Published on the web September 5, 2011
1053
Palladium-catalyzed Highly Regioselective C-3 Arylation of Imidazo[1,5-a]pyridine
Chunhui Huang, Alexandros Giokaris, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, Illinois 60607-7061, USA
(Received July 14, 2011; CL-110602; E-mail: vlad@uic.edu)
Table 1. Optimization of reaction conditionsa
A direct palladium-catalyzed highly regioselective C-3
arylation of imidazo[1,5-a]pyridine with aryl bromides has been
developed. This reaction is quite general with respect to the aryl
or hetaryl bromide.
5 mol % Pd(OAc)2
N
+
N
Br
NO2
N
N
Ligand, Base
Toluene, 100 °C
H
C6H4-p-NO2
1
4a
3a
Entry
Ligand
Base
Yield/%b
N-Fused bicyclic heteroarenes have attracted increasing
attention due to their unique biological activities and photo-
physical properties.1 Among them, imidazo[1,5-a]pyridines
(2-azaindolizines) have been actively investigated as photofunc-
tional materials,2 precursors of N-heterocyclic carbenes,3 as well
as versatile pharmaceuticals4 (e.g., cardiotonic agents,5 cortico-
tropin releasing hormone receptors,6 and HIV-protease inhib-
itors7). Therefore, efficient assembly of functionalized imi-
dazo[1,5-a]pyridine derivatives is of high demand. To date, most
synthetic efforts have been devoted to building the imidazole
ring of imidazo[1,5-a]pyridine,8 largely relying on the Vilsmeier-
type cyclization of N-(2-pyridylmethyl)amides.9 However, these
methods either require multistep syntheses of starting materials
or are limited to the particular types of substrates. In contrast,
a direct, late-stage modification of imidazo[1,5-a]pyridine core
is much less studied. Precedented two-step C-3 arylation of
imidazo[1,5-a]pyridine (1) involves its electrophilic bromination
in the presence of HOAc/Br2, followed by the Suzuki cross-
coupling reaction of the formed hetaryl bromide 2 with
arylboronic acids to produce 3 in good yields (eq 1, route A).4a,10
Recently, aryl-aryl bond formation via transition-metal-
catalyzed C-H bond arylation approach achieved enormous
progress in both aromatic and heteroaromatic systems.11 How-
ever, direct C-H bond arylation of imidazopyridine 1 is limited
to a few examples of cationic Pd-catalyzed C-1 arylation of C-3-
substituted imidazo[1,5-a]pyridines.12 To the best of our knowl-
edge, there are no reports on a direct C-3 C-H arylation of 1.
Based on our previous regioselective Pd-catalyzed electrophilic
arylation of indolizines,13 we envisioned that the structural
similarity of imidazo[1,5-a]pyridine and indolizine might allow
the same type of transformations to occur. Herein, we report
an efficient and practical approach toward regioselective C-3
arylation of imidazo[1,5-a]pyridine (eq 1, route B).
1
2
3
4
5
6
7
8
N/A
N/A
N/A
N/A
PPh3
PCy3
Bu4NOAc
Cs2CO3
AgOAc
18
6
17
4
86
71
7
KOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
TDMPPc
t-Bu2MeP¢HBF4
28
aConditions: imidazo[1,5-a]pyridine (1) (1 equiv), p-NO2C6-
H4Br (1 equiv), Pd(OAc)2 (5 mol %), ligand (10 mol %), base
(2 equiv), toluene, 100 °C, 8 h. bNMR yield. cTDMPP:
Tris(2,6-dimethoxyphenyl)phosphine.
(2 equiv) as the base in toluene at 100 °C (Table 1, Entry 1). A
brief screening of various bases resulted in no improvement
of the reaction efficiency (Entries 2-4). Remarkably, addition
of phosphine ligands, such as triphenylphosphine or tricyclo-
hexylphosphine, dramatically increased the efficiency of the
reaction producing 3a in 86% and 71% yield, respectively
(Entries 5 and 6). Employment of more electron-rich and
sterically bulkier ligands was not beneficial for this trans-
formation (Entries 7 and 8). Remarkably, in all cases, no traces
of the regioisomeric C-1-arylated product were detected by the
GC/MS analyses of crude reaction mixtures.
Next, the scope of the regioselective C-3 arylation14 of 1
was examined (Table 2). Gratifyingly, it was found that this
method is quite efficient and very general. A variety of
functional groups, such as nitro (3a), F (3b), CF3 (3d), OMe
(3f), ester (3g), aldehyde (3h), and nitrile (3i), were perfectly
tolerated under these reaction conditions, producing the corre-
sponding biaryls in good to excellent yields. Remarkably, in
all cases, the arylation reactions uniformly gave C-3-arylated
imidazo[1,5-a]pyridines. Of note, 2-bromonaphthalene (4j),
as well as heteroaromatic bromides such as 2-bromopyridine
(4k) and 2-bromothiophene (4l), were competent in this reaction
to produce C-3-naphthyl- and hetaryl-substituted imidazo-
[1,5-a]pyridines in moderate yields. Interestingly, 3k was shown
to be a good ligand for C-1 arylation of 3f.12
Route A
R
R
R
1
HOAc/Br2
ArB(OH)2
2
N
N
3
N
ð1Þ
N
N
N
R ≠ H
Suzuki coupling
Br
H
Ar
1
2
3
At this point, the exact mechanism of this transformation is
unclear. The lack of the kinetic isotope effect (kH/kD = 1.0 for
arylation of 1 and C-3-deuterated analog 1-d)15 could suggest
an electrophilic pathway.13,16 However, since arylation did not
occur at the most nucleophilic C-1 position of this hetero-
cycle,9,17 a concerted metalation-deprotonation (CMD)18 path-
way could be responsible for the observed regiochemistry.
Route B
ArBr (4), Pd/L, Base
First, we tested the cross-coupling reaction of unsubstituted
imidazo[1,5-a]pyridine (1) and 4-bromonitrobenzene (4a).
Promisingly, the C-3-arylated product 3a was formed in 18%
NMR yield by using Pd(OAc)2 catalyst (5 mol %) and Bu4NOAc
Chem. Lett. 2011, 40, 1053-1054
© 2011 The Chemical Society of Japan