A convenient synthesis of 2-sulfanylbenzoselenazole derivatives via the reaction of 2-lithiophenyl isothiocyanates with selenium

Article abstract of DOI:10.1002/hlca.201200014

The title compounds have been prepared from 2-bromophenyl isothiocyanates 1. Thus, 2-lithiophenyl isothiocyanates 2, obtained from 1 and BuLi through Br/Li exchange, reacted with Se at -78° to form lithium benzoselenazole-2- thiolates 3, which, upon aqueo

Full text of DOI:10.1002/hlca.201200014

Helvetica Chimica Acta – Vol. 95 (2012)
761
A Convenient Synthesis of 2-Sulfanylbenzoselenazole Derivatives via the
Reaction of 2-Lithiophenyl Isothiocyanates with Selenium
by Kazuhiro Kobayashi*a) and Yuki Yokoia)
a) Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
The title compounds have been prepared from 2-bromophenyl isothiocyanates 1. Thus, 2-
lithiophenyl isothiocyanates 2, obtained from 1 and BuLi through Br/Li exchange, reacted with Se at
ꢀ 788 to form lithium benzoselenazole-2-thiolates 3, which, upon aqueous workup, afforded benzose-
lenazole-2(3H)-thiones 4. The thiolates 3 were alkylated with reactive alkyl halides and acylated with
carboxylic acid chlorides to give 2-(alkylsulfanyl)benzoselenazoles 5 and S-(benzoselenazol-2-yl)
thiocarboxylates 6, respectively.
Introduction. – Some compounds with the benzoselenazole skeleton have been
reported to exhibit biological activities [1], and some general procedures are available
for the preparation of benzoselenazoles [1][2]. For example, Fujiwara et al. have
reported an efficient method based on Cu-catalyzed cyclization of the adducts derived
from the addition reactions of 2-halophenyl isoselenocyanates with amines, alcohols,
and thiols [2a]. The preparation of N-substituted benzoselenazol-2-amines by Cu-
catalyzed additionꢀcyclization of 2-iodobenzenamines with isoselenocyanates has
been reported by Sashida and co-workers [2b]. On the other hand, we have recently
reported that 2-lithiophenyl isothiocyanates, generated from 2-bromophenyl isothio-
cyanates and BuLi through Br/Li exchange, react with electrophiles, such as aldehydes,
ketones, butenolide, or isothiocyanates, to give 1,4-dihydro-3,1-benzoxazine-2-thiones
[3] or benzoquinazoline-2,4(1H,3H)-dithiones [4]. As part of our continuing study on
the synthesis of benzo-fused heterocycles utilizing 2-lithiophenyl isothiocyanates, we,
therefore, investigated the possibility of the preparation of 2-sulfanylbenzoselenazole
derivatives via the reaction of these Li compounds with Se. Here, we report the results
of our investigation, which offer an efficient preparation of benzoselenazole-2(3H)-
thiones 4, 2-(alkylsulfanyl)benzoselenazoles 5, and S-(benzoselenazol-2-yl) thiocar-
boxylates 6. To the best of our knowledge, this is the first report for the preparation of
benzoselenazoles of type 6.
Results and Discussion. – First, the synthesis of benzoselenazole-2(3H)-thiones 4
was conducted as illustrated in Scheme 1. 2-Bromophenyl isothiocyanates 1 were
treated with BuLi in THF at ꢀ 788 to generate 2-lithiophenyl isothiocyanates 2, which
were then allowed to react with Se. Attack of these carbanions on Se and the
subsequent ring closure of the resulting 2-isothiocyanatobenzeneselenide by the
intramolecular addition of selenide to the isocyanate C-atom proceeded rapidly at this
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1
temperature to lead to the formation of lithium benzoselenazole-2-thiolate intermedi-
ates 3, which were protonated by acidic aqueous workup to give 4 in relatively good
yields.
The preparation of 2-(alkylsulfanyl)benzoselenazoles 5 was then accomplished
outlined as in Scheme 2. The intermediates 3, generated as described above, were
treated with alkyl halides, and the temperature was raised to room temperature. The S-
alkylation could be achieved only using reactive alkyl halides compiled in the Table.
However, the yields of 5 were relatively good as can be seen from this Table.
Butylsulfanyl derivatives, which might be expected from the S-alkylation of 3 with 1-
bromobutane, could not be detected. It is natural that EtBr did not react under these
reaction conditions.
Scheme 2
Table. Preparation of 2-Sulfanyl-benzoselenazoles 5
Entry
1
R’X
5
Yielda) [%]
1
2
3
4
5
6
1a (R ¼ H)
MeI
EtI
5a
5b
5c
5d
5e
5f
68
64
74
69
68
68
1a
1a
1a
CH2¼CHCH2Br
BnBr
1b (R ¼ Me)
CH2¼CHCH2Br
MeI
1c (R ¼ Cl)
a) Yields of isolated products.
Subsequently, S-(benzoselenazol-2-yl) thiocarboxylates 6 were obtained as shown
in Scheme 3. When carboxylic acid chlorides were reacted with intermediate 3a, S-
acylation proceeded rapidly even at ꢀ 788 to afford the desired products 6 in moderate-
to-fair yields.

Helvetica Chimica Acta – Vol. 95 (2012)
763
Scheme 3
In conclusion, we have demonstrated that the reactions of 2-lithiophenyl
isothiocyanates with Se allow convenient syntheses of benzoselenazole-2(3H)-thiones,
2-(alkylsulfanyl)benzoselenazoles, and S-(benzoselenazol-2-yl) thiocarboxylates. The
ready availability of the starting materials coupled with the ease of operations render
the presented procedures attractive.
Experimental Part
General. All of the org. solvents used were dried on the appropriate drying agents and distilled under
Ar prior to use. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-200E. M.p.:
Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR Spectra: PerkinꢀElmer
Spectrum65 FT-IR spectrophotometer; ˜n in cmꢀ1 1H-NMR Spectra: JEOL ECP 500 FT and JEOL
.
LA400FT NMR spectrometers, at 500 and 400 MHz, resp.; d in ppm rel. to Me4Si as internal standard, J
in Hz. 13C-NMR: JEOL ECP 500 FT and JEOL LA400FT NMR spectrometers, at 125 and 100 MHz,
resp.; d in ppm rel. to Me4Si as internal standard. LR-EI-MS (70 eV): JEOL JMS AX 505 HA
spectrometer; in m/z.
2-Bromo-4-chloro-1-isothiocyanatobenzene (1c) was prepared by the procedure reported previously
by us [3]. BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were
commercially available; 1a from Tokyo Chemical Industry Co., Ltd., and 1b from Wako Pure Chemical
Industries, Ltd..
Benzoselenazole-2(3H)-thione (4a) [5][6]. General Procedure. To a stirred soln. of 1a (0.21 g,
1.0 mmol) in THF (4 ml) at ꢀ 788 was added dropwise BuLi (1.6m in hexane; 1.0 mmol). After 5 min, Se
(79 mg, 1.0 mmol) was added, and stirring was continued for an additional 30 min at the same temp. Aq.
sat. NH4Cl (10 ml) was added, and the mixture was warmed to r.t. and extracted with AcOEt (3 ꢁ 10 ml).
The combined extracts were washed with brine (10 ml), dried (Na2SO4), and evaporated. The residue
was purified by CC (SiO2) to give 4a (0.15 g, 75%). White solid. Rf (AcOEt/hexane 1:5) 0.60. M.p. 155 –
1
1578 (hexane/Et2O) ([6]: 1578). IR (KBr): 3105, 1500, 1426, 1316, 1006. H-NMR (500 MHz, CDCl3):
7.24 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.30 (d, J ¼ 8.0, 1 H); 7.35 (td, J ¼ 7.4, 1.1, 1 H); 7.51 (d, J ¼ 7.4, 1 H); 10.99
(br. s, 1 NH).
6-Methylbenzoselenazole-2(3H)-thione (4b). White solid. M.p. 164 – 1678 (hexane/CHCl3). IR
(KBr): 3102, 1497, 1478, 1319, 1025. 1H-NMR (500 MHz, CDCl3): 2.39 (s, 3 H); 7.15 (d, J ¼ 8.4, 1 H); 7.18
(d, J ¼ 8.4, 1 H); 7.35 (s, 1 H); 10.85 (br. s, 1 H). 13C-NMR (125 MHz, CDCl3): 21.14; 113.07; 124.98;
128.16; 130.38; 135.04; 139.34; 193.32. MS: 229 (100, Mþ). Anal. calc. for C8H7NSSe (228.95): C 42.11, H
2.35, N 6.54; found: C 42.08, H 2.38, N 6.44.
6-Chlorobenzoselenazole-2(3H)-thione (4c). White solid. M.p. 230 – 2338 (hexane/CH2Cl2). IR
1
(KBr): 3100, 1489, 1458, 1313, 1025. H-NMR (500 MHz, (D6)DMSO): 7.27 (d, J ¼ 9.2, 1 H); 7.41 (dd,
J ¼ 9.2, 1.6, 1 H); 7.87 (d, J ¼ 1.6, 1 H); 13.69 (br. s, 1 H). 13C-NMR (125 MHz, (D6)DMSO): 114.60;
125.14; 127.24; 128.66; 131.55; 141.70; 194.18. MS: 249 (100, Mþ). Anal. calc. for C7H4ClNSSe (248.59): C
33.82, H 1.62, N 5.63; found: C 33.74, H 1.69, N 5.50.
2-(Methylsulfanyl)benzoselenazole (5a) [7]. General Procedure. Compound 1a (0.21 g, 1.0 mmol) in
THF (4 ml) was treated with BuLi (1.0 mmol) and Se (79 mg, 1.0 mmol) as described for the preparation

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Helvetica Chimica Acta – Vol. 95 (2012)
of 4. After 30 min, MeI (0.14 g, 1.0 mmol) was added, and then the temp. was raised to r.t. over 30 min.
The resulting mixture was worked up as described for the preparation of 4, and the residue was purified
by CC (SiO2) to give 5a (0.13 g, 58%). Yellow oil. Rf (AcOEt/hexane 1:20) 0.36. IR (neat): 1610, 1473,
1434. 1H-NMR (400 MHz, CDCl3): 2.78 (s, 3 H); 7.23 (ddd, J ¼ 7.8, 7.3, 1.0, 1 H); 7.41 (ddd, J ¼ 8.3, 7.4, 1.0,
1 H); 7.79 (d, J ¼ 7.8, 1 H); 7.89 (d, J ¼ 8.3, 1 H). 13C-NMR (100 MHz, CDCl3): 16.74; 122.78; 124.15;
124.24; 126.17; 137.98; 154.78; 169.70.
2-(Ethylsulfanyl)benzoselenazole (5b). Yellow oil. Rf (AcOEt/hexane 1:20) 0.54. IR (neat): 1624,
1474, 1436. 1H-NMR (400 MHz, CDCl3): 1.49 (t, J ¼ 7.3, 3 H); 3.34 (q, J ¼ 7.3, 2 H); 7.21 (ddd, J ¼ 7.8, 7.3,
1.0, 1 H); 7.40 (ddd, J ¼ 7.8, 7.3, 1.0, 1 H); 7.78 (d, J ¼ 7.8, 1 H); 7.88 (d, J ¼ 7.8, 1 H). 13C-NMR (100 MHz,
CDCl3): 14.44; 28.61; 122.83; 124.17; 124.23; 126.10; 138.02; 154.75; 168.63. MS: 243 (100, Mþ). Anal.
calc. for C9H9NSSe (242.20): C 44.63, H 3.75, N 5.78; found: C 44.72, H 3.70, N 5.71.
2-[(Prop-2-en-1-yl)sulfanyl]benzoselenazole (5c). Yellow oil. Rf (AcOEt/hexane 1:5) 0.41. IR
(neat): 1634, 1473, 1450. 1H-NMR (500 MHz, CDCl3): 3.99 (dt, J ¼ 6.9, 1.1, 2 H); 5.22 (dd, J ¼ 10.3, 1.1,
1 H); 5.40 (dd, J ¼ 13.2, 1.1, 1 H); 5.99 – 6.08 (m, 1 H); 7.22 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.40 (ddd, J ¼ 8.0,
7.4, 1.1, 1 H); 7.78 (dd, J ¼ 8.0, 1.1, 1 H); 7.88 (dd, J ¼ 8.0, 1.1, 1 H). 13C-NMR (125 MHz, CDCl3): 36.76;
119.20; 122.96; 124.25; 124.32; 126.13; 132.28; 138.24; 154.55; 167.64. MS: 255 (100, Mþ). Anal. calc. for
C10H9NSSe (254.21): C 47.25, H 3.57, N 5.51; found: C 47.08, H 3.66, N 5.38.
2-[(Phenylmethyl)sulfanyl]benzoselenazole (5d). Yellow oil. Rf (AcOEt/hexane 1:10) 0.61. IR
(neat): 1625, 1471, 1434. 1H-NMR (500 MHz, CDCl3): 4.59 (s, 2 H); 7.22 (dd, J ¼ 8.0, 7.4, 1 H); 7.28 (dd,
J ¼ 8.0, 7.4, 1 H); 7.33 (t, J ¼ 7.4, 2 H); 7.41 (t, J ¼ 7.4, 1 H); 7.46 (d, J ¼ 7.4, 2 H); 7.78 (d, J ¼ 8.0, 1 H); 7.91
(d, J ¼ 8.0, 1 H). 13C-NMR (125 MHz, CDCl3): 38.14; 122.94; 124.29; 124.34; 126.15; 127.72; 128.69;
129.16; 136.12; 138.28; 154.50; 167.79. MS: 305 (100, Mþ). Anal. calc. for C14H11NSSe (304.27): C 55.26, H
3.64, N 4.60; found: C 55.21, H 3.69, N 4.37.
5-Methyl-2-[(prop-2-en-1-yl)sulfanyl]benzoselenazole (5e). Yellow oil. Rf (AcOEt/hexane 1:5)
0.59. IR (neat): 1634, 1479, 1453. 1H-NMR (500 MHz, CDCl3): 2.42 (s, 3 H); 3.97 (d, J ¼ 6.9, 2 H); 5.21 (d,
J ¼ 9.9, 1 H); 5.39 (d, J ¼ 17.6, 1 H); 5.99 – 6.07 (m, 1 H); 7.20 (d, J ¼ 8.4, 1 H); 7.58 (s, 1 H); 7.76 (d, J ¼
8.4, 1 H). 13C-NMR (125 MHz, CDCl3): 21.26; 36.80; 119.12; 122.42; 124.23; 127.45; 132.36; 134.42;
138.36; 152.60; 166.19. MS: 269 (100, Mþ). Anal. calc. for C11H11NSSe (268.24): C 49.25, H 4.13, N 5.22;
found: C 49.07, H 4.15, N 5.13.
5-Chloro-2-(methylsulfanyl)benzoselenazole (5f). Pale-yellow solid. M.p. 81 – 838 (hexane/Et2O).
IR (KBr): 1628, 1477, 1444. 1H-NMR (500 MHz, CDCl3): 2.78 (s, 3 H); 7.36 (dd, J ¼ 8.8, 2.0, 1 H); 7.76 (d,
J ¼ 2.0, 1 H); 7.77 (d, J ¼ 8.8, 1 H). 13C-NMR (125 MHz, CDCl3): 16.72; 123.22; 123.86; 126.76; 129.88;
139.05; 153.36; 170.16. MS: 263 (100, Mþ). Anal. calc. for C8H6ClNSSe (262.62): C 36.59, H 2.30, N 5.33;
found: C 36.46, H 2.41, N 5.29.
S-(Benzoselenazol-2-yl) Thiobenzoate (6a). General Procedure. Compound 1a (0.21 g, 1.0 mmol) in
THF (4 ml) was treated with BuLi (1.0 mmol) and Se (79 mg, 1.0 mmol) in as described for the
preparation of 4. After 30 min, BzCl (0.14 g, 1.0 mmol) was added, and stirring was continued for an
additional 5 min. The resulting mixture was worked up as described for the preparation of 4, and the
residue was purified by CC (SiO2; AcOEt/hexane 1:10) to give 6a (0.18 g, 55%). Yellow solid. M.p. 120 –
1238 (Et2O/THF). IR (KBr): 1658, 1620, 1480, 1426. 1H-NMR (400 MHz, CDCl3): 7.37 (ddd, J ¼ 7.8, 7.3,
1.0, 1 H); 7.50 (ddd, J ¼ 7.8, 7.3, 1.0, 1 H); 7.57 (t, J ¼ 7.3, 2 H); 7.70 (tt, J ¼ 7.3, 1.4, 1 H); 8.00 (dd, J ¼ 7.8,
1.0, 1 H); 8.06 (dd, J ¼ 7.8, 1.0, 1 H); 8.08 (dd, J ¼ 7.3, 1.4, 2 H). 13C-NMR (100 MHz, CDCl3): 123.63;
125.19; 126.59; 127.51; 129.02; 129.65; 129.72; 134.76; 135.48; 149.74; 160.67; 187.32. MS: 319 (8.6, Mþ),
105 (100). Anal. calc. for C14H9NOSSe (318.25): C 52.84, H 2.85, N 4.40; found: C 52.60, H 2.95, N 4.34.
S-(Benzoselenazol-2-yl) 3-Methylthiobenzoate (6b). Pale-yellow solid. M.p. 111 – 1138 (hexane/
CHCl3). IR (KBr): 1657, 1602, 1480, 1422. 1H-NMR (400 MHz, CDCl3): 2.47 (s, 3 H); 7.37 (ddd, J ¼ 7.8,
7.3, 1.0, 1 H); 7.42 – 7.51 (m, 3 H); 7.87 – 7.88 (m, 2 H); 8.00 (d, J ¼ 7.8, 1 H); 8.06 (d, J ¼ 7.8, 1 H).
13C-NMR (100 MHz, CDCl3): 21.35; 124.01; 124.10; 124.86; 125.21; 126.31; 128.01; 129.04; 135.57; 135.59;
136.94; 139.23; 152.01; 160.88; 187.62. MS: 333 (8.5, Mþ), 119 (100). Anal. calc. for C15H11NOSSe
(332.28): C 54.22, H 3.34, N 4.22; found: C 54.06, H 3.62, N 4.16.
S-(Benzoselenazol-2-yl) Thiopropanoate (6c). White solid. M.p. 52 – 568 (hexane/Et2O). IR (KBr):
1702, 1460, 1429. 1H-NMR (500 MHz, CDCl3): 1.33 (t, J ¼ 7.4, 3 H); 2.86 (q, J ¼ 7.4, 2 H); 7.34 (dd, J ¼ 8.0,
7.4, 1 H); 7.47 (dd, J ¼ 8.0, 7.4, 1 H); 7.96 (d, J ¼ 8.0, 1 H); 8.02 (d, J ¼ 8.0, 1 H). 13C-NMR (100 MHz,

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CDCl3): 9.25; 37.71; 123.99; 124.07; 125.27; 126.28; 136.97; 151.77; 160.29; 195.76. MS: 270 (3.1, Mþ), 213
(100). Anal. calc. for C10H9NOSSe (270.21): C 44.45, H 3.36, N 4.22; found: C 44.46, H 3.27, N 4.11.
This work was supported in part by a Grant-in-Aid for Scientific Research (C) 22550035 from Japan
Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu of our university for recording
mass spectra and performing combustion analyses.
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Received January 9, 2012