Microwave-assisted generation and reactions of nitrile sulfides

Article abstract of DOI:10.1081/SCC-200050948

An improved practical method is described for the generation of benzonitrile sulfide based on microwave-assisted decarboxylation of 5-phenyl-1,3,4-oxathiazol-2-one. Reaction times for the preparation of cycloadducts (e.g. isothiazoles and 1,2,4-thiadiazoles) derived from the nitrile sulphide are reduced from typically 15-30 h to approximately 15 min.

Full text of DOI:10.1081/SCC-200050948

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Microwave‐Assisted Generation and Reactions
of Nitrile Sulfides
a
b
b
Angus J. Morrison , R. Michael Paton & Robert D. Sharp
a
Organon Research , Newhouse, Lanarkshire, U.K.
b
School of Chemistry , University of Edinburgh , Edinburgh, Scotland, UK
Published online: 20 Aug 2006.
To cite this article: Angus J. Morrison , R. Michael Paton & Robert D. Sharp (2005) Microwave‐Assisted
Generation and Reactions of Nitrile Sulfides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:6, 807-813, DOI: 10.1081/SCC-200050948
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Synthetic Communications , 35: 807–813, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050948
Microwave-Assisted Generation and
Reactions of Nitrile Sulfides
Angus J. Morrison
Organon Research, Newhouse, Lanarkshire, U.K.
R. Michael Paton and Robert D. Sharp
School of Chemistry, University of Edinburgh, Edinburgh
Scotland, UK
Abstract: An improved practical method is described for the generation of benzonitrile
sulfide based on microwave-assisted decarboxylation of 5-phenyl-1,3,4-oxathiazol-2-
one. Reaction times for the preparation of cycloadducts (e.g. isothiazoles and 1,2,4-
thiadiazoles) derived from the nitrile sulphide are reduced from typically 15–30 h to
approximately 15 min.
Keywords: Microwave-assisted cycloadditions, nitrile sulfides, 1,3,4-oxathiazol-2-ones
INTRODUCTION
þ
2
The chemistry of nitrile sulfides (R–C ;; N –S ) has received much
less attention than that of the other nitrilium betaines: the nitrile ylides
[
1]
[2]
þ
þ
2
2
þ
2
(
R–C ;; N –CR ), nitrile imines (R–C ;; N –NR ), and nitrile oxides
2
(
R–C ;; N –O ). And yet nitrile sulfides are uniquely well suited for the
synthesis of five-membered heterocycles incorporating the C ¼ N–S unit
via their 1,3-dipolar cycloaddition reactions with double- and triple-bonded
dipolarophiles (Scheme 1). Examples of such heterocycles accessible by
Received in the U.K. November 3, 2004
Address correspondence to R. Michael Paton, School of Chemistry, University of
Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, Scotland,
UK. E-mail: r.m.paton@ed.ac.uk

8
08
A. J. Morrison, R. M. Paton, and R. D. Sharp
Scheme 1.
[
3–6]
[7]
2-isothiazolines, 1,2,4-thiadiazoles,
[8–
this means include isothiazoles,
[13]
1
2]
[14]
1
,3,4-oxathiazoles,
and 1,4,2-dithiazoles.
As nitrile sulfides are short-lived intermediates that are prone to
decompose to sulphur and the corresponding nitrile, for preparative
purposes they are always generated in the presence of the dipolarophile.
[3]
The most widely used precursors are 1,3,4-oxathiazol-2-ones,
which
undergo decarboxylation to the nitrile sulphide on heating (Scheme 2). The
oxathiazolones usually have a good shelf life and can readily be prepared
by treatment of the corresponding carboxamide with chlorocarbonylsulfenyl
[
3,15]
chloride.
Their utility as a source of nitrile sulfides is, however, restricted
by the forcing conditions required to accomplish the decarboxylation. For
example, typical experimental procedures involve heating at reflux in chloro-
[3,13]
benzene or p-xylene (130–1358C)
for prolonged periods (5–170 h). Such
lengthy reaction times and the need for high boiling solvents are not ideal for
rapid throughput synthesis. To reduce the reaction times and extend the range
of solvents, we have investigated the feasibility of using microwave
irradiation to accelerate the rate-determining decarboxylation. This
[
16]
technique is now finding widespread application
has been used to promote various cycloaddition reactions including those
in organic synthesis and
[
17,18]
[18,19]
involving nitrile oxides
and nitrile imines,
but not nitrile sulfides.
RESULTS AND DISCUSSION
For initial experiments we selected as a representative example the synthesis
of ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate (1) from benzonitrile sulfide
[
3,15]
(
2), generated from 5-phenyl-1,3,4-oxathiazol-2-one (3),
and ethyl cyano-
[
8]
formate as the dipolarophile (Scheme 3). For comparison, an authentic
sample of the thiadiazole 1 was prepared by the conventional thermolysis
method. A solution of the phenyloxathiazolone 3 and ethyl cyanoformate
Scheme 2.

Nitrile Sulfides
809
Scheme 3.
(
ꢀ1:10 reactant ratio) in p-xylene was heated under reflux for 18 h. Removal
of the solvent and excess dipolarophile afforded an oily solid from which the
target compound was isolated in 62% yield by crystallization and recrystalli-
zation from hexane. A repeat experiment was then carried out with the same
solvent and reactant ratio, but using microwave irradiation (200 W, 10 min,
1
3
1
608C) instead of conventional heating. The C NMR spectrum of the
crude product obtained after removal of the solvent and excess ethyl cyanofor-
mate indicated that the thiadiazole 1 had been formed in near quantitative
yield. It showed characteristic signals for the thiadiazole ring at 178.8 (C-5)
and 174.4 ppm (C-3) in addition to those of the ethoxycarbonyl and phenyl
substituents, and was indistinguishable from that of the authentic sample. Sig-
nificantly, neither the oxathiazolone precursor nor the expected by-product,
benzonitrile, was detectable. A series of experiments was then carried out
under various reaction conditions. The isolated yield remained high (89%)
at a lower temperature (1408C) and also for a smaller excess of dipolarophile
(3:1) (82%). In both cases NMR spectroscopy gave no indication of by-
product formation. One of the advantages of the microwave technique is the
ability to routinely use lower boiling solvents and thus facilitate workup of
the reaction mixture. In the present case, replacing the p-xylene with THF
and with chloroform resulted in yields of 72% and 76% respectively. Ethyl
acetate proved to be particularly useful, affording the target thiadiazole in a
9
4% isolated yield.
Cycloaddition of nitrile sulfides, generated by conventional thermolysis
of oxathiazolones, to trichloroacetonitrile afforded 5-trichloromethyl-1,2,4-
thiadiazoles in moderate to good yields (45–65%),
[10,20]
although the
reaction times are reported to be long (3–4 days). A typical reaction was
therefore carried out under microwave conditions. Irradiation (300 W) of
oxathiazolone 3 and trichloroacetonitrile (molar ratio 1:10) in acetonitrile at
1
608C for 10 min, followed by workup, afforded the target 1,2,4-thiadiazole
in 61% yield. It is noteworthy that the nitrile sulphide reacts with the
4
cyano group of the trichloroacetonitile rather than the acetonitrile solvent.
[8–12]
This observation is consistent with previous reports
that electron-with-
drawing substituents increase the dipolarophilic activity of nitriles in their
cycloaddition reactions with nitrile sulfides.
Having established that 1,2,4-thiadiazoles could readily be prepared from
activated nitriles and nitrile sulfides generated by this approach, attention was

8
10
A. J. Morrison, R. M. Paton, and R. D. Sharp
turned to other classes of dipolarophiles (Scheme 4). Dimethyl acetylenedi-
carboxylate (DMAD) was the dipolarophile originally employed by Franz
[
21]
and Black to trap benzonitrile sulfide
used for the preparation of isothiazole-4,5-dicarboxylates.
and has subsequently been widely
Under
[1a,3]
forcing conditions, however, the product is sometimes contaminated by
DMAD-derived by-products, and it was anticipated that this could be
avoided using the microwave technique. Irradiation (200 W) of oxathiazolone
3
and DMAD (molar ratio 1:3) in chloroform at 1608C for 10 min afforded,
after workup, the isothiazoledicarboxylate 5 in 56% yield. Under similar con-
ditions the reaction of oxathiazolone 3 with ethyl propiolate (EP) (molar ratio
1
4
:10) yielded a regioisomeric mixture of ethyl 3-phenylisothiazole-5- and
-carboxylates 6 and 7. The isomer ratio (6:7) was measured as 13:14 from
1
the H NMR spectrum of the mixture by comparison of the 4-H peak of the
5
9
-carboxylate at 8.04 ppm with that of the 5-H peak of the 5-carboxylate at
.26 ppm. This approximately 1:1 ratio is similar to that reported for the cor-
[3]
responding conventional thermolysis reaction. The corresponding reaction
with the activated alkene dimethyl fumarate afforded the expected cyclo-
1
adduct 8; the trans configuration of the product was evident from the H
3
NMR spectrum in which there was a J coupling for 4-H/5-H of 3.4 Hz.
In conclusion, these results demonstrate that using microwave irradiation
reduces the reaction times for the generation of nitrile sulfides from hours/
days to 10–15 minutes. Furthermore, the workup of the reaction mixtures is
facilitated by the use of low boiling-point solvents and the yields of
Scheme 4.

Nitrile Sulfides
811
cycloadducts are comparable to or greater than those observed under
traditional thermal conditions.
EXPERIMENTAL
Microwave experiments were conducted in a CEM Discoverer microwave with
1 13
a 5-min ramp time and 20min cooling. H and C NMR spectra were recorded
with Brucker WP200SY or AX250 spectrometers on solutions in CDCl with
3
Me Si as internal standard. Positive-ion FAB and high-resolution mass
4
spectra were obtained on a Kratos MS50TC instrument using either glycerol
or thioglycerol matrices. Merck aluminium-backed plates coated with
Kieselgel GF254 (0.2mm) were used for analytical TLC; detection was by
UV or sulfuric acid charring. Preparative chromatography was carried out,
either using Kieselgel GF254 and eluted under water pump vacuum or using
Strata Si-1 silica (55 mm, 70A) columns with 10g/60ml tubes. 5-Phenyl-
[3]
1,3,4-oxathiazol-2-one was prepared as previously reported. Typical pro-
cedures for the nitrile sulfide cycloaddition reactions are given below.
Typical Procedures
Ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate 1
Conventional thermolysis. A solution of oxathiazolone 3 (193 mg, 1.08 mmol)
and ethyl cyanoformate (ECF) (1.0 ml, ꢀ10.1 mmol) in p-xylene (6 ml) was
heated at reflux for 16 h. After removal of the excess ECF and the solvent
under reduced pressure, the residue was recrystallized from hexane to afford
[8]
the compound 1 as white crystals (156 mg, 62%); mp 678C (lit. 70–
1
7
18C); H NMR d (200 MHz, CDCl ) 8.30 (2H, m, PhH), 7.35–7.45 (3H,
H
3
m, PhH), 4.46 (2H, q, J ¼ 7.1 Hz, OCH ), 1.41 ppm (3H, t, J ¼ 7.1 Hz,
2
1
CH ); C NMR dC (40 MHz, CDCl ) 178.8 (C-5), 174.4 (C-3), 158.3
3
3
3
(
C 55 O), 131.8 (PhC), 130.7, 128.6, 128.3 (5 PhC), 63.1 (CH ), 14.0 (CH );
2 3
þ
þ
HRMS (FAB) Found: M þ 1, 235.0547. C H NO S requires M þH
1
1
10
2
2
35.054413.
Microwave irradiation. A solution of oxathiazolone 3 (100 mg,
.56 mmol) and ethyl cyanoformate (ECF) (0.5 ml, ꢀ5.0 mmol) in p-xylene
0
(3 ml) was heated in the microwave at 1608C and with a 200-W power
input for 10 min. After cooling, the excess ECF and the solvent were
1
removed under reduced pressure and the residue examined by H and
1
3
C NMR spectroscopy. The resulting spectra were almost indistinguishable
from those of the authentic sample of compound 1, indicating that it had
been formed in near quantitative yield. The reaction was repeated at 1408C
(89% isolated yield), and using a three-fold excess of ECF at 1608C (82%).

8
12
A. J. Morrison, R. M. Paton, and R. D. Sharp
Reactions were also carried out (1608C/1:10 reactant ratio) in THF (72%),
chloroform (76%), and ethyl acetate (94%). Compounds 4–8 were prepared
similarly.
ACKNOWLEDGMENT
We thank the EPSRC and Organon Research for financial support.
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