Published on the web September 5, 2011
939
Direct Sequential C3 and C1 Arylation Reaction of Imidazo[1,5-a]pyridine Catalyzed
by a 1,10-Phenanthroline-Palladium Complex
Eiji Yamaguchi, Fumitoshi Shibahara,* and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193
(Received April 26, 2011; CL-110355; E-mail: fshiba@gifu-u.ac.jp, mtoshi@gifu-u.ac.jp)
Table 1. Pd-Catalyzed C3 arylation of imidazo[1,5-a]pyridine:
Screening of the reaction conditionsa
The direct sequential arylation reaction at the C3 and C1
positions of imidazo[1,5-a]pyridines with a variety of aryl
iodides catalyzed by [Pd(phen)2](PF6)2 is described. The
reaction of unsubstituted imidazo[1,5-a]pyridine with various
aryl iodides proceeded selectively at the C3 position to
exclusively give the corresponding C3-arylated products. The
one-pot double-arylation reaction at the C3 and C1 positions of
unsubstituted imidazo[1,5-a]pyridine with different aryl groups
was also achieved.
Entry
X
Conc./M
3a/%b
4a/%b
1
2
3
4
I
1
1
0.5
0.5
86
74
59
98
10
10
3
Br
Br
I
Imidazo[1,5-a]pyridines are an attractive class of com-
pounds due to their potential for application in electronic- and
photofunctional materials such as organic thin-layer field effect
transistors (FETs)1 and organic light-emitting diodes (OLEDs),2
and as precursors of N-heterocyclic carbenes (NHCs).3 In
addition, due to their bioactive properties, imidazo[1,5-a]pyri-
dines have been used in pharmaceuticals such as HIV-protease
inhibitors,4 cardiotonic agents,5 aromatase inhibitors in estrogen-
dependent diseases,6 and thromboxane A2 synthetase inhibi-
tors.7 Hence, synthesis of imidazo[1,5-a]pyridine derivatives has
recently attracted increasing attention. Several methods for the
synthesis of substituted imidazo[1,5-a]pyridines, where the
imidazo[1,5-a]pyridine ring is constructed via the condensa-
tion-cyclization of 2-pyridylmethylamine, have been report-
ed.8-10 However, these reactions require stoichiometric amounts
of metal salts and/or oxidants that are not incorporated into the
products. Therefore, more straightforward methods that lead to
substituted imidazo[1,5-a]pyridines are still needed. In addition,
from the perspective of green chemistry, new reactions with
by-products that pose less of an environmental burden are
desired.
trace
aReactions were carried out using imidazo[1,5-a]pyridine (1)
(0.5 mmol) and aryl iodide (1.1 equiv) in the presence of
[Pd(phen)2](PF6)2 (5 mol %) and Cs2CO3 (1.1 equiv) in DMA at
b
150 °C for 20 h. Isolated yield.
First, the efficiency and selectivity of the [Pd(phen)2](PF6)2-
catalyzed reaction between 1 and 4-iodo(trifluoromethyl)ben-
zene (2a) were examined (Table 1). The reaction in 1 M solution
gave 3a and 4a in respective yields of 86% and 10% (Entry 1).
Products derived from the cleavage of other C-H bonds in 1
were not observed. These results clearly indicated that the
arylation that was accompanied by C-H bond cleavage takes
place initially at the C3 position, and then at the C1 position of
C3-arylated imidazo[1,5-a]pyridine 3a. To improve the selec-
tivity of the reaction, the use of bromide and/or a diluted
solution was examined. Finally, C3 arylation took place
exclusively with 2aI under low-concentration conditions to give
3a in 98% yield (Entry 4).
With the optimum reaction conditions in hand, the direct
arylation reaction of 1 and a variety of aryl halides was
examined. The results are summarized in Table 2. When
[Pd(phen)2](PF6)2 was used as a catalyst, the desired arylated
products 3 were obtained in moderate to high yields regardless
of the aryl iodides 2. The reaction proceeded smoothly with both
electron-rich (Entries 3-5) and -poor (Entries 1 and 6-8) aryl
iodides 2 to give the monoarylated products 3 in good to high
yields. In the reactions with 4-nitro- (2g) and 4-ethoxycarbon-
ylphenyl iodide (2h) as coupling partners, K2CO3 worked as a
suitable base (Entries 7 and 8). The reactions of 1 with sterically
hindered 2-iodotoluene (2i) and 1-iodo-2,4-dimethylbenzene
(2k) also took place to give the corresponding products 3i and
3k in good yields, whereas those with 2-iodoanisole (2j) gave
3j in a lower yield (Entries 9-11). 2-Iodopyridine (2l) was a
sluggish substrate, and the reaction afforded the product 3l
in only moderate yield (Entry 12). The reaction with diiodo-
fluorene 2m gave the bis(imidazopyridine) 3m in 90% yield
(Entry 13). Finally, the use of m-diiodobenzene (2n) as a
coupling partner led to 1,3-bis(3-imidazopyridyl)benzene 3n,
ð1Þ
Recently, direct C-H arylation has emerged as an alternative
to cross-coupling reactions of organometallic reagents and aryl
halides since it does not require the preparation of these
substrates.11 In this context, we have also reported that Pd-
phenanthroline complexes such as [Pd(phen)2](PF6)2 (phen:
1,10-phenanthroline) catalyzed multiple arylation reactions of
imid-, ox-, and thiazoles.12 We then speculated on the ap-
plicability of this direct C-H arylation to unsubstituted imidazo-
[1,5-a]pyridine (1), which is prepared by phosphoryl trichloride-
mediated condensation-cyclization of N-formyl-2-pyridyl-
methylamine. However, 1 possesses several C-H bonds, which
can participate in direct arylation reactions. We report herein
the selective C3 arylation reaction of
1 catalyzed by
[Pd(phen)2](PF6)2 (eq 1). The one-pot double-arylation reaction
of 1 with different aryl groups is also described.
Chem. Lett. 2011, 40, 939-940
© 2011 The Chemical Society of Japan