Cu-Pybox catalyzed synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines from 2-aminopyridines and propargyl alcohol derivatives

Article abstract of DOI:10.1016/j.tet.2016.09.013

A highly efficient cascade sequence for syntheses of 2,3-disubstituted imidazo[1,2-a]pyridines with exclusive regioselectivity in moderate to excellent yields has been developed. This cascade was initiated through propargylation of 2-aminopyridines at pyridine-nitrogen with propargyl alcohol derivatives using Cu(II)-Pybox as catalyst and followed by an intramolecular cyclization and isomerization. Besides 2-aminopyridine, less reactive 2-aminopyrimidine, 2-aminopyrazine and 3-aminopyridazine were also suitable in this cascade.

Full text of DOI:10.1016/j.tet.2016.09.013

Tetrahedron xxx (2016) 1e9
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Tetrahedron
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Cu-Pybox catalyzed synthesis of 2,3-disubstituted imidazo[1,2-a]
pyridines from 2-aminopyridines and propargyl alcohol derivatives
Cang Cheng a, Luo Ge a, Xuehe Lu a, Jianping Huang a, Haocheng Huang a, Jie Chen a,
,
a,b,
*
Weiguo Cao a , Xiaoyu Wu
*
a Department of Chemistry, Shanghai University, 99 Shangda Rd, Shanghai 200444, PR China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient cascade sequence for syntheses of 2,3-disubstituted imidazo[1,2-a]pyridines with ex-
clusive regioselectivity in moderate to excellent yields has been developed. This cascade was initiated
through propargylation of 2-aminopyridines at pyridine-nitrogen with propargyl alcohol derivatives
using Cu(II)-Pybox as catalyst and followed by an intramolecular cyclization and isomerization. Besides
2-aminopyridine, less reactive 2-aminopyrimidine, 2-aminopyrazine and 3-aminopyridazine were also
suitable in this cascade.
Received 5 August 2016
Received in revised form 7 September 2016
Accepted 9 September 2016
Available online xxx
Keywords:
Propargylation
Ó 2016 Elsevier Ltd. All rights reserved.
Imidazo-pyridine
Propargyl alcohol derivative
Cascade reaction
Cyclization
1. Introduction
Because of the utilities of imidazo[1,2-a]pyridines, in the past
decade tremendous efforts have been devoted to the investigation
Imidazo[1,2-a]pyridine is a well-known privileged structural
motif present in various biologically active and pharmaceutically
important compounds.1 In particular, imidazo[1,2-a]pyridine moiety
isalso a core structure of severalmarketed drugs, including Zolpidem,
Zolimidine, Olprinone, Alpidem, Necopidem and Saripidem (Fig. 1).
into the construction of imidazo[1,2-a]pyridines with different
substitute patterns from either 2-aminopyridines or unfunction-
alized pyridines.2e4 These efforts have led to the discovery of var-
ious approaches toward privileged imidazo[1,2-a]pyridine
structure. However, it is notable that a majority these methods
require harsh reaction conditions, e.g., high temperature, and the
use of polar solvents of high boiling point such as DMF and DMSO.
Harsh conditions will limit the use of reaction components bearing
sensitive functionalities, while the use of high boiling point sol-
vents makes work-up a tedious job. Therefore, straightforward
construction of the imidazo[1,2-a]pyridine moiety from easily
available start materials under mild conditions is still highly
desirable.
On the other hand, recently propargylic alcohols bearing a ter-
minal acetylenic group and their derivatives are frequently used in
propargylation with carbon-, nitrogen- or oxygen-based nucleo-
philes catalyzed by thiolate-bridged diruthenium complexes or
complexes of copper salts and various bidentate or tridentate li-
gands.5 When well-designed bis-nucleophiles were employed as
reaction components, the propargylation at one nucleophilic site
and following intramolecular cyclization between alkyne func-
tionality and the other nucleophilic site rendered the preparation of
various cyclic or bicyclic compounds in the presence of ruthenium-
N
N
N
NC
O
N
O
S
O
N
N
O
N
H
N
Zolimidine
Olprinone
Zolpidem
N
N
N
N
N
Cl
Cl
N
Cl
O
N
N
N
O
O
Saripidem
Necopidem
Alpidem
Fig. 1. Drugs containing an imidazo[1,2-a]pyridine moiety.
* Corresponding authors. Fax: þ86 21 66134856; e-mail addresses: wgcao@staff.
shu.edu.cn (W. Cao), wuxy@shu.edu.cn (X. Wu).
http://dx.doi.org/10.1016/j.tet.2016.09.013
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
C. Cheng et al. / Tetrahedron xxx (2016) 1e9
or copper-based catalysts.6 Considering that 2-aminopyridine has
two potential nucleophilic nitrogen atoms, the exo-cyclic amino
nitrogen and the pyridine nitrogen, we surmised that the catalytic
reaction between 2-aminopyridine and propargyl alcohol de-
rivatives would lead to 2,3-disubstituted imidazo[1,2-a]pyridines in
a cascade manner. 2-Aminopyridine is commercially available in
both quantity and diversity, while propargyl alcohol bearing ter-
minal acetylenic group can be prepared easily from ethy-
nylmagnesium bromide and corresponding aldehyde. Furthermore,
the catalytic reaction between propargyl alcohol derivatives bear-
ing terminal acetylenic group and various nucleophiles usually
takes place smoothly under relatively mild conditions.5,6 Very re-
cently, Jiang et al. disclosed a similar catalytic system, wherein the
reactions were performed with catalytic amount of copper salt
without any ligand. However, high temperature and high loading of
copper salts were required to secure high yield. Furthermore, the
regioselectivity in Jiang and co-workers’ catalytic system was dif-
ferent to that of ours.7 Therefore, successful implementation of our
new strategy would lead to general and straightforward prepara-
tion of imidazo[1,2-a]pyridines under mild conditions.
propargylation step occurred exclusively at pyridine nitrogen to
afford 2-methyl-3-phenylimidazo[1,2-a]pyridine (3a) as the sole
product in excellent yield after cyclization and isomerization.8
Surprisingly, 2,20:60,200-terpyridine (B), a type of tridentate N-do-
nor ligands similar to Pybox was totally ineffective in this reaction
(entry 2). As for bidentate N-donor ligands screened, ligand C de-
rived from valinol and diethyl oxalate delivered the desired 3a in
a rather modest yield of 35% (entry 3), while combination of CuI
with easily available bipyridine or 1,10-phenanthroline failed to
promote this reaction (entries 4e5). Other Pybox ligands derived
from chiral amino alcohols were also examined, and found to be
inferior to ligand A, possibly due to the steric hindrance of sub-
stituents on oxazoline moiety (entries 6e11).
Next, various copper salts were examined. CuBr and CuCl
worked well to afford 3a in yields comparable to that of CuI (en-
tries 12e13). Cu(CH3CN)4PF6, Cu(CH3CN)4BF4, and Cu(CH3CN)4
-
ClO4 were less efficient than simple copper(I) halogenides, as
a dramatic drop of the yield was observed for reactions with this
type of copper salts (entries 14e16 vs entries 1, 12e13). Re-
placement of copper(I) salts with copper(II) salts, led to an obvious
increase in the yield, and copper(II) acetylacetonate proved to be
the best, affording 3a in highest yield of 94% (entries 17e18). Ef-
forts to further improve the performance of this reaction by
changing the base or the solvent were unsuccessful, as no better
results were obtained (Table 2).
2. Results and discussion
We commenced our investigation with the reaction between 2-
aminopyridine (1a) and 1-phenylprop-2-yn-1-yl acetate (2a) pro-
moted by a combination of CuI (5 mol %) and an achiral Pybox (A,
6 mol %) at 20 ꢀC with methanol as the solvent and DIPEA as the
base (Table 1, entry 1). Despite the fact that 1a has two potential
nucleophilic nitrogen atoms, to our delight the initial
Table 2
Screening of bases and solvents for cyclization between 1a and 2aa
Entry
Solvent
Base
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
EtOH
DCM
THF
Toluene
Et3N
DMAP
DBU
Cs2CO3
DIPEA
DIPEA
DIPEA
DIPEA
6
70
18
18
18
6
18
18
18
dc
dc
dc
78
Table 1
Survey of copper salts and ligands for cyclization between 1a and 2aa
dc
dc
dc
a
General conditions: 1a (0.2 mmol), 2a (0.24 mmol), Cu(acac)2 (5 mol %), ligand A
(6 mol %), and base (2 equiv) in methanol (1.5 mL) at rt.
b
Yield referred to isolated pure 3a.
No formation of 3a was observed as shown by TLC.
c
With optimized reaction condition in hand (Table 1, entry 18),
we set out to explore the scope of the reaction concerning dif-
ferent substituents on the pyridine ring of 1. As shown in Fig. 2,
remarkable dependence of the reactivity of 2-aminopyridine on
the electronic nature of the substituents on the pyridine ring was
observed. 2-Aminopyridines with electron-donating groups, such
as methyl or methoxy group performed very well to afford
cyclized products in excellent yields (87e92%) in relatively shorter
reaction time of 6 h (3bed, 3f). However, when aminopyridine
substrates with electron-withdrawing groups, such as chloro,
bromo and trifluoromethyl group, were employed, longer reaction
time of 18 h was required to secure complete conversion of start
material, with the yields ranged from 50% to 74% (3gej, 3lem).
Notably, 2-aminopyridines with substituents at C(3), C(4) or C(5),
all participated well to afford the desired products, but derivatives
with either electron-donating or electron-withdrawing sub-
stituents at C(6) did not afford the expected product even after
longer reaction time (3e, 3k). This is possibly due to the steric
hindrance of substituent at C(6) preventing the approach of the
nucleophilic site toward electrophilic site of allenylidene com-
plexes in situ generated from propargyl alcohol derivatives.5,6
Similar phenomena was also reported by other research groups
for reactions between C(6)-substituted 2-aminopyridine with
other coupling components.3r,s
Entry
Ligand
Copper salts
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
I
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
6
84
dc
40
dc
dc
80
78
83
40
78
73
78
82
67
41
63
89
94
18
18
18
18
6
6
6
6
6
6
6
6
6
6
6
6
6
9
10
11
12
13
14
15
16
17
18
J
K
A
A
A
A
A
A
A
CuCl
Cu(CH3CN)4PF6
Cu(CH3CN)4ClO4
Cu(CH3CN)4BF4
Cu(OTf)2
Cu(acac)2
a
General conditions: 1a (0.2 mmol), 2a (0.24 mmol), Copper salt (5 mol %), ligand
(6 mol %), and DIPEA (2 equiv) in methanol (1.5 mL) at rt.
b
Yield referred to isolated pure 3a.
No formation of 3a was observed as shown by TLC. Cu(acac)2: copper(II)
c
acetylacetonate.
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C. Cheng et al. / Tetrahedron xxx (2016) 1e9
3
The generality of the cascade was further shown by the prepa-
ration of related N-fused imidazoles other than imidazo[1,2-a]
pyridines (Fig. 4). It is noteworthy that like imidazo[1,2-a]pyridine,
other N-fused imidazoles and their derivatives are also therapeu-
tically important,10 yet their preparation was less investigated as
compared with imidazo[1,2-a]pyridine. Thus, when reacting 2a
with 4a, 4b, or4d under above optimal conditions, the corre-
sponding imidazo-fused heterocycles imidazo[1,2-a]pyrimidine
(5a), imidazo[1,2-a]pyrazine (5b), and imidazo[1,2-b]pyridazine
(5d) were obtained in good yields. On the other hand, when 4c was
employed as a reaction component there was no reaction even after
longer reaction time. Considering that substrates 4aed are known
to be less reactive as compared with 2-aminopyridine,11 the gen-
erality of current method is remarkable, even though this method
failed in the case of substrate 4c.
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
3c
3d
3e
3b
a
-
6 h, 90% yield
6 h, 91% yield
6 h, 92% yield
Br
N
Cl
N
MeO
N
N
N
N
N
N
3g
Br
Ph
Ph
3f
Ph
3h
3i
Ph
6 h, 87% yield
18 h, 74% yield
18 h, 70% yield 18 h, 73% yield
CF3
N
N
N
N
N
N
N
Cl
N
F3C
Ph
Ph
Cl
Ph
3j
Ph
3l
3m
3k
a
18 h, 71% yield
18 h, 50% yield
-
18 h, 61% yield
a No formation of desired product was observed
N
NH2
NH2
NH2
NH2
Fig. 2. Scope of the reaction regarding 2-aminopyridines.
N
N
4a
N
N
N
N
N
N
4b
4c
4d
N
N
N
N
N
We next investigated the substrate scope of the reaction with
regard to diversely substituted propargylic acetates (Fig. 3). To
our pleasure, phenyl-substituted substrates with either electron-
donating groups, such as methyl, methoxyl, benzyloxyl and
methoxymethoxyl (MOMO) group, or electron-withdrawing
groups, such as chloro, bromo, and trifluoromethyl group, on
the benzene ring all performed well to deliver the cyclized
products in good to excellent yields (3oez). The reaction of 1a
with propargylic substrate bearing two trifluoromethyl groups on
the benzene ring proceeded smoothly to afford 3v, albeit in
N
N
N
N
N
N
Ph
Ph
Ph
Ph
5a
5d
5c
5b
a
18 h, 71% yield
18 h, 78% yield
18 h, 71% yield
-
a No formation of desired product was observed
Fig. 4. Further expansion of substrate scope.
a lower yield of 73%.
a-Naphthyl substituted propargylic sub-
The structure and regiochemistry of imidazo[1,2-a]pyridines 3
were determined by comparison of 1H NMR spectrum of repre-
sentative compounds 3a, 3b, 3o and 3s with that of known com-
pounds, and further confirmed by single crystal analysis of 3i
(Fig. 5).12 The structure of other cyclized products could be assigned
by analogy.
strate was also fit in the current system, and produced 3aa in
highest yield of 97%. Employment of heteroaryl substituted
propargyl alcohol derivatives uneventfully led to bisheteroaryl
compounds (3abead) in excellent yields. Moreover, styryl or
hept-1-enyl substituted propargylic components gave the cor-
responding products with good yields (3aeeah). However, less
reactive aliphatic substituted propargyl alcohol derivatives, such
as 1-phenylbut-3-yn-2-yl acetate and hept-1-yn-3-yl acetate, did
not afford the desired products (3aieaj). Notably, imidazo[1,2-a]
pyridine 3z can be transformed into a key intermediate for
preparation of liver X receptor agonist by removal of methox-
ymethyl group.9
N
N
H3C
N
N
N
N
N
N
Ar
Ar
Ar
Ar or R
3ae: Ar = C6H5
6 h, 75% yield
3o: Ar = 4-CH3-C6H4
3aa: Ar = -Naphthyl
3w: Ar = 4-CH3-C6H4
6 h, 90% yield
6h, 97% yield
6 h, 84% yield
3p: Ar = 4-CH3O-C6H4
3ab: Ar = 2-furanyl
3af: Ar = 4-F-C6H4
3x: Ar = 4-Cl-C6H4
6 h, 88% yield
6h, 88% yield
6 h, 78% yield
6 h, 85% yield
3q: Ar = 4-BnO-C6H4
N
3y: Ar = 3-Br-C6H4
Fig. 5. Single crystal X-ray analysis of 3i.
3ag: Ar = 4-CH3O-C6H4
6 h, 84% yield
6 h, 82% yield
6 h, 72% yield
N
3r: Ar = 3-MOMO-C6H4
6 h, 86% yield
3ah: R = n-pentyl
CF3
N
N
Boc
10 h, 72% yield
A plausible mechanism for the cascade reaction is illustrated in
Fig. 6. Propargylic substrate 2a was activated by Cu-Pybox complex
via the formation of allenylidene-copper intermediate (I).5,6 Then,
2-aminopyridine 1a coordinated with copper as depicted in II,
followed by nucleophilic addition of the pyridine nitrogen atom of
3ac
3s: Ar = 4-Cl-C6H4
6 h, 81% yield
N
N
6 h, 85% yield
N
3t: Ar = 4-CF3-C6H4
N
R
6 h, 83% yield
N
S
3ai: R = Bn
3u: Ar = 3-Br-C6H4
OMOM
a
6 h, 91% yield
-
3aj: R = n-pentyl
3z
3ad
1a to
g-position of allenylidene moiety affording intermediate III.
3v: Ar = 3,5-(CF3)2-C6H3
a
6 h, 61% yield
6 h, 85% yield
-
6 h, 73% yield
Protonation and subsequent intra-molecular cyclization in a 5-exo-
a No formation of desired product was observed
dig manner via p-activation of the triple bond by copper led to the
formation of V.8 Finally, intermediate V could be preferably iso-
merized into the thermodynamic stable imidazo[1,2-a]pyridine 3a
in the presence of a base.
Fig. 3. Scope of the reaction regarding propargyl alcohol derivatives.
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4
C. Cheng et al. / Tetrahedron xxx (2016) 1e9
Pybox
Cu
rotations were taken on JASCO P1030. High-resolution mass spectra
were recorded on Bruker ApeXIII 7.0 TESLA FTMS.
Pybox
Cu
Pybox
H
N
Cu-Pybox
DIPEA
Cu
1a
H
2a
NH
4.2. General procedure for preparation of propargylic ace-
tates 2
N
Ph
N
Ph
I
Ph
II
III
Ethynylmagnesium bromide (0.5 M in THF, 50.0 mL, 25.0 mmol)
was added dropwise to a solution of benzaldehyde (2.12 g,
20.0 mmol) in THF (20 mL) cooled to 0 ꢀC. After addition was com-
plete, the reaction mixture was warmed to ambient temperature and
stirred for 2 h after completion of reaction. The reaction was
quenched with saturated aqueous NH4Cl (100 mL) and extracted
with diethyl ether (50 mLꢁ3). The combined organic extracts were
rinsed with brine (100 mL), dried over MgSO4 and concentrated. The
residue was purified by flash chromatography on silica gel to afford
the corresponding propargylic alcohol (2.0 g,15.1 mmol) in 75% yield.
To a solution of propargylic alcohol (1.06 g, 8.0 mmol) in an-
hydrous DCM (20 mL), Et3N (1.22 mL, 8.8 mmol) and DMAP (97 mg,
0.8 mmol) were added successively. The reaction mixture was
cooled with an ice bath for 5 min. Then Ac2O (0.8 mL, 8.4 mmol)
was added dropwise. The reaction was gradually warmed to room
temperature and stirred for 0.5 h at this temperature. After com-
plete consumption of 1-phenylprop-2-yn-1-ol as followed by TLC,
water (20 mL) was added to quench the reaction. The organic phase
was isolated, and the aqueous phase was extracted with DCM
(15 mLꢁ2). The combined organic layers were washed with brine,
dried over MgSO4, filtered and evaporated under reduced pressure.
The residue was purified by flash chromatography on silica gel to
afford pure 2a (1.50 g, 6.94 mmol) as a colorless oil in a yield of 87%.
L
Cu
N
N
DIPEA
NH
N
N
N
Ph
IV
Ph
Ph
3a
V
Fig. 6. The proposed mechanism.
In order to show the application potential of our method, we
next carried out the reaction between 1a and 2a in relatively larger
scale and further elaboration of cyclized product 3a (Scheme 1). The
reaction performed on gram scale between 1a and 2a led to
cyclized product 3a in 88% yield with as low as 1 mol % Cu(acac)2
and 1.2 mol % ligand A. Bromination of the methyl group of 3a in the
presence of N-bromosuccinimide (NBS) and azobisisobutyronitrile
(AIBN) with DCE as a solvent at reflux for 3 h afforded 6 (68% yield),
which provided valuable opportunities for further elaboration.
Thus, reaction between bromide 6 with various nitrogen- or
oxygen-based nucleophiles proceeded smoothly to provide further
functionalized imidazo[1,2-a]pyridines in excellent yields.
OAc
Cu(acac)2, 1 mol%
ligand A, 1.2 mol%
2 equiv DIPEA
CH3OH, rt, 24 h
88% yield
N
+
N
3a
N
1a
NH2
2a
Ph
1.46 g, 8.4 mmol
1.28 g, 6.2 mmol
4.2.1. 1-Phenylprop-2-ynyl acetate (2a).13 Pale yellow oil, 1.50 g,
0.66 g, 7 mmol
87% yield; 1H NMR (500 MHz, CDCl3):
d 7.52e7.54 (m, 2H),
NBS (1.1 equiv)
AIBN (0.1 equiv)
Nu
N
Br
N
NuH
7.36e7.41 (m, 3H), 6.45 (s, 1H), 2.65 (s, 1H), 2.11 (s, 3H).
N
N
DCE, reflux 3 h
68% yield
Ph
7
4.2.2. 1-p-Tolylprop-2-ynyl acetate (2b).13 Pale yellow oil, 1.30 g,
6
Ph
87% yield; 1H NMR (500 MHz, CDCl3):
d 7.42e7.43 (m, 2H), 7.19e7.21
7a: NuH = pyrrolidine, 90% yield; 7b: NuH = imidazole, 88% yield;
7c: NuH = (CH3)2NH, 88% yield; 7d: NuH = EtNH2, 92% yield;
7e: NaOAc as a nucleophile, Nu = OAc, 91% yield
(m, 2H), 6.41e6.42 (m, 1H), 2.64 (s, 1H), 2.36 (s, 3H), 2.10 (s, 3H).
Scheme 1. Gram scale synthesis of 3a and its further derivatization.
4.2.3. 1-(4-Methoxyphenyl)prop-2-ynyl acetate (2c).13 Pale yellow
oil, 1.35 g, 82% yield; 1H NMR (500 MHz, CDCl3):
d 7.46e7.47 (m,
3. Conclusions
We have developed
2H), 6.89e6.91 (m, 2H), 6.40e6.41 (m, 1H), 3.80 (s, 3H), 2.66 (s, 1H),
2.08 (s, 3H).
a
cascade process between 2-
aminopyridines and propargyl alcohol derivatives bearing termi-
nal alkyne functionality in the presence of catalytic amount of
copper salt and Pybox ligand under mild conditions, which provide
access to various densely substituted imidazo[1,2-a]pyridines in
moderate to excellent yields. The reaction proceeded through
regioselective propargylation at pyridine nitrogen of 2-
aminopyridine following an intramolecular cyclization catalyzed
by copper-Pybox complex. The utility of this method was demon-
strated by gram scale synthesis of 3a, and further elaboration of 3a
by bromination and following coupling with various nucleophiles.
Furthermore, this methodology was found to be also applicable to 2-
aminopyrimidine, 2-aminopyrazine, and 2-aminopyridazine.
4.2.4. 1-(4-(Benzyloxy)phenyl)prop-2-yn-1-yl acetate (2d). White
solid, 1.97 g, yield 88%; 1H NMR (500 MHz, CDCl3)
d 7.53e7.34 (m,
7H), 7.03e7.00 (m, 2H), 6.46 (d, J¼2.2 Hz, 1H), 5.10 (s, 2H), 2.69 (d,
J¼2.2 Hz, 1H), 2.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 169.8, 159.4,
136.8, 129.4, 129.0, 128.7, 128.1, 127.5, 115.0, 80.5, 75.3, 70.1, 65.1,
21.1; HRMS (ESI) calcd for (C18H16NaO3)þ 303.0992, found 303.0999.
4.2.5. 1-(3-(Methoxymethoxy)phenyl)prop-2-yn-1-yl
acetate
7.32
(2e).14 Brown oil, 2.0 g, 86% yield; 1H NMR (500 MHz, CDCl3)
d
(t, J¼7.9 Hz, 1H), 7.21e7.20 (m, 1H), 7.17 (d, J¼7.7 Hz, 1H), 7.06e7.04
(m, 1H), 6.41 (d, J¼2.2 Hz, 1H), 5.18 (d, J¼1.1 Hz, 2H), 3.48 (s, 3H),
2.66 (d, J¼2.2 Hz, 1H), 2.11 (s, 3H).
4. Experimental
4.2.6. 1-(4-Chlorophenyl)prop-2-ynyl acetate (2f).13 Pale yellow oil,
1.38 g, 83% yield; 1H NMR (500 MHz, CDCl3):
d 7.46e7.47 (m, 2H),
4.1. General information
7.34e7.36 (m, 2H), 6.41 (s, 1H), 2.67 (s, 1H), 2.10 (s, 3H).
Thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel plates visualized with UV light and/or by staining with ethanolic
phosphomolybdic acid (PMA) or iodine. Flash column chromatog-
4.2.7. 1-(4-(Trifluoromethyl)phenyl)prop-2-ynyl acetate (2g).13 Pale
yellow oil, 1.73 g, yield 89%; 1H NMR (500 MHz, CDCl3):
4H), 6.48 (s, 1H), 2.69 (s, 1H), 2.12 (s, 3H).
d 7.65 (s,
raphy was performed on silica gel H (10e40
recorded on Bruker AM500 (500 MHz). Chemical shifts (
in ppm relative to TMS, coupling constants (J) in Hz. Optical
m
). NMR spectra were
d) are given
4.2.8. 1-(3-Bromophenyl)prop-2-yn-1-yl acetate (2h).15 Pale yellow
oil, 1.69 g, 84% yield; 1H NMR (500 MHz, CDCl3)
7.68 (s, 1H), 7.49
d
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C. Cheng et al. / Tetrahedron xxx (2016) 1e9
5
(dd, J¼7.9, 1.2 Hz, 1H), 7.44 (d, J¼7.9 Hz, 1H), 7.25 (td, J¼7.9, 1.2 Hz,
1H), 6.40 (d, J¼2.2 Hz, 1H), 2.68 (d, J¼2.2 Hz, 1H), 2.12 (s, 3H).
0.012 mmol). Anhydrous MeOH (1.0 mL) was added, and the mix-
ture was magnetically stirred at 20 ꢀC for 15 min. Then a solution of
1-phenylprop-2-yn-1-yl acetate 2a (0.24 mmol), 2-aminopyridine
1a (0.2 mmol) and diisopropylethylamine (0.07 mL, 0.4 mmol) in
MeOH (0.5 mL) were added dropwise. The reaction flask was kept
at room temperature for 6 h. After 1a was completely consumed as
monitored by TLC, H2O (10 mL) was added to quench the reaction.
The resulting mixture was then extracted three times with diethyl
ether (10 mLꢁ3). The combined organic layer was dried over
Na2SO4. After evaporation of the volatile solvent under reduced
pressure, the residue was purified by flash chromatography on
silica gel to afford pure 3a (39 mg, 0.19 mmol) as a brown oil in
a yield of 94%.
4.2.9. 1-(3,5-bis(Trifluoromethyl)phenyl)prop-2-ynyl
(2i).16 Pale yellow oil, 2.13 g, 86% yield; 1H NMR (500 MHz, CDCl3):
7.99 (s, 2H), 7.89 (s, 1H), 6.52 (s, 1H), 2.74 (s, 1H), 2.15 (s, 3H).
acetate
d
4.2.10. 1-(Naphthalen-1-yl)prop-2-ynyl acetate (2j).13 White solid,
85% yield; 1H NMR (500 MHz, CDCl3)
d
8.25 (d, J¼8.6 Hz, 1H),
7.93e7.89 (m, 3H), 7.63e7.60 (m, 1H), 7.57e7.50 (m, 2H), 7.16 (t,
J¼2.3 Hz, 1H), 2.78 (d, J¼2.3 Hz, 1H), 2.15 (s, 3H).
4.2.11. 1-(Furan-2-yl)prop-2-yn-1-yl acetate (2k).6d Pale yellow oil,
1.14 g, yield 87% of 2k; 1H NMR (500 MHz, CDCl3)
0.9 Hz, 1H), 6.50e6.49 (m, 1H), 6.44 (d, J¼2.3 Hz, 1H), 6.33 (dd,
J¼3.3, 1.8, Hz, 1H), 2.61 (d, J¼2.3 Hz, 1H), 2.02 (s, 3H).
d
7.37 (dd, J¼1.8,
4.3.1. 2-Methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyridine
(3a).18 Brown oil, 39 mg, 94% yield; 1H NMR (500 MHz, CDCl3)
d
8.08 (d, J¼6.8 Hz, 1H), 7.56e7.50 (m, 3H), 7.45e7.39 (m, 3H), 7.15
4.2.12. tert-Butyl 3-(1-acetoxyprop-2-yn-1-yl)-1H-indole-1-
(t, J¼6.8, Hz, 1H), 6.70 (t, J¼6.8, Hz, 1H), 2.47 (s, 3H).
carboxylate (2l).17 White solid, 2.05 g, 82% yield; 1H NMR
(500 MHz, CDCl3)
1H), 7.38e7.35 (m, 1H), 7.30e7.27 (m, 1H), 6.74 (dd, J¼2.3, 0.7 Hz,
1H), 2.67 (d, J¼2.3 Hz, 1H), 2.12 (s, 3H), 1.68 (s, 9H).
d
8.18 (d, J¼7.8 Hz, 1H), 7.81 (s, 1H), 7.74e7.72 (m,
4.3.2. 2,8-Dimethyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyridine
(3b).19 White solid, 40 mg, 90% yield; 1H NMR (500 MHz, CDCl3)
d
7.90 (d, J¼6.9 Hz, 1H), 7.48e7.45 (m, 2H), 7.40e7.33 (m, 3H), 6.88
(d, J¼6.9 Hz, 1H), 6.55 (t, J¼6.9 Hz, 1H), 2.59 (s, 3H), 2.47 (s, 3H).
4.2.13. 1-(Benzo[b]thiophen-2-yl)prop-2-yn-1-yl
acetate
(2m). White solid, 1.53 g, 83% yield; 1H NMR (500 MHz, CDCl3)
4.3.3. 2,7-Dimethyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyridine
d
7.84e7.76 (m, 2H), 7.51 (s, 1H), 7.39e7.34 (m, 2H), 6.78 (dd, J¼2.3,
(3c). Brown solid, 40.5 mg, 91% yield; 1H NMR (500 MHz, CDCl3)
0.8 Hz, 1H), 2.77 (d, J¼2.3 Hz, 1H), 2.15 (s, 3H); 13C NMR (125 MHz,
d
7.95 (d, J¼7.0 Hz,1H), 7.50 (t, J¼7.0 Hz, 2H), 7.42e7.35 (m, 3H), 7.28
CDCl3)
d
149.5, 145.1, 142.5, 135.5, 129.3, 126.0, 125.0, 124.0, 123.1,
(s, 1H), 6.51 (d, J¼7.0 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H); 13C NMR
120.2, 116.9, 115.7, 113.7, 111.7, 109.2, 84.4, 28.2, 14.1; HRMS (ESI)
(125 MHz, CDCl3) d 145.0, 140.6, 135.0, 129.7, 129.3, 129.1, 127.8,
calcd for (C13H10NaO2S)þ 253.0294, found 253.0303.
122.3, 120.8, 115.4, 114.4, 21.2, 13.9; HRMS (ESI) calcd for
(C15H15N2)þ 223.1230, found 223.1237.
4.2.14. (E)-1-Phenylpent-1-en-4-yn-3-yl acetate (2n).13 Pale yellow
oil, 1.36 g, 85% yield; 1H NMR (500 MHz, CDCl3)
d
7.43e7.27 (m, 5H),
4.3.4. 2,6-Dimethyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyridine
6.91 (d, J¼15.8 Hz, 1H), 6.27 (dd, J¼15.8, 6.5 Hz, 1H), 6.08e6.06 (m,
(3d). Brown solid, 41 mg, 92% yield; 1H NMR (500 MHz, CDCl3)
d
7.88
(s, 1H), 7.56e7.51 (m, 3H), 7.48e7.42 (m, 3H), 7.02 (dd, J¼9.1, 1.6 Hz,
1H), 2.47 (s, 3H), 2.27 (s, 3H); 13C NMR (125 MHz, CDCl3)
143.4,
1H), 2.67 (d, J¼2.2 Hz, 1H), 2.13 (s, 3H).
d
4.2.15. (E)-1-(4-Fluorophenyl)pent-1-en-4-yn-3-yl
(2o). Pale yellow oil, 1.46 g, 85% yield; 1H NMR (500 MHz, CDCl3)
7.38e7.35 (m, 2H), 7.03 (t, J¼8.7 Hz, 2H), 6.85 (d, J¼15.7 Hz, 1H),
6.14 (dd, J¼15.7, 6.5 Hz, 1H), 6.03 (d, J¼6.5 Hz, 1H), 2.66 (d, J¼2.2 Hz,
1H), 2.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
169.6, 163.8, 161.9,
acetate
140.4, 129.6, 129.5, 129.1, 128.0, 127.4, 121.6, 121.2, 120.7, 116.2, 18.3,
13.7; HRMS (ESI) calcd for (C15H15N2)þ 223.1230, found 223.1234.
d
4.3.5. 6-Methoxy-2-methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyr-
d
idine (3f). Brown solid, 42 mg, 87% yield; 1H NMR (500 MHz, CDCl3)
133.7, 131.7, 131.7, 128.63, 128.56, 123.1, 115.7, 115.6, 79.3, 75.5, 63.9,
21.0; HRMS (ESI) calcd for (C13H11FNaO2)þ 241.0635, found 241.0643.
d
7.61 (d, J¼2.3 Hz, 1H), 7.54e7.51 (m, 2H), 7.46e7.39 (m, 4H), 6.94
(dd, J¼9.7, 2.3 Hz, 1H), 3.70 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 149.0, 141.6, 141.0, 129.8, 129.3, 129.2, 128.1, 122.3, 118.9,
4.2.16. (E)-1-(4-Methoxyphenyl)pent-1-en-4-yn-3-yl
(2p). Pale yellow oil, 1.46 g, 85% yield; 1H NMR (500 MHz, CDCl3)
7.34 (dt, J¼8.6, 2.2 Hz, 2H), 6.86e6.81 (m, 3H), 6.10 (dd, J¼15.6,
acetate
117.1, 105.3, 56.2, 14.0; HRMS (ESI) calcd for (C15H15N2O)þ 239.1179,
found 239.1183.
d
6.7 Hz, 1H), 6.03 (ddd, J¼6.7, 2.2, 1.0 Hz, 1H), 3.78 (s, 3H), 2.66 (d,
4.3.6. 8-Bromo-2-methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyri-
J¼2.2 Hz, 1H), 2.10 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
169.7, 159.9,
dine (3g). Brown solid, 43 mg, 74% yield; 1H NMR (500 MHz, CDCl3)
134.5, 128.3, 128.2, 121.0, 114.1, 79.6, 75.3, 64.2, 55.3, 21.1; HRMS
(ESI) calcd for (C14H14NaO3)þ 253.0835, found 253.0846.
d
8.05 (dd, J¼6.8, 1.0 Hz, 1H), 7.54e7.51 (m, 2H), 7.45e7.40 (m, 4H),
6.60 (t, J¼6.8 Hz,1H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 142.3,
141.8, 129.6, 129.3, 129.1, 128.5, 126.5, 123.3, 122.5, 111.9, 111.0, 14.1;
4.2.17. (E)-Dec-4-en-1-yn-3-yl acetate (2q). Pale yellow oil, 1.24 g,
HRMS (ESI) calcd for (C14H12BrN2)þ 287.0178, found 287.0186.
80% yield; 1H NMR (500 MHz, CDCl3)
d 6.00e5.94 (m, 1H),
5.78e5.77 (m, 1H), 5.49 (ddt, J¼15.3, 6.5, 1.3 Hz, 1H), 2.53 (d,
4.3.7. 6-Bromo-2-methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyri-
J¼2.2 Hz, 1H), 2.05e2.00 (m, 5H), 1.39e1.33 (m, 2H), 1.28e1.22 (m,
dine (3h). Brown solid, 40 mg, 70% yield; 1H NMR (500 MHz, CDCl3)
4H), 0.85 (t, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
169.5, 137.0,
d
8.19 (dd, J¼1.8, 0.8 Hz, 1H), 7.56e7.53 (m, 2H), 7.46e7.43 (m, 4H),
124.3, 79.8, 74.7, 64.0, 31.9, 31.3, 28.3, 22.4, 21.0, 14.0; HRMS (ESI)
7.20 (dd, J¼9.5, 1.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3)
calcd for (C12H18NaO2)þ 217.1199, found 217.1207.
d
142.9, 142.0, 129.4, 129.3, 128.8, 128.5, 127.3, 123.1, 122.0, 117.6,
106.7, 14.0; HRMS (ESI) calcd for (C14H12BrN2)þ 287.0178, found
287.0186.
4.3. General procedure for Cu-Pybox catalyzed synthesis of
2,3-disbustituted imidazo[1,2-a]pyridines (3) and related N-
fused imidazoles (5)
4.3.8. 7-Chloro-2-methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyri-
dine (3i). White solid, 36 mg, 73% yield; a crystalline sample suit-
able for X-ray diffraction analysis was developed from a solvent
mixture of ethyl acetate and petroleum ether. Mp 114e116 ꢀC; 1H
Under an atmosphere of nitrogen, a 25 mL dry Schlenk flask was
placed with Cu(acac)2 (1.6 mg, 0.01 mmol) and ligand A (2.6 mg,
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6
C. Cheng et al. / Tetrahedron xxx (2016) 1e9
NMR (500 MHz, CDCl3)
d
7.97 (dd, J¼7.3, 0.7 Hz, 1H), 7.52e7.49 (m,
CDCl3)
d
8.03 (dt, J¼6.8, 1.1 Hz 1H), 7.55 (dt, J¼9.0, 1.1 Hz, 1H),
3H), 7.42e7.39 (m, 3H), 6.67 (dd, J¼7.3, 2.1 Hz, 1H), 2.43 (s, 3H); 13
C
7.50e7.47 (m, 2H), 7.39e7.37 (m, 2H), 7.16 (ddd, J¼9.0, 6.8, 1.1 Hz
NMR (125 MHz, CDCl3)
d 144.2, 141.9, 130.37, 129.4, 129.3, 128.9,
1H), 6.73 (td, J¼6.8, 1.1 Hz, 1H), 2.44 (s, 3H).
128.4, 123.3, 121.7, 115.8, 113.4, 14.0; HRMS (ESI) calcd for
(C14H12ClN2)þ 243.0684, found 243.0690.
4.3.17. 2-Methyl-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroimidazo
[1,2-a]pyridine (3t). Brown solid, 46 mg, 83% yield; 1H NMR
4.3.9. 6-Chloro-2-methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyri-
(500 MHz, CDCl3)
7.61e7.57 (m, 3H), 7.20 (ddd, J¼9.0, 6.8, 1.2 Hz, 1H), 6.77 (td, J¼6.8,
1.2 Hz, 1H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3)
144.9, 141.8,
133.3, 129.9 (q, J¼32.8 Hz), 129.8, 129.54, 129.47, 126.2 (q, J¼3.6 Hz),
124.8, 124.0 (q, J¼270.5 Hz), 122.8, 120.1, 117.2, 112.4, 13.9; HRMS
(ESI) calcd for (C15H12F3N2)þ 277.0947, found 277.0960.
d
8.10 (d, J¼6.8 Hz, 1H), 7.78 (d, J¼8.0 Hz, 2H),
dine (3j). White solid, 35 mg, 71% yield; 1H NMR (500 MHz, CDCl3)
d
8.09 (dd, J¼2.0, 0.8 Hz, 1H), 7.54e7.51 (m, 2H), 7.49 (dd, J¼9.5,
0.8 Hz, 1H), 7.44e7.42 (m, 3H), 7.09 (dd, J¼9.5, 2.0 Hz, 1H), 2.45 (s,
3H); 13C NMR (125 MHz, CDCl3)
142.8, 142.1, 129.4, 129.3, 128.8,
d
d
128.5, 125.2, 122.1, 120.9, 120.2, 117.3, 14.0; HRMS (ESI) calcd for
(C14H12ClN2)þ 243.0684, found 243.0690.
4.3.18. 3-(3-Bromophenyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyri-
4.3.10. 2-Methyl-3-phenyl-8-(trifluoromethyl)-2,3-dihydroimidazo
[1,2-a]pyridine (3l). Brown solid, 28 mg, 50% yield; 1H NMR
dine (3u). Brown solid, 52 mg, 91% yield; 1H NMR (500 MHz, CDCl3)
d
8.02 (d, J¼6.8 Hz, 1H), 7.55e7.47 (m, 3H), 7.35e7.33 (m, 2H), 7.12
(ddd, J¼9.0, 6.8, 1.2 Hz, 1H), 6.69 (td, J¼6.8, 1.2 Hz, 1H), 2.42 (s, 3H);
13C NMR (125 MHz, CDCl3)
144.7, 141.6, 132.1, 131.6, 131.0, 130.7,
(500 MHz, CDCl3)
7.51e7.46 (m, 2H), 7.46e7.43 (m, 2H), 6.80 (t, J¼6.7 Hz, 1H), 2.53 (s,
3H); 13C NMR (125 MHz, CDCl3)
142.5, 139.8, 129.7, 129.4, 128.74,
d
8.21 (d, J¼6.7 Hz, 1H), 7.57e7.54 (m, 2H),
d
d
128.0, 124.4, 123.1, 122.8, 119.9, 117.1, 112.2, 14.0; HRMS (ESI) calcd
for (C14H12BrN2)þ 287.0178, found 287.0183.
128.68, 127.4, 126.3, 123.0 (q, J¼270.6 Hz), 122.6, 122.5 (q, J¼5.4 Hz),
121.9, 118.5 (q, J¼33.1 Hz), 110.2, 14.1; HRMS (ESI) calcd for
(C15H12F3N2)þ 277.0947, found 277.0955.
4.3.19. 3-(3,5-bis(Trifluoromethyl)phenyl)-2-methyl-2,3-
dihydroimidazo[1,2-a]pyridine (3v). Brown solid, 50 mg, 73% yield;
4.3.11. 2-Methyl-3-phenyl-6-(trifluoromethyl)-2,3-dihydroimidazo
[1,2-a]pyridine (3m). Brown solid, 34 mg, 61% yield; 1H NMR
1H NMR (500 MHz, CDCl3)
d
8.04 (d, J¼6.8 Hz, 1H), 7.91 (s, 3H), 7.60
(d, J¼9.0 Hz, 1H), 7.25 (ddd, J¼9.0, 6.8, 1.2 Hz, 1H), 6.84 (td, J¼6.8,
1.2 Hz, 1H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3)
145.3, 142.7,
(500 MHz, CDCl3)
d
8.40 (s, 1H), 7.66 (d, J¼9.4 Hz, 1H), 7.58e7.55 (m,
d
2H), 7.49e7.44 (m, 3H), 7.30 (dd, J¼9.4, 1.7 Hz 1H), 2.49 (s, 3H); 13
C
132.8 (q, J¼33.6 Hz), 132.0, 129.1 (q, J¼3.7 Hz), 125.2, 123.1 (q,
J¼271.4 Hz), 122.3, 121.7e121,5 (m), 118.6, 117.5, 112.9, 13.9; HRMS
(ESI) calcd for (C16H11F6N2)þ 345.0821, found 345.0823.
NMR (125 MHz, CDCl3)
d 144.1, 143.1, 129.52, 129.49, 128.8, 128.4,
123.7 (q, J¼268.8 Hz), 122.8, 122.0 (q, J¼5.5 Hz), 119.8 (q, J¼2.7 Hz),
117.6, 116.3 (q, J¼33.7 Hz), 14.0; HRMS (ESI) calcd for (C15H12F3N2)þ
277.0947, found 277.0955.
4.3.20. 2,7-Dimethyl-3-(p-tolyl)-2,3-dihydroimidazo[1,2-a]pyridine
(3w). Brown solid, 40 mg, 84% yield; 1H NMR (500 MHz, CDCl3)
4.3.12. 2-Methyl-3-(p-tolyl)-2,3-dihydroimidazo[1,2-a]pyridine
d
7.89 (d, J¼7.0 Hz, 1H), 7.26e7.25 (m, 5H), 6.46 (d, J¼7.0, 1H), 2.40
(3o).18 Brown solid, 40 mg, 90% yield; 1H NMR (500 MHz, CDCl3)
d
8.05
(s, 3H), 2.37 (s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
144.8,
(d, J¼6.8 Hz,1H), 7.66 (d, J¼9.0 Hz,1H), 7.32 (s, 4H), 7.17 (ddd, J¼9.0, 6.8,
140.3, 137.7, 134.7, 129.8, 129.2, 126.7, 122.3, 120.8, 115.3, 114.2, 21.3,
21.2, 13.9; HRMS (ESI) calcd for (C16H17N2)þ 237.1386, found
237.1393.
1.1 Hz, 1H), 6.73 (td, J¼6.8, 1.1 Hz, 1H), 2.45 (s, 3H), 2.43 (s, 3H).
4.3.13. 3-(4-Methoxyphenyl)-2-methyl-2,3-dihydroimidazo[1,2-a]
pyridine (3p). Brown solid, 42 mg, 88% yield; 1H NMR (500 MHz,
4.3.21. 3-(4-Chlorophenyl)-2,7-dimethyl-2,3-dihydroimidazo[1,2-a]
CDCl3)
d
8.01 (dt, J¼6.8, 1.2 Hz, 1H), 7.54 (dt, J¼9.0, 1.2 Hz, 1H),
pyridine (3x). Brown solid, 44 mg, 85% yield; 1H NMR (500 MHz,
7.37e7.34 (m, 2H), 7.13 (ddd, J¼9.0, 6.8, 1.2 Hz, 1H), 7.06e7.03 (m,
CDCl3)
d
7.85 (d, J¼7.0 Hz,1H), 7.42e7.40 (m, 2H), 7.30e7.24 (m, 3H),
2H), 6.70 (td, J¼6.8, 1.2 Hz, 1H), 3.87 (s, 3H), 2.44 (s, 3H); 13C NMR
6.48 (dd, J¼7.0 Hz,1H), 2.37 (s, 3H), 2.32 (s, 3H); 13C NMR (125 MHz,
(125 MHz, CDCl3)
d
159.4, 144.3, 140.6, 130.9, 123.8, 123.0, 121.6,
CDCl3) d 145.1, 140.8, 135.3, 133.7, 130.5, 129.4, 129.3, 129.1, 128.1,
121.2, 116.9, 114.6, 111.7, 55.4, 13.9; HRMS (ESI) calcd for
122.1, 119.6, 115.5, 114.6, 21.2, 13.9; HRMS (ESI) calcd for
(C15H15N2O)þ 239.1179, found 239.1175.
(C15H14ClN2)þ 257.0840, found 257.0848.
4.3.14. 3-(4-(Benzyloxy)phenyl)-2-methyl-2,3-dihydroimidazo[1,2-a]
4.3.22. 3-(3-Bromophenyl)-2,7-dimethyl-2,3-dihydroimidazo[1,2-a]
pyridine (3q). Brown solid, 53 mg, 84% yield; 1H NMR (500 MHz,
pyridine (3y). Brown solid, 50 mg, 82% yield; 1H NMR (500 MHz,
CDCl3)
d
7.99 (d, J¼6.8 Hz, 1H), 7.53 (d, J¼9.0 Hz, 1H), 7.46 (d,
CDCl3)
d
7.90 (d, J¼7.0 Hz,1H), 7.53e7.45 (m, 2H), 7.33e7.29 (m, 2H),
J¼7.3 Hz, 2H), 7.40 (t, J¼7.3 Hz, 2H), 7.34e7.31 (m, 3H), 7.12e7.06
7.25 (s, 1H), 6.52 (dd, J¼7.0, 1.6 Hz, 1H), 2.39 (s, 3H), 2.33 (s, 3H); 13
C
(m, 3H), 6.66 (t, J¼6.8, Hz, 1H), 5.10 (s, 2H), 2.44 (s, 3H). 13C NMR
NMR (125 MHz, CDCl3) d 145.2,141.2,135.4,131.9,131.8,130.8,130.6,
(125 MHz, CDCl3)
d
158.7, 144.3, 140.6, 136.7, 130.9, 128.7, 128.1,
127.8, 123.1, 122.1, 119.3, 115.5, 114.7, 21.2, 13.9; HRMS (ESI) calcd for
127.5, 123.8, 123.0, 121.8, 121.2, 116.8, 115.5, 111.8, 70.1, 13.9. HRMS
(C15H14BrN2)þ 301.0335, found 301.0341.
(ESI) calcd for (C21H19N2O)þ 315.1492, found 315.1501.
4.3.23. 3-(3-(Methoxymethoxy)phenyl)-2-methyl-8-(tri-
4.3.15. 3-(3-(Methoxymethoxy)phenyl)-2-methyl-2,3-
fluoromethyl)-2,3-dihydroimidazo[1,2-a]pyridine (3z). Brown solid,
dihydroimidazo[1,2-a]pyridine (3r). Brown solid, 46 mg, 86% yield;
41 mg, 61% yield; 1H NMR (500 MHz, CDCl3)
d
8.25 (d, J¼6.9 Hz, 1H),
7.51e7.45 (m, 2H), 7.16e7.07 (m, 3H), 6.80 (t, J¼6.9 Hz, 1H), 5.23 (s,
2H), 3.51 (s, 3H), 2.54 (s, 3H); 13C NMR (125 MHz, CDCl3)
158.0,
1H NMR (500 MHz, CDCl3)
d
8.13 (d, J¼6.8 Hz, 1H), 7.55 (d, J¼9.0 Hz,
1H), 7.44 (t, J¼7.9 Hz, 1H), 7.14e7.08 (m, 4H), 6.71 (td, J¼6.8, 1.1 Hz,
d
1H), 5.21 (s, 2H), 3.50 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz,
142.5, 139.9, 130.5, 130.0, 126.4, 124.1, 123.0, 123.0 (q, J¼270.6 Hz),
122.5 (q, J¼5.5 Hz), 122.3, 118.5 (q, J¼32.8 Hz), 117.6, 116.4, 110.2,
94.6, 56.2, 14.2; HRMS (ESI) calcd for (C17H16F3N2O2)þ 337.1158,
found 337.1166.
CDCl3)
d 157.8, 144.5, 141.1, 130.8, 130.2, 124.1, 123.1, 122.8, 121.1,
117.3, 117.0, 115.8, 111.9, 94.5, 56.1, 14.0; HRMS (ESI) calcd for
(C16H17N2O2)þ 269.1285, found 269.1292.
4.3.16. 3-(4-Chlorophenyl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyri-
4.3.24. 2-Methyl-3-(naphthalen-1-yl)-2,3-dihydroimidazo[1,2-a]
dine (3s).18 Brown solid, 41 mg, 85% yield; 1H NMR (500 MHz,
pyridine (3aa).18 Brown solid, 50 mg, 97% yield; 1H NMR (500 MHz,
Please cite this article in press as: Cheng, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.013

C. Cheng et al. / Tetrahedron xxx (2016) 1e9
7
CDCl3)
d
7.95 (d, J¼8.5 Hz, 1H), 7.93 (d, J¼6.8 Hz, 1H), 7.61 (d,
CDCl3)
d
8.02 (d, J¼6.8 Hz, 1H), 7.47 (d, J¼9.0 Hz, 1H), 7.08 (ddd,
J¼9.0 Hz, 1H), 7.57 (d, J¼7.5 Hz, 1H), 7.51e7.46 (m, 3H), 7.38e7.31
J¼9.0, 6.8, 1.2 Hz, 1H), 6.74 (td, J¼6.8, 1.1 Hz, 1H), 6.41 (d, J¼16.4 Hz,
1H), 6.05 (dt, J¼16.4, 6.8 Hz, 1H), 2.48 (s, 3H), 2.33e2.18 (m, 2H),
1.57e1.41 (m, 2H), 1.38e1.22 (m, 4H), 0.93e0.82 (m, 3H); 13C NMR
(m, 2H), 7.12 (ddd, J¼9.0, 6.8, 1.1 Hz, 1H), 6.57 (td, J¼6.8, 1.1 Hz, 1H),
2.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 144.8, 142.2, 134.0, 132.3,
129.7, 129.6, 128.8, 126.9, 126.6, 126.4, 125.7, 125.2, 124.0, 123.8,
119.7, 116.8, 111.7, 13.9.
(126 MHz, CDCl3) d 143.9, 141.2, 133.1, 123.3, 123.1, 119.2, 116.8,
115.8, 111.8, 33.9, 31.4, 29.2, 22.5, 14.8, 14.0; HRMS (ESI) calcd for
(C15H21N2)þ 229.1699, found 229.1693.
4.3.25. 3-(Furan-2-yl)-2-methyl-2,3-dihydroimidazo[1,2-a]pyridine
(3ab). Brown solid, 35 mg, 88% of yield; 1H NMR (500 MHz, CDCl3)
4.3.32. 2-Methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidine
d
8.44 (dt, J¼6.8, 1.2 Hz, 1H), 7.53 (dd, J¼1.9, 0.5 Hz, 1H), 7.51 (d,
(5a). Brown oil, 30 mg, 71% yield; 1H NMR (500 MHz, CDCl3)
d 8.48
J¼9.0 Hz,1H), 7.13 (ddd, J¼9.0, 6.8,1.2 Hz,1H), 6.75 (td, J¼6.8,1.2 Hz,
1H), 6.53 (dd, J¼3.3, 1.9 Hz, 1H), 6.48 (dd, J¼3.3, 0.5 Hz, 1H), 2.52 (s,
(dd, J¼4.1, 2.0 Hz, 1H), 8.39 (dd, J¼6.8, 2.0 Hz, 1H), 7.54e7.51 (m,
2H), 7.45e7.42 (m, 3H), 6.80 (dd, J¼6.8, 4.1 Hz, 1H), 2.52 (s, 3H); 13
C
3H); 13C NMR (125 MHz, CDCl3)
d
144.8, 144.7, 142.5, 141.8, 124.7,
NMR (125 MHz, CDCl3) d 149.0, 147.6, 143.0, 130.4, 129.4, 129.3,
124.5, 116.8, 113.5, 112.3, 111.3, 108.1, 14.7; HRMS (ESI) calcd for
128.6, 128.2, 112.0, 108.4, 14.1; HRMS (ESI) calcd for (C13H12N3)þ
210.1026, found 210.1035.
(C12H11N2O)þ 199.0866, found 199.0869.
4.3.26. tert-Butyl 3-(2-methyl-2,3-dihydroimidazo[1,2-a]pyridin-3-
4.3.33. 2-Methyl-3-phenyl-2,3-dihydroimidazo[1,2-a]pyrazine
yl)-3a,7a-dihydro-1H-indole-1-carboxylate (3ac). Brown solid,
(5b). Brown solid, 29 mg, 70% yield; 1H NMR (500 MHz, CDCl3)
56 mg, 81% yield; 1H NMR (500 MHz, CDCl3)
d
8.25 (d, J¼7.9 Hz,1H),
d
9.01 (s, 1H), 8.01 (dd, J¼4.6, 1.2 Hz, 1H), 7.80 (d, J¼4.6 Hz, 1H), 7.56
7.86 (d, J¼6.8 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J¼9.0 Hz, 1H), 7.40e7.36
(m, 1H), 7.23e7.19 (m, 2H), 7.15 (ddd, J¼9.0, 6.8, 1.1 Hz, 1H), 6.68 (td,
J¼6.8, 1.1 Hz, 1H), 2.46 (s, 3H), 1.70 (s, 9H); 13C NMR (125 MHz,
(t, J¼7.5 Hz, 2H), 7.50e7.40 (m, 3H), 2.53 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 143.7, 143.0, 139.7, 129.6, 129.4, 129.2, 128.9, 128.0, 123.0,
115.9, 14.1; HRMS (ESI) calcd for (C13H12N3)þ 210.1026, found
210.1033.
CDCl3)
d 149.5, 145.1, 142.5, 135.5, 129.3, 126.0, 125.0, 124.0, 123.1,
120.2, 116.9, 115.7, 113.7, 111.7, 109.2, 84.4, 28.2, 14.1; HRMS (ESI)
calcd for (C21H22N3O2)þ 348.1707, found 348.1713.
4.3.34. 2-Methyl-3-phenyl-2,3-dihydroimidazo[1,2-b]pyridazine
(5d). Brown solid, 33 mg, 78% yield; 1H NMR (500 MHz, CDCl3)
4.3.27. 3-(Benzo[b]thiophen-2-yl)-2-methyl-2,3-dihydroimidazo[1,2-
d
8.28 (d, J¼4.4 Hz, 1H), 7.91 (d, J¼9.0 Hz, 1H), 7.71 (d, J¼7.4 Hz, 2H),
7.54 (t, J¼7.4 Hz, 2H), 7.43 (t, J¼7.4 Hz, 1H), 7.01 (dd, J¼9.0, 4.4 Hz,
1H), 2.61 (s, 3H); 13C NMR (125 MHz, CDCl3)
142.2, 141.1, 138.2,
a]pyridine (3ad). Brown solid, 45 mg, 85% yield; 1H NMR (500 MHz,
CDCl3)
d
8.30 (d, J¼6.8 Hz, 1H), 7.84e1.79 (m, 2H), 7.56 (d, J¼8.9 Hz,
d
1H), 7.39e7.32 (m, 3H), 7.16 (ddd, J¼8.9, 6.8, 1.1 Hz, 1H), 6.74 (td,
129.3, 128.7, 128.6, 128.1, 125.2, 124.6, 116.2, 15.0; HRMS (ESI) calcd
for (C13H12N3)þ 210.1026, found 210.1038.
J¼6.8, 1.1 Hz, 1H), 2.57 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 145.2,
143.6, 140.0, 139.8, 130.5, 124.78, 124.75, 124.72, 124.2, 123.7, 122.2,
117.0, 115.1, 112.4, 14.5. HRMS (ESI) calcd for (C16H13N2S)þ 265.0794,
found 265.0803.
4.4. Gram scale synthesis of 3a and procedures for its further
elaboration
4.3.28. (E)-2-Methyl-3-styryl-2,3-dihydroimidazo[1,2-a]pyridine
4.4.1. Gram scale synthesis of 3a. Under an atmosphere of nitrogen,
a 50 mL dry round-bottom flask was placed with Cu(acac)2
(11.4 mg, 0.07 mmol) and ligand A (18.2 mg, 0.084 mmol). Anhy-
drous MeOH (15.0 mL) was added, and the mixture was magneti-
cally stirred at 20 ꢀC for 15 min. Then a solution of 1-phenylprop-2-
yn-1-yl acetate 2a (1.46 g, 8.4 mmol), 2-aminopyridine 1a (0.66 g,
7.0 mmol) and diisopropylethylamine (2.45 mL, 14 mmol) in MeOH
(5.0 mL) were added dropwise. The reaction flask was kept at room
temperature for 8 h. After 1a was completely consumed as moni-
tored by TLC, H2O (30 mL) was added to quench the reaction. The
resulted mixture was then extracted three times with diethyl ether
(50 mLꢁ3). The combined organic layer was dried over Na2SO4.
After evaporation of the volatile solvent under reduced pressure,
the residue was purified by flash chromatography on silica gel to
afford pure 3a (1.28 g, 6.2 mmol) as a brown oil in a yield of 88%.
(3ae).20 Brown oil, 35 mg, 75% yield; 1H NMR (500 MHz, CDCl3)
d
8.21 (d, J¼7.0 Hz, 1H), 7.56 (d, J¼7.0 Hz, 1H), 7.53 (d, J¼7.5 Hz, 2H),
7.38 (t, J¼7.5 Hz, 2H), 7.28 (d, J¼7.5 Hz, 1H), 7.18 (d, J¼16.4 Hz, 1H),
7.16 (td, J¼7.0, 1.2 Hz, 1H), 6.93 (d, J¼16.4 Hz, 1H), 6.85 (td, J¼7.0,
1.2 Hz, 1H) 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 144.7, 143.1,
137.5, 128.8, 128.3, 127.6, 126.1, 124.1, 123.4, 119.4, 117.1, 114.4, 112.5,
15.4; HRMS (ESI) calcd for (C16H15N2)þ 235.1230, found 235.1232.
4.3.29. (E)-3-(4-Fluorostyryl)-2-methyl-2,3-dihydroimidazo[1,2-a]
pyridine (3af). Brown solid, 39 mg, 78% yield; 1H NMR (500 MHz,
CDCl3)
d
8.19 (d, J¼6.8 Hz, 1H), 7.56 (d, J¼9.0 Hz, 1H), 7.49e7.46 (m,
2H), 7.18 (ddd, J¼9.0, 6.8, 1.1 Hz, 1H), 7.10e7.04 (m, 3H), 6.89 (d,
J¼16.4 Hz, 1H), 6.85 (td, J¼6.8, 1.1 Hz, 1H), 2.62 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
162.3 (d, J¼246 Hz), 144.7, 143.1, 133.7, 127.6 (d,
J¼8.3 Hz), 127.2, 124.2, 123.3, 117.2, 115.8 (d, J¼21.0 Hz), 115.7, 114.2
(d, J¼2.8 Hz), 112.5, 15.4; HRMS (ESI) calcd for (C16H14FN2)þ
253.1136, found 253.1139.
4.4.2. Bromination of 3a. A mixture of 2-methyl-3-phenylimidazo
[1,2-a]pyridine 3a (1.0 g, 4.8 mmol), N-bromosuccinimide (0.95 g,
5.2 mmol) and azodiisobutyronitrile (0.078 g, 0.480 mmol) in DCE
(20 mL) was refluxed for 3 h. The solvent was removed and the
resulting material was partitioned between dichloromethane and
water. The layers were separated and the aqueous layer was further
extracted with dichloromethane. The combined dichloromethane
layer was dried over Na2SO4. After evaporation of the volatile sol-
vent under reduced pressure, the residue was purified by flash
chromatography on silica gel to afford compound 6 (0.93 g,
3.24 mmol) as a white solid in a yield of 68%.
4.3.30. (E)-3-(4-Methoxystyryl)-2-methyl-2,3-dihydroimidazo[1,2-a]
pyridine (3ag). Brown solid, 38 mg, 72% yield; 1H NMR (500 MHz,
CDCl3)
d
8.11 (d, J¼6.8 Hz, 1H), 7.50 (d, J¼8.7 Hz, 1H), 7.41 (d,
J¼8.7 Hz, 2H), 7.09 (ddd, J¼8.7, 6.8, 1.1 Hz, 1H), 6.97 (d, J¼16.4 Hz,
1H), 6.88 (d, J¼8.7 Hz, 2H), 6.83 (d, J¼16.4 Hz, 1H), 6.76 (dt, J¼6.8,
1.1 Hz, 1H), 3.79 (s, 3H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
159.3, 144.4, 142.4, 130.2, 128.3, 127.3, 123.8, 123.2, 119.6, 117.0,
114.2, 112.3, 112.2, 55.3, 15.3; HRMS (ESI) calcd for (C17H17N2O)þ
265.1335, found 265.1338.
4.4.3. 2-(Bromomethyl)-3-phenylimidazo[1,2-a]pyridine (6). White
4.3.31. (E)-3-(Hept-1-en-1-yl)-2-methyl-2,3-dihydroimidazo[1,2-a]
solid, 0.93 g, 68% yield; 1H NMR (500 MHz, CDCl3)
J¼6.8 Hz, 1H), 7.63 (d, J¼9.0 Hz, 1H), 7.58e7.43 (m, 5H), 7.23 (ddd,
d
8.10 (d,
pyridine (3ah). Brown oil, 34 mg, 72% yield; 1H NMR (500 MHz,
Please cite this article in press as: Cheng, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.013

8
C. Cheng et al. / Tetrahedron xxx (2016) 1e9
J¼9.0, 6.8, 1.1 Hz, 1H), 6.77 (t, J¼6.8 Hz, 1H), 4.75 (s, 2H); 13C NMR
temperature. After 6 was completely consumed as monitored by
TLC. Then 15 mL EA was added, the resulted mixture was washed
with H2O (10 mLꢁ3). The organic layer was dried over Na2SO4. After
evaporation of the volatile solvent under reduced pressure, the
residue was purified by flash chromatography on silica gel to afford
pure 7e (48 mg, 0.182 mmol) as a white solid in 91% yield. 1H NMR
(125 MHz, CDCl3)
d 145.0, 139.8, 129.5, 129.5, 129.0, 128.0, 125.3,
123.7, 123.4, 118.1, 112.8, 39.4; HRMS (ESI) calcd for (C14H12BrN2)þ
287.0178, found 287.0187.
4.4.4. Addition of nucleophiles to bromide 6. To a solution of 6
(57.4 mg, 0.2 mmol) in DMSO (2 mL) was added pyrrolidine (71 mg,
1 mmol). The mixture was stirred for 30 h at room temperature.
After 6 was completely consumed as monitored by TLC, K2CO3
(5 mL, 0.5 N) was added to basify the reaction. Then 10 mL EA was
added, the resulted mixture was washed three times with H2O
(10 mLꢁ3). The combined organic layer was dried over Na2SO4.
After evaporation of the volatile solvent under reduced pressure,
the residue was purified by flash chromatography on silica gel to
afford pure 7a (50 mg, 0.180 mmol) as white solid in a yield of 90%.
(500 MHz, CDCl3)
d
8.08 (d, J¼6.8 Hz, 1H), 7.65 (d, J¼9.0 Hz, 1H),
7.55e7.52 (m, 2H), 7.49e7.44 (m, 3H), 7.22 (ddd, J¼9.0, 6.8, 1.1 Hz,
1H), 6.76 (t, J¼6.8 Hz, 1H), 5.22 (s, 2H), 2.07 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d 170.9, 145.0, 138.2, 129.8, 129.3, 128.9, 128.1,
125.1, 124.2, 123.6, 118.0, 112.7, 60.1, 21.0; HRMS (ESI) calcd for
(C16H15N2O2)þ 267.1128, found 267.1136.
Acknowledgements
The generous financial support from the National Natural Sci-
ence Foundation of China (No. 21272150 and No. 21672137) is
acknowledged.
4.4.5. 3-Phenyl-2-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridine
(7a). White solid, 50 mg, 90% yield; 1H NMR (500 MHz, CDCl3)
d
8.04 (d, J¼6.8 Hz, 1H), 7.60 (d, J¼9.0 Hz, 1H), 7.52e7.48 (m, 4H),
7.43e7.40 (m, 1H), 7.15 (ddd, J¼9.0, 6.8, 1.1 Hz, 1H), 6.71 (td, J¼6.8,
Supplementary data
1.1 Hz, 1H), 3.82 (s, 2H), 2.65 (s, 4H), 1.75e1.74 (m, 4H); 13C NMR
Supplementary data (The original spectra of 1H NMR and 13C
NMR of all products are supplied.) related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2016.09.013.
(125 MHz, CDCl3)
d 144.7, 141.0, 130.0, 129.2, 128.9, 128.5, 124.4,
123.4, 123.2, 117.7, 112.2, 53.9, 51.6, 23.5; HRMS (ESI) calcd for
(C18H20N3)þ 278.1652, found 278.1659.
4.4.6. 2-((1H-Imidazol-1-yl)methyl)-3-phenylimidazo[1,2-a]pyridine
(7b).21 Compound 7b was prepared in the same manner as ex-
ample 7a but using imidazole in place of pyrrolidine; white solid,
References and notes
1. For selected reviews, see: (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev.
Med. Chem. 2007, 7, 888; (b) Monti, J. M.; Warren Spence, D.; Pandi-Perumal, S.
R.; Langer, S. Z.; Hardeland, R. Clin. Med. Ther. 2009, 1, 123.
2. For selected reviews, see: (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem.
Commun. 2015, 1555; (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A.
Synthesis 2015, 47, 887; (c) Goel, R.; Luxami, V.; Paul, K. Org. Biomol. Chem. 2015,
13, 3525.
3. For selected recent examples of imidazo[1,2-a]pyridine syntheses from 2-
aminopyridine, see: (a) Shinde, M. H.; Kshirsagar, U. A. Green Chem. 2016,
18, 1455; (b) Huo, C. D.; Tang, J.; Xie, H. S.; Wang, Y. J.; Dong, J. Org. Lett.
2016, 18, 1016; (c) Roslan, I. I.; Ng, K.-H.; Chuah, G.-K.; Jaenicke, S. Adv.
Synth. Catal. 2016, 358, 364; (d) Zhai, L. H.; Guo, L. H.; Sun, B. W. RSC Adv.
2015, 5, 93631; (e) Rassokhina, I. V.; Shirinian, V. Z.; Zavarzin, I. V.; Ge-
vorgyan, V.; Volkova, Y. A. J. Org. Chem. 2015, 80, 11212; (f) Wen, Q. D.; Lu,
P.; Wang, Y. G. Chem. Commun. 2015, 15378; (g) Nguyen, T. B.; Corbin, M.;
Retailleau, P.; Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2015, 17, 4956; (h)
Xiao, X. S.; Xie, Y.; Bai, S. Y.; Deng, Y. F.; Jiang, H. F.; Zeng, W. Org. Lett.
2015, 17, 3998; (i) Zhan, H. Y.; Zhao, L. M.; Liao, J. Q.; Li, N. Y.; Chen, Q. L.;
Qiu, S. X.; Cao, H. Adv. Synth. Catal. 2015, 357, 46; (j) Wang, Y. X.; Frett, B.;
Li, H.-Y. Org. Lett. 2014, 16, 3016; (k) Cao, H.; Liu, X. H.; Zhao, L. M.; Cen, J.
H.; Lin, J. X.; Zhu, Q. X.; Fu, M. L. Org. Lett. 2014, 16, 146; (l) Bagdi, A. K.;
Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355,
1741; (m) Mohan, D. C.; Rao, S. N.; Adimurthy, S. J. Org. Chem. 2013, 78,
48 mg, 88% yield; 1H NMR (500 MHz, CDCl3)
d
8.00 (d, J¼6.8 Hz,1H),
7.61 (d, J¼9.1 Hz, 1H), 7.56e7.48 (m, 4H), 7.34 (d, J¼7.0 Hz, 2H), 7.22
(t, J¼6.8 Hz, 1H), 6.97 (s, 2H), 6.78 (t, J¼6.8 Hz, 1H), 5.20 (s, 2H); 13
C
NMR (125 MHz, CDCl3)
d 145.2, 138.9, 137.4, 130.3, 130.1, 129.8,
129.6, 128.2, 125.8, 124.1, 123.8, 119.7, 118.3, 113.3, 44.6; HRMS (ESI)
calcd for (C17H15N4)þ 275.1291, found 275.1299.
4.4.7. N,N-Dimethyl-1-(3-phenylimidazo[1,2-a]pyridin-2-yl)methan-
amine (7c). Compound 7c was prepared in the same manner as
example 7a but using dimethylamine in place of pyrrolidine; white
solid, 46 mg, 91% yield; 1H NMR (500 MHz, CDCl3)
d 8.04 (d,
J¼6.8 Hz, 1H), 7.69e7.34 (m, 6H), 7.24e7.08 (m, 1H), 6.73 (t,
J¼6.8 Hz, 1H), 3.74 (s, 2H), 2.37 (s, 6H); 13C NMR (125 MHz, CDCl3)
d
144.7, 139.2, 129.9, 129.3, 128.8, 128.5, 124.8, 124.2, 123.5, 117.7,
112.4, 54.9, 44.6; HRMS (ESI) calcd for (C16H18N3)þ 252.1495, found
252.1503.
ꢀ
1266; (n) Stasyuk, A. J.; Banasiewicz, M.; Cyranski, M. K.; Gryko, D. T. J.
4.4.8. N-((3-Phenylimidazo[1,2-a]pyridin-2-yl)methyl)ethanamine
(7d). To a solution of 6 (57.4 mg, 0.2 mmol) in EtOH (2 mL) was
added ethanamine (70% in H2O) (64 mg, 1 mmol). The mixture was
stirred for 24 h at room temperature. After 6 was completely con-
sumed as monitored by TLC, K2CO3 (5 mL, 0.5 N) was added to
basify the reaction mixture. Then 10 mL H2O was added, the
resulting mixture was then extracted with diethyl ether (10 mLꢁ3).
The combined organic layer was dried over Na2SO4. After evapo-
ration of the volatile solvent under reduced pressure, the residue
was purified by flash chromatography on silica gel to afford pure 7d
(46 mg, 0.183 mmol) as a white solid in 92% yield. 1H NMR
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(500 MHz, CDCl3)
d
8.04 (d, J¼6.8 Hz, 1H), 7.62e7.42 (m, 6H),
7.20e7.17 (m, 1H), 6.76 (t, J¼6.8 Hz, 1H), 6.08 (s, 1H), 4.10 (s, 2H),
2.96e2.91 (m, 2H), 1.23 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
144.9, 138.4, 129.9, 129.4, 128.9, 127.9, 125.2, 123.6, 123.4, 117.6,
112.6, 44.3, 44.0, 13.2; HRMS (ESI) calcd for (C16H18N3)þ 252.1495,
found 252.1499.
4.4.9. (3-Phenylimidazo[1,2-a]pyridin-2-yl)methyl acetate (7e). To
a solution of 6 (57.4 mg, 0.2 mmol) in DMF (2 mL) was added NaOAc
(82 mg, 1 mmol). The mixture was stirred for 24 h at room
Please cite this article in press as: Cheng, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.09.013

C. Cheng et al. / Tetrahedron xxx (2016) 1e9
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