Palladium-catalyzed multiple arylation of thiophenes

Article abstract of DOI:10.1021/ja0259279

Secondary 2-thiophenecarboxamides efficiently undergo unique triarylation accompanied by formal decarbamoylation under palladium catalysis. 3-Substituted thiophenes, especially having an electron-withdrawing group, can also be triarylated. Copyright

Full text of DOI:10.1021/ja0259279

Published on Web 04/20/2002
Palladium-Catalyzed Multiple Arylation of Thiophenes
Toru Okazawa, Tetsuya Satoh, Masahiro Miura,* and Masakatsu Nomura
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received February 13, 2002
Table 1. Reaction of N-(2-Thenoyl)amines with Bromobenzenesa
Palladium-catalyzed aryl-aryl coupling is now widely used for
products, % yieldb
preparing various biologically active compounds and organic
functional materials having biaryl skeletons.1-3 The reaction is
usually carried out with aryl halides and arylmetals. It is also known
that the direct intermolecular arylation of appropriately function-
alized aromatic compounds4 and five-membered heteroaromatics4,5
can regioselectively occur via C-H cleavage. We recently reported
that aromatic substrates such as phenols, aryl ketones, and benzyl
alcohols undergo direct multiple (two to five times) arylation on
treatment with excess aryl halides in the presence of palladium
catalysts to give the corresponding oligoaryl compounds.6 As part
of our study of the catalytic multisubstitution of aromatics,6,7 we
have examined the reaction of thiophenes,8 since poly- and oligoaryl
compounds involving a thiophene unit have recently attracted much
attention as the organic components of electronic devices.9 Con-
sequently, it has been found that certain monosubstituted thiophenes
can effectively undergo unprecedented 2,3(or 4),5-triarylation as
well as 2,5- and 3,5-diarylation, which is reported herein.
entry
bromide
amide
time (h)
thiophene
ArNHR
Ar2NR
c
1
1a
1a
1b
1c
1a
1a
2a
2a
2a
2a
2b
2c
18
24
24
24
18
20
3, 96 (83)
3, 84
4, 73 (68)
5, 77 (71)
3, 83
-
82
83
97
64
4
2d
3
-
-
4
19
73
-
5e
6
3, 52
-
a Reaction conditions: [1]:[2]:[Pd(OAc)2]:[L ) L1]:[Cs2CO3] ) 6:1:
0.1:0.2:6 (in mmol), in refluxing o-xylene under N2. b Determined by GLC.
The value in parentheses is isolated yield. c Not detected or negligible. d L
) L2. e [1a]:[Cs2CO3] ) 4:4 (in mmol).
ation. (a) The reaction of 2a with phenyl triflate in toluene at 110
°C for 24 h gave 3-monophenylated and 3,5-diphenylated products,
6 and 7, in 71% and 8% yields, respectively (eq 2), while that with
The triarylation found first is shown in eq 1 with 2-thiophene-
carboxamides as substrates, in which an unusual formal decarbam-
oylation via C-C cleavage is involved. In a typical experiment,
1a was sluggish under the conditions. (b) Analysis of the reaction
mixture with 1a in refluxing o-xylene at 4 h confirmed the formation
of 6 (17%), 7 (7%), 3-phenylthiophene (8) (19%), 2,4-diphenylth-
iophene (9) (21%), 2,3-diphenylthiophene (10) (10%), and 3 (4%)
along with aniline (20%) and diphenylamine (10%) (Scheme 1).
Scheme 1
N-(2-thenoyl)aniline (2a) (1 mmol) with bromobenzene (1a) (6
mmol) in the presence of Pd(OAc)2 (0.1 mmol), P(o-biphenyl)-
(t-Bu)2 (L1) (0.2 mmol), and Cs2CO3 (6 mmol) in refluxing o-xylene
for 18 h gave 2,3,5-triphenylthiophene (3a) in 96% yield (83% after
purification) (entry 1 in Table 1). Triphenylamine (82%) was
detected as the product derived from the carbamoyl moiety. This
indicates that aniline liberated from the substituent was also
diphenylated. P(t-Bu)3 (L2) could be used in place of the Buch-
wald’s ligand (L1), while it was somewhat less effective (entry
2).10,11 The reactions of 2a with 4-methoxy- and 4-fluorobenzenes
(1b and 1c) similarly proceeded to give the corresponding 2,3,5-
triarylthiophenes (4 and 5), in good yields (entries 3 and 4). N-(2-
Thenoyl)-2-methylaniline (2b) reacted with 1a (4 equiv) to give 3
in 83% yield. In this case, N-(2-methylphenyl)aniline was produced
as the major byproduct, indicating that in the triarylthiophene
preparation, the amount of 1 can be reduced by using the amide
2b (entry 5). The reaction of N-(2-thenoyl)cyclohexylamine (2c)
with 1a also gave 3 (entry 6), although it was less efficient.
The following experimental results seem to be informative in
considering the reaction sequence of this unique thiophene triaryl-
Thus, 2a appears to be phenylated successively at the 3- and
5-positons to give 6 and 7. Then, both the compounds undergo
decarbamoylation to give 8 and 9, which are further di- and
monophenylated, respectively, to give 3. It was confirmed that 8
was quantitatively diphenylated under the present conditions to give
3 (vide infra). However, the reaction of 2-phenylthiophene (11)
with 1a gave 2,5-diphenylthiophene (12) as the predominant product
along with only a minor amount of 3 (eq 3). Thus, the route via 11
and 12 does not seem to participate in the reaction.
* Corresponding author. E-mail: miura@ap.chem.eng.osaka-u.ac.jp.
9
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J. AM. CHEM. SOC. 2002, 124, 5286-5287
10.1021/ja0259279 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction of 3-Substituted Thiophenes with
only a small amount of 20a (entry 6), showing that the identity of
ligands significantly affects the multiple arylation. The reaction of
2g was also found to be influenced by the substituent of bromoben-
zene (entries 8 and 9). Thus, triarylation with 1d (X ) 3-CF3) pro-
ceeded smoothly, whereas that with 1b (X ) 4-OMe) was relatively
slow. This suggests that the reaction at the 4-position is enhanced
by increasing the electrophilic character of arylpalladium(II) species.
In summary, we have reported that secondary 2-thiophenecar-
boxamides efficiently undergo unique triarylation accompanied by
formal decarbamoylation under palladium catalysis. 3-Substituted
thiophenes, especially having an electron-withdrawing group, are
also triarylated, while selective diarylation of them can be per-
formed. The present method appears to be useful for preparing vari-
ous oligoaryl compounds having a thiophene unit.
Bromobenzenesa
products, % yieldb
bromide
(mmol)
entry
thiophene
time (h)
dic
trid
e
1
2
3
4
5
6f
7
8
9
1a (2.4)
1a (4)
8
24
18
3, 97 (88)
17, 86 (80)
17, 44
-
2f
2f
2g
2g
2g
2g
2g
2g
18, 10
18, 33
1a (4)
72
1a (2.4)
1a (6)
1a (6)
1b (2.4)
1b (6)
1d (6)
36
19a, 96 (83)
19a, 4
-
70
20a, 76 (65)
20a, 7
72
19a, 90
48
19b, 92 (80)
19b, 28
-
-
140
52
20b, 48
20d, 78 (72)
a Reaction conditions: [thiophene]:[Pd(OAc)2]:[L ) L1] ) 1:0.1:0.2 (in
mmol), [1] ) [Cs2CO3], in refluxing o-xylene under N2. b Determined by
GLC. The value in parentheses is isolated yield. c Diarylated product.
d Triarylated product. e Not detected or negligible. f L ) L2.
Acknowledgment. This work was partly supported by a Grant-
in-Aid from the ministry of Education, Culture, Sports, Science
and Technology, Japan. We thank Ms. Y. Miyaji for the measure-
ment of NMR spectra.
To obtain some insight into the mode of decarbamoylation in
Scheme 1,12 diphenylated amide 7 (0.2 mmol) was heated in the
presence of Pd(OAc)2 (0.02 mmol), L1 (0.04 mmol), and Cs2CO3
(1 mmol) in o-xylene for 24 h. The amide disappeared to produce
9 quantitatively together with aniline. No reaction occurred with
use of Pd(dba)2 in place of Pd(OAc)2 (Pd(dba)2 could be used in
the arylation of 2a) or in the absence of any palladium species or
base. On the basis of these results, it is reasonable to consider that
the process involves Pd(II)-catalyzed and base-promoted hydrolytic
C-N fission, followed by decarboxylative C-C cleavage,13 though
further studies are required to establish the detailed mechanism.
In contrast to the results with 2a-c, treatment of N-(2-thenoyl)-
piperidine (2d) with 1a gave corresponding 5-monophenylated and
3,5-diphenylated compounds, 13 and 14, and tertiary amide products
resisted C-C cleavage (eq 3). It is worth noting that initial phen-
ylation of 2a takes place preferably at the 3-position, followed by
the second phenylation at the 5-position, whereas the reaction of
2d occurs in the reverse order. This sharp contrast leads us to deduce
that 3-arylation of 2a proceeds by a coordination assisted mecha-
nism,6c while that of 2d occurs either via carbopalladation or
electrophilically.14 The 5-phenylation may proceed electrophilically
in both reactions.8b As expected, the reaction of 2-benzoylthiophene
(2e) with 1a proceeded in a manner similar to that of 2d (eq 3).
As described above, 3-phenylthiophene (8) was efficiently di-
phenylated at the 2- and 5-positions (eq 4 and entry 1 in Table 2).
Similarly, the reaction of 3-benzoylthiophene (2f) with 1a (4 equiv)
for 18 h gave 3-benzoyl-2,5-diphenylthiophene (17) in 86% yield
(entry 2). Interestingly, a small, but meaningful amount of triphen-
ylated compound (18) (10%) was formed in this reaction, this being
the second example of thiophene triarylation. The yield of 18 was
increased up to 33% by prolonging the reaction time (entry 3).
3-Cyanothiophene (2g) was found to be effectively triphenylated
to afford 3-cyano-2,4,5-triphenylthiophene (20a) as the predominant
product (entry 5), while selective 2,5-diarylation of the substrate was
achieved by using a limited amount of 1a (entry 4). These results
indicate that an electron-withdrawing group at the 3-position, which
may increase the acidity of 4-hydrogen, enables the triarylation.8b
It is noted that the reaction of 2g with L2 as ligand could give
Supporting Information Available: Standard experimental pro-
cedure and characterization data for new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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