One-pot synthesis of 2,3-disubstituted benzo[b]thiophene derivatives from 2-mercaptophenyl ketones

Article abstract of DOI:10.3987/COM-07-11262

2-Mercaptophenyl ketones have been found to react with activated alkyl bromides (BrCH₂EWG's), such as bromoacetates, bromoacetonitrile, and bromomethyl phenyl ketone, in the presence of two molar amounts of sodium hydride in THF at 0 °C to affo

Full text of DOI:10.3987/COM-07-11262

HETEROCYCLES, Vol. 75, No. 4, 2008
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HETEROCYCLES, Vol. 75, No. 4, 2008, pp. 919 - 924. © The Japan Institute of Heterocyclic Chemistry
Received, 9th November, 2007, Accepted, 17th December, 2007, Published online, 18th December, 2007. COM-07-11262
ONE-POT SYNTHESIS OF 2,3-DISUBSTITUTED BENZO[b]THIOPHENE
DERIVATIVES FROM 2-MERCAPTOPHENYL KETONES
Kazuhiro Kobayashi,* Daizo Nakamura, Shuhei Fukamachi, and Hisatoshi
Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101
Koyama-minami, Tottori 680-8552, Japan
Abstract - 2-Mercaptophenyl ketones have been found to react with activated alkyl
bromides (BrCH2EWG’s), such as bromoacetates, bromoacetonitrile, and
bromomethyl phenyl ketone, in the presence of two molar amounts of sodium
hydride in THF at 0 ˚C to afford 2,3-disubstituted benzo[b]thiophenes in generally
good to excellent yields.
The benzo[b]thiophene skeleton is found in many biologically active compounds.1 Accordingly, we2 and
others3 have been recently developing new methods for the preparation of this class of heterocycles. The
synthesis of 3-aminobenzo[b]thiophene derivatives by reactions of 2-mercaptobenzonitriles with
XCH2EWG’s (EWG = electron-withdrawing group) in the presence of an appropriate base has been
reported previously.4 2-Mercaptobenzaldehydes have been reported to give 2-substituted
benzo[b]thiophene derivatives under similar conditions.5 However, the use of 2-mercaptophenyl ketones
for the preparation of 2,3-disubstituted benzo[b]thiophenes has been extremely limited. The synthesis of
3-methyl-2-pivaloylbenzo[b]thiophene by treating 2-mercaptophenyl methyl ketone with bromomethyl
t-butyl ketone in the presence of cesium carbonate at 70 ˚C for 3 d has been reported by Shen and
Doherty.6 We reasoned that preparation of 2,3-disubstituted benzo[b]thiophene derivatives under milder
reaction conditions would be achieved by reactions of 2-mercaptophenyl ketones with BrCH2EWG’s
using an appropriate base. We have found that 2,3-disubstituted benzo[b]thiophene derivatives (2) can be
prepared by treating 2-mercaptophenyl ketones (1) with BrCH2EWG’s in the presence of two molar
amounts of sodium hydride at 0 ˚C.
Our one-pot synthesis of 2,3-disubstituted benzo[b]thiophenes (2) from 2-mercaptophenyl ketones (1),
which were readily prepared by treatment of 2-mercaptobenzoic acid with appropriate organolithiums,
was conducted as illustrated in Scheme 1. Thus, treatment of the starting mercapto ketones (1) with an
equimolar amount of sodium hydride in THF at 0 ˚C was followed by addition of activated alkyl
bromides, such as bromoacetates, bromoacetonitrile, and bromomethyl phenyl ketone. The mixture was
then subjected to further treatment with an additional equimolar amount of sodium hydride at the same

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HETEROCYCLES, Vol. 75, No. 4, 2008
temperature. The usual aqueous workup and subsequent purification by preparative TLC on silica gel
afforded the desired products (2). The results using five 2-mercaptophenyl ketones and four
BrCH2EWG’s are summarized in Table 1, which indicates that the yields are generally good to excellent.
The lower yield of the product (2b) may be ascribed to the liability of the methoxycarbonyl function to
saponification with sodium hydroxide, generated in the reaction mixture.
1. NaH, THF, 0 ˚C
2. BrCH2EWG, 0 ˚C
3. NaH, 0 ˚C
SH
S
EWG
R
R
O
1
2
Scheme 1
Table 1: Preparation of 2,3-Disubstituted Benzo[b]thiophenes (2)
Entry
1
1a (R = n-Bu)
1a
1a
1a
1b (R = t-Bu)
1b
1c (R = Ph)
1d (R = 4-ClC6H4)
1d
1d
1e (R = 4-MeOC6H4)
EWG
CO2t-Bu
CO2Me
CN
COPh
CO2t-Bu
CN
CN
CO2t-Bu
CN
COPh
CO2t-Bu
2 (Yield/%)a
1
2
3
4
5
6
7
8
9
10
2a (86)
2b (40)
2c (95)
2d (99)
2e (76)
2f (71)
2g (82)
2h (83)
2i (87)
2j (91)
2k (75)
11
aIsolated yields.
The further treatment with sodium hydride proved to be essential for the satisfactory production of 2.
For example, the treatment of 1c with bromoacetonitrile in the presence of an equimolar amount of
sodium hydride resulted in the formation of the desired (2g) in 29% yield, accompanied by
3-hydroxy-3-phenyl-2,3-dihydrobenzo[b]thiophene-2-carbonitrile (3) in 49% yield, even at an elevated
temperature and after a prolonged reaction time (see Experimental), as shown in Scheme 2. Although
compound 3 was shown to be one of the possible two diastereomers, its explicit stereochemistry could
not been determined.
In summary, we have shown that the reaction of 2-mercaptophenyl ketones with activated alkyl
bromides, such as bromoacetates, bromoacetonitrile, and bromomethyl phenyl ketone, in the presence of
sodium hydride gives 2,3-disubstituted benzo[b]thiophene derivatives. This preparation may be of value
in heterocyclic synthesis because of the ready availability of the starting materials as well as simple

HETEROCYCLES, Vol. 75, No. 4, 2008
921
manipulations.
1. NaH, THF, 0 ˚C
2. BrCH2CN, 0 ˚C to rt
S
CN
OH
1c
2g
+
Ph
3
Scheme 2
EXPERIMENTAL
The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus
1
and are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. The H
NMR spectra were determined in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT
NMR spectrometer operating at 500 MHz. J values are given in Hz. Low-resolution mass spectra (EI)
were recorded on a JEOL JMS-AX505 HA spectrometer. Thin-layer chromatography (TLC) was carried
out on Merck Kieselgel 60 PF254.
Starting Materials. 2-Mercaptophenyl ketones (1a),2 (1b),2 (1c),7 (1d),8 and (1e)8 were prepared by the
appropriate reported procedures. All other chemicals used in this study were commercially available.
Typical Procedure for the Preparation of 2,3-Disubstituted Benzo[b]thiophene Derivatives (2).
1,1-Dimethylethyl 3-Butylbenzo[b]thiophene-2-carboxylate (2a). To a stirred suspension of NaH
(60% in oil; 68 mg, 1.7 mmol) in THF (5 mL) at 0 ˚C was added a solution of 1a (0.34 g, 1.7 mmol) in
THF (2 mL). After 15 min, 1,1-dimethylethyl bromoacetate (0.33 g, 1.7 mmol) was added, and stirring
was continued for additional 30 min at the same temperature. The resulting mixture was then treated
with the second portion of NaH (60% in oil; 68 mg, 1.7 mmol) and further stirred for 30 min before
saturated aqueous NH4Cl (10 mL) was added. The resulting mixture was extracted with Et2O three times
(10 mL each), and the combined extracts were washed with brine and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was purified by preparative TLC on silica gel to give
1
2a (0.39 g, 86%); a colorless oil; Rf 0.82 (1:3 AcOEt–hexane); IR (neat) 3061, 1709 cm–1; H NMR δ
0.96 (3H, t, J 7.3), 1.46 (2H, sextet, J 7.3), 1.61–1.68 (11H, m including s at 1.62), 3.25 (2H, t, J 7.8),
7.39 (1H, ddd, J 7.8, 7.3, 1.4), 7.43 (1H, ddd, J 7.8, 7.3, 1.4), 7.80–7.83 (2H, m); MS m/z 290 (M+, 29),
234 (100). Anal. Calcd for C17H22O2S: C, 70.31; H, 7.64. Found: C, 70.28; H, 7.75.
Methyl 3-Butylbenzo[b]thiophene-2-carboxylate (2b): a colorless oil; Rf 0.60 (1:5 Et2O–hexane); IR
(neat) 3061, 1715 cm–1; 1H NMR δ 0.96 (3H, t, J 7.3), 1.47 (2H, sextet, J 7.3), 1.62–1.69 (2H, m), 3.30
(2H, t, J 7.8), 3.93 (3H, s), 7.42 (1H, ddd, J 8.2, 6.9, 0.9), 7.46 (1H, ddd, J 8.2, 6.9, 1.4), 7.83–7.87 (2H,
m); MS m/z 248 (M+, 85), 206 (100). Anal. Calcd for C14H16O2S: C, 67.71; H, 6.49. Found: C, 67.54; H,
6.51.

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3-Butylbenzo[b]thiophene-2-carbonitrile (2c): a yellow oil; Rf 0.64 (1:5 AcOEt–hexane); IR (neat)
3061, 2214 cm–1; 1H NMR δ 0.97 (3H, t, J 7.3), 1.45 (2H, sextet, J 7.3), 1.69–1.77 (2H, m), 3.08 (2H, t,
J 7.8), 7.48 (1H, ddd, J 7.8, 7.3, 1.4), 7.52 (1H, ddd, J 7.8, 7.3, 1.4), 7.84 (2H, dd, J 7.8, 1.4); MS m/z
215 (M+, 35), 172 (100). Anal. Calcd for C13H13NS: C, 72.52; H, 6.09; N, 6.51. Found: C, 72.26; H,
6.10; N, 6.30.
(3-Butylbenzo[b]thiophen-2-yl)(phenyl)methanone (2d): a yellow oil; Rf 0.51 (1:5 AcOEt–hexane);
1
IR (neat) 3059, 1643 cm–1; H NMR δ 0.90 (3H, t, J 7.3), 1.38 (2H, sextet, J 7.3), 1.63–1.69 (2H, m),
3.09 (2H, t, J 7.8), 7.44–7.50 (4H, m), 7.60 (1H, tt, J 7.3, 1.4), 7.85 (1H, dd, J 7.3, 1.4), 7.88–7.91 (3H,
m); MS m/z 294 (M+, 27), 251 (100). Anal. Calcd for C19H18OS: C, 77.51; H, 6.16. Found: C, 77.33; H,
6.21.
1,1-Dimethylethyl 3-(1,1-Dimethylethyl)benzo[b]thiophene-2-carboxylate (2e): white powder; mp
1
123–125 ˚C (hexane–Et2O); IR (KBr disk) 3063, 1722 cm–1; H NMR δ 1.06 (9H, s), 1.44 (9H, s),
7.08–7.11 (2H, m), 7.21 (1H, ddd, J 7.8, 7.3, 1.4), 7.26 (1H, dd, J 7.8, 1.4); MS m/z 290 (M+, 26), 234
(100). Anal. Calcd for C17H22O2S: C, 70.31; H, 7.64. Found: C, 70.30; H, 7.69.
3-(1,1-Dimethylethyl)benzo[b]thiophene-2-carbonitrile (2f): pale-yellow powder; mp 72–74 ˚C
(hexane–Et2O); IR (KBr disk) 3060, 2208 cm–1; 1H NMR δ 1.70 (9H, s), 7.43 (1H, ddd, J 8.2, 7.3, 1.4),
7.48 (1H, ddd, J 8.2, 7.3, 1.4), 7.81 (1H, d, J 8.2), 8.19 (1H, d, J 8.2); MS m/z 215 (M+, 29), 200 (100).
Anal. Calcd for C13H13NS: C, 72.52; H, 6.09; N, 6.51. Found: C, 72.39; H, 6.26; N, 6.68.
3-Phenylbenzo[b]thiophene-2-carbonitrile (2g): white powder; mp 79–81 ˚C (hexane–Et2O) (lit.,9
78–81 ˚C). The IR and 1H NMR data for this product were identical to those reported previously.9
1,1-Dimethylethyl 3-(4-Chlorophenyl)benzo[b]thiophene-2-carboxylate (2h): white powder; mp
148–150 ˚C (hexane–Et2O); IR (KBr disk) 3061, 1690 cm–1; 1H NMR δ 1.40 (9H, s), 7.32 (2H, d, J 8.2),
7.34 (1H, ddd, J 7.8, 7.3, 1.4), 7.45–7.48 (4H, m), 7.87 (1H, dd, J 7.8, 1.4); MS m/z 344 (M+, 23), 288
(100). Anal. Calcd for C19H17ClO2S: C, 66.17; H, 4.97. Found: C, 66.14; H, 4.99.
3-(4-Chlorophenyl)benzo[b]thiophene-2-carbonitrile (2i): white powder; mp 162–163 ˚C
(hexane–Et2O); IR (KBr disk) 3072, 2216 cm–1; 1H NMR δ 7.49 (1H, dd, J 8.2, 7.3), 7.54–7.60 (5H, m),
7.81 (1H, d, J 8.2), 7.91 (1H, d, J 8.2); MS m/z 269 (M+, 100). Anal. Calcd for C15H8ClNS: C, 66.79; H,
2.99; N, 5.19. Found: C, 66.64; H, 2.93; N, 5.05.
[3-(4-Chlorophenyl)benzo[b]thiophen-2-yl](phenyl)methanone (2j): pale-yellow powder; mp 89–91
1
˚C (hexane–Et2O); IR (KBr disk) 3061, 1645 cm–1; H NMR δ 7.21–7.24 (6H, m), 7.40 (1H, t, J 7.3),
7.43 (1H, dd, J 8.2, 7.3), 7.52 (1H, dd, J 8.2, 7.3), 7.63 (2H, dd, J 8.2, 0.9), 7.71 (1H, d, J 8.2), 7.95 (1H,
d, J 8.2); MS m/z 348 (M+, 100). Anal. Calcd for C21H13ClOS: C, 72.30; H, 3.76; S, 9.19. Found: C,
72.23; H, 3.88; S, 9.46.
1,1-Dimethylethyl 3-(4-Methoxyphenyl)benzo[b]thiophene-2-carboxylate (2k): white powder; mp
121–123 ˚C (hexane–Et2O); IR (KBr disk) 3061, 1713 cm–1; 1H NMR δ 1.40 (9H, s), 3.88 (3H, s), 7.01

HETEROCYCLES, Vol. 75, No. 4, 2008
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(2H, d, J 8.7), 7.30–7.34 (3H, m), 7.44 (1H, dd, J 8.2, 7.3), 7.52 (1H, d, J 8.2), 7.85 (1H, d, J 8.2); MS
m/z 340 (M+, 29), 284 (100). Anal. Calcd for C20H20O2S: C, 70.56; H, 5.92; S, 9.42. Found: C, 70.55; H,
5.97; S, 9.59.
Reaction of 1c with BrCH2CN in the Presence of an Equimolar Amount of NaH. To a stirred
suspension of NaH (60% in oil; 0.12 g, 2.9 mmol) in THF (5 mL) at 0 ˚C was added dropwise a solution
of 1d (0.63 g, 2.9 mmol) in THF (3 mL). After 15 min, BrCH2CN (0.35g, 2.9 mmol) was added, and the
temperature was allowed to warm to rt; stirring was continued overnight. The reaction mixture was
worked up in a manner similar to that described for the preparation of 2a, and the crude product was
purified by preparative TLC on silica gel to give 2g (0.20 g, 29%), along with
3-hydroxy-3-phenyl-2,3-dihydrobenzo[b]thiophene-2-carbonitrile (3) (0.36 g, 49%): white powder; mp
122–124 ˚C (hexane–Et2O); IR (KBr disk) 3417, 2249 cm–1; 1H NMR δ 2.99 (1H, s), 4.65 (1H, s), 7.06
(1H, dd, J 7.8, 0.9), 7.20 (1H, ddd, J 7.8, 7.3, 0.9), 7.33 (1H, J 7.8), 7.38 (1H, ddd, J 7.8, 7.3, 0.9),
7.40–7.44 (3H, m), 7.52 (2H, dd, J 7.8, 1.8). C15H11NOS: C, 71.12; H, 4.38; N, 5.53. Found: C, 70.92; H,
4.47; N, 5.33.
ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of this Faculty for determining mass spectra and performing
combustion analyses.
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