I. Synthesis of Diverse Structures from Quinone Monoketal and Quinone Imine Ketal with Efficiency and Control II

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I. Synthesis of Diverse Structures from Quinone Monoketal and Quinone Imine Ketal with Efficiency and Control II. Synthetic Study of Phalarine

Zhiwei Yin The Graduate Center, City University of New York

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This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] I. Synthesis of Diverse Structures from Quinone Monoketal and Quinone Imine Ketal with Efficiency and Control II. Synthetic Study of Phalarine

Zhiwei Yin

A dissertation submitted to the Graduate Faculty in Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York

ii iii

This manuscript has been read and accepted for the Graduate Faculty in Chemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy.

Shengping Zheng

Date Chair of Examining Committee

Brian Gibney

Date Executive Officer

Shengping Zheng

Mark Biscoe

Wayne Harding Supervisory Committee

THE CITY UNIVERSITY OF NEW YORK Abstract

Author: Zhiwei Yin

Advisor: Professor Shengping Zheng

Quinonoids are quinone derivatives that have carbonyl or carbonyl equivalent and even number of double bonds embedded in six member rings. As a result of the intrinsic α,β-unsaturated ketone or imine structures, quinonoids, such as quinone monoketals, quinols, quinol ethers and quinone imine ketals, can accommodate a wide range of reactions including 1,2-additon, 1,4-addtion, SN2’ reaction

(allylic substitution) to the α-carbon of the carbonyl or imine and cycloaddition reactions (e.g.

Diels-Alder reaction). Quinonoids are eﬀective building blocks for synthesizing heterocycles, which are ubiquitous in pharmaceutically useful agents. Developing new quinonoid based methodologies is essential to expanding the boundary of synthetic organic chemistry and providing viable pathway to synthesis of molecules of pharmaceutical interests. The ﬁrst three chapters of this thesis describes three methodologies on synthesis of diverse heterocycles from quinone monoketal and quinone imine ketal, the process of methodology development and how each methodology inspired the consequential methodology.

Besides the research on quinonoids based synthetic methodologies, we have also been working on a concise formal synthesis of an indole alkaloid–phalarine. This project, though not ﬁnished, aﬀorded interesting products, that provided mechanistic insight into the reactivity and chemoselectivity of

iv v tetrahydro-beta-carboline. This project is covered in chapter 4.

I. Synthesis of Diverse Structures from Quinone Monoketal and

Quinone Imine Ketal with Eﬃciency and Control

Chapter 1

Previously our group has developed a variation of Fischer indole synthesis using quinone monoketal and aliphatic hydrazine. Literature reported reaction of quinone monoketal and nucleophiles, such as hydrazine, amine and hydroxylamine, gave either 1,2-addition or 1,4-addition products. Due to lack of studies on reaction of quinone monoketal and N-protected hydroxylamine, we were intrigued to explore this reaction. A probe into the reaction of quinone monoketal and BnNHOH gave rise to an unexpected product, which was characterized as a bridged isoxazolidine. This isoxazolidine compound, which reveals to be the double Michael addition product of BnNHOH to quinone monoketal, provides an alternative to conventional synthesis of isoxazolidines by nitrone-alkene cycloaddition. To explore the scope of this reaction, a number of quinone monoketals were reacted with BnNHOH or BocNHOH and a wide range of isoxazolidines were prepared. Interestingly, the reaction of BnNHOH and BocNHOH with mono-sbustituted quinone monoketals gave isoxazolidine products with opposite regio-selectivity. The reductive N-O cleavage of bridged isoxazolidine gives

1,3-syn-aminoalcohols, which are backbone for a number of bioactive compounds. To demonstrate the application of this methodology, facilely functionalized aminocyclitols were synthesized in short sequence from a bridged isoxazolidine. vi

Chapter 2

Inspired by the former discovered N,O-double Michael addition reaction, the possibility of N,N- double Michael addition reaction was explored. Under same conditions, the reaction of quinone monoketal with MeNHNHMe·2HCl did not give the desired pyrazodiline product. However, an unexpected allylic substitution of quinone monoketal was discovered. This leads to a general synthesis of o-chlorophenols from quinone monoketal under mild conditions. Various quinone monoketals were subjected to this protocol and a number of selective o-chlorination products were aﬀorded in high yields. The mechanism of this reaction was closely examined by mixed quinone monoketals and solvent scrambling experiment. Also the relative ability of methoxyl and siloxy as leaving groups were also studied. Eventually the pyrazolidine synthesis was achieved in the presence of protic solvent.

Chapter 3

The discovery of o-chlorination in chapter 2 inspired us to explore the allylic substitution of quinone imine ketals. An indole synthesis from quinone imine ketal and alkenyl ether was envisioned and explored. In the presence of catalytic amount of SnCl4 or tetra-ﬂuoro-benzene-1,4-dicarboxylic acid,

N-tosyl protected quinone imine ketals react with alkenyl ethers to give indole or indoline products.

The N-acyl protected quinone imine ketals, however, react with alkenyl ethers to give preferentially

1,4-addition products. The eﬀectiveness of this indole methodology was demonstrated in a concise synthesis of natural product Lycoranine A. vii

II. Synthetic Study of Phalarine

Chapter 4

Phalarine is an indole alkaloid separated from the perennial grass P. coerulescens. It possesses a novel furanobisindole framework, which is a propeller-like structure. The unique structure of phalarine has interested several groups to work on the relevant synthetic studies. Speciﬁcally,

Danishefsky group has reported the total synthesis of phalarine in 2007 and an asymmetric total synthesis of (-)-phalarine in 2010. Chen published a formal synthesis of (-)- and (+)-phalarine in 2011. Due to our continuing interest in indole alkaloid synthesis, a phalarine formal synthesis project was initialted. This project aims to furnish a concise biomimetic synthetic pathway to a junction compound in Danishefsky’s phalarine synthesis. Even though not ﬁnished, this project has yielded several interesting results. Chapter 4 will give a brief review of the previous synthesis of phalarine and describe our ongoing eﬀorts in achieving a formal synthesis of phalarine. Acknowledgements

I would like to express my sincere appreciation to all members of Shengping Zheng Lab. Most of all, I want to express my gratitude to my mentor Prof. Zheng for guiding and supervising me in my research studies. He is a truly knowledgeable organic chemist. Without his advice, I cannot

ﬁnish the research projects without tedious struggles. Beyond chemistry, Prof. Zheng taught me many lessons in life, which I shall cherish for the rest of my life. Also I would like to thank all my lab mates, Dr. Jinzhu Zhang, Jing Wu, Sihan li, Riana Green and Haisu Zeng for helping me, inspiring me and making my time in this lab a very enjoyable experience.

I would also like to thank my committee members, Dr. Wayne Harding and Dr. Mark Biscoe.

They helped me through my graduate study and provided me with supportive and motivating suggestions. I would like to extend my gratitude to Dr. Klaus Grohmann, Dr. David Mootoo and

Dr. Akira Kawamura for their advice and discussions.

I am also thankful to Dr. Matthew Devany for his help in collecting NMR spectra. Dr. Devany maintains a highly eﬃcient NMR lab, which is crucial to the progress of my work. Thanks to

Dr. Srinivas Chakravartula, Dr. Cliﬀ Soll and Dr. Lijia Yang for their help with collecting high resolution mass data. Thanks to Dr. Chunhua Hu for providing single crystal x-ray diﬀraction analysis for my compounds.

I want to thank all members of Hunter College Chemistry Department. Thanks for their support. They are amazing to work with. It was a wonderful time to share wine and talks with

viii ix them. Specially I am grateful to members of Harding Lab, Mootoo Lab and Biscoe Lab for sharing their knowledge and chemicals.

In the end, I would like to thank my family and partner for their unconditional love and support.

Note (publisher right): The dissertation work covered in Chapter 1 and Chapter 2 has been previously published in peer reviewed journals. The research described in Chapter 1 is published in Or- ganic Letters, ACS (American Chemical Society): http://pubs.acs.org/doi/abs/10.1021/ol401235z.

The research described in Chapter 2 is published in Organic and Biomolecular Chemistry, RSC

(Royal Society of Chemistry): http://pubs.rsc.org/en/Content/ArticleLanding/2014/OB/c4ob00391h.

The thesis is produced in LATEX. Contents

Abstract...... iv

Acknowledgements ...... viii

Contents...... xiii

ListofSymbolsandAbbreviations ...... xiv

ListofFigures ...... xvi

ListofSchemes...... xviii

ListofTables ...... xix

1 Double Michael Addition 1

1.1 Overview of the Quinone Monoketal Chemistry ...... 2

1.2 A Variation of Fischer Indole Synthesis from QMK ...... 6

1.3 Discovery of the Hetero Double-Michael Addition ReactionofQMK ...... 8

1.4 Conventional Isoxazolidine Synthesis ...... 10

1.5 Isoxazolidine Synthesis via Double Michael Addition ...... 12

1.5.1 Synthesis of isoxazolidines from 2,3-unsubstituted QMKs ...... 12

1.5.2 Synthesis of isoxazolidines from 2 or 3 monosubstitutedQMKs ...... 13

1.5.3 Isolation of the Mono-Michael Addition Intermediate ...... 14

1.6 Synthesis of Functionalized Aminocyclitols from Isoxazolidine ...... 15

x CONTENTS xi

1.7 Conclusion ...... 16

1.8 ExperimentalSection...... 17

1.8.1 Preparation of Quinone Monoketals ...... 17

1.8.2 Preparation of BnNHOH Hetero Michael Addition Derivatives ...... 18

1.8.3 Preparation of BocNHOH Hetero Michael Addition Derivatives ...... 26

1.8.4 Preparation of MeNHOH Hetero Michael Addition Derivatives ...... 32

1.8.5 Preparation of AcNHOH Hetero Michael Addition Derivatives ...... 32

1.8.6 Synthesis of Aminocyclitol Derivatives ...... 33

2 o-Chlorination 39

2.1 Discovery of the o-Chlorination Reaction ...... 41

2.2 Reaction Condition Optimization ...... 42

2.3 Exploration of the Reaction Scope ...... 43

2.3.1 Chlorination of Spiral QMKs and mono-Substituted QMKs ...... 43

2.3.2 Chlorination of di-Substituted Flourine-rich QMKs ...... 45

2.3.3 Quinonoids and miscellaneous nucleophiles ...... 46

2.4 MechanismExploration ...... 46

2.5 N, N-double Michael Addition Reaction ...... 49

2.6 Conclusion ...... 50

2.7 ExperimentalSection...... 51

2.7.1 Preparation of Quinone Monoketals ...... 51

2.7.2 Synthesis of o-Chlorophenols ...... 56

2.7.3 Quinonoids and miscellaneous nucleophiles ...... 65

2.7.4 Preparation of N,N-double Michael addition Derivatives ...... 67

2.7.5 Chlorination of Mixed Quinone Monoketals ...... 69 xii CONTENTS

2.7.6 Mechanism Study: synthesis of 14 and scrambling experiments ...... 71

3 QIK Based Indole Synthesis 73

3.1 Introduction...... 74

3.2 FromQIKtoIndoleSynthesis...... 76

3.3 ProposedIndoleSynthesis ...... 78

3.4 Reaction Condition Optimization ...... 79

3.5 ReactionScopeExploration ...... 80

3.5.1 Reaction of N-Tosyl QIK with alkenyl ether ...... 80

3.5.2 Reaction of N-Acyl QIKs with alkenyl ethers ...... 82

3.6 Mechanism ...... 84

3.7 Concise synthesis of natural product Lycoranine A ...... 85

3.8 Conclusion ...... 86

3.9 ExperimentalSection...... 87

3.9.1 Synthesis of N-Ts-protected indoles and indolines ...... 88

3.9.2 Reaction of N-Acyl QIKs with alkenyl ethers ...... 91

3.9.3 Synthesis of natural product Lycoranine A ...... 95

4 Synthetic Study of Phalarine 99

4.1 Introduction...... 100

4.2 Synthesis of Phalarine by Danishesky Group ...... 100

4.2.1 The Biosynthesis of Palarine and Biomimetic Synthesis ...... 100

4.2.2 The Racemic Synthesis of Phalarine ...... 102

4.2.3 The Asymmetric Synthesis of Phalarine ...... 104

4.3 FormalSynthesisofPhalarinebyChen...... 106 CONTENTS xiii

4.3.1 Retrosynthesis of Phalarine by Chen ...... 107

4.3.2 Formal Synthetic Route of (-)-Phalarine and (+)-Phalarine ...... 107

4.4 Synthetic Study of Phalarine by Zheng Group ...... 109

4.4.1 A Short Introduction of Biomimetic Synthesis ...... 109

4.4.2 OurPlannedSynthesis...... 109

4.4.3 Concise preparation of the starting material via selective methylation . . . . 110

4.4.4 Coupling Reaction of the Chloroindolenine and Phenols ...... 112

4.5 Summary ...... 117

4.6 ExperimentalSection...... 118

4.6.1 Preparation of selective methylation product ...... 118

4.6.2 Preparation of 3-methylphenol coupling product ...... 119

4.6.3 Preparation of 3-methylphenol coupling product ...... 120

4.6.4 Preparation of silver catalyzed 3-methylphenol couplingproduct ...... 124

References 126

Appendix 135 List of Symbols and Abbreviations

Ac Acetyl

Ac2O Acetic anhydride

BF3·Et2O Boron triﬂuoride etherate

Bn Benzyl

Brine Saturated aqueous sodium chloride solution

Boc t-butyl carbonate or t-butyl carbamate

brsm Based on recovering starting materials

Bu Butyl

◦C Degree Celsius

CAM stain Cerium Ammonium Molybdate stain

COSY Correlation spectroscopy

CSA Camphorsulfonic acid

δ Chemical shift

DBU 1,8-diazabicyclo[5,4,0]undec-7-ene

DCM Dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzenoquinone

DMAP 4-(dimethylamino)pyridine

DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

Eq Equivalent

EtOAc Ethyl acetate

HRMS High resolution mass spectroscopy

HSQC Heteronuclear single-quantum correlation spectroscopy xiv Hz Hertz

J Coupling constant

KHMDS Potassium bis(trimethylsilyl)amide

M Molar mg Milligram

MHz Megahertz min Minutes mmol Millimole mp Melting point m.s. Mass spectroscopy

µL Micro liter

NMR Nuclear magnetic resonance nOe Nuclear Overhauser eﬀect

PIDA Phenyliodine Diacetate

PIFA Phenyliodine bis(triﬂuoroacetate)

Ph Phenyl

Ppm Parts per million r. t. Room temperature

TBAF tetra-n-butylammonium ﬂuoride

TBS t-butyldimethylsilyl

TBDPS t-butyldiphenylsilyl

TFA Triﬂuoroacetic acid

TFBDA Tetraﬂuorobenzene-1,4-dicarboxylic acid

TLC Thin layer chromatography

xv List of Figures

1.1 StructuresofQuinoneMonoketal ...... 2

1.2 1,3-syn-amino alcohol containing bioactive compounds ...... 11

3.1 StructureandoriginoflycoranineA ...... 85

4.1 Structureandoriginofphalarine ...... 100

xvi List of Schemes

1.1 QMK based reaction methodologies ...... 3

1.2 Synthesis of complex natural products via QMK ...... 5

1.3 Variation of Fischer indole synthesis ...... 8

1.4 Discovery of the hetero double Michael addition reaction...... 9

1.5 Intermolecular and intramolecular nitrone-alkene cycloaddition ...... 10

1.6 Isolation of the mono-Michael addition intermediate ...... 14

1.7 Synthesis of aminocyclitol derivatives ...... 15

2.1 Double hetero-Michael addition reaction reported by Aubegroup ...... 40

2.2 Discovery of the o-chlorination reaction ...... 41

2.3 Plausiblemechanisms ...... 48

2.4 Mechanismexploration...... 48

2.5 Synthesis of the bridged pyrazolidine products ...... 49

3.1 ReactionscopeofQIKs ...... 75

3.2 Traditionalindolesynthesis ...... 76

3.3 Synthesis of dihydro-benzofuran or indole by acid catalyzed [3+2] coupling of quinonoids

3.4 Indole synthesis via [3+2] coupling of QIK and vinyl ether...... 79

xvii xviii LIST OF SCHEMES

3.5 Reactionmechanism ...... 85

3.6 ConcisesynthesisofLycoranineA ...... 86

4.1 The biomimetic sythesis modelling study of phalarine ...... 101

4.2 Proposed phalarine synthesis via a ring expansion strategy...... 103

4.3 Realization of the ring expansion strategy and the racemic synthesis of phalarine . . 104

4.4 Failed approach: substantial enantiopure intermediate gave racemic product . . . . . 105

4.5 Traceless transfer of chirality ...... 106

4.6 Proposed synthesis of phalarine by oxidative coupling strategy ...... 107

4.7 Formal synthesis of (-)-phalarine by Chen ...... 108

4.8 Proposedformalsynthesisofphalarine ...... 110

4.9 Preparation of the starting material ...... 111

4.10 One-pot selective methylation of amide via penta-valent silane intermediate . . . . . 112

4.11 Generation of the chloroindolenine coupling precursor ...... 112

4.12 Coupling reaction of chloroindolenine with 3-methylphenol...... 113

4.13 Coupling reaction of chloroindolenine with 3-methoxyphenol...... 114

4.14 Proposed mechanism for the coupling reaction of chloroindolenine with phenols . . . 115

4.15 Proposed coupling reaction of chloroindolenine with silver phenoxide ...... 116 List of Tables

1.1 Synthesis of isoxazolidines from 2,3-unsubstituted QMKs...... 12

1.2 Synthesis of isoxazolidines with regio-selectivities ...... 13

2.1 Screeningofthechloridesource ...... 42

2.2 Chlorination of spiral QMKs and mono-substituted QMKs ...... 44

2.3 Chlorination of di-substituted ﬂourine-rich QMKs ...... 45

2.4 Nucleophilic addition of other nucleophiles or quinonoids...... 46

2.5 ChlorinationofmixedQMKs ...... 47

3.1 Indole synthesis via [3+2] coupling of QIK and vinyl ether...... 80

3.2 Reaction of N-Ts QIK with alkenyl ethers ...... 81

3.3 Reaction of N-Acyl QIKs with alkenyl ethers ...... 83

xix xx LIST OF TABLES Chapter 1

Double Michael Addition

1 2 CHAPTER 1. DOUBLE MICHAEL ADDITION

1.1 Overview of the Quinone Monoketal Chemistry

Heterocycles are a key component of organic chemistry and inextricably woven into chemistry of life. They serve as the most ubiquitous structure in pharmaceutical industry: more than half of the known organic compounds and over 90% of the new drugs contain heterocycles[1]. Quinone is widely present in nature; quinonoids, such as quinone monoketals (QMK), quinols, quinol ethers and quinone imine ketals (QIK) can be handily employed in the synthesis of heterocycles. Con- ventionally they can be easily prepared in one step from commercially available phenols or anilides using the most convenient method (Figure 1.1), Tamura-Pelter protocol[2, 3], in which hypervalent iodine species, such as PhI(OAc)2 (PIDA) or PhI(OCOCF3)2 (PIFA) serve as oxidants. Quinonoid synthetic protocols using oxone[4, 5], Tl(NO3)3[6], LiClO4[7] or electrochemical oxidation[8–11] were also reported. Interestingly, due to the intrinsic α,β-unsaturated ketone or imine structure, quinonoids could accommodate miscellaneous reactions with diﬀerent reagents under various conditions. Using QMK as an example, a wide variety of reactivities were reported from literature, such as 1,2-additon[12–14], 1,4-addtion[15, 16], SN2’ reaction (allylic substitution) to the α carbon of the carbonyl[17, 18] and cycloaddition (e.g. Diels-Alder reaction)[19].

1,2 addition OH Annulations eg Diels-Alder O [O] SN2' rxn R2OH 1,4 addition R1 R1 OR2 Quinone Monoketal

Figure 1.1: Structures of Quinone Monoketal

QMKs are important building blocks for synthesis of natural products and molecules of pharmaceutical interests. Diverse frameworks can be synthesized by QMK based methodologies (Scheme 1.1).

Evans reported the 1,2-addition of phenylethyl carbanions of 2 to QMK 1 to aﬀord quinols 3, which were then treated with Lewis acid to give phenanthrenoid compounds 4.[12] Morrow used 1.1. OVERVIEW OF THE QUINONE MONOKETAL CHEMISTRY 3

1,2-addition

OMe OMe OMe O MeO OMe MeO OMe MeO OMe LDA OMe Lewis acid + MeO MeO MeO OMe OH CO2Me CO2Me CO2Me 1 2 3 4 Evans, D. A. J. Am. Chem. Soc. 1977, 99 (21), 7083-5

O R R R

n-BuLi BF3 Et2O + Br MeO MeOH MeO MeO OMe MeO OH 1 5 6 7 Morrow, G. W. Tetrahedron 1995, 51 (37), 10115-24.

1,4-addition

H N O O O tBu n-BuNH2 tBu tBu

NHBu PhH PhH N MeO OMe MeO OMe MeO OMe 9 8 10 Ciufolini, M. A. Tetrahedron Lett. 1996, 37 (17), 2881-4.

SN2' reaction

O OMe OMe OH MT clay +

OMe MeO OMe OMe 1 11 OMe 12 Kita, Y. Angewandte Chemie International Edition 2011, 50 (27), 6142-6146.

O EWG R1 EWG SnCl MeO + 4 R2 SMe MeS SMe 2 O MeO OMe R 13 R1 14 Liu, Q. Adv. Synth. Catal. 2012, 354 (14-15), 2678-2682, S2678/1-S2678/34.

Diels-Alder reaction

O O Me Me H Me chiral Ti(IV) Me + catalyst

OO OOH 15 16 17 Corey, E. J. Org. Lett. 2001, 3 (10), 1559-1562.

Scheme 1.1: QMK based reaction methodologies 4 CHAPTER 1. DOUBLE MICHAEL ADDITION a similar strategy to construct phenanthrene nucleus. Aryl lithium reagents, which were derived from halogen-metal exchange of 5, react cleanly with QMKs to aﬀord quinols 6, which under acid catalysis were transformed into phenanthrene derivatives 7.[20] Ciufolini reported the nucleophilic addition of numerous primary amines and cyclic secondary amines to QMK 8 to give

1,4-addition products such as 9 and 10, and applied of this methodology in a synthesis of polycyclic heterocycles.[21] The allylic substitution was not extensively studied until in the last ten years. In an early report by Sartori, biaryl compounds were synthesized from QMKs and electron rich phenols; Et2AlCl was used as catalyst and the reaction only gave moderate yields.[22] Kita reported the allylic substitution of dimethylresorcinol 11 to QMK 1, aﬀording biaryl compound

12 in high yields.[23] Liu discovered a SnCl4 catalyzed SN2’ reaction of ketene dithioacetals 13 to

QMKs, aﬀording benzofuran 14 in good to excellent yields.[24] The Diels-Alder reaction of regular

QMK with diene does not occur easily. Corey group ﬁrst reported an enantioselective Diels-Alder reaction of diene 16 and QMK 15, which has a cyclic ketal moiety, catalyzed by a chiral Ti(IV)

Lewis acid.[25] In addition to the above described reaction types, [5+2] cycloaddition reaction or photochemical rearrangements of QMKs were also reported.[26, 27]

QMKs are also used in the synthesis of complex natural products (Scheme 1.2). Simple methods for the rapid construction of complex molecules have been desired by organic chemists. Since many natural products contain densely functionalized cyclohexane moieties, QMKs provide a very good precursor to them for the sake of substituents on QMK assisting regio or facial selectivities.

Some prominent examples of natural products that have fused rings and congested stereocenters were synthesized using QMKs as starting material or intermediate products. Danishefsky, in his concise synthesis of ﬂuostatin C, utilized a Diels-Alder reaction of 18 and 19 to construct the backbone of the molecule 20 in one step.[28] Though the reversed regioselective product was afforded, the beneﬁt of using QMK is that the ketal moiety can be hydrolyzed and converted to the 1.1. OVERVIEW OF THE QUINONE MONOKETAL CHEMISTRY 5

Samuel Danishefsky's synthesis of Fluostatin C

MOM HO Ti catalyzed MOM O OH O O O Diels-Alder O Me reaction Me Me H O HO O O O 19 18 20 Fluostatin C

K. C. Nicolaou's total synthesis of viridicatumtoxin B

Michael-Dieckmann Michael-Dieckmann Me cascade cascade Teoc Me MeO O MeO OMe O O Me OH D C OH O B A N MeO D C B A O O OBn O O OPh OBn OH OH OH O O NH2 1 21 22 viridicatumtoxin B

John A. Porco's total synthesis of Kinamycin C and kibdelone A/C

N OH O OTBS OH O OTBS MOMO OMOM N O OH asymmetric AcO epoxidation O Stille coupling B A D B A HO C Br Br Bu Sn D OO OO 3 Me OMOM O AcO OAc

23 24 25 (-)-kinamycin C

Cl OH Me ClMeO OMe Me AB C acid catalyzed N OMe AB Me N SN2 like coupling D Me O OH HO O O O OMe E OH D kibdelone C O 26 HO OTBDPS kibdelone A (C ring oxidized) F HO 27 OH

Scheme 1.2: Synthesis of complex natural products via QMK 6 CHAPTER 1. DOUBLE MICHAEL ADDITION desired keto functional group.[19] In Nicolaou’s total synthesis of viridicatumtoxin B, QMK 1 was used as a linchpin to construct the tetracycline antibiotic core framework, in which two Michael-

Dieckmann cascade sequences (1 and 22, 1 and 21) were employed to link A-B ring and B-C ring separately.[29] Porco group used QMK extensively in a number of methodologies and synthesis of natural products.[30–32] In the total synthesis of the diazobenzoﬂuorene antibiotic (-)-kinamycin

C, a poly functionalized QMK 24 was constructed through asymmetric epoxidation from QMK

23, and it was then subjected to Stille coupling with 25 and eventually was transformed into the poly substituted ring D of the target molecule.[33] Polycyclic xanthone natural products, such as kibdelone A/C, are characterized by their highly oxygenated hexacyclic framework and are a class of compounds with diverse biological activities.[34] A synthetic approach was developed by

Porco group, that was initiated with bicyclic QMK 26 undergoing SN2’ coupling with 27 to give a biphenyl compound, which then served as a common intermediate to ﬁnish the total synthesis of kidbelone A and C.[35–37] It is worth mentioning that ortho-quinone monoketal (o-QMK), which displays similar reactivities, was also extensively used as building blocks in methodology studies or natural product total synthesis.[38]

1.2 A Variation of Fischer Indole Synthesis from QMK

QMKs are relatively simple molecules, but they could be readily used to synthesize diverse structures. As part of our continuing interests in developing methodologies of synthesizing heterocyclic compounds, quinonoids, such as QMK, have been consistently used as a tool to develop different frameworks. Indole was the very first structure that we devoted our attention to. Indole is one of the most ubiquitous heterocycles in nature. It was first discovered from the treatment of the natural dye indigo with oleum (fuming sulfuric acid), which gave its name, indole. In 1866, Adolf von Baeyer first reduced oxindole, a product of indigo, with zinc powder to indole, and thus ini- 1.2. A VARIATION OF FISCHER INDOLE SYNTHESIS FROM QMK 7 tiated the era of producing indole by organic synthesis.[39, 40] Following his work, a number of new methods were developed.[41–45] The most classical one of them is the Fischer indole synthesis, which is applauded for its simplicity and efficiency.[46, 47] Along with the development of indole chemistry, indole and indole analogues became significant players in a diverse array of markets such as dye/pigments, perfumery, flavor enhancers, plastics, and agriculture.[48] Above all, indole- containing natural products are best known for their importance in pharmaceutical industry. Indole is one of the largest classes of nitrogen containing natural products, and displays a wide range of biological activities.[49–51] Many indole natural products bind to receptors with high affinity and were used in medicine.[52]

Intrigued by the structure complexity and biological activities, a number of indole containing natural products and medicinal compounds were synthesized. In this process, Fischer indole synthesis was widely used.[53–59] However despite the popularity of Fischer indole synthesis, this method suﬀers from using phenyl hydrazine, which was usually prepared form phenyl diazonium salt–a potentially explosive intermediate. A number of variations of Fischer indole synthesis were developed to overcome this problem, and the majority of them rely on transition metal catalyzed coupling reactions.[60–82] Due to their eﬃciency and miscellaneous catalyst capabilities, transition metal (such as Pd, Pt and Rh) catalyzed reactions brought a big leap to the scope of organic chemistry reactions. Albeit powerful, many of them tend to be expensive, toxic and hard to remove, thus their usage was limited.

Taking these circumstances into consideration, we developed a variation of Fischer indole synthesis that does not involve diazonium intermediate or transition metal (Scheme 1.3).[83–90] We envisioned by switching functionalities–using QMK 28 and aliphatic hydrazine 29–a 1,2 addition product 30 could be formed. After aromatization and isomerization, an arylhydrazone intermediate 32 could be formed and eventually give indole 34 as ﬁnal product after [3,3]-sigmatropic 8 CHAPTER 1. DOUBLE MICHAEL ADDITION

Conventional Fischer indole synthesis

1 R1 R + acid NH2 R2 N O R2 H N H

Our work:

OMe OMe OMe 1,2-addition H dehydration R R O H R O 28 HN N NH R1 + N H R1 30 1 31 2 29 R2 R R 2 H2NHN R aromatization Pyr HCl one-pot CHCl3

1 MeO 1 R R 2 MeO R isomerization N N R1 R2 NH N N 32 R2 34 H 33 H

Scheme 1.3: Variation of Fischer indole synthesis rearrangement. The ideal reaction condition was optimized after extensive experimentation and 27 indole products were prepared via this strategy.

1.3 Discovery of the Hetero Double-Michael Addition Reaction of

QMK

QMK can undergo either 1,2[13], 1,4[16, 83–90] or SN2’ nucleophilic additions[12] with a variety of nucleophiles (O, N, S, C, etc). A question occurred to us: what would a reaction of QMK and

N-substituted hydroxyl amine produce (Scheme 1.4)? In our indole synthesis, reaction of QMK with aliphatic hydrazine would give 1,2-addition product, hydrazones. Ciufolini reported the a range of 1,4-addition products of QMK and aliphatic primary amines.[21] In the case of amino alcohols, only the N-Michael addition product was isolated. He also observed that cyclic secondary 1.3. DISCOVERY OF THE HETERO DOUBLE-MICHAEL ADDITION REACTION OF QMK9 amines, such as pyrrolidine, react with QMK to give Michael addition products in high yields, while acyclic secondary amine, such as diethyl amine, does not react at all. Also, It is known that the condensation of QMK with hydroxylamine would undergo a 1,2-addition reaction and isomerization to eventually give aryl nitroso products.[91]

In the reaction of QMK with N-substituted hydroxylamines, the regioselectivity (1,2-addition or 1,4-addition) and competitive nucleophilicity between N and O need to be addressed. Following this idea, QMK 1 and N-benzyl hydroxylamine hydrochloride (BnNHOH·HCl) were chosen as our candidates. Gratifyingly, we soon found that when using acetonitrile as solvent in the presence of

Nu Literature reported products

O RNHNH2 1,2-addition

N 1,4-addition HO NH2 MeO OMe H N 1 1,4-addition

RNHOH Et Et ? N No reaction H

NH2OH 1,2-addition

Anticipated products:

O R O N O OH N R O NH MeO OMe R MeO OMe MeO OMe 35 36 37 1,2-addition N-1,4-addition O-1,4-addition

Experimental result: Bn N O O BnNHOH HCl O DBU MeO MeCN OMe 38 MeO OMe 97 % yield bridged isoxazolidine 1 product

Scheme 1.4: Discovery of the hetero double Michael addition reaction 10 CHAPTER 1. DOUBLE MICHAEL ADDITION

DBU (2 eq), a white solid product was isolated in high yield. The 1H NMR and 13C NMR spectra of this compound, however, do not ﬁt any of the proposed structures of 35, 36 or 37. A careful examination of the spectra revealed the compound to be isoxazolidine 38, which is the N,O-double

Michael addition product of the BnNHOH to QMK 1.

1.4 Conventional Isoxazolidine Synthesis

Isoxazolidine is conventionally synthesized from the 1,3-dipolar cycloaddition reaction between a nitrone and an alkene (Scheme 1.5).[92–99] It is a powerful synthetic intermediate to produce complex heterocyclic structures. For intermolecular nitrone-alkene cycloadditions, the nitrone 39 and alkene 40 can approach each other in two regio-selective arrangements and in either exo or endo fashion, giving 4 possible products, 41, 42, 43 and 44. Similarly, the regio-selective intramolecular cycloaddition of nitrone and alkene 45, can give either fused structure 46 or bridged structure

47[100–102], which can equilibrate under thermal conditions.[103, 104] Regarding the regioselectivity and stereoselectivity of intermolecular and intramolecular nitrone-alkene cycloadditions, much

Intermolecular nitrone-alkene cycloaddition R R endo R2 N R2 N O + O R R1 R1 R2 N O R3 R3 1 41 42 R 39 + R R 3 R R2 N R2 N O + O 40 R1 R1 exo R3 R3 43 44 Intramolecular nitrone-alkene cycloaddition

R R R N N N O O O and/or 45 46 47

Scheme 1.5: Intermolecular and intramolecular nitrone-alkene cycloaddition 1.4. CONVENTIONAL ISOXAZOLIDINE SYNTHESIS 11 research has been done to allow the prediction of the major products of a particular reaction based upon the electronic characteristics and substitution patterns of both the nitrone and alkene.[105,

106]

Isoxazolidines are associated with a range of bioactivities and many isoxazolidine containing compounds are being screened in drug discovery.[107–109] Moreover, natural products that contain isoxazolidines were isolated from marine sponges[110, 111] and plants[112]. Equally important, reductive cleavage[113, 114] of the N-O bond of isoxazolidine would produce 1,3-syn-amino alcohols[115], which are present in a number of valuable bioactive compounds (Figure 1.2). For example, N-octyl-4-epi-β-valienamine (NOEV) and its analogues are glucosidase inhibitors that serve as key targets in diabetes research.[116] Cortistatin A, as a potent anti-cancer drug candi- date, inhibits the proliferation of human umbilical vein endothelial cells (HUVECs, IC50) at 1.8 nM, with no evident toxicity toward healthy cells.[117] Tamiflu is the first commercial developed orally administered neuraminidase inhibitor, and is a common antiviral medication for swine flu and bird flu.[118, 119]

OH CO2Et OH HO Me N HO

( )7 Me O H HO N H2N O H Me N H OH NHAc 2

N-octyl-4-epi- Tamiflu Cortistatin A β-valienamine

Figure 1.2: 1,3-syn-amino alcohol containing bioactive compounds

The formerly discovered N,O-double Michael addition reaction could provide an alternative to isoxazolidine synthesis. Such reaction scheme was not reported before; however, we found, in one literature report, hydroxylamine reacted with santonin to aﬀord an isoxazolidine side product through a double conjugate addition.[120] With this serendipitous result in hand, the scope and practicality of the N,O-double Michael addition reaction between QMK and N-substituted 12 CHAPTER 1. DOUBLE MICHAEL ADDITION hydroxylamines need to be explored.

1.5 Isoxazolidine Synthesis via Double Michael Addition

In the screening of reactions, unsubstituted QMKs with mixed ketal moiety or spiral ketal moiety and 2 or 3 mono-substituted QMKs were used. Commercially available hydroxylamines, such as

BnNHOH, BocNHOH, AcNHOH and MeNHOH were subjected to the double Michael protocol.

Among them, BnNHOH and BocNHOH give good yields reacting with QMK. Since Bn and Boc are common protecting groups, in this study these two N-substituted hydroxylamines were chosen to test the generality of the double Michael addition reaction.

1.5.1 Synthesis of isoxazolidines from 2,3-unsubstituted QMKs

Overall, BnNHOH or BocNHOH react with 2,3-unsubstituted QMKs to give excellent yields, while

AcNHOH and MeNHOH give lower reaction yields (Table 1.1). QMKs with mixed ketal moiety,

57, 60, and 63, would give a pair of facial isomers and the major product is the one that formed

Table 1.1: Synthesis of isoxazolidines from 2,3-unsubstituted QMKs

QMK product (%yield) QMK product (%yield)

O O R 1 R 38 R = Bn, 97% N 2 N O O 58 R = Bn(1.07:1), 81% O 48 R = Boc, 99% O 3 MeO R = Boc(1.23:1), 93% MeO 49 R = Me, 62% 59 MeO OMe MeO OEt OEt 1 OMe 50 R = Ac, 76% 57

O R O nOe R N O N O 52 R =Bn, 50% O O 61 R = Bn(1.23:1), 99% EtO 53 R = Boc, 96% MeO EtO OEt 62 R = Boc(1.14:1), 86% OEt MeO OAllyl OAllyl 51 60

O R O R N O 55 R = Bn, 77% nOe N O O 64 R = Bn(1.31:1), 99% 56 R = Boc, 88% O O MeO OO 65 R = Boc(4:1), 86% O MeO OiPr 54 63 OiPr 1.5. ISOXAZOLIDINE SYNTHESIS VIA DOUBLE MICHAEL ADDITION 13 by nucleophile approaching QMK from the less sterically hindered side. This phenomenon was observed from NMR. In 1H NMR, the OMe peak is not a singlet but instead split; nOe conﬁrms that the major isomer has N,O bridge on the less hindered side of the QMK. The ratio of the two isomers was calculated from the integration of the split OMe signal in 1H NMR. It can be seen that, in the case of QMK 57, 60, and 63, with increased bulkiness, from Et to Allyl to i-Pr, the ratio of reaction product isomers (major to minor) increased correspondingly.

1.5.2 Synthesis of isoxazolidines from 2 or 3 monosubstituted QMKs

The more interesting regio-selectivity results come when screening substituted QMKs with BnNHOH and BocNHOH (Table 1.2). It was known that N-substituted hydroxylamines can behave as am- bident nuleophiles: usually alkylation would take place on nitrogen but acylation and phospho- rylation take place on oxygen.[121–123] The mono substituted QMKs only give moderate yields, however in these double Michael addition reactions, BnNHOH and BocNHOH gave opposite selec-

Table 1.2: Synthesis of isoxazolidines with regio-selectivities

N-Bn isoxazolidine QMK N-Boc isoxazolidine product(% yield) product(% yield)

Bn O O Boc N O HMBC O nOe H N H H O H MeO MeO H Me H Me OMeMe MeO OMe OMe 67 77% 66 68 40%

Bn O O Boc N O O O Me N MeO Me MeO Me

OMe MeO OMe OMe 70 42% 69 71 43%

O Boc Bn Bn O N N Cl N O O O O Cl O MeO MeO Cl + MeO Cl OMe OMe MeO OMe OMe 73 74 72 75 16% ratio = 2 : 1, overall yield =32% 14 CHAPTER 1. DOUBLE MICHAEL ADDITION tivities. BnNHOH give products that have Bn on the less hindered side of the molecule, however

BocNHOH give products that have Boc on the more hindered side of the molecule, even though Boc is a much more bulky functional group. A reaction mechanism was proposed from these results: in the reactions of BnNHOH, N would attack the less hindered side of QMK to furnish the ﬁrst

Michael addition reaction, which then delivers O to complete the second Michael addition; in the reactions of BocNHOH, the order of Michael additions is reversed. Since Boc is both bulky and electron withdrawing, in this case, O will be more nucleophilic that N. Therefore the oxygen will attack the less hindered side of the QMK to do the ﬁrst Michael addition while the nitrogen will next complete the second Michael addition on to the more hindered side of the QMK. It is worth noting that in the reaction of QMK 72 with BnNHOH, a mixture of products was formed. This is due to electron withdrawing chlorine atom, the hindered side of QMK become more electron deﬁcient and thus more reactive with nucleophile.

1.5.3 Isolation of the Mono-Michael Addition Intermediate

O Bn O BnNHOH HCl Me N O Me DBU O Bn + MeO Me HO N MeCN MeO OMe MeO OMe OMe 69 70 DBU, MeCN 76

Scheme 1.6: Isolation of the mono-Michael addition intermediate

This speculation was also further validated from the separation of a mono Michael addition product (Scheme 1.6). In the reaction of QMK 69 with BnNHOH, a N-mono Michael addition 1.6. SYNTHESIS OF FUNCTIONALIZED AMINOCYCLITOLS FROM ISOXAZOLIDINE 15 product 76 was isolated along with 70. When 76 is treated with base, the double Michael addition product 70 could be formed. The structures of these compounds were conﬁrmed unambiguously by x-ray diﬀraction analysis.

1.6 Synthesis of Functionalized Aminocyclitols from Isoxazolidine

O Boc two steps Boc N N O BocNHOH O O 1) NaBH 4 O O MeO DBU, MeCN Me 2)4-Br-Bz-Cl, Py O Ph-4-Br MeO OTBS O OTBS TBS 77 78 84% 79 69%

OBz-4-Br Mo(CO) 6 OBz-4-Br OBz-4-Br MeCN/H 2O reflux K2CO 3, Acetone + BocHN OH BocHN OH BocHN OTBS TBSO OMe MeO OTBS reflux O 80 % 81 % 82 91 %

1)NaBH 4 OBz-4-Br OBz-4-Br 2)Ac 2O, Et 3N + two steps BocHN OTBS BocHN OTBS OAc OAc 83 47% 84 12%

Scheme 1.7: Synthesis of aminocyclitol derivatives

Isoxazolidines are precursors to 1,3-syn amino alcohols. To showcase that the isoxazolidine framework made in this study can be applied to synthesize bioactive compounds, we designed a reaction pathway to synthesize aminocyclitols from the double Michael addition product of QMK

77and BocNHOH (Scheme 1.7). Aminocyclitols are cyclohexanes with at least 1 amino group and 3 or more hydroxyl groups on the ring.[124] A wide range of bioactivities were reported on them[125] and hence aminocyclitols are valuable targets to synthesize. Dimethoxy ketal is usually hydrolyzed under harsh acidic conditions; to circumvent this problem, a mixed silyl methoxy ketal

77 was used. By starting with 77 and applying the double Michael protocol, a pair of facial isomers 16 CHAPTER 1. DOUBLE MICHAEL ADDITION

78 was formed. Reduction of the keto group followed by acylation gave 79 in 69 % yield. Next reductive cleavage of the N-O bond by Mo(CO)6 aﬀorded a pair of column separable products 81

(67 %) and 80 (16 %). 81 was then treated with K2CO3, which afforded the trans-silylation ketone product 82 in 91 % yield. Reduction of the ketone and subsequent acetylation gave two protected aminocyclitol derivatives 83 (47 %) and C-2 epimer 84 (12 %) as a minor product. The single crystal x-ray diffraction analysis of 83 was performed to validate the stereo-confirmation of the structure.

1.7 Conclusion

In summary, we have developed an eﬃcient synthesis of bridged isoxazolidines through a double

Michael addition of QMK and N-protected hydroxylamines. This method provides an alternative to the existing nitrone-alkene [3+2] cylcoaddition synthesis of isoxazolidine. This methodology accommodates substrate-based regio-selectivity. Various functionalities in the isoxazolidines allow facile derivatization to give numerous structures. Notably bridged isoxazolidines after reductive

N-O cleavage could furnish 1,3-syn amino alcohols, which are embedded in a number of bioactive compounds. Moreover, stimulated by our result, Maruoka group has recently developed an enantioselective double Michael additions of hydroxamic acid to QIKs in the presence of a chiral boronic acid, which further aﬃrmed the utility of our developed method.[126] 1.8. EXPERIMENTAL SECTION 17

1.8 Experimental Section

General Information

Anhydrous acetonitrile was distilled from CaCl2 under an atmosphere of argon. The reactions were run under argon and solvents were degassed with bubbling argon as well. All reagents were purchased from commercial sources or synthesized using literature methods. 1H and 13C NMR spectra were recorded on BRUKER 500 MHz spectrometers. Chemical shifts (δ values, ppm) were

1 13 reported in ppm downﬁeld from internal TMS ( H NMR) or CDCl3 ( C NMR), respectively. All mass spectra were run by Dr. Cliﬀ Soll at the Hunter College Mass Spectrometry Facility and taken on an Agilent 6520A Q-TOF using electrospray ionization and Dr. Lijia Yang at City College on an Applied Biosystems 4000 QTRAP spectrometer. X-ray crystallography was performed on a

Bruker AXS SMART APEXII Single Crystal Diﬀractometer by Dr. Chunhua Hu at Department of Chemistry of New York University. All infrared spectra were taken on a Thermo Nicolet IR100 spectrometer. Column chromatography was performed over silica with a porosity of 60 Å and a particle size of 40-63 µm.

1.8.1 Preparation of Quinone Monoketals

Qunione monoketals were made from oxidation of phenols by phenyliodoso diacetate (PIDA) following general procedures of Tamura, Pelter and Taylor2, and veriﬁed by 1H and 13C NMR. General scheme as follows:

OH O PIDA R R MeOH OMe MeO OMe

77 is a known compound which was previously made by anodic oxidation(J. Org. Chem., 1987,

52 (13), pp 2763 – 2768), herein we applied the same protocol as above to give 77 in 80% yield. 18 CHAPTER 1. DOUBLE MICHAEL ADDITION

OH O PIDA (1.2eq) MeOH

OTBS MeO OTBS 77

4-((tert-butyldimethylsilyl)oxy)-4-methoxycyclohexa-2,5-dienone(77): 8.5 g TBS mono-protected hydroquinone (37.9 mmol, 1 eq) was dissolved in 50 mL MeOH and stirred at 0◦C for 10 min. To this solution, 14.6 g PIDA (45.5 mmol, 1.2 eq) was slowly added in small portions. TLC monitoring shows reaction complete in 1 hr and hence the reaction was quenched with saturated NaHCO3, extracted with DCM for 3 times. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂush chromatography

(EtOAc: Hexane, 1:20 to 1:10) to give product 77 as a liquid 8.19 g.

1 80 % yield; H NMR (500 MHz, CDCl3) δ 6.71 (d, J = 10.0 Hz, 2 H), 6.18 (d, J = 10.0 Hz, 2 H),

13 3.32 (s, 3 H), 0.90 (s, 9 H), 0.14 (s, 6 H); C NMR (125 MHz, CDCl3) δ 185.40, 146.36, 128.17,

90.93, 50.31, 25.60, 18.12, -2.86.

1.8.2 Preparation of BnNHOH Hetero Michael Addition Derivatives

All the procedures in this section follow the preparation of 38 unless elsewise stated, except in small variations of polarity of solvent for ﬂash column chromatography.

O Bn N O BnNHOH HCl (1.2 eq) O DBU (2 eq) MeO MeO OMe MeCN OMe 1 38

7-benzyl-8,8-dimethoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(38):

BnNHOH·HCl (160 mg, 1.00 mmol, 1.2 eq) was added into a solution of quinone monoketal 1 (128 mg, 0.83 mmol, 1.0 eq) in 2 mL MeCN at room temperature. To the solution, DBU (252 mg, 1.66 1.8. EXPERIMENTAL SECTION 19 mmol, 2.0 eq) was slowly added and the reaction was stirred under Argon for 1 hr. Solvent was removed under reduced pressure and the crude product was puriﬁed with (EtOAc: Hexane, 1:10 to

1:4) to give product 38 as a white solid 244 mg.

◦ 1 97 % yield; mp 72-74 C; H NMR (500 MHz, CDCl3) δ 7.38 - 7.25 (m, 5 H), 4.53 (s, 1 H), 4.34

(d, J = 13.0 Hz, 1 H), 4.13 (d, J = 12.5 Hz, 1 H), 3.45 (s, 3 H), 3.40 (s, 1 H), 3.34 (s, 3 H), 2.70 -

13 2.61 (m, 2 H), 2.57-2.49 (m, 2 H); C NMR (125 MHz, CDCl3) δ 207.68, 137.19, 128.89, 128.51,

127.49, 108.90, 73.40, 62.38, 59.65, 51.59, 49.54, 45.47, 45.28; IR (KBr disk) ν 2962, 1719, 1457,

1393, 1348, 1138, 1090; HRMS m/z Calcd C15H20NO4+ (M+H)+: 278.1392, Found: 278.1388.

O Bn N O BnNHOH HCl (1.2 eq) O DBU (2 eq) EtO EtO OEt MeCN OEt 51 52

7-benzyl-8,8-diethoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(52). Procedure was used as described above for compound 38. The crude product was puriﬁed by ﬂash column chromatography (SiO2,

1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 50 % yield; mp 53-55 C; H NMR (500 MHz, CDCl3) δ 7.37-7.24 (m, 5 H), 4.53 (t, J = 2.5

Hz, 1 H), 4.36 (d, J = 12.5 Hz, 1 H), 4.16 (d, J = 12.5 Hz, 1 H), 3.75-3.63 (m, 3 H), 3.47 (m, 1

H), 3.41 (t, J = 2.5 Hz, 1 H), 2.65 (m, 2 H), 2.52 (m, 2 H), 1.37 (t, J = 7.0 Hz, 3 H), 1.20 (t, J =

13 7.0 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 207.96, 137.33, 128.94, 128.48, 127.45, 108.34, 73.90,

62.49, 60.20, 59.86, 57.66, 45.66, 45.45, 15.41, 15.05; IR (KBr disk) ν 2975, 1719, 1458, 1398, 1343;

HRMS m/z Calcd C17H24NO4+ (M+H)+: 306.1705, Found: 306.1701.

O Bn N O BnNHOH HCl (1.2 eq) O DBU (2 eq) O OO MeCN O 54 55 20 CHAPTER 1. DOUBLE MICHAEL ADDITION

7-benzyl-6-oxa-7-azaspiro[bicyclo[3.2.1]octane-8,2’-[1,3]dioxolan]-3-one(55). Procedure was used as described above for compound 38. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 77 % yield; mp 107-109 C; H NMR (500 MHz, CDCl3) δ 7.37-7.25 (m, 5 H), 4.36 (d, J = 12.5

Hz, 1 H), 4.24-4.20 (m, 2 H), 4.18-4.14(m, 2 H), 4.05-3.98 (m, 2 H), 3.24 (t, J = 2.5 Hz, 1 H), 2.78

(d, J = 17.5 Hz, 1 H), 2.74 (d, J = 18.0 Hz, 1 H), 2.65 (d, J = 18.0 Hz, 1 H), 2.54 (d, J = 17.0 Hz,

13 1 H); C NMR (125 MHz, CDCl3) δ 207.48, 137.06, 128.96, 128.48, 127.47, 114.29, 75.41, 65.60,

65.34, 62.15, 60.84, 46.11; IR (KBr disk) ν 2893, 1712, 1497, 1455, 1394, 1350, 1212, 1143; HRMS m/z Calcd C15H18NO4+ (M+H)+276.1236, Found: 276.1231.

O Bn Bn N BnNHOH HCl (1.2 eq) N O O DBU (2 eq) O O MeO + EtO MeO OEt MeCN OEt OMe 57 Major Minor ratio = 1.07 : 1 58

7-benzyl-8-ethoxy-8-methoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(58). Procedure was used as described above for compound 38. Major: minor = 1.07: 1(calculated based on methyl integration of two isomers in 1H NMR). The crude product which was puriﬁed by ﬂash column chromatography

(SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 81 % yield; H NMR (500 MHz, CDCl3) δ 7.37-7.24 (m, 5 H), 4.52 (s, 1 H), 4.37-4.32 (m, 1 H),

4.17-4.11 (m, 1 H), 3.73-3.69 (m, 1.5 H), 3.69-3.62 (m, 1 H), 3.50-3.46 (m, 0.5 H), 3.44 (s, 1.4 H),

3.40 (t, J = 2.5 Hz, 1 H), 3.34 (s, 1.5 H), 2.64 (m, 2 H), 2.52 (m, 2 H), 1.39 (t, J = 7.3 Hz, 1.5 H),

13 1.21 (t, J = 7.0 Hz, 1.5 H); C NMR (125 MHz, CDCl3) δ 207.76, 137.29, 137.24, 128.89, 128.86,

128.46, 127.43, 108.62, 108.58, 73.79, 73.51, 62.47, 62.35, 59.99, 59.88, 59.84, 57.73, 51.58, 49.50,

45.53, 45.34, 15.38, 15.01; IR (KBr disk) ν 2977, 1719, 1453, 1393, 1347, 1082; HRMS m/z Calcd

C16H22NO4+ (M+H)+292.1549, Found: 292.1544. 1.8. EXPERIMENTAL SECTION 21

O Bn Bn N BnNHOH HCl (1.2 eq) N O O DBU (2 eq) O O MeO + AllylO MeO OAllyl MeCN OAllyl OMe 60 Major Minor ratio = 1.23 : 1 61

8-(allyloxy)-7-benzyl-8-methoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(61). Procedure was used as described above for compound 38. Major: minor = 1.23: 1(calculated based on methyl integration of two isomers in 1H NMR). The crude product was puriﬁed by ﬂash column chromatography

(SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 52% yield; H NMR (500 MHz, CDCl3) δ 7.37-7.26 (m, 5 H), 6.06 (m, 0.4 H), 5.88 (m, 0.5 H), 5.46

(d, J = 17.3 Hz, 0.4 H), 5.29 (s, 0.5 H), 5.26 (d, J = 10.5 Hz, 0.5 H), 5.18 (d, J = 10.5 Hz, 0.6 H),

4.55 (dd, J = 10.5 Hz, J = 2.5 Hz, 1 H), 4.36 (m, 1 H), 4.22 -4.18 (m, 0.4 H), 4.17-4.13 (m, 2 H),

3.99 (m, 0.6 H), 3.46 (s, 1.6 H), 3.43 (s, 1 H), 3.35 (s, 1.3 H), 2.67 (m, 2 H), 2.53 (m, 2 H); 13C

NMR (125 MHz, CDCl3) δ 207.57, 137.22, 137.15, 133.79, 133.02, 128.91, 128.88, 128.50, 127.49,

127.48, 117.02, 116.95, 108.90, 108.75, 73.91, 73.51, 65.20, 63.30, 62.47, 62.35, 60.04, 59.88, 51.83,

49.74, 45.55, 45.33; IR (KBr disk) ν 3030, 1718, 1647, 1455, 1393, 1347, 1139, 1095; HRMS m/z

Calcd C17H22NO4+ (M+H)+304.1549, Found: 304.1544.

O Bn Bn N BnNHOH HCl (1.2 eq) N O O DBU (2 eq) O O MeO + iPr O MeO OiPr MeCN OMe 63 OiPr Major Minor ratio = 1.31 : 1 64

7-benzyl-8-isopropoxy-8-methoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(64). Procedure was used as described above for compound 38. Major: minor = 1.31: 1(calculated based on methyl integration of two isomers in 1H NMR). The crude product was puriﬁed by ﬂash column chromatography

(SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product. 22 CHAPTER 1. DOUBLE MICHAEL ADDITION

1 99 % yield; H NMR (500 MHz, CDCl3) δ 7.38-7.26 (m, 5 H), 4.58 (s, 0.4 H), 4.53 (s, 0.6 H), 4.39

(d, J = 12.5 Hz, 0.4 H), 4.33 (d, J = 12.5 Hz, 0.6 H), 4.20 (d, J = 12.5 Hz, 1 H), 4.15 (d, J =

13.0 Hz, 0.6 H), 3.95 (qn, J = 6.0 Hz, 0.6 H), 3.46 (s, 1.7 H), 3.43 (s, 0.6 H), 3.37 (s, 1.3 H), 3.35

(s, 0.4 H), 2.68-2.50 (m, 4 H), 1.38 (d, J = 6.5 Hz, 1.3 H), 1.35 (d, J = 6.0 Hz, 1.3 H), 1.27 (d,

13 J = 6.0 Hz, 1.8 H), 1.19 (d, J = 6.5 Hz, 1.8 H); C NMR (125 MHz, CDCl3) δ 207.97, 207.92,

137.45, 137.31, 129.02, 128.90, 128.50, 128.46, 127.46, 127.43, 109.29, 109.16, 74.01, 73.77, 69.21,

66.65, 62.32, 61.25, 60.60, 51.89, 49.73, 45.53, 45.50, 24.61, 23.86, 23.77, 23.61; IR (KBr disk) ν

2974, 1720, 1496, 1455, 1386, 1081; HRMS m/z Calcd C17H24NO4+ (M+H)+306.1705, Found:

306.1703.

O Bn N O BnNHOH HCl (1.2 eq) O DBU (2 eq) Me MeO MeO OMe Me MeCN OMe 66 67

7-benzyl-8,8-dimethoxy-5-methyl-6-oxa-7-azabicyclo[3.2.1]octan-3-one(67). Procedure was used as described above for compound 38. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 77 % yield; mp 90-94 C; H NMR (500 MHz, CDCl3) δ 7.37-7.26 (m , 5 H), 4.29 (d, J = 11.5 Hz, 1

H), 4.05 (d, J = 12.7 Hz, 1 H), 3.52 (s, 1 H), 3.45 (s, 3 H), 3.36 (s, 3 H), 2.70 (dd, J = 17.9 Hz, J =

13 3.1 Hz, 1 H), 2.58 (s, 2 H), 2.53 (d, J = 17.8 Hz, 1 H), 1.40 (s, 3 H); C NMR (125 MHz, CDCl3) δ

208.06, 137.09, 128.82, 128.54, 127.52, 106.50, 99.99, 81.41, 62.00, 59.27, 51.76, 50.04, 49.88, 45.66,

19.01; IR (KBr disk) ν 2946, 1669, 1453, 1103; HRMS m/z Calcd C16H22NO4+ (M+H)+292.1549,

Found: 292.1545.

O Bn O Me N O BnNHOH HCl (1.2 eq) O HO DBU (2 eq) MeO Me + N MeO OMe Bn MeCN OMe MeO OMe 69 70 76 1.8. EXPERIMENTAL SECTION 23

7-benzyl-8,8-dimethoxy-4-methyl-6-oxa-7-azabicyclo[3.2.1]octan-3-one(70). Procedure was used as described above for compound 38. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 42 % yield; mp 65-68 C; H NMR (500 MHz, CDCl3) δ 7.36-7.23 (m, 5 H), 4.31 (d, J = 12.5 Hz,

1 H), 4.30 (s, 1 H), 4.17 (d, J = 12.5 Hz, 1 H), 3.45 (s, 3 H), 3.37 (s, 1 H), 3.35 (s, 3 H), 2.59 (m,

13 1 H), 2.50 (m, 2 H), 1.21 (d, J = 7.0 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 209.84, 137.30,

128.73, 128.45, 127.36, 108.94, 78.29, 61.97, 59.92, 51.56, 49.47, 46.55, 45.06, 11.91; IR (KBr disk)

ν 2945, 1716, 1454, 1335, 1207, 1135, 1063; HRMS m/z Calcd C16H22NO4+ (M+H)+292.1549,

Found: 292.1545.

The crystal structure of 70 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 931741). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

5-(benzyl(hydroxy)amino)-4,4-dimethoxy-2-methylcyclohex-2-enone(76). Procedure: this compound was prepared from a 3 gram reaction of 2-methyl quinone monoketal 69 with BnNHOH·HCl as described above and then was purified by flash chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether). TLC with CAM stain of later fractions of double Michael product indicated a 24 CHAPTER 1. DOUBLE MICHAEL ADDITION new spot below the hetero Michael addition product. These fractions were gathered and put into a hood for one week to allow solvent evaporation and crystal formation. While diamond-shaped crystals formed give product 70, a very small amount of scale-like crystals was formed in the last few fractions and confirmed by x-ray crystallography to be 76. About 200 mg of pure product were

1 aﬀorded after rinsing the crystals with a small amount of hexane. H NMR (500 MHz, CDCl3) δ

7.35-7.25 (m, 5 H), 6.41 (s, 1 H), 4.76 (s, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 3.76 (d, J = 12.5 Hz,

1 H), 3.52 (t, J = 4.5 Hz, 1 H), 3.29 (s, 6 H), 3.05 (dd, J = 17.0 Hz, J = 4.0 Hz, 1 H), 2.75 (dd,

13 J = 17.0 Hz, J = 4.5 Hz, 1 H), 1.82 (d, J = 1.5 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 197.60,

140.11, 138.71, 137.18, 129.43, 128.39, 127.55, 97.65, 65.61, 61.52, 49.69, 48.94, 34.09, 15.75; IR

(KBr disk) ν 2941, 1715, 1453, 1332, 1174, 1162.

The crystal structure of 76 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 931740). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

O Bn Me N O HO DBU(1eq) O MeO Me N MeCN Bn MeO OMe OMe 76 70

Procedure: 25mg of single Michael product 76 was dissolved in 3 mL of MeCN. To this solution

1 eq of DBU was added and the reaction was stirred at room temperature for 1 hr. TLC with CAM 1.8. EXPERIMENTAL SECTION 25 stain showed decrease of 76 and increase of 70. Solvent was removed and 13 mg of 70 and 8 mg of 76 were aﬀorded after column chromatography (EtOAc: Hexane =1:20 to 1:4).

O Bn Bn Cl BnNHOH HCl (1.2 eq) N O O N DBU (2 eq) O Cl O MeO Cl + MeO MeO OMe MeCN OMe OMe 72 73 74 Major Minor ratio = 2 : 1

7-benzyl-4-chloro-8,8-dimethoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(73) and 7-benzyl-2-chloro-

8,8-dimethoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(74). Procedure was used as described above for compound 38. Major: minor = 2: 1(calculated based on methyl integration of two isomers in 1H

NMR). The crude product was purified by flash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired products. (Note: 73 and 74 cannot be separated by column chromatography, however after crystallization 73 can be selectively picked out from the co-crystals, which is confirmed by NMR and X-ray)

◦ 1 32 % overall yield; 73: mp 124-127 C; H NMR (500 MHz, CDCl3) δ 7.35-7.26 (m, 5 H), 4.67 (s,

2 H), 4.36 (d, J = 12.5 Hz, 1 H), 4.20 (d, J = 12.5 Hz, 1 H), 3.49 (s, 3 H), 3.41 (t, J = 2.5 Hz,

1 H), 3.38 (s, 3 H), 2.61 (dd, J = 16.5 Hz, J = 3.0 Hz, 1 H), 2.54 (dd, J = 16.5 Hz, J = 2.5 Hz,

13 1 H); C NMR (125 MHz, CDCl3) δ 199.46, 136.69, 128.94, 128.55, 127.60, 109.31, 79.16, 63.83,

61.95, 59.69, 51.81, 49.95, 44.07; IR (KBr disk) ν 2931, 1735, 1454, 1324, 1200, 1080, 1017; HRMS m/z Calcd C15H19ClNO4+ (M+H)+312.1003, Found: 312.0997.

The crystal structure of 73 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 919302). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

1 73 and 74 mixture(ratio 2:1): H NMR (500 MHz, CDCl3) δ 7.42-7.29 (m, 5 H), 4.70 (s, 1.3 H),

4.60 (s, 0.3 H), 4.55 (s, 0.3 H), 4.39 (d, J = 12.5 Hz, 0.6 H), 4.35 (d, J = 13.5 Hz, 0.3 H), 4.23 (d,

J = 12.5 Hz, 0.7 H), 4.11 (d, J = 13.0 Hz, 0.3 H), 3.63 (s, 0.3 H), 3.51 (s, 2 H), 3.49 (s, 1 H), 3.46 26 CHAPTER 1. DOUBLE MICHAEL ADDITION

(s, 1 H), 3.44 (s, 0.7 H), 3.40 (s, 2 H), 2.83 (dd, J = 17.3 Hz, J = 2.8 Hz, 0.3 H), 2.71 (dd, J =

17.3 Hz, J = 2.8 Hz, 0.3 H), 2.63 (dd, J = 16.5 Hz, J = 3.0 Hz, 0.7 H), 2.57 (dd, J = 16.8 Hz,

13 J = 1.8 Hz, 0.7 H); C NMR (125 MHz, CDCl3) δ 199.49, 199.02, 136.70, 136.43, 129.32, 128.95,

128.57, 128.28, 127.64, 127.62, 109.32, 108.93, 79.16, 74.01, 67.32, 63.85, 63.61, 63.15, 61.95, 59.70,

51.93, 51.82, 49.97, 49.78, 43.81.

1.8.3 Preparation of BocNHOH Hetero Michael Addition Derivatives

All the procedures in this section follow the preparation of 48 unless elsewise stated, except in small variations of polarity of solvent for ﬂash column chromatography.

O Boc N O BocNHOH (1.2 eq) O DBU (1 eq) MeO MeO OMe MeCN OMe 1 48

tert-butyl-8,8-dimethoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(48): BocNHOH (133 mg, 1.00 mmol, 1.2 eq) was added into a solution of quinone monoketal (128 mg, 0.83 mmol, 1.0 eq) in 2 mL MeCN at room temperature. To the solution, DBU (154 mg, 1.00 mmol, 1.2 eq) was slowly added and the reaction was stirred under Argon for 1 hr. Solvent was removed under reduced pressure and the residue was puriﬁed with (EtOAc: Hexane, 1:10 to 1:4) to give white solid

◦ 1 product 254 mg in 99% yield; mp 68-72 C; H NMR (500 MHz, CDCl3) δ 4.63 (s, 1 H), 4.56 (s,

13 1 H), 3.39 (s, 3 H), 3.36(s, 3 H), 2.75-2.59 (m, 4 H), 1.51 (s, 9 H); C NMR (125 MHz, CDCl3) δ 1.8. EXPERIMENTAL SECTION 27

205.74, 158.34, 106.87, 82.61, 74.97, 57.10, 52.02, 50.01, 44.71, 42.83, 28.10; IR (KBr disk) ν 2979,

1719, 1458, 1341, 1256, 1161; HRMS m/z Calcd C13H21NNaO6+ (M+Na)+: 310.1267, Found:

310.1260.

O Boc BocNHOH (1.2 eq) N O DBU (1 eq) O EtO EtO OEt MeCN OEt 51 53

tert-butyl-8,8-diethoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(53). Procedure was used as described above for compound 48. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 96 % yield; mp 81-84 C; H NMR (500 MHz, CDCl3) δ 4.57 (s, 2 H), 3.64-3.60 (m, 4 H), 2.74-2.61

13 (m, 4 H), 1.51 (s, 9 H), 1.26-1.21 (m, 6 H); C NMR (125 MHz, CDCl3) δ 206.04, 158.08, 106.18,

82.49, 75.56, 60.34, 58.14, 57.28, 44.87, 43.10, 28.15, 15.07, 15.02; IR (KBr disk) ν 2932, 1699,

1456, 1051; HRMS m/z Calcd C15H25NNaO6+ (M+Na)+: 338.1580, Found: 338.1599.

O Boc N O BocNHOH (1.2 eq) O DBU (1 eq) O OO MeCN O 54 56

tert-butyl-3-oxo-6-oxa-7-azaspiro[bicyclo[3.2.1]octane-8,2’-[1,3]dioxolane]-7-carboxylate(56). Pro- cedure was used as described above for compound 48. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 88 % yield; mp 98 - 101 C; H NMR (500 MHz, CDCl3) δ 4.34 (s, 2 H), 4.16-4.08 (m, 4 H),

13 2.87-2.71 (m, 4 H), 1.51 (s, 9 H); C NMR (125 MHz, CDCl3) δ 205.58, 157.12, 111.96, 82.71,

76.24, 66.37, 65.43, 58.38, 45.52, 43.66, 28.13; IR (KBr disk) ν 2970, 1716, 1477, 1164; HRMS m/z 28 CHAPTER 1. DOUBLE MICHAEL ADDITION

Calcd C13H19NNaO6+ (M+Na)+: 308.1110, Found: 308.1122.

O Boc Boc N N O O BocNHOH (1.2 eq) O O DBU (1 eq) MeO + EtO MeO OEt OMe MeCN OEt 57 Major Minor ratio = 1.23 : 1 59

tert-butyl-8-ethoxy-8-methoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(59). Proce- dure was used as described above for compound 48. Major: minor = 1.23: 1(calculated based on methyl integration of two isomers in 1H NMR). The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 93 % yield; H NMR (500 MHz, CDCl3) δ 4.58 (s, 2 H), 3.66-3.59 (m, 2 H), 3.39 (s , 1.3 H), 3.36

(s, 1.6 H), 2.74-2.61 (m ,4 H), 1.51 (s, 9 H), 1.28-1.23 (q, J = 7.0 Hz, 3 H); 13C NMR (125 MHz,

CDCl3) δ 205.86, 158.06, 106.51, 82.46, 82.44, 75.14, 60.39, 58.15, 57.14, 51.94, 49.95, 44.74, 42.94,

42.86, 28.08, 28.03, 14.99, 14.96; IR (KBr disk) ν 2980, 1716, 1457, 1369, 1255, 1164, 1058; HRMS m/z Calcd C14H23NNaO6+ (M+Na)+: 324.1423, Found: 324.1413.

Boc Boc O N BocNHOH (1.2 eq) N O O DBU (1 eq) O O MeO + AllylO MeCN OAllyl OMe MeO OAllyl Major Minor 60 ratio = 1.14 : 1 62

tert-butyl-8-(allyloxy)-8-methoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(62). Pro- cedure was used as described above for compound 48. Major: minor = 1.14: 1(calculated based on methyl integration of two isomers in 1H NMR). The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 84 % yield; H NMR (500 MHz, CDCl3) δ 5.90 (m, 1 H), 5.36 (dd, J = 17.5 Hz, J = 1.5 Hz, 0.5

H), 5.29 (dd, J = 17.0 Hz, J = 1.5 Hz, 0.6 H), 5.23-5.19 (m, 1 H), 4.67 (s, 1 H), 4.59 (s, 1 H), 4.10 1.8. EXPERIMENTAL SECTION 29

(m, 2 H), 3.40 (s, 1.4 H), 3.38 (s, 1.7H), 2.76-2.62 (m, 4 H), 1.51 (s, 9 H); 13C NMR (125 MHz,

CDCl3) δ 205.67, 158.11, 133.33, 132.62, 106.75, 106.70, 82.67, 82.63, 75.14, 65.61, 63.72, 57.32,

52.21, 50.23, 44.78, 44.77, 43.01, 42.92, 28.15, 28.09; IR (KBr disk) ν 2977, 1718, 1458, 1057, 921;

HRMS m/z Calcd C15H23NNaO6+ (M+Na)+: 336.1423, Found: 336.1428.

Boc Boc O N BocNHOH (1.2 eq) N O O O DBU (1 eq) O MeO + iPr O MeCN MeO OiPr OiPr OMe 63 Major Minor ratio = 4: 1 65

tert-butyl-8-isopropoxy-8-methoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(65). Pro- cedure was used as described above for compound 48. Major: minor = 4: 1(calculated based on integration of proton on the secondary carbon of isopropyl peak). The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 86 % yield; H NMR (500 MHz, CDCl3) δ 4.64 (s, 1 H), 4.60 (s, 1 H), 4.12 (minor, sept, J =

6.0 Hz, 0.3 H), 4.01 (major, sept, J = 6.0 Hz, 1.0 H), 3.43 (minor, s, 0.7 H), 3.38 (major, s, 3 H),

2.70 (major, m, 4H; minor, m, 1 H), 1.51 (major, s, 9 H; minor, s, 2 H), 1.25 (major, m,6 H; minor,

13 m, 1.5 H); C NMR (125 MHz, CDCl3) δ 206.06, 158.22, 107.01, 82.52, 74.90, 69.63, 58.15, 50.30,

44.99, 43.26, 28.20, 28.13, 23.75, 23.52; IR (KBr disk) ν 2977, 1715, 1456, 1056, 907; HRMS m/z

Calcd C15H25NNaO6+ (M+Na)+: 338.1580, Found: 338.1602.

O Boc O O BocNHOH (1.2 eq) N DBU (1 eq) MeO Me OMeMe MeO OMe MeCN 66 68

tert-butyl-8,8-dimethoxy-1-methyl-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(68). Pro- cedure was used as described above for compound 48. Before loading the residue to flush column, 30 CHAPTER 1. DOUBLE MICHAEL ADDITION it was first extracted with dichloromethane and 1 M HCl solution, then the organic layer was washed with brine and dried over Na2SO4. The crude product then was purified by flash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

1 40 % yield; H NMR (500 MHz, CDCl3) δ 4.53 (t, J = 2.8 Hz, 1 H), 3.47 (s, 3 H), 3.46 (s, 3

H), 3.19 (d, J = 18.0 Hz, 1 H), 2.80 (dd, J = 17.5 Hz, J = 2.0 Hz, 1 H), 2.72 (d, J = 17.5 Hz, 1

13 H), 1.63 (s, 3 H), 1.47 (s, 9 H); C NMR (125 MHz, CDCl3) δ 205.45, 154.05, 105.45, 82.31, 72.86,

65.24, 50.33, 50.28, 47.30, 44.57, 28.30, 19.35; IR (KBr disk) ν 3325, 2979, 1723,1456, 1369, 1167;

HRMS m/z Calcd C14H23NNaO6+ (M+Na)+: 324.1423, Found: 324.1420.

O O Boc BocNHOH (1.2 eq) O Me N DBU (1 eq) MeO Me MeCN OMe MeO OMe 69 71

tert-butyl-8,8-dimethoxy-2-methyl-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(71). Pro- cedure was used as described above for compound 48. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

The crystal structure of 71 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 919301). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html 1.8. EXPERIMENTAL SECTION 31

◦ 1 43 % yield; mp 130-134 C; H NMR (500 MHz, CDCl3) δ 4.55 (s, 2 H), 3.41 (s, 3 H), 3.36

13 (s, 3 H), 2.68 (m, 3 H), 1.51 (s, 9 H), 1.20 (d, J = 7.0 Hz, 3 H); C NMR (125 MHz, CDCl3) δ

207.80, 159.04, 106.64, 82.47, 75.35, 62.81, 51.97, 49.88, 44.58, 44.50, 28.10, 12.12; IR (KBr disk)

ν 2977, 1716, 1458, 1344, 1161, 1066; HRMS m/z Calcd C14H23NNaO6+ (M+Na)+: 324.1423,

Found: 324.1416.

O Boc O Cl BocNHOH (1.2 eq) N O DBU (1 eq) MeO Cl OMe MeO OMe MeCN 72 75

tert-butyl-2-chloro-8,8-dimethoxy-3-oxo-6-oxa-7-azabicyclo[3.2.1]octane-7-carboxylate(75). Pro- cedure was used as described above for compound 48. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

The crystal structure of 75 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 919300). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

◦ 1 16 % yield; mp 124-127 C; H NMR (500 MHz, CDCl3) δ 4.86 (s, 1 H), 4.69 (d, J = 2.5 Hz, 32 CHAPTER 1. DOUBLE MICHAEL ADDITION

1 H), 4.59 (s, 1 H), 3.45 (s, 3 H), 3.39 (s, 3 H), 2.92 (dd, J = 17.5 Hz, J = 4.0 Hz, 1 H), 2.70 (d, J

13 = 17.5 Hz, 1 H), 1.52 (s, 9 H); C NMR (125 MHz, CDCl3) δ 197.78, 106.98, 83.19, 75.44, 64.30,

61.10, 52.29, 50.40, 43.60, 28.04; IR (KBr disk) ν 2983, 1742, 1458, 1346, 1247, 1157; HRMS m/z

Calcd C13H20ClNNaO6+ (M+Na)+: 344.0877, Found: 344.0860.

1.8.4 Preparation of MeNHOH Hetero Michael Addition Derivatives

O Me MeNHOH HCl (1.2 eq) N O DBU (2 eq) O MeO MeCN MeO OMe OMe 1 49

8,8-dimethoxy-7-methyl-6-oxa-7-azabicyclo[3.2.1]octan-3-one(49). MeNHOH·HCl (46 mg, 0.55 mmol, 1.2 eq) was added into a solution of quinone monoketal (70 mg, 0.45 mmol, 1.0 eq) in 2 mL

MeCN at room temperature. To the solution, DBU (166 mg, 1.09 mmol, 2.0 eq) was slowly added and the reaction was stirred under Argon for 1 hr. Solvent was removed under reduced pressure and the residue was puriﬁed with (EtOAc: Hexane, 2:1) to give product 49 as oil 56 mg.

1 62 % yield; H NMR (500 MHz, CDCl3) δ 4.46 (s, 1 H), 3.41 (s, 3 H), 3.36 (s, 3 H), 3.31 (s, 1

13 H), 2.85 (s, 3 H), 2.67-2.57 (m, 4 H); C NMR (125 MHz, CDCl3) δ 207.46, 108.93, 73.62, 62.40,

51.56, 49.49, 46.40, 45.27; IR (KBr disk) ν 2963, 1716, 1459, 1393, 1348, 1090; HRMS m/z Calcd

C9H16NO4+ (M+H)+202.1079, Found: 202.1070.

1.8.5 Preparation of AcNHOH Hetero Michael Addition Derivatives

Ac O N O AcNHOH (1.2 eq) O DBU (1.2 eq) MeO

MeO OMe MeCN OMe 1 50

7-acetyl-8,8-dimethoxy-6-oxa-7-azabicyclo[3.2.1]octan-3-one(50). AcNHOH (70 mg, 0.93 mmol, 1.8. EXPERIMENTAL SECTION 33

1.2 eq) was added into a solution of quinone monoketal (120 mg, 0.78 mmol, 1.0 eq) in 2 mL MeCN at room temperature. To the solution, DBU (142 mg, 0.93 mmol, 1.2 eq) was slowly added and the reaction was stirred under Argon for 1 hr. Solvent was removed under reduced pressure and the residue was puriﬁed with (EtOAc: Hexane, 2:1) to give white solid product 50 (150 mg).

◦ 1 76 % yield; mp 84-87 C; H NMR (500 MHz, CDCl3) δ 4.81 (s, 1 H), 4.50 (s, 1 H), 3.32 (s, 3

13 H), 3.27 (s, 3 H), 2.69-2.58 (m, 4 H), 2.03 (s, 3 H); C NMR (125 MHz, CDCl3) δ 205.24, 174.28,

106.09, 75.49, 54.51, 51.93, 50.07, 44.61, 42.47, 20.16; IR (KBr disk) ν 2949, 1721, 1685, 1351, 1214,

1095; HRMS m/z Calcd C10H15NNaO5+ (M+H)+252.0848, Found: 252.0856.

1.8.6 Synthesis of Aminocyclitol Derivatives

O Boc Boc BocNHOH (1.2 eq) N O N O DBU (1 eq) O O O + O Me TBS MeCN MeO OTBS O O TBS Me 77 Major Minor ratio = 5 : 1 78

tert-butyl-8-((tert-butyldimethylsilyl)oxy)-8-methoxy-3-oxo-6-oxa-7-azabicyclo [3.2.1]octane-7 - carboxylate (78). Major: minor = 5: 1(calculated based on methyl integration of two isomers in 1H

NMR). Procedure was used as described above for compound 48. The crude product was puriﬁed by ﬂash column chromatography (SiO2, 1:10 to 1:4, ethyl acetate: petroleum ether) to give the desired product.

◦ 1 84 % yield; mp 90-94 C; H NMR (500 MHz, CDCl3) δ 4.59 (s, 2 H), 3.44 (s, 0.5 H), 3.40

(s, 2.5 H), 2.79-2.65 (m, 4 H), 1.51 (s, 9 H), 0.94 (s, 1.4 H), 0.88 (s, 7.7 H), 0.24 (s, 0.5 H), 0.24

13 (s, 2.5 H), 0.23 (s, 0.5 H), 0.21 (s, 2.5 H); C NMR (125 MHz, CDCl3) δ 206.17, 205.68, 157.55,

105.18, 104.57, 82.48, 75.32, 59.40, 52.13, 51.26, 45.12, 45.01, 43.99, 43.30, 28.30, 28.13, 25.74,

17.99, -2.97, -3.31, -3.39, -3.65; IR (KBr disk) ν 2932, 1723, 1392, 1256, 1163, 1099; HRMS m/z 34 CHAPTER 1. DOUBLE MICHAEL ADDITION

Calcd C18H33NNaO6Si+ (M+Na)+: 410.1975, Found: 410.1975.

Boc Boc N O O N O 1) NaBH O O 4 Me MeO O Ph-4-Br O 2)4-Br-BzCl, pyridine, reflux TBS OTBS 78 79

tert-butyl-3-(4-bromo-benzoyloxy)-8-((tert-butyldimethylsilyl)oxy)-8-methoxy-6-oxa-7-azabicyclo

[3.2.1]octane-7-carboxylate((±)-79): To a solution of 78 (50 mg, 0.12 mmol, 1 eq) in 10 mL methanol add NaBH4 (6 mg, 0.14 mmol, 1.2 eq). TLC monitoring showed reaction ﬁnish in 20 minutes. Reaction was then concentrated under vacuum and puriﬁed with chromatography (EtOAc:

Hexane, 1:4) to give gross intermediate product as liquid. Then to the solution of intermediate product dissolved in 3 mL of freshly distilled pyridine add 4-bromo benzoyl chloride (31 mg, 0.14 mmol, 1.2 eq). The reaction was reﬂuxed under Argon for 1 hr. Reaction solution was washed with

1 M HCl, saturated NaHCO3 and brine, dried over Na2SO4 and then concentrated and puriﬁed with (EtOAc: Hexane, 1:15) to give 49 mg product.

◦ 1 69 % yield; mp 52-55 C; H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 9.0 Hz, 2 H), 7.57 (d,

J = 8.5 Hz, 2 H), 5.49 (m, 1 H), 4.44 (s, 2 H), 3.37 (s, 1 H), 3.34 (s, 3 H), 2.49 (m, 2 H), 2.04

13 (m, 2 H), 1.56 (s, 9 H), 0.99 (s, 9 H), 0.23 (s, 3 H), 0.20 (s, 3 H); C NMR (125 MHz, CDCl3)

δ 164.78, 158.21, 156.81, 131.67, 131.50, 131.04, 129.23, 127.99, 104.29, 82.07, 68.04, 61.49, 60.04,

50.59, 50.41, 33.16, 31.55, 28.32, 28.17, 25.95, 25.89, 18.17, 18.02, -3.21, -3.45; IR (KBr disk) ν

2955, 1720, 1367, 1270, 1169, 1103; HRMS m/z Calcd C25H38BrNNaO7Si+ (M+Na)+: 594.1499,

Found: 594.1492.

Boc OBz-4-Br OBz-4-Br N O O Mo(CO)6, MeCN/H2O = 10:1 MeO O Ph-4Br + reflux OTBS BocHN OH BocHN OH MeO OTBS TBSO OMe 79 81 80 1.8. EXPERIMENTAL SECTION 35

To a solution of 79 (120 mg, 0.20 mmol, 1.0 eq) in 10 mL MeCN and 1 mL H2O add Mo(CO)6 (80 mg, 0.15 mmol, 1.5 eq). Reaction was refluxed for 2 hrs until TLC show reaction finished. Reaction solution was first filtered through a short plug of silica gel with EtOAc and then concentrated under vacuum. The residue was purified with (EtOAc: Hexane, 1:20) to give 80 mg major product 81 and 19 mg minor product 80.

3-((tert-butoxycarbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxy-4- methoxycyclohexyl-p-bromo-benzoate ((±)-81, major product): 67 % yield; mp 56-60 ◦C; 1H NMR

(500 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H), 5.73 (s, 1 H), 5.43 (m, 1

H), 4.12 (m, 1 H), 3.94 (s, 1 H), 3.36 (s, 3 H), 2.49 (s, 1 H), 2.25 (m, 1 H), 2.09 (m, 1 H), 2.05 (m

,1 H), 1.98 (m, 1 H), 1.44 (s, 9 H), 0.94 (s, 9 H), 0.20 (s, 3 H), 0.17 (s, 3 H); 13C NMR (125 MHz,

CDCl3) δ 165.15, 155.10, 131.68, 131.15, 129.34, 128.02, 97.67, 79.52, 74.10, 67.25, 51.72, 49.87,

34.19, 33.71, 28.42, 25.88, 18.46, -2.38, -3.41; IR (KBr disk) ν 3420, 2954, 1717, 1502, 1366, 1273,

1171, 1115; HRMS m/z Calcd C25H40BrNNaO7Si+ (M+Na)+: 596.1655, Found: 596.1650.

3-((tert-butoxycarbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxy-4- methoxycyclohexyl-p-bromo-benzoate ((±)-80, minor product): 16 % yield; 1H NMR (500 MHz,

CDCl3) δ 7.92 (d, J = 8.5 Hz, 2 H), 7.56 (d, J = 8.5 Hz, 2 H), 5.87 (s, 1 H), 5.28 (s, 1 H), 3.99 (s, 1

H), 3.83 (s, 1 H), 3.42 (s, 3 H), 2.51 (s, 1 H), 2.26 (m, 1 H), 2.14 (m, 3 H), 1.34 (s, 9 H), 0.91 (s, 9 H),

13 0.19 (s, 3 H), 0.16 (s, 3 H); C NMR (125 MHz, CDCl3) δ 165.01, 155.05, 131.67, 131.26, 129.42,

127.99, 97.86, 79.23, 72.83, 68.35, 50.58, 49.77, 32.82, 32.45, 28.35, 25.84, 18.45, -2.52, -3.45; ; IR

(KBr disk) ν 3423, 2954, 1714, 1503, 1366, 1273, 1114; HRMS m/z Calcd C25H40BrNNaO7Si+

(M+Na)+: 596.1655, Found: 596.1657.

OBz-4-Br OBz-4-Br

K2CO3, Acetone reflux BocHN OH BocHN OTBS MeO OTBS O 81 82 36 CHAPTER 1. DOUBLE MICHAEL ADDITION

3-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-4-oxocyclohexyl-p-bromo- benzoate((±)-

82). K2CO3 (138 mg, 1.00 mmol, 1.0 eq) was added to a solution of 81 (610 mg, 1.03 mmol, 1.0 eq) in acetone. The reaction was reﬂuxed under Argon for 1 hr. Solvent was removed under reduced pressure and the residue was puriﬁed with (EtOAc: Hexane, 1:4) to give a solid product.

◦ 1 91 % yield; mp 201-204 C; H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.5 Hz, 2 H), 7.62 (d, J

= 8.5 Hz, 2 H), 5.52 (m, 2 H), 4.70 (m , 2 H), 2.87 (m, 1 H), 2.65 (m, 1 H), 2.05 (m, 1 H), 1.74

13 (m, 1 H), 1.44 (s, 9 H), 0.89 (s, 9 H), 0.12 (s, 3 H). 0.03 (s, 3 H); C NMR (125 MHz, CDCl3)

δ 204.90, 164.84, 155.16, 131.99, 131.17, 128.67, 128.62, 80.04, 72.61, 68.20, 53.82, 41.64, 39.33,

28.33, 25.69, 18.45, -4.72, -5.32; IR (KBr disk) ν 2930, 1712, 1509, 1272, 1165; HRMS m/z Calcd

C24H37BrNO6Si+ (M+H)+542.1574, Found: 542.1566.

OBz-4-Br OBz-4-Br OBz-4-Br

1) NaBH 4 + BocHN OTBS BocHN OTBS 2) Et3N, (AcO)2O, reflux BocHN OTBS O OAc OAc 82 83 84

To a solution of 82 (80 mg, 0.15 mmol, 1.0 eq) in methanol, NaBH4 (7 mg, 0.18 mmol, 1.2 eq) was slowly added at room temperature. TLC monitoring showed reaction ﬁnished in 10 minutes.

Solvent was removed under reduced pressure and purified with (EtOAc: Hexane, 1:1) to afford gross product 64 mg. The gross product was dissolved in 4 mL dry Et3N and 1 mL (AcO)2O was added to the solution. Reaction was refluxed for 1 hr under Argon. Solvent was removed under reduced pressure and the residue was purified with (EtOAc: Hexane, 1:20 to 1:4) to give two products: major product 83 42 mg (47 % yield) and minor product 84 11 mg (12 % yield).

4-acetoxy-3-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy) cyclohexyl-p-bromo-benzoate((±)-83, major product): 47% yield; mp 52-55 ◦C; 1H NMR (500

MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2 H), 7.60 (d, J = 8.5 Hz, 2 H), 5.41 (s, 1 H), 4.98 (s, 1 H), 1.8. EXPERIMENTAL SECTION 37

4.74 (t, J = 8.0 Hz, 1 H), 4.09 (m, 2 H), 2.23 (m, 1 H), 2.14 (m, 1 H), 2.10 (s, 3 H), 1.84 (t, J =

10.0 Hz, 1 H), 1.76 (t, J = 10.0 Hz, 1 H), 1.42 (s, 9 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.06 (s, 3 H);

13 C NMR (125 MHz, CDCl3) δ 170.73, 164.88, 155.19, 131.84, 131.12, 129.00, 128.30, 79.55, 76.34,

68.80, 68.27, 48.62, 36.95, 34.77, 28.33, 25.59, 21.09, 17.86, -4.80, -4.99; IR (KBr disk) ν 2930, 1722,

1590, 1512, 1392, 1241, 1170, 1097; HRMS m/z Calcd C26H40BrNNaO7Si+ (M+Na)+: 608.1655,

Found: 608.1661.

The crystal structure of 83 has been deposited at the Cambridge Crystallographic Data Centre

(CCDC 921687). The data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

4-acetoxy-3-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)

1 cyclohexyl-p-bromo-benzoate((±)-84, minor product): 12% yield; H NMR (500 MHz, CDCl3) δ

7.87 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 5.66 (s, 1 H), 5.46 (sept, J = 4.3 Hz, 1 H),

4.98 (s, 1 H), 4.25 (m, 2 H), 2.18 (m, 2 H), 2.10 (s, 3 H), 1.90 (m, 1 H), 1.77 (t, J = 10.0 Hz, 1

13 H), 1.44 (s, 9 H), 0.94 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H); C NMR (125 MHz, CDCl3) δ 170.16,

165.03, 155.60, 131.75, 131.09, 129.13, 128.17, 79.27, 71.81, 69.40, 67.40, 47.77, 36.26, 34.14, 28.35,

25.66, 21.03, 17.99, -5.02, -5.19; IR (KBr disk) ν 3422, 2955, 1717, 1505, 1392, 1251, 1172; HRMS m/z Calcd C26H40BrNNaO7Si+ (M+Na)+: 608.1655, Found: 608.1657. 38 CHAPTER 1. DOUBLE MICHAEL ADDITION Chapter 2 o-Chlorination

39 40 CHAPTER 2. O-CHLORINATION

Quinone monoketal (QMK) has been used as building blocks in organic synthesis in numerous ways, since a diversity of natural products possess aromatic or quinoid nucleus, which can be constructed readily from quinone monoketals.[127–130] The inherent α, β- unsaturated carbonyl template and the ketal moiety entails its richness in chemistry, such as 1,2-addition, 1,4-addition and allylic substitution reaction to the α position of carbonyl group. In chapter 1, we described a general methodology to make bridged isoxazolidines from a hetero double-Michael addition of

N-substituted hydroxylamines to QMK.

The double Michael addition reaction of QMK is rarely studied. Previous to our report, one of such reactions was reported by Aube group (Scheme 2.1).[15] Under basic conditions, ethyl acetoacetate 86 can either do a C,O-double Michael addition or C,C-double Michael addition to

Me O O O 86 O CO2Et EWG OEt EtO OH KO-t-Bu, THF EWG EtO OEt OEt 85 87 EWG = CO2Me, C(O)NHPh Aubé, J.Org. Lett. 2005, 7 (15), 3167-3170.

EtO C O O 2 NO2 O EtO NO2 MeO EtO OEt LDA OMe 51 88

Me Alloc O OAc N N Me

13 steps, 9.2 % yield O N N H according to Fukuyama's t-BuO2C O 89 work MOM gelsemine Formal synthesis intermediate

Aube, J. Org. Lett. 2007, 9 (16), 3153-6. Fukuyama, T. J. Am. Chem. Soc., 1996, 118 (31), 7426-7427.

Scheme 2.1: Double hetero-Michael addition reaction reported by Aube group 2.1. DISCOVERY OF THE O-CHLORINATION REACTION 41

QMK 85, depending on the electron withdrawing group on the α carbon of QMK. Subsequently they used this strategy in a formal synthesis of a complex natural product–gelsemine.[131] The unique polycyclic structure of gelsemine has attracted signiﬁcant amount of attention from the synthetic community.[132–134] In Aube’s synthesis, ethyl 3-nitropropionate and QMK 51 was used to construct a bridged molecule 88 through a C,C-double Michael addition. This molecule 88, which bears a gelsemine core, was converted into an advanced intermediate 89 in Fukuyama’s total synthesis of gelsemine.[134] Hetero-double Michael addition reaction of QMK can produce heterocyclic structures of pharmaceutical interests or synthetic value. To explore the potential of this, we envisioned a reaction scheme of N,N-double Michael addition.

2.1 Discovery of the o-Chlorination Reaction

The possibility of N,N-double-Michael addition of N,N-disubstituted hydrazines to quinone monoketals under the same conditions to N,O-double Michael addition reaction was ﬁrst attempted. How- ever to our surprise, when N,N-dimethyl hydrazine hydrochloride 90 and QMK 1 was treated with

DBU in MeCN, the anticipated double-Michael addition product 91 was not formed. The majority of 1 did not react, and under TLC and CAM stain a less polar product was observed. This product was isolated and characterized as 2-chloro-4-methoxy-phenol 92 (2 % yield). The reaction was repeated a number of times and we found this product only forms when DBU was added last in the reaction. Soon we found DBU is not needed in the reaction to form 92; once DBU was added,

O Me OH N N N 2HCl Me O Cl H H (1.2 eq) N 90 MeO DBU (3 eq) MeO OMe OMe OMe 1 MeCN 91 92 not found only product

Scheme 2.2: Discovery of the o-chlorination reaction 42 CHAPTER 2. O-CHLORINATION the reaction will be quenched. Without base, the reaction of QMK 1 and N,N-dimethyl hydrazine hydrochloride 90 gave 92 in 82 % yield at room temperature. Evidently the accompanying HCl salt of the 90 not only provides a chloride as nucleophile, but also provides a mild acidic pH to allow the reaction happen. This goes well in accordance with the literature reported allylic substitution

(SN2’) to the 2 position of QMK while under basic conditions, nucleophiles usually attack the 3 position of the QMK and carbonyl in the case of hydrazine or unsubstituted hydroxylamine.

2.2 Reaction Condition Optimization

Table 2.1: Screening of the chloride source

O OH chloride source Cl

MeCN MeO OMe OMe 1 92

Entry Chloride Temperature(°C) Time Yield (%)

1 90 25 1h 82 2 93 25 1h 80 3 94 25 1h 62 4 95 25 1h 56 5 HCl (1M) 25 1h 55 6 90 reflux 20 min 99 7 Pyr·HCl reflux 1h 83 8 TMSCl reflux 1h 32

9 Et3N·HCl reflux 1h 0 10 TBAC reflux 1h 0

11 ZnCl2 reflux 1h 0

MeNHNHMe•2HCl MeONHMe•HCl NH2NH2•HCl sec-BuNHNH2•2HCl 90 93 94 95

With this interesting result, next we directed our attention to reaction condition optimization

(Table 2.1). First a number of different hydrochloride salts of organic bases were screened for their effectiveness for the o-chlorination reaction. 90, the one which first led to the discovery of this reaction, serves the o-chlorination reaction well. 93, N,O-dimethyl-hydroxylamine works too. 2.3. EXPLORATION OF THE REACTION SCOPE 43

Hydrochloride salts of hydrazine, 94 and 95, catalyze the reaction as well (under basic conditions,

94 and 95 would form hydrazone products with QMK). Reﬂux was found to improve the yields:

Pyr·HCl gave excellent yield under reflux condition while 90 afford the product quantitatively under reflux condition. However Et3N·HCl and TBAC did not give any product at all. Other chloride sources were explored as well. TMSCl gave a poor yield (32 %); HCl (1 M) gave 55 % yield, because the QMK was partially hydrolyzed to give quinone; ZnCl2 could not catalyze the reaction at all. Summarizing the screening result, N,N-dimethyl hydrazine hydrochloride 90 works best for the reaction, which might be attributed to two reasons: 1) the accompanying HCl provide the ideal pH for the reaction; 2) hydrogen bonding could play a role in this transformation.

2.3 Exploration of the Reaction Scope

2.3.1 Chlorination of Spiral QMKs and mono-Substituted QMKs

With the ideal reagent and reaction condition in hand, next we explored the scope of the QMKs. All

QMKs in the following table are prepared in a similar fashion to Chapter 1 by oxidation of phenols with PIDA. QMKs with at least one unsubstituted alpha carbon worked well for the nucleophilic addition (Table 2.2). QMKs with spiral ketal moiety, 54 and 97, aﬀorded the corresponding chlorophenol, 96 and 98, in good yields. Both 96 and 98 were validated by single crystal x-ray diﬀraction analysis. All the 2-substituted QMKs give o-chlorophenols (100, 102, 103, 105 and

106) in excellent yields. For the 3-substituted QMKs, nucleophilic chlorination prefer the less hindered side. Since methyl and methoxyl are electron donating groups, QMK 107 and 66 only form one regio-isomer. In the cases of 3-halide-QMK, 112, 115 and 118, the more hindered side of QMK was activated and two regio-isomers were obtained. 44 CHAPTER 2. O-CHLORINATION

Table 2.2: Chlorination of spiral QMKs and mono-substituted QMKs

QMK chlorophenol product(yield %) QMK chlorophenol product(yield %)

spiral QMK

O OH O OH Cl Cl 54 96 97 98 77 % 75 % OO OO O O OH OH

2-substituted QMK

O OH O OH I I Cl F F Cl 99 100 101 102 78 % 87 % MeO OMe OMe MeO OMe OMe

O OH O O O OH t-Bu t-Bu Cl Cl MeO MeO 8 103 104 105 84 % 88 % MeO OMe OMe MeO OMe OMe

O OH Cl Cl Cl 72 106 99 % MeO OMe OMe

3-substituted QMK

O OH O OH Cl Cl 107 108 66 109 MeO MeO 85 % Me Me 81 % MeO OMe OMe MeO OMe OMe

O OH O OH OH Cl Cl Cl 113 114 111 112 F 110 Cl 74 % 16 % F 88 % Cl Cl MeO OMe MeO OMe OMe OMe OMe

O OH OH O OH OH Cl Cl Cl Cl 115 116 117 118 119 120 Br 18 % I Br 59 % Br I 68 % I 30 % MeO OMe MeO OMe OMe OMe OMe OMe 2.3. EXPLORATION OF THE REACTION SCOPE 45

2.3.2 Chlorination of di-Substituted Flourine-rich QMKs

Fluorinated compounds are desired for their thermal and metabolic stability, increased lipophilicity to increase bioavailability.[135] 18F substituted phenols are used in labeling and imaging techniques.[136]

Herein we synthesized 6 new QMKs, which are mono or di-fluoro substituted. These QMKs were subjected to the same protocol and the corresponding o-chlorophenols were afforded in very high yields (Table 2.3). Note in all cases, even with electron withdrawing groups on α position of QMK, no chlorination products on the 3 position of QMK (Michael addition) was isolated. Since phenols, specifically phenols with halogen substitution, are used frequently as building blocks in organic synthesis, this regio-selective chlorination method is useful to prepare phenols, which were hard to synthesize by conventional methods.[137, 138]

Table 2.3: Chlorination of di-substituted ﬂourine-rich QMKs

QMK chlorophenol product(yield %) QMK chlorophenol product(yield %)

O OH O OH F F Cl F F Cl 121 122 124 F F 123 F 90 % F 92 % MeO OMe MeO OMe OMe OMe

O OH O OH Br Br Cl F F Cl 125 126 127 128 F Me Me F 92 % 98 % MeO OMe OMe MeO OMe OMe

O OH Me Me Cl 129 130 F F 89 % MeO OMe OMe 46 CHAPTER 2. O-CHLORINATION

2.3.3 Quinonoids and miscellaneous nucleophiles

Eventually in the extension of this methodology, quinone imine ketal and other nucleophiles were also explored (Table 2.4). Tosyl quinone imine ketal 131 under the same reaction condition gave the o-chloro-aniline product 132 in quantitative yield. TMSBr reacts with QMK 1 to give o-bromo- phenol 133 in 70 % yield; PhSH reacts in a similar fashion to QMK 1 give o-thiophenyl-phenol

134.[139] Styrene, in the presence of acid (trace amount of diluted H2SO4), act as a nucleophile to give benzofuran product 135.[17, 139]

Table 2.4: Nucleophilic addition of other nucleophiles or quinonoids

nucleophilic addition nucleophilic addition Quinonoid Quinonoid product(yield %) product(yield %)

Ts N NHTs O OH Cl Br 131 132 1 133 90 % 75 % MeO OMe MeO OMe OMe OMe

Ph O OH O O SPh 1 134 1 135 78 % 87 % MeO OMe MeO OMe OMe OMe

2.4 Mechanism Exploration

To study the mechanism of this reaction, a number of experiments were performed: 1) chlorination of mixed QMKs; 2) solvent scrambling experiment.

Mixed QMKs generally gave a mixture of inseparable o-chlorophenol products (Table 2.5). In the following table, the ketal part is composed of one OMe and one OR. In the case of 57 or 63, the reaction would give a mixture of o-chlorophenol products. The major product is formed with

MeOH as the leaving group since MeOH is a better leaving group than EtOH and i-PrOH. In the 2.4. MECHANISM EXPLORATION 47 case of 136, only 2-chloro-4-methoxyl-phenol was formed. Because of the electron withdrawing alkyne, propargyl alcohol is a much better leaving group than MeOH. In the case of QMK 77, the product with MeOH as leaving group is the major product, which indicates MeOH is a slightly better leaving group than TBSOH.[140] Since there was scarce physical chemical study on the comparison of silyl alcohol and alkyl alcohol as leaving group, this could serve as preliminary data to future studies.

Table 2.5: Chlorination of mixed QMKs

O OH OH Cl MeNHNHMe•2HCl Cl + MeCN, reflux R R' R R'

57 (R = Me, R' = Et) 92 (R = Me) 137 (R' = Et) 85% (1 : 3.5) 63 (R = Me, R' = iPr) 92 (R = Me) 138 (R' = iPr) 85% (1 : 7.5)a 136 (R = Me, R' = propargyl) 92 81%b (R = Me as the sole product) 77 (R = Me, R' = TBS)c 92 (R = Me) 139 (R' = TBS) 71%(1: 1.8)b

a NMR ratio of an inseparable mixture. b Isolated yield. c The crude NMR ratio is 1 : 1.6.

Based on previous results, two mechanisms can be proposed for this chlorination transformation

(Scheme 2.3): a) SN2’-type nucleophilic substitution; or b) a regio-selective 1,4-addition to the more electron withdrawing oxocarbenium cation, which is reminiscent of the Thiele reaction.[141]

Additional experiments were performed to distinguish the two mechanisms(Scheme 2.4). To conﬁrm the existence of the oxocarbenium cation, a solvent scrambling experiment was designed.

QMK 1 was treated with hydrazine salt 90 and reﬂuxed in ethanol. If the oxocarbenium cation is present in the reaction, 137 should also be produced. To our delight, phenol 92 and 137 were puriﬁed as an inseparable mixture from column chromatography and their ratio is determined by

1H NMR. More evidence were derived from the reaction of two mixed QMKs. QMK 142 was 48 CHAPTER 2. O-CHLORINATION

Mechanism a

O O OH Cl Cl Cl 1 MeO OMe OMe OMe HA 140 92

Mechanism b

O O

1 140 92 MeO OMe O Me HA 141

Scheme 2.3: Plausible mechanisms

treated with hydrazine salt in microwave reactor at 120 ◦C for 2 hrs to produce the chlorination product 143 in high yield while QMK 144 would not give any chlorination product even under harsh conditions. This result could be better explained by mechanism b. However, a mechanism involving oxocarbenium formation followed by mechanism a cannot be ruled out, a quantitative calculation to compare the two transitional states could shed more light onto the nature of this reaction.

O OH OH MeNHNHMe•2HCl Cl Cl + EtOH, reflux MeO OMe OMe OEt 1 92 137 ratio 1 : 4.3

O OH O MeNHNHMe•2HCl Cl MeNHNHMe•2HCl no reaction MeCN MeCN Ph OMe Me OMe Ph 142 143 144

Scheme 2.4: Mechanism exploration 2.5. N, N-DOUBLE MICHAEL ADDITION REACTION 49

2.5 N, N-double Michael Addition Reaction

The inability to synthesize double Michael addition product from QMK and N,N-dimethyl hydrazine hydrochloride was particularly puzzling. From previous N,O-double Michael addition reaction project, we have known that alcohol, such as MeOH, could form Michael addition product, and thus such solvents have been avoided. In the screening of N,N-double Michael addition reaction, various bases in MeCN were used. However under these reactions, TLC (EtOAc/Hexane 1:4) monitoring with CAM stain shows QMK was completely not reactive. When MeOH is used as solvent, TLC shows that QMK completed disappeared. Subsequent column chromatography puriﬁcation only aﬀorded QMK-MeOH mono-Michael addition product with 20 % yield. TLC (MeOH/EtOAc 1:4) revealed the presence of a very polar compound, which was separated and resolved to be the long awaited N,N-double Michael addition product.

O Me N O 90 N Me MeO DBU, iPrOH, reflux MeO OMe OMe 1 145 94%

Me Me N N Me O O N N Me MeO Me MeO OMe OMeMe 146 26 % 147 56 %

Scheme 2.5: Synthesis of the bridged pyrazolidine products

With this pyrazolidine product in hand, our attention was directed to optimizing the reaction condition to minimize the MeOH Michael addition product (Scheme 2.5). More bulky solvents were used for the reaction, when i-PrOH was used as the solvent, the undesired side product could be completely suppressed and the pyrazolidine product 145 was aﬀorded in high yield (94 %).

Substituted QMKs gave pyrazolidine products 146 and 147 in moderate yields. 50 CHAPTER 2. O-CHLORINATION

2.6 Conclusion

In summary, we discovered an unexpected regio-selective nucleophilic chlorination reaction of QMK.

The nucleophilic addition of halogen to QMK is ﬁrst time reported and can be used to synthesize a variety of phenols. The mechanism of this reaction is proposed and interpreted from experimental results. The N,N-double Michael addition reaction aﬀorded a number of pyrazolidine products, which further enriched the heterocyclic chemistry of QMKs. 2.7. EXPERIMENTAL SECTION 51

2.7 Experimental Section

General Informaiton

Anhydrous acetonitrile was distilled from CaCl2 under an atmosphere of argon. All reagents were purchased from commercial sources or synthesized using literature methods. Microwave reactions are done in a CEM microwave reactor, Discover R SP System. 1H and 13C NMR spectra were recorded on BRUKE 500 MHz spectrometers; 19F NMR spectra were done on a BRUKE 400

MHz spectrometer. 1H and 13C NMR Chemical shifts (δ values) were reported in ppm from

1 13 19 downfield using internal standard TMS ( H NMR) or CDCl3 ( C NMR), respectively; F NMR were reported from down field using hexafluorobenzene as internal standard. All mass spectra were run by Dr. Cliff Soll at the Hunter College Mass Spectrometry Facility and taken on an Agilent

6520A Q-TOF using electrospray ionization and Dr. Lijia Yang at City College on an Applied

Biosystems 4000 QTRAP spectrometer. X-ray crystallography was performed on a Bruker AXS

SMART APEXII Single Crystal Diﬀractometer by Dr. Chunhua Hu at Department of Chemistry of New York University. All infrared spectra were taken on a Thermo Nicolet IR100 spectrometer.

Column chromatography was performed over silica with a porosity of 60 Å and a particle size of

40-63 µm.

2.7.1 Preparation of Quinone Monoketals

Quinone monoketals were made from oxidation of phenols by phenyliodoso diacetate (PIDA) following general procedures (same to 1.8.1) of Tamura, Pelter and Taylor, and veriﬁed by 1H and

13C NMR.

2-ﬂuoro-4,4-dimethoxycyclohexa-2,5-dienone (101): 1 g 2-ﬂuoro-phenol(8.92 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution, 6.3 g PIDA (19.63 mmol,

2.2 eq) was slowly added in small portions. TLC monitoring (EtOAc: Hexane, 1:4) shows reaction 52 CHAPTER 2. O-CHLORINATION

OH O F PIDA F

MeOH MeO OMe 101

complete in 1 hr and hence the reaction was quenched with saturated NaHCO3, extracted with

DCM for 3 times. The organic layer was washed with , dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂash chromatography (EtOAc: Hexane,

1:10 to 1:4) to give product 101 as a liquid 0.49 g. (Note: 101 is very unstable and it must be freshly prepared and used right away; when exposed to air, product became dark in 5 minutes)

1 32 % yield; H NMR (500 MHz, CDCl3) δ 6.87 (dd, J = 10.5 Hz, J = 3.0 Hz, 1 H), 6.42 (dd,

J = 13.0 Hz, J = 3.0 Hz, 1 H), 6.27 (dd, J = 10.5 Hz, J = 7.0 Hz, 1 H), 3.39 (s, 6 H); 13C NMR

(125 MHz, CDCl3) δ 178.03 (d, J = 23.8 Hz), 153.58 (d, J = 270.0 Hz), 144.46 (d, J = 2.5 Hz),

127.92 (d, J = 3.8 Hz), 118.96 (d, J = 11.3 Hz), 95.77 (d, J = 11.3 Hz), 50.54; 19F NMR (377

MHz, CDCl3) δ -129.88.

OH O F PIDA F

MeOH F F MeO OMe 121

2,5-diﬂuoro-4,4-dimethoxycyclohexa-2,5-dienone(121): 1 g 2,5-diﬂuorophenol (7.69 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution, 5.5 g PIDA

(16.91 mmol, 2.2 eq) was slowly added in small portions. TLC monitoring (EtOAc: Hexane, 1:4) shows reaction complete in 1 hr and hence the reaction was quenched with saturated NaHCO3, extracted with DCM for 3 times. The organic layer was washed with , dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂash chromatography 2.7. EXPERIMENTAL SECTION 53

(EtOAc: Hexane, 1:10 to 1:4) to give product 121 as a liquid 0.43 g.

1 29 % yield; H NMR (500 MHz, CDCl3) δ 6.28 (dd, J = 11.5 Hz, J = 8.5 Hz, 1 H), 6.00 (dd, J =

13 13.5 Hz, J = 6.0 Hz, 1 H), 3.45 (d, J = 3.8 Hz, 6 H); C NMR (125 MHz, CDCl3) δ 178.43 (dd, J

= 25.0 Hz, J = 17.5 Hz), 171.13 (dd, J = 301.3 Hz, J = 2.5 Hz), 153.29 (dd, J = 271.3 Hz, J =

1.3 Hz), 116.36 (dd, J = 13.8 Hz, J = 5.0 Hz), 109.25 (dd, J = 11.3 Hz, J = 5.0 Hz), 95.36 (dd, J

19 = 22.5 Hz, J = 12.5 Hz), 51.71 (d, J = 1.3 Hz); F NMR (377 MHz, CDCl3) δ -100.45, -129.44.

LRMS: HRMS m/z 212.8 [M+Na]+

OH O F PIDA F

F MeOH F OMe MeO OMe 123

2,3-diﬂuoro-4,4-dimethoxycyclohexa-2,5-dienone(123): 1 g 2,3-diﬂuoro-4-methoxy-phenol(6.25 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution, 2.41 g PIDA (7.49 mmol, 1.2 eq) was slowly added in small portions. TLC monitoring (EtOAc: Hex- ane, 1:4) shows reaction complete in 1 hr and hence the reaction was quenched with saturated

NaHCO3, extracted with DCM for 3 times. The organic layer was washed with brine water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂash chromatography (EtOAc: Hexane, 1:10 to 1:4) to give product 123 as a white solid 1.01 g.

◦ 1 85 % yield; m. p. = 35-37 C; H NMR (500 MHz, CDCl3) δ 6.69 (dd, J = 10.0 Hz, J = 4.0 Hz,

1 H), 6.28 (dd, J = 10.5 Hz, J = 6.5 Hz, 1 H), 3.46 (d, J = 3.8 Hz, 6 H); 13C NMR (125 MHz,

CDCl3) δ 178.75 (dd, J = 22.2 Hz, J = 7.5 Hz), 153.31 (dd, J = 295.0 Hz, J = 6.3 Hz), 141.20 (t,

J = 2.5 Hz), 140.67 (dd, J = 265.0 Hz, J = 5.0 Hz), 127.64 (t, J = 2.5 Hz), 96.20 (dd, J = 18.8

19 Hz, J = 3.8 Hz), 51.79 (d, J = 1.3 Hz); F NMR (377 MHz, CDCl3) δ -134.15 (d, J = 7.9 Hz),

-159.14 (d, J = 8.3 Hz). LRMS: HRMS m/z 212.8 [M+Na]+ 54 CHAPTER 2. O-CHLORINATION

OH O Br PIDA Br

MeOH F F MeO OMe 125

2-bromo-3-ﬂuoro-4,4-dimethoxycyclohexa-2,5-dienone(125): 1 g 2-bromo-3-ﬂuorophenol (5.24 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution,

3.71 g PIDA (11.52 mmol, 2.2 eq) was slowly added in small portions. TLC monitoring (EtOAc:

Hexane, 1:4) shows reaction complete in 1 hr and hence the reaction was quenched with saturated

1 6 % yield; H NMR (500 MHz, CDCl3) δ 6.71 (t, J = 10.0 Hz, 1 H), 6.45 (d, J = 10.0 Hz, 1 H),

13 3.44 (d, J = 1.5 Hz, 6 H); C NMR (125 MHz, CDCl3) δ 179.20 (d, J = 7.5 Hz), 167.57 (d, J =

298.8 Hz), 140.85 (d, J = 5.0 Hz), 128.77 (d, J = 2.5 Hz), 107.63 (d, J = 11.3 Hz), 94.41 (d, J =

19 + 21.3 Hz), 51.88; F NMR (377 MHz, CDCl3) δ -90.57. LRMS: 272.7 [M+Na]

OH O F PIDA F

Me MeOH Me MeO OMe 127

2-ﬂuoro-4,4-dimethoxy-3-methylcyclohexa-2,5-dienone(127): 1 g 2-ﬂuoro-3-methylphenol (7.93 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution,

5.62 g PIDA (17.44 mmol, 2.2 eq) was slowly added in small portions. TLC monitoring (EtOAc:

Hexane, 1:10) shows reaction complete in 1 hr and hence the reaction was quenched with saturated

NaHCO3, extracted with DCM for 3 times. The organic layer was washed with brine water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂash 2.7. EXPERIMENTAL SECTION 55 chromatography (EtOAc: Hexane, 1:20 to 1:10) to give product 127 as a liquid 0.55 g.

1 37 % yield; H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 10.0 Hz, 1 H), 6.41 (d, J = 10.5 Hz, J =

13 7.0 Hz, 1 H), 3.25 (s, 6 H), 1.90 (d, J = 3.0 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 177.29 (d, J

= 23.8 Hz), 152.13 (d, J = 325.5 Hz), 144.95 (d, J = 2.5 Hz), 132.06 (d, J = 8.8 Hz), 130.34 (d, J

19 = 3.8 Hz), 98.01 (d, J = 10.0 Hz), 51.16, 8.35 (d, J = 3.8 Hz); F NMR (377 MHz, CDCl3) δ -

108.79. LRMS: 208.8 [M+Na]+

OH O Me PIDA Me

F MeOH F MeO OMe 129

3-ﬂuoro-4,4-dimethoxy-2-methylcyclohexa-2,5-dienone(129): 1 g 3-ﬂuoro-2-methylphenol (7.93 mmol, 1 eq) was dissolved in 20 mL MeOH and stirred at 0◦C for 10 min. To this solution,

5.62 g PIDA (17.44 mmol, 2.2 eq) was slowly added in small portions. TLC monitoring (EtOAc:

Hexane, 1:10) shows reaction complete in 1 hr and hence the reaction was quenched with saturated

NaHCO3, extracted with DCM for 3 times. The organic layer was washed with brine water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was puriﬁed with ﬂash chromatography (EtOAc: Hexane, 1:20 to 1:10) to give product 129 as a liquid 0.24 g. 16 % yield;

1 H NMR (500 MHz, CDCl3) δ 6.65 (t, J = 10.0 Hz, 1 H), 6.33 (d, J = 10.5 Hz, 1 H), 3.41 (d, J

13 = 1.5 Hz, 6 H), 1.87 (d, J = 3.5 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 186.55 (d, J = 13.8

Hz), 165.62 (d, J = 287.5 Hz), 140.19 (d, J = 5.0 Hz), 130.17 (d, J = 2.5 Hz), 118.77 (d, J = 7.5

19 Hz), 93.20 (d, J = 22.5 Hz), 51.61, 6.53 (d, J = 5.0 Hz); F NMR (377 MHz, CDCl3) δ - 108.79;

HRMS m/z Calcd C9H12FO3+ (M+H)+: 187.0770, Found: 187.0759. 56 CHAPTER 2. O-CHLORINATION

2.7.2 Synthesis of o-Chlorophenols

General protocol follows 92: reactions in this section were carried out on a scale of 100-300 mg;

MeNHNHMe·2HCl (1.2 eq) was added to a solution of QMK in MeCN, and reaction was then reﬂuxed and monitored by TLC with CAM stain. Structures were conﬁrmed by 1H NMRand 13C

NMR; known compounds were compared and confirmed with literature reported data, while many of the first time synthesized phenols were further confirmed by HRMS.

O OH Cl MeNHNHMe 2HCl, 1.2 eq

MeCN, reflux MeO OMe OMe 1 92

2-chloro-4-methoxyphenol(92): To a stirred solution of 1 (203 mg, 1.317 mmol, 1 eq) in 5 ml

MeCN, add MeNHNHMe·2HCl (210 mg, 1.580 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:4) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was puriﬁed via

ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product 207 mg.

1 99 % yield. H NMR(500 MHz, CDCl3)δ6.93 (d, J = 9.0 Hz, 1 H), 6.87 (d, J = 3.0 Hz, 1 H), 6.47

13 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 5.25 (s, 1 H), 3.74 (s, 3 H); C NMR(125 MHz, CDCl3)δ153.64,

145.49, 119.86, 116.58, 114.51, 114.08, 55.93.

O OH Cl MeNHNHMe 2HCl

MeCN, reflux OO O OH 54 96

4-(2-hydroxyethoxy)phenol(96): To a stirred solution of 54 (110 mg, 0.723 mmol, 1 eq) in 5 ml

MeCN, add MeNHNHMe·2HCl (115 mg, 0.868 mmol, 1.2 eq) at room temperature. The reaction was then refluxed for 1 hr, TLC monitoring (EtOAc: Hexane, 1:1) with CAM stain showed reac- 2.7. EXPERIMENTAL SECTION 57 tion complete. Solvent was removed under reduced pressure and the mixture was purified via flash chromatography (EtOAc: Hexane, 1:2 to 1:1) to give solid product 105 mg.

1 77 % yield; H NMR (500 MHz, CDCl3) δ 6.94 (d, J = 9.0 Hz, 1 H), 6.91 (d, J = 3.0 Hz, 1 H),

6.78 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 5.28 (s, 1 H), 4.02 (t, J = 4.5 Hz, 2 H), 3.94 (t, J = 5.0

13 Hz, 2 H), 2.05 (t, J = 5.8 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 152.61, 145.92, 119.91, 116.64,

115.21, 115.08, 70.10, 61.43.

54 was subject to Winterfeldt conditions (HCl, THF/H2O; Baesler, S.; Brunck, A.; Jautelat, R.;

Winterfeld, E. Helv. Chim. Acta 2000, 83, 1854.) and still led to formation 96 and chlorohydro- quinone. The structure was determined by X-ray crystallographic analysis using 96 recrystallized from hexane/EtOAc. The crystal structure of 96 has been deposited at the Cambridge Crystallo- graphic Data Centre (CCDC 971456). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/conts/retrieving.html

O OH Cl MeNHNHMe 2HCl

MeCN, reflux OO O OH

97 98

2-chloro-4-(3-hydroxypropoxy)phenol(98): reaction procedure refer to 96.

1 75% yield; H NMR (500 MHz, CDCl3) δ 6.93 (d, J = 8.5 Hz, 1 H), 6.90 (d, J = 3.0 Hz, 1 H), 6.75 58 CHAPTER 2. O-CHLORINATION

(dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 5.32 (s, 1 H), 4.05 (t, J = 6.0 Hz, 2 H), 3.86 (t, J = 6.0 Hz, 2

13 H), 2.02 (qnt, J = 6.0 Hz, 2 H), 1.77(s, 1 H); C NMR (125 MHz, CDCl3) δ 152.78, 145.72, 119.89,

116.59, 115.12, 114.93, 66.59, 60.41, 31.92; HRMS m/z Calcd C9H12ClO3+ (M+H)+: 203.0475,

Found: 203.0472.

The structure was conﬁrmed by X-ray crystallographic analysis using 98 recrystallized from hexane/EtOAc. The crystal structure of 98 has been deposited at the Cambridge Crystallographic

Data Centre (CCDC 921686). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/conts/retrieving.html

O OH I I Cl MeNHNHMe 2HCl

MeCN, reflux MeO OMe OMe 99 100

2-chloro-6-iodo-4-methoxyphenol(100): reaction procedure refer to 92.

◦ 1 78 % yield; mp 54 - 55 C; H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 3.0 Hz, 1 H), 6.91 (d, J =

13 3.0 Hz, 1 H), 5.55 (s, 1 H), 3.74 (s, 3 H); C NMR (125 MHz, CDCl3) δ 153.80, 145.23, 123.17,

118.83, 115.65, 83.04, 56.08.

O OH F F Cl MeNHNHMe 2HCl

MeCN, reflux MeO OMe OMe 101 102 2.7. EXPERIMENTAL SECTION 59

2-chloro-6-ﬂuoro-4-methoxyphenol(102): 101 must be freshly prepared and used right away; reaction procedure refer to 92.

◦ 1 87 % yield; mp 67-68 C; H NMR (500 MHz, CDCl3) δ 6.68 (dd, J = 2.8 Hz, J = 2.3 Hz, 1 H),

13 6.63 (dd, J = 11.8 Hz, J = 2.8 Hz, 1 H), 5.23 (s, 1 H), 3.74 (s, 3 H); C NMR (125 MHz, CDCl3)

δ 152.82 (d, J = 11.3 Hz), 151.44 (d, J = 242.5 Hz), 134.68 (d, J = 15.0 Hz), 121.57 (J = 5.0 Hz),

19 109.88 (d, J = 2.5 Hz), 102.25 (d, J = 21.3 Hz), 56.01; F NMR (377 MHz, CDCl3) δ -135.72.

O OH tBu tBu Cl MeNHNHMe 2HCl

MeCN, reflux MeO OMe OMe 8 103

2-(tert-butyl)-6-chloro-4-methoxyphenol(103): reaction procedure refer to 92.

1 88 % yield; H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 3.0 Hz, 1 H), 6.74 (d, J = 3.0 Hz, 1 H),

13 5.48 (s, 1 H), 3.74 (s, 3 H), 1.38 (s, 9 H); C NMR (125 MHz, CDCl3) δ 151.85, 143.30, 137.78,

119.78, 112.82, 109.56, 55.09, 34.67, 28.52; HRMS m/z Calcd C11H16ClO2+ (M+H)+: 215.0839,

Found: 215.0836.

O O O OH Cl O MeNHNHMe 2HCl O MeCN, reflux MeO OMe OMe 104 105

methyl 3-chloro-2-hydroxy-5-methoxybenzoate(105): reaction procedure refer to 92.

1 84 % yield; H NMR (500 MHz, CDCl3) δ 10.85 (s, 1 H), 7.23 (d, J = 3.0 Hz, 1 H), 7.16 (d, J =

13 3.5 Hz, 1 H), 3.95 (s, 3 H), 3.75 (s, 3 H); C NMR (125 MHz, CDCl3) δ 170.00, 151.80, 151.54,

123.62, 122.62, 112.95, 111.46, 56.01, 52.77.

2,6-dichloro-4-methoxyphenol(106): reaction procedure refer to 92.

1 13 99 % yield; H NMR (500 MHz, CDCl3) δ 6.84 (s, 2 H), 5.47 (s, 1 H), 3.75 (s, 3 H); C NMR (125 60 CHAPTER 2. O-CHLORINATION

O OH Cl Cl Cl MeNHNHMe 2HCl

MeCN, reflux MeO OMe OMe 72 106

MHz, CDCl3) δ 152.97, 142.09, 121.17, 114.20, 56.02.

O OH Cl MeNHNHMe 2HCl

MeO MeCN, reflux MeO MeO OMe OMe 107 108

2-chloro-4, 5-dimethoxyphenol(108): reaction procedure refer to 92.

1 85 % yield; H NMR (500 MHz, CDCl3) δ 6.80 (s, 1 H), 6.61 (s, 1 H), 5.24 (s, 1 H), 3.84 (s, 3 H),

13 3.82 (s, 3 H); C NMR (125 MHz, CDCl3) δ 149.19, 145.57, 143.35, 111.87, 109.30, 100.53, 56.63,

56.11.

O OH Cl MeNHNHMe 2HCl

Me MeCN, reflux Me MeO OMe OMe 66 109

2-chloro-4-methoxy-5-methylphenol(109): reaction procedure refer to 92.

1 81 % yield; H NMR (500 MHz, CDCl3) δ 6.80 (s, 1 H), 6.74 (s, 1 H), 5.17 (s, 1 H), 3.75 (s, 3 H),

13 2.15 (s, 3 H); C NMR (125 MHz, CDCl3) δ 151.85, 144.88, 127.35, 118.15, 116.15, 110.74, 56.01,

15.94; HRMS m/z Calcd C8H8ClO2- (M-H)-: 171.0213, Found: 171.0214.

2-chloro-5-ﬂuoro-4-methoxyphenol(111): 110 need to be freshly prepared; reaction procedure refer to 92.

1 88 % yield; mp 64 - 69δ; H NMR (500 MHz, CDCl3) δ 6.92 (d, J = 8.5 Hz, 1 H), 6.81 (d, J =

13 11.5 Hz, 1 H), 5.32 (s, 1 H), 3.83(s, 3 H); C NMR (125 MHz, CDCl3) δ 151.86 (d, J = 245.0

Hz), 145.49 (d, J = 11.3 Hz), 141.95 (d, J = 12.5 Hz), 114.20 (d, J = 3.8 Hz), 113.74 (d, J = 3.8 2.7. EXPERIMENTAL SECTION 61

O OH Cl MeNHNHMe 2HCl

F MeCN, reflux F MeO OMe OMe 110 111

19 Hz), 104.97 (d, J = 22.5 Hz), 57.20; F NMR (377 MHz, CDCl3) δ -136.15; HRMS m/z Calcd

C7H5ClFO2- (M-H)-: 174.9962, Found: 174.9940.

O OH OH Cl Cl MeNHNHMe 2HCl + Cl MeCN, reflux Cl Cl MeO OMe OMe OMe 112 113 114

To a stirred solution of 112 (270 mg, 1.432 mmol, 1 eq) in 5 mL MeCN, add MeNHNHMe·2HCl

(229 mg, 1.718 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:4) with CAM stain showed reaction complete (Rf: 113 = 0.35; 3l

= 0.4; 114 = 0.2). Solvent was removed under reduced pressure and the mixture was puriﬁed via

ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product 113 204 mg and 114 43 mg.

1 2,5-dichloro-4-methoxyphenol(113):74 % yield; H NMR (500 MHz, CDCl3) δ 7.11 (s, 1 H), 6.92

13 (s , 1 H), 5.21 (s, 1 H), 3.87 (s, 3 H); C NMR (125 MHz, CDCl3) δ 149.34, 145.52, 122.22, 117.89,

117.85, 112.74, 56.91.

1 2,3-dichloro-4-methoxyphenol(114):16 % yield; H NMR (500 MHz, CDCl3) δ 6.92 (d, J = 9.0 Hz,

13 1 H), 6.81 (d, J = 9.5 Hz, 1 H), 5.36 (s, 1 H), 3.86 (s, 3 H); C NMR (125 MHz, CDCl3) δ 150.12,

146.38, 121.42, 120.17, 113.56, 111.55, 56.99.

O OH OH Cl Cl MeNHNHMe 2HCl + Br MeCN, reflux Br Br MeO OMe OMe OMe 115 116 117

To a stirred solution of 115 (50 mg, 0.214 mmol, 1 eq) in 5 mL MeCN, add MeNHNHMe·2HCl 62 CHAPTER 2. O-CHLORINATION

(34 mg, 0.257 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:4) with CAM stain showed reaction complete (Rf: 115 = 0.35; 116

= 0.4; 117 = 0.2). Solvent was removed under reduced pressure and the mixture was puriﬁed via

ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product 1480 mg and 149 mg.

1 5-bromo-2-chloro-4-methoxyphenol(116): 59 % yield; H NMR (500 MHz, CDCl3) δ 7.25 (s, 1 H),

13 6.86 (s , 1 H), 5.24 (s, 1 H), 3.84 (s, 3 H); C NMR (125 MHz, CDCl3) δ 150.25, 145.81, 120.72,

118.72, 112.51, 110.85, 56.99; HRMS m/z Calcd C7H5BrClO2- (M-H)-: 234.9161, Found: 234.9139.

1 3-bromo-2-chloro-4-methoxyphenol(117): 18 % yield; H NMR (500 MHz, CDCl3) δ 6.98 (d, J =

13 9.0 Hz, 1 H), 6.80 (d, J = 9.0 Hz, 1 H), 5.30 (s, 1 H), 3.86 (s, 3 H); C NMR (125 MHz, CDCl3)

δ 151.19, 146.40, 121.94, 114.44, 112.24, 111.54, 57.09; HRMS m/z Calcd C7H5BrClO2- (M-H)-:

234.9161, Found: 234.9160.

O OH OH Cl Cl MeNHNHMe 2HCl + I MeCN, reflux I I MeO OMe OMe OMe 118 119 120

To a stirred solution of 118 (150 mg, 0.536 mmol, 1 eq) in 5 mL MeCN, add MeNHNHMe·2HCl

(85 mg, 0.643 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete (Rf: 118 = 0.35;

119 = 0.4; 120 = 0.3). Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc: Hexane, 1:20 to 1:10) to give solid product 119 104 mg and

120 46 mg.

1 2-chloro-5-iodo-4-methoxyphenol(119): 68 % yield; mp 112 - 114 δ; H NMR (500 MHz, CDCl3)

13 δ 7.45 (s, 1 H), 6.77 (s , 1 H), 5.27 (s, 1 H), 3.82 (s, 3 H); C NMR (125 MHz, CDCl3) δ 152.63,

146.09, 126.44, 119.88, 111.27, 84.34, 57.11; HRMS m/z Calcd C7H5ClIO2- (M-H)-: 282.9023,

Found: 282.9019. 2.7. EXPERIMENTAL SECTION 63

1 2-chloro-3-iodo-4-methoxyphenol(120): 30 % yield; mp 66- 71δ; H NMR (500 MHz, CDCl3) δ

7.00 (d, J = 9.0 Hz, 1 H), 6.74 (d, J = 9.0 Hz, 1 H), 5.26 (s, 1 H), 3.85 (s, 3 H); 13C NMR (125

- MHz, CDCl3) δ 153.76, 145.88, 125.49, 115.71, 110.79, 90.28, 57.25; HRMS m/z Calcd C7H5ClIO2

(M-H)-: 282.9023, Found: 282.9015.

O OH F F Cl MeNHNHMe 2HCl

F MeCN, reflux F MeO OMe OMe 121 122

2-chloro-3,6-diﬂuoro-4-methoxyphenol(122): 121 need to be freshly prepared; reaction procedure refer to 92.

◦ 1 90 % yield; mp 76 - 80 C; H NMR (500 MHz, CDCl3) δ 6.75 (dd, J = 6.5 Hz, J = 2.5 Hz, 1 H),

13 5.21 (s , 1 H), 3.84 (s , 3 H); C NMR (125 MHz, CDCl3) δ 146.42 (dd, J = 238.6 Hz, J = 4.8

Hz), 145.54 (dd, J = 249.4 Hz, J = 10.0 Hz), 141.21 (dd, J = 12.5 Hz, J = 10.0 Hz), 134.61 (d,

J = 1.6 Hz), 111.05 (dd, J = 18.8 Hz, J = 5.0 Hz), 101.10 (dd, J = 23.1 Hz, J = 1.9 Hz), 57.32;

19F NMR (377 MHz, CDCl3) δ -142.51 (d, J = 11.3 Hz), -142.70 (d, J = 11.3 Hz) ); HRMS m/z

Calcd C7H4ClF2O2 - (M-H)-: 192.9868, Found: 192.9841.

O OH F F Cl MeNHNHMe 2HCl

F MeCN, reflux F MeO OMe OMe 123 124

6-chloro-2,3-diﬂuoro-4-methoxyphenol(124): 123 can be stored under Argon in fridge; reaction procedure refer to 92 (note: 124 has almost identical Rf as 123 (Rf: 123 = 0.3, 124 =0.32), while

TLC upon CAM stain, 124 gives a darker spot).

◦ 1 92 % yield; mp 70 - 73 C; H NMR (500 MHz, CDCl3) δ 6.75 (dd, J = 7.5 Hz, J = 2.5 Hz, 1 H),

13 5.40 (s , 1 H), 3.85 (s , 3 H); C NMR (125 MHz, CDCl3) δ 142.21(dd, J = 8.8 Hz, J = 2.5 Hz), 64 CHAPTER 2. O-CHLORINATION

141.38 (dd, J = 245.0 Hz, J = 13.8 Hz), 141.18 (dd, J = 247.5 Hz, J = 12.5 Hz), 135.74 (dd, J =

11.3 Hz, J = 1.3 Hz), 114.73 (t, J = 4.4 Hz), 108.41 (d, J = 2.5 Hz), 57.23; 19F NMR (377 MHz,

- CDCl3) δ -158.59 (d, J = 19.6 Hz), -160.28 (d, J = 19.3 Hz); HRMS m/z Calcd C7H4ClF2O2

(M-H)-: 192.9868, Found: 192.9875.

O OH Br Br Cl MeNHNHMe 2HCl

F MeCN, reflux F MeO OMe OMe 125 126

2-bromo-6-chloro-3-ﬂuoro-4-methoxyphenol(126): 125 need to be freshly prepared; reaction procedure refer to 92.

◦ 1 92 % yield; mp 82- 84 C; H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 8.5 Hz, 1 H), 5.59 (s , 1

13 H), 3.85 (s , 3 H); C NMR (125 MHz, CDCl3) δ 149.12 (d, J = 246.3 Hz), 143.39 (d, J = 2.5

Hz), 142.09 (d, J = 12.5 Hz), 114.21 (d, J = 3.8 Hz), 113.68 (d, J = 2.5 Hz), 99.71 (d, J = 22.5

19 - - Hz), 57.38; F NMR (377 MHz, CDCl3) δ -128.15); HRMS m/z Calcd C7H4BrClFO2 (M-H) :

252.9067, Found: 252.9058.

O OH F F Cl MeNHNHMe 2HCl

Me MeCN, reflux Me MeO OMe OMe 127 128

6-chloro-2-ﬂuoro-4-methoxy-3-methylphenol(128): 127 need to be freshly prepared; reaction procedure refer to 92.

1 98 % yield; mp 96 - 99 δ; H NMR (500 MHz, CDCl3) δ 6.57 (d, J = 2.5 Hz, 1 H), 5.22 (s , 1 H),

13 3.76 (s , 3 H), 2.10 (d, J = 2.5 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 151.24 (d, J = 8.8 Hz),

150.20 (d, J = 238.8 Hz), 134.74 (d, J = 16.3 Hz), 117.28 (d, J = 5.0 Hz), 114.10 (d, J = 17.5

19 Hz), 106.32 (d, J = 2.5 Hz), 56.15, 7.85 (d, J = 3.8 Hz); F NMR (377 MHz, CDCl3) δ -139.80); 2.7. EXPERIMENTAL SECTION 65

HRMS m/z Calcd C8H7ClFO2 - (M-H)-: 189.0119, Found: 189.0117.

O OH Me Me Cl MeNHNHMe 2HCl

F MeCN, reflux F MeO OMe OMe 129 130

6-chloro-3-ﬂuoro-4-methoxy-2-methylphenol(130): 129 need to be freshly prepared; reaction

1 procedure refer to 92. 89 % yield; mp 65 - 66 δ; H NMR (500 MHz, CDCl3) δ 6.77 (d, J = 8.0

13 Hz, 1 H), 5.30 (s , 1 H), 3.81 (s , 3 H), 2.21 (d, J = 2.5 Hz, 3 H); C NMR (125 MHz, CDCl3)

δ 150.40 (d, J = 241.3 Hz), 144.07 (d, J = 7.5 Hz), 141.68 (d, J = 13.8 Hz), 114.59 (d, J = 18.8

Hz), 112.98 (d, J = 3.8 Hz), 110.61 (d ,J = 2.5 Hz), 57.02, 8.62 (d, J = 6.3 Hz); 19F NMR (377

- - MHz, CDCl3) δ -140.25); HRMS m/z Calcd C8H7ClFO2 (M-H) : 189.0119, Found: 189.0125.

2.7.3 Quinonoids and miscellaneous nucleophiles

Ts Ts N HN Cl MeNHNHMe 2HCl

MeCN, reflux MeO OMe OMe 131 132

N-(2-chloro-4-methoxyphenyl)-4-methylbenzenesulfonamide(132): To a stirred solution of 131

(200 mg, 0.651 mmol, 1 eq) in 5 mL MeCN, add MeNHNHMe·2HCl (104 mg, 0.781 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 1 hr, TLC monitoring (EtOAc: Hexane,

1:4) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product

198 mg. (The structure was conﬁrmed by tosylation of commercial 2- chloro-4-methoxyaniline)

1 98 % yield; H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2 H), 7.55 (d, J = 9.0 Hz, 1

H), 7.18 (d, J = 8.0 Hz, 2 H), 6.85 (s, 1 H), 6.78 (dd, J =4.0 Hz, J = 2.5 Hz, 1 H), 6.75 (d, J = 66 CHAPTER 2. O-CHLORINATION

13 3.0 Hz, 1 H), 3.72 (s, 3 H), 2.35 (s, 3 H); C NMR (125 MHz, CDCl3) δ 157.80, 143.95, 135.93,

129.52, 127.99, 127.26, 126.11, 114.56, 113.55, 55.62, 21.52.

O OH Br TMSBr

MeCN, r.t. MeO OMe OMe 1 133

2-bromo-4-methoxyphenol(133): To a stirred solution of 1 (120 mg, 0.778 mmol, 1 eq) in 3 ml

MeCN, add TMSBr (123 ul, 0.934 mmol, 1.2 eq) at room temperature. The reaction was stirred for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:4) with CAM stain showed reaction complete.

Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography

(EtOAc: Hexane, 1:20 to 1:10) to give product 110 mg.

1 70 % yield; H NMR (500 MHz, CDCl3) δ 7.01 (d, J = 3.0 Hz, 1 H), 6.94 (d, J = 9.0 Hz, 1 H),

13 6.79 (d, J = 9.0 Hz, J = 3.0 Hz, 1 H), 5.17 (s , 1 H), 3.74 (s, 3 H); C NMR (125 MHz, CDCl3)

δ 155.83, 146.50, 116.83, 116.32, 115.35, 109.92, 55.98.

O OH SPh PhSH, H2NNH2 H2SO4

MeCN MeO OMe OMe 1 134

4-methoxy-2-(phenylthio)phenol(134): To a stirred solution of 1 (50 mg, 0.324 mmol, 1 eq) in

3 mL MeCN, add PhSH (43 mg, 0.389 mmol, 1.2 eq) and H2NNH2·H2SO4 (50 mg, 0.389 mmol,

1.2 eq) at room temperature. The reaction was stirred for 1 hr, TLC monitoring (EtOAc: Hexane,

1:4) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc: Hexane, 1:10 to 1:4) to give product

52 mg.

1 69 % yield; H NMR (500 MHz, CDCl3) δ 7.25-7.09 (m, 5 H), 7.05 (d, J = 3.0 Hz, 1 H), 7.00 2.7. EXPERIMENTAL SECTION 67

(d, J = 9.0 Hz, 1 H), 6.95 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 6.12 (s, 1 H), 3.75 (s, 3 H); 13C NMR

(125 MHz, CDCl3) δ 153.52, 151.40, 135.70, 129.23, 126.91, 126.17, 120.31, 118.88, 116.29, 116.12,

55.88.

Ph O O H2SO4 cat. + Ph MeCN MeO OMe OMe 1 135

5-methoxy-2-phenyl-2,3-dihydrobenzofuran(135): To a stirred solution of 1 (70 mg, 0.454 mmol,

1 eq) in 3 mL MeCN, add styrene (96 mg, 0.908 mmol, 2 eq) and 50 ul H2SO4 acetonitrile solution(solution was prepared by diluting 0.5 mL concentrated H2SO4 in 10 mL acetonitrile) at room temperature. The reaction was stirred for 1 hr, TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete. Acid was neutralized by small amount of Li2CO3 and solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc:

Hexane, 1:10) to give product 36 mg.

1 35 % yield; H NMR (500 MHz, CDCl3) δ 7.34-7.22 (m, 5 H), 6.70 (m, 2 H), 6.63 (dd, J = 8.5

Hz, J = 3.0 Hz, 1 H), 5.66 (t, J = 9.0 Hz, 1 H), 3.67 (s, 3 H), 3.52 (dd, J = 15.5 Hz, J = 9.5

13 Hz, 1 H), 3.12 (dd, J = 15.5 Hz, J = 8.5 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 154.30, 153.78,

142.02, 128.66, 128.03, 127.53, 125.80, 112.99, 111.20, 109.22, 84.26, 56.05, 38.90.

2.7.4 Preparation of N,N-double Michael addition Derivatives

O Me N MeNHNHMe 2HCl, DBU N Me O MeO iPrOH, reflux MeO OMe OMe 1 145

8,8-dimethoxy-6,7-dimethyl-6,7-diazabicyclo[3.2.1]octan-3-one(145): To a solution of 1 (120 68 CHAPTER 2. O-CHLORINATION mg, 0.778 mmol, 1 eq) in 5 mL iPrOH add MeNHNHMe·2HCl (124 mg, 0.934 mmol, 1.2 eq)and

DBU (443 mg, 2.907 mmol, 4 eq). Reaction was reﬂuxed for 3 hr; product 145 is very polar; TLC monitoring (EtOAc: Hexane, 1:4; Rf(1) = 0.4, Rf (145) = 0)/ (EtOAc: MeOH, 1:4; Rf(1) = 1,

Rf (145) = 0.5) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (pure EtOAC to EtOAc: MeOH,1:

10) to give product as a liquid 154 mg.

1 94 % yield; H NMR (500 MHz, CDCl3) δ 3.40 (s, 3 H), 3.36 (d, J = 2.0 Hz, 2 H), 3.35 (s, 3

13 H), 2.70-2.57 (m, 4 H), 2.54 (s, 6 H); C NMR (125 MHz, CDCl3) δ 209.17, 106.46, 61.92, 50.68,

49.15, 42.80, 41.45.

O Me Me N MeNHNHMe 2HCl, DBU N Me O MeO iPrOH, reflux Me MeO OMe OMe 1 146

8,8-dimethoxy-2,6,7-trimethyl-6,7-diazabicyclo[3.2.1]octan-3-one(146): reaction procedure refer to 145.

◦ 1 26 % yield; mp 57 - 60 C; H NMR (500 MHz, CDCl3) δ 3.54 (dd, J = 5.0 Hz, J = 3.0 Hz,

1 H), 3.39 (s, 3H), 3.36 (s, 3 H), 2.86 (t, J = 2.0 Hz, 1 H), 2.78 (dd, J = 17.0 Hz, J = 3.0 Hz, 1

H), 2.62 (q, J = 6.5 Hz, 1 H), 2.56 (s, 3 H), 2.51 (m, 1 H), 2.40 (s, 3 H), 1.11 (d, J = 7.0 Hz, 3

H); 13C NMR (125 MHz, CDCl3) δ 210.40, 106.25, 68.76, 61.86, 50.64, 49.04, 46.94, 44.89, 39.46,

38.36, 12.24.

O Me N MeNHNHMe 2HCl, DBU N Me O MeO Me iPrOH, reflux Me MeO OMe OMe 1 147

8,8-dimethoxy-1,6,7-trimethyl-6,7-diazabicyclo[3.2.1]octan-3-one(147): reaction procedure refer 2.7. EXPERIMENTAL SECTION 69 to 145.

1 56 % yield; H NMR (500 MHz, CDCl3) δ 3.43 (s, 3 H), 3.42 (s, 3 H), 3.20 (t, J = 3.0 Hz, 1

H), 2.74 (dd, J = 17.0 Hz, J = 8.0 Hz, 1 H), 2.62 (dd, J = 17.5 Hz, J = 2.5 Hz, 1 H), 2.58 (s, 3

H), 2.52 (dt, J = 16.5 Hz, J = 2.5 Hz, 1 H), 2.46 (d, J = 17.5 Hz, 1 H), 2.36 (s, 3 H), 1.22 (s, 3

H); 13C NMR (125 MHz, CDCl3) δ 209.27, 105.06, 66.34, 61.17, 49.89, 49.61, 46.58, 46.48, 43.86,

35.69, 18.73.

2.7.5 Chlorination of Mixed Quinone Monoketals

O OH OH Cl MeNHNHMe•2HCl Cl + MeCN, reflux R R' R R'

a NMR ratio of an inseparable mixture. b Isolated yield. c The crude NMR ratio is 1 : 1.6.

O OH OH MeNHNHMe 2HCl Cl Cl + MeCN, reflux MeO OEt OMe OEt 57 92 137 ratio 1 : 3.5

To a stirred solution of 57 (28 mg, 0.166 mmol, 1 eq) in 3 mL MeCN, add MeNHNHMe·2HCl

(27 mg, 0.200 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete (Rf: 57 = 0.3; 92

= 137 = 0.4). Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash 70 CHAPTER 2. O-CHLORINATION chromatography (EtOAc: Hexane, 1:10) to give solid product 24 mg. 1H NMR (refer to attached spectra) showed mixture of 92 and 137, and the ratio of 92: 137 is 1: 3.5.

O OH OH MeNHNHMe 2HCl Cl Cl + MeCN, reflux i MeO O Pr OMe OiPr 63 92 138 ratio 1 : 7.5

To a stirred solution of 63 (80 mg, 0.439 mmol, 1 eq) in 3 mL MeCN, add MeNHNHMe·2HCl

(44 mg, 0.527 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete (Rf: 63 = 0.3; 92

= 138 = 0.4). Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product 65 mg. 1H NMR (refer to attached spectra) showed mixture of 92 and 138, and the ratio of 92: 138 is 1: 7.5.

O OH MeNHNHMe 2HCl Cl

MeCN, reflux MeO O OMe 136 92

To a stirred solution of 136 (75 mg, 0.421 mmol, 1 eq) in 3 mL MeCN, add MeNHNHMe·2HCl

(67 mg, 0.505 mmol, 1.2 eq) at room temperature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete (Rf: 136 = 0.3;

92 = 0.4). Solvent was removed under reduced pressure and the mixture was puriﬁed via ﬂash chromatography (EtOAc: Hexane, 1:10) to give solid product 54 mg. 1H NMR (refer to attached spectra) showed 92 as the only product, yield 81 %.

4-((tert-butyldimethylsilyl)oxy)-2-chlorophenol(139): To a stirred solution of 77 (170 mg, 0.669 mmol, 1 eq) in 5 mL MeCN, add MeNHNHMe·2HCl (107 mg, 0.803 mmol, 1.2 eq) at room tem- 2.7. EXPERIMENTAL SECTION 71

O OH OH Cl Cl MeNHNHMe 2HCl + MeCN, reflux MeO OTBS OMe OTBS 77 92 139 perature. The reaction was then reﬂuxed for 0.5 hr, TLC monitoring (EtOAc: Hexane, 1:10) with

CAM stain showed reaction complete (Rf: 77 = 0.55; 139 = 0.45; 92 = 0.3). Solvent was removed under reduced pressure and a 1H NMR spectra (refer to the attached spectra) was taken for the crude product (ratio of 92: 139 = 1: 1.6). Then the mixture was puriﬁed via ﬂash chromatography

(EtOAc: Hexane, 1:40 to 1:20) to give solid product 139 80 mg (yield 46 %) and 92 27 mg (yield

25 %).

1 3w, 46 % yield; H NMR (500 MHz, CDCl3) δ 6.87 (d, J = 9.0 Hz, 1 H), 6.82 (d, J = 3.0 Hz, 1 H),

6.67 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 5.24 (s, 1 H), 0.97 (s, 9 H), 0.17 (s, 6 H); 13C NMR (125

MHz, CDCl3) δ 149.29, 145.94, 120.24, 120.02, 119.52,116.27, 25.63, 18.13, -4.57; HRMS HRMS m/z Calcd C12H18ClO2Si- (M-H)-: 57.0765, Found: 257.0756.

2.7.6 Mechanism Study: synthesis of 14 and scrambling experiments

O OH Cl MeNHNHMe 2HCl, 1.2 eq

MeCN, m. w., 120 C, 2hr Ph OMe Ph 142 143

3-chloro-[1, 1’-biphenyl]-4-ol(143):12 To a solution of 13 (100 mg, 0.500 mmol, 1 eq) in 3 ml

MeCN in a CEM microwave tube add MeNHNHMe·2HCl (80 mg, 0.600 mmol, 1.2 eq). Set reaction parameter as 120 ◦C, 120 min; TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was puriﬁed via

ﬂash chromatography (EtOAc: Hexane, 1:20 to 1:10) to give product 82 mg. 72 CHAPTER 2. O-CHLORINATION

1 80 % yield; H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 2.0 Hz, 1 H), 7.49-7.48 (m, 2 H), 7.41-7.37

13 (m, 3 H), 7.32-7.29 (m, 1 H), 7.06 (d, J = 8.5 Hz, 1 H); C NMR (125 MHz, CDCl3) δ 150.71,

139.52, 134.94, 128.84, 127.47, 127.23, 127.11, 126.68, 120.24, 116.48.

O OH OH Cl Cl MeNHNHMe 2HCl + EtOH, reflux MeO OMe OMe OEt 1 137 92 ratio 1 : 4.3

To a solution of 1 (100 mg, 0.649 mmol, 1 eq) in 3 mL MeCN add MeNHNHMe·2HCl (104 mg, 0.779 mmol, 1.2 eq). Reaction was refluxed for 1 hr; TLC monitoring (EtOAc: Hexane, 1:10) with CAM stain showed reaction complete. Solvent was removed under reduced pressure and the mixture was purified via flash chromatography (EtOAc: Hexane,1: 10) to give product as a inseparable mixture of 92 and 137, 62 mg. The ratio of 92: 137 on 1H NMR is 1: 4.3. Chapter 3

QIK Based Indole Synthesis

73 74 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

3.1 Introduction

As our interests in developing synthetic methodologies from quinonoids, we discovered two hetero- double Michael addition reaction (Chapter 1 and Chapter 2) and o-chlorination of QMK to synthesize o-chlorophenols (Chapter 2). Also we reported the synthesis of bicyclic oxazolidinones from quinols and isocyanates.[142] Quinone imine ketal (QIK), which is another important player of quinonoids family, will be discussed in details in this chapter. It has a N-protected imine moety and can be prepared by a one-step oxidation reaction of N-protected aniline by PIDA (phenyli- doso diacetate). QIK has similar reaction scaﬀolds as QMK (refer to 1.1), but compared to QMK, it is less frequently used in complex natural product synthesis. Literature reported QIK reactions include 1,2-addition, 1,4-addition (Michael addition), allylic substitution and cycloaddition reactions (eg. Diels-Alder reaction) (Scheme 3.1). Swenton reported various nucleophilic additions to QIKs, resulting in either 2-substituted products (Nu = SEt, Cl) via allylic substitution or 3-substituted products (Nu = OAc, OMe, SEt, N3) via Michael addition reaction.[143] He also reported the 1,2-addition reaction of organolithium reagents with QIKs. In a separate study, he found, in dichloromethane and using TsOH as acid, QIKs 150 and trans-β-methylstyrene, could give indoline 151, 4,5-dihydrobenzo[d][1,3]oxazepine 152 or dihydro-benzofuran 153 albeit with low selectivity.[144] Kerr reported the Diels-Alder reaction of QIK 154 with dienes, which after oxidative oleﬁn cleavage, give a number of 5-methoxyl-indole products 156.[145] On the other hand, starting with QIK and a diene with siloxyl ether moiety, the Diels-Alder reaction product 155 was used to prepare the ergot skeleton 157.[146] Maruoka reported the 1,4-addition of N-Acyl enamine

159 to N-Acyl protected QIK 158. A chiral dicarboxylic acid 160 was used and various α-amino-

β-aryl ethers 161 were aﬀorded with high ee.[147] Zhang reported, in 2014, Lewis acid catalyzed

[3+2] coupling reaction of 3-substituted-indole 162 with QMK 163 or QIK 131. A wide variety of benzofuroindolines 164 and tetrahydroindolo[2,3-b]indoles 165 were prepared in high yields by this 3.1. INTRODUCTION 75

Bz Me Me N Ar EtO Me Me TsOH EtO BzHN + Ar + O DCM N + Ar Ar N O EtO OEt Bz Ph 150 151 152 153 Swenton, J. S. J. Org. Chem. 1993, 58 (18), 4802-4.

2 Bz Bz Bz R Bz N NH R1 1. Diels-Alder N N 2 R1 reaction R ref a + R R R O 2. Acid catalyzed R R3 MeO OMe rearomatization R3 4 154 OMe R OMe R4 OMe 155 157 a) Kerr, M. A. Org. Lett. 2001, 3 (21), 3325-3327. ref b 156 b) Kerr, M. A. Synlett 2001, (3), 436-438.

R Boc NHBoc N CO H 2 160 1 CO2H NHR NHR1 + (5 mol%) * R2 R * OMe 2 t OMe R MeO OMe 159 R = 2,6-Me2-4- BuC6H2 158 161 (high ee) Maruoka, K. J. Am. Chem. Soc. 2013, 135 (43), 16010-16013.

MeO Ts MeO O N R3 2 R3 163 R 131 R2 2 MeO OMe R 164 R1 MeO OMe 1 O 165 R Zn(OTf) , TolN Zn(OTf) , Tol R1 N 2 H 2 Ts N H N H H 162 H Zhang, X.-M.Eur. J. Org. Chem. 2014, 2014 (21), 4467-4471.

R PG HN PG O O 168 R3 P N O OH PG = Boc,Ac Bz, Cbz 1 2 R (5 mol%) 3 R R + R OMe N i 1 2 H R = 2,4,6-( Pr)3C6H2 R R (high ee) MeO OMe N 166 167 169 Shi, F. Angew. Chem., Int. Ed. 2014, 53 (50), 13912-13915

Scheme 3.1: Reaction scope of QIKs 76 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

Zn(OTf)2 catalyzed allylic substitution reaction.[148] Shi reported Michael addition reactions of indole 166 to N-Acyl protected QIK 167 to give 3-substituted anilines.[149, 150] In the presence of a chiral binaphthyl-derived phosphoric acid 168, asymmetric arylative dearomatization of indoles

169 was achieved with high ee.

3.2 From QIK to Indole Synthesis

Fischer Indole Synthesis R1 R1 H+ + R2 NH2 N O R2 N H H

• Phenl hydrazine is usually made from phenyl diazonium salt, which is a potentially explosive compound

Bartoli Indole Synthesis 1 R2 R 1) R3 THF, -40 °C R2 O BrMg N N 1 2) aq. NH Cl H R O 4 R1

• Grignard reagent is water and air sensitive.

Larock Indole Synthesis

R3 I R2 R3 R2 Pd(OAc) , Base NH 2 N 1 R R1

• Some trasition metal could be toxic and expensive

Gassman Indole Synthesis 1) tBuOCl O SMe 2) MeS 2 Raney Ni R R2 R2 NH N N 3) Et3N R1 R1 R1

• Lengthy procedures

Scheme 3.2: Traditional indole synthesis

Indole is one of the most valued heterocyclic frameworks in pharmaceutical industry. Indole 3.2. FROM QIK TO INDOLE SYNTHESIS 77 displays a wide range of bioactivities and is a common synthetic target for medicinal chemists. Since

Fischer’s first synthesis of indole, a number of indole synthesis were developed. These methods are suitable for different indole scaffolds, but in general, they suffer one or more of the shortcomings

(Scheme 3.2): 1) requires strong acid or base; 2) requires heating or very low temperature; 3) requires expensive transition metal catalyst; 4) involves toxic or explosive substances; 5) lengthy steps; 6) delicate reaction conditions (air free or moisture free). Some common indole synthesis methods are listed in Scheme 3.2. Traditional Fischer indole synthesis requires phenyl hydrazine, which is usually prepared from diazonium salt–a potential explosive intermediate. Bartoli indole synthesis requires grignard reagent, which is a strong base and water sensitive. Gassman indole synthesis suffers from a lengthy procedure. A number of transition metal mediated indole synthesis, including Larock indole synthesis, were developed. However many transition metal catalysts are expensive and toxic and removing traces of metal is difficult and often requires dedicate instruments and processes. Therefore, because of the high need and interest in indole, it is necessary to find new chemical reactions to make indole that lack these obstacles.

QIK, like QMK, can be used to synthesize diverse frameworks. Our group ﬁrst reported a variation of Fischer indole synthesis from QMK and double Michael addition reactions of QMK.

Due to the discovery of o-chlorination of QMK, our interests gradually shifted from the 1,4-addition of quinonoids to the allylic substitution of quinonoids. Inspired by our discoveries described in

Chapter 1 and 2 and the literature reports of quinonoids, we envisioned an indole synthesis from

QIK and alkenyl ethers.

Our goal was to develop an indole synthesis from QIK and alkenyl ethers under mild conditions. QIK can be prepared in one step by oxidation of N-protected anilines while alkenyl ether, such as vinyl ethers, are cheap commercially available reagents. Herein, two other groups’ work also served as our inspirational source (Scheme 3.3). Kita reported a number of [3+2] coupling 78 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

R' O O Bronsted acid + R' R R MeO OMe alkene OMe

Kita, Y. Organic Letters 2011, 13 (18), 4814-4817 Kita, Y. Angewandte Chemie International Edition 2011, 50 (27), 6142-6146.

BF3•OEt2 Me PhO2SHN Ar O O Me OR + RO N Ar SO2Ph Me HO excess Ar i N TiCl4, Ti(O Pr)4 RO SO2Ph Engler, T. A.The Journal of Organic Chemistry 2000, 65 (8), 2444-2457.

Scheme 3.3: Synthesis of dihydro-benzofuran or indole by acid catalyzed [3+2] coupling of quinonoids reaction of QMK with alkenes to give dihydrobenzofurans.[17, 18, 139] Engler, on the other hand, reported [3+2] condensation of benzoquinoneimines with alkene to give either dihydrobenzofurans or indolines.[151] In both cases, acid was used as catalyst to give the desired allylic substitution products.

3.3 Proposed Indole Synthesis

Our hypothesis was vinyl ether 170 could do a nucleophilic SN2’ attack on the 2 position of QIK

171 under acidic conditions (Scheme 3.4). The intermediate product 172 after aromatization and cyclization could give indoline product 173. The indoline product under acidic condition could be hydrolyzed to give the desired indole product.

N-Tosyl QIK 131 and vinyl ethyl ether 170 were ﬁrst selected as our candidates to try this reaction. To our delight, in the presence of catalytic amount of sulfuric acid in acetonitrile, this 3.4. REACTION CONDITION OPTIMIZATION 79

Proposed indole synthesis

OMe H MeO MeO + OEt OEt R' NPG R' NPG AH 171 170 172

R H+ R OEt N R' N PG R' PG 174 173 Hit finding

Ts N H2SO4 MeO OEt (diluted) + N MeCN Ts MeO OMe 170 131 175

Scheme 3.4: Indole synthesis via [3+2] coupling of QIK and vinyl ether reaction worked smoothly to give a 2,3-unsubstituted-indole product 175 in 35 % yield.

3.4 Reaction Condition Optimization

With this result in hand, subsequently we devoted our attention to optimizing the reaction condition

(Table 3.1). Ethyl vinyl ether has a boiling point (33 ◦C) slightly above room temperature while n-butyl vinyl ether has a much higher boiling point of 94 ◦C. Since n-butyl vinyl ether gives similar reaction yields compared to ethyl vinyl ether, n-butyl vinyl ether was used in the following reactions. Also it was found that using excessive amount of vinyl ether could lead to formation of polymerized side products, which is diﬃcult to remove by column chromatography. 2 equivalent of n-butyl vinyl ether was found to be the optimal condition and was thus used for most reactions.

In the screening of acid catalysts, we found that a number of Brønsted acids and Lewis acids could catalyze the reaction (Table 3.1). PTSA (p-Toluenesulfonic acid), CSA (camphorsulfonic acid), 80 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

Table 3.1: Indole synthesis via [3+2] coupling of QIK and vinyl ether

Ts N n MeO O Bu acid + 0 C to r.t. N MeO OMe (2 eq) Ts 131 176 175

Entry Acid Solvent Yield (%)

1. PTSA (0.1 eq)MeCN 54 %

2. BF3 Et2O (0.1eq) THF 43 % 3. CSA (0.1 eq)MeCN 20 % 4. Cu(OTf)2 (0.1 eq)MeCN 61 % 5. HCOOH (0.1 eq)MeCN 31 %

6. SnCl4 5H2O (0.1 eq) MeCN 59 %

7. SnCl4 (0.1 eq)MeCN 75 % 8. TFBDA (0.1 eq)MeCN 67 % 9. TFBDA (0.2 eq)MeCN 86 % 10. TFBDA (0.4 eq)MeCN 65 % PTSA = p-toluenesulfonic acid; CSA = camphorsulfonic acid, TFBDA = tetrafluorobenzene-1,4-dicarboxylic acid formic acid and TFBDA (tetraﬂuorobenzene-1,4-dicarboxylic acid) give moderate to good reaction yields. TFBDA gave the best yield among all Brønsted acids and when 0.2 eq was used, the reaction gave indole at 86 % yield. Lewis acids, such as Cu(OTf)2 and SnCl4, could catalyze the reaction and gave good yields as well. When SnCl4 (0.1 eq of SnCl4 in dry acetonitrile) was used as acid catalyst, indole was produced in 75 % yield. TFBDA and SnCl4 were selected as optimal conditions to probe the scope of this reaction.

3.5 Reaction Scope Exploration

3.5.1 Reaction of N-Tosyl QIK with alkenyl ether

The reaction scope of this indole synthesis methodology was then explored. In the case of N-Tosyl

QIK, the reaction gave indole or indoline products in moderate to good yields (Table 3.2). 2-Me or 2-OMe substituted QIK 177 and 178, both could react with 189 in the presence of TFDBA to 3.5. REACTION SCOPE EXPLORATION 81

Table 3.2: Reaction of N-Ts QIK with alkenyl ethers

Ts N R acid indole + alkenyl ether 0 C to r.t. or indoline (2 eq) MeO OMe MeCN

Entry QIK Alkenyl ether Product and Yield (%)

MeO OnBu 1. 177 183 (52 %a) 176 N R = Me Me Ts

MeO OnBu 2. 178 184 (71 %a) 176 N R = OMe OMe Ts

OEt Me 179 MeO 3. 131 185 (66 %a) cis & trans R = H N Ts

OEt Et 180 MeO 4. 131 186 (59 %a) cis & trans R = H Et N Ts

O 181 5. 131 MeO 187 R = H O (72 %b; 0 %a) N Ts O 131 MeO O 6. 182 THP 188 R = H N (32 %b; 0 %a) Ts

a b The reaction was catalyzed by 0.2 eq of TFBDA; The reaction was catalyzed by 0.1 eq of SnCl4 (0.1 M SnCl4 in MeCN); THP = tetrahydropyran. 82 CHAPTER 3. QIK BASED INDOLE SYNTHESIS give corresponding indole product 183 and 184 in good yields. Next we explored the reactivity of other vinyl ether reagents. For ethyl-1-propenyl-ether (179, cis and trans), the reaction worked smoothly to give 3-methyl-indole 185, while reaction of QIK 131 and 180 gave 3-ethyl-indole

186. However in the reaction of 131 with 2-methoxy-propene, no 2-methyl-indole product was separated. For dihydrofuran 181, this reaction gives a furoindoline product 187. Since furoindoline moiety appear in a number of bioactive compounds such as Physovenine and Aspidophylline A,[152,

153] this reaction could potentially be used to prepare natural products with such backbone. For dihydropyran 182, the reaction did not give indoline product but aﬀorded indole 188 with hydroxyl group protected by tetrahydropyran under mild acidic conditions. Peculiarly TFBDA did not work for the reaction of 131 with 181 and 182.

3.5.2 Reaction of N-Acyl QIKs with alkenyl ethers

Next we explored the protecting group tolerance of this reaction and we found varied but interesting results (Table 3.3). In the case of Ac, Boc and Bz protected QIK, they react in the same fashion and gave products in similar yields. In most cases the major product was not indole but 1,4 addition products-aldehyde and acetal. Instead of attacking the α position of QIK, vinyl ether preferentially attack the β position of QIKs. In general the aldehyde products of Bz protected QIK are more stable than products of Ac or Boc protected QIK. Thus after TLC indicated the completion of reaction, reactions of Bz protected QIK were worked up by 1M HCl to give corresponding aldehyde and indole products. While the reactions of Ac/Boc protected QIK were neutralized and give acetal (with or without aldehyde as minor products) and indole products. For 2,3-unsubstituted

QIK, 190, 158 and 196 all give aldehyde/acetal as major products in high yields. For 2-methoxy or 2-methyl substituted QIK, 199, 201 and 203 aﬀorded indole 200, 202 and 204 in moderate yields. Lastly 3-methoxy substituted N-Ac QIK 205 give acetal 206 in high yield. Most noteworthy 3.5. REACTION SCOPE EXPLORATION 83

Table 3.3: Reaction of N-Acyl QIKs with alkenyl ethers

R R R1 1 1 N MeO NH NH OnBu acid + + O OBu 0 C to r.t. N R2 or R2 R2 R MeCN 2 (2 eq) R1 OMe MeO OMe OMe OMe

Product and Yield (%)

Entry QIK indole aldehyde acetal

Ac Ac NH NH 1. 190 0 %a 191 OBu 192 R1 = Ac O 9%a a OMe 78% OMe OMe

Boc MeO NH Boc NH 2. 9 %a 158 193 O 194 N OBu 195 R1 = Boc 9%a Boc 68%a OMe OMe OMe

MeO Bz 197 NH 3. 196 N (20%a; 11%b) O 198 R1 = Bz Bz 72%a; 81%b

OMe MeO 4. 199 200 29%b N b 0%b R1 = Ac 0% Ac R2 = 2-OMe OMe

MeO b 5. 201 202 24% b b N 0% 0% R1 = Bz Bz R2 = 2-OMe OMe

MeO 6. 203 204 28%b 0%b 0%b R1 = Bz N Bz R2 = 2-Me Me Ac NH

7. 205 OBu 206 a b b R1 = Ac 0% 0% 76% MeO OMe R2 = 3-OMe OMe

a b The reaction was catalyzed by 0.2 eq of TFBDA; The reaction was catalyzed by 0.1 eq of SnCl4 (0.1 M SnCl4 in MeCN). 84 CHAPTER 3. QIK BASED INDOLE SYNTHESIS is the unique fragrance of these aldehyde products; especially during workup of the reactions, a strong ﬂoral scent is released. Phenylacetaldehyde is fragrant compound produced by many plants as a secondary metabolite to attract insects, such as moths, and it is also used commercially as a fragrance.[154–156] Such molecules are not only of entomology interests, but also could be potentially used as a new type of ﬂavor/fragrance.

3.6 Mechanism

It was puzzling to find that N-Tosyl QIK give mostly allylic substitution products (indole or indoline), while N-Acyl QIK give mainly 1,4-addition products. This could be a result of the difference of electron effects of Tosyl and Acyl on QIK: Brønsted acid or Lewis acid activate the ketal moiety of N-Ts QIK however activate the imine group in N-Acyl QIK. This is in accordance with

Zhang[148] and Shi’s work[149, 150]: under acidic conditions, nucleophile, which is indole, attacks the 2 position of N-Tosyl QIKs to form tetrahydroindolo[2,3-b]indoles, while attacks the 3-position of N-Acyl QIKs to form 3-indolyl-anilines. Similarly in Maruoka’s report, the majority of N-Acyl enamines attack the 3-position of N-Acyl QIKs.[147] Only in one case, N-Boc-2-methoxyl-QIK reacted with enamine to give indoline as the only isolable product in low yield. The mechanism of

N-Bz QIK reacting with vinyl ether to form phenyl acetaldehyde or ketal products is shown in the following scheme (Scheme 3.5). Under acidic condition, the imine moiety of 196 was activated and attacked by butyl vinyl ether 176 to give Michael addition product 207. After aromatization and intramolecular nucleophilic attack of the methoxyl group to oxocarbenium cation, an acetal product 208 could be formed. 208, when treated with acid, will be eventually transformed into phenylacetaldehyde product 198. 3.7. CONCISE SYNTHESIS OF NATURAL PRODUCT LYCORANINE A 85

Bz H Bz HN N NHBz NHBz OnBu H+ H OBu O MeO OMe MeO OMe O Bu 176 O OMe OMe 196 Me 207 208 198

Scheme 3.5: Reaction mechanism

3.7 Concise synthesis of natural product Lycoranine A

To demonstrate the applicability of this new methodology, eventually we designed and completed a short synthesis of Lycoranine A. Lycoranine A (Figure 3.1) is an indole alkaloid isolated from the bulbs of lycoris radiate, an Amaryllidaceae species collected from Zhejiang, China.[157] The crude extracts of this plant has been used in folk medicine for treatment of boils and carbuncles.

Pyrrolophenanthridinone skeleton appears in a number of natural products and is associated with a wide range of bioactivities.[158–160] Synthesis of pyrrolophenanthridinone type of structures has been extensive, but the total synthesis of Lycoranine A was only reported once.[161–164] We envisioned a dibromo-indole intermediate product like 209 could be made by our methodology and readily give Lycoranine A by transition metal catalyzed aryl coupling reaction.

O N O

OMe Lycoranine A

Figure 3.1: Structure and origin of lycoranine A

Starting from 211, after Pinnick oxidation, crude product 212 was aﬀorded and then converted into acyl chloride (Scheme 3.6). Using pyridine as base, coupling product 214 was aﬀorded with an overall yield of 82 % for two steps. Next employing the common QIK protocol, 214 was 86 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

O O O NH2 O PIDA O O (COCl)2 NH N R Br Py Et3N O Br O Br O Br + Br MeOH Br 211 R = H OMe MeO OMe Pinnick OMe oxidation 213 214 (82%) 215 (89 %) 212 R = OH OnBu

SnCl4 (0.1 eq) MeCN

O O O (Bu3Sn)2, O O O N Pd(Ph3)2Cl2 N NH Br O O + O Br Bu4NBr, Li2CO3 PhMe Br Br 210 OMe OMe OMe O Lycoranine A (48 %) 209 (38 %) 216 (39%)

Scheme 3.6: Concise synthesis of Lycoranine A oxidized by PIDA to give QIK 215. With this QIK 215, the desired dibromo-indole product 209 was afforded in 38 % while the aldehyde 216 was afforded in 39 % yield. Eventually we applied Stille coupling condition to 209 and Lycoranine A 210 was given as final product with 48 % yield.[165]

3.8 Conclusion

In summary we developed a new reaction to give indole and phenylacetadehyde by a coupling reaction of QIK and alkenyl ether under mild conditions. Compared to conventional indole synthesis, this method does not require strong base/acid or expensive transition metal catalyst, also all the reagents are widely available. Furthermore we demonstrated the utility of this new methodology in a concise synthesis of Lycoranine A. 3.9. EXPERIMENTAL SECTION 87

3.9 Experimental Section

General Informaiton

Anhydrous acetonitrile was distilled from CaCl2 under an atmosphere of argon. All reagents were purchased from commercial sources or synthesized using literature methods. 1H and 13C NMR spectra were recorded on BRUKE 500 MHz spectrometers; 19F NMR spectra were done on a

Bruker 400 MHz spectrometer. 1H and 13C NMR Chemical shifts (δ values) were reported in ppm

1 13 from downﬁeld using internal standard TMS ( H NMR) or CDCl3 ( C NMR), respectively. All mass spectra were run by Dr. Srinivas V Chakravartula at the Hunter College Mass Spectrometry

Facility and taken on an Agilent 6520A Q-TOF using electrospray ionization. All infrared spectra were taken on a Thermo Nicolet IR100 spectrometer. Column chromatography was performed over silica with a porosity of 60 Å and a particle size of 40-63 µm.

Procedure a: To a solution of QIK (1 mmol) and 2 eq of alkenyl ethers in 3 mL MeCN at 0 ◦C slowly add 0.1 mL SnCl4 (1M in MeCN). The reaction was allowed to warm up to r.t. and stirred for 3 hrs.

The reaction was then treated with 1 mL HCl (1M in water) and stirred for 0.5 hr (in case of N-Ac

QIK or N-Boc QIK, this step is skipped). The reaction was neutralized by NaHCO3 and extracted by DCM. The organic layer was then dried over Na2SO4 and concentrated under reduced pressure.

The concentrated organic layer was subsequently puriﬁed by ﬂash column chromatography (Hexane and EtOAc) to give desired products.

Procedure b: To a solution of QIK (1 mmol) and 2 eq of alkenyl ethers in 3 mL MeCN at 0 ◦C slowly add 0.2 eq of TFBDA. The reactiion was allowed to warm up to r.t. and stirred for 3 hrs.

The reaction was then treated with 1 mL HCl (1M in water) and stirred for 0.5 hr (in case of N-Ac

QIK or N-Boc QIK, this step is skipped). The reaction was neutralized by NaHCO3 and extracted by DCM. The organic layer was then dried over Na2SO4 and concentrated under reduced pressure. 88 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

The concentrated organic layer was subsequently puriﬁed by ﬂash column chromatography (Hexane and EtOAc) to give desired products.

3.9.1 Synthesis of N-Ts-protected indoles and indolines

Ts N OnBu procedure a MeO + 0 C to r.t. N MeO OMe (2 eq) Ts 131 176 175

5-methoxy-1-tosyl-1H-indole(175).

1 Yield 86 %; H NMR(500 MHz, CDCl3) δ 7.87 (d, J = 9.0 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 2 H), 7.51

(d, J = 3.5 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 2 H), 6.96 (d, J = 2.5 Hz, 1 H), 6.92 (dd, J = 9.0 Hz, J =

13 2.5 Hz, 1 H), 6.57 (d, J = 3.5 Hz, 1 H), 3.80 (s, 3 H), 2.33 (s, 3 H); C NMR(125 MHz, CDCl3) δ

156.38, 144.80, 135.26, 131.75, 129.81, 129.58, 127.12, 126.74, 114.41, 113.67, 109.16, 103.60, 55.62,

21.55. HRMS m/z Calcd C16H16NO3S+ (M+H)+: 302.0845, found: 302.0838.

Ts N OMe OnBu procedure a MeO + 0 C to r.t. N (2 eq) MeO OMe OMe Ts 177 176 183

5-methoxy-7-methyl-1-tosyl-1H-indole(183).

1 Yield 52 %; H NMR(500 MHz, CDCl3) δ 7.71 (d, J = 4.0 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 2 H),

7.20 (d, J = 8.5 Hz, 2 H), 6.82 (d, J = 2.5 Hz, 1 H), 6.63 (d, J = 2.5 Hz, 1 H), 6.60 (d, J = 3.5

13 Hz, 1 H), 3.79 (s, 3 H), 2.53 (s, 3 H), 2.35 (s, 3 H); C NMR(125 MHz, CDCl3) δ 153.88, 142.12,

134.35, 131.76, 128.39, 127.45, 127.34, 124.06, 124.01, 114.47, 106.90, 98.90, 53.10, 19.42, 19.21.

HRMS m/z Calcd C17H18NO3S+ (M+H)+: 316.1002, found: 316.0994. 3.9. EXPERIMENTAL SECTION 89

Ts N OMe OnBu procedure a MeO + 0 C to r.t. N (2 eq) MeO OMe OMe Ts 178 176 184

5,7-dimethoxy-1-tosyl-1H-indole(184).

1 Yield 71 %; H NMR(500 MHz, CDCl3) δ 7.69 (d, J = 3.5 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.16

(d, J = 8.0 Hz, 2 H), 6.50 (d, J = 2.5 Hz, 1 H), 6.47 (d, J = 3.5 Hz, 1 H), 6.23 (d, J = 2.5 Hz, 1

13 H), 3.70 (s, 3 H), 3.58 (s, 3 H), 2.30 (s, 3 H); C NMR(125 MHz, CDCl3) δ 157.15, 147.84, 144.10,

137.25, 133.80, 129.32, 129.18, 127.31, 119.59, 107.18, 97.32, 95.04, 55.64, 55.39, 21.59. HRMS m/z

Calcd C17H18NO4S+ (M+H)+: 332.0951, found: 332.0954.

Ts N Me OnBu procedure a MeO + 0 C to r.t. N MeO OMe Ts (2 eq) 131 179 185

5,7-dimethoxy-3-methyl-1-tosyl-1H-indole(185).

1 Yield 66 %; H NMR(500 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 2 H),

7.21 (d, J = 8.5 Hz, 2 H), 6.94 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H), 6.89 (d, J = 2.5 Hz, 1 H), 3.85

13 (s, 3 H), 2.35 (s, 3 H), 2.23 (d, J = 1.5 Hz, 3 H); C NMR(125 MHz, CDCl3) δ 156.37, 144.53,

135.36, 132.83, 129.96, 129.72, 126.69, 123.93, 118.69, 114.64, 113.37, 101.97, 55.69, 21.54, 9.77.

HRMS m/z Calcd C17H18NO3S+ (M+H)+: 316.1002, found: 316.1003.

3-ethyl-5-methoxy-1-tosyl-1H-indole(186).

1 Yield 59 %; H NMR(500 MHz, CDCl3) δ 7.78 (dd, J = 9.0 Hz, J = 0.5 Hz, 1 H), 7.62 (d, J = 90 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

Ts N Et OnBu procedure a MeO + N Et 0 C to r.t. MeO OMe Ts (2 eq) 131 180 186

8.5 Hz, 2 H), 7.18 (s, 1 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 2.5 Hz, 1 H), 6.81 (dd, J =

6.5 Hz, J = 2.5 Hz, 1 H), 3.72 (s, 3 H), 2.54 (qd, J = 7.5 Hz, J = 1.0 Hz, 2 H), 2.22 (s, 3 H),

13 1.20 (t, J = 7.5 Hz, 3 H); C NMR(125 MHz, CDCl3) δ 155.24, 143.50, 134.28, 131.07, 129.08,

128.67, 125.62, 124.33, 121.84, 113.63, 112.23, 101.07, 54.63, 20.47, 17.15, 12.07. HRMS m/z Calcd

C18H20NO3S+ (M+H)+: 330.1158, found: 330.1151.

Ts N O procedure a MeO + O 0 C to r.t. N MeO OMe (2 eq) Ts 131 181 187

5-methoxy-8-tosyl-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole(187).

1 Yield 72 %; H NMR(500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 9.0 Hz, 1 H),

7.22 (d, J = 8.5 Hz, 2 H), 6.71 (dd, J = 8.5 Hz, J = 2.5 Hz, 1 H), 6.67 (d, J = 2.0 Hz, 1 H), 6.17

(d, J = 6.5 Hz, 1 H), 3.96 (t, J = 7.5 Hz, 1 H), 3.80 (t, J = 7.5 Hz, 1 H), 3.74 (s, 3 H), 3.37-3.30

13 (m, 1 H), 2.36 (s, 3 H), 2.29-2.21 (m, 1 H), 2.00 (m, 1 H); C NMR(125 MHz, CDCl3) δ 156.68,

143.81, 136.30, 135.10, 133.16, 129.58, 127.32, 114.17, 113.31, 110.91, 96.24, 66.48, 55.67, 45.75,

33.58, 21.54; HRMS m/z Calcd C18H20NO4S+ (M+H)+: 346.1108, found: 346.1101.

Ts N O procedure a MeO O + THP 0 C to r.t. N MeO OMe (2 eq) Ts 131 182 188 3.9. EXPERIMENTAL SECTION 91

5-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1-tosyl-1H-indole(188).

1 Yield 32 %; H NMR(500 MHz, CDCl3) δ 7.84 (d, J = 10.0 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 2 H),

7.27 (s, 1 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.89 (m, 2 H), 4.55 (dd, J = 4.5 Hz, J = 2.5 Hz, 1 H),

3.86-3.80 (m, 1 H), 3.78 (s, 3 H), 3.77-3.75 (m, 1 H), 3.50 (m, 1 H), 3.40 (m, 1 H), 2.71-2. 67

(m, 2 H), 2.30 (s, 3 H), 1.97-1.93 (m, 2 H), 1.82 (m, 1 H), 1.72 (m, 1 H), 1.57-1.52 (m, 4 H); 13C

NMR(125 MHz, CDCl3) δ 156.31, 144.56, 135.27, 132.17, 130.12, 129.72, 126.68, 123.64, 123.04,

114.71, 113.34, 102.16, 99.11, 66.71, 62.59, 55.70, 30.82, 28.83, 25.48, 21.57, 21.55, 19.80; HRMS m/z Calcd C24H29NNaO5S + (M+Na)+: 466.1659, found: 466.1662.

3.9.2 Reaction of N-Acyl QIKs with alkenyl ethers

Ac Ac Ac N NH NH n O Bu acid + O OBu 0 C to r.t. + MeCN OMe MeO OMe (2 eq) OMe OMe 190 176 191 192

N-(4-methoxy-3-(2-oxoethyl)phenyl)acetamide(191).

1 Yield 9 % (procedure a); H NMR(500 MHz, CDCl3) δ 9.68 (t, J = 2.0 Hz, 1 H), 7.67 (s, 1 H),

7.41 (dd, J = 9.0 Hz, J = 3.0 Hz, 1 H), 7.29 (d, J = 2.5 Hz, 1 H), 6.84 (d, J = 9.0 Hz, 1 H), 3.80

13 (s, 3 H), 3.62 (d, J = 2.0 Hz, 2 H), 2.14 (s, 3 H); C NMR(125 MHz, CDCl3) δ 200.12, 168.60,

154.44, 131.15, 123.85, 121.56, 121.07, 110.73, 55.67, 45.36, 24.23; HRMS m/z Calcd C11H14NO3+

(M+H)+: 208.0968, found: 208.0971.

N-(3-(2-butoxy-2-methoxyethyl)-4-methoxyphenyl)acetamide(192).

1 Yield 78 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.82 (s, 1 H), 7.47 (dd, J = 8.0 Hz, J =

2.5 Hz, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 4.65 (t, J = 5.5 Hz, 1 H), 4.64

(s, 3 H), 3.78-3.56 (m, 1 H), 3.41-3.37 (m, 1 H), 3.31 (s, 3 H), 2.88 (d, J = 5.5 Hz, 1 H), 2.17 (s, 3 92 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

H), 2.11 (s, 3 H), 1.53-1.47 (m, 2 H), 1.35-1.30 (m, 2 H), 0.87 (t, J = 7.0 Hz, 3 H); 13C NMR(125

MHz, CDCl3) δ 207.22, 168.61, 154.42, 130.85, 125.91, 123.80, 119.97, 110.40, 103.22, 66.29, 55.56,

53.16, 34.64, 31.87, 30.92, 24.14, 19.29, 13.85; HRMS m/z Calcd C16H26NO4+ (M+H)+: 296.1856, found: 296.1856.

Boc N Boc Boc n NH NH O Bu acid MeO + O OBu 0 C to r.t. N + + MeO OMe (2 eq) MeCN Boc OMe 158 176 OMe OMe 193 194 195

tert-butyl 5-methoxy-1H-indole-1-carboxylate(193).

1 Yield 9 % (procedure a); H NMR(500 MHz, CDCl3) δ 8.01 (s, 1 H), 7.56 (s, 1 H), 7.02 (d, J = 2.5

Hz, 1 H), 6.92 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H), 6.49 (d, J = 3.5 Hz, 1 H), 3.84 (s, 3 H), 1.66 (s,

13 9 H); C NMR(125 MHz, CDCl3) δ 155.82, 131.36, 126.51, 115.83, 112.96, 107.10, 103.46, 83.48,

55.68, 28.21.

tert-butyl (4-methoxy-3-(2-oxoethyl)phenyl)carbamate(194).

1 Yield 9 % (procedure a); H NMR(500 MHz, CDCl3) δ 9.69 (t, J = 2.0 Hz, 1 H), 7.24 (d, J =

9.0 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 6.37 (s, 1 H), 3.81 (s, 3 H), 3.64 (d, J = 2.0 Hz, 2 H),

13 1.53 (s, 9 H); C NMR(125 MHz, CDCl3) δ 153.77, 153.16, 131.14, 125.93, 122.51, 118.45, 110.72,

103.85, 55.69, 53.19, 34.11, 28.39; HRMS m/z Calcd C14H19NNaO4 + (M+Na)+: 288.1206, found:

288.1201.

tert-butyl (3-(2-butoxy-2-methoxyethyl)-4-methoxyphenyl)carbamate(195).

1 Yield 68 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.27 (s, 1 H), 7.07 (d, J = 2.5 Hz, 1 H),

6.75 (d, J = 8.5 Hz, 1 H), 6.39 (s, 1 H), 4.65 (t, J = 5.5 Hz, 1 H), 3.77 (s, 3 H), 3.61-3.56 (m,

1 H), 3.40-3.35 (m, 1 H), 3.31 (s, 3 H), 2.88 (d, J = 5.5 Hz, 2 H), 1.53-1.47 (m, 2 H), 1.49 (s, 9 3.9. EXPERIMENTAL SECTION 93

13 H), 1.35-1.30 (m , 2 H), 0.87 (t, J = 7.0 Hz, 3 H); C NMR(125 MHz, CDCl3) δ 153.79, 153.14,

131.08, 126.15, 122.61, 118.35, 110.65, 103.24, 80.09, 66.21, 55.68, 53.14, 34.61, 31.91, 28.38, 19.33,

13.88; HRMS m/z Calcd C19H31NNaO5 + (M+Na)+: 376.2094, found: 376.2097.

Bz N Bz n NH O Bu acid MeO + O 0 C to r.t. N + MeO OMe (2 eq) MeCN Bz 196 176 OMe 197 198

(5-methoxy-1H-indol-1-yl)(phenyl)methanone(197).

1 Yield 20 % (procedure a); 11 % (procedure b). H NMR(500 MHz, CDCl3) δ 8.24 (d, J = 9.0 Hz,

1 H), 7.64 (m, 2 H), 7.52 (m, 1 H), 7.44 (m, 2 H), 7.19 (d, J = 3.0 Hz, 1 H), 6.99 (d, J = 2.5 Hz,

1 H), 6.92 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H), 6.47 (dd, J = 4.0 Hz, J = 0.5 Hz, 1 H), 3.81 (s, 3

13 H); C NMR(125 MHz, CDCl3) δ 168.39, 156.73, 134.62, 131.79, 131.77, 130.73, 129.11, 128.57,

128.28, 117.23, 113.39, 108.53, 103.61, 55.71. HRMS m/z Calcd C16H14NO2+ (M+H)+: 252.1019, found: 252.1029.

N-(4-methoxy-3-(2-oxoethyl)phenyl)benzamide(198).

1 Yield 72 % (procedure a); 81 % (procedure b). H NMR(500 MHz, CDCl3) δ 9.55 (t, J = 2.0 Hz,

1 H), 8.15 (s, 1 H), 7.76 (d, J = 7.5 Hz, 2 H), 7.46-7.43 (m, 1 H), 7.41 (d, J = 7.0 Hz, 1 H), 7.33

(d, J = 7.5 Hz, 2 H), 6.74 (d, J = 9.0 Hz, 1 H), 3.68 (s, 3 H), 3.48 (d, J = 1.5 Hz, 2 H); 13C

NMR(125 MHz, CDCl3) δ 200.13, 165.91, 154.59, 134.81, 131.72, 131.20, 128.66, 127.13, 124.21,

121.62, 121.46, 110.75, 55.67, 45.37; HRMS m/z Calcd C16H16NO3+ (M+H)+: 270.1125, found:

270.1121. 94 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

Ac N n OMe O Bu acid MeO + 0 C to r.t. N MeO OMe MeCN (2 eq) OMe Ac 199 176 200

1-(5,7-dimethoxy-1H-indol-1-yl)ethan-1-one(200).

1 Yield 29 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.61 (d, J = 3.5 Hz, 1 H), 6.67 (d, J = 2.0

Hz, 1 H), 6.53 (d, J = 3.5 Hz, 1 H), 6.50 (d, J = 2.0 Hz, 1 H), 3.95 (s, 3 H), 3.88 (s, 3 H), 2.67 (s,

13 3 H); C NMR(125 MHz, CDCl3) δ 169.58, 157.42, 148.53, 134.51, 128.21, 119.49, 108.03, 97.25,

95.24, 55.72, 55.68, 25.81. HRMS m/z Calcd C12H14NO3+ (M+H)+: 220.0968, found: 220.0964.

Ac N n OMe O Bu acid MeO + 0 C to r.t. N MeO OMe MeCN (2 eq) OMe Ac 201 176 202

(5,7-dimethoxy-1H-indol-1-yl)(phenyl)methanone(202).

1 Yield 24 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.77 (d, J = 6.5 Hz, 2 H), 7.58 (m, 1

H), 7.46 (m, 2 H), 7.39 (d, J = 3.5 Hz, 1 H), 6.68 (d, J = 2.0 Hz, 1 H), 6.54 (d, J = 3.5 Hz, 1

13 H), 6.39 (d, J = 2.0 Hz, 1 H), 3.86 (s, 3 H), 3.58 (s, 3 H); C NMR(125 MHz, CDCl3) δ 167.73,

157.52, 148.57, 134.98, 133.38, 132.50, 129.72, 129.36, 128.28, 120.78, 107.57, 97.01, 94.83. HRMS m/z Calcd C17H16NO3+ (M+H)+: 282.1125, found: 282.1125.

Bz N n Me O Bu acid MeO + 0 C to r.t. N MeO OMe MeCN (2 eq) Me Bz 203 176 204 3.9. EXPERIMENTAL SECTION 95

(5-methoxy-7-methyl-1H-indol-1-yl)(phenyl)methanone(204).

1 Yield 28 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.95 (d, J = 5.0 Hz, 2 H), 7.68 (m, 1 H),

7.58 (m, 2 H), 7.21 (d, J = 3.5 Hz, 1 H), 6.96 (d, J = 2.5 Hz, 1 H), 6.85 (d, J = 2.5 Hz, 1 H), 6.55

13 (d, J = 4.0 Hz, 1 H), 3.90 (s, 3 H), 2.50 (s, 3 H); C NMR(125 MHz, CDCl3) δ 167.49, 156.82,

134.12, 133.00, 132.91, 130.60, 130.34, 129.88, 128.71, 127.35, 116.13, 107.92, 100.97, 55.66, 21.75.

HRMS m/z Calcd C17H16NO2+ (M+H)+: 266.1176, found: 266.1173.

Ac Ac N NH n O Bu acid + OBu OMe 0 C to r.t. MeCN MeO OMe MeO OMe (2 eq) OMe 176 190 206

N-(3-(2-butoxy-2-methoxyethyl)-4,5-dimethoxyphenyl)acetamide(206).

1 Yield 76 % (procedure a); H NMR(500 MHz, CDCl3) δ 7.44 (d, J = 2.0 Hz, 1 H), 7.18 (s, 1 H),

6.66 (d, J = 2.5 Hz, 1 H), 4.63 (t, J = 5.5 Hz, 1 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.65-3.60 (m,

1 H), 3.45-3.40 (m, 1 H), 3.35 (s, 3 H), 2.92 (d, J = 5.5 Hz, 2 H), 2.17 (s, 3 H), 1.56-1.53 (m, 2

13 H), 1.38-1.34 (m, 2 H), 0.91 (t, J = 7.0 Hz, 3 H); C NMR(125 MHz, CDCl3) δ 165.90, 150.38,

141.70, 131.46, 128.68, 111.44, 101.73, 101.52, 64.35, 58.36, 53.47, 51.19, 32.07, 29.60, 22.30, 17.04,

11.58. HRMS m/z Calcd C17H27NNaO5+ (M+Na)+: 348.1781, found: 348.1782.

3.9.3 Synthesis of natural product Lycoranine A

O O O O NH O NaClO2, NaH2PO4 1) oxalyl chloride O OH O Br tBuOH O Br 2) py, NH2 Br O 211 Br Br 212 213 OMe OMe 214 (82%) 96 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

A solution of NaClO2 (3.0 g, 32.75 mmol, 1.5 eq) and NaH2PO4·H2O (5.3 g, 43.66 mmol, 2 eq) in H2O (50 mL) was added dropwisely to a suspension of 6-bromo-piperonal 211 (5.0 g, 21.83 mmol, 1 eq) in 50 mL t-BuOH containing 5 mL 2,3-dimethyl-butene (65.49 mmol, 3 eq), keeping the temperature below 30 ◦C. The mixture was stirred vigorously for 3 h, then adjusted to pH1 with concentrated aqueous HCl and extracted with EtOAc (3 × 50 mL). The combined organic phase was ﬁrst dried over Na2SO4 and concentrated under reduced pressure to give white gross product 6.6 g. Next 3.8 g product (around 12.6 mmol) was added to a solution of oxalyl chloride

(5.0 mL, excessive), and reaction was refluxed for 1 hr. Then oxalyl chloride was removed under reduced pressure and reaction was further dried by vacuum pump for 1 hr. 50 mL dry THF was added to the flask of acid chloride following by adding a solution of 2-bromo-p-anisidine 213 (2.55 g, 12.6 mmol) dissolved in 10 mL THF at 0 ◦C. Pyridine (1 mL, 12.6 mmol) was then added dropwisely and the reaction was slowly warmed up to room temperature and stirred overnight. 50 mL hexane was added to the reaction and reaction was filtered to give a purple solid, which was purified by flash chromatography with pure dichloromethane to give 4.4 g white solid.

◦ 1 Two step overall yield 82 %; m.p. 129-131 C; H NMR(500 MHz, CDCl3) δ 8.23 (d, J = 9.0 Hz,

1 H), 7.90 (s, 1 H), 7.08 (s, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 6.98 (s, 1 H), 6.84 (dd, J = 9.0 Hz, J

13 = 2.5 Hz, 1 H), 5.98 (s, 2 H), 3.73 (s, 3 H); C NMR(125 MHz, CDCl3) δ 163.82, 155.80, 149.12,

146.66, 129.84, 127.89, 122.48, 116.74, 113.86, 112.91, 112.50, 110.05, 108.73, 101.47, 54.78; HRMS m/z Calcd C15H12Br2NO4+ (M+H)+: 427.9126, Found: 427.9133.

O O PIDA O NH O N Et3N O Br O Br Br MeOH Br

OMe MeO OMe 214 215 (89 %) 3.9. EXPERIMENTAL SECTION 97

To a solution of 214 (5.8 g, 13.52 mmol, 1 eq) in 50 mL MeOH and Et3N (5.6 mL, 46.2 mmol,

3eq), add PIDA (5.2 g, 16.22 mmol, 1.2 eq), then reaction was stirred for 3 hr at room temperature

(note: product has the same Rf value with starting material). After the reaction was complete, the solvent was removed under reduced pressure and the residue was dissolved in a slurry of silica jel

(neutralized by Et3N). Then the solvent was removed again and the compound loaded on dry silica was puriﬁed by ﬂash chromatography (EtOAc/Hexane 1/10 with 2 % of Et3N to EtOAc/Hexane

1/4 with 2 % of Et3N) to give a light red solid 5.5 g.

◦ 1 89 % yield; m.p. 104-108 C; H NMR(500 MHz, CDCl3) δ 7.38 (s, 1 H), 7.11 (d, J = 2.5 Hz, 1 H),

7.11 (s, 1 H), 6.53 (dd, J = 10.0 Hz, J = 2.5 Hz, 1 H), 6.49 (d, J = 10.5 Hz, 1 H), 6.07 (s, 2 H),

13 3.35 (s, 6 H); C NMR(125 MHz, CDCl3) δ 177.89, 151.57, 151.36, 147.28, 141.32, 139.30, 126.95,

124.46, 122.83, 114.77, 114.75, 111.88, 102.68, 94.92, 50.48; HRMS m/z Calcd C16H14Br2NO5+

(M+H)+: 457.9234, Found: 457.9239.

O O O OnBu O O N O NH N Br + Br O Br O O Br Br Br SnCl4 (0.1 eq) MeCN MeO OMe OMe OMe O 215 209 (38 %) 216 (39%)

To a solution of 215 (880g, 1.917 mmol, 1 eq) in 10 mL dry MeCN and butyl-vinyl-ether (495

◦ ul, 3.834 mmol, 2 eq) add 0.1 M SnCl4 (2 mL, 0.1 eq) via a syringe pump over 20 min at 0 C, reaction was stirred overnight. Add 5 mL aqueous 1N HCl, and reaction was stirred for 1 hr and then neutralized with NaHCO3 and extracted with DCM. The organic layers were concentrated under reduced pressure and puriﬁed by ﬂash column chromatography (EtOAc/Hecane, 1/20 to 1/4) to give 209 330 mg and 216 360 mg.

1 209 38 % yield; m.p. ; H NMR(500 MHz, CDCl3) δ 7.22 (d, J = 2.0 Hz, 1 H), 7.13 (s, 1 H), 7.06 (d, 98 CHAPTER 3. QIK BASED INDOLE SYNTHESIS

J = 4.0 Hz, 1 H), 7.06 (s, 1 H), 7.03 (d, J = 2.5 Hz, 1 H), 6.52 (d, J = 4. 0 Hz, 1 H), 6.10 (s, 2 H),

13 3.86 (s, 3 H); C NMR(125 MHz, CDCl3) δ 164.79, 156.77, 150.12, 147.66, 130.84, 128.88, 123.40,

117.73, 114.77, 113.91, 113.50, 111.04, 109.73, 102.44, 55.77; HRMS m/z Calcd C17H12Br2NO4+

(M+H)+: 451.9131, Found: 451.9133.

◦ 1 216 39 % yield; m.p. 164-168 C; H NMR(500 MHz, CDCl3) δ 9.69 (t, J = 1.5 Hz, 1 H), 8.38 (d,

J = 9.0 Hz, 1 H), 8.04 (s, 1 H), 7.19 (s, 1 H), 7.10 (s, 1 H), 6.98 (d, J = 9.0 Hz, 1 H), 6.09 (s, 2

13 H), 4.02 (d, J = 1.0 Hz, 2 H), 3.87 (s, 3 H); C NMR(125 MHz, CDCl3) δ 198.31, 164.94, 155.23,

150.15, 147.68, 130.84, 129.14, 122.71, 122.44, 118.85, 113.52, 111.05, 109.97, 109.66, 102.45, 56.22,

45.23; HRMS m/z Calcd C17H14Br2NO5+ (M+H)+: 469.9222, Found: 469.9239.

O O (Bu3Sn)2, O O N N Br Pd(Ph3)2Cl2 O O Br Bu4NBr, Li2CO3 PhMe OMe 210 OMe 209 Lycoranine A (48 %)

To a schlenk tube in glovebox, add 209 (50 mg, 0.11 mmol, 1 eq), Bu4NBr (55 mg, 0.17 mmol,

1.5 eq), Li2CO3 (8 mg, 0.11 mmol, 1 eq), PdCl2 (2 mg, 0.01 mmol, 0.1 eq), PPh3 (7 mg, 0.03 mmol,

0.25 eq), (Bu3Sn)2 (56 ul, 0.11 mmol, 1 eq) and 5 mL dry toluene. The schlenk tube was sealed and refluxed at 120 ◦C for 24 hrs. Next reaction was concentrated under reduced pressure and purified by column chromatography (EtOAc/Hexane 1:10 to 1:4) to afford 14 mg 210 (Lycoranine A) as white solid while 5 mg starting material was recovered.

1 Yield 48 %; H NMR(500 MHz, CDCl3) δ 8.01 (d, J = 3.5 Hz, 1 H), 7.99 (s, 1 H), 7.60 (s, 1 H),

7.50 (d, J = 2.0 Hz, 1 H), 7.31 (d, J = 2.0 Hz, 1 H), 6.83 (d, J = 3.5 Hz, 1 H), 6.17 (s, 2 H),

13 3.97 (s, 3 H); C NMR(125 MHz, CDCl3) δ 157.93, 157.59, 152.52, 148.66, 131.27, 128.92, 126.28,

124.10, 122.82, 116.92, 110.71, 108.21, 107.35, 105.97, 102.32, 101.85, 56.35. HRMS m/z Calcd

C17H12NO4+ (M+H)+: 294.0761, Found: 294.0756. Chapter 4

Synthetic Study of Phalarine

99 100 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

Part I (Chapter 1, 2 and 3) of this thesis described the research studies of quinonoids (mainly

QMK and QIK) based methodologies to synthesize various heterocycles, Part II of this thesis will be dedicated to the synthetic studies of natural product—phalarine.

4.1 Introduction

Phalarine is an indole alkaloid separated from the perennial grass P. coerulescens by Colegate and coworkers and its structure was determined by intensive NMR and MS studies.[166] Although it does not possess promising bioactivities, the novel fused furanobisindole framework (Figure 4.1) has attracted attention from synthetic organic community. Speciﬁcally, along the axis of two stereocenters C4a and C9a, three rings are fused onto this axis to give a unique propeller-like structure.

Danishefsky group, among all, was particularly interested in the synthesis of this alkaloid[167–171].

D C 6' OMe O 5' 7' 4 E 5 Me 7'a 4' 6 4a N 3'a NH A F B 9a 7 3' 2' 8a N 8 H Phalaris coerulescens NMe 2 view through C-9a/C-4a bond (-)-phalarine

Figure 4.1: Structure and origin of phalarine

4.2 Synthesis of Phalarine by Danishesky Group

4.2.1 The Biosynthesis of Palarine and Biomimetic Synthesis

The proposed biosynthesis of phalarine is the oxidative coupling of tetrahydro-beta-carboline 218 and an oxygenated gramine unit 219 (Scheme 4.1).[167] A biomimetic synthetic strategy, if suc- ceeded, could readily construct the fused furanobisindole moiety and facilitate the total synthesis 4.2. SYNTHESIS OF PHALARINE BY DANISHESKY GROUP 101

Proposed biosynthesis of phalarine:

HO OMe OMe O [O] NH NH NMe 4a NMe enzyme

9a N NMe N NMe H 2 H 2 218 219 217

Biomimetic synthesis model studies by Danishefsky group:

OMe OMe biomimetic oxidative coupling NCO2Me HO OMe O + N NCO2Me H OMe 220 221 N 222 H desired coupling product OMe OMe case a) case b) NCO2Me OH PIFA, MeCN 1) t-BuOCl 220 + 221 N 2) CSA, bezene H O NCO2Me OMe N 223 MeO H 224 product of wrong regioselectivity

IR2 O OMe MeO a) OMe O MeO

NCO2Me NCO2Me 223

N N H 220

SN2' Cl Cl NCO Me t-BuOCl 2 NCO2Me 221 b) 220 224 CH2Cl2 CSA, bezene N N 225 H 226

221 OMe CSA, benzene OMe

SN2 [3, 3]-sigmatropic rearrangement O NCO2Me

N H 227

Scheme 4.1: The biomimetic sythesis modelling study of phalarine

of phalarine. Following this goal, Danishefsky group ﬁrst attempted the construction of phalarine backbone via this approach, however this early trial was not successful (Scheme 4.1). The oxida- 102 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE tive coupling of a tetrahydro-beta-carboline 218 and an oxygenated gramine 219 is not feasible because of steric and electric reasons. tetrahydro-beta-carboline 220 and a phenol 221 were selected to test the possibility of the biomimetic oxidative coupling in the aim of forming compound

222. In the modelling study, when oxidant PIFA was used, an intermediate product 223 with wrong regio-selectivity was aﬀorded, while in the case of t-BuOCl, the desired product was not given either. Mechanistically the occurrence of the product 223 in case a) is due to the carbon

C4a of carboline 220 possess stronger nucleophilicity than C9a. The formation of intermediate is directly followed by the oxygen approaching C9a to deliver a product with wrong regio-selectivity.

On the other hand, in case b), once compound 225 was formed. It could give compound 226, which followed by a SN2’ attack of the compound 221 to give product 224. Alternatively, the desired C-O bond could be formed to give product 227, however the reaction pathway did not proceed toward the desired product but instead underwent tautomerizaiton of [3, 3]-sigmatropic rearrangement to give product 224. These eﬀorts, though not successful, provided mechanistic insight to the oxidative coupling of tetrahydro-beta-carboline and phenol.

4.2.2 The Racemic Synthesis of Phalarine

The Ring Expansion Strategy

Given the above results, a new synthetic route via ring expansion was formulated to address the its total synthesis (Scheme 4.2).[168, 169] Starting with an oxindole compound 228, an iminium intermediate such as 229 could be formed. Under acidic conditions, an azaspiroindolenine rearrangement would give compound 230, which is followed by the phenol O attacking C4a to give the desired product 231. This compound 231 could be eventually transformed into phalarine. During an early trial, an imine product 232 was formed. This intermediate, which was expected to do an azaspiroindolenine rearrangement under acidic conditions, did not deliver the desired product 4.2. SYNTHESIS OF PHALARINE BY DANISHESKY GROUP 103

Proposed synthesis:

PG2 R1 N R2 HO

O 3 N OR N PG1 PG1 228 229

OR3

OR3 O HO 2 PG phalarine N PG2 N 4a 9a N N 230 PG1 231 PG1

Observation: hydrogen bonding prevent the free rotation of the aryl group.

CO2Me N O P N

N N (P = CO2Me) H O Ts 232 233

Scheme 4.2: Proposed phalarine synthesis via a ring expansion strategy

233. All the attempts under various acidic conditions led to primarily the recovery of 232. The failure of this seemingly straight forward transformation could be accounted for by the following reasons: a) the migratory aptitude of the urethane-bound methylene carbon could be rather low, b) the hydrogen bonding formed by the phenolic proton and imine nitrogen would restrict the free rotation of the aryl group. This observation suggests a strong protecting group at oxindole nitrogen would be necessary to block the formation of the hydrogen bond while ensure the desired azaspiroindolenine rearrangement to proceed.

Given all the lessons from the previous experiments, the racemic synthesis of phalarine was achieved by the following approach (Scheme 4.3). A tosyl protected spiral oxindole 234 was treated with aryl lithium 235 to form ring opening product 236. Next, the protecting group MOM was removed by TFA to give 237. 237, in the presence of CSA and under reﬂux condition, could give a cyclized intermediate 238, which would further undergo Wagner-Meerwein rearrangement 104 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

Me Me Me N N N OMOM Li O TFA, CH2Cl2 O + OMOM OH O 0 ºC, 98 % N MeO NH NH Ts Ts 234 Ts 235 236 OMe 237 OMe

Me HO OMe O OMe N Me CSA, tolene 4a Me N OH Wagner- N 130 ºC, 72 % 9a Meerwein N N N Ts Ts OMe Ts 238 240 239 key intermediate

OMe Gassman indole O synthesis (10 steps) Me N NH N H NMe2 rac-phalarine

Scheme 4.3: Realization of the ring expansion strategy and the racemic synthesis of phalarine to aﬀord the desired fused ring product 239.

Having this product in hand, next they moved onto the completion of the gramine moiety.

Their initial attempt to ﬁnish the synthesis of molecule by Fischer indole synthesis was not successful. This obstacle was solved by using Gassman indole synthesis. Starting from 239, the target molecule—phalarine—was ﬁnished in 10 steps.

4.2.3 The Asymmetric Synthesis of Phalarine

Once the racemic synthesis of phalarine was accomplished, Danishefsky group aimed to undertake the asymmetric synthesis of phalarine.[170, 171] They assumed by synthesizing enantiopure 234, an asymmetric route could be established to ultimately give enantiopure phalarine (Scheme 4.4).

L-tryptophan, a naturally occurring amino acid, which was frequently employed in the asymmetric synthesis on indole alkaloids, was used as starting material.[172–174] After the enantiopure 234 4.2. SYNTHESIS OF PHALARINE BY DANISHESKY GROUP 105

I 1) Me CO2H OMOM Me N N t-BuLi, THF O NH -78 ºC, 83 % CSA Me 2 O N OH O 2) TFA, CH Cl N 2 2 N N 85 % NH H Ts Ts Ts L-tryptophan (S)- 234 (S)- 241 242 (racemic) Me Me N N N Me 4a OH Retro- OH Pictet- OH 9a Mannich Spengler N 242 (S)- 241 Ts N N (racemic) Ts Ts (S)- 243 244 racemic 245

Scheme 4.4: Failed approach: substantial enantiopure intermediate gave racemic product

was afforded, utilizing the same strategy as in the racemic synthesis depicted in Scheme 4.3, after the reaction with aryl lithium reagent and TFA deprotection of MOM group, enantiopure 241 was afforded. The following step—the acid catalyzed rearrangement—however resulted in a racemic product 242. The formerly proposed Wagner-Meerwein rearrangement could not account for this result, a new mechanism was proposed. The most plausible pathway for this reaction was the reaction intermediate 243 first underwent retro-Mannich to give an iminium cation 244, which upon Pictet-Spengler reaction and C-O bond formation would give the racemic 242.

In the light of this outcome, a diﬀerent strategy was proposed and carried out to transfer the inherent chirality in L-tryptophan to phalarine in a traceless fashion (Scheme 4.5). To build a molecule that carries chiral amino acid moiety on the beta-carbon, they started with L-tryptophan methyl ester 246. Applying known chemistry to convert 246 into iodo compound 247, which serves as a coupling partner. After speciﬁc protection of amino group and indole nitrogen, a Pd catalyzed Suzuki coupling installed the aryl group to the C-2 carbon to give compound 248. After deprotection of the MOM group and Boc group, the amino nitrogen was reprotected by Benzyl group to give 249. This intermediate, in the presence of CSA and molecular sieves, reacted with 106 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

OMOM NH • HCl NH NHBoc 2 2 B(pin)

1) Pd(OAc)2 1) Boc2O, CO Me CO2Me CO2Me 2 MeO 2) I2 NaHCO3, THF I I 3) 1,10-phen 2) TsCl, NaOH Pd(PPh ) , LiCl, N N N 3 4 Na CO , DME:H O H H Ts 2 3 2 246 247 252

NHBoc NHBn

CO Me CO Me 2 2 1) HCl,dioxane CO2Me formalin, CSA N Bn 2) PhCHO 4Å MS, tol OMe OMe 3) NaCHBH N 3 N N Ar Ts OMOM Ts OH Ts 248 249 250

CO2Me CO2Me N CO2Me N Bn Bn O OMe O OMe N OH 4a Ts Bn Me N 4 steps N 9a OMe or N N N Ts HO OMe Ts 251 Ts 239 C3 cyclization product C2 cyclization product single diastereometer junction compound 253 254

Scheme 4.5: Traceless transfer of chirality

formalin to give iminium 250, which further cyclize to afford a single diastereomer 251 in excellent yield. The absolute configuration of this product was validated by NMR and single crystal x-ray diffraction analysis. Next, 251 was converted into the enantiopure junction compound 239. 239 was then subject to similar protocol in the previous racemic synthesis to eventually give enantiopure phalarine.

4.3 Formal Synthesis of Phalarine by Chen

Besides the work of Danishefsky’s group, a number of other research groups also undertook the synthesis of phalarine or relevant methodologies.[175, 176] Among them, Chen group accomplished the formal synthesis of (-)- and (+)-phalarine.[177] 4.3. FORMAL SYNTHESIS OF PHALARINE BY CHEN 107

4.3.1 Retrosynthesis of Phalarine by Chen

Retrosynthetic analysis of (-)-phalarine by Chen: b MeO a OMe O O Me 4' OH N 4a NH a 4' OH b 9a O N 9a H 4a oxidative OH Pd O a NMe coupling 2 b coupling NHTs 256 (-)-phalarine 255

Palladium-catalyzed tandem C-N and C-O bond formation reported by Muniz group.

HO Pd(OAc)2 (0.1 eq) NaOAc/NMe4Cl (1.1 eq) O PhI(OAc)2 (1.6 eq) DMF, 16 h, r.t. NHTs N (87 % yield) Ts 257 258

Scheme 4.6: Proposed synthesis of phalarine by oxidative coupling strategy

Chen envisioned in a retrosynthesis the core structure of phalarine could built from a precursor 255 by an oxidative C-N bond and C-O bond formation (Scheme 4.6). Also by preparing optically pure precursors, diﬀerent enantiomers may give rise to either (-)- or (+)-phalarine. Previously,

Muniz group reported a highly eﬃcient Palladium catalyzed C-N and C-O bond formation to construct bisindoline and fused indoline tetrahydrobenzofuran.[178] In one case, compound 257 in the presence of Pd(OAc)2 could give 258 in 87 % yield. This report provided experimental inspirations for the transformation of 255 to phalarine, while 255 can be prepared by Pd coupling reactions of 256 and aryl reagents.

4.3.2 Formal Synthetic Route of (-)-Phalarine and (+)-Phalarine

Following the proposed strategy, a formal synthesis of phalarine was accomplished by preparing junction compound 239 (Scheme 4.7). Starting from readily available chiral compound 259, iodination gave optically pure cyclopentenone 260, which under Stille coupling conditions with aryl 108 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

O O SnMe3 O O I I , pyr. 2 NO2 K-selectride O O O2N O O2N O 64 % PdCl2(PhCN)2, 86 % O O 63% O O 259 260 261 262

OMe MeO MeO

OTf OBOM H2, Pd/C NaH, PhNTf OBOM OBOM 2 B(OH)2 TsCl, pyr. O2N O O O 90 % Pd(PPh3)4 94 % O 83 % O O NO2 NHTs 263 264 265

MeO Pd(OAc)4 HO 1) H2, Pd(OH)2 O OMe MeNH2 O OMe 2) AcOH OH PIFA NaBH(OAc)3 N 55 % OH 68 % 71 % OH dr = 9:1 N N (junction OH Ts Ts compound) NHTs 266 267 239

Scheme 4.7: Formal synthesis of (-)-phalarine by Chen

stannane to afford 2-aryl enone 261. K-selectride would reduce compound 261 via 1,4-reduction to give compound 262, which was converted into 263 and further treated under Suzuki-Miyaura conditions with aryl boronic acid to give cyclopentene 264. Reduction of the nitro functionality and subsequential tosyl protection gives compound 265. Deprotection of BOM group and hydrolysis of the acetal afforded the intermediate product 266. 266, when subject to the Muniz protocol, afforded 267 and its diastereomer in only 12 % yield. Unsatisfied with this result, a number of oxidants were screened and they found hypervalent-iodine-based reagent PIFA could give the best yield (68 % with a diastereomer ratio of 9:1). 267 and its diastereomer were then separately subjected to a two-step procedure involving oxidative diol cleavage and double reduction amination to afford piperidines 239 and ent-239. These two compounds, following Danishefsky’s protocol, could ultimately give rise to (-)- and (+)-phalarine. 4.4. SYNTHETIC STUDY OF PHALARINE BY ZHENG GROUP 109

4.4 Synthetic Study of Phalarine by Zheng Group

4.4.1 A Short Introduction of Biomimetic Synthesis

The instinctual desire of organic chemists to challenge synthesizing complex natural products has never ebbed and this has been the driving force for innovation in synthetic chemistry over long time.[179] In laboratory, the synthesis of complex chemical structures were often painstakingly done in long sequences of chemical reactions, while in nature, many of these delicate transformations of chemical structures could be achieved in much shorter steps with the assistance of enzymes.

Although graceful and elegant, these transformations are not immediately translatable in laboratory settings. Biomimetic chemistry, which imitates natural reactions and enzymatic processes through organic chemistry reactions, bridges this gap. The successful cases of biomimetic natural product synthesis in the last few decades have greatly boradened the scope of organic chemistry and deepened our understanding of the chemical logic of biochemical transformations in nature.[180,

181] Reported biomimetic synthesis are frequently the result of creative design and experimentation of trials and errors. A biomimetic concise synthesis of phalarine would not only shed light on the chemistry of indole natural products, but also provide mechanistic insight and inspirations to new designs of indole alkaloid synthesis.

4.4.2 Our Planned Synthesis

The works reported by Danishefsky and other groups laid out foundation for this project, which is to design a biomimetic synthesis of phalarine. In a close examination of the synthesis by Danishefsky as also evidenced in Chen’s formal synthesis, much of eﬀorts was devoted the construction of the intermediate 239. A biomimetic approach to build 239, if successful, could substantially reduce the number of steps in phalarine synthesis.

With lessons drawn from Danishefsky’s initial attempts to synthesize phalarine via biomimetic 110 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

OH X N Me X R N Me N Me N O R N O N O Lewis Acid H H HO 268 269 X = Halogen, S-R or Se-R 270

O O

X N Me Phalarine O O N N N O H R HO N N O 239 H Ts 272 271

Scheme 4.8: Proposed formal synthesis of phalarine approach,[167] we envisioned the strategy in Scheme 4.8 to form the junction compound 239.

Essentially, the task is to form the desired C9a-C and C4a-O linkage from an easily available precursor such as 268. 268 could be potentially constructed in short steps. Since C1 adjacent to methylated nitrogen in 268 is masked by carbonyl, this could prevent undesired [3, 3]-sigmatropic rearrangement or SN2’ reaction to form 224 as observed in Scheme 4.1. 268, when subjected to oxidative substitution, could give intermediate 269 with substitution on C4a carbon. The electron rich phenol could then attack 269 at C9a position to form the desired C-C bond, which followed by the subsequential C4a-O bond formation to build the core structure. This compound after tosyl protection and amide reduction could give the key intermediate 239 in Danishefsky’s phalarine synthesis and hence complete a concise formal synthesis of phalarine.

4.4.3 Concise preparation of the starting material via selective methylation

Using known chemistry, 273 is prepared in one step from indole-3-propionic acid in 94 % yield.[182,

183] Starting with 274, DPPA could convert 274 into carbonyl azide, which was treated with

BF3·Et2O, gave 273 after Curtius rearrangement and Pictet-Spengler-like reaction. Now to selectively protect the amide nitrogen with methyl group to make 268, we encountered some obstacles. 4.4. SYNTHETIC STUDY OF PHALARINE BY ZHENG GROUP 111

2 COOH 1) DPPA N R one-step N Me

N 2) BF3·Et2O N O ? N O H (94 % yield) R1 273 H 268 274 275 276 (R1= Boc, R2 = H) (R1= Boc, R2 = Me)

Scheme 4.9: Preparation of the starting material

The indole nitrogen is considerably more reactive than the amide nitrogen. Initially we developed a procedure to first protect the indole nitrogen by Boc group (273−→275), then methylate the amide nitrogen (275−→276) and finally deprotect the indole nitrogen (276−→268). However during the methylation step, strong base would deprotect the Boc group and result in doubly methylated products. This three step sequence on one hand (273−→275−→276−→268) resulted in very low overall yield, on the other comprised the efficiency of our planed synthesis. To develop a one-step selective methylation procedure became imminent.

Luckily, when searching literature, we came across a procedure that give chemo-selective methylation of amide in the presence of other more nucleophilic groups (Scheme 4.10).[184] For example, an aniline with amide moiety 277 when treated with chloromethyldimethylsilyl chloride 278 could produce 279, which is a penta-valent silane intermediate. The formation of this particular penta- coordinated silane complex was conﬁrmed by x-ray in earlier reports.[185] Compound 279 was treated with CsF, desilylation would convert the methylene silyl chloride group into Methyl group and thus aﬀord the selective methylation product 280 in 85 % yield. To our delight, after an un- successful trial with the original protocol, Et3N was used instead of HMDS and the desired product

268 was afforded in 73 % yield. We were worried however that, instead of forming the five-member ring silane intermediate 281, a six-member ring silane intermediate 282 could be formed in com- petition. However, TLC indiated that 281 was the sole intermediate. This is likely attributed to the high stability of five-member ring silane complex as were evidenced in crystallographic analysis 112 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE of related compounds. In this case, 7 g of 268 could be afforded in only two steps from 10 g of

274, which provided us abandant material to experiment the proposed formal synthesis.

Chemoselective methylation of amide (Tetrahedron Lett. 2000, 41, 4933-4936)

Me Me Me Cl Me Me Si O NH2 Cl Si O NH Cl 278 O NH CsF (85 % yield)

HMDS 280 NH2 279 NH2 277 NH2

One-pot selective methylation using chloromethyldimethylsilyl chloride

Me Me Cl Si N H 1. Et N N Me Cl 3 N O 2. CsF, diglyme N O H 273 H 268

N Me NH Si Me N O N O Cl H Si Cl 281 Me Me 282

Scheme 4.10: One-pot selective methylation of amide via penta-valent silane intermediate

4.4.4 Coupling Reaction of the Chloroindolenine and Phenols

Preparation of Chloroindolenine

Me Cl Cl N N Me tBuOCl N Me H2O N Me O CH2Cl2 N O N O O O H N OH N H H 268 283 284 285

Scheme 4.11: Generation of the chloroindolenine coupling precursor

As shown in Scheme 4.8, our plan is to generate a C-4a substituted coupling precursor 269.

Compound 268 was treated with t-BuOCl and the chloroindolenine compound 283 was aﬀorded 4.4. SYNTHETIC STUDY OF PHALARINE BY ZHENG GROUP 113

(Scheme 4.11) while the other attempts to give C4a-selenation or thiolation products failed.[186]

C4a halide-substituted carbolines, such as 283, are prone to nucleophilic attack and were frequently employed in the synthesis of spiral oxindoles.[187–189] This compound 283 once exposed to moisture would produce oxindole 285, thus was generated in situ and used directly to couple with phenols.

Coupling of Chloroindolenine with 3-methylphenol

Compound 283 was first treated with 3-methylphenol in CH2Cl2 and an interesting coupling product was afforded (Scheme 4.12). This product, which was purified by Et3N neutralized column chromatography, is not a stable compound and would diassociate to give 285 and 286 in 1:1 ratio overnight. Two plausible structures, 287 and 288, could account for this change. However after close examination of the NMR, the possibility of 288 was ruled out.

Me Me N Cl OH N Me CH2Cl2 O + O N O O N Me N Me 283 286 N O Me 287 288

Me Me N H O OH 287 2 O O + N Me O N H Me N OHO H 285 286 289 1 : 1

Scheme 4.12: Coupling reaction of chloroindolenine with 3-methylphenol 114 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

Coupling of Chloroindolenine with 3-methoxyphenol

Next, we examined the coupling reaction of 283 and 290 (Scheme 4.13). Ideally, we want to form the C4a-O and C9a-C linkage in one step to give 272. In this case, 272 was not formed, but we did observe the formation of the C9a-C bond. 283 formed in situ, was treated with 290, would give product 291, which has the desired C9a-C linkage, and product 292. It was noted compound

292 has very low solubility and thus resulted in difficult separation. A modified procedure was applied to convert 292 into the Tosyl protected product 293, which upon separation delivered better yield. Danishefsky, in his racemic phalarine synthesis via ring expansion (Scheme 4.2), examined the possibility of converting 232 into 233.[168] Similar to 232, compound 291, under numerous acidic conditions, failed to give a desired ring expansion product and mainly led to the recovery of compound 291. Nonetheless, an interesting Boron complex 294 was afforded as the result of 291 refluxing with BF3·Et2O overnight. All the products in Scheme 4.13 were verified by x-ray single crystal diffraction analysis.

OH Me N Me 290 N Cl OMe N Me O + CH 2Cl 2 O N N O N HO OMe 283 MeO OH 291 45 % 292 30 %

OH Me Me 1) 290 N N OMe O O CH 2Cl 2 + N N 2) TsCl, Et 3N HO OMe MeO OTs

291 45 % 293 40 %

Me Me N N BF 3 • Et 2O O O reflux N N OMe HO OMe F B O F 291 294 78 %

Scheme 4.13: Coupling reaction of chloroindolenine with 3-methoxyphenol 4.4. SYNTHETIC STUDY OF PHALARINE BY ZHENG GROUP 115

The formation of these products are both encouraging and perplexing. On one hand, in the case of the coupling reaction of chloroindolenine 283 and phenol 286, we observed the formation of the C4a-O linkage, while on the other hand, in the case of chloroindolenine 283 and phenol

290, we obtained the C9a-C linkage products. After speculation, the following mechanistical pathway was deduced to account for the observed chemo-selectivity (Scheme 4.14). The methoxy group in 290 is a better electron donating group than the methyl group in 286, thus resulted in the nucleophilic diﬀerences in the two. 286, possessing a less electron-rich arene ring, would attack 283 via phenolic oxygen to give 287 through SN1. As for 3-methoxyphenol, however, the

Coupling reaction of chloroindolenine and 3-methylphenol

Me OH

SN1 N Me Me 283 O N Me N O 287 N O

Coupling reaction of chloroindolenine and 3-methoxyphenol

Me Cl Me N Me N N pathway a O + O 283 N O N N HO OMe MeO OH HO OMe 291 292

pathway b

Cl Cl O N Me Cl N O N N Me N N Me HO O HO O HO O N

N O 295 H 296 OMe OMe 272 MeO desired product

Scheme 4.14: Proposed mechanism for the coupling reaction of chloroindolenine with phenols 116 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE electron rich arene would attack 283 through the para position of either OH or OMe (pathway a), followed by the subsequential ring contraction to deliver either 291 or 292. While in pathway b, followed by the initial arene attack of 283, the phenolic oxygen would attack C4a. This seemingly straightforward pathway b to deliver the desired product 272 did not occur. This is probably due to fused bicyclo[4,3,0] system prefer a cis conformation,[190] while in this case, 3-methoxyphenol would attack C9a via the same side of chlorine to give an intermediate 296. This compound, adopting a cis conformation, would preferentially allow the carbonyl shift and attack C4a from the back side of cholorine.

A new approach was hence developed (Scheme 4.15). Instead of forming the C9a-C linkage,

283 could react with in situ formed silver phenoxide to ﬁrst construct the C4a-O linkage. With the assistance of silver promoted chloride abstraction, 297 could be aﬀorded. 297, followed by the arene attacking C9a, could deliver 272. In pursuing this goal, we tested several silver reagents.

Among them, when Ag2O, AgF and Ag2CO3 were used, a new spot was detected on TLC. This compound, however, is very diﬃcult to separate. Repeated eﬀorts to separate this compound via column chromatography or Prep TLC resulted, in a similar fashion to 287, the mixture of spiral oxindole 285 and 3-methoxyphenol.

OAg MeO O

Cl OMe N Me O O N Me N N O O N O 283 N H 297 272

Scheme 4.15: Proposed coupling reaction of chloroindolenine with silver phenoxide 4.5. SUMMARY 117

4.5 Summary

In summary, though the formal synthesis of phalarine is not accomplished, we have synthesized several interesting compounds bearing either C4a-O or C9a-C linkage. Also we have developed a short protocol to synthesize compound 268 via selective methylation. The coupling products formed in this study provided mechanistic insights into the reactivity and chemo-selectivity of tetrahydro- beta-carboline system. Yet some results are particularly puzzling, and can not be accounted for.

The further exploration of this project might be able to help answering these puzzles and hopefully provide an alternative synthetic strategy to the existing phalarine synthesis. 118 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

4.6 Experimental Section

General Information

Anhydrous CH2Cl2 and dioxane was distilled from CaH2 under an atmosphere of argon. All reagents were purchased from commercial sources or synthesized using literature methods. 1H and 13C NMR spectra were recorded on BRUKE 500 MHz spectrometers; 1H and 13C NMR Chemical shifts (δ

1 values) were reported in ppm from downﬁeld using internal standard TMS ( H NMR) or CDCl3

(13C NMR), respectively. All mass spectra were run by Dr. Srinivas V Chakravartula at the

Hunter College Mass Spectrometry Facility and taken on an Agilent 6520A Q-TOF using electrospray ionization. All infrared spectra were taken on a Thermo Nicolet IR100 spectrometer. X-ray crystallography was performed on a Bruker AXS SMART APEXII Single Crystal Diﬀractometer by Dr. Chunhua Hu at Department of Chemistry of New York University. All infrared spectra were taken on a Thermo Nicolet IR100 spectrometer. Column chromatography was performed over silica with a porosity of 60 Å and a particle size of 40-63 µm.

4.6.1 Preparation of selective methylation product

Me Me Cl Si N H 1. Et N N Me Cl 3 N O 2. CsF, diglyme N O H H 273 268

To a solution of 273 (8.86 g, 47.58 mmol, 1 eq) in 300 mL dry MeCN, add Et3N (13.26 mL,

95.16 mmol, 2 eq) at room temperature. To the mixture, chloro(chloromethyl)dimethyl silane (6.27 mL g, 57.58 mmol, 1 eq) was added dropwisely. The mixture was then refluxed overnight, cooled down to r.t. and the acetonitrile was removed on a rotatory-evaporator. Dry 2-methoxyethyl 4.6. EXPERIMENTAL SECTION 119 ether (300 mL) and cesium fluoride (14.5 g, 95.16 mmol, 2 eq) was added to the residue and the mixture refluxed overnight. After cooling, the solvent was removed under reduced pressure. Water

(500 mL) was added to the reaction residue and this mixture was extracted with EtOAc (5×300 mL). The organic solvent was concentrated and the crude product was then puriﬁed by column chromatography (DCM:EtOAc 1/10 to 1/2) to give 268 6.8 g.

2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (268).

1 Yield 71 %; H NMR(500 MHz, CDCl3) δ 10.46 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.54 (d, J =

8.5 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 3.75 (t, J = 7.0 Hz, 2 H), 3.24

13 (s, 3 H), 3.12 (t, J = 7.0 Hz, 2 H); C NMR(125 MHz, CDCl3) δ 162.11, 137.69, 127.08, 125.27,

124.57, 120.00, 119.98, 117.82, 112.72, 50.21, 34.19, 20.61.

4.6.2 Preparation of 3-methylphenol coupling product

Me Me OH tBuOCl overnight in N Me OH N Et3N CDCl3 + O + CH Cl O N O 2 2 O Me N H Me N H Me 268 286 N O 285 286 287 1 : 1

◦ To a stirred solution of 268 (150 mg, 0.75 mmol, 1 eq) in 3 mL dry CH2Cl2 at 0 C, add t-BuOCl

(0.1 mL, 0.90 mmol, 1.2 eq) dropwisely. The solution was allowed to warm up to room temperature.

To the reaction, 3-methylphenol (162 mg, 1.5 mmol, 2 eq) and Et3N (0.21 mL, 1.5 mmol, 2 eq) were added. The mixture was stirred at room temperature for 0.5 h and refluxed for 1 h. TLC indicated a new spot (Rf = 0.4, EtOAc/DCM 1/10) above 268. After cooling, the solvent was removed and the residue was purified by flash column chromatography (pure DCM to EtOAc/DCM 1/10) with

3 % Et3N to give solid product 287 50 mg. This product is not stable and it would deassociate overnight into two compounds in 1:1 ratio, 285 (Rf = 0.1, EtOAc/DCM 1/10) and 286 (Rf = 0.8, 120 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

EtOAc/DCM 1/10).

1 287, yield 22 %; H NMR(500 MHz, CDCl3) δ 7.29 (d, J = 7.5 Hz, 1 H), 7.21 (m, 2 H), 7.14

(d, J = 7.0 Hz, 1 H), 7.04 (m, 3 H), 7.98 (d, J = 7.5 Hz, 1 H), 3.66 (m, 2 H), 2.96 (s, 3 H), 2.76 (m,

13 1 H), 2.46 (m, 1 H), 2.29 (s, 3 H); C NMR(125 MHz, CDCl3) δ 178.38, 170.11, 153.24, 139.97,

137.64, 129.41, 129.01, 126.88, 124.59, 121.50, 121.37, 119.66, 117.87, 61.00, 47.19, 30.69, 28.02,

21.39.

1 285. H NMR(500 MHz, CDCl3) δ 8.67 (s, 1 H), 7.20 (td, J = 7.5 Hz, J = 1.0 Hz, 1 H), 7.14

(d, J = 7.0 Hz, 1 H), 7.03 (td, J = 7.5 Hz, J = 0.5 Hz, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 3.79 (m,

13 1 H), 3.62 (m, 1 H), 3.01 (s, 3 H), 2.74 (m, 1 H), 2.41 (m, 1 H); C NMR(125 MHz, CDCl3) δ

179.79, 172.96, 144.09, 132.69, 131.22, 125.23, 125.06, 112.68, 60.54, 49.56, 32.84, 31.66.

4.6.3 Preparation of 3-methylphenol coupling product

Procedure a Me OH N Me N N Me tBuOCl O OMe + O O N N CH2Cl2 N H HO OMe MeO OH 268 291 45 % 292 30%

Procedure a): to a stirred solution of 273 (150 mg, 0.75 mmol, 1 eq) in 3 mL dry CH2Cl2 at 0

◦C, add t-BuOCl (0.1 mL, 0.90 mmol, 1.2 eq) dropwisely. The reaction was stirred for 0.5 h. To the reaction, 3-methoxyphenol (186 mg, 1.5 mmol, 2 eq) was added. The solution was allowed to warm up to room temperature and stirred overnight. The reaction was concentrated under reduced pressure and the residue was puriﬁed by ﬂash column chromatography (EtOAc/DCM 1/10 to 1/2) to give yellow solid 291 (108 mg, 45 % yield), while yellow solid compound 292 (72 mg, 30 % yield) was eventually washed down by MeOH. 4.6. EXPERIMENTAL SECTION 121

Procedure b

OH Me Me N N 1) N Me tBuOCl OMe O + O N O CH2Cl2 N H N 268 2) TsCl, Et3N HO OMe MeO OTs 291 45 % 293 40 %

Procedure b): to a stirred solution of 273 (500 mg, 2.5 mmol, 1 eq) in 5 mL dry CH2Cl2 at 0

◦C, add t-BuOCl (0.34 mL, 3 mmol, 1.2 eq) dropwisely. The reaction was stirred for 0.5 h. To the reaction, 3-methoxyphenol (620 mg, 5 mmol, 2 eq) was added. The solution was allowed to warm up to room temperature and stirred overnight. To the mixture, Et3N (0.65 mL, 5 mmol, 2 eq) and

TsCl (715 mg, 5 mmol, 2 eq) was added. The reaction was stirred for 4 h and concentrated under reduced pressure. The residue was puriﬁed by ﬂash column chromatography (EtOAc/DCM 1/10 to 1/2) to give yellow solid 291 (365 mg, 45 % yield) and yellow solid 293 (477 mg, 40 % yield).

1 291. H NMR(500 MHz, CDCl3) δ 13.91 (s, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0

Hz, 1 H), 7.33 (d, J = 7.0 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 1 H), 6.65 (d, J

= 2.5 Hz, 1 H), 6.50 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H), 3.96 (m, 1 H), 3.86 (s, 3 H), 3.84 (m, 1 H),

13 3.14 (s, 3 H), 2.89 (m, 1 H), 2.38 (m, 1 H); C NMR(125 MHz, CDCl3) δ 178.23, 171.53, 164.24,

163.85, 152.13, 140.27, 129.15, 129.12, 125.96, 120.82, 119.66, 108.52, 107.66, 101.80, 64.45, 55.51,

47.20, 30.79, 30.65. The structure was conﬁrmed by X-ray crystallographic analysis. 122 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE

291

292. 1H NMR(500 MHz, MeOD) δ 7.58 (d, J = 9.0 Hz, 1 H), 7.48 (d, J = 7.0 Hz, 1 H),

7.43 (d, J = 7.0 Hz, 1 H), 7.28 (m, 2 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.51 (s, 1 H), 3.99 (m, 1

H), 3.96 (s, 3 H), 3.82 (m, 1 H), 3.00 (s, 3 H), 2.74 (m, 1 H), 2.35 (m, 1 H); 13C NMR(125 MHz,

MeOD) δ 177.33, 172.17, 169.60, 165.30, 145.03, 139.73, 135.94, 130.88, 129.11, 123.28, 117.96,

112.28, 108.28, 101.00, 67.17, 57.27, 48.48, 32.92, 31.10. The structure was conﬁrmed by X-ray crystallographic analysis.

292 4.6. EXPERIMENTAL SECTION 123

1 293. H NMR(500 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.71

(d, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 6.5 Hz, 1

H), 7.26 (t, J = 7.5 Hz, 1 H), 6.80 (d, J = 2.0 Hz, 1 H), 6.53 (dd, J = 8.5 Hz, J = 2.0 Hz, 1 H),

3.79 (m, 1 H), 3.77 (s, 3 H), 3.49 (td, J = 9.5 Hz, J = 3.0 Hz, 1 H), 3.05 (s, 3 H), 2.70 (m, 1 H),

13 2.48 (s, 3 H), 2.24 (m, 1 H); C NMR(125 MHz, CDCl3) δ 175.76, 171.16, 158.39, 152.44, 145.77,

141.90, 132.25, 131.95, 129.92, 128.83, 128.61, 126.59, 121.17, 120.85, 114.63, 106.61, 67.31, 55.83,

47.31, 30.47, 26.99, 21.76. The structure was conﬁrmed by X-ray crystallographic analysis.

293

Me Me N N BF3 • Et2O O O CH2Cl2, reflux N N OMe HO OMe F B O F 291 294

To a solution of 291 (50 mg, 0.155 mmol, 1 eq) in dry DCM, add BF3·Et2O (0.1 mL, 0.36 mmol, 2.2 eq). The mixture was reﬂuxed overnight. After cooling, the reaction was neutralzied by

NaHCO3 and extracted by DCM. The ogranic solution was then concentrated and puriﬁed by ﬂash column chromatography (EtOAc/Hexane 1/1 to 4/1) to provide solid product 294 36 mg with 10 124 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE mg of 291 recovered. 294, yield 78 %.

1 H NMR(500 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 1 H), 7.50 (m, 1 H), 7.37 (m, 2 H), 7.29 (m,

1 H), 6.68 (d, J = 2.0 Hz, 1 H), 6.60 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H), 4.00 (m, 1 H), 3.92 (m, 1

13 H), 3.91 (s, 3 H),3.17 (s, 3 H), 2.97 (m, 1 H), 2.54 (m, 1 H); C NMR(125 MHz, CDCl3) δ 173.77,

169.31, 168.30, 163.39, 143.85, 137.78, 129.98, 128.48, 127.31, 121.32, 118.20, 111.30, 105.89, 102.57,

62.65, 55.94, 47.04, 32.53, 30.95. The structure was conﬁrmed by X-ray crystallographic analysis.

294

4.6.4 Preparation of silver catalyzed 3-methylphenol coupling product

OH AgF, MeO Me Ag2O N or Ag CO OH Me OMe 2 3 N O O + dioxane N Me O N O N H H OMe 268 N O 285 290 297 1 : 1 Unknown product with proposed structure

◦ To a stirred solution of 268 (100 mg, 0.5 mmol, 1 eq) in 1 mL dry CH2Cl2 at 0 C, add t-BuOCl

(0.66 mL, 0.6 mmol, 1.2 eq) dropwisely. The reaction was stirred for 0.5 h and the solvent was 4.6. EXPERIMENTAL SECTION 125 removed under reduced pressure. In the meantime, to a suspended solution of Ag2O (116 mg, 0.5 mmol, 1 eq) in 1 mL dry dioxane, add 3-methoxyphenol (124 mg, 1 mmol, 2 eq, in 2 mL dry dioxane

) dropwisely at 0 ◦C. This mixture was sonicated for 0.5 h at r.t. and then added dropwisely to the former solution at 0 ◦C. The mixture was allowed to warm up to r.t. and stirred for 2 h.

TLC indicated the formation of a new spot (Rf=0.45, EtOAc/DCM 1/1) slightly lower than 268.

However, the repeated eﬀorts to separate this spot resulted in the separation of spiral oxindole 285 and phenol 290. (Note: the use of AgF and Ag2CO3 could produce similar results) 126 CHAPTER 4. SYNTHETIC STUDY OF PHALARINE References

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135 136 3.315 0.900 0.136 6.721 6.701 6.191 6.171

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.00 9.31 6.08 1.95 1.91 90.93 50.31 25.60 18.12 −2.86 185.40 146.36 128.17

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 137 138 2.489 7.375 7.361 7.333 7.319 7.303 7.274 7.260 7.245 4.527 4.349 4.323 4.144 4.119 3.449 3.400 3.344 2.695 2.690 2.659 2.653 2.647 2.641 2.611 2.605 2.568 2.562 2.533 2.527 2.494

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.00 1.98 1.99 5.12 0.95 0.95 1.01 2.81 1.07 108.90 73.40 62.38 59.65 51.59 49.54 45.47 45.28 207.68 137.19 128.89 128.51 127.49

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 139 140 2.515 2.512 1.388 1.374 1.360 1.209 1.195 1.181 7.367 7.352 7.329 7.326 7.315 7.312 7.300 7.270 7.260 7.255 7.241 4.538 4.533 4.528 4.376 4.351 4.176 4.151 3.748 3.744 3.734 3.730 3.719 3.716 3.700 3.695 3.686 3.681 3.674 3.671 3.667 3.660 3.656 3.653 3.646 3.642 3.628 3.499 3.485 3.481 3.471 3.466 3.457 3.452 3.413 3.407 3.402 2.658 2.652 2.518

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.96 2.00 2.00 2.93 3.00 5.02 0.96 0.96 0.98 3.01 1.00 108.34 73.90 62.49 60.20 59.86 57.66 45.66 45.43 15.41 15.05 207.96 137.33 128.94 128.48 127.45

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 141 142 7.373 7.359 7.324 7.320 7.310 7.307 7.294 7.264 7.250 4.374 4.349 4.237 4.231 4.226 4.221 4.213 4.209 4.208 4.196 4.181 4.173 4.168 4.165 4.155 4.151 4.147 4.138 4.051 4.040 4.035 4.023 4.019 4.012 4.005 3.992 3.990 3.976 3.247 3.242 3.237 2.799 2.793 2.764 2.759 2.727 2.723 2.678 2.673 2.668 2.642

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.96 2.05 1.08 0.98 4.98 1.00 2.01 2.05 2.15 75.41 65.60 65.34 62.16 60.84 46.11 207.48 137.06 128.96 128.48 127.47 114.29

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 143 144 3.665 3.651 3.648 3.634 3.619 3.495 3.481 3.476 3.467 3.462 3.440 3.406 3.401 3.396 3.333 2.648 2.643 2.635 2.630 2.521 2.516 2.510 2.504 1.400 1.385 1.371 1.220 1.206 1.192 7.366 7.351 7.323 7.319 7.309 7.305 7.293 7.290 7.262 7.259 7.248 7.244 4.521 4.374 4.348 4.316 4.171 4.146 4.138 4.113 3.734 3.730 3.720 3.716 3.705 3.702 3.688 3.679

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.41 1.00 1.50 2.00 2.00 1.52 1.46 4.91 0.98 0.99 1.00 0.52 1.02 0.50 108.62 108.58 73.79 73.51 62.47 62.35 59.99 59.88 59.84 57.73 51.58 49.50 45.53 45.34 15.38 15.01 207.76 137.29 137.24 128.89 128.86 128.46 127.43

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 145 146

Std proton 4.345 4.320 4.211 4.186 4.160 4.134 3.974 3.962 3.950 3.937 3.925 3.458 3.428 3.370 3.351 2.682 2.677 2.660 2.583 2.578 2.534 2.500 1.385 1.373 1.357 1.344 1.277 1.265 1.191 1.179 7.378 7.364 7.332 7.317 7.302 7.271 7.260 4.577 4.529 4.406 4.381

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.28 0.45 4.17 1.30 1.32 1.83 1.81 2.00 2.06 1.30 0.42 0.57 0.44 0.57 0.87 0.61 0.57 1.71 0.62 Std proton 109.29 109.16 74.01 73.77 69.21 66.65 62.32 61.25 60.60 51.89 49.73 45.53 45.50 24.61 23.86 23.77 23.61 207.97 207.92 137.45 137.31 129.02 128.90 128.50 128.46 127.46 127.43

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 147 148 2.678 2.672 2.655 2.650 2.543 2.537 2.528 2.525 7.372 7.368 7.358 7.351 7.329 7.315 7.299 7.270 7.259 7.256 5.885 5.872 5.862 5.851 5.478 5.475 5.444 5.440 5.292 5.288 5.285 5.282 5.271 5.268 5.251 5.247 5.191 5.188 5.170 5.167 4.566 4.561 4.556 4.540 4.357 4.350 4.324 4.165 4.157 4.155 4.146 4.139 4.129 4.120 4.002 3.992 3.462 3.430 3.427 3.350

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.20 1.99 2.00 4.89 0.37 0.54 0.38 0.49 0.47 0.56 0.95 0.97 0.42 1.97 0.59 1.71 0.97 108.90 108.75 73.91 73.51 65.20 63.30 62.47 62.35 60.04 59.88 51.83 49.74 45.55 45.33 207.57 137.22 137.15 133.79 133.02 128.91 128.88 128.50 127.49 127.48 117.02 116.95

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 149 150

DEPT 4.302 4.279 4.063 4.038 3.520 3.452 3.450 3.356 3.355 2.724 2.718 2.688 2.682 2.581 2.553 2.517 1.399 7.366 7.351 7.326 7.311 7.296 7.270 7.262 7.260 7.255

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.02 1.04 1.86 1.07 3.00 5.19 0.87 0.96 0.95 3.01 DEPT 106.50 99.99 81.41 62.00 59.27 51.76 50.04 49.88 45.68 19.01 208.06 137.09 128.82 128.54 127.52

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 151 152 4.323 4.298 4.295 4.178 4.153 3.445 3.370 3.354 2.617 2.613 2.603 2.598 2.588 2.584 2.574 2.570 2.550 2.545 2.516 2.511 2.477 2.471 2.443 2.437 1.216 1.202 7.363 7.348 7.318 7.304 7.301 7.289 7.246 7.232

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.99 3.00 1.07 2.09 3.01 5.50 1.92 1.06 3.13 108.94 78.29 61.97 59.92 51.56 49.47 46.55 45.06 11.91 209.84 137.30 128.73 128.45 127.36

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 153 154

DEPT 2.612 2.583 2.580 2.550 2.546 7.416 7.401 7.378 7.363 7.349 7.335 7.319 7.298 7.287 4.698 4.603 4.552 4.402 4.377 4.367 4.340 4.238 4.213 4.123 4.097 3.633 3.511 3.487 3.459 3.440 3.404 2.845 2.840 2.811 2.805 2.728 2.724 2.693 2.690 2.651 2.645 2.618

major

minor major

9.55 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.71 2.08 0.27 0.28 0.66 0.72 5.00 1.27 0.27 0.27 0.60 0.33 0.70 0.28 0.28 2.02 0.88 0.85 Std proton 109.32 108.93 79.16 74.01 67.32 63.85 63.61 63.15 61.95 59.70 51.93 51.82 49.97 49.78 43.81 199.49 199.02 136.70 136.43 129.32 128.95 128.57 128.28 127.64 127.62

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 155 156 4.672 4.377 4.352 4.212 4.187 3.486 3.419 3.414 3.409 3.379 2.627 2.620 2.593 2.587 2.558 2.553 2.525 2.520 7.352 7.338 7.322 7.319 7.309 7.293 7.272 7.261 7.258

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.98 2.97 2.00 5.22 1.93 1.01 1.08 3.00 109.31 79.16 63.83 61.95 59.69 51.81 49.95 44.07 199.46 136.69 128.94 128.55 127.60

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 157 158 4.759 4.074 4.048 3.776 3.751 3.525 3.516 3.507 3.287 3.072 3.064 3.038 3.030 2.768 2.757 2.733 2.724 1.821 1.819 7.346 7.333 7.326 7.312 7.296 7.275 7.272 7.250 7.248 6.406

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 5.98 1.01 1.01 3.00 5.77 0.96 0.89 1.01 1.01 1.00 97.65 65.61 61.52 49.69 48.94 34.09 15.75 197.60 140.11 138.71 137.18 129.43 128.39 127.55

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 159 160

DEPT 4.632 4.561 3.389 3.383 3.360 3.353 2.745 2.709 2.703 2.632 2.627 2.595 2.591 1.514 1.507

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 2.92 4.16 8.99 1.74 3.08 106.87 82.61 74.97 57.10 52.02 50.01 44.71 42.83 28.10 205.74 158.34

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 161 162 4.572 3.643 3.638 3.624 3.610 3.596 2.736 2.698 2.693 2.648 2.611 1.512 1.508 1.255 1.248 1.240 1.239 1.234 1.225 1.220 1.210

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 4.08 9.04 6.07 1.95 4.00 106.16 82.49 75.56 60.34 58.14 57.28 44.87 43.10 28.15 15.07 15.02 206.04 158.08 158.082

160 ppm

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 163 164 9 6 1 7 1 2 8 7 9 6 6 1 0 0 0 95 63 33 26 1 13 6 62 5 53 21 16 12 40 4 5 139 129 125 116 1 1 3 336 161 151 1 .870 .8 .8 .8 .8 .8 .78 .777 .77 .7 .7 .7 .7 .74 .7 .7 .7 . 4. 4. 4. 4. 4. 4. 4.0 4.08 4.08 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 4. 4. 4. 4. 4.

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 9 7 9 .00 . 4.01 9 1.7 3 82.71 76.24 66.37 65.43 58.38 45.52 43.66 28.13 205.58 157.12 111.96 157.119

160 ppm

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 165 166

DEPT 4.576 3.660 3.645 3.631 3.625 3.614 3.599 3.585 3.394 3.361 2.735 2.728 2.719 2.712 2.698 2.691 2.653 2.649 2.643 2.616 2.612 2.606 1.511 1.274 1.260 1.245 1.231

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.63 4.30 9.00 3.20 1.94 2.10 1.30 DEPT 106.51 82.46 82.44 75.14 60.39 58.15 57.14 51.94 49.95 44.74 42.94 42.86 28.08 28.03 14.99 14.96 205.86 158.06

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 167 168 4.639 4.601 4.151 4.139 4.127 4.114 4.102 4.090 4.077 4.047 4.035 4.022 4.010 3.998 3.986 3.973 3.426 3.376 2.738 2.730 2.704 2.698 2.691 2.686 1.515 1.256 1.250 1.243 1.238

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 4.95 7.55 0.72 1.40 0.25 1.00 0.73 3.01 11.30 107.01 82.52 74.90 69.63 58.15 50.30 44.99 43.26 28.20 28.13 23.75 23.52 206.06 158.22 158.217

160 ppm

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 169 170 5.210 5.208 5.190 5.187 4.592 4.134 4.123 4.115 4.104 4.093 3.396 3.375 2.759 2.753 2.747 2.737 2.729 2.723 2.717 2.709 2.703 2.662 2.658 2.652 2.626 2.620 2.615 1.515 1.499 5.957 5.947 5.936 5.923 5.919 5.912 5.909 5.902 5.898 5.895 5.887 5.885 5.874 5.864 5.853 5.375 5.371 5.340 5.337 5.318 5.315 5.312 5.309 5.281 5.278 5.274 5.231 5.228

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.75 4.36 9.39 1.00 1.06 1.05 0.73 1.23 2.12 1.37 106.75 106.70 82.67 82.63 75.14 65.61 63.72 57.32 52.21 50.23 44.78 44.77 43.01 42.92 28.15 28.09 205.67 158.11 133.33 132.62 158.106

160155 ppm

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 171 172 1.626 1.472 4.533 4.528 4.522 3.466 3.454 3.208 3.172 2.816 2.810 2.779 2.773 2.734 2.697 2.612 2.575

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.00 0.96 2.22 1.06 3.22 9.32 0.97 3.07 105.45 82.31 72.86 65.24 50.33 50.28 47.30 44.57 28.30 19.35 205.45 154.05

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 173 174 4.546 3.405 3.359 2.725 2.719 2.690 2.683 2.673 2.668 2.647 2.644 2.611 2.609 1.510 1.214 1.200

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.06 3.03 9.24 3.05 1.89 3.00 106.64 82.47 75.35 62.81 51.97 49.88 44.58 44.50 28.10 12.12 207.80 159.04 159.044

160 ppm

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 175 176 1.517 4.857 4.697 4.692 4.587 3.453 3.391 2.937 2.930 2.902 2.895 2.717 2.682

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.00 1.00 0.98 9.40 0.84 0.97 0.93 3.01 106.98 83.19 75.44 64.30 61.10 52.29 50.40 43.60 28.04 197.78

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 177 178

DEPT 4.462 3.405 3.359 3.312 2.848 2.673 2.637 2.611 2.607 2.581 2.574

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 0.88 3.22 4.45 1.00 3.19 3.18 DEPT 108.93 73.62 62.40 51.56 49.49 46.40 45.27 207.46

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 179 180 4.806 4.504 3.323 3.270 2.686 2.680 2.649 2.643 2.623 2.619 2.601 2.597 2.586 2.583 2.027

10 9 8 7 6 5 4 3 2 1 ppm 3.06 2.96 4.05 3.00 0.91 0.93 106.09 75.49 54.51 51.93 50.07 44.61 42.47 20.16 205.24 174.28

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 181 182 4.590 3.440 3.401 2.796 2.788 2.759 2.752 2.743 2.712 2.707 2.702 2.697 2.680 2.678 2.676 2.665 2.660 2.656 2.650 1.509 0.941 0.880 0.241 0.235 0.227 0.209

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 4.00 9.00 1.38 7.71 0.51 2.24 0.50 2.45 1.55 0.45 2.53 104.57 82.48 75.32 59.40 52.13 51.26 45.12 45.01 43.99 43.30 28.30 28.13 25.74 17.99 −2.97 −3.31 −3.39 −3.65 206.17 205.68 157.55 105.18 157.549

160 ppm

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 183 184 5.461 5.313 5.301 4.439 3.371 3.335 2.512 2.499 2.486 2.474 2.103 2.055 2.046 2.034 2.010 1.560 0.992 0.230 0.198 7.843 7.825 7.576 7.559 5.527 5.508 5.494 5.480

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.11 2.07 2.12 9.17 9.46 6.35 2.00 2.23 1.04 2.06 0.76 82.07 68.04 61.49 60.04 50.59 50.41 33.16 31.55 28.32 28.17 25.95 25.89 18.17 18.02 −3.21 −3.45 164.78 158.21 156.81 131.67 131.50 131.04 129.23 127.99 104.29

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 185 186 5.414 4.143 4.129 4.115 4.101 3.937 3.362 2.494 2.263 2.240 2.097 2.062 2.055 2.045 2.035 2.016 2.008 1.984 1.961 1.443 0.943 0.198 0.174 7.892 7.875 7.583 7.566 5.728 5.454 5.442 5.434 5.425

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 0.83 0.91 0.96 2.31 8.99 9.00 2.87 2.94 1.94 1.92 0.85 1.03 1.07 1.04 2.95 79.52 74.10 67.25 51.72 49.87 34.19 33.71 28.42 25.88 18.46 −2.38 −3.41 165.15 155.10 131.68 131.15 129.34 128.02 97.67

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 187 188 3.988 3.827 3.415 2.507 2.259 2.231 2.144 1.340 0.913 0.193 0.164 7.930 7.913 7.573 7.556 5.872 5.275

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 0.83 0.99 2.99 9.20 9.37 3.03 2.99 1.97 1.97 0.83 1.00 0.89 1.03 3.00 97.86 79.23 72.83 68.35 50.58 49.77 32.82 32.45 28.35 25.84 18.45 −2.52 −3.45 165.01 155.05 131.67 131.26 129.42 127.99

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 189 190 4.704 4.679 4.665 2.897 2.891 2.877 2.869 2.863 2.857 2.672 2.659 2.651 2.637 2.631 2.080 2.075 2.051 2.045 2.027 2.022 1.766 1.760 1.737 1.734 1.712 1.706 1.439 0.888 0.116 0.030 7.929 7.912 7.632 7.615 5.534 5.517 5.504 4.747 4.722

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1.00 1.00 1.08 1.00 8.75 9.20 3.17 3.11 2.02 1.99 1.88 1.94 80.04 72.61 68.20 53.82 41.64 39.33 28.33 25.69 18.45 −4.72 −5.32 204.90 164.84 155.16 131.99 131.17 128.67 128.62

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 191 192 4.757 4.741 4.725 4.091 4.088 2.240 2.230 2.221 2.212 2.155 2.144 2.137 2.102 1.862 1.842 1.820 1.780 1.757 1.736 1.417 0.874 0.064 0.056 7.896 7.879 7.604 7.587 5.411 4.978

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1.04 1.20 3.00 1.05 1.03 9.49 9.29 2.92 3.06 2.05 2.06 1.04 0.82 1.11 1.98 79.55 76.34 68.80 68.27 48.62 36.95 34.77 28.33 25.59 21.09 17.86 −4.80 −4.99 170.73 164.88 155.19 131.84 131.12 129.00 128.30

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 193 194 5.447 5.437 5.429 4.984 4.249 4.243 2.202 2.157 2.096 1.924 1.917 1.905 1.898 1.891 1.879 1.871 1.789 1.769 1.749 1.437 0.943 0.117 0.095 7.878 7.861 7.589 7.572 5.660 5.481 5.473 5.463 5.455

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 1 7 3 8 9 9 96 3 69 .11 . .04 1. 3 1.12 0. 9 8.8 2. 3 2.00 2.04 0. 1.02 0.88 1.82 79.27 71.81 69.40 67.40 47.77 36.26 34.14 28.35 25.66 21.03 17.99 −5.02 −5.19 170.16 165.03 155.60 131.75 131.09 129.13 128.17

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 195 196 6.888 6.882 6.867 6.862 6.434 6.428 6.409 6.402 6.284 6.269 6.263 6.249 3.390

9 8 7 6 5 4 3 2 1 ppm 0.97 1.00 1.01 6.00 95.81 95.72 50.54 178.12 177.93 154.66 152.50 144.47 144.45 127.93 127.90 119.00 118.91

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 197 198 −129.88

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 6.297 6.280 6.274 6.257 6.023 6.011 5.996 5.984 3.448 3.445

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 199 0.98 0.98 6.00 200 95.50 95.40 95.32 95.22 51.71 51.70 178.60 178.46 178.40 178.25 172.34 172.32 169.93 169.90 154.38 154.37 152.21 152.20 116.43 116.39 116.32 116.28 109.31 109.28 109.22 109.18

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −100.45 −129.44 201

−20 −4 0 −6 0 −8 0 −100 −120 −14 0 −16 0 −18 0 p p m 202 6.711 6.693 6.691 6.673 6.300 6.287 6.279 6.266 3.461 3.458

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.96 0.95 6.00 95.29 95.26 95.14 95.11 51.79 51.78 178.85 178.79 178.70 178.64 154.51 154.46 152.15 152.09 141.75 141.71 141.22 141.20 141.18 139.63 139.58 127.66 127.64 127.62

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 203 204 −134.14 −134.16 −159.13 −159.15 −134.140 −134.161 −159.128 −159.150

−134 ppm ppm

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 6.732 6.712 6.692 6.461 6.441 3.445 3.442

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 205 5.97 0.98 0.95 206 94.49 94.32 51.88 179.23 179.17 168.76 166.37 140.87 140.83 128.78 128.76 107.67 107.58

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −90.57 207

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 208 6.806 6.786 6.423 6.409 6.402 6.388 3.250 1.903 1.897

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 6.00 3.07 0.98 0.96 98.05 97.97 51.16 8.36 8.33 177.38 177.19 153.18 151.08 144.96 144.94 132.09 132.02 130.35 130.32

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 209 210 6.668 6.648 6.627 6.341 6.320 3.407 3.404 1.872 1.865

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.09 1.00 1.00 6.22 93.29 93.11 51.61 6.55 6.51 186.60 186.49 166.78 164.45 140.21 140.17 130.18 130.16 118.80 118.74

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 211 212 −108.79

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 6.939 6.921 6.877 6.871 6.759 6.753 6.741 6.735 5.254 3.744

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 213 1.00 0.99 1.00 0.97 3.16 214 55.93 153.64 145.49 119.86 116.58 114.51 114.08

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6.947 6.929 6.913 6.907 6.789 6.783 6.771 6.765 5.279 4.026 4.017 4.008 3.953 3.943 3.935 2.062 2.051 2.039

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 215 0.96 1.00 1.02 1.05 1.01 2.17 2.17 216 70.10 61.43 152.61 145.92 119.91 116.64 115.21 115.08

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6.934 6.917 6.899 6.893 6.766 6.760 6.748 6.742 5.324 4.065 4.053 4.041 3.868 3.856 3.845 2.045 2.033 2.021 2.009 1.997 1.772

9 8 7 6 5 4 3 2 1 ppm 217 1.00 1.02 1.04 1.05 2.23 2.21 2.37 1.12 218

DEPT 66.59 60.41 31.92 152.78 145.72 119.89 116.59 115.12 114.93

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 7.182 7.176 6.913 6.907 5.545 3.738

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 219 0.91 0.91 0.89 3.00 220 83.04 56.08 153.80 145.23 123.17 118.83 115.65

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6.689 6.685 6.684 6.679 6.641 6.635 6.617 6.612 5.229 3.740

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 221 0.92 0.92 0.82 3.00 222 102.33 102.16 56.01 152.86 152.77 152.41 150.47 134.74 134.62 121.59 121.55 109.89 109.87

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −135.72 223

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 224 6.798 6.792 6.746 6.740 5.475 3.736 1.384

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 9.00 0.95 0.91 0.89 2.96 55.09 34.67 28.52 151.85 143.30 137.78 119.78 112.82 109.56

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 225 226 10.850 7.228 7.222 7.167 7.160 3.946 3.750

12 11 10 9 8 7 6 5 4 3 2 1 ppm 3.00 3.08 0.88 0.88 0.86 56.01 52.77 170.00 151.80 151.54 123.62 122.62 112.95 111.46

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 227 228 6.801 6.607 5.237 3.841 3.819

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.00 0.97 0.94 2.96 3.07 100.53 56.63 56.11 149.19 145.57 143.35 111.87 109.30

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 229 230 6.803 6.738 5.172 3.748 2.146

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 2.94 0.90 0.96 0.91 3.00 56.01 15.94 151.85 144.88 127.35 118.15 116.15 110.74

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 231 232 2 5 39 .8 .47 .74 6 5 3

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm .00 1.82 0.88 3 56.02 152.97 142.09 121.17 114.20

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 233 234 6.933 6.916 6.825 6.802 5.316 3.831

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.93 0.93 0.89 3.00 104.88 57.20 152.84 150.88 145.53 145.44 142.00 141.90 114.21 114.18 113.75 113.72 105.06

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 235 236 −136.15

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 7.108 6.919 5.213 3.870

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 237 1.00 1.06 1.00 3.15 238 56.91 149.34 145.52 122.22 117.89 117.85 112.74

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6.926 6.908 6.822 6.803 5.357 3.861

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 239 0.92 0.93 0.84 3.00 240 56.99 150.12 146.38 121.42 120.17 113.56 111.55

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 7.248 6.864 5.239 3.835

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 241 0.87 0.90 0.88 3.00 242 2 2 5 1 25 51 99 . .8 . 0. 0.7 8.7 0.8 5 4 56 15 1 12 11 112 11

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6.987 6.969 6.813 6.795 5.300 3.861

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 243 1.00 1.03 0.96 3.22 244 4 4 4 9 19 9 2 5 . . . . .40 4.44 6 7.0 4 5 151 1 121 11 112 111

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 7.453 6.770 5.272 3.815

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 245 0.91 0.94 0.86 3.00 246 9 7 4 63 2 3 11 . .44 .88 . .0 6 7. 4 84. 5 152 1 126 119 111

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 7.021 7.003 6.748 6.730 5.259 3.847

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 247 0.91 0.95 0.87 3.00 248 90.28 57.25 153.76 145.88 125.49 115.71 110.79

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 6 8 5 0 0 6 53 3 2 .7 .7 .74 .7 . .844 6 6 6 6 5 3 8 5 0 6 53 3 .7 .7 .74 .7 6 6 6 6

6.8 ppm

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1 5 9 .1 249 1.00 0. 3 250 101.18 101.01 101.00 57.32 147.40 147.36 146.57 146.49 145.49 145.45 144.58 144.50 141.30 141.22 141.20 141.12 134.67 134.54 111.14 111.10 110.99 110.95 101.20 147.397 147.359 146.574 146.494 145.488 145.451 144.579 144.498

146 ppm

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −142.50 −142.53 −142.68 −142.71 −142.499 −142.529 −142.681 −142.711

−142.5 ppm 251

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 252 6.757 6.752 6.742 6.737 5.397 3.851

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.96 0.93 3.00 57.23 142.41 142.30 142.25 142.22 142.18 142.16 142.12 140.45 140.34 140.24 140.14 135.79 135.78 135.70 135.69 114.77 114.73 114.70 108.42 108.40 142.412 142.304 142.251 142.218 142.120 140.452 140.344 140.241 140.142

142 ppm

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 253 254 -158.56 -158.61 -160.26 -160.31 -158.563 -158.615 -160.259 -160.310

-159 ppm

-20 -40 -60 -80 -100 -120 -140 -160 -180 ppm 6.982 6.965 5.589 3.853

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 255 0.92 0.88 3.00 256 99.80 99.62 57.38 150.10 148.13 143.40 143.38 142.14 142.04 114.22 114.19 113.69 113.67

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −128.15 257

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 258 6.577 6.572 5.218 3.761 2.103 2.098

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.05 0.94 0.93 3.00 56.15 7.86 7.83 151.27 151.20 151.15 149.24 134.80 134.67 117.30 117.26 114.17 114.03 106.33 106.31

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 259 260 −139.80

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 6.782 6.766 5.295 3.811 2.209 2.204

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 261 2.97 0.95 0.72 3.00 262 57.02 8.64 8.59 151.36 149.43 144.10 144.04 141.73 141.62 114.66 114.51 112.99 112.96 110.62 110.60

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm −140.25 263

−20 −40 −60 −80 −100 −120 −140 −160 −180 ppm 264 6.875 6.857 6.822 6.816 6.677 6.671 6.659 6.654 5.235 0.968 0.169

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 9.00 5.90 0.95 0.91 0.95 0.91 25.63 18.13 −4.57 149.29 145.94 120.24 120.02 119.52 116.27

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm 265 266 7.586 7.570 7.559 7.541 7.187 7.171 6.851 6.792 6.787 6.769 6.757 6.751 3.722 2.352

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 2.97 1.85 0.95 1.87 0.93 0.98 0.91 3.00 55.62 21.52 157.80 143.95 135.93 129.52 127.99 127.26 126.11 114.56 113.55

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 267 268 7.012 7.006 6.945 6.927 6.805 6.799 6.787 6.782 5.169 3.744

9 8 7 6 5 4 3 2 1 ppm 0.94 0.94 0.95 0.89 3.00 3 3 0 8 32 35 5 92 9 .8 .8 . . . . . 6 9 4 0 55 153 1 116 116 115 1

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 269 270 7.221 7.166 7.163 7.161 7.152 7.149 7.145 7.136 7.134 7.132 7.106 7.104 7.089 7.087 7.052 7.046 7.009 6.991 6.962 6.956 6.944 6.938 6.116 3.750 7.251 7.247 7.236

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 2.08 1.00 1.88 0.95 0.95 0.98 0.91 3.00 153.52 151.40 135.70 129.23 126.91 126.17 120.31 118.88 116.29 116.12 55.88

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 271 272 7.333 7.319 7.304 7.300 7.289 7.274 7.248 7.245 7.242 7.236 7.231 7.226 7.217 6.708 6.701 6.691 6.637 6.631 6.620 6.614 5.674 5.656 5.639 3.689 3.547 3.528 3.516 3.497 3.142 3.126 3.111 3.094 7.337

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.03 4.94 1.90 0.99 0.98 3.00 1.06 154.30 153.78 142.02 128.66 128.03 127.53 125.80 112.99 111.20 109.22 84.26 56.05 38.90

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 273 274 3.398 3.362 3.358 3.348 2.699 2.694 2.661 2.656 2.571 2.566 2.536

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.93 3.19 2.16 1.43 6.68 3.01 106.46 61.92 50.68 49.15 42.80 41.45 209.17

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 275 276 3.549 3.544 3.540 3.534 3.393 3.360 2.858 2.855 2.851 2.802 2.796 2.768 2.762 2.643 2.629 2.616 2.603 2.564 2.530 2.529 2.525 2.523 2.496 2.494 2.490 2.489 2.402 1.115 1.101

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.04 1.00 1.03 1.03 3.05 1.10 3.07 3.07 1.00 3.02 106.25 68.76 61.86 50.64 49.04 46.94 44.89 39.46 38.36 12.24 210.40

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 277 278 2 9 9 5 0 0 7 8 0 3 8 0 0 44 0 04 7 44 0 33 22 56 5 22 1 99 3 2 196 19 6 639 6 6 5 5 53 533 51 5 36 215 .4 .4 . . . .7 .7 .7 .7 ...... 4 .47 .4 . . 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3 8 6 3 99 9 .00 .0 .02 3 0. 1.0 1.07 2. 1.11 1.0 3 3 2.87 105.06 66.34 61.17 49.89 49.61 46.58 46.48 43.86 35.69 18.73 209.27

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 279 280

DEPT 6.931 6.913 6.874 6.869 6.755 6.750 6.738 6.732 5.180 3.974 3.961 3.947 3.933 3.751 1.395 1.381 1.367

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.00 1.23 1.20 1.24 1.10 1.96 0.86 DEPT 64.33 55.94 14.81 153.66 152.98 145.48 145.41 119.78 116.56 116.51 115.20 114.80 114.53 114.05 119.782 116.560 116.510 115.195 114.799 114.529

120 ppm

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 281 282

DEPT 6.905 6.887 6.868 6.863 6.735 6.729 6.717 6.712 5.216 4.404 4.392 4.380 4.368 4.356 4.344 4.332 3.731 1.285 1.272

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 6.00 1.00 1.04 1.01 0.97 0.95 0.40 DEPT 71.40 55.94 22.00 151.81 145.56 119.79 116.97 116.91 116.58 116.48 114.52 114.07 119.785 116.973 116.909 116.577 116.485 114.521

ppm

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 283 284 0.969 0.169 6.952 6.934 6.883 6.880 6.874 6.866 6.821 6.815 6.761 6.755 6.743 6.737 6.675 6.670 6.658 6.652 5.572 5.385 3.751

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 9.00 5.75 0.55 1.47 0.84 0.58 0.91 1.54 1.85 1.405 1.393 6.966 6.954 6.952 6.939 6.907 6.902 6.897 6.778 6.773 6.763 6.758 5.300 3.994 3.982 3.971 3.959 3.773 1.416

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 3.02 1.21 1.21 1.21 1.04 2.00 0.70 285 286 7.535 7.531 7.495 7.492 7.478 7.476 7.409 7.394 7.392 7.387 7.378 7.375 7.370 7.322 7.320 7.317 7.309 7.305 7.302 7.293 7.290 7.288 7.071 7.054 5.614

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.03 2.09 3.15 1.04 1.02 1.00 150.71 139.52 134.94 128.84 127.47 127.23 127.11 126.68 120.24 116.48

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 287 288 3.802 2.329 7.881 7.863 7.734 7.731 7.720 7.717 7.513 7.506 7.209 7.192 6.963 6.958 6.927 6.922 6.909 6.904 6.576 6.569

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 2.98 0.97 1.94 0.95 1.94 0.96 0.98 0.95 3.00 103.60 55.62 21.55 156.38 144.80 135.26 131.75 129.81 129.58 127.12 126.74 114.41 113.67 109.16

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 289 290 7.718 7.710 7.521 7.504 7.206 7.189 6.821 6.816 6.637 6.632 6.608 6.601 3.787 2.526 2.354

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.98 2.02 2.00 1.00 0.99 0.99 3.20 3.15 3.22 98.90 53.10 19.42 19.21 153.88 142.12 134.35 131.76 128.39 127.45 127.34 124.06 124.01 114.47 106.90 291

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 292 7.696 7.689 7.632 7.615 7.166 7.150 6.508 6.503 6.477 6.470 6.229 6.224 3.704 3.575 2.295

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.00 2.02 2.23 0.96 1.05 1.02 3.39 3.21 3.34 97.32 95.04 55.64 55.39 21.59 157.15 147.84 144.10 137.25 133.80 129.32 129.18 127.31 119.59 107.18 293

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 294 7.798 7.780 7.629 7.612 7.179 7.177 7.101 7.085 6.844 6.839 6.826 6.821 6.781 6.776 3.740 2.232 2.117 2.115

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.00 1.93 1.08 1.95 0.99 0.97 3.06 3.06 3.04 0 9 8 4 7 5 93 4 9 32 6 59 33 29 92 6 6 . 6 2 . .7 . .88 . . 3 4. 8. 8. 7. 00. 4. 0.4 4 1 5 2 8.7 155 1 13 131 12 12 125 122 11 113 112 295

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 296 7.792 7.791 7.774 7.774 7.625 7.608 7.176 7.091 7.075 6.833 6.828 6.815 6.810 6.802 6.798 3.724 2.561 2.559 2.546 2.544 2.531 2.529 2.516 2.514 2.218 1.215 1.200 1.185

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.00 1.97 1.04 1.98 1.00 0.98 3.14 2.06 3.10 3.41 101.07 54.63 20.47 17.15 12.07 155.24 143.50 134.28 131.07 129.08 128.67 125.62 124.33 121.84 113.63 112.23 297

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 298 7.786 7.769 7.338 7.320 7.229 7.212 6.725 6.720 6.708 6.703 6.672 6.668 6.174 6.161 3.973 3.957 3.942 3.817 3.802 3.787 3.741 3.366 3.357 3.349 3.342 3.333 3.325 3.316 3.304 2.363 2.293 2.278 2.277 2.269 2.261 2.253 2.245 2.237 2.230 2.229 2.213 2.009 1.999

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.87 0.97 1.94 1.00 0.96 0.94 1.09 1.28 3.00 1.25 2.96 1.05 1.19 96.24 66.48 55.67 45.75 33.58 21.54 156.68 143.81 136.30 135.10 133.16 129.58 127.32 114.17 113.31 110.91 299

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 300 7.853 7.833 7.682 7.666 7.267 7.170 7.153 6.896 6.891 6.881 6.877 4.555 4.550 4.546 4.541 3.862 3.840 3.795 3.785 3.779 3.772 3.766 3.753 3.498 3.487 3.428 3.415 3.408 3.402 3.396 3.383 2.709 2.695 2.684 2.680 2.670 2.303 1.967 1.954 1.940 1.925 1.815 1.716 1.710 1.570 1.552 1.547 1.543 1.539 1.531 1.526 1.516

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1.02 1.96 1.03 2.01 1.97 0.98 1.21 4.14 1.13 1.10 1.96 3.00 2.13 1.36 1.33 4.14 99.11 66.71 62.59 55.70 30.82 28.83 25.48 21.57 21.55 19.80 156.31 144.56 135.27 132.17 130.12 129.72 126.68 123.64 123.04 114.71 113.34 102.16 301

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 302 9.681 9.677 9.673 7.671 7.422 7.416 7.404 7.399 7.296 7.291 7.287 6.851 6.833 3.799 3.626 3.622 2.139

10 9 8 7 6 5 4 3 2 1 ppm 0.88 0.92 0.93 1.06 0.93 3.00 1.89 3.28 110.73 55.67 45.36 24.23 200.12 168.60 154.44 131.15 123.85 121.56 121.07 303

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 304 7.821 7.478 7.473 7.460 7.455 7.179 7.175 6.769 6.751 4.660 4.649 4.638 3.782 3.607 3.594 3.588 3.580 3.575 3.562 3.411 3.398 3.392 3.384 3.379 3.366 3.305 2.890 2.879 2.166 2.105 1.529 1.516 1.503 1.486 1.473 1.345 1.330 1.314 1.300 0.887 0.872 0.858

9 8 7 6 5 4 3 2 1 0 ppm 0.94 1.07 0.97 1.04 1.04 3.00 1.08 1.15 3.14 1.90 3.31 2.94 2.19 2.22 3.16 110.40 103.22 66.29 55.56 53.16 34.64 31.87 30.92 24.14 19.29 13.85 207.22 168.61 154.42 130.85 125.91 123.80 119.97 305

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 306 3.843 1.659 8.014 7.561 7.023 7.018 6.933 6.928 6.915 6.910 6.492 6.485

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 9.32 0.88 0.92 0.97 0.97 0.95 3.00 103.46 83.48 55.68 28.21 155.82 131.36 126.51 115.83 112.96 107.10

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 307 308 9.691 9.687 9.683 7.248 7.230 6.865 6.848 6.365 3.813 3.645 3.641 1.533

10 9 8 7 6 5 4 3 2 1 ppm 0.87 1.22 1.03 0.85 3.00 2.07 9.32 55.69 53.19 34.11 28.39 153.77 153.16 131.14 125.93 122.51 118.45 110.72 103.85 309

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 310 7.274 7.070 7.065 6.760 6.743 6.386 4.657 4.646 4.635 3.773 3.609 3.595 3.590 3.582 3.577 3.564 3.402 3.389 3.383 3.375 3.370 3.357 3.347 3.307 2.894 2.883 1.533 1.517 1.515 1.511 1.504 1.493 1.473 1.346 1.331 1.316 1.301 0.887 0.873 0.858

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm 0.93 0.95 0.99 0.89 0.98 3.05 1.09 1.18 2.98 2.00 2.10 3.00 11.27 4 9 4 2 9 8 4 8 1 15 61 35 65 . 21 6 1 61 91 3 33 .7 . .08 . . 3 ...... 88 8. 0. 0 4. 8. 1 80.0 66 55 53 3 31 2 19 13 153 153 131 126 122 11 11 311

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 312 8.252 8.234 7.660 7.646 7.643 7.540 7.525 7.510 7.465 7.449 7.435 7.192 7.186 6.996 6.991 6.934 6.929 6.916 6.911 6.476 6.476 6.469 6.468 3.808

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 1.00 2.07 1.05 2.15 0.97 1.02 1.01 0.97 3.22 55.71 168.39 156.73 134.62 131.79 131.77 130.73 129.11 128.57 128.28 117.23 113.39 108.53 103.61 313

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 314 9.555 9.551 9.547 8.154 7.767 7.752 7.457 7.452 7.439 7.434 7.429 7.414 7.400 7.341 7.326 7.311 6.744 6.726 3.683 3.488 3.485

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 0.90 0.97 2.01 1.17 0.87 2.06 1.00 3.00 1.96 200.13 165.91 154.59 134.81 131.72 131.20 128.66 127.13 124.21 121.62 121.46 110.75 55.67 45.37 315 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 316 7.616 7.609 6.671 6.667 6.531 6.524 6.499 6.495 3.946 3.877 2.672

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1.00 1.00 1.01 1.01 3.19 3.22 3.13 97.25 95.24 55.72 55.68 25.81 169.58 157.42 148.53 134.51 128.21 119.49 108.03 317

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 318 7.776 7.774 7.763 7.759 7.757 7.587 7.572 7.559 7.557 7.554 7.467 7.465 7.452 7.440 7.436 7.392 7.385 6.681 6.677 6.547 6.540 6.394 6.390 3.859 3.578

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.92 1.00 2.00 0.96 0.97 0.98 0.97 3.00 3.02 167.73 157.52 148.57 134.98 133.38 132.50 129.72 129.36 128.28 120.78 107.57 97.01 94.83 55.71 55.31 319

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 320 7.442 7.438 7.184 6.660 6.655 4.644 4.633 4.622 3.874 3.812 3.647 3.634 3.629 3.621 3.615 3.602 3.449 3.435 3.430 3.422 3.417 3.404 3.347 2.926 2.915 2.170 1.559 1.554 1.545 1.529 1.382 1.367 1.352 1.337 0.924 0.910 0.895

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.95 0.88 0.99 1.00 3.42 3.01 1.04 1.13 3.21 2.04 3.11 2.36 2.26 3.30 101.52 64.35 58.36 53.47 51.19 32.07 29.60 22.30 17.04 11.58 165.90 150.38 141.70 131.46 128.68 111.44 101.73 321

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 322 8.236 8.218 7.902 7.081 7.053 7.048 6.984 6.854 6.849 6.836 6.831 5.978 3.727

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.93 0.93 0.86 0.95 0.91 1.02 2.05 3.00 101.47 54.78 163.82 155.80 149.12 146.66 129.84 127.89 122.48 116.74 113.86 112.91 112.50 110.05 108.73

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 323 324 7.378 7.111 7.106 6.543 6.538 6.523 6.518 6.498 6.477 6.066 3.354

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 0.90 1.87 0.97 0.96 2.04 6.00 102.68 94.92 50.48 177.89 151.57 151.36 147.28 141.32 139.30 126.95 124.46 122.83 114.77 114.75 111.88 325

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 326 7.226 7.222 7.131 7.066 7.058 7.055 7.032 7.027 6.521 6.513 6.096 3.859

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm 0.93 0.90 1.87 0.97 0.99 2.06 3.00 102.44 55.77 164.79 156.77 150.12 147.66 130.84 128.88 123.40 117.73 114.77 113.91 113.50 111.04 109.73 327

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 328 9.694 9.691 9.688 8.384 8.366 8.043 7.186 7.099 6.990 6.972 6.088 4.016 4.014 3.874

10 9 8 7 6 5 4 3 2 1 ppm 0.91 0.93 0.95 0.98 1.16 1.01 2.28 2.01 3.00 109.66 102.45 56.22 45.23 198.31 164.94 155.23 150.15 147.68 130.84 129.14 122.71 122.44 118.85 113.52 111.05 109.97 329

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 330 8.017 8.010 7.986 7.598 7.502 7.498 7.308 7.304 6.837 6.830 6.169 3.967

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 ppm 1.00 0.96 1.04 1.08 1.16 1.03 2.17 3.24 124.10 122.82 116.92 110.71 108.21 107.35 105.97 102.32 101.85 56.35 157.93 157.59 152.52 148.66 131.27 128.92 126.28 331

200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 ppm 332 10.460 7.607 7.591 7.552 7.535 7.336 7.334 7.320 7.305 7.304 7.175 7.160 7.145 3.760 3.746 3.732 3.238 3.131 3.116 3.102

10 9 8 7 6 5 4 3 2 1 ppm 0.97 1.01 0.98 0.98 2.05 3.00 2.02 0.97 AAACRYOCARBON CDCl3 /opt/topspin robert 12 50.21 34.19 20.61 162.11 137.69 127.08 125.27 124.57 120.00 119.98 117.82 112.72 333

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 334 2.770 2.759 2.748 2.744 2.732 2.479 2.467 2.464 2.453 2.441 2.437 2.426 2.288 7.295 7.280 7.229 7.213 7.206 7.197 7.191 7.178 7.147 7.133 7.051 7.046 7.039 7.023 6.986 6.971 3.691 3.679 3.672 3.660 3.656 3.644 3.633 3.614 2.955 2.786 2.775

9 8 7 6 5 4 3 2 1 ppm 2.11 3.00 1.02 1.04 3.15 0.98 2.15 1.04 2.93 1.00 AAACRYOCARBON CDCl3 /opt/topspin robert 2 61.00 47.19 30.69 28.02 21.39 178.38 170.11 153.24 139.97 137.64 129.41 129.01 126.88 124.59 121.50 121.37 119.66 117.87 335

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm AAACRYOPROTON CDCl3 /opt/topspin robert 12 336 8.671 7.215 7.213 7.200 7.197 7.184 7.182 7.144 7.130 7.045 7.043 7.029 7.028 7.014 7.013 6.840 6.825 3.813 3.801 3.796 3.794 3.784 3.782 3.777 3.765 3.645 3.635 3.627 3.618 3.616 3.608 3.599 3.009 2.770 2.760 2.753 2.743 2.733 2.726 2.717 2.441 2.429 2.423 2.414 2.412 2.402 2.397 2.385

10 9 8 7 6 5 4 3 2 1 0 ppm 1.01 0.99 1.01 0.96 1.01 1.02 3.00 1.02 1.05 0.96 AAACRYOCARBON CDCl3 /opt/topspin robert 12 49.56 32.84 31.66 179.79 172.96 144.09 132.69 131.22 125.23 125.06 112.68 60.54 337

200 180 160 140 120 100 80 60 40 20 0 ppm 338 3.958 3.941 3.863 3.844 3.824 3.144 2.933 2.915 2.906 2.896 2.888 2.869 2.390 2.377 2.366 2.350 13.912 7.583 7.567 7.412 7.397 7.381 7.335 7.321 7.245 7.230 7.215 7.203 7.186 6.652 6.647 6.513 6.508 6.495 6.490 3.994 3.977

14 13 12 11 10 9 8 7 6 5 4 3 2 1 ppm 1.00 1.03 0.96 1.00 1.00 1.03 1.01 0.97 1.00 1.19 3.13 1.03 3.00 0.50 AAACRYOCARBON CDCl3 /opt/topspin robert 3 64.45 55.51 47.20 30.79 30.65 178.23 171.53 164.24 163.85 152.13 140.27 129.15 129.12 125.96 120.82 119.66 108.52 107.66 101.80 339

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm AAACRYOPROTON128 MeOD /opt/topspin robert 3 340 2.771 2.752 2.728 2.709 2.370 2.354 2.344 2.328 7.585 7.567 7.481 7.467 7.435 7.421 7.284 7.277 7.269 6.599 6.583 6.508 4.009 3.993 3.975 3.958 3.864 3.833 3.812 3.794 3.002

9 8 7 6 5 4 3 2 1 ppm 1.16 3.02 1.09 3.07 0.97 1.05 1.00 1.11 1.05 2.13 1.02 0.99 AAACRYOCARBON MeOD /opt/topspin robert 3 57.27 48.48 32.92 31.10 177.33 172.17 169.60 165.30 145.03 139.73 135.94 130.88 129.11 123.28 117.96 112.28 108.28 101.00 67.17 341

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm AAACRYOPROTON128 CDCl3 /opt/topspin robert 1 342 7.937 7.920 7.759 7.742 7.710 7.695 7.416 7.401 7.386 7.355 7.339 7.307 7.294 7.271 7.257 7.242 6.808 6.804 6.544 6.540 6.527 6.523 3.828 3.812 3.793 3.777 3.768 3.513 3.507 3.494 3.488 3.475 3.469 3.047 2.731 2.716 2.712 2.705 2.697 2.690 2.686 2.671 2.476 2.268 2.262 2.252 2.245 2.243 2.236 2.226

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.04 2.02 1.02 1.09 2.09 0.98 1.05 0.98 0.99 1.05 3.16 1.04 3.11 1.05 3.10 1.00 AAACRYOCARBON CDCl3 /opt/topspin robert 1 55.83 47.31 30.47 26.99 21.76 175.76 171.16 158.39 152.44 145.77 141.90 132.25 131.95 129.92 128.83 128.61 126.59 121.17 120.85 114.63 106.61 67.31 343

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm AAACRYOPROTON CDCl3 /opt/topspin robert 3 344 7.908 7.893 7.522 7.518 7.505 7.492 7.488 7.380 7.369 7.365 7.351 7.336 7.296 7.287 7.278 6.683 6.679 6.615 6.610 6.597 6.592 4.047 4.030 4.010 3.993 3.982 3.918 3.908 3.882 3.879 3.175 2.998 2.980 2.971 2.962 2.952 2.934 2.568 2.565 2.552 2.549 2.541 2.537 2.525 2.522

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm 1.01 1.99 1.38 0.98 1.05 1.35 3.02 0.83 3.42 1.13 1.10 1.00 AAACRYOCARBON CDCl3 /opt/topspin robert 3 62.65 55.94 47.04 32.53 30.95 173.77 169.31 168.30 163.39 143.85 137.78 129.98 128.48 127.31 121.32 118.20 111.30 105.89 102.57 345

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm 346