A Dissertation

entitled

Applications of Ugi Four Component Cascade Coupling Reactions for the Synthesis of Bioactive Diverse Heterocyclic Molecules and Natural Products

by

Amarendar Reddy Maddirala

Submitted to the Graduate Faculty as partial fulfillment of the requirements for the

Doctor of Philosophy Degree in

Chemistry

______Dr. Peter R. Andreana, Committee Chair

______Dr. Joseph A. R. Schmidt, Committee Member

______Dr. Jianglong Zhu, Committee Member

______Dr. L. M. V. Tillekeratne, Committee Member

______Dr. Patricia R. Komuniecki, Dean College of Graduate Studies

The University of Toledo

May, 2016

Copyright 2016, Amarendar Reddy Maddirala

This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of

Applications of Ugi Four Component Cascade Coupling Reactions for the Synthesis of Bioactive Diverse Heterocyclic Molecules and Natural Products

by

Amarendar Reddy Maddirala

Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry

The University of Toledo

May, 2016

Isocyanide-based multicomponent reactions (IBMRs) have great advantages towards the assembly of complex molecules and are concise for the synthesis of higher ordered core structural motifs accomplished in a single synthetic transformation.

Complexity generating reactions have become quite useful in assembling molecules containing a variety of stereocenters in an economical and time-saving manner.

Particularly, the Ugi four component reaction sequence, followed by a variety of post condensation or transformational modifications allow the synthetic chemist to synthesize many biologically active molecules including those with diverse heterocyclic scaffolds and natural products. Of those types of molecules, 3-substituted-2-indolinone scaffolds have many important functions in biological systems including a wide-range of beneficial activities. From this perspective, the syntheses of 3-substituted-2-indolinones are an interesting target for an organic synthetic chemist to study the applications in medicinal chemistry. Our approach demands the efficient synthesis of 3-substituted-2-indolinones through microwave irradiation and selective intramolecular transamidation of the Ugi four component condensation derivative(s). Additionally, investigation for the ability of iii symmetrical versus unsymmetrical amine component(s) and carboxylic component(s) to eliminate the formation of rotameric mixtures obtained during the practice, simplifies

NMR analysis and allows for further molecular design amplification. Likewise, the synthesis of spiro-[indoline-3,2'-pyrrolidine]-2,5'-diones via post-Ugi-

4CR/transamidation/cyclization sequential process has been achieved in three steps in a one-pot reaction using methyl isocyanide as a convertible isocyanide. Variation in the carboxylic acid moiety allows for the generation of new quaternary carbon centers under basic reaction conditions and provides the molecular diversity in a small library of spirocyclic oxindole -lactams. Finally, bioactive natural products, xenortides A-D and their stereoisomers, were synthesized in a one-pot, two-step reaction using the methodology learned from the Ugi four component reaction.

iv

Acknowledgements

First of all I would like to express gratefulness to my research advisor Dr. Peter R.

Andreana for giving me an opportunity to carry out my research by motivating, mentoring and teaching me through every challenge that came in my way throughout my graduate studies. I would like to thank my committee members Dr. Joseph A.R Schmidt,

Dr. Jianglong Zhu, and Dr. L. M. V. Tillekeratne for helpful suggestions and criticisms for my Ph.D. Due acknowledgement is given to my past and present group members for the very useful discussions; chemistry related, maintenance of the laboratory and for keeping an extremely cordial environment in my work place. Also special thanks to my lab mate Krishnakant who was always there when I need help. My sincere appreciation for training and the help provided by Dr. Yong Wah Kim in NMR and MS experiments and Dr. Kristin Kirschbaum for providing X-ray crystallographic analysis, and Steve

Moder for making new glassware and repairing broken glass ware. I really appreciated everyone from stockroom for their help and Charlene Hansen and Pam for their help related to administration and teaching.

With deep gratitude I thank everyone from the department of chemistry and biochemistry at the University of Toledo, who helped me bring this graduate study to a successful completion and made my stay a meaningful one.

I am extremely grateful to my family members and friends for their constant encouragement and support throughout my study which made the tedious research look simple and easy

v

Table of Contents

Abstract ...... iii

Acknowledgements ...... v

Table of Contents ...... vi

List of Tables ...... ix

List of Figures ...... x

List of Schemes ...... xi

List of Abbreviations ...... xiii

List of Symbols ...... xv

1. Multicomponent Reactions Background...... 1

1.1. Introduction…………… ...... 1

1.2. History of multicomponent reactions……………...... 2

1.3. History of isocyanides……………...... 3

1.3.1. Isocyanide synthesis………………...... 3

1.4. Named isocyanide based multicomponent reactions ...... 7

1.4.1. Passerini reaction ...... 7

1.4.2. Ugi reaction ...... 9

1.4.3. Ugi-Smiles reaction ...... 10

1.5. Application of Ugi four component reaction ...... 12

1.5.1. Heterocyclic scaffolds synthesis ...... 12

1.5.2. Total synthesis of natural products ...... 13

1.5.3. Applications in Drug discovery ...... 16

vi

References……...... 19

2. Synthesis of 3-Substituted-2-Indolinones via a Multicomponent Coupling

Isocyanide Dependent Microwave-Assisted Intramolecular Transamidation

Process...... 25

2.1. Introduction…………… ...... 25

β.β. Results and Discussion…………… ...... 28

2.2.1. Feasibility study for intramolecular transamidation …………… ...28

2.2.2. Effect of isocyanide substitution and TFA catalyzed transamidation

reactions …………… ...... 30

2.2.3. Rotamers formation and challenges in NMR analysis …………… 34

2.2.3.1. Studying the effect of amine component on rotamer

formation………… ...... 35

2.2.3.2. Studying the effect of carboxylic acid component on rotamer

formation…………………………………………………………………37

β.γ. Conclusion…………… ...... 38

Experimental Section …………… ...... 40

References…………… ...... 77

3. Methyl Isocyanide as a Convertible Functional Group for the Synthesis of

Spirocyclic Oxindole –lactams via Post Ugi-4CR/Transamidation/Cyclization in

a One-pot Three Step Sequence...... …...... 82

3.1. Introduction…………… ...... 82

γ.β. Results and Discussion…………… ...... 85

3.2.1. Feasibility studies for one pot, three step reaction …………… ...... 85

vii

3.2.2. Optimization studies for base catalyzed cyclization …………… ...87

3.2.3. Investigation of substrate scope …………… ...... 88

3.2.4. Scope of base-catalyzed cyclization …………… ...... 89

γ.γ. Conclusion…………… ...... 91

Experimental Section…………… ...... 93

References…………… ...... 103

4. A One-Pot, Two-Step Total Synthesis of Natural Products Xenortide A-D and the

Complete Set of Stereoisomers Utilizing the Ugi MCR Process...... 106

4.1. Introduction…………… ...... 106

4.β. Results and Discussion…………… ...... 108

4.3. Conclusion…………… ...... 113

Experimental Section…………… ...... 114

References…………… ...... 120

Appendix A ...... 122

Supporting Information for Chapter 2 ...... 122

Appendix B ...... 134

Supporting Information for Chapter 3 ...... 134

Appendix C ...... 139

Supporting Information for Chapter 4 ...... 139

Appendix D ...... 157

X-ray crystallographic data ...... 157

viii

List of Tables

1.1 List of commonly used formylation and dehydrating agents, base...... 5

2.1 Reaction conditions leading to the formation of 8a and 9a...... 28

2.2 Scope of reaction conditions for compounds 1h, 8h and 9h when methyl

isocyanide is incorporated into 2h...... 32

3.1 Optimization conditions for intramolecular cyclization ...... 87

4.1 Effect of temperature on the one-pot synthesis...... 111

4.2 Scope of the one-pot reaction...... 112

ix

List of Figures

1.1 Known Convertible Isocyanides ...... 7

1.2 Passerini-3CR mechanism ...... 8

1.3 Ugi-4CR mechanism ...... 9

1.4 Ugi-Smiles 4-CR mechanism ...... 11

2.1 ORTEP diagram for compound 1h ...... 34

1 2.2 Temperature dependent H NMR (DMSO-d6) spectra showing rotameric mixtures

of 1h at 10.5-10.1 ppm (NH) when benzyl amine is used as a starting reagent

1 versus H NMR (DMSO-d6) spectra of 1i at 22 °C at ~ 10.3 ppm (NH) where

isopropyl amine is a starting reagent and rotamers are not evidenced ...... 36

2.3 Differences in amine starting reagents lead to 3-substituted-2-indolinone (analogs

for library - 1) amide rotameric mixtures ...... 37

2.4 Carboxylic acids as starting reagents do not influence the formation of rotamers

when the N-isopropyl substituent is a component of the 3o amide (2-indolinone

analogs for library - 2) ...... 38

3.1 ORTEP diagram for compound 7a ...... 86

3.2 Readily available and accessible starting materials ...... 88

3.3 Library of spiro[indoline-3,2'-pyrrolidine]-2,5'-diones analogs ...... 91

4.1 Library of natural products xenortides A-D and their epimers ...... 112

x

List of Schemes

1-1 Allyl isocyanide synthesis...... 4

1-2 Ethyl isocyanide synthesis ...... 4

1-3 General dehydration method for isocyanide synthesis ...... 4

1-4 Pirrung’s isocyanide synthesis ...... 5

1-5 Burgess reagent dehydrated isocyanide synthesis ...... 6

1-6 Leuckart-Wallach protocol for isocyanide synthesis ...... 6

1-7 Passerini-3CR sequence ...... 8

1-8 Ugi-4CR sequence ...... 9

1-9 Ugi-Smiles 4-CR sequence ...... 10

1-10 Hulme's UDC Strategy ...... 13

1-11 Concise total synthesis of (±)-veridic acid ...... 14

1-12 (-)-muraymycin D2 total synthesis ...... 15

1-13 ustiloin D total synthesis ...... 15

1-14 (±)-Praziquantel Synthesis ...... 17

1-15 Scalable Ugi-4CR synthesis for (R)-Lacosamide ...... 17

2-1 Retrosynthetic analysis for 2-indolinones 1 arising from an intramolecular Ugi

transamidation process following Bechamp-type reduction 2 made possible from

α-acylamino-2-nitrophenylacetamide precursors 3 ...... 27

2-2 Bulky isocyanides and 10% TFA lead to the formation of

3,4-dihydroquinazolines...... 31

xi

3-1 Previously reported post Ugi-CR methods for 2-oxindoles and spirocyclic 2-

oxindole synthesis ...... 84

3-2 Post Ugi 4-CR/transamidation/cyclization sequence ...... 84

3-3 Feasibility reaction for base-promoted cyclization ...... 86

3-4 Scope of the reaction ...... 89

3-5 Reaction scope and synthesis of spiro[indoline-3,2'-pyrrolidine]-2,5'-diones ...... 90

3-6 Synthesis of 5-HT6 (h5-HT6) receptors antagonist 8j ...... 91

4-1 Structures of natural product xenortides A-D and a retrosynthetic analysis ...... 108

4-2 Synthesis of 3a and 3b ...... 108

4-3 Two step synthesis of xenortide A (1a) and epi-xenortide A (1a’) ...... 109

4-4 One pot two step synthesis for 1a and 1a’ ...... 110

xii

List of Abbreviations

13C NMR Carbon-13 nuclear magnetic resonance spectroscopy

1H NMR Proton nuclear magnetic resonance spectroscopy

CSA Camphorsulphonic acid

DCE Dichloroethane

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMSO Dimethyl sulfoxide

Epi Epimer eq. Equivalents

ESI-MS Electrospray ionization mass spectroscopy

HIV Human immunodeficiency virus

HRMS High resolution mass spectroscopy

HT Hydroxy tryptamine

Leu Leucine

LRMS Low resolution mass spectroscopy

MCR Multicomponent reaction

MHz Megahertz

MsOH Methane sulfonic acid

MW Microwaves n-BuLi n-Butyl lithium

xiii

NMM N-Methylmorpholine

NMR Nuclear magnetic resonance spectroscopy

PMA Phosphomolybdic acid

P-TSA p-Toluene sulfonic acid

RT Room temperature

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TsCl p-Toluene sulfonyl chloride

Val Valine

xiv

List of Symbols

(COCl)2 Oxalyl chloride

AgCN Silver cyanide

AgOTf Silver triflate

AlCl3 Aluminum chloride

Ar Argon

BEt3 Triethyl borane

CeCl3 Cerium chloride

CH2Cl2 Dichloromethane

CH3CN Acetonitrile

CH3COOH Acetic acid

CH3OH Methanol

CHCl3 Chloroform

Cs2CO3 Cesium carbonate

Et2O Diethyl ether

Et3N Triethylamine

EtOAc Ethyl acetate

H2O Water

HCl Hydrochloric acid

HCO2Et Ethyl formate

HCO2H Formic acid

xv

HCO2Me Methyl formate

Hz Hertz

InCl3 Indium chloride

K2CO3 Potassium carbonate

KOtBu Potassium tertiary butoxide

M Molar

MeCN Acetonitrile

MeOH Methanol mL Milliliter mM Millimolar

Na2SO4 Sodium sulphate

NaHCO3 Sodium bicarbonate

NaOH Sodium hydroxide

NH4Cl Ammonium chloride

P2O5 Phosphorus pentoxide

PBr3 Phosphorous tribromide

Ph Phenyl

POCl3 Phosphoryl chloride

Sc(OTf)3 Scandium triflate

SOCl2 Thionyl chloride

TiBr4 Titanium tetrabromide

TiCl4 Titanium tetrachloride

Y(OTf)3 Ytterbium triflate

xvi

ZnCl2 Zinc chloride

xvii

Chapter 1

Multicomponent Reactions

1.1. Introduction

Traditional synthetic procedures in organic chemistry mainly utilize stepwise formation of new individual bonds which can lead to long and drawn-out routes to target molecules. There are several disadvantages with multi-step synthesis; it is not efficient, economically questionable and it can be time consuming, as well as a hurdle for synthesizing chemical libraries for high-throughput screening. Drug discovery is a challenging area of science since we need to choose highly atom economical, short reaction times, develop structurally diverse, and less complex reactions with readily available starting materials. All these important factors provide the opportunity to work on combinatorial chemistry which counts as a fundamental phenomenon in finding novel molecules for medicinal chemistry. In contrast to multi-step processes, one-pot transformations involving multicomponent reactions (MCR) and post modifications of

MCRs leads to highly valuable heterocyclic compounds, synthetic building blocks and also allows for the access of natural products; all have great importance in medicinal chemistry. A brief introduction of MCRs isocyanide-based multi component reactions,

Ugi four component cascade coupling reaction applications in heterocyclic compounds,

1

total synthesis of natural products, and drug discovery is given in the following sections.

1.2. History of Multi Component Reactions

Reactions in which three or more compounds combine and react with each other in a single pot to obtain a desired product are known as multi component reactions (MCRs)1.

MCRs have simple reaction procedures which are less time consuming, efficient and very atom economical. Due to the above mentioned qualities, the MCRs have great advantages and are very popular in all the areas of synthetic organic chemistry. The history of MCRs began with the first multi component reaction reported by Strecker2 in

1850 in which α-amino acid were synthesized by hydrolysis of α-amino nitriles. Later

Hantzsch3 in 1882 reported MCR method for the synthesis of dihydropyridines. In 1891,

Beginelli4 synthesized 3,4-dihydropyrimidin-2(1H)-one compounds using ethylacetoacetate, benzaldehyde, and urea similar to a one-pot, three component reaction.

Later, the Mannich reaction5 was reported in 1912 describing an amino alkylation of an enol with an aldehyde (formaldehyde) and amine (secondary amine or ammonia). In the year 1921, Passerini reported7 a new type of isocyanide-based reaction for α-acyloxy amide derivatives using carboxylic acid, aldehyde or ketone and isocyanide which assisted in the further evolution of isocyanide chemistry in multicomponent reactions.

The Ugi four component reaction6 was discovered in 1959 by Ivar Karl Ugi for α- aminoacyl amide synthesis (dipeptide type skeleton) from the key variables of aldehyde or ketone, amine, carboxylic acid and isocyanide (isonitrile) and this led to the emergence of isocyanide-based multicomponent developments in organic synthesis. Later,

2

variations in Passerini reaction (Passerini-Smiles reaction)8 and Ugi reaction (Ugi-Smiles reaction)9 were developed and other isocyanide-based MCRs are documented in the literature as a powerful tool in combinatorial chemistry and drug discovery process.

1.3. History of Isocyanides

Isocyanides, also known as isonitriles or carbylamines, are characterized by an R-

NC functional group and pungent odor. The first naturally occurring isocyanide,

Xanthocillin, was isolated by Rothe in 1950 and since then several other naturally occurring isocyanides10 have been isolated. In the last 3-4 decades, isocyanides were widely studied and used in the field of organic chemistry. It is well known that commercially available isocyanides are volatile with a pungent odor and they can cause intense dreams and sensory disorders.11 They have a potential to be used as non-lethal weapons.12 When Passerini, and Ivar Karl Ugi reported isocyanide-based multi component reactions it allowed the scientific community to use these reactions to develop processes focused on new isocyanide-based MCRs.

1.3.1. Isocyanide Syntheses

Isocyanides are key substances and play very important roles in MCRs to generate various functional group transformations. Previous literature about the utility of isocyanide applications are shown in following sections. However, there is still a need for a new synthetic approach to synthesize isocyanides.

The first synthetic isocyanide was reported by Leike13 in 1859 to make allyl isocyanide

3

(A3) using allyl iodide (A1) and silver cyanide (A2) (Scheme 1-1).

Scheme 1-1. Allyl isocyanide synthesis.

Hoffmann reported the synthesis of ethyl isocyanide14 (A5) by treating ethyl amine (A4) with chloroform and sodium hydroxide in the year 1868 (Scheme 1-2).

Scheme 1-2. Ethyl isocyanide synthesis.

The most famous isocyanide synthesis is the one reported by Ugi which involves the dehydration of formamide derived from amines.15 This method has helped in developing new variations of dehydration methods,16 and widely used in organic synthesis (Scheme

1-3). Various aliphatic, aromatic and chiral isocyanides synthesis have been reported in the literature, wherein the formylation of the amine A6 was performed using various formylating agents followed by the dehydration of formamide intermediates A7 under basic conditions using dehydrating agents16b, 16d (Table 1.1).

Scheme 1-3. General dehydration method for isocyanide synthesis.

4

Table 1.1. List of commonly used formylation and dehydrating agents, base.

formylating agents dehydrating agent base

triethylamine,

POCl3, P2O5, SOCl2, PBr3, DIPEA, HCO2H, HCO2Et,

(COCl)2, TsCl, phosgene, diphosgene, pyridine, NMM HCO2Me,

formylacetate triphosgene, EtOPOCl2 2,6-lutidine,

quinoline

Mike Pirrung11 reported a new synthetic route (Scheme 1-4) for 2-isocyanophenolate

(A10) from benzoxazole (A9) by deprotonation with n-BuLi and trapping using acyl chloride.

Scheme 1-4. Pirrung’s isocyanide synthesis.

McCarthy reported17 isocyanide synthesis (Scheme 1-5) using the Burgess reagent. The dehydration of formamide A11 using the Burgess reagent in dichloromethane under reflux condition yields isocyanide A12. This method was successfully applied for synthesizing various isocyanides.

5

Scheme 1-5. Burgess reagent dehydrated isocyanide synthesis.

Very recently, Dömling reported18 a novel synthetic route to synthesizing isocyanides via the alkyl or aryl formamide A13 intermediate synthesized from aldehyde A12 via the

Leuckart-Wallach procedure19 (Scheme 1-6).

Scheme 1-6. Leuckart-Wallach protocol for isocyanide synthesis.

To increase the molecular complexity and diversity by post modifications of isocyanide- based multi component reactions derived compounds, the convertible isocyanides A15-

A2620 have been developed and used in MCRs chemistry. A variety of functionality embedded in convertible isocyanides (Figure 1.1)21 have allowed us to generate new chemical bonds for new synthetic frameworks,22 including the exceptional ability of selective bond cleavage after incorporation of the desired stereocenter which is very useful for the synthesis of biologically valuable heterocyclic molecules and natural products.

6

Figure 1.1. Known convertible isocyanides.

1.4. Named Isocyanide-based Multicomponent Reactions

Isocyanides are key synthons for multicomponent reactions in constructing a wide variety of organic molecules and there are a few important isocyanide-based multicomponent reactions that were extensively used in making heterocyclic scaffolds.

Some of the important and popular reactions are as follows.

1.4.1. Passerini Reaction

The first isocyanide-based three component reaction was developed by Mario

Passerini (1921),7a in which an aldehyde or ketone A27, carboxylic acid A28 and isocyanide A29 are the key variable starting materials which react together in a one-pot reaction and form α-acyloxycarboxamide derivatives A30 (Scheme 1-7).

7

Scheme 1-7. Passerini-3CR sequence.

The most accepted mechanism of the Passerini reaction (Figure 1.2)7, 23 proceeds through simultaneous cyclic intermediates I-III formation by condensation of aldehyde or ketone

A27, carboxylic acid A28 and isocyanide A29. The intramolecular hydrogen bonding followed by the Mumm’s rearrangement,24 which is a key step for this reaction, provides the Passerini product A30.

Figure 1.2. Passerini-3CR mechanism.

8

1.4.2. Ugi Reaction

Isocyanide-based four component reactions were developed by Ivar K. Ugi in

1959 and involve aldehydes or ketones, amine carboxylic acids and isocyanides as the four key starting materials that are combined in a single pot to yield α-acyloxyamino- carboxamide derivatives A35 (Scheme 1-8). Variation in any of the four key components in the Ugi reaction exemplifies the diversity in product substitution patterns allowing the synthesis of very useful peptidomimetics25 in identifying drug-like molecules.

Scheme 1-8. Ugi-4CR sequence.

Figure 1.3. Ugi-4CR mechanism.

9

As per the most accepted mechanism26 (Figure 1.3) for the Ugi-4CR, the reaction begins with the formation of an imine by condensation between aldehyde (A31) and an amine

A32 followed by the attack of the isonitrile group A29 at the imine carbon which, in the presence of carboxylic acid A34, forms a nitrolium intermediate-V followed by acyl transfer resulting in intermediate VI. This intermediate VI under equilibrium with intermediate VII followed by Mumm’s rearrangement forms the final α-acyloxyamino- carboxamide derivative A35.

1.4.3. Ugi-Smiles Reaction

Laurent Kaïm and co-workers developed9 efficient and new variation of Ugi four component reaction (Scheme 1-9) for N-aryl amides A35, in which carboxylic acid A28 is replaced by 2-nitro or 4-nitrophenol.

Scheme 1-9. Ugi-Smiles 4-CR sequence.

10

Figure 1.4. Ugi-Smiles 4-CR mechanism.

The mechanism of the Ugi-Smiles reaction (Figure 1.4) is very similar to the Ugi reaction itself, but differs at the last step where the Mumm-type rearrangement is replaced by the Smiles rearrangement,27 due to the presence of 2-nitro or 4-nitrophenol component. In this mechanism, the reaction is initiated by formation of imine intermediate IV (condensation between aldehyde A31 and amine A32) activated in the presence of phenol by protonation, which makes the imine highly electrophilic and the isocyanide attacks at the electrophilic center to form nitrolium intermediate V and then phenolate attacks the nitrolium ion generating the intermediate VI which upon Smiles rearrangement gives intermediate VI leading to the formation of the final product A35.

Day to day use of isocyanide and isocyanide-based multi component reactions are

11

increasing rapidly. There are many variations in multi component reactions including

Passerini-Smiles-3CR reaction,28 Ugi-Diels-Alder 4CR reaction,29 Ugi-Buchwald-

Hartwig reaction,30 and Ugi-Heck reaction.31 Apart from the aforementioned reactions, the Asinger-Ugi reaction is a new version of multi-component reaction which has seven different reactive species.32 Furthermore, development of multi-component reactions have been reported which include Ugi-Pictet-Spengler reaction,26 Petasis-Ugi reaction,33 and the Danishefsky two component reaction.34

1.5. Applications of Ugi-Four Component Reaction

Multicomponent reactions are very useful synthetic tools for combinatorial and of

Ugi four component coupling reaction have great importance for accessing the synthetic heterocyclic chemistry to synthesize potential pharmaceutically bioactive scaffolds. Post- modified transformation building blocks for complex natural products and its analogues to test for their viability in treating various diseases.

1.5.1. Heterocyclic Scaffolds Synthesis

One of the post modifications of Ugi-4CR derivatives is the cyclization reaction which allows the formation of diverse heterocyclic scaffolds. In order for the derivatives to undergo the cyclization reactions starting with the reagents having varied functionalities would be fruitful. Ugi-deprotection cyclization (UDC) post modification strategy is very popular to get the desired heterocyclic compounds like diketo-piperizines,35 1,4- benzodiazepines,36 dyhydroquinoxalines,37 imidazolines,38 benzimidazoles,39 mono

12

and bicyclic -lactams.40 In this approach towards the synthesis of the scaffolds, the protected amine is used as the starting material in the Ugi reaction. The amine upon deprotection allows the Ugi derivative to undergo cyclization41 (Scheme 1-10).

Scheme 1-10. Hulme's UDC Strategy.

Some other strategies include the use of Ugi-RCM strategy42 Ugi-

4CR/deprotection+activation/cyclization (UDAC),43 Ugi/Diels-Alder reaction,44 Ugi-

Heck reaction,45 Ugi-Buchwald-Hartwig-cyclization,46 Ugi ring closing metathesis,47 and

Ugi-aza-Wittig reactions.48

1.5.2. Total Synthesis of Natural Products

Most of the natural products have complex structures and chemical synthesis is always a challenge. As mentioned earlier, designing an easy to approach and efficient synthetic route is very important compared to the time consuming, multi-step, low- yielding synthesis. Natural products can be obtained by minor modifications to the Ugi-

13

4CR products in greater yields. The only drawback of the MCRs protocols is that the end result is a mixture of equal isomers or racemic mixture if there is no chiral component in the starting reagents, which can be overcome by starting with at least one compound which is chiral. Mentioned below are a few examples which showcase the utility of the

Ugi four component reactions in the total synthesis of natural products.

The total synthesis of antibacterial (±)-veridic acid (A46) reported by Wessjohann and co-worker49 in simple two step synthesis involving Ugi-4CR and ester hydrolysis with good yields (Scheme 1-11).

Scheme 1-11. Concise total synthesis of (±)-veridic acid.

Akira Mastuda research group reported50 the total synthesis of the very complex and challenging (-)-muraymycin D2 (A50) and its stereoisomer using Ugi-4CR as a key synthetic step (Scheme 1-12) followed by three successful post modifications resulting in overall yield of 54% and this report showcases the advantages of MCRs in total synthesis.

14

Scheme 1-12. (-)-muraymycin D2 total synthesis.

Craig Hutton and co-worker reported,51 total synthesis of ustiloxin D (A56) and in which key Ugi-4CR derivative was synthesized in one pot reaction followed by three synthetic manipulations, finally gave the product ustiloxin D (Scheme 1-13).

Scheme 1-13. ustiloxin D total synthesis.

There are many other simple and complex natural products like Ecteinascidin 743,52

15

lemonomycin,53 Furanomycin,54 (-)-Dysibetaine,55 Uracil Polyoxin C Analogues,56 (±)-

Thaxtomin A57 for which synthesis have been reported in the literature.

1.5.3. Applications in Drug Discovery

Multi component reaction protocols are widely implemented in research pertaining to the drug discovery to find new lead compounds from a large variety of synthetic scaffold libraries using combinatorial chemistry and high speed parallel synthesis technology. Again, Ugi-4CR protocol has played an extensive role attributing to its ease in deriving different products by simple modifications in the starting materials.

This allows in synthesizing libraries within a short duration of time utilizing advanced techniques and instruments. These libraries can be screened for their activities against various drug targets in order to find cures for current diseases. The following are a few drug molecules synthesized via multicomponent reaction.

Praziquantel (A62) (Known as Biltricide®) was developed by Bayer AG and

Merck KGaA in 1970 as an Anthehelmitic drug to treat tapeworms and flukes. The original synthetic route58 had multiple synthetic steps which made the drug expensive.

Among other synthetic routes59 that were developed, the most simple and efficient route was developed by Dömling and co-workers60 using Ugi-4CR reaction and followed by methanesulfonic acid catalyzed Pictet-Spengler reaction to achieve the drug molecule in two synthetic steps (Scheme 1-14).

16

Scheme 1-14. (±)-Praziquantel synthesis.

Lacosamide (A68) (known as Vimpat®) is used for the treatment of partial-onset seizures and diabetic neuropathic pain. The drug was discovered by Harold Kohn and developed by Union Chimique Belge (UCB) by multi step synthetic route,61 but recently

Hermut Wehlan and co-workers developed an efficient and scalable two step synthetic route62 for Lacosamide using Ugi-4CR process (Scheme 1-15).

Scheme 1-15. Scalable Ugi-4CR synthesis for (R)-Lacosamide.

In recent years, application of MCRs, especially Ugi –4CRs have been used as a powerful

17

tool in the drug discovery process and number of Ugi-4CRs derived synthetic molecules showed very promising results as a drug candidates. There were many drug molecules developed using Ugi –4CRs protocols, in which, Indinavir (Crixivan®),63 Omuralide,64

Epelsiban,65 Retosiban66 showcases the power of Ugi-4CR process in drug discovery practice in pharmaceutical industry.

18

References

1. Lutz, W. Curr. Med. Chem. 2002, 9, 2085-2093.

2. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27-45.

3. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637-1638.

4. Biginelli, P. Ber. Dtsch. Chem. Ges. 1891, 24, 1317-1319.

5. Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647-667.

6. Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8-21.

7. (a) Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–29. (b) Banfi, L.;

Riva, R., The Passerini Reaction. In Organic Reactions, John Wiley & Sons, Inc.: 2004.

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24

Chapter 2

Synthesis of 3-Substituted-2-Indolinones via a Multicomponent Coupling Isocyanide Dependent Microwave-Assisted Intramolecular Transamidation Process

(Reproduced in part with permission from

Maddirala, A. R.; Andreana, P. R. Eur. J. Org. Chem. 2016, 2016, 196-209

Copyright© Wiley-VCH Verlag GmbH & Co. KGaA)

2.1. Introduction

Recent developments in diversity oriented synthesis (DOS)1 have led to reaction transformations that allow synthetic chemists to impart post-reaction modifications leading to molecular complexity in core scaffolds allowing for the construction of regio- and stereo-specific frameworks.2 Many of these processes are conducive towards the syntheses of libraries containing useful building blocks and biologically validated motifs of pharmaceutical and medicinal chemistry importance.3 Within the concept of DOS, multicomponent reactions (MCRs)4 followed by chemical modifications such as nucleophilic addition,5 aromatic substitution,6 metal catalyzed transformations,7 and

Lewis/Brønsted acid8 mediated intra-/inter-molecular additions have allowed for the

25

preparation of natural products,9 diverse library sets of small molecule motifs and derivatives thereof.10 Through the combination of three or more reaction-compatible reagents employed in a one-pot or multi-step process, new types of hetero/aromatic and macromolecular connectivity11 can be achieved in a cost effective and highly atom economical process. The validation of these approaches is confirmed by numerous examples found in the literature,2c, 12 where an increased interest towards the development of chemical libraries aimed at producing cost effective drugs with rationalized biologically validated scaffolds predominates. One particularly interesting motif containing a fused ring system is the 2-indolinone core found abundantly in natural products13 as well as in a wide range of biologically validated compounds such as anti- depressants,14 anti-cancer (Sutent®),15, 16 anti-inflammatory,17 and anti-HIV.18

Synthetic strategies for diversifying the indolinone scaffold have remarkably increased likely due to aforementioned biological activities. Over the last decade, several versatile synthetic methods for indolinone preparation have been reported including those utilizing C-H bond activation,19 C-N coupling reactions,20 and modifications of natural products amongst others.21 Albeit these approaches have worked well, the urge for more efficient and effective syntheses leading to structurally diverse indolinones remains significant. The latest efforts from the research groups of Kalinski22 and Zhu20a, 23, 24 have focused on the preparation of 1,3-substituted-2-indolinones via palladium catalyzed

N-aryl amidation strategy derived from peptide-based coupling.25 Their chemistry allows for facile 1,3-substitution, however, limitations include the formation of N-alkylated products, and the use of expensive metal catalysts and ligands. Herein, we report on the

26

synthesis of 3-substituted-2-indolinones 1 utilizing an intramolecular transamidation26 reaction arising from multicomponent condensation products generated through microwave irradiation. Selective intramolecular acyl transfer27 (i.e., preponderance for an acyl group transfer from a 2o amide over a 3o amide bond) is important in synthetic transformations and our approach selects for the migration to occur on an ortho- substituted aniline scaffold 2. The reaction sequence (Scheme 2-1) involves an ortho- aniline intermediate 2, which is derived from a Bechamp-type reduction28 of a α- acylamino-2-nitrophenylacetamide 3. A MCR reaction from the exclusive use of cost effective and readily available 2-nitrobenzaldehydes 4 (2-(boc amino) benzaldehydes not used, due to additional synthetic steps29), methyl isocyanide 5, as well as amine derivatives 6 and carboxylic acids 7 gives rise to acyclic intermediate 3 which ultimately leads to the desired final compounds.

Scheme 2-1. Retrosynthetic analysis for 2-indolinones 1 arising from an intramolecular

Ugi transamidation process following Bechamp-type reduction 2 made possible from α- acylamino-2-nitrophenylacetamide precursors 3.

27

2.2. Results and Discussion

2.2.1. Feasibility study for intramolecular transamidation

Initial attempts towards the synthesis of 3-substituted-2-indolinones began with the formation and optimization of acyclic dipeptide compounds 2. As previous work

30 emanating from our lab has demonstrated, using Fe/NH4Cl (10:1) in a γ:1→EtOH:H2O solution for ortho-nitro group reduction of compounds 3 to 2 gave key aniline intermediates in excellent yields. However, efforts towards the synthesis of 1a required some finesse as we initially observed 3,4-dihydroquinazolines31 compounds 8a and/or transamidation products 9a, both of which most likely resulted from initial amine condensation on the 3o amide. In these early efforts, the cyclization attempts of compounds 2 to 1 were conducted with the cyclopentyl substituted aniline 2a (Table 2.1).

Table 2.1. Reaction conditions leading to the formation of 8a and 9a.

28

product 8a product 9a entrya additive(s) (equiv) solvent T (°C)a time (% yield)b (% yield) b 1 BF3·OEt2 (2) DCM 50 10 min 70 20

2 BF3·OEt2 (2) MeCN 100 10 min 75 20

3 ZnCl2 (2) DCM 50 10 min NA NA

BEt3 (1 M in 4 DCE 100 10 min NA NA hexanes) (2.5)

5 TiCl4 (2) DCM 45 30 min NA NA

6 TiBr4 (2) DCM 50 30 min 57 40

7 AlCl3 (1) DCM 40 20 min NA NA

8 p-TSA (0.5) DCM 50 10 min 50 40

9 Et2O·HCl (2 M) (2) Et2O 50 10 min 80 <5

10 Sc(OTf)3 (2) DCE 100 30 min 67 3

11 Sc(OTf)3 (2) Toluene 110 30 min NA NA

12 Y(OTf)3 (2) DCM 50 20 min 40 35

13 (S)-CSA (0.5) DCM 50 10 min 45 30

aMicrowave conditions (CEM® Discover microwave reactor) - 300 W and 10 bar. bIsolated yield. NA = not available/not observed.

Efforts to delineate pathway selectivity for either 8a or 9a mostly yielded reaction mixtures, however, favorable outcomes occurred when 2 equiv of Et2O·HCl (2 M solution) or Sc(OTf)3 in DCE was used leading to the major product 8a (Table 1; entries

9 and 10). Although we examined a number of reaction conditions, pathway selectivity for transamidation leading to major product 9a was elusive. We rationalized that the

29

formation of 8a and 9a were the direct result of amine condensation and acyl group transfer, respectfully, on the 3o amide carbonyl and not the 2o amide because of steric bulk imposed by the cyclopentyl ring and also due to a high energy barrier for the generation of a cyclopentyl amine byproduct.32

2.2.2. Effect of isocyanide substitution and TFA catalyzed transamidation reactions

Although we were pleased to obtain compounds 8a and 9a, our attention did not deviate from synthesizing 3-substituted-2-indolinones. Upon reading the literature for alternative conditions, we came across microwave-irradiation reports based on TFA catalyzed reactions26a,27a,33 designed to synthesize heterocyclic ring structures.34 Using modified procedures, we conducted cyclization experiments with compounds 2b-2g that contained various substituted 2o amides to probe reactivity and confirm sterically- controlled selectivity. Substituents (2,6-dimethyl phenyl (2b), cyclohexyl (2c), p-anisyl

(2d), t-butyl (2e), i-propyl (2f) and n-pentyl (2g) were used. In all instances, the microwave-assisted reactions were run in DCE with 10% TFA at 100 oC but the only observable products were of type 8 (8b-g) obtained in good to excellent yields

(compounds of type 9 were not detected) (Scheme 2-2). Based on these results we concluded that the bulky 2o amide substituents, from isocyanide starting reagents, play an important role in selecting for products of type 8 directing amine condensation toward the

3o amide and forming 3,4-dihydroquinazoline products 8b-g.

30

Scheme 2-2. Bulky isocyanides and 10% TFA lead to the formation of 3,4- dihydroquinazolines.

In an attempt to lower the steric demands of the 2o amides found in substrates 2b- g and encourage transamidation for the desired 2-indolinones, we turned our attention to methyl isocyanide35a and the preparation of aniline precursor 2h (Table 2.2). Methyl isocyanide was synthesized on a 50 g quantity using a dehydrative distillation procedure.32b With 2h in hand, the cyclization for 2-indolinones using Lewis/Brønsted acids and a variety of solvents under the influence of microwave irradiation was attempted (Table 2.2). In many instances we observed the formation of the desired product 1h along with products 8h and 9h when BF3·OEt2 in DCM or DCE at 40 °C was used (Table 2.2; entries 1 and 2). Taking these results into consideration we decided to use Lewis acids InCl3, AlCl3, ZnCl2, CeCl3, TiCl4, Sc(OTf)3, Y(OTf)3 with solvents such as DCM, THF, toluene and DCE (Table 2.2; entries 3-10). Unfortunately, these conditions did not lead to any appreciable improvements in product ratios or yields.

31

Table 2.2. Scope of reaction conditions for compounds 1h, 8h and 9h when methyl isocyanide is incorporated into 2h.

1h 8h 9h additive(s) entrya solvent T (°C) time (equiv) (% yield)b (% yield)b (% yield)b

1 BF3·OEt2 (2) DCM 40 10 min <5 60 20

2 BF3·OEt2 (2) DCE 70 10 min <5 40 20

3 InCl3 (2) DCM 45 1 h <5 20 20

4 AlCl3 (2) DCE 100 10 min <5 35 35

5 ZnCl2 (2) Toluene 80 10 min 10 35 30

6 ZnCl2 (2) DCE 80 1 h 15 40 20

7 CeCl3 (4) THF 120 1 h 30 20 20

8 TiCl4 (2) DCE 80 1 h <5 60 20

9 Sc(OTf)3 (2) MeCN 80 20 min <5 40 5

10 Y(OTf)3 (1) DCE 120 30 min 10 40 35

11 (S)-CSA (1) DCE 50 10 min 30 20 35

12 p-TSA (1) DCE 60 20 min 35 30 25

13 10% TFA DCM 30 10 min 80 10 10

14 10% TFA DCM 45 10 min 80 10 10

32

15 10% TFA Toluene 100 10 min 50 30 20

16 10% TFA CHCl3 45 10 min 40 20 10

17 10% TFA Et2O 45 30 min 38 25 10

18 10% TFA DCE 120 10 min 90 NA NA

19 5% TFA DCE 120 10 min 80 NA NA

20 20% TFA DCE 120 10 min 90 NA NA

21 40% TFA DCE 120 10 min 85 trace NA aMicrowave conditions (CEM® Discover microwave reactor): 300 Watts, 10 bar. bIsolated yields.

NA = not available/not observed.

It is known that Lewis acid complexes will form with 3o amide carbonyls over 2o amide nitrogens increasing the electrophilic potential.36 In our case this leads to a general preponderance for compounds 8h and 9h. We decided to move forward to study the effects of Brønsted acids such as camphorsulfonic acid, p-toluene sulfonic acid and trifluoroacetic acid in solvents DCM, DCE, CHCl3, toluene, and diethyl ether (Table 2.2; entries 11-17). In many of these experiments we observed an increase in yields of the desired product 1h, notably when 10% TFA in DCE was employed. Encouraged with the use of TFA, several more conditions were screened including 5, 20, and 40% TFA in

DCE (Table 2.2; entries 18-21). The results indicated that 10% TFA in DCE proved superior in product yield and pathway selectivity for 1h. One plausible explanation might be that the highly acidic TFA acts to increase the electrophilicity of the more polarizable 2o amide carbonyl through protonation and hence promote lactamization. The characterization of 1h was verified using NMR and MS and unequivocally confirmed through X-ray crystal structure analysis (Figure 2.1). Combined with previous data, these

33

results indicate that the steric environment of the 2o amide is critical for product selectivity and we believe that the formation of methyl amine gas is a driving force for the formation of 2-indolinones via our intramolecular transamidation.37

Figure 2.1. ORTEP diagram for compound 1h.

2.2.3. Rotamers formation and challenges in NMR analysis

In light of the structure of 2-indolinone 1h being directly confirmed using X-ray diffraction (Figure 2.1), it must be noted that substantial difficulty in interpreting 1H

NMR for compound was encountered (Figure 2.2).38 We attributed this challenge to the formation of amide rotomers which were also noted and apparent in a previous report.20a

In good practice, we attempted to resolve spectral complexity by screening NMR solvents under variable temperature (VT) NMR,39 however this did not provide a viable solution to our problem as we continued to observe peak broadening and further complexity.40

34

2.2.3.1. Studying the effect of amine component on rotamer formation

To resolve the rotameric issue, we elected to study nitrogen substituents on the 3o amide of the 3-substituted-2-indolinones, where symmetrical and sterically demanding groups could be utilized to favor a single conformer.41 To this end, we synthesized compound 1i containing an isopropyl substituent (isopropyl amine was the starting reagent) on the 3o amide and observed clean, highly resolved peak splitting patterns in 1H

NMR analysis (Figure 2.1; 1i). Based on these observations, we turned our attention to utilizing straight chain 1h, and 1o-r and branched symmetrical substituents 1j-n for the synthesis of 2-indolinone derivatives (Figure 2.3). The 1H NMR spectra of compounds

1j-n provided sharp well-defined peaks and splitting patterns at room temperature while the spectral data for 1o-r was similar to that observed for compound 1h.

35

72 °C

62 °C

52 °C

42 °C

32 °C 22 °C

22 °C

1 Figure 2.2. Temperature dependent H NMR (DMSO-d6) spectra showing rotameric mixtures of 1h at ~ 10.5-10.1 ppm (NH) when

1 benzyl amine is used as a starting reagent versus H NMR (DMSO-d6) spectra of 1i at 22 °C at ~10.3 ppm (NH) where isopropyl amine is a starting reagent and rotamers are not evidenced.

36

Figure 2.3. Differences in amine starting reagents lead to 3-substituted-2-indolinone (analogs for library - 1) amide rotameric mixtures.

2.2.3.2. Studying the effect of carboxylic acid component on rotamer formation

To further examine the scope of the transamidation process and to determine if carboxylic acid components would influence rotamer formation, compounds 1s-1bb

(Figure 2.4) were prepared in very good isolated yields. The 3-step sequence was well tolerated by aliphatic, aromatic, and unsaturated carboxylic acids. Compounds 1s-1bb gave well-defined 1H NMR data suggesting that in the presence of branched amide substitution a major conformation is preferred. This trend also suggests that branched symmetrical N-substitution on the amide bond forces the 2-indolinone products 1i-n into a single conformation avoiding the complex 1H NMR peak patterns observed from rotamers of compounds 1h, 1o-r.

37

Figure 2.4. Carboxylic acids as starting reagents do not influence the formation of rotamers when the N-isopropyl substituent is a component of the 3o amide (2-indolinone analogs for library - 2).

2.3. Conclusion

In conclusion, we have developed a selective intramolecular transamidation strategy for the synthesis of 3-substituted-2-indolinones, 3,4-dihydroquinazolines and other transamidation products. The strategy takes advantage of an atom economical cascade coupling reaction, a Bechamp-type reduction and microwave assisted cyclization. Through this process we have learned that when varying alkyl- or aryl- isocyanides are used, with the exception of methyl isocyanide (5), 3,4- dihydroquinazolines 8 and/or 3o amide transamidation products 9 are obtained in reasonable yields. Although the process is efficient and leads to good compound yields, we encountered rotameric issues with 3-substituted-2-indolinone compounds. To overcome this challenge and for legible 1H NMR spectral data, we discovered that the use

38

of symmetrical branched 2o N-amide or N-aryl substituents diminished rotameric conformers and simplified NMR characterization and we identified methyl isocyanide as a convertible isocyanide and a very useful source of CO functionality for installation of

2-indolinone scaffold. This work is extended toward the synthesis of spirocyclic- indolinones and other bio-relevant scaffolds.

39

Experimental Section

General Methods. All reagents and solvents were commercially available and used without purification unless otherwise stated. Reaction progress was monitored using thin layer chromatography (TLC). TLC was visualized using UV followed by staining with ninhydrin or PMA solutions. Column chromatography was performed using silica gel.

Yields refer to chromatographically and spectroscopically pure compounds. 1H and 13C

NMR were recorded using 600 MHz spectrometer at 22 °C (default) unless otherwise

1 13 noted. The residual CDCl3 H singlet at δ 7.27 ppm and C triplet at δ 77.23 ppm,

1 13 1 CD2Cl2 H triplet at δ 5.32 ppm and C quintet at δ 54.00, and DMSO-d6 H quintet at δ

13 1 2.50 ppm and residual C septet at δ 39.51 ppm, CD3OD H singlet at δ 4.87 ppm and

13 1 13 C triplet at δ 49.15 ppm, CD3CN H quintet at δ 1.94 ppm and C singlet at δ 118.69,

1 13 and Acetone-d6 H quintet at δ 2.05 ppm and residual C heptet at δ 29.92 ppm, were used as the standards for 1H NMR and 13C NMR spectra respectively. Signal patterns are indicated as s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; dd: doublet of doublets; br: broad and coupling constants are reported in hertz (Hz). Low resolution mass spectra (LRMS) were acquired on an Esquire-LC electrospray ionization (ESI) mass spectrometer. High resolution mass spectra (HRMS) were obtained with a Bruker

Maxis 4G mass spectrometer. Melting points were recorded on a MEL-TEMP® electro thermal apparatus. A CEM Discovery® microwave system (ESP 1500 Plus model) was used for all microwave reactions. X-ray crystallographic analysis was performed on an

Apex Duo.

40

General Procedure for Ugi Product 3a-3bb. Amine 6 (1 eq) was added to a clear solution of 2-nitrobenzaldehyde (4) (1 eq) in methanol (5 mL) and allowed to stir for 10 minutes at room temperature and then carboxylic acid 7 (1 eq), and isocyanide 5 (1 eq) were subsequently added. The reaction was continually stirred until no noticeable starting reagents were visualized using TLC. Upon completion of the reaction, methanol was evaporated under reduced pressure. After obtaining the mass of unpurified product(s) the material was dissolved in CH2Cl2. The organic layer was washed with a saturated NaHCO3 solution (2 x 5mL) followed by brine (5 mL) and then the organic layer was dried over anhydrous Na2SO4 (1-2 g). Complete removal of solvent was carried out under reduced pressure on a rotoevaporator. The crude product was subjected to flash column chromatography (EtOAc:hexanes – isocratic or gradient depending on measured Rf from TLC) to yield pure compound.

N-benzyl-N-(2-(cyclopentylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3a).

The compound was obtained as an off-white solid; m.p: 102-104 °C; yield: 90%; 1H

NMR (600 MHz, CDCl3):  8.03-7.85 (m, 1H), 7.66-7.08 (m, 8H), 6.46-5.99 (m, 1H),

5.37-4.65 (m, 2H), 4.29-3.93 (m, 1H), 2.47-2.24 (m, 2H), 1.85-1.65 (m, 2H), 1.56-0.90

13 (m, 11H) (rotamers) ppm; C NMR (150 MHz, CDCl3):  175.75, 167.83, 149.68,

137.02, 133.22, 131.18, 129.94, 129.16, 128.81, 128.62, 127.51, 126.35, 125.20, 59.82,

51.79, 50.83, 33.04, 32.54, 27.29, 23.83, 9.63 ppm; EIMS [M+Na]+ calcd for

C23H27N3NaO4: 432.2; found: 432.3.

N-benzyl-N-(2-((2,6-dimethylphenyl)amino)-1-(2-nitrophenyl)-2- oxoethyl)propionamide (3b). The compound was obtained as a light brown solid;

1 m.p:101-103 °C; yield: 80%; H NMR (600 MHz, CDCl3):  7.92 (d, J= 7.0 Hz, 1H), 41

7.82 (d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.23-7.01 (m, 9H), 6.48 (s,

1H), 4.85 (d, J = 16.9 Hz, 1H), 4.59 (d, J = 16.9 Hz, 1H), 2.51 (s, 2H), 2.38 (s, 6H), 1.61

13 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  175.47, 166.83,

149.91, 136.61, 135.42, 133.27, 133.07, 131.05, 129.85, 129.57, 128.83, 128.36, 128.19,

127.57, 127.31, 126.51, 124.94, 58.93, 51.16, 27.28, 18.42, 9.50 ppm; EIMS [M+Na]+ calcd for C26H27N3NaO4: 468.2; found: 468.5.

N-benzyl-N-(2-(cyclohexylamino)-1-(2-nitrophenyl)-2-oxoethyl)propionamide (3c).

The compound was obtained as a pale yellow solid; m.p: 123-125 °C; yield: 87%; 1H

NMR (600 MHz, CDCl3):  8.03-7.84 (m, 2H), 7.66-7.29 (m, 8H), 6.42-6.25 (m, 1H),

5.87 (d, J = 3.6 Hz, 1H), 5.28-5.05 (m, 1H), 4.79 (d, J = 17.2 Hz, 1H), 4.65-4.63 (d, J =

17.2 Hz, 1H), 4.26 (d, J = 11.64 Hz, 1H), 3.57-3.49 (m, 2H), 2.49-2.27 (m, 3H), 1.82-

13 0.74 (m, 13H) (rotamers) ppm; C NMR (150 MHz, CDCl3):  175.85, 167.44, 149.74,

137.03, 133.52, 133.22, 131.10, 130.10, 129.64, 129.23, 128.84, 128.68, 128.07, 127.55,

126.42, 125.79, 125.18, 62.47, 51.02, 49.68, 48.94, 32.84, 32.52, 27.33, 25.63, 24.85,

+ 24.79, 9.63 (rotamers) ppm; EIMS [M+Na] calcd for C24H29N3NaO4: 446.2; found:

446.6.

N-benzyl-N-(2-((4-methoxyphenyl)amino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3d). The compound was obtained as a dark brown solid; m.p: 179-181

1 °C; Yield: 79%; H NMR (600 MHz, CDCl3):  8.10-7.85 (m, 2H), 7.65-7.33 (m, 5H),

7.09-6.46 (m, 10H), 5.18-4.29 (m, 2H), 3.76 (s, 3H), 2.50-2.29 (m, 2H), 1.17 (s, 3H)

13 (rotamers) ppm; C NMR (150 MHz, CDCl3):  176.19, 166.76, 156.84, 149.71, 136.62,

42

133.33, 130.49, 130.31, 129.51, 128.96, 127.68, 126.45, 125.27, 122.21, 60.78, 55.66,

+ 51.40, 27.36, 9.62 ppm; EIMS [M+Na] calcd for C25H25N3NaO5: 470.2; found: 470.5.

N-benzyl-N-(2-(tert-butylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3e).

The compound was obtained as a yellow solid; m.p: 142-144 °C; yield: 85%; 1H NMR

(600 MHz, CDCl3):  8.04-7.88 (m, 1H), 7.87-7.49 (m, 3H), 7.32-7.25 (m, 4H), 7.09 (d, J

= 5.6 Hz, 1H), 6.48-6.21 (m, 1H), 5.78-5.23 (m, 1H), 1.36-1.07 (m, 12H) (rotamers)

13 ppm; C NMR (150 MHz, CDCl3):  175.78, 167.45, 149.84, 137.15, 133.50, 133.40,

133.23, 132.56, 131.58, 129.64, 129.49, 129.37, 129.08, 128.89, 128.84, 128.81, 128.57,

128.44, 128.09, 127.66, 127.51, 126.31, 125.65, 125.26, 124.72, 60.55, 52.07, 50.65,

+ 28.86, 28.37, 27.27, 9.66 (rotamers) ppm; EIMS [M+Na] calcd for C25H27N3NaO4:

420.2; found 420.5.

N-benzyl-N-(2-(isopropylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3f).

The compound was obtained as a pale brown solid; m.p: 166-168 °C; yield: 83%; 1H

NMR (600 MHz, CDCl3):  8.03-7.99 (m, 1H), 7.86-7.09 (m, 8H), 6.46 (m, 1H), 5.79-

4.99 (m, 1H), 4.80-4.32 (m, 2H), 3.86-3.78 (m, 1H), 2.47-2.27 (m, 2H), 1.17 (t, J = 7.3

13 Hz, 3H), 1.06-0.79 (m, 6H) (rotamers) ppm; C NMR (150 MHz, CDCl3):  175.77,

167.46, 149.72, 137.03, 133.54, 133.23, 131.15, 130.01, 129.62, 129.20, 128.98, 128.82,

128.63, 128.45, 128.04, 127.67, 127.53, 126.36, 125.80, 125.65, 125.21, 27.29, 22.57,

+ 22.21, 9.63 ppm; EIMS [M+Na] calcd for C21H25N3NaO4: 406.2; found: 406.6.

N-benzyl-N-(1-(2-nitrophenyl)-2-oxo-2-(pentylamino)ethyl) propionamide (3g). The compound was obtained as an off-white solid; m.p: 90-92 °C; yield: 79%; 1H NMR (600

MHz, CDCl3):  8.02-7.83 (m, 1H), 7.65-7.40 (m, 4H), 7.23-7.07 (m, 4H), 6.43-6.31 (m,

43

1H), 5.92-5.38 (m, 1H), 4.97-4.37 (m, 2H), 3.13-2.79 (m, 2H), 2.46-2.30 (m, 2H), 1.37-

13 1.16 (m, 8H), 0.86 (s, 3H) (rotamers) ppm; C NMR (150 MHz, CDCl3):  175.77,

168.35, 149.74, 136.93, 133.22, 130.30, 129.30, 129.09, 128.83, 128.44, 127.56, 126.39,

125.17, 59.76, 51.00, 39.99, 29.16, 28.96, 27.30, 22.44, 14.16, 9.60 (rotamers) ppm;

+ EIMS [M+Na] calcd for C23H29N3NaO4: 434.2; found: 434.6.

N-benzyl-2-(2-bromophenyl)-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) acetamide (3h). The compound was obtained as a white solid; m.p: 156-158 °C; yield:

1 95%; H NMR (600 MHz, CDCl3):  7.49 (d, J = 7.9 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H),

7.17-7.12 (m, 5H), 7.08 (t, J = 7.6 Hz, 2H), 6.95 (d, J = 7.1 Hz, 2H), 6.67 (d, J = 7.3 Hz,

1H), 6.62 (t, J = 7.2 Hz, 1H), 6.50 (s, 1H), 4.94 (d, J = 17.7 Hz, 1H), 4.83 (d, J = 17.7 Hz,

1H), 3.81 (d, J = 16.7 Hz, 1H), 3.50 (d, J = 16.7 Hz, 1H), 2.79 (d, J = 4.7 Hz, 3H) ppm;

13 C NMR (150 MHz, CDCl3):  173.32, 170.34, 146.17, 137.94, 135.43, 132.69, 131.73,

130.22, 128.77, 128.60, 127.65, 127.11, 126.40, 125.16, 119.06, 118.60, 116.34, 57.42,

+ 50.25, 42.07, 26.55 (rotamers) ppm; EIMS [M+Na] calcd for C23H29BrN3NaO4: 518.1; found: 518.3.

2-(2-bromophenyl)-N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) acetamide (3i). The compound was obtained as a white solid; m.p: 168-170 °C; yield:

1 90%; H NMR (600 MHz, CDCl3):  8.01-8.00 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 6.2 Hz,

1H), 7.59 (s, 2H), 7.49-7.16 (m, 4H), 5.74 (s, 1H), 4.37 (s, 1H), 4.11 (d, J = 15.8 Hz, 1H),

3.88 (d, J = 15.8 Hz, 1H), 2.68 (s, 3H), 1.43 (s, 3H), 1.00 (s, 3H) ppm; 13C NMR (150

MHz, CDCl3):  170.99, 168.69, 149.16, 134.96, 133.67, 132.88, 131.86, 131.59, 130.74,

44

129.27, 129.09, 127.96, 125.24, 124.74, 57.30, 50.65, 41.58, 27.01, 21.66, 21.10 ppm;

+ EIMS [M+Na] calcd for C20H22N3NaO4: 470.1; found: 472.3.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3j).

The compound was obtained as a light yellow solid; m.p: 122-124 °C; yield: 86%; 1H

NMR (600 MHz, CDCl3):  8.01 (d, J= 7.1 Hz, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.51 (d, J =

6.0 Hz, 1H), 5.67 (s, 1H), 5.21 (s, 1H), 4.24 (s, 1H), 2.58 (d, J = 7.9 Hz, 3H), 2.50-2.46

(m, 2H), 1.45 (d, J = 5.0 Hz, 3H), 1.21 (s, 3H), 0.96 (d, J = 5.1 Hz, 3H) ppm; 13C NMR

(150 MHz, CDCl3):  177.66, 169.06, 149.16, 133.70, 131.96, 130.46, 129.25, 125.26,

57.05, 49.79, 27.50, 27.03, 21.51, 21.14, 9.51 ppm; EIMS [M+Na]+ calcd for

C15H21N3NaO4: 330.1; found: 330.3.

N-cyclopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide

(3k). The compound was obtained as an off-white solid; m.p: 176-178 °C; yield: 81%;

1 H NMR (600 MHz, CDCl3):  8.08 (d, J = 4.2 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.64 (t,

J = 7.6 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 2.66-2.62

(m, 2H), 2.61 (d, J = 4.5 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H), 0.98-0.96 (m, 1H), 0.63-0.55

13 (m, 3H) ppm; C NMR (150 MHz, CDCl3):  176.25, 167.70. 149.39, 132.92, 131.80,

129.15, 128.62, 124.39, 61.31, 29.45, 26.85, 26.02, 9.10, 8.66, 8.51 ppm; EIMS [M+Na]

+ calcd for C15H19N3NaO4: 328.1; found: 328.3.

N-cyclopentyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3l).

The compound was obtained as a light yellow solid; m.p: 101-103 °C; yield: 84%; 1H

NMR (600 MHz, DMSO-d6):  8.06 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.62 (t,

J = 7.5 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.22 (s, 1H), 2.64-2.58

45

13 (m, 6H), 1.02-0.93 (m, 4H), 0.60-0.54 (m, 3H) ppm; C NMR (150 MHz, CDCl3): 

178.26, 170.08, 149.55, 132.83, 130.95, 130.73, 129.20, 124.76, 63.66, 31.69, 27.99,

+ 26.82, 9.96, 9.93, 9.20 ppm; EIMS [M+Na] calcd for C17H23N3NaO4: 356.2; found:

356.6.

N-cyclohexyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) propionamide (3m).

The compound was obtained as an off-white solid; m.p: 168-170 °C; yield: 89%; 1H

NMR (600 MHz, CDCl3):  8.02 (s, 1H), 7.59-7.50 (m, 3H), 5.75 (s, 1H), 5.23 (s, 1H),

3.76-3.48 (m, 1H), 2.84-2.73 (m, 3H), 2.59-1.94 (m, 4H), 1.81-1.65 (m, 3H), 1.48-1.11

13 (m, 8H) ppm; C NMR (150 MHz, CDCl3):  174.73, 169.11, 149.14, 133.58, 131.95,

130.39, 129.16, 125.28, 58.65, 58.13, 32.22, 31.75, 27.59, 27.06, 26.21, 25.92, 25.24,

+ 9.59 ppm; EIMS [M+Na] calcd for C18H25N3NaO4: 370.2; found: 370.6.

N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl)-N-phenylpropionamide (3n). The compound was obtained as a light yellow solid; m.p: 204-206 °C; yield: 85%; 1H NMR

(600 MHz, CDCl3):  7.81 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.29-7.27 (m,

1H), 7.18 (s, 4H), 6.50 (s, 1H), 5.96 (s, 1H), 2.87 (d, J = 2.7 Hz, 3H), 2.09-2.07 (m, 2H),

13 1.06 (t, J = 7.1 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  174.68, 170.01, 150.17,

139.88, 132.64, 132.51, 130.27, 129.53, 129.27, 128.91, 128.52, 124.47, 59.84, 28.47,

+ 26.83, 9.45 ppm; EIMS [M+Na] calcd for C18H19N3NaO4: 364.1; found: 364.3.

N-methyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) benzamide (3o). The compound was obtained as a white solid; m.p: 178-180 °C; yield: 75%; 1H NMR (600

13 MHz, CDCl3):  7.98 (s, 1H), 7.65-7.45 (m, 8H), 6.66 (s, 1H), 3.03-2.84 (m, 6H); C

NMR (150 MHz, CDCl3):  173.16, 168.96, 150.07, 135.23, 133.15, 130.69, 129.93,

46

129.42, 128.82, 127.61, 125.37, 59.19, 36.15, 26.68; EIMS [M+Na]+ calcd for

C17H17N3NaO4: 350.1; found: 350.3.

N-ethyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) benzamide (3p). The compound was obtained as a white solid; m.p: 190-192 °C; yield: 76%; 1H NMR (600

MHz, CDCl3):  7.97 (s, 1H), 7.67-7.44 (m, 8H), 6.65 (s, 1H), 6.28 (s, 1H), 3.53-3.40 (m,

13 2H), 2.89 (s, 3H), 0.96 (s, 3H) ppm; C NMR (150 MHz, CDCl3):  173.46, 169.61,

149.72, 135.92, 133.24, 130.21, 129.37, 128.81, 126.93, 125.34, 66.05, 60.37, 44.90,

+ 26.68, 15.47, 14.86 ppm; EIMS [M+Na] calcd for C18H19N3NaO4: 350.1364.1; found:

364.3.

2-(2-bromophenyl)-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl)-N- propylacetamide (3q). The compound was obtained as a white solid; m.p: 193-195 °C;

1 yield: 87%; H NMR (600 MHz, CDCl3):  7.94 (d, J = 7.9 Hz, 1H), 7.59-7.56 (m, 3H),

7.49 (t, J = 7.5 Hz, 1H), 7.33-7.28 (m, 3H), 7.16 (t, J = 7.1 Hz, 1H), 6.41 (d, J = 2.9 Hz,

1H), 6.33 (s, 1H), 3.99 (d, J = 16.1 Hz, 1H), 3.87 (d, J = 16.1 Hz, 1H), 3.42-3.38 (m, 2H),

2.78 (d, J = 4.6 Hz, 3H), 1.62-1.58 (m, 1H), 1.52-1.48 (m, 1H), 0.84 (t, J = 7.4 Hz, 3H)

13 (rotamers) ppm; C NMR (150 MHz, CDCl3):  171.50, 169.35, 149.73, 135.01, 133.09,

132.85, 131.75, 130.16, 129.18, 129.06, 127.88, 125.13, 124.90, 60.69, 50.52, 41.16,

+ 26.65, 23.10, 11.56 (rotamers) ppm; EIMS [M+Na] calcd for C20H22N3NaO4: 470.1; found: 470.3.

2-(2-bromophenyl)-N-butyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) acetamide (3r). The compound was obtained as a light brown solid; m.p: 101-103 °C;

1 yield: 83%; H NMR (600 MHz, CDCl3):  7.93 (d, J = 8.0 Hz, 1H), 7.58-7.56 (m, 3H),

47

7.49-7.47 (m, 1H), 7.33-7.29 (m, 2H), 7.17-7.14 (m, 1H), 6.27 (s, 1H), 6.22 (d, J = 4.1

Hz, 1H), 3.97 (d, J = 16.0 Hz, 1H), 3.87 (d, J = 16.0 Hz, 1H), 3.43 (t, J = 8.3 Hz, 3H),

2.82 (d, J = 4.9 Hz, 3H), 1.53-1.44 (m, 2H), 1.28-1.22 (m, 2H), 0.86 (t, J =7.4 Hz, 3H)

13 (rotamers) ppm; C NMR (150 MHz, CDCl3):  171.51, 169.39, 149.77, 135.00, 133.12,

132.90, 131.81, 130.24, 129.23, 121.12, 127.93, 125.14, 124.92, 61.03, 48.93, 41.22,

+ 31.78, 26.73, 20.37, 13.84(rotamers) ppm; EIMS [M+Na] calcd for C21H24N3NaO4:

484.1; found: 484.3.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) benzamide (3s). The compound was obtained as a white solid; m.p: 131-133 °C; yield: 85%; 1H NMR (600

MHz, CDCl3):  8.03 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.68 (t, J = 7.1 Hz,

1H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 (s, 5H), 5.81 (s, 1H), 5.43 (s, 1H), 4.15 (s, 1H), 2.79

(d, J = 2.1 Hz, 3H), 1.40 (d, J = 5.1 Hz, 3H), 0.91 (s, 3H) ppm; 13C NMR (150MHz,

CDCl3):  172.85, 168.82, 149.46, 136.59, 133.81, 131.87, 130.54, 130.01, 129.53,

128.90, 126.31, 125.44, 52.07, 27.13, 21.62, 21.24 ppm; EIMS [M+Na]+ calcd for

C19H21N3NaO4: 378.1; found: 378.3.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) cyclopropanecarboxamide (3t). The compound was obtained as a light yellow solid;

1 m.p: 133-135 °C; yield: 78%; H NMR (600 MHz, CDCl3):  8.05-7.45 (m, 4H), 7.17 (s,

1H), 6.27-5.89 (m, 1H), 4.55 (s, 2H), 1.42 (s, 3H), 1.31-0.59 (m, 7H) ppm; 13C NMR

(150 MHz, CDCl3):  172.90, 167.73, 149.56, 132.98, 132.65, 131.26, 129.29, 129.10,

128.77, 128.38, 124.84, 124.29, 79.12, 55.95, 48.39, 26.48, 22.05, 21.81, 21.05, 20.39,

48

+ 20.11, 13.36, 12.46, 8.40, 7.74, 6.84 ppm; EIMS [M+Na] calcd for C16H21N3NaO4:

342.1; found: 342.4.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) pentanamide (3u).

The compound was obtained as a white solid; m.p: 110-112 °C; yield: 82%; 1H NMR

(600 MHz, CDCl3):  8.00 (d, J = 6.3 Hz, 1H), 7.59 (t, J = 7.4 Hz, 2H), 7.50 (d, J = 5.5

Hz, 1H), 5.67 (s, 1H), 5.21 (s, 1H), 4.24 (s, 1H), 2.71 (s, 3H), 2.53 (d, J = 6.5 Hz, 1H),

2.45 (d, J = 6.5 Hz, 1H), 1.68 (d, J = 5.8 Hz, 2H), 1.45 (d, J = 4.3 Hz, 3H), 1.41 (s, 2H),

13 0.96 (d, J = 4.3 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  174.37, 169.24, 149.41,

133.86, 132.20, 130.68, 129.44, 125.47, 57.27, 50.15, 34.27, 27.62, 27.23, 22.98, 21.77,

+ 21.44, 14.33 ppm; EIMS [M+Na] calcd for C17H25N3NaO4: 358.2; found: 358.3.

3-(4-fluorophenyl)-N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) propanamide (3v). The compound was obtained as a cream white solid; m.p: 67-69 °C;

1 yield: 85%; H NMR (600 MHz, CDCl3):  8.01 (d, J = 7.0 Hz, 1H), 7.56-6.99 (m, 8H),

5.69 (s, 1H), 5.19 (s, 1H), 4.23-4.21 (m, 1H), 3.03-3.00 (m, 2H), 2.88-2.83 (m, 2H), 2.74

(t, J = 7.3 Hz, 3H), 1.42 (d, J = 6.0 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H) ppm; 13C NMR (150

MHz, CDCl3):  172.80, 168.83, 162.44, 160.82, 149.15, 136.80, 133.62, 131.64, 130.42,

130.17, 130.12, 129.31, 125.29, 115.52, 115.38, 57.10, 49.95, 35.97, 30.42, 27.04, 21.49,

+ 21.16 ppm; EIMS [M+Na] calcd for C21H24N3NaO4: 424.2; found: 424.3.

4-bromo-N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) benzamide

(3w). The compound was obtained as a white solid; m.p: 176-178 °C; yield: 89%; 1H

NMR (600 MHz, CDCl3):  8.03-7.34 (m, 8H), 5.79 (s, 1H), 5.38 (s, 1H), 4.07 (s, 1H),

13 2.77 (s, 3H), 1.38 (s, 3H), 0.91 (d, J = 4.1 Hz, 3H) ppm; C NMR (150 MHz, CDCl3): 

49

171.82, 168.53, 149.20, 135.51, 133.84, 132.07, 130.47, 129.63, 127.95, 125.43, 124.43,

+ 52.11, 31.73, 27.06, 21.56 ppm; EIMS [M+Na] calcd for C19H20BrN3NaO4:456.1; found: 456.1 and 458.1.

2-(3,4-difluorophenyl)-N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2- oxoethyl) acetamide (3x). The compound was obtained as a white solid; m.p: 137-139

1 °C; yield: 89%; H NMR (600 MHz, CDCl3): 8.01 (d, J = 7.5 Hz, 1H), 7.57-7.50 (m,

3H), 7.15 (s, 1H), 7.04 (s, 1H), 5.68 (s, 1H), 5.15 (s, 1H), 4.42 (s, 1H), 3.85 (d, J = 15.3

Hz, 1H), 3.79 (d, J = 15.3 Hz, 1H), 2.71 (s, 3H), 1.37 (d, J = 5.0 Hz, 3H), 0.91 (d, J = 5.0

13 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  171.40, 168.60, 149.25, 133.90, 131.74,

130.42, 129.63, 125.52, 118.46, 118.36, 117.88, 117.78, 57.21, 50.91, 40.78, 27.19,

+ 21.72, 21.12 ppm; EIMS [M+Na] calcd for C20H21N3NaO4: 428.1; found: 428.2.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) acrylamide (3y). The compound was obtained as a white solid; m.p: 130-132 °C; yield: 79%; 1H NMR (600

MHz, CDCl3, 55 °C):  8.01 (d, J = 7.6 Hz, 3H), 7.70-7.58 (m, 3H), 6.90-6.77 (m, 2H),

6.90-5.68 (m, 3H), 4.38-4.24 (m, 1H), 2.58 (d, J = 3.7 Hz, 3H), 7.20 (t, J = 7.3 Hz, 1H),

7.12 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 5.67 (s, 1H), 5.24 (d, J = 4.3 Hz, 1H), 1.38 (d, J =

13 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H) (rotamers) ppm; C NMR (150 MHz, CDCl3): 

167.47, 166.34, 149.62, 132.65, 130.85, 129.61, 129.51, 128.56, 128.28, 127.64, 124.43,

+ 56.00, 48.88, 26.49, 21.91, 21.04 ppm; EIMS [M+Na] calcd for C15H19N3NaO4: 328.1; found: 328.3.

4-(1H-indol-3-yl)-N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) butanamide (3z). The compound was obtained as a yellow solid; m.p: 86-88 °C; yield:

50

1 85%; H NMR (600 MHz, CDCl3):  8.07-8.01 (m, 2H), 7.63-7.59 (m, 3H), 7.51-7.48

(m, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.06

(s, 1H), 5.67 (s, 1H), 5.24 (d, J = 4.3 Hz, 1H), 4.14-4.10 (m, 1H), 2.94-2.84 (m, 2H),

2.61-2.47 (m, 2H), 2.19-2.07 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H)

13 ppm; C NMR (150 MHz, CDCl3):  174.03, 169.08, 149.17, 136.60, 133.73, 131.98,

130.55, 129.29, 127.65, 125.29, 122.15, 121.99, 119.38, 119.09, 115.74, 111.35, 57.13,

+ 49.88, 33.56, 27.09, 25.44, 24.69, 21.52, 21.12; EIMS [M+Na] calcd for C24H28N4NaO4:

459.2; found: 459.5.

N-isopropyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl)-1-naphthamide

(3aa). The compound was obtained as a light yellow solid; m.p: 108-110 °C; yield: 80%;

1 H NMR (600 MHz, CDCl3):  8.43 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.09 (d,

J = 7.9 Hz, 1H), 7.91-7.84 (m, 3H), 7.78-7.50 (m, 5H), 7.44 (d, J = 6.8 Hz, 1H), 5.89-

5.81 (m, 1H), 5.36-5.35 (m, 1H), 3.98-3.82 (m, 1H), 2.84 (t, J = 4.8 Hz, 3H), 1.26 (d, J =

13 6.5 Hz, 3H), 0.81 (t, J = 6.6 Hz, 3H) (rotamers) ppm; C NMR (150 MHz, CDCl3): 

172.61 172.43, 168.72, 168.37, 149.45, 149.28, 134.64, 134.47, 134.32, 134.24, 133.72,

133.65, 132.71, 132.09, 131.43, 130.64, 130.07, 129.86, 129.80, 129.76, 129.43, 129.36,

128.99, 128.19, 127.69, 127.29, 127.08, 126.57, 125.94, 125.61, 125.59, 125.52, 125.03,

124.19, 124.19, 123.93, 122.60, 56.97, 56.36, 52.37, 52.05, 27.28, 21.98, 21.90, 21.10,

+ 20.43 (rotamers) ppm; EIMS [M+Na] calcd for C23H23N3NaO4: 428.2; found: 428.2.

N-benzyl-N-(2-(methylamino)-1-(2-nitrophenyl)-2-oxoethyl) pivalamide (3bb). The compound was obtained as a yellow solid; m.p: 209-211 °C; yield: 83%; 1H NMR (600

MHz, CDCl3 , 55°C):  7.58 (s, 1H), 7.09 (s, 1H), 6.15 (d, J =1.2 Hz, 1H), 6.13 (d, J =

51

1.2 Hz, 1H), 5.64 (s, 1H), 5.24 (m, 1H), 4.23-4.19 (m, 1H), 4.23 (d, J = 4.6 Hz, 3H),

2.59-2.52 (m, 1H), 2.49-2.43 (m, 1H), 1.43 (d, J =6.5 Hz, 3H), 1.21 (t, J = 7.3 Hz, 3H),

13 0.95 (d, J = 6.6 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  174.80, 169.01, 152.51,

147.99, 143.17, 129.87, 109.57, 106.22, 103.42, 57.37, 49.84, 27.54, 27.09, 21.58, 21.01,

+ 9.52 ppm; EIMS [M+Na] calcd for C21H25N3NaO4: 406.2; found: 406.3.

General Procedure for the Synthesis of Aniline Intermediates 2a-2bb. Into a mixture of product 3 (1 eq) in a 25% water in ethanol (3.2 mL) solution was added iron powder

(10 eq) and ammonium chloride (1 eq). The reaction mixture was allowed to stir at 60-70

°C for 1-2 hours. The reaction progress was monitored by TLC. Upon completion of the reaction the mixture was allowed to cool to room temperature and subsequently filtered through a pad of Celite®. The filtrate was collected and evaporated under reduced pressure to obtain a crude mass. The material was then diluted with CH2Cl2 and the organic layer was washed with saturated NaHCO3 solution (3 mL) followed by washing with a brine solution (5 mL). The organic layer was then dried over anhydrous Na2SO4

(1-2 g). Complete removal of solvent was carried out under reduced pressure and the reaction mixture was then purified using flash column chromatography (EtOAc:hexanes) to yield pure product 2.

N-(1-(2-aminophenyl)-2-(cyclopentylamino)-2-oxoethyl)-N-benzylpropionamide

(2a). The compound was obtained as a white solid; m.p: 128-130 °C; yield: 90%; 1H

NMR (600 MHz, DMSO-d6):  8.07 (d, J = 5.3 Hz, 1H), 7.11-6.93 (m, 7H), 6.64 (d, J =

7.1 Hz, 1H), 6.42 (s, 1H), 6.26 (s, 1H), 5.44 (s, 1H), 5.04 (s, 2H, D2O exchangeable),

4.70-4.60 (dd, J1 =19.8 Hz, J2 = 17.4 Hz 2H), 4.03 (d, J = 8.9 Hz, 1H) 2.25-2.22 (m, 1H),

1.91-1.87 (m, 1H), 1.58-1.28 (m, 6H), 0.84(s, 3H) (rotamers) ppm; 13C NMR (150 MHz, 52

DMSO-d6):  175.23, 169.33, 147.46, 139.27, 128.92, 128.81, 127.98, 126.28, 125.88,

119.18, 115.98, 114.89, 55.89, 50.41, 48.68, 32.16, 31.66, 26.73, 23.45, 23.42, 9.27 ppm;

+ EIMS [M+Na] calcd for C23H29N3NaO2: 402.2; found: 402.3.

N-(1-(2-aminophenyl)-2-((2,6-dimethylphenyl)amino)-2-oxoethyl)-N- benzylpropionamide (2b). The compound was obtained as a yellow solid; m.p: 118-120

1 °C; yield: 85%; H NMR (600 MHz, DMSO-d6):  9.48 (s, 1H), 7.17-6.98 (m, 10H), 6.69

(d, J = 7.7 Hz, 1H), 6.49-6.41 (m, 2H), 5.15 (s, 2H, D2O exchangeable), 4.70 (d, J = 17.8

Hz, 1H), 4.59 (d, J = 17.8 Hz, 1H), 2.33-2.29 (m, 1H), 2.14 (s, 3H), 2.00-1.96 (m, 1H),

13 0.89 (t, J = 6.8 Hz, 1H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  175.02,

168.46, 147.20, 138.88, 135.18, 134.59, 129.68, 128.82, 127.55, 127.30, 126.11, 125.92,

118.29, 115.89, 115.30, 57.40, 48.09, 30.57, 26.42, 17.76, 8.96 ppm; EIMS [M+Na]+ calcd for C25H26N3NaO4: 423.2; found: 423.5.

N-(1-(2-aminophenyl)-2-(cyclohexylamino)-2-oxoethyl)-N-benzylpropionamide (2c).

The compound was obtained as a white solid; m.p: 132-134 °C; yield: 87%; 1H NMR

(600 MHz, DMSO-d6):  7.97 (d, J = 7.3 Hz, 1H), 7.11-6.92 (m, 7H), 6.64-6.4 (m, 1H),

6.42 (s, 1H), 6.26 (s, 1H), 5.03 (s, 2H, D2O exchangeable), 4.69-4.60 (dd, J1 = 19.7 Hz,

J2 = 17.5 Hz, 2H), 3.33-2.11 (m,1H), 1.92-1.87 (m, 1H), 1.71-1.69 (m, 1H), 1.51-1.21

(m, 5H), 1.19-1.00 (m, 5H), 0.84 (t, J = 7.1 Hz, 3H) (rotamers) ppm; 13C NMR (150

MHz, DMSO-d6):  175.24, 168.85, 147.28, 139.27, 128.99, 128.81, 127.98, 127.33,

126.28, 125.90, 119.20, 115.99, 114.88, 55.86, 48.69, 32.22, 32.05, 26.74, 25.17, 24.65,

+ 24.51, 9.28 ppm; EIMS [M+Na] calcd for C24H31N3NaO2: 416.2; found: 416.7.

53

N-(1-(2-aminophenyl)-2-((4-methoxyphenyl)amino)-2-oxoethyl)-N- benzylpropionamide (2d). The compound was obtained as a brown solid; m.p: 103-105

1 °C; yield: 83%; H NMR (600 MHz, DMSO-d6, 65 °C):  9.88 (s, 1H), 7.48 (d, J = 8.3

Hz, 2H), 7.14-6.95 (m, 9H), 6.68 (d, J = 7.0 Hz, 1H), 6.47 (s, 1H), 6.38 (s, 1H), 4.96 (s,

2H, D2O exchangeable), 4.74-4.62 (m, 2H), 2.38-2.32 (m, 1H), 2.05 (s, 1H), 0.93 (s, 3H)

13 (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  175.49, 168.66, 155.22, 147.41,

139.14, 132.09, 129.14, 128.03, 126.37, 125.94, 120.72, 118.40, 116.21, 115.17, 113.85,

+ 57.19, 55.16, 48.59, 26.79, 9.25 ppm; EIMS [M+Na] calcd for C25H27N3NaO2: 440.2; found: 440.5.

N-(1-(2-aminophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-benzylpropionamide (2e).

The compound was obtained as an off-white solid; m.p: 98-100 °C; yield: 85%; 1H NMR

(600 MHz, DMSO-d6):  7.73 (s, 1H), 7.10-6.85 (m, 9H), 6.63 (d, J = 7.5 Hz, 1H), 6.44-

6.43 (m, 1H), 6.28 (s, 1H), 5.01 (s, 2H, D2O exchangeable), 4.70-4.64 (m, 2H), 2.24-2.20

(m, 1H), 1.90-1.86 (m, 1H), 1.23 (s, 9H), 0.84 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (150

MHz, DMSO-d6):  175.11, 169.50, 147.29, 139.38, 128.78, 128.68, 127.95, 127.30,

126.23, 125.87, 119.62, 115.94, 114.86, 55.77, 50.35, 48.71, 28.40, 26.73, 9.73 ppm;

+ EIMS [M+Na] calcd for C22H29N3NaO2: 390.2 found 390.6.

N-(1-(2-aminophenyl)-2-(isopropylamino)-2-oxoethyl)-N-benzylpropionamide (2f).

The compound was obtained as a white solid; m.p: 118-120 °C; yield: 85%; 1H NMR

(600 MHz, DMSO-d6):  7.30-7.03 (m, 5H), 6.81 (d, J = 6.7 Hz, 2H), 6.64 (d, J = 7.9 Hz,

1H), 6.57-6.52 (m, 2H), 5.36 (d, J = 7.2 Hz, 1H), 4.81 (d, J = 17.8 Hz, 1H), 6.64 (d, J =

17.8 Hz, 1H), 4.41 (s, 2H, D2O exchangeable), 4.16-4.12 (m, 1H), 2.42-2.37 (m, 1H),

54

2.08-2.04 (m, 1H), 1.13 (s, 3H), 1.12-1.03 (m, 9H) ppm; 13C NMR (150 MHz, DMSO- d6):  175.24, 168.85, 147.29, 139.25, 128.98, 128.83, 127.98, 126.29, 125.86, 119.13,

116.00, 114.89, 55.81, 54.94, 48.68, 40.54, 26.73, 22.16, 22.08, 9.27 ppm; EIMS

+ [M+Na] calcd for C21H27N3NaO2: 376.2; found: 376.6.

N-(1-(2-aminophenyl)-2-oxo-2-(pentylamino)ethyl)-N-benzylpropionamide (2g). The compound was obtained as a light yellow solid; m.p: 80-82 °C; yield: 87%; 1H NMR

(600 MHz, DMSO-d6 ):  7.12-7.03 (m, 5H), 6.81-6.80 (d, J = 6.7 Hz, 2H), 6.64-6.6 (d, J

=7.9 Hz, 1H), 6.57-6.53 (m, 2H), 5.5 (s, 1H), 4.83-4.80 (d, J = 17.8 Hz, 1H), 4.69-4.67

(d, J = 17.8 Hz, 1H), 4.41 (s, 2H, D2O exchangeable), 3.33-3.23 (m, 2H), 2.43-2.38 (m,

1H), 2.09-2.05 (m, 1H), 1.56-1.29 (m, 2H), 1.28-1.23 (m, 6H), 1.04 (t, J =7.3 Hz, 3H),

13 0.89-0.84 (m, 4H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  175.72, 170.14,

147.77, 139.64, 129.67, 129.34, 129.25, 128.44, 127.72, 127.29, 126.76, 126.31, 119.45,

116.40, 115.37, 56.54, 49.09, 39.00, 29.01, 28.97, 28.90, 27.18, 22.25, 22.22, 14.39, 9.71

+ ppm; EIMS [M+Na] calcd for C23H31N3NaO2: 404.2; found: 404.3.

2-(2-aminophenyl)-2-(N-benzyl-2-(2-bromophenyl)acetamido)-N-methylacetamide

(2h). The compound was obtained as a white solid; m.p: 194-196 °C; yield: 97%; 1H

NMR (600 MHz, DMSO-d6):  8.01 (d, J = 4.5 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.29-

7.05 (m, 8H), 6.96 (t, J = 7.5 Hz, 2H), 6.67 (d, J = 7.9 Hz, 1H), 6.43 (t, J = 7.3 Hz, 1H),

6.21 (s, 1H), 5.06 (s, 2H, D2O exchangeable), 4.82 (d, J = 17.9 Hz, 1H), 4.73 (d, J = 17.9

Hz, 1H), 3.81 (d, J = 16.8 Hz, 1H), 3.39-3.36 (m, 1H), 2.60 (d, J = 4.4 Hz, 3H)

13 (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  173.34, 170.27, 135.42, 132.75,

131.76, 130.33, 130.27, 128.83, 128.66, 127.74, 127.18, 125.18, 57.40, 50.33, 42.10,

55

+ 29.91, 26.63 (rotamers) ppm; EIMS [M+Na] calcd for C24H24BrN3NaO2: 488.1; found:

488.3 and 490.3.

2-(2-aminophenyl)-2-(2-(2-bromophenyl)-N-isopropylacetamido)-N- methylacetamide (2i). The compound was obtained as a white solid; m.p: 171-173 °C;

1 yield: 94%; H NMR (600 MHz, DMSO-d6, 65 °C):  7.58 (d, J = 7.9 Hz, 1H), 7.37-7.04

(m, 5H), 6.73 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 6.8 Hz, 1H), 5.65 (s, 1H), 4.75 (s, 2H, D2O exchangeable), 3.96-3.80 (m, 3H), 2.62 (s, 3H), 1.43 (s, 3H), 0.91 (s, 3H); 13C NMR (150

MHz, DMSO-d6 ):  170.18, 169.96, 169.69, 169.01, 146.82, 136.48, 132.49, 132.29,

132.08, 129.27, 128.56, 127.43, 124.68, 116.14, 115.96, 114.98, 56.62, 49.23, 48.15,

42.29, 41.95, 25.82, 21.85, 20.95, 19.92, 19.66 ppm; EIMS [M+Na]+ calcd for

C20H24BrN3NaO2: 440.1; found: 440.1 and 442.1.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-isopropylpropionamide (2j).

The compound was obtained as a cream-white solid; m.p: 148-150 °C; yield: 90%; 1H

NMR (600 MHz, DMSO-d6, 65 °C):  7.51 (s, 1H), 7.03-6.99 (m, 2H), 6.71 (d, J = 6.84

Hz, 1H), 6.57 (s, 1H), 7.70-5.66 (m, 1H), 4.69 (s, 2H, D2O exchangeable), 3.79 (s, 1H),

2.61 (s, 3H), 2.43-2.22 (m, 2H),1.38 (d, J = 6.18 Hz, 1H), 1.05 (s, 3H), 0.18 (s, 3H)

13 (rotamers) ppm; C NMR (150 MHz, DMSO-d6, 65 °C):  173.53, 169.76, 146.50,

128.81, 128.24, 119.89, 116.15, 115.61, 47.53, 27.40, 25.38, 20.45, 9.54 (rotamers) ppm;

+ EIMS [M+Na] calcd for C15H23N3NaO2: 300.2; found: 300.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-cyclopropylpropionamide

(2k). The compound was obtained as a light-yellow solid; m.p: 160-162 °C; yield: 89%;

1 H NMR (600 MHz, DMSO-d6 ):  7.79 (d, J = 3.6 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 6.91

56

(d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.56 (t, J = 7.3 Hz, 1H), 5.77 (s, 1H), 4.57

(s, 2H, D2O exchangeable), 2.60 (d, J = 4.6 Hz, 3H), 2.57-2.53 (m, 2H), 2.14-2.13 (m,

1H), 1.03 (t, J = 7.3 Hz, 3H), 0.61-0.59 (m, 2H), 0.21-0.19 (m, 1H) ppm; 13C NMR (150

MHz, DMSO-d6):  176.76, 170.53, 146.57, 130.19, 128.25, 119.70, 115.99, 114.93,

+ 59.03, 27.40, 26.76, 25.80, 9.40, 8.59; EIMS [M+Na] calcd for C15H21N3NaO2: 298.2; found: 298.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-cyclopentylpropionamide (2l).

The compound was obtained as a light-yellow solid; m.p: 132-134 °C; yield: 85%; 1H

NMR (600 MHz, DMSO-d6, 65 °C):  7.53 (s, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.98 (d, J =

7.6 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.58 (t, J = 7.3 Hz, 1H), 5.56 (s, 1H), 4.62 (s, 2H,

D2O exchangeable), 3.84 (s, 1H), 2.64 (d, J = 4.3 Hz, 3H), 2.44-2.33 (m, 1H), 2.29-2.25

(m, 1H), 1.91 (s, 1H), 1.66-1.56 (m, 3H), 1.37-1.20 (m, 2H), 1.05-1.03 (m, 4H) ppm; 13C

NMR (150 MHz, DMSO-d6, 65 °C):  173.18, 169.57, 146.39, 128.59, 128.16, 120.37,

116.24, 115.35, 57.51, 29.36, 27.13, 25.41, 24.10, 23.89, 9.44 ppm; EIMS [M+Na]+ calcd for C17H25N3NaO2: 326.2; found: 326.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-cyclohexylpropionamide

(2m). The compound was obtained as a cream-white solid; m.p: 174-176 °C; yield: 85%;

1 H NMR (600 MHz, DMSO-d6, 65 °C):  7.38 (s, 1H), 7.03 (s, 2H), 6.69 (d, J = 7.1 Hz,

1H), 6.58 (t, J = 7.3 Hz, 1H), (m, 2H), 5.59 (s, 1H), 4.68 (s, 2H, D2O exchangeable), 3.42

(s, 1H), 2.61 (d, J = 4.5 Hz, 1H), 2.46-2.21 (m, 3H), 1.73-1.71 (m, 2H), 1.47-0.82 (m,

13 10H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6, 65 °C):  173.50, 169.64, 146.38,

57

128.73, 128.13, 120.23, 116.06, 115.23, 56.23, 30.56, 27.39, 25.98, 25.71, 25.46, 24.78,

+ 9.64 (rotamers) ppm; EIMS [M+Na] calcd for C18H27N3NaO2: 340.2; found: 340.4.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-phenylpropionamide (2n).

The compound was obtained as an off-white solid; m.p: 170-172 °C; yield: 91%; 1H

NMR (600 MHz, DMSO-d6, 65 °C):  7.92 (s, 1H), 7.09-6.54 (m, 4H), 6.53-6.47 (m,

2H), 6.22-6.19 (s, 1H), 6.00 (s, 1H), 4.87 (s, 2H, D2O exchangeable), 2.62 (s, 3H), 2.03-

13 1.82 (m, 2H), 0.89 (d, J = 6.9 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6, 65 °C): 

173.23, 170.68, 146.76, 139.69, 129.79, 128.40, 128.01, 127.42, 118.80, 115.84, 114.95,

+ 59.01, 27.84, 25.75, 9.30 ppm; EIMS [M+Na] calcd for C18H21N3NaO2: 334.2 found

334.4.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-methylbenzamide (2o). The compound was obtained as a light yellow solid; m.p: 110-112 °C; yield: 86%; 1H NMR

(600 MHz, DMSO-d6, 65 °C):  7.90 (s, 1H), 7.44-7.40 (m, 5H), 7.08-7.06 (m, 2H), 6.76

(d, J = 7.9 Hz, 1H), 6.60 (t, J = 7.2 Hz, 1H), 6.10 (s, 1H), 4.94 (s, 2H, D2O

13 exchangeable), 2.67-2.66 (d, 6H) ppm; C NMR (150 MHz, DMSO-d6):  171.43,

169.96, 147.04, 136.32, 129.60, 129.41, 128.99, 128.39, 126.84, 118.26, 116.16, 115.12,

+ 56.67, 34.60, 25.63 ppm; EIMS [M+Na] calcd for C17H19N3NaO2: 320.1; found: 320.8.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-ethylbenzamide (2p). The compound was obtained as a white solid; m.p: 178-180 °C; yield: 84%; 1H NMR (600

MHz, DMSO-d6 ):  7.78 (s, 1H), 7.46-7.38 (m, 5H), 7.08-7.01 (m, 2H), 6.74-6.72 (m,

1H), 6.61-6.58 (m, 1H), 6.01-5.87 (m, 1H), 4.83 (s, 2H, D2O exchangeable), 3.28 (d, 2H),

13 2.66 (d, J = 4.5 Hz, 3H), 0.94 (s, 3H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6): 

58

172.10, 170.06, 147.44, 137.19, 129.33, 129.19, 129.06, 128.37, 126.28, 118.56, 116.19,

+ 114.92, 56.87, 41.14, 30.96, 25.69, 14.75 ppm; EIMS [M+Na] calcd for C18H21N3NaO2:

334.2; found: 334.7.

2-(2-aminophenyl)-2-(2-(2-bromophenyl)-N-propylacetamido)-N-methylacetamide

(2q). The compound was obtained as a white solid; m.p: 145-147 °C; yield: 92%; 1H

NMR (600 MHz, DMSO-d6, 65 °C):  7.74 (s, 1H), 7.59 (d, J = 6.3 Hz, 1H), 7.37-7.33

(m, 2H), 7.19 (s, 1H), 7.07-7.02 (m, 2H), 6.01 (s, 1H), 4.72 (s, 2H, D2O exchangeable),

3.96-3.84 (m, 2H), 3.31 (s, 2H), 2.62 (s, 3H), 1.43 (s, 1H), 0.79 (s, 1H), 0.54 (s, 3H) ppm;

13 C NMR (150 MHz, DMSO-d6, 65 °C ):  170.34, 169.69, 147.25, 136.19, 132.16,

132.13, 129.04, 128.98, 128.66, 127.54, 124.74, 119.08, 116.08, 114.72, 55.97, 47.39,

+ 40.50, 25.64, 22.31, 11.21 ppm; EIMS [M+Na] calcd for C15H21N3NaO2: 440.1; found:

440.1.

2-(2-aminophenyl)-2-(2-(2-bromophenyl)-N-butylacetamido)-N-methylacetamide

(2r). The compound was obtained as a cream white solid; m.p: 154-156 °C; yield: 95%;

1 H NMR (600 MHz, DMSO-d6 ):  7.94 (d, J = 4.3 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H),

7.38-7.32 (m, 2H), 7.22-7.19 (m, 1H), 6.97-6.96 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.9 Hz,

1H), 6.59-6.56 (m, 2H, D2O exchangeable), 3.95 (d, J = 16.5 Hz, 1H), 3.81 (d, J = 16.5

Hz, 1H), 2.60 (d, J = 4.3 Hz, 3H), 1.44-1.42 (m, 1H), 1.02-0.84 (m, 2H), 0.64-0.61 (m,

13 1H), 0.58 (t, J = 7.3 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  170.31, 170.00,

147.28, 136.16, 132.16, 132.12, 129.14, 128.94, 128.67, 127.54, 124.73, 119.03, 116.14,

114.71, 56.03, 45.04, 40.50, 30.90, 25.64, 19.54, 13.38 ppm; EIMS [M+Na]+ calcd for

C21H26BrN3NaO2: 454.1 found 454.1; and: 456.1.

59

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-isopropylbenzamide (2s). The compound was obtained as a light-yellow solid; m.p: 198-200 °C; yield: 92%; 1H NMR

(600 MHz, DMSO-d6, 65 °C):  7.45-7.24 (m, 6H), 7.05 (d, J = 7.1 Hz, 2H), 6.73-6.72

(d, J = 7.9 Hz, 1H), 6.62 (t, J = 7.5 Hz, 1H), 5.17 (s, 1H), 4.56 (s, 2H, D2O exchangeable), 2.63 (d, J = 4.6 Hz, 3H), 1.38 (s, 3H), 0.80 (d, J = 6.6 Hz, 3H) ppm; 13C

NMR (150 MHz, DMSO-d6):  170.71, 169.65, 146.39, 137.96, 128.95, 128.84, 128.44,

128.05, 125.73, 119.96, 116.60, 115.60, 49.44, 25.49, 20.11, 19.91 ppm; EIMS [M+Na]+ calcd for C19H23N3NaO2: 348.2; found: 348.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N- isopropylcyclopropanecarboxamide (2t). The compound was obtained as a light-

1 yellow solid; m.p: 149-151 °C; yield: 86%; H NMR (600 MHz, DMSO-d6, 65 °C): 

7.65 (s,1H), 7.05-7.01 (m, 2H), 6.69 (d, J = 7.3 Hz, 1H), 6.59 (d, J = 6.4 Hz, 1H), 5.96 (s,

1H), 4.69 (s, 2H, D2O exchangeable), 3.91 (s, 1H), 2.61 (s, 3H), 1.83 (s, 1H), 1.48 (s,

3H), 0.88 (m, 1H), 0.85 (d, J = 6.5 Hz, 3H), 0.79-0.74 (m, 3H) ppm; 13C NMR (150

MHz, DMSO-d6, 65 °C):  173.24, 169.81, 146.59, 128.78, 128.32, 119.54, 115.96,

114.83, 57.22, 47.28, 25.29, 21.65, 21.37, 20.65, 13.24, 7.58, 7.40 ppm; EIMS [M+Na]+ calcd for C16H23N3NaO2: 312.2; found: 312.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-isopropylpentanamide (2u).

The compound was obtained as a yellow solid; m.p: 130-132 °C; yield: 90%; 1H NMR

(600 MHz, DMSO-d6, 65 °C):  7.50 (s, 1H), 7.03-7.00 (m, 2H), 6.71 (d, J = 6.6 Hz, 1H),

6.59 (s, 1H), 5.69 (s, 1H), 4.69 (s, 2H, D2O exchangeable), 3.80 (s, 1H), 2.61 (s, 3H),

2.41-2.29 (m, 2H), 1.55 (s, 2H), 1.39-1.38 (d, J = 6.4 Hz, 3H), 1.33-1.32 (d, J = 6.7 Hz,

60

2H), 0.89 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (150 MHz,

DMSO-d6, 65 °C):  172.84, 169.76, 146.48, 128.82, 128.25, 119.87, 116.11, 115.10,

47.58, 33.96, 27.13, 25.37, 21.58, 20.55, 13.43 ppm; EIMS [M+Na]+ calcd for

C17H27N3NaO2: 328.2; found: 328.4.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-3-(4-fluorophenyl)-N- isopropylpropanamide (2v). The compound was obtained as a light-yellow solid; m.p:

1 122-124 °C; yield: 94%; H NMR (600 MHz, DMSO-d6, 65 °C):  7.29 (s, 1H), 7.26 (s,

2H), 7.07-7.04 (m, 4H), 6.72 (d, J = 5.8 Hz, 3H), 6.56 (s, 1H), 5.63 (s, 1H), 4.66 (s, 2H,

D2O exchangeable), 2.89 (d, J = 5.9 Hz, 2H), 2.74-2.71 (m, 1H), 2.62-2.61 (m, 4H), 1.37

13 (d, J = 6.5 Hz, 3H), 0.79 (s, 3H) ppm; C NMR (150 MHz, DMSO-d6, 65 °C):  171.83,

169.66, 161.22, 159.62, 146.45, 137.24, 129.78, 129.73, 128.85, 128.27, 119.76, 116.17,

115.20, 114.58, 114.44, 47.68, 40.05, 35.93, 29.96, 25.40 ppm; EIMS [M+Na]+ calcd for

C21H26FN3NaO2: 394.2; found: 394.6.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-4-bromo-N-isopropylbenzamide

(2w). The compound was obtained as a light-yellow solid; m.p: 160-162 °C; yield: 87%;

1 H NMR (600 MHz, DMSO-d6, 65 °C):  7.64 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.2 Hz,

3H), 7.06-7.04 (m, 2H), 6.74-6.73 (d, J = 8.0 Hz, 1H), 6.61 (t, J = 7.3 Hz, 1H), 5.14 (s,

1H), 4.54 (s, 2H, D2O exchangeable), 3.68 (s, 1H), 2.63 (s, 3H), 1.38 (s, 3H), 0.80-079

13 (d, J = 6.0 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6, 65 °C):  169.76, 169.41,

146.40, 137.08, 131.10, 128.64, 128.50, 127.91, 122.17, 119.85, 116.69, 115.73, 49.47,

+ 40.04, 25.45. 19.98, 19.84 ppm; EIMS [M+Na] calcd for C19H22BrN3NaO2: 426.1; found: 426.1 and 428.1.

61

2-(2-aminophenyl)-2-(2-(3,4-difluorophenyl)-N-isopropylacetamido)-N- methylacetamide (2x). The compound was obtained as a cream-white solid; m.p: 100-

1 102 °C, yield: 87%; H NMR (600 MHz, DMSO-d6, 65 °C):  7.59 (s, 1H), 7.34-7.27 (m,

3H), 7.09-7.01 (m, 3H), 6.72 (d, J = 7.9 Hz, 1H), 6.58 (t, J = 7.3 Hz, 1H), 5.58 (s, 1H),

4.69 (s, 2H, D2O exchangeable), 3.79 (d, J = 15.5 Hz, 2H), 3.71 (d, J = 13.7 Hz, 1H),

2.62 (d, J = 4.5 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.2 Hz, 1H) ppm; 13C

NMR (150 MHz, DMSO-d6, 65 °C):  170.27, 169.50, 149.61, 146.48, 133.55, 128.91,

128.40, 125.78, 125.76, 125.74, 125.72, 119.62, 118.06, 117.95, 116.57, 116.46, 116.29,

+ 115.38, 48.20, 25.43, 20.49 ppm; EIMS [M+Na] calcd for C20H23F2N3NaO2: 398.2; found: 398.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-isopropylacrylamide (2y).

The compound was obtained as a light-yellow solid; m.p: 126-128 °C; yield: 85%; 1H

NMR (600 MHz, DMSO-d6, 65 °C):  7.69 (s, 1H), 7.05-7.01 (m, 2H), 6.70-6.58 (m,

3H), 6.15 (d, J = 16.0 Hz, 1H), 5.92 (d, J = 9.8 Hz, 1H), 5.67 (d, J = 8.5 Hz, 1H), 4.69 (s,

2H, D2O exchangeable), 3.85 (s, 1H), 2.63 (d, J = 4.3 Hz, 3H), 1.43 (d, J = 6.8 Hz, 3H),

13 0.82 (d, J = 6.2 Hz, 3H); C NMR (150 MHz, DMSO-d6, 65 °C):  169.58, 166.04,

146.58, 130.54, 128.84, 128.44, 126.29, 119.23, 116.08, 114.99, 47.79, 40.04, 25.31

+ ppm; EIMS [M+Na] calcd for C15H21N3NaO2: 298;.2 found: 298.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-4-(1H-indol-3-yl)-N- isopropylbutanamide (2z). The compound was obtained as a yellow solid; m.p: 109-

1 111 °C; yield: 91%; H NMR (600 MHz, DMSO-d6, 65 °C):  10.59 (s, 1H), 7.53 (d, J =

7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.08-6.56 (m, 7H), 5.72-5.62 (m, 1H), 4.70 (s, 2H,

62

D2O exchangeable), 3.79 (s, 1H), 2.73 (s, 2H), 2.61 (d, J = 4.3 Hz, 3H), 1.86-1.85 (m,

13 2H), 1.35-1.26 (m, 3H), 0.88-0.76 (m, 3H); C NMR (150 MHz, DMSO-d6):  173.46,

169.90, 146.72, 136.29, 129.04, 128.58, 127.17, 122.33, 120.80, 118.37, 118.08, 116.01,

114.88, 111.30, 56.09, 47.64, 40.04, 34.37, 31.33, 26.62, 25.76, 24.29, 22.08, 21.08 ppm;

+ EIMS [M+Na] calcd for C24H30N4NaO2: 429.2; found: 429.3.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-isopropyl-1-naphthamide

(2aa). The compound was obtained as a white solid; m.p: 110-112 °C; yield: 85%; 1H

NMR (600 MHz, CD2Cl2):  8.07 (d, J = 5.3 Hz, 1H), 7.11-6.93 (m, 9H), 6.64-6.42 (m,

2H), 6.26 (s, 1H), 5.44-5.04 (m, 2H), 4.70-4.60 (m, 2H, D2O exchangeable), 4.25-4.02

(m, 1H), 2.25-2.21 (m, 1H), 1.91-1.87 (m, 1H), 1.76-1.28 (m, 8H), 1.00-0.84 (m, 3H)

13 ppm; C NMR (150 MHz, DMSO-d6):  171.57, 171.48, 169.34, 169.19, 144.52, 135.50,

135.25, 133.62, 133.48, 130.07, 129.91, 129.44, 129.26, 129.08, 128.80, 128.72, 128.47,

128.05, 127.10, 127.04, 126.66, 126.44, 125.78, 125.30, 125.13, 124.79, 123.33, 122.59,

122.01, 119.60, 119.39, 117.43, 117.23, 57.62, 56.89, 51.97, 51.69, 26.66, 26.59, 22.71,

+ 21.30, 21.16, 20.28, 13.94 ppm; EIMS [M+Na] calcd for C23H25N3NaO2: 398.2; found:

398.4.

N-(1-(2-aminophenyl)-2-(methylamino)-2-oxoethyl)-N-benzylpivalamide (2bb). The compound was obtained as a light-brown solid; m.p: 113-115 °C; yield: 90%; 1H NMR

(600 MHz, DMSO-d6, 65 °C):  7.36-7.31 (m, 1H), 6.57 (s, 1H), 6.37 (s, 1H), 5.84 (d, J

= 10.0 Hz, 2H), 5.44 (s, 1H), 4.46 (s, 2H, D2O exchangeable), 3.81 (s, 1H), 2.60 (d, J =

4.1 Hz, 3H), 2.45-2.27 (m, 2H), 1.37 (d, J = 6.7 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H), 0.87 (d,

13 J = 5.9 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6, 65 °C):  173.25, 169.68, 147.09,

63

141.76, 138.44, 111.96, 108.29, 99.98, 97.13, 47.57, 40.04, 27.22, 25.47, 20.49, 9.47

+ ppm; EIMS [M+Na] calcd for C21H27N3NaO2: 344.3; found: 344.5.

General Procedure for Synthesis of 3-Substituted-2-Indolinones 1h-1bb and 8a-8g.

Compound 2 (100 mg, 1 eq) and 10% TFA were taken up in dichloroethane (1 mL) in a

Discovery® microwave reactor-based test-tube and subjected to microwave irradiation at

300 W, 10 bar pressure, 120 °C, for 10 minutes. After the allotted microwave time, the reaction was allowed to cool to room temperature and then diluted with CH2Cl2 (5 mL).

Saturated NaHCO3 (5 mL) was then slowly added while the test-tube sat on an ice bath.

The organic layer was washed with a brine solution (5 mL) and dried over anhydrous

Na2SO4. The contents were concentrated under reduced pressure and the mixture was then purified using flash column chromatography (CH3OH:CH2Cl2) to yield pure compounds 1h-1bb & 8a-8g.

N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl) acetamide (1h). The compound was obtained as a white solid; m.p: 194-196 °C; yield: 90%; 1H NMR (600 MHz,

DMSO-d6, 52 °C):  10.48-10.21 (m, 1H), 7.60-6.72 (m, 13H), 5.89-4.80 (m, 1H), 4.34-

13 4.10 (m, 2H), 3.97-3.81 (m, 2H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6): 

174.63, 174.53, 170.94, 142.30, 142.25, 137.49, 136.26, 135.66, 132.31, 132.22, 132.11,

131.98, 129.30, 128.75, 128.70, 127.75, 127.61, 127.44, 126.59, 125.37, 124.93, 124.54,

124.22, 121.58, 120.94, 110.01, 109.13, 60.13, 46.94 (rotamers) ppm; HRMS(TOF-ESI):

+ [M+Na] calcd for C23H19BrN2NaO2: 457.0528; found: 457.0549.

2-(2-bromophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl) acetamide (1i). The compound was obtained as a white solid; m.p: 196-198 °C; yield: 90%; 1H NMR (600 MHz,

DMSO-d6):  10.23 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.28-7.22 (m, 2H), 7.15-7.10 (m, 64

2H), 7.04 (d, J = 7.3 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 4.82 (s,

1H), 4.32-4.30 (m, 1H), 3.83 (dd, J1 = 16.3 Hz, J2 = 6.2 Hz, 2H), 1.38 (d, J = 6.5 Hz,

13 3H), 1.29-1.28 (d, J = 6.5 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.31,

167.09, 142.40, 135.67, 132.00, 131.43, 128.48, 127.95, 127.41, 127.28, 124.37, 122.21,

120.71, 54.76, 48.16, 40.00, 21.84, 21.12 ppm; HRMS (TOF-ESI): [M]+ calcd for

C19H19BrN2O2: 386.0630; found: 386.0649.

N-isopropyl-N-(2-oxoindolin-3-yl) propionamide (1j). The compound was obtained as

1 an off-white solid; m.p: 136-138 °C; yield: 85%; H NMR (600 MHz, DMSO-d6): 

10.24 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.85-6.84 (m, 1H), 4.70

(s, 1H), 4.21 (d, J = 12.5 Hz, 3H), 2.33-2.31 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H), 1.24 (d, J

13 = 6.5 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.78,

170.69, 142.55, 128.50, 127.48, 122.19, 120.88, 108.96, 54.72, 47.49, 25.76, 22.08,

+ 21.28, 9.15 ppm; HRMS (TOF-ESI): [M+H] calcd for C14H19N2O2: 247.1447; found:

247.1443.

N-Cyclopropyl-N-(2-oxoindolin-3-yl)propionamide (1k). The compound was obtained

1 as a white solid; m.p: 142-144 °C; yield: 79%; H NMR (600 MHz, DMSO-d6, 52 °C): 

10.25 (s, 1H), 7.13-6.74 (m, 5H), 4.71 (s, 1H), 3.20-3.07 (m, 1H), 2.68-2.48 (m, 2H),

13 1.27-0.86 (m, 4H), 0.84-0.82 (t, J = 9.0 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6): 

175.26, 175.11, 142.18, 127.89, 122.21, 121.24, 109.07, 62.32, 39.93, 32.29, 26.39,

+ 10.38, 8.76 ppm; HRMS (TOF-ESI): [M+Na] calcd for C14H16N2NaO2: 267.1109; found: 267.1098.

65

N-Cyclopentyl-N-(2-oxoindolin-3-yl) propionamide (1l). The compound was obtained

1 as a white solid; m.p: 168-170 °C; yield: 78%; H NMR (600 MHz, DMSO-d6):  10.27

(s, 1H), 7.13 (t, J = 5.0 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.76

(d, J = 7.6 Hz, 1H), 4.71 (d, J = 8.3 Hz, 1H), 4.42-4.36 (m, 1H), 2.41-2.32 (m, 2H), 2.09

(t, J = 3.6 Hz, 1H), 1.93 (t, J = 8.5 Hz, 1H),1.70-1.56 (m, 6H), 0.87 (t, J = 7.4 Hz, 3H)

13 ppm; C NMR (150 MHz, DMSO-d6):  175.67, 171.15, 142.51, 128.33, 127.57, 121.99,

120.89, 109.00, 57.74, 55.63, 30.92, 29.51, 25.85, 23.67, 23.41, 9.21 ppm; HRMS (TOF-

+ ESI): [M+H] calcd for C16H21N2O2: 273.1603; found: 273.1611.

N-Cyclohexyl-N-(2-oxoindolin-3-yl)propionamide (1m). The compound was obtained

1 as a white solid; m.p: 140-142 °C; yield: 79%; H NMR (600 MHz, DMSO-d6):  10.22

(s, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 6.87-6.84 (dd, , J1 = 7.4 Hz, J2

= 7.0 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 4.73 (s, 1H), 3.76-3.71 (m, 1H), 2.38-2.30 (m,

2H), 1.98 (d, J = 11.5 Hz, 1H), 1.83-1.36 (m, 8H), 1.13-1.08 (m, 1H), 0.86 (t, J = 7.4 Hz,

13 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.67, 170.84, 142.45, 128.51, 127.44,

122.14, 120.82, 108.92, 55.60, 55.55, 32.15, 31.42, 25.81, 25.44, 25.25, 24.57, 9.13 ppm;

+ HRMS: EIMS [M+Na] calcd for C17H22N2NaO2: 309.1579; found: 309.1589.

N-(2-oxoindolin-3-yl)-N-phenylpropionamide (1n). The compound was obtained as a

1 yellow solid; m.p: 65-69 °C; yield: 82%; H NMR (600 MHz, DMSO-d6):  10.29 (s,

1H), 7.39-7.32 (m, 7H), 7.15 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.1

13 Hz, 1H), 2.05 (m, 2H), 0.94 (t, J = 6.7 Hz, 2H) ppm; C NMR (150 MHz, DMSO-d6): 

174.07, 142.09, 129.08, 128.53, 128.15, 127.77, 121.08, 109.23, 26.51, 8.92 ppm; HRMS

+ (TOF-ESI): [M+H] calcd for C17H17N2O2: 281.1285; found: 281.1290.

66

N-methyl-N-(2-oxoindolin-3-yl)benzamide (1o). The compound was obtained as a

1 creamy-white solid; m.p: 142-144 °C; yield: 80%; H NMR (600 MHz, DMSO-d6): 

10.70-10.61 (m, 1H), 7.60-7.26 (m, 7H), 7.04-7.01 (dd, J1 = 7.3 Hz, J2 = 6.5 Hz, 1H),

6.86 (d, J = 5.9 Hz, 1H), 5.26 (s, 1H), 2.76-2.56 (m, 3H) (rotamers) ppm; 13C NMR (150

MHz, DMSO-d6):  174.36, 174.27, 171.78, 142.88, 142.32, 135.40, 135.20, 129.96,

129.83, 129.67, 128.93, 128.69, 128.49, 127.10, 124.38, 124.11, 123.85, 122.12, 121.79,

110.26, 109.77, 61.82, 28.91(rotamers) ppm; HRMS (TOF-ESI): [M+Na]+ calcd for

C16H14N2NaO2: 289.0953; found: 289.0941.

N-ethyl-N-(2-oxoindolin-3-yl) benzamide (1p). The compound was obtained as a

1 yellow solid; m.p: 121-123 °C; yield: 78%; H NMR (600 MHz, DMSO-d6, 67 °C): 

10.32 (s, 1H), 7.45-7.21 (m, 7H), 6.98 (s, 1H), 6.84 (d, J = 6.7 Hz, 1H), 5.22 (s, 1H), 3.35

13 (m, 2H), 1.09 (s, 3H) (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  174.98,

174.73, 142.48, 135.80, 129.67, 128.67, 128.54, 126.98, 126.37, 121.97, 121.30, 110.25,

109.32, 61.91, 14.86, 13.67 (rotamers) ppm; HRMS (TOF-ESI): [M+Na]+ calcd for

C17H16N2NaO2: 303.1109; found: 303.1116.

2-(2-bromophenyl)-N-(2-oxoindolin-3-yl)-N-propyl acetamide (1q). The compound was obtained as a misty rose solid; m.p: 141-143 °C; yield: 80%; 1H NMR (600 MHz,

DMSO-d6, 52 °C):  10.60-10.22 (m, 1H), 7.60-6.76 (m, 8H), 5.76-4.81 (m, 1H), 4.17-

3.86 (m, 2H), 3.50-3.38 (m, 2H), 1.69-1.09 (m, 2H), 0.94-0.61 (m, 3H) (rotamers) ppm;

13 C NMR (150 MHz, DMSO-d6, 32 °C):  174.60, 174.38, 142.09, 135.49, 131.86,

131.40, 128.30, 127.14, 124.16, 122.61, 120.83, 109.04, 64.52, 59.93, 22.34, 10.64

67

+ (rotamers) ppm; HRMS (TOF-ESI): [M+Na] calcd for C19H19BrN2O2: 409.0528; found:

409.0547.

N-butyl-N-(2-oxoindolin-3-yl)-2-phenylacetamide (1r). The compound was obtained

1 as a light pink solid; m.p: 108-110 °C; yield: 79%; H NMR (600 MHz, DMSO-d6, 65

°C):  10.54-10.18 (m, 1H), 7.61-7.20 (m, 1H), 7.17-7.04 (m, 6H), 6.93-6.77 (m, 2H),

5.73-4.92 (m, 1H), 4.17-3.83 (m, 2H), 3.50 (s, 2H), 1.64-0.82 (m, 4H), 0.66 (s, 3H)

13 (rotamers) ppm; C NMR (150 MHz, DMSO-d6):  174.82, 170.35, 142.28, 135.79,

132.13, 131.78, 128.67, 127.47, 125.03, 124.50, 122.40, 121.94, 120.98, 110.53, 109.58,

31.52, 30.19, 29.90, 19.57, 19.32, 13.67, 13.13 (rotamers) ppm; HRMS (TOF-ESI):

+ EIMS [M+Na] calcd for C20H21BrN2NaO3: 447.0684; found: 447.1447.

N-isopropyl-N-(2-oxoindolin-3-yl)benzamide (1s). The compound was obtained as a

1 white solid; m.p: 238-240 °C; yield: 81%; H NMR (600 MHz, DMSO-d6):  10.37 (s,

1H), 7.44 (t, J = 2.8 Hz, 3H), 7.30-7.29 (dd, J1 = 3.5 Hz, J2 = 2.4 Hz, 2H), 7.19-7.15 (dd,

J1 = 8.9 Hz, J2 = 7.9 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 7.44 (t, J

= 2.8 Hz, H), 7.30 (q, J = 2.4 Hz, 2H), 7.17 (q, J = 7.9 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H),

6.79 (d, J = 7.6 Hz, 1H), 4.95 (s,1H), 3.95 (t, J = 6.0 Hz, 1H), 1.36 (d, J = 6.6 Hz, 3H),

13 1.21 (d, J = 6.5 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.37, 168.72,

142.74, 136.20, 129.45, 128.62, 127.94, 127.81, 125.97, 122.35, 121.12, 109.10, 54.65,

+ 50.02, 21.58, 21.20 ppm; HRMS (TOF-ESI): [M+Na] calcd for C18H18N2NaO2:

317.1266; found: 317.1279.

N-isopropyl-N-(2-oxoindolin-3-yl)cyclopropanecarboxamide (1t). The compound was obtained as a cream white solid; m.p: 76-78 °C, yield: 80%; 1H NMR (600 MHz,

68

DMSO-d6):  10.20 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.86 (t, J =

7.4 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 4.75 (s, 1H), 4.67-4.62 (m, 1H), 2.00-1.96 (m, 1H),

1.40 (d, J = 6.5 Hz, 3H), 1.31 (d, J = 6.5 Hz, 3H), 0.72-0.60 (m, 2H), 0.54-0.53 (m, 2H)

13 ppm; C NMR (150 MHz, DMSO-d6):  175.66, 170.33, 142.50, 128.50, 127.46, 122.12,

120.88, 108.94, 55.01, 47.49, 22.27, 21.52, 10.89, 6.94, 6.57 ppm; HRMS (TOF-ESI):

+ [M] calcd for C15H18N2O3: 258.1390; found: 258.1368.

N-isopropyl-N-(2-oxoindolin-3-yl)pentanamide (1u). The compound was obtained as a

1 yellow solid; m.p: 59-61 °C; yield: 82%; H NMR (600 MHz, DMSO-d6):  10.24 (s,

1H), 7.12 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.74 (d, J

= 7.6 Hz, 1H), 4.70 (s, 1H), 4.25-4.23 (m, 1H), 2.31-2.27 (m, 2H), 1.34 (d, J = 6.2 Hz,

5H), 1.25 (d, J = 6.4 Hz, 3H), 1.22-0.90 (m, 6H), 0.82 (t, J = 7.3 Hz, 3H) ppm; 13C NMR

(150 MHz, DMSO-d6):  175.65, 169.97, 142.41, 128.40, 127.34, 121.98, 120.74,

108.85, 54.61, 47.57, 32.10, 26.74, 22.02, 21.58, 21.23, 13.72 ppm; HRMS (TOF-ESI):

+ [M+H] calcd for C16H23N2O2: 275.1760; found: 275.1767.

3-(4-fluorophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl)propanamide (1v). The compound was obtained as a white solid; m.p: 166-168 °C; yield: 85%; 1H NMR (600

MHz, DMSO-d6):  10.28 (s, 1H), 7.22-7.20 (m, 2H), 7.14-7.12 (t, J = 7.6 Hz, 1H), 7.07-

7.04 (t, J = 8.9 Hz, 2H), 6.97-6.96 (d, J = 7.3 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.76 (d, J

= 7.7 Hz, 1H), 4.73 (s, 1H), 4.26-4.21 (m, 1H), 2.68-2.57 (m, 4H), 1.30 (d, J = 6.5 Hz,

13 3H), 1.23 (d, J = 6.5 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.69, 169.31,

161.47, 159.87, 142.54, 137.31, 137.29, 130.22, 130.16, 128.33, 127.51, 122.27, 120.84,

69

114.87, 114.74, 108.97, 54.77, 47.65, 34.20, 29.70, 22.00, 21.26 ppm; 19F NMR (188

+ MHz, CDCl3):  117.58 (s, 1F) ppm; HRMS (TOF-ESI): [M+Na] calcd for

C20H21FN2NaO2: 363.1485; found: 363.1498.

4-bromo-N-isopropyl-N-(2-oxoindolin-3-yl)benzamide (1w). The compound was obtained as a cream white solid; m.p: 218-220 °C; yield: 87%; 1H NMR (600 MHz,

DMSO-d6):  10.39 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.17 (q, J

= 7.0 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.97 (s, 1H), 3.93-3.89

(m, 1H), 1.36 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.5 Hz, 3H) ppm; 13C NMR (150 MHz,

DMSO-d6):  175.23, 167.77, 142.72, 135.26, 131.68, 128.23, 127.74, 122.81, 122.39,

121.14, 109.12, 54.70, 50.18, 21.52, 21.16 ppm; HRMS (TOF-ESI): [M+Na]+ calcd for

C18H17BrN2NaO2: 395.0371; found: 395.0353.

2-(3, 4-difluorophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl) acetamide (1x). The compound was obtained as a white solid; m.p: 178-180 °C; yield: 87%; 1H NMR (600

MHz, DMSO-d6):  10.27 (s, 1H), 7.36-7.31 (m, 1H), 7.18-7.11 (m, 2H), 6.99-6.95 (m,

2H), 6.88 (t, J = 7.2 Hz, 1H), 6.75-6.74 (d, J = 7.7 Hz, 1H), 4.77 (s, 1H), 4.28-4.23 (m,

1H), 3.76-3.70 (q, J = 15.8 Hz, 2H), 1.26 (d, J = 6.5 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H)

13 ppm; C NMR (150 MHz, DMSO-d6):  175.52, 167.89, 142.57, 128.08, 127.62, 125.79,

125.77, 125.73, 122.13, 120.92, 117.94, 117.82, 117.14, 117.03, 109.07, 54.86, 38.56,

19 21.91, 21.09 ppm; F NMR (188 MHz, CDCl3):  137.50 to -137.71 (m, 1F), -140.47 to

+ -140.64 (m, 1F) ppm; HRMS (TOF-ESI): [M+Na] calcd for C19H18F2N2NaO2: 367.1234 found 367.1245.

70

N-isopropyl-N-(2-oxoindolin-3-yl)acrylamide (1y). The compound was obtained as a

1 light-yellow solid; m.p: 144-146 °C; yield: 79%; H NMR (600 MHz, DMSO-d6): 

10.32 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H),

6.83-6.76 (m, 2H), 5.96-5.92 (dd, J1 = 14.5 Hz, J2 = 2.0 Hz, 1H), 5.65-5.63 (dd, J1 = 8.5

Hz, J2 = 2.0 Hz, 1H), 4.48 (s, 1H), 4.46-4.41 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 1.28 (d, J

13 = 6.5 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.44, 163.78, 142.61, 128.29,

127.65, 127.62, 122.27, 120.94, 109.02, 54.99, 47.92, 22.13, 21.49 ppm; HRMS (TOF-

+ ESI): [M] calcd for C14H17N2O2: 245.1290; found: 245.1301.

4-(1H-indol-3-yl)-N-isopropyl-N-(2-oxoindolin-3-yl)butanamide (1z). The compound was obtained as a light-yellow solid; m.p: 138-140 °C; yield: 86%; 1H NMR (600 MHz,

DMSO-d6):  10.74 (s, 1H), 10.26 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.0 Hz,

1H), 7.12 (t, J = 7.7 Hz, 1H), 7.05-6.99 (m, 3H), 6.93 (t, J = 7.1 Hz, 1H), 6.86 (t, J = 7.4

Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H), 4.18-4.14 (m, 1H), 2.62 (t, J = 7.4 Hz,

2H), 2.38-2.33 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H), 1.22 (t, J = 6.5 Hz, 3H) ppm; 13C NMR

(150 MHz, DMSO-d6):  175.79, 170.07, 142.53, 136.25, 128.57, 127.47, 122.29,

122.14, 120.85, 120.80, 118.06, 114.08, 111.30, 108.98, 54.74, 47.66, 32.09, 25.61,

+ 23.90, 22.08, 21.25 ppm; HRMS (TOF-ESI): [M] calcd for C23H25N3O2: 375.1947; found: 375.1951.

N-isopropyl-N-(2-oxoindolin-3-yl)-1-naphthamide (1aa). The compound was obtained

1 as an off-white solid; m.p: 284-286 °C; yield: 87%; H NMR (600 MHz, DMSO-d6): 

10.50 (s, 1H), 8.03-7.97 (m, 3H), 7.60-7.53 (m, 3H), 7.36-7.20 (m, 3H), 7.09-6.99 (m,

1H), 6.87 (t, J = 9.8 Hz, 1H), 5.11 (d, J = 9.6 Hz, 1H), 3.73-3.62 (m, 1H), 1.32-1.23 (dd,

71

13 J1 = 6.6 Hz, J2 = 6.5 Hz, 3H), 1.21-1.13 (dd, J1 = 6.6 Hz, J2 = 6.5 Hz, 3H) ppm; C NMR

(150 MHz, DMSO-d6):  175.73, 168.19, 142.71, 133.99, 133.05, 129.42, 128.68,

128.22, 127.98, 127.88, 126.80, 126.65, 125.35, 124.88, 122.44, 122.38, 121.28. 109.31,

54.83, 50.16, 21.64, 21.06 (rotomers) ppm; HRMS (TOF-ESI): [M+Na]+ calcd for

C22H20N2NaO2: 367.1422; found: 367.1440.

N-benzyl-N-(2-oxoindolin-3-yl) pivalamide (1bb). The compound was obtained as a

1 yellow solid; m.p: 106-108 °C; yield: 83%; H NMR (600 MHz, DMSO-d6):  10.08 (s,

1H), 6.59 (s, 1H), 6.41 (s, 1H), 5.90 (q, J = 0.8 Hz, 2H), 4.60 (s, 1H), 4.21-4.17 (m, 1H),

2.38-2.26 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.5 Hz, 3H), 0.87 (t, J = 7.4 Hz,

13 3H) ppm; C NMR (150 MHz, DMSO-d6):  175.08, 170.70, 146.23, 141.59, 136.68,

120.04, 104.20, 104.18, 100.46, 92.75, 92.73, 54.89, 47.50, 47.47, 25.80, 21.97, 21.32,

+ 9.16 ppm; HRMS (TOF-ESI): [M+Na] calcd for C15H18N2NaO4 : 3313.1159; found:

313.1170.

3-benzyl-N-cyclopentyl-2-ethyl-3, 4-dihydroquinazoline-4-carboxamide (8a). The compound was obtained as a white solid; m.p: 122-124 °C, yield: 61%; 1H NMR (600

MHz, CDCl3):  7.31-6.96 (m, 9H), 5.55 (d, J = 6.0 Hz, 1H), 4.96 (d, J = 16.2 Hz, 1H),

4.78 (s, 1H), 4.49 (d, J = 16.2 Hz, 1H), 4.08-4.06 (m, 1H), 2.63 (q, J = 7.2 1H), 2.53-2.49

(m, 1H), 1.89-1.83 (m, 2H) 1.52-1.50 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H), 1.25-1.15 (m,

13 2H) ppm; C NMR (150 MHz, CDCl3):  169.97, 160.23, 142.55, 135.96, 129.45,

128.98, 128.64, 128.20, 127.86, 126.80, 125.73, 124.91, 124.38, 120.19, 62.01, 60.02,

53.25, 51.35, 33.08, 32.82, 28.25, 23.57, 23.54, 23.47, 11.63 ppm; HRMS (TOF-ESI):

+ [M+H] calc for C23H28N3O: 362.2232; found: 362.2222.

72

3-benzyl-N-(2,6-dimethylphenyl)-2-ethyl-3,4-dihydroquinazoline-4-carboxamide

(8b). The compound was obtained as a pale yellow solid; m.p: 91-93 °C; yield: 79%; 1H

NMR (600 MHz, CDCl3):  7.37-7.01 (m, 12H), 6.91 (s, 1H), 5.09 (d, J = 16.2 Hz, 1H),

5.02 (s, 1H), 4.70 (d, J = 16.2 Hz, 1H), 2.70-2.64 (m, 1H), 2.60-2.54 (m, 1H), 2.01 (s,

13 6H), 1.34 (t, J = 7.5 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  169.10, 160.39,

141.92,135.94, 135.06, 132.91, 129.389, 129.07, 128.24, 127.96, 127.56, 126.93, 125.81,

125.05, 124.81, 120.24, 62.19, 53.29, 28.36, 18.08, 11.68 ppm; HRMS (TOF-ESI):

+ [M+H] calc for C26H28N3O:398.2232; found: 398.2243.

3-benzyl-N-cyclohexyl-2-ethyl-3,4-dihydroquinazoline-4-carboxamide (8c). The compound was obtained as an off-white solid; m.p: 159-161 °C; yield: 81%; 1H NMR

(600 MHz, CDCl3):  7.32 (s, 2H), 7.26 (s, 3H), 7.22-7.19 (m, 4H), 7.03-6.99 (m, 2H),

5.52 (s, 1H), 4.99 (d, J = 16.0 Hz, 1H), 4.80 (d, J = 4.4 Hz, 1H), 4.51 (d, J = 16.0 Hz,

1H), 3.68 (s, 1H), 2.64-2.52 (m, 2H), 1.80-1.72 (m, 2H), 1.62-1.55 (m, 6H), 1.33-1.32

13 (m, 6H), 1.12-0.98 (m, 3H) ppm; C NMR (150 MHz, CDCl3):  169.65, 160.20, 141.72,

136.11, 129.49, 129.05, 127.92, 126.89, 125,81, 124.92, 124.57, 120.38, 62.17, 53.24,

48.34, 32.88, 32.61, 28.43, 25.41, 24.59, 24.54, 11.74 ppm; HRMS (TOF-ESI):

+ [M+H] calc for C24H30N3O: 376.2389; found: 376.2401.

3-benzyl-2-ethyl-N-(4-methoxyphenyl)-3,4-dihydroquinazoline-4-carboxamide (8d).

The compound was obtained as a brown solid; m.p: 187-189 °C; yield: 78%; 1H NMR

(600 MHz, CDCl3):  7.35-7.23 (m, 9H), 7.09 (t, J = 5.94 Hz, 2H), 6.82-6.81 (dd, J1 =

4.7 Hz, J2 = 2.2 Hz, 2H), 5.03 (d, J = 16.2 Hz, 1H), 4.96 (s, 1H), 4.61 (d, J = 16.2 Hz,

1H), 3.77 (s, 3H), 2.72-2.66 (m, 1H), 2.61-2.55 (m, 1H), 1.37 (t, J =7.62 3H) ppm; 13C

73

NMR (150 MHz, CDCl3):  168.71, 160.46, 157.12, 136.23, 130.47, 129.99, 129.29,

128.20, 126.06, 125.38, 125.13, 121.93, 114.47, 63.10, 55.74, 53.73, 28.50, 11.84 ppm;

+ HRMS (TOF-ESI): [M+H] calc for C25H26N3O2: 400.2025; found: 400.2038.

3-benzyl-N-(tert-butyl)-2-ethyl-3,4-dihydroquinazoline-4-carboxamide (8e). The compound was obtained as a yellow solid; m.p: 150-152 °C; yield: 78%; 1H NMR (600

MHz, DMSO-d6):  7.70 (s, 1H), 7.36 (d, J = 6.9 Hz, 2H), 7.29 (d, J = 5.5 Hz, 1H), 7.25

(d, J = 6.9 Hz, 2H), 7.09 (t, J = 8.1 Hz, 2H), 4.91 (d, J = 16.5 Hz, 1H), 4.86 (s, 1H), 3.910

(d, J = 16.2 Hz, 1H), 2.36 (q, J = 5.9 Hz 1H), 1.18 (s, 9H), 1.11 (t, J = 7.1 Hz 3H) ppm;

13 C NMR (150 MHz, DMSO-d6):  169.26, 159.42, 137.24, 128.69, 128.10, 127.34,

126.70, 125.15, 123.51, 121.57, 61.44, 51.43, 50.27, 28.27, 26.75, 11.05 ppm; HRMS

+ (TOF-ESI): [M+H] calc for C22H28N3O2: 350.2232; found: 350.2254.

3-benzyl-2-ethyl-N-isopropyl-3,4-dihydroquinazoline-4-carboxamide (8f). The compound was obtained as an off-white solid; m.p: 120-122 °C; yield: 73%; 1H NMR

(600 MHz, CDCl3):  7.79 (d, J = 5.5 Hz, 1H), 7.38-7.11 (m, 6H), 6.91 (d, J = 5.4 Hz,

2H), 4.92 (d, J = 16.6 Hz, 1H), 4.85 (s, 1H), 3.99 (d, J = 16.3 Hz, 1H), 3.84-3.74 (m, 1H),

2.60-2.53 (m, 1H), 2.42-2.38 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H), 1.07 (d, J = 5.5 Hz, 3H),

13 0.96 (t, J = 5.5 Hz, 3H) ppm; C NMR (150 MHz, CDCl3):  169.66, 160.64, 136.04,

129.73, 129.24, 128.15, 127.06, 125.96, 125.25, 124.44, 120.25, 62.29, 53.46, 41.97,

+ 29.92, 22.78, 22.57, 11.86 ppm; HRMS (TOF-ESI): [M+H] calc for C21H26N3O:

336.2076; found: 336.2081.

3-benzyl-2-ethyl-N-pentyl-3,4-dihydroquinazoline-4-carboxamide (8g). The

1 compound was obtained as a colorless syrup; Yield: 83%; H NMR (600 MHz, CDCl3): 

74

7.38-7.22 (m, 8H), 7.07 (t, J = 7.5 Hz, 1H), 5.26 (s, 1H), 4.97 (d, J = 19.1 Hz, 1H), 4.53

(d, J = 16.1 Hz, 1H), 3.24-3.11 (m, 2H), 2.89 (q, J = 7.5 Hz, 2H), 1.44-1.39 (m, 2H), 1.37

(t, J = 7.5 Hz, 3H), 1.25-1.14 (m, 4H), 0.82 (t, J = 7.14 Hz, 3H) ppm; 13C NMR (150

MHz, CDCl3):  169.01, 162.61, 134.35, 129.90, 129.43, 128.69, 127.31, 126.42, 121.35,

119.23, 62.27, 53.95, 39.99, 29.91, 29.12, 29.09, 26.82, 22.41, 14.17, 11.74 ppm; HRMS

+ (TOF-ESI): [M+H] calc for C23H30N3O: 364.2495; found: 364.2495.

3-benzyl-2-(2-bromobenzyl)-N-methyl-3,4-dihydroquinazoline-4-carboxamide (8h).

The compound was obtained as a brown solid; m.p: 98-100 °C; 1H NMR (600 MHz,

CDCl3):  8.11 (d, J = 4.6 Hz, 8H), 7.81 (dd, J1 = 1.2 Hz, 1H), 7.60 (dd, J1 = 1.0 Hz, 1H),

7.38-7.10 (m, 11H), 4.90 (s, 1H), 4.64 (d, J = 16.6 Hz, 1H), 3.94-3.91 (d, J = 16.4 Hz,

2H), 3.83 (d, J = 16.6 Hz, 1H), 2.59 (d, J = 4.6 Hz, 3H) ppm; 13C NMR (150 MHz,

CDCl3):  170.80, 156.95, 135.91, 135.56, 133.51, 129.80, 129.57, 129.57, 129.51,

128.15, 128.04, 127.25, 126.46, 125.71, 124.92, 124.75, 120.32, 61.86, 53.85, 41.65,

+ 29.92, 26.49 ppm; HRMS (TOF-ESI): [M+H] calc for C24H23BrN3O: 448.1025; found:

448.1030.

N-(2-(1-(benzylamino)-2-(cyclopentylamino)-2-oxoethyl)phenyl)propionamide (9a).

The compound was obtained as a white solid; m.p: 116-118 °C; 1H NMR (600 MHz,

CDCl3):  10.27 (s, 1H), 8.07 (d, J = 8.4 Hz,1H), 7.36-7.09 (m, 9H), 5.32 (s, 1H), 4.27 (s,

1H), 4.07-4.05 (m, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 2.38-2.34

13 (m, 2H), 1.87-1.58 (m, 2H) ppm; C NMR (150 MHz, CDCl3):  172.45, 171.03, 170.95,

138.71, 137.55, 137.42, 129.23, 128.73, 128.65, 128.20, 127.45, 127.03, 124.25, 123.79,

123.73, 64.03, 60.04, 60.02, 51.62, 51.62, 51.30, 51.17, 32.99, 32.96, 32.52, 32.49, 30.90,

75

+ 30.86, 29.68, 23.47, 9.79 ppm; HRMS (TOF-ESI):[M+H] calc for C23H30N3O2:

380.2338; found: 380.2345.

2-(benzylamino)-2-(2-(2-(2-bromophenyl)acetamido)phenyl)-N-methylacetamide

(9h). The compound was obtained as a light brown solid; m.p: 99-101 °C; 1H NMR (600

MHz, CDCl3):  10.54 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.69 (d,

J = 7.8 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.34-7.19 (m, 10H), 7.10 (t, J = 7.4 Hz, 1H),

4.32 (s, 1H), 3.76 (d, J = 2.0 Hz, 2H), 3.53 (s, 2H), 3.05 (s, 1H), 2.60 (d, J = 4.6 Hz, 3H)

13 ppm; C NMR (150 MHz, CDCl3):  170.64, 156.80, 135.40, 133.35, 129.65, 129.41,

128.99, 127.99, 127.88, 127.09, 126.30, 125.55, 124.76, 124.59, 61.71, 53.70, 41.49,

+ 29.76, 26.33 ppm; HRMS (TOF-ESI): [M+H] calc for C24H25BrN3O2: 466.1130; found:

466.1154.

76

References

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Chapter 3

Methyl Isocyanide as a Convertible Functional Group for the Synthesis of Spirocyclic Oxindole γ–lactams via Post Ugi-4CR/Transamidation/Cyclization in a One-pot Three Step Sequence

3.1. Introduction

The Ugi multicomponent reaction,1 post-modification reactions involving tandem reaction sequences2 and the Ugi-deprotection-cyclization (UDC) strategies3 have been extensively studied as a powerful tool to access biological and pharmaceutical high-value heterocyclic scaffolds.4 These reactions are appealing in that they are atom economical, simple and diverse with the ease of using readily available starting materials. Developing new post-modified Ugi four component reaction transformations in domino cyclization5 sequences are very important to achieve new chemical bonds and functional groups in order to construct new synthetic scaffolds. Synthesis of spirocyclic oxindoles has always been of key interest to organic chemists because of significant biological activity6 and because they are present in naturally occurring substances.7 Significant efforts have been made to design new synthetic strategies for spirocyclic oxindole molecules, of which, isatin-based domino reactions8 were most versatile and have been successful.9 However 82

finding a simple and efficient synthetic method for molecules with structural diversity is important. Taking this into consideration, we were interested in synthesizing spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione and spiro[indoline-3,2'-pyrrolidine]-2,5'- dione scaffolds, which are a class of spirocyclic oxindole -lactams. There have been other research groups in the past, including our research group who reported post modified Ugi four component synthetic strategies (Scheme 3-1) for the synthesis of 2- oxindoles and spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione and spiro[indoline-3,2'- pyrrolidine]-2,5'-diones. Zhu et al10 reported 3-substituted-2-indolinones via microwave- assisted post Ugi-4CR/Buchwald-Hartwig reaction and another similar approach was showcased by Eycken et al11 for spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione. In our previous efforts to study the 3-substituted 2-indolinone synthesis through three step post

Ugi-4CR/Bechamp type-reduction followed by transamidation sequence strategy,12 we came across some interesting results, i.e., when only methyl isocyanide13 was used for

Ugi four-component reaction and subsequent post intramolecular transamidation under acidic conditions, particularly in the presence of TFA, which achieves the desired 3- subtituted 2-indolinone in three step process.12 It turns out that methyl isocyanide operates under the mechanism of convertible isocyanides, which is synthetically equivalent to ‘CO’ for the functional insertion in 2-indolinone backbone (shown in

Scheme 3-1). To further elaborate our research in understanding the role of methyl isocyanide as a convertible isocyanide, we designed an efficient synthetic strategy for a very important class of spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione and spiro[indoline-

3,2'-pyrrolidine]-2,5'-diones via a one pot three step reaction sequence. The advantages of this strategy includes a minimal number of synthetic steps and no tedious work-up 83

procedures, respectively, and the use of starting materials which were either readily available or were easy to synthesize.

Scheme 3-1. Previously reported post Ugi-CR methods for 2-oxindoles and spirocyclic

2-oxindoles synthesis.

Scheme 3-2. Post Ugi 4-CR/transamidation/cyclization sequence. 84

The reaction sequence follows a one pot, three step strategy involving the Ugi four component reaction and acid promoted intramolecular transamidation followed by base mediated cyclization to obtain spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione. The Boc deprotection in Ugi derivative 5, under acidic media, gives us the amine intermediate I which simultaneously undergoes the cyclization through intramolecular transamidation and produces the compound 6. Then compound 6 undergoes cyclization under basic conditions to form the final compound 7 (Scheme 3-2).

3.2. Results and Discussion

3.2.1. Feasibility studies for one pot, three step reaction

Our initial synthetic attempts began with the Ugi four component reaction involving stoichiometrically equal amounts of 2-(Boc-amino)benzaldehyde 1{a}, aniline

2{a}, tetrolic acid 3{a}, and methyl isocyanide 4 in methanol at room temperature to generate the adduct 5a which was confirmed by mass spectroscopic analysis.

Intermediate 5{a,a,a,4}, which was not purified, underwent an intramolecular transamidation reaction in 50% TFA in DCM at room temperature for 5 h to provide 6

{a,a,a,4}. Followed by complete removal of TFA, the crude compound was tested for reaction feasibility for cyclization. We began our studies for cyclization and the crude intermediate 6 {a,a,a,4} was dissolved in acetonitrile followed by the addition of 2 eq. of

K2CO3 and the reaction was refluxed for 1 h. The reaction was monitored by TLC which indicated the disappearance of starting material and formation of the new spot. Post 85

work-up and purification, spectroscopic analysis of the product matched with the most

׳likely 5-endo-dig cyclization product 7a not the 4-exo-dig-cyclization product 7a

(Scheme 3-3). This could be explained by the fact that the 5-endo-dig cyclization (1,4-

Michael addition) is more favorable than the 4-exo-dig-cyclization14 and the structure of compound 7a was also confirmed by X-ray crystallography analysis (Figure 3.1).

Scheme 3-3. Feasibility reaction for base-promoted cyclization.

Figure 3.1. ORTEP diagram for compound 7a.

86

3.2.2. Optimization studies for base catalyzed cyclization

We elected to carry out further optimization studies of the cyclization reactions using various combinations of solvents and reagents and reaction temperatures (Table

3.1) in order to observe the behavior and outcome of the reactions. All the reaction conditions, except for AgOTf/DCM (entry 6) led to the formation of the desired product

5-endo-dig-cyclized product 7a, and not the 4-exo-dig-cyclization product 7a’. Entries 2-

5 and 7 gave moderate yields whereas entries 1 and 8 gave better yields (more than 80%).

However, due to the fact that the reaction conditions for entry 1 used a milder base, we proceeded to further investigate the reaction scope using different starting materials under these conditions.

Table 3.1. Optimization conditions for intramolecular cyclization.

yield (7a) yield (7a’) entry reagent solvent temperature time (%) (%) 1 K2CO3 MeCN reflux 1 h 82 N.O.

2 K2CO3 methanol rt 2 h 72 N.O.

3 K2CO3 toluene reflux 2 h 70 N.O.

4 Cs2CO3 toluene reflux 2 h 72 N.O.

5 Et3N DCM rt 4 h 65 N.O

6 AgOTf DCM rt 24 h NR NR

7 KOtBu THF rt 30 min 75 N.O.

8 KOtBu MeCN rt 30 min 80 N.O

N.O.: not observed, NR: no reaction.

87

3.2.3. Investigation of substrate scope

With the optimized reaction conditions in hand (Scheme 3-3) the scope of the substrate was validated by one-pot Ugi-CR/transamidation/cyclization sequence with various combinations of readily available and synthetically accessible starting materials

(Figure 3.2). The intramolecular cyclization proceeded smoothly under K2CO3/MeCN, reflux conditions and the products 7b-k were obtained in good yields (Scheme 3-4).

Figure 3.2. Readily available and accessible starting materials.

88

Scheme 3-4. Scope of the reaction.

3.2.4. Scope of base-catalyzed cyclization

To further explore the scope of this methodology, we tested the reaction conditions for the synthesis of some spiro[indoline-3,2'-pyrrolidine]-2,5'-dione scaffolds

(Scheme 3-5). For this reaction we used 2-(Boc-amino)benzaldehyde 1{a}, aniline 2{a}, methyl isocyanide 4 and 3-chloropropanoic acid 3{e} in a one pot reaction to generate intermediate 6{c,a,e,4},derivatives from Ugi-4CR product 5{c,a,e,4}. In this case, the

Michael acceptor intermediate II was generated in situ from intermediate 6{c,a,e,4} under the same basic conditions (K2CO3/MeCN/reflux) and cyclization proceeded through a 1,4-Michael addition to form an exclusive 5-endo-trig-cyclization

89

spiro[indoline-3,2'-pyrrolidine]-2,5'-dione product 8a (Scheme 3-5). Compound 8a was confirmed by mass spectral analysis and NMR spectroscopic analysis.

Scheme 3-5. Reaction scope and synthesis of spiro[indoline-3,2'-pyrrolidine]-2,5'- diones.

Encouraged by the above results, we prepared a library of spiro[indoline-3,2'- pyrrolidine]-2,5'-diones 8b-i from readily available synthons. The yields were moderate to good (Figure 3.3). Furthermore, the application of this reaction was observed by the synthesis of the 5-HT6 receptors antagonist15 8j (Scheme 3-6).

90

Figure 3.3. Library of spiro[indoline-3,2'-pyrrolidine]-2,5'-dione analogs.

Scheme 3-6. Synthesis of 5-HT6 (h5-HT6) receptors antagonist 8j.

3.3. Conclusion

In conclusion, we successfully investigated and developed an efficient method for spirocyclic α,-unsaturated -lactam oxindole and spirocyclic -lactam synthesis using a one pot, three step post-Ugi-4CR intramolecular transamidation/cyclization approach.

We synthesized a small library of spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione and spiro[indoline-3,2'-pyrrolidine]-2,5'-dione analogs, showing the utility of the method for

91

biologically useful compounds. We are also successfully utilized methyl isocyanide as a convertible isocyanide for spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-diones and spiro[indoline-3,2'-pyrrolidine]-2,5'-diones.

92

Experimental Section

General Methods. All reagents and solvents purchased were used without further purification unless otherwise stated. Reaction progress was monitored by thin layer chromatography (TLC). TLC was visualized using UV. Column chromatography was performed using silica gel. Yields refer to chromatographically and spectroscopically pure compounds. 1H and 13C NMR were recorded using a 600 MHz. The residual

1 13 1 DMSO-d6 H quintet at δ 2.50 ppm and residual C septet at δ 39.51 ppm, CDCl3 H singlet at δ 7.27 ppm and 13C triplet at δ 77.23 ppm were used as the standards for 1H

NMR and 13C NMR spectra respectively. Signal patterns are indicated as s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; dd: doublet of doublets; br: broad and coupling constants are reported in hertz (Hz). High resolution mass spectra (HRMS) were obtained with a Bruker Maxis 4G mass spectrometer.

General Procedure for 7a-k. Into a clear solution of 2-(Boc-amino)benzaldehyde 1 (1 eq) in methanol (5 mL) was added amine 2 (1 eq) and stirred for 5 minutes at room temperature, then carboxylic acid 3 (1 eq) and methyl isocyanide 4 (1 eq) were added.

The reaction was continuously stirred until no noticeable starting reagents were visualized using TLC. Upon completion of the reaction, methanol was evaporated under reduced pressure. After obtaining the mass of unpurified product(s) dissolved in CH2Cl2

(1 mL), trifluoroacetitic acid (1 mL) was added the reaction mass was stirred at room temperature for 5 h, with the completion of the reaction monitored by TLC. The contents were concentrated completely under reduced pressure and the crude compound was then dissolved in acetonitrile (2 mL), K2CO3 (2 eq) was added and the reaction mass was 93

heated to reflux and maintain the reflux for 1 h and the completion of the reaction was monitored by TLC. Cool the reaction mass to room temperature and the solvent was evaporated completely and crude compound(s) was subjected for flash column chromatography (EtOAc/Hexanes) to yield pure compounds 7a-k.

3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7a). The compound

1 was obtained as an orange solid; yield: (107 mg, 82%); H NMR (600 MHz, DMSO-d6):

 11.10 (s, 1H), 7.31-7.28 (m, 1H), 7.24 (t, J = 8.1 Hz, 2H), 7.15 (d, J = 7.4 Hz, 1H),

7.12-7.08 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.31 (q, J = 1.4 Hz,

13 1H), 1.64 (d, J = 1.3 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  172.78, 170.91,

156.93, 142.19, 136.78, 130.60, 128.92, 125.96, 124.30, 124.19, 123.94, 123.33, 122.99,

+ 110.94, 77.06, 11.91 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C18H15N2O2:

291.1134; found: 291.1138.

3'-methyl-1'-(4-nitrophenyl)spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7b). The compound was obtained as a yellow solid; yield: (111 mg, 74%); 1H NMR (600 MHz,

DMSO-d6):  1.42 (s, 1H), 8.17 (t, J = 3.2 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.43 (t, J =

3.2 Hz, 1H), 7.42 (t, J = 2.2 Hz, 1H), 7.39-7.36 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.08 (d,

J = 7.8 Hz, 1H), 7.04-7.01 (m, 1H), 6.41 (q, J = 1.6 Hz, 1H), 1.66 (d, J = 1.5 Hz, 3H)

13 ppm; C NMR (150 MHz, DMSO-d6):  172.08, 171.09, 158.53, 143.17, 142.85, 141.87,

131.05, 124.89, 123.95, 123.67, 123.39, 122.93, 120.24, 111.51, 76.50, 11.71 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C18H14N3O4 : 336.0984; found: 336.0996.

1'-(4-methoxyphenyl)-3'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7c).

The compound was obtained as an off-white solid; yield: (130 mg, 75%); 1H NMR (600

94

MHz, DMSO-d6):  10.86 (s, 1H), 7.37-7.31 (m, 3H), 7.27-7.26 (m, 2H), 7.06 (s, 1H),

6.95 (d, J = 2.5 Hz, 1H), 6.91-6.89 (m, 2H), 6.84-6.82 (m, 3H), 6.78 (d, J = 8.5 Hz, 1H),

13 3.68 (s, 3H), 3.65 (s, 3H) ppm; C NMR (150 MHz, DMSO-d6):  173.02, 170.32,

158.62, 130.74, 130.27, 129.08, 129.02, 128.00, 126.51, 126.46, 123.98, 116.08, 114.17,

111.64, 111.23, 76.07, 55.61, 55.26 ppm; HRMS (ESI-Q-TOF): [M+H]+ calcd for

C25H21N2O4: 413.1501; found: 413.1518.

1'-(4-bromophenyl)-3'-ethylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7d). The compound was obtained as a light-yellow solid; yield: (133 mg, 78%); 1H NMR (600

MHz, DMSO-d6):  11.15 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.30 (m, 1H), 7.15 (d, J = 7.3

Hz, 1H), 7.04-7.00 (m, 3H), 6.96 (d, J = 7.8 Hz, 1H), 6.33 (t, J = 1.6 Hz, 1H), 1.93-1.87

(m, 1H), 1.74-1.68 (m, 1H), 1.46-1.37 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H) ppm; 13C NMR

(150 MHz, DMSO-d6):  172.70, 170.90, 161.30, 142.21, 136.00, 131.92, 130.79,

125.66, 124.34, 124.07, 123.05, 122.04, 118.39, 111.06, 76.69, 27.94, 19.54, 13.42 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C20H18BrN2O2:397.0552; found:397.0544.

5-chloro-1'-cyclopropyl-3'-methylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7e).

The compound was obtained as an off-white solid; yield: (86 mg, 76%); 1H NMR (600

MHz, DMSO-d6):  11.17 (s, 1H), 7.41 (dd, J1 = 6.2 Hz, J2 = 2.2 Hz, 1H), 7.17-7.16 (d, J

= 2.1 Hz, 1H), 7.01-7.00 (d, J = 8.3 Hz, 1H), 6.09 (d, J = 1.6 Hz, 1H), 2.42-2.20 (m, 1H),

1.56 (d, J = 1.5 Hz, 3H), 0.51-0.43 (m, 3H), 0.34-0.31 (m, 1H) ppm; 13C NMR (150

MHz, DMSO-d6):  173.19, 172.69, 155.62, 141.44, 130.38, 127.06, 126.87, 124.07,

123.90, 112.24, 76.44, 23.13, 11.91, 3.99 ppm; HRMS (ESI-Q-TOF): [M+H]+ calcd for

C15H14ClN2O2: 289.0744; found: 297.0753.

95

1'-isopropyl-5,6-dimethoxy-3'-methylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione

(7f). The compound was obtained as a pink solid; yield: (67 mg, 60%); 1H NMR (600

MHz, DMSO-d6):  10.77 (s, 1H), 6.66 (s, 1H), 6.61 (s, 1H), 6.00 (d, J = 1.6 Hz, 1H),

3.79 (s, 3H), 3.66 (s, 3H), 3.39-3.34 (m, 1H), 1.52 (d, J = 1.5 Hz, 3H), 1.10 (t, J = 6.9 Hz,

13 6H) ppm; C NMR (150 MHz, DMSO-d6):  173.98, 171.06, 155.49, 150.71, 144.91,

136.21, 123.95, 114.17, 108.81, 69.24, 76.33, 56.30, 55.67, 45.32, 20.41, 20.10, 11.78

+ ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C17H21N2O4 : 317.1501; found: 317.1499.

5-methoxy-1'-(3-methoxybenzyl)-3'-propylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)- dione (7g). The compound was obtained as a yellow solid; yield: (122 mg, 81%); 1H

NMR (600 MHz, DMSO-d6):  10.73 (s, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.79-6.78 (m, 2H),

6.97 (d, J = 7.2 Hz, 1H), 6.67 (dd, J1 = 5.9 Hz, J2 = 2.3 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H),

6.49 (s, 1H), 6.29 (d, J = 1.6 Hz, 1H), 6.20 (t, J = 1.6 Hz, 1H), 4.35 (d, J = 15.4 Hz, 1H),

3.95 (d, J = 15.4 Hz, 1H), 3.61 (s, 1H), 3.53 (s, 1H), 1.88-1.84 (m, 1H), 1.83-1.75 (m,

13 1H), 0.97-0.95 (t, J= 7.4 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6):  172.55,

171.65, 162.43, 158.80, 155.14, 138.50, 135.65, 128.91, 124.87, 121.28, 120.18, 115.97,

113.26, 112.70, 111.09, 110.32, 75.99, 55.28, 54.76, 43.85, 19.50, 11.01 ppm; HRMS

+ (ESI-Q-TOF): [M+H] calcd for C22H23N2O4 : 379.1658; found: 379.1651.

1'-benzyl-3'-phenyl-6-(trifluoromethyl)spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione

(7h). The compound was obtained as an off-white solid; yield: (114 mg, 76%); 1H NMR

(600 MHz, DMSO-d6):  11.44 (s, 1H), 7.34-7.29 (m, 3H), 7.14-7.05 (m, 6H), 6.97 (d, J

= 7.8 Hz, 1H), 6.94-6.93 (m, 2H), 4.41 (d, J = 15.6 Hz, 1H), 4.04 (d, J = 15.6 Hz, 1H)

13 ppm; C NMR (150 MHz, DMSO-d6):  172.43, 170.52, 154.75, 143.33, 136.61, 132.00,

96

130.29, 130.25, 129.13, 127.85, 127.79, 127.14, 126.13, 126.02, 124.51, 123.99, 119.60,

+ 107.09, 73.21, 43.50 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C25H18F3N2O2:

435.1242; found: 435.1313.

1'-(4-chlorobenzyl)-3'-ethylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7i). The compound was obtained as an off-white solid; yield: (124 mg, 78%); 1H NMR (600 MHz,

DMSO-d6):  10.91 (s, 1H), 7.28-7.25 (m, 1H), 7.18-7.16 (m, 2H), 6.97-6.95 (m, 1H),

6.89-6.86 (m, 2H), 6.77 (d, J = 7.3 Hz, 1H), 6.22 (t, J = 1.8 Hz, 1H), 4.16 (q, J = 15.6 Hz,

2H), 1.88-1.81 (m, 1H), 1.74-1.67 (m, 1H), 0.95 (t, J= 7.3 Hz, 3H) ppm; 13C NMR (150

MHz, DMSO-d6):  172.57, 171.69, 162.61, 142.64, 135.86, 131.58, 130.42, 129.76,

127.80, 124.54, 123.57, 122.41, 121.28, 110.60, 75.40, 43.08, 40.04, 19.52, 11.02 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C20H18ClN2O2:353.1057; found: 353.1049.

3-ethyl-1-isopropylspiro[pyrrole-2,7'-[1,3]dioxolo[4,5-f]indole]-5,6'(1H,5'H)-dione

(7j). The compound was obtained as a light-yellow solid; yield: (75 mg, 63%); 1H NMR

(600 MHz, DMSO-d6):  10.81 (s, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.02 (s, 1H), 6.00 (s,

1H), 5.99 (t, J = 2.3 Hz, 1H), 3.34-3.29 (m, 2H), 1.82-1.75 (m, 1H), 1.71-1.64 (m, 1H),

13 1.12-1.09 (m, 6H), 0.94 (t, J = 7.4 Hz, 3H) ppm; C NMR (150 MHz, DMSO-d6): 

173.95, 170.99, 161.21, 148.63, 143.05, 137.01, 122.26, 115.69, 105.37, 101.30, 94.05,

75.95, 45.27, 40.04, 20.32, 20.15, 19.11, 10.96 ppm; HRMS (ESI-Q-TOF): [M+H]+calcd for C17H19N2O4: 315.1345; found: 315.1348.

1'-(2-bromobenzyl)-3'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7k). The compound was obtained as a white solid; yield: (165 mg, 82%); 1H NMR (600 MHz,

DMSO-d6):  11.11 (s, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.33-7.27 (m, 3H), 7.25-7.19 (m,

97

5H), 7.09-7.06 (m, 2H), 6.92 (dd, J1 = 7.7 Hz, J2 = 7.4 Hz, 2H), 6.38 (t, J = 7.6 Hz, 1H),

4.36 (d, J = 16.2 Hz, 1H), 4.25 (d, J= 16.2 Hz, 1H) ppm; 13C NMR (150 MHz, DMSO- d6):  172.54, 170.84, 155.81, 142.70, 135.10, 132.02, 130.85, 130.58, 130.17, 129.83,

129.13, 127.42, 126.28, 124.86, 124.03, 123.35, 122.75, 122.21, 111.08, 73.85, 43.28

+ ppm; HRMS (ESI-Q-TOF): [M+Na] calcd for C24H17BrN2NaO2: 467.0371; found:

467.0363.

General Procedure for 8a-j. Into a clear solution of 2-(Boc-amino)benzaldehyde 1 (1 eq) in methanol (5 mL) was added amine 2 (1 eq) and stirred for 5 minutes at room temperature, then 3-chloropropanoic acid 3 (1 eq) and methyl isocyanide 4 (1 eq) were added. The reaction was continuously stirred until no noticeable starting reagents were visualized using TLC. Upon completion of the reaction, methanol was evaporated under reduced pressure. After obtaining the mass of unpurified product(s) dissolved in CH2Cl2

(1 mL), trifluoroacetitic acid (1 mL) was added the reaction mass was stirred at room temperature for 5 h, with the completion of the reaction monitored by TLC. The contents were concentrated completely under reduced pressure and the crude compound was then dissolved in acetonitrile (2 mL), K2CO3 (2 eq) was added and the reaction mass was heated to reflux and maintain the reflux for 1 h and the completion of the reaction was monitored by TLC. Cool the reaction mass to room temperature and the solvent was evaporated completely and crude compound(s) was subjected for flash column chromatography (EtOAc/Hexanes) to yield pure compounds 8a-j.

7-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8a). The compound

1 was obtained as an off-white solid; yield: (98 mg, 80%); H NMR (600 MHz, DMSO-d6):

 10.77 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.28-7.23 (m, 3H), 7.18-7.15 (m, 1H), 6.97-6.95 98

(m, 2H), 6.79 (d, J = 8.3 Hz, 1H), 2.79-2.69 (m, 2H), 2.46-2.42 (m, 1H), 2.37-2.32 (m,

13 1H) ppm; C NMR (150 MHz, DMSO-d6):  177.52, 174.84, 140.32, 136.62, 130.81,

129.69, 128.93, 127.06, 126.48, 126.17, 124.85, 111.68, 69.91, 30.65, 29.29 ppm; HRMS

+ (ESI-Q-TOF): [M+H] calcd for C17H14ClN2O2: 313.0744; found: 313.0747.

1'-cyclopentylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8b). The compound was

1 obtained as a white solid; yield: (99 mg, 81%); H NMR (600 MHz, DMSO-d6):  10.62

(s, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.88 (t, J =

7.4 Hz, 1H), 3.14-3.11 (m, 1H), 2.47-2.20 (m, 4H), 1.75-174 (m, 2H), 1.51-1.25 (m, 6H)

13 ppm; C NMR (150 MHz, DMSO-d6):  178.47, 174.89, 141.54, 129.77, 129.74, 124.16,

122.43, 110.29, 69.15, 54.92, 30.58, 29.64, 28.44, 23.70, 23.59 ppm; HRMS (ESI-Q-

+ TOF): [M+H] calcd for C16H19N2O2: 271.1447; found: 271.1437.

1'-(cyclohexylmethyl)spiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8c). The compound

1 was obtained as a white solid; yield: (106 mg, 79%); H NMR (600 MHz, DMSO-d6): 

10.65 (s, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H),

6.89 (d, J = 7.7 Hz, 1H), 2.71 (d, J = 7.6 Hz, 2H), 2.60-2.51 (m, 2H), 2.28-2.27 (m, 1H),

2.13-2.09 (m, 1H), 1.55-1.39 (m, 5H), 1.02-0.89 (m, 2H), 0.88-0.85 (m, 1H), 0.71-0.61

13 (m, 2H) ppm; C NMR (150 MHz, DMSO-d6):  178.00, 175.59, 141.70, 129.90,

128.59, 124.49, 122.28, 110.23, 68.24, 46.80, 40.04, 35.79, 30.29, 30.26, 30.15, 28.98,

+ 25.82, 25.24 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C18H23N2O2: 299.1760; found:

299.1767.

1'-benzylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8d). The compound was obtained

1 as an off-white solid; yield: (101 mg, 79%); H NMR (600 MHz, CDCl3):  7.55 (s, 1H),

99

7.14-7.09 (m, 3H), 6.93 (d, J = 6.7 Hz, 2H), 6.79 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz,

1H), 6.50 (s, 1H), 4.36 (d, J = 14.8 Hz, 1H), 4.20 (d, J = 14.7 Hz, 1H), 3.66 (s, 3H), 2.99-

2.93 (m, 1H), 2.67-2.62 (m, 1H), 2.42-2.38 (m, 1H), 2.18-2.13 (m, 1H) ppm; 13C NMR

(150 MHz, DMSO-d6):  178.17, 176.16, 156.41, 136.22, 133.82, 129.36, 129.06,

128.15, 127.75, 115.60, 111.11, 110.98, 68.96, 55.90, 45.22, 31.37, 29.64 ppm; HRMS

+ (ESI-Q-TOF): [M+H] calcd for C19H19N2O3 : 323.1396; found: 323.1398.

7-chloro-1'-(3,4-dimethoxybenzyl)spiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8e).

The compound was obtained as a white solid; yield: (121 mg, 80%); 1H NMR (600 MHz,

DMSO-d6):  10.58 (s, 1H), 7.23-7.21 (dd, J1 = 6.2 Hz, J2 = 2.1 Hz, 1H), 7.13 (d, J = 2.0

Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.40-6.37 (m, 2H), 4.10 (d, J

= 14.6 Hz, 1H), 3.97 (d, J= 14.8 Hz, 1H), 3.67 (s, 3H), 3.59 (s, 3H), 2.64-2.53 (m, 2H),

13 2.25-2.20 (m, 2H) ppm; C NMR (150 MHz, DMSO-d6):  177.30, 175.08, 147.99,

140.59, 130.01, 129.39, 128.43, 126.11, 125.12, 120.79, 112.12, 111.24, 111.23, 67.92,

55.41, 55.07, 43.96, 40.04, 30.05, 28.84 ppm; HRMS (ESI-Q-TOF): [M+H]+calcd for

C20H20ClN2O4 : 387.1112; found: 387.1103.

1'-(benzo[d][1,3]dioxol-5-ylmethyl)spiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8f).

The compound was obtained as an off-white solid; yield: (127 mg, 77%); 1H NMR (600

MHz, DMSO-d6):  10.45 (s, 1H), 7.24-7.21 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.93-6.90

(m, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 6.26-

6.24 (m, 1H), 5.92-5.91 (m, 2H), 4.05 (d, J= 14.9 Hz, 1H), 3.88 (d, J = 14.9 Hz, 1H),

2.67-2.58 (m, 1H), 2.56-2.52 (m, 1H), 2.26-2.22 (m, 1H), 2.17-2.12 (m, 1H) ppm; 13C

NMR (150 MHz, DMSO-d6):  177.55, 175.27, 146.74, 146.22, 141.91, 130.12, 129.76,

100

127.70, 124.72, 121.99, 121.48, 109.99, 108.63, 107.52, 100.75, 67.81, 43.83, 30.28,

+ 28.96 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C19H17N2O4 : 337.1188; found:

337.1183.

7-methoxy-1'-phenethylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8g). The compound was obtained as an off-white solid; yield: (111 mg, 80%); 1H NMR (600 MHz,

DMSO-d6):  10.71 (s, 1H), 7.33-7.28 (m, 2H), 7.20 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.3

Hz, 1H), 7.05-7.03 (m, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 7.1 Hz, 2H), 2.99-2.96

(m, 2H), 2.63-2.57 (m, 1H), 2.55-2.48 (m, 2H), 2.32-2.27 (m, 1H), 2.18-2.12 (m, 1H)

13 ppm; C NMR (150 MHz, DMSO-d6):  178.22, 175.15, 141.94, 138.48, 130.07, 128.47,

128.24, 128.18, 126.28, 124.63, 122.48, 110.31, 68.19, 42.43, 33.76, 29.94, 29.02 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C19H19N2O2: 307.1447; found: 307.1439.

1'-(2-bromobenzyl)spiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8h). The compound

1 was obtained as a white solid; yield: (137 mg, 82%); H NMR (600 MHz, DMSO-d6): 

10.55 (s, 1H),7.37 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.12-

7.02 (m, 2H), 6.82 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 4.26 (d, J = 16.0 Hz, 1H),

3.96 (d, J = 16.0 Hz, 1H), 2.72-2.59 (m, 2H), 2.34-2.30 (m, 1H), 2.25-2.20 (m, 1H) ppm;

13 C NMR (150 MHz, DMSO-d6):  177.42, 175.75, 141.96, 135.16, 131.92, 129.82,

129.77, 129.05, 127.53, 127.36, 124.55, 122.26, 122.06, 110.18, 68.26, 44.10, 30.14,

+ 28.89 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C18H16BrN2O2 : 370.0317; found:

370.0315.

1'-isopropyl-5,6-dimethoxyspiro[indoline-3,2'-pyrrolidin]-2-one (8i). The compound

1 was obtained as a white solid; yield: (67 mg, 62%); H NMR (600 MHz, DMSO-d6): 

101

10.39 (s, 1H), 7.09 (s, 1H), 6.51 (s, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.13-3.06 (m, 1H),

2.48-2.38 (m, 2H), 2.17-2.07 (m, 2H), 1.10 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H)

13 ppm; C NMR (150 MHz, DMSO-d6):  179.14, 174.78, 150.33, 144.72, 135.30, 119.33,

109.67, 95.89, 69.10, 56.43, 55.70, 45.56, 30.40, 29.73, 19.80, 19.68 ppm; HRMS (ESI-

+ Q-TOF): [M+Na] calcd for C16H20N2NaO4: 327.1321; found: 327.1323.

1'-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)spiro[indoline-3,2'-pyrrolidine]-2,5'- dione (8j). The compound was obtained as a brown solid; yield: (102 mg, 65%); 1H

NMR (600 MHz, DMSO-d6):  10.61 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.19 (t, J = 7.6

Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.78-6.76 (d, J = 7.7 Hz, 1H),

6.73 (s, 1H), 6.59 (d, J = 7.9 Hz, 1H), 2.78-2.72 (m, 2H), 2.69-2.64 (m, 9H), 2.43-2.39

13 (m, 1H), 2.31-2.24 (m, 1H) ppm; C NMR (150 MHz, DMSO-d6):  177.77, 174.97,

142.98, 141.40, 141.38, 134.39, 129.70, 129.38, 128.92, 127.10, 124.55, 123.36, 122.41,

110.16, 69.93, 48.19, 48.05, 40.04, 30.86, 29.37 ppm; HRMS (ESI-Q-TOF):

+ [M+H] calcd for C21H22N3O2 : 347.1634; found:347.1636.

102

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6527-6530. (c) Bacher, N.; Tiefenthaler, M.; Sturm, S.; Stuppner, H.; Ausserlechner, M.

J.; Kofler, R.; Konwalinka, G. Br. J. Haematol. 2006, 132, 615-622.

8. (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104-6155. (b) Zhou, B.;

Yang, Y.; Shi, J.; Luo, Z.; Li, Y. J. Org. Chem. 2013, 78, 2897-2907. (c) Lv, H.; Tiwari,

B.; Mo, J.; Xing, C.; Chi, Y. R. Org. Lett. 2012, 14, 5412-5415. (d) Zhang, B.; Feng, P.;

Sun, L.-H.; Cui, Y.; Ye, S.; Jiao, N. Chem. Eur. J. 2012, 18, 9198-9203. (e) Dalpozzo,

R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247-7290.

9. (a) Liu, Y.; Wang, H.; Wan, J. Asian J. Chem. Org. 2013, 2, 374-386. (b) Sun, Y.;

Sun, J.; Yan, C.-G. Beilstein J. Org. Chem. 2013, 9, 8-14. (c) Miyamoto, H.; Hirano, T.;

Okawa, Y.; Nakazaki, A.; Kobayashi, S. Tetrahedron 2013, 69, 9481-9493.

10. Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351-4354.

11. Sharma, N.; Li, Z.; Sharma, U. K.; Van der Eycken, E. V. Org. Lett. 2014, 16,

3884-3887.

12. Maddirala, A. R.; Andreana, P. R. Eur. J. Org. Chem. 2016, 2016, 196-209.

13. (a) Gautier, A. Justus Liebigs Ann. Chem. 1868, 146, 119-124. (b) Eckert, H.;

Nestl, A.; Ugi, I. Methyl Isocyanide. In Encyclopedia of Reagents for Organic Synthesis,

John Wiley & Sons, Ltd: 2001.

14. (a) Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011, 133,

12608-12623. (b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513-6556. 104

15. Hostetler, G.; Dunn, D.; McKenna, B. A.; Kopec, K.; Chatterjee, S. Chem. Biol.

Drug. Des. 2014, 83, 149-153.

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Chapter 4

A One-Pot, Two-Step Total Synthesis of Natural Products Xenortide A-D and the Complete Set of Stereoisomers Utilizing the Ugi MCR Process

4.1. Introduction

Malaria is one of the major detrimental diseases of the world, particularly in tropical regions, and is responsible for more than 600,000 deaths every year.1 Natural products such as chloroquine and artemisinin have played a fundamental role in the treatment of malaria.2 Unfortunately, increasing resistance to effective antimalarial drugs has become a serious concern in the world, and to rectify this issue novel drugs with great activity are indeed required. Natural products prove to be a great choice of drug molecules effective against such diseases. Recently, new classes of natural products, xenortides A-D were isolated from the bacterium Xenorhabdus nematophilus.3 These compounds have shown very potent biological activity against leishmaniasis, malaria, sleeping sickness and

Chagas disease. On one hand, widespread resistance in Plasmodium falciparum and on the other, the efficiency of natural products as a source of anti-malarial drugs4 have encouraged our research group to develop a very effective, highly efficient and straightforward approach for synthesizing the entire class of xenortides A-D (Scheme 4-

106

1) as potential anti-malarial natural products. Of all of the forms of xenortides, xenortide

B is a novel candidate which has shown exceptional activities against P falciparum NF54 and T.brucei rhodiense STIB900 with an IC50 value of 0.76 µM and 1.57 µM, respectively.

On the grounds of the biological significance of xenortide A-D family, the development of simple, efficient and economical synthetic route is essential. Having a simple synthetic route can assist in providing a large scale-up of materials for further biological investigations. Despite the presence of classical peptides synthetic approaches5 applied for the total synthesis of linear dipeptide similar to xenortides, there are some disadvantages, which include multi-step synthesis, product racemization, poor yields, expensive coupling reagents, and considerable amount of time and effort. These drawbacks have undeniably limited the use of traditional coupling approaches toward the synthesis of xenortides. Along those lines, one-pot or short-step natural products synthesis-based Ugi four component reaction processes have been studied,6 which are of great importance in making key synthetic building blocks for the synthesis of complex natural products7 and additional small libraries of analogues can readily be accessed. In context of developing new synthetic routes, we designed an efficient and short synthetic strategy using post-modified Ugi four component reaction processes.8 This novel synthetic strategy, involving only two steps, allows us to obtain four natural products, xenortides A, B, C, and D by using commercially available starting materials. The retro- synthetic analysis for those compounds is shown in Scheme 4-1.

107

Scheme 4-1. Structures of natural product xenortides A-D and a retrosynthetic analysis.

4.2. Results and Discussion

To begin with, we synthesized phenylethyl isocyanide 3a9 and indoleethyl isocyanide

3b10 following the well-known formylation11 and dehydration12 procedures using phenyl ethylamine (3aʺ) and indole ethylamine (3bʺ) as the starting materials respectively

(Scheme 4-2).

Scheme 4-2. Synthesis of 3a and 3b.

Having precursors 3a and 3b in hand we began our initial two step strategy

(Scheme 4-3) for the synthesis of xenortide A (1a) and epi-xenortide A (1a’) using Ugi four component reactions. For the noted reaction we used stoichiometrically equal amounts of phenylethyl isocyanide 3a, phenyl acetaldehyde 4, methylamine 5 (33 wt. % in ethanol), and Boc-N-methyl-L-leucine 6a dissolved in methanol and stirred at room

108

temperature for 24 h. The reaction was monitored by TLC. Two new spots with very close Rf values were formed which were characterized as two diastereomers arising from our reaction conditions. From the 1H-NMR analysis of crude diastereomeric mixture (2a and 2a’) we were unable to identify the diastereomeric ratio. This was due to the formation of the rotamers during 1H NMR analysis. After separation of diastereomers

(2a and 2a’), 1H NMR analysis was conducted for each diastereomer. Unfortunately, we were unable to determine the diastereomeric ratio even with variable 1H-NMR spectral analysis.

Scheme 4-3. Two step synthesis of xenortide A (1a) and epi-xenortide A (1a’).

In order to determine the diastereoselectivity, we carried out a Boc deprotection reaction on intermediates 2a and 2a’ using 50% TFA in DCM at 0 °C for 2 h. Complete deprotection of the Boc group was observed. Post isolation and purification of the individual xenortide A (1a) and epi-xenortide A (1a’), characterization by NMR spectral analysis was conducted. We did not encounter any rotameric mixtures during NMR analysis as was seen in the previous described case when the molecules were Boc protected. All of the spectral analysis and the optical rotation values that were recorded

109

for compounds 1a and 1a’ matched literature values of the reported naturally occurring xenortide A and epi-xenortide A. Based on all the challenges encountered with the initial two step approach (Scheme 4-3) such as the rotameric mixtures in NMR analysis and tedious work-up and purifications of Boc-protected Ugi derivatives 2a and 2a’, we elected to change our synthetic strategy and re-design a process that captured a one-pot, two-step synthetic route (Scheme 4-4).

Scheme 4-4. One pot two step synthesis for 1a and 1a’.

When the one-pot synthesis of xenortide A (1a) and epi-xenortide A (1a’) (Scheme 4-4) was attempted, similar conditions were followed as was used for the initial two-step synthetic attempt and stirred for 24 h at room temperature. Upon completion of the reaction, methanol was evaporated under reduced pressure and without any further purification, the crude mixture (2a and 2a’) was used in the Boc deprotection reaction employing 50% TFA in DCM at 0 °C and stirred for 2 h. The reaction was monitored by mass spectroscopic analysis and upon noted completion, the solvent was removed under reduced pressure. The unpurified mixture was analyzed to determine the diastereomeric ratio using 1H-NMR and then purified using silica-gel column chromatography. After

110

purification, further spectral analysis was conducted and the NMR peak shift values matched perfectly with literature reports for both compounds 1a and 1a’.

Furthermore, we explored the effect of temperature on the diastereoselectivity employing the Ugi four component reaction. We conducted reactions at 0 °C, rt, and at

40 °C. The results are summarized in Table 4.1 and reveal that the best conditions to conduct this reaction would be at room temperature for 24 h; the diastereoselectivity of

2.2:1 was clearly the best achieved and the yields are superb over other reaction conditions.

Table 4.1. Effect of temperature on the one-pot synthesis.

diastereoselectivity yield (%) yield (%) entry conditions [1a (S,S):1a’ (S,R)]a 1a (S, S) 1a (S, R)

1 MeOH, 0 °C, 24 h 2.1:1 15 <5

2 MeOH, rt, 24 h 2.2:1 38 17

3 MeOH, 40 °C, 24 h 1.6:1 33 12

aUnpurified mixtures. bDiastereomeric ratios determined using 1H NMR analysis.

Based on optimized reaction conditions, we decided to conduct more reactions to obtain xenortide derivatives using the conditions noted in entry 2 (Table 4.1). There were very few changes that were made in order to access the derivatives or other forms of 111

xenortides, such as using two different isocyanides (3a and 3b) and using L-leucine and

L-valine derivatives. The diastereoselectivities and yields for these reactions can be seen in Table 4.2 and Figure 4.1, respectively.

Table 4.2. Scope of the one-pot reaction.

Diastereoselectivity entry R’ R product [(S,S):(S, R)]a Xen-A (1a)\epi- 1 Ph i-Bu, (L-leu) 2.2:1 Xen-A (1a’) Xen-B (1b)\epi- 2 Indole i-Bu, (L-leu) 1.3:1 Xen-B (1b’) Xen-C (1c)\epi- 3 Ph i-Pr, (L-val) 1.7:1 Xen-C (1c’) Xen-D (1d)\epi- 4 Indole i-Pr, (L-val) 1.5:1 Xen-D (1d’) aunpurified mixtures. bdiastereomeric ratios determined using 1H NMR analysis.

Figure 4.1. Library of natural products xenortides A-D and their epimers.

112

4.3. Conclusion

We have developed a one-pot, two-step synthetic strategy for preparing natural product xenortides A-D and subsequent stereoisomers in moderate to good yields. We firmly believe that this synthetic route will help in synthesizing these molecules on a large-scale so that further evaluation of their biological activity can be made clear.

113

Experimental Section

General Methods. All reagents and solvents purchased were used without further purification unless otherwise stated. Reaction progress was monitored using thin layer chromatography (TLC). TLC was visualized using UV. Column chromatography was performed using silica gel. Yields refer to chromatographically and spectroscopically pure compounds. 1H and 13C NMR were recorded using a 600 MHz spectrometer at 22

1 °C (default) unless otherwise noted. The residual CD3OD H singlet at δ 4.87 ppm and

13C triplet at δ 49.15 ppm were used as the standards for 1H NMR and 13C NMR spectra respectively. Signal patterns are indicated as s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; dd: doublet of doublets; br: broad and coupling constants are reported in hertz (Hz). Low resolution mass spectra (LRMS) were acquired on an Esquire-LC electrospray ionization (ESI) mass spectrometer. High resolution mass spectra (HRMS) were obtained with a Bruker Maxis 4G mass spectrometer.

General Procedure. Into a solution of phenyl acetaldehyde (3) (1 eq) in methanol (5 mL), methylamine (33 wt. % in ethanol) (4) (1 eq) was added and stirred for 5 minutes at room temperature, Then, carboxylic acid 5 (1 eq), and isocyanide 6 (1 eq) were added.

The reaction was continually stirred until no noticeable starting reagents were visualized using TLC. Upon completion of the reaction, methanol was evaporated under reduced pressure. After obtaining the mass of unpurified product type 2 was dissolved in CH2Cl2

(1mL) and trifluoroacetitic acid (1 mL) was added under ice bath cooling and the reaction mass was stirred at ice bath cooling for 2 h. The completion of the reaction was monitored by TLC and the contents were concentrated completely under reduced 114

pressure and the crude compound subjected to flash column chromatography

(EtOAc/Hexanes) to yield pure compounds of type 1.

(S)-N,4-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3- phenylpropan-2-yl)pentanamide (1a). The compound was obtained as a white solid;

20 3a 1 yield: (258 mg, 38%); [α]D = -55.2 (c 0.2, MeOH); lit -54 (c 0.2, MeOH); H NMR

(600 MHz, CD3OD) showed the presence of two rotamers in a ratio of 3.6/1, major rotamer shown:  7.29-7.24 (m, 6H), 7.21-7.17 (m, 4H), 5.41 (dd, J1 = 12.0 Hz, J2 = 6.0

Hz,1H), 3.42 (t, J = 7.2 Hz, 2H), 3.36-3.38 (m, 1H), 3.19 (dd, J1 = 5.4 Hz, J2 = 14.4 Hz,

1H), 3.00-3.11 (m, 1H), 2.97 (s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 1.74 (s, 3H), 1.25-1.30 (m,

13 2H), 1.14-1.15 (m, 1H), 0.89-0.92 (m, 6H); C NMR (150 MHz, CD3OD) major rotamer shown:  175.84, 170.75, 138.97, 137.13, 128.87, 128.74, 128.51, 128.14, 126.34,

126.01, 58.01, 57.57, 42.04, 40.46, 35.04, 34.22, 32.72, 30.70, 24.24, 22.49, 20.97 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C25H36N3O2: 410.2808; found: 410.2807.

(S)-N,4-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3- phenylpropan-2-yl)pentanamide (1a’). The compound was obtained as a white solid;

20 1 yield: (88 mg, 1γ%); [α]D = +54.0 (c 0.2, MeOH); H NMR (600 MHz, CD3OD); 

7.28-7.20 (m, 10H), 5.54-5.51 (dd, J1 = 6.0 Hz, J2 = 12.0 Hz, 1H), 3.77-3.75 (m, 1H),

3.48-3.44 (m, 2H), 3.28 (dd, J1 = 12.0 Hz, J2 = 6.0 Hz, 1H), 3.00-2.92 (m, 4H), 2.81 (t, J

= 6.0 Hz, 2H), 2.37 (s, 3H), 1.10-1.07 (m, 2H), 0.89- 0.85 (m, 1H), 0.74 (d, J = 6.0 Hz,

13 3H), 0.69-0.68 (d, J = 6.0 Hz, 3H) ppm; C NMR (150 MHz, CD3OD): 174.85, 170.78,

138.98, 136.87, 128.49, 128.45, 128.20, 128.13, 126.55, 126.02, 57.45, 57.21, 41.03,

115

40.56, 35.01, 34.35, 32.61, 30.46, 23.83, 21.92, 21.33 ppm; HRMS (TOF-ESI):

+ [M+H] calcd for C25H36N3O2: 410.2808; found: 410.2820.

(S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4- dimethyl-2-(methylamino)pentanamide (1b). The compound was obtained as a

20 3a yellowish solid; yield: (βγ7 mg, β6%); [α]D = -56.8 (c 0.3, MeOH); lit -58 (c 0.3,

1 MeOH); H NMR (600 MHz, CD3OD) showed the presence of two rotamers in a ratio of

2.6/1, major rotamer shown:  7.56 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.23-

7.26 (m, 4H), 7.16-7.19 (m, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.99-7.04 (m, 2H), 5.40 (dd, J1

= 12.0, J2 = 6.0 Hz, 1H), 3.50-3.57 (m, 2H), 3.35-3.36 (m, 1H), 3.16 (dd, J1 = 14.4 Hz, J2

= 5.4 Hz, 1H), 2.95-3.01 (m, 6H), 1.73 (s, 3H), 1.21-1.37 (m, 2H), 1.06-1.07 (m, 1H),

13 0.84-0.98 (m, 6H) ppm; C NMR (150 MHz, CD3OD) major rotamer shown:  175.72,

170.68, 136.78, 128.74, 128.43, 128.13, 127.39, 126.32, 121.05, 120.96, 118.23, 117.88,

111.61, 110.89, 58.17, 57.56, 39.84, 39.77, 32.67, 30.77, 30.64, 24.77, 24.26, 22.41,

+ 20.98 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C27H37N4O2: 449.2917 found;

449.2933.

(S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4- dimethyl-2-(methylamino)pentanamide (1b’). The compound was obtained as a

20 1 yellowish solid; yield: (173 mg, 19%); [α]D = +55.8 (c 0.3, MeOH); H NMR (600

MHz, CD3OD) showed the presence of two rotamers in a ratio of 6.3/1, major rotamer shown:  7.57 (d, J = 7.8Hz, 1H), 7.32 (d, J = 7.8Hz, 1H), 7.25-7.20 (m, 4H), 7.18 (t, J =

7.2Hz, 1H), 7.09-7.06 (m, 2H), 7.02 (t, J = 7.8 Hz, 1H), 5.53 (dd, J1 = 11.4 Hz, J2 = 5.4

Hz, 1H), 3.52-3.55 (m, 2H), 3.37-3.40 (m, 1H), 3.16 (1H, dd, J1 = 15.0, J2 = 5.4 Hz),

2.94-2.99 (m, 3H), 2.88 (s, 3H), 2.21 (s, 3H), 0.95-0.96 (m, 2H), 0.79-0.84 (m, 1H), 0.69 116

13 (d, J = 6.0 Hz, 3H), 0.65 (d, J = 6.0 Hz, 3H) ppm; C NMR (150 MHz, CD3OD) major rotamer shown:  176.17, 170.78, 136.95, 136.77, 128.65, 128.16, 127.42, 126.46,

122.17, 120.96, 118.23, 117.91, 111.58, 110.86, 57.45, 57.19, 41.58, 39.87, 34.13, 30.34,

30.25, 24.63, 24.34, 22.47, 21.42 ppm; HRMS (ESI-QTOF): [M+H]+calcd for

C27H37N4O2: 449.2917 found 449.2931.

(S)-N,3-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3- phenylpropan-2-yl)butanamide (1c). The compound was obtained as a white solid;

20 yield: (267 mg, β7%); [α]D = – 54.0 (c 0.2, CD3OD);  7.29-7.27 (m, 6H), 7.22-7.7.19

(m, 4H), 5.50 (dd, J1 = 11.4Hz, J2 = 5.4 Hz, 1H), 4.02 (d, J = 5.2 Hz, 1H), 3.50-3.44 (t, J

=7.2 Hz, 2H), 3.26 (dd, J1 = 14.4 Hz, J2 = 5.4 Hz, 1H), 3.06-3.00 (m, 4H), 2.80 (t, J = 7.2

Hz, 2H), 2.07-2.04 (m, 1H), 1.97 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz,

13 3H) ppm; C NMR (150 MHz, CD3OD) major rotamer shown:  170.13, 167.65, 138.92,

136.91, 128.46, 128.23, 128.18, 128.13, 126.54, 126.03, 63.45, 58.06, 40.44, 34.98,

34.97, 34.05, 31.17, 29.81, 17.67, 16.10 ppm; HRMS (ESI-Q-TOF): [M+H]+calcd for

C24H34N3O2: 396.2651; found: 396.2645.

(S)-N,3-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3- phenylpropan-2-yl)butanamide (1c’). The compound was obtained as a white solid;

20 1 yield: (βγ7 mg, β4%); [α]D = +29.0 (c 0.2, MeOH); H NMR (600 MHz, CD3OD) showed the presence of two rotamers in a ratio of 2.4/1, major rotamer shown:  7.29-

7.26 (m, 6H), 7.22-7.20 (m, 4H), 5.55-5.49 (dd, J1 = 12.0 Hz, J2 = 5.4 Hz, 1H), 3.43 (s,

1H), 3.50-3.46 (m, 2H), 3.27-3.23 (m, 1H), 3.02-2.98 (m, 4H), 2.82 (t, J = 7.2 Hz, 2H),

2.48 (s, 3H), 1.66-1.59 (m, 1H), 0.75 (d, J = 6.6 Hz, 3H), 0.53 (d, J = 6.6 Hz, 3H) ppm;

117

13 C NMR (150 MHz, CD3OD) major rotamer shown:  170.53, 170.19, 138.98, 136.79,

128.52, 128.50, 128.34, 128.14, 126.60, 126.04, 63.97, 57.91, 40.59, 34.99, 34.28, 30.76,

+ 29.51, 17.47, 15.66, 13.04 ppm; HRMS (ESI-Q-TOF): [M+H] calcd for C24H34N3O2:

396.2651; found: 396.2640.

(S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3- dimethyl-2-(methylamino)butanamide (1d). The compound was obtained as a

20 1 yellowish solid; yield: (β47 mg, β8%); [α]D = ‒57.9 (c 0.3, MeOH); H NMR (600

MHz, CD3OD) showed the presence of two rotamers in a ratio of 2.9/1, major rotamer shown:  7.55-7.54 (d, J = 7.8Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.23-7.18 (m, 4H), 7.16-

7.15 (m, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.04 (s, 1H), 7.00 (t, J = 7.2 Hz, 1H), 5.47 (dd, J1

= 10.8 Hz, J2 = 6.0 Hz, 1H), 3.52-3.50 (m, 2H), 3.18-3.14 (m, 1H), 3.09 (d, J = 6.0Hz,

1H), 2.99-2.91 (m, 6H), 1.68 (s, 3H), 1.60-1.57 (m, 1H), 0.84 (d, J = 6.6 Hz, 3H), 0.81 (d,

13 J = 6.6 Hz, 3H) ppm; C NMR (150 MHz, CD3OD) major rotamer shown:  175.35,

170.66, 137.15, 136.80, 128.72, 128.35, 128.11, 126.30, 122.07, 120.95, 118.22, 117.87,

111.50, 110.86, 64.47, 57.65, 39.64, 34.03, 33.03, 30.93, 30.57, 24.79, 18.55, 16.40 ppm;

+ HRMS (ESI-Q-TOF): [M+H] calcd for C26H35N4O2: 435.2760; found: 435.2754.

(S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3- dimethyl-2-(methylamino)butanamide (1d’). The compound was obtained as a white

20 1 solid; yield: (15γ mg, 17%); [α]D = +27.9 (c 0.3, CD3OD); H NMR (600 MHz,

CD3OD) showed the presence of two rotamers in a ratio of 6.6/1, major rotamer shown: 

7.56-7.55 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.24-7.21 (m, 4H), 7.17-7.7.15

(m, 1H), 7.08 (t, J = 7.2Hz, 1H), 7.05 (s, 1H), 7.00 (t, J = 7.2 Hz, 1H), 5.51 (dd, J1 = 11.4

118

Hz, J2 = 5.4 Hz, 1H), 3.52 (t, J = 6.6 Hz, 2H), 3.22-3.18 (m, 2H), 2.96-2.90 (m, 6H), 2.08

(s, 3H), 1.36-1.29 (m, 1H), 0.61 (d, J = 6.6 Hz, 3H), 0.51 (d, J = 6.6 Hz, 3H) ppm; 13C

NMR (150 MHz, CD3OD) major rotamer shown:  175.36, 170.85, 137.06, 136.78,

128.62, 128.17, 127.39, 126.36, 122.15, 120.96, 118.23, 117.89, 110.43, 110.86, 64.38,

57.60, 39.79, 33.38, 33.49, 30.49, 30.25, 24.66, 18.32, 16.21 ppm; HRMS (ESI-Q-TOF):

+ [M+H] calcd for C26H35N4O2: 435.2760; found 435.2775.

119

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121

Appendix A

Supporting information for Chapter 2

Page 124: 1H NMR of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl)acetamide

(1h).

Page 127: 13C NMR of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl)acetamide

(1h).

Page 128: 1H NMR of 2-(2-bromophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl)acetamide

(1i).

Page 129: 13C NMR of2-(2-bromophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl)acetamide

(1i).

Page 130: 1H NMR of 3-benzyl-N-cyclopentyl-2-ethyl-3,4-dihydroquinazoline-4- carboxamide (8a).

Page 131: 13C NMR of 3-benzyl-N-cyclopentyl-2-ethyl-3, 4-dihydroquinazoline-4- carboxamide (8a).

Page 132: 1H NMR of N-(2-(1-(benzylamino)-2-(cyclopentylamino)-2-oxoethyl)phenyl) propionamide (9a).

122

Page 133: 13C NMR of N-(2-(1-(benzylamino)-2-(cyclopentylamino)-2-oxoethyl) phenyl) propionamide (9a).

123

1H NMR of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl) acetamide (1h).

124

72 °C

62 °C

52 °C

42 °C

32 °C

22 °C

1H NMR (variable temperature) of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl) acetamide (1h).

125

CDCl3

CD3Cl2

C3D6O

CD3OD

CD3CN

DMSO-d6

1H NMR (variable solvent) of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl) acetamide (1h).

126

13C NMR of N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3-yl) acetamide (1h). 127

1H NMR of 2-(2-bromophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl) acetamide (1i).

128

13C NMR of 2-(2-bromophenyl)-N-isopropyl-N-(2-oxoindolin-3-yl) acetamide (1i).

129

1H NMR of 3-benzyl-N-cyclopentyl-2-ethyl-3, 4-dihydroquinazoline-4-carboxamide (8a).

130

13C NMR of 3-benzyl-N-cyclopentyl-2-ethyl-3, 4-dihydroquinazoline-4-carboxamide (8a).

131

1H NMR of N-(2-(1-(benzylamino)-2-(cyclopentylamino)-2-oxoethyl) phenyl) propionamide (9a).

132

13C NMR of N-(2-(1-(benzylamino)-2-(cyclopentylamino)-2-oxoethyl) phenyl) propionamide (9a).

133

Appendix B

Supporting information for Chapter 3

Page 135: 1H NMR of 3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione

(7a).

Page 136: 13C NMR of 3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione

(7a).

Page 137: 1H NMR of 7-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8a).

Page 138: 13C NMR of 7-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione (8a).

134

1H NMR of 3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7a).

135

13C NMR of 3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-2,5'(1'H)-dione (7a).

136

1H NMR of 7-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione 8a.

137

13C NMR of 7-chloro-1'-phenylspiro[indoline-3,2'-pyrrolidine]-2,5'-dione 8a.

138

Appendix C

Supporting information for Chapter 4

Page 141: 1H NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a).

Page 142: 13C NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a).

Page 143: 1H NMR of(S)-N,4-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a’).

Page 144: 13C NMR of(S)-N,4-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a’).

Page 145: 1H NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino)pentanamide (1b).

Page 146: 13C NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino)pentanamide (1b).

Page 147: 1H NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino)pentanamide (1b’).

139

Page 148: 13C NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino)pentanamide (1b’).

Page 149: 1H NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c).

Page 150: 13C NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c).

Page 151: 1H NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c’).

Page 152: 13C NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-

(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c’).

Page 153: 1H NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino)butanamide (1d).

Page 154: 13C NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino)butanamide (1d).

Page 155: 1H NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino)butanamide (1d’).

Page 156: 13C NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3- phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino)butanamide (1d’).

140

1H NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a).

141

13C NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a).

142

1H NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a’).

143

13C NMR of (S)-N,4-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)pentanamide (1a’).

144

1H NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino) pentanamide (1b).

145

13C NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino) pentanamide (1b).

146

1H NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino) pentanamide (1b’).

147

13C NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,4-dimethyl-2-(methylamino) pentanamide (1b’).

148

1 H NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c).

149

13 C NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((S)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c).

150

1H NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c’).

151

13C NMR of (S)-N,3-dimethyl-2-(methylamino)-N-((R)-1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)butanamide (1c’).

152

1H NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino) butanamide (1d).

153

13C NMR of (S)-N-((S)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino) butanamide (1d).

154

1H NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino) butanamide (1d’).

155

13C NMR of (S)-N-((R)-1-((2-(1H-indol-3-yl)ethyl)amino)-1-oxo-3-phenylpropan-2-yl)-N,3-dimethyl-2-(methylamino) butanamide (1d’).

156

Appendix D

X-ray crystallographic data

Page 158: X-ray crystal structure details for N-benzyl-2-(2-bromophenyl)-N-(2- oxoindolin-3-yl) acetamide (1h) from chapter 2.

Page 161: X-ray crystal structure details for 3'-methyl-1'-phenylspiro[indoline-3,2'- pyrrole]-2,5'(1'H)-dione (7a) from chapter 3.

157

X-ray crystal structure details for N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3- yl)acetamide (1h).

A specimen of C24H23BrN2O3, approximate dimensions 0.041 mm x 0.067 mm x

0.378 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured with the total of 2904 frames were collected. The total exposure time was

48.40 hours. The frames were integrated with the Bruker SAINT Software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 19785 reflections to a maximum θ angle of β6.γ7° (0.80 Å resolution), of which

8403 were independent (average redundancy 2.355, completeness = 99.9%, Rint = 2.94%) and 7446 (88.61%) were greater than βσ (F2). The final cell constants of a = 9.969(3) Å, b = 10.512(4) Å, c = 11.β5γ(4) Å, α = 80.696(9)°, = 85.4γ6(10)°, = 68.779(9)°, volume = 1084.5(6) Å3, are based upon the refinement of the XYZ-centroids of 9806 reflections above β0 σ(I) with 4.877° < βθ < 55.75°. Data were corrected for absorption effects using the multi-scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.822. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.6130 and 0.7460.

The final anisotropic full-matrix least-squares refinement on F2 with 704 variables converged at R1 = 2.95%, for the observed data and wR2 = 6.90% for all data. The goodness-of-fit was 1.065. The largest peak in the final difference electron density synthesis was 0.701 e-/Å3 and the largest hole was -0.352 e-/Å3 with an RMS deviation of

0.045 e-/Å3. On the basis of the final model, the calculated density was 1.431 g/cm3 and

F(000), 480 e-.

158

Sample and crystal data for 1h.

Identification N-benzyl-2-(2-bromophenyl)-N-(2-oxoindolin-3- code yl)acetamide

Chemical formula C24H23BrN2O3 Formula weight 467.35 Temperature 140(2) K Wavelength 0.71073 Å Crystal size 0.041 x 0.067 x 0.378 mm Crystal system triclinic Space group P 1 Unit cell a = 9.969(3) Å dimensions α = 80.696(9)° b = 10.512(4) Å = 85.4γ6(10)° c = 11.253(4) Å = 68.779(9)° Volume 1084.5(6) Å3

Z 2 Density 1.431 g/cm3 (calculated) Absorption 1.923 mm-1 coefficient F(000) 480

Data collection and structure refinement for 1h.

Theta range for data 1.83 to 26.37° collection Index ranges -12<=h<=12, -13<=k<=13, -14<=l<=14 Reflections collected 19785 Independent reflections 8403 [R(int) = 0.0294] Coverage of independent 99.9% reflections Absorption correction multi-scan Max. and min. 0.7460 and 0.6130 transmission

159

Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2013 (Sheldrick, 2013) 2 2 2 Function minimized Σ w(Fo - Fc ) Data / restraints / 8403 / 3 / 704 parameters Goodness-of-fit on F2 1.065

Δ/σmax 0.022 7446 data; Final R indices R1 = 0.0295, wR2 = 0.0652 I>βσ(I) all data R1 = 0.0385, wR2 = 0.0690 2 2 2 w=1/[σ (Fo )+(0.0285P) ] Weighting scheme 2 2 where P=(Fo +2Fc )/3 Absolute structure 0.0(0) parameter Largest diff. peak and hole 0.701 and -0.352 eÅ-3 R.M.S. deviation from 0.045 eÅ-3 mean

ORTEP diagram for compound 1h.

160

X-ray crystal structure details for 3'-methyl-1'-phenylspiro[indoline-3,2'-pyrrole]-

2,5'(1'H)-dione (7a).

A specimen of C18H14N2O2 was used for the X-ray crystallographic analysis. The

X-ray intensity data were measured. The integration of the data using a monoclinic unit cell yielded a total of 23672 reflections to a maximum θ angle of 33.03° (0.65 Å resolution), of which 4886 were independent (average redundancy 4.845, completeness =

2 95.9%, Rint = 2.10%, Rsig = 1.47%) and 4423 (90.52%) were greater than βσ(F ). The final cell constants of a = 8.610(2) Å, b = 15.226(4) Å, c = 10.416(2) Å, = 98.327(3)°, volume = 1351.1(5) Å3, are based upon the refinement of the XYZ-centroids of 9908 reflections above β0 σ(I) with 4.772° < βθ <65.99°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.914. The structure was solved and refined using the Bruker

SHELXTL Software Package, using the space group P 1 21/n 1, with Z = 4 for the formula unit, C18H14N2O2. The final anisotropic full-matrix least-squares refinement on

F2 with 255 variables converged at R1 = 3.63%, for the observed data and wR2 = 10.25% for all data. The goodness-of-fit was 1.079. The largest peak in the final difference electron density synthesis was 0.529 e-/Å3 and the largest hole was -0.226 e-/Å3 with an

RMS deviation of 0.055 e-/Å3. On the basis of the final model, the calculated density was

1.427 g/cm3 and F(000), 608 e-.

Sample and crystal data for compound 7a

Chemical formula C18H14N2O2 Formula weight 290.31 g/mol

161

Temperature 100(2) K Wavelength 0.71073 Å Crystal system monoclinic Space group P 1 21/n 1 Unit cell dimensions a = 8.610(2) Å α = 90° b = 15.226(4) Å = 98.γβ7(γ)°

c = 10.416(2) Å = 90°

Volume 1351.1(5) Å3

Z 4 Density (calculated) 1.427 g/cm3 Absorption coefficient 0.095 mm-1 F(000) 608

Data collection and structure refinement for compound 7a. Theta range for data 2.39 to 33.03° collection Index ranges -12<=h<=13, -23<=k<=22, -15<=l<=15 Reflections collected 23672 Independent reflections 4886 [R(int) = 0.0210] Coverage of independent 95.9% reflections Absorption correction Multi-Scan Structure solution direct methods technique Structure solution XT, VERSION 2014/4 program Refinement method Full-matrix least-squares on F2 Refinement program SHELXL-2014/7 (Sheldrick, 2014) 2 2 2 Function minimized Σ w(Fo - Fc ) Data / restraints / 4886 / 0 / 255 parameters Goodness-of-fit on F2 1.079

Δ/σmax 0.001 Final R indices 44βγ data; I>βσ(I) R1 = 0.0363, wR2 = 0.0986 162

all data R1 = 0.0405, wR2 = 0.1025

2 2 2 w=1/[σ (Fo )+(0.0590P) +0.3554P] Weighting scheme 2 2 where P=(Fo +2Fc )/3 Largest diff. peak and 0.529 and -0.226 eÅ-3 hole R.M.S. deviation from 0.055 eÅ-3 mean

ORTEP diagram for compound 7a.

163