Applications of Asymmetric Catalysis and Green Chemistry ...

APPLICATIONS OF ASYMMETRIC CATALYSIS AND GREEN CHEMISTRY

PRINCIPLES TOWARDS THE SYNTHESIS OF CHIRAL MULTIFUNCTIONAL

ALCOHOLS AND ORGANOFLUORINE COMPOUNDS

A Dissertation

submitted to the Faculty of the

Graduate School of Arts and Sciences

of Georgetown University

in partial fulfillment of the requirements for the

degree of

Doctor of Philosophy

in Chemistry

By

Menachem S Moskowitz, M.S.

Washington, D.C.

December 21, 2018

ii

Copyright 2018 by Menachem S Moskowitz

All Rights Reserved

iii

APPLICATIONS OF ASYMMETRIC CATALYSIS AND GREEN CHEMISTRY PRINCIPLES

TOWARDS THE SYNTHESIS OF CHIRAL MULTIFUNCTIONAL ALCOHOLS AND

ORGANOFLUORINE COMPOUNDS

Menachem S Moskowitz, M.S.

Thesis Advisor: Christian Wolf, Ph.D.

ABSTRACT

Asymmetric reaction development and synthesis of chiral building blocks are fundamental to

the pharmaceutical and agrochemical sciences. Specifically, the field of asymmetric catalysis has

amassed a growing body of reactions that permit the stereoselective introduction of complex

functionalities into organic compounds. In this dissertation, the optimization of two

enantioselective reactions catalyzed by a readily available chiral catalyst was achieved. It was

shown that the asymmetric Reformatsky reaction between ethyl iodoacetate and aldehydes in the

presence of a bisoxazolidine ligand, dimethylzinc and air produces ethyl 3-hydroxy-3-(4-

aryl)propanoates in high yields and in 75 to 80% ee at room temperature within one hour. The

scalable asymmetric addition of ynamides to isatins in the presence of the same ligand and

copper(I) triflate produces novel, highly functional, 3-hydroxy-2-oxoindolines in high yields and

89 to 98% ee in a base-free environment. This reaction simplifies access to multifunctional 3-

hydroxyoxindoles and natural products such as (S)-Chimonamidine.

Green chemistry syntheses that are environmentally benign and address the increasing emphasis

on operational safety, waste minimization and efficiency have become generally important in

recent years. To this end, a highly diastereoselective organocatalytic method that produces 3-

fluoro-3’-hydroxy-3,3’-bisoxindoles in protic solvents at room temperature, without the need of

chromatographic product purification was developed. The reaction occurs within 30 minutes in the

iv

presence 10 mol% of triethylamine as catalyst and the bisoxindole formation can be scaled without

compromising yields and diastereoselectivity.

The successful role of organofluorines and organochlorines in the pharmaceutical and

agrochemical industries requires the development of new synthetic methodologies. An efficient

organocatalytic method that achieves decarboxylative cyanomethylation using cyanoacetic acid

and difluoromethyl and trifluoromethyketones in the presence of catalytic amounts of

triethylamine to give β-hydroxynitriles in 90-99% yields without concomitant water elimination

was accomplished. The reaction protocol is scalable and was extended to an asymmetric Mannich

reaction with a tert-butylsulfinyl difluoromethyl ketimine derivative. A mild catalytic procedure

accomplished by detrifluoroacetylative in situ generation of dihalogenated enolates from readily

available geminal diols was developed and used to prepare bromochlorofluoromethyl ketones in

82-98% yield. The synthetic utility of these ketones was showcased with high-yielding

dibromoalkenylations, Wittig and Horner-Wadsworth-Emmons reactions.

As a result of the continuing difficulty with the regulated use of atropisomeric compounds, a

chiral DHPLC study was undertaken. The on-column enantiomerization of 1-(o-tolyl)naphthalene

and 2-cyclohexyl-2’-dimethylaminobiphenyl between 10 °C and 35 °C, generating characteristic

HPLC elution profiles was investigated. Computer simulation of the experimentally obtained

chromatograms allowed determination of the Gibbs free energies of activation, ΔG‡, as 93.2 kJ/mol

and 88.4 kJ/mol, respectively.

v

ACKNOWLEDGEMENTS

With characteristic consistency Dr. Christian Wolf has provided from the first day to the last

day of my tenure support, guidance and direction at every juncture. Through his encouragement,

this work was made possible even in the face of personal hardships. I would like to express my

appreciation and gratitude for the opportunities afforded to me and for the knowledge and

experience imparted to me.

I would like to thank my thesis committee members, Dr. Timothy Warren, Dr. Travis Holman

and Dr. Jennifer Swift for their patience and advice throughout.

Many professors have provided invaluable assistance through their instructive courses and their

personal support. I would especially like to thank Dr. Steven Metallo, the Director of Graduate

Studies, for his tireless efforts in ensuring that graduate students need only concern themselves

with their work.

Current and former group members have helped create an environment in which to grow and

succeed. I would like to give special thanks to Dr. Kimberly Yearick Spangler, Dr. Daniel Iwaniuk,

Dr. Hanhui Xu, Dr. Andrea Cook and Dr. Balaraman Kaluvu without whom this achievement

would not have been possible. Their work provided the foundation for my own and their inspiration

and guidance taught me the patience and focus necessary to achieve success.

There are those individuals who work in the background ensuring that the department runs like

a well-oiled machine. I would like to thank the current and former administrative staff of the

Department of Chemistry, the Graduate School of the Arts and Sciences and Georgetown

University. I want to give special thanks to Ms. Kay Bayne, Ms. Inez Traylor, Ms. Yen Miller,

vi

Ms. Valencia Boyd, Ms. Tabi Lemlem, Ms. Jacquelyn Pruitt, Mr. John Ndiritu, Ms. Nga Le and

Dr. Mohammed Itani.

I would also like to thank the National Science Foundation and the Georgetown Environment

Initiative for providing funding for my work.

Finally, I would like to thank my family and especially my brother Ely for their encouragement

and support through sickness and health. It is a rare circumstance to have ones work and interest

combined into a singular focus. It is even rarer for ones work, interest and family to be united. I

would like to thank my colleague, friend and spouse Yushra Thanzeel for the opportunity of a

lifetime.

vii

TABLE OF CONTENTS

Chapter 1. Trends and Challenges in Medicinal Chemistry ........................................................... 1

1.1. The Importance of Chirality ................................................................................................. 1

1.2. Green Chemistry and Sustainable Processes ...................................................................... 10

1.3. Fluorinated Compounds ..................................................................................................... 15

Chapter 2. Objectives .................................................................................................................... 20

Chapter 3. Bisoxazolidine Catalyzed Enantioselective Reformatsky Reaction ............................ 23

3.1. Introduction ........................................................................................................................ 23

3.2. Results and Discussion ....................................................................................................... 24

3.3. Conclusion .......................................................................................................................... 29

3.4. Experimental Section ......................................................................................................... 29

3.4.1. General Procedures ...................................................................................................... 29

3.4.2. Syntheses and Characterizations ................................................................................. 30

Chapter 4. Organocatalytic Stereoselective Synthesis of Fluorinated 3,3’-Linked Bisoxindoles 36

4.1. Introduction ........................................................................................................................ 36


4.3. Conclusion .......................................................................................................................... 44


viii


4.4.2. Large Scale Synthesis of 3 .......................................................................................... 45


4.4.4. Crystallographic Analysis of Selected Products.......................................................... 55

Chapter 5. Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl- and

Trifluoromethyl Ketones ............................................................................................................... 56

5.1. Introduction ........................................................................................................................ 56


5.3. Conclusion .......................................................................................................................... 63




5.4.3. Crystallographic Analysis of Selected Products.......................................................... 71

Chapter 6. Enantiomerization Kinetics of 2,2’-Disubstituted Biphenyls: A Dynamic Chiral HPLC

Investigation .................................................................................................................................. 72

6.1. Introduction ........................................................................................................................ 72


6.3. Conclusion .......................................................................................................................... 79


ix


6.4.2. DHPLC Characterizations ........................................................................................... 80

Chapter 7. Detrifluoroacetylative Generation of Halogenated Enolates: Practical Access to

Perhalogenated Ketones and Alkenes ........................................................................................... 85

7.1. Introduction ........................................................................................................................ 85


7.3. Conclusion .......................................................................................................................... 93


7.4.1. General Information .................................................................................................... 94


7.4.3. Crystallographic Analysis of Selected Products........................................................ 101

Chapter 8. Catalytic Enantioselective Ynamide Addition to Isatins ........................................... 102

8.1. Introduction ...................................................................................................................... 102

8.2. Results and Discussion ..................................................................................................... 103

8.3. Conclusion ........................................................................................................................ 112

8.4. Experimental Section ....................................................................................................... 113

8.4.1. General Information .................................................................................................. 113

8.4.2. Catalytic Asymmetric Addition of Ynamides to Isatins............................................ 113

8.4.3. Product Syntheses and Characterizations .................................................................. 114

x

8.4.4. Product Derivatization and Characterization............................................................. 127

8.4.5. Crystallographic Analysis ......................................................................................... 134

References and Notes .................................................................................................................. 136

xi

LIST OF FIGURES

Figure 1.1. Structures of Quinine, Progesterone and Penicillin ...................................................... 1

Figure 1.2. Multibillion dollar blockbuster drugs ........................................................................... 3

Figure 1.3. Structures of commercially available statin analogues ................................................ 6

Figure 1.4. Compactin and the evolution of statin analogues ......................................................... 8

Figure 1.5. Structure of Sildenafil................................................................................................. 12

Figure 1.6. Structures of important organofluorine drugs ............................................................ 16

Figure 1.7. Electrophilic fluorinating reagents ............................................................................. 18

Figure 3.1. Structure of bisoxazolidine 4 ...................................................................................... 25

Figure 3.2. Radical generation and subsequent formation of the methylzinc enolate .................. 26

Figure 4.1. Structures of Maxipost and biologically active 3,3’-bisoxindoles ............................. 37

Figure 4.2. X-ray structure of 3,3’-bisoxindole 15 ....................................................................... 41

Figure 4.3. Crystal structure of 3-Fluoro-3'-hydroxy-1,1'-dimethyl-[3,3'-biindoline]-2,2'-dione,

15................................................................................................................................................... 55

Figure 5.1. Structures of CJ-17,493, (+)-ZK 216348, Efavirenz and Eflornithine ....................... 57

Figure 5.2. Crystal structure of 4-Chloro-4,4-difluoro-3-hydroxy-3-phenylbutanenitrile (7) ...... 71

Figure 6.1. Enantiomerization mechanism of axially chiral biaryls ............................................. 74

Figure 6.2. Structures of the biaryls investigated (top) ................................................................. 75

Figure 6.3. Experimentally obtained DHPLC elution profiles with 6 ......................................... 76

xii

Figure 6.4. Experimentally obtained DHPLC elution profiles with 7 ......................................... 77

Figure 6.5. Eyring plots for 6 (left) and 7 (right) .......................................................................... 79

Figure 6.6. DHPLC characterizations of 1-(o-Tolyl)naphthalene, 6 at 35 °C .............................. 81




Figure 6.10. DHPLC characterizations of 2-Cyclohexyl-2’-dimethylaminobiphenyl, 7

at 25 °C ......................................................................................................................................... 83


at 20 °C ......................................................................................................................................... 83


at 15 °C ......................................................................................................................................... 84


at 10 °C ......................................................................................................................................... 84

Figure 7.1. Crystal structure of Benzyl (E)-4-bromo-4-chloro-4-fluoro-3-(naphthalen-2-yl)but-2-

enoate (17) .................................................................................................................................. 101

Figure 8.1. Previous work towards the synthesis of chimonamidine ......................................... 102

Figure 8.2. Chiral ligands used in the asymmetric addition of ynamides ................................... 104

Figure 8.3. Substrate scope of the catalytic asymmetric addition............................................... 109

xiii

Figure 8.4. Crystal structure of (S)-N-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-

dimethylbenzenesulfonamide (16l) ............................................................................................. 134

Figure 8.5. Crystal structure of 3-Hydroxy-1-methyl-3-(2-(methylamino)phenyl)pyrrolidin-2-one

(22a) ............................................................................................................................................ 135

xiv

LIST OF SCHEMES

Scheme 1.1. Racemization of Thalidomide under physiological conditions .................................. 2

Scheme 1.2. Mechanism of action for Omeprazole ........................................................................ 4

Scheme 1.3. Final steps in the total synthesis of Omeprezole ........................................................ 5

Scheme 1.4. Enantioselective synthesis of Esomeprazole from the oxidation of sulfide 13 .......... 5

Scheme 1.5. Rate limiting step in the biosynthesis of cholesterol .................................................. 7

Scheme 1.6. Synthesis of the chiral side chain from L-ascorbic acid ............................................. 9

Scheme 1.7. Paal-Knorr synthesis of Atorvastatin ....................................................................... 10

Scheme 1.8. Catalytic oxidation of primary and secondary alcohols ........................................... 11

Scheme 1.9. Copper catalyzed oxidation of a Rosuvastatin intermediate .................................... 12

Scheme 1.10. Initial synthesis of Sildenafil .................................................................................. 13

Scheme 1.11. Commercial synthesis of Sildenafil........................................................................ 15

Scheme 1.12. Synthesis of fluorinated precursors of gibberellins ................................................ 18

Scheme 1.13. Synthesis of fluticasone propionate........................................................................ 19

Scheme 3.1. Asymmetric Reformatsky reaction using 1 and 2 .................................................... 24

Scheme 3.2. Bisoxazolidine catalyzed Reformatsky reaction with 4-bromobenzaldehyde ......... 26

Scheme 4.1. Synthesis of 3,3’-bridged bisoxindoles 3-17 (only one enantiomer is shown) ........ 40

Scheme 4.2. Additions to N-Boc imine 18 and the Michael acceptor 22 ..................................... 43

xv

Scheme 5.1. Decarboxylative cyanomethylation/condensation of a trifluoromethyl

acetophenone................................................................................................................................. 58

Scheme 5.2. Substrate scope of the cyanomethylation of trifluoromethyl ketones ...................... 61

Scheme 5.3. Decarboxylative cyanomethylation of difluoromethyl ketones ............................... 62

Scheme 5.4. Decarboxylative cyanomethylation of 6 and 8 ......................................................... 63

Scheme 7.1. Synthesis of bromochlorofluoromethyl-derived alcohols, ketones and alkenes ...... 86

Scheme 7.2. Synthesis of 1-aryl 2-chloro-2,4,4,4-tetrafluorobutane-1,3-diones 3-6 by stepwise

chlorination/fluorination of trifluoromethylated 1,3-diones ......................................................... 88

Scheme 7.3. In situ cleavage of 3 and formation of 8 and 9 ......................................................... 89

Scheme 7.4. Copper catalyzed synthesis of bromochlorofluoromethyl ketones 8 and 10-12 ...... 91

Scheme 7.5. Results of dibromoalkenylations (Dr. Balaraman Kaluvu), Wittig and Horner-

Wadsworth-Emmons reactions of bromochlorofluoromethyl ketones. Crystallographic analysis

of 17 shows E-configuration ......................................................................................................... 93

Scheme 8.1. Retrosynthetic analysis for the synthesis of multifunctional 3-hydroxyoxindoles. 103

Scheme 8.2. Reduction of the ynamide-isatin addition products................................................ 110

Scheme 8.3. Synthesis of chimonamidines by the reductive cleavage of the sulfonamide ........ 111

Scheme 8.4. Derivatization of the ynamide-isatin addition product ........................................... 112

xvi

LIST OF TABLES

Table 3.1. Bisoxazolidine catalyzed enantioselective Reformatsky reaction ............................... 27

Table 4.1. Optimization of the organocatalytic C-C bond formation with N-phenyl-3-

fluorooxindole, 1, and isatin, 2 ..................................................................................................... 38

Table 5.1. Optimization of the cyanomethylation of 2,2,2-trifluoroacetophenone ...................... 59

Table 7.1. Optimization of the cleavage/bromination sequence using hydrate 3 ......................... 90

Table 8.1. Screening of the catalytic system for the asymmetric addition of ynamides to

isatins .......................................................................................................................................... 105

Table 8.2. Optimization of Isatin N-substitution, temperature and reaction time ....................... 106

Table 8.3. Optimization of the solvent ........................................................................................ 107

Table 8.4. Screening of chiral bisoxazolidine ligands ................................................................ 108

xvii

LIST OF ABBREVIATIONS

ABNO 9-azabicyclo[3.3.1]nonane N-oxyl

ACN acetonitrile

Ac acetyl

Ar aryl

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene

BINOL 1,1′-binaphthalene-2,2′-diol

Bn benzyl

Boc tert-butyloxycarbonyl

nBu n-butyl

tBu tert-butyl

Bz benzoyl

DABCO 1,4-diazabicyclo[2.2.2]octane

DAST (diethylamino)sulfur trifluoride

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

DHPLC dynamic high performance liquid chromatography

DIPEA N,N-diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DMSO dimethyl sulfoxide

dr diastereomeric ratio

xviii

EDG electron withdrawing group

ee enantiomeric excess

Et ethyl

GC gas chromatography

GMP guanosine monophosphate

cGMP cyclic guanosine monophosphate

HIV human immunodeficiency virus

HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A

HPLC high performance liquid chromatography

HWE Horner–Wadsworth–Emmons reaction

LDL low-density lipoproteins

LHMDS lithium bis(trimethylsilyl)amide

Me methyl

mCPBA meta-chloroperbenzoic acid

NADPH nicotinamide adenine dinucleotide phosphate

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NFSI N-fluorobenzenesulfonimide

NMI N-methylimidazole

NMP N-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

PDE phosphodiesterase

xix

PMP para-methoxyphenyl

i-Pr isopropyl

Ph phenyl

RME reaction mass efficiency

SFC supercritical fluid chromatography

TBAF tetra-N-butylammonium fluoride

TBDMS tert-butyldimethylsilyl

TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl

THF tetrahydrofuran

TLC thin layer chromatography

TMEDA N,N,N′,N′-tetramethylethylenediamine

TMS tetramethylsilane

Tf trifluoromethanesulfonate

Tol toluene

Ts toluenesulfonyl

UV ultraviolet

1

Chapter 1. Trends and Challenges in Medicinal Chemistry

1.1. The Importance of Chirality

Friedrich Wöhler challenged the philosophical idea of vitalism with the synthesis of the

natural product urea and grounded the constituents of living organisms firmly in chemistry.1

Although it took time for the implications of this discovery to be accepted, this past century has

seen the syntheses of an abundance of natural products and pharmaceuticals that are essential to

our quality of life such as 1-3 (Figure 1.1).2 Many synthetic methods have been developed to

improve the biological activity of compounds isolated from nature and to construct entirely new

classes of compounds. Efforts to further refine synthetic methods and to make increasingly

challenging target compounds are ongoing.3

Figure 1.1. Structures of Quinine, Progesterone and Penicillin.

The presence of chirality in many biologically active compounds including agrochemicals,

flavors, fragrances and especially pharmaceuticals, presents a synthetic challenge. Enantiomers

may have dramatically dissimilar physiological effects. The enantiomers of a flavor molecule may

provide an entirely distinct smell and taste. Unfortunately, the difference may be less benign with

one enantiomer acting as a beneficial drug and the other having extremely detrimental effects. This

latter scenario was realized in the pharmaceutical Thalidomide that was administered to pregnant

woman in the 1960s for the relief of morning sickness. While the R enantiomer, 4a, exhibited

2

sedative properties, the S enantiomer, 4b, is teratogenic and caused severe birth defects. In

addition, it was found that the R enantiomer racemizes under physiological conditions causing

severe side effects regardless of which enantiomer is administered (Scheme 1.1).4 This example

underscores the importance of chirality and dynamic stereochemistry and the necessity of synthetic

methodology development for the construction of enantiomerically pure compounds.

Scheme 1.1. Racemization of Thalidomide under physiological conditions.

An analysis of market trends for the production of chiral molecules shows a dramatic

increase in the development of single enantiomer drugs with a concurrent decrease in the marketing

of racemates between 1985 and 2014.5 This is in part due to the increased efficacy and reduced

adverse effects of some single enantiomer drug molecules as well as an increased effort to protect

the consumer through governmental regulations for the marketing of racemates. Among the most

successful multibillion dollar drugs including Pfizer’s Atorvastatin (Lipitor) and AstraZeneca’s

Esomeprazole (Nexium), the majority are sold as single enantiomers (Figure 1.2).6 The synthetic

challenges presented by these two drugs illustrates the difficulties that may be encountered and the

ingenious solutions that were devised.

3

Figure 1.2. Multibillion dollar blockbuster drugs.

Omeprazole (Prilosec) is a proton-pump inhibitor that was marketed in 1988 for the

treatment of acid related diseases such as excessive gastric acid resulting in symptoms ranging

from mild heartburn to life threatening peptic ulcers. The chemical structure contains a chiral

sulfoxide group and the drug was synthesized and sold as a racemate. An in-vitro study of the two

enantiomers showed identical dose-response curves for the inhibition of acid production from

isolated gastric glands. The mechanism of action was well studied and it was found that

omeprazole, 6, behaves as a prodrug that is converted into an achiral sulfenamide, 8, upon exposure

to an acidic environment (Scheme 1.2).7 While this drug was proven to be a success, it also showed

a significant variability in its efficacy amongst a range of individuals with some patients requiring

higher or multiple doses to achieve similar results. After screening several hundred derivatives in

an effort to increase the bioavailability of omeprazole, it was found that only a single compound

surpassed omeprazole in its effectiveness. This compound was Esomeprazole, the S enantiomer of

omeprazole. Even though the active form of the drug is achiral, the enantiomers of the prodrug are

metabolized to different degrees resulting in pharmaceuticals with different therapeutic values.8

4

Scheme 1.2. Mechanism of action for Omeprazole.

This discovery led to the need to develop a means of synthesizing the pure enantiomer of

the chiral sulfoxide. Initial methods to obtain Esomeprazole were accomplished through the

resolution of racemic Omeprazole.9 This process was not economically feasible on an industrial

scale due to the 50% loss of material and the development of an enantioselective synthesis was

required.

In the original total synthesis of Omeprazole,10 the final oxidation makes use of mCPBA

to convert sulfide 1 to the racemic sulfoxide (Scheme 1.3). Under the guidance of Sverker von

Unge, the asymmetric oxidation of sulfide 1 was explored. Building upon the work of Barry

Sharpless for the epoxidation of allylic alcohols, Henri Kagan had developed a modified procedure

for the highly enantioselective oxidation of sulfides to sulfoxides.11 The unmodified Sharpless

reagent resulted in racemic product while the inclusion of one equivalent of water or the use of

two equivalents of diethyl tartrate provided enantioselectivities of up to 93%. Unfortunately, the

use of this method for the oxidation of 1 yielded racemic product. Most reported examples of

sulfide oxidation require the sulfide atom to bear two very differently sized groups which might

5

explain the lack of success with 13. Another important goal was to develop a catalytic method that

would be economically feasible at industrial scales. All current literature procedures required

stoichiometric quantities of the titanium complex.

Scheme 1.3. Final steps in the total synthesis of Omeprezole.

After careful screening of reaction variables, three innovations were introduced that

independently increased the asymmetric induction. The preparation of the titanium complex was

conducted in the presence of 13, the titanium complex was equilibrated at elevated temperatures

and the oxidation was performed in the presence of an amine. The resulting sulfoxide was obtained

catalytically in 92% yield and 94% ee after one hour and with a sulfoxide to sulfone ratio of 76:1.

This remarkable achievement was extended to seven different Esomeprazole analogues (Scheme

1.4).12

Scheme 1.4. Enantioselective synthesis of Esomeprazole from the oxidation of sulfide 13.

6

Atorvastatin (Lipitor) is a member of a class of pharmaceuticals known as statins that have

transformed the field of cardiovascular medicinal care (Figure 1.3).13 The significance of this

achievement can be framed by recognizing that heart disease was reported by the Centers for

Disease Control and Prevention as the leading cause of death within the United States as of 2016.14

Figure 1.3. Structures of commercially available statin analogues.

Since the 1950s, the epidemiological connection between cholesterol in the form of low density

lipoprotein (LDL) and coronary atherosclerosis has been well studied and it was understood that

patients with higher levels of blood cholesterol were more prone to myocardial infarction within a

few years.15 The regulation of cholesterol metabolism within the body proceeds by the suppression

of de novo synthesis when blood levels due to dietary sources meet the required levels. However

even with the excessive ingestion of dietary cholesterol, it was found that liver production still

surpasses this quantity.16 This suggested that the most effective means of lowering the cholesterol

in blood plasma would be the disruption of its biosynthesis using its own feedback mechanism.

Cholesterol synthesis is facilitated by the action of HMG-CoA reductase that catalyzes the rate

limiting transformation of HMG-CoA into mevalonate (Scheme 1.5). Inhibition of this reaction

was targeted since changes in HMG-CoA reductase activity were correlated with the overall rate

of the thirty step synthesis of cholesterol from acetyl-coenzyme.17

7

Scheme 1.5. Rate limiting step in the biosynthesis of cholesterol.

Statins were first isolated as natural products from fungi cultures and showed remarkable

ability at lowering cholesterol. They exhibit motifs structurally similar to HMG-CoA in their acid

form and behave as competitive inhibitors of HMG-CoA reductase. The original statin, Compactin

was abandoned due to issues of toxicity, but its high potency enshrined it as a standard (Figure 1.4,

19).18 Under the direction of A. K. Willard, research towards the development of structurally

simplified synthetic analogues began with an analysis of the structure activity relationships for

various statin derivatives (Figure 1.4, 20).19 While the compounds evaluated in the study only

showed moderate efficacy as drugs, their relative potency provided insight into the structural

features that affected the binding to the enzyme. An analysis of these simplified analogues by B.

D. Roth et al. further suggested that the main feature required for binding was a large lipophilic

group tethered with a specific orientation to a 4-hydroxypyran-2-one scaffold. A pyrrole ring was

selected as the opposing terminus due to the synthetic versatility it would provide with respect to

the introduction of various substituents (Figure 1.4, 21).20 During initial studies, positions 2 and 5

in the pyrrole ring were varied to compare different substitution patterns. Subsequent optimization

at positions 3 and 4 resulted in a compound with an IC50 value of 0.025 µM that slightly improved

upon existing therapeutics such as Merck’s Mevastatin with an IC50 value of 0.030 µM. The drug

8

was synthesized as a racemate with respect to the orientation of the 4-hydroxypyran-2-one and the

breakthrough with regard to its efficacy was only discovered upon its resolution. The (R,R)

enantiomer now marketed as Lipitor showed an IC50 value of 0.007 µM while the (S,S) enantiomer

showed an IC50 value of only 0.44 µM.21

Figure 1.4. Compactin and the evolution of statin analogues.

Similar to the synthesis of Esomeprazole, it was necessary to develop an asymmetric

methodology for the large scale production of Atorvastatin. P. Bower conceived of the molecule

as ultimately the union of two fragments connected by a tether, the pyrrole scaffold and the chiral

side chain. The convergent synthesis of both fragments proceeded from commercially available

starting material and underwent stepwise transformations to obtain the required intermediates. The

initial chirality was incorporated into the side chain by using an enantiopure compound available

from the chiral pool. The construction of the chiral side chain begins with the synthesis of 25 as

documented by M. Sletzinger for the assembly of statin 20.22 The hydrogen peroxide degradation

of L-ascorbic acid, 22, into L-threonic acid, 23, was followed by treatment with hydrobromic acid

and methanol and selective hydrogenolysis yielding compound 25. Protection of 25 with TBDMS

followed by substitution of the bromide with NaCN gave the nitrile 26 after deprotection with

TBAF. A cross-claisen condensation with the preformed lithiated enolate, LiCH2CO2tBu, provided

9

access to β-hydroxyester 27. Diastereoselective reduction in a cryogenic reactor followed by

protection of the chiral diol resulted in the intermediate 28 in >99.5% ee and 100:1 dr.

Recrystallization was used to increase the dr to 350:1.23 Reduction of the nitrile to the amine

resulted in the protected chiral side chain 29.

Scheme 1.6. Synthesis of the chiral side chain from L-ascorbic acid.

The final construction of the pyrrole ring was accomplished by a Paal-Knorr reaction between the

diketone scaffold containing the substitution of the resultant ring and the chiral side chain 29 that

anchors the tethered chiral side chain to the heterocycle (Scheme 1.7).24 This convergent synthesis

features yields greater than 75% at every step, avoids the use of chromatographic purification and

is scalable to ton quantities to meet the needs of a drug with one the highest lifetime sales.

10

Scheme 1.7. Paal-Knorr synthesis of Atorvastatin.

1.2. Green Chemistry and Sustainable Processes

In recent years, synthetic chemists have become increasingly aware of environmental

consequences25 which has led to the development of sustainable processes and green chemistry

guidelines.26 Sustainability mandates that the rate of use for a given resource cannot exceed the

rate at which it is naturally replaced and the generation of waste cannot exceed the rate at which it

is redressed.27 Green chemistry as defined by the Environmental Protection Agency is the

development of products and methods that reduce or exclude the use or production of hazardous

chemicals.28 These two disciplines are not only fields in their own right, but provide guiding

principles applicable to all areas of chemical research.

Despite increasingly stringent worldwide environmental regulations, concerns regarding

the future of our biosphere have continued to rise as well.29 While many scientists have seen the

value in pursuing a greener approach to production, it took years before clearly stated strategies

and tactics emerged.30 In 1998, Paul Anastas and John Warner published the “Twelve Principles

of Green Chemistry” which has eclipsed all other proposals to become enshrined as the defining

guide.31 A consortium of pharmaceutical companies realizing that they share green chemistry

interests sought to foster global collaboration for the development of sustainable methodologies

11

and educational initiatives. The Green Chemistry Institute Pharmaceutical Roundtable was formed

in 2005 and currently includes corporations such as AstraZeneca, Bristol-Myers Squibb,

GlaxoSmithKline, Novartis, Pfizer and many others. Among other accomplishments, they have

supported the development of many green reactions that serve to replace hazardous methods.32

Scheme 1.8. Catalytic oxidation of primary and secondary alcohols.32

A representative example is the oxidation of alcohols to aldehydes and ketones which

traditionally requires toxic and environmentally hazardous chemicals such as chromium salts in

stoichiometric quantities. A range of copper catalysts using either 2,2,6,6-tetramethylpiperidine 1-

oxyl (TEMPO) or 9-azabicyclo[3.3.1]-nonane N-oxyl (ABNO), 33, with air as the stoichiometric

oxidant were developed by Stahl to replace the conventional oxidants (Scheme 1.8).33 This method

was then further improved by the incorporation of the more economical copper iodide and the use

of lower catalyst loadings with its application showcased in the catalytic oxidation of a an

intermediate in the total synthesis of Rosuvastatin (Crestor) (Scheme 1.9).34

12

Scheme 1.9. Copper catalyzed oxidation of a Rosuvastatin intermediate.

It is important to ensure that these green methods are commercially viable on an industrial

scale. The success of this approach can be observed by an analysis of the commercial synthetic

route for the lifestyle drug Sildenafil (Viagra) (Figure 1.5).35 In 1998, both the United States and

the European Union approved the drug Sildenafil for the treatment of male erectile dysfunction

and it has since become one of the fastest selling pharmaceuticals. The drug acts as a

phosphodiesterase (PDE) enzyme inhibitor which is itself responsible for the transformation of

cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). During sexual

stimulation, the release of nitric oxide induces the synthesis of cGMP which reduces the

intracellular Ca2+ ion concentration leading to decreased smooth muscle contractility. By

inhibiting the action of PDE in the hydrolysis of cGMP, Sildenafil enhances the natural action of

nitric oxide and allows for the treatment of any dysfunction in this process.36

Figure 1.5. Structure of Sildenafil.

13

The initial synthesis of Sildenafil used for early clinical trials was an important

achievement, but could not be used at the industrial scale due to a number of concerns including

the use of hazardous materials such as thionyl chloride (Scheme 1.10). Chlorosulfonation of high

molecular weight compounds requires the use of large quench volumes resulting in a large increase

in the production of aqueous waste. The use of SOCl2 in the later synthetic stages also requires

multiple recrystallizations for its removal from the final product which further increases waste

production. The reduction of 39 using SnCl2, the use of SOCl2 as solvent in the amide formation

of 39 and the sheer quantity of chlorinated solvent waste presented additional obstacles towards

the development of a viable commercial synthesis. The largest concern was that this linear total

synthesis resulted in only a 7.5% total yield from 37.35

To combat these issues, a more efficient convergent synthesis was envisioned (Scheme

1.11).26 The SnCl2 reduction was abandoned in favor of a cleaner catalytic hydrogenation of 39,

excess use of thionyl chloride was reduced to stoichiometric amounts in toluene and chlorinated

solvent were entirely eliminated. The use of the early-stage and therefore less expensive material

43 for the chlorosulfonation mitigated losses from hydrolysis during extended quench time.35

Scheme 1.10. Initial synthesis of Sildenafil.26

14

A comparison of the commercial and initial syntheses is striking. For the production of

1000 kg of Sildenafil, the total solvent volume has been reduced from 125,000 L to 13,500 L while

the range of solvents has been reduced from six including dichloromethane to two non-chlorinated

solvents. The volume of aqueous waste produced was decreased by a factor of five and the overall

synthetic yield was increased to 76%. In order to quantify the efficiency and sustainability of these

methods, Reaction Mass Efficiency (RME), the ratio of the mass of product to the mass of reactants

was analyzed.37 The RME was increased from 10% to 26%, more than doubling the efficiency.

The environmental impact was analyzed by calculating the Process Mass Intensity (PMI) which is

defined as the ratio of the total mass of materials to the mass of isolated product.37 This metric is

directly related to the important Environmental Factor (E-factor), where PMI = E + 1, which serves

to provide a quantitative measure to describe the adherence of a process to green chemistry

principles. A comparison of the PMI calculated for the two synthetic routes resulted in a decrease

from an initial value of 134 to 16. Previously, the need for green chemistry had been undeniable,

but feasibility in its implementation had been questioned. The revised synthesis of Sildenafil, with

reported sales of 1.2 billion dollars in 2017 alone, proved that it is a realistic and achievable goal.

15

Scheme 1.11. Commercial synthesis of Sildenafil.26

1.3. Fluorinated Compounds

In the design of medicinal agents with increased efficacy and reduced toxicity,

bioisosterism represents a unique approach that has become prevalent in the pharmaceutical

industry.38 This concept originates from the development of structure activity relationships and

allows for rational modification of existing compounds.39 Bioisosters can be defined as groups of

molecular functionalities that may be exchanged with one another to elicit similar physiological

properties with beneficial deviations.40 Within this field, the introduction of organofluorine

derivatives of natural products and pharmaceuticals has come to dominate one quarter of

manufactured drugs.41 Organofluorine analogues in 2008 included 30% of the most successful

16

drugs on the market42 and have contributed to the treatment of a wide range of diseases including

depression, cancer, bacterial and viral infections and inflammatory diseases (Figure 1.6).43

Figure 1.6. Structures of important organofluorine drugs.

Fluoxetine (Prozac), 48, is an antidepressant marketed for the treatment of obsessive

compulsive disorder and bulimia. These diseases have been linked to low levels of the

neurotransmitter serotonin and this drug acts as a selective serotonin reuptake inhibitor that allows

the neurotransmitter to continue to activate its receptor. In a comparison of Fluoxetine to its non-

fluorinated analogue, the presence of the trifluoromethyl group in the phenolic ring yields a six

time increase in the inhibition of the reuptake mechanism.44 Erythromycin, a highly effective

antibiotic used for the treatment of severe infections, is incompatible with the treatment of gastritis

caused by an infection with Helicobacter pylori. This compound decomposes under the highly

acidic conditions present in the stomach and concentrations of the drug in tissues are too low to be

effective. Flurithromycin (Pharmacia), 49, the fluorinated analogue of Erythromycin, possesses

enhanced stability under acidic conditions resulting in longer biological half-life, higher

bioavailability and increased tissue concentrations.45 Efavirenz (Sustiva), 50, is a reverse

17

transcriptase inhibitor used in the treatment of HIV infections by suppressing replication of the

virus. The trifluormethyl group in the molecule lowers the pKa of the cyclic carbamate N-H which

increases the hydrogen bonding interactions and therefore the binding to the target protein.46 Each

of these drugs presents different mechanisms by which fluorine contributes to superior therapeutic

effects.

Fluorinated functionalities owe their unique properties to the element’s high

electronegativity and small van der Waals radius. With a van der Waals radius of 1.47 Å, the

element has been used to replace both hydrogen and oxygen with radii of 1.20 Å and 1.52 Å,

respectively.47 These fluorinated analogues have been shown to possess greater metabolic stability,

distinct physiochemical properties, increased binding affinity and bioavailability.42 Metabolic

stability is achieved by decreasing the molecule’s vulnerability to oxidation by cytochrome P450

monooxygenases or by reduced reactivity at a metabolically active neighboring site.48 Unique

properties are a direct result of the high electronegativity that can alter the polarity of nearby groups

and induce a conformational bias in the compound. Binding of the molecule with a target protein

is not interrupted due to the similarity in size, but the dissimilarity of the C-F motif may improve

the affinity and selectivity for this interaction by affecting hydrogen bonding interactions. The

effect on pKa and increased lipophilicity can also impact bioavailability by allowing the molecule

to better permeate certain membranes enhancing its absorption and distribution.43 The primary

limitations in the development of fluorine containing drugs are the synthetic challenges they

present.

The pharmaceutical significance of organofluorine compounds has stimulated the

development of novel methods for the construction of fluorinated compounds. The two main

classifications of synthetic methods are direct fluorinations and the use of fluorine containing

18

building blocks.49 Direct methods involve the transformation of a C-H bond into a C-F bond

through the use of either an electrophilic or nucleophilic fluorinating reagent. Nucleophilic

fluorinating reagents can be alkali metal fluorides, tetrasubstituted ammonium salts or

deoxyfluorination reagents such as diethylaminosulfur trifluoride (DAST), 54, (Scheme 1.12). The

latter require careful handling as they are highly reactive.50

Scheme 1.12. Synthesis of fluorinated precursors of gibberellins.51

Electrophilic fluorinating reagents are usually N-fluoro species and behave as a formal source of

F+. Two of the most commonly used reagents are the commercially available Selectfluor and N-

fluorobisphenylsulfonimide (NFSI) (Figure 1.7). The use of building blocks for the construction

of organofluorines theoretically involves traditional chemical transformation, but with the caveat

that the fluorine substitutions tends to introduce uncharacteristic behavior. Reactions that may

work for non-fluorinated analogues may need to be optimized for these substrates.49

Figure 1.7. Electrophilic fluorinating reagents.

19

Fluticasone propionate is a glucocorticoid steroid developed for use against a wide range

of anti-inflammatory diseases.52 It is one of two active ingredients marketed as part of the Advair

Diskus inhaler for the treatment of asthma and it has earned fourth place in the top selling

pharmaceuticals of 2008 with 3.6 billion dollars in sales. It has also been used topically for the

treatment of inflammation in patients with psoriasis and dermatoses.41 The structure contains a

steroid scaffold with three distinct fluorine substituents, two located on chiral centers. The

construction of this organofluorine pharmaceutical uses both types of direct fluorination as well as

the inclusion of fluorine through building blocks (Scheme 1.13). The introduction of fluorine into

58 proceeds through electrophilic fluorination by the reaction of Selectfluor with an in-situ

generated conjugated enol acetate.

Scheme 1.13. Synthesis of fluticasone propionate.41

The addition of the second fluorine into 59 is accomplished by a nucleophilic fluorination of the

epoxide ring with hydrofluoric acid. The third fluorine is introduced to 62 as part of a fluoromethyl

building block to give the final drug 63.

20

Chapter 2. Objectives

The continued development of synthetic methods has allowed chemists to construct natural

products and synthetic analogues with a wide variety of applications in the health and natural

sciences. Often the complex structure displaying several functional groups and chirality centers

creates a major synthetic challenge. The disparity between biological effects of enantiomers

generally requires that drugs be synthesized in enantiopure form. The incorporation of fluorine

into medicinal compounds provides an important means for increasing the efficacy of a drug

without compromising existing interactions. However, the synthesis of organofluorines remains

difficult because the fluorine moiety can drastically affect the reactivity and stability of organic

compounds. The introduction of green chemistry methods presents another challenge. Traditional

methods often include the use of hazardous materials and may generate large amounts of waste.

For environmental protection, it is essential for chemists to develop alternative syntheses that are

sustainable and adhere to green chemistry principles.

The main objectives of this thesis were:

(1) The development of catalytic enantioselective procedures for the synthesis of

important chiral building blocks

a. At the beginning of this work, existing methods for the catalytic enantioselective

Reformatsky reaction were limited to two procedures using commercially available

chiral ligands. It was envisioned that the development of an inexpensive high yielding

procedure with high stereoselectivity would advance this important C-C bond forming

reaction.

21

b. The catalytic asymmetric addition of terminal ynamides had only been accomplished

with aldehydes and trifluoromethyl ketones. Given the synthetic versatility of the

polarized triple bond and the biological significance of 3-hydroxyoxindoles, the

addition of terminal ynamides to isatins would allow new access to biologically

important classes of compounds.

c. Atropisomerism presents unique difficulties in the development of single enantiomer

drugs partly because of the possibility of racemization reactions. DHPLC studies can

illuminate rotational energy barriers that can be used to design confrontationally stable

compounds.

(2) The establishment of synthetic methods using fluorine and other halogen containing

compounds

a. At the onset of this work, the use of cyanomethylation for the synthesis of fluorinated

β-hydroxynitriles was elusive due to uncontrolled formation of elimination products.

The development of a procedure that resolves this issue would provide a route to these

highly functionalized compounds.

b. Perhalogenated compounds are important for the synthesis of future drugs and can

provide an incredible amount of synthetic versatility. A streamlined synthesis of

compounds exhibiting fluorine, chlorine and bromine and the development of their

utility would introduce new building blocks for synthetic chemistry.

22

(3) The application of green chemistry principles towards the development of important

compounds

a. Bisoxindoles represent a biologically significant scaffold and the construction of

fluorinated analogues may expand the existing library of medicinal compounds. The

development of a green synthesis method would provide further momentum towards

safe and environmentally benign production of pharmaceutically relevant targets.

23

Chapter 3. Bisoxazolidine Catalyzed Enantioselective Reformatsky Reactioni

3.1. Introduction

The classical Reformatsky reaction produces β-hydroxy esters through insertion of zinc

into α-halo esters and subsequent nucleophilic addition of the zinc enolate to aldehydes or ketones.

Since its introduction in 1887, this reaction has become one of the most successful carbon-carbon

bond formations and it has found numerous synthetic applications which can certainly be attributed

to its remarkable functional group tolerance and generally mild reaction conditions.53 The advance

of procedures that generate zinc enolates under homogeneous conditions, for example in the

presence of dimethylzinc, set the stage for asymmetric variants.54 Prior to 2008, few examples of

diastereoselective55 and enantioselective56 Reformatsky reactions were known and ee’s obtained

were generally low unless stoichiometric amounts of chiral ligands were used. A breakthrough in

the development of catalytic enantioselective procedures was made when Cozzi and Feringa

reported that ephedrine and BINOL derivatives 1 and 2 effectively catalyze the Me2Zn-promoted

addition of ethyl iodoacetate to aromatic aldehydes in the presence of air or tert-butyl

hydroperoxide which accelerate the zinc enolate generation.57 Employing 25 mol% of N-

pyrrolidinylephedrine and catalytic amounts of triphenylphosphine oxide in the Reformatsky

reaction between ethyl iodoacetate and benzaldehyde, Cozzi’s group obtained ethyl 3-hydroxy-3-

(4-bromophenyl)propanoate, 3, in 40% yield and 84% ee after 100 hours. Feringa et al. were able

to produce 3 in the presence of 20 mol% of 2 in 70% yield and 80% ee (Scheme 3.1).58

i Reproduced with permission from J. Org. Chem. 2011, 76, 6372-6376. Copyright 2011 American Chemical

Society.

24

3.2. Results and Discussion

The synthesis of bisoxazolidine 4 from aminoindanol and cyclohexadione was reported by

Wolf et al. in 2006 and since then several applications of this C2-symmetric N,O-diketal in

asymmetric catalysis have been shown (Figure 3.1).59 This ligand catalyzes the

Scheme 3.1. Asymmetric Reformatsky reaction using 1 and 2.

dimethylzinc-mediated enantioselective alkynylation of a wide range of aldehydes towards

propargylic alcohols with excellent yields and ee’s.60 It has also been used successfully in the

alkylation of aldehydes with Me2Zn and Et2Zn,61 in the asymmetric Henry reaction which can be

performed either in the presence of excess of dimethylzinc or catalytic amounts of copper(I)

acetate,62 in the nitroaldol reaction of trifluoromethyl ketones and α-keto esters and in an

asymmetric Friedel-Crafts reaction.63

25

Based on the success with asymmetric reactions involving organozinc species, it was

decided to introduce 4 into the Reformatsky reaction. During optimization, it was realized that 4-

bromobenzaldehyde is significantly less prone to decomposition than benzaldehyde and is,

therefore, a better choice for method development.

Figure 3.1. Structure of bisoxazolidine 4.

The Reformatsky reaction proved to be very sensitive to unusual parameters, such as the size of

the flask used, the timing of the exposure to air and the addition sequence of dimethylzinc. It is

generally assumed that dimethyl zinc and oxygen generate a methyl radical which initiates the

formation of the Reformatsky reagent (Figure 3.2).64 Since dioxygen has to diffuse into the reaction

mixture to affect the radical process, the subsequent production of the intermediate methylzinc

enolate is dependent on several parameters including flask size and reaction volume which

determine the surface area at the gas-liquid interface. It was found that a change in the parameters

mentioned above and in the rate of addition of the aldehyde or in the amount of ethyl iodoacetate

strongly affect yields. For example, when the amount of ethyl iodoacetate was reduced from two

to one equivalent no product was isolated. Addition of stoichiometric amounts of

trimethoxyborane led to a 10% increase in yield which may be attributed to formation of a borate

complex with the Reformatsky product. This transmetalation process should facilitate catalyst

turnover and avoid interference of the alkoxide formed with the catalytically active zinc complex.

26

By contrast, it was observed that the enantioselectivity of this reaction was considerably less

sensitive and variation of the reaction temperature between 0 and 35 °C did not change ee’s.

Figure 3.2. Radical generation and subsequent formation of the methylzinc enolate.

Careful optimization of solvent, catalyst loading, introduction of air, concentration of ethyl

iodoacetate, amount of dimethylzinc and trimethoxyborane, and the addition sequence of the latter

and the substrate resulted in a procedure that gives ethyl 3-hydroxy-3-(4-bromophenyl)propanoate,

3, in 90% yield and 78% ee (Scheme 3.2). This method involves only 10 mol% of the ligand and

is completed at room temperature within one hour.

Scheme 3.2. Bisoxazolidine catalyzed Reformatsky reaction with 4-bromobenzaldehyde.

The scope of this method was explored by screening various aldehyde substrates (Table

3.1). Benzaldehyde gave ethyl 3-hydroxy-3-(4-bromophenyl)propanoate, 5, in 79% yield and 77%

ee (Table 3.1, entry 1) and similar results were obtained with a range of other aromatic aldehydes.

In general, yields up to 94% were achieved with this method while ee’s varied between 75 and

27

80% (Table 3.1, entries 1-11). Aliphatic substrates gave good yields but low to moderate ee’s even

at reduced temperatures and at higher catalyst loading (Table 3.1, entries 12-14). The results

obtained with both linear and branched aldehydes are comparable with those reported by Cozzi

and Feringa.

Table 3.1. Bisoxazolidine catalyzed enantioselective Reformatsky reaction.a

Entry Substrate Product Yieldb eec

1

5

79 77 (S)

2

6

70 76

3

7

86 78 (S)

4

3

90 76 (S)

5

8

82 79

6

9

79 79

Table 3.1. (Cont.)

28

7

10

83 78

8

11

77 77 (S)

9

12

89 79

10

13

94 80

11

14

77 75

12

15

89 51

13

16

86 36

14

17

75 26

a General reaction conditions: Ethyl iodoacetate (59.1 µL, 0.50 mmol) was added to a solution of bisoxazolidine 4 (9.6

mg, 0.024 mmol) in 5.0 mL of anhydrous Et2O. After 5 min, B(OMe)3 (27.9 µL, 0.25 mmol) and 1.2 M Me2Zn in

toluene (0.85 mL, 1.0 mmol) were added at once, followed by dropwise addition of the aldehyde (0.25 mmol) in 1.0

mL of anhydrous Et2O over 10 min. Within 4 min of the substrate addition, another portion of 1.2 M Me2Zn in toluene

(0.85 mL, 1.0 mmol) was added and the reaction was stirred for 1 h. bIsolated yields. cDetermined by chiral HPLC on

Chiralcel OD and Chiralpak AS or by GC on 6-O-TBDMS-2,3-di-O-methyl-β-cyclodextrin and Lipodex E. Absolute

configurations were determined as described in the literature.57a

29

3.3. Conclusion

In summary, the bisoxazolidine catalyzed asymmetric Reformatsky reaction produces 3-

hydroxy-3-(4-aryl)propanoates in high yields and in 75 to 80% ee at room temperature within one

hour. This method requires only 10 mol% of 4 and the results compare well with previously

reported procedures. However, effective asymmetric induction with aliphatic substrates remains a

challenge and future work is needed to further improve ee’s.

3.4. Experimental Section

3.4.1. General Procedures

All commercially available reagents and solvents were used without further purification.

NMR spectra were obtained at 400 MHz (1H NMR) and 100 MHz (13C NMR). Chemical shifts

are reported in ppm relative to TMS. Reaction products were purified by column chromatography

on silica gel (particle size 32 – 63 μm). Aldehydes were purified prior to use by distillation under

reduced pressure or by flash chromatography on silica gel using 4% ethyl acetate in hexanes as

mobile phase.

A 150 mL three-neck flask was fitted with a CaCl2 drying tube sealed with a stopper.

Bisoxazolidine 4 (9.6 mg, 0.024 mmol) was dissolved in 5.0 mL of anhydrous Et2O at room

temperature, transferred into the flame-dried flask and the solution was stirred for five minutes

under inert atmosphere until ethyl iodoacetate (59.1 µL, 0.50 mmol) was added. After five minutes,

B(OMe)3 (27.9 µL, 0.25 mmol) was added. Then, the reaction was opened to the atmosphere by

removing the stopper from the CaCl2 drying tube. After another five minutes, 1.2 M Me2Zn in

toluene (0.85 mL, 1.0 mmol) was added at once followed immediately by dropwise addition of the

substrate (0.25 mmol) in 1.0 mL of anhydrous Et2O using a syringe pump (10 µL drops over 10

30

minutes). After four minutes within the automated addition, another portion of 1.2 M Me2Zn in

toluene (0.85 mL, 1.0 mmol) was added to the reaction flask. The reaction was allowed to proceed

for one hour and was quenched with 10 mL of 1 M HCl. The mixture was extracted with three

portions of Et2O, dried over MgSO4 and solvents were removed in vacuo. The product was purified

by flash chromatography on silica gel as described below.

3.4.2. Syntheses and Characterizations

Ethyl 3-(4-bromophenyl)-3-hydroxypropanoate (3).57a Following the general procedure

described above, 3 was obtained after purification by flash chromatography (pentane/Et2O/EtOH

= 296:100:4) as a colorless oil (90% yield, 76% ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J =

7.2 Hz, 3H), 2.65 – 2.74 (m, 2H), 3.46 (bs, 1H), 4.17 (q, J = 7.2 Hz, 2H), 5.08 (m, 1H), 7.25 (d, J

= 8.3 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 13.1, 42.1, 60.0, 68.6,

120.6, 126.4, 130.6, 140.5, 171.2. Ee determination by chiral HPLC analysis on Chiralpak AS

using hexanes/i-PrOH (98:2) as mobile phase; retention times: t1 (minor) = 11.3 min, t2 (major) =

13.4 min.

Ethyl 3-hydroxy-3-phenylpropanoate (5).57a Following the general procedure described above,

5 was obtained after purification by flash chromatography (pentane/Et2O/EtOH = 296:100:4) as a

colorless oil (79% yield, 77% ee). 1H NMR (400 MHz, CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.67

– 2.79 (m, 2H), 3.31 (d, J = 3.5 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 5.12 (m, 1H), 7.25 – 7.39 (m,

5H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.3, 60.8, 70.2, 125.6, 127.7, 128.5, 142.5, 172.4. Ee

determination by chiral HPLC analysis on Chiralcel OD using hexanes/i-PrOH (90:10) as mobile

phase; retention times: t1 (major) = 13.8 min, t2 (minor) = 15.6 min.

31

Ethyl 3-(4-fluorophenyl)-3-hydroxypropanoate (6).65 Following the general procedure



7.2 Hz, 3H), 2.64 – 2.76 (m, 2H), 3.39 (bs, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.09 (m, 1H), 7.03 (dd,

J = 8.6 Hz, 8.6 Hz, 2H), 7.34 (dd, J = 5.6 Hz, 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1,

43.3, 60.9, 69.6, 115.3 (d, JC-F = 21.4 Hz), 127.3 (d, JC-F = 8.1 Hz), 138.3 (d, JC-F = 3.1 Hz), 162.2

(d, JC-F = 245.7 Hz), 172.2. Ee determination by chiral HPLC analysis on Chiralpak AS using

hexanes/i-PrOH (98:2) as mobile phase; retention times: t1 (minor) = 10.5 min, t2 (major) = 12.1

min.

Ethyl 3-(4-chlorophenyl)-3-hydroxypropanoate (7).57a Following the general procedure



7.1 Hz, 3H), 2.65 – 2.74 (m, 2H), 3.44 (bs, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.10 (m, 1H), 7.21 - 7.41

(m, 4H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.2, 61.0, 69.6, 127.0, 128.6, 133.4, 141.0, 172.2.

Ee determination by chiral HPLC analysis on Chiralpak AS using heptanes/i-PrOH (95:5) as

mobile phase; retention times: t1 (minor) = 21.1 min, t2 (major) = 26.4 min.

Ethyl 3-hydroxy-3-(4-isopropylphenyl)propanoate (8).57a Following the general procedure

described above, 8, was obtained after purification by flash chromatography (pentane/Et2O/EtOH

= 296:100:4) as a colorless oil (82 % yield, 79 % ee). 1H NMR (400 MHz, CDCl3) δ = 1.24 (d, J

= 6.9 Hz, 6H), 1.26 (t, J = 7.1 Hz, 3H), 2.66 – 2.80 (m, 2H), 2.90 (sept, J = 6.9 Hz,1H), 3.18 (d, J

= 3.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.11 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H) 7.30 (d, J = 8.0 Hz,

2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 23.9, 33.8, 43.3, 60.8, 70.2, 125.7, 126.6, 139.9, 148.5,

32

172.4. Ee determination by chiral HPLC analysis on Chiralpak AS using hexanes/i-PrOH (96:4)

as mobile phase; retention times: t1 (minor) = 20.1 min, t2 (major) = 22.7 min.

Ethyl 3-(4-tert-butylphenyl)-3-hydroxypropanoate (9).57a Following the general procedure


= 296:100:4) as a colorless oil (79 % yield, 79 % ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J

=7.2 Hz, 3H), 1.31 (s, 9H), 2.67 – 2.80 (m, 2H), 3.17 (d, J = 3.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),

5.11 (m, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =

14.1, 31.3, 34.5, 43.2, 60.8, 70.1, 125.4, 139.5, 150.7, 172.4. Ee determination by chiral HPLC

analysis on Chiralpak AS using hexanes/i-PrOH (96:4) as mobile phase; retention times: t1 (minor)

= 18.3 min, t2 (major) = 20.8 min.

Ethyl 3-hydroxy-3-(4-tolyl)propanoate (10).64 Following the general procedure described above,

10 was obtained after purification by flash chromatography (pentane/Et2O/EtOH = 296:100:4) as

a colorless oil (83 % yield, 78 % ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.1 Hz, 3H),

2.34 (s, 3H), 2.66 – 2.74 (m, 2H), 3.22 (bs, 1H), 4.17 (q, J = 7.1 Hz, 2H), 5.08 (m, 1H), 7.15 (d, J

= 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 21.1, 43.3, 60.8,

70.2, 125.6, 129.2, 137.4, 139.6, 172.4. Ee determination by chiral HPLC analysis on Chiralpak

AS using hexanes/i-PrOH (95:5); retention times: t1 (minor) = 18.4 min, t2 (major) = 21.1 min.

Ethyl 3-hydroxy-3-(4-methoxyphenyl)propanoate (11).57a Following the general procedure



7.2 Hz, 3H), 2.64 – 2.79 (m, 2H), 3.19 (d, J = 3.1 Hz, 1H), 3.81 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H),

5.08 (m, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ =

14.1, 43.3, 55.2, 60.8, 69.9, 113.9, 126.9, 134.7, 159.2, 172.4. Ee determination by chiral HPLC

33

analysis on Chiralpak AS using hexanes/i-PrOH (95:5); retention times: t1 (minor) = 10.4 min, t2

(major) = 14.6 min.

Ethyl 3-hydroxy-3-(2-naphthyl)propanoate (12).57a Following the general procedure described

above, 12 was obtained after purification by flash chromatography (pentane/Et2O/EtOH =

296:100:4) as a colorless oil (89% yield, 79% ee). 1H NMR (400 MHz, CDCl3) δ = 1.25 (t, J = 7.1

Hz, 3H), 2.76 – 2.86 (m, 2H), 3.44 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.29 (m, 1H), 7.46 – 7.48 (m,

3H), 7.81 – 7.83 (m, 4H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.3, 60.9, 70.4, 123.7, 124.4,

125.9, 126.2, 127.6, 128.0, 128.3, 133.0, 133.2, 139.9, 172.4. Ee determination by chiral HPLC

analysis on Chiralpak AS using hexanes/i-PrOH (95:5); retention times: t1 (minor) = 29.8 min, t2

(major) = 34.6 min.

Ethyl 3-hydroxy-3-(1-naphthyl)propanoate (13).66 Following the general procedure described


296:100:4) as a colorless oil (94% yield, 80% ee). 1H NMR (400 MHz, CDCl3) δ = 1.27 (t, J = 7.1

Hz, 3H), 2.79 – 2.92 (m, 2H), 3.44 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 5.91 (m, 1H), 7.45 – 7.53 (m,

3H), 7.69 (d, J = 7.1 Hz, 1H) 7.78 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.7 Hz ,1H), 8.05 (d, J = 8.2

Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 14.2, 42.7, 61.0, 67.3, 122.8, 122.9, 125.5, 125.6, 126.2,

128.2, 129.0, 130.0, 133.7, 138.0, 172.7. Ee determination by chiral HPLC analysis on Chiralcel

OD using heptanes/i-PrOH (90:10); retention times: t1 (major) = 16.2 min, t2 (minor) = 21.3 min.

Ethyl 3-hydroxy-3-(thiophen-2-yl)propanoate (14).57a Following the general procedure



7.2 Hz, 3H), 2.82 – 2.91 (m, 2H), 3.47 (d, J = 4.2 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 5.37 (m, 1H),

6.95 – 6.98 (m, 2H), 7.25 (m, 1H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 43.1, 66.5, 69.1, 123.6,

34

124.8, 126.7, 146.2, 171.9. Ee determination by chiral HPLC analysis on Chiralcel OD using

heptanes/i-PrOH (90:10); retention times: t1 (major) = 11.7 min, t2 (minor) = 30.3 min.

Ethyl 3-hydroxy-4-methylpentanoate (15).67 Following the general procedure described above,


a colorless oil (89% yield, 51% ee). 1H NMR (400 MHz, CDCl3) δ = 0.92 (d, J = 6.8 Hz, 3H), 0.94

(d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.71 (m, 1H), 2.40 (dd, J = 9.5 Hz, 16.3 Hz, 1H), 2.50

(dd, J = 2.8 Hz, 16.3 Hz, 1H), 2.89 (d, J = 3.2 Hz, 1H), 3.78 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H). 13C

NMR (100 MHz, CDCl3) δ = 14.1, 17.7, 18.3, 33.1, 38.4, 60.6, 72.6, 173.4. Ee determination by

chiral GC analysis on Lipodex E (25 m x 0.25 mm). Initial temperature 50 °C for 60 min, then 10

°C/min until 70 °C, then 70 °C for 20 min; retention times: t1 (major) = 69.3 min, t2 (minor) = 69.9

min.

Ethyl 3-cyclohexyl-3-hydroxypropanoate (16).57c Following the general procedure described


494:100:6) as a colorless oil (86% yield, 36% ee). 1H NMR (400 MHz, CDCl3) δ = 0.96 – 1.31

(m, 5H), 1.27 (t, J = 7.2 Hz, 3H), 1.38 (m, 1H), 1.62 – 1.71 (m, 2H), 1.71 – 1.81 (m, 2H), 1.86 (m,

1H), 2.41 (dd, J = 9.5 Hz, 16.3 Hz, 1H), 2.51 (dd, J = 2.9 Hz, 16.3 Hz, 1H), 2.87 (d, J = 3.8 Hz,

1H), 3.78 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 26.0, 26.1,

26.4, 28.2, 28.8, 38.6, 43.0, 60.6, 72.1, 173.5. Ee determination by chiral GC analysis on 6-O-

TBDMS-2,3-di-O-methyl-β-cyclodextrin (5 m x 0.25 mm). Temperature at 60 °C; retention times:

t1 (major) = 150 min, t2 (minor) = 175 min.

Ethyl 3-hydroxy-5-phenylpentanoate (17).68 Following the general procedure described above,


a colorless oil (75% yield, 26% ee). 1H NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.2 Hz, 3H), 1.74

35

(m, 1H), 1.85 (m, 1H), 2.44 (dd, J = 8.6 Hz, 16.6 Hz, 1H), 2.50 (dd, J = 3.5 Hz, 16.5 Hz, 1H), 2.70

(m, 1H), 2.83 (m, 1H), 3.09 (bs, 1H), 4.02 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 7.16 – 7.20 (m, 3H),

7.25 – 7.30 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 14.1, 31.7, 38.1, 41.3, 60.7, 67.1, 125.9,

128.3, 128.4, 141.7, 173.0. Ee determination by chiral HPLC analysis on Chiralcel OD using

heptanes/i-PrOH (90:10); retention times: t1 (major) = 12.1 min, t2 (minor) = 14.2 min.

36

Chapter 4. Organocatalytic Stereoselective Synthesis of Fluorinated 3,3’-Linked

Bisoxindolesii

4.1. Introduction

The unique physicochemical properties and widespread use of fluorinated organic

compounds in the health sciences continues to attract considerable attention. Numerous studies

have shown that incorporation of fluorine can improve the therapeutic index of biologically active

compounds.69 The introduction of synthetic methods that produce fluorinated derivatives of natural

compounds and future drug candidates therefore remains of considerable interest. The construction

of carbon-carbon bonds with reactive organofluorine intermediates, however, is often limited by

undesirable side reactions and decomposition pathways. Various synthetic strategies that address

these issues, for example by mild in situ production of fluoroenolates, have emerged in recent

years.70 The 3,3-disubstituted oxindole scaffold is a privileged structural motif and a challenging

synthetic target,71 especially if multiple stereocenters are present.72 The medicinal utility and

potential of 3-fluorooxindoles, including the potassium ion channel modulator Maxipost (Figure

4.1),73 has inspired the development of several methods that accomplish direct fluorination of 3-

alkyl and 3-aryloxindoles.74 More recently, synthetic alternatives that accomplish C-C bond

formation with 3-fluorooxindoles have emerged.75

ii Reproduced with permission from J. Org. Chem. 2018, 83, 1661-1666. Copyright 2018 American Chemical

Society.

37

Figure 4.1. Structures of Maxipost and biologically active 3,3’-bisoxindoles.


A remaining drawback of fluorooxindole transformations is that the use of inert reaction

conditions and elaborate work-up procedures, generating substantial amounts of chemical waste,

are required in most cases. Because environmental and sustainability aspects together with

operational safety, time efficiency and overall cost considerations play an increasingly important

role in industrial and academic laboratories, a practical method was developed that addresses these

issues using 3-fluorooxindoles as starting material. The reaction with isatins was of particular

interest as it produces a challenging dimeric oxindole scaffold exhibiting a 3,3’-linkage with two

adjacent chirality centers.

The search for an environmentally benign, economically attractive method began by

screening the reaction of N-phenyl-3-fluorooxindole, 1, and isatin, 2, in water and alcoholic

solvents in the presence of catalytic amounts of inexpensive triethylamine at room temperature

(Table 4.1). It was found that the reaction proceeds smoothly in the presence of 20 mol% of base

in water and is almost complete after stirring for two hours at room temperature (Table 4.1, entry

1). The formation of the bisoxindole 3 was almost quantitative and occurred with high

stereoselectivity. There was no detectable formation of by-products and it was determined that the

diastereomeric ratio, dr, of 3 was 24:1. As expected, catalytic amounts of the base are required for

38

this reaction and 3 was not formed in the absence of Et3N (Table 4.1, entry 2). Screening of other

protic solvents revealed that the conversion, reaction time and diastereoselectivity can be further

improved (Table 4.1, entries 3-6). In addition to optimization of the reaction conditions, the

possibility of non-chromatographic product isolation was examined to minimize the overall

solvent consumption and labor. Using 10 mol% of triethylamine in isopropyl alcohol it was

observed that 3 is produced quantitatively from 1 and 2 with 49:1 dr in just 30 minutes (Table 4.1,

entry 6). Under these conditions, the bisoxindole precipitated quantitatively which greatly

facilitates product isolation and renders chromatographic work-up unnecessary. The

diastereomeric ratio, dr, of 3 was determined to be 49:1.

Table 4.1. Optimization of the organocatalytic C-C bond formation with N-phenyl-3-

fluorooxindole, 1, and isatin, 2.

Entry Solvent Base (mol%) Time (min) Conversiona (%) Diastereomeric ratioa

1 water Et3N (20) 120 93 24:1

2 water none 120 0 n/a

3 MeOH Et3N (20) 60 99 49:1

4 MeOH/water (1:1) Et3N (20) 60 95 24:1

5 EtOH Et3N (20) 60 96 24:1

6 iPrOH Et3N (20) 30 99 49:1

7 iPrOH Et3N (10) 30 99 49:1

General reaction conditions: Et3N (10-20 mol%) was added to a mixture of oxindole 1 (45.4 mg, 0.2 mmol) and

isatin 2 (30.0 mg, 0.2 mmol) in 1.0 mL of the solvent at room temperature. a Based on 19F and 1H NMR analysis.

39

Having optimized reaction conditions and a work-up procedure that are both practical and

environmentally benign, the reaction scope of the organocatalytic bisoxindole formation was

studied. 3-Fluoro-3'-hydroxy-1-phenyl-3,3'-bisoxindole, 3, was isolated in 96% yield and 99:1 dr

(Scheme 4.1). The reaction between fluorooxindole 1 and isatins carrying a halide or a methyl

group at position 5 in the fused benzene ring gave the corresponding bisoxindoles 4-7 in 90-96%

yield and with at least 95:5 dr. The reaction tolerates substituents at all positions in the isatin

electrophile and the chlorinated bisoxindoles 8-10 were produced with very similar results. When

other brominated and fluorinated isatins were employed in this reaction 11-13 were obtained in

91-92% yields and very high dr’s. The isatin compound can also be substituted at the nitrogen. 3-

Fluoro-3'-hydroxy-1,1'-diphenyl-3,3'-bisoxindole, 14, and the N-methyl analogue 15 were isolated

in almost quantitative amounts and in excellent diastereomeric ratio. The reaction with N-

methylisatin and N-methyl-3-fluorooxindole was also conducted in the presence of 20 mol% of

triethylamine using either THF or dichloromethane as solvent. In both cases, the reaction occurs

under homogeneous conditions and without precipitation of the product 15 which was obtained in

quantitative yield and with >99:1 dr. This suggests that the high diastereoselectivity is achieved in

solution and not a result of preferential crystallization of one diastereomer from a mixture of

rapidly interconverting isomers of 15 (asymmetric transformation of the second kind). Finally the

introduction of a strong electron-withdrawing nitro group and an electron-donating methoxy group

into the isatin ring showed little effects on the chemical and stereochemical outcome. Compounds

16 and 17 were obtained in 92-94% yield and very high dr. The triethylamine catalyzed reaction

thus affords a variety of 3,3’-bridged bisoxindoles exhibiting two adjacent quaternary chiral

centers in almost quantitative yields and with remarkable diastereoselectivity. This organocatalytic

method is operationally simple and leads to multifunctional bisoxindole alkaloid scaffolds.

40

Scheme 4.1. Synthesis of 3,3’-bridged bisoxindoles 3-17 (only one enantiomer is shown).

The protocol has several attractive features in addition to the high yields and dr values that are

noteworthy. The C-C bond formation is accomplished within 30 minutes using mild reaction

conditions, i.e. at room temperature and under air, and by-product formation was not observed. All

41

products 3-17 were isolated by precipitation and purified by careful washing with isopropyl

alcohol-petroleum ether mixtures. The work-up does not require any chromatography which

typically is time-consuming and increases both cost and waste production.76

X-ray crystallography was used to reveal the stereochemical outcome of this reaction. A

single crystal of racemic 3-fluoro-3'-hydroxy-1,1'-dimethyl-3,3'-bisoxindole, 15, was grown by

slow evaporation of a solution containing small amounts of ethyl acetate in hexanes.

Crystallographic analysis confirmed that the reaction favors formation of the homochiral

diastereomer (Figure 4.2).77

Figure 4.2. X-ray structure of rac-3,3’-bisoxindole 15 (only one enantiomer is shown, Zeus De

los Santos).

The synthesis of 3-fluoro-3’-hydroxy-3,3’-bisoxindoles has not been reported to date and

3-17 are new compounds. Few examples of palladium catalyzed carbon-carbon bond formation

with fluorooxindole 1 in dichloromethane and toluene, respectively, are known.75d,78 These

methods accomplish asymmetric allylic alkylations and arylations with high yields and

stereoselectivities but long reaction times and chromatographic work-up are required. Han and

42

Soloshonok introduced a noncatalytic diastereoselective Mannich reaction via

detrifluoroacetylative generation of intermediate 3-fluorooxindole enolates which achieves

carbon-carbon bond formation with yields and dr’s very similar to this method.75c,79 This reaction

is fast and proceeds in etheral solvents or acetonitrile but large excess of base and LiBr additives

are required in addition to chromatographic product purification. A very similar copper catalyzed

asymmetric aldol-type reaction that utilizes the same detrifluoroacetylation concept was recently

reported.80 An inherent drawback of the detrifluoroacetylative enolate generation, however, is the

production of stoichiometric amounts of trifluoroacetic acid waste. In comparison to these

methods, this protocol establishes a significant green chemistry advance as waste resulting from

by-products or additives, chromatographic work-up and the use of transition metals are avoided.

Thakur and Meshram reported an interesting diastereoselective formation of 3-hydroxy-3,3’-

bisoxindoles through catalyst-free on-water synthesis.81 It was found, however, that this protocol

cannot be generally used for the synthesis of the fluorinated bisoxindoles 3-17. While the

aforementioned results were successfully reproduced with oxindole and isatin, the reaction

between N-phenyl-3-fluorooxindole and either isatin or N-phenylisatin using the on-water protocol

gave 3 and 14, respectively, in only 3-5% yield after 24 hours.

The reaction between 1 and 2 was run at the gram scale to determine if the overall

efficiency and the environmentally attractive features can be maintained without compromising

yield and diastereoselectivity (see 4.4. Experimental Section). It was found that even at the

increased reaction scale the product formation is complete within 30 minutes and 3 was isolated

in 95% yield and with 99:1 dr. More than one gram of the bisoxindole 3 was thus obtained with

an E-factor of 22 and without the use of expensive catalysts and additives or hazardous solvents.82

43

This method is not limited to isatin electrophiles. When it was applied to the

fluorooxindoles 1 and 20 in the reaction with N-Boc imine 18, it was found that the corresponding

amines 19 and 21 were produced in 90-92% yield and with very high dr using the same method

(Scheme 4.2). The reactivity of 3-fluorooxindoles in protic solvents and the utility of this

environmentally benign C-C bond formation procedure also extends to Michael additions.83

Employing 1 and 1,1-bis(phenylsulfonyl)ethane, 22, in essentially the same protocol used above

allowed for the preparation of 23 in 99% yield.75a,84 This reaction occurs in isopropyl alcohol in

the presence of 10 mol% of triethylamine and is complete within 30 minutes. Again,

chromatographic product purification is not necessary.

Scheme 4.2. Additions to N-Boc imine 18 and the Michael acceptor 22.

44

4.3. Conclusion

In summary, an organocatalytic method has been introduced that produces 3-fluoro-3’-

hydroxy-3,3’-bisoxindoles or the corresponding 3-fluoro-3’-amines carrying two vicinal chirality

centers in high yields and stereoselectivities. The reaction occurs in non-hazardous isopropyl

alcohol or other protic solvents at room temperature within 30 minutes in the presence 10 mol%

of triethylamine as catalyst and the bisoxindole formation can be upscaled without compromising

yields and diastereoselectivity. Furthermore, the formation of by-products was not observed and

chromatographic product purification is not necessary.



Commercially available isatins, reagents and solvents were used as purchased without

further purification. 3-Fluorooxindole was synthesized by following literature procedures.75d NMR

spectra were obtained at 400 MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz (13C NMR) in

deuterated dimethylsulfoxide, acetone or chloroform. Proton chemical shifts are reported in ppm

relative to the solvent peak or TMS.

3-Fluoro-1-phenylindolin-2-one (45 mg, 0.20 mmol) and an isatin (0.20 mmol) were

dissolved in 1.0 mL of isopropyl alcohol. Triethylamine (2.8 µL, 0.020 mmol) was added and the

solution was stirred for 30 minutes. The resulting solid was isolated after addition of 1.0 mL of

petroleum ether and decanting off the liquid. The crude product was purified by washing the solid

three times with 1.0 mL of petroleum ether/isopropyl alcohol (1:1).

45

4.4.2. Large Scale Synthesis of 3

A mixture of 3-fluoro-1-phenylindolin-2-one (911 mg, 4.0 mmol) and isatin (602 mg, 4.0

mmol) was stirred in 4.0 mL of isopropyl alcohol. Triethylamine (56.5 µL, 0.40 mmol) was added

and the solution was stirred for an additional 30 minutes. The resulting product 3 was obtained as

a white solid in 95% yield (1.43 g, 3.8 mmol) and >99:1 dr after adding 6.0 mL of isopropyl

alcohol, filtration and washing the solid with a total of 20 mL of petroleum ether/isopropyl alcohol

(1:1).


3-Fluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (3). Compound 3 was obtained as a

white crystalline solid in 96% yield (72 mg, 0.19 mmol) and >99:1 dr from 3-fluoro-1-

phenylindolin-2-one (45 mg, 0.20 mmol) and isatin (30 mg, 0.20 mmol) after sonication in

isopropyl alcohol for 30 minutes as described above. Decomp. 204 oC. 1H NMR (399 MHz,

DMSO-d6): δ = 10.44 (s, 1H), 7.51 – 7.33 (m, 4H), 7.28 (dd, J = 7.6, 7.6 Hz, 1H), 7.15 (dd, J =

7.5, 7.5 Hz, 1H), 6.98 (s, 1H), 6.95 – 6.90 (m, 2H), 6.84 – 6.77 (m, 2H), 6.62 (d, J = 8.0 Hz, 1H),

6.37 (d, J = 6.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 173.8 (d, JC-F = 2.4 Hz), 168.5 (d,

JC-F = 21.6 Hz), 144.4 (d, JC-F = 5.1 Hz), 142.9, 132.9, 132.0 (d, JC-F = 2.6 Hz), 130.7, 129.7, 128.6,

126.9, 126.4, 125.7 (d, JC-F = 4.1 Hz), 124.8, 123.2 (d, JC-F = 2.5 Hz), 121.6 (d, JC-F = 18.8 Hz),

121.3, 109.8, 109.2, 94.0 (d, JC-F = 205.3 Hz), 77.0 (d, JC-F = 23.8 Hz). 19F NMR (376 MHz,

DMSO-d6): δ = -177.2. Anal. Calcd. for C22H15FN2O3: C, 70.58; H, 4.04; N, 7.48. Found: C, 70.39;

H, 4.20; N, 7.40.

5'-Chloro-3-fluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (4). Compound 4 was

obtained as a white solid in 94% yield (77 mg, 0.19 mmol) and 96:4 dr from 3-fluoro-1-

46

phenylindolin-2-one (45 mg, 0.20 mmol) and 5-chloroisatin (37 mg, 0.20 mmol) after stirring in

isopropyl alcohol for 30 minutes as described above. 1H NMR (400 MHz, DMSO-d6): δ = 10.62

(s, 1H), 7.54 - 7.38 (m, 5H), 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.01 – 6.93 (m,

2H), 6.82 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.26 (bs, 1H). 13C NMR (101 MHz, DMSO-

d6): δ = 173.4 (d, JC-F = 2.2 Hz), 168.2 (d, JC-F = 21.6 Hz), 144.4 (d, JC-F = 5.1 Hz), 141.8, 132.9,

132.3 (d, JC-F = 2.6 Hz), 130.5, 129.8, 128.7, 127.6 (d, JC-F = 4.1 Hz), 127.0, 126.3, 125.3, 124.8,

123.4 (d, JC-F = 2.4 Hz), 121.2 (d, JC-F = 19.0 Hz), 111.4, 109.2, 93.9 (d, JC-F = 206.4 Hz), 77.1 (d,

JC-F = 24.2 Hz). 19F NMR (376 MHz, DMSO-d6): δ = -177.9. Anal. Calcd. for C22H14ClFN2O3: C,

64.64; H, 3.45; N, 6.85. Found: C, 64.46; H, 3.50; N, 6.71.

5'-Bromo-3-fluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (5). Compound 5 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 5-bromoisatin (48 mg, 0.20 mmol) after stirring in

isopropyl alcohol for 30 minutes as described above. 1H NMR (400 MHz, acetone-d6): δ = 9.40 (s,

1H), 7.48 – 7.41 (m, 3H), 7.40 – 7.26 (m, 2H), 7.24 – 7.16 (m, 2H), 7.10 (s, 1H), 6.95 (dd, J = 7.3,

7.3 Hz, 1H), 6.82 – 6.73 (m, 2H), 6.63 (d, J = 7.7 Hz, 1H), 5.85 (s, 1H). 13C NMR (101 MHz,

DMSO-d6): δ = 173.3 (d, JC-F = 2.0 Hz), 168.2 (d, JC-F = 21.6 Hz), 144.4 (d, JC-F = 5.0 Hz), 142.1,

133.3, 132.8, 132.3, 129.8, 128.7, 128.0 (d, JC-F = 4.4 Hz), 127.6, 127.0, 126.3, 123.4, 121.2 (d,

JC-F = 19.1 Hz), 112.8, 111.9, 109.2, 94.0 (d, JC-F = 206.9 Hz), 77.0 (d, JC-F = 24.1 Hz). 19F NMR

(376 MHz, DMSO-d6): δ = -177.4. Anal. Calcd. for C22H14BrFN2O3: C, 58.30; H, 3.11; N, 6.18.

Found: C, 58.30; H, 3.19; N, 6.08.

3,5'-Difluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (6). Compound 6 was obtained

as a white solid in 96% yield (75 mg, 0.19 mmol) and 96:4 dr from 3-fluoro-1-phenylindolin-2-

one (45 mg, 0.20 mmol) and 5-fluoroisatin (34 mg, 0.20 mmol) after stirring in isopropyl alcohol

47

for 30 minutes as described above. 1H NMR (400 MHz, DMSO-d6): δ = 10.50 (s, 1H), 7.54 – 7.47

(m, 2H), 7.46 – 7.40 (m, 2H), 7.34 (m, 1H), 7.21 – 7.12 (m, 3H), 7.04 – 6.96 (m, 2H), 6.81 (dd, J

= 8.6, 4.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.14 (m, 1H). 13C NMR (101 MHz, DMSO-d6): δ =

173.7 (d, JC-F = 2.4 Hz), 168.2 (d, JC-F = 21.6 Hz), 157.4 (d, JC-F = 237.8 Hz), 144.4 (d, JC-F = 5.2

Hz), 139.1 (d, JC-F = 1.9 Hz), 132.9, 132.3 (d, JC-F = 2.5 Hz), 129.8, 128.7, 127.2 (dd, JC-F = 7.8,

4.0 Hz), 126.9, 126.3, 123.3 (d, JC-F = 2.4 Hz), 121.2 (d, JC-F = 19.0 Hz), 117.1 (d, JC-F = 23.1 Hz),

112.4 (d, JC-F = 25.0 Hz), 110.8 (d, JC-F = 7.8 Hz), 109.3, 93.8 (d, JC-F = 205.7 Hz), 77.4 (d, JC-F =

24.1 Hz). 19F NMR (376 MHz, DMSO-d6): δ = -122.5 (m), -177.51. Anal. Calcd. for

C22H14F2N2O3: C, 67.35; H, 3.60; N, 7.14. Found: C, 67.05; H, 3.56; N, 7.03.

3-Fluoro-3'-hydroxy-5'-methyl-1-phenyl-[3,3'-biindoline]-2,2'-dione (7). Compound 7 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 5-methylisatin (33 mg, 0.20 mmol) after sonication

in isopropyl alcohol for 30 minutes as described above. 1H NMR (399 MHz, DMSO-d6): δ = 10.31

(s, 1H), 7.54 – 7.37 (m, 4H), 7.27 (m, 1H), 7.17 – 7.07 (m, 2H), 6.99 – 6.93 (m, 2H), 6.87 (s, 1H),

6.67 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.23 (bs, 1H), 2.06 (s, 3H). 13C NMR (100 MHz,

DMSO-d6): δ = 174.2 (d, JC-F = 2.8 Hz), 168.9 (d, JC-F = 21.7 Hz), 144.9 (d, JC-F = 5.1 Hz), 140.8,

133.5, 132.4 (d, JC-F = 2.7 Hz), 131.1, 130.6, 130.2, 129.0, 127.3, 126.9, 126.2 (d, JC-F = 3.8 Hz),

126.1, 123.5 (d, JC-F = 2.4 Hz), 122.1, 121.9, 109.7 (d, JC-F = 48.5 Hz), 94.4 (d, JC-F = 205.1 Hz),

77.8 (d, JC-F = 23.8 Hz), 21.0. 19F NMR (376 MHz, DMSO-d6): δ = -177.6. Anal. Calcd. for

C23H17FN2O3: C, 71.13; H, 4.41; N, 7.21. Found: C, 70.76; H, 4.51; N, 7.13.


obtained as a white solid in 91% yield (74 mg, 0.18 mmol) and >99.1 dr from 3-fluoro-1-


48


(s, 1H), 7.54 – 7.40 (m, 4H), 7.40 – 7.32 (m, 2H), 7.23 – 7.14 (m, 2H), 7.01 – 6.95 (m, 2H), 6.87

(dd, J = 7.9, 7.9 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.36 (m, 1H). 13C NMR (101 MHz, DMSO-d6):

δ = 173.7 (d, JC-F = 2.3 Hz), 168.2 (d, JC-F = 21.6 Hz), 144.4 (d, JC-F = 5.1 Hz), 140.6, 132.9, 132.3

(d, JC-F = 2.7 Hz), 130.6, 129.8, 128.7, 127.6 (d, JC-F = 4.1 Hz), 126.9, 126.4, 123.4, 123.3 (d, JC-F

= 2.5 Hz), 122.7, 121.3 (d, JC-F = 18.8 Hz), 114.0, 109.3, 93.8 (d, JC-F = 205.7 Hz), 77.5 (d, JC-F =

24.1 Hz). 19F NMR (376 MHz, DMSO-d6): δ = -177.0. Anal. Calcd. for C22H14ClFN2O3: C, 64.64;

H, 3.45; N, 6.85. Found: C, 64.40; H, 3.47; N, 6.78.





(s, 1H), 7.58 – 7.52 (m, 2H), 7.47 (m, 1H), 7.38 – 7.30 (m, 2H), 7.25 – 7.20 (m, 2H), 7.02 (d, J =

8.1 Hz, 1H), 6.97 (dd, 7.6, 7.6 Hz, 1H), 6.83 (m, 1H), 6.79 (s, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.66

(d, J = 7.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 173.6 (d, JC-F = 6.0 Hz), 168.6 (d, JC-F =

22.1 Hz), 144.8, 144.4 (d, JC-F = 5.2 Hz), 138.9, 133.2, 132.2 (d, JC-F = 2.8 Hz), 132.1, 131.6,

129.7, 128.5, 126.5, 126.3, 123.6, 122.9 (dd, JC-F = 6.3, 2.1 Hz), 121.9 (d, JC-F = 18.7 Hz), 109.4,

108.7, 93.5 (d, JC-F = 206.1 Hz), 80.0 (d, JC-F = 24.9 Hz). 19F NMR (376 MHz, DMSO-d6): δ = -

169.5. Anal. Calcd. for C22H14ClFN2O3: C, 64.64; H, 3.45; N, 6.85. Found: C, 64.38; H, 3.48; N,

6.75.




49


(s, 1H), 7.53 – 7.38 (m, 5H), 7.21 – 7.14 (m, 2H), 7.02 – 6.95 (m, 2H), 6.89 (d, J = 8.0, 1H), 6.83

(s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.35 (m, 1H). 13C NMR (101 MHz, DMSO-d6): δ = 173.7 (d, JC-

F = 2.2 Hz), 168.3 (d, JC-F = 21.6 Hz), 144.4, 144.3 (d, JC-F = 5.1 Hz), 135.1, 132.9, 132.3 (d, JC-F

= 2.6 Hz), 129.8, 128.7, 127.0, 126.3, 124.6 (d, JC-F = 4.3 Hz), 123.4 (d, JC-F = 2.5 Hz), 121.4,

121.2, 121.2, 109.9, 109.3, 93.9 (d, JC-F = 205.8 Hz), 76.7 (d, JC-F = 24.1 Hz). 19F NMR (376 MHz,

DMSO-d6): δ = -177.1. Anal. Calcd. for C22H14ClFN2O3: C, 64.64; H, 3.45; N, 6.85. Found: C,

64.49; H, 3.63; N, 6.69.

3,6'-Difluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (11). Compound 11 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 6-fluoroisatin (34 mg, 0.20 mmol) after stirring in


(bs, 1H), 7.54 – 7.37 (m, 5H), 7.18 (dd, J = 7.5, 7.5 Hz, 1H), 7.08 (s, 1H), 7.03 – 6.96 (m, 2H),

6.69 – 6.59 (m, 3H), 6.36 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 174.0 (d, JC-F = 2.2 Hz),

168.4 (d, JC-F= 21.7 Hz), 163.6 (d, JC-F = 245.3 Hz), 144.8 (d, JC-F = 12.7 Hz), 144.3 (d, JC-F = 5.1

Hz), 132.9, 132.2 (d, JC-F = 2.7 Hz), 129.8, 128.6, 127.0, 126.5 (m), 126.3, 123.3 (d, JC-F = 2.4

Hz), 121.7 (dd, JC-F = 4.4, 2.8 Hz), 121.4 (d, JC-F = 18.9 Hz), 109.3, 107.6 (d, JC-F = 22.5 Hz), 98.0

(d, JC-F = 27.0 Hz), 93.9 (d, JC-F = 205.5 Hz), 76.5 (d, JC-F = 24.1 Hz). 19F NMR (376 MHz, DMSO-

d6): δ = -109.8 (m), -176.7. Anal. Calcd. for C22H14F2N2O3: C, 67.35; H, 3.60; N, 7.14. Found: C,

66.96; H, 3.76; N, 7.08.

6'-Bromo-3-fluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (12). Compound 12 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 6-bromoisatin (46 mg, 0.20 mmol) after stirring in

50


(s, 1H), 7.54 – 7.36 (m, 5H), 7.22 – 7.12 (m, 2H), 7.06 – 6.93 (m, 4H), 6.65 (d, J = 7.9 Hz, 1H),

6.29 (m, 1H). 13C NMR (100 MHz, DMSO-d6): δ = 173.5 (d, JC-F = 2.3 Hz), 168.3 (d, JC-F = 21.4

Hz), 144.5, 144.3 (d, JC-F = 5.2 Hz), 132.9, 132.2 (d, JC-F = 2.7 Hz), 129.7, 128.7, 126.9, 126.5,

126.3, 125.0 (d, JC-F = 4.2 Hz), 124.1, 123.5, 123.3 (d, JC-F = 2.5 Hz), 121.3 (d, JC-F = 18.9 Hz),

112.6, 109.3, 93.8 (d, JC-F = 206.0 Hz), 76.8 (d, JC-F = 24.2 Hz). 19F NMR (376 MHz, DMSO-d6):

δ = -177.2. Anal. Calcd. for C22H14BrFN2O3: C, 58.30; H, 3.11; N, 6.18. Found: C, 58.04; H, 3.29;

N, 6.07.

3,5',6'-Trifluoro-3'-hydroxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (13). Compound 13 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 5,6-difluoroisatin (38 mg, 0.20 mmol) after stirring


(bs, 1H), 7.55 – 7.51 (m, 2H), 7.47 – 7.43 (m, 2H), 7.33 (m, 1H), 7.28 – 7.14 (m, 3H), 7.09 – 7.04

(m, 2H), 6.89 (dd, J = 10.3, 6.8 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.36 (m, 1H). 13C NMR (100

MHz, DMSO-d6): δ = 173.7 (d, JC-F = 2.6 Hz), 168.1 (d, JC-F = 21.8 Hz), 150.9 (dd, JC-F = 247.8,

13.9 Hz), 144.9 (dd, JC-F = 240.0, 13.5 Hz), 144.3 (d, JC-F = 5.3 Hz), 139.8 (d, JC-F = 10.2 Hz),

132.9, 132.3, 129.8, 128.7, 126.8, 126.2, 123.4, 121.7, 121.0 (d, JC-F = 18.9 Hz), 114.3 (d, JC-F =

20.2 Hz), 109.3, 99.9 (d, JC-F = 22.4 Hz), 93.6 (d, JC-F = 205.6 Hz), 77.0 (d, JC-F = 24.5 Hz). 19F

NMR (376 MHz, DMSO-d6): δ = -135.0 (m), -148.5 (m), -177.0. Anal. Calcd. for C22H13F3N2O3:

C, 64.39; H, 3.19; N, 6.83. Found: C, 64.30; H, 3.24; N, 6.81.

3-Fluoro-3'-hydroxy-1,1'-diphenyl-[3,3'-biindoline]-2,2'-dione (14). Compound 14 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 1-phenylisatin (46 mg, 0.20 mmol) after sonication

51

in methyl alcohol for 30 minutes as described above. 1H NMR (400 MHz, DMSO-d6): δ = 7.58 –

7.37 (m, 9H), 7.36 – 7.19 (m, 4H), 7.01 – 6.83 (m, 3H), 6.66 (dd, J = 12.6, 8.0 Hz, 2H), 6.42 (bs,

1H). 13C NMR (101 MHz, DMSO-d6): δ = 171.7 (d, JC-F = 1.4 Hz), 168.5 (d, JC-F = 21.6 Hz), 144.4

(d, JC-F = 5.2 Hz), 144.0, 133.7, 132.8, 132.3 (d, JC-F = 2.5 Hz), 130.9, 129.8, 129.7, 128.7, 128.3,

127.2, 126.6, 126.4, 124.9, 124.7 (d, JC-F = 4.4 Hz), 123.4 (d, JC-F = 2.4 Hz), 122.6, 121.3 (d, JC-F

= 18.9 Hz), 109.3, 109.0, 94.5 (d, JC-F = 207.4 Hz), 76.7 (d, JC-F = 23.7 Hz). 19F NMR (376 MHz,

DMSO-d6): δ = -176.8. Anal. Calcd. for C28H19FN2O3: C, 74.66; H, 4.25; N, 6.22. Found: C, 74.55;

H, 4.27; N, 6.21.

3-Fluoro-3'-hydroxy-1,1'-dimethyl-[3,3'-biindoline]-2,2'-dione (15). Compound 15 was

obtained as a white crystalline solid in 99% yield (65 mg, 0.20 mmol) and >99:1 dr from 3-fluoro-

1-methylindolin-2-one (33 mg, 0.20 mmol) and 1-methylisatin (33 mg, 0.20 mmol) after

sonication in methanol for 30 minutes by as described above. Decomp. 196 oC. 1H NMR (399

MHz, CDCl3): δ = 7.72 (d, J = 7.1 Hz, 1H), 7.46 (dd, J = 7.8, 7.8 Hz, 1H), 7.31 (dd, J = 7.8, 7.8

Hz, 1H), 7.22 (dd, J = 7.6, 7.6 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.79 – 6.73 (m, 2H), 6.10 (d, J =

7.5 Hz, 1H), 5.68 (s, 1H), 3.26 (s, 3H), 2.85 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 173.4 (d,

JC-F = 8.3 Hz), 171.4 (d, JC-F = 21.2 Hz), 144.9 (d, JC-F = 4.8 Hz), 144.6, 132.3 (d, JC-F = 3.0 Hz),

131.3, 127.0 (d, JC-F = 3.0 Hz), 125.2, 124.3, 123.7, 123.2 (d, JC-F = 2.6 Hz), 121.5 (d, JC-F = 18.2

Hz), 109.3, 108.4, 90.4 (d, JC-F = 200.8 Hz), 79.2 (d, JC-F = 24.6 Hz), 26.4, 26.1. 19F NMR (376

MHz, CDCl3): δ = -174.4. Anal. Calcd. for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found: C,

66.39; H, 4.68; N, 8.71.

3-Fluoro-3'-hydroxy-5'-nitro-1-phenyl-[3,3'-biindoline]-2,2'-dione (16). Compound 16 was


phenylindolin-2-one (45 mg, 0.20 mmol) and 5-nitroisatin (36 mg, 0.20 mmol) after stirring in

52


(bs, 1H), 8.25 (dd, J = 8.7, 2.3 Hz, 1H), 7.56 – 7.41 (m, 6H), 7.25 (dd, J = 7.6, 7.6 Hz, 1H), 7.11

(s, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.97 – 6.87 (m, 2H), 6.67 (d, J = 7.9 Hz, 1H). 13C NMR (100

MHz, DMSO-d6): δ = 174.0 (d, JC-F = 1.7 Hz), 168.0 (d, JC-F = 21.5 Hz), 149.2, 144.2 (d, JC-F =

5.1 Hz), 141.7, 132.7, 132.5 (d, JC-F = 2.7 Hz), 129.8, 128.7, 127.8, 127.2, 126.4, 126.1, 123.6 (d,

JC-F = 2.2 Hz), 120.8 (d, JC-F = 19.0 Hz), 120.4, 110.2, 109.5, 93.8 (d, JC-F = 207.0 Hz), 76.5 (d,

JC-F = 24.5 Hz). 19F NMR (376 MHz, DMSO-d6): δ = -177.5. Anal. Calcd. for C22H14FN3O5: C,

63.01; H, 3.37; N, 10.02. Found: C, 63.10; H, 3.57; N, 9.90.

3-Fluoro-3'-hydroxy-6'-methoxy-1-phenyl-[3,3'-biindoline]-2,2'-dione (17). Compound 17

was obtained as a white solid in 94% yield (76 mg, 0.19 mmol) and 99:1 dr from 3-fluoro-1-

phenylindolin-2-one (45 mg, 0.20 mmol) and 6-methoxyisatin (36 mg, 0.20 mmol) after stirring


(s, 1H), 7.49 – 7.30 (m, 5H), 7.11 (dd, J = 7.2, 6.7 Hz, 1H), 6.96 – 6.90 (m, 2H), 6.80 (s, 1H), 6.58

(d, J = 7.9 Hz, 1H), 6.33 – 6.27 (m, 2H), 6.25 – 6.16 (m, 1H), 3.67 (s, 3H). 13C NMR (100 MHz,

DMSO-d6): δ = 174.2 (d, JC-F = 2.2 Hz), 168.6 (d, JC-F = 21.7 Hz), 161.4, 144.4 (d, JC-F = 6.9 Hz),

133.0, 132.0 (d, JC-F = 2.7 Hz), 129.7, 128.6, 126.9, 126.4, 125.8, 123.2 (d, JC-F = 2.4 Hz), 121.8,

121.7, 117.4 (d, JC-F = 4.4 Hz), 109.2, 106.3, 96.4, 94.0 (d, JC-F = 205.4 Hz), 76.7 (d, JC-F = 23.9

Hz), 55.4. 19F NMR (376 MHz, DMSO-d6): δ = -176.4. Anal. Calcd. for C23H17FN2O4: C, 68.31;

H, 4.24; N, 6.93. Found: C, 68.26; H, 4.29; N, 6.91.

tert-Butyl(1'-benzyl-3-fluoro-2,2'-dioxo-1-phenyl-[3,3'-biindolin]-3'-yl)carbamate (19).

Compound 19 was obtained as a white crystalline solid in 92% yield (104 mg, 0.18 mmol) and

>99:1 dr from 3-fluoro-1-phenylindolin-2-one (45 mg, 0.20 mmol) and tert-butyl (1-benzyl-2-

oxoindolin-3-ylidene)carbamate (67 mg, 0.20 mmol) after stirring in isopropyl alcohol for 24

53

hours as described above. Decomp. 178 oC. 1H NMR (399 MHz, CDCl3): δ = 7.70 (d, J = 7.5 Hz,

1H), 7.59 – 7.40 (m, 6H), 7.32 (dd, J = 7.8, 7.8 Hz, 1H), 7.24 – 7.02 (m, 5H), 6.74 – 6.56 (m, 5H),

5.83 (d, J = 7.5 Hz, 1H), 4.89 (d, J = 15.7 Hz, 1H), 4.45 – 4.28 (m, 1H), 1.28 (s, 9H). 13C NMR

(100 MHz, CDCl3): δ = 172.4 (d, JC-F = 8.0 Hz), 170.0 (d, JC-F = 21.8 Hz), 154.09, 145.1 (d, JC-F

= 5.1 Hz), 144.0, 135.2, 133.1, 132.1 (d, JC-F = 2.4 Hz), 130.1, 129.8, 128.8, 128.6, 127.2, 126.9,

126.8, 126.0, 125.4 (d, JC-F = 2.8 Hz), 123.2 (d, JC-F = 2.4 Hz), 123.1, 120.5 (d, JC-F = 18.0 Hz),

110.0, 109.1, 90.5 (d, JC-F = 204.3 Hz), 80.3, 66.6 (d, JC-F = 22.9 Hz), 44.3, 28.1. 19F NMR (376

MHz, CDCl3): δ = -170.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C34H30FN3O4Na 586.2118;

Found 586.2111.

tert-Butyl(1,1'-dibenzyl-3-fluoro-2,2'-dioxo-[3,3'-biindolin]-3'-yl)carbamate (21). Compound

21 was obtained as a white solid in 91% yield (105 mg, 0.18 mmol) and 96:4 dr from 1-benzyl-3-

fluoroindolin-2-one (48 mg, 0.20 mmol) and tert-butyl (1-benzyl-2-oxoindolin-3-

ylidene)carbamate (67 mg, 0.20 mmol) after stirring in isopropyl alcohol for 24 hours as described

above. 1H NMR (399 MHz, CDCl3): δ = 7.67 (d, J = 7.4 Hz, 1H), 7.54 (s, 1H), 7.44 – 7.37 (m,

2H), 7.33 – 7.24 (m, 4H), 7.18 (dd, J = 7.5, 7.5 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.99 (dd, J = 7.5,

7.5 Hz, 2H), 6.68 – 6.59 (m, 3H), 6.57 – 6.45 (m, 2H), 5.69 (d, J = 7.5 Hz, 1H), 5.13 (d, J = 15.9

Hz, 1H), 4.93 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.8 Hz, 1H), 4.47 – 4.25 (m, 1H), 1.29 (s, 9H).

13C NMR (100 MHz, CDCl3): δ = 172.2 (d, JC-F = 7.5 Hz), 170.7 (d, JC-F = 23.1 Hz), 154.1, 144.1

(d, JC-F = 5.0 Hz), 143.9, 135.2, 134.5, 132.1 (d, JC-F = 3.1 Hz), 130.0, 128.9, 128.6, 127.8, 127.4,

127.1, 126.9, 125.9, 125.5 (d, JC-F = 3.0 Hz), 123.1, 122.9 (d, JC-F = 2.7 Hz), 120.9 (d, JC-F = 17.8

Hz), 110.2, 109.1, 91.4 (d, JC-F = 201.9 Hz), 80.3, 66.2 (d, JC-F = 23.1 Hz), 44.5, 44.3, 28.2. 19F

NMR (376 MHz, CDCl3): δ = -167.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C35H32FN3O4Na 600.2275; Found 600.2267.

54

3-(2,2-Bis(phenylsulfonyl)ethyl)-3-fluoro-1-phenylindolin-2-one (23). Compound 23 was

obtained as a white crystalline solid in 99% yield (106 mg, 0.20 mmol) from 3-fluoro-1-

phenylindolin-2-one (45 mg, 0.20 mmol) and 1,1-bis(phenylsulfonyl)ethene (65 mg, 0.20 mmol)

after stirring in isopropyl alcohol for 30 minutes as described above. Mp. 127-128 oC. 1H NMR

(399 MHz, DMSO-d6): δ = 7.99 – 7.87 (m, 4H), 7.84 – 7.76 (m, 2H), 7.72 -7.56 (m, 7H), 7.54 –

7.41 (m, 4H), 7.23 (dd, J = 7.5, 7.5 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.69 (dd, J = 4.4, 4.4 Hz,

1H), 3.42 (ddd, J = 17.9, 14.1, 4.3 Hz, 1H), 3.02 (ddd, J = 32.4, 17.3, 4.5 Hz, 1H). 13C NMR (100

MHz, DMSO-d6): δ = 170.4 (d, JC-F = 23.0 Hz), 143.1 (d, JC-F = 5.2 Hz), 137.8, 136.9, 135.1,

134.9, 132.9, 132.2 (d, JC-F = 2.9 Hz), 129.8, 129.5, 129.4, 129.4, 129.0, 128.7, 126.4, 125.3, 124.1,

123.9 (d, JC-F = 2.1 Hz), 110.1, 89.3 (d, JC-F = 188.9 Hz), 76.1, 30.3 (d, JC-F = 30.6 Hz). 19F NMR

(376 MHz, DMSO-d6): δ = -155.2 (dd, J = 32.4, 13.9 Hz). HRMS (ESI-TOF) m/z: [M + Na]+

Calcd for C28H22FNO5S2Na 558.0821; Found 558.0816.

55

4.4.4. Crystallographic Analysis of Selected Products

Figure 4.3. Crystal structure of rac-3-Fluoro-3'-hydroxy-1,1'-dimethyl-[3,3'-biindoline]-2,2'-

dione, 15.

A single crystal of 15 was obtained by slow evaporation of a solution of the product in a

mixture of ethyl acetate and hexanes. Single crystal X-ray analysis was performed by Zeus De los

Santos at 100 K using a Siemens platform diffractometer with graphite monochromated Mo-Kα

radiation (λ = 0.71073 Å). Data were integrated and corrected using the APEX 3 program. The

structures were solved by direct methods and refined with full-matrix least-square analysis using

SHELX-97-2 software. Non-hydrogen atoms were refined with anisotropic displacement

parameters. Crystal data: C18H15FN2O3, M = 326.32, colorless block, 0.3 x 0.2 x 0.2 mm3, triclinic,

space group P-1, a = 7.8941(5), b =8.26666(5), c = 11.9759(8) Å, V = 748.38(8) Å3, Z = 2.

56

Chapter 5. Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl- and

Trifluoromethyl Ketonesiii

5.1. Introduction

The unique pharmacological properties of fluorinated compounds continues to motivate

the introduction of a large variety of organofluorines in today’s drug design and discovery.85 As a

result of the successful role of the carbon-fluorine bioisostere in medicinal chemistry,86 the

development of an increasing number of therapeutics with organofluorine moieties has been

stimulated.87 Trifluoromethyl groups, for instance, are key structural motifs in several

anticonvulsants,88 metalloproteinase inhibitors,89 CJ-17,493, a Neurokinin 1 receptor antagonist,90

(+)-ZK 216348, a potent glucocorticoid receptor agonist,91 and HIV drugs such as the antiretroviral

Efavirenz.92 Therapeutics containing a difluoromethyl group include the HIV-1 protease inhibitor,

A-7928593 and Eflornithine, an inhibitor of ornithine decarboxylase used for the treatment of facial

hirsutism and African sleeping sickness.94 Synthetic methods that accomplish carbon-carbon bond

formation with trifluoromethyl or difluoromethyl ketones have therefore become important in

accessing novel fluorinated pharmaceuticals (Figure 5.1).

iii The content of this chapter has been published by Wiley and has been reproduced from Adv. Synth. Catal. 2018,

doi: 10.1002/adsc.201800876. Copyright 2018 Wiley-VCH Verlag GmbH & Co. KGaA.

57

Figure 5.1. Structures of CJ-17,493, (+)-ZK 216348, Efavirenz and Eflornithine.

In contrast to the many reports on Henry reactions and other variants of aldol-type additions

to fluorinated ketones, relatively few methods have been reported that accomplish efficient

cyanomethylation. The formation of the synthetically versatile β-hydroxynitrile motif in general

often requires a large excess of acetonitrile due to its low acidity (pKa 31.3 in DMSO) and in some

cases the products further react in an uncontrolled elimination toward unsaturated nitrile

derivatives. Synthetic alternatives have been used to address these limitations. With regards to the

cyanomethylation of aldehydes and imines, these obstacles have been navigated by the

introduction of Me3SiCH2CN or other masked cyanomethyl precursors95 and through the

development of mild transition metal-catalyzed96 and superbase-catalyzed procedures.97 As an

example of the use of a masked precursor, the Shibasaki group developed the generation of

cyanomethyl nucleophiles by the copper(I)-catalyzed extrusion of CO2 from carboxylic acids and

their subsequent addition to imines.98 This method was developed further to make use of simple

cyanoacetic acid and was later expanded with the addition to isatins catalyzed by quinine derived

thioureas.99

58


An application of decarboxylative cyanomethylation to triflouromethyl ketones has been

previously reported by Imamura et al. during the synthesis and study of potential anti-cancer

agents. The method described made use of TiCl4 and pyridine to mediate the reaction of ethyl

cyanoacetate and a trifluoromethyl acetophenone derivative. The reaction resulted in an

unsaturated nitrile product and was unsuccessful in producing the addition product without further

elimination (Scheme 5.1).100 It was decided that the development of a method for the

cyanomethylation of fluorinated ketones that resolves the prevailing issues would provide practical

access to synthetically useful β-hydroxynitriles.

Scheme 5.1. Decarboxylative cyanomethylation/condensation of a trifluoromethyl acetophenone.

Method development for the synthesis of trifluoromethylated β-hydroxynitriles was carried

out by Dr. Balaraman Kaluvu by screening of the reaction between 2,2,2-trifluoroacetophenone,

1a, and cyanoacetic acid, 2, in the presence of various organic and inorganic bases. It was found

that 1a is converted to the desired 4,4,4-trifluoro-3-hydroxy-3-phenylbutanenitrile, 3a, in 49%

yield at room temperature after 42 hours when three equivalents of 2 and 50 mol% of DBU were

employed in THF (Table 5.1, entry 1). Importantly, the formation of by-products was not observed

under these conditions. The prospect of mild cyanomethylation of 1a without subsequent

dehydration lead to the testing of several amines. The results show that similar yields can be

59

obtained with Et3N or Barton’s base (Table 5.1, entries 2-9). When the reaction was carried out in

the absence of base no product was observed (Table 5.1, entry 10).

Table 5.1. Optimization of the cyanomethylation of 2,2,2-trifluoroacetophenone (Dr. Balaraman

Kaluvu).a

Entry Base (mol%) Solvent Time (h) Temp (oC) Yield (%)b

1 DBU (50) THF 42 25 49

2 Et3N (50) THF 42 25 45

3 DIPEA (50) THF 42 25 29

4 DABCO (50) THF 42 25 13

5 TMEDA (50) THF 42 25 23

6 DMAP (50) THF 42 25 36

7 Barton’s base (50) THF 42 25 42

8 K2CO3 (50) THF 42 25 <5

9 Cs2CO3 (50) THF 42 25 9

10 none THF 42 25 n.r.

11 Et3N (50) CH2Cl2 48 25 <5

12 Et3N (50) 1,4-dioxane 48 25 27

13 Et3N (50) toluene 48 25 <5

14 Et3N (50) CH3CN 48 25 8

15 Et3N (50) CH3OH 48 25 <5

16 Et3N (50) water 48 25 n.r.

17 Et3N (10) neat, MW 0.75 100 89

18 Et3N (50) THF 16 60 99

19 Et3N (20) THF 21 60 98d

20c Et3N (20) THF 24 60 98d

21c Et3N (10) THF 36 60 91

a Conditions: 0.3 mmol of 1a, 0.9 mmol of 2, 1 mL of solvent. b Analysis by 1H and 19F NMR. c Two equivalents of 2

were used. d Isolated yields. n.r. = no reaction. MW = microwave conditions.

60

The optimization was continued with the solvent, temperature and loading of base. Et3N

was chosen because it is commonly available and less expensive than DBU or Barton’s base (Table

5.1, entries 11-21). The use of dichloromethane, 1,4-dioxane, toluene, acetonitrile, methanol and

water as solvent did not improve the results. High yields of 3a, with concomitant formation of by-

products, were achieved under solvent-free microwave conditions using 10 mol% of Et3N at 100

oC (Table 5.1, entry 17). Because milder conditions were considered important with regard to a

wide functional group tolerance it was decided to further investigate ambient temperature

procedures using THF as solvent. Finally, it was found that 3a could be produced in 98% yield

after 21 hours using two equivalents of 2 and 20 mol% of Et3N in THF (Table 5.1, entry 20).

With the optimized reaction conditions, organocatalytic decarboxylative

cyanomethylations were carried out by Balaraman Kaluvu with a series of trifluoromethyl ketones

to determine the substrate scope (Scheme 5.2). The reactions with aromatic trifluoromethyl

ketones 1a-c proceeded quantitatively and gave the benzyl alcohols 3a-3c in 97-98% yield.

Halogen substituents in ortho or para positions of the trifluoroacetophenones 1d-g were well

tolerated and 3d-3g were isolated in 93-99% yield. The reaction is also applicable to the

trifluoroacetophenones 1h-l carrying a wide range of electron-withdrawing or electron-donating

groups. The corresponding tertiary alcohols 3h-3l were obtained in 93-99% yield and side

reactions, for example at the ester group, were not observed. Importantly, heteroaryl and aliphatic

trifluoromethyl ketones can be used. 4,4,4-Trifluoro-3-hydroxy-3-(thiophen-2-yl)butanenitrile,

3m, was produced with excellent yield and the enolizable trifluoromethyl ketone 1n underwent

decarboxylative cyanomethylation to the aliphatic tertiary alcohol 3n in 92% yield. To further

demonstrate the general utility of the method, the reaction between 1a and 2 was performed on a

61

gram scale using the same reaction conditions described in Scheme 4.2. The β-hydroxynitrile 3a

was obtained in 93% yield after 24 hours.

Scheme 5.2. Substrate scope of the cyanomethylation of trifluoromethyl ketones (Dr. Balaraman

Kaluvu).

The scope of the reaction was then extended to the decarboxylative cyanomethylation of

difluormethyl ketones. A series of difluoromethyl ketones were synthesized by following

previously reported literature protocols.101 After minor changes of the reaction procedure

62

described above, β-difluoromethyl-β-hydroxynitriles 5a-5h were successfully prepared (Scheme

5.3). The cyanomethylation of the phenyl, tolyl, and 2-napthyl ketones 4a-c gave 5a-5c in 92-99%

yield. Other functional groups are well tolerated and the 2-nitro, 4-fluoro and 4-chloro derivatives

5d-f were obtained 92-99% yield. Excellent results were also achieved with heteroaromatic

difluoromethyl ketones and 5g and 5h, carrying a 2-furyl and 2-thienyl ring, respectively, were

formed in 90-94% yield.

Scheme 5.3. Decarboxylative cyanomethylation of difluoromethyl ketones.

Extending the reaction scope further, chlorordifluoromethyl ketone 6 was employed in the

reaction protocol (Scheme 5.4). The cyanomethyl alcohol 7 was produced in high yield, which

demonstrates that additional halogens on the alkyl side chain are well tolerated. Interestingly, this

reaction is compatible with the use of activated imines. The diastereoselective Mannich reaction

with enantiomerically pure tert-butylsulfinyl difluoromethyl imide 8 gave 9 with 82% yield and

89:11 diastereoselectivity.102,103

63

Scheme 5.4. Decarboxylative cyanomethylation of 6 and 8.

5.3. Conclusion

In summary, we have introduced a practical organocatalytic method for the synthesis of

difluoromethyl and trifluoromethyl substituted β-hydroxynitriles. The decarboxylative

cyanomethylation of fluorinated ketones with cyanoacetic acid occurs under mild conditions in the

presence of 20 mol% of inexpensive triethylamine and affords a wide variety of multifunctional

tertiary alcohols in 90-99% yield without concomitant water elimination. The general reaction

protocol was successfully scaled up to gram quantities and was extended to an asymmetric

Mannich reaction with a tert-butylsulfinyl difluoromethyl ketimine derivative.



Commercially available difluoromethyl ketone (4a), chlorodifluoromethyl ketone (6),

cyanoacetic acid (2), reagents, catalysts and solvents were used as purchased without further

purification. Difluoromethyl ketones (4b-4h)104 and tert-butylsulfinyl imide 8105 were synthesized

by following literature procedures. NMR spectra were obtained at 400 MHz (1H NMR), 376 MHz

64

(19F NMR) and 100 MHz (13C NMR). Chemical shifts are reported in ppm relative to TMS.

Reaction products were purified by column chromatography on silica gel (particle size 32–63 μm)

as described below.

To a solution of a difluoromethyl ketone (0.3 mmol) and cyanoacetic acid (0.6 mmol) in

THF (1.0 mL) was added Et3N (20 mol%). The resulting mixture was stirred at 70 oC for 48 hours

and the reaction was monitored by 19F NMR for the disappearance of the difluoromethyl ketone.

The crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate

as mobile phase as described below.


4,4-Difluoro-3-hydroxy-3-phenylbutanenitrile (5a). Compound 5a was obtained as a colorless

oil in 99% yield (58 mg, 0.297 mmol) from 2,2-difluoro-1-phenylethan-1-one (47 mg, 0.3 mmol)

and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N in 1 mL of THF after

48 hours at 70 oC by following the general procedure described above. Rf = 0.16 (hexanes/EtOAc,

8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.51 (dd, J = 7.7, 2.0 Hz, 2H), 7.48 – 7.40 (m, 3H),

5.83 (t, J = 55.6 Hz, 1H), 3.30 (s, 1H), 3.07 (s, 2H); 13C NMR (100 MHz, Chloroform-d) δ = 136.3

(t, JC-F = 1.4 Hz), 129.5, 129.1, 125.8 (t, JC-F = 1.5 Hz), 115.8, 115.6 (t, JC-F = 251.0 Hz), 74.6 (t,

JC-F = 22.1 Hz), 25.7 (t, JC-F = 3.3 Hz); 19F NMR (376 MHz, Chloroform-d) δ = -129.0 (dd, J =

282.0, 56.4 Hz, 1F), -130.0 (dd, J = 282.0, 56.4 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for

C10H9F2NO 197.0652, found 197.0648.

65

4,4-Difluoro-3-hydroxy-3-(p-tolyl)butanenitrile (5b). Compound 5b was obtained as a colorless

oil in 92% yield (58 mg, 0.276 mmol) from 2,2-difluoro-1-(p-tolyl)ethan-1-one (51 mg, 0.3 mmol)

and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N in 1 mL of THF after

48 hours at 70 oC by following the general procedure described above. Rf = 0.13 (hexanes/EtOAc,

8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.42 – 7.36 (m, 2H), 7.28 – 7.23 (m, 2H), 5.83 (t, J

= 55.6 Hz, 1H), 3.07 (s, 2H), 2.93 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, Chloroform-d) δ =

139.6, 133.3, 129.9, 125.7 (t, JC-F = 1.5 Hz), 115.7, 115.6 (t, JC-F = 250.1 Hz), 74.6 (t, JC-F = 22.2

Hz), 25.7 (t, JC-F = 3.3 Hz), 21.2; 19F NMR (376 MHz, Chloroform-d) δ = -129.1 (dd, J = 280.9,

56.4 Hz, 1F), -130.2 (dd, J = 281.0, 56.3 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for

C11H11F2NO 211.0809, found 211.0800.

4,4-Difluoro-3-hydroxy-3-(naphthalen-2-yl)butanenitrile (5c). Compound 5c was obtained as

a colorless solid in 93% yield (69 mg, 0.279 mmol) from 2,2-difluoro-1-(naphthalen-2-yl)ethan-

1-one (62 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol%

Et3N in 1 mL of THF after 48 hours at 70 oC by following the general procedure described above.

Mp. 80.0-82.9 °C; Rf = 0.13 (hexanes/EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d) δ = 8.03

(s, 1H), 7.95 – 7.80 (m, 3H), 7.62 – 7.48 (m, 3H), 5.92 (t, J = 55.5 Hz, 1H), 3.30 (s, 1H), 3.16 (s,

2H); 13C NMR (100 MHz, Chloroform-d) δ = 133.6 (t, JC-F = 1.5 Hz), 133.5, 133.0, 129.1, 128.6,

66

127.8, 127.3, 127.0, 125.8 (t, JC-F = 1.5 Hz), 122.7 (t, JC-F = 1.6 Hz), 115.7, 115.6 (t, JC-F = 250.5

Hz), 74.8 (t, JC-F = 22.1 Hz), 25.8 (t, JC-F = 3.2 Hz); 19F NMR (376 MHz, Chloroform-d) δ = -128.7

(dd, J = 281.6, 56.4 Hz, 1F), -129.6 (dd, J = 282.4, 56.4 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+

calcd for C14H11F2NO 247.0809, found 247.0803.

4,4-Difluoro-3-hydroxy-3-(2-nitrophenyl)butanenitrile (5d). Compound 5d was obtained as a

colorless oil in 99% yield (72 mg, 0.297 mmol) from 2,2-difluoro-1-(2-nitrophenyl)ethan-1-one

(60 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N in 1

mL of THF after 48 hours at 70 oC by following the general procedure described above. Rf = 0.1

(hexanes/EtOAc, 1:1); 1H NMR (400 MHz, Chloroform-d) δ = 7.68 – 7.61 (m, 2H), 7.60 – 7.52

(m, 2H), 6.36 (t, J = 56.0 Hz, 1H), 3.44 (s, 1H), 3.34 (d, J = 17.2 Hz, 1H), 3.21 (d, J = 17.2 Hz,

1H); 13C NMR (100 MHz, Chloroform-d) δ = 150.5, 132.0, 130.9, 128.9 (t, JC-F = 1.9 Hz), 128.8

(t, JC-F = 1.6 Hz), 125.3, 115.1, 114.3 (t, JC-F = 250.5 Hz), 75.6 (t, JC-F = 22.1 Hz), 25.3 (t, JC-F =

3.8 Hz); 19F NMR (376 MHz, Chloroform-d) δ = -129.0 (dd, J = 286.1, 55.3 Hz, 1F), -130.4 (dd,

J = 286.1, 56.4 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for C10H8F2N2O3 242.0503, found

242.05.

4,4-Difluoro-3-(4-fluorophenyl)-3-hydroxybutanenitrile (5e). Compound 5e was obtained as a

colorless solid in 92% yield (59 mg, 0.276 mmol) from 2,2-difluoro-1-(4-fluorophenyl)ethan-1-

67

one (52 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N

in 1 mL of THF after 48 hours at 70 oC by following the general procedure described above. Mp.

71.2-72.6 °C; Rf = 0.18 (hexanes/EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.50 – 7.46

(m, 2H), 7.12 (dd, J = 8.6, 7.8 Hz, 2H), 5.77 (t, J = 55.6 Hz, 1H), 3.49 (s, 1H), 3.05 (s, 2H); 13C

NMR (100 MHz, Chloroform-d) δ = 163.3 (d, JC-F = 249.1 Hz), 132.1 (t, JC-F = 2.6 Hz), 128.0 (dt,

JC-F = 8.6, 1.6 Hz), 116.0 (d, JC-F = 21.7 Hz), 115.7, 115.4 (t, JC-F = 251.3 Hz), 74.3 (t, JC-F = 22.2

Hz), 25.7 (t, JC-F = 3.3 Hz); 19F NMR (376 MHz, Chloroform-d) δ = -112.1 (m, 1F), -129.1 (dd, J

= 282.0, 56.4 Hz, 1F), -129.8 (dd, J = 282.0, 56.4 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for

C10H8F3NO 215.0558, found 215.0554.

3-(4-Chlorophenyl)-4,4-difluoro-3-hydroxybutanenitrile (5f). Compound 5f was obtained as a

colorless solid in 99% yield (68 mg, 0.297 mmol) from 1-(4-chlorophenyl)-2,2-difluoroethan-1-

one (57 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N

in 1 mL of THF after 48 hours at 70 oC by following the general procedure described above. Mp.

64.2-64.8 °C; Rf = 0.13 (hexanes/EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.56 – 7.33

(m, 4H), 5.79 (t, J = 55.5 Hz, 1H), 3.30 (s, 1H), 3.05 (s, 2H); 13C NMR (100 MHz, Chloroform-d)

δ = 135.8, 134.7, 129.3, 127.4 (t, JC-F = 1.5 Hz), 115.5, 115.3 (t, JC-F = 250.5 Hz), 74.4 (t, JC-F =

22.3 Hz), 25.8 (t, JC-F = 3.3 Hz); 19F NMR (376 MHz, Chloroform-d) δ = -128.9 (dd, J = 282.4,

56.4 Hz, 1F), -129.8 (dd, J = 282.4, 56.4 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for

C10H8ClF2NO 231.0262, found 231.0256.

68

4,4-Difluoro-3-(furan-2-yl)-3-hydroxybutanenitrile (5g). Compound 5g was obtained as a

colorless oil in 90% yield (51 mg, 0.27 mmol) from 2,2-difluoro-1-(furan-2-yl)ethan-1-one (44

mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N in 1 mL

of THF after 48 hours at 70 oC by following the general procedure described above. Rf = 0.12

(hexanes/EtOAc, 7:3); 1H NMR (400 MHz, Chloroform-d) δ = 7.49 (m, 1H), 6.58 (d, J = 3.4 Hz,

1H), 6.45 (dd, J = 3.4, 1.8 Hz, 1H), 5.95 (t, J = 55.3 Hz, 1H), 3.32 (s, 1H), 3.14 – 3.02 (m, 2H);

13C NMR (100 MHz, Chloroform-d) δ = 148.9 (t, JC-F = 1.5 Hz), 144.0, 115.3, 114.3 (t, JC-F =

251.1 Hz), 111.2, 109.8 (t, JC-F = 1.3 Hz), 72.0 (t, JC-F = 23.6 Hz), 23.8 (t, JC-F = 3.2 Hz); 19F NMR

(376 MHz, Chloroform-d) δ = -130.0 (dd, J = 282.7, 56.4 Hz, 1F), -131.0 (dd, J = 282.5, 56.4 Hz,

1F); HRMS (ESI-TOF) m/z: [M]+ calcd for C8H7F2NO2 187.0445, found 187.044.

4,4-Difluoro-3-hydroxy-3-(thiophen-2-yl)butanenitrile (5h). Compound 5h was obtained as a

colorless oil in 94% yield (57 mg, 0.282 mmol) from 2,2-difluoro-1-(thiophen-2-yl)ethan-1-one

(49 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in the presence of 20 mol% Et3N in 1

mL of THF after 48 hours at 70 oC by following the general procedure described above. Rf = 0.17

(hexanes/EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.41 (d, J = 5.1 Hz, 1H), 7.16 (d, J

= 3.6 Hz, 1H), 7.07 (dd, J = 4.9, 3.9 Hz, 1H), 5.87 (t, J = 55.6 Hz, 1H), 3.49 (s, 1H), 3.12 – 3.03

(m, 2H); 13C NMR (100 MHz, Chloroform-d) δ = 139.8 (t, JC-F = 1.6 Hz), 127.7, 127.2, 126.2 (t,

69

JC-F = 1.6 Hz), 115.4, 114.9 (t, JC-F = 251.9 Hz), 74.0 (t, JC-F = 23.4 Hz), 26.6 (t, JC-F = 3.0 Hz);

19F NMR (376 MHz, Chloroform-d) δ = -128.9 (dd, J = 281.2, 56.0 Hz, 1F), -129.7 (dd, J = 281.2,

55.6 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for C8H7F2NOS 203.0216, found 203.021.

4-Chloro-4,4-difluoro-3-hydroxy-3-phenylbutanenitrile (7). To a solution of 2-chloro-2,2-

difluoro-1-phenylethan-1-one (6) (57 mg, 0.3 mmol) and cyanoacetic acid (51 mg, 0.6 mmol) in

THF (1.0 mL) was added triethylamine (20 mol%). The resulting mixture was stirred at 70 oC for

48 hours and the reaction was monitored by 19F NMR for the disappearance of

chlorodifluoromethyl ketone 6. The crude product was purified by flash chromatography on silica

gel using hexanes-ethyl acetate (9:1) as mobile phase. Compound 7 was obtained as a colorless

solid in 96% yield (66 mg, 0.288 mmol). mp: 102.9-103.5 °C; Rf = 0.2 (hexanes/EtOAc, 8:2); 1H

NMR (400 MHz, Chloroform-d) δ = 7.57 (dd, J = 7.7, 1.9 Hz, 2H), 7.48 – 7.44 (m, 3H), 3.45 (s,

1H), 3.34 – 3.18 (m, 2H); 13C NMR (100 MHz, Chloroform-d) δ = 135.0, 130.0, 129.9 (t, JC-F =

300.0 Hz), 128.9, 126.4 (t, JC-F = 1.8 Hz), 115.1, 78.8 (t, JC-F = 25.3 Hz), 27.4 (t, JC-F = 2.2 Hz);

19F NMR (376 MHz, Chloroform-d) δ = -64.2; HRMS (ESI-TOF) m/z: [M]+ calcd for

C10H8ClF2NO 231.0262, found 231.0255.

70

(R)-N-(3-cyano-1,1-difluoro-2-(naphthalen-2-yl)propan-2-yl)-2-methylpropane-2-

sulfinamide (9). To a solution of 2-chloro-2,2-difluoro-1-phenylethan-1-one (4c) (250 mg, 1.21

mmol) and (R)-2-methylpropane-2-sulfinamide (161mg, 1.33 mmol) in THF (5.0 mL) was added

Ti(OEt)4 (552 mg, 2.42 mmol) and the reaction was refluxed for 48 hours. Cyanoacetic acid (308

mg, 3.63 mmol) and Et3N (20 mol%) were added to the reaction mixture and stirred at 70 oC for

another 48 hours. The crude product was purified by flash chromatography on silica gel using

hexanes/ethyl acetate (8:2) as mobile phase. Compound 9 was obtained as a pale yellow solid in

82% yield (347 mg, 0.992 mmol). mp: 109.2-110.1 °C; Rf = 0.21 (hexanes/EtOAc, 7:3); 1H NMR

(400 MHz, Chloroform-d) δ = 8.01 (s, 1H), 7.97 – 7.81 (m, 3H), 7.64 (dd, J = 8.9, 2.0 Hz, 1H),

7.58 – 7.52 (m, 2H), 6.64 (t, J = 54.5 Hz, 1H), 4.41 (s, 1H), 3.34 – 3.13 (m, 2H), 1.29 (s, 9H); 13C

NMR (100 MHz, Chloroform-d) δ = 133.3, 132.7, 131.6, 129.1, 128.7, 127.5, 127.5, 127.1, 126.9,

124.0, 115.7, 115.6 (t, JC-F = 243.8 Hz), 63.1 (t, JC-F = 20.6 Hz), 57.3 , 25.1 (t, JC-F = 3.4 Hz), 22.6;

19F NMR (376 MHz, Chloroform-d) δ = Major diastereomer: -122.5 (dd, J = 282.0, 54.7 Hz, 1F),

-129.5 (dd, J = 282.0, 54.3 Hz, 1F); Minor diastereomer: -125.3 (dd, J = 279.1, 55.6 Hz, 1F), -

127.3 (dd, J = 279.1, 54.5 Hz, 1F); HRMS (ESI-TOF) m/z: [M]+ calcd for C18H20F2N2OS

350.1264, found 350.1265.

71


Figure 5.2. Crystal structure of rac-4-Chloro-4,4-difluoro-3-hydroxy-3-phenylbutanenitrile (7).

A single crystal was obtained by slow evaporation of a solution containing the chiral

alcohol in a mixture of hexanes and ethyl acetate (4:1). Single crystal X-ray analysis was

performed by Zeus De los Santos at 100 K using a Siemens platform diffractometer with graphite

monochromated Mo-Kα radiation (λ = 0.71073 Å). Data were integrated and corrected using the

Apex 3 program. The structures were solved by direct methods and refined with full-matrix least-

square analysis using SHELX-97-2 software. Non-hydrogen atoms were refined with anisotropic

displacement parameter. Crystal data: C10H8ClF2NO, M = 231.03, colorless prism, 0.89 x 0.73 x

0.52 mm3, triclinic, space group P-1, a = 6.2345(3), b = 12.8524(6), c = 13.8297(6) Å, V =

99.7.34(8) Å3, Z = 4.

72

Chapter 6. Enantiomerization Kinetics of 2,2’-Disubstituted Biphenyls: A Dynamic Chiral

HPLC Investigationiv

6.1. Introduction

The universal ubiquity and fundamental role of chirality in nature has fascinated scientists

since Pasteur’s historic characterization and separation of enantiomorphous tartrate crystals more

than 150 years ago.106 The resolution of enantiomers has remained immensely important in the

chemical and life sciences to date and various analytical and preparative techniques that can be

used to achieve this task with nano- to kilogram amounts of racemic mixtures have been developed

in the 20th century. Among all these accomplishments and advances, the introduction of chiral

chromatography based on the formation of transient diastereomeric adducts on a chiral stationary

phase by Emanuel Gil-Av and his coworkers in 1966 undoubtedly constitutes a groundbreaking

landmark that continues to inspire and promote chemical research and discoveries today.107

The general significance of chiral chromatography cannot be overstated and extends far

beyond the originally intended use for separation of enantiomers. A very elegant application of

chiral chromatography is the direct kinetic analysis of enantiomerization reactions by computer

simulation of characteristic elution profiles that result from concurrent separation and

interconversion of enantiomers on the column.108 Typically, a successful separation of enantiomers

yields a chromatogram with two baseline-separated peaks. If the chromatographic run is conducted

at a temperature at which the enantiomers interconvert, a plateau between the two peaks appears.

As the rate of enantiomerization increases with temperature so does the plateau height until the

original peaks coalesce when the interconversion of the isomers is fast compared to the

iv Reproduced with permission from Isr. J. Chem. 2016, 56, 1052 – 1056. Copyrights 2016 John Wiley & Sons, Inc.

73

chromatography time scale. Simulation of the experimentally obtained elution profiles provides a

practical means to determine the rate constant of the observed on-column isomerization. This can

be accomplished by an iterative optimization procedure that is completed when the calculated and

the experimental elution profiles are superimposable. Schurig109 and Horváth110 were first to

recognize and exploit the potential of this technique, which is generally referred to as dynamic

chromatography, for the analysis of enantiomerization and diastereomerization reactions,

respectively. Schurig et al. introduced a computer program that simulates the separation and

enantiomerization processes using a theoretical plate model and several user-friendly simulation

packages have been developed since then.111 Following seminal work from Schurig and Trapp,112

several groups including Mannschreck,113 Villani114 and König115 have used dynamic HPLC, GC,

SFC, electrokinetic chromatography, and electrophoresis for the analysis of enantiomerization

kinetics of a wide variety of chiral compounds.116

The axial chirality and atropisomerism of biaryls, first reported by Christie and Kenner in

1922,117 are key structural features in numerous compounds, including natural compounds,118

pharmaceutical drugs,119 and BINOL,120 BINAP121 or other chiral ligands.122 The Wolf group has

exploited biaryls and triaryls extensively for the development of chirality chemosensors.123 The

properties and applications of axially chiral biaryls are closely related to the energy barrier to

rotation about the pivotal aryl-aryl bond. For example, the successful use of enantiopure BINAP

and other atropos ligands in asymmetric catalysis typically necessitates high stability to rotation

upon metal complexation while the conformationally unstable tropos analogues are often a key

design feature in stereodynamic systems and chiral amplification processes. This has fueled

considerable interest in understanding steric and electronic contributions of substituents on the rate

of enantiomerization.124 The energy barrier to rotation is primarily determined by steric repulsion

74

between ortho substituents as they occupy proximate positions in the almost coplanar transition

state. This repulsion increases when groups in the adjacent meta positions are present because they

exhibit a buttressing effect on the ortho substituents. Compared to steric contributions, electronic

effects on the conformational stability of biaryls are relatively small. Electron-donating groups in

ortho and para positions have been reported to facilitate out-of-plane bending at the carbon atoms

of the central aryl-aryl bond which ultimately reduces the steric repulsion in the crowded transition

state (Figure 6.1).125

Figure 6.1. Enantiomerization mechanism of axially chiral biaryls. EDG = electron-donating

group.


This study was begun by screening Lux Amylose-2, Chirex 3001, Chirex 3014, Chiralpak

IB and Lux Cellulose-4 columns for the HPLC separation of the enantiomers of biaryls 1-8, which

were available from previous work on palladium-phosphinous acid catalyzed Negishi cross-

coupling reactions.126 It was found that all analytes tested can be separated on the Lux Cellulose-

75

4 column using hexanes as mobile phase at room temperature. The successful separation of the

enantiomers of 1-8 which include some very hydrophobic structures exhibiting only the aromatic

biaryl core and aliphatic groups but are devoid of other functionalities underscores the usefulness

of the Lux Cellulose-4 column. The enantioseparations of 6 and 7 are shown in Figure 6.2.

Figure 6.2. Structures of the biaryls investigated (top). Separation of the enantiomers of 6 and 7

on Lux Cellulose-4 column using hexane as mobile phase at 1 mL/min, at 10 °C, UV detection at

254 nm.

Interestingly, the biaryls 6 and 7 showed temperature dependent plateau formation which

results from interconversion of the enantiomers during the chiral separation process as explained

above. Comparison of the structures of the biaryls tested reveals that 1-4 are tri-ortho-substituted

76

biphenyl derivatives which generally have higher rotational energy barriers due to significant steric

hindrance in the transition state than biphenyls carrying only two ortho-groups. The biphenyls 5-

8 exhibit two ortho-groups and are therefore expected to undergo rotation about the chiral aryl-

aryl axis more easily. When 1-5 and 8 were subjected to HPLC analysis at 50 °C,127 plateau

formation was still not observed and therefore the DHPLC behavior of 6 and 7 was examined

further.

Figure 6.3. Experimentally obtained DHPLC elution profiles with 6, Lux Cellulose-4, hexanes

as mobile phase, 1 mL/min flow rate, 254 nm UV detection. Column temperature: a) 20.3 °C, b)

24.8 °C, c) 30.0 °C, d) 34.2 °C.

The HPLC separation of the enantiomers of 1-(o-tolyl)naphthalene, 6, at 20 °C shows slow

enantiomerization on the chromatographic time scale and a low plateau between the well resolved

77

peaks (Figure 6.3). The plateau height increased steadily as the HPLC runs were performed at

higher temperatures which was varied in approximately 5 °C increments up to 34 °C. The

occurrence of on-column enantiomerization under these conditions indicates a rotational energy

barrier below 100 kJ/mol and isolated enantiomers would not be stable to racemization at room

temperature.128 The HPLC analysis of 2-cyclohexyl-2’-dimethylaminobiphenyl, 7, shows even

faster enantiomerization (Figure 6.4). A small plateau is already visible at 10 °C and the plateau

between the enantiomer peaks reaches about 50% of the peak heights at 25 °C. Isolated enantiomers

of 7 would racemize within a few minutes at room temperature.

Figure 6.4. Experimentally obtained DHPLC elution profiles with 7, Lux Cellulose-4, hexanes

as mobile phase, 1 mL/min flow rate, 254 nm UV detection. Column temperature: a) 10.2 °C, b)

15.2 °C, c) 20.1 °C, d) 24.7 °C.

78

The elution profiles shown in Figures 6.3 and 6.4 were then simulated to determine the

enantiomerization rate constants assuming reversible first-order kinetics. The rotation about the

chiral axis in biaryls typically has a negative activation entropy which is attributed to the sterically

crowded transition state in which both aryl planes are in the same plane and experience reduced

rotational and vibrational freedom of the ortho-substituents. Eyring plots were used to calculate

the activation parameters for the enantiomerization reaction of biaryls 6 and 7 (Figure 6.5). For

biaryl 6, the Gibbs free energy of activation was determined, ΔG‡, as 93.2 kJ/mol and the activation

enthalpy and entropy contributions, ΔH‡ and ΔS‡, as 81.7 kJ/mol and -38.6 J/K mol, respectively.

These results are in perfect agreement with the observed on-column enantiomerization at room

temperature and the generally expected negative activation entropy. In the case of 7, the Gibbs free

energy of activation, ΔG‡, was determined as 88.4 kJ/mol and an activation enthalpy, ΔΔH‡, of

89.8 kJ/mol was obtained. This biphenyl shows an unusual low activation entropy, ΔS‡, which was

calculated as 4.5 J/K mol. The latter can be explained with a significant contribution of the out-of-

plane bending mechanism shown in Figure 6.1 on the enantiomerization reaction. The electron-

donating dimethylamino group in 7 is likely to favor a nonplanar transition state that facilitates

rotation about the aryl-aryl bond without compromising the rotational and vibrational freedom of

the two ortho-substituents. The concomitant N-inversion is expected to affect the activation

parameter of 7 in similar ways.

79

Figure 6.5. Eyring plots for 6 (left) and 7 (right).

6.3. Conclusion

In summary, the enantiomers of eight axially chiral biaryls have been separated by chiral

HPLC and observed on-column enantiomerization of 1-(o-tolyl)naphthalene and 2-cyclohexyl-2’-

dimethylaminobiphenyl. Computer simulation of the experimentally observed elution profiles at

various temperatures yielded Gibbs free energies of activation, G‡, of 93.2 kJ/mol and 88.4

kJ/mol, respectively. The results of this kinetic study, in particular the striking effect of the ortho-

dimethylamino group on the enthalpic and entropic activation parameters provide important

information for the synthesis and applications of axially chiral biaryls, including the utilization as

chiroptical sensors or as tropos ligands in catalytic asymmetric reactions. The practicality of

DHPLC for the stereodynamic analysis of biaryls is also noteworthy. The DHPLC measurements

and analysis are easily conducted with generally available HPLC instrumentation and simulation

packages, do not require preparative enantioseparation and can be performed with minute sample

amounts. Clearly, the introduction of chiral chromatography by Gil-Av 50 years ago remains to be

of the highest impact to date and has yielded unexpected opportunities, for example practical

kinetic analysis of enantiomerization reactions by dynamic chromatography, that continue to build

on his pioneering work.

80



All compounds were available from previous work.126 For the kinetic measurements, the

chiral column was fully inserted into a water-filled dewar and equilibrated at the desired

temperature for 10 minutes prior to injection of the sample. The temperature was measured with a

calibrated thermometer and kept constant during the HPLC run. The computer simulation of the

experimentally obtained chromatograms was performed with Mimesis 3.1 using retention times,

void volume, theoretical plate numbers, chart speed, and peak heights which can all be readily

determined from the HPLC runs. The rate constant of enantiomerization was altered until the

experimental and simulated elution profiles were superimposable.

6.4.2. DHPLC Characterizations

All eight biaryls were separated on Lux Cellulose-4 using hexanes as mobile phase at 1

mL/min flow rate. Approximately 1 mg of the biaryl was dissolved in 1 mL of hexanes. Injection

volume was 10 µL, 254 nm UV detection. The simulated (left) and experimentally obtained (right)

HPLC elution profiles for 6 and 7 are shown below.

81

6.4.2.1. DHPLC Characterizations of 1-(o-Tolyl)naphthalene, 6.

T = 307.35 K, Enantiomerization rate constant = 0.048 min-1, 8.0 x 10-4 s-1

ΔG‡ = 93.6 kJ/mol

Figure 6.6. DHPLC characterizations of 1-(o-Tolyl)naphthalene, 6 at 35 °C.

T=303.15 K, Enantiomerization rate constant = 0.030 min-1, 5.0 x 10-4 s-1



82







83

6.4.2.2. DHPLC Characterizations of 2-Cyclohexyl-2’-dimethylaminobiphenyl, 7.



Figure 6.10. DHPLC characterizations of 2-Cyclohexyl-2’-dimethylaminobiphenyl, 7 at 25 °C.




84







85

Chapter 7. Detrifluoroacetylative Generation of Halogenated Enolates: Practical Access to

Perhalogenated Ketones and Alkenesv

7.1. Introduction

The development of synthetic methods that produce halogenated compounds continues to

receive increasing attention. The general interest in organohalide chemistry originates at least in

part from the widespread use of organofluorines and organochlorines in the pharmaceutical and

agrochemical industries as well as the outstanding synthetic utility of carbon-halide bonds.129 The

presence of fluorine and chlorine substituents can improve bioavailability, lipophilicity, metabolic

stability and other important pharmacological properties of drugs and the incorporation of halides

into synthetic intermediates provides unique opportunities for subsequent modifications aimed at

the synthesis of increasingly complex target structures. While chlorinated and fluorinated

pharmaceuticals play central roles in the pharmaceutical market,130 drug discovery efforts are

gradually extended to the screening of candidates containing less frequently used bromides and

iodides. Despite a continuing interest in the synthesis and use of compounds exhibiting a

bromochlorofluoromethyl group131 and some success based on ring opening of fluorinated

cyclopropanes with bromine or trapping of Julia-Kocienski intermediates with a brominating

agent,132 the preparation of this moiety has remained challenging (Scheme 7.1).133

v Reproduced with permission from Synthesis. 2016, 48, 2376-2384. Copyrights 2016 Georg Thieme Verlag

Stuttgart.

86

Scheme 7.1. Synthesis of bromochlorofluoromethyl-derived alcohols, ketones and alkenes.132b

Traditional synthetic routes and established methods developed with nonhalogenated

substrates and reagents can often not be applied to halogenated analogues because the presence of

halogen atoms in close proximity to the reaction center can alter the stability of intermediates and

ultimately change reactivity and reaction pathways. These complications have limited the

versatility and general usefulness of halogenated enolates in aldol type reactions. In the search for

practical alternatives to reactions with halogenated silyl enolates, several groups have focused on

an orthogonal strategy that is based on mild in situ generation of halogenated nucleophiles from

readily available trifluoroacetyl derived precursors.134 Prager and Ogden demonstrated almost 50

years ago that the cleavage of hexafluoroacetone and its ester derivatives with excess of base,

metal salts and other additives produces fluorinated carbanions suitable for C-C bond formation.135

The full potential of this concept in aldol reactions with difluoroenolates generated in situ from a

bench-stable trifluoroacetyl-derived precursor was first demonstrated by Colby et al.136 This

seminal work has led to a variety of interesting applications and developments reported by

Prakash,137 Colby,138 Zhu,139 Soloshonok and Han,140 Hong and Wang,141 Fang and Wu,142 and

Wolf.143 Inspired by the successful halogenation of difluoroenolates prepared by

detrifluoroacetylation in the presence of excess of lithium salts and triethylamine,144 the synthesis

of a small series of 1-aryl 2-chloro-2,4,4,4-tetrafluoro-butan-1,3-dione hydrates were initiated. The

following is a describtion of the mild catalytic cleavage of these gem-diols and subsequent

87

bromination of intermediate chlorofluoroenolates to chiral bromochlorofluoromethyl ketones, and

the use of these products in alkene synthesis.


The difluorination of 1-aryl 4,4,4-trifluorobutane-1,3-diones with Selectfluor is a well-

established reaction that typically proceeds with high yields. For example, the fluorination of the

trifluoroacetylated acetophenone derivative 1 gives the geminal diol of 1-phenyl-2,2,4,4,4-

pentafluorobutan-1,3-dione, 2, in 95% yield (Scheme 7.2).143a The adjacent trifluoromethyl and

difluoromethylene groups significantly increase the electrophilicity of the central ketone unit

which readily attracts water to afford the hydrate 2. It was expected that the diol form would also

predominate over the free diketone in the corresponding 1-aryl 2-chloro-2,4,4,4-tetrafluorobutane-

1,3-diones. The development of a consecutive fluorination/chlorination procedure for the synthesis

of 3, however, proved difficult. The first attempts to prepare the mixed dihalide via

monofluorination of 1 with Selectfluor failed because the second fluorination step is fast and thus

favors formation of 2. It was therefore decided to reverse the halogenation sequence and start

investigating the possibility of monochlorination of 1. Stavber et al. reported successful

monohalogenation of trifluoromethyl substituted 1,3-diketones with N-halosuccinimides but they

isolated the hydrates which cannot be further fluorinated.145 Therefore, a two-step protocol was

developed by Dr. Balaraman Kaluvu and Yang Liu in which 1 is first chlorinated by grinding with

N-chlorosuccinimide, NCS, under inert atmosphere to avoid the water addition. The crude reaction

mixture was then dissolved in anhydrous acetonitrile and subjected to fluorination with Selectfluor.

This gave 2-chloro-2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenylbutan-1-one, 3, in 76% yield. With

this procedure in hand, it was possible to synthesize the 2-naphthyl, 4-chlorophenyl and 2-furanyl

88

analogues 3-6 in 69 to 84% yield (Scheme 7.2). As expected, all pentahalogenated compounds

spontaneously add water to form the gem-diols upon exposure to air.

Scheme 7.2. Synthesis of 1-aryl 2-chloro-2,4,4,4-tetrafluorobutane-1,3-diones 3-6 by stepwise

chlorination/fluorination of trifluoromethylated 1,3-diones.

In analogy to the copper(II) bisoxazoline catalyzed C-C bond formation of difluoroenolates

prepared in situ via base promoted cleavage of 2 or derivatives thereof,143b it was anticipated that

the diol 3 can be converted to α-bromo-α-chloro-α-fluoroacetophenone, 8, in the presence of

triethylamine and a brominating agent (Scheme 7.3). It was rationalized that the synthesis of

haloform 8 and other bromochlorofluoromethyl ketones would provide new access toward a

variety of perhalogenated compounds, for example via modification of the carbonyl or carbon-

bromide bond.

89

Scheme 7.3. In situ cleavage of 3 and formation of 8 and 9.

Initial studies performed by Dr. Balaraman Kaluvu and Yang Liu showed that bromination

of the intermediate enolate 7 in the presence of 10 mol% of Cu(II) triflate, bromine and

triethylamine is relatively slow compared to the formation of the -chloro- -fluoroacetophenone,

9. To minimize the effect of the competing protonation path, inorganic bases (potassium carbonate

or phosphate) and NBS were employed in the reaction, and 8 and 9 were obtained in 60% and 40%

yield, respectively. It was found by Dr. Balaraman Kaluvu and Yang Liu that the cleavage of 3

requires two equivalents of base but predominantly produces 9 unless Cu(OTf)2 is present. In fact,

a mixture containing only 19% of 8 and 81% of the chlorofluoromethyl ketone 9 was formed when

the reaction was conducted with equimolar amounts of NBS and 2.5 equivalents of K2CO3 in THF

in the absence of a copper complex. The effect of several solvents and ligands on the reaction

outcome was then investigated by Dr. Balaraman Kaluvu and the results of the optimization study

are summarized in Table 7.1.

90

Table 7.1. Optimization of the cleavage/bromination sequence using hydrate 3. (Dr. Balaraman

Kaluvu)

Entry Ligand Solvent Time (h) % Yield 8 (9)a

1 none THF 2 60 (40)

2

THF 2 57 (43)

3

THF 2 57 (43)

4

THF 2 38 (62)

5

THF 2 79 (21)

6

THF 2 89 (11)

7

THF 2 75 (25)

8

THF 1 94 (6)

9 L7 CH2Cl2 18 96 (4)

10 L7 CHCl3 46 88 (n.d.)

11 L7 (CH2Cl)2 46 97 (3)

12 L7 ACN 18 <70 (n.d.)

a Analysis by 1H and 19F NMR. n.d. = not determined.

91

The addition of bipyridine or phenanthroline gave no improvement and TMEDA proved

detrimental compared to the ligand-free procedure (Table 7.1, entries 1-4). The introduction of

BINAP and bisoxazolines L5 and L6, however, showed promise and favored conversion to 8

(Table 4.1, entries 5-7). Finally, it was found that the cleavage and subsequent bromination of 3

gives 8 almost exclusively within one hour at room temperature when 10 mol% of copper triflate

and bisoxazoline L7, NBS and two equivalents of potassium carbonate are used in THF (Table

7.1, entry 8). The reaction is relatively slow in chlorinated solvents and unidentified by-products

were observed in chloroform and acetonitrile (Table 7.1, entries 9-12). With an optimized

procedure in hand, it was possible to prepare the bromochlorofluoromethyl ketones 8 and 10-12 in

82-98% yield (Scheme 7.4). The bromination reaction of the in situ enolate can also be

accomplished under noncatalytic conditions when large excess of lithium bromide is used to

suppress the competing protonation.144 For example, 11 was obtained from diol 5 in 95% yield in

the presence of five equivalents of LiBr under otherwise similar conditions.146

Scheme 7.4. Copper catalyzed synthesis of bromochlorofluoromethyl ketones 8 and 10-12.

The high-yielding synthesis of these mixed trihalo ketones via mild cleavage of the diol

precursors 3-6 effectively complements previously reported routes aimed at generating a

bromochlorofluoromethyl group.132,133,147 At this point, it was decided to further explore the

92

general synthetic versatility of bromochlorofluoromethyl ketones including the possibility of

Wittig and Horner-Wadsworth-Emmons (HWE) reactions. It was found by Dr. Balaraman Kaluvu

that treatment of α-bromo-α-chloro-α-fluoroacetophenone, 8, with carbon tetrabromide and

triphenylphosphine gives the dibromoalkene 13 in almost quantitative amounts (Scheme 7.5).148

The same reaction furnished the dibromoalkenes 14 and 15 in 86-88% yield. Similarly, both Wittig

and HWE reactions were successful. Treatment of 8 with benzyl

(triphenylphosphoranylidene)acetate at room temperature gave the (E)-alkene 16 with high

diastereoselectivity in 81% yield.149 When the triaholmethyl ketones 10 and 11 were employed in

the same protocol, (E)-17 and (E)-18 in were obtained 91-92% yield. The formation of the (E)-

isomer was confirmed by crystallographic analysis and is consistent with literature procedures

using α-halogenated acetophenone derivatives.150 Finally, the Horner-Wadsworth-Emmons

reaction using 8 and triethyl phosphonoacetate produced ethyl (E)-4-bromo-4-chloro-4-fluoro-3-

phenylbut-2-enoate, 19, in almost quantitative amounts.

93

Scheme 7.5. Results of dibromoalkenylations (Dr. Balaraman Kaluvu), Wittig and Horner-

Wadsworth-Emmons reactions of bromochlorofluoromethyl ketones. Crystallographic analysis

of 17 shows E-configuration.

7.3. Conclusion

In summary, a mild catalytic procedure that exploits detrifluoroacetylative in situ

generation of dihalogenated enolates from readily available geminal diols has been developed for

the synthesis of bromochlorofluoromethyl ketones which were obtained in 82-98% yield. The

94

copper(bisoxazoline) catalyzed reaction successfully favors bromination of intermediate

chlorofluoroenolates over the competing protonation pathway. It is notable that the base promoted

cleavage of the chlorofluoro-derived diols 3-6 and analogues thereof provides simple access to

chlorofluoromethyl ketones such as 9 and other dihalomethyl ketones if desired. The synthetic

utility of bromochlorofluoromethyl ketones was demonstrated with high-yielding

dibromoalkenylations, Wittig and Horner-Wadsworth-Emmons reactions.


7.4.1. General Information

Commercially available bisoxazoline ligands, trifluoromethyl diketones, reagents and

solvents were used as purchased without further purification. NMR spectra were obtained at 400

MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz (13C NMR) in deuterated chloroform or

DMSO. Chemical shifts are reported in ppm relative to TMS or relative to the DMSO-d6 solvent

peak. Reaction products were purified by column chromatography on silica gel (particle size 40-

63 μm) as described below.


7.4.2.1. General procedure for the synthesis of 1-aryl-2-chloro-2,4,4,4-tetrafluoro-3,3-

dihydroxybutanones.

The corresponding 1-aryl-4,4,4-trifluoro-butane-1,3-dione (1.0 equiv.) and N-

chlorosuccinimide (1.2 equiv.) were triturated together in a mortar under inert atmosphere. The

reaction was monitored by 19F NMR and trituration was continued until full conversion was

achieved. The crude reaction mixture was then dissolved in anhydrous acetonitrile and stirred

together with Selectfluor (1.5 equiv.) at room temperature. After full conversion was achieved

95

based on 19F NMR analysis, the solvent was removed and replaced with dichloromethane. The

insoluble Selectfluor was filtered from the reaction mixture and the filtrate was extracted with

water. The combined organic layers were dried over sodium sulfate and the solvent was removed

in vacuo. The crude product was purified by flash chromatography on silica gel using with

hexanes/ethyl acetate (90:10) as mobile phase.

2-Chloro-2,4,4,4-tetrafluoro-3,3-dihydroxy-1-phenylbutan-1-one (3). Compound 3 was

obtained as a colorless solid in 76% yield (4.34 g, 15.2 mmol) from 4,4,4-trifluoro-1-

phenylbutane-1,3-dione (4.32 g, 20.0 mmol) by following the general procedure described above.

mp: 53-55 °C; Rf = 0.4 (hexanes / EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d): δ = 8.09 (d,

J = 7.4 Hz, 2H), 7.70 (dd, J = 7.5, 7.4 Hz, 1H), 7.53 (dd, J = 7.5, 7.4 Hz, 2H), 5.14 (s, 1H), 4.99

(s, 1H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 193.8 (d, JC-F = 29.2 Hz), 135.3, 131.4 (d,

JC-F = 3.0 Hz), 130.6 (d, JC-F = 6.6 Hz), 128.8, 121.5 (qd, JC-F = 289.6, 2.5 Hz), 103.9 (d, JC-F =

275.9 Hz), 94.9 (qd, JC-F = 32.5, 23.9 Hz) ppm; 19F NMR (376 MHz, Chloroform-d) δ = -78.8 (d,

J = 14.8 Hz), -127.9 (q, J = 14.7 Hz) ppm; Anal. Calcd. for C10H7ClF4O3: C, 41.91; H, 2.46. Found:

C, 41.84; H, 2.44.

2-Chloro-2,4,4,4-tetrafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one (4). Compound 4

was obtained as a pale yellow solid in 84% yield (2.82 g, 8.4 mmol) from 4,4,4-trifluoro-1-

(naphthalen-2-yl)butane-1,3-dione (2.66 g, 10.0 mmol) by following the general procedure

described above. mp: 82-84 °C; Rf = 0.3 (hexanes / EtOAc, 8:2); 1H NMR (400 MHz, DMSO-d6)

δ 8.78 (s, 1H), 8.59 (m, 1H), 8.12 – 8.05 (m, 4H), 7.73 – 7.58 (m, 2H) ppm; 13C NMR (100 MHz,

Chloroform-d) δ 193.5 (d, JC-F = 28.7 Hz), 171.4, 136.4, 133.8 (d, JC-F = 9.3 Hz), 132.3, 130.3,

130.1, 128.7, 127.8 (d, JC-F = 1.6 Hz), 127.3, 124.9 (d, JC-F = 4.4 Hz), 121.6 (qd, JC-F = 289.7, 2.4

Hz), 104.2 (d, JC-F = 276.1 Hz), 95.0 (qd, JC-F = 32.3, 23.9 Hz) ppm; 19F NMR (376 MHz, DMSO-

96

d6) δ = -77.6 (d, J = 13.4 Hz), -118.3 (d, J = 13.4 Hz); Anal. Calcd. for C14H9ClF4O3: C, 49.95; H,

2.69. Found: C, 49.91; H, 2.64.

2-Chloro-1-(4-chlorophenyl)-2,4,4,4-tetrafluoro-3,3-dihydroxybutan-1-one (5). Compound 5

was obtained as a colorless solid in 81% yield (2.08 g, 6.48 mmol) from 1-(4-chlorophenyl)-4,4,4-

trifluorobutane-1,3-dione (2.0 g, 8.0 mmol) by following the general procedure described above.

mp: 68-70 °C; Rf = 0.4 (hexanes / EtOAc, 8:2); 1H NMR (400 MHz, DMSO-d6) δ = 8.83 (s, 1H),

8.61 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H) ppm; 13C NMR (100 MHz,

Chloroform-d) δ = 192.4 (d, JC-F = 29.3 Hz), 142.3, 132.0 (d, JC-F = 6.8 Hz), 129.7 (d, JC-F = 3.7

Hz), 129.3, 121.4 (qd, JC-F = 289.7, 2.4 Hz), 103.9 (d, JC-F = 275.2 Hz), 94.8 (qd, JC-F = 32.5, 23.6

Hz) ppm; 19F NMR (376 MHz, DMSO-d6) δ = -77.7 (d, J = 13.5 Hz), -118.6 (q, J = 13.4 Hz) ppm;

Anal. Calcd. for C10H6Cl2F4O3: C, 37.41; H, 1.88. Found: C, 37.53; H, 1.92.

2-Chloro-2,4,4,4-tetrafluoro-1-(furan-2-yl)-3,3-dihydroxybutan-1-one (6). Compound 6 was

obtained as a colorless solid in 69% yield (1.90 g, 6.9 mmol) from 4,4,4-trifluoro-1-(furan-2-

yl)butane-1,3-dione (2.06 g, 10.0 mmol) by following the general procedure described above. mp:

48-50 °C; Rf = 0.5 (hexanes / EtOAc, 8:2); 1H NMR (400 MHz, Chloroform-d) δ = 7.87 (bs, 1H),

7.69 (m, 1H), 6.71 (m, 1H), 4.92 (s, 2H) ppm; 13C NMR (100 MHz, Chloroform-d) δ = 179.8 (d,

JC-F = 28.4 Hz), 150.8, 146.7 (d, JC-F = 4.4 Hz), 126.4 (dd, JC-F = 14.8, 2.0 Hz), 121.5 (qd, JC-F =

289.4, 2.4 Hz), 113.6 (d, JC-F = 2.9 Hz), 103.8 (d, JC-F = 272.9 Hz), 94.6 (qd, JC-F = 32.6, 23.3 Hz)

ppm; 19F NMR (376 MHz, Chloroform-d) δ = -79.1 (d, J = 14.3 Hz), -131.0 (q, J = 14.3 Hz) ppm;

Anal. Calcd. for C8H5ClF4O4: C, 34.74; H, 1.82. Found: C, 34.82; H, 1.85.

97

6.4.2.2. General procedure for the synthesis of 2-bromo-2-chloro-2-fluoromethyl ketones.

Copper(II) triflate (0.10 equiv.) and (4R,5S)-bis(4,5-diphenyl-4,5-dihydrooxazol-2-yl)methane

(0.12 equiv.) in 0.5 mL of anhydrous tetrahydrofuran were stirred together under inert atmosphere

for one hour. The complex solution was added to a solution of the corresponding 1-aryl-2-chloro-

2,4,4,4-tetrafluoro-3,3-dihydroxybutanone (1.0 equiv.), N-bromosuccinimide (1.5 equiv.) and

potassium carbonate (2.5 equiv.) in 0.5 mL of anhydrous tetrahydrofuran under inert atmosphere.

The mixture was stirred vigorously until conversion of the starting material was complete based

on 19F NMR analysis. The crude product was loaded onto a silica gel column and purified by flash

chromatography using hexanes as mobile phase.

2-Bromo-2-chloro-2-fluoro-1-phenylethan-1-one (8). Compound 8 was obtained as a colorless

liquid in 90% yield (45 mg, 0.18 mmol) from 2-chloro-2,4,4,4-tetrafluoro-3,3-dihydroxy-1-

phenylbutan-1-one (57 mg, 0.2 mmol) by following the general procedure described above. Rf =

0.5 (hexanes); 1H NMR (400 MHz, Chloroform-d): δ = 8.19 (d, J = 7.9 Hz, 2H), 7.66 (dd, J = 7.9,

7.5 Hz, 1H), 7.52 (dd, J = 7.5, 7.5 Hz, 2H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 182.3

(d, JC-F = 24.7 Hz), 134.7, 131.0 (d, JC-F = 3.5 Hz), 129.0 (d, JC-F = 2.2 Hz), 128.7, 103.6 (d, JC-F =

319.3 Hz) ppm; 19F NMR (376 MHz, Chloroform-d) δ = -60.6 ppm; Anal. Calcd. for C8H5BrClF:

C, 38.21; H, 2.00. Found: C, 37.91; H, 1.88.

2-Bromo-2-chloro-2-fluoro-1-(naphthalen-2-yl)ethan-1-one (10). Compound 10 was obtained

as a colorless liquid in 98% yield (59 mg, 0.19 mmol) from 2-chloro-2,4,4,4-tetrafluoro-3,3-

dihydroxy-1-(naphthalen-2-yl)butan-1-one (67 mg, 0.2 mmol) by following the general procedure

described above. Rf = 0.4 (hexanes); 1H NMR (400 MHz, Chloroform-d): δ = 8.80 (s, 1H), 8.16

(d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 10.1, 10.7 Hz, 2H), 7.67 (dd, J = 8.2,

8.1 Hz, 1H), 7.60 (dd, J = 7.1, 7.9 Hz, 1H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 182.3

98

(d, JC-F = 24.6 Hz), 136.0, 133.6 (d, JC-F = 4.5 Hz), 132.1, 130.1, 129.7, 128.5, 127.8, 127.2, 126.1

(d, JC-F = 2.1 Hz), 125.6 (d, JC-F = 2.6 Hz), 103.9 (d, JC-F = 319.5 Hz) ppm; 19F NMR (376 MHz,

Chloroform-d) δ = -59.9 ppm; Anal. Calcd. for C12H7BrClFO: C, 47.80; H, 2.34. Found: C, 47.78;

H, 2.36.

2-Bromo-2-chloro-1-(4-chlorophenyl)-2-fluoroethan-1-one (11). Compound 11 was obtained

as a colorless liquid in 82% yield (47 mg, 0.16 mmol) from 2-chloro-1-(4-chlorophenyl)-2,4,4,4-

tetrafluoro-3,3-dihydroxybutan-1-one (64 mg, 0.2 mmol) by following the general procedure

described above. Rf = 0.5 (hexanes); 1H NMR (400 MHz, Chloroform-d): δ = 8.14 (d, J = 8.4 Hz,

2H), 7.49 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 181.3 (d, JC-F = 25.1

Hz), 141.5, 132.4 (d, JC-F = 3.7 Hz), 129.1, 127.5, 103.5 (d, JC-F = 318.8 Hz) ppm; 19F NMR (376

MHz, Chloroform-d) δ = -61.0 ppm; Anal. Calcd. for C8H4BrCl2FO: C, 33.61; H, 1.41. Found: C,

33.85; H, 1.39.

2-Bromo-2-chloro-2-fluoro-1-(furan-2-yl)ethan-1-one (12). Compound 12 was obtained as a

colorless liquid in 85% yield (41 mg, 0.17 mmol) from 2-chloro-2,4,4,4-tetrafluoro-1-(furan-2-yl)-

3,3-dihydroxybutan-1-one (55 mg, 0.2 mmol) by following the general procedure described above.

Rf = 0.6 (hexanes); 1H NMR (400 MHz, Chloroform-d): δ = 7.78 (d, J = 1.8 Hz, 1H), 7.55 (m, 1H),

6.66 (dd, J = 3.7, 1.7 Hz, 1H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 171.5 (d, JC-F = 26.5

Hz), 149.3 , 144.9, 123.9 (d, JC-F = 6.6 Hz), 112.9, 102.4 (d, JC-F = 317.8 Hz) ppm; 19F NMR (376

MHz, Chloroform-d) δ = -64.1 ppm; Anal. Calcd. for C6H3BrClFO2: C, 29.85; H, 1.25. Found: C,

29.97; H, 1.29.

99

7.4.2.3 General procedure for the Wittig olefination of 2-bromo-2-chloro-2-fluoromethyl

ketones.

The 2-bromo-2-chloro-2-fluoromethyl ketone (1.0 equiv.) and benzyl 2-(triphenyl-

phosphanylidene)acetate (1.2 equiv.) were dissolved in 1 mL of anhydrous tetrahydrofuran under

inert atmosphere at room temperature. The reaction was monitored by TLC using hexanes/ethyl

acetate (96:4) as mobile phase. The crude product was purified by flash chromatography on silica

gel using hexanes/ethyl acetate (96:4).

Benzyl (E)-4-bromo-4-chloro-4-fluoro-3-phenylbut-2-enoate (16). Compound 16 was obtained

as a colorless solid in 81% yield (62 mg, 0.16 mmol) from 2-bromo-2-chloro-2-fluoro-1-

phenylethan-1-one (50.3 mg, 0.2 mmol) by following the general procedure described above. Rf =

0.4 (hexanes / EtOAc, 9:1); 1H NMR (400 MHz, Chloroform-d) δ = 7.45 – 7.35 (m, 5H), 7.29 (m,

3H), 7.16 – 7.05 (m, 2H), 6.57 (s, 1H), 4.97 (s, 2H) ppm; 13C NMR (100 MHz, Chloroform-d) δ =

164.1 (d, JC-F = 1.2 Hz), 152.9 (d, JC-F = 18.4 Hz), 135.0, 132.4 (d, JC-F = 1.5 Hz), 130.0, 129.1,

128.5, 128.4, 128.3, 127.8, 120.1 (d, JC-F = 9.8 Hz), 105.4 (d, JC-F = 310.7 Hz), 66.9 ppm; 19F NMR

(376 MHz, Chloroform-d) δ = -54.2 ppm. Anal. Calcd. for C17H13O2BrClF: C, 53.22; H, 3.42.

Found: C, 53.30; H, 3.04.

Benzyl (E)-4-bromo-4-chloro-4-fluoro-3-(naphthalen-2-yl)but-2-enoate (17). Compound 17

was obtained as a colorless solid in 92% yield (43 mg, 0.11 mmol) from 2-chloro-2,4,4,4-

tetrafluoro-3,3-dihydroxy-1-(naphthalen-2-yl)butan-1-one (36 mg, 0.12 mmol) by following the

general procedure described above. mp: 102-105 °C; Rf = 0.2 (hexanes / EtOAc, 98:2); 1H NMR

(400 MHz, Chloroform-d): δ = 7.88 – 7.81 (m, 4H), 7.57 – 7.51 (m, 2H), 7.47 (d, J = 8.3 Hz, 1H),

7.20 (dd, J = 7.5, 7.4 Hz, 1H), 7.10 (dd, J = 7.6, 7.5 Hz, 2H), 6.91 (d, J = 7.4 Hz, 2H), 6.67 (s,

1H), 4.93 (s, 2H) ppm; 13C NMR (100 MHz, Chloroform-d): δ = 164.2, 152.6 (d, JC-F = 18.5 Hz),

100

134.7, 133.3, 132.5, 129.9, 129.4, 128.4, 128.3, 128.2, 128.2, 127.8, 127.6, 127.3, 126.9, 126.4,

120.5 (d, JC-F = 9.8 Hz), 105.5 (d, JC-F = 310.8 Hz), 66.9 ppm; 19F NMR (376 MHz, Chloroform-

d) δ = -53.8 ppm; Anal. Calcd. for C21H15BrClFO2: C, 58.16; H, 3.49. Found: C, 58.22; H, 3.55.

Benzyl (E)-4-bromo-4-chloro-3-(4-chlorophenyl)-4-fluorobut-2-enoate (18). Compound 18

was obtained as a colorless solid in 91% yield (62 mg, 0.15 mmol) from 2-bromo-2-chloro-1-(4-

chlorophenyl)-2-fluoroethan-1-one (46 mg, 0.16 mmol) by following the general procedure

described above. mp: 51-52 °C; Rf = 0.3 (hexanes / EtOAc, 98:2); 1H NMR (400 MHz,

Chloroform-d) δ = 7.36 – 7.28 (m, 7H), 7.15 – 7.10 (m, 2H), 6.58 (s, 1H), 5.00 (s, 2H) ppm; 13C

NMR (100 MHz, Chloroform-d) δ = 163.8 (d, JC-F = 1.6 Hz), 151.6 (d, JC-F = 18.8 Hz), 135.4,

134.7, 131.4, 130.8 (d, JC-F = 1.5 Hz), 128.6, 128.5, 128.4, 128.1, 120.6 (d, JC-F = 9.8 Hz), 105.0

(d, JC-F = 310.7 Hz), 67.1 ppm; 19F NMR (376 MHz, Chloroform-d) δ = -54.71 ppm. Anal. Calcd.

for C17H12BrCl2FO2: C, 48.84; H, 2.89. Found: C, 48.83; H, 2.89.

Ethyl (E)-4-bromo-4-chloro-4-fluoro-3-phenylbut-2-enoate (19). To a solution of 2-bromo-2-

chloro-2-fluoro-1-phenylethan-1-one (50 mg, 0.2 mmol) in anhydrous tetrahydrofuran was added

sodium hydride (10 mg, 0.24 mmol) at 0 °C under inert atmosphere. After stirring for 30 minutes,

triethyl phosphonoacetate (0.047 mL, 0.24 mmol) was added. The resulting solution was stirred

for 2 h at 0 oC and quenched with water. The organic phase was washed with brine, dried over

anhydrous sodium sulfate and the solvent was removed in vacuo. The crude product was purified

by flash chromatography on silica gel using hexanes/ethyl acetate (95:5) as mobile phase.

Compound 19 was obtained in 95% yield as a colorless liquid (61 mg, 0.19 mmol); Rf = 0.4

(hexanes / EtOAc, 19 : 1); 1H NMR (400 MHz, Chloroform-d): δ = 7.51 – 7.33 (m, 5H), 6.53 (s,

1H), 3.99 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, Chloroform-d):

δ = 164.3, 152.4 (d, JC-F = 18.5 Hz), 132.6 (d, JC-F = 1.5 Hz), 130.1, 129.0, 127.7, 120.4 (d, JC-F =

101

9.6 Hz), 105.4 (d, JC-F = 310.5 Hz), 60.9, 13.7 ppm; 19F NMR (376 MHz, Chloroform-d) δ = -54.3

ppm; Anal. Calcd. for C12H11BrClFO2: C, 44.82; H, 3.45. Found: C, 44.35; H, 3.61.


Figure 7.1. Crystal structure of rac-Benzyl (E)-4-bromo-4-chloro-4-fluoro-3-(naphthalen-2-

yl)but-2-enoate (17).

A single crystal of 17 was obtained by slow evaporation of a solution of the compound in

a mixture of ethyl acetate and hexanes (5% EtOAc in hexanes). Single crystal X-ray analysis was

performed by Zeus De los Santos at 296 K using a Siemens platform diffractometer with graphite

monochromated Mo-Kα radiation (λ = 0.71073 Å). Data were integrated and corrected using the

APEX II program. The structures were solved by SHELXT and refined with full-matrix least-

square analysis using SHELX-97-2 software. Non-hydrogen atoms were refined with anisotropic

displacement parameter. Crystal data: C21H15BrClFO2, M = 433.69, colorless needle, 0.12 x 0.07

x 0.05 mm3, orthorombic, space group P212121, a = 5.9238(9), b = 8.0989(12), c = 37.622(6) Å, V

=1805.0(5) Å3, Z = 4.

102

Chapter 8. Catalytic Enantioselective Ynamide Addition to Isatins

8.1. Introduction

The natural occurrence and pharmaceutical relevance of chiral oxindoles displaying a

tetrasubstituted stereogenic carbon center at the 3-position has received considerable attention

from medicinal and synthetic chemists in recent years.151 This is particularly the case for the family

of 3-substituted 3-hydroxyindolin-2-ones, which share an important structural motif commonly

found in alkaloids such as chimonamidine and various emerging drug candidates.152 To this end,

it was noticed that few reports on the asymmetric synthesis of chimonamidine 1, all suffering from

low overall yields, have appeared in the literature (Figure 8.1).

Figure 8.1. Previous work towards the synthesis of chimonamidine.151c,g,i

Retrosynthetic analysis pointed toward an unprecedented 3-(aminoethynyl)-3-hydroxyindolin-2-

one scaffold 2 that could be generated via catalytic enantioselective addition of terminal ynamides

to isatins 3 of which a wide variety is commercially available (Scheme 8.1). In contrast to alkyne

additions,153 incorporation of an ynamide moiety into readily available isatins generates unique

synthetic opportunities via late stage functionalization of the highly polarized N-substituted triple

bond to chiral 1,3-amino alcohols, β-hydroxy amides, β-hydroxy enamines and α-

acyloxyenamides. It was expected that this would ultimately streamline access to multifunctional

3-hydroxyoxindoles 4-7 and chimonamidine or other important alkaloids.

103

Scheme 8.1. Retrosynthetic analysis for the synthesis of multifunctional 3-hydroxyoxindoles.

Internal ynamides have found wide utility in numerous reactions, most notably cycloadditions,

cycloisomerizations, cross-couplings and ring-closing metathesis, and several examples of natural

product syntheses are known.154 Although terminal ynamides are readily available building

blocks,155 they remain underutilized compared to regular alkynes which have been exploited in

countless asymmetric 1,2-addition reactions with carbonyl electrophiles.156 This might be

attributed to the general difficulty with the enamide like reactivity of ynamides which are 103-105

times more nucleophilic than alkynes.157 Catalytic enantioselective additions with terminal

ynamides have not been applied in natural product synthesis to date.


The search for a catalytic asymmetric method that affords the key 3-(aminoethynyl)-3-

hydroxyindolin-2-one scaffold was initiated using N-methylisatin, 15a, and N-butyl-N-ethynyl-4-

methylbenzenesulfonamide, 14a, as test compounds. Following previous work on asymmetric

104

ynamide additions to aldehydes and trifluoromethylketones reported by Cook and Wolf,

stoichiometric amounts of Hünig’s Base and catalytic amounts of zinc triflate with chiral ligands

8 and 9 were tested (Figure 8.2).156c,e

Figure 8.2. Chiral ligands used in the asymmetric addition of ynamides.

Unfortunately, these conditions consistently provided high yields, but negligible asymmetric

induction regardless of the chiral ligands paired with the metal (Table 8.1, entries 1-4 and 16).

Exchanging the zinc catalyst for various copper salts revealed distinct counterion effects on the

yield and ee (Table 8.1, entries 5-6 and 8-15). With the exception of copper iodide, all copper

sources including CuOTf·Tol, Cu(OTf)2 and Cu(OAc)2 resulted in complete conversion to

product. Importantly, only the Wolf bisoxazolidine 10 provided significant enantioselectivity

across different copper catalysts. It was found that the use of copper(I) triflate in conjunction with

10 even in the absense of Hünig’s base resulted in 99% yield and 76% ee after 48 hours at 25 °C

(Table 8.1, entry 8).

105

Table 8.1. Screening of the catalytic system for the asymmetric addition of ynamides to isatins.

Entry Catalyst Ligand DIPEA Solvent Yield (%)b Ee (%)d

1 Zn(OTf)2 9 1.1 DCE 86 <1

2 Zn(OTf)2 8 1.1 Benzene 99 <1

3 Zn(OTf)2 11 1.1 DCE 94 +2

4 Zn(OTf)2 12 1.1 DCE 89 +1

5 CuI 11 1.1 DCM 64 +16

6 CuI 12 1.1 DCM 51 +17

7 13 none 1.1 DCE 54 +4

8 Cu(OTf)2 10 none CHCl3 99c -76

9 Cu(OTf)2 11 none CHCl3 <5 c n.d.

10 (CuOTf)2·Tol e 10 none CHCl3 99 c -79

11 (CuOTf)2·Tol e 12 none CHCl3 <5 c n.d.

12 Cu(OAc)2 10 none CHCl3 99 c -20

13 Cu(OAc)2 11 none CHCl3 99 c +2

14 CuI 10 none CHCl3 <50 c -80

15 CuI 11 none CHCl3 <50 c -9

16 Zn(OTf)2 10 none CHCl3 <5 c n.d.

a Reaction Conditions: 14a (75.4 mg, 0.3 mmol, 1.5 equiv.), 15a (33.2 mg, 0.2 mmol, 1 equiv.), catalyst (10 mol%),

ligand (15 mol%) in 0.1 mL of solvent. b Isolated yield. c Conversion determined by HPLC of the crude reaction

mixture on a Phenomenex Lux 5µ Cellulose-3 column (mobile phase = 85:15 hexanes-EtOH, flow rate = 1.0 mL/min,

λ = 254 nm). d Ee determined by chiral HPLC on a Phenomenex Lux 5µ Cellulose-3 column (mobile phase = 85:15

hexanes-EtOH, flow rate = 1.0 mL/min, λ = 254 nm), n.d. = not determined, +/- signs were assigned based on the

elution order where the major peak was the first/second to elute. e Reaction Conditions: 14a (75.4 mg, 0.3 mmol, 1.5

equiv.), 15a (33.2 mg, 0.2 mmol, 1 equiv.), catalyst (5 mol%), ligand (15 mol%) in 0.1 mL of solvent.

106

Table 8.2. Optimization of Isatin N-substitution, temperature and reaction time.a

Entry Isatin R Temperature (°C) Time (h) Yield (%)b Ee (%)c

1 Me 30 24 67 -84

2 Me 0 60 93 -90

3 Ph 30 24 78 -90

4 Ph 0 60 99 -98

5 Ac 30 24 75 -17

6 Ts 30 24 Decomposed n.d.

7 Bn 30 24 78 -83

8 Bn 0 60 54 -93

a Reaction Conditions: 14a (75.4 mg, 0.3 mmol, 1.5 equiv.), 15 (0.2 mmol, 1 equiv.), (CuOTf)2·Tol (10 mol%), 10

(15 mol%) in 0.1 mL of solvent. b Isolated yield. c Ee determined by chiral HPLC on a Phenomenex Lux 5µ Cellulose-

3 column (mobile phase = 85:15 hexanes-EtOH, flow rate = 1.0 mL/min, λ = 254 nm), n.d. = not determined.

Optimization of the reaction conditions proceeded by screening the reaction temperature and time

in an effort to improve the enantiomeric excess. Lowering the reaction temperature was found to

increase the enantiomeric excess, but required increased reaction times. Increasing the reactivity

of the electrophile by variation of the N-substitution on the isatin did not accelerate the reaction

(Table 8.2). Addition of N-butyl-N-ethynyl-4-methylbenzenesulfonamide, 14a, to N-phenylisatin,

15b, resulted in 99% yield and 98% ee after 60 hours at 0 °C (Table 8.2, entry 4). The effect of

solvent was studied and it was observed that chlorinated solvents provided the highest yields and

enantioselectivity (Table 8.3, entries 3 and 7). Chloroform is preferred over dichloromethane to

avoid issues due to solvent evaporation. It was also found that the exclusion of water was necessary

107

for this reaction to run successfully. The presence of water resulted in a byproduct that affected

both the yield and ee of the desired product.

Table 8.3. Optimization of the solvent.

Entry Isatin R Solvent Yield (%)b Ee (%)c

1 Me THF 46 -65

2 Me ACN 63 -3

3 Ph DCM 97 -90

4 Ph THF 36 -96

5 Ph Et2O 42 -68

6 Ph MTBE 61 -66

7 Ph CHCl3 99 -98

a Reaction Conditions: 14a (75.4 mg, 0.3 mmol, 1.5 equiv.), 15b (0.2 mmol, 1 equiv.), (CuOTf)2·Tol (10 mol%), 10

(15 mol%) in 0.1 mL of solvent. b Isolated yield. c Ee determined by chiral HPLC on a Phenomenex Lux 5µ Cellulose-

3 column (mobile phase = 85:15 hexanes-EtOH, flow rate = 1.0 mL/min, λ = 254 nm).

The Wolf bisoxazolidine was the only chiral ligand that provided sufficient asymmetric induction

and other bisoxazolidine ligands were evaluated to determine their efficacy. Compounds 17-19

outperformed other classes of chiral ligands, but 10 still provided the highest yields and

enantiomeric excess (Table 8.4). In addition to its performance, it can either be obtained

commercially or synthesized in a single step.

The catalysis proved to be ligand-accelerated and no reaction was observed after 48 hours

by 1H NMR and HPLC in the absence of 10. The reaction also does not proceed in the presence of

108

Hunig’s base without the necessary catalyst complex. The use of phenylacetylene in place of

ynamide 14 resulted in no observable reaction.

Table 8.4. Screening of chiral bisoxazolidine ligands.a

Entry Ligand Yield (%)b Ee (%)c

1 10 99 -98

2 17 99 -91

3 18 98 -85

4 19 93 -90

a Reaction Conditions: 14a (75.4 mg, 0.3 mmol, 1.5 equiv.), 15b (44.6 mg, 0.2 mmol, 1 equiv.), (CuOTf)2·Tol (5

mol%), ligand (15 mol%) in 0.1 mL of solvent. b Isolated yield. c Ee determined by chiral HPLC on a Phenomenex

Lux 5µ Cellulose-3 column (mobile phase = 85:15 hexanes-EtOH, flow rate = 1.0 mL/min, λ = 254 nm).

The optimized conditions were then applied to a range of substituted isatins and the

protocol was shown to tolerate various functional groups. The presence of halogens at the 5-

position on the isatin ring did not impact the yields or ee’s to any significant extent (Figure 8.3,

16b-16e, 16h). The introduction of a methyl group resulted in a slight lowering of the yield and

the OCF3 moiety resulted in a slight lowering of both yield and ee (Figure 8.3, 16g and 16i).

109

Substitution of the 4-position on the isatin ring also diminished the yield which is most likely a

result of steric interactions at the reaction site. N-PMP or N-methyl protected isatins were tolerated,

but the products of these substrates did incur small losses to yield and/or ee. Retrosynthetic analysis

of chimonamidine revealed that the ynamide must bear a methyl group rather than the n-butyl

substituent used in the current procedure. The protocol was therefore modified using N-ethynyl-

N-methyltolylsulfonamide as ynamide. The reaction proceeded with only minor modification

providing 16l in 99% yield and 96% ee in 60 hours at 10 °C. It should be noted that this method

can be applied to unprotected isatin with reasonable success over a similar timeframe.

Figure 8.3. Substrate scope of the catalytic asymmetric addition.

110

Crucial for the development of any synthetic process, it was found that this method can be scaled

from 50 mg to at least 1.5 g while maintaining similar yields and ee’s.

The advantages of these novel building blocks derive from the wide applicability of the 3-

hydroxyoxindole scaffold to the development of biologically relevant compounds and the synthetic

versatility of the ynamide functional group. The synthesis of chimonamidine continued with the

complete reduction of 16 to sulfonamide 20b by Pd catalyzed hydrogenation. During optimization

of this procedure, it was found that careful control of the reaction time and catalyst loading could

achieve selective hydrogenation and provide access to the (Z)-β-hydroxyenamide (Scheme 8.2).

Scheme 8.2. Reduction of the ynamide-isatin addition products.

The final step in the synthesis of chimonamidine required the deprotection of the

sulfonamide and subsequent transamidation of the newly formed amine. Sulfonamides are

111

notoriously difficult to cleave and this was further complicated by the presence of the acid-

sensitive chiral alcohol and the lactam ring in isatin. After screening literature methods to no avail,

it was found that magnesium in large excess could cleanly cleave the sulfonamide with

concomitant transamidation in a single step yielding 77% (S)-chimonamidine with 93% ee over

three steps (Scheme 8.3). This procedure was also successfully applied to other analogous

compounds resulting in novel variants of the natural product.

Scheme 8.3. Synthesis of chimonamidines by the reductive cleavage of the sulfonamide.

The absolute configuration of the natural product was determined by Zeus De los Santos using X-

ray crystallography of single crystals grown from slow evaporation of hexanes-ethyl acetate

solutions. The major enantiomer of the asymmetric addition product was determined to be in the

S configuration. Subsequent synthesis of the natural product from this compound did not break

any bonds about this stereogenic center and the major enantiomer of chimonamidine was assigned

the S configuration by analogy.

112

The products of the catalytic asymmetric ynamide addition provide access to

multifunctional 3-hydroxyoxindoles and the synthetic utility of the ynamide can be observed by

unique addition reactions of the polarized triple bond. Ynamides are well known to undergo

regioselective hydration and this can be exploited to provide access to unique amides. As a result

of the acid-sensitive tertiary alcohol present 16, it was necessary to devise a carefully controlled

protocol and 23 was obtained from 16l in 89% yield without loss of enantiomeric excess (Scheme

8.4). In contrast, the addition of excess benzoic acid to 16l under anhydrous conditions proceeded

smoothly to the N,O-ketene acetal 24 (Scheme 8.4).

Scheme 8.4. Derivatization of the ynamide-isatin addition product.

8.3. Conclusion

The first catalytic enantioselective addition of terminal ynamides to isatins was developed

and successfully used in the synthesis of the natural product (S)-Chimonamidine. The protocol

uses (CuOTf)2·Tol and commercially available 10 under base-free conditions to provide access to

113

synthetically versatile 3-hydroxyoxindoles in high yields and ee’s. The reaction can be upscaled

to at least 1.5 g. The versatility of the ynamide functionality was shown with its transformation to

a variety of functionalities including chiral 1,3-amino alcohols, β-hydroxy amides, β-hydroxy

enamines and α-acyloxyenamides produced in 99-78% yields.


8.4.1. General Information

Reagents, catalysts, ligands and anhydrous solvents were purchased and used without

further purification, unless otherwise stated. N-Substituted isatins and bisoxazolidines were

synthesized following literature procedures. Reactions were monitored by HPLC and/or thin layer

chromatography (TLC) carried out on EMD Millipore silica plates (60F 254), using 254 nm UV

light. Flash column chromatography was performed using a Biotage Isolera automated purification

systems on Luknova SuperSep silica cartridges (50 µm particle size). NMR spectra were recorded

at 400 MHz (1H NMR), 376 MHz (19F NMR) and 100 MHz (13C NMR) and were calibrated using

residual undeuterated solvent as an internal reference (CDCl3: 7.26 ppm 1H NMR, 77.16 ppm 13C

NMR). The following abbreviations were used to assign NMR peak multiplicities: s = singlet, d =

doublet, t = triplet, q = quartet, m = multiplet, br = broad.

8.4.2. Catalytic Asymmetric Addition of Ynamides to Isatins

The catalyst was prepared by stirring a solution of (CuOTf)2·Tol complex (5.3 mg, 0.010

mmol, 5 mol%) and bisoxazolidine 1 (11.5 mg, 0.030 mmol, 15 mol%) in anhydrous chloroform

(0.1 mL) at room temperature under N2 atmosphere for 1.5 h. This solution was added to a vial

containing ynamide (0.3 mmol, 1.5 equiv.) and isatin (0.2 mmol, 1 equiv.) at room temperature

under nitrogen atmosphere. The vial was sealed, cooled to the desired temperature and the resulting

114

solution was stirred until complete conversion of starting material. The reaction was monitored by

1H NMR and chiral HPLC on a Phenomenex Lux 5µ Cellulose-3. The crude product was purified

by column chromatography on silica gel and eluted with a gradient of dichloromethane-ethyl

acetate, as described below. Solvents were removed by evaporation under reduced pressure at 35

°C.

8.4.3. Product Syntheses and Characterizations

N-Butyl-N-((3-hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-4-methylbenzenesulfonamide

(16a). Compound 16a was obtained as an off-white solid in 93% yield (76.7 mg, 0.19 mmol) from

1-methylisatin (32.2 mg, 0.20 mmol) and N-butyl-N-ethynyl-4-methylbenzenesulfonamide (75.4

mg, 0.30 mmol) after 2.5 days at 10 °C by following the general procedure described above. The

crude product was purified using a gradient of dichloromethane-ethyl acetate (100:0 – 94:6); mp

= 108-113 °C (decomp.); The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-

3, hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254 nm): 90% ee, tR (minor) = 10.1 min, tR

(major) = 14.0 min; 1H NMR (400 MHz, chloroform-d): δ = 7.60 (d, J = 8.1 Hz, 2H), 7.43 (d, J =

7.4 Hz, 1H), 7.28 (dd, J = 7.7, 7.7 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.07 (dd, J = 7.7, 7.7 Hz, 1H),

6.75 (d, J = 7.9 Hz, 1H), 3.70 (bs, 1H), 3.19 (dd, J = 7.3, 7.3 Hz, 2H), 3.10 (s, 3H), 2.33 (s, 3H),

1.55 – 1.41 (m, 2H), 1.25 – 1.15 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, chloroform-

d): δ = 173.6, 144.7, 142.9, 134.1, 130.4, 129.8, 129.2, 127.8, 124.4, 123.6, 108.9, 80.2, 69.4, 68.7,

115

51.1, 29.9, 26.6, 21.7, 19.4, 13.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H24N2O4SNa:

435.1354; Found: 435.1351.

N-Butyl-N-((3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-methylbenzenesulfonamide

(16b). Compound 16b was obtained as an off-white amorphous solid in 99% yield (94.0 mg, 0.20

mmol) from 1-phenylisatin (44.6 mg, 0.20 mmol) and N-butyl-N-ethynyl-4-

methylbenzenesulfonamide (75.4 mg, 0.30 mmol) after 2.5 days at 0 °C by following the general

procedure described above. The crude product was purified using a gradient of dichloromethane-

ethyl acetate (100:0 – 96:4); The ee was determined by chiral HPLC (Phenomenex Lux 5µ

Cellulose-3, hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254 nm): 98% ee, tR (minor) = 10.3

min, tR (major) = 13.8 min; 1H NMR (400 MHz, chloroform-d): δ = 7.70 (d, J = 8.3 Hz, 2H), 7.58

(d, J = 7.4 Hz, 1H), 7.55 – 7.50 (m, 2H), 7.42 (m, 1H), 7.40 – 7.36 (m, 2H), 7.29 (dd, J = 7.8, 7.8

Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (dd, J = 7.6, 7.6 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.53 (s,

1H), 3.36 – 3.27 (m, 2H), 2.40 (s, 3H), 1.63 – 1.55 (m, 2H), 1.35 – 1.27 (m, 2H), 0.87 (t, J = 7.4

Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 172.9, 144.8, 143.0, 134.2, 133.9, 130.3, 129.8,

129.8, 128.8, 128.5, 127.9, 126.5, 124.9, 124.1, 110.2, 80.9, 69.7, 68.9, 51.1, 30.0, 21.7, 19.5, 13.6.

Anal. Calcd. for C27H26N2O4S: C, 68.33; H, 5.52; N, 5.90. Found: C, 67.97; H, 5.77; N, 5.82.

116

N-Butyl-N-((5-fluoro-3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16c). Compound 16c was obtained as an off-white amorphous solid

in 97% yield (95.6 mg, 0.19 mmol) from 5-fluoro-1-phenylisatin (48.2 mg, 0.20 mmol) and N-

butyl-N-ethynyl-4-methylbenzenesulfonamide (75.4 mg, 0.30 mmol) after 2.5 days at 0 °C by

following the general procedure described above. The crude product was purified using a gradient

of dichloromethane-ethyl acetate (100:0 – 96:4); The ee was determined by chiral HPLC

(Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254 nm):

95% ee, tR (minor) = 9.0 min, tR (major) = 12.8 min; 1H NMR (400 MHz, chloroform-d): δ = 7.72

(d, J = 8.0 Hz, 2H), 7.52 (dd, J = 7.7, 7.7 Hz, 2H), 7.42 (dd, J = 7.4, 7.4 Hz, 1H), 7.37 (d, J = 7.8

Hz, 2H), 7.30 – 7.23 (m, 3H), 6.98 (dd, J = 8.8, 8.8 Hz, 1H), 6.74 (dd, J = 8.7, 4.0 Hz, 1H), 3.85

(s, 1H), 3.40 – 3.27 (m, 2H), 2.41 (s, 3H), 1.64 – 1.54 (m, 2H), 1.35 – 1.27 (m, 2H), 0.87 (t, J =

7.4 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 172.7, 159.8 (d, 1JC-F = 243.3 Hz), 145.0,

138.9 (d, J = 2.3 Hz), 134.1, 133.8, 130.3 (d, J = 8.1 Hz), 129.9, 129.9, 128.6, 127.9, 126.4, 116.7

(d, 2JC-F = 23.6 Hz), 112.7 (d, 2JC-F = 25.1 Hz), 111.0 (d, 3JC-F = 7.8 Hz), 81.2, 69.6 (d, 4JC-F = 1.6

Hz), 68.3, 51.1, 30.0, 21.7, 19.5, 13.6. 19F NMR (376 MHz, chloroform-d): δ = -118.3 (ddd, J =

8.9, 7.4, 4.1 Hz, 1F). Anal. Calcd. for C27H25FN2O4S: C, 65.84; H, 5.12; N, 5.69. Found: C, 65.67;

H, 5.31; N, 5.77.

117

N-Butyl-N-((5-chloro-3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16d). Compound 16d was obtained as an off-white amorphous solid

in 96% yield (97.7 mg, 0.19 mmol) from 5-chloro-1-phenylisatin (51.5 mg, 0.20 mmol) and N-






(d, J = 8.3 Hz, 2H), 7.58 – 7.48 (m, 3H), 7.44 (dd, J = 7.5, 7.5 Hz, 1H), 7.37 (d, J = 7.0 Hz, 2H),

7.30 (d, J = 8.1 Hz, 2H), 7.28 – 7.21 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.60 (bs, 1H), 3.43 – 3.27

(m, 2H), 2.43 (s, 3H), 1.66 – 1.54 (m, 2H), 1.37 – 1.27 (m, 2H), 0.89 (t, J = 7.4, Hz, 3H). 13C NMR

(100 MHz, chloroform-d): δ = 172.5, 145.0, 141.5, 134.1, 133.6, 130.3, 130.3, 129.9, 129.9, 129.4,

128.8, 128.0, 126.4, 125.3, 111.3, 81.4, 69.5, 68.2, 51.2, 30.1, 21.8, 19.5, 13.6. Anal. Calcd. for

C27H25ClN2O4S: C, 63.71; H, 4.95; N, 5.50. Found: C, 63.59; H, 5.23; N, 5.48.

118

N-((5-Bromo-3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-N-butyl-4-

methylbenzenesulfonamide (16e). Compound 16e was obtained as an off-white amorphous solid

in 98% yield (108 mg, 0.20 mmol) from 5-bromo-1-phenylisatin (60.4 mg, 0.20 mmol) and N-






(d, J = 8.3 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.7, 7.7 Hz, 2H), 7.44 (dd, J = 7.4, 7.4

Hz, 1H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.69 (d, J =

8.4 Hz, 1H), 3.66 (bs, 1H), 3.41 – 3.29 (m, 2H), 2.43 (s, 3H), 1.65 – 1.56 (m, 2H), 1.37 – 1.28 (m,

2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 172.5, 145.0, 142.0, 134.1,

133.6, 133.1, 130.7, 129.9, 128.7, 128.1, 128.0, 127.9, 126.4, 116.5, 111.7, 81.4, 69.4, 68.3, 51.1,

30.0, 21.8, 19.5, 13.6. Anal. Calcd. for C27H25BrN2O4S: C, 58.59; H, 4.55; N, 5.06. Found: C,

58.37; H, 4.61; N, 5.02.

119

N-Butyl-N-((4-chloro-3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16f). Compound 16f was obtained as an off-white amorphous solid

in 87% yield (88.6 mg, 0.17 mmol) from 4-chloro-1-phenylisatin (51.5 mg, 0.20 mmol) and N-






(d, J = 8.3 Hz, 2H), 7.53 (dd, J = 7.5, 7.5 Hz, 2H), 7.44 (dd, J = 7.5, 7.5 Hz, 1H), 7.40 – 7.33 (m,

2H), 7.28 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 8.1, 8.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.69 (d, J =

7.9 Hz, 1H), 3.56 (bs, 1H), 3.41 – 3.28 (m, 2H), 2.41 (s, 3H), 1.69 – 1.59 (m, 2H), 1.33 (m, 2H),

0.88 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 171.7, 144.8, 144.6, 134.1, 133.5,

131.9, 131.2, 129.9, 129.8, 128.8, 127.9, 126.6, 125.6, 124.7, 108.6, 80.8, 69.6, 67.2, 51.2, 29.9,

21.7, 19.5, 13.6. Anal. Calcd. for C27H25ClN2O4S: C, 63.71; H, 4.95; N, 5.50. Found: C, 63.51; H,

5.18; N, 5.47.

120

N-Butyl-N-((3-hydroxy-5-methyl-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16g). Compound 16g was obtained as an off-white amorphous solid

in 93% yield (90.9 mg, 0.19 mmol) from 5-methyl-1-phenylisatin (47.5 mg, 0.20 mmol) and N-






(d, J = 8.2 Hz, 2H), 7.51 (dd, J = 7.7, 7.7 Hz, 2H), 7.46 – 7.33 (m, 4H), 7.24 (d, J = 7.6 Hz, 2H),

7.08 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 3.67 (bs, 1H), 3.39 – 3.23 (m, 2H), 2.40 (s, 3H),

2.38 (s, 3H), 1.67 – 1.51 (m, 2H), 1.38 – 1.27 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100

MHz, chloroform-d): δ = 172.9, 144.8, 140.6, 134.2, 134.1, 133.9, 130.6, 129.8, 129.7, 128.8,

128.3, 127.9, 126.4, 125.5, 109.9, 80.7, 69.8, 69.0, 51.1, 30.0, 21.7, 21.2, 19.5, 13.6. Anal. Calcd.

for C28H28N2O4S: C, 68.83; H, 5.78; N, 5.73. Found: C, 68.43; H, 5.94; N, 5.67.

121

N-Butyl-N-((3-hydroxy-5-methoxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16h). Compound 16h was obtained as an off-white amorphous solid

in 97% yield (97.9 mg, 0.19 mmol) from 5-methyoxy-1-phenylisatin (50.7 mg, 0.20 mmol) and

N-butyl-N-ethynyl-4-methylbenzenesulfonamide (75.4 mg, 0.30 mmol) after 2.5 days at 0 °C by





(d, J = 8.0 Hz, 2H), 7.52 (dd, J = 7.7, 7.7 Hz, 2H), 7.45 – 7.36 (m, 3H), 7.25 (d, J = 7.3 Hz, 2H),

7.19 (d, J = 2.6 Hz, 1H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H), 3.41

(s, 1H), 3.32 (dd, J = 7.2, 7.2 Hz, 2H), 2.41 (s, 3H), 1.67 – 1.53 (m, 2H), 1.37 – 1.26 (m, 2H), 0.88

(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 172.7, 157.1, 144.8, 136.3, 134.2,

134.2, 129.9, 129.8, 129.8, 128.3, 127.9, 126.3, 115.6, 111.1, 110.9, 81.0, 70.0, 68.9, 56.1, 51.1,

30.0, 21.8, 19.5, 13.7. Anal. Calcd. for C28H28N2O5S: C, 66.65; H, 5.59; N, 5.55. Found: C, 66.36;

H, 5.80; N, 5.50.

122

N-Butyl-N-((3-hydroxy-2-oxo-1-phenyl-5-(trifluoromethoxy)indolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16i). Compound 16i was obtained as an off-white amorphous solid

in 92% yield (103 mg, 0.18 mmol) from 5-trifluoromethyoxy-1-phenylisatin (61.4 mg, 0.20 mmol)

and N-butyl-N-ethynyl-4-methylbenzenesulfonamide (75.4 mg, 0.30 mmol) after 2.5 days at 0 °C

by following the general procedure described above. The crude product was purified using a

gradient of dichloromethane-ethyl acetate (100:0 – 96:4); The ee was determined by chiral HPLC

(Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 95:5, flow rate 1.0 mL/min, λ = 254 nm): 89%

ee, tR (minor) = 14.0 min, tR (major) = 18.4 min; 1H NMR (400 MHz, chloroform-d): δ = 7.72 (d,

J = 8.1 Hz, 2H), 7.54 (dd, J = 7.7, 7.7 Hz, 2H), 7.47 – 7.42 (m, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.27

(d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.98 (s, 1H), 3.41 – 3.24

(m, 2H), 2.41 (s, 3H), 1.66 – 1.51 (m, 2H), 1.36 – 1.27 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR

(100 MHz, chloroform-d): δ = 172.8, 145.63 (q, 3JC-F = 2.0 Hz), 145.0, 141.6, 134.1, 133.6, 130.2,

130.0, 129.9, 128.8, 127.9, 126.4, 123.4, 120.62 (q, 1JC-F = 257.1 Hz), 118.6, 110.9, 81.4, 69.5,

68.2, 51.1, 30.0, 21.7, 19.5, 13.5. 19F NMR (376 MHz, chloroform-d): δ = -58.3 (s, 3F). Anal.

Calcd. for C28H25F3N2O5S: C, 60.21; H, 4.51; N, 5.02. Found: C, 60.64; H, 4.94; N, 4.94.

123

N-Butyl-N-((3-hydroxy-1-(4-methoxyphenyl)-2-oxoindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide (16j). Compound 16j was obtained as an off-white amorphous solid

in 91% yield (91.8 mg, 0.18 mmol) from 1-(4-methoxyphenyl)isatin (50.7 mg, 0.20 mmol) and N-






(d, J = 8.3 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.30 – 7.22 (m, 5H), 7.16 (dd, J = 7.5, 7.5 Hz, 1H),

7.03 (d, J = 8.9 Hz, 2H), 6.74 (d, J = 7.9 Hz, 1H), 3.86 (s, 3H), 3.35 – 3.26 (m, 2H), 2.41 (s, 3H),

1.64 – 1.51 (m, 2H), 1.35 – 1.27 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, chloroform-

d): δ = 173.2, 159.5, 144.8, 143.4, 134.1, 130.3, 129.8, 128.8, 127.9, 127.9, 126.4, 124.8, 124.0,

115.1, 110.1, 80.7, 69.6, 68.9, 55.7, 51.1, 29.9, 21.7, 19.5, 13.6. Anal. Calcd. for C28H28N2O5S: C,

66.65; H, 5.59; N, 5.55. Found: C, 66.27; H, 5.78; N, 5.51.

124

N-((3-Hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-N,4-dimethylbenzenesulfonamide

(16k). Compound 16k was obtained as a yellow-white solid in 87% yield (75.3 mg, 0.17 mmol)

from 1-phenylisatin (44.6 mg, 0.20 mmol) and N-ethynyl-N,4-dimethylbenzenesulfonamide (62.8

mg, 0.30 mmol) after 2.5 days at 0 °C by following the general procedure described above. The

crude product was purified using a gradient of dichloromethane-ethyl acetate (100:0 – 94:6); mp

= 83-87 °C (decomp.); The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3,

hexanes/ethanol, 75:25, flow rate 1.0 mL/min, λ = 254 nm): 97% ee, tR (minor) = 21.0 min, tR


7.4 Hz, 1H), 7.52 (dd, J = 7.7, 7.7 Hz, 2H), 7.45 – 7.37 (m, 3H), 7.32 – 7.24 (m, 3H), 7.18 (dd, J

= 7.5, 7.5 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 3.85 (s, 1H), 3.05 (s, 3H), 2.41 (s, 3H). 13C NMR (100


128.1, 126.5, 125.0, 124.2, 110.2, 82.0, 69.5, 67.2, 38.9, 21.8. HRMS (ESI-TOF) m/z: [M + Na]+

Calcd for C24H20N2O4SNa: 455.1041; Found: 455.1033.

125

(S)-N-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-dimethylbenzenesulfonamide

(16l). Compound 16l was obtained as a white solid in 99% yield (73.3 mg, 0.20 mmol) from 1-

methylisatin (32.2 mg, 0.20 mmol) and N-ethynyl-N,4-dimethylbenzenesulfonamide (62.8 mg,

0.30 mmol) after 2.5 days at 10 °C by following the general procedure described above. The crude

product was purified using a gradient of dichloromethane-ethyl acetate (100:0 – 92:8); mp = 140-

143 °C; The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3,



7.4 Hz, 1H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.08 (dd, J = 7.5, 7.5 Hz, 1H),

6.76 (d, J = 7.8 Hz, 1H), 3.62 (bs, 1H), 3.10 (s, 3H), 2.95 (s, 3H), 2.34 (s, 3H). 13C NMR (100


108.9, 81.6, 69.3, 67.0, 38.9, 26.7, 21.8. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C19H18N2O4SNa: 393.0885; Found: 393.0881.

126

N-((3-Hydroxy-2-oxoindolin-3-yl)ethynyl)-N,4-dimethylbenzenesulfonamide (16m).

Compound 16m was obtained as a yellow crystal in 75% yield (53.5 mg, 0.15 mmol) from isatin

(29.4 mg, 0.20 mmol) and N-ethynyl-N,4-dimethylbenzenesulfonamide (62.8 mg, 0.30 mmol)

after 3 days at 10 °C by following the general procedure described above. The crude product was

purified using a gradient of dichloromethane-ethyl acetate-methanol (99:0:1 – 93:6:1); mp = 139-

142 °C (decomp.); The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3,


(major) = 22.1 min; 1H NMR (400 MHz, chloroform-d): δ = 8.21 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H),

7.50 (d, J = 7.6 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.13 (dd, J = 7.6, 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz,

1H), 4.02 (s, 1H), 3.00 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ = 175.7, 145.2,

139.9, 133.0, 130.5, 130.0, 129.7, 128.0, 125.1, 123.8, 110.7, 81.9, 69.7, 66.8, 38.9, 21.8. HRMS

(ESI-TOF) m/z: [M + Na]+ Calcd for C18H16N2O4SNa: 379.0728; Found: 379.0724.

127

8.4.4. Product Derivatization and Characterization

8.4.4.1. Reduction of the Ynamide-Isatin Addition Products

N-Butyl-N-(2-(3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethyl)-4-methylbenzenesulfonamide

(20a). N-Butyl-N-((3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-4-

methylbenzenesulfonamide, 16b, (100 mg, 0.21 mmol, 1 equiv.) and 10 wt% Pd/C (22.3 mg, 0.021

mmol, 10 mol%) were stirred in dichloromethane (9 mL) under H2 atmosphere (15 bar) for 72 h.

The reaction mixture was filtered through Celite and the crude product was purified by column

chromatography on silica gel and eluted with a gradient of dichloromethane-ethyl acetate (100:0 -

94:6). Compound 20a was obtained as an amorphous solid in 81% yield (81.4 mg, 0.17 mmol).

The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 85:15,

flow rate 1.0 mL/min, λ = 254 nm): 97% ee, tR (minor) = 10.7 min, tR (major) = 14.3 min; 1H NMR

(400 MHz, chloroform-d): δ = 7.56 (d, J = 8.2 Hz, 2H), 7.47 (dd, J = 7.6, 7.6 Hz, 2H), 7.43 – 7.37

(m, 2H), 7.35 – 7.31 (m, 2H), 7.25 (m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.12 (dd, J = 7.5, 7.5 Hz,

1H), 6.78 (d, J = 7.9 Hz, 1H), 3.73 (s, 1H), 3.33 – 3.16 (m, 2H), 3.14 – 3.00 (m, 2H), 2.37 (s, 3H),

2.25 (dd, J = 8.1, 8.1 Hz, 2H), 1.47 – 1.37 (m, 2H), 1.28 – 1.21 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H).

13C NMR (100 MHz, chloroform-d): δ = 176.9, 143.1, 143.0, 136.5, 133.8, 129.8, 129.6, 129.5,

129.4, 128.3, 127.1, 126.4, 124.2, 123.7, 109.9, 75.1, 48.1, 42.4, 37.5, 30.3, 21.5, 19.8, 13.7.

HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H30N2O4SNa: 501.1824; Found: 501.1816.

128

N-(2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethyl)-N,4-dimethylbenzenesulfonamide (20b).

N-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-dimethylbenzenesulfonamide, 16l, (100

mg, 0.27 mmol, 1 equiv.) and 10 wt% Pd/C (28.7 mg, 0.027 mmol, 10 mol%) were stirred in

dichloromethane (9 mL) under H2 atmosphere (15 bar) for 72 h. The reaction mixture was filtered

through Celite and the crude product was purified by column chromatography on silica gel and

eluted with a gradient of dichloromethane-ethyl acetate (100:0 – 92:8). Compound 20b was

obtained as a white solid in 92% yield (93.0 mg, 0.25 mmol). mp = 140-143 °C; The ee was

determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 85:15, flow rate

1.0 mL/min, λ = 254 nm): 93% ee, tR (minor) = 25.4 min, tR (major) = 28.4 min; 1H NMR (400

MHz, chloroform-d): δ = 7.54 (d, J = 8.0 Hz, 2H), 7.36 (dd, J = 7.6, 7.6 Hz, 2H), 7.28 – 7.24 (m,

2H), 7.12 (dd, J = 7.5, 7.5 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 3.31 (s, 1H), 3.18 (s, 3H), 3.16 – 3.07

(m, 1H), 2.91 (m, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H). 13C NMR (100 MHz,

chloroform-d): δ = 177.4, 143.7, 143.5, 134.0, 130.2, 129.7, 129.3, 127.6, 123.8, 123.3, 109.0,

75.2, 45.5, 35.6, 34.9, 26.4, 21.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H22N2O4SNa:

397.1198; Found: 397.1190.

129

8.4.4.2. Partial Reduction of Ynamide-Isatin Addition Products

(Z)-N-Butyl-N-(2-(3-hydroxy-2-oxo-1-phenylindolin-3-yl)vinyl)-4-

methylbenzenesulfonamide (21). N-Butyl-N-((3-hydroxy-2-oxo-1-phenylindolin-3-yl)ethynyl)-

4-methylbenzenesulfonamide, 16b, (100 mg, 0.21 mmol, 1 equiv.) and 10 wt% Pd/C (5.0 mg,

0.0047 mmol, 2.2 mol%) were stirred in dichloromethane (15 mL) under H2 atmosphere (10 bar)

for 16 h. The reaction mixture was filtered through Celite and the crude product was purified by

column chromatography on silica gel and eluted with a gradient of dichloromethane-ethyl acetate

(100:0 – 96:4). Compound 21 was obtained as a white solid in 95% yield (93.0 mg, 0.25 mmol).

mp = 117-119 °C; The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3,

hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254 nm): 92% ee, tR (major) = 10.7 min, tR

(minor) = 19.3 min; 1H NMR (400 MHz, chloroform-d): δ = 7.69 (d, J = 8.0 Hz, 2H), 7.62 (d, J =

7.3 Hz, 1H), 7.54 – 7.45 (m, 4H), 7.39 (dd, J = 7.1, 7.1 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.28 –

7.23 (m, 2H), 7.13 (dd, J = 7.5, 7.5 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 5.67 (d, J = 8.5 Hz, 1H),

5.34 (d, J = 8.6 Hz, 1H), 5.21 (s, 1H), 3.21 (m, 1H), 2.91 (m, 1H), 2.43 (s, 3H), 1.64 – 1.56 (m,

2H), 1.41 – 1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 174.7,

144.4, 143.4, 134.3, 133.5, 133.0, 130.0, 129.9, 129.9, 129.7, 128.3, 128.2, 128.0, 126.7, 125.7,

123.8, 109.9, 77.8, 51.6, 29.8, 21.7, 20.1, 13.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

C27H28N2O4SNa: 499.1667; Found: 499.1658.

130

8.4.4.3. Acid-Mediated Hydration of Ynamide-Isatin Addition Products

2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)-N-methyl-N-tosylacetamide (23). N-((3-Hydroxy-

1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-dimethylbenzenesulfonamide, 16l (100 mg, 0.27 mmol,

1 equiv.) and conc. HCl (2.2 µL, 0.027 mmol, 10 mol%) were stirred in 1:1 acetonitrile-water (4

mL) under nitrogen atmosphere for 72 h. The reaction mixture was extracted with ethyl acetate (3

x 15 mL) and the combined organics were washed with brine (1 x 15 mL) and dried over Na2SO4

followed by evaporation of solvents under reduced pressure. The crude product was purified by

column chromatography on silica gel and eluted with a gradient of dichloromethane-ethyl acetate

(100:0 - 90:10). Compound 23 was obtained as a white solid in 89% yield (93.3 mg, 0.24 mmol).

mp = 145-147 °C (decomp.); The ee was determined by chiral HPLC (Phenomenex Lux 5µ

Cellulose-3, hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254 nm): 91% ee, tR (major) = 28.1

min, tR (minor) = 32.8 min; 1H NMR (400 MHz, chloroform-d): δ = 7.69 (d, J = 8.0 Hz, 2H), 7.35

– 7.26 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 6.99 (dd, J = 7.5, 7.5 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H),

4.31 (s, 1H), 3.59 (d, J = 17.0 Hz, 1H), 3.21 (d, J = 17.4 Hz, 1H), 3.18 (s, 3H), 3.15 (s, 3H), 2.44

(s, 3H). 13C NMR (100 MHz, chloroform-d): δ = 175.9, 171.2, 145.5, 143.7, 135.7, 130.3, 130.2,

129.6, 127.5, 124.0, 123.2, 108.7, 74.2, 42.7, 33.1, 26.4, 21.8. HRMS (ESI-TOF) m/z: [M + Na]+

Calcd for C19H20N2O5SNa: 411.0991; Found: 411.0986.

131

8.4.4.4. Stereoselective Hydrobenzyloxylation of the Ynamide-Isatin Addition Products

(E)-1-((N,4-Dimethylphenyl)sulfonamido)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)vinyl

benzoate (24). N-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-

dimethylbenzenesulfonamide, 16l (100 mg, 0.27 mmol, 1 equiv.) and benzoic acid (330 mg, 2.7

mmol, 10 equiv.) were stirred in dichloromethane under a nitrogen atmosphere for 72 h. The

reaction mixture was purified by column chromatography on silica gel and eluted with a gradient

of dichloromethane-ethyl acetate (100:0 - 96:4). Compound 24 was obtained as an off-white solid

in 95% yield (126 mg, 0.26 mmol). mp = 169-172 °C (decomp.); The ee was determined by chiral

HPLC (Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 80:20, flow rate 1.0 mL/min, λ = 254

nm): 93% ee, tR (minor) = 19.3 min, tR (major) = 26.7 min; 1H NMR (400 MHz, chloroform-d): δ

= 7.64 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 6.7 Hz, 4H), 7.37 (dd, J = 7.7, 7.7 Hz, 1H), 7.29 (dd, J =

7.8, 7.8 Hz, 2H), 7.18 – 7.09 (m, 3H), 6.89 (d, J = 7.8 Hz, 1H), 6.08 (s, 1H), 4.04 (s, 1H), 3.28 (s,

3H), 2.76 (s, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, chloroform-d): δ = 175.4, 163.5, 143.9, 139.5,

134.7, 133.7, 130.1, 130.1, 130.0, 129.9, 129.9, 129.5, 128.2, 128.2, 124.4, 123.3, 123.0, 108.7,

74.6, 36.0, 26.5, 21.4.HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C26H24N2O6SNa: 515.1253;

Found: 515.1244.

132

8.4.4.5. Magnesium-Mediated Sulfonamide Cleavage of Reduced Ynamide Addition

Products

(S)-3-Hydroxy-1-methyl-3-(2-(methylamino)phenyl)pyrrolidin-2-one, (S)-Chimonamidine

(22a). N-(2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethyl)-N,4-dimethylbenzenesulfonamide,

20b, (50.0 mg, 0.13 mmol, 1 equiv.) and magnesium turnings (312 mg, 13 mmol, 100 equiv.) were

stirred in methanol under nitrogen atmosphere for 16 h. The reaction mixture was extracted with

ethyl acetate (3 x 15 mL) and the combined organics were washed with brine (1 x 15 mL) and

dried over Na2SO4 followed by evaporation of solvents under reduced pressure. The crude product

was purified by column chromatography on silica gel and eluted with a gradient of

dichloromethane-ethyl acetate (100:0 - 90:10). Compound 22a was obtained as a clear crystal in

85% yield (24.3 mg, 0.11 mmol). mp = 137-146 °C (decomp.); The ee was determined by chiral

HPLC (Phenomenex Lux 5µ Cellulose-3, hexanes/ethanol, 85:15, flow rate 1.0 mL/min, λ = 254

nm): 93% ee, tR (major) = 6.3 min, tR (minor) = 15.0 min; 1H NMR (400 MHz, chloroform-d): δ

= 7.21 (dd, J = 7.8, 7.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.63 (dd, J =

7.5, 7.5 Hz, 1H), 5.81 (bs, 1H), 4.29 (bs, 1H), 3.30 (dd, J = 8.7, 8.7 Hz, 1H), 3.22 (m, 1H), 2.96

(s, 3H), 2.83 (s, 3H), 2.71 (dd, J = 12.8, 6.2 Hz, 1H), 2.39 (m, 1H). 13C NMR (100 MHz,

chloroform-d): δ = 175.2, 148.3, 129.4, 125.4, 124.6, 116.6, 111.7, 79.7, 45.7, 33.1, 30.3, 30.2.

HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H17N2O2: 221.1290; Found: 221.1286.

133

3-Hydroxy-1-methyl-3-(2-(phenylamino)phenyl)pyrrolidin-2-one (22b). N-(2-(3-Hydroxy-2-

oxo-1-phenylindolin-3-yl)ethyl)-N,4-dimethylbenzenesulfonamide, 20a, (50.0 mg, 0.10 mmol, 1

equiv.) and magnesium turnings (243 mg, 10 mmol, 100 equiv.) were stirred in methanol under

nitrogen atmosphere for 16 h. The reaction mixture was extracted with ethyl acetate (3 x 15 mL)

and the combined organics were washed with brine (1 x 15 mL) and dried over Na2SO4 followed

by evaporation of solvents under reduced pressure. The crude product was purified by column

chromatography on silica gel and eluted with a gradient of dichloromethane-ethyl acetate (100:0 -

90:10). Compound 22b was obtained as a white solid in 78% yield (25.3 mg, 0.11 mmol). mp =

137-140 °C; The ee was determined by chiral HPLC (Phenomenex Lux 5µ Cellulose-3,

hexanes/ethanol, 95:5, flow rate 1.0 mL/min, λ = 254 nm): 93% ee, tR (minor) = 7.8 min, tR (major)

= 8.6 min; 1H NMR (400 MHz, chloroform-d): δ = 7.67 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.28 –

7.25 (m, 2H), 7.18 (dd, J = 7.7, 7.7 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 7.02 (dd, J = 7.7, 1.3 Hz,

1H), 6.93 (dd, J = 7.3, 7.3 Hz, 1H), 6.84 (dd, J = 7.5, 7.5 Hz, 1H), 4.27 (s, 1H), 3.49 (m, 1H), 3.37

– 3.29 (m, 2H), 3.23 (m, 1H), 2.68 (dd, J = 12.2, 5.6 Hz, 1H), 2.42 (m, 1H), 1.62 – 1.54 (m, 2H),

1.41 – 1.32 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, chloroform-d): δ = 174.8,

143.2, 143.1, 129.5, 129.4, 129.1, 126.4, 121.0, 120.8, 119.2, 118.5, 79.8, 43.8, 43.2, 34.1, 29.4,

20.3, 13.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H25N2O2: 325.1916; Found: 325.1908.

134

8.4.5. Crystallographic Analysis

Figure 8.4. Crystal structure of (S)-N-((3-Hydroxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-N,4-

dimethylbenzenesulfonamide (16l).

A single crystal of 16l was obtained by slow evaporation of a solution of the chiral product

in hexanes-ethyl acetate (90:10). Single crystal X-ray analysis was performed by Zeus De los





parameter. Crystal data: C19H18N2O4S, M = 370.41, colorless prism, 0.31 x 0.28 x 0.08 mm3,

monoclinic, space group P21 a = 9.1609(8), b = 5.7992(5), c = 16.5758(15) Å, V =879.65(13) Å3,

Z = 2. Absolute structure parameter = 0.045(61).

135

Figure 8.5. Crystal structure of 3-Hydroxy-1-methyl-3-(2-(methylamino)phenyl)pyrrolidin-2-

one (22a).

A single crystal of 22a was obtained by slow evaporation of a solution of the chiral product

in hexanes-ethyl acetate (90:10). Single crystal X-ray analysis was performed by Zeus De los





parameter. Crystal data: C12H16N2O2, M = 220.27, colorless prism, 0.43 x 0.28 x 0.11 mm3,

monoclinic, space group C2, a = 24.61(6), b = 6.578(16), c = 15.25(4) Å, V = 2219(10) Å3, Z = 8.

136

References and Notes

1 Wöhler, F. Ann. Phys. 1828, 88, 253-256.

2 Nicolaou, K. C.; Sorensoen, E. J.; Winssinger, N. J. Chem. Ed. 1998, 75, 1225-1258.

3 Nicolaou, K. C.; Snyder, S. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11929-11936.

4 Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008-2022.

5 a) Shena, Z.; Lu, C.; Zeng, S. J. Pharm. Anal. 2016, 6, 1-10. b) Murakami, H. Top. Curr. Chem.

2007, 269, 273-299.

6 Branca, M. A. C&EN Supplement 2014, September, 8.

7 Lindberg, P.; Brandstrom, A.; Wallmark, B. Trends Pharmacol. Sci. 1987, 8, 399–402.

8 Olbe, L.; Carlsson, E.; Lindberg, P. Nat. Rev. Drug Discov. 2003, 2, 132-139.

9 Erlandsson, P.; Isaksson, R.; Lorentzon, P.; Lindberg, P. J. Chromatogr. 1990, 532, 305-319.

10 a) Carlsson, E. I.; Junggren, U. K.; Larsson, H. S.; von Wittken Sundell, G. W. Patent Appl. EP

074341 (Priority date: Aug. 13, 1981). b) Lindberg, P.; Brändström, A.; Wallmark, B.; Mattsson,

H; Rikner, L.; Hoffman, K.-J. J. Med. Res. Rev. 1990, 1, 1-54.

11 Brunel, J.-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J. Org. Chem. 1995, 60, 8086-8088.

12 Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Sörenson, H.; von Unge, S. Tetrahedron:

Asymmetry 2000, 11, 3819-3825.

13 LaMattina, J. C&EN 2009, 87, 31-63.

137

14 Heron, M. National Vital Statistics Reports 2018, 67, 1-74;

https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_06.pdf (accessed on 11/02/2018).

15 Wilson, P. W.; Garrison, R. J.; Castelli, W. P.; Feinleib, M.; McNamara, P. M.; Kannel, W. B.

Am. J. Cardiol. 1980, 46, 649–654.

16 Siperstein, M. D.; Fagan, V. M. J. Biol. Chem. 1966, 241, 602–609.

17 Popják, G.; Cornforth, J. W. Adv. Enzyme Regul. 1960, 22, 281–335.

18 Endo, A. Proc. Jpn. Acad., Ser. B 2010, 86, 484-493.

19 a) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe Jr., E. J.; Deana, A. A.; Gilfillan, J.

L.; Huff, J. W. ; Novello, F. C.; Prugh, J. D.; Smith, R. L.; Willard, A. K. J. Med. Chem. 1985,

28, 347-358. b) Stokker, G. E.; Alberts, A. W.; Anderson, P. S. Cragoe Jr., E. J.; Deana, A. A.;

Gilfillan, J. L.; Hirshfield, J.; Holtz, W. J.; Hoffman, W. F.; Huff, J. W.; Lee, T. J.; Novello, F. C.;

Prugh, J. D.; Rooney, C. S.; Smith, R. L.; Willard, A. K. J. Med. Chem. 1986, 29, 170-181.

20 Roth, B. D.; Ortwine, D. F.; Hoefle, M. L.; Stratton, C. D.; Sliskovic, D. R. ; Wilson, M. W.;

Newton, R. S. J. Med. Chem. 1990, 33, 21-31.

21 Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine, D. F.;

Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson, M. W. J. Med. Chem.

1991, 34, 357-366.

22 Sletzinger, M.; Verhoeven, T. R.; Volante, R. P.; McNamara, J. M.; Corley, E. G.; Liu, T. M.

H. Tetrahedron Lett. 1985, 26, 951-2954.

23 Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.; Roth, B. D.

Tetrahedron Lett. 1992, 33, 2279-2282.

138

24 Roth, B. D. Prog. Med. Chem. 2002, 40, 1-22.

25 a) Collins, T. J. J. Clean. Prod. 2017, 140, 93-110. b) Collins, T. J. Science 2001, 291, 48-49.

26 Welton T. Proc. R. Soc. A 2015, 471, 20150502.

27 Cséfalvay, E.; Akien, G. R.; Qi, L.; Horváth, I.T. Catal. Today 2015, 239, 50–55.

28 https://www.epa.gov/greenchemistry/basics-green-chemistry#definition (accessed on

11/02/2018).

29 Brundtland C. G. 1987 Oxford, UK: World Commission on Environment and Development,

Oxford University Press.

30 Dahl, R. Environ. Health Perspect. 2010, 118, A246-A252.

31 https://www.epa.gov/greenchemistry/basics-green-chemistry#twelve (accessed on

111/02/2018).

32 Koenig, S. G.; Leahy, D. K.; Wells, A. S. Org. Process Res. Dev. 2018, 22, 1344−1359.

33 Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742-15747.

34 a) Hawkins, J. M.; Stahl, S. S. Org. Process Res. Dev. 2015, 19, 1548-1553. b) Greene, J. F.;

Hoover, J. M.; Mannel, D. S.; Root, T. W.; Stahl, S. S. Org. Process Res. Dev. 2013, 17, 1247-

1251.

35 Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P.

M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17-22.

36 Moreland, R. B.; Goldstein, I.; Kim, N.; Traish, A. Trends Endocrinol. Metab. 1999, 10, 97-

104.

139

37 Dunn, P. J.; Galvin, S.; Hettenbach, K. Green Chem. 2004, 6, 43–48.

38 Burger, A. Prog. Drug Res. 1991, 37, 287-371.

39 Hansch, C. Drug Dev. Res. 1981, 1, 267.

40 b) Líma, L. M.; Barreiro, E. J. Curr. Med. Chem. 2005, 12, 23-49. b) Patani, G. A.; LaVoie, E.

J. Chem. Rev. 1996, 96, 3147-3176.

41 O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071-1081.

42 Shah, P.; Westwell, A. D. J. Enzyme Inhib. Med. Chem. 2007, 22, 527-540.

43 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.

44 Wong, D. T.; Bymaster, F. P.; Engleman, E. A. Life Sci. 1995, 57, 411-441.

45 Mabe, S.; Eller, J.; Champney, W. S. Curr. Microbiol. 2004, 49, 248-254.

46 Rabel, S. R.; Patel, M.; Sun, S.; Maurin, M. B. AAPS PharmSci. 2001, 3, 26-29.

47 Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015,

58, 8315−8359.

48 Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis Jr., H. R.; Yumibe, N.; Clader, J. W.; Burnett,

D. A. J. Med. Chem. 1998, 41, 973-980.

49 Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214–231.

50 L'Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; Laflamme, F.; Mirmehrabi,

M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401–3411.

51 Boulton, K.; Cross, B. E. J. Chem. Soc., Perkin Trans. 1 1981, 0, 427-432.

140

52 Zhou, J.; Jin, C.; Su, W. Org. Process Res. Dev. 2014, 18, 928−933.

53 (a) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210-1211. (b) Cozzi, P. G. Angew.

Chem., Int. Ed. 2007, 46, 2568-2571. (c) Greszler, S. N.; Malinowski, J. T.; Johnson, J. S. J. Am.

Chem. Soc. 2010, 132, 17393-17395.

54 (a) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549-2551. (b) Petrini, M.;

Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530-4535. (c) Adrian Jr., J. C.; Snapper, M. L. J.

Org. Chem. 2003, 68, 2143-2150. (d) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem.

Soc. 2003, 125, 11176-11177. (e) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,

128, 4976-4985. (f) Hlavinka, M. L.; Hagadorn, J. R. Tetrahedron Lett. 2006, 47, 5049-5053. (g)

Cozzi, P. G.; Mignogna, A.; Zoli, L. Pure Appl. Chem. 2008, 80, 891-901.

55 (a) Clark, J. D.; Weisenburger, G. A.; Anderson, D. K.; Colson, P.-J.; Edney, A. D.; Gallagher,

D. J.; Kleine, H. P.; Knable, C. M.; Lantz, M. K.; Moore, C. M. V.; Murphy, J. B.; Rogers, T. E.;

Ruminski, P. G.; Shah, A. S.; Storer, N.; Wise, B. E. Org. Proc. Res. Dev. 2004, 8, 51-61. (b)

Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymm. 2005, 16, 1913-1918. (c)

Yu, L.-T.; Ho, M.-T.; Chang, C.-Y.; Yang, T.-K. Tetrahedron: Asymm. 2007, 18, 949-962.

56 (a) Fujiwara, Y.; Katagiri, T.; Uneyama, K. Tetrahedron Lett. 2003, 44, 6161-6163. (b)

Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Tetrahedron: Asymm. 2005, 16, 213-221. (c)

Ribeiro, C. M. R.; de Farias, F. M. C. Mini-Rev. Org. Chem. 2006, 3, 1-10. (d) Kloetzing, R. J.;

Thaler, T.; Knochel, P. Org. Lett. 2006, 8, 1125-1128. (e) Shin, E.-K.; Kim, H. J.; Kim, Y.; Kim,

Y.; Park, Y. S. Tetrahedron Lett. 2006, 47, 1933-1935. (f) Xu, X.-H.; Qiu, X.-L.; Qing, F.-L.

Tetrahedron 2008, 64, 7353-7361.

141

57 (a) Fernandez-Ibanez, M. A.; Macia, B.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed.

2008, 47, 1317-1319. (b) Cozzi, P. G.; Benfatti, F.; Capdevila, M. G.; Mignogna, A. Chem.

Commun. 2008, 3317-3318. (c) Cozzi, P. G.; Mignogna, A.; Vicennati, P. Adv. Synth. Catal. 2008,

350, 975-978.

58 For examples of catalytic asymmetric Reformatsky reaction with ketones, see: (a) Cozzi, P. G.

Angew. Chem., Int. Ed. 2006, 45, 2951-2954. (b) Fernandez-Ibanez, M. A.; Macia, B.; Minnaard,

A. J.; Feringa, B. L. Chem. Commun. 2008, 2571-2573. (c) Cozzi, P. G.; Mignogna, A.; Zoli, L.

Synthesis 2007, 2746-2750. (d) Fernandez-Ibanez, M. A.; Macia, B.; Minnaard, A. J.; Feringa, B.

L. Org. Lett. 2008, 10, 4041-4044. For examples of catalytic enantioselective imino Reformatsky

reaction, see: (e) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600-3603. (f) Cozzi,

P. G.; Rivalta, E. Pure Appl. Chem. 2006, 78, 287-291. (g) Cozzi, P. G. Adv. Synth. Catal. 2006,

348, 2075-2079.

59 This ligand is commercially available at Strem (catalogue no. 07-0488), US Patent, 11/737,371,

2007. For a general overview on bisoxazolidine catalysis: Wolf, C.; Xu, H. Chem. Commun. 2011,

47, 3339-3350.

60 Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996-10997.

61 Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965-2968.

62 (a) Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831-1834. (b) Yearick Spangler, K.; Wolf, C. Org.

Lett. 2009, 11, 4724-4727.

63 (a) Xu, H.; Wolf, C. Chem. Commun. 2010, 46, 8026-8028. (b) Xu, H.; Wolf, C. Synlett 2010,

2765-2770. (c) Wolf, C.; Zhang, P. Adv. Synth. Catal. 2011, 353, 760-766.

142

64 Benfatti, F.; Cozzi, P. G. Tetrahedron: Asymmetry 2010, 21, 1503-1506.

65 Zhou, Y.; Tang, W.; Wang, W.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952-4953.

66 Soai, K.; Yamanoi, T.; Hikima, H.; Oyamada, H. J. Chem. Soc., Chem., Commun. 1985, 138-

139.

67 Fukuzawa, S. ; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000, 65, 1702-1706.

68 Chena, X.; Zhang, C.; Wu, H.; Yu, X.; Su, W.; Cheng, J. Synthesis 2007, 3233-3239.207

69 Zhou, Y. ; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K. ;

Liu, H. Chem. Rev. 2016, 116, 422-518.

70 (a) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802-5805. (b) Zhang, P.;

Wolf, C. J. Org. Chem. 2012, 77, 8840-8844. (c) Saidalimu, I.; Fang, X.; He, X. P.; Liang, J.;

Yang, X. Y.; Wu, F. H. Angew. Chem. Int. Ed. 2013, 52, 5566-5570. (d) Zhang, P.; Wolf, C.

Angew. Chem. Int. Ed. 2013, 52, 7869-7873. (e) Wu, C.; Li, G.; Sun, W.; Zhang, M.; Hong, L.;

Wang, R. Org. Lett. 2014, 16, 1960-1963. (f) Xie, C.; Wu, L.; Han, J.; Soloshonok, V. A.; Pan, Y.

Angew. Chem. Int. Ed. 2015, 54, 6019-6023. (g) Xie, C.; Dai, Y.; Mei, H.; Han, J.; Soloshonok,

V. A.; Pan, Y. Chem. Commun. 2015, 51, 9149-9152. (h) Saadi, J.; Wennemers, H. Nat. Chem.

2016, 8, 276-280. (i) Ding, R.; Wolf, C. Chem. Commun. 2016, 52, 3576-3579. (j) Balaraman, K.;

Moskowitz, M.; Liu, Y.; Wolf, C. Synthesis 2016, 48, 2376-2384. (k) Ding, R.; Bakhshi, P. R.;

Wolf, C. J. Org. Chem. 2017, 82, 1273-1278. For a general review: (l) Mei, H.; Acena, J. L.;

Soloshonok, V. A.; Roeschenthaler, G.-V.; Han, J. Eur. J. Org. Chem. 2015, 6401-6412.

71 (a) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2009, 48,

8037-8041. (b) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schürmann, M.; Preut,

143

H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735-740. (c) Mitsunuma, H.;

Shibasaki, M.; Kanai, M.; Matsunaga, S. Angew. Chem. Int. Ed. 2012, 51, 5217-5221. (d) Biswas,

P.; Paul, S.; Guin, J. Angew. Chem. Int. Ed. 2016, 55, 7756-7760.

72 (a) Wu, M.-Y.; He, W.-W.; Liu, X.-Y.; Tan, B. Angew. Chem. Int. Ed. 2015, 54, 9409-9413. (b)

Ohmatsu, K.; Ando, Y.; Ooi, T. J. Am. Chem. Soc. 2013, 135, 18706-18709. (c) Tan, B.; Candeias,

N. R.; Barbas, C. F. Nat. Chem. 2011, 3, 473-477. (d) Zhao, J.; Fang, B.; Luo, W.; Hao, X.; Liu,

X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2015, 54, 241-244. (e) Engl, O. D.; Fritz, S. P.;

Wennemers, H. Angew. Chem. Int. Ed. 2015, 54, 8193-8197.

73 (a) Gribkoff, V. K.; Starrett Jr., J. E.; Dworetzky, S. L.; Hewawasam, P.; Boissard, C. G.; Cook,

D. A.; Frantz, S. W.; Heman, K.; Hibbard, J. R.; Huston, K.; Johnson, G.; Krishnan, B. S.; Kinney,

G. G.; Lombardo, L. A.; Meanwell, N. A.; Molinoff, P. B.; Myers, R. A.; Moon, S. L.; Ortiz, A.;

Pajor, L.; Pieschl, R. L.; Post-Munson, D. J.; Signor, L. J.; Srinivas, N.; Taber, M. T.; Thalody,

G.; Trojnacki, J. T.; Wiener, H.; Yeleswaram, K.; Yeola, S. W. Nat. Med. 2001, 7, 471-477. (b)

Hewawasam, P.; Gribkoff, V. K.; Pendri, Y.; Dworetzky, S. I.; Meanwell, N. A.; Martinez, E.;

Boissard, C. G.; Post-Munson, D. J.; Trojnacki, J. T.; Yeleswaram, K.; Pajor, L. M.; Knipe, J.;

Gao, Q.; Perrone, R.; Starrett Jr., J. E. Bioorg. Med. Chem. Lett. 2002 12, 1023-1026.

74 Selected examples: (a) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001,

123, 7001-7009. (b) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am.

Chem. Soc. 2005, 127, 10164-10165. (c) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.;

Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2005, 44, 4204-4207. (d) Ishimaru,

T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int.

Ed. 2008, 47, 4157-4161. (e) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Chem. Eur. J., 2011, 17,

14922-14928. (f) Shen, K.; Liu, X. H.; Lin, L. L.; Feng, X. M. Chem. Sci. 2012, 3, 327-334.

144

(g) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X. J. Org. Chem. 2012, 77, 9148-9155. (h)

Gu, X.; Zhang, Y.; Xu, Z.-J.; Che, C.-M. Chem. Commun. 2014, 50, 7870-7873. For an orthogonal

approach based on asymmetric ring construction, see (i) Wu, L.; Falivene, L.; Drinkel, E.; Grant,

S.; Linden, A.; Cavallo, L.; Dorta, R. Angew. Chem. Int. Ed. 2012, 51, 2870-2873.

75 (a) Dou, X.; Lu, Y. Org. Biomol. Chem. 2013, 11, 5217-5221. (b) Wang, T.; Hoon, D. L.; Lu,

Y. Chem. Commun. 2015, 51, 10186-10189. (c) Xie, C.; Zhang, L.; Sha, W.; Soloshonok, V. A.;

Han, J.; Pan, Y. Org. Lett. 2016, 18, 3270-3273. (d) Balaraman, K.; Wolf, C. Angew. Chem. Int.

Ed. 2017, 56, 1390-1395.

76 In some cases, sonication of the reaction mixture facilitates product precipitation and isolation

(see Experimental Section).

77 CCDC 1557938 contains the supplementary crystallographic data for bisoxindole 15. These data

can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the

Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (44)

1223-336-033; or [email protected])

78 Jin, Y.; Chen, M.; Ge, S.; Hartwig, J. F. Org. Lett. 2017, 19, 1390-1393.

79 Xie, C.; Sha, W.; Zhu, Y.; Han, J.; Soloshonok, V. A.; Pan, Y. RSC Adv. 2017, 7, 5679-5683.

80 Zhang, L.; Zhang, W.; Mei, H.; Han, J.; Soloshonok, V. A.; Pan, Y. Org. Biomol. Chem. 2017,

15, 311-315.

81 Thakur, P. B.; Meshram, H. M. RSC Adv. 2014, 4, 5343-5350.

82 1.43 g of 3 was isolated using 0.911 g of 1, 0.602 g of 2, 56.5 µL of Et3N and a total solvent

amount of 30 mL (reaction solvent and for product purification). For discussion of the E-factor:

145

(a) Sheldon, R. A. Chem. Ind. 1997, 12-15. (b) Andraos, J.; Sayed, M. J. Chem. Ed. 2007, 84,

1004-1010. (c) Sheldon, R. A. Green Chem. 2007, 9, 1273-1283.

83 Balaraman, K.; Ding, R.; Wolf, C. Adv. Synth. Catal. 2017, 359, 4165-4169.

84 Zhu, Y.; Zhang, W.; Mei, H.; Han, J.; Soloshonok, V. A.; Pan, Y. Chem. Eur. J. 2017, 23, 11221-

11225.

85 (a) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;

Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432-2506. (b) Smith, B. R.; Eastman, C. M.;

Njardarson, J. T. J. Med. Chem. 2014, 57, 9764-9773.

86 (a) Patani, G. A.; LaVoie, E. J. Chem. Rev., 1996, 96, 3147–3176. (b) Meanwell, N. A. J. Med.

Chem. 2018, 61, 5822−5880.

87 (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214-8264. (b) Yang,

X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826-870. (c) Zhou, Y.; Wang, J.; Gu,

Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116,

422-518.

88 Schenck, H. A.; Lenkowski, P. W.; Choudhury-Mukherjee, I.; Ko, S.-H.; Stables, J. P.; Patel,

M. K.; Brown, M. L. Bioorg. Med. Chem. 2004, 12, 979-993.

89 Sani, M.; Belotti, D.; Giavazzi, R.; Panzeri, W.; Volonterio, A.; Zanda, M. Tetrahedron Lett.

2004, 45, 1611-1615.

90 Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Org. Process Res. Dev. 2007, 11,

1015-1024.

146

91 Betageri, R.; Zhang, Y.; Zindell, R. M.; Kuzmich, D.; Kirrane, T. M.; Bentzien, J.; Cardozo, M.;

Capolino, A. J.; Fadra, T. N.; Nelson, R. M.; Paw, Z.; Shih, D.-T.; Shih, C.-K.; Zuvela-Jelaska, L.;

Nabozny, G.; Thomson, D. S. Bioorg. Med. Chem. Lett. 2005, 15, 4761-4769.

92 Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bacheler, L. T.;

Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.; Trainor, G. L.;

Anderson, P. S.; Erickson-Viitanen, S. K. J. Med. Chem. 2000, 43, 2019-2030.

93 Silva, A. M.; Cachau, R. E.; Sham, H. L.; Erickson, J. W. J. Mol. Biol. 1996, 255, 321-346.

94 Perrin, S. R.; Hauck, W.; Ndzie, E.; Blehaut, J.; Ludemann-Hombouger, O.; Nicoud, R.-M.;

Pirkle, W. H. Org. Process Res. Dev. 2007, 11, 817-824.

95 (a) Palomo, C.; Aizpurua, J. M.; Lopez, M. C.; Lecea, B. J. Chem. Soc. Perkin Trans. 1 1989,

1692-1694. (b) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003,

5, 3147-3150. (c) Yoshikazu, K.; Nobuya, K.; Teruaki, M. Chem. Lett. 2005, 34, 1508-1509. (d)

Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra Jr, J. R. J. Am. Chem. Soc. 2007, 129,

14864-14865. (e) Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009, 74, 5683-5686. (f) Fan, Y.-C.;

Du, G.-F.; Sun, W.-F.; Kang, W.; He, L. Tetrahedron Lett. 2012, 53, 2231-2233. (g) Kondo, M.;

Nishi, T.; Hatanaka, T.; Funahashi, Y.; Nakamura, S. Angew. Chem. Int. Ed. 2015, 54, 8198-8202.

(h) Kondo, M.; Kobayashi, N.; Hatanaka, T.; Funahashi, Y.; Nakamura, S. Chem. Eur. J. 2015,

21, 9066-9070. (i) Kondo, M.; Saito, H.; Nakamura, S. Chem. Commun. 2017, 53, 6776-6779.

96 (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 3147-

3150. (b) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632-13633.

(c) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Chem. Commun. 2005, 3600-3602. (d) Suto, Y.;

Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7, 3757-3760. (e) Fan, L.; Ozerov, O. V.

147

Chem. Commun. 2005, 4450-4452. (f) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Tetrahedron

2007, 63, 8598-8608. (g) Goto, A.; Endo, K.; Ukai, Y.; Irle, S.; Saito, S. Chem. Commun. 2008,

2212-2214. (h) Chakraborty, S.; Patel, Y. J.; Krause, J. A.; Guan, H. Angew. Chem. Int. Ed. 2013,

52, 7523-7526. (i) Sureshkumar, D.; Ganesh, V.; Kumagai, N. Shibasaki, M. Chem. Eur. J. 2014,

20, 15723-15726.

97 (a) Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J. J. Org. Chem. 1999, 64, 3090-3094.

98 Yin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610-9611.

99 (a) Hyodo, K.; Kondo, M.; Funahashi, Y.; Nakamura, S. Chem. Eur. J. 2013, 19, 4128-4134.

(b) Ren, Q.; Huang, J.; Wang, L.; Li, W.; Liu, H.; Jiang, X.; Wang, J. ACS Catal. 2012, 2, 2622-

2625. (c) Gajulapalli, V. P. R.; Vinayagam, P.; Kesavan, V. Org. Biomol. Chem. 2014, 12, 4186-

4191. For examples of decarboxylative aldol reactions with trifluoromethyl ketones: (d)

Khodakovskiy, P. V.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis 2009, 1099-1104. (e)

Zheng, Y.; Xiong, H.-Y.; Nie, J.; Hua, M.-Q.; Ma, J.-A. Chem. Commun. 2012, 48, 4308-4310.

100 Imamura, K.; Tomita, N.; Kawakita, Y.; Ito, Y.; Ono, K.; Nii , N.; Miyazaki, T.; Yonemori, K.;

Tawada, M.; Sumi, H.; Satoh, Y.; Yamamoto, Y.; Miyahisa, I.; Sasaki, M.; Satomi, Y.; Hirayama,

M.; Nishigaki, R.; Maezaki, H. Bioorg. Med. Chem. 2017, 25, 3768-3779.

101 (a) Leng, D. J.; Black, C. M.; Pattison, G. Org. Biomol. Chem. 2016, 14, 1531-1535. (b)

Balaraman, K.; Wolf, C. Angew. Chem. Int. Ed. 2017, 56, 1390-1395.

102 Cyanomethylations of acetophenone and 2’-fluoroacetophenone under optimized reaction

conditions were unsuccessful.

148

103 For Mannich-type reactions with β-phenylsulfonyl nitriles: (a) Gonzalez, P. B.; Lopez, R.;

Palomo, C. J. Org. Chem. 2010, 75, 3920-3922. (b) Ohmatsu, K.; Goto, A.; Ooi, T. Chem.

Commun. 2012, 48, 7913-7915.

104 (a) Leng, D. J.; Black, C. M.; Pattison, G. Org. Biomol. Chem. 2016, 14, 1531-1535. (b)

Balaraman, K.; Wolf, C. Angew. Chem. Int. Ed. 2017, 56, 1390-1395.

105 (a) Hua, W.; Xiaoming, Z.; Youhua, L.; Long, L. Org. Lett. 2006, 8, 1379-1381. (b) Tao, G.;

Ran, S.; Bin-Hua, Y.; Xiao-Yang, C.; Xing-Wen, S.; Guo-Qiang, L. Chem. Commun., 2013, 49,

5402-5404. (c) Wenchao, Y.; Laijun Z.; Chuanfa, N.; Jian, R.; Jinbo, H. Chem. Commun., 2014,

50, 10596-10599.

106 Pasteur, L. Ann. Chim. Physique 1848, 24, 442-459.

107 Gil-Av, E.; Feibush, B., Sigler, R. Tetrahedron Lett. 1966, 7, 1009-1015.

108 (a) Wolf, C. Chem. Soc. Rev. 2005, 34, 595-608. (b) Trapp, O. Chirality 2006, 18, 489-497. (c)

Trapp, O. Top. Curr. Chem. 2013, 341, 231-269.

109 (a) Schurig, V.; Bürkle, W. J. Am. Chem. Soc. 1982, 104, 7573-7580. (b) Bürkle, W.;

Karfunkel, H.; Schurig, V. J. Chromatogr. 1984, 288, 1-14. (c) Jung, M.; Schurig, V. J. Am. Chem.

Soc. 1992, 114, 529-534. (d) Schurig, V; Jung, M; Schleimer, M.; Klärner, F.-G. Chem. Ber. 1992,

125, 1301-1303.

110 (a) Melander, W. R.; Lin, H.-J.; Jacobsen, J.; Horváth, C. J. Chromatogr. 1982, 234, 269-276.

(b) Melander, W. R.; Lin, H.-J.; Jacobsen, J.; Horváth, C. J. Phys. Chem. 1984, 88, 4527-4536. (c)

Jacobsen, J.; Melander, W. R.; Vaisnis, G.; Horváth, C. J. Phys. Chem. 1984, 88, 4536-4542.

149

111 (a) Trapp, O.; Schurig, V. Comput. Chem. 2001, 25, 187-195. (b) Trapp, O. Chirality 2006, 18,

489-497.

112 (a) Cabrera, K.; Jung, M.; Fluck, M.; Schurig, V. J. Chromatogr. A 1996, 731, 315-321. (b)

Schoetz, G.; Trapp, O.; Schurig, V. Anal. Chem. 2000, 72, 2758-2764. (c) Trapp, O.; Schoetz, G.;

Schurig, V. Chirality 2001, 13, 403-414. (d) Schoetz, G.; Trapp, O.; Schurig, V. Electrophoresis

2001, 22, 3185-3190 (e) Trapp, O.; Schurig, V. Chirality 2002, 14, 465-470. (f) Trapp, O.; Schurig,

V.; Kostyanovsky, R. G. Chem. Eur J. 2004, 10, 951-957. (g) Wistuba, D.; Trapp, O.; Gel-Moreto,

N.; Galensa, R.; Schurig, V. Anal. Chem. 2006, 78, 3424-3433. (h) Trapp, O. Electrophoresis

2006, 27, 2999-3006. (i) Maier, F.; Trapp, O. Angew. Chem. Int. Ed. 2012, 51, 2985-2988. (j)

Maier, F.; Trapp, O. Chirality 2013, 25, 126-132. (k) Kamuf, M.; Trapp, O. Chirality 2013, 25,

224-229.

113 (a) Mannschreck, A.; Zinner, H.; Pustet, N. Chimia 1989, 43, 165-166. (b) Mannschreck, A.;

Kießl, L. Chromatographia 1989, 28, 263-266. (c) Stephan, B.; Zinner, H.; Kastner, F.;

Mannschreck, A. Chimia 1990, 44, 336-338.

114 (a) Villani, C.; Pirkle, W. H. Tetrahedron Asymm. 1995, 6, 27-30. (b) Villani, C.; Gasparrini,

F.; Pierini, M.; Mortera, S. L.; D'Acquarica, I.; Ciogli, A.; Zappia, G. Chirality 2009, 21, 97-103.

(c) Sabia, R.; Ciogli, A.; Pierini, M.; Gasparrini, F.; Villani, C. J. Chromatogr. A. 2014, 1363, 144-

149. (d) Sabia, R.; De Martino, M.; Cavazzini, A.; Villani, C. Chirality 2016, 28, 17-21.

115 (a) Wolf, C.; Pirkle, W. H.; Welch, C. J.; Hochmuth, D. H.; König, W. A.; Chee, G.-L.;

Charlton, J. L. J. Org. Chem. 1997, 62, 5208-5210. (b) Hochmuth, D. H.; König, W. A.

Tetrahedron Asymm. 1999, 10, 1089-1097. (c) Wolf, C.; Hochmuth, D. H.; König, W. A.; Roussel,

C. Liebigs Ann. 1996, 357-363.

150

116 (a) Klärner, F.-G.; Schröer, D. Angew. Chem. Int. Ed. Engl. 1987, 26, 1294-1295. (b) Veciana,

J.; Crespo, M. I. Angew. Chem. Int. Ed. 1991, 30, 74-77. (c) Oxelbark, J.; Allenmark, S. J. Chem.

Soc., Perkin Trans. 2 1999, 1587-1589. (d) Wolf, C.; Tumambac, G. E. J. Phys. Chem. 2003, 107,

815-817. (e) Wolf, C.; Xu, H. Tetrahedron Lett. 2007, 48, 6886-6889. (f) Díaz, J. E.; Vanthuyne,

N.; Rispaud, H.; Roussel, C.; Vega, D.; Orelli, L. R. J. Org. Chem. 2015, 80, 1689-1695.

117 Christie, G. H.; Kenner, J. J. Chem. Soc. 1922, 121, 614-620.

118 (a) Baudoin, O.; Guéritte, F. Stud. Nat. Prod. Chem. 2003, 29, 355-418. (b) Bringmann, G.;

Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563-639.

119 (a) Rao, A.V.R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem. Rev. 1995, 95, 2135-2167. (b)

Nicolaou, K. C.; Boddy, C. N. C.; Bräse, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38,

2096-2152. (c) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M.J.; Garner, J.;

Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.

120 Brunel, J. M. Chem. Rev. 2005, 105, 857-897.

121 Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801-1836.

122 Wolf, C. Dynamic Stereochemistry of Chiral Compounds, RSC Publishing, Cambridge, 2008,

p. 215.

123 (a) Mei, X.; Wolf, C. Chem. Commun. 2004, 2078-2079. (b) Tumambac, G. E.; Mei, X.; Wolf,

C. Eur. J. Org. Chem. 2004, 3850-3856. (c) Mei, X.; Wolf, C. J. Am. Chem. Soc. 2004, 126, 14736-

14737. (d) Tumambac, G. E.; Wolf, C. Org. Lett. 2005, 7, 4045-4048. (e) Wolf, C.; Liu, S.;

Reinhardt, B. C. Chem. Commun. 2006, 4242-4444. (f) Mei, X.; Wolf, C. Tetrahedron Asymm.

2006, 47, 7901-7904. (g) Mei, X.; Martin, R. M.; Wolf, C. J. Org. Chem. 2006, 71, 2854-2861.

151

(h) Mei, X.; Wolf, C. J. Am. Chem. Soc. 2006, 128, 13326-13327. (i) Liu, S.; Pestano, J. P. C.;

Wolf, C. J. Org. Chem. 2008, 73, 4267-4270. (j) Ghosn, M. W.; Wolf, C. J. Am. Chem. Soc. 2009,

131, 16360-16361. (k) Ghosn, M. W.; Wolf, C. J. Org. Chem. 2011, 76, 3888-3897. (l) Iwaniuk,

D. P.; Yearick-Spangler, K.; Wolf, C. J. Org. Chem. 2012, 77, 5203-5208. (m) Bentley, K. W.;

Wolf, C. J. Am. Chem. Soc. 2013, 135, 12200-12203. (n) Bentley, K. W.; Nam, Y. G.; Murphy, J.

M.; Wolf, C. J. Am. Chem. Soc. 2013, 135, 18052-18055. (o) Bentley, K. W.; Wolf, C. J. Org.

Chem. 2014, 79, 6517-6531. (p) Bentley, K. W.; Joyce, L. A.; Sherer, E. C.; Sheng, H.; Wolf, C;

Welch, C. J. J. Org. Chem. 2016, 81, 1185-1191.

124 Wolf, C. Dynamic Stereochemistry of Chiral Compounds, RSC Publishing, Cambridge, 2008,

pp.84-94.

125 (a) Rieger, M.; Westheimer, F. H. J. Am. Chem. Soc. 1950, 72, 19-28. (b) Hall, D. M.; Harris,

M. M. J. Chem. Soc. 1960, 490-494. (c) Melander, L.; Carter, R. E. J. Am. Chem. Soc. 1964, 86,

295-296. (d) Ling, C. K.; Harris, M. M. J. Chem. Soc. 1964, 1825-1835. (e) Mislow, K.; Gust, D.

J. Am. Chem. Soc. 1973, 95, 1535-1547. (f) Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc.

1980, 102, 5618-5626. (g) Wolf, C.; König, W. A.; Roussel, C. Liebigs Ann. 1995, 781-786. (h)

Weseloh, G.; Wolf, C.; König, W. A. Angew. Chem., Int. Ed. Engl. 1995, 34, 1635-1636. (i)

Weseloh, G.; Wolf, C.; König, W. A. Chirality 1996, 8, 441-445. (j) Wolf, C.; Ghebremariam, B.

T. Tetrahedron Asymm. 2002, 13, 1153-1156. (k) Tumambac, G. E.; Wolf, C. J. Org. Chem. 2004,

69, 2048-2055. (l) Tumambac, G. E.; Wolf, C. J. Org. Chem. 2005, 70, 2930-2938.

126 Xu, H.; Ekoue-Kovi, K.; Wolf, C. J. Org. Chem. 2008, 73, 7638-7650.

127 HPLC at higher temperatures was not conducted because of the limited thermal stability of the

chiral column.

152

128 Note that enantiomerization and racemization are related processes but not the same. A

racemization is complete when one enantiomeric form is converted to its racemate. An

enantiomerization is complete when one enantiomeric form is fully converted to the other

enantiomer. Therefore: kenantiomerization = 0.5 kracemization.

129 (a) Smith, B. R.; Eastman, C. M.; Njardarson, J. T. J. Med. Chem. 2014, 57, 9764-9773. (b)

Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;

Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432-2506.

130 Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.;

Liu, H. Chem. Rev. 2016, 116, 422-518.

131 (a) Hargreaves, M. K.; Barrett, G. C.; Hall, D. M.; Modarai, B. J. Chem. Soc. C 1971, 279-282.

(b) Hargreaves, M. K.; Modarai, B. J. Chem. Soc. C 1971, 1013-1015. (c) Doyle, T. R.; Vogl, O.

J. Am. Chem. Soc. 1989, 111, 8510-8511. (d) Doyle, T. R.; Vogl, O. Monatsh. Chem. 1990, 121,

31-43.

132 (a) Yang, Z.-Y. J. Org. Chem. 2003, 68, 4410-4416. (b) Zhao, Y.; Gao, B.; Hu, J. J. Am. Chem.

Soc. 2012, 134, 5790-5793.

133 (a) Kvicala, J.; Stambasky, J.; Skalicky, M.; Paleta, O. J. Fluorine Chem. 2005, 126, 1390-

1395. (b) Petko, K. I.; Kot, S. Y.; Yagupolskii, L. M. J. Fluorine Chem. 2008, 129, 1119-1123. (c)

Matsnev, A. V.; Qing, S.-Y.; Stanton, M. A.; Berger, K. A.; Haufe, G.; Thrasher, J. S. Org. Lett.

2014, 16, 2402-2405. (d) Shiosaki, M.; Inoue, M. J. Fluorine Chem. 2015, 175, 160-168.

134 Mei, H.; Nie, C.; Acena, J. L.; Soloshonok, V. A.; Roeschenthaler, G.-V.; Han, J. Eur. J. Org.

Chem. 2015, 6401-6412.

153

135 Prager, J. H.; Ogden, P. H. J. Org. Chem. 1968, 33, 2100-2102.

136 Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802-5805.

137 Prakash, G. K. S.; Zhang, Z.; Wang, F.; Munoz, S.; Olah, G. A. J. Org. Chem. 2013, 78, 3300-

3305.

138 (a) Han, C.; Kim, E. H.; Colby, D. A. Synlett 2012, 1559-1563. (b) Riofski, M. V.; Hart, A. D.;

Colby, D. A. Org. Lett. 2013, 15, 208-211.

139 Li, W.; Zhu, X.; Mao, H.; Tang, Z.; Cheng, Y.; Zhu, C. Chem. Commun. 2014, 50, 7521-7523.

140 (a) Xie, C.; Wu, L.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y. Tetrahedron Lett. 2014, 55,

5908-5910. (b) Xie, C.; Wu, L.; Zhou, J.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y. J. Fluorine

Chem. 2015, 172, 13-21. (c) Xie, C.; Wu, L.; Mei, H.; Soloshonok, V. A.; Han, J.; Pan, Y. Org.

Biomol. Chem. 2014, 12, 7836-7843. (d) Xie, C.; Wu, L.; Han, J.; Soloshonok, V. A.; Pan, Y.

Angew. Chem. Int. Ed. 2015, 54, 6019–6023. (e) Xie, C.; Dai, Y.; Mei, H.; Han, J.; Soloshonok,

V. A.; Pan, Y. Chem. Commun. 2015, 51, 9149-9152.

141 Wu, C.; Li, G.; Sun, W.; Zhang, M.; Hong, L.; Wang, R. Org. Lett. 2014, 16, 1960-1963.

142 (a) Saidalimu, I.; Fang, X.; He, X. P.; Liang, J.; Yang, X. Y.; Wu, F. H. Angew. Chem. Int. Ed.

2013, 52, 5566–5570. (b) Saidalimu, I.; Fang, X.; Lv, W.; Yang, X.; He, X.; Zhang, J.; Wu, F. H.

Adv. Synth. Catal. 2013, 355, 857-863.

143 (a) Zhang, P.; Wolf, C. J. Org. Chem. 2012, 77, 8840-8844. (b) Zhang, P.; Wolf, C. Angew.

Chem. Int. Ed. 2013, 52, 7869-7873.

144 John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163-9168.

145 Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191-5199.

154

146 The reaction was carried out with 5 equivalents of LiBr, 2.5 equivalents of K2CO3 and 2

equivalents of NBS using THF as solvent at rt. Complete conversion of 5 was observed within 1

hour.

147 The trapping of chlorofluoro-substituted enolates such as 7 with NIS or iodine is also possible

but the corresponding chlorofluoroiodomethyl ketones are considerable less stable than 8 and its

analogues.

148 Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745-1747.

149 The (Z)-isomer was not detected.

150 (a) Burton, D. J.; Koppes, W. M. J. Org. Chem. 1975, 40, 3026-3032. (b) Eguchi, T.; Aoyama,

T.; Kakinuma, K. Tetrahedron Lett. 1992, 33, 5545-5546.

151 a) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M.;

Angew. Chem., Int. Ed. 2008, 47, 4157-4161. b) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz,

B. M. Angew. Chem. Int. Ed. 2009, 48, 8037-8041. c) Bui, T.; Syed, S.; Barbas III, C. F. J. Am.

Chem. Soc. 2009, 131, 8758-8759. d) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.;

Schürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735-740. e)

Tan, B.; Candeias, N. R.; Barbas, C. F. Nat. Chem. 2011, 3, 473-477. f) Guo, C.; Song, J.; Huang,

J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong, L.-Z. Angew. Chem. Int. Ed. 2012, 51, 1046-1050. g) Wu,

L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden, A.; Cavallo, L.; Dorta, R. Angew. Chem. Int. Ed.

2012, 51, 2870-2873. h) Xie, W.; Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.;

Mae, D. Angew. Chem. Int. Ed. 2013, 52, 12924-12927. i) Mitsunuma, H.; Shibasaki, M.; Kanai,

M.; Matsunaga, S. Angew. Chem. Int. Ed. 2012, 51, 5217-5221. j) Zong, L.; Du, S.; Chin, K. F.;

Wang, C.; Tan, C.-H. Angew. Chem. Int. Ed. 2015, 54, 9390-9393. k) Zhao, J.; Fang, B.; Luo, W.;

155

Hao, X.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2015, 54, 241-244. l) Yu, J.-S.; Liao,

F.-M.; Gao, W.-M.; Liao, K.; Zuo, R.-L.; Zhou, J. Angew. Chem. Int. Ed. 2015, 54, 7381-7385. m)

Engl, O. D.; Fritz, S. P.; Wennemers, H. Angew. Chem. Int. Ed. 2015, 54, 8193-8197. n) Wu, M.-

Y.; He, W.-W.; Liu, X.-Y.; Tan, B. Angew. Chem. Int. Ed. 2015, 54, 9409-9413. o) Biswas, P.;

Paul, S.; Guin, J. Angew. Chem. Int. Ed. 2016, 55, 7756-7760. p) Sankar, M. G.; Garcia-Castro,

M.; Golz, C.; Strohmann, C.; Kumar, K. Angew. Chem. Int. Ed. 2016, 55, 9709-9713. q) Kong,

W.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2016, 55, 9714-9718. r) Balaraman, K.; Wolf, C.

Angew. Chem. Int. Ed. 2017, 56, 1390-1395. s) Balaraman, K.; Ding, R.; Wolf, C. Adv. Synth.

Catal. 2017, 359, 4165-4169. t) Ding, R.; Wolf, C. Org. Lett. 2018, 20, 892-895.

152 Selected examples: a) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593-1595. b) Itoh,

T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854-3857. c) Chen, W.-B.; Du, X.-L.; Cun, L.-

F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441-1446. d) Guo, Q.; Bhanushali, M.;

Zhao, C.-G. Angew. Chem. Int. Ed. 2010, 49, 9460-9464. e) Hara, N.; Nakamura, S.; Funahashi,

Y.; Shibata, N. Adv. Synth. Catal. 2011, 353, 2976-2980. f) Yang, Y.; Moinodeen, F.; Chin, W.;

Ma, T.; Jiang, Z.; Tan, C.-H. Org. Lett. 2012, 14, 4762-4765. g) Zhu, B.; Zhang, W.; Lee, R.; Han,

Z.; Yang, W.; Tan, D.; Huang, K.-W.; Jiang, Z. Angew. Chem. Int. Ed. 2013, 52, 6666-6670. h)

Ding, R.; Wolf, C. J. Org. Chem. 2017, 82, 1273-1278. i) Reddy, U. V. S.; Chennapuram, M.;

Seki, K.; Ski, C.; Anusha, B.; Kwon, E.; Okuyama, Y.; Uwai, K.; Tokiwa, M.; Takeshita, M.;

Nakano, H. Eur. J. Org. Chem. 2017, 3874-3885. j) Moskowitz, M. Balaraman, K.; Wolf, C. J.

Org. Chem. 2018, 83, 1661-1666. For asymmetric synthesis of isoindolinones, see k) Li, T.; Zhou,

C.; Yan, X.; Wang, J. Angew. Chem. Int. Ed. 2018, 57, 4048-4052.

156

153 a) Xu, N.; Gu, D.-W.; Zi, J.; Wu, X.-Y.; Guo, X.-X.; Org. Lett. 2016, 18, 2439-2442. b) Chen,

Q.; Tang, Y.; Huang, T.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2016, 55, 5286-5289.

c) Chen, L.; Huang, G.; Liu, M.; Huang, Z.; Chen, F.-R. Adv. Synth. Catal. 2018, 360, 3497-3501.

154 a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001,

57, 7575-7606. b) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840-2859.

c) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.

2010, 110, 5064-5106. d) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski,

B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560-578.

155 Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833-835.

156 a) Wang, X.-N.; Hsung, R. P.; Qi, R.; Fox, S. K.; Lv, M.-C. Org. Lett. 2013, 15, 2514-2517. b)

Wang, X.-N.; Hsung, R. P.; Fox, S. K.; Lv, M.-C.; Qi, R. Heterocycles 2014, 88, 1233-1254. c)

Cook, A. M.; Wolf, C. Chem. Commun. 2014, 50, 3151-3154. d) Cook, A. M.; Wolf, C.

Tetrahedron Lett. 2015, 56, 2377-2392. e) Cook, A. M.; Wolf, C. Angew. Chem. Int. Ed. 2016, 55,

2929-2933.

157 Laub, H. A; Evano, G.; Mayr, H. Angew. Chem. Int. Ed. 2014, 53, 4968-4971.

Applications of Asymmetric Catalysis and Green Chemistry ...

Documents

Transcript of Applications of Asymmetric Catalysis and Green Chemistry ...