Palladium-catalyzed selective 2,3-diarylation of α,α- disubstituted 3-thiophenemethanols via cleavage of C-H and C-C bonds

Article abstract of DOI:10.1021/jo061412e

α,α-Disubstituted 3-thiophenemethanols undergo selective diarylation accompanied by cleavage of the C-H and C-C bonds of the 2- and 3-positions, respectively, upon treatment with aryl bromides in the presence of a palladium catalyst to give the correspond

Full text of DOI:10.1021/jo061412e

and chemoselective points of view, and various catalytic
processes involving different modes to activate the relatively
inert bonds have been developed. While the above direct
arylation of heteroarenes is a useful example, among the most
promising and general activation strategies is to utilize the
proximate effect by coordination of a functional group in a given
substrate to the metal center of a catalyst. As one of the
representative reactions, we reported the palladium-catalyzed
coupling of tert-benzyl alcohols with aryl halides.7 The reaction
proceeds not only via C-H cleavage but also via C-C cleavage
in the key arylpalladium(II) alcoholate species (Scheme 1). The
precedence of the bond cleavages depends on both the substrate
and catalyst structures. In the reaction using R,R-diphenyl-2-
thiophenemethanol as a heterocyclic substrate, the thienyl moiety
was found to couple with aryl halides selectively via C-C
cleavage with extrusion of benzophenone to give 2-arylth-
iophenes, which can be further arylated at the 5 position via
C-H cleavage (Scheme 2, a).7b,d In our continuous study of
catalytic arylation, we observed that in sharp contrast to the
reaction of the 2-thiophenemethanol derivative, its 3-thienyl
isomer undergo sequential diarylation via initial C-H cleavage
followed by C-C cleavage to give 2,3-diarylthiophenes selec-
tively (Scheme 2, b), which is reported herein.
Palladium-Catalyzed Selective 2,3-Diarylation of
r,r-Disubstituted 3-Thiophenemethanols via
Cleavage of C-H and C-C Bonds
Masaya Nakano, Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka UniVersity, Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
ReceiVed July 6, 2006
R,R-Disubstituted 3-thiophenemethanols undergo selective
diarylation accompanied by cleavage of the C-H and C-C
bonds of the 2- and 3-positions, respectively, upon treatment
with aryl bromides in the presence of a palladium catalyst
to give the corresponding 2,3-diarylthiophenes in good yields.
When R,R-diphenyl-3-thiophenemethanol (2a) (0.5 mmol)
was treated with bromobenzene (1a) (2 mmol) in the presence
of Pd(OAc)2 (0.05 mmol) and PPh3 (0.2 mmol) using Cs2CO3
(2 mmol) as base in refluxing toluene for 10 h, 2,3-diphenylth-
iophene (3a) (58%) was formed together with 2,3,5-triphenylth-
iophene (4) (41%) (Table 1, entry 1). The reaction using PCy3
or P(biphenyl-2-yl)(t-Bu)2 (0.1 mmol) as ligand in place of PPh3
also gave 3a and 4 (entries 2 and 3). Notably, with the latter
ligand, the diphenylated product 3a was produced selectively
in 86% yield. At an elevated temperature in refluxing o-xylene
in the presence of PPh3 or PCy3 (entries 4 and 5), the
triphenylated product 4 was obtained as the predominant
product, whereas using the bulky biphenylphosphine a consider-
able amount of 3a remained (entry 6). These results indicate
that all the ligands examined can promote the phenylation at
the 2- and 5-positions via C-H cleavage and that at the
3-position via C-C cleavage, while the reaction of the 5-position
is relatively slow, especially with the biphenylphosphine ligand.
Poly- and oligoaryl compounds involving a thiophene unit
have recently attracted much attention as the organic components
of electronic devices.1 Arylated thiophenes may also exhibit
interesting biological activities.2 One of the most useful methods
to prepare such aryl heteroarenes is the palladium-catalyzed
cross-coupling of aryl halides with heteroarylmetals or of
heteroaryl halides with arylmetals.3 It is also known that a
number of five-membered heteroarenes including thiophenes can
couple with aryl halides directly at their 2- and 5-positions under
the influence of palladium catalysts.4
Meanwhile, catalytic reactions via cleavage of C-H4,5 and
C-C6 bonds have attracted much attention from atom-economic
(1) (a) Roncali, J. Chem. ReV. 1997, 97, 173. (b) Mitschke, U.; Ba¨uerle,
P. J. Mater. Chem. 2000, 10, 1471. (c) Katz, H. E.; Bao, Z.; Gilat, S. L.
Acc. Chem. Res. 2001, 34, 359. (c) Sun, Y.; Liu, Y.; Zhu, D. J. Mater.
Chem. 2005, 15, 53. (d) Perepichaka, I. F.; Perepichaka, D. F.; Meng, H.;
Wudl, F. AdV. Mater. 2005, 17, 2281.
(2) (a) Veeramaneni V. R. Pal, M.; Yeleswarapu, K. R. Tetrahedron Lett.
2003, 59, 3283. (b) Tordjman, C.; Sauveur, F.; Droual, M.; Briss, S.; Andre,
N.; Bellot, I.; Deschamps, C.; Wierzbicki, M. Arzneim. Forsch. 2003, 53,
774. (c) Nesterov, E. E.; Skoch, J.; Hyman, B. T.; Klunk, W. E.; Bacskai,
B. J.; Swager, T. M. Angew. Chem., Int. Ed. 2005, 44, 5452.
(3) (a) de Meijere, A., Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany 2004. (b) Tsuji, J.
Palladium Reagents and Catalysts, 2nd ed.; John Wiley & Sons: Chichester,
UK, 2004.
(4) Reviews: (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,
211. (b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359. (c) Miura, M.; Satoh, T. Top. Organomet. Chem.
2005, 14, 55. (d) Miura, M.; Satoh, T. In Handbook of C-H Transforma-
tions; Dyker, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1, p
229.
(5) Reviews: (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97,
2879. (b) Kakiuchi, F.; Murai, S. Top. Organomet. Chem. 1999, 3, 47. (c)
Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (d) Kakiuchi, F.; Murai,
S. Acc. Chem. Res. 2002, 35, 826. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. ReV. 2002, 102, 1731. (f) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077. (g) Miura, M.; Satoh, T. In Handbook of C-H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005;
Vol. 1, p 223.
Monitoring the reaction of 2a with 1a under the conditions
for entry 3 by GC-MS confirmed that in the early stage, a
considerable amount of monophenylated product, that is R,R,2-
triphenyl-3-thiophenemethanol, is found together with 3a and
the former is disappeared to afford 3a as the predominant
(6) Reviews: (a) Crabtree, R. H. Chem. ReV. 1985, 85, 245. (b)
Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870. (c)
Murakami, M.; Ito, Y. Top. Organomet. Chem. 1999, 3, 97. (d) Mitsudo,
T.; Kondo, T. Synlett 2001, 309. (e) Jun, C.-H.; Moon, C. W.; Lee, D.-Y.
Chem. Eur. J. 2002, 8, 2423. (f) Perthuisot, C.; Edelbach, B. L.; Zubris, D.
L.; Simhai, N.; Iverson, C. N.; Mu¨ller, C.; Satoh, T.; Jones, W. D. J. Mol.
Catal. A 2002, 189, 157. (g) Catellani, M. Synlett 2003, 298. (h) Nishimura,
T.; Uemura, S. Synlett 2004, 201. (i) Satoh, T.; Miura, M. Top. Organomet.
Chem. 2005, 14, 1.
(7) (a) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am.
Chem. Soc. 2001, 123, 10407. (b) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh,
T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 5236. (c) Terao, Y.;
Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2004, 69,
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60, 6757.
10.1021/jo061412e CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 8309-8311
8309

TABLE 1. Reaction of r,r-Diphenyl-3-thiophenemethanol (2a)
SCHEME 1
SCHEME 2
with Bromobenzene (1a)a
% yield b
entry
L
solvent
3a
4
c
1
2
3
4
5
6
PPh3
PCy3
toluene
toluene
toluene
o-xylene
o-xylene
o-xylene
58
72
86
4
5
39
41
20
10
91
92
57
P(biphenyl-2-yl)(t-Bu)2
c
SCHEME 3
PPh3
PCy3
P(biphenyl-2-yl)(t-Bu)2
a Reaction conditions: [1a]/[2a]/[Pd(OAc)2]/[L]/[Cs2CO3] ) 2:0.5:0.05:
0.1:2 (in mmol), in refluxing toluene or o-xylene under N2 for 10 h. b GLC
yield based on the amount of 2a used. c [L] ) 0.2 mmol.
TABLE 2. Reaction of r,r-Diphenyl-3-thiophenemethanol (2a)
with Various Aryl Bromides (1b-g)a
SCHEME 4
a Reaction conditions: [1]/[2]/[Pd(OAc)2]/[ligand]/[Cs2CO3] ) 2:0.5:
0.05:0.1:2 (in mmol), in refluxing toluene under N2 for 8 h. b Determined
by GC.
SCHEME 5
a Reaction conditions: [1a]/[2a]/[Pd(OAc)2]/[ligand]/[Cs2CO3] ) 2:0.5:
0.05:0.1:2 (in mmol), in refluxing toluene under N2 for 8-10 h. b Deter-
mined by GC. The value in parentheses is the isolated yield.
a Reaction conditions: [1]/[2]/[Pd(OAc)2]/[ligand]/[Cs2CO3] ) 2:0.5:
0.05:0.1:2 (in mmol), in refluxing toluene under N2 for 8 h. b Determined
by GC. The value in parentheses is the isolated yield.
product along with 4. This observation is consistent with the
successive 2,3-diphenylation in this order.
of the 2,4-isomer is, if any, negligible and the 2,3-isomer 3a
can be obtained effectively under controlled conditions, which
appeared to be a remarkable aspect. Consequently, we next
undertook the preparation of various 2,3-diarylthiophenes by
the present method.
Table 2 summarizes the results for the reactions of the
thiophenemethanol 2a with various aryl bromides 1b-g. The
diarylation proceeded effectively using both electron-rich
bromide 1b and those having an electron-withdrawing substitu-
ent 1c-f to give 3b-f. 4-Bromobiphenyl (1g) was also
applicable to afford 3g.
We previously reported that N-phenyl-2-thiophenecarboxa-
mide also undergoes triphenylation upon treatment with excess
bromobenzene under similar conditions to give 4 (Scheme 3).8
The reaction is considered to proceed through coordination-
assisted 3-phenylation followed by either 5-phenylation or
decarbamoylation at the 2-position, and thus, both 2,4- and 2,3-
diphenylthiophenes are formed in comparable amounts as the
precursors of 4. In contrast, in the reaction of 2a, participation
2-(Thienyl-3-yl)-2-propanol (2b) and its benzothiophene
analogue 2c in place of 2a could also be reacted with a number
of aryl bromides to afford the corresponding 2,3-diarylated
(8) (a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286. (b) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2003, 59, 5685.
8310 J. Org. Chem., Vol. 71, No. 21, 2006

analysis of the mixture by GC confirmed formation of compound
3b (127 mg, 86%). The product (89 mg, 60%) was also isolated
by filtration of the mixture with a filter paper with ether, evaporation
of the solvents, and chromatography on silica gel using hexanes-
products 3 and 5 with substantial yields with the exception of
the coupling of 2b with 1b (Schemes 4 and 5). In the latter
case, a considerable amount of the starting alcohol was
recovered. The reason the combination is sluggish is not
definitive at the present stage.
In summary, we have shown that R,R-disubstituted 3-thiophen-
emethanols undergo selective 2,3-diarylation accompanied by
cleavage of the C-H and C-C bonds of 2- and 3-positions,
respectively, by treatment with aryl bromides in the presence
of a palladium catalyst system. This appears to provide a useful,
general synthetic route leading to 2,3-diarylthiophenes.
1
ethyl acetate (98:2, v/v). Compound 3b:2b mp 105-106 °C; H
NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 3.80 (s, 3H), 6.79-6.84
(m, 4H), 7.10 (d, J ) 5.1 Hz, 1H), 7.19-7.25 (m, 4H), 7.25 (d, J
) 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.2, 55.2, 113.8,
113.9, 123.30 127.0, 129.2, 130.1, 130.3, 130.5, 137.0, 137.7, 158.4,
158.9; MS m/z 296 (M+). Anal. Calcd for C18H16O2S: C, 72.94;
H, 5.44. Found: C, 72.76; H, 5.26.
Acknowledgment. This work was partly supported by
Grants-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Experimental Section
2,3-Bis(4-methoxyphenyl)thiophene (3b). In a 20 mL two-
necked flask were added the bromide 1b (2 mmol, 374 mg), the
alcohol 2a (0.5 mmol, 133 mg), Pd(OAc)2 (0.05 mmol, 11.2 mg),
P(biphenyl-2-yl)(t-Bu)2 (0.1 mmol, 20.1 mg), Cs2CO3 (2 mmol, 652
mg), 1-methylnaphthalene (ca. 50 mg) as internal standard, and
toluene (2.5 mL). The resulting mixture was stirred under N2
(balloon) at 130 °C (bath temperature) for 8 h. After cooling,
Supporting Information Available: Standard experimental
procedure and characterization data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO061412E
J. Org. Chem, Vol. 71, No. 21, 2006 8311