Development of Nucleophile Assisting Leaving Groups (Nalgs)

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DEVELOPMENT OF NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS)

AND NEW STEREOSELECTIVE REACTIONS USING TITANIUM(IV) REAGENTS

Deboprosad Mondal

A Dissertation Submitted to the Faculty of

The Charles E. Schmidt College of Science

in Partial Fulfillment of the Requirements for the Degree of

Doctor of Philosophy

Florida Atlantic University

Boca Raton, Florida

December 2010

ACKNOWLEDGEMENTS

I would like to thank my advisor, Dr. Salvatore D. Lepore, for his excellent guidance throughout my PhD. Dr. Lepore has opened for me a door to the art and science of chemical synthesis and methodology development. His talent, passion and motivation in synthesis and his kind personality have always inspired me to improve myself; I am grateful for his encouragement, patience and financial support.

I want to thank my committee professors Predrag Cudic, Stanislaw Wnuk and

Guodong Sui for their time and insightful advice on my research. I would also like to express my gratitude towards all the past and current members of the Lepore Research

Group, especially Change He, Pradip, Ravi and Songye for their help and friendship throughout my PhD. Finally, I thank Drs. Anjan Bhunia and Maximilian Silvestri for their guidance during first year of my PhD.

Now I wish to express my thanks to all my friends who have continually inspired me. I am deeply indebted to my parents, especially my father who was my ‘Guru’, my inspiration; my dada for his affection and love; maa-bapi, bhai, kaka for their unconditional love, support and inspiration. Finally, my wife Pinki, I am really proud of her for her love, inspiration and support.

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ABSTRACT

Author: Deboprosad Mondal

Title: Development of Nucleophile Assisting Leaving Groups (NALGs) and New Stereoselective Reactions Using Titanium(IV) Reagents

Institution: Florida Atlantic University

Thesis Advisor: Dr. Salvatore D. Lepore

Degree: Doctor of Philosophy

Year: 2010

We report here the development of very efficient sulfonate based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), to accelerate the rate of nucleophilic substitution reactions involving poor nucleophiles and/or substrates traditionally considered too hindered to undergo nucleophilic attack. Indeed NALGs have shown exceptional ability in improving rate of nucleophilic substitution reactions.

New very mild stereoretentive halogenations and azidation reactions have also been developed for secondary cyclic alcohols using NALGs involving titanium(IV) reagents. This reaction is particularly significant since the carbon-halogen bond is found widely in natural products and is used extensively as a synthesis intermediate. Azide is also a synthetically important functional group from which a variety of biologically important functional groups are conveniently obtained. Though stereoretentive chlorination and bromination reactions are known, we have developed, for the first time,

iv a stereoretentive azidation reaction using titanium(IV) azide, a reagent not previously used in organic synthesis.

During our development of stereoretentive reactions, we eventually developed very efficient, mild, two-step one-pot stereoretentive halogenations (chlorination and bromination) using titanium(IV) halides as catalysts or stoichiometric reagents. These reactions were found to be particularly efficient for cyclic alcohols.

An efficient one pot stereoretentive amidation reaction for secondary cyclic alcohols is also reported. The important features of this reaction are that, for the first time, chlorosulfite (prepared in situ from alcohol using thionylchloride) has been used as a leaving group and titanium(IV)fluoride as an activator. Utilization of those two reagents is unique as thionylchloride has never been used for nucleophilic substitution reactions except in chlorination procedures. In addition, this work has found new and creative applications for titanium(IV) fluoride, a reactant rarely used in organic synthesis.

Further exploiting the unique reactivity of titanium(IV), reactions of alkenes with various nucleophiles have been developed with this reagent in both catalytic and stoichiometric quantities. It was observed that α-substituted aromatic conjugated alkenes dimerize to generate important indan class of compounds which are very important in the polymer industry. In addition, non conjugated unactivated alkenes react with various nucleophiles to yield the adduct.

To My Parents and Beloved Wife Pinki DEVELOPMENT OF NUCLEOPHILE ASSISTING LEAVING GROUPS AND NEW

STEREOSELECTIVE REACTIONS USING TITANIUM(IV) REAGENTS

LIST OF FIGURES ...... viii

LIST OF TABLES...... ix

LIST OF SCHEMES ...... x

CHAPTER ONE NEW LEAVING GROUPS - NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) ...... 1

1.1 Introduction...... 1

1.2 Nucleophile Assisting Leaving Groups (NALGs)...... 2

1.3 The background of NALGs...... 3

1.4 First aryl sulfonate based NALGs from Lepore’s group: First generation NALGs and their synthesis...... 7

1.5 Synthesis of second generation NALGs...... 9

1.6 Results of nucleophilic substitution reactions with lithium bromide ...... 10

1.7 Experimental section...... 13

CHAPTER TWO TWO STEP STEREORETENTIVE REACTIONS OF SECONDARY CYCLIC ALCOHOLS USING NALGS AND Ti(IV) REAGENTS...... 20

2.1 Introduction...... 20

2.2 The stereoretentive chlorination reactions...... 21

2.3 Stereoretentive bromination and azidation reactions...... 23

2.4 Experimental section...... 29 vi

CHAPTER THREE ONE-POT STEREORETNTIVE HALOGENATION REACTIONS OF CHIRAL SECONDARY ALCOHOLS CATALYZED BY Ti(IV) HALIDES ...... 35

3.1 Introduction...... 35

3.2 The background of chlorination using thionylchloride...... 35

3.3 Development of very mild stereoretentive chlorination reactions: Results and discussion ...... 38

3.4 Mechanistic Discussion...... 47

3.5 Experimental section...... 62

CHAPTER FOUR ONE-POT TWO STEP STEREORETENTIVE AMIDATION REACTIONS OF SECONDARY CYCLIC ALCOHOLS ...... 67

4.1 Introduction...... 67

4.2 Development of stereoretentive amidation reactions: Results and discussion ...... 68

4.3 Mechanistic discussion...... 76

4.4 Experimental section...... 79

CHAPTER FIVE TiF4 MEDIATED REACTIONS OF ALKENE WITH NUCLEOPHILES...... 87

5.1 Introduction...... 87

5.2 Cyclodimerization of styrene: synthesis of indan class of compounds ...... 87

5.3 Addition of nitrile to unactivated alkene ...... 90

5.4 Addition of carboxylic acid to alkene...... 92

5.5 Experimental section...... 93

CHAPTER SIX REFERENCES...... 96

CHAPTER SEVEN SELECTED SPECTRA...... 101

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LIST OF FIGURES

Figure 1. Methylating agents containing crown ether leaving groups and structure of K222 ...... 5

Figure 2. Transition state for methylation of 8 and 10 ...... 6

Figure 3. Possible transition state for stereoretentive halogenation and azidation reactions ...... 27

Figure 4. General structure of indan class of copounds ...... 88

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LIST OF TABLES

Table 1. Bromination reaction times with 3-phenylpropyl substrates containing various leaving groups ...... 11

Table 2. Reaction of various sulfonate esters with TiCl 4 leading to alkyl chlorides...... 22

Table 3. Leaving group effect on bromination ...... 24

Table 4. Role of leaving group, solvent, and reaction temperature in azidation reactions ...... 26

Table 5. Substrates generality for stereoretentive bromination and azidation...... 27

Table 6. Optimization of catalytic chlorination...... 39

Table 7. Substrate generality for catalytic chlorination...... 40

Table 8. Chlorination of trans - and cis -4-methylcyclohexanols ...... 41

Table 9. Chlorination of trans -and cis -3-methylcyclohexanols ...... 43

Table 10. Results of chlorination for cis -3,3,5-trimethylcyclohexanol and 3 β - cholestanol ...... 44

Table 11. Results of chlorination of ( S)-(+)-2-octanol ...... 45

Table 12. Effect of TiF4 on amidation yield ...... 70

Table 13. Nitrile generality for stereoretentive amidation...... 71

Table 14. Substrate generality for amidation with benzonitrile...... 73

Table 15. Cyclodimerization study of α-substituted styrene ...... 89

LIST OF SCHEMES

Scheme 1 . Rationale for the rate enhancement observed with nucleophile assisting leaving groups ...... 3

Scheme 2. Podand-catalyzed nucleophilic aromatic substitution reaction of 1- chloroanthraquinone ...... 4

Scheme 3 . Rate of methylation of metal thiolate ...... 6

Scheme 4 . Rate acceleration of acetylating reaction with the substrate 15 , containing an oligoether as chelating arm ...... 7

Scheme 5 . Synthesis of NALG sulfonylchlorides ( 20 ) and NALG sulfonate esters ( 21 ) of primary alcohol, 3-phenyl-1-propanol...... 8

Scheme 6 . Synthesis of second generation NALGs sulfonyl chlorides ( 23 ) and NALG sulfonate esters ( 24 )...... 10

Scheme 7 . Reactions of Neopentyl NALG sulfonates resulting in rearrangement products and the possible transition state...... 23

Scheme 8 . Key step in Kim’s total synthesis ...... 29

Scheme 9. Decomposition of chlorosulfite ( 54 ) in neat and relatively polar non-chelating solvents ...... 36

Scheme 10 . Decomposition of chlorosulfite ( 54 ) in pyridine and dioxane...... 36

Scheme 11 . Cross experiment with chlorosulfite ( 62 ) and TiBr 4...... 46

Scheme 12 . Stereoretentive bromination of l-menthol...... 47

Scheme 13 . C-H and C-C hyperconjomers of methyl substituted tertiary carbocations ...... 48

Scheme 14 . Catalytic cycles involving six-membered transition states...... 51

Scheme 15 . One possible way to obtain inversion products ...... 52

Scheme 16 . Possible explanation for hydride shift products via non classical carbocation...... 53

Scheme 17 . Possible ring flip in trans -2-methylcyclohexyl and l-menthyl substrates...... 55

Scheme 18 . Catalytic chlorination cycle involving “nonclassical” carbocations...... 56

Scheme 19 . Equilibrium between the C-C hyperconjomer ( 116 ) and the C-H hyperconjomer ( 117 )...... 57

Scheme 20 . A possible explanation for the inversion products and stereoselective hydride shift products ...... 58

Scheme 21 . Explanation for the stereochemical outcome of 3 β-cholestanol substrate ( 81 )……………………………………………..…………………60

Scheme 22 . Possible explanation for no hydride shift or inversion for 2- and 3,3,5- substituted substrates ...... 61

Scheme 23 . Current azide approach to the stereospecific synthesis of amide starting from secondary alcohols ...... 68

Scheme 24 . Stereoretentive amidation reaction ...... 68

Scheme 25 . Amidation in cis - and trans -4-methylcyclohexanol ...... 74

Scheme 26 . Amidation in cis - and trans -3-methylcyclohexanol ...... 75

Scheme 27 . Amidation of acyclic alcohols ...... 76

Scheme 28 . A possible general mechanism and intermediates for the amidation reactions via non classical carbocations ...... 78

Scheme 29 . Back-side attack by free nitrile is slightly favored due to more nucleophilic compare to nitrile complexed with TiF 4 from front side...... 78

Scheme 30 . Cyclodimerization of α-methylstyrene...... 90

Scheme 31 . Plausible mechanism of cyclodimerization of styrene catalyzed by TiF 4 ...... 90

Scheme 32 . Addition of benzonitrile to 4-phenyl-2-butene in presence of Ti(IV) ...... 91

Scheme 33 . Reaction mechanism for nitrile addition to alkene ...... 92

Scheme 34 . Addition of carboxylic acid to alkene...... 93

Scheme 35 . Catalytic mechanism for addition of carboxylic acid to alkene...... 93

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CHAPTER ONE NEW LEAVING GROUPS - NUCLEOPHILE ASSISTING

LEAVING GROUPS (NALGS)

1.1 Introduction

One of our key research areas is the development of new aryl sulfonate based

leaving groups. Leaving groups have been defined as the part of a substrate that becomes

cleaved by the action of a nucleophile. 1 The IUPAC definition specifies a leaving group

as a molecular fragment (charged or uncharged) that becomes ‘detached from an atom in

what is considered to be the residual or main part of the substrate’ in a given reaction. 2 A leaving group that carries away an electron pair is called a nucleofuge. 3 However, these terms are not synonymous since a nucleofuge may be a functional group that simply receives an electron pair during a nucleophilic attack without itself being cleaved away from the substrate. Leaving groups could be electronically neutral or anionic. Common

− − − anionic leaving groups are halides such as Cl , Br , I , and sulfonate esters, such as para -

− tuluenesulfonate or “tosylate” (TsO ). Common neutral molecule leaving groups are

water, ammonia and alcohols.

Leaving group ability has been correlated with the pKa of the conjugate acid.

Leaving groups should be able to polarize the bond which connects it with the rest of the

molecule so that there is development of partial positive charge on the atom that serves as

the point of attachment. Therefore, leaving groups with electron withdrawing moieties

are often highly effective; trifluoromethanesulfonate (triflate) is a noteworthy example.

Leaving groups are ubiquitous in organic chemistry, playing a key role in a wide range of reactions, including nucleophilic substitution (aliphatic and aromatic), electrophilic substitution, and elimination reactions. A survey of 135 named organic reactions widely utilized in modern preparative organic chemistry 4 reveals that 38 reactions involve heterolytic nucleofugal leaving groups at some stage of their reaction mechanism. If this selection of named reactions is representative, then it could be inferred that leaving groups play an important role in as many as 25% of all organic reactions.

Despite the wide variety of available leaving groups, there is still a need to improve their performance in terms of selectivity, reaction rates, scalability, environmental compatibility, atom economy, stability and other parameters. Thus, research on leaving groups continues to be an area of fruitful endeavor. Therefore, we have turned our attention to the development of a new class of leaving groups that we have termed “Nucleophile Assisting Leaving Groups (NALGs).” As will be seen, these leaving groups are uniquely stable under typical storage and handling conditions and reacting primarily in the presence of nucleophilic reagents unlike, for example, compounds containing the leaving group triflate which are very unstable on bench top.

1.2 Nucleophile Assisting Leaving Groups (NALGs)

Nucleophile assisting leaving group (NALG) may be defined as a leaving group that contains a chelating unit capable of stabilizing the transition state of a nucleophilic reaction. 5 A chelating arm can help the reaction also entropically by chelating the metal

cation of a nucleophilic metal salt in the reacting state. But the most important point

about the NALGs is that it can lower the transition state energy of the rate limiting step in

the course of reaction which in turn increases the rate of the reaction. This has been 2 rationalized in scheme 1. In the case of the substrate 1, which represents a generic

NALG, it is expected that the negative charge imparted to the leaving group moiety (LG) by an incoming nucleophile (Nuc) in the transition state 3, provides a more favorable chelation complex relative to its neutral precursor ligand 2.

- + LG R LG R LG R M Nuc- - + Nuc + - M M Nuc Ea X X X X 1 X X X X X 1 2 3

+ + - M M Nuc - - LG R LG R Nuc R Nuc Ea 2 4

Scheme 1 . Rationale for the rate enhancement observed with nucleophile assisting leaving groups

Depending on the specific nucleophilic substitution reaction mechanism, cation chelation in the transition state should stabilize the transition state by decreasing the electronic energy. As a result of that activation energy ( Ea 1) of NALG substrates relative to substrates containing traditional leaving groups should be reduced. Without the added stabilizing effect of nucleophilic metal salt chelation with a nearby multidentate ligand, the energy of activation ( Ea 2) for reactions involving traditional leaving groups (leading

to a transition state such as 4) is expected to be higher ( Ea 1

1.3 The background of NALGs

The podand-catalyzed reaction was one of the initial examples where the NALG effect was observed. The reaction of 1-chloroanthraquinone ( 5) with a variety of alkanols

in NaH failed to give the desired nucleophilic substitution product under refluxing 3 condition in THF. However, the desired product resulted when the reaction was performed in the presence of catalytic amounts of oligo-ethylene glycols.

OH O O O 3 (cat)

OH O Cl 15 O O 5 NaH, THF 6 15 O

R O O O O Na O O 7

Scheme 2 . Podand-catalyzed nucleophilic aromatic substitution reaction of 1- chloroanthraquinone

In the case of n-hexadecanol, the substitution product 6 was obtained in 80% yield

using 24% of triethylenegylcol (scheme 2). 6 It was suggested by X-ray crystal structure

data that, initially acting as nucleophile, triethylene glycol added to 5 to produce intermediate 7, which is coordinated the sodium cation. This cation-complexed intermediate most likely played an important role in both coordinating the stoichiometric alkoxide nucleophile as well as stabilizing the negative charge forming on the oxygen atom of the leaving group.

Crown ether-based phenolate and carboxylate nucleophile assisting leaving groups exhibited enhanced nucleofugacity in methylation and acylation reactions. The rates of nucleophilic displacement of the electrophilc methyl group of substrates 8, 9, 10,

11 and 12 (figure 1) by benzyl thiolate varied markedly depending on the metal ions as well as the stabilizing ability of the transition state. 7 With potassium benzyl tholate, the

4 metal was sequestered using a well-known potassium cation chelating agent

[4,7,13,16,21,24]-hexaoxa-1,10-diazabicyclo-[8,8,8]-hexacosane (K222) leading to a loss of rate enhancement. To help assess the relative contribution of the metal counteraction, all methylation reactions in the study were compared to experiments involving K222 to give relative rates ( krel ).

N O O O O OMe O O O O O O O O O n Me O O N O 8 (n = 3) 9 (n = 5) 10 K222

OMe CO2Me 12 11

Figure 1 . Methylating agents containing crown ether leaving groups and structure of

K222

In scheme 3, results for only sodium and potassium benzyl thiolate have been

shown among results with other metal salts. For methylether crown ether NALG 8, both

sodium and potassium salts gave the peak values of k rel 565 and 826, respectively.

Although 9 is also a crown ether NALG, k rel are only 3 and 53 for sodium and potassium salts respectively. This clearly indicates that NALG effect depends on the size of the metal ions and the cavity size of the crown ether.

− + S M k SMe + Me LG 8-12

M krel(8) krel(9) krel(10) krel(11) krel(12) K.K222 1 1 1 1 1 Na 565 3 47 0.43 0.57 K 826 53 17 O.43 0.66

Scheme 3 . Rate of methylation of metal thiolate

Interestingly though it was observed that peak values for k rel methylation with the crown ether ester NALG 10 were 47 and 17 for sodium and potassium salts respectively.

In the case of methyl ether the transition state is more stable because oxygen has more

electron density in its transition state ( 13 ) compare to methyl ester, where electron

density is delocalized over two oxygen atoms in its transition state ( 14) (figure 2).

Therefore 13 becomes more stable because of strong electrostatic interaction compared to

14 where this interaction is relatively weak.

Me − O S Ph Me O − S Ph O O O O + O O M O M+ O O O O 13 14

Figure 2 . Transition state for methylation of 8 and 10

A similar NALG effect was observed for the acyl transfer reaction, in the

presence of metal methoxide in methanol of an aryl acetate substrate ( 15 ) having a

tetra(oxyethylene) chain in the ortho position (scheme 4). 8 The general mechanism

involves the rate-determining formation of a tetrahedral intermediate. For 15 , the presence of a nearby chelating ligand was supposed to stabilize the transition state 16 by placing the metal cation in a position to stabilize the negative charge on the oxygen atom

6 of the tetrahedral intermediate. Peak rates were observed for alkaline earth metals Ba 2+ and Sr 2+ which is due to strong electrostatic interaction between the negatively charged

oxygen and the doubly positively charged metal ion which in turn better stabilizes the

transition state.9 Probably Ba 2+ fits better into the crown ether pocket compare to Sr 2+ which explains more than a four fold rate enhancement.

OMe O Me − O − + O + O O O MeO M fast O M O OAc O slow Me OMe O O O O 15 16 salt conc ∼ 0.1M

M Me4N Na K Ba Sr krel 1 1.6 3.7 79 17

Scheme 4 . Rate acceleration of acetylating reaction with the substrate 15 , containing an oligoether as chelating arm

1.4 First aryl sulfonate based NALGs from Lepore’s group: First generation NALGs and their synthesis

So far we have presented from the literature some examples of aryloxy and arylcarboxyl based NALGs. Though sulfonate based leaving groups (tosylate, triflate, mesylate etc) are widely used in synthetic organic chemistry, the NALG concept was rarely applied in this type of leaving group. Because of strong electron withdrawing effect though triflate is very good leaving group; it is less selective and unstable (easily decomposing under purification conditions). So it would be very important to develop leaving groups which would be very reactive only in the presence of nucleophilic metal salts and very stable unlike triflate or other electron withdrawing leaving groups. The

Lepore group was the first to developed such types of leaving groups which exhibit 7 reaction rates comparable to triflates but are far more stable.10,11 Importantly, these

leaving groups only react in the presence of nucleophilic metal salts. These leaving

groups are aryl sulfonate based NALGs, containing an oligo-ether unit at the ortho-

position, which can chelate the metal cation in the transition state facilitating the

electrostatic interaction between the metal ion and the negative charge developed on the

sulfonate oxygen atom. The first generation aryl sulfonate NALGs ( 21 ) developed by

Lepore group contain oligo -ether chelating arm which is connected to aromatic ring

through a carbonyl carbon and were synthesized from a very cheap starting material,

sulfobenzoic acid cyclic anhydride ( 17 ) in two steps (scheme 5). The initial synthesis

approach was path A, which takes more than thirty hours. 10

O O PCl5 O O S HO CH3 S (2.0 equiv) Cl O n Cl o o 90 C, 6h Cl 60 C, 30h O CH3 DMAP(1.2 equiv) Path A O n CH2Cl2 O O O O 18 20 66-95% S O O O S O Ph PCl5 (2.0 equiv) HO CH3 O O O CH O O 60oC, 3-4h 3 17 n S O (1.5 equiv) OH n Path B O O CH O 3 72-96% CH2Cl2, rt, 1.5h n 21 19 O

Scheme 5 . Synthesis of NALG sulfonylchlorides ( 20 ) and NALG sulfonate esters

(21 ) of primary alcohol, 3-phenyl-1-propanol.

In path A, diacid chloride intermediate 18 was prepared by heating with PCl 5 at

90 oC for 6h. Then heating of 18 with oligo-ethyleneglycols at 60 oC for 30h yielded the corresponding NALG sulfonylchloride ( 20) . Subsequently, we developed an efficient

two step one-pot synthesis of 20 (path B). 11 Oligo-ethyleneglycols react at room temperature to produce NALG sulfonic acids ( 19 ) which on heating with PCl 5 for 3-4h

8 yielded 20 in very good yields. The NALG sulfonate esters 21 were synthesized by treating with 3-phenyl-1-propanol in the presence of DMAP at room temperature. With these NALG sulfonate esters in hand, nucleophilic substitution reactions were performed with various alkali metal halides in acetone at room temperature exhibiting excellent rate enhancement relative to traditional leaving groups.10 Results of this study will be discussed later in this section along with the data for "second generation" NALGs for a more convenient comparison of our various NALG configurations and conventional leaving groups (such as tosylate and triflate).

1.5 Synthesis of second generation NALGs

After the successful design of first generation NALGs, we further attempted to extend our strategy to second generation NALGs where we changed the connectivity of the chelating oligo-ethyleneglycol to the aromatic ring. Instead of the carbonyl group, now oligo-ethylene glycol chelating units are directly connected to aromatic ring ortho to the sulfonyl group (scheme 6). A series of second generation NALGs have been synthesized with both electron donating and withdrawing substituents in the aromatic ring. A synthesis procedure is shown in scheme 6. 11 Initially aryl-oligoether derivatives

(22 ) were synthesized by heating substituted phenols with polyethylene glycol tosylates at 60-65 oC in DMF. Arylethers 22 on treatment with chlorosulfonic acid at 0 oC yielded

the corresponding sulfonylchlorides 23 by electrophilic substitution reaction. But it was observed that in this step the yield of sulfonylchloride was limited to 20-40%. Then we realized that probably in this reaction step products were a mixture of both sulfonic acid and sulfonylchloride. Therefore, we performed another step to convert sulfonic acid to sulfonylchloride by treating the presumed reaction mixture obtained in first step with 9 thionylchloride in presence of DMF at 60-65oC. The strategy led to substantially

improved yields of 72-88%. Subsequent esterification of 23 with 3-phenyl-1-propanol

generated the secondary NALG sulfonate esters 24 . But it was observed that under our

previous conditions (scheme 5) the esterification step did not work well. However, by

increasing the nucleophilicity of the alcohol by converting it to alkoxide with sodium

hydride, good yields of esters were obtained.

X SO R SO3R remove carbonyl 3 O O add electron O O n withdrawing n O groups X and Y Y First generation NALGs Second generation NALGs

i) HSO3Cl X TsO X o X SO2Cl O n 0 C, 2-4h NaH/DMF O ii) SOCl , DMF O OH O 2 O 60-65oC, 20h, n 60-65oC, 2h n Y Y Y 90-95% 22 72-88% 23 X = tBu, F Y = F, H O O X S Ph OH O Ph O NaH (1.5 equiv) O DMAP, CH Cl , n 2 2 Y rt, 30 min, 72-80% 24

Scheme 6 . Synthesis of second generation NALGs sulfonyl chlorides ( 23 ) and NALG

sulfonate esters ( 24 )

1.6 Results of nucleophilic substitution reactions with lithium bromide

A complete study of nucleophilic substitution reactions of first generation NALGs

sulfonate esters ( 21 ) with various alkalimetal halides was reported from our group. 10 In

Table 1, rate enhancements by first generation NALGs as well as second generation

NALGs have been shown, where LiBr is used as nucleophilic metal salt. 11

LG LiBr, acetone-d6 Br room temp 25 reaction entry structure n compound time (h)a

1 Ph OTs 26 32.0 27 2.0 2 Ph OTf

3 O O 1 21a 12.0 S 4 O Ph 2 21b 5.0 5 O 3 21c 3.3 O n 4 21d 2.3 6 O 25.0 7 O O 1 24a S 8 O Ph 2 24b 8.8 9 O 3 24c 6.8 O n

10 O O 1 24d (X=H) 10.0 F S 11 O Ph 2 24e (X=H) 4.0 O 12 O 3 24f (X=H) 2.5 n 13 X 2 24g (X=F) 2.5 14 3 24h (X=F) 1.8

a All reaction were carried out in acetone-d6 and end point was determined by the disappearence of starting material resonance peaks in 1H NMR.

Table 1 . Bromination reaction times with 3-phenylpropyl substrates containing

various leaving groups

All the reactions were performed in acetone-d6 at room temperature and

monitored by NMR to determine the end point of the reactions. We note that the widely-

used tosylate leaving group was found to give the slowest rate. Not surprisingly, the

triflate reacted 16 times faster than tosylate; however as previously noted its reactivity is

due to high polarization of the of C-O bond brought about by the highly electronegative

CF 3 moiety. As a result, this triflate was exceptionally unstable and moisture sensitive

requiring special care in handling and to storage. First generation NALG substrate 21d

with five oxygen atoms in the chelating arm and second generation NALG substrate 24h ,

with four oxygen atoms in the chelating arm and two fluorine atoms in the aromatic ring

gave a similar rates to triflate. The NALG effect is clearly observed and the above results 11 indicate that the transition state could be stabilized due to both the electronic effect by the substituent (including the chelating arm) and the electrostatic interaction between the metal ion and the partial negative charge developed on the oxygen atom in the transition state which is possible because of the chelating arm. Rates for the first generation NALG substrates (Table 1, entry 3-5), where the chelating arm connected to the aromatic ring via an electron withdrawing carbonyl group, are nearly two fold faster than second generation NALG substrates with an electron donating substituent tert -butyl group (Table

1, entry 7-9). Also, the chelating arm itself in second generation NALG substrates is an electron donating group in the aromatic ring. Probably this extra electron density in the aromatic ring destabilizes the electron density on the sulfonate oxygen atom in the transition state. But replacement of an electron donating group with an electron withdrawing fluorine improves the rates for second generation NALG substrates (Table

1, entry 10-14) which are nearly the same or better rates than those of first generation

NALGs. Not surprisingly, these data indicate that the electronic effect of the fluoro substituents also play a role in stabilizing the transition state.

In this chapter, we have demonstrated a proof of concept for the NALG design leading to the design and synthesis of a few highly effective leaving groups. Future efforts to create improved NALGs will center on new modes of connectivity of the chelating arm as well as incorporation of other heteroatoms in the chelating arm. NALG sulfonyl chloride and NALG sulfonates are very stable, easy to purify and store which is not true for most reactive conventional leaving groups. NALG sulfonates only react when specific nucleophilic metal salts are present whereas triflate reacts with any type of nucleophiles with or without metal ion involvement.

1.7 Experimental section

63 µ). Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F

plates. Visualization was accomplished with UV light or aqueous potassium

permanganate solution staining followed by air heating.

1H NMR spectra were recorded on a Varian Mercury 400 (400 MHz) spectrometer and are reported in ppm using solvent as internal standard (CDCl 3 at

7.26ppm). Data are reported as: (b = broad, s = singlet, d = doublet, t = triplet, q =

quartet, p = pentet, m = multiplet; coupling constant(s) in Hz, integration). 13 C NMR

spectra were recorded on Varian Mercury 400 (100 MHz) spectrometer. Chemical shifts

are reported in ppm tetramethylsilane, with solvent resonance employed as the internal

standard (CDCl 3 at 77.0 ppm). High-resolution mass spectra were obtained from

University of Florida Mass Spectrometry Laboratory.

Materials: Stabilized/Certified ACS dichloromethane, N,N -dimethylformamide and acetone were obtained from commercial sources. All other reagents were also commercially available and were used without further purification.

General Procedure for preparation of aryl ether derivatives (22 ): To an ice-cooled suspension of NaH (1.5 equiv) in N,N - dimethylformamide, the phenol derivative (1.0 equiv) was added slowly followed by stirring for 30-60 min. The tosylate derivative (1.5 equiv) of oligoethylene glycol was then added and reaction mixture was heated to 60-

65 oC for 16-18h followed by cooling and quenching with aqueous HCl (2.0M) and water

13 dilution. The mixture was extracted three times with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purified product was obtained by flash column chromatography using hexane-ethyl acetate as the eluent. Reaction yields varied from 85-96%.

General Procedure for preparation of sulfonyl chloride derivatives ( 23 ): Aryl ether derivative (1.0 equiv) was added over 30 min to neat chlorosulfonic acid (5.0 equiv) cooled to 0oC. After complete addition, the reaction mixture was stirred at room temperature for 3-6 h. The reaction mixture was then re-cooled to 0 oC and N,N -

dimethylformamide (5.5 equiv) was added slowly followed by thionyl chloride (10.0

equiv). The reaction mixture was heated at 60-65 oC for 2 h and cooled to 0 oC and then

added slowly to a mixture of ice and ether with constant stirring. The ether layer was

extracted and aqueous layer was washed twice with ether. The ether washings were

collected, washed with saturated sodium bicarbonate solution, and dried over anhydrous

sodium sulfate. Purified product was obtained by flash column chromatography using

hexane-ethyl acetate as the eluent. Reaction yields varied from 60-85%.

General Procedure for preparation of sulfonyl chloride derivatives ( 20 ) (modified

method): To solid powder sulfobenzoic cyclic anhydride (1.0 equiv) oligo-ethylene

glycol (1.5 equiv) was added and stirred at room temperature for 1-1.5h. Then to the

reaction mixture phosphorus pentachloride (2.0 equiv) was added and heat at 60-65 oC for

3-4h. Then reaction mixture was cooled to room temperature followed by in ice. Then

ether was added followed by ice-cold water. Ether layer was collected. Aqueous layer

was washed with ether two more times and collected together and dried over anhydrous

14 sodium sulfate. Purified product was obtained by flash column chromatography using hexane-ethyl acetate as the eluent. Reaction yields varied from 66-95%.

General procedure for esterification reactions ( 24a-c): To a cooled (0 oC)

suspension of sodium hydride (1.5 equiv) in dichloromethane (0.2 M) was added 3-

phenyl-1-propanol (1.5 equiv) under argon. After 1 h of stirring aryl sulfonyl chloride

(1.0 equiv) and 4-(dimethylamino)pyridine (1.0 equiv) were added to the previous

solution. The reaction was maintained at room temperature for 4-6 h. Following

completion, the reaction mixture was quenched with deionised water and extracted

several times with dichloromethane. The collected organic extracts were concentrated

and the resulting oil was purified by silica gel chromatography (using ethyl

acetate/hexanes as eluent). Reaction yields varied from 70-85%.

General procedure for esterification reactions of 2,4-Difluoro-NALGs ( 24d-h):

To a cooled (0 oC) suspension of sodium hydride (1.5 equiv) in dichloromethane (0.15 M) was added 3-phenyl-1-propanol (1.0 equiv) under argon protection. After 1 h stirring

NALGs (1.5 equiv) and 4-(dimethylamino)pyridine (0.2 equiv) were added to the previous solution. The reaction was maintained at room temperature overnight. Following completion, the reaction mixture was quenched with deionised water and extracted several times with dichloromethane. The collected organic extracts were concentrated and the resulting oil was purified by silica gel chromatography (using ethyl acetate/hexanes as eluent). Reaction yields varied from 72-80%.

General procedure for substitution reactions: To a solution of lithium bromide

(4.0 eq) at RT in acetone-d6 (0.08 M) was added NALG-esters (1.0 equiv). The reaction

was maintained at room temperature until completion (2-12 h, see Table 1) which was

15 determined by the point at which starting material resonance peaks were no longer visible in the 1H NMR of the reaction mixture. Following completion, the reaction mixture was

concentrated under vacuum, quenched with deionised water, and extracted several times

with ether. The collected organic extracts were concentrated and the resulting oil was

purified by silica gel chromatography (using pure hexane as eluent). Reaction yields

were > 95%.

3-Phenylpropyl-2-(2-methoxyethoxy)ethoxy)ethoxy-5-tert-butylbenzene-1-

1 sulfonyl chloride ( 24a ). H NMR (400 MHz, CDCl 3) δ 7.93 (d, J = 2.53 Hz, 1H), 7.60-

7.57 (dd, J = 8.71, 2.55 Hz, 1H), 7.30-7.22 (m, 2H), 7.20-7.16 (m, 1H), 7.14-7.12 (m,

2H), 7.01-6.99 (d, J = 8.74 Hz,1H), 4.25-4.23 (m, 2H), 4.22-4.19 (t, J = 6.22 Hz, 2H),

3.81-3.79 (m, 2H), 3.41 (s, 3H), 2.74-2.70 (t, J = 7.39 Hz, 2H), 2.05-1.98 (m, 2H), 1.32

13 (s, 9H); C NMR (100 MHz, CDCl 3) δ 154.5, 143.8, 140.7, 132.4, 128.4, 128.3, 128.0,

126.0, 124.0, 113.5, 70.7, 70.2, 68.9, 59.2, 34.3, 31.5, 31.2, 30.8; HRMS (ESI+) calc. for

+ C22 H30 NaO 5S [M+Na] : 429.1706. Found: 429.1712.

3-Phenylpropyl-2-(2-(2-methoxyethoxy)ethoxy)ethoxy-5-tert-butylbenzene-1-

1 sulfonyl chloride ( 24b ). H NMR (400 MHz, CDCl 3) δ 7.92-7.91 (d, J = 2.53 Hz, 1H),

7.60-7.57 (dd, J = 8.71, 2.54 Hz, 1H), 7.27-7.24 (m, 2H), 7.20-7.17 (m, 1H), 7.13-7.01

(m, 2H), 7.02-7.00 (d, J = 8.75 Hz, 1H), 4.28-4.25 (m, 2H), 4.20-4.17 (t, J = 6.18 Hz,

2H), 3.93-3.90 (m, 2H), 3.74-3.72 (m, 2H), 3.53-3.51 (m, 2H), 3.35 (s, 3H), 2.73-2.69 (t,

13 J = 7.37 Hz, 2H), 2.03-1.99 (m, 2H), 1.32 (s, 9H); C NMR (100 MHz, CDCl 3) δ 154.4,

143.7, 140.6, 132.4, 128.4, 128.3, 128.0, 126.0, 123.8, 113.4, 71.9, 70.8, 70.2, 69.3, 69.0,

+ 59.0, 34.3, 31.5, 31.2, 30.7; HRMS (ESI+) calc. for C 24 H34 NaO 6S [M+Na] : 473.1968.

Found: 473.1975.

3-Phenylpropayl-2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy-5-tert-butylbenzene-1-

1 sulfonyl chloride (24c ). H NMR (400 MHz, CDCl 3) δ 7.86 (d, J = 2.14 Hz, 1H), 7.54-

7.52 (dd, J = 8.68, 2.02 Hz, 1H), 7.22-7.18 (m, 2H), 7.14-7.11 (m, 1H), 7.07-7.06 (m,

2H), 6.97-6.95 (d, J = 8.71 Hz, 1H), 4.22-4.19 (m, 2H), 4.14-4.11 (t, J = 6.14 Hz, 2H),

3.87-3.84 (m, 2H), 3.70-3.68 (m, 2H), 3.59-3.55 (m, 4H), 3.49-3.47 (m, 2H), 3.31 (s,

3H), 2.68-2.64 (t, J = 2.68-2.64 Hz, 2H), 1.99-1.92 (m, 2H), 1.27 (s, 9H); 13 C NMR (100

MHz, CDCl 3) δ 154.5, 143.7, 140.6, 132.4, 128.4, 128.3, 127.9, 126.0, 123.8, 113.4,

71.8, 70.8, 70.5, 70.4, 70.1, 69.3, 68.9, 58.9, 34.3, 31.5, 31.2, 30.7; HRMS (ESI+) calc.

+ for C 26 H38 NaO 7S [M+Na] : 517.2230. Found: 517.2222.

3-Phenylpropyl-2-(2-methoxyethoxy)ethoxy)ethoxy-5-fluorobenzene-1-sulfonyl

1 chloride ( 24d ). H NMR (400 MHz, CDCl 3) δ 7.67-7.64 (dd, J = 7.79, 3.19 Hz, 1H),

7.30-7.24 (m, 3H), 7.20-7.18 (m, 1H), 7.14-7.12 (m, 2H), 7.08-7.04 (dd, J = 9.13, 3.98

Hz, 1H), 4.24-4.21 (m, 2H), 4.23-4.19 (t, J = 6.23 Hz, 2H), 3.80-3.77 (m, 2H), 3.40 (s,

13 3H), 2.73-2.69 (t, J = 7.36 Hz, 2H), 2.05-1.99 (m, 2H); C NMR (100 MHz, CDCl 3) δ

156.8, 154.4, 153.0 (d, J = 2.39 Hz), 140.4, 128.4, 128.3, 126.1, 122.1-121.8 (d, J =

23.03 Hz, 1C), 118.1-117.8 (d, J = 26.45 Hz, 1C), 115.5-115.4 (d, J = 7.39 Hz, 1C), 70.8,

+ 70.6, 69.6, 59.1, 31.4, 30.6; HRMS (ESI+) calc. for C 18 H21 FNaO 5S [M+Na] : 391.0986.

Found: 391.0978.

3-Phenylpropyl-2-(2-(2-methoxyethoxy)ethoxy)ethoxy-5-fluorobenzene-1-

1 sulfonyl chloride ( 24e ). H NMR (400 MHz, CDCl 3) δ 7.67-7.64 (dd, J = 7.78, 3.16 Hz,

1H), 7.31-7.25 (m, 3H), 7.21-7.17 (m, 1H), 7.14-7.12 (m, 2H), 7.08-7.05 (dd, J = 9.13,

3.96 Hz, 1H), 4.27-4.25 (m, 2H), 4.21-4.18 (t, J = 6.20 Hz, 2H), 3.92-89 (m, 2H), 3.72-

3.70 (m, 2H), 3.52-3.50 (m, 2H), 3.35 (s, 3H), 2.73-2.69 (t, J = 7.37 Hz, 2H), 2.05-1.98

13 (m, 2H); C NMR (100 MHz, CDCl 3) δ 156.7, 154.3, 153.0 (d, J = 2.32 Hz, 1C), 140.3,

128.3, 128.3, 126.0, 122.0-121.8 (d, J = 22.92 Hz, 1C), 118.1-117.8 (d, J = 26.55 Hz,

1C), 115.4-115.3 (d, J = 7.39 Hz, 1C), 71.8, 70.8, 70.7, 79.7, 69.2, 58.9, 31.4, 30.6;

+ HRMS (ESI+) calc. for C 20 H25 FNaO 6S [M+Na] : 435.1248 Found: 435.1236.

3-Phenylpropyl-2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy-5-fluorobenzene-1-

1 sulfonyl chloride ( 24f ). H NMR (400 MHz, CDCl 3) δ 7.68-7.66 (dd, J = 7.79, 3.17 Hz,

1H), 7.33-7.26 (m, 3H), 7.22-7.19 (m, 1H), 7.16-7.14 (m, 2H), 7.12-7.09 (dd, J = 9.15,

3.98 Hz, 1H), 4.28-4.26 (m, 2H), 4.23-4.20 (t, J = 6.20 Hz, 2H), 3.93-3.90 (m, 2H), 3.76-

3.73 (m, 2H), 3.65-3.62 (m, 4H), 3.56-3.54 (m, 2H), 3.38 (s, 3H), 2.74-2.71 (t, J = 7.39

13 Hz, 2H), 2.06-2.00 (m, 2H); C NMR (100 MHz, CDCl 3) δ 156.7, 154.3, 153.0 (d, J =

2.26 Hz, C), 140.3, 128.3, 128.2, 126.0, 122.0-121.8 (d, J = 22.82 Hz, 1C), 118.0-117.7

(d, J = 26.47 Hz, 1C), 115.5-115.4 (d, J = 7.41 Hz, 1C), 71.7, 70.7 (2), 70.5, 70.3, 69.7,

+ 69.2, 58.9, 31.3, 30.6; HRMS (ESI+) calc. for C 22 H29 FNaO 7S [M+Na] : 479.1510.

Found: 479.1507.

3-Phenylpropyl-2-(2-(2-methoxyethoxy)ethoxy)ethoxy-3,5-difluorobenzene-1-

1 sulfonyl chloride ( 24g ). H NMR (400 MHz, CDCl 3) δ 7.54-7.50 (dd, J = 8.66, 6.36 Hz,

1H), 7.29-7.26 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.12 (m, 2H), 7.06-7.01 (dd, J = 10.09,

9.15 Hz, 1H), 4.25-4.22 (m, 2H), 4.19-4.16 (t, J = 6.22 Hz, 2H), 3.90-3.88 (m, 2H), 3.73-

3.71 (m, 2H), 3.59-3.57 (m, 2H), 3.39 (s, 3H), 2.73-2.69 (t, J = 7.34 Hz, 2H), 2.07-2.00

13 (m, 2H); C NMR (100 MHz, CDCl 3) δ 157.3-154.6 (dd, J = 260.11, 10.75 Hz, 1C),

154.6-152,.0 (dd, J = 249.42, 5.41 Hz, 1C), 143.7-143.5 (dd, J = 11.09, 3.46 Hz, 1C),

140.1, 128.5, 128.3, 126.2, 116.3-116.2 (d, J = 3.93 Hz, 1C), 106.9-106.7 (d, J = 23.12

Hz, 1C), 106.6-106.4 (d, J = 23.17 Hz, 1C), 71.8, 70.8, 70.7, 70.0, 69.4, 59.0, 31.3, 30.4;

HRMS (CI+) calc. for C 20 H24 NaF 2O6S [M+Na]+: 453.1180. Found: 453.1154.

3-Phenylpropyl-2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy-3,5-dfluorobenzene-1-

1 sulfonyl chloride ( 24h ). H NMR (400 MHz, CDCl 3) δ 7.53-7.49 (dd, J = 8.66, 6.36 Hz,

1H), 7.28-7.24 (m, 2H), 7.20-7.18 (m, 1H), 7.13-7.11 (m, 2H), 7.05-7.00 (dd, J = 10.11,

9.17 Hz, 2H), 4.18-4.22 (t, J = 6.22 Hz, 2H), 3.89-3.87 (m, 2H), 3.74-3.72 (m, 2H), 3.68-

3.64 (m, 4H), 3.56-3.53 (m, 2H), 3.37 (s, 3H), 2.72-2.68 (t, J = 7.34 Hz, 2H), 2.06-1.99

13 (m, 2H); C NMR (100 MHz, CDCl 3) δ 157.2-154.5 (dd, J = 260.28, 10.85 Hz, 1C),

154.5-151.9 (dd, J = 250.14, 6.23 Hz, 1C), 143.6-143.4 (dd, J = 11.25, 3.25 Hz, 1C),

140.0, 128.4, 128.3, 126.1, 116.2-116.1 (d, J = 3.82 Hz, 1C), 106.9-106.6 (d, J = 23.26

Hz, 1C), 106.6-106.4 (d, J = 23.14 Hz, 1C), 71.8, 70.8, 70.7, 70.5, 70.4, 69.9, 69.3, 58.9,

31.2, 30.3.

CHAPTER TWO TWO STEP STEREORETENTIVE REACTIONS OF

SECONDARY CYCLIC ALCOHOLS USING NALGS AND Ti(IV) REAGENTS

2.1 Introduction

Nucleophilic substitution reactions at secondary sp 3 hybridized carbon bearing a

leaving group represent a fundamental and important transformation in synthesis organic

chemistry. Depending on the stereochemical outcome, the mechanism is either SN2,

where the outcome is inversion or S N1 where racemization happens via a carbocation.

The third possible stereochemical outcome for substitution is retention of configuration

12 where the mechanism is designated as S Ni. Stereo defined reactions are very important especially when considering the synthesis of complex molecules; in this regard reactions mediated by the SN2 and S Ni mechanisms are often considered more important than

SN1-based reactions which are racemic. The entire synthesis strategy could be altered dramatically depending on which mechanism would be suitable to install functional groups stereoselectively (giving either inversion or retention). While SN2 and S N1 are very common reaction mechanisms, the SNi mechanism is exceptionally rare. If

neighboring-group participation 13 and metal-catalyzed allylic substitution14 are excluded, there are exceedingly few reports of nucleophilic displacement reactions on unactivated saturated carbon leading to products with a high degree of retention of configuration. 15

In the previous chapter we have demonstrated that NALGs are excellent leaving

groups mainly due to stabilization of the transition state by electrostatic interaction 20 between an alkali metal ion and negative charge on oxygen atom of the leaving group.

Based on this conception, we further envisioned that a Lewis acidic metal which can accept an electron pair should be able to stabilize the transition state even better than alkali metal ions. We then surmised that Lewis acids containing nucleophilic ligands would lead to nucleophilic addition products. Indeed this hypothesis proved accurate leading to our development of very mild and efficient halogenations and azidation reactions where the stereochemical outcome for the products was retention. 16,17

2.2 The stereoretentive chlorination reactions

We initially developed a very mild stereoretentive chlorination reaction of

16 secondary cyclic alcohols using TiCl 4 as the nucleophilic Lewis acidic metal salt. A

series of secondary alcohols first were reacted with aryl sulfonylchloride containing a

diethylene glycol unit to give sulfonate esters 28 (Table 2). In general, the treatment of

o sulfonate esters 28 with TiCl 4 in dichloromethane at -78 C led to high yields of the

corresponding alkyl chlorides in just two minutes with complete retention of

configuration. It was observed that NALG and tosylate esters of 1,3-diphenyl-2-propanol

primarily give elimination product in the presence of alkali metal halides. This chloride

has only been prepared by radical chlorodecarboxylative methods. 18 However, on

treatment of the NALG ester 28a with TiCl 4, the respective chloride was obtained in 91%

yield (Table 2, entry 1). With chiral cyclic secondary alcohols, the chloride products were

obtained as a single diastereomers with complete retention of configuration (Table 2,

entry 2-4). By proton NMR the formation of single diastereomer with retention of

configuration was confirmed.

In the 2-adamentyl system where back side attack is very unfavorable because of steric crowding 19 , we observed a 90% yield with no side product arising from

rearrangement of the adamentane nucleus (Table 2, entry 5). 20 Thus, the chlorination reaction likely proceeds via a front-side S Ni-type of mechanism. Generally, reactions

21,22 involving the SNi mechanism are mediated by four center cyclic transition state. In

our case primarily we believe that this reaction is going through six member transition

state where Ti(IV) is chelated by the chelating arm and delivers the chloride from the

same side of the leaving group (scheme 7) thus leading to retention. As chelated Ti(IV)

can stabilize the transition state to a greater extent due to Lewis acidity, the reaction is

very rapid.

O O O S OR TiCl4, CH2Cl2 O RCl O -78oC, 2 min

O 28 29

Entry ROH Substrate Yield(%)a Product

28a 91 29a 1 Ph Ph OH HO 88 29b 2 28b

HO 28c 93 29c 3

H C6H13 28d 85 29d 4 HO

H H

28e 90 29e 5 OH

OH 28f 66b 29f 6

aIsolated yield. bElimination product also observed (21%, 1.5:1 E/Z)

Table 2. Reaction of various sulfonate esters with TiCl 4 leading to alkyl chlorides 22

We also performed reactions with neopentyl NALG substrates ( 30 ) which lead to complete rearrangement products ( 31 ) via 1,2-methyl shift (scheme 7). We believe that, possibly after chelation of TiCl 4, a strong partial positive charge develops on the carbon atom which is connected to the leaving group leads to a rapid 1,2-shift of methyl group to generate stable tertiary carbocation. As no direct substitution product was observed at all, the rate of rearrangement should be very fast compared to nucleophilic attack by chloride.

o It was also observed that the tosylate of secondary alcohols reacted with TiCl 4 at -78 C

forming the corresponding chloride with complete stereoretention at a somewhat slow

rate (10 min).

O O S Cl O TiCl4, CH2Cl2 R -78oC, 2 min O O R O R = H (30a) R = H (97%) (31a) R = CH3 (30b) R = CH3 (98%) (31b) δ+ R O Cl S δ− O O Cl O O Ti MeO O Cl Cl TS

Scheme 7 . Reactions of Neopentyl NALG sulfonates resulting in rearrangement products and the possible transition state

2.3 Stereoretentive bromination and azidation reactions

After the initial success of stereoretentive chlorination of secondary NALG sulfonates with TiCl 4, we realized that this reaction is of significantly broader scope.

Here we demonstrate the successful development of stereoretentive bromination and

azidation reactions primarily of cyclic secondary alcohols. Though tosylate gave a

23 reasonable rate for chlorination reaction with TiCl4, the analogous reaction with TiBr 4 was far more sluggish and performed unacceptably with Ti(N 3)4. Thus, for the bromination reaction for l-menthyl substrates ( 32 ), tosylate ( 32a ) gave the slowest rate

(Table 3). Diethylene oxide-containing leaving group substrate 32b exhibited an improved reaction rate with very good yield (91%). But still we wanted similar level of reactivity as with TiCl 4. We envisioned that a more Lewis basic chelator in the leaving

group might be helpful to achieve further enhancement of the bromination reaction. Thus,

we turned our attention to 8-quinoline sulfonate (quisylate) as the leaving group. 23

Br O R TiBr4 S o O O CH2Cl2, -78 C 32 33

entry R substrate time (min) Yield(%) 1 32a 60 77

O O 32b 30 91 2 O

N 3 32c 5 90

Table 3 . Leaving group effect on bromination

To our knowledge, the quisylate leaving group has only been used twice as leaving group, in E1-type pyrolysis reactions 24 and in nucleophilic bromination reactions

25 o leading to inversion of configuration. Menthyl quisylate 32c reacted with TiBr 4 at -78 C

very rapidly (5 min) to give the menthylbromide in very good yield. This stereoretentive

bromination reaction was found to be fairly general for cyclic alcohols and acyclic

alcohol (Table 5). All the chiral cyclic alcohols afforded corresponding bromides with 24 complete retention of configuration (Table 5, entry 1-3). The only acyclic alcohol ( S)-1-

o phenyl-2-butanlol reacted with TiBr 4 at -78 C yielded the bromide with complete retention of configuration (Table 5, entry 6). For TiCl 4, the same stereoretentive result is

obtained with the quisylate 1-phenyl-2-butanol. Notably, the NALG and quisylate esters

o of α-hydroxypropionate were completely unreactive at -78 C towards TiBr 4 (Table 5, entry 8). At room temperature, it reacted with the TiBr 4 very slowly, afforded 71% yield after 40h, and led to the complete inversion of configuration in the product, suggesting a change in mechanism.

In seeking to extend further the scope of this titanium(IV) reaction, we developed for the first time stereoretentive azidation reaction using Ti(N 3)4. Ti(N 3)4 was prepared

26 following a literature procedure in situ by a reaction between TiF 4 and TMSN 3 and

reacted with tosylate 32a and quisylate 32c under a variety of conditions (Table 4). To

our knowledge this is a first time application of titanium(IV) azide in organic synthesis.

Menthyl azide 34 was obtained from both substrates with complete retention of

configuration. However, tosylate 32a gave a significant proportion of elimination product

35 (Table 4, entry 1-3), whereas quisylate 32c showed high selectivity for the substitution

product, especially when 1,2-dichloroethane was used as the reaction solvent (Table 4,

entry 6 & 7). Substrates generality for the azidation reaction has been shown in Table 5

with quisylate substrates ( 36a-h). The reaction works very well for cyclic alcohols. The

only acyclic alcohol used, ( S)-1-phenyl-2-butanol reacted with Ti(N 3)4 to give the azide

product with complete stereoretention. But surprisingly, this substrate reacts very slowly

at 0 oC, and a reasonable rate was obtained only when the reaction was performed at room

temperature. Almost no reaction was observed with α-hydroxy ester quisylate (Table 5,

25 entry 8). Primary alcohol quisylate ( 36g ) reacted very slowly to give an 80% yield after

70h at room temperature (Table 5, entry 7).

N Ti(N3)4 3 substrate 32a or 32c + solvent time, temp 34 35

Entry Substrate T(oC) Solvent t(min) 34:35a Yield 34b(%)

1 32a RTCH2Cl2 60 2.7:1 72

2 32a 0 CH2Cl2 180 2.8:1 68

3 32a RT ClCH2CH2Cl 60 2.7:1 48

4 32c 0 CH2Cl2 540 19:1 80

5 32c RTCH2Cl2 120 19:1 63

6 32c RT ClCH2CH2Cl 60 34 only 97

7 32c 0 ClCH2CH2Cl 480 34 only 97

a Based on NMR analysis. b Yield of isolated products; complete retention of configuration

Table 4 . Role of leaving group, solvent, and reaction temperature in azidation reactions

In terms of formulating a mechanistic rationale for these titanium(IV) reactions,

two reactivity trends were observed. Firstly, the poor reactivity of the primary alcohol

and α-hydroxy ester can be rationalized in terms of partial positive charge formation at

the carbinol carbon in the transition state. The argument is that carbinol carbons of

primary alcohols and α-hydroxy ester are less able to stabilize the partial positive charge

developed in the transition state relative to secondary carbinol carbon centers. Secondly,

we hypothesized that aromatic nitrogen of the quisylate group stabilizes a concerted S Ni-

type (or non solvent separated SN1) mechanism with Ti(IV) reagents.

O O O δ + S R' X TiX3 R H N

Figure 3 . Possible transition state for stereoretentive halogenation and azidation reactions

O O OR O O O S S OR O TiX4 N RX or O

O quisylate (36) NALG (37)

% yield of RX (reaction time)a Product b c X = Br X = N3 X=Br X = N3 Entry ROH NALG (37a-h) Quis.(36a-h) Quis.(36a-h)

OH 33 34 1 91 90 97 (30 min) (5 min) (8h)

C6H13

H 95 93 85 38 45 2 H H (15 min) (10 min) (3h) HO

OH 3 79 66 69 39 46 (15 min) (10 min) (5h)

88 82 89 40 47 4 Ph Ph (2.5h) (10min) (7h) OH

98 85 93 41 48 5 OH (15 min) (10 min) (5h)

81 79 63d 42 49 Ph 6 (30 min) (30 min) (4h) OH 92e 89e 80e 43 50 Ph OH 7 (14h) (5.5h) (72h) OH O 42f 71f <5f 44 51 8 (20h) (40h) (24h) O a b o c Yield of isolated products. Reaction conditions: -78 C,CH2Cl2. Reaction conditions: o d e 0 C, ClCH2CH2Cl. Reaction conditions:Room temperature . Reaction conditions: Room temperature. f Reaction conditions: Room temperature. Substrates have undergone complete retention of configuration.

Table 5 . Substrates generality for stereoretentive bromination and azidation 27

By comparison tosylate substrate (devoid of aromatic nitrogen) undergo significant ionization, leading to elimination product 35 (Table 4, entry 1-3). The quisylate nitrogen also appears to increase the rate of the reaction in most cases (for example, compare entries 1&3, Table 3). A possible transition state for quisylate where the nitrogen atom is believed to be coordinated to Ti(IV), involves a stable six- membered-ring geometry (figure 3). Because of the coordination of the nitrogen to

Ti(IV), Lewis acidity is balanced to such an extent that, unlike tosylate, ionization of the quisylate substrate is less probable.

We are happy to report here that our stereoretentive reaction was successfully applied in total synthesis by the Kim group. 27 In the synthesis of (+)-Microcladallene B

(53 ), at the late stage of their synthesis the author needed to install bromide stereoretentively from an intermediate alcohol derivative (52 ) (scheme 8). As reported,

the Kim group tried nearly all known bromination procedures. However, these methods

failed to yield the desire product. Only when they applied our NALG bromination

technique was the expected product obtained (in 63% yield), along with deprotection of

the silyl protection group.

H TBDPSO O

Other HO H O Literature N procedures 52 O X

H TBDPSO O H HO O TiBr , CH Cl O O 4 2 2 O O H Br ° O O S N 0 C to rt, 2 h H O O N O 63% 53 O O

Scheme 8 . Key step in Kim’s total synthesis

In conclusion, a series of titanium(IV) reagents have been utilized to develop

stereoretentive halogenations (chlorination and bromination) and azidation. The yields

are very good to excellent. For the first time Ti(N3)4 has been utilized to developed stereoretentive azidation reaction. Also this reaction was successfully applied by other researchers to the total synthesis of a complex natural product.

2.4 Experimental section

Materials: S tabilized/Certified ACS dichloromethane and anhydrous 1,2- dichloroethane were obtained from commercial sources. All other reagents are also commercially available and were used without further purification.

General procedure for synthesis of NALG sulfonates or quisylate ( 36 & 37 )

(method A): To a suspension of NaH (1.5 equiv) in DCM alcohol (1.0 equiv) was added and stirred at room temperature for 30-60 min. Then NALG sulfonylchloride or quisylchloride (1.2 equiv) was added followed by DMAP slowly. It was stirred at room temperature for 18-20h. Then reaction mixture was cooled in ice and quenched with ice-

29 cold water. Organic layer was collected and dried over anhydrous sodium sulfate.

Products were purified by flash column using 2-15% acetone-hexane. Yield: 70-85%.

General procedure for synthesis of NALG sulfonates or quisylate ( 36 & 37 )

(method B): To a solution of alcohol (1.0 equiv) in pyridine NALG sulfonylchloride or quisylchloride was added and stirred at room temperature for 18-20h. Then reaction mixture was cooled in ice, DCM was added and quenched with 2M HCl solution.

Organic layer was collected and dried over anhydrous sodium sulfate. Products were purified by flash column using 2-15% acetone-hexane. Yield: 65-80%.

General procedure for chlorination reactions: A cold (-78 oC) solution of quisylate

o ester (1.0 eq) in dichloromethane (1.5 M) was added to a cold (-78 C) solution of TiCl 4

(2.0 eq) in dichloromethane (0.15 M). Following completion (usually within 2 min), reaction mixture was quenched with water and extracted three times with dichloromethane. The collected organic extracts were concentrated and the resulting oil was purified by silica gel chromatography (using pure hexane as eluent).

General procedure for bromination reactions: A cold (-78oC) solution of quisylate

o ester (1.0 eq) in dichloromethane (1.5 M) was added to a cold (-78 C) solution of TiBr 4

(2.0 eq) in dichloromethane (0.15 M). Following completion (usually within 15 min), reaction mixture was quenched with water and extracted three times with dichloromethane. The collected organic extracts were concentrated and the resulting oil was purified by silica gel chromatography (using pure hexane as eluent).

General procedure for azidation reactions: To a room temp solution of TiF 4 (6.0 eq) in 1,2-dichloroethane (0.2 M) was added azidotrimethylsilane (25 eq). After stirring for 30 min, the solution was cooled (0 °C) followed by the addition of quisylate ester (1.0

30 eq) as a 2-dichloroethane solution (1.5 M). The reaction was maintained at 0 °C until

completion (<8 h). Following completion the reaction mixture was quenched with water

and extracted three times with dichloromethane. The collected organic extracts were

concentrated and the resulting oil was purified by silica gel chromatography (using pure

hexane as eluent).

(1 R, 2 S, 5 R)–2-isopropyl-5-methylcyclohexyl quinoline-8-sulfonate ( 36a ). 1H

NMR (400 MHz, CDCl 3) δ 9.18-9.17 (dd, J = 4.24, 1.79 Hz, 1H), 8.53-8.52 (dd, J = 7.36,

1.46 Hz, 1H), 8.27-8.25 (dd, J = 8.34, 1.79 Hz, 1H), 8.12-8.10 (dd, J = 8.22, 1.45 Hz,

1H), 7.67-7.64 (dd, J = 8.15, 7.40 Hz, 1H), 7.58-7.55 (dd, J = 8.35, 4.25 Hz, 1H), 4.58-

4.51 (td, J = 10.86, 4.55 Hz, 1H), 2.20-2.16 (m,1H), 1.86-1.79 (m, 1H), 1.63-1.56 (m,

2H), 1.46-1.36 (m, 2H), 1.27-1.18 (m, 1H), 0.96-0.76 (m, 2H), 0.84 (d, J = 6.53 Hz, 3H),

0.68 (d, J = 7.02 Hz, 3H), 0.21 (d, J = 6.90 Hz, 3H).

1,3-diphenylpropan-2-yl quinoline-8-sulfonate ( 36d ). 1H NMR (400 MHz,

CDCl 3) δ 9.03-9.02 (dd, J = 4.25, 1.80 Hz, 1H), 8.31-8.29 (dd, J = 7.38, 1.46 Hz, 1H),

8.12-8.10 (dd, J = 8.34, 1.79 Hz, 1H), 7.95-7.93 (dd, J = 8.22, 1.43 Hz, 1H), 7.51-7.47

(dd, J = 8.13, 7.44 Hz, 1H), 7.48-7.45 (dd, J = 8.29, 4.23 Hz, 1H), 7.01-6.96 (m, 10H),

5.41-5.35 (p, J = 6.30 Hz, 1H), 3.05-3.00 (dd, J = 14.09, 6.48 Hz, 2H), 2.96-2.91 (dd, J =

14.09, 6.17 Hz, 2H).

1 2-adamentyl quinoline-8-sulfonate ( 36e ). H NMR (400 MHz, CDCl 3) δ 9.14-9.13

(dd, J = 4.21, 1.78 Hz, 1H), 8.53-8.51 (dd, J = 7.35, 1.43 Hz, 1H), 8.27-8.24 (dd, J =

8.34, 1.76 Hz, 1H), 8.11-8.09 (dd, J = 8.21, 1.40 Hz, 1H), 7.66-7.62 (dd, J = 7.99, 7.46

Hz, 1H), 7.56-7.53 (dd, J = 8.32, 4.22 Hz, 1H), 5.18-5.17 (br m, 1H), 2.10-2.07 (m, 2H),

1.99 (br s, 2H), 1.81-1.67 (m, 8H), 1.46-1.43 (m, 2H).

(1 S, 2 R, 4 R)–2-bromo-1-isopropyl-4-methylcyclohexane ( 33 ). 1H NMR (400

MHz, CDCl 3) δ 4.01-3.94 (td, J = 11.44, 4.14 Hz, 1H), 2.42-2.31 (m, 2H), 1.77-1.71 (m,

2H), 1.52-1.41 (m, 2H), 1.07-0.97 (m, 3H), 0.92 (d, J = 4.18 Hz, 3H), 0.90 (d, J = 3.64

13 Hz, 3H), 0.75 (d, J = 6.93 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 59.3, 50.8, 48.2, 34.8,

+ 34.5, 29.2, 24.9, 22.1, 21.4, 15.1; HRMS (CI+) calc. for C 10 H18 Br [M-H] : 217.0586.

α 25 Found: 217.0579. [ ]D –49.3 ( c 1.4, EtOH) (NALG); –49.7 ( c 1.4, EtOH) (quisylate).

1 3β –bromo-5-cholestene ( 38 ). H NMR (400 MHz, CDCl 3) δ 5.34-5.33 (m, 1H),

3.96-3.86 (m, 1H), 2.18-2.11 (m, 1H), 2.05-1.91 (m, 3H), 1.86-1.75 (m, 2H), 1.53-1.19

(m, 14H), 1.15-1.04 (m, 8H), 1.01 (s, 3H), 0.88 (d, J = 6.55 Hz, 3H), 0.84 (dd, J = 6.62,

13 1.84 Hz, 6H), 0.66 (s, 3H); C NMR (100 MHz, CDCl 3) δ 141.7, 122.5, 56.9, 56.3, 52.9,

50.4, 44.5, 42.5, 40.5, 39.9, 39.7, 36.6, 36.4, 36.0, 34.5, 32.0, 31.9, 28.4, 28.2, 24.5, 24.0,

+ 23.1, 22.8, 21.1, 19.5, 18.9, 12.1; HRMS (DIP-CI+) calc. for C 27 H46 Br [M] : 449.2777.

α 25 Found: 449.2779. [ ]D –21.2 ( c 0.3, CHCl 3) (NALG); –22.5 ( c 2.6, CHCl 3) (quisylate).

1 (2-bromopropane-1,3-diyl)dibenzene ( 40 ). H NMR ( 400 MHz, CDCl 3) δ 7.33-

7.29 (m, 4H), 7.26-7.22 (m, 2H), 7.20-7.18 (m, 4H), 4.40-4.33 (m, 1H), 3.22 (dd, J =

13 14.36, 5.77 Hz, 2H), 3.13 (dd, J = 14.36, 8.22 Hz, 2H); C NMR (100 MHz, CDCl 3) δ

+ 138.7, 129.4, 128.7, 127.1, 57.3, 45.2; HRMS (CI+) calc. for C 15 H15 Br [M] : 274.0352.

Found: 274.0374.

(1 R, 2 R)-1-bromo-2-methycyclohexane (racemic) ( 39 ). 1H NMR (400 MHz,

CDCl 3) δ 3.75-3.68 (td, J = 11.58, 4.19 Hz, 1H), 2.39-2.33 (m, 1H), 1.90-1.83 (m, 2H),

1.78-1.70 (m, 4H), 1.37-1.28 (m, 2H), 1.12 (d, J = 6.47 Hz, 3H); 13 C NMR (100 MHz,

+ CDCl 3) δ 62.3, 41.6, 38.9, 35.4, 27.7, 25.7, 22.1; HRMS (CI+) calc. for C 7H12 Br [M-H] :

175.0117. Found: 175.0122.

2-adamentylbromide ( 41 ). 1H NMR (400 MHz, CDCl 3) δ 4.68 (m, 1H), 2.35 (m,

1H), 2.32 (m, 1H), 2.15 (m, 2H), 1.98 (m, 1H), 1.96 (m, 1H), 1.88 (m, 4H), 1.76 (m, 2H),

13 1.64 (m, 1H), 1.61 (m, 1H); C NMR (100 MHz, CDCl 3) δ 64.2, 38.9, 38.0, 36.6, 31.8,

+ 27.7, 27.1; HRMS (CI+) calc. for C 10 H14 Br [M-H] : 213.0273. Found: 213.0279.

1 3β –Azido-5-cholestene ( 45 ). H NMR (400 MHz, CDCl 3) δ 5.38-5.37 (m, 1H),

3.25-3.16 (m, 1H), 2.29-2.27 (m, 2H), 2.03-1.94 (m, 2H), 1.92-1.78 (m, 2H), 1.61-1.27

(m, 14H), 1.15-1.04 (m, 8H), 0.99 (s, 3H), 0.91 (d, J = 6.56 Hz, 3H), 0.86 (dd, J = 6.62-

13 1.87 Hz, 6H), 0.67 (s, 3H); C NMR (100 MHz, CDCl 3) δ 140.0, 122.8, 61.4, 56.9, 56.3,

50.3, 42.5, 39.9, 39.7, 38.3, 37.8, 36.4, 36.1, 32.1, 32.0, 28.5, 28.3, 28.2, 24.5, 24.1, 23.1,

+ 22.8, 21.2, 19.5, 18.9, 12.1; HRMS (ESI+) calc. for C 27 H46 N [M+H-N2] : 384.3625.

α 25 Found: 384.3633. [ ]D –5.5 ( c 0.9, CHCl 3).

(1S, 2 R, 4 R) – 2-azido-1-isopropyl-4-methylcyclohexane ( 34 ). 1H NMR (400

MHz, CDCl 3) δ 3.08-3.02 (td, J = 11.25, 4.13 Hz, 1H), 2.14-2.03 (m, 2H), 1.77-1.63 (m,

3H), 1.48-1.37 (m, 1H), 1.22-1.14 (m, 2H), 1.05-0.98 (m, 1H), 0.94 (d, J = 6.59 Hz, 3H),

13 0.91 (d, J = 7.05 Hz, 3H), 0.79 (d, J = 6.93 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 62.6,

47.4, 40.6, 34.4, 32.1, 27.1, 23.8, 22.5, 21.1, 16.1; HRMS (CI+) calc. for C 10 H20 N3

+ α 25 [M+H] : 182.1665. Found: 182.1657. [ ]D –64.4 ( c 1.6, CHCl 3).

1 (2-azidopropane-1, 3-diyl)dibenzene ( 47 ). H NMR (400 MHz, CDCl 3) δ 7.36-

7.32 (m, 4H), 7.29-7.25 (m, 2H), 7.24-7.22 (m, 4H), 3.83-3.76 (m, 1H), 2.92-2.87 (dd, J

= 13.89, 5.47 Hz, 2H), 2.85-2.80 (dd, J = 13.89, 8.19 Hz, 2H); 13 C NMR (100 MHz,

CDCl 3) δ 137.9, 129.5, 128.8, 127.0, 65.6, 40.9. HRMS (CI+) calc. for C 15 H16 N3

[M+H] +: 238.1300. Found: 238.1376.

(1 R, 2 R)-1-azido-2-methycyclohexane (racemic) ( 46 ). 1H NMR (400 MHz,

CDCl 3) δ 2.80-2.74 (td, J = 10.61, 3.95 Hz, 1H), 2.05-2.01 (m, 1H), 1.82-1.71 (m, 2H),

1.67-1.62 (m, 2H), 1.56-1.49 (m, 2H), 1.39-1.31 (m, 2H), 1.00 (d, J = 6.47 Hz, 3H); 13 C

NMR (100 MHz, CDCl 3) δ 67.3, 36.8, 34.2, 31.8, 25.3, 22.5, 19.7. HRMS (CI+) calc. for

+ 28 C7H14 N3 [M+H] : 140.1200. Found: 140.1188. Previously reported.

1 2-adamentylazide ( 48 ). H NMR (400 MHz, CDCl 3) δ 3.80 (m, 1H), 2.00-1.97

(m, 4H), 1.91-1.82 (m, 4H), 1.73-1.70 (4H), 1.57-1.55 (m, 1H), 1.54-1.53 (m, 1H); 13 C

NMR (100 MHz, CDCl 3) δ 66.7, 37.5, 36.9, 31.9, 31.8, 27.4, 27.2; HRMS (CI+) calc. for

+ C10 H16 N3 [M+H] : 178.1300. Found: 178.1344.

1 (S)-(2-bromobutyl)benzene ( 42 ). H NMR (400 MHz, CDCl 3) δ 7.35-7.20 (m,

5H), 4.17-410 (m, 1H), 3.20-3.09 (m, 2H), 1.92-1.82 (m, 1H), 1.80-1.69 (m, 1H), 1.08 (t,

13 J = 7.24 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 138.9, 129.4, 128.7, 127.0, 59.8, 45.6,

+ α 25 31.4, 12.4; HRMS (EI+) calc. for C 10 H13 Br [M] : 212.0201. Found: 212.0207. [ ]D +11.1

(c 1.8, CHCl 3) (NALG); +10.7 ( c 1.5, CHCl 3) (quisylate).

1 (S)-(2-bromobutyl)benzene ( 49 ). H NMR (400 MHz, CDCl 3) δ 7.35-7.20 (m,

5H), 3.47-3.41 (m, 1H), 2.81-2.79 (m, 2H), 1.67-1.48 (m, 2H), 1.02 (t, J = 7.40 Hz, 3H);

13 α 25 C NMR (100 MHz, CDCl 3) δ 138.1, 129.5, 128.8, 126.9, 65.9, 40.8, 27.3, 10.8. [ ]D –

23.5 ( c 0.6, CHCl 3).

CHAPTER THREE ONE-POT STEREORETNTIVE HALOGENATION

REACTIONS OF CHIRAL SECONDARY ALCOHOLS CATALYZED BY Ti(IV)

HALIDES

3.1 Introduction

As noted in the previous chapter, the stereospecific conversion of alcohols to halides (chloride and bromide) is a very important and useful transformation in organic synthesis. Our investigation in the development of two-step stereoretentive halogenation reactions using Ti(IV) reagents led us to successfully engineer more convenient one-pot stereoretentive reactions. The concept behind this development was the formation of the leaving group in situ which has a potential chelating unit can be considered a rudimentary

NALG. In this chapter, we report a very mild, efficient one-pot stereoretentive chlorination reaction of cyclic secondary alcohols using thionylchloride catalyzed by

TiCl 4 where the in situ generated leaving group is a chlorosulfite.

3.2 The background of chlorination using thionylchloride

Thionyl chloride is widely used in organic chemistry for the chlorination of alcohols, and this is one of the very well known reagents used to prepare chlorides from secondary alcohols stereospecifically depending on the reaction conditions. 29 At temperatures greater than 50 oC are nearly always required for this reaction with elimination as a common side reaction. 29 The stereochemical course of the classical

35 thionylchloride reaction has been widely commented on in the literature and is strongly dependant on the solvent used in the reaction. In scheme 9 and scheme 10, mechanisms of decomposition of chlorosulfite ( 54 ) have been shown to explain solvent dependence of stereochemical outcome. 29

O O H H R H R1 S R1 S 1 O Cl O Cl OH R R2 54 R2 54 2 realtively polar and neat or non chelating non-polar solvents solvent e.g. toluene H Cl O O R1 R + H H H O 1 S R1 S R1 S S or O− Cl + R O O O+ 2 O R2 R R − 2 55 − 2 56 57 (tight-ion pair) Cl Cl R H R Cl SNi 1 SN2 1 Cl H R2 R2 Retention Inversion 59 58

Scheme 9. Decomposition of chlorosulfite (54 ) in neat and relatively polar non-

chelating solvents 29

H O N O OO R H + R H R1 + 1 S 1 S SO O N O Cl O + 2 SN2 R2 SN2 R R2 − 2 at carbon − O 60 at sulfur 54 Cl Cl 61

SN2 at carbon SN2

Cl H R1 R1 H Cl R2 R2 Inversion Retention 58 59

Scheme 10 . Decomposition of chlorosulfite ( 54 ) in pyridine and dioxane 29

It was reported that on heating with pure thionyl chloride or in non-polar solvents

(for example toluene, hexane), secondary chiral alcohols were converted to

corresponding chloride with complete inversion following the mechanism as shown in

scheme 9. Under these conditions, instead of the carbon-oxygen bond, the sulfur-chlorine 36 bond breaks because of the unstability of the carbocation in non-polar solvents to generate free chloride and cation 55 (referred to as a sulfur dioxide solvated carbocation).

Then free chloride attacks 55 as a nucleophile from the back-side with SO 2 acting as a leaving group, leading to complete inversion product ( 58 ). But, when relatively more

polar albeit non-chelating solvents (for example ethylene chloride, dichloromethane)

were used, nearly 50% ee were observed favoring retention of configuration. In this case,

it is believed that products form in two ways. One way is the same as discussed for neat

or non-polar solvents reaction conditions where 55 is formed and inversion of

configuration happens due to an SN2 pathway. But as solvent has now polarity, it can

stabilize the partial positive charge on the carbinol carbon in transition state 56 or it can

stabilize a non-solvent separated tight ion-pair ( 57 ) where carbon bears positive charge.

So now the chlorosulfite decomposes through a four member transition state ( 56 ) (S Ni)

yielding stereoretentive product 59 . As two mechanisms are thought to operate

simultaneously, complete stereoretention has never been observed.

However, complete stereoretention is possible if a polar hard nuclophilic solvent

is used such as dioxane. It was found that dioxane actually is the perfect hard donor

solvent which gives complete retention. But the most interesting point is that this is not

actually S Ni, but a double inversion mechanism (scheme 10). Being a hard nucleophile, dioxane first attacks the carbon of chlorosulfite from the back-side (typical S N2) to

generate the intermediate 61 releasing sulfur dioxide and chloride. In the next step,

chloride attacks 61 in an S N2 fashion which eventually leads to stereoretention. So

basically it is a solvent assisted double inversion mechanism which generates the

retention product, not S Ni. However, a soft nucleophilic solvent (can also be used as

37 catalyst), such as pyridine, prefers to attack the sulfur atom of chlorosulfite leading to intermediate 60 (scheme 10). Chloride then attacks the electrophilic carbon from the

backside leading to complete stereoinversion.

3.3 Development of very mild stereoretentive chlorination reactions: Results and

discussion

After the development of two step stereoretentive chlorination reactions from

NALG sulfonate esters reacting with TiCl 4, we thought about in situ generated leaving

group where eventually the same chemistry could be applied. We knew that thionyl

chloride is one of the reagents which can give stereoretentive chlorides from chiral

alcohols where chlorosulfite is the intermediate. We envisioned that the chlorosulfite

could be decomposed to chloride with stereoretention using TiCl 4. On the basis of this concept, which is basically extended idea of our two step stereoretentive chlorination using NALG sulfonate esters, we have developed a very mild one-pot stereoretentive chlorination reaction of cyclic alcohols using thionyl chloride and TiCl 4. The reaction was also found to be catalytic depending on the alcohol substrates. Catalytic optimization for this chlorination reaction is shown in Table 6 where l-menthol has been chosen as

substrate. As TiCl 4 is cheap and environmental friendly, we limited our catalytic amount to 10% to perform the reaction at an optimum rate with the concentration of alcohol maintained at 1.0M. Though a bit sluggish, the reaction proceeds at -78 oC using two

o equivalents TiCl 4. Under catalytic condition the reaction at -78 C becomes prohibitively slow. In each case, excellent yields of l-menthyl chloride ( 63 ) were obtained (91-93%). It is worth mentioning here that heating of l-menthol with thionyl chloride in dichloromethane at 60 oC for 18h yielded both retention and inversion chlorides in a 4:1 38 ratio with 82% overall yield. This observation is consistent with the literature 29 where it is reported that in a solvent such as dichloromethane, both retention and inversion products are observed with retention being major product. The optimum catalytic conditions (Table 6, entry 1) were applied to a series of alcohols and in Table 7, results have been shown for those alcohols which yielded chlorides with complete retention of configuration. Complete stereoretention were observed for cis -2-methylcyclohexanol and steroid compounds (Table 7, entry 6-8). A series of cycloalkanols were also successfully converted to chlorides efficiently without the formation of side product like elimination

(Table 7, entry 1-3). For the cyclohexanol, the reaction was performed in deuterated chloroform and complete conversion was observed without any elimination product

(Table 7, entry 1). Also both 1- and 2- adamentanols were successfully converted to chloride in very good yield (Table 7, entry 4 & 5).

a b TiX4 time SOCl entry (mol%) (min) OH 2 O Cl (1.5 eq) S 1 10 15 ° O 0 C, 1 h 2 20 15 DCM 62 3 25 15 4 50 15 Cl c TiCl4 5 200 120 ° 0 C a time Conc. of alcohol is 1.0 M b 91-93% Time after addition of TiCl4 63 cReaction at -78 °C

Table 6 . Optimization of catalytic chlorination

In our previous work for stereoretentive halogenations and azidation, we suggested that our stereoretentive products are likely achieved via an S Ni type

mechanism. 30 However, in their recent rebuttal to our paper, Braddock and Burton argue that these reactions are under diastereoslective control proceeding through a carbocation

39 and, in the case of steroid substrates, the reaction are assisted (neighboring group participation) by the nearby double bond. 31 However, we maintain that this reaction is not

under diastereoselective control. Thus while the double bond in the steroid produces a

neighboring group effect in some cases for stereoretentive outcome,32 we contend that this may not be true in our case.

a) SOCl2 (1.5 eq) DCM, 0 °C, 1h ROH RCl b) TiCl4 (10%) 0 °C, 0.5h

a Entry ROH Yield (%) Product

OH 1 100b 64

2 OH 85 65

OH 3 92 66

OH 67 4 91

5 88 68 OH

OH 6 85 69

C6H13

7 H 94 70 H H HO O

H 8 96 71 H H HO a Isolated yields bYield determined by NMR

Table 7. Substrates generality for catalytic chlorination

To prove that our chlorination technique indeed proceeds through a pure substitution mechanism and not an assisted mechanism, we choose a few substrates, chlorination results of which will support the S Ni-type mechanism. Results for such alcohols will be discussed individually in the coming paragraphs. During this study we also observed that the concentration of alcohols and amount of TiCl 4 have pronounced

effects on the stereochemical outcome of the products.

H OSOCl H Cl 72 Cl TiCl4 H OSOCl Cl H H Cl H 74 75 76 77 73

o Substrate Entry Con.(M) Tem( C) t (h) TiCl4 (equiv) 74 75 76 77

1 0.5 0 0.5 0.1 5.4 1.4 1.0 1.0

2 1.0 0 0.5 0.1 5.4 1.4 1.0 1.0

trans 3 1.0 -78 2.0 2.0 5.4 1.4 1.0 1.0 a (72) 4 0.05 0 1.0 1.0 13.7 2.5 1.0 2.0

5 0.1 0 0.5 0.2 13.7 2.5 1.0 2.0

6 0.1 0 0.5 2.0 49.0 8.5 1.0 5.0

7 0.1 -78 10.0 2.0 15.0 2.0 0.0 1.0

8 0.5 0 0.5 0.1 1.4 6.0 1.0 9.3

9 1.0 0 0.5 0.1 1.4 6.0 1.0 9.3

10 0.05 0 2.0 1.0 1.0 6.8 1.1 5.6 cis (73)b 11 0.1 0 1.0 0.2 1.0 6.8 1.1 5.6 12 0.1 0 0.5 2.0 1.3 8.2 1.0 6.3

13 0.1 -78 12.0 2.0 1.0 62.0 1.5 63.9

14 1.0 -78 8.0 2.0 1.0 58.4 2.6 61.2

a Average isolated yield of 77%. bAverage isolated yield of 61%. Both 72 and 73 gave complete conversion to the corresponding chloride as observed by NMR in CDCl3 without any elimination product

Table 8 . Chlorination of trans - and cis -4-methylcyclohexanols

In Table 8, the results for chlorination reactions for trans - and cis -4- methylcyclohexanol are presented. For both alcohols, chlorosulfites 72 and 73 generated all four products 74 , 75 , 76 and 77 . Also, the concentration of alcohols becomes

important for the stereochemical outcome, and 0.1M was found to be the optimum

concentration. At both concentrations, 1.0M and 0.5M, under catalytic conditions similar

product distributions were observed (Table 8, entries 1-3). The ratio of retention product

(74 ) to inversion product ( 75 ) was ~4:1 along with formation of hydride shifted products

76 and 77 in the same ratio (1:1). At 1.0M concentration, lowering temperature also did not show any product ratio improvement (Table 8, entry 3). At 0 oC, the same product distributions resulted (Table 8, entry 4 and 5) when concentrations were maintained at

0.1M and 0.05M. However, at these concentrations, improved ratios for retention versus inversion resulted (~5.5:1) compared to reactions at higher concentrations. Also 77 is formed in twice the amount of 76 . When 2.0 equivalents TiCl 4 used at 0.1M concentration, no improvement in the retention to inversion ratio was observed (Table 8, entry 6). Interestingly the ratio of overall direct substitution to overall hydride shifted products was increased (~9:1) compared to reaction under catalytic conditions (~5:1)

(Table 8, entry 5 and 6). Also 77 is now generated in five time the amount of 76 . Further lowering of the temperature to -78 oC improved the retention to inversion ratio ( 74 :75 ~

7.5:1.0) (Table 8, entry 7). Interestingly, in this case, the hydride shifted product 77 was not observed by 1HNMR and the ratio of overall direct substitution to overall hydride shifted products improved to ~17:1. A similar trend was also observed for cis -4- methylcyclohexyl chlorosulfite ( 73 ) and an optimum result was obtained at -78 oC with a

very good selectivity for retention ( 74 :74 ~62:1) (Table 8, entry 13). However, in this

42 case, hydride shift becomes very prominent with direct substitution versus hydride shift nearly a 1:1 ratio with high preference for hydride shifted product 77 . This indicates that probability of getting hydride shift is very high for the substrate where leaving group at the axial position.

H H Cl OSOCl TiCl H 78 4 Cl H Cl H Cl OSOCl 74 75 76 77 79 H Substrate Entry Conc.(M) Temp(oC) t (h) TiCl4 equiv) 74 75 76 77

1 1.0 0 0.5 0.1 0.0 1.0 36.0 5.0 cis 2 1.0 -78 8.0 2.0 0.0 1.0 11.3 1.1 (79)a

3 0.1 0 0.5 2.0 0.0 1.0 51.8 4.4

4 0.1 -78 12.0 2.0 Exclusive Retention

trans 5 0.1 0 0.5 2.0 1.0 4.8 1.1 4.7 (78)b 6 0.1 -78 12.0 2.0 2.6 570.7 1.0 605.1

a Average isolated yield 80%. b Average isolated yield 63%. Both 78 and 79 gave complete conversion to corresponding chloride as was observed by NMR in CDCl3 without any elimination.

Table 9 . Chlorination of trans -and cis -3-methylcyclohexanols

Then we examined the 3-methylcyclohexanol systems. Here also, both trans - and

cis -3-methylcyclohexyl chlorosulfites 78 and 79 yielded the same products ( 74 , 75 , 76 ,

and 77) as observed for 4-methylcyclohexanols. In the case of cis -3-methylcyclexyl

chlorosulfite ( 79 ) under non optimized conditions three products 75 , 76 , and 77 were

generated with the retention product being the major (Table 10, entries 1, 2 and 3).

However, exclusive retention product 76 was obtained when the reaction was performed

o at -78 C using 2 equivalents TiCl 4 and maintaining a 0.1M concentration of alcohol

(Table 9, entry 4). Under similar conditions, though trans -chlorosulfite 78 yielded

exclusive stereoretentive product 77 but the hydride shifted product 75 was also 43 generated exclusively in nearly equal amount to that of 77 . One interesting point to be noted is that, in the case of 3-methylcyclohexyl chlorosulfites, a hydride shift never happens from position 2, but rather is always observed selectively from position 6 leading to 74 and 75 .

Substrate Entry Conc.(M) Temp(oC) t (h) TiCl4 (equiv) Ret:Inv

H 1 1.0 0 5.0 0.1 7.1:1.0 OSOCl 2 1.0 0 1.0 2.0 Exclusive retention (80)a 3 0.1 0 3.0 2.0 Exclusive Retention

4 0.1 -78 15.0 2.0 Exclusive Retention

ClOSO 5b 1.0 0 0.25 0.1 2.5: 1.0

H 6b 0.1 0 0.25 0.1 2.5: 1.0 H 7b 0.1 -78 10.0 2.0 2.5: 1.0 H H 8c 0.1 0 0.25 5.0 Exclusive Retention 9c 0.1 0 0.25 10.0 ExclusiveRetention 81 C6H13

a Average isolated yield 78%. b Average isolated yield 90%. c Average isolated yield 80%.

Table 10 . Results of chlorination for cis -3,3,5-trimethylcyclohexanol and 3 β-

cholestanol

Results for two other substrates, 80 and 81 have been shown in Table 10. It is

interesting to see that though under catalytic conditions, in the case of cis -3,3,5- trimethylcyclohexanol ( 80 ), both retention and inversion was observed in the ratio of

o o ~7:1, exclusive retention was obtained at both 0 C and -78 C when 2.0 equivalents TiCl 4 were used at any concentration. This indicates that the amount of TiCl 4 also has an important role in the stereochemical outcome (Table 10, entry 1 and 2). A similar TiCl 4 stoichiometry effect was observed for 3 β-cholestanol ( 81 ). Under catalytic conditions as

o well as using 2.0 equivalents of TiCl 4 at -78 C, the retention product was only favored by

44 a~2.5:1 ratio (Table 10, entry 5-7). However, we were happy to see that, using 5.0

o equivalents TiCl 4 at 0 C exclusive stereoretention was observed. We believe this result to

be highly significant from a mechanistic standpoint. The Braddock group had argued that

in the case of steroid substrates (Table 7, entry 7 and 8) complete stereoretention was

observed due to an anchimeric effect provided by the double bond. 31 However, in 3 β- cholestanol, no anchimeric assistance is possible due to the absence of a double bond strongly suggesting an S Ni type mechanism as we originally proposed.

SOCl2, TiCl4 Cl + 4 DCM, 0 °C 4 OH Cl 4 82 83

Entry conc time TiCl 4 [α]a b (M) (h) (equiv) direct:H-shift 1 1.0 0.5 0.2 -2.6 1.2:1.0 2c 1.0 12 2.0 -3.5 1.0:1.0 3 0.1 1.0 1.0 +4.6 0.8:1.0 4 0.1 1.0 5.0 +4.4 0.8:1.0 5 0.1 1.0 10 +5.5 0.8:1.0 6 0.1 1.0 20 +5.7 0.8:1.0 7 0.05 24 0.2 -7.4 3.3:1.0 8 0.05 20 1.0 +4.3 0.9:1.0 Average yield at 1.0M and 0.1M is 83% and at 0.05M, the yield is 55%. a Optical rotation of the mixture and optical rotation of (R)-2-chlorooctane reportedas -31.9 (4.5, CHCl3) bTwo H-shifted products were observed, other minor hydride shifted product was the 4-substituted. The ratio provided here including both. cReaction temperature was -78 °C

Table 11 . Results of chlorination of ( S)-(+)-2-octanol

Primarily our relatively mild chlorination method was found to work well for cyclic alcohols. To examine whether it can work for acyclic linear alcohols, we performed a detailed study of chlorination for ( S)-(+)-2-octanol (Table 11). One major problem was the formation of hydride shifted product ( 83 ) under the many conditions we attempted. Reaction was not selective at all under any conditions. Regarding our

45 chlorination reactions we were also interested to know whether chloride is being delivered directly from chlorosulfite or from TiCl 4. To determine the chloride source we performed two cross experiments by treating chlorosulfite 62 with TiBr 4 in a catalytic

amount as well as a stoichiometric amount (scheme 11). When l-menthyl chlorosulfite 62 was treated with catalytic TiBr 4 (10 mol%) both the chloride 63 and bromide 84 were

obtained in 72% and 20%, yields respectively, with complete stereoretention. But when

the chlorosulfite 62 was treated with 2.0 equivalents of TiBr 4, the bromide product 84 was obtained as the major product in 82% yield. These two experiments have two consequences: 1) it is the halide on Ti(IV) that is being delivered; and 2) chlorosulfite can be used to install nucleophiles other than chloride. When a catalytic amount of TiBr 4 is used, it is probable that initially bromide from TiBr4 attacks the chlorosulfite, generating the bromide product 84 with the concomitant generation of mixed titanium(IV) reagents

(TiBr 4-xCl x). As the catalytic cycle goes on and on, the number of chloride on Ti(IV) increases and bromide decreases, and the probability of attack by chloride increases.

TiBr4 (10 mol%) 0oC, DCM Cl Br + OSOCl 4h

63 84 TiBr4 (2.0 equiv) 72% 20% (catalytic TiBr4) 62 o 0 C, DCM 5% 82% (2.0equivTiBr4) 15 min

Scheme 11 . Cross experiment with chlorosulfite ( 62 ) and TiBr 4

In the presence of excess TiBr 4 on the other hand, though mixed Ti(IV) halides

generated, the probability of attack by bromide is now high due to the presence of higher

number of bromides on Ti(IV) compare to chloride. This analysis is further complicated

by the kinetic consequences resulting from bromide being a significantly better 46 nucleophile than chloride. In addition, though we did not perform the study in detail, it is also possible to synthesize an alkyl bromide stereoretentively from the corresponding bromosulfite using catalytic TiBr 4. Thus when a solution of bromosulfite 85 (1.0M) was

o treated with catalytic TiBr 4 at 0 C, l-menthylbromide was obtained in more than 90% yield.

SOBr Br OH 2 O Br (1.5 eq) S TiBr4 O 0 °C 0 °C, 1 h 30 min DCM 84 85 >90%

Scheme 12 . Stereoretentive bromination of l-menthol

3.4 Mechanistic Discussion

We have recently begun ab initio computational studies on this reactive system through collaboration with an Italian group; however, the computational results are too preliminary for discussion at this point. Nonetheless, it is possible to illuminate important features of the mechanism of our TiCl 4-catalyzed chlorination reaction taking as a

backdrop a few exciting literature precedents.

As discussed briefly in the previous section, stereoretentive chlorination reactions

involving thionyl chloride have been widely discussed in the literature. The most

accepted mechanism involves a four-membered transition state (structure 56 , scheme

9). 29,33 As shown in scheme 9, when the sulfur chloride bond in chlorosulfite 54 breaks, chloride attacks from the back-side (S N2 mechanism) to generate the inversion product.

34 Shreiner et al. designated this mechanism as S N2i. This mechanistic designation is

somewhat confusing since, by analogy with the S Ni mechanism, it implies intramolecular

47 attack by the nucleophile. However, the authors explain the "i" is meant to indicate that the nucleophile is generated intramolecularly. Peter Wipf 33 has proposed an

intramolecular transition state for stereoretention in their chlorination reaction involving

oxachlorocarbene. Prof. Wipf's mechanistic hypothesis of inversion product via a four-

membered transition state is further substantiated by theoretical calculations.

A many of the chiral cyclic alcohols examined in our study are six-membered, it

will be important to discuss the properties and nature of the substituted cyclohexyl

carbocations, which can help in understanding the mechanism of chlorination.

Prof. Sorensen and his group did extensive studies on methyl substituted tertiary

cyclohexyl carbocations. 35, 36, 37 They have established that methyl substituted tertiary cyclohexyl carbocations exist as two “nonclassical” isomeric structures which are in equilibrium. In describing these isomers they have coined the term "hyperconjomers".

These two structures have distorted pyramidal chair conformations but differ in having

“axially” ( 86 ) and “equatorially” ( 87 ) oriented carbocation LUMO-orbital (scheme 13). It is important to note that Sorensen is hypothesizing a non-planarized carbocation and, in this sense are non-classical. They have designated structure 86 and 87 as the C-H hyperconjomer and the C-C hyperconjomer respectively.

86 87 (C-H hyperconjomer) (C-C hyperconjomer)

Scheme 13 . C-H and C-C hyperconjomers of methyl substituted tertiary carbocations

Sorensen provided convincing evidence that the position of the substituent also

has an effect on the stability of hyperconjomers. For 3-methylsubstituted carbocation the

C-C hyperconjomer is more stable and for 4-methyl substituted carbocations, it is the C- 48

H hyperconjomer which exists exclusively. 35 Which hyperconjomers will form initially also depends on the position of the leaving group. Loss of an axial leaving group would lead to the C-H hyperconjomer, while equatorial loss would give the C-C structure.

Regarding nucleophilic capture of these carbocations, geometry and electronic distribution of the LUMO orbital showed that in the C-C hyperconjomer, the nucleophile would attack from the equatorial face, and from the axial face for the C-H hyperconjomer. These trajectories are not determined by steric effects, but by the electronic structure of the given cation. 37 If the rate of C-H and C-C interconversion is slow with respect to nucleophile capture, one would get retention of configuration from either an axial or equatorial leaving group. However, if the interconversion rate is faster than nucleophile capture, then there would be a chance of getting both retention and inversion of configuration. In this scenario, we also hypothesize that the ratio of retention to conversion will be the same regardless of the position of the leaving group in the substrates provided the hyperconjomers are given enough time to reach equilibrium.

That means the major product would always be the one which will form by capturing the more stable hyperconjomer. One such example reported by the Whiting group is solvolysis of 2,5-dimethyl-2-adamentyl substrates where one product always resulted regardless of the position of the leaving group. 37, 38

It is important to note that no methods have yet been reported in which an initially

generated hyperconjomer is captured for stereoretentive product formation. 37 We believe

that, for the first time, we have developed such a unique reaction. Specifically, we argue

that in our previously described chlorination reaction, a chloride nucleophile captures the

initially generated hyperconjomer before it equilibrates with other hyperconjomer form.

Although all of Sorensen's studies were performed on tertiary cyclohexyl carbocations, we believe the energetic principles remain valid for our substituted secondary cyclohexyl system.

Before proposing a plausible mechanism to explain our experimental chlorination results, a few important observations are summarized: a) no hydride shift or inversion product was observed for 2-substituted cyclohexanols (Table 6 and entry 6, Table 7) and retentions were always exclusive products from various 3-and 4-substituted cyclohexanols (Table 8, 9, and 10). Also no hydride shift for 3,3,5-trimethylsubstituted substrate ( 80 ). These data appear to indicate that the reaction does not proceed through classical carbocations. Sorenson et. al. have also shown that 2-methyl substituted

carbocations undergo rapid 1,2 hydride shift that can not be frozen out at any accessible

temperature;35 b) stereoretention is not necessarily due to assistance from a double bond

in steroid substrates (entry 7 and 8, Table 7 and entry 7, Table 10); c) The amount of

TiCl 4 has a pronounced effect on stereochemical outcome (Table 10); d) The hydride

shift product is obvious for alcohols where the leaving group situated at the axial position

with hydrogen anti-periplanar to the leaving group (Table 8 and Table 9); e) Between two

hydride shifted products, the major product is always the one with chloride at the axial

position, that is, chlorine takes the same position as that of the hydrogen that departs, and

the ratio between two products increases with decreasing temperature (Table 8 and Table

9); f) Decreasing temperature increases the amount of stereoretentive product; g) Cross

experiment indicates that most probably it is the ligand from titanium(IV) that is

delivered to the electrophilic carbon.

Based on the above discussion and observations, we propose two possible mechanisms. The first mechanistic possibility involves a concerted six-membered transition state similar to the literature proposed four-membered transition state for the

SNi mechanism where the nucleophile attacks from the same side of the leaving group in the transition state.

TiX4 TiX4

X SO2 R1 O X X Ti OSOX + R2 Catalytic S 91 R R1 cycle I X 1 Catalytic X 88 O X O H R2 cycle II R2 S O X R1 O R + H O X H 1 O O S 88 S X = Cl, Br R2 X R2 − Ti X Ti H X X X H X X X 89 Possibile Transition State: 90

O X R O R O 1 S X 1 S O R X R2 X 2 Ti Ti H X H X X X X X 92 93

Scheme 14 . Catalytic cycles involving six-membered transition states

Two possible catalytic cycles have been shown in scheme 14. Though oxygen is

more prone to chelate Ti(IV), theoretically both the halogen and oxygen of halosulfite

can chelate Ti(IV). Depending on the chelating atom, we can propose two catalytic cycles

– Catalytic cycle I (when oxygen is chelator) and catalytic cycle II (when halogen is

chelator) (scheme 14). In cycle I, TiX 4 chelates the oxygen of halosulfite ( 88 ) to generate

the complex 89. Complex 89 breaks down to the halide product with concomitant

generation of titanium(IV) halide-sulfonyl halide complex 91 via the six-member transition state 93 which then decomposes to regenerate the catalyst TiX 4 and SO 2, the

actual leaving group. In cycle II, TiX 4 chelates the halides of the halosulfite 88 to make

51 the complex 90 which then decomposes to halide product, SO 2 and the catalyst in one

step via the six-member transition state 92 . In this cycle, catalyst and products are

generated in just a single step, so entropically it should be favorable. But as far as

chelating ability is considered, oxygen should be a better chelator than halide which

favors catalytic cycle I.

As previously described, inversion products resulted in our chlorination reaction

of other alcohols other than 2-substituted cyclohexanols. One possible way to explain

this anomaly would be to postulate a six-membered ring transition state where the

nucleophile can attack from the back-side. In the literature such mechanisms have been

assigned S Ni-back-side; these have been shown by theoretical calculations to proceed by retention and inversion via a four-member ring transition state. 33, 39

R 1 Cl R1 R + O Cl + 1 R2 R O O S Ti Cl 2 S R2 S Cl O H O Cl H O Cl H 90 94 Cl − Ti Cl Cl Cl

S 2 TiCl4 N R 1 R2 O Cl R2 S R Cl 1 + SO2 H O H 88 95

Scheme 15 . One possible way to obtain inversion products

Another way to explain the appearance of inversion products is through an alternative decomposition of halosulfite intermediate (scheme 15). Thus when TiCl 4 chelates the chlorine atom of chlorosulfite 88 to give intermediate 90 , there is also a possibility that the sulfur-chlorine bond breaks and generates the sulfur dioxide solvated carbocation 94 along with nucleophilic titanium(IV)-pentachloride complex. A chloride

− from the [TiCl 5] complex now can attack from the back-side (S N2) of 94 to varying

extents depending on the steric properties of the substrate to generate the inversion

product ( 95 ). However this proposed inversion mechanism fails to explain the fact that

for trans-4-methylcyclohexanol more inversion was observed compare to cis-4-

methylcyclohexanol (Table 8). Ideally inversion by S N2 should be more favorable with

the cis -subtrate since the nucleophile can approach from the sterically favored equatorial

position.

Cl − H + H S TiCl + O + O 4 − H TiCl4 + H O O 96 97 S 98 99 Cl − Cl S TiCl O + O 4 H + + H 100 H 101 102 Cl − H + H S TiCl + O + O 4 − H TiCl + 4 H O O 103 104 S 105 106 Cl Cl − S TiCl O + O 4

H + + 107 H 108 109 H

Scheme 16 . Possible explanation for hydride shift products via non classical

carbocation

Hydride shift products derived from 3-and 4-substituted isomeric cyclohexanols

also deserve mention. In complexes 100 and 107, the leaving group is axial and thus (as

anti-periplanar orientation is the required geometry for a hydride shift) the hydride shift

proceeds with facility leading to non classical carbocations 101 (scheme 16). According to Sorensen’s work, the C-H hyperconjomer 101 should be generated initially from 53 substrate 100 which can then equilibrate with the C-C hyperconjomer 102 . Being a

secondary carbocation, the initially formed carbocation isomer (101 ) should be very

reactive and captured by chloride before it equilibrates completely with isomer 102 . This

should be true for the substrate 107 also. We believe this explanation accounts for why

the formation of the hydride shift product with chloride at the axial position is very

selective for substrates 73 and 78 (Tables 8 and 9).

To explain hydride shift products resulting from substrates 96 or 103, we may

hypothesize that the substrates must first undergo an unfavorable “ring flip”. In this

mechanistic conception, a ring flip brings a hydrogen and the leaving group into anti-

periplanar orientation. For example, complex 96 is expected to undergo a conformational

conversion to give 97 so that hydrogen and leaving group are properly oriented for a

hydride shift. Ideally, a hydride shift should initially generate the carbocation C-H

hyperconjomer 98 . But now if we apply the same theory as we applied for 100 & 107 , the

C-H hyperconjomer 98 should react with chloride before it equilibrates with C-C

hyperconjomer 99, and in that case the major hydride shift product would be the one

where chloride is at the equatorial position after ring flip. But this is in contradiction with

the experimental results, where in every case, the hydride shifted product is selective for

axial chloride. This contradiction with experimental results will be resolved only if we

consider that major attack happens from the C-C hyperconjomer. Similarly this should be

true for the complex 103 .

Therefore it appears that, if the literature (especially Sorensen’s work) is correct,

the ring flip mechanism is not supported. Our experimental results for 2-substituted

cyclohexanols (Table 6 and entry 6, Table 7) also are against this ring flip hypothesis as

54 we never observed any hydride shift products for these substrates. As shown in scheme

17, although the ring flip is prohibitive for l-menthyl substrate ( 112 ) (as it will bring all

the groups axial position), this should not be true for trans -2-methyl substrate 110 . If 96 can undergo ring flip, energetically 110 should have no problem conformational

interconvesion to give structure 111, which can then easily undergo a hydride shift.

However, we do not observe hydride shift products for this substrate. Also, on the basis of above mechanistic discussion, it is very hard to explain why decreasing the temperature and increasing the amount of TiCl 4 eventually makes the reaction exclusive

stereoretentive, especially for 3β -cholestanol (Table 9 and 10).

Cl − H S TiCl4 O + O − H TiCl4 + O O 110 111 S Cl

− O X Cl S − TiCl4 + + TiCl4 O O O S 112 113 Cl

Scheme 17 . Possible ring flip in trans -2-methylcyclohexyl and l-menthyl substrates

To better account for these discrepancies, we propose a second mechanism on the basis of works done by Sorensen et. al. on substituted tertiary cyclohexyl carbocations.

As shown in scheme 13, substituted tertiary cyclohexyl carbocations exist as two

“nonclassical” isomeric structures: 86 (C-H hyperconjomer) and 87 (C-C hyperconjomer) where both structures are in chair conformations. Though our system is substituted secondary alcohols, theoretically all the “nonclassical” properties should be equally applicable to our secondary carbocation system. On the basis of these assumptions we propose a mechanism which can be termed as “nonclassical S N1”. 55

TiCl4 SO2

H Cl S Cl3Ti O O O S O 114 Cl H Cl

Cl H H Cl − + + S S O + O O O − − Ti Cl Cl Ti 116 Cl 115 4 Cl Cl

Scheme 18 . Catalytic chlorination cycle involving “nonclassical” carbocations

In scheme 18, the catalytic cycle for stereoretentive chlorination using thionyl chloride and TiCl 4 for a general substrate 114 with the leaving group at equatorial position (as an example) has been shown. Only one catalytic cycle is presented, where

TiCl 4 binds to the oxygen atom of chlorosulfite. Another cycle is also possible where

TiCl 4 chelates chloride of chlorosulfite similar to the cycle II presented in scheme 14.

TiCl 4 chelates with the oxygen of chlorosulfite 114 to generate complex 115 . Following

TiCl 4 chelation, the “nonclassical” carbocation 116 is formed which is actually C-C hyperconjomer. Because it is secondary, 116 probably exists for a very short interval of time, and the leaving group TiCl 4-OSOCl does not move appreciably from the

carbocation center. Perhaps this is a non-solvent separated tight-ion pair. Then one of the

chlorides bonded to Ti(IV) captures the C-C hyperconjomer from the equatorial position

to produce the retention product. Because of chelation with the oxygen of chlorosulfite,

chlorine bonded to the now anionic Ti(IV) center should be more nucleophilic than

chlorine on the sulfur atom. In this conception, the inversion product should result if the

equilibrium between the C-C hyperconjomer ( 116 ) and the C-H hyperconjomer ( 117 ) is

faster than nucleophilic capture of carbocation by chloride (scheme 19). Furthermore the

56 rate of equilibrium should be dependent on the stability of hyperconjomer and temperature. For example, if 116 is more stable, being generated directly from the substrate, the equilibrium rate between 116 and 117 should be slow and the retention versus inversion ratio should be high. But if 116 is less stable, then the equilibrium will try to shift towards 117 at a higher rate. Faster equilibrium can result in a relatively low retention versus inversion ratio. Therefore the experimental stereochemical outcome mainly depends on how quickly the nucleophile can capture the hyperconjomer, which is generated directly from the substrate and rate of equilibrium between two hyperconjomers or stability of hyperconjomers. Temperature should also have the similar effect. Lowering the temperature should decrease the rate of conversion between hyperconjomers, which could lead to the better retention to inversion ratio.

H + + H

H H 116 117

Scheme 19 . Equilibrium between the C-C hyperconjomer ( 116 ) and the C-H hyperconjomer ( 117 )

In scheme 20 experimental results for various 3-and 4-substituted cyclohexanols are rationalized on the basis of “nonclassical” carbocations. Trans -4-methylcyclohexyl chlorosulfite 72 generates the complex 96 which then breaks down to the C-C hyperconjomer 118 . 118 can then equilibrate with the C-H hyperconjomer 119 . As soon as 119 is formed, the hydride shift happens easily as it is in ideal conformation for the hydride shift, to produce 3-substituted C-H hyperconjomer 121 . 121 then can equilibrate with the C-C hyperconjomer 120 .

H Cl − H + + S TiCl4 O + O H

H H H 96 118 119 hydride shift

H + + Cl − 120 H 121 +S TiCl4 H O O + + H H H H 100 H 119 118 hydride shift

+ +H 120 H 121 H Cl − H + + S+ TiCl4 O O H H H H 103 120 121 H hydride shift + + H 119 Cl − 118 +S TiCl4 H O O + + H H H H 121 120 107 hydride shift H + + H 119 118

Scheme 20 . A possible explanation for the inversion products and stereoselective hydride shift products

As 118 is formed directly from 96, it should exist in a major amount during nucleophilic attack which would explain the major stereoretentive product. As only 119 is responsible for hydride shift and exists in minor amount, 121 should also be minor but more than 120 . Because of this, product 77 is the major hydride shifted diastereomer formed albeit in very low yields compares to direct substitution product (Table 8).

Similarly cis -4-methylcyclohexyl chlorosulfite-TiCl 4 complex 100 decomposes to the C-

H hyperconjomer 119, which should exist in the major amount during nucleophilic capture. As now 119 is in ideal conformation for a hydride shift and exists in major amount, 121 should form to a large extent. This appears to explain why the amount of hydride shifted product 77 (Table 8) is very high compare to when trans -4-methyl cyclohexyl is the substrate. It also seems to account for the low ratio of the direct to

hydride shift product in case of cis -4-methyl substrate compared to trans -4-methyl

substrate. The temperature dependence of equilibrium between hyperconjomers accounts

for the improved ratio between retention and inversion products as well as between

hydride shifted products 77 and 76 at lower temperatures (Table 8). Similar explanations

hold for 3-substituted cyclohexanols. Also, the better stereoretentive outcome of the

products, when excess TiCl 4 was used especially for 3-substituted cyclohexanols and 3 β-

cholestanol, can now be explained. As the amount of TiCl 4 increases, thus increasing the amount of the nucleophile chloride, the rate of nucleophilic capturing of carbocations accelerates compared to the rate of equilibrium between the hyperconjomers. For example, let us consider the situation of 3β-cholestanol where the leaving group actually is situated at an equatorial position. Therefore, decomposition of the leaving group should generate the C-C hyperconjomer 122 (scheme 21) but probably in this case the rate of equilibrium between the two hyperconjomers is large compared to the rate of nucleophilic attack. That’s why when less than 2.0 equivalents TiCl 4 was used, the

retention to inversion ratios were low (~2.5:1). But when 5.0 equivalents TiCl 4 was used, exclusive stereoretention was observed (Table 10). This may be explained by the presence of excess TiCl 4 which helps to capture the C-C hyperconjomer before it

converts to C-H hyperconjomer.

C6H13 Ret. vs Inv. H ∼ TiCl4 (2.0 equiv) 2.5 : 1

H H Exclusive ClOSO TiCl4 (5.0 equiv) retention H 81

+ H ClOSO + H H H H H 81 122 123

Scheme 21 . Explanation for the stereochemical outcome of 3β-cholestanol substrate

(81 )

At last we come to three questions – 1) why is there no inversion or hydride shift

for 2-substituted cyclohexanols; 2) why is there no hydride shift from position 2 for 3-

methylsubstituted cyclohexanols and no hydride shift for 3,3,5-trisubstituted substrate

(80 ); and 3), why is there no selectivity for linear alcohol. Perhaps the answers for the first two questions are related to subtle electronic factors that are best elucidated by computational studies. It may also be useful to undertake another large set of experiments with various electronically different 2-substituted cyclohexanols.

One possible hypothesis is that the 2-substituted C-C hyperconjomer 125

(generated from trans -2-substituted substrate where the leaving group at equatorial position) is exceptionally stable compared to the C-H hyperconjomer 126 (scheme 22).

Though Sorensen has shown the stability of 3- and 4-substituted hyperconjomer of tertiary cyclohexyl carbocations, they were unable to perform any studies for two- substituted carbocations due to very rapid 1,2-hydride shift regardless the temperature. If we assume a high stability, before any interconversion happens, the C-C hyperconjomer

125 is captured by chloride to give the complete stereoretention product. As the C-H

60 hyperconjomer 126 does not form, no hydride shift or inversion product was obtained.

Due to the presumed greater degree of instability of the 2-substituted C-H

hyperconjomer, no hydride shift was ever observed from the position 2, but rather always

happens selectively from position 6 to yield 4-substituted hydride shift products in case

of 3-substituted substrate 78 . Also, probably for the same reason, no hydride shift product

was observed under any conditions in case of cis -3,3,5-trimethylcyclohexanol where any

type of hydride shift (either from position 2 or position 6) will lead to a 2-substituted C-H

hyperconjomer 129 or 130 carbocation which we hypothesized to be unstable (entry 1-4,

Table 10).

H + + X H 125 126 C-C hyperconjomer C-H hyperconjomer (very stable) (very unstable)

H+ + H OSOCl X 124 125 126 H + + OSOCl H H H H H H H 80 127 128 X

or +H +H 129 130 OSOCl + H X +H H H H H 78 121 126

Scheme 22 . Possible explanation for no hydride shift or inversion for 2- and 3,3,5- substituted substrates

Finally, regarding the third question relating to the lack of stereocontrol in acylic systems, we argue that these open systems have a lower barrier to planarization in the

61 ionization step. In cyclic systems, ionization to give a classical carbocation would force the ring into a half-chair structure leading to severe torsional strain. By contrast, acyclic systems react with the Lewis acid to give classical carbocations. Importantly, these acyclic cations are not expected to retain their "configuration" along the Sorensen hyperconjomer model and will likely be attacked from either face with equal ease unless impeded by a nearby stereocenter (diastereocontrol).

In conclusion, we have developed very mild, catalytic, and stoichiometric chlorination reactions for secondary cyclic alcohols. These reactions appear to be independent of diastereocontrol or anchimeric assistance (e.g. steroid substrates). Our current hypothesis is that these reactions proceed through nonclassical carbocation intermediates expanding upon a theory developed by Sorensen et. al. To our knowledge, our reaction systems are very unique to generate stereoretention product and could be the first experimental proof in support of Sorensen’s theory of nonclassical carbocations in simple cyclohexyl systems.

3.5 Experimental section

General Information: All the reactions were carried out under an atmosphere of nitrogen or argon in oven-dried glassware with magnetic stirring. Purification of reaction products were carried out by flash column chromatography using Flash Silica gel 40-63 µ using hexane or pentane as eluant. Analytical thin layer chromatography was performed on 0.25mm silica gel 60-F plates. Visualization was accomplished with UV light and aqueous potassium permanganate solution staining followed by air heating.

1H NMR were recorded on a Varian Mercury400 (400 MHz) spectrometer and are reported in ppm using solvent as internal standard (CDCl 3 at 7.26ppm). Data are reported 62 as: (b = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet; coupling constant(s) in Hz, integration). 13 C NMR were recorded on Varian Mercury400

(100 MHz) spectrometer. Chemical shifts are reported in ppm trimethylsilane, with

solvent resonance employed as the internal standard (CDCl 3 at 77.0 ppm). High-

resolution mass spectra were obtained from University of Florida Mass Spectrometry

Laboratory. Optical rotation was recorded on Jasco P-2000 Polarimeter. Complete

characterization provided only for the compound which are not reported or well

characterized. For reported well known compounds only proton NMRs are provided to

show the purity of compounds.

Materials: Anhydrous Dichloromethane and other chemicals were obtained from

commercial sources and were used without further purification.

General procedure for chlorination (high concentration): To an ice-cold 1.0M

solution of alcohol in dichloromethane 1.5 equivalent thionylchloride was added and

stirred at that cold for one hour. Hydrogen chloride which is generated during this step

was released out of the reaction container using a needle. After that TiCl 4 was added

(catalalytic to stoichiometric amount) and stirred for required time (15-30min). Reaction was quenched with deionised water and stirred until both layers were clear and transparent. Organic dichloromethane was extracted and collected. Water layer was washed with two more times with dichloromethane and collected together. Organic layer was dried over anhydrous sodium sulphate and concentrated in vacuum. Then product was purified by flash using pure hexane or pentane (in case of low boiling chlorides).

General procedure for diluted reactions: To an ice-cold 1.0M solution of alcohol in dichloromethane 1.5 equivalent thionylchloride was added and stirred at that cold for

63 one hour. Hydrogen chloride which is generated during this step was released out of the reaction container using a needle. Then reaction mixture was diluted to required concentration (0.5-0.01M) by adding required amount dichloromethane using syringe and cooled to required temperature (-78-0°C). After that TiCl 4 was added (catalytic to stoichiometric amount) and stirred for required time. Then rest of the working procedure is same as mentioned above.

General procedure for preparation of pure (in those case where mixture of chlorides were resulted) chlorides: To a solution of tosylate of required alcohol in DMF

(0.5M) 5.0equivalent LiCl was added and heated at 60 oC for more than 15h . Then reaction was cooled down, hexane or pantane (in case of low boiling chlorides) was added and then quenched with 2M HCl. Organic layer was collected and dried over anhydrous sodium sulphate. Then it was passed through silica gel column and concentrated in vacuum to get pure product.

(1 R, 2 R)–1-chloro-2-methylcyclohexane(racemic) ( 69). 1H NMR (400 MHz,

CDCl 3) δ 3.53-3.47 (td, J = 10.59, 4.19 Hz, 1H), 2.25-2.17 (m, 1H), 1.83-1.74-1.71 (m,

2H), 1.68-1.54 (m, 4H), 1.31-1.24 (m, 2H), 1.07(d, J = 6.47 Hz, 3H); 13 C NMR (100

MHz, CDCl 3) δ 67.7, 41.1, 37.5, 34.8, 26.5, 25.4, 20.2.

(1 S, 3 R)–1-chloro-3-methylcyclohexane (racemic) ( 76 ). 1H NMR (400 MHz,

CDCl 3) δ 3.88-3.80 (tt, J = 11.69, 4.14 Hz, 1H), 2.19-2.14 (m, 2H), 1.82-1.75 (m, 1H),

1.66-1.61 (m, 1H), 1.53-1.41 (m, 2H), 1.33-1.21 (m, 2H), 0.92 (d, J = 6.54 Hz, 3H), 0.90-

13 0.80 (m, 1H); C NMR (100 MHz, CDCl 3) δ 59.7, 45.9, 36.9, 33.5, 33.1, 25.9, 22.2.

(1 R, 3 R)–1-chloro-3-methylcyclohexane(racemic) ( 77 ). 1H NMR (400 MHz,

CDCl 3) δ 4.50-4.47 (b m, 1H), 1.99-1.89 (m, 3H), 1.82-1.65 (m, 3H), 1.57-1.52 (m, 1H),

1.45-1.38 (m, 1H), 0.99-0.93 (m, 1H), 0.89 (d, J = 6.53 Hz, 3H); 13 C NMR (100 MHz,

CDCl 3) δ 60.1, 42.3, 34.1, 33.9, 26.4, 21.7, 20.2.

1 trans-1-chloro-4-methylcyclohexane (74 ). H NMR (400 MHz, CDCl 3) δ 3.85-

3.77 (tt, J = 11.60, 4.19 Hz, 1H), 2.19-2.14 (m, 2H), 1.77-1.73 (m, 2H), 1.67-1.59 (m,

2H), 1.44-1.35 (m, 1H), 1.06-0.96 (m, 2H), 0.87 (d, J = 6.56 Hz, 3H); 13 C NMR (100

MHz, CDCl 3) δ 60.1, 37.1, 34.8, 31.2, 21.8.

1 cis-1-chloro-4-methylcyclohexane (75 ). H NMR (400 MHz, CDCl 3) δ 4.42-4.39

(b m, 1H), 1.98-1.93 (m, 2H), 1.81-1.73 (m, 2H), 1.51-1.43 (m, 5H), 0.93 (d, J = 5.29 Hz,

13 3H); C NMR (100 MHz, CDCl 3) δ 59.8 33.6, 28.9, 22.3, 14.0.

(1 S, 5 S) -1-chloro-3,3,5-trimethylcyclohexane (racemic) (Table 10). 1H NMR

(400 MHz, CDCl 3) δ 4.07-3.99 (tt, J = 12.11, 4.19 Hz, 1H), 2.19-2.13 (m, 1H), 1.91-1.86

(m, 1H), 1.70-1.61 (m, 1H), 1.36-1.31 (m, 2H), 1.18-1.09 (m, 1H), 0.95 (s, 3H), 0.91 (d,

13 J = 6.51 Hz, 3H), 0.90 (s, 3H), 0.84-0.78 (m, 1H); C NMR (100 MHz, CDCl 3) δ 57.4,

49.5, 46.9, 45.7, 33.4, 32.8, 28.7, 25.1, 22.1.

1 5-Cholesten-3β-chloride ( 70 ). H NMR (400 MHz, CDCl 3) δ 5.37-5.36 (m, 1H),

3.81-3.73 (tt, J = 11.77, 4.75 Hz, 1H), 2.60-2.45 (m, 2H), 2.01-1.80 (m, 6H), 1.58-0.93

(m. 20H), 1.02 (s, 3H), 0.91 (d, J = 6.51 Hz, 3H), 0.87 (d, J = 6.60 Hz, 3H), 0.86 (d, J =

13 6.59 Hz, 3H), 0.67 (s, 3H); C NMR (100 MHz, CDCl 3) δ 140.7, 122.5, 60.3, 56.6, 56.1,

49.9, 43.3, 42.2, 39.6, 39.4, 39.0, 36.3, 36.1, 35.7, 33.3, 31.8, 31.7, 28.2, 28.0, 24.2, 23.8,

α 25 22.8, 22.5, 20.9, 19.2, 18.7, 11.8; [ ]D –24.7( c 3.85 CHCl 3).

1 3β-chloro-androst-5-en-17-one ( 71 ). H NMR (400 MHz, CDCl 3) δ 5.41-5.40 (m,

1H), 3.81-3.73 (tt, J = 11.78, 5.16 Hz, 1H), 2.61-2.43 (m, 3H), 2.17-2.05 (m, 3H), 1.98-

1.80 (m, 4H), 1.69-1.43 (m, 5H), 1.32-1.24 (m, 2H), 1.18-1.11 (m, 1H), 1.06 (s, 3H),

13 1.03-0.97 (m, 1H), 0.89 (s, 3H); C NMR (100 MHz, CDCl 3) δ 221.1, 141.1, 121.7,

60.0, 51.6, 50.1, 47.5, 43.2, 39.0, 36.4, 35.8, 33.2, 31.3, 30.6, 21.8, 20.2, 19.2, 13.5.

1 5-Cholestan-3β-chloride (Table 10) . H NMR (400 MHz, CDCl 3) δ 3.90-3.82 (tt,

J = 11.77, 4.69 Hz, 1H), 2.05-1.94 (m, 2H), 1.82-1.72 (m, 4H), 1.68-1.62 (m, 2H), 1.56-

1.43 (m, 4H), 1.36-0.96 (m, 19H), 0.89 (d, J = 6.59 Hz, 3H), 0.87 (d, J = 6.61 Hz, 3H),

13 0.86 (d, J = 6.60 Hz, 3H), 0.83 (s, 3H), 0.64 (s, 3H); C NMR (100 MHz, CDCl 3) δ

140.7, 122.4, 60.3, 56.6, 56.1, 50.0, 43.3, 42.2, 39.6, 39.5, 39.0, 36.3, 36.1, 35.7, 33.3,

α 25 31.8, 31.7, 28.2, 28.0, 24.2, 23.8, 22.8, 22.5, 20.9, 19.2, 18.7, 11.8 . [ ]D +25.0 ( c 0.9

CH 2Cl 2).

(1 S, 2 R, 4 R)-2-chloro-1-isopropyl-4-methylcyclohexane ( 63 ). 1H NMR (400

MHz, CDCl 3) δ 3.81-3.75 (td, J = 11.09, 4.23 Hz, 1H), 2.38-2.31 (m, 1H), 2.24-2.21 (m,

1H), 1.74-1.67 (m, 2H), 1.42-1.34 (m, 1H), 1.42-1.34 (m, 2H), 1.07-0.87 (m, 2H), 0.92

(d, J = 7.15 Hz, 3H), 0.91 (d, J = 5.95 Hz, 3H), 0.77 (d, J = 6.94 Hz, 3H); 13 C NMR (100

α 25 MHz, CDCl 3) δ 63.9, 50.3, 46.7, 34.2, 33.3, 27.1, 24.2, 21.9, 21.0, 15.1. [ ]D –41.2 ( c

9.05 EtOH).

CHAPTER FOUR ONE-POT TWO STEP STEREORETENTIVE AMIDATION

REACTIONS OF SECONDARY CYCLIC ALCOHOLS

4.1 Introduction Amides are among the most abundant functional groups in nature and, understandably, decades of creative research have been devoted towards their efficient synthesis with the majority of these studies centering on the dehydrative coupling of amines with carboxylic acids. 41 As a tool for the direct conversion of alcohols to amides,

the Ritter reaction has received substantial attention over the year. However, if we

exclude anchimeric assistance 42 or diastereomeric control, 43 this reaction is well-known to proceed by a non-stereospecific carbocation mechanism and is often limited to alcohols where such intermediates are stabilized. Thus many stereospecific approaches to amides from chiral alcohols require multistep procedures. Among these, nucleophilic azidation reactions followed by a reduction/acyl coupling protocol have proved useful for the synthesis of amides (scheme 23). 44

To synthesize amide 132 from alcohol 131 , before the development of our stereoretentive azidation reaction, several steps were traditionally required including an initial inversion of alcohol (path A, scheme 23). Using our new stereoretentive azidation method no inversion of alcohol is required (path B, scheme 23). However path B still requires four steps. We are delighted to report here that we have developed a mild

67 stereoretentive amidation reaction using nitrile as the source of amide nitrogen instead of azide.

2 Path A R2 R R2 - R2 R1 R1 N R1 3 R1 OH HO LG N3 H 131 inversion H H inversion H reduce R3COX O R2 O R1 S Ti(N ) R2 1 R2 O O 3 4 1 reduce R R N 3 3 H NALG X 3 H N R retention H R COX X X H Path B 132

Scheme 23. Current azide approach to the stereospecific synthesis of amide starting from secondary alcohols

4.2 Development of stereoretentive amidation reactions: Results and discussion

A stereoretentive amidation reaction for cyclic alcohols was initially observed when reacting a quisylate (QsO) ( 133 ) with titanium(IV) fluoride in the presence of alkyl or aryl nitriles (scheme 24).

O O 2 R S 1 R O N QsO H 2 1. TiF4 1 R2 O R 133 3 R R1 R CN OH Cl 3 + H N R 2 − 2. H2O H R S 1 O H R O retention NALG H 134

Scheme 24. Stereoretentive amidation reaction

However the yields for this two step reaction were modest. Then we thought to extend our chelating leaving group concept to chlorosulfite which can be generated in situ. We realized that chlorosulfite could be applied as a leaving group for a nucleophilic substitution reaction with nucleophiles other than chloride. We have also shown in 68 chapter 3 that bromide can be synthesized from chlorosulfite. To our knowledge, chlorosulfites have never been exploited as leaving groups being primarily relegated to use as intermediates in classic SOCl 2 chlorination reactions. Here we developed the first application of chlorosulfite ( 134 ) as leaving group in one-pot, two-step stereoretentive amidation reaction of secondary cyclic alcohols (scheme 24). The initial aim to use TiF4 in our reactions with chelating leaving groups was based on our desire to develop stereoretentive fluorination reaction as a follow-up our chlorination and bromination using the corresponding Ti(IV) halide reagents. Although currently under study by various groups for use in dental varnishes, 45 titanium(IV) fluoride has received only modest attention from the organic synthesis community 46 probably due to its moderate complexing ability, 47 propensity for oligoemr complex formation, and sparing solubility in typical reaction solvents for trimeric structure of TiF 4 complexation. TiF 4 is very

soluble in Lewis basic solvent such as nitriles and acetone. Since Lewis acidity is very

critical to our mechanism, solvents such as nitriles have been avoided since they greatly

diminish the Lewis acidity especially when present in large amounts. As titanium(IV) has

six coordination sites we thought that probably the addition of stoichiometric amount of

nitriles can break the trimeric structure of TiF 4 and help to dissolve it in a non-chelating

solvent like dichloromethane. Indeed, we observed the same result after doing the above

experiment. Hoping that this dissolved TiF 4-nitrile complex would react with quisylate

(133 ) and chlorosulfite ( 134 ) to yield stereoretentive fluoride, we performed the reaction using a benzonitrile/CH 2Cl 2 as solvent system with the chlorosulfite of l-menthol. To our surprise, instead of forming the expected product fluoride, amide product ( 135a) was obtained after aqueous workup with complete retention of configuration (Table 12). The

69 major side product in this reaction was chloride 136 . In attempting to optimize this new amidation reaction, l-menthol was chosen since this substrate presents challenges in terms of steric hindrance and propensity for side reactions such as eliminations and hydride shifts. Others have previously reported that TiF 4 forms a variety of oligomeric complexes with some preference for the trimer form in the presence of benzonitrile depending on the concentration. 48 Based on this earlier work, we suspected that multiple equivalents of

TiF 4 and nitrile would be necessary for our amidation reaction. With this in mind, we performed an optimization study to identify the ideal concentration and stoichiometry necessary for high yielding amidation reactions.

H OSOCl N Ph Cl PhCN, TiF4 + ° O CH2Cl2, 0 C 135a 136 2.0 h

Equiv Conc Yield(%)a b Entry PhCN TiF4 TiF4(M) 135a 136 1 4 2 0.2 30 55 2 4 2 1.0 45 43 3 8 4 1.0 52 35 4 8 4 2.5 56 33 5 16 4 2.5 62 25 6 16 4 5.0 62 25 7 24 6 2.5 67 22 8 32 8 2.5 75 13 9 40 10 2.5 84 5 10 40 10 5.0 84 5 11 48 12 2.5 84 5 aIsolated yields. bChlorides formed with complete retention of configuration

Table 12 . Effect of TiF4 on amidations yield

The chlorosulfite of l-menthol was prepared by treating the alcohol with 1.5

equivalents of thionylchloride at 0°C. This chlorosulfite was then added to

dichloromethane solutions of TiF 4/benzonitrile of various concentrations and allowed to

70 stir for two hours at 0°C. It was soon observed that the amount of chloride side product formed varied significantly with the equivalents of TiF4 (Table 12). Furthermore, the

optimal ratio of benzonitrile to TiF 4 is 4:1. Using ten equivalents of TiF 4 (2.5 M), an

optimum yield of 84% of amide 135a was obtained. It is worth to mention here that this

yield represents a six fold increase over the highest yield achieved in literature using the

classic Ritter reaction with menthol. 49 It was also observed that under all reaction

conditions both amide and chloride products were obtained with complete retention of

configuration.

H TiF4 (10 eq) OSOCl RCN (40 eq) N R

CH2Cl2 (2.5 M) O 0 °C, 2.0 h 135

Entry RCN Product Yielda CN 1 135b 65b Cl CN 2 135c 72b O CN 3 135d 85

4 CN 135e 80

NR 5 Cl3CCN 135f

6 H3CCN 135g 92 a b Isolated yield. Reactions 1.0 M in TiF4

Table 13 . Nitrile generality of stereoretentive amidation

To generalize this amidation reaction, further studies with l-menthol substrate revealed that stereoretentive amidation reaction is successful with both aromatic and aliphatic nitriles (Table 13). The primary limitation appeared to be with strongly electron deficient nitriles such as trichloroacetonitrile (Table 13, entry 5) presumably due to their 71 poor liganding ability. Sparingly soluble nitriles such as 4-chlorobenzonitrile and 4- methoxybenzonitrile required more dilute dichloromethane solutions for full dissolution leading to a non-optimal Ti(IV) concentration of 1.0 M possibly explaining their diminished amidation yields (entries 1 and 2, Table 13). We noted that methyl amide product 135g was produced in an excellent yield of 92% (entry 6, Table 13) using acetonitrile.

Using benzonitrile as a convenient coupling (because of UV-activity it was easy to monitor the reaction) partner, a variety of substrate alcohols were examined using our optimized amidation conditions (Table 14). Very similar to the previously mentioned menthol example, we observed that a number of cyclic chiral alcohols were converted to amide products with complete retention of configuration (Table 14, entries 1 - 4). Here again, solubility in the optimal solvent (CH 2Cl 2) for this reaction appears to be an important factor. In this regard, the sparing solubility of the steroid substrates (entries 3 and 4, Table 14) and other examples (entries 9 and 11, Table 14) required more dilute conditions (1.0 M in TiF 4) leading to slightly lower yields of the corresponding amide

products. In some cases, significant inversion product (~25%) was observed under these

reaction conditions (entries 5 and 6, Table 14). In particular, the reaction outcome of

cholestanol (entry 5, Table 14) attracted our attention since others have commented that

this substrate should proceed by a different mechanism in our system due to the absence

of a nearby double bond. 50 Though only 42% retention yield of amide was obtained for

cholestanol, exclusive stereoretention was observed for chloride product which has been

discussed in previous chapter. In general, our reaction gives high yielding results with

cycloalkanols of varying ring sizes under mild conditions (entries 7 - 10). However, our

72 conditions failed to yield amides with tertiary alcohol substrates giving the chloride products instead. An interesting exception to this trend is 1-adamantanol which was converted to amide 147 in rather low yield.

TiF (10 eq) 4 H PhCN (40 eq) N Ph ROSOCl R CH2Cl2 (2.5 M) O 0 °C, 2.0 h

Entry ROH Product Yielda

137 88 1 OH

OH 2 138 94 H C6H13

H 3b 139 75 H H HO O

H 4b 140 76 H H HO C6H13

5 H H 141 42c HO H

OH 6 142 63d OH 7 143 90

8 OH 144 80

9b OH 145 65

10 146 90

b 11 OH 147 40

12 Ph OH - NR

aYield of retention product only. bIntermediate chlorosulfite ° prepared at -78 C with TiF4 conc. maintained at 1.0 M. c,dInversion product produced in 25% yield.

Table 14 . Substrate generality for amidation with benzonitrile 73

This reactivity profile is highly complementary to the classic Ritter reaction which strongly favors easily ionized systems such as tertiary alcohols. In light of our hypothesized mechanism for this reaction (discussed below), the absence of reactivity with primary alcohols was not surprising and consistent with our previous work with titanium(IV) mediated reactions (halogenations and azidation). Even at room temperature after 24 h, 3-phenylpropanol failed to yield the desired amide product (entry 12, Table

14).

To understand the mechanism better and to confirm that the stereoselectivity of the reaction is not governed by nearby stereocenters, we examined a number of simple cyclohexanol systems. We hypothesized that if the reaction is under diastereocontrolled through a classical carbocation (SN1), then we should see the same product distribution from both trans - ( 148 ) and cis - ( 149) chlorosulfite. In fact we observed different results.

We saw a clear preference (~3:1) for retention in these amidation reactions (scheme 25).

NHCOPh

OSOCl NHCOPh 150 151 148 TiF4 OR OSOCl PhCN NHCOPh

NHCOPh 153 149 152

150 151 152 153 Yield(%)a trans (148) 99 37 10 1 91 cis (149) 2.5 8.1 8.7 1 85 aIsolated overall yield. Ratios deterimed by NMR

Scheme 25. Amidation in cis - and trans -4-methylcyclohexanol

Thus trans-4-methylcyclohexylchlorosulfite ( 148 ) led to primarily trans -product

150 and the cis -substrate led to mainly cis -amide product 151 . But at the same time both

substrates generated the hydride shifted products 152 and 153 with a preference for the

74 amide product 152 where amide group is always axial. It was also noted that the amount

of hydride shifted product increases for cis- substrate when there is hydrogen with anti -

periplanar orientation of the leaving group.

NHCOPh

OSOCl NHCOPh 150 151 154 TiF4 OR OSOCl PhCN NHCOPh NHCOPh 155 152 153

150 151 152 153 Yield(%)a cis (154) 0.0 0.0 1.0 4.0 91 trans (155) 1.0 59.0 57.0 19.0 83 aIsolated overall yield. Ratios deterimed by NMR

Scheme 26. Amidation in cis - and trans -3-methylcyclohexanol

An analogous study of 3-methylcyclohexanol revealed a similar preference for

retention of configuration (scheme 26). Thus cis -3-methylcyclohexanol chlorosulfite

(154 ) primarily led to cis -amide 153 and trans -substrate 155 led to mainly trans -product

152. Results for the trans -3-methylcyclohexyl substrate ( 155) is very similar to the

results for cis -4-methylcylohexyl substrate ( 149) as per as hydride shift is concerned. But

interestingly no hydride shifted product was observed for cis -3-methylcyclohexyl

substrate ( 154 ) where the leaving group is at equatorial position.

Though good stereospecificity was observed for cyclic alcohols, in case of acyclic

alcohols reactions were found to be non stereospecific. We conducted a study of acyclic

alcohols using ( S)-2-octanol and ( S)-1-phenylethanol. In a reaction of the non-racemic phenyl ethanol chlorosulfite ( 156 ) with benzonitrile and TiF 4, amide 157 was obtained entirely as the racemate in excellent yield (scheme 27). It is also to be noted that in this case 4 equivalents TiF 4 was enough to achieve excellent yield. Also as chlorosulfite of 75 phenyl ethanol readily converts to chloride product at 0°C, the chlorosulfite was prepared

o at -78 C and then added to TiF 4-benzonitrile solution at 0°C.

NHCOPh OSOCl TiF4(4 eq) Ph Ph PhCN(8 eq) 156 90% 157 (racemic)

NHCOPh TiF4(10 eq) + 4 PhCN(40 eq) 4 OSOCl 91% NHCOPh 4 158 159 (28% ee) 2.9:1 160

Scheme 27. Amidation of acyclic alcohols

The amidation reaction with 2-octanol produced a mixture of direct substitution

product 159 and hydride shifted product 160 (2.9:1). Polarimetry measurements of

purified hydride shifted product 160 indicated that it was essentially racemic. However, direct substitution product 159 gave an enantiomeric excess of 28% favoring inversion

(scheme 27).

4.3 Mechanistic discussion

Mechanism of amidation reactions also can be explained on the basis of

“nonclassical” carbocation similar to the chlorination reactions of the previous chapter and termed as “nonclassical S N1”. Amidation results can be explained same way as we explained for chlorination reactions in chapter 3. The main difference between amidation and chlorination reaction is that, except for 2-substituted cyclohexanols retention vs inversion ratios are lower for amidation reactions. We propose this difference is to be related to the poorer nucleophilicity of nitriles to chlorides. As a result, capturing of nonclassical carbocations should be relatively slow allowing time for the carbocation hyperconjomer which is directly formed from chlorosulfite to convert to other

76 hyperconjomer. Therefore, rapid conversion between hyperconjomer is responsible for relatively low retention to inversion ratio for amidation reaction. A particularly good example of this stereospecificity difference is the amidation and chlorination for 3 β-

chloestanol. Though exclusive retention for chlorination was observed for 3 β-chloestanol without any side product (Table 10, entry 7, chapter 3), 42% retention, 25% inversion and

10% hydride shift amide products were resulted for amidation reaction (entry 5, Table

14). This clearly indicates that in the case of chlorination reaction for 3 β-cholestanol, initially formed the C-C hyperconjomer 122 is quickly captured by the chloride before equilibrating with the C-H hyperconjomer 123 (scheme 21). However, for the amidation reaction, because of the low nucleophilicity of nitrile, now the C-C and C-H hyperconjomers get enough chance to equilibrate with each other, which accounts for the low retention vs inversion ratio. In addition, the persistent existence of the C-H hyperconjomer gives more time for hydride to shift to produce the hydride shifted product. A general mechanism for the amidation reaction has been shown in scheme 28.

Once the TiF 4-nitrile complex chelates to the chlorosulfite 114 , the nonclassical carbocation C-C hyperconjomer 162 formed which could then be captured by either chloride or nitrile. Probably 162 exists as tight ion pair; the nitrile complexed to TiF 4 then attacks the carbocation to generate either the nitrilium ion 163b or imidoyl chloride 163a ;

this complex then decomposes in water to yield stereoretentive amide 164 . Since chloride

is more nucleophilic, when small amounts of nitrile is present, the chloride product is

formed in large percentage. Only in the presence of excess nitrile, were good yields of

amide observed (Table 12).

H Cl H − Cl S + O O H Cl + S TiF4 O O + S N O O TiF TiF− 4 RCN N − 4 114 162 161 R R

O R H H H − + Cl R H2O Cl + SO N N and/or N 2 H TiF R 164 163a 4 163b

Scheme 28. A possible general mechanism and intermediates for the amidation reactions via non classical carbocations

In the case of linear alcohols, the reaction appears to proceed through a classical carbocation and hence no stereoselectivity was observed. Little selectivity for inversion product from 2-octanol is probably due to the attack by free nitrile from the back-side of the carbocation. Front side of carbocation probably is blocked due to tight ion pair formation with TiF 4-nitrile complex. As the nitrile, complexed to TiF 4, should be less

nucleophilic than free nitrile, back-side attack may be slightly favored over front side

attack by complexed nitrile (scheme 29). Since benzyl carbocation is more stable, it

exists probably as a dissociated carbocation, and hence captured from both sides leading

to complete racemization.

Cl − O − O O +S TiF4 Cl F N S 4− + O Cl S Ti R1 TiF4 O + O H less R N R nucleophilic 1 RCN R 1 N 165 166 R 167 R more nucleophilic

Scheme 29. Back-side attack by free nitrile is slightly favored due to more nucleophilicity compare to nitrile complexed with TiF 4 from front side

In conclusion, we have discovered an exciting variation of Ritter reaction using a very inexpensive and unexplored Ti(IV)F 4/nitrile reagent to prepare amide directly from

secondary alcohols. Critical to design of this new reaction is the first ever use of

chlorosulfites, formed by well-known reaction of alcohols and thionyl chloride, as in situ formed chelating leaving groups. Again the mechanism can be termed as “nonclassical

SN1” and provides perhaps a rare modern example of the S Ni mechanism.

4.4 Experimental section

General Information: All the reactions were carried out under an atmosphere of

nitrogen or argon in oven-dried glassware with magnetic stirring. Purification of reaction

products were carried out by flash column chromatography using Flash Silica gel 40-63 µ.

Analytical thin layer chromatography was performed on 0.25mm silica gel 60-F plates.

Visualization was accomplished with UV light and aqueous potassium permanganate solution staining followed by air heating.

1H NMR were recorded on a Varian Mercury400 (400 MHz) spectrometer and are reported in ppm using solvent as internal standard (CDCl 3 at 7.26ppm). Data are reported

as: (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet;

coupling constant(s) in Hz, integration). 13 C NMR were recorded on Varian Mercury400

(100 MHz) spectrometer. Chemical shifts are reported in ppm with trimethylsilane or

solvent resonance employed as the internal standard (CDCl 3 at 77.0 ppm). High-

resolution mass spectra were obtained from University of Florida Mass Spectrometry

Laboratory. Melting points were determined using Digimelt from Stanford Research

Systems and IR was recorded on Jasco FT-IR 4100 and optical rotation was recorded on

Jasco P-2000 Polarimeter. Complete characterization provided only for the compounds 79 which are not well characterized or not reported. For well known compounds only proton

NMRs have been provided to show the purity of the compounds. In case where both diastereomers were resulted, pure diastereomer was prepared by four steps reaction via

SN2. Pure enantiomeric compound also was prepared in the same way.

Materials: Anhydrous dichloromethane, titanium(IV)fluoride, all nitriles and alcohols are commercially available and used without further purification.

General procedure for stereoretentive amidation reactions: To an ice-cold solution of alcohol (1.0 equivalent) in dichloromethane (1.0M), 1.5 equivalent thionylchloride was added and stirred for 1h. During one hour reaction generated HCl gas was released by a needle. In another container to a suspension of TiF 4 (10 equivalent) in

dichloromethane (4.0M) nitrile (40.0 equivalent) was added and stirred until all TiF 4 dissolved. Then it was cooled in ice and resulted chlorosulfite was added to it by transferring using a cannula under argon pressure. Chlorosulfite container was washed with required amount of dichloromethane so that final concentration of TiF 4 is maintained 2.5M. Then it was stirred at ice-cold for another 2.0h. After that reaction was quenched with deionised water and stirred until organic layer become clear. Organic layer was extracted and aqueous layer was washed twice with dichloromethane and collected together with first extraction and dried over anhydrous sodium sulphate.

Solvent was removed in vacuum. Product was purified by flash using ethylacetate-hexane solvent combination.

NB: In this experiment as TiF 4 is very moisture sensitive, it was weighed first under argon and then other chemicals were measured accordingly.

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]benzamide ( 135a). 1H NMR

(400 MHz, CDCl 3) δ 7.77-7.75 (m, 2H), 7.51-7.46 (m, 1H), 7.44-7.40 (m, 2H), 5.88 (d, J

= 9.28Hz, 1H), 4.04-3.95 (m, 1H), 2.10-2.05 (m, 1H), 2.01-1.94 (m, 1H), 1.76-1.69 (m,

2H), 1.59-1.48 (m, 1H), 1.22-1.09 (m, 2H), 0.91 (d, J = 7.38Hz, 3H), 0.90-0.89 (m, 1H),

0.89 (d, J = 6.94Hz, 3H), 0.86-0.85 (m, 1H), 0.84 (d, J = 6.88Hz, 3H); 13 C NMR (100

MHz, CDCl 3) δ 166.6, 135.0, 131.2, 128.5, 126.7, 50.3, 48.3, 43.1, 34.5, 31.8, 26.9, 23.8,

+ 22.1, 21.2, 16.2; HRMS (ESI+) calc. for C 17 H26 NO [M+H] : 260.2009. Found: 260.2000.

-1 α 25 [ ]D –57.8 ( c 1.10 CHCl 3); IR (cm ): 3296, 2920, 2853, 1626, 1538, 1341; M.P.:151-

152 oC (Reported M.P.: 150-152 oC). 51

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]-4-chlorobenzamide ( 135b).

1 H NMR (400 MHz, CDCl 3) δ 7.71-7.68 (m, 2H), 740-7.37 (m, 2H), 5.88 (br s, 1H),

4.02-3.93 (m, 1H), 2.07-2.03 (m, 1H), 1.98-1.90 (m, 1H), 1.76-1.69 (m, 2H), 1.57-1.49

(m, 1H), 1.19-1.11(m, 2H), 0.91 (d, J = 7.18 Hz, 3H), 0.98-0.90 (m, 1H), 0.90 (d, J =

13 6.74 Hz, 3H), 0.86-0.80 (m, 1H), 0.83(d, J = 6.88 Hz, 3H); C NMR (100 MHz, CDCl 3)

δ 165.6, 137.3, 133.3, 128.6, 128.2, 50.47, 48.2, 43.0, 34.4, 31.8, 27.0 23.8, 22.1, 21.1,

+ α 25 16.2 ; HRMS (ESI+) calc. for C 17 H25 ClNO [M+H] : 294.1619. Found: 294.1614; [ ]D –

-1 51.8 ( c 3.0 CHCl 3); IR (cm ): 3289, 2984, 1627, 1547, 1484, 1392, 1155, 1094; M.P.:

143-145 oC.

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]-4-methoxybenzamide ( 135c).

1 H NMR (400 MHz, CDCl 3) δ 7.74-7.71 (m, 2H), 6.94-6.90 (m, 2H), 5.73 (br d, J = 7.61

Hz, 1H), 4.02-3.94 (m, 1H), 3.84 (s, 3H), 2.10-2.05 (m, 1H), 2.00-1.93 (m, 1H), 1.76-

1.69 (m, 2H), 1.57-1.50 (m, 1H), 1.17-1.13 (m, 2H), 0.98-0.89 (m, 1H), 0.91 (d, J = 6.84

Hz, 3H), 0.89 (d, J = 6.33 Hz, 3H), 0.88-0.85 (m, 1H), 0.83 (d, J = 6.94 Hz, 3H); 13 C

NMR (100 MHz, CDCl 3) δ 166.1, 161.9, 128.5, 127.3, 113.6, 55.4, 50.2, 48.4, 43.2, 34.5,

+ 31.9, 26.9, 23.8, 22.1, 21.2, 16.2; HRMS (ESI+) calc. for C 18 H28 NO 2 [M+H] : 290.2115 .

-1 α 25 Found: 290.2108; [ ]D –60.0 ( c 2.1 CHCl 3); IR (cm ): 3310, 2927, 2871, 1724, 1625,

1605, 1502, 1254; M.P.: 179-181 oC.

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]acetamide ( 135g). 1H NMR

(400 MHz, CDCl 3) δ 5.23 (s, 1H), 3.81-3.72 (m, 1H), 2.03-1.87 (m, 2H), 1.97 (s, 3H),

1.73-1.65 (m, 2H), 1.51-1.44 (m, 1H), 1.10-0.95 (m, 2H), 0.89 (d, J = 7.24 Hz, 3H), 0.88

(d, J = 7.28 Hz, 3H), 0.79 (d, J = 6.90 Hz, 3H), 0.84-0.72 (m, 2H); 13 C NMR (100 MHz,

CDCl 3) δ 169.1, 49.8, 48.0, 43.1, 34.4, 31.7, 26.7, 23.6, 23.5, 22.1, 21.1, 16.1; HRMS

+ α 25 (ESI+) calc. for C 12 H24 NO [M+H] : 198.1852. Found: 198.1852; [ ]D –64.3 ( c 1.00

-1 o CHCl 3); IR (cm ): 3276, 2925, 2861, 1639, 1555, 1370; M.P.: 122-124 C.

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]pivalamide ( 135e). 1H NMR

(400 MHz, CDCl 3) δ 5.26 (d, J = 8.28 Hz, 1H), 3.80-3.71 (m, 1H), 1.95-1.92 (m, 1H),

1.85-1.81 (m, 1H), 1.72-1.65 (m, 2H), 1.52-1.44 (m, 1H), 1.19 (s, 9H), 1.12-1.02 (m,

2H), 0.89 (d, J = 7.75 Hz, 3H), 0.87 (d, J = 6.75Hz, 3H), 0.84-0.73 (m, 2H), 0.78 (d, J =

13 6.89 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 177.4, 49.5, 48.2, 43.1, 38.6, 34.5, 31.8,

+ 27.6, 26.9, 23.8, 22.1, 21.0, 16.1; HRMS (ESI+) calc. for C 15 H30 NO [M+H] : 240.2322.

-1 α 25 Found: 240.2317; [ ]D –66.2 ( c 2.85 CHCl 3); IR (cm ): 3337, 2930, 2850, 1633, 1541,

1207; M.P.: 134-135 oC.

N-[(1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl]-3-phenylpropanamide ( 135d).

1 H NMR (400 MHz, CDCl 3) δ 7.29-7.25 (m, 2H), 7.21-7.19 (m, 3H), 5.04 (s,1H), 3.77-

3.68 (m, 1H), 3.02-3.89 (m, 2H), 2.45 (t, J = 7.54 Hz, 2H), 1.89-1.85 (m, 1H), 1.70-1.59

(m, 3H), 1.48-1.41 (m, 1H), 1.09-0.90 (m, 2H), 0.85 (d, J = 6.52 Hz, 3H), 0.81 (d, J =

13 7.05 Hz, 3H), 0.76-0.63 (m, 2H), 0.72 (d, J = 6.86 Hz, 3H); C NMR (100 MHz, CDCl 3)

δ 171.0, 140.8, 128.5, 128.3, 126.1, 49.7, 47.9, 43.0, 38.8, 34.4, 31.8, 31.7, 26.4, 23.6,

+ 22.1, 21.1, 16.0; HRMS (ESI+) calc. for C 19 H30 NO [M+H] : 288.2322. Found: 288.2321;

-1 α 25 [ ]D –48.8 ( c 1.60 CHCl 3); IR (cm ): 3286, 2965, 1636, 1552, 1385, 1264, 736; M.P.:

84-85 oC.

1 N-[(3 β)-17-oxoandrost-5-en-3-yl]benzamide ( 140 ). H NMR (400 MHz, CDCl 3)

δ 7.77-7.75 (m, 2H), 7.49-7.47 (m, 1H), 7.44-7.40 (m, 2H), 6.07 (d, J = 8.01 Hz, 1H),

5.44 (d, J = 5.07Hz, 1H), 3.97-3.87 (m, 1H), 2.50-2.44 (m, 2H), 2.26-2.19 (m, 1H), 2.16-

2.07 (m, 2H), 2.01-1.93 (m, 2H), 1.92-1.84 (m, 2H), 1.74-1.66 (m, 3H), 1.59-1.45 (m,

3H), 1.37-1.21 (m, 3H), 1.11-1.05 (m, 1H), 1.05 (s, 3H), 0.89 (s, 3H); 13 C NMR (100

MHz, CDCl 3) δ 221.2, 166.7, 140.4, 134.8, 131.3, 128.5, 126.8, 121.3, 51.6, 50.1, 49.9,

47.5, 39.2, 37.8, 36.7, 35.8, 31.4, 31.3, 30.7, 29.1, 21.8, 20.2, 19.4, 13.5; HRMS (ESI+)

+ α 25 calc. for C 26 H34 NO 2 [M+H] : 392.2584. Found: 392.2592. [ ]D +26.7 ( c 1.8 CHCl 3); IR

(cm -1): 3403, 2942, 2836, 1735, 1640, 1517, 1490; M.P.: 264-266 oC.

1 N-[(3 β)-cholest-5-en-3-yl]benzamide ( 139). H NMR (400 MHz, CDCl 3) δ 7.76-

7.75 (m, 2H), 7.48-7.46 (m, 1H), 7.43-7.41 (m, 2H), 6.06 (d, J = 8.02Hz, 1H), 5.40 (br s,

1H), 3.96-3.87 (m, 1H), 2.45-2.40 (m, 1H), 2.23-2.16 (m, 1H), 2.03-1.73 (m, 6H), 1.60-

0.99 (m, 20H), 1.02 (s, 3H), 0.92 (d, J = 6.49 Hz, 3H), 0.87 (dd, J = 6.60, 1.80 Hz, 6H),

13 0.68 (s, 3H) ; C NMR (100 MHz, CDCl 3) δ 166.6, 140.1, 134.8, 131.2, 128.4, 126.8,

122.1, 56.6, 56.0, 50.1, 50.0, 42.2, 39.7, 39.4, 39.3, 37.8, 36.5, 36.1, 35.8, 31.8, 31.8,

29.2, 28.2, 27.9, 24.2, 23.7, 22.8, 22.5, 20.93, 19.3, 18.7, 11.8; HRMS (ESI+) calc. for

+ -1 α 25 C34 H52 NO [M+H] : 490.4043. Found: 490.4052; [ ]D –5.3 ( c 1.7 CHCl 3); IR (cm ):

3331, 2935, 2865, 1630, 1525, 1267; M.P.: 235-237 oC.

N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide ( 138 ). 1H NMR (400

MHz, CDCl 3) δ 7.72-7.70 (m, 2H), 7.51-7.47 (m, 1H), 7.45-7.41 (m, 2H), 6.08 (d, J =

7.73 Hz, 1H), 4.14-4.09 (m, 1H), 1.99-1.93 (m, 1H), 1.81-1.58 (m, 4H), 1.40-1.1.34 (m,

1H), 1.24-1.18 (m, 1H), 1.01 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H); 13 C NMR (100 MHz,

CDCl 3) δ 166.7, 135.1, 131.2, 128.5, 126.6, 57.0, 48.8, 47.1, 44.8, 39.2, 35.8, 27.0, 20.3,

20.2, 11.8; IR (cm -1): 3334, 2949, 284,1629, 1525, 1487, 1287, 1079; M.P.: 130-131 oC

(Reported M.P.: 130 oC). 52

N-[(1 R, 2 R)-2-methylcyclohexyl]benzamide (racemic) ( 137 ). 1H NMR (400

MHz, CDCl 3) δ 7.78-7.75 (m, 2H), 7.51-7.47 (m, 1H), 7.44-7.41 (m, 2H), 5.90 (br s, 1H),

3.75-3.66 (m, 1H), 2.07-2.04 (m, 1H), 1.81-1.68 (m, 3H), 1.42-1.31 (m, 2H), 1.28-1.12

13 (m, 3H), 0.99 (d, J = 6.52 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 166.9, 135.1, 131.2,

128.5, 126.7, 54.4, 38.7, 34.3, 33.7, 25.7, 25.4, 19.1; HRMS (ESI+) calc. for C 14 H20 NO

[M+H] +: 218.1539. Found: 218.1539; IR (cm -1): 3232, 2924, 2852, 1627, 1549, 1449,

1334; M.P.: 137-139 oC.

1 N -(trans -4-methylcyclohexyl)benzamide ( 150 ). H NMR (400 MHz, CDCl 3) δ

7.76-7.73 (m, 2H), 7.49-7.45 (m, 1H), 7.43-7.39 (m, 2H), 6.00 (br s, 1H), 3.95-3.85 (m,

1H), 2.08-2.04 (m, 2H), 1.76-1.72 (m, 2H), 1.40-1.31 (m, 1H), 124.-1.04 (m, 4H), 0.91

13 (d, J = 6.51Hz, 3H), C NMR (100 MHz, CDCl 3) δ 166.7, 134.9, 131.2, 128.4, 126.7,

+ 48.9, 33.8, 33.2, 31.9, 22.1; HRMS (ESI+) calc. for C 14 H20 NO [M+H] : 218.1539.

Found: 218.1535; IR (cm -1): 3304, 2926, 2851, 1626, 1539, 1491, 1333; M.P.: 179-

180 oC.

1 N-(cis -4-methylcyclohexyl)benzamide ( 151 ). H NMR (400 MHz, CDCl 3) δ

7.77-7.75 (m, 2H), 7.52-7.48 (m, 1H), 7.46-7.42 (m, 2H), 6.20 (br s, 1H), 4.24-4.20 (m,

1H), 1.82-1.56 (m, 7H), 1.24-1.15 (m, 2H), 0.95 (d, J = 6.62Hz, 3H); 13 C NMR (100

MHz, CDCl 3) δ 166.7, 135.2, 131.2, 128.5, 126.8, 45.7, 30.6, 30.1, 29.3, 21.2; HRMS

+ -1 (ESI+) calc. for C 14 H20 NO [M+H] : 218.1539. Found: 218.1542; IR (cm ): 3305, 2933,

2853, 1624, 1540, 1492, 1319; M.P.: 128-129 oC.

N-[(1 S, 3 R)-3-methylcyclohexyl]benzamide(racemic) ( 153 ). 1H NMR (400

MHz, CDCl 3) δ 7.76-7.73 (m, 2H), 7.50-7.46 (m, 1H), 7.44-7.40 (m, 2H), 5.93 (br s, 1H),

4.02-3.92 (m, 1H), 2.08-2.05 (m, 2H), 1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.60-1.53

(m, 1H), 1.48-1.36 (m, 1H), 1.13-1.03 (m, 1H), 0.91 (d, J = 6.57Hz, 3H), 0.85-0.78 (m,

13 2H); C NMR (100 MHz, CDCl 3) δ 166.6, 135.0, 131.2, 128.5, 126.8 48.9, 42.0, 34.2,

+ 32.9, 31.8, 24.8, 22.4; HRMS (ESI+) calc. for C 14 H20 NO [M+H] : 218.1539. Found:

218.1533; IR (cm -1): 3294, 2924, 2858, 1630, 1536 ; M.P.: 125-127 oC

N -[(1 R, 3 R)-3-methylcyclohexyl]benzamide(racemic) ( 152 ). 1H NMR (400

MHz, CDCl 3) δ 7.77-7.75 (m, 2H), 7.51-7.46 (m, 1H), 7.45-7.40 (m, 2H), 6.24 (br s, 1H),

4.36-4.33 (m, 1H), 1.80-1.64 (m, 6H), 1.51-1.35 (m, 2H), 1.12-1.04 (m, 1H), 0.95 (d, J =

13 6.50 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 166.6, 135.1, 131.2, 128.5, 126.7, 45.1,

+ 38.6, 33.6, 30.6, 27.6, 21.5, 20.8; HRMS (ESI+) calc. for C 14 H20 NO [M+H] : 218.1539.

Found: 218.1539; IR (cm -1): 3301, 2931, 2857, 1628, 1538, 1489, 1312 ; M.P.: 101-

102 oC.

N-[(1 R, 5R)-3,3,5-trimethylcyclohexyl]benzamide(racemic) ( 142 ). 1H NMR (400

MHz, CDCl 3) δ 7.76-7.73 (m, 2H), 7.49-7.45 (m, 1H), 7.43-7.39 (m, 2H), 5.97 (br s, 1H),

4.21-4.11 (m, 1H), 2.09-2.07 (m, 1H), 1.75-1.72 (m, 2H), 1.39-1.36 (m, 1H), 1.02-0.96

(m, 1H), 0.99 (s, 3H), 0.94 (s, 3H), 0.89 (d, J = 6.50Hz, 3H), 0.80-0.65 (m, 2H); 13 C

NMR (100 MHz, CDCl 3) δ 166.6, 134.9, 131.2, 128.4, 126.7, 47.6, 45.9, 45.5, 41.9, 33.0,

+ 31.9, 27.4, 25.4, 22.3; HRMS (ESI+) calc. for C 16 H24 NO [M+H] : 246.1852. Found:

246.1847. IR (cm -1): 3299, 2947, 2856, 1631, 1530, 1324; M.P.: 103-104 oC.

N-[(1 R)-octan-2-yl]benzamide (made in four steps from ( S)-(+)-2-Octanol)

1 (159). H NMR (400 MHz, CDCl 3) δ 7.76-7.74 (m, 2H), 7.51-7.47 (m, 1H), 7.45-7.40

(m, 2H), 5.90(d, J = 7.15 Hz, 1H), 4.24-4.14 (m, 1H), 1.56-1.50 (m, 2H), 1.37-1.22 (m,

13 8H), 1.23 (d, J = 6.59 Hz, 3H), 0.89-0.86 (m, 3H); C NMR (100 MHz, CDCl 3) δ 166.7,

135.0, 131.2, 128.4, 126.7, 45.7, 37.0, 31.7, 29.2, 26.0, 22.5, 21.0, 14.0; HRMS (ESI+)

+ α 25 calc. for C 15 H24 NO [M+H] : 234.1852. Found: 234.1855. [ ]D -15.7 ( c 3.55, CHCl 3);

α 25 [ ]D -4.4 ( c 5.5, CHCl 3) for the N-2-octanylbenzamide prepared from our developed

method]; IR (cm -1): 3289, 2922, 2853, 1632, 1536, 1351, 1311; M.P.: 98-100 oC.

CHAPTER FIVE TiF4 MEDIATED REACTIONS OF ALKENE WITH

NUCLEOPHILES

5.1 Introduction

Nucleophilic addition reactions to olefins catalyzed by various catalysts are fundamental reactions in organic synthesis and important in synthesis of complex molecules. Addition of halogens and pseudo halogens, carboxylic acids, phenols and nitriles are some of the most important reactions. Such reactions are generally mediated by acids or stoichiometric amounts of toxic reagents. 53 Presently, there are now many

catalysts such as platinum, 54 ruthenium, 55 palladium, 56 gold, 57 and cobalt58 available to catalyze these reactions. Though all these catalyst have proved useful but there remain problems such as hydride shift and β-elimination. Therefore, there continues to be need for new catalyst or reagents. Here we report some important reactions of unactivated alkenes and activated alkenes (styrene) mediated by TiF 4; this reagent is very rarely used

in organic synthesis, though it is cheap and non toxic. Here in this chapter, we present

only some preliminary data to show that TiF 4 can indeed mediate nucleophilic addition

reactions to alkenes.

5.2 Cyclodimerization of styrene: synthesis of indan class of compounds

Indans are an important class of compounds (figure 4) in polymer chemistry.

They are widely used as photo and thermo stabilizers,59 plasticizers60 as well as mobility

87 and viscosity modifiers61 in the production of polystyrene or ABS resins. Most general processes available in the literature are mainly catalyzed by Bronsted acid at high temperature using ionic liquids,62 polymeric acidic complex,63 and Lewis acids like

64 o BiCl 3. Since all these processes require high temperature (from 60-170 C), decomposition and polymerization of styrene are major problems. We have developed a mild (room temperature) method to synthesize indan compounds from α-substituted

styrene using TiF 4 as a catalyst.

R1 R

Figure 4 . General structure of indan class of compounds

A preliminary optimization of this reaction was performed using 1,1-diphenyl

ethylene at room temperature in dichloromethane solvent (Table 15). Initially we

performed the reaction by dissolving TiF 4 (1.0 equivalent) in acetone or acetonitrile (2.0

equivalents with respect to TiF 4) in dichloromethane. In both cases, the reaction took

nearly 24h to complete to generate the product 169 in very good yields (entry 1 & 2,

Table 15).

TiF4 DCM rt

168 169

a Entry additive (equiv) TiF4( equiv) t(h) Yield(%)

1 acetonitrile (2.0) 1.0 24.0 >90

2 acetone (2.0) 1.0 24.0 >90 3 - 1.0 4.0 73

4b acetone (0.4) 0.2 35.0 70

5 - 0.2 16.0 93

aIsolated yields. b Reaction was incomlete.

Table 15 . Cyclodimerization study of α-substituted styrene

Initially, we used acetone or acetonitrile just to dissolve TiF 4 in dichloromethane

so that reaction would be homogeneous. Later performing the reaction without any

additive was found to be 6 times faster though yield was low (entry 3, Table 15). This

was expected as addition of additives decreases the Lewis acidity of TiF 4 substantially.

However on using 20 mol% TiF 4, a very good yield (93%) was achieved within 16h.

When same experiment was done in presence of acetone, the reaction was very slow and after 35h a 70% yield was achieved. The reaction was also performed with α- methylstyrene using 20 mol % TiF 4 which produced the corresponding indan derivative

170 , in moderate yield within 30 min (scheme 30).

TiF4 (20 mol%) DCM rt, 0.5h 170 (70%)

Scheme 30 . Cyclodimerization of α-methylstyrene

TiF4 R R R R H R

+ R R TiF4 172 TiF4 + R

R 171 − TiF4

Scheme 31 . Plausible mechanism of cyclodimerization of styrene catalyzed by TiF 4

A plausible mechanism for our indan synthesis is given in scheme 31. Chelation

of TiF 4 to alkene activates the α-position of the styrene derivative. Then the β-carbon of another molecule attacks the α-carbon as a nucleophile of the alkene complexed with

TiF 4 to generate the intermediate 171 . Intermediate 171 then undergoes a Friedel Crafts cyclization to yield intermediate 172 which then aromatizes to produce the expected product.

5.3 Addition of nitrile to unactivated alkene

Amides are very important class of functional group and common in natural products. Among various methods to synthesize amides, addition of nitriles to alkene is one of them. There are two methods available to synthesize amide from alkene – 90

Bronsted acid catalyzed Ritter reaction 65 and Brown’s oxymercuration-demercuration method. 66 However, strong harsh acidic conditions or the use of toxic mercury are the

main drawbacks of these two methods. We have observed that TiF 4 actually mediate the

addition of nitrile at room temperature to unactivated alkene. In scheme 32 addition of

benzonitrile to 4-phenyl-2-butene is shown.

O H N CN TiF4 (1.5eqv) 1. + DCM, rt 20h 60% 1.0eqv 1.5 eqv. O H TiF (1.5eqv) N CN 4 2. + TMSOTf (1.5eqv.) DCM, rt 82% 4h 1.0eqv 1.5 eqv. 173

Scheme 32. Addition of benzonitrile to 4-phenyl-2-butene in presence of Ti(IV)

When just TiF 4 was used after 20h reaction was incomplete resulting in a 60%

yield of the corresponding benzylamide 173 . Then we realized that enhancement of

Lewis acidity of Ti(IV) would accelerate the rate of the reaction. We then performed the

reaction in presence of TMSOTf hypothesizing the formation Ti(IV)OTf type of complex

where Ti(IV) would be more Lewis acidic. Indeed when the reaction was performed in

presence of same equivalents TMSOTf as of TiF 4 (1.5 equivalents), the reaction was

completed within 4h at room temperature with 82% yield of amide. The mechanism for

this reaction is presented in scheme 33.

Ph R N N Ph F F R Ti F TiF + 2 PhCN F Ti N Ph 4 F N F F 174 F 175 O Ph R R Ph HN Ph H O 2 + − N + − N F4Ti R F4Ti Ph 176

Scheme 33. Reaction mechanism for nitrile addition to alkene

Ti(IV) first complexed with benzonitrile to form 174 type complex. The alkene then chelates with Ti(IV), replacing one benzonitrile molecule to give complex 175 and thus activated. Then nitrile attacks the more substituted carbon to generate the nitrilium ion 176 which is then hydrolyzed by water to amide.

5.4 Addition of carboxylic acid to alkene

One of the most recent literature methods of addition of carboxylic acid to alkene involves gold catalyst. 57 Interestingly, we observed that carboxylic acid also can add to

alkene in presence of TiF 4. Thus 3-methoxybenzoic acid adds to 4-phenyl-2-butene in presence of 1.0 equivalent TiF 4 at room temperature to yield the ester 177 in 82% yield after 24h. However when 30 mol % of TiF 4 was used reaction becomes very slow and only 26% yield was obtained after 24h (scheme 34). We did not perform any further study to optimize the catalytic reactions. But this result indicates that optimization may lead to promising results. A plausible mechanism for this reaction has been shown in scheme 35. Initially complex 178 is formed, where both alkene and carboxylic acid

chelated to TiF 4. Then carboxylate oxygen attacks the activated alkene at the more substituted carbon to generate the intermediate 179 which then collapses to give ester.

O O O O

OH TiF4 + DCM, rt 177

O 24h 82% (1.0 equivalent TiF4) 26% (0.3 equivalent TiF4)

Scheme 34. Addition of carboxylic acid to alkene

TiF4 O R1 + 1 R R OH O O R1 R H O O R1 + F4Ti 178 H O O R − F4Ti R 179

Scheme 35. Catalytic mechanism for addition of carboxylic acid to alkene

In conclusion, we are able to show by some preliminary data that rarely used TiF 4 can indeed catalyze and mediate some important reactions of alkenes. Though most of the results given here are not optimized but we believe further optimization may reveal these methods to be viable alternatives to reactions requiring costly catalysts.

5.5 Experimental section

General procedure for indan synthesis (in absence of additive): To a suspension of

TiF 4 (0.2 equiv) in dichloromethane α-substituted styrene was added and stirred at room

temperature. Reaction was quenched after reaction was done with water and stirred until

organic layer was clear. Organic layer was extracted. Aqueous layer was washed two

more time with dichloromethane and collected together. Organic layer was dried over

anhydrous sodium sulfate. Product was purified by flash using hexane.

General procedure for indan synthesis (in presence of additive): To a suspension of TiF 4 (0.2 equiv) in dichloromethane acetone or acetonitrile (0.4 equiv) was added to dissolve TiF 4. Then α-substituted styrene was added and stirred at room temperature.

Reaction was quenched after reaction was done with water and stirred until organic layer

was clear. Organic layer was extracted. Aqueous layer was washed two more time with

dichloromethane and collected together. Organic layer was dried over anhydrous sodium

sulfate. Product was purified by flash using hexane.

1-methyl-1,3,3-triphenyl-2,3-dihydro1 H-indene ( 169). 1H NMR (400 MHz,

CDCl 3) δ 7.31-7.00 (m, 19H), 3.39 (d, J = 13.51 Hz, 1H), 3.09 (d, J = 13.51 Hz, 1H),

13 1.53 (s, 3H); C NMR (100 MHz, CDCl 3) δ 150.5, 149.3, 148.8, 148.4, 147.4, 128.7,

128.6, 127.9, 127.8, 127.5, 127.4, 127.3, 126.8, 126.7, 125.9, 125.6, 125.5, 124.9, 61.3,

60.9, 51.1, 28.8.

General procedure for amide synthesis: To a suspension of TiF 4 (1.5 equiv) in

dichloromethane benzonitrile (3.0 equiv) was added to dissolve TiF 4. Then 4-phenyl-2-

butanol was added (0.1M) and stirred at room temperature for 20h. Then reaction was

quenched with water and stirred until organic layer was clear. Organic layer was

extracted. Aqueous layer was washed two more time with dichloromethane and collected

together. Organic layer was dried over anhydrous sodium sulfate. Product was purified by

flash column using 2-15% ethyl acetate-hexane.

General procedure for amide synthesis in presence TMSOTf: To a suspension of

TiF 4 (1.5 equiv) in dichloromethane benzonitrile (1.5equiv) was added to dissolve TiF 4.

Then TMSOTf was added to the solution and stirred for 15 min. Then 4-phenyl-2-butanol

was added (0.1M) and stirred at room temperature for 4h. Then reaction was quenched

94 with water and stirred until organic layer was clear. Organic layer was extracted.

Aqueous layer was washed two more time with dichloromethane and collected together.

Organic layer was dried over anhydrous sodium sulfate. Product was purified by flash column using 2-15% ethyl acetate-hexane.

1 N-(4-phenylbutan-2-yl)benzamide ( 173 ). H NMR (400 MHz, CDCl 3) δ 7.69-7.67

(m, 2H), 7.50-7.45 (m, 1H), 7.42-7.38 (m, 2H), 7.29-7.25 (m, 2H), 7.22-7.16 (m, 3H),

5.98 (br s, 1H), 4.31-4.24 (m, 1H), 2.74-2.70 (m, 2H), 1.92-1.85 (m, 2H), 1.28 (d, J =

13 6.61 Hz, 3H); C NMR (100 MHz, CDCl 3) δ 166.8, 141.7, 134.8, 131.3, 129.5, 128.4,

128.3, 126.7, 125.9, 45.6, 38.5, 32.5, 21.0.

General procedure for ester synthesis: To a suspension of TiF 4 (1.5 equiv) in dichloromethane 3-methoxybenzoic acid (1.5 equiv) was added to dissolve TiF 4. Then 4-

phenyl-2-butanol was added (0.1M) and stirred at room temperature for 24h. Then

reaction was quenched with water and stirred until organic layer was clear. Organic layer

was extracted. Aqueous layer was washed two more time with dichloromethane and

collected together. Organic layer was dried over anhydrous sodium sulfate. Product was

purified by flash column using 2-15% ethyl acetate-hexane.

1 4-phenylbutan-2-yl-3-methoxybenzoate ( 177 ). H NMR (400 MHz, CDCl 3) δ

7.65-7.57 (m, 1H), 7.37-7.09 (m, 8H), 5.20-5.15 (m, 1H), 3.86 (s, 3H), 2.80-2.67 (m,2H),

2.15-2.03 (m, 1H), 1.99-1.89 (m, 1H), 1.38 (d, J = 6.25 Hz, 3H); 13 C NMR (100 MHz,

CDCl 3) δ 166.0, 159.5, 141.4, 132.0, 129.3, 128.4, 128.3, 125.9, 121.8, 119.1, 114.0,

71.2, 55.4, 37.7, 31.8, 20.1.

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100

CHAPTER SEVEN SELECTED SPECTRA

O O S O O O

24a

101

O O F S O O O

24d

102

O O F S O O O O F 24g

103

0.0

O S O O N

36a

5.0

10.0 ppm (f1)

104

0.0

O S

O O N

5.0 36e

10.0

ppm (f1)

105

0.0

O S

O O N

36d

5.0

ppm (f1)

106

107

108

109

N 3 49

110

N 3

111

H H H

N3 45

112

113

114

115

Cl 76

116

Cl 77

117

Cl 74

118

Cl 75

119

120

H H Cl

121

H N

135a

122

H N O

135d

123

O H

O H H N H 140

124

H N O H 138

125

H N

137

126

H N O

150

127

H N

151

128

H N O

153

129

H N

O 152

130

0.0

3.12 1.0

3.17

3.20

2.0 1.00 1.00

3.0

4.0

170 5.0

6.0

7.0

8.15

ppm (f1)

131

0.0

1.0

2.0

3.0

4.0

5.0

169

6.0

7.0

8.0

ppm (f1)

132

173

133

0.0 1.0

O 2.0 O

177 3.0 4.0 5.0 6.0 7.0 8.0 ppm ppm (f1) 9.0

134