efficient methodology for the synthesis of 2,4...
TRANSCRIPT
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EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF 2,4-BENZODIAZEPIN-1-
ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE SULFONAMIDES, THIOCARBAMATES, DITHIOCARBAMATES AND
THIOAMIDES
By
VALERIE RODRIGUEZ-GARCIA
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
2004
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I owe my achievements to my family, my mother Iris Garcia, my father Francisco V. Rodriguez, my brothers Emmanuel and Rasik, my cousins Sonia, Mia Alexandra and Roberto Mateo. I have been raised in their deepest love, and it continues today also. This I do for them.
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ACKNOWLEDGMENTS
I want to mention first that I believe nothing happens without a purpose. My life
these past years has been guided to make much sense, for all the things I have seen I
never thought I would, all the places I have visited and all the caring beings that have
been included in the story of my life. I definitely owe so much to graduate school and to
those who made it possible.
Forever my respect and gratitude go to my supervisor, Professor Alan R. Katritzky,
and to my supervisory committee members, Dr. William R. Dolbier, Dr. Eric Enholm,
Dr. Steven A. Benner and Dr. Dinesh O. Shah. I immensely thank Dr. Jeffrey L. Krause;
the date of my final defense would not have been possible if he had not agreed to assist.
I thank Dr. Dennis Hall for correcting my thesis, and thanks go to Dr. Suman
Majumder and to Dr. Sanjay Singh for their help always in English and content
corrections. I thank all Katritzky members for their friendship and encouragement.
I want to give special thanks to Eladio Rivera and Wigberto Hernandez for their
help during my undergraduate studies and for their friendship through distance.
I thank my husband Igor V. Schweigert and my other loves in the Chemistry
Department, Rachel Witek, Hongfang Yang and Chaya Pooput, for their support and their
genuine interest in my well being.
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TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................. iii
LIST OF TABLES ............................................................................................................ vii
LIST OF FIGURES......................................................................................................... viiii
LIST OF SCHEMES ........................................................................................................ ixx
ABSTRACT....................................................................................................................... xi
CHAPTER
1 GENERAL INTRODUCTION...................................................................................1
2 ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING BENZOTRIAZOLE METHODOLOGY....................................................................5
2.1 Introduction ..........................................................................................................5 2.2 Results and Discussion.........................................................................................8 2.3 Conclusion..........................................................................................................12 2.4 Experimental Section .........................................................................................12
2.4.1 General Procedure for the Preparation of N, N-bis(Benzotriazolylmethyl)alkyl amines 2.9a-d ...................................12
2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides 2.11a-d.................................................................................................13
2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin-1-ones 2.13a-h .................................................................................................15
3 A GENERAL AND EFFICIENT SYNTHESIS OF SULFONYLBENZOTRIAZOLES FROM N-CHLOROBENZOTRIAZOLE AND SULFINIC ACID SALTS...............................................................................19
3.1 Introduction ........................................................................................................19 3.2 Results and Discussion.......................................................................................24
3.2.1 Preparation of Benzotriazole Reagents 3.27..........................................24 3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27 ...................28
3.3 Conclusion..........................................................................................................29 3.4 Experimental Section .........................................................................................31
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3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles 3.27a−j .................................................................................................31
3.4.2 General Procedure for the Preparation of Sulfonamides 3.29−3.37 ......34 4 1-[2-BENZOTRIAZOL-1-YL)ETHYL]SULFONYLBENZOTRIAZOLE: A
VERSATILE SYNTHON FOR THE PREPARATION OF ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS................38
4.1 Introduction ........................................................................................................38 4.2 Results and Discussion.....................................................................................433
4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h ............444 4.2.2 Preparation of Ethylenesulfonamides 4.8a, f.......................................455
4.3 Conclusion..........................................................................................................46 4.4 Experimental Procedure .....................................................................................46
4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5 .......................466 4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g............47 4.4.3 Procedure for the Preparation of Sulfonate ester 4.7h...........................49 4.4.4 General Procedure for the Synthesis of Ethylenesulfonamides 4.8a, f .50
5 VERSATILE SYNTHESIS OF THIOCARBAMOYLBENZOTRIAZOLES, THIOAMIDES, THIOCARBAMATES AND DITHIOCARBAMATES FROM BIS(BENZOTRIAZOLYL)METHANETHIONE ...................................................52
5.1 Introduction ........................................................................................................52 5.2 Results and Discussion.......................................................................................55
5.2.1 Preparation of 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 .............55 5.2.2 Preparation of Thioamides 5.9a-j ..........................................................57 5.2.3 Preparation of Thiocarbamates (5.10) and Dithiocarbamates (5.11)
from Thiocarbamoylbenzotriazoles 5.5 ...............................................59 5.3 Conclusion..........................................................................................................62 5.4 Experimental Section .........................................................................................63
5.4.1 General Procedure for the Preparation of 1-Alkyl- and 1-Aryl-thiocarbamoylbenzotriazoles 5.5a-k....................................................63
5.4.2 General Procedure for the Preparation of Mono-substituted Thioamides 5.9a-f ................................................................................67
5.4.3 General Procedure for the Preparation of Di-substituted Thioamides 5.9g-j ....................................................................................................69
5.4.4 General Procedure for the Preparation of Di-substituted Thiocarbamates 5.10a-b .....................................................................70
5.4.5 General Procedure for the Preparation of Di-substituted Dithiocarbamates 5.11a .......................................................................71
5.4.6 General Procedure for the Preparation of Mono-substituted Dithiocarbamates 5.11b-d....................................................................72
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6 CONCLUSION.........................................................................................................74
REFERENCES...................................................................................................................75
BIOGRAPHICAL SKETCH..............................................................................................83
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LIST OF TABLES
Table page 2-1 Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d .............................8
2-2 Yield of benzamides prepared....................................................................................9
2-3 Yields of 2, 4-Benzodiazepine-1-ones prepared ......................................................11
3-1 Alkyl/arylsulfonylbenzotriazoles 3.27 .....................................................................28
3-2 Sulfonamides 3.29-3.37 prepared using reagents 3.27.............................................30
4-1 Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared ..........................................45
5-1 1-(Alkyl/arylthiocarbamoyl)benzotriazoles 5.5 prepared ........................................56
5-2 Preparation of mono-substituted thioamides from thiocarbamoylbenzotriazoles....58
5-3 Preparation of di-substituted thioamides from thiocarbamoylbenzotriazoles..........59
5-4 Preparation of thiocarbamates 5.10 ..........................................................................61
5-5 Preparation of dithiocarbamates 5.11 ......................................................................62
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LIST OF FIGURES
Figure page 2-1 Biologically active benzodiazepines ..........................................................................6
2-2 1H NMR spectrum of 2.13b .....................................................................................18
3-1 Prontosil 3.1 and the active metabolite sulfanilamide 3.2........................................19
3-2 Various clinically used sulfonamide drugs ..............................................................20
1H NMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h)3-3 ..........27
4-1 Intermediate 4.1 used in the preparation of ethylenesulfonamides ..........................43
5-1 Organometallic reagents used ..................................................................................57
5-2 Alcohols and thiols used ..........................................................................................60
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LIST OF SCHEMES
Scheme page 1-1 Some isomers of N-substituted benzotriazoles ..........................................................2
2-1 Literature methods to synthesize 2,4-benzodiazepines ..............................................7
2-2 Retrosynthetic analysis...............................................................................................7
2-3 Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d ..........................8
2-4 Preparation of benzamides .........................................................................................9
2-5 Synthesis of 2, 4-Benzodiazepine-1-ones ................................................................11
3-1 Example of the preparation of sulfonamides............................................................21
3-2 Various methods for the synthesis of sulfonamides.................................................22
3-3 Synthesis of benzenesulfonamides and aryl benznesulfonates from 1-phenylsulfonylbenzotriazole .................................................................................23
3-4 Synthesis of p-tolylsulfonylbenzotriazole using our method...................................25
3-5 Proposed mechanism for the formation of sulfonylbenzotriazoles ..........................25
3-6 Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27 ...........................................28
3-7 Preparation of sulfonamides.....................................................................................29
4-1 Transformations of ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters.........................................................................................................................39
4-2 Desulfonation Reactions ..........................................................................................40
4-3 Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and ethylenesulfonamides ...............................................................................................42
4-4 Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5 ......................43
4-5 Attempt to prepare 4.2..............................................................................................44
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4-6 Preparation of sulfonamides and sulfonate ester 4.7 ................................................45
4-7 Synthesis of ethylenesulfonamides ..........................................................................46
5-1 Preparation of bis(benzotriazolyl)methanethione 5.3 ..............................................52
5-2 Use of bis(benzotriazolyl)methanethione 5.3 in the preparation of thioureas 5.7 ...53
5-3 Synthetic utility of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5 .........................55
5-4 Preparation of 1-(alkyl/arylthiocarbamoyl)benzotriazoles 5.5.................................56
5-5 Preparation of thioamides 5.9...................................................................................58
5-6 Synthesis of thiocarbamates 5.10 and dithiocarbamates 5.11 ..................................61
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Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES, SULFONYLBENZOTRIAZOLES, SULFONAMIDES, ETHYLENE SULFONAMIDES, THIOCARBAMATES, DITHIOCARBAMATES AND
THIOAMIDES
By
Valerie Rodriguez-Garcia
August 2004
Chair: Alan R. Katritzky Major Department: Chemistry
Benzotriazole, as a synthetic auxiliary, provided an efficient methodology for the
preparation of various pharmaceutically and industrially important compounds.
Benzodiazepines display potent pharmacological activity. Published synthetic
routes to 2,4-benzodiazepines-1-ones are scarce. N, N-Bis(benzotriazolylmethyl)-
alkylamines are excellent nitrogen centered 1, 3-dication synthons, which taken in one-
pot reactions with ortholithiated benzamides in the presence of zinc bromide provided
novel 2,4-benzodiazepin-1-ones in moderate to good yields. The details are shown in
Chapter 2.
Sulfonylbenzotriazoles are very stable and efficient sulfonylating agents. In
Chapter 3 N-(alkane-, arene- and heteroarene-sulfonyl)benzotriazoles were prepared in
one-pot, in yields of 41–93% by reaction of N-chlorobenzotriazole with various sulfinic
acid salts (produced from organometallic reagents with SO2). Reactions of
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sulfonylbenzotriazoles with primary and secondary amines at 20–80oC afforded
sulfonamides in 64–100% yield. Sulfonamides are used as antibacterial and anti
microbial drugs.
In Chapter 4 other alkyl sulfonamides, some ethylene sulfonamides and an
alkylsulfonate ester were also prepared in good yields utilizing the stable solid 1-{[2-(1H-
1,2,3-benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole. 1-{[2-(1H-1,2,3-
Benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole is a potential replacement for
2-chloroethylsulfonyl-1-chloride, which is commonly used in these type of reactions.
Thioamides, thiocarbamates and dithiocarbamates are also industrially important.
Reactions of thiocarbamoylbenzotriazoles with carbon, oxygen, and sulfur nucleophiles
afforded the corresponding thioamides, thiocarbamates, and dithiocarbamates in 36-99%
yields. Some thiocarbamoylbenzotriazoles, prepared in yields of 76-100%, act as
efficient isothiocyanate analogues (Chapter 5).
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CHAPTER 1 GENERAL INTRODUCTION
Benzodiazepines, sulfonamides, thiocarbamates dithiocarbamates and thioamides
display potent pharmacological activity. Some benzodiazepines are naturally occurring
antitumor antibiotics [99JOC290] and others are industrially important anti-psychotic
drugs [02JMC5136]. Sulfonamides include bactericidal and anti-infective drugs
[90MI_255]. Examples of thiocarbamates are good insecticides [90JAE293], herbicides
[75MI_675] and nematocides [89MI_158]. Some dithiocarbamates are fungicides and
others are used as additives in the rubber industry. Various thioamides exhibit
antileprosy [85MI_587], anthelmintic [01MI_1000], immunosuppressive [98MI_2203]
and antituberculotic [02IF71] activity. Also, thiocarbamates, dithiocarbamates and
thioamides are precursors of interesting molecular functionalities.
In the field of synthesis, new pathways to efficiently produce scientifically
attractive compounds are constantly being sought. It is important industrially to find
synthetic approaches that can produce as many derivatives as possible, in good quantities
and with easy purification methods. For more than 20 years our group has been
exploiting the versatility of benzotriazole [98CRV409], towards new and better
methodologies for the synthesis of organic compounds. Benzotriazole is an effective
synthetic auxiliary. It is easily introduced at the beginning of a synthetic sequence and
easy to remove at the end of a synthetic sequence. Benzotriazole intermediates are stable
under many synthetic conditions. In addition to being a good leaving group, when
activated by an electron donor group, benzotriazole also selectively activates the part of
1
-
2
the molecule to which it is attached without affecting the chemical properties of other
functionalities in the molecule. Benzotriazole, as a byproduct of a reaction, is easily
removed in the workup by a mild base wash.
Some N-substituted benzotriazoles exist as 1- and 2-substituted isomers (Scheme
1–1). This happens when a benzotriazole anion can dissociate from a molecule and
reattach itself at a different position. The isomers often exist in equilibrium and show the
same reactivity and stability, so it is not necessary to separate them for subsequent
reactions.
NN
N
XR
NN
N
R
XN
NN
H
RX
+
1-substituted Bt 2-substituted Bt
-
1.3
tendency for X=NR2, OR, SR
1.2 1.4
Scheme 1-1. Some isomers of N-substituted benzotriazoles
Many properties of N-substituted benzotriazoles are comparable to those of the
halogen analogues, but with the advantage of extra stability, easier preparation, versatility
and non-toxicity. Other than the easy preparation of the benzotriazole derivatives studied
here, the efficient and selective elimination of benzotriazole from the molecules upon
reaction with nucleophilic carbons, amines, alcohols and mercaptans justifies the
importance of the methodology presented here. Many reactions utilizing substituted
benzotriazoles as reagents are more convenient than commonly used methods.
Particularly N, N-bis(benzotriazolylmethyl)alkyl amines are very interesting reagents.
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3
They act as bis-electrophiles, liberating benzotriazole in the presence of acids or strong
nucleophiles, allowing for one pot procedures. This is the advantage that makes them
good synthons for the preparation of 2,4-benzodiazepin-1-ones (Chapter 2).
Sulfonylbenzotriazoles are efficient sulfonating reagents, much more stable than
the commonly used sulfonyl halides. Many of them are solids, easy to handle and store.
The benzotriazole in sulfonylbenzotriazoles can be substituted by amines or alcohols to
give sulfonamides and sulfonate esters under mild conditions and without the need for a
base. Utilizing N-chlorobenzotriazole and sulfinic acid salts these sulfonylbenzotriazoles
are readily prepared (Chapters 3). The synthesis of ethylenesulfonamides also takes
advantage of the stability that benzotriazole induces in a molecule, and the selectivity
when attempting substitution and elimination of benzotriazole. The ethylenesulfonamide
generating derivative, 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole, contains two
benzotriazole moieties that can be eliminated to afford a variety of ethylenesulfonamides.
Due to its characteristics, the first nucleophilic attack by an amine displaces the
benzotriazole attached to the sulfur atom, the second one leaving by elimination upon
reaction with a strong base (Chapter 4).
Thioamides, thiocarbamates and dithiocarbamates are now synthesized from
thiocarbamoylbenzotriazoles for the first time (Chapter 5). Many
thiocarbamoylbenzotriazoles act as effective isothiocyanate equivalents, which are
building blocks in many synthetic operations such as in the formation of heterocycles
[03JOC8693]. Bisbenzotriazolylmethanethione, a benzotriazole derivative of
thiophosgene, is the precursor to thiocarbamoylbenzotriazoles. This derivative exhibits
great stability and tremendous selectivity towards nucleophilic substitution.
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4
In summary, efficient approaches for the preparation of 2,4-benzodiazepin-1-ones,
N-(alkyl- and aryl-sulfony)lbenzotriazoles, sulfonamides, ethylenesulfonamides,
thiocarbamates, thioamides and dithiocarbamates were discovered utilizing benzotriazole
methodology. N-(Alkyl- and aryl-sulfonyl)benzotriazoles were synthesized from scratch
for the first time, and applied to the preparation of novel sulfonamides. The procedures
herein take advantage of the benzotriazole anion as a selective but good leaving group,
which can be displaced by carbon nucleophiles, amines, mercaptans and alcohols.
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CHAPTER 2 ONE POT SYNTHESIS OF 2,4-BENZODIAZEPIN-1-ONES USING
BENZOTRIAZOLE METHODOLOGY
2.1 Introduction
Benzodiazepines are a class of compounds that have selective activity against a
diverse array of biological targets. Their basic structure comprises a benzene ring fused
to a seven-membered ring heterocycle, which contains two nitrogen atoms within the ring
(Figure 2-1). The names of the benzodiazepines are derived from the location of the
nitrogen atoms within the heterocycle ring.
2,3-Benzodiazepines have been evaluated for their anticonvulsant, anti epileptic
and anti seizure properties [99JMC4414; 00JMC4834]. 1,4-Benzodiazepines are the
most commonly studied because their derivatives display a wide variety of properties,
and they have the ability to mimic natural ligands [88JMC2235]. For example, pyrrolo-
1,4-benzodiazepin-5-ones occur as antitumor agents (2.1), gene regulators, and DNA
probes [99JOC290] whereas 1,4-benzodiazepin-2,5-diones are anticonvulsants
[89JHC1807] and potent inhibitors of platelet aggregation [94JA5077]. Drugs currently
in use in the treatment of anxiety, panic, schizophrenia, and sleep disorders contain the
1,4-benzodiazepine core (Valium (2.2) and Xanax (2.3)) and 1,5-benzodiazepines are
being investigated for their central nervous system depressant properties [02JMC5136;
00JMC3596]. Additionally, many benzodiazepine alkaloids found in nature, such as
Circumdatin F (2.4) and Circumdatin C (2.5), are isolated from the fungus Aspergillus
ochraceus [01JOC2784].
5
-
6
O
NH
MeHN N
O
R
N
N
O
Cl
Me
NCl
NN
NMe
N
O
OH
N
H
MeO
Antibiotic DC-81
2.1 Valium Xanax2.2 2.3
F: R = HC: R = OH
2.42.5
Circumdatin
Figure 2-1. Biologically active benzodiazepines
Much of the literature to date has focused on the development of structure-activity
relationship (SAR) studies and synthetic (library) strategies for 1,4-benzodiazepines
[99OL1835; 97JOC1240; 98JOC8021], 1,5-benzodiazepines [00JMC3596; 00OL3555;
00JCB513], and 2,3-benzodiazepines [99JMC4414; 00JMC4834]. Very little has been
reported on the synthesis of 2,4-benzodiazepines. Bocelli et al. [99TL2623] synthesized
a 2,4-benzodiazepin-1,3-dione derivative by the palladium-catalyzed intramolecular
cyclization of 1-butyl-1(o-iodobenzyl)-3-phenylurea (Scheme 2-1, reaction a) and Mohrle
and Lessel reported the synthesis of 2,4-benzodiazepin-1-one by electrolysis of 2-
[(dimethylamino)methyl]benzamide (Scheme 2-1, reaction b) [91AP367]. These
previous methods produce low yields of the desired 2,4-benzodiazepine and the method
described in reaction (b) utilizes toxic mercury.
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7
I
N NHBu
PhO
N
N
O
Bu
O
Ph
N Bu
O
NNH2
O
NH
N
O
N
O
CO, Pd(0)
80oC+(a)
(b)Hg(II)-EDTA +
Scheme 2-1. Literature methods to synthesize 2,4-benzodiazepines
We envisioned that a facile synthetic route to 2,4-benzodiazepin-1-ones would be
achieved by the connection of benzamides to bis electrophilic alkyl/aryl amines (Scheme
2-2). This requires connection of the ortho position and the nitrogen atom of the
benzamide to a nitrogen centered 1,3-dicarbocation to form the seven membered ring.
N
N
O R
R
NH
OR
N
XX
R
1
1
Scheme 2-2. Retrosynthetic analysis
N, N-Bis(benzotriazolylmethyl)alkylamines 2.9 (Scheme 2-3) have been used
previously for the synthesis of julolidines [96JOC3117], 1,3-oxazolidines [98TL6835]
and 3-arylpyrrolidines [98H2535]. Bis(benzotriazolylmethyl)amines 2.9 are nitrogen
centered 1, 3-dication synthons, as exemplified by the synthesis of substituted piperidines
[99JOC3328].
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8
N-Alkylbenzamides afford dianions upon treatment with 2 equivalents of a strong
base. Coordination of the base to either heteroatom, N or O, in the amide moiety, directs
the deprotonation of the ortho position in the phenyl ring. This synthetic strategy is well
known in directed ortho metalation chemistry [90CRV879]. N-Alkyl- and N-aryl-
benzamides 2.11a-d were prepared (Scheme 2-4), and were then used in the directed
ortho metalation process to generate ortholithiated benzamides.
Below we report the use of benzotriazole methodology combined with an ortho
metalation procedure to produce 2,4-benzodiazepin-1-ones in one pot.
2.2 Results and Discussion
N, N-Bis(benzotriazolylmethyl)alkyl amines 2.9a-d were easily prepared by the
reaction of primary amines, benzotriazole and formaldehyde following published
procedures [87JCS(P1)799; 90CJC446] (Scheme 2-3, Table 2-1 ).
NH
NN
H H
O
N
NN
NN N
NR
NH2R1
(2eqs)+ + (2eqs)1
MeOH/H2O
p-TsOH
2.9a-d
2.6 2.7 2.8
Scheme 2-3. Preparation of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d
Table 2-1. Synthesis of N, N-bis(benzotriazolylmethyl)alkyl amines 2.9a-d
R1 2.9 Yield (%)
a C4H9 60 b Phenethyl 92 c Cyclohexyl 70
d C2H5 69
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9
Compounds 2.9a-d were characterized by 1H and 13C NMR spectra. For the four
compounds the 1H NMR showed the characteristic singlet peak due to Bt-CH2-N at 5.6-
6.0 ppm and integrating for four protons. In the 13C NMR the Bt-CH2-N carbons were
found at 63.0-64.0 ppm. Compounds 2.9a and b showed various degrees of
isomerization to the 2-benzotriazole systems. In these instances, where 1-substituted
benzotriazole and 2-substituted benzotriazole were present together, all the peaks in the
spectra appeared as a double set of signals.
Reactions of benzoyl chloride with the respective amines provided benzamides
2.11a-d. These were also identified by 1H and 13C NMR spectra. For example, the 1H
NMR of 2.11 b displayed the expected signal characteristic of a tert-butyl group at 1.42
ppm as a singlet with an integral of nine protons. The signals for the phenyl ring were
also visible as five protons at 7.38-7.73 ppm. The N-H peak was found as a singlet at
5.99 ppm. The carbonyl peak (C=O) was visible in the 13C NMR at 167.0 ppm.
Cl
O
NH
ORNH2R
NEt3CH2Cl2
2.10 2.11
Scheme 2-4. Preparation of benzamides
Table 2-2. Yield of benzamides prepared 2.11 R Yield (%)
a CH3 71
tBu b 80
c C6H5 63
p-ClC6H6d 42
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10
N-Methylbenzamide 2.11a was treated with butyllithium at –78oC in
tetrahydrofuran, then stirred for 1 h at room temperature and reacted with
bisbenzotriazolyl derivative 2.9a (Scheme 2-5). After workup, only the starting materials
were recovered. Tetramethylene diamine (TMEDA) was then used to help in the
formation of the dimetalated benzamide. TMEDA was added to 2.11a in THF, followed
by butyllithium at –78oC and reagent 2.9a. The starting materials were recovered once
more. However, when ZnBr2 was added to the reaction mixture the reaction took place
as desired. After addition of 2.9a, the reaction mixture was stirred overnight at room
temperature. Aqueous workup and isolation yielded the benzodiazepin-1-one 2.13a in
22% yield but the yield of 2.13a was improved to 64% by conducting the reaction at
- 10oC. The ZnBr2 acts in this reaction as a Lewis acid, by activating the benzotriazole
and thus facilitating C-N bond scission, a common feature of benzotriazole chemistry
[99JOC3328].
Bis(benzotriazolylmethylalkyl)amines prepared from other primary amines reacted
similarly under the modified conditions giving the corresponding 2,4 benzodiazepin-1-
ones 2.13b-h in good to moderate yields. The results are summarized in Table 2-3.
The 1H and 13C NMR spectra of 2.13a-h were in accordance with the proposed
structures. 1H NMR and 13C NMR showed no evidence for the presence of benzotriazole.
Two distinct singlets in the region between 3.5-5.8 ppm appeared in the 1H NMR for
compounds 2.13 a, c- d. Each singlet integrated for two protons and both were assigned
to the two new bonds formed with -CH2-NR-CH2-. Compound 2.13b is a very
interesting example, where instead of two singlets the 1H NMR spectra displayed only a
singlet at 3.77 ppm integrating for four hydrogens (Figure 2-2). This denotes that the
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11
protons in -CH2-NR-CH2-, after the new bonds formed in 2.13b, are accidentally
equivalent.
CH3-C4H9C6H5
R
NH
OR N
OLiR
Li
N
N
O R
RN BtBtR1
1
C4H9C6H5(CH2)2
C2H5cyclohexyl
NN
N
-ClC6H4
R12.11abc
d
2.11a-d 2.12
1. ZnBr2BuLi/-10o C
THF2.
2.9a-d
t
2.9a
bcd
2.13a-h
Bt =
p
Scheme 2-5. Synthesis of 2, 4-Benzodiazepine-1-ones
Table 2-3. Yields of 2, 4-Benzodiazepine-1-ones prepared Entry R R1 Yield(%)
2.13a CH3 C4H9 64
2.13b tBu C4H9 82
2.13c C6H5 Phenethyl 53
2.13d pCl-C6H4 C4H9 57
2.13e C6H5 C4H9 47
2.13f tBu Phenethyl 36
2.13g C6H5 cyclohexyl 74
2.13h CH3 cyclohexyl 57
-
12
2.3 Conclusion
We have demonstrated the capability of benzotriazole reagents 2.9 as dication
sources. Utilizing simple chemistry we have carried out a one-pot synthesis of 2,4-
benzodiazepin-1-ones starting from easily affordable starting materials.
2.4 Experimental Section
Melting points were determined using a Bristoline hot-stage microscope and are
uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300
MHz NMR spectrometer in chloroform-d solution. Column chromatography was
performed on silica gel (300-400 mesh). Elemental analyses were performed on a Carlo
Erba-1106 instrument. THF was distilled from sodium-benzophenone ketal prior to use.
All the reactions were performed under a nitrogen atmosphere and in oven dried
glassware.
2.4.1 General Procedure for the Preparation of N, N-bis(Benzotriazolylmethyl)alkyl amines 2.9a-d
The respective primary amine (20 mmol) and benzotriazole (40 mmol) were
dissolved in methanol/water (4:1). Formaldehyde was added (40 mmol) and a catalytic
amount of para-toluenesulfonic acid. The mixture was stirred for 18 h. The precipitate
was filtered and washed with hexanes.
N-bis(Benzotriazolyl-1-methyl)butylamine (2.9a): Filtered, washed with
hexanes and obtained as colorless crystals (60%), mp 85-87 °C (Lit. mp 111-114oC,
[90JCS(P1)541]). 1H NMR δ 0.80 (t, J = 7.1 Hz, 3H), 1.22 (q, J = 7.3 Hz, 2H), 1.58 (t, J
= 7.7 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 5.63 (s, 4H), 7.42 (t, J = 7.6 Hz, 2H), 7.54 (t, J =
8.1 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.2 Hz, 2H). 13C NMR δ 13.69, 20.0,
29.6, 50.3, 64.4, 109.9, 120.1, 124.4, 127.9, 133.3, 146.1.
-
13
N-bis(Benzotriazolyl-1-methyl)phenethylamine (2.9b): Filtered, washed with
hexanes and obtained as white crystals (92%), mp 117-118°C (Lit. mp 122-124oC,
[87JCS(P1)799]). 1H NMR δ 2.63−2.67 (m, 2H), 2.97−3.03 (m, 2H), 5.94 (s, 4H), 6.97
(s, 2H), 7.12 (m, 3H), 7.42−7.47 (m, 2H), 7.54−7.59 (m, 2H), 7.95 (d, J = 8.4 Hz, 2H),
8.09 (d, J = 8.4 Hz, 2H). 13C NMR δ 34.1, 52.3, 64.5, 109.9, 120.1, 124.3, 126.5, 128.0,
128.5, 128.6, 133.2, 138.7, 146.1.
N-bis(Benzotriazolyl-1-methyl)cyclohexylamine (2.9c): Filtered, washed with
hexanes and obtained as white crystals (70%), mp 119.0–120.0°C, (Lit. mp 118-119oC,
[87JCS(P1)799]). 1H NMR δ 8.09 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H),
7.34−7.52 (m, 4H), 5.71 (s, 4H), 3.06 (m, 1H), 1.45−1.82 (m, 6H), 0.09−1.04 (m, 4H).
13C NMR in DMSO δ 25.1, 25.5, 30.2, 59.1, 63.3, 111.1, 119.2, 124.1, 127.4, 132.6,
145.4.
N-bis(Benzotriazolyl-1-methyl)ethylamine (2.9d): Recrystallized in ethanol,
filtered and washed with hexanes. Obtained as white crystals (69%), mp 79-81°C (Lit.
mp 82-84oC, [87JCS(P1)799]). 1H NMR δ 1.26 (t, J = 7.2 Hz, 3H), 2.98 (q, J = 7.2 Hz,
2H), 5.68 (s, 4H), 7.46 (t, J = 7.8 Hz, 2H), 7.58 (t, J = 7.8 Hz, 2H), 7.75 (d, J = 8.1 Hz,
2H), 8.15 (d, J = 8.1Hz, 2H). 13C NMR δ 13.0, 45.0, 63.9, 109.9, 120.1, 124.3, 128.0,
133.3, 146.1.
2.4.2 General Procedure for the Preparation of N-Alkyl-arylbenzamides 2.11a-d
The respective amine (28 mmol) was dissolved in CH2Cl2 (50 mL). Triethyl
amine (28 mmol) was added and the mixture stirred under an ice bath. Benzoyl chloride
(28 mmol) was added dropwise and the mixture stirred for 2 h at room temperature. The
-
14
solvent was evaporated and ethyl acetate added. The organic layer was washed with
water (x2), dried over sodium sulfate, filtered and concentrated.
N-Methylbenzamide (2.11a): Recrystallized in ethyl acetate and obtained as
white crystals (71%), mp 78°C (Lit. mp 79oC, [87H1313]). 1H NMR δ 2.97 (d, J = 4.8
Hz, 3H), 6.56 (s, 1H), 7.37−7.50 (m, 3H), 7.78 (d, J = 7.5 Hz, 2H). 13C NMR δ 26.8,
126.8, 128.5, 131.3, 134.5, 168.3.
N-t-Butylbenzamide (2.11b): Recrystallized in ethyl acetate and obtained as
white crystals (80%), mp 133-134°C (Lit. mp 135-137oC, [87S487]). 1H NMR δ 1.42 (s,
9H), 5.99 (s, 1H), 7.38−7.49 (m, 3H), 7.72 (d, J = 7.2 Hz, 2H). 13C NMR δ 28.9, 51.6,
126.7, 128.5, 131.1, 135.9, 167.0.
N-Phenylbenzamide (2.11c): Recrystallized in ethyl acetate and obtained as
colorless crystals (63%), mp 155-158°C (Lit. mp 163oC, [01SC1803]). 1H NMR δ
7.11−7.16 (m, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.54−7.63 (m, 3H), 7.81−7.83 (m, 2H),
7.98−8.01 (m, 2H), 10.3 (s, 1H). 13C NMR δ 120.3, 124.5, 127.1, 128.7, 129.0, 131.7,
134.9, 138.0, 165.8.
N-(p-Chlorophenyl)benzamide (2.11d): Obtained as white crystals (42%), mp
189°C (Lit. mp 190-191oC, [83S791]). 1H NMR δ 7.33−7.36 (m, 2H), 7.46−7.62 (m,
5H), 7.80 (s, 1H), 7.85−7.88 (m, 2H). 13C NMR δ 122.0, 127.4, 127.8, 128.6, 128.7,
131.9, 134.9, 138.3.
N-Cyclohexylbenzamide (2.11e): Obtained as white crystals (81%), mp 146-
147°C (Lit. mp 151-152oC, [88H323]). 1H NMR δ 1.17−1.48 (m, 6H), 1.63−1.77 (m,
3H), 1.99−2.03 (m, 2H), 3.96−3.98 (m, 1H), 6.10 (s, 1H), 7.38−7.50 (m, 3H), 7.74−7.77
(m, 2H). 13C NMR δ 25.0, 25.6, 33.2, 48.7, 126.9, 128.5, 131.2, 135.1, 166.7.
-
15
2.4.3 General Procedure for the Preparation of 2,4-Benzodiazepin-1-ones 2.13a-h
The N-substituted benzamide (3mmol) was dissolved in THF (30 ml). n-BuLi
(6.6 mmol) was added dropwise at –10oC. The mixture was gradually warmed to 0oC
and stirred for 30 min. After being cooled to –10oC, ZnBr2 (7 mmol) was added to the
mixture followed by the addition of the N,N-bis(benzotriazolyl)amine (3 mmol). The
resulting mixture was allowed to warm to room temperature and stirred for 24 h. The
reaction was quenched with 2 M NaOH, washed with brine and extracted with ethyl
acetate. Column chromatography (Al2O3, from 10/1 to 6/1 hexanes/EtOAc) afforded the
analytically pure benzodiazepines.
2-Methyl-4-Butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13a):
Yellow oil (64%). 1H NMR δ 7.77−7.74 (m, 1H), 7.44−7.40 (m, 2H), 7.26−7.24 (m, 1H),
4.09 (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.71 (t, J = 7.3Hz, 2H), 1.62−1.56 (m, 2H),
1.44−1.37 (m, 2H), 0.97 (t, J = 7.4Hz, 3H). 13C NMR δ 171.1, 136.5, 134.4, 131.1,
129.0, 128.5, 128.2, 68.1, 55.2(2), 36.3, 30.1, 20.4, 13.9. HRMS (FAB): Calcd For
C14H20N2O (M+H) 233.1654, Found 233.1629.
2-(tert-Butyl)-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13b):
Isolated as colorless oil (82%). 1H NMR δ 7.76 (dd, J = 6.7, 2.2 Hz, 1H), 7.43−7.37 (m,
2H), 7.10 (dd, J = 6.5, 1.9 Hz, 1H), 3.78 (s, 4H), 2.31 (t, J = 7.0 Hz, 2H), 1.59 (s, 9H),
1.51−1.46 (m, 2H), 1.40−1.35 (m, 2H), 0.93 (t, J = 7.2Hz, 3H). 13C NMR δ 172.1, 138.3,
131.5, 130.8, 128.8, 128.2, 128.0, 63.2, 57.1, 53.6, 51.8, 30.1, 28.7, 20.5, 14.0. Anal.
Calcd. For C17H26N2O C, 74.41; H, 9.55; N, 10.21. Found: C, 74.35; H, 10.06; N, 10.40.
2-Phenyl-4-phenyethyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one
(2.13c): Isolated as yellow oil (53%). 1HNMR δ 7.85 (dd, J = 6.9, 1.6Hz, 1H), 7.50−7.40
-
16
(m, 6H), 7.39−7.17 (m, 5H), 6.98 (d, J = 6.7Hz, 2H), 4.56 (s, 2H), 3.92 (s, 2H),
2.84−2.79 (m, 2H), 2.74−2.69 (m, 2H). 13C NMR δ 170.7, 143.2, 139.4, 136.3, 134.0,
131.6, 129.3, 129.1, 129.1, 128.6, 128.4, 126.7, 126.2, 126.1, 68.1, 56.6, 55.3, 34.6.
Anal. Calcd. For C23H22N2O C, 80.67; H, 6.48; N, 8.18. Found: C, 80.53; H, 6.46; N,
8.19.
2-(4-Chlorophenyl)-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one
(2.13d): Isolated as colorless oil (57%). 1H NMR δ 7.52−7.39 (m, 6H), 7.33−7.26 (m,
2H), 4.65 (s, 2H), 4.00 (s, 2H), 2.55 (t, J = 7.3Hz, 2H), 1.40−1.24 (m, 4H), 0.83 (t, J
=7.3Hz, 3H). 13C NMR δ 171.0, 136.0, 135.6, 130.9, 129.6, 128.6, 128.4, 127.5, 126.7,
126.3, 125.3, 66.0, 53.0, 52.3, 29.7, 20.3, 13.9. Anal. Calcd. For C19H21ClN2O C, 69.4;
H, 6.74; N, 8.52. Found: C, 69.3; H, 6.57; N, 8.52.
2-Phenyl-4-butyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one (2.13e):
Isolated as yellow oil (47%). 1H NMR δ 7.84 (dd, J = 6.9, 1.9Hz, 1H), 7.52−7.39 (m,
6H), 7.33−7.26 (m, 2H), 4.50 (s, 2H), 3.86 (s, 2H), 2.57 (t, J = 7.3Hz, 2H), 1.43−1.38 (m,
2H), 1.29−1.22 (m, 2H), 0.83 (t, J = 7.3Hz, 3H). 13C NMR δ 170.8, 143.3, 136.4, 134.2,
131.6, 129.3, 129.1, 129.0, 128.5, 126.6, 126.2, 68.6, 55.2, 54.7, 29.8, 20.3, 13.8. Anal.
Calcd. For C19H22N2O C, 77.52; H, 7.53; N, 9.52. Found: C, 76.57; H, 8.64; N, 9.43.
2-(tert-Butyl)-4-phenylethyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one
(2.13f): Isolated as yellow oil (36%) 1H NMR δ 7.78−7.75 (m, 1H), 7.41−7.37 (m, 2H),
7.31−7.25 (m, 2H), 7.22−7.18 (m, 3H), 7.11−7.08 (m, 1H), 3.84 (s, 2H), 3.82 (s, 2H),
2.82 (t, J = 7.0Hz, 2H), 2.58 (t, J = 7.0Hz, 2H), 1.56 (s, 3H). 13C NMR δ 172.1, 139.9,
138.2, 131.3, 130.9, 128.7, 128.6, 128.4, 128.2, 128.1, 126.2, 63.1, 57.1, 54.0, 53.7, 34.8,
-
17
28.6. Anal. Calcd. For C21H26N2O C, 78.22; H, 8.13; N, 8.69. Found: C, 78.09; H, 8.19;
N, 8.72.
2-Phenyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one
(2.13g): Isolated as colorless crystals (EtOAc/Hexane), 74%, mp 102-103oC. 1H NMR δ
7.98−7.81 (m, 1H), 7.58−7.25 (m, 8H), 4.62 (s, 2H), 3.96 (s, 2H), 2.55−2.40 (m, 1H),
1.90−1.45 (m, 6H), 1.20−1.05 (m, 4H). 13C NMR δ 170.8, 142.6, 136.3, 134.9, 131.7,
129.3, 129.2, 129.0, 128.4, 126.6, 126.3, 64.8, 60.5, 52.8, 31.1, 25.8, 25.0. Anal. Calcd.
For C21H24N2O C, 78.71; H, 7.55; N, 8.74. Found: C, 76.01; H, 7.55; N, 7.96.
2-Methyl-4-cyclohexyl-2,3,4,5-tetrahydro-1H-2,4-benzodiazepin-1-one
(2.13h): Isolated as colorless liquid (57%) 1H NMR δ 7.77−7.75(m, 1H), 7.46−7.39 (m,
2H), 7.25−7.37 (m, 1H), 4.21 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.65−2.55 (m, 1H),
2.17−2.07 (m, 2H), 1.90−1.78 (m, 2H), 1.38−1.21 (m, 6H). 13C NMR δ 171.2, 136.4,
135.0, 131.3, 129.2, 128.4, 128.2, 64.4, 60.7, 52.4, 35.6, 31.3, 25.9, 25.3. Anal. Calcd.
For C16H22N2O C, 74.38; H, 8.58; N, 10.84. Found: C, 72.21; H, 9.75; N, 10.35.
-
18
N NO
Figure 2-2. 1H NMR spectrum of 2.13b
-
CHAPTER 3 A GENERAL AND EFFICIENT SYNTHESIS OF SULFONYLBENZOTRIAZOLES
FROM N-CHLOROBENZOTRIAZOLE AND SULFINIC ACID SALTS
3.1 Introduction
The sulfonyl group plays a very important role as key constituent of a number of
biologically active molecules. Sulfonyl compounds are of interest to the synthetic
chemist due to their bioactive nature and chemical applications. Sulfonamides occupy a
unique position in the drug industry. Also known as sulfa drugs, sulfonamides have a
history that dates back 70 years, during which their action as antiinfective drugs and their
effective bactericidal properties in vivo in small animals was discovered [90MI_255].
The first clinically used sulfonamide was named prontosil 3.1 (Figure 3-1), a red
azo dye that showed protective action against streptococci in mice. Prontosil was active
in vivo, but ineffective in vitro, which led to the conclusion that prontosil itself was not
the active drug. When metabolized in the body prontosil produces sulfanilamide 3.2, the
real active agent [90MI_255], it interferes with p-aminobenzoic acid utilization by
bacteria. This discovery started rapid progress in the investigation and production of new
sulfonamides.
NH2
NN
SO2NH2NH2
NH2
SO2NH2
3.1 3.2
Figure 3-1. Prontosil 3.1 and the active metabolite sulfanilamide 3.2
19
-
20
At present, over 30 drugs containing the sulfonamide moiety are used clinically, as
therapeutic agents and for the treatment of bacterial and viral infections. Examples of
well-known drugs are sulfamethoxazole 3.3, sulfisoxazole 3.4, sulfasalazine 3.5, and
Celebrex 3.6 (Figure 3-2). Sulfonamides are also diuretics, anticonvulsants and
hypoglycemic agents as well as protease inhibitors [98JA10994]. Arylsulfonyl
substituents have been used as effective protecting groups for oxygen and nitrogen
functionalities [92JOC4775]. Sulfonamides introduced into azo dyes improve the
properties of these dyes by giving extra light stability, greater water solubility and a
better fixation to fibre [90MI_255].
N
SNH2
N
MeF
F
F
O
O
NH2
SNH
O
O
ON
Me
N
SNH
O
O
N
N
OH
O OH
NH2
SNH
O
O
NO
MeMe
3.3
Antibacterial and antiprotozoal
3.5
Antiinflammatory
3.6
For the treatment of arthritisand osteoarthritis
3.4
Urinary tract antibacterial
Figure 3-2. Various clinically used sulfonamide drugs
Sulfonamides are commonly prepared by the reaction of ammonia, a primary amine
3.8 or a secondary amine with a sulfonyl chloride 3.7 in the presence of a base 3.9
[79COC345] (Scheme 3-1). However, this approach is limited by the availability of the
sulfonyl halide, some of which can be difficult to prepare, store and handle. Also, side
-
21
reactions are possible due to the presence of the base, even with relatively stable
substrates if harsh conditions are applied. The formation of a disulfonamide 3.11 is a
common side reaction when primary amines or ammonia are utilized [79COC345]
(Scheme 3-1).
Me
SCl
O
O
Me
SNH
O
O
NO2
NH2
NO2
Me
SN
O
OSO
O
Me
NO2
CaCO3+
3.7 3.8
3.9
3.10
3.11
Scheme 3-1. Example of the preparation of sulfonamides
Because of their importance and their relative difficulty in preparation numerous
synthetic methods have been developed with the purpose of solving problems of
sulfonamide synthesis (Scheme 3-2). Thus, sulfonamides can be prepared (i) by reaction
of sulfinic acid salts with hydroxylamine-O-sulfonic acid [86S1031]; (ii) by reduction of
arylsulfonyl azides [97SL1253; 98SC1721]; (iii) from aromatic and aliphatic sulfinic acid
salts using bis(2,2,2-trichloroethyl) azodicarboxylate as an electrophilic nitrogen source
[02TL4537]; (iv) from alkyl or aryl halides by means of sodium 3-methoxy-3-
oxopropane-1-sulfinate as a sulfinate transfer reagent [02TL8479]; (v) by the radical
addition of organo halides to pentafluorophenyl ethylenesulfonate [02OL2549] followed
by substitution of the pentafluorophenyl moiety by amines and (vi) by the sulfamoylation
of aromatics using sulfamoyl chloride [02SL1928]. Alkyl/aryl sulfonyl imidazoles,
-
22
prepared from sulfonyl halides and 1H-imidazole or 1-trimethylsilyl imidazole, have also
been used as sulfonyl transfer reagents in the preparation of sulfonamides ((vii) in
Scheme3-2) [92JOC4775]. However, the imidazole ring requires activation as its 3-
methylimidazolium triflate to act as a leaving group in its reactions with N- and O-
nucleophiles.
R SO
ON3
2 [H]
R SO2M
R SO2M
R=Ar
SR
O
ON N
N NO
O
OO
CCl3
Cl3C
SO
ON
R1R
R2
(vii)
TfO
(vi) R=Ar
ArH
R X
In(OTf)3
(v)
Cl SO
ON
R1
R2
OS
NaO CO2Me
SO
OOF
F
F F
F RI HNR1
R2
R=Ar R1=R2=H
R=Ar, R 1=R 2=H
R =
alkyl
R =alkyl/arylR1=R2=H
R1 =
R2 =
H
++(i)
(ii)
(iii)
+
(iv)
+
HNR1R2 R=alkylR1=R2=alkyl/aryl
R1=R2=alkyl
+ +
H2NOSO3HH2NOSO3H
Scheme 3-2. Various methods for the synthesis of sulfonamides
Although these additional synthetic methodologies help to overcome some of the
problems, they are mostly utilized for specific classes of substrates. A straightforward
and general method towards accessing sulfonamides is highly desirable, where a
sulfonating reagent would react under mild conditions in the absence of a strong base or
competing nucleophile.
-
23
Previously, our group reported the preparation of 1-phenylsulfonylbenzotriazole
3.12 and its utility in the synthesis of benzenesulfonamides and aryl benzenesulfonates
[94SC205]. 1-Phenylsulfonylbenzotriazole 3.12 is a convenient benzenesulfonylating
reagent which reacts with primary 3.14 and secondary amines 3.15 and with alcohols
3.13 under mild conditions (usually stirring in THF at rt) to give the corresponding
sulfonamides 3.17, 3.18 and sulfonates 3.16 [94SC205] (Scheme 3-3) in yields of
51-99%.
S
O
O N NNPh
S
O
O NH
Ph R
S
O
O NPh R
R
S
O
O OPh Ar
NHR
R
NH2R
OH Ar
1
1
3.12
3.14
3.15
3.133.16
3.17
3.18
Scheme 3-3. Synthesis of benzenesulfonamides and aryl benzenesulfonates from 1-phenylsulfonylbenzotriazole
The sulfonylbenzotriazole motif was shown to be a good substitute for the highly
reactive, frequently labile and often difficult to access sulfonyl halide unit. Other than its
use as a benzenesulfonating agent, 3.12 and its analogues have also been widely used in
the preparation of i) N-acylbenzotriazoles (well-known synthetic equivalents to acyl
halides [00JOC8210; 92T7817]; ii) N-imidoylbenzotriazoles [99OL577], and iii) for the
benzotriazolylalkylation of aromatic compounds [94H345].
However, the preparation of aryl/alkylsulfonylbenzotriazoles involved the
corresponding sulfonyl halides by reactions with either 1H-benzotriazole or 1-
-
24
trimethylsilylbenzotriazoles [94SC205]. This limits their application in the synthesis of
sulfonamides. We believe that a general method to prepare sulfonylbenzotriazoles
avoiding the sulfonyl halides and starting from easily available materials would be useful.
We have developed such an approach starting from aryl/alkyl lithiums or Grignard
reagents by reacting successively with SO2 and N-chlorobenzotriazole. We demonstrate
here that the aryl/alkylsulfonylbenzotriazoles prepared in this way react easily with
amines to give sulfonamides in excellent yields.
3.2 Results and Discussion
3.2.1 Preparation of Benzotriazole Reagents 3.27
Pinnic and co-workers reported the reactions of organometallic reagents with sulfur
dioxide to give sulfinic acid salts [79JOC160]. Furukawa reported the oxidation of
sulfinic acids with chloramines to produce a 50:50 mixture of sulfonamide and sulfonyl
chloride [83CPB1374]. Utilizing this information together with existing benzotriazole
methodology we have envisioned the synthesis of sulfonylbenzotriazoles as follows.
Sulfur dioxide is condensed in THF at –78°C and an organometallic reagent is
added, which forms a sulfinic acid salt. At room temperature, addition of N-
chlorobenzotriazole to the intermediate sulfinic acid salt gives the corresponding
sulfonylbenzotriazole. For example, the reaction of p-tolylmagnesium bromide 3.19 and
sulfur dioxide 3.20 followed by treating the intermediate sulfinic acid salt 3.21 with N-
chlorobenzotriazole 3.22 proceeded smoothly at 20oC to give the p-
tolylsulfonylbenzotriazole 3.27d in 68% yield (Scheme 3-4). This was confirmed by 1H
and 13C NMR, as the spectra of the product were in accordance with those previously
reported [94SC205].
-
25
SO2SOMgBr
O
Me
THF SO
ON
NN
MeMe
MgBr
N
NN
Cl
+-78-25 oC
3.27d3.19 3.20 3.21
3.22
Scheme 3-4. Synthesis of p-tolylsulfonylbenzotriazole using our method
Use of one equivalent of triethylamine with the N-chlorobenzotriazole 3.22 gave a
significant improvement: p-tolylsulfonylbenzotriazole 3.27d was isolated in 93% yield
under this modified condition.
N-Chlorobenzotriazole has been described previously as a good oxidizing agent,
liberating the chloro atom acts as an electrophile together with the benzotriazole anion
[69JCS(C)1474; 69JCS(CC)365; 69JCS(C)1478]. The mechanism of this reaction
involves the formation of a sulfinic acid salt 3.24 followed by attack of the sulfur atom of
this salt on the chloro atom in N-chlorobenzotriazole 3.22. Then, the benzotriazole anion
3.26 may attack the intermediate sulfonyl chloride 3.25 formed in situ (Scheme 3-5). The
effect of triethylamine may be to coordinate with the magnesium cation. Other
organomagnesium reagents also afforded the corresponding sulfonylbenzotriazoles 3.27
in good to excellent yields, as shown in Table 3-1.
RS
O
OM
RSO
OCl N
NN
M
RSO
ON
NN
N
NN
Cl
+ +
3.24 3.25 3.26 3.273.22
NEt3
Scheme 3-5. Proposed mechanism for the formation of sulfonylbenzotriazoles
Aryl organolithiums can also be used in the preparation of
arylsulfonylbenzotriazoles. Thus, thiophene was lithiated at C2 and the lithium reagent
-
26
was allowed to react with SO2 and N-chorobenzotriazole under the conditions described
above. Thiophene-2-sulfonylbenzotriazole was isolated in 82% yield (Table 3-1, entry
3.27h). The 1H NMR spectrum of 3.27h reveals signals of the four protons of 1-
substituted benzotriazole as two doublets of triplets at 8.11 ppm (H9) and 8.08 ppm (H6),
and two doublets of doublets of doublets (ddd) at 7.70 (H7) and at 7.51 ppm (H8). The
three protons of 2-substituted thienyl are presented as three doublets of doublets at 7.96
ppm (H4), 7.76 ppm (H2) and 7.13 ppm (H3) respectively (Figure 3-3).
We have used a variety of alkyl- and aryl- organometallic reagents to check the
general applicability and functional group tolerance of this method. The respective N-
sulfonylbenzotriazoles were isolated mostly in good yields (41-93%, Table 3-1). The
yields are largely dependent on the difficulty of formation of the organometallic reagents.
In the case of 1-methylindole, the reaction provided a mixture of many products. Only
after extensive column chromatography purification were two products isolated and
identified. The expected 2-sulfonylated product 3.27i was isolated in 20% yield along
with 11% of 2-benzotriazolyl-1-methylindole, which might have formed by the addition
of 2-lithio-1-methylindole to N-chlorobenzotriazole.
Attempts to react prop-2-ene sulfinic acid salt, formed from the reaction of
allylmagnesium bromide and SO2, with N-chlorobenzotriazole to prepare
allylsulfonylbenzotriazole gave only unidentifiable by-products and benzotriazole. Prop-
2-ene sulfinic acids are known to be very unstable and to undergo acid catalyzed
decomposition to SO2 and the olefin [78JA4634]. Similar unsatisfactory results were
also obtained with acetylenic Grignard reagents.
-
27
N NN S
O
O S 2
3
45
6
78
9
10
Figure 3-3. 1H NMR spectrum of 1-(2-thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h)
-
28
RM
OS
OR
SO
O
M
NN N Cl
RSO
O N NN
++
3.20 3.28
THF, -78oC
3.24 3.273.22
Scheme 3-6. Preparation of 1-alkyl/arylsulfonylbenzotriazoles 3.27
Table 3-1. Alkyl/arylsulfonylbenzotriazoles 3.27 3.27 R M Yield(%) Mp(oC)
a n-Butyl Li 65 Oil
b Cyclohexyl MgCl 71 117−119
c Isobutyl MgBr 75 Oil
d p-CH3C6H5 MgBr 93 133−134a
e 2-Pyridyl Li 71 132−135
f 3-Pyridyl Li 41 128−129
g 2-Furyl Li 83 107−109
h 2-Thienyl Li 82 143−144
i 1-Methyl-2-indolyl Li 20 131−132
j 1-Methylimidazolyl Li 80 147−150
a Ref. [01H1703] gives mp 134-135: all other compounds are novel.
3.2.2 Synthesis of Sulfonamides 3.29-3.37 using Reagents 3.27
The benzotriazolylsulfonamides 3.27a-j reacted as expected with diverse amines to
generate novel sulfonamides (Scheme 3-7). Based on our previous experience
[94SC205], we tried the reaction in THF at rt in the absence of a base. Thus, when 3.27a
was treated with cyclohexylamine, the corresponding sulfonamide 3.29 was obtained in
89% yield (Table 3-2). Sulfonylbenzotriazoles 3.27c and 3.27h also reacted under the
-
29
same conditions with N-methylbenzylamine and piperidine yielding the resultant
sulfonamides in 72% and 85% yields, respectively. However, for reagents 3.27f, 3.27g,
3.27j, and 3.27i the smooth displacement of benzotriazole took place with aliphatic
amines (Table 3-2) in DMF at 80°C but not in refluxing THF or acetonitrile. With this
method it was possible to obtain various sulfonamides in quantitative yields.
RSO
O N NN
RSO
O NR
R
NH
RR
RR
1 2
1
21= H or alkyl
2= alkyl
3.27 3.29-3.37
Scheme 3-7. Preparation of sulfonamides
3.3 Conclusion
N-Chlorobenzotriazole is a useful reagent for converting sulfinate salts to
sulfonylbenzotriazoles, which offer access to a wide variety of sulfonamides where the
corresponding sulfonyl halide is not readily available. In addition, the approach obviates
the formation of disulfonimides that can arise during the ammonolysis of sulfonyl halides
[79COC345]. The particular usefulness of the method lies in the ease with which
benzotriazole group can be replaced by N-nucleophiles. The easy accessibility of sulfinic
acid salts from SO2 and organometallics and the preparative ease of N-
chlorobenzotriazole should afford the approach substantial utility.
-
30
Table 3-2. Sulfonamides 3.29-3.37 prepared using reagents 3.27. Reagent 3.27 Amine Condition Sulfonamide Yield (%)
SBt
O
O
Cyclohexylamine
THF/rt/
18 h S
O
O
NH
3.29
89
SBt
O
O
N-Methylbenzyl-
amine
THF/rt/
15 h S
O
O
N Ph
3.30
72
SBt
O
OS
Piperidine
THF/rt/
42 h S N
O
OS
3.31
85
SBt
O
OO
2-Aminopentane
DMF/80 oC
/24 h SNH
O
OO
3.32
99
SBt
O
O
N
Piperidine
DMF/80oC
/48 h S N
O
O
N 3.33
99
SBt
N
N
O
O
Morpholine
DMF/80oC
/24 h SN
N
N
O
OO
3.34
91
SBt
O
O
Piperidine
THF/rt/
20 h SN
O
O
3.35
99
SBt
N
N
O
O
1, 5- Dimethyl-
hexylamine
DMF/80oC
/24 h S
NH
N
N
O
O
3.36
64
SBt
O
OS
Phenethylamine
DMF/80oC
/48 h S
NH
O
OS
3.37
80
-
31
3.4 Experimental Section
Melting points were determined on a hot-stage apparatus and are uncorrected. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 MHz NMR
spectrometer in chloroform-d solution unless stated. Column chromatography was
performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone
ketyl prior to use. All the reactions were performed under a nitrogen atmosphere and in
oven dried glasswares. Commercially available Grignard reagents were used for the
preparation of sulfinic acid salts. Organolithium reagents were prepared following
literature methods [79OR; 82OR]. All sufinic acid salts were prepared from organo
magnesium or lithium reagents and commercially available sulfur dioxide following the
method described by Pinnick and co-workers [79JOC160].
3.4.1 General Procedure for the Preparation of Sulfonylbenzotriazoles 3.27a−j
Sulfur dioxide was bubbled into THF (20 mL) at –78oC in excess (for about 10
min). The organometallic reagent (7 mmol) was added to the previous solution at –78oC.
The mixture was stirred at that temperature for 15 min, then at room temperature for 1 h.
N-Chlorobenzotriazole (1.07 g, 7 mmol) was then added in one portion and the mixture
was stirred for 2 h at rt. Triethylamine (0.92 mL, 7 mmol) was added followed by
stirring at rt for 10 h. Water (ca 100 mL) was added and the mixture was extracted with
ethyl acetate (3 × 100 mL). The combined organic layers were washed with water, brine,
dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure
gave an oil, which was further purified either by re-crystallization or column
chromatography.
1-(Butane-l-sulfonyl)-1H-1,2,3-benzotriazole (3.27a): Purified by column
chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as a brown oil (65%).
-
32
1H NMR δ 0.88 (t, J = 7.4 Hz, 3H), 1.35−1.48 (m, 2H), 1.69−1.79 (m, 2H), 3.62 (t, J =
8.0 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H),
8.17 (d, J = 8.4 Hz, 1H). 13C NMR δ 13.1, 20.9, 24.6, 55.3, 111.8, 120.4, 125.8, 130.3,
132.1, 145.0. Anal. Calcd For C10H13N3O2S: C, 50.19; H, 5.48; N, 17.56. Found: C,
50.41; H, 5.39; N, 17.89.
1-(Cyclohexylsulfonyl)-1H-1,2,3-benzotriazole (3.27b): Purified by column
chromatography with hexanes/EtOAc = 2:1 as eluent and obtained as colorless prisms
(71%), mp 117−119oC. 1H NMR δ 1.10−1.30 (m, 3H), 1.50−1.70 (m, 3H), 1.85−1.90 (m,
2H), 2.02−2.06 (m, 2H), 3.51−3.62 (m, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.66 (t, J = 7.2 Hz,
1H), 8.01 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H). 13C NMR δ 24.6, 24.7, 25.8, 65.2,
112.1, 120.5, 125.8, 130.3, 132.6, 145.0. Anal. Calcd For C12H15N3O2S: C, 54.32; H,
5.70; N, 15.84. Found: C, 54.47; H, 5.68; N, 15.71.
1-(Isobutylsulfonyl)-1H-1,2,3-benzotriazole (3.27c): Purified by column
chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as brown oil (75%).1H
NMR δ 1.09 (d, J = 6.9 Hz, 6H), 2.30 (sep, J= 6.6 Hz, 1H), 3.51 (d, J = 6.6 Hz, 2H), 7.53
(t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.4 Hz,
1H). 13C NMR δ 22.1, 24.6, 63.2, 111.9, 120.5, 125.9, 130.4, 132.0, 145.1. Anal. Calcd
For C10H13N3O2S: C, 50.19; H, 5.48; N, 17.56. Found: C, 50.08; H, 5.23; N, 17.55.
1-[(4-Methylphenyl)sulfonyl]-1H-1,2,3-benzotriazole (3.27d): Colorless
needles (from EtOAc, 93%), mp 126−129oC (Lit. mp 128−129oC) [01H1703]. 1H NMR
δ 2.39 (s, 3H), 7.32 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H),
8.00 (d, J = 8.1 Hz, 2H), 8.10 (t, J = 9.6 Hz, 2H). 13C NMR δ 21.7, 112.0, 120.5, 125.8,
128.0, 130.2, 130.3, 131.5, 134.0, 145.4, 146.7.
-
33
1-(2-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.27e): Purple needles (from
EtOAc, 71%), mp 132−135oC. 1H NMR δ 7.48−7.59 (m, 2H), 7.67−7.73 (m, 1H), 8.02
(dt, J = 7.8, 1.8 Hz, 1H), 8.08−8.12 (m, 1H), 8.21−8.25 (m, 1H), 8.36 (dt, J = 8.1, 0.9
Hz, 1H), 8.59 (ddd, J = 4.8, 1.5, 0.6 Hz, 1H). 13C NMR δ 112.7, 120.4, 123.4, 126.0,
128.6, 130.4, 132.7, 138.7, 145.4, 150.7, 154.7. Anal. Calcd For C11H8N4O2S: C, 50.76;
H, 3.10; N, 21.53. Found: C, 50.81; H, 3.05; N, 21.51.
1-(3-Pyridinylsulfonyl)-1H-1,2,3-benzotriazole (3.27f): Cream needles (from
EtOAc, 41%), mp 128−129oC. 1H NMR δ 7.49−7.56 (m, 2H), 7.64−7.74 (m, 1H),
8.10−8.15 (m, 2H), 8.42 (ddd, J = 8.1, 2.4, 1.8 Hz, 1H), 8.87 (dd, J = 4.8, 1.8 Hz, 1H),
9.30−9.31 (m, 1H). 13C NMR 111.9, 120.8, 124.1, 126.3, 130.8, 131.5, 134.1, 135.7,
145.5, 148.4, 155.5. Anal. Calcd For C11H8N4O2S: C, 50.76; H, 3.10; N, 21.52. Found: C,
50.60; H, 3.01; N, 21.13.
1-(2-Furylsulfonyl)-1H-1,2,3-benzotriazole (3.27g): Amber needles (from
EtOAc, 83%), mp 107−109oC. 1H NMR δ 6.60 (dd, J = 3.6, 1.8 Hz, 1H), 7.51−7.56 (m,
2H), 7.60−7.61 (m, 1H), 7.71 (dt, J = 8.1, 0.9 Hz, 1H), 8.11 (t, J = 8.6 Hz, 2H). 13C NMR
δ 112.0, 112.3, 120.6, 121.1, 126.1, 130.5, 131.5, 144.9, 145.4, 149.1. Anal. Calcd For
C10H7N3O3S: C, 48.19; H, 2.83; N, 16.86. Found: C, 47.82; H, 2.57; N, 16.52.
1-(2-Thienylsulfonyl)-1H-1,2,3-benzotriazole (3.27h): Needles (from EtOAc,
82%), mp 143−144oC. 1H NMR δ 7.13 (dd, J = 5.1, 3.9 Hz, 1H), 7.48−7.54 (m, 1H),
7.66−7.72 (m, 1H), 7.76 (dd, J = 5.1, 1.2 Hz, 1H), 7.96 (dd, J = 3.6, 1.2 Hz, 1H),
8.08−8.09 (m, 1H), 8.10−8.12 (m, 1H). 13C NMR δ 112.0, 120.6, 126.0, 128.2, 130.4,
131.2, 135.8, 136.3, 136.4, 145.4. Anal. Calcd For C10H7N3O2S2: C, 45.27; H, 2.66; N,
15.84. Found: C, 45.36; H, 2.34; N, 15.71.
-
34
1-[(1-Methyl-1H-indol-2-yl)sulfonyl]-1H-1,2,3-benzotriazole (3.27i): Purified
by column chromatography with hexanes/EtOAc = 6:1 as eluent and obtained as colorless
prisms (20%), mp 150−152oC. 1H NMR δ 4.08 (s, 3H), 7.19 (t, J = 6.9 Hz, 1H), 7.33-
7.51 (m, 3H), 7.60−7.69 (m, 3H), 8.06−8.11 (m, 2H).13C NMR δ 31.7, 110.7, 112.0,
113.6, 120.7, 121.9, 123.2, 124.6, 126.0, 127.3, 129.5, 130.3, 131.2, 140.2, 145.6. Anal.
Calcd For C15H12N4O2S: C, 57.68; H, 3.87; N, 17.94. Found: C, 57.54; H, 3.76; N, 17.82.
1-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]-1H-1,2,3-benzotriazole (3.27j):
Purified by column chromatography with hexanes/EtOAc = 3:7 as eluent and obtained as
colorless prisms (80%), mp 147−150oC. 1H NMR δ 4.18 (s, 3H), 7.13 (d, J = 3.6 Hz, 2H),
7.51(t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.4
Hz, 1H). 13C NMR δ 36.1, 112.5, 120.4, 126.2, 127.9, 130.6, 130.7, 131.6, 138.5, 145.3.
Anal. Calcd For C10H9N5O2S: C, 45.62; H, 3.45; N, 26.60. Found: C, 45.64; H, 3.35; N,
26.49.
3.4.2 General Procedure for the Preparation of Sulfonamides 3.29−3.37
The respective sulfonylbenzotriazole 3.27 (1 equiv.) was heated at the established
temperature in the chosen solvent with the appropriate primary or secondary amine
(1 equiv.) for the established time (See Table 3-2). Water (ca 100 mL) was added and the
mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers
were washed with water, 1M HCl, brine, dried over anhydrous sodium sulfate and
filtered. Concentration under reduced pressure gave an oil, which was further purified
either by re-crystallization or column chromatography over silica gel (200−400 Mesh).
N-Cyclohexyl-1-butanesulfonamide (3.29): Purified by column chromatography
with CHCl3 as eluent and obtained as colorless prisms (89%), mp 64-65oC (Lit. mp
-
35
71.8oC) [42CB42]. 1H NMR δ 0.95 (t, J = 7.2 Hz, 3H), 1.14–1.49 (m, 7H), 1.56–1.84
(m, 5H), 1.95–1.99 (m, 2H), 3.01 (t, J = 8.0 Hz, 2H), 3.20-3.33 (m, 1H), 4.31 (d, J = 6.6
Hz, 1H). 13C NMR δ 13.6, 21.5, 24.8, 25.1, 25.8, 34.7, 52.7, 53.9. Anal. Calcd For
C10H21NO2S: C, 54.76; H, 9.65; N, 6.39. Found: C, 54.77; H, 9.67; N, 6.34.
N-Benzyl-N,2-dimethyl-1-propanesulfonamide (3.30): Purified by column
chromatography with hexanes/Et2O = 6:1 as eluent and obtained as colorless needles
(72%), mp 32-34oC. 1H NMR δ 1.13 (d, J = 6.6 Hz, 6H), 2.32 (sep, J = 6.6 Hz, 1 H),
2.76 (s, 3H), 2.83 (d, J = 6.6 Hz, 2H), 4.32 (s, 2H), 7.31–7.36 (m, 5H).13C NMR δ 22.7,
24.5, 34.1, 53.7, 57.4, 127.9, 128.3, 128.7, 135.9. Anal. Calcd For C12H19NO2S: C, 59.72;
H, 7.93; N, 5.80. Found: C, 59.88; H, 8.10; N, 5.92.
1-(2-Thienylsulfonyl)piperidine (3.31): Purified by column chromatography with
CHCl3 as eluent and obtained as colorless prisms (85%), mp 76–77oC (Lit. mp 65oC)
[95CB1195]. 1H NMR δ 1.41–1.49 (m, 2H), 1.64–1.72 (m, 4H), 3.04 (t, J = 5.6 Hz, 4H),
7.14 (dd, J = 4.8, 3.6 Hz, 1H), 7.52 (dd, J = 3.6, 1.2 Hz, 1H), 7.61 (dd, J = 4.8, 1.2 Hz,
1H). 13C NMR δ 23.4, 25.0, 47.0, 127.5, 131.7, 132.1, 136.7. Anal. Calcd For
C9H13NO2S2: C, 46.73; H, 5.66; N, 6.05. Found: C, 46.98; H, 5.64; N, 6.15.
N-(1-Methylbutyl)-2-furansulfonamide (3.32): Purified by column
chromatography with hexanes/EtOAc = 4:1 as eluent and obtained as cream prisms
(100%), mp 57–58oC. 1H NMR δ 0.82–0.87 (m, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.21–1.38
(m, 4H), 3.33-3.45 (m, 1H), 4.45 (d, J = 7.8 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 7.03
(d, J = 3.3 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H). 13C NMR δ 13.6, 18.6, 21.9, 39.5, 50.2,
103.4, 111.2, 116.0, 145.7. Anal. Calcd For C9H15NO3S: C, 49.75; H, 6.96; N, 6.45.
Found: C, 49.95; H, 6.97; N, 6.37.
-
36
1-(3-Pyridinylsulfonyl)piperidine (3.33): Purified by column chromatography
with hexanes/EtOAc/CHCl3 = 4:1:5 as eluent and obtained as white prisms (100%), mp
88–89oC (Lit. mp 94oC) [83S822]. 1H NMR δ 1.43–1.49 (m, 2H), 1.63–1.71 (m, 4H),
3.05 (t, J = 5.6 Hz, 4H), 7.49 (dd, J = 2.7, 5.1 Hz, 1H), 8.05 (dt, J = 8.1, 1.8 Hz, 1H), 8.82
(dd, J = 4.8, 1.5 Hz, 1H), 8.99 (d, J = 2.1 Hz, 1H). 13C NMR δ 23.4, 25.1, 46.8, 123.6,
133.3, 135.2, 148.4, 153.2. Anal. Calcd For C10H14N2O2S: C, 53.08; H, 6.24; N, 12.38.
Found: C, 53.10; H, 6.32; N, 11.96.
4-[(1-Methyl-1H-imidazol-2-yl)sulfonyl]morpholine (3.34): Colorless oil (91%).
1H NMR δ 3.40 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 6.91 (s, 1H),
7.01 (s, 1H). 13C NMR δ 34.7, 46.5, 66.2, 124.6, 128.4, 141.9. Anal. Calcd For
C8H13N3O3S: C, 41.55; H, 5.67; N, 18.17. Found: C, 41.45; H, 6.04; N, 15.99.
1-[(4-Methylphenyl)sulfonyl]piperidine (3.35): White prisms (from EtOAc,
100%), mp 93oC (Lit. mp 96–98oC) [81JOC5077]. 1H NMR δ 1.36–1.45 (m, 2H), 1.60–
1.67 (m, 4H), 2.43 (s, 3H), 2.97 (t, J = 5.7 Hz, 4H), 7.32 (d, J = 8.1 Hz, 2H), 7.64 (d, J =
8.1 Hz, 2H). 13C NMR δ 21.5, 23.4, 25.1, 46.9, 127.6, 129.5, 133.2, 143.2. Anal. Calcd
For C12H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.01; H, 7.27; N, 5.95.
N-(1,5-Dimethylhexyl)-1-methyl-1H-imidazole-2-sulfonamide (3.36): Purified
by column chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as white
prisms (64%), mp 82–84oC. 1H NMR δ 0.84 (d, J = 6.6 Hz, 6H), 1.06–1.35 (m, 7H),
1.38–1.55 (m, 3H), 3.46-3.55 (m, 1H), 3.94 (s, 3H), 5.25 (s, 1H), 6.96 (s, 1H), 7.09 (s,
1H). 13C NMR δ 21.4, 22.5, 23.3, 27.8, 35.1, 37.7, 38.5, 51.1, 124.6, 128.1, 143.4. Anal.
Calcd For C12H23N3O2S: C, 52.72; H, 8.48; N, 15.37. Found: C, 52.54; H, 8.07; N, 15.84.
-
37
N-Phenethyl-2-thiophenesulfonamide (3.37): Purified by column
chromatography with hexanes/EtOAc = 3:1 as eluent and obtained as yellow oil (80%).
1H NMR δ 2.81 (t, J = 6.9 Hz, 2H), 3.32 (q, J = 6.6 Hz, 2H), 4.54 (br s, 1H), 7.06–7.13
(m, 3H), 7.20–7.32 (m, 3H), 7.56–7.59 (m, 2H). 13C NMR δ 35.6, 44.4, 126.9, 127.4,
128.7, 128.8, 131.8, 132.1, 137.5, 140.9. Anal. Calcd For C12H13NO2S2: C, 53.91; H,
4.90; N, 5.24. Found: C, 54.21; H, 4.89; N, 5.59.
-
CHAPTER 4 1-[2-BENZOTRIAZOL-1-YL)ETHYL]SULFONYLBENZOTRIAZOLE: A
VERSATILE SYNTHON FOR THE PREPARATION OF ETHYLENESULFONAMIDES AND ALKYLSULFONATE ESTERS
4.1 Introduction
In the previous chapter we mentioned that many compounds containing the
sulfonyl group are interesting from the medicinal and industrial point of view.
Ethylenesulfonamides and sulfonate esters are a significant subset of the extensive family
of compounds containing the sulfone (SO2) moiety. Most importantly, the addition of
vinyl functionality to sulfones enriches the chemistry of these compounds by providing
an opening to further transformations. Transformations such as i) epoxidation
[87TL1101], ii) aziridination [83S816], iii) Diels-Alder cycloaddition [80JA853], and iv)
nitrone cycloaddition [87H101] can be carried out with the vinyl functional group of the
ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters (Scheme 4-1).
Modifications to the ethylene functionality increase the synthetic range of sulfur
containing compounds. Additionally, new carbon-carbon and carbon-hydrogen bonds
can be generated concurrently with loss of the sulfone moiety [90T6951]. Examples of
desulfonation reactions include reductive and alkylative desulfonations, base eliminations
and methods using tin (Scheme 4-2) [90T6951].
Vinyl sulfones, ethylenesulfonamides, and ethylenesulfonate esters are also known
to be excellent Michael acceptors [90T6951; 91JOC3549] {Scheme 4-1, (v)}. Peptide
Michael acceptors are inhibitors of some protease enzymes [84JMC711; 86JMC104],
which regulate physiological functions by processing peptides and proteins.
38
-
39
SO3EtO
SO3Bu4N
NR
SO2XSO2X SO2X
BrBr R NH2, DMSO
SO2Ph
SO2N(Et)2O
NR
R
N(Et)2SO2
N+
HR
OR
SO2N(PMB)2
SO2Ph
R
CO2Me
R
SO2N(PMB)2
CO2Me
1) t-BuOOH, Triton B, THF
2) Bu4NHSO4, CH2Cl2-H2O
(i) Epoxidation
(ii) Aziridination
Br2
X = NHR, OR
(iii) Diels-Alder cycloaddition
(iv) Nitrone cycloaddition
+
(v) Michael addition
+
+ 250 0C, 110 h
1
1
2
2
K2CO3
11
Scheme 4-1. Transformations of ethylenesulfonamides, vinyl sulfones and ethylenesulfonate esters
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40
RR
RR
PhO2S
SO2MePh Bu
PhBu3B
SO2Ph
OAc
R R
RR'
SO2Ph
RR'
SO2PhSnBu3 R
R'Bu3SnLi
2 mol % Ni(acac)2
2 eq. n-BuMgCl
(i) Reductive- with transition metal catalysts
(iii) Base-Elimination
(iii) Tin method
(ii) Alkylative
tBuOK
mixture of isomers
Scheme 4-2. Desulfonation Reactions
Vinyl sulfones and ethylenesulfonamides are believed to bind irreversibly to
cysteine proteases, enzymes implicated in a number of diseases such as osteoporosis,
arthritis, Alzheimer’s disease, cancer metastasis, and programmed cell death
[95JMC3193] thus inhibiting their action [99JMC3789]. Certain vinyl sulfones have
-
41
proven effective against Trypanosoma cruzi, a protozoa agent of Chaga’s disease
[98JEM725], and as antimalarial agents [96AAC1600]. Sulfonamides have been used for
almost a century as antibiotics, as antimigrain agents, and as drugs in the treatment of
diseases caused by diverse pathogenic microorganisms, such as the hemolytic
streptococci, by inhibiting their cell division. Not surprisingly, the development of new
methodology to synthesize vinyl sulfones, ethylenesulfonamides and ethylenesulfonate
esters attracts great attention.
Known approaches to ethylenesulfonate esters and ethylenesulfonamides are: i) the
Horner-Wadsworth-Emmons reaction of α-phosphorylmethanesulfonate with an
aldehyde or ketone [98JA10994]; ii) elimination of a β-halo or β-aceto-substituted
sulfone in the presence of a base [91JOC3549]; iii) addition of a sulfone carbanion to a
carbonyl compound followed by elimination; iv) the Peterson reaction [90T6951]; v)
amidation or esterification reactions of sulfonyl chlorides [98JA10994] or sulfonates
[02OL2549], with the desired amines (Scheme 4-3).
Recently, Caddick [02OL2549] and co-workers reported the preparation of a variety of
sulfonamides using the novel pentafluorophenyl vinyl sulfonate 4.1 as an intermediate
(Figure 4-1). It is interesting to see that the intermediate 4.1 is stable. This intermediate
is a potential replacement for the sulfonyl chloride unit, because on exposure to
nucleophiles it does not liberate hydrochloric acid. However, alkylations to the olefin
were performed before amidation to avoid possible side reactions of the nucleophile with
the vinyl double bond. Also, the alkylations were performed only by radical reactions
and not by carbon-carbon nucleophilic attack. It is probable that there is no selectivity in
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42
SO2ClR
BocNHH
O
CH2CH2Ph PO
SO3EtEtOEtO
BuLi, THFBocN
CH2CH2Ph
SO3EtH
SO2ClCl
ClCH2CH2Cl-H2O
OHSO3Ph
PhS
SO2Ph
R
O
SPh
SO2Ph
Ac2O
NEt3, DMAP
R
PhS
SO2Ph
O
O
OO
OSO2Ph
SO2PhMe3Si
BuLi, DME
R NH2
R OH
RSO2NHR
SO3RR
DBU
(i)
(ii)
(iii)
(iv)
(v)
25 % NaOH, 0OC+
1) BuLi
2) RCHO
1
1
1
2
2
2
2
Scheme 4-3. Synthetic protocols toward ethylenesulfonate esters, vinyl sulfones and ethylenesulfonamides
the reactivity of the vinyl bond vs. the ester site if both are present and a nucleophile is
used.
We therefore thought of preparing a similar intermediate 4.2 and by taking
advantage of the characteristics of benzotriazole, as stabilizer and as activator of certain
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43
functional groups, we would solve the limitations of previously published procedures.
The program would include a study on target 4.2 and a study of its reactivity. Thus, this
chapter describes an approach to sulfonate esters and ethylenesulfonamides utilizing a
synthetic equivalent formed with benzotriazole.
O
F
FF
F
F
SO
ON
N N
SO
O
4.1 4.2
Figure 4-1. Intermediate 4.1 used in the preparation of ethylenesulfonamides
4.2 Results and Discussion
Our approach employs a novel intermediate 1-[2-benzotriazol-1-
yl)ethyl]sulfonylbenzotriazole 4.5 easily obtained from the reaction of 2-
chloroethanesulfonyl chloride 4.3 and benzotriazole 4.4 in 88% yield (Scheme 4-4).
Intermediate 4.5 is a solid, compared to the starting material and many other sulfonyl
chlorides, which are often liquids. It liberates benzotriazole instead of hydrochloric acid
and it is stable to air and at room temperature.
ClS
Cl
O
O NH
NN
NS
N
O
N NN NOCH2Cl2
NEt3+
0 oC-rt4.3 4.4 4.5 (88%)
Scheme 4-4. Synthesis of 1-[2-benzotriazol-1-yl)ethyl]sulfonylbenzotriazole 4.5
The preparation of benzotriazolyl reagent 4.2 from 4.5 failed. Elimination of the
benzotriazole attached to the ethyl chain was attempted using potassium tert-butoxide and
triethyl amine. The reaction did not generate 4.2 or allow recovery of the starting
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44
material (Scheme 4-5). Attempts to perform an intramolecular Michael addition using
hydrazine or hydroxylamine also failed.
NS
N
O
N NN NO
SN
O
N NO
4.5 4.2
KOBut
orNEt3
Scheme 4-5. Attempt to prepare 4.2
Our attention then shifted to intermediate 4.5. We noticed that upon exposure to
nucleophiles the reactive site is only at sulfur. The ethyl chain is not attacked by
nucleophiles because it is protected by the presence of benzotriazole. Thus 4.5 resembles
a sulfonyl chloride with a masked double bond. Nucleophilic attack occurs without the
need of a base, which shows that the reactions proceed via direct displacement of
benzotriazole by the nucleophile. Nitrogen and oxygen nucleophiles can be employed in
these reactions. Herein, we describe the facile preparation of alkylsulfonamides,
sulfonate esters and ethylenesulfonamides utilizing the novel intermediate 4.5.
4.2.1 Preparation of Sulfonamides 4.7a-g and Sulfonate ester 4.7h
Displacement of the benzotriazole attached to the sulfonyl moiety was achieved
by the reaction of 4.5 in THF or CH2Cl2 at room temperature with oxygen and nitrogen
nucleophiles. No base was necessary for the reactions to occur with nitrogen
nucleophiles. Only the desired products and benzotriazole were observed in the reaction
mixtures, and most of the products were purified by a mild basic wash. As expected, the
corresponding sulfonate ester and sulfonamides were formed in good to excellent yields
as shown in Scheme 4-6 and Table 4-1. The 1H and 13C NMR of the new products
-
45
showed the absence of the benzotriazole group and the introduction of the nucleophile
used.
NS
N
O
N NN NO NuN
SO
N NO
Nu
THF/rt4.5 4.7a-h
Scheme 4-6. Preparation of sulfonamides and sulfonate ester 4.7
Table 4-1. Sulfonamides 4.7a-g and sulfonate ester 4.7h prepared
NH2
ONa
Nu
NH
NH
NH2O
NH2
Nu
NH2
MeO
NH2
a
b
c
d
%yield
99
71
77
e
74
f
g
h
%yield
68
99
84
52
4.7 4.7
4.2.2 Preparation of Ethylenesulfonamides 4.8a, f
Base catalyzed elimination of benzotriazole from sulfonamides 4.7a and f was
carried out to afford the ethylenesulfonamides 4.8a, f (Scheme 4-7). The starting
material had first to be dissolved by heating in THF, then treated with potassium tert-
butoxide at 0°C. Mild water workup afforded the corresponding ethylenesulfonamides
4.8a and 4.8f in excellent yields.
-
46
N NN
S
O
O
NH
S
O
O
NH
N N
NS
O
O
NH
SO
O
NH
4.7a 4.8a
tBuOK
THF, 0oC, 10min
93% yield
4.7f 4.8f
tBuOK
THF, 0oC, 10min
94% yield
Scheme 4-7. Synthesis of ethylenesulfonamides
4.3 Conclusion
The use of intermediate 4.5 makes this new approach simple and versatile to afford
high yields of a variety of products under mild conditions and with easy purification. We
have described the facile preparation of alkyl sulfonamides, sulfonate esters and ethylene
sulfonamides utilizing novel intermediate 4.5.
4.4 Experimental Procedure
Melting points were determined on a hot-stage apparatus and are uncorrected. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on a 300 MHz NMR
spectrometer in chloroform-d solution unless stated. Column chromatography was
performed on silica gel (300-400 mesh). THF was distilled from sodium-benzophenone
ketyl prior to use.
4.4.1 Procedure for the Synthesis of Novel Intermediate 4.5
A solution of benzotriazole (3 g, 24.54 mmol) and triethylamine (4.5 mL, 30.68
mmol) in dichloromethane was cooled to 0°C. 2-Chloroethylsulfonyl chloride (1.29 mL,
12.27 mmol) was added dropwise and the mixture left stirring overnight. The solvent
was removed under vacuo and the residue was dissolved in ethyl acetate. The mixture in
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47
ethyl acetate was washed with water (x3) and brine. It was dried, filtered, concentrated,
and recrystallized from ethyl acetate to afford 3.56 g (88%) of 1-{[2-(1H-1,2,3-
benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole.
1-{[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (4.5):
White flakes (88%), mp 98.1–98.8°C. 1H NMR δ 4.93 (t, J = 6.3 Hz, 2H), 5.26 (t, J = 6.3
Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.4, 15.6 Hz, 2H), 7.68 (J = 7.2 Hz, 1H),
7.80–7.94 (m, 3H), 8.18 (d, J = 8.1 Hz, 1H). 13C NMR δ 41.4, 54.0, 108.8, 111.6, 117.8,
120.12, 120.3, 120.7, 124.4, 126.0, 126.2, 126.9, 128.1, 130.7. Anal. Calcd. For
C14H20N4O2S: C, 51.21; H, 3.68; N, 25.59. Found: C, 51.52; H, 3.61; N, 25.69
4.4.2 General Procedure for the Preparation of Sulfonamides 4.7a-g
A solution of the respective amine (3.03 mmol) and 1-{[2-(1H-1,2,3-benzotriazol-
1-yl)ethyl]sulfonyl}-1H-1,2,3-benzotriazole (1.0 g, 3.03 mmol) in THF was stirred at
room temperature 24 h. The solvent was evaporated and ethyl acetate added. After
washing with water and 1M NaOH (x1) the solution was dried over anhydrous sodium
sulfate and filtered. Concentration under reduced pressure gave an oil, which was further
purified by re-crystallization or column chromatography over silica gel (200-400 Mesh).
2-(1H-1,2,3-Benzotriazol-1-yl)-N-benzyl-1-ethanesulfonamide (4.7a): Colorless
prisms (99%), mp 151.8–152.9°C. 1H NMR δ 3.63 (t, J = 6.6 Hz, 2H), 4.12 (d, J = 6.0
Hz, 2H), 4.58 (s, 1H), 5.04 (t, J = 6.6 Hz, 2H), 7.14–7.16 (m, 2H), 7.26–7.28 (m, 3H),
7.40 (m, 1H), 7.52 (m, 2H), 8.10 (m, 1H). 13C NMR in DMSO δ 40.3, 42.2, 45.9, 50.6,
110.7, 119.1, 124.0, 127.3, 127.6, 128.4, 128.4, 132.1, 145.
2-(1H-1,2,3-Benzotriazol-1-yl)-N-(4-methoxybenzyl)-1-ethanesulfonamide
(4.7b): Purified by column chromatography with hexanes/ ethyl acetate/ chloroform =
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48
1:2:7 as eluent and obtained as colorless prisms (71%), mp 115.0°C. 1H NMR δ 3.58 (t,
J = 6.8 Hz, 2H), 3.75 (s, 3H), 4.08 (d, J = 5.7 Hz, 2H), 4.80 (s, 1H), 5.00 (t, J = 6.6 Hz,
2H), 6.77 (d, J =8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.38–7.42 (m, 1H), 7.48–7.52 (m,
2H), 8.06 (d, J = 8.4 Hz, 1H). 13C NMR δ 42.5, 46.7, 51.8, 55.3, 109.1, 114.2, 120.2,
124.4, 128.0, 128.2, 129.4, 132.9, 145.8, 159.5.
1-[2-(Piperidine-1-sulfonyl)-ethyl]-1H-benzotriazole (4.7c): Colorless prisms
(77%), mp 130.0–130.8°C. 1H NMR δ 1.50–1.63 (m, 6H), 3.16–3.18 (m, 4H), 3.69 (t, J
= 7.1 Hz, 2H), 5.10 (t, J = 7.2