One-step synthesis of 5-acylisothiazoles from furans

Article abstract of DOI:10.1039/b101157j

Premixed ethyl carbamate, thionyl chloride and pyridine (which generate thiazyl chloride, N≡SCl) in boiling benzene or toluene convert 2,5- and 2,3,5-substituted furans into 5-acylisothiazoles regiospecifically. The reactions are much faster and generally higher yielding in boiling chlorobenzene with more thionyl chloride and with pyridine or isoquinoline as base. Under the more vigorous conditions, even fully substituted 3-bromofurans give isothiazoles, with the displacement of bromine. Deactivated furans, with electron-withdrawing groups such as ester, cyano, benzoyl and phenylsulfonyl in the α-position, react under the more vigorous conditions to give 5-acylisothiazoles with the electronegative group in the 3-position. The 'activated' 2-methyl-5-phenyl- and 5-phenyl-2-phenylthio-furans react analogously, with the more electron-releasing group becoming part of the 5-acyl substituent, exclusively or predominantly. These results are explained by initial electrophilic attack of the furan ring to give a β-thiazyl derivative which spontaneously ring-opens and closes to the isothiazole. The X-ray structures of five of the differently substituted isothiazole compounds are reported. All have very similar patterns of bonding within their isothiazole rings that appear to be independent of the electron-withdrawing or -donating nature of the substituents. Three of the compounds (8a, 8g and 13) have loosely linked chain structures in the solid state, adjacent molecules being connected by combinations of hydrogen bonding and π-π stacking interactions.

Full text of DOI:10.1039/b101157j

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One-step synthesis of 5-acylisothiazoles from furans
Jérôme Guillard,a Christelle Lamazzi,a Otto Meth-Cohn,a Charles W. Rees,a,b
Andrew J. P. Whiteb and David J. Williamsb
1
a Department of Chemistry, University of Sunderland, Sunderland, UK SR1 3SD
b Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY
Received (in Cambridge, UK) 5th February 2001, Accepted 12th April 2001
First published as an Advance Article on the web 15th May 2001
᎐
Premixed ethyl carbamate, thionyl chloride and pyridine (which generate thiazyl chloride, N᎐SCl) in boiling benzene
᎐
or toluene convert 2,5- and 2,3,5-substituted furans into 5-acylisothiazoles regiospecifically. The reactions are much
faster and generally higher yielding in boiling chlorobenzene with more thionyl chloride and with pyridine or
isoquinoline as base. Under the more vigorous conditions, even fully substituted 3-bromofurans give isothiazoles,
with the displacement of bromine. Deactivated furans, with electron-withdrawing groups such as ester, cyano,
benzoyl and phenylsulfonyl in the α-position, react under the more vigorous conditions to give 5-acylisothiazoles
with the electronegative group in the 3-position. The ‘activated’ 2-methyl-5-phenyl- and 5-phenyl-2-phenylthio-furans
react analogously, with the more electron-releasing group becoming part of the 5-acyl substituent, exclusively or
predominantly. These results are explained by initial electrophilic attack of the furan ring to give a β-thiazyl
derivative which spontaneously ring-opens and closes to the isothiazole. The X-ray structures of five of the differently
substituted isothiazole compounds are reported. All have very similar patterns of bonding within their isothiazole
rings that appear to be independent of the electron-withdrawing or -donating nature of the substituents. Three of the
compounds (8a, 8g and 13) have loosely linked chain structures in the solid state, adjacent molecules being connected
by combinations of hydrogen bonding and π–π stacking interactions.
Introduction
We have recently shown that the one-step conversion of
2,5-disubstituted furans into 5-acyl-3-substituted furans by
trithiazyl trichloride, (NSCl)3,1 can be achieved much more
conveniently by replacing the inorganic reagent by a mixture of
ethyl carbamate, thionyl chloride and pyridine.2 This and other
closely related mixtures were shown by Katz and co-workers to
be the equivalent of (NSCl)3 in the conversion of quinones into
their fused 1,2,5-thiadiazole derivatives.3 This mixture, the Katz
(NSCl)3 and with the Katz reagent, especially with the polar-
᎐
reagent, probably generates thiazyl chloride, N᎐SCl, which is in
᎐
ised furan 1d, suggested that the reactions had a common
intermediate, most reasonably thiazyl chloride, NSCl.1,2 This
electrophilic species probably substitutes the furan to give a
β-thiazyl derivative which spontaneously rearranges to the
isothiazole.1
Since this new reaction provides an attractive one-step route
from readily available furans to isothiazoles, we have now
explored the reagents and reaction conditions in more
detail and extended the furan substrates to include electron-
withdrawing and electron-releasing functional groups.
equilibrium with its trimer. We found that the Katz reagent
behaved exactly like (NSCl)3 in transforming 2,5-diaryl-
and 2,5-di-tert-butyl-furans into the 5-acyl-3-substituted iso-
thiazoles, though in even higher yield.2 Thus, following earlier
work,3 a solution of ethyl carbamate (4.3 mmol), thionyl
chloride (4.3 mmol) and pyridine (2 ml) in benzene (20 ml) was
stirred at room temperature for 30 min (Method A). The furan
1a–d (1 mmol) was then added and the mixture heated at reflux
until the furan was consumed, to give the isothiazoles 2a–d in
98, 94, 66 and 76% yield, respectively. The trisubstituted furans
3a,b gave the analogous isothiazoles 4a,b similarly in 56 and
99% yield respectively.2
Results and discussion
Reagent variation
With the aim of reducing reaction times and, where necessary,
increasing yields, we examined the conversion of 2,5-diphenyl-
furan 1a and 2,3,5-triphenylfuran 3a into the isothiazoles 2a
and 4a, respectively, under more vigorous conditions (Table 1).
Replacing the solvent benzene by toluene (Method B)
decreased the reaction time from 24 to 6 h for 1a though with
a drop in yield, and from 18 to 1 h for 3a, with a large increase
in yield. This trend continued with chlorobenzene as solvent
and with pyridine optionally replaced by isoquinoline as the
base, the amount of thionyl chloride being doubled to take
account of its volatility (Method C); both 1a and 3a gave high
The reactions are regiospecific giving only the 5-acyl, and
none of the 3-acyl isomer. The similarity of the results with
1304
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101157j

View Online
Table 1 Treatment of furans 1a and 3a with ethyl carbamate, thionyl chloride and a base in a boiling solvent
Urethane/
mmol
SOCl2/
mmol
Reaction
time/h
Yield of 2a/4a
(%)
Furan
Base
Solvent
1a
3a
3a
3a
1a
3a
3a
1a
3a
3a
3a
3a
3a
1a
1a
4.3
4.3
4.3
4.3
4.3
4.3
2.15
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
4.3
8.6
8.6
8.6
8.6
8.6
8.6
8.6
8.6
Pyridine
Pyridine
Pyridine
4 Å mol. sieves
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Benzene
Benzene
None
Benzene
Toluene
Toluene
Toluene
PhCl
PhCl
PhCl
PhCl
PhCl
24
18
1
7
6
2a (98)
4a (56)
4a (77)
4a (5)
2a (70)
4a (85)
4a (71)
2a (77)
4a (88)
No reaction
4a (26)
4a (56)
4a (82)
2a (80)
2a (95)
1
3.5
0.5
0.5
None
Quinoline
2,6-Lutidine
DMAP
Isoquinoline
Isoquinoline
48
12
0.5
0.5
0.5
PhCl
PhCl
PhCl
yields of the respective isothiazoles (80 and 95%) in a mere 30
min of heating under reflux. These hotter reactions in toluene
and in chlorobenzene, with premixing of the carbamate, thionyl
chloride and base at room temperature before the addition of
the furan, became our standard procedures for most of the later
reactions. Quinoline and 2,6-lutidine were less efficient than
isoquinoline in chlorobenzene reactions, though the more
expensive DMAP was equally good. There was no reaction in
the absence of added base though 4 Å molecular sieves, which
absorb hydrogen chloride, did give very slow reaction in boiling
benzene. Replacement of thionyl chloride by thionyl bromide
gave much lower yields. No advantage was gained by using
methyl, allyl or phenyl carbamate in place of urethane.
These higher temperature conditions were then tested on
3-bromo-2,5-diphenylfuran 3b, 3,4-dibromo-2,5-diphenylfuran
5 and 3-bromo-2,4,5-triphenylfuran 6 readily made by bromin-
ation of 1a and 3a. With pyridine in benzene, the trisubstituted
furan 3b gave the isothiazole 4b in virtually quantitative yield,
though in a relatively long time (16 h); with isoquinoline in
chlorobenzene it gave 4b in 80% yield in 10 min.
The tetrasubstituted furans 5 and 6 were not expected to
react with the Katz reagent since they had been found not to
react with (NSCl)3.1b This seemed reasonable since the reaction
stoichiometry involved the loss of hydrogen chloride, with the
hydrogen being displaced from the furan ring.1b These com-
pounds were reported not to react in boiling benzene,2 though a
reinvestigation has shown that 5 does react very slowly, giving,
after 48 h, 13% of the same isothiazole 4b as from the mono-
bromo furan 3b. When this reaction was repeated with iso-
quinoline in chlorobenzene, 4b was isolated in 68% yield after
1 h. Furan 6 also reacted with the Katz reagent to give low
yields of the same isothiazole 4a as from triphenylfuran 3a;
with pyridine in toluene consumption of 6 was slow giving 15%
of 4a in 24 h, with starting material remaining, and with iso-
quinoline in chlorobenzene it was fast but complex, giving 12%
of 4a in 45 min.
the absence of acid, which is generated in the ethyl carbamate–
thionyl chloride reaction.
2,5-Di-tert-butylfuran 1c gave the isothiazole 2c in moder-
ately good yield (66%) with pyridine in benzene, but much more
slowly (6 days) than the diaryl compounds. With isoquinoline in
chlorobenzene the reaction time was reduced to 12 h but with
some decomposition and a lower yield (40%).
All of these results indicate the much enhanced reactivity of
the isoquinoline–chlorobenzene modification of the Katz
reagent.
Deactivated furans
We next examined a series of 5-phenylfurans 7 bearing an
electron-withdrawing group, X, at the 2-position (X = CO2H,
CO Et, CH᎐NOH, CH᎐NOMe, CN, COMe, COPh and
᎐
᎐
2
SO2Ph) to see if these deactivated rings would undergo the
same reaction.
With the exception of the oxime none of these compounds
reacted significantly with the benzene–pyridine reagent, but
they did react under the more vigorous conditions. 5- Phenyl-
furan-2-carboxylic acid 7a decomposed but its ethyl ester 7b
gave the ethyl 5-benzoylisothiazole-3-carboxylate 8b in 25%
yield with pyridine in toluene after 3 days and in 52% yield in
chlorobenzene after 48 h.
In this unexpected conversion of bromofurans 5 and 6 into
isothiazoles with one fewer bromine atom, bromine is lost pre-
sumably as Brϩ by electrophilic displacement e.g. by acid or
NSCl. However, a brief attempt to intercept Brϩ, or BrCl, with
anisole added to the reaction mixture was unsuccessful.
Similar furan to isothiazole conversions were obtained in
chlorobenzene with X = CN (24%, 2 days), X = CH᎐NOMe
᎐
(27%, 2 days), X = COPh (51%, 2.5 h) and X = SO2Ph (60%, 6 h
and 55% with pyridine in toluene for 48 h) to give 8c, d, f and g
respectively. With X = Ac however, rapid decomposition ensued
in toluene and chlorobenzene, possibly involving the enol
The lack of reaction of 5 and 6 with (NSCl)3 in boiling tetra-
chloromethane1b may result from the lower temperature and/or
tautomer. Treatment of the isomeric oximes 7, X = CH᎐NOH,
᎐
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313
1305

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Table 2 Isothiazole bond lengths (Å) for structures 8a, 8g, 8j, 9j and
13
8a
8g
8j
9j
13
S(1)–N(2)
N(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(5)–S(1)
1.635(2)
1.327(2)
1.404(3)
1.368(3)
1.707(2)
1.642(2)
1.311(3)
1.410(3)
1.368(3)
1.714(2)
1.644(2)
1.335(3)
1.424(3)
1.364(3)
1.701(2)
1.635(3)
1.298(3)
1.432(3)
1.381(3)
1.704(3)
1.639(2)
1.323(3)
1.422(3)
1.365(3)
1.708(2)
Fig. 1 The molecular structure of 8a.
with the thionyl chloride reagent in boiling benzene, or better,
toluene not surprisingly gave the cyanide 7c very efficiently
(92%), but the isomeric oxime ethers 7d resulted in the iso-
thiazole 8d, presumably as the more stable anti-isomer. The
structures of the isothiazoles 8 followed from their spectro-
scopic properties, compared with other 5-benzoylisothiazoles
made in the same way, and were confirmed by X-ray crystal-
lography for the carboxylic acid 8a, prepared by hydrolysis of
its ethyl ester 8b, and for the sulfone 8g. Thus the regio-
chemistry of these reactions is as expected for the initial
substitution of the polarised furan ring at the more nucleophilic
β-position, via 10 which is thought to rearrange by ring-
opening and ring-closing (Scheme 1) to give the 5-benzoyl-
isothiazole exclusively.1a
Fig. 2 Part of one of the continuous chains of molecules present in
the structure of 8a. The respective mean interplanar and ring
centroid ؒ ؒ ؒ ring centroid separations are (a) 3.59, 3.84 Å. The O ؒ ؒ ؒ C
separation (b) is 3.15 Å. The O–H ؒ ؒ ؒ O hydrogen bond (c) has O ؒ ؒ ؒ O,
H ؒ ؒ ؒ O distances 2.65, 1.75 Å, and O–H ؒ ؒ ؒ O angle 175Њ.
Scheme 1
The structure of the carboxylic acid 8a (Fig. 1) shows the
carboxylic acid group to lie almost coplanar with the iso-
thiazole ring, the torsional twist about the C(3)–C(13) bond
being only ca. 6Њ. The phenyl ring is fairly steeply inclined, by
ca. 49Њ, to the isothiazole ring plane, the inclination being
produced by torsional twists of 22 and 33Њ about the C(5)–C(6)
and C(6)–C(7) bonds respectively. The O(1) carbonyl group is
oriented syn to the isothiazole ring sulfur atom. The isothiazole
ring is almost perfectly planar (maximum deviation of <0.001
Å), but C(6) lies 0.106 Å out of this plane whereas C(13) devi-
ates by only 0.043 Å in the opposite sense. The bonding within
the isothiazole ring is fairly typical of that reported previously
for this ring system, there being a distinct pattern of bond
ordering with the C(3)–N(2) and C(4)–C(5) bonds each dis-
playing significant double bond character (Table 2). Adjacent
centrosymmetrically related pairs of molecules pack with their
isothiazole rings overlying each other, this stacking interaction
(a in Fig. 2) being supplemented by a pair of carbonyl ؒ ؒ ؒ carb-
oxylic OδϪ ؒ ؒ ؒ Cδϩ interactions (b in Fig. 2). These “dimer
pairs” are then linked via carboxylic ؒ ؒ ؒ carboxylic hydrogen
bonds (c in Fig. 2) to form continuous chains. Neighbouring
chains are weakly cross-linked by π–π interactions between the
phenyl rings in one chain and the opposite face of the carb-
oxylic group involved in the δϩ ؒ ؒ ؒ δϪ interaction (b) in the next
Fig. 3 The molecular structure of 8g.
The solid state structure of the sulfone 8g is illustrated in
Fig. 3. The isothiazole phenyl sulfone adopts an open-book con-
formation analogous to that invariably observed for unstrained
diphenyl sulfones,4 the torsional twists about the C(3)–S(6) and
S(6)–C(14) linkages being ca. 89 and 85Њ respectively. The ter-
minal phenyl ring B is less steeply inclined to the isothiazole
ring than in 8a, the 40Њ inclination being comprised of torsional
twists of 18 and 25Њ about C(5)–C(15) and C(15)–C(21) respec-
tively. As observed in 8a, the carbonyl oxygen is oriented syn to
the isothiazole sulfur. The pattern of bonding in the isothiazole
ring does not differ markedly from that observed in 8a. Unlike
in 8a, the C(15) and S(6) substituents lie only 0.056 and 0.008 Å
respectively above and below the isothiazole ring plane (which
is planar to within 0.007 Å). C2 related molecules stack with the
isothiazole ring A of one molecule overlaying the phenyl ring B
of the next and vice versa (a in Fig. 4). This stacking interaction
is supplemented by a pair of C–H ؒ ؒ ؒ π interactions between
one of the meta C–H hydrogen atoms of ring B in one molecule
and the phenyl sulfone ring C in the next (b in Fig. 4). These
“dimer pairs” are linked by C–H ؒ ؒ ؒ O hydrogen bonds between
and vice versa; the Ph(ring
ؒ ؒ ؒ C(13) distance is 3.48 Å.
centroid)
There are no short intermolecular S ؒ ؒ ؒ N contacts.
1306 J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313

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Fig. 5 The molecular structure of 13.
Fig. 4 Part of one of the continuous chains of linked ‘‘dimers’’
present in the structure of 8g. The respective mean interplanar and
ring centroid ؒ ؒ ؒ ring centroid separations are (a) 3.68, 3.91 Å. The
Fig. 6 Part of one of the continuous chains of molecules in the
structure of 13. The mean interplanar and centroid ؒ ؒ ؒ centroid
separations are (a) 3.60, 3.93 Å and (b) 3.58, 3.98 Å respectively. The
C–H ؒ ؒ ؒ O hydrogen bond (c) has C ؒ ؒ ؒ O, H ؒ ؒ ؒ O distances 3.30, 2.56
Å, and C–H ؒ ؒ ؒ O angle 135Њ.
C–H ؒ ؒ ؒ π interaction (b) has H ؒ ؒ ؒ π 2.82
Å and C–H ؒ ؒ ؒ π
147 Њ. The C–H ؒ ؒ ؒ O hydrogen bond (c) has C ؒ ؒ ؒ O, H ؒ ؒ ؒ O distances
3.31, 2.40 Å, and C–H ؒ ؒ ؒ O angle 157Њ.
the isothiazole methine hydrogen in one molecule and one of
the sulfone oxygen atoms O(8) in the next (c in Fig. 4). These
interactions combine to form continuous chains of molecules,
though here there are no obvious interchain interactions of
note.
As with the 5-phenyl derivatives, 5-tert-butylfuran-2-carb-
oxylic acid also decomposed under the standard conditions, but
its ethyl ester reacted cleanly to give ethyl 5-pivaloylisothiazole-
3-carboxylate in 57 and 80% yield respectively in pyridine–
toluene and in isoquinoline–chlorobenzene. A limited range of
activated 2-phenylfurans was also examined. 2-Phenylfuran
itself did not give any isothiazole with the Katz reagent in tolu-
ene, but instead a low yield (15%) of bis(5-phenylfuran-2-yl)
sulfide 11 together with much decomposition. The structure of
Finally and more interestingly, 5-phenyl-2-phenylthiofuran
12 reacted with the Katz reagent in toluene (8 h) and in
chlorobenzene (30 min) to give both possible isomeric 5-acyl-
isothiazoles 13 and 14 in the yields shown (Table 3). The struc-
tures of 13 and 14 followed from the spectroscopic data, and
structure 13 was confirmed by X-ray crystallography. In the
starting furan 12 the β-position adjacent to the phenylthio
group is the more nucleophilic and preferential attack here
leads to the major isothiazole 13. This result should be con-
trasted with the same reaction of the corresponding sulfone 7g
which gave exclusively the isothiazole 8g resulting from attack
at the β-position non-adjacent to the phenylsulfonyl group, as
expected. This illustrates, once more, that the more electron-
withdrawing α-substituent of the furan becomes the isothiazole
3-substituent and the more electron-releasing one becomes part
of the isothiazole 5-acyl substituent.
The X-ray analysis of 13 (Fig. 5) shows the isothiazole and its
adjacent phenyl ring (B) to be in almost perfect conjugation
with each other, the torsional twist about the C(3)–C(11)
linkage being only ca. 2Њ. The carbonyl oxygen is again oriented
syn to the ring sulfur atom, though the group lies much closer
to the isothiazole ring plane [torsional twist of ca. 8Њ about
C(15)–C(12)]. The terminal phenyl ring C is oriented almost
orthogonally to the remainder of the molecule, there being a ca.
80Њ rotation about the S(13)–C(19) bond. Within the isothiazole
ring, the bond lengths show only minor variations compared
with those in 8a and 8g (Table 2). The molecules are linked by
π–π stacking interactions to form continuous chains (Fig. 6).
There is (i) a centrosymmetric reverse-stacking of the phenyl-
isothiazole ring systems, ring A overlaying ring B and vice versa
(a in Fig. 6) and (ii) a parallel stacking of rings C about an
independent inversion centre (b in Fig. 6). This latter inter-
action is supplemented by a pair of possible weak C–H ؒ ؒ ؒ O
hydrogen bonding interactions across the same inversion centre
between the para hydrogen on ring C in one molecule and the
11 was confirmed by a more obvious synthesis from 2-phenyl-
furan and sulfur dichloride in the presence of pyridine. The
formation of 11 with the Katz reagent is not too surprising
since the free α-position of 2-phenylfuran is highly susceptible
to electrophilic attack, for example by thionyl chloride to give
the furansulfinyl chloride which can react again with starting
furan to give the bis-furanyl sulfoxide;5 this could be reduced by
more thionyl chloride, a known process,6 or by a related inter-
mediate species, to the sulfide 11. Substitution of the free
α-position of the 2-phenylfuran by thiazyl chloride, NSCl, is
also possible but this does not lead to a reasonably low energy
ring-opening and ring-closing sequence to give an isothiazole,
as the β-thiazyl derivatives do. With both α-positions blocked,
2-methyl-5-phenylfuran did give the expected 5-benzoyl-3-
methylisothiazole 8, X = Me in 40 and 50% yield in toluene and
chlorobenzene respectively.
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313
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Table 3 Treatment of 5-phenyl-2-phenylthiofuran 12 with ethyl carbamate, thionyl chloride and a base in a boiling solvent
Base
Solvent
Reaction time/h
Yield (%) 13
Yield (%) 14
Pyridine
Isoquinoline
Toluene
Chlorobenzene
8
0.5
34
30
17
12
Table 4 Conversion of furans into 5-acylisothiazoles
Method A
Method B
Method C
Furan
Isothiazole
Time/h
Yield (%)
Time/h
Yield (%)
Time/h
Yield (%)
1a
1c
3a
3b
5
2a
24
6
18
16
48
98
66
56
99
13
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6
1
70
—
85
—
—
15
25
14
20
2
55
8h: 38
8i: 47
—
8j: 35
—
0.5a
12a
0.5a
10 mina
1a
80
40
95
80
68
12
52
24
2c
4a
4b
4b
6
4a
24
3
2
0.75a
48a
2a
7b
7c
7d
7f
7g
7h
7i
8b
8c
8d
5
2a
27
51
60
9m: 35
8i: 6; 9i: 25
8i: 38; 9i: 11
8j: 12; 9j: 41
8j: 31; 9j: 47
8j: 24; 9j: 36
8j: 80; 9j: 13
30
8f
12
48
24
48
2.5a
6a
8g
8h/9m
1.5b
2b
8i/9i
7i
8i/9i
2b,c
6a
7j
8j/9j
24
7j
8j/9j
6a
7j
8j/9j
—
—
34
17
40
57
6a,d
6a,e
0.5a
0.5a
72a
24a
7j
8j/9j
12
13
8
8
5
ϩ14
12
50
80
2-Me-5-Ph
5-PhCO-3-Me
5-But-2-CO2Et
3-EtO2C-5-COBut
24
a Isoquinoline used as base. b Pyridine used as base. c Half of the thionyl chloride added at the start of reaction and the other half added after half
reaction time. d Only 4.3 mmol thionyl chloride used. e Thionyl chloride added dropwise throughout the reaction.
carbonyl oxygen O(12) of the next (c in Fig. 6). Adjacent chains
are loosely linked by aromatic edge-to-face interactions
between the edges of rings C in one chain and the faces of rings
A in the next (the centroid ؒ ؒ ؒ centroid separations are 5.14 Å).
isothiazole ring hydrogen. Comparative spectral data together
with X-ray crystallography on both of the isothiazoles derived
from 7j, revealed, surprisingly, that the chlorinated product was
the rearranged 3-chloro-4-silylated-5-benzoylisothiazole 9j.
Furthermore, the isolated isothiazole 8j was not transformed,
as expected, into the rearranged product by further Katz
treatment in chlorobenzene! The starting furans were also not
chlorinated by treatment with thionyl chloride in refluxing
chlorobenzene, or by pyridine hydrochloride in the same solv-
ent. The yield of the rearranged products is greatest when tech-
nical grade thionyl chloride is utilised, suggesting possibly that
sulfur chlorides are the key chlorinating agents bringing about
the rearrangement. Thus with technical grade thionyl chloride
using pyridine in chlorobenzene, after 6 h reflux the yields of
8j and 9j were 58 and 31% respectively; using purified thionyl
chloride under the same conditions, the same products were
isolated in 70 and 21% yields.
At present we have no evidence for the mechanism of this
novel silyl rearrangement and chlorination process. Optimis-
ation of the conditions allowed the triisopropylsilylfuran 7j to
give 80% of the unrearranged isothiazole 8j together with 13%
rearranged product 9j by addition of thionyl chloride dropwise
during the 6 h reflux in chlorobenzene with pyridine as base.
Alternatively, using the standard mode of reaction 31% un-
rearranged together with 47% rearranged isothiazole were
isolated.
Silylated furans
Because of the well known replaceability of a silyl group by a
wide range of other substituents, we finally investigated the
transformation of silylated furans into the corresponding
silylated isothiazoles. This would be of particular value in that,
for example, simple acylisothiazoles are hardly known, and
could be made by appropriate protodesilylation.
Both 5-silylated-2-phenylfurans 7h–7j and 2,5-di-silylated
furans were readily synthesised by reaction of the correspond-
ing organolithium derivative with a trialkylsilyl chloride. The
silyl groups investigated were trimethylsilyl, dimethyl-tert-
hexylsilyl, and triisopropylsilyl.
Reaction of the 5-silylated-2-phenylfurans 7h–7j with the
Katz reagent in refluxing toluene with pyridine as the base,
generated the expected 5-benzoyl-3-silylated isothiazoles 8h–8j
in 38, 47 and 35% respectively (Table 4). However, in boiling
chlorobenzene with pyridine or isoquinoline as the base the
trimethylsilylfuran 7h gave instead the chlorodesilylated prod-
uct, 9m (38%). The more heavily substituted silylfuran deriv-
atives 7i and 7j in hot chlorobenzene gave the expected products
8i and 8j in slightly lower yields, together with an analogous
isothiazole bearing an extra chlorine substituent in place of the
These silylated isothiazoles have so far proved impervious
to the action of a variety of electrophiles including mineral
1308
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within statistical significance, those for C(4)–C(5), C(5)–S(1)
and S(1)–N(2) are unchanged (Table 2). There are, however, no
obvious correlations between the small changes in the N(2)–
C(3) and C(3)–C(4) bond lengths and the electron-withdrawing
or -donating nature of the substituents on C(3) and C(4). The
marginally longer value for C(4)–C(5) in 9j is probably due to
the absence of any possible conjugation with the Ph–C᎐O
᎐
group attached to C(5), vide supra.
The transformation of furans reported in this paper provides
a novel and very simple route to a new range of functional-
ised isothiazoles of considerable interest as components of
natural products and as pharmaceutical and agrochemical
compounds.
Experimental
Fig. 7 The molecular structure of 8j.
General details
Melting points were taken on a Reichert hot-stage apparatus.
Infrared spectra were recorded on a Unicam Research Series 1
FTIR instrument as liquid films (for oils) or KBr discs. NMR
spectra were recorded on a JEOL 270 spectrometer. Chemical
shifts are given in ppm and are referenced to the residual peak
of the solvent or tetramethylsilane. Coupling constants are
given in hertz. Low resolution mass spectra were recorded on a
Kratos MS8ORF and accurate mass measurements on a VG
Autospec mass spectrometer using chemical ionisation employ-
ing ammonia. TLC was performed using Merck silica 60F254
plates and flash chromatography with Fluka silica gel 60. Light
petroleum refers to the fraction boiling between 60 and 80 ЊC.
Organic layers were dried over Na2SO4.
The following compounds were prepared by literature
methods: 2,5-diphenylfuran 1a,1a 2,5-di-tert-butylfuran 1c,7 3-
bromo-2,4,5-triphenylfuran 6,1a 3,4-dibromo-2,5-diphenylfuran
5,1a 2-phenylfuran,8,9 2-methyl-5-phenylfuran1c,8 and 5-tert-
butylfuran-2-carboxylic acid.7 5-Phenylfuran-2-carbaldehyde
was prepared9,10 by the formylation of 2-phenylfuran to give an
oil (84%), νmax (neat)/cmϪ1 3114, 2815, 1673, 1523, 1475, 1390,
1257, 1029; δH (CDCl3) 6.83 (1H, d, J 3.62), 7.31 (1H, d, J 3.62),
7.36–7.48 (3H, m), 7.77–7.85 (2H, m), 9.64 (1H, s, CHO); m/z
173 (M ϩ 1, 100%).
Fig. 8 The molecular structure of 9j.
acid, bromine or NBS and iodine and silver trifluoroacetate.
Tetrabutylammonium fluoride in refluxing THF caused
decomposition of the substrates.
In the structure of 8j, the replacement of the carboxylic acid
in 8a by a triisopropylsilyl unit is accompanied by a dramatic
Oxidation9 of this aldehyde gave 5-phenylfuran-2-carboxylic
acid 7a (65%), mp 147 ЊC (methanol) (lit.9 146–148 ЊC), νmax
(KBr)/cmϪ1 3143–2800, 1677, 1523, 1475, 1265, 1164, 1027;
δH (DMSO-d6) 7.12 (1H, d, J 3.63), 7.26 (1H, d, J 3.63), 7.35–
7.43 (1H, m), 7.44–7.52 (2H, m), 7.76–7.83 (2H, m); m/z 189
(M ϩ 1, 100%), 171 (7). Ethyl 5-phenylfuran-2-carboxylate 7b
was prepared from the above acid 7a and catalytic sulfuric acid
in ethanol under reflux for 12 h to give a colourless oil (70%),
νmax (neat)/cmϪ1 2983, 1714, 1481, 1335, 1301, 1141, 1018;
δH (CDCl3) 1.39 (2H, t, J 7.1), 4.38 (2H, q, J 7.1), 6.72 (1H, d,
J 3.3), 7.22 (1H, d, J 3.3), 7.25–7.45 (m, 3H), 7.72–7.85 (2H, m);
m/z 217 (M ϩ 1, 100%), 189 (M Ϫ C2H5, 48), 171, 149.
5-Phenylfuran-2-carbaldehyde oxime was prepared from the
aldehyde and aqueous hydroxylamine in ethanol to give a mix-
ture of the isomeric oximes as yellow crystals (99%), mp 193–
194 ЊC (lit.10 194–195 ЊC), νmax (KBr)/cmϪ1 3218, 2923, 1633,
1484, 1448, 1297, 987, 908; δH (CDCl3 ϩ D2O) (signals for two
geometrical isomers, a and b) 6.70 (2H, s, Hfuran-a), 6.77 (1H, d,
change in the orientation of the Ph–C᎐O substituent with
᎐
respect to the isothiazole ring. As in 8a, the phenyl and iso-
thiazole ring planes are fairly steeply inclined (by ca. 60Њ), the
inclination being a result of torsional twists of ca. 34 and 32Њ
about C(5)–C(6) and C(6)–C(7) respectively. However, here in 8j
the carbonyl oxygen is anti to the ring sulfur atom (Fig. 7) cf. syn
orientations in 8a, 8g and 13. The bond length within the iso-
thiazole ring are again little changed compared with those in
the preceding structures (Table 2). The only intermolecular
packing interaction of note is a parallel π–π stacking of centro-
symmetrically related pairs of phenyl rings for which the mean
interplanar and centroid ؒ ؒ ؒ centroid separations are 3.54 and
3.87 Å respectively. The formation of linked chains is here
prevented by the steric bulk and hydrophobic exterior of the
triisopropylsilyl substituent.
The X-ray structure of 9j is shown in Fig. 8. Here, the pres-
ence of the bulky triisopropylsilyl group on the 4-position
forces the Ph–C᎐O unit to adopt an orientation nearly ortho-
᎐
J 3.85, Hfuran-b), 7.23–7.45 (7H, m, Ha,b), 7.60 (1H, s, -CH ᎐N-),
᎐
b
gonal to the isothiazole ring plane; the torsional twists about
the C(5)–C(6) and C(6)–C(7) bonds are 82 and 5Њ respectively.
Again there are only small differences in the pattern of bonding
within the isothiazole ring compared with those in the other
four structures (Table 2). There are no intermolecular packing
interactions of note, again presumably because of the con-
gested environment of the ring systems.
Although the differences in the patterns of bonding within
the isothiazole rings throughout the five structures investigated
are small, there are, over the range, noticeable differences in the
relative values for the N(2)–C(3) and C(3)–C(4) distances;
7.68–7.79 (4H, m, Ha,b), 8.04 (1H, s, -CH ᎐N-); m/z 188 (M ϩ 1,
᎐
a
40%), 170 (M ϩ 1 Ϫ H2O, 75), 85 (100).
5-Phenylfuran-2-carbaldehyde O-methyloxime 7d
A solution of 5-phenylfuran-2-carbaldehyde (500 mg, 2.89
mmol) and methoxylamine hydrochloride (241 mg, 2.89 mmol)
in pyridine (5 ml) was stirred under nitrogen for 2 h. The reac-
tion mixture was poured into a mixture of ice–water and
Na2CO3 and the aqueous layer was extracted with dichloro-
methane (3 × 30 ml). The organic layer was washed with water,
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313
1309

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dried and the solvent removed under reduced pressure. The
residue was purified by flash chromatography (1% ethyl
acetate–light petroleum) to give the title compound as a brown
oil (500 mg, 86%). Found m/z [M]ϩ, 201.0789. C12H11NO2
requires m/z [M]ϩ, 201.0790; νmax (neat)/cmϪ1 2937, 2819, 1616,
1519, 1481, 1448, 1054, 890; δH (CDCl3) (signals for two geo-
metrical isomers, a and b) 3.99 (1H, s, CH3a), 4.05 (1H, s, CH3b),
6.67 (2H, s, Hfuran-a), 6.73 (1H, d, J 3.63, Hfuran-b), 7.20–7.42 (7H,
7.32 (1H, d, J 3.63), 7.33–7.65 (6H, m), 7.77–7.87 (2H, m),
7.96–8.05 (2H, m); δC (CDCl3) 107.4, 122.8, 125.1, 128.4, 128.9,
129.3, 132.4, 137.6, 151.5, 158.40, 182.1; m/z 249 (M ϩ 1, 57%),
171 (M Ϫ Ph, 8), 105 (PhCO, 13), 29 (100).
5-Phenyl-2-phenylthiofuran 12
This compound was prepared by the literature method13 from
2-phenylfuran by treatment of its 5-lithio derivative with
diphenyl disulfide as colourless crystals (94%), mp 84 ЊC
(ethanol) (lit.14 84–86 ЊC); νmax (KBr)/cmϪ1 3040, 2918, 1581,
1471, 1440, 1018; δH (CDCl3) 6.71 (1H, d, J 3.3), 6.82 (1H, d,
J 3.3), 7.10–7.32 (6H, m), 7.34–7.41 (2H, m), 7.65–7.75 (2H, m).
m, Ha,b), 7.47 (1H, s, -CH ᎐N-), 7.65–7.74 (4H, m, Ha,b), 7.95
᎐
b
(1H, s, –CH ᎐N–); δ (CDCl ) (signals for two geometrical iso-
᎐
a
C
3
mers) 62.2, 62.7, 106.9, 107.6, 114.5, 119.75, 124.3, 124.3, 128.1,
128.2, 128.63, 128.75, 129.9, 135.8, 138.9, 138.95, 144.6, 146.5,
154.3, 155.5; m/z 202 (M ϩ 1, 13%), 170 (M Ϫ OCH3, 55), 85
(80), 57 (C᎐N–OCH , 100).
᎐
3
5-Phenyl-2-phenylsulfonylfuran 7g
To a solution of 5-phenyl-2-phenylthiofuran (1.0 g, 3.96 mmol)
in acetic acid (10 ml) was added a 35% solution of hydrogen
peroxide (6 ml). After 12 h, the solution was quenched with a
saturated solution of NaHCO3 and the aqueous layer was
extracted with ethyl acetate (3 × 30 ml). The organic layer
was dried and evaporated under reduced pressure. The residue
was purified by flash chromatography (5% ethyl acetate–light
petroleum) to give 7g as pale yellow crystals (789 mg, 70%), mp
86–88 ЊC (ethanol) (Found C, 67.4; H, 4.35. C16H12O3S requires
C, 67.6; H, 4.2%); νmax (KBr)/cmϪ1 3129, 3066, 1473, 1446,
1330, 1184, 1147; δH (CDCl3) 6.70 (1H, d, J 3.7), 7.26 (1H, d,
J 3.7), 7.32–7.44 (3H, m), 7.47–7.70 (5H, m), 8.0–8.08 (2H, m);
δC (CDCl3) 106.3, 119.5, 124.8, 127.8, 128.9, 129.4, 133.7,
140.20, 148.5, 159.0; m/z 285 (M ϩ 1, 100%), 207 (M Ϫ Ph, 5),
184, 144.
5-Phenylfuran-2-carbonitrile 7c
A solution of ethyl carbamate (2.46 g, 27.74 mmol), pyridine
(10 ml) and thionyl chloride (2.17 ml, 27.74 mmol) in toluene
(30 ml) was stirred under a nitrogen atmosphere at ambient
temperature for 30 min. To the yellow suspension was added 5-
phenylfuran-2-carbaldehyde oxime (1.20 g, 6.45 mmol) and the
reaction mixture was heated at reflux for 2 h. The solvent was
evaporated under reduced pressure and the resulting residue
was dissolved in dichloromethane (20 ml), washed with aque-
ous hydrochloric acid (2 M, 2 × 10 ml) and H2O (2 × 10 ml).
The organic layer was dried and evaporated under reduced
pressure. The crude product was purified by flash chromato-
graphy (5% ethyl acetate–light petroleum) to give 7c as pale
yellow crystals (1.00 g, 92%), mp 70 ЊC (ethanol) (lit.11 72 ЊC),
νmax (KBr)/cmϪ1 3118, 2923, 2229, 1450, 1035; δH (CDCl3) 6.72
(1H, d, J 3.63), 7.17 (1H, d, J 3.62), 7.35–7.44 (3H, m), 7.67–
7.76 (2H, m); m/z 170 (M ϩ 1, 100%), 85 (91).
Ethyl 5-tert-butylfuran-2-carboxylate
A solution of 5-tert-butylfuran-2-carboxylic acid (5.0 g, 29.76
mmol) and sulfuric acid (catalytic amount) in ethanol (50 ml)
was stirred under reflux for 12 h. The reaction mixture was then
cooled and concentrated under reduced pressure. The residue
was poured into water and neutralised with saturated aqueous
NaHCO3 and the aqueous layer was extracted with dichloro-
methane (3 × 50 ml). The organic layer was washed with water
and brine, and dried. The solvent was evaporated under
reduced pressure and the residue was purified by flash chrom-
atography (5% ethyl acetate–light petroleum) to give the title
compound as a colourless oil (1.17 g, 85%) (Found [M ϩ 1]ϩ,
197.1176. C11H16O3 requires [M ϩ 1]ϩ, 197.1178); νmax (neat)/
cmϪ1 2969, 1727, 1521, 1365, 1303, 1201, 1139, 1014;
δH (CDCl3) 1.31 (9H, s, CH3), 1.36 (3H, t, J 6.93, CH3), 4.34
(2H, q, J 6.93, CH2), 6.08 (1H, d, J 3.30), 7.05 (1H, d, J 3.30);
δC (CDCl3) 14.7, 29.2, 33.4, 60.8, 104.9, 118.9, 143.5, 159.3,
169.1; m/z 197 (M ϩ 1, 100%), 181 (M Ϫ CH3, 12), 169 (21),
187 (33), 151 (27).
The nitrile 7c was identical to that prepared from the
aldehyde, hydroxylamine and formic acid12 in low yield
(20%).
2-Acetyl-5-phenylfuran 7e
To a solution of 2-phenylfuran (200 mg, 1.39 mmol) in benzene
(5 ml) were added acetic acid (0.8 ml, 13.90 mmol) and phos-
phorus pentaoxide (986 mg, 6.96 mmol).12 The solution was
stirred and heated under reflux for 2 h. The reaction mixture
was cooled to 0 ЊC, hydrolysed with a saturated solution of
NaHCO3 and the aqueous layer extracted with ethyl acetate
(3 × 20 ml). The organic layer was dried and the solvent evap-
orated under reduced pressure. The residue was purified by
flash chromatography (5% ethyl acetate–light petroleum) to
give 7e as a pale red oil (155 mg, 60%). Found m/z [M ϩ 1]ϩ,
187.0759. C12H10O2 requires m/z [M ϩ 1]ϩ, 187.0759;
νmax (neat)/cmϪ1 3118, 3064, 2925, 1671, 1519, 1475, 1272;
δH (CDCl3) 2.5 (3H, s, OMe), 6.77 (1H, d, J 3.79), 7.26 (1H, d,
J 3.79), 7.34–7.50 (3H, m), 7.76–7.85 (2H, m); δC (CDCl3) 25.5,
107.1, 119.2, 124.6, 128.55, 128.9, 129.0, 151.5, 157.3, 185.9;
m/z 187 (M ϩ 1, 100%), 171 (M Ϫ Me, 5).
General procedure for the preparation of the silylated derivatives
of 2-phenylfuran
To a solution of 2-phenylfuran (2.0 g, 13.80 mmol) in dry tetra-
hydrofuran (20 ml) at Ϫ10 ЊC was added n-butyllithium (6.6 ml
of a 2.5 M solution in hexanes, 16.7 mmol). The mixture was
stirred for 2 h and then allowed to warm to 0 ЊC. The trialkyl-
chlorosilane (1.2 equiv.) was then added dropwise and the
solution stirred overnight, after which it was hydrolysed with
aqueous ammonium chloride (10%, 30 ml) and the aqueous
layer extracted with ethyl acetate (3 × 50 ml). The organic layer
was dried and concentrated under reduced pressure and the
residue purified by flash chromatography (5% ethyl acetate–
light petroleum) to give 7h–7j as colourless oils (80%, 85%, 85%
respectively).
2-Benzoyl-5-phenylfuran 7f
To a solution of 2-phenylfuran (1.0 g, 6.95 mmol) in benzene
(10 ml) were added benzoic acid (8.5 g, 69.5 mmol) and phos-
phorus pentaoxide (4.94 g, 34.7 mmol). The solution was
stirred and heated under reflux for 24 h. The reaction mixture
was cooled to 0 ЊC, hydrolysed with a saturated solution of
NaHCO3 and the aqueous layer extracted with ethyl acetate
(3 × 30 ml). The organic layer was dried and the solvent evap-
orated under reduced pressure. The residue was purified by
flash chromatography (5% ethyl acetate–light petroleum) to
give 7f as pale yellow crystals (1.37 g, 80%), mp 86–87 ЊC
(ethanol) (lit.11 95–96 ЊC) (Found C, 82.1; H, 4.9; C17H12O2
requires C, 82.25; H, 4.8%); νmax (KBr)/cmϪ1 3062, 1637, 1515,
1471, 1319, 1270, 1072, 881; δH (CDCl3) 6.83 (1H, d, J 3.63),
2-Phenyl-5-(trimethylsilyl)furan 7 h. Isolated as an oil (Found
[M]ϩ, 216.0969. C13H16OSi requires [M]ϩ, 216.0970); νmax (neat)/
cmϪ1 3089, 2958, 1608, 1469, 1249, 1120, 1018; δH (CDCl3) 0.29
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(9H, s, CH3)3Si), 6.62 (1H, d, J 3.3), 6.63 (1H, d, J 3.3), 7.19–
7.25 (1H, m), 7.31–7.40 (2H, m), 7.65–7.72 (1H, m); δC (CDCl3)
0.35, 106.6, 123.05, 125.65, 128.9, 130.1, 132.85, 159.5, 161.6;
m/z 217 (M ϩ 1, 100%), 201 (M Ϫ CH3, 61), 73 (Si(CH3)3,
58).
isoquinoline (2.8 ml) and the amount of thionyl chloride
increased to 8.6 mmol (see Table 4).
The following isothiazoles were made by these methods in the
yields shown in Table 4: 5-benzoyl-3-phenylisothiazole 2a,1b 5-
benzoyl-3,4-diphenylisothiazole 4a,1b 5-benzoyl-4-bromo-3-
phenylisothiazole 4b,1b,2 3-tert-butyl-5-pivaloylisothiazole 2c,1b
5-benzoyl-3-methylisothiazole;1c these compounds were identi-
cal with those reported previously.
2-Phenyl-5-[dimethyl(1,1,2-trimethylpropyl)silyl]furan
7i.
Isolated as an oil (Found [M]ϩ, 286.1753. C18H26OSi requires
[M]ϩ, 286.1753); νmax (neat)/cmϪ1 2958, 1608, 1469, 1251, 1157,
757; δH (CDCl3) 0.32 (6H, s, Si(CH3)2), 0.87 (6H, d, J 6.92,
CH(CH3)2), 0.94 (6H, s, -(CH3)2-), 1.65 (1H, septet, J 6.92,
–CH–), 6.61 (1H, d, J 3.30), 6.66 (1H, d, J 3.30), 7.21–7.26 (1H,
m), 7.32–7.39 (2H, m), 7.65–7.71 (1H, m); δC (CDCl3) 18.6,
21.0, 23.9, 34.8, 105.1, 123.4, 123.95, 124.0, 127.2, 128.6, 131.2,
157.7, 159.5; m/z 287 (M ϩ 1, 100%), 271 (M Ϫ CH3, 41), 201
(M Ϫ C6H13, 45), 143 (M Ϫ SiC8H19, 28).
Ethyl 5-benzoylisothiazole-3-carboxylate 8b. Isolated as an oil
(Found [M ϩ 1]ϩ, 262.0533. C13H11NO3S requires [M ϩ 1]ϩ,
262.0538); νmax (neat)/cmϪ1 2981, 2929, 1722, 1650, 1596, 1511,
1448, 1380, 1234, 1139, 1024, 842; δH (CDCl3) 1.46 (3H, t,
J 7.26, CH3), 4.48 (2H, q, J 7.26, CH2), 7.52–7.61 (2H, m),
7.65–7.74 (1H, m), 7.92–7.98 (2H, m), 8.18 (1H, s); δC (CDCl3)
14.15, 62.2, 128.5, 128.9, 129.3, 134.0, 136.3, 159.6, 160.3,
166.3, 185.5; m/z 262 (M ϩ 1, 100%), 214 (15), 148 (33).
2-Phenyl-5-(triisopropylsilyl)furan 7j. Isolated as an oil
(Found [M]ϩ, 300.1904. C19H28OSi requires [M]ϩ, 300.1909);
νmax (neat)/cmϪ1 2942, 2865, 1608, 1465, 1382, 1189, 1018, 883;
δH (CDCl3) 1.13 (18H, d, J 6.93, CH3), 1.31 (3H, septet, J 6.93,
CH), 6.65 (1H, d, J 3.30), 6.73 (1H, d, J 3.30), 7.17–7.27 (1H,
m), 7.31–7.40 (2H, m), 7.64–7.72 (1H, m); δC (CDCl3) 10.98,
18.73, 104.91, 123.45, 123.88, 127.14, 128.62, 131.28, 156.80,
157.73; m/z 301 (M ϩ 1, 71%), 257 (M Ϫ CH(CH3)2, 72), 215
(M Ϫ [CH(CH3)2]2, 15), 187 (33), 171 (M Ϫ [CH(CH3)2]3, 30),
157 (Si(CH(CH3)2)3, 100).
5-Benzoylisothiazole-3-carboxylic acid 8a. By alkaline
hydrolysis of the above ester, mp 138 ЊC (Found [M]ϩ, 233.0139.
C11H7NO3S requires [M]ϩ, 233.0147); νmax (KBr)/cmϪ1 3189–
2838, 1644, 1513, 1446, 1255, 715; δH (CDCl3) 7.58–7.69 (2H,
m), 7.72–7.81 (1H, m), 7.93–8.19 (2H, m), 8.20 (1H, s); δC
(CDCl3) 128.7, 128.9, 129.1, 129.4, 134.2, 135.9, 160.9, 161.25,
165.7, 185.7; m/z 233 (Mϩ, 56%), 188 (M Ϫ CO2H, 7), 156 (15),
105 (100).
Crystal data for 8a. C11H7NO3S, M = 233.2, monoclinic,
P21/c (no. 14), a = 6.313(1), b = 10.912(1), c = 15.324(2) Å,
β = 96.85(1) Њ, V = 1048.1(1) Å3, Z = 4, Dc = 1.478 g cmϪ3,
µ(Cu-Kα) = 26.9 cmϪ1, T = 293 K, colourless blocks; 1698
independent measured reflections, F2 refinement, R1 = 0.034,
wR 2 = 0.091, 1548 independent observed absorption corrected
reflections [|Fo| > 4σ(|Fo|), 2θ ≤ 126Њ], 150 parameters. CCDC
reference number 157793. See http://www.rsc.org/suppdata/p1/
b1/b101157j/ for crystallographic files in.cif or other electronic
format.
2,5-Bis[dimethyl(1,1,2-trimethylpropyl)silyl]furan 1e
To a solution of furan (5.0 g, 73.5 mmol) in dry tetrahydrofuran
(20 ml) at Ϫ10 ЊC was added n-butyllithium (59 ml of a 2.5 M
solution in hexanes, 0.147 mol). The mixture was stirred for 2 h
and allowed to warm to 0 ЊC. Dimethyl(1,1,2-trimethylpropyl)-
chlorosilane (57.7 g, 147 mmol equiv.) was then added dropwise
and the solution stirred overnight at ambient temperature. The
reaction mixture was hydrolysed with aqueous ammonium
chloride (30 ml) and the aqueous layer was extracted with ethyl
acetate (3 × 50 ml). The organic layer was dried and concen-
trated under reduced pressure and the residue purified by flash
chromatography (5% ethyl acetate–light petroleum) to give the
title compound as a colourless oil (22.5 g, 87%) (Found [M]ϩ,
352.2629. C20H40OSi2 requires [M]ϩ, 352.2618; νmax (neat)/cmϪ1
2960, 2871, 1465, 1376, 1249, 1049, 923; δH (CDCl3) 0.31 (12H,
s, CH3Si), 0.89 (12H, d, J 6.92, CH3), 0.92 (12H, s, CH3),
1.63 (2H, q, J 6.92, CH), 6.62 (2H, s); δC (CDCl3) Ϫ3.85, 18.5,
21.0, 23.9, 34.9, 120.0, 163.75; m/z 352 (M, 55%), 147 (C8H18Si,
100).
5-Benzoylisothiazole-3-carbonitrile 8c. Mp 88 ЊC (Found
[M ϩ 1]ϩ, 215.0280. C11H6N2OS requires [M ϩ 1]ϩ, 215.0279);
νmax (neat)/cmϪ1 3108, 2923, 2856, 2240, 1646, 1596, 1448, 1370,
1276, 1106; δH (CDCl3) 7.54–7.64 (2H, m), 7.68–7.78 (1H, m),
7.88–7.95 (2H, m), 7.96 (1H, s); δC (CDCl3) 129.2, 129.3,
129.85, 129.9, 134.5, 135.9, 139.7, 167.1, 184.5; m/z 215 (M ϩ 1,
100%).
5-Benzoylisothiazole-3-carbaldehyde O-methyloxime 8d. Isol-
ated as an oil (Found [M ϩ 1]ϩ, 247.0549. C12H10N2O2S
requires [M ϩ 1]ϩ, 247.0541); νmax (neat)/cmϪ1 2937, 1650, 1598,
1448, 1413, 1286, 1056; δH (CDCl3) 4.01 (3H, s, OCH3), 7.50–
7.58 (m, 2H), 7.63–7.71 (1H, m), 7.92–7.96 (2H, m), 7.97 (1H,
s), 8.21 (1H, s); δC (CDCl3) 62.6, 123.5, 128.8, 129.3, 133.7,
136.5, 144.1, 162.25, 164.8, 186.1; m/z 247 (M ϩ 1, 38%), 215
General procedures for the reactions with ethyl carbamate,
thionyl chloride and a base
Method A. A solution of ethyl carbamate (383 mg, 4.3
mmol), thionyl chloride, freshly distilled from quinoline (512
mg, 0.31 ml, 4.3 mmol) and pyridine (2 ml) in benzene (20 ml)
was stirred under nitrogen at ambient temperature for 30 min.
The furan (1 mmol) was added to the yellow solution and the
mixture heated under reflux until the furan was consumed
(TLC) (see Table 4). The solvent was evaporated under reduced
pressure and the resulting residue dissolved in dichloromethane
(15 ml); the solution washed with aqueous hydrochloric acid
(2 M, 2 × 10 ml), water (2 × 10 ml) and dried. The organic
solvent was evaporated under reduced pressure and the crude
product purified by flash chromatography (Table 4) and
crystallisation.
(M Ϫ OCH , 85), 57 (–C᎐N-OCH ).
᎐
3
3
3,5-Dibenzoylisothiazole 8f. Isolated as an oil (Found
[M ϩ 1]ϩ, 294.0589. C17H11NO2S requires [M ϩ 1]ϩ, 294.0589;
νmax (neat)/cmϪ1 3062, 1650, 1596, 1448, 1236, 844; δH (CDCl3)
7.45–7.72 (6H, m), 7.92–8.01 (2H, m), 8.28 (1H, s), 8.29–8.33
(2H, m); δC (CDCl3) 128.3, 128.9, 129.4, 130.9, 133.5, 133.9,
135.6, 136.25, 165.4, 166.9, 185.9, 186.2; m/z 294 (M ϩ 1,
100%), 216 (M Ϫ Ph, 25), 105 (PhCO, 39).
5-Benzoyl-3-phenylsulfonylisothiazole 8g. Mp 131–133 ЊC
(Found C, 58.4; H, 3.3; N, 4.25. C16H11NO3S2 requires C, 58.4;
H, 3.3; N, 4.25%); νmax (KBr)/cmϪ1 3102, 3064, 1649, 1596,
1448, 1330, 1080; δH (CDCl3) 7.52–7.63 (4H, m), 7.65–7.76 (2H,
m), 7.88–7.96 (2H, m), 8.06–8.12 (2H, m), 8.14 (1H, m);
δC (CDCl3) 125.6, 128.7, 129.0, 129.25, 129.4, 134.3, 134.35,
135.7, 138.3, 167.15, 167.6, 184.8; m/z 329 (M ϩ 1, 100%), 160
(18).
Method B. As with Method A but with benzene replaced by
an equal volume of toluene (see Table 4).
Method C. As with Method A but with benzene replaced by
an equal volume of chlorobenzene, the pyridine replaced by
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313
1311

View Online
Crystal data for 8g. C16H11NO3S2, M = 329.4, monoclinic,
C2/c (no. 15), a = 21.714(3), b = 9.275(1), c = 15.384(1) Å,
β = 101.43(1)Њ, V = 3036.8(5) Å3, Z = 8, Dc = 1.441 g cmϪ3,
µ(Mo-Kα) = 3.61 cmϪ1, T = 293 K, colourless blocks; 2660
independent measured reflections F2 refinement, R1 = 0.040,
wR2 = 0.099, 2195 independent observed reflections [|Fo| >
4σ(|Fo|), 2θ ≤ 50 Њ], 176 parameters. CCDC reference number
157791. See http://www.rsc.org for crystallographic files in.cif
or other electronic format.
c = 30.694(3) Å, V = 4091(1) Å3, Z = 8, Dc = 1.234 g cmϪ3,
µ(Cu-Kα) = 32.0 cmϪ1, T = 293 K, colourless blocks; 3392
independent measured reflections, F2 refinement, R1 = 0.047,
wR2 = 0.123, 2853 independent observed absorption corrected
reflections [|Fo| > 4σ(|Fo|), 2θ ≤ 128 Њ], 206 parameters. CCDC
reference number 157789. See http://www.rsc.org/suppdata/p1/
b1/b101157j/ for crystallographic files in.cif or other electronic
format.
5-Benzoyl-3-chloroisothiazole 8k. Yellow oil (Found C,
53.9; H, 2.5; N, 6.2. C10H6NSOCl requires C, 54.0; H, 2.8; N,
6.3%); νmax (neat)/cmϪ1 3104, 3064, 2955, 2924, 1694, 1597,
1579, 1504, 1447, 1310, 1277, 1140, 833; δH (CDCl3) 7.49
(1H, s), 7.56 (2H, t, J 7.6, HPh-meta), 7.7 (1H, t, J 7.4, HPh-para),
7.93 (2H, d, J 7, HPh-ortho); δC (CDCl3) 126.64, 129.48, 129.64,
134.44, 136.58, 150.16, 166.28, 185.32; m/z (CIϩ) 224 (M ϩ 1,
100%), 188 (M Ϫ [Cl], 19.5), 146 (M Ϫ [C6H5], 7), 105 (15), 59
(87).
5-Benzoyl-3-(trimethylsilyl)isothiazole 8h. Isolated as an oil
(Found [M ϩ 1]ϩ, 262.0726. C13H15NOSiS requires [M ϩ 1]ϩ,
262.0722); νmax (neat)/cmϪ1 3108, 2923, 2856, 2240, 1646, 1596,
1448, 1370, 1276, 1106; δH (CDCl3) 7.50–7.61 (2H, m), 7.63–
7.71 (1H, m), 7.80 (1H, s), 7.91–7.98 (2H, m); m/z 262 (M ϩ 1,
100%), 246 (M Ϫ CH3, 22), 156 (M Ϫ PhCO, 12).
5-Benzoyl-3-[dimethyl(1,1,2-trimethylpropyl)silyl]isothiazole
8i. Isolated as an oil (Found [M ϩ 1]ϩ, 332.1504. C18H25NOSiS
requires [M ϩ 1]ϩ, 332.1504); νmax (neat)/cmϪ1 3064, 2958, 2867,
1650, 1590, 1465, 875; δH (CDCl3) 0.42 (6H, s, Si(CH3)2), 0.83
(6H, d, J 6.9, CH(CH3)2), 0.93 (6H, s, -(CH3)2-), 1.64 (1H, sep-
tet, J 6.9, -CH-), 7.48–7.58 (2H, m), 7.61–7.69 (1H, m), 7.80
(1H, s), 7.90–7.96 (2H, m); δC (CDCl3) Ϫ3.5, 18.5, 20.95, 24.05,
34.6, 128.8, 129.25, 130.15, 133.4, 137.7, 162.6, 179.8, 186.8;
m/z 332 (M ϩ 1, 100%), 316 (M Ϫ CH3, 18).
S-Phenyl 3-phenylisothiazole-5-carbothioate 13. As pale pink
crystals, mp 77 ЊC (Found [M ϩ 1]ϩ, 298.0363. C16H11NOS2
requires [M ϩ 1]ϩ, 298.0360); νmax (KBr)/cmϪ1 3000, 2923, 1670,
1384, 1164, 1021, 919; δH (CDCl3) 7.40–7.55 (8H, m), 7.92–8.10
(2H, m), 8.12 (1H, s); δC (CDCl3) 122.8, 125.75, 126.9, 128.9,
129.5, 129.8, 130.1, 133.85, 134.7, 163.9, 168.1, 180.9; m/z 298
(M ϩ 1, 100%), 188 (M Ϫ PhS, 72).
¯
Crystal data for 13. C16H11NOS2, M = 297.4, triclinic, P1
5-Benzoyl-3-(triisopropylsilyl)isothiazole 8j. Mp 58 ЊC (Found
C, 65.9; H, 7.8; N, 4.0. C19H27NOSiS requires C, 66.0; H, 7.9;
N, 4.05%); νmax (KBr)/cmϪ1 2942, 2863, 1650, 1596, 1459, 1324,
1228, 1018, 883; δH (CDCl3) 1.17 (18H, d, J 7.26, CH3), 1.46
(3H, septet, J 7.26, CH), 7.47–7.57 (2H, m), 7.62–7.69
(1H, m), 7.79 (1H, s), 7.91–7.98 (2H, m); δC (CDCl3) 11.25,
18.4, 128.8, 129.3, 133.5, 134.0, 137.8, 162.4, 176.8, 186.8;
m/z 346 (M ϩ 1, 100%), 302 (M Ϫ CH(CH3)2, 52), 157
(Si(CH(CH3)2)3, 12).
(no. 2), a = 8.867(1), b = 8.972(1), c = 10.346(1) Å, α = 88.03(1),
β = 68.42(1), γ = 68.79(1)Њ, V = 708.9(1) Å3, Z = 2, Dc = 1.393 g
cmϪ3, µ(Mo-Kα) = 3.69 cmϪ1, T = 293 K, pale pink prisms;
2481 independent measured reflections, F2 refinement,
R1 = 0.042, wR2 = 0.108, 1974 independent observed reflections
[|Fo| > 4σ(|Fo|), 2θ ≤ 50Њ], 158 parameters. CCDC reference
number 157792. See http://www.rsc.org/suppdata/p1/b1/
b101157j/ for crystallographic files in.cif or other electronic
format.
¯
Crystal data for 8j. C19H27NOSiS, M = 345.6, triclinic, P1
5-Benzoyl-3-phenylthioisothiazole 14. Isolated as an oil
(Found [M ϩ 1]ϩ, 298.0360. C16H11NOS2 requires [M ϩ 1]ϩ,
298.0360); νmax (neat)/cmϪ1 3060, 2928, 2852, 1650, 1598, 1440,
1309, 1276; δH (CDCl3) 7.31 (1H, s), 7.37–7.45 (3H, m), 7.46–
7.55 (2H, m), 7.60–7.68 (3H, m), 7.84–7.91 (2H, m); δC (CDCl3)
126.6, 128.9, 129.3, 129.6, 130.7, 133.8, 133.9, 134.75, 136.8,
164.1, 164.2, 185.8; m/z 297 (Mϩ, 55%), 192 (M Ϫ PhCO, 13),
109 (SPh, 49), 105 (PhCO, 79), 77 (Ph, 100).
(no. 2), a = 8.079(1), b = 8.191(1), c = 15.983(2) Å, α = 77.49(1),
β = 86.74(1), γ = 71.46(1)Њ, V = 978.9(2) Å3, Z = 2, Dc = 1.172 g
cmϪ3, µ(Cu-Kα) = 20.7 cmϪ1, T = 293 K, colourless needles;
3064 independent measured reflections, F2 refinement, R1 =
0.037, wR2 = 0.101, 2750 independent observed absorption
corrected reflections [|Fo| > 4σ(|Fo|), 2θ ≤ 124Њ], 209 parameters.
CCDC reference number 157790. See http://www.rsc.org/
suppdata/p1/b1/b101157j/ for crystallographic files in.cif or
other electronic format.
Ethyl 5-pivaloylisothiazole-3-carboxylate. Isolated as an oil
(Found [M ϩ 1]ϩ, 242.0857. C11H15NO3S requires [M ϩ 1]ϩ,
242.0851); νmax (neat)/cmϪ1 2975, 1724, 1666, 1513, 1236, 989,
977; δH (CDCl3) 1.40 (9H, s, CH3), 1.45 (3H, t, J 7.75, CH3),
4.49 (2H, q, J 7.75, CH2), 8.20 (1H, s); δC (CDCl3) 14.55, 27.45,
44.6, 62.5, 127.4, 160.1, 160.75, 165.7, 198.3; m/z 242 (M ϩ 1,
37%), 189 (30), 95 (100).
5-Benzoyl-3-chloro-4-[dimethyl(1,1,2-trimethylpropyl)silyl]-
isothiazole 9i. Colourless needles mp 36 ЊC (Found [M ϩ 1]ϩ,
366.1113. C18H25NOSSiCl requires [M ϩ 1]ϩ, 366.1109); νmax
(KBr /cmϪ1 2952, 2900, 2871, 1661 (C᎐O), 1590, 1456, 1351,
᎐
1251, 1225, 1171, 1096, 810, 740; δH (CDCl3) 0.26 (6H, s,
SiMe2), 0.83 (6H, d, J 6.6, CHMe2), 0.97 (6H, s, CHMe2), 1.81
(1H, septet, J 6.6, -CH-), 7.51 (2H, t, J 7.26, HPh-meta), 7.66 (1H,
t, J 7.4, HPh-para), 7.87 (2H, d, J 7.26, HPh-ortho); δC (CDCl3)
Ϫ0.59, Ϫ0.94, 18.94, 22.17, 25.71, 34.16, 129.21, 130.55,
134.98, 136.38, 137.58, 155.13, 172.02, 189.69; m/z 366 (M ϩ 1,
100%), 280 (M Ϫ [Me2CHCMe2], 25).
Bis(5-phenylfuran-2-yl) sulfide 11. Mp 115–117 ЊC (Found
[M ϩ 1]ϩ, 319.0789. C20H14O2S requires [M ϩ 1]ϩ, 319.0789);
νmax (neat)/cmϪ1 3060, 2925, 1504, 1469; δH (CDCl3) 6.61 (2H, d,
J 3.3), 6.71 (2H, d, J 3.3), 7.20–7.31 (2H, m), 7.32–7.42 (4H, m),
7.62–7.71 (4H, m); δC (CDCl3) 106.8, 118.9, 124.0, 127.9, 128.8,
130.2, 142.2, 157.0. Compound 10 was also obtained (30%) by
treatment of 2-phenylfuran in pyridine with sulfur dichloride
(1 equiv.) at ambient temperature for 15 h; the same yield was
obtained, with extensive decomposition, upon heating under
reflux for 2 h.
5-Benzoyl-3-chloro-4-(triisopropylsilyl)isothiazole 9j. As col-
ourless needles from ethanol, mp 69 ЊC (Found [M ϩ 1]ϩ,
380.1271. C9H27NOSiCl requires [M ϩ 1]ϩ, 380.1263); νmax
(KBr)/cmϪ1 2946, 2885, 2865, 1657 (C᎐O), 1593, 1578, 1452,
᎐
1352, 1233, 1212, 1171, 1091, 885; δH (CDCl3) 1.06 (18H, d,
J 7.6, CH3), 1.60 (3H, septet, CHMe2), 7.51 (2H, t, J 7.9,
HPh-meta), 7.67 (1H, t, J 7.3, HPh-para), 7.92 (2H, d, J 7.3, H ortho);
δC (CDCl3) 12.55, 19.39, 129.14, 130.74, 134.98, 137.32, 155.58,
173.08, 189.32; m/z 380 (M ϩ 1, 100%), 336 (M Ϫ [Me2CH],
17).
Acknowledgements
We are grateful to Zeneca, SB, Pfizer, Parke-Davis, MDL
Information Systems (UK) Ltd and the University of Sunder-
land for financial support and Miss Yolande Caro, University
of Santiago de Compostela, Spain for some experimental
assistance.
Crystal data for 9j. C19H26NOSiSCl, M = 380.0, ortho-
rhombic, Pbca (no. 61), a = 7.493(1), b = 17.788(4),
1312
J. Chem. Soc., Perkin Trans. 1, 2001, 1304–1313

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7 J. E. Fitzpatrick, D. J. Milner and P. White, Synth. Commun., 1982,
489.
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