Synthesis of 1,3-diarylated imidazo[1,5-a]pyridines with a combinatorial approach: metal-catalyzed cross-coupling reactions of 1-halo-3-arylimidazo[1,5-a]pyridines with arylmetal reagents

Article abstract of DOI:10.1016/j.tet.2009.02.062

The halogenation of 3-arylimidazo[1,5-a]pyridines was carried out with iodine, bromine, N-chlorosuccinimide, and 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as halogenating agents to give selectively halogenated products 1-halo-3-arylimidazo[1,5-

Full text of DOI:10.1016/j.tet.2009.02.062

Tetrahedron 65 (2009) 5062–5073
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Synthesis of 1,3-diarylated imidazo[1,5-a]pyridines with a combinatorial
approach: metal-catalyzed cross-coupling reactions of 1-halo-3-arylimidazo-
[1,5-a]pyridines with arylmetal reagents
*
*
Fumitoshi Shibahara , Eiji Yamaguchi, Asumi Kitagawa, Akio Imai, Toshiaki Murai
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The halogenation of 3-arylimidazo[1,5-a]pyridines was carried out with iodine, bromine, N-chloro-
succinimide, and 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as halogenating agents to give
selectively halogenated products 1-halo-3-arylimidazo[1,5-a]pyridines in good to excellent yields.
Kumada–Tamao–Corriu cross-coupling of the obtained 1-iodo-3-arylimidazo[1,5-a]pyridines and aryl
Grignard reagents led to 1,3-diarylated imidazo[1,5-a]pyridines in good to excellent yields. Suzuki–
Miyaura cross-coupling of the 1-bromo-3-phenylimidazo[1,5-a]pyridine and p- or m-methoxy-
carbonylphenylboronic acids furnished the coupling product in respective yields of 91% and 61%. The
obtained 1,3-diarylated imidazo[1,5-a]pyridines showed a wide variety of fluorescent emissions in
a wavelength range of 449–533 nm with improved quantum yields compared to monoarylated ones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 January 2009
Received in revised form 23 February 2009
Accepted 24 February 2009
Available online 3 March 2009
Keywords:
Halogenation
Cross-coupling
Imidazo[1,5-a]pyridine
Fluorescence
1. Introduction
were expected to be an expandable platform for 1,3-di
arylated imidazo[1,5-a]pyridines by a selective halogenation–
Imidazo[1,5-a]pyridines are an important class of compounds
due to their unique photophysical and biological properties.1 As
a part of our ongoing interest in the synthesis of this family to
explore photo-functional materials, we were interested in methods
cross-coupling sequence.
S
I2 (3 equiv)
pyridine (3 equiv)
N
N
R
N
H
THF
0 °C then rt
15 min
ð1Þ
ð2Þ
N
R
for synthesizing a series of imidazopyridines involving
p-conju-
1
2
gated systems such as aryl and alkynyl groups.2,3 During our studies
on the transformation of thioamides,4 we developed two methods
for forming imidazo[1,5-a]pyridine rings: (1) thioamides 1 that
bear a 2-pyridylmethyl group at a thioamide nitrogen smoothly
undergo oxidative desulfurization–cyclization in the presence of
iodine and pyridine (Eq. 1).5 The reaction gives a wide variety of 3-
substituted imidazo[1,5-a]pyridines 2 in high to excellent yields. In
addition, (2) oxidative condensation–cyclization of aldehyde and
aryl-2-pyridylmethyl amine 3 using elemental sulfur as an oxidant
gives 1,3-diarylated imidazopyridines 4 directly (Eq. 2),6 but less
commonly available 3 must be prepared by a multistep synthesis
from 2-pyridylcarboaldehyde.3a Thus, a more straightforward and
efficient method for synthesizing diverse 1,3-diarylated imid-
azo[1,5-a]pyridines is needed. Meanwhile, 3-arylated imidazo[1,5-
a]pyridines 2, which are readily obtained by the former method,
high to excellent yields
Ar'
Ar'
O
+
1/8 S8 (1.1 equiv)
H2N
N
N
Ar
DMSO
80 °C
N
Ar
good to high yields
3.5 - 40 h
3
4
The transition metal-catalyzed cross-coupling reaction of aryl
halides and arylmetal reagents is one of the most straightforward
synthetic strategies for obtaining a biaryl moiety, and many ex-
amples have been reported.7–12 However, there are few reported
examples in which electron-rich nitrogen-containing heteroaryls
such as imidazopyridines are used as one or both of the coupling
partners (e.g., heteroaryl halide and/or heteroaryl metal),13 since
the oxidative addition of electron-rich aryl halides to low-valence
metals is usually sluggish, and an unprotected nitrogen moiety
readily binds to metal catalysts to possibly inhibit the reaction
(e.g., oxidative addition and transmetallation). In addition,
* Corresponding authors. Tel.: þ81 58 293 2616; fax: þ81 58 293 2794 (F.S.);
tel.: þ81 58 293 2614; fax þ81 58 293 2794 (T.M.).
E-mail addresses: fshiba@gifu-u.ac.jp (F. Shibahara), mtoshi@gifu-u.ac.jp
(T. Murai).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.062

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5063
Table 2
8
5
1
Bromination of 3-arylimidazo[1,5-a]pyridines 2
E
E
E
N
N
N
Br
N
3
Br2 (1.1 equiv)
dioxane, rt, time
E = CH or N
N
N
N
Figure 1. Three main mesomeric contributors of imidazopyridine family.
Ar
Ar
6
2
Entry
Ar
2a
2b
2c
2d
2e
2f
Time (h)
Yielda (%)
electron-rich heteroaryl metal species are usually unstable and
readily undergo protodemetalation due to their high nucleophilic
character.14 In fact, in most previous reports on cross-coupling
with such electron-rich nitrogen-containing heteroaryl substrates,
the substrates were modified by attaching some electron-with-
drawing groups directly to the heteroaryl moiety to reduce the
electron density.13 Therefore, it is important to investigate
methods to achieve such a reaction with high efficiency but in the
absence of electron-withdrawing groups. We report here the
selective halogenation of 3-arylimidazo[1,5-a]pyridines and tran-
sition metal-catalyzed cross-coupling reactions, with Kumada–
Tamao–Corriu (KTC) and Suzuki–Miyaura protocols, with
electron-rich substrates. Under the optimal conditions, the cross-
coupling reactions of the imidazopyridine substrates and aryl-
metal reagents proceeded with high efficiency in the absence of
a protecting group on nitrogen moiety and an electron-with-
drawing group.
1
2
3
4
5
6
7
1.5
2
1.5
2
0.5
1
1.5
6a
6b
6c
6d
6e
6f
82
97
93
99
56
92
89
2h
6h
a
Isolated yields.
an electron-donating or electron-withdrawing substituent at the
4-position of the phenyl group on C3 was carried out. The io-
dination proceeded smoothly to give the desired products 5 in
high to excellent yields (entries 2–6). Meanwhile, the reaction of
imidazopyridine bearing a highly electron-rich 4-dimethylami-
nophenyl group 2g consumed the starting material within 30 min
but resulted in the formation of a complex mixture, maybe due to
competitive iodination at the dimethylaminophenyl group. In-
terestingly, an internal pyridyl group did not inhibit the iodin-
ation, and the reaction of imidazopyridine bearing a 2-pyridyl
group 2h gave the corresponding iodination product 5h in 86%
yield.
2. Results and discussion
2.1. Halogenation
Electrophilic substitution of indolizine-related compounds and
electrophiles is expected to occur at the C1 or C3 position of the
ring due to the electron-rich character of the five-membered ring
moiety and the main mesomeric contributors that are stabilized
by the formation of pyridinium moiety, as shown in Figure 1.1b
Thus, to obtain selective halogenated imidazopyridines 5–8, we
investigated conventional electrophilic halogenations.
2.1.2. Bromination
We then turned to selective bromination with Br2 as a bromine
source.16 Although the reactions in THF or dichloromethane did not
proceed at all, the product 6a was obtained in 82% yield in dioxane
(Table 2, entry 1). Other imidazopyridines were treated with Br2 in
dioxane. Bromination took place with 2 having not only an elec-
tron-donating or -withdrawing group, but also a basic 2-pyridyl
group to give the desired products 6 in excellent yields (entries 2–4,
6, and 7), except for 3-(4-tolyl)imidazopyridine 2e (entry 5). The
reaction of 2e gave 6e in a significantly lower yield (56%), probably
due to the competitive radical bromination at the benzylic position
of the tolyl group.17
2.1.1. Iodination
The iodination of imidazo[1,5-a]pyridines was investigated
first. When 3-phenylimidazo[1,5-a]pyridine (2a) was treated with
3 equiv of iodine in THF under reflux conditions for 2 h, as
expected, the iodination proceeded selectively at the 1-position of
imidazopyridine 2a to give the desired product 5a in 87% yield
(Table 1, entry 1). In the presence of Lewis acid or base such as
AlCl3 or pyridine, no reaction took place.15 Under similar condi-
tions, the C1-selective iodination of imidazopyridines 2 bearing
2.1.3. Chlorination
Chlorination of
2 was also performed with N-chloro-
succinimide (NCS) in dichloromethane. The reactions of 2a,c–f
with a slight excess amount of NCS at room temperature afforded
the desired products 7 in high yields (Table 3, entries 1 and 3–6).
Although the reaction required an excess amount (3 equiv) of
Table 1
Iodination of 3-arylimidazo[1,5-a]pyridines 2
I
Table 3
Chlorination of 3-arylimidazo[1,5-a]pyridines 2
I2 (X equiv)
N
N
Cl
N
N
THF, reflux, time
Ar
Ar
5
NCS (X equiv)
N
N
2
N
N
CH2Cl2, rt, time
Ar
Ar
7
2
Entry
Ar
X (equiv)
Time (h)
Yielda (%)
Entry
Ar
X (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Ph–
4-MeOC6H4–
4-FC6H4–
4-CF3C6H4–
4-MeC6H4–
4-BrC6H4–
4-Me2NC6H4–
2-pyridyl
2a
2b
2c
2d
2e
2f
3
2
3
3
3
3
3
3
2
1
5a
5b
5c
5d
5e
5f
87
99
96
98
82
81
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
1.3
3
1.5
1.5
1.5
2
1.5
2
7a
7b
7c
7d
7e
7f
80
80
84
86
90
84
88
1.5
0.5
1
0.6
0.5
1
1.3
1.5
1.3
1.5
3
2g
2h
5g
5h
Complex mixture
86
2h
2
7h
a
a
Isolated yields.
Isolated yields.

5064
F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
NCS, 4-MeO-phenyl- and 2-pyridyl-substituted 2b and 2h were
also chlorinated in isolated yields of 80% and 88%, respectively
(entries 2 and 7).
not affect the yield, and the reaction under reflux conditions
furnished 4ab in 40% yield along with similar byproducts (entry
2). Treatment with Grignard reagent at ꢀ78 ꢁC followed by stir-
ring at room temperature was not effective for the conversion of
5a (entry 3). In this case, the reaction gave us a complex mixture
after 19 h, though 5a still remained. The use of Ni(acac)2 as
a catalyst and diisopropylaluminum hydride (DIBAL-H) as a re-
ductant for catalyst to prepare Ni(0) species in situ did not give
a good result (entry 4). Meanwhile, the use of diphenylphosphino-
propane (dppp) as a ligand slightly improved the yield of 4ab
(entry 4 vs 5). Although the yield of 4ab did not improve (44%), the
use of Ni(dppp)Cl2 suppressed the formation of 11b (entry 6).
Harsh conditions gave a complex mixture (entry 7). Finally, we
found that immediate workup after complete conversion of the
substrate 5a, which was monitored by TLC analysis, was effective
and the reaction at room temperature for 1 h gave 4ab in 86% yield
(entry 8). The results suggested that the product 4ab is unstable
under these reaction conditions.
2.1.4. Fluorination
Whereas a cross-coupling reaction rarely occurs on a carbon–
fluorine bond, heterocycles bearing fluorine often play an impor-
tant role in pharmaceutical, agrochemical, and material science.18
Thus, we also investigated the fluorination of imidazopyridine 2a.
1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (9) was
chosen as a fluoronium source for fluorination due to its ready
availability. The reaction of 9 in dichloromethane or benzene gave
a small amount of the desired product 8a in 5.6% and 13% yields,
respectively. After the optimization of the solvents, we found that
DMF was a suitable solvent. Concentration of the solution also
slightly affected the product yield and the reaction in 0.25 M DMF
solution of 2a gave the best result, with an isolated yield of 53%
(Eq. 3).
2.2.1.2. Scope of substrates. With the optimum conditions in hand,
the KTC cross-coupling of 5 and a variety of Grignard reagents 10 was
examined with a combinatorialapproach. The results are summarized
in Table 5. The coupling with substituted aryl Grignard reagents 10
proceeded smoothly to give the products 4 in good to excellent NMR
yields and moderate to high isolated yields. The use of tolyl Grignard
10e tends to decrease the isolated yields of the products 4ae–4de,
maybe due to the instability of the product on silica gel. p-Tri-
fluoromethyl imidazopyridine 5d was a relatively sluggish substrate
and the reaction required a slightly longer reaction time (4da–4df).
Since the crystallization of 4bb is quite fast and the product crystal-
lized in a column under purification by column chromatography on
silica gel, the isolated yield of 4bb was significantly less than the NMR
yield. The heteroaryl Grignard reagent 2-thienylmagnesium bromide
(10g) also acted as a coupling partner of 5 to give the products 4ag–
4dg in moderate to high yields, though the reactions needed ca. 36 h
for complete conversion. In addition, no reactions were observed in
the reaction of pyridyl imidazopyridine 5h and any of the Grignard
reagents tested under these conditions.
N
-
F
F
BF4
9
ð3Þ
(2 equiv)
N
N
N
N
DMF (0.25 M)
rt, 2 h then 60 °C, 15 h
Ph
Ph
53% yield
2a
8a
2.2. Cross-coupling reactions
2.2.1. Nickel-catalyzed KTC cross-coupling using 1-iodoimidazo-
pyridines
KTC cross-coupling was examined as the first choice for a cross-
coupling reaction with iodoimidazopyridines 5 due to the ready
availability of Grignard reagents.
2.2.1.1. Optimization of reaction conditions. First, KTC cross-cou-
pling of 5a and 4-methoxyphenylmagnesium bromide (10b) un-
der different typical conditions was examined (Table 4). A mixture
of 5a and NiCl2 (10 mol %) was treated with 10b at room tem-
perature to give the coupling product 4ab in 44% yield along with
significant amounts of homocoupling product 11b and reduced
starting imidazopyridine 2a (entry 1). A higher temperature did
2.2.2. Palladium-catalyzed Suzuki–Miyaura cross-coupling reaction
Although we succeeded in the KTC cross-coupling of 5 and aryl
Grignard reagents 10, the compatibility of the substituents (e.g., the
use of ester, nitrile, and nitro groups) was still problematic under
Table 4
Optimization of KTC cross-coupling of 5a and 4-methoxyphenylmagnesium bromide
MeO
MeO
+
MeO
I
conditions
+
+
2a
N
N
N
MgBr
N
Ph
5a (0.5 mmol) 10b (3 equiv.)
Ph
OMe
11b
4ab
Entry
Conditions
Yielda (%)
1
2
3
4
5
6
7
8
NiCl2 (10 mol %), rt, 3 h
44
40
NiCl2 (10 mol %), 0 ꢁC then reflux, 2.5 h
NiCl2 (10 mol %), ꢀ78 ꢁC then rt, 19 h
Complex mixture
13
40
44
Complex mixture
86
Ni(acac)2 (10 mol %), DIBAL-H(20 mol %), 0 ꢁC then rt, 4 h
Ni(acac)2 (10 mol %), DIBAL-H (20 mol %), dppp (20 mol %), 0 ꢁC then rt, 3 h
Ni(dppp)Cl2 (10 mol %), 0 ꢁC then rt, 3 h
Ni(dppp)Cl2 (10 mol %), 0 ꢁC then reflux, 2.5 h
Ni(dppp)Cl2 (10 mol %), 0 ꢁC then rt, 1 h
a
Isolated yields.

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5065
Table 5
Substrate scope of KTC cross-couplinga
I
Ar'
Ar'
MgBr
Ni(dppp)Cl2 (10 mol%)
THF, 0 °C then rt
+
N
N
N
N
Ar
Ar
4
5 (0.5 mmol)
10 (3 equiv.)
MeO
F
Me
S
N
N
N
N
N
N
N
N
N
N
4aa
4ab
4ac
4ae
4ag
b
36 h, nd (52%)
30 min, 99%(80%)
1 h, 90%(83%)
1 h, 83%(58%)
1 h, 85%(52%)
MeO
F
Me
S
N
N
N
N
N
N
N
N
N
N
MeO
MeO
MeO
MeO
MeO
4bg
4ba
4bb
4bc
4be
b
37 h, nd (68%)
1 h, 93%(81%)
1 h, 83%(62%)
1 h, 98%(96%)
1 h, 90%(58%)
MeO
F
Me
S
N
N
N
N
N
N
N
N
N
N
F
F
F
F
F
4cg
4ca
4cb
4cc
4ce
b
36 h, nd (81%)
1 h, 95%(89%)
1 h, 88%(83%)
1 h, 83%(83%)
1 h, 80%(52%)
MeO
F
Me
Me2N
S
N
N
N
N
N
N
N
N
N
N
N
N
F3C
F3C
F3C
F3C
F3C
F3C
4da
4db
4dc
4de
4df
4dg
b
36 h, nd (93%)
1.5 h, 68%(37%)
a
1 h, 68%(66%)
2 h, 83%(55%)
1.5 h, 70%(58%)
2 h, 98%(48%)
NMR yields are shown. Isolated yields are shown in parentheses.
bNot determined.
these conditions. Therefore, Suzuki–Miyaura cross-coupling was
investigated next.
product, and starting 5a was recovered in 54% yield (Table 6, entry
1). The use of Pd(PPh3)4 instead of Pd(OAc)2 in the reaction with 5d
led to the reduced product 2d in quantitative yield (entry 2). On the
other hand, the use of brominated imidazopyridine 6a in the
presence of Pd(OAc)2 or Pd(PPh3)2Cl2 gave the coupling product
4aa in respective yields of 38% and 59% (entries 3 and 4). After
several optimizations, we found that the treatment of 6a with
In our first unsuccessful attempts at Suzuki–Miyaura cross-
coupling, iodinated imidazopyridine 5a or 5d was used in the re-
action as a coupling partner. For example, the treatment of 5a with
a catalytic amount of Pd(OAc)2 and a stoichiometric amount of
Cs2CO3 and phenylboronic acid (12a) did not give the coupling

5066
F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
Table 6
MeOOC
Optimization of Suzuki–Miyaura cross-coupling of 5 and phenylboronic acid (12a)
MeOOC
Br
N
Pd cat (5 mol%
base (2 equiv.)
ligand
)
X
+
+
+
2a
N
N
N
conditions
N
B(OH)2
N
N
Ph
6a
B(OH)2
12a (1.1 equiv.)
N
Ph
5a or 6a
Pd(dba)2 (5 mol%)
12i (1.1 equiv.)
Ph
4ai
KOH (2 equiv.)
Ph
(0.5 mmol)
91%
(0.5 mmol)
4aa
P(t-Bu)3 (10 mol%)
COOMe
DMF, 80 °C, 7 h
Entry
X
Pd cat
Base
Ligand
Conditions
Yielda (%)
COOMe
Br
1
I
I
Br
Br
Br
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(dba)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
d
50 ꢁC, 30 h
90 ꢁC, 27 h
80 ꢁC, 90 h
80 ꢁC, 90 h
80 ꢁC, 3 h
db
dd
38
59
84
2c
3
d
+
N
N
d
N
B(OH)2
N
4
5
d
Ph
e
P(t-Bu)3
6a
12j(1.1 equiv.)
Ph
4aj
(0.5 mmol)
a
61%
Isolated yield.
Starting 5a was recovered in 54% yield.
Compound 5d was used as a substrate.
Compound 2d was obtained as a reduced product in 97% yield.
10 mol %.
b
c
Scheme 1. Suzuki–Miyaura cross-coupling of 6a and 11h-i.
d
e
are summarized in Table 7. As a result, trends in absorption,
emission, and quantum yield are still unclear due to the compli-
cated dual influences of two aryl groups, whereas the introduction
of an aryl group into imidazo[1,5-a]pyridines obviously affected
emission color and improved the quantum yield compared with
those of parent 2a–h (entries 1–8 vs 9–29). Nonetheless, the
emissions of p-fluorophenyl substituted at C3 4ca–4cg were sig-
nificantly influenced by the substituents at the C1 positions com-
pared to other substrates (entries 19–23). Similarly, the emissions
of a p-tolyl or 2-thienyl group at C1 4ae–4de (entries 12, 17, 22, and
27) and 4ag–4dg (entries 13, 18, 23, and 28) were quite sensitive to
the substituents on C3. The emission efficiencies for a strong
electron-withdrawing carboxymethyl group-substituted 4ai and
4aj were significantly decreased as in the case of 3-(4-nitro-1,10-
biphen-40-yl)imidazo[1,5-a]pyridine.19
Pd(dba)2 and P(t-Bu)3 as a catalyst and KOH as a base for 3 h gave
the product in 84% yield (entry 5).
Subsequently, the reactions of p- or m-methoxycarbonyl
phenylboronic acids 12i,j were carried out under these conditions
(Scheme 1). The reaction of 12i afforded the product 4ai in high
yield. Although the yield was slightly decreased, the reaction of 12j
also gave the product 4aj in 61% yield. In both cases, no hydrolysis of
ester was observed.
2.3. Photophysical properties of imidazo[1,5-a]pyridines
The obtained products emitted a variety of fluorescence, as
shown in Figure 2. To better understand the details of the photo-
physical properties, UV/vis and fluorescent spectra of the products
F
Me2N
N
MeO
N
MeO
N
F
S
S
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
MeO
F
MeO
F3C
F3C
F3C
MeO
F
Figure 2. Selected emissions of obtained imidazo[1,5-a]pyridines in CHCl3 under 365 nm irradiation.

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5067
Table 7
Table 7 (continued)
Photophysical studies on obtained imidazo[1,5-a]pyridines
Entry
Compound
UV/visa
Fluorescencea
Entry
Compound
UV/visa
Fluorescencea
b
lmax (nm) log
3
lmax (nm) FF
b
lmax (nm) log
3
lmax (nm) FF
F
N
N
11
308
293
4.30 461
0.14
0.20
N
N
N
N
1
317
306
4.25 461
0.072
0.052
4ac
2a
12
13
3.92 457
N
2
3
4
5
4.05 469
N
4ae
2b
MeO
N
322
4.16 533
0.087
N
S
N
312
340
314
4.11 465
4.12 459
4.11 458
0.060
0.039
0.064
N
4ag
2c
F
N
N
14
301
4.25 465
0.18
N
N
4ba
2d
MeO
F3C
OMe
N
N
15
16
17
18
303
317
303
316
4.31 479
4.25 461
4.25 521
4.05 483
0.22
0.063
0.13
N
N
4bb
2e
MeO
F
N
N
N
269,
322
4.14,
482
6
7
8
0.076
0.025
0.022
N
N
N
4.33
4bc
2f
MeO
Me2N
N
340
348
4.12 475
N
S
4be
2g
MeO
N
N
0.14
4.04 425
S
N
N
N
4bg
2h
MeO
N
N
N
19
20
304
268
4.11 449
0.19
0.17
9
308
308
4.18 454
0.14
0.17
N
N
4ca
4aa
F
OMe
N
OMe
N
4.12 526
10
4.35 471
N
4cb
4ab
F

5068
F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
Table 7 (continued)
Table 7 (continued)
Entry
Compound
UV/visa
Fluorescencea
Entry
Compound
UV/visa
Fluorescencea
b
b
lmax (nm) log
3
lmax (nm) FF
lmax (nm) log
3
lmax (nm) FF
F
N
N
COOMe
N
30
339
339
4.38 477
0.080
21
297
293
4.11 486
0.20
0.16
N
4cc
4ai
F
N
31
4.92 474
<0.01
N
N
N
22
4.10 523
COOMe
4aj
4ce
F
a
Measured in CHCl3.
b
Quantum yields (FF) were determined with reference to quinine sulfate in 0.1 M
aqueous sulfuric acid (excited at 350 nm).20
N
23
319
4.12 511
0.12
S
N
4cg
F
3. Conclusion
In conclusion, we have investigated a set of halogenations for
imidazo[1,5-a]pyridines. The iodinated and brominated imidazo-
pyridines obtained could be used in KTC or Suzuki–Miyaura cross-
coupling. Although the trend in emission is still unclear, a series of
imidazopyridines showed a wide variety of fluorescent emissions.
N
N
301,
343
3.85,
479
24
0.11
0.16
0.15
0.11
3.87
4da
F3C
Further investigations on introduction of some other
p-system
into imidazo[1,5-a]pyridines and the theoretical design of such
compounds for functional materials are in progress in our
laboratory.
OMe
N
N
301,
353
4.02,
467
25
3.94
4. Experimental
4.1. General
4db
F3C
The IR spectra were obtained on a JASCO FT-IR spectropho-
tometer. The 1H NMR, 13C NMR, and 19F NMR spectra were
F
N
N
291,
353
3.95,
478
26
3.90
recorded on a JEOL
ical shifts of 1H and 13C are reported in
tetramethylsilane and CDCl3 as an internal standard, re-
spectively. The 19F chemical shifts are expressed in
value
a
-400 (400, 100, 376 MHz) in CDCl3. Chem-
d
values referred to
4dc
F3C
d
deshielded with respect to CF3COOH as an external standard.
The mass spectra (MS) and high resolution mass spectra (HRMS)
were taken on a JEOL JNM 700 mass spectrometer. Elemental
analyses were carried out by Elemental Analysis Center of Kyoto
University. Melting points were determined using a Yanagimoto
melting point apparatus and are uncorrected. UV/vis spectra
were measured on a JAI Ubest-55 spectrophotometer. Fluores-
cence spectra were measured on a Hitachi F-4500 spectropho-
tometer. Preparative recycling gel permeation chromatography
(GPC) was performed on a Japan Analytical Industry LC-908
recycling preparative HPLC equipped with JAIGEL-1H and -2H
columns (chloroform as an eluent). Unless otherwise noted, re-
agents were commercially available and were used without
purification. Imidazo[1,5-a]pyridines 2 were prepared according
to our previously reported method.5 Tetrahydrofuran (dehy-
drated) was purchased from Kanto Chemical Co., and used
without further purification. DMF was distilled over calcium
hydride under reduced pressure. Silica gel used for column
chromatography was Silica gel 60 N (Spherical, Neutral, 100–
210 mm) from Kanto Chemical Co., Inc.
N
296,
359
4.16,
487
27
N
4.08
4de
F3C
NMe2
N
28
313
4.12 508
0.12
0.11
N
4df
F3C
N
269,
309
4.00,
474
29
S
N
3.77
4dg
F3C

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5069
4.2. General procedure for the iodination
of 3-arylimidazo[1,5-a]pyridines 2
4.2.6. 1-Iodo-3-(4-bromophenyl)imidazo[1,5-a]pyridine (5f)
Yield 81%, pale green solid, mp 134–135 ꢁC, Rf¼0.63 (hexane/
AcOEt¼4:1). IR (KBr): 2931, 1627, 1497, 1359, 1260, 1003, 833,
To a solution of 3-arylimidazo[1,5-a]pyridine 2 (2 mmol) in THF
(4 mL) was added iodine (1.53 g, 6 mmol, 3 equiv) at room tem-
perature under an Ar atmosphere. The resulting mixture was stir-
red at reflux temperature. The reaction mixture was quenched with
saturated Na2S2O3 aq, neutralized with NaHCO3 aq, and extracted
with CH2Cl2 (30 mLꢂ3). The combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give 1-iodo-3-
arylimidazo[1,5-a]pyridine 5.
740 cmꢀ1
.
1H NMR (CDCl3):
d
6.56 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.74
(dd, J¼6.3, 8.2 Hz, 1H, Ar), 7.29 (d, J¼9.3 Hz, 2H, Ar), 7.55–7.58 (m,
4H, Ar), 8.09 (d, J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 114.3, 119.1,
120.4, 121.6, 123.1, 128.2, 129.3, 132.2, 133.6, 139.3 (Ar). HRMS (EI)
m/z: calcd for C13H789BrIN2 (Mþ) 397.8916; found: 397.8905.
4.2.7. 1-Iodo-3-(2-pyridyl)imidazo[1,5-a]pyridine (5h)
Yield 86%, pale yellow solid, mp 157–158 ꢁC, Rf¼0.45 (hexane/
AcOEt¼4:1). IR (KBr): 2358, 1586, 1495, 1353, 1013, 754, 738 cmꢀ1
.
1H NMR (CDCl3):
d
6.72 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.90 (dd, J¼6.3,
4.2.1. 1-Iodo-3-phenylimidazo[1,5-a]pyridine (5a)
8.7 Hz,1H, Ar), 7.17 (ddd, J¼1.5, 4.8, 6.3 Hz,1H, Ar), 7.37 (d, J¼8.3 Hz,
1H, Ar), 7.73 (ddd, J¼1.5, 6.3, 8.3 Hz, 1H, Ar), 8.30 (d, J¼8.7 Hz, 1H,
Ar), 8.58 (d, J¼4.8 Hz, 1H, Ar), 9.90 (d, J¼7.3 Hz, 1H, Ar). 13C NMR
Yield 87%, brownish solid, mp 118–119 ꢁC, Rf¼0.52 (hexane/
AcOEt¼4:1). IR (KBr): 1629.6, 1511.0, 1453.1, 1356.7, 1257.4, 1005.7,
942.1, 773.3, 740.5, 698.1, 682.7 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
(CDCl3): d 114.2, 118.2, 121.4, 121.8, 121.9, 126.5 (two carbon atoms
d
6.52 (t, J¼7.3 Hz, 1H), 6.72 (dd, J¼7.3, 9.3 Hz, 1H), 7.27 (d, J¼9.3 Hz,
were overlapped), 134.5, 136.5, 137.7, 148.0, 150.2 (Ar). HRMS (EI)
1H), 7.36 (d, J¼7.3 Hz, 1H), 7.43 (t, J¼7.3 Hz, 2H), 7.68 (d, J¼7.3 Hz,
m/z: calcd for C12H8IN3 (Mþ) 320.9763; found: 320.9780.
2H), 8.13 (d, J¼7.3 Hz, 1H). 13C NMR (CDCl3):
d 74.1, 113.9, 119.0,
4.3. General procedure for the bromination
of 3-arylimidazo[1,5-a]pyridines 2
120.2, 121.8, 128.0, 129.0, 129.1, 129.3, 133.4, 140.5. HRMS (EI) m/z:
calcd for C13H9IN2 (Mþ), 319.9810; found 319.9820.
To a solution of 3-arylimidazo[1,5-a]pyridine 2 (5.0 mmol) in
dioxane (10 mL) was added a solution of bromine (0.27 mL,
5.5 mmol, 1.1 equiv) in dioxane (10 mL) at 0 ꢁC under an air atmo-
sphere. The resulting solution was stirred at room temperature for
1.5 h. The reaction mixture was quenched with saturated Na2S2O3
aq, neutralized with NaOH aq, and extracted with CH2Cl2. The or-
ganic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel to give 1-bromo-3-arylimidazo[1,5-a]pyridine 6.
4.2.2. 1-Iodo-3-(4-methoxyphenyl)imidazo[1,5-a]pyridine (5b)
Yield 99%, green solid, mp 114.0–114.5 ꢁC, Rf¼0.23 (hexane/
AcOEt¼4:1). IR (KBr): 3009, 2935, 2835, 1606, 1525, 1505,
1455 cmꢀ1
.
1H NMR (CDCl3):
d
3.80 (s, 3H, OMe), 6.51 (dd, J¼6.3,
7.3 Hz, 1H, Ar), 6.70 (dd, J¼6.3, 9.3 Hz, 1H, Ar), 6.93 (d, J¼8.8 Hz, 2H,
Ar), 7.27 (d, J¼9.3 Hz, 1H, Ar), 7.61 (d, J¼8.8 Hz, 2H, Ar), 8.07 (d,
J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 55.4 (OMe), 113.7, 114.4,
114.7, 118.9, 119.9, 121.7, 129.5, 129.8, 133.0, 140.0, 160.1 (Ar). HRMS
(EI) m/z: calcd for C14H11IN2O (Mþ) 349.9916; found: 349.9911.
4.3.1. 1-Bromo-3-phenylimidazo[1,5-a]pyridine (6a)
4.2.3. 1-Iodo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (5c)
Yield 96%, colorless solid, mp 125.0–125.5 ꢁC, Rf¼0.51 (hexane/
AcOEt¼4:1). IR (KBr): 3055, 3020, 1520, 1503, 1230 cmꢀ1. 1H NMR
Yield 82%, brownish solid, mp 127–129 ꢁC, Rf¼0.53 (hexane/
AcOEt¼4:1). IR (KBr): 3390, 1632, 1513, 1264, 1010, 740 cmꢀ1
.
1H
NMR (CDCl3)
d
6.54 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.72 (dd, J¼6.3,
(CDCl3):
d
6.63 (t, J¼6.8 Hz, 1H, Ar), 6.82 (dd, J¼6.8, 9.1 Hz, 1H, Ar),
8.8 Hz, 1H, Ar), 7.35–7.48 (m, 4H, Ar), 7.72 (d, J¼8.3 Hz, 2H, Ar), 8.15
7.22 (t, J¼8.8 Hz, 2H, Ar), 7.37 (d, J¼9.1 Hz, 1H, Ar), 7.75 (q, J¼8.8 Hz,
(d, J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 106.5, 113.2, 113.9, 118.0,
2H, Ar), 8.14 (d, J¼6.8 Hz, 1H, Ar). 13C NMR (CDCl3):
d 114.1 (Ar),
119.6, 121.5, 127.9, 128.9, 129.1, 129.3, 137.6 (Ar). HRMS (EI) m/z:
116.2 (d, J¼21.9 Hz, F–C–C), 119.1, 120.2, 121.5, 125.5, 126.0 (Ar),
130.0 (d, J¼8.8 Hz, F–C–C]C), 133.4, 139.5, 162.2 (d, J¼272 Hz, F–C).
calcd for C13H799BrN2 (Mþ) 271.9949; found: 271.9952.
19F NMR (CDCl3)
d
ꢀ111.8 (F). HRMS (EI) m/z: calcd for C13H8FIN2
4.3.2. 1-Bromo-3-(4-methoxyphenyl)imidazo[1,5-a]pyridine (6b)
Yield 97%, yellow solid, mp 89–89.5 ꢁC, Rf¼0.34 (hexane :
(Mþ) 337.9716; found: 337.9719.
AcOEt¼4 : 1). IR (KBr): 2935, 1523, 1247 cmꢀ1
.
1H NMR (CDCl3):
3.80 (s, 3H, OMe), 6.51 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.70 (dd, J¼6.3,
4.2.4. 1-Iodo-3-(4-trifluoromethylphenyl)imidazo-
[1,5-a]pyridine (5d)
d
9.3 Hz, 1H, Ar), 6.93 (d, J¼8.8 Hz, 2H, Ar), 7.27 (d, J¼9.3 Hz, 1H, Ar),
Yield 98%, off-white solid, mp 91.0–91.5 ꢁC, Rf¼0.47 (hexane/
7.61 (d, J¼8.8 Hz, 2H, Ar), 8.07 (d, J¼7.3 Hz, 1H, Ar). 13C NMR
AcOEt¼4:1). IR (KBr): 3109, 3078,1586,1523,1503,1321 cmꢀ1.1H NMR
(CDCl3):
d 55.4 (OMe), 113.7, 114.4, 114.7, 118.9, 119.9, 121.7, 129.5,
(CDCl3):
d
6.57 (dd, J¼6.4, 5.6 Hz,1H, Ar), 6.76 (dd, J¼5.6, 8.6 Hz,1H, Ar),
79
129.8, 133.0, 140.0, 160.1 (Ar). HRMS (EI) m/z: calcd for C14
H BrN2O
11
7.28 (d, J¼8.6 Hz,1H, Ar), 7.65 (d, J¼7.6 Hz, 2H, Ar), 7.80(d, J¼7.6 Hz, 2H,
(Mþ) 302.0055; found: 302.0059.
Ar), 8.13 (d, J¼6.4 Hz, 1H, Ar). 13C NMR (CDCl3):
d 114.7, 119.3, 120.8,
121.6, 123.9 (q, J¼272.1 Hz, F3C), 126.0 (q, J¼4.1 Hz, F3C–C]C), 128.0
(two carbon peaks were overlaped) (Ar), 130.7 (q, J¼33.1 Hz, F3C–C),
4.3.3. 1-Bromo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (6c)
Yield 93%, pale yellow solid, mp 82–83 ꢁC, Rf¼0.68 (hexane/
132.8,134.0,138.9 (Ar); 19F NMR (CDCl3)
d
ꢀ63.4 (CF3). HRMS (EI) m/z:
AcOEt¼2:1). IR (KBr): 3083,1520,1231,1009 cmꢀ1. 1H NMR (CDCl3):
calcd for C14H18F3IN2 (Mþ) 387.9684; found: 387.9687.
d
6.53 (dd, J¼6.8, 7.4 Hz, 1H, Ar), 6.72 (dd, J¼7.4, 9.2 Hz, 1H, Ar),
7.10–7.16 (m, 2H, Ar), 7.34 (d, J¼9.2 Hz, 1H, Ar), 7.62–7.71 (m, 2H,
Ar), 8.06 (d, J¼6.8 Hz, 1H, Ar). 13C NMR (CDCl3):
d 106.2, 114.0 (Ar),
4.2.5. 1-Iodo-3-(4-methylphenyl)imidazo[1,5-a]pyridine (5e)
Yield 82%, green solid, mp 80.5–82 ꢁC, Rf¼0.50 (hexane/
AcOEt¼4:1). IR (KBr): 2918, 2361, 1712, 1630, 1523, 1504, 1455, 1361,
115.1 (d, J¼21.8 Hz, F–C–C), 117.8, 119.6, 121.1, 125.3, 128.7 (Ar), 129.6
(d, J¼8.3 Hz, F–C–C]C), 136.4 (Ar), 162.7 (d, J¼250 Hz, F–C). 19F
1260, 1113, 1005, 741 cmꢀ1. 1H NMR (CDCl3):
d 2.34 (s, 3H, Me), 6.49
NMR (CDCl3):
d
ꢀ111.8 (F). HRMS (EI) m/z: calcd for C13H8F79BrN2
(Mþ) 289.9855; found: 289.9850.
(dd, J¼6.8, 7.3 Hz, 1H, Ar), 6.68 (dd, J¼6.8, 8.7 Hz, 1H, Ar), 7.18–7.27
(m, 3H, Ar), 7.56 (d, J¼7.8 Hz, 2H, Ar), 8.10 (d, J¼7.3 Hz, 1H, Ar). 13C
NMR (CDCl3):
d
21.3 (Me), 113.6, 118.8, 119.9, 121.8, 126.4, 127.8 (two
4.3.4. 1-Bromo-3-(4-trifluoromethylphenyl)imidazo-
[1,5-a]pyridine (6d)
Yield 99%, brownish solid, mp 111–113 ꢁC, Rf¼0.23 (hexane/
AcOEt¼4:1). IR (KBr): 2923, 1714, 1617, 1362, 1324, 1221, 1119, 1066,
carbon atoms were overlapped.), 129.6, 133.1, 139.0, 140.5 (Ar).
HRMS (EI) m/z: calcd for C14H11IN2 (Mþ) 333.9967; found:
333.9936.

5070
F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
35
1012 cmꢀ1. 1H NMR (CDCl3):
d
6.62 (dd, J¼6.5, 7.3 Hz, 1H, Ar), 6.78
125.9, 129.3, 135.9, 160.9 (Ar). HRMS (EI) m/z: calcd for C H ClN2O
14 11
(dd, J¼6.5, 9.3 Hz, 1H, Ar), 7.39 (d, J¼9.3 Hz, 1H, Ar), 7.69 (d, J¼8.3 Hz,
(Mþ) 258.0560; found: 258.0542.
2H, Ar), 7.84 (d, J¼8.3 Hz, 2H, Ar), 8.18 (d, J¼7.3 Hz, 1H, Ar). 13C NMR
(CDCl3):
d
107.2,114.6,118.1,120.2,121.2 (Ar),123.9 (q, J¼272 Hz, F3C),
4.4.3. 1-Chloro-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (7c)
125.9 (q, J¼3.3 Hz, F3C–C]C), 127.7, 129.5 (Ar), 130.4 (q, J¼32.2 Hz,
Yield 84%, brownish solid, mp 83–85 ꢁC, Rf¼0.55 (hexane/
F3C–C), 132.6, 135.8 (Ar). 19F NMR (CDCl3):
d
ꢀ63.4 (CF3). HRMS (EI)
AcOEt¼3:1). IR (KBr): 2922, 1524, 1232, 1023 cmꢀ1
.
1H NMR
m/z: calcd for C14H789BrF3N2 (Mþ) 339.9823; found: 339.9818.
(CDCl3):
d
6.65 (dd, J¼6.4, 7.3 Hz, 1H, Ar), 6.81 (dd, J¼6.4, 9.3 Hz, 1H,
Ar), 7.22–7.30 (m, 2H, Ar), 7.49 (d, J¼9.3 Hz, 1H, Ar), 7.76–7.80 (m,
2H, Ar), 8.16 (d, J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 114.0 (Ar),
4.3.5. 1-Bromo-3-(4-methylphenyl)imidazo[1,5-a]pyridine (6e)
Yield 56%, pale green solid, mp 107–109 ꢁC, Rf¼0.68 (hexane/
116.1 (d, J¼21.9 Hz, F–C–C), 117.6, 119.2, 121.0, 125.4, 125.5, 126.4
AcOEt¼2:1). IR (KBr): 3064, 1502, 1366 cmꢀ1
.
1H NMR (CDCl3):
(Ar),129.8 (d, J¼7.7 Hz, F–C–C]C), 134.9 (Ar), 162.9 (d, J¼249 Hz, F–
C). 19F NMR (CDCl3):
d
ꢀ111.8 (F). HRMS (EI) m/z: calcd for
d
2.40 (s, 3H, Me), 6.49 (dd, J¼7.3, 8.3 Hz, 1H, Ar), 6.68 (dd, J¼8.3,
C13H385ClFN2 (Mþ) 246.0360; found: 246.0347.
9.3 Hz, 1H, Ar), 7.22 (d, J¼8.3 Hz, 2H, Ar), 7.32 (d, J¼9.3 Hz, 1H, Ar),
7.56 (d, J¼8.3 Hz, 2H, Ar), 8.10 (d, J¼7.3 Hz,1H, Ar). 13C NMR (CDCl3):
d
21.45 (Me),113.7,118.0,119.4,121.5,126.4,127.8,128.7,129.6,129.7,
4.4.4. 1-Chloro-3-(4-trifluoromethylphenyl)imidazo[1,5-a]-
pyridine (7d)
BrN2 (Mþ)
79
131.7, 139.0 (Ar). HRMS (EI) m/z: calcd for C14
286.0106; found: 286.0099.
H
11
Yield 86%, brownish solid, mp 104–105 ꢁC, Rf¼0.43 (hexane/
AcOEt¼4:1). IR (KBr): 2914, 1743, 1706, 1657, 1617, 1461, 1414, 1325,
1165, 1122, 1067 cmꢀ1. 1H NMR (CDCl3):
d
6.66 (dd, J¼6.3, 7.3 Hz,1H,
4.3.6. 1-Bromo-3-(4-bromophenyl)imidazo[1,5-a]pyridine (6f)
Yield 92%, yellow solid, mp 132–133 ꢁC, Rf¼0.69 (hexane/
Ar), 6.81 (dd, J¼6.3, 9.0 Hz,1H, Ar), 7.48 (d, J¼9.0 Hz, 1H, Ar), 7.74 (d,
AcOEt¼3:1). IR (KBr): 3083,1500,1368 cmꢀ1. 1H NMR (CDCl3)
d 6.56
J¼8.2 Hz, 2H, Ar), 7.89 (d, J¼8.2 Hz, 2H, Ar), 8.22 (d, J¼7.3 Hz, 1H,
Ar). 13C NMR (CDCl3):
d 114.7, 117.8, 119.8, 120.7, 121.2 (Ar), 123.9 (q,
(dd, J¼6.8, 7.3 Hz, 1H, Ar), 6.74 (dd, J¼6.8, 9.1 Hz, 1H, Ar), 7.35 (dd,
J¼4.9, 7.6 Hz, 1H, Ar), 7.54–7.59 (m, 4H, Ar), 8.09 (d, J¼7.3 Hz, 1H,
Ar). 13C NMR (CDCl3): 106.7, 114.4, 118.2, 119.9, 121.3, 123.1, 128.2,
129.1, 129.2, 132.2, 136.4 (Ar). HRMS (EI) m/z: calcd for C13H789Br2N2
(Mþ) 349.9054; found: 349.9050.
J¼272 Hz, F3C), 126.0 (q, J¼3.9 Hz, F3C–C]C), 127.2, 127.9 (Ar), 130.5
(q, J¼32.7 Hz, F3C–C), 132.8, 134.3 (Ar). 19F NMR (CDCl3):
d
ꢀ63.4
(CF3). HRMS (EI) m/z: calcd for C14H385ClF3N2 (Mþ) 296.0328; found:
296.0337.
4.3.7. 1-Bromo-3-(2-pyridyl)imidazo[1,5-a]pyridine (6h)
4.4.5. 1-Chloro-3-(4-methylphenyl)imidazo[1,5-a]pyridine (7e)
Yield 90%, brownish solid, mp 68–69 ꢁC, Rf¼0.48 (hexane/
AcOEt¼3:1). IR (KBr): 3064, 1507, 1376, 1024 cmꢀ1. 1H NMR (CDCl3):
Yield 89%, yellow solid, mp 126–127 ꢁC, Rf¼0.65 (hexane/
AcOEt¼3:1). IR (KBr): 3116, 1587, 1495, 1369 cmꢀ1. 1H NMR (CDCl3):
d
6.68 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.84 (dd, J¼6.3, 9.3 Hz, 1H, Ar), 7.11
d
2.34 (s, 3H, Me), 6.49 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.66 (dd, J¼6.3,
(dd, J¼4.9, 7.6 Hz, 1H, Ar), 7.38 (d, J¼9.3 Hz, 1H, Ar), 7.77 (dd, J¼7.6,
8.2 Hz, 1H, Ar), 8.22 (d, J¼7.3 Hz, 1H, Ar), 8.53 (d, J¼4.9 Hz, 1H, Ar),
9.85 (d, J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3): 106.9, 114.3, 117.2, 121.0,
121.7, 121.8, 126.2, 130.2, 134.7, 136.5, 148.1, 150.2 (Ar). HRMS (EI)
m/z: calcd for C12H881BrN3 (Mþ) 274.9881; found: 274.9852.
9.3 Hz, 1H, Ar), 7.22 (d, J¼7.8 Hz, 2H, Ar), 7.35 (d, J¼9.3 Hz, 1H, Ar),
7.58 (d, J¼7.8 Hz, 2H, Ar), 8.09 (d, J¼7.3 Hz, 1H, Ar). 13C NMR
(CDCl3):
d 21.3 (Me), 113.7, 117.4, 119.0, 119.5, 121.4, 126.1, 126.4,
35
127.7, 129.6, 136.0, 139.0 (Ar). HRMS (EI) m/z: calcd for C14
H ClN2
11
(Mþ) 242.7035; found: 242.0610.
4.4. General procedure for the chlorination
of 3-arylimidazo[1,5-a]pyridines 2
4.4.6. 1-Chloro-3-(4-bromophenyl)imidazo[1,5-a]pyridine (7f)
Yield 84%, brownish solid, mp 124–126 ꢁC, Rf¼0.23 (hexane/
AcOEt¼10:1). IR (KBr): 2935, 1526, 1249, 1020 cmꢀ1
.
1H NMR
To a solution of 3-arylimidazo[1,5-a]pyridine 2 (0.50 mmol) in
CH2Cl2 (1 mL) was added NCS (0.09 g, 0.65 mmol,1.3 equiv) at room
temperature under an Ar atmosphere. The resulting solution was
stirred at room temperature for 1.5 h. The reaction mixture was
quenched with saturated Na2S2O3 aq, neutralized with NaHCO3 aq,
and extracted with CH2Cl2 (30 mLꢂ3). The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give 1-chloro-3-
arylimidazo[1,5-a]pyridine 7.
(CDCl3):
d
6.54 (dd, J¼6.3, 6.8 Hz, 1H, Ar), 6.70 (dd, J¼6.8, 9.3 Hz, 1H,
Ar), 7.36 (d, J¼9.3 Hz, 1H, Ar), 7.52–7.57 (m, 4H, Ar), 8.06 (d,
J¼6.8 Hz, 1H, Ar). 13C NMR (CDCl3):
d 114.3, 117.6, 119.4, 120.0, 121.1,
122.9, 126.6, 128.1, 129.1, 132.2, 134.6 (Ar). HRMS (EI) m/z: calcd for
C13H881Br37ClFN2 (Mþ) 309.9530; found: 309.9516.
4.4.7. 1-Chloro-3-(2-pyridyl)imidazo[1,5-a]pyridine (7h)
Yield 88%, colorless solid, mp 104–105 ꢁC, Rf¼0.50 (hexane/
AcOEt¼3:1). IR (KBr): 3118, 1590, 1495, 1377, 1031 cmꢀ1
.
1H NMR
(CDCl3):
d
6.68 (dd, J¼6.3, 7.8 Hz, 1H, Ar), 6.84 (dd, J¼6.3, 9.1 Hz, 1H,
4.4.1. 1-Chloro-3-phenylimidazo[1,5-a]pyridine (7a)
Ar), d 7.12 (dd, J¼4.4, 7.3 Hz, 1H, Ar), 7.43 (d, J¼9.1 Hz, 1H, Ar), 7.69
(dd, J¼7.3, 7.5 Hz, 1H, Ar), 8.21 (d, J¼7.8 Hz, 1H, Ar), 8.54 (d,
J¼4.4 Hz, 1H, Ar), 9.86 (d, J¼7.5 Hz, 1H, Ar). 13C NMR (CDCl3):
Yield 80%, colorless solid, mp 118–120 ꢁC, Rf¼0.51(hexane/
AcOEt¼4:1). IR (KBr) 2963, 1515, 1375 cmꢀ1. 1H NMR (CDCl3):
d 6.51
(dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.68 (dd, J¼6.3, 8.3 Hz, 1H, Ar), 7.31–7.44
d 106.7, 114.2, 117.1, 120.9, 121.6, 121.7, 126.1, 130.1, 134.5, 136.4,
(m, 5H, Ar), 7.68 (d, J¼8.3 Hz, 1H, Ar), 8.12 (d, J¼7.3 Hz, 1H, Ar). 13C
148.0, 150.1 (Ar). HRMS (EI) m/z: calcd for C12H385ClN3 (Mþ)
NMR (CDCl3):
d
113.8, 117.5, 119.2, 119.7, 121.3, 126.3, 127.8, 128.9,
229.0407; found: 229.0405.
129.0, 129.3, 135.8 (Ar). HRMS (EI) m/z: calcd for C13H395ClN2 (Mþ)
228.0454; found: 228.0442.
4.5. Synthesis of 1-fluoro-3-phenylimidazo[1,5-a]-
pyridine (8a)
4.4.2. 1-Chloro-3-(4-methoxyphenyl)imidazo[1,5-a]pyridine (7b)
Yield 80%, brownish solid, mp 85.5–86.5 ꢁC, Rf¼0.10 (hexane/
To a solution of 3-phenylimidazo[1,5-a]pyridine (2a) (0.10 g,
0.50 mmol) in DMF (2 mL) was added 1-fluoro-2,4,6-trimethyl-
pyridinium tetrafluoroborate (9) (0.23 g,1.0 mmol, 2 equiv) at room
temperature under an Ar atmosphere. The resulting solution was
stirred at 60 ꢁC for 2 h. The reaction mixture was quenched with
1 N NaOH aq and extracted with CH2Cl2. The organic layer was
AcOEt¼10:1). IR (KBr): 2963, 1515, 1375 cmꢀ1
.
1H NMR (CDCl3):
d
3.79 (s, 3H, OMe), 6.48 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.68 (dd, J¼6.3,
9.1 Hz, 1H, Ar), 6.96 (d, J¼8.8 Hz, 2H, Ar), 7.34 (d, J¼9.1 Hz, 1H, Ar),
7.61 (d, J¼8.8 Hz, 2H, Ar), 8.04 (d, J¼7.3 Hz, 1H, Ar). 13C NMR
(CDCl3):
d 55.3 (OMe), 1113.6, 114.4, 117.5, 118.8, 119.4, 121.3, 121.7,

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5071
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/
AcOEt¼3:1) to give 1-fluoro-3-phenyl-2-azaindolizine (8a, 0.05 g,
0.27 mmol, 53%, Rf¼0.47) as a pale yellow solid, mp 103–104 ꢁC. IR
(KBr): 2080, 3049, 2922, 1643, 1558, 1521, 1443, 1358, 1258,
1542, 1518, 1500, 1459 cmꢀ1
.
1H NMR (CDCl3):
d
2.32 (s, 3H, Me),
6.37 (t, J¼6.5 Hz, 1H, Ar), 6.57 (t, J¼7.6 Hz, 1H, Ar), 6.90 (d,
J¼7.8 Hz, 2H, Ar), 7.30 (t, J¼6.8 Hz, 1H, Ar), 7.39 (t, J¼7.1 Hz, 2H,
Ar), 7.62 (d, J¼9.2 Hz, 1H, Ar), 7.72 (dd, J¼8.3, 17 Hz, 4H, Ar), 8.05
(d, J¼6.5 Hz, 1H, Ar). 13C NMR (CDCl3):
d 21.3 (Me), 113.2, 113.4,
1076 cmꢀ1. 1H NMR (CDCl3):
d
6.43–6.46 (m, 1H, Ar), 6.54 (dd, J¼6.3,
118.8, 118.9, 121.8, 126.8, 127.5, 128.4, 128.8, 129.1, 129.5, 130.3,
132.2, 136.6, 138.0 (Ar). HRMS (EI) m/z: calcd for C20H16N2 (Mþ)
284.1313; found: 288.1313.
9.3 Hz, 1H, Ar), 7.31–7.36 (m, 2H, Ar), 7.40–7.45 (m, 2H, Ar), 7.69 (d,
J¼8.3 Hz, 2H, Ar), 8.07 (d, J¼7.3 Hz,1H, Ar). 13C NMR (CDCl3):
d 112.2
(J¼38.5 Hz, F–C]C), 113.7 (Ar), 116.9 (J¼5.9 Hz, F–C–N]C), 117.1
(J¼2.9 Hz, F–C]C–C), 120.4, 127.7, 128.7, 129.0 (three carbon atoms
were overlapped), 129.6 (Ar), 147.9 (J¼233 Hz, F–C). 19F NMR
4.6.5. 1-(2-Thienyl)-3-phenylimidazo[1,5-a]pyridine (4ag)
The product was isolated by GPC. 52% isolated yield, yellow
solid, mp 115–116 ꢁC. IR (KBr): 3060, 1600, 1559, 1522, 1442,
(CDCl3):
212.0750; found: 212.0706.
d
ꢀ140.1 (F). HRMS (EI) m/z: calcd for C13H9FN2 (Mþ)
928 cmꢀ1
.
1H NMR (CDCl3):
d
6.54 (t, J¼6.3 Hz, 1H, Ar), 6.79 (dd,
J¼6.3, 9.2 Hz, 1H, Ar), 7.12 (dd, J¼3.7, 5.6, 1H, Ar), 7.25 (dd, J¼5.9,
8.0 Hz, 1H, Ar), 7. 41–7.53 (m, 4H, Ar), 7.78–7.81 (m, 3H, Ar), 8.18 (d,
J¼6.3 Hz, 1H, Ar). 13C NMR (CDCl3): 113.4, 119.0, 119.9, 121.8, 122.2,
123.3, 124.3, 127.0, 127.6, 128.4, 128.9, 129.0, 129.8, 131.5, 137.9 (Ar).
HRMS (EI) m/z: calcd for C17H12N2S (Mþ) 276.0721; found:
276.0719.
4.6. General procedure for KTC cross-coupling of 3-
arylimidazo[1,5-a]pyridines 5 and aryl Grignard reagents 10
To a solution of 1-iodo-3-arylimidazopyridine 5 (0.5 mmol) and
Ni(dppp)Cl2 (10 mol %, 27 mg) in THF (1 mL) in a flame-dried two-
necked round-bottom flask was added dropwise aryl Grignard re-
agent 10 (1.5 mmol, 3 equiv) at 0 ꢁC under an Ar atmosphere. After
addition of Grignard reagent, the reaction mixture was stirred at
room temperature. When the reaction was complete, the mixture
was immediately quenched with satd NH4Cl aq (1 mL), and
extracted with CH2Cl2 (20 mLꢂ3). The combined organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. Unless
otherwise noted, the residue was purified by column chromato-
graphy on silica gel to give 1,3-diarylimidazo[1,5-a]pyridine 4.
4.6.6. 1-Phenyl-3-(4-methoxyphenyl)imidazo[1,5-a]-
pyridine (4ba)21
Isolated yield 81% (93% NMR yield). 1H NMR (CDCl3)
d 3.29 (s,
3H, OMe), 6.50 (t, J¼6.3 Hz, 1H, Ar), 6.71 (dd, J¼6.3, 8.8 Hz, 1H, Ar),
7.01 (d, J¼8.8 Hz, 2H, Ar), 7.24(dd, J¼6.3, 7.8 Hz, 1H, Ar), 7.41 (d,
J¼7.5 Hz, 2H, Ar), 7.71(d, J¼8.8 Hz, 2H, Ar), 7.77 (d, J¼8.8 Hz, 1H, Ar),
7.89 (d, J¼7.8 Hz, 2H, Ar), 8.11 (d, J¼6.3 Hz, 1H, Ar).
4.6.7. 1-(4-Methoxyphenyl)-3-(4-methoxyphenyl)imidazo[1,5-a]-
pyridine (4bb)
4.6.1. 1-Phenyl-3-phenylimidazo[1,5-a]pyridine (4aa)
Isolated yield 80% (99% NMR yield), yellow solid, mp 111–112 ꢁC,
Isolated yield 62% (83% NMR yield), yellow solid, mp 175–176 ꢁC,
Rf¼0.30 (hexane/AcOEt/Et3N¼3:1:1 vol %). IR (KBr): 2360, 1608,
Rf¼0.38 (hexane/AcOEt¼5:1). IR (KBr): 1598, 1516, 1457 cmꢀ1
.
1H
NMR (CDCl3)
d
6.50 (t, J¼6.5 Hz, 1H, Ar), 6.73 (dd, J¼6.5, 7.3 Hz, 1H,
1503, 1459, 1288, 1241, 1169, 1028 cmꢀ1. 1H NMR (CDCl3)
d 3.79 (s,
Ar), 7.23 (t, J¼7.3 Hz, 1H, Ar), 7.37–7.50 (m, 5H, Ar), 7.78 (dd, J¼1.7,
7.3 Hz, 3H, Ar), 7.87 (dd, J¼1.0, 7.3 Hz, 2H, Ar), 8.18 (d, J¼7.3 Hz, 1H,
3H, OMe), 3.81 (s, 3H, OMe), 6.45 (t, J¼6.5 Hz, 1H, Ar), 6.65 (m, 1H,
Ar), 6.97 (q, J¼9.3 Hz, 4H, Ar), 7.69 (d, J¼8.3 Hz, 3H, Ar), 7.78 (d,
Ar). 13C NMR (CDCl3):
d
113.3, 119.1, 119.7, 121.7, 126.5, 126.8, 127.6,
J¼8.3 Hz, 2H, Ar), 8.07 (d, J¼6.5 Hz, 1H, Ar). 13C NMR (CDCl3):
d 55.3,
128.3, 128.7, 128.8, 129.0, 130.1, 131.9, 134.9, 138.1 (Ar). HRMS (EI)
55.4 (OMe), 114.2, 114.5, 114.5, 119.1, 119.2, 119.5, 121.6, 121.7, 126.5,
126.8, 128.2, 128.7, 129.9, 160.1, 160.2 (Ar). HRMS (EI) m/z: calcd for
C21H18N2O2 (Mþ) 330.1367; found: 330.1367.
m/z: calcd for C19H14N2 (Mþ) 270.1157; found: 270.1149.
4.6.2. 1-(4-Methoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (4ab)
Isolated yield 83% (90% NMR yield), yellow solid, mp 111.5–
113.0 ꢁC, Rf¼0.33 (hexane/AcOEt¼4:1). IR (KBr): 3063, 2990, 2959,
4.6.8. 1-(4-Fluorophenyl)-3-(4-methoxyphenyl)imidazo-
[1,5-a]pyridine (4bc)
1600, 1573, 1541, 1502, 1458 cmꢀ1
.
1H NMR (CDCl3):
d
3.72 (s, 3H,
Isolated yield 96% (98% NMR yield), yellow solid, mp 171.5–
171.2 ꢁC, Rf¼0.25 (hexane/AcOEt¼4:1). IR (KBr): 1516, 1501, 1465,
OMe), 6.37 (t, J¼6.7 Hz, 1H, Ar), 6.57 (dd, J¼6.7, 9.1 Hz, 1H, Ar), 6.90
(d, J¼7.7 Hz, 2H, Ar), 7.30 (t, J¼6.8 Hz, 1H, Ar), 7.39 (d, J¼7.2 Hz, 2H,
Ar), 7.62 (d, J¼9.1 Hz, 1H, Ar), 7.69–7.80 (m, 4H, Ar), 8.05 (d,
1221, 1173 cmꢀ1 1H NMR (CDCl3):
. d 3.81 (s, 3H, OMe), 6.48 (t,
J¼6.3 Hz, 1H, Ar), 6.69 (dd, J¼2.4, 6.3 Hz, 1H, Ar), 6.99 (dd, J¼5.1,
8.8 Hz, 2H, Ar), 7.08 (t, J¼8.8 Hz, 2H, Ar), 7.63–7.68 (m, 3H, Ar), 7.81
(t, J¼8.8 Hz, 2H, Ar), 8.08 (d, J¼6.3 Hz, 1H, Ar). 13C NMR (CDCl3):
J¼6.7 Hz, 1H, Ar). 13C NMR (CDCl3):
d 55.2 (OMe), 113.0, 113.3, 114.1,
119.1, 121.4, 123.6, 126.8, 127.5, 127.9, 128.1, 128.8, 130.0, 131.8, 137.5,
158.4 (Ar). HRMS (EI) m/z: calcd for C20H16N2O (Mþ) 300.1262;
found: 300.1264.
d
55.4 (OMe), 113.1, 114.5 (Ar), 115.5 (d, J¼21.5 Hz, F–C]C), 118.8,
119.6, 121.7, 122.3, 127.0, 128.3, 128.3, 129.7 (Ar), 130.8 (d, J¼8.8 Hz,
F–C]C–C), 138.5, 160.1 (Ar), 162.9 (d, J¼248.8 Hz, F–C). 19F NMR
4.6.3. 1-(4-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (4ac)
Isolated yield 58% (83% NMR yield), yellow solid, mp 134.5–
135.0 ꢁC, Rf¼0.32 (hexane/AcOEt/Et3N¼4:1:1 vol %). IR (KBr): 1601,
(CDCl3):
d
ꢀ116.8 (F). HRMS (EI) m/z: calcd for C20H15FN2O (Mþ)
318.1168; found: 318.1159.
1542, 1518, 1500, 1461, 1221 cmꢀ1
.
1H NMR (CDCl3):
d
6.51 (t,
4.6.9. 1-(4-Methylphenyl)-3-(4-methoxyphenyl)imidazo-
[1,5-a]pyridine (4be)
J¼7.0 Hz, 1H, Ar), 6.72 (dd, J¼7.0, 9.2 Hz, 1H, Ar), 7.06–7.11 (m, 2H,
Ar), 7.37–7.49 (m, 3H, Ar), 7.69–7.83 (m, 5H, Ar), 8.16 (d, J¼7.0 Hz,
1H, Ar). 13C NMR (CDCl3): 113.3 (Ar), 119.3 (d, J¼21.0 Hz, F–C]C),
121.7, 126.8, 127.3, 128.3, 128.8, 129.0, 129.4 (Ar), 129.9 (d, J¼8.3 Hz,
F–C]C–C), 131.7, 131.9, 136.3, 137.8 (Ar), 161.5 (d, J¼248.0 Hz, F–C).
Isolated yield 58% (90% NMR yield), yellow solid, mp 151.0–
151.5 ꢁC, Rf¼0.26 (hexane/AcOEt¼4:1). IR (KBr): 3008, 2911, 1609,
1527, 1514, 1464, 1008 cmꢀ1 1H NMR (CDCl3):
. d 2.31 (s, 3H, Me),
3.82 (s, 3H, OMe), 6.49 (t, J¼6.8 Hz, 1H, Ar), 6.69 (dd, J¼6.8,
8.8 Hz, 1H, Ar), 7.00 (d, J¼8.8 Hz, 2H, Ar), 7.21 (d, J¼7.8 Hz, 2H,
Ar), 7.69–7.77 (m, 5H, Ar), 8.08 (d, J¼6.8 Hz, 1H, Ar). 13C NMR
19F NMR (CDCl3):
d
ꢀ116.6 (F). HRMS (EI) m/z: calcd for C29H13N2F
(Mþ) 288.1063; found: 288.1058.
(CDCl3):
d 21.3 (Me), 55.5 (OMe), 113.0, 114.5, 119.1, 119.3, 121.6,
4.6.4. 1-(4-Methylphenyl)-3-phenylimidazo[1,5-a]pyridine (4ae)
Isolated yield 52% (85% NMR yield), yellow solid, mp 134.0–
134.5 ꢁC, Rf¼0.41 (hexane/AcOEt¼4:1). IR (KBr): 3054, 2915, 1601,
122.6, 126.7, 127.1, 129.4, 129.8, 131.7, 132.1, 136.1, 137.9, 160.0 (Ar).
HRMS (EI) m/z: calcd for C21H18N2O (Mþ) 314.1419; found:
314.1413.

5072
F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
4.6.10. 1-(2-Thienyl)-3-(4-methoxyphenyl)imidazo[1,5-a]-
pyridine (4bg)
The product was isolated by GPC. Isolated yield 68%, yellow
solid, mp 130.0–130.5 ꢁC. IR (KBr): 1516, 1501, 1465, 1221,
(d, J¼8.8 Hz, F–C]C–C), 136.9, 137.8 (Ar), 162.9 (d, J¼248.8 Hz, F–C).
19F NMR (CDCl3)
d
ꢀ112.1. HRMS (EI) m/z: calcd for C17H11FN2S (Mþ)
294.0627; found: 294.0614.
1173 cmꢀ1. 1H NMR (CDCl3):
d
3.86 (s, 3H, OMe), 6.53 (t, J¼6.5 Hz,
4.6.16. 1-Phenyl-3-(4-trifluoromethylphenyl)imidazo-
[1,5-a]pyridine (4da)
1H, Ar), 6.76 (dd, J¼6.3, 9.2 Hz, 1H, Ar), 7.02 (d, J¼7.8 Hz, 2H, Ar),
7.11 (dd, J¼2.8, 3.6 Hz, 1H, Ar), 7.25 (t, J¼2.8 Hz, 1H, Ar), 7.46 (d,
J¼3.6 Hz,1H, Ar), 7.71 (d, J¼7.8 Hz, 2H, Ar), 7.78 (d, J¼9.2 Hz,1H, Ar),
Isolated yield 37% (68% NMR yield), yellow solid, mp 149–151 ꢁC,
Rf¼0.42 (hexane/AcOEt¼4:1). IR (KBr) 2927, 1617, 1517, 1465,
8.11 (d, J¼6.5 Hz, 1H, Ar). 13C NMR (CDCl3):
d
55.4 (OMe), 113.1,
1323 cmꢀ1
;
1H NMR (CDCl3)
d
6.60 (t, J¼6.3 Hz, 1H, Ar), 6.78 (dd,
114.4, 118.9, 119.6, 121.7, 122.1, 122.2, 123.1, 126.7, 126.8, 127.5, 129.8,
137.9, 138.1, 160.1 (Ar). HRMS (EI) m/z: calcd for C18H14N2OS (Mþ)
306.0827; found: 306.0829.
J¼6.3, 7.8 Hz, 1H, Ar), 7.26 (t, J¼7.8 Hz, 1H, Ar), 7.41 (t, J¼7.8 Hz, 2H,
Ar), 7.72 (d, J¼8.3 Hz, 2H, Ar), 7.80–7.94 (m, 5H, Ar), 8.20 (d,
J¼6.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 113.9, 119.2, 120.2, 121.4 (Ar),
123.9 (q, J¼272 Hz, F3C), 125.9 (q, J¼3.3 Hz, CF3–C]C), 126.8, 128.1,
128.2 (Ar), 130.3 (q, J¼33.1 Hz, F3C–C), 132.7, 133.6, 134.5, 136.3 (Ar).
4.6.11. 1-Phenyl-3-(4-fluorophenyl)-2-azaindolizine (4ca)21
Isolated yield 89% (95% NMR yield). 1H NMR (CDCl3):
d
6.52 (t,
19F NMR (CDCl3)
d
ꢀ63.4 (CF3). HRMS (EI) m/z: calcd for C20H13F3N2
J¼6.3 Hz, 1H, Ar), 6.73 (dd, J¼6.3, 8.8 Hz, 1H, Ar), 7.14–7.25 (m, 3H,
(Mþ) 338.1031; found: 338.1008.
Ar), 7.40 (t, J¼7.8, 2H, Ar), 7.73–7.79 (m, 3H, Ar), 7.85 (d, J¼8.3 Hz,
2H, Ar), 8.08 (d, J¼6.5 Hz, 1H, Ar). 19F NMR (CDCl3):
d
ꢀ112.2 (F).
4.6.17. 1-(4-Methoxyphenyl)-3-(4-trifluoromethylphenyl)-
imidazo[1,5-a]pyridine (4db)
4.6.12. 1-(4-Methoxyphenyl)-3-(4-fluorophenyl)imidazo-
[1,5-a]pyridine (4cb)
Isolated yield 66% (68% NMR yield), yellow solid, mp 187.5–
188.5 ꢁC, Rf¼0.31 (hexane/AcOEt¼4:1). IR (KBr): 2951, 1614, 1542,
Isolated yield 83% (88% NMR yield), yellow solid, mp 158.5–
159.5 ꢁC, Rf¼0.37 (hexane/AcOEt/Et3N¼4:1:1 vol %). IR (KBr): 3076,
1518, 1502, 1323, 1066 cmꢀ1. 1H NMR (CDCl3):
d 3.85 (s, 3H, OMe),
6.61 (t, J¼6.5 Hz, 1H, Ar), 6.79 (dd, J¼6.5, 7.6 Hz, 1H, Ar), 7.01 (d,
2952, 2841, 1609, 1573, 1221 cmꢀ1 1H NMR (CDCl3):
. d 3.84 (s, 3H,
J¼8.8 Hz, 2H, Ar), 7.75–7.98 (m, 5H, Ar), 7.97 (d, J¼7.5 Hz, 2H, Ar), 8.22
OMe), 6.53 (t, J¼6.3 Hz,1H, Ar), 6.72 (dd, J¼6.3, 9.1 Hz,1H, Ar), 6.95 (d,
(d, J¼6.5 Hz, 1H, Ar). 13C NMR (CDCl3):
d 55.3 (OMe), 113.9, 114.3,
J¼8.5 Hz, 2H, Ar), 7.20 (d, J¼8.5 Hz, 2H, Ar), 7.73–7.83 (m, 5H, Ar), 8.10
119.4,119.7,121.3 (Ar),123.9 (q, J¼272 Hz, 3C),126.0 (q, J¼3.3 Hz, F3C–
C]C), 126.9, 127.7, 128.1, 128.2 (Ar), 130.3 (q, J¼33.1 Hz, F3C–C), 132.6,
(d, J¼6.3 Hz,1H, Ar).13C NMR (CDCl3):
d 55.4 (OMe),113.4,114.2,115.9
(Ar),116.2 (d, J¼21.8 Hz, F–C]C),119.2,121.3,126.2,126.9,127.3,128.0
(Ar), 130.2 (d, J¼8.3 Hz, F–C]C–C), 131.8, 136.6, 158.5 (Ar), 162.89 (d,
133.4,136.1,158.7 (Ar).19F NMR (CDCl3):
d
ꢀ63.4 (CF3). HRMS (EI) m/z:
calcd for C21H15F3N2O (Mþ) 368.1136; found: 368.1136.
J¼248.8 Hz, F–C). 19F NMR (CDCl3):
ꢀ112.5 (F). HRMS (EI) m/z: calcd
d
for C20H15FN2O (Mþ) 318.01168; found: 318.1182.
4.6.18. 1-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)-
imidazo[1,5-a]pyridine (4dc)
4.6.13. 1-(4-Fluorophenyl)-3-(4-fluorophenyl)imidazo-
[1,5-a]pyridine (4cc)
Isolated yield 55% (83% NMR yield), yellow solid, mp 209.0–
209.5 ꢁC, Rf¼0.48 (hexane/AcOEt¼4:1). IR (KBr): 2345, 1614, 1538,
Isolated yield 83% (83% NMR yield), yellow solid, mp 180.0–
180.5 ꢁC, Rf¼0.48 (hexane/AcOEt¼4:1). IR (KBr): 1604, 1529, 1515,
1417, 1108 cmꢀ1
;
1H NMR (CDCl3):
d
6.60 (t, J¼6.8 Hz, 1H, Ar), 6.80
(dd, J¼6.8, 8.3 Hz, 1H, Ar), 7.10 (d, J¼8.3 Hz, 2H, Ar), 7.72–7.83 (m,
5H, Ar), 7.92 (d, J¼8.3 Hz, 2H, Ar), 8.20 (d, J¼6.8 Hz,1H, Ar). 13C NMR
(CDCl3): 114.0 (Ar), 115.7 (d, J¼21.5 Hz, F–C]C), 119.1, 120.3, 121.5
(Ar), 123.9 (d, J¼272 Hz, F3C), 126.0 (d, J¼3.3 Hz, CF3–C]C–C),
128.0, 128.2 (Ar), 128.5 (d, J¼7.7 Hz, F–C]C–C), 130.3 (Ar), 130.8 (q,
J¼32.3 Hz, F3C–C), 131.9, 133.5, 136.4 (Ar), 162.9 (d, J¼248.9 Hz, F–C)
1499, 1469, 1228, 1154 cmꢀ1. 1H NMR (CDCl3):
d
6.60 (t, J¼6.3 Hz, 1H,
Ar), 6.80 (dd, J¼6.3, 9.3 Hz, 1H, Ar), 7.13–7.26 (m, 4H, Ar), 7.76–7.90
(m, 5H, Ar), 8.14 (d, J¼6.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 113.6 (Ar),
115.7 (d, J¼21.4 Hz, F–C]C), 116.2 (d, J¼21.5 Hz, F–C]C), 119.0,119.9,
121.5, 126.1, 127.4 (Ar), 128.4 (d, J¼7.7 Hz, F–C]C–C), 130.3 (d,
J¼8.3 Hz, F–C]C–C), 130.9, 131.0, 137.0 (Ar), 161.9 (d, J¼245.5 Hz, F–
(Ar). 19F NMR (CDCl3):
d
ꢀ63.3 (CF3), ꢀ116.1 (F). HRMS (EI) m/z:
C), 163.1 (d, J¼249.3 Hz, F–C). 19F NMR (CDCl3):
d
ꢀ112.1, ꢀ116.4 (F).
calcd for C20H12F4N2 (Mþ) 356.0937; found: 356.0932.
HRMS (EI) m/z: calcd for C19H12F2N2 (Mþ) 306.0961; found: 306.0961.
4.6.19. 1-(4-Methylphenyl)-3-(4-trifluoromethylphenyl)-
imidazo[1,5-a]pyridine (4de)
4.6.14. 1-(4-Methylphenyl)-3-(4-fluorophenyl)imidazo-
[1,5-a]pyridine (4ce)
Isolated yield 58% (70% NMR yield), yellow solid, mp 120.0–
120.5 ꢁC, Rf¼0.48 (hexane/AcOEt¼4:1). IR (KBr): 2925, 1615, 1541,
Isolated yield 52% (80% NMR yield), yellow solid, mp 106.0–
107.0 ꢁC, Rf¼0.45 (hexane/AcOEt¼4:1). IR (KBr): 1524, 1459,
1518, 1501, 1321 cmꢀ1. 1H NMR (CDCl3):
d 2.34 (s, 3H, Me), 6.56 (t,
1223 cmꢀ1. 1H NMR (CDCl3):
d
6.59 (dd, J¼6.4, 6.8 Hz, 1H, Ar), 6.82
J¼6.8 Hz, 1H, Ar), 6.75 (dd, J¼6.8, 9.1 Hz, 1H, Ar), 7.22 (d, J¼8.1 Hz,
(dd, J¼6.4, 8.8 Hz, 1H, Ar), 7.01–7.26 (m, 4H, Ar), 7.50 (d, J¼8.8 Hz,
2H, Ar), 7.70–7.79 (m, 5H, Ar), 7.92 (d, J¼8.1 Hz, 2H, Ar), 8.18 (d,
1H, Ar), 8.20–8.39 (m, 4H, Ar), 8.11 (d, J¼6.8 Hz, 1H, Ar). 13C NMR
J¼6.8 Hz, 1H, Ar). 13C NMR (CDCl3):
d 21.3 (Me), 113.8, 119.3, 119.8,
121.3 (Ar), 123.9 (q, J¼272 Hz, F3C), 125.8 (q, J¼3.3 Hz, F3C–C]C),
(CDCl3):
d
21.3 (Me), 113.4 (Ar), 116.1 (d, J¼21.8 Hz, F–C]C), 119.3,
119.4, 121.4, 126.7, 126.9, 127.3, 127.4, 128.6 (Ar), 130.2 (d, J¼8.2 Hz,
F–C]C–C), 131.8, 132.1, 136.3 (Ar), 162.9 (d, J¼248.3 Hz, F–C) (Ar).
126.6, 128.0, 128.1, 129.4 (Ar), 130.2 (q, J¼32.7 Hz, F3C–C), 131.7,
132.8, 133.6, 136.1, 136.5 (Ar). 19F NMR (CDCl3):
d
ꢀ63.3 (CF3). HRMS
19F NMR (CDCl3):
d
ꢀ112.4 (F). HRMS (EI) m/z: calcd for C20H15FN2
(EI) m/z: calcd for C21H15F3N2 (Mþ) 352.1187; found: 352.1180.
(Mþ) 302.1219; found: 302.1222.
4.6.20. 1-[4-(N,N-Dimethylamino)phenyl]-3-(4-trifluoromethyl-
phenyl)imidazo[1,5-a]pyridine (4df)
4.6.15. 1-(2-Thienyl)-3-(4-fluorophenyl)imidazo[1,5-a]-
pyridine (4cg)
Isolated yield 48% (98% NMR yield), yellow solid, mp 174.0–
174.5 ꢁC, Rf¼0.32 (hexane/AcOEt¼4:1). IR (KBr): 2922, 1613, 1543,
The product was isolated by GPC. Isolated yield 81%, yellow
solid, mp 157.5–158.5 ꢁC. IR (KBr): 1629, 1518, 1311, 1006 cmꢀ1. 1H
1520,1505,1323 cmꢀ1. 1H NMR (CDCl3):
d 3.00 (s, 6H, NMe2), 6.57 (t,
NMR (CDCl3):
Ar), 7.13–7.26 (m, 3H, Ar), 7.76–7.90 (m, 5H, Ar), 8.14 (d, J¼6.3 Hz,
1H, Ar). 13C NMR (CDCl3):
113.6 (Ar), 116.1 (d, J¼21.5 Hz, F–C]C),
118.9, 119.9, 120.2, 121.4, 122.2, 123.3, 125.9, 126.8, 127.0 (Ar), 130.2
d
6.60 (t, J¼6.3 Hz, 1H, Ar), 6.80 (dd, J¼6.3, 9.2 Hz, 1H,
J¼6.5 Hz, 1H, Ar), 6.73 (dd, J¼6.5, 9.2 Hz, 1H, Ar), 6.86 (d, J¼8.8 Hz,
2H, Ar), 7.74–7.80 (m, 5H, Ar), 7.97 (d, J¼7.5 Hz, 2H, Ar), 8.20 (d,
d
J¼6.5 Hz,1H, Ar). 13C NMR (CDCl3):
d 40.7 (NMe2),112.9,113.8,119.0,
119.6, 121.2, 122.3 (Ar), 123.9 (q, J¼271 Hz, F3C), 125.8 (q, J¼3.3 Hz,

F. Shibahara et al. / Tetrahedron 65 (2009) 5062–5073
5073
F3C–C]C), 127.4, 127.8, 128.1 (Ar),129.8 (q, J¼32.6 Hz, F3C–C), 133.5,
Transformations of Carbon Resources’) from the Ministry of Edu-
cation, Culture, Sports, Science and Technology of Japan.
133.8, 135.8, 149.5 (Ar). 19F NMR (CDCl3)
d
ꢀ62.9. HRMS (EI) m/z:
calcd for C22H18F3N3 (Mþ) 381.1453; found: 381.1452.
4.6.21. 1-(2-Thienyl)-3-(4-trifluoromethylphenyl)imidazo-
[1,5-a]pyridine (4dg)
References and notes
1. (a) Hajos, G.; Riedl, Z. Sci. Synth. 2002, 12, 613; (b) Joule, J. A.; Mills, K.
Heterocyclic Chemistry, 4th ed.; Blackwell Science: Oxford, 2000; pp 489–
503.
2. For recent advances in the synthesis of imidazo[1,5-a]pyridines via an acetic
acid-mediated condensation pathway, see: (a) Wang, J.; Mason, R.; VanDerveer,
K.; Feng, D.; Bu, X. R. J. Org. Chem. 2003, 68, 5415; (b) Dyers, J. W. L., Jr.; Mason,
R., Jr.; Amoyaw, P.; Bu, X. R. J. Org. Chem. 2005, 70, 2353; (c) Siddiqui, S. A.;
Potewar, T. M.; Lahoti, R. J.; Srinivasan, K. V. Synthesis 2006, 17, 2849 and ref-
erences cited therein.
The product was isolated by GPC. Isolated yield 93%, yellow
solid, mp 152.0–152.5 ꢁC. IR (KBr): 1614, 1505, 1323, 1123 cmꢀ1. 1H
NMR (CDCl3):
d
6.64 (dd, J¼6.5, 6.8 Hz, 1H, Ar), 6.86 (dd, J¼6.8,
9.1 Hz, 1H, Ar), 7.12 (dd, J¼3.1, 4.6 Hz, 1H, Ar), 7.28 (d, J¼4.6 Hz, 1H,
Ar), 7.48 (d, J¼3.1 Hz, 1H, Ar), 7.76 (d, J¼7.8 Hz, 2H, Ar), 7.85 (d,
J¼9.1 Hz,1H, Ar), 7.96 (d, J¼7.8 Hz, 2H, Ar), 8.22 (d, J¼6.5 Hz,1H, Ar).
13C NMR (CDCl3):
d 114.1, 119.3, 120.5, 121.5, 122.8, 123.7 (Ar), 123.9
3. For recent advances in the synthesis of imidazo[1,5-a]pyridines via an oxidative
pathway, see: (a) Bluhm, M. E.; Ciesielski, M.; Go¨rls, H.; Do¨ring, M. Angew.
Chem., Int. Ed. 2002, 41, 2962; (b) Bluhm, M. E.; Folli, C.; Pufky, D.; Kro¨er, M.;
Walter, O.; Do¨ring, M. Organometallics 2005, 24, 4139; (c) Ostermeier, M.;
Limberg, C.; Ziemer, B.; Karunakaran, V. Angew. Chem., Int. Ed. 2007, 46, 5329;
(d) Moulin, A.; Garcia, S.; Martinez, J.; Fehrentz, J.-A. Synthesis 2007, 17, 2667
and references cited therein.
4. (a) Murai, T.; Niwa, H.; Kimura, T.; Shibahara, F. Chem. Lett. 2004, 33, 508; (b)
Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968;
(c) Murai, T.; Sano, H.; Kawai, H.; Aso, H.; Shibahara, F. J. Org. Chem. 2005, 70,
8148; (d) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62, 6312; (e) Shi-
bahara, F.; Suenami, A.; Yoshida, A.; Murai, T. Chem. Commun. 2007, 2354; (f)
Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780; (g) Shibahara, F.; Yoshida, A.;
Murai, T. Chem. Lett. 2008, 37, 646; (h) Murai, T.; Asai, F. J. Org. Chem. 2008, 73,
9518.
(q, J¼272 Hz, F3C), 125.9 (q, J¼3.3 Hz, F3C–C]C), 127.5, 127.7, 127.8,
128.3 (Ar), 130.5 (q, J¼32.6 Hz, F3C–C), 133.1, 136.3, 137.5 (Ar). 19F
NMR (CDCl3)
d
ꢀ63.4 (CF3). HRMS (EI) m/z: calcd for C18H11F3N2S
(Mþ) 344.0595; found: 344.0531.
4.7. Suzuki–Miyaura cross-coupling reaction of
1-bromo-3-phenylimidazo[1,5-a]pyridine (6a) and
methoxycarbonylphenylboronic acids 12
4.7.1. 1-(4-Methoxycarbonylphenyl)-3-phenylimidazo-
[1,5-a]pyridine (4ai)
To a solution of 1-bromo-3-phenylimidazo[1,5-a]pyridine 6a
(0.08 g, 0.25 mmol) in DMF (2 mL) were added 4-methoxy-
carbonylphenylboronic acid 12i (0.05 g, 0.28 mmol, 1.1 equiv),
potassium hydroxide (0.03 g, 0.50 mmol, 2 equiv), tris(dibenzyli-
deneacetone)dipalladium(0) (23 mg, 0.025 mmol), and tri-tert-
butylphosphine (0.048 mL, 0.050 mmol) at room temperature
under an Ar atmosphere, and mixture was heated at 80 ꢁC for 7 h
with stirring. The reaction mixture was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane/AcOEt¼4:1) to give 1-(4-methoxycarbonylphenyl)-3-phe-
nylimidazo[1,5-a]pyridine (4ai, 0.075 g, 0.23 mmol, 91%, Rf¼0.29)
as a pale yellow solid: mp 118–120 ꢁC. IR (KBr): 3053, 1716, 1608,
5. Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org. Lett. 2006, 8, 5621.
6. Shibahara, F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.; Murai. T. J. Org. Chem., in
press.
7. For reviews of Kumada–Tamao–Corriu cross-coupling (Mg), see: (a) Tamao, K.
In Comprehensive Organic Synthesis; Torst, B., Ed.; Permagon: Oxford, 1991; Vol.
3, pp 435–480; (b) Corriu, R. J. P. J. Organomet. Chem. 2002, 653, 20; (c) Tamao,
K. J. Organomet. Chem. 2002, 653, 23.
8. For a review of Negishi cross-coupling (Zn), see: Negishi, E. Bull. Chem. Soc. Jpn.
2007, 80, 233.
9. For reviews of Migita–Kosugi–Stille cross-coupling (Sn), see: (a) Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) Kosugi, M.; Fugami, K. J. Orga-
nomet. Chem. 2002, 653, 50.
10. For reviews of Suzuki–Miyaura cross-coupling (B), see: (a) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Miyaura, N. J. Organomet. Chem.
2002, 653, 54.
11. For reviews of Hiyama-Hatanaka cross-coupling (Si), see: (a) Hiyama, T.;
Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471; (b) Denmark, S. E.; Sweis, R. F. Acc.
Chem. Res. 2002, 35, 835.
12. For recent general reviews of cross-coupling reactions, see: (a) Hassan, J.;
Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359;
(b) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Die-
derich, F., Eds.; Wiley-VHC: Weinheim, 2004; (c) Corbet, J.-P.; Mignani, G.
Chem. Rev. 2006, 106, 2651; (d) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36,
1036.
1276 cmꢀ1
.
1H NMR (CDCl3):
d
3.86 (s, 3H, OMe), 6.51 (dd, J¼6.3,
7.3 Hz, 1H, Ar), 6.70 (dd, J¼6.3, 9.3 Hz, 1H, Ar), 6.93 (d, J¼8.8 Hz, 2H,
Ar), 7.27 (d, J¼9.3 Hz, 1H, Ar), 7.61 (d, J¼8.8 Hz, 1H, Ar), 8.07 (d,
J¼7.3 Hz, 1H, Ar). 13C NMR (CDCl3):
d 51.9 (Me), 113.4, 118.9, 120.8,
122.1, 126.0, 127.5, 128.3 (two carbon atoms are overlapped), 128.5,
129.0, 129.8, 130.0, 130.5, 138.7, 139.5 (Ar), 167.1 (C]O). HRMS (EI)
m/z: calcd for C21H16N2O2 (Mþ) 328.1212; found: 328.1174.
13. For example, see: (a) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.;
Haenen, G. R. M. M. Eur. J. Org. Chem. 2000, 3763; (b) Handy, S. T.; Zhang, Y.;
Bregman, H. J. Org. Chem. 2004, 69, 2362; (c) Olsen, C. A.; Parera, N.; Albericio,
4.7.2. 1-(3-Methoxycarbonylphenyl)-3-phenylimidazo-
[1,5-a]pyridine (4aj)
´
F.; Alvarez, M. Tetrahedron Lett. 2005, 46, 2041; (d) Handy, S. T.; Sabatini, J. J.
Org. Lett. 2006, 8, 1537.
4-Methoxycarbonylphenylboronic acid 12j was used as a cou-
pling partner. The procedure of the reaction was the same as that of
4ai. Pale yellow solid, mp 111–113 ꢁC, Rf¼0.33 (hexane/AcOEt¼4:1).
14. For an example with arylboronic acid, see: Milne, J. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2004, 126, 13028. Also see Ref. 13b.
15. In the electrophilic substitution of imidazo[1,5-a]pyridines with acetyl chloride,
the course of the reaction is entirely different from usual electrophilic sub-
stitution. The imidazole nitrogen atom first attacks the electrophile. Next, the
intermediate salt is deprotonated at the C1 (or C3) position. Finally, migration
of the electrophile to this position gives the product. Therefore, Lewis acid or
base additive may inhibit iodination. See: Hlasta, D. J. Tetrahedron Lett. 1990, 31,
5833.
16. The bromination of imidazopyridines has been noted, but no actual example
has been reported. See: Paudler, W. W.; Kuder, J. E. J. Org. Chem. 1967, 32,
2430.
IR (KBr): 3066,1719,1602,1263 cmꢀ1. 1H NMR (CDCl3):
d 3.87 (s, 3H,
OMe), 6.52 (dd, J¼6.3, 7.3 Hz, 1H, Ar), 6.76 (ddd, J¼1.0, 6.3, 9.3 Hz,
1H, Ar), 7.36–7.48 (m, 4H, Ar), 7.75 (d, J¼7.8 Hz, 2H, Ar), 7.79 (d,
J¼9.3 Hz,1H, Ar), 7.88 (d, J¼7.8 Hz,1H, Ar), 8.09 (d, J¼7.8 Hz,1H, Ar),
8.17 (d, J¼7.3 Hz, 1H, Ar), 8.51 (s, 1H, Ar). 13C NMR (CDCl3):
d 52.1
(Me), 113.4, 118.9, 120.3, 121.9, 127.4, 127.5, 128.0, 128.3, 128.8, 128.9,
129.0, 129.9, 130.5, 130.7, 131.1, 135.3, 138.6 (Ar),167.2 (C]O). HRMS
(EI) m/z: calcd for C21H16N2O2 (Mþ) 328.1212; found: 328.1190.
17. Shaw, H.; Perlmutter, H. D.; Gu, C.; Arco, S. D.; Quibuyen, T. O. J. Org. Chem. 1997,
62, 236.
18. (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer:
Berlin, 2000; (b) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006.
19. 3-(4-Nitro-1,10-biphen-40-yl)imidazo[1,5-a]pyridine did not show fluorescence
emission. See Ref. 5.
20. Demas, J. N.; Crosby, G. A. J. Phys. Chem. 1971, 75, 991.
21. Kovtun, P. Y.; Prostota, A. Y. Chem. Heterocycl. Compd. 2000, 36, 557.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas (no. 19020020, ‘Advanced Molecular