Programmed synthesis of tetraarylthiophenes through sequential C-H arylation

Article abstract of DOI:10.1021/ja906215b

A general protocol for the programmed synthesis of tetraarylthiophenes has been established. The utilization of three catalysts, RhCl(CO){P[OCH(CF ₃)₂]₃}₂, PdCl₂/ P[OCH(CF₃)₂]

Full text of DOI:10.1021/ja906215b

Published on Web 09/29/2009
Programmed Synthesis of Tetraarylthiophenes through Sequential C-H Arylation
Shuichi Yanagisawa, Kirika Ueda, Hiromi Sekizawa, and Kenichiro Itami*
Department of Chemistry, Graduate School of Science, Nagoya UniVersity, Nagoya 464-8602, Japan
Received July 24, 2009; E-mail: itami@chem.nagoya-u.ac.jp
Multiply arylated thiophenes are privileged structures with many
interesting functions, including optoelectronic1 and biological2 proper-
ties. In order to accelerate the discovery and structure-property
relationship studies of new functional molecules of this class, a flexible
method for accessing all possible isomers in a programmable format
is much needed. We herein report a general protocol for the
programmed synthesis of tetraarylthiophenes3,4 through the sequential
C-H/C-O arylation of 3-methoxythiophene (1). The development
of regioselective C-H bond arylation catalysts has been a key to
realizing our concept.
development of a catalyst promoting the hard-to-achieve arylation at
the ꢀ-position of thiophene ring was crucial. Extensive screening led
to the development of two catalysts (Cat-B and Cat-C) for the second
and third arylations of 1, respectively.
Table 1. Ligand-Controlled Regiodivergent Arylation of 2aa
entry
Ar2
ligand
major product
% yield (3:4)b
1
2
3
C6H5 (a)
C6H5 (a)
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
P[OCH(CF3)2]3
2,2′-bipyridyl
3aa
4aa
3ab
4ab
3ac
4ac
3ad
4ad
3ae
4ae
3af
80 (97:3)
89 (1:99)
88 (98:2)
98 (2:98)
83 (96:4)
91 (1:99)
75 (98:2)
83 (1:>99)
71 (95:5)
80 (1:>99)
69 (93:7)
69 (2:98)
77 (95:5)
77 (1:>99)
o-MeC6H4 (b)
o-MeC6H4 (b)
p-MeC6H4 (c)
p-MeC6H4 (c)
p-MeOC6H4 (d)
p-MeOC6H4 (d)
p-AcC6H4 (e)
p-AcC6H4 (e)
p-NO2C6H4 (f)
p-NO2C6H4 (f)
p-CF3C6H4 (g)
p-CF3C6H4 (g)
4
5c
6
7c
8
9
10
11
12
13
14
4af
3ag
4ag
To realize a programmed synthesis of tetraarylthiophenes, a general
method allowing regioselective arylations onto a thiophene core had
to be developed. As a means for installing aryl groups onto the core,
we selected the metal-catalyzed C-H bond arylation of thiophenes in
view of synthetic expediency.5,6 Though this approach was conceptu-
ally attractive, obstacles to overcome included insufficient reactivity
and the control of regioselectivity of thienyl C-H bonds toward
catalytic C-H arylation reactions.5 For example, several groups have
demonstrated that certain Pd,5,7 Cu,8 Rh,9 and Ir10 catalysts can
promote the C2/C5 diarylation of thiophenes, but arylation at the C3/
C4 position is very difficult. Very recently, the Miura group has
demonstrated that 3-thiophenecarboxylic acid undergoes Pd-catalyzed
tetraarylation with bromoarenes, accompanied by cleavage of three
C-H bonds and decarboxylation.11 However, the installation of four
different aryl groups onto thiophene ring has not been realized.3
We selected 3-methoxythiophene (1) as our first-generation plat-
form12 for tetraarylthiophene synthesis because of its high reactivity
and selectivity in catalytic C-H bond arylation with iodoarenes.9,10
For example, 1 reacts with iodobenzene in the presence of
RhCl(CO){P[OCH(CF3)2]3}2 catalyst (Cat-A) and Ag2CO3 to afford
3-methoxy-2-phenylthiophene (2a) in 80% yield with virtually com-
plete regioselectivity. This C2-selective arylation occurs with various
iodoarenes.9 Thus, the focal point of this study was to establish a C4-
and/or C5-selective catalyst for the arylation of 2-aryl-3-methox-
ythiophenes 2. However, we identified that Cat-A is problematic for
further arylations. For example, the reaction of 2a (1.5 equiv) and
iodobenzene (1 equiv) in the presence of Cat-A (3 mol %) and Ag2CO3
(1 equiv) in m-xylene at 150 °C furnished the C5 phenylation product
(4aa) in only 38% yield. Even more critically, further arylation (C4
arylation) of 4aa did not take place with Cat-A. Thus, the need for a
new catalytic system was obvious at this point. In particular, the
a Conditions: 2a (1.5 equiv), Ar2I (1 equiv), PdCl2 (5 mol %), ligand
(10 mol %), Ag2CO3 (1 equiv), m-xylene, 120 °C. b Isolated yield.
Isomer ratio was determined by 1H NMR and GC analyses. c PdCl2 (10
mol %) and P[OCH(CF3)2]3 (20 mol %) were employed.
We first found that the otherwise difficult C4-selective arylation of
2a with iodoarenes can be promoted by the catalyst PdCl2/P[OCH-
(CF3)2]3 (Cat-B) and Ag2CO3 in m-xylene at 120 °C, furnishing 3
with high regioselectivity (93-98% C4) (Table 1). Given the C5
selectivity of Cat-A for the arylation of 2a (see above), an interesting
metal-controlled regiodivergency13 (C5 for RhI, C4 for PdII) has been
identified in P[OCH(CF3)2]3-bound metal catalysts. More interestingly,
we found that the C4 selectivity of Cat-B can be switched to C5
selectivity (98 to >99%) by changing the supporting neutral ligand to
2,2′-bipyridyl14 (Cat-C). This ligand-controlled regiodivergent C-H
arylation13 (C4 for P[OCH(CF3)2]3, C5 for 2,2′-bipyridyl) turned out
to be general for PdCl2/Ag2CO3 catalysis (Table 1).15
With two regiodivergent C-H arylation catalysts in hand, the third
C-H arylation for making 2,4,5-triaryl-3-methoxythiophenes 5 was
next examined for two possible routes via either 3 or 4. Gratifyingly,
the Cat-C system promoted the C5 arylation of 2,4-diaryl-3-methox-
ythiophenes 3 with iodoarenes, giving 5 in good yields (Table 2). Under
otherwise identical conditions, the Cat-B system was unable to promote
the arylation for both 3 and 4.
Finally, the fourth arylation to obtain the targeted tetraarylthiophenes
7 was investigated. Extensive screening of reaction conditions estab-
lished a high-yield procedure involving Suzuki-Miyaura coupling16
(Table 3). Thus, the BBr3-promoted demethylation of 5 followed by
treatment of the thus-obtained crude alcohols with Tf2O/i-Pr2NEt/
9
14622 J. AM. CHEM. SOC. 2009, 131, 14622–14623
10.1021/ja906215b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
a
Table 2. Arylation of 3 Catalyzed by Pd/bipy/Ag2CO3
functional organic materials where the structure-property relationships
are often not easily predictable. These studies as well as the mechanistic
investigations of the newly developed catalysts are now the focus of
our ongoing efforts.
Acknowledgment. This work was supported in part by a Grant-
in-Aid for Scientific Research from MEXT and JSPS. S.Y. is a
recipient of a JSPS Predoctoral Fellowship.
entry
Ar2
Ar3
5 (% yield)
1
C6H5 (a)
C6H5 (a)
5aaa (87)
5acf (61)
5acg (70)
5aec (65)
5aef (73)
5agc (70)
2
p-MeC6H4 (c)
p-MeC6H4 (c)
p-AcC6H4 (e)
p-AcC6H4 (e)
p-CF3C6H4 (g)
p-NO2C6H4 (f)
p-CF3C6H4 (g)
p-MeC6H4 (c)
p-NO2C6H4 (f)
p-MeC6H4 (c)
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
3b
4b
5
6b
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a Conditions:
3
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Table 3. Synthesis of Tetraarylthiophenes 7a
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1-butanol/H2O (5:4), 65 °C.
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In summary, we have established a general protocol for the
programmed synthesis of tetraarylthiophenes. The utilization of three
catalysts, RhCl(CO){P[OCH(CF3)2]3}2, PdCl2/P[OCH(CF3)2]3, and
PdCl2/bipy, enables regioselective sequential arylations at the three
C-H bonds of 3-methoxythiophene with iodoarenes. Interesting metal-
and ligand-controlled regiodivergent C-H arylations have been
uncovered during this study. Noteworthy features of the present method
are that (i) all of the aryl groups assembled on the thiophene core
stem from readily available aryl iodides or boronic acids, (ii) the
installation of aryl groups at the desired positions can be achieved,
and (iii) simple alteration of the application order of aryl reagents in
the sequence results in the production of all possible isomers of
tetraarylthiophenes. Although we focused on the synthesis of tet-
raarylthiophenes in this work, our strategy is also applicable to the
regioselective synthesis of di- or triarylated thiophenes by skipping
one or two of the C-H arylation steps prior to the final C-O bond
arylation. The present strategy should find many uses for combinatorial
lead-structure identification and optimization in the development of
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Y.; Osakada, K.; Mori, A. Chem. Lett. 2006, 35, 1100. (b) Reference 1a.
(15) The C4 selectivity exerted by the PdCl2/P[OCH(CF3)2]3/Ag2CO3 catalytic
system appears to be unprecedented and is the subject of further investiga-
tion. A full study of this newly developed catalyst will be reported in due
course.
(16) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(17) See the Supporting Information for details.
(18) For the use of Ba(OH)2 in Suzuki-Miyaura coupling, see: Watanabe, T.;
Miyaura, N.; Suzuki, A. Synlett 1992, 207.
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