Tandem amination/cycloisomerization of aryl propargylic alcohols with 2-aminopyridines as an expedient route to imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/ejoc.201101053

A new tandem route leading to imidazo[1,2-a]pyridines has been explored through the direct amination of aryl propargylic alcohols with 2-aminopyridines and their subsequent intramolecular cycloisomerization. A ZnCl₂/CuCl system has been develop

Full text of DOI:10.1002/ejoc.201101053

FULL PAPER
DOI: 10.1002/ejoc.201101053
Tandem Amination/Cycloisomerization of Aryl Propargylic Alcohols with
2-Aminopyridines as an Expedient Route to Imidazo[1,2-a]pyridines
Ping Liu,[a] Chun-Lin Deng,[a] Xinsheng Lei,*[a] and Guo-qiang Lin*[a]
Keywords: Synthesis design / Medicinal chemistry / Nitrogen heterocycles / Alkynes / Cycloisomerization
A new tandem route leading to imidazo[1,2-a]pyridines has
been explored through the direct amination of aryl propar-
gylic alcohols with 2-aminopyridines and their subsequent
intramolecular cycloisomerization. A ZnCl2/CuCl system has
been developed to promote this transformation, which re-
sulted in various imidazo[1,2-a]pyridines in moderate to good
yields.
Introduction
erization of alkynes catalyzed by transition metals is well
established.[6] In principle, a combination of direct propar-
gylic substitution and subsequent cycloisomerization could
open a new window of tandem reactions for the synthesis
of various heterocyclic structures.[7]
The design and exploration of new tandem reactions
with two or more components has emerged as one of the
current topics in organic synthesis due to their contribution
to the diversity and complexity of the compound library,
synthetic efficiency of target molecules, and usually the
Imidazo[1,2-a]pyridine is recognized as a “drug preju-
atom economics of the reaction as well.[1] The commonly dice” scaffold because of its broad occurrence in a number
devised strategy for tandem reactions depends on two or of drug candidates and clinical drugs, which include Zolpi-
more separate functional groups in the participants, of dem, Alpidem, Olprinone, and Minodronic acid,[8] and sev-
which one functionality is initiated in the first process and eral synthetic approaches for the scaffold are available.[9]
then the others are sequentially evoked to proceed to the However, these approaches can suffer from inappropriate
next process. Propargyl alcohols, a class of readily-available substitution patterns, precursors that are difficult to obtain,
bifunctional components, which contain both hydroxy and poor atom economics, and sluggish reactions (up to
alkynyl groups, are of great potential in tandem reactions. 10 d).[10] Recently, both we and Gevorgyan et al. have inde-
Recently, direct propargylic substitution reactions of pro- pendently explored a new approach to imidazo[1,2-a]pyr-
pargylic alcohols with C- or heteroatom-centered nucleo- idines by a three-component tandem reaction of 2-amino-
philes[2–5] have been accomplished with propargylic cations pyridines, aldehydes, and alkynes.[11] This one-pot reaction
or metal–allenylidene complexes. Intramolecular cycloisom- is believed to undergo three cascade processes according to
Scheme 1. Routes to imidazo[1,2-a]pyridines.
[a] Department of Chemistry and School of Pharmacy,
Fudan University,
path a, namely imination/addition/cycloisomerization
(Scheme 1); however, path b, namely addition/amination/cy-
cloisomerization, has not been absolutely excluded. To the
best of our knowledge, the reaction sequence according to
path b has not been explored to date, despite the fact that
it could afford an alternative method for the synthesis of
220 Handane Road, Shanghai 200433, China
Fax: +86-21-51980128
E-mail: leixs@fudan.edu.cn
lingq@sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101053.
7308
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7308–7316

An Expedient Route to Imidazo[1,2-a]pyridines
imidazo[1,2-a]pyridines and have the same attractiveness in Table 1. Screening of acids and transition metal salts for the model
reaction of 1a and 2a under different conditions.[a,b]
terms of atom-economics as path a. This prompted us to
envisage a new tandem reaction route to imidazo[1,2-a]pyr-
idines through the amination and cycloisomerization of
propargylic alcohols with 2-aminopyridines.
In the envisaged reaction, the first challenge is the direct
amination of propargylic alcohols with basic 2-aminopyr-
idines because basic amines as N-nucleophiles are seldom
Entry
Catalyst (equiv.)
Yield of 4a (3a) [%][c]
able to directly aminate propargylic alcohols.[4c–4d,4g–4j]
However, many neutral and acidic N-nucleophiles, such as
amides or sulfonamides, have been reported for propar-
gylation.[4] The challenge stems from the transformation
mechanism regarding the formation of the propargylic cat-
ion: amines as nucleophiles are not only basic but also coor-
dinative and could neutralize acidic catalysts or coordinate
transition-metal catalysts commonly used in the transfor-
mation, which would interrupt the formation of the propar-
gylic cation. The second challenge is the risk of competing
allenyl cations.[4a–4b,7e–1] In addition, Friedel–Crafts reac-
tions[2] or Meyer–Schuster rearrangement[12] usually occur
in the propargylation process. Herein, we present our efforts
to overcome these problems and develop a tandem amin-
ation/cycloisomerization reaction of aryl propargylic
alcohols with 2-aminopyridines.
1
2
3
4
5
6
7
8
pTsOH·H2O (1.0)
CF3COOH (1.0)
pTsOH·H2O (0.5)
pTsOH·H2O (1.5)
FeCl3 (1.0)
FeBr2 (1.0)
BiCl3 (1.0)
AlMe2Cl (1.0)
ZnCl2 (1.0)
ZnBr2 (1.0)
39 (16)
35 (0)
5 (0)
trace (0)
27 (0)
52 (0)
15 (trace)
29 (13)
57 (0)
54 (0)
37 (0)
51 (0)
13 (0)
20 (trace)
44 (0)
42 (trace)
56 (0)
9
10
11
12
13
14
15
16
17
18
ZnI2 (1.0)
BF3·OEt (1.0)
NH4BF4 (1.0)
AgOTf (1.0)
CuBr2 (1.0)
CuCl2 (1.0)
CuCl (1.0)
CuBr (1.0)
25 (0)
[a] Other Lewis acids, such as FeCl2, Ti(OiPr)4, TiCl4, MoCl5,
CdCl2, AlCl3, Zn(OAc)2, Cu(OTf)2, CuI, CrCl3, H3Mo12O40P·
xH2O, and trimethylsilyl trifluoromethanesulfonate, did not pro-
mote the desired reaction of 1a and 2a under these conditions,
which usually resulted in either no reaction or undesired reactions.
Notably, catalytic amounts of InCl3, AuCl3 or Yb(OTf)3 did not
enable the transformation either (not shown). [b] Reaction condi-
tions: 1a (0.5 mmol), 2a (1.05 equiv.), catalyst, toluene (2 mL),
heating to reflux under Ar for 24 h. [c] Isolated yields.
Results and Discussion
Initially, we conducted the reaction of 1a, which was eas-
ily prepared from phenylacetylene and benzaldehyde, with
2a (Table 1) under the standard conditions [Cu(OTf)2/CuCl
or TsOH/CuSO4] adopted for the three-component tandem
reaction of 2-aminopyridines, aldehydes, and alkynes[11] and
found that no reaction took place. This result demonstrated
that the previous three-component tandem reaction might and N,N-dimethylformamide (DMF), were tested but even
proceed by path a rather than path b. We then reacted 1a worse results were obtained. In addition, higher or lower
with 2a in hot toluene in the presence of a variety of other amounts of pTsOH dramatically suppressed the reaction
acids and transition metal salts, and observed that some of (Table 1, Entries 3–4).
these additives promoted the reaction, although in quanti-
tative instead of catalytic amounts (Table 1).
In the presence of Lewis acids, we observed that a
number of Fe, Bi, Al, Zn, B, Ag, and Cu salts promoted
In the presence of Brønsted acids, 1a was almost totally the desired reaction (Table 1, Entries 5–18) but long reac-
consumed by pTsOH (pKa = –2.80)[13] and CF3CO2H (pKa tion times were required to convert 1a or 3a into 4a. The
= –0.25) and converted to the major product 4a in isolable most promising results were provided by FeBr2, ZnCl2,
yields (Table 1, Entry 1–2). In particular, pTsOH gave the BF3·OEt2, and CuCl (Table 1, Entries 6, 9, 12, 17).
best result of 4a in 39% yield accompanied by intermediate
Considering that bromide or iodide catalysts could con-
3a. However, other Brønsted acids, such as CF3SO3H (pKa taminate the product due to the generation of bromine or
= –14), H3PO4 (pKa = 2.12), AcOH (pKa = 4.76), and iodine during the reaction, which could additionally affect
B(OH)3 (pKa = 9.23), did not lead to the desired product the overall cascade process, we focused our attention on
even when the reaction time was prolonged. In search of a four catalysts (pTsOH, BF3·OEt2, ZnCl2, CuCl) and se-
clue to improve the pTsOH-mediated reaction, our attempts arched for a breakthrough among them. Thus, we investi-
to isolate and purify the other side products (besides 3a) gated the behavior of the four catalysts with 1a, 2a, and 3a
from the reaction mixture were unsuccessful due to their under the same conditions.
low amounts or instabilities. The attempt to improve selec-
When 1a was treated with the catalysts, it was converted
tivity by reducing the reaction temperature to 100 °C also completely into low polarity products in the presence of
failed, and 1a was recovered almost quantitatively. To re- pTsOH, BF3·OEt2 or ZnCl2, which indicates the formation
duce the possible side products from the Friedel–Crafts re- of the propargylic cation. However, 1a was stable in the
action of the propargylic cation[3] with toluene, other sol- presence of CuCl and could be recovered quantitatively.
vents, such as EtOH, CH3CN, dioxane, dimethyl sulfoxide, The results of the reactions of 2a with the four catalysts
Eur. J. Org. Chem. 2011, 7308–7316
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Liu, C.-L. Deng, X. Lei, G.-q. Lin
FULL PAPER
demonstrated that 2-aminopyridine was not decomposed. able to tolerate various substituents on the aromatic ring
Compound 3a was partially consumed in the presence of attached to the triple bond and resulted in good yields
pTsOH, which afforded many side products accompanied (Table 3, 4a–f, 4l–m). However, ester groups were not com-
with a trace amount of 4a (Scheme 2), whereas it was con- patible with the reaction to some extent because of the am-
sumed in the presence of ZnCl2 or BF3·OEt2 to give 4a in monolysis of the ester with 2-aminopyridine (Table 3, 4g).
50 and 37% yield, respectively, together with some unidenti- The use of an acid-sensitive cyano group led to a lower
fied side products. Interestingly, CuCl converted 3a into 4a yield (Table 3, 4h). The substrate bearing a nitro group did
in 79% yield with less side products and the same result not afford the desired product 4i, possibly due to the diffi-
was achieved with only 0.1 equiv. loading of the catalyst culty in forming the corresponding propargylic cation.[4c]
over 3 h.
The thienyl-substituted substrate was also tolerant to the
reaction, whereas the furanyl-substituted substrate gave a
lower yield due to the instability of the corresponding
alcohol (Table 3, 4j–k). The same substituent on the other
aromatic ring (Ar1) of the propargylic alcohols led to
slightly lower yields than when the substituted aryl group
was attached to the triple bond (Table 3, 4n–q). The pos-
sible side products 4b–d were not observed via the allenynic
cation[4a,4b,7e–7i] in the preparation of 4n–p. Similarly, dif-
ferent substituents on the pyridine ring of 2a gave the de-
sired product in moderate to good yields (Table 3, 4r–v) ex-
cept with the amino group, possibly because of the competi-
tive amination of the propargylic alcohol (Table 3, 4w).
Scheme 2. Cycloisomerization of the propargylic amines with the
four catalysts.
Table 3. Synthesis of polysubstituted imidazo[1,2-a]pyridines by
tandem amination/cycloisomerization of aryl propargylic
alcohols.[a]
Based on these results, we applied the ZnCl2/CuCl sys-
tem to the tandem amination/cycloisomerization, in which
ZnCl2 was an efficient promoter for the formation of the
propargylic cation to give 3a, and CuCl was an accelerator
for the cycloisomerization of 3a to 4a. The reaction was
optimized as shown in Table 2, and the optimum conditions
were 1a/2a/ZnCl2/CuCl (1.0:1.5:1.5:0.1, molar equiv.) in hot
toluene for 24 h, which resulted in 4a in 78% yield (Table 2,
Entry 6).
Product Ar1
Ar3
R2
Yield [%][b]
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
78
72
64
67
72
66
40
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-MeO2C-C6H4 Ph
4-NC-C6H4
4-NO2-C6H4
2-thienyl
2-furanyl
3-Cl-C6H4
2-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Table 2. Optimization of the conditions for the model reaction.[a]
Entry Equiv. of Equiv. of
Catalyst
(equiv.)
Additive
(equiv.)
Yield[b]
[%]
1a
2a
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.83
0.67
1.0
1.5
1.5
1.5
1.0
1.5
1.5
1.5
1.5
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.5)
ZnCl2 (1.5)
–
ZnCl2 (1.5)
–
ZnCl2 (1.0)
ZnCl2 (0.5)
–
–
–
–
45[c]
42[c]
57
30
61
79
56
78
trace
65
Ph
Ph
Ph
Ph
Ph
Ph
17
n.d.[c]
59
4j
4k
4l
–
20
74
51
58
38
61
81
68
CuCl (1.0)
CuCl (1.0)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
CuCl (0.1)
4m
4n
4o
4p
4q
4r
4s
4t
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
3-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
44
H
[a] Reaction conditions: 1a (0.5 mmol), 2a, catalyst/additive,
120 °C, toluene (2 mL), under Ar, 24 h. [b] Isolated yield of 4a.
[c] Yield based on 2a.
5-Me
5-Cl
5-Br
3-MeO
3-F
3-NH2
57
53
50
4u
4v
4w
Ph
Ph
70
n.d.[c]
With the optimized conditions in hand, we examined the
scope and limitations of the tandem reaction (Table 3). For
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.5 equiv.), ZnCl2/CuCl
(1.5/0.1 equiv.), toluene (2 mL), 120 °C, under Ar, 24 h. [b] Yield of
the aryl-substituted propargylic alcohols, the reaction was isolated product. [c] Not determined.
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An Expedient Route to Imidazo[1,2-a]pyridines
Subsequently, the tandem reaction was performed with
2-aminopyridine and other propargylic alcohols, such as
6a–d with R1 and R3 being alkyl or SiMe3, respectively
(Scheme 3). Unexpectedly, 6a and 6b were consumed and
led to many complicated products under the above condi-
tions, and neither the corresponding propargylic amine nor
the desired product 7 was isolated, which suggests that the
resultant propargylic cation did not undergo the nucleo-
philic substitution with 2-aminopyridine. A plausible expla-
nation is that the propargylic cations derived from 6a and
6b were less stable than those from aryl-substituted propar-
gylic alcohols and did not have long enough lifetimes to
trap the N-centered nucleophile. In contrast to 6a and 6b,
6c and 6d might not produce the corresponding propargylic
cation under the standard conditions, which was demon-
strated by their almost quantitative recovery from the reac-
tion mixture. The reason could be that the formation of
the propargylic cation was more sensitive to the electron-
stabilizing effect of R1 than that of R3, in other words, when
R1 is alkyl (6c and 6d) instead of aryl (6a and 6b) the forma-
tion of the corresponding cation is more difficult due to the
lack of conjugation from R1.
Scheme 4. Proposed processes and mechanism for the tandem reac-
tion.
Conclusions
A tandem amination/cycloisomerization of aryl-substi-
tuted propargylic alcohols with 2-aminopyridine has been
explored in the presence of ZnCl2/CuCl, which provides a
concise method for the preparation of polysubstituted imid-
azo[1,2-a]pyridines. Various substituents on the aryl ring
tolerate the reaction conditions and give the corresponding
products in moderate to good yields.
Scheme 3. Other propargylic alcohols used in the tandem reaction
conditions.
A plausible mechanism was proposed for the tandem re-
action (Scheme 4). The propargylic alcohol 1a was first
converted into IA in the presence of ZnCl2. The possible
allenyl IB was excluded on the basis that no regioisomers
were observed when the Ar1 and Ar3 groups were ex-
changed (4b–d vs. 4n–4p). The possible Meyer–Schuster re-
arrangement was also ruled out because the reaction of 5
Experimental Section
with 2a did not provide 4a under the reaction conditions. General Remarks: Solvents were distilled from appropriate drying
agents before use. All the reagents were purchased from Acros, Alfa
Aesar, and National Chemical Reagent Group Co. Ltd., P. R.
China and used as received. The progress of the reactions was mon-
itored by TLC (silica-coated glass plates and visualized under UV
Although 2-aminopyridine has two potential nucleophilic
N atoms,[16] the propargylic cation IA should be attacked
by the NH2 group to give propargylic amine 3a instead of
IIB. This was strongly supported by the fact that neither
IIB nor its cycloisomerized product 8[17] were detected.
Subsequently, 3a underwent intramolecular cyclization in
the common 5-exo-dig manner[6d–6k] catalyzed by CuCl to
give intermediate IV together with the release of a proton.
After protonation and isomerization, IV was converted into
1
light or in iodine). H NMR spectra were recorded in CDCl3 with
a 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm
using SiMe4 (δ = 0.0 ppm) as an internal standard. Multiplicities
of NMR signals are designated as s (singlet), d (doublet), t (triplet),
q (quartet), br (broad), m (multiplet, for unresolved lines). 13C
NMR spectra were recorded with a 100 MHz spectrometer. HRMS
4a and CuCl was recovered. Interestingly, the deuterium- were recorded with a Finnigan-Mat-95 mass spectrometer equipped
with an ESI source. Flash column chromatography was performed
with silica gel (300–400 mesh).
labeling experiment (from 9 to 10) showed 74% deuterium
substitution at the benzylic position, which indicates a pos-
sible partial [1,3] H-shift during the CuCl-promoted cyclo-
isomerization process (from V to 4a).
General Procedure for the Synthesis of Aryl Propargylic Alcohols
1a–q and 9 (except 1i): A hexane solution of nBuLi (1.32 mL,
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P. Liu, C.-L. Deng, X. Lei, G.-q. Lin
3.3 mmol, 2.5 m) was added to a THF (dry, 6 mL) solution of phen- dropwise. The reaction mixture was stirred for 24 h, and quenched
FULL PAPER
ylacetylene (0.36 mL, 3.3 mmol) at –78 °C under Ar. The mixture
was stirred for 1 h at –78 °C before benzaldehyde (0.305 mL,
with water (20 mL). The aqueous solution was extracted with
EtOAc (3ϫ 20 mL), and the combined organic layers were washed
3.0 mmol) was added. The reaction mixture was warmed to room with brine (30 mL). After the organic layer was dried with NaSO4,
temperature and stirred for 1 h, and quenched with a saturated
aqueous NH4Cl solution. The aqueous solution was extracted with
EtOAc (2 ϫ 15 mL), and the combined organic layers were washed
with brine (20 mL). After the organic layer was dried with NaSO4,
the solvent was removed under reduced pressure. The residue was
purified by silica gel chromatography with petroleum ether and
EtOAc (PE/EA) to give propargylic alcohola 1a–h, 1j–q. All the
aryl propargylic alcohols are known products and the 1H NMR
spectroscopic data were consistent with the literature.[14]
the solvent was removed under reduced pressure. The residue was
purified by silica gel chromatography (PE/EA = 9:1) to give 1i
(0.201 g, 26%) as a light yellow solid (59% of 4-nitrobenzaldehyde
was also recovered). Rf = 0.37 (PE/EA = 4:1). 1H NMR (400 MHz,
CDCl3): δ = 8.27 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.8 Hz, 2 H),
7.47 (dd, J1 = 7.6, J2 = 0.8 Hz, 2 H), 7.32–7.39 (m, 3 H), 5.80 (d,
J = 5.2 Hz, 1 H), 2.55 (d, J = 6.0 Hz, 1 H) ppm. ESI-MS: m/z =
236.1 [M – OH]+.
3-Phenyl-1-(thiophen-2-yl)prop-2-yn-1-ol (1j): Yield 96%; Rf = 0.34
1
1,3-Diphenylprop-2-yn-1-ol (1a): Yield 97%; Rf = 0.42 (PE/EA =
(PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3): δ =
1
9:1); light yellow oil. H NMR (400 MHz, CDCl3): δ = 7.62 (d, J
7.48–7.50 (m, 2 H), 7.31–7.37 (m, 4 H), 7.25–7.26 (m, 1 H), 6.99–
= 6.8 Hz, 2 H), 7.46–7.49 (m, 2 H), 7.30–7.43 (m, 6 H), 5.69 (d, J 7.02 (m, 1 H), 5.89 (d, J = 7.6 Hz, 1 H), 2.55 (d, J = 6.8 Hz, 1 H)
= 6.4 Hz, 1 H), 2.39 (d, J = 4.8 Hz, 1 H) ppm. ESI-MS: m/z =
ppm. ESI-MS: m/z = 197.1 [M – OH]+.
191.1 [M – OH]+.
1-(Furan-2-yl)-3-phenylprop-2-yn-1-ol (1k): Yield 95%; Rf = 0.25
1
3-Phenyl-1-(p-tolyl)prop-2-yn-1-ol (1b): Yield 97%; Rf = 0.27 (PE/
(PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3): δ =
EA = 9:1); light yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.46– 7.45–7.50 (m, 3 H), 7.30–7.37 (m, 3 H), 6.53 (d, J = 3.6 Hz, 1 H),
7.52 (m, 4 H), 7.29–7.33 (m, 3 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.66
6.38–6.39 (m, 1 H), 5.69 (d, J = 3.2 Hz, 1 H), 2.45 (d, J = 4.4 Hz,
(d, J = 6.4 Hz, 1 H), 2.37 (s, 3 H), 2.26 (d, J = 6.0 Hz, 1 H) ppm. 1 H) ppm. ESI-MS: m/z = 181.0 [M – OH]+.
ESI-MS: m/z = 205.1 [M – OH]+.
1-(3-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1l): Yield 98%; Rf
=
1
1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (1c): Yield 98%; Rf =
0.42 (PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3):
1
0.41 (PE/EA = 4:1); white solid. H NMR (400 MHz, CDCl3): δ = δ = 7.61 (s, 1 H), 7.45–7.50 (m, 3 H), 7.30–7.37 (m, 5 H), 5.66 (d,
7.54 (d, J = 8.4 Hz, 2 H), 7.46–7.48 (m, 2 H), 7.28–7.32 (m, 3 H),
6.92 (d, J = 8.8 Hz, 2 H), 5.64 (d, J = 6.0 Hz, 1 H), 3.81 (s, 3 H),
3.35 (d, J = 6.4 Hz, 1 H) ppm. ESI-MS: m/z = 221.2 [M – OH]+.
J = 4.8 Hz, 1 H), 2.52 (d, J = 5.6 Hz, 1 H) ppm. ESI-MS: m/z =
224.9 [M – OH]+.
1-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1m): Yield 95%; Rf
=
1
1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-ol (1d): Yield 98%; Rf
0.31 (PE/EA = 9:1); colorless oil. H NMR (400 MHz, CDCl3): δ
=
0.36 (PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3):
δ = 7.83–7.85 (m, 1 H), 7.46–7.49 (m, 2 H), 7.40–7.42 (m, 1 H),
7.27–7.36 (m, 5 H), 6.05 (d, J = 5.6 Hz, 1 H), 2.58 (d, J = 5.6 Hz,
1
= 7.57–7.61 (m, 2 H), 7.46–7.47 (m, 2 H), 7.29–7.36 (m, 3 H), 7.08
(t, J = 8.8 Hz, 2 H), 5.67 (d, J = 5.6 Hz, 1 H), 2.41 (d, J = 5.6 Hz, 1 H) ppm. ESI-MS: m/z = 224.9 [M – OH]+.
1 H) ppm. ESI-MS: m/z = 209.1 [M – OH]+.
1-Phenyl-3-(p-tolyl)prop-2-yn-1-ol (1n): Yield 95%; Rf = 0.30 (PE/
1
1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (1e): Yield 97%; Rf
=
EA = 9:1); white solid. H NMR (400 MHz, CDCl3): δ = 7.62 (d,
1
0.25 (PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3):
δ = 7.55 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.32–7.38
(m, 5 H), 5.67 (s, 1 H), 2.39 (s, 1 H) ppm. ESI-MS: m/z = 225.1
[M – OH]+.
J = 6.8 Hz, 2 H), 7.33–7.43 (m, 5 H), 7.12 (d, J = 7.6 Hz, 2 H),
5.68 (d, J = 6.4 Hz, 1 H), 2.35 (s, 3 H), 2.32 (d, J = 6.4 Hz, 1 H)
ppm. ESI-MS: m/z = 205.1 [M – OH]+.
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-ol (1o): Yield 96%; Rf =
1
1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol (1f): Yield 96%; Rf
=
0.49 (PE/EA = 3:1); light yellow oil. H NMR (400 MHz, CDCl3):
0.24 (PE/EA = 9:1); light yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 7.45–7.54 (m, 6 H), 7.30–7.35 (m, 3 H), 5.65 (d, J =
5.6 Hz, 1 H), 2.35 (d, J = 6.0 Hz, 1 H) ppm. ESI-MS: m/z = 269.0
[M – OH]+.
δ = 7.61–7.63 (m, 2 H), 7.32–7.42 (m, 5 H), 6.82–6.86 (m, 2 H),
5.68 (d, J = 5.6 Hz, 1 H), 3.80 (s, 3 H), 2.34 (d, J = 6.4 Hz, 1 H)
ppm. ESI-MS: m/z = 221.1 [M – OH]+.
3-(4-Fluorophenyl)-1-phenylprop-2-yn-1-ol (1p): Yield 97%; Rf
=
1
Methyl 4-(1-Hydroxy-3-phenylprop-2-ynyl)benzoate (1 g): Yield
79%; Rf = 0.39 (PE/EA = 4:1); light yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 8.06 (d, J = 8.4 Hz, 2 H), 7.68 (d, J =
8.8 Hz, 2 H), 7.45–7.47 (m, 2 H), 7.29–7.34 (m, 3 H), 5.74 (s, 1 H),
3.92 (s, 3 H), 2.92 (br., 1 H) ppm. ESI-MS: m/z = 249.1
[M – OH]+.
0.60 (PE/EA = 3:1); colorless oil. H NMR (400 MHz, CDCl3): δ
= 7.61 (d, J = 7.6 Hz, 2 H), 7.34–7.47 (m, 5 H), 7.01 (t, J = 9.2 Hz,
2 H), 5.68 (d, J = 6.0 Hz, 1 H), 2.34 (d, J = 5.6 Hz, 1 H) ppm.
ESI-MS: m/z = 209.1 [M – OH]+.
3-(3-Chlorophenyl)-1-phenylprop-2-yn-1-ol (1q): Yield 98%; Rf
0.34 (PE/EA = 9:1); light yellow oil. H NMR (400 MHz, CDCl3):
=
1
4-(1-Hydroxy-3-phenylprop-2-ynyl)benzonitrile (1h): Yield 94%; Rf
δ = 7.59–7.61 (m, 2 H), 7.29–7.46 (m, 6 H), 7.22–7.25 (m, 1 H),
= 0.31 (PE/EA = 4:1); white solid. 1H NMR (400 MHz, CDCl3): δ 5.68 (d, J = 5.2 Hz, 1 H), 2.42 (d, J = 5.6 Hz, 1 H) ppm. ESI-MS:
= 7.72 (m, 4 H), 7.45–7.47 (m, 2 H), 7.32–7.38 (m, 3 H), 5.75 (d,
J = 4.4 Hz, 1 H), 2.54 (d, J = 5.6 Hz, 1 H) ppm. ESI-MS: m/z =
216.1 [M – OH]+.
m/z = 224.9 [M – OH]+.
N-(1,3-Diphenylprop-2-ynyl)pyridin-2-amine (3a): To a THF solu-
tion (dry, 15 mL) of phenylacetylene (0.55 mL, 5.0 mmol) was
added a hexane solution of BuLi (3.13 mL, 5.0 mmol, 1.6 m) at
–78 °C under Ar. After the mixture was stirred for 1 h, BF3·Et2O
(0.63 mL, 5.0 mmol) and a THF solution (dry, 5 mL) of (E)-N-
benzylidenepyridin-2-amine (0.456 g, 2.5 mmol) were added. The
reaction mixture was warmed to room temperature, stirred over-
night, and quenched with saturated aqueous NH4Cl solution
1-(4-Nitrophenyl)-3-phenylprop-2-yn-1-ol (1i): According to a re-
ported method,[15]
a toluene solution of Me2Zn (3.75 mL,
4.5 mmol,1.2 m) was added to a toluene (dry, 2 mL) solution of
phenylacetylene (0.53 mL, 4.8 mmol) at room temperature under
Ar. After the mixture was stirred for 1 h, a toluene (dry, 5 mL)
solution of 4-nitrobenzaldehyde (0.453 g, 3.0 mmol) was added
7312
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7308–7316

An Expedient Route to Imidazo[1,2-a]pyridines
(10 mL). The aqueous solution was extracted with EtOAc (3ϫ
20 mL), and the combined organic layers were washed with brine
(20 mL). After the organic layer was dried with NaSO4, the solvent
was removed under reduced pressure. The residue was purified by
silica gel chromatography (PE/EA = 20:1) to give 3a (0.517 g) as
light yellow solid; yield 73%; m.p. 112–113 °C, Rf = 0.31 (PE/EA
= 9:1). 1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 4.0 Hz, 1 H),
7.66 (d, J = 7.6 Hz, 2 H), 7.36–7.46 (m, 5 H), 7.24–7.33 (m, 4 H),
6.64 (dd, J = 6.8, 2.0 Hz, 1 H), 6.51 (d, J = 8.0 Hz, 1 H), 6.09 (d,
J = 8.4 Hz, 1 H), 5.04 (d, J = 7.6 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.1, 148.1, 139.7, 137.4, 131.7, 128.6,
128.2, 128.2, 127.9, 127.1, 122.7, 113.9, 108.0, 88.4, 84.3, 47.8 ppm.
ESI-MS: m/z = 285.1 [M + H]+. HRMS (ESI): calcd. for C20H17N2
[M + H]+ 285.1392; found 285.1392.
29.8 ppm. ESI-MS: m/z = 303.1 [M + H]+. HRMS (ESI): calcd.
for C20H16FN2 [M + H]+ 303.1298; found 303.1296.
3-Benzyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (4e): Yield 72%;
m.p. 124–125 °C, Rf = 0.56 (PE/EA/Et3N = 1:1:0.04); white solid.
1H NMR (400 MHz, CDCl3): δ = 7.65–7.74 (m, 4 H), 7.39 (d, J =
8.8, 2.0 Hz, 2 H), 7.22–7.33 (m, 3 H), 7.15–7.20 (m, 1 H), 7.11 (d,
J = 6.8 Hz, 2 H), 6.69–6.72 (m, 1 H), 4.46 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.9, 143.0, 136.5, 133.6, 133.0, 129.4,
129.1, 128.8, 127.6, 127.0, 124.4, 123.4, 117.8, 117.6, 112.3,
29.8 ppm. ESI-MS: m/z = 319.1 [M + H]+. HRMS (ESI): calcd.
for C20H16ClN2 [M + H]+ 319.1002; found 345.1001.
3-Benzyl-2-(4-bromophenyl)imidazo[1,2-a]pyridine (4f):[11] Yield
66%; m.p. 169–171 °C, Rf = 0.26 (PE/EA = 2:1); white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.65–7.71 (m, 4 H), 7.55 (d, J =
8.0 Hz, 2 H), 7.24–7.33 (m, 3 H), 7.17–7.21 (m, 1 H), 7.12 (d, J =
7.6 Hz, 2 H), 6.71–6.74 (m, 1 H), 4.47 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.9, 143.0, 136.4, 133.5, 131.7, 129.6,
129.1, 127.6, 127.0, 124.4, 123.4, 121.9, 117.8, 117.6, 112.3,
29.8 ppm. ESI-MS: m/z = 363.1 [M + H]+.
General Procedure for the Synthesis of Imidazo[1,2-a]pyridines 4a–
v: To a 25 mL flask were sequentially added anhydrous ZnCl2
(dried before the reaction, 136 mg, 0.75 mmol, 1.5 equiv.), CuCl
(5 mg, 0.05 mmol, 0.1 equiv.), a toluene (dry, 2 mL) solution of aryl
propargylic alcohol
1 (0.5 mmol), and 2-aminopyridine 2
(0.75 mmol) under Ar. The reaction mixture was stirred at 120 °C
for 24 h, cooled to room temperature, and the reaction mixture was
quenched with NH3·H2O (1.5 mL), diluted with water (5 mL), and
extracted with CH2Cl2 (2ϫ 10 mL). The combined organic layers
were washed with brine (10 mL), dried with MgSO4, and the sol-
vent was removed under reduced pressure. The residue was purified
by silica gel chromatography (PE/EA/Et3N = 16:2:1) to afford the
desired product.
Methyl 4-(3-Benzylimidazo[1,2-a]pyridin-2-yl)benzoate (4 g): Yield
40%; m.p. 176–178 °C, Rf = 0.45 (PE/EA = 1:1); white solid. 1H
NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 2 H), 7.88 (d,
J = 8.4 Hz, 2 H), 7.68–7.74 (m, 2 H), 7.24–7.33 (m, 3 H), 7.19–
7.23 (m, 1 H), 7.14 (d, J = 7.2 Hz, 2 H), 6.72–6.76 (m, 1 H), 4.51
(s, 2 H), 3.92 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.9, 145.0, 142.9, 139.1, 136.3, 129.9, 129.1, 129.1, 127.9, 127.6,
127.0, 124.6, 123.4, 118.6, 117.7, 112.5, 52.1, 29.9 ppm. ESI-MS:
m/z = 343.1 [M + H]+. HRMS (ESI): calcd. for C21H19N2O [M +
H]+ 343.1447; found 343.1422.
4-(3-Benzylimidazo[1,2-a]pyridin-2-yl)benzonitrile (4h):[11] Yield
17%; m.p. 164–166 °C, Rf = 0.44 (PE/EA = 1:1); light yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8.0 Hz, 2 H), 7.68–
7.75 (m, 4 H), 7.22–7.35 (m, 4 H), 7.12 (d, J = 6.8 Hz, 2 H), 6.75–
6.79 (m, 1 H), 4.50 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 145.1, 141.9, 139.1, 135.9, 132.4, 129.2, 128.4, 127.5, 127.1, 124.9,
123.4, 119.0, 118.9, 117.7, 112.7, 110.9, 29.8 ppm. ESI-MS: m/z =
310.1 [M + H]+.
3-Benzyl-2-phenylimidazo[1,2-a]pyridine (4a): Yield 78%; m.p. 159–
160 °C, Rf = 0.44 (PE/EA = 4:1); white solid. 1H NMR (400 MHz,
CDCl3): δ = 7.86 (d, J = 7.2 Hz, 2 H), 7.72–7.75 (m, 2 H), 7.47–
7.50 (m, 2 H), 7.27–7.42 (m, 4 H), 7.18–7.23 (m, 3 H), 6.71–6.74
(m, 1 H), 4.53 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.8, 144.1, 136.8, 134.5, 129.0,128.6, 128.2, 127.7, 127.7, 126.9,
124.1, 123.4, 117.6, 117.5, 112.1, 29.8 ppm. ESI-MS: m/z = 285.1
[M + H]+. HRMS (ESI): calcd. for C20H17N2 [M + H]+ 285.1392;
found 285.1390.
3-Benzyl-2-(p-tolyl)imidazo[1,2-a]pyridine (4b): Yield 72%; m.p.
161–162 °C, Rf = 0.58 (PE/EA/Et3N = 1:1:0.04); light yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.66–7.71 (m, 4 H), 7.23–7.32
(m, 5 H), 7.13–7.18 (m, 3 H), 6.66–6.69 (m, 1 H), 4.48 (s, 2 H),
2.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8, 144.2,
137.5, 136.9, 131.6, 129.3, 129.0, 128.0, 127.7,126.9,
124.0,123.3,117.4,117.4, 112.1, 29.9, 21.3 ppm. ESI-MS: m/z =
299.2 [M + H]+. HRMS (ESI): calcd. for C21H19N2 [M + H]+
299.1548; found 299.1544.
3-Benzyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (4j): Yield 59%;
m.p. 152–153 °C, Rf = 0.32 (PE/EA = 3:1); light yellow solid. 1H
NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 6.8 Hz, 1 H), 7.65 (d,
J = 8.8 Hz, 1 H), 7.40 (d, J = 4.0 Hz, 1 H), 7.34 (d, J = 5.2 Hz, 1
H), 7.21–7.30 (m, 3 H), 7.14–7.18 (m, 3 H), 7.07–7.10 (m, 1 H),
6.68–6.72 (m, 1 H), 4.54 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 144.7, 138.6, 137.5, 136.3, 128.9, 127.7, 127.7, 126.9,
125.5, 124.4, 124.4, 123.1, 117.3, 117.3, 112.3, 29.8 ppm. ESI-MS:
m/z = 291.1 [M + H]+. HRMS (ESI): calcd. for C18H15N2S [M +
H]+ 291.0956; found 291.0943.
3-Benzyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (4c): Yield
64%; m.p. 152–153 °C, Rf = 0.41 (PE/EA = 2:1); white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 9.2 Hz, 2 H), 7.65–7.68
(m, 2 H), 7.22–7.32 (m, 3 H), 7.13–7.18 (m, 3 H), 6.97 (d, J =
9.2 Hz, 2 H), 6.67–6.70 (m, 1 H), 4.47 (s, 2 H), 3.83 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.5, 144.9, 144.2, 137.1, 129.5,
129.2, 127.9, 127.3, 127.0, 124.1, 123.4, 117.5, 117.1, 114.3, 112.2,
55.5, 30.1 ppm. ESI-MS: m/z = 315.1 [M + H]+. HRMS (ESI):
calcd. for C21H19N2O [M + H]+ 315.1497; found 315.1492.
3-Benzyl-2-(furan-2-yl)imidazo[1,2-a]pyridine (4k):[11] Yield 20%;
1
m.p. 121–123 °C, Rf = 0.37 (PE/EA = 2:1); white solid. H NMR
(400 MHz, CDCl3): δ = 7.73 (d, J = 6.4 Hz, 1 H), 7.61 (d, J =
9.2 Hz, 1 H), 7.50 (d, J = 1.2 Hz, 1 H), 7.25–7.28 (m, 2 H), 7.12–
7.22 (m, 4 H), 6.91 (dd, J = 3.6, 0.8 Hz, 1 H), 6.66–6.70 (m, 1 H),
6.52–6.53 (m, 1 H), 4.62 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.1, 145.0, 142.1, 136.8, 135.2, 128.8, 127.9, 126.7,
124.5, 123.2, 118.0, 117.3, 112.2, 111.4, 107.6, 29.6 ppm. ESI-MS:
m/z = 275.2 [M + H]+.
3-Benzyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (4d): Yield 67%;
m.p. 71–73 °C, Rf = 0.33 (PE/EA = 3:1); white solid. 1H NMR
(400 MHz, CDCl3): δ = 7.66–7.77 (m, 4 H), 7.24–7.34 (m, 3 H), 3-Benzyl-2-(3-chlorophenyl)imidazo[1,2-a]pyridine (4l): Yield 74%;
1
7.17–7.22 (m, 1 H), 7.09–7.15 (m, 4 H), 6.71–6.74 (m, 1 H), 4.47
m.p. 110–111 °C, Rf = 0.25 (PE/EA = 3:1); white solid. H NMR
(400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.66–7.73 (m, 2 H), 7.61–
7.64 (m, 1 H), 7.23–7.37 (m, 5 H), 7.17–7.22 (m, 1 H), 7.13 (d, J
= 7.2 Hz, 2 H), 6.71–6.74 (m, 1 H), 4.49 (s, 2 H) ppm. 13C NMR
1
(s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.6 (d, JCF
=
244.6 Hz), 144.8, 143.2, 136.6, 130.6, 129.8, 129.8, 129.1, 127.6,
2
127.0, 124.3, 123.4, 117.5, 115.6 (d, JCF = 21.4 Hz), 112.3,
Eur. J. Org. Chem. 2011, 7308–7316
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7313

P. Liu, C.-L. Deng, X. Lei, G.-q. Lin
(100 MHz, CDCl3): δ = 144.8, 142.6, 136.4, 136.3, 134.6, 129.8, [M + H]+. HRMS (ESI): calcd. for C21H19N2 [M + H]+ 299.1548;
FULL PAPER
129.0, 128.2, 127.7, 127.6, 127.0, 126.0, 124.4, 123.4, 118.1, 117.6,
112.4, 29.8 ppm. ESI-MS: m/z = 319.1 [M + H]+. HRMS (ESI):
calcd. for C20H16ClN2 [M + H]+ 319.1002; found 319.1003.
found 299.1547.
3-Benzyl-6-chloro-2-phenylimidazo[1,2-a]pyridine (4s): Yield 57%;
m.p. 195–196 °C, Rf = 0.58 (PE/EA = 2:1); light yellow solid. 1H
NMR (400 MHz, CDCl3): δ = 7.73–7.78 (m, 3 H), 7.62 (d, J =
9.6 Hz, 1 H), 7.41–7.45 (m, 2 H), 7.28–7.38 (m, 4 H), 7.13–7.16 (m,
3 H), 4.47 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.2,
143.2, 136.1, 134.0, 129.1, 128.7, 128.1, 128.0, 127.6, 127.1, 125.5,
121.1, 120.4, 118.3, 117.9, 29.8 ppm. ESI-MS: m/z = 319.1
[M + H]+. HRMS (ESI): calcd. for C20H16ClN2 [M + H]+
319.1002; found 319.0994.
3-Benzyl-2-(2-chlorophenyl)imidazo[1,2-a]pyridine (4m): Yield 51%;
1
m.p. 126–127 °C, Rf = 0.38 (PE/EA = 2:1); white solid. H NMR
(400 MHz, CDCl3): δ = 7.65–7.68 (m, 2 H), 7.53–7.56 (m, 1 H),
7.47–7.50 (m, 1 H), 7.30–7.33 (m, 2 H), 7.14–7.26 (m, 4 H), 7.06
(d, J = 7.2 Hz, 2 H), 6.68 (t, J = 6.8 Hz, 1 H), 4.28 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 144.6, 142.2, 136.5, 134.0, 133.6,
132.5, 129.7, 129.4, 128.7, 127.8, 126.6, 126.6, 124.0, 123.7, 119.6,
117.7, 112.1, 29.9 ppm. ESI-MS: m/z = 319.1 [M + H]+. HRMS
(ESI): calcd. for C20H16ClN2 [M + H]+ 319.1002; found 319.1004.
3-Benzyl-6-bromo-2-phenylimidazo[1,2-a]pyridine (4t): Yield 53%;
m.p. 212–214 °C, Rf = 0.58 (PE/EA = 2:1); light yellow solid. 1H
NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 0.8 Hz, 1 H), 7.76 (d,
J = 8.0 Hz, 2 H), 7.58 (d, J = 9.6 Hz, 1 H), 7.41–7.45 (m, 2 H),
7.23–7.38 (m, 5 H), 7.13 (d, J = 7.6 Hz, 2 H), 4.47 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 145.0, 143.2, 136.1, 133.9, 129.1,
128.7, 128.1, 128.0, 127.6, 127.5, 127.1, 123.3, 118.2, 106.9,
29.7 ppm. ESI-MS: m/z = 363.1 [M + H]+. HRMS (ESI): calcd.
for C20H16BrN2 [M + H]+ 363.0497; found 363.0508.
3-(4-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (4n): Yield 58%;
m.p. 93–94 °C, Rf = 0.35 (PE/EA = 2:1); white solid. 1H NMR
(400 MHz, CDCl3): δ = 7.79–7.82 (m, 2 H), 7.67–7.72 (m, 2 H),
7.41–7.46 (m, 2 H), 7.33–7.38 (m, 1 H), 7.15–7.20 (m, 1 H), 7.12
(d, J = 8.0 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 6.68–6.72 (m, 1 H),
4.46 (s, 2 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 144.8, 144.0, 136.5, 134.5, 133.6, 129.7, 128.6, 128.1, 127.6, 127.5,
124.0, 123.4, 117.8, 117.5, 112.1, 29.4, 21.0 ppm. ESI-MS: m/z =
299.2 [M + H]+. HRMS (ESI): calcd. for C21H19N2 [M + H]+
299.1548; found 299.1544.
3-Benzyl-8-methoxy-2-phenylimidazo[1,2-a]pyridine (4u): Yield
50%; m.p. 178–180 °C, Rf = 0.26 (PE/EA = 1:1); white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.38–7.42
(m, 2 H), 7.22–7.35 (m, 5 H), 7.13 (d, J = 7.2 Hz, 2 H), 6.59–6.62
(m, 1 H), 6.46 (d, J = 7.6 Hz, 1 H), 4.47 (s, 2 H), 4.03 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 149.0, 143.3, 139.2, 136.9,
134.4, 128.9, 128.3, 128.2, 127.6, 127.5, 126.7, 118.6, 116.3, 112.0,
100.3, 55.7, 30.0 ppm. ESI-MS: m/z = 315.2 [M + H]+. HRMS
(ESI): calcd. for C21H19N2O [M + H]+ 315.1497; found 315.1502.
3-(4-Methoxybenzyl)-2-phenylimidazo[1,2-a]pyridine (4o): Yield
38%; m.p. 98–100 °C, Rf = 0.25 (PE/EA = 2:1); light yellow solid.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.81 (m, 2 H), 7.67–7.72
(m, 2 H), 7.42–7.46 (m, 2 H), 7.33–7.37 (m, 1 H), 7.15–7.20 (m, 1
H), 7.06 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.69–6.72
(m, 1 H), 4.44 (s, 2 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.5, 144.8, 143.9, 134.5, 128.6, 128.6, 128.5, 128.1,
127.6, 124.0, 123.4, 118.0, 117.5, 114.4, 112.1, 55.2, 29.0 ppm. ESI-
MS: m/z = 315.2 [M + H]+. HRMS (ESI): calcd. for C21H19N2O
[M + H]+ 315.1497; found 315.1498.
3-Benzyl-8-fluoro-2-phenylimidazo[1,2-a]pyridine (4v): Yield 70%;
m.p. 159–160 °C, Rf = 0.56 (PE/EA = 3:1); white solid. H NMR
(400 MHz, CDCl3): δ = 7.81–7.84 (m, 2 H), 7.53 (d, J = 6.8 Hz, 1
H), 7.41–7.46 (m, 2 H), 7.24–7.39 (m, 4 H), 7.14 (d, J = 7.2 Hz, 2
1
H), 6.88 (dd, J = 10.0, 7.6 Hz, 1 H), 6.59–6.65 (m, 1 H), 4.50 (s, 2
3-(4-Fluorobenzyl)-2-phenylimidazo[1,2-a]pyridine (4p): Yield 61%;
m.p. 98–99 °C, Rf = 0.30 (PE/EA = 2:1); white solid. 1H NMR
(400 MHz, CDCl3): δ = 7.76–7.79 (m, 2 H), 7.66–7.71 (m, 2 H),
7.42–7.46 (m, 2 H), 7.34–7.38 (m, 1 H), 7.17–7.22 (m, 1 H), 7.08–
1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.6 (d, JCF
=
251.6 Hz), 144.5, 136.4, 134.0, 129.1, 128.6, 128.3, 128.0, 127.6,
127.0, 119.8, 119.8, 119.4, 111.2, 111.2, 106.9, 106.7, 30.1 ppm.
ESI-MS: m/z = 303.2 [M + H]+. HRMS (ESI): calcd. for
C20H16FN2 [M + H]+ 303.1298; found 303.1300.
7.12 (m, 2 H), 6.97–7.02 (m, 2 H), 6.70–6.75 (m, 1 H), 4.46 (s, 2
1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8 (d, JCF
=
=
3
2-Benzyl-3-phenylimidazo[1,2-a]pyridine (8): A CHCl3 (2 mL) solu-
tion of Br2 (0.815 g, 5.1 mmol, 0.26 mL) was added dropwise to a
CHCl3 (3 mL) solution of 1,3-diphenylpropan-2-one (1.051 g,
5.0 mmol) at room temperature. The reaction mixture was stirred
for 3 h and quenched with saturated aqueous Na2S2O3 (10 mL).
The aqueous solution was extracted with CH2Cl2 (3ϫ 10 mL), the
combined organic layers were washed with brine (10 mL), dried
with MgSO4, and evaporated to give 1-bromo-1,3-diphenylpropan-
2-one (1.587 g, crude). The crude bromide (0.174 g), 2-aminopyr-
idine (0.047 g, 0.5 mmol), and Na2CO3 (0.064 g, 0.6 mmol) were
added to dry DMF (5 mL). The reaction mixture was stirred at 100
°C under Ar for 4 h. After cooling to room temperature, the reac-
tion mixture was diluted with EtOAc (20 mL) and washed with
water (20 mL). The aqueous layer was extracted with EtOAc (2ϫ
10 mL), and the combined organic layers were washed with brine
(2ϫ 10 mL), dried with Na2SO4, and the solvents evaporated to
dryness. The residue was purified by silica gel chromatography (PE/
EA/Et3N = 16:2:1) to give 8 (0.046 g, 30% two steps) as yellow
243.8 Hz), 144.9, 144.1, 134.3, 132.3, 132.3, 129.1 (d, JCF
8.8 Hz), 128.6, 128.1, 127.8, 124.2, 123.2, 117.6, 117.4, 115.8
(d,2JCF = 20.6 Hz), 112.2, 29.1 ppm. ESI-MS: m/z = 303.2
[M + H]+. HRMS (ESI): calcd. for C20H16 FN2 [M + H]+ 303.1298;
found 303.1296.
3-(3-Chlorobenzyl)-2-phenylimidazo[1,2-a]pyridine (4q): Yield 81%;
Rf = 0.29 (PE/EA = 3:1); colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 7.73–7.76 (m, 3 H), 7.67 (d, J = 6.8 Hz, 1 H), 7.43–
7.47 (m, 2 H), 7.35–7.39 (m, 1 H), 7.20–7.25 (m, 3 H), 7.16 (s, 1
H), 6.98–7.00 (m, 1 H), 6.74–6.77 (m, 1 H), 4.46 (s, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 145.0, 144.3, 138.9, 135.0, 134.1,
130.4, 128.7, 128.2, 128.0, 127.9, 127.3, 125.8, 124.6, 123.2, 117.6,
116.8, 112.6, 29.6 ppm. ESI-MS: m/z = 319.0 [M + H]+. HRMS
(ESI): calcd. for C20H16ClN2 [M + H]+ 319.1002; found 319.1007.
3-Benzyl-6-methyl-2-phenylimidazo[1,2-a]pyridine (4r): Yield 68%;
1
m.p. 208–209 °C, Rf = 0.24 (PE/EA = 3:1); white solid. H NMR
(400 MHz, CDCl3): δ = 7.76–7.80 (m, 2 H), 7.60 (d, J = 8.8 Hz, 1
H), 7.49 (s, 1 H), 7.40–7.44 (m, 2 H), 7.24–7.36 (m, 4 H), 7.16 (d, solid. M.p. 95–96 °C, Rf = 0.40 (PE/EA = 3:1). 1H NMR
J = 7.2 Hz, 2 H), 7.04 (dd, J = 9.2, 1.6 Hz, 1 H), 4.47 (s, 2 H), 2.24
(400 MHz, CDCl3): δ = 8.03–8.05 (m, 1 H), 7.59–7.61 (m, 1 H),
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 143.9, 143.9, 7.49–7.53 (m, 2 H), 7.41–7.44 (m, 3 H), 7.21–7.24 (m, 4 H), 7.11–
137.0, 134.6, 129.0, 128.6, 128.0, 127.7, 127.5, 127.3, 126.8, 121.8,
120.9, 117.3, 116.9, 29.8, 18.4 ppm. ESI-MS: m/z 299.2
7.18 (m, 2 H), 6.68–6.71 (m, 1 H), 4.14 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.7, 143.4, 140.3, 129.8, 129.2, 128.6,
=
7314
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7308–7316

An Expedient Route to Imidazo[1,2-a]pyridines
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128.4, 128.3, 125.9, 124.1, 123.2, 122.0, 117.4, 111.9, 34.0 ppm.
ESI-MS: m/z = 285.1 [M + H]+. HRMS (ESI): calcd. for C20H17N2
[M + H]+ 285.1392; found 285.1392.
[1D]-1,3-Diphenylprop-2-yn-1-ol (9): Yield 64%; Rf = 0.45 (PE/EA
= 9:1); light yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.59–
7.62 (m, 2 H), 7.46–7.49 (m, 2 H), 7.28–7.42 (m, 6 H), 2.47 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.6, 131.8, 128.7,
128.6, 128.5, 128.3, 126.8, 122.4, 88.7, 86.6, 64.8 (t, 1JCD = 22.6 Hz)
ppm. ESI-MS: m/z = 192.1 [M – OH]+. HRMS (ESI): calcd. for
C15H10D [M – OH]+ 192.0924; found 192.0930.
Deuterium-Labeling Experiment: To a 25 mL flask were sequen-
tially added anhydrous ZnCl2 (dried before the reaction, 136 mg,
0.75 mmol), CuCl (5 mg, 0.05 mmol), a toluene (dry, 2 mL) solu-
tion of
9 (0.105 g, 0.5 mmol), and 2-aminopyridine (0.07 g,
0.75 mmol) under Ar. The reaction mixture was stirred at 120 °C
for 24 h before it was cooled to room temperature and quenched
with NH3·H2O (1.5 mL), diluted with water (5 mL), and extracted
with CH2Cl2 (2ϫ 10 mL). The combined organic layers were
washed with brine (10 mL), dried with MgSO4, and the solvent was
removed under reduced pressure. The residue was purified by silica
gel chromatography (petroleum ether/EtOAc/Et3N = 16:2:1) to af-
ford a mixture of 10 and 4a (37:13, determined by 1HNMR;
0.103 g, 72%) as light yellow solid, m.p. 155–158 °C, Rf = 0.44 (PE/
[5]
[6]
1
EA = 4:1). H NMR (400 MHz, CDCl3): δ = 7.77–7.80 (m, 2 H),
7.67–7.69 (m, 2 H), 7.41–7.45 (m, 2 H), 7.23–7.37 (m, 4 H), 7.13–
7.19 (m, 3 H), 6.67–6.71 (m, 1 H), 4.49 (s, 0.52 H of 4a), 4.47 (s,
0.74 H of 10) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.9, 144.2,
136.8, 136.7, 134.5, 129.0, 128.6, 128.2, 127.7, 126.9, 124.1, 123.4,
1
117.6, 117.6, 112.2, 29.8, 29.6 (t, JCD = 19.6 Hz) ppm. ESI-MS:
m/z = 285.1 (4a, 31) [M + H]+, 286.0 (10, 100) [M + D]+. HRMS
(ESI): calcd. for C20H16DN2 [M + H]+ 286.1455; found 286.1449.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra.
Acknowledgments
We thank the National Natural Foundation of China (NSFC)
(20872019) and Fudan University for financial support. We are
grateful to Dr. Bangguo Wei and Dr. Hanqing Dong for helpful
discussions.
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Received: July 20, 2011
Published Online: November 11, 2011
7316
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7308–7316