Heterogeneous copper-catalyzed decarboxylative cyclization of 2-benzoylpyridines with α-amino acids leading to imidazo[1,5-a]pyridines

Article abstract of DOI:10.1016/j.jorganchem.2018.11.030

The heterogeneous decarboxylative cyclization reaction between 2-benzoylpyridines and α-amino acids was achieved in toluene at 120 °C in the presence of 15 mol% of L-proline-functionalized MCM-41-supported copper(II) complex [L-Proline-MCM-41-Cu(OTf)

Full text of DOI:10.1016/j.jorganchem.2018.11.030

Accepted Manuscript
Heterogeneous copper-catalyzed decarboxylative cyclization of 2-benzoylpyridines
with α-amino acids leading to imidazo[1,5-a]pyridines
Yang Liao, Chenyu Yan, Rongli Zhang, Mingzhong Cai
PII:
S0022-328X(18)30772-1
DOI:
https://doi.org/10.1016/j.jorganchem.2018.11.030
JOM 20650
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 2 September 2018
Revised Date: 13 November 2018
Accepted Date: 24 November 2018
Please cite this article as: Y. Liao, C. Yan, R. Zhang, M. Cai, Heterogeneous copper-catalyzed
decarboxylative cyclization of 2-benzoylpyridines with α-amino acids leading to imidazo[1,5-a]pyridines,
Journal of Organometallic Chemistry (2018), doi: https://doi.org/10.1016/j.jorganchem.2018.11.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Heterogeneous copper-catalyzed decarboxylative cyclization
of 2-benzoylpyridines with α-amino acids leading to
imidazo[1,5-a]pyridines
Yang Liao, Chenyu Yan, Rongli Zhang, Mingzhong Cai*

ACCEPTED MANUSCRIPT
Heterogeneous copper-catalyzed decarboxylative cyclization
of 2-benzoylpyridines with α-amino acids leading to
imidazo[1,5-a]pyridines
a
b
a
a
Yang Liao, Chenyu Yan, Rongli Zhang and Mingzhong Cai*
a
Key Laboratory of Functional Small Organic Molecule, Ministry of Education and
College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang
30022, China
3
b
Affiliated Middle School of Jiangxi Normal University, Nanchang 330022, China
E-mail: mzcai@jxnu.edu.cn
ABSTRACT
The heterogeneous decarboxylative cyclization reaction between 2-benzoylpyridines
and α-amino acids was achieved in toluene at 120 ºC in the presence of 15 mol% of
L-proline-functionalized MCM-41-supported copper(II) complex [L-Proline-MCM-
4
1-Cu(OTf) ] and iodine with di-tert-butyl peroxide (DTBP) as oxidant, yielding a
2
variety of 1,3-disubstituted imidazo[1,5-a]pyridines in good to excellent yields. The
new supported copper catalyst can be prepared from commercially available and
inexpensive reagents, and recovered from the reaction mixture by a simple filtration
and recycled up to eight times with almost consistent activity.
Keywords: Copper; Decarboxylative cyclization; Imidazo[1,5-a]pyridine; α-Amino
acid; Heterogeneous catalysis
1
. Introduction
Imidazo[1,5-a]pyridines are important scaffolds present in natural products and
synthetic compounds of high utility and have been widely used in many areas of
research such as pharmaceutical and materials chemistry [1-3]. However, only a few
*
Corresponding author.
1
E-mail address: mzcai@jxnu.edu.cn (M. Cai).

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synthetic routes mainly relied on conventional Vilsmeier-type cyclizations [4,5] and
other alternative methods [6,7] are available for these compounds so far, in spite of
their wide range of biological and photophysical activities. Therefore, the develop-
ment of more efficient and practical synthetic approaches for construction of imidazo-
[
1,5-a]pyridines from readily available starting materials is highly desirable.
Transition-metal-catalyzed intermolecular or intramolecular direct oxidative amina-
tions of the C–H bonds have been developed into a powerful tool for the construction
of C–N bonds with high atom and step economy and have been widely applied for the
preparation of azaheterocycles [8-15]. Various transition metal catalysts such as
ruthenium [16-18], rhodium [19-22] and palladium [23-27] based catalytic systems
have been used for C–H bond amination. Recently, copper-catalyzed construction of
3
imidazo[1,5-a]pyridines via oxidative aminations of C(sp )–H bonds has attracted
considerable interest due to their high efficiency and low cost of copper catalysts,
which included Cu(I)-catalyzed transannulation of N-heteroaryl aldehydes or ketones
with alkylamines [28], Cu(I) or Cu(II)-catalyzed annulation of 2-(pyridine-2-yl)-
acetates or 2-benzoylpyridines with benzylamines [29, 30], Cu(II)-catalyzed decar-
boxylative annulation between 2-benzoylpyridines and α-amino acids [31], and Cu(I)-
catalyzed denitrogenative transannulation of pyridotriazoles with benzylamines or
α-amino acids [32]. Although these copper-catalyzed oxidative amination/annulation
protocols were highly efficient for construction of imidazo[1,5-a]pyridines, high
loading of copper salts (typically 10-20 mol%) were used to obtain high yields, and
they are difficult to separate from the reaction mixture and not recyclable, which is of
2

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particular environmental and economic concerns in large-scale syntheses and in
industry. Furthermore, homogeneous copper catalysis might cause unacceptable
copper contamination of the desired product because of the formation of complexes of
imidazo[1,5-a]pyridines with copper, which restricts the application of such catalytic
systems in electronics and biomedicine. The heterogenization of the existing homo-
geneous copper catalysts could be a logical solution to these problems; the use of
immobilized catalysts could give rise to facile removal, recovery, and reusability of
the copper catalysts, thereby minimizing both copper contamination of the desired
isolated product and waste derived from reaction workup [33-37]. In recent years,
heterogeneous copper-catalyzed carbon-carbon [38-41] and carbon-heteroatom [42-49]
bond formation reactions have received much attention. However, to the best of our
knowledge, no examples of heterogeneous copper-catalyzed oxidative aminations of
3
C(sp )–H bonds for construction of C–N bonds have been described until now.
Mesoporous MCM-41 materials have recently emerged as promising supports for
immobilization of homogeneous catalysts because of their remarkable advantages
such as ultrahigh surface areas, large and defined pore sizes, big pore volumes and the
existence of a large number of Si–OH groups on the inner surface, in comparison with
other solid supports [50-52]. Recently, various MCM-41-supported transition metal
catalysts such as palladium [53-58], rhodium [59], molybdenum [60,61], gold [62-66]
and copper [40,41,47-49] based catalytic systems have been successfully employed in
many organic reactions as recyclable catalysts. In continuation of our effort to develop
economical and eco-friendly synthetic routes for organic transformations from the
3

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viewpoint of green and sustainable chemistry [40,41,47-49,66], herein we report the
synthesis of L-proline-functionalized MCM-41-supported copper(II) complex [L-
Proline-MCM-41-Cu(OTf) ] and its successful application to the decarboxylative
2
cyclization between 2-benzoylpyridines and α-amino acids leading to a variety of
1
,3-disubstituted imidazo[1,5-a]pyridines in good to excellent yields (Scheme 1).
2
. Results and discussion
2
.1. Preparation and characterization of L-Proline-MCM-41-CuX complexes
n
A series of L-proline-functionalized MCM-41-supported copper(I) or (II) complexes
[
L-Proline-MCM-41-CuX ] were easily prepared from commercially available and
n
inexpensive reagents according to the procedure as shown in Scheme 2. Firstly, the
mesoporous MCM-41 was condensed with 4-(chloromethyl)phenyltrichlorosilane in
toluene, followed by the treatment with anhydrous ethanol and then the silylation with
Me SiCl to generate the chloromethyl-functionalized MCM-41 (ClCH -MCM-41).
3
2
The latter was then treated with N-Boc-trans-4-hydroxy-L-proline in THF with NaH
as base, followed by deprotection with TFA in CH Cl to afford the L-proline-
2
2
functionalized MCM-41 (L-Proline-MCM-41). Finally, the reaction of L-Proline-
MCM-41 with various copper salts [CuX = CuI, CuBr, CuCl , CuBr , Cu(OAc) ,
n
2
2
2
Cu(OTf) ] in acetone afforded a series of L-proline-functionalized MCM-41-
2
supported copper(I) or (II) complexes [L-Proline-MCM-41-CuX ] as light yellow or
n
pale blue powders.
The small angle X-ray diffraction (XRD) patterns of the parent MCM-41 and
4

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L-Proline-MCM-41-Cu(OTf) are shown in Fig. 1. The pattern of the parent MCM-41
2
exhibits an intense (100) diffraction peak at 2.32 2-theta and two additional high order
peaks (110 and 200) with lower intensities at 3.91 and 4.46 2-theta, respectively [50].
The diffraction pattern of L-Proline-MCM-41-Cu(OTf) was similar to that of parent
2
MCM-41, the (100) diffraction peak of L-Proline-MCM-41-Cu(OTf) with decreased
2
intensity was observed after introduction of the copper complex, while the (110) and
(200) diffraction peaks became weak and diffuse. The decrease in intensity may be
mainly due to contrast matching between the silica walls and organic moieties located
inside the channels of MCM-41. These results indicate that the basic structure of the
mesoporous MCM-41 remains unchanged after grafting the copper complex and the
copper complex is well dispersed on the inner channel walls.
FT-IR spectra of MCM-41, L-Proline-MCM-41, L-Proline-MCM-41-Cu(OTf) and
2
the recovered L-Proline-MCM-41-Cu(OTf) are shown in Fig. 2. The FT-IR spectrum
2
-1
(
Fig. 2a) of MCM-41 shows the Si–O stretching absorption at 1080 and 805 cm . In
-1
the FT-IR spectrum (Fig. 2b) of L-Proline-MCM-41 absorptions at 3435 cm (N–H),
-1
1
631 and 1414 cm (COOH) were observed indicating the presence of silylated
L-Proline groups. After the complexion of Cu ions with MCM-41-ligand, the N–H
-1
stretching frequency is shifted to a higher frequency 3447 cm , while the two absor-
-1
ption bands of COOH are red shifted and appear at 1617 and 1395 cm , respectively,
demonstrating that –NH and –OH coordinate with the metal Cu (Fig. 2c). Finally, the
FT-IR spectrum (Fig. 2d) of the eighth reused catalyst indicated that the structure of
the catalyst was maintained during the reaction.
5

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The N adsorption-desorption isotherms for MCM-41 and L-Proline-MCM-41-
2
Cu(OTf) recorded at 77 K are illustrated in Fig. 3. The isotherms in Fig. 3 have
2
remarkable changes as expected before and after grafting the copper complex because
the organic moieties entered the channels of MCM-41, but both samples gave similar
adsorption-desorption isotherms of type IV (definition by IUPAC), indicating that the
mesoporous structure was remained. Fig. 4 shows pore size distributions for MCM-41
and L-Proline-MCM-41-Cu(OTf) . Compared to MCM-41, the obvious decreases in
2
pore volume and size were observed for L-Proline-MCM-41-Cu(OTf) owing to the
2
incorporation of organic moieties into the channels of MCM-41, but L-Proline-MCM-
4
1-Cu(OTf) still exhibited a narrow pore size distribution. After the anchoring the
2
L-Proline-Cu(OTf) complex onto MCM-41, the BET specific surface area and pore
2
2
2
diameter decreased from 912 m /g and 2.7 nm to 583 m /g and 2.5 nm, respectively.
The energy dispersive spectroscopy (EDS) analysis carried out with fresh L-Proline-
MCM-41-Cu(OTf) complex showed the presence of Si, O, C, N, S, F and Cu
2
elements (Fig. 5), which further confirming the successful anchoring of the L-Proline-
Cu(OTf) complex onto MCM-41.
2
The TGA curves of MCM-41, L-Proline-MCM-41-Cu(OTf) and the recovered
2
L-Proline-MCM-41-Cu(OTf) show the mass loss of the organic materials as they
2
decompose upon heating (Fig. 6). TGA curve (Fig. 6a) of MCM-41 showed only one
mass loss step between 120 and 200 ºC due to the loss of physically adsorbed water,
indicating its outstanding thermal stability. For L-Proline-MCM-41-Cu(OTf) , two
2
weight loss steps were observed (Fig. 6b). The first weight loss step occurs in the
6

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temperature range of 120-300 ºC, which is related to the loss of physically and
chemically adsorbed water and solvents. The second one occurs in the temperature
range of 300-800 ºC corresponding to the thermal decomposition of organic moieties
in the catalytic material. TGA analysis indicated that this supported copper catalyst
was stable up to 280 ºC. TGA curve (Fig. 6c) of the eighth reused catalyst showed that
the catalyst still remained high thermal stability even after eight consecutive cycles.
2
2
.2. Heterogeneous copper-catalyzed decarboxylative cyclization reaction between
-benzoylpyridines and α-amino acids.
In our initial screening experiments, the decarboxylative cyclization reaction
between 2-benzoylpyridine 1a and leucine 2a was investigated to optimize the
reaction conditions, and the results are listed in Table 1. First, the efficiency of various
heterogeneous copper catalysts was screened with molecular iodine as a co-catalyst
and di-tert-butyl peroxide (DTBP) as oxidant in toluene. The results showed that
L-Proline-MCM-41-Cu(OTf) [E] was the most efficient catalyst for this reaction
2
(entry 5), whilst other heterogeneous copper catalysts such as L-Proline-MCM-41-CuI
[
A], L-Proline-MCM-41-CuBr [B], L-Proline-MCM-41-CuCl [C], L-Proline-MCM-
2
4
1-CuBr [D] and L-Proline-MCM-41-Cu(OAc) [F] afforded low yields (entries 1-4
2 2
and 6). When a homogeneous Cu(OTf) was used as the catalyst, the desired product
2
3
a was also isolated in 92% yield (Table 1, entry 7), which indicating that catalytic
activity of L-Proline-MCM-41-Cu(OTf) was comparable to that of Cu(OTf) . In the
2
2
absence of any copper catalyst, the reaction generated the target product 3a in only
3
8% yield (entry 8). Then, the effect of different oxidants on this transformation was
7

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examined. When tert-butyl hydroperoxide (TBHP) or dibenzoyl peroxide (BPO) was
used as oxidant, the desired 3a was obtained in lower yields (entries 9 and 10), so
DTBP as oxidant was the best choice (entry 5). With L-Proline-MCM-41-Cu(OTf) in
2
other solvents, the yields of 3a were 86%, 69%, 67%, and 55%, respectively, in
dioxane, DCE, MeCN, and DMF (entries 11-14), which indicating that toluene was
the optimal solvent. By raising or lowering the reaction temperature, no improvement
in yield of 3a was observed (entries 15 and 16). When the amount of leucine 2a was
decreased from 3.0 equiv to 2.0 equiv, a remarkable decrease in the yield of 3a was
observed (entry 17). Finally, reducing the amount of the catalyst to 8 mol% resulted in
a lower yield and required a long reaction time (entry 18). Increasing the amount of
the catalyst to 30 mol% could shorten the reaction time, but did not improve the yield
significantly (entry 19). Thus, the optimized conditions for this decarboxylative
cyclization are the use of leucine 2a (3.0 equiv), L-Proline-MCM-41-Cu(OTf) (15
2
mol%), I (15 mol%) as cocatalyst with DTBP as oxidant in toluene at 120 °C for 12 h
2
(Table 1, entry 5).
With this promising result in hand, we started to investigate the substrate scope of
this heterogeneous copper(II)-catalyzed decarboxylative cyclization reaction under
the optimized conditions. First, the substrate scope of pyridine ketones was examined
by evaluating a variety of 2-benzoylpyridine derivatives and the results are listed in
Table 2. As shown in Table 2, para-substituted 2-benzoylpyridines 1b-1j bearing
electron-donating or electron-withdrawing groups could undergo the decarboxylative
cyclization with leucine (2a) smoothly to give the corresponding 3-isobutyl-1-aryl-
8

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imidazo[1,5-a]pyridines 3b-3j in moderate to excellent yields. These results indicate
that the electronic nature of the substituents on the benzene ring has limited influence
on the heterogeneous copper(II)-catalyzed decarboxylative cyclization reaction. When
meta-substituted 2-benzoylpyridines 1k-1l or 3,5-disubstituted 2-benzoylpyridines
1
m-1n were used as substrates, the decarboxylative cyclization reaction also worked
well to afford the desired products 3k-3n in high yields. However, ortho-substituted
-benzoylpyridine 1o showed a relatively lower reactivity and gave the expected 3o in
2
only 75% yield. Notably, a heteroaryl containing pyridine ketone 1p was compatible
with the standard conditions and afforded the target product 3p in 62% yield. Bulky
naphthalene-1-yl(pyridine-2-yl)methanone 1q proved to be also a good substrate and
produced the cyclized product 3q in 82% yield. In addition, when 2-benzoylquinoline
1
r was used as the substrate, the desired product 3r was isolated in 81% yield.
Unfortunately, when 1-(pyridin-2-yl)ethanone 1s was employed as the substrate, no
desired cyclized product was detected. Various functional groups such as methyl,
methoxy, fluoro, chloro, trifluoromethyl, cyano, hydroxy, amide, ester and heteroaryl
were tolerated well in this reaction.
Under the optimized reaction conditions, we next examined the scope of α-amino
acids by using various aliphatic α-amino acids and α-aryl-substituted amino acids as
substrates and the results are summarized in Table 3. The decarboxylative cyclization
reactions of linear or branched aliphatic α-amino acids 2b-2d with 2-benzoylpyridine
1
a proceeded effectively to give the corresponding cyclized products 3t-3v in 73-83%
yields. The reaction of phenylglycine 2e with 1a furnished the expected product 3w in
9

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excellent yield. In addition, para- and meta-halogenated phenylglycines 2f-2h were
all compatible with the standard conditions and the reactions with 1a afforded the
desired products 3x-3z in high yields. To further extend the utility of this hetero-
geneous copper(II)-catalyzed decarboxylative cyclization reaction, we next turned our
attention to the reaction of phenylglycine 2e with a variety of 2-benzoylpyridine
derivatives. As shown in Table 3, the reactions of phenylglycine 2e with 2-benzoyl-
pyridines (1b, 1c, 1f, 1h, 1k, 1l and 1o) bearing various substituents, regardless of
their electronic properties and substitution positions, generated the corresponding
cyclized products 3a'-3g' in 82-91% yields. 3,5-Disubstituted 2-benzoylpyridines
proved to be also suitable substrates and the reactions with 2e furnished the desired
products 3h'-3l' in high yields. Besides, the reaction of bulky naphthalene-1-yl-
(pyridine-2-yl)methanone 1q with 2e could give the cyclized product 3m' in 89%
yield. Finally, 2-benzoylquinoline 1r was also successfully employed as a substrate to
yield the corresponding product 3n' in 84% yield. We also carried out the reaction of
α-amino acids bearing a heteroaryl ring such as tryptophan and histidine with
2
-benzoylpyridine 1a, unfortunately, the formation of a complex mixture was
observed.
2
.3. Leaching test for L-Proline-MCM-41-Cu(OTf)2
To determine whether the supported copper catalyst is actually functioning in a
heterogeneous manner, or whether it is merely a reservoir for more active soluble
forms of Cu, the heterogeneity of L-Proline-MCM-41-Cu(OTf) was tested by hot
2
filtration [67]. For this, the decarboxylative cyclization reaction of 2-benzoylpyridine
1
0

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1
a with leucine 2a was carried out until an approximately 30% conversion of 1a.
Then L-Proline-MCM-41-Cu(OTf) was removed by filtration of the reaction mixture
2
at 120 ºC and the filtrate was allowed to react further at 120 ºC for 10 h. In this case,
no significant increase in conversion was observed, confirming that leached copper
species from L-Proline-MCM-41-Cu(OTf) (if any) are not responsible for the
2
observed conversion. The determination of the copper content in the filtrate by
ICP-AES analysis showed that no copper could be detected in the solution. These
results indicated that L-Proline-MCM-41-Cu(OTf) was stable during the decarboxy-
2
lative cyclization reaction and is actually functioning in a heterogeneous manner.
2
.4. Possible mechanism for the heterogeneous copper-catalyzed decarboxylative
cyclization reaction.
A possible mechanism for the heterogeneous copper(II)-catalyzed decarboxylative
cyclization reaction between 2-benzoylpyridines and α-amino acids is shown in
Scheme 3. First, 2-benzoylpyridine 1a undergoes a condensation reaction with
α-amino acid 2 to give imine A. The deprotonation of the imine A in the presence of a
nitrogen source as the base produces an organic acid anion, which then reacts with
L-Proline-MCM-41-Cu(OTf) to forms an MCM-41-immobilized L-Proline-Cu(II)
2
carboxylate intermediate B. Subsequent decarboxylation of intermediate B generates
intermediate C, which then undergoes an oxidative iodination to produce intermediate
D. The C–Cu bond in intermediate D could dissociate by the aid of triflate anion to
give the azomethine ylide-type intermediate E [68,69] and regenerate the L-Proline-
MCM-41-Cu(OTf) complex. Subsequently, the elimination of iodide anion from
2
11

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intermediate E provides intermediate F [30,32], which further isomerizes into
intermediate G. Finally, the intramolecular cyclization of intermediate G happens to
afford the cyclized intermediate H [70], which then undergoes an oxidative dehydro-
genation and rearrangement to give 1,3-disubstituted imidazo[1,5-a]pyridine 3.
2
.5. Recycling of the catalyst
In order to check the stability and recyclability of L-Proline-MCM-41-Cu(OTf)2,
the decarboxylative cyclization between 2-benzoylpyridine 1a and phenylglycine 2e
as model reaction was investigated under the optimized conditions, and the results are
summarized in Table 4. After carrying out the reaction, the reaction mixture was
diluted with ethyl acetate. Filtration of the reaction mixture followed by washing of
the resulting solid with ethanol allowed the easy recovery of L-Proline-MCM-41-
Cu(OTf) . The recovered catalyst could be reused at least seven times, and almost
2
consistent activity was observed. Besides, the copper content of the recovered catalyst
-1
after eight consecutive runs was determined to be 0.63 mmol g by ICP-AES analysis,
which showing almost the same Cu content as the fresh catalyst. In our opinion, the
excellent catalytic behavior of the supported copper catalyst should be attributed to
the efficient site isolation, to the optimal dispersion of the active sites on the inner
channel walls and to the relatively strong interaction between bidentate L-Proline
ligand and the copper centre anchored on the MCM-41.
3
. Conclusions
1
2

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In conclusion, we have developed an efficient heterogeneous copper(II)-catalyzed
decarboxylative cyclization reaction between 2-benzoylpyridines and α-amino acids
for construction of 1,3-disubstituted imidazo[1,5-a]pyridines, which are found in a
number of drug-relevant molecules and biologically active agents. This heterogeneous
decarboxylative cyclization has many attractive features, such as: (1) the substrate
scope is broad, and a wide range of α-amino acids and 2-benzoylpyridine derivatives
are allowed; (2) a variety of 1,3-disubstituted imidazo[1,5-a]pyridines were obtained
in good to excellent yields; (3) the reaction has opened a new route to construct
3
-alkyl-1-arylimidazo[1,5-a]pyridines, which are difficult to obtain by the existing
protocols; (4) this new heterogeneous copper(II) catalyst can easily be prepared from
commercially readily available and inexpensive reagents, and recovered from the
reaction mixture by a simple filtration, and recycled up to eight times with almost
consistent activity.
4
. Experimental
4
.1. General remarks
All chemicals were reagent grade and used as received without further purification.
All solvents were dried and distilled before use. The products were purified by flash
column chromatography on 230-400 mesh silica gel. A mixture of petroleum ether
1
13
(
60-90 ºC) and ethyl acetate was generally used as eluent. H and C NMR spectra
were recorded with a Bruker Avance 400 NMR spectrometer (400 MHz or 100 MHz,
1
3

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respectively) in CDCl as solvent. Melting points are uncorrected. X-ray powder
3
diffraction patterns were recorded on Damx-rA (Riguka). Copper content was
determined with a Jarrell-Ash 1100 ICP. The BET surface areas and pore analysis
were performed using a ASAP2010 analyzer by nitrogen adsorption/desorption at
7
7.4 K. Samples were degassed at 413 K overnight before measurements. Energy
dispersive X-ray spectroscopy (EDS) was obtained using a microscope. HRMS
spectra were taken on an AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer
using the electrospray mode (ES). Mesoporous material MCM-41 [50] and pyridine
ketones 1 [30] were prepared according to literature methods.
4
4
.2. Synthesis of supported copper catalysts
.2.1. Preparation of ClCH -MCM-41
2
To a suspension of 5.5 g of the MCM-41 in 140 mL of dry toluene was added a
solution of 5.0 g of 4-(chloromethyl)phenyltrichlorosilane in 10 mL of dry toluene.
The mixture was stirred for 24 h at 100 °C under Ar. The solid product was filtered
and washed by CHCl (20 mL), and dried in vacuum at 110 °C for 3 h. The dried
3
white solid was then treated with dry ethanol (50 mL) at 80 °C for 5 h under Ar. The
resulting solid was filtered, washed with diethyl ether (3 × 20 mL), and then soaked in
a solution of 5.0 g of Me SiCl in 100 mL of dry toluene at 25 ºC with stirring for 24 h.
3
Then the solid was filtered, washed with acetone (3 × 20 mL) and diethyl ether (3 ×
2
0 mL), and dried in vacuum at 130 °C for 5 h to obtain 7.45 g of hybrid material
ClCH -MCM-41. The chlorine content was found to be 1.66 mmol/g by elemental
2
1
4

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analysis.
4
.2.2. Preparation of L-Proline-MCM-41
To a solution of N-Boc-trans-4-hydroxy-L-proline (1.27 g, 5.5 mmol) in 100 mL of
dry THF was added NaH (0.28 g, 11.6 mmol) and the reaction mixture was stirred at
5 ºC for 2 h under Ar. Then 2.23 g of ClCH -MCM-41 was added and the mixture
2
2
was refluxed for 24 h. After being cooled to room temperature, the solid product was
filtered, washed with distilled water (2 × 20 mL), ethanol (2 × 20 mL), and dried in
vacuum at 110 °C for 4 h. The dried white solid (1.553 g) was treated with TFA (8 mL)
in CH Cl (10 mL) at reflux for 3 h, then filtered, and washed with Et N (6 mL),
2
2
3
CH Cl (10 mL) and Et O (10 mL), and dried in vacuum at 110 °C for 4 h to afford
2
2
2
1
1
.278 g of hybrid material L-Proline-MCM-41. The nitrogen content was found to be
.08 mmol/g by elemental analysis.
4
.2.3. Preparation of L-Proline-MCM-41-Cu(OTf)2
In a small Schlenk tube, 1.121 g of the above-functionalized MCM-41 (L-Proline-
MCM-41) was mixed with 0.362 g (1.0 mmol) of Cu(OTf) in 20 mL of acetone. The
2
reaction mixture was stirred at room temperature for 12 h under Ar. The solid product
was filtered by suction, washed with distilled water and acetone, and dried at
7
0 °C/26.7 Pa under Ar for 4 h to give 1.382 g of a pale blue powder copper complex
[
L-Proline-MCM-41-Cu(OTf) ]. The nitrogen and copper contents were found to be
2
0
.75 mmol/g and 0.64 mmol/g, respectively.
The L-Proline-MCM-41-CuI [A], L-Proline-MCM-41-CuBr [B], L-Proline-MCM-
1
5

ACCEPTED MANUSCRIPT
4
1-CuCl [C], L-Proline-MCM-41-CuBr [D] and L-Proline-MCM-41-Cu(OAc) [F]
2
2
2
were also prepared by using L-Proline-MCM-41 (1.12 g) and the corresponding
copper salts (1.0 mmol) as the starting materials in the same manner, the copper
-1
-1
-1
contents were determined to be 0.57 mmol g , 0.53 mmol g , 0.60 mmol g , 0.59
-1
-1
mmol g , and 0.66 mmol g , respectively.
4
.3. General procedure for the heterogeneous copper(II)-catalyzed synthesis of 1,3-
disubstituted imidazo[1,5-a]pyridines
To a 10 mL reaction tube were added L-Proline-MCM-41-Cu(OTf) (71 mg, 0.045
2
mmol), 2-benzoylpyridine 1 (0.3 mmol), amino acid 2 (0.9 mmol), molecular iodine
(
0.045 mmol), DTBP (0.75 mmol), and toluene (2 mL). The reaction tube was sealed
and placed in an oil bath at room temperature. The reaction mixture was stirred at
20 °C for 12 h. After being cooled to room temperature, the reaction mixture was
1
diluted with 15 mL of EtOAc, and filtered. The L-Proline-MCM-41-Cu(OTf)2
complex was washed with EtOAc (2 × 5 mL) and ethanol (2 × 5 mL), and reused in
the next run. The filtrate was concentrated in vacuo and the residue was purified by
flash column chromatography on silica gel (petroleum ether : EtOAc = 15:1–20:1) to
provide the desired product 3.
1
4
.3.1. 3-Isobutyl-1-phenylimidazo[1,5-a]pyridine (3a) [32]. Pale green oil. H NMR
(
400 MHz, CDCl ): δ 7.86 (d, J = 7.2 H , 2H), 7.75-7.70 (m, 2H), 7.43 (t, J = 7.2 Hz,
3 Z
2
H), 7.25 (t, J = 7.0 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.51 (t, J = 6.4 Hz, 1H), 2.91 (d,
1
3
J = 6.8 Hz, 2H), 2.30-2.23 (m, 1H), 1.01 (d, J = 6.0 Hz, 6H). C NMR (100 MHz,
CDCl ): δ 138.5, 135.2, 130.1, 128.7, 126.6, 126.4, 126.2, 121.1, 119.0, 118.6, 112.4,
3
1
6

ACCEPTED MANUSCRIPT
3
5.5, 27.9, 22.7.
.3.2. 3-Isobutyl-1-(p-tolyl)imidazo[1,5-a]pyridine (3b) [31]. Pale green oil. H NMR
1
4
(
400 MHz, CDCl ): δ 7.75 (d, J = 8.0 Hz, 2H), 7.72-7.68 (m, 2H), 7.24 (d, J = 8.0 Hz,
3
2
2
1
2
H), 6.66-6.62 (m, 1H), 6.50-6.46 (m, 1H), 2.89 (d, J = 7.2 Hz, 2H), 2.37 (s, 3H),
1
3
.31-2.20 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl ): δ 138.3,
3
35.7, 132.5, 130.4, 129.4, 126.5, 126.1, 121.0, 119.1, 118.1, 112.2, 35.6, 27.9, 22.7,
1.2.
4
.3.3. 3-Isobutyl-1-(4-methoxyphenyl)imidazo[1,5-a]pyridine (3c) [31]. Pale green oil.
1
H NMR (400 MHz, CDCl ): δ 7.77 (dd, J = 6.8, 2.0 Hz, 2H), 7.71-7.65 (m, 2H), 6.98
3
(dd, J = 6.8, 2.0 Hz, 2H), 6.64-6.60 (m, 1H), 6.50-6.46 (m, 1H), 3.83 (s, 3H), 2.89 (d,
1
3
J = 7.2 Hz, 2H), 2.29-2.22 (m, 1H), 1.01 (d, J = 6.4 Hz, 6H). C NMR (100 MHz,
CDCl ): δ 158.3, 138.2, 130.2, 128.1, 127.8, 125.7, 120.9, 119.1, 117.9, 114.2, 112.2,
3
5
5.3, 35.6, 27.9, 22.7.
4
.3.4. N-(4-(3-Isobutylimidazo[1,5-a]pyridin-1-yl)phenyl)acetamide (3d). Pale yellow
1
oil. H NMR (400 MHz, CDCl ): δ 7.80 (d, J = 8.0 Hz, 2H), 7.75-7.69 (m, 2H), 7.59
3
(d, J = 8.0 Hz, 2H), 6.73-6.68 (m, 1H), 6.55 (t, J = 6.6 Hz, 1H), 2.92 (d, J = 7.2 Hz,
1
3
2
H), 2.29-2.22 (m, 1H), 2.18 (s, 3H), 1.01 (d, J = 6.4 Hz, 6H). C NMR (100 MHz,
CDCl ): δ 168.4, 138.5, 137.5, 136.2, 131.3, 129.7, 127.1, 121.1, 120.2, 119.1, 118.6,
3
+
+
1
3
4
1
12.5, 35.6, 27.9, 24.7, 22.7. HRMS calcd for C H N O [M ]: 307.1685, found
19 21 3
07.1677.
.3.5. 4-(3-Isobutylimidazo[1,5-a]pyridin-1-yl)phenol (3e). Light yellow solid. Mp
1
05-106 °C. H NMR (400 MHz, DMSO-d ): δ 9.39 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H),
6
1
7

ACCEPTED MANUSCRIPT
7
.77 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.76-6.72
(m, 1H), 6.62 (t, J = 6.6 Hz, 1H), 2.89 (d, J = 7.2 Hz, 2H), 2.21-2.11 (m, 1H), 0.96 (d,
13
J = 6.8 Hz, 6H). C NMR (100 MHz, DMSO-d ): δ 156.3, 138.1, 129.3, 127.5, 126.6,
6
1
25.0, 122.6, 119.0, 118.9, 116.0, 112.6, 34.8, 27.7, 22.8. HRMS calcd for
+
+
C H N O [M ]: 266.1419, found 266.1413.
17
18
2
1
4
.3.6. 1-(4-Chlorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3f). Pale green oil. H
NMR (400 MHz, CDCl ): δ 7.79 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.2 Hz, 1H), 7.68 (d,
3
J = 9.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.73-6.68 (m, 1H), 6.54 (t, J = 7.4 Hz, 1H),
1
3
2
.89 (d, J = 7.2 Hz, 2H), 2.29-2.22 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). C NMR (100
MHz, CDCl ): δ 138.7, 133.9, 131.6, 129.0, 128.8, 127.6, 126.5, 121.2, 119.0, 118.7,
3
+
+
1
2
4
12.4, 35.6, 27.8, 22.7. HRMS calcd for C H ClN [M ]: 284.1080, found
17 17 2
84.1076.
.3.7. 1-(4-Fluorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3g). Pale green oil. H
1
NMR (400 MHz, CDCl ): δ 7.82-7.78 (m, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.67 (d, J =
3
9
.6 Hz, 1H), 7.12 (t, J = 8.8 Hz, 2H), 6.71-6.67 (m, 1H), 6.53 (t, J = 6.6 Hz, 1H), 2.90
1
3
(
d, J = 7.6 Hz, 2H), 2.30-2.23 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). C NMR (100 MHz,
1
4
CDCl ): δ 161.6 (d, J = 243.5 Hz), 138.5, 131.5 (d, J = 3.1 Hz), 129.3, 128.1 (d,
3
C-F
C-F
3
2
JC-F = 7.8 Hz), 126.1, 121.1, 118.8, 118.6, 115.5 (d, J = 21.3 Hz), 112.4, 35.6,
C-F
+
+
2
7.8, 22.6. HRMS calcd for C H FN [M ]: 268.1376, found 268.1385.
17 17 2
4
.3.8. 3-Isobutyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (3h) [31]. Pale
1
green oil. H NMR (400 MHz, CDCl ): δ 7.98 (d, J = 8.0 Hz, 2H), 7.78-7.74 (m, 2H),
3
7
.66 (d, J = 8.0 Hz, 2H), 6.80-6.76 (m, 1H), 6.58 (t, J = 6.8 Hz, 1H), 2.91 (d, J = 7.6
1
8

ACCEPTED MANUSCRIPT
1
3
Hz, 2H), 2.31-2.25 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl ): δ
3
2
3
1
1
4
1
39.1, 138.9, 128.5, 127.6 (q, JC-F = 32.1 Hz), 127.3, 126.2, 125.6 (q, J = 3.8 Hz),
C-F
1
24.5 (q, J = 269.9 Hz), 121.4, 119.7, 118.6, 112.6, 35.5, 27.8, 22.6.
C-F
.3.9. 4-(3-Isobutylimidazo[1,5-a]pyridin-1-yl)benzonitrile (3i). Pale green solid. Mp
1
01-102 °C. H NMR (400 MHz, CDCl ): δ 7.98 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 7.2
3
Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 6.87-6.82 (m, 1H), 6.63 (t,
J = 6.8 Hz, 1H), 2.91 (d, J = 7.2 Hz, 2H), 2.33-2.23 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H).
1
3
C NMR (100 MHz, CDCl ): δ 139.9, 139.5, 132.4, 127.9, 127.8, 126.2, 121.7, 120.5,
3
+
+
1
19.6, 118.5, 112.8, 108.5, 35.5, 27.7, 22.6. HRMS calcd for C H N [M ]:
18 17 3
2
75.1422, found 275.1423.
.3.10. Methyl 4-(3-isobutylimidazo[1,5-a]pyridin-1-yl)benzoate (3j). Pale green oil.
4
1
H NMR (400 MHz, CDCl ): δ 8.09 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H),
3
7
.80-7.76 (m, 2H), 6.80-6.76 (m, 1H), 6.60-6.56 (m, 1H), 3.92 (s, 3H), 2.91 (d, J =
1
3
7
.2 Hz, 2H), 2.33-2.22 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). C NMR (100 MHz,
CDCl ): δ 167.2, 139.9, 139.2, 130.7, 128.8, 127.5, 127.1, 125.8, 121.5, 119.8, 118.8,
3
+
+
1
3
4
12.6, 51.9, 35.5, 27.8, 22.6. HRMS calcd for C H N O [M ]: 308.1525, found
19 20 2 2
08.1520.
.3.11. 3-Isobutyl-1-(m-tolyl)imidazo[1,5-a]pyridine (3k) [31]. Pale green oil. H
1
NMR (400 MHz, CDCl ): δ 7.76-7.70 (m, 3H), 7.63 (d, J = 7.6 Hz, 1H), 7.32 (t, J =
3
7
.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.70-6.65 (m, 1H), 6.51 (t, J = 6.8 Hz, 1H),
13
2
.91 (d, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.30-2.22 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). C
NMR (100 MHz, CDCl ): δ 138.4, 138.3, 135.2, 130.4, 128.5, 127.4, 127.0, 126.4,
3
1
9

ACCEPTED MANUSCRIPT
1
23.7, 121.1, 119.2, 118.3, 112.3, 35.6, 27.9, 22.7, 21.6.
4
.3.12. 1-(3-Chlorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3l) [31]. Pale green oil.
1
H NMR (400 MHz, CDCl ): δ 7.87 (t, J = 1.8 Hz, 1H), 7.75-7.70 (m, 3H), 7.34 (t, J
3
=
7.8 Hz, 1H), 7.22-7.18 (m, 1H), 6.75-6.71 (m, 1H), 6.56-6.52 (m, 1H), 2.89 (d, J =
1
3
7
.2 Hz, 2H), 2.30-2.23 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl )
3
δ 138.8, 137.2, 134.6, 129.8, 128.6, 126.8, 126.3, 125.9, 124.4, 121.3, 119.3, 118.7,
12.5, 35.6, 27.8, 22.7.
1
4
.3.13. 1-(3,5-Dimethylphenyl)-3-isobutylimidazo[1,5-a]pyridine (3m) [31]. Pale
1
green oil. H NMR (400 MHz, CDCl ): δ 7.76-7.70 (m, 2H), 7.48 (s, 2H), 6.91 (s, 1H),
3
6
2
1
2
4
.68-6.63 (m, 1H), 6.50 (t, J = 6.8 Hz, 1H), 2.91 (d, J = 7.6 Hz, 2H), 2.38 (s, 6H),
1
3
.29-2.22 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl ): δ 138.3,
3
38.1, 135.1, 130.5, 128.0, 126.3, 124.5, 121.1, 119.3, 118.2, 112.3, 35.6, 27.9, 22.6,
1.5.
.3.14. 1-(3,5-Difluorophenyl)-3-isobutylimidazo[1,5-a]pyridine (3n) [31]. Pale green
1
oil
.
H NMR (400 MHz, CDCl ): δ 7.78 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H),
3
7
2
.41-7.38 (m, 2H), 6.83-6.78 (m, 1H), 6.70-6.64 (m, 1H), 6.60 (t, J = 6.4 Hz, 1H),
1
3
.90 (d, J = 7.2 Hz, 2H), 2.31-2.24 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H). C NMR (100
1
MHz, CDCl ): δ 163.4 (dd, J = 244.9, 13.4 Hz), 138.9, 127.1, 121.4, 119.9, 118.5,
3
C-F
2
2
1
12.6, 108.7 (dd, J = 18.7, 7.3 Hz), 101.0 (t, J = 25.6 Hz), 35.5, 27.7, 22.6.
C-F
C-F
1
4
.3.15. 3-Isobutyl-1-(o-tolyl)imidazo[1,5-a]pyridine (3o) [31]. Pale green oil. H
NMR (400 MHz, CDCl ): δ 7.73 (d, J = 7.2 Hz, 1H), 7.44-7.41 (m, 1H), 7.34 (d, J =
3
8
.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.26-7.22 (m, 2H), 6.63-6.58 (m, 1H), 6.52 (t, J = 6.2
2
0

ACCEPTED MANUSCRIPT
Hz, 1H), 2.91 (d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.32-2.26 (m, 1H), 1.03 (d, J = 6.8 Hz,
1
3
6
1
4
H). C NMR (100 MHz, CDCl ): δ 137.6, 137.3, 134.0, 130.8, 130.7, 130.3, 127.2,
3
27.0, 125.5, 120.7, 119.0, 117.6, 112.2, 35.6, 27.7, 22.7, 20.5.
1
.3.16. 3-Isobutyl-1-(thiophen-2-yl)imidazo[1,5-a]pyridine (3p). Pale yellow oil. H
NMR (400 MHz, CDCl ): δ 7.75-7.71 (m, 2H), 7.41-7.39 (m, 1H), 7.24-7.22 (m, 1H),
3
7
2
1
2
.12-7.09 (m, 1H), 6.75-6.71 (m, 1H), 6.55 (t, J = 7.0 Hz, 1H), 2.90 (d, J = 7.6 Hz,
1
3
H), 2.31-2.20 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl ): δ
3
38.5, 132.1, 128.8, 128.3, 127.5, 122.8, 121.7, 121.1, 119.0, 118.7, 112.5, 35.4, 27.9,
+
+
2.6. HRMS calcd for C H N S [M ]: 256.1034, found 256.1029.
1
5
16
2
4
.3.17. 3-Isobutyl-1-(naphthalen-1-yl)imidazo[1,5-a]pyridine (3q) [31]. Pale green oil.
1
H NMR (400 MHz, CDCl ): δ 8.31-8.28 (m, 1H), 7.90-7.87 (m, 1H), 7.83 (d, J = 8.4
3
Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.55-7.51 (m, 1H),
7
2
1
1
4
.48-7.43 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 6.63-6.53 (m, 2H), 2.98 (d, J = 7.2 Hz,
1
3
H), 2.38-2.31 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H). C NMR (100 MHz, CDCl ): δ
3
38.3, 134.3, 132.2, 132.1, 129.7, 128.2, 127.9, 127.6, 127.5, 126.6, 126.0, 125.7,
25.4, 120.9, 119.1, 118.0, 112.4, 35.7, 27.8, 22.8.
1
.3.18. 1-Isobutyl-3-phenylimidazo[1,5-a]quinoline (3r) [31]. Pale green oil
.
H NMR
(
400 MHz, CDCl ): δ 8.06 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.59-7.53 (m,
3
2
H), 7.50-7.41 (m, 3H), 7.36-7.26 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 3.28 (d, J = 6.8
1
3
Hz, 2H), 2.46-2.40 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H). C NMR (100 MHz, CDCl ): δ
3
1
1
43.3, 135.0, 133.3, 132.3, 128.7, 128.5, 127.8, 127.4, 126.7, 126.3, 126.0, 124.8,
21.1, 117.7, 116.6, 41.1, 26.6, 22.6.
2
1

ACCEPTED MANUSCRIPT
1
4
.3.19. 3-Methyl-1-phenylimidazo[1,5-a]pyridine (3t) [32]. Pale green oil. H NMR
(
400 MHz, CDCl ): δ 7.86 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.65 (d, J =
3
7
6
1
4
.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 6.74-6.70 (m, 1H),
1
3
.59-6.55 (m, 1H), 2.69 (s, 3H). C NMR (100 MHz, CDCl : δ 135.1, 134.9, 129.9,
3
28.7, 126.4, 126.2, 121.0, 119.0, 118.6, 112.6, 12.5.
1
.3.20. 1-Phenyl-3-propylimidazo[1,5-a]pyridine (3u) [31]. Pale green oil
.
H NMR
(
400 MHz, CDCl ): δ 7.86 (dd, J = 8.2, 1.0 Hz, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.71 (d,
3
J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.27-7.23 (m, 1H), 6.71-6.66 (m, 1H),
6
3
1
4
.54-6.50 (m, 1H), 3.00 (t, J = 7.6 Hz, 2H), 1.93-1.84 (m, 2H), 1.06 (t, J = 7.4 Hz,
1
3
H). C NMR (100 MHz, CDCl ): δ 138.9, 135.3, 130.1, 128.7, 126.5, 126.4, 126.1,
3
21.0, 119.1, 118.6, 112.4, 28.7, 20.7, 14.0.
1
.3.21. 3-(sec-Butyl)-1-phenylimidazo[1,5-a]pyridine (3v) [31]. Pale green oil
.
H
NMR (400 MHz, CDCl ): δ 7.86 (dd, J = 8.2, 1.0 Hz, 2H), 7.75-7.71 (m, 2H), 7.42 (t,
3
J = 7.6 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 6.68-6.63 (m, 1H), 6.51-6.47 (m, 1H),
3
0
1
.15-3.06 (m, 1H), 2.07-1.97 (m, 1H), 1.83-1.69 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H),
1
3
.94 (t, J = 7.4 Hz, 3H). C NMR (100 MHz, CDCl ): δ 142.8, 135.5, 130.2, 128.7,
3
26.7, 126.4, 126.1, 120.9, 119.1, 118.4, 112.2, 33.1, 28.2, 18.3, 12.1.
4
.3.22. 1,3-Diphenylimidazo[1,5-a]pyridine (3w) [30]. Yellow solid. Mp 111-112 °C.
1
H NMR (400 MHz, CDCl ): δ 8.23 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H),
3
7
.85-7.82 (m, 3H), 7.53 (t, J = 7.4 Hz, 2H), 7.49-7.44 (m, 3H), 7.30 (t, J = 7.4 Hz,
1
3
1
1
H), 6.80-6.76 (m, 1H), 6.56 (t, J = 6.8 Hz, 1H). C NMR (100 MHz, CDCl ): δ
3
38.2, 135.0, 132.1, 130.2, 129.0, 128.8, 128.7, 128.4, 127.7, 126.8, 126.5, 121.8,
2
2

ACCEPTED MANUSCRIPT
119.7, 119.2, 113.2.
4
.3.23. 3-(4-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3x) [32]. Yellow solid.
1
Mp 168-169 °C. H NMR (400 MHz, CDCl ): δ 8.12 (d, J = 6.8 Hz, 1H), 7.92 (d, J =
3
7
.6 Hz, 2H), 7.84-7.76 (m, 3H), 7.46 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.21
13
(
t, J = 8.0 Hz, 2H), 6.76 (t, J =7.6 Hz, 1H), 6.56 (t, J = 6.6 Hz, 1H). C NMR (100
1
3
MHz, CDCl ): δ 162.9 (d, J = 247.6 Hz), 137.2, 134.9, 132.0, 130.3 (d, J = 8.3
3
C-F
C-F
4
Hz), 128.8, 127.7, 126.8, 126.6, 126.4 (d, JC-F = 3.1 Hz), 121.5, 119.7, 119.2, 116.1
2
(
d, J = 21.7 Hz), 113.4.
C-F
4
.3.24. 3-(4-Chlorophenyl)-1-phenylimidazo[1,5-a]pyridine (3y) [30]. Yellow solid.
1
Mp 172-173 °C. H NMR (400 MHz, CDCl ): δ 8.17 (d, J = 7.2 Hz, 1H), 7.92 (d, J =
3
6
2
6
1
4
.8 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz,
H), 7.45 (t, J = 8.0 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 6.81-6.76 (m, 1H), 6.59 (t, J =
1
3
.8 Hz, 1H). C NMR (100 MHz, CDCl ): δ 136.9, 134.8, 134.7, 132.4, 129.5, 129.3,
3
28.8, 128.7, 127.9, 126.8, 126.7, 121.5, 119.8, 119.3, 113.6.
.3.25. 3-(3-Fluorophenyl)-1-phenylimidazo[1,5-a]pyridine (3z) [32]. Yellow solid.
1
Mp 150-151 °C. H NMR (400 MHz, CDCl ): δ 8.24 (d, J = 7.6 Hz, 1H), 7.93 (d, J =
3
7
7
1
.2 Hz, 2H), 7.85 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.59-7.56 (m, 1H),
.52-7.44 (m, 3H), 7.31 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.83-6.78 (m,
1
3
1
H), 6.61 (t, J = 7.4 Hz, 1H). C NMR (100 MHz, CDCl ): δ 163.1 (d, J = 245.4
3
C-F
4
3
3
Hz), 136.7 (d, J = 3.0 Hz), 134.8, 132.4, 132.3 (d, J = 8.1 Hz), 130.6 (d, J =
C-F
C-F
C-F
4
8
.4 Hz), 128.8, 128.0, 126.9, 126.7, 123.7 (d, JC-F = 3.0 Hz), 121.6, 119.9, 119.3,
2
2
1
15.7 (d, J = 21.0 Hz), 115.3 (d, J = 22.8 Hz), 113.7.
C-F C-F
2
3

ACCEPTED MANUSCRIPT
4
1
5
6
.3.26. 3-Phenyl-1-(p-tolyl)imidazo[1,5-a]pyridine (3a') [30]. Yellow solid. Mp
1
33-134 °C. H NMR (400 MHz, CDCl ): δ 8.20 (d, J = 7.2 Hz, 1H), 7.84-7.77 (m,
3
H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H),
1
3
.75-6.71 (m, 1H), 6.52 (t, J = 6.8 Hz, 1H), 2.39 (s, 3H). C NMR (100 MHz,
CDCl ): δ 138.0, 136.2, 132.2, 132.1, 130.3, 129.4, 129.0, 128.8, 128.3, 127.4, 126.8,
3
1
21.7, 119.4, 119.3, 113.2, 21.3.
4
.3.27. 1-(4-Methoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (3b') [30]. Yellow solid.
1
Mp 115-116 °C. H NMR (400 MHz, CDCl ): δ 8.20 (d, J = 7.2 Hz, 1H), 7.86-7.81
3
(m, 4H), 7.76 (d, J = 9.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H),
1
3
7
.01 (d, J = 8.8 Hz, 2H), 6.74-6.70 (m, 1H), 6.52 (t, J = 6.2 Hz, 1H), 3.85 (s, 3H). C
NMR (100 MHz, CDCl ): δ 158.6, 137.8, 132.1, 130.3, 129.0, 128.7, 128.3, 128.1,
3
1
4
1
2
1
1
27.8, 127.1, 121.6, 119.2, 119.1, 114.3, 113.2, 55.4.
.3.28. 1-(4-Chlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3c'). Yellow solid. Mp
1
38-139 °C. H NMR (400 MHz, CDCl ) δ 8.24 (d, J = 7.2 Hz, 1H), 7.90-7.86 (m,
3
H), 7.83-7.76 (m, 3H), 7.54 (t, J = 7.6 Hz, 2H), 7.48-7.40 (m, 3H), 6.83-6.79 (m,
1
3
H), 6.59 (t, J = 6.8 Hz, 1H). C NMR (100 MHz, CDCl ): δ 138.3, 133.6, 132.1,
3
30.8, 130.0, 129.1, 129.0, 128.9, 128.3, 127.9, 127.8, 121.9, 120.1, 118.9, 113.3.
+
+
HRMS calcd for C H ClN [M ]: 304.0767, found 304.0769.
1
9
13
2
4
.3.29. 3-Phenyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]pyridine (3d') [32].
1
Yellow solid. Mp 184-185 °C. H NMR (400 MHz, CDCl ): δ 8.26-8.24 (m, 1H), 8.06
3
(d, J = 8.4 Hz, 2H), 7.85-7.80 (m, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 8.0 Hz,
13
2
H), 7.47 (t, J = 7.4 Hz, 1H), 6.88-6.84 (m, 1H), 6.61 (t, J = 7.4 Hz, 1H). C NMR
2
4

ACCEPTED MANUSCRIPT
(
100 MHz, CDCl ): δ 138.7, 138.6, 130.9, 130.3, 129.9, 128.8, 128.5, 128.4, 128.0 (q,
3
2
3
1
JC-F = 32.2 Hz), 126.5, 125.6 (q, J = 3.8 Hz), 124.5 (q, J = 270.0 Hz), 122.1,
C-F
C-F
1
20.8, 118.7, 113.4.
4
.3.30. 3-Phenyl-1-(o-tolyl)imidazo[1,5-a]pyridine (3e') [32]. Yellow solid. Mp
1
1
18-119 °C. H NMR (400 MHz, CDCl ): δ 8.28 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2
3
Hz, 2H), 7.54-7.48 (m, 3H), 7.45-7.41 (m, 2H), 7.35-7.31 (m, 1H), 7.30-7.26 (m, 2H),
1
3
6
.73-6.68 (m, 1H), 6.57 (t, J = 6.8 Hz, 1H), 2.46 (s, 3H). C NMR (100 MHz,
CDCl ): δ 137.5, 137.4, 133.6, 132.8, 130.8, 130.4, 129.0, 128.6, 128.5, 128.1, 127.5,
3
1
25.6, 121.5, 119.2, 118.9, 113.2, 20.6.
4
.3.31. 3-Phenyl-1-(m-tolyl)imidazo[1,5-a]pyridine (3f') [32]. Yellow solid. Mp
1
1
12-113 °C. H NMR (400 MHz, CDCl ): δ 8.21 (d, J = 7.2 Hz, 1H), 7.84-7.78 (m,
3
4
7
H), 7.70 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.46-7.41 (m, 1H), 7.35 (t, J =
.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.78-6.73 (m, 1H), 6.54 (t, J = 6.8 Hz, 1H), 2.43
1
3
(
s, 3H). C NMR (100 MHz, CDCl ): δ 138.4, 138.1, 134.9, 132.2, 130.3, 129.0,
3
1
28.8, 128.6, 128.4, 127.7, 127.6, 127.4, 123.9, 121.7, 119.5, 119.3, 113.2, 21.6.
4
.3.32. 1-(3-Chlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3g') [30]. Yellow solid.
1
Mp 131-132 °C. H NMR (400 MHz, CDCl ): δ 8.23 (d, J = 7.2 Hz, 1H), 7.95 (t, J =
3
1
.8 Hz, 1H), 7.83-7.80 (m, 4H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37
1
3
(
t, J = 8.0 Hz, 1H), 7.26-7.23 (m, 1H), 6.85-6.81 (m, 1H), 6.59 (t, J = 6.6 Hz, 1H). C
NMR (100 MHz, CDCl ): δ 138.4, 136.9, 134.7, 130.4. 130.0, 129.9, 129.1, 129.0,
3
1
28.4, 128.0, 126.6, 126.4, 124.6, 122.0, 120.4, 118.8, 113.4.
4
.3.33. 1-(3,5-Dimethylphenyl)-3-phenylimidazo[1,5-a]pyridine (3h') [30]. Yellow
2
5

ACCEPTED MANUSCRIPT
1
solid. Mp 125-126 °C. H NMR (400 MHz, CDCl ): δ 8.22 (d, J = 7.2 Hz, 1H),
3
7
.85-7.81 (m, 3H), 7.57-7.51 (m, 4H), 7.44 (t, J = 7.2 Hz, 1H), 6.95 (s, 1H), 6.77 (t, J
1
3
=
7.4 Hz, 1H), 6.55 (t, J = 6.4 Hz, 1H), 2.40 (s, 6H). C NMR (100 MHz, CDCl ): δ
3
1
38.2, 138.0, 134.8, 132.3, 130.3, 129.0, 128.8, 128.4, 127.6, 124.7, 121.7, 119.4,
113.2, 21.5.
4
.3.34. 1-(3,5-Dimethoxyphenyl)-3-phenylimidazo[1,5-a]pyridine (3i') [30]. Yellow
1
solid. Mp 178-179 °C. H NMR (400 MHz, CDCl ): δ 8.22 (d, J = 7.2 Hz, 1H),
3
7
.86-7.81 (m, 3H), 7.53 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 2.0
Hz, 2H), 6.80-6.75 (m, 1H), 6.56 (t, J = 6.4 Hz, 1H), 6.44 (t, J = 2.2 Hz, 1H), 3.87 (s,
1
3
6
1
4
H). C NMR (100 MHz, CDCl ): δ 161.1, 138.0, 136.9, 131.9, 130.2, 129.0, 128.9,
3
28.4, 127.9, 121.8, 119.9, 119.2, 113.3, 104.9, 99.2, 55.5.
.3.35. 1-(3,5-Difluorophenyl)-3-phenylimidazo[1,5-a]pyridine (3j') [30]. Yellow
1
solid. Mp 164-165 °C. H NMR (400 MHz, CDCl ): δ 8.27-8.25 (m, 1H), 7.84-7.81
3
(m, 3H), 7.56 (t, J = 7.6 Hz, 2H), 7.50-7.46 (m, 3H), 6.92-6.87 (m, 1H), 6.74-6.69 (m,
1
3
1
1
H), 6.65-7.62 (m, 1H). C NMR (100 MHz, CDCl ) δ 163.5 (dd, J = 244.8, 13.4
3 C-F
Hz), 138.6, 138.2, 129.8, 129.6, 129.2, 129.1, 128.4, 128.3, 122.2, 121.0, 118.6, 113.4,
2
1
09.0 (dd, J = 18.8, 7.3 Hz), 101.5.
C-F
4
.3.36. 1-(3,5-Dichlorophenyl)-3-phenylimidazo[1,5-a]pyridine (3k') [30]. Yellow
1
solid. Mp 188-189 °C. H NMR (400 MHz, CDCl ): δ 8.25 (d, J = 7.2 Hz, 1H),
3
7
1
1
.85-7.80 (m, 5H), 7.55 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.26-7.24 (m,
1
3
H), 6.92-6.87 (m, 1H), 6.63 (t, J = 7.0 Hz, 1H). C NMR (100 MHz, CDCl ): δ
3
38.7, 138.0, 135.2, 129.7, 129.2, 129.1, 129.0, 128.4, 126.0, 124.6, 122.2, 121.1,
2
6

ACCEPTED MANUSCRIPT
118.6, 113.5.
4
.3.37. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-phenylimidazo[1,5-a]pyridine (3l') [30].
1
Yellow solid. Mp 134-135 °C. H NMR (400 MHz, CDCl ): δ 8.40 (s, 2H), 8.29 (d, J
3
=
7.2 Hz, 1H), 7.85-7.80 (m, 3H), 7.75 (s, 1H), 7.59-7.48 (m, 3H), 6.96 (t, J = 7.8 Hz,
1
3
1
H), 6.68 (t, J = 6.6 Hz, 1H). C NMR (100 MHz, CDCl ): δ 139.1, 137.2, 132.0 (q,
3
2
1
JC-F = 32.9 Hz), 129.6, 129.4, 129.2, 128.7, 128.4, 126.0, 123.6 (q, J = 271.0 Hz),
C-F
3
1
22.4, 121.7, 119.4 (q, J = 3.9 Hz), 118.2, 113.6.
C-F
4
.3.38. 1-(Naphthalen-1-yl)-3-phenylimidazo[1,5-a]pyridine (3m') [30]. Yellow solid.
1
Mp 118-119 °C. H NMR (400 MHz, CDCl ): δ 8.37 (d, J = 8.0 Hz, 1H), 8.30 (d, J =
3
7
.6 Hz, 1H), 7.92-7.85 (m, 4H), 7.74 (d, J = 6.8 Hz, 1H), 7.57-7.51 (m, 3H),
13
7
.49-7.41 (m, 4H), 6.71-6.67 (m, 1H), 6.57 (t, J = 6.8 Hz, 1H). C NMR (100 MHz,
CDCl ): δ 138.0, 134.3, 132.2, 131.8, 131.7, 130.4, 129.3, 129.0, 128.8, 128.3, 127.9,
3
1
4
1
3
27.8, 126.6, 126.1, 125.8, 125.5, 121.6, 119.3, 119.2, 113.4.
.3.39. 1,3-Diphenylimidazo[1,5-a]quinoline (3n') [30]. Yellow solid. Mp
1
36-137 °C. H NMR (400 MHz, CDCl ): δ 7.91 (d, J = 7.2 Hz, 2H), 7.69-7.63 (m,
3
H), 7.58 (d, J = 7.6 Hz, 1H), 7.54-7.42 (m, 6H), 7.34-7.23 (m, 2H), 7.14 (t, J = 7.6
1
3
Hz, 1H), 7.04 (d, J = 9.6 Hz, 1H). C NMR (100 MHz, CDCl ): δ 142.2, 134.6, 133.9,
3
1
1
33.8, 132.6, 129.8, 129.5, 128.9, 128.7, 128.5, 127.5, 127.0, 126.5, 125.8, 125.2,
22.0, 117.6, 117.5.
Acknowledgements
We thank the National Natural Science Foundation of China (No. 21462021) and
2
7

ACCEPTED MANUSCRIPT
Key Laboratory of Functional Small Organic Molecule, Ministry of Education (No.
KLFS-KF-201704) for financial support.
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[
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