Development and Applications of Nucleophile Assisting Leaving Groups (Nalgs) with Titanium (IV) and Grignard Reagents

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DEVELOPMENT AND APPLICATIONS OF NUCLEOPHILE ASSISTING LEAVING

GROUPS (NALGS) WITH TITANIUM (IV) AND GRIGNARD REAGENTS

Songye Li

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

August 2011

DEVELOPMENT AND APPLICATIONS OF NUCLEOPHILE ASSISTING LEAVING

GROUPS (NAI.JGS) WITI-I TITANIUM (IV) AND GRIGNARD REAGENTS

Songye Li

1'his dissertation was prepared under the direction of the candidate's dissertation advisor, Dr. Salvatore- D. Lepore, Department of Chemistry and Biochemistry, and .has been approved by the members of her supervisory cornmittee.. It was submitted to the faculty of the Charles E. Schmidt College of Science and was accepted in partial fulfillment of the requirements for the degree ofDoctor ofPhilosophy'.

SUPERVISORY COMMITTEE: _~~~ -J! In-/)~_ Dr. Salvatore D. Lepor~1 D.issertation Advisor

'-"~'~~~~--'~'JZ(~~~L.,J'L-~-=--_.- fl;a!~4. r Dr. Guodong Sui Cy Parkanyi, Ph.D. Chair, Depa en fCh y and Biochemistry

Gary W. Perry, Ph.D. Dean, The Charles E. Schnlidt ollege ofScien.ce ~n:? 7~~ .__..._~._. __ Barry T. Rosson, Ph.D. Dean, Graduate College

11 ACKNOWLEDGEMENTS

I would like to thank my advisor, Dr. Salvatore D. Lepore, for his excellent guidance throughout my PhD. Dr. Lepore is truly an outstanding mentor that anyone could ask for. He taught me not only the philosophy of chemistry and also the philosophy of being a person. His talent, passion and motivation in chemistry and his kind personality have always inspired and will inspire me in the future.

I want to thank my committee professors Cyril Parkanyi, 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 Deboprosad, Pradip and Mohammad for their help and friendship.

I wish to express my thanks to all my family and friends who have continually supported me. The endless support, care and love from my grandparents, my parents, my brother and my sister-in-law are always the mainstay in my life. I sincerely appreciate their help and affection, I cannot achieve what I have today without them.

iii

ABSTRACT

Author: Songye Li

Title: Development and Applications of Nucleophile Assisting Leaving Groups (NALGs) with Titanium (IV) and Grignard Reagents

Institution: Florida Atlantic University

Thesis Advisor: Dr. Salvatore D. Lepore

Degree: Doctor of Philosophy

Year: 2011

We report here the development of very efficient aryl- and quinolinyl- sulfonate

based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), which substantially accelerate the rate of nucleophilic substitution reactions with metal halides.

Detailed synthesis and kinetics study are described herein. Our synthesized NALGs have

shown great reactivity towards poor nucleophiles and/or substrates traditionally

considered too hindered to undergo nucleophilic attack.

The abundant existence of halide, azide and amine in natural products demands

new synthetic pathway. To fulfill this requirement, new mild stereoretentive

halogenations (chlorination, bromination and iodination) reactions have also been

developed for secondary cyclic alcohols using NALGs involving titanium (IV) reagents.

The novel methodology can be extended to Azidation reactions as well with

titanium (IV) azide, in which Ti (N3)4 is the first time being engaged in organic synthesis.

Beased on the NALGs theory we discover the chlorosulfite can be a simplest NALG and

applied as the intermediate in mild 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.

Finally, an efficient mild bromination and iodination reaction for primary and

secondary alcohols with Grignard reagents is also reported. This reaction exhibits the

generality with substrates with various leaving groups. The important features of this reaction are that, for the first time, bromide formation using Grignard reagents without the Cu (I) catalysts.

SYNTHESIS OF NUCLEOPHILE ASSISTING LEAVING GROUPS AND NEW

APPLICATIONS FOR TITANIUM (IV) AND GRIGNARD REAGENTS

LIST OF FIGURES ...... ix

LIST OF TABLES ...... x

LIST OF SCHEMES...... xi

CHAPTERS

1. NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) AND

RADIOFLUORINATIONS ...... 1

1.1 Leaving groups...... 1

1.2 Sulfonate and carboxylate leaving groups ...... 3

1.3 Chiral leaving groups ...... 7

1.4 Organometallic leaving groups ...... 9

1.5 Heterocyclic leaving groups ...... 10

1.6 The background of NALGs ...... 11

1.7 Nucleophile Assisting Leaving Groups (NALGs) ...... 15

1.8 Nucleophilic substitutions ...... 19

1.9 Pyridine and quinoline sulfonate based leaving groups ...... 21

1.10 Current progress of radiofluorination ...... 23

2. SYNTHESIS AND KINETICS STUDY ON ESTER, ETHER AND

QUINOLINE-SULFONATE BASED NALGS AND COLLABORATION

WITH NIH ...... 27

2.1 First generation of aryl sulfonate based NALGs ...... 27

2.2 Reactivity and kinetics study of first generation NALGs ...... 29

2.3 Synthesis of second generation NALGs ...... 42

2.4 Synthesis of quinoline-sulfonate based NALGs ...... 45

2.5 Synthesis of other related NALGs ...... 49

2.6 Results of nucleophilic substitution reactions with lithium bromide...... 51

2.7 Collaboration with NIH ...... 55

2.8 Metal selectivity with HSAB theory ...... 57

2.9 Experimental section ...... 59

3. STEREORETENTIVE REACTIONS OF SECONDARY CYCLIC

ALCOHOLS USING NALGS AND TI(IV) REAGENTS ...... 66

3.1 Bromination and azidation with Titanium (IV) reagents ...... 66

3.2 Iodination reaction with Ti (IV) reagents ...... 74

3.3 Stereoretentive chlorination with chlorosulfite ...... 77

3.4 Experimental section ...... 92

4. NEW APPLICATIONS WITH GRIGNARD REAGENTS ...... 100

4.1 Introduction of Grignard reagents ...... 100

4.2 Cuperate reagents facilitated carbon-carbon bond formation ...... 101

4.3 Grignard and Titanium reagents facilitated carbon-carbon bond formation ...103

4.4 Grignard substrates used as brominating reagents with the aid of Cu (I) ...... 106

vii

4.5 Mild bromination reaction without the addition of Cu (I) catalyst ...... 106

4.6 Experimental section ...... 110

5. SELECTED SPECTRA ...... 112

REFERENCES ...... 127

viii

LIST OF FIGURES

Figure 1 Methylating agents containing crown ether leaving groups and

structure of K222 ...... 13

Figure 2 Transition states for methylation reaction of a and c ...... 14

Figure 3 The hypothesis of new NALGs ...... 17

Figure 4 Pentavalent transition state for a bimolecular substitution reaction ...... 20

Figure 5 First order plot for the reactions that one of the reactants is in excess ...... 34

Figure 6 The second order plot for the reaction of NALG with lithium iodide ...... 35

Figure 7 The crystal structure of the sodium salt of the tri (ethylene glycol)

NALG 8 ...... 44

Figure 8 Proposed benzocrown and open armed NALGs ...... 51

Figure 9 Possible transition state for stereoretentive halogenation and azidation

reactions ...... 71

Figure 10 Proposed orbital explanation of chlorination mechanism [1,5]

suprafacial retentive shift ...... 86

Figure 11 Orbital overlap configuration from computational study ...... 87

Figure 12 Grignard reagents react with a variety of carbonyl derivatives ...... 101

Figure 13 Grignard reagents react with other electrophiles ...... 101

LIST OF TABLES

Table 1 The rate constants for the substitution reactions ...... 36

Table 2 The rate constants of NALGs reacted with various metal salts ...... 37

Table 3 Bromination reaction times with 3-phenylpropyl substrates containing

various leaving groups ...... 53

Table 4 [18F]Fluorination of various NALGs ...... 55

Table 5 Reactivity of quinoline-sulfonate based NALG with various metal halides .....58

Table 6 Leaving group effect on bromination reactions ...... 67

Table 7 Optimization of bromination reactions ...... 68

Table 8 Substrate generality for bromination and azidation ...... 70

Table 9 Chemoselectivity of Ti(IV) reaction with substrates containing two

sulfonate leaving groups ...... 71

Table 10 Optical rotation of substrates ...... 73

Table 11 Optimization of reaction conditions ...... 75

Table 12 Substrates generality for iodination reaction ...... 76

Table 13 Mixed-Titanium (IV) reagents study ...... 77

Table 14 Results with trans-4-methylcyclohexanol and cis-4-methylcyclohexanol ...... 83

Table 15 The generality of bromination reaction with ester NALG ...... 107

Table 16 Bromination results with various leaving groups ...... 108

LIST OF SCHEMES

Scheme 1 Ingold’s four main classes of nucleophilic substitution ...... 2

Scheme 2 Conversion of amines to alcohols and azides with benzenedisulfonylimide

leaving groups ...... 4

Scheme 3 Vinylogous sulfonate and alkyl sulfonyl leaving groups in palladium–

catalyzed reactions ...... 5

Scheme 4 The cross-coupling of a vinylogous acyl triflate with a lithium enolate ...... 5

Scheme 5 Substitution reaction with imidazoleates as leaving ...... 6

Scheme 6 Perfluorobutyrate leaving group in solvolysis ...... 7

Scheme 7 Synthesis of chiral binaphthyls in a nucleophilic aromatic substitution

reaction ...... 8

Scheme 8 Lewis acid-activated addition reaction involving chiral leaving groups ...... 8

Scheme 9 Asymmetric addition with cuperate and enolate reagents ...... 9

Scheme 10 Reaction of bismuthonium with benzyl alcohol ...... 9

Scheme 11 Methylation reactions involving carborane and 7-isomer of

Me(CB11Me5Br6) ...... 10

Scheme 12 Representative substitution reaction with benzoisothiazole-3-ones as

leaving group ...... 11

Scheme 13 Podand-catalyzed nucleophilic aromatic substitution reaction of

1-chloroanthraquinone ...... 12 xi

Scheme 14 Rate of methylation of metal thiolate with various leaving groups ...... 13

Scheme 15 Rate acceleration of acetylating reaction with the substrate

containing oligoether chelating arm...... 15

Scheme 16 Rationale for rate the enhancement observed with nucleophile

assisting leaving groups ...... 16

Scheme 17 General substitution reactions with NALGs ...... 16

Scheme 18 Key step in Kim’s total synthesis ...... 19

Scheme 19 Transformation of 2-pyridyl sulfonates to alkyl bromides with inversion

of configuration ...... 21

Scheme 20 Pyrolysis of 8-quinoline sulfonate to give cyclohexene ...... 22

Scheme 21 Use of indole as a leaving group in dinucleoside synthesis ...... 22

Scheme 22 Radiosynthesis of [18F]FDG from [18F]fluoride ion ...... 23

Scheme 23 Syntheses of [18F]2-fluoropyridine and [18F]3-fluoropyridine from

[18F]fluoride ion ...... 24

Scheme 24 Introduction of fluorine-18 into arenes through the reactions of

diaryliodonium salts with [18F]fluoride ion ...... 25

Scheme 25 Reaction of N-aryl-α-bromo acetamindes with [18F]fluoride ion ...... 25

Scheme 26 Synthesis of NALG sulfonylchlorides 4 and sulfonate esters 5 of

primary alcohol ...... 28

Scheme 27 The mechanistic possibilities ...... 38

Scheme 28 The 1H-NMR spectrum of the NALG of 12-crown-4 and lithium

tetrafluoroborate ...... 40

xii

Scheme 29 Synthesis of second generation NALGs sulfonyl chlorides and NALG

sulfonate esters...... 45

Scheme 30 Quinolinyl leaving groups containing an oligoether moiety ...... 47

Scheme 31 The attempted approach from 2-hydroxyquinoline ...... 47

Scheme 32 The attempted approach of chlorosulfonation ...... 48

Scheme 33 Syntheis of new quinoline-sulfonate based NALG ...... 49

Scheme 34 The synthesis pathway of hydrogen-bonding ester NALGs ...... 50

Scheme 35 The synthesis pathway of rigid NALG ...... 51

Scheme 36 Synthesis of 4-t-butylalcohol ...... 56

Scheme 37 Synthesis of quinoline-sulfonate NALGs and metal selectivity study ...... 57

Scheme 38 Synthesis of chiral alcohol and mixed lewis acid ...... 72

Scheme 39 Catalytic cycle for stereoretentive chlorination ...... 78

Scheme 40 Literature proposed chlorination mechanism with SOCl2 ...... 80

Scheme 41 Chlorination of trans- and cis-4-methylcyclohexanol ...... 81

Scheme 42 Cross experiment with chlorosulfite and TiBr4 ...... 85

Scheme 43 Possible non-classical “frozen” carbocation mechanism ...... 88

Scheme 44 C-H and C-C hyperconjomers of methyl substituted tertiary

carbocations ...... 88

Scheme 45 Comparison between concerted mechanism and non-classical

carbocation mechanism...... 89

Scheme 46 Equilibrium between the C-C hyperconjomer and the C-H

hyperconjomer...... 91

Scheme 47 Secondary sp3 bond formation using cuperate chemistry ...... 102

xiii

Scheme 48 Secondary sp3 bond formation using nucleophilic substitution ...... 105

Scheme 49 Originally hypothesized mechanism ...... 108

Scheme 50 The results with hindered secondary alcohol substrates ...... 109

xiv

CHAPTER ONE

NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) AND

RADIOFLUORINATIONS

1.1 Leaving groups

Even though the mechanistic role of leaving group was developed much earlier the

term “leaving groups” was first proposed in chemistry literature about only 50 years ago,

instead of “departing ionizing groups”.1 Leaving groups have been defined as that part of a substrate that becomes cleaved by the action of a nucleophile.2 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.3 Common anionic leaving groups are halides such as Cl-,

Br-, I-, and sulfonate esters, such as “tosylate” (TsO-). Common neutral molecule leaving

groups are water, ammonia and alcohols. Thus, from the viewpoint of charge type, there

are four main classes of nucleophilic substitutions, as first depicted by Ingold.4 It can be

seen that in equations 1 and 4 charge is conserved, while in equation 2 charge is created,

and in equation 3 charge is destroyed.

Nu + RX R Nu + X

Scheme 1. Ingold’s four main classes of nucleophilic substitution

Leaving groups are ubiquitous in organic chemistry and playing a key role in a

wide range of reactions, for example, nucleophilic substitution, electrophilic substitution

and elimination reactions, which constitute fundamental reaction types in organic

chemistry. A survey of 135 named organic reactions widely utilized in modern

preparative organic chemistry reveals that leaving groups play an important role in as many as 25% of all organic reactions.5

In a nucleophilic reaction, an important step in mechanism manner is the departure

of a leaving group covalently bonded in the reactant substrates. In this step, a heterolytic

bond cleavage occurs and the leaving group or “nucleofuge” takes up the bonding

electron pair from the substrate. For an atom or a group to be a good leaving group, it

must be able to exist independently as a relatively stable, weakly basic anion or molecule,

which is capable of accommodating the negative charge through electronegativity or by

delocalization.

The leaving group ability or its nucleofugacity has been correlated with the pKa of

the conjugate acid. In order to master the nature of the leaving group, it is important to

understand the factors that help determine whether a species is a strong base. Leaving

group is a unit that is able to accept electrons, so the leaving group is considered as a

weak base. As electronegativity increases, or size increases, basicity will decrease, the 2

species will be less likely to share its electrons. The formation of a resonance stabilized structure results in a species that is less willing to share its electrons. The increase in electronegativity results in a species that wants to hold onto its electrons rather than donate them. With an increase in size, the ability of a leaving group to leave increases.

Leaving groups that form resonance structures upon leaving are also classified to be excellent leaving groups.

There are two problems about leaving groups in the substitution reaction. 1) When bimolecular substitutions are in acidic media the nucleophile will be protonated and its nucleophilicity will then drop dramatically. 2) Weak nucleophiles cannot effectively stabilize the charge buildup in the transition state of a substitution reaction.6

Researchers devoted a lot effort in the performance improvement of leaving groups

by modifying traditional leaving group motifs, which will be described in the following

sections. Despite the wide variety and thorough study 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).”

1.2 Sulfonate and carboxylate leaving groups

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, and this is also due to the formation of a resonance

stabilized structure upon leaving; trifluoromethanesulfonate (triflate) is a noteworthy

example. The relative reactivity of most common leaving groups has been estimated to

be: substituted benzonates < halides < sulfonates < perfluoroalkane sulfonates. Mostly employed sulfonate leaving groups include: tosylate(-OTs), mesylate(-OMs), triflate(-

OTf), and so on. Recently some new sulfonate leaving groups have been developed.

Fiksdahl and co-workers reported benzenedisulfonylimides, which contains bis- sulfonyl group and turns to be a good leaving group of amines. They successfully converted primary amines to secondary alcohols and azides with invertion of configuration. 7

KN02 NH 2 Et3N, CH 2CI 2 18-crown-6 OH 0 28 802 70% R N 802CI DMF,20oC Ph inversion R 83% (R =Ph) 802CI NaN , DM80 47% (R =Ph) 3 N 38% (R =Cy) 20°C, 4 d 3 99% 53% (R =Cy) Cy inversion

Scheme 2. Conversion of amines to alcohols and azides with benzenedisulfonylimide leaving groups

Palladium-catalyzed rearrangement and substitution has served as a versatile

carbon-carbon bond formation via a π–allylpalladium intermediate. 8 Vinylogous

sulfonates and alkyl sulfonyl has been engaged as improved leaving groups in such

substitution reactions as the Suzuki–Miyaura coupling9 and the Tsuji–Trost reaction10 in

Evans11 and Robins’12 work. In those reactions the enhanced reaction rates relative to

vinylogous carbonates can be achieved by involving two proximal alkenes, then the

4 palladium oxidative insertion is entropically favored. The stereochemical outcome relative to vinylogous carbonates can be rationalized using palladium catalysis involving chiral ligands.

PhO2S Ph O cat. Pd(0), ligand Ph CH(CO2Me)2

Ph R NaCH(CO2Me)2 Ph R entry R %yield %ee 1 Me 94 91 2 n-Pr 75 95

3 BnOCH2 61 95 4 TBSO(CH2)3 78 95

Scheme 3. Vinylogous sulfonate and alkyl sulfonyl leaving groups in palladium–catalyzed reactions

Dudley13 also used vinylogous sulfonate leaving groups in Claisen condensations, in which a cross-coupling of vinylogous acyl triflates with lithium enolates produced an alkyne bearing a 1,3-diketone functionality. A plausible mechanism is shown in Scheme

4. A lithium enolate first adds to the carbonyl and results in expelling triflate leaving group. The excellent leaving ability of triflate and the keto-enol stability leads the reaction to the formation of alkyne upon aqueous workup.

R' 0 R' 0 OLi Li R R' 0 0 R 0 on n on R n n

Scheme 4. The cross-coupling of a vinylogous acyl triflate with a lithium enolate.

Imidazylates,14 or imidazole-1-sulfonates, can be synthesized from an alcohol and

sulfuryl chloride followed by reaction with imidazole or from one-step reaction with N,

15 N’-sulfuryldiimidazole. This enhanced leaving group allows rapid SN2 reactions with a

variety of nucleophiles under mild conditions. The presence of an electron-withdrawing

heterocycle increases the reactivity relative to an ordinary aryl sulfonate, and the leaving

group also offers the advantage of remote activation by transforming the heterocycle into

an imidazolium salt during the reaction to increase the nucleofugacity.

00 OOH S02CI2 S N N Nuc 25°C X 0 Imidazole 00 o 0 0 0 0 0 -40°C to rt 0 0 0 81% 0 0 0

entry Nuc X %yield

1 BU4NF F 75 2 BU4NI I 81 3 Mel I 78 4 BU4NN3 N3 81

Scheme 5. Substitution reaction with imidazoleates as leaving

16 Ruhardt group has found that heptafluorobutyrate (OCOC3F7, perfluorobutyrate,

OHFB) has a nucleofugality similar to that of halides, furthermore, in synthesis manner,

the preparation of fluorocarboxylate ester is more convenient and with avoidance of

rearrangement compare to the formation of halides from alcohols. The electron- withdrawing property of fluorine facilitates fluorocarboxylates to be better leaving groups. The 1-adamantanyl perfluorobutyrate analog exhibited faster solvolysis rates

(Scheme 6).

18 o EtOH / H2 0 (80/20) OEt + o C3F7 94% 64:36

Scheme 6. Perfluorobutyrate leaving group in solvolysis.

1.3 Chiral leaving groups

Asymmetric synthesis, also called enantioselective is an organic synthesis that

introduces one or more new and desired elements of chirality.17 This is very crucial in the

field of total synthesis and pharmaceuticals since different enantiomers or diastereomers

often have different biological activities. The methods for asymmetric synthesis have

been classified into four types; each based either on chirality of the substrate, auxiliary,

added reagent or catalyst.18 Conversion of prochiral substrate to a chiral substrate using a

chiral leaving group attracted more attention. It offers advantages of an efficient

alternative to traditional chiral auxiliary, and chiral leaving groups do not require removal

step. Currently existing chiral leaving groups include BINOL derivatives, chiral amines,

chiral sulfonates and chiral carboxylates. Our group hypothesized a new approach to

form carbon-carbon bond stereoselectively with prochiral substrates, which will be

discussed later.

The binaphthyl unit has enjoyed extensive use in the designs and synthesis of chiral

catalyst for carbon-carbon bond or carbon-hydrogen bond making. The degrees of chiral

recognition, induction, and transfer observed for these binaphthyl compounds have been attributed to the rigidity and freedom from conformational ambiguity. Wilson and Cram synthesized chiral leaving groups from chiral alkoxy naphthyl moieties through a nucleophilic aromatic substitution (Scheme 7). 19 Then this Lewis acid-assisted chiral

leaving group is cleaved through a breakage of C-O bond during the substitution and addition reactions (Scheme 8).20

OR N M o R' -ROM +

R = L-menthyl, u-fenchyl, R' = H, OCH3 barnyl, quininyl, M =Li, MgBr R' =H, OCH3

Scheme 7. Synthesis of chiral binaphthyls in a nucleophilic aromatic substitution reaction.

A A R LG* LG* + D + * R + o B o B C D -LA C LA

Scheme 8. Lewis acid-activated addition reaction involving chiral leaving groups

The amino groups usually are considered as weak leaving groups, however the quaternary ammonium salt is a very good leaving group since when it leaves, it produces a neutral amine. The elimination of the quaternary ammonium salt, Hoffmann elimination usually takes place via the E2 mechanism.21 Yamamoto and co-workers developed a new

chiral cyclic amine leaving group derived from proline.22 These proline-derived chiral leaving groups have been used to induce asymmetry in many alkene or enolate addition reactions.23, 24, 25 The enantioselective outcome can be explained by the shielding effect

of pyrrolidine ring or steric bulky group on the chiral amine leaving groups, which allows

the addition happen on only one side of the molecule. Similarly chiral sulfonate and

chiral carboxylate leaving groups also afford excellent enantioselectivity and diasteroselectivity in various reactions. 26,27

OMe 1) BU2CuLi·LiBr OMe o THF, -90-0oC o o CH CN 3 N added salt + 25°C, 1h HN 2) NH4CI (55 - 95%) n n n Bu

Scheme 9. Asymmetric addition with cuprate and enolate reagents.

1.4 Organometallic leaving groups

Nucleofugality is one of the measures of a leaving group in substitution reactions, and usually the enhancement of nucleofugality is attained from incorporating an electron withdrawing group (EWG) as part of the departing moiety. Oragnometallic leaving groups offer the possibility of improved nucelofugacity through redox processes not available to second-row heteroatoms.

The excellent nucleofugality of triarylbismuth has been applied to alkylation and alkenylation, which exhibits great rate improvement relative to triflate.

Triarylbismuthonium salt was oxidized to generate a pentacoordinated intermediate, which can be quickly cleaved and reduced to a stable trivalent bismuth compound. A typical reaction is shown in Scheme 10.

BF; Ph Ph tBu N But Ph PhCH20H + Bi Ph OMe + Bi Ph CHCI3, rt Ph + Me 95% yield Ph

Scheme 10. Reaction of bismuthonium with benzyl alcohol.

Carboranes (specifically CHB11Me5X6) represent yet another class of leaving group which incorporates a very stable anionic boron cluster framework into the departing

moiety. Carboranes are weakly coordinating, very non-basic, very inert, and exceptionally non-nucleophilic. They are also non-oxidizing and are not a source of halide ions. They are the strongest Brønsted acids and the strongest alkylating agent known to date. The major drawback to using carborane leaving groups is that the technology is very expensive, so their main usage is restricted to special applications, such as nucleophilic substitutions that fail with traditional electrophilic alkylating agents.

H C Me Me Me B B B B B PhH R+ Y- RH Me Me Me Y- + CH4 Br B B H B B Br + Br B Br RH =linear or branched Br B Y =CHB11MesBrs (C4H1Q. CSH12• CSH14) Me Br

Scheme 11. Methylation reactions involving carborane and 7-isomer of Me(CB11Me5Br6)

1.5 Heterocyclic leaving groups

Heterocycles can be tolerant to a wide range of reaction conditions, behave as

efficient leaving groups and be easily introduced into a molecule. Pyridines are among

the most widely used heterocyclic leaving groups in organic synthesis. The advantage of

using a neutral pyridine leaving group is that the reaction media does not need to have a

high dielectric constant for a unimolecular dissociation process because there is no

departure of an anionic leaving group. As mentioned earlier, in the transition state of a

unimolecular dissociation process for a neutral substrate dissociating into two charged

species, there is anion charge buildup in the transition state. Quinoline is another type of

heterocyclic leaving groups, in which the quinoline species is oxidized to quinolium salt. 10

Upon the attack of nucleophiles the cleavage was performed on the electrophilic position

with the formation of neutral quinoline as byproduct.28 The best leaving groups are stable

molecules that depart as gases, which drive the equilibrium toward the products.

Diazonium salts are so reactive that they have been used to isolate unstable species such

as phenyl cations.

Other tertiary neutral leaving groups, such as benzoisothiazole-3-ones (Scheme 12), indoles and 3,5-dichloropyridine, have been developed for certain applications.29, 30, 31

C02Me 0 C0 Me S PhNH2 2 NaOMe NHPh MeOH MeOH 0 N S reflux S reflux S 94% NHPh 76%

Scheme 12. Representative substitution reaction with benzoisothiazole-3-ones as leaving group.

1.6 The background of NALGs

Nucleophile assisting leaving groups (NALGs) may be defined as a leaving group that contains a chelating unit capable of stabilizing the transition state of a nucleophilic reaction. The podand-catalyzed reaction was one of the initial examples where the NALG effect was observed.32 The nucleophilic substitution reaction of 1-chloroanthraquinone

following the regular protocols failed to give the desired product even under reflux

condition. However, the desired product was obtained with the addition of catalytic

amounts of oligo-ethylene glycols.

O OH O O O 3 (cat)

OH R O O 15 O O Cl O O O Na O NaH, THF 15 O

Scheme 13. Podand-catalyzed nucleophilic aromatic substitution reaction of 1-chloroanthraquinone

In the reaction of n-hexadecanol (Scheme 13), the product was received in 80% yield with 24% of triethyleneglycol catalyst. X-ray crystal structure suggested that,

triethyleneglycol initially act as a nucleophile to produce an intermediate, in which the

coordination between the sodium cation and the oxygen atoms in triethyleneglycol was

observed. 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 leaving groups exhibited enhanced nucleofugacity in methylation and acylation reactions. Mandolini group33 mastered this

category of leaving group. The displacement of electrophilc methyl group of substrates

(Figure 1) by benzyl thiolate revealed substantially different rates that are highly dependent on the metal ions as well as the stabilizing ability of the transition state. In the experiment with Kryptand (K222), a well-known potassium cation chelating agent, the metal was sequestered leading to a loss of rate enhancement. To help assess the relative contribution of the metal counteraction, methylation reactions were compared to experiments involving K222 to give relative rates (krel).

N O O O O O OMe CO2Me O OMeO O O K222 O Me O O O O n O N O a n=3 c d e b n=5

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

The results for sodium and potassium benzyl thiolate were summarized in Scheme

14. For methylether crown ether a, both sodium and potassium salts gave the peak values

of krel 565 and 826, respectively. Compare to the crown ether b krel 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.

8M k 8Me + Me LG a-e

M krel(a) krel(b) krel(c) krel(d) krel(e) K.K222 1 1 1 1 1 Na 565 3 47 0.43 0.57 K 826 53 17 0.43 0.66

Scheme 14. Rate of methylation of metal thiolate with various leaving groups

For the crown ether ester c the observed peak values for krel were 47 and 17 for

sodium and potassium salts respectively. It suggested that in the case of methyl ether the

transition state is more stable because oxygen has more electron density in its transition state f compare to methyl ester, where electron density is delocalized over two oxygen

atoms of the carbonyl ester function group (Figure 2). Therefore f becomes more stable

because of strong electrostatic interaction compared to g where this interaction is relatively weak. This information advises us in designing new NALGs.

Me 0 S Ph Me 0 0 S Ph 0 0 0 0 0 M 0 0 M 0 0 0 f 9

Figure 2. Transition states for methylation reaction of a and c

A similar NALG effect was observed for the acyl transfer reaction, in the presence of metal methoxide in methanol of an aryl acetate substrate h having a tetra(oxyethylene)

chain in the ortho position (Scheme 15).34 The general mechanism involves the rate-

determining formation of a tetrahedral intermediate. For h, the presence of a nearby

chelating ligand was supposed to stabilize the transition state i by placing the metal cation in a position to stabilize the negative charge on the oxygen atom of the tetrahedral intermediate. Peak rates were observed for alkaline earth metals Ba2+ and Sr2+ 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.35

aMe a Me a a a a a Mea M fast a M a aAe a slow Me aMe a salt cone - 0.1 M a a a h

M Me4N Na K Sa Sr krel 1.6 3.7 79 17

Scheme 15. Rate acceleration of acetylating reaction with the substrate containing oligoether chelating arm

1.7 Nucleophile Assisting Leaving Groups (NALGs)

In the methylation reaction we realized that the rate enhancement afforded by a

NALG is not necessarily due to an increase in the nucleofugacity of the leaving group

upon cation chelation. Instead, a NALG should also interact with nucleophiles in the

course of a reaction to lower the transition state energy of the rate limiting step. For

example, in the case of substrate j, it is expected that the negative charge imparted to the leaving group moiety (LG) by an incoming nucleophile (Nuc) in transition state l should

provide a more favorable chelation complex relative to its neutral precursor ligand k

(Scheme 16). Depending on the specific nucleophilic reaction mechanism, cation

chelation in the transition state should reduce the energy of activation (Ea1) of NALG

substrates relative to substrates containing traditional leaving groups. Without the added

stabilizing effect of nucleophilic salt chelation with a nearby multidentate ligand, the

energy of activation (Ea2) for reactions involving traditional leaving groups (leading to a

transition state such as m) is expected to be higher (Ea2 > Ea1).

o- LG R LG R LG R M+Nuc- NALG reaction Nuc 0+ o M+ M Nuc - Ea1 X X X X X X X X X

Reacting state k Transition state I

M+ M+Nuc- Traditional 0- o LG R LG R Nuc - R Nuc J reaction Ea2 m

Scheme 16. Rationale for rate the enhancement observed with nucleophile assisting leaving groups

The leaving group is a highly stabilized salt (Scheme 17), with electron density

delocalized through the oxygens of the chelating arm onto the chelated metal cation. The change in entropy associated with the rate-determining step for NALGs is smaller than the entropy change for tosylate. In the case of tosylate, the change in entropy associated with the conversion from a free unbound state to the fixed geometrical constraints of the

SN2 transition state is much greater than for the NALG because the nucleophile must

shed solvent molecules in order to approach the electrophile intermolecularly.

o 0 S R o 0 o S 0- ~ Nuc- X X R Nuc J + X X X X

Metal chelating unit Leaving group as a highly stabilized salt

Scheme 17. General substitution reactions with NALGs

The second way that the NALG increases the rate of substitution is by affecting the

enthalpy of the transition state leading to products. In the transition state, a chelated metal

delocalizes the charge buildup on the sulfonate oxygens and lowers the enthalpy of

activation leading to the products for the NALG relative to the tosylate and thus increases the rate of reaction. In the case of the tosylate the metal is less closely associated with the sulfonate due to solvation.

Sulfonate leaving groups containing an oligoether metal-chelating moiety have

been recently reported. 36 The chelating units were designed to stabilize developing

negative charge on the oxygens of the sulfonate leaving group in the transition state

analogous to previously described work involving aryloxy and arylcarboxyl leaving

groups that contained metal chelating units. The detailed synthesis and applications of

NALGs will be discussed in the following chapters.

From the observed NALG effect from previous leaving groups we recognized that

the linker connecting the chelation unit and the aryl ring could play a significant role in

the reactivity of NALGs. To avoid this nonideal chelation geometry, a series NALGs

have been put forward to consideration (Figure 3). Possible linkers are: alkane ether, ether, alkane, alkene, alkyl and alkyne.

o 0 Ph So 0 0 linker 0 0

Figure 3. The hypothesis of new NALGs

Another important role-player in NALGs system is the stabilization of the transition state may be affected by the chelation property of different chelators. Nitrogen proved to be an excellent chelator in the study of substitution reactions with ionic and Lewis acidic metal halides. Details will be provided in each chapter, accordingly. 17

The previous research in our lab showed that the alkali cations as lithium, sodium

and potassium are readily bound by the NALGs with 12-c-4, 15-c-5 and 18-c-6

respectively. By attaching an ion-selective coordinating arm to the NALG, a degree of

cation specificity can be achieved, which leads to the development of leaving groups that

can be activated by the presence of certain metals in a salt.

We postulated the reaction proceeds via a SNi mechanism, in which the concerted

delivery of the nucleophile as part of a tight-ion pair occurs from the same face of the

substrate as the departure of the leaving group; 37 however Braddock underlined the

mechanism of halide substitution with NALGs in their recent publication. 38 The

incorporation of their theory will be acknowledged in chapter 3.

In summary, 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. A chelating arm can help the reaction also entropically by

chelating the metal cation of a nucleophilic metal salt in the reacting state. NALGs 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.

We are happy to report here that our stereoretentive reaction was successfully applied in total synthesis by the Kim group.39 In the synthesis of (+)-Microcladallene B,

at the late stage of their synthesis the author needed to install bromide stereoretentively from an intermediate alcohol derivative (Scheme 18). As reported they tried all the literature procedures, but all the methods failed to yield desire product. Only when they

applied our bromination technique expected product was resulted in 63% yield, along

with deprotection of the silyl protection group.

TBDPSO OH

Other HO Literature N X procedures o

TBDPSO HO ("0/ 0'" i 0 TiBr. I H H. ". I O O=S H f N :0 ~0\6'h oIT \ 63% H H o~ H Sr (+)-Microcladallene B

Scheme 18. Key step in Kim’s total synthesis

1.8 Nucleophilic substitutions

There are two general classes of substitution reactions, unimolecular (SN1) and

bimolecular (SN2). The SN1 mechanism proceeds with the formation of a discrete

carbocation and bond-breaking is the driving force, and is less synthetically useful than a

bimolecular process. This is due to the racemization of stereoconfiguration, which alters the function of synthetic molecules. The bimolecular substitution reaction proceeds through a concerted mechanism, in which bond-making and bond-breaking occur simultaneously. Both types represent mechanistic extremes, and most reactions exist

along a continuum between the two mechanisms.

The kinetics of the bimolecular substitution process is governed by the interplay

between bond-forming and bond-breaking, which compete with each other to produce

substitution and elimination products. As the activation energy required to reach the

transition state decreases, the reaction rate increases. Many factors contribute to the 19

overall reaction kinetics for a bimolecular substitution process, such as bulkiness of the

substrate, choice of solvent, nucleophile and leaving group.

There are very few approaches to enhance leaving group ability. In order to

increase bond-breaking in the transition state, chemists have employed highly electron-

withdrawing leaving groups, which lower the energy of the transition state by polarizing

the bond from the leaving group to the electrophilic center through induction. Another

approach involves highly polarizable atoms as leaving groups, such as iodine, which have electron clouds that can be distorted to accommodate the negative charge formed on the leaving group in the transition state. These two approaches increase the general reactivity of an electrophilic center toward a variety of nucleophiles. In a bimolecular substitution

reaction, a nucleophile must be able to accommodate some of the negative-charge

buildup in the pentavalent transition state, as shown in Figure 4.

~uc C L& (5

Figure 4. Pentavalent transition state for a bimolecular substitution reaction

Nucleophilic substitution reactions at secondary sp3 hybridized carbon bearing a

leaving group represent a fundamental and important transformation in synthetic organic chemistry. Depending on the stereochemical outcome, the mechanism is either SN2, where the outcome is inversion or SN1 where racemization happens via a carbocation.

The third possible stereochemical outcome for substitution is retention of configuration where the mechanism is designated as SNi.

1.9 Pyridine and quinoline sulfonate based leaving groups

As described earlier many leaving groups are heteroatom nitrogen containing, such as indole, pridine, quinoline and their sulfonates. The electron lone pair of nitrogen is perpendicular to the aromatic ring, so the electrons cannot be delocalized in the π-system, which determines nitrogen to be an exceptional lewis base willing to donate the electron density to lewis acids.

Although alkylpyridine and quinoline sulfonates have a broad application in biosynthesis, it was not recognized to be an excellent leaving group until Hanessian started looking into 2-pyridyl sulfonate in 1989. It is well known that metal cations promote the reaction of functional groups proximal to pyridine nitrogen. They synthesized 2-alkyl pyridyl sulfonates from commercially available 2-chloropyridine. In the subsequent study they proved that this leaving group can be displaced by halide ions at cold temperature to give the corresponding alkyl halides. They claimed that the enhanced substitution reactivity was attributed to the pre-coordination of a divalent metal salt to pyridyl nitrogen, thus promoting nucleophilic displacement with release of an intramolecularly coordinated 2-pyridylsulfonate salt.40

00 o 0 o 0 RO S RO S MgBr2oEt20 fast So + N ~ N N CH2CI2.O°C Br Mg 80-99% Mg inversion of Br (from ROH) Br configuration

Scheme 19. Transformation of 2-pyridyl sulfonates to alkyl bromides with inversion of configuration.

During the observation of decompostion of secondary ester of 2-pyridine and 8- quinolinesulfonic acid, Corey and co-workers noticed the olefin formation through an E1

type of elimination. By reason of the rate-determining carbocation formation the leaving ability of leaving groups becomes critical in this reaction. They proposed two possible

mechanisms: one is concerted E2 type of elimination; the other one is carbocation

intermediate involved elimination. After a few pyrolysis experiments they concluded that

the formation of olefins from alcohol was accomplished through ionization and

deprotonation facilitated by the basic nitrogen.41

N +N 150°C S 0 H so; o o + 92% yield

Scheme 20. Pyrolysis of 8-quinoline sulfonate to give cyclohexene.

Indole can be applied in nucleoside synthesis as a leaving group, in the nucleophilic

substitution the P-N bond was replaced by a bit stronger P-O bond.42 The leaving moiety

in this case is a highly stable compound indole.43

0 0

NH NH OTBS OTBS N N 0 0 0 0 0 3'-0-TBDPS- 0 0 thymidine NH P P N 0 DBU,50°C H C N H3C 3 0 0 0.5 h TBDPSO

Scheme 21. Use of indole as a leaving group in dinucleoside synthesis.

Our group has been studying the theory of heteroatom containing leaving groups,

and we tried to bring multiple lewis basic chelators into one substrate and introduce

electron withdrawing groups onto the aryl system. With this notion we believe the new

NALGs not only be more reactive but also more selective in chemo-, regio- and stereo-

manners.

1.10 Current progress of radiofluorination

With the development of PET (Positron Emission Tomography) technology,

Fluorine-18 is a short-lived (t1/2=109.7 min) positron-emitting isotope which now finds

immense importance as a label for radiotracer used with the molecular imaging

technique. 44 A successful example of biochemical processes is the incorporation of fluorine-18 into 2-deoxy-D-glucose to give [18F]2-fluoro-2-deoxy-D-glucose ([18F]-

FDG).45 [18F]-FDG is now widely used as a clinical research tool and a diagnostic agent

in PET. Fluorine-18 comes from a cyclotron through the proton irradiation of 18O-

enriched water, 46 which renders the ion poorly reactive due to its high degree of

hydration.47

OAe OH on AeO 0 HO 0 AeO OAe HO OH 18F 8 CF]FDG

Scheme 22. Radiosynthesis of [18F]FDG from [18F]fluoride ion.

The fluorine atom is most electronegative, and the carbon-fluorine bond is

intrinsically strong. Traditional methods for the preparation of fluoro-organic compounds

are predominantly based on the use of electrophilic reagents (F2, XeF2). Incorporation of

fluoride ion into position originally occupied by an aryl amino group is a long known

transformation and may be achieved by both Balz-Schiemann48 and Wallach49 reaction.

Currently the most common and effective approach for introducing fluorine-18 on aryl carbons is direct nucleophilc substitution under harsh conditions. In this reaction a good leaving group and one or two electron withdrawing groups on o- or p- position on aryl ring are necessary. 50 Related to the discussion in the earlier section, the fluoride

substitution with 2- or 3- substituted pyridine has been studied intensively.51

18F-, K2.2.2-K+

X N Solvent, heat 18F N

RCY upto 96%

x 18F-, K2.2.2-K+ N R Solvent, heat N R

x=CI, Br RCY =67-98% R =CN, CONH2

Scheme 23. Syntheses of [18F]2-fluoropyridine and [18F]3-fluoropyridine from [18F]fluoride ion.

Because of the strong electronegativity of fluorine it is very difficult to introduce

fluorine-18 onto the electron rich arenes. Pike group developed a new method to install

the fluorine-18 using diaryliodonium salt. An interesting feature of this reaction is its

chemoselectivity. An o-substituent on one of the aryl rings preferentially directs the

radiofluorination to that ring. 52 In the absence of the ortho effect, the fluorine-18 is

incorporated into the less electron rich ring. The diaryliodonium salt can be prepared

from Koser’s reagents and arylboronic acids53 or organostannanes.54

X 18F 18F- R1 R2 R1 + R2

or 18F R1 + R2

Scheme 24. Introduction of fluorine-18 into arenes through the reactions of diaryliodonium salts with

[18F]fluoride ion.

Aliphatic nucleophilic substitution with fluorine-18 is highly efficient. The reaction

follows an SN2 type of substitution with sulfonates or halogens as leaving group. This

reaction is usually carried out in polar aprotic solvent in favor of primary substrates. A

recent example is the reaction of N-aryl-α-bromo acetamides with fluorine-18 ion in the

presence of trace amount of water.55 The fluorine-18 compound also can be obtained through nucleophilic addition56 and radioactive/nonradioactive exchange reaction.57

o o Br 18F-, 18-crown-6-K+ HN HN MeCN, trace water 130oC,10min RCY = 20-60%

Scheme 25. Reaction of N-aryl-α-bromo acetamindes with [18F]fluoride ion.

Occasionally the fluorine-18 cannot be directly transferred to the desired molecules,

indirect methodology using a labeled intermediate that is directly labeled with fluorine -

18 with the synthesis mentioned above. A researcher in radiochemistry field has been

working on the improvement of current technology. The fluorination can be enzyme-

catalyzed,58 microwave-enhanced,59 using micro-reactor60 or supported by polymer,61 which results in better reactivity and higher radiochemical yield. 25

In the following chapters, we will report the synthesis and design of various configuration of aryl sulfonated-based nucleophile assisting leaving groups (NALGs).

The reactivity of NALGs was examined with substitution reaction using dissociated nucleophiles (alkali metal halides). The results exhibited the NALGs in general gave enhanced reaction rates, and the substitutents of the aryl group, the size of chelation arm and the spatial and steric effect are key factors of designing NALGs by better stabilizing the transition state rather than stronger chelating in reaction state. The outcome of radiofluorination study demonstrated that NALGs can be potential diagnostic PET tracers. Also the NALGs were studied with new methodology using associated lewic acid

(transition metal halides). For the first time direct stereoretentive halogenations and azidation on cyclic secondary alcohols were developed using NALGs and titanium (IV) reagents, in which the lewis basic oxygen and nitrogen atoms are believed to be coordinated with Ti(IV), involving a stable transition state of six-membered-ring geometry. Titanium (IV) tetrazide as proved to be an excellent azidation reagent in our study has never been applied in organic chemistry. With thorough research on the chlorosulfite and quisylate NALGs, and with support from computational calculation as well, we proposed these reactions more likely went through a non-classical carbocation

(frozen carbocation) mechanism instead of a concerted SNi mechanism. With these unique chelation units halogenation reactions can be realized through an SN2 mechanism using Grignard reagents, which are convinced to be the source of exclusive alkyl- and aryl- nucleophiles, without any additives.

CHAPTER TWO

SYNTHESIS OF ESTER, ETHER AND QUINOLINE-SULFONATE BASED NALGS

AND SUBSEQUENT KINETICS AND RADIOFLUORINATION STUDIES

2.1 First generation of aryl sulfonate based NALGs.

Because of their good electron withdrawing effect sulfonate based leaving groups such as tosylate, mesylate and triflate have been widely used in organic chemistry. To our knowledge the concept of nucleophilic assistance has not been applied in this class of leaving groups. Starting with literature examples of aryloxy and arylcarboxyl based nucleofuges, we envisioned a class of sulfonate based nucleophilic assisting leaving groups (NALGs). One of our goals with this new class of leaving groups was to provide an alternative to leaving groups whose nucleofugacity is based in electron withdrawing capability; foremost among these is trifluoromethyl sulfonate (triflate) considered the fastest leaving group by reason of the electron withdrawing trifluoromethane group.

While this leaving group has found many useful applications in synthesis, it suffers from a number of serious drawbacks such as difficulty in isolation, poor stability and propensity to react with nucleophiles at the sulfur center. On account of these disadvantages, it would be very necessary for the newly designed NALGs to be highly reactive in the presence of nucleophilic metal salts and otherwise fairly stable during the purification and storage.

Our group was the first to develop such types of leaving groups and termed them as

NALGs.62 One of our earliest designs involved an aryl sulfonate based leaving group,

containing an oligo-ether unit, which is connected to aromatic ring through a carbonyl carbon at the ortho- position. This oligo-ether arm chelates 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 of NALGs was synthesized from a very cheap starting material, sulfobenzoic acid cyclic anhydride

1, in two steps (Scheme 26).

The initial synthesis approach was route A, which takes more than thirty hours and two purification processes.

PCI o 0 o 0 5 8 (2.0 equiv) 8 CI CI Phenylpropanol Route A 90oC,6h CI o (1.5 equiv.) DMAP(1.2 equiv) o 0 2 0 CH2CI 2 8 o 0 o 8 0 Ph PCI5 (2.0 equiv) HO o CH3 o 0 o o n 60oC,3-4h o CH3 8 n Route B (1.5 equiv) 0H o o 72-96% 5 3 0

Scheme 26. Synthesis of NALG sulfonylchlorides 4 and sulfonate esters 5 of primary alcohol

o In route A, starting material anhydride was heat up with PCl5 neat at 90 C for 6 h to

generate the bisacid chloride product. Then heating of 2 with oligo-ethyleneglycols at

60oC for 30 h yielded the corresponding NALG sulfonyl chloride 4, which then was

treated with 3-phenyl-1-propanol in the presence of DMAP at room temerature to give

the sulfonate esters. Subsequently, a more efficient one-pot synthesis of 4 (route B) was

developed.63 At room temperature oligo-ethyleneglycols opened up the cyclic anhydride

to produce sulfonic acids with oligo-ether arm 3 which then react with PCl5 for 3-4h

yielded 4 in very good overall yield. The NALG sulfonate esters were synthesized

following the same procedures.

With these chelating sulfonate esters in hand, nucleophilic substitution reactions

were performed with various alkali metal halides at room temperature exhibiting

excellent rate enhancement relative to traditional leaving groups. Results with LiBr of

this study will be discussed later in this section along with the data for "second

generation" NALGs for a more convenient comparison.

2.2 Reactivity and kinetics study of first generation NALGs

Kinetic experiments were designed to quantify the rate enhancement observed for the first

generation NALGs and to understand the mechanism better. In the past, the rates of the

substitution reactions were monitored crudely by the time required for the starting material to

completely disappear according to Thin Layer Chromatography (TLC). The reactivity and

kinetics study eventually can help us to format a rational approach to NALGs in future. In kinetics study of organic chemistry there are various ways to investigate the rate of the reaction based on the different nature of the reactions. These analytical methods must be specific, sufficiently accurate and rapid. Generally there are two classes: direct and indirect methods. In direct methods we can use the chemical analysis and measure the precipitates. The indirect methods include NMR, absorbance and chromatography.

UV-vis: Due to the UV activity of the NALGs the substitution reaction can be scanned under the full wavelength of UV-vis range, and then the specific UV absorption wavelength or the maximum absorption can be determined. The measurement of the 29 difference of the absorption will exhibit the rate and completion of the reaction. An observed rate constant equation will be generated to confirm the mechanisms. Titration:

Because of the involved halogen ions, we can monitor the reaction by forming the silver- halogen precipitate in the reaction system. The mass of the precipitate can reveal the

percent completion of the reactions. Acetone and water are selected as the solvent of substitution reaction and silver nitrate solution respectively for acetone and water are miscible with each other. Excess silver nitrate solution is applied in the titration in order to quench the reaction instantly because the ionic precipitation happens faster than the substitution reaction.

We chose to monitor the concentration of starting material with 1H-NMR spectroscopy for multiple reasons. It is not requisite to use any transient kinetic techniques as the observed rate relatively low. The concentration of starting material relative to an inert internal standard is linear with the ratio of the area of the starting material’s signal to the area of the internal standard’s signal. 64 An internal standard

should be inert, structurally similar to the analyte, so it has the same response to the

detector (same relaxation time), and appear in a portion of the spectrum relatively free from the analyte signals. Upon determination of analyte (NALGs) concentration as a

function of time, the rate constant can be determined by mathematical manipulation of

the data and through the use of integrated plots.

The concentration of the starting NALG esters as a function of time is directly

proportional to the 1H-NMR peak area of the signal it generates. This proportionality constant is termed as the response factor (F) that accounts for the differential response of

the detector to the analyte and the internal standard. Various analytes will exhibit

different responses to the instrument, thus F must be calculated for every single

experiment. Equation 1 showed the calculation of F, which is related to the concentration

and peak area of both internal standard and the analyte. The experimental conditions

used to analyze an internal standard must be identical to those used to analyze the

analyte. Experimentally, the peak area generated by the starting NALG esters

corresponded to As, the initial concentration of NALG ester corresponded to [A0], the peak area generated by the internal standard corresponded to AIS, and the concentration

of internal standard corresponded to [IS].

F = Response Factor

AS x [IS] AS = Area of the Peak A (NALG) F= [A ] = Concentration of A at t = 0 Eqn. 1 AIS x [A0] 0 AIS = Area of the Peak of Internal Standard [IS] = Concentration of Internal Standard

Equation 1. Calculation of the response factor (F).

Once the response factor is known, the concentration of the analyte is calculated at

each time point using the response factor and the NMR peak area of the analyte signal at

that time (Equation 2). From this data, a plot of concentration versus time is obtained.

Because one of the reactants is a metal salt, which cannot be detected by NMR, the

concentration of the salt is extrapolated from the concentration of the starting NALG ester using the relationship between the starting NALG ester (A) and the salt (B) described in Equation 3 and Equation 4.65

As x [IS] Eqn.2 A JS x F

X t = Concentration of Product at Time t Eqn.3

B = Concentration of Reactant B at Time t Eqn.4 t

Equations 2-4. Calculation of the concentration of the analyte and salt at each time point.

The rate law or rate equation for a chemical reaction is an equation that links the

reaction rate with concentrations of reactants and constant parameters. For a generic

reaction mA + nB → C with no intermediate steps in its reaction mechanism, the rate is given by r = k [A]x[B]y.

A first-order reaction depends on the concentration of only one reactant (a

unimolecular reaction). The rate law for a reaction that is first order with respect to

reactant A is r = -d[A]/dt = -k[A]. A plot of ln[A] vs. time t gives a straight line with a

slope of − k. A second-order reaction will be dependent on both reactants, or second-

order with reference to one reactant and zero-order to the other reactant. Linearity in a

second-order plot supports a bimolecular mechanism. Now the concentrations of both

reactants as a function of time are known, the integrated rate plots may be obtained. We seek to prove or disprove this hypothesis by the linearity of various plots. The data is fitted to integrated rate plots for first-order to each reactant and second-order overall rate processes. If the concentration of one of the reactants remains constant, its concentration can be grouped with the rate constant, obtaining a pseudo constant: If B is the reactant whose concentration is constant, then r = k[A][B] = k'[A]. The second-order rate equation can be reduced to a pseudo-first-order rate equation.

Linear First Order Plot In [At] vs. time

Linear 1 [Bo] x [At] In vs. time Second Order Plot [A ] - [80] [Ao] x [Bt] o

Equation 5. Reaction rate determination with the linearity of integrated plot.

Toluene was chosen as an ideal internal standard for our rate studies due to its

inertness and NMR spectral properties. Toluene gave signal peaks in an area of the NMR

spectrum that is relatively unpopulated by signals arising from the starting NALG esters.

One problem we realized during the experiment with crown-ether NALGs, a different

internal standard should have been used, one that did not resonate on the other side of the frequency spectrum from the peak of interest. The peaks of the crown-ether NALGs

analyzed in our rate studies appeared in the aromatic region of their corresponding NMR spectra, hence the only NMR resonance of toluene that was discernible was its methyl singlet at δ 2.3 ppm.

If a metal salt is completely insoluble in the solvent used, the cation will be very hard to coordinate to the linear polyether NALGs, due to their poor phase-transfer ability.

The crown-ether NALGs do not require as polar a solvent as the linear polyether NALGs because crown-ethers are better phase-transfer catalysts. The solvent can enhance or retard a NALG effect (which is the observed rate enhancement and cation-selectivity of

the NALG substitution reactions) by affecting the ion pair of the metal salt. In solvents

with high dielectric constants, the rate is enhanced for the substitution reaction, which is

expected for bimolecular substitution reactions. However, the cation-selectivity is lost

due to the metal salt not being associated in a tight ion-pair, but existing rather as a

33 solvent-separated ion pair. In the solvent-separated ion pair, the cation coordinates the

NALG but fails to bring the anionic portion of the metal salt with it. The anion is solvated by the solvent and the rate of substitution on the electrophilic center is controlled by diffusion of the solvated-anion. In a solvent with a low dielectric constant, the NALG effect is the most pronounced because the cationic and anionic portions of the metal salt are tightly associated to one another. We wanted the salt to be soluble enough to coordinate the metal, but to keep the salt associated in a tight-ion pair. The solvent used in the experiments was d6-acetone, which has an intermediate dielectric constant.

We first conducted two experiments using a large excess of triethyleneglycol

NALG ester or lithium iodide, respectively, in order to establish the order of the NALG and the nucleophile. The disappearance of NALG ester was monitored by NMR, and then plots of concentration versus time were acquired for each reaction. Then the first order plots of the natural log of the concentration of each reactant versus time were obtained for each experiment (Figure 5). The first order plot shows that the reaction is first order with respect to lithium iodide and triethyleneglycol NALG ester, respectively.

-3 TIme min -3 Time min 20 40 60 80 100 20 40 60 80 -3.•.5 -3.5

-4 !::' ::::i i -4 :E -4.5 ,5-4.5

-5 Y=-o.017x - 3.767 -5 Y = -0.022x - 3.685 R2 =0.987 R2 = 0.983 -S.S -5.5

Figure 5. First order plot for the reactions that one of the reactants is in excess.

Then a second order plot of the concentration of both reactants was obtained, which supports the reaction being second-order overall (Figure 6).

~ u ~ [801[AJ u '0 lAo] [BJ )

- [8 1 "• 'A,,' 0 • y = O.185x + 1.134 ,• R Z = 0.988 0 0 ...... llrne(mh)

Figure 6. The second order plot for the reaction of NALG with lithium iodide.

In the following experiments we kept the metal salt in excess (4 equivalents) all

time, so the reaction order will be reduced to pseudo-first-order, which is much less

complicated. Using the slope form the plot, we wanted to establish observed rate

constants for each of the NALG esters reacting with a particular metal salt. The peak area

of a resonance corresponding to the starting material (NALGs) was measured relative to the internal standard, whose integrated peak area was set to equal one proton. A series of ten spectra were acquired every ten to twenty minutes to generate ten data points depending on the reaction speed. A response factor was calculated for each new NALG studied, and then the concentration of the NALG was calculated for each data point.

The results of substitution reactions were shown below. Sodium bromide and lithium bromide gave ordinary rate enhancement due to their poor phase transfer ability

when the salts are insoluble in reaction solvent. Table 1 showed the rate constants of different NALGs.

Table 1. The rate constants for the substitution reactions

0 0 s 0 Ph LiX Ph X OR Acetone X=Br, I 0 Rate Constant (M-1 min- -OR 1) Li-I Li-Br

0 0 0.0948 0.0981

0 0 0 0.1120 0.1120

0 0 0 0 0.1486 0.1520

0 0 0 0 0 0.3140 0.2140

-OTs 0.0149

The NALGs were reacted with the metal bromide series in order to validate the method. The observed rate constants are consistent with the rates generated by monitoring the completion of the substitution reactions with lithium bromide from TLC.

The tosylate of 3-phenyl-1-propanol was synthesized and reacted with the metal iodides as a control for the rate enhancement observed. The rate enhancement for NALG esters reacted with lithium iodide was 5-10 times that of tosylate. The tosylate did not give any reaction with lithium bromide in this NMR experiment.

We wanted to evaluate rate enhancement of the NALGs with different metal halides that are soluble in acetone, then we may be able to observe the cation selectivity.

However, the metal iodide series has the same solubility issue in acetone, that is, sodium and potassium iodides are insoluble. We cannot use the metal iodide series to compare selectivity toward the various metal salts unless we compare the rate enhancements of the

NALGs against the tosylate. Surprisingly 12-crown-4 reaction series is the twenty-six 36 fold rate enhancement with sodium iodide, and this observed rate enhancement might be the result of a phase-transfer effect by the crown-ether. We could perform a reaction between the tosylate and free 12-crown-4 to determine if the 12-crown-4 NALG is enhancing the reaction rate through a phase-transfer effect.

Table 2. The rate constants of NALGs reacted with various metal salts

0 0 S 0 Ph MI Ph OR Acetone

0 Rate Constants (M-1min-1) -OR Lil Nal KI

0 0 0.0948 0.0486 0.0235

0 0 0 0.1120 0.1250 0.0182

0 0 0 0 0.1486 0.3430 0.0219

0 0 0 0.3140 0.1910 0.0408 0 0

0.0149 0.0073 0.0103 -OT5

We did not observe any apparent correlation between the length of the linear oligo- ether chain and the rate enhancement. These findings contradict the observed trends for the reactions of the NALG esters with metal bromide series. One possible explanation for the discrepancy comes from ion-pair theory. The lithium iodide salts may be present as solvent-separated ion-pairs, and the observed rates are for an intermolecular substitution reaction rather than an intramolecular substitution reaction.

With all these data in hand we tried to elucidate the mechanistic possibility. One possibility is that there is no intermediate step (coordination) involved in this reaction, thus the process is a simple, one-step bimolecular substitution. The second possibility is the reaction first forms certain type of intermediate or transition state, followed by the conversion of alkyl halides. If the reaction follows the mechanism of SN1 reaction, it would contradict the results of rate law. As we mentioned earlier, the substitution is first order with respect to both the NALG and the nucleophile. Therefore, both reactants appear in the rate-determining step. In addition, it seems unlikely that an equilibrium appears in the second step because of the stability of the non-nucleophilic sulfonate salt generated in the reaction. In SN2 mechanism the breaking of the carbon-leaving group bond and the formation of the new C-nucleophile bond occur simultaneously to form a transition state in which the carbon under nucleophilic attack is pentacoordinate. In this transition state both nucleophilic metal salt and NALG ester exist. Most likely the substitution reaction with our new NALG esters agrees bimolecular substitution reaction.

The rationale of the rate enhancement will be discussed later.

o 0 o 0 R 8 8 0 k 0 + M X X ~ X X X X o 0 o 0 o 0 R R 8 8 8 0 k 0 1 Nuc- k2 0 + M+ X X M ~ k_ X 1 X X X X X X

Scheme 27. The mechanistic possibilities

We tried to find the most important factor which affects the reaction rate most. One 38

interesting experiment revealed that their rate of reaction with metal halides to produce

alkyl halides is not heavily dependent on the chelating ability of the ortho-oligoether unit

attached to the leaving group. During the comparison between NALG 6 containing a 12-

crown-4 chelating unit with NALG 7, which possesses a linear unit containing the same number of Lewis basic oxygens, the time required for both substrates to be completely

converted to bromide product indicates that they proceed at very similar rates despite the

substantial difference (103) in their intrinsic lithium cation chelating abilities.

One explanation for this small rate difference in the bromination reactions of

NALGs 6 and 7 might be that the 12-crown-4 unit of 6 is hindered from effectively

chelating lithium cation by its arylsulfonate. To explore this possibility, NALG 6 was

1 examined by H NMR in the presence of a non-nucleophilic lithium salt (LiBF4). We set out to answer these questions by trying to isolate the complex through the reaction of the

NALGs with non-nucleophilic salts, where the only possible product would be a complex of metal salt with the NALG. If a complex does form with the metal salt, there should be a discernable chemical shift in NMR in the methylene protons on the coordinating arm.

For the linear oligo-ether NALGs, no reaction was observed by NMR and no such

chemical shift was detectable. We conclude that the superior chelating ability of 12-

crown-4 over tetraethylene glycol holds in our NALG systems. When the NALG of 12-

crown-4 6 was reacted with four equivalents of LiBF4, a chemical shift downfield of the

starting material (about 0.1 ppm) was detectable in the methylene protons in the coordinating arm at δ 4.35 to δ 4.45 ppm within 10 minutes of adding the salt (Scheme

28). This indicated that k1 is a lot larger than k-1 (Scheme 27), and the equilibrium for the

pre-ass ociation of NALG with the salt must lie toward the complex. The starting material

is not present after the addition of metal salt.

complex LiBF4

I I \ I I I I I I I I I I 1\ I I I I I I I I 00 4.50 4.4iJ 4.30 4.50 4.40 4.30 S 0 fh 0 00 00 4 0 S 0 fh S 0 fh o o 0 0 0 7 o Li o 0 o 0 0 LiBF4: Non-nucleophilic H H o lithium salt o H H 6

Scheme 28. The 1H-NMR spectrum of the NALG of 12-crown-4 and lithium tetrafluoroborate.

The lithium cation is expected to be available for chelation of the sulfonate unit of 6

in the transition state since 12-crown-4 is known to hold this cation in a perched rather

than buried position.66 Therefore, we surmise that the failure of NALG 6 to provide highly superior leaving group ability over linear NALG systems such as 7 may be due to

an inability of the crown ether to effectively present the lithium cation in transition states.

Others have observed a preference for straight-chain chelators (podands) over crown

ethers in nucleophilic processes, arguing that a chelating macrocycle draws a cation into its cavity and away from the reactive site.67 Another possibility may be that the carbonyl

group linking the 12-crown-4 unit to phenyl sulfonate in 6 does not afford the

conformation mobility required for the macrocyclic chelating unit to assist in the

nucleophilic reaction. In this regard, the superior flexibility of our NALGs containing

acyclic chelating units may be better poised to stabilize the growing negative charge in

transition state despite their poor chelating abilities.

Similar result was observed in the reaction with LiBr, after the addition of LiBr,

within ten minutes of the time the salt was added, the NMR spectrum showed complexed

NALG and the product salt, no starting material. This suggested that k1 is very large in

comparison to k2. This also suggests that k2 for the conversion of the complex to the

products is rate-determining. For the linear polyether NALGs, no complex is observed,

which indicates that either there is no complex at all, or that it is present in very small

concentrations so that the second step of the complex mechanism is fast. An alternative

hypothesis for the failure to observe a complex with the linear polyether NALGs is that k-

1 is greater than k1, in which case the slow step is still k2, yet the complex never

accumulates in solution because reactant formation is favored in the first step.

In order to quantify the individual rate constants, NMR relaxation experiments

should be performed in order to measure how much faster k1 is compared to k2. It is possible to examine NALG design with the goal of maximizing the rate of the second step, which is the largest contributor to the observed rate constant. Once the focus shifts from maximizing the initial binding of the metal salt with the coordinating arm, effort can be spent to enhance the rate of the second step, which is primarily an entropically driven process. The enthalpic benefit is the same for the cyclic and the acyclic oligo-ethers, but the entropic benefit changes in going from a conformationally unrestrained acyclic system to a more rigid crown ether NALG. With every constraint implemented in the coordinating arm’s geometry, the degrees of conformational freedom decrease for the coordinating arm, which has the nucleophile in close proximity to the bound metal cation.

As the bulk of the entropic penalty is paid in the initial binding of the metal cation to the

coordinating arm, the entropy change in achieving an SN2 transition state becomes

smaller as the rigidity of the NALG increases, until a point is reached where the fixed

conformational geometry actually prevents the nucleophile from achieving the proper

geometry with the electrophilic center. With the mechanistic insight obtained from the

kinetic studies, we can proceed to complete a structure activity relationship (SAR) study

of the various linkers for the coordinating arm to the electrophilic center.

For the NALGs, in the slow step transition state, the entropic penalty is much

smaller than the tosylate. In the case of the tosylate, the change in entropy associated with

the conversion from a free unbound state to the fixed geometrical constraints of the SN2 transition state is much greater than for the NALG because the nucleophile must shed solvent molecules in order to approach the electrophile intermolecularly and two

molecules must come together in the transition state to achieve the proper electronic

configuration.

The second way that the NALG increases the rate of substitution is by affecting the

enthalpy of the transition state leading to products. In the transition state, a chelated metal

delocalizes the charge buildup on the sulfonate oxygens and lowers the enthalpy of

activation leading to the products for the NALG relative to the tosylate and thus increases

the rate of reaction. In the case of the NALG, the metal is locked into a conformation that

allows it to stabilize the transition state in the slow step and results in a lower enthalpy of

activation.

2.3 Synthesis of second generation NALGs

In order to understand the cation-binding geometry of the NALG and provide

additional evidence for the NALG effect, the sodium salt of 8 was crystallized and

42 analyzed with X-ray crystallography. Initial attempts to crystallize the lithium salt failed.

The compound proved too hygroscopic for efficient crystal growth. The crystal structure reveals that 8 forms a dimer in the solid phase. Three of the coordinating arm ether oxygens of 8 complex the sodium cation, while both the ester carbonyl and one of the sulfonyl oxygens coordinate to the sodium of an adjacent monomer. The ester carbonyl is out of the plane of conjugation with the benzene ring and this suggests that the ester linkage for the coordinating arm is not the ideal geometry for chelation in the solution- phase. The ester carbonyl might also be geometrically distorted due to the process of chelating another sodium atom from an adjacent monomer of NALG. It should be kept in mind that the crystal structure represents the geometry of the sulfonate salt of the NALG in solid phase, which may behave very differently than in solution. However, this data suggests that the linker for the coordinating arm of the NALG is not ideal for chelation.

One of the oxygens next to the carbonyl in the ester linkage does not chelate the sodium cation. The design of new NALGs with alternative types of linkers for the coordinating arm might exhibit greater rate enhancements than the NALGs containing an ester linkage.

0 0 S ONa 0 0 3 0 8

0 0 0 0 0 0 Na 0 s 0 0 s 0 0 0 0 Na 0 0 0

Figure 7. The crystal structure of the sodium salt of the tri(ethylene glycol) NALG 8.

We 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 29). A series of second generation NALGs have been synthesized with both electron donating and withdrawing substituents in the aromatic ring. Initially aryl-oligoether derivatives 9 were synthesized

by heating substituted phenols with polyethylene glycol tosylates at 60-65oC in DMF.

Arylethers 9 on treatment with chlorosulfonic acid at 0oC followed by the treatment with thionylchloride in presence of DMF at 60-65oC yielded the corresponding

sulfonylchlorides 10 by electrophilic substitution reaction with 72-88%. Subsequent

esterification of 10 with 3-phenyl-1-propanol generated the secondary NALG sulfonate

esters 11.

remove carbonyl X o add electron o o n withdrawing n Y o groups X and Y First generation NALGs Second generation NALGs

i) HS03CI X TsO X X S02CI On OOC,2-4h NaHIDMF 0 ii) SOCI , DMF 0 OH 0 2 0 60-65°C, 20h, n 60-65°C,2h n Y Y Y 10 90-95% 9 72-88% X = lBu, F Y= F, H 0 0 X Ph OH So Ph o NaH (1.5 equiv) 0 DMAP, CH CI , n 2 2 Y rt, 30 min, 72-80% 11

Scheme 29. Synthesis of second generation NALGs sulfonyl chlorides and NALG sulfonate esters

2.4 Synthesis of quinoline-sulfonate based NALGs

Our preliminary studies on the substitution reaction using alkalimetal halides of various primary NALG sulfonates suggest a number of modifications in chelating arm as well as in aryl ring which lead to improved rate of substitution. These favorable molecular feature modifications include change in connectivity of the chelating arm to the aromatic ring: an ester unit ortho to the sulfonate or a chelating moiety comprised of ethylene oxide units; change in chelating atoms: an aromatic ring nitrogen or electron withdrawing groups on the arylsulfonyl ring.

We reasoned that a more Lewis basic chelator in the leaving group might be necessary to achieve further enhancement of the substitution reaction. Thus, we turned our attention to commercially available 8-quinoline sulfonyl (quisyl group68). The quisyl group was initially reported as a leaving group in E1-type pyrolysis reactions 69 and only once thereafter in nucleophilic bromination reactions leading to inversion of configuration. 45

In the LiBr substitution reaction quisylate showed an apparent rate enhancement, perhaps the strong Lewis basic chelator N provided the similar function as oligo-ether oxygens. So far, our designed NALGs all demonstrated great reactivity in terms of the substitution reaction with metal halides. We hypothesized that the addition of an extra chelating arm would lead to a new quisylate derivative with improved leaving group capabilities. Reaction of 11 with nucleophiles is expected to lead to transition state where both the quinoline nitrogen and the oligoether unit are chelated to the metal cation. This

NALG configuration may be ideal in the sense that it contains a rigidly held aromatic nitrogen which is more Lewis basic than ether oxygens. This should lead to more favorable binding to softer metal cations. In this new configuration, the flanking oligoether unit should serve as the flexible chelator adapting to the steric demands of the nucleophilic addition transition state.

Initially, we thought that we can follow the protocols of making ether NALGs to install the chelation arm at the 2-position of quinoline, but soon we realized this became a semi-total synthesis project. We started with low cost starting material 2-chloroquinoline,

2-hydroxyquinoline or 8-chlorosulfonylquinoline. We also attempted to synthesize 12 with pre-synthesized quisylate ester.

o o SO R LiBr N 0 o o 12

oligo-ether quinoline NALG Pathway A Pathway C Pathway B nucleophilc substitution o substitution o SO R substitution S02C1 N R' N N R' =CI, OH

Scheme 30. Quinolinyl leaving groups containing an oligoether moiety.

Our first approach failed in the installation of oligoether arm through a SN2 reaction as nitrogen is a stronger competitor compared to hydroxy group. Our model study with methyl iodide showed that the electrophile preferred to react with more nucleophilc nitrogen yielding N-methylated product.

N OH TsO 0 0 N 0 0 0

NaH, DMF, reflux 13

Me substituent N OH N 0 H Mel N 0 N 0

Scheme 31. The attempted approac h from 2-hydroxyquinoline

Then we hoped that an aromatic nucleophile substitution (SNAr) on 2-

chloroquinoline could lead to the expected product 13, in the subsequent sulfonation on

8-position we did not observe any formation of the designed NALG. The chelation ether arm did not survive in the strong sulfonation condition, possible mechanistic reason is the

oxygen in ether arm can be protonated under acid condition, then as a leaving group, it

was easily removed. NMR and MS spectra proved our hypothesis.

o o CI o N CI HO 0 0 HCI03S, SOCI2 o S o o OMF N o N o NaH, OMF, reflux S02CI2,OCM catalyst catalyst =AICI 3, AgN03, ZnO

Scheme 32. The attempted approach of chlorosulfonation

We sought some milder sulfonation conditions such as Friedel-Crafts reaction with

various catalysts to introduce the chlorosulfonyl group on 8-position. However activated

chloromethylene substitution product from solvent dichloromethane was obtained.

Based on the previous experimental results we switched the sequence of the

introduction of chlorosulfonyl and oligo-ether groups. Sulfonation of 2-chloroquinoline

afforded the product with 6-position chlorosulfonated. We searched the availability of 2-

chloro-6-methylquinoline, then from there we were able to achieve the new NALG

combining two different chelation properties with a median yield. The intermediate X

was converted to its corresponding ammonium salt under the hydroysis with

triethylamine and water as catalyst. This ammonium salt was then treated with diethylene

glycol monomethyl ether followed by the chlorination with thionyl chloride to recover

salt back to sulfonyl chloride. At last the esterification has been performed with 3-phenyl-

1-propanol and dimethylaminopyridine in dichoromethane. The overall yield is 7%.

0 CI N CI o S N CI 0 HCI03S, SOCI2 N CI o S DMF CI

0 CI oOs ONHEt3 o S N CI Et N, cat. H O HCI03S N CI 3 2 N CI THF,24h

30-40% Ph 0 CI 0 1) NaH, DMF, HO 0 0 o S 3-Phenyl-1-propanol 0 DMAP o S Reflux, 90°C, 18 h N 0 P N 0 2) SOCI2, 60°C, 4 h DCM, r. t., 4 h P

30% 82%

Scheme 33. Synthesis of new quinoline-sulfonate based NALG

Other approaches also have been tested, such as N-oxide from oxidation followed

by the substitution and reduction; deprotonation on 2-position followed by substitution with the pre-synthesized quisylate ester.

Other synthetically accessible and potentially advantageous NALG configurations include substituted pyridine systems. Indeed, substrates containing a 2-pyridyl sulfonate leaving group have been shown to exhibit enhanced reactivity towards magnesium bromide (a nucleophilic salt) through an “internal activation” effect.70

2.5 Synthesis of other related NALGs

We explored the effect of hydrogen-bonding in the coordinating arm of the linear polyether in order to chelate the anionic portion of the metal salts. By incorporating non- nucleophilic nitrogen atoms into the coordinating arm of the NALGs, such as ureas, carbamates, and nitrogen tosylates, the NALGs could chelate anions through hydrogen- bonding effects as well. In these new NALGs, (A) contains a nitrogen tosylate, which

has a strong electron-withdrawing tosyl group, and (B) contains two non-nucleophilic

nitrogens serving as potential hydrogen bonding donors. The synthesis pathway is shown

in Scheme 34.

NCO H H TsCl Ts HO O NH2 HO O N N DMAP + DCM HO O NH2 HO O N Ph DCM H (a) (b) O Ph O O S SO2Cl SO O 1) (a), DCM 2 (A) O H Ph(CH2)3OH 2) PCl O O N H 5 DMAP O O N Ts Ts O CH2Cl2 O O Ph O O S SO2Cl SO2O (B) 1) (b), DCM Ph(CH2)3OH O H H H H 2) PCl O O N N DMAP O O N N 5 Ph Ph CH2Cl2 O O O O O

Scheme 34. The synthesis pathway of hydrogen-bonding ester NALGs

As the salt selectivity and huge rate enhancement were observed in the kinetic

study of 12-c-4 containing NALG, two other lariat crown NALGs were proposed. These are 15-crown-5 and 18-crown-6 containing NALGs, which has a specific metal selectivity of potassium and sodium, respectively.

The discovery of macrocrown ethers was an important turning point in the history of organic chemistry, and for developing new NALGs the macrocrown ether function groups were considered as an ideal system because of the cricoids, which is ring-shaped, ether metal chelating moiety. A reasonably polar solvent and high dilution are two critical terms in the synthesis of benzo-macrocrown NALGs. The crown can not only stabilize

negative charge on the oxygens of sulfonate leaving group in the transition state but also

possesses the potential salt selectivity. By introducing double chelating arms the cationic

50 portion of salt was locked closer and stronger. We thought the selectivity and rapidity of the leaving groups should be improved in these cases. The synthesis of two benzocrown

NALGs and open-armed NALGs were attempted and unsuccessful.

0 0 0 0 0 0 S020R 0 0 0 0 0 0 0 S020R S020R S020R 0 0 0 0 0 CI CI 0 0

Figure 8. Proposed benzocrown and open armed NALGs

In order to make the anionic metal in salt chelating with the oxygen-containing arms without rotating the rigid function groups was used to fix the configuration of the chelating arms. This chelating arm has strong rigidity that keeps the arm stay stably without spinning. In this case the rate of the substitution reaction has the potential to increase. The rigid NALG and its synthesis pathway are shown below. However, no significant improvement was observed.

o 0 OH 00 o 0 o 0 SOH Ph S OMe S CI S 0 0 DCM PCls 0 OMe 0 OMe 0 OMe 55°C 0 0 0 0

Scheme 35. The synthesis pathway of rigid NALG

2.6 Results of nucleophilic substitution reactions with lithium bromide

We chose to study bromination reactions of substrates 11–19 to form 3-phenyl-1- bromopropane (2) using the quite soluble LiBr salt in acetone. The completion of the

reactions was monitored by both TLC and NMR of the disappearance of starting

materials. Primary tosylate 5 was used as bench marker for this series of reactions and it

required 32 h for conversion to the corresponding bromide. Substrate 6 containing the

triflate leaving group, which is considered to be among the best nucleofuges71, required only 2 h under the same conditions due to high polarization of C-O bond and high electronegative CF3. First generation NALG substrate 21d with four oligo-ether units in

the chelating arm and second generation NALG substrate 24h, with three oligo-ether

units in the chelating arm and two fluorine atoms in the aromatic ring gave a similar rates

to triflate. The NALG with 12-crown-4 as the chelation arm provided the highest rate.

In general, the NALG effect is clearly observed and the above results indicate that

the transition state could be stabilized due to both the electronic effect by the substituent

and the electrostatic interaction between the metal ion and the partial negative charge

developed on the oxygen atom in the transition state.

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

LG LiBr, acetone-d6 Br room temp 12 reaction entry structure n compound time (h)a 1 Ph OTs 13 32.0 14 2.0 2 Ph OTf 3 O O 1 15a 12.0 S 4 O Ph 2 15b 5.0 5 O 3 15c 3.3 O n 4 15d 2.3 6 O

7 O O 1 16a 25.0 S 8 O Ph 2 16b 8.8 9 O 3 16c 6.8 O n 10 O O 1 17d (X=H) 10.0 F S 11 O Ph 2 17e (X=H) 4.0 O 12 O 3 17f (X=H) 2.5 n 13 X 2 17g (X=F) 2.5 14 Ph 3 17h (X=F) 1.8 O O S O 15 O O 1 6a 1.3 16 O 2 6b 0.75 O O O n

O O S Ph O 17 N 18 4.5

O O S Ph O O 18 N O 19 16

a All reaction were carried out in aceto ne-d6 and end poit was determined by the disappearence of starting mate rial resonance peaks in 1HNMR.

The bromination reaction of NALGs 16a-c containing a tert-butyl group para to the oligo-ethylene oxide chelating unit reacted m ore slowly than their ester analogs. This modest rate decrease was likely due to the fact that both the tert-butyl and ether linkage in 16a-c release electron density into the arylsulfonyl ring destabilizing partial negative

53 charge of the sulfonate leaving group in the transition state. But replacement of an electron donating group with an electron withdrawing fluorine improves the rates for second generation NALG substrates (entry 10-14) which are the same or better rates than those of ester NALGs. This clearly indicates that the electronic effect by the substituents is also involved in the stabilization of the transition state. In each series, 15a-c, 16a-c,

17d-f, and 17g-h, addition of the second ethylene oxide unit exerts the greatest rate enhancement, leading to between double and triple the reaction rate. In the three aryl ether series of compounds, 16a-c, 17d-f, and 17g-h, the rate of bromination is influenced by the substituent on aromatic ring meta to the sulfonyl group and follows the order: tert- butyl

In conclusion, the theory of NALG was successfully applied to the development of a practical series of NALGs, which eventually are far better than conventional leaving groups. NALGs sulfonyl chloride and NALGs sulfonates are very stable, easy to purify and store which is not true for the most reactive conventional leaving group triflate.

NALG sulfonates only react when specific nucleophilic metal salts are present whereas triflate reacts with any type of nucleophiles with or without any metal ions.

2.7 Radiofluorination studies

Table 4. [18F] Fluorination of various NALGs

o R K18F o S 0 x microwave no additive R= link 0 o n

Compound Structure n %RCY (microwave, no additive)

Tosylate 9

Ester NALG 17

Ester NALG 3 22

Ether NALG (R=f-butyl, R'=H) 3 16

Quisylate 19

The substantially enhanced rate observed in the reaction of NALG containing substrates towards bromination encouraged us to test whether such advantages might also be realized in nucleophilic radiofluorination for possible applications in preparing radiotracers for PET. Our collaborators Dr. Lu and Dr. Pike at PET Radiopharmaceutical

Sciences Section in National Institute of Health (NIH) established the optimal conditions of these experiments and conducted most of the radiofluorination experiments. The initial studies involved the use of the NALG esters of 3-phenylpropanol. However, the fluorination product proved too volatile for convenient handling in the radiosynthesis apparatus, where the reaction was heated for 5 x 2 min at 90 W (reaching 130oC) under

microwave conditions or at 130oC for 10 min under thermal conditions. Thus we

prepared analogues of compounds containing a 4-tert-butyl group on the phenyl ring. As expected, radiofluorinated product, resulting from the tert-butyl containing substrates, was far easier to handle and measure.

o o o OH OMe LiAIH 4 THF

Scheme 36. Synthesis of 4-t-butylalcohol

With K2CO3 and K2.2.2, the desired product was obtained with a variety of NALG

substrates under both thermal and microwave conditions in good radiochemical yields.

In the absence of K2.2.2, the fluoride product was only obtained under microwave conditions. Our benchmark substrate tosylate gave a radiochemical yield (RCY) of 9%.

In general, we found that our chelating groups provided significantly less rate enhancement with K18F in acetonitrile than our previous studies with LiBr in acetone.

NALG (new quinoline NALG) was essentially unreactive toward potassium fluoride even

under microwave conditions. It is likely that the oligo-ether unit served to provide either

steric hindrance to the nucleophilic salt or pull nucleophilic salt into its cavity with the

strong affinity between oxygen and potassium. A marked preference for three ethylene

oxide units in the side chain in ester NALGs series was observed. It gave an average

RCY of 22%, a 2 to 3 fold enhancement relative to tosylate. To our knowledge, this

fluorination is the highest reported radiochemical yield of a primary substrate using

18 K F/CH3CN unassisted by additives. Eventhough the RCY% of NALGs without

additive cryptand is not practical enough in radiofluorination reaction, these results reveal that we are heading to right direction in optimizing NALGs design.

2.8 Metal selectivity with HSAB theory

As seen in Table 1, the newly synthesized quinoline sulfonate NALG showed

unexpectedly slow rates and low reactivity towards both bromination substitution and

radiofluorination. This could be due to the steric hindrance by the oligo-ether arm. The

original idea of this NALG was try to combine two different types of chelators into one

leaving group. The combination of a hard chelating unit (oligo-ether) oxygen and soft

chelator (aryl nitrogen) holds the possibility of metal selectivity (Scheme 11). To

examine the potential for metal selectivity, we chose seven metal halides that spread in

both hard and soft categories (Table 5).

R o o Ph o X R X o SO o o SO M M 0 MX or OSO N o N 0 O O N o 2 2

soft metal hard metal

Scheme 37. Synthesis of quinoline-sulfonate NALGs and metal selectivity study

The HSAB concept, Pearson acid base concept,72 is an acronym for hard and soft

(Lewis) acids and bases. Hard applies to species which have high charge state, and are weakly polarizable. Soft is the opposite. 73 We envisioned soft metal halides would

chelate soft nitrogen and stay close enough to facilitate the nucleophile attack the

electrophilic center. With the hard oligo-ether chelator hard metal cation stay further

away from the electrophilic center, which will lead to a slow reaction.

We did not observe any clear trend based on our hard-soft hypothesis. Manganese

bromide and zinc bromide are fully soluble in acetone, but no product was observed even 57 after 72 hours. Perhaps these metal halides are highly solvated and surrounded with solvent shell, there is no existence of “naked” metal halide molecules to approach to

NALGs. Copper (I) bromide is highly sensitive to light, moisture and air, it extremely ready to be oxidize to copper (II), so dissociation from bromine may be unfavorable.

Upon treatment with Lewis base, it stays as a molecular complex adduct. Copper (II) bromide and magnesium bromide are widely used brominating reagents in organic synthesis, however in our study, their poor solubility in acetone may explain the observed lack of reactivity.

Table 5. Reactivity of quinoline-sulfonate based NALG with various metal halides

0 Ph 08 0 N 0 MBr Ph Br O 2 Reaction Time (h)

CuBr NR

CuBr2 24 h 80ft Metal ZnBr2 NR

CsBr NR

LiBr 16 h

MgBr2 30 h Hard Metal MnBr2 NR

MgBr2 etherate 7h

8eBr4 10 min

Interestingly the bromination reaction with selenium tetrabromide was extremely fast. One possible reason is selenium tetrabromide dissociates into tribromide, dibromide and bromine ion in aprotic polar solvent,74 eventually it will stay as monobromide dimer 58 configuration, in this case, and the overall concentration of bromine ion is in large excess compare to other metal halides. The other explanation is because selenium (IV) has outer empty p orbitals that are energetically favored to be sequestered by the electron lone pairs on nitrogen and oxygen. It can better stabilize the negative charge generated in the transition state, which results in a rapid reaction.

2.9 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 was carried out by flash column chromatography using Flash Silica gel (40-63μ).

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 the solvent as internal standard (CDCl3 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). 13C 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 (CDCl3 at

77.0 ppm). High-resolution mass spectra were obtained from the 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: 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

˚C for 16-18h followed by cooling and quenching with aqueous HCl (2 M) and water 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: Aryl ether

derivative (1.0 equiv) was added over 30 min to neat chlorosulfonic acid (5.0 equiv) cooled to 0 ˚C. After complete addition, the reaction mixture was stirred at room temperature for 3-6 h. The reaction mixture was then re-cooled to 0 ˚C 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 ˚C for 2 h and cooled to 0 ˚C 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 (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 60-65oC 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 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: To a cooled (0 ˚C) suspension of sodium hydride (2.0 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 DI 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 50-85%.

General procedure for esterification reactions of 2,4-Difluoro-NALGs: To a cooled

(0 ˚C) 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 DI 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 35-55%.

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

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 deionized 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-sulfonyl

1 chloride. H NMR (400 MHz, CDCl3) 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 (s, 9H); 13C NMR (100

MHz, CDCl3) 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 C22H30NaO5S [M+Na] :

429.1706. Found: 429.1712.

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

1 sulfonyl chloride. H NMR (400 MHz, CDCl3) 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, J =

13 7.37 Hz, 2H), 2.03-1.99 (m, 2H), 1.32 (s, 9H); C NMR (100 MHz, CDCl3) 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 C24H34NaO6S [M+Na] : 473.1968.

Found: 473.1975.

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

1 sulfonyl chloride. H NMR (400 MHz, CDCl3) 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,

13 J = 2.68-2.64 Hz, 2H), 1.99-1.92 (m, 2H), 1.27 (s, 9H); C NMR (100 MHz, CDCl3) 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 C26H38NaO7S

[M+Na]+: 517.2230. Found: 517.2222.

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

1 chloride. H NMR (400 MHz, CDCl3) 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, 3H), 2.73-

13 2.69 (t, J = 7.36 Hz, 2H), 2.05-1.99 (m, 2H); C NMR (100 MHz, CDCl3) 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 C18H21FNaO5S [M+Na] : 391.0986. Found:

391.0978.

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

1 chloride. H NMR (400 MHz, CDCl3) 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 (m, 2H); 13C

NMR (100 MHz, CDCl3) 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

+ C20H25FNaO6S [M+Na] : 435.1248 Found: 435.1236.

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

1 sulfonyl chloride. H NMR (400 MHz, CDCl3) 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 Hz,

13 2H), 2.06-2.00 (m, 2H); C NMR (100 MHz, CDCl3) 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 C22H29FNaO7S [M+Na] : 479.1510. Found:

479.1507.

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

1 sulfonyl chloride. H NMR (400 MHz, CDCl3) δ 7.54-7.50 (dd, J = 8.66, 6.36Hz, 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 (m,

13 2H); C NMR (100 MHz, CDCl3) 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 C20H24NaF2O6S [M+Na]+: 453.1180. Found: 453.1154.

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

1 sulfonyl chloride. H NMR (400 MHz, CDCl3) 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 (m,

13 2H); C NMR (100 MHz, CDCl3) 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 THREE

STEREORETENTIVE REACTIONS OF SECONDARY CYCLIC ALCOHOLS USING

NALGS AND TI(IV) REAGENTS

3.1 Bromination and azidation with titanium (IV) reagents

In the previous chapter our experimental results have demonstrated that NALGs are

excellent leaving groups mainly due to stabilization of the transition state by chelating interaction between metal cation and negative charge on oxygen atoms of the leaving group. One strategy to increase the likelihood of front-side attack (leading to stereoretentive products) is to minimize charge repulsion between nucleophile and leaving group.75 From this aspect we thought Lewis acids usually act as electron-pair

acceptor, and they should accommodate the possibility to stabilize the transition state, at the same time, deliver their nucleophilic ligand to the substrate from the front face

through a possible SNi mechanism. Especially the introduction of Lewis basic Nitrogen

chelator would help us to rationale this hypothesis. Based on this assumption using the

nucleophilic Lewis acidic transition metal titanium (IV) salt, we have developed very

mild and efficient halogenations and azidation reactions with retention of configuration

for mainly cyclic alcohols and some acyclic alcohols.

Stereospecific functional group conversions of non-racemic alcohols are of

increasing importance. If metal-catalyzed allylic substitution76 and neighboring group

participation 77 are excluded, there are exceedingly few reports of nucleophilic

displacement reactions on saturated carbon leading to products with a high degree of

78 retention of configuration. We have recently validated this strategy using TiCl4 to bring

about stereoretentive chlorination of secondary alkyl sulfonates.79

A variety of both new and existing leaving groups are examined. Using diethylene

oxide containing leaving group, substrate 25 exhibited a slightly improved reaction rate.

A related leaving group also containing the diethylene oxide unit gave a similar result

(Table 6, entry 6). l-Menthyl quisylate 24 reacted with TiBr4 to give menthyl bromide

product at over ten times the rate of naphthyl leaving group 23 (Table 6, entries 3 and 4).

The quisylate leaving group in substrate 24 also out-performed leaving groups in 25 and

26 each containing multiple ether oxygens.

Table 6. Leaving group effect on bromination reactions

0 TiBr4 Br Os R OMe 0 00 CH2CI 2 2 -78c C S OMenthyl 21 - 24 27 o 0 25 entry R Comp'd time (h) % yield

1 H3C 21 6 42 2 toluyl 22 1 77 0 2 0Me 3 naphthyl 23 0.83 68 S OMenthyl 4 8-quinolyl 24 0.08 84 F 5 25 0.5 91 o 0 26 6 26 0.42 83

Table 7. Optimization of bromination reactions

Equivalent Test:

0.8 equiv. 1.0 1.5 2.0 OTs TB Br I r4 40% 65% 70% 77% (s. m.left) 10 h 6h 3h 1 h

Solvent Test:

CHzClz CHCI3 CCI4 Toluene THF Diethyl ether

77% 65% 53% 80% <5% <5%

1 h 1 h 1 h 3h 24 h 24 h

Temperature Test:

25°C ooc -20°C -42°C -78°C -100°C

82% 75% 81% 72% 77% 80% (eli. & sub.) (eli. & sub.)

0.5 h 0.5 h 0.75 h 0.75 h 1 h 2h

The optimization of reaction conditions was carried out (Table 7). This new

stereoretentive bromination reaction appears to be fairly general for secondary substrates

80 o (Table 8). The only acyclic alcohol (S)-1-phenyl-2-butanlol reacted with TiBr4 at -78 C

yielded the bromide 35 with complete retention of configuration (Table 8, entry 6).

Notably, the NALG 28h and quisylate esters 29h of α-hydroxypropionate were

o completely unreactive at -78 C towards TiBr4 (Table 8, entry 8). The only acyclic alcohol

used, (S)-1-phenyl-2-butanol reacted with Ti(N3)4 to give the azide product 43 with

complete stereoretention. But surprisingly, this substrate reacts very slowly at 0oC, 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 8, entry 8).

Primary alcohol quisylate 29g reacted very slowly to give an 80% yield after 70h at room temperature (Table 8, entry 7).

In seeking to further extend the scope of this Ti(IV) reaction, we prepared Ti(N3)4

81 following a recently reported procedure in situ by a reaction between TiF4 and TMSN3 and reacted this reagent with quisylate leaving group, the azidation reaction works with a variety of secondary substrates (Table 8). To our knowledge, this is the first reported stereoretentive azidation reaction of alcohol derivatives not involving a double inversion technique.

In addition to stereoretention, reactions using Ti(IV) reagents also afford chemoselectivity in favor of secondary sulfonate substrates, which is opposite of SN2 reactivity. To compare the reactivity of primary versus secondary sulfonates, a series of bistosylates and bisquisylates were reacted with TiCl4 and TiBr4 (Table 9). In general, the

bisquisylates were better yielding and significantly more reactive furnishing halogenated

products. Ti(IV) reactions with 1,2-bistosylate 48 gave the 3-haloproducts (n=2) presumably from a hydride shift (Table 9, entry 1), whereas the 1,2-bisquisylate substrate

49 led to 2-haloproducts in good yields (Table 9, entry 2). No rearrangement was observed in the reaction of 1,3-bistosylate 50 with Ti(IV) chloride and bromide leading to the corresponding 3-halo products (Table 9, entry 3). Reasonable yields were also obtained with diol systems containing an unprotected tertiary alcohol (Table 9, entries 4

and 5).

Table 8. Substrate generality for bromination and azidation

0 0 OR 0 0 S o S OR TiX N 0 4 or 0 ~

quisylate (28) o NALG (29)

% yield of RX (reaction time)8 Product b c X = Br X = N3 X=Br X = N3 Entry ROH NALG (28a-h) Quis.(29a-h) Quis.(29a-h)

OH 91 90 97 30 38 (30 min) (5 min) (8h)

C6H13

H 95 93 85 39 2 H H 31 (15 min) (10 min) (3h) HO

OH 3 79 66 69 32 40 (15 min) (10 min) (5h)

88 82 89 33 41 4 Ph Ph (2.5h) (10min) (7h) OH

98 85 93 34 42 5 OH (15 min) (10 min) (5h)

81 79 63d 35 43 6 Ph (30 min) (30 min) (4h) OH 92e 8ge 80e 36 44 7 Ph OH (14h) (5.5h) (72h) OH 0 421 71 1 <51 37 45 8 (20h) (40h) (24h) 0 D 8 Yield of isolated products. b Reaction conditions: -78 C, CHzClz. C Reaction conditions: ODC, CICHzCHzCI. d Reaction conditions:Roo temperature .e Reaction conditions: Room temperature. I Reaction conditions: Room temperature. Substrates have undergone complete retention of configuration.

Table 9. Chemoselectivity of Ti(IV) reaction with substrates containing two sulfonate leaving groups

X OH X TiX4 substrate LG or 47a,b CH 2CI 2, temp R n 46a,b product yield (rxn time) entry substrate LG temp (DC) X=CI X = Br

1 LG TsO 48 rt 81 (1.5 h)a 20 (15 h)a 2 LG Os049 -78 88 (1 h) 75 (2 h) LG 3 LG TsO 50 rt 76 (1 h) 74 (1 h) 2 OH LG 4 TsO 51 rt 45 (2 h) 54 (2 h) 5 Os052 -78 61 (2 h) 85 (2.5 h) aproduct formed contained halogen at the 3-position (n=2)

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

0 0 0 8+ S R' X TiX R 3 H N 31

Figure 9. Possible transition state for stereoretentive halogenation and azidation reactions

The quisylate nitrogen also appears to increase the rate of the reaction in most

cases (for example, compare entries 1 and 3, Table 8). 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 9).

cal. Cui OH + MgBr 0 THF, -30°C 53

DCM TMSN 3 (3 eq.) TfOTiF TfOTi(N h TMSOTf + TiF4 3 3 r. 1.,15 min r. 1.,15 min 54 55

Scheme 38. Synthesis of chiral alcohol and mixed lewis acid

These data strongly suggested that we demonstrate our reaction using an acyclic

example, so we wanted to expand this application to acyclic system. We synthesized (S)-

1-phenylbutan-2-ol 53 following the procedures by Toru (Scheme 38).82 The quisylate

NALG of this chiral acyclic alcohol was evaluated. Although our azidation reactions

proceed in reasonable reaction times (8 h), we sought to increase the Lewis acidity and

hence the reaction rate through the use of a mixed titanium (IV) reagent containing a non-

transferable ligand with more electron-withdrawing capacity than azide. As seen in

Scheme 38, trimethylsilyl triflate (TMSOTf, 1 equiv) was first added to TiF4, most likely forming TfOTiF3 54. Subsequent addition of TMSN3 (3 equiv) led to a Lewis acid

(presumably TfOTi(N3)3 55) which was significantly more reactive towards quisylate

substrates. For example, the quisylate of menthol was converted into the azide product in

o o 6 h at -78 C (compared to 8 h at 0 C using Ti(N3)4). With the quisylate of 1-phenyl-2- butanol, the mixed Lewis acid gave azide products in less than 1 h at 0oC with complete

stereoretention. Using optical measurements, evidence that halogenations and azidation

of the hindered or non-hindered secondary alcohols were completely stereoretentive

(Table 10).

Table 10. Optical rotation of substrates83, 84

0 OMe Ti~ RO S 0 or 2 !.2J 00 N S OR quisylate NALG o 0

Optical Rotation [a]~5 (conca, solv) X= N X=CI X = Br 3 ROH ref quisylate ref NALG quisylate ref quisylate

-49.3 -49.7 -65.77 -64.4 OH (1.4, EtOH) (1.4, EtOH) (0.4, CHCI3) (1.6, CHCI3)

8 H -22.3 -21.2 -22.5 -5.51 (2.92, CHCI3) (0.3, CHCI3) (2.6, CHCI3) (0.9, CHCI3) HH HO b b Ph -11.2 11.0 -12.1 b 11.1 10.7 -26.5 +23.5 OH (1.1, CHCI3) (0.6, CHCI3) (1.4, CHCI3) (1.8, CHCI3) (1.5, CHCI3) (1.2, CHCI3) (0.6, CHCI3)

a Unit of concentration is g/1 OOmL. bObtained from SN2 reaction of tosylate of (S)-1-phenyl-2-butanol with either PPh3/CBr4 or NaN3 to give (R) product

We believe that the use of triflate as a ligand to activate the Ti(IV) azidation reagent will prove a useful strategy in the development of future titanium(IV) reactions

with NALGs. Non-transferable electron donating properties, such as trifluoroacetate and

isopropoxyl were also tested leading to no product formation. These and other

experiments provide additional evidence for the concept of adjustable Lewis acidity of

the Ti(IV) reagents.

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

stereoretentive halogenations (chlorination and bromination) and azidation. The yields 73

are very good to excellent. For the first time Ti(N3)4 has been utilized to developed

stereoretentive azidation reaction. The reaction activity can be modified by the adjustable

Lewis acidity of Ti(IV) reagents.

3.2 Iodination reaction with Ti(IV) reagents

The synthesis of alkyl iodides has attracted, for a long time, wide interest in organic

synthesis. In order to explore the generality of NALG technology we discovered a highly

efficient method to convert NALGs and quisylates of hindered alcohols to the

corresponding chlorides, bromides and azides using TiCl4, TiBr4 and Ti(N3)4 respectively. Then the iodide moved towards our mind as the heavier element from the halogen group. To the best of our knowledge, stereoretentive preparation of alkyl iodides from hinder alcohols has not been reported in the literature yet. We demonstrated the synthesis of a variety of alkyl iodides from primary and secondary allylic alcohols.

Menthyl quisylate was converted into the corresponding iodo product in 86% yield with

o complete retention of configuration using TiI4 at 0 C in Dichloromethane. The quisylate

of 1,3-diphenyl-2-propanol was converted into the corresponding iodide in 90% yield.

Optimization results (Table 11), and the optimized reaction condition was mixing TiF4 and TMSI in dichloromethane for 15min at 0oC, then quenching the reaction with sodium sulfite and diluted acid solution to minimize the formation of iodine.

Table 11. Optimization of reaction conditions

Os 00 N 35

Reaction Conditions time Yield (%)

Temperature DoC 2.5 h

-78°C 10 h

Iodine Sources Til4 84% (6 eq.)

TiF4 + TMSI 86% (6eq. +24 eq.)

Work-up Conditions wI Na2S03/HCI 83%

without 86%

Stirring Time of Reagents 15 min 45 min 86%

30 min 2.7 h 76%

1 h 4h 83%

Solvent Dichloromethane 2.5 h 86%

1,2-dichloroethane 2h 79%

Titanium-halogen bond in Ti (IV) reagents hold two characteristics, electron negativity and nucleophilicity that have an important influence on the chemical behavior.

We know for a given group of the periodic table, nucleophilicity increases from top to bottom. On one hand the iodide anion (I-) has strongest nucleophilicity in halogen group, but on the other hand since iodide anion has the least electron negativity that makes

Lewis acidity of the metal center in the titanium (IV) reagent decrease most. We believe that the Lewis acidity of metal center predominates in this type of reaction. We are attempting to improve iodination of secondary substrates following our strategy for azidation using mixed-titanium reagents. The results of mixed-Ti(IV) reagents study were

75 shown in Table 8. With the increase equivalents of the triflate the reaction enhanced accordingly, which proved our hypnosis. One problem needs to be addressed is that when the equivalents of the three substrates (TiF4: TMSOTf: TMSI) went up to 4:8:8 ratio elimination became inevitable.

Table 12. Substrates generality for iodination reaction

DCM TMSI + TiF Til 4 15 min 4

RO Til4 S DCM,OoC ~ 00 N quisylate

entry ROH % yield of RI (rxn time)

86 OH 56 (4 h) Alk

H 82 57 2 (5 h) HH HO 90 Ph Ph 3 (5 h) 58 OH

OH 75 (4 h) 4 59

OH 84 5 (4 h) 60

85 6 (4 h) 61 OH

Table 13. Mixed-Titanium (IV) reagents study

Equivalents of substrates Reaction Condition Results o TiF4 TMSOTf TMSI Temperature( C) Time 2.01 0.00 8.00 0 5.5 h

2.04 2.06 6.07 0 3h

Starting 2.06 4.06 2.00 -78 1.25 h Material 2.07 4.04 3.98 0 1.5 h

N 2.04 6.08 2.06 0 1h O S O O 3.05 3.08 3.12 0 1h menthyl- quisylate 3.01 3.03 5.99 0 30 min

3.01 3.04 9.05 0 5min

3.03 6.02 6.07 -78 1.5 h

3.02 0.00 12.09 0 8h

4.08 8.03 8.07 10 min 0

3.3 Stereoretentive chlorination with chlorosulfite

After developing two step stereoretentive halogenation reactions using Ti(IV) reagents, we were able to successfully develop one-pot stereoretentive halogenation reactions. The concept behind this development was the formation of the leaving group in situ which eventually can be considered as NALG. In this section we report a very mild, efficient one-pot stereoretentive chlorination reaction of cyclic secondary alcohols using thionyl chloride catalyzed by TiCl4 where the in situ generated leaving group is chlorosulfite.

CI OH CI i) SOCI2• OCM 0 0 8+ S R' CI Ti CI R' R ii) TiCI4 (cat) R' R R O°C H CI CI retention o CI OS CI R' R R' R o

oS CI o 0 CI CI 3Ti S R' R CI R' R

Scheme 39. Catalytic cycle for stereoretentive chlorination

Thionyl chloride is widely used in organic synthesis especially for the conversion

of carboxylic and sulfonic acids to acyl chlorides85 and sulfonyl chlorides86 respectively.

It is preferred over other reagents since the byproducts of this chlorination reaction, HCl

and SO2, are gaseous, which simplifies the purification step. Excess thionyl chloride also

can be readily removed by distillation or evaporation. Traditionally, thionyl chloride is

used to convert alcohols to the corresponding alkyl chlorides under reflux condition, and

elimination is an inevitable side reaction.87 However, this reaction often requires less

than mild conditions thus limiting its application in the synthesis of delicate molecules.

Traditional alcohol chlorination reactions with thionyl chloride are thought to involve

either inversion or retention configuration depending on the involvement of the reaction

solvent. 88 In these systems, retention of configuration is achieved mechanistically

through a double inversion in the presence of nucleophilic solvents. For secondary chiral

alcohols, whether this reaction proceeds via an internal nucleophilic substitution (SNi) with stereoretention through ionic or concerted mechanism is still under debate.89 Our new chlorination method also raises mechanistic questions and may provide a rare modern example of a SNi mechanism. 78

Lewis and Boozer performed a thorough study on the chlorination with thionyl

chloride. 90 They found that the stereo-configuration of the resulting chloride was dependent on both reaction temperature and solvent and proposed a set of ionic

mechanism according to different reaction conditions. When the reaction is carried out in

toluene or heat without solvent, the first stage, ionization of the chlorine-sulfur bond, may

occur, and consequently weaken the carbon-oxygen bond. However the loss of sulfur

dioxide, which is the autocatalyst in the decomposition of chlorosulfite, has to be

facilitated by the attack of chlorine ion from the back side of the carbocation by an SN2 mechanism.

If a nucleophilic solvent, such as dioxane, is present, continuous double SN2 reactions will generate an absolute retention of configuration. Other non-nucleophilic solvents will provide a good solvating environment for the ionization of the chlorosulfite and the dissociation of ion-pairs is no longer prohibitively difficult. Depending on the polarity or the dielectric constant of different solvents, the cleavage of either chlorine- sulfur bond or carbon-oxygen bond will vary, and allow the front side, backside attack, or racemic SN1 mechanisms to bring about the chlorination of alcohols. Pyridine was an exception as a nucleophilic solvent. The inversion of configuration is obtained from either the pyridinium chloride salt attacking from the backside of the chlorosulfite or the exchange between the pyridine and chloride of the chlorosulfite followed by the chlorine attacking from the backside.91

Heat without any solvent or in Toluene:

OH R Os CI SOCI2 1 o SCI R 0 2 R2 0 CI R2 Inversion

Dioxane (Nucleophilic solvent) as solvent:

Retention o o CI

Pyridine as solvent:

0 R CI N R H S 1 0 1 H H 0 N R1 R2 OS CI R2 SN2 Inversion R 2 at sulfur CI

Scheme 40. Literature proposed chlorination mechanism with SOCl2

On the basis of the NALGs concept, a very mild one-pot stereoretentive

chlorination reaction of cyclic alcohols using thionyl chloride and TiCl4 will be reported

here. The reaction was found to be catalytic depending on the alcohols. As TiCl4 is inexpensive and environmental friendly, we limited our catalytic amount to 10% to get the reaction at an optimal rate with the concentration of alcohol at 1.0M. We note that, using classical conditions, the reaction of l-menthol with thionyl chloride under reflux for

18h in dichloromethane led to the expected mixture of inversion and retention products in a ratio of 1:3.9 with an overall yield 82%. By contrast, the present methodology affords menthyl chloride product with complete retention of configuration in 93% yield.

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

However, Braddock and Burton tried to prove in their recent publication that the reaction

is diastereoslective control via a carbocation and in the case of steroid substrates; the

reaction is assisted by the double bond as neighboring group participation.92 To prove that our chlorination technique indeed proceeds through a pure mechanism and not an assisted mechanism we choose a few substrates (Scheme 41).

Studies of the chlorination reaction for these cyclohexanols revealed that cold

o temperature (-78 C), a concentration of alcohols at 0.1 M, and 2 equivalents of TiCl4 gave the best results. For both alcohols 62 and 63, retention of configuration was predominant which eliminates the possibility of a classical ionization reaction.

Specifically, this result is not consistent with the mechanism involving the neighboring group participation or diastereoselective attack on a carbocation, in which both trans- and cis- alcohols should lead to the same distribution of products.

H OH , SOCI2, TiCI4 SOCI2 TiCI4 Me OH X Me X Me H via classic SN1 via classic SN1 66 cis- 62 trans- 64 distortion

Me 67 1) SOCI2 CI 1) SOCI2 2) TiCI4 2) TiCI4 H CI + H H Me CI Me CI

Me CI trans- cis- Me H 63 65 63 cis- 65 trans- major product major product

Scheme 41. Chlorination of trans- and cis-4-methylcyclohexanol

Our studies of 4-methylcyclohexanol (Table 14) revealed that some inversion of configuration and hydride shift products attain. While both concerted and non-classical

81 carbocation mechanism hypotheses, which will be elucidated later, provide an explanation for stereoretentive direct substitution, they do not account for the minor amounts of inversion products observed. This perhaps is because the SNi backside

93 attack or bimolecular complex attack through SN2 mechanism. Even though accelerating the nucleophile capture by increasing the concentration of Titanium (IV) chloride could diminish the potential interconversion of the two isomers in non-classical carbocation mechanism; trace of this interconversion still can give the substitution product with inversion of configuration. These chlorination reactions also underwent

Wagner-Meerwein rearrangement 94 to afford hydride shift products. The ratio of the distribution of products was determined from NMR.

Table 14. Results with trans-4-methylcyclohexanol and cis-4-methylcyclohexanol

H H CI i) SOCI2, DCM CI H OH CI H ii)TiCl4 H CI retention inversion H-shift 1 H-shift 2

a ROH Con.(M) Tem(°C) T(h) TiCI4 (eq.) Ret:inv:H-shift 1:H-shift 2 Yield(%)b,C

0.5 0 0.5 0.1 3.8:1.0: 0.7: 0.7

1.0 0 0.5 0.1 3.8: 1.0: 0.7: 0.7

1.0 -78 2.0 2.0 3.8: 1.0 :0.7: 0.7 OH 72-83 0.05 0 1.0 1.0 5.5: 1.0: 0.4: 0.8

0.1 0 0.5 0.2 5.5: 1.0: 0.4: 0.8

0.1 -78 10.0 2.0 7.5: 1.0: 0.0: 0.5

0.5 0 0.5 0.1 4.2: 1.0: 0.7: 6.5

1.0 0 0.5 0.1 4.2: 1.0: 0.7: 6.5 OH 0.05 0 2.0 1.0 6.8: 1.0: 1.1: 5.6 60-62 0.1 0 1.0 0.2 6.8: 1.0: 1.1: 5.6

0.1 -78 20 2.0 62.0: 1.0: 1.5: 63.9

1.0 -78 8.0 2.0 58.4: 1.0: 2.6: 61.2 aH-shifte1 is cis-1-Chloro-3-methylcyclohexane, H-shift 2 is trans-1-chloro-3-methylcyclohexane b Isolated yield c 100% conversion to chloride was observed in CDCI 3 without any other products (elimination) formation

The results for chlorination reactions for trans- and cis-4-methylcyclohexanol have been presented. For both alcohols, the chlorosulfites generated all four products. Also, the concentration of alcohols becomes important for the stereochemical outcome, and 0.1M was found to be the optimal concentration. At both concentrations, 1.0M and 0.5M, similar product distributions were observed (Table 14, entries 1-3). The ratio of retention product to inversion product was ~4:1 along with formation of hydride shifted products in the same ratio (1:1). At 1.0M concentration, lowering temperature also did not show any products ratio improvement (Table 14, entry 3). At 0oC, the same product

distributions resulted (Table 14, entry 4 and 5) when the concentration were maintained 83

0.1M and 0.05M. But now improved ratios for retention vs inversion resulted (~5.5:1)

compare to reactions at higher concentrations. Further lowering of temperature to -78oC

improved the ratio (~7.5:1.0) (Table 14, entry 6). Interestingly in this case the hydride

shifted product was not observed by 1HNMR. A similar trend was also observed for cis-

4-methylcyclohexyl chlorosulfite and an optimum result was obtained at -78oC with a very good selectivity for retention (~62:1) (Table 14, entry 11). But now hydride shift becomes very prominent with direct substitution vs. hydride shift nearly 1:1 with highly preference for hydride shift product.

Regarding our chlorination reactions we were also interested to know whether chloride is being delivered directly from chlorosulfite or from TiCl4. To check it we did two cross experiments by treating chlorosulfite 68 with TiBr4 in a catalytic amount as

well as a stoichiometric amount (Scheme 42). When l-menthyl chlorosulfite 68 was

treated with catalytic TiBr4 (10 mol%) both the chloride 69 and bromide 70 were

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

the chlorosulfite 68 was treated with 2.0 equivalents of TiBr4, the bromide product 70

was obtained as major the 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 TiBr4 is used, it is probable that initially bromide from TiBr4 attacks the chlorosulfite, generating

the bromide product 70 with the concomitant generation of mixed titanium (IV) reagents

(TiBr4-xClx). 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%) OOC,OCM CI Br + OSOCI 4h

69 70 TiBr4 (2.0 equiv) 72% 20% (catalytic TiBr4) 68 OOC,OCM 5% 82% (2.0 equiv TiBr4) 15 min

Scheme 42. Cross experiment with chlorosulfite and TiBr4

With the support of literature and the computation study from our collaborator we

can conclude the most plausible mechanism for this stereosepecific chlorination reaction.

Schleyer reinvestigated this hypothesis suggesting a different mechanism based on the

HOMO/LUMO frontier orbital theory. He assumed the nucleophilic chlorine atom to be derived from the chlorosulfite moiety via a 1,3-sigmatropic shift. 95 In analyzing the

possible shift geometries, we note that a suprafacial 1,3-invertive shift is both

geometrically and symmetry allowed. Thus a purely 1,3-sigmatropic shift mechanism

should lead to chlorination products with inversion of configuration without the

intervention of nucleophilic solvents. Since this is often not the case, many have

concluded that the classical thionyl chloride reaction of alcohols proceeds by an ionic

mechanism.

In our study, we have observed a pattern retention of configuration with cyclic

alcohols prompting us to examine the 1,3-sigmatropic shift hypothesis of Schleyer in the

context of our reactive system. With the introduction of the titanium Lewis acid, we

envision a rapid chelation with the electron rich oxygen of the chlorosulfite intermediate.

This chelation opens up the possibility of a 1,5-sigmatropic shift. Using an analysis

similar to that of the 1,3-shift, a suprafacial 1,5-retentive shift is both geometrical and

symmetrical allowed. Our envisioned transition state for this 1,5-shift involves a stable

six-member ring geometry (Figure 10). Based on our experimental and conceptual

observations, initially, we suggest that our titanium (IV) catalyzed chlorination reaction is

successful with cyclic alcohols since carbocation formation is more prohibitive in these

systems thus favoring a concerted intramolecular 1,5-shift pathway, in which two addition bonds were introduced by the chelation of titanium and oxygen in chlorosulfite.

However, the computational results did not affirm our hypothesis (Figure 11). The orientation of the orbital in optimized transition state did not supply the necessary overlap as in SNi mechanism. This suggests us the possible existence of an alternative or

competing mechanism.

R R' H C CI 0 0 H CI CI s+ Q R 0 0 R' TI CI Q+ Q 0 Ti - S CI CI CI CI CI Q 0 CI 0

Figure 10. Proposed orbital explanation of chlorination mechanism [1,5] suprafacial retentive shift

(symmetry and geometry allowed).

Figure 11. Orbital overlap configuration from computational study

As in our study all the chiral cyclic alcohols are six-membered, it will be very

important to discuss the properties and nature of substituted cyclohexyl carbocations,

which can help in understanding the mechanism of chlorination. We contend that our

chlorination reaction does not proceed through a classical SN1 mechanism. As discussed below, our study of trans- and cis-4-methylcyclohexanol clearly dem onstrate that these two starting materials lead to different product distributions that would not be expected if a classical ionization mechanism were operative. However, more recent studies of carbocation mediated reactions suggest an alternative or perhaps competing mechanism to our 1,5-shift hypothesis.

The work of Sorensen on cyclohexyl carbocations suggests that cyclohexyl carbocations remain in a chair conformer even after ionization.96 In the present work, we note that whether the carbocation keeps the sp3 configuration or distorts to sp2 configuration could be the key factor of the stereoselectivity. Thus a carbocation might be generated under relatively mild conditions with the assistance of titanium tetrachloride.

In this scenario, since the intermediate cation does not transfer to the planar conformer,

we believe that the cation continues to maintain the sp3 hybridization, that is, the empty

orbital is ready to capture the coming nucleophile.

H H CI H OH i) SOCI2 , DCM Nu R' R R' R R' R ii) TiCI4 (cat) DOC Stays in sp3 retention hybridization X Distortion

H H CI

R' R R' R

no stereoselectivity

Scheme 43. Possible non-classical “frozen” carbocation mechanism o

71 72 (C-H hyperconjomer) (C-C hyperconjomer)

Scheme 44. C-H and C-C hyperconjomers of methyl substituted tertiary carbocations

In a follow-up study by the Sorensen group, it was proposed that two isomers

with chair conformations, one isomer, with a C-C bond distorted to maximize Cβ-γ

97 hyperconjugation, the other, with a C-H bond to maximize Cβ-Haxial hyperconjugation.

These two "hyperconjomers" can interconvert rapidly and in equilibrium, hence, the key feature of the stereoselectivity would be the competition between the rate of the hyperconjomer interconversion and the rate of nucleophile capture. We hypothesize that our titanium-promoted reactions involve a nucleophilic chlorine from titanium filling an empty sp3 orbital on the carbocation center. Perhaps this is a lower energy pathway than

the chlorine from the simple decomposition of chlorosulfite. By increasing the 88

concentration of the titanium (IV) chloride, perhaps the rate of cation capture of the

nucleophile is increased at the expense of hyperconjomer interconversion (leading to an

erosion of stereospecificity).

H CI H CI H i)SOClz S+ [1,5] CI OH Ti- ii) TiCI o shift 4 CI 0 CI CI retention

CI H H H 0+ S + Nu 0 0 CI o· Ti CI retention CI CI CI

Scheme 45. Comparison between concerted mechanism and non-classical carbocation mechanism in the chlorination of trans-4-methylcyclohexanol on direct substitution and H-shift substitution

Scheme 45 demonstrated the mechanisms of both possible concerted and non-

classic carbocation mechanisms with trans-4-methylcyclohexanol. We think the non-

classical carbocation mechanism dominates in the formation of hydride products.

Approximately 1:1 ratio of trans- and cis- hydride products were observed. This perhaps is because ring-flip and the interconversion between the two hyperconjomers took similar amount of time, then the stereoselectivity was not noticed. Cis-4-methylcyclohexanol was ready to proceed to hydride shift product, which explicated the overall substituted product and the overall hydride-shift product constituted equally.

Dr. 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. These two structures have distorted pyramidal chair conformations but differ

in having “axially” 71 and “equatorially” 72 oriented carbocation p-orbital (Scheme 7). 89

They have designated structure 71 and 72 as the C-H hyperconjomer and the C-C hyperconjomer respectively.

Now we propose our mechanism on the basis of works done by Sorensen et al. on

substituted tertiary cyclohexyl carbocations. As shown is scheme 13, substituted tertiary

cyclohexyl carbocations exist as two “nonclassical” isomeric structures: 71 (C-H

hyperconjomer) and 72 (C-C hyperconjomer) where both structures are in chair conformations. Though our system is substituted secondary alcohols, theoretically all the

“nonclassical” property should be equally applicable or even may be strongly applicable because of the unstability of secondary carbocations. That means the reaction of a secondary system may be even more specific. On the basis of these assumptions we want to propose a mechanism which can be termed as “nonclassical SN1i”. They have shown

that if the carbocation is stable, then reaction will go through a classical carbocation which is captured by chloride from the leaving group from both side of carbocation.98

As soon as TiCl4 chelates, the “nonclassical” carbocation 73 is formed which is

actually C-C hyperconjomer. Because it is secondary, 73 probably exists for a very short

interval of time, and the leaving group TiCl4-sulfochloridite does not get separation from

the carbon center. 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 Ti(IV) should be more nucleophilic than chlorine on the sulfur atom. Now the inversion product will be resulted

if the equilibrium between the C -C hyperconjomer 73 and the C-H hyperconjomer 74 is

faster than nucleophilic capture of carbocation by chloride. Also the rate of equilibrium

should be dependent on the stability of hyperconjomer and temperature also. For

example, if 73 is more stable, being generated directly from the substrate, the equilibrium

rate between 73 and 74 should be slow and the retention vs inversion ratio should be

high. But if 73 is less stable, then the equilibrium will try to shift towards 74 at a higher

rate. Faster equilibrium can result in a relatively low retention vs 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 better the retention to inversion ratio.

H ~ o H H H 73 74

Scheme 46. Equilibrium between the C-C hyperconjomer and the C-H hyperconjomer

In conclusion, we have discovered an exciting variation of the well-known and

widely used alcohol chlorination reaction using thionyl chloride. Critical to the design of

this new reaction is the first ever use of chlorosulfites as in situ formed chelating leaving

groups. Though its stereospecificity is limited to cyclic alcohols, this reaction raises

interesting mechanistic questions and provides perhaps a rare modern example of the

nonclassical carboncation mechanism independent of diastereocontrol or anchimeric

assistance. To our knowledge, our reaction systems are very unique to generate

stereoretention product and could be the direct proof for the first time Sorensen’s theory.

3.4 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 40-63μ 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 (CDCl3 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). 13C NMR were recorded on Varian Mercury400

(100 MHz) spectrometer. Chemical shifts are reported in ppm trimethylsilane, with solvent resonance employed as the internal standard (CDCl3 at 77.0 ppm). High- resolution mass spectra were obtained from the 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: Stabilized/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 (method A): To a suspension of NaH (1.5 equiv) in DCM alcohol (1.0 equiv) was added and stirred at

92 room temperature for 30-60 min. Then NALG sulfonylchloride or qusylchloride (1.2 equiv) was added followed DMAP slowly. It was stirred at room temperature for 18-20h.

Then reaction mixture was cooled in ice and quenched with ice-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 bromination reactions: A cold (-78˚C) solution of quisylate ester (1.0 eq) in dichloromethane (1.5 M) was added to a cold (-78˚C) solution of TiBr4

(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 TiF4 (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 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).

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 TiCl4 was added

(catalalytic to stoichiometric amount) and stirred for required time (15 min). 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 thionyl chloride 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. Then reaction mixture was diluted to required concentration (0.5-0.01M) by adding required amount dichloromethane using syringe and

o cooled to required temperature (-78-0 C). After that TiCl4 was added (catalalytic 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 60oC 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 sulfate. Then it was passed through silica gel column and concentrated in vacuum to get pure product.

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

(400MHz, CDCl3) 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 1,3-diphenylpropan-2-yl quinoline-8-sulfonate. H NMR (400MHz, CDCl3) 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-adamantyl quinoline-8-sulfonate. H NMR (400MHz, CDCl3) 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).

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

CDCl3) 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 Hz,

13 3H), 0.75 (d, J = 6.93 Hz, 3H); C NMR (100MHz, CDCl3) 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 C10H18Br [M-H] : 217.0586. Found:

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

1 3-β–bromo-5-cholestene. H NMR (400 MHz, CDCl3) 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, 1.84

13 Hz, 6H), 0.66 (s, 3H); C NMR (100MHz, CDCl3) 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 C27H46Br [M] : 449.2777. Found:

25 449.2779. α ][ D –21.2 (c 0.3, CHCl3) (NALG); –22.5 (c 2.6, CHCl3) (quisylate).

1 (2-bromopropane-1,3-diyl)dibenzene. H NMR (400MHz, CDCl3) 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 = 14.36, 5.77

13 Hz, 2H), 3.13 (dd, J = 14.36, 8.22 Hz, 2H); C NMR (100MHz, CDCl3) δ 138.7, 129.4,

+ 128.7, 127.1, 57.3, 45.2; HRMS (CI+) calc. for C15H15Br [M] : 274.0352. Found:

274.0374.

1 (1R, 2R)-1-bromo-2-methycyclohexane (racemic). H NMR (400 MHz, CDCl3) 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

13 (m, 4H), 1.37-1.28 (m, 2H), 1.12 (d, J = 6.47 Hz, 3H); C NMR (100MHz, CDCl3) δ

+ 62.3, 41.6, 38.9, 35.4, 27.7, 25.7, 22.1; HRMS (CI+) calc. for C7H12Br [M-H] : 175.0117.

Found: 175.0122.

2-adamantylbromide. 1H NMR (400 MHz, CDCl3) 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), 1.64

13 (m, 1H), 1.61 (m, 1H); C NMR (100MHz, CDCl3) δ 64.2, 38.9, 38.0, 36.6, 31.8, 27.7,

+ 27.1; HRMS (CI+) calc. for C10H14Br [M-H] : 213.0273. Found: 213.0279.

1 3-β–Azido-5-cholestene. H NMR (400 MHz, CDCl3) 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 = 6.62-1.87

13 Hz, 6H), 0.67 (s, 3H); C NMR (100MHz, CDCl3) 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 C27H46N [M+H-N2] : 384.3625. Found:

25 384.3633. α ][ D –5.5 (c 0.9, CHCl3).

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

CDCl3) 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), 0.91

13 (d, J = 7.05 Hz, 3H), 0.79 (d, J = 6.93 Hz, 3H); C NMR (100MHz, CDCl3) 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 C10H20N3 [M+H] :

25 182.1665. Found: 182.1657. α ][ D –64.4 (c 1.6, CHCl3).

1 (2-azidopropane-1, 3-diyl)dibenzene. H NMR (400 MHz, CDCl3) 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 13.89, 5.47 Hz, 2H), 2.85-2.80 (dd, J = 13.89, 8.19 Hz, 2H); C NMR (100MHz, CDCl3)

+ δ 137.9, 129.5, 128.8, 127.0, 65.6, 40.9. HRMS (CI+) calc. for C15H16N3 [M+H] :

238.1300. Found: 238.1376.

(1R, 2R)-1-azido-2-methycyclohexane (racemic). 1H NMR (400 MHz, CDCl3) 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); 13C NMR

(100MHz, CDCl3) δ 67.3, 36.8, 34.2, 31.8, 25.3, 22.5, 19.7. HRMS (CI+) calc. for

+ C7H14N3 [M+H] : 140.1200. Found: 140.1188.

1 2-adamantylazide. H NMR (400 MHz, CDCl3) 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); 13C NMR

(100MHz, CDCl3) δ 66.7, 37.5, 36.9, 31.9, 31.8, 27.4, 27.2; HRMS (CI+) calc. for

+ C10H16N3 [M+H] : 178.1300. Found: 178.1344.

1 (1R, 2R)–1-chloro-2-methylcyclohexane(racemic). H NMR (400MHz, CDCl3) 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-

13 1.54 (m, 4H),1 .31-1.24 (m, 2H), 1.07(d, J = 6.47 Hz, 3H); C NMR (100MHz, CDCl3) δ

67.7, 41.1, 37.5, 34.8, 26.5, 25.4, 20.2.

1 (1S, 3R)–1-chloro-3-methylcyclohexane (racemic). H NMR (400MHz, CDCl3) 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), 0.90-0.80 (m,

13 1H); C NMR (100MHz, CDCl3) δ 59.7, 45.9, 36.9, 33.5, 33.1, 25.9, 22.2.

1 (1R, 3R)–1-chloro-3-me thylcyclohexane(racemic). H NMR (400MHz, CDCl3) 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

13 (m, 1H),0.99-0.93 (m, 1H), 0.89 (d, J = 6.53 Hz, 3H); C NMR (100MHz, CDCl3) δ 60.1,

42.3, 34.1, 33.9, 26.4, 21.7, 20.2.

1 trans-1-chloro-4-methylcyclohexane (racemic). H NMR (400MHz, CDCl3) 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); 13C NMR

(100MHz, CDCl3) δ 60.1, 37.1, 34.8, 31.2, 21.8.

1 cis-1-chloro-4-methylcyclohexane (racemic). H NMR (400MHz, CDCl3) 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

13 Hz, 3H); C NMR (100MHz, CDCl3) δ 59.8 33.6, 28.9, 22.3, 14.0.

(1S, 2R, 4R)-2-chloro-1-isopropyl-4-methylcyclohexane. 1H NMR (400MHz,

CDCl3) 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); 13C NMR (100MHz,

25 CDCl3) δ 63.9, 50.3, 46.7, 34.2, 33.3, 27.1, 24.2, 21.9, 21.0, 15.1. α ][ D –41.2 (c 9.05

EtOH).

CHAPTER FOUR

NEW APPLICATIONS WITH GRIGNARD REAGENTS

4.1 Introduction of Grignard reagents

Grignard reagents usually provide carbon nuchleophiles, which attack electrophilic

carbon atoms that are within a polar bond to yield a new carbon-carbon bond, thus,

altering the hybridization of the reaction center. Usually the addition of a Grignard reagent proceeds through either a six-member ring transition state or transfer of a single electron.99 The reactions involving Grignard reagents are summarized in the following

figures. The Grignard reaction is an important tool in the formation of carbon-

phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatom

bonds. The Grignard reagents can also be involved in coupling reactions.100

100

OH H OH R H H 0 R R'

H H R OH 0 0 OH R" R' R" R' R" R' H R R' CUi 0 0 OH R' R" OH R R' R" R' + R"OH "--- RMg;,.) R' R" 0 R R 0 C 0 R' OR" 0 0 0 o 0 MeO N R' R' R OH NR'z H Y R' R Me Y = halogen, OC(=O)R', SR' 0 0 R R' R H

Figure 12. Grignard reagents react with a variety of carbonyl derivatives

R R Y = halogen R S R' Y R R' + R' Y R'' SH CuI R' S S R'' Y R' = alkyl OH R SH RMgX R S8 O

R' CN NR''' OO O H O R' R'' R O

R R' NR''' R'' R OH R R'

Figure 13. Grignard reagents react with other electrophiles

4.2 Cuperate reagents facilitated carbon-carbon bond formation

In organic chemistry though palladium catalyzed carbon-carbon bond formation reactions are very vastly utilized, the methods are generally limited to sp2-sp2, sp2-sp3 carbon-carbon bond formation. sp3-sp3 carbon bond formation very rare because of the

101 possibility of β-hydride elimination. Development of organocopper chemistry partially solved this problem where sp3-sp3 carbon-carbon bond is formed by nucleophilic substitution reaction of primary halides, tosylates and triflates using lower order, Gilman

101 cuprates (R2CuLi) and higher order cyano cuprates [R2Cu(CN)Li2]. Usually the reaction limited to only primary substrates, furthermore when organocopper reagents react with secondary substrates the stereochemistry is not specified. Though iodides and triflates are most reactive they are not common substrates due to lower stability. Because of less reactivity, halides and tosylates react only with more reactive Gilman cuprates and higher order cyano cuprates where excess organolithium and toxic copper (I) cyanide is required. The reaction also is chemoselective for 1,4-addition of a α,β-unsaturated carbonyl compound in the presence of halides and sulfonates.102 Besides, homocoupling reactions by radical coupling may occur when organocopper reagents are exposed to oxidizing agents (including atmospheric oxygen and copper (II) ions) or when organocopper (I) reagents are heated or even kept at room temperature. An alternative strategy is to active a mono-organo cooperate using a chelating leaving group by chelating copper (I) with nitrogen. By this means, the organocopper (I) may react at cooler temperatures and milder conditions to minimize the self-coupling reaction.

weakening of bond R' I R Cu- S020R o 2 0 0 N 0 R'MgBr 0 0 MgBr+O S /;- Cui N 0 ~ THF

Scheme 47. Secondary sp3 bond formation using cuprate chemistry

102

As Cu(I) is categorized as a soft metal center,103 compared to oxygen, nitrogen is

the better chelating ligand for Cu(I) as nitrogen is softer than oxygen because of lower

electronegativity (HSAB principle). As shown in Scheme 47 we believe that NALGs

where nitrogen is the chelating unit, would probably open a new door for sp3-sp3 carbon- carbon bond formation by nucleophilic substitution reaction using RCu(I) as alkylating reagents thus avoiding use of excess organolithium and toxic copper(I) cyanide. Because of complexation, reaction not only will be entropically favorable but it will activate

RCu(I) also. Chelation of aromatic nitrogen lone pair to copper will increase the nucleophilicity by weakening R-Cu bond. Furthermore, there will be a certain possibility of chemoselectivity for NALG sulfonates over halides and tosylates as well as 1,4- addition because of complexation of RCu(I) with NALG which will help to localize the nucleophile near the electrophilic carbon of NALG sulfonate.

4.3 Hypothesis of Grignard and titanium reagents facilitated carbon-carbon bond formation

An essential part of most organic syntheses is the construction of the carbon skeleton of the desired end product. There are three ways in which such a bond may be formed: first, each carbon atom contributed one electron to the shared pair, which is the

interactions of two carbon radicals; second, one of the carbons provides both electrons for

the shared pair, in which a nucleophile reacts with an electrophile; and third, reduction

and oxidation are involved in the coupling reaction to form the carbon-carbon bond. In

the second mechanism, nucleophilic carbon species include Grignard and related

organometallic reagents, stabilized carbanions, alkenes, arenes and heteroarenes. 104

103

However, the formation of an sp3-sp3 C-C bond has been one of the most significant but

challenging subjects in organic synthesis. The direct and selective formation of these

bonds has been the subject of intense investigation.105

Secondary sp3 carbon bond formation can be traced back to the development of

Grignard reaction; 106 however, there are several drawbacks of this reaction. First,

Grignard reagents readily react with protic solvents or functional groups with acidic

protons. Secondly, Grignard reagents are sometimes difficult to prepare. Lastly, the

Grignard reaction mainly works with aldehydes, ketones, and esters and must therefore create a stereocenter upon bond formation. To our knowledge, there is no nucleophilic

carbon-carbon bond forming leading to stereoretention without any chiral auxilliary.

Grignard reagents addition can be stereocontrolling when reacts with a prochiral ketone

or aldehydes following Cram’s rule.107

Our study has been focused on the synthesis of improved sulfonate based leaving

groups and new applications with these leaving groups in organic chemistry. In previous

chapter we discussed stereoretentive halogenation ana azidation with Ti (IV) reagents.

Apply the same theory on the stabilization of transition state with chelation property, and

we hypothesized two possible carbon-carbon bond formation methods with retention of

configuration incorporating Grignard and Ti (IV) reagents.

First, titanium(IV) reagents will be prepared using a literature approach, alkyl

Grignard reagents (alkyl magnesium halides) react with TiCl4 to generate corresponding

108 TiR4. The challenging task is the stereoretentive carbon-carbon bond formation because there is no literature of stereoretentive substitution with carbon nucleophiles at

secondary electrophilic carbon. The equivalents of the substrates can be adjusted to

104

obtain the right Lewis acidity of the Titanium center. Then, quisylate of alcohols will

react with the in situ prepared titanium-nucleophile reagents to yield the expected

stereoretentive products (Scheme 48).

0 00 8 TiF _ R'n 1 0 R'MgBr + TiGI 4 n 8 Ti(IV) reagent R 4 0 0 N R' R' R n=1,2,3,4 OOG, DGM 2 J R2 1 N R R2 R' Ti F F quisylate F 8 8 R'= Scheme 48. Secondary sp3 bond formation using nucleophilic substitution

Secondly, Diethyl ether is an especially good solvent for Grignard reagents.

Coordination to an Et2O solvent molecule lengthens both the Mg–C and Mg–X bonds. A

second solvent molecule reinforces this effect. Carbon-magnesium bond in a Grignard

reagent is polar covalent with carbo n being the negative end of the dipole. So we predicted our ester NALGs perhaps can serve the similar function as diethyl ether to

stabilize the Grignard reagents and weaken the Mg-C bond, which provide the possibility

of the nucleophile in Grignard reagents to be delivered. In another word, the Grignard

reagents are “solvated” and activated by the Lewis basic character of oligo-ether arm.

This “Lewis base activated Lewis acid” theory has been pioneered by Denmark.109

Our approach is based on the principle that association of a Lewis base to an alkylmagnesium halide may cause distribution of electron density, affording a Lewis base•RMgX complex that exhibits enhanced nucleophilicity and perhaps a different mode of reactivity. The possibility of elevated nucleophilicity is supported by an increase

110 in C-Mg bond lengths of the derived Et2O complexes (vs. alkylmetal), which is also

111 observed in the X-ray structure of an NHC•MgEt2. Hoveyda group has developed a

105

catalytic enantioselective additions to γ-chloro-α,β-unsaturated esters using Lewis base

activation of Grignard reagents with a chiral ligand.112

4.4 Hypothesis of Grignard substrates used as brominating reagents with the aid of

Cu(I)

Bromination with Grignard reagents has been noticed as a side reaction during the

addition of alkyl- or aryl- groups, however to my knowledge the reported bromination all

involved the addition of Cu (I) reagents. Dias reported that in the total synthesis of (-)- pironetin, when using the copper catalyzed Grignard reagents as alkyling source bromide

was the only product along with unreacted starting material.113 Baskaran studied the

solvent effect in cuprate displacement reaction and showed that with THF as the solvent

the Grignard reagents favor to donate halides rather than alkyl groups.114 With titanium

tetrachloride as the catalyst Grignard reagents can chemoselectively open the epoxide

from the less hindered position with halogen as incoming nucleophile than alkyl or aryl

group.115

4.5 Mild bromination reaction without the addition of Cu (I) catalyst

In the attempt of stereoretentive C-C bond formation with grignard reagents and our first generation NALGs, unexpected bromide products were observed. To our knowledge, this is the first time a halogentation has been achieved using a Grignard reagent without the aid of Cu (I) catalyst. The NALG esters was dissolved in THF or diethyl ether depending on the commercially available solution of Grignard reagents.

Under the cold conditions was added Grignard reagents dropwise. The reaction mixture

106 was then warmed up to room temperature until the completion. Table 15 shows the generality of alkyl and aryl Grignard reagents. Bromination reactions with aryl Grignard reagents, in general, are faster than alkyl Grignard reagents. This could be due to the stronger lewis base stablization of phenyl derivatives than that for the magnesium compounds containing alkyl groups. No obvious difference was observed when different solvents were employed.

Table 15. The generality of bromination reaction with ester NALG

00 S 0 Ph RMgX Ph X 0 0 THF 0 0

R X product time yield (%)

Me Ph 30 min 86%

Et CI Ph CI N/R N/R Ph Br Et Br 5h 71% Ph Br Ph Br 3.5 h 89% Ph CI Bn CI N/R N/R N/R: No Reaction

A few experiements were conducted in order to prove our proposed mechanism

(Scheme 49). The reactivity of various halogens followed a familiar nucleophilicity trend; iodide is more reactive than bromide while chloride did not react at all. The ester NALGs afforded the highest yield among the NALGs and tosylate. Originally we anticipated that the R group in Grignard reagents first attack the ester carbonyl carbon. In this hypothesis, the tetiary alkoxy group generated chelates with magnesium along with oxygens on the oligo-ether arm in the transition state (Scheme 49). The bromine then dissociated easily

107

from the magnesium metal and reacts with the electrophilic carbon of the substrate to

yield the 3-bromo-1-phenylpropane. When the reaction was quenched with H2O, a

sulfonic acid with a tetiary alcohol at its ortho position should be collected. However, this

byproduct has not been observed.

o 0 o 0 Br Ph 8 0 8 0 Ph PhMgBr 0 Mg 0 -0 Ph Br 0 THF, rt 0 0 0 0 Ph

Scheme 49. Originally hypothesized mechanism.

Table 16. Bromination results with various leaving groups

PhMgBr GL 0 Ph Ph Br THF

0 80 0 LG time yield (%) 80 0 2 2 0 2 3.5 h 89% 0

2 0 5h 78% 80 0 2 4 80 0 N 3 10 h 12% 2 3

4 9h 15% 0 0 0

The leaving groups comparison apparently demonstrated that the carbonyl unit was

not neccisity. The reaction with tosylate as leaving group gave similar results as ester

NALG, but ether NALG and quisylate required extensive amount of time with only 15%

yield. NMR dispalyed that the collected byproduct was the corresponding sulfonic acid of each leaving group. We also tested the reaction with the sulfonate of hindered secondary alcohol. The iodination furnished stereoinvertive iodides within 2 hours at 81% yield, while the bromination constituted a mixture of biphenyl, ketone and stereoinvertive

108 bromide in 1:2:1 ratio with overall yield 70% (Scheme 50).

00 00 SO-menthol PhMgBr Br SO-menthol + + 0 0 THF 0 Ph 0 inversion of o 00 configuration SO-menthol MeMgl

0 0 THF 0 inversion of configuration 0

Scheme 50. The results with hindered secondary alcohol substrates

We initially hypothesized that organomagnesium reagents would be activated upon chelation with the oligo-ether arm in our NALG. In Grignard reagents the Mg-X bond is largely ionic and thus benefits greatly from being effectively coordinated. Our NALGs appear to possess the ability to solvate cations. Because the ether C-O bond is relatively polar, we anticipated that the oligo-ether arm would stabilize (electrostatically) the magnesium ion. However THF and diethyl ether solvent used to generate Grignard reagents in the first place are stronger solvating agents. Perhaps they provide the nearly equal solvation to Grignard reagents in the reactions with different leaving groups. The low yield in the reaction with ether NALG perhaps is due to electron donating effect from both substituents on the aromatic ring. When the magnesium and ether oxygens are coordinated, the interactions of Mg-X is weakened to a large extend than that of Mg-C.

According to the Schlenk equilibrium116 in THF the Grignard reagents RMgX stay in equilibrium of a dihalide-bridged dimer and two dissociates dialkylmagnesium (R2Mg) and magnesium dihalide (MgX2). Thus magnesium halides also can act as a source of halogen.

109

4.6 Experimental section

General Information: All the reactions were carried out under an atmosphere of

argon in oven-dried glassware with magnetic stirring. Purification of reaction products

were carried out by flash column chromatography using Flash Silica gel 40-63μ using

hexane or ethyl acetate as eluant. Analytical thin layer chromatography was performed on

0.50mm 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 Mercury 400 (400 MHz) spectrometer and

are reported in ppm using solvent as internal standard (CDCl3 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). 13C NMRs were recorded on Varian

Mercury 400 (100 MHz) spectrometer. Chemical shifts are reported in ppm, with solvent

resonance employed as the internal standard (CDCl3 at 77.0 ppm). High-resolution mass

spectra were obtained from University of Florida Mass Spectrometry Laboratory.

Complete characterization provided only for the compound that are not reported or well

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

show the purity of compounds.

Materials: Stabilized/Certified ACS dichloromethane and anhydrous THF were

obtained from commercial sources and dried with the solvent purification system. All

other reagents are also commercially available and were used without further purification.

General procedure for bromination and iodination reactions: To a cold (0˚C)

solution of quisylate ester (1.0 eq) in THF or diethyl ether (1.5 M) was added a solution

of Grignard reagents (1.05 eq) in THF or diethyl ether (1-2 M). The reaction mixture then

110

was kept at room temperature. Following completion (usually within 2 h), reaction

mixture was quenched with acidic water and extracted three times with dichloromethane or Diethyl ether. The collected organic extracts were concentrated and the resulting oil was purified by silica gel chromatography (using hexanes as eluent).

111

CHAPTER FIVE

SELECTED SPECTRA

112

o o

0 N 0 0 S 0 0 0 C! 16a ("')

o """

o LO 1

o .....

E E 0.. 0.. 0.. 0.. oE '0.. COo.. 113

o o

O O F S O O O o N

17d

M "

..o

0 0 '" ~ 0 " 0 ~ M -'" 0 N '" 0 .., 0 '" "' ..0 0 '" 0 0 .. ~ '" 0 '" ~ "''"~ " - '"0 Ro'" S 0. '0. 0. '"0. 0 0. 0. 114

o o

O O F S O O o O O N F 17g

..o

0 0 0 .. ~ M 0 0 ~ ~ 0 M ~ 0 - '"M 0 0 ~ N ~ M 0 q

M 0 M '" '"0 ~

M '"0 0 0 .. ..~ 0 0 -.. ~ O~ ~ 0= ~- N- ""';C ----- ~ E E .. ~ ~ --- c ~ ~ - E ~ ----- ~ 115

0.0

O S O O N

5.0

10.0 ppm (f1) 116

0.0

N ° ° 5.0 2ge

10.0

ppm (f1) 117

0.0

° ° N 29d

5.0

ppm (f1) 118

o 0;

o N

o ..

119

Br 33

E c. c.

E a. a. 120

o o

)

o N

Br 35

0 ..0 0 0 1.0 ..~

0 0 ..'"

0 0 L[)

o .....

E c. c. 121

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