; ArH), 7.10–7.60 (m, 17H; 17 × ArH), 7.76

(td, J = 7.7, 1.7, 1H; ArH), 7.99 (dt, J = 7.8, 1.1, 1H; ArH), 8.11 (dd, J = 7.7,

0.5, 1H; ArH), 8.16 (s, 1H; ArH), 8.69 (ddd, J = 4.8, 1.7, 0.9, 1H; ArH);

selected NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 2.71

(s, 2H; CH2), 4.14 (s, 3H; CH3), 6.38 (dd, J = 7.5, 1.9 Hz, 1H; ArH), 6.61 (s,

1H; ArH), 8.65 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH); NMR data of the mixture

of rotamers: 13

C NMR (75 MHz, CDCl3) δ 41.0, 42.2 (CH3), 62.5, 62.6 (CH2),

106.1, 109.4, 113.9, 115.7, 120.0, 120.2, 121.3, 122.2, 122.6, 122.7, 126.3,

126.4, 127.1, 127.2, 127.6, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 129.0,

129.2, 129.9, 136.9, 148.6, 148.8 (CH), 124.2, 125.9, 126.3, 131.8, 135.6,

Experimental Part

218

138.6, 139.4, 155.6, 155.8, 156.0, 157.7 (ArC), 188.6, 189.3 (CO); MS (DIP)

m/z 520 (M++1, 17), 519 (M

+, 45), 429 (33), 428 (100), 322 (24), 78 (9);

Elemental analysis calcd. for C36H29N3O: C 83.21, H 5.63, N 8.09, found C

83.12, H 5.67, N 7.91.

(E)-3-{1-[Methyl(phenethyl)amino]-3-

phenylindolizin-7-yl}-3-phenyl-1-

(pyridin-2-yl)prop-2-en-1-one (11aea).

Violet semisolid; Rf 0.57 (hexane/EtOAc,

6:4); IR (neat) ῦ 3056, 3023, 2934, 2840,

2790, 1655 (C=O), 1599, 1534, 1509, 1489, 1472, 1358, 1205, 1048, 1025,

995, 940, 802, 748, 697, 674; NMR data of the major rotamer: 1H RMN (300

MHz, CDCl3) δ 2.68–2.74 (m, 2H; CH2CH2N), 2.79 (s, 3H; CH3), 3.13–3.24

(m, 2H; CH2N), 6.54 (s, 1H; ArH), 6.86 (dd, J =7.8, 1.9, 1H; ArH), 7.03–7.61

(m, 17H; 17 × ArH), 7.75 (td, J = 7.7, 1.7, 1H; ArH), 8.00 (d, J =7.8, 1H;

ArH), 8.09 (d, J = 7.7, 1H; ArH), 8.14 (s, 1H; ArH), 8.66–8.73 (m, 1H; ArH);


(s, 3H; CH3), 6.38 (dd, J =7.5, 1.9 Hz, 1H; ArH), 6.65 (s, 1H; ArH); NMR data

of the mixture of rotamers: 13

C NMR (75 MHz, CDCl3) δ 33.9, 34.0, 59.4,

59.9 (CH2), 42.3, 43.4 (CH3), 106.0, 106.5, 109.5, 113.9, 115.9, 119.9, 120.2,

121.3, 122.0, 122.6, 122.7, 125.9, 126.1, 126.2, 126.4, 127.6, 127.8, 127.9,

128.2, 128.3, 128.4, 128.8, 129.0, 129.1, 129.2, 129.7, 129.8, 136.9, 148.6,

148.7, 148.9 (CH), 124.2, 126.0, 126.3, 131.8, 134.6, 139.4, 139.9, 140.2,

155.8, 156.1 (ArC), 188.6, 189.0 (CO); MS m/z 534 (M++1, 20), 533 (M

+, 51),

443 (35), 442 (100), 427 (11), 206 (11), 78 (7); Elemental analysis calcd. for

C37H31N3O: C 83.27, H 5.86, N 7.87, found C 83.75, H 5.56, N 7.79.

(E)-3-{1-[Methyl(phenethyl)amino]-3-

phenylindolizin-7-yl}-3-phenyl-1-(pyridin-2-

yl)prop-2-en-1-one (11aaa). Orange solid; Rf

0.60 (hexane/EtOAc, 6:4); m.p. 137.1–139.9 ºC

(EtOH); IR (neat) ῦ 3055, 2928, 2848, 2789,

1655 (C=O), 1557, 1536, 1472, 1464, 1378,

Experimental Part

219

1360, 1343, 1203, 1048, 1024, 994, 762, 697; NMR data of the major rotamer: 1H RMN (300 MHz, CDCl3) δ 1.46–1.56 (m, 2H; CH2CH2CH2N), 1.58–1.73

(m, 4H; 2 × CH2CH2N), 2.93 (s, 4H; 2 × CH2N), 6.56 (s, 1H; ArH), 6.84 (dd, J

= 7.7, 1.8, 1H; ArH), 7.25–7.60 (m, 12H; 12 × ArH), 7.78 (dd, J = 7.7, 1.7,

1H; ArH), 8.00 (dt, J = 7.9, 1.0, 1H; ArH), 8.06–8.13 (m, 1H; ArH), 8.16 (s,

1H; CHCO), 8.69 (ddd, J = 4.8, 1.7, 0.8, 1H; ArH); selected NMR data of the

minor rotamer: 1H RMN (300 MHz, CDCl3) δ 6.33 (dd, J = 7.8 Hz, 1H; ArH),

6.62 (s, 1H; ArH); NMR data of the mixture of rotamers: 13

C NMR (75 MHz,

CDCl3) δ 24.4, 26.1, 29.8, 54.7 (CH2), 106.0, 109.6, 115.9, 121.3, 122.2,

122.6, 122.7, 126.3, 126.4, 126.5, 127.5, 127.6, 127.8, 127.9, 128.1, 128.4,

128.7, 129.0, 129.1, 129.2, 129.6, 129.7, 136.9, 148.6, 148.8 (CH), 131.9,

136.1, 139.5, 155.6, 155.8, 156.2 (ArC), 188.7 (CO); MS m/z 484 (M++1, 40),

483 (M+, 100), 413 (5), 377 (7), 242 (6), 227 (5), 78 (5); Elemental analysis

calcd. for C33H29N3O: C 81.96, H 6.04, N 8.69, found C 81.66, H 6.15, N 8.80.

(E)-3-[1-(Dibutylamino)-3-phenylindolizin-

7-yl]-3-phenyl-1-(pyridin-2-yl)prop-2-en-1-

one (11aba). Violet semisolid; Rf 0.71

(hexane/EtOAc, 6:4); IR (neat) ῦ 3060, 2956,

2929, 2869, 1671 (C=O), 1625, 1596, 1561,

1516, 1489, 1466, 1363, 1298, 1272, 1241, 1206, 1048, 1025, 994, 921, 767,

697; NMR data of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J

= 7.3, 6H; 2 × CH3), 1.11–1.24 (m, 4H; 2 × CH2CH2CH2N), 1.29–1.45 (m,

4H; 2 × CH2CH2N), 2.93 (t, J = 7.5, 4H; 2 × CH2N), 6.51 (s, 1H; ArH), 6.88

(dd, J = 7.8, 2.0, 1H; ArH), 7.19–7.63 (m, 12H; 12 × ArH), 7.73–7.80 (m, 1H;

ArH), 8.00 (dt, J = 7.9, 1.1, 1H; ArH), 8.07 (d, J = 7.8, 1H; ArH), 8.13 (s, 1H;

ArH), 8.69 (ddd, J = 4.8, 1.7, 0.9, 1H; ArH); NMR data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 6.40 (d, J = 6.9 Hz, 1H; ArH), 6.62 (s, 1H;

ArH), 8.16 (dd, J = 7.9, 0.9 Hz, 1H; ArH); NMR data of the mixture of

rotamers: 13

C NMR (101 MHz, CDCl3) δ 14.2 (CH3), 20.4, 20.5, 30.3, 55.3,

56.1 (CH2), 93.7, 106.7, 109.2, 115.5, 121.3, 122.2, 122.6, 122.7, 123.3, 126.2,

126.4, 126.5, 126.6, 127.5, 127.6, 127.9, 128.2, 128.4, 128.7, 129.0, 129.1,

129.6, 129.7, 130.1, 132.8, 136.9, 137.2, 148.6, 148.8, 149.4 (CH), 125.4,

Experimental Part

220

126.1, 126.3, 131.9, 134.2, 139.6, 149.9, 155.9, 156.3 (ArC), 188.5 (CO); MS

(DIP) m/z 528 (M++1, 41), 527 (M

+, 100), 470 (14), 442 (11), 427 (11), 322

(11), 321 (12), 206 (10), 78 (7); Elemental analysis calcd. for C36H37N3O: C

81.94, H 7.07, N 7.96, found C 81.67, H 6.96, N 7.87.

(E)-3-{1-[Methyl(phenyl)amino]-3-


(pyridin-2-yl)prop-2-en-1-one (11afa).

Purple solid; Rf 0.28 (hexane/EtOAc, 3:7);

m.p. 125.6–128.8 ºC (EtOH); IR (neat) ῦ

3060, 3049, 2994, 2870, 1662 (C=O), 1596, 1492, 1212, 1025, 748, 693; NMR

data of the major rotamer: 1H NMR (300 MHz, CDCl3) δ 3.28 (s, 3H; CH3),

6.78 (d, J = 8.1 Hz, 2H; 2 × ArH), 6.81 (s, 1H; ArH), 6.86 (dd, J = 7.7, 2.0 Hz,

1H; ArH), 7.09–7.24 (m, 5H; 5 × ArH), 7.34–7.54 (m, 8H; 8 × ArH), 7.61 (m,

2H; 2× ArH), 7.78 (td, J = 7.8, 1.7 Hz, 1H; ArH), 8.00 (dt, J = 7.9, 1.0 Hz, 1H;

ArH), 8.11 (s, 1H; ArH), 8.24 (dd, J = 7.7, 0.6 Hz, 1H; ArH), 8.71 (ddd, J =

4.7, 1.7, 0.9 Hz, 1H; ArH); selected NMR data of the minor rotamer: 1H NMR

(300 MHz, CDCl3) δ 3.28 (s, 3H; CH3), 6.45 (dd, J = 7.4, 1.9 Hz, 1H; ArH),

8.03 (dt, J = 7.9, 1.1 Hz, 1H; ArH); NMR data of the mixture of rotamers: 13

C

NMR (75 MHz, CDCl3) δ 40.9 (CH3), 110.2, 112.5, 113.4, 113.9, 114.1,

117.1, 117.8, 118.1, 120.0, 120.5, 121.1, 121.9, 122.5, 122.7, 122.8, 126.5,

126.6, 127.5, 127.8, 128.0, 128.1, 128.2, 128.4, 128.8, 128.9, 129.1, 129.2,

129.5, 129.8, 136.9 (CH), 126.2, 127.7, 127.8, 129.1, 131.7, 132.1, 138.9,

141.8, 148.7, 148.8, 149.7, 155.6, 155.9 (ArC), 189.2, 189.7 (CO); MS (DIP)

m/z 506 (M++1, 39), 505 (M

+, 100), 491 (12), 490 (29), 252 (11), 230 (12), 78

(12), 77 (13); Elemental analysis calcd. for C35H27N3O: C 82.14, H 5.38, N

8.31, found C 82.31, H 5.49, N 8.08.

(E)-3-{5-Methyl-1-

[methyl(phenyl)amino]-3-

phenylindolizin-7-yl}-1-(6-

methylpyridin-2-yl)-3-phenylprop-2-en-

1-one (11cfa). Purple solid; Rf 0.22

Experimental Part

221

(hexane/EtOAc, 8:2); m.p. 127.1–134.9 ºC; IR (neat) ῦ 3050, 2915, 2869,

1652 (C=O), 1543, 1496, 1293, 1267, 1049, 772, 748, 694; NMR data of the

major rotamer: 1H NMR (300 MHz, CDCl3) δ 2.15 (s, 3H; CH3), 2.62 (s, 3H;

CH3), 3.26 (s, 3H; CH3), 6.56 (s, 1H; ArH), 6.65 (s, 1H; ArH), 6.73 (d, J = 8.7

Hz, 2H; 2 × ArH), 7.03–7.25 (m, 7H; 7 × ArH), 7.30–7.50 (m, 8H; 8 × ArH),

7.63 (t, J = 7.7 Hz, 1H; ArH), 7.66 (d, J = 7.0 Hz, 1H; ArH), 8.05 (s, 1H;

ArH); NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 2.08,

2.58, 3.26 (3s, 9H; 3 × CH3), 6.19 (s, 1H; ArH), 6.62 (s, 1H; ArH); NMR data

of the mixture of rotamers: 13

C NMR (75 MHz, CDCl3) δ 23.0, 23.2, 24.5,

24.6, 40.8, 40.9 (CH3), 111.4, 113.3, 113.9, 114.9, 115.2, 115.4, 116.7, 117.5,

117.9, 118.3, 118.4, 119.8, 119.9, 121.7, 126.1, 127.1, 127.3, 127.6, 127.9,

128.0, 128.1, 128.2, 128.8, 128.9, 129.3, 129.5, 129.6, 130.9, 131.1, 137.0

(CH), 124.7, 126.7, 127.2, 129.1, 129.2, 129.4, 134.3, 135.0, 135.4, 139.1,

149.8, 155.0, 155.1, 155.8, 156.4, 157.6 (ArC), 189.6 (CO); MS (DIP) m/z 534

(M++1, 40), 533 (M

+, 100), 518 (12), 416 (10), 397 (6), 266 (11), 251 (12), 92

(21); Elemental analysis calcd. for C37H31N3O: C 83.27, H 5.86, N 7.87, found

C 83.41, H 5.72, N 7.88.

(E)-3-{1-[Bis(4-

methoxyphenyl)amino]-3-


(pyridin-2-yl)prop-2-en-1-one

(11aha). Dark solid; Rf 0.58

(hexane/EtOAc, 6:4); m.p. 95.3–

96.7 ºC; IR (neat) ῦ 3054, 2953,

2927, 2854, 2833, 1656 (C=O), 1599, 1500, 1467, 1235, 1027, 823, 730, 697;

NMR data of the major rotamer: 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 6H; 2

× CH3), 6.65–6.74 (m, 5H; 5 × ArH), 6.86–7.02 (m, 7H; 7 × ArH), 7.25–7.41

(m, 6H; 6 × ArH), 7.47 (t, J = 7.5 Hz, 2H; 2 × ArH), 7.55–7.60 (m, 2H; 2 ×

ArH), 7.71–7.83 (m, 1H; ArH), 7.95 (d, J = 7.9 Hz, 1H; ArH), 8.05 (s, 1H;

ArH), 8.17 (d, J = 7.7 Hz, 1H; ArH), 8.67 (dd, J = 4.7, 0.7 Hz, 1H; ArH);


(s, 3H; CH3), 6.42 (dd, J = 7.5, 1.6 Hz, 1H; ArH), 8.01 (d, J = 7.9 Hz, 1H;

Experimental Part

222

ArH); NMR data of the mixture of rotamers: 13


55.6 (CH3), 109.4, 111.7, 114.4, 114.5, 116.9, 121.8, 122.4, 122.7, 122.8,

123.3, 126.3, 126.5, 127.6, 127.7, 127.9, 128.1, 128.3, 128.8, 129.1, 129.2,

129.6, 136.9, 137.0, 148.6 (CH), 126.4, 127.8, 131.6, 138.8, 141.7, 154.7,

155.6, 155.7 (ArC), 188.9 (CO); MS (DIP) m/z 628 (M++1, 44), 627 (M

+,

100), 313 (30), 299 (9), 78 (6); Elemental analysis calcd. for C42H33N3O3: C

84.36, H 5.30, N 6.69, found C 84.61, H 5.69, N 6.79.

(E)-3-{5-Methyl-1-

[methyl(phenyl)amino]-3-phenylindolizin-

7-yl}-1-(6-methylpyridin-2-yl)-3-

phenylprop-2-en-1-one (11aia). Dark solid;

Rf 0.58 (hexane/EtOAc, 6:4); m.p. 95.3–96.7

ºC; IR (neat) ῦ 3054, 2953, 2927, 2854, 2833, 1656 (C=O), 1599, 1500, 1467,

1235, 1027, 823, 730, 697; NMR data of the major rotamer: 1H NMR (300

MHz, CDCl3) δ 1.33 (d, J = 6.8 Hz, 3H; CH3), 3.88, 4.03 (AB system, J = 14.2

Hz, 2H; CH2), 4.26 (q, J = 6.8 Hz, 1H; CHCH3), 6.64 (s, 1H; ArH), 6.91 (dd, J

= 7.7, 2.0 Hz, 1H; ArH), 7.07–7.53 (m, 21H; 21 × ArH), 7.80 (td, J = 7.7, 1.7

Hz, 1H; ArH), 8.04 (d, J = 7.8 Hz, 1H; ArH), 8.10 (d, J = 7.6 Hz, 1H; ArH),

8.16 (s, 1H; ArH), 8.71 (dd, J = 4.8, 0.8 Hz, 1H; ArH); selected NMR data of

the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 3.73 (s, 3H; CH3), 6.35 (dd,

J = 7.3, 1.8 Hz, 1H; ArH), 6.60 (s, 1H; ArH), 8.01 (d, J = 7.9 Hz, 1H; ArH);

NMR data of the mixture of rotamers: 13

C NMR (75 MHz, CDCl3) δ 18.5

(CH3), 55.3 (CH2), 63.3, 109.2, 111.4, 116.3, 121.8, 122.4, 122.7, 126.4,

126.5, 127.5, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 129.0, 129.1,

137.0, 148.6 (CH), 126.0, 127.6, 129.4, 130.4, 132.0, 139.6, 140.0, 143.7,

155.7, 156.1 (ArC), 188.9 (CO); MS (DIP) m/z 628 (M++1, 44), 627 (M

+,

100), 313 (30), 299 (9), 78 (6); Elemental analysis calcd. for C43H35N3O: C

84.07, H 5.79, N 6.89, found C 84.17, H 5.92, N 6.79.

Experimental Part

223

EXPERIMENTAL PART OF CHAPTER IV

General procedure for the obtention of nitrosocompounds 15.

The corresponding amine (1 mmol) was dissolved in CH2Cl2 and added

to a solution of Oxone in H2O or to a solution of m-chloroperbonzoic acid in

CH2Cl2. After completion of the reaction, the crude was extracted with

CH2Cl2, dried with MgSO4 and evaporated under vacuum. The

nitrosocompounds were used without further purification in the next step.

General procedure for the synthesis of β-enaminones 16.

The indolizine 4 (0.3 mmol) was dissolved in MeCN in the reactor

tube, followed by the addition of ArNO 15 (0.3 mmol) and stirring at ambient

temperature overnight. The solvent was removed under vacuum. Purification

of the reaction crude by column chromatography (silica gel, hexane/EtOAc)

afforded the pure β-enaminones 16.

(Z)-3-Phenyl-3-(phenylamino)-1-(pyridin-2-yl)prop-2-

en-1-one (16agaa): yellow solid, m.p. 110.3–113.8 (74.6

mg, 83%); tR 19.26; Rf 0.46 (hexane/EtOAc, 8:2); IR

(neat) ν 3064, 3026, 2989, 2921, 1604, 1590, 1560, 1477,

1331, 1222, 1057, 766, 744; 1H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 8.3

Hz, 1H; ArH), 6.86 (s, 1H; ArH), 6.97- 7.03 (m, 1H; ArH), 7.10-7.16 (m, 2H;

ArH), 7.28-7.45 (m, 6H; ArH), 7.83 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.18 (dt, J

= 7.9, 1.1 Hz, 1H; ArH), 8.64 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.93 (s ,

1H); 13

C NMR (75 MHz, CDCl3) δ 96.4, 121.7, 123.3, 124.3, 125.5, 128.4,

128.5, 128.7, 129.6, 136.8, 148.6 (15 × ArCH), 135.6, 139.4, 155.7, 162.5,

187.8 (5 × ArC); MS (EI) m/z 301 (M+

+ H, 11), 300 (M+, 50), 271 (44), 223

(19), 222 (100), 195 (34), 194 (86), 193 (18), 180 (41), 165 (10), 107 (11), 79

(42), 78 (29), 77 (32); HRMS (ESI) m/z: [M + H]+ Calcd for C20H16N2O

300.1263; Found 300.1257.

(Z)-3-(Phenylamino)-1-(pyridin-2-yl)-3-(p-

tolyl)prop-2-en-1-one (16agba): yellow solid, m.p.

Experimental Part

224

95.1 – 95.9 (94 mg, 88%); tR 21.31; Rf 0.40 (hexane/EtOAc, 8:2); IR (neat) ν

3052, 3027, 2973, 2919, 1560, 1517, 1482, 1330, 1220, 1057, 815, 746, 690; 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H; CH3), 6.84 (d, J = 7.4 Hz, 2H;

ArH), 6.84 (s, 1H; ArH), 7.01 (t, J = 7.4 Hz, 1H; ArH), 7.11- 7.18 (m, 3H,

ArH), 7.29-7.40 (m, 4H, ArH) 7.84 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.17 (dt, J

= 7.8 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.92 (s, 1H); 13

C NMR (75 MHz, CDCl3) δ 21.4 (CH3), 96.2, 121.7, 123.3, 124.2, 125.5,

128.4, 128.5, 128.7, 129.1, 136.9, 148.6 (15 × ArCH), 132.6, 135.6,

(139.6),139.9, 155.9, 162.9, 187.6 (5 × ArC); MS (EI) m/z 315 (M+ + H, 12),

314 (M+, 52), 313 (10), 285 (36), 237 (18), 236 (90), 222 (11), 209 (31), 208

(100), 207 (28), 194 (47), 79 (33), 78 (23), 77 (26); HRMS (ESI) m/z: [M +

H]+ Calcd for C21H18N2O 314.1419; Found 314.1418.

(Z)-3-(4-methoxyphenyl)-3-(phenylamino)-1-

(pyridin-2-yl)prop-2-en-1-one (16agca):

yellow solid, m.p. 135.2 – 136.7 (77 mg, 78%);

tR 25.88; Rf 0.27 (hexane/EtOAc, 8:2); IR (neat)

ν 3055, 3026, 2967, 2930, 1613, 1336, 1254, 1059, 1028, 745; 1H NMR (300

MHz, CDCl3) δ 3.82 (s, 3H; CH3), 6.81-6.87 (m, 5H; ArH), 6.99 – 7.04 (m,

1H; ArH), 7.14-7.19 (m, 2H; ArH), 7.36-7.41 (m, 3H; ArH), 7.84 (td, J = 7.7,

1.8 Hz, 1H; ArH), 8.17 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7,

0.9 Hz, 1H;ArH), 12.92 (s, 1H); 13

C NMR (100 MHz, CDCl3) δ 55.2 (CH3),

96.0, 113.8, 121.7, 123.3, 124.2, 125.4, 128.7, 130.1, 136.8, 148.6 (14 ×

ArCH), 127.7, 139.7, 155.9, 160.8, 162.4, 187.4 (6 × ArC); MS (EI) m/z 330

(M+, 24), 301 (15), 252 (44), 225 (26), 224 (100), 210 (41), 209 (34), 79 (38),

78 (35), 77 (44); HRMS (ESI) m/z: [M + H]+ Calcd for C21H18N2O2 330.1368;

Found 330.1355.

(Z)-3-(phenylamino)-1-(pyridin-2-yl)-3-(4-

(trifluoromethyl)phenyl)prop-2-en-1-one

(16agda): yellow solid, m.p. 133.8 – 136.4 (72

mg, 65%); tR 17.46; Rf 0.44 (hexane/EtOAc, 8:2);

IR (neat) ν 3060, 2943, 2923, 1598, 1560, 1322,

Experimental Part

225

1108, 1052, 831, 742, 698; 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 7.6 Hz,

2H; ArH), 6.87 (s, 1H; ArH), 7.04 (t, J = 7.4 Hz, 1H; ArH), 7.15- 7.19 (m, 2H;

ArH), 7.40 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H; ArH), 7.55- 7.60 (m, 4H; ArH), 7.85

(td, J = 7.7, 1.7 Hz, 1H; ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J

= 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.81 (s, 1H); 13


96.9, 121.8, 123.4, 124.7, 125.4 (q, J =3.3 Hz), 125.8, 128.9, 129.0, 136.9,

148.7 (14 × ArCH), 123.7 (q, J = 272.2 Hz), 131.5 (q, J = 32.6 Hz), 138.9,

139.3, 155.3, 160.5, 188.2 (7 × ArC); MS (EI) m/z 368 (M+, 30), 349 (14), 340

(14), 339 (43), 291 (29), 290 (100), 263 (36), 262 (36), 261 (15), 248 (38), 208

(16), 207 (49), 191 (11), 107 (27), 79 (63), 78 (27), 77 (32); HRMS (ESI) m/z:

[M + H]+ Calcd for C21H15F3N2O 368.1136; Found 368.1140.

Methyl (Z)-4-(3-oxo-1-(phenylamino)-3-

(pyridin-2-yl)prop-1-en-1-yl)benzoate

(16agea): yellow solid, m.p. 112.8 – 113.1

(81.8 mg, 76%); Rf 0.29 (hexane/EtOAc, 8:2);

IR (neat) ν 3056, 2987, 2923, 1722, 1604,

1583, 1550, 1270, 1103, 1056, 746, 694; 1H NMR (300 MHz, CDCl3) δ 3.91

(s, 3H; CH3),6.80 (d, J = 7.6 Hz, 2H; ArH), 6.88 (s, 1H; ArH), 7.01 – 7.04 (m,

1H; ArH), 7.11- 7.16 (m, 2H; ArH), 7.39 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H; ArH),

7.51, 7.99 (AA’XX’ system, 4H; 4 × ArH), 7.84 (td, J = 7.7, 1.7 Hz, 1H;

ArH), 8.18 (dt, J = 7.9, 0.9 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.6, 0.8 Hz,

1H;ArH), 12.83 (s, 1H); 13

C NMR (75 MHz, CDCl3) δ 52.1 (CH3), 96.7,

121.8, 123.3, 124.5, 125.7, 128.5, 128.6, 128.8, 129.6, 136.9, 148.6 (14 ×

ArCH), 131.0, 139.0, 140.0, 155.4, 161.0, 166.3, 188.1 (7 × ArC); MS (EI)

m/z 359 (M+

+ H, 15), 358 (M+, 61), 330 (16), 329 (60), 281 (24), 280 (100),

266 (21), 253 (46), 252 (84), 251 (15), 239 (10), 238 (54), 221 (10), 220 (26),

193 (17), 192 (13), 191 (11), 169 (11), 165 (13), 107 (32), 106 (14), 79 (87),

78 (46), 77 (41); HRMS (ESI) m/z: [M + H]+ Calcd for C22H18N2O3 358.1317;

Found 358.1315.

(Z)-1-(6-methylpyridin-2-yl)-3-phenyl-3-

(phenylamino)prop-2-en-1-one (16cgaa): yellow solid,

Experimental Part

226

m.p. 126.5 – 127.8 (66 mg, 70%); tR 21.31; Rf 30.50 (hexane/EtOAc, 8:2); IR

(neat) ν 3057, 3026, 2921, 2852, 1606, 1560, 1479, 1328, 1218, 1063, 759,

696; 1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H; CH3), 6.81 (d, J = 7.5 Hz, 2H;

ArH),6.87 (s, 1H; ArH), 7.00 (t, J = 7.4 Hz, 1H; ArH), 7.11-7.15 (m, 2H;

ArH), 7.24 (d, J = 7.6 Hz, 1H; ArH), 7.31-7.41 (m, 3H; ArH), 7.43-7.45 (m,

2H; ArH), 7.71 (t, J = 7.7 Hz, 1H; ArH), 7.96 (d, J = 7.7 Hz, 1H; ArH), 12.93

(s, 1H); 13

C NMR (100 MHz, CDCl3) δ 24.6 (CH3), 96.5, 118.8, 123.2, 124.2,

125.2, 128.4, 128.5, 128.7, 129.6, 136.9 (14 × ArCH), 135.8, 139.5, 155.2,

157.5, 162.3, 188.3 (6 × ArC); MS (EI) m/z 314 (M+, 34), 286 (15), 285 (37),

223 (17), 222 (100), 209 (41), 207 (41), 194 (28), 193 (16), 180 (28), 165

(12),121 (14), 93 (59), 92 (26), 77 (39); HRMS (ESI) m/z: [M + H]+ Calcd for

C21H18N2O 314.1419; Found 314.1397.

(Z)-1-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-3-

phenyl-3-(phenylamino)prop-2-en-1-one (16dgaa):

yellow solid, m.p. 165.7 – 168.3 (38 mg, 28%); Rf 0.32

(hexane/EtOAc, 6:4); IR (neat) ν 3015, 2968, 2918, 2850,

1607, 1592, 1557, 1478, 1314, 1224, 1148, 1081, 950,

799, 763, 701; Seleted data for the major rotamer: 1H

NMR (400 MHz, CDCl3) δ 3.06 (s, 3H; CH3), 6.41 (s, 1H;

ArH), 6.82 – 6.86 (m, 2H; ArH), 7.01 – 7.05 (m,

1H,ArH), 7.13 – 7.19 (m, 3H; ArH), 7.35 – 7.53 (m, H; ArH), 7.75 – 7.84 (m,

2H; ArH), 7.88 – 7.91 (m, 2H; ArH), 7.95 – 8.01 (m, 4H; ArH), 8.04 – 8.06

(m, 1H; ArH), 8.25 – 8.28 (m, 1H; ArH), 12.73 (s, 1H); 13

C NMR (100 MHz,

CDCl3) δ 44.5 (CH3), 97.4, 121.3, 123.4, 124.4, 127.4, 127.8, 127.9, 128.5,

128.8, 131.6, 137.9 (18 × ArCH), 139.6, 139.9, 140.8, 143.7, 154.1, 155.0,

158.5, 190.4 (8 × ArC); Seleted data for the minor rotamer: 1H NMR (400

MHz, CDCl3) δ 3.08 (s; CH3), 6.99 (s; ArH), 8.22 (dd, J = 7.7; ArH), 12.99 (s,

1H); 13

C NMR (100 MHz, CDCl3) δ 44.6 (CH3), 96.3, 122.8, 123.3, 124.5,

127.9, 128.6, 129.9, 138.1 (ArCH), 133.7, 139.3, 140.6, 144.1, 153.9, 155.9,

162.8, 187.3 (ArC); MS (DIP) m/z 454 (M+, 22), 425 (17), 350 (18), 349 (74),

270 (10), 234 (16), 233 (100), 223 (12), 222 (78), 194 (45), 193 (12), 180 (28),

Experimental Part

227

154 (14), 153 (13), 77 (28); HRMS (ESI) m/z: [M + H]+ Calcd for

C27H22N2O3S 454.1351; Found 454.1344.

(Z)-1-(4-((E)-3-oxo-1-phenyl-3-(pyridin-

2-yl)prop-1-en-1-yl)pyridin-2-yl)-3-

phenyl-3-(phenylamino)prop-2-en-1-one

(16aga’): yellow solid (652 mg, 64%,

scale 2 mmol); Rf 0.56 (hexane/EtOAc, 6:4); IR (neat) ν 3057, 2973, 2895,

1667, 1562, 1482, 1327, 1217, 1047, 877, 805, 754, 691; Seleted data for the

major rotamer: 1H NMR (400 MHz, CDCl3) δ 6.78 – 6.82 (m, 2H; ArH), 6.91

(s, 1H; ArH), 6.95 – 7.02 (m, 2H; ArH), 7.07 – 7.13 (m, 4H; ArH), 7.19 – 7.26

(m, 2H; ArH), 7.28 – 7.48 (m, 8H; ArH), 7.81 (td, J = 7.7, 1.7 Hz, 1H; ArH),

7.99 (dt, J = 7.8, 1.0 Hz, 1H; ArH), 8.06 (d, J = 0.9 Hz, 1H; ArH), 8.25 (s, 1H;

ArH), 8.69 – 8.72 (m, 2H; ArH), 12.92 (s , 1H); Seleted data for the minor

rotamer: 1H NMR (400 MHz, CDCl3) δ 6.86 (s; ArH), 8.00 (dt, J = 7.8, 1.0

Hz; ArH), 8.18 (s, ArH) 8.29 (d, J = 1.2 Hz; ArH), 8.63 (dd, J = 5.1, 0.5 Hz;

ArH); NMR data for the mixture of rotamers:13


96.7, 96.8, 120.6, 120.7, 121.8, 112.2, 122.8, 123.3, 123.4, 124.3, 124.5,

124.6, 124.8, 125.9, 127.0, 127.1, 127.9, 128.5, 128.6, 128.7, 128.8, 128.9,

129.4, 129.8, 129.9, 130.1, 130.2, 137.1, 148.6, 148.9, 149.0, 149.1 (24 × CH),

135.6, 135.7, 137.9, 139.4, 139.5, 139.8, 149.4, 150.0, 153.7, 154.1, 154.5,

154.6, 155.8, 156.3, 162.6, 162.9, 187.4, 187.6, 189.1, 190.1 (10 × ArC); MS

(EI) m/z 507 (M+, 8), 415 (13), 402 (18), 401 (25), 287 (11), 286 (48), 222

(37), 194 (13), 193 (10), 180 (33), 78 (13), 77 (20), 44 (100); HRMS (ESI)

m/z: [M + H]+ Calcd for C34H25N3O2 507.1947; Found 507.2007.

(Z)-3-phenyl-1-(pyridin-2-yl)-3-(p-

tolylamino)prop-2-en-1-one (16agab): yellow

solid, m.p. 147.5 – 148.3 (43 mg, 46%); tR 21.26; Rf

0.44 (hexane/EtOAc, 8:2); IR (neat) ν 3041, 2997,

2913, 1593, 1558, 1477, 1332, 1223, 1061, 914, 744,

698; 1H NMR (300 MHz, CDCl3) δ 2.25 (s, 3H; CH3), 6.72 (d, J = 8.4 Hz, 2H;

ArH), 6.81 (s, 1H; ArH), 6.94 (d, J = 8.2 Hz, 2H; ArH), 7.29 – 7.45 (m, 6H;

Experimental Part

228

ArH), 7.87 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.19 (d, J = 7.9 Hz, 1H; ArH), 8.66

(d, J = 4.4 Hz, 1H;ArH), 12.95 (s, 1H); 13

C NMR (75 MHz, CDCl3) δ 20.8

(CH3), 95.9, 121.7, 123.2, 125.4, 127.4, 128.3, 128.4, 128.5, 128.6, 129.3,

129.5, 136.7, 148.6 (14 × ArCH), 134.0, 135.7, 136.8, 155.8, 162.8, 187.4 (6 ×

ArC); MS (EI) m/z 314 (M+, 30), 253 (24), 236 (100), 195 (36), 194 (66), 193

(29), 133 (19), 104 (41), 78 (49), 77 (19); HRMS (ESI) m/z: [M + H]+ Calcd

for C21H18N2O 314.1419; Found 314.1400.

(Z)-3-((4-acetylphenyl)amino)-3-phenyl-1-

(pyridin-2-yl)prop-2-en-1-one (16agac): yellow

solid, m.p. 146.8 – 151.1 (65 mg, 63%); tR 32.45;

Rf 0.17 (hexane/EtOAc, 8:2); IR (neat) ν 3062,

3001, 2923, 1670, 1587, 1547, 1475, 1336, 1269,

1059, 856, 796, 754, 694; 1H NMR (300 MHz,

CDCl3) δ 2.50 (s, 3H; CH3), 6.80 – 6.83 (m, 2H; ArH), 6.97 (s, 1H; ArH), 7.33

– 7.47 (m, 7H; ArH), 7.72 – 7.76 (m, 2H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H;

ArH), 8.18 (dd, J = 7.9, 0.9 Hz, 1H; ArH), 8.66 (ddd, J = 4.7, 1.6, 0.8 Hz,

1H;ArH), 12.86 (s , 1H); 13

C NMR (75 MHz, CDCl3) δ 26.3 (CH3), 98.3,

121.7, 121.9, 125.9, 128.2, 128.7, 129.3, 130.1, 136.9, 148.7 (14 × ArCH),

132.2, 135.2, 144.0, 155.2, 160.9, 188.6, 196.7 (7 × ArC); MS (EI) m/z 343

(M+, 10), 342 (28), 313 (36), 236 (43), 222 (100), 194 (61), 135 (26), 79 (35),

78 (45); HRMS (ESI) m/z: [M + H]+ Calcd for C22H18N2O2 342.1368; Found

342.1361.

(Z)-3-((4-(dimethylamino)phenyl)amino)-3-

phenyl-1-(pyridin-2-yl)prop-2-en-1-one

(16agad): brown oil (64 mg, 62%); Rf 0.25

(hexane/EtOAc, 8:2); IR (neat) ν 2989, 2919,

2859, 1601, 1519, 1361, 1331, 1226, 1114, 1062,

817, 727; 1H NMR (300 MHz, CDCl3) δ 2.87 (s,

6H; 2 x CH3), 6.48 – 6.52 (m, 2H; ArH), 6.75 (s, 1H; ArH), 6.72 – 6.75 (m,

2H; ArH), 7.25 – 7.44 (m, 6H; ArH), 7.83 (td, J = 7.7, 1.6 Hz, 1H; ArH), 8.18

(d, J = 7.9 Hz, 1H; ArH), 8.63 (d, J = 4.1 Hz, 1H;ArH), 13.05 (s , 1H); 13

C

Experimental Part

229

NMR (75 MHz, CDCl3) δ 40.6 (2 x CH3), 94.9, 112.5, 121.6, 124.7, 125.2,

128.3, 128.6, 129.4, 136.8, 148.6 (14 × ArCH), 128.5, 135.8, 147.8, 156.1,

163.2, 186.6 (6 × ArC); MS (DIP) m/z 344 (M+ + H, 25), 343 (M

+, 100), 265

(13), 249 (16), 237 (18), 224 (15), 223 (83), 222 (19), 208 (21), 195 (23), 193

(12), 135 (16), 134 (21), 105 (10), 78 (20); HRMS (ESI) m/z: [M + H]+ Calcd

for C22H21N3O 343.1685; Found 343.1681.

(Z)-3-((4-bromophenyl)amino)-3-phenyl-1-

(pyridin-2-yl)prop-2-en-1-one (16agae): yellow

solid, m.p. 149.7 – 152.1 (77 mg, 68%); tR 26.64;

Rf 0.52 (hexane/EtOAc, 8:2); IR (neat) ν 3042,

2995, 2918, 1596, 1552, 1475, 1330, 1279, 1221,

1057, 819, 746, 699; 1H NMR (300 MHz, CDCl3)

δ 6.68, 7.24 (system AA’XX’, J = 8.8 Hz, 4H; 4 × ArH), 6.88 (s, 1H; ArH),

7.34 – 7.43 (m, 6H; ArH), 7.85 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.17 (dt, J =

7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.83 (s, 1H); 13

C NMR (75 MHz, CDCl3) δ 97.1, 121.9, 124.7, 125.9, 128.6, 128.8, 130.1,

131.9, 137.1, 148.8 (14 × ArCH), 117.4, 135.3, 138.8, 155.6, 162.2, 188.3 (6 ×

ArC); MS (EI) m/z 378 (M+, 10), 299 (14), 281 (10), 271 (10), 260 (17), 257

(17), 221 (15), 208 (22), 207 (39), 195 (13), 193 (52), 192 (12), 191 (14), 165

(16), 156 (13), 154 (14), 107 (20), 102 (11), 79 (100), 78 (66), 77 (26), 76

(23); HRMS (ESI) m/z: [M + H]+ Calcd for C20H15BrN2O 378.0368; Found

378.0370.

(Z)-3-phenyl-1-(pyridin-2-yl)-3-(o-tolylamino)prop-

2-en-1-one (16agaf): yellow solid, m.p. 98.2 – 99.7

(58 mg, 62%); tR 19.97; Rf 0.4 (hexane/EtOAc, 8:2); IR

(neat) ν 3061, 3022, 2979, 2904, 1649, 1616, 1560,

1459, 1336, 1232, 1063, 831, 744, 698; 1H NMR (300

MHz, CDCl3) δ 2.48 (s, 3H; CH3), 6.53 (d, J = 7.8 Hz, 1H; ArH), 6.84 (td, J

=7.7, 1.2,1H;ArH), 6.88 (s, 1H; ArH), 6.95 (td, J = 7.4, 1.1 Hz, 1H; ArH),

7.18 (d, J = 7.2 Hz, 1H; ArH),7.26- 7.40 (m, 6H; ArH), 7.82 (td, J = 7.7, 1.7

Hz, 1H; ArH), 8.19 (d, J = 7.9 Hz, 1H; ArH), 8.64 (dd, J = 4.7, 0.8 Hz,

Experimental Part

230

1H;ArH), 12.90 (s , 1H); 13

C NMR (75 MHz, CDCl3) δ 18.3 (CH3), 96.1,

121.7, 124.8, 125.0, 125.4, 125.9, 128.2, 128.3, 129.6, 130.5, 136.8, 148.6 (14

× ArCH), 131.1, 135.7, 138.1, 155.8, 163.4, 187.7 (6 × ArC); MS (EI) m/z 314

(M+, 36), 236 (85), 209 (37), 208 (100), 194 (61), 193 (31), 79 (57), 78 (34);

HRMS (ESI) m/z: [M + H]+ Calcd for C21H18N2O 314.1419; Found 314.1414.

(Z)-3-((2-bromophenyl)amino)-3-phenyl-1-(pyridin-

2-yl)prop-2-en-1-one (16agag): yellow oil (84 mg,

74%); tR 23.42; Rf 0.28 (hexane/EtOAc, 8:2); IR (neat)

ν 3058, 3027, 2925, 2852, 1590, 1556, 1457, 1326,

1282, 1215, 1059, 994, 746, 697; 1H NMR (300 MHz,

CDCl3) δ 6.53 (dd, J = 7.6, 2.0 Hz, 1H; ArH), 6.90 (qd,

J = ¿?, 2H; ArH), 7.0 (s, 1H; ArH), 7.27 – 746 (m, 1H; ArH), 7.60 (dd, J =

7.6, 1.9 Hz, 1H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.25 (d, J = 7.9 Hz,

1H; ArH), 8.68 (ddd, J = 4.6, 1.6, 0.8 Hz, 1H;ArH), 12.77 (s , 1H); 13

C NMR

(75 MHz, CDCl3) 97.8, 117.4, 125.5, 125.9, 127.3, 128.6, 128.7, 130.1, 133.1,

135.6, 137.4, 148.3 (14 × ArCH), , 122.4, 135.6, 138.6, 161.8, 188.0 (6 ×

ArC); MS (EI) m/z 380 (M+ 81

Br, 23), 378 (M+ 79

Br, 26), 351 (11), 349 (19),

302 (40), 301 (13), 300 (47), 299 (100), 274 (25), 273 (12), 272 (28), 271 (27),

260 (35), 258 (28), 222 (12), 221 (59), 220 (16), 209 (13), 208 (39), 207 (32),

195 (70), 193 (72), 165 (28), 154 (13), 107 (33), 106 (17), 80 (12), 79 (79), 77

(13), 76 (13), 75 (12); HRMS (ESI) m/z: [M + H]+ Calcd for C20H15BrN2O

378.0368; Found 378.0371.

(Z)-2-((3-oxo-1-phenyl-3-(pyridin-2-yl)prop-1-en-1-

yl)amino)benzonitrile (16agah): yellow solid, m.p.

142.1 – 144.3 (34 mg, 35%); tR 19.31; Rf 0.44

(hexane/EtOAc, 8:2); IR (neat) ν 3064, 3026, 2989,

2921, 1604, 1590, 1560, 1477, 1330, 1211, 1056, 766,

744, 700; 1H NMR (300 MHz, CDCl3) δ 6.80 – 6.84

(m, 2H; ArH), 6.85 (s, 1H; ArH), 6.98 – 7.02 (m, 1H; ArH), 7.11 – 7.17(m,

2H; ArH), 7.29 – 7.46 (m, 6H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.19

(d, J = 7.9 Hz, 1H; ArH), 8.66 (d, J = 4.6 Hz, 1H;ArH), 12.94 (s , 1H); 13

C

Experimental Part

231

NMR (75 MHz, CDCl3) δ 96.4, 121.8, 123.3, 124.3, 125.6, 128.4, 128.5,

128.7, 129.7, 137.1, 148.4 (14 × ArCH), 115.1, 117.9, 135.5, 139.3, 155.5,

162.7, 187.4 (7 × ArC); MS (EI) m/z 326 (M+ + H, 0.6), 300 (46), 271 (41),

222 (100), 195 (36), 194 (91), 193 (24), 180 (48), 165 (12), 79 (49), 78 (35),

77 (42); HRMS (ESI) m/z: [M - CN]+ Calcd for C20H15N2O 299.1184; found

299.1182.

(Z)-3-((4-(dimethylamino)phenyl)amino)-1-

(pyridin-2-yl)hept-2-en-1-one (16agid): brown

oil (58 mg, 60%); tR 23.27; Rf 0.32

(hexane/EtOAc, 8:2); IR (neat) ν 3057, 2952,

2925, 2864, 1579, 1547, 1502, 1344, 1301, 1211,

1108, 829, 796, 761; 1H NMR (300 MHz, CDCl3)

δ 0.83 (t, J = 7.3 Hz, 3H; CH3), 1.23-1.35 (m, 2H; CH2), 1.51 – 1.61 (m, 2H;

CH2), 2.37 – 2.42 (m, 2H; CH2), 2.96 (s, 6H; CH3), 6.58 (s, 1H; ArH), 6.68 –

6.75 (m, 2H; ArH), 7.03 – 7.08 (m, 2H; ArH), 7.16 – 7.39 (m, 7H; ArH), 7.81

(td, J = 7.7, 1.7 Hz, 1H; ArH), 8.15 (d, J = 7.9 Hz, 1H; ArH), 8.65 (d, J = 4.0

Hz, 1H;ArH), 13.01 (s, 1H); 13

C NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.7,

30.7, 32.2 (3 x CH2), 40.7 (2 x CH3), 91.5, 112.7, 121.7, 125.1, 126.7, 136.9,

148.6 (9 × ArCH), 127.3, 149.2, 156.6, 169.9, 185.8 (5 × ArC); MS (EI) m/z

324 (M+ + H, 36), 323 (M

+, 100), 203 (72), 136 (43), 135 (91), 79 (18), 78


Found 323.1992.

Procedure for the synthesis of compound 18.

NH2-OH·HCl (0.33 mmol) and Na2CO3 (0.17 mmol) were added to a

stirred solution of 16agaa (0.3 mmol) in MeOH (3 mL) and water (1.5 mL) at

room temperature. Then, the reaction was acidified with acetic acid and

refluxed for 2 h. After cooling, the reaction was basified with NH4OH and

extracted with DCM. The organic phase was dried over MgSO4 and filtered.

The crude was purified by column chromatography.

Experimental Part

232

5-Phenyl-3-(pyridin-2-yl)isoxazole (18):162

white

solid (52 mg, 78 %); tR 13.08; Rf 0.13 (hexane/EtOAc,

8:2); 1H NMR (300 MHz, CDCl3) 7.29 (s, 1H; ArH),

7.36 (dd, J = 7.5, 4.8 Hz, 1H; ArH), 7.45 – 7.52 (m,

3H; ArH), 7.82 – 7.91 (m, 3H; ArH), 7.97 (d, J = 7.9 Hz, 1H; ArH), 8.71 (d, J

= 4.8 Hz, 1H; ArH); 13

C NMR (101 MHz, CDCl3) δ 100.6, 121.1, 124.7,

127.0, 129.1, 130.3, 137.4, 150.0 (10 × ArCH), 128.9, 146.5, 163.4, 169.6 (4 ×

ArC); MS (EI) m/z 223 (M+ + H, 14), 222 (M

+, 88), 194 (14), 193 (13), 144

(100), 116 (18), 78 (19), 77 (27).

General procedure for the synthesis of compound 19.

N2H4·H2O (1.5 mmol) was added to a stirred solution of 16agaa (0.3

mmol) in DMF and the reaction mixture was heated to 100°C during 2 h. After

that time, the reaction was diluted with EtOAc and the crude was purified by

column chromatography.

3-Phenyl-5-(2-pyridil)pyrazole (19):163

white solid

(56 mg, 85%); tR 14.41; Rf 0.21 (hexane/EtOAc, 6:4); 1H NMR (300 MHz, CDCl3) 7.10 (s, 1H; ArH),7.25 –

7.29 (m, 1H; ArH), 7.32 – 7.37 (m, 1H; ArH), 7.45 –

7.49 (m, 2H; ArH), 7.77 – 7.79 (m, 2H;ArH), 7.87 (d, J = 8.0, 2H; ArH), 8.69

(d, J = 3.7 Hz, 1H; ArH); 13

C NMR (75 MHz, CDCl3) δ 100.6, 120.3, 123.1,

125.8, 128.2, 128.9, 137.3, 149.5 (9 × ArCH), 132.7, 144.7, 148.7, 151.8 (4 ×

ArC); MS (EI) m/z 222 (M+ + H, 15), 221 (M

+, 100),192 (45), 165 (8), 115

(7).


To a stirred solution of 16agaa (0.3 mmol) in EtOH, PhNHNH2·HCl

(1.5 mmol) was added, and the reaction mixture was heated to 70°C during 8

162

Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Comunn. 2011, 47, 3198. 163

Yu, W.-S.; Cheng, C.-C.; Cheng, Y.-M.; Wu, P.-C.; Song, Y.-H.; Chi, Y.; Chou, P.-T. J. Am. Chem. Soc.

2003, 125, 10800.

Experimental Part

233

hours. After that time, the reaction was concentrated under vacuum and the

crude was purified by column chromatography.

3-Phenyl-5-(2-pyridil)pyrazole (19): yellow oil (49 mg,

56%); tR 18.54; Rf 0.29 (hexane/EtOAc, 8:2); 1H NMR

(400 MHz, CDCl3) 7.15 – 7.17 (m, 2H; ArH), 7.21 – 7.24

(m, 1H; ArH), 7.29 – 7.45 (m, 10H; ArH), 7.61 (t, J = 7.8

1.8 Hz, 1H; ArH), 7.92 – 7.95 (m, 2H;ArH), 8.63 (ddd, J =

4.8 Hz, 1H; ArH); 13

C NMR (101 MHz, CDCl3) δ 106.6, 123.0, 123.8, 125.6,

126.0, 127.9, 128.2, 128.8, 129.1, 136.7, 149.6 (15 × ArCH), 132.9, 140.4,

143.4, 149.3, 152.3 (5 × ArC); MS (EI) m/z 298 (M+ + H, 16), 297 (M

+,

100),296 (90), 191 (15), 77 (15).

General procedure for the synthesis of the compound 21.

DMF was added to a mixture of compound 16agaa (0.3 mmol), N-

bromosuccinimide (0.33 mmol), iodine (0.015 mmol) and potassium carbonate

(0.35 mmol). The reaction was heated to 100°C for 1 h. Then, the reaction was

cooled to room temperature and was quenched with aqueous ammonia and

extracted with EtOAc. The combined organic layers were dried over MgSO4

and filtered. The crude was purified by column chromatography.

(2-Phenyl-1H-indol-3-yl)(pyridin-2-yl)methanone

(21): white solid (61 mg, 68%); tR 26.62; Rf 0.08


2865, 1610, 1479, 1448, 1419, 1220, 1083, 1001, 883,

744, 698; 1H NMR (300 MHz, CDCl3) 7.08 – 7.18 (m,

4H; ArH), 7.26 – 7.29 (m, 4H; ArH), 7.43 – 7.47 (m, 1H;

ArH), 7.64 (td, J = 7.7, 1.6 Hz, 1H; ArH), 7.72 (d, J = 7.7 Hz, 1H; ArH), 8.11

– 8.14 (m, 1H; ArH), 8.21 (d, J = 4.4 Hz, 1H; ArH), 906 (br s, 1H; NH); 13

C

NMR (75 MHz, CDCl3) δ 111.2, 121.9, 122.7, 123.8, 1241, 125.3., 128.2,

128.6, 129.3, 137.1, 147.5 (13 × ArCH), 132.1, 135.7, 146.0, 146.8 (7 × ArC);

MS (EI) m/z 299 (M+ + H, 9), 298 (M

+, 46),269 (24), 221 (17), 220 (100), 191

(19), 165 (23), 134 (8).

Experimental Part

234

General procedure for the synthesis of the 1,3-dicarbonyl compound 22.

The compound 22 was prepared from acetophenone (10 mmol) and

ethyl picolinate (15 mmol) in the presence of K-t-BuO (30 mmol) as base and

t-BuOH as solvent, the mixture was stirred all night at ambient temperature.

The solvent was removed and the crude was extracted with EtOAc and a few

drops of HOAc. The organic layer was dried over MgSO4 and the crude was

purified by column chromatography.

1-Phenyl-3-(pyridin-2-yl)propane-1,3-dione (22): brown

solid (1128 mg, 50%); tR 16.45; Rf 0.38 (hexane/EtOAc,

8:2); IR (neat) ν 3059, 1599, 1535, 456, 1280, 1213, 1068,

993, 929, 771, 750, 707, 687; 1H NMR (300 MHz, CDCl3)

7.43 – 7.61 (m, 4H; ArH), 7.61 (s, 1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H;

ArH), 8.08 – 8.11 (m, 2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd,

J = 4.7, 1.7, 0.9 Hz, 1H; ArH), 16.49 (s , 1H); 13


93.6, 122.1, 126.3, 127.4, 128.6, 132.6, 137.1, 149.1 (10 × ArCH), 135.2,

152.4, 183.4, 186.3 (4 × ArC); MS (EI) m/z 225 (M+, 56), 197 (25), 196 (45),

148 (18), 147 (61), 106 (31), 105 (100), 102 (11), 96 (18), 79 (57), 78 (84), 77

(88), 69 (55), 51 (82); HRMS (ESI) m/z: [M + H]+ Calcd for C14H11NO2

225.0790; Found 225.0790.

(Z)-1-Phenyl-3-(phenylamino)-3-(pyridin-2-yl)prop-2-

en-1-one (23): yellow oil (35 mg, 59%); tR 19.47; Rf 0.28

(hexane/EtOAc, 8:2); IR (neat) ν 3050, 2923, 1592, 1553,

1515, 1455, 1422, 1321, 1287, 1213, 1054, 991; 1H NMR

(300 MHz, CDCl3) 6.38 (s, 1H; ArH), 6.67 – 6.69 (m, 2H; ArH), 6.98 – 7.02

(m, 1H; ArH), 7.11 – 7.16 (m, 2H; ArH), 7.28 – 7.33 (m, 2H; ArH), 7.42 –

7.51 (m, 3H; ArH), 7.61 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.00 – 8.02 (m,

2H;ArH), 8.67 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H; ArH), 12.68 (s , 1H); 13

C NMR

(75 MHz, CDCl3) δ 97.7, 122.9, 124.1, 124.2, 124.3, 127.4, 128.3, 128.8,

131.5, 136.4, 149.7 (15 × ArCH), 139.5, 139.6, 153.9, 158.6, 190.4 (5 ×

ArC); MS (EI) m/z 300 (M+, 9), 196 (16), 195 (100), 181 (13), 105 (20), 78

Experimental Part

235


Found 300.1257.

General procedure for the reaction of pyrroles 17: The indolizine 4

(0.3 mmol) was dissolved in EtOH in the reactor tube, followed by the

addition of ArNO 15 (0.3 mmol) and stirring at ambient temperature

overnight. The solvent was removed under vacuum. Purification of the

reaction crude by column chromatography (silica gel, hexane/EtOAc) afforded

the pure pyrroles 7.

N,N-Dibenzyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-

1H-pyrrol-3-amine (17agia): yellow solid, m.p.

118.1–119.7 (132 mg, 96%); tR 38.74; Rf 0.48


1493, 1328, 1205, 1027, 746, 694; 1H NMR (300 MHz, CDCl3) δ 0.64 (t, J =

7.3 Hz, 3H; CH3), 1.03 (m, 2H; CH2), 2.26 (m, 2H; CH2), 4.03 (s, 4H; CH2),

6.60 (d, J = 8.1 Hz, 1H; ArH), 6.85 (ddd, J = 7.4, 4.9, 1.1 Hz; ArH), 6.93 (s,

1H; ArH), 7.09 – 7.12 (m, 2H; ArH), 7.18 – 7.33 (m, 10H; ArH), 7.36 (d, J =

7.1 Hz, 4H; ArH), 8.40 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13

C NMR (75

MHz, CDCl3) δ 14.0 (CH3), 22.2, 25.9, 60.5 (CH2), 107.2, 119.6, 120.9,

126.6, 127.4, 127.9, 128.5, 128.8, 129.1, 135.4, 149.0 (17 × ArCH), 120.5,

131.1, 133.3, 134.7, 139.9, 151.5 (5 × ArC); MS (EI) m/z 458 (M+ + 1, 35),

457 (M+, 100), 428 (26), 367 (20), 366 (70), 338 (29), 337 (35), 336 (23), 275

(55), 274 (16), 260 (22), 231 (10), 91 (35), 77 (12); HRMS (ESI) m/z: [M +

H]+ Calcd for C32H31N3 457.2518; Found 457.2524.

2-(1-Phenyl-4-(piperidin-1-yl)-5-propyl-1H-pyrrol-

2-yl)pyridine (17aaia): yellow oil (67 mg, 65%); tR

17.63; Rf 0.46 (hexane/EtOAc, 8:2); IR (neat) ν 3054,

2931, 2867, 1712, 1589, 1494, 1438, 1382, 1151,

1049, 746, 694; 1H NMR (300 MHz, CDCl3) δ 0.74 (t,

J = 7.3 Hz, 3H; CH3), 1.20 – 1.32 (m, 2H; CH2), 1.5

(m, 2H; CH2), 1.71 (m, 4H; CH2), 2.53 (s, 2H; CH2), 2.91 (s, 4H; CH2), 6.57

Experimental Part

236

(dt, J = 8.1, 1.0 Hz, 1H; ArH), 6.79 (s, 1H; ArH), 6.87 (ddd, J = 7.3, 5.0, 0.8

Hz; ArH), 7.20 – 7.29 (m,3H; ArH), 7.35 – 7.40 (m, 3H; ArH), 8.41 (ddd, J =

4.9, 1.8, 0.9 Hz, 1H; ArH) 13

C NMR (75 MHz, CDCl3) δ 14.0 (CH3), 22.2,

25.9, 60.5 (CH2), 107.2, 119.6, 120.9, 126.6, 127.4, 127.9, 128.5, 128.8,

129.1, 135.4, 149.0 (17 × ArCH), 120.5, 131.1, 133.3, 134.7, 139.9, 151.5 (5 ×

ArC); MS (EI) m/z 346 (M+ + 1, 11), 345 (M

+, 43), 317 (24), 316 (100), 233

(4), 181 (4), 77 (4); HRMS (ESI) m/z: [M + H]+ Calcd for C23H27N3 345.2205;

Found 345.2216.


1H-pyrrol-3-amine (17afia): yellow solid (88 mg,


ν 3066, 3029, 2915, 2847, 1597, 1492, 1471, 1292,

1070, 752, 699; 1H NMR (300 MHz, CDCl3) δ 0.68 (t,

J = 7.4 Hz, 3H; CH3), 1.18 – 1.31 (m, 2H; CH2), 2.36 – 2.41 (m, 2H; CH2),

3.30 (s, 3H; CH3), 6.69 – 6.81 (m, 4H;ArH), 6.95 (ddd, J = 7.5, 4.9, 1.0 Hz;

ArH), 7.19 – 7.47 (m, 8H; ArH), 8.42 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H; ArH) 13

C

NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.2, 26.5 (CH2), 40.4 (CH3), 110.2,

112.8, 116.3, 120.1, 121.4, 127.7, 128.5, 128.8, 129.0, 135.7, 148.9 (15 ×

ArCH), 130.5, 131.7, 134.2, 150.0, 151.2 (6 × ArC); MS (EI) m/z 368 (M+ + 1,

30), 367 (M+, 100), 339 (21), 338 (77), 322 (13), 246 (17), 245 (57), 181 (21),

168 (11), 77 (12); HRMS (ESI) m/z: [M + H]+ Calcd for C25H25N3 367.2048;

Found 367.2059.

N-Benzyl-N-methyl-1-phenyl-2-propyl-5-(pyridin-2-

yl)-1H-pyrrol-3-amine (17adia): yellow oil (81 mg,

71%); tR 21.03; Rf 0.38 (hexane/EtOAc, 8:2); IR (neat) ν

3060, 3029, 2958, 2930, 2839, 1587, 1494, 1452, 1384,

1154, 992, 774, 740, 696; 1H NMR (300 MHz, CDCl3)

δ 0.74 (t, J = 7.3 Hz, 3H; CH3), 1.23 – 1.30 (m, 2H; CH2), 2.49 – 2.53 (m, 2H;

CH2), 2.62 (s, 3H; CH3), 4.01 (s, 2H; CH2), 6.60 (d, J = 8.1 Hz, 1H; ArH),

6.87 – 6.90 (m, 2H; ArH), 7.20 – 7.43 (m, 11H; ArH), 8.40 (ddd, J = 4.8, 1.5,

0.8 Hz, 1H; ArH) 13

C NMR (75 MHz, CDCl3) δ 14.2, 43.3 (2 × CH3), 22.7,

Experimental Part

237

26.4, 63.8 (3 × CH2), 105.9, 119.8, 121.1, 126.9, 127.7, 128.2, 128.5, 128.7,

128.9, 129.0, 135.4, 149.3 (15 × ArCH), 131.1, 131.2, 137.6, 139.9, 140.1,

151.7 (6 × ArC); MS (EI) m/z 382 (M+ + 1, 23), 381 (M

+, 72), 353 (19), 352

(64), 291 (19), 290 (82), 275 (16), 262 (32), 261 (25), 260 (37), 233 (10), 231

(12), 91 (100), 78 (12), 77 (24), 64 (17); HRMS (ESI) m/z: [M + H]+ Calcd for

C26H27N3 381.2205; Found 381.2199.

N,N-Dibutyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-

1H-pyrrol-3-amine (17acia): brown oil (51.6mg,

74%, scale 0.18mmol); tR 16.01; Rf 0.68


2867, 1590, 1496, 1371, 1151, 742, 696; 1H NMR (300 MHz, CDCl3) δ 0.72

(t, J = 7.3 Hz, 3H; CH3), 0.89 (t, J = 7.2 Hz, 6H; 2 x CH3), 1.13 – 1.49 (m,

11?H; CH2), 2.47 – 2.52 (m, 2H; CH2), 2.81 – 2.86 (m, 4H; 2 x CH2), 6.61 (dt,

J = 8.1, 0.9 Hz, 1H; ArH), 6.80 (s, 1H; ArH), 6.87 (dd, J = 6.8, 5.1 Hz; ArH),

7.22 – 7.41 (m, 6H; ArH), 8.41 (dd, J = 4.8, 0.7 Hz, 1H; ArH) 13

C NMR (75

MHz, CDCl3) δ 14.1 (3 x CH3), 20.6, 22.6, 26.2, 30.4 (8 x CH2), 106.9, 119.6,

120.9, 127.4, 128.5, 128.9, 135.3, 149.2 (10 × ArCH), 120.6, 130.9, 133.5,

134.6, 139.8, 139.9, 151.5 (7 × ArC); MS (EI) m/z 390 (M+ + 1, 23), 389 (M

+,

77), 361 (16), 360 (56), 347 (28), 346 (100), 289 (16), 260 (16), 151 (10);



1H-pyrrol-3-amine (17cgia): yellow solid, m.p.

110.9–112.3 (47 mg, 33%); tR 39.04; Rf 0.64


2871, 1597, 1571, 1492, 1451, 1360, 1201, 1161,

1028, 906, 782, 748, 698; 1H NMR (300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz,

3H; CH3), 0.99 – 1.11 (m, 2H; CH2), 2.27 – 2.32 (m, 2H; CH2), 2.35 (s, 3H;

CH3), 4.03 (s, 4H, CH2), 6.53 (d, J = 7.9 Hz, 1H; ArH), 6.73 (d, J = 7.5 Hz,

1H; ArH), 6.88 (s, 1H; ArH), 7.09-7.12 (m, 3H; ArH), 7.17-7.38 (m, 13H;

ArH); 13

C NMR (75 MHz, CDCl3) δ 14.0, 24.3 (CH3), 22.3, 25.9, 60.4 (CH2),

106.8, 118.1, 119.1, 126.6, 127.1, 127.9, 128.3, 128.5, 128.6, 129.1, 135.7 (19

Experimental Part

238

× ArCH), 132.9, 134.6, 137.7, 139.9, 140.2, 150.9, 157.3 (8 × ArC); MS (EI)

m/z 472 (M+ + 1, 36), 471 (M

+, 100), 442 (22), 381 (23), 380 (74), 352 (26),

351 (32), 350 (18), 289 (45), 274 (16), 207 (16), 91 (23), 77 (10); HRMS

(ESI) m/z: [M + H]+ Calcd for C33H33N3 471.2674; Found 471.2682

N,N-Dibenzyl-2-ethyl-1-phenyl-5-(pyridin-2-yl)-1H-

pyrrol-3-amine (17agja): yellow solid, m.p. 115.1–

118.1 (80 mg, 60%); tR 37.02; Rf 0.40 (hexane/EtOAc,

8:2); IR (neat) ν 3076, 3053, 3027, 2962, 2827, 1594,

1494, 1452, 1390, 1363, 773, 698; 1H NMR (400 MHz, CDCl3) δ 0.62 (t, J =

7.5 Hz, 3H; CH3), 2.34 (q, J = 7.5 Hz, 2H; CH2), 4.04 (s, 4H; CH2), 6.61 (d, J

= 8.1 Hz, 1H; ArH), 6.87 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H; ArH), 6.94 (s, 1H;

ArH), 7.12 – 7.14 (m, 2H; ArH), 7.18 – 7.21 (m, 2H; ArH), 7.25 – 7.30 (m,

5H; ArH), 7.32 – 7.38 (m, 7H; ArH), 8.40 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13

C NMR (75 MHz, CDCl3) δ 138 (CH3), 17.1, 60.6 (CH2), 107.3, 119.6,

120.9, 126.7, 127.5, 127.9, 128.5, 128.8, 129.1, 135.5, 148.9 (17 × ArCH),

131.0, 134.2, 134.8, 139.8, 139.9, 151.4 (7 × ArC); MS (EI) m/z 444 (M+ + 1,

25), 443 (M+, 62), 353 (26), 352 (100), 261 (41), 260 (32), 91 (22), 77 (13);


N,N-Dibenzyl-2-pentyl-1-phenyl-5-(pyridin-2-

yl)-1H-pyrrol-3-amine (17agka): yellow oil (64

mg, 44%); tR 47.03; Rf 0.46 (hexane/EtOAc,

8:2); IR (neat) ν 3059, 3027, 2952, 2925, 2856,

1591, 1495, 1390, 1072, 904, 742, 696; 1H NMR (300 MHz, CDCl3) δ 0.75 (t,

J = 6.8 Hz, 3H; CH3), 1.03 – 1.08 (m, 6H; CH2), 2.30 (t, J = 7.2 Hz, 2H; CH2),

4.07 (s, 4H; CH2), 6.63 (d, J = 8.1 Hz, 1H; ArH), 6.91 (dd, J = 6.4, 4.9 Hz;

ArH), 6.98 (s, 1H; ArH), 7.13 – 7.41 (m, 16H; ArH), 8.45 (d, J = 4.2 Hz, 1H;

ArH) 13

C NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.1, 23.8, 29.7, 31.7, 60.5

(CH2), 107.3, 119.6, 120.9, 126.6, 127.4, 127.8, 128.5, 128.8, 129.1, 135.4,

148.9 (17 × ArCH), 120.6, 130.9, 133.5, 134.6, 139.8, 139.9, 151.5 (7 × ArC);

MS (EI) m/z 486 (M+ + 1, 38), 485 (M

+, 100), 429 (10), 428 (25), 394 (24),

Experimental Part

239

338 (63), 303 (21), 274 (31), 179 (11), 91 (36), 77 (19); HRMS (ESI) m/z: [M

+ H]+ Calcd for C34H35N3 485.2831; Found 485.2835.

N,N-Dibenzyl-2-(3-chloropropyl)-1-phenyl-5-

(pyridin-2-yl)-1H-pyrrol-3-amine (17agla):

yellow semisolid (59 mg, 40%); Rf 0.36


2850, 1590, 1495, 1384, 1360, 1070, 779, 742, 698; 1H NMR (400 MHz,

CDCl3) δ 1.24 – 1.35 (m, 2H; CH2), 2.33 – 2.37 (m, 2H; CH2), 3.15 (t, J = 6.6

Hz, 2H; CH2), 4.03 (s, 4H; CH2), 6.63 (d, J = 8.1 Hz, 1H; ArH), 7.01 (s, 1H;

ArH), 7.08 – 7.13 (m, 2H; ArH), 7.20 – 7.23 (m, 2H; ArH), 7.25 – 7.30 (m,

4H; ArH), 7.32 – 7.36 (m, 7H; ArH), 8.43 (d, J = 4.2 Hz, 1H; ArH) 13

C NMR

(75 MHz, CDCl3) δ 21.5, 31.5, 44.6, 60.8 (4 × CH2), 107.5, 119.9, 121.1,

126.8, 127.7, 127.9, 128.4, 128.8, 129.0, 135.8, 148.8 (17 × ArCH), 131.8,

133.3, 135.0, 139.4, 139.7, 151.1 (7 × ArC); MS (EI) m/z 494 (9) [M+ + 1,

37Cl], 493 (27) [M

+,

37Cl], 492 (25) [M

+ + 1,

35Cl], 491 (70) [M

+,

35Cl], 428

(17), 402 (22), 401 (18), 400 (62), 366 (12), 365 (44), 339 (15), 338 (59), 337

(33), 336 (23), 275 (21), 274 (100), 273 (13), 272 (31), 260 (10), 233 (10), 232

(10), 231 (14), 182 (14), 181 (36), 91 (60), 78 (10), 77 (19); HRMS (ESI) m/z:

[M + H]+ Calcd for C32H30ClN3 491.2128; Found 491.2121.

3-(3-(Dibenzylamino)-1-phenyl-5-(pyridin-2-yl)-

1H-pyrrol-2-yl)propanenitrile (17agma): brown

oil (51 mg, 36%); Rf 0.25 (hexane/EtOAc, 8:2); IR

(neat) ν 3059, 3027, 2923, 1587, 1494, 1453, 1436,

1388, 1153, 1072, 909, 777, 739, 697; 1H NMR (400 MHz, CDCl3) δ 1.49 –

1.54 (m, 2H; CH2), 2.40 – 2.45 (m, 2H; CH2), 4.03 (s, 4H; 2 × CH2), 6.69 (dt,

J = 8.1, 1.0 Hz, 1H; ArH), 6.94 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H; ArH), 7.00 (s,

1H; ArH), 7.08 – 7.13 (m, 2H; ArH), 7.20 – 7.23 (m, 2H; ArH), 7.25 – 7.30

(m, 4H; ArH), 7.04 – 7.07 (m, 2H; ArH), 7.20 – 7.38 (m, 14H; ArH), 8.43

(ddd, J = 4.8, 1.8, 0.9 Hz, 1H; ArH) 13

C NMR (75 MHz, CDCl3) δ 16.0, 20.5,

61.5 (4 × CH2), 107.3, 120.4, 121.2, 127.0, 128.1, 128.2, 129.3, 129.4, 135.6,

149.2 (20 × ArCH), 119.4, 129.3, 132.8, 135.1, 138.9, 139.4, 151.1 (8 × ArC);

Experimental Part

240

MS (EI) m/z 469 (M+ + H, 33), 468 (M

+, 92), 429 (31), 428 (92), 378 (27), 377

(97), 338 (25), 337 (100), 336 (62), 286 (13), 285 (24), 260 (13), 258 (11), 233

(17), 232 (14), 231 (17), 218 (10), 181 (11), 91 (61), 78 (10), 77 (18); HRMS

(ESI) m/z: [M + H]+ Calcd for C32H28N4 468.2314; Found 468.2323.

N,N-Dibenzyl-2-propyl-5-(pyridin-2-yl)-1-(p-tolyl)-

1H-pyrrol-3-amine (17agib): yellow oil (79 mg,


ν 3027, 2957, 2926, 2868, 16698, 1587, 1512, 1436,

1354, 1151, 1100, 962, 826, 775, 739, 697; 1H NMR

(300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz, 3H; CH3),

0.98 – 1.08 (m, 2H; CH2), 2.21 – 2.26 (m, 2H; CH2),

2.37 (s, 3H; CH3), 4.03 (s, 4H; CH2), 6.57 (d, J = 8.1 Hz, 1H; ArH), 6.88 (ddd,

J = 7.4, 4.9, 0.9 Hz, 1H; ArH), 6.97 – 7.00 (m, 3H; ArH), 7.12 – 7.14 (m, 2H;

ArH), 7.17 – 7.22 (m, 2H; ArH), 7.25 – 7.32 (m, 5H; ArH), 7.35 – 7.38 (m,

4H; ArH), 8.43 (ddd, J = 4.9, 1.7, 0.8 Hz, 1H; ArH) 13

C NMR (75 MHz,

CDCl3) δ 14.1, 21.2 (2 × CH3), 22.3, 25.9, 60.5 (4 × CH2), 107.4, 119.6,

120.9, 126.6, 127.9, 128.2, 129.1, 129.5, 135.7, 148.7 (19 × ArCH), 130.7,

133.6, 134.7, 137.1, 137.3, 139.9, 151.3 (8 × ArC); MS (EI) m/z 471 (M+, 28),

380 (35), 351 (15), 289 (19), 207 (29), 91 (100), 78 (10), 77 (15), 65 (15);


1-(4-(3-(Dibenzylamino)-2-propyl-5-(pyridin-2-yl)-

1H-pyrrol-1-yl)phenyl)ethan-1-one (17agic): yellow


(neat) ν 3060, 3027, 2958, 2927, 2869, 1736, 1683,

1598, 1496, 1358, 1261, 956, 777, 740, 698; 1H NMR

(300 MHz, CDCl3) δ 0.64 (t, J = 7.3 Hz, 3H; CH3),

0.98 – 1.03 (m, 2H; CH2), 2.28 – 2.33 (m, 2H; CH2),

2.28 (s, 3H, CH3), 4.03 (s, 4H; CH2), 6.86 (d, J = 8.0 Hz, 1H; ArH), 6.87 (s,

1H; ArH), 6.89 (ddd, J = 7.5, 4.9, 1.0 Hz; ArH), 7.7 – 7.38 (m, 13H; ArH),

7.91 (d, J = 8.5 Hz, 2H; ArH), 8.31 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13

C

NMR (75 MHz, CDCl3) δ 14.0 (CH3), 22.2, 25.9, 26.6 (CH2), 60.4 (CH3),

Experimental Part

241

107.7, 119.9, 121.3, 126.7, 127.9, 128.4, 128.8, 129.1, 135.6, 149.0 (19 ×

ArCH), 128.6, 131.2, 132.9, 135.1, 139.7, 144.5, 151.4, 197.2 (9 × ArC); MS

(EI) m/z 500 (M+ + H, 38), 499 (M

+, 100), 471 (10), 470 (28), 409 (30), 408

(96), 380 (32), 379 (41), 378 (26), 318 (15), 317 (63), 316 (17), 302 (19), 264

(16), 231 (11), 172 (11), 91 (65); HRMS (ESI) m/z: [M + H]+ Calcd for

C34H33N3O 499.2624; Found 499.2630.

N,N-Dibenzyl-1-(4-bromophenyl)-2-propyl-5-

(pyridin-2-yl)-1H-pyrrol-3-amine (17agie): yellow


(neat) ν 3062, 3026, 2961, 2938, 2902, 2868, 1588,

1573, 1489, 1386, 1363; 1069, 959, 838, 775, 742,

695; 1H NMR (300 MHz, CDCl3) δ 0.66 (t, J = 7.3 Hz,

3H; CH3), 0.98 – 1.06 (m, 2H; CH2), 2.23 – 2.28 (m,

2H; CH2), 4.02 (s, 4H;2 × CH2), 6.76 (dd, J = 8.1, 0.9 Hz, 1H; ArH), 6.86 (s,

1H; ArH), 6.90 (ddd, J = 7.5, 4.9, 1.0 Hz; ArH), 6.97, 7.43 (system AA’BB’, J

= 8.6 Hz, 4H; ArH), 7.17 – 7.24 (m, 2H; ArH), 7.27 – 7.30 (m, 4H; ArH), 7.32

– 7.38 (m, 5H; ArH), 8.35 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H; ArH) 13

C NMR (75

MHz, CDCl3) δ 14.0 (CH3), 22.3, 25.8, 60.4 (3 × CH2), 107.4, 119.8, 121.1,

126.7, 127.9, 129.3, 130.0, 131.9, 135.6, 148.9 (19 × ArCH), 121.0, 131.0,

133.1, 134.8, 139.1, 136.7, 151.3 (8 × ArC); MS (EI) m/z 538 (M+ + 1, 25),

537 (M+, 77), 536 (M

+ + 1, 26), 535 (M

+, 75), 508 (22), 506 (21), 447 (22),

446 (72), 445 (24), 444 (77), 418 (23), 417 (34), 416 (40), 415 (31), 414 (19),

356 (12), 355 (55), 354 (24), 353 (57), 352 (16), 340 (16), 338 (19), 261 (10),

260 (11), 259 (15), 258 (18), 232 (13), 231 (32), 172 (22), 157 (12), 155 (11),

91 (100), 78 (16); HRMS (ESI) m/z: [M + H]+ Calcd for C32H30BrN3

535.1623; Found 535.1621.

2-(1-Phenyl-4-(piperidin-1-yl)-5-propyl-1H-pyrrol-

2-yl)pyridine (17agif): yellow oil (96 mg, 68%); tR

38.06; Rf 0.56 (hexane/EtOAc, 8:2); IR (neat) ν 3026,

2957, 2928, 2868, 2823, 1698, 1646, 1587, 1492,

1454, 1435, 1386, 1150, 961, 775, 738, 697; 1H NMR

Experimental Part

242

(300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz, 3H; CH3), 0.97 – 1.04 (m, 2H; CH2),

1.59 (s, 3H, CH3), 1.78 – 1.88 (m, 1H; CH2), 2.16 – 2.26 (m, 1H; CH2),3.99,

4.09 (AB system, J = 13.1, 4H; 2 × CH2), 6.51 (d, J = 8.2 Hz, 1H; ArH), 6.86

(ddd, J = 7.4, 4.9, 0.8 Hz; ArH), 7.01 (s, 1H; ArH), 7.13 – 7.29 (m, 11H;

ArH), 7.36 – 7.38 (m, 4H; ArH), 8.42 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13

C

NMR (75 MHz, CDCl3) δ 14.1, 16.9 (2 × CH3), 22.2, 25.9, 60.8 (3 × CH2),

107.0, 119.3, 119.6, 126.3, 126.6, 127.9, 128.3, 129.1, 129.2, 135.6, 148.8 (19

× ArCH), 133.4, 134.5, 135.9, 137.2, 138.8, 139.9, 151.1 (8 × ArC); MS (EI)

m/z 472 (M+ + 1, 31), 471 (M

+, 100), 442 (21), 381 (22), 380 (62), 352 (15),

351 (16), 289 (21), 274 (11), 260 (12), 207 (16), 91 (26); HRMS (ESI) m/z:

[M + H]+ Calcd for C33H33N3 471.2674; Found 471.2689.


Ethylmagnesium bromide (3 mL) was added to a solution of 1-hexyne

(12 mmol) in dry THF at room temperature for 30 min. Then, pyridine-2-

carboxaldehyde (10 mmol) was added dropwise at 0 ºC. The reaction was

stirred for 2 h at 0 ºC and quenched with NH4Clsat and extracted wit EtOAc.

The organic layers were dried over MgSO4 and concentrated under vacuum.

The crude propargylic alcohol was used without further purification.

DMSO was added to a solution of oxalyl chloride in dichloromethane

at –78 ºC and the mixture was stirred for 45 min. The crude alcohol in

dichloromethane was added dropwise. After 45 min, Et3N was added and the

resulting mixture was allowed to warm to room temperature. After 4 h, the

reaction was quenched with NH4Clsat and extracted. The crude was purified by

column chromatography.

1-(Pyridin-2-yl)hept-2-yn-1-one (24): dark oil (539 mg,

29%); tR 16.45; Rf 0.38 (hexane/EtOAc, 8:2); 1H NMR

(300 MHz, CDCl3) 7.43 – 7.61 (m, 4H; ArH), 7.61 (s,

1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.08 – 8.11

(m, 2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd, J = 4.7, 1.7, 0.9

Hz, 1H; ArH), 16.49 (s , 1H); 13

C NMR (75 MHz, CDCl3) δ 13.5 (CH3), 19.3,

22.1, 29.8 (3 × CH2), 80.5, 99.5, 153.1, 178.2 (4 × ArCH), 80.5, 99.5, 153.1,

Experimental Part

243

178.2 (4 × ArC); MS (EI) m/z 187 (M+, 1), 186 (6), 159 (21), 158 (36), 146

(13), 145 (100), 144 (12), 130 (31), 117 (32), 106 (13), 79 (24), 78 (36).


Dibenzylamine (1.1 mmol) was added to a solution of compound 24 (1

mmol) in MeOH and stirred until completion of the reaction (TLC). The

mixture was concentrated by rotatory evaporation and purified by column

chromatography to obtain compound 26.

(E)-3-(Dibenzylamino)-1-(pyridin-2-yl)hept-2-en-1-one

(25): yellow oil (230 mg, 60%); tR 31.37; Rf 0.20


1512, 1470, 1450, 1353, 1189, 1081, 945, 745, 696,

687; 1H NMR (300 MHz, CDCl3) 7.43 – 7.61 (m, 4H;

ArH), 7.61 (s, 1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.08 – 8.11 (m,

2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd, J = 4.7, 1.7, 0.9 Hz,

1H; ArH), 16.49 (s , 1H); 13

C NMR (75 MHz, CDCl3) δ 14.0 (CH3), 23.3,

29.6, 31.2, 52.5 (5 × CH2), 90.9, 121.8, 125.0, 126.9, 127.7, 129.0, 136.7,

148.1 (15 × ArCH), 136.6, 157.8, 169.1, 185.9 (5 × ArC); MS (EI) m/z 384

(M+, 5), 294 (19), 293 (86), 223 (13), 196 (25), 189 (48), 188 (22), 159 (15),

106 (24), 91 (100), 78 (31). HRMS (ESI) m/z: [M + H]+ Calcd for C26H28N2O2

384.2202; Found 384.1995.

SELECTED NMR SPECTRA

NMR selected spectra

247


248


249


250


251


252


253


254

ABBREVIATIONS

Abbreviations

257

Abs Absorbance

aq. Aqueous

br broad

C Activated carbon

calcd. calculated

CDC Cross-dehydrogenative coupling

COSY Correlation spectroscopy

CSP Carbon spheres

d doublet

DIP Direct Inlet Probe

GC-MS Gas Chromatography-Mass Spectroscopy

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene,

DCM Dichloromethane

DIP Direct injection process

DMF dimethylformaldehyde

DMSO Dimethyl sulfoxide

d.r. Diastereomeric ratio

DTBB Di-tert-butylbiphenyl

ε Dielectric constant

E+ electrophile

EDX Energy-dispersive X-ray

EG Ethylene glycol

EI Electron impact

eq. equivalents

EWG Electronwithdrawing group

FDA Food and drug administration

HIPS High-impact polystyrene

HMBC Heteronuclear Multiple Bond Correlation

HPLC High Performance Liquid Chromatography

HSQC Heteronuclear Single Quantum Coherence

ICP-MS Inductively Coupled Plasma-Mass Spectrometry

IR Infrared radiation

L ligand

MCR Multicomponent reaction

m multiplet

max maximum

Abbreviations

258

MK Montmorillonite-K

MNPs Metallic nanoparticles

Ms mesylate

NMR Nuclear magnetic resonance

NOESY Nuclear Overhauser effect spectroscopy

NPs Nanoparticles

OIDD Open innovation drug discovery

OMIM 1-octyl-3-methylimidazolium

Pip Piperidinium

Piv Pivaloyl

PP Polpropylene

PS Polystyrene

PVC Poly(vinyl chloride)

rt Room temperature

s Singlet

SEM Scanning Electron Microscope

SB Styrene-butadiene

t triplet

TBS tert-butylsilyl

TEM Transmission Electron Microscopy

TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl

THF Tetrahydrofuran

Tf Triflate

TLC Thin layer chromatography

TMCl Trimethylsilyl chloride

TOF Turnover frequency

TON Turnover number

UV-Vis Ultraviolet-Visible

wt weight

XPS X-Ray Photoelectron Spectroscopy

XRD X-Ray Difraction

ZSM Zeolite Socony Mobil

Selective synthesis and reactivity of indolizines · indolizines and nitrosocompounds”...

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