DEVELOPMENT OF METAL-CATALYZED REACTIONS OF ALLENES WITH IMINES AND THE INVESTIGATION OF BRΘNSTED ACID CATALYZED ENE REACTIONS

BY

LINDSEY O. DAVIS

A Dissertation Submitted to the Graduate Faculty of

WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES

in Partial Fulfillment of the Requirements

for the Degree of

DOCTOR OF PHILOSOPHY

in the Department of Chemistry

December 2009

Winston-Salem, North Carolina

Approved By:

Paul B. Jones, Ph.D., Advisor ______

Examining Committee:

Christa L. Colyer, Ph.D., chair ______

S. Bruce King, Ph. D. ______

Dilip K. Kondepudi, Ph.D. ______

Suzanne L. Tobey, Ph.D. ______

ACKNOWLEDGMENTS

I must first acknowledge my family for their support throughout my

education. My mother has always encouraged me to ask questions and seek

answers, which has guided my inquisitive nature as a scientist. My grandparents

have taught me the importance of character and my father taught me the value in

hard work. I’d also like to thank my husband for moving away from Georgia, a

sacrifice I greatly appreciate. Also, his cheerful disposition helped me stay

relatively positive, especially when I had bad research days.

My friends also played a very important role in keeping me positive during

my time at Wake. Particularly my roommates put up with me more than most.

I’d like to thank Lauren Eiter for her sense of humor, Tara Weaver for her taste in books and movies, and Jenna DuMond, for her encouragement and loyalty. Also

I’ve made lifetime friends with Meredith and Kavita, and even though they left me at Wake, they were always willing to offer their support. I’d also like to thank

other people in the department that were a great asset as friends and fellow

chemists: Erika Klorig, Ranjan Banerjee, John Solano, Zhidong Ma, Salwa

Elkazaz, Lu Rao, Julie Reisz, and Carl Young.

My labmates have spent more time with me than anyone else over the

course of the past few years. I would like to thank the members of the Tobey and

Jones lab for putting up with me and enriching my time at Wake. No one

understands what it is like to be a graduate student in the Tobey lab other than

Katherine House. We have had some very memorable experiences in the lab

II and her persistence encouraged me to finish when I wanted to quit. I have also

been very fortunate to have good undergraduates in our lab: Mallory, James,

Lauren, and Ritu. James and Lauren in particular assisted on my project, so I

thank them for their time and effort. In addition, the members of the Jones lab

(Salwa, Saurav, Swapna, Eric) were supportive colleagues and their input was

invaluable.

I have been fortunate enough to have several amazing chemistry teachers

throughout my education. My high school chemistry teacher, Ms. Roberson,

gave me a priceless foundation in chemistry, which gave me the initial interest in the subject. My undergraduate career was marked with several great teachers, but none as important as Dr. Gary Breton. Working in his lab not only gave me invaluable lab skills, but it also sparked a love for organic chemistry. At Wake, I would like to first thank my committee members, Dr. Christa Colyer, Dr. Bruce

King (especially for stepping in at the last minute), Dr. Welker, and Dr. Kondepudi for reading my thesis and proposals, and for their thoughtful input. I would also like to thank Dr. Marcus Wright not only for his contribution to my education and my project, but also for his spiritual guidance and example.

Lastly I would like to thank each of my advisors, Dr. Suzanne Tobey and

Dr. Paul Jones. I can’t thank Dr. Tobey enough for her unrelenting dedication to

see me through to a doctorate. She is a phenomenal chemist, teacher, and

mentor, and I am so glad I was a part of her group. I also want to thank Paul for

not only allowing me to join his group, but also his guidance and input to my

project. He has been an excellent advisor and teacher.

III

This dissertation is dedicated in loving memory to

Jerel Dale Oliver

IV TABLE OF CONTENTS

Page

List of Tables VIII

List of Figures VIII

List of Schemes X

Abstract XIII

Chapter 1 Introduction and Background

1.1.0 Introduction 1

1.2.0 Allenes 2

1.2.1 Synthesis and reactivity of allenes 3

1.2.2 Allenes in the Baylis–Hillman reaction 6

1.3.0 The ene reaction 8

1.3.1 Lewis acid catalysis of the ene reaction 9

1.3.2 Brønsted acid catalysis 11

1.3.3 Brønsted acid catalysis in nature 13

1.3.4 Small molecule organocatalysis 15

1.3.5 Imines and hydrazones 20

1.3.6 Types of ene reactions 22

1.3.6.1 Aza-ene and thio-ene reactions 23

1.3.6.2 The carbonyl-ene reaction 24

1.3.6.3 The imino-ene reaction 29

1.4.0 Unnatural amino acids 31

V 1.5.0 References 33

Chapter 2 Reaction Discovery of allenes and imines 40

2.1.0 Introduction 40

2.2.0 Screening of allenes and imines 41

2.3.0 Optimization of aza-Baylis−Hillman-type reaction 42

2.3.1 Mechanistic studies 46

2.3.2 Other Lewis acids used to promote an alkylation reaction 50

2.3.3 Scope of the reaction 52

2.4.0 Future work 57

2.5.0 Experimental data 60

Chapter 3 Brønsted acid catalyzed ene reactions 81

3.1.0 Introduction 81

3.2.0 Carbonyl-ene reaction 81

3.2.1 Scope of the carbonyl-ene reaction 84

3.2.2 Intramolecular carbonyl-ene reaction 85

3.3.0 Imino-ene reaction 86

3.3.1 Optimization of a Brønsted acid catalyzed imino-ene reaction 87 3.3.2 Scope of the imino-ene reaction 89

3.3.3 1H NMR titration studies of imino-ene reaction 90

3.4.0 Reactions of hydrazones 95

3.4.1 Reaction optimization 97

3.4.2 Scope of the reaction 102

3.4.3. Proposed mechanism and 1H NMR studies 103

VI 3.4.4 Intermolecular hydrazone substrates 107

3.4.5 Future work 108

3.5.0 Experimental Data 109

3.5.1 Carbonyl-ene data 110

3.5.2 Imino-ene data 111

3.5.3 Hydrazone data 119

3.6.0 References 126

Appendix I 129

Appendix II 132

Appendix 136 III Scholastic 149 Vita

VII

LIST OF TABLES

Table I. Optimization of concentration and substrate ratio 44

Table II. Optimization of temperature and time 45

Table III. The effects of additives to probe mechanism 48

Table IV. Other Lewis acids used to promote alkylation of the 51 allene

Table V. Scope of the reaction 53

Table VI. Elimination of α-pre-eliminated products 55

Table VII. Styrene optimization results 83

Table VIII. Scope of the carbonyl-ene reaction 84

Table IX. Optimization of imino-ene reaction 88

Table X. Scope of the Brønsted acid catalyzed imino-ene 90 reaction

Table XI. Optimization of hydrazone cyclization 98

Table XII. The effect of time on the cyclization reaction 99

Table XIII. The effect of additional Brønsted acids on the cyclization reaction 100

Table XIV. Scope of the reaction 102

Table XV. The effect of water on the cyclization reaction 105

LIST OF FIGURES

Figure 1.1 Orbitals and hybridization of allenes. 3

Figure 1.2 Reactivity of donor-substituted allenes. 5

VIII Figure 1.3 HOMO-LUMO interaction between ene and enophile. 8

Figure 1.4 Transition states of thermal and Lewis acid catalyzed 10 ene reactions.

Figure 1.5 Activation of carbonyls and imines through hydrogen bonding and metal chelation. 11

Figure 1.6 Thiourea and urea general structures. 15

Figure 1.7 Thiourea dual hydrogen-bond activation of an imine. 16

Figure 1.8 General structures for amidine and guanidine moieties. 16

Figure 1.9 General structures for phosphoric acid, phosphoric acid esters, and phosphoramidates. 18

Figure 1.10 General hydrazone structure. 21

Figure 1.11 Titanium-BINOL dinuclear complex. 26

Figure 1.12 Structure of gymnangiamide. 32

Figure 2.1 Allenes and imines prepared for screening for an allenyl imino-ene reaction. 41

Figure 2.2 Additional allenes tested for an alkyation reaction. 50

Figure 3.1 Structure of diethyl phosphoramidate. 89

Figure 3.2 Graphical representation of the dilution of diethyl phosphate. 91

Figure 3.3 Graphical representation of the titration of tosyl imine into diethyl phosphate. 92

Figure 3.4 Stacked 1H NMR spectroscopy plots of the kinetic experiment of the tosyl imine and diethyl phosphate. 93

Figure 3.5 Graphical representation of the disappearance of the tosyl imine and appearance of ethyl glyoxylate. 94

Figure 3.6 Potential structure of dimerized diethyl phosphate. 95

Figure 3.7 Job plot resulting from the interaction of diethyl phosphate and hydrazone 86 106

IX

LIST OF SCHEMES

Scheme 1.1 The oxidation of a homopropargylic alcohol. 4

Scheme 1.2 Copper mediated substitution reaction to generate an allene. 4

Scheme 1.3 Pd-catalyzed coupling reaction to generate an allene. 5

Scheme 1.4 General mechanism of the Baylis–Hillman reaction. 6

Scheme 1.5 Aza-Baylis–Hillman between tosylated aldimines and an allene. 7

Scheme 1.6 MgBr2-mediated Baylis–Hillman-type reaction. 8

Scheme 1.7 General ene reaction mechanism. 8

Scheme 1.8 Biradical mechanism of the ene reaction. 9

Scheme 1.9 Step-wise mechanism for a Lewis acid catalyzed ene reaction. 10

Scheme 1.10 General mechanisms for specific acid catalysis and general acid catalysis. 12

Scheme 1.11 Mechanism of serine protease. 14

Scheme 1.12 Proline catalyzed aldol cyclization. 17

Scheme 1.13 Proposed mechanism for a proline-catalyzed aldol cyclization. 18

Scheme 1.14 Proposed mechanism for a phosphonic acid catalyzed aza-ene reaction. 19 Scheme 1.15 Organic transformations from imines to other functional 21 groups.

Scheme 1.16 Intramolecular [3+2] cycloaddition of hydrazones. 22

Scheme 1.17 Intermolecular cyclization/ene reaction between an olefin and a hydrazone. 22

X

Scheme 1.18 Lewis acid and Brønsted acid catalyzed aza-ene reactions. 23

Scheme 1.19 Thio-ene reaction. 24

Scheme 1.20 Carbonyl-ene reaction. 24

Scheme 1.21 Titanium-BINOL catalyzed glyoxylate-ene reaction. 25

Scheme 1.22 Copper bis-oxazoline catalyzed glyoxylate-ene reaction. 27

Scheme 1.23 Enantioselective N-triflylphosphoramide catalyzed carbonyl-ene reaction. 28

Scheme 1.24 Takagaso synthesis of menthol. 28

Scheme 1.25 Examples of a thermal allenyl imino-ene and Lewis acid catalyzed allenyl imino-ene reaction. 30

Scheme 1.26 Enantioselective imino-ene reaction catalyzed by copper-BINAP complex. 30

Scheme 1.27 Imino-ene reaction catalyzed by Yb(OTf)3. 31

Scheme 2.1 Allenyl-imino ene reaction with silylallenes . 40

Scheme 2.2 Example of a test reaction with a silyl allene and an imine. 42

Scheme 2.3 Reaction of allene 30 and imine 33 under Lewis acid conditions. 43

Scheme 2.4 Proposed step-wise mechanism in which a vinyl cation is generated and trapped by a halide. 47

Scheme 2.5 Plausible mechanism for the formation of the alkylation products. 49

Scheme 2.6 Alkylation of a phenyl substituted ketoallene with tosyl imine. 52

Scheme 2.7 Reaction of K OtBu added directly to alkylation reaction. 56

Scheme 2.8 General mechanisms for E1CB and E2 elimination. 56

XI Scheme 2.9 Elimination of diastereomers to form allene product. 58

Scheme 2.10 Preliminary data for an enantioselective aza-Baylis– Hillman-type reaction. 59

Scheme 2.11 Alkylation reaction between ethyl glyoxylate and allene 30 under Lewis acid conditions. 59

Scheme 3.1 General carbonyl-ene reaction. 81

Scheme 3.2 Anticipated intramolecular phosphonic acid catalyzed carbonyl-ene reaction and other various substrates that were tested. 85

Scheme 3.3 General imino-ene reaction. 86

Scheme 3.4 Imino-ene reaction in which a masked amino acid is produced. 86

Scheme 3.5 Decomposition of tosyl imine under phosphonic acid conditions. 95

Scheme 3.6 Proposed ene cyclization of a hydrazone catalyzed by a phosphonic acid. 96

Scheme 3.7 Observed cyclization of a hydrazone to form a pyrazolidine derivative. 96

Scheme 3.8 Hydrazone cyclization under a step-wise mechanism and a concerted [3+2] mechanism. 103

Scheme 3.9 Proposed phosphonic acid catalyzed intermolecular ene reaction. 107

Scheme 3.10 Reaction of methylated hydrazone 96 under phosphonic acid conditions. 108

XII

ABSTRACT

Lindsey O. Davis

DEVELOPMENT OF METAL-CATALYZED REACTIONS OF ALLENES WITH IMINES AND THE INVESTIGATION OF BRΘNSTED ACID CATALYZED ENE REACTIONS

Dissertation under the direction of Dr. Paul B. Jones, Associate Professor of Chemistry Dr. Suzanne L. Tobey, Assistant Professor of Chemistry

Since the birth of organic chemistry in the 19th century, scientists have

been discovering new reactions to generate interesting synthetic targets. As

these new reactions have emerged, they are constantly tweaked so that an array

of substrates can be synthesized and better catalysts can be discovered. The

focus of our research is to two-fold: (1) to study the reaction chemistry between

allenes and imines, and (2) to discover new catalysis and novel substrates for the

ene reaction.

Reactions between allenes and imines have been mostly unexplored

despite their ability to generate useful synthetic intermediates. Described herein is the initial screening of the reaction conditions for the intended allenyl imino-ene reaction, however the primary focus of this project is on the development of an unexpected aza-Baylis–Hillman-type reaction between ketoallenes and imine- containing electrophiles. This chemistry shows promise for a new single step,

XIII atom economical reaction for the generation of unnatural amino acids containing

densely functionalized alkenes and allene moieties.

In addition to studying new reactions, we have worked on the further

development of the established ene reaction. The ene reaction is one of the

most powerful carbon–carbon bond-forming reactions in organic chemistry. The

resulting products can be used as synthons for natural products, as well as substrates for drug targets. Lewis acid catalyzed ene reactions provide access to homoallylic amines and alcohols. However, the scope of this type of catalysis is limited because of the need for inert conditions, the metal waste generated, and the metal’s stronger chelation to the product than the starting material. As an alternative, we have developed Brønsted acid catalyzed ene reactions. A

phosphonic acid has been identified as a viable catalyst for the carbonyl-ene and

imino-ene reaction. In addition, this phosphonic acid was shown to promote a

cyclization reaction of hydrazones to generate pyrazolidine derivatives. This chemistry shows the potential of a phosphonic acid as a more general catalyst for these types of reactions.

XIV CHAPTER ONE

INTRODUCTION AND BACKGROUND

1.1.0 INTRODUCTION

Since the birth of organic chemistry in the 19th century, scientists have

been discovering new reactions to generate interesting synthetic targets. As

these new reactions have emerged, they are constantly tweaked so that an array

of substrates can be synthesized and better catalysts can be discovered. The

focus of our research is two-fold: (1) to study the reaction chemistry between

allenes and imines, and (2) to discover new catalysis and novel substrates for the

ene reaction.

Reactions between allenes and imines have been mostly unexplored

despite their ability to generate useful synthetic intermediates. In the 1990s

work1-3 with the allenyl imino-ene reaction brought this chemistry to the forefront; however other types of reactions between these substrates have not been fully investigated. We have developed a halide initiated Baylis–Hillman reaction between allenes and imines to produce protected unnatural amino acids.

Development of this new methodology included: (1) reaction optimization through the screening of allene and imine substrates, and (2) the study of steric and electronic effects upon the reaction by varying functional groups on each reaction partner.

In addition to studying new reactions, we have worked on the further

development of the established ene reaction.4 The ene reaction is one of the

1

most powerful carbon–carbon bond-forming reactions in organic chemistry. The

resulting products can be used as synthons for natural products, as well as

substrates for drug targets. Lewis acid catalyzed ene reactions provide access

to homoallylic amines and alcohols. However, the scope of this type of catalysis

is limited because of the need for inert conditions, the metal waste generated,

and the metal’s stronger chelation to the product than the starting material. As an alternative, we have developed Brønsted acid catalyzed ene reactions. The

application of Brønsted acids as ene catalysts included: (1) screening Brønsted

acids and substrates for the ene reaction, (2) integration of enophiles containing

carbonyl, imine, and hydrazone groups, and (3) investigating the physical

interaction between catalyst and substrate.

The background information relevant to all aspects of the research

described in this dissertation is discussed below.

1.2.0 ALLENES

Allenes are a unique class of compounds containing two adjacent carbon–

carbon double bonds. They were first discovered in 1887,5 but were thought to be highly unstable molecules, which delayed the progress of allene chemistry. It was not until infared (IR) and Raman spectroscopy were used to prove their existence in the 1950s that the general chemistry community finally believed that earlier work actually produced a stable allene molecule.6

The geometry of the allene is unique: there are two adjacent π-bonds, which places the π- systems perpendicular to each other (Figure 1.1). As a

2

result, the two methylene groups sp2 sp2

attached to each end of the allene are H H H also perpendicular to each other. The H

central carbon atom of an allene is sp sp hybridized and the terminal carbon Figure 1.1. Orbitals and hybridization of allenes.

atoms are sp2 hybridized. The shape of the allene gives it distinctive symmetrical characteristics and as a result 1,3-substituted allenes are chiral.

1.2.1 Synthesis and reactivity of allenes

Allenes can be synthesized through a variety of methods including

isomerization and sigmatropic rearrangements, metal-mediated methods, and transition metal catalyzed syntheses. They also participate in a range of reactions depending on the substituents attached to the allene. The following discussion is not exhaustive, but does highlight common syntheses of allenes and explores their general reactivity.

Isomerization reactions take place by changing the connectivity of a

molecule. The base-catalyzed isomerization of an alkyne is a common way in

which an allene is created. Ketones and aldehydes possess the highest α-acidity

and specifically this allows terminal propargyl ketones to isomerize to allenyl

ketones. For example, the oxidation of a homopropargylic alcohol 1, directly yields the allenyl ketone 3 rather than the propargyl ketone 2 (Scheme 1.1).

3

O OH oxidation O work-up R R R 1 23

Scheme 1.1. The oxidation of a homopropargylic alcohol

Allenes are also commonly made through metal-mediated reactions.

These reactions differ from transition metal mediated reactions, in that these reactions use stoichiometric amounts of organometallic reagents and unsaturated electrophiles to generate allene-containing products. The most relevant reaction of this class is a copper-mediated SN2′ substitution of propargyl electrophiles. Discovered in 1968,7, 8 this reaction has been expanded to tolerate many substrates including: acetates (Scheme 1.2), benzoates, carbonates,

9, 10 2 ethers, and acetals, and 2 R R 3 4 R R 2CuLi R1 R3 halides11, 12 among others as OAc R1 4 R leaving groups. In addition, Scheme 1.2. Copper mediated substitution reaction to generate an allene. allenes with a carbonyl group appended (allenoates) are often synthesized through a Grignard reaction between an aldehyde and propargyl magnesium bromide.

The last major reaction used to synthesize allenes employs transition metal catalysis. This reaction type is not as general as the methods already discussed, as it uses less common metal catalysts, but it is nevertheless an important type of synthesis of allenes. While there are several transition metals that are used in this type of synthesis, the most popular and versatile metal employed is palladium. Recently, a palladium-catalyzed cyanation reaction

4

between carbonates and methylsilyl cyanide has been reported to yield

cyanoallenes (Scheme 1.3).13 This method provides access to allenic starting materials which can easily undergo additional organic transformations.

Pd(PPh3)4 R2 1 R3 R1 (5mol%) R R3 TMSCN 4 R OCO2 R2 CN

Scheme 1.3. Pd-catalyzed coupling reaction of propargyl carbonate and methylsilyl cyanide.

Because of the cumulated carbon–carbon double bonds, allenes are also

very reactive molecules. Particularly, allenes having an appended electron-

withdrawing group (EWG) have an electron-deficient “inner” carbon–carbon

double bond, making addition to the central carbon atom (Figure 1.2, C-2) more

favorable. Nucleophilic addition can occur by phosphines, 1° and 2° amines,

halides, alcohols, and thiols.14 In addition this type of allene undergoes ring

closure to produce heterocycles and carbocycles.

Allenes containing an electron-donating group or donor allenes exhibit

similar reactivity to an enol ether or an enamine in that they react as a

nucleophile. These allenes are usually Nuc E oxygen, nitrogen, sulfur, or selenium XR

weakly 123 substituted. Donor allenes are similar to acidic H H acidic

X= O, N, S, Se allenes with electron-withdrawing groups in Figure 1.2. Reactivity of donor- substituted allenes. that the central carbon atom is susceptible to

nucleophilic attack. However, they differ in most other ways. Because of the

hyperconjugation through the allenic system, the C-3 carbon atom is nucleophilic

5

(Figure 1.2). In addition, the donor group increases the CH-acidity on the C-1

carbon atom, allowing easy lithiation and subsequent reaction with a variety of

electrophiles (Figure 1.2).14 Although more rare, deprotonation can also occur at

the C-3 carbon atom causing it to have nucleophilic character. Together, these

reactivities allow donor allenes to participate in addition reactions and

cycloadditions to generate highly functionalized products.

1.2.2 Allenes in the Baylis–Hillman reaction

Work within the past 20 years has established allenes as viable reactive

and selective partners in a variety of reactions.15 However, allenes have not

been fully developed as substrates in the Baylis–Hillman reaction. This reaction

usually occurs between an electron-poor alkene and a carbon electrophile.

Mechanistically, it is similar to the aldol reaction, the main difference being that

the enolate generated after the first step occurs because of conjugate addition of

the catalyst (Scheme 1.4, step a). Usually catalysts are nitrogen- or phosphine-

O O O O O OH O O OH a R H EtO EtO R EtO R c EtO N b EtO R N N N N N N N N N

Scheme 1.4. General mechanism of Baylis-Hillman reaction. based such as DABCO (1,4-diazabicyclo[2.2.2]octane) or PPh3, respectively.

The enolate produced from addition then adds into the electrophile, commonly an aldehyde (Scheme 1.4, step b). The resulting intermediate tautotomerizes and elimination by an E1CB mechanism regenerates the catalyst and forms the α, β-

unsaturated ketone (Scheme 1.4, step c). Ketoallenes can be used as

6

substrates instead of alkenes in a Baylis–Hillman-type reaction to generate an

allene product. The inclusion of allenes as a reactive substrate in the Baylis–

16 Hillman reaction has been reported.

Recent work by Shi and co-workers produced an unusual aza-Baylis-

Hillman reaction between tosyl-protected aldimines and activated allenes or

alkynes.17 The unexpected products obtained were a result of either a formal

[2+2], [3+2], or [4+2] cycloaddition, all of which were dependent upon the nitrogen- or phosphine-derived Lewis base used to catalyze the reaction. When

DABCO was used as the Lewis base, the expected Baylis-Hillman adduct 5 was produced in small amounts along with an azetidine derived product 4 (Scheme

1.5).

O Ts CO Et TsHN O DABCO 2 OEt N Ar Ar OEt RT, 5 h, PhH N Ar H Ts 4 5 45-69% yield 8-41% yield Scheme 1.5. Aza-Baylis-Hillman between tosylated aldimines and 2,3-butadienoate

In addition to nitrogen- and phosphine-based catalysts, halides have also

been used as Lewis bases in Baylis-Hillman-type reactions. These reactions are

less common and are currently limited to those containing alkyne and carbonyl

substrates. Several reports of halide catalysts have recently been reported

wherein promoters such as TMSI,18 magnesium bromide (Scheme 1.6),19 and aluminum iodide were used.20 Despite the current limitations with respect to

types of substrates that can be tolerated, this methodology has led to the

7 synthesis of vinyl halides OH O O MgBr2 (1.2 equiv.) which can be further COMe Ph Ph H DCM, RT, 5 h H Br manipulated using 82% yield E/Z = 17/83 organometallic coupling

Scheme 1.6. MgBr2-mediated Baylis-Hillman-type reaction chemistry.

1.3.0 THE ENE REACTION

The ene reaction is H Y YH X X Scheme 1.7 an effective carbon–carbon 67 bond–forming reaction in 6: alkene, alkyne, arene, allene organic chemistry first made 7: (X=Y): C=C, C=O, C=N, C=S known by Alder in 1943 and documented in his Nobel Lecture in 1950.21, 22 The substrates, usually an alkene with an allylic hydrogen atom (an “ene” 6) and an

“enophile” 7, react in such a way to affect a 1,5-H shift23 and formation of a carbon–carbon bond (shown in red in Scheme 1.7).

Formally, the thermal pericyclic ene reaction proceeds through a concerted six- HOMO ene electron pathway with a suprafacial three component orbital interaction between the H LUMO enophile highest occupied molecular orbital (HOMO) of the ene and the lowest unoccupied molecular Figure 1.3 HOMO-LUMO interaction between ene and enophile. orbital (LUMO) of the enophile24 (Figure 1.3).

8

Alternatively, a thermal ene reaction may proceed in a stepwise fashion if the system is too strained to achieve the necessary geometry, thereby

generating a biradical intermediate 8 (Scheme 1.8). Usually, the stepwise

reaction produces a cyclobutane side product (9). It is assumed if this product is

not present, the ene reaction proceeded in a concerted fashion.4

H

H H

H 8

9 Scheme 1.8. Biradical mechanism of the ene reaction

1.3.1 Lewis acid catalysis of the ene reaction

The first ene reactions were promoted thermally,4 but required

temperatures could exceed 300°C, limiting the synthetic utility of the reaction.25

Consequently, Lewis acids such as AlCl3, SnCl4, TiCl4, and alkylaluminum

halides (RnAlX3-n) have been successfully employed to promote inter- and

intramolecular ene reactions.25 Lewis acids, electron acceptors, lower the activation energy of the enophile through chelation (see Figure 1.5c), thereby

allowing ene reactions to occur under milder reaction conditions.

It is not clear if a Lewis acid catalyzed ene reaction occurs in a concerted

or step-wise fashion (Scheme 1.9). Available evidence suggests that both overall mechanisms are close in energy and it is dependent on the ene, enophile, and catalyst.25 It is known that a positive charge builds up on the ene

9

component,26 therefore more electron-rich alkenes can best stabilize this charge.

As a result, 1,1-disubstitued alkenes react more readily as ene components than

monosubstituted or 1,2-disubstituted double bonds.

ML ML ML O n n n O O

H H H

Scheme 1.9. Step-wise mechanism for a Lewis acid catalyzed ene reaction.

The transition-state geometry is also different for a Lewis acid catalyzed ene reaction versus a thermal ene. In a thermal ene, the transition state occurs early, meaning the “envelope-like” transition state looks more like the reactants than the product based on Hammond’s postulate (Figure 1.4a).27 The Lewis acid

catalyzed ene on the other hand develops a late “chair” conformation transition

state and looks more like the product (Figure 1.4b).28

AlCl3 H H H O H O

a b

Figure 1.4. a "Envelope-like" thermal ene transition state b "Chair" Lewis acid catalyzed ene reaction transition state Lewis acid catalysis has provided an easily accessible way for the ene reaction to proceed, increasing its synthetic utility. However, there are several disadvantages associated with Lewis acid catalysis. The main difficulty is that the product of a reaction usually contains a Lewis-basic moiety which binds to the Lewis acid.29 This results in little to no catalytic turnover, limiting the use of

10

these catalysts in aqueous media. Despite this drawback, Lewis acids are highly tunable and have well-defined interactions. These characteristics have led them to be successfully incorporated into both carbonyl-ene26, 30 and imino-ene

reactions,31, 32 leading to the expansion of the reaction arsenal for synthetic

chemists.

1.3.2 Brønsted acid catalysis

Brønsted acids are proton donors that work as catalysts by activating an electrophilic substrate. Current precedent33 suggests that this occurs through

hydrogen bonding. The hydrogen bond can occur as single-point interaction or as a bifurcated hydrogen-bond motif (Figure 1.5). The single-point hydrogen

bond is analogous to Lewis acid activation of substrates which occur through

chelation (Figure 1.5c).33

Hydrogen-bond strength is Z R R B B MLn dependent upon each partner involved H H X X X in the hydrogen bond as well as the Y

solvent. These numbers can range a b c from less than 4 kcal/mol, for bonds X, Y= O, N; BR= Bronsted Acid; Z=counter ion

Figure 1.5. a. Single point hydrogen bond moiety involving CH (CH–N or CH–O) donors b. Bifurcated hydrogen bond c. Metal Lewis Acid/Base Interaction to nitrogen or oxygen acceptors, to 14-

40 kcal/mol for NH-N hydrogen bonds within the conjugate acid of a proton

sponge.33

11

The strongest hydrogen bonds occur when the X—H···A angle is 180°, but

strength also depends on acidity of the partners involved and solvent. A hydrogen bond is shared equally if the two partners have the same pKa value and as the acceptor becomes more basic and the donor more acidic, the strength of a hydrogen bond increases. Hydrogen bonds are also weaker in aqueous media and polar protic solvents compared to those formed in nonpolar solvents.

This weaker interaction is a result of the competing hydrogen-bond interactions between the protic solvent and the substrate. The hydrogen bonding found in peptide helices and sheets is more moderate (4-15 kcal/mol),33 and similar to the

strength of most hydrogen bonds thought to occur in most organocatalysis

reactions.33

Brønsted acids can catalyze reactions by two possible mechanisms:

specific acid catalysis or general acid catalysis. In specific acid catalysis,

reversible protonation occurs in a pre-equilibrium step prior to nucleophilic attack

(Scheme 1.10a). Conversely, general acid catalysis is defined by proton transfer

occurring at the transition state in the rate-determining step (Scheme 1.10b).

H O O rds OH OH a HOH2 OEt OEt OEt OH2 OEt OH2 O OH H H OH O H-A OH OEt A OEt H3O a OEt rds O OH2 OH OH2 H H

Scheme 1.10. a. Specific acid catalysis. b. General acid catalysis. Each Brønsted acid catalyzed reaction contains different substrates and catalysts

therefore the prevalent mechanism is dependent on several variables. It is

12

known that these mechanisms occur in enzymatic reactions, and it is highly likely

these exist in organocatalysis. This aspect of organocatalysis is fascinating, and

is an unexplored area. Understanding the general catalysis mechanisms are

useful for identifying the nature of the interaction between the substrate and

catalyst, however, an in depth study is not presented herein.

There are several advantages of Brønsted acid catalysis versus Lewis

acid catalysis. First, the interaction between a Brønsted acid and an electrophile

is generally weaker than that between a Lewis acid and an electrophile.

Although this may cause longer reaction times, it also means the Brønsted acid

does not interact as strongly with the product as in the case of Lewis acids,

thereby allowing the catalyst to be more easily regenerated. This weaker

interaction reduces the need for special solvents34 or additives31 which are

sometimes necessary in the Lewis acid catalyzed reactions to help the

regeneration of the catalyst by minimizing the interaction between the product

and catalyst. In addition, many metals are poisonous and can present a problem

in terms of production in the chemical and pharmaceutical industries.35 Lastly, metal-free reactions can be run under aerobic reaction conditions adding to the practical aspect of these types of catalysts.

1.3.3 Brønsted acid catalysis in nature

Many parallels can be drawn between catalysts used in nature and the design of Brønsted acids for organocatalysis. Hydrogen-bonding interactions play a crucial role in biological systems to help activate electrophiles. Serine

13

proteases, enzymes that catalyze amide hydrolysis, show the crucial hydrogen

bonding necessary for biological catalysis. The mechanism of these enzymes

has been studied extensively using kinetic and spectroscopic techniques, giving

a good picture for how these enzymes operate.36

The amide carbonyl group, usually a poor electrophile, is activated in the

“oxyanion hole” by two hydrogen bonds, while the Asp-102/His-57 act through

general base catalysis activating the hydroxyl group on Ser-195 for nucleophilic

attack (a, Scheme 1.11).36 A tetrahedral intermediate results and the hydrogen

atom on His-57 forms a hydrogen bond with the nitrogen center on the amide to

assist this leaving group to form the resulting ester (b). Computational and

Gly-193 Ser-195 N N H H Gly-193 Ser-195 "Oxyanion hole" N N O H H R N R' O H R His-57 His-57 NH R' Asp-102 Asp-102 O O O O H N H N H N O O N Ser-195 Ser-195 H

a b

O R R'CO H N R' 2 H O RNH H 2 2

Gly-193 Ser-195 Gly-193 Ser-195 N N N N H H H H O O

His-57 HO R' His-57 Asp-102 H R' Asp-102 O O O O O H H N H N N N Ser-195 O H Ser-195 O d c

Scheme 1.11. Mechanism of serine protease: example of double hydrogen bonding activation.

14

model studies of chymotrypsin acylenzyme suggest the bonding of the ester in the oxyanion hole helps stabilize it by 4-7.5kcal/mol.37 Water adds to the

activated ester producing another tetrahedral intermediate (c). Lastly, the Asp-

102/His-57 proton shuttle assists the Ser-195 oxygen as a leaving group reforming the original Ser-195 and the resulting carboxylic acid (d). Site-directed mutagenesis studies have highlighted the importance of the aspartate and histidine moieties in activating various groups.38, 39 This system has inspired

chemists in their design multifunctional organocatalysts.

1.3.4 Small molecule organocatalysis

The following discussion of small molecule hydrogen-bonding catalysts is

not comprehensive, but it underlines the recent work that is central to this field as

chemists try to extend the scope of catalysis used for organic transformations to

include Brønsted acids.40

One subset of multifunctional organocatalysts that X R R has been developed is that containing urea and thiourea N N H H moieties (Figure 1.6). They have been used to catalyze X= O, urea S, thiourea 41 asymmetric hydrocyanation reactions, Claisen Figure 1.6. Thiourea and urea moieties rearrangements,42, 43 Diels Alder cycloadditions,44, 45 nitro-Mannich reactions,46 and others. The mechanism by which these catalysts activate imines, like in the case of hydrocyanation reactions, has been studied by several techniques including structural modification, NMR, kinetic, and computational studies.47

These studies conclude that two hydrogen bonds form between the two acidic

15

NH protons on the urea and the lone pair of electrons on S R3 R4 the electrophile. This dual hydrogen bond allows ureas N N H H to interact with structurally diverse acceptors (Figure NR2

1.7). Because they can be easily prepared and tuned, R1 H Figure 1.7. Thiourea dual this catalyst class now can be used to activate hydrogen-bond activation of an imine nitroalkenes, aldehydes, ketones, and carboxylic acids.33

Structurally similar to urea and thiourea moieties, guanidinium and

amidinium functional groups can also participate in dual hydrogen-bonding

NH NH interactions (Figure 1.8). In biological

R NH2 H2N NH2 systems, guanidinium-containing arginine ab Figure 1.8. a. amidine functional group often is used as a dual hydrogen-bond donor. b. guanidine moiety These Brønsted acids are used in similar

reactions as the urea catalysts such as Diels-Alder,48 Strecker,49 and nitro-

Mannich reactions.50

Unlike the previous catalysts discussed, creating a Brønsted acid containing a single hydrogen-bond donor for enantioselective catalysis can be more challenging because of the lack of rigidity achieved in the substrate catalyst complex. For this reason they are less common, however several single- hydrogen-bond donors contain other functional groups allowing them to act as bifunctional catalysts despite their ability to only donate one hydrogen bond.

Specifically, proline- and binaphthol-derived phosphonic acids have led to an increase in the number of published single-hydrogen-bond donor catalysts that produce good enantioselectivity and good yields.

16

Amino acids are one of the simplest bifunctional catalysts, containing both

an acidic and basic moiety. Despite the fact that many are commercially

available as enantiopure compounds, they were ignored as catalysts until recently.51 In the 1970s the groups Hajos and Parrish at Hoffman-La-Roche and

Eder, Sauer, and Wiechert at Schering AG simultaneously discovered the cyclic amino acid L-proline (10) could be used to catalyze an aldol cyclization of triketones producing chiral bicylic enones, starting materials for the synthesis of steroid structures (Scheme 1.12).52, 53

CO H O N 2 Me O Me O H (3mol%) 10 o DMF, 23 C O O O O OH 93% ee >99% yield

Scheme 1.12. Proline catalyzed aldol cyclization. In 2000, a more general proline-catalyzed direct, asymmetric aldol

cyclization was reported by List, Lerner, and Barbas54 and today proline catalysts

have been shown to catalyze carbon–carbon, carbon–nitrogen, carbon–oxygen,

and carbon–halogen bond-forming reactions α to a ketone or aldehyde.33

The mechanism of proline-catalyzed aldol reactions was proposed by

Jung in 1976,55 and recently has been confirmed by kinetic56 and computational

methods (Scheme 1.13).57-59 Proline is bifunctional in that it forms an enamine

with the substrate giving it enhanced nucleophilicity while the carboxylic acid

group on the proline activates the carbonyl group through hydrogen bond

formation, making it more electrophilic. The highly organized transition state

allows one stereoisomer to be formed, giving the reaction high enantioselectivity.

17

Building upon the advantages of this type of readily available catalyst, several

unnatural analogs have been made and has led to the development of proline- derived catalyzed Mannich reactions.60

OH O

R3 R2 O R1 CO H R1 N 2 R2 H

H2O H2O

N 1 CO H R 2 N 2 R O OH O R3 R2 R1

O

N R3 H 1 R 2 O R O H O R3

Scheme 1.13. Proposed mechanism for proline-catalyzed aldol cyclization.

Perhaps the most recent central class of organocatalysts that has been

developed is the phosphonic acid group which includes phosphoric acid, phosphoric acid esters, and O O O P P P HO OH RO OH H N OR phosphoramidates (Figure 1.9). This OH OR 2 OR Figure 1.9. General structures for phosphoric group has advantages because acid (left), phosphoric acid ester catalysts (center) and phosphoramidates (right). phosphonic acids have an appropriate pKa value ranging from approximately

~1.5 to 3,61 a range in which they can interact with substrates through hydrogen

bonding without forming loose cation–anion pairs.62 In addition, the phosphoryl

18 oxygen atom can function as a Brønsted basic site and endow this single- hydrogen-bond donor catalyst with dual functionality.

Phosphonic acids also have great potential as enantioselective catalysts.

BINOL (1,1′-bi-2-naphthol) derivatives of phosphonic acids have been used extensively to catalyze the Mannich reaction,63 aza-ene,64 and Friedel-Craft

65 alklyations. The C2-symmetry of the BINOL catalyst is essential because the same catalyst molecule is regenerated when the acidic proton migrates to the phosphoryl oxygen atom (e.g., the aza-ene reaction, see Scheme 1.14).62

The fundamental mechanism proposed for all phosphonic acid catalyzed reactions is similar, but this discussion will be focused on the aza-ene reaction

O O H O O R N N R O O O O R NH N R P P H Ar Ph O O O O 13 14 Ar Ph H H 11 12 12

O O O O O P O P H O R H O R O O N N H Ar H H O Ar O N N R R Ph Ph 15 Scheme 1.14. Proposed mechanism for phosphonic acid catalyzed aza-ene reaction.

19

(Scheme 1.14). The key aspect of this catalyst is the dual functionality of the

phosphonic acid. It activates the enecarbamate 13 by hydrogen-bond formation

between its Brønsted acidic proton (shown in red) and the Brønsted-basic site on

the enecarbamate (shown in blue). The catalyst also contains a Brønsted-basic

site (in blue) which is a hydrogen-bond acceptor interacting with the Brønsted-

acidic site on the enamide 14 (in red) to form intermediate 15 (Scheme 1.14).62

After the ene-type reaction has occurred, the acidic proton from the phosphonic acid is now incorporated into the product 11, and the proton from the enamine has now helped to regenerate the catalyst 12.

It is crucial to the proposed mechanism that the phosphonic acid exists in a monomeric form so the transition state involves only one molecule of phosphonic acid. Previous work with BINOL-derived acids has shown that it is likely that these compounds exist in monomeric form;66 however, studies of non-

chiral phosphonic acid species suggests that these compounds aggregate at

concentrations ranging from 0.0270M to 0.0532M.67

1.3.5 Imines and Hydrazones

Imines, compounds containing a carbon–nitrogen double bond, are used

extensively in organic synthesis. Because of the electronegativity difference

between the oxygen and nitrogen atoms, imines are usually less electrophilic

than carbonyl groups. However, they form stronger hydrogen bonds and are

more Lewis-basic groups because the electrons are held farther away from the

20 nitrogen center and can more easily participate in metal chelation or hydrogen- bonding interactions.

Imines are convenient synthons because they can be easily transformed into other functional groups (Scheme 1.15). They can tautomerize into enamines which can be used as nucleophiles. They can easily be reduced to amines, or hydrolyzed to aldehydes, as well as undergo attack by cyanide to form an aminonitrile, which can be hydrolyzed to make an amino acid.

R2 NH R2 1 NH R H H R1 H enamine R2 NaBH4 amine N R1 H H O 2 R2 R2 O NH H O NH NaCN CN 2 CO H R1 R1 R1 2 H H HCl H aldehyde amino acid

Scheme 1.15. Organic transformations from imines to other functional groups.

Hydrazones (Figure 1.10) are less electrophilic than imines because of the additional nitrogen atom in the hydrazone, which can delocalize the electrons in the imine double bond. This decreases the electron density R2 HN on the hydrazone carbon atom, and makes it less susceptible N H R1 to attack. Hydrazones can be easily made by the reaction of Figure 1.10. General hydrazone structure. an aldehyde and hydrazine, and they undergo decomposition to a hydrocarbon and nitrogen gas through strong base and heat (Wolff–Kishner reduction).

21

Recently Kobayashi and co-workers developed a catalytic asymmetric intramolecular [3+2] cycloaddition of hydrazones (16) containing olefins catalyzed

68 by a chiral zirconium Lewis acid (Scheme 1.16) or Sc(OTf)3. The chiral

pyrazolidine derivatives produced are biologically interesting and cleavage of the

N-N bond by SmI2 afforded chiral diamine derivatives.

H N Ar H H N Zr/BINOL catalyst N Ar O N H O H 16 >99% trans

Scheme 1.16. Intramolecular [3+2] cycloaddition of hydrazones They also later developed an intermolecular [3+2] cycloaddition of glyoxylate derived hydrazones and olefins promoted by a stoichiometric amount of BF3·OEt2. In the reaction of α-methyl styrene and hydrazone 17, they found

not only their desired cycloaddition product, but also an ene-type product

(Scheme 1.17).69

Bz BzHN Me BzHN N N NH 1.2 equiv BF3 OEt2 HN Ph OEt EtO Ph DCM, 0oC, 18 h Ph EtO C O 2 O 17 58% yield 12% yield

Scheme 1.17. Intermolecular cyclization/ene reaction between an olefin and a hydrazone.

1.3.6 Types of ene reactions

Two main types of ene reactions have emerged: (1) all-carbon ene-

reactions, wherein both the ene and enophile are alkenes, alkynes, or allenes and (2) hetero-ene-reactions, wherein either the ene or enophile contain at least one heteroatom.24 The second category can be broken down further into: (a)

22

type I: reactions with all-carbon enes and hetero-enophiles, (b) type II: reactions

with hetero-ene components with all-carbon enophiles, and (c) type III: reactions

with both hetero-ene and enophile components. For the purposes of this

dissertation, the primary focus will be on type II reactions wherein all-carbon

enes react with hetero-enophiles.

1.3.6.1 Aza-ene and thio-ene reactions

The thermal aza-ene was first introduced by Hoffmann in the late 1960s,4 however more recently Lewis acid70 and Brønsted acid catalysts64, 71 have been

developed to promote the aza-ene reaction (Scheme 1.18). The Brønsted acid

catalyzed aza-ene reaction utilizes less traditional substrates, an imine and

enamine, but it has led to the development of a tandem aza-ene type

reaction/cyclization cascade for one-pot synthesis of enantioenriched piperdines

(not shown).71

Cu(OTf) Troc a Troc 2 R N or Yb(OTf) R N 2 NH H N Troc H Troc

O O O O

2 3 18 b N R HN R R2 NH N R3

1 4 1 4 R H R Ar R R

O O 18: P O OH

Ar

Scheme 1.18. a. Lewis-acid catalyzed aza-ene reaction. b. Phopshonic acid catalyzed aza-ene reaction.

23

The thio-ene reaction was first reported in 1965 by Middleton.72 It proceeds with greater ease than the carbonyl-ene reaction because of the weak carbon–sulfur π-bond.73 Interestingly, instead of producing the expected thiol product (Scheme 1.19, path b), the reaction yields the sulfide product (Scheme

1.19, path a).73 Hoffmann argued that this is the result of a relatively weak

sulfur–hydrogen bond, giving sulfides a slightly lower energy compared to thiols.4,

73

SH S a S b Scheme 1.19 H R1 1 2 R1 R2 R R R2

Recently, the related thiol-ene has emerged as an important reaction in

synthetic chemistry. The thiol-ene occurs between a thiol, as the ene, and a

variety of enophiles. Dondoni and co-workers have used this reaction to

generate 1,6-linked S-disaccharides through photoinduced coupling of anomeric

sugar thiols with sugar alkenes.74 This “photoclick chemistry” shows the potential of the thiol-ene as an efficient, operationally simple reaction in glycochemistry.

1.3.6.2 The carbonyl-ene reaction

The carbonyl-ene reaction is perhaps the most widely investigated type of

ene reaction. The substrates, an all-carbon ene and a carbonyl-containing

enophile, are used to generate homoallylic alcohols. The glyoxylate-ene

(Scheme 1.20) is a special subset of the carbonyl-ene reaction that provides an

O OH OEt OEt Scheme 1.20 or Lewis Acid O O

24

atom-economical route to synthetically useful homoallylic alcohols. Many types

of catalysts, both Lewis acids and Brønsted acids, have been employed in this

reaction. The focus of this discussion will be on recent work done with titanium

Lewis acids, copper Lewis acids, and organocatalysts.

Mikami and co-workers reported the first asymmetric glyoxylate-ene

reaction using a chiral titanium–BINOL complex prepared in situ.75, 76 The reaction produced moderate to excellent yields (69-98%) and excellent %ee values (up to 98%) for methyl glyoxylate and a variety of 1,1-disubstituted alkenes (Scheme 1.21). Their well developed titanium–BINOL system has been used by Roche on a multi 100-kg scale ene reaction between a glyoxylate derivative and methylene cyclohexane in a pilot process.77

O X Ti O X OH O OEt OEt 19 O O X= Br, Cl, ClO4, OTf, OPri X= Br 98%, 94%ee Cl 97%, 97%ee Scheme 1.21. Titanium-BINOL catalyzed glyoxylate-ene reaction.

It was found that when titanium catalyst 19 was prepared from only

i partially resolved (R)-BINOL and Ti(O Pr)2X2, a positive nonlinear effect was

observed.78, 79 The complex made from (R)-BINOL with only 33%ee gave the

product with a 92% yield and a 92%ee. Mikami and co-workers attributed this

effect to the isostructural dinuclear chelate complex 20 (Figure 1.11). They

proposed a major difference in catalytic activity between the homochiral dimer

25

((R,R) or (S,S)) and the heterochiral meso dimer (R,S). The less reactive meso

dimer is formed preferentially, allowing the excess (R)-BINOL to form the

enantiomerically pure (R,R) dimer after the (S)-BINOL is consumed. This

produces an ene product that results from interaction with the (R,R)-homochiral dimer only.

X X O Ti O O Ti O X X

Figure 1.11. Titanium-BINOL dinuclear complex. The titanium catalysts Mikami produced indicate a nonchelating interaction,80 however the copper catalysts developed by Evans and co-workers indicate a bidentate chelate of α-dicarbonyl compounds. These compounds are

more Lewis acidic than Mikami’s titanium complexes and therefore more

reactive.81 They were able to effectively catalyze the reaction between some 1,2-

disubstituted olefins and ethyl glyoxylate (Scheme 1.22a) with good

enantioselectivities and yields.82 Amazingly these catalysts were also able to

promote a reaction between a less nucleophilic monosubstituted alkene, which

reacted with ethyl glyoxylate to give the ene product with 98%ee and high E

olefin selectivity (Scheme 1.22b).

26

OH O H OEt 21 CO2Et

O 70% (E/Z= 95:5), 94%ee O OH OEt 22

CO2Et O 96% (E/Z= 91:9), E 98%ee, Z>90%ee 2 O O 2X N N Cu R R

21 R=Ph, X=OTf t 22 R=Bu , X=SbF6 Scheme 1.22. a. Copper bis-oxazoline catalyzed glyoxylate-ene reaction with 1,2-disubstituted olefin. b. Copper bis-oxazoline catalyzed glyoxylate-ene reactino with a monosubstituted olefin.

The glyoxylate-ene reaction has not only been catalyzed by Lewis acids,

but as recently as 2007, Brønsted acids have also been employed for this

reaction. A Brønsted acid containing a thiourea moiety was utilized to promote the carbonyl-ene reaction; however the ene products were formed with modest enantioselectivity and low turnover frequencies.83

Another type of Brønsted acid, N-triflylphosphoramides, were used by

Reuping and co-workers in a highly enantioselective carbonyl-ene reaction

(Scheme 1.23).66 They obtained a crystal structure of the chiral catalyst showing

a dimer, however DOSY (diffusion ordered spectroscopy) NMR experiments

showed no dimeric activity demonstrating that the actual catalyst used to activate

the carbonyl group is the monomeric N-triflylphosphoramide. This result is

noteworthy as it suggests that phosphoramidates exist as monomers, where as

27

R

O O P O NH F C OH SO CF 3 O R 2 3 R CO2Et R F C CO Et R= p-MeOC H 3 2 6 4 55-96%, 92-97%ee R= alkyl, aryl

Scheme 1.23. Enantioselective N-triflylphosphoramide catalyzed carbonyl-ene reaction. the literature suggests phosphonic acids dimerize.67, 84 Additionally, this reaction

is the first example of an enantioselective Brønsted acid catalyzed carbonyl-ene

reaction which proceeds under mild reaction conditions with an air-stable catalyst to product α-hydroxyesters.

The carbonyl-ene reaction has been used extensively in the synthesis of

pharmaceutically significant products and also compounds found in the food

industry. This atom-economical reaction reduces the number of steps required to

make several significant products. One such example is the Takagaso process

for the synthesis of menthol (Scheme 1.24).85 Menthol is responsible for the

H2 O ZnBr2 OH OH

23 24 25 26

H Me O ZnBr2 H

27 Scheme 1.24. Takagaso synthesis of menthol and chair transition state of carbonyl-ene reaction.

28

peppermint taste in many food products. The synthesis starts with β-pinene (23),

which is transformed into R-citronellal (24). Using the Lewis acid ZnBr2, a carbonyl-ene reaction affords L-isopulegol (25) with great selectivity. This is a result of the chair-like conformation 27 which is adopted in the transition state.

Menthol (26) is then formed by the hydrogenation of the L-isopulegol. Menthol cannot be easily extracted from mint leaves, however, β-pinene is readily available in large quantities from pine trees. The development of the carbonyl- ene reaction has made the manufacturing of menthol much quicker and facile.

1.3.6.3 The imino-ene reaction

The imino-ene reaction provides a powerful method to access homoallylic and homopropargylic amines. Although it is less well represented than the carbonyl-ene reaction, recent attention has led to a variety of catalytic and enantioselective reactions generating ene products having biological significance.

Some of the first imino-ene reactions were those occurring between an allene and an imine. An early report describes the intermolecular reaction between a methyl allene and sulfonylimino acetate in a thermal imino-ene reaction to give the corresponding homopropargylic amine. (Scheme 1.25a).86

This is the only example to date of an imino-ene occurring between an all-carbon allene and an imine. Allenylsilanes87 have been shown to be more efficient

components in imino-ene reactions. Weinreb and co-workers utilized an

intramolecular silylallenyl imino-ene reaction as a key step in the synthesis of a

29

marine natural product, papuamine (Scheme 1.25b).88, 89 They found that only

one conformation is properly disposed stereoelectronically for the concerted

pericylic ene reaction, leading to cis-amino silyl acetylenes in five- and six-

membered rings.3

C H Ts 6 6 N 130oC CO2Et a 33% NHTs CO2Et

H SiMe Ph O 2 H NHBn 1. BnNH , RT b 2 H 2. 300oC or SnCl 4 H 3. TBAF, THF

70%

Scheme 1.25. a. Thermal intermolecular allenyl imino-ene reaction b. Intramolecular imino-ene reaction Imino-ene reactions with alkene “ene” components have also been

reported. Almost simultaneously, the groups of Lectka34, 90 and Jørgensen91 reported enantioselective, catalytic ene reactions used to synthesize α-imino esters.34 Both groups developed chiral copper–BINAP systems as efficient Lewis acids for a variety of ene substrates (Scheme 1.26). To date, these are still the only enantioselective catalytic imino-ene reactions.

Ts Ts N HN OEt Ph Ph CO Et R 2 O R 92% yield P 99% ee

CuClO4 P R R

R= 4-MeC6H5 Scheme 1.26. Enantioselective imino-ene reaction reported by Letcka catalyzed by copper BINAP complex.

30

Although this research has provided great progress in imino-ene chemistry, the imines are limited to those derived from glyoxylate. Nakagawa and co-workers expanded the scope of the imines involved in imino-ene reactions to include those derived from benzaldehyde, through the use of a lanthanide metal based catalysts.31, 32 The catalytic activities of several lanthanoid metals were surveyed and activity was found to increase as oxophilicity increased, where ytterbium was the most successful Lewis acid

(Scheme 1.27). It was also found that an additive, TMSCl, was effective in

Ts Ts N Yb(OTf)3 (5 mol%) HN

Ph Ph TMSCl (5mol%) Ph Ph 94% Scheme 1.27. Imino-ene reaction between aldimines and 1,1-disubstituted alkenes catalyzed by a lanthanoid metal. helping the reaction proceed with higher efficiency. Without the use of TMSCl, the yields dropped to about 48%. This is most likely because the chloride anion weakens the chelation interaction between the product and the Lewis acid and allows the Lewis acid to be regenerated.

1.4.0 UNNATURAL AMINO ACIDS

Amino acids are the basic structural pieces of proteins. All species, from bacteria to humans have proteins constructed from 20 naturally occurring α- amino acids. An amino acid that is not a part of the 20 amino acid repertoire is called a nonproteinogenic α-amino acid (AAA). These include those that are naturally made, but not found in proteins, and those that are synthesized in a lab.

Their applications span the areas of both chemistry and biology and new uses

31

are regularly discovered. The following discussion of nonproteinatious AAA is

not comprehensive, but to provide examples for how these amino acids are used

in a variety of biology and chemistry fields.

Organic chemists use nonproteinatious α-amino acids as synthetic targets because they are found in natural products with biological significance. One such example is a cytotoxic pentapeptide called gymnangiamide (Figure 1.12).92

This natural product OH NH O 2 H contains three N N H2N N N H H CF COO O OMe O unnatural amino 3 HO NH Ph O acids, including α- HOOC OH Figure 1.12. Structure of gymnangiamide. guanidino-L-serine

(shown in red), which has not been isolated in any other natural product.93

Because it is structurally unique and has biological activity, the total synthesis of this molecule was reported in 2009.93

In biochemistry and molecular biology, unnatural amino acids are used as

molecular probes in order to discover protein function and structure. In 1989, the first general methodologies were developed where synthetic amino acids could be incorporated into proteins through a biosynthetic pathway.94-96 Since then

over 100 unnatural amino acids have been incorporated into proteins.97 They

can be used to identify protein-protein interactions, determine structural and

functional domains, and investigate conformational changes.97

Finally, some nonproteinatious AAA have medicinal and therapeutic value which makes their synthesis important for the pharmaceutical industry. L-dopa, a

32

precursor for neurotransmitters dopamine, norepinephrine, and epinephrine, is

used in the treatment of Parkinson’s disease. In addition, peptide chains

containing unnatural amino acids have been generated to mimic naturally

occurring peptides that can induce apoptosis. As a result, in 2004, Walensky

and co-workers developed a peptide mimic that reduced the size of a human

leukemia xenograph.98 These recent developments illustrate the utility of

unnatural amino acids as pharmaceutical and therapeutic agents.

Nonproteinatious AAAs are used as building blocks and synthetic targets

in organic chemistry, as tools for probing protein function in biochemistry, and small molecule drug targets in medicinal chemistry. Methods of making these molecules are varied, but creating complementary methods are always advantageous to the growth of this field.

1.5.0 REFERENCES

1. Jin, J.; Smith, D. T.; Weinreb, S. M., Novel Intramolecular Ene Reactions of Allenylsilanes. Journal of Organic Chemistry 1995, 60, (17), 5366-5367. 2. Jin, J.; Weinreb, S. M., Application of a stereospecific intramolecular allenylsilane imino ene reaction to enantioselective total synthesis of the 5,11- methanomorphanthridine class of Amaryllidaceae alkaloids. Journal of the American Chemical Society 1997, 119, (25), 5773-5784. 3. Weinreb, S. M.; Smith, D. T.; Jin, J., Thermal and Lewis acid catalyzed intramolecular ene reactions of allenylsilanes. Synthesis-Stuttgart 1998, 509-521. 4. Hoffmann, H. M. R., The Ene Reaction. Angewandte Chemie-International Edition 1969, 8, (8), 556-569. 5. Burton, B. S.; Pechman, H. V., Chem. Ber. 1887, 20, 145. 6. Jones, E. R. H.; Mansfield, G. H.; Whiting, M. C. , Acetylenic compounds. XLVII. The prototropic rearrangements of some acetylenic dicarboxylic acids. Journal of the Chemical Society 1954, 3208-3212. 7. Rona, P.; Crabbe, P., A novel allene synthesis. Journal of the American Chemi cal Society 1968, 90, (17), 4733-4734. 8. Rona, P.; Crabbe, P., Novel synthesis of substituted allenes. Journal of the American Chemical Society 1969, 91, (12), 3289-3292.

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58. Bahmanyar, S.; Houk, K. N., Transition States of Amine-Catalyzed Aldol Reactions Involving Enamine Intermediates: Theoretical Studies of Mechanism, Reactivity, and Stereoselectivity. Journal of the American Chemical Society 2001, 123, (45), 11273-11283. 59. Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B., Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions. Journal of the American Chemical Society 2003, 125, (9), 2475-2479. 60. Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., Amine-catalyzed direct asymmetric Mannich-type reactions. Tetrahedron Letters 2001, 42, (2), 199-201. 61. Quin, L. D., A Guide to Organophosphorus Chemistry. John Wiley and Sons: New York, 2000; p ch. 5, p.133. 62. Terada, M., Binaphthol-derived phosphoric acid as a versatile catalyst for enantioselective carbon-carbon bond forming reactions. Chemical Communications (Cambridge) 2008, (35), 4097-4112. 63. Uraguchi, D.; Terada, M., Chiral Bronsted Acid-Catalyzed Direct Mannich Reactions Via Electrophilic Activation. Journal of the American Chemical Society 2004, 126, (17), 5356-5367. 64. Terada, M.; Machioka, K.; Sorimachi, K., High substrate/catalyst organocatalysis by a chiral bronsted acid for an enantioselective aza-ene-type reaction. Angewandte Chemie-International Edition 2006, 45, (14), 2254-2257. 65. Uraguchi, D.; Sorimachi, K.; Terada, M., Organocatalytic Asymmetric Aza- Friedel Crafts Alkylation of Furan. Journal of the American Chemical Society 2004, 126, (38), 11804-11805. 66. Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs, R. M., Highly Enantioselective Organocatalyic Carbonyl-Ene Reaction with Strongly Acidic, Chiral Bronsted Acids as Efficient Catalysts. Angewandte Chemie-International Edition 2008, 47, 6798-6801. 67. Chu, F.; Flatt, L. S.; Anslyn, E. V., Complexation of Phosphoric Acid Diesters with Polyaza-Clefts in Chloroform: Effects of Phosphodiester Dimerization, Changing Cavity Size, and Preorganizing Amine Recognition Units. Journal of the American Chemical Society 1994, 116, (10), 4194-4204. 68. Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J., Asymmetric Intramolecular [3+2] Cycloaddition Reactions of Acylhydrazones/Olefins Using a Chiral Zirconium Catalyst. Journal of the American Chemical Society 2002, 124, (46), 13678-13679. 69. Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.; Yamashita, Y., Lewis acid-mediated [3+2] cycloaddition between hydrazones and olefins. Tetrahedron Letters 2003, 44, (16), 3351-3354. 70. Pompiliu, S. A., Zhuang, W., Hazell, R. G., Jorgensen, K. A., Catalytic and enantioselective aza-ene and hetero-Diels-Alder reactions of alkenes and dienes with azodicarboxylates. Organic and Biomolecular Chemistry 2005, 3, 2344- 2349. 71. Terada, M., Machioka, K., Sorimachi, K., Chiral Bronsted Acid-Catalyzed Tandem Aza-Ene Type Reaction/Cyclization Cascade for a One-Pot Entry to

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Enantioenriched Piperdines. Journal of the American Chemical Society 2007, 129, 10336-10337. 72. Middleton, W. J., Fluorothiocarbonyl compounds. IV. Hexafluorothioacetone-olefin adducts. Journal of Organic Chemistry 1965, 30, 1395-1398. 73. Bachrach, S. M., Jiang, S., Ab Initio Study of the Thio-Ene Reaction. 1. The Enophile Substituent Effect. Journal of Organic Chemistry 1997, 62, 8319- 8324. 74. Fiore, M.; Marra, A.; Dondoni, A., Photoinduced Thiol-Ene Coupling as a Click Ligation Tool for Thiodisaccharide Synthesis. Journal of Organic Chemistry 2009, 74, 4422-4425. 75. Mikami, K.; Terada, M.; Nakai, T., Catalytic asymmetric glyoxylate-ene reaction: a practical access to alpha-hydroxy esters in high enantiomeric purities. Journal of the American Chemical Society 1990, 112, (10), 3949-3954. 76. Mikami, K.; Terada, M.; Nakai, T., Asymmetric glyoxylate-ene reaction catalyzed by chiral titanium complexes: a practical access to alpha-hydroxy esters in high enantiomeric purities. Journal of the American Chemical Society 1989, 111, (5), 1940-1941. 77. Blaser, H.-U.; Pugin, B.; Spindler, F., Progress in enantioselective catalysis assessed from an industrial point of view. Journal of Molecular Catalysis 2005, 231, 1-20. 78. Terada, M.; Mikami, K.; Nakai, T., Remarkable positive nonlinear effect in the enantioselective glyoxylate-ene reaction catalyzed by a chiral titanium complex. Journal of the Chemical Society, Chemical Communications 1990, 22, 1623-1624. 79. Mikami, K.; Terada, M., Chiral titanium complex-catalyzed carbonyl-ene reaction with glyoxylate: remarkable positive nonlinear effect. Tetrahedron 1992, 48, (27), 5671-5680. 80. Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N., A transition-state model for the Mikami enantioselective ene reaction. Tetrahedron Letters 1997, 38, (37), 6513-6516. 81. Clarke, M. L.; France, M. B., The carbonyl-ene reaction. Tetrahedron 2008, 64, 9003-9031. 82. Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W., C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Enantioselective Catalysis of the Glyoxylate-Ene Reaction. Journal of the American Chemical Society 1998, 120, (23), 5824-5825. 83. Clarke, M. L.; Jones, C. E. S.; France, M. B., The first organocatalytic carbonyl-ene reaction: isomerisation-free C-C formations catalysed by H-bonding thio-ureas. Beilstein Journal of Organic Chemistry 2007, 3, (art 24). 84. DeFord, J.; Chu, F.; Anslyn, E. V., Dimerization constants for phosphoric acid diesters. Tetrahedron Letters 1996, 37, (12), 1925-1928. 85. Nakatani, Y.; Kawashima, K., A highly stereoselective preparation of l- isopulegol. Synthesis 1978, 2, 147-148. 86. Baumann, H.; Duthaler, R. O., Synthesis of Ethyl (2rs,3sr)-1-Tosyl-3- Vinylazetidine-2-Carboxylate and Ethyl (2rs,E)-3-Ethylidene-1-Tosylazetidine-2-

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39

CHAPTER TWO

REACTION DISCOVERY OF ALLENES AND IMINES

2.1.0 INTRODUCTION

New reaction discovery is at the foundation of organic chemistry.

Methodologies are developed through the testing of viable substrates, catalysts,

and reaction conditions to generate desired products, and in some instances new

unexpected products. The additional investigations into how these new and

unexpected products are formed have led to many of the new reactions we know

today. Our work has focused on the discovery of reactions between allenes and imines.

Silyated and metallated allenes are reported to react with imines to yield

formal ene products (Scheme 2.1).1, 2 This report provided the foundation for our goal of developing a Lewis acid X Lewis R1 NR1 acid NH catalyzed ene reaction or heat 2 R2 R between allenes and imines to X= silyl group, Sn Scheme 2.1. Allenyl-imino ene reaction with silylallenes generate homopropargylic and metallated allenes. amines. The development of such a reaction was expected to make the reaction more general, extending it to more easily accessible starting materials and developing more mild reaction conditions. The homopropargylic amine products were particularly interesting as they have synthetic utility as precursors for natural products with anti-tumor and anti-fungal properties,3 and they make viable drug candidates.4-6

40

As we began to screen substrates for the imino-ene reaction, we included

non-silylated allenes as their ene chemistry with imine partners was mostly unexplored. They are easily synthesized, making them excellent substrates for the discovery of new reactions. During initial screenings, we found that an

unexpected alkylation reaction had occurred between a ketoallene and a

glyoxylate derived imine, under Lewis acid conditions, to yield unnatural amino

acid derivatives. Described herein is the initial screening of the reaction

conditions for the intended ene reaction, however the primary focus of this

chapter is on the development of an unexpected aza-Baylis–Hillman-type

reaction between ketoallenes and imine-containing electrophiles. This chemistry

shows promise for a new single step, atom economical reaction for the

generation of unnatural amino acids containing densely functionalized alkenes

and allene moieties.

2.2.0 SCREENING OF ALLENES AND IMINES

Initially, several allenes and imines (Figure 2.1) were prepared for

screening their reactivity in the presence of Lewis acids (see scheme 2.1) such

as SnCl4, TiCl4, AlCl3, Yb(OTf)3, HfBr4, and Cu(OTf)2 (Appendix I). The

O SiMe Ph Ph 2 Ts Ts Ph N N N OEt Ph Ph O 28 29 30 31 32 33

Figure 2.1. Allenes and imines prepared for screening for an allenyl imino- ene reaction.

41 electronic features of each substrate were tuned to provide a range of substrate reactivities to explore the addition of the allene to the imine. Electron-donating groups, such as silyl groups, were appended to the allene7 (28) on the C-1 carbon atom (see chapter 1, Figure 1.2) to increase the nucleophilicity of the C-3 carbon atom. Electron-withdrawing groups were affixed to the imine either at the nitrogen atom (32 and 33) or the carbon atom (33) in the carbon–nitrogen double bond to produce a more electrophilic center imine. Gas chromatography/mass spectrometry (GC/MS) and thin layer chromatography (TLC) methods were used to monitor changes in the reactions over time. We found several instances where a reaction occurred to produce a complex mixture of products (see

Appendix I, table 1 and scheme 2.2 below), however these reactions need to be revisited to characterize the products more carefully.

SiMe2Ph Ts N AlCl3 GC/MS showed mass matching the addition of allene and imine Ph

28 32

Scheme 2.2. Example of a test reaction with AlCl3 where GC/MS showed an appropriate mass for some addition of the two starting materials.

2.3.0 OPTIMIZATION OF AZA-BAYLIS–HILLMAN-TYPE REACTION

During the initial screening with acetylallene (30) and sulfonylimino acetate (33), alkylation at either the γ- or the α-position of the allene was observed to yield both the halogenated α, β-unsaturated ketone 34 and the 1,1- disubstituted allene 35, respectively (Scheme 2.3). The anticipated ene products

(see scheme 2.1 above) were not observed in the reaction mixture, however the

42

α, β-unsaturated ketone 34 and the 1,1-disubstituted allene 35 were of interest

because of the unique amino acid-containing components. The mechanism of

the reaction was also of interest and so we chose to pursue this unprecedented reaction chemistry.

O O Ts O MgBr2 OEt2 O HN N 36 OEt EtO Ts Br Scheme 2.3 O

TsHN CO2Et 30 33 34 35

Formally the α-product (35) is the result of an aza-Baylis-Hillman reaction

(see chapter 1, scheme 1.4), a reaction which is documented to proceed using

traditional Lewis bases.8, 9 The γ-product (34), while not formally an aza-Baylis–

Hillman product, may arise from an intermediate generated in the first step of the

Baylis–Hillman pathway. The product 34 also has an interesting feature: it

contains a vinyl bromide which can be easily manipulated through metal coupling reactions to yield advanced compounds for synthesis. Because both products have interesting chemistry, our goal was to first optimize the yield of each product by varying several reaction parameters, including the number of equivalents of each substrate used and the concentration of the reaction mixture

(Table I).

These results show that the reaction proceeds best when the Lewis acid is

used catalytically relative to using a stoichiometric amount of catalyst (compare

entries 2 and 3 to entry 1 in Table I): half of an equivalent of MgBr2•OEt2 leads to a moderate yield of products. Running the reaction in a more concentrated

43 reaction solution (1.0 M) generates both products in moderate yields, but with a greater difference in the ratio of the α-product to the γ-product (Table I, entry 4).

When the concentration was decreased to 0.25 M, lower product yields were obtained and the ratio of products approached 1:1 (Table I, entry 5). Lastly, the number of equivalents of allene and imine were varied. A significant increase in yield of both the α- and γ-products occurred when the equivalents of the imine were doubled (Table I, entry 6). However an excess of allene did not seem to enhance the yield of the reaction (Table I, entry 7).

Table I. Optimization of concentration and substrate ratioa

O O Ts O MgBr2 OEt2 O HN N 36 OEt EtO Ts Br O

TsHN CO2Et 30 33 34 35 Entry Ratio [30] %34b,c,d %35b Mol ratioe (30:33:36) (M) (34:35) 1 1:1:1 0.5 7 31 1: 4.6

2 1:1:0.5 0.5 14 44 1: 3.2

3 1:1:0.25 0.5 10 21 1:2

4 1:1:0.5 1 8 49 1: 6.2

5 1:1:0.5 0.25 7 23 1:3.1

6 1:2:0.5 0.5 18 73 1: 4.2

7 2:1:0.5 1 9 30 1:3.1

8 1:2:0.5 1 10 49 1:4.8

a b All reactions were run at 0°C for 30 minutes in a (11:1) C H2Cl2:THF so lvent mixture. Yields based on allene 30. c Product 34 was found to contain t race amount s of product 48 (see section 2.3.3). d E stereochemistry determined by NOESY 1H NMR data. e Ratios determined by 1H NMR analysis of the crude reaction mixture.

44

Because a more concen trated re action and an ex cess of imine seemed to give the best conditions, we tried increasing the concentration and doubling the number of imine equivalents simultaneously, but found that this did not give the desired increase in yield (Table I, entry 8).

Using the optimized reaction conditions identified above, in which 2 equivalents of imine, half an equivalent of Lewis acid, and a concentration of 0.5

M were used, reaction parameters, such as reaction time and temperature were varied to additionally optimize the reaction conditions (Table II).

Table II. Optimization of temperature and timea

O Ts O O HN O MgBr2 OEt2 OEt N 36 EtO Ts Br O

TsHN CO2Et 30 33 34 35 Entry T(°C) t (min) %34b,c,d %35b Mol ratioe (34:35) 1 -78 30 13 25 1:1.9

2 -78 60 11 33 1: 3

3 -78 240 10 27 1:2.8

4 -45 30 16 37 1:2.4

5 -45 60 13 33 1:2.5

6 0 60 15 47 1: 3.2

7 25 30 18 36 1:2

8 45 30 11 43 1:3.9

a All reactions were run in an 11:1 CH2Cl2:THF solution at 0.5M concentration based on 30 at a ratio of 1:1:0.5 (30:33:36). b Yields base d on allene 30. c Product 34 was found to conta in trace amounts of product 48 (see sec tion 2.3.3). d E stereochemistry determine d by NOESY 1H NMR data. e Ratios determined by 1H NMR methods.

45

The reactio n proceed ed at low er temperatures (-78°C); however the yields

were still low relative to the reaction at 0°C even after extending the reaction time

to four hours (Table II, entries 1-3). Warming the reaction mixture to -45°C did

not seem to greatly affect the product yields of the reaction, even with stirring the

reaction mixture for an additional 30 minutes beyond the standard time of 30

minutes (Table II, entries 4-5). Additionally, allowing the reaction to proceed for a

longer time at 0°C did not increase the product yields significantly (Table II, entry

6). Finally, heating the reaction to room temperature resulted in a decrease in

both the yield and product ratio (Table II, entry 7). Heating the reaction mixture

beyond room temperature did not significantly affect the yield or ratio of the

products relative to those reactions conducted at lower temperatures (Table II, entry 8).

2.3.1 Mechanistic Studies

Two plausible mechanisms were explored when considering the alkylation

chemistry observed. The first proposed mechanism involves a stepwise reaction

in which the vinyl cation 37, generated by the addition of the allene (at the C-3

carbon atom) into the imine, is trapped by the counter ion (e. g. Br- in the case of

MgBr2•OEt2) to the Lewis acid (Scheme 2.4). This mechanism is rooted in the

chemistry of silyl allenes undergoing a stepwise ene reaction.7 To probe the

probability of this mechanism, several experiments were conducted to determine

the role of both the Lewis acid metal and the Lewis acid anion. The results are

tabulated in Table III.

46

O O O Ts Mg N O H X OEt OEt X TsHN CO2Et N O 34 Ts Mg X= Br 38X= Cl 30 33 37 39 X= I

Scheme 2.4. Proposed step-wise mechanism in which a vinyl cation is generated and trapped by a halide. The formation of mixed α, β-unsaturated ketone products, bromide 34 and iodide 39, in the presence of MgBr2•OEt2 and TBAI, can potentially be explained

by the mechanism above (Table III, entry 1). According to the proposed mechanism, any nucleophilic halide could trap the vinyl cation, therefore if more than one nucleophilic halide is added to the reaction, a mixture of products would be expected. In addition, the need for a nucleophilic halide was confirmed because there was no mixture of α, β-unsaturated ketone products (34 and 39) when an electrophilic iodine source was used (Table III, entry 2). Control reactions with a nucleophilic halide source but without a Lewis acid did not promote a reaction (Table III, entry 3) and other magnesium halides could be used to form the vinyl halide product from the respective Lewis acids (Table III, entries 4 and 5). However, when using a Lewis acid containing magnesium and a non-halide counter anion (Mg(OTf)2) and an external halide source (TBAB), we

did not discover either α- or γ-product (Table III, entry 6). This result implies that

not only is this reaction specific to nucleophilic halides that serve as anions to a

metal center, but the metal used to deliver the halide is also instrumental to the

formation of products. Magnesium performs the best as demonstrated by

47

experiments in which other metals having halide counter ions, such as HfCl4,

CuBr2, and ZnBr2 were not able to promote the reaction.

Table III. The effects of additives to probe mechanisma

O O O Ts Mg N O H X OEt OEt X TsHN CO2Et N O 34 Ts Mg X= Br 38X= Cl 30 33 37 39 X= I

Entry Lewis acid Additive 34(%)b 35(%) Mol ratio (34:35)

c 1 MgBr2•OEt2 TBAI 7 (34,39) 42 1:6

2 MgBr2•OEt2 I2 8 21 ---

3 --- TBAI ------

4 MgCl2 --- 2.2 6.8 1:3

5 MgI2 --- trace 34

d 6 Mg(OTf)2 TBAB ------

a All yields are low relative to optimal conditions identified in Table I. All rea ctions were run in CH2Cl2/THF (11:1) at a concentration of 0.5 M with molecu lar sieves at 0˚C for 30 minutes. bHalide substituted on α,β- unsaturated ketone corresponds to counter ion on Lewis acid. c Ratio of halide products is (3: 1) d respectively. Reaction with MgBr2•OEt2 and TBAB gave product 34.

Although we were able to identify the roles of the Lewis acid, it was clear

that the proposed step-wise mechanism did not fully account for the formation of

both the α- and γ-products. An additional mechanistic possibility stems from a

similar reaction between a ketoallene and an imine wherein a Lewis base such

8 as PPh3 or DABCO were reported to promote an aza-Baylis–Hillman reaction. It is important to note that while we are using a Lewis acid to promote the reaction

48

by activating the allene, the counter ion may be acting as a Lewis base. Our

alternative proposed mechanism proceeds through nucleophilic attack of the

bromide ion onto the central carbon atom of the allene resulting in enolate 40, a

common intermediate to both the α- and γ-reaction pathways (Scheme 2.5).

Subsequent addition to the imine occurs at the α- or γ-position of the allene.

Base Mg O Ts O NTs O NHTs N H OEt OEt R O R R O EtO O Mg Br Br O 40 33 41 35 R

Mg O Br O Ts R= Me N R R 30 O Br Br EtO TsHN CO2Et 40 33 34

Scheme 2.5. Plausible mechansim for formation of alkylation products. Alkylation at the α-position gives rise to 41 which undergoes elimination to provide the isolated allene 35. The base that facilitates elimination is potentially the nitrogen anion, which is generated by the addition of the allene to the imine

(33); however it is unlikely to occur through an intramolecular deprotonation because that would lead to an energetically unfavorable four-ring transition state.

The addition of the bromide by the mechanism proposed above has since been substantiated because an analogous structure to 41, where R= phenyl, has been isolated in reactions. These compounds have been converted into the allene using external bases (discussed in detail in section 2.3.3).

49

To further understand the specificity of this reaction, traditional Baylis–

Hillman bases, such as PPh3, were tested under optimized reaction conditions established for the halide-promoted aza-Baylis–Hillman reaction. The expected aza-Baylis–Hillman product was not identified. This result as well as previous results obtained when no Lewis acid was used led us to believe that activation of the carbonyl group through Lewis acid chelation was necessary for a reaction to

take place. To confirm that the Lewis acid OH OAc was activating the carbonyl group, the

allenic alcohol 42 and the protected 42 43 Figure 2.2. Additional allenes tested for allenic alcohol 43 were tested under an alkylation reaction with sulfonyliminoacetate. standard reaction conditions (see Table I, entry 2) with the imine (Figure 2.2). As expected, a reaction was not observed when either of these substrates were used, thereby demonstrating that the very likely chelation interaction between the carbonyl group of the allene and the

Lewis acid is indeed necessary.

2.3.2 Other Lewis acids used to promote an alkylation reaction

Several other metal halide salts were screened to observe their activity in the alkylation reactions. Both AlCl3 and HfBr4 generated both the α- and γ- products (Table IV). Unoptimized reaction conditions show that HfBr4 gave a low yielding 1:1 mixture of α- and γ-products (Table IV, entry 1) relative to the 1:6 ratio obtained for the reaction employing MgBr2•OEt2. Doubling the number of

50

equivalents of imine and doubling the concentration increased the product yields,

but neither product was greatly favored (1:1) (Table IV, entry 2).

Table IV. Other Lewis acids used to promote alkylation of the allenea

O Ts O O HN O Lewis acid N OEt EtO Ts X O

TsHN CO2Et 30 33 34 X=Br 35 38 X=Cl Mol Lewis Ratio T [30] t Entry %38b %35b ratioc acid (30:33:acid) (°C) (M) (min) (38:35) d 1 HfBr4 1:1:0.5 0 0.5 30 8 8 1:1

d 2 HfBr4 1:2:0.5 0 1 30 23 28 1: 1.2

3 AlCl3 1:1:0.5 0 0.5 30 9 9 1:1

4 AlCl3 1:1:0.5 -78 0.5 50 10 5 2.2:1

e 5 AlCl3 1:1:0.5 -78 0.5 120 11 -- --

e 6 AlCl3 1:1:1 -78 0.5 120 9 -- --

a b c 1 All re action s were run in a (11:1) CH2Cl2:THF solution. Yields based on allene 30. Ratios determi ned by H NMR methods. dYiel d of 34. e Product 38 was found to contain a mixture of 38 and 48, where the halide is a chloride (6%), see section 3.3.

We also found that AlCl3 promoted the reaction (Table IV, entry 3), and at

-78°C the γ-product 38 was favored relative to the α-product 35 (Table IV, entry

4). This is the opposite trend found when MgBr2•OEt2 was employed as a

catalyst. Presumably this preference is a result of AlCl3 being very reactive with

allenes, and lower temperatures slow down any degradation of products by the

Lewis acid reactivity. Extending the reaction time of the AlCl3-promoted alkylation reaction generated the γ-product exclusively, however the yield

51

suffered, even when a stoichiometric amount of Lewis acid was used (Table IV,

entries 5 and 6). This decrease in yield could be related to the high reactivity of

the AlCl3 with the products. The results here serve as an indication for future

studies into the tuning of reaction conditions to provide either the desired α- or γ-

product depending on the Lewis acid that is used. In addition, the identification

of better reaction conditions in which AlCl3 can be used to promote this alkyation

reaction will be investigated.

2.3.3 Scope of the reaction

In addition to understanding the mechanism of alkylation and the role of the Lewis acid, the scope of the reaction was tested in terms of allene substrates.

Initially, the ketoallene was substituted wherein R= phenyl, so steric effects could

be explored (Scheme 2.6). The corresponding γ-product (45) was produced as

O Ts O O HN O MgBr2 OEt2 36 R OEt R N R EtO Ts Br O Br TsHN CO Et 2 46 R=Ph (R/R, S/S diastereomer) 33 44 R=Ph 45 R=Ph 47 R=Ph (R/S, S/R diastereomer) Scheme 2.6. Alkylation of a phenyl substituted ketoallene with a tosyl imine. expected, but the aza-Baylis-Hillman product was not formed. Instead alkenes

46 and 47 were formed, which corresponds to the proposed intermediate 41

which undergoes the final elimination to generate allene 35 (see scheme 2.5).

The absence of the expected product resulting from the elimination led to the

synthesis of a variety of para-substituted phenyl groups appended to the

52

allenoate in order to investigate the electronic parameters necessary for elimination. The results are shown below (Table V).

Table V. Scope of the reaction

O O MgBr OEt Ts O 2 2 O HN 36 R R N OEt EtO Ts Br R O Br TsHN CO2Et 30 R=Me 33 44 R=Ph 34 R=Me 48, 49 R=Me (R/R, S/S), (R/S, S/R) 45 R=Ph 50 R=p-MeOC6H4 46, 47 R=Ph (R/R, S/S), (R/S, S/R) 55 R=p-MeOC H 51 R=p-BrC6H4 6 4 60, 61 R=p-MeOC6H4 (R/R, S/S), (R/S, S/R) 56 R=p-BrC H 52 R=C6H11 6 4 62, 63 R=p-BrC6H4 (R/R, S/S), (R/S, S/R) 53 R=OEt 57 R=C6H11 64, 65 R=C6H11 (R/R, S/S), (R/S, S/R) 58 R=OEt 54 R=p-NO2C6H4 66, 67 R=OEt (R/R, S/S), (R/S, S/R) 59 R=p-NO2C6H42 68, 69 R=p-NO2C6H4 (R/R, S/S), (R/S, S/R) Entry Allene Ratio T t %γa %αa,b (dr) (allene:33: 36) (°C) (hrs) 1c,d 30 1:1:0.5 0 1 14 (34) 44 (48, 49), (1:3.2)

2e 44 1:2:1 0 4 7 (45) 63 (46, 47), (1: 2.5)

3 50 1:1:0.5 0 4 5 (55) 45 (60, 61), (1: 2.75)

4 51 1:2:1 0 2 5 (56) 53 (62, 63), (1: 2.12)

5 52 1:2:1 0 4 15 (57) 19 (64, 65), (1: 2.17)

6 53 1:1:0.5 25 2.5 ------

a Product numbers are in parentheses. b Stereochemistry determined by NOESY data. c 17% of allene product d e isolated. Reaction run on a 250mg scale. H2O work-up was used.

We found that the phenyl ketoallene 44 needed a longer reaction time to

give similar results to those found with the methyl ketoallene 30 (Table V, entries

1 and 2). The original optimization reactions with the methyl ketoallene did not

produce a R/S, S,R diastereomer (see Table I), however, on a larger reaction

scale, this product (49) was isolated. When an electron-donating group (OCH3) was present on the aryl ring (50), the reaction proceeded with moderate yield to generate the terminal vinyl compound (60 and 61), and the product arising from

53

the elimination step was not observed (Table V, entry 3). This reactivity was

expected because electron-donating groups destabilize the negative charge build

up that occurs on the α-carbon during the deprotonation step that leads to the

final product. When a weakly electron-withdrawing group (Br) was added the

allene product was not observed (Table V, entry 4). A nitro group (NO2), a more

strongly electron-withdrawing group, was also employed as a substituent (54),

and products 68 and 69 were found in trace amounts but the allene product was

not observed. This suggests that electronic factors do not greatly influence the

elimination. The ketoallene bearing a cyclohexyl group (52) was used to

investigate the steric effects upon the elimination, and it was found that only the

α- and γ-alkene products were generated (Table V, entry 5). While phenyl-

substituted allenes were the most common substrate studied, it should be noted

that a commercially available ethylester ketoallene (53) was also tested and we

found it did not undergo a reaction at all (Table V, entry 6). These results

demonstrate that there is not a substantial electronic effect upon elimination,

however bulky groups hinder elimination.

A base, which is most likely generated under the reaction conditions, was

unable to produce the aza-Baylis-Hillman product in phenyl- and cyclohexyl-

substituted ketoallenes 44 and 52, respectively. We anticipated the possibility

that an external base may be able to facilitate the elimination. Triethylamine was

unable to convert the alkene α-product (47) into the allene. However potassium t-butoxide was able to generate the desired allene for both the phenyl ketoallene

and the p-methoxyphenyl ketoallene with high yields (Table VI, entries 1-4).

54

Table VI. Elimination of α-pre-eliminated products

Ts Ts O HN O HN OEt K OtBu OEt R R 0oC O O Br

47 R= C6H5 70 R= C6H5 61 R= p-MeOC6H4 71 R= p-MeOC6H4 Entry Terminal Equiv. of t (min) solvent [alkene] Yielda Alkene KOtBu (M) (%) 1 47 1 5 CH2Cl2 0.5 32 (70)

2 47 1 30 THF 0.1 89 (70)

3 61 1 30 CH2Cl2 0.5 83 (71)

4 61 1 30 THF 0.1 74 (71)

a Compound numbers are in parentheses.

The pKa of t-butanol (ca.~18) is similar to what is expected for the tosyl

amine. The conjugate base of these species has an appropriate basicity to

remove the α-proton in the elimination step to generate allene product.

Potassium t-butoxide is much smaller than the tosyl nitrogen anion and therefore

sterically it can better access the proton for elimination. In a control experiment,

potassium t-butoxide was added directly to the reaction containing the Lewis acid

after TLC confirmed the presence of the vinyl bromide product 61 (Scheme 2.7).

However, the expected allene product was not observed. This result suggests

that the chelation of the magnesium on the pre-eliminated product (61) interferes with the access to the α-proton. Since an elimination occurs under Lewis acid reaction conditions with the methyl ketoallene, we suspect that the phenyl group is involved in the chelation arrangement causing a rigid structure that precludes the elimination from occurring.

55

O O NHTs O MgBr2 OEt2 CO2Et N EtO Ts MeO MeO Br TLC confirmation

K OtBu

O NHTs

CO2Et MeO

Scheme 2.7. Reaction in which K OtBu is added directly to the reaction without the isolation of the terminal vinyl alpha product.

The exact means by which the chelation interrupts the elimination is dependent on the mechanism of elimination. A strong base, such as potassium t-butoxide will participate in two possible elimination reaction mechanisms. The first of which is an E1cB elimination. In this mechanism the deprotonation occurs first resulting in enolate formation (Scheme 2.8a). The carbonyl group then collapses and allene formation results upon the simultaneous departure of the bromide leaving group. The E2 mechanism differs in that an enolate is not formed and instead the deprotonation and departure of the leaving group occur within the same step (Scheme 2.8b). Under an E1cB mechanism, chelation could interrupt enolate formation shutting down the elimination. In an E2 scenario, chelation could occur in such a way so that the proton is not physically accessible causing there to be no elimination. Determining the exact mechanism can be difficult, and requires kinetic studies or computational studies. Although

56

we would like to study this eventually, we currently understand that chelation

affects the elimination step, and the detailed examination of the mechanism is a

goal of our future studies.

Ts Ts Ts O HN O HN O HN H OtBu OEt OEt a OEt R R R O O O Br Br

Ts Ts O HN O HN OtBu b H OEt OEt R R O O Br Scheme 2.8. a Elimination under an E1cB mechanism b Elimination under an E2 mechanism

2.4.0 FUTURE WORK

The future work on the development of reactions between allenes and

imines includes several aspects of the reaction, the groundwork for which has

been described herein. First, in the initial screening of allenes and imines for an ene reaction (section 2.2.0), it is important to revisit the reactions that produced a product having a mass, as determined by GC/MS, matching the expected ene product (homopropargylic amine). The reactions can be rerun to isolate the potential products. The synthesis of additional allenes and imines for screening

is also necessary to discover and develop an allenyl imino-ene reaction.

To additionally develop the newly discovered aza-Baylis-Hillman reaction,

several aspects of this chemistry must be explored. First, a simple and efficient

method for the synthesis of the ketoallenes needs to be developed. The current

57

procedures used to create the allenes are low yielding which causes most of the focus and time to be placed on the synthesis rather than exploring other aspects of the reaction chemistry.

Also, exploration into the mechanism of the elimination is necessary. This

undertaking will involve running kinetic studies and/or computational studies such

as kinetic isotope effect experiments. In addition, we would like to find out

whether the elimination occurs through a syn- or anti-pathway. This could be

determined by isolating each diastereomer of the terminal vinyl bromide and then

subjecting each isomer to potassium t-butoxide reaction conditions (Scheme

2.9). We know that the R/S, S/R diasteromers undergo elimination, but we have

not confirmed that this is the case for the R/R, S/S diastereomer.

O NHTs

CO2Et K OtBu MeO Br O NHTs CO Et R/S, S/R diastereomer 2 MeO K OtBu O NHTs

CO2Et MeO Br

R/R, S/S diastereomer Scheme 2.9. Established elimination of the R/S, S/R diastereomer (top), and proposed elimination of the R/R, S/S diastereomer (bottom).

58

Investigation into an enantioselective aza-Baylis Hillman reaction through

the use of chiral magnesium ligands would significantly increase the utility and

importance of this reaction type. Preliminary results show that bis-oxazolines are

a promising ligand for this reaction (Scheme 2.10) as the isolation of the allene

with approximately a 15%ee was possible.

O O O O N N Ts O O HN Ph Ph N 30mol% OEt EtO Ts MgBr2 OEt2 Br O

TsHN CO2Et 30 33 34 35 15%ee Scheme 2.10. Preliminary reaction for a bis-oxazoline ligand used for an enantioselective aza-Baylis-Hillman type reaction.

Lastly, the expansion of the scope of the reaction with respect to the

enophiles used will be explored. A preliminary reaction of methyl ketoallene 30

and ethyl glyoxylate (72) was tested under Lewis acid reaction conditions with

MgBr2•OEt2. We found that this reaction was successful; however the desired

product underwent elimination to form diene 73 (Scheme 2.11). We would like to

revisit this reaction to expand the scope of the reaction to encompass carbonyl-

containing enophiles.

O O O OH O O CO2Et OH MgBr2 OEt2 OEt CO2Et and Br CO Et O 2 Br 30 72 73 Scheme 2.11. Alkylation reaction between an allenoate and ethyl glyoxylate to produce a diene. (Compounds in brackets are the expected products.)

59

2.5.0 EXPERIMENTAL DATA

General Information and Materials.

Reagents and Materials. Dichloromethane and tetrahydrofuran were obtained through a solvent system containing activated alumina column under Argon developed by J.C. Meyer. All commercially available reagents were obtained from Aldrich, Fisher Scientific, or Alfa Aesar and used as received unless otherwise indicated. Deuterated solvents were purchased from Cambridge

Isotope Laboratory and used as received. Thin layer chromatography (TLC) was performed by using Macherey-Nagel POLYGRAM SIL G/UV254 pre-coated plates

(0.20mm), and visualized using a combination of UV, anisaldehyde, and potassium permanganate stain. Purification of compounds performed on columns packed with Bodman silica gel (32-62D, 60 Å).

NMR Data. 1H NMR spectra were obtained by using a Bruker Avance 500 MHz spectrometer and a Bruker Avance 300 MHz spectrometer operating at 500.13

MHz and 300.13 MHz, respectively. Chemical shifts are reported in parts per million relative to the residual proton resonance in the indicated deuterated solvent. Coupling constants were reported in hertz and multiplicities were indicated by using the following symbols: s (singlet), d (doublet), t (triplet), q

(quartet), bs (broad singlet), m (multiplet). Data for 13C NMR obtained by using

Bruker Avance 500 MHz spectrometer operating at 125.77 MHz. Data is reported in terms of chemical shift.

60

Synthesis of Ketoallenes. 1-(Dimethyl)phenylsilyl-1,2-butadiene (28),10 3,4-

Pentadien-2-one (30),11 1-phenylbuta-2,3-dien-1-one (44),12 1-(4- nitrophenyl)buta-2,3-dien-1-one (54),13, 14 were prepared according to the

published procedures.

General procedure A: Synthesis of ketoallene 50 and 52.12, 15

O O HNCH3(OCH3) R Cl R N OMe

A solution of N,O-dimethylhydroxylamine was prepared in situ by stirring a

suspension of N,O-dimethylhydroxylamine hydrochloride (8.36g, 85.7 mmol, 1.5

equiv.) in THF (60 mL) at room temperature for 30 minutes. Water (2.0 mL) was

added and the reaction mixture was allowed to stir for an additional 20 minutes.

The reaction mixture was cooled to ~10°C where K2CO3 (18.0g) was added. The reaction mixture was stirred vigorously while maintaining the temperature at

~10°C for 30 minutes. The solid was filtered off and rinsed with THF (10 mL).

The resulting solution of N,O-dimethylhydroxylamine was added slowly to a solution of the appropriate benzoyl chloride (57.1 mmol, 1 equiv.) in THF (60 mL) at -78°C. This was stirred for 3 hours while allowing the mixture to warm to 0°C.

Saturated sodium bicarbonate was added to the mixture and the phases were separated. The aqueous phase was extracted 3 times with diethyl ether. The combined organic layers were washed with saturated sodium bicarbonate, water, and then dried over Na2SO4. The solution was filtered and the solvent was

61

removed in vacuo to afford a crude oil. This product was purified by column

chromatography (40/60, ethyl acetate/hexanes) to afford the title compound.

o O 1)Mg , HgCl2 R Br 2) O R N OMe To a flame dried 100-mL 3-necked round bottom flask equipped with a

condenser, was added magnesium metal (814 mg, 33.5 mmol, 2 equiv.), HgCl2

(14 mg, 0.051 mmol, 0.003 equiv.) and dry diethyl ether (38 mL). Freshly distilled propargyl bromide (1.97 mL, 25.22 mmol, 1.5 equiv.) in dry diethyl ether

(19 mL) was added slowly under argon. The reaction was allowed to stir for ~1.5 hours during which time the formation of the Grignard reagent was recognized because the reaction changed to a dark gray color and warmed causing the ether to reflux. Once the reaction mixture cooled down to room temperature, it was cooled further to 0°C. The Weinreb amide was added (10.8 mmol, 1 equiv.) in diethyl ether (22 mL). The reaction mixture was then stirred for ~1.5 hours upon which time it was quenched with brine. The product was then extracted with ether, dried over Na2SO4, and the solvent was removed in vacuo to afford the

crude allene. This product was then purified by column chromatography with a

30/70 ethyl acetate/hexanes mixture.

62

O Synthesis of 1-(4-methoxyphenyl)buta-2,3-dien-1-one (50).

The title compound was prepared in a 17% overall yield over 2 MeO steps from 4-methoxylbenzaldehyde, as per General

Procedure A. The product was isolated as a dark red oil that solidifies at subzero

1 temperatures. H NMR (300.1 MHz, CDCl3) δ 7.92 (d, J=8.76 Hz, 2H, ArH), 6.93

(d, J=8.80 Hz, 2H, ArH), 6.44 (t, J=6.54 Hz, 1H, RCH=C=CH2), 5.24 (d, J=6.52

Hz, RCH=C=CH2), 3.87 (s, 3H, C6H4OCH3).

O Synthesis of 1-cyclohexylbuta-2,3-dien-1-one (52). Allene was

prepared from a modified General Procedure A from 4-

cyclohexylbenzaldehyde. At the Grignard step, the reaction was run in THF instead of diethyl ether in the same amounts indicated in the procedure above. The title compound was isolated as a faint yellow oil in an overall 12%

1 yield. H NMR (300.1 MHz, CDCl3) δ 5.74 (t, J=6.50 Hz, 1H, RCH=C=CH2), 5.22

(d, J=6.52 Hz, 2H, RCH=C=CH2), 2.85 (tt, J=11.26, 3.14 Hz, 1H, O=C–CH–

C5H10), 1.76-1.80 (m, 4H, -CH2-), 1.64-1.69 (m, 2H, -CH2-), 1.22-1.40 (m, 4H, -

CH2-).

63

Synthesis of 1-(4-bromophenyl)buta-2,3-dien-1-one (51).14, 16

CuBr, OH O SnCl2 2H2O Br Br Br

To a 2-necked 25-mL round bottom flask equipped with a condenser, was added stannous chloride dihydrate (803 mg, 3.56 mmol, 2 equiv.), copper (II) bromide

(40 mg, 0.178 mmol, 0.1 equiv.) and THF (3.5 mL). To this suspension a solution of 4-bromobenzaldehyde (329 mg, 1.78 mmol, 1 equiv.) and freshly distilled propargyl bromide (0.32 mL, 3.56 mmol, 2 equiv.) in THF (3.5 mL) was slowly added at room temperature. The reaction mixture was heated to reflux and stirred at reflux for 4 hours. The reaction mixture was then cooled to room temperature and a 15% aqueous ammonium fluoride solution (20 mL) was added. The solution was then extracted with diethyl ether (3 x 30 mL). The organic layers were combined and washed with water (2 x 20 mL) and brine (2 x

20 mL). The solution was dried with Na2SO4 and the solvent was removed in vacuo to afford the crude reaction product. Column chromatography (5/95 ethyl acetate/hexanes) afforded pure 1-(4-bromophenyl)-3-butyn-1-ol as an oil (41%

1 yield). H NMR (300.1 MHz, CDCl3) δ 7.49 (d, J=8.46 Hz, 2H, ArH), 7.27 (d,

J=8.41 Hz, 2H, ArH), 4.84 (t, J=6.23 Hz, 1H, HOCHC6H4Br), 2.60-2.63 (m, 2H, -

CH2C≡CH), 2.40 (bs, 1H, -OH), 2.08 (t, J=2.62 Hz, 1H, CH2C≡CH).

64

OH O 1) Dess-Martin

2) silica gel Br Br

To a solution of 1-(4-bromophenyl)-3-butyn-1-ol (200 mg, 0.888 mmol, 1 equiv.)

in dichloromethane (7.7 mL) was slowly added Dess-Martin periodane (15% wt in

CH2Cl2, 3.3 mL, 1.596 mmol, 2 equiv.) at 0°C. This solution was allowed to stir

for 2 hours upon which time the solvent was removed in vacuo and the crude

reaction mixture was directly loaded onto a silica column. The product was

isolated through column chromatography (30/70 ethyl acetate/ hexanes) to afford

the allene as a dark oil that solidified upon freezing (29% yield). 1H NMR (300.1

MHz, CDCl3) δ 7.75 (d, J=8.57 Hz, 2H, ArH), 7.58 (d, J=8.61 Hz, 2H, ArH), 6.38

(t, J=6.52 Hz, 1H, RCH=C=CH2), 5.26 (d, J=6.52 Hz, RCH=C=CH2).

OH Synthesis of penta-3,4-dien-2-ol (42). To a suspension of lithium

aluminum hydride (LAH) (0.746g, 19.66 mmol, 1.08 equiv.) in THF (36.5

mL) at 0°C was added dropwise a solution of penta-3,4-dien-2-one (1.5g,

18.27 mmol, 1 equiv.) in THF (36.5 mL) under argon. The reaction mixture was stirred for 1 hour and quenched with water slowly. The solution was warmed to room temperature and sodium sulfate was added. The salt was filtered off and the filter cake was washed with THF. The solvent was removed in vacuo while keeping the rotary evaporator bath cold and the product was isolated cleanly as a

1 colorless oil in a 30% yield. H NMR (300.1 MHz, CDCl3) δ 5.27 (m, 1H,

65

HC=C=CH2), 4.84 (dd, J=6.67, 2.54 Hz, 2H, HC=C=CH2), 4.35 (bs, 1H, -OH),

1.30 (d, J=6.33 Hz, 3H, H3CCH(OH)), 1.19 (m, 1H, CHOH).

OAc Synthesis of penta-3,4-dien-2-yl acetate (43). To a solution of penta-

3,4-dien-2-ol (0.442g, 5.26 mmol, 1 equiv.) in THF (5.5 mL) at -45°C,

was added freshly distilled triethylamine (TEA) (0.85 mL, 6.38 mmol, 1.2

equiv.) slowly. Acetic anhydride (0.693 mL, 7.35 mmol, 1.4 equiv.) was then

added slowly. The reaction mixture was warmed to room temperature and stirred

for an hour when an additional 0.43 mL of TEA was added. The reaction was

stirred for 3 hours and a small amount of DMAP (dimethylaminopyridine) was

added. After half an hour, 0.69 mL of acetic anhydride was added and TLC

indicated the reaction had gone to completion. A saturated solution of sodium

carbonate was added and the product was extracted with dichloromethane. The

solution was dried with Na2SO4 and the solvent was removed in vacuo. Column

chromatography (eluent 100% pentanes) afforded the pure compound as a

colorless oil. The 1H NMR specturm was in agreement with the literature.17

O Synthesis of ethyl-2-tosyl iminoacetate (33). To a S N flame-dried 100-mL round bottom flask equipped with a O EtO condenser, was added ethyl glyoxylate (13.02 g, 0.1276 O mol in 63 mL benzene) that was freshly distilled over P4O10. p-Toluenesulfonyl

isocyanate (19.8 mL, 25.6 g, 0.130 mol) was then added slowly and the solution

was refluxed for 2 days to give a bright yellow solution. The solvent was removed

66

in vacuo to give a yellow oil. The excess isocyanate was removed by Kugelrohr-

distillation (145 ˚C, 0.03 torr) and the imine was collected (150-155 ˚C, 0.03 torr)

giving a colorless oil that solidified upon cooling to room temperature in an 80-

1 90% yield. H NMR (300.1 MHz, CDCl3) δ 8.26 (s, 1H, HC=NR), 7.86 (d, J=8.31

Hz, 2H, ArH), 7.38 (d, J=8.15 Hz, 2H, ArH), 4.37 (q, J=7.10 Hz, 2H, -OCH2CH3),

2.46 (s, 3H, Ar-CH3), 1.35 (t, J=7.16 Hz, 3H, -OCH2CH3).

General Procedure B: Addition of allenes to ethyl-2-tosyl iminoacetate

catalyzed by MgBr2•OEt2. To a 1-dram vial containing a stir bar and 3Å

molecular sieves was added ethyl-2-tosyl iminoacetate, MgBr2•OEt2, and a

solution of CH2Cl2 and THF (11:1 CH2Cl2 : THF). The vial was cooled to 0°C and

allene was added. The reaction was stirred at 0°C for the indicated time. The

solvent was reduced in vacuo and the residue was loaded onto a silica gel flash

column and eluted with the indicated solvent system to provide the alkylation

products.

Preparation of (E)-ethyl 4-bromo-6-oxo-2-(tosylamino)hept-4- O enoate (34). Prepared according to General Procedure B by

Br using 3,4-Pentadien-2-one (100 mg, 1.22 mmol), ethyl-2-tosyl

EtO2C NHTs iminoacetate (622 mg, 2.44 mmol) and MgBr2•OEt2 (157 mg,

0.61 mmol) in a 0.5M solution of CH2Cl2 and THF to provide title compound as a

orange oil in a 18% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H

NMR (300.1 MHz, CDCl3) δ 7.71 (d, J=8.18 Hz, 2H, ArH), 7.27 (d, J=7.91 Hz, 2H,

67

ArH), 6.78 (s, 1H, BrC=CH), 5.57 (d, J= 9.38, 1H, NH), 4.31 (dt, J=9.62, 3.71 Hz,

-CH(NH)), 3.96 (m, 2H, -OCH2CH3), 3.71 (dd, J=13.76, 10.42 Hz, 1H, -CH2-

BrC=CH), 2.98 (dd, J=13.78, 4.55 Hz, 1H, -CH2-BrC=CH), 2.41 (s, 3H, ArCH3),

13 2.21 (s, 3H, CH3C=O), 1.11 (t, J=7.15 Hz, 3H, -OCH2CH3). C NMR (125.8

MHz, CDCl3) δ 196.44, 170.06, 143.45, 140.91, 137.31, 133.62, 129.46, 127.25,

61.98, 54.68, 40.83, 31.47, 21.51, 13.87.

Ts Preparation of ethyl 3-acetyl-4-bromo-2-(tosylamino)pent-4- O NH OEt enoate (48). Prepared according to General Procedure B by O Br using 3,4-Pentadien-2-one (100 mg, 1.22 mmol), ethyl-2-tosyl

iminoacetate (622 mg, 2.44 mmol) and MgBr2•OEt2 (157 mg, 0.61 mmol) in a

0.5M solution of CH2Cl2 and THF to provide title compound as a orange oil in a

5% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1

MHz, CDCl3) δ 7.74 (d, J=6.94 Hz, 2H, ArH), 7.27 (d, J=7.91 Hz, 2H, ArH), 5.69

(d, J=2.69 Hz, 2H,-C=CH2), 5.66 (d, J=12.02 Hz, 1H, NH), 5.61 (d, J=2.67 Hz,

1H,-C=CH2), 4.43 (dd, J=10.08, 4.28 Hz, 1H, -CH(NH)), 4.14 (d, J=4.40 Hz, -CH-

C=CBr), 3.97 (m, 2H, -OCH2CH3), 2.41 (s, 3H, ArCH3), 2.24 (s, 3H, CH3C=O),

1.05 (t, J=7.17 Hz, 3H, -OCH2CH3).

Ts Preparation of ethyl 3-acetyl-2-(tosylamino)penta-3,4- O NH OEt dienoate (35). Prepared according to General Procedure B by O using 3,4-Pentadien-2-one (100 mg, 1.22 mmol), ethyl-2-tosyl

iminoacetate (622 mg, 2.44 mmol) and MgBr2•OEt2 (157 mg, 0.61 mmol) in a

68

0.5M solution of CH2Cl2 and THF to provide title compound as a orange oil in a

73% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1

MHz, CDCl3) δ 7.70 (d, J=8.21 Hz, 2H, ArH), 7.27 (d, J=8.23 Hz, 2H, ArH), 5.70

(d, J=8.40 Hz, 1H, -NH), 5.39 (d, J=14.93 Hz, 1H, -C=C=CH2), 5.32 (d, J=14.95

Hz, 1H, -C=C=CH2), 4.68 (d, J= 8.43 Hz, 1H, -CH(NH)), 4.06 (q, J=7.14 Hz, -

OCH2CH3), 2.41 (s, 3H, ArCH3), 2.12 (s, 3H, CH3C=O), 1.12 (t, J=7.15 Hz, 3H, -

13 OCH2CH3). C NMR (125.8 MHz, CDCl3) δ 216.14, 196.65, 168.78, 143.57,

137.40, 129.58, 127.35, 106.71, 82.09, 62.39, 54.83, 26.62, 21.58, 13.94.

O Preparation of (E)-ethyl 4-bromo-6-oxo-6-phenyl-2- Ph (tosylamino)hex-4-enoate (45). Prepared according to General Br Procedure B by using 1-phenylbuta-2,3-dien-1-one (150 mg, 1.04 EtO2C NHTs

mmol), ethyl-2-tosyl iminoacetate (266 mg, 1.04 mmol) and MgBr2•OEt2 (134 mg,

0.52 mmol) in a 0.5M solution of CH2Cl2 and THF to provide title compound as a

orange oil in a 5% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H

NMR (300.1 MHz, CDCl3) δ 7.90 (d, J=7.96 Hz, 2H, ArH), 7.78 (d, J=8.24 Hz, 1H,

ArH), 7.73 (d, J=8.23 Hz, 1H, ArH), 7.60 (m, 1H, ArH), 7.50 (d, J=7.57 Hz, 1H,

ArH), 7.45 (d, J=7.81 Hz, 1H, ArH), 7.41 (s, 1H, Br-C=CH), 7.28 (d, J=6.11 Hz,

1H, ArH), 7.22 (d, J=8.32 Hz, 1H, ArH), 6.04 (d, J=7.98 Hz, 1H, NH), 4.40 (dt,

J=10.32, 3.67 Hz, -CH(NH)), 4.02 (q, J=4.54 Hz, 2H, -OCH2CH3), 3.69 (dd,

J=13.79, 10.50 Hz, -CH2-BrC=CH), 3.05 (dd, J=13.82, 4.59 Hz, -CH2-BrC=CH),

13 2.38 (s, 3H, ArCH3), 1.14 (t, J=7.12 Hz, 3H, -OCH2CH3). C NMR (125.8 MHz,

CDCl3) δ

69

Ts Ts Preparation of (R, R)/(S,S)-ethyl 3-phenyl- O NH O NH OEt OEt Ph Ph 4-bromo-2-(tosylamino)pent-4-enoate (46). O O Br Br Prepared according to General Procedure B

by using 1-phenylbuta-2,3-dien-1-one (150 mg, 1.04 mmol), ethyl-2-tosyl

iminoacetate (266 mg, 1.04 mmol) and MgBr2•OEt2 (134 mg, 0.52 mmol) in a

0.5M solution of CH2Cl2 and THF to provide title compound as a orange oil in a

18% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1

MHz, CDCl3) δ 7.90 (d, J=7.96 Hz, 2H, ArH), 7.78 (d, J=8.24 Hz, 2H, ArH), 7.60

(m, 1H, ArH), 7.50 (d, J=7.57 Hz, 1H, ArH), 7.45 (d, J=7.81 Hz, 1H, ArH), 7.28 (d,

J=7.73 Hz, 2H, ArH), 6.01 (d, J=9.96 Hz, 1H, NH), 5.58 (d, J=2.93 Hz, 1H, -

C=CH2), 5.55 (d, J=2.92 Hz, 1H, -C=CH2), 4.92 (d, J=3.95 Hz, 1H, -CH-CBr),

4.66 (dd, J=10.30, 3.94 Hz, -CH(NH)), 3.96 (q, J=7.11 Hz, 2H, -OCH2CH3), 2.41

(s, 3H, ArCH3), 1.00 (t, J=7.11 Hz, 3H, -OCH2CH3).

The 13 C NMR data is a mixture of compounds 45 and 46. 13C NMR (125.8 MHz,

CDCl3) δ 196.48, 190.10, 170.24, 169.78, 143.33, 143.18, 138.10, 137.44,

134.58, 134.20, 133.83, 133.64, 129.76, 129.42, 129.30, 128.81, 128.76, 127.28,

124.67, 124.44, 62.44, 62.20, 61.98, 60.21, 55.81, 54.62, 54.18, 46.30, 41.19,

29.68, 21.50, 13.89, 13.86, 13.70.

Preparation of (R, S)/(S,R)-ethyl 3-phenyl- Ts Ts O NH O NH OEt OEt 4-bromo-2-(tosylamino)pent-4-enoate Ph Ph O O Br Br (47). Prepared according to General

Procedure B by using 1-phenylbuta-2,3-dien-1-one (150 mg, 1.04 mmol), ethyl-2-

70

tosyl iminoacetate (266 mg, 1.04 mmol) and MgBr2•OEt2 (134 mg, 0.52 mmol) in

a 0.5M solution of CH2Cl2 and THF to provide title compound as a orange solid in

a 35% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1

MHz, CDCl3) δ 7.90 (d, J=7.30 Hz, 2H, ArH), 7.78 (d, J=8.25 Hz, 2H, ArH), 7.58

(m, 1H, ArH), 7.43 (d, J=7.42 Hz, 2H, ArH), 7.27 (d, J=8.34 Hz, 2H, ArH), 5.67 (s,

2H, -C=CH2), 5.56 (d, J=7.35 Hz, 1H, -NH), 4.92 (d, J=6.43 Hz, 1H, -CH-CBr),

4.50 (t, J=7.17 Hz, -CH(NH)), 4.04 (m, 1H, -OCH2CH3), 3.94 (m, 1H, -OCH2CH3),

13 2.40 (s, 3H, ArCH3), 1.09 (t, J=7.12 Hz, 3H, -OCH2CH3). C NMR (125.8 MHz,

CDCl3) δ 194.64, 169.60, 143.74, 136.55, 135.08, 133.94, 129.61, 128.73,

127.41, 125.68, 123.85, 62.13, 60.70, 55.29, 21.51, 13.67.

Stereochemistry determined by NOESY interaction detailed below.

71

O NHTs Synthesis of Compound 70. Potassium t-butoxide (23 CO Et 2 mg, 0.202 mmol, 1 equiv.) was added to a solution of (R,

S)/(S,R)-ethyl 3-phenyl-4-bromo-2-(tosylamino)pent-4- enoate (97.056 mg, 0.202 mmol, 1 equiv.) in THF (2.0 mL) at 0°C. The reaction mixture was stirred for 1 hour and then the crude reaction mixture was filtered through a plug of silica gel. The solvent was removed in vacuo to produce the crude product. After column chromatography (eluent v/v 50/50 ethyl acetate/hexanes), the purified allene was isolated as a white solid in an 89%

1 yield. H NMR (300.1 MHz, CDCl3) δ 7.75 (d, J=8.25 Hz, 2H, ArH), 7.59 (d,

J=7.15 Hz, 2H, ArH), 7.50 (t, J=7.39 Hz, 1H, ArH), 7.36 (d, J=7.81 Hz, 2H, ArH),

7.25 (d, J=7.18 Hz, 2H, ArH), 5.26 (d, J=14.81 Hz, 1H, -C=C=CH2), 5.20 (d,

J=14.84 Hz, 1H, -C=C=CH2), 4.88 (d, J= 7.92 Hz, 1H, -NH), 4.14 (m, 1H, -

CH(NHTs)), 4.22 (q, J= 7.12 Hz, 2H, -OCH2CH3), 2.38 (s, 3H, ArCH3), 1.15 (t,

13 J=7.11 Hz, 3H, -OCH2CH3). C NMR (125.8 MHz, CDCl3) δ 216.41, 192.12,

168.83, 143.54, 137.40, 136.87, 132.72, 129.60, 129.03, 127.95, 127.31, 104.59,

81.80, 62.44, 56.12, 21.50, 13.94.

O Preparation of (E)-ethyl 4-bromo-6-(4-methoxyphenyl)-

6-oxo-2-(tosylamino)hex-4-enoate (55). Prepared MeO Br according to General Procedure B by using 1-(4- EtO2C NHTs methoxyphenyl)buta-2,3-dien-1-one (106 mg, 0.61 mmol), ethyl-2-tosyl iminoacetate (155.5 mg, 0.61 mmol) and MgBr2•OEt2 (78.5 mg, 0.305 mmol) in a

72

0.5M solution of CH2Cl2 and THF to provide title compound as a orange oil in a

5% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1 MHz,

CDCl3) δ 7.89 (d, J=8.71 Hz, 2H, ArH), 7.72 (d, J=8.20 Hz, 2H, ArH), 7.37 (s, 1H,

C=CH), 7.22 (d, J=8.30, 2H, ArH), 6.96 (d, J=8.45 Hz, 2H, ArH), 6.27 (d, J=8.50

Hz, 1H, NH), 4.37 (ddd, J=12.71, 8.50, 4.27 Hz, 1H, CH(NH)), 3.95 (q, J=7.12

Hz, 2H, -OCH2CH3), 3.89 (s, 3H, ArOCH3), 3.67 (dd, J=13.77, 10.65 Hz, 1H

-CH2-BrC=CH), 2.97 (dd, J=13.83, 4.38 Hz, 1H, -CH2-BrC=CH), 2.38 (s, 3H,

ArCH3), 1.14 (t, J=7.07 Hz, 3H, -OCH2CH3).

Preparation of (R,R)/(S,S)-ethyl 3-(4-methoxyphenyl)-4-bromo-2-

O NHTs O NHTs (tosylamino)pent-4-enoate CO Et CO2Et 2 (60). Prepared according to MeO Br MeO Br General Procedure B by using 1-(4-methoxyphenyl)buta-2,3-dien-1-one (106 mg, 0.61 mmol), ethyl-2- tosyl iminoacetate (155.5 mg, 0.61 mmol) and MgBr2•OEt2 (78.5 mg, 0.305

mmol) in a 0.5M solution of CH2Cl2 and THF to provide title compound as a

orange oil in a 12% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H

NMR (300.1 MHz, CDCl3) δ 7.88 (d, J=8.87 Hz, 2H, ArH), 7.78 (d, J=8.21 Hz, 2H,

ArH), 7.26 (d, J=8.12 Hz, 2H, ArH), 6.93 (d, J=8.71 Hz, 2H, ArH), 6.06 (d,

J=10.28 Hz, 1H, NH), 5.56 (d, J=2.87 Hz, 1H, -C=CH2), 5.44 (d, J=2.86 Hz, 1H, -

C=CH2), 4.86 (d, J=3.84 Hz, 1H, -CH-CBr), 4.63 (dd, J=10.30, 3.82 Hz, -

CH(NH)), 3.95 (q, J=7.12 Hz, 2H, -OCH2CH3), 3.86 (s, 3H, ArOCH3), 2.41 (s, 3H,

ArCH3), 0.99 (t, J=7.11 Hz, 3H, -OCH2CH3).

73

Preparation of (S,R)/(R,S)-ethyl 3-(4-methoxyphenyl)-4-bromo-2-

O NHTs O NHTs (tosylamino)pent-4-enoate CO Et CO2Et 2 (61). Prepared according to MeO Br MeO Br General Procedure B by

using 1-(4-methoxyphenyl)buta-2,3-dien-1-one (106 mg, 0.61 mmol), ethyl-2-

tosyl iminoacetate (155.5 mg, 0.61 mmol) and MgBr2•OEt2 (78.5 mg, 0.305

mmol) in a 0.5M solution of CH2Cl2 and THF to provide title compound as a

orange oil in a 38% yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H

NMR (500.1 MHz, CDCl3) δ 7.85 (d, J=8.81 Hz, 2H, ArH), 7.74 (d, J=8.08 Hz, 2H,

ArH), 7.24 (d, J=6.10 Hz, 2H, ArH), 6.89 (d, J=8.81 Hz, 2H, ArH), 5.62 (s, 2H,

-C=CH2), 5.49 (d, J=7.18 Hz, 1H, NH), 4.82 (d, J=6.09 Hz, 1H, -CH-CBr), 4.63 (t,

J=7.07 Hz, -CH(NH)), 4.04 (m, 1H, -OCH2CH3), 3.91 (m, 1H, -OCH2CH3), 3.84

13 (s, 3H, ArOCH3), 2.38 (s, 3H, ArCH3), 1.06 (t, J=7.12 Hz, 3H, -OCH2CH3). C

NMR (125.8 MHz, CDCl3) δ 192.92, 169.68, 164.22, 143.74, 136.51, 131.20,

129.63, 128.10, 127.43, 126.21, 123.40, 113.97, 62.09, 60.63, 55.54, 55.29,

21.52, 13.69.

O NHTs Synthesis of Compound 71. Potassium t-butoxide

CO2Et (17.5 mg, 0.156 mmol, 1 equiv.) was added to a MeO solution of (S,R)/(R,S)-ethyl 3-(4-methoxyphenyl)-4-

bromo-2-(tosylamino)pent-4-enoate (79.65 mg, 0..156 mmol, 1 equiv.) in THF

(1.6 mL) at 0°C. The reaction mixture was stirred for 35 minutes and then the

74

crude reaction mixture was filtered through a plug of silica gel. The solvent was

removed in vacuo to produce the crude product. After column chromatography

(eluent v/v 50/50 ethyl acetate/hexanes), the purified allene was isolated as a

1 solid in an 74% yield. H NMR (300.1 MHz, CDCl3) δ 7.81 (d, J=8.24 Hz, 2H,

ArH), 7.74 (d, J=8.34 Hz, 2H, ArH), 7.30 (d, J=8.31 Hz, 2H, ArH), 6.84 (d, J=8.78

Hz, 2H, ArH), 5.87 (d, J=8.18 Hz, 1H, -NH), 5.24 (d, J=14.47 Hz, 1H, -C=C=CH2),

5.18 (d, J=14.53 Hz, 1H, -C=C=CH2), 4.05-4.14 (m, 1H, -CH(NHTs)), 4.05-4.14

(m, 2H, -OCH2CH3), 3.84 (s, 3H, ArOCH3), 2.42 (s, 3H, ArCH3), 1.13 (t, J=7.11

Hz, 3H, -OCH2CH3).

O Preparation of (E)-ethyl 4-bromo-6-(4-nitrophenyl)-6-

oxo-2-(tosylamino)hex-4-enoate (59). Prepared according

O2N Br to General Procedure B by using 1-(4-nitrophenyl)buta-2,3- EtO2C NHTs dien-1-one (50 mg, 0.264 mmol), ethyl-2-tosyl iminoacetate (135 mg, 0.529

mmol) and MgBr2•OEt2 (68.2 mg, 0.264 mmol) in a 0.5M solution of CH2Cl2 and

THF to provide title compound as an oil in a ~32% yield (flash chromatography:

1 EtOAc : hexanes 40 : 60). H NMR (300.1 MHz, CDCl3) δ 8.33 (d, J=8.98 Hz,

2H, ArH), 8.07 (d, J=8.92 Hz, 2H, ArH), 7.71 (d, J=8.31, 2H, ArH), 7.46 (s, 1H,

C=CH), 7.25 (d, J=7.42 Hz, 2H, ArH), 6.62 (d, J=9.30 Hz, 1H, NH), 4.39 (td,

J=9.58, 4.75 Hz, 1H, CH(NH)), 4.00 (m, 2H, -OCH2CH3), 3.76 (dd, J=13.83,

10.20 Hz, 1H, -CH2-BrC=CH), 3.15 (dd, J=13.76, 4.60 Hz, 1H, -CH2-BrC=CH),

2.39 (s, 3H, ArCH3), 1.12 (t, J=7.14 Hz, 3H, -OCH2CH3).

75

O Preparation of (E)-ethyl 4-bromo-6-(4-bromophenyl)-6-

oxo-2-(tosylamino)hex-4-enoate (56). Prepared according Br Br to General Procedure B by using 1-(4-bromophenyl)buta-2,3- EtO2C NHTs dien-1-one (136.1 mg, 0.61 mmol), ethyl-2-tosyl iminoacetate (311.4 mg, 1.22

mmol) and MgBr2•OEt2 (157 mg, 0.61 mmol) in a 0.5M solution of CH2Cl2 and

THF to provide title compound as an oil in a ~5% yield (flash chromatography:

1 EtOAc : hexanes 40 : 60). H NMR (300.1 MHz, CDCl3) δ 7.77 (d, J=8.78 Hz,

2H, ArH), 7.72 (d, J=8.30 Hz, 2H, ArH), 7.61 (d, J=6.22, 2H, ArH), 7.37 (s, 1H,

C=CH), 7.23 (d, J=8.47 Hz, 2H, ArH), 5.87 (d, J=8.98 Hz, 1H, NH), 4.78 (td,

J=10.45, 4.68 Hz, 1H, CH(NH)), 3.99 (m, 2H, -OCH2CH3), 3.70 (dd, J=13.79,

10.41 Hz, 1H, -CH2-BrC=CH), 3.06 (dd, J=13.87, 4.62 Hz, 1H, -CH2-BrC=CH),

2.38 (s, 3H, ArCH3), 1.13 (t, J=7.16 Hz, 3H, -OCH2CH3).

Preparation of (R,R)/(S,S)- O NHTs O NHTs

CO2Et CO2Et ethyl 3-(4-bromophenyl)-4- Br Br Br Br bromo-2-(tosylamino)pent-

4-enoate (62). Prepared according to General Procedure B by using 1-(4-

bromophenyl)buta-2,3-dien-1-one (136.1 mg, 0.61 mmol), ethyl-2-tosyl iminoacetate (311.4 mg, 1.22 mmol) and MgBr2•OEt2 (157 mg, 0.61 mmol) in a

0.5M solution of CH2Cl2 and THF to provide title compound as an oil in a ~17%

yield (flash chromatography: EtOAc : hexanes 40 : 60). 1H NMR (300.1 MHz,

CDCl3) δ 7.77 (d, J=8.78 Hz, 2H, ArH), 7.76 (d, J=8.63 Hz, 2H, ArH), 7.64 (d,

76

J=6.00 Hz, 2H, ArH), 7.27 (d, J=8.43 Hz, 2H, ArH), 5.93 (d, J=10.28 Hz, 1H, NH),

5.58 (d, J=2.97 Hz, 1H, -C=CH2), 5.44 (d, J=2.94 Hz, 1H, -C=CH2), 4.85 (d,

J=3.90 Hz, 1H, -CH-CBr), 4.64 (dd, J=10.27, 3.92 Hz, 1H, -CH(NH)), 3.96 (q,

J=7.10 Hz, 2H, -OCH2CH3), 2.42 (s, 3H, ArCH3), 1.00 (t, J=7.14 Hz, 3H, -

OCH2CH3).

The 13 C NMR data is a mixture of compounds 56 and 62. 13C NMR (125.8 MHz,

CDCl3) δ 195.42, 187.69, 171.09, 169.66, 143.37, 143.22, 142.55, 138.04,

137.29, 135.58, 133.26, 132.15, 132.10, 130.86, 130.18, 130.10, 129.60, 129.41,

129.28, 127.33, 127.20, 124.84, 124.08, 62.23, 61.98, 60.19, 55.75, 54.57,

41.23, 21.46, 20.99, 13.84, 13.67.

O Preparation of (E)-ethyl-4-bromo-6-cyclohexyl-6-oxo-2-

(tosylamino)hex-4-enoate (57). Prepared according to General Br Procedure B by using 1-cyclohexylbuta-2,3-dien-1-one (70.9 mg, EtO2C NHTs

0.472 mmol), ethyl-2-tosyl iminoacetate (241 mg, .944 mmol) and MgBr2•OEt2

(122 mg, 0.472 mmol) in a 0.5M solution of CH2Cl2 and THF to provide title

compound as an oil in a ~15% yield (flash chromatography: EtOAc : hexanes 30 :

1 70). H NMR (300.1 MHz, CDCl3) δ 7.69 (d, J=8.05 Hz, 2H, ArH), 7.25 (d,

J=7.66 Hz, 2H, ArH), 6.79 (s, 1H, C=CH), 5.71 (d, J=9.14 Hz, 1H, NH), 4.26 (m,

1H, CH(NH)), 3.90-4.00 (m, 2H, -OCH2CH3), 3.68 (dd, J=13.76, 10.67 Hz, 1H, -

CH2-BrC=CH), 2.92 (dd, J=13.75, 4.39 Hz, 1H, -CH2-BrC=CH), 2.51 (m, 1H,

O=CCH), 2.40 (s, 3H, ArCH3), 1.6-1.8 (m, 6H, -CH2-), 1.2-1.3 (m, 4H, -CH2-),

1.10 (t, J=7.13 Hz, 3H, -OCH2CH3).

77

O NHTs O NHTs Preparation of (R,R)/(S,S)-ethyl CO Et CO2Et 2 3-(cyclohexyl)-4-bromo-2- Br Br (tosylamino)pent-4-enoate (64).

Prepared according to General Procedure B by using 1-cyclohexylbuta-2,3-dien-

1-one (70.9 mg, 0.472 mmol), ethyl-2-tosyl iminoacetate (241 mg, .944 mmol) and MgBr2•OEt2 (122 mg, 0.472 mmol) in a 0.5M solution of CH2Cl2 and THF to

provide title compound as an oil in a ~6% yield (flash chromatography: EtOAc :

1 hexanes 30 : 70). H NMR (300.1 MHz, CDCl3) δ 7.72 (d, J=7.79 Hz, 2H, ArH),

7.25 (d, J=8.63 Hz, 2H, ArH), 5.81 (d, J=10.26 Hz, 1H, NH), 5.62 (d, J=2.65 Hz,

1H, -C=CH2), 5.49 (d, J=2.61 Hz, 1H, -C=CH2), 4.42 (dd, J=10.24, 4.09 Hz, 1H, -

CH(NH)), 4.26 (m, 1H, -CH(C=O)), 3.90-4.00 (m, 2H, -OCH2CH3), 2.51 (m, 1H,

O=CCH), 2.40 (s, 3H, ArCH3), 1.6-1.8 (m, 6H, -CH2-), 1.2-1.3 (m, 4H, -CH2-),

1.04 (t, J=7.16 Hz, 3H, -OCH2CH3).

O NHTs O NHTs Preparation of (R,S)/(S,R)-ethyl CO Et CO2Et 2 3-(cyclohexyl)-4-bromo-2- Br Br (tosylamino)pent-4-enoate (65).

Prepared according to General Procedure B by using 1-cyclohexylbuta-2,3-dien-

1-one (70.9 mg, 0.472 mmol), ethyl-2-tosyl iminoacetate (241 mg, .944 mmol) and MgBr2•OEt2 (122 mg, 0.472 mmol) in a 0.5M solution of CH2Cl2 and THF to

provide title compound as an oil in a ~13% yield (flash chromatography: EtOAc :

1 hexanes 30 : 70). H NMR (300.1 MHz, CDCl3) δ 7.75 (d, J=8.31 Hz, 2H, ArH),

7.29 (d, J=7.99 Hz, 2H, ArH), 5.73 (m, 2H, C=CH2), 5.82 (d, J=6.96 Hz, 1H, NH),

78

4.27 (m, 1H, -CH(NH)), 4.23 (m, 1H, -CH(C=O)), 3.99-4.05 (m, 2H, -OCH2CH3),

3.80-3.86 (m, 2H, -OCH2CH3), 2.54 (tt, J=11.23, 3.23 Hz, 1H, O=CCH), 2.41 (s,

3H, ArCH3), 1.89-1.94 (m, 2H, -CH2-), 1.67-1.76 (m, 4H, -CH2-), 1.17-1.24 (m,

4H, -CH2-), 1.09 (t, J=7.14 Hz, 3H, -OCH2CH3).

2.6.0 REFERENCES

1. Borzilleri, R. M.; Weinreb, S. M., Imino Ene Reactions in Organic Synthesis. Synthesis 1995, 347-360. 2. Fuchibe, K.; Hatemata, R.; Akiyama, T., One-pot synthesis of chiral dehydroproline esterss: [3+2]-type cycloaddition reaction of allenylstannane and alpha-imino ester. Tetrahedron 2006, 62, 11304-11310. 3. Borzilleri, R. M.; Weinreb, S. M.; Parvez, M., Total Synthesis of Papuamine Via a Stereospecific Intramolecular Imino Ene Reaction of an Allenylsilane. Journal of the American Chemical Society 1994, 116, (21), 9789- 9790. 4. Natchus, M. G.; Bookland, R. G.; Laufersweiler, M. J.; Pikul, S.; Almstead, N. G.; De, B.; Janusz, M. J.; Hsieh, L. C.; Gu, F.; Pokross, M. E.; Patel, V. S.; Garver, S. M.; Peng, S. X.; Branch, T. M.; King, S. L.; Baker, T. R.; Foltz, D. J.; Mieling, G. E., Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines. Journal of Medicinal Chemistry 2001, 44, (7), 1060-1071. 5. Kotha, S.; Sreenivasachary, N., Synthesis of 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives by cycloaddition approaches. European Journal of Organic Chemistry 2001, (17), 3375-3383. 6. Qiao, C. H.; Jeon, H. B.; Sayre, L. M., Selective inhibition of bovine plasma amine oxidase by homopropargylamine, a new inactivator motif. Journal of the American Chemical Society 2004, 126, (25), 8038-8045. 7. Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A., Scope and Stereochemical Course of the (Trimethylsilyl)Cyclopentene Annulation. Tetrahedron 1983, 39, (6), 935-947. 8. Zhao, G. L.; Shi, M., Aza-Baylis-Hillman reactions of N-tosylated aldimines with activated allenes and alkynes in the presence of various Lewis base promoters. Journal of Organic Chemistry 2005, 70, (24), 9975-9984. 9. Guan, X.; Wei, Y.; Shi, M., Beyond the Aza-Morita-Baylis-Hillman Reaction: Lewis Base-Catalyzed Reactions of N-Boc-imines with Ethyl 2,3- Butadienoate. Journal of Organic Chemistry 2009, 74, (16), 6343-6346. 10. Marshall, J. A.; Maxson, K., Stereoselective synthesis of stereotriad subunits of polyketides through additions of nonracemic allenylsilanes to (R)- and (S)-2-methyl-3-oxygenated propanals. Journal of Organic Chemistry 2000, 65, (2), 630-633.

79

11. Buono, G., A new convenient synthesis of 1,2-pentadien-4-one (acetylallene). Synthesis 1981, 11, 872. 12. Nagao, Y.; Lee, W. S.; Kim, K., New intramolecular five-endo-mode cyclization of allenyl aryl ketones. Chemistry Letters 1994, (2), 389-392. 13. Shim, J.-G., Catalytic propargylation of aldehydes with allenyltributylstannane by ytterbium triflate. Journal of Organometallic Chemistry 1999, 588, (1), 20-21. 14. Hashmi, A. S. K.; Bats, J. W.; Choi, J.-H.; Schwarz, L., Isomerizations on Silica Gel: Synthesis of Allenyl Ketones and the First Nazarov Cyclizations of Vinyl Allenyl Ketones. Tetrahedron Letters 1998, 39, (41), 7491-7494. 15. Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T. A.; Hisler, K.; Dewis, M. L.; Carling, R., Direct Conversion of N- Methoxy-N-methylamides (Weinreb Amides) to Ketones via a Nonclassical Wittig Reaction. Organic Letters 2005, 7, (7), 1427-1429. 16. Kundu, A.; Prabhakar, S.; Vairamani, M.; Roy, S., A Novel Copper (II)/Tin (II) Reagent for Regio- and Chemoselective Carbonyl Propargylation. Organometallics 1999, 18, (15), 2782-2785. 17. Wright, M. W.; Smalley, T. L. Jr.; Welker, M. E.; Rheingold, A. L., Synthesis of cobalt substituted 1,3-diene complexes with unusual structures and their exo selective Diels-Alder reactions. Journal of the American Chemical Society 1994, 116, (15), 6777-6791.

80

CHAPTER THREE

BRΘNSTED ACID CATALYZED ENE REACTIONS

3.1.0 INTRODUCTION

The ene reaction is a valuable carbon–carbon bond forming reaction in organic chemistry. Lewis acids have surfaced as the primary catalysts for the ene reaction, however the scope of this reaction is limited because of the need for inert conditions, the metal waste generated, and the metal’s strong chelation to the product, which causes little regeneration of the catalyst. As an alternative to traditional metal catalysts, Brønsted acids have emerged as viable environmentally friendly and economically advantageous catalysts for many organic transformations.

Our research focused on the development of a Brønsted acid catalyzed ene reaction between all-carbon enes and carbonyl-, imine-, and hydrazone- containing enophiles. In addition we also explored the physical interaction between the catalyst and substrate using 1H NMR techniques. The results of these investigations will be discussed in the following chapter.

3.2.0 CARBONYL-ENE REACTION

Carbonyl compounds have been used extensively as enophiles in Lewis acid catalyzed ene R1 O OH H Scheme 3.1 2 or Lewis Acid R1 R2 reactions to generate R homoallylic alcohols, precursors for many biologically significant compounds

81

(Scheme 3.1).1-3 However, the development of a Brønsted acid catalyzed

carbonyl-ene reaction is lacking. In an effort to develop this type of catalysis,

several Brønsted acids were screened in a carbonyl-ene reaction. These included compounds containing urea-, thiourea-,4, 5 guanidine-,6-8 amidine-,

pyridine-, phosphonic acid-,9, 10 and imidazole-moieties. These types of catalysts

were chosen because they span a range of pKa values and can activate an

electrophile through either a one-point or two-point binding mode. We found that

a phosphonic acid, diethyl phosphate, gave the cleanest and highest yielding

reaction. Initial optimization of the reaction conditions was performed using α-

methyl styrene (74) and ethyl glyoxylate (72), with diethyl phosphate (75) as the

catalyst (Table VII).

We were pleased to find that the thermal reaction produced almost no

product (Table VII, entry 1) compared to the analogous reaction conditions with

the phosphonic acid 75 (Table VII, entry 3). Importantly, the commercially

available catalyst contained an impurity of phosphoric acid (25%), but we found

that phosphoric acid alone was unable to catalyze the reaction, thereby

highlighting the importance of the phosphonic acid (Table VII, entry 2). We

varied the number of equivalents of both the catalyst and the glyoxylate (Table

VII, entries 4-6) and found that excess glyoxylate almost doubles the yield. Also,

it is noteworthy that halving the number of equivalents of phosphonic acid gave a

similar yield to a full equivalent. We also varied the concentration of the styrene,

and lowering the concentration resulted in decreased yield (Table VII, entry 7).

The product yield also decreased as the concentration increased beyond 1.0M

82 with respect to the ene, presumably this caused the glyoxylate to dimerize and become an ineffective enophile. Lastly, we tried a variety of solvents including tetrahydrofuran (THF), acetonitrile, and toluene. Of reactions run in different solvents, the one employing toluene produced enough product to be isolated

(Table VII, entry 8), but the yield was significantly lower than the yields of the reactions run in dichloromethane.

Table VII. Styrene optimization results

O P EtO OH OH O OEt O OEt 75 OEt O 48 h 25oC 74 72 76

Entry Equiv. of 72 Equiv. of 75a Additive [74] (M) Solvent Yield 76 (%)

1 1.2 0 none 1 CH2Cl2 3

2 2 0 H3PO4 2 CH2Cl2 trace

3 1 1 none 1 CH2Cl2 25

4 2 1.5 none 1 CH2Cl2 35

5 2 0.5 none 1 CH2Cl2 43

6 3 1 none 1 CH2Cl2 44

7 1.3 1.3 none 0.7 CH2Cl2 19

8 1.3 1.3 none 0.5 toluene 2

a The phosphonic acid used contained a 25% impurity of phosphoric acid.

83

3.2.1 Scope of the carbonyl-ene reaction

After identifying optimal reaction conditions for α-methyl styrene, we submitted other olefin substrates to the reaction conditions (Table VIII).

Table VIII. Scope of the carbonyl-ene reactiona Entry Ene Component Ene Product Yield (%)

O

OEt 1 30 OH

O

OEt 2 23 OH

O 3 OEt 21 OH

OH O 4 36

O

OEt 5 0 OH

OH 6 OEt 0 O

a Reactions run under optimized conditions described in Table I, entry 5.

The reaction tolerates di- and tri-substituted cyclic and straight-chained substrates (Table VIII, entries 1-3). The reaction also proceeds in moderate yield for an intramolecular substrate (Table VIII, entry 4). The reaction of

84 monosubstituted alkenes did not proceed to product because of the electron deficiency of the alkenes (Table VIII, entries 5 and 6).

3.2.2 Intramolecular carbonyl-ene reaction

The intramolecular carbonyl-ene is more entropically favored than the intermolecular reaction, therefore we anticipated the intramolcular carbonyl-ene to proceed with a variety of substrates (Scheme 3.2a). A variety of commercially

O O P OH HO OEt a OEt

77

O O b O

78 79 80

O

OMe O MeO OMe 81 82

Scheme 3.2. a. Anticipated intramolecular phosphonic acid catalyzed carbonyl-ene reaction. b. Other substrates used to screen in a phosphonic acid catalyzed intramolecular carbonyl-ene reaction. available substrates (78, 79, 80, 82), and a few compounds which were easily synthesized (77 and 81) were used for preliminary testing (Scheme 3.2b).

Initially, reaction conditions that were favorable for the cyclization of citronellal were used (see Table II, entry 4). However, under these conditions significant amounts of product were not observed with any of the substrates tested. Heating

85

the reactions to temperatures above 25°C did not result in the detection of the

desired ene products. These substrates contain electron-rich alkene

components, but lack very electron-deficient carbonyl groups. This preliminary

work demonstrates the need for more electron-deficient centers for addition of

the alkene. Consequently, a phosphonic acid catalyzed intramolecular carbonyl-

ene reaction will be developed by synthesizing substrates with more electron-

deficient carbonyl groups.

3.3.0 IMINO-ENE REACTION

The imino-ene reaction provides a valuable method for the generation of

homoallylic amines (Scheme 3.3) through the formation of a carbon–carbon bond

H NR NHR Scheme 3.3

ene enophile between an all-carbon alkene (ene) and an imine (enophile). The reaction of an

alkene with a glyoxylate derived imine leads to the formation of an olefin and a

masked α-amino acid, both of which build synthetic utility into the products

(Scheme 3.4).

masked Pg NHPg amino acid R N H Scheme 3.4 R CO2Et CO2Et diversity through different alkyl and aryl groups Traditionally Lewis acids have been used to catalyze the imino-ene

reaction with high enantioselectivity and good yields; however the scope of the reaction is limited. The significant interaction between the Lewis acid and the

86

resulting product amine can preclude the regeneration of the catalysts thereby

necessitating the addition of compounds to interrupt chelation11 or special

solvents.12

Conversely, Brønsted acids offer a milder activation mode through

hydrogen bonding. The average hydrogen-bond strength between a donor and

an acceptor in organic media (1-8 kcal/mol)13 can be sufficiently activating for a

reaction to occur, although it is significantly weaker than metal–nitrogen chelation. Our goal was to take advantage of this weaker interaction in

anticipation of creating a Brønsted acid catalyzed imino-ene reaction. The

screening and optimization of substrates is reported below.

3.3.1 Optimization of a Brønsted acid catalyzed imino-ene reaction

Previous screening with the carbonyl-ene reaction led us to identify diethyl

phosphate as a viable catalyst for an ene reaction (see section 2.0). We used

our previously optimized conditions from the carbonyl-ene reaction as a starting

point for the optimization of the phosphonic acid catalyzed imino-ene reaction

between α-methyl styrene (74) and tosyl iminoester 33 (Table IX).

The yield of the thermal reaction between α-methyl styrene (74) and the

tosyl imine 33 is higher than the yield of the analogous carbonyl-ene reaction,

demonstrating the increased reactivity of imines versus carbonyl-containing

analogues. Most notably, the catalyst helped to more than double the yield of 83

(Table IX, entries 1 and 2). The acid catalyst was modified by using other organic acids with a range of suitable pKa values, however they were unable to promote the reaction as efficiently as the thermal or phosphonic acid catalyzed

87

reaction (Table IX, entries 3-5). We also tested multiple solvents. As for the

carbonyl-ene reaction, dichloromethane was the most suitable (Table IX, entries

6-7). The use of excess imine increased the yield, even with a lower catalyst

loading (Table IX, entry 8).

Table IX. Optimization of imino-ene reaction

Ts N Ts conditions NH OEt OEt Ph O O 74 33 83 Equiv. of 74 Equiv. of 75a Solvent Additive Yield 83 (%)

1 2 1 CH2Cl2 none 90

2 2 0 CH2Cl2 none 42 Organic Acid

3 1 0 CH2Cl2 AcOH 8 CH Cl 4 1 0 2 2 H3PO4 22 CH Cl 5 1 0 2 2 p-tolSO2H 7 Solvent

6 1 0.5 CH2Cl2 none 36 7 1 0.5 THF none 18 Reactant

Ratios

8 1 1 CH2Cl2 none 61

9 2 0.5 CH2Cl2 none 68 a Diethyl phosphate is 75.

These results show that the phosphonic acid is instrumental and unique in

promoting the imino-ene reaction.

88

3.3.2 Scope of the imino-ene reaction

The scope of the reaction was then investigated by using similar alkenes

to those that were tested in the carbonyl-ene reaction (Table X). Electron-rich

1,1-disubstituted olefins are traditionally the best substrates for ene chemistry,

and this held true for p, α-dimethyl styrene (Table X, entry 1); however because

this olefin is especially electron-rich, the thermal reaction performed equally as

well. Cyclic structures tend to be poor substrates because the resulting ene

product contains a cycloalkene, which increases the ring strain in the molecule.

This was the case for the six-membered rings (Table X, entries 3 and 4),

whereas the methylene cyclopentane proceeded with high yields (Table X, entry

5). Monosubstituted olefins are typically not very good substrates because they

are not as electron–rich. Although the carbonyl-ene chemistry (see Table VIII)

demonstrated that monosubstituted alkenes did not proceed to product at all, we

did find trace product when submitting allyl benzene to the imino-ene reaction

conditions (Table X, entry 6).

Alternatively, the addition of 2 mol% phosphoramidate (Figure 3.1) gave

similar results indicating a somewhat increased reactivity O P H N OEt relative to diethyl phosphate (Table X, entries 3 and 5). These 2 OEt Figure 3.1. Diethyl results demonstrate the potential of a Brønsted acid catalyzed phosphoramidate imino-ene reaction that tolerates a variety of substrates with high to moderate yields.

89

Table X. Scope of the Brønsted acid catalyzed imino-ene reactiona Entry Ene Component Ene Product Yieldb (%)

Ts HN c 61 1 OEt

O

O c 91 2 OEt HN Ts

O

3 OEt 45 (24) NHTs

O

4d OEt 39e NHTs

O 5d 25 (25) OEt NHTs

O 6 trace OEt NHTs

a Reactions run under optimized conditions described in Table V, entry 1. b Yields reported in parentheses are of the isolated product when using diethyl phosphoramidate. cReaction yield not significantly higher than thermal reaction. dMixture of diastereomers. e The dr= 5:1 as determined by 1H NMR spectroscopy.

3.3.3 1H NMR titration studies of the imino-ene reaction

The investigations discussed above revealed three interesting observations: 1) as the numbers of equivalents of the catalyst or imine were lowered, the product yields significantly decreased, 2) the product yield resulting

90

after a 12 hour reaction compared to that obtained for the 48 hour reaction was

not significantly different, and 3) the reaction produced a white precipitate which

was not product. Intrigued by these findings, we investigated the physical aspects of the interaction between the catalyst and imine.

A hydrogen bond can cause proton signal peaks of the proton(s) involved

in the hydrogen bond to shift downfield in an 1H NMR spectrum. Also, a proton

near the atoms involved in the hydrogen bond may shift downfield. Therefore if a hydrogen bond is formed between the imine and phosphonic acid, the –OH

proton and potentially the imine HC=N were expected to shift downfield. In some

cases, proton signal peaks will shift based on concentration due to a change of

electronic environment of a particular proton. To confirm if a proton shift occurs

as the concentration is changed for the phosphonic acid, a dilution titration was

performed between concentrations ranging from 0.06M to 0.03M (Figure 3.2).

Figure 3.2 Graphical representation of the dilution of diethyl phosphate between the concentrations of 0.03M to 0.06M where the difference in the change in shift of –OH proton in the 1H NMR spectrum was followed.

91

It was found that the –OH peak does shift as concentration changes, suggesting an aggregated state of the phosphonic acid.

Because the shift of the proton changes with concentration, the diethyl phosphate concentration was kept constant (0.01M) while the tosyl imine was added incrementally (Figure 3.3).

Figure 3.3 Graphical representation of the titration of tosyl imine into diethyl phosphate where the ratio of substrates is plotted against the change in the 1H NMR shift of the –OH proton. This titration was designed to explore the imine–diethyl phosphate interaction through hydrogen bonding. Throughout the course of the titration the resonance for the –OH peak shifted as the imine was added, indicating that an interaction was present and observable. If a 1:1 binding of substrate and catalyst existed, the graph of the ratio of substrate to catalyst versus the delta shift should show saturation at a concentration ratio of 1:1. However, we found that the Δδ changed linearly up to the 1:1 concentration ratio, and instead of saturation at

92

this point, the Δδ decreased until about 2:1 and then began to increase again.

This data concurs with the dilution data which suggests a more complex interaction in which aggregation of the diethyl phosphate may be occurring and complicating the titration results.14

Additionally, 1H NMR spectroscopy was used to study any potential

reactions that may occur between the imine and phosphonic acid in the absence

of the ene component. A 10mM solution containing both the imine and the

phosphonic acid were monitored over 15 hours, and 1H NMR spectra were

recorded every half hour until five hours had passed (Figure 3.4). The spectra

Figure 3.4. Stacked 1H NMR spectroscopy plots of the kinetic experiment in which the imine decomposed and ethyl glyoxylate was formed over time. were then taken every hour. The proton shift of the imine (HC=N) was monitored

at δ = 8.17 ppm. It was found that the phosphonic acid promotes the hydrolysis

of the imine as evidenced by the disappearance of the signal for imine peak and

93

the appearance of a signal at δ =9.35 ppm, which is indicative of the presence of ethyl glyoxylate (Figure 3.4).

The disappearance of the imine peak (t1/2=2 h) and the formation of the

glyoxylate peak is graphed over time (Figure 3.5).

Figure 3.5 A graphical representation of the disappearance of the imine and the appearance of ethyl glyoxylate. Squares = the integration of the imine peak versus time. Diamonds = the integration of the aldehyde proton peak of ethyl glyoxylate versus time. It is implicit that the decomposition of the imine not only produces ethyl

glyoxylate (72) but also p-toluenesulfonamide (84) which has been isolated in our reactions. The proton signals that correspond to this product overlap either the imine or the phosphonic acid, which is why were unable to confirm its presence in the 1H NMR spectra. In addition we also found that the white precipitate

previously discovered in our reaction is the result of a disubstituted imine product

85 (Scheme 3.5). This decomposition is slowed down when the ene is added

(t1/2=6 h). These results suggest that the excess imine is necessary because of a

competing hydrolysis of the imine.

94

O P Ts EtO OH N OEt O Ts H NH OEt 75 OEt Ts N Ts OEt H N O O H O 33 72 84 85 Scheme 3.5. Decomposition of tosyl imine under phosphonic acid conditions. In an effort to limit or shut down the competing hydrolysis reaction, small amounts of water in the reaction were removed through activated molecular sieves. A range of differently sized molecular sieves were employed, where 3Å molecular sieves resulted in only a 46% yield of the reaction product. As the pore size increased, the product yield decreased. Potentially, the sieves may have absorbed the catalyst as well, and as a result rigorous dry techniques were employed instead of sieves in an attempt to remove water from the reaction.

However, running the reaction under an inert atmosphere, and removing as much water from the catalyst as possible (through azeotroping) resulted in a

OEt decrease of product yield. These result s suggest H O P OEt O O water may be involved in the interaction between EtO P O H EtO catalyst and substrate or that the water might be Figure 3.6. Potential structure of a dimerized diethyl phosphate. necessary to interrupt the potential aggregated state of the phosphonic acid (Figure 3.6) .14, 15

3.4.0 REACTIONS WITH HYDRAZONES

The primary focus of the Brønsted acid catalyzed ene chemistry was on those reactions that included carbonyl- or imine-containing enophiles. To expand

95

the scope of this type of chemistry beyond these enophiles, hydrazones were

introduced as a viable substrate for an ene reaction. A citronellal-derived hydrazone was synthesized and subjected to the phosphonic acid reaction

conditions established for the imino-ene reaction (see Table III, entry 1 and

Scheme 3.6).

Ar O Ar O O HN HN N P HO OEt NH OEt H

Scheme 3.6. Proposed ene cyclization of a hydrazone catalyzed by a phosphonic acid. However, the reaction did not produce the expected hydrazine, and instead a

pyrazolidine derivative was discovered as the major product (Scheme 3.7).

Ar O O HN N P HO OEt H OEt N Ar H N 25oC, 48 hrs O

76% Scheme 3.7. Cyclization of a hydrazone to form a pyrazolidine derivative. Pyrazolidine derivatives can easily be converted into 1,3-diamines after N–N bond cleavage.16 Chiral 1,3-diamines have utility as chiral ligands for asymmetric

catalysis, as well as biologically important cisplatin derivatives.17, 18 Recent work

with similar hydrazones has led to the development of an asymmetric

intramolecular [3+2] cycloaddition catalyzed by a chiral zirconium Lewis acid (for

a full discussion, see chapter 1, section 1.3.5).16, 19 However, the full potential of

96

this reaction has not been explored. We chose to further examine this reaction in

terms of reaction optimization as well as mechanistic aspects.

3.4.1 Reaction optimization

The initial hydrazone cyclization proceeded under reaction conditions

established for the imino-ene reaction (1 equivalent of diethyl phosphate, 2M in

CH2Cl2, 25°C, 48 hours) with moderate yield (76%). To explore the full potential

of this reaction, several reaction parameters were varied including temperature,

equivalents of catalyst and concentration. The results are summarized below

(Table XI).

When the temperature was decreased from room temperature to 4°C, the

product yield d ecreased (Table XI, entry 2 to entry 1). However, decreasing the concentration (from 2M to 1M) at the lower temperature increased the product yield so that it was comparable to a reaction proceeding at the higher temperature (Table XI, entry 3). An additional decrease in concentration to 0.5M at 4°C led to a high product yield (Table XI, entry 4); however an additional decrease in concentration to 0.1M lowered the product yield (Table XI, entry 5).

When the equivalents of acid were halved at the optimized concentration, the product yield decreased (Table XI, entry 6). The d.r. ratios were consistently around 2:1, except for the reaction proceeding at a 0.1M concentration, in which the d. r. increased to 4:1 (Table XI, entry 5).

97

Table XI. Optimization of hydrazone cyclizationa

O2N O O NO2 P HO OEt HN OEt N H H 75 N H CH2Cl2 N O H 86 87 b c,d Entry Equiv. of 75 [86] (M) T (°C) Yield 87 (%) d.r.

1 1 2 25 76 1.5:1

2 1 2 4 56 2:1

3 1 1 4 76 2.2:1

4 1 0.5 4 83 2.5:1

5 1 0.1 4 67 4:1

6 0.5 0.5 4 50 2.8:1

a All reactions were run for 48 hours. b Diethyl p hosphate used contained a 25% phosphoric acid impurity. c Ratios determined by 1H NMR spectroscopy. d Stereochemistry of major diastereomer confirmed by crystal s tructure. See experimental data.

Additionally, the reaction was allowed to proceed for varying time periods

(Table XII). At six hours, the reaction yielded over half of what was produced at

48 hours (compare entries 1 and 4 in Table XII). The yield at twelve hours increased about 20% more than that obtained after six hours of reaction time

(Table XII, entry 2), and at 24 hours the yield had not significantly changed compared to that for the 12 hour reaction point, but was comparable to that of the

48 hour reaction (Table XII, entry 3). When the phosphonic acid was used catalytically (0.25 equivalents) and stirred for 48 hours, the product was formed in moderate yield and was comparable to the 24 hour reaction with a full

98

equivalent of acid (Table XII, entry 5). When 0.25 equivalents of acid were used

and the reaction was allowed to proceed for a week, a noticeable difference in

product yield was not observed between the week time point and that just stirred

for 48 hours (Table XII, entry 6). The d.r. values decreased slightly over time, but

after submitting an isolated known ratio of product diastereomers to reaction

conditions, we did not find the d.r. change over a 48 hour period.

Table XII. The effect of time on the cyclization reaction

O2N O O NO2 P OEt HN HO N OEt H H 75 N N H CH2Cl2 O H

86 87 a Entry Equiv of 75a t (hrs) [86] (M) T (˚C) Yield 87 (%) d.r.b

1 1 6 0.5 4 47 4.4:1

2 1 12 0.5 4 62 3:1

3 1 24 0.5 4 64 2.9:1

4 1 48 0.5 4 74 3:1

5 0.25 48 0.5 25 64 2.8:1

6 0.25 1 week 0.5 4 62 3.5:1

The phosphonic acid used was synthesized and contained a 25% impurity of crystalline b H3PO4 dissolved in it. Stereochemistry of major diastereomer confirmed by crystal structure. See experimental data.

In addition to the reaction condition modifications discussed, several

Brønsted acids were tested as catalysts including tosic acid and acetic acid, but

they were poor or unsuccessful catalysts. Previous work by Shimizu and co-

99 workers20 repo rted HCl as an effective catalys t under reflux conditions , but currently we have not tried HCl as a catalyst at mil der temperatu res.

In addition to exploring the unique catalytic activit y of the diethyl phosphate, the im portance o f the phosphoric acid impurity was investigated by add ing a variety o f other acids t o diethyl phosphate. The results are presented in

Table XIII.

Table XIII. The effect of additional Brønsted acids on the cyclization reaction

ON2 O O NO2 P OEt HN HO N OEt H H N 75 H CH2Cl2 N O H

86 87 Entry Equiv of [86] T Additive Equiv of Yield d.r.a 75 (M) (˚C) additive 87 (%) 1 1 2 4 none 0 48 4:1

b 2 0 0.5 4 H3PO4 0.25 14 3.7:1

b 3 0 0.5 4 H3PO4 1 12 4.8:1

b 4 0.75 0.5 4 H3PO4 0.25 74 3:1

c 5 0.75 0.5 4 H3PO4 0.25 78 2.6:1

6 0.75 0.5 4 H2SO4 0.25 67 3.3:1

7 0.75 0.5 4 CH3COOH 0.25 60 2.9:1

a Stereochemistry of major diastereomer confirmed by crystal structure. See experimental data. b crystalline acid c 85% acid (liquid)

When pure diethyl phosphate was used alone as a catalyst, the yield significantly decreased from those that contained phosphoric acid (Table XIII,

100

entry 1 v ersus entry 4), high lighting the importance of the add ition of p hosphor ic

acid. It was first imperative to understand if phosphoric acid a lone could catalyze

the cyclization of the hydrazone. S ince, the ph osphoric acid is a 25% impurity in

the commercially available diethyl phosphate catalyst, 0.25 equ ivalents o f

phosphoric acid were used as cata lyst, resultin g in a low y ielding reac tion (Table

XIII, entry 2). In addition, ad ding a full equivalent of phospho ric acid re sulted in a

low product yield (Table XIII, entry 3). Diethyl phosphate w as also s ynthesize d

as a pu re compou nd and th en pho sphoric acid was added. Phosphoric acid can

be purchased as a liquid (85% H3PO4) or as a solid. When eith er type o f

phosphoric acid (solid or liquid) was added to diethyl phosphate as a 25%

additive, both reactions resulted in moderate yield (Table XIII, entries 4 and 5).

These product yields are comparable to those found under the optimized reaction conditions (see table XI, entry 4). To investigate if phosphoric acid was unique in this type of catalysis, other acids were used as additives with diethyl phosphate.

Sulfuric acid (25% in diethyl phosphate) gave a lower product yield than using phosphoric acid (Table XIII, entry 6). In addition, acetic acid (25% in diethyl phosphate) also resulted in a decrease in the product yield (Table XIII, entry 7).

The small changes in d.r. values did not seem significant as the reaction parameters were changed. These results show that phosphoric acid is a necessary and unique, effective additive for this Brønsted acid catalyzed cyclization reaction of a hydrazone.

101

3.4.2 Scope of the reaction

Several hydrazones were synthesized to expand the scope of the reaction

beyond the citronellal-derived hydrazone. These hydrazones were expected to

react to form two fused five-membered rings instead of the six-membered and

five-membered ring observed with citronellal-derived hydrazone. The results of the expansion of the scope of the reaction are tabulated in Table XIV.

Table XIV. Scope of the reaction

NO 2 O H 1 NO N P R2 R 2 N HO OEt H 1 OEt R NH O 75 R2 N CH2Cl2 H O

1 2 88 R1=Me, R2=H 90 R =Me, R =H 1 2 89 R1=R2=Me 91 R =R =Me Entry Substrate Equiv t (hrs) [hydrazone] T (˚C) Yield d.r.a of 75 (M) (%) 1 88 0.5b 48 0.5 25 33 1:0

2 88 1b 48 0.5 25 39 1:0

3 88 1c 48 0.5 25 73 1:0

4 89 1b 48 0.5 25 21 1.2:1

5 89 1c 48 0.5 25 67 5.3:1

a Stereochemistry of major diastereomer for product 90 confirmed by NOESY. See experimental data. b Commercially available 75% pure diethyl phosphate was used. c Synthesized diethyl phosphate was used with a 25% additive of crystalline phosphoric acid.

The α-methyl hydrazone proceeded with moderate yield using half an

equivalent of the commercially available phosphonic acid and produced only one

diastereomer (Table XIV, entry 1). When the number of equivalents of acid was

102

increased to 1 equivalent, there was not a significant change in the product yield

(Table XIV, entry 2). An interesting difference in product yield was noted when

the acid catalyst was changed from commercially available diethyl phosphate which contained a 25% impurity of phosphoric acid to a synthesized diethyl phosphate that contained a 25% impurity of crystalline phosphoric acid: the reaction proceeded with much higher yield (Table XIV, entry 3) for the latter case.

A similar trend was found with the α-dimethyl hydrazone. When 1 equivalent of the commercially available catalyst was used, the yield was moderate and the diasteromeric ratio (d.r.) approached 1:1 (Table XIV, entry 4). However, when the synthesized catalyst was used with 25% H3PO4, the yield more than tripled

and the d.r. increased to significantly favor one isomer (Table XIV, entry 5).

These results show that this reaction proceeds well for other hydrazones which

are not highly activ ated. In addition the peculiar trend we obse rved pro mpted us to investigate the physical and mechanistic aspects of this reaction.

3.4.3 Proposed mechanism and 1H NMR studies

There are two central mechanistic pathways that the cyclization could

undergo: (1) a step-wise cyclization (Scheme 3.8a), and (2) a concerted [3+2]

cycloaddition (Scheme 3.8b). In the step-wise reaction, nucleophilic addition and

successive cyclization leads to the pyrazolidine product. In the [3+2]

cycloaddition, a simultaneous cyclization occurs of a 1,3-dipole equivalent with

an olefin. Reported mechanistic studies19 with the analogous Lewis acid

catalyzed cyclization of hydrazones suggests that the mechanism proceeds in a

103 concerted manner, but additional investigation is necessary to see if this applies to the Brønsted acid cyclization reaction.

Ar O

HN N H N Ar Ar O N O HN N a

H

b Ar OH

N H N N Ar N H O

Scheme 3.8. (a) A step-wise cyclization and (b) a concerted [3+2] cyclization of a hydrazone to form a pyrazolidine derivative. During the optimization of the phosphonic acid catalyzed cyclization, it was discovered that the composition of the phosphonic acid played a significant role on the performance of the catalyst (see table XII and table XIII). We also found that the presence of water affected the yield of the reaction. The results are shown in Table XV.

Under inert conditions in which the catalyst was also azeotroped to remove any water, the product yield of 87 decreased to 48% (Table XV, entry 1).

Mole equivalents of water were added to the reaction to identify the amount of water required to give the optimized conditions. It was found at 0.2 equivalents of water, the yield was similar to that found under inert conditions (Table XV, entry 2). Adding a full equivalent of water slightly decreased the product yield

(Table XV, entry 3), and 3 equivalents gave a comparable yield to that found at 1

104 equivalent (Table XV, entry 4). These results suggest that a trace amount of water is necessary to achieve optimized conditions, but less than 0.2 equivalents.

The investigation into the role of water in the reaction is part of the future work on this project.

Table XV. The effect of water on the cyclization reaction

O2N O O NO2 P OEt HN HO N OEt H H 75 N H CH2Cl2 N O H 86 87 Entry Mol Equiv. of Equiv. of 75a [86] (M) T (˚C) Yield d.r. H2O (%) 1 0 1 0.5 4 48 4:1

2 0.2 1 0.5 4 51 2:1

3 1 1 0.5 4 47 2.4:1

4 3 1 0.5 4 45 2.1:1

a The diethyl phosphate used was purchased pure.

In addition to understanding the role of water in the reaction, we also wanted to study the interaction between the catalyst and the hydrazone substrate. 1H NMR spectroscopy was used as the method for identifying and qualifying this interaction. Previous work indicated that the –OH proton signal of the phosphonic acid shifted as the concentration changed (see section 3.3 and appendix II). For this reason the concentration of diethyl phosphate was kept constant while the hydrazone was added incrementally between concentrations of 0.002M to 0.5M (Appendix II). The proton signal of the phosphonic acid did

105

shift indicating an interaction, but the conclusions were unclear in terms of

stoichiometry. For this reason, Job plot analyses were employed to identify the stoichiometry of the catalyst-substrate interaction.

Job plots21 are conducted through the preparation of a series of solutions of catalyst (diethyl phosphate) and substrate (hydrazone) so that the sum of the total catalyst and substrate concentrations are kept constant. The Job Method was used with 31P NMR spectroscopy data, where the phosphorus signal in

diethyl phosphate was monitored (see appendix II). The maximum value on the

y-axis gives information on the ratio of the complex. For example, if the value of

y occurs when x = 0.5, then the substrate-catalyst ratio is 1:1.

A Job plot of the citronellal-derived hydrazon e (86) and diethyl p hosphate

(75) shows a maxim um y-value at 0.6, indicating the interaction between the

hydrazone and phosphonic acid is not 1:1 (Figure 3.7). We plan to further

investigate the interesting stoichiometry suggested by the Job plot.

Figure 3.7. Job plot that resulted from the interaction between diethyl phosphate and hydrazone 86. The graph peaks at a 0.6 mol fraction of the hydrazone.

106

3.4.4 Intermolecular hydrazone substrates

The literature reports an intermolecular cyclization reaction between a glyoxylate derived hydrazone and α-methyl styrene under Lewis acid

conditions.22 Ene products were also produced under these conditions in small

amounts. Because these substrates show potential as ene reactants, we chose

to further explore their chemistry. A variety of hydrazones were synthesized for a

reaction with α-methyl styrene under phosphonic acid conditions (Scheme 3.9).

O O R2 P OEt H HO N R2 OEt HN HN N 75 O R1 R1 1 2 92 R =CO2Et, R =p-NO2CH 6 4 1 2 93 R =CO2Et, R =Ph 1 2 94 R =CO2Et, R =p-BrC6H4 95 R1=t-Bu, R2=Ph

Scheme 3.9. Proposed phosphonic acid catalyzed intermolecular ene reaction between an all-carbon ene and a hydrazone.

Hydrazone 92, derived from ethyl glyoxylate and p-nitrobenzoic hydrazine was

not soluble in dichloromethane or toluene. When the nitro-group was removed

(93), the solubility increased, however the reaction resulted in isomerization of

the hydrazone only. A hydrazone derived from p-bromobenzoic hydrazine was used (94) to prevent the isomerization from occurring and to increase the solubility of the hydrazone in dichloromethane. However, this hydrazone was only partially soluble and also isomerized under acidic conditions. Lastly, a

hydrazone derived from pivaldehyde (95) was submitted to reaction conditions,

where only the isomerization of the hydrazone was noted.

107

3.4.5 Future Work

In the future, we plan to synthesize soluble hydrazones that are activated for an ene reaction in order to develop an intermolecular ene reaction between all-carbon enes and hydrazone-containing enophiles.

In addition to creating an intermolecular hydrazone ene reaction, we would

also like to understand the mechanism of the intramolecular cyclization of the

hydrazones. A preliminary experiment was conducted to test a methylated hydrazone 96. The presence of the methylated nitrogen atom was expected to

Ar O O P OEt N HO N OEt 75 no reaction H CH2Cl2

96

Scheme 3.10. The reaction of a methylated hydrazone when subjected to phosphonic acid conditions. preclude the formation of a negative charge on the nitrogen atom (as seen in the

non-methylated analogue), as well as prevent a potential tautomerization

necessary for a [3+2] cycloaddition. If the cyclization was working under a step-

wise mechanism, we would expect to see the addition of the alkene into the

hydrazone and then the trapping of the subsequent cation by a nucleophile.

However, under phosphonic acid reaction conditions, the starting hydrazone was

the only compound recovered from the reaction (Scheme 3.10).

While this result does not exclude a step-wise mechanism, it does

highlight the importance of the nitrogen proton. We would like to examine the

108

importance of other functional groups to shed light on the potential mechanism

involved in the reaction.

Related to understanding the mechanism of the cyclization, we also want to better understand the physical interaction between the hydrazone and

phosphonic acid catalyst. The Job plot analysis did not show a clean 1:1 ratio of

substrate to catalyst; however the results were not completely clear. More

conclusive Job plot analyses and 1H NMR titration may better indicate the

stoichiometry of the reaction.

3.5.0 EXPERIMENTAL DATA

General Information and Materials.

Reagents and Materials. Dichloromethane and benzene were obtained through

a solvent system containing activated alumina column under Argon developed by

J.C. Meyer. All commercially available reagents were obtained from Aldrich,

Fisher Scientific, or Alfa Aesar and used as received unless otherwise indicated.

Deuterated solvents were purchased from Cambridge Isotope Laboratory and

used as received. Thin layer chromatography (TLC) was performed by using

Macherey-Nagel POLYGRAM SIL G/UV254 pre-coated plates (0.20mm), and

visualized using a combination of UV, anisaldehyde, and potassium

permanganate stain. Purification of compounds performed on columns packed with Bodman silica gel (32-62D, 60 Å).

NMR Data. 1H NMR spectra were obtained by using a Bruker Avance 500 MHz

spectrometer and a Bruker Avance 300 MHz spectrometer operating at 500.13

109

MHz and 300.13 MHz, respectively. Chemical shifts are reported in parts per

million relative to the residual proton resonance in the indicated deuterated solvent. Coupling constants were reported in hertz and multiplicities were

indicated by using the following symbols: s (singlet), d (doublet), t (triplet), q

(quartet), bs (broad singlet), m (multiplet). Data for 13C NMR obtained by using

Bruker Avance 500 MHz spectrometer operating at 125.77 MHz. Data is reported

in terms of chemical shift.

3.5.1 Carbonyl-ene data

Synthesis of intramolecular aldehydes. Ethyl 2,2,6-trimethyl-hept-5-enoate

(77)23 and 2,2-dimethoxy-5-methylhex-5-enal (81)24 were synthesized according

to the literature procedures.

General Procedure: Additon of olefins to ethyl glyoxylate catalyzed by diethyl phosphate. To a 1-dram vial containing a stir bar was added ethyl

glyoxylate (2 mmol), the olefin (1 mmol), diethyl phosphate (0.50 mmol), and

CH2Cl2 (1 mL). The reaction was stirred at room temperature for 48 hours. The

solvent was reduced in vacuo and the residue was loaded onto a silica gel flash

column and eluted with the indicated solvent system to provide the carbonyl-ene

products. The 1H NMR spectra of the ene products matched those reported in

the literature.25

110

3.5.2 Imino-ene data

The synthesis of ethyl-2-tosyl iminoacetate (33) was reported in chapter 2.

General Procedure: Addition of olefins to ethyl-2-tosyl iminoacetate

catalyzed by diethyl phosphate. To a 1-dram vial containing a stir bar was

added ethyl-2-tosyl iminoacetate (1 mmol), the olefin (0.50 mmol), diethyl

phosphate (0.50 mmol), and CH2Cl2 (0.5 mL). The reaction was stirred at room

temperature for 48 hours. The solvent was reduced in vacuo and the residue was

loaded onto a silica gel flash column and eluted with the indicated solvent system

to provide the imino-ene products.

Ts Preparation ethyl 4-phenyl-2-(tosylamino)pent-4-enoate NH

CO2Et (3a). Prepared according to the above described general

procedure by using α-methylstyrene (59 mg, 0.5 mmol), ethyl-2-tosyl iminoacetate (255.1 mg, 1 mmol), and diethyl phosphate (77 mg, 0.5 mmol) to provide pure product as a white solid in 90 % yield (flash

1 chromatography, EtOAc : hexanes 30 : 70). H NMR (500.1 MHz, CDCl3) δ 7.63

(d, J=8.14 Hz, 2H, ArH), 7.26 (m, 5H, ArH), 7.20 (d, J=8.28 Hz, 2H, ArH), 5.31 (s,

1H, C=CH), 5.16 (d, J=9.10 Hz, 1H, NH), 5.11 (s, 1H, C=CH), 3.98 (m, 1H,

CH(NH)), 3.72 (m, 2H, -OCH2CH3), 2.87 (dd, J=14.04, 6.32 Hz, 2H, -CH2-), 2.81

(dd, J=13.37, 5.96 Hz, 2H, -CH2-), 2.38 (s, 3H, ArCH3), 1.02 (t, J=7.12 Hz, 3H, -

13 OCH2CH3); C NMR (125.8 MHz, CDCl3) δ 170.95, 143.41, 142.53, 139.38,

111

136.44, 129.44, 128.28, 127.74, 127.13, 126.21, 117.06, 61.42, 54.51, 39.26,

21.41, 13.73.

O Preparation of ethyl 3-cyclopentenyl-2- OEt (tosylamino)propanoate (3b). Prepared according to the NHTs above described general procedure by using methylenecyclopentane (41 mg,

0.50 mmol), ethyl-2-tosyl iminoacetate (255.2 mg, 1 mmol), and diethyl phosphate (77 mg, 0.50 mmol) to provide pure product as a white solid in 91 % yield (flash chromatography, EtOAc : hexanes 30 : 70). 1H NMR (300.1 MHz,

CDCl3) δ 7.71 (d, J=8.27 Hz, 2H, ArH), 7.27 (d, J=8.42 Hz, 2H, ArH), 5.42 (s, 1H,

C=CH), 5.13 (d, J=8.93 Hz, 1H, NH), 4.02 (m, 1H, CH(NH)), 3.93 (q, J=7.14 Hz,

2H, -OCH2CH3), 2.48 (d, J=6.48 Hz, 2H, -CH2-), 2.40 (s, 3H, ArCH3), 2.11 (m,

13 2H, -CH2-), 1.78 (m, 2H, -CH2-), 1.11 (t, J=7.16 Hz, 3H, -OCH2CH3); C NMR

(125.8 MHz, CDCl3) δ 171.44, 143.65, 143.49, 137.97, 136.83, 129.47, 129.25,

129.01, 127.22, 61.44, 54.45, 34.98, 34.55, 32.34, 23.37, 21.43, 13.85.

O Preparation of ethyl 3-cyclohexenyl-2- OEt (tosylamino)propanoate (3c). Prepared according to the NHTs above described general procedure by using methylenecyclohexane (48 mg,

0.50 mmol), ethyl-2-tosyl iminoacetate (255.2 mg, 1 mmol), and diethyl

phosphate (77 mg, 0.50 mmol) to provide pure product as a white solid in 45%

yield (flash chromatography: EtOAc : hexanes 30 : 70). 1H NMR (300.1 MHz,

CDCl3) δ 7.73 (d, J=8.24 Hz, 2H, ArH), 7.28 (d, J=8.55 Hz, 2H, ArH), 5.43 (s, 1H,

112

C=CH), 4.94 (d, J=8.83 Hz, 1H, NH), 3.98 (m, 1H, CH(NH)), 3.95 (q, J=7.14 Hz,

2H, -OCH2CH3), 2.41 (s, 3H, ArCH3), 2.28 (t, J=6.36 Hz, 2H, -CH2-), 1.94 (bs,

2H, -CH2-), 1.80 (m, 2H, -CH2-), 1.50 (m, 4H, -CH2-), 1.12 (t, J=7.10 Hz, 3H, -

13 OCH2CH3); C NMR (125.8 MHz, CDCl3) δ 171.70, 131.85, 129.54, 127.31,

126.60, 113.97, 61.39, 54.34, 42.07, 27.80, 25.25, 22.60, 21.97, 13.96.

O Preparation of ethyl 3-cyclohexenyl-2-

OEt (tosylamino)butanoate (3d). Prepared according to the NHTs above described general procedure by using

ethylidenecyclohexane (55 mg, 0.50 mmol), ethyl-2-tosyl iminoacetate (255.2

mg, 1 mmol), and diethyl phosphate (77 mg, 0.50 mmol) to provide a white solid

in 39% yield (flash chromatography: EtOAc : hexanes 30 : 70). The product was

1 a mixture of diastereomers in a 5:1 ratio. Major: H NMR (300.1 MHz, CDCl3) δ

7.69 (d, J=8.26 Hz, 2H, ArH), 7.25 (d, J=7.63 Hz, 2H, ArH), 5.39 (s, 1H, C=CH),

5.02 (d, J=10.29 Hz, 1H, NH), 3.77 (q, J=7.16 Hz, 2H, -OCH2CH3), 2.39 (s, 3H,

ArCH3), 2.29 (m, 1H, CH(NH)), 1.89 (m, 4H, -CH2-), 1.57 (m, 1H, -CH-), 1.48 (m,

4H, -CH2-), 1.07 (d, J=7.00 Hz, 3H, -CH3), 1.04 (t, J=7.16 Hz, 3H, -OCH2CH3);

13 C NMR (125.8 MHz, CDCl3) δ 171.47, 143.48, 136.78, 136.57, 129.42, 127.33,

125.36, 61.04, 59.45, 45.31, 25.19, 24.99, 22.64, 22.22, 21.43, 14.75, 13.88.

1 Minor: H NMR (300.1 MHz, CDCl3) δ 7.70 (d, J=7.60 Hz, 2H, ArH), 7.27 (d,

J=7.70 Hz, 2H, ArH), 5.46 (s, 1H, C=CH), 4.90 (d, J=8.13 Hz, 1H, NH), 3.91 (q,

J=7.16 Hz, 2H, -OCH2CH3), 2.40 (s, 3H, ArCH3), 2.29 (m, 1H, CH(NH)), 1.89 (m,

4H, -CH2-), 1.57 (m, 1H, -CH-), 1.48 (m, 4H, -CH2-), 1.12 (t, J=7.16 Hz, 2H, -

113

13 OCH2CH3), 1.00 (d, J=7.03 Hz, 2H, -CH3); C NMR (125.8 MHz, CDCl3) δ

171.28, 143.42, 136.62, 136.55, 129.45, 127.33, 124.53, 61.20, 58.68, 44.18,

25.24, 25.15, 22.60, 22.22, 21.45, 15.76, 13.91.

Preparation of ethyl 4-ethyl-2-(tosylamino)hex-4-enoate O

OEt (3e). Prepared according to the above described general NHTs procedure by using 3-methylenepentane (42 mg, 0.50

mmol), ethyl-2-tosyl iminoacetate (255.2 mg, 1 mmol), and diethyl phosphate (77 mg, 0.50 mmol) to provide pure product as a clear oil in 25% yield (flash

1 chromatography: EtOAc : hexanes 30 : 70). Major: H NMR (300.1 MHz, CDCl3)

δ 7.70 (d, J=8.31 Hz, 2H, ArH), 7.27 (d, J=7.46 Hz, 2H, ArH), 5.16 (q, J=6.75 Hz,

1H, C=CH), 4.98 (d, J=8.90 Hz, 1H, NH), 3.95 (m, 1H, CH(NH)), 3.91 (q, J=7.12

Hz, 2H, -OCH2CH3), 2.40 (s, 3H, ArCH3), 2.32 (dd, J=13.18, 6.52 Hz, 2H, -CH2-),

1.90 (m, 2H, -CH2CH3), 1.53 (d, J=6.70 Hz, 3H, CH3C=C), 1.11 (t, J=7.15 Hz, 3H,

13 -OCH2CH3), 0.89 (t, J=7.60 Hz, 3H, -CH2CH3); C NMR (125.8 MHz, CDCl3) δ

171.64, 143.48, 136.88, 135.67, 129.47, 127.28, 123.59, 61.32, 54.57, 40.26,

1 21.93, 21.47, 13.90, 13.08, 12.36. Minor: H NMR (300.1 MHz, CDCl3) δ 7.70 (d,

J=8.31Hz, 2H, ArH), 7.27 (d, J=7.46 Hz, 2H, ArH), 5.34 (q, J=6.84 Hz, 1H,

C=CH), 5.04 (d, J=9.45 Hz, 1H, NH), 3.95 (m, 1H, CH(NH)), 3.91 (q, J= 7.12 Hz,

2H, -OCH2CH3), 2.40 (s, 3H, ArCH3), 2.36 (dd, J=13.18, 6.52 Hz, 1H, -CH2-),

1.90 (m, 2H, -CH2CH3), 1.53 (d, J=6.66 Hz, 3H, CH3C=C), 1.10 (t, J=7.15 Hz, 3H,

13 -OCH2CH3), 0.92 (t, J=7.42 Hz, 3H, -CH2CH3); C NMR (125.8 MHz, CDCl3) δ

114

171.74, 143.52, 136.83, 135.26, 129.47, 127.28, 122.08, 61.48, 54.51, 40.26,

33.63, 29.04, 13.86, 13.45, 12.38.

Titration Data

Titration of tosyl imino ester (2) and diethyl phosphate. A starting solution of

10 mM diethyl phosphate and 154.17 mM imine was titrated into a NMR tube containing 10 mM diethyl phosphate in d-CH2Cl2. The first 25 μL were added in 5

μL increments. The next three additions included one 10 μL aliquot and two 20

μL aliquots, bringing the total volume added to 75 μL and the total concentration

of imine 2 to 57.8 mM. The last two additions were made at 75 μL and 150 μL. A

1H NMR was taken after each addition. The change in the shift of the OH peak of diethyl phosphate was monitored and plotted versus the ration of the concentrations of imine 2 to diethyl phosphate.

0.6

0.5

0.4

0.3 S p 0.2 Delta ( hift pm) 0.1

0 01234567 [imine]: [diethyl phosphate]

115

Titration of diethyl phosphate into d-CH2Cl2. A 153.34 mM solution of diethyl

phosphate was titrated into d-CH2Cl2. The first 55 μL were added in 5 μL increments. Then 20 μL was added bringing the total volume added to 75 μL.

Next, 75 μL was added incrementally until the total volume added reached 300

μL and the final concentration of the diethyl phosphate was 57.5 mM. The

change in the shift of the OH peak of the diethyl phosphate was monitored and

plotted versus the concentration of the diethyl phosphate.

116

0.8

0.7

0.6

0.5

0.4

0.3 Delta Shift (ppm) (ppm) Delta Shift 0.2

0.1

0 0.025 0.03 0.035 0.04 0.045 0.05 0.055 0.06 0.065 [diethyl phosphate] (M)

117

Kinetics study of tosyl imine (2) and diethyl phosphate. A solution of diethyl phosphate and imine 2 in a 1 : 1 ratio (each 10 mM) was prepared and 1H NMR spectra was taken every 30 minutes over a 5 hour time period. The changes in the integration of the imine peak (8.17 ppm) and the aldehyde peak (9.35 ppm) were monitored and plotted against time.

118

3.5.3 Hydrazone data

Synthesis of intramolecular hydrazone substrates.

General Procedure: The following procedure is adapted from the literature.16 A solution of hydrazine (1 equivalent, 0.5 M) in DMF was added to a solution of aldehyde (1 equivalent, 0.5 M) in DMF. The reaction was stirred at room

temperature overnight. The reaction mixture was diluted with ethyl acetate and

quenched with water. After an extraction with ethyl acetate, the combined

organic layers were washed with water and brine. The organic layer was dried

with Na2SO4 and concentrated in vacuo. The resulting hydrazone was purified

via column chromatography to afford the hydrazone as a yellow solid.

Synthesis of compound 86. This was prepared O2N O according to the above described general procedure

HN N using citronellal (1 g, 6.48 mmol) and 4-nitrobenzoyl H hydrazine (1.17g, 6.48 mmol) to provide the crude

product as a yellow solid. After column

chromatography (eluent 50/50 ethyl acetate/ hexanes), a light yellow solid

resulted. In lieu of column chromatography, a wash of the crude solid with

diethyl ether results in pure hydrazone (50% yield). 1H NMR (500.1 MHz,

DMSO) δ 11.74 (s, 1H, NH), 8.38 (d, J=8.26 Hz, 2H, ArH), 8.13 (d, J=8.34 Hz,

2H, ArH), 7.81 (t, J=5.60 Hz, 1H, N=CH), 5.13 (t, J=6.08 Hz, 1H, C=CH), 2.32

(m, 1H, -CH2-), 2.18 (m, 1H, -CH2-), 2.02 (m, 2H, -CH2-), 1.76 (m, 1H, CH), 1.69

(s, 3H, CH3), 1.61 (s, 3H, CH3), 1.39 (m, 1H, -CH2-), 1.24 (m, 1H, -CH2-), 0.96 (d,

119

13 J=6.53 Hz, 3H, CH3); C NMR (125.8 MHz, DMSO) δ 160.93, 152.94, 149.05,

139.15, 130.66, 128.94, 124.26, 123.46, 36.22, 30.40, 25.40, 24.85, 19.33,

17.44.

NO2 Synthesis of compound 88. This was prepared H N N according to the above described general procedure O using 2,6-dimethylheptenal (2 g, 14.26 mmol) and 4-

nitrobenzoyl hydrazine (2.58 g, 14.26 mmol) to provide

the pure product as a yellow solid (46% yield). 1H NMR (500.1 MHz, DMSO) δ

11.71 (s, 1H, NH), 8.38 (d, J=8.76 Hz, 2H, ArH), 8.12 (d, J=8.76 Hz, 2H, ArH),

7.71 (d, J=6.02 Hz, 1H, N=CH), 5.15 (t, J=7.01 Hz, 1H, C=CH), 2.45 (m, 1H,

CH), 2.03 (m, 2H, -CH2-), 1.69 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.54 (m, 1H, -

13 CH2-), 1.44 (m, 1H, -CH2-), 1.11 (d, J=6.82 Hz, 3H, CH3); C NMR (125.8 MHz,

DMSO) δ 161.04, 157.42, 149.03, 139.21, 131.09, 128.93, 123.88, 123.45,

35.80, 34.03, 25.41, 25.00, 17.49, 17.38.

Synthesis of compound 89. This was prepared NO2 H N N according to the above described general procedure O using ethyl 2,2,6-trimethyl-hept-5-enoate (77)23 (500 mg,

3.24 mmol) and 4-nitrobenzoyl hydrazine (585 mg, 3.24 mmol) to provide the pure product as a yellow solid (58% yield). 1H NMR (500.1

MHz, DMSO) δ 11.68 (s, 1H, NH), 8.39 (d, J=8.79 Hz, 2H, ArH), 8.12 (d, J=8.80

Hz, 2H, ArH), 7.73 (s, 1H, N=CH), 5.12 (t, J=7.03 Hz, 1H, C=CH), 1.95 (m, 2H, -

120

CH2-), 1.67 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.46 (m, 2H, -CH2-), 1.13 (s, 3H,

13 CH3); C NMR (125.8 MHz, DMSO) δ 161.04, 159.96, 149.03, 139.30, 130.72,

128.92, 124.31, 123.46, 40.48, 37.57, 25.38, 24.80, 22.74, 17.43.

O2N Synthesis of compound 96. To a flask containing O K2CO3 (2.18g, 15.74 mmol), and hydrazone 86 (1.0g, N N 3.15 mmol) in acetone (32 mL) was added methyl H iodide (235.4 μL, 3.78 mmol) via syringe. The reaction mixture was heated to reflux for 3.5 hours where the color of the mixture changed from orange to yellow. The reaction was cooled to room temperature and stirred for 48 hours. The product was extracted with ethyl acetate. The organic layer was washed with brine and water, then dried over sodium sulfate. The solvent was removed in vacuo to afford to crude compound. Column chromatography was used (eluent 30:70, ethyl acetate: hexanes) to afford the pure title compound

1 as a pearly solid in a 18% yield. H NMR (300.1 MHz, CDCl3) δ 8.22 (d, J=8.88

Hz, 2H, ArH), 7.73 (d, J=8.89 Hz, 2H, ArH), 7.14 (t, J=5.56 Hz, 1H, N=CH), 5.03

(t, J=7.05 Hz, 1H, C=CH), 3.41 (s, 3H, N-CH3), 2.20 (m, 1H, -CH2-), 2.05 (m, 1H,

-CH2-), 1.94 (m, 2H, -CH2-), 1.67 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.1-1.4 (m, 2H,

-CH2-), 0.89 (d, J=6.68 Hz, 3H, CH3).

Synthesis of pyrazolidine derivitives.

General Procedure: To a 1-dram vial containing a stir bar was added the hydrazone (0.5mmol), diethyl phosphate (0.5mmol), and CH2Cl2 (1 mL). The

121

reaction was stirred for 48 hours. The solvent was reduced in vacuo and the

residue was loaded onto a silica gel flash column and eluted with the indicated

solvent system to provide the cyclization products.

NO2 Synthesis of compound 87. Prepared according to

H the above described general procedure by using N N hydrazone 86 (159 mg, 0.50 mmol), and diethyl O phosphate (77 mg, 0.50 mmol) at 4°C for 48 hours to

provide pure product as a yellow solid in 83% yield (flash chromatography: ether

1 : hexanes 50 : 50). Major: H NMR (300.1 MHz, CDCl3) δ 8.20 (d, J= 8.80 Hz,

2H, ArH), 7.72 (d, J= 8.77 Hz, 2H, ArH), 4.32 (d, J= 14.14 Hz, 1H, NH), 3.51 (m,

1H, CH), 1.90 (m, 2H, CH2), 1.73 (m, 2H, CH2), 1.64 (s, 3H, CH3), 1.62 (s, 3H,

CH3), 1.26-1.44 (m, 4H, CH2), 0.88 (d, J= 5.84 Hz, 3H, CH3). Minor: δ 8.20 (d,

J= 8.80 Hz, 2H, ArH), 7.72 (d, J= 8.77 Hz, 2H, ArH), 3.83 (d, J= 13.38 Hz, 1H,

NH), 2.71 (m, 1H, CH), 1.90 (m, 2H, CH2), 1.73 (m, 2H, CH2), 1.68 (s, 3H, CH3),

13 1.65 (s, 3H, CH3), 1.26-1.44 (m, 4H, CH2), 1.00 (d, J= 6.60 Hz, 3H, CH3). C

NMR (125.8 MHz, CDCl3) δ 165.98, 147.90, 143.98, 128.76, 122.94, 67.59,

56.29, 50.34, 33.10, 32.94, 26.95, 25.78, 23.11, 22.19, 21.82.

A crystal structure determined that the major product contained a cis-ring junction

(see Appendix III).

122

NO2 Synthesis of compound 90. Prepared according to the

H above described general procedure by using hydrazone 88 N N (152 mg, 0.50 mmol), and diethyl phosphate (77 mg, 0.50 O mmol) at room temperature for 48 hours to provide pure

product as a yellow solid in 73% yield (flash chromatography: ether : hexanes 50

1 : 50). H NMR (300.1 MHz, CDCl3) δ 8.19 (d, J= 8.85 Hz, 2H, ArH), 7.76 (d, J=

8.78 Hz, 2H, ArH), 4.15 (bs, 1H, NH), 3.28 (m, 1H, CH), 2.55 (q, J= 8.60 Hz, 1H,

CHCH3), 1.9-2.0 (m, 1H, CH), 1.8-1.83 (m, 2H, CH2), 1.63 (s, 3H, CH3), 1.53 (s,

13 3H, CH3), 1.18-1.25 (m, 2H, CH2), 1.07 (d, J= 6.82 Hz, 3H, CH3). C NMR

(125.8 MHz, CDCl3) δ 165.58, 148.09, 143.66, 129.34, 122.88, 70.18, 65.98,

57.74, 38.61, 34.32, 26.76, 26.27, 22.50, 19.30.

Stereochemistry determined by NOESY interactions detailed below.

123

NO2 Synthesis of compound 91. Prepared according to the

H above described general procedure by using hydrazone N N 89 (159 mg, 0.50 mmol), and diethyl phosphate (77 mg, O 0.50 mmol) at room temperature for 48 hours to provide

pure product as a yellow solid in 67% yield (flash chromatography: ether :

1 hexanes 50 : 50). Major: H NMR (500.1 MHz, CDCl3) δ 8.20 (d, J= 8.62 Hz, 2H,

ArH), 7.72 (d, J= 8.49 Hz, 2H, ArH), 3.72 (d, J= 13.69 Hz, 1H, NH), 2.88 (t, J=

12.57 Hz, 1H, CH), 2.17 (td, J= 12.20, 6.32 Hz, 1H, CH), 1.9-2.0 (m, 2H, CH2),

1.72 (s, 3H, CH3), 1.6-1.7 (m, 2H, CH2), 1.51 (s, 3H, CH3), 1.16 (s, 3H, CH3),

0.96 (s, 3H, CH3). Minor: δ 8.20 (d, J= 8.62 Hz, 2H, ArH), 7.72 (d, J= 8.49 Hz,

2H, ArH), 4.10 (bs, 1H, NH), 3.31 (m, 1H, CH), 2.70 (q, J= 8.43 Hz, 1H, CH), 1.9-

2.0 (m, 2H, CH2), 1.72 (s, 3H, CH3), 1.6-1.7 (m, 2H, CH2), 1.51 (s, 3H, CH3), 1.16

13 (s, 3H, CH3), 0.99 (s, 3H, CH3). C NMR (125.8 MHz, CDCl3) δ 166.14, 148.10,

143.86, 128.95, 122.89, 74.94, 64.04, 61.93, 57.32, 44.60, 33.86, 29.70, 26.99,

23.05, 19.10.

Synthesis of intermolecular hydrazone substrates.

26 NO2 Synthesis of compound 92. A solution of ethyl glyoxylate

O (2.25 g, 11.04 mmol, in a 50% in toluene solution) in methanol HN N (22 mL) was added to a solution of p-nitrobenzoyl hydrazine (2

CO2Et g, 11.04 mmol) in of methanol (22 mL). The mixture was

heated for 5 minutes and a white solid precipitated out of solution. The solid was

isolated and washed with methanol to afford the title compound as a white solid

124

in an 85% yield. 1H NMR (300.1 MHz, DMSO) δ 12.45 (s, 1H, NH), 8.40 (d,

J=8.76 Hz, 2H, ArH), 8.15 (d, J=8.48 Hz, 2H, ArH), 7.83 (s, 1H, N=CH), 4.30 (q,

J=7.09 Hz, 2H, -OCH2CH3), 1.32 (t, J=7.08 Hz, 3H, -OCH2CH3).

Synthesis of compound 93. To a solution of benzoyl hydrazine O Ph

HN (5 g, 36.7 mmol) in ethanol (50 mL) was added ethyl glyoxylate N

CO2Et (7.5 g, 36.7 mmol, in a 50% toluene solution). The reaction

mixture was heated to reflux for 2 hours. The mixture was cooled and the solvent was removed in vacuo to afford the pure title compound as a white solid in a 94% yield. (E/Z = 15:1) 1H NMR (300.1 MHz, DMSO) δ 12.33 (s,

1H, NH), 7.93 (d, J=7.44 Hz, 2H, ArH), 7.83 (s, 1H, N=CH), 7.60 (d, J=7.63 Hz,

2H, ArH), 4.29 (q, J=7.09 Hz, 2H, -OCH2CH3), 1.31 (t, J=7.12 Hz, 3H, -

OCH2CH3).

Br Synthesis of compound 94. To a solution of p-bromobenzoyl

O hydrazine (3.95 g, 18.35 mmol) in ethanol (25 mL) was added HN N ethyl glyoxylate (3.75 g, 18.35 mmol, in a 50% toluene solution). CO Et 2 The reaction mixture was heated to reflux for 2 hours. The

mixture was cooled and the solvent was removed in vacuo to afford the pure title

compound as a white solid in a 94% yield. 1H NMR (300.1 MHz, DMSO) δ 12.37

(s, 1H, NH), 7.82 (m, 5H, ArH, N=CH), 4.28 (q, J=6.92 Hz, 2H, -OCH2CH3), 1.31

(t, J=7.01 Hz, 3H, -OCH2CH3).

125

O Ph Synthesis of compound 95. To a solution of benzoyl hydrazine

HN N (2.5 g, 18.35 mmol) in ethanol (25 mL) was added pivaldehyde (1.58

g, 18.35 mmol). The reaction mixture was heated to reflux for 2.5

hours. The mixture was cooled and the solvent was removed in vacuo to afford

1 the pure title compound as a white solid. H NMR (300.1 MHz, CDCl3) δ 7.80

(bs, 1H, N=CH), 7.49 (m, 5H, ArH), 1.18 (s, 9H, CH3).

3.6.0 REFERENCES

1. Clarke, M. L.; France, M. B., The carbonyl-ene reaction. Tetrahedron 2008, 64, 9003-9031. 2. Dias, L. C., Chiral Lewis acid catalyzed ene-reactions. Current Organic Chemistry 2000, 4, (3), 305-342. 3. Mikami, K.; Shimizu, M., Asymmetric Ene Reactions in Organic-Synthesis. Chemical Reviews 1992, 92, (5), 1021-1050. 4. Joly, G. D.; Jacobsen, E. N., Thiourea-Catalyzed Enantioselective Hydrophosphonylation of Imines: Practical Access to Enantiomerically Enriched alpha-Amino Phosphonic Acids. Journal of the American Chemical Society 2004, 126, (13), 4102-4103. 5. Sigman, M. S.; Vachal, P.; Jacobsen, E. N., A general catalyst for the asymmetric Strecker reaction. Angewandte Chemie-International Edition 2000, 39, (7), 1279-1281. 6. Corey, E. J.; Grogan, M. J., Enantioselective Synthesis of alpha-amino nitriles from N-benzhydryl imines and HCN with a chiral Bicyclic Guanidine as Catalyst. Organic Letters 1999, 1, (1), 157-160. 7. Alcazar, V.; Moran, J. R.; de Mendoza, J., Guanidinium catalyzed conjugate addition of pyrrolidine to unsaturated lactones. Tetrahedron Letters 1995, 36, (22), 3941-3944. 8. Ma, D.; Cheng, K., Enantioselective synthesis of functionalized alpha- amino acids via a chiral guanidine catalyzed Michael addition reaction. Tetrahedron: Asymmetry 1999, 10, (4), 713-719. 9. Kang, Q.; Zhao, Z. A.; You, S. L., Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. Journal of the American Chemical Society 2007, 129, (6), 1484-+. 10. Terada, M., Binaphthol-derived phosphoric acid as a versatile catalyst for enantioselective carbon-carbon bond forming reactions. Chemical Communications (Cambridge) 2008, (35), 4097-4112.

126

11. Yamanaka, M.; Nishida, A.; Nakagawa, M., Ytterbium(III) triflate/TMSCI: Efficient catalyst for imino ene reaction. Organic Letters 2000, 2, (2), 159-161. 12. Drury, W. J.; Ferraris, D.; Cox, C.; Young, B.; Lectka, T., A novel synthesis of alpha-amino acid derivatives through catalytic, enantioselective ene reactions of alpha-imino esters. Journal of the American Chemical Society 1998, 120, (42), 11006-11007. 13. Vachal, P.; Jacobsen, E. N., Structure-based analysis and optimization of a highly enantioselective catalyst for the Strecker reaction. Journal of the American Chemical Society 2002, 124, (34), 10012-10014. 14. Chu, F.; Flatt, L. S.; Anslyn, E. V., Complexation of Phosphoric Acid Diesters with Polyaza-Clefts in Chloroform: Effects of Phosphodiester Dimerization, Changing Cavity Size, and Preorganizing Amine Recognition Units. Journal of the American Chemical Society 1994, 116, (10), 4194-4204. 15. DeFord, J.; Chu, F.; Anslyn, E. V., Dimerization constants for phosphoric acid diesters. Tetrahedron Letters 1996, 37, (12), 1925-1928. 16. Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J., Asymmetric Intramolecular [3+2] Cycloaddition Reactions of Acylhydrazones/Olefins Using a Chiral Zirconium Catalyst. Journal of the Americ an Chemical Society 2002, 124, (46), 13678-13679. 17. Shurig, J. E.; Brandner, W. T.; Huflutalen, J. B.; Doyle, G. J.; Gylys, J. A., Cispla tin. Academic Press: New York, 1980; p 227. 18. Armarego, W. L. F.; Kobayashi, T., Quinazolines. XIV. Absolute configurations of cis- and trans-(+) and (-)-decahydroquinazolines and 2-amino- octahydroquinazolines. Journal of the Chemical Society 1970, (11), 1597-1600. 19. Yamashita, Y.; Kobayashi, S., Zirconium-Catalyzed Enantioselective [3+2] Cycloaddition of Hydrazones to Olefins Leading to Optically Active Pyrazolidine, Pyrazoline, and 1,3-Diamine Derivatives. Journal of the American Chemical Society 2004, 126, (36), 11279-11282. 20. Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura, K., Reactions of aldehydes with hydrazine hydrochlorides in the presence of dipolarophiles; intra- and intermolecular [3+ + 2] cycloadditions. Journal of Organic Chemistry 1987, 52, (11), 2277-2285. 21. Connors, K. A., Binding Constants: The Measurement of Molecular Complex Stability. 1st ed.; Wiley-Interscience: New York, 1987; p 411. 22. Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.; Yamashita, Y., Lewis acid-mediated [3+2] cycloaddition between hydrazones and olefins. Tetrahedron Letters 2003, 44, (16), 3351-3354. 23. Trost, B. M.; Toste, F. D., Mechanistic Dichotomy in CpRu(CH3CN)3PF6 Catalyzed Enyne Cycloisomerizations. Journal of the American Chemical Society 2002, 124, (18), 5025-5036. 24. Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N., Enantioselective catalytic carbonyl-ene cyclization reactions. Angewandte Chemie-International Edition 2008, 47, (8), 1469-1472. 25. Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T., C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Catalytic

127

Enantioselective Carbonyl-Ene Reactions with Glyoxylate and Pyruvate Esters. Journal of the American Chemical Society 2000, 122, (33), 7936-7943. 26. Oh, L. M.; Wang, H.; Shilcrat, S. C.; Herrmann, R. E.; Patience, D. B.; Spoors, P. G.; Sisko, J., Development of a Scalable Synthesis of GSK183390A, a PPAR alpha/gamma Agonist. Organic Process Research and Development 2007, 11, (6), 1032-1042.

128

Appendix I

The allenyl-imino ene reactivity of the allenes and imines shown below were

examined by screening several Lewis acids. The general procedure is as follows:

To a 1-dram vial containing a stir bar was added the imine (~1mmol), the Lewis acid

(~0.5mmol), and CH2Cl2 (~2 mL) at -78˚C. This solution was stirred for ~10 minutes and then the allene (~1mmol) was added. The reaction was allowed to stir for an

hour and then was checked by GC and TLC methods. If no reaction was observed

the vial was warmed to 0˚C. The reaction mixture was then stirred for 1-2 hours,

after which it was checked by TLC and GC methods. If no reaction was observed,

the reaction mixture was warmed to room temperature, stirred for one hour, and then

analyzed by using TLC and GC methods. If no reaction was observed, the mixture

was allowed to stir overnight and then checked in the morning by TLC and GC

methods. When a potential reaction took place, the solvent was reduced in vacuo

and the residue was loaded onto a silica gel prep plate and eluted with a solvent system to provide potential products. An attempted characterization of these compounds was done by 1H NMR, however, except in the cases discussed in chapter 2, full characterization was not completed.

129 Table I. Screening of Lewis acids for allenyl imino-ene reaction

O SiMe Ph Ph 2 Ts Ts Ph N N N OEt Ph Ph O 28 29 30 31 32 33

Allene Imine Lewis acid Reaction observeda

28 31 MgBr2 no

28 31 Yb(OTf)3 no

28 31 Cu(OAc)2 no

28 32 AlCl3 yes

28 32 ZnBr2 yes

28 32 Yb(OTf)3 no

28 32 Mg(OTf)2 yes

28 32 Hf(OTf)4 yes

29 33 TMSOTf no

29 33 Yb(OTf)3 no

29 33 MgBr2•OEt2 yes

29 33 BiBr2 no

29 33 Sc(OTf)2 no

30 32 SnCl4 no

30 32 AlCl3 yes

30 32 MgBr2 no

30 32 Cu(OTf)2 no

30 32 BF3•OEt2 no

130

30 33 ZnCl no 2 30 33 ZnBr2 no

30 33 Cu(OTf) no 2 30 33 Zn(OTf)2 no

30 33 Mg(OTf)2 no

30 33 Mg Br2•OEt2 yes

30 33 In(OTf)3 no a Only reactions observed that did not include hydrolysis of the imine or decomposition of the allene were recorded.

131 Appendix II

Dilution titrations of diethyl phosphate. A 0.2 M solution of diethyl phosphate

was diluted by d-CH2Cl2. The first 20 μL were added in 5 μL increments. Then 10

μL was added followed by 20 μL, bringing the total volume added to 50 μL. Next,

25 μL was added incrementally until the total volume added reached 100 μL.

Then 50 μL was added to increase the total volume added to 200 μL. Finally 100

μL increments were added until the total volume was equal to 500 μL and the

final concentration of the diethyl phosphate was 0.1M. A 31P NMR was taken

after each addition. The change in the shift of the phosphorus peak

(O=P(OEt)2OH) of the diethyl phosphate was monitored and plotted versus the concentration of the diethyl phosphate.

Then a 100 μL aliquot was taken from the 0.1M solution and diluted to 500 μL total, giving a 0.02M solution. This solution was diluted in the same increments as listed above for the 0.2M solution so that the total volume added equaled 500

μL and the concentration was equal to 0.01M.

132

Titration of hydrazone 86 into diethyl phosphate. A starting solution of 0.2 M diethyl phosphate and 99.7 mM hydrazone was titrated into a NMR tube containing 0.2 M diethyl phosphate in d-CH2Cl2. The first 10 μL were added in 5

μL increments. The next six additions were three 10 μL aliquots and three 20 μL aliquots, bringing the total volume added to 100 μL and the total concentration of hydrazone 86 to 0.17 M. Next, two 50μL increments were added followed by three 100 μL increments to bring the total volume added to 500 μL. A 31P NMR was taken after each addition. The change in the shift of the phosphorus peak of diethyl phosphate (O=P(OEt)2OH) was monitored and plotted versus the ratio of the concentrations of hydrazone 86 to diethyl phosphate.

133

Titration of Titration of hydrazone 86 into diethyl phosphate. A starting

solution of 0.02 M diethyl phosphate and 204 mM hydrazone was titrated into a

NMR tube containing 0.02 M diethyl phosphate in d-CH2Cl2. The first 10 μL were

added in 5 μL increments. The next six additions were three 10 μL aliquots and

three 20 μL aliquots, bringing the total volume added to 100 μL and the total

concentration of hydrazone 86 to 0.034 M. Next, two 50μL increments were

added followed by three 100 μL increments to bring the total volume added to

500 μL. A 31P NMR was taken after each addition. The change in the shift of the

phosphorus peak of diethyl phosphate (O=P(OEt)2OH) was monitored and

plotted versus the ratio of the concentrations of hydrazone 86 to diethyl

phosphate.

Job plot of hydrazone 86 and diethyl phosphate. A 0.200M stock solution of hydrazone 86 and a 0.0992M stock solution of diethyl phosphate were used to prepare a series of solutions of hydrazone and diethyl phosphate so that the sum of the total catalyst and substrate concentrations were kept constant, as the mol

134 fraction of each varied in 0.1 increments. A 1H NMR was taken of each solution and (the Δδ of the –OH proton)* mole fraction of the diethyl phosphate was plotted against the mole fraction of the hydrazone.

135

Appendix III

Figure AIII.1 Crystal structure of 87 (C17H23N3O3).

Experimental. Pale yellow single crystals of C17H23N3O3 are, at 193(2) K, monoclinic,

5 space group P21/n ( an alternate setting of P21/c – C 2h (No. 14)) with a = 8.091(1) Å, b =

11.382(2) Å, c = 36.319(6) Å, β = 95.861(2)°, V = 3327.3(10) Å3, and Z = 8 {dcalcd =

-3 -1 1.267gcm ; μa(MoKα ) = 0.088 mm }. A full hemisphere of diffracted intensities (1968

30-second frames with an ω scan width of 0.30°) was measured for a single-domain

specimen using graphite-monochromated MoKα radiation (λ= 0.71073 Å) on a Bruker

SMART APEX CCD Single Crystal Diffraction System. X-rays were provided by a fine-

focus sealed x-ray tube operated at 50kV and 30mA.

Lattice constants were determined with the Bruker SAINT software package

using peak centers for 3918 reflections having 7.65˚ ≤ 2θ ≤ 45.28˚. A total of 25875

136 integrated reflection intensities having 2θ((MoKα )≤ 51.00° were produced using the

Bruker program SAINT; 6151 of these were unique and gave Rint = 0.060 with a

coverage which was 99.5% complete. The data were corrected empirically for variable absorption effects using the SADABS program; the range of minimum and maximum transmission values was 0.6073 to 0.7460 .

The Bruker software package SHELXTL was used to solve the structure using

“direct methods” techniques. All stages of weighted full-matrix least-squares refinement

2 were conducted using Fo data with the SHELXTL software package. The resulting structural parameters have been refined to convergence {R1 (unweighted, based on F) =

o 2 2 0.0605 for 4508 independent reflections having 2Θ(MoKα ) < 51.00 and F >2σ(F )} {R1

2 (unweighted, based on F) = 0.0850 and wR2 (weighted, based on F ) = 0.1612 for all 6151

reflections} using counter-weighted full-matrix least-squares techniques and a structural

model which incorporated anisotropic thermal parameters for all nonhydrogen atoms.

Hydrogen atoms bonded to nitrogen were located from a difference Fourier map and

included in the structural model as individual isotropic atoms whose parameters were

allowed to vary in least-squares refinement cycles. The remaining hydrogen atoms were

included in the structural model as fixed atoms (using idealized sp2- or sp3- hybridized

geometry and C-H bond lengths of 0.95 – 1.00Å) "riding" on their respective carbon atoms.

The isotropic thermal parameters for hydrogen atoms H2NA and H2N B refined to final values

2 of 0.025(6) and 0.033(7) Å , respectively. The isotropic thermal parameters for the

remaining hydrogen atoms were fixed at a value 1.2 (nonmethyl) or 1.5 (methyl) times the

equivalent isotropic thermal parameter of the carbon atom to which they are covalently bonded. A total of 429 parameters were refined using no restraints and 6151 data.

137 The largest shift/s.u. was 0.000 in the final refinement cycle. The final difference map

3 had maxima and minima of 0.516 and -0.222 e-/Å , respectively.

Table AIII.1. Crystal data and structure refinement for C17H23N3O3

Empirical formula C17 H23 N3 O3 Formula weight 317.38 Temperature 193(2) K Wavelength 0.71073 Å Crystal system Monoclinic 5 Space group P2(1)/n (an alternate setting of P21/c – C 2h (No. 14)) Unit cell dimensions a = 8.091(1) Å b = 11.382(2) Å, β = 95.861(2)° c = 36.319(6) Å Volume 3327.3(10) Å3 Z 8 Density (calculated) 1.267 g/cm3 Absorption coefficient 0.088 mm-1 F(000) 1360 Crystal size 0.45 x 0.10 x 0.07 mm3 Theta range for data collection 3.83 to 25.50° Index ranges -9≤h≤9, -13≤k≤13, -43≤l≤42 Reflections collected 25875 Independent reflections 6151 [R(int) = 0.0605] Completeness to theta = 25.50° 99.5 % Absorption correction Multi-scan (SADABS) Max. and min. transmission 0.9939 and 0.9615 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6151 / 0 / 429 Goodness-of-fit on F2 1.054

Final R indices [4508 I>2σ(I) data] R1 = 0.0605, wR2 = 0.1480

R indices (all data) R1 = 0.0850, wR2 = 0.1612 Largest diff. peak and hole 0.516 and -0.222e-/Å3

138 Table AIII.2 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for C17H23N3O3 . U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______Molecule A O(1A) 2434(2) -639(1) 1080(1) 41(1) O(2A) 7010(4) -2882(2) 2724(1) 96(1) O(3A) 6949(4) -4209(2) 2305(1) 86(1) N(1A) 3880(2) 970(2) 1264(1) 31(1) N(2A) 5055(3) 1574(2) 1520(1) 36(1) N(3A) 6651(3) -3226(2) 2411(1) 58(1) C(1A) 3461(3) -157(2) 1307(1) 32(1) C(2A) 4643(3) 2823(2) 1444(1) 38(1) C(3A) 4216(3) 2852(2) 1023(1) 35(1) C(4A) 3123(3) 1746(2) 957(1) 34(1) C(5A) 4292(3) -881(2) 1624(1) 31(1) C(6A) 4310(4) -2085(2) 1559(1) 47(1) C(7A) 5058(4) -2849(2) 1817(1) 52(1) C(8A) 5770(3) -2407(2) 2144(1) 42(1) C(9A) 5726(4) -1234(2) 2226(1) 48(1) C(10A) 4992(3) -469(2) 1960(1) 43(1) C(11A) 6052(4) 3642(2) 1592(1) 48(1) C(12A) 7539(3) 3630(2) 1375(1) 47(1) C(13A) 6987(4) 3811(2) 967(1) 49(1) C(14A) 5757(3) 2869(2) 821(1) 44(1) C(15A) 8793(4) 4567(3) 1527(1) 70(1) C(16A) 3212(3) 1190(2) 576(1) 43(1) C(17A) 1318(3) 2001(2) 1016(1) 49(1) Molecule B O(1B) 7534(2) 19(2) 1230(1) 48(1) O(2B) 12588(3) -2280(2) 2809(1) 76(1) O(3B) 12406(3) -419(2) 2880(1) 80(1) N(1B) 8740(2) -1541(2) 986(1) 34(1)

139 N(2B) 9947(3) -2468(2) 1019(1) 35(1) N(3B) 12125(3) -1308(3) 2699(1) 57(1) C(1B) 8507(3) -823(2) 1270(1) 37(1) C(2B) 9427(3) -3218(2) 700(1) 35(1) C(3B) 8810(3) -2346(2) 392(1) 33(1) C(4B) 7857(3) -1435(2) 604(1) 35(1) C(5B) 9481(3) -1020(2) 1640(1) 37(1) C(6B) 10021(3) -21(2) 1837(1) 43(1) C(7B) 10889(3) -111(2) 2182(1) 45(1) C(8B) 11178(3) -1210(2) 2333(1) 44(1) C(9B) 10627(4) -2215(2) 2150(1) 49(1) C(10B) 9781(4) -2113(2) 1802(1) 45(1) C(11B) 10765(3) -4068(2) 607(1) 40(1) C(12B) 12141(3) -3528(2) 402(1) 40(1) C(13B) 11374(3) -2797(2) 78(1) 41(1) C(14B) 10264(3) -1843(2) 209(1) 36(1) C(15B) 13300(4) -4476(3) 276(1) 56(1) C(16B) 7934(3) -191(2) 451(1) 42(1) C(17B) 6041(3) -1809(3) 611(1) 48(1) ______a The numbers in parentheses are the estimated standard deviations in the last significant digit. b Atoms are labeled in agreement with Figures 1 and 2. c U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

140 Table AIII.3 Bond lengths [Å] and angles [°] for C17H23N3O3 ______Molecule A Molecule B O(1A)-C(1A) 1.238(3) O(1B)-C(1B) 1.239(3)

O(2A)-N(3A) 1.209(3) O(2B)-N(3B) 1.222(3) O(3A)-N(3A) 1.216(3) O(3B)-N(3B) 1.216(3)

N(1A)-C(1A) 1.340(3) N(1B)-C(1B) 1.346(3)

N(3A)-C(8A) 1.475(3) N(3B)-C(8B) 1.468(4)

N(1A)-N(2A) 1.436(3) N(1B)-N(2B) 1.434(3)

N(1A)-C(4A) 1.503(3) N(1B)-C(4B) 1.498(3) N(2A)-C(2A) 1.480(3) N(2B)-C(2B) 1.466(3)

N(2A)-H(2NA) 0.89(2) N(2B)-H(2NB) 0.89(3)

C(1A)-C(5A) 1.516(3) C(1B)-C(5B) 1.503(4)

C(2A)-C(11A) 1.527(4) C(2B)-C(11B) 1.515(3) C(2A)-C(3A) 1.532(3) C(2B)-C(3B) 1.539(3) C(3A)-C(14A) 1.509(4) C(3B)-C(14B) 1.522(3) C(3A)-C(4A) 1.543(3) C(3B)-C(4B) 1.544(3) C(4A)-C(17A) 1.526(3) C(4B)-C(16B) 1.524(3) C(4A)-C(16A) 1.527(4) C(4B)-C(17B) 1.532(3) C(11A)-C(12A) 1.503(4) C(11B)-C(12B) 1.529(4) C(12A)-C(13A) 1.516(4) C(12B)-C(13B) 1.520(4) C(12A)-C(15A) 1.536(4) C(12B)-C(15B) 1.529(4) C(13A)-C(14A) 1.521(4) C(13B)-C(14B) 1.516(3)

C(5A)-C(10A) 1.376(3) C(8A)-C(9A) 1.369(4) C(5A)-C(6A) 1.390(3) C(5B)-C(10B) 1.387(4) C(6A)-C(7A) 1.373(4) C(5B)-C(6B) 1.390(4) C(7A)-C(8A) 1.364(4) C(6B)-C(7B) 1.377(4)

141 C(7B)-C(8B) 1.376(4) C(8B)-C(9B) 1.375(4) C(9A)-C(10A) 1.387(4) C(9B)-C(10B) 1.379(4)

C(1A)-N(1A)-N(2A) 122.76(19) C(1B)-N(1B)-N(2B) 122.0(2) C(1A)-N(1A)-C(4A) 124.11(19) C(1B)-N(1B)-C(4B) 124.8(2) N(2A)-N(1A)-C(4A) 113.06(17) N(2B)-N(1B)-C(4B) 113.16(18) O(2A)-N(3A)-O(3A) 124.0(3) O(3B)-N(3B)-O(2B) 122.8(3) O(2A)-N(3A)-C(8A) 117.8(3) O(3B)-N(3B)-C(8B) 118.6(3) O(3A)-N(3A)-C(8A) 118.2(3) O(2B)-N(3B)-C(8B) 118.6(3)

N(1A)-N(2A)-C(2A) 102.52(17) N(1B)-N(2B)-C(2B) 102.97(17) N(1A)-N(2A)-H(2NA) 101.6(15) N(1B)-N(2B)-H(2NB) 106.1(16) C(2A)-N(2A)-H(2NA) 108.8(15) C(2B)-N(2B)-H(2NB) 110.4(16)

O(1A)-C(1A)-N(1A) 120.4(2) O(1B)-C(1B)-N(1B) 121.1(2) O(1A)-C(1A)-C(5A) 118.7(2) O(1B)-C(1B)-C(5B) 119.3(2) N(1A)-C(1A)-C(5A) 120.8(2) N(1B)-C(1B)-C(5B) 119.6(2) C(10A)-C(5A)-C(6A) 118.4(2) C(10B)-C(5B)-C(6B) 118.9(2) C(10A)-C(5A)-C(1A) 126.8(2) C(10B)-C(5B)-C(1B) 124.5(2) C(6A)-C(5A)-C(1A) 114.8(2) C(6B)-C(5B)-C(1B) 116.6(2) C(7A)-C(6A)-C(5A) 121.4(3) C(7B)-C(6B)-C(5B) 120.8(3) C(8A)-C(7A)-C(6A) 118.6(2) C(8B)-C(7B)-C(6B) 118.7(3) C(7A)-C(8A)-C(9A) 122.0(2) C(9B)-C(8B)-C(7B) 122.0(3) C(7A)-C(8A)-N(3A) 118.2(2) C(9B)-C(8B)-N(3B) 119.2(3) C(9A)-C(8A)-N(3A) 119.7(3) C(7B)-C(8B)-N(3B) 118.7(3) C(8A)-C(9A)-C(10A) 118.7(2) C(8B)-C(9B)-C(10B) 118.7(3) C(5A)-C(10A)-C(9A) 120.8(2) C(9B)-C(10B)-C(5B) 120.9(2)

N(2A)-C(2A)-C(11A) 112.0(2) C(17A)-C(4A)-C(16A) 109.9(2) N(2A)-C(2A)-C(3A) 103.43(19) N(2B)-C(2B)-C(11B) 113.2(2) C(11A)-C(2A)-C(3A) 115.0(2) N(2B)-C(2B)-C(3B) 104.09(18) C(14A)-C(3A)-C(2A) 111.8(2) C(11B)-C(2B)-C(3B) 115.9(2) C(14A)-C(3A)-C(4A) 115.0(2) C(14B)-C(3B)-C(2B) 110.67(19) C(2A)-C(3A)-C(4A) 101.81(18) C(14B)-C(3B)-C(4B) 114.38(19) N(1A)-C(4A)-C(17A) 109.33(19) C(2B)-C(3B)-C(4B) 102.33(18) N(1A)-C(4A)-C(16A) 111.95(19) N(1B)-C(4B)-C(16B) 112.29(19)

142 N(1B)-C(4B)-C(17B) 109.2(2) C(16B)-C(4B)-C(17B) 109.8(2) N(1A)-C(4A)-C(3A) 100.43(17) C(17A)-C(4A)-C(3A) 111.3(2) C(16A)-C(4A)-C(3A) 113.6(2) C(12A)-C(11A)-C(2A) 114.8(2) C(11A)-C(12A)-C(13A) 109.8(2) C(11A)-C(12A)-C(15A) 109.9(3) C(13A)-C(12A)-C(15A) 112.1(2) C(12A)-C(13A)-C(14A) 111.2(2) C(3A)-C(14A)-C(13A) 112.5(2) N(1B)-C(4B)-C(3B) 101.02(18) C(16B)-C(4B)-C(3B) 113.7(2) C(17B)-C(4B)-C(3B) 110.5(2) C(2B)-C(11B)-C(12B) 115.1(2) C(13B)-C(12B)-C(15B) 111.7(2) C(13B)-C(12B)-C(11B) 109.6(2) C(15B)-C(12B)-C(11B) 111.1(2) C(14B)-C(13B)-C(12B) 111.0(2) C(13B)-C(14B)-C(3B) 112.1(2)

______a The numbers in parentheses are the estimated standard deviations in the last significant digit. b Atoms are labeled in agreement with Figures 1 and 2.

143 Figure AIII.4. Anisotropic displacement parameters (Å2x 103) for C17H23N3O3 . The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ______U11 U22 U33 U23 U13 U12 ______Molecule A O(1A) 42(1) 34(1) 44(1) 1(1) -7(1) -13(1) O(2A) 137(3) 61(2) 78(2) 23(1) -50(2) -23(2) O(3A) 114(2) 52(2) 89(2) 19(1) -4(2) 33(1) N(1A) 30(1) 23(1) 37(1) 1(1) -4(1) -2(1) N(2A) 39(1) 25(1) 42(1) 3(1) -5(1) -5(1) N(3A) 58(2) 54(2) 60(2) 19(1) -11(1) -10(1) C(1A) 32(1) 27(1) 36(1) 0(1) 4(1) -5(1) C(2A) 43(1) 26(1) 47(2) 0(1) 7(1) 2(1) C(3A) 39(1) 22(1) 43(1) 6(1) -1(1) 3(1) C(4A) 33(1) 29(1) 39(1) 6(1) -2(1) 0(1) C(5A) 30(1) 28(1) 37(1) 1(1) 6(1) -4(1) C(6A) 61(2) 29(1) 47(2) 0(1) -9(1) -2(1) C(7A) 69(2) 27(1) 58(2) 1(1) -7(2) 3(1) C(8A) 43(2) 33(1) 48(2) 14(1) -2(1) -3(1) C(9A) 61(2) 42(2) 39(2) 7(1) -6(1) -15(1) C(10A) 62(2) 28(1) 39(1) 3(1) 0(1) -9(1) C(11A) 64(2) 31(1) 48(2) -6(1) -1(1) 1(1) C(12A) 43(2) 37(2) 59(2) 6(1) -2(1) -8(1) C(13A) 49(2) 39(2) 59(2) 4(1) 10(1) -5(1) C(14A) 50(2) 35(1) 47(2) 2(1) 5(1) -2(1) C(15A) 67(2) 58(2) 82(2) -1(2) -4(2) -29(2) C(16A) 48(2) 40(1) 39(1) 5(1) -8(1) -7(1) C(17A) 35(1) 43(2) 68(2) 10(1) -3(1) 4(1) Molecule B O(1B) 47(1) 48(1) 49(1) -7(1) 5(1) 11(1) O(2B) 99(2) 78(2) 51(1) 9(1) -1(1) 23(1) O(3B) 97(2) 83(2) 54(1) -17(1) -17(1) -2(1) N(1B) 33(1) 34(1) 36(1) -1(1) 2(1) -2(1) N(2B) 35(1) 29(1) 41(1) -1(1) 1(1) -4(1)

141

N(3B) 60(2) 70(2) 41(1) -5(1) 6(1) 5(1) C(1B) 36(1) 36(1) 41(1) -2(1) 8(1) -8(1) C(2B) 36(1) 30(1) 38(1) -1(1) 4(1) -9(1) C(3B) 32(1) 30(1) 35(1) -3(1) -2(1) -5(1) C(4B) 31(1) 37(1) 38(1) -3(1) 0(1) -4(1) C(5B) 36(1) 39(1) 37(1) -5(1) 12(1) -6(1) C(6B) 50(2) 36(1) 43(2) -5(1) 7(1) 2(1) C(7B) 52(2) 43(2) 42(2) -11(1) 5(1) -3(1) C(8B) 44(2) 53(2) 36(1) -3(1) 8(1) 2(1) C(9B) 66(2) 42(2) 41(2) 4(1) 11(1) -2(1) C(10B) 60(2) 36(2) 40(2) -2(1) 8(1) -11(1) C(11B) 46(2) 26(1) 48(2) 0(1) 3(1) -4(1) C(12B) 39(1) 38(1) 43(1) -3(1) 2(1) 1(1) C(13B) 43(2) 40(1) 41(1) 0(1) 9(1) 0(1) C(14B) 37(1) 34(1) 36(1) 3(1) 2(1) 0(1) C(15B) 60(2) 46(2) 63(2) 0(1) 11(2) 15(1) C(16B) 49(2) 36(1) 42(2) -1(1) 4(1) 6(1) C(17B) 33(1) 52(2) 57(2) -4(1) 3(1) -3(1) ______a The numbers in parentheses are the estimated standard deviations in the last significant digit. b 2 2 2 2 The form of the anisotropic thermal parameter is: exp[-2π2 (U11h a* + U22k b* 2 2 + U33l c* + 2U12hka*b* + 2U13hla*c* + 2U23klb*c*)]. c Atoms are labeled in agreement with Figures 1 and 2.

142

Table AIII.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) a,b for C17H23N3O3 ______x y z U(eq) ______Molecule A H(2NA)c 6010(30) 1410(20) 1430(6) 25(6) H(2A) 3625 3028 1565 46 H(3A) 3532 3566 954 42 H(6A) 3793 -2385 1332 56 H(7A) 5079 -3669 1768 63 H(9A) 6190 -948 2460 58 H(10A) 4971 349 2011 52 H(11A) 5616 4454 1594 57 H(11B) 6417 3420 1851 57 H(12A) 8083 2842 1406 56 H(13A) 7969 3788 826 58 H(13B) 6463 4594 931 58 H(14A) 5432 3009 554 53 H(14B) 6304 2092 846 53 H(15A) 8274 5344 1503 105 H(15B) 9766 4547 1387 105 H(15C) 9140 4407 1789 105 H(16A) 4346 914 556 65 H(16B) 2907 1776 384 65 H(16C) 2441 525 546 65 H(17A) 700 1261 1017 74 H(17B) 820 2503 815 74 H(17C) 1275 2404 1253 74 Molecule B H(2NB)c 10920(30) -2130(20) 992(7) 33(7) H(2B) 8451 -3691 762 42 H(3B) 8024 -2752 203 39 H(6B) 9789 734 1732 51 H(7B) 11280 572 2314 54

143

H(9B) 10825 -2965 2261 59 H(10B) 9398 -2800 1672 54 H(11C) 10233 -4709 453 48 H(11D) 11277 -4424 840 48 H(12B) 12812 -2993 577 48 H(13C) 12268 -2434 -50 49 H(13D) 10715 -3313 -100 49 H(14C) 9831 -1357 -6 43 H(14D) 10928 -1328 387 43 H(15D) 12663 -5021 108 84 H(15E) 13806 -4908 493 84 H(15F) 14174 -4107 148 84 H(16D) 7241 330 586 63 H(16E) 7525 -191 188 63 H(16F) 9086 88 482 63 H(17D) 5999 -2627 694 71 H(17E) 5458 -1737 362 71 H(17F) 5506 -1302 782 71 a Hydrogen atoms bonded to nitrogen were located from a difference Fourier map and included in the structural model as individual isotropic atoms whose parameters were allowed to vary in least-squares refinement cycles. The remaining hydrogen atoms were included in the structural model as fixed atoms (using idealized sp2- or sp3- hybridized geometry and C-H bond lengths of 0.95 – 1.00Å) "riding" on their respective carbon atoms. The isotropic

thermal parameters for hydrogen atoms H2NA and H2N B refined to final values 2 of 0.025(6) and 0.033(7) Å , respectively. The isotropic thermal parameters for the remaining hydrogen atoms were fixed at a value 1.2 (nonmethyl) or 1.5 (methyl) times the equivalent isotropic thermal parameter of the carbon atom to which they are covalently bonded.

b Hydrogen atoms are labeled with the same numerical subscript(s) as their respective oxygen, nitrogen or carbon atoms with an additional literal subscript (N) to distinguish between hydrogens bonded to nitrogen. An additional literal subscript (a-f) is used to distinguish between hydrogens bonded to carbon.

144 c The numbers in parentheses are the estimated standard deviations in the last significant digit.

Table AIII.6. Torsion angles [°] for C17H23N3O3. ______C(1A)-N(1A)-N(2A)-C(2A) -159.6(2) C(4A)-N(1A)-N(2A)-C(2A) 17.6(2) N(2A)-N(1A)-C(1A)-O(1A) 179.6(2) C(4A)-N(1A)-C(1A)-O(1A) 2.6(3) N(2A)-N(1A)-C(1A)-C(5A) -3.4(3) C(4A)-N(1A)-C(1A)-C(5A) 179.7(2) N(1A)-N(2A)-C(2A)-C(11A) -161.8(2) N(1A)-N(2A)-C(2A)-C(3A) -37.5(2) N(2A)-C(2A)-C(3A)-C(14A) -79.6(2) C(11A)-C(2A)-C(3A)-C(14A) 42.8(3) N(2A)-C(2A)-C(3A)-C(4A) 43.7(2) C(11A)-C(2A)-C(3A)-C(4A) 166.1(2) C(1A)-N(1A)-C(4A)-C(17A) 69.2(3) N(2A)-N(1A)-C(4A)-C(17A) -107.9(2) C(1A)-N(1A)-C(4A)-C(16A) -52.8(3) N(2A)-N(1A)-C(4A)-C(16A) 130.0(2) C(1A)-N(1A)-C(4A)-C(3A) -173.6(2) N(2A)-N(1A)-C(4A)-C(3A) 9.2(2) C(14A)-C(3A)-C(4A)-N(1A) 89.8(2) C(2A)-C(3A)-C(4A)-N(1A) -31.2(2) C(14A)-C(3A)-C(4A)-C(17A) -154.5(2) C(2A)-C(3A)-C(4A)-C(17A) 84.4(2) C(14A)-C(3A)-C(4A)-C(16A) -29.9(3) C(2A)-C(3A)-C(4A)-C(16A) -150.9(2) O(1A)-C(1A)-C(5A)-C(10A) -156.2(2) N(1A)-C(1A)-C(5A)-C(10A) 26.6(4) O(1A)-C(1A)-C(5A)-C(6A) 23.0(3) N(1A)-C(1A)-C(5A)-C(6A) -154.2(2) C(10A)-C(5A)-C(6A)-C(7A) -2.5(4) C(1A)-C(5A)-C(6A)-C(7A) 178.3(3)

145

C(5A)-C(6A)-C(7A)-C(8A) 1.1(4) C(6A)-C(7A)-C(8A)-C(9A) 1.5(4) C(6A)-C(7A)-C(8A)-N(3A) -176.6(3) O(2A)-N(3A)-C(8A)-C(7A) -166.6(3) O(3A)-N(3A)-C(8A)-C(7A) 12.2(4) O(2A)-N(3A)-C(8A)-C(9A) 15.2(4) O(3A)-N(3A)-C(8A)-C(9A) -166.0(3) C(7A)-C(8A)-C(9A)-C(10A) -2.6(4) N(3A)-C(8A)-C(9A)-C(10A) 175.5(2) C(6A)-C(5A)-C(10A)-C(9A) 1.3(4) C(1A)-C(5A)-C(10A)-C(9A) -179.5(2) C(8A)-C(9A)-C(10A)-C(5A) 1.2(4) N(2A)-C(2A)-C(11A)-C(12A) 73.2(3) C(3A)-C(2A)-C(11A)-C(12A) -44.5(3) C(2A)-C(11A)-C(12A)-C(13A) 51.0(3) C(2A)-C(11A)-C(12A)-C(15A) 174.7(2) C(11A)-C(12A)-C(13A)-C(14A) -58.1(3) C(15A)-C(12A)-C(13A)-C(14A) 179.6(3) C(2A)-C(3A)-C(14A)-C(13A) -50.3(3) C(4A)-C(3A)-C(14A)-C(13A) -165.8(2) C(12A)-C(13A)-C(14A)-C(3A) 59.3(3) C(1B)-N(1B)-N(2B)-C(2B) 163.0(2) C(4B)-N(1B)-N(2B)-C(2B) -19.7(2) N(2B)-N(1B)-C(1B)-O(1B) 175.3(2) C(4B)-N(1B)-C(1B)-O(1B) -1.6(4) N(2B)-N(1B)-C(1B)-C(5B) -2.7(3) C(4B)-N(1B)-C(1B)-C(5B) -179.6(2) N(1B)-N(2B)-C(2B)-C(11B) 163.41(19) N(1B)-N(2B)-C(2B)-C(3B) 36.8(2) N(2B)-C(2B)-C(3B)-C(14B) 81.7(2) C(11B)-C(2B)-C(3B)-C(14B) -43.3(3) N(2B)-C(2B)-C(3B)-C(4B) -40.6(2) C(11B)-C(2B)-C(3B)-C(4B) -165.57(19) C(1B)-N(1B)-C(4B)-C(16B) 50.2(3) N(2B)-N(1B)-C(4B)-C(16B) -126.9(2) C(1B)-N(1B)-C(4B)-C(17B) -71.9(3)

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N(2B)-N(1B)-C(4B)-C(17B) 111.0(2) C(1B)-N(1B)-C(4B)-C(3B) 171.7(2) N(2B)-N(1B)-C(4B)-C(3B) -5.5(2) C(14B)-C(3B)-C(4B)-N(1B) -92.6(2) C(2B)-C(3B)-C(4B)-N(1B) 27.1(2) C(14B)-C(3B)-C(4B)-C(16B) 27.9(3) C(2B)-C(3B)-C(4B)-C(16B) 147.6(2) C(14B)-C(3B)-C(4B)-C(17B) 151.9(2) C(2B)-C(3B)-C(4B)-C(17B) -88.4(2) O(1B)-C(1B)-C(5B)-C(10B) 139.7(3) N(1B)-C(1B)-C(5B)-C(10B) -42.3(3) O(1B)-C(1B)-C(5B)-C(6B) -36.3(3) N(1B)-C(1B)-C(5B)-C(6B) 141.7(2) C(10B)-C(5B)-C(6B)-C(7B) 2.2(4) C(1B)-C(5B)-C(6B)-C(7B) 178.4(2) C(5B)-C(6B)-C(7B)-C(8B) -1.5(4) C(6B)-C(7B)-C(8B)-C(9B) -0.1(4) C(6B)-C(7B)-C(8B)-N(3B) 179.1(2) O(3B)-N(3B)-C(8B)-C(9B) -169.9(3) O(2B)-N(3B)-C(8B)-C(9B) 9.6(4) O(3B)-N(3B)-C(8B)-C(7B) 10.9(4) O(2B)-N(3B)-C(8B)-C(7B) -169.6(3) C(7B)-C(8B)-C(9B)-C(10B) 1.0(4) N(3B)-C(8B)-C(9B)-C(10B) -178.1(2) C(8B)-C(9B)-C(10B)-C(5B) -0.3(4) C(6B)-C(5B)-C(10B)-C(9B) -1.2(4) C(1B)-C(5B)-C(10B)-C(9B) -177.2(2) N(2B)-C(2B)-C(11B)-C(12B) -77.4(3) C(3B)-C(2B)-C(11B)-C(12B) 42.8(3) C(2B)-C(11B)-C(12B)-C(13B) -48.6(3) C(2B)-C(11B)-C(12B)-C(15B) -172.6(2) C(15B)-C(12B)-C(13B)-C(14B) -178.6(2) C(11B)-C(12B)-C(13B)-C(14B) 57.8(3) C(12B)-C(13B)-C(14B)-C(3B) -61.9(3) C(2B)-C(3B)-C(14B)-C(13B) 52.5(3) C(4B)-C(3B)-C(14B)-C(13B) 167.5(2)

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Table AIII.7. Hydrogen bonds for C17H23N3O3 [Å and °]. ______D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ______N(2A)-H(2NA)...O(1B) 0.89(2) 2.18(2) 2.950(3) 145(2) N(2B)-H(2NB)...O(1A)#1 0.89(3) 2.10(3) 2.888(3) 147(2) ______Symmetry transformations used to generate equivalent atoms: #1 x+1, y, z

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SCHOLASTIC VITA

LINDSEY OLIVER DAVIS

BORN: August 13, 1984 Savannah, Georgia

UNDERGRADUATE STUDY: Berry College Rome, Georgia B. S., Chemistry, 2005

GRADUATE STUDY: Wake Forest University

SCHOLASTIC AND PROFESSIONAL EXPERIENCE: Research Assistant, Wake Forest University 2007-2009 Winston-Salem, North Carolina, USA

Teaching Assistant, Wake Forest University 2005-2007 Winston-Salem, North Carolina, USA

PUBLICATIONS: Oliver, L. H.; Puls, L. A.; Tobey, S. L. Brønsted acid promoted imino-ene reactions. Tetrahedron Letters, 2008, 49, 4636-4639. Breton, G. W.; Nickerson, J. E.; Greene, A. M.; Oliver, L. H. Thermal decomposition of meso- and d,l-3,4-diethyl-3,4-dimethyldiazetine N,N’-dioxide. Organic Letters, 2007, 9, 3005-3008.

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Breton, G. W.; Oliver, L. H.; Nickerson, J. E. Synthesis of a stereochemically defined 1,2-diazetine N,N’-dioxide and a study of its thermal decomposition. Journal of Organic Chemistry, 2007, 72, 1412-1416.

PRESENTATIONS: Oliver, L. H.; Puls, L. A.; Tobey, S. L. Brønsted acid catalyzed ene reactions. 60th Southeast Regional Meeting of the American Chemical Society, Nashville, TN, November, 2008. Oliver, L. H.; Tobey, S. L. Lewis acid promoted alkylation reactions of ketoallenes for the generation of unnatural amino acids. 60th Southeast Regional Meeting of the American Chemical Society, Nashville, TN, November, 2008. Oliver, L. H., Puls, L. A., Tobey, S. L. Methodologies for generation of unnatural amino acids. 59th Southeast Regional Meeting of the American Chemical Society, Greenville, SC, October, 2007. Oliver, L. H., Tobey, S. L. Investigations into Lewis acid promoted reaction of allenes. 40th National Organic Symposium, Durham, NC, June, 2007.

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