3,4,5-Triarylisothiazoles via C-C coupling chemistry

Article abstract of DOI:10.1039/b702154b

The regiocontrolled preparation of triarylisothiazoles is presented. 3-Halo-5-phenylisothiazole-4-carbonitriles, 1 (hal = Cl) and 18 (hal = I), are converted into the corresponding 4-bromo derivatives 5 (3-hal = Cl) and 24 (3-hal = I) via a Hunsdiecker strategy while the 4-iodo analogues 7 (3-hal = Cl) and 22 (3-hal = I) are prepared via a Hoffmann and Sandmeyer strategy. Regioselective Suzuki, Stille and Negishi reactions occur at C-4 with both the 4-bromo- and 4-iodoisothiazoles 5 and 7, the latter being more reactive than the former. 3-Iodoisothiazoles 22 and 24 fail to give regiocontrolled Suzuki, Stille or Negishi couplings, however, 4-bromo-3-iodo-5-phenylisothiazole 24 gives the regiospecific palladium catalysed Ullmann-type reaction product 3,3′-bi(4-bromo-5-phenylisothiazole) 25. Alkali hydrolysis of 3-chloro-4,5-diphenylisothiazole 8 gives the 3-hydroxy analogue 12 which is converted into 3-bromo-4,5-diphenylisothiazole 13 with POBr₃. 3-Bromoisothiazole 13 reacts with phenylzinc chloride to give 3,4,5-triphenylisothiazole 17 but fails to undergo effective Suzuki or Stille couplings. 3,5-Diphenylisothiazole-4-carbonitrile 26 is converted into the 4-bromo- and 4-iodo-3,5-diphenylisothiazoles 30 and 34 both of which are effective for Suzuki and Stille couplings. A series of triarylisothiazoles are prepared in this manner and fully characterised. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b702154b

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
3,4,5-Triarylisothiazoles via C–C coupling chemistry†
Irene C. Christoforou and Panayiotis A. Koutentis*
Received 12th February 2007, Accepted 2nd March 2007
First published as an Advance Article on the web 21st March 2007
DOI: 10.1039/b702154b
The regiocontrolled preparation of triarylisothiazoles is presented. 3-Halo-5-phenylisothiazole-
4-carbonitriles, 1 (hal = Cl) and 18 (hal = I), are converted into the corresponding 4-bromo derivatives
5 (3-hal = Cl) and 24 (3-hal = I) via a Hunsdiecker strategy while the 4-iodo analogues 7 (3-hal = Cl)
and 22 (3-hal = I) are prepared via a Hoffmann and Sandmeyer strategy. Regioselective Suzuki, Stille
and Negishi reactions occur at C-4 with both the 4-bromo- and 4-iodoisothiazoles 5 and 7, the latter
being more reactive than the former. 3-Iodoisothiazoles 22 and 24 fail to give regiocontrolled Suzuki,
Stille or Negishi couplings, however, 4-bromo-3-iodo-5-phenylisothiazole 24 gives the regiospecific
palladium catalysed Ullmann-type reaction product 3,3ꢀ-bi(4-bromo-5-phenylisothiazole) 25. Alkali
hydrolysis of 3-chloro-4,5-diphenylisothiazole 8 gives the 3-hydroxy analogue 12 which is converted
into 3-bromo-4,5-diphenylisothiazole 13 with POBr3. 3-Bromoisothiazole 13 reacts with phenylzinc
chloride to give 3,4,5-triphenylisothiazole 17 but fails to undergo effective Suzuki or Stille couplings.
3,5-Diphenylisothiazole-4-carbonitrile 26 is converted into the 4-bromo- and 4-iodo-3,5-
diphenylisothiazoles 30 and 34 both of which are effective for Suzuki and Stille couplings. A series of
triarylisothiazoles are prepared in this manner and fully characterised.
isothiazoles and the latter route is product-specific. Recently,
Introduction
Pd catalysed cross-coupling methods25,26 have been used to ac-
cess 3,4,5-triarylpyrazole 1-oxides via sequential metalation and
functionalisation of pyrazole 1-oxides27 and 3,4,5-triarylisoxazoles
via the modification of suitably substituted isoxazolylsilanols.28
An analogous approach starting from an appropriately func-
tionalised isothiazole could provide a general route to 3,4,5-
triarylisothiazoles. Our work on the development of C–C cou-
pling methods for the readily available 3,5-dichloroisothiazole-
4-carbonitrile 29 afforded a route to 5-aryl-3-chloroisothiazole-4-
carbonitriles30 and 3,5-diarylisothiazole-4-carbonitriles.31 We now
report the logical extension of this work to provide two routes to
3,4,5-triarylisothiazoles following the arylation sequence C-5:C-
4:C-3 and C-5:C-3:C-4.
1,2-Heteroazoles such as pyrazoles, isoxazoles, and isothiazoles are
found in many biologically active compounds and synthetic meth-
ods for their preparation are well documented.1 These 5-membered
heterocycles are frequently interchanged as broadly equivalent
isosteres. Synthetic routes involving acyclic precursors that afford
either 3,4,5-triarylpyrazoles2–9 or 3,4,5-triarylisoxazoles10,11 have
been reported. Surprisingly, analogous strategies have not been
reported for the preparation of 3,4,5-triarylisothiazoles.12–16
Nevertheless 3,4,5-triphenylisothiazole, the only reported triaryl-
isothiazole, has been prepared from 1,3-dithiazolium17 and 1,4,2-
dithiazolium precursors.18 Interestingly the very first reported
synthesis19 of 3,4,5-triphenylisothiazole was incorrect.20
Our interest in pursuing a new general route to triarylisoth-
iazoles arises due to the growing importance of isothiazoles.
R
Important isothiazoles include the Kathonꢀ preservatives, the
Arylation sequence C-5:C-4:C-3
artificial sweetener Saccharin and the antibacterial sulfa drug,
Sulfasomizole. Recently, isothiazoles have been reported as po-
tential anticancer agents which act via inhibition of the MEK-1
and MEK-2 kinases,21,22 as useful prodrugs for the treatment of
hyperproliferative disorders,23 and as novel active site inhibitors
for the hepatitis C virus NS5B polymerase.24
Possible strategies to triarylisothiazoles include ring formation
via 2 + 3 cycloadditions of aryl nitrile sulfides with diarylacetylenes
and the oxidative cyclisation of 3-amino-1,2,3-triarylprop-2-ene-
1-thiones. These strategies however, have drawbacks since the
former cycloaddition route could lead to isomeric mixtures of
Synthesis of 3-chloro-4-bromo-5-phenylisothiazole and coupling
reactions at C-4
Initially, a sequential arylation of the isothiazole at the C-5,
then C-4 and finally the C-3 ring carbons was investigated.
Aryl and heteroaryl substituents can be introduced at the
isothiazole C-5 position starting from the readily available 3,5-
dichloroisothiazole-4-carbonitrile using Suzuki, Stille and Negishi
coupling reactions.30,31 The 4-cyano substituent could be readily
converted into either a bromo substituent via a Hunsdiecker
strategy (Scheme 1) or into an iodo substituent via a Sandmeyer
strategy (Scheme 2) allowing for the possibility of introducing aryl
substituents at the isothiazole C-4 position.
Hydration of the cyano group in concentrated sulfuric acid32
proceeded smoothly to afford the carboxamide 2 in high yield
(97%). Formation of the desired carboxylic acid 3 by addition of
aqueous NaNO2 to a solution of carboxamide 2 in concentrated
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678,
Nicosia, Cyprus. E-mail: koutenti@ucy.ac.cy; Fax: +357 22 892809;
Tel: +357 22 892783
† Electronic supplementary information (ESI) available: Experimental
procedures and full characterization data for all new compounds. See
DOI: 10.1039/b702154b
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1381–1390 | 1381
©

View Article Online
phenylisothiazole 6. Then a Sandmeyer iodination using isoamyl
nitrite and I2 saturated MeCN gave the desired 3-chloro-4-iodo-5-
phenylisothiazole 7 in good yield (Scheme 2).
As expected, the 3-chloro-4-iodo-5-phenylisothiazole 7 was
more reactive than the analogous 4-bromoisothiazole 5. The 4-
iodoisothiazole 7 readily participated in Suzuki and Stille coupling
reactions to afford regioselectively the 4-arylated isothiazole
products 8–10 in high yields. The 4-bromoisothiazole 5 gave a
successful Suzuki coupling with phenylboronic acid but failed to
give the Stille reaction with tributylphenyltin (up to 4 equiv.).
Both the 4-bromo- and 4-iodoisothiazoles 5 and 7 did not give
the desired Negishi or the homocoupled Ullmann products. In
these cases, the bromoisothiazole 5 was unreactive while the
iodoisothiazole 7 gave predominantly the protodeiodinated 3-
chloro-5-phenyl-isothiazole 11 (Table 1).
Scheme 1 Reagents and conditions: (i) c. H2SO4, 20–100 ◦C, 2 h + 40 min,
97%; (ii) s. NaNO2 (10 equiv.), c. H2SO4, 20–100 ◦C, 2.5 h, 88%; (iii) KOH
(1 equiv.), H2O, AgNO3 (1 equiv.), 20 ◦C, 100%; (iv) CCl4, Br2 (1.2 equiv.),
20 ◦C, 1 h, 80%.
Coupling reactions at the less reactive C-3 isothiazole position
Palladium catalysed C–C coupling reactions at the isothiazole C-
3 position were recently reported for 3-halo-5-phenylisothiazole-
4-carbonitriles31 and required either a bromo or iodo halogen
since a chloro substituent at C-3 was not sufficiently reactive. Not
surprisingly, 3-chloro-4,5-diphenylisothiazole 8 also failed to give
successful Suzuki, Stille, Negishi and Ullmann type C–C coupling
reactions. Consequently, the introduction of a more reactive group
at the isothiazole C-3 position was investigated.
Scheme 2 Reagents and conditions: (i) NaOH (5 equiv.), H2O, Br2
(1.5 equiv.), 0–70 ◦C, 1 h, 83%; (ii) isoamylONO (4 equiv.), I2 (2.5 equiv.),
MeCN, 80 ◦C, 20 min, 82%.
sulfuric acid was complicated by the presence of minor
by-products arising from nitration of the phenyl substituents.
These nitrated by-products could be avoided if water was elim-
inated from the reaction mixture. As such, the portionwise
addition of solid NaNO2 (10 equiv.) to a solution of carboxamide
2 in concentrated sulfuric acid at 100 ◦C gave 3-chloro-5-
phenylisothiazole-4-carboxylic acid 3 in 88% yield. The silver salt
4 was precipitated quantitatively, thoroughly dried and treated
with bromine in tetrachloromethane to give the desired 4-bromo-
3-chloro-5-phenylisothiazole 5 in 80% yield.
Activation of 3-chloro-4,5-diphenylisothiazole
The introduction of a 3-bromo substituent was achieved in
two steps starting from 3-chloro-4,5-diphenylisothiazole 8 via
the 3-hydroxy-4,5-diphenylisothiazole 12. Unlike 3-chloro-5-
phenylisothiazole-4-carbonitrile 1 which can be readily trans-
formed into the 3-hydroxy derivative with NaNO2 in refluxing
DMF,33 3-chloro-4,5-diphenylisothiazole 8 did not react. Hydroly-
sis of 3-chloro-4,5-diphenylis◦othiazole 8 was nevertheless achieved
using aqueous KOH at 200 C and 250 psi in a pressure reactor
The conversion of the carboxamide 2 into 3-chloro-4-iodo-
5-phenylisothiazole 7 was achieved in two steps. First, a Hoff-
mann degradation of the carboxamide gave 4-amino-3-chloro-5-
Table 1 Pd catalysed C–C coupling reactions of 3-chloro-4-halo-5-phenylisothiazole 5 or 7 (0.094 mmol) in anhydrous DMF under an argon atmosphere
heated from 20 to 100 ◦C
Hal
Reagent (equiv.)
Catalyst (mol%)
Base (equiv.)
Time/min
Yields (%)
Br
I
Br
I
I
I
PhB(OH)3 (3)
PhB(OH)3 (3)
PhSnBu3 (4)
PhSnBu3 (1.2)
2-ThienylSnBu3 (1.2)
2-FurylSnBu3 (1.2)
PhZnCl (3)
PhZnCl (1.5)
PhZnCl (3)
—
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
(PPh3)2PdCl2 (5)
(PPh3)2PdCl2 (5)
(PPh3)2PdCl2 (5)
Pd(OAc)2 (100)
Pd(OAc)2 (100)
K2CO3 (1.5)
K2CO3 (1.5)
75
40
>24 h
25
15
15
>24 h
>24 h
35
>24 h
48 h
8 (96)
8 (98)
a
—
—
—
—
—
—
—
—
—
8 (99)
9 (100)
10 (100)
a
Br
I
a
I
8 (20) + 11 (80)
Brb
Ib
a
—
11 (98)
a Mainly unreacted isothiazole by TLC after 24 h. b Heated from 20 to 140 ◦C.
1382 | Org. Biomol. Chem., 2007, 5, 1381–1390
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
to afford the desired 3-hydroxyisothiazole 12 in 95% yield. The
reaction of 3-hydroxy-4,5-diphenylisothiazole 12 with POBr3 gave
the desired 3-bromo-4,5-diphenylisothiazole 13 in 85% yield. 3-
Hydroxy-4,5-diphenylisothiazole 12 was resistant to POCl3 at
100 ◦C and was recovered unreacted after 24 h. Conversion
of the hydroxyisothiazole 12 back into the 3-chloroisothiazole
8 was however, achieved after 72 h at 150 ◦C in a sealed
tube (Scheme 3). 3-Hydroxy-4,5-diphenylisothiazole 12 reacted
with trfluoromethanesulfonic anhydride to give the potentially
useful 4,5-diphenylisothiazol-3-yl trifluoromethanesulfonate 14
in 71% yield together with the N-trifluoromethylsulfonylated
isothiazolone 15 (29%).
higher temperatures the use of between 4–10 equivalents increased
reaction times but reduced yields (59–67%). In contrast 3-chloro-5-
phenylisothiazole-4-carbonitrile 1 and sodamide in refluxing THF
gave a complex reaction mixture.31
The Sandmeyer iodination of 3-amino-4,5-diphenylisothiazole
16 using KI (1.5 equiv.) and NaNO2 (1.5 equiv.) in sulfuric acid
gave 3-hydroxy-4,5-diphenylisothiazole 12 as the main product.
Diazotisation using nitrosyl tertafluoroborate in a 1 : 1 mixture
of acetic and propionic acids gave a complex reaction mixture.
The reaction of 3-amino-4,5-diphenylisothiazole 16 with isoamyl
nitrite (4 equiv.) in the presence of various sources of iodine (I2,
NIS, BnEt3NI) (3 equiv.) in MeCN at 0 or 80 ◦C gave incomplete
reactions, however one main colourless product was observed by
TLC. Isolation of this product by chromatography and subsequent
spectroscopic analysis revealed the colourless material to be a
mixture of inseparable compounds. Mass spectrometry gave a
weak peak for the expected molecular ion at 363 (19%), a
stronger peak at 331 (33%) and a base peak at 204 Da (100%).
IR spectroscopy supported the presence of a nitrile m(C≡N) at
2208 cm−1 that indicated cleavage of the isothiazole ring. 1H-NMR
spectroscopy gave a poorly resolved set of multiplets in the range
of 7.60–7.14 ppm which was not informative, however 13C NMR
spectroscopy indicated 22 carbon signals in the range of 142.0–
115.8 ppm, 12 of which in the range of 130.7–128.3 ppm could
be assigned to CHs by DEPT-90 NMR. The signals at 116.8 and
115.8 ppm supported the presence of at least 1 cyano group. Based
on the above data the mixture was very tentatively proposed to be
a mixture of 3-iodo-2,3-diphenylacrylonitrile and the desired 3-
iodoisothiazole.
Scheme 3 Reagents and conditions: (i) KOH (4 equiv.), 200 ◦C, 250 psi,
pressure reactor, 24 h, 95%; (ii) POCl3, 20–150 ◦C, sealed tube, 72 h, 98%;
(iii) POBr3, 20–100 ◦C, 24 h, 85%; (iv) Tf2O (1 equiv.), Et3N (1 equiv.),
DCM, 0–10 ◦C, 30 min.
Attempts to introduce a 3-iodo substituent to the 4,5-diphenyl
substituted isothiazoles 8 (3-Cl) and 12 (3-OH) failed. Lithiation
of the 3-chloro-4,5-diphenylisothiazole 8 with n-BuLi at −78 ◦C in
Et2O followed by an I2 quench led to a complex reaction mixture
and on workup a strong odour of H2S was detected. No reaction
was observed when the reaction was repeated with Li, LDA or
MeMgCl in either Et2O or THF at −78 to 40 ◦C. Treatment of 3-
hydroxy-4,5-diphenylisothiazole 12 with neat HI, HI-KI at 100 ◦C,
excess of KI-I2 in refluxing THF, Ph3P-I2 in DMF at 50 ◦C, P2I4 in
CS2 or PI3 in refluxing DCM also gave only unreacted 3-hydroxy-
4,5-diphenylisothiazole 12 while the use of neat PI3 at 100 ◦C led to
decomposition of the starting material. No reaction was observed
when the 3-chloro- or 3-bromo-4,5-diphenylisothiazoles 8 and 13
were treated with KI or KI-Et4NI in refluxing acetone or THF.
Iodine at the isothiazole C-3 position has been introduced
to 3-amino-5-phenylisothiazole-4-carbonitrile by a Sandmeyer
iodination.31 The introduction of the 3-amino substituent in
isothiazole 1 was achieved in two steps by heating a mixture of
3-chloro-5-phenylisothiazole-4-carbonitrile 1 in neat benzylamine
at 80 ◦C to afford the 3-(benzylamino)-isothiazole followed by
oxidative debenzylation with bromine. A heated mixture of 3-
chloro-4,5-diphenylisothiazole 8 and neat benzylamine however,
gave no reaction probably owing to reduced electrophilicity of
3-chloro-4,5-diphenylisothiazole 8 in comparison to that of the
analogous 4-cyano-5-phenylisothiazole 1. The use of aqueous or
gaseous ammonia at 80 ◦C and an attempted Gabriel synthesis
with potassium phthalimide gave only unreacted starting material.
3-Amino-4,5-diphenylisothiazole 16 was eventually prepared from
3-chloro-4,5-diphenylisothiazole 8 using sodamide (10 equiv.) in
THF at 20 ◦C for 13 h. The use of only 2 equivalents of sodamide in
refluxing THF led to incomplete reactions after 24 h while at these
C–C coupling chemistry at the isothiazole C-3 position
The C–C coupling chemistry of 4,5-diphenylisothiazol-3-yl tri-
fluoromethanesulfonate 14 and 3-bromo-4,5-diphenylisothiazole
13 was then examined following procedures developed for C–C
coupling reactions of 3-bromo- and 3-iodo-5-phenylisothiazole-
4-carbonitrile.31 Suzuki, Stille, and Ullmann-type reactions on
4,5-diphenylisothiazol-3-yl trifluoromethanesulfonate 14 gave
mainly unreacted starting material while the Negishi reaction
was complex (by TLC) and the presence of 3-hydroxy-4,5-
diphenylisothiazole 12 suggested a competing hydrolysis of the
triflate. Similarly, 3-bromo-4,5-diphenylisothiazole 13 did not
participate effectively in either the Suzuki or the Stille reactions.
Although the desired 3,4,5-triphenylisothiazole 17 could be iden-
tified by TLC neither reaction could be driven to completion
even with excess reagents and prolonged reaction times (>24 h).
Furthermore, no reaction was observed when an Ullmann-type
homocoupling with Pd(OAc)2 (1 equiv.) was attempted in DMF
at 140 ◦C.
Nevertheless the Negishi reaction gave 3,4,5-triphenyliso-
thiazole 17 in 72% yield when 3-bromo-4,5-diphenylisothiazole 13
was treated with phenylzinc chloride (4 equiv.) and (PPh3)2PdCl2
(5 mol%) in DMF at 100 ◦C under argon (Scheme 4).
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1381–1390 | 1383
©

View Article Online
at 317 (100%) and 315 Da (93%) corresponding to the 4-bromo-
1
3,5-diphenylisothiazole 30. H-NMR of this mixture gave three
multiplets in the range of 7.86–7.83 (2H), 7.69–7.65 (2H) and 7.54–
7.40 ppm (4H) and elemental analysis after one recrystallization
gave the percentages C: 55.76; H: 3.05; N: 4.01 which also favoured
the 4-bromo-3,5-diphenylisothiazole 30 to be the major product
over the 3-iodo-◦4,5-diphenylisothiazole. At elevated reaction tem-
peratures (140 C) 3,3ꢀ-bi(4-bromo-5-phenylisothiazole) 25 was
also identified in the reaction mixture and the structure of this 3,3ꢀ-
biisothiazole 25 was supported by a semi-independent synthesis via
an Ullmann-type reaction of 4-bromo-3-iodo-5-phenylisothiazole
24 with Pd(OAc)2 (1 equiv.) in DMF at 140 ◦C under argon
in 74% yield. The analogous Ullmann reaction of 3,4-diiodo-5-
phenylisothiazole 22 gave a complex mixture of products (by TLC)
presumably owing to reduced regiocontrol in comparison to the
4-bromo-3-iodo-analogue.
Scheme 4 Reagents and conditions: (i) PhZnCl (4 equiv.), (PPh3)2PdCl2
(5 mol%) DMF, Ar, 20–100 ◦C, 40 min, 72%.
The triarylation of the isothiazole ring system was achieved
but the failure to perform both Suzuki and Stille reactions was
limiting. As such, an additional effort was made to prepare the
potentially more reactive 3-iodo-4,5-diphenylisothiazole starting
from the known 3-iodo-5-phenylisothiazole-4-carbonitrile 18.31
4-Bromo-3-iodo- and 3,4-diiodo-5-phenylisothiazoles 24 and
22 were therefore prepared (Scheme 5) following similar routes
for the preparation of 4-bromo-3-chloro and 3-chloro-4-iodo-5-
phenylisothiazoles 5 and 7.
Arylation sequence C-5:C-3:C-4
The triarylation described above follows the sequence C-5, then
C-4 and finally C-3, however difficulties were encountered in the
final arylation at C-3 since only the Negishi reagent phenylzinc
chloride (4 equiv.) reacted with 3-bromo-4,5-diphenylisothiazole
13 to afford the desired triphenylisothiazole 17. Furthermore,
the synthetic route to the potentially more reactive 3-iodo-4,5-
diphenylisothiazole failed. As such, an alternative sequential
arylation was pursued which followed the triarylation sequence
C-5 then C-3 and finally C-4. This triarylation sequence offered
several advantages since Suzuki, Stille, Negishi and Ullmann-
type couplings have all been successfully employed to prepare
a variety of 3,5-diarylisothiazole-4-carbonitriles starting from
3,5-dihaloisothiazole-4-carbonitriles.31 Furthermore this route
avoided the issue of regioselectivity between the isothiazole C-3
and C-4 positions since the C-4 position was “protected” as a
nitrile group which could later readily be converted into either
a bromo substituent via a Hunsdiecker strategy or into an iodo
substituent via a Sandmeyer strategy using methods similar to
those described above.
Scheme 5 Reagents and conditions: (i) c. H2SO4, 20–100 ◦C, 2 h, 100%;
(ii) NaNO2 (25 equiv.), c. H2SO4, 20–100 ◦C, 3 h, 78%; (iii) NaOH
(5 equiv.), H2O, Br2 (1.5 equiv.), 0–70 ◦C, 1 h, 89%; (iv) isoamylONO
(4 equiv.), I2 (2.5 equiv.), MeCN, 80 ◦C, 20 min, 85%; (v) KOH (1.2 equiv.),
AgNO3 (1.2 equiv.), H2O, 20 ◦C, 100%; (vi) Br2 (1.2 equiv.), CCl4, 20 ◦C,
1 h, 75%.
Despite the successful syntheses of these 3,4-dihalogenated
isothiazoles both the 3,4-diiodo- and the 4-bromo-3-iodo-5-
phenylisothiazoles 22 and 24 gave mixtures of mono-, di- and
sometimes triphenylated isothiazoles with either phenylboronic
acid or tributylphenyltin in DMF. Nevertheless some regioselec-
tivity was observed with the Suzuki coupling reaction between 4-
bromo-3-iodo-5-phenylisothiazole 24 and phenylboronic acid. A
spectroscopic analysis of the product mixture, that was inseparable
by chromatography or recrystallisation, supported the mixture
to be predominantly 4-bromo-3,5-diphenylisothiazole 30 (an
independent synthesis of this compound is presented later in this
paper) together with a trace of 3-iodo-4,5-diphenylisothiazole.
Mass spectrometry indicated the presence of two parent ions with
a weak peak at 363 (15%) corresponding to the 3-iodoisothiazole
and two strong peaks supporting a monobromine isotope pattern
Synthesis of 3,5-diphenyl-4-bromo and 4-
iodoisothiazoles
Treatment of 3,5-diphenylisothiazole-4-carbonitrile 26 with
concentrated sulfuric acid gave 3,5-diphenylisothiazole-4-
carboxamide 27 in quantitative yield. The portionwise addition
of solid sodium nitrite to a solution of the carboxamide in concen-
trated sulfuric acid gave 3,5-diphenylisothiazole-4-carboxylic acid
28 in 87% yield. As before, it was necessary to avoid the use of
aqueous sodium nitrite since this led to some undesired nitration
on the phenyl substituents. The Hunsdiecker reaction was applied
to the 3,5-diphenylisothiazole-5-carboxylic acid 28 to afford 3,5-
diphenyl-4-bromoisothiazole 30 in 80% (Scheme 6).
1384 | Org. Biomol. Chem., 2007, 5, 1381–1390
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Scheme 7 Reagents and conditions: (i) Na (4 equiv.), Br2(1–2 equiv.),
MeOH, 20–70 ◦C, 1 h, 95%; (ii) aq. HBr (48%), 100 ◦C, 7 h, 97%; (iii)
isoamylONO (4 equiv), I2 (3 equiv.), MeNO2, 110 ◦C, 1 h, 80%.
Coupling reactions of 3,5-diphenyl-4-bromo- and 4-iodoisothiazoles
Both the 4-bromo- and 4-iodo-3,5-diphenylisothiazoles 30 and
34 readily undergo the Suzuki reaction with phenylboronic acid
(3 equiv.), powdered K2CO3 (1.5 equiv.) and Pd(OAc)2 (5 mol%)
in DMF at 110 ◦C under argon atmosphere to provide a
route to triphenylisothiazole 17. The 4-iodoisothiazole 34 reacted
marginally faster than the 4-bromoisothiazole 30. A variety
of arylboronic acids were subsequently screened to provide a
non-product specific route to triarylisothiazoles in good yields
(Table 2).
Scheme 6 Reagents and conditions: (i) c. H2SO4, 20–100 ◦C, 3 h, 100%;
(ii) NaNO2 (10 equiv.), c. H2SO4, 20–100 ◦C, 1 h, 87%; (iii) KOH
(1.2 equiv.), AgNO3 (1.2 equiv.), H2O, 20 ◦C, 100%; (iv) Br2 (1.2 equiv.),
CCl4, 20 ◦C, 1 h, 80%; (v) TsOH.H2O (10 mol%), Ph2, 20–250 ◦C, 20.5 h,
94%.
An alternative strategy to the 4-bromo-3,5-diphenylisothiazole
30 via electrophilic bromination of the 3,5-diphenylisothiazole
31 was also investigated. The thermal decarboxylation of 3,5-
diphenylisothiazole-4-carboxylic acid 28 required prolonged heat-
ing at 250 ◦C in biphenyl in the presence of catalytic TsOH·H2O
(Scheme 6) and the resulting 3,5-diphenylisothiazole 31 was
unreactive to bromine in refluxing acetic acid and to N-
bromosuccinimide in refluxing tetrachloromethane. Iodination
at C-4 using iodine in hydrogen peroxide at 20 ◦C or N-
iodosuccinimide in refluxing tetrachloromethane gave only un-
reacted 3,5-diphenylisothiazole 31 while iodination on phenyl
substituents was observed with the use of iodine in con-
centrated HNO3 at 100 ◦C. Attempted nitration of the 3,5-
diphenylisothiazole C-4 position with HNO3 in concentrated
H2SO4 at 0–5 ◦C also led to undesired nitration on the phenyl
substituents.
Owing to these difficulties in controlling the regiochemistry of
the above electrophilic substitution reactions, the preparation of
the 4-iodo-3,5-diphenylisothiazole 34 was subsequently attempted
in a two step procedure involving first a Hoffmann degradation
to afford the 4-amino-3,5-diphenylisothiazole 33 followed by
the Sandmeyer iodination. Initially, Hoffmann degradation of
3,5-diphenylisothiazole-4-carboxamide 27 with NaOH (4 equiv.)
and bromine (1.5 equiv.) was attempted but the reaction was
incomplete and quite complex. Modified Hoffmann degradation
conditions using methanol as solvent, sodium (4 equiv.) and
bromine (1.2 equiv.) however, gave methyl 3,5-diphenylisothiazole-
4-carbamate 32 in 95% yield based on recovered unreacted carbox-
amide 27 (3–5%), the presence of which could not be overcome.
Treatment of the isothiazolecarbamate 32 with aqueous HBr
(48%) at 100 ◦C gave 4-amino-3,5-diphenylisothiazole 33 in 97%.
Diazotization of the 4-aminoisothiazole 33 with isoamyl nitrite
(4 equiv.) and iodine (3 equiv.) in refluxing nitromethane gave the
4-iodo-3,5-diphenylisothiazole 34 in 80% yield (Scheme 7). Lower
reaction temperatures led to more complicated reaction mixtures
and reduced yields of the 4-iodoisothiazole 34.
When 4-bromo-3,5-diphenylisothiazole 30 reacted with the
sterically more demanding 2-tolylboronic acid or the 2-chloro-
benzeneboronic acid, protodebromination gave 3,5-diphenyl-
isothiazole 31 in 51 and 19% yields respectively. A similar
result was observed between the reaction of 4-iodo-3,5-diphenyl-
isothiazole 34 and 2-tolylboronic acid, however pronounced
protodeiodination occurred with 2-chlorobenzeneboronic acid
affording 3,5-diphenylisothiazole 31 in 88% yield. Despite this,
4-iodo-3,5-diphenylisothiazole 34 reacted cleanly with 2-thienyl-
boronic acid to give 3,5-diphenyl-4-(thien-2-yl)iso-thiazole 46
while the 4-bromo anologue failed to reach completion within 24 h.
In the case of 3- and 4-chlorobenzeneboronic acids the expected
triarylisothiazoles reacted further with the excess boronic acid
reagents to give minor amounts of isothiazoles 48 and 47 both in
11% yield. No reaction was observed with methylboronic acid.
Unlike the above Suzuki reactions where both the 4-bromo-
and 4-iodo-3,5-diphenylisothiazoles 30 and 34 showed similar
reactivities there was a significant difference with the Stille
reaction. The reaction of 4-bromo-3,5-diphenylisothiazole 30 with
tributylphenyltin (3 equiv.) and Pd(OAc)2 (5 mol%) in DMF at
100 ◦C remained incomplete after 24 h while the 4-iodo-3,5-
diphenylisothiazole 34 gave the desired Stille products in high
yield (Table 3).
Both 4-bromo- and 4-iodo-3,5-diphenylisothiazoles 30 and 34
reacted with the Negishi reagent phenylzinc chloride (4 equiv.)
and (PPh3)2PdCl2 (5 mol%) in DMF at 100 ◦C for 4 h under
argon to give 3,4,5-triphenylisothiazole 17 in 29 and 18% yields,
respectively. The Negishi reactions gave considerable amounts
of the protodehalogenation product 3,5-diphenylisothiazole
31 (71 and 77% respectively) accounting for the low yields of
triphenylisothiazole 17. The Ullmann-type homocoupling of
Pd(OAc)2 (1 equiv.) with 4-bromoisothiazole 30 gave a complex
reaction mixture, however, with 3-iodoisothiazole 34 only the
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1381–1390 | 1385
©

View Article Online
Table 2 Reaction of 4-halo-3,5-diphenylisothiazoles 30 and 34 with
arylboronic acid (3 equiv.), powdered K2CO3 (1.5 equiv.), Pd(OAc)2
(5 mol%) in DMF at 20–110 ◦C under Ar
Summary
Successful synthetic methodologies for triarylation on the isoth-
iazole ring system, with C–C-coupling reactions, were demon-
strated following the arylation sequences C-5 then C-4 and
finally C-3 and also C-5 then C-3 and finally C-4 with the
latter triarylation sequence proving to be more versatile. Several
new 3,4,5-triarylisothiazoles were synthesised in high yields. In
general, the reactivity of haloisothiazoles towards the coupling
methodology followed the anticipated order I > Br > Cl. Methods
for converting the cyano substituent at the isothiazole C-4 position
to bromo or iodo using Hunsdiecker or Hoffmann degradation
followed by Sandmeyer iodination techniques were developed.
Several novel 3,5-diphenyl-4-haloisothiazoles and 3,4-dihalo-5-
phenylisothiazoles were synthesised in good yield.
Experimental
CCl4 and MeOH were freshly distilled from CaH2 under argon.
DMF was azeotropically distilled with PhH then distilled under
Hal
Ar
Time/min
Yields (%)
˚
vacuum from anhydrous MgSO4 and stored over 4 A molecular
sieves. THF was freshly distilled from potassium under argon.
Anhydrous K2CO3 was freshly powdered using an agate pestle and
mortar before use. Reactions were protected by CaCl2 drying tubes
or performed under an argon atmosphere. Anhydrous Na2SO4 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 throughout for all
non-TLC scale chromatographic separations using Merck Silica
Gel 60 (less than 0.063 mm). A Hastelloy B-2 Parr pressure vessel
with a teflon sleeve and a 600 mL capacity (3000 psi limit) was used
for the autoclave reactions. Melting points were determined using
a PolyTherm-A, Wagner & Munz, Koefler-Hotstage Microscope
apparatus. Solvents used for recrystallization are indicated after
the melting point. UV spectra were obtained using a Perkin-
Elmer Lambda-25 UV/vis spectrophotometer and inflections are
identified by the abbreviation “inf”. IR spectra were recorded
on a Shimidazu FTIR-NIR Prestige-21 spectrometer with Pike
Miracle Ge ATR accessory, and strong, medium and weak peaks
Br
I
Ph
Ph
60
40
55
40
40
30
45
30
4.5 h
80
30
50
1.5 h
60
17 (98)
17 (100)
35 (99)
36 (98)
37 (98)
38 (99)
39 (98)
40 (99)
41 (49)
41 (41)
42 (89)
43 (83)
44 (81)
44 (12)
45 (100)
Br
Br
Br
Br
Br
Br
Br
I
Br
Br
Br
I
3-NO2C6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-Tol
3-Tol
2-Tol
31 (51)
31 (59)
47 (11)
48 (11)
31 (19)
31 (88)
2-Tol
4-ClC6H4
3-ClC6H4
2-ClC6H4
2-ClC6H4
3-Thienyl
2-Thienyl
2-Thienyl
Br
Br
I
25
a
6 h
46 (99)
a Incomplete reaction after 24 h.
Table 3 Reaction of 4-halo-3,5-diphenylisothiazoles 30 and 34 with
aryltributyltin in the presence of Pd(OAc)2 (5 mol%) in DMF at 20–100 ◦C
under Ar
1
are represented by s, m and w respectively. H and 13C NMR
spectra were recorded on a Bruker Avance 300 machine (at 300
and 75 MHz respectively). CH assignments were supported by 13
C
NMR DEPT 90 experiments. Deuterated solvents were used for
homonuclear lock and the signals are referenced to the deuterated
solvent peaks. Low resolution (EI) mass spectra were recorded on
a Shimadzu Q2010 GCMS with direct inlet probe whilst high res-
olution spectra were recorded on a VG Autospec “Q” mass spec-
trometer. Petrol refers to light petroleum, bp 40–60◦C. 3-Chloro-5-
phenylisothiazole-4-carbonitrile 1,30 3-iodo-5-phenylisothiazole-
4-carbonitrile 1831 and 3,5-diphenylisothiazole-4-carbonitrile 2631
were prepared according to literature procedures.
Hal
Ar
RSnBu3 (equiv.)
Time/h
Yield (%)
a
Br
I
I
I
I
Ph
Ph
Ph
2-Thienyl
2-Furyl
3
1
1.5
1.5
1.5
24
17 (99b)
17 (98)
46 (99)
49 (98)
0.75
16.25
4.25
a Incomplete reaction after 24 h. b Based on recovered 4-iodo-3,5-diphenyl-
isothiazole 34 (11%).
4-Bromo-3-chloro-5-phenylisothiazole 5
protodeiodination product 3,5-diphenylisothiazole 31 was
To a stirred mixture of 3-chloro-5-phenylisothiazole-4-carboxylic
isolated in 43% yield.
acid 3 (1.0 g, 4.18 mmol) in H2O (30 ml) was added a solution of
1386 | Org. Biomol. Chem., 2007, 5, 1381–1390
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
KOH (234 mg, 4.18 mmol, 1 equiv.) in H2O (10 ml) and the mixture
was allowed to stirred at ca. 20 ◦C until the starting material had
completely dissolved. To the reaction mixture was added, in one
portion, a solution of silver nitrate (710 mg, 4.18 mmol, 1 equiv.)
in H2O (5 ml) to afford a grey-white precipitate. The grey-white
precipitate was filtered, washed first with H2O and then with
acetone and dried in a vacuum oven at ca. 80 ◦C for 12 h to
give silver 3-chloro-5-phenylisothiazole-4-carboxylate 4 (1.45 g,
100%). To a stirred mixture of silver 3-chloro-5-phenylisothiazole-
4-carboxylate 4, (100 mg, 0.29 mmol) in tetrachloromethane (3 ml)
protected with CaCl2 drying tube was added in one portion Br2
(18 ll, 0.35 mmol, 1.2 equiv.) and the reaction was kept at 20 ◦C
for 1 h. The reaction mixture was filtred and the filtrate was
absorbed on silica. Chromatography (hexane–DCM 8 : 2) gave
the title compound 5 (63 mg, 80%) as colourless needles, mp
isothiazole 6 (30 mg, 0.143 mmol). The mixture was kept at ca.
80 ◦C until no starting material remained (TLC), allowed to cool
to ca. 20 ◦C and absorbed on silica. Chromatography (hexane–
DCM, 7 : 3) gave the title compound 7 (37.7 mg, 82%) as colourless
needles, mp 67–68 ◦C (from pentane); (Found: C, 33.5; H, 1.5; N,
4.3. C9H5ClINS requires C, 33.6; H, 1.6; N, 4.4%); kmax(DCM)/nm
275 (log e 2.70); mmax/cm−1 3046w (Ph CH), 1471m, 1442m, 1381m,
1335w, 1325w, 1286m, 1270s, 1238w, 1207w, 1077w, 1033m, 990m,
966w, 921w, 893m, 841w, 822m, 783w, 750s; dH(300 MHz; CDCl3)
7.60–7.57 (2H, m, Ph CH), 7.53–7.51 (3H, m, Ph CH); dC(75 MHz;
CDCl3) 168.0, 154.5, 130.7 (Ph C), 130.4 (Ph CH), 129.1 (Ph CH),
128.5 (Ph CH), 79.5; m/z (EI) 323 (M+ + 2, 36%), 321 (M+, 100),
194 (13), 159 (74), 148 (4), 133 (58), 127 (60), 121 (7), 113 (17), 100
(14), 89 (31), 77 (14), 75 (13), 74 (13), 73 (4), 69 (8), 63 (20), 51 (26).
◦
40–41 C (lit.,34 44–46 ◦C) (from pentane); (Found: C, 39.3; H,
3-Chloro-4,5-diphenylisothiazole 8 via Suzuki reaction at C-4
1.9; N, 5.0. C9H5BrClNS requires C, 39.4; H, 1.8; N, 5.1%);
kmax(DCM)/nm 274 (log e 3.91); mmax/cm−1 3049w (Ar CH), 1577w,
1559w, 1517w, 1507w, 1476m, 1457w, 1443m, 1388m, 1336w,
1313w, 1294s, 1278m, 1245w, 1217w, 1076w, 1032m, 996m, 920w,
901m, 819m; dH(300 MHz; CDCl3) 7.67–7.60 (2H, m, Ph CH),
7.53–7.45 (3H, m, Ph CH); dC(75 MHz; CDCl3) 163.4, 151.0, 130.4
(Ph CH), 129.3 (Ph C), 129.1 (Ph CH), 128.2 (Ph CH), 106.2; m/z
(EI) 277 (M+ + 4, 28%), 275 (M+ + 2, 100), 273 (M+, 58), 240 (4),
238 (4), 229 (7), 227 (5), 196 (5), 194 (14), 193 (4), 159 (50), 150
(4), 148 (4), 137 (3), 133 (17), 127 (29), 121 (6), 113 (11), 100 (10),
89 (18), 77 (11), 74 (10), 63 (12), 51 (19) (Found: M+, 272.9015,
C9H5BrClNS requires M, 272.9004).
A stirred mixture of 4-bromo-3-chloro-5-phenylisothiazole 5
(30 mg, 0.11 mmol), phenylboronic acid (40 mg, 0.33 mmol,
3 equiv.), powdered K2CO3 (22.8 mg, 0.165 mmol, 1.5 equiv.)
and Pd(OAc)2 (1.2 mg, 5 mol%) in dry and degassed DMF (2 ml)
under an argon atmosphere, was heated to ca. 100 ◦C, until no
starting material remained (TLC). The mixture was allowed to
cool to ca. 20 ◦C, diluted with DCM (15 ml) and washed with
H2O (4 × 10 ml). The organic layer was separated, dried and
absorbed on silica. Chromatography (hexane–DCM, 6 : 4) gave
the title compound 8 (28.7 mg, 96%) as colourless needles, mp 106–
107 ◦C (from pentane); (Found: C, 66.4; H, 3.6; N, 5.2. C15H10ClNS
requires C, 66.3; H, 3.7; N, 5.2%); kmax(DCM)/nm 275 (log e 2.74);
mmax/cm−1 3055w (Ar CH), 1599w, 1574w, 1537w, 1499w, 1477w,
1377w, 1346m, 1312w, 1236m, 1182w, 1143w, 1076w, 1034w, 995w,
988w, 920w, 907w, 843w, 833m, 802m, 770m, 748s, 710w, 694s;
dH(300 MHz; CDCl3) 7.44–7.22 (10H, m, Ph CH); dC(75 MHz;
CDCl3) 164.4, 150.0, 132.6, 131.8, 130.3 (Ph CH), 130.1 (Ph C),
129.5 (Ph CH), 128.9 (Ph CH), 128.6 (Ph CH), 128.3 (Ph CH),
128.2 (Ph CH); m/z (EI) 273 (M+ + 2, 34%), 271 (M+, 100), 258
(7), 256 (19), 236 (27), 203 (30), 190 (20), 178 (12), 165 (13), 135
(3), 104 (15), 89 (4), 77 (15), 63 (4), 51 (10) (Found: M+, 271.0207,
C15H10ClNS requires M, 271.0222).
4-Amino-3-chloro-5-phenylisothiazole 6
To a stirred solution of NaOH (42 mg, 1.05 mmol, 5 equiv.)
in water (2 ml) cooled to ca. 0 ◦C was first added Br2 (13 ll,
0.25 mmol, 1.2 equiv.) and then 3-chloro-5-phenylisothiazole-4-
carboxamide 2 (50 mg, 0.21 mmol). The reaction mixture was
allowed to warm to ca. 20 ◦C and was kept at this temperature
until the starting material had completely dissolved. The reaction
mixture was then heated to ca. 70 ◦C for 1 h. The mixture was
allowed to cool to ca. 20 ◦C, diluted with water (5 ml) and washed
with DCM (4 × 10 ml). The organic layer was separated, dried and
absorbed on silica. Chromatography (hexane–DCM, 5 : 5) gave the
title compound 6 (36.7 mg, 83%) as colourless plates, mp 58–59 ◦C
(from cyclohexane); (Found: C, 51.2; H, 3.2; N, 13.3. C9H7ClN2S
requires C, 51.3; H, 3.4; N, 13.3%); kmax(DCM)/nm 315 (log e
2.79), 262 (2.66); mmax/cm−1 3373w and 3309w (NH2), 3212w,
3061w (Ph CH), 1623w, 1576w, 1492w, 1445w, 1420m, 1374m,
1316w, 1282w, 1136w, 1086w, 1061w, 1027w, 994w, 974w, 926w,
823m, 764s; dH(300 MHz; CDCl3) 7.50–7.37 (5H, m, Ph CH), 3.76
(2H, br s, NH2); dC(75 MHz; CDCl3) 140.8, 139.8, 134.0, 130.6 (Ph
C), 129.5 (Ph CH), 128.8 (Ph CH), 127.1 (Ph CH); m/z (EI) 212
(M+ + 2, 31%), 210 (M+, 82), 175 (11), 148 (29), 142 (62), 121
(100), 104 (16), 93 (9), 89 (14), 77 (63), 69 (14), 63 (15), 62 (15),
53 (14), 51 (37).
3-Chloro-4,5-diphenylisothiazole 8 via Stille reaction at C-4
(typical Stille conditions for coupling at C-4: see Table 1)
A stirred mixture of 3-chloro-4-iodo-5-phenylisothiazole 7 (30 mg,
0.093 mmol), tributylphenylstannane (36.6 ll, 0.112 mmol,
1.2 equiv.) and Pd(OAc)2 (1.0 mg, 5 mol%) in dry and degassed
DMF (2 ml) under an argon atmosphere, was heated to ca.
◦
100 C, until no starting material remained (TLC). The mixture
was allowed to cool to ca. 20 ◦C, diluted with DCM (15 ml) and
washed with H2O (4 × 10 ml). The organic layer was separated,
dried and absorbed on silica. Chromatography (hexane–DCM, 6 :
4) gave the title compound 8 (25 mg, 99%) as colourless needles,
mp 106–107 ◦C (from pentane) identical to that described above.
3-Chloro-4-iodo-5-phenylisothiazole 7
3-Chloro-5-phenylisothiazole 11
To a stirred mixture of I2 (90.5 mg, 0.358 mmol, 2.5 equiv.) and
isoamyl nitrite (77 ll, 0.573 mmol, 4 equiv.) in MeCN (2 ml)
protected with a CaCl2 drying tube at ca. 80 ◦C was added
dropwise an MeCN (1 ml) solution of 4-amino-3-chloro-5-phenyl-
A stirred mixture of 3-chloro-4-iodo-5-phenylisothiazole 7 (30 mg,
0.093 mmol) and Pd(OAc)2 (20.9 mg, 0.093 mmol, 1 equiv.) in dry
and degassed DMF (2 ml) under an argon atmosphere, was heated
to ca. 140 ◦C, until no starting material remained (TLC). The
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1381–1390 | 1387
©

View Article Online
mixture was allowed to cool to ca. 20 ◦C, diluted with DCM (15 ml)
and washed with H2O (4 × 10 ml). The organic layer was separated,
dried and absorbed on silica. Chromatography (hexane–DCM,
6 : 4) gave the title compound 11 (17.8 mg, 98%) as colourless
material remained (TLC). Chromatography (hexane–DCM, 3 : 7)
gave the title compound 16 (45 mg, 97%) as colourless needles, mp
130–131 ◦C (from cyclohexane); (Found: C, 71.4; H, 4.8; N, 10.9.
C15H12N2S requires C, 71.4; H, 4.8; N, 11.1%); kmax(DCM)/nm
276 (log e 3.71); mmax/cm−1 3458w and 3302w (NH), 3196 (Ar
CH), 1622m, 1576w, 1558w, 1541w, 1506w, 1495m, 1458m, 1443w,
1402m, 1339w, 1161w, 1072w, 1053w, 1028w, 999w, 934w, 924w,
851w, 843m, 772m, 756s, 739w, 704s; dH(300 MHz; CDCl3) 7.42–
7.23 (10H, m, Ph CH), 4.37 (2H, br s, NH2); dC(75 MHz; CDCl3)
162.9, 161.5, 133.0 (Ph C), 131.0 (Ph C), 129.9 (Ph CH), 129.2 (Ph
CH), 128.9 (Ph CH), 128.7 (Ph CH), 128.2 (Ph CH), 128.1 (Ph
CH), 122.7; m/z (EI) 253 (M+ + 1, 27%), 252 (M+, 100), 251 (59),
234 (5), 218 (12), 209 (7), 190 (13), 178 (10), 176 (10), 165 (28),
152 (7), 139 (4), 126 (6), 121 (4), 104 (8), 89 (8), 77 (12), 74 (9), 69
(3), 63 (5), 51 (10) (Found: M+, 252.0718, C15H12N2S requires M,
252.0721).
◦
needles, mp 50–51 C (lit.,34 56 ◦C) (from pentane) identical to
that described above.
3-Hydroxy-4,5-diphenylisothiazole 12
A mixture of 3-chloro-4,5-diphenylisothiazole 8 (1 g, 3.68 mmol)
and KOH (825 mg, 14.7 mmol, 4 equiv.) in H2O (150 ml) was
placed in a bomb reactor with a teflon liner. The bomb reactor
was sealed and heated to ca. 200 ◦C (250 psi) for 24 h. The bomb
reactor was cooled to ca. 20 ◦C and opened. The reaction mixture
was filtered and the filtrate was acidified to give a white precipitate.
The white precipitate was filtered, washed (H2O) and dried to give
the title compound 12 (885 mg, 95%) as colourless needles, mp
◦
233–235 C (lit.,35 245–247 ◦C) (from cyclohexane); (Found: C,
Sandmeyer iodination reaction of 3-amino-4,5-diphenylisothiazole
16
71.0; H, 4.4; N, 5.6. C15H11NOS requires C, 71.1; H, 4.4; N, 5.5%);
kmax(DCM)/nm 234 (log e 3.94), 280 (3.90); mmax/cm−1 3059w (Ar
CH), 1607w, 1583w, 1566w, 1500m, 1481m, 1444w, 1342w, 1265m,
1184w, 1081w, 1073w, 1057w, 1033w, 1024w, 943w, 880m, 851w,
844w, 770m, 754s; dH(300 MHz; DMSO-d6) 11.97 (1H, br s, OH),
7.34–7.29 (6H, m, Ph CH), 7.27–7.21 (4H, m, Ph CH); dC(75 MHz;
DMSO-d6) 166.8, 160.5, 132.3 (Ph C), 131.1 (Ph C), 129.8 (Ph
CH), 129.2 (Ph CH), 129.0 (Ph CH), 128.3 (Ph CH), 127.9 (Ph
CH), 127.4 (Ph CH), 122.1; m/z (EI) 254 (M+ + 1, 20%), 253 (M+,
100), 252 (54), 238 (6), 219 (7), 209 (17), 205 (10), 190 (6), 178 (29),
165 (32), 152 (10), 139 (4), 126 (6), 121 (4), 104 (12), 89 (8), 77
(11), 63 (6), 51 (10) (Found: M+, 253.0567, C15H11NOS requires
M, 253.0561).
To a stirred mixture of benzyltriethylammonium iodide (113.9 mg,
0.357 mmol, 3 equiv.) and isoamyl nitrite (63.9 ll, 0.476 mmol,
4 equiv.) in MeCN (2 ml) protected with a CaCl2 drying tube
at ca. 20 ◦C was added dropwise an MeCN (1 ml) solution of
3-amino-4,5-diphenyl-isothiazole 16 (30 mg, 0.119 mmol). The
mixture was kept at ca. 20 ◦C for 30 min and then was heated◦to
◦
ca. 80 C for 1 h. The mixture was allowed to cool to ca. 20 C
and absorbed on silica. Chromatography (hexane–DCM, 7 : 3)
gave a colourless material which was a mixture of inseparable
compounds: mmax/cm−1 2954w, 2923m, 2854w, 2208w (C≡N),
1594w, 1582w, 1576w, 1564w, 1485w, 1467w, 1457w, 1444m,
1378w, 1363w, 1331w, 1262w, 1222w, 1180w, 1157w, 1134w, 1078w,
1046w, 1031w, 998w, 985w, 969w, 919w, 900w, 873w, 854w, 822w,
793w, 768s, 746m, 738s; dH(300 MHz; CDCl3) 7.63–7.60 (m, Ph
CH), 7.54–7.40 (m, Ph CH), 7.26-7.12 (m, PhCH); dC(75 MHz;
CDCl3) 142.0, 141.1, 137.9, 133.8, 130.7 (Ph CH), 130.4 (Ph
CH), 129.6 (Ph CH), 129.6, 129.1 (Ph CH), 129.1 (Ph CH),
128.9 (Ph CH), 128.8 (Ph CH), 128.7 (Ph CH), 128.6 (Ph CH),
128.5 (Ph CH), 128.4 (Ph CH), 128.3 (Ph CH), 125.1, 121.1,
121.0, 116.8, 115.8; m/z (EI) 364 (M+ + 1%), 363 (M+, 19), 332
(6), 331 (C15H10IN+, 33), 236 (8), 205 (17), 204 (100), 203 (37),
202 (7), 177 (22), 176 (17), 127 (8), 102 (10), 88 (13), 77 (33),
51 (29).
3-Bromo-4,5-diphenylisothiazole 13
A stirred mixture of 3-hydroxy-4,5-diphenylisothiazole 12 (30 mg,
0.12 mmol) and POBr3 (1.5 g), protected with a CaCl2 drying
tube, was heated to ca. 100 ◦C for 24 h. The reaction mixture
was cooled to ca. 20 ◦C, diluted with water and extracted with
DCM (4 × 10 ml). The organic extracts were combined, dried
and absorbed on silica. Chromatography (hexane–DCM, 7 : 3)
gave the title◦compound 13 (32 mg, 85%) as colourless crystals,
mp 112–113 C (from pentane); (Found: C, 56.9; H, 3.3; N, 4.3.
C15H10BrNS requires C, 57.0; H, 3.2; N, 4.4%); kmax(DCM)/nm
276 (log e 3.01); mmax/cm−1 1533w, 1498w, 1474w, 1444w, 1372w,
1339m, 1227m, 1182w, 1138w, 1075w, 1034w, 988w, 920w, 898w,
849w, 843w, 825m, 785w, 769m, 747s; dH(300 MHz; CDCl3) 7.43–
7.40 (3H, m, Ph CH), 7.35–7.26 (5H, m, Ph CH), 7.22–7.17
(2H, m, Ph CH); dC(75 MHz; CDCl3) 164.0, 140.0, 135.3, 132.5,
130.4 (Ph CH), 130.0, 129.5 (Ph CH), 128.9 (Ph CH), 128.6 (Ph
CH), 128.3 (Ph CH), 128.3 (Ph CH); m/z (EI) 317 (M+ + 2,
97%), 315 (M+, 100), 302 (7), 300 (7), 236 (71), 235 (61), 221
(4), 208 (15), 203 (65), 190 (21), 178 (16), 165 (24), 152 (9),
139 (6), 121 (12), 118 (16), 104 (22), 89 (11), 77 (77), 63 (12),
51 (49).
3,4,5-Triphenylisothiazole 17
A stirred mixture of 3-bromo-4,5-diphenylisothiazole 13 (30 mg,
0.095 mmol), phenylzinc chloride (570 ll, 0.5 M in THF, 3 equiv.)
and (PPh3)2PdCl2 (3.3 mg, 5 mol%) in dry and degassed DMF
(2 ml) under an argon atmosphere, was heated to ca. 100 ◦C, until
no starting material remained (TLC). The mixture was allowed
to cool to ca. 20 ◦C, diluted with DCM (15 ml) and washed with
H2O (4 × 10 ml). The organic layer was separated, dried and
absorbed on silica. Chromatography (hexane–DCM, 5 : 5) gave
the title compound 17 (21.4 mg, 72%) as colourless crystals, mp
3-Amino-4,5-diphenylisothiazole 16
◦
◦
210–211 C (lit.,17 211.5–212.5 C) (from cyclohexane); (Found:
C, 80.5; H, 4.8; N, 4.4. C21H15NS requires C, 80.5; H, 4.8; N, 4.5%);
kmax(DCM)/nm 241 (log e 4.06), 284 (3.85); mmax/cm−1 3063w (Ph
CH), 1601w, 1576w, 1539w, 1533w, 1499w, 1479w, 1440w, 1398w,
A stirred mixture of 3-chloro-4,5-diphenylisothiazole 8 (50 mg,
0.184 mmol) and sodium amide (71.8 mg, 1.84 mmol, 10 equiv.) in
dry THF (2 ml) was kept to ca. 20 ◦C, under argon, until no starting
1388 | Org. Biomol. Chem., 2007, 5, 1381–1390
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
1363w, 1291w, 1272w, 1188w, 1179w, 1159w, 1153w, 1073w, 1030w,
977w, 920w, 908w, 842w, 802w, 782w, 764m, 748s, 726m, 701m;
dH(300 MHz; CDCl3) 7.44–7.41 (2H, m, Ph CH), 7.37–7.23 (11H,
m, Ph CH), 7.13–7.10 (2H, m, Ph CH); dC(75 MHz; CDCl3) 167.6,
164.0, 135.7, 134.2, 134.1, 131.0, 130.6 (Ph CH), 128.9 (Ph CH),
128.7 (Ph CH), 128.7 (Ph CH), 128.7 (Ph CH), 128.5 (Ph CH),
128.4 (Ph CH), 128.0 (Ph CH), 127.5 (Ph CH); m/z (EI) 314
(M+ + 1, 30%), 313 (M+, 98), 312 (100), 297 (3), 280 (3), 278 (3),
236 (4), 210 (5), 208 (5), 178 (10), 165 (24), 155 (7), 149 (10), 139
(4), 126 (3), 121 (4), 103 (4), 89 (5), 77 (14), 63 (4), 51 (9).
3,5-Diphenylisothiazole 31
A stirred mixture of 3,5-diphenylisothiazole-4-carboxylic acid 28
(50 mg, 0.178 mmol), p-toluenesulfonic acid (3.4 mg, 10 mol%)
and biphenyl (1 g) protected with a CaCl2 drying tube, was heated
to ca. 250 ◦C until no starting material remained (TLC). The
mixture was allowed to cool to ca. 20 ◦C and absorbed on silica.
Chromatography (hexane–DCM, 8 : 2) gave the ◦title compound
31 (39.7 mg, 94%) as colourless needles, mp 80–81 C (lit.,37 81 ◦C)
(from pentane); (Found: C, 75.9; H, 4.6; N, 5.8. C15H11NS requires
C, 75.9; H, 4.7; N, 5.9%); kmax(DCM)/nm 256 (log e 4.13), 280
(4.06); mmax/cm−1 3055w (Ph CH), 1530w, 1448m, 1453w, 1447w,
1391w, 1370w, 1337w, 1306w, 1206w, 1188w, 1157w, 1153w, 1087w,
1075w, 1027w, 1000w, 970w, 965w, 920w, 909w, 878m, 851w, 830m,
770w, 759m, 752s; dH(300 MHz; CDCl3) 8.03–7.99 (2H, m, Ph
CH), 7.76 (1H, s, isothiazole CH), 7.68–7.64 (2H, m, Ph CH),
7.53–7.39 (6H, m, Ph CH); dC(75 MHz; CDCl3) 168.2, 168.2,
134.8, 130.9 (Ph CH), 129.5 (Ph CH), 129.2 (Ph CH), 128.8 (Ph
CH), 126.8 (Ph CH), 126.5 (Ph CH), 117.5 (isothiazole H-4) one
peak missing; m/z (EI) 238 (M+ + 1, 19%), 237 (M+, 100), 204 (6),
159 (3), 134 (23), 121 (5), 118 (3), 108 (5), 103 (9), 89 (10), 77 (21),
76 (8), 69 (4), 63 (6), 51 (15).
3,3ꢀ-Bi(4-bromo-5-phenylisothiazole) 25
A stirred mixture of 4-bromo-3-iodo-5-phenylisothiazole 24
(30 mg, 0.082 mmol) and Pd(OAc)2 (18.4 mg, 0.082 mmol, 1 equiv.)
in DMF (2 ml) under an argon atmosphere, was heated to ca.
◦
140 C, until no starting material remained (TLC). The mixture
was allowed to cool to ca. 20 ◦C, diluted with DCM (15 ml) and
washed with H2O (4 × 10 ml). The organic layer was separated,
dried and absorbed on silica. Chromatography (hexane–DCM, 2 :
8) gave the title compound 25 (14.5 mg, 74%) as colourless needles,
mp 208–209 ◦C (from cyclohexane); (Found: C, 45.4; H, 2.2; N, 6.0.
C18H10Br2N2S2 requires C, 45.2; H, 2.1; N, 5.9%); kmax(DCM)/nm
285 (log e 4.09); mmax/cm−1 3062w (Ph CH), 1684w, 1653w, 1576w,
1559w, 1539w, 1506w, 1473m, 1445m, 1357w, 1288w, 1243s, 1213w,
1181w, 1159w, 1077w, 1056w, 1035w, 1000w, 977w, 967w, 912w,
882s, 846w, 829m, 754m, 746s, 728w, 724w; dH(300 MHz; CDCl3)
7.74–7.66 (4H, m, Ph CH), 7.59-7.48 (6H, m, Ph CH); dC(75 MHz;
CDCl3) 163.0, 161.3, 130.1 (Ph CH), 129.4 (Ph C), 129.1 (Ph CH),
128.7 (Ph CH), 107.3; m/z (EI) 480 (M+ + 2, 54%), 478 (M+ + 2,
100), 476 (M+, 50), 399 (3), 397 (3), 318 (15), 239 (8), 214 (4), 159
(18), 145 (8), 133 (42), 127 (10), 121 (13), 101 (4), 89 (40), 77 (10),
63 (6), 51 (8).
Methyl 3,5-diphenylisothiazole-4-carbamate 32
To a stirred solution of 3,5-diphenylisothiazole-4-carboxamide 27
(0.2 g, 0.713 mmol) in methanol (3 ml) at ca. 20 ◦C, protected with
a CaCl2 drying tube, was added sodium (65.6 mg, 2.85 mmol,
4 equiv.) and then Br2 (43.9 ll, 0.856 mmol, 1.2 equiv.). The
reaction mixture was heated to ca. 70 ◦C for 1 h. The mixture
was allowed to cool to ca. 20 ◦C and absorbed on silica.
Chromatography (hexane–DCM 5 : 5) gave the title compound
32 (0.20 g, 95%) as colourless needles, mp 163–164 ◦C (from
cyclohexane); (Found: C, 65.9; H, 4.7; N, 9.2. C17H14N2O2S
requires C, 65.8; H, 4.6; N, 9.0%); kmax(DCM)/nm 243 (log e 4.00),
276 inf (3.90); mmax/cm−1 3286w (NH), 1712s (C O), 1582w, 1555w,
=
3,5-Diphenylisothiazole-4-carboxylic acid 28
1522m, 1506m, 1484w, 1451w, 1424w, 1370w, 1251s, 1190w, 1181w,
1157w, 1097m, 1076w, 1037w, 1030w, 1017w, 1000w, 915w, 852w,
840w, 777w, 761s, 746s, 722w; dH(300 MHz; CDCl3) 7.72–7.69 (2H,
m, Ph CH), 7.51–7.42 (8H, m, Ph CH), 6.44 (1H, br s, NH), 3.62
(3H, br s, CH3); dC[75 MHz; CD2Cl2 with Cr(acac)3] 165.3, 162.0,
155.6, 135.2, 130.3, 130.0, 129.9 (Ph CH), 129.5 (Ph CH), 129.5
(Ph CH), 128.9 (Ph CH), 128.2 (Ph CH), 127.9 (Ph CH), 114.8, 1
peak missing; m/z (EI) 311 (M+ + 1, 20%), 310 (M+, 98), 279 (17),
278 (18), 265 (6), 251 (16), 233 (4), 218 (10), 173 (5), 162 (5), 148
(29), 130 (5), 121 (100), 120 (7), 104 (13), 89 (8), 77 (62), 59 (18), 51
(22). Further elution gave 3,5-diphenylisothiazole-4-carboxamide
27 (6 mg, 3%) as colourless needles, mp 210–211 ◦C (from PhH)
identical to that described above.
To a stirred solution of 3,5-diphenylisothiazole-4-carboxamide 27
(1 g, 3.57 mmol) in c. H2SO4 (10 ml) cooled to ca. 0 ◦C and
protected with a CaCl2 drying tube, was added in portions sodium
nitrite (2.46 g, 35.7 mmol, 10 equiv.). The reaction mixture was
heated to ca. 100 ◦C, until no starting material remained (TLC).
The mixture was allowed to cool to ca. 20 ◦C and then was
poured into ice–water to afford a white precipitate. The white
precipitate was filtered, washed (H2O) and dried under vacuum
to give the title compound 28 (0◦.87 g, 87%) as colourless needles,
◦
mp 202–203 C (lit.,36 204–206 C) (from cyclohexane); (Found:
C, 68.5; H, 3.9; N, 5.0. C16H11NO2S requires C, 68.3; H, 3.9; N,
5.0%); kmax(DCM)/nm 251 (log e 4.00); mmax/cm−1 3055w (Ph CH),
=
1679s (C O), 1559w, 1539w, 1533w, 1510m, 1476s, 1442m, 1356m,
1296m, 1208w, 1151w, 1077w, 1025w, 1005w, 990w, 953w, 917w,
856m, 821w, 801w, 769w, 755s; dH(300 MHz; CD2Cl2) 7.65–7.62
(2H, m, Ph CH), 7.56–7.53 (2H, m, Ph CH), 7.52–7.39 (6H, m, Ph
CH) OH peak missing; dC(75 MHz; CD2Cl2) 171.8, 168.4, 167.5,
135.6, 130.4 (Ph CH), 130.0, 129.7 (Ph CH), 129.2 (Ph CH), 129.0
(Ph CH), 128.7 (Ph CH), 128.7 (Ph CH), 125.8; m/z (EI) 282
(M+ + 1, 24%), 281 (M+, 100), 280 (57), 264 (21), 252 (5), 248 (7),
237 (57), 220 (3), 204 (7), 190 (4), 178 (3), 176 (3), 165 (7), 141 (7),
134 (19), 133 (20), 129 (14), 121 (16), 103 (15), 89 (32), 77 (44), 69
(8), 63 (13), 51 (28).
4-Amino-3,5-diphenylisothiazole 33
A stirred solution of methyl 3,5-diphenylisothiazole-4-carbamate
32 (0.5 g, 1.61 mmol) in 48% aq. HBr (20 ml) was heated to ca.
100 ◦C until no starting material remained (TLC). The mixture
was allowed to cool to ca. 20 ◦C, diluted with water (10 ml)
and extracted with DCM (4 × 10 ml). The organic extracts
were combined, dried and absorbed on silica. Chromatography
(hexane–DCM, 5 : 5) gave the title compound 33 (394 mg, 97%) as
◦
colourless needles, mp 113–114 C (from cyclohexane); (Found:
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1381–1390 | 1389
©

View Article Online
C, 71.4; H, 4.9; N, 11.0. C15H12N2S requires C, 71.4; H, 4.8; N,
11.1%); kmax(DCM)/nm 238 (log e 3.11), 327 (4.01); mmax/cm−1
3430w and 3349 (NH), 3055w (Ph CH), 1734w, 1718w, 1700w,
1684w, 1653w, 1613m, 1559w, 1506w, 1487w, 1449m, 1417s, 1387w,
1340w, 1316w, 1291w, 1278w, 1232w, 1182w, 1116w, 1103w, 1079w,
1042w, 1029m, 1018m, 997w, 974w, 919w, 836m, 774w, 762w,
719w; dH(300 MHz; CDCl3) 7.81 (2H, m, Ph CH), 7.59–7.37 (8H,
m, Ph CH), 3.61 (2H, br s, NH); dC(75 MHz; CDCl3) 159.4, 140.7,
136.2, 135.1, 131.3, 129.4 (Ph CH), 129.0 (Ph CH), 128.9 (Ph
CH), 128.3 (Ph CH), 127.7 (Ph CH), 127.7 (Ph CH); m/z (EI) 253
(M+ + 1, 19%), 252 (M+, 100), 180 (2), 149 (22), 121 (68), 104 (51),
89 (8), 77 (31), 51 (10).
12 D. L. Pain, B. J. Peart and K. R. H. Wooldridge, in Comprehensive
Heterocyclic Chemistry, ed. K. T. Potts (eds in Chief A. R. Katritzky
and C. W. Rees), Pergamon, Oxford, 1984, vol. 6, ch. 4.17, p. 131.
13 R. F. Chapman and B. J. Peart, in Comprehensive Heterocyclic
Chemistry II, ed. I. Shinkai (eds in Chief A. R. Katritzky, C. W. Rees
and E. F. V. Scriven), Pergamon, Oxford, 1996, vol. 3, ch. 3.05, p. 319.
14 R. V. Kaberdin and V. I. Potkin, Russ. Chem. Rev., 2002, 71, 673.
15 D. W. Brown and M. Sainsbury, Isothiazoles, in Science of Synthesis,
Product Class 15, ed. E. Schaumann, 2002, vol. 11, p. 567.
16 A.-S. S. H. Elgazwy, Tetrahedron, 2003, 59, 7445.
17 J. Nakayama, A. Sakai, A. Tokiyama and M. Hoshino, Tetrahedron
Lett., 1983, 24, 3729.
18 K. Yanemoto, I. Shibuya and K. Honda, Bull. Chem. Soc. Jpn., 1988,
61, 2232.
19 A. Chinone, K. Inouye and M. Ohta, Bull. Chem. Soc. Jpn., 1972, 45,
213.
20 C. G. Newton, W. D. Ollis and G. P. Rowson, Tetrahedron, 1992, 48,
8127.
21 H. El Abdellaoui, C. V. N. S. Varaprasad, D. Barawkar, S. Chakravarty,
A. Maderna, R. Tam, H. Chen, M. Allan, J. Z. Wu, T. Appleby, S. Yan,
W. Zhang, S. Lang, N. Yao, R. Hamatake and Z. Hong, Bioorg. Med.
Chem. Lett., 2006, 16, 5561.
22 C. V. N. S. Varaprasad, D. Barawkar, H. El Abdellaoui, S. Chakravarty,
M. Allan, H. Chen, W. Zhang, J. Z. Wu, R. Tam, R. Hamatake, S. Lang
and Z. Hong, Bioorg. Med. Chem. Lett., 2006, 16, 3975.
23 E. R. Larson, M. C. Noe and T. G. Gant, US Pat., 6 235 764,2001.
24 S. Yan, T. Appleby, E. Gunic, J. H. Shim, T. Tasu, H. Kim, F. Rong,
H. Chen, R. Hamatake, J. Z. Wu, Z. Hong and N. Yao, Bioorg. Med.
Chem. Lett., 2007, 17, 28.
Acknowledgements
The authors wish to thank Cyprus Research Promotion Founda-
tion (Grant No. DRASI/TEXNO/0603/18) and 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.
25 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
26 J. Hassan, M. Se´vignon, C. Gozzi, E. Schulz and M. Lemaire, Chem.
Rev., 2002, 102, 1359.
27 A. S. Paulson, J. Eskildsen, P. Vedsø and M. Begtrup, J. Org. Chem.,
2002, 67, 3904.
References
1 A. R. Katritzky and A. F. Pozharskii, Handbook of Heterocyclic
Chemistry, Pergamon, 2nd edn, 2000.
2 A. M. Comrie, J. Chem. Soc. C, 1968, 446.
3 A. M. Comrie, J. Chem. Soc. C, 1971, 2807.
4 A. M. Comrie, J. Chem. Soc., Perkin Trans. 1, 1972, 1193.
5 J. Van Alphen, Recl. Trav. Chim. Pays-Bas, 1933, 52, 525.
6 W. Kirmse, Liebigs Ann. Chem., 1958, 614, 1.
7 W. E. Parham and W. R. Hasek, J. Am. Chem. Soc., 1954, 76,
799.
28 S. E. Denmark and J. M. Kallemeyn, J. Org. Chem., 2005, 7, 2839.
29 W. R. Hatchard, J. Org. Chem., 1964, 29, 660.
30 I. C. Christoforou, P. A. Koutentis and C. W. Rees, Org. Biomol. Chem.,
2003, 1, 2900.
31 I. C. Christoforou and P. A. Koutentis, Org. Biomol. Chem., 2006, 4,
3681.
32 W. R. Hatchard, US Pat., 3 155 678, 1964.
33 R. J. A. Walsh and K. R. H. Wooldridge, J. Chem. Soc., Perkin Trans.
1, 1972, 1247.
34 J. Faust, Z. Chem., 1968, 8, 170.
35 M. D. Scott, J. Chem. Soc., Perkin Trans. 1, 1972, 1432.
36 H. Gotthardt, Chem. Ber., 1972, 105, 196.
37 D. Leaver, D. M. McKinnon and W. A. H. Robertson, J. Chem. Soc.,
1965, 32.
8 M. W. Klett and R. P. Johnson, J. Am. Chem. Soc., 1985, 107,
3963.
9 S. Ito, Y. Tanaka, A. Kakehi, T. Fukuyama, N. Osawa and N. Sayo,
Bull. Chem. Soc. Jpn., 1983, 56, 545.
10 D. E. Worrall, J. Am. Chem. Soc., 1935, 57, 2299.
11 C. F. Beam, M. C. D. Dyer, R. A. Schwarz and C. R. Hauser, J. Org.
Chem., 1970, 35, 1806.
1390 | Org. Biomol. Chem., 2007, 5, 1381–1390
This journal is
The Royal Society of Chemistry 2007
©