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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
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Copyright 2006
By
Hui Tao
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Dedicated to my family, my father Banghe Tao, my mother Pingfen Li and my twin sister Yong Tao
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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.
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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.
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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
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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).
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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
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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
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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.
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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
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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,
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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-
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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.
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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.
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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.
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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.
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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-
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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.
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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.
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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.
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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,
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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.
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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.
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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
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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
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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.
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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.
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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
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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