New syntheses of aryl isothiocyanates from N-arylimino-1,2,3-dithiazoles
Thierry Besson,a Je´roˆme Guillard,a Charles W. Reesb and Michel The´risodc
a Laboratoire de Ge´nie Prote´ique et Cellulaire, Poˆle Sciences et Technologie, Universite´ de La Rochelle, Avenue Marillac,
F-17042 La Rochelle cedex 1, France
b Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
c S.E.S.N.AB., Poˆle Sciences et Technologie, Universite´ de La Rochelle, Avenue Marillac, F-17042 La Rochelle cedex 1, France
Treatment of N-arylimino-1,2,3-dithiazoles
2
with
equiv.) in THF was added dropwise to a heated solution of the
iminodithiazole 2 in THF under argon, and heated at reflux for
1 h. Hydrolysis followed by extraction of the product with
dichloromethane and purification by column chromatography
afforded the isothiocyanates 13 (45–60%) (Method A, Table 1).
Similar yields were obtained from reactions run at room
temperature overnight. Transposing this procedure to a open
microwave oven specially designed for organic synthesis gave
very similar results (reaction times, yields). An excess of
ethylmagnesium bromide (5–6 equiv.) gave more complex
reactions with lower yields of isothiocyanates.
The ready conversion of iminodithiazoles 2 into aryl
isothiocyanates 13 is a new reaction of the heterocyclic ring,
which provides a novel route to isothiocyanates. This mild two-
step conversion of primary aromatic amines into isothio-
cyanates avoids the use of carbon disulfide and thiophosgene,
and high temperature reactions.7
ethylmagnesium bromide (2 equiv.) gives the corresponding
aryl isothiocyanates 13, providing a very mild two-step
conversion of ArNH2 into ArNCS avoiding hazardous
reagents; alternatively the iminodithiazoles 2 can be con-
verted into cyanothioformanilides 11 which rapidly give the
same isothiocyanates with 1 equiv. of the Grignard rea-
gent.
4,5-Dichloro-1,2,3-dithiazolium choride 1, which is readily
prepared from chloroacetonitrile and disulfur dichloride, reacts
rapidly with anilines in dichloromethane at room temperature to
give the stable 5-(N-arylimino)-4-chloro-5H-1,2,3-dithiazoles 2
usually in very high yield.1–3 These iminodithiazoles are
susceptible to intramolecular (e.g. 3) and intermolecular (e.g. 4)
nucleophilic substitution at both sulfur and both carbon atoms
of the dithiazole ring and, in consequence, have proved to be
very versatile synthetic intermediates. They can be converted in
one step into the 2-cyano derivatives of benzoxazoles 5,2
benzothiazoles 6,2 benzimidazoles 7,4 benzoxazin-4-ones 8,3
benzothiazin-4-ones 93 and 4-alkoxyquinazolines 10,5 and into
the acyclic N-arylcyanothioformamides 11.3 Opening of the
dithiazole ring by aliphatic amines (e.g. 4) has also been shown
by Kim and co-workers to be synthetically useful.6 In all of
these reactions the latent cyano group in the reagent 1 has been
generated and retained in the products. We now find that with
the more powerfully nucleophilic Grignard reagents, opening of
the dithiazole ring is accompanied by elimination of the cyano
group. A commercial solution of ethylmagnesium bromide (2
Opening of the dithiazole ring by the Grignard reagent is
probably initiated by attack at S-2 and generation of the cyano
group (Scheme 1), as with other nucleophiles.6 Attack by a
second molecule of the Grignard reagent on the same sulfur
could result in formation of the isothiocyanate, dialkyl sulfide
Table 1 Synthesis of aryl isothiocyanates 13 from 5-(N-arylimino)-
1,2,3-dithiazoles 2 and cyanothioformanilides 11a,b
Starting
material
Product
13
R
Yield (%)
Mp/°C
2a
2b
2c
H
2-F
2-CN
a
b
c
54
50
oilc
oilc
64
Cl
Cl
Cl
55 (A); 76 (B)d
N
2d
2e
2f
4-MeO
4-CN
d
e
f
g
h
d
g
h
44 (A); 75 (B)
60
50
oilc
123c
oil
134
74
oil
134
74
+
R
N
S
N
S
Cl –
S
1
S
3,4-(MeO)2
2-CN, 4,5-(MeO)2
3,4-(OCH2CH2O)
4-MeO
2-CN, 4,5-(MeO)2
3,4-(OCH2CH2O)
2
e
2g
46 (A); 54 (B)
2h
11d
11g
11h
47 (A); 73 (B)
93f
70f
92f
Cl
Cl
N
N
11
R
N
R
N
5, 7, 8
S
S
• •
S
S
a
b
Nu
All compounds were characterised by IR, NMR and HRMS. Aryl
isothiocyanates 13: typical procedures from 5-(N-arylimino)-4-chloro-
5H-1,2,3-dithiazoles 2. Method A: Under an argon atmosphere, a solution of
ethylmagnesium bromide (2 mmol, 1 m in THF) was added dropwise to a
solution of the 5-imino-1,2,3-dithiazole 2 (1 mmol) in boiling THF (5 ml).
The brown mixture obtained was heated for about 1 h, the reaction being
followed by TLC. After addition of CH2Cl2 (20 ml) the solution was washed
with water, the organic layer dried over sodium sulfate and the solvent
evaporated. The crude product was then purified by column chromatog-
raphy with light petroleum–CH2Cl2. The same procedure was transposed to
a open microwave oven in a quartz reactor (Synthewave S402 Prolabo®
microwave reactor monomode system which has variable speed rotation,
visual control, irradiation monitor, infrared measurement and continuous
feedback temperature controlled by PC computer). The products were
• •
Nu
3
4
• •
Nu
N
CN
CN
N
X
R
R
R
R
CN
X
O
5 X = O
6 X = S
7 X = NR
8 X = O
9 X = S
H
N
N
CN
c
d
N
S
purified as above. Compound commercially available. (A): method A;
(B): method B (see above). Treatment of the iminodithiazole 2g with
e
OR′
benzylmagnesium bromide gave the same yield of isothiocyanate 13g as
EtMgBr. f EtMgBr (1 equiv.), THF 50 °C, 30 min.
10
11
Chem. Commun., 1997
881