Synthesis of 3-substituted benzo[b]thiophenes via the reaction of α-substituted 2-lithio-β-methoxystyrenes with sulfur

Article abstract of DOI:10.3987/COM-10-11970

3-Substitued benzo[b]thiophenes were synthesized in reasonable overall yields from α-substituted 2-bromo-β-methoxystyrenes. Thus, the bromine-lithium exchange between these bromostyrenes with butyllithium in diethyl ether at 0 °C followed by reaction with sulfur afforded the corresponding a-substituted β-methoxy-2-sulfanylstyrenes. These were then treated with an equimolar amount of concentrated hydriodic acid in acetonitrile at room temperature to give the desired products. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-11970

HETEROCYCLES, Vol. 81, No. 7, 2010
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HETEROCYCLES, Vol. 81, No. 7, 2010, pp. 1703 - 1709. © The Japan Institute of Heterocyclic Chemistry
Received, 7th May, 2010, Accepted, 31st May, 2010, Published online, 31st May, 2010
DOI: 10.3987/COM-10-11970
SYNTHESIS OF 3-SUBSTITUTED BENZO[b]THIOPHENES VIA THE
REACTION OF ꢀ-SUBSTITUTED 2-LITHIO-ꢁ-METHOXYSTYRENES
WITH SULFUR
Kazuhiro Kobayashi,* Daisuke Nakai, Shuhei Fukamachi, and Hisatoshi
Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology,
Graduate School of Engineering, Tottori University, 4-101 Koyama-minami,
Tottori 680-8552, Japan; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract – 3-Substitued benzo[b]thiophenes were synthesized in reasonable
overall yields from ꢀ-substituted 2-bromo-ꢁ-methoxystyrenes. Thus, the
bromine-lithium exchange between these bromostyrenes with butyllithium in
diethyl ether at 0 ˚C followed by reaction with sulfur afforded the corresponding
ꢀ-substituted ꢁ-methoxy-2-sulfanylstyrenes. These were then treated with an
equimolar amount of concentrated hydriodic acid in acetonitrile at room
temperature to give the desired products.
The hydriodic acid-catalyzed or -mediated cyclization of ꢁ-methoxystyrene derivatives carrying an
appropriate functional group at the o-position has been successfully employed by us for the synthesis of
several benzene-fused heterocyclic compounds.1 On the other hand, compounds having the
benzo[b]thiophene skeleton have held considerable interest not only for organic chemists, but also for
medicinal chemists, because of their useful biological activities.2 Accordingly, a number of efficient
methods for the preparation of this class of heterocycles have recently been reported.3 As contribution
from our laboratory, we have recently reported four convenient methods starting mainly from
2-sulfanylphenyl ketones and related compounds.4 We now wish to report a new method for the
preparation of 3-substituted benzo[b]thiophenes (3) starting from ꢀ-substituted 2-bromo-ꢁ-
methoxystyrenes (1), which are easily prepared from readily available starting materials according to the
previously reported methods.1,5-7
Our two-step synthesis of 3-substituted benzo[b]thiophenes (3) was performed as illustrated in Scheme 1.
The ꢀ-substituted 2-lithio-ꢁ-methoxystyrenes were first generated by the bromine-lithium exchange
between 1 and butyllithium in diethyl ether at 0 ˚C. These lithium compounds were allowed to react with
sulfur to give, after the usual aqueous workup, the corresponding ꢀ-substituted ꢁ-methoxy-2-

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sulfanylstyrenes (2), which were then immediately subjected, without any purification, to treatment with
concentrated hydriodic acid. Thus, the solutions of 2 in acetonitrile were bubbled with argon gas to
remove oxygen gas, which may cause the oxidation of 2 to the corresponding disulfides, and then were
treated with an equimolar amount of concentrated hydriodic acid at room temperature for 1 h. After the
usual aqueous workup the resulting crude products were purified by preparative TLC on silica gel to
afford the desired products in reasonable overall isolated yields from 1, as summarized in Scheme 1.
R3
Br
R3
R3
R1
R2
R1
R2
OMe
R1
R2
OMe
conc. HI, MeCN, rt
1) n-BuLi, Et2O, 0 ˚C
2) S, 0 ˚C, 3) H3O+
S
SH
1
2
3a R1 = R2 = H, R3 = Me 34%
3b R1 = R2 = H, R3 = Ph 41%
3c R1 = R2 = H, R3 = 4-t-BuC6H4 44%
3d R1 = R2 = H, R3 = 4-MeOC6H4 46%
3e R1 = OMe, R2 = H, R3 = 3,4-Xylyl 37%
3f R1 = H, R2 = OMe, R3 = m-Tol 45%
3g R1 = H, R2 = OMe, R3 = p-Tol 45%
Scheme 1
When the cyclization reactions were carried out using a catalytic amount (0.2–0.5 equiv) of concentrated
hydriodic acid under similar reaction conditions, they proceeded sluggishly and did not complete even
after extended reaction times. Although the preparation of chlorine substituted 3-arylbenzo[b]thiophenes
was attempted using ꢀ-aryl-2-bromo-ꢁ-methoxystyrenes carrying a chloro substituent in either of the
benzene nuclei as substrates under the same conditions, only trace amounts of the desired products were
obtained as mixtures with other products, whose structure could not be established, as judged by 1H NMR
spectra. We may ascribe this poor result to the decrease of reactivity towards the present acid catalyzed
cyclization due to the electron-withdrawing group.
In summary, we have demonstrated that the reaction of ꢀ-substituted 2-lithio-ꢁ-methoxystyrenes with
sulfur, followed by hydriodic acid mediated cyclization of the resulting ꢀ-substituted
ꢁ-methoxy-2-sulfanylstyrenes provides a new and convenient method for the preparation of 3-substituted
benzo[b]thiophenes. Although yields of the products are moderate, the present method may prove useful
in organic synthesis because of some advantages; it employs readily available starting materials and is
experimentally simple, and the sulfur source is inexpensive. Applications of the reaction of 2-lithiostyrene
derivatives with sulfur to the preparation of other heterocyclic compounds are now in progress in our
laboratory.

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EXPERIMENTAL
The melting point of (2-bromo-5-methoxyphenyl)(3,4-dimethylphenyl)methanone was obtained on a
Laboratory Devices MEL-TEMP II melting apparatus and is uncorrected. IR spectra were determined
1
with a Shimadzu FTIR-8300 spectrophotometer. 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 or a
13
JEOL LA400 FT NMR spectrometer operating at 400 MHz. The C NMR spectra were determined in
CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125
MHz. Low-resolution MS spectra (EI, 70 eV) m were measured by a JEOL JMS AX505 HA spectrometer.
TLC was carried out on a Merck Kieselgel 60 PF254. Column chromatography was performed using
Merck Kieselgel 60 (0.063–0.200 mm). All of the organic solvents used in this study were dried over
appropriate drying agents and distilled prior to use.
Starting Materials. 2-Bromo-ꢀ-(methoxyvinyl)styrenes (1a),5 (1b),6 (1c),7 (1d),7 2-bromo-5-
methoxybenzaldehyde,8 and 2-bromo-4-methoxybenzaldehyde9 were prepared by previously reported
appropriate methods.
Aryl(2-bromophenyl)methanols. These compounds were prepared by reacting the respective
2-bromobenzaldehydes with the appropriate arylmagnesium bromides in THF at 0 ˚C.
(2-Bromo-5-methoxyphenyl)(3,4-dimethylphenyl)methanol: 89% yield; a pale-yellow oil; Rf 0.22 (1:5
Et2O–hexane); IR (neat) 3397 cm–1; 1H NMR (500 MHz) ꢁ 2.23 (s, 3H), 2.24 (s, 3H), 2.25 (d, J = 3.7 Hz,
1H), 3.80 (s, 3H), 6.06 (d, J = 3.7 Hz, 1H), 6.71 (dd, J = 8.7, 2.7 Hz, 1H), 7.08–7.11 (m, 2H), 7.16 (s, 1H),
7.21 (d, J = 2.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H). Anal. Calcd for C16H17BrO2: C, 59.83; H, 5.33. Found:
C, 59.72; H, 5.39.
(2-Bromo-4-methoxyphenyl)(3-methylphenyl)methanol: 93% yield; a yellow oil; Rf 0.85 (1:5
1
Et2O–hexane); IR (neat) 3391, 1605 cm–1; H NMR (400 MHz) ꢁ 2.27 (d, J = 3.6 Hz, 1H), 2.33 (s, 3H),
3.78 (s, 3H), 6.13 (d, J = 3.6 Hz, 1H), 6.87 (dd, J = 8.4, 2.6 Hz, 1H), 7.07–7.10 (m, 2H), 7.16–7.24 (m,
3H), 7.40 (d, J = 8.4 Hz, 1H). Anal. Calcd for C15H15BrO2: C, 58.65; H, 4.92. Found: C, 58.41; H, 5.01.
(2-Bromo-4-methoxyphenyl)(4-methylphenyl)methanol: 92% yield; a pale-yellow oil; Rf 0.35 (1:5
1
THF–hexane); IR (neat) 3383, 1605 cm–1; H NMR (500 MHz) ꢁ 2.24 (d, J = 4.1 Hz, 1H), 2.33 (s, 3H),
3.79 (s, 3H), 6.12 (d, J = 4.1 Hz, 1H), 6.87 (dd, J = 8.7, 2.3 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.14 (d, J =
8.7 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H). Anal. Calcd for C15H15BrO2: C, 58.65; H,
4.92. Found: C, 58.43; H, 4.97.
Aryl(2-bromophenyl)methanones. These compounds were prepared by the PCC oxidation of the above
alcohols in CH2Cl2 at rt.
(2-Bromo-5-methoxyphenyl)(3,4-dimethylphenyl)methanone: 73% yield; a pale-yellow solid; mp
1
85–86 ˚C (hexane–Et2O); IR (KBr) 1659, 1601 cm–1; H NMR (500 MHz) ꢁ 2.31 (s, 3H), 2.33 (s, 3H),
3.80 (s, 3H), 6.85 (d, J = 3.2 Hz, 1H), 6.89 (dd, J = 9.2, 3.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.47–7.52

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(m, 2H), 7.65 (s, 1H). Anal. Calcd for C16H15BrO2: C, 60.21; H, 4.74. Found: C, 60.18; H, 4.85.
(2-Bromo-4-methoxyphenyl)(3-methylphenyl)methanone: 81% yield; a pale-yellow oil; Rf 0.11 (1:10
Et2O–hexane); IR (neat) 1668, 1599 cm–1; 1H NMR (500 MHz) ꢀ 2.40 (s, 3H), 3.87 (s, 3H), 6.92 (dd, J =
8.7, 2.3 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.40 (d, J =
7.3 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.64 (s, 1H). Anal. Calcd for C15H13BrO2: C, 59.04; H, 4.29. Found:
C, 59.01; H, 4.28.
(2-Bromo-4-methoxyphenyl)(4-methylphenyl)methanone: 53% yield; a pale-yellow oil; Rf 0.32 (1:4
C6H6–hexane); IR (neat) 1667, 1605 cm–1; 1H NMR (500 MHz) ꢀ 2.43 (s, 3H), 3.86 (s, 3H), 6.92 (dd, J =
8.7, 2.3 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.71 (d, J =
8.2 Hz, 2H). Anal. Calcd for C15H13BrO2: C, 59.04; H, 4.29. Found: C, 58.95; H, 4.50.
1-Bromo-2-(1-aryl-2-methoxyethenyl)benzenes 1e-g. These compounds were prepared by reacting the
above ketones with (methoxymethylene)triphenylphosphorane in THF at 0 ˚C in a manner similar to that
for the preparation of 1a-d.5-7
1-Bromo-4-methoxy-2-[2-methoxy-1-(3,4-dimethylphenyl)ethenyl]benzene (1e): 61% yield as a
mixture of stereoisomers (E:Z = ca. 6:4). The analytical specimen of each isomer was obtained by
fractional column chromatography on silica gel. E-1e: a colorless oil; Rf 0.32 (1:3 CH2Cl2–hexane); IR
(neat) 1643 cm–1; 1H NMR (400 MHz) ꢀ 2.13 (s, 3H), 2.14 (s, 3H), 3.71 (s, 3H), 3.72 (s, 3H), 6.12 (s, 1H),
6.66 (dd, J = 8.7, 3.2 Hz, 1H), 6.79 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz,
1H), 7.11 (s, 1H), 7.38 (d, J = 8.7 Hz, 1H). Anal. Calcd for C18H19BrO2: C, 62.26; H, 5.52. Found: C,
1
62.13; H, 5.66. Z-1e: a colorless oil; Rf 0.21 (1:3 CH2Cl2–hexane); IR (neat) 1634 cm–1; H NMR (400
MHz) ꢀ 2.20 (s, 3H), 2.21 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 6.61 (s, 1H), 6.73 (dd, J = 8.7, 2.6 Hz, 1H),
6.77 (d, J = 2.6 Hz, 1H), 6.84 (dd, J = 7.7, 2.2 Hz, 1H), 6.92 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 7.44 (d, J =
8.7 Hz, 1H). Anal. Calcd for C18H19BrO2: C, 62.26; H, 5.52. Found: C, 61.98; H, 5.53.
1-Bromo-5-methoxy-2-[2-methoxy-1-(3-methylphenyl)ethenyl]benzene (1f): 66% yield as a mixture of
stereoisomers (E:Z = ca. 6:4). The analytical specimen of each isomer was obtained by fractional column
chromatography on silica gel. E-1f: a pale-yellow oil; Rf 0.29 (1:10 CH2Cl2–hexane); IR (neat) 1634,
1601 cm–1; 1H NMR (500 MHz) ꢀ 2.29 (s, 3H), 3.72 (s, 3H), 3.80 (s, 3H), 6.64 (s, 1H), 6.88 (dd, J = 8.2,
2.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.94 (s, 1H), 6.98 (d, J = 7.8 Hz, 1H), 7.128 (t, J = 7.8 Hz, 1H),
7.132 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H). Anal. Calcd for C17H17BrO2: C, 61.28; H, 5.14. Found:
1
C, 61.25; H, 5.34. Z-1f: a pale-yellow oil; Rf 0.14 (1:10 CH2Cl2–hexane); IR (neat) 1645, 1601 cm–1; H
NMR (500 MHz) ꢀ 2.29 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 6.20 (s, 1H), 6.85 (dd, J = 8.2, 2.7 Hz, 1H),
6.97 (d, J = 7.8 Hz, 1H), 7.14–7.16 (m, 3H), 7.20 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H). Anal. Calcd for
C17H17BrO2: C, 61.28; H, 5.14. Found: C, 61.25; H, 5.14.
1-Bromo-5-methoxy-2-[2-methoxy-1-(4-methylphenyl)ethenyl]benzene (1g): 48% yield as a mixture
of stereoisomers (E:Z = ca. 6:4). The analytical specimen of each isomer was obtained by fractional

HETEROCYCLES, Vol. 81, No. 7, 2010
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column chromatography on silica gel. E-1g: a pale-yellow oil; Rf 0.20 (1:5 CH2Cl2–hexane); IR (neat)
1634 cm–1; 1H NMR (500 MHz) ꢀ 2.31 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 6.18 (s, 1H), 6.85 (dd, J = 8.7,
2.7 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.2
Hz, 2H). Anal. Calcd for C17H17BrO2: C, 61.28; H, 5.14. Found: C, 61.24; H, 5.37. Z-1g: a pale-yellow
oil; Rf 0.08 (1:5 CH2Cl2–hexane); IR (neat) 1643, 1601 cm–1; 1H NMR (500 MHz) ꢀ 2.23 (s, 3H), 3.64 (s,
3H), 3.73 (s, 3H), 6.54 (s, 1H), 6.80 (dd, J = 8.7, 2.7 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz,
2H), 7.06 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H). Anal. Calcd for C17H17BrO2: C, 61.28; H, 5.14.
Found: C, 61.09; H, 5.13.
Typical Procedure for the Preparation of Benzo[b]thiophenes (3). 3-Methylbenzo[b]thiophene (3a).
To a stirred solution of 1a (0.22 g, 0.95 mmol) in Et2O (5 mL) at 0 ˚C was added n-BuLi (1.6 M solution
in hexane; 1.05 mmol) dropwise. After 1 h sulfur (34 mg, 1.05 mmol) was added, and the mixture was
stirred for an additional 10 min at the same temperature. Et2O (10 mL), saturated aqueous NH4Cl (5 mL)
and water (5 mL) were added. The layers were separated and the aqueous layer was extracted with Et2O
twice (10 mL each). The combined extracts were washed with brine and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was dissolved in MeCN (3 mL). After Ar gas was
bubbled through this solution for 5 min, concentrated HI (0.21 g, 0.95 mmol) was added and the mixture
was stirred at rt for 1 h. Saturated aqueous NaHCO3 (15 mL) was added, and the organic materials were
extracted with Et2O three times (10 mL each). The combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated by evaporation. The residue was purified by preparative TLC on
silica gel to give 3a (48 mg, 34%); a pale-yellow oil; Rf 0.72 (1:2 CH2Cl2–hexane). The spectral data of
this product were identical to those reported previously.10
3-Phenylbenzo[b]thiophene (3b): a pale-yellow oil; Rf 0.50 (1:20 CH2Cl2–hexane). The spectral data of
this product were identical to those reported previously.10
3-(4-t-Butylphenyl)benzo[b]thiophene (3c): a pale-yellow oil; Rf 0.52 (hexane); IR (neat) 3065 cm–1; 1H
NMR (500 MHz) ꢀ 1.39 (s, 9H), 7.36–7.40 (m, 3H), 7.50 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H),
13
7.90–7.96 (m, 2H); C NMR ꢀ 31.38, 34.64, 122.88, 123.01, 123.06, 124.21, 124.31, 125.63, 128.35,
133.11, 138.00, 138.02, 140.69, 150.51; MS m/z 266 (M+, 63), 251 (100). Anal. Calcd for C18H18S: C,
81.15; H, 6.81. Found: C, 80.96; H, 6.81.
3-(4-Methoxyphenyl)benzo[b]thiophene (3d): a pale-yellow oil; Rf 0.49 (1:10 AcOEt–hexane). The
spectral data of this product were identical to those reported previously.8
3-(3,4-Dimethylphenyl)-5-methoxybenzo[b]thiophene (3e): a pale-yellow oil; Rf 0.36 (1:10
CH2Cl2–hexane); IR (neat) 3013 cm–1; 1H NMR (500 MHz) ꢀ 2.34 (s, 6H), 3.83 (s, 3H), 7.03 (dd, J = 8.7,
2.3 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.35–7.37 (m, 3H), 7.76 (d, J = 8,7 Hz,
13
1H); C NMR ꢀ 19.54, 19.88, 55.61, 105.40, 114.50, 123.46, 124.20, 125.90, 129.83, 130.01, 133.06,
133.72, 135.97, 137.02, 137.86, 139.15, 157.66; MS m/z 268 (M+, 100). Anal. Calcd for C17H16OS: C,

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76.08; H, 6.01. Found: C, 75.92; H, 6.07.
6-Methoxy-3-(3-methylphenyl)benzo[b]thiophene (3f): a yellow oil; Rf 0.44 (1:3 CH2Cl2–hexane); IR
(neat) 3096, 1603 cm–1; 1H NMR (500 MHz) ꢀ 2.43 (s, 3H), 3.86 (s, 3H), 7.01 (dd, J = 8.7, 2.7 Hz, 1H),
13
7.20 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.36–7.39 (m, 4H), 7.78 (d, J = 8.7 Hz, 1H); C NMR ꢀ 21.49,
55.63, 105.22, 114.38, 120.53, 123.62, 125.67, 128.25, 128.58, 129.30, 132.12, 136.09, 137.85, 138.35,
142.11, 154.25; MS m/z 254 (M+, 100). Anal. Calcd for C16H14OS: C, 75.55; H, 5.55. Found: C, 75.58; H,
5.78.
6-Methoxy-3-(4-methylphenyl)benzo[b]thiophene (3g): a colorless oil; Rf 0.24 (hexane); IR (neat) 3102,
1603 cm–1; 1H NMR (500 MHz) ꢀ 2.42 (s, 3H), 3.88 (s, 3H), 7.00 (dd, J = 9.2, 2.7 Hz, 1H), 7.17 (s, 1H),
7.20 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 9.2 Hz, 1H); 13C
NMR ꢀ 21.22, 55.61, 105.23, 114.34, 120.23, 123.58, 128.44, 129.38, 132.15, 133.25, 137.24, 137.68,
142.11, 157.47; MS m/z 254 (M+, 100). Anal. Calcd for C16H14OS: C, 75.55; H, 5.55. Found: C, 75.80; H,
5.50.
ACKNOWLEDGEMENT
We are grateful to Mrs. Miyuki Tanmatsu of this university for determining mass spectra and performing
combustion analyses.
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