synthetic application in thioacylation...

SYNTHETIC APPLICATION IN THIOACYLATION, ACYLATION AND

SULFONYLATION

By

HUI TAO

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2006

Copyright 2006

By

Hui Tao

Dedicated to my family, my father Banghe Tao, my mother Pingfen Li and my twin sister Yong Tao

iv

ACKNOWLEDGMENTS

It is a great pleasure to acknowledge the support and assistance I have received

from people around me. I would not have achieved my Ph.D. without their guidance,

support and encouragement.

My deepest gratitude goes to my supervisor, Professor Alan R. Katritzky, whose

supervision, guidance and support are essential in my chemistry journey. I greatly thank

my committee members, Dr. William R. Dolbier, Dr. Lisa McElwee-White, Dr. Daniel R.

Talham and Dr. Kenneth Sloan, for their time and help. Particularly, I thank Dr. Dolbier

for excellent teaching in physical organic chemistry and the organic bull session he holds

every semester, which brought my understanding of organic chemistry to a new level,

and Dr. Kenneth Sloan, who opened the door of medicinal chemistry for me and led me

to a new world where I can fully apply the knowledge and skills I learned and challenge

my potential in a different way.

I also want to express my deepest appreciation to my colleagues in the Katritzky

group for their collaboration and friendship. My special thanks are given to Dr.

Chunming Cai, Dr. Kostyantyn Kirichenko and Dr. Sanjay Singh for their constant help

and encouragement, carefully checking my thesis and shaping my approaches to research.

v

TABLE OF CONTENTS page

ACKNOWLEDGMENTS ................................................................................................. iv

LIST OF TABLES............................................................................................................ vii

LIST OF FIGURES ......................................................................................................... viii

LIST OF SCHEMES.......................................................................................................... ix

ABSTRACT...................................................................................................................... xii

CHAPTER

1 GENERAL INTRODUCTION ....................................................................................1

2 SYNTHESIS OF N-MONO AND N,N-DISUBSTITUTED THIOUREAS FROM (BENZOTRIAZOL-1-YL)CARBOXIMIDAMIDES ..................................................7

2.1 Introduction.............................................................................................................7 2.2 Results and Discussion .........................................................................................11 2.3 Conclusion ............................................................................................................14 2.4 Experimental Section............................................................................................15

3 EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1-SULFONYLBENZOTRIAZOLES ............................................................................20

3.1 Introduction...........................................................................................................20 3.2 Results and Discussion .........................................................................................21

3.2.1 Preparation of Sulfonylbenzotriazoles 3.1 .................................................21 3.2.2 Synthesis of α-Cyano Sulfones ..................................................................22 3.2.3 Synthesis of α-Sulfonyl Sulfones...............................................................25

3.3 Conclusion ............................................................................................................26 3.4 Experimental Section............................................................................................27

4 NOVEL SYNTHESES OF γ-AMINO ACID DERIVATIVES UTILIZING N-PROTECTED AMINOACYLBENZOTRIAZOLES FROM GLUTAMIC ACID ...35

4.1 Introduction...........................................................................................................35 4.2 Results and Discussion .........................................................................................39

vi

4.2.1 Preparation of 1-(N-Tfa-α-Aminoacyl)benzotriazoles 4.10 .......................39 4.2.2 Syntheses of γ-Keto-γ-amino Esters 4.11...................................................40 4.2.3 Preparation of δ-Aryl-γ-amino Esters 4.12 and δ-Aryl-γ-amino Acids

4.13 by Reduction of γ-Keto-γ-amino Esters 4.11. ..........................................41 4.2.4 Configuration Study of δ-Aryl-γ-amino Acids 4.13...................................42

4.3 Conclusion ............................................................................................................43 4.4 Experimental Section............................................................................................44

5 MICROWAVE MEDIATED SYNTHESIS OF β-ENAMINO THIOIC ACID DERIVATIVES FROM DIBENZOTRIAZOLYLMETHANETHIONE ..................50

5.1 Introduction...........................................................................................................50 5.2 Results and Discussion .........................................................................................52 5.3 Conclusion ............................................................................................................60 5.4 Experimental Section............................................................................................61

6 THE GENERATION AND REACTIVITY OF POLYANION DERIVED FROM 1,1-DIBENZOTRIAZOLYLETHANE......................................................................70

6.1 Introduction...........................................................................................................70 6.2 Results and Discussion .........................................................................................73 6.3 Conclusion ............................................................................................................76 6.4 Experimental Section............................................................................................76

7 CONCLUSION...........................................................................................................80

LIST OF REFERENCES...................................................................................................82

BIOGRAPHICAL SKETCH .............................................................................................96

vii

LIST OF TABLES

Table page 2-1 Preparation of N-Mono- and N,N-Disubstituted Thioureas 2.3a–e from 1-

Benzotriazole-1-carbothioamide 2.2. .......................................................................10

2-2 Preparation of Mono- and N,N-Disubstituted Thioureas 2.3a–d,f–j. .......................13

3-1 Synthesis of 1-Sulfonylbenzotriazoles 3.1a–i from Corresponding Alkyl or Aryl Sulfonyl Chlorides 3.2 or Organolithium Reagents 3.3. ..........................................22

3-2 Preparation of α-Cyano Sulfones 3.5a−i via C-Sulfonylation of Nitriles 3.4a–f with Sulfonylbenzotriazoles 3.1a-f. .........................................................................24

3-3 Preparation of α-Sulfonyl Sulfones 3.7a−g via C-Sulfonylation of Sulfones 3.6a–d with Sulfonylbenzotriazoles 3.1a,b,d,e,g......................................................26

4-1 Syntheses of γ-Keto-γ-Amino Esters 4.11................................................................41

4-2 Preparation of δ-Aryl-γ-amino Esters 4.12e,f. .........................................................41

4-3 Preperation of δ-Aryl-γ-amino Acids 4.13...............................................................42

4-4 The Comparison of Chiral HPLC Results of 4.13b (L) with Corresponding DL-Mixtures 4.13g. ........................................................................................................43

5-1 The Synthesis of Benzotriazolyl β-Enaminothiones 5.5. .........................................54

5-2 Microwave-mediated Synthesis of β-Enamino Thioic Acid Derivatives 5.6–5.8....55

5-3 C-Thioacylation of Ketimines 5.2a with Thioacylbenzotriazoles 5.9a–c. ...............57

viii

LIST OF FIGURES

Figure page 1-1 Benzotriazole Intermediate 1.1. .................................................................................2

1-2 New Types of Benzotriazole Intermediates 1.2–1.6. .................................................3

2-1 The Tautomarization of N-Aryl(benzotriazol-1-yl)carboximidamides 2.4a,d,j. ......14

3-1 Sulfonyl Group, a Termporary Transformer of Chemical Reactivity. .....................20

4-1 Known Biologically Active Compounds Containing Fragments of γ-Amino Acids Derivatives. ....................................................................................................36

5-1 The Structure of ZnBr2-Thioacylbenzotriazole Complex 5.12. ...............................59

ix

LIST OF SCHEMES

Scheme page 1-1 Classical Prototype of Benzotriazole-mediated α-Hetero-alkylations.......................2

1-2 The Synthesis of Mono- and N,N-Disubstituted Thioureas from (Benzotriazol-1-yl)carboximidamides 1.2. ...........................................................................................3

1-3 N-Sulfonylbenzotriazoles as Advantageous Reagents for C-Sulfonylation...............4

1-4 Novel Syntheses of Chiral γ-Amino Acid Derivatives Utilizing N-(Protected aminoacyl)benzotriazoles from L-Glutamic Acid......................................................4

1-5 The Synthesis of β-Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5. ..............5

1-6 The Synthesis of Benzotriazolyl β-Enaminothiones 1.6. ...........................................5

1-7 The Synthesis of β-Enamino Thioic Acid Derivatives...............................................6

2-1 Well-known Routes to Substituted Thioureas............................................................9

2-2 Attempted Synthesis of 1-Benzotriazole-1-Carbothioamide 2.2 from 1-Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide.....................10

2-3 N-Mono- and N,N-Disubstituted Thioureas 2.3a–e from 1-Cyanobenzotriazole 2.1 via 1-Benzotriazole-1-carbothioamide 2.2. ........................................................10

2-4 Preparation of (Benzotriazol-1-yl)carboximidamides 2.4a–d,f–j. ...........................12

2-5 Previous Study on Nucleophilic Displacement of Benzotriazole in (Benzotriazol-1-yl)carboximidamides 2.4. ..............................................................13

2-6 The Proposed Mechanism for the Reaction of (Benzotriazol-1-yl)carboximidamides with Hydrogen Sulfide. .........................................................14

3-1 1-Sulfonylbenzotriazoles 3.1 as Activating Reagents in N-Acylation of Benzotriazole and Benzotriazolylalkylation of Aromatic Compounds....................21

3-2 1-Sulfonylbenzotriazoles 3.1 as Effective Reagents for N-Sulfonylation of Amines and O-Sulfonylation of Phenols..................................................................21

3-3 Preparation of 1-Sulfonylbenzotriazoles 3.1a–i. ......................................................22

x

3-4 Known Approaches to α-Cyano Sulfones................................................................23

3-5 A Novel Approach to α-Cyano Sulfones 3.5a–i. .....................................................24

3-6 A Novel Approach to α-Sulfonyl Sulfones..............................................................26

4-1 Literature Methods of Synthesis of γ-Amino Acids from α-Amino Acids..............37

4-2 γ-Amino Acids from Glutamic Acid. .......................................................................38

4-3 Novel Syntheses of β-amino Acid Derivatives, γ-Aryl-β-amino Acids 4.6.............39

4-4 Preparation of N-(Tfa-α-aminoacyl)benzotriazoles, Tfa-Glu(OMe)-Bt 4.10...........39

4-5 Chiral N-Protected (α-Aminoacyl)benzotriazoles as Acylating Reagents in Friedel-Craft Acylation. ...........................................................................................40

4-6 Syntheses of γ-Keto-γ-amino Esters 4.11.................................................................40

4-7 Preparation of δ-Aryl-γ-amino Esters 4.12e,f by the Reduction of γ-Keto-γ-amino Esters 4.11e,f. ................................................................................................41

4-8 Preparation of δ-Aryl-γ-amino Acids 4.13a,b by the Reduction of γ-Keto-γ-amino Esters 4.11a,b. ...............................................................................................42

4-9 Synthesis of Compounds 4.13g (DL). ......................................................................43

5-1 Novel Approach to Dibenzotriazolylmethanethione 5.1..........................................52

5-2 Known Reactions of Benzotriazole and Related Derivatives with Thiphosgene.....53

5-3 The Reactivity of Dibenzotriazolylmethanethione 5.1 toward Ketimines, Aldimines and Enamines..........................................................................................54

5-4 Novel Approach to β-Enamino Thioic Acid Derivatives 5.6–5.8............................55

5-5 Plausible Mechanism for the Reaction of Benzotriazolyl β-Enaminothiones 5.5 with Nucleophiles.....................................................................................................56

5-6 Published Benzotriazole-Mediated Thioacylation. ..................................................57

5-7 Novel Approach to β-Enaminothiones 5.10.............................................................57

5-8 Attempts to Obtain β-Enaminothiones 5.10 from Diverse Ketimines. ....................58

5-9 Ketimine with High Reactivity Reacts Through the Enamino Form with the Complex 5.12. ..........................................................................................................60

xi

5-10 Ketimine with Low Reactivity Reacts through Imino Form with the Complex 5.12. ..........................................................................................................................60

6-1 The Generation of Dianion 6.2 from 1-Vinylbenzotriazole 6.1 and its Reactivity toward Diverse Electrophiles. ..................................................................................71

6-2 The Generation of Polyanion 6.7 from Dibenzotriazolylmethane 6.6 and its Reactivity toward Different Electrophiles................................................................72

6-3 The Generation of Dianion 6.15 and its Reactivity toward a Range of Electrophiles.............................................................................................................74

6-4 Attempted Trapping of Dianion 6.15 with 1,3-Dielectrophiles. ..............................75

xii

Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

SYNTHETIC APPLICATIONS IN THIOACYLATION, ACYLATION AND SULFONYLATION

By

Hui Tao

August, 2006

Chair: Alan R. Katritzky Major Department: Chemistry

Novel synthetic applications of benzotriazole methodology in thioacylation,

acylation and sulfonylation have been developed to synthesize a wide range of

biologically and synthetically useful compounds.

Chapter 2 describes the reaction of (benzotriazol-1-yl)carboximidamides with

hydrogen sulfide, which provide N-mono and N,N-disubstituted thioureas under mild

conditions in 21–99% yields.

1-Sulfonylbenzotriazoles, as advantageous sulfonylating reagents, have been

applied in N-sulfonylation and O-sulfonylation. In a logical sequel, C-sulfonylation with

1-sulfonylbenzotriazoles was investigated, which is discussed in Chapter 3. The

subsequent investigation led to novel syntheses of α-cyano sulfones and α-sulfonyl

sulfones, which are not easy to synthesize by known methods (i.e., via classic

sulfonylation of nitriles and sulfones) in synthetic useful yields.

xiii

Recently, katritzky group has extensively studied 1-acylbenzotriazoles as powerful

neutral acylating reagents. In a further extension of this methodology, a novel approach

to γ-amino acid derivatives utilizing N-protected aminoacylbenzotriazoles was achieved

and described in Chapter 4. Friedel-Crafts reactions of readily available N-protected α-

aminoacylbenzotriazoles with hetero- and benzenoid- aromatics give α-amino ketones

which can be reduced by either triethyl silane or sodium borohydride to form

corresponding γ-amino acid derivatives. The preservation of chirality throughout this

process was confirmed by chiral HPLC results.

In Chapter 5, the synthesis of air and moisture stable benzotriazole derivatives,

benzotriazolyl β-enaminothiones, from dibenzotriazolylmethanethione is discussed.

Subsequent investigation of their synthetic utilities led to a simple and efficient approach

to β-enamino thioic acid derivatives, including thioamides, thioesters and dithioesters via

microwave mediated nucleophlic substitution of the benzotriazolyl moiety in

benzotriazolyl β-enaminothiones in 74–99% yields. C-Thioacylation with 1-

thioacylbenzotriazoles has also been studied in this chapter.

At the end, continuing efforts to develop new routes to heterocycles led to the

generation of polyanion from 1,1-dibenzotriazolylethane and the subsequent investigation

of the reactivity of polyanions toward a variety of mono-, di- and trielectrophiles was

described in Chapter 6. In one case, when the generated polyanion reacted with

dielectrophile diethyl oxalate, the heterocyclization took place to give a novel

triazoloquinolinone in high yield.

1

CHAPTER 1 GENERAL INTRODUCTION

Benzotriazole has found wide application as an efficient synthetic auxiliary in

organic chemistry. Its derivatives are employed in the photographic, dye and

pharmaceutical industries. Diverse applications of benzotriazole as a synthetic auxiliary

are due to its unique properties, which allow benzotriazole to (i) be easily introduced at

the beginning of a synthetic sequence; (ii) activate attached functionality; (iii) be easily

substituted with various nucleophiles; (iv) be recycled at the end of a reaction sequence

by simple washing with a weak aqueous basic solution, such as sodium carbonate or

bicarbonate (benzotriazole is an acid of appreciable strength with pKa ≈ 8.2). The

benzotriazole ring system is stable under diverse reaction conditions, and the presence of

both pyrrole and pyridine-like nitrogen atoms as well as the aromatic system endows

benzotriazole with either electron donor or electron acceptor properties, depending on the

nature of the attached substituent, and the reaction conditions. The above special

chemical dichotomy gives benzotriazole unique chemical characteristics: the ability to act

as a nucleofuge and the ability to activate the α-CH toward proton loss are close to those

of cyano and phenylsulfonyl groups, and better than both phenyl and vinyl groups.

The applications of benzotriazole methodology as a versatile synthetic tool and

chemical properties of benzotriazole derivatives have been periodically reviewed

[91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555]. Readily

available benzotriazole intermediates of type 1.1 (Fig. 1-1) can react with a variety of

nucleophiles providing access to products of substitution of the benzotriazolyl moiety.

2

Extensive exploration of the utility of benzotriazole derivatives 1.1 resulted in

development of highly important processes of amino-alkylation (X = NR2), amido-

alkylation (X = NHCOR), thioamido-alkylation (X = NHCSR), sulfonamide-alkylation

(X = NHSO2R), alkoxy-alkylation (X = OR), alkylthio-alkylation (X = SR) and silyl-

alkylation (X = SiR3) (Scheme1-1). Typical nucleophiles utilized in these reactions

[91T2683, 94S445, 94AA31, 98CR409, 98AA35, 03CEJ4586, 05T2555] include

Grignard, organozinc, organolithium, organosamarium and tin reagents, enolates, silyl

enol ethers, allyl trimethyl silane, active methylenes, amines, thiols, alcohols, phosphates,

and metal hydrides.

R1

X

Bt

Bt = benzotriazol-1-ylX = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3R1 = alkyl, aryl

1.1

Figure 1-1. Benzotriazole Intermediate 1.1.

R

X

Bt1.1

+ Nu-R

X

Nu+ Bt-

X = NR2, NHCOR, NHCSR, NHSO2R, OR, SR, SiR3

Scheme 1-1. Classical Prototype of Benzotriazole-mediated α-Hetero-alkylations.

Further effort to develop new benzotriazole intermediates and investigate their

synthetic applications is of great importance. In the present thesis, new types of

benzotriazole intermediates, including (benzotriazol-1-yl)carboximidamides 1.2, 1-

sulfonylbenzotriazoles 1.3, 1-acylbenzotriazoles 1.4, 1-thioacylbenzotriazoles 1.5, and

benzotriazolyl β-enaminothiones 1.6, have been developed and utilized for the synthesis

3

of various synthetically useful compounds (Fig. 1-2). Novel and useful aspects of these

benzotriazole intermediates are investigated.

NH

Bt NSO

OBt R

R = alkyl, aryl, heteroaryl,R' = H, alkyl, aryl, R1 = Bu, R2 = H, alkyl, R3 = alkyl, aryl

1.2 1.3

Bt

O

R Bt'

S

R

1.4 1.5

BtS

1.6

HN

R3

R1

R2

Bt' =

NN

NO2N

R

R'

Figure 1-2. New Types of Benzotriazole Intermediates 1.2–1.6.

The results of studies on transformations of (benzotriazol-1-yl)carboximidamides

1.2 to N-mono- and N,N-disubstituted thioureas are discussed in Chapter 2.

(Benzotriazol-1-yl)carboximidamides 1.2 reacted with hydrogen sulfide in THF giving

the corresponding mono- and N,N-disubstituted thioureas in moderate to high yields

under mild conditions (Scheme 1-2). The possible mechanism and potential synthetic

advantages are discussed.

Bt

NH

NR'

RH2STHF R N

S

NH2R'

1.2

Scheme 1-2. The Synthesis of Mono- and N,N-Disubstituted Thioureas from (Benzotriazol-1-yl)carboximidamides 1.2.

In Chapter 3, a novel approach to α-functionalized sulfones is discussed. Reactions

of readily available N-(alkyl-, aryl-, and heteroarylsulfonyl)benzotriazoles 1.3 with

anions, generated from nitriles or sulfones, produce α-cyanoalkyl sulfones and α-

sulfonylalkyl sulfones respectively, in moderate to high yields (Scheme 1-3).

4

In Chapter 4, novel syntheses of chiral γ-amino acid derivatives, utilizing N-

protected aminoacylbenzotriazoles, prepared from L-glutamic acid is discussed. The

preservation of chirality throughout this process is confirmed by chiral HPLC tests

(Scheme 1-4).

R1

CNR2

R1CNR2

RO2SSO

OBt R

1.3

n-BuLi

THF

R1

O2SR2

R1

O2SR2

SO2Rn-BuLi

THF

Scheme 1-3. N-Sulfonylbenzotriazoles as Advantageous Reagents for C-Sulfonylation.

Et3SiH

NH

O

Ar

TFA

OMeO

TiCl4

NH

O

Bt

TFA

OMeO

NaBH4

CF3COOH

NH Ar

TFA

OHO

NH Ar

TFA

OMeO

46-88%

Aromatics

TFA-Glu(OMe)-Bt

DMF/H2O1.4

Scheme 1-4. Novel Syntheses of Chiral γ-Amino Acid Derivatives Utilizing N-Protected aminoacylbenzotriazoles from L-Glutamic Acid.

In Chapter 5, the syntheses and synthetic applications of two benzotriazole

derivatives, 1-thioacylbenzotriazoles 1.5 and benzotriazolyl β-enaminothiones 1.6, are

discussed.

The reactivity of thioacylbenzotriazoles 1.5 toward various nucleophiles is

investigated and it is found that the reactive ketimines 1.7 reacted with

5

thioacylbenzotriazoles 1.5 smoothly to give β-enaminothiones 1.8 in moderate to good

yields (Scheme 1-5).

Inspired by the results obtained in the synthesis of β-enaminothiones 1.8, this

methodology is extended to the synthesis of novel benzotriazole intermediates,

benzotriazolyl β-enaminothiones 1.6, from dibenzotriazolylmethanethione 1.9 and

ketimines 1.7 (Scheme 1-6).

R1

NR3

R2 NN

NR4

S

O2N ZnBr2THF, r.t.

R1

NH S

R4

R3

R2+

1.7 R1 = Ph, R2 = HR3 = Bu

1.5 1.8

Scheme 1-5. The Synthesis of β-Enaminothiones 1.8 from Thioacylbenzotriazoles 1.5.

SBt

Bt

THF

R1

NHR3

Bt

S

R2R1

NR3

R2r.t. 6h

1.71.9

+

1.6

Scheme 1-6. The Synthesis of Benzotriazolyl β-Enaminothiones 1.6.

Further investigations support benzotriazolyl β-enaminothiones 1.6 as effective

synthetic precursors to β-enamino thioic acid derivatives 1.10, including thioamides,

thioesters (thiocarboxylic-O-esters) and dithioesters (thiocarboxylic-S-esters) (Scheme 1-

7).

R1

NHR3

Bt

S

R2

+ HXR4

X = O, S, NR4microwave irradiation

base

R1

NHR3

XR4

S

R2

1.6 1.10

6

Scheme 1-7. The Synthesis of β-Enamino Thioic Acid Derivatives.

As mentioned previously, besides acting as a leaving group, a benzotriazolyl group

also activates the deprotonation of α-H. Futhermore, treatment of some benzotriazole

derivatives by excess base leads to deprotonation of the benzotriazolyl group at the 7-

position giving a polyanion. The reactivity of polyanions, generated from 1,1-

dibenzotriazolylethane, toward electrophiles, including reactions with a variety of mono-,

di-, and trielectrophiles, is discussed in Chapter 6.

7

CHAPTER 2 SYNTHESIS OF N-MONO AND N,N-DISUBSTITUTED THIOUREAS FROM

(BENZOTRIAZOL-1-YL)CARBOXIMIDAMIDES

2.1 Introduction

Thiourea-containing compounds are important because of their numerous chemical

and pharmaceutical applications. For example, thiourea derivatives are efficient

guanylating agents both in solution [86JOC1882, 98S460] and on solid support

[98T15063, 98TL2663, 02EJOC3909]. Thermal decomposition of N-arylthioureas gives

aryl isothiocyanates [56JCS659, 56OS56]. Oxidation of arylthioureas with lead

tetraacetate [51OS19] or iodic acid [30JA3647] affords arylcyanamides. Thioureas are

also widely used as building blocks to construct libraries of small heterocyclic ring

systems that have potential utility in pharmaceutical applications and related areas. Solid-

phase Biginelli pyrimidine synthesis [03ARK(iv)93] and synthesis of imidazolone

derivatives [99OL1351] using resin-bound thioureas were recently reported. Thioureas

also condense with α-halocarbonyl compounds to afford 2-amino-1,3-thiazoles

[96CL1409, 98JOC196, 98ACIE1402, 99JCSP(1)11363, 01ARK(v)119, 02ARK(x)72],

which are potential drug candidates for the treatment of allergies [83JMC1158],

hypertension [92JMC2562], inflammation [88JMC1719], bacterial infections

[94BMCL1601], and HIV [95JMC4929]. Benzothiazoles can be prepared from

arylthioureas in the presence of bromine [84JOC997]. The utility of thioureas to prepare

1,3-thiazines [97S573], 1,3-diazines [86S1041], 1,3-quinazolines [00JCC378] and 1,2,4-

triazin-5-ones [01TL4433] was also described recently. In particular, 1,2,4-triazin-5-ones

8

have exhibited anticancer [88CL29], antiulcer [86JP61134389] and anti-inflammatory

[73RC2199] activities. Commercially, thioureas are used in industries as diverse as dye

products, photographic films, elastomers, plastics and textiles. Some thiourea derivatives

are insecticides, preservatives, rodenticides and pharmaceuticals [55CR181].

Furthermore, the ability of thioureas to form crystalline complexes with branched

hydrocarbons and cycloaliphatic structures has led to their use in the characterization and

separation of mixtures of organic compounds [51USP2520715].

Synthetic approaches to thioureas have been investigated extensively [55CR181,

95COFGT569]. Well-known routes to substituted thioureas (Scheme 2-1) involve

reactions of (i) anilines with sodium [72JMC1024] or ammonium thiocyanate [63OS180]

in the presence of strong acids (TFA or concentrated HCl); (ii) aroyl isothiocyanates with

amines followed by basic hydrolysis [34JA1408, 55OS735, 88S456]; most recently,

mono and N,N-disubstituted thioureas were also prepared on solid support using Fmoc-

isothiocyanate followed by subsequent deprotection [99OL1351]; (iii) silicon

tetraisothiocyanate with primary or secondary amines [73OS801]; (iv) unsubstituted

thioureas with primary alkyl amines at 170–180 oC [56JOC483]; (v) isothiocyanates with

ammonia or amines [55OS617, 01ARK(iii)33, 02ARK(i)7]; (vi) primary amines with

carbon disulfide in the presence of mercury acetate and aqueous ammonia [51JACS906];

(vii) disubstituted cyanamides with hydrogen chloride and LiAlHSH [01TL6333] or

hydrogen sulfide and ammonia [55OS609].

Although these synthetic approaches have proven to be of great utility for specific

classes of the title compounds, method (i) was limited to monosubstituted thioureas;

methods (ii), (iii), (v) and (vii) require aroyl isothiocyanates, silicon tetraisothiocyanate,

9

isothiocyanates and disubstituted cyanamides respectively; methods (iv) and (vi) need

either harsh reaction conditions (170–180 oC) or the presence of mercury salt while

method (vi) was also limited to the preparation of monosubstituted thioureas.

LiAlHSH orH2S/NH3

PhCONCS

R1NH2

Si(NCS)4

R1

NR2

N

N

SR1

R2NH

S

NH2H2N

R1NH2

R1R2NH

CS2

R3NCS

Hg(OAc)2NH3

R1NH2

R1 =ArylMSCN

1. R1R2NH2. OH-

1. R1R2NH2. H+R3 = H

(i)

(ii) (iii) (iv)

(v)

(vi)(vii)

M = Na, NH4

R3

R2, R3 = HR3 = H

R2, R3 = H

R3 = PhCOR2, R3 = H

Scheme 2-1. Well-known Routes to Substituted Thioureas.

Inspired by the wide applications of thiourea, new approaches to the synthesis of

thioureas were attempted. The synthesis of mono and N,N-disubstituted thioureas from

(benzotriazol-1-yl)carboximidamides is addressed in this chapter.

Recently, a new and efficient reagent, benzotriazole-1-carboxylic acid amide, for

the preparation of mono and N,N-disubstituted ureas (Scheme 2-2) [03ARK(viii)8] was

developed.

Attempts to prepare 1-benzotriazole-1-carbothioamide from the previously

described benzotriazole-1-carboxylic acid amide [03ARK(viii)8] with Lawesson’s

reagent gave only benzotriazole (Scheme 2-2). Reactions of benzotriazole or 1-

10

trimethylsilyl benzotriazole with sodium thiocyanate, sodium hydrogen sulfide or

trimethylsilyl isothiocyanate failed under various conditions. Finally, the desired 1-

benzotriazole-1-carbothioamide 2.2 was prepared by Nataliya Kirichenko in 84% yield

from 1-cyanobenzotriazole 2.1 in DME under hydrogen sulfide gas flow (Scheme 2-3).

Bt NBt

O

NH2R1

N

O

NH2R2

2.1

R1R2NH

THF

30% H2O2(n-C4H9)4N+HSO4-

CH2Cl2, r.t.

Bt

S

NH2

Lawesson's reagent

2.2

Scheme 2-2. Attempted Synthesis of 1-Benzotriazole-1-Carbothioamide 2.2 from 1-Cyanobenzotriazole 2.1 via Benzotriazole-1-carboxylic Acid Amide.

Nataliya Kirichenko in the Katritzky research group found that 1-benzotriazole-1-

carbothioamide 2.2 was unreactive toward amines in THF at 20 oC and only reacted

sluggishly under reflux. Treatment of 2.2 with amines in refluxing toluene gave the

corresponding thioureas 2.3a–e in moderate yields (39–71%) (Scheme 2-3, Table 2-1)

[04S1799].

Bt N

H2S

Bt

S

NH2R1

N

S

NH2R2

2.1 2.2 2.3a-e

R1R2NHtoluenereflux

DME, r. t.

Scheme 2-3. Mono- and N,N-Disubstituted Thioureas 2.3a–e from 1-Cyanobenzotriazole 2.1 via 1-Benzotriazole-1-carbothioamide 2.2.

11

Table 2-1. Preparation of Mono- and N,N-Disubstituted Thioureas 2.3a–e from 1-Benzotriazole-1-carbothioamide 2.2.

Entry Prodcut R1 R2 Yield (%)1 2.3a 4-CH3O-C6H4 H 54 2 2.3b Benzyl Benzyl 67 3 2.3c pyrrolidinyl 54 4 2.3d Phenyl H 71 5 2.3e PhNH H 39

2.2 Results and Discussion

The moderate yields of thioureas 2.3a–e (Table 2.1), under relatively harsh reaction

conditions make it necessary to find an alternative approach via (benzotriazol-1-

yl)carboximidamides 2.4. (Benzotriazol-1-yl)carboximidamides 2.4a–d,f–j (Scheme 2-4)

were prepared from di(benzotriazolyl)methanimine 2.5, available as mixture of isomers

2.5′ and 2.5″ (Scheme 2-4), and primary or secondary amines in 56-82% yield

[00JOC8080]. The displacement of the first benzotriazole moiety was affected by the

addition of an amine of choice to a solution of isomers 2.5′ and 2.5″ in THF. Compounds

2.4a–d,f–j were obtained exclusively as pure Bt1 isomers, probably due to the

preferential displacement of the Bt2 group in the 2.5″ isomer. Furthermore, compared to

the previous approach via 1-cyanobenzotriazole 2.1, di(benzotriazolyl)methanimine 2.5 is

more air and moisture stable, more crystalline-like (1-cyanobenzotriazole 2.1,

amorphous, mp 73–75 oC [67JA4760]; di(benzotriazolyl)methanimine 2.5, white

microneedles, mp 162–163 oC [00JOC8080]), and is prepared under mild conditions (no

NaH required). These chemical and physical properties make

di(benzotriazolyl)methanimine 2.5 a better starting material for the synthesis of thioureas.

Nucleophilic displacement of benzotriazole in (benzotriazol-1-

yl)carboximidamides 2.4a–d,f–j by a variety of amines with the formation of tri- and

tetrasubstituted guanidines has been reported previously [00JOC8080]. Previous reports

12

[91RRC573, 00JOC8080] also indicate that mono-substituted (benzotriazol-1-

yl)carboximidamides 2.4a,d,h,i,j are stable compounds which are resistant to

displacement of benzotriazole by amines [00JOC8080] and to elimination in highly basic

conditions (Scheme 2-5) [91RRC573].

NN

NBt = Bt1 =

Bt1

NH

Bt1

THF

Bt

NH

NR1

R2

2.4a-d,f-j

2.5'

r. t.

Bt2 =N

NN

Bt1

NH

Bt2

2.5"

+2 BtHBrCN

2.5'& 2.5" mixture +R1

HNR2

H2STHF R

1N

S

NH2R2

2.3a-d, f-j

Scheme 2-4. Preparation of (Benzotriazol-1-yl)carboximidamides 2.4a–d,f–j.

Continuing the efforts in benzotriazole methodology, the reactivity of

(benzotriazol-1-yl)carboximidamides 2.4 toward substitution of benzotriazolyl group

with hydrogen sulfide has investigated. (Benzotriazol-1-yl)carboximidamides 2.4b,c,f–i

reacted with hydrogen sulfide smoothly in THF at 20 oC and gave the desired mono and

N,N-disubstituted thioureas 2.3b,c,f–i (method A). However, N-aryl(benzotriazol-1-

yl)carboximidamides 2.4a,d,j, did not react with hydrogen sulfide at room temperature.

In refluxing THF, rapid desorption of hydrogen sulfide from the reaction mixture

apparently occurred resulting in no reaction. Heating the reaction mixture in a sealed tube

at 90 oC in THF saturated with hydrogen sulfide, results in successful conversion of N-

13

aryl substituted compounds 2.4a,d,j into the desired thioureas 2.3a,d,j in 21–78%

isolated yields (method B) (Scheme 2-4, Table 2-2).

Bt

NH

NR1

R2

2.4

+R3

HNR4

R1 = alkyl, aryl

R2 = alkyl

THF, reflux

THF, reflux

R2 = HKOH/MeOH

no reaction

N

NH

NR1

R2R3

R4

R2 = H

R2 = alkylPhCl, heat

N CNR1

R2

Scheme 2-5. Previous Study on Nucleophilic Displacement of Benzotriazole in (Benzotriazol-1-yl)carboximidamides 2.4.

Table 2-2. Preparation of Mono- and N,N-Disubstituted Thioureas 2.3a–d,f–j. Entry Prodcut R1 R2 Methoda Yield (%)1 2.3a 4-CH3O-C6H4 H B 59 2 2.3b Benzyl Benzyl A 86 3 2.3c pyrrolidinyl A 85 4 2.3d Phenyl H B 78 5 2.3f (CH2)2O(CH2)2 A 99 6 2.3g Ethyl Ethyl A 92 7 2.3h Benzyl H A 76 8 2.3i n-Butyl H A 94 9 2.3j 4-Cl-C6H4 H B 21 a: Method A: THF, rt; Method B: THF, sealed tube, 90 ºC.

These reaction results suggest a plausible mechanism of substitution, which

involves initial formation of the cationic carbodiimide 2.4′, followed by the nucleophilic

addition of hydrogen sulfide and tautomarization to afford 2.3 as final product (Scheme

2-6). This mechanism was also supported by previous research results (Scheme 2-5)

[91RRC573, 00JOC8080].

14

Bt

NH

NR1

R2 THF R1 N

S

NH2R2

NHCN

R1 R2Bt-

SH2R1 N

NH

SH2R2

2.4 2.3

Scheme 2-6. The Proposed Mechanism for the Reaction of (Benzotriazol-1-yl)carboximidamides with Hydrogen Sulfide.

As depicted in Scheme 2-6, the formation of the cationic carbodiimide 2.4′ would

be facilitated by aliphatic chains on the quarternary nitrogen. These cationic

carbodiimides readily react with hydrogen sulfide followed by tautomerization to give the

desired thioureas, in a total effect of benzotriazole substitution. However, in the presence

of an aromatic substitutent on the nitrogen, structural tautomers play an important role.

Compounds 2.4a,d,j prefer to exist in the more conjugated tautomeric form 2.4″a,d,j

(Figure 2-1). This fact is supported by the NMR spectra of aryl substituted (benzotriazol-

1-yl)carboximidamides 2.4a,d,j, where a 2-proton broad signal, corresponding to NH2 in

the range of 5.76–5.80 ppm is observed. The formation of cationic carbodiimide requires

higher energy.

Bt

NH

NHR1

2.4"a,d,jR1 = aryl

Bt

NH2

NR1

2.4a,d,j Figure 2-1. The Tautomerization of N-Aryl(benzotriazol-1-yl)carboximidamides 2.4a,d,j.

2.3 Conclusion

In summary, di(benzotriazolyl)methanimine 2.5 [00JOC8080] readily reacts with

primary and secondary amines to give (benzotriazol-1-yl)carboximidamides 2.4a–d,f–j,

which are easily converted into mono and N,N-disubstituted thioureas 2.3a–d,f–j with

hydrogen sulfide under mild reaction conditions. The present procedure is advantageous

in comparison to literature methods by avoiding the use of strong acids [63OS180,

15

72JMC1024], strong bases [34JA1408, 55OS735, 88S456], difficult to handle reagents

(such as silicon tetraisothiocyanate [73OS801] or LiAlHSH [01TL6333]), high reaction

temperatures [56JOC483] and environmentally hazardous heavy metal salts [51JA906].

Furthermore, since the preparation of (benzotriazol-1-yl)carboximidamides

[02JCC285, 02JCC290] on solid support has been described, the development of this

protocol could be valuable in combinatorial synthesis.

2.4 Experimental Section

General. All reactions were carried out under nitrogen atmosphere. THF and DME

were freshly distilled over sodium / benzophenone; toluene was distilled over sodium

before use. Other materials were used as supplied. Melting points were determined by

using a capillary melting point apparatus equipped with a digital thermometer and

Bristoline hot-stage microscope and were uncorrected. 1H NMR (300 MHz) and 13C

NMR (75 MHz) spectra were recorded on a Varian Gemini 300 spectrometer in CDCl3

(with TMS for 1H and CDCl3 for 13C as the internal reference), unless otherwise stated.

The elemental analyses were performed on a Carlo Erba EA–1108 instrument. Column

chromatography was conducted on silica gel 200−425 mesh.

Di(benzotriazolyl)methanimine 2.5 was prepared according to published procedure

[00JOC8080] as off-white microcrystals (62%), mp 162−163 °C, (lit. mp 162-163 °C

[00JOC8080]).

Compounds 2.4a–d,f–j were prepared according to the published

procedures[00JOC8080, 01S897]: benzotriazol-1-yl(tetrahydro-1H-pyrrol-1-

yl)methanimine (2.4c), yellow oil [00JOC8080] (70%); N′-phenyl benzotriazole-1-

carboximidamide (2.4d), white prisms from methanol (56%), mp 123–124 °C (lit. mp

16

123–124 °C [00JOC8080]); benzotriazol-1-yl(tetrahydro-4H-1,4-oxazin-4-

yl)methanimine (2.4f), light yellow oil [00JOC8080] (65%); N,N-diethyl-1H-

benzotriazole-1-carboximidamide (2.4g), yellow oil [01S897] (60%); N-

(benzyl)benzotriazole-1-carboximidamide (2.4h), colorless needles (82%), mp 97–98 °C

(lit. mp 97–98 °C [00JOC8080]).

N’-(4-Methoxyphenyl)-1H-1,2,3-benzotriazole-1-carboximidamide (2.4a). Light

yellow microcrystals (87%); mp 140–141 °C; 1H NMR δ 3.82 (s, 3H), 5.80 (br s, 2H),

6.93–6.97 (m, 2H), 7.04–7.07 (m, 2H), 7.43–7.49 (m, 1H), 7.57–7.62 (m, 1H), 8.10 (d, J

= 8.1 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H); 13C NMR δ 55.5, 115.0, 115.4, 119.7, 122.8,

125.2, 129.3, 131.2, 139.5, 144.4, 146.7, 156.2. Anal. Calcd for C14H13N5O: C, 62.91; H,

4.90; N, 26.20. Found: C, 63.14; H, 4.75; N, 26.56.

N,N-Dibenzyl-1H-1,2,3-benzotriazole-1-carboximidamide (2.4b). Colorless oil

(55%); 1H NMR δ 4.49 (s, 4H), 7.25–7.36 (m, 11H), 7.40–7.50 (m, 1H), 7.53–7.59 (m,

1H), 7.69 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H); 13C NMR δ 51.7, 111.0, 120.3,

124.9, 127.7, 127.9, 128.7, 129.2, 132.1, 136.2, 145.7, 152.0. Anal. Calcd for C21H19N5:

C, 73.88; H, 5.61; N, 20.51. Found: C, 74.16; H, 5.77; N, 20.97.

N-Butyl-1H-1,2,3-benzotriazole-1-carboximidamide (2.4i). Off-white

microcrystals (92%), mp 56–58 °C; 1H NMR (DMSO-d6) δ 0.98 (t, J = 7.1 Hz, 3H),

1.50–1.52 (m, 2H), 1.66–1.70 (m, 2H), 3.33 (t, J = 6.8 Hz, 2H), 7.06 (br s, 2H), 7.53 (t, J

= 7.3 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H);

13C NMR (DMSO-d6) δ 13.9, 20.3, 33.0, 46.3, 115.2, 119.2, 124.9, 128.7, 131.0, 144.8,

145.8. Anal. Calcd for C11H15N5: C, 60.81; H, 6.96; N, 32.23. Found: C, 61.25; H, 7.13;

N, 32.49.

17

N’-(4-Chlorophenyl-1H-1,2,3-benzotriazole-1-carboximidamide (2.4j). Off-

white microcrystals (45%), mp 146–148 °C; 1H NMR δ 5.76 (br s, 2H), 7.05 (d, J = 8.4

Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.1 Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 8.12

(d, J = 8.1 Hz, 1H), 8.51 (d, J = 8.1 Hz, 1H); 13C NMR δ 115.3, 119.8, 123.2, 125.3,

129.1, 129.5, 129.7, 131.2, 144.2, 145.2, 146.7. Anal. Calcd for C13H10ClN5: C, 57.47; H,

3.71; N, 25.78. Found: C, 57.93; H, 3.64; N, 25.56.

General Procedure for the Preparation of Compounds 2.3a–d,f–j from 2.4a–

d,f–j. Hydrogen sulfide was bubbled into THF (40 mL) for 2 minutes under dry

conditions. The (benzotriazol-1-yl)carboximidamide 2.4 (2.0 mmol) was added and the

reaction mixture was stirred at room temperature for 1 h (for 2.3b–c,f–i) under a flow of

hydrogen sulfide. Completion of the reaction was monitored by TLC.

For compounds 2.3a,d,j the reaction was very slow at room temperature. After

bubbling hydrogen sulfide into the reaction mixture for 1 h at room temperature, the

hydrogen sulfide flow was stopped and the reaction mixture was allowed to react at 90 °C

for 4 h in a sealed tube. The solvent was removed under reduced pressure and the residue

was dissolved in dichloromethane and washed with 10 % aqueous Na2CO3. The organic

layer was separated, dried over anhydrous MgSO4 and concentrated under reduced

pressure. For thioureas 2.3b,c,g no further purification was required; 2.3d,f,h–j were

purified by gradient column chromatography on silica gel with ethyl acetate/hexanes

from 1/6 to 1/1.

Compound 2.3a precipitated from the reaction mixture, was filtered and washed

with hexanes.

18

p-Methoxyphenylthiourea (2.3a). Off-white microcrystals (59%), mp 209–210 °C

(lit. mp 210–210 °C [60JOC770]); 1H NMR (DMSO-d6) δ 3.74 (s, 3H), 6.90 (d, J = 8.8

Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.24–7.62 (m, 2H, NH2), 9.48 (s, 1H, NH); 13C NMR

(DMSO-d6) δ 55.2, 114.0, 125.6, 131.7, 156.6, 181.1.

N,N-Dibenzylthiourea (2.3b). White microcrystals (86%), mp 137–138 °C (lit. mp

138–139 °C [79CB1956]); 1H NMR δ 4.92 (br s, 4H), 5.84 (br s, 2H), 7.26–7.39 (m,

10H); 13C NMR δ 54.6, 126.9, 127.9, 129.0, 135.2, 183.8.

1-Thiocarbamoylpyrrolidine (2.3c). Off-white microcrystals (54%), mp 194–

196 °C (lit. mp 193–197 °C [56AC545]); 1H NMR (DMSO-d6) δ 1.80–1.92 (m, 4H),

3.27–3.38 (m, 2H), 3.54–3.60 (m, 2H), 7.09 (br s, 2H); 13C NMR (DMSO-d6) δ 24.6,

25.9, 47.5, 51.4, 178.3.

Phenylthiourea (2.3d). White microcrystals (71%), mp 153–154 °C (lit. mp 154–

154 °C [60JOC770]); 1H NMR (acetone-d6) δ 6.90–7.10 (m, 4H), 7.20 (t, J = 7.2 Hz,

1H), 7.35–7.46 (m, 4H), 9.16 (br s, 1H); 13C NMR (acetone-d6) δ 124.8, 126.3, 130.0,

139.7, 183.3.

4-Thiocarbamoylmorpholine (2.3f). White microcrystals (99%), mp 159–161 °C

(lit. mp 160–161 °C [72USP3700664]); 1H NMR (DMSO-d6) δ 3.55–3.58 (m, 4H), 3.70–

3.73 (m, 4H), 7.50 (br s, 2H); 13C NMR (DMSO-d6) δ 47.9, 66.0, 182.7.

1,1-Diethylthiourea (2.3g). Light-yellow microcrystals (92%), mp 82–84 °C (lit.

mp 98–101 °C [01TL6333]); 1H NMR δ 1.18 (t, J = 7.1 Hz, 6H), 3.58 (br s, 4H), 5.91 (br

s, 2H); 13C NMR δ 12.3, 46.0, 180.3.

Benzylthiourea (2.3h). Colorless microcrystals (76%), mp 154–155 °C (lit. mp

155–156°C [88LAC983]); 1H NMR (DMSO-d6) δ 4.66 (s, 2H), 6.60 (s, 1H), 7.11 (br s,

19

1H), 7.28–7.39 (m, 5H), 8.03 (br s, 1H); 13C NMR (DMSO-d6) δ 47.5, 127.0, 127.4,

128.4, 139.3, 183.5.

Butylthiourea (2.3i). White microcrystals (94%), mp 67–69 °C (lit. mp 71–72 °C

[71P3155]); 1H NMR δ 0.94 (t, J = 7.3 Hz, 3H), 1.36–1.43 (m, 2H), 1.55–1.65 (m, 2H),

3.20 (br s, 2H), 5.88 (br s, 2H), 6.39 (br s, 1H); 13C NMR δ 13.5, 19.9, 30.5, 44.2, 44.9,

180.4, 182.8 (mixture of rotamers).

(4-Chlorophenyl)thiourea (2.3j). Off-white microcrystals (21%), mp 178–179 °C

(lit. mp 180–181 °C [00JMC2362]); 1H NMR (DMSO-d6) δ 7.37–7.51 (m, 6H), 9.78 (s,

1H); 13C NMR (DMSO-d6) δ 124.6, 128.1, 128.5, 138.2, 181.2.

20

CHAPTER 3 EFFICIENT C-SULFONYLATION OF NITRILES AND SULFONES WITH 1-

SULFONYLBENZOTRIAZOLES

3.1 Introduction

Sulfones are one of the fundamental classes of intermediates in organic synthesis

[88MI, 93MI, 97CL1023] and have wide applicability in fields as diverse as

agrochemicals [88USP4780127], pharmaceuticals [90JOC955, 03USP6525042] and

polymers [93USP5260489]. Sulfones have been described as “chemical chameleons” and

therefore have sustained the interest of chemists all over the world. The sulfonyl group

has the ability to serve as a temporary transformer of chemical reactivity [84JA7260], it

can function as an electrophile via the sulfur atom or as a leaving group (Figure 3-1)

[94TL6017]. This, coupled with its powerful stabilizing properties for the adjacent

carbanions in carbon-carbon bond forming reactions [94JOC2014, 97CL1025,

97JCSCC1210, 97T307], gives sufficient driving force to the intramolecular nucleophilic

substitution in the formation of cyclopropanes [69JOC3085, 75JCSP(1)897].

R1

CR2

RO2S H =R1

CR2

Figure 3-1. Sulfonyl Group, a Termporary Transformer of Chemical Reactivity.

1-Sulfonylbenzotriazoles have been previously used in the preparation of N-

acylbenzotriazoles [00JOC8210]. They also act as an activating moiety of aldehydes in

the benzotriazolylalkylation of aromatic compounds (Scheme 3-1) [94H345].

21

RCO2H, Et3N

THF, r.t.

PhSO2Bt

3.1aAr1CHO

Ar2H

Ar1

Ar2 BtRCOBt

Scheme 3-1. 1-Sulfonylbenzotriazoles 3.1 as Activating Reagents in N-Acylation of

Benzotriazole and Benzotriazolylalkylation of Aromatic Compounds.

1-Sulfonylbenzotriazoles have also been used as effective N-sulfonylation agents of

amines and O-sulfonylation agents of phenols to give the corresponding sulfonamides

and sulfonates, respectively (Scheme 3-2) [94SC205, 04JOC1849].

THFR1SO2Bt + NHR2R3 r.t.

R1 = aryl, alkyl, heteroaryl

THFR1SO2Bt + NHR2R3 r.t.

15 examples (yield: 51-99%)

THFR1SO2Bt + ArOH R1SO3Arr.t.

10 examples (yield: 51-99%)R1 = aryl, alkyl

3.1

3.1

R1SO2NR2R3R1SO2NR2R3

Scheme 3-2. 1-Sulfonylbenzotriazoles 3.1 as Effective Reagents for N-Sulfonylation of

Amines and O-Sulfonylation of Phenols.

Using this approach, C-sulfonylation with 1-sulfonylbenzotriazoles was

investigated. Novel syntheses of α-cyano sulfones and α-sulfonyl sulfones, which are not

easily available by known methods i.e. via classic sulfonylation of nitriles and sulfones,

are developed in this chapter.

3.2 Results and Discussion

3.2.1 Preparation of Sulfonylbenzotriazoles 3.1

Sulfonylbenzotriazoles 3.1 were prepared according to the literature procedures

[92T7817]. The reaction of alkyl or aryl sulfonyl chlorides with benzotriazole in the

presence of pyridine afforded the corresponding alkyl- and arylsulfonylbenzotriazoles

3.1a–e, while the reaction of organolithium reagents with sulfur dioxide at –78 oC gave

22

lithium sulfinates that reacted with N-chlorobenzotriazole in the presence of triethylamine

to give heteroarylsulfonylbenzotriazoles 3.1f–i (Scheme 3-3, Table 3-1) [04JOC1849].

RSO2Cl BtSO2R RLiBtH, C5H5N

R = alkyl or aryl3.2 3.1a-g

i) SO2ii) BtCl, NEt3R = heteroaryl

3.3method A method B

Scheme 3-3. Preparation of 1-Sulfonylbenzotriazoles 3.1a–i. Table 3-1. Synthesis of 1-Sulfonylbenzotriazoles 3.1a–i from Corresponding Alkyl or

Aryl Sulfonyl Chlorides 3.2 or Organolithium Reagents 3.3. Prodcut R Method Yield (%) 3.1a Methyl A 97 3.1b 4-Tolyl A 78 3.1c Phenyl A 81 3.1d Butyl A 81 3.1e 4-NO2C6H4 A 87 3.1f 2-Thienyl B 82 3.1g 2-Pyridinyl B 71 3.1h 3-Pyridinyl B 52 3.1i Benzofur-2-yl B 81 3.2.2 Synthesis of α-Cyano Sulfones

α-Cyano sulfones are important precursors in synthetic chemistry [77S690,

80S565, 92S552, 94JOC1518, 95SL645, 96SL1067, 97JOC4562]. They are utilized in

the preparation of numerous compounds, including pyridones [99S1169], 4-

aminopyrimidines [84S1045], 5,6-dihydro-4H-pyrans [75S260], tetrahydrofurans,

[98JOC3067] tetrasubstituted cylcobutanes [75S260], and cyclopropanes [85JOC2806,

03CC536]. In addition, they are also valuable building blocks for constructing

biologically active compounds such as β-amido sulfones [39JA3386] and L-indospicines

[96BMCL111].

Published synthetic routes to α-cyano sulfones include (Scheme 3-4): (i) oxidation

of the corresponding sulfides [87S453]; (ii) alkylation of benzenesulfinate salts with α-

23

halo nitriles either under the conditions of anionic activation [77S690, 84JOC1125] or

heat in two-phase system (solid-liquid) in the presence of phase-transfer catalyst [87S56]

or alkylation of phenyl sulfonyl chloride with α-halo acetonitriles in the presence of

sodium diethylphosphorotellurite [90SC2291]; (iii) Cp2TiCl2-catalyzed addition of

Reformatsky reagents to geminal cyanosulfonylalkenes [01SC2089] and (iv)

sulfonylation of nitriles with phenyl tosylate [95SC4063]. Although these synthetic

approaches are of great utility for specific classes of the title compounds, there are

drawbacks. Method (i) suffers from foul smelling starting material while approaches (ii)

and (iii) require α-halo nitriles and geminal cyanosulfonylalkenes which are not usually

readily available. They are also limited by their functional tolerance. The method (iv) was

reported for the tosylation of arylacetonitriles only.

R1

CNRSO3Ph

RS

R1

CN

RS

O

OR1

CN

RSO2

R3 R2

CN

R1

CNHal

RSO2Cl or RSO2Na

Oxidation(i)

+(ii)

(iii)

R = p-tolyl(iv)

+ R4ZnX

R1 = CR2 R3R4R = aryl, R1 = H R2 = R3

Scheme 3-4. Known Approaches to α-Cyano Sulfones.

With the objective to develop a general and efficient route to α-cyano sulfones, the

reactions of nitriles 3.4 with 1-sulfonylbenzotriazoles 3.1 were investigated. It was found

that 1-sulfonylbenzotriazoles 3.1 reacted with nitriles 3.4 smoothly in the presence of

24

either n-BuLi or t-BuOK to afford the desired α-cyano sulfones in good to high yields

(Scheme 3-5, Table 3-2).

R1

CN

2) BtSO2R

3.4a-f A) n-BuLi, THF, -78 0CB) t-BuOK, DMSO, r.t.

3.5a-i

R2

R1CNR2

RO2S

1) Base

Scheme 3-5. A Novel Approach to α-Cyano Sulfones 3.5a–i. Table 3-2. Preparation of α-Cyano Sulfones 3.5a−i via C-Sulfonylation of Nitriles 3.4a–f

with Sulfonylbenzotriazoles 3.1a–f. Product R R1 R2 Method Yield (% ) 3.5a Phenyl Phenyl H A 76 3.5b Phenyl H H A 50 3.5c 2-Thienyl 2,4-Cl2C6H3 H A 90 3.5d 2-Pyridinyl n-Hexyl H A 54 3.5e 3-Pyridinyl Phenyl Methyl A 73 3.5f Methyl 4-BrC6H4 H B 82 3.5g* Methyl 2,4-Cl2C6H3 H B 87 3.5h* 4-Tolyl 4-BrC6H4 H A 93 3.5i* 4-Tolyl 2,4-Cl2C6H3 H B 97 *: compounds 3.5f,g,h,i were prepared by Dr. Ashraf A. A. Abdel-Fattah, which were not included in experimental part. Spectroscopic and analytical data of these compounds are available in the corresponding published paper [05JOC9191].

Initially, 4-bromophenyl acetonitrile 3.4f was successively treated with 1.2 molar

equivalents n-butyllithium and 1-(4-tolyl)sulfonyl benzotriazole 3.1b at –78 oC in THF.

The reaction mixture was allowed to stir at room temperature overnight. Aqueous workup

gave 4-bromophenyl(toluene-4-sulfonyl)acetonitrile 3.5h in 43% yield along with about

50% of the starting material nitrile 3.4a. The yield of 3.5h was improved to 93% by using

two-fold excess of n-butyllithium. To simplify the procedure, the reaction of nitrile 3.4f

with 3.1b was examined in the presence of of t-BuOK in DMSO (2 eq.) at room

temperature. This reaction proceeded smoothly and provided α-cyano sulfone 3.5h in

88% yield. The use of a two-fold excess of either n-BuLi in THF at –78 oC or t-BuOK in

25

DMSO at room temperature proved effective for the sulfonylation of nitriles. The

reactions of 1-sulfonylbenzotriazoles 3.1a–f with nitriles 3.4a−f were performed under

these optimized conditions. In all cases, the reaction proceeded smoothly to give the

corresponding α-cyano sulfones 3.5a−i (Scheme 3-5 and Table 3-1). Success with a wide

range of 1-sulfonylbenzotriazoles and nitriles demonstrates the general applicability of

this procedure. It can be used for alkylsulfonylbenzotriazoles for preparation of α-

cyanoalkyl sulfones 3.5f,g in 82% and 87% yields, respectively.

Arylsulfonylbenzotriazoles were also used to convert acetonitrile itself or α-

arylacetonitriles into the corresponding sulfonylated products 3.5a,b,h,i in 50−97%

yields. Heterocyclic sulfonylating reagents, 1-(2-thienyl, 2-pyridinyl-, or 3-

pyridinyl)sulfonylbenzotriazoles 3.1d–f, reacted with a variety of nitriles to give the

desired products 3.5c−e in 54−90% yields.

The structures of compounds 3.5a−i were supported by NMR spectral data and

elemental analyses. The 1H NMR and 13C NMR spectra of α-cyano sulfones 3.5a−i

showed characteristic signals in the regions 4.10−5.85 ppm and 45.7−62.5 ppm which

were assigned to the proton and carbon alpha to the cyano group.

3.2.3 Synthesis of α-Sulfonyl Sulfones

α-Sulfonyl methyl sulfones are valuable intermediates in the synthesis of

carbocycles [02JOC922, 02JOC5197, 04AGIE2402], and heterocycles [97JCS(P1)695].

They are also reactive substrates in Ramberg-Backlund olefinations [86JA2358,

87JOC1703], Knoevenagel condensation [91S1205] and metal-catalyzed cross-coupling

reactions [98JOC9608, 03EJOC1064]. In addition, some α-sulfonyl sulfones are useful

for the synthesis of α-aryl propanoic acids, ibuprofen analogs [03JMC3].

26

In spite of these applications, approaches to their syntheses are scarce: the well-

known route to α-sulfonyl sulfones involves the oxidation of the corresponding disulfides

[00T8263] or α-sulfonyl sulfides [89JA779]. The lack of available methods prompts us to

study the generality of the benzotriazole-mediated C-sulfonylation methodology. A high

yielding and general method to a diverse range of target molecules is herein reported.

Treatment of sulfones 3.6 with 2 molar equivalents of n-BuLi at –78 oC followed

by the addition of 1-sulfonyl]benzotriazole 3.1 gave the corresponding α-sulfonyl

sulfones in moderate to excellent yields (Scheme 3-6 and Table 3-3).

R3

SO2R4 2) BtSO2R3.1a,b,d,e,g

1) n-BuLi, THF

3.6a-d

R3

SO2R4RO2S

3.7a-g

Scheme 3-6. A Novel Approach to α-Sulfonyl Sulfones. Table 3-3 Preparation of α-Sulfonyl Sulfones 3.7a−g via C-Sulfonylation of Sulfones

3.6a–d with Sulfonylbenzotriazoles 3.1a,b,d,e,g. Product R R3 R4 Yield (%) 3.7a Phenyl Methyl Ethyl 91 3.7b 2-Pyridinyl Methyl Ethyl 87 3.7c Benzofur-2-yl (-CH2-)3 67 3.7d 2-Thienyl Ethyl Ethyl 71 3.7e* 4-Tolyl Phenyl Phenyl 96 3.7f* 4-Tolyl H Phenyl 87 3.7g* 4-Tolyl (-CH2-)3 78 *: compounds 3.7e,f,g were prepared by Dr. Ashraf A. A. Abdel-Fattah, which were not included in experimental part. Spectroscopic and analytical data of these compounds are available in the corresponding published paper [05JOC9191].

3.3 Conclusion

A high yielding and convenient method for the syntheses of two classes of C-

sulfonylated products has been developed by the treatment of 1-sulfonylbenzotriazoles

with appropriate nitriles and sulfones. In general, the use of 1-sulfonylbenzotriazoles as

27

C-sulfonylating agents compared with sulfonyl halides is advantageous because of their

neutral character, easy accessibility and high stability. In addition, the approach offers a

general protocol for the preparation of a variety of α-cyano sulfones and α-sulfonyl

sulfones where the corresponding sulfonyl halides or sulfides are not readily available.

The present procedure, combining readily available reagents, simple manipulations and

high yields, should be valuable for obtaining the targeted sulfone derivatives. The present

work provides additional evidence for the good leaving ability of a benzotriazole group.

3.4 Experimental Section

General. Melting points were determined by a capillary melting point apparatus

equipped with a digital thermometer and Bristoline hot-stage microscope and were

uncorrected. NMR spectra were recorded in CDCl3 or DMSO-d6 with tetramethylsilanes

as internal standard for 1H (300 MHz) or as the internal standard for 13C (75 MHz). The

elemental analyses were performed on a Carlo Erba EA–1108 instrument.. Anhydrous

THF was freshly distilled over sodium/benzophenone before use. Column

chromatography was conducted on silica gel 200-245 mesh.

General procedure for the preparation of sulfonylbenzotriazoles 3.1.

Method A: The mixture of benzotriazole (20 mmol), alkyl or aryl sulphonyl

chloride (20 mmol) and pyridine (28 mmol) in methylene chloride (50 mL) was stirred at

room temperature for 10 h. After quenching the reaction by adding water (50 mL), the

product was extracted with ethyl acetate (3×30 mL). The combined organic layer was

dried over anhydrous MgSO4. After evaporation of solvent under reduced pressure, the

residue was recrystallized from ethyl acetate to give pure products 3.1a–e.

28

Method B: A solution of heteroaryl compound (35 mmol) in anhydrous THF (120

mL) was cooled to -78 oC under nitrogen and then treated dropwise with n-BuLi (21.8

mL of 1.55 M in hexanes, 35 mmol) to afford a clear solution, which was stirred at this

temperature for 15 minutes, and then at room temperature for 1 h. Sulfur dioxide was

bubbled into the reaction mixture at -78 oC and stirred at this temperature for 15 minutes,

and then at room temperature for 1 h. N-Chlorobenzotriazole (5.4 g, 35 mmol) was added

in one portion at room temperature. The mixture was stirred for 2 h. Triethylamine (5.3

mL, 40 mmol) was added followed by stirring at room temperature for 10 h. Water (300

mL) was added to the reaction mixture, and the product was extracted with ethyl acetate

(3×300 mL). The combined organic layers were washed with water and brine and dried

over anhydrous MgSO4. After evaporation of solvent under reduced pressure, the residue

was recrystallized from ethyl acetate to give pure products 3.1f–i.

1-(Methylsulfonyl)-1H-1,2,3-benzotriazole (3.1a). Colorless microcrystals (97%),

mp 109−111 oC (Lit. mp 110-112 oC [00JOC8210]); 1H NMR δ 8.15 (d, J = 8.4 Hz, 1H),

8.01 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 3.52 (s, 3H).

13CNMR δ 145.2, 131.6, 130.5, 126.0, 120.6, 111.9, 42.8.

1-(4-Methylbenzenesulfonyl)-1H-1,2,3-benzotriazole (3.1b). Colorless

microcrystals (78%), mp 126−129 oC (Lit. mp 128-129 oC [92T7817]); 1H NMR δ 8.13-

8.06 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.66 (dt, J = 7.8, 0.8 Hz, 1 H), 7.47 (dt, J = 7.8,

0.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H). 13CNMR δ 146.8, 145.5, 134.0, 131.6,

130.3, 130.2, 128.0, 125.8, 120.6, 112.1, 21.8.

1-(Benzensulfonyl)-1H-1,2,3-benzotriazole (3.1c). Colorless microcrystals (81%),

mp 124−125 oC (Lit. mp 123-126 oC [92T7817]); 1H NMR δ 8.07-8.14 (m, 4H), 7.64-

29

7.70 (m, 2H), 7.46-7.57 (m, 3H). 13CNMR δ 145.4, 139.4, 137.0, 135.2, 130.3, 129.7,

127.9, 125.9, 120.6, 112.0.

1-(Butane-1-sulfonyl)-1H-1,2,3-benzotriazole (3.1d). Yellow microcrystals

(78%), mp 32−34 oC (Lit. yellow oil [04JOC1849]); 1H NMR δ 8.17 (d, J = 8.3 Hz, 1H),

8.02 (d, J = 8.3 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.56-7.51 (m, 1H), 3.65-3.6-0 (m, 2H),

1.77-1.69 (m, 2H), 1.45-1.37 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13CNMR δ 145.1, 132.2,

130.4, 125.9, 120.6, 111.9, 55.4, 24.7, 21.1, 13.2.

1-(4-Nitrobenzenesulfonyl)-1H-1,2,3-benzotriazole (3.1e). Yellow microcrystals

(87%), mp 172−174 oC; 1H NMR δ 8.40-8.32 (m, 4H), 8.11 (d, J = 8.3 Hz, 2H), 7.75-7.70

(m, 1H), 7.57-7.51 (m, 1H). 13CNMR δ 151.3, 145.4, 142.2, 131.4, 130.9, 129.4, 126.4,

124.9, 120.9, 111.7. Anal. Calcd. For C12H8N4O4S: C, 47.37; H, 2.65; N, 18.41. Found:

C, 47.65; H, 2.53; N, 18.34.

1-(2-Thienylsulfonyl)-1H-1,2,3-benzotriazole (3.1f). Purple microcrystals (82%),

mp 143−144 oC (Lit. mp 143-144 oC [04JOC1849]); 1H NMR δ 8.12-8.11 (m, 1H), 8.09-

8.08 (m, 1H), 7.96 (dd, J = 3.8, 1.4 Hz, 1H), 7.75 (dd, J = 5.0, 1.4 Hz, 1H), 7.72-7.67 (m,

1H), 7.54-7.49 (m, 1H), 7.14-7.11 (m, 1H). 13CNMR δ 145.4, 138.5, 136.2, 135.8, 131.3,

130.4, 128.2, 126.0, 120.6, 112.0.

1-(2-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.1g). Light red microcrystals

(71%), mp 132−133 oC (Lit. mp 133-135 oC [04JOC1849]); 1H NMR δ 8.59 (d, J = 4.7

Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.02

(td, J = 7.9, 1.8Hz, 1H), 7.73-7.67 (m, 1H) 7.59-7.49 (m, 2H). 13CNMR δ 154.6, 150.7,

145.3, 138.7, 132.6, 130.4, 128.7, 125.9, 123.3, 120.3, 112.6.

30

1-(3-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.1h). Colorless microcrystals

(52%), mp 128−129 oC (Lit. mp 129 oC [04JOC1849]); 1H NMR δ 9.30 (d, J = 2.0 Hz,

1H), 8.87 (d, J=3.8Hz, 1H), 8.42 (d, J = 8.2 Hz, 1H), 8.14-8.10 (m, 2H), 7.71 (t, J = 5.5

Hz, 1H), 7.55-7.50 (m, 1H). 13CNMR δ 155.5, 148.4, 145.4, 135.7, 134.0, 131.5, 130.8,

126.3, 124.1, 120.8, 111.8.

1-(Benzofuran-2-ylsulfonyl)-1H-1,2,3-benzotriazole (3.1i). Colorless

microcrystals (81%), mp 147−148 oC; 1H NMR δ 8.16 (d, J = 8.4 Hz, 1H), 8.12 (d, J =

8.4 Hz, 1H), 7.86 (s, 1H), 7.75−7.70 (m, 2H), 7.56−7.46 (m, 3H), 7.38-7.32 (m, 1H).

13CNMR δ 156.5, 145.5, 131.6, 130.7, 129.4, 126.2, 125.2, 124.9, 123.6, 120.7, 116.9,

112.7, 112.2. Anal. Calcd. For C14H9N3O3S: C, 56.18; H, 3.03; N, 14.04. Found: C, 56.4;

H, 2.83; N, 14.12.

General procedure for the preparation of α-cyano sulfones 3.5a-f.

Method A: A solution of the nitrile 3.4 (2 mmol) in anhydrous THF (15 mL) was

cooled to -78 oC under nitrogen and then treated dropwise with n-BuLi (2.6 mL of 1.55

M in hexanes 4 mmol) to afford a clear solution, which was stirred at this temperature for

1 h. A solution of 1-sulfonylbenzotriazole 3.1 in anhydrous THF (5–10 ml) was added

dropwise to the stirred mixture. The reaction mixture was allowed to warm to room

temperature while stirring overnight. After quenching the reaction by addition of

saturated aqueous NH4Cl, the product was extracted with ethyl acetate. The organic

extract was washed with 10 % aqueous Na2CO3 and brine, and dried over anhydrous

MgSO4. After evaporation of solvent under reduced pressure, the residue was purified by

flash chromatography (hexanes/ethyl acetate, 5/1) to afford the desired product 3.5.

31

Method B: A mixture of nitrile 3.4 (2 mmol) and t-BuOK (0.45 g, 4 mmol) in

DMSO (10 mL) was stirrred below 10 oC for 10 minutes. After addition of 1-

sulfonylbenzotriazole 3.3 (2 mmol) in DMSO (5 mL), the mixture was allowed to warm

to room temperature and stirred for 8 h. The mixture was poured into water (40 mL),

acidified with NH4Cl and then extracted with ethyl acetate (3×30 mL). The extracts were

washed with water, dried over anhydrous Na2SO4 and the solvent removed under reduced

pressure. The residue was purified by flash chromatography (hexanes/ethyl acetate, 5/1)

on silica gel to give the pure product 3.5.

Benzenesulfonyl-phenyl-acetonitrile (3.5a). Colorless crystals (76%), mp

148−150 oC (Lit. mp 147.0-148 oC [03JOC8003]); 1H NMR δ 7.73−7.70 (m, 3H),

7.55−7.26 (m, 7H), 5.14 (s, 1H). 13CNMR δ 135.2, 134.3, 130.5, 130.1, 129.7, 129.2,

129.0, 125.3, 113.4, 63.1. Anal. Calcd. For C14H11NO2S: N, 5.44. Found: N, 5.71.

Benzenesulfonyl acetonitrile (3.5b). Colorless crystals (50%), mp 87−88 °C (lit.

mp 88 °C [70CB2775]); 1H NMR δ 8.06−8.02 (m, 2H), 7.82−7.77 (m, 1H), 7.69−7.64

(m, 2H), 4.10 (s, 2H). 13CNMR δ 136.6, 135.4, 129.8, 128.8, 110.4, 45.7. Anal. Calcd.

For C8H7NO2S: C, 53.03; H, 3.89; N, 7.73. Found: C, 53.09; H, 3.81; N, 7.62.

2,4-Dichlorophenyl(thiophene-2-sulfonyl)acetonitrile (3.5c). Pale yellow plates

(90%), mp 142−144 oC; 1H NMR δ 7.91 (d, J = 4.9 Hz, 1H), 7.73 (d, J = 3.8 Hz, 1H),

7.48 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 7.25

(dd, J = 4.9, 3.3 Hz, 1H), 5.85 (s, 1H). 13C NMR δ 137.9, 137.8, 137.5, 135.9, 134.6,

131.8, 130.1, 128.6, 128.1, 122.7, 112.8, 59.4. Anal. Calcd. For C12H7Cl2NO2S: C, 43.38;

H, 2.12; N, 4.22. Found: C, 43.43; H, 2.01; N, 4.07.

32

2-Methyl-2-(2-pyridinylsulfonyl)hexanenitrile (3.5d). Red oil (54%); 1H NMR δ

8.82− 8.80 (m, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.06 (td, J = 7.8, 1.6 HZ, 1H), 7.67(dd, J =

7.7, 4.8 Hz, 1H), 4.64 (dd, J = 10.2, 5.0 Hz, 1H), 2.25−2.13 (m, 2H), 1.76−1.50 (m, 2H),

1.45−1.21 (m, 6H), 0.90 (t, J = 6.6 Hz, 3H). 13C NMR δ 154.5, 150.5, 138.6, 128.5,

123.6, 113.4, 63.1, 31.0, 28.2, 26.4, 25.0, 22.2, 13.8. Anal. Calcd. For C13H18N2O2S: C,

58.62; H, 6.81; N, 10.52. Found: C, 59.39; H, 7.13; N, 10.48.

2-Phenyl-2-(3-pyridinylsulfonyl)propanenitrile (3.5e). Colorless microcrystals

(73%), mp 121−122 oC; 1H NMR δ 8.85 (dd, J = 4.9, 1.7 Hz, 1H), 8.57 (d, J = 2.2Hz,

1H), 7.95 (d, J = 8.0 Hz, 1H), 7.46−7.37 (m, 6H), 2.28 (s, 3H). 13C NMR δ 155.1, 150.8,

138.3, 130.6, 130.1, 129.5, 129.0, 128.1, 123.4, 116.8, 67.2, 19.2. Anal. Calcd. For

C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.77; H, 4.44; N, 10.05.

4-Bromophenyl methanesulfonyl acetonitrile (3.5f). Colorless plates (82%), mp

111−113 oC; 1H NMR δ 7.64 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.7 Hz, 2H), 5.07 (s, 1H),

3.07 (s, 3H). 13C NMR δ 132.8, 131.1, 125.7, 123.4, 113.0, 60.5, 38.1. Anal. Calcd. For

C9H8BrNO2S: C, 39.43; H, 2.94; N, 5.11. Found: C, 39.60; H, 2.84; N, 5.00.

General procedure for the preparation of α-sulfonyl sulfones 3.7a-d. A solution

of the sulfone 3.6 (2 mmol) in anhydrous THF (15 mL) was cooled to -78 oC under

nitrogen and thereafter treated dropwise with n-BuLi (2.6 mL of 1.55 M in hexane, 4

mmol) to afford a clear solution, which was stirred at this temperature for 1h. Then

sulfonylbenzotriazole 3.1 (dissolved in 5–10 mL anhydrous THF) was added dropwise.

The reaction mixture was allowed to warm to room temperature while stirring overnight.

After the reaction was quenched by addition of saturated aqueous NH4Cl, the reaction

mixture was extracted with ethyl acetate. The organic extracts were combined, washed

33

with 10% aqueous Na2CO3 and brine, and dried over anhydrous MgSO4. After

cencetration under vacuum, the residue was purified by flash chromatography

(hexanes/ethyl acetate, 5/1) to afford the desired product 3.7.

(1-Ethanesulfonyl-ethanesulfonyl)benzene (3.7a). Colorless crystals (91%), mp

96−97 oC (Lit. mp 93−94 oC [74LAC1315]); 1H NMR δ 7.97 (d, J = 7.4 Hz, 2H),

7.76−7.71 (m, 1H), 7.63−7.58 (m, 2H), 4.38 (q, J = 7.4 Hz, 1H), 3.67−3.47 (m, 2H), 1.69

(d, J = 7.3 Hz, 3H), 1.49 (t, J = 7.4 Hz, 3H). 13C NMR δ 135.7, 134.9, 130.1, 129.1, 76.0,

48.2, 9.5, 6.2. Anal. Calcd. For C10H14O4S2: C, 45.78; H, 5.38. Found: C, 45.73; H, 5.37.

2-(1-Ethanesulfonyl-ethanesulfonyl)-pyridine (3.7b). Red microcrystals (87%),

mp 118−120 oC; 1H NMR δ 8.77 (br d, J = 4.5 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.04−

7.99 (m, 1H), 7.64−7.60 (m, 1H), 5.14 (q, J = 7.6 Hz, 1H), 3.60−3.33 (m, 2H), 1.86 (d, J

= 7.5 Hz, 3H), 1.45 (t, J = 7.6 Hz, 3H). 13C NMR δ 155.8, 150.2, 138.3, 128.0, 123.4,

72.4, 46.7, 8.8, 5.5. Anal. Calcd. For C9H13NO4S2: C, 41.05; H, 4.98; N, 5.32. Found: C,

41.20; H, 4.94; N, 5.17.

2-(1-Benzofuran-2-ylsulfonyl)tetrahydrothiophene-1,1-dione (3.7c). Colorless

crystals (67%), mp 147−148 °C; 1H NMR δ 7.97 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.82

(d, J = 8.1 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 5.42 (t, J = 8.5 Hz,

1H), 3.42−3.35 (m, 1H), 3.28−3.18 (m, 1H), 2.54−2.46 (m, 2H), 2.25−2.17 (m, 1H),

2.07−1.99 (m, 1H). 13CNMR δ 155.8, 148.3, 129.1, 125.6, 124.0, 117.1, 112.6, 76.7,

52.4, 25.3, 19.0. Anal. Calcd. For C12H12O5S2: C, 47.99; H, 4.03. Found: C, 47.58; H,

4.15.

Ethyl 1-(2-thienylsulfonyl)ethyl sulfone (3.7d). Yellow oil (71%); 1H NMR δ

7.87 (dd, J = 4.9, 1.2 Hz, 1H), 7.83 (dd, J = 3.8, 1.2 Hz , 1H), 7.22 (dd, J = 4 .8, 4.0 Hz,

34

1H), 4.50 (q, J = 7.3 Hz, 1H), 3.62-3.46 (m, 2H), 1.75 (d, J = 7.3 Hz, 3H), 1.47 (t, J = 7.4

Hz, 3H). 13C NMR δ 137.4, 136.4, 135.5, 128.0, 76.1, 48.3, 9.5, 6.0. Anal. Calcd. For

C8H12O4S3: C, 35.80; H, 4.51. Found: C, 35.95; H, 4.37.

35

CHAPTER 4 NOVEL SYNTHESES OF γ-AMINO ACID DERIVATIVES UTILIZING N-

PROTECTED AMINOACYLBENZOTRIAZOLES FROM GLUTAMIC ACID

4.1 Introduction

Non-natural γ-amino acids have gained considerable attention due to their

important roles in design and synthesis of bioactive molecules as well as in the study of

biomimetic polymers that contain both secondary and tertiary structural analogous to

those of natural proteins. Typically, γ-amino acids play an important part in the structure

of natural products with antitumor activity such as hapalosin [94JOC7219, 99SL1118,

99TL9309], dolastatin [94JOC6287], caliculins [86JA2780, 91Tl5983], and of various

enzyme inhibitor GABA-analogues (Figure 4-1) [97TL5503]. In addition, they are

attractive starting materials for the formation of peptides with helical secondary

structures [98HCA983, 98JA8569].

Given this significance of γ-amino acids, the development of efficient methods for

the synthesis of enantiomerically pure γ-amino acids is important. Four methods for the

synthesis of γ-amino acids from natural α-amino acids have been reported (Scheme 4-1).

(i) Double Arndt-Eistert homologation [69RC299, 77HCA2747]. However, the Arndt-

Eistert homologation protocol is not suitable for large scale synthesis due to the high cost

of the silver catalyst and difficult handling of the hazardous reagent CH2N2 [02T7991].

Although Longobarbo’s modification provided a method to avoid using the silver catalyst

and CH2N2, the procedure took four steps [95T12337]. (ii) Wittig reaction of

Ph3P=CHCO2Et with aldehydes available from natural α-amino acids followed by

36

reduction, which is limited to γ-alkyl γ-amino acid derivatives [97TL163]. (iii) Reaction

of diethyl potassiomalonate with N-tosylaziridines generated in situ from N,O-ditosyl

protected α-amino alcohols derived from α-amino acids [77CPB29]. However, removal

of N-tosyl group requires harsh reaction conditions (reflux in 47% aqueous HBr), which

may be incompatible with sensitive functionalities [77CPB29]. Smreina et al. reported

the synthesis of γ-substituted γ-amino acid via N-Boc-5-substituted pyrrolidinones

(Scheme 4-1, route iv), but the decarboxylative ring closure requires high temperature (77

to 110 ºC) [97T12867].

NHN

N N

O

NHO

MeO

S

N

OMe

O

O

Dolastatin

O

N

O

OHO

nC7H15

O

O

Hapalosin

MeO NH N

O

OH

O

OO

POHHO

O

OMe

OH

OH

R1R2

R3OH

OH

O

N

Calyculins Figure 4-1. Known Biologically Active Compounds Containing Fragments of γ-Amino

Acid Derivatives.

37

O

OHNH

PGR

NH

PGR

OH

O1) SOCl22) CH2N2

3) H2O/Ag2O 2) CH2N2NH

PGR O

N2 cat. Ag+

NH

PGR

OH

O

R1OMe

O

NH

1) DIBALH, then Ph3P=CHCO2R2

2) Pd/C, H2, MeOHR1

NHOR2

OBase R1

NHOR2

O

EPG PGPG

E+/THFR1 = Bn, iPr, Me, iBu

O

OHH2N

Ph

H2N

Ph

OTsHN

Ph

OH Ts

TsCl

Pyridine NPh

Ts

K2CO3

NH2OH

O1) diethyl potassiomalonate

2) 47% HBr, reflux, 17 hr

Ph

(i)

(ii)

(iii)

O

OHBocHN

R

O

O

OBocHN

RO

O

O

O

BocHN

RO

O

BocN

R

OBocHN

ROH

O

a b c d(iv)

a) Meldrum's acid, DCC, DMAP; b) NaBH4, AcOH; c) Toluene, reflux; d) NaOH, acetone/water.

1) SOCl2

Scheme 4-1. Literature Methods of Synthesis of γ-Amino Acids from α-Amino Acids.

Other reported syntheses of optically pure γ-amino acids from glutamic acid are

(Scheme 4-2): (i) the nucleophilic substitution of iodo derivatives of glutamic acid with

organocuprates [92S1104] and (ii) coupling of organozinc reagent of glutamic acid with

aryl iodides in the presence of Pd [99JOC7579]. However, a major limitation of using

organometallic reagents is the incompatibility with many functionalities [92S1104,

97T12867, 99JOC7579].

The Katritzky research group has investigated 1-acylbenzotriazoles as efficient

acylating agents for N-acylation [98S153, 00JOC8210, 02ARK(viii)134, 02BMC1809,

04ARK(xii)14, 04S2645], C-acylation [00JOC3679, 03JOC1443, 03JOC4932,

03JOC5720, 04CCA175, 04JOC6617], O-acylation [96LA881, 99JHC777, 04JOC6617]

and S-acylation reactions [04S1806]. In particular, 1-acylbenzotriazoles, which are

advantageously stable toward moisture and storable for a long period of time, are

efficient for the C-acylation of electron rich heterocycles, such as indole, pyrrole

[03JOC5720], furan, and thiophene [04CCA175] in the presence of Lewis acids, such as

38

AlCl3. Recently, the preparation of N-TFA- and Fmoc-α-amino ketones by C-acylation of

pyrroles and indoles with chiral N-protected α-aminoacylbenzotriazoles

[02ARK(viii)134, 04S2645, 05S297] was successfully achieved in the presence of AlCl3

with preservation of chirality, as demonstrated by configurational analysis [05JOC4993].

Subsequently, Dr. Rong Jiang and Dr. Kostyantyn Kiricheko in Katritzky’s group

developed a novel synthesis of γ-aryl-β-amino acids 4.6, from L-aspartic acid via (N-

protected) aminoacylbenzotriazoles 4.5 (Scheme 4-3) [1475].

HO OR1

OO

NHPG

i) ClCO2Etii) NaBH4

HO OR1

O

NHPG

i) TsCl/Py

ii) NaI I OR1

O

NHPG

R2Cu/THF

R2 OR1

O

NHPG

i) Hydrolysis

ii) DeprotectionR2 OH

O

NH2

HO OR1

OO

NHPG

NHS, DCCO OR1

OO

NHPG

N

O

O

NaBH4 HO OR1

O

NHPG

I2, PPh3, imidazole

I OR1

O

NHPG

i) Zn, Pd2(dba)3, Ar-I, (o-Tol)3PAr OH

O

NH2ii) Hydrolysisii) Deprotection

i)

ii)

Scheme 4-2. γ-Amino Acids from Glutamic Acid.

Here, a novel and practical method for the synthesis with preservation (>99%) of

the chirality of γ-amino acid derivatives, δ-aryl-γ-amino esters 4.12 and acids 4.13 by the

Friedel-Crafts acylation of aromatics with chiral N-protected (α-aminoacyl)benzotriazoles

39

4.10, readily available from L-glutamic acid, followed by the reduction of formed γ-keto-

γ-amino esters 4.11 is presented.

NH

OOMe

O

TFA

OH

TFA-Asp(OMe)-Bt (4.4)

H2NOOH

O

OH

SOCl2

MeOH H3NOOMe

O

OHCl

CF3COOEt

Et3N, MeOHBtH, SOCl2

CH2Cl2 NHOOMe

O

TFA

Bt80% 87% 91%4.1 4.2 4.3

TiCl4TFA

NH

OOMe

O

ArAromatics

4.5 (45-89%)

reductionTFA

NH

OX

O

Ar

X = H or Me

4.6

TFA = CF3CO

Scheme 4-3. Novel Syntheses of β-amino Acid Derivatives, γ-Aryl-β-amino Acids 4.6. 4.2 Results and Discussion

4.2.1 Preparation of 1-(N-Tfa-α-Aminoacyl)benzotriazoles 4.10

L-Glutamic acid 4.7 reacted with methanol and thionyl chloride to form the δ-mono

methyl amino ester 4.8 in 80% yield (Scheme 4-4) [01CC1710]. Amino ester 4.8 was

protected with N-trifluoroacetyl (TFA) group using ethyl trifluoroacetate in the presence

of Et3N (2 eq.) in methanol to generate N-TFA-glutamic monoester 4.9. [72JOC2805] On

treatment with a mixture of thionyl chloride (4 eq.) and benzotriazole (4 eq.), N-Tfa-

glutamic ester 4.9 gave the corresponding acylbenzotriazole TFA-Glu(OMe)-Bt 4.10 in

93% yield (overall yield: 66%).

NH

OTFA

OH

TFA-Glu(OMe)-Bt (4.10)

H2NO

OH

SOCl2

MeOH H3NO

OHCl

CF3COOEt

Et3N, MeOHBtH, SOCl2

CH2Cl2 NHOTFA

Bt

OHO OMeO OMeO OMeO

80%89% 93%

4.7 4.8 4.9

Scheme 4-4. Preparation of N-(TFA-α-aminoacyl)benzotriazoles, TFA-Glu(OMe)-Bt 4.10.

40

4.2.2 Syntheses of γ-Keto-γ-amino Esters 4.11

Previously, the synthesis of α-amino ketones by Friedel-Craft acylation of N-

heterocycles utilizing chiral N-protected α-aminoacylbenzotriazoles in presence of AlCl3

had been achieved by Katritzky’s research group (Scheme 4-5) [05JOC4993].

PGNH

OH

R

O

BtH, SOCl2 PG NH

Bt

R

O

N-Heterocycles

AlCl3

PGNH

Het

R

O

PG = TFA, Fmoc;R = H, phenyl, indol-3-yl, CH2SMe

Scheme 4-5. Chiral N-Protected α-Aminoacylbenzotriazoles as Acylating Reagents in Friedel-Craft Acylation.

Unfortunately, efforts to extend this method to the preparation of γ-keto-γ-amino

esters 4.11 by acylation of aromatics with TFA-Glu(OMe)-Bt 4.10 under the same

reaction conditions failed. The starting material 4.10 was decomposed in one hour, and

no desired product formed. The results from Lewis acids screening led to TiCl4 as a

promising catalyst (starting materials were recovered when BF3 or ZnBr2 was used). The

reaction of Tfa-Glu(OMe)-Bt 4.10 with aromatics (1.1 eq.) in the presence of TiCl4 (1.5

eq.) at room temperature for 1 h gave the corresponding γ-keto-γ-amino esters 4.11a−f in

46−88% yield (Scheme 4-6, Table 4-1).

NH

O

Bt

OMeO

TFA

Tfa-Glu(OMe)-Bt 4.10

TiCl4

Aromatics

NH

O

Ar

OMeO

TFA

4.11a-f

Scheme 4-6. Syntheses of γ-Keto-γ-amino Esters 4.11.

41

Table 4-1. Syntheses of γ-Keto-γ-Amino Esters 4.11. Entry Aromatics γ-Keto-γ-amino esters 4.11 (%) 1 Indole 4.11a (80) 2 N-Methylindole 4.11b (88) 3* N-Methylpyrrole 4.11c (69) 4* Pyrrole 4.11d (50) 5 1,3-(MeO)2C6H4 4.11e (48) 6 1,3,5-(MeO)3C6H3 4.11f (46) *: compounds 4.11c,d were prepared by Dr. Rong Jiang, which were not included in experimental part. Spectroscopic and analytical data of these compounds are available in Dr. Rong Jiang’s Ph. D. dissertation. 4.2.3 Preparation of δ-Aryl-γ-amino Esters 4.12 and δ-Aryl-γ-amino Acids 4.13 by

Reduction of γ-Keto-γ-amino Esters 4.11.

The reduction of γ-keto-γ-amino esters 4.11e,f by triethylsilane in trifluoroacetic

acid at room temperature gave the corresponding δ-aryl-γ-amino esters 4.12e,f in 84%

and 88% yield respectively (Scheme 4-7, Table 4-2) [73JOC2675].

Et3SiH

NH

O

Ar

OMeO

TFA CF3COOH NH Ar

OMeO

TFA

4.11e,f 4.12e,f

Scheme 4-7. Preparation of δ-Aryl-γ-amino Esters 4.12e,f by the Reduction of γ-Keto-γ-amino Esters 4.11e,f.

Table 4-2. Preparation of δ-Aryl-γ-amino Esters 4.12e,f. Entry Aromatics δ-Aryl-γ-amino esters 4.12 (%) 1 1,3-(MeO)2C6H4 4.12e (84) 2 1,3,5-(MeO)3C6H3 4.12f (88)

However, the attempts to reduce γ-keto-γ-amino esters 4.11a,b with triethyl silane

in trifluoroacetic acid were unsuccessful. Unlike their phenyl analogs, 4.11e,f, carbonyl

group in 4.11a,b could not be reduced to methylene under these conditions. On the other

42

hand, when γ-keto-γ-amino esters 4.11a,b were treated with 4 molar equivalents sodium

borohydride in DMF/H2O (v/v = 5/1) mixture for two hours, the corresponding δ-aryl-γ-

amino acids 4.13a,b were isolated in 87% and 73% yield, respectively (Scheme 4-8,

Table 4-3) [03TL8229].

NH

O

Ar

OMeO

TFA NH Ar

OHO

TFANaBH4DMF/H2O

4.11a,b 4.13a,b

Scheme 4-8. Preparation of δ-Aryl-γ-amino Acids 4.13a,b by the Reduction of γ-Keto-γ-amino Esters 4.11a,b.

Table 4-3. Preparation of δ-Aryl-γ-amino Acids 4.13. Entry Aromatics δ-Aryl-γ-amino acids 4.13 (%) 1 Indole 4.13a (87) 2 N-Methylindole 4.13b (73) 4.2.4 Configuration Study of δ-Aryl-γ-amino Acids 4.13.

Since the key feature of biologically active amino acid derivatives is associated

with the absolute configuration of the α-carbon to the amino group, total control of

chirality represents a major goal in the synthesis of amino acid derivatives. To evaluate

the chiral integrity of these reactions, (DL)-5-(1-methyl-1H-indole-3-yl)-4-[(2,2,2-

trifluoroacetyl)amino]pentanoic acid 4.13g was prepared starting from DL-glutamic acid,

following the procedure for 4.13b (Scheme 4-9). The chiral resolution of 4.13g (DL) by

chiral HPLC [CHIROBIOTIC T column; eluted with 60/40 (v/v) 0.1% TEAA

(triethylamine acetate) methanol solution/water; flow rate 0.4 mL/min at room

temperature; UV detection at 210 nm] gave two distinct signals with equal intensity at

13.22 min and 13.68 min, while 4.13b (L) gave only one signal at 13.7 min under same

43

conditions that demonstrated the complete chiral preservation (>99%) of synthesis of δ-

aryl-γ-amino acid derivitaives 4.12 and 4.13 (Table 4-4).

NH

O

Bt

OMeO

TFA

DL-TFA-Glu(OMe)-Bt (4.10g)

TiCl4

N-methyl indole 83% NH

O

OMeO

TFA

N

NH

OHO

TFA

N

4.13g (DL)

NaBH4

DMF/H2O 71%

4.11g (DL)

Scheme 4-9. Synthesis of Compounds 4.13g (DL). Table 4-4. The Comparison of Chiral HPLC Results of 4.13b (L) with Corresponding

DL-Mixtures 4.13g. Retention Time (min) Entry Compound L D

1 4.13b (L) 13.7 -a 2 4.13g (DL) 13.7 13.2 ano peak detected.

The complete preservation of chirality of this process is due to th

synthetic application in thioacylation...

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