Functionalization of the C-H Bond Adjacent to a Secondary Nitrogen ...

Functionalization of the C-H Bond Adjacent to a Secondary Nitrogen Atom

Liang Zhao

A thesis submitted to McGill University in partial fulfillment of the requirements for the degree of

Doctor of Philosophy

Department of Chemistry

McGill University, Montréal

August 2009

Liang Zhao, 2009

Functionalization of the C-H Bond Adjacent to a Secondary Nitrogen Atom Liang Zhao Advisor: Prof. Chao-Jun Li McGill University

This thesis is about the development of new methods to introduce functionalities

directly to compounds with a secondary nitrogen atom via C-H bond oxidation.

A copper-mediated oxidative coupling between glycine derivatives (including

short peptides) and nucleophiles (including malonates, aryl alkynes, arylboronic acids

and indoles) were developed. Later, a chiral chlorosilane induced asymmetric indolation

of imino amides was also studied. In addition, a study on the α-arylation of

tetrahydroisoquinoline with iodobenzene was presented. The reaction was proposed to

undergo via palladium catalyzed β-hydride elimination, imine insertion pathway.

This thesis also described a three-component coupling reaction of aldehyde,

alkyne and alkyl hydroxylamine catalyzed by CuCl/bipy complex to synthesize β-lactam

was presented.

In the end of the thesis, a collaboration work with the Department of

Biochemistry on the study of thioxothiazolidinone derivatives as the cellular inhibitor of

protein tyrosine phosphatase 1B was presented. The thioxothiazolidinone derivatives

were synthesized and the bioactivities were studied.

Fonctionnalisation de liaisons C-H adjacentes à un atome d’azote secondaire Liang Zhao Superviseur: Prof. Chao-Jun Li Université McGill

Cette thèse a pour sujet le développement de nouvelles méthodes pour la

fonctionnalisation directe de composés possédant des amines secondaires via l’oxydation

de liaisons C-H.

Dans la première partie de cette thèse, un couplage oxydant au cuivre entre des

dérivés de la glycine (incluant des peptides de petite taille) et des nucléophiles est

présenté. L’indolisation asymétrique d’amides aminés induit par une silicone chlorée est

également étudiée. Cette partie se termine par une étude de l’arylation-alpha de la

tetrahydroisoquinoline avec de l'iodobenzène. Une voie mécanistique catalysée par le

palladium, faisant intervenir une β-H élimination suivie d’une insertion d’imine est

proposée.

Dans la deuxième partie de cette thèse, est présenté une réaction de couplage à

trois composés entre aldéhydes, alcynes et hydroxylamines alkyles, catalysée par un

complexe CuCl/bipy, pour la synthèse de β-lactames.

Dans la dernière partie de cette thèse, est présenté un travail en collaboration avec

le département de biochimie sur l’étude de dérivés de thioxothiazolidinone comme

inhibiteurs cellulaires de la protéine tyrosine phosphatase 1B. Ces dérivés de

thioxothiazolidinone furent synthétisés et leurs activités biologiques furent étudiées.

i

Acknowledgements

First, I gratefully acknowledge the support of my supervisor, Dr. Chao-Jun

Li, whose guidance and encouragement have seen me through these years.

I am also indebted to the following people at McGill for their assistance and

support:

• Dr. Michel L. Tremblay, for the initiation and collaboration of the

project “Cellular Inhibition of Protein Tyrosine Phosphatase 1B by

Uncharged Thioxothiazolidinone Derivatives”. His students Matthew

Stuible and Isabelle Aubry have been very helpful and finished the

biological test and preparing the manuscript during the collaboration.

• Dr. Zhiheng Xia, for the training and discussion of NMR data.

• Dr. Nadim and Dr. Lesimple for obtaininig HRMS data.

• Dr. Gleason, Dr. Bohle, Dr. Auclair, Dr. Hay, Dr. Arndtsen and Dr.

Moitessier labs, for allowing me to borrow a variety of chemicals

and equipments through my studies.

• Chantal Marotte, without whom no graduate student would last very

long. Her kindness and support have been greatly appreciated.

• Oliver Baslé, for his assistant with the experiment.

• Xiaohong Liao, for help with synthesis.

• Patricia D. Macleod, Steven, Haipeng Bi and Dr. Yang for proof-

reading of this thesis.

• Oliver Baslé, Maxime and Johan for translation of the abstract into

French.

I would also like to thank Dr. Chao-Jun Li, McGill University for financial

support.

ii

I am extremely grateful to the people whom I have worked with every day in

the lab. Dr. Yao, Dr. Li, Dr. Zhang, Dr. Herrerias, Dr. Deng, Dr. Feng, Dr. Yoo,

Oliver, and Haipeng have been a consistent source of friendship, good advice, and

interesting discussion. I am also happy to have shared the lab with other lab

members, including Nicolas, Patricia, Rene, Ryan, Steven, Lei, Camille, Xiangyu,

Wenwen, Dong, Tieqiang, Maxime, Leon, Sarim, and Rachid.

My special thanks go to my family. My parents’ and sister’s constant faith in

me has been a blessing and a motivation. Their encouragement was always

appreciated, and their pride is deeply touching.

iii

Table of Contents Acknowledgements ..................................................................................................i Table of Contents................................................................................................... iii List of Tables ....................................................................................................... viii List of Figures..........................................................................................................x List of Abbreviations ..............................................................................................xi Part I – Copper-Mediated Oxidative Coupling of Glycine Derivatives with

Malonate, Aryl Alkynes and Arylboronic Acid Chapter 1 – Introduction to α-Functionalization of Amino Acids and Oxidative

Coupling of C-H Bond Adjacent of a Nitrogen Atom ...................1 1.1 Recent Development to α-Functionalize Amino Acid Derivatives..............1

1.1.1 Functionalization via Enolates Intermediate..........................................2

1.1.2 Functionalization via α-Carbon-Centered Radicals ..............................5

1.2 C-C Bond Formation via C-H Activation Adjacent to Heteroatom .............6 References for Chapter 1 .......................................................................................13 Chapter 2 – Oxidative Coupling between N-Acetyl Glycine Ester and Malonate

..........................................................................................................19 2.1 Background................................................................................................19 2.2 Discovery of the Oxidative Coupling between N-Acetyl Glycine Ester and

Malonate; Optimization of the Reaction Conditions ................................. 20 2.3 Scope of the Copper-Mediated Oxidative Coupling of N-Acetyl Glycine

Esters and Malonates .................................................................................24 2.4 Proposed Reaction Mechanism ..................................................................26

iv

2.5 Conclusion .................................................................................................27 2.6 Experimental Section.................................................................................27 References for Chapter 2 .......................................................................................33 Chapter 3 – Site-Specific Alkynylation of Free (NH) Glycine Derivatives and

Peptides via Direct C-H Bond Functionalization ........................ 35 3.1 Background................................................................................................35 3.2 Discovery of the Oxidative Coupling of N-PMP Glycine Amide with

Phenylacetylene .........................................................................................35 3.3 Scope of the Oxidative Coupling of N-PMP Glycine Amide with Aryl

Alkynes ......................................................................................................37 3.4 Mechanism..................................................................................................40 3.5 Conclusion ..................................................................................................41 3.6 Experimental Section..................................................................................41 References for Chapter 3 .......................................................................................49 Chapter 4 – Site-Specific Arylation of Free (NH) Glycine Derivatives and

Peptides via Direct C-H Bond Functionalization ........................51 4.1 Background.................................................................................................51 4.2 Oxidative Coupling of N-PMP Glycine Amide with Aryl Boronic Acid...51 4.3 Oxidative Arylation of Short Peptides........................................................53 4.4 Importance of N-PMP Protecting Group ....................................................55 4.5 Racemization Test ......................................................................................55 4.6 Deprotection of PMP Group and Further Functionalization ......................56 4.7 Proposed Reaction Mechanism ..................................................................55 4.8 Conclusion ..................................................................................................59

v

4.9 Experimental Section.................................................................................59 References for Chapter 4 .......................................................................................79 Part II – Approach to α-Indoly Glycine Derivatives via Enantioselective

Friedel-Crafts Reaction with Imino Amide Chapter 5 – Approach to α-Indoly Glycine Derivatives via Enantioselective

Friedel-Crafts Reaction with Imino Amide ................................. 80 5.1 Background................................................................................................80 5.2 Discovery of the Enantioselective Indolation to Imino Amide .................80 5.3 Scope of the Copper-Mediated Oxidative Coupling of N-Acetyl Glycine

Esters and Malonates .................................................................................83 5.4 Conclusion ..................................................................................................83 5.5 Experimental Section..................................................................................84 References for Chapter 5 .......................................................................................90 Part III –“Three-Component” Synthesis of β-Lactams via Kinugasa Reaction Chapter 6 – Introduction to β-Lactam Formation via Kinugasa Reaction ...93 References for Chapter 6 .......................................................................................98 Chapter 7 – Highly Efficient “Three-Component” Synthesis of β-Lactams

From N-Alkyl Hydroxylamine, Aldehydes, and Phenylacetylene........................................................................................................100

7.1 Background of the “Three-Component” Synthesis of β-Lactam ............100 7.2 Discovery of the “Three-Component” Synthesis of β-Lactam and

Optimization of the Reaction Conditions ................................................101 7.3 Scope of the “Three-Component” Synthesis of β-Lactam .......................102 7.4 Conclusion ................................................................................................101

vi

7.5 Experimental Section................................................................................101 References for Chapter 7 .....................................................................................114 Part IV – α-Arylation of Tetrahydroisoquinoline with Aryl iodide via C-H

Functionalization Chapter 8 – Introduction to α-Arylation Reaction via 1,2-Addition to Imines

Catalyzed by Transitional Metal Compounds ........................... 115 8.1 α-Arylation Reaction via 1,2-Addition to Imines Catalyzed by Rhodium

Compounds .............................................................................................. 115

8.1.1 Organoboron as the Nucleophile ........................................................116

8.1.1.1 1,2-Addition without Enantioselecitivity..................................116 8.1.1.2 Asymmetric 1,2-Addition of Aryl Boron Reagent to Imines ...117

8.1.2 Organostannane as the Nucleophile....................................................122

8.2 α-Arylation Reaction via 1,2-Addition to Imines Catalyzed by Palladium Compounds ..............................................................................................123

References for Chapter 8 .....................................................................................125 Chapter 9 – α-Arylation of Tetrahydroisoquinoline with Aryl

Iodide via C-H Functionalization ............................................. 128 9.1 Background and Initiation of the Project....................................................128 9.2 Optimization of Reaction Conditions .........................................................129 9.3 Discussion and Proposed Reaction Mechanism .........................................135 9.4 Experimental Section..................................................................................136 References for Chapter 9 .....................................................................................138 Conclusions and Claims to Original Knowledge ............................................139

vii

Supplementary Information – Synthesis of Thioxothiazolidinone Derivatives-Cellular Inhibitor of Protein Tyrosine Phosphatase 1B ..............................................141

S.1 Background ..............................................................................................141 S.2 Synthesis of the Thioxothiazolidinone Derivatives and Study of Their

Inhibition Activities Towards PTP1B......................................................142 S.3 Conclusion................................................................................................145 S.4 Experimental Section ...............................................................................145 References for Supporting Material ....................................................................152

viii

List of Tables Table 2.1 Screening of the Oxidants for the Oxidative Coupling

between N-Acetyl Glycine Ethyl Ester and Diethyl Malonate...........................................................................................21

Table 2.2 Screening of the Ligands for Oxidative Coupling between

N-Acetyl Glycine Ethyl Ester and Diethyl Malonate.......................22 Table 2.3 Screening of the Base for the Oxidative Coupling

between N-Acetyl Glycine Ethyl Ester and Diethyl Malonate...........................................................................................23

Table 2.4 Attempts to Use O2 as the Terminal Oxidant for the

Oxidative Coupling between N-Acetyl Glycine Ethyl Ester and Diethyl Malonate .......................................................................24

Table 2.5 Functionalization of N-Acetyl Glycine Ester by CDC Reaction

with Malonates .................................................................................25 Table 3.1 Functionalization of N-PMP Glycine Amides 3d by CDC

Reaction with Alkynes 3e.................................................................38 Table 4.1 Optimization of the Reaction Conditions for the Arylation

of N-PMP Glycine Amide ................................................................52 Table 4.2 Arylation of Glycine Amides............................................................53 Table 4.3 Arylation of Short Peptide ................................................................54 Table 4.4 Test of Other Protecting Groups .......................................................55 Table 4.5 Arylation of Imino Amides...............................................................58 Table 5.1 Screening Asymmetric indolation Conditions Using

Glycine Amide as the Substrate .......................................................82 Table 5.2 Screening Asymmetric Indolation Conditions Using Imino Amide

as the Substrate .................................................................................83 Table 5.3 Scope of Asymmetric Indolation of Imino Amide ...........................84 Table 7.1 Optimization of the Reaction Conditions .......................................101

ix

Table 7.2 Synthesis of β-lactam via the Coupling of N-Methyl Hydroxylamine, Aldehyde and Phenyl Acetylene .........................102

Table 7.3 Synthesis of β-lactam via the Coupling of N-Benzyl

Hydroxylamine, Aldehyde and Phenyl Acetylene .........................103 Table 9.1 Screening of Catalyst, Base and Temperature for the α-Arylation

of THIQ with Iodobenzene.............................................................130 Table 9.2 Screening of Co-catalyst for the α-Arylation of THIQ with

Iodobenzene....................................................................................131 Table 9.3 Screening of Co-catalyst for the α-Arylation of THIQ with

Iodobenzene....................................................................................132 Table 9.4 Screening of Solvent for the α-Arylation of THIQ with

Iodobenzene.................................................................................... 133 Table 9.5 Screening of Ratios of Pd(OAc)2/Cu(OMe)2 in the α-

Arylation of THIQ with Iodobenzene ............................................134 Table 9.6 Tests of Ar-X in the α-Arylation of THIQ ......................................135 Table S.1 Chemical Structures and IC50 Values of Monosubstituted Ring

Derivatives for PTP1B ...................................................................144 Table S.2 Chemical Structures and IC50 Values of Tri-substituted Ring

Derivatives for PTP1B ...................................................................145

x

List of Figures Figure 2.1 Stable Imines ..................................................................................20 Figure 4.1 Tautomerization between the Amide and the Iminol .......................59 Figure S.1 Leading Compound for the Uncharged PTP1B Inhibitor Family..142 Figure S.2 Comparison of Cellular Inhibition between 10a and 10b ............. 143

xi

List of Abbreviations Ac acetyl ACN acetonitrile acac acetylacetone Ar aryl BHT 2,6-di-tert-butyl-4-methyl phenol Bn benzyl Boc tert-butoxycarbonyl BQ 1,4-benzoquinone br broad (1H NMR) nBu n-butyl tBu tert-butyl C-C carbon-carbon C-H carbon-hydrogen cod 1,5-cyclooctadiene coe cyclooctene Cy cyclohexyl d doublet (1H NMR) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

xii

DFMP difluoromethylenephosphonates DIPEA N,N-diisopropylethylamine DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppb bis(diphenylphosphino)butane dppbenz 1,2-bis(diphenylphosphino)benzene dppe bis(diphenylphosphino)ethane dppp bis(diphenylphosphino)propane dr diastereomeric ratio ee enantiomeric excess Et ethyl eth ethylene equiv equivalence HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3

tetramethyluronium hexafluorophosphate) HOBt hydroxybenzotriazole IR infrared spectroscopy m multiplet (1H NMR) or medium (IR) Me methyl NBE norbornylene NHPI N-hydroxyphthalimide NMR nuclear magnetic resonance spectroscopy HRMS high-resolution mass spectroscopy

xiii

Nu nucleophile NMP N-methyl-2-pyrrolidinone [O] oxidative conditions OTf trifluoromethanesulfonate Ph phenyl PMP para-methoxyphenyl PTK protein tyrosine kinase PTP phosphatase ppm parts per million iPr isopropyl q quartet (1H NMR) RT room temperature s singlet (1H NMR) or strong (IR) SDS sodium dodecyl sulfonate SET single electron transfer t triplet (1H NMR) TBAB tetrabutyl ammonium bromide TBHP tert-butyl hydroperoxide temp. temperature TCCA trichloroisocyanuric acid TFA trifluoroacetyl THF tetrahydrofuran THIQ tetrahydroisoquinoline

xiv

T-HYDRO® tert-butyl hydroperoxide, 70 wt% in water TLC thin-layer chromatography Ts para-toluene sulfonyl w weak (IR) Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Part I – Copper-Mediated Oxidative Coupling of Glycine Derivatives with Malonate, Aryl

Alkynes and Arylboronic Acid

Chapter 1: Introduction to α-Functionalization of Amino Acids and Oxidative

Coupling of C-H Bond Adjacent of a Nitrogen Atom

Chapter 2: Oxidative Coupling between N-Acetyl Glycine Ester and Malonate

Chapter 3: Site-Specific Alkynylation of Free (NH) Glycine Derivatives and

Peptides via Direct C-H Bond Functionalization

Chapter 4: Site-Specific Arylation of Free (NH) Glycine Derivatives and Peptides

via Direct C-H Bond Functionalization

Chapter 1: Introduction to α-Functionalization of Amino Acids and Oxidative

Coupling of C-H Bond Adjacent of a Nitrogen Atom

1

Chapter 1 – Introduction to α-Functionalization of Amino Acids and

Oxidative Coupling of C-H Bond Adjacent of a Nitrogen Atom

It is well known that some of the most important nitrogen containing

compounds are α-amino acids. With the recent advances in proteomics, there has

been a great interest in study the properties and functions of natural and non-

natural (synthetic) amino acids. By using non-natural (synthetic) α-amino acids,

the conformation and/or stability of biologically active peptides can be modified.

For example, by incorporating α -aminoisobutyric acid into oligopeptides, the

peptide backbone could be rigidified through the formation of β-turns or α-

helices. In the area of functionalization of α-amino acid derivatives, the

conventional methods such as enolate chemistry are still the most prevalent

method. However, recent advances in proteomics demand innovative methods to

rapidly generate and modify peptides and α-amino acids. Direct and site-specific

modification of α-amino acids and peptides takes advantage of the existing

structure and provides a convenient way to generate large arrays of diverse α-

amino acids and peptides for biomedical applications. In this chapter, a brief

introduction of the developments to α-functionalize amino acid derivatives, as

well as a detailed review of the oxidative coupling reaction of the C-H bonds

adjacent to nitrogen will be presented.

1.1– Recent Development to α-Functionalize Amino Acid Derivatives

The most popular way to introduce an electrophilic functionality to α-

amino acid derivatives is through enolate chemistry. Due to the presence of the

amide carbonyl group in the α-amino acid derivative, it is straightforward to

deprotonate the hydrogen on the C-H bond using a strong base. Subsequently, by

adding an electrophilic substrate into the mixture, the enolate will be able to

undergo a substitution or an addition to afford the coupling product.

2

1.1.1– Functionalization via Enolate Intermediates

Seebach and co-workers did the most intensive work in the enolate

alkylation area.1-5 They used strong bases to deprotonate the peptides at low

temperature. The so-formed enolate can then be trapped with alkyl halides,

aldehydes or CO2 to give the corresponding products. In many cases, they could

apply this method to peptide modifications without racemization of other

stereogenic centers in other α-amino acid moieties. By using this methodology,

they demonstrated that both linear and cyclic peptides up to 11 units in length can

be specifically alkylated at a glycine residue (Scheme 1.1).3 However, the success

of the deprotonation requires that the nitrogen of the adjacent α-amino acid be N-

alkylated.

Scheme 1.1 Selective Modification of Cyclosporin A Using Enolate Chemistry

O’Donnell and co-workers firstly reported the asymmetric alkylation of α-

amino acid derivatives. By using the activated α-amino acid derivative as the

substrate and cinchonidine-derived ammonium as the phase transfer catalyst, the

alkylation went smoothly at room temperature, affording the coupling product in

good yields and moderate enantioselectivities.6-8 Later, different versions of

cinchonidine catalysts, [Cu]-salen complex and various chiral ammonium phase

transfer catalysts were reported from other groups, affording the coupling

products with better enantioselectivities (Scheme 1.2).9-28

3

Ph2C NOR1

O

R1 = tBu iPr

catalyst50% aq NaOH

CH2Cl220oC

+ R2-Br Ph2C N * OR1

O

R2

R2 = ArCH2

N N

H

HO Cl

N

NH

O

O'Donnell Lygo

N N

H

HO Cl

Br

Corey

N

BrAr

Ar

Maruoka

N

NH

OF

F

Br

Jew, Park

F

N

NH

O N

HO

N

Jew, Park

N N

O OCu

Belokon

NH

N

NH OO

R

HOMe

R

H

MeO

Cl

Nagasawa

O

O

Me

tBu

N

N

Me

Me

4-MeOC6H4

4-MeOC6H44-MeOC6H4

4-MeOC6H4

2X

Shibasaki

NMe

N

O O

Bu Bu2OTf

Me

MacFarland

N PhOH OH

HO

OTf

Takabe, Mase

2Br

Scheme 1.2 Active Catalysts for the Asymmetric Alkylation of α-Amino Acid Derivatives

Later, O’Donnell and co-workers also successfully incorporated this

method into peptide synthesis on solid support. They reported that the use of

Schwesinger-type bases (organic-soluble, nonionic iminophosphorane) is

important for the success of this high-yielding alkylation which retains its

enantiopurity (Scheme 1.3).29,30

4

NPh

PhAA

O

ORBr (2 equiv)

BEMP (2 equiv)NMP, RT, overnight

NPh

PhAA

O

OR

R = ArCH2 Ar2CH allyl propargyl

PN NEt2N

N

tBuMe

Me

BEMP

Scheme 1.3 Alkylation in Solid-Phase Unnatural Peptide Synthesis

Maruoka and co-workers have incorporated phase transfer catalyst into

short peptide modifications. They found that using a substrate-control method or a

chiral phase transfer catalyst gave the alkylated peptides in good yields and

selectivities by using their C2-symmetric chiral quaternary ammonium bromide or

a simple tetrabutyl ammonium bromide (TBAB) as the phase transfer catalyst

(Scheme 1.4).20,21

Ph2C NO

L-AA-AA-OButTBAB or 1a (2 mol%)

toluene-50% KOH0oC, 2-8 h

Ph2C N *

O

L-AA-AA-OBut

R

R = PhCH2 ally propargyl

N

BrAr

Ar

RBr (1.1 equiv)

+

1a

Scheme 1.4 Asymmetric Alkylation of the N-Terminus in Peptide Modification Also using the enolate chemistry, by applying an amino allyl ester as the

substrate, in the presence of base, the so-formed enolate can undergo a Claisen

rearrangement to introduce an allyl group on the α-position of the α-amino acid

derivative (Scheme 1.5).31-36

5

Scheme 1.5 Applying Claisen Rearrangement into Amino Acid α-

Functionalization With the enolate in hand, aryl halides can be coupled under the catalysis of

a transition metal. Hartwig, Buchwald and co-workers have successfully

incorporated α-amino acid derivatives into their α-arylation reaction of carbonyls

and nitriles (Scheme 1.6).37-40

Scheme 1.6 Palladium-Catalyzed α-Arylation of Amino Acid Esters 1.1.2– Functionalization via α-Carbon-Centered Radicals

The formation of α-carbon-centered radicals of glycine derivatives could

be achieved from radicals such as Br•, (CH3)2CO• or tBuO•,41,42 which are

generated from the abstraction of a hydrogen radical or the homo-cleavage of Br2

or tBuOOtBu. The generated radical could then couple with Br• to afford α-

bromo glycine derivatives (Scheme 1.7, path a), or toluene to afford α-benzyl

glycine derivative (Scheme 1.7, path b), or tBuO• to afford the α-methyl glycine

derivatives and diglycine derivatives (Scheme 1.7, path c).

6

OR3

ONR1

O

R2

Br

Me Me

OPhMe

OR3

ONR1

O

R2

OR3

ONR1

O

R2

OR3

ONR1

O

R2

Br

CH2Ph

Me

OR3

ONR1

O

R2

R3O

ON R1

O

R2

+

path a

path b

path c

tBuO

Scheme 1.7 Functionalization of Glycine Esters via α-Carbon-Centered Radicals 1.2– C-C Bond Formation via C-H Activation Adjacent to a Heteroatom

Carbon-carbon bond formation is fundamental in organic chemistry. The

most common ways to constitute C-C bonds often occur between electrophiles

and nucleophiles (e.g., nucleophilic displacement, nucleophilic addition to

unsaturated bonds or transition metal catalyzed cross coupling reactions).

However, almost all electrophiles and nucleophiles need to be pre-synthesized

(e.g., from hydrocarbons, halides, alcohols or amines). On the other hand, a

coupling reaction via the in situ activation of C-H bonds provides a comparatively

faster, more convenient and more environmentally friendly pathway.

The main challenges in the field of C-H bond activation chemistry are the

high strength of C-H bonds in alkanes and arenes (e.g., methane, 105 kcal/mol;

benzene, 110 kcal/mol) and selectivity issues. Over the past 30 years, there has

been a great effort to achieve C-H bond activation by transition metal complexes.

One of the most well studied fields is the activation of C-H bonds adjacent to a

heteroatom. In the following section, a review covers the functionalization of α-

amino C-H bond via radical formation, metal-catalyzed direct C-H bond

activation and oxidative couplings and metal-catalyzed carbene insertion will be

7

presented. α-Functionalization of amines via C-H activation by a directing group

will not be discussed in this section.

The pioneering work of electrochemical, anodic oxidation of N-

heterocycles was disclosed by Shono and co-workers. They have shown that the

N-acyliminium ion formed by electrochemical oxidation can be trapped by

solvent such as alcohol to afford aminals (Scheme 1.8).43,44

Scheme 1.8 Formation of Aminals via Electrochemical Oxidation of N-Heterocycles

Yoshida and co-workers later successfully developed this electrochemical

oxidation method for C-C bond formation. They have demonstrated that high

concentrations of N-acyliminium carbocations (cation pool) 1b could be

generated via low-temperature electrolysis of N-(methoxycarbonyl)pyrrolidine.

Afterwards, the N-acyliminium carboncation 1b could be manipulated by reacting

with nucleophiles such as vinylethers, allylsilanes, electron-rich arenes and 1,3-

dicarbonyl compounds (Scheme 1.9, path a).45 Meanwhile, by applying

electrochemical reduction, the corresponding N-acyliminium carbocation could be

generated and trapped in the presence of electron-deficient olefins (Scheme 1.9,

path b).46 Furthermore, Yoshida and co-workers has recently shown that N-

acyliminium carboncation can also be coupled with alkyl radical generated in situ

(Scheme 1.9, path c).47

8

NCOOMe

-2e, -H+

-72 oCNCOOMe

Nucleophile

+ eNCOOMe

EWD

+ eNCOOMe

EWD

R

NCHOOMe

RBu3SnSnBu3

NCOOMe

R

1b

NCOOMe

NuNu = TMS OR

Ar-HR1 R2

O Opath a

path b

path c

Scheme 1.9 “Cation Pool” Based C-H Bond Activation via an Iminium

Intermediate Murahashi and co-workers first demonstrated the direct sp3 C-H bond

activation α to nitrogen followed by trapping with a cyanide anion. They

proposed that the ruthenium catalyst used in this transformation first activates the

α-C-H bond of tertiary amines 1c to give an iminium ion intermediate. The

iminium could then react with CN anion to form the α-amino cyanide 1d.

Regeneration of the ruthenium catalyst was achieved by using molecular oxygen

or H2O2 in acidic conditions (Scheme 1.10).48,49 Later, Sain and co-workers

showed that vanadium-based catalyst (V2O5) could also catalyze this cyanation

reaction with good yields and selectivities using molecular oxygen as the

oxidant.50

Ncat. RuCl3

O2 (1 atm) or H2O2AcOH, MeOH, 60oC

NaCN+

1c 1dR2

ArR1

NR2

ArR1

NC

Scheme 1.10 Ruthenium-Catalyzed Oxidative Cyanation of Tertiary Amines with Sodium Cyanide

Ishii and co-workers reported a new type activation of the C-H bond

adjacent to an imine catalyzed by an iridium complex.51 They proposed that

9

during the reaction, the [Ir(cod)Cl]2 catalyst first activates the C-H bond adjacent

to the imine which was formed by the amine and aldehyde. Subsequent insertion

of the alkyne, followed by reductive elimination, affords the allyl compound 1e as

the final product (Scheme 1.11).

nPr H

OnPr NH2

nHexcat. [Ir(COD)Cl]2

60oC+ +

nPr N nPr

nHex

1e

Scheme 1.11 Iridium Catalyzed Three Component Coupling Reaction of Aldehydes, Amines and Alkynes

Davies and co-workers achieved the direct asymmetric insertion of the C-

H bond adjacent to a cyclic N-Boc-protected amine into a metal catalyst. The

reported chiral dirhodium complex 1h catalyzed the coupling of diazo compound

with sily ether 1f and N-Boc cyclic amide 1g with a high degree of regio-,

diastereo-, and enantioselectivities (Scheme 1.12).52-56 Later, similar catalysts

with variation of the ligands were reported as improved catalysts for this C-H

bond transformation.57,40

N

(CH2)n

Boc

1. 1h,COOMeAr

N2

2. TFA NH

(CH2)n

NH

(CH2)n

H

Ar

COOMe H

Ar

COOMe

1g major product minor product

NSO2Ar

H

O

O Rh

Rh

4Rh2(S-DOSP)4

Ar=p-(CH3(CH2)10-12)Ph1h

OSiR1

3R2

1h,COOMeAr

N2 OSiR13MeOOC

Ar

R21f

Scheme 1.12 Dirhodium Complex Catalyzed Asymmetric Coupling of Carbenoids via C-H Bond Activation

The direct activation of the C-H bond adjacent to an unprotected nitrogen

was reported by Yi and co-workers by applying (PCy3)2(CO)RuHCl as the

catalyst.58 Through the use of this ruthenium catalyst, a variety of N-heterocycles

10

could be alkylated with alkenes, affording the alkylated cyclic imines as the major

products (Scheme 1.13).

NH

H

(PCy3)2(CO)RuHCl

THF, 70-120oC N+

RR N

HR

major product minor product Scheme 1.13 Ru-Catalyzed Oxidative Coupling of Cyclic Amines with Alkenes

Through the delicate design of the substrate, Sames and co-workers

reported an iridium-carbene complex-catalyzed tandem alkene directed C-H

activation, alkene insertion, followed by a β-hydride elimination reaction to

synthesize pyrrolizidinone derivatives (Scheme 1.14).59

N

O

HFG

N

OFG

5 mol% [Ir(coe)2Cl]210 mol% IPr, 3 equiv NBE

C6H12, 150oC IPr: NN

iPr

iPr iPr

iPr

Scheme 1.14 Ir-Catalyzed Cyclization of Alkene-Amide Derivatives

The first example of azole alkylation via C-H activation was demonstrated

by Bergaman, Ellman and Tan in their intramolecular annulations of imidazoles

and benzimidazole derivatives.60 The Rh(I) catalyst in combination with electron

rich phosphine ligand (PCy3) proved itself to be an active catalyst for both intra-

(Scheme 1.15, path a) and inter-molecular (Scheme 1.15, path b) alkylation with

alkenes.61-66 Moreover, when aryl iodides were applied to the reaction, arylation

products of azoles via direct C-H activation were obtained (Scheme 1.15, path

c).67

11

N

X

X = NH NR1

O S

[Rh]

R2

Ar-X

[Rh]

N

X

R2

N

XAr

[Rh]N N n

n = 1,2

N N npath a

path b

path c

Scheme 1.15 Rh-Catalyzed C-H Functionalization of N-Heterocycles

In another scenario, Yoshimitsu, Tanaka and co-workers have shown that

activation of the C-H bond adjacent to an amide or tertiary amine could be

achieved by subjecting the substrates to BEt3 in the presence of O2. With the

assistance of BEt3/O2 as the radical source, the so-formed α-amino radical could

be trapped by aldehydes or isocyanates to afford the corresponding coupling

products in good yields (Scheme 1.16).68-70

Scheme 1.16 BEt3 Promoted C-H Activation via a Radical Pathway

Li and co-workers found that using CuBr as catalyst and tert-butyl

hydroperoxide (TBHP) as oxidant, N-aryl tertiary amines could undergo Cross

Dehydrogenative Coupling (CDC) reaction with various nucleophiles (Scheme

1.17).71-78 They proposed that the first step of the reaction is the oxidation of the

tertiary amine to an iminium intermediate. Afterwards, a Mannich-type reaction

12

occurs with the nucleophiles to afford the coupling product. Later, this

methodology has shown that an amide could be also incorporated as the

nucleophile.79 Furthermore, it was reported that the CDC reaction could also take

place using O2 or N-Bromosuccinimide (NBS) as the terminal oxidant.80,81

Scheme 1.17 Cross Dehydrogenative Coupling Reactions of Tertiary Amines Li and co-workers have also shown that the C-H bond adjacent to

heteroatoms such as oxygen can also be activated to form new C-C bonds. Under

the catalysis of Cu(OTf)2/InCl3, it is possible to activate the C-H bond of benzylic

ethers using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or O2 as the

terminal oxidant to couple them with malonates (Scheme 1.18). 82,83

Scheme 1.18 Oxidative Alkylation of Benzyl Ethers with Malonates

Analogous to the CDC reaction, Doyle and co-workers demonstrated that

a dirhodium complex Rh2(cap)4 could catalyze the oxidative coupling reaction of

tertiary amines with 2-siloxyfurans to generate γ–aminoalkyl butenolides (Scheme

1.19).84 Later, Guo, Tan and co-workers achieved the same transformation

utilizing simple CuBr2 as the catalyst and TBHP, O2 or H2O2 as the oxidant.85

13

Scheme 1.19 Rhodium-Catalyzed Oxidative Mannich Reaction of Tertiary Amines with 2-Siloxyfuranes

Through the use of a chiral cationic palladium(II) species 1i, Sodeoka and

co-workers achieved the asymmetric oxidative alkylation of

tetrahydroisoquinoline derivative with good yields and enantioselectivity.86,87

The reaction is believed to occur through the in situ generation of the iminium ion

achieved by the slow addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DDQ) dissolved in CH2Cl2.

NBoc

R1

+O

R2O OR2

O

O

O

O

O

PAr2

PAr2

Ar = 3,5-Me2C6H3

Pd2+(OH)21i

DDQ, CH2Cl2, rt ∗N

Boc

R1

R2OOC COOR2

1i

Scheme 1.20 Palladium-Catalyzed Asymmetric Alkylation References for Chapter 1 1. Seebach, D.; Bossler, H.; Grundler, H.; Shoda, S.; Wenger, R. Helv. Chim.

Acta 1991, 74, 197.

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14

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Chapter 2: Oxidative Coupling between N-Acetyl Glycine Ester and Malonate

19

Chapter 2 – Oxidative Coupling between N-Acetyl Glycine Ester and

Malonate

As illustrated in Chapter 1, activation of the α-position of amines could be

achieved using a variety of different methods. However, the vast majority of the

examples demonstrated are tertiary amines or amides. Oxidative formation of C-C

bonds through the direct use of secondary amines, especially α-amino acid

derivatives, is still in scarce in literature.1

2.1 – Background Recent work from the Li group demonstrated that under oxidative

conditions, using TBHP as the oxidant and CuBr as the catalyst, tertiary amines

2a could be transformed into iminium 2b and be further functionalized (Scheme

2.1).2-9

NR2

R1CuBr (5 mol%) Nu

H NR2

R1NuN

R2

R1t-BuOOH

2a 2b

R3 R3 R3

2c

Scheme 2.1 Copper-Catalyzed Cross-Dehydrogenative Couplings of Tertiary Amines

Preliminary experiments have been carried out to extend the scope of the

substrates to secondary amines during their studies. However, the problem

associated with secondary amines is that after oxidative formation of imine (N-

methyl aniline 2d for example), the imine intermediate 2e is not stable and will

decompose to aniline and formaldehyde 2f. The so-formed formaldehyde will

then undergo an addition with another molecule of N-methyl aniline 2d to

generate iminium 2g, which is more electrophilic than the imine intermediate 2e.

In the end, alkynylation occurs on the iminium intermediate 2g to afford the

tertiary amine adduct 2h instead of the secondary amine adduct (Scheme 2.1).

20

HNMe CuBr

TBHP

NHCHO

HN Me

N Ph N

PhNH2

2d 2e 2f 2g 2h

Me

Ph

H2O

Scheme 2.2 Problem Associated with Oxidative Coupling with Secondary Amine

At this stage, the main issue associated with secondary amines seems to be

the question of how to stabilize the imine intermediate. Meanwhile, there are

imines which are stable and can even be isolated (Scheme 2.2). All of these

imines are N-substituted imino esters which provides us an opportunity to apply

our oxidative cross coupling methodology to glycine derivative functionalization

reactions.

NR1

OOR

O

NTs OR

ONAr OR

ONP OR

O

EtOO

EtO

Figure 2.1 Stable Imines. 2.2 – Discovery of the Oxidative Coupling between N-Acetyl Glycine Ester

and Malonate; Optimization of the Reaction Conditions Our first hypothesis was that by using N-acetyl glycine ester 2i, under

oxidative conditions, N-acetyl imino ester 2j could be generated. This so-formed

imino ester would then be trapped by a nucleophile to give the coupling product

2k (Scheme 2.3).

Me NH

OOEt

O

[O]Me N

OOEt

O

NuMe N

H

OOEt

O

Nu

2i 2j 2k

Scheme 2.3 Proposed Reaction To start with, we exposed compound 2i to the previously reported

CuBr/TBHP conditions. We did not observe any reaction after heating of the

21

mixture to 80 oC for 8 hours. This result is not surprising because the oxidation

potential of an amide is usually higher than that of an amine. Consequently, we

switched to totally different reaction conditions. We hypothesized that by using

Pd(OAc)2 as the catalyst and Cu(OAc)2 as the oxidant, the N-acetyl amide 2i

could be oxidized to the imino ester 2j via β-hydride elimination by Pd(OAc)2.

The Pd(0) can then be oxidized by Cu(OAc)2 to regenerate the Pd(II) catalyst. We

performed this reaction in toluene at 150oC. To our satisfaction, the corresponding

coupling product 2l was obtained in 5 % yield (Scheme 2.4). Later, blank

reactions were carried out to test if both metal compounds are necessary in this

transformation. It was found that without Pd(OAc)2, the reaction afforded the

coupling product in similar yield.

Me NH

OEtO

O

EtO OEt

O O+

Toluene, 150oC, 8 h

5 mol%Pd(OAc)21 equiv Cu(OAc)2

Me NH

OEtO

O

OEtEtO

O O

2lyield: ~ 5%

Scheme 2.4 Attempts to Functionalize the α-Position of N-Acetyl Glycine Ester

First, we screened the oxidant for this reaction. Among all the oxidants

tested, only Cu(OAc)2 gave promising results (Table 2.1, entry 2). Organic

oxidants such as 1,4-benzoquinone and TBHP did not give any desired product

(Table 2.1, entries 3 and 7). Surprisingly, other Cu(II) oxidants were not effective

for this transformation either (Table 2.1, entries 4-6).

Table 2.1 Screening of the Oxidants for the Oxidative Coupling between N-

Acetyl Glycine Ethyl Ester and Diethyl Malonate.a

Me NH

OEtO

O

EtO OEt

O O+

Toluene, 150oC, 8 hMe N

HOEt

O

O

OEtEtO

O O

oxidant

22

entry oxidant (20 mol%) yield (%)b 1 O2 (1 atm) NR 2 Cu(OAc)2 5 3 1,4-benzoquinone NR 4 CuCl2 NR 5 CuO NR 6 CuBr2 NR 7 TBHP trace

a N-Acetyl glycine ethyl ester (0.125 mmol), diethyl malonate (0.25 mmol), ligand (20 mol%) in toluene (1 mL) , 150oC, 8 h.

b Determined by 1H NMR using benzaldehyde as an internal standard. Ligands are known to modify the nature of the metal catalyst. Next,

different ligands were tested in combination with Cu(OAc)2. We found that

adding a nitrogen ligand was beneficial to the reaction (Table 2.2, entries 2-8).

After intensive investigation of a series of ligands, di(2-pyridyl) ketone gave a

considerably better result (Table 2.2, entry 8). This high reactivity is probably due

to the fact that, after coordinating with copper, di(2-pyridyl) ketone forms a six-

membered ring complex, which is more reactive than the five-membered ring

complex formed with other nitrogen ligands.

Table 2.2 Screening of the Ligands for Oxidative Coupling between N-Acetyl

Glycine Ethyl Ester and Diethyl Malonate.a

Me NH

OEtO

O

EtO OEt

O O+


HOEt

O

O

OEtEtO

O O2 equiv Cu(OAc)2

ligandN

O

N

di(2-pyridyl) ketone

entry ligand (20 mol%) yield (%)b

1 none 5 2c pyridine 19 3 2,2’-bipyridine 30 4 4,4’-dimethyl-2,2’-bipyridine 30 5 1,10-phenanthroline 12 6 TMEDA 23 7 2,2':6',2''-terpyridine 21 8 di(2-pyridyl) ketone 56

a N-Acetyl glycine ethyl ester (0.125 mmol), diethyl malonate (0.25 mmol), Cu(OAc)2 (2 equiv), ligand (20 mol%) in toluene (1 mL) , 150oC, 8 h.

b Determined by 1H NMR using benzaldehyde as an internal standard. c 50 mol% pyridine was added. TMEDA=N,N,N’,N’-tetramethylethylene-diamine.

23

Based on the fact that the second step of this transformation might be the

nucleophilic addition of malonate anion to N-acetyl imino ester, we hypothesized

that basic conditions should be beneficial in this process. Indeed, by adding a

catalytic amount base, the yield of the reaction increased considerably. Among all

the bases tested, 20 mol% of Cs2CO3 gave the best yield (Table 2.3, entry 4). The

use of 1.2 equivalents of Cu(OAc)2 furnished a lower yield (Table 2.3, entry 7);

however, it demonstrated that Cu(OAc)2 served as a stoichiometric oxidant in the

reaction.

Table 2.3 Screening of the Base for the Oxidative Coupling between N-Acetyl

Glycine Ethyl Ester and Diethyl Malonate.a

Me NH

OEtO

O

EtO OEt

O O+


HOEt

O

O

OEtEtO

O O2 equiv Cu(OAc)220 mol% di(2-pyridyl) ketone

base

entry base (20 mol%) yield (%)b 1 none 56 2 NaOAc 70 3 KHCO3 71 4 Cs2CO3 84 5 K2CO3 54 6 K3PO4 65 7c Cs2CO3 68

a N-Acetyl glycine ethyl ester (0.125 mmol), diethyl malonate (0.25 mmol), Cu(OAc)2 (2 equiv), ligand (20 mol%), base (20 mol%) in toluene (1 mL), 150oC, 8 h.

b Determined by 1H NMR using benzaldehyde as an internal standard. c 1.2 equiv of Cu(OAc)2 was used as the oxidant.

Inspired by the Wacker Oxidation process, we attempted the catalytic

version of this oxidative coupling using O2 as the terminal oxidant. Unfortunately,

a catalytic amount of Cu(OAc)2 under 1 atm O2 with or without Pd(OAc)2 gave

only low yields of the desired products (Table 2.4, entries 1 and 2).

24

Table 2.4 Attempts to Use O2 as the Terminal Oxidant for the Oxidative Coupling between N-Acetyl Glycine Ethyl Ester and Diethyl Malonate.a

Me NH

OEtO

O

EtO OEt

O O+


HOEt

O

O

OEtEtO

O O20 mol% Cu(OAc)2

20 mol% di(2-pyridyl) ketone20 mol% Cs2CO3

additive

entry additive yield (%)b

1 O2 (1 atm) 15 2 5 mol% Pd(OAc)2/ O2 (1 atm) 15

a N-Acetyl glycine ethyl ester (0.125 mmol), diethyl malonate (0.25 mmol), Cu(OAc)2 (2 equiv), ligand (20 mol%), base (20 mol%) in toluene (1 mL) , 150oC, 8 h.

b Determined by 1H NMR using benzaldehyde as an internal standard. 2.3 – Scope of the Copper-Mediated Oxidative Coupling of N-Acetyl Glycine

Esters and Malonates

Under the optimized reaction conditions, a variety of malonates as well as

other glycine derivatives were tested for this oxidative coupling reaction (Table

2.5).

Due to the fact that for most functionalized products decomposition

occurred after intensive heating, all reactions were performed and stopped at 4 h

to compare the relative reactivity (the corresponding yields are shown in

parentheses). Diisopropyl or diethyl malonates furnished better yields (Table 2.5,

entries 1, 3, 4, and 7) than the corresponding dimethyl malonate (Table 2.5,

entries 2 and 8), indicating that a more electron-rich malonate is beneficial to the

reaction. Increased steric hindrance at the carbon center decreased the reactivity

(Table 2.5, entries 4, 6 and 9). For the amino acid moiety, the electronic effect

was shown to be more significant than the steric effect. The iPr- and Et-

substituted esters furnished higher yields (Table 2.5, entries 1 and 5) than the Me-

substituted substrate (Table 2.5, entry 10). The effect of the substituent on the

amide moiety was also studied. As shown in Table 2.5, when R1 was changed

from Me (Table 2.5, entries 6 and 9) and Et (Table 2.5, entries 11 and 14) to an

iPr group (Table 2.5, entries 12 and 15), the yield decreased dramatically.

25

Furthermore, when R1 was changed to a tBu group (Table 2.5, entries 13 and 16),

the reaction was completely shut down.

Table 2.5 Functionalization of N-Acetyl Glycine Ester by CDC Reaction with

Malonates.a

R1 NH

O R2

O

O

R4 O O R4

O O+

Toluene, 150oCR1 N

HO R2

O

O

OR4

OR4

O OCu(OAc)2, 20 mol% Cs2CO320 mol% di(2-pyridyl) ketone

R3 R3

2o2m 2n

entry reaction time (h) R1 R2 R3 R4 2o yield (%)b

1 6 Me iPr H Et 2oa 82(73) 2 10 Me iPr H Me 2ob 85(40) 3 6 Me iPr H iPr 2oc 80(62) 4 10 Me iPr Me Et 2od 94(48) 5 8 Me Et H Et 2oe 84(72) 6 10 Me Et Me Me 2of 75(48) 7 6 Me Et H iPr 2og 73(63) 8 6 Me Et H Me 2oh 63(46) 9 10 Me Et Me Et 2oi 75(32) 10 6 Me Me H Et 2oj 65(55) 11 10 Et Et Me Et 2ok 75 12 10 iPr Et Me Et 2ol 53 13 10 tBu Et Me Et 2om NR 14 10 Et Et Me Me 2on 78 15 10 iPr Et Me Me 2oo 60 16 10 tBu Et Me Me 2op NR

a Reaction conditions: 2m (0.125 mmol), 2n (0.25 mmol), Cu(OAc)2 (0.25 mmol), di(2-pyridyl) ketone (0.025 mmol), toluene (1 mL) b Isolated yields are based on 2m, and the yields of 4 h reaction are given in parentheses. NR=No Reaction.

Furthermore, it should be noted that α-amino acid derivatives bearing a

substituent on the α-position 2p did not react under the present conditions

possibly because of steric effects (Scheme 2.5).

26

Me NH

OEtO

O

EtO OEt

O O+

Toluene, 150oC

Cu(OAc)2, 20 mol% Cs2CO320 mol% di(2-pyridyl) ketone

Me

NR

2p

Scheme 2.5 Attempt to Couple α-Substituted N-Acetyl Glycine Derivative with Diethyl Malonate

2.4 – Proposed Reaction Mechanism

The mechanism of this novel transformation was explored briefly. Adding

1 equiv of radical inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) did not have a

significant influence on the reaction, suggesting the unlikely involvement of a free

radical intermediate. We tentatively propose that coordination of nitrogen with

Cu(II) followed by oxidation will generate an imino intermediate (Scheme 2.6).

Then a Cu(II) catalyzed Mannich-type reaction between the imino ester and

malonate will occur to afford the final coupling product. The di(2-pyridyl) ketone

serves as a better ligand in this reaction probably owing to its electron-

withdrawing nature which renders the Cu(II) center in the transition state more

Lewis acidic. As a result, abstraction of the NH proton occurs more easily.

Cs2CO3 neutralizes the generated acetic acid and helps the enolization of

malonate.

Me NH

OEtO

O

EtO OEt

O

Cu(OAc)2

Me NH

OEtO

O

OEtEtO

O O

Me NOEt

O

O

Cu(OAc)2HH

H

Me NOEt

O

O

OCuOAc

2q 2j

2r 2l

Scheme 2.6 Proposed Reaction Mechanism

27

2.5 – Conclusion In conclusion, a Cu(OAc)2 mediated oxidative coupling between N-acetyl

glycine ester and malonates was developed. Starting from commercially

inexpensive starting materials, a range of α-functionalized amino acid derivatives

can be readily obtained.

2.6 – Experimental Section Chemicals were purchased from Aldrich Chemicals Company and Acros

Chemicals, and were used without further purification. All experiments were

carried out without inert gas protection. Flash column chromatography was

performed over SORBENT silica gel 30-60 µm. 1H NMR and 13C NMR spectra

were acquired with Varian 400 MHz and 100 MHz, or 300 MHz and 75 MHz,

respectively. IR spectra were recorded with ABB Bomem MB 100 interferometer.

MS data were obtained by using KRATOS MS25RFA Mass Spectrometer.

HRMS-ESI measurements were performed at McGill University.

Typical procedure for the synthesis of compound 2i Acetyl chloride (1.8 g, 24 mmol) in CH2Cl2 (10 mL) was added dropwise to a

mixture of glycine (1.50 g, 20 mmol) and Et3N (2.4 g, 24 mmol) in CH2Cl2 (20

mL) at 0oC. The resulting mixture was allowed to warm to RT, then stirred for 6

h. Then water (30 mL) was added to quench the reaction. The organic layer was

then separated and the water layer was extracted with CH2Cl2 (3×10 mL). The

organic layers were combined and dried over Na2SO4. CH2Cl2 was removed in

vacuo. The resulting solid was then dissolved in EtOH (50 mL), and p-toluene

sulfonic acid (340 mg, 2 mmol) was added. Then solution was refluxed overnight.

EtOH was later removed in vacuo, the resulting mixture was dissolved in CH2Cl2

and washed with saturated Na2CO3, then washed with water and dried over

Na2SO4. CH2Cl2 was then removed in vauo, and the product was purified by

vacuum distillation (2.5 g, 86% in yield).

A typical procedure for the synthesis of compound 2oa-2oo

28

Cu(OAc)2 (45 mg, 0.25 mmol), di-2-pyridyl ketone (4.6 mg, 0.025 mmol),

Cs2CO3 (8.2 mg, 0.025 mmol), N-acetylglycine ethyl ester (18 mg, 0.125 mmol)

and diethyl malonate (40 mg, 0.25 mmol) were added into a 5 ml reaction tube,

then toluene (1 mL) was added to the mixture. The reaction tube was then sealed

and heated up to 150oC for 8 h. After the reaction was finished, the mixture was

filtered through a small pad a silica gel, and then concentrated in vacuo. Flash

chromatography using ethyl acetate/ hexanes (1/4 to 1/1) furnished the final

product 2oe (28 mg, 72% in yield). Unless otherwise specified, all the reactions

were performed under similar conditions.

Compound 2oa IR (KBr pellet): νmax 2987, 2939, 1742, 1675, 1467, 448, 1374, 1344, 1107, 1036,

950, 831, 615, 543 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.57 (d, J=8.7 Hz,

1H), 5.18 (dd, J=8.7 Hz, 4.2 Hz, 1H), 4.99 (sept, J=6.3 Hz, 1H), 4.14 (m, 5H),

1.97 (s, 3H), 1.21 (m, 12H) ; 13C NMR (75 MHz, CDCl3, ppm): δ 169.9, 168.7,

167.7, 166.9, 69.9, 61.9, 61.8, 53.0, 50.9, 22.9, 21.5, 21.3, 13.9, 13.8; MS(EI): m/z

(%) 317, 230, 188 (100), 116, 70; HRMS exact mass calc’d for [C14H23O7N]:

317.1474; found m/z: 317.1477.

Compound 2ob IR (KBr pellet): νmax 3380, 2984, 2956, 1743, 1654, 1560, 1437, 376, 1376, 1279,

1107, 1029, 833 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.52 (d, J=8.4 Hz,

1H), 5.2 (dd, J=8.4 Hz, 4.2 Hz, 1H), 5.03 (sept, J=6.3 Hz, 1H), 4.17 (d, J=4.2 Hz,

1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.01(s, 3H), 1.20 (m, 6H); 13C NMR (75 MHz,

CDCl3, ppm): δ 170.0, 168.7, 168.0, 167.4, 70.2, 52.9, 52.8, 52.7, 51.0, 23.0,

29

21.6, 21.4; MS(EI): m/z (%) 289, 230, 202, 160 (, 100), 128; HRMS exact mass

calc’d for [C12H19O7N]: 289.1162; found m/z: 289.1164.

Compound 2oc

IR (KBr pellet): νmax 2983, 2939, 1735, 1685, 1375, 1274, 1180, 1146, 1105, 954,

825 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.59 (d, J=9.0 Hz, 1H,), 5.19 (dd,

J=9.0 Hz, 3.9 Hz, 1H), 4.99 (m, J=6.3 Hz, 3H), 4.04 (d, J=3.9 Hz, 1H), 1.97 (s,

3H), 1.19 (m, 18H) ; 13C NMR (75 MHz, CDCl3, ppm): δ 169.8, 168.9, 167.5,

166.3, 69.8, 69.8, 69.6, 53.2, 50.8, 22.9, 21.5, 21.4, 21.4, 21.3; MS (EI): m/z (%)

345, 286, 258 (100), 244, 216, 130, 112, 88, 70; HRMS exact mass calc’d for

[C16H27O7N]: 345.1788; found m/z: 345.1783.

Compound 2od IR (KBr pellet): νmax 3306, 2984, 2940, 1741, 1690, 1670, 1466, 1375, 1253,

1106, 1023, 863, 780, 634 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.33 (d,

J=9.6 Hz, 1H), 5.14 (d, J=9.6 Hz, 1H), 4.98 (sept, J=6.3 Hz, 1H), 4.18 (m, 4H),

2.00 (s, 3H), 1.54 (s, 3H), 1.21 (m, 15H) ; 13C NMR (75 MHz, CDCl3, ppm):

δ 170.4, 170.2, 170.1, 169.0, 69.7, 61.9, 61.7, 57.6, 55.4, 23.1, 21.6, 21.36, 19.8,

13.8; MS(EI): m/z (%) 331, 244, 202(100), 72, 126, 84; HRMS exact mass calc’d

for [C15H25O7N]: 331.1631; found m/z: 331.1633.

30

Compound 2oe IR (KBr pellet): νmax 2986, 2940, 1739, 1670, 1517, 1373, 1279, 1218, 1178,

1029, 860, 615 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.64 (d, J=8.7 Hz, 1H),

5.17 (dd, , J=8.7 Hz, J=4.2 Hz, 1H), 4.09 (m, 7H), 1.93 (s, 3H), 1.16(m, 9H) ; 13C

NMR (75 MHz, CDCl3, ppm): δ 169.8, 169.2, 167.6, 166.7, 61.8, 61.8, 61.7, 52.8,

50.7, 22.7, 13.7, 13.7; MS(EI): m/z (%) 303, 230, 188 (100), 143, 116, 70; HRMS

exact mass calc’d for [C13H21O7N]: 303.1318; found m/z: 303.1315.

Compound 2of IR (KBr pellet): νmax 3386, 3007, 2942, 1744, 1711, 1686, 1522, 1446, 1316,

1285, 1221, 1112, 1095, 888, 866 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.33

(d, J=9.6 Hz, 1H), 5.19 (d, J=9.6 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.74 (s, 3H),

3.72 (s, 3H), 2.02(s, 3H), 1.54 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 170.9, 170.8, 170.1, 169.4, 61.9, 57.7, 55.4, 52.9, 52.8, 23.1,

19.7, 13.9; MS (EI): m/z (%) 289, 216, 174 (100), 115, 102; HRMS exact mass

calc’d for [C12H19O7N]: 289.1161; found m/z: 289.1165.

Compound 2og IR (KBr pellet): νmax 2983, 2940, 1735, 1375, 1277, 1104, 1026, 830 cm-1; 1H

NMR (300 MHz, CDCl3, ppm): δ 6.62 (d, J=9.0 Hz, 1H), 5.21 (dd, J=9.0 Hz, 4.2

Hz, 1H), 4.99 (m, 2H), 4.14 (m, 2H), 4.03 (d, J=4.2Hz, 1H), 1.96 (s, 3H), 1.19

(m, 15H) ; 13C NMR (75 MHz, CDCl3, ppm): δ 169.8, 169.5, 167.5, 166.3, 69.75,

69.7, 61.9, 53.1, 50.7, 22.9, 21.5, 21.4, 21.3, 21.3, 13.9; MS (EI): m/z (%) 289,

216, 174 (100), 115, 102; HRMS exact mass calc’d for [C15H25O7N]: 331.1631;

found m/z: 331.1627.

31

Compound 2oh IR (KBr pellet): νmax 3386, 3007, 1942, 1744, 1711, 1686, 1449, 1287, 1221,

1112, 1095, 888, 866 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.58 (d, J=8.4

Hz, 1H), 5.21 (dd, J=8.4 Hz, 4.2 Hz, 1H), 4.17 (m, 3H), 3.73 (s, 3H), 3.72 (s, 3H),

2.00 (s, 3H), 1.22 (t, J=7.2 Hz, 3H) ; 13C NMR (75 MHz, CDCl3, ppm): δ 170.0,

169.3, 168.2, 167.5, 62.3, 53.0, 52.8, 51.0, 23.1, 14.0; MS (EI): m/z(%) 275, 216,

202, 260 (100), 128, 70; HRMS exact mass calc’d for [C11H17O7N]: 275.1005;

found m/z: 275.0999.

Compound 2oi IR (KBr pellet): νmax 2985, 1741, 1689, 1539, 1465, 1370, 1253, 1108, 1025, 862,

772 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.39 (d, J=9.9 Hz, 1H), 5.16 (d,

J=9.9 Hz, 1H), 4.15 (m, 6H), 1.99 (s, 3H), 1.53 (s, 3H), 1.22 (m, 12H) ; 13C NMR

(75 MHz, CDCl3, ppm): δ 170.4, 170.2, 170.0, 169.5, 61.9, 61.8, 61.7, 57.5, 55.3,

23.0, 19.7, 13.8, 13.8; MS (EI): m/z (%) 317, 272, 244, 202 (100), 126, 84;

HRMS exact mass calc’d for [C14H23O7N]: 317.1474; found m/z: 317.1471.

Compound 2oj IR (KBr pellet): νmax 3264, 3026, 2960, 2922, 1737, 1652, 1442, 1362, 1269,

1218, 1191, 995, 935, 716, 615, 545, 502 cm-1; 1H NMR (300 MHz, CDCl3,

ppm): δ 6.62 (d, J=9.0 Hz, 1H), 5.29 (dd, J=9.0 Hz, 3.6 Hz, 1H), 4.16 (m, 5H),

3.71 (s, 3H), 2.00 (s, 3H), 1.24 (q, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3,

32

ppm): δ 170.0, 169.9, 167.9, 166.9, 62.1, 62.0, 52.9, 52.9, 50.8, 23.0, 13.9, 13.8;

MS (EI): m/z (%) 289, 230, 188 (100), 174, 70; HRMS exact mass calc’d for

[C12H19O7N]: 289.1162; found m/z: 289.1164.

Compound 2ok IR (KBr pellet): νmax 2985, 2940, 1741, 1689, 1465, 1375, 1253, 1108, 1029,

862cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.34 (d, J=9.6 Hz, 1H), 5.18 (d,

J=9.6 Hz, 1H), 4.16 (m, 7H), 2.23 (q, J=7.8 Hz, 2H), 1.54 (s, 3H), 1.23 (m, 9H),

1.12 (t, J=7.8Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 173.7, 170.5, 170.3,

169.6, 61.9, 61.8, 61.7, 57.6, 55.2, 29.5, 19.7, 13.8, 13.8, 9.6; MS (EI): m/z (%)

331, 286, 258, 202 (100), 174, 156, 128, 102, 87, 57; HRMS exact mass calc’d for

[C15H25O7N]: 331.1631; found m/z: 331.1628.

Compound 2ol IR (KBr pellet): νmax 2991, 2934, 1741, 1689, 1539, 1478, 1375, 1261, 1025, 996,

862, 772 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 6.37 (d, J=9.6 Hz, 1H), 5.18

(d, J=9.6 Hz, 1H), 4.16 (m, 7H), 2.39 (m, 1H), 1.54 (s, 3H), 1.19 (m, 15H); 13C

NMR (75 MHz, CDCl3, ppm): δ 176.8, 170.5, 170.4, 169.7, 61.9, 61.8, 61.7, 57.6,

55.1, 35.5, 19.8, 19.4, 19.3, 13.9; MS (EI): m/z (%) 345, 300, 226, 202 (100), 174,

156, 128, 100, 71; HRMS exact mass calc’d for [C16H27O7N]: 345.1787; found

m/z: 345.1784.

33

Compound 2on IR (KBr pellet): νmax 3354, 2994, 1744, 1711, 1686, 1522, 1446, 1316, 1285,


Hz, 1H), 5.20 (d, J=9.6 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.72 (s,

3H), 2.25 (q, J=7.5 Hz, 2H), 1.54 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.8

Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 173.8, 170.9, 170.8, 169.5, 61.8,

57.7, 55.3, 52.8, 29.5, 19.7, 13.9, 9.7; MS (EI): m/z (%) 303, 272, 244, 230, 174

(100), 142, 116, 84, 57; HRMS exact mass calc’d for [C13H21O7N]: 303.1318;

found m/z: 303.1314.

Compound 2oo IR (KBr pellet): νmax 3386, 3011, 2942, 1744, 1723, 1691, 1522, 1446, 1316,


J=9.3 Hz, 1H), 5.19 (d, J=9.3 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 3.73

(s, 3H), 2.40 (m, 1H), 1.56 (s, 3H), 1.16 (m, 9H) ; 13C NMR (75 MHz, CDCl3,

ppm): δ 176.9, 171.0, 170.9, 169.6, 61.8, 57.8, 55.2, 52.9, 52.8, 35.6, 19.8, 19.4,

19.3, 13.9; MS (EI): m/z (%) 317, 286, 272, 244, 188, 174 (100), 142, 116, 102,

71, 43; HRMS exact mass calc’d for [C14H23O7N]: 317.1474; found m/z:

317.1472.

1. Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004, 23, 5392.


34



5. Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997.





Chapter 3: Site-Specific Alkynylation of Free (NH) Glycine Derivatives and


35

Chapter 3 – Site-Specific Alkynylation of Free (NH) Glycine Derivatives and


In chapter 2, N-acetyl glycine ester was shown to undergo oxidative

coupling with malonate in the presence of Cu(OAc)2 as the oxidant and bi(2-

pyridyl) ketone as the ligand. However, nucleophiles such as alkynes and indoles

were not effective under the optimized conditions. In this chapter, the

development of site-specific alkynylation of glycine derivatives as well as short

peptides will be presented.

3.1 – Background

Introducing ethynyl substituents to the α position of amino acids is

important in organic synthesis since it is now being recognized that this can

remarkably change the biological properties of certain natural amino acids.1,2 The

most common ways to access α-alkynyl amino acid derivatives are: (i) a coupling

reaction between an alkynyl metal reagent and a α-halo amino acid derivative;3,4

or (ii) the nucleophilic addition of an alkyne to an imino ester catalyzed by a

copper salt.5-9 For both of the methods, pre-functionalizations of amino acid

derivatives on the α-position are essential. On the other hand, direct site-specific

alkynylation of amino acids takes advantage of the existing structure and provides

a convenient way to generate large arrays of diverse amino acids and peptides for

biomedical applications. With the success of coupling N-acetyl glycine ester with

malonate, we then turned our attention to the alkynylation of glycine derivatives.

3.2 – Discovery of the Oxidative Coupling of N-PMP Glycine Amide with

Phenylacetylene Using the previous optimized conditions, the N-acetyl glycine ester 2i did

not react with phenylacetylene at all. The main product obtained was the

homocoupling (Scheme 3.1) of the phenylacetylene mediated by Cu(OAc)2. This

result is not surprising considering that the harsh conditions (stoichiometric

36

amount of Cu(OAc)2 at 150oC are not compatible with nucleophiles such as

phenylacetylene. Thus, switching to milder conditions was necessity.

Consequently, we hypothesized that by switching the acetyl group to a p-

methoxyphenyl (PMP) protecting group, the oxidation potential of the substrate

would be reduced. Meanwhile, the so-formed imino ester would be a stable imine

due to the presence of the ester group.

Scheme 3.1 Attempt to Couple N-Acetyl Glycine Derivative with Phenylacetylene

Next, N-PMP glycine ethyl ester 3a was synthesized and exposed to the

CuBr/TBHP system. The reaction worked and afforded a trace amount of the

coupling product 3b. Although the yield was far from satisfactory, this result

supported our hypothesis that the N-PMP glycine derivative could be oxidized

under less harsh conditions. After intensive screening of catalyst, co-catalyst, base,

solvent, ligand and temperature, we found that the best conditions for this

coupling reaction involve 10 mol% CuBr as the catalyst, 5 mol% AuBr3 as the co-

catalyst, TBHP as the oxidant and dichloroethane (DCE) as the solvent at 80oC.

The alkynylation product was obtained in 42% yield (Scheme 3.2).

Me NH

OEt

O

O

+Toluene, 150oC, 4 h

Cu(OAc)2, 20 mol% Cs2CO3

20 mol% di(2-pyridyl) ketone

Ph No Coupling Product

NH

OEt

O

+neat, 100oC, 4 h

10 mol% CuBr1 equiv TBHP

Ph

NH

OEt

O

Ph

trace

MeO

MeO

2i

3a 3b

37

Scheme 3.2 Optimized Condition for the Coupling of N-PMP Glycine Ester with

Phenylacetylene

In order to further increase the yield, we turned our attention to the

modification of the substrate. We hypothesized that by switching the ester group

to an amide group in the glycine derivative, the electronic nature of the substrate

might be improved. As a result, compound N-PMP glycine methyl amide 3c was

synthesized and exposed to the previously optimized CuBr/AuBr3/TBHP

conditions. To our great delight, the coupling product was obtained in 73% yield.

After further optimization of the reaction condition, it was found that 10 mol%

CuBr as the catalyst, 1 equivalent of TBHP and dichloromethane as the solvent at

room temperature are the best conditions, affording the coupling product in

almost quantitative yield (Scheme 3.3).

Scheme 3.3 Optimized Condition for the Coupling of N-PMP Glycine Amide

with Phenylacetylene 3.3 – Scope of the Oxidative Coupling of N-PMP Glycine Amide with Aryl

Alkynes

Under these optimized reaction conditions, a variety of substituted glycine

derivatives could be coupled with aromatic alkynes (Table 3.1). Secondary (Table

3.1, entries 1-4) and tertiary (Table 3.1, entry 5) amides all reactedwell. For the

NH

OEt

O

+DCE, 80oC, 4 h

10 mol% CuBr

5 mol% AuBr3

1 equiv TBHP

Ph

NH

OEt

O

Ph

42%

MeO

MeO

3b3a

NH

HN

Me

O

+

CH2Cl2, RT, 12 h


Ph

NH

HN

O

Ph

93%

MeO

MeO

Me

3c

38

aromatic alkyne counterparts, 4-ethynylbiphenyl (Table 3.1, entry 6), 1-bromo-4-

ethynylbenzene (Table 3.1, entry 7) and 4-ethynyltoluene (Table 3.1, entry 8) all

afforded the correspond products in moderate yields. However, 2-

methoxyphenylacetylene (Table 3.1, entry 9) is less reactive than the other

substrates, indicating that the steric hindrance on the alkyne retarded its reactivity.

Meanwhile, R1 being a substituted amine moiety is very important for the success

of this transformation. By switching R1 to an OEt group (Table 3.1, entry 10), the

coupling reaction did not occur at all at room temperature. By switching R1 to a

phenyl group (Table 3.1, entry 11), the reaction afforded a messy unidentified

mixture. This indicates that R1 being a substituted amine moiety could probably

reduce the oxidation potential of the substrate and stabilize the formed imine

intermediate.

Table 3.1 Functionalization of N-PMP Glycine Amides 3d by CDC Reaction

with Alkynes 3e.a

Entry R1 R2 3f Yield (%)b 1 NHMe H 3fa 68(93) 2 NHEt H 3fb 55(73) 3 NH(CH2)3CH3 H 3fc 62(79) 4 NH(CH2)3Ph H 3fd 76(93) 5 1-pyrrolidinyl H 3fe 67(90) 6 NHMe 4-Ph 3ff 72(86) 7 NHMe 4-Br 3fg 78(89) 8 NHMe 4-Me 3fh 60(81) 9 NHMe 2-OMe 3fi 50(63) 10 OEt H NA NR 11 Ph H NA ND

a Reaction conditions: 3d (0.30 mmol), 3e (0.90 mmol), TBHP (18 µL, 5-6 M in decane), CuBr (0.03 mmol), CH2Cl2 (0.5 mL). b Isolated yields are based on 3d, and 1H NMR yields using benzaldehyde as an internal standard are given in parentheses. NR=No Reaction. NA=Not Availabe. ND=Not Determined.

NH

R1

O

+

Ar, CH2Cl2, RT

12-16 h


NH

R1

O

MeO

MeO

R2

R2

3d 3e 3f

39

Encouraged by this promising result, and with an eye for peptide

functionalizations, we tested this methodology on a simple dipeptide 3g and

tripeptide 3h. With a little modification of the reaction conditions, the coupling

reaction proceeded at 70oC in dichloroethane, affording the coupling product 3i

and 3j in 63% and 52% isolated yield respectively (Scheme 3.4). Compared with

previous methods in functionalizing glycine derivatives,10-14 this present method

distinguished itself by specifically introducing the alkynyl group at the protected

glycine terminus. In contrast, the carbanion- or radical-based methods will not

have any significant selectivity between the CH2 groups in peptides.

Scheme 3.4 Functionalization of Simple Peptides 3g and 3h

This current methodology provides a versatile method to synthesize the

homophenylalanine derivative (Scheme 3.5), which is an important synthon in

many important angiotensin converting enzyme inhibitors.15,16 Hydrogenation of

the alkynylation product 3fa provided compound 3k. Subsequent deprotection of

PMP group afforded the homophenylalanine product 3l.

NH

HN

O

+ Ph

PMPOEt

O

NH

HN

O

PMPNH

O

O

OEt

Ar, DCE, 70oC


NH

HN

O

PMPOEt

O

NH

HN

O

PMPNH

O

O

OEt

Ph

Ph

4 h, 63%

1 h, 52%

3g

3h

3i

3j

40

Scheme 3.5 Application for the Synthesis of Homophenylalanine Derivative 3.4 – Mechanism

A plausible reaction mechanism to explain the results of the copper-

catalyzed oxidative alkylation of phenylacetylene with N-PMP glycine amide is

proposed in Scheme 3.6. Copper imino amide intermediate 3n generated from a

copper salt, TBHP and N-PMP glycine amide 3m could potentially complex with

phenylacetylene to generate complex 3o. The following 1,2-insertion will give the

final alkylated glycine derivative 3p.

Scheme 3.6 Proposed Mechanism for the Alkylation Reaction

PMP

HN

NH

Me

O

Pd/C, 50 psi H2

MeOH, RT

PMP

HN

NH

Me

O

84%

TCCA, 2 equiv. HCl

H2O/CH3CN, RT

-Cl+H3NNH

Me

O

88%

3fa 3k 3l

NH

O

RHN

PMP

NH

O

RNPMP

NH

O

RHN

PMP

[Cu]

[Cu]

+ TBHP

NH

O

RNPMP

[Cu]

Ph

Ph

Ph

3m

3n3o

3p

41

The initial formation of the copper imino amide intermediate might occur

by a radical pathway. First, the N-PMP glycine amide 3m could undergo a H-

abstraction by TBHP to give radical intermediate 3r, then a single electron

transfer (SET) and deprotonation afford the intermediate 3n. Alternatively, the

reaction could start with SET to give intermediated 3t, final H-abstraction and

deprotonation afford the intermediate 3n.

Scheme 3.7 Possible Pathway for the Formation of the Copper Imino Amide

Intermediate

3.5 – Conclusion

In conclusion, a copper-catalyzed oxidative alkynylation between an

arylalkyne and N-PMP glycine amide was achieved using TBHP as an oxidant.

The current method could also be applied to short peptide modifications.






respectively. IR spectra were recorded with ABB Bomem MB 100 interferometer.

MS data were obtained by using KRATOS MS25RFA Mass Spectrometer.

HRMS-ESI measurements were performed at McGill University.

Typical procedure for the synthesis of compound 3c

CH2 NH

O

RHN

PMP

H

SET

CH NH

O

RHN

PMP

CH2 NH

O

RHN

PMP

H

SETNH

O

RNPMP

[Cu]

H+

H++

3m3r

3t

3n

42

2-Bromoacetyl bromide (2.4 g, 1.2 mmol) in CH2Cl2 (10 ml) was added dropwise

to a mixture of MeNH2 (1.0 g, 30 wt% in H2O, 1.0 mmol) and K2CO3 (1.66 g, 1.2

mmol) in CH2Cl2/H2O (30 mL/10 mL) at 0oC. The mixture was stirred for 6 h.

The organic layer was then separated and water layer was extracted with CH2Cl2

(3×5 mL). Then organic layers were combined and dried over Na2SO4, CH2Cl2

was removed in vacuo. Then EtOH (5 mL), p-anisidine (1.23 g, 1 mmol) and

NaOAc (0.84 g, 1 mmol) were added to the residue. The resulting mixture was

refluxed for 6 h. The reaction mixture was then filtered. The solvent of the filtrate

was removed in vacuo. Recrystallization (CH2Cl2/hexanes) was then performed to

afford the pure product 3c 2-(4-methoxyphenylamino)-N-methylacetamide (1.5 g,

80% in yield).

Typical procedure for the synthesis of compound 3f

To a test tube, 2-(4-methoxyphenylamino)-N-methylacetamide (59 mg, 0.30

mmol), CuBr (4.2 mg, 0.03 mmol), phenylacetylene (90 mg, 0.90 mmol) and

TBHP (54 µl, 5-6 M in decane) are successively added with CH2Cl2 (0.5 mL).

The test tube was purged with argon. Then the mixture was then stirred for 15 h.

Then mixture was filtered through a small pad a silica gel and concentrated in

vacuo. Flash chromatography using ethyl acetate/hexanes (1/4 to 1/2) furnished

the final coupling product (60 mg, 68% in yield).

Synthesis of compound 3fa

To a stirred solution of compound 3fa (60 mg, 0.2 mmol) in MeOH (2 mL), Pd/C

(64 mg, 10% on carbon) was added. The mixture was pressurized to 50 psi under

an atmosphere of H2 and stirred overnight. Then, the reaction mixture was filtered

HN

MeO

NH

Me

O

Pd/C, 50 psi H2

MeOH, RT

HN

MeO

NH

Me

O

84%

3fa3k

43

and the filtrate was concentrated in vacuo. Flash chromatography using ethyl

acetate/ hexanes (1/2) furnished the final product 3k (52 mg, 84% in yield).

Synthesis of compound 3l

To a stirred solution of compound 3k (30 mg, 0.1 mmol) in CH3CN/H2O (1 mL/1

mL), HCl (100 µL, 2M) and trichloroisocyanuric acid (TCCA) (6 mg, 0.05 mmol)

were successively added. Then, the reaction mixture was stirred at room

temperature for 4 h and the CH3CN was later removed in vacuo. Next, the

aqueous solution was extracted with CH2Cl2 (2×1 mL) and water of the aqueous

solution was then removed in vacuo at 40oC. Then MeOH (2 mL) was added to

the residue and the non-soluble inorganic residue was filtered off and the product

3l (20 mg, 88% in yield) was obtained by removing MeOH in vacuo from the

solution.

Compound 3fa

IR (KBr pettlet): νmax 3350, 3289, 3062, 2996, 2936, 2831, 2054(w), 1677, 1515,

1246, 1232, 1033, 815, 753, 686, 578, 519 cm-1; 1H NMR (400 MHz, CDCl3,

ppm): δ 7.41 (m, 2H), 7.30 (m, 3H), 7.02 (s, 1H, br), 6.79 (d, J=8.8 Hz, 2H), 6.69

(d, J=8.8 Hz, 2H), 4.71 (s, 1H), 4.50 (s, 1H, br), 3.74 (s, 3H), 2.88 (d, J=5.2 Hz,

3H); 13C NMR (100 MHz, CDCl3, ppm): δ 168.7, 153.5, 139.8, 131.8, 128.7,

HN

MeO

NH

Me

O

TCCA, 2 equiv. HCl

H2O/ CH3CN, RT

-Cl+H3NNH

Me

O

88%

3k3l

44

128.2, 121.9, 115.7, 114.7, 85.2, 84.9, 55.6, 52.8, 26.5; MS (EI): m/z (%) 294

(100), 172, 132, 118, 77; HRMS exact mass calc’d for [C18H18O2N2]: 294.1368;

found m/z: 294.1366.

Compound 3fb

IR (KBr pettlet): νmax 3327, 2974, 2933, 2832, 2058(w), 1664, 1511, 1442, 1238,

1035, 823, 757, 691, 528 cm-1; 1H NMR (400 MHz, CDCl3, ppm): δ 7.43 (m, 2H),

7.30 (m, 3H), 6.95 (t, J=5.6 Hz, 1H, br), 6.80 (d, J=9.2 Hz, 2H), 6.71 (d, J=9.2 Hz

2H), 4.68 (s, 1H), 3.75 (s, 3H), 3.70 (m, 2H), 1.15 (t, J=7.6 Hz, 3H); 13C NMR

(100 MHz, CDCl3, ppm): δ 167.8, 153.5, 140.0, 131.8, 128.7, 128.2, 121.9, 115.7,

114.7, 85.2, 85.0, 55.6, 53.0, 34.7, 14.6; MS (EI): m/z (%) 308 (100), 263, 234,

186, 146, 104, 77; HRMS exact mass calc’d for [C19H20O2N2]: 308.1525; found

m/z: 308.1521.

Compound 3fc


1243, 1313, 1129 cm-1; 1H NMR (400 MHz, CDCl3, ppm): δ 7.41 (m, 2H), 7.28

(m, 3H), 6.98 (t, J=5.6 Hz, 1H, br), 6.79 (d, J=9.2 Hz, 2H), 6.70 (d, J=9.2 Hz,

2H), 4.69 (s, 1H), 3.74 (s, 3H), 3.31 (m, 2H), 1.49 (m, 2H), 1.30 (m, 2H), 0.89 (t,

J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 167.9, 153.5, 139.9, 131.78,

128.6, 128.2, 122.0 115.7, 114.7, 85.1, 85.1, 55.6, 52.90 39.5, 31.4, 19.9, 13.6;

45

MS (EI): m/z (%) 336 (100), 236, 214, 134, 104; HRMS exact mass calc’d for

[C21H24O2N2]: 336.1838; found m/z: 336.1830.

Compound 3fd

IR (KBr pettlet): νmax 3309, 3060, 3026, 2933, 2832, 2054(w), 1663, 1511, 1241,


J=6.0 Hz, 2H), 7.28 (m, 5H), 7.12 (d, J=6.0 Hz, 2H), 7.07 (t, J=5.6 Hz, 1H), 6.81

(d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.80 (s, 1H, br), 4.73 (s, 1H), 3.74 (s,

3H), 3.37 (m, 2H), 2.62 (t, J=8.0 Hz, 2H), 1.86 (m, 2H); 13C NMR (100 MHz,

CDCl3, ppm): δ 168.1, 153.5, 141.1, 139.7, 131.8, 128.6, 128.3, 128.2, 128.1,

125.9, 121.9, 115.6, 114.7, 85.1, 85.0, 55.5, 52.8, 39.2, 32.9, 30.8; MS (EI): m/z

(%) 398 (100), 294, 276, 236, 172, 132, 91, 77; HRMS exact mass calc’d for

[C26H26O2N2]: 398.1994; found m/z: 398.1998.

Compound 3fe


1437, 1239, 1039, 834, 795, 540 cm-1; 1H NMR (400 MHz, CDCl3, ppm): δ 7.36

(m, 2H), 7.26 (m, 3H), 6.79 (m, 4H), 4.89 (s, 1H), 3.86 (m, 1H), 3.74 (s, 3H), 3.55

(m, 3H), 2.03 (m, 2H), 1.88 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm): δ 165.2,

152.6, 139.8, 131.7, 128.4, 128.1, 122.2, 115.7, 114.6, 84.7, 83.8, 55.5, 49.2, 46.5,

46.2, 25.9, 23.9; MS (EI): m/z (%) 334, 236 (100), 193, 92; HRMS exact mass

calc’d for [C21H22O2N2]: 334.1681; found m/z: 334.1674.

46

Compound 3ff

IR (KBr pettlet): νmax 3375, 3292, 2062(w), 1654, 1484, 1249, 1236, 1037, 844,

827, 763, 720, 693 cm-1; 1H NMR (300 MHz, CDCl3, ppm): δ 7.50 (m, 9H), 6.99

(s, 1H, br), 6.82 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 4.73 (s, 1H), 3.76 (s,

3H), 2.91 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.6, 153.7,

141.5, 140.1, 139.8, 132.3, 128.8, 127.7, 127.0, 126.9, 120.8, 115.7, 114.8, 85.5,

85.3, 55.6, 53.1, 26.6; MS (EI): m/z (%) 370 (100), 312, 248, 208, 178, 167, 129,

122, 105; HRMS exact mass calc’d for [C24H22O2N2]: 370.1681; found m/z:

370.1677.

Compound 3fg



Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.98 (s, 1H, br), 6.78 (d, J=9.0 Hz, 2H), 6.68 (d,

J=9.0 Hz, 2H), 4.68 (s, 1H), 3.75 (s, 3H), 2.89 (d, J=3.6 Hz, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 168.4, 153.7, 139.7, 133.3, 131.5, 123.1, 120.9, 115.7,

114.8, 86.0, 84.2, 55.6, 53.0, 26.6; MS (EI): m/z (%) 374, 372 (100), 316, 314,

252, 250, 211, 196, 171, 147, 122, 92, 77; HRMS exact mass calc’d for

[C18H17O2N2Br]: 372.0473; found m/z: 372.0463.

47

Compound 3fh



Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.98 (s, 1H, br), 6.80 (d, J=9.0 Hz, 2H), 6.69 (d,

J=9.0 Hz, 2H), 4.68 (s, 1H), 3.75 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.33 (s, 3H); 13C

NMR (75 MHz, CDCl3, ppm): δ 168.8, 153.5, 140.0, 138.9, 131.7, 129.0, 118.8,

115.6, 114.7, 85.5, 84.2, 55.6, 52.9, 26.6, 21.5; MS (EI): m/z (%) 308, 250 (100),

186, 147, 115, 92; HRMS exact mass calc’d for [C19H20O2N2]: 308.1525; found

m/z: 308.1527.

Compound 3fi

IR (KBr pettlet): νmax 3339, 2954, 2058(w), 1669, 1490, 1314, 1243, 1178, 1152,

751 cm-1; 1H NMR (400 MHz, CDCl3, ppm): δ 7.38 (d, J=7.2 Hz, 1H), 7.28 (t,

J=8.0 Hz, 1H), 7.21 (s, 1H, br), 6.80 (m, 6H), 4.73 (s, 1H), 3.87 (s, 3H), 3.75 (s,

3H), 2.91 (d, J=5.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.6, 160.3,

153.4, 140.4, 133.4, 130.2, 120.4, 115.8, 114.7, 111.1, 110.5, 89.3, 82.4, 55.8,

55.6, 52.8, 26.7; MS (EI): m/z (%) 324 (100), 293, 266, 202, 148, 129, 91; HRMS

exact mass calc’d for [C19H20O3N2]: 324.1474; found m/z: 324.1466.

48

Compound 3i

IR (KBr pettlet): νmax 3533, 2983, 2936, 2906, 2833, 2062(w), 1744, 1512, 1241,

1202, 1033, 823, 758, 692, 529 cm-1; 1H NMR (400 MHz, CDCl3, ppm): δ7.51 (t,

J=4.8 Hz,1H, br), 7.42 (m, 2H), 7.29 (m, 3H), 6.80 (d, J=8.8 Hz, 2H), 6.73 (d,

J=8.8 Hz, 2H), 4.78 (s, 1H), 4.20 (q, J=6.8 Hz, 2H), 4.09 (d, J=5.6 Hz, 2H), 3.74

(s, 3H), 1.25 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 169.2,

168.5, 153.6, 139.8, 131.8, 128.7, 128.2, 121.8, 115.9, 114.7, 85.5, 84.5, 61.5,

55.6, 52.8, 41.6, 14.0; MS (EI): m/z (%) 366 (100), 337, 280, 236, 149, 123, 103,

77; HRMS exact mass calc’d for [C21H22O4N2]: 366.1580; found m/z: 366.1568.

Compound 3j


1031, 812, , 692, 512 cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 7.72 (t, J=5.6

Hz, 1H,=), 7.42 (d, J=7.6 Hz, 2H), 7.31-7.25 (m, 4H), 6.79 (d, J=8.8 Hz, 2H),

6.73 (d, J=8.8 Hz, 2H), 4.81 (s, 1H), 4.44 (s, 1H, br), 4.19 (q, J=6.8 Hz, 2H),

4.08-4.06 (m, 4H), 3.97 (d, J=5.6 Hz, 2H), 3.73 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3, ppm): d 169.5, 169.0, 168.6, 153.7, 139.7, 131.9,

128.8, 128.3, 121.8, 115.9, 114.8, 85.6, 84.4, 61.6, 55.6, 52.7, 43.2, 41.3, 14.1;

HRMS exact mass calc’d for [C23H26N3O5]: 424.1867; found m/z: 424.2867.

49

Compound 3k 1H NMR (400 MHz, CDCl3, ppm): δ 7.29-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.92

(s, 1H, br), 6.76 (d, J=8.8 Hz, 2H), 6.45 (d, J=8.8 Hz, 2H), 3.74 (s, 3H), 3.63 (dd,

J=8.0 Hz, 4.0 Hz, 1H), 2.78 (d, J=4.8 Hz, 3H), 2.76 (m, 2H), 2.32 (m, 1H), 1.99

(m, 1H); 13C NMR (100 MHz, CDCl3, ppm): δ 174.07, 152.97, 140.79, 140. 65,

128.53, 128.37, 126.17, 114.77, 114.63, 60.39, 55.63, 35.01, 32.66, 25.94; MS

(EI): m/z (%) 298, 240 (100), 149, 134, 91; HRMS exact mass calc’d for

C18H23O2N2 ([M+H]): 299.1754; found m/z: 299.1759.

Compound 3l 1H NMR (300 MHz, D2O/CD3CN, ppm): δ 7.61-7.56 (m, 2H), 7.52-7.49 (m,

3H), 4.19 (t, J=8.8 Hz, 1H), 2.98 (s, 3H), 2.94-2.88 (m, 2H), 2.39-2.35 (m, 2H); 13C NMR (300 MHz, D2O/CD3CN, ppm): δ 169.84, 140.73, 129.21, 128.92,

126.96, 53.65, 33.10, 30.97, 26.27

References for Chapter 3 1. Abdulganeeva, S. A.; Erzhanov, K. B. Uspekhi Khimii 1991, 60, 1318.

2. Angst, C. Pure Appl. Chem. 1987, 59, 373.

3. Williams, R. M.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1990, 55, 4657.

50

4. Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.; Krantz, A. Tetrahedron 1988, 44, 5451.

5. Shao, Z. H.; Pu, X. W.; Li, X. J.; Fan, B. M.; Chan, A. S. C. Tetrahedron: Asymmetry 2009, 20, 225.

6. Shao, Z. H.; Chan, A. S. C. Synthesis 2008, 2868.

7. Hayashi, T.; Chan, A. S. C. Lett. Org. Chem. 2006, 3, 328.

8. Ji, J. X.; Wu, J.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11196.

9. Ji, J. X.; Au-Yeung, T. L.; Wu, J.; Yip, C. W.; Chan, A. S. C. Adv. Synth. Catal. 2004, 346, 42.

10. Beak, P.; Zajdel, W. J.; Reitz, D. B. Chem. Rev. 1984, 84, 471.

11. Easton, C. J.; Hutton, C. A.; Rositano, G.; Tan, E. W. J. Org. Chem. 1991, 56, 5614.

12. Easton, C. J.; Scharfbillig, I. M.; Tan, E. W. Tetrahedron Lett. 1988, 29, 1565.

13. Knowles, H. S.; Hunt, K.; Parsons, A. F. Tetrahedron Lett. 2000, 41, 7121.

14. Meyers, A. I. Aldrichimica Acta. 1985, 18, 59.

15. Brunner, H. R.; Nussberger, J.; Waeber, B. J. Cardiovasc. Pharmacol. 1985, 7, S2.

16. Wyvratt, M. J. Physiol. Biochem. 1988, 6, 217-229.

Chapter 4: Site-Specific Arylation of Free (NH) Glycine Derivatives and Peptides

via Direct C-H Bond Functionalization

51

Chapter 4 – Site-Specific Arylation of Free (NH) Glycine Derivatives and


In chapters 2 and 3, oxidative couplings of glycine derivatives with

malonate and aryl alkynes were described. In this chapter, the development of

site-specific arylation of glycine derivatives and short peptides will be presented.

4.1 – Background

An interesting and important nonproteinogenic class of amino acids is the

arylglycines. They have attracted more and more attention since the frequency of

isolating arylglycines is increasing rapidly in the past few decades. For example,

vancomycin,1-3 which was the first discovered glycopeptide antibiotic, contains a

heptapeptide in which three of the amino acid residues are arylglycines. Besides

that, arylglycines are important intermediates in the commercial production of β-

lactam antibiotics. Phenylglycine (ampicillin, cefachlor) and p-

hydroxyphenylglycine (amoxicillin, cefadroxil) are the predominant

representatives in this family. According to WHO data, ampicillin and amoxicillin

totally accounted for almost half of the β-lactam antibiotics produced globally in

the year 2000.4 Although the Strecker synthesis,5-7 the Ugi reaction8-10 and the

Petasis reaction8-10 are important tools in the construction of arylglycine

derivatives, the direct arylation of glycine derivatives or glycine moieties in

peptides would be more powerful in cases where the glycine moiety is already

present. Herein, a detailed study of a general method for site-specific C-arylation,

vinylation of α-C-H bonds of glycines and short peptides at the N-terminus will

be presented.

4.2 – Oxidative Coupling of N-PMP Glycine Amide with Arylboronic Acid

With our success of the alkynylation of N-PMP glycine amide, we

examined the C-arylation of N-PMP glycine methyl amide 4a with other

nucleophiles. Among all the examined nucleophiles, including tributylphenyltin

52

(Bu3SnPh), trimethylphenylsilane (Me3SiPh), and phenylboronic acid 4b, only

phenylboronic acid afforded the desired arylation product. With 10 mol% CuBr

and 1.0 equivalent TBHP in 1,2-dichloroethane (DCE), the arylation reaction

proceeded efficiently at 100oC, affording the coupling product 4c in 81% isolated

yield, using only a slight excess of N-PMP glycine amide (1.5 equiv, Table 4.1,

entry 3). Other non-chlorinated solvents such as THF, 1,6-dioxane or toluene

afforded low yields of the coupling product (Table 4.1, entries 4-8).

Table 4.1 Optimization of the Reaction Conditions for the Arylation of N-PMP

Glycine Amide.

entry 4a (equiv) 4b (equiv) solvent yield (%)a 1 1.0 1.5 DCE 25 2 1.0 1.0 DCE 50 3 1.5 1.0 DCE 81 4 1.5 1.0 Toluene 25 5 1.5 1.0 Dioxane NP 6 1.5 1.0 DME 13 7 1.5 1.0 ACN 43 8 1.5 1.0 THF 13

a 1H NMR yields using an internal standard. DCE: Dichloroethane. DME=Dimethoxyethane. THF=Tetrahydrofuran. ACN=Acetonitrile. NP=No Product

With this result in hand, we then briefly investigated the scope of this

arylation reaction (Table 4.2). Aryl boronic acids bearing electron-donating

groups (Table 4.2, entries 2 and 5), a weak electron-withdrawing group (Table

4.2, entry 4) or a steric hindered functional group (Table 4.2, entry 3) all afforded

the corresponding coupling products in good yields. Heterocyclic boronic acids

(Table 4.2, entries 7 and 9) and vinylboronic acid (Table 4.2, entry 8) underwent

the coupling reaction smoothly as well. However, arylboronic acids bearing

strong electron-withdrawing groups (Table 4.2, entries 10 and 11) were non-

reactive under the optimized conditions. Other N-PMP glycine amide derivatives

NH

HN

MeO

O

+

10 mol% CuBr1.0 equiv TBHP

solvent, 100 oC NH

HN

MeO

O

B(OH)2

4a 4b 4c

MeMe

53

reacted equally well with arylboronic acids (Table 4.2, entries 12 and 13).

However, the coupling reaction did not proceed at all when N-PMP glycine

amides without hydrogen on the amide nitrogen (Table 4.2, entries 15 and 16) or a

N-PMP glycine ester (Table 4.2, entry 14) were used.

Table 4.2 Arylation of Glycine Amides.a

entry R Aryl reation time (h) Yield (%)b 1 NHMe Ph 20 75 (81) 2 NHMe PMP 20 71 (80) 3 NHMe 2-MeC6H4 9 82 (100) 4 NHMe 4-BrC6H4 6 74 (100) 5 NHMe 4-CH2=CHC6H4 6 47 (61) 6 NHMe naphthalen-2-yl 6 83 (93) 7 NHMe furan-2-yl 11 71 (85) 8 NHMe PhCH=CH 10 83 (89) 9 NHMe thiophen-2-yl 10 84 (96) 10 NHMe 4-CF3C6H4 12 ND 11 NHMe 4-CH3COC6H4 12 ND 12 NHCH2Ph Ph 12 70 (88) 13 NH (CH2)3Ph Ph 12 85 (100) 14 OEt Ph 12 ND 15 1-pyrrolidinyl Ph 12 NR 16 N(iPr)2 Ph 12 NR

a Reaction conditions: 4e (0.20 mmol), 4d (0.30 mmol), TBHP (36 µL, 5-6 M in decane), CuBr (0.02 mmol), DCE (0.5 mL). b Isolated yields are based on aryl boronic acid, and 1H NMR yields using benzaldehyde as an internal standard. ND=Not Determined. NR=No Reaction.

4.3 – Oxidative Arylation of Short Peptides

Having achieved the functionalization of glycine derivatives, we decided

to tackle the more challenging task of functionalizing peptides. Considering that

α‐aryl peptides are more prevalent in nature and more important synthons in

organic syntheses, we decided to focus on the arylation of these peptides. Simple

dipeptides (Table 4.3, 4ja-4jh) and tripeptides (Table 4.3, 4ji-4jp) all reacted with

PMP

HN

O

NHR Aryl B(OH)2CuBr/TBHP

DCE, 100 oCPMP

HN

O

NHR

Aryl

+

4d 4e 4f

54

arylboronic acids, affording the coupling products in goodyields in most cases.

The scope of arylboronic acids is very similar to the one examined for N-PMP

Table 4.3 Arylation of Short Peptides.a,b

a Reaction conditions: aryl boronic acid (0.20 mmol), peptide (0.30 mmol), TBHP (36 µL, 5-6 M in decane), CuBr (0.02 mmol), DCE (0.5 mL). b Isolated yields are based on aryl boronic acid. c d.r. (diastereomer ratio) was determined by HPLC analysis. d.r. of the product is 4:5. d d.r. (diastereomer ratio) was determined by HPLC analysis. d.r. of the product is 3:5.

PMP

HN

O

NH

OEt

O CuBr/TBHPPMP

HN

O

NH

R

Ar

+

PMP

HN

NH

O

OEt

OPh

PMP

HN

NH

O

OEt

OPMP

Me

PMP

HN

NH

O

OEt

OPMP

PMP

HN

NH

O

OEt

O

PMP

HN

NH

O

OEt

O

PMP

HN

NH

O

OEt

OS

PMP

HN

NH

O

OEt

OO

Me

Cl

PMP

HN

NH

O

OEt

O

R1

PMP

HN

O

NH

HN

O

OEt

O

PMP

HN

NH

OHN

O

OEt

O

Ph

PMP

HN

NH

OHN

O

OEt

O

PMP

PMP

HN

NH

OHN

O

OEt

O

Me

PMP

HN

NH

OHN

O

OEt

O

S

PMP

HN

NH

OHN

O

OEt

O

O

PMP

HN

NH

OHN

O

OEt

O

Me

Me

Ph

PMP

HN

NH

OHN

O

OEt

O

MePh

PMP

HN

NH

OHN

O

OEt

O

R2

or4g

4h

4j

4ja 6 h 77%

4jbc 12 h 57%

4jc 3 h 94%

4jd 11 h 73%

4je 11 h 76%

4jf 10 h 71%

4jg 12 h 61%

4jh 12 h 74%

4ji 6 h 57%

4jj 12 h 84%

4jk 11 h 54%4jp 12 h 68%

4jo 24 h 47%

4jn 36 h 57%

4jld 10 h 59%

4jmd 12 h 65%

100oCArB(OH)2

4i

55

glycine amide. A dipeptide (Table 4.3, 4jb) and tripeptides (Table 4.3, 4jl and

4jm) with an amino acid moiety other than glycine also afforded the cross

coupling products. Interestingly, similar diasteroselectivities were observed when

the pre-existing chiral center is either one (Table 4.3, 4jb) or two (Table 4.3, 4jl

and 4jm) amino acid units away from the N-terminal glycine moiety.

4.4 – Importance of N-PMP Protecting Group

It is well-known that there are other useful protecting groups for nitrogen

compounds, such as benzyl, Boc(tert-butoxycarbonyl) and Ts (p-toluene

sulfonamide). Accordingly, the protected dipeptides with those protecting groups

were synthesized and tested for the oxidative coupling reactions with phenyl

boronic acid (Table 4.4, entries 2-4). However, no desired coupling product was

obtained by using those protecting groups, which illustrates the importance of the

N-PMP group in the oxidative coupling process.

Table 4.4 Test of Other Protecting Groups.

entry PG yield (%)a 1 PMP 83 2 Bn NP 3 Boc NP 4 Ts NP

a 1H NMR yields using benzaldehyde as an internal standard. NP=No Product.

4.5 – Racemization Test

Traditional methods to functionalize amino acid derivatives are not

applicable to peptide modifications due not only to the site-specificity issue but

also the fact that the most popular method to functionalize amino acid derivatives

is via the enolate chemistry, which usually requires the use of an excess amount

PGNH

HN

O

+

10 mol% CuBr1.0 equiv TBHP

DCE, 100 oC PGNH

HN

O

B(OH)2OEt

O

OEt

O

1.5 equiv 1.0 equiv

56

of strong bases such as potassium tert-butoxide or LDA (lithium diisopropyl

amide). Therefore, theα-protons adjacent to the amides in most cases can not

tolerate such strong basic conditions and would racemize quickly. To test whether

our present method can still maintain the pre-existing chiral center on the peptide,

we used the optically pure compound 4gb. Under the standard reaction

conditions, the coupling product 4jb was generated without any racemization of

the adjacent stereocenter (Scheme 4.1).

Scheme 4.1 Racemization Test

4.6 – Deprotection of PMP Group and Further Functionalization

To test the compatibility of this novel functionalization method with state-

of-the-art peptide-syntheses, the functionalized glycine derivative 4c was

deprotected readily by TCCA to afford the amine salt 4k. Compound 4k could

then be coupled with Fmoc-Gly efficiently using HBTU/HOBt as coupling

reagents to afford the desired peptide 4l (Scheme 4.2).

Scheme 4.2 Deprotection of PMP Group and Further Functionalization

PMP

HN

O

NH

* OEt

O

MeB(OH)2

+CuBr/TBHP

DCE, 100 oC

OMe

PMP

HN

O

NH

* OEt

O

Me

OMe

(R, S),(S, S)

dr=4:5

(S)

4gb 4jb4ib

PMP

HN

O

NH

Me H3N

O

NH

MeHN

O

NH

Me

O

FmocHN

TCCA2 equv HCl

H2O/ ACNRT, 3 h

Fmoc-GlyDIPEA

HBTU, HOBt

DMFRT, 10 h

4c 4k 4l

Cl

57% over two steps

57

4.7 – Proposed Reaction Mechanism

As mentioned before, during the course of our study of the substrate

scope, we found that neither the glycine ester nor the tertiary glycine amide were

able to undergo the arylation reaction (Table 4.2, entries 14-16). This led us to

investigate the mechanism of this new type of arylation reaction (Scheme 4.3).

We proposed that after the formation of the iminoamide 4n from glycine

derivative 4m, it will tautomerize to its iminol form 4o. Then, the so-formed

hydroxyl group will coordinate with the phenyl boronic acid to give intermediate

4p. An intramolecular delivery of the phenyl group occurs to afford the arylation

product 4q.

Scheme 4.3 Proposed Mechanism for the Arylation Reaction

To support our proposed mechanism, we synthesized the precursor (imino

amide). The general procedure is: L-diethyl tartrate was first converted to

dibenzyl tartaric amide by reacting with benzylamine. Oxidative cleavage of the

diol by periodic acid generates the glyoxylic amide in situ which was efficiently

transformed to imino amide by reaction with PMPNH2 (Scheme 4.4). We have

been able to develop this procedure so that it may be easily carried out on

multigram scale, with isolation of the reagent accomplished by simple silica gel

column filtration followed by recrystallization. With the imino amide in hand, we

examined the coupling reaction with arylboronic acids.

NH

O

RHN

PMP

NH

O

RNPMP

N

OH

RNPMP

N

OH

RNPMP

BPhOH

HO

NH

O

RHN

PMP

Ph

4m

4n

4o

4p

4q

[Cu]

[Cu]

+

TBHP

PhB(OH)2

58

Scheme 4.4 Synthesis of the Imino Amide for the Arylation Reaction

With the imino amide in hand, we did a survey of the arylation reaction.

Electron rich aryl boronic acids (Table 4.5, entries 2, 5, 7, 9) generally are more

reactive than their electron deficient (Table 4.5, entries 3, 8) or sterically hindered

(Table 4.5, entry 4) counterparts.

Table 4.5 Arylation of Imino Amides.a

entry R1 Ar yield (%)

1 Bn Ph 65 2 Bn 4-MeOC6H4 97 3 Bn 4-ClC6H4 78 4 Bn 2-MeC6H4 56 5 Bn 2-naphthyl 99 6 Me Ph 96 7 Me 4-MeOC6H4 81 8 Me 4-BrC6H4 82 9 Me 2-naphthyl 94 10 Ph Ph 17

a Reaction conditions: imino amide (0.10 mmol), aryl boronic acid (0.15 mmol), DCE (0.5 mL), 5 h at 100 oC.

For the imino amide substrate, N-alkyl amides (Table 4.5, entries 1-9) are

much more reactive than the N-phenyl amide (Table 4.5, entry 1). This might due

to the fact that in the case of the N-phenyl amide, the phenyl group will withdraw

electrons from amide. This withdrawing effect will make the tautomerization to

EtOOEt

O

OH

OH

O

RNH2+cat. K2CO3

MeOH, refluxRHN

NHR

O

OH

OH

O

H5IO6

THF, RT

RHN CHO

O

PMPNH2

CH2Cl2, RTRHN

O

NPMP

R: Bn

Me

R = Bn

Me

PMPN

NH

R1

O

+ ArB(OH)2 PMP

HN

NH

R1

O

Ar100 oC

ClCH2CH2Cl

59

the iminol more difficult than the case of N-alkyl amides with the current reaction

conditions (Figure 4.1). This reduced activity is consistent with our previously

proposed reaction mechanism.

Figure 4.1 Tautomerization between the Amide and the Iminol

4.8 – Conclusion

A novel efficient way to functionalize glycine derivatives and short

peptides with various aryl boronic acids is described. Additionally, the

configurations of other stereocenters in the peptide are maintained. The current

method could also be integrated into subsequent peptide syntheses.






respectively. MS data were obtained by using KRATOS MS25RFA Mass

Spectrometer. HRMS-ESI measurements were performed at McGill University.

General procedure for the preparation of PMP protected glycine derivatives;

2-(4-methoxyphenylamino)-N-methylacetamide:

2-Bromoacetyl bromide (2.4 g, 1.2 mmol) in CH2Cl2 (10 ml) was added dropwise

to a mixture of MeNH2 (1.0 g, 30 wt% in H2O, 1.0 mmol) and K2CO3 (1.66 g, 1.2

mmol) in CH2Cl2/H2O (30 mL/10 mL) at 0oC. The mixture was then allowed to

warm up to room temperature and stirred for 6 h. Then the organic layer was

NNH

R

O

O

NNR

OH

O

60

separated and the aqueous layer was extracted with CH2Cl2 (3×5 mL). Then

organic layers were then combined and dried over Na2SO4 and CH2Cl2 was

removed in vacuo. Subsequently, EtOH (5 mL), p-anisidine (1.23 g, 1 mmol), and

NaOAc (0.84 g, 1 mmol) were added to the residue. The resulting mixture was

refluxed for 6 h. Then the reaction mixture was filtered. The solvent of the filtrate

was removed in vacuo. Recrystalization (CH2Cl2/hexanes) gave the pure product

2-(4-methoxyphenylamino)-N-methylacetamide (1.5 g, 80% in yield).

General procedure for the preparation of PMP protected peptide derivative;

N-(N-p-methoxyphenylglycyl)-glycine ethyl ester:

SOCl2 (3.6 g, 30 mmol) was added slowly to EtOH (30 mL) at 0oC. After stirring

at this temperature for 10 minutes, glycine (0.75 g, 10 mmol) was added to the

solution. Then the reaction was stirred at 70oC for 3 h. EtOH was removed in

vacuo. The resulting solid was then mixed with CH2Cl2 (30 mL) and NEt3 (2.2 g,

22 mmol). The reaction mixture was then cooled to -78oC, and BrCH2COBr (2.0

g, 10 mmol) was added slowly to the solution at this temperature. The solution

was allowed to warm up to room temperature and the stirring was continued for 6

h. After that, the solution was washed with H2O (10 mL). The organic layer was

dried over Na2SO4 and CH2Cl2 was removed in vacuo to afford

BrCH2CONHCH2COOEt (1.8 g, 81%). BrCH2CONHCH2COOEt (1.1 g, 5 mmol)

was added to EtOH (4 mL). Then NaOAc (0.50 g, 6 mmol) and p-anisole (0.74g,

6 mmol) were successively added to the mixture. The reaction tube was heated at

80 oC for 6 h. EtOH was removed in vacuo and the residue was dissolved in

CH2Cl2 (20 mL) and washed with H2O (5 mL). The organic layer was dried over

Na2SO4, and CH2Cl2 was removed in vacuo. Flash column chromatography on

silica gel using ethyl acetate/hexanes (1:1) furnished the final product N-(N-p-

methoxyphenylglycyl)-glycine ethyl ester (0.95 g, 72% in yield).

General procedure for the arylation of glycine and peptide derivatives:

N-PMP-Gly-Gly-OEt (80 mg, 0.30 mmol) and CuBr (2.8 mg, 0.02 mmol) were

dissolved in DCE (0.5 mL) and TBHP (36 µl, 5-6 M in decane) was then added.

The solution was stirred at room temperature for 10 min, followed by addition of

61

PhB(OH)2 (25 mg, 0.2 mmol). The test tube was capped and stirred at 100oC for 6

h. Then the reaction mixture was filtered through a small pad of silica gel,

concentrated in vacuo. Flash column chromatography on silica gel using ethyl

acetate/ hexanes (1/5 to 1/3) furnished the final coupling product (52 mg, 77% in

yield).

General procedure for the deprotection of N-PMP-Gly(Ph)-OEt and

subsequent coupling reaction with Fmoc-Gly:

To a stirred solution of compound N-PMP-Gly(Ph)-OEt (27 mg, 0.1 mmol) in

CH3CN/H2O (1 mL/1 mL), HCl (100 µL, 2M) and trichloroisocyanuric acid

(TCCA) (12 mg, 0.1 mmol) were successively added. The reaction mixture was

stirred at room temperature for 4 h, later CH3CN was removed in vacuo. The

aqueous solution was extracted with CH2Cl2 (2×1 mL), and water in the aqueous

solution was then removed in vacuo at 40oC. The resulting residue was used for

the next step without further purification. The residue was dissolved in DMF (0.5

mL). Then HBTU (38 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), DIPEA (N,N-

diisopropyl ethyl amine) (25µL, 0.25 mmol) and Fmoc-Gly (30 mg, 0.1 mmol)

were successively added. The reaction mixture was stirred at room temperature

for 10 h. H2O (5 mL) was added to quench the reaction. The product was

extracted with EtOAc (3×2 mL). The EtOAc layer was dried over Na2SO4. After

evaporation of the EtOAc in vacuo, the product was isolated using flash column

chromatography on silica gel eluting with ethyl acetate/NEt3 (100/3) (25 mg, 57%

in yield).

Procedure for the synthesis of N-PMP glyoxyl benzyl amide

D-(–)-Diethyl tartrate (3.1 g, 15 mmol), benzyl amine (3.9 g, 36 mmol) and

K2CO3 (0.42 g, 3 mmol) were successively added to MeOH (50 mL). The solution

EtOOEt

O

OH

OH

O

BnNH2+cat. K2CO3

MeOH, refluxBnHN

NHBn

O

OH

OH

O

H5IO6

THF, RT

BnHN CHO

OPMPNH2

DCM, RTBnHN

O

NPMP

62

was refluxed for 8 h. It was then cooled to room temperature to afford a white

solid, which was filtered, washed with water, and recrystallised from 50% ethanol

in water to obtain compound Dibenzyl tartaric amide as white crystals (4.6 g, 94%

in yield).11

Dibenzyl tartaric amide (3.3 g, 10 mmol) and H5IO6 (2.7 g, 12 mmol) were added

to THF (20 mL). The mixture was stirred at room temperature for 4 h. After the

reaction, the formed precipitate was filtered. The THF in the filtrate was removed

in vacuo below 30oC. CH2Cl2 (20 mL) was then added to the resulting liquid

residue. p-Anisidine (3.0 g, 24 mmol) was added to the CH2Cl2 solution, stirred at

room temperature for 1 h. After CH2Cl2 was removed in vacuo, the mixture was

filterred on silica gel (washed with ethyl acetate) to remove the inorganic residue.

After removal of ethyl acetate in vacuo, the product N-PMP glyoxyl benzyl amide

was obtained (3.3 g, 62%) after recrystallization in ethyl acetate/hexanes.

Procedure for the synthesis of N-PMP glyoxyl methyl amide

D-(–)-Diethyl tartrate (2.1 g, 10 mmol), methyl amine (33 % ethanol solution, 2.8

ml, 40 mmol) and K2CO3 (0.28 g, 2 mmol) were successively added to MeOH (25

mL). The flask was then sealed and heated up at 70oC for 8 h. After the reaction,

methanol was removed in vacuo. To the residue, H5IO6 (2.7 g, 12 mmol) and THF

(30 mL) were added. The mixture was stirred at room temperature for 4 h. After

the reaction, the formed precipitate was filtered. The THF in the filtrate was

removed in vacuo below 30oC. CH2Cl2 (20 mL) was then added to the resulting

liquid residue. p-Anisidine (3.0 g, 24 mmol) was added to the CH2Cl2 solution,

stirred at room temperature for 1 h. After CH2Cl2 was removed in vacuo, the

mixture was filter on silica gel quickly (washed with 1/1 mixture of ethyl

acetate/hexanes) to remove the inorganic residue. After removal of ethyl acetate

EtOOEt

O

OH

OH

O

MeNH2+cat. K2CO3

MeOH, refluxMeHN

NHMe

O

OH

OH

O

H5IO6

THF, RT

MeHN CHO

OPMPNH2

DCM, RTMeHN

O

NPMP

63

in vacuo, the product was obtained (1.76 g, 46% in yield) after recrystallization in

ethyl acetate/hexanes.

Typical procedure for the arylation reaction

The N-PMP imine amide (0.10 mmol) and aryl boronic acid (0.15 mmol) were

added to DCE (0.5 mL) in a test tube. The test tube was sealed and heated at

100oC for 5 h. After the reaction was finished, DCE was removed in vacuo. Flash

chromatography using ethyl acetate/hexanes (1/4 to 1/2) afforded the arylated

product.

Compound 4gb 1H NMR (300 MHz, CDCl3, ppm): δ 7.34 (d, J=7.8 Hz, 1H), 6.72 (d, J=8.7 Hz,

2H), 6.52 (d, J=8.7 Hz, 2H), 4.55 (m, 1H), 4.23 (s, 1H, br), 4.09 (q, J=7.2 Hz,

2H), 3.68 (s, 2H), 3.67 (d, 3H), 1.32 (d, J=6.9 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H); 13C

NMR (75 MHz, CDCl3, ppm): δ 172.3, 170.6, 152.7, 141.3, 114.6, 114.2, 61.2,

55.4, 49.3, 47.5, 17.9, 13.8; HRMS exact mass calc’d for C14H21N2O4 ([M+H])

m/z: 281.1496; found m/z: 281.1495.

Compound 4ha 1H NMR (300 MHz, CDCl3, ppm): δ 7.61 (t, J=5.7 Hz, 1H), 7.04 (t, J=5.4 Hz,

1H), 6.74 (d, J=8.7 Hz, 2H), 6.54 (d, J=8.7 Hz, 2H), 4.28 (s, 1H, br), 4.14 (q,

J=7.2 Hz, 2H), 3.98 (d, J=5.7 Hz, 2H), 3.94 (d, J=5.4 Hz, 2H), 3.75 (s, 2H), 3.70

(s, 3H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.0, 169.7,

64

169.2, 152.8, 141.1, 114.9, 114.2, 61.5, 55.6, 49.1, 42.6, 41.1, 14.0; HRMS exact

mass calc’d for C15H22N3O5 ([M+H]) m/z: 324.1554; found m/z: 324.1556.

Compound 4hb 1H NMR (300 MHz, CDCl3, ppm): δ 7.61 (t, J=5.4 Hz, 1H), 7.05 (d, J=9.1 Hz,

1H), 6.73 (d, J=8.7 Hz, 2H), 6.52 (d, J=8.7 Hz, 2H), 4.55-4.47 (m, 1H), 4.32 (s,

1H, br), 4.15-3.96 (m, 4H), 3.72 (s, 2H), 3.69 (s, 3H), 1.64-1.42 (m, 3H), 1.22 (t,

J=7.2 Hz, 3H), 0.89-0.86 (m, 6H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.8,

171.8, 168.7, 152.7, 141.2, 114.8, 114.1, 61.2, 55.5, 50.7, 49.1, 42.5, 41.0, 24.6,

22.6, 21.7, 14.00; HRMS exact mass calc’d for C19H30N3O5 ([M+H]) m/z:

380.2180; found m/z: 380.2177.

Compound 4hc 1H NMR (300 MHz, CDCl3, ppm): δ 7.68 (t, J=5.4 Hz, 1H), 7.29 (d, J=7.2 Hz,

1H), 6.67 (d, J=9.0 Hz, 2H), 6.47 (d, J=9.0 Hz, 2H), 4.49-4.39 (m, 2H), 4.11-4.02

(m, 2H), 3.92 (d, J=5.4 Hz, 2H), 3.68 (s, 2H), 3.63 (s, 3H), 1.27 (d, J=7.5 Hz,

3H), 1.17 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.5, 171.9,

168.5, 152.4, 141.2, 114.6, 113.8, 61.1, 55.3, 48.8, 47.8, 42.2, 17.5, 13.8; HRMS

exact mass calc’d for C12H24N3O5 ([M+H]) m/z: 338.1711; found m/z: 338.1712.

Compound 4fa (Table 4.2, entry 1)

65

1H NMR (300 MHz, CDCl3, ppm): δ 7.44-7.31 (m, 5H), 6.87 (s, 1H, br), 6.78 (d,

J=8.7 Hz, 2H), 6.57 (d, J=8.7 Hz, 2H), 4.66 (s, 1H), 4.26 (s, 1H, br), 3.74 (s, 3H),

2.83 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.0, 153.1, 140.7,

138.9, 129.1, 128.5, 127.3, 114.9, 114.8, 65.0, 55.7, 26.3; HRMS exact mass

calc’d for C16H19N2O2 ([M+H]) m/z: 271.1441; found m/z: 271.1444.

Compound 4fb (Table 4.2, entry 2) 1H NMR (300 MHz, CDCl3, ppm): δ 7.32 (d, J=8.7 Hz, 2H), 6.88 (s, 1H, br), 6.87

(d, J=8.7 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 6.55 (d, J=9.0 Hz, 2H), 4.61 (s, 1H),

4.22 (s, 1H, br), 3.78 (s, 3H), 3.73 (s, 3H), 2.81 (d, J=4.8 Hz, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 172.4, 159.6, 153.0, 140.8, 131.0, 128.5, 114.8, 114.8,


m/z: 301.1547; found m/z: 301.1549.

Compound 4fc (Table 4.2, entry 3) 1H NMR (400 MHz, CDCl3, ppm): δ 7.28-7.10 (m, 4H), 7.10 (s, 1H, br), 6.78 (d,

J=12.4 Hz, 2H), 6.59 (d, J=12.4 Hz, 2H), 4.88 (s, 1H), 4.20 (s, 1H, br), 3.75 (s,

3H), 2.88 (d, J=4.8 Hz, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm):

δ 172.6, 153.1, 141.1, 137.3, 137.0, 131.1, 128.3, 126.6, 126.5, 114.8, 114.6, 61.8,

55.6, 26.2, 19.6; HRMS exact mass calc’d for C17H21N2O2 ([M+H]) m/z:

285.1598; found m/z: 285.1600.

66

Compound 4fd (Table 4.2, entry 4) 1H NMR (300 MHz, CDCl3, ppm): δ 7.49 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz,

2H), 6.78 (s, 1H, br), 6.76 (d, J=9.0 Hz, 2H), 6.56 (d, J=9.0 Hz, 2H), 4.63 (s, 1H),

4.20 (s, 1H, br), 3.73 (s, 3H), 2.81 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 171.5, 153.2, 140.3, 137.9, 132.2, 132.0, 122.5, 115.0, 114.8, 64.2, 55.6,

26.3; HRMS exact mass calc’d for C17H18N2O2Br ([M+H]) m/z: 349.0546; found

m/z: 349.0549.

Compound 4fe (Table 4.2, entry 5) 1H NMR (300 MHz, CDCl3, ppm): δ 7.41-7.39 (m, 4H), 6.79-6.74 (m, 4H), 6.58

(d, J=9.0 Hz, 2H), 5.76 (d, J=17.7 Hz, 1H), 5.26 (d, J=17.7 Hz, 1H), 4.66 (s, 1H),

4.40 (s, 1H, br), 3.74 (s, 3H), 2.83 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 171.9, 153.1, 140.7, 138.3, 137.8, 136.1, 127.5, 126.9, 114.9, 114.8,

114.6, 64.7, 55.7, 26.3; HRMS exact mass calc’d for C18H21N2O2 ([M+H]) m/z:

297.1598; found m/z: 297.1596.

Compound 4ff (Table 4.2, entry 6) 1H NMR (300 MHz, CDCl3, ppm): δ 7.89-7.81 (m, 4H), 7.54-7.48 (m, 3H), 6.85

(s, 1H, br), 6.75 (d, J=8.7 Hz, 2H), 6.61 (d, J=8.7 Hz, 2H), 4.85 (s, 1H), 4.43 (s,

67

1H, br), 3.73 (s, 3H), 2.81 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm):

δ 171.9; 153.0, 140.7, 136.4, 133.3, 133.1, 129.1, 127.9, 127.7, 126.6, 126.4,

126.3, 124.8, 114.9, 114.8, 64.8, 55.6, 26.3; HRMS exact mass calc’d for

C20H21N2O2 ([M+H]) m/z: 321.1598; found m/z: 321.1600.

Compound 4fg (Table 4.2, entry 7) 1H NMR (300 MHz, CDCl3, ppm): δ 7.394-7.388 (m, 1H), 6.95 (s, 1H, br), 6.78

(d, J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz. 2H), 6.39-6.35 (m, 2H), 4.84 (s, 1H), 3.74

(s, 3H), 2.85 (d, J=4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 169.9, 153.2,

150.7, 142.5, 140.3, 115.0, 114.8, 110.8, 108.2, 58.7, 55.6, 26.4; HRMS exact


Compound 4fh (Table 4.2, entry 8) 1H NMR (300 MHz, CDCl3, ppm): δ 7.40-7.23 (m, 5H), 6.85-6.73 (m, 4H), 6.63

(d, J=9.0 Hz, 2H), 6.29 (dd, J=15.9, 7.5 Hz, 1H), 4.36 (d, J=7.5 Hz, 1H), 4.20 (s,

1H, br), 3.75 (s, 3H), 2.84 (d, J=5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm):

δ 172.0, 153.2, 140.5, 135.9, 133.7, 128.6, 128.2, 126.6, 126.1, 115.1, 114.8, 62.6,

55.7, 26.3; HRMS exact mass calc’d for C18H21N2O2 ([M+H]) m/z: 297.1598;

found m/z: 297.1596.

68

Compound 4fi (Table 4.2, entry 9) 1H NMR (300 MHz, CDCl3, ppm): δ 7.26 (d, J=5.1 Hz, 2H), 7.14-7.12 (m, 1H),

6.98 (dd, J=5.4, 3.6 Hz, 1H), 6.88 (s, 1H, br), 6.77 (d, J=9.0 Hz, 2H), 6.60 (d,

J=9.0 Hz, 2H), 4.96 (s, 1H), 4.40 (s, 1H, br), 3.74 (s, 3H), 2.82 (d, J=4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 171.1, 153.3, 141.7, 140.2, 127.0, 126.0,

125.7, 115.1, 114.8, 60.2, 55.6, 26.4; HRMS exact mass calc’d for C14H17N2O2S

([M+H]) m/z: 277.1005; found m/z: 277.1008.

Compound 4fj (Table 4.2, entry 12)12 1H NMR (300 MHz, CDCl3, ppm): δ 7.46-7.36 (m, 5H), 7.28-7.13 (m, 5H), 6.77

(d, J=9.0 Hz, 2H), 6.59 (d, J=9.0 Hz, 2H), 4.73 (s, 1H), 4.55 (dd, J=14.7, 6.3 Hz,

1H), 4.40 (dd, J=14.7, 6.3 Hz, 1H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 171.4, 153.2, 140.6, 138.8, 138.0, 129.2, 128.6, 127.6, 127.4, 127.3,

127.3, 115.1, 114.8, 65.2, 55.7, 43.4

Compound 4fk (Table 3, entry 13) 1H NMR (300 MHz, CDCl3, ppm): δ 7.44-7.34 (m, 5H), 7.29-7.15 (m, 3H), 7.07

(d, J=6.9 Hz, 2H), 6.95 (t, J=4.8 Hz, 1H), 6.78 (d, J=8.7 Hz, 2H), 6.60 (d, J=8.7

Hz, 2H), 4.66 (s, 1H), 3.74 (s, 3H), 3.31 (q, J=6.6 Hz, 2H), 2.55 (t, J=4.2 Hz,

2H,), 1.80 (pent, J=6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3, ppm): δ 171.4,

153.2, 141.2, 140.6, 138.9, 129.2, 128.5, 128.4, 128.3, 127.3, 125.9, 115.0, 114.8,


m/z: 375.2067; found m/z: 375.2070.

69

Compound 4ja 1H NMR (300 MHz, CDCl3, ppm): δ 7.49 (d, J=7.8 Hz, 2H), 7.42-7.26 (m, 4H),

6.79 (d, J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz. 2H), 4.72 (s, 1H), 4.23-4.14 (m, 4H),

3.93 (dd, J=17.7, 5.4 Hz, 1H), 3.74 (s, 3H), 1.24 (t, J=6.9 Hz, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 171.8, 169.5, 153.2, 140.6, 138.6, 129.2, 128.6, 127.5,



Compound 4jb (mixture of inseparable two diastereomers) 1H NMR (400 MHz, CDCl3, ppm): δ 7.47 (d, J=8.4 Hz, 2H), 7.41-7.33 (m, 5H),

6.88 (d, J=8.8 Hz, 4H), 6.78-6.75 (m, 4H), 6.62-6.56 (m, 4H), 4.64-4.53 (m, 4H),

4.20-4.08 (m, 4H), 3.78 (s, 6H), 3.73 (s, 3H), 3.72 (s, 3H), 1.40 (d, J=7.6 Hz, 3H),

1.33 (d, J=7.6 Hz, 3H), 1.26 (t, J=6.8 Hz, 3H), 1.18 (t, J=6.8 Hz, 3H); 13C NMR

(100 MHz, CDCl3, ppm): δ 172.6, 172.2, 171.4, 171.2, 159.5, 159.5, 153.0, 140.7,

140.6, 130.8, 130.6, 128.7, 128.4, 115.1, 114.8, 114.6, 114.6, 114.4, 114.3, 64.3,

64.3, 61.4, 61.3, 55.5, 55.2, 48.0, 47.7, 18.1, 18.1, 14.0, 13.9; HRMS exact mass

calc’d for C21H27N2O5 ([M+H]) m/z: 387.1915; found m/z: 387.1915; HPLC for

the racemic compound (Daicel Chiralcel OD-H, hexane/isopropanol=2/1, flow

rate=0.5 ml/min), tR=12.2 min, tR=12.2 min, tR=15.6 min, tR=17.7 min; HPLC for

the (R,S) and (S,S) diastereomers (Daicel Chiralcel OD-H,

hexane/isopropanol=2/1, flow rate=0.5 ml/min), tR=12.2 min, tR=17.7 min.

70

Compound 4jc 1H NMR (300 MHz, CDCl3, ppm): δ 7.42-7.38 (m, 3H), 6.88 (d, J=8.7 Hz, 2H),

6.77 (d, J=9.3 Hz, 2H), 6.59 (d, J=9.3 Hz, 2H), 4.66 (s, 1H), 4.23-4.13 (m, 4H),

3.92 (dd, J=17.7, 5.4 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.1, 169.6, 159.6, 153.1, 140.7, 130.7,

128.7, 115.0, 114.7, 114.4, 64.3, 61.4, 55.6, 55.2, 41.1, 14.0; HRMS exact mass


Compound 4jd 1H NMR (300 MHz, CDCl3, ppm): δ 7.60 (t, J=5.1 Hz, 1H), 7.43-7.40 (m, 1H),

7.24-7.19 (m, 3H), 6.78 (d, J=8.7 Hz, 2H), 6.62 (d, J=9.3 Hz, 2H), 4.92 (s, 1H),

4.27-4.10 (m, 3H), 4.01 (s, 1H, br), 3.90 (dd, J=17.7, 5.4 Hz, 1H), 3.74 (s, 3H),

2.36 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.5,

169.6, 153.1, 141.0, 137.1, 136.9, 130.9, 128.4, 126.6, 126.6, 114.8, 114.6, 61.7,


m/z: 357.1809; found m/z: 357.1809.

Compound 4je

71

1H NMR (300 MHz, CDCl3, ppm): δ 7.42-7.39 (m, 3H), 7.34 (d, J=8.4 Hz, 2H),

6.77 (d, J=8.7 Hz, 2H), 6.58 (d, J=8.7 Hz, 2H), 4.70 (s, 1H), 4.21-4.13 (m, 4H),

3.89 (dd, J=18.3, 5.1 Hz, 1H), 3.73 (s, 3H), 1.25 (t, J=4.8 Hz, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 171.5, 169.4, 153.3, 140.2, 137.0, 134.5, 129.3, 128.9,


C19H22N2O4Cl ([M+H]) m/z: 377.1263; found m/z: 377.1263.

Compound 4jf 1H NMR (300 MHz, CDCl3, ppm): δ 7.40-7.25 (m, 6H), 6.82-6.78 (m, 3H), 6.65

(d, J=9.0 Hz, 2H), 6.31 (dd, J=16.2, 7.5 Hz, 1H), 4.42 (d, J=7.2 Hz, 1H), 4.18 (q,

J=7.2 Hz, 2H), 4.11-3.92 (m, 3H), 3.74 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); 13C NMR

(75 MHz, CDCl3, ppm): δ 171.9, 169.5, 153.2, 140.4, 135.8, 134.0, 128.6, 128.2,

126.6, 125.5, 115.2, 114.8, 62.5, 61.5, 55.6, 41.3, 14.0; HRMS exact mass calc’d

for C21H25N2O4 ([M+H]) m/z: 369.1809; found m/z: 369.1809.

Compound 4jg 1H NMR (300 MHz, CDCl3, ppm): δ 7.36 (t, J=4.8 Hz, 1H), 7.28 (d, J=5.1 Hz,

1H), 7.21 (d, J=3.6 Hz, 1H), 7.01-6.98 (m, 1H), 6.78 (d, J=8.7 Hz, 2H), 6.63 (d,

J=8.7 Hz, 2H), 5.01 (s, 1H), 4.21-4.10 (m, 3H), 4.13-3.91 (m, 2H), 3.74 (s, 3H),

1.25 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 170.9, 169.4, 153.4,

141.1, 140.2, 127.1, 126.2, 125.9, 115.3, 114.8, 61.5, 60.16, 55.6, 41.3, 14.1;

HRMS exact mass calc’d for C17H21N2O4S ([M+H]) m/z: 349.1217; found m/z:

349.1214.

72

Compound 4jh 1H NMR (300 MHz, CDCl3, ppm): δ 7.44 (t, J=5.1 Hz, 1H), 7.39 (s, 1H), 6.78 (d,

J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.42 (d, J=3.0 Hz, 1H), 6.35-6.34 (m, 1H),

4.88 (s, 1H), 4.21-4.09 (m, 3H), 4.14-3.93 (m, 2H), 3.73 (s, 3H), 1.24 (t, J=6.9


140.2, 115.1, 114.7, 110.8, 108.4, 61.5, 58.6, 55.6, 41.3, 14.0; HRMS exact mass


Compound 4ji 1H NMR (300 MHz, CDCl3, ppm): δ 7.66 (t, J=5.7 Hz, 1H), 7.44 (d, J=7.2 Hz,

2H), 7.38-7.30 (m, 3H), 6.75 (d, J=8.7 Hz, 2H), 6.58 (d, J=8.7 Hz, 2H), 4.76 (s,

1H), 4.37 (s, 1H, br), 4.16 (q, J=7.2 Hz, 2H), 4.04 (dd, J=16.5, 6.0 Hz, 1H), 3.91-

3.85 (m, 4H), 3.71 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 172.4, 169.5, 168.9, 153.1, 140.4, 138.4, 129.2, 128.6, 127.3, 114.9,

114.8, 64.5, 61.5, 55.6, 42.8, 41.1, 14.1; HRMS exact mass calc’d for C21H26N3O5

([M+H]) m/z: 400.1867; found m/z: 400.1866.

Compound 4jj 1H NMR (300 MHz, CDCl3, ppm): δ 7.73 (t, J=5.4 Hz, 1H), 7.33 (d, J=8.7 Hz,

2H), 6.91 (t, J=5.1 Hz, 1H), 6.83 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 6.55

73

(d, J=9.0 Hz, 2H), 4.71 (s, 1H), 4.38 (s, 1H, br), 4.13 (q, J=7.2 Hz, 2H), 4.10-3.76

(m, 4H), 3.74 (s, 3H), 3.69 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 172.7, 169.5, 169.0, 159.5, 152.8, 140.5, 130.4, 128.5, 114.8,

114.7, 114.3, 63.6, 61.4, 55.5, 55.1, 42.7, 41.0, 14.0; HRMS exact mass calc’d for


Compound 4jk 1H NMR (300 MHz, DMSO-d6, ppm): δ 8.36 (t, J=5.7 Hz, 1H), 8.26 (t, J=5.7 Hz,

1H), 7.41 (d, J=6.6 Hz, 1H), 7.17-7.11 (m, 3H), 6.69 (d, J=9.0 Hz, 2H), 6.61 (d,

J=9.0 Hz, 2H), 5.66 (d, J=6.3 Hz, 1H), 4.93 (d, J=6.3 Hz, 1H), 4.07 (q, J=7.2 Hz,

2H), 3.85-3.77 (m, 4H), 3.61 (s, 3H), 2.32 (s, 3H), 1.16 (t, J=7.2 Hz, 3H); 13C

NMR (75 MHz, DMSO-d6, ppm): δ 172.4, 170.4, 169.9, 152.1, 142.6, 138.2,

137.5, 130.9, 128.1, 127.9, 126.5, 115.1, 114.7, 61.2, 60.2, 55.9, 42.4, 41.28, 19.8,

14.7; HRMS exact mass calc’d for C22H28N3O5 ([M+H]) m/z: 414.2024; found

m/z: 414.2024.

Compound 4jl (mixture of inseparable two diastereomers) 1H NMR (300 MHz, CDCl3, ppm): δ 7.61 -7.58 (m, 2H), 7.49 (t, J=8.4 Hz, 4H),

7.40-7.32 (m, 6H), 6.79-6.75 (m, 4H), 6.61-6.57 (m, 4H), 6.47 (d, J=8.4 Hz, 2H),

4.74 (s, 2H), 4.56-4.48 (m, 2H), 4.15 (q, J=6.9 Hz, 4H), 4.12-3.75 (m, 6H), 3.72

(s, 6H), 1.58-1.30 (m, 6H), 1.28-1.22 (m, 6H), 0.93-0.83 (m, 12H); 13C NMR (75

MHz, CDCl3, ppm): δ 172.6, 172.3, 172.3, 168.4, 168.4, 153.2, 153.1, 140.5,

140.4, 138.5, 138.4, 129.3, 129.2, 128.6, 128.6, 127.3, 114.9, 114.9, 64.7, 64.7,

61.4, 55.6, 50.8, 50.7, 43.1, 43.0, 41.2, 41.2, 24.7, 24.6, 22.7, 21.8, 21.8, 14.1;

74

HRMS exact mass calc’d for C25H34N3O5 ([M+H]) m/z: 456.2493; found m/z:

456.2489; HPLC for the compounds with (D, L) and (L, L) configurations (Daicel

Chiralcel OD-H, hexane/isopropanol=2/1, flow rate=0.5 ml/min), tR=12.2 min,

tR=13.5 min

Compound 4jm (mixture of inseparable two diastereomers) 1H NMR (300 MHz, CDCl3, ppm): δ 7.64-7.57 (m, 2H), 7.48-7.27 (m, 10H), 6.75

(d, J=9.0 Hz, 4H), 6.69 (s, 2H, br), 6.58 (d, J=9.0 Hz, 4H), 4.75 (s, 2H), 4.51-4.45

(m, 2H), 4.37 (s, 2H, br), 4.18 (q, J=6.9 Hz, 4H), 4.12-3.81 (m, 4H), 3.72 (s, 6H),

1.31-1.22 (m, 12H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.6, 172.2, 168.1,

168.0, 153.1, 140.5, 138.5, 129.2, 129.2, 128.6, 127.3, 114.9, 114.8, 64.6, 61.5,

55.6, 48.1, 48.0, 42.9, 18.1, 14.1; HRMS exact mass calc’d for C22H28N3O5

([M+H]) m/z: 414.2024; found m/z: 414.2020; HPLC for the compounds with (D,

L) and (L, L) configurations (Daicel Chiralcel OD-H, hexane/isopropanol=2/1,

flow rate=0.5 ml/min), tR=15.3 min, tR=17.7 min

Compound 4jn 1H NMR (300 MHz, CDCl3, ppm): δ 7.66 (t, J=5.7 Hz, 1H), 7.40 (s, 1H), 6.77 (d,

J=9.0 Hz, 2H), 6.68 (t, J=4.8 Hz, 1H), 6.61 (d, J=9.0 Hz, 2H), 6.41 (d, J=3.3 Hz,

1H), 6.36-6.34 (m, 1H), 4.92 (s, 1H), 4.44 (s, 1H, br), 4.19 (q, J=6.9 Hz, 2H),

4.11-4.02 (m, 2H), 3.96 (d, J=5.4 Hz, 2H), 3.72 (s, 3H), 1.26 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 170.3, 169.5, 168.7, 153.3, 150.1, 142.9,

139.9, 115.1, 114.8, 110.8, 108.7, 61.6, 58.4, 55.6, 42.9, 41.2, 14.1; HRMS exact


75

Compound 4jo 1H NMR (300 MHz, CDCl3, ppm): δ 7.62 (t, J=5.4 Hz, 1H), 7.24 (d, J=4.5 Hz,

1H), 7.17 (d, J=3.0 Hz, 1H), 6.98-6.96 (m, 1H), 6.75 (d, J=8.7 Hz, 2H), 6.70 (t,

J=5.1 Hz, 1H), 6.61 (d, J=8.7 Hz, 2H), 5.07 (s, 1H), 4.49 (s, 1H, br), 4.16 (q,

J=7.2 Hz, 2H), 4.08-3.88 (m, 4H), 3.72 (s, 3H), 1.26 (t, J=6.9 Hz, 3H); 13C NMR

(75 MHz, CDCl3, ppm): δ 171.5, 169.5, 168.7, 153.3, 141.0, 140.0, 127.2, 126.2,


for C19H24N3O5S ([M+H]) m/z: 406.1431; found m/z: 406.1430.

Compound 4jp 1H NMR (500 MHz, CDCl3, ppm): δ 7.54 (t, J=5.5 Hz, 1H), 7.39 (d, J=7.5 Hz,

2H), 7.30 (t, J=7.5 Hz, 2H), 7.26 (d, J=6.0 Hz, 1H), 6.81-6.77 (m, 3H), 6.64 (d,

J=9.0 Hz, 2H), 6.61 (s, 1H, br), 6.31 (dd, J=16.0, 7.5 Hz, 1H), 4.46 (d, J=7.0 Hz,

1H), 4.19 (q, J=6.0 Hz, 2H), 4.07-3.97 (m, 2H), 3.94 (d, J=5.5 Hz, 2H), 3.73 (s,

3H), 1.25 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3, ppm): δ 172.5, 169.5,

168.9, 153.3, 140.2, 135.9, 134.2, 128.6, 128.2, 126.7, 125.4, 115.3, 115.0, 62.4,


m/z: 426.2024; found m/z: 426.2021.

Compound 4l

76

1H NMR (400 MHz, DMSO-d6, ppm): δ 8.43 (d, J=8.0 Hz, 1H), 8.25 (d, J=4.4

Hz, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.68 (d, J=7.6 Hz, 2H), 7.54 (t, J=6.0 Hz, 1H),

7.40-7.23 (m, 9H), 5.38 (d, J=8.0 Hz, 1H), 4.27-4.20 (m, 3H), 3.70 (d, J=6.4 Hz,

2H), 2.55 (d, J=4.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6, ppm): δ 170.8,

169.3, 157.2, 144.5, 141.4, 139.5, 129.0, 128.4, 128.2, 127.8, 127.7, 125.9, 120.8,


m/z: 444.1918; found m/z: 444.1916.

N-PMP glyoxyl benzyl amide 1H NMR (300 MHz, CDCl3, ppm): δ 7.91 (s, 1H), 7.58 (s, 1H, br), 7.35-7.26 (m,

3H), 6.92 (d, J=8.1 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 3.83 (s, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 163.6, 160.2, 150.3, 140.4, 137.8, 128.7, 127.8, 127.6,

123.4, 114.6, 55.5, 43.2; HRMS exact mass calc’d for [C16H16O2N2]: 268.1212;

found m/z: 268.1215.

N-PMP glyoxyl methyl amide 1H NMR (300 MHz, CDCl3, ppm): δ 7.34 (s, 1H), 7.29 (s, 1H, br), 7.22 (d, J=8.7

H 2H), 6.88 (d, J=8.7Hz, 2H), 3.79 (s, 3H), 2.93 (d, J=5.1 Hz, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 164.3, 160.0, 150.4, 140.4, 123.2, 114.4, 55.4, 25.7:

HRMS exact mass calc’d for [C10H12O2N2]: 192.0899; found m/z: 192.0891.

N-PMP glyoxyl phenyl amide

1H NMR (400 MHz, CDCl3, ppm): δ 9.13 (s, 1H), 7.91 (s, 1H), 7.70 (d, J=8.0

Hz, 2H), 7.38-7.32 (m, 4H), 7.13 (t, J=7.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 3.82

77

(s, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 161.3, 160.3, 150.3, 139.7, 137.1,

129.0, 124.3, 123.6, 119.5, 114.5, 55.4; HRMS exact mass calc’d for

[C15H14O2N2]: 254.1042; found m/z: 254.1047.

Compound 4fl 1H NMR (300 MHz, CDCl3, ppm): δ 7.35 (d, J=8.4 Hz, 2H), 7.28-7.13 (m, 6H),

6.90 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 4.68 (s,

1H), 4.53 (dd, J=15.0 Hz, 5.7 Hz, 1H), 4.38 (dd, J=15.0 Hz, 5.7 Hz, 1H), 4.23 (s,

1H, br), 3.80 (s, 3H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 171.7,

159.6, 153.1, 140.6, 138.0, 130.9, 128.5, 128.5, 127.5, 127.3, 115.0, 114.7, 114.4,

64.3, 55.6, 55.3, 43.2; HRMS exact mass calc’d for C23H25N2O5 ([M+H]) m/z:

377.1862; found m/z: 377.1860.

Compound 4fm 1H NMR (300 MHz, CDCl3, ppm): δ 7.36-7.32 (m, 4H), 7.28-7.25 (m, 3H), 7.15-

7.12 (m, 3H), 6.77 (m, J=9.0 Hz, 2H), 6.58 (m, J=9.0 Hz, 2H), 4.70 (s, 1H), 4.53

(dd, J=15.0 Hz, 5.4 Hz, 1H), 4.37 (dd, J=15.0 Hz, 5.4 Hz, 1H), 4.21 (s, 1H, br),

3.75 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 170.9, 153.3, 140.2, 137.8,

137.3, 134.4, 129.8, 128.7, 128.6, 127.6, 127.5, 115.2, 114.8, 64.4, 55.7, 43.4;

HRMS exact mass calc’d for C22H22N2O2Cl ([M+H]) m/z: 381.1362; found m/z:

381.1364.

78

Compound 4fn 1H NMR (300 MHz, CDCl3, ppm): δ 7.42-7.34 (t, J=5.7 Hz, 1H, br), 7.33-7.17

(m, 9H), 6.79 (d, J=9.0 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 4.96 (d, J=2.4 Hz, 1H),

4.61 (dd, J=15.0 Hz, 6.3 Hz, 1H), 4.46 (dd, J=15.0 Hz, 6.3 Hz, 1H), 3.96 (s, 1H,

br), 3.76 (s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 171.9, 153.2,

141.0, 138.1, 137.4, 137.0, 131.1, 128.6, 128.4, 127.6, 127.4, 126.6, 126.4, 114.8,


m/z: 361.1912; found m/z: 361.1911.

Compound 4fo 1H NMR (300 MHz, CDCl3, ppm): δ 7.90-7.79 (m, 4H), 7.56-7.49 (m, 3H), 7.27-

7.14 (m, 6H), 6.77 (d, J=8.7 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 4.91 (s, 1H), 4.58

(dd, J=14.7 Hz, 6.3 Hz, 1H), 4.38 (dd, J=14.7 Hz, 6.3 Hz, 1H), 4.39 (s, 1H, br),


136.3, 133.3, 133.2, 129.2, 128.6, 128.0, 127.7, 127.6, 127.4, 126.6, 126.5, 126.4,

124.8, 115.1, 114.8, 65.0, 55.7, 43.4; HRMS exact mass calc’d for C26H25N2O2

([M+H]) m/z 397.1912; found: m/z 397.1911.

Compound 4fp13

79

1H NMR (300 MHz, CDCl3, ppm): δ 8.91 (s, 1H, br), 7.55-7.28 (m, 9H), 7.12 (t,

J=7.5 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 6.68 (d, J=7.5 Hz, 2H), 4.75 (s, 1H), 4.21

(s, 1H, br), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 169.7, 153.6, 140.4,

138.5, 137.3, 129.3, 129.0, 128.8, 127.4, 124.5, 119.8, 115.4, 115.0, 66.3, 55.6;

HRMS exact mass calc’d for C21H21N2O2 ([M+H]) m/z 333.1525; found: m/z

333.1526.

References for Chapter 4 1. Nagarajan, R. Antimicrob. Agents Chemother. 1991, 35, 605.

2. Perkins, H. R. Pharmacol. Ther. 1982, 16, 181.

3. Williams, D. H. Acc. Chem. Res. 1984, 17, 364.

4. Elander, R. P. Appl. Microbiol. Biotechnol. 2003, 61, 385.

5. Connon, S. J. Angew. Chem. Int. Ed. 2008, 47, 1176.

6. Groger, H. Chem. Rev 2003, 103, 2795.

7. Yet, L. Angew. Chem. Int. Ed. 2001, 40, 875.

8. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.


10. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.

11. Chen, W.; Liu, Y.; Chen, Z. Eur. J. Org. Chem. 2005, 1665.

12. Pan, S. C.; List, B. Angew. Chem. Int. Ed. 2008, 47, 3622.

13. Zhao, L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4106.

Part II – Approach to α-Indoly Glycine Derivatives via Enantioselective Friedel-Crafts Reaction with

Imino Amide

Chapter 5: Approach to α-Indoly Glycine Derivatives via Enantioselective Friedel-

Crafts Reaction with Imino Amide

Chapter 5: Approach to α-Indoly Glycine Derivatives via Enantioselective Friedel-

Crafts Reaction with Imino Amide

80

Chapter 5 – Approach to α-Indoly Glycine Derivatives via Enantioselective

Friedel-Crafts Reaction with Imino Amide

In the previous chapters, site-specific malonation, alkynylation and

arylation of free (NH)-peptides and glycine derivatives via direct C-H bond

functionalization were described. This functionalization was proposed to undergo

via an iminol intermediate. In this chapter, the development of enantioselective α-

indolation of imino amides via a Friedel-Crafts reaction will be presented.

5.1 – Background Indole structures exist widely in natural products and interesting

pharmaceutical compounds.1-3 Substituted indoles are referred to as “privileged

structures” since they are capable of binding to many receptors with high

affinity.4,5 Complementary to the powerful traditional methods to construct the

indole core,6-11 the enantioselective Friedel-Crafts alkylation of indoles to an

electron deficient unsaturated bond12,13 has attracted more and more attention in

recent years. Much work has been done on the Michael addition with indoles

catalyzed either by a chiral metal complex14-16 or organocatalyst.17-20 Later,

asymmetric indolation of 3,3,3-trifluoropyruvate was also developed.21,22

Meanwhile, the Pictet-Spengler reaction was achieved in an enantioselective

manner.23-25 To this end, activated imines can also be used as electrophiles for

asymmetric indolation.26-31

5.2 – Discovery of the Enantioselective Indolation to Imino Amide

In the course of our approach to functionalize amino acid derivatives, we

achieved the arylation, alkynylation, alkylation and indolation on the α-position

of glycine and short peptide derivatives using an oxidative coupling method.32,33

However, the enantioselective version of these transformations has not been

realized. Recently, Leighton’s group achieved asymmetric Pictet-Spengler

reaction.25 In their report, they used a chiral chlorosilane to complex with an

imino amide to afford the cyclized product in good enantioselectivity (Scheme

81

5.1). Inspired by this novel work, we hypothesized that this process could be

analogous to our α-functionalization of glycine derivatives, since in our proposed

mechanism, the intermediate imino amide 5c could tautomerize to afford an

iminol 5f. That could give us an opportunity to enantioselectively introduce a

functional group to a glycine derivatives (Scheme 5.1, path b).

NH

N

R1

N

OSiPh

ON

HPh

MeMe Cl-

NH

OR

HN

PMP N

OHRN

PMPNH

ORN

PMP

5a 5b 5c

NH

OR

HN

PMPNu5d

Nu[O]

NSi

OPh

Me

Ph

Cl

Me

* NH

OR

HN

PMPNu5e

(a)

(b)

Proposed transition state by Leighton

5f

NH

N

R1 N

OH

NSi

OPh

Me

Ph

Cl

Me

+R2

NH

NH

R1

R2

NHR2

O

Proposed enantioselective indolation of imino amide

Nu

Scheme 5.1 Inspiration from Leighton’s Leighton’s Chiral Silicane Reagent

Subsequently, different nucleophiles were tested by incorporating this

chiral chlorosilane into our oxidative coupling reaction. Unfortunately, neither the

arylation nor the alkynylation afforded the corresponding product (Table 5.1,

entries 1 and 3). Only the indolation reaction gave the coupling product.

However, no enantioselectivity was observed (Table 5.1, entry 2). Decreasing the

reaction temperature did not help the enantioselectivity either (Table 5.1, entry 4)

and adding 4Å MS (molecular sieves) shut down the coupling reaction (Table 5.1,

entry 5). We reason that this might due to the fact that in the oxidation process

82

with TBHP (tert-butyl hydroperoxide), one equivalent of tert-butanol and H2O are

generated and this will react with the chlorosilane. Using 4Å MS proved to be

efficient in absorbing the generated H2O, but they might be inefficient in

absorbing the generated tert-butanol. Then we used the imino amide, which was

proposed to be the intermediate of the oxidative coupling, to test whether this

would give us a better result. Again, the arylation and alkynylation did not

proceed (Table 5.1, entries 1 and 3). For the arylation, the fact that no reaction

occurred supported our proposed mechanism. With the coordination between Si

and O atoms from the iminol, the B atom from phenyl boronic acid could not

complex with the iminol to deliver the phenyl group in an intramolecular fashion.

However, indolation afforded the coupling product at ambient temperature.

Unfortunately, once again, no enantioselectivity was observed (Table 5.1, entry

2).

Table 5.1 Screening Asymmetric Indolation Conditions Using Glycine Amide as

the Substrate.a

PMPHN

NH

BnO

+ PMPHN

NH

Bn

Nu

Nu

CuBr/ TBHP2 equiv. 5fDCE, 24 h

O

entry Nu temp. (oC) additive yield (%) ee

1 phenylacetylene RT NA 0 NA 2 indole RT NA 71 0 3 phenyl boronic acid 100 NA 0 NA 4 indole -25 NA 57 0 5 indole -25 4Å MS 0 0

a Reaction were carried out using 0.10 mmol glycine amide, 0.15 mmol nucleophile, 10 mol% CuBr, 1 equiv of TBHP in 0.5 mL DCE. NA=Not Available.

Later, we found that decreasing the reaction temperature from room

temperature to -25oC gave us a surprising result (Table 5.2, entry 4). The

enantiomeric excess increased from 0 to 89%.

83

Table 5.2 Screening Asymmetric Indolation Conditions Using Imino Amide as

the Substrate.a

PMPN

NH

BnO

+ PMPHN

NH

Bn

NuNu

DCE

O2 equiv. 5f

entry Nu temp. (oC) yield (%) ee (%)

1b phenylacetylene rt 0 NA 2 indole rt 91 0 3 phenyl boronic acid 100 0 NA 4 indole -25 87 89

a Reaction conditions: imino amide (0.10 mmol), nucleophile (0.15 mmol) in 0.5 mL DCE. b 10 mol% of CuBr was used. NA=Not Available.

5.3 – Scope of the Copper-Mediated Oxidative Coupling of N-Acetyl Glycine

Esters and Malonates

With this exciting result in hand, we did a quick survey of the scope of this

indolation reaction. Indole reacts with both the N-methyl and N-benzyl imine with

good yield and enantioselectivity (Table 5.3, 5ha, 5he). Furthermore, the

enantioselectivity could be sustained at a very high level for additions of a wide

variety of indoles substituted with electron-donating or -withdrawing groups at

different positions (Table 5.3, 5hb, 5hc, 5hd, 5hf, 5hg, 5hh, 5hi).

5.4 – Conclusion

In summary, we have developed a new approach for the asymmetric

synthesis of α-indolyl amino amides. Various indoles could be applied in this

process. Incorporating this asymmetric indolation to short peptide derivatives is in

progress.

84

Table 5.3 Scope of Asymmetric Indolation of Imino Amide.a

PMPN

NH

R1O

+PMP

HN

NH

R1

DCE, -25oC

N

R2

N

R3

R3

R2

PMPHN

NH

BnO

HN

PMPHN

NH

MeO

HN

PMPHN

NH

BnO

N

PMPHN

NH

MeO

N

PMPHN

NH

MeO

HN

Me

Me

Me

NSi

OPh

MeMe

Cl

Ph

2 equiv

PMPHN

NH

MeO

HN

PMPHN

NH

MeO

HN

OMe

PMPHN

NH

BnO

HN

PMPHN

NH

BnO

HN

OMe

24 - 48 h

Cl

Cl

5b 5g 5h

5ha 5hb 5hc

5hd 5he 5hf

5hg 5hh5hi

87% yield89% ee

99% yield90% ee

57% yield94% ee

81% yield97% ee

86% yield93% ee

99% yield91% ee

95% yield87% ee

73% yield90% ee

69% yield97% ee

O

a Reaction conditions: imino amide (0.10 mmol), nucleophile (0.15 mmol) in 0.5 mL DCE.






85

respectively. MS data were obtained by using KRATOS MS25RFA Mass

Spectrometer. HRMS-ESI measurements were performed at McGill University.

A Procedure for the preparation of phenyl pseudoephedrine silicon chloride

5f30

NSi

OPh

MeMe

Cl

Ph

NH

OHPh

MeMe

+ PhSiCl3Et3N

DCM, 0oC

5f Triethylamine (2.7 mL, 19 mmol) was added to a cooled (0oC) solution of

phenyltrichlorosilane (15 mL, 9.5 mmol) in CH2Cl2 (20 mL) under argon.

(1R,2R)-(-)-Pseudoephedrine (1.5 g, 9.1 mmol) was then added portionwise over

15 min maintaining an internal temperature below 15oC. The mixture was then

allowed to warm up to room temperature and stirred for 12 h. CH2Cl2 was then

removed in vacuo. Pentane (150 mL) was added to the residue and the mixture

was vigorously stirred for 4 hours to ensure complete precipitation of all

triethylamine salts. Filtration of the suspension through a pad of celite and

concentration of the filtrate by distillation afforded the crude product as a pale-

orange oil. Purification by distillation under reduced pressure gave (1R,2R)-(-)-

phenyl pseudoephedrine silicon chloride 9f as a colorless oil (2 g, 75 %)

Typical procedure for the asymmetric indolation reaction

PMPN

NH

R1O

+PMP

HN

NH

R1

DCE, -25oC

N

R2

N

R3

R3

R2

NSi

OPh

MeMe

Cl

Ph

2 equiv

24 - 48 h

O

The N-PMP imine amide (0.10 mmol) and phenyl pseudoephedrine silicon

chloride (60 mg, 0.20 mmol) were added to 1 mL DCE in the test tube. The test

tube was sealed and the mixture was stirred at room temperature for 10 min. The

resulting mixture was cooled to -30oC, indole derivative (0.15 mmol) in DCE

(200 µl) was added to the mixture slowly via a syringe. After the injection, the

86

mixture was cooled to -25oC in a freezer. When the reaction was complete, the

mixture was separated right away by column chromatography.

Compound 5ha

The ee was determined by HPLC on a Daicel Chiralcel AD column (Hexanes/iso-

Propanol =2/1, 0.8 mL/min) with tr (major) 14.9 min, tr (minor) 17.2 min. 1H NMR (300 MHz, CDCl3, ppm):δ 8.90 (s, 1H, br), 7.69 (t, J=6.0 Hz, 1H), 7.59

(d, J=7.8 Hz, 1H), 7.27-7.05 (m, 9H), 6.83 (d, J=9.0 Hz, 2H), 6.63 (d, J=9.0 Hz,

2H), 5.02 (s, 1H), 4.59 (dd, J=15.0 Hz, 6.0 Hz, 1H), 4.45 (dd, J=15.0 Hz, 6.0 Hz,

1H), 4.20 (s, 1H, br), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 172.5,

153.1, 141.0, 137.9, 136.4, 128.5, 127.6, 127.3, 125.3, 123.5, 122.3, 119.8, 118.8,


C24H24N3O2 ([M+H]) m/z 386.1863; found: m/z 386.1859.

Compound 5hb


Propanol =2/1, 0.8 mL/min) with tr (major) 21.8 min, tr (minor) 27.4 min. 1H NMR (300 MHz, CDCl3, ppm):δ 7.62 (d, J=7.8 Hz, 1H), 7.57 (t, J=6.6 Hz,

1H, br), 7.37-7.18 (m, 7H), 7.14-7.06 (m, 2H), 6.81 (d, J=9.0 Hz, 2H), 6.65 (d,

J=9.0 Hz, 2H), 5.06 (s, 1H), 4.25 (dd, J=15.0 Hz, 6.6 Hz, 1H), 4.35 (dd, J=15.0

Hz, 6.6 Hz, 1H), 4.25 (s, 1H, br), 3.77 (s, 3H), 3.73 (s, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 172.0, 153.1, 141.1, 138.1, 137.2, 128.5, 127.7, 127.5, 127.3,

126.0, 122.1, 119.6, 119.1, 114.9, 114.8, 112.0, 109.6, 58.3, 55.6, 43.3, 32.7;


400.2022.

87

Compound 5hc


Propanol =2/1, 0.8 mL/min) with tr(major) 17.6 min, tr (minor) 19.8 min. 1H NMR (500 MHz, CDCl3, ppm):δ 8.96 (s, 1H), 7.72 (t, J=5.5 Hz, 1H), 7.42 (d,

J=8.0 Hz, 1H), 7.30-7.15 (m, 6H), 7.00 (d, J=8.5 Hz, 1H), 6.87-6.81 (m, 3H),

6.30 (d, J=9.0 Hz, 2H), 4.96 (s, 1H), 4.64 (dd, J=15.0 Hz, 5.5 Hz, 1H), 4.45 (dd,

J=15.0 Hz, 5.5 Hz, 1H), 4.12 (s, 1H, br), 3.78 (s, 3H); 13C NMR (125 MHz,

CDCl3, ppm): δ 172.3, 153.4, 140.8, 137.8, 136.8, 128.7, 128.3, 127.7, 127.6,

124.3, 123.8, 120.5, 119.6, 115.1, 114.9, 112.9, 111.6, 58.5, 55.7, 43.5; HRMS

exact mass calc’d for C24H22ClN3O2 ([M+H]) m/z 419.1401; found: m/z

419.1403.

Compound 5hd


Propanol =2/1, 0.8 mL/min) with tr (minor) 21.7 min, tr (major) 28.7 min. 1H NMR (400 MHz, CDCl3, ppm):δ 8.47 (s, 1H), 7.61 (s, 1H, br), 7.26-7.24 (m,

3H), 7.15-7.09 (m, 3H), 7.00 (d, J=8.0 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J=8.4 Hz,

2H), 6.57 (d, J=8.4 Hz, 2H), 6.49 (d, J=8.0 Hz, 1H), 5.41 (s, 1H), 4.87 (s, 1H, br),

4.57 (dd, J=14.4 Hz, 6.4 Hz, 1H), 4.32 (dd, J=14.4 Hz, 6.4 Hz, 1H), 3.71 (s, 3H),


138.3, 138.1, 128.6, 127.6, 127.3, 122.9, 122.3, 115.7, 114.9, 114.7, 113.8, 105.5,


m/z 416.1969; found: m/z 416.1974.

88

Compound 5he


Propanol =2/1, 0.8 mL/min) with tr (major) 9.3 min, tr (minor) 12.0 min. 1H NMR (400 MHz, CDCl3, ppm):δ 8.84 (s, 1H, br), 7.70 (d, J=8.0 Hz, 1H),

7.34 (d, J=8.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.11 (t, J=8.0

Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.80 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H),

4.96 (s, 1H), 4.25 (s, 1H, br), 3.76 (s, 3H), 2.88 (d, J=5.2 Hz, 3H); 13C NMR (100

MHz, CDCl3, ppm): δ 173.0, 153.2, 141.3, 136.6, 125.6, 123.5, 122.4, 120.0,

118.7, 114.9, 114.9, 113.1, 111.8, 58.4, 55.7, 26.3; HRMS exact mass calc’d for

C18H20N3O2 ([M+H]) m/z 310.1550; found: m/z 310.1545.

Compound 5hf


Propanol =2/1, 0.8 mL/min) with tr (major) 10.3 min, tr (minor) 16.2 min. 1H NMR (300 MHz, CDCl3, ppm):δ 7.61 (d, J=7.8 Hz, 1H), 7.31 (t, J=8.1 Hz,

1H), 7.25-7.09 (m, 4H), 6.81 (d, J=8.7 Hz, 2H), 6.22 (d, J=8.7 Hz, 2H), 4.99 (s,

1H), 4.29 (s, 1H, br), 3.76 (s, 3H), 3.75 (s, 3H), 2.88 (d, J=4.8 Hz, 3H); 13C NMR

(75 MHz, CDCl3, ppm): δ 172.7, 153.1, 141.3, 137.1, 127.5, 126.1, 122.1, 119.7,


for C19H22N3O2 ([M+H]) m/z 324.1707; found: m/z 324.1703.

89

Compound 5hg

The ee was determined by HPLC on a Daicel Chiralcel OD-H column

(Hexanes/iso-Propanol =2/1, 0.8 mL/min) with tr (major) 12.4 min, tr (minor) 19.6

min. 1H NMR (400 MHz, CDCl3, ppm):δ 8.80 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=8.4

Hz, 2H), 7.02 (d, J=8.8 Hz, 1H), 6.86-6.80 (m, 3H), 6.61 (d, J=9.2 Hz, 2H), 4.94

(s, 1H), 4.26 (s, 1H, br), 3.77 (s, 3H), 2.88 (d, J=4.8 Hz, 3H), 2.43 (s, 3H); 13C

NMR (100 MHz, CDCl3, ppm): δ 173.1, 153.0, 141.3, 134.8, 129.2, 125.8, 124.0,

123.6, 118.2, 114.8, 114.8, 112.4, 111.4, 58.2, 55.7, 26.2, 21.5; HRMS exact mass

calc’d for C19H22N3O2 ([M+H]) m/z 324.1707; found: m/z 324.1707.

Compound 5hh


Propanol =2/1, 0.8 mL/min) with tr (major) 11.9 min, tr (minor) 13.8 min. 1H NMR (400 MHz, CDCl3, ppm):δ 9.04 (s, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.32

(s, 1H, br), 7.22 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=8.8 Hz,

2H), 6.61 (d, J=8.8 Hz, 2H), 4.91 (s, 1H), 3.76 (s, 3H), 2.90 (d, J=5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 173.0, 153.3, 140.9, 136.8, 128.3, 124.2,

124.0, 120.6, 119.5, 114.9, 113.0, 111.7, 58.2, 55.7, 26.3; HRMS exact mass

calc’d for C18H29N3O2Cl ([M+H]) m/z 344.1160; found: m/z 344.1160.

90

Compound 5hi

The ee was determined by HPLC on a Daicel Chiralcel OD-H column

(Hexanes/iso-Propanol =2/1, 0.8 mL/min) with tr (major) 11.0 min, tr (minor) 17.9

min. 1H NMR (400 MHz, CDCl3, ppm):δ 8.58 (s, 1H), 7.22 (s, 1H, br), 7.11 (t, J=8.0

Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 6.73 (d, J=8.8 Hz, 2H), 6.58-6.54

(m, 3H), 5.34 (s, 1H), 4.72 (s, 1H, br), 3.87 (s, 3H), 3.72 (s, 3H), 2.83 (d, J=4.8


122.9, 122.3, 115.9, 115.0, 114.7, 113.8, 105.4, 99.9, 57.2, 55.7, 55.3, 26.4;


340.1656.

References for Chapter 5 1. Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.

2. Bosch, J.; Bennasar, M. L. Synlett 1995, 587.

3. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1.

4. Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.

5. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.

6. Gilchrist, T. L. J. Chem. Soc. Perkin Trans. 1 2001, 2491.

7. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.

8. Robinson, B. Chem. Rev. 1963, 63, 373.

9. Robinson, B. Chem. Rev. 1969, 69, 227.

10. Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1.

11. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 7, 1045.

91

12. Jorgensen, K. A. Synthesis 2003, 1117.

13. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550.

14. Evans, D. A.; Fandrick, K. R.; Song, H. J. J. Am. Chem. Soc. 2005, 127, 8942.

15. Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780.

16. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154.

17. Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.

18. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172.

19. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem. Int. Ed. 2005, 44, 6576.

20. Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.

21. Torok, B.; Abid, M.; London, G.; Esquibel, J.; Torok, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086.

22. Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2001, 66, 1009.

23. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.

24. Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.

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92

29. Kang, Q.; Zhao, Z. A.; You, S. L. J. Am. Chem. Soc. 2007, 129, 1484.

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Part III – “Three-Component” Synthesis of β-Lactams via Kinugasa Reaction

Chapter 6: Introduction to β-Lactam Formation via Kinugasa Reaction

Chapter 7: Highly Efficient “Three-Component” Synthesis of β-Lactams From N-

Alkyl Hydroxylamine, Aldehydes, and Phenylacetylene

Chapter 6: Introduction to β-Lactam Formation via Kinugasa Reaction

93

Chapter 6 – Introduction to β-Lactam Formation via Kinugasa Reaction

β-Lactams are among the best known and most extensively investigated

heterocyclic ring systems as a result of both their biological activities such as

antibiotic properties and their wide use as synthetic intermediates. General

methods for the construction of the β-lactam ring include:1-4 1) Formation of the

N1-C2 bond, such as the cyclization between ketene and imine5 and the

cyclization of β-amino acid;6 2) Formation of the C2-C3 bond, such as a

trialkylstannane-mediated closure of the C2-C3 bond;7 3) Formation of the C3-C4

bond, such as intramolecular nucleophilic displacement8-11 and oxidative coupling

of dianions of acyclic amides;12 and 4) Formation of C4-N1 bond, such as the

SN2-type displacements of primary halogens by an amide nitrogen under basic

conditions.13-17 Among the different approaches for the synthesis ofβ-lactams,

the Kinugasa reaction18 is an efficient method to construct the four-membered β-

lactam ring via a [3+2] cycloaddition/rearrangement from nitrones and copper

phenylacetylide complexes.

The Development of Kinugasa Reaction The formation of β-lactam from an in situ generated Cu(I)-acetylide 6b

and a nitrone 6a is known as the Kinugasa reaction. In 1972, Kinugasa reported

this reaction using preformed copper acetylide and nitrone in anhydrous pyridine

(Scheme 6.1). The corresponding cis-products are isolated in 51-60% yields.19

pyridineNO R2

R1+ Cu

N

R1Ph

R2

H H

ON

R1Ph

R2

H H

O

+

main product6a 6b

Scheme 6.1 The First Report of Kinugasa Reaction

In 1976, Irwin and Ding first proposed the mechanism of Kinugasa

reaction. Their proposal (Scheme 6.2) involves a formal [3+2] cycloaddition

94

between a nitrone 6a and a copper acetylide (generated in situ) to form an

isoxazoline intermediate 6c. Protonation via the formation of oxaziridine 6d and

subsequent rearrangement of the oxaziridine ring provides the β-lactam 6e.

Furthermore, the cis isomer (initially formed) can be equilibrated to the trans

isomer 6h at C3 position under basic conditions.19

Ph CuLL

L

R1

HC NR2

O NO

R2HR1Ph Cu

L

LL

OH

H

NO

R2HR1Ph Cu

L

LLH

OH

-Cu(OH)L3

NR2

OPhH

R1

HNR2

OPhR1

HNR2

O

R1

HNR2

OPh

R1H

HOH- H+

6a 6c 6d

6e 6f 6g 6h

Ph

Scheme 6.2 Proposed Mechanism of Kinugasa Reaction by Irwin and Ding

However, this proposed mechanism involves a highly strained, fused

bicyclic intermediate 6d, which is usually not stable. Thus, an alternative

mechanism involving a ketene intermediate 6j was proposed by Fu (Scheme

6.3).20

95

NO

R2

HR1Ph Cu

L

LL

OH

-Cu(OH)L3

NH

C

R2

HR1Ph

O

NR2

OPhR1

H

H-OH

NR2

OPh H

R1

HNR2

OH Ph

R1

H

6i 6j

6k 6e 6h

Scheme 6.3 Alternative Mechanism Involving a Ketene Intermediate

Miura and co-workers have also studied the reaction between alkyne and

nitrone. They reported that under the catalysis of CuI/DPPE, instead of the

formation of propargyl N-hydroxylamines by nucleophilic addition of alkyne to

nitrone, they obtained the dehydrated alkynyl imine in good yield (Scheme 6.4).

Meanwhile, they could also obtain trace amounts of β-lactam, which was formed

by Kinugasa rearrangement after the [3+2] dipolar cyclization. When nitrogen

based ligands such pyridine or 1,10-phenathroline were applied to the reaction,

both diastereomers of the β-lactam were obtained as the major products (Scheme

6.4).21,22

NO Ph

Ph+ Ph H

10 mol% CuI/Ligand

1.1 equiv K2CO3/DMF

NPh

PhPh

+

NOPh

Ph Ph

+

NPh

Ph

PhCH2COOH

+ NOPh

Ph Ph

Scheme 6.4 Reaction between Nitrone and Alkyne Catalyzed by CuI/ligand Reported by Miura

96

In 2002, Basak and co-workers reported a substrate-induced

diastereoselective Kinugasa reaction using oxazolidinyl propynes as the chiral

substrate and CuI as the catalyst. The corresponding trans- and cis-β-lactams

were formed with up to 95% enantiomer excess (Scheme 6.5).22

NO Ph

R1

+ +O N

O

R

R=CH2Ph Ph

CuI/Et3N

DMF N NO Ph O Ph

R1 R1NO

O

R

NO

O

R

Scheme 6.5 Substrate Induced Diastereo-Selective Synthesis of β-Lactam

In 2004, Basak and co-workers also reported an L-proline mediated

Kinugasa reaction for the one-pot synthesis of 3-exomethylene β-lactam (Scheme

6.6).23 They proposed that the amphoteric functionalities in the L-proline catalyst

are important for the propargyl alcohol to form the eliminated 3-exomethylene

products.

HO

NO Ph

R

CuI/L-proline

DMSO+

NO Ph

R

NO Ph

RH2O+

NO Ph

RHO+

Scheme 6.6 L-Proline-Mediated Synthesis of 3-Exomethylene β-Lactam

In 2002, Fu and co-worker reported a highly diastereo- and

enantioselective catalytic Kinugasa reaction using their C2-symmetric, planar-

chiral bis(azaferrocene) ligand in combination with sterically hindered N,N-

dimethylcyclohexylamine as the base (Scheme 6.6). Excellent

diastereoselectivities (up to 90%) and good enantioselectivities (69%-91%) were

acheieved.24

97

Ph+ N

O R

Ar

1-2.5 mol% CuCl(R,R)-ligand

Cy2NMe, ACN, 0oC N

Ph Ar

O RN

FeN

Fe

MeMe

Me MeMe

MeMe

MeMe

MeMe

Me

ligand

Scheme 6.7 Enantioselective Intermoledular Kinugasa Reaction Reported by Fu

Shortly after Fu’s first report on the intermolecular asymmetric Kinugasa

reaction in 2003, they reported an intramolecular asymmetric Kinugasa reaction

using the planar-chiral phosphaferrocenyl-substituted oxazolines (Scheme 6.8).

The use of this novel ligand greatly increased the enantioselectivity compared

with the previously mentioned planar-chiral bis(azaferrocene) ligand.25

NO

Ar

CuBr (5 mol%)Ligand (5.5 mol%)

Cy2NMe (0.5 equiv)ACN, 0oC

N

O

Ar

PFe

Me

MeMe

MeMe

Me

O

NR

MeMe

R = iPr tBu

Scheme 6.8 Enantioselective Intramolecular Kinugasa Reaction Reported by Fu

In 2004, Tang and co-workers demonstrated that an air-stable and water-

tolerant tri(oxazoline)/Cu(ClO4)26H2O complex is efficient in catalyzing the

Kinugasa reaction with good enantioselectivities (Scheme 6.9). 26

R3NO R2

R1 N

R1R3

R2O

Cu(ClO4)2 6H2OLigand

Cy2NH (1 equiv)ACN, 0oC

+ O

NN

O

O

N

Scheme 6.9 Enantioselective Kinugasa Reaction Reported by Tang

98

References for Chapter 6 1. Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226.

2. Alcaide, B.; Almendros, P. 2002, 381.

3. Georg, G. I. The Organic chemistry of β-lactams; VCH Publishers: New York, N.Y., 1993.

4. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett 2001, 1813.

5. Staudinger, H.; Klever, H. W.; Kober, P. Liebigs Ann. Chem. 1910, 371, 1.

6. Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067.

7. McGarvey, G. J.; Kimura, M. J. Org. Chem. 1985, 50, 4655.

8. Sheehan, J. C.; Bose, A. K. J. Am. Chem. Soc. 1950, 72.

9. Sheehan, J. C.; Bose, A. K. J. Am. Chem. Soc. 1951, 73, 1761.

10. Fetter, J.; Lempert, K.; Kajtar-Peredy, M.; Simig, G.; Hornyak, G.; Horvath, J. J. Chem. Res. (S) 1985, 368.

11. Simig, G.; Doleschall, G.; Hornyak, G.; Fetter, J.; Lempert, K.; Nyitral, J.; Huszthy, P.; Gizur, T.; Kajtar-Peredy, M. Tetrahedron 1985, 41, 479.

12. Kawabata, T.; Sumi, K.; Hiyama, T. J. Am. Chem. Soc. 1989, 111, 6843.

13. Abdulla, R. F.; Williams Jr, J. C. Tetrahedron Lett. 1980, 21, 997.

14. Takahata, H.; Ohnishi, Y.; Yamazaki, T. Heterocycles 1980, 14, 467.

15. Floyd, D. M.; Fritz, A. W.; Plusec, J.; Weaver, E. R.; Cimarusti, C. M. J. Org. Chem. 1982, 47, 5160.

16. Commercon, A.; Ponsinet, G. Tetrahedron Lett. 1983, 24, 3725.

17. Sebti, S.; Foucaud, A. Tetrahedron 1984, 40, 3223.

18. Marco-Contelles, J. Angew. Chem. Int. Ed. 2004, 43, 2198.

19. Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972, 466.

99

20. Fu, G. C. Acc. Chem. Res. 2006, 39, 853.

21. Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60, 4999.

22. Basak, A.; Ghosh, S. C.; Bhowmick, T.; Das, A. K.; Bertolasi, V. Tetrahedron Lett. 2002, 43, 5499.

23. Basak, A.; Ghosh, S. C. Synlett 2004, 1637.

24. Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572.

25. Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 4082.

26. Ye, M. C.; Zhou, J.; Huang, Z. Z.; Tang, Y. Chem. Commun. 2003, 2554.

Chapter 7: Highly Efficient “Three-Component” Synthesis of β-Lactams From N-


100

Chapter 7 – Highly Efficient “Three-Component” Synthesis of β-Lactams From N-


As illustrated in chapter 7, there has been increased attention to the development

of the Kinugasa reaction in recent years. In this chapter, the development of a copper-

catalyzed three-component coupling between aldehydes, N-alkyl hydroxylamines and

aryl alkynes will be discussed.

7.1 – Background of the “Three-Component” Synthesis of β-Lactam

Recently, we have developed various Aldehyde-Alkyne-Amine Couplings (A3-

Coupling)1-12 (Scheme 7.1, route a) and Asymmetric Aldehyde-Alkyne-Amine Couplings

(AA3-Coupling).13 With our continued interest in extending the scope of Aldehyde-

Alkyne-Amine Couplings, we tried to extend this type of coupling reaction by replacing

normal amines with N-methyl hydroxylamine. Surprisingly, instead of the alkynylation

product, we obtained the corresponding β-lactam product (Scheme 7.1, route b). As

shown in the previous chapter, all the previous reported Kinugasa-type reactions are

restricted to the synthesis of N-aryl β-lactam. On the other hand, the synthesis of N-alkyl

substituted β-lactams, which are more prevalent in natural products and biological

compounds, are still unexplored. Furthermore, in all the previous methods, the nitrone

has to be pre-synthesized. It is interesting to note that replacing the simple amines with

N-alkyl hydroxylamines changed the product from the A3 coupling product to the β-

lactams formation completely.

Scheme 7.1

101

7.2 – Discovery of the “Three-Component” Synthesis of β-Lactam and Optimization of the Reaction Conditions

In our initial study, we found that CuCl was effective in catalyzing the β-lactam

formation using N-methyl hydroxylamine, benzaldehyde and phenylacetylene in 37%

yield in 18 h at 70oC. Various solvents were examined for the reaction and the optimal

yield was obtained under neat conditions. Adding 30 mol% of another base was found to

be beneficial for the reaction. Subsequent to these preliminary investigations, the effects

of catalyst, ligand, and base on the three-component reaction were examined (Table 7.1).

Among the various copper salts that we examined (Table 7.1, entries 1-5), CuCl provided

the best yield of the desired product with 2,2’-dipyridyl as the ligand and NaOAc as the

base. Using an additional amount of KHCO3, instead of NaOAc, as the base diminished

the product yield (Table 7.1, entry 6). On the other hand, the same result was obtained

with K3PO4 and NaOAc as bases (Table 7.1, entries 3 and 7). Surprisingly, almost no

desired product was observed when either NEt3 or DBU were used as the bases (Table

7.1, entries 8 and 10); whereas decreased yields were obtained with (iPr)2NEt and K2CO3

(Table 7.1, entries 9 and 11). The use of pyridine (Table 7.1, entry 12), 1,10-

phenanthroline (Table 7.1, entry 13), and phosphines (Table 7.1, entries 14 and 15) as

ligands also decreased the yield of the desired product. Thus, the combination of CuCl as

the catalyst, 2,2’-dipyridyl as the ligand, and NaOAc as the base was used as the standard

conditions for the three-component synthesis of the β-lactams.

Table 7.1 Optimization of the Reaction Conditions.a

MeNHOH.HClPhCHO[Cu], ligand

base, 1 equiv KHCO3, 70oC, neatPh

N

Ph

Ph

O

Me

entry catalyst ligand base yield (%)b cis:transc

1 CuI 2,2'-dipyridyl NaOAc 77 74/26 2 CuBr 2,2'-dipyridyl NaOAc 83 81/19 3 CuCl 2,2'-dipyridyl NaOAc 97 80/20 4 CuOTf 2,2'-dipyridyl NaOAc 81 79/21 5 Cu2O 2,2'-dipyridyl NaOAc 92 79/21 6 CuCl 2,2'-dipyridyl KHCO3 57 76/24 7 CuCl 2,2'-dipyridyl K3PO4 97 80/20

102

entry catalyst ligand base yield (%)b cis:transc

8 CuCl 2,2'-dipyridyl NEt3 trace NA 9 CuCl 2,2'-dipyridyl (iPr)2NEt 78 79/21 10 CuCl 2,2'-dipyridyl DBU trace NA 11 CuCl 2,2'-dipyridyl K2CO3 85 82/18 12 CuCl Pyridined NaOAc 31 72/28 13 CuCl 1,10-phenanthroline NaOAc 89 78/22 14 CuCl PPh3

d NaOAc 49 76/24 15 CuCl DPPPe NaOAc 24 83/17

a Reaction conditions: MeNHOH·HCl (0.2 mmol), benzaldehyde (0.3 mmol), phenyl acetylene (0.4 mmol), KHCO3 (0.2 mmol)3, catalyst (5 mol%) and ligand (5 mol%) were used unless otherwise noted, and all reactions were carried out under a N2 atmosphere for 18 h. b 1H NMR yields were based on MeNHOH·HCl and determined by NMR using mesitylene as the internal standard. c The ratio of two diastereomers was determined by 1H NMR of the crude reaction mixture. d Using 10 mol% of the ligand. e 1,2-bis(diphenylphosphino)propane.

7.3 – Scope of the “Three-Component” Synthesis of β-Lactam

Various aldehydes were coupled with N-methyl hydroxylamine and

phenylacetylene under the optimized conditions, and good to excellent yields were

obtained in all cases (Table 7.2). Benzaldehyde and electron-rich aromatic aldehydes

gave higher yields than electron-deficient aromatic aldehydes in most cases. Halogens

such as bromo, chloro and fluoro groups on the aromatic ring of the aldehyde survived

the reaction conditions (Table 7.2, entries 4-6). Heteroaromatic 2-furaldehyde (Table 7.2,

entry 3) and aliphatic aldehyde (Table 7.2, entry 11) also provided excellent yields of the

corresponding β-lactams. Aliphatic alkynes are also effective under the present reaction

conditions; however, in these cases the reaction generated a mixture of products, which

are still under investigation.

Table 7.2 Synthesis of β-lactam via the Coupling of N-Methyl Hydroxylamine,

Aldehyde and Phenyl Acetylene.a

103

entry R product yieldb (%) cis:transc 1 Ph 7aa 97 (86) 80/20 2 2,5-(MeO)2-C6H4 7ab 87 (55) 76/24 3 furan-2-yl 7ac 85 (79) 63/37 4d 4-F-C6H4 7ad 78 (70) 78/22 5e 4-Cl-C6H4 7ae 88 (83) 80/20 6 4-Br-C6H4 7af 72 (70) 80/20 7 2-Me-C6H4 7ag 88 (67) 84/16 8 4-Me-C6H4 7ah 99 (95) 89/11 9 4-MeO-C6H4 7ai 96 (69) 76/24 10 2-MeO-C6H4 7aj 93 (66) 75/25 11 CH3(CH2)4 7ak 75 (55) 63/37

a Reaction conditions: MeNHOH·HCl (0.4 mmol), aldehyde (0.6 mmol), phenyl acetylene (0.8 mmol), NaOAc (0.12 mmol), KHCO3 (0.4 mmol), CuCl (5 mol%) and 2,2’-dipyridyl (5 mol%) were used unless otherwise noted, and all reactions were carried out under a N2 atmosphere for 18 h. b 1H NMR yields were based on MeNHOH·HCl and determined by NMR using mesitylene as the internal standard; isolated yields of the two diastereomers are given in parentheses. c The ratio of two diastereomers was determined by 1H NMR of the crude reaction mixture. d Using 5 mol% 4,4’-dimethyl-2,2’-dipyridyl as ligand. e Using 120 µL of phenylacetylene, and preheated at 90oC for 30 minutes to melt the reaction mixture.

Furthermore, N-benzylhydroxylamine is also highly effective for this three-

component β-lactam formation (Table 7.3). Because the benzyl group on the β-lactam

nitrogen can be removed readily via standard hydrogenolysis, the three-component

reaction provides a very effective method for the synthesis of β-lactams that do not have

any substituents on the nitrogen.14 In these cases, it is interesting to note that the

electronic nature of the substituent on the aldehyde did not significantly influence the

reaction (Table 7.3, entries 1-4).

Table 7.3 Synthesis of β-lactam via the Coupling of N-Benzyl Hydroxylamine,

Aldehyde and Phenylacetylene.a

BnNHOHRCHO5 mol% CuCl, 5 mol% 2,2'-dipyridyl

30 mol% NaOAc, 70oC, neat

7b

PhN

Ph

R

O

Bn

104

entry R product yield (%)b cis:transc 1 Ph 7ba 85 (75) 78/22 2 4-Cl-C6H4 7bb 83 (75) 78/22 3 4-Br-C6H4 7bc 79 (78) 80/20 4 4-Me-C6H4 7bd 81 (80) 79/21

a Reaction conditions: BnNHOH (0.4 mmol), aldehyde (0.6 mmol), phenyl acetylene (0.8 mmol), NaOAc (0.12 mmol), CuCl (5 mol%) and 2,2’-dipyridyl (5 mol%) were used, all reactions were carried out under a N2 atmosphere for 18 h. b 1H NMR yields were based on BnNHOH and determined by NMR using mesitylene as the internal standard; isolated yields of the two diastereomers are given in parentheses. c The ratio of two diastereomers was determined by 1H NMR of the crude reaction mixture.

7.4 – Conclusion

A simple “three-component” method was developed to synthesize β-lactams from

N-substituted hydroxylamine, aldehydes, and phenylacetylene catalyzed by copper. The

reactivities of different N-substituted hydroxylamines and various aldehydes were

examined. The method provided various N-alkyl β-lactam derivatives efficiently. The

scope and application of this multi-component is under investigation.

7.5 – Experimental Section

Chemicals were purchased from Aldrich Chemicals Company and Acros

Chemicals, and were used without further purification. All experiments were carried out

under an atmosphere of N2, unless otherwise noted. 1H NMR and 13C NMR spectra were

acquired with Varian 400 MHz and 100 MHz, or 300 MHz and 75 MHz, respectively,

and referenced to the internal solvent signals. IR spectra were recorded with ABB

Bomem MB 100 interferometer. MS data were obtained by using KRATOS MS25RFA

Mass Spectrometer. HRMS-ESI measurements were performed at McGill University. N-

Benzyl hydroxylamine was prepared according to the literature method.15

1-Methyl-3,4-diphenyl-2-azetidinone (7aa)

CuCl (2.0 mg, 0.02 mmol), 2,2’-dipyridyl (3.2 mg, 0.02 mmol), NaOAc (10 mg, 0.12

mmol), KHCO3 (40 mg, 0.40 mmol) and N-methyl hydroxylamine hydrochloride (33 mg,

105

0.40 mmol) were added to a test tube, which was then sealed and flushed with nitrogen

gas. Then benzaldehyde (60 mL, 0.60 mmol) and phenylacetylene (85 mL, 0.80 mmol)

were added into the mixture with syringe, and the test tube was heated at 70oC for 18 h

under N2. The reaction mixture was cooled to room temperature and filtered through a

short silica gel column to remove the inorganic salts. The final product was obtained by

Thin Layer Chromatography (TLC) using hexanes-ethyl acetate (2/1) as eluent (cis-

isomer: 65 mg (Rf=0.2); trans-isomer: 17 mg (Rf=0.3), 86% overall yield). cis isomer: IR

(KBr): υmax 3061, 3026, 2918, 1756, 1419, 1189, 983, 768, 699, 584; 1H NMR (400

MHz, CDCl3, ppm): δ 7.15-6.98 (m, 10H), 4.95 (d, J=5.6 Hz, 1H), 4.86 (d, J=5.6 Hz,

1H), 2.91 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm): δ 168.10, 134.61, 132.47, 128.41,

127.96, 127.75, 127.64, 127.02, 126.62, 62.04, 61.14, 27.30; MS (EI) m/z (%) 237,

180(100), 165, 152, 139, 118, 102, 90, 77, 63, 51; HRMS exact mass calc’d for

C16H16NO ([M+H]) m/z: 238.1226; found m/z: 238.1225; trans isomer: IR (KBr): υmax

3061, 3026, 2918, 1757, 1497, 1457, 1388, 1068, 699, 631, 523; 1H NMR (400 MHz,

CDCl3, ppm): δ 7.44-7.24(m, 10H), 4.44 (d, J=2.0 Hz, 1H), 4.16 (s, 1H), 2.86 (s, 3H); 13C

NMR (75 MHz, CDCl3, ppm): δ 168.2, 137.2, 134.9, 129.1, 128.8, 128.6, 127.5, 127.2,

126.2, 65.7, 65.3, 27.1; MS (EI) m/z (%) 237, 180(100), 165, 152, 139, 118, 102, 89, 76,

63, 51; HRMS exact mass calc’d for C16H16NO ([M+H]) m/z: 238.1226; found m/z:

238.1226.

4-(2,5-Dimethoxyphenyl)-1-methyl-3-phenyl-2-azetidinone (7ab)

The titled product was prepared following the same procedure as described for 1-methyl-

3,4-diphenyl-2-azetidinone. Isolated yields of the two diastereomers: 55%. cis isomer:

υmax 3061, 3030, 2998, 2940, 2834, 1753, 1591, 1498, 1464, 1452, 1387, 1280, 1218,

1047, 1025, 988, 699; 1H NMR (400 MHz, CDCl3, ppm): δ 7.04-6.96 (m, 5H), 6.57-6.50

(m, 3H), 5.22 (d, J=6.0 Hz, 1H), 4.82 (d, J=6.0 Hz, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 2.96

(s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.8, 152.9, 151.0, 132.7, 128.4, 127.5,

126.6, 124.7, 113.1, 112.6, 110.6, 60. 9, 57.4, 55.7, 55.4, 28.0; MS (EI) m/z (%) 297, 266,

240, 225, 210, 197, 179, 164, 148 (100), 118, 104, 90, 77, 63, 51; ; HRMS exact mass

calc’d for C18H20NO3 ([M+H]) m/z: 298.1438; found m/z: 298.1437; trans isomer: υmax

3069, 3027, 3004, 2935, 2835, 1748, 1506, 1388, 1270, 1219, 1045, 990, 858, 831, 745,

106

726, 104, 694, 633, 514; 1H NMR (400 MHz, CDCl3, ppm): δ 7.37-7.24 (m, 5H), 6.84 (s,

3H), 4.86 (d, J=2.0 Hz, 1H), 4.20 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.86 (s, 3H); 13C

NMR (75 MHz, CDCl3, ppm): δ 168.7, 153.8, 151.6, 135.4, 128.5, 127.3, 127.2, 126.6,

113.5, 112.6, 111.9, 64.2, 59.6, 56.0, 55.8, 27.4; MS (EI) m/z (%) 297, 266, 240 (100),

225, 210, 197, 180, 164, 148, 118, 104, 90, 77, 63, 51; HRMS exact mass calc’d for

C18H20NO3 ([M+H]) m/z: 298.1438; found m/z: 298.1437.

4-(Furan-2-yl)-1-methyl-3-phenyl-2-azetidinone (7ac)


3,4-diphenyl-2-azetidinone. Isolated yield of the two diastereomers: 55%. cis isomer: IR

(KBr): υmax 3138, 3061, 3026, 2912, 1752, 1421, 1383, 1143, 1066, 763, 501; 1H NMR

(400 MHz, CDCl3, ppm): δ 7.15-7.10 (m, 6H), 6.12 (dd, J=3.2 Hz, 1.6 Hz, 1H), 6.01 (d,

J=3.6 Hz, 1H), 4.95 (d, J=5.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 1H), 2.89(s, 3H); 13C NMR (75

MHz, CDCl3, ppm): δ 168.0, 149.1, 142.9, 133.0, 128.5, 128.2, 127.4, 110.5, 109.3, 61.0,

56.5, 27.7; MS (EI) m/z (%) 227, 170, 141, 128, 118, 115, 110(100), 90, 81, 63, 51;

HRMS exact mass calc’d for C14H14NO2 ([M+H]) m/z: 228.1019; found m/z: 228.1019;

trans isomer: IR (KBr): υmax 3061, 3026, 2918, 1758, 1497, 1388, 1152, 1070, 1014, 926,

729, 698, 598, 527; 1H NMR (400 MHz, CDCl3, ppm): δ 7.46 (s, 1H), 7.35-7.24 (m, 5H),

6.39 (s, 2H), 4.48 (s, 2H), 2.82 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 167.8, 149.9,

143.2, 134.5, 128.7, 127.5, 127.2, 110.5, 109.2, 61.9, 58.0, 27.1; MS (EI) m/z (%) 227,

170(100), 141, 128, 118, 115, 110, 90, 77 , 63, 51; HRMS exact mass calc’d for

C14H14NO2 ([M+H]) m/z: 228.1019; found m/z: 228.1020.

4-(4-Fluorophenyl)-1-methyl-3-phenyl-2-azetidinone (7ad)


3,4-diphenyl-2-azetidinone, except using 5 mol% 4,4’-dimethyl-2,2’-dipyridyl as the

ligand. Isolated yields of the two diastereomers: 70%. cis isomer: IR (KBr): υmax 3061,

3026, 2918, 1741, 1607, 1510, 1388, 1217, 1081, 983, 842, 703; 1H NMR (400 MHz,

CDCl3, ppm): δ 7.06-6.93 (m, 7H), 6.82 (t, J=8.8 Hz, 2H), 4.92 (d, J=5.6 Hz, 1H), 4.85

(d, J=5.6 Hz, 1H), 2.89 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.4, 163.6, 161.2,

107

132.7, 130.8, 130.8, 129.1, 129.0, 128.8, 128.3, 127.2, 115.6, 115.3, 61.9, 61.6, 27.7; MS

(EI) m/z (%) 255, 198, 183, 177, 170, 138, 118(100), 109, 98, 90, 75, 63, 51; HRMS

exact mass calc’d for C16H15NOF ([M+H]) m/z: 256.1132; found m/z: 256.1132; trans

isomer: υmax 3063, 3030, 2910, 1756, 1603, 1509, 1426, 1388, 1225, 1157, 1069, 989,

841, 697, 509; 1H NMR (300 MHz, CDCl3, ppm): δ 7.36-7.26 (m, 7H), 7.12 (t, J=8.7 Hz,

2H), 4.43 (d, J=2.1 Hz, 1H), 4.13 (s, 1H), 2.85 (s, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 168.3, 164.1, 161.6, 134.8, 133.1, 133.1, 128.9, 128.0, 127.9, 127.7, 127.3,

116.3, 116.1, 65.9, 64.7, 27.0; MS (EI) m/z (%) 255, 198(100), 183, 177, 170, 138, 118,

109, 98, 90, 75, 63, 51; HRMS exact mass calc’d for C16H15NOF ([M+H]) m/z:

256.1132; found m/z: 256.1132.

4-(4-Chlorophenyl)-1-methyl-3-phenyl-2-azetidinone (7ae)


3,4-diphenyl-2-azetidinone, except that the reaction mixture was heated at 90oC for 30

minutes and then at 70oC for another 18 hr. Isolated yields of the two diastereomers:

83%. cis isomer: IR (KBr): υmax 3061, 3026, 2909, 1751, 1492, 1425, 1388, 1090, 1014,

985, 825, 721, 699, 468; 1H NMR (300 MHz, CDCl3, ppm): δ 7.12-6.92 (m, 9H), 4.91 (d,

J=5.7 Hz, 1H), 4.86 (d, J=5.7 Hz, 1H), 2.87 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ

167.9, 133.4, 133.3, 132.2, 128.4, 128.3, 128.2, 128.0, 126.9, 61.5, 61.2, 27.3; MS (EI)

m/z (%) 271, 214, 179, 154, 118(100), 90, 76, 63, 51; HRMS exact mass calc’d for

C16H15NOCl ([M+H]) m/z: 272.0837; found m/z: 272.0836; trans isomer: IR (KBr): υmax

3061, 3026, 2918, 1757, 1491, 1424, 1388, 1090, 1013, 988, 840, 741, 699, 575, 498; 1H

NMR (400 MHz, CDCl3, ppm): δ 7.39 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.27-

7.24 (m, 5H), 4.42 (d, J=2.0 Hz, 1H), 4.12 (s, 1H), 2.85 (s, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 168.0, 135.8, 134.6, 134.4, 129.3, 128.8, 127.6, 127.5, 127.2, 65.9, 64.7,

27.1; MS (EI) m/z (%) 271, 214(100), 179, 152, 118, 89, 76, 63, 51; HRMS exact mass

calc’d for C16H15NOCl ([M+H]) m/z: 272.0837; found m/z: 272.0835.

4-(4-Bromophenyl)-1-methyl-3-phenyl-2-azetidinone (7af)

108


3,4-diphenyl-2-azetidinone. Isolated yields of the two diastereomers: 70%. cis isomer: IR

(KBr): υmax 3061, 3028, 2906, 1757, 1488, 1423, 1386, 1069, 1010, 837, 698, 575, 493;

1757; 1H NMR (300 MHz, CDCl3, ppm): δ 7.27 (d, J=8.1 Hz, 2H), 7.09-7.04 (m, 3H),

7.00-6.97 (m, 2H), 6.88 (d, J=8.1 Hz, 2H), 4.90 (d, J=5.4 Hz, 1H), 4.87 (d, J=5.4 Hz,

1H), 2.87 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.1, 134.0, 132.3, 131.3, 128.9,

128.5, 128.2, 127.1, 121.8, 61.6, 61.2, 27.3; MS (EI) m/z (%) 315, 258, 198, 178, 152,

118(100), 90, 76, 63, 51; HRMS exact mass calc’d for C16H15NOBr ([M+H]) m/z:

316.0331; found m/z: 316.0330; trans isomer: υmax 3061, 3028, 2907, 1754, 1423, 1386,

1070, 1010, 986, 821, 716, 699, 655, 512; 1H NMR (400 MHz, CDCl3, ppm): δ 7.56 (d,

J=8.4 Hz, 2H), 7.38-7.34 (m, 2H), 7.32-7.26 (m, 3H), 7.21 (d, J=8.4 Hz, 2H), 4.42 (d,

J=2.4 Hz, 1H), 4.12 (s, 1H), 2.86 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.2,

136.4, 134.6, 132.4, 128.9, 127.9, 127.8, 127.3, 122.6, 65.8, 64.8, 27.1; MS (EI) m/z (%)

315, 258, 198, 178(100), 165, 152, 118, 89, 76, 63, 51; HRMS exact mass calc’d for

C16H15NOBr ([M+H]) m/z: 316.0331; found m/z: 316.0330.

1-Methyl-3-phenyl-4-o-tolyl-2-azetidinone (7ag)



(KBr): υmax 3061, 3029, 2949, 2903, 1757, 1458, 1424, 1390, 1339, 1202, 1080, 986,

773, 697, 667, 490; 1H NMR (400 MHz, CDCl3, ppm): δ 7.05-6.89 (m, 9H), 5.10(d,

J=5.6 Hz, 1H), 4.82 (d, J=5.6 Hz, 1H), 2.98 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 168.5, 135.2, 132.8, 132.0, 130.0, 128.6, 127.6, 127.2, 126.9, 125.6,

125.3, 61.1, 59.7, 28.0, 19.2; MS (EI) m/z (%) 251, 236, 194, 179, 165, 152, 134,

118(100), 96, 90, 77, 63, 51; HRMS exact mass calc’d for C17H18NO ([M+H]) m/z:

252.1383; found m/z: 252.1382; trans isomer: IR (KBr): υmax 3061, 3026, 2918, 1757,

1654, 1388, 755, 698, 630; 1H NMR (400 MHz, CDCl3, ppm): δ 7.36-7.16 (m, 9H), 4.74

(d, J=2.0 Hz, 1H), 4.05 (s, 1H), 2.95 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 168.6, 135.8, 135.7, 135.1, 130.8, 128.8, 127.8, 127.6, 127.3, 126.6, 124.0, 65.7,

62.2, 27.6, 19.5; MS (EI) m/z (%) 251, 236, 194(100), 179, 165, 152, 134, 118, 96, 90,

109

77, 63, 51; HRMS exact mass calc’d for C17H18NO ([M+H]) m/z: 252.1383; found m/z:

252.1383.

1-Methyl-3-phenyl-4-p-tolyl-2-azetidinone (7ah)


3,4-diphenyl-2-azetidinone. Isolated yields of the two diastereomers: 95%. cis isomer: cis

isomer: IR (KBr): υmax 3061, 3026, 2918, 1757, 1424, 1385, 1080, 816, 700, 511; 1H

NMR (400 MHz, CDCl3, ppm): δ 7.06-6.98 (m, 5H), 6.92 (d, J=7.6 Hz, 2H), 6.87 (d,

J=7.6 Hz, 2H), 4.90 (d, J=5.6 Hz, 1H), 4.82 (d, J=5.6 Hz, 1H), 2.87 (s, 3H), 2.19 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.6, 137.8, 133.1, 131.9, 129.1, 128.9, 128.2,

127.5, 127.0, 62.4, 61.4, 27.6, 21.5; MS (EI) m/z (%) 251, 194(100), 179, 165, 152, 134,

118, 105, 96, 89, 77, 63, 51; HRMS exact mass calc’d for C17H18NO ([M+H]) m/z:

252.1383; found m/z: 252.1383; trans isomer: IR (KBr): υmax 3061, 3026, 2918, 1757,

1514, 1423, 1387, 1069, 698, 592, 517; 1H NMR (400 MHz, CDCl3, ppm): δ 7.32 (d,

J=6.0 Hz, 2H), 7.28-7.21 (m, 7H), 4.40 (d, J=2.0 Hz, 1H), 4.13 (s, 1H), 2.83 (s, 3H), 2.38

(s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.3, 138.5, 135.0, 134.1, 129.7, 128.7,

127.5, 127.2, 126.1, 65.7, 65.2, 27.0, 21.3; MS (EI) m/z (%) 251, 236, 194, 179, 165, 152,

134(100), 118, 105, 96, 90, 77, 63, 51; HRMS exact mass calc’d for C17H18NO ([M+H])

m/z: 252.1383; found m/z: 252.1382.

4-(4-Methoxyphenyl)-1-methyl-3-phenyl-2-azetidinone (7ai)



(KBr): υmax 3061, 3026, 2922, 2834, 1735, 1612, 1513, 1391, 1245, 1173, 984, 830, 700;

1H NMR (400 MHz, CDCl3, ppm): δ 7.07-6.98 (m, 5H), 6.89 (d, 2H), 6.50 (d, J=8.4 Hz,

2H), 4.89 (d, 1H), 4.81 (d, 1H), 3.66 (s, 3H), 2.85 (s, 3H); 13C NMR (75 MHz, CDCl3,

ppm): δ 168.1, 158.8, 132.7, 128.3, 128.3, 127.8, 126.5, 126.4, 113.4, 61.6, 61.0, 55.0,

27.1; MS (EI) m/z (%) 267, 210, 165, 150 (100), 118, 90, 77, 63, 51; HRMS exact mass

calc’d for C17H18NO2 ([M+H]) m/z: 268.1332; found m/z: 268.1332; trans isomer: IR

(KBr): υmax 3061, 3026, 2918, 1752, 1611, 1513, 1388, 1249, 1175, 1031, 837, 698, 595,

110

520; 1H NMR (400 MHz, CDCl3, ppm): δ 7.35-7.23 (m, 7H), 6.94 (d, J=8.4 Hz, 2H),

4.39 (d, J=2.4 Hz, 1H), 4.13 (s, 1H), 3.82 (s, 3H), 2.83 (s, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 168.3, 159.7, 135.0, 128.9, 128.7, 127.4, 127.4, 127.2, 114.4, 65.7, 65.0,

55.4, 26.9; MS (EI) m/z (%) 267, 210 (100), 195, 179, 165, 150, 118, 90, 82, 77, 63, 51;

HRMS exact mass calc’d for C17H18NO2 ([M+H]) m/z: 268.1332; found m/z: 268.1331.

4-(2-Methoxyphenyl)-1-methyl-3-phenyl-2-azetidinone (7aj)



(KBr): υmax 3061, 3026, 2938, 2837, 1752, 1492, 1465, 1388, 1243, 1111, 1027, 984,

751, 699, 594, 502; 1H NMR (400 MHz, CDCl3, ppm): δ 7.05-6.93 (m, 7H), 6.74 (t,

J=7.2 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 5.23 (d, J=5.6 Hz, 1H), 4.82 (d, J=5.6 Hz, 1H),

3.67 (s, 3H), 2.97 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.8, 156.6, 132.8,

128.4, 128.4, 127.4, 126.6, 126.4, 123.7, 119.7, 109.6, 61.0, 57.6, 54.9, 28.0; MS (EI) m/z

(%) 267, 210, 165, 150 (100), 118, 90, 77, 63, 51; ; HRMS exact mass calc’d for

C17H18NO2 ([M+H]) m/z: 268.1332; found m/z: 268.1331; trans isomer: IR (KBr): υmax

3061, 3026, 2940, 1838, 1755, 1601, 1492, 1388, 1245, 1026, 986, 756, 697, 628, 527; 1H NMR (400 MHz, CDCl3, ppm): δ 7.38-7.24 (m, 7H), 7.01 (t, J=7.6 Hz, 1H), 6.92 (d,

J=8.0 Hz, 1H), 4.88 (d, J=2.0 Hz, 1H), 4.22 (s, 1H), 3.80 (s, 3H), 2.86 (s, 3H); 13C NMR

(75 MHz, CDCl3, ppm): δ 169.1, 157.8, 135.9, 129.6, 128.8, 127.7, 127.5, 126.9, 125.8,

121.1, 111.0, 64.4, 60.1, 55.7, 27.7; MS (EI) m/z (%) 267, 210 (100), 195, 179, 165, 150,

118, 90, 82, 77, 63, 51; HRMS exact mass calc’d for C17H18NO2 ([M+H]) m/z: 268.1332;

found m/z: 268.1331.

1-Methyl-4-n-pentyl-3-phenyl-2-azetidinone (7ak)



υmax 2955, 2931, 2858, 1753, 1603, 1497, 1467, 1453, 1421, 1392, 1259, 1078, 1031,

733, 723, 700, 623, 616; 1H NMR (400 MHz, CDCl3, ppm): δ 7.32-7.17 (m, 5H), 4.49 (d,

J=5.2 Hz, 1H), 3.70 (ddd, J=6.0 Hz, 6.0 Hz, 6.0 Hz, 1H), 2.89 (s, 3H), 1.44-0.88 (m, 8H),

111

0.72 (t, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.4, 133.1, 129.3, 128.3,

127.4, 58.6, 58.4, 31.5, 29.0, 27.2, 25.3, 22.1, 13.7; MS (EI) m/z (%) 231, 174, 117, 104

(100), 91, 77, 65, 55; HRMS exact mass calc’d for C15H22NO2 ([M+H]) m/z: 232.1696;

found m/z: 232.1697; trans isomer: υmax 2955, 2929, 2858, 1755, 1497, 1467, 1454, 1422,

1392, 1253, 1079, 731, 698, 573; 1H NMR (400 MHz, CDCl3, ppm): δ 7.35-7.23 (m,

5H), 3.89 (s, 1H), 3.47 (ddd, J=9.6 Hz, 4.8 Hz, 2.4 Hz, 1H), 2.87 (s, 3H), 1.94-1.89 (m,

1H), 1.63-1.54 (m, 1H), 1.44-1.24 (m, 6H), 0.89 (t, J=8.0 Hz, 3H); 13C NMR (75 MHz,

CDCl3, ppm): δ 168.1, 135.7, 128.8, 127.4, 127.3, 62.3, 60.9, 32.4, 31.8, 26.7, 25.4, 22.5,

13.9; MS (EI) m/z (%) 231, 174, 131, 117 (100), 104, 91, 77, 65, 55; HRMS exact mass

calc’d for C15H22NO2 ([M+H]) m/z: 232.1696; found m/z: 232.1693.

1-Benzyl-3,4-diphenyl-2-azetidinone (7ba)

CuCl (2.0 mg, 0.02 mmol), 2,2’-dipyridyl (3.2 mg, 0.02 mmol), NaOAc (10 mg, 0.12

mmol), and N-benzyl hydroxylamine (50 mg, 0.40 mmol) were added to a test tube,

which was then sealed and flushed with nitrogen gas. Then, benzaldehyde (60 mL, 0.60

mmol) and phenylacetylene (85 mL, 0.80 mmol) were added into the mixture with

syringe. The test tube was heated at 70oC for 18 h under N2. The reaction mixture was

filtered through a short silica gel column to remove the inorganic salts and the final

product was obtained by Thin Layer Chromatography (TLC) using hexanes-ethyl acetate

(3/1) as eluent. Isolated yields of the two diastereomers: 75%. cis isomer:16 (Rf=0.3); 1H

NMR (400 MHz, CDCl3, ppm): δ 7.32-6.95 (m, 15H), 5.01 (d, J=14.8 Hz, 1H), 4.84 (d,

J=5.6 Hz, 1H), 4.83 (d, J=5.6 Hz, 1H), 3.92 (d, J=14.8 Hz, 1H); 13C NMR (75 MHz,

CDCl3, ppm): δ 168.1, 135.4, 134.6, 132.6, 128.8, 128.6, 128.1, 128.0, 127.8, 127.8,

127.4, 126.8, 60.9, 59.6, 44.6; MS (EI) m/z (%) 313, 196, 180 (100), 165, 118, 91, 77, 65,

51; trans isomer (corresponds to the inseparable mixture of two diastereomers) : (Rf=0.3)

υmax 3061, 3029, 2916, 1755, 1496, 1454, 1395, 1360, 1075, 1028, 941, 770, 753, 698,

595, 498; 1H NMR (400 MHz, CDCl3, ppm): δ 7.41-7.18 (m, 15H), 4.98 (d, J=15.0 Hz,

1H), 4.34 (d, J=2.4 Hz, 1H), 4.20 (d, J=2.4 Hz, 1H), 3.83 (d, J=15.0 Hz, 1H); 13C NMR

(75 MHz, CDCl3, ppm): δ 168.2, 137.2, 135.6, 135.0, 129.1, 128.9, 128.8, 128.5, 127.8,

127.6, 127.4, 126.5, 65.2, 63.1, 44.6; MS (EI) m/z (%) 313, 196, 180 (100), 165, 152,

112

118, 91, 77, 65, 51; HRMS exact mass calc’d for C22H20NO ([M+H]) m/z: 314.1539;

found m/z: 314.1534.

1-Benzyl-4-(4-chlorophenyl)-3-phenyl-2-azetidinone (7bb)

The titled product was prepared following the same procedure as described for 1-benzyl-


υmax 3061, 3029, 2917, 1752, 1496, 1453, 1391, 1090, 1014, 824, 744, 721, 699, 599,

507; 1H NMR (400 MHz, CDCl3, ppm): δ 7.32-7.28 (m, 3H), 7.18 (dd, J=8.0 Hz, 1.6 Hz,

2H), 7.08-6.97 (m, 7H), 6.88 (d, J=8.4 Hz, 2H), 4.94 (d, J=14.8 Hz, 1H), 4.80 (d, J=5.6

Hz, 1H), 4.79 (d, J=5.6 Hz, 1H), 3.89 (d, J=14.8 Hz, 1H); 13C NMR (75 MHz, CDCl3,

ppm): δ 167.8, 135.1, 133.6, 133.2, 132.2, 128.8, 128.7, 128.5, 128.4, 128.3, 128.1,

127.8, 127.0, 60.8, 59.0, 44.7; MS (EI) m/z (%) 347, 230, 214, 178, 118 (100), 91, 77, 65,

51; HRMS exact mass calc’d for C22H19NOCl ([M+H]) m/z: 348.1150; found m/z:

348.1143; trans isomer: υmax 3061, 3029, 2916, 1757, 1491, 1454, 1091, 1013, 751, 700,

503; 1H NMR (400 MHz, CDCl3, ppm): δ 7.39-7.18 (m, 14H), 4.96 (d, J=16.0 Hz, 1H),

4.31 (d, J=2.0 Hz, 1H), 4.16 (d, J=2.0 Hz, 1H), 3.83 (d, J=16.0 Hz, 1H); 13C NMR (75

MHz, CDCl3, ppm): δ 168.0, 135.7, 135.3, 134.6, 134.5, 129.3, 128.9, 128.9, 128.5,

127.9, 127.8, 127.8, 127.3, 65.2, 62.4, 44.7; MS (EI) m/z (%) 347, 230, 214 (100), 178,

118, 91, 77, 65, 51; HRMS exact mass calc’d for C22H19NOCl ([M+H]) m/z: 348.1143;

found m/z: 348.1143.

1-Benzyl-4-(4-bromophenyl)-3-phenyl-2-azetidinone (7bc)



υmax 3061, 3029, 2917, 1757, 1496, 1488, 1454, 1390, 1070, 1010, 751, 699; 1H NMR

(400 MHz, CDCl3, ppm): δ 7.32-7.28 (m, 3H), 7.25-7.22 (m, 3H), 7.18 (dd, J=8.0 Hz, 1.6

Hz, 2H), 7.09-7.05 (m, 2H), 6.99-6.97 (m, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.95 (d, J=14.8

Hz, 1H), 4.81 (d, J=6.0 Hz, 1H), 4.77 (d, J=6.0 Hz, 1H), 3.89(d, J=14.8 Hz, 1H); 13C

NMR (75 MHz, CDCl3, ppm): δ 167.8, 135.1, 133.8, 132.2, 131.2, 129.1, 128.8, 128.6,

128.47, 128.2, 127.9, 127.1, 121.8, 60.8, 59.1, 44.7; MS (EI) m/z (%) 391, 274, 258, 178,

113

165, 152, 118 (100), 91, 65, 51; HRMS exact mass calc’d for C22H19NOBr ([M+H]) m/z:

392.0644; found m/z: 392.0638; trans isomer: υmax 3061, 3029, 2917, 1757, 1496, 1488,

1454, 1412, 1391, 1070, 1010, 751, 699, 597, 499; 1H NMR (400 MHz, CDCl3, ppm): δ

7.52 (d, J=8.4 Hz, 2H), 7.32-7.25 (m, 7H), 7.19-7.17 (m, 3H), 7.15 (d, J=8.4 Hz, 2H),

4.96 (d, J=16.0 Hz, 1H), 4.28 (d, J=2.0 Hz, 1H), 4.15 (d, J=2.0 Hz, 1H), 3.82 (d, J=16.0

Hz, 1H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.0, 136.3, 135.3, 134.6, 132.3 128.9,

128.9, 128.5, 128.1, 127.9, 127.8, 127.3, 122.6, 65.2, 62.5, 44.7; MS (EI) m/z (%) 391,

274, 258 (100), 178, 165, 152, 118, 91, 65, 51; HRMS exact mass calc’d for C22H19NOBr

([M+H]) m/z: 392.0644; found m/z: 392.0639.

1-Benzyl-4-(4-methylphenyl)-3-phenyl-2-azetidinone (7bd)



υmax 3062, 3031, 2926, 1735, 1513, 1495, 1433, 1396, 1345, 1267, 1183, 820, 750, 700,

604, 518; 1H NMR (400 MHz, CDCl3, ppm): δ 7.35-7.30 (m, 3H), 7.22-7.20 (m, 2H),

7.11-7.03 (m, 5H), 6.94 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 5.01 (d, J=14.8 Hz,

1H), 4.83 (d, J=5.6 Hz, 1H), 4.81 (d, J=5.6 Hz, 1H), 3.90 (d, J=14.8 Hz, 1H), 2.21 (s,

3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.1, 137.5, 135.4, 132.8, 131.4, 128.8, 128.7,

128.6, 128.5, 127.9, 127.7, 127.4, 126.7, 60.7, 59.4, 44.4, 21.0; MS (EI) m/z (%) 327,

312, 224, 210 (100), 194, 179, 165, 118, 91, 77, 65, 51; HRMS exact mass calc’d for

C23H22NO ([M+H]) m/z: 328.1696; found m/z: 328.1689; trans isomer (corresponds to

the inseparable mixture of two diastereomers) : υmax 3062, 3029, 2924, 1752, 1496, 1454,

1395, 1355, 1043, 820, 750, 700, 604; 1H NMR (300 MHz, CDCl3, ppm): δ 7.32-7.03 (m,

14H), 4.96 (d, J=15.0 Hz, 1H), 4.31 (d, J=2.1 Hz, 1H), 4.18 (d, J=2.1 Hz, 1H), 3.89 (d,

J=15.0 Hz, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm): δ 168.3, 138.5, 135.6,

135.1, 134.1, 129.8, 128.8, 128.5, 127.5, 127.3, 126.5, 65.1, 62.9, 44.4, 21.2; MS (EI) m/z

(%) 327, 312, 224, 210 (100), 194, 179, 165, 118, 91, 77, 65, 51; HRMS exact mass

calc’d for C23H22NO ([M+H]) m/z: 328.1696; found m/z: 328.1689;

114

References for Chapter 7

1. Wei, C. M.; Li, C.-J. Lett. Org. Chem. 2005, 2, 410.

2. Chen, L.; Li, C.-J. Org. Lett. 2004, 6, 3151.

3. Wei, C. M.; Li, Z. G.; Li, C.-J. Synlett 2004, 1472.

4. Wei, C. M.; Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5749.

5. Li, Z. G.; Wei, C. M.; Chen, L.; Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45, 2443.

6. Wei, C. M.; Li, Z. G.; Li, C.-J. Org. Lett. 2003, 5, 4473.

7. Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.

8. Wu, W.; Li, C.-J. Chem. Commun. 2003, 1668.

9. Wang, M. W.; Yang, X. F.; Li, C.-J. Eur. J. Org. Chem. 2003, 998.

10. Yang, X. F.; Wang, M. W.; Varma, R. S.; Li, C.-J. Org. Lett. 2003, 5, 657.

11. Zhang, J. H.; Wei, C. M.; Li, C.-J. Tetrahedron Lett. 2002, 43, 5731.

12. Li, C.-J.; Wei, C. M. Chem. Commun. 2002, 268.

13. Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638.

14. Evans, D. A.; Siogren, E. B. Tetrahedron Lett. 1985, 26, 3783.

15. Maskill, H.; Jencks, W. P. J. Am. Chem. Soc. 1987, 109, 2062.

16. Sheradsky, T.; Zbajda, D. J. Org. Chem. 1980, 45, 2169.

Part IV – α-Arylation of Tetrahydroisoquinoline with Aryl iodide via C-H Functionalization

Chapter 8: Introduction to α-Arylation Reaction via 1,2-Addition to Imines

Catalyzed by Transitional Metal Compounds

Chapter 9: α-Arylation of Tetrahydroisoquinoline with Aryl Iodide via C-H

Functionalization

Chapter 8: Introduction to α-Arylation Reaction via 1,2-Addition to Imines

Catalyzed by Transitional Metal Compounds

115

Chapter 8 – Introduction to α-Arylation Reaction via 1,2-Addition to Imines

Catalyzed by Transition Metal Compounds

The reaction between a nucleophile and an imine is very important in

organic synthesis. In fact, it is the most important approach to introduce

functionalities adjacent to a nitrogen atom. The well-known Strecker reaction,1,2

aza-Henry reaction,3 Petasis reaction,4-8 A3 (aldehyde, amine, alkyne) coupling

reaction etc. are all based on the electrophilic properties of imine derivatives.

Presently, for the arylation of imines the traditional methods use reactive

compounds such as Grignard reagents or organoboron compounds (Petasis

reaction). However, the drawbacks of these two methods are functional group

compatibility issues associated with Grignard reagent and the necessity of a

directing group or activated substrate associated with Petasis reaction.4-8 In the

past few decades, great efforts have been made by organic chemists to achieve the

1,2-addition to imines catalyzed by transition metal catalysts. In this chapter, a

detailed review of transition metal compound-catalyzed 1,2-additions to imines

will be presented.

8.1– α-Arylation Reaction via 1,2-Addition to Imines Catalyzed by Rhodium

Compounds

Among all the transition metal-catalyzed 1,2-addition to imines, rhodium

is the most studied catalyst. The general mechanism of rhodium-catalyzed 1,2-

addition to imines is shown below (Scheme 8.1). Starting from arylation precursor

8a, transmetalation with rhodium compound generates the aryl-rhodium complex

8b. Coordination of the imine with the rhodium intermediate followed by

insertion of the imine to the aryl-rhodium complex affords intermediate 8d. Final

hydrolysis gives the arylation product 8e and reproduces the rhodium precursor

8a.

116

[Rh]

[Rh] Ar

[Rh] Ar

NR1

R2 H

N

R2 Ar

R1[Rh]

Ar-M

transmetalation

coordination

N

R2 Hinsersion

H2O

hydrolysis

HN

R2 Ar

R1

R1

8a

8b

8c

8d

8e

Scheme 8.1 General Mechanism of the Rhodium-Catalyzed 1,2-Arylation to Imines

8.1.1– Organoboron as the Nucleophile 8.1.1.1– 1,2-Addition without Enantioselecitivity

In 2000, Miyaura and co-worker reported that a cationic rhodium complex,

together with 1,4-bis(diphenylphosphino)butane (dppb) as the ligand, catalyzes

the addition of sodium tetraphenylborate to electron-deficient N-sulfonyl

aldimines in aqueous dioxane.9 The low reactivities with normal imines such as

N-butyl, N-benzyl, N-phenyl imines suggested that the 1,2-addition proceeds via a

nucleophilic attack of the rhodium-aryl intermediate on the C=N bond (Scheme

8.2).

N

HR

SO2Ar+ Ph4BNa

[Rh(cod)(MeCN)2]BF4/dppb

dioxane, 90oCHN

PhR

SO2Ar

Scheme 8.2 Rhodium Catalyzed 1,2-Addition of N-Sulfonylimines Using Ph4BNa as the Arylation Reagent

Later, the same group found that [Rh(cod)(MeCN)2]BF4 alone can

catalyze the addition of aryl boronic acid to N-sulfonyl aldimines (Scheme 8.3).

117

N

HAr2

SO2Ar1

+ Ar3B(OH)2[Rh(cod)(MeCN)2]BF4

dioxane, 95oC, 16 hHN

Ar3Ar2

SO2Ar1

Scheme 8.3 Rhodium Catalyzed 1,2-Addition of N-Sulfonylimines using Arylboronic Acid as the Arylation Reagent

In 2006, Murai and co-workers reported the rhodium-catalyzed arylation

of sodium tetraphenylborate with unactivated N-arylimines. The reaction proceeds

with low loading of [RhCl(cod)]2, affording the arylated products in good yield at

elevated temperature (160oC) in o-xylene (Scheme 8.4).10

NaBPh4 +N Ar2

Ar1 [RhCl(cod)]2 (1 mol%)NH4Cl (1 equiv)o-xylene, 160oC HN Ar2

Ar1 Ph

Scheme 8.4 Rhodium Catalyzed 1,2-Addition of N-Arylimines With NaBPh4

8.1.1.2– Asymmetric 1,2-Addition of Aryl Boron Reagent to Imines

In 2004, Tomioka and co-workers reported the first example of the

asymmetric rhodium-catalyzed 1,2-addition of aryl boron reagent to imines

(Scheme 8.5).11 By employing a N-Boc-L-valine-connected

amidomonophosphane ligand together with Rh(acac)(C2H4)2, the arylation of N-

tosylimines with arylboroxine proceeded smoothly in n-PrOH, affording the

arylated product in both good yield (83%-99%) and good enantioselectivity (ee:

72%-94%).

N

HAr1

Ts+ O

B O BOB

Ar2

Ar2Ar2

[Rh(acac)(C2H4)2]2/L*

n-PrOH60-100oC, 1-3 h

HN

Ar2Ar1

Ts N

ONHBoc

PPh2

L*

Scheme 8.5 N-Boc-L-Valine-Connected Amidomonophosphane Rhodium(I) Catalyzed Asymmetric Arylation of N-Tosylimines with Arylboroxines

118

Shortly after Tomioka’s report, Hayashi and co-workers reported that C2-

symmetric bicyclo[2.2.2]octadiene (bod) serves as a better chiral ligand in the

rhodium-catalyzed 1,2-addtion of arylboroxines to N-tosylimines (Scheme 8.6).12

The asymmetric arylation was performed in aqueous KOH solution, affording the

coupling product with excellent enantioselectivities (ee: 95%-99%).

N

HAr1

Ts+ O

B O BOB

Ar2

Ar2Ar2

[RhCl(C2H4)2]2/L*

KOH/H2Odioxane, 60oC, 6 h

HN

Ar2Ar1

Ts

Ph

Ph

L*: (R,R)-Ph-bod*

Scheme 8.6 C2-Symmetric Bicyclo[2.2.2]octadiene Rhodium(I) Catalyzed

Asymmetric Arylation of N-Tosylimines with Arylboroxines While the use of C2-symmetric bicyclo[2.2.2]octadienes gives excellent

enantioselectivity of the arylation of N-tosylimines, the removal of the tosyl group

appears to be difficult in the later process. The 4-nitrobenzenesulfonyl (Ns) group

is much easier to be deprotected than the tosyl group. However, the

enantioselectivity of the asymmetric arylation catalyzed by the rhodium/(R,R)-Ph-

bod* complex is much lower for N-4-nitrobenzenesulfonylimines. In 2005,

Hayashi and co-workers reported a practical procedure for the asymmetric

arylation of N-Ns imines with arylboroxines using a C2-symmetric

bicyclo[3.3.1]nonadiene as the chiral ligand (Scheme 8.7).13

N

HAr1

Ns+ O

B O BOB

Ar2

Ar2Ar2

[RhCl(R,R)-Ph-bnd*]2

KOH/H2Odioxane, 60oC, 6 h

HN

Ar2Ar1

Ts

Ns = NO2SO2

(R.R)-Ph-bnd*

Scheme 8.7 C2-Symmetric Bicyclo[3.3.1]nonadiene Rhodium(I) Catalyzed Asymmetric Arylation of N-Ns Imines with Arylboroxines

119

In 2005, Ellman and co-worker reported a diastereoselective and

enantioselective rhodium(I)-catalyzed addition of arylboronic acids to N-tert-

butanesulfinyl and N-diphenylphosphinoyl aldimines.14 By employing chiral N-

tert-butanesulfinyl aldimines as the substrate, Rh-Ar could be preferentially added

to afford the corresponding arylated products with high diastereoselectivities with

the assists of 1,2-Bis(diphenylphophino)benzene (dppbenz) (Scheme 8.8).

N S

HAr1

O + Ar2B(OH)2

5 mol% Rh(acac)(coe)25.5 mol% dppbenz

dioxane70oC

HN S

Ar2Ar1O Ph2P PPh2

dppbenz

Scheme 8.8 Diastereoselective Arylation of N-tert-Butanesulfinyl imines

catalyzed by Rh(I)/dppbenz

Meanwhile, by employing N-diphenylphosphinoyl aldimines as the

substrates and (R,R)-DeguPHOS as the chiral ligand, the arylation of arylboronic

acid affords the products with up to 97% ee (Scheme 8.9).14 In 2007, Ellman and

co-workers reported a procedure where N-Boc imines can be applied into the

Rh(I)/DeguPHOS catalyzed asymmetric 1,2-addition with arylboronic acids.15 It

is reported that the N-Boc imines are generated in situ from stable and easily

prepared α-carbamoyl sulfones.

N PPh2

HPh

O

+

5 mol% Rh(acac)(coe)25.5 mol% (R,R)-DeguPHOS

1 equiv Et3N, 3AMSdioxane, 70oC, 24 h

HN∗

PPh2

ArPh

O N

Ph2P PPh2

Bn

(R,R)-DeguPHOS

ArB(OH)2

Scheme 8.9 Enantioselective Arylation of N-diphenylphosphinoyl aldimines catalyzed by Rh(I)/DeguPHOS

Similarly, in 2005, Batey and co-worker reported that N-sulfinylimines

could be diastereoselectively arylated using various arylboron compounds at room

120

temperature. They also demonstrated that the sufinamide adducts could be readily

converted to enantiomerically enriched diarylmethylamines (Scheme 8.10).16

N

HR1

+ [Rh(cod)(CH3CN)2]BF4

Et3N (2 equiv)dioxane/H2O

rt, 2 h

S O R2

R2 = B(OH)2

B

B(OiPr)2

BF3K

O

O

HN

ArR1

S OMeOH/HCl

1 h

NH2

ArR1

HClAr

Scheme 8.10 Protocol for the Rhodium(I) Catalyzed Addition of Arylboron Compounds to Sulfinimines

In 2006, Vries, Feringa, Minnaard and co-workers reported a

rhodium/phosphoramidite-catalyzed asymmetric arylation of N,N-

dimethylsulfamoyl protected aldimines (Scheme 8.11).17 The asymmetric

approach to α-arylated amines has the advantage of low catalyst loading, low

loading of arylboronic acid and the use of inexpensive, easy removable N,N-

dimethylsulfamoyl as the activating group. In 2007, Gennari, Piarulli and co-

workers reported an similar approach for the synthesis α-arylated N-tosylimines

using Rh(I)/phosphoramidite ligand. Moderate to good enantioselectivities were

obtained.18 Most recently, Yamamoto, Miyaura and co-worker reported that an N-

linked bidentate phosphoramidite (N-Me-BIPAM) ligand can also be applied to

the Rh(I)-catalyzed asymmetric addtion of arylboronic acids to N-

sulfonylarylaldimines.19

N S

HAr1

O + Ar2B(OH)2

Rh(acac)(eth)2/L*

acetone, 40oC, 4 h

O N

N S

Ar2Ar1

O

O N O

OP N

H

OL*

Scheme 8.11 Enantioselective Arylation of N,N-dimethylsulfamoyl protected aldimines

121

In 2006, Zhou and co-workers reported rhodium(I)/(S)-SHIP as the active

complex which catalyzed the asymmetric arylation of N-tosylarylimines with

arylboronic acids.20 The reaction proceeded in aqueous toluene to give

diarylmethylamines in good yield with up to 96% ee (Scheme 8.12).

N

HAr1

Ts+

Rh(acac)(CH2CH2)2/L*

KF (4 equiv)toluene/H2O (1/1), 35oC

HN

Ar2Ar1

TsAr2B(OH)2

O OP

O

L*

Scheme 8.12 Rhodium(I)/(S)-SHIP Catalyzed Asymmetric Arylation of N-

Tosylarylimines with Arylboronic Acids.

In 2006, Ellman and co-worker reported a rhodium-catalyzed

diastereoselective addition of arylboronic acids to N-tert-butanesulfinyl imino

ester (Scheme 8.13).21 The reported procedure provides an efficient way for the

synthesis of optically pure protected arylglycine derivatives.

NS

H

OOMe

O

+

5 mol% Rh(acac)(coe)25 mol% dppbenz

dioxane70oC

NHS

Ar

OOMe

O

ArB(OH)2

Scheme 8.13 Rhodium (I)/dppbenz Catalyzed Diastereoselective Arylation of N-tert-Butanesulfinyl Imino Ester with Arylboronic Acid

In 2007, Lin and co-workers designed a C2-symmetric tetrahydropentalene

as a new chiral diene ligand for the enantioselective Rh(I)-catalyzed arylation of

N-tosylarylimines with arylboronic acids (Scheme 8.14).22 The arylation proceed

efficiently in toluene at 55oC, affording the arylated products with excellent

enantioselectivities in all the cases (ee>98%).

122

N

HAr1

Ts+

[RhCl(C2H4)2]/L*

toluene, Et3N55oC, 4-5 h

HN

Ar2Ar1

TsAr2B(OH)2

Ph

Ph

H

HL*

Scheme 8.14 C2-symmetric Tetrahydropentalene Rhodium(I) Catalyzed Asymmetric Arylation of N-tosylimines with Arylboronic Acids

In 2008, Ellman and co-worker reported for the first time the application

of aliphatic imines into the asymmetric Rh-catalyzed arylation with arylboronic

acids. The use of K3PO4 as the inorganic base and DeguPHOS as the ligand are

both important for achieving the high yields and high enantioselectivities in the

reaction (Scheme 8.15).23

NR2

HR1

+

Rh(acac)(coe)2(R,R)-DeguPHOS

K3PO4 (20 mol%), 4AMS dioxane, 70oC, 20 h

HN∗

R2

ArR1

N

Ph2P PPh2

Bn

(R,R)-DeguPHOS

PPh2

O

ArB(OH)2

R2 = Ts

Scheme 8.15 8.1.2– Organostannane as the Nucleophile

In a similar manner, organostannanes can also be used as the arylation

reagent in the rhodium catalyzed 1,2-addition to imines.

The highly enantioselective addition of aryl and alkenylstannanes to

imines has been developed by Hayashi and co-workers in 2000 using a Rh(I)/

monodentate phosphine (MOP’s) complex. The reaction proceeds at 110oC in

dioxane, affording the arylated products in good yield and enantioselectivities

(Scheme 8.16).24,25

123

N

HAr1

SO2Ar3

+ Ar2SnMe3

Rh(acac)(C2H4)2(R)-MOP

LiF, dioxane110oC, 12 h

HN

Ar2Ar1

SO2Ar3

Ph2P Me

Me

OMeOMe

Ph2P

L* =

(R)-MeO-MOP (R)-Ar*-MOP

Scheme 8.16 Rh(I)/MOP Catalyzed arylation of Organostannanes with N-Sulfonylimines

In 2003, Oi and co-workers reported a [Rh(cod)(MeCN)2]BF4-catalyzed

arylation of aryl and alkenyltrimethylstannanes with various aromatic aldimines.

The reaction is applicable to N-tosyl, N-diehoxyphophoryl, N-benzoyl and N-

tertbutylcarboxyl imines.26

8.2– α-Arylation Reaction via 1,2-Addition to Imines Catalyzed by

Palladium Compounds

Compared with the rhodium-catalyzed 1,2-addition to imines, the

palladium-catalyzed imine insertion is relatively less studied. However, the early

work on palladium catalyzed allylation and carbonylation of imines and iminiums

was reported starting the late 1990’s.27-30

It was in 2007 that Lu and co-workers reported the first palladium/bipy

complex-catalyzed addition of arylboronic acids to chiral N-tert-butanesulfinyl

imines. The reaction yields the optical active arylglycine derivative with moderate

yield and high diastereoselectivity.31 They proposed that in the addition step of

Pd-Ar intermediate 8f, the Pd(II) coordinates with the oxygen on the sulfinyl

group, so that it could selectively deliver the aryl group from the opposite site of

the tert-butyl group (Scheme 8.17).

124

Pd

HO

PdOH

N

N

N

N

OHPd

OTf

N

N

PdN

NAr

PdN

NAr

NS

H OEt

O

O

favored

disfavored

NS

Ar OEt

O

OPd

N

N

NS

H OEt

O

O

ArB(OH)2

N

N= bipy

protonolysis

NHS

Ar OEt

O

O

8f

Scheme 8.17 Pd(II)/bipy Catalyzed Diastereoselective Arylation of Arylboronic Acids with N-Sulfinylimines

In 2007, Hu and co-workers reported an active phosphite-based

palladacycle catalyzed addition of arylboronic acids with N-sulfonylimines.32 The

palladacycle allows the arylation proceed at room temperature, affording the

products in good yields (Scheme 8.18).

t-Bu

t-Bu PdP

O

OAr

OAr

Cl

Ar1B(OH)2 +Ar2

NR

HR = Bs Ts

palladacycleK3PO4/toluene, RT, 24-48 h Ar1

NHR

Ar2

palladacycle

Scheme 8.18 Active Pallacycle Catalyzed Arylation of Arylboronic Acids with

N-Sulfonylimines

125

In 2008, Wu, Cheng and co-workers reported a palladium-catalyzed

addition of arylation using N-tosylimines as the electrophile and arylboronic acids

as the arylating reagent (Scheme 8.19).33 It is surprising to notice that the i-

Pr2NPPh2 is much better than any other ligands in catalyzing this addition. The

reaction proceeds in dioxane at 80oC, affording the desired products in good

yields.

Ar1B(OH)2 + NTs

Ar2

PdCl2(PhCN)2, i-Pr2NPPh2

K2CO3, 4A MS, dioxaneNH

Ts

Ar2

Ar1

Scheme 8.19 Pd(II) Catalyzed Arylation of Arylboronic Acids with N-Sulfonylimines

In 2009, Wu and co-workers reported the palladacycle-catalyzed arylation

of normal imines with arylboronic acids. To achieve optimum yields, the reaction

requires the use of NH4Cl as the acidic additive and sodium dodecyl sulfonate

(SDS) as the phase transfer catalyst (Scheme 8.20).34

Ar1CHO + Ar2NH2 + Ar3B(OH)2palladacycle

NH4Cl, SDS, H2O100oC, 12 h

NH

Ar1 Ar3

Ar2Fe Pd N

N N

N

N= bipy

Cl-palladacycle

SDS: sodium dodecyl sulfonate

Scheme 8.20 Palladacycle-Catalyzed Arylation of Arylboronic Acids with

Normal Imines


1. Yet, L. Angew. Chem. Int. Ed. 2001, 40, 875.

2. Connon, S. J. Angew. Chem. Int. Ed. 2008, 47, 1176.


126

4. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.

5. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.



8. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.

9. Ueda, M.; Miyaura, N. J. Organomet. Chem. 2000, 595, 31.

10. Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem. 2006, 691, 2821.

11. Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128.

12. Tokunaga, N.; Otomaru, Y.; Okamoto, K.; K., U.; R., S.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

13. Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

14. Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2004, 127, 1092.

15. Nakamura, H.; Rech, J. C.; Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155.

16. Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481.

17. Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.; Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Angew. Chem. Int. Ed. 2006, 45, 2789.

18. Marelli, C.; Monti, C.; Gennari, C.; Piarulli, U. Synlett 2007, 2213.

19. Kurihara, K.; Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal. 2009, 351, 260.

20. Duan, H.-F.; Jia, Y.-X.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 2567.

21. Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304.

127

22. Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336.

23. Trincado, M.; Ellman, J. A. Angew. Chem. Int. Ed. 2008, 47, 5623.

24. Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976.

25. Hayashi, T.; Ishigedani, M. Tetrahedron 2001, 57, 2589-2595.

26. Oi, S.; Moro, M.; Fukuhara, H.; Kawanishi, T.; iInoue, Y. Tetrahedron 2004, 59, 4351.

27. Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem. Int. Ed. 2001, 40, 3228.

28. Kacker, S.; Kim, J. S.; Sen, A. Angew. Chem. Int. Ed. 1998, 37, 1251.

29. Nakamura, H.; Iwama, H.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 6641.

30. Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998, 120, 4242.

31. Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077.

32. He, P.; Lu, Y.; Hu, Q.-S. Tetrahedron Lett. 2007, 48, 5283.

33. Zhang, Q.; Chen, J.; Liu, M.; Wu, H.; Cheng, J.; Qin, C.; Su, W.; Ding, J. Synlett 2008, 935.

34. Yu, A.; Wu, Y.; Cheng, B.; Wei, K.; Li, J. Adv. Synth. Catal. 2009, 351, 767.

Chapter 9: α-Arylation of Tetrahydroisoquinoline with Aryl Iodide via C-H

Functionalization

128

Chapter 9 – α-Arylation of Tetrahydroisoquinoline with Aryl iodide via

C-H Functionalization

As illustrated in chapter 8, there has been increased attention to the α-

arylation of imines catalyzed by transition metals. However, the feedstocks for

these arylations are all organometallic reagents (arylboronic compound and

arylstannanes compounds). Extra steps of synthesis are needed to access those

reagents. Furthermore, the imines used in the arylation are all synthesized via a

condensation between aldehydes and amines. The beauty of organic synthesis is

that it requires versatile approaches to obtain the desired product. In this chapter,

the development of a palladium-catalyzed α-arylation of 1,2,3,4-

tetrahydroisoquinoline with aryl iodide via C-H functionalization will be

discussed.

9.1– Background and Initiation of the Project

Due to the importance of the amine in natural products and bio-active

compounds, and as a continuous work of Cross Dehydrogenative Coupling

(CDC) reaction developed in our lab (Scheme 9.1, path a),1-9 we decided to

apply aryl halides to the C-H functionalization adjacent to a nitrogen atom

(Scheme 9.1, path b).

Scheme 9.1

Our proposal is that, by using a late transition metal catalyst, a secondary

amine 9b will first undergo a β-hydride elimination reaction to afford imine 9c.

129

In the meantime, oxidative addition between the aryl halide Ar-X with another

molecule of catalyst will occur to give the [M]-Ar-X complex 9a. After that, a

late transition metal-catalyzed 1,2-addition between the generated imine and

[M]-Ar will finally give the arylated product 9d (Scheme 9.2).

R2

NHR1

R2

NHR1

[M]

[M]-H

R2

NR1

Ar-X[M']

Ar-[M']-X

R2

NR1 [M']-Ar

+ H

[M]

R2

NR1 [M']

R2

NHR1

Ar

Ar

9a

9b9c

9d

Scheme 9.2 Proposal Arylation Pathway

To begin our study, we chose 1,2,3,4-tetrahydroisoquinoline (THIQ) as

the survey substrate, because of the strong nucleophilicity of the secondary

nitrogen and also because it is much easier to activate the benzyl group adjacent

to the nitrogen.

9.2 – Optimization of Reaction Conditions

The first reaction investigated was using iodobenzene as the arylating

reagent. Before the experiment, we were anticipating a possible N-arylation as

the competing reaction. However, to our delight, the reaction afforded the

desired C-arylated product in less than 1% yield (Scheme 9.3) without forming

the N-arylated product (detected by GC-MS by comparing with the standard

sample).

130

NH+ PhI

2.5 mol% Pd(OAc)21 equiv K2CO3

neat, 150oC, 8 h

NH

< 1%

Scheme 9.3

To test the efficiency of the catalyst, base and temperature were tested

under neat conditions. It turned out that Cs2CO3 gave relatively higher yield

than other bases (Table 9.1, entry 2). Decreased temperature shut down the

reaction (Table 9.1, entries 6 and 7). Meanwhile, increased temperature afforded

the decomposed starting compound and the decomposed arylated product (Table

9.1, entry 8). Other palladium catalysts or ruthenium and rhodium catalysts

afforded similar decresed yields. It is also surprising that when a combination of

4.0 equiv of KHCO3 as the base was used in the reaction, the yield increased

slightly.

Table 9.1 Screening of Catalyst, Base and Temperature for the α-Arylation of

THIQ with Iodobenzenea

NH+ PhI

2.5 mol% Pd(OAc)21 equiv base

neat, temp, 8 h

NH

entry catalyst base temperature (oC) yield (%)b 1 Pd(OAc)2 K2CO3 150 <1 2 Pd(OAc)2 Cs2CO3 150 7 3 Pd(OAc)2 NaOAc 150 <1 4 Pd(OAc)2 K3PO4 150 NR 5 Pd(OAc)2 KHCO3 150 NR 6 Pd(OAc)2 Cs2CO3 80 NR 7 Pd(OAc)2 Cs2CO3 120 NR 8 Pd(OAc)2 Cs2CO3 180 NAc 9 PdCl2 Cs2CO3 150 4% 10 PdCl2(PPh3)2 Cs2CO3 150 6 11 Pd2(dba)3CHCl3 Cs2CO3 150 3 12 Ru3(CO)12 Cs2CO3 150 NR 13 RhCl(PPh3)3 Cs2CO3 150 NR

131

entry catalyst base temperature (oC) yield (%)b 14 [Rh(cod)Cl]2 Cs2CO3 150 NR 15d Pd(OAc)2 KHCO3 150 9

a Reaction conditions: THIQ (1.0 mmol), iodobenzene (2.0 mmol), Pd(OAc)2 (0.025 mmol), base (1.0 mmol) in neat condition for 8 h. b 1H NMR yields using mesitylene as an internal standard c Formation of isoquinoline (6%) and 1-phenylisoquinoline (3%) from the decomposition of starting material and product was obtained. d KHCO3 (4.0 equiv) were used. NR=No Reaction, NA=Not Available

Next, a screening of co-catalyst was carried out. Group 11 metals gave

increased yields of the coupling product (Table 9.2, entries 2, 7 and 8). A co-

catalyst such as [Rh(cod)Cl]2, which is frequently used in the imine insertion,

turned out not effective in the arylation (Table 9.2, entry 5). Other co-catalysts

such as CoCl2, RuCl3, AuClPPh3 afforded decreased yields.

Table 9.2 Screening of Co-catalyst for the α-Arylation of THIQ with

Iodobenzenea

NH+ PhI

2.5 mol% Pd(OAc)22.5 mol% co-catalyst

4.0 equiv KHCO3

neat, 150oC, 8 h

NH

entry co-catalyst yield (%)b 1 AgOTf 2 2 AuCl 12 3 AuClPPh3 4.2 4 RuCl3 trace 5 [Rh(cod)Cl]2 5 6 CoCl2 trace 7 AgCl 10 8 CuCl 19

a Reaction conditions: THIQ (1.0 mmol), iodobenzene (2.0 mmol), Pd(OAc)2 (0.025 mmol), co-catalyst (0.025 mmol), KHCO3 (4.0 mmol) in neat condition at 150oC for 8 h. b 1H NMR yields using mesitylene as an internal standard

Later, we did a study on how the group 11 co-catalyst affected the

reaction. At this stage, the yields of the formed over-oxidized products 1-

phenyl-3,4-dihydroisoquinoline, 1-phenyl-isoquinoline are also considered to

132

evaluate the efficiency of the co-catalyst. Among all the co-catalysts

investigated, Cu(OMe)2 gave the best result in terms of the combined yield (52

%) of the three arylation products (Table 9.3, entry 3). Most group 11 co-

catalysts are also efficient in the arylation.

Table 9.3. Screening of Co-catalyst for the α-Arylation of THIQ with

Iodobenzenea

NH+ PhI

2.5 mol% Pd(OAc)22.5 mol% co-catalyst

4.0 equiv KHCO3

neat, 150oC, 8 h

NH N N+ +

entry co-catalyst

1 CuBr2 17 12 13 2 CuCl2 12 17 17 3 Cu(OMe) 2 25 19 8 4 Cu(OH) 2 10 12 15 5 CuSCN 18 14 10 6 Cu(OAc) 2 15 12 7 7 CuI 15 11 10 8 Cu(OH)F 9 9 12 9 Cu(acac) 2 9 12 14 10 Cu2O 12 20 13 11 CuO 15 13 16 12 Cu(TFA) 2 16 15 11 13 CuF2 5 5 17 14 CuCN 22 11 12 15 CuCl 19 8 13 16 CuOTf 23 10 4 17 AgCl 17 7 0 18 AgBr 0 0 16 19 AgTFA 18 9 trace 20 AgI 17 9 trace 21 AgF 14 11 trace 22 AuCl 15 8 4

a Reaction conditions: THIQ (1.0 mmol), iodobenzene (2.0 mmol), Pd(OAc)2 (0.025 mmol), co-catalyst (0.025 mmol), KHCO3 (4.0 mmol) in neat condition at 150oC for 8 h; 1H NMR yields using mesitylene as an internal standard

133

The screening of solvents was performed in the next step. Solvents such

as dioxane, 1,2-dichloroethane, DMSO, t-BuOH, and DMF gave very low yield

of the product or no reaction at all (Table 9.4, entries 1-5). To our surprise,

when the reaction was done in H2O, an increased yield (28%) of the product was

obtained and in the meantime, the over oxidation of the product was suppressed

(Table 9.4, entry 6).

Table 9.4 Screening of Solvent for the α-Arylation of THIQ with Iodobenzenea

NH+ PhI

2.5 mol% Pd(OAc)22.5 mol% Cu(OMe)2

4.0 equiv KHCO3

solvent, 150oC, 8 h

NH N N+ +

entry solvent

1 dioxane 3 0 0 2 DCE 0 0 0 3 DMSO 0 0 0 4 t-BuOH 6 0 0 5 DMF 0 0 0 6 H2O 28 6 3 7 neat 25 19 8

a Reaction conditions: THIQ (1.0 mmol), iodobenzene (2.0 mmol), Pd(OAc)2 (0.025 mmol), Cu(OMe)2 (0.025 mmol), KHCO3 (4.0 mmol), solvent (0.5 mL) at 150oC for 8 h; 1H NMR yields using mesitylene as an internal standard.

During the course of optimization of the reaction conditions, we found

that the ratio of the catalyst and co-catalyst is very important in terms of the

conversion and combined yields of the three arylated products. As a

consequence, we did a survey on how the ratio of Pd(OAc)2/Cu(OMe)2

influences of yields of the arylation in H2O. It was found that in the absence of

Cu(OMe)2 as the co-catalyst, the arylated product was obtained as the sole

product. Increasing the amount of Cu(OMe)2 gave increased yields of the

arylated product. In the presence of 1 mol% Cu(OMe)2 as the co-catalyst, the

best yield (33%) of C1-arylated product was obtained (Table 9.5, entry 3).

134

However, when the loading of Pd(OAc)2 was increased to 5 mol%, N-phenyl

THIQ was obtained as the sole product (Table 9.5, entries 8-10).

Table 9.5 Screening of Ratios of Pd(OAc)2/Cu(OMe)2 in the α-Arylation of

THIQ with Iodobenzenea

NH+ PhI

Pd(OAc)2, Cu(OMe)24.0 equiv KHCO3

H2O, 150oC, 8 h

NH N N+ +

entry Pd(OAc)2 (%)

Cu(OMe)2 (%)

1 2.5 0 13 0 0 2 2.5 0.5 29 4 trace 3 2.5 1 33 8 5 4 2.5 1.5 26 6 8 5 2.5 2 26 3 3 6 2.5 4 26 7 8 7 2.5 10 20 7 7 8b 5 2.5 0 0 0 9b 5 5 0 0 0 10b 5 10 0 0 0

a Reaction conditions: THIQ (1.0 mmol), iodobenzene (2.0 mmol), KHCO3 (4.0 mmol), H2O (0.5 mL) at 150oC for 8 h; 1H NMR yields using mesitylene as an internal standard. b 16~22% of N-arylated product was obtained instead of the C1-arylated product.

It is well known that ligand has a very important effect on the transition

metal catalyzed reaction. However, applying ligands such as PPh3, PCy3,

P(OEt)3, dppf, dppe, dppp, dppb, bipy, TMEDA afforded the desired product in

inferior yields.

To further increase the yield of the arylation of THIQ, we decided to test

other aryl halides which are also frequently used in the transition metal

catalyzed cross coupling reaction. Unfortunately, PhOTs, PhOTf, PhCl did not

gave any arylated product (Table 9.6, entries 1, 2, and 4). PhBr and electron-rich

aryl iodide p-MeOC6H4I afforded the arylated product with less yields (Table

135

9.6, entries 3 and 5). To our surprise, switching the ArX to electron-deficient

iodide p-AcC6H4I afforded no arylated product either (Table 9.6, entry 6). These

results indicated that our oxidative arylation process might be very sensitive to

the reaction conditions and at the meantime; the optimized conditions for

different substrates might vary from case to case.

Table 9.6 Tests of Ar-X in the α-Arylation of THIQa

NH+ ArX

2.5 mol% Pd(OAc)21.0 mol% Cu(OMe)2

4.0 equiv KHCO3

H2O, 150oC, 8 h NH

Ar

entry ArX yieldb (%) 1 PhOTs NP 2c PhOTf NP 3 PhBr 14 4 PhCl NP 5 p-MeOC6H4I 18 6 p-AcC6H4I NP

a Reaction conditions: THIQ (1.0 mmol), ArX (2.0 mmol), Pd(OAc)2 (0.025 mmol), Cu(OMe)2 (0.01 mmol), KHCO3 (4.0 mmol), H2O (0.5 mL) at 150oC for 8 h. b 1H NMR yields using mesitylene as an internal standard. c Formation of PhOH as a result of hydrolysis from PhOTf was observed. NP=No Product.

9.3 –Discussion and Proposed Reaction Mechanism

Based on the information we obtained during the optimization of the

reaction conditions, we proposed the following mechanism. First, Pd(OAc)2

coordinates with the nitrogen on THIQ to form the intermediate 9e. β-Hydride

elimination then occurs to give the 3,4-dihydroisoquinoline 9f as the precursor

of the imine insertion. The so-formed HPdOAc from β-hydride elimination will

then undergo a reductive elimination to give the Pd(0) as an active catalyst for

the oxidative addition with PhI. After the formation of the PhPd(II)I, Cu(OMe)2

will do an ion-exchange with PhPd(II)I to afford PhPd(II)OMe 9g. The Pd(II) in

the so-formed PhPd(II)OMe intermediate is more cationic than the PhPd(II)I

counterpart due to the fact the OMe anion is a harder base than the I anion. As a

136

result, this cationic PhPd(II)OMe intermediate coordinates with 3,4-

dihydroisoquinoline to give intermediate 9h through dative bond. Imine

insertion then occurs to give the Pd complex 9i. Finally, hydrolysis gives 1-

phenyl-1,2,3,4-tetrahydroisoquinoline 9k as the arylated product and reproduce

the Pd(II) catalyst. It is necessary to point out that in the last step of hydrolysis,

the intermediate 9i could also undergo β-hydride elimination to give 1-phenyl-

3,4-dihydroisoquinoline 9j as the byproduct.

Pd(OAc)2

N

Ph-Pd(I

I)-OMe

NPd(II)OMe

Ph

Cu(OMe)2Ph-I

Ph-Pd(II)-I

Pd(0)Ph-Pd(II)

NH

NPd(II)OAc

N

Cu(OMe)I

OMe

HOAc

HPd(II)OAc

HOAc

2 HOAc

NH

Ph

+ MeOH

HPd(II)OMe

N

Ph9e

9h

9i

9f

9g

9j

9k

MeOH

Cu(OMe)2 + HI

Scheme 9.4 Proposed Arylation Mechanism

9.4 –Experimental Section

Chemicals were purchased from Aldrich Chemicals Company and Acros

Chemicals, and were used without further purification. 1H NMR and 13C NMR

spectra were acquired with Varian 400 MHz and 100 MHz.

137

General procedure for the reaction of 1,2,3,4-tetraisoquinoline(THIQ) with

iodobenzene

To a 10 mL microwave reaction tube, 200 mg KHCO3, 2.2 mg Pd(OAc)2 and

0.7 mg Cu(OMe)2 and 0.4 mL H2O were successively added, the mixture was

stirred for 1 min. Then 67 µL THIQ and 113 µL iodobenzene were added, the

reaction tube was then sealed and heated to 150oC for 8 h. To separate the

product, a TLC plate pre-treated with TEA was used (eluent: EA/Hexanes=1/5).

NH

1-Phenyl-1,2,3,4-tetrahydroisoquinoline10 1H NMR (400 MHz, CDCl3, ppm): δ 2.90-3.00 (m, 1H), 3.10-3.20 (m, 1H),

3.20-3.25 (m, 1H), 3.30-3.35 (m, 1H), 4.03 (s, 2H), 5.49 (s, 1H), 6.69 (d, J=7.9

Hz, 1H), 7.11 (t, J =6.1 Hz, 1H), 7.20-7.25 (m, 2H), 7.30-7.45 (m, 5H); 13C

NMR (100 MHz, CDCl3, ppm): δ 138.9, 133.0, 132.9, 129.5, 128.9, 128.8,

128.2, 128.2, 127.6, 126.6, 59.9, 39.5, 26.6.

N

1-Phenyl-3,4-dihydroisoquinoline11 1H NMR (400 MHz, CDCl3, ppm):δ 2.81 (t, J=7.6 Hz, 2H), 3.86 (t, J=7.6Hz,

2H), 7.25-7.29 (2H, m), 7.37-7.45 (5H, m), 7.59-7.61 (2H, m); 13C NMR (100

MHz, CDCl3, ppm): δ 165.7, 138.6, 138.6, 130.7, 129.3, 128.5, 128.1, 128.0,

127.6, 127.1, 126.7, 47.1, 25.6.

138

N

1-Phenyl-isoquinoline11 1H NMR (400 MHz, CDCl3, ppm):δ 8.62 (d, J=5.6 Hz, 1H), 8.11 (d, J=8.8 Hz,

1H), 7.90 (d, J=8.4 Hz, 1H), 7.65-7.72 (m, 4H), 7.50-7.56 (m, 4H); 13C NMR

(100 MHz, CDCl3, ppm): δ 160.9, 142.4, 139.8, 137.1, 130.2, 130.1, 128.8,

128.6, 127.8, 127.4, 127.2, 126.9, 120.1.


1. Basle, O.; Li, C.-J. Green Chem. 2007, 9, 1047.



4. Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997.






10. Bender, C.; Liebscher, J. ARKIVOC 2009, vi, 111.

11. Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.

139

Conclusions and Claims to Original Knowledge

Through the use of oxidative coupling strategy, we have demonstrated

that secondary amines derived from glycine could be integrated into the Cross-

Dehydrogenative-Coupling (CDC) reaction. Specifically, N-acetyl glycine esters

could be coupled with malonates using Cu(OAc)2 as the oxidant, di(2-pyridyl)

ketone as the ligand; N-PMP glycine amide, including short peptides could be

coupled with aryl alkynes, indoles, aryl boronic acids using TBHP as the

oxidant and CuBr as the oxidant. For the dehydrogenative coupling of N-PMP

glycine derivatives, we found that the amide derivatives are much more reactive

than the ester derivatives. While a variety of protocols have been reported for

the functionalization of peptide derivatives, the methodology reported in this

thesis represents one of the few examples in which site-specific modification

could be achieved without influncing other stereocenters.

At the meantime, we have also demonstrated that the

tetrahydroisoquinoline could be coupled with iodobenzene at the C-1 position.

This example presents a useful pathway to arylate the α-position of a secondary

amine via a β-hydride elimination followed by imine insertion process.

A copper-catalyzed three-component coupling between alkynes,

aldehydes and hydroxylamine was developed to synthesize β-lactam. This

reaction was found to be very efficient and atom economical with water being

the only by-product. This transformation is believed to occur through a tandem

imine formation and Kinugasa reaction.

The above-mentioned chemistry contributes potentially practical

methodologies to α-functionalize important secondary amine compounds.

Future work include expanding the scope of substrate to glycine units inside a

peptide, application of the CDC reaction to aqueous media, and increase the

efficiency of α-arylation of tetrahydroisoquinoline derivatives.

The work from this thesis produced the following publications:

140

1. Zhao, L.; Li, C. J. Synlett 2009, 18, 2953-2956.

2. Zhao, L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4106-4111.

3. Zhao, L.; Li, C.-J. Angew. Chem. Int. Ed. Engl. 2008, 47, 7075-7078.

4. Stuible, M.; Zhao, L.; Aubry, I.; Schmidt-Arras, D.; Bohmer, F. D.; Li, C.-J.; Tremblay, M. L. ChemBioChem 2007, 8, 179-186.

5. Zhao, L.; Li, C.-J. Chem.-Asian J. 2006, 1, 203-209.

141

Supplementary Material

Synthesis of Thioxothiazolidinone Derivatives-Cellular Inhibitor of Protein Tyrosine

Phosphatase 1B (PTP1B)

S.1 – Background

The control of cellular tyrosine phosphorylation levels requires the precise

balance of protein tyrosine kinase (PTK) and phosphatase (PTP) activities. Similar to the

expression of oncogenic PTKs,1 nonspecific inhibition of PTPs results in a massive

increase in cellular phosphotyrosine content.2 The human PTP superfamily consists of

over 100 cysteine-dependent enzymes.3 They contain a range of noncatalytic motifs and

domains that typically mediate protein–protein interactions or target PTPs to particular

subcellular compartments.3 Individual PTPs play specific roles in cellular signal

transduction, including the regulation of metabolic and mitogenic signaling, cell adhesion

and migration, and gene transcription. The mutation or genetic ablation of PTPs in mice

causes generally adverse phenotypes, often involving immune4,5 or neuronal development

effects.6,7 However, one notable exception is PTP1B (EC 3.1.3.48). Mice lacking this

enzyme are healthy and display resistance to diet-induced diabetes and obesity,8,9 this is

likely to be due to its function as a negative modulator of insulin10 and leptin11 signaling.

This phenotype generated interest in PTP1B as a drug target for type II diabetes. Indeed,

numerous small-molecule PTP1B inhibitors with varying specificity and cell-

permeability have been reported.12,13

The PTP catalytic mechanism involves nucleophilic attack by an anionic cysteine

residue on the phosphotyrosyl phosphate group.14 This cysteine, part of the PTP signature

motif, HC(X)5R, is situated at the base of a flexible active site pocket. By

crystallography, similar binding interactions have been reported for PTP1B in complex

with phosphotyrosine and peptide substrates.15-17 Specifically, the phenyl ring of the

substrate phosphotyrosine forms aromatic–aromatic interactions with Y46, at one side of

the pocket, and F182, which is part of the flexible WPD loop that closes over substrates

upon binding. In addition, extensive hydrogen bond interactions occur between the

142

negatively charged phosphate group and residues within the active site pocket. Rational

design and library screening projects for PTP1B inhibitors have identified several

nonhydrolyzable phosphotyrosine analogs or mimetics, including aryl

difluoromethylenephosphonates (DFMP)18 and N-aryl oxamic acid derivatives.19 These

compounds commonly bear one or more negative charges, and additional charged

moieties have been included to target a secondary phosphate binding site unique to

PTP1B and the closely related TCPTP.15 Despite achieving excellent (low nanomolar)

potency in vitro,20,21 these charged compounds have poor cell permeability and often

require additional strategies, such as prodrug esterification22,23 or fatty acid

conjugation,24,25 to improve cellular activity.

At the very beginning, Trembly and co-workers at the McGill Cancer Centre and

Department of Biochemistry indentified compound a as an uncharged competitive

PTP1B inhibitor (IC50: 5.4±0.8 µM) by in vitro screening of a chemical library at Kinetek

Pharmaceuticals (Vancouver, Canada). In order to understand how the functional groups

on the leading compound influence the cellar inhibition activity, a series of derivatives

with alternations of four functional groups needed to be synthesized.

Cl

N S

O

S

O

OHNO2

a

IC50: 5.4±0.8 µM

Figure S.1 Leading Compound for the Uncharged PTP1B Inhibitor Family S.2 – Synthesis of the Thioxothiazolidinone Derivatives and Study of Their

Inhibition Activities Towards PTP1B In order to understand the effect of the substituents on the leading compound, we

decide to alter the position and change the substituents on both aromatic rings in the

substrate.

The synthesis of the thioxothiazolidinone is straightforward (Scheme S.1).

Reaction between di-(carboxymethyl)-trithiocarbonate d and aryl amines c affords the 3-

143

aryl-rhodanine e. Subsequent condensation between the rhodanine derivative with

aldehyde gives the thioxothiazolidinone produc.

NH2R1

HOOC S S COOH

S+ N S

O

SR1

CHOR2

N S

O

SR1 R2

c d e

Scheme S.1 Synthesis of Thioxothiazolidinone

Previously, a series of azolidinedione derivatives were reported to have PTP1B

inhibitory activity in vitro, and antihyperglycemic properties in murine models of

diabetes.26 These compounds generally consisted of a singly substituted azolidinedione

ring, an aliphatic spacer, and one or more aromatic groups. However, a detailed enzyme

kinetic analysis of these inhibitors was not performed. Since compound a contains a

similar thioxothiazolidinone ring that is doubly substituted, we prepared compound b,

which lacks the additional chlorophenyl substituent. The IC50 value of compound b for

PTP1B (55±5 µM) was more than tenfold higher than compound a, indicating that the

chlorophenyl substituent is essential, and that the binding mode of compound a is likely

to be distinct from the previously reported compounds.

Cl

N S

O

S

O

OHNO2

a

HN S

O

S

O

OHNO2

b

IC50: 5.4±0.8 µM IC50: 55±5 µM

Figure S.2 Comparison of Cellular Inhibition between a and b Subsequently, a variety of the thioxothiazolidinons with different substitutions on

the monosubstituted ring were synthesized and tested for their activities: removal of the

chloro substituent (Table S.1, entry 1) increases the IC50 to over 100 µM. However the

position of the substitution is not critical, since a p-chlorophenyl derivative (Table S.1,

144

entry 2) was as potent as compound e (m-chlorophenyl). Furthermore, derivatives bearing

substituents of different hydrophobicity and electro-negativity at these two positions

retain considerable activity (Table S.1, entries 3-10). In particular, a range of substituents

were well tolerated at the para position: derivatives bearing methyl, methoxy, and nitro

groups gave IC50 values of less than 10 µM. Therefore, while a 2’ or 3’ substituent is

required, derivatives with a variety of functional groups at these positions remain active.

Table S.1 Chemical Structures and IC50 Values of Monosubstituted Ring Derivatives for

PTP1B

compound No. R1 R2 IC50 (µM) (PTP1B) 1 H H >100 2 H Cl 5.4±0.8 3 F H 12±1 4 CH3 H 29±3 5 OCH3 H 16±1 6 H OH 29±1 7 H CH3 8.8±0.1 8 H OCH3 6.3±0.3 9 H NO2 7.0±1 10 Cl Cl 7.0±0.7

The trisubstituted phenyl ring contains hydrogen bond acceptors that could

mediate the active site interactions found in most PTP1B–substrate and PTP1B–inhibitor

complexes. Removal of the methoxy or nitro groups from this ring (Table S.2, entries 1

and 2) reduced potency considerably (Table S.2, IC50>40 µM). Derivation of the methoxy

to a hydroxyl group (Table S.2, entry 3) resulted in only a modest loss of activity, while a

dimethoxy derivative lacking the nitro group (Table S.2, entry 4) did not show significant

inhibition of PTP1B at 100 µM. Interestingly, the derivative in which the nitro group was

replaced with a bioisosteric carboxyl group (Table S.2, entry 5) had only slightly reduced

activity compared to compound 1. However, replacement with a methylene phosphonate

group (Table S.2, entry 6) at this position resulted in a dramatic loss of activity. The

145

effect of alterations in the central linker structure between the two substituted phenyl

rings was also investigated (data not shown). Replacement of the extracyclic sulfur of the

thioxothiazolidinone ring with oxygen had little effect. However, linkers consisting of

various five-, or six-membered rings, such as imidazolidinedione and tetrahydropyridine,

resulted in dramatically decreased activity (no inhibition at 50 µM). Thus, the

thioxothiazolidinone core is also an important structural component of compound a.

Table S.2 Chemical Structures and IC50 Values of Trisubstituted Ring Derivatives for

PTP1B

compound No. R1 R2 R3 IC50 (µM)

(PTP1B) 1 H OH NO2 68±6 2 OMe OH H 44±6 3 OH OH NO2 18.1±0.4 4 OMe OMe H No Inhibition 5 OMe OH COOH 7.3±0.5 6 OMe OH CH2PO(OH)2 >100

S.3 – Conclusion In conclusion, various thioxothiazolidinone derivatives were synthesized and

tested for the cellular inhibition activities of protein tyrosine phosphatase 1B.

S.4 – Experimental Section Chemicals were purchased from Aldrich Chemicals Company and Acros Chemicals, and

were used without further purification. All experiments were carried out without inert gas

protection. Flash column chromatography was performed over SORBENT silica gel 30-

60 µm. 1H NMR and 13C NMR spectra were acquired with Varian 400 MHz and 100

146

MHz, or 300 MHz and 75 MHz, respectively. MS data were obtained by using KRATOS

MS25RFA Mass Spectrometer. HRMS-ESI measurements were performed at McGill

University.

Synthesis of 5-formyl-2-hydroxy-3-methoxybenzoic acid:27

2.1 g (0.0125 mol) 2-Hydroxy-3-methoxybenoic acid was dissolved in 20 mL CF3COOH,

and 1.75 g (0.125 mol) hexamethylenetetramine was added with stirring. After heating

under reflux for 3 h, the CF3COOH was removed under diminished pressure and the

residue poured into a mixture of 25 mL (2 N) HCl and 15 mL ether. This mixture was

stirred at room temperature for 2 h, and after standing overnight; the solid product was

collected and recrystallized from EtOH-H2O to give 0.9 g (37%) of 5-formyl-2-hydroxy-

3-methoxybenzoic acid.

General procedure for the synthesis of 3-aryl-rhodanine derivatives:28

To 115 mg (0.5 mmol) of di-(carboxymethyl)-trithiocarbonate in 2 mL of water, 0.5

mmol aryl amine was added. The test tube was sealed and heated at 100oC overnight. The

precipitate was then collected, washed with cold water and extracted with 5 mL EtOAc.

The crude rhodanine derivative was obtained after removal of EtOAc in vacuo and used

without further purification.

General procedure for the synthesis of thioxothiazolidinone derivatives:29

NS

O

S

CHOR2

R1 NS

O

SR2

R1 +NaOAc/HOAc

120oC, 2 h

In a test tube, 0.25 mmol of rhodanine derivative and 0.25 mmol of aryl aldehyde were

combined. 1 mL AcONa/AcOH (40 mg/mL) was then added. The tube was capped and

stirred at 120°C for 2 h. At this point, the solution turned clear. Heating was stopped and

147

5 ml water was added. Yellow precipitate was thus formed. Finally, filtration of the

solution in vacuo gave the desired thioxothiazolidinone product.

(yield: 78%) 1H NMR (300 MHz, DMSO-d6): δ 7.83 (s, 1H), 7.78 (d, J=2.0 Hz, 1H),

7.62-7.57 (m, 3H), 7.51 (d, J=2.0 Hz, 1H), 7.44-7.42 (m, 1H), 3.96 (s, 3H); 13C NMR (75

MHz, DMSO-d6): δ 193.6, 167.3, 151.1, 147.1, 138.1, 137.1, 134.0, 132.5, 131.6, 130.3,


C17H10ClN2O5S2 ([M-H]) m/z: 420.9725; found m/z: 420.9725.

(yield: 80%) 1H NMR (300 MHz, DMSO-d6): δ 7.64 (s, 1H), 7.57 (s, 1H), 7.37 (s, 1H),

3.92 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 199.5, 170.3, 153.1, 144.2, 137.6, 136.8,

129.9, 120.5, 118.2, 115.0, 57.4; HRMS exact mass calc’d for C11H7N2O5S2 ([M-H]) m/z:

310.9802; found m/z: 310.800.

(yield: 73%) 1H NMR (300 MHz, CD3Cl): δ 11.06 (s, 1H) 7.93 (d, J=2.0 Hz, 1H), 7.69

(s, 1H), 7.61-7.53 (m, 3H), 7.28 (d, J=8.0 Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 4.05 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.7, 167.4, 150.9, 146.4, 137.9, 135.8, 132.2, 130.2,


C17H11N2O5S2 ([M-H]) m/z: 387.0115; found m/z: 387.0115.

(yield: 78%) 1H NMR (300 MHz, DMSO-d6): δ 7.78 (s, 1H), 7.74 (s, 1H), 7.62 (d, J=8.0

Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO-

d6): δ 193.7, 167.3, 151.1, 147.0, 138.0, 134.9, 134.7, 132.4, 131.4, 130.1, 123.0, 121.9,

148

120.3, 116.7, 57.3; HRMS exact mass calc’d for C17H10ClN2O5S2 ([M-H]) m/z: 420.9725;

found m/z: 420.9724.

(yield: 65%) 1H NMR (300 MHz, DMSO-d6): δ 11.50 (s, 1H, br), 7.82 (s, 1H), 7.77 (d,

J=1.6 Hz, 1H), 7.60 (q, J=7.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.41-7.37 (m, 2H), 7.29

(d, J=8.4 Hz, 1H), 3.96 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.6, 167.2, 150.7,

145.6, 138.1, 137.2, 137.1, 132.1, 131.7, 131.6, 126.0, 126.0, 123.9, 122.6, 119.6, 117.5,

117.3, 117.2, 116.9, 57.5; HRMS exact mass calc’d for C17H10FN2O5S2 ([M-H]) m/z:

405.0021; found m/z: 405.0021.

(yield: 72%) 1H NMR (300 MHz, CD3Cl): δ 11.01 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.66

(s, 1H), 7.43(t, J=8.0 Hz, 1H), 7.31(d, J=7.6 Hz, 1H), 7.23(d, J=2.0 Hz, 1H), 7.07-7.05

(m, 2H), 4.04 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.7, 167.5,

151.0, 146.6, 139.6, 138.0, 135.8, 132.2, 130.8, 129.8, 129.6, 126.4, 123.3, 122.1, 120.1,

116.9, 57.4, 21.5; HRMS exact mass calc’d for C18H13N2O5S2 ([M-H]) m/z: 401.0271;

found m/z: 401.0272.

(yield: 81%) 1H NMR (300 MHz, CD3Cl): δ 11.04 (s, 1H, br), 7.94 (d, J=1.6 Hz, 1H),

7.68 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.05 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.88-

6.81 (m, 2H), 4.05 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.7, 167.5,

160.4, 151.0, 146.6, 139.6, 138.0, 133.8, 129.8, 129.6, 122.1, 120.5, 120.1, 117.4, 116.9,

104.7, 57.5, 56.4; HRMS exact mass calc’d for C18H13N2O6S2 ([M-H]) m/z: 418.0293;

found m/z: 418.0294.

149

(yield: 86%) 1H NMR (300 MHz, DMSO-d6): δ 11.04 (s, 1H), 9.91 (s, 1H), 7.78 (d,

J=2.0 Hz, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.12 (dd, J=8.0 Hz, 1.6 Hz, 2H), 6.88 (dd,

J=8.0 Hz, 1.6 Hz, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.7, 167.3,

151.1, 147.9, 138.1, 134.7, 134.4, 132.4, 131.3, 130.1, 123.3, 122.2, 120.3, 115.7, 57.4;

HRMS exact mass calc’d for C17H11N2O6S2 ([M-H]) m/z: 403.0064; found m/z: 403.0064.


(s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 2H), 4.05 (s,

3H), 2.45(s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.8, 167.5, 150.5, 145.5, 139.9,

138.0, 133.1, 131.9, 130.5, 129.1, 124.1, 122.7, 119.6, 117.3, 57.4, 21.5; HRMS exact

mass calc’d for C18H13N2O5S2 ([M-H]) m/z: 401.0271; found m/z: 401.0270.


(s, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 4.04 (s,

3H), 3.86 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 194.1, 167.5, 160.4, 150.8, 145.9,

138.1, 132.0, 130.5, 128.1, 123.8, 122.5, 119.8, 117.1, 115.2, 57.4, 56.1; HRMS exact

mass calc’d for C18H13N2O6S2 ([M-H]) m/z: 417.0220; found m/z: 417.0222.

(yield: 86%) 1H NMR (300 MHz, DMSO-d6): δ 8.40 (d, J=8.4 Hz, 2H), 7.84 (s, 1H),

7.79-7.76 (m, 3H), 7.47 (s, 1H), 3.95 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.4,

167.2, 151.4, 148.5, 148.0, 141.5, 138.1, 132.9, 131.3, 125.2, 122.4, 121.3, 120.8, 116.4,

150

57.3; HRMS exact mass calc’d for C17H10N3O7S2 ([M-H]) m/z: 431.9966; found m/z:

431.9966.


(s, 1H), 7.63 (d, J=12.0 Hz, 1H), 7.42 (d, J=3.2 Hz, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.16

(dd, J=12.0 Hz, 3.2 Hz, 1H), 4.05(s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 193.0, 167.2,

159.7, 155.0, 137.5, 136.1, 135.5, 133.0, 132.2, 131.9, 131.8, 130.3, 126.1, 114.7, 114.5,

112.0, 56.4; HRMS exact mass calc’d for C17H9Cl2N2O5S2 ([M-H]) m/z: 454.9335; found

m/z: 454.9338.

(yield: 68%) 1H NMR (300 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.84 (s, 1H), 7.81 (dd,

J=9.2 Hz, 1.6Hz, 1H), 7.62-7.58 (m, 3H), 7.44-7.39 (m, 1H), 7.29 (d, J=9.2 Hz, 1H); 13C

NMR (75 MHz, DMSO-d6): δ 194.0, 167.4, 154.9, 138.4, 137.2, 136.6, 134.0, 131.8,


C16H8ClN2O4S2 ([M-H]) m/z: 390.9619; found m/z: 390.9616.

(yield: 70%) 1H NMR (300 MHz, DMSO-d6): δ 10.10 (s, 1H, br), 7.75 (s, 1H), 7.58 (m,

3H), 7.41 (m, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.16 (dd, J=1.6 Hz, 8.8 Hz, 1H), 6.94 (d,

J=8.8 Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 194.2, 167.5, 151.1,

148.9, 137.3, 134.7, 134.0, 131.6, 130.2, 129.7, 128.6, 126.0, 125.1, 119.2, 117.2, 115.3,

56.4; HRMS exact mass calc’d for C17H11ClNO3S2 ([M-H]) m/z: 375.9874; found m/z:

375.9870.

151

(yield: 85%) 1H NMR (300 MHz, DMSO-d6): δ 10.90 (s, br, 2H), 7.79 (s, 1H), 7.75 (s,

1H), 7.60-7.56 (m, 3H), 7.42-7.38 (m, 1H), 7.28 (s, 1H); 13C NMR (75 MHz, DMSO-d6):

δ 193.6, 167.4, 153.7, 151.5, 137.4, 136.9, 134.3, 134.0, 131.5, 130.2, 129.6, 128.6,

123.4, 118.7, 117.8, 114.3; HRMS exact mass calc’d for C16H8ClN2O5S2 ([M-H]) m/z:

406.9569; found m/z: 406.9567.

(yield: 75%) 1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.62-7.56 (m, 3H), 7.44-

7.41 (m, 1H), 7.29-7.27 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H); 13C

NMR (75 MHz, DMSO-d6): δ 194.6, 167.5, 151.7, 150.4, 137.3, 134.9, 134.0, 131.6,

130.2, 129.7, 128.6, 126.0, 125.8, 119.5, 117.0, 115.1, 56.4, 56.6; HRMS exact mass

calc’d for C18H13ClNO3S2 ([M-H]) m/z: 392.0176; found m/z: 392.0176.

(yield: 82%) 1H NMR (300 MHz, DMSO-d6): δ 7.79 (s, 1H), 7.67 (d, J=2.0 Hz, 1H),

7.61-7.56 (m, 3H), 7.44 (d, J=2.0 Hz, 1H), 7.43-7.40 (m, 1H), 3.86 (s, 3H); 13C NMR (75

MHz, DMSO-d6): δ 193.6, 173.2, 172.5, 152.1, 147.5, 138.1, 137.1, 134.0, 132.5, 131.6,


C18H11ClNO5S2 ([M-H]) m/z: 419.9773; found m/z: 419.99783.

(yield: 62%) 1H NMR (300 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.59-7.54 (m, 3H), 7.41-

7.38 (m, 2H), 7.02-6.98 (m, 2H), 3.79 (s, 3H), 2.83 (d, J=18.8 Hz, 2H); 13C NMR (75

MHz, DMSO-d6): δ 194.3, 167.5, 151.9, 150.4, 137.4, 135.3, 133.9, 131.5, 130.2, 129.7,

152

128.6, 126.3, 125.4, 123.7, 120.4, 118.3, 113.1, 56.4, 37.8 (d, J=143 Hz); HRMS exact

mass calc’d for C18H14ClNO6PS2 ([M-H]) m/z: 469.9694; found m/z: 469.9692.

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Functionalization of the C-H Bond Adjacent to a Secondary Nitrogen ...

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