Synthesis of benzo[b]thiophenes by cyclization of arylketene dithioacetal monoxides under pummerer-like conditions

Article abstract of DOI:10.1021/ol702643j

Treatment of arylketene bis(methylthio)acetal monoxide with trifiuoromethanesulfonic anhydride leads to ring-closure to afford 2-methylthiobenzo-[b]thiophene in high yield. The reaction is useful for synthesizing multisubstituted benzo[b]thiophenes.

Full text of DOI:10.1021/ol702643j

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5573-5576
Synthesis of Benzo[b]thiophenes by
Cyclization of Arylketene Dithioacetal
Monoxides under Pummerer-like
Conditions
Suguru Yoshida, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received October 18, 2007
ABSTRACT
Treatment of arylketene bis(methylthio)acetal monoxide with trifluoromethanesulfonic anhydride leads to ring-closure to afford 2-methylthiobenzo-
[b]thiophene in high yield. The reaction is useful for synthesizing multisubstituted benzo[b]thiophenes.
The benzo[b]thiophene skeleton is a ubiquitous structure
found in various compounds ranging from biologically
intriguing molecules1 to advanced organic materials.2 Con-
struction of the benzo[b]thiophene skeleton is hence impor-
tant. There are several representative methods for the
construction, most of which employ benzenethiol derivatives
as the starting materials.3,4 However, methods for synthesis
of multisubstituted benzo[b]thiophenes are still limited, and
hence have to be explored.
We have been interested in ketene dithioacetal monoxides
as interesting synthetic intermediates.5 Here we report a new
approach to benzo[b]thiophenes starting from ketene dithio-
acetal monoxides. Our idea is outlined in Scheme 1.
Treatment of aryl-substituted ketene dithioacetal monoxide
1 with an oxophilic electrophile would result in cleavage of
the oxygen-sulfur bond with concomitant Friedel-Crafts-
type electrophilic aromatic substitution to yield 4. Removal
of the methyl group on the cationic sulfur would afford
3-substituted 2-(methylthio)benzo[b]thiophene 5. The syn-
thesis of the starting material 1 was facile and scalable,
starting from aryl ketone and formaldehyde dimethyl dithio-
acetal S-oxide (FAMSO) in 3 steps.6 Thus, our approach to
(1) Selected examples: (a) Graham, S. L.; Shepard, K. L.; Anderson, P.
S.; Baldwin, J. J.; Best, D. B.; Christy, M. E.; Freedman, M. B.; Gautheron,
P.; Habecker, C. N.; Hoffman, J. M.; Lyle, P. A.; Michelson, S. R.;
Ponticello, G. S.; Robb, C. M.; Schwam, H.; Smith, A. M.; Smith, R. L.;
Sondey, J. M.; Strohmaier, K. M.; Sugrue, M. F.; Varga, S. L. J. Med.
Chem. 1989, 32, 2548-2554. (b) Witter, D. J.; Belvedere, S.; Chen, L.;
Secrist, J. P.; Mosley, R. T.; Miller, T. A. Bioorg. Med. Chem. Lett. 2007,
17, 4562-4567. (c) Grese, T. A.; Cho, S.; Bryant, H. U.; Cole, H. W.;
Glasebrook, A. L.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L.
L. Bioorg. Med. Chem. Lett. 1996, 6, 201-206.
(2) Selected examples: (a) Kim, M.-S.; Maruyama, H.; Kawai, T.; Irie,
M. Chem. Mater. 2003, 15, 4539-4543. (b) Camaioni, N.; Ridolfi, G.;
Fattori, V.; Facaretto, L.; Barbarella, G. J. Mater. Chem. 2005, 15, 2220-
2225. (c) Seed, A. J.; Toyne, K. J.; Goodby, J. W.; Hird, M. J. Mater.
Chem. 2000, 10, 2069-2080. (d) Mazzeo, M.; Vitale, V.; Sala, F. D.;
Pisignano, D.; Anni, M.; Barbarella, G.; Favaretto, L.; Zanelli, A.; Cingolani,
R.; Gigli, G. AdV. Mater. 2003, 15, 2060-2063. (e) Yokoyama, Y.;
Shiraishi, H.; Tani, Y.; Yokoyama, Y.; Yamaguchi, Y. J. Am. Chem. Soc.
2003, 125, 7194-7195. (f) Irie, M. Chem. ReV. 2000, 100, 1685-1716.
(3) Rayner, C. M.; Graham, M. A. In Science of Synthesis (Houben-
Weyl), Category 2; Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart,
Germany, 2000; Vol. 10, Chapter 10.4.
(4) Selected recent examples: (a) Nakamura, I.; Sato, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2006, 45, 4473-4475. (b) Larock, R. C.; Yue,
D. Tetrahedron Lett. 2001, 42, 6011-6013. (c) Flynn, B. L.; Verdier-Pinard,
P.; Hamel, E. Org. Lett. 2001, 3, 651-654. (d) Allen, D.; Callaghan, O.;
Cordier, F. L.; Dobson, D. R.; Harris, J. R.; Hotten, T. M.; Owton, W. M.;
Rathmell, R. E.; Wood, V. A. Tetrahedron Lett. 2004, 45, 9645-9647. (e)
Kobayashi, K.; Nakamura, D.; Miyamoto, K.; Morikawa, O.; Konishi, H.
Bull. Chem. Soc. Jpn. 2007, 80, 1780-1784. (f) Yang, S.-M.; Shie, J.-J.;
Fang, J.-M.; Nandy, S. K.; Chang, H.-Y.; Lu, S.-H.; Wang, G. J. Org. Chem.
2002, 67, 5208-5215. (g) Jeong, H. J.; Yoon, U. Y.; Jang, S. H.; Yoo,
U.-A.; Kim, S. N.; Truong, B. T.; Shin, S. C.; Yoon, Y.-J.; Singh, O. M.;
Lee, S.-G. Synlett 2007, 1407-1410 and references cited therein.
(5) Yoshida, S.; Yorimitsu, H.; Oshima, K. Synlett 2007, 1622-1624.
(6) Ogura, K.; Mitamura, S.; Kishi, K.; Tsuchihashi, G. Synthesis 1979,
880-882.
10.1021/ol702643j CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

Scheme 1
Table 1. Synthesis of Benzo[b]thiophenes from 1
5 will be useful for the synthesis of multisubstituted benzo-
[b]thiophenes.
The synthesis of the starting material 1 is summarized in
Figure 1.6,7 Although all the results were unoptimized, the
a In the reactions of 1c-f, ca. 1:1 mixtures of stereoisomers were used.
In the reaction of 1g, a 7:1 mixture of the stereoisomers was used, although
the stereochemistry of each isomer could not be assigned.
mixture provided benzo[b]thiophene 5a in 86% yield (Table
1, entry 1).8 It is worth noting that no addition of a
nucleophile at the diphenyl-substituted olefinic carbon was
(7) Experimental procedure: Formaldehyde dimethyl dithioacetal S-
oxide (1.0 mL, 10 mmol) and THF (10 mL) were placed in a flask under
an atmosphere of argon. n-Butyllithium in hexane (1.62 M, 6.0 mL, 10
mmol) was added to the solution at -20 °C, and the mixture was stirred at
the same temperature for 30 min. Benzophenone (2.2 g, 12 mmol) was
added to the reaction mixture, and the mixture was stirred at -20 °C for 6
h. Acetic anhydride (1.0 mL, 11 mmol) was added to the reaction mixture,
and the mixture was stirred at -20 °C for 12 h. Saturated aqueous NH4Cl
was poured into the mixture, and the product was extracted with ethyl acetate
(20 mL × 3). The combined organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude mixture, benzene (10 mL),
and tert-butyl alcohol (10 mL) were placed in a flask under an atmosphere
of argon. Potassium tert-butoxide was added to the solution at 25 °C, and
the mixture was stirred for 1 h. Saturated aqueous NH4Cl was poured into
the mixture and the product was extracted with ethyl acetate (3 × 20 mL).
The combined organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification by chromatography on silica gel provided
methyl 1-methylsulfinyl-2,2-diphenylethenyl sulfide (1a, 1.84g, 66%).
Figure 1. Synthesis of ketene dithioacetal monoxides, precursors
of benzo[b]thiophenes.
overall transformations were facile to give 1a-g in satisfac-
tory yields. The products except for 1a were obtained as 1:1
stereoisomeric mixtures. The stereoisomers of 1b were
separable from each other on silica gel.
Treatment of 1a with trifluoromethanesulfonic anhydride
(Tf2O) in the presence of potassium carbonate in toluene at
25 °C followed by addition of ethanolamine to the reaction
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Org. Lett., Vol. 9, No. 26, 2007

observed under the Pummerer-like conditions.9 None of 5a
was obtained when trifluoroacetic anhydride, p-toluenesulfo-
nyl chloride, or trifluoromethanesulfonic acid was used
instead of Tf2O.10
Trifluoromethyl-substituted (E)-1b was subjected to the
cyclization reaction to yield benzo[b]thiophene 5b11,12 having
a trifluoromethyl group at the 3 position in high yield (entry
2). Interestingly, its stereoisomer (Z)-1b also underwent the
cyclization to afford 5b in good yield (entry 3). The
participation of (Z)-1b in the cyclization suggests a detailed
reaction mechanism (Scheme 2). The sulfur-oxygen bond
methoxy group selectively (entry 5). Neither C-S bond
formation at the ortho position to the methoxy group nor on
the other phenyl group was observed. The cyclization
reaction of a stereoisomeric mixture of 1e also took place
absolutely onto the methoxyphenyl group (entry 6). In the
reaction of 1f, the cyclization onto the naphthalene is highly
preferable to that onto the phenyl ring (entry 7). The reaction
of 1g bearing a trifluoromethylphenyl group and a phenyl
group yielded 5g selectively (entry 8). In cases where R2
are alkyl groups such as methyl and ethyl, the reactions
afforded complex mixtures.
The methylthio group of 1 plays an important role for the
synthesis (Scheme 3). Treatment of 9 bearing no methylthio
Scheme 2
Scheme 3
cleavage by Tf2O would produce a highly stabilized dication
7. The Ca-Cb single bond of 7 would rotate to form 8. The
dication 8 has a suitable conformation for the cyclization to
yield 3b.
When a 1:1 stereoisomeric mixture of 1c was treated under
the cyclization conditions, the cyclization onto the more
electron-rich methoxyphenyl group took place exclusively
(entry 4). The reaction of m-methoxyphenyl-substituted 1d
led to the C-S bond formation at the para position to the
group under the same conditions afforded a complex mixture.
On the other hand, methyl 1,2,2-triphenylethenyl sulfoxide
(10) reacted to provide 2,3-diphenylbenzo[b]thiophene (12)
in good yield. These results suggest that sufficient stability
of the dicationic intermediate 13/14 would be quite important
for the success of the ring-closure.
(8) Experimental procedure: Methyl 1-methylsulfinyl-2,2-diphenylethe-
nyl sulfide (1a, 54.9 mg, 0.19 mmol), K2CO3 (90.4 mg, 0.66 mmol), and
toluene (4.0 mL) were placed in a flask under an atmosphere of
argon. Trifluoromethanesulfonic anhydride (0.045 mL, 0.27 mmol) was
added, and the mixture was stirred at 25 °C for 1 h. Ethanolamine
(0.060 mL, 1.0 mmol) was added to the reaction mixture, and the mixture
was stirred at 25 °C for 3 h. Saturated aqueous NaHCO3 was poured
into the mixture and the product was extracted with ethyl acetate (3 × 20
mL). The combined organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. Purification by chromatography on silica gel
provided 2-methylthio-3-phenylbenzo[b]thiophene (5a, 42.2 mg, 0.16 mmol,
86%).
The synthesis of 18, a highly substituted benzo[b]thio-
phene, underscores the utility of the present method (Scheme
Scheme 4
(9) (a) Craig, D.; Daniels, K.; McKenzie, A. R. Tetrahedron 1993, 49,
11263-11275. (b) Padwa, A.; Nara, S.; Wang, Q. Tetrahedron Lett. 2006,
47, 595-597. (c) Arai, S.; Kawashita, N.; Satoh, H.; Wada, Y.; Kakiguchi,
K.; Kuriwaki, I.; Kita, Y. Org. Lett. 2004, 6, 3793-3796. (d) Feldman, K.
S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869-1871. (e) Ogura, K.;
Tsuchihashi, G. Synthesis 1980, 736-739.
(10) High oxophilicity of Tf2O and its applications were summarized:
Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000,
56, 3077-3119.
(11) The biological activity of 3-trifluoromethylbenzo[b]thiophene has
been attracting attention. (a) Nussbaumer, P.; Petranyi, G.; Stu¨tz, A. J. Med.
Chem. 1991, 34, 65-73. (b) Gokhale, V. M.; Kulkarni, V. M. Bioorg. Med.
Chem. 2000, 8, 2487-2499. (c) Gokhale, V. M.; Kulkarni, V. M. J. Med.
Chem. 1999, 42, 5348-5358.
(12) Synthesis of 3-trifluoromethylbenzo[b]thiophenes is not easy. (a)
Sawada, H.; Nakayama, M.; Yoshida, M.; Yoshida, T.; Kamigata, N. J.
Fluorine Chem. 1990, 46, 423-431. (b) Akiyama, T.; Kato, K.; Kajitani,
M.; Sakaguchi, Y.; Nakamura, J.; Hayashi, H.; Sugimori, A. Bull. Chem.
Soc. Jpn. 1988, 61, 3531-3537. (c) Owton, W. M. Tetrahedron Lett. 2003,
44, 7147-7149.
Org. Lett., Vol. 9, No. 26, 2007
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4). Bromination of o-chlorophenol13 followed by methylation
yielded 15. Trifluoroacetylation of magnesiated 15 yielded
trifluoromethyl ketone 16 on a large scale.14 Nucleophilic
addition of lithiated FAMSO to 16 followed by elongating
conjugation6 yielded 17. The ring-closure of 17 by Tf2O
afforded 18.
Multisubstituted benzo[b]thiophenes can find many ap-
plications in various fields of chemistry. The present protocol
provides a conceptually new and useful approach to the
benzo[b]thiophene skeleton.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and COE Research from
MEXT and JSPS.
Supporting Information Available: Characterization
data of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL702643J
(14) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org. Chem.
2006, 71, 3545-3550.
(13) Oberhauser, T. J. Org. Chem. 1997, 62, 4504-4506.
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