Regiospecific Suzuki coupling of 3,5-dichloroisothiazole-4-carbonitrile

Article abstract of DOI:10.1039/b306005e

3,5-Dichloroisothiazole-4-carbonitrile 1 reacts with aryl- and methylboronic acids to give in high yields the 3-chloro-5-(aryl and methyl)-isothiazole-4-carbonitrile 2 regiospecifically. The reaction was optimized with respect to base, phase transfer agent and palladium catalyst. Suzuki coupling at C-5 was also achieved in high yield using potassium phenyltrifluoroborate. The regiospecificity of either coupling method is maintained with 3,5-dibromoisothiazole-4-carbonitrile 4 to give exclusively 3-bromo-5-phenylisothiazole-4-carbonitrile 5. Suzuki cross-coupling conditions applied to 3-chloro-5-phenylisothiazole-4-carbonitrile 2a gave 3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, which was prepared independently, and not the 3-phenyl derivative. All isothiazole products were fully characterized.

Full text of DOI:10.1039/b306005e

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Regiospecific Suzuki coupling of 3,5-dichloroisothiazole-4-
carbonitrile
Irene C. Christoforou,a Panayiotis A. Koutentis*a and Charles W. Reesb
a Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus.
E-mail: koutenti@ucy.ac.cy
b Department of Chemistry, Imperial College, London, UK SW7 2AZ
Received 29th May 2003, Accepted 30th June 2003
First published as an Advance Article on the web 14th July 2003
3,5-Dichloroisothiazole-4-carbonitrile 1 reacts with aryl- and methylboronic acids to give in high yields the 3-chloro-
5-(aryl and methyl)-isothiazole-4-carbonitrile 2 regiospecifically. The reaction was optimized with respect to base,
phase transfer agent and palladium catalyst. Suzuki coupling at C-5 was also achieved in high yield using potassium
phenyltrifluoroborate. The regiospecificity of either coupling method is maintained with 3,5-dibromoisothiazole-4-
carbonitrile 4 to give exclusively 3-bromo-5-phenylisothiazole-4-carbonitrile 5. Suzuki cross-coupling conditions
applied to 3-chloro-5-phenylisothiazole-4-carbonitrile 2a gave 3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, which
was prepared independently, and not the 3-phenyl derivative. All isothiazole products were fully characterized.
A recent series of articles have described the broad antiviral
Reaction of isothiazole 1 with organoboronic acids
activity of 3-methylthio-5-arylisothiazole-4-carbonitrile deriv-
atives.1–4 These isothiazoles were prepared by cyclisation of
Initial attempts at Suzuki coupling of phenylboronic acid and
arylmethylene-malononitriles with disulfur dichloride and
pyridine to afford the 3-chloro-5-arylisothiazole-4-carbo-
nitriles1,5 which were then converted into the 3-methylthio
derivatives by treatment with sodium sulfide followed by iodo-
methane or alternatively by treating aryl thioesters with
malononitrile followed by heating with elemental sulfur and
treatment with iodomethane.1 Both routes require the prepar-
ation of product specific intermediates; this could be overcome
by starting from an appropriate halogenated isothiazole com-
bined with modern aryl–aryl C–C bond forming techniques.6
Whilst working on the synthesis and chemistry of 3-halo-
3,5-dichloroisothiazole-4-carbonitrile 1 in biphasic mixtures of
water and hydrocarbon solvents could not readily be driven to
completion without significant reduction in the product yields
to 60–70%. A variety of bases and several solvent systems were
screened without overcoming this problem; nevertheless the
reaction was qualitatively shown to proceed faster as the
base strength and cation size increased for NaHCO3, M2CO3
(M = Na or K), and MOH, (M = Li, Na and K). Similar
observations have appeared elsewhere and the effect has been
attributed to faster transmetallation rates.19–21 It is possible
that reaction pathways such as protodeboronation, hydrolytic
deboronation and homocoupling of the boronic acid to give
biphenyl (observed by TLC) were competing with the desired
coupling. Fluoride ion has been used to replace traditional
bases in such situations and can enhance the nucleophilicity of
the boronic acid by increasing the valence of the boron
atom,20,22–24 making the rate of Suzuki coupling more competi-
tive. The use of KF in a biphasic system gave only marginally
better reaction rates and yields.
isothiazole-4,5-dicarbonitriles7–9
carbonitrile 1 was identified as a possible alternative synthetic
3,5-dichloroisothiazole-4-
precursor to 3-chloro-5-arylisothiazole-4-carbonitriles
(Scheme 1).
2
A report of anhydrous conditions in a case of a difficult
cross-coupling25 prompted the use of non-aqueous conditions.
The use of Pd(OAc)2, 18-crown-6, and vacuum oven-dried KF
in dry toluene gave near quantitative conversions of dichloro-
isothiazole 1 into 3-chloro-5-phenylisothiazole-4-carbonitrile
2a. Replacing KF by anhydrous K2CO3 (3.5 equiv.) resulted in a
longer reaction time (16 h) and lower yield (81%), and combin-
ations of KF and K2CO3 were also less effective than neat KF.
The reaction was initially optimized with respect to phenyl-
boronic acid, KF and temperature (Table 1). The reactions,
which were performed in air (protected by calcium chloride
drying tubes), progressed faster at higher temperatures and
required at least 1.5 equivalents of phenylboronic acid. The
reaction times improved significantly with three or more equiv-
alents of dry KF, although no significant advantage was gained
by use of more than three equivalents. Interestingly the progress
of the reaction was sensitive to the timing of the applied heat-
ing. Placing the reaction mixture into a preheated oil bath at
140 ЊC resulted in increased biphenyl production (TLC) and
when only 1.5 equivalents of phenylboronic acid were present
this led to incomplete consumption of isothiazole 1. Presum-
ably the rate of phenylboronic acid homocoupling increases
with temperature and becomes competitive.
Scheme 1
3,5-Dichloroisothiazole-4-carbonitrile 1 is readily available
by condensation of malononitrile and carbon disulfide, fol-
lowed by chlorination (55%).10 The 5-chlorine of isothiazole 1
can be regioselectively displaced by a range of nucleophiles.10
Activation of the 5-chlorine by both the 4-cyano substituent
and the ring nitrogen results in its enhanced activity. Thus a
regioselective Suzuki reaction was considered as an alternative
route to the above 5-aryl isothiazoles 2. A search of the liter-
ature revealed no Suzuki couplings for the isothiazole system,
though palladium catalysed cross-coupling reactions were
reported for several bromo and iodo halogenated isothiazoles
to give alkenyl and alkynyl substituted isothiazoles.11,12
The Suzuki reaction is important for C–C bond formation
and continues to be extensively investigated for the form-
ation of biaryls.13 Regiocontrolled heteroaryl Suzuki couplings
are known for several heteroaromatic systems such as pyr-
imidine,14,15 quinoline,16 1,10-phenanthroline17 and thiophene18
and we now report rapid high yielding Suzuki couplings at C-5
of the isothiazole 1.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Reaction of 3,5-dichloroisothiazole-4-carbonitrile 1 (0.3 mmol) with PhB(OH)2, KF, 18-crown-6 (0.5 equiv.) and Pd(OAc)2 (5 mol%)
PhB(OH)2 (equiv.)
KF (equiv.)
Solvent
Temp.a (ЊC)
Time (h)
Yield 2a (%)
c
1.5
1.5
1.5
2
2
2
1.5
1.5
1.3
1.1
2
3
4
3.5
3.5
3.5
3.5
3.5
3.5
3.5
PhMe
PhMe
PhMe
PhH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
20–140
20–140
20–140
20–110
20–140
140b
12
3
3
26
3
3
3
12
3
93
95
91
97
95
20–140
96
c
140b
20–140
20–140
79
72
24
a Oil bath temperature. b Preheated to 140 ЊC. c Incomplete reaction.
Table
2
Reaction of 3,5-dichloroisothiazole-4-carbonitrile
(0.3 mmol) with PhB(OH)2 (1.5 equiv.), KF (3.5 equiv.), Pd(OAc)2
1
(5 mol%) and various PTC in PhMe at reflux
PTC
PTC (equiv.)
Time (h)
Yield 2a (%)
Bn(Et)3NϩClϪ
Et4NϩBrϪ
0.5
0.5
0.5
0.5
1.0
0.5
0.25
0.15
0.5
0.25
0.15
0.1
33
24
48
8
24
14
30
27
3
69
60
70
Scheme 2 Reagents and conditions: i) RB(OH)2 (2 equiv.), KF
(3.5 equiv.), 18-crown-6 (0.5 equiv.), Pd(OAc)2 (5 mol%), PhMe, 110 ЊC.
CH3(CH2)15Nϩ(CH3)3BrϪ
Bn(Et)3NϩIϪ
Adogen 464®
Adogen 464®
Adogen 464®
Adogen 464®
18-Crown-6
75
completion. Whilst 3-thienylboronic acid reacted in high yield
the 2-thienylboronic acid reaction showed no consumption of
starting isothiazole. The poor reactivity of 2-thienylboronic
acid compared to that of 3-thienylboronic acid could arise from
a more ready protodeboronation of 2-thienylboronic acid.30–32
Similar problems have been solved by the use of anhydrous
conditions.20,25 Rigorous drying of the reagents and employing
anhydrous reaction conditions under an argon atmosphere
failed to give the desired Suzuki coupling with 2-thienylboronic
acid, however. The 2- and 3-thienyl derivatives were prepared
independently from the corresponding thienyl-methylene-
malononitriles 3 on treatment with disulfur dichloride and
pyridine in ca. 30% yields (Scheme 3).
a
86
97
96
96
90
96
18-Crown-6
18-Crown-6
18-Crown-6
18-Crown-6
4.5
7
9
95
a
0.05
24
a Incomplete reaction.
Next the choice of phase transfer catalyst was examined
(Table 2). 18-Crown-6 was preferred since various tetraalkyl-
ammonium salts gave either lower yields or required longer
reaction times. Reducing the amount of 18-crown-6 gave slower
reactions but had little effect on the product yield. The use of
crown ethers in Suzuki reactions is not common,21 but pal-
ladium-catalysed aminations of aryl halides26–28 and Ullmann-
type couplings29 have been performed in good yields with
crown ethers.
Finally a series of commercially available palladium catalysts
were compared against Pd(OAc)2. Pd(PPh3)4 and (Ph3P)2PdCl2
gave significantly slower rates of reaction (by TLC) whilst
(PhCN)2PdCl2, (CH3CN)2PdCl2, (dibenzylideneacetone)3Pd2,
and [1,1Ј-bis(Ph2P)ferrocene]PdCl2ؒCH2Cl2 gave significantly
better initial activity than Pd(OAc)2, however, with the latter,
traces of unreacted isothiazole 1 remained even after prolonged
reaction times. For these catalysts the following conditions were
investigated; increasing the catalyst loading from 5 to 10 mol%,
degassing the reactions and performing them under argon
atmosphere, varying the reaction temperatures and rate of
applied heating; increasing the quantity of phenylboronic
acid from 1.5 to 2 equivalents, however, did not give complete
consumption of the starting isothiazole. Having optimized
the reaction conditions for the phenylboronic acid coupling a
variety of boronic acids were investigated (Scheme 2, Table 3).
Generally electron rich boronic acids led to faster reactions
and substituents in the ortho positions had little steric influence
on the reaction. Electron poor boronic acid gave lower yields or
required further addition of reagents to drive the reaction to
Scheme 3 Reagents and conditions: i) S2Cl2 (4 equiv.), C5H5N, 80 ЊC,
16 h.
Reaction of isothiazole 1 with organotrifluoroborates
For comparison, the above Suzuki couplings were reinvesti-
gated using the readily available and air stable organo-
trifluoroborates33 which have recently found use in several such
couplings.15,34–39 The reaction of 3,5-dichloroisothiazole-4-c-
arbonitrile 1 with organotrifluoroborate was optimized in the
open atmosphere with respect to potassium phenyltrifluoro-
borate (1.5 equiv.), 18-crown-6 (0.5 equiv.), Pd(OAc)2 (5 mol%)
in refluxing solvents in the presence of various bases (1 equiv.)
such as K3PO4, KHCO3, K2CO3, KOH and KF. The reaction
proceeded to completion rapidly and in high yield with K2CO3
(2 h) and somewhat less rapidly with KHCO3. The use of KF or
K3PO4 failed to drive the reaction to completion after 12 h and
no consumption of isothiazole 1 was observed with KOH.
Increasing the quantity of base to 1.5 equivalents gave no addi-
tional benefit, but with less than 1 equivalent of base over 24 h
was required for the reaction to reach completion (Scheme 4,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
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Table 3 Reaction of 3,5-dichloroisothiazole-4-carbonitrile 1 (0.3 mmol) with RB(OH)2 (2 equiv.), KF (3.5 equiv.), Pd(OAc)2 (5 mol%) and
18-crown-6 (0.5 equiv.)
R
Solvent
Temp. (ЊC)
Time (h)
Yield 2 (%)
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
PhH
80
110
110
110
110
110
110
80
110
110
110
110
110
110
110
80
26
3
1
1.5
1.5
1.5
1
91
97
95
99
89
96
80
95
89
91
97
43
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhH
2-MeC6H4
3-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-NO2C6H4
4-Vinylphenyl
2-Thienyl
3-Thienyl
3-Thienyl
Me
2f
2
2g
2h
2i
2j
2k
2l
2m
2m
2n
77a
74b
4
30c
24
24
3
30d
e
93
93
67
24
21.5
PhMe
110
a Extra 2-ClC6H4B(OH)2 (0.7 equiv.) and Pd(OAc)2 (3 mol%). b Extra 3-ClC6H4B(OH)2 (0.7 equiv.) and Pd(OAc)2 (3 mol%). c Extra KF (2 equiv.),
3-NO2C6H4B(OH)2 (0.7 equiv.), and Pd(OAc)2 (5 mol%). d Low yield due to unidentified co-running by-product which required repeated fractional
recrystallization to separate. e Compound 1 was not consumed.
Table 4 Reaction of dichloroisothiazole 1 (0.3 mmol) with PhBF3K (1.5 equiv.), K2CO3, Pd(OAc)2 (5 mol%) and 18-crown-6 (0.5 equiv.)
Solventa
K2CO3 (equiv.)
Temp. ( ЊC)
Time (h)
Yield 2a (%)
c
c
PhH
PhMe
1.5
0
1
80
110
110
110
110
110
110
140
12
12
2
2
2
12
12
2
PhMe
99
93
PhMeb
1
PhMe
1.5
1.5
1.5
1.5
96
c
PhMe–H2O (4 : 1)
PhMe–H2O (20 : 1)
Xylene
c
57
a Reactions performed in open air atmosphere with undried solvents. b Anhydrous toluene and argon atmosphere. c Incomplete reaction.
The above studies with anhydrous toluene show the reactions
proceed to completion in comparable times and the partici-
pation of trifluoroborate is possible, although the presence and
effect of trace amounts of water cannot be excluded.
Coupling reactions of 3,5-dibromoisothiazole-4-carbonitrile 4
Scheme 4 Reagents and conditions: i) PhBF3K (1.5 equiv.), K2CO3
(1–1.5 equiv.), 18-crown-6 (0.5 equiv.), Pd(OAc)2 (5 mol%), PhMe,
110 ЊC.
3,5-Dibromoisothiazole-4-carbonitrile 4 can be prepared in an
analogous manner to dichloroisothiazole 1 but in significantly
lower yield 11%.10 Both the phenylboronic acid and potassium
phenyltrifluoroborate couplings proceed regiospecifically at
C-5 to afford 3-bromo-5-phenylisothiazole-4-carbonitrile 5 in
almost quantitative yield (Scheme 5).
Table 4). The reaction required at least 1.5 equivalents of
phenyltrifluoroborate and traces of biphenyl were observed by
TLC. Interestingly the coupling with trifluoroborates is
reported to require water as co-solvent,34,35 however under the
above conditions the reaction between 3,5-dichloroisothiazole-
4-carbonitrile 1 and phenyltrifluoroborate proceeded to com-
pletion in high yield as rapidly in anhydrous toluene as in
undried toluene. The presence of additional water (PhMe : H2O
= 4 : 1 or 20 : 1) significantly delayed the reaction from reaching
completion. Higher temperatures (refluxing xylene) margin-
ally improved reaction times but gave considerably reduced
yields. Silver() oxide is known to be a beneficial additive, in
particular for alkylboronic acid Suzuki couplings;40,41 however,
in our reactions added Ag2O led to an increase in the biphenyl
production (TLC) and was not investigated further.
Scheme 5 Reagents and conditions: A) PhB(OH)2 (2 equiv.), KF
(3.5 equiv.), 18-crown-6 (0.5 equiv.), Pd(OAc)2 (5 mol%), PhMe, 110 ЊC,
2 h, 97%; B) PhBF3K (1.5 equiv.), K2CO3 (1–1.5 equiv.), 18-crown-6
(0.5 equiv.), Pd(OAc)2 (5 mol%), PhMe, 110 ЊC, 18 h, 99%.
Phenylboronic acid and KF are proposed to yield phenyltri-
fluoroborate22,42 but had the borate been the only active species
in the transmetallation step then the reaction with phenyltri-
fluoroborate should have proceeded rapidly even in the absence
of base, which was not the case. It has been proposed34,35,37,39,43
Aryl bromides are more reactive than aryl chlorides in Suzuki
couplings and the reaction of phenylboronic acid with di-
bromoisothiazole 4 reached completion slightly faster than
with dichloroisothiazole 1. Contrary to expectations the potas-
sium phenyltrifluoroborate reaction proceeded significantly
slower with dibromoisothiazole 4 than with the dichloroiso-
thiazole 1. The possibility that bromide anions were interfering
was considered and a series of experiments were conducted
Ϫ
that the intermediate boronates PhBF(OH)2 and PhBF2-
(OH)Ϫ, which are formed in the presence of trace amounts of
water and base, could be involved in the transmetallation step.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
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with both isothiazoles in the presence of 1 equivalent of oven
dried KCl or KBr. The dichloroisothiazole reaction times were
not significantly affected by the addition of either KCl or KBr
and reactions were complete in approximately 3.5 h. However,
the dibromoisothiazole reactions were affected; addition of
KBr inhibited the reaction from reaching completion within 12
h, whilst addition of KCl resulted in a shortened reaction time
of 6 h. This peculiar response is under investigation.
Attempted phenylation at C-3 was unsuccessful and under
forcing conditions gave only the 3-phenoxy derivative 6 that was
prepared independently from 3-chloro-5-phenylisothiazole-4-
carbonitrile 2a and potassium phenoxide. Further attempts to
achieve coupling at C-3 are under way.
Experimental
Benzene and toluene were freshly distilled from CaH2 under
argon. Potassium salts PhOK, K2CO3 and KF were powdered
and vacuum dried at 130 ЊC/2 Torr. Reactions were protected by
CaCl2 drying tubes. Anhydrous sodium sulfate was used for
drying organic extracts, and all volatiles were removed under
reduced pressure. All reaction mixtures and column eluents
were monitored by TLC using commercial glass backed thin-
layer chromatography (TLC) plates (Merck Kieselgel 60 F254).
The plates were observed under UV light at 254 and 365 nm.
The technique of dry flash chromatography was used through-
out for all non-TLC scale chromatographic separations using
Merck Silica Gel 60 (less than 0.063 mm). Melting points were
determined using a Stuart Scientific SMP 1 apparatus. Solvents
used for recrystallization are indicated after the melting point.
UV spectra were obtained using a Shimadzu UV-1601 spec-
trometer and inflections are identified by the abbreviation “inf”.
IR spectra were recorded on a Jasco FT/IR-460 plus spectro-
meter and strong and medium peaks are represented by s
and m respectively. 1H and 13C NMR spectra were recorded on
a Bruker Avance 300 machine (at 300 and 75 MHz respectiv-
ely). Deuterated solvents were used for homonuclear lock
and the signals are referenced to the deuterated solvent peaks.
Mass spectra were recorded on a VG Autospec “Q” mass spec-
trometer. Petrol refers to light petroleum, bp 40–60 ЊC. 3,5-
Dichloroisothiazole-4-carbonitrile 1,10 2-(2-thienylmethylene)-
malononitrile 3a,48 2-(3-thienylmethylene)-malononitrile 3b,49
3,5-dibromoisothiazole-4-carbonitrile 410 and potassium
phenyltrifluoroborate35 were prepared according to literature
procedures.
Attempted Suzuki coupling at C-3 of isothiazole 2a
An attempt to perform a Suzuki coupling at C-3 with 3-chloro-
5-phenylisothiazole-4-carbonitrile 2a was unsuccessful, but
gave an interesting product. The reaction with PhB(OH)2–KF
showed a long delay (24 h) before a product spot appeared
(TLC) and the starting material was only then gradually con-
sumed following further addition of reagents. The isothiazole
2a was consumed fully after 7 days, but the product isolated by
chromatography contained an oxygen atom. The stability of the
parent ion (m/z 278, 92%) in the MS did not support the pres-
ence of an S-oxide or an N-oxide and two alternative structures
were considered. The first 4-cyano-N,5-diphenylisothiazol-3-
one is known44 and could be eliminated by its melting point and
the absence of a ν(C᎐O) in the IR, whilst the second possibility,
᎐
3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, was unknown.
This ether was prepared independently in high yield by treating
3-chloro-5-phenylisothiazole-4-carbonitrile 2a with potassium
phenoxide in refluxing toluene in the presence of 18-crown-6
(Scheme 6), and the spectral data of the two specimens were
identical.
Scheme 6 Reagents and conditions: i) PhOK (1.5 equiv.), 18-crown-6
(0.5 equiv.), PhMe, 20–140 ЊC, 3 h, 91%; ii) PhOK (2 equiv.), 18-crown-
6 (0.5 equiv.), PhMe, 20–140 ЊC, 3.5 h, 66%; iii) PhB(OH)2, PdOAc2,
KF, 18-crown-6, 95% (see Experimental section).
3-Chloro-5-phenylisothiazole-4-carbonitrile 2a
(typical organoboronic acid procedure)
A stirred mixture of 3,5-dichloroisothiazole-4-carbonitrile 1
(53.4 mg, 0.3 mmol), phenylboronic acid (73.2 mg, 0.6 mmol),
KF (61 mg, 1.05 mmol), Pd(OAc)2 (3.4 mg, 5 mol%) and
18-crown-6 (40 mg, 0.15 mmol) in toluene (2 ml) was heated
to ca. 110 ЊC until no starting material remained (TLC). The
mixture was allowed to cool to ca. 20 ЊC and chromatography
(hexane–DCM, 3 : 1) gave the title compound 2a (60 mg, 91%)
as colourless needles, mp 87–88 ЊC (from cyclohexane) (lit.,5 85–
Phenylboronic acid can afford phenol and this conversion is
often effected by hydrogen peroxide.45–47 The mechanisms pro-
posed suggest the phenol oxygen arises from the phenylboronic
acid itself. In the above reaction the conversion could be aided
by air oxidation. Furthermore possible mediation at any stage
of the mechanism by complexation with the adjacent ring
nitrogen atom cannot be discounted. Treatment of 3-bromo-5-
phenylisothiazole-4-carbonitrile 5 with potassium phenoxide
(2 equivalents) gave the ether in 66%. Interestingly the reaction
could not be driven to completion with 1.5 equivalents of
potassium phenoxide and TLC analysis indicated a more com-
plex reaction mixture with at least two minor byproducts that
were not isolated. This complexity could arise from additional
nucleophilic attack by phenoxide directly onto the bromine at
C-3 and/or the ring sulfur atom.
86 ЊC); λmax(DCM)/nm 280 (log ε 4.30); νmax(Nujol)/cmϪ1 3036m
᎐
(Ar CH), 2231s (C᎐N), 1517s, 1489s, 1447s, 1397s, 1389m,
᎐
1348s, 1313m, 1242m, 1108s, 1055s, 1029m, 999m, 951s, 920m,
831s, 817m, 765s, 693s, 685s, 664s; δH (300 MHz; CDCl3) 7.78–
7.75 (2H, m, Ar H ), 7.59–7.53 (3H, m, Ar H ); δC (75 MHz;
CDCl3) 176.4, 151.3, 132.3 (Ar CH), 129.8 (Ar CH), 127.3 (Ar
ϩ
᎐
C), 127.2 (Ar CH), 112.1 (C᎐N), 105.0; m/z (EI) 220 (M ,
᎐
100%), 185 (Mϩ Ϫ Cl, 18), 174 (Mϩ Ϫ NS, 4), 159 (9), 153 (2),
141 (6), 127 (Mϩ Ϫ CClNS, 6), 114 (5), 100 (3), 93 (CClNSϩ, 5),
77 (C6H5ϩ, 7), 69 (3), 51 (8) (Found: Mϩ, 219.9864. C10H5ClN2S
requires M, 219.9862).
Summary
To summarize, optimal conditions for high yielding regio-
selective Suzuki couplings at C-5 of the readily available 3,5-
dichloroisothiazole-4-carbonitrile 1 have been achieved using
ligandless palladium catalysis and 18-crown-6 as PTC in reflux-
ing toluene with either organoboronic acid–KF or organo-
trifluoroborate–K2CO3. The regioselectivity and high yields are
maintained with 3,5-dibromoisothiazole-4-carbonitrile 4. The
use of 18-crown-6 and this relatively high temperature signifi-
cantly shorten the reaction times. Regiospecific displacement of
the 5-Cl over the 3-Cl is presumably because the 5-Cl is activ-
ated by both the cyano group and the ring nitrogen atom.
3-Chloro-5-(2-tolyl)isothiazole-4-carbonitrile 2b
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 2-tolylboronic acid, KF, Pd(OAc)2 and 18-crown-6 gave
the title compound 2b (95%) as colourless crystals, mp 91–92 ЊC
(from cyclohexane) (Found: C, 56.2; H, 2.9; N, 12.0.
C11H7ClN2S requires C, 56.3; H, 3.0; N, 11.9%); λmax(DCM)/nm
269 (log ε 4.02); νmax(Nujol)/cmϪ1 2233s (C᎐N), 1516s, 1488s,
᎐
᎐
1454s, 1391s, 1380m, 1344s, 1243s, 1200m, 1120m, 1058s,
1044m, 1036m, 948m, 837s, 809s, 784m, 762s, 719s, 657m,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
2903

View Article Online
600m, 596m; δH (300 MHz; CDCl3) 7.49–7.31 (4H, m, Ar H ),
2.41 (3H, s, CH3); δC (75 MHz; CDCl3) 177.0, 150.4, 136.35
(Ar C), 131.5 (Ar CH), 131.4 (Ar CH), 129.7 (Ar CH), 126.6
(Mϩ Ϫ CH3, 1), 221 (Mϩ Ϫ CHO, 24), 215 (Mϩ Ϫ Cl, 1), 207
(12), 200 (1), 185 (13), 171 (8), 159 (6), 146 (22), 141 (3), 125 (3),
114 (7), 108 (3), 102 (3), 93 (CClNSϩ, 4), 88 (3), 69 (5), 63 (6),
51 (3) (Found: Mϩ, 249.9957. C11H7ClN2OS requires M,
249.9968).
᎐
(Ar CH), 126.4 (Ar C), 111.5 (C᎐N), 108.7, 20.2 (CH ); m/z
᎐
3
(EI) 234 (Mϩ, 49%), 199 (Mϩ Ϫ Cl, 100), 172 (Mϩ Ϫ CHClN,
41), 165 (2), 155 (8), 145 (5), 140 (11), 134 (11), 128 (4), 114 (3),
113 (3), 99 (2), 93 (CClNSϩ, 4), 91 (C7H7ϩ, 4), 89 (4), 75 (4), 63
(6), 51 (5) (Found: Mϩ, 234.0022. C11H7ClN2S requires M,
234.0018).
3-Chloro-5-(4-methoxyphenyl)isothiazole-4-carbonitrile 2f
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 4-methoxyphenylboronic acid, KF, Pd(OAc)2 and 18-
crown-6 gave the title compound 2f (95%) as colourless needles,
mp 133–134 ЊC (from cyclohexane) (lit.,1 122–126 ЊC);
3-Chloro-5-(3-tolyl)isothiazole-4-carbonitrile 2c
λmax(DCM)/nm 285 inf (log ε 4.01), 320 (4.35); νmax(Nujol)/cmϪ1
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 3-tolylboronic acid, KF, Pd(OAc)2 and 18-crown-6 gave
the title compound 2c (99%) as colourless crystals, mp 86–87 ЊC
(from cyclohexane) (Found: C, 56.3; H, 2.9; N, 11.7. C11H7-
ClN2S requires C, 56.3; H, 3.0; N, 11.9%); λmax(DCM)/nm 281
᎐
3013m (Ar CH), 2230s (C᎐N), 1603s, 1573s, 1527m, 1495s,
᎐
1465s, 1451s, 1404s, 1379m, 1347s, 1315s, 1270s, 1182s, 1151m,
1137m, 1126m, 1048s, 1027s, 1006s, 955s, 834s, 811s, 803s,
781m, 724m, 688s, 629s, 579s, 571s, 516s; δH (300 MHz; CDCl3)
7.74 (2H, d, J 8.6, Ar H-2), 7.04 (2H, d, J 8.7, Ar H-3), 3.89
(log ε 4.32); νmax(Nujol)/cmϪ1 2233s (C᎐N), 1516s, 1486m,
᎐
᎐
(3H, s, CH3O); δC (75 MHz; CDCl3) 176.15, 162.8, 151.2, 128.8
1462m, 1392m, 1379m, 1346s, 1321m, 1265m, 1068s, 919m,
᎐
(Ar CH-2 & 6), 119.9, 115.2 (Ar CH-3 & 5), 112.6 (C᎐N),
᎐
817m, 792s, 773m, 702s, 689m, 596m, 591m; δH (300 MHz;
CDCl3) 7.56–7.54 (2H, m, Ar H ), 7.47–7.37 (2H, m, Ar H ),
2.45 (3H, s, CH3); δC (75 MHz; CDCl3) 176.7, 151.3, 139.9
103.6, 56.6 (CH3O); m/z (EI) 250 (Mϩ, 100%), 235 (Mϩ Ϫ CH3,
14), 220 (Mϩ Ϫ CHO, 1), 207 (20), 181 (2), 171 (4), 157 (2), 146
(20), 114 (6), 108 (2), 102 (2), 93 (CClNSϩ, 3), 88 (4), 69 (4), 63
(4), 51 (2) (Found: Mϩ, 249.9956. C11H7ClN2OS requires M,
249.9968).
(Ar C), 133.2 (Ar CH), 129.7 (Ar CH), 127.7 (Ar CH), 127.2
᎐
(Ar C), 124.3 (Ar CH), 112.2 (C᎐N), 104.8, 21.3 (CH );
᎐
3
m/z (EI) 234 (Mϩ, 100%), 206 (3), 199 (Mϩ Ϫ Cl, 85), 172
(Mϩ Ϫ CHClN, 31), 165 (4), 155 (11), 145 (5), 140 (12), 134 (6),
128 (6), 117 (6), 114 (5), 113 (4), 93 (CClNSϩ, 4), 91 (C7H7ϩ, 4),
69 (4), 65 (8), 63 (6), 51 (5) (Found: Mϩ, 234.0019. C11H7ClN2S
requires M, 234.0018).
3-Chloro-5-(2-chlorophenyl)isothiazole-4-carbonitrile 2g
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 2-chlorophenylboronic acid, KF, Pd(OAc)2 and 18-crown-
6 required after 48 h an extra addition of 2-chlorophenyl-
boronic acid (0.7 equiv.) and Pd(OAc)2 (3 mol%) to drive the
reaction to completion and gave the title compound 2g (89%) as
colourless needles, mp 99 ЊC (from cyclohexane) (lit.,5 97–98
ЊC); λmax(DCM)/nm 235 inf (log ε 3.79), 277 (4.23); νmax(Nujol)/
3-Chloro-5-(2-methoxyphenyl)isothiazole-4-carbonitrile 2d
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 2-methoxyphenylboronic acid, KF, Pd(OAc)2 and 18-
crown-6 gave the title compound 2d (89%) as colourless
needles, mp 157–158 ЊC (from cyclohexane) (Found: C, 52.8;
H, 2.7; N, 11.3. C11H7ClN2OS requires C, 52.7; H, 2.8; N,
11.2%); λmax(DCM)/nm 284 (log ε 4.24), 294 (4.17), 331 (4.12);
cmϪ1 2234s (C᎐N), 1589m, 1512m, 1464s, 1436m, 1387m,
᎐
᎐
1348s, 1076s, 1040s, 950m, 836m, 755s, 719m, 710m, 694m,
648m, 595m, 585m; δH (300 MHz; CDCl3) 7.66–7.59 (2H, m,
Ar H ), 7.54–7.43 (2H, m, Ar H ); δC (75 MHz; CDCl3)
νmax(Nujol)/cmϪ1 2220s (C᎐N), 1600s, 1576s, 1507s, 1468s,
᎐
᎐
173.0, 150.5, 132.8, 132.7 (Ar CH), 131.0 (Ar CH), 130.7
1436s, 1397m, 1340s, 1302s, 1262s, 1234s, 1192m, 1128s, 1057m,
᎐
(Ar CH), 127.7 (Ar CH), 126.3 (Ar C), 111.5 (C᎐N), 108.9;
᎐
1033s, 1016s, 944m, 837s, 823s, 757s, 741m, 690s, 661s, 603m,
583m, 570m; δH (300 MHz; CDCl3) 8.39 (1H, dd, J 7.9, 1.6, Ar
H ), 7.54 (1H, ddd, J 8.4, 7.4, 1.55, Ar H ), 7.16 (1H, ddd, J 8.0,
7.4, 1.1, Ar H ), 7.10 (1H, app d, J 8.4, Ar H ), 4.06 (3H, s,
m/z (EI) 254 (Mϩ, 100%), 219 (Mϩ Ϫ Cl, 23), 208 (Mϩ Ϫ NS, 4),
193 (Mϩ Ϫ CClN, 8), 184 (Mϩ Ϫ Cl2, 12), 175 (7), 161
(Mϩ Ϫ CClNS, 10), 158 (14), 139 (2), 126 (4), 114 (9), 111 (4),
99 (6), 93 (CClNSϩ, 12), 87 (3), 75 (10), 69 (4), 50 (6) (Found:
Mϩ, 253.9462. C10H4Cl2N2S requires M, 253.9472).
CH3O); δC (75 MHz; CDCl3) 169.9, 156.6, 150.0, 133.4 (Ar
᎐
CH), 127.2 (Ar CH), 121.6 (Ar CH), 117.2, 113.7 (C᎐N), 111.5
᎐
(Ar CH), 103.2, 55.8 (CH3O); m/z (EI) 250 (Mϩ, 100%), 235
(Mϩ Ϫ CH3, 1), 223 (Mϩ Ϫ CHN, 6), 221 (Mϩ Ϫ CHO, 12), 215
(Mϩ Ϫ Cl, 74), 207 (12), 200 (6), 187 (14), 183 (11), 182 (11), 174
(11), 171 (7), 156 (Mϩ Ϫ CHClNS, 5), 146 (35), 137 (6), 133 (7),
127 (5), 120 (7), 114 (12), 109 (5), 102 (6), 93 (CClNSϩ, 5),
88 (6), 69 (9), 63 (7), 51 (6), 50 (5) (Found: Mϩ, 249.9956.
C11H7ClN2OS requires M, 249.9968).
3-Chloro-5-(3-chlorophenyl)isothiazole-4-carbonitrile 2h
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 3-chlorophenylboronic acid, KF, Pd(OAc)2 and 18-crown-
6 required after 48 h an extra addition of 3-chlorophenyl-
boronic acid (0.7 equiv.) and Pd(OAc)2 (3 mol%) to drive the
reaction to completion and gave the title compound 2h (91%) as
colourless needles, mp 103–104 ЊC (from cyclohexane) (lit.,1
3-Chloro-5-(3-methoxyphenyl)isothiazole-4-carbonitrile 2e
99.5–101 ЊC); λmax(DCM)/nm 277 (log ε 4.25); νmax(Nujol)/cmϪ1
᎐
3057s (Ar CH), 2237s (C᎐N), 1566s, 1512s, 1476s, 1414m,
᎐
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 3-methoxyphenylboronic acid, KF, Pd(OAc)2 and 18-
crown-6 gave the title compound 2e (96%) as colourless needles,
mp 103–104 ЊC (from cyclohexane) (Found: C, 52.7; H, 2.7; N,
11.1. C11H7ClN2OS requires C, 52.7; H, 2.8; N, 11.2%);
λmax(DCM)/nm 247 (log ε 4.18), 280 (4.32), 310 inf (3.88);
1392m, 1347s, 1312m, 1106s, 1084s, 1061s, 997m, 905s, 861m,
814m, 795s, 728s, 701s, 683s, 600m, 590m; δH (300 MHz;
CDCl3) 7.72–7.66 (2H, m, Ar H ), 7.59–7.49 (2H, m, Ar H ); δC
(75 MHz; CDCl3) 174.6, 151.6, 136.0 (Ar C), 132.3 (Ar CH),
131.2 (Ar CH), 128.9 (Ar C), 127.3 (Ar CH), 125.4 (Ar CH),
ϩ
ϩ
᎐
111.7 (C᎐N), 105.8; m/z (EI) 254 (M , 100%), 219 (M Ϫ Cl,
᎐
νmax(Nujol)/cmϪ1 3074m, 3013m (Ar CH), 2235s (C᎐N), 1605s,
᎐
᎐
21), 208 (Mϩ Ϫ NS, 3), 193 (Mϩ Ϫ CClN, 6), 184 (Mϩ Ϫ Cl2, 8),
175 (7), 161 (Mϩ Ϫ CClNS, 5), 158 (8), 139 (1), 126 (2), 114 (6),
111 (5), 99 (4), 93 (CClNSϩ, 9), 87 (2), 75 (10), 69 (4), 50 (5)
(Found: Mϩ, 253.9480. C10H4Cl2N2S requires M, 253.9472).
1579s, 1514s, 1483s, 1427m, 1389s, 1345s, 1320m, 1290s, 1275s,
1208s, 1175s, 1105m, 1059s, 1036s, 973s, 886s, 867s, 816s, 795s,
773s, 702s, 689s, 662m, 595m, 565m, 546m; δH (300 MHz;
CDCl3) 7.47 (1H, app t, J 7.9, Ar H ), 7.34–7.28 (2H, m, Ar H ),
7.12 (1H, app d, J 8.3, Ar H ), 3.89 (3H, d, J 1.2, CH3O); δC (75
MHz; CDCl3) 176.3, 160.3, 151.2, 130.95 (Ar CH), 128.3
(Ar C), 119.5 (Ar CH), 118.15 (Ar CH), 112.2 (Ar CH), 112.1
3-Chloro-5-(4-chlorophenyl)isothiazole-4-carbonitrile 2i
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 4-chlorophenylboronic acid, KF, Pd(OAc)2 and 18-crown-
ϩ
᎐
(C᎐N), 105.0, 55.5 (CH O); m/z (EI) 250 (M , 100%), 235
᎐
3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
2904

View Article Online
6 gave the title compound 2i (97%) as colourless needles, mp
117–119 ЊC (from cyclohexane) (lit.,5 119 ЊC); λmax(DCM)/nm
812m, 805m, 786s, 759m, 704s, 696s, 632s, 550s; δH (300 MHz;
CDCl3) 8.10 (1H, dd, J 2.8, 1.4, thienyl H-2), 7.53 (1H, dd,
J 5.2, 2.9, thienyl H ), 7.47 (1H, dd, J 5.2, 1.4, thienyl H ); δC (75
285 (log ε 4.44); νmax(Nujol)/cmϪ1 2229s (C᎐N), 1910m, 1595s,
᎐
᎐
1517s, 1483s, 1404s, 1395s, 1378m, 1341s, 1305m, 1272m, 1251s,
MHz; CDCl3) 170.0, 151.0, 128.5 (thienyl CH), 127.7 (thienyl
᎐
1188m, 1114m, 1098s, 1048s, 1014s, 967m, 842s, 823s, 715s,
690s, 608s, 579m; δH (300 MHz; CDCl3) 7.72 (2H, d, J 8.8, Ar
H ), 7.54 (2H, d, J 8.8, Ar H ); δC (75 MHz; CDCl3) 175.0, 151.6,
138.8 (Ar C), 130.2 (Ar CH), 128.5 (Ar CH), 125.7, (Ar C),
CH), 127.3 (thienyl C), 125.4 (thienyl CH), 112.4 (C᎐N), 104.0;
᎐
m/z (EI) 226 (Mϩ, 100%), 199 (Mϩ Ϫ CHN, 6), 191 (Mϩ Ϫ Cl,
15), 182 (3), 180 (Mϩ Ϫ NS, 2), 165 (Mϩ Ϫ CClN, 37), 147 (13),
133 (Mϩ Ϫ CClNS, 6), 127 (3), 121 (4), 93 (CClNSϩ, 6), 82 (4),
69 (6), 58 (5) (Found: Mϩ, 225.9419. C8H3ClN2S2 requires M,
225.9426).
ϩ
ϩ
᎐
111.9 (C᎐N), 105.4; m/z (EI) 254 (M , 100%), 219 (M Ϫ Cl,
᎐
18), 208 (Mϩ Ϫ NS, 4), 193 (Mϩ Ϫ CClN, 6), 184 (Mϩ Ϫ Cl2, 8),
175 (6), 161 (Mϩ Ϫ CClNS, 7), 158 (5), 139 (1), 126 (3), 114 (6),
111 (5), 99 (3), 93 (CClNSϩ, 8), 87 (2), 75 (9), 69 (4), 50 (5)
(Found: Mϩ, 253.9479. C10H4Cl2N2S requires M, 253.9472).
3-Chloro-5-methylisothiazole-4-carbonitrile 2n
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with methylboronic acid, KF, Pd(OAc)2 and 18-crown-6 gave
the title compound 2n (67%) as colourless crystals, mp 53–54 ЊC
(from cyclohexane) (Found: C, 38.0; H, 1.8; N, 17.6. C5H3-
ClN2S requires C, 37.9; H, 1.9; N, 17.7%); λmax(DCM)/nm 259
3-Chloro-5-(3-nitrophenyl)isothiazole-4-carbonitrile 2j
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 3-nitrophenylboronic acid, KF, Pd(OAc)2 and 18-crown-6
required after 48 h an extra addition of 3-nitrophenylboronic
acid (0.7 equiv.), KF (2 equiv.) and Pd(OAc)2 (5 mol%) to drive
the reaction to completion and gave the title compound 2j
(43%) as colourless needles, mp 135–136 ЊC (from cyclohexane)
(Found: C, 45.0; H, 1.3; N, 15.7. C10H4ClN3O2S requires C,
45.2; H, 1.5; N, 15.8%); λmax(DCM)/nm 265 (log ε 4.38);
(log ε 3.96); νmax(Nujol)/cmϪ1 2233s (C᎐N), 1520m, 1403m,
᎐
᎐
1380m, 1345s, 1193s, 1105m, 954m, 816m, 645m, 546m; δH (300
MHz; CDCl3) 2.74 (3H, s, CH3); δC (75 MHz; CDCl3)
᎐
175.2 (C-3), 150.0 (C-5), 111.0 (C᎐N), 109.1 (C-4), 13.7 (CH );
᎐
3
δC (75 MHz; coupled, CDCl3) 175.2 (q, J 6.9, C-3), 150.0 (q,
᎐
J 1.1, C-5), 111.0 (C᎐N), 109.1 (q, J 4.8, C-4), 13.7 (q, J 132.3,
᎐
CH3); m/z (EI) 158 (Mϩ, 100%), 131 (Mϩ Ϫ CHN, 5), 123
(Mϩ Ϫ Cl, 92), 108 (3), 96 (Mϩ Ϫ CHClN, 20), 93 (CClNSϩ,
14), 79 (6), 70 (17), 64 (11), 59 (10) (Found: Mϩ, 157.9717.
C5H3ClN2S requires M, 157.9705).
νmax(Nujol)/cmϪ1 2233m (C᎐N), 1616m, 1532s, 1508s, 1479s,
᎐
᎐
1463s, 1354s, 1343s, 1293m, 1063s, 908m, 896m, 826m, 810s,
738s, 709s, 698s, 671m; δH (300 MHz; CDCl3) 8.56 (1H, t, J 2.0,
Ar H-2), 8.46 (1H, app d, J 8.3, Ar H ), 8.14 (1H, app d, J 7.8,
Ar H ), 7.82 (1H, dd, J 8.2, 7.9, Ar H-5); δC (75 MHz; CDCl3)
3-Chloro-5-(2-thienyl)isothiazole-4-carbonitrile 2l from
2-(2-thienylmethylene)malononitrile 3a
173.3, 152.0, 148.8, 132.75 (Ar CH), 131.3 (Ar CH), 128.8 (Ar
᎐
C), 126.55 (Ar CH), 122.5 (Ar CH), 111.4 (C᎐N), 106.8; m/z
᎐
(EI) 265 (Mϩ, 100%), 235 (Mϩ Ϫ NO, 5), 219 (18), 207 (18), 199
(3), 184 (23), 158 (25), 146 (8), 114 (34), 93 (CClNSϩ, 8), 69 (7),
56 (10) (Found: Mϩ, 264.9720. C10H4ClN3O2S requires M,
264.9713).
To a stirred solution of 2-(2-thienylmethylene)malononitrile 3a
(160 mg, 1 mmol) in pyridine (3 ml) at ca. 20 ЊC, S2Cl2 (320 µl,
4 mmol) was added and the mixture was heated to ca. 115 ЊC for
24 h. The mixture was allowed to cool to ca. 20 ЊC and chrom-
atography (hexane–DCM, 3 : 1) gave the title compound 2l (29%)
as colourless crystals, mp 115–117 ЊC (from cyclohexane);
3-Chloro-5-(4-vinylphenyl)isothiazole-4-carbonitrile 2k
λmax(DCM)/nm 327 (log ε 4.14), 279 (3.91); νmax(Nujol)/cmϪ1
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 4-vinylphenylboronic acid, KF, Pd(OAc)2 and 18-crown-6
gave after chromatography the crude product together with a
co-running insoluble yellow by-product. Repeated fractional
crystallization gave the title compound 2k (30%) as pale yellow
needles, mp 104–105 ЊC (from cyclohexane) (Found: C, 58.7; H,
2.7; N, 11.5. C12H7ClN2S requires C, 58.4; H, 2.8; N, 11.4%);
᎐
3106m, 3082m (thienyl CH), 2227m (C᎐N), 1537s, 1523m,
᎐
1482s, 1466m, 1418s, 1347s, 1338s, 1231m, 1063m, 1037s, 859m,
850m, 811s, 736m, 710s, 693m; δH (300 MHz; CDCl3) 7.76 (1H,
dd, J 3.8, 1.1, thienyl H-3), 7.66 (1H, dd, J 5.1, 1.1, thienyl H-5),
7.23 (1H, dd, J 5.1, 3.8, thienyl H-4); δC (75 MHz; CDCl3)
168.8, 151.0, 131.2 (thienyl CH), 129.7 (thienyl CH), 129.0
᎐
λmax(DCM)/nm 295 inf (log ε 4.28), 317 (4.46); νmax(Nujol)/cmϪ1
(thienyl CH), 128.4 (thienyl C), 112.1 (C᎐N), 103.6; m/z (EI)
᎐
226 (Mϩ, 100%), 199 (Mϩ Ϫ CHN, 4), 191 (Mϩ Ϫ Cl, 17), 182
(7), 180 (Mϩ Ϫ NS, 4), 165 (Mϩ Ϫ CClN, 10), 159 (2), 147 (17),
133 (Mϩ Ϫ CClNS, 10), 127 (3), 121 (5), 93 (CClNSϩ, 6), 82 (4),
69 (10), 58 (8) (Found: Mϩ, 225.9419. C8H3ClN2S2 requires M,
225.9426).
᎐
2229s (C᎐N), 1628m, 1600m, 1557m, 1525m, 1496s, 1464m,
᎐
1424m, 1401s, 1340s, 1298m, 1245m, 1133m, 1051s, 1035m,
1025m, 992s, 953m, 919s, 840s, 817m, 770m, 692s; δH (300
MHz; CDCl3) 7.75 (2H, d, J 8.5, Ar H ), 7.57 (2H, d, J 8.5,
Ar H ), 6.51 (1H, dd, J 17.6, 10.9, CH᎐CH trans), 5.90 (1H, d,
᎐
2
J 17.6, CH᎐CH ), 5.44 (1H, d, J 10.9, CH᎐CH cis); δ (75
᎐
᎐
2
2
C
3-Chloro-5-(3-thienyl)isothiazole-4-carbonitrile 2m from
2-(3-thienylmethylene)malononitrile 3b
MHz; CDCl3) 176.0, 151.5, 141.6, 135.4 (Ar CH or
CHC᎐CH ), 127.5 (Ar CH or CHC᎐CH ), 127.45 (Ar CH or
᎐
᎐
2
2
᎐
CHC᎐CH ), 126.45 (Ar C), 117.25 (CH᎐CH ), 112.3 (C᎐N),
᎐
᎐
᎐
2
2
Similar treatment of 2-(3-thienylmethylene)malononitrile 3b
with S2Cl2 in pyridine gave the title compound 2m (30%) as
colourless crystals, mp 117–118 ЊC (from cyclohexane) identical
to that described above.
104.7; m/z (EI) 246 (Mϩ, 100%), 220 (Mϩ Ϫ CN, 3), 211 (Mϩ Ϫ
Cl, 10), 184 (8), 178 (5), 167 (3), 157 (6), 153 (Mϩ Ϫ CNClS, 5),
140 (10), 114 (3), 102 (3), 93 (CNClSϩ, 6), 82 (2), 77 (6), 70 (5),
63 (5), 51 (6) (Found: Mϩ, 246.0017. C12H7ClN2S requires M,
246.0018).
3-Bromo-5-phenylisothiazole-4-carbonitrile 5
A stirred mixture of 3,5-dibromoisothiazole-4-carbonitrile 4
(80.4 mg, 0.3 mmol), phenylboronic acid (73.2 mg, 0.6 mmol),
KF (61 mg, 1.05 mmol), Pd(OAc)2 (3.4 mg, 5 mol%), 18-crown-
6 (0.5 equiv.) in toluene (2 ml) was heated to ca. 110 ЊC until no
starting material remained (TLC). The mixture was allowed to
cool to ca. 20 ЊC and chromatography (hexane–DCM, 3 : 1)
gave the title compound 5 (77 mg, 97%) as colourless crystals,
mp 93–94 ЊC (from cyclohexane) (Found: C, 45.6; H, 2.0;
N, 10.4. C10H5BrN2S requires C, 45.3; H, 1.9; N, 10.6%);
λmax(DCM)/nm 281 (log ε 4.26); νmax(Nujol)/cmϪ1 3034m
3-Chloro-5-(3-thienyl)isothiazole-4-carbonitrile 2m
Similar treatment of 3,5-dichloroisothiazole-4-carbonitrile 1
with 3-thienylboronic acid, KF, Pd(OAc)2 and 18-crown-6 gave
the title compound 2m (93%) as colourless crystals, mp 117–
118 ЊC (from cyclohexane) (Found: C, 42.1; H, 1.1; N, 12.2.
C8H3ClN2S2 requires C, 42.4; H, 1.3; N, 12.4%); λmax(DCM)/nm
293 (log ε 4.38); νmax(Nujol)/cmϪ1 3103s, 3076m, 3070m
᎐
(Ar CH), 2230s (C᎐N), 1533s, 1524s, 1508s, 1485m, 1464m,
᎐
1456m, 1432s, 1384s, 1360s, 1338s, 1212s, 1058s, 863m, 828m,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
2905

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᎐
(Ar CH), 2236s (C᎐N), 1517s, 1483s, 1457m, 1445s, 1393s,
chromatography (hexane–DCM, 3 : 1) gave the title compound
6 (91%) as colourless needles, mp 118–119 ЊC (from cyclo-
hexane) identical to that described above.
᎐
1377m, 1337s, 1318m, 1249m, 1240s, 1287m, 1080m, 1040s,
1021m, 998s, 966m, 823m, 789m, 762s, 694s, 667s, 585m, 576m;
δH (300 MHz; CDCl3) 7.79–7.75 (2H, m, Ar H ), 7.62–7.53 (3H,
m, Ar H ); δC (75 MHz; CDCl3) 176.4, 139.8, 132.3 (Ar CH),
Acknowledgements
᎐
129.9 (Ar CH), 127.3 (Ar CH), 127.2 (Ar C), 112.7 (C᎐N),
᎐
108.4; m/z (EI) 264 (Mϩ, 100%), 218 (Mϩ Ϫ NS, 4), 185 (38),
184 (Mϩ Ϫ Br, 14), 158 (Mϩ Ϫ CBrN, 18), 153 (6), 141 (21), 127
(6), 114 (12), 100 (4), 84 (53), 77 (C6H5ϩ, 7), 69 (4), 63 (4), 51 (4),
49 (68) (Found: Mϩ, 263.9356. C10H5BrN2S requires M,
263.9357).
We thank the following organisations in Cyprus for generous
donations of chemicals and glassware: the State General
Laboratory, the Agricultural Research Institute and the
Ministry of Agriculture. Furthermore we thank the A. G.
Leventis Foundation for helping to establish the NMR facility
in the University of Cyprus, MDL Information Sytems (UK)
Ltd for financial support and the Wolfson Foundation
for establishing the Wolfson Centre for Organic Chemistry in
Medical Science at Imperial College. We thank the referees
for their valuable comments regarding the formation of
phenoxyisothiazole 6.
3-Chloro-5-phenylisothiazole-4-carbonitrile 2a (typical
organotrifluoroborate procedure)
A stirred mixture of 3,5-dichloroisothiazole-4-carbonitrile 1
(53.4 mg, 0.3 mmol), potassium phenyltrifluoroborate (83 mg,
0.45 mmol), powdered K2CO3 (62 mg, 0.45 mmol), Pd(OAc)2
(3.4 mg, 5 mol%) and 18-crown-6 (40 mg, 0.15 mmol) in toluene
(2 ml) was heated to ca. 110 ЊC until no starting material
remained (TLC). The mixture was allowed to cool to ca. 20 ЊC
and chromatography (hexane–DCM, 3 : 1) gave the title com-
pound 2a (65 mg, 99%) as colourless needles, mp 87–88 ЊC
(from cyclohexane) identical to that described above.
References
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(C᎐N), 1593m, 1541s, 1488s, 1452s, 1436m, 1393s, 1336m,
᎐
1312m, 1262m, 1205s, 1161s, 1126m, 1069m, 1023m, 1005m,
929m, 915m, 872s, 771s, 717s, 704s, 685s, 632m; δH (300 MHz;
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ϩ
(C᎐N), 94.0; m/z (EI) 278 (M , 92%), 277 (Mϩ Ϫ H, 100), 265
᎐
᎐
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 – 2 9 0 7
2907