TABLE 3. Preparation of Isothiocyanates via TsCl-Mediated
Dithiocarbamate Decompositiona
more difficult, use of excess reagents and longer reaction times
generally afforded the desired intermediates. In the case of
electron-deficient arylamines, it was necessary to employ NaH
and higher temperature to achieve high conversion to the
dithiocarbamic acid salts. However, in all cases, once the
dithiocarbamic acid salt was obtained, TsCl proved an effective
reagent for decomposition to the desired isothiocyanate
Experimental Section
Representative Procedure for Alkylamines. A 50 mL round-
bottomed flask was charged with 3-propylphenylamine (1.6 mL,
11.0 mmol), triethylamine (5.0 mL, 36.2 mmol), and THF (10 mL),
then cooled with an ice bath under N2 atmosphere. Carbon disulfide
(0.66 mL, 11.0 mmol) was then added to the reaction mixture by
syringe pump over 0.5 h. After the addition was completed, the
mixture was stirred at room temperature. After 1 h, 1H NMR of an
aliquot indicated that conversion into dithiocarbamate salt was
complete. The reaction mixture was cooled with an ice bath, tosyl
chloride (2.3 g, 12.1 mmol) was added, and the reaction was allowed
to warm to room temperature. After 0.5 h, 1 N HCl (10 mL) and
MTBE (10 mL) were added to the mixture. The aqueous layer was
separated and back extracted with MTBE (10 mL). The organic
layers were then combined, dried over Na2SO4, and filtered. The
filtrate was concentrated in vacuo to obtain an oil, which was passed
through a silica plug with 100% hexane as eluent. 3-Propyl
phenylisothiocyanate (1.48 g) was obtained as a colorless oil in
1
75% yield. H NMR (400 MHz, DMSO-d6) δ 7.30 (m, 2H), 7.20
(m, 3H), 3.64 (t, J ) 6.8 Hz, 2H), 2.66 (t, J ) 7.6 Hz, 2H), 1.94
(q, J ) 10.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 140.4,
128.5, 128.4, 126.2, 44.3, 32.0, 30.9. IR 3061.1 (m), 3025.5 (m),
2925.4 (m), 2857.7 (m), 2181.4 (s), 2088.9 (s).
a Reaction conditions: The substrate was treated with 1.5 equiv of NaH
in THF at 0 °C; after the solution was warmed to 22 °C, 3 equiv of CS2
was added over 1 h. The mixture was then stirred at reflux for 20 h. After
the solution was cooled to 0 °C, 2.2 equiv of Et3N and 1.1 equiv of TsCl
were added, and the mixture was stirred at 22 °C for 1 h. b Isolated yield
after purification via column chromatography on silica gel.
Representative Procedure for Arylamines. A 50 mL round-
bottomed flask was charged with p-bromoaniline (1.89 g, 11.0
mmol), Et3N (5.03 mL, 36.2 mmol), and THF (10 mL), then cooled
with an ice bath under N2 atmosphere. CS2 (0.66 mL, 11.0 mmol)
was added by syringe pump over 0.5 h. More CS2 (0.66 mL, 11.0
1
mmol) and Et3N (1.8 mL, 12.1 mmol) were added after H NMR
of an aliquot indicated incomplete conversion into the dithiocar-
bamate. Once conversion of the salt was completed, (18 h) the
mixture was cooled with an ice bath and TsCl (2.30 g, 12.1 mmol)
was added. The reaction was stirred at room temperature for 1 h.
The material was subjected to workup (as above) and 1.76 g of
p-bromophenyl isothiocyanate was obtained in 77% yield. 1H NMR
(400 MHz, DMSO-d6) δ 7.64 (d, J ) 8.4 Hz, 2H), 7.40 (d, J ) 8.8
Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 134.6, 132.7, 129.4,
127.9, 120.6. IR 2923.6 (w), 2076.5 (m).
ethylaniline, Et3N, and CS2 in THF also failed to afford the
dithiocarbamate salt. We next investigated the use of stronger
bases to generate the more nucleophilic amide anions prior to
CS2 addition. After testing various bases, the use of NaH was
found to be ideal. After 20 h at reflux, full conversion to the
dithiocarbamic acid salt was observed13 and the mixture was
cooled to room temperature, then treated with tosyl chloride.
In this manner, we were able to obtain reasonable yields of
several aryl-isothiocyanates with strong electron-withdrawing
groups such as CO2Me and CF3 (Table 3, entries 1, 2, and 7,
41-89% yield). This method was also effective for o-halide
substitiuents (entries 5 and 6, 53-55% yield). Disappointingly,
neither NO2- nor CN-substituted anilines afforded clean conver-
sion to the related dithiocarbamic acid salts, and after treatment
with TsCl, no isothiocyanate was isolated (entries 3 and 4).15
We have developed a general, economical, and simple one-
pot method for the preparation of a variety of alkyl- and
arylisothiocyanates from amines and CS2 via TsCl-mediated
decomposition of the corresponding dithiocarbamic acid salts.
By comparison, previously reported methods for dithiocarbamate
decomposition were not as mild or high yielding. While
formation of dithiocarbamic acid salts from arylamines proved
Representative Procedure for Electron Poor Arylamines with
NaH as Base. A 50 mL round-bottomed flask was charged with
4-aminobenzotrifluoride (1.38 mL, 11.0 mmol), THF (10 mL), and
sodium hydride (60% in mineral oil; 0.66 g, 16.5 mmol) in an ice
bath under N2 atmosphere. CS2 (1.98 mL, 32.9 mmol) was added
via syringe pump as the reaction was brought up to room
temperature over 1 h. The mixture was then refluxed at 75 °C for
20 h. The mixture was then cooled on an ice bath, and TsCl (2.30
g, 12.1 mmol) and Et3N (3.35 mL, 26.1 mmol) were added. The
mixture was stirred at room temperature for 0.5 h. The reaction
mixture was subjected to workup (as above) and column chroma-
tography to yield 1.44 g of p-CF3-phenyl isothiocyanate in 63%
1
yield. H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J ) 8.4 Hz),
7.64 (d, J ) 8.4 Hz). 13C NMR (100 MHz, DMSO-d6) δ 136.0,
134.0, 127.7 (q, J ) 32.2 Hz), 126.9, 126.8, 122.3 (t, J ) 270 Hz).
IR 3447.3 (s), 2923.7 (m), 2090.7 (s).
Supporting Information Available: Experimental procedures
and characterization data. This material is available free of charge
(15) To the best of our knowledge, 1-isothiocyanato-4-nitrobenzene has
never been reported. 1-Isothiocyanato-4-cyanobenzene has been prepared
from 4-nitroaniline with thiophosgene in 50 % yield (Benati, L.; Leardini,
R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. J. Org. Chem. 2000,
65 (8), 8669-8674).
JO070246N
J. Org. Chem, Vol. 72, No. 10, 2007 3971