Microwave-induced generation and reactions of nitrile sulfides: An improved method for the synthesis of isothiazoles and 1,2,4-thiadiazoles

Article abstract of DOI:10.1016/j.tet.2010.06.068

The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation of 1,3,4-oxathiazol-2-ones, have been investigated. By this approach ethyl 1,2,4-thiadiazole-5-carboxylates 3 were prepared in good yield by cycloaddition of the nitrile sulfides to ethyl cyanoformate. Similarly, reaction of benzonitrile sulfide with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 3-phenylisothiazole-4,5- dicarboxylate (5). In contrast, o-hydroxybenzonitrile sulfide, generated from the corresponding oxathiazolone 2d, reacted with DMAD to give methyl 4-oxo-4H-[1]benzopyrano[4,3-c]isothiazole-3-carboxylate (8) in high yield. A ca. 1:1 mixture of ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7) was formed from benzonitrile sulfide and ethyl propiolate. The corresponding reaction with diethyl fumarate gave diethyl trans-4,5-dihydro-3-phenylisothiazole-4,5- dicarboylate (10). 3-Arylisothiazoles, unsubstituted at both the 4- and 5-positions, were prepared from the reaction of 5-aryl-1,3,4-oxathiazolones with norbornadiene by a pathway involving cycloaddition of the nitrile sulfide to the norbornadiene, followed by retro-Diels-Alder extrusion of cyclopentadiene from the resulting isothiazoline cycloadduct 12. In summary, the use of microwave irradiation, rather than conventional heating methods, allows nitrile sulfide generation and reactions to be carried out in shorter times, with easier work-up and, in some cases, in higher yields.

Full text of DOI:10.1016/j.tet.2010.06.068

Tetrahedron 66 (2010) 7192e7197
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-induced generation and reactions of nitrile sulfides: an improved
method for the synthesis of isothiazoles and 1,2,4-thiadiazoles
,
Euan A.F. Fordyce a, Angus J. Morrison b, Robert D. Sharp a, R. Michael Paton a
*
a School of Chemistry, The University of Edinburgh, The King’s Buildings, Edinburgh EH9 3JJ, UK
b MSD, Medicinal Chemistry Department, Newhouse, Lanarkshire ML1 5SH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2010
Received in revised form 7 June 2010
Accepted 24 June 2010
Available online 3 July 2010
The 1,3-dipolar cycloaddition reactions of nitrile sulfides, generated by microwave-assisted decarboxylation
of 1,3,4-oxathiazol-2-ones, have been investigated. By this approach ethyl 1,2,4-thiadiazole-5-carboxylates 3
were prepared in good yield by cycloaddition of the nitrile sulfides to ethyl cyanoformate. Similarly, reaction
of benzonitrile sulfide with dimethyl acetylenedicarboxylate (DMAD) afforded dimethyl 3-phenyl-
isothiazole-4,5-dicarboxylate (5). In contrast, o-hydroxybenzonitrile sulfide, generated from the corre-
sponding oxathiazolone 2d, reacted with DMAD to give methyl 4-oxo-4H-[1]benzopyrano[4,3-c]isothiazole-
3-carboxylate (8) in high yield. A ca. 1:1 mixture of ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7)
was formed from benzonitrile sulfide and ethyl propiolate. The corresponding reaction with diethyl fu-
marate gave diethyl trans-4,5-dihydro-3-phenylisothiazole-4,5-dicarboylate (10). 3-Arylisothiazoles, un-
substituted at both the 4- and 5-positions, were prepared from the reaction of 5-aryl-1,3,4-oxathiazolones
with norbornadiene by a pathway involving cycloaddition of the nitrile sulfide to the norbornadiene, fol-
lowed by retro-DielseAlder extrusion of cyclopentadiene from the resulting isothiazoline cycloadduct 12. In
summary, the use of microwave irradiation, rather than conventional heating methods, allows nitrile sulfide
generation and reactions to be carried out in shorter times, with easier work-up and, in some cases, in higher
yields.
Keywords:
Nitrile sulfides
1,3,4-Oxathiazol-2-ones
1,2,4-Thiadiazoles
Isothiazoles
Microwave-assisted reactions
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the tendency of nitrile sulfides to decompose to the corresponding
nitriles and the forcing conditions often required to generate these
The 1,3-dipolar cycloaddition reactions of nitrile ylides, nitrile
imides and nitrile oxides (ReC^NþeXꢀ; X¼CR2, NR, O) are widely
used for the preparation of five-membered heterocycles in-
corporating the C]NeX unit.1 In contrast, less attention has been
paid to the corresponding reactions of nitrile sulfides
(ReC^NþeSꢀ).2 Nitrile sulfides are uniquely well suited for the
synthesis of the analogous C]NeS heterocycles via their cycload-
dition reactions with double- and triple-bonded dipolarophiles
(Scheme 1), and by this means various isothiazoles,2,3 2-iso-
thiazolines,2,4 1,2,4-thiadiazoles,2,3e,f,4a,5 1,3,4-oxathiazoles,2,6 1,2,4-
thiazaphospholes7 and 1,4,2-dithiazoles8 have been prepared. More
general application of this chemistry is, however, limited both by
short-lived intermediates. One potential solution to this problem is
the use of microwave technology.9
In recent years there has been rapid growth in the use of micro-
wave irradiation to facilitate organic reactions.9 Among the advan-
tages of this method, compared with conventional heating, are
reduced reaction times and the potential for improved productyields.
A wide range of reactions have been shown to benefit from this
technique. These include 1,3-dipolar cycloadditions10 involving ni-
trile
imides
(ReC^NþeNRꢀ)11
and
nitrile
oxides
(ReC^NþeOꢀ).11b,12 We now report on the application of microwave
irradiation for the generation of nitrile sulfides.13
2. Results and discussion
R
R
X
S
X
S
X
Y
X
Y
R
N S
Y
Y
The most efficient and commonly used method of generating
nitrile sulfides (1) involves the thermal decarboxylation of 1,3,4-
oxathiazol-2-ones (2),2 which are usually prepared from the cor-
responding carboxamide by treatment with chlorocarbonylsulfenyl
chloride, and this was the approach adopted for the current work
(Scheme 2). To test the effectiveness of the microwave technique to
promote the generation and reactions of nitrile sulfides we selected
N
N
Scheme 1.
* Corresponding author. Fax: þ44 131 650 4743; e-mail address: r.m.paton@ed.ac.
uk (R.M. Paton).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.068

E.A.F. Fordyce et al. / Tetrahedron 66 (2010) 7192e7197
7193
R
N
S
CO2Et
N
NCCO2Et
R
O
ClCOSCl
heat
3
RCONH2
R
N S
O
S
N
- CO2
S
1
RCN
2
Scheme 2. [1e3: a R¼Ph; b R¼p-ClC6H4; c R¼m-ClC6H4; d R¼o-HOC6H4; e R¼2-thienyl; f R¼Me; g R¼ClCH2; h R¼Cl2CH; i R¼EtO2C].
for initial study the known reaction of benzonitrile sulfide (1a) and
ethyl cyanoformate (ECF), which is a reactive dipolarophile towards
nitrile sulfides.14 An authentic sample of the cycloadduct (ethyl 3-
phenyl-1,2,4-thiadiazole-5-carboxylate, 3a) was prepared by the
conventional thermolysis method,14 involving heating a solution of
the oxathiazolone 1a with excess ECF (w1:10 reactant ratio) in
p-xylene at reflux for 18 h. Work-up of the reaction mixture affor-
ded compound 3a in 62% yield. The experiment was then repeated
with the same solvent and reactant ratio, but using microwave ir-
radiation (200 W, 10 min, 160 ꢁC) (Table 1, entry 1). The crude
product obtained after removal of the solvent and excess ECF was
examined by 13C NMR spectroscopy, which showed that the
cycloadduct 3a had been formed in near quantitative yield. The
spectrum was indistinguishable from that of the authentic sample,
with characteristic heterocyclic ring peaks at 178.8 (C-5) and
174.4 ppm (C-3), in addition to those of the phenyl and ethox-
ycarbonyl substituents. Neither the starting material 2a nor ben-
zonitrile, the expected by-product resulting from the competing
desulfuration of the nitrile sulfide, could be detected. A pure sample
of 2a was isolated from the crude product in 83% yield by trituration
with toluene and recrystallisation of the resulting solid from hex-
ane. Similarly high yields were obtained at lower temperature
(140 ꢁC) and for a smaller excess of dipolarophile (1:3) (Table 1,
entries 2 and 3). One of the advantages of the microwave technique
is the ability to use low-boiling solvents, thus allowing easier work-
up, and good yields of product were obtained for reactions carried
out in THF (72%), chloroform (76%), ethyl acetate (94%) and 1,2-
dichloroethane (96%) (Table 1, entries 4e7).
The p-chloro-, m-chloro- and o-hydroxy-phenyl oxathiazolones
2bed reacted similarly in ethyl acetate, affording the correspond-
ing thiadiazoles 3bed in good yield (70e84%) (Table 1, entries
8e10). Likewise, the 2-thienyl thiadiazole 3e, derived from thio-
phene-2-carbonitrile sulfide 1e, was obtained from oxathiazolone
2e. The methyl, chloromethyl and dichloromethyl oxathiazolones
2feh were also examined (Table 1, entries 12e14). All yielded the
expected thiadiazoles 3feh, although the chloro-substituted pre-
cursors proved to be more stable and required higher temperatures
and/or longer reaction times. In contrast, attempts to use ECF to
trap ethoxycarbonylformonitrile sulfide (1i), generated from the
oxathiazolone 2i, were not successful.
Having established the advantages of the microwave method
for nitrile sulfide cycloadditions to ECF, the corresponding reaction
of benzonitrile sulfide with trichloroacetonitrile was examined.
Using conventional heating this reaction is reported to afford 5-
trichloromethyl-substitited 1,2,4-thiadiazoles in 45e65% yields,
although reaction times are long (3e4 days).15 Using microwave
irradiation (300 W) a similar yield (61%) was achieved after 10 min
in acetonitrile at 160 ꢁC (Table 1, entry 17). As expected the nitrile
Table 1
Microwave irradiation of 1,3,4-oxathiazol-2-ones
Entry
Oxathiazolone
Dipolarophilea
Reactant ratio
Solvent
Power/W
Time/min.
Temp/ꢁC
Product (Yield/%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
ECF
1:10
1:10
1:3
p-xylene
p-xylene
p-xylene
THF
CHCl3
EtOAc
DCE
EtOAc
EtOAc
EtOAc
EtOAc
DCE
PhMe
PhMe
EtOAc
PhMe
MeCN
CHCl3
CHCl3
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
200
200
200
200
200
200
300
300
300
300
300
300
300
300
300
300
300
200
200
300
200
300
300
300
200
300
300
10
10
10
10
10
10
10
10
20
10
10
10
10
30
10
10
10
10
10
10
10
10
10
30
30
30
30
160
140
160
160
160
160
160
160
160
160
160
160
190
200
160
200
160
160
160
160
160
160
160
170
170
170
170
3a (83)
3a (89)
3a (82)
3a (72)
3a (76)
3a (94)
3a (96)
3b (70)
3c (80)
3d (84)
3e (85)
3f (78)
3g (90)
3h (42)
3i (0)
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2g
2h
2i
2i
3i (0)
4 (61)
5 (56)
2a
2a
2a
2d
2a
2a
2f
2a
2b
2d
2e
Cl3CCN
DMAD
EP
DMAD
DEF
NB
1:10
1:2
6,7 (48)
8 (94)
1:10
1:10
1:10
1:10
1:10
1:10
1:10
10 (b)
11a (47)
11f (16)
13a (68)c
13b (97)
13d (32)c
13e (68)c
NB
NBD
NBD
NBD
NBD
a
ECF¼ethyl cyanoformate; DCE¼1,2-dichloroethane; DMAD¼dimethyl acetylenedicarboxylate; EP¼ethyl propiolate; DEF¼diethyl fumarate; NB¼norbornene;
NBD¼norbornadiene.
b
Not determined, isolated together with traces of DEF-derived side-products.
Isolated together with traces of NBD-derived side-products.
c

7194
E.A.F. Fordyce et al. / Tetrahedron 66 (2010) 7192e7197
sulfide reacts with the more reactive cyano group of tri-
chloroacetonitrile rather than that of the acetonitrile solvent.15 In
summary, the cycloaddition reactions of nitrile sulfides with
nitriles are uniquely well suited for the preparation of un-
symmetrically substituted 1,2,4-thiadiazoles and the use of
microwave irradiation provides a rapid means of preparing these
compounds.
by chromatography afforded only compound 8, for which the OMe
peak is at 4.00 ppm. The peaks at 3.94 and 3.90 ppm were therefore
attributed to the intermediate isothiazole 9. Such values are typical
of dimethyl isothiazole-4,5-dicarboxylates.17 The signals for the
protons of the arene ring of compound 9 were also very similar to
those of the corresponding 1,2,4-thiadiazole (3d), vide supra.
Electron-poor alkenes are also reported to undergo cycloaddition
to nitrile sulfides affording 2-isothiazolines (4,5-dihydro-
isothiazoles).2,4 Thus irradiation of phenyloxathiazolone 2a with
diethyl fumarate (1:10) in ethyl acetate yielded diethyl trans-2-iso-
thiazoline-4,5-dicarboxylate (10) (Table 1, entry 21). The trans con-
figuration of the product was deduced from the 1H NMR spectrum in
which there was a 3J coupling of 3.4 Hz for H-4/H-5. Whereas most
simple alkenes are unreactive towards nitrile sulfides, cycloadducts
are formed with norbornene-type dipolarophiles, although reaction
times are long and yields low;14,22 for example, benzonitrile sulfide
andnorbornenearereportedtoaffordisothiazoline 11a in19%yield.22
The use of microwave irradiationinsteadof conventional heating lead
to an improved yield (47%) after 10 min at 160 ꢁC (Table 1, entry 22).
Acetonitrile sulfide, generated from methyl oxathiazolone 2f, reacted
similarly to yield isothiazoline 11f.
The corresponding reaction of aryl nitrile sulfides with norbor-
nadiene (NBD) has been shown to lead directly to 3-arylisothia-
zoles,22 a process which is believed to involve initial cycloaddition of
the nitrile sulfide to one of the alkene units in NBD to form the
isothiazoline 12 (presumably as a mixture of exo and endo isomers),
which under the reaction conditions (w100 h, w130 ꢁC) undergoes
a DielseAlder cycloreversion to form the isothiazole 13 with ex-
pulsion of cyclopentadiene, as shown in Scheme 4. With microwave
irradiation the reactions were complete in 30e60 min at 170 ꢁC
(Table 1, entries 24e27). For the 3-(p-chlorophenyl)isothiazole 13b
the yield was near quantitative (98%). The products were readily
identified from their characteristic NMR spectra. In addition to the
expected 13C peaks for C-3 (161e168), CH-4 (120e121) and CH-5
The cycloaddition reactions of nitrile sulfides are also well suited
for the preparation of isothiazoles via their reactions with alkynes,
provided that the dipolarophile is activated by electron-with-
drawing groups. For example, dimethyl acetylenedicarboxylate
(DMAD) was the first dipolarophile used to trap benzonitrile sul-
fide.16 Microwave irradiation (Table 1, entry 18) of a solution of
phenyloxathiazolone 2a and DMAD (1:3) in chloroform afforded
the isothiazole cycloadduct 5 (56%), which was identified by com-
parison of its spectroscopic properties with those previously
reported.17,18 In the 13C NMR spectrum there are characteristic
peaks for the isothiazole ring at 133.6 ppm (C-4), 155.4 (C-5) and
159.1 (C-3), and at 165.7, 164.8 (C]O) and 53.1, 53.0 (OMe) for the
methoxycarbonyl substituents. In this case the use of microwave
irradiation, rather than conventional heating, avoids the long re-
action times which can sometimes lead to contamination of the
product by DMAD-derived by-products. The corresponding re-
action of 2a with ethyl propiolate (1:10) afforded a mixture of
regioisomeric isothiazoles 6 and 7 in 48% combined yield. The
isomer ratio (6:7¼13:14) was measured by comparison of the
characteristic signals in the 1H NMR spectrum for H-4 (8.04 ppm) of
isomer 7 and H-5 (9.26 ppm) of isomer 6. Similar low levels of
regioselectivity with alkyl propiolates have been reported pre-
viously for various nitrile sulfides,3e,17e19b and are in marked con-
trast to the corresponding reactions with nitrile oxides, which
afford predominantly the isoxazole-5-carboxylates.20 This effect
has been attributed to a greater degree of HOMO-dipole control for
the nitrile sulfide reactions.17,18
R1
CO2Et
Ph
Ph
Ph
R
N
CCl3
R2
CO2Et
N
N
N
N
S
S
S
S
5 R1 = R2 = CO2Me
6 R1 = CO2Et, R2 = H
7 R1 = H; R2 = CO2Et
11a R = Ph
11f R = Me
4
10
Under similar conditions the reaction of the o-hydroxy-
phenyloxathiazolone 2d with DMAD (1:2) in ethyl acetate afforded
the known21 benzopyrano[4,3-c]isothiazole 8 in excellent yield
(94%) (Scheme 3). The isolation of compound 8, rather than the
usual isothiazoledicarboxylate 9, can be attributed to facile intra-
molecular elimination of methanol between the phenolic hydroxyl
group and the methyl ester at the 4-position in the first-formed
adduct 9,21 as illustrated in Scheme 3. Evidence in support of this
pathway was provided from the NMR and mass spectra of the crude
product before chromatography, which showed the presence of
both 9 and 8 in a ca. 4:1 ratio. In the 1H NMR spectrum of the
mixture there were three OMe signals at 4.00, 3.94 and 3.90 ppm
with relative intensities 1:4:4. Attempts to separate these products
(147e149 ppm),13 there were characteristic 1H signals for H-4
(7.4e7.6) and H-5 (8.6 ppm) with a mutual coupling of 4.7 Hz. The
isothiazolines 12 were not isolated and could not be detected
spectroscopically. A common by-product was observed for all of the
NBD reactions; on the basis of its spectroscopic properties this was
tentatively assigned as compound 1423 resulting from DielseAlder
cycloaddition of NBD, acting as the dienophile, with the cyclo-
pentadiene generated on fragmentation of the isothiazoline 12. This
process, in which NBD is acting as an acetylene equivalent, thus of-
fers a short and efficient route to isothiazoles unsubstituted at both
4- and 5-positions. A similar approach has previously been repor-
ted24 for the corresponding reactions of NBD with nitrile oxides and
nitrile imides, leading to isoxazoles and pyrazoles, respectively.
OH
OH
O
O
heat
DMAD
CO2Me
CO2Me
MeOH
2d
O
- CO2
C
N S
OMe
N
N
S
S
9
8
Scheme 3.

E.A.F. Fordyce et al. / Tetrahedron 66 (2010) 7192e7197
7195
p-xylene (3 mL) was heated in the microwave at 160 ꢁC and with
a 200 W power input for 10 min. After cooling the excess ECF and
the solvent were removed under reduced pressure and the residue
examined by 1H and 13C NMR spectroscopy. The resulting spectra
were indistinguishable from those of the authentic sample of
compound 3a, indicating that it had been formed in near quanti-
tative yield.
R
R
heat
RCNS
N
N
C5H6
S
S
12
13
14
Scheme 4. [12e13: a R¼Ph; b R¼p-ClC6H4; d R¼o-HOC6H4; e R¼2-thienyl].
In conclusion, these results show that the use of microwave ir-
radiation, rather than conventional heating methods, allows nitrile
sulfide generation and reactions to be carried out in shorter times,
with easier work-up and, in some cases, in higher yields.
3.3.2. Ethyl 3-(4-chlorophenyl)-1,2,4-thiadiazole-5-carboxylate (3b)25
.
Yield 69%; white needles (from hexane); mp 78e80 ꢁC (lit.25
82e84 ꢁC); dH (360 MHz, CDCl3) 1.40 (3H, t, J 7.1 Hz, CH3), 4.48 (2H,
q, J 7.1 Hz, CH2), 7.39 (2H, d, J8.7 Hz,H-20), 8.23(2H, d,J 8.7 Hz, H-30); dC
(91 MHz, CDCl3) 14.0 (CH3), 63.3 (CH2),128.9,129.7,130.4,137.0 (ArC),
158.3 (C]O), 173.5 (C-3), 179.1 (C-5).
3. Experimental
3.1. General
3.3.3. Ethyl 3-(3-chlorophenyl)-1,2,4-thiadiazole-5-carboxylate (3c).
Yield 80%; yellow needles; mp 86e88 ꢁC; dH (360 MHz, CDCl3) 1.40
(3H, t, J 7.1 Hz, CH3), 4.47 (2H, q, J 7.1 Hz, CH2), 7.36 (2H, m, H-50, H-
60), 8.16 (1H, d, J 7.3 Hz, H-40), 8.28 (1H, s, H-20); dC (91 MHz, CDCl3)
14.0 (CH3), 63.3 (CH2), 126.4, 128.3, 129.9, 130.8, 133.3, 134.7 (ArC),
158.2 (C]O), 173.1 (C-3), 179.1 (C-5); m/z (EI) found: Mþ 268.0074.
C11H9N235ClO2S requires 268.0073.
Melting points were measured on a Gallenkamp capillary appa-
ratusandare uncorrected. The 1Hand13CNMRspectrawererecorded
with Brucker WP200SY, AX250 or WH360 spectrometers on solu-
tions in CDCl3 with Me4Si as an internal standard. Positive-ion FAB
and high resolution mass spectra were obtained on a Kratos MS50TC
instrument using either glycerol or thioglycerol matrices. Merck al-
uminium-backed plates coated with Kieselgel GF254 (0.2 mm) were
used foranalytical TLC, with detectionbyUV or sulfuric acid charring.
Preparative chromatography was carried out, either using Kieselgel
GF254 and eluting under water pump vacuum, or with Isolute or
Strata pre-packed silica columns. Solvents and reagents were stan-
dard laboratory grade and used as supplied, unless otherwise stated.
THF was dried over calcium hydride and distilled before use.
Microwave irradiation experiments were conducted in a CEM
Discoverer microwave with ramp times of between 5 and 15 min,
and with 20 min cooling. The reaction mixture was contained in
a sealed tube in the microwave oven and irradiated at the power
specified in Table 1, which also gives the solvent, reactant ratio and
the reaction time. The products were purified by crystallisation and/
or dry-flash chromatography, and identified from their NMR and
mass spectra and by comparison with those previously reported.
3.3.4. Ethyl 3-(2-hydroxyphenyl)-1,2,4-thiadiazole-5-carboxylate(3d)21.
Yield 84%; pale yellow solid; mp 93e95 ꢁC (lit.21 93e95 ꢁC); dH
(360 MHz, CDCl3) 1.40 (3H, t, J 7.1 Hz, CH3), 4.48 (2H, q, J 7.1 Hz,
CH2), 6.92 (1H, m, H-40), 7.00 (1H, dd, J 8.0,1.1 Hz, H-60), 7.33 (1H, m,
H-50), 8.27 (1H, dd, J 7.9, 1.7 Hz, H-30), 10.51 (1H, s, OH); dC (91 MHz,
CDCl3) 14.0 (CH3), 63.5 (CH2), 115.9, 117.6, 119.7, 129.7, 133.0 (ArC),
157.6 (COH), 157.8 (C]O), 173.8 (C-3), 177.8 (C-5).
3.3.5. Ethyl 3-(2-thienyl)-1,2,4-thiadiazole-5-carboxylate (3e). Yield
85%; pale yellow solid; mp 72e74 ꢁC; dH (360 MHz, CDCl3) 1.39 (3H,
t, J 7.1 Hz, CH3), 4.47 (2H, q, J 7.1 Hz, CH2), 7.07 (1H, t, J 5.0, 3.7 Hz,
H-30), 7.41 (1H, dd, J 5.0, 1.2 Hz, H-20), 7.90 (1H, dd, J 3.7, 1.2 Hz, H-
40); dC (91 MHz, CDCl3) 14.0 (CH3), 63.3 (CH2), 127.9, 129.4, 129.8,
135.3 (C-thiophene), 158.1 (C]O), 169.7 (C-3), 178.8 (C-5); m/z (EI)
found: Mþ 240.0027. C9H8N2O2S requires 240.0027.
3.2. 1,3,4-Oxathiazol-2-ones
3.3.6. Ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (3f)19. Yield
78%; pale yellow oil; dH (250 MHz, CDCl3) 1.34 (3H, t, J 7.1 Hz, CH3),
2.70 (3H, s, CH3), 4.45 (2H, q, J 7.1 Hz, CH2); dC (63 MHz, CDCl3) 13.9
(CH3), 18.8 (CH3), 63.0 (CH2), 158.2 (C]O), 174.8 (C-3), 178.5 (C-5).
The following oxathiazolones were prepared from the corre-
sponding carboxamides by treatment with chlorocarbonylsulfenyl
chloride as previously reported. 5-Phenyl-1,3,4-oxathiazol-2-one
(2a),17 5-(4-chlorophenyl)-1,3,4-oxathiazol-2-one (2b),17 5-(3-chloro-
phenyl)-1,3,4-oxathiazol-2-one (2c),17 5-(2-hydroxyphenyl)-1,3,4-
oxathiazol-2-one (2d),21 5-(2-thienyl)-1,3,4-oxathiazol-2-one (2e).4a
5-methyl-1,3,4-oxathiazol-2-one (2f),17 5-chloromethyl-1,3,4-oxa-
thiazol-2-one (2g),17 5-dichloromethyl-1,3,4-oxathiazol-2-one (2h),
5-ethoxycarbonyl-1,3,4-oxathiazol-2-one (2i).17
3.3.7. Ethyl 3-chloromethyl-1,2,4-thiadiazole-5-carboxylate (3g).
Yield 90%; pale yellow oil; dH (360 MHz, CDCl3) 1.39 (3H, t, J 7.1 Hz,
CH3), 4.47 (2H, q, J 7.1 Hz, CH2), 4.81 (2H, s, CH2Cl); dC (91 MHz,
CDCl3) 13.9 (CH3), 39.7 (CH2Cl), 63.4 (CH2), 157.8 (C]O),172.6 (C-3),
179.9 (C-5).
3.3. 1,2,4-Thiadiazoles
3.3.8. Ethyl 3-dichloromethyl-1,2,4-thiadiazole-5-carboxylate (3h).
Yield 42%; yellow oil; dH (250 MHz, CDCl3) 1.40 (3H, t, J 7.1 Hz, CH3),
4.48 (2H, q, J 7.1 Hz, CH2), 6.91 (1H, s, CHCl2); dC (63 MHz, CDCl3) 14.0
(CH3), 63.7, 63.9 (CH2O, CHCl2),157.6 (C]O),172.3 (C-3),180.9 (C-5).
3.3.1. Ethyl 3-phenyl-1,2,4-thiadiazole-5-carboxylate (3a)25. Con-
ventional thermolysis. A solution of oxathiazolone 2a (193 mg,
1.08 mmol) and ethyl cyanoformate (ECF) (1.0 mL, w10.1 mmol) in
p-xylene (6 mL) was heated at reflux for 16 h. After removal of the
excess ECF and the solvent under reduced pressure the residue
was recrystallised from hexane to afford the compound 3a as
white crystals (156 mg, 62%); mp 67 ꢁC (lit.25 70e71 ꢁC); dH
(200 MHz, CDCl3) 1.41 ppm (3H, t, J 7.1 Hz, CH3), 4.46 (2H, q, J
7.1 Hz, CH2), 7.35e7.45 (3H, m, PhH), 8.30 (2H, m, PhH); dC
(50 MHz, CDCl3) 14.0 (CH3), 63.1 (CH2), 128.3, 128.6, 130.7 (PhCH),
131.8 (PhC), 158.3 (C]O), 174.4 (C-3), 178.8 (C-5); m/z (FAB) found:
Mþþ1, 235.0547. C11H10NO2S requires 235.0544.
3.3.9. 3-Phenyl-5-trichloromethyl-1,2,4-thiadiazole (4)15. Yield 61%;
paleyellow solid; mp 70e72 ꢁC (lit.15 74e75 ꢁC); dH (250 MHz, CDCl3)
7.37e7.62 ppm (3H, m, PhH), 8.25 (2H, m, PhH); dC (63 MHz, CDCl3)
88.1 (CCl3), 131.8 (PhC), 128.3, 128.7, 130.9 (PhCH), 174.0 (C-3), 190.6
(C-5); m/z (FAB) found: Mþþ1, 280.9282. C9H6N237Cl35Cl2S requires 1
280.9309; found: Mþþ1, 278.9374. C9H6N235Cl3S requires 278.9317.
3.4. Isothiazoles
Microwave irradiation. A solution of oxathiazolone 2a (100 mg,
0.56 mmol) and ethyl cyanoformate (ECF) (0.5 mL, w5.0 mmol) in
3.4.1. Dimethyl 3-phenylisothiazole-4,5-dicarboxylate (5)17. Yield
56%; white solid (from hexane); mp 69e71 ꢁC (lit.17 72e73 ꢁC); dH

7196
E.A.F. Fordyce et al. / Tetrahedron 66 (2010) 7192e7197
(250 MHz, CDCl3) 4.01 (3H, s, CH3), 4.05 (3H, s, CH3), 7.30e7.48 (3H,
m, PhH) 7.62 (2H, m, PhH); dC (63 MHz, CDCl3) 53.1, 53.0 (CH3),
127.5,128.6,129.7 (PhCH),132.7,133.6,155.4,159.1 (PhC, C-3, C-4, C-
5), 164.8, 165.7 (C]O); m/z (FAB) found: Mþþ1, 278.0486.
C13H11NO4S requires 278.0487.
PhH), 7.7 (2H, m, PhH), the expected quartets for CH2 were masked
by diethyl fumarate peaks; m/z (FAB) found: Mþþ1, 308.0958.
C15H17NO4S requires 308.0957.
3.5.2. exo-3a,7a-4,5,6,7-Hexahydro-4,7-methano-3-phenyl-1,2-benz-
isothiazole (11a)22. Yield 47%; pale yellow oil; dH (360 MHz, CDCl3)
1.13e1.62 (6H, m, H-5, H-6, H-8), 2.34 (1H, m, H-4), 2.57 (1H, s, H-7),
3.72 (1H, d, J 9.6 Hz, H-3a), 3.87 (1H, dd, J 9.6, 1.8 Hz, H-7a) 7.29 (3H,
m, Ph), 7.66 (2H, m, Ph); dC (91 MHz, CDCl3) 27.2 (C-5), 28.5 (C-6),
33.2 (C-8), 42.2 (C-4), 44.8 (C-7), 56.7 (C-3a), 63.1 (C-7a), 127.3,
128.3, 129.2, 133.6 (PhC), 166.7 (C-3).
3.4.2. Ethyl 3-phenylisothiazole-4- and 5-carboxylates (6,7)17. Yield
48% combined yield; pale yellow solid (from hexane); mp 66e67 ꢁC
(lit.17 63e65 ꢁC); dH (250 MHz, CDCl3) 1.16 (3H, t, J 7.1 Hz, CH3 of 6),
1.33 (3H, t, J 7.1 Hz, CH3 of 7), 4.16 (2H, q, J 7.1 Hz, CH2 of 6), 4.35 (2H,
q, J 7.1 Hz, CH2 of 7), 9.26 (1H, s, H-5 of 6) 8.04 (1H, s, H-4 of 7),
7.22e7.40 (3H, m, PhH), 7.90 (2H, m, PhH); dC (63 MHz, CDCl3) 13.2,
13.3 (CH3), 29.0, 30.2 (CH2), 124.1 (CH-4 of 7), 126.7, 127.1, 128.2,
128.6, 128.9 (PhCH), 133.3, 134.3, 159.4, 161.4 (PhC, C-3, C-4 of 6, C-5
of 7), 155.1 (CH-5 of 6), 159.4, 161.4 (C-4 of 6, C-5 of 7), 167.3, 167.9
(C]O); m/z (FAB) found: Mþþ1, 234.0579. C12H11NO2S requires
234.0589.
3.5.3. exo-3a,7a-4,5,6,7-Hexahydro-4,7-methano-3-methyl-1,2-benz-
isothiazole (11b). Yield 16%; pale yellow oil; dH (360 MHz, CDCl3)
1.16e1.33, 1.45e1.62 (6H, m, H-5, H-6, H-8), 1.93 (3H, s, CH3), 2.28
(1H, m, H-4), 2.46 (1H, d, J 1.7 Hz, H-7a), 3.11 (1H, d, J 9.4 Hz, H-3a),
3.69 (1H, dd, J 9.4, 1.7 Hz, H-7a); dC (91 MHz, CDCl3) 19.2 (CH3), 27.1
(C-5), 28.3 (C-6), 33.0 (C-8), 40.8 (C-4), 44.8 (C-7), 55.4 (C-3a), 67.5
(C-7a), 168.3 (C-3); m/z (EI) found: Mþ 167.0768. C9H13NS requires
167.0769.
3.4.3. 3-Phenylisothiazole (13a)22,26. Yield 68%, yellow oil, together
with norbornadiene derived side-products; dH (250 MHz, CDCl3)
7.35 (3H, m, PhH), 7.53 (1H, d, J 4.7 Hz, H-4), 7.89 (2H, m, PhH), 8.60
(1H, d, J 4.7 Hz, H-5); dC (63 MHz, CDCl3) 121.1 (CH-4), 126.8, 128.7,
129.0, 134.5 (PhC), 148.8 (CH-5), 167.5 (C-3).
Acknowledgements
We are grateful to the EPSRC for research grants, and to Organon
Research for financial support.
3.4.4. 3-(4-Chlorophenyl)isothiazole (13b)22. Yield 97%; pale yellow
solid; dH (360 MHz, CDCl3) 7.34 (2H, d, J 8.8 Hz, H-20), 7.49 (1H, d, J
4.7 Hz, H-4), 7.81 (2H, d, J 8.8 Hz, H-30), 8.62 (1H, d, J 4.7 Hz, H-5); dC
(91 MHz, CDCl3) 120.9 (CH-4), 128.0, 128.8, 133.2, 134.9 (ArC), 149.2
(CH-5), 166.2 (C-3); m/z (EI) found: Mþ 194.9911. C9H6NClS requires
194.9910.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.068.
3.4.5. 3-(2-Hydroxyphenyl)isothiazole (13d). Yield 32%, yellow oil,
together with norbornadiene derived side-products; dH (250 MHz,
CDCl3) 6.88 (1H, m, H-40), 7.01 (1H, m, H-60), 7.23 (1H, m, H-50), 7.64
(2H, m, H-30þH-4), 8.63 (1H, d, J 4.9 Hz, H-5), 11.75 (1H, br s, OH); dC
(63 MHz, CDCl3) 117.7, 119.1 (ArC), 120.5 (CH-4), 127.5, 131.1 (ArC),
147.3 (CH-5), 157.5 (COH), 168.2 (C-3).
References and notes
1. For reviews of nitrilium betaine chemistry see: (a) 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, NY, 1984, Chapters 2 and 3, and
references therein; (b) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, NY, 2002, Chapters 6 and 7.
2. For reviews of nitrile sulfide chemistry see: (a) Paton, R. M. Chem. Soc. Rev. 1989,
18, 33e52; (b) Wentrup, C.; Kambouris, P. Chem. Rev. 1991, 91, 363e373; (c)
Kanemasa, S. Sci. Synth. 2004, 19, 17e40.
3. (a) Buffel, D. K.; Simons, B. P.; Deceuninck, J. A.; Hoornaert, G. J. Nucleic Acid
Chem. 1991, 4, 155e162; (b) Buffel, D. K.; Meerpoel, L.; Toppet, S. M.; Hoor-
naert, G. J. Nucleosides Nucleotides 1994, 13, 719e736; (c) Bridson, J.; Copp, S.;
Schriver, M.; Zhu, S. Phosphorus Sulfur Silicon Relat. Elem. 1994, 93e94,
457e458; (d) Bridson, J.; Copp, S.; Schriver, M.; Zhu, S. Can. J. Chem. 1995, 73,
212e222; (e) Crosby, J.; Grant, K. J.; Greig, D. J.; Paton, R. M.; Rankin, J. G.; Ross,
J. F. ARKIVOC 2002, iii, 121e129; (f) Shen, L.; Zhang, Y.; Wang, A.; Sieber-
McMaster, E.; Chen, X.; Pelton, P.; Xu, J. Z.; Yang, M.; Zhu, P.; Zhou, L.; Reuman,
M.; Hu, Z.; Russell, R.; Gibbs, A. C.; Ross, H.; Demarest, K.; Murray, W. V.; Kuo,
G.-H. Bioorg. Med. Chem. 2008, 16, 3321e3341.
3.4.6. 3-(2-Thienyl)isothiazole (13e). Yield 68%, yellow oil, together
with norbornadiene derived side-products; dH (250 MHz, CDCl3) 7.01
(1H, m, H-20), 7.28 (1H, m, H-10), 7.40 (2H, m, H-4þH-30), 8.54 (1H, d, J
4.7 Hz, H-5); dC (91 MHz, CDCl3) 120.6 (C-4),125.6,126.9,127.5,138.6
(C-thiophene), 148.8 (C-5), 161.9 (C-3); m/z (EI) Mþ found 166.9864.
C7H5NS2 requires Mþ 166.9863. In the 1H NMR spectrum additional
signals at 0.9e1.4, 2.4e2.7 and 6.0e6.2 ppm were attributed to the
aliphatic and olefinic protons of compound 14.23b
4. (a) Krayushin, M. M.; Kalik, M. A.; Kurdryavsteva, A. Y. Izv. Akad. Nauk, Ser. Khim.
1992, 1892e1897; (b) Crosby, J.; McKie, M. C.; Paton, R. M.; Ross, J. F. ARKIVOC
2000, v, 720e734.
3.4.7. Methyl 4-oxo-4H-[1]benzopyrano[4,3,-c]isothiazole-3-carboxy-
late (8)21. Yield 96%; white crystals (from EtOAc); mp 160e163 ꢁC
(lit.21 158e160 ꢁC); dH (360 MHz, CDCl3) 4.00 (3H, s, CH3), 7.26e7.30
(2H, m, H-7, H-9), 7.50 (1H, m, H-8), 8.17 (1H, dd, J 6.7, 1.7 Hz, H-6);
dC (91 MHz, CDCl3) 53.8 (CH3), 116.3 (C-9a), 117.1, 124.2, 124.9, 132.4
(C-6eC-9), 120.8 (C-3a), 152.4 (C-5a), 154.1 (C-4), 158.9 (C]O),
162.3 (C-9b), 163.4 (C-3); m/z (EI) found: Mþ 261.0094. C12H7NO4S
requires 261.0096. The crude product also contained dimethyl 3-(2-
hydroxyphenyl) isothiazole-4,5-dicarboxylate (9). dH (360 MHz,
CDCl3) 3.90 (3H, s, CH3), 4.94 (3H, s, CH3), 6.84 (1H, m, H-40), 7.01
(1H, dd, J 8.3, 1.2 Hz, H-60), 7.20e7.50 (1H, m, H-50), 8.22 (1H, dd, J
8.7, 1.7 Hz, H-30), 10.50 (1H, s, OH).
5. (a) Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier, D. J. J. Med.
Chem. 1992, 35, 3691e3698; (b) Unangst, P. C.; Shrum, G. P.; Connor, D. T. J.
Heterocycl. Chem. 1993, 30, 357e359; (c) McKie, M. C.; Paton, R. M. ARKIVOC
2002, vi, 15e21; (d) Castro, A.; Castano, T.; Encinas, A.; Porcal, W.; Gil, C. Bioorg.
Med. Chem. 2006, 15, 1644e1652; (e) Shen, L.; Zhang, Y.; Wang, A.; Sieber-
McMaster, E.; Chen, X.; Pelton, P.; Xu, J. Z.; Yang, M.; Zhu, P.; Zhou, L.; Reuman,
M.; Hu, Z.; Russell, R.; Gibbs, A. C.; Ross, H.; Demarest, K.; Murray, W. V.; Kuo,
G.-H. J. Med. Chem. 2007, 50, 3954e3963; (f) Reuman, M.; Hu, Z.; Kuo, G.-H.; Li,
X.; Russell, R. K.; Shen, L.; Youells, S.; Zhang, Y. Org. Process Res. Dev. 2007, 11,
1010e1014; (g) Porcal, W.; Hernandez, P.; Gonzalez, M.; Ferreira, A.; Olea-Azar,
C.; Cerecetto, H.; Castro, A. J. Med. Chem. 2008, 51, 6150e6159; (h) Castro, A.;
€
Encinas, A.; Gil, C.; Brase, S.; Porcal, W.; Perez, C.; Moreno, F. J.; Martinez, A.
Bioorg. Med. Chem. 2008, 16, 3321e3341.
6. Aida, T.; Nagasawa, A.; Tsunetsugu, J. J. Chem. Res., Synop. 1996, 8e9.
€
€
7. (a) Rosch, W.; Richter, H.; Regitz, M. Chem. Ber. 1987, 120, 1809e1813; (b) Rosch,
3.5. 4,5-Dihydroisothiazoles (2-isothiazolines)
€
€
W.; Regitz, M. Synthesis 1987, 689e694; (c) Markl, G.; Holzl, W. Tetrahedron Lett.
1988, 29, 4535e4538.
3.5.1. Diethyl trans-3-phenyl-2-isothiazoline-4,5-dicarboxylate (10)4b
Clear oil, isolated as a mixture with unreacted diethyl fumarate; dH
(250 MHz, CDCl3) 1.07 (3H, t, J 7.0 Hz, CH3), 1.24 (3H, t, J 7.0 Hz, CH3),
4.73 (1H, d, J 4.1 Hz, H-4), (1H, d, J 4.1 Hz, H-5), 7.26e7.37 (3H, m,
.
8. (a) Wai, K.-F.; Sammes, M. P. J. Chem. Soc., Chem. Commun. 1988, 852e853;
(b) Wai, K.-F.; Sammes, M. P. J. Chem. Soc., Perkin Trans. 1 1991, 183e187.
9. For reviews of the use of microwave techniques in organic synthesis see:
(a) Lidstrom, P.; Tierney, J.; Wathey, B.; Westmann, J. Tetrahedron 2001,
57, 9225e9283; (b) Kappe, O. Angew. Chem., Int. Ed. 2004, 43,
€

E.A.F. Fordyce et al. / Tetrahedron 66 (2010) 7192e7197
7197
6250e6284; (c) Loupy, A. Microwaves in Organic Synthesis, 2nd ed.; Wi-
ley-VCH: Weinheim, Germany, 2006.
10. Pineiro, M.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2009, 5287e5307 and
references therein.
47, 189e196; (m) Micuch, P.; Fisera, L.; Cyranski, M.; Krygowski, T. M.; Krajcik, J.
Tetrahedron 2000, 56, 5465e5472; (n) Giacomelli, G.; De Luca, L.; Porcheddu, A.
Tetrahedron 2003, 59, 5437e5440; (o) Chiacchio, M. A.; Borrello, L.; Di Pasquale,
G.; Pollicino, A.; Bottino, F. A.; Rescifina, A. Tetrahedron 2005, 61, 7986e7993;
(p) Chu, J.-H.; Li, W.-S.; Chao, I.; Lee, G. H.; Chung, W.-S. Tetrahedron 2006, 62,
7380e7389; (q) Alvaro, M.; Atienzar, P.; de la Cruz, P.; Delgado, J. L.; Troiani, V.;
Garcia, H.; Langa, F.; Palkar, A.; Echegoyen, L. J. Am. Chem. Soc. 2006, 128,
6626e6635; (r) Mabrour, M.; Bougrin, K.; Benhida, K.; Rachid, L.; Loupy, A.;
Soufiaoui, M. Tetrahedron Lett. 2007, 48, 443e447; (s) Singh, M.; Singh, B.;
Singal, K. K. Asian J. Chem. 2008, 20, 745e750; (t) Lasri, J.; Mukhopadhyay, S.;
Charmier, M. A. J. J. Heterocycl. Chem. 2008, 45, 1385e1389; (u) Willy, B.; Ro-
minger, F.; Mueller, T. J. J. Synthesis 2008, 293e303.
11. (a) de la Cruz, P.; Diaz Ortiz, A.; Garcai, J. J.; Gomez-Escalonilla, M. J.; de la Hoz,
A.; Langa, F. Tetrahedron Lett. 1999, 40, 1587e1590; (b) Kaddar, H.; Hamelin, J.;
Benhaoua, H. J. Chem. Res., Synop. 1999, 718e719; (c) Azizian, J.; Soozangarza-
deh, S.; Jadidi, K. Synth. Commun. 2001, 31, 1069e1073; (d) Langa, F.; Gomez-
Escalonilla, M. J.; Diez-Barra, E.; Garcia-Martinez, J. C.; de la Hoz, A.; Rodriguez-
Lopez, J.; Gonzalez-Cortes, A.; Lopez-Arza, V. Tetrahedron Lett. 2001, 42,
3435e3438; (e) Langa, F.; de la Cruz, P.; Espildora, E.; de la Hoz, A.; Bourde-
lande, J. L.; Sanchez, L.; Martin, N. J. Org. Chem. 2001, 66, 5033e5041; (f) Ar-
maroli, N.; Accorsi, G.; Gisselbrecht, J.-P.; Gross, M.; Krasnikov, V.; Tsamouras,
D.; Hadziioannou, G.; Gomez-Escalonilla, M. J.; Langa, F.; Eckert, J.-F.; Nier-
engarten, J.-F. J. Mater. Chem. 2002, 12, 2077e2087; (g) Xia, M. J. Chem. Res.,
Synop. 2003, 418e419; (h) Delgado, J. L.; de la Cruz, P.; Lopez-Arza, V.; Langa, F.;
Kimball, D. B.; Haley, M. M.; Araki, Y.; Ito, O. J. Org. Chem. 2004, 69, 2661e2668;
(i) Atir, R.; Mallouk, S.; Bougrin, K.; Soufiaoui, M.; Laghzizil, A. Synth. Commun.
2006, 36, 111e120.
13. Preliminary report: Morrison, A. J.; Paton, R. M.; Sharp, R. D. Synth. Commun.
2005, 35, 839e845.
14. Howe, R. K.; Franz, J. E. J. Org. Chem. 1978, 43, 3742e3745.
15. Greig, D. J.; McPherson, M.; Paton, R. M.; Crosby, J. Phosphorus Sulfur Relat. Elem.
1986, 26, 151e154.
16. Franz, J. E.; Black, L. L. Tetrahedron Lett. 1970, 1381e1384.
17. Howe, R. K.; Franz, J. E. J. Org. Chem. 1978, 43, 3736e3742.
12. (a) Touaux, B.; Klein, B.; Texier-Boullet, F.; Hamelin, J. J. Chem. Res., Synop. 1994,
116e117; (b) Diaz-Ortiz, A.; Diaz-Barra, E.; de la Hoz, A.; Prieto, P.; Moreno, A. J.
Chem. Soc., Perkin Trans. 11994, 3595e3598; (c) Diaz-Ortiz, A.; Diaz-Barra, E.; de
la Hoz, A.; Moreno, A.; Gomez-Escalonilla, M. J.; Loupy, A. Heterocycles 1996, 43,
1021e1030; (d) Corsaro, A.; Chiacchio, U.; Librando, V.; Fisichella, S.; Pistara, V.
Heterocycles 1997, 45, 1567e1572; (e) Syassi, B.; Bougrin, K.; Soufiaoui, M.
Tetrahedron Lett. 1997, 38, 8855e8858; (f) Touaux, B.; Texier-Boullet, F.; Ha-
melin, J. Heteratom. Chem. 1998, 9, 351e354; (g) Karmakar, D.; Prajapati, D.;
Sandhu, J. S. Synth. Commun. 1998, 28, 2415e2420; (h) Librando, V.; Chiacchio,
U.; Corsaro, A.; Pistara, V.; Romano, L. Acqua Aria 1998, 79e83; (i) Micuch, P.;
Fisera, L.; Cyranski, M.; Krygowski, T. M. Tetrahedron Lett. 1999, 40, 167e170; (j)
de la Cruz, P.; Espildora, E.; Garcia, J. J.; de la Hoz, A.; Langa, F.; Martin, N.;
Sanchez, L. Tetrahedron Lett. 1999, 40, 4889e4892; (k) Langa, F.; de la Cruz, P.;
Espildora, E.; de la Hoz, A.; Gonzalez-Corts, A.; Lopez-Arza, V. J. Org. Chem.
2000, 65, 4889e4892; (l) Lu, T.-J.; Tzeng, G.-W. J. Chin. Chem. Soc. (Taipei) 2000,
18. (a) Sanders, M. J.; Dye, S. L.; Miller, A. G.; Grunwell, J. R. J. Org. Chem. 1979, 44,
510e513; (b) Sanders, M. J.; Grunwell, J. R. J. Org. Chem. 1980, 45, 3753e3756.
19. (a) Paton, R. M.; Robertson, F. M.; Ross, F. R.; Crosby, J. J. Chem. Soc., Chem.
Commun. 1980, 714e715; (b) Paton, R. M.; Robertson, F. M.; Ross, J. F.; Crosby, J.
J. Chem. Soc., Perkin Trans. 1 1985, 1517e1521.
20. Grundmann, C. Synthesis 1970, 344e359.
21. Brownsort, P. A.; Paton, R. M. J. Chem. Soc., Perkin Trans. 1 1987, 2339e2344.
22. McKie, M. C.; Paton, R. M. J. Chem. Res., Synop. 1987, 245.
23. (a) Stille, J. K.; Frey, D. A. J. Am. Chem. Soc. 1959, 81, 4273e4275; (b) Mantzaris, J.;
Weissberger, E. J. Org. Chem. 1974, 39, 726e728.
24. (a) Huisgen, R.; Christl, M. Angew. Chem., Int. Ed. 1967, 6, 456e457; (b) Huisgen,
R.; Seidel, M.; Wallbillich, G.; Knupper, H. Tetrahedron 1962, 17, 3e29.
25. Howe, R. K.; Franz, J. E. J. Org. Chem. 1974, 39, 962e964.
26. Olofson, R. O.; Landesburg, J. M.; Berry, R. O.; Leaver, D.; Robertson, W. A. H.;
McKinnon, D. M. Tetrahedron 1966, 22, 2119e2134.