Synthesis of imidazo[1,2-a]pyridines by the bis(acetyloxy)(phenyl)- λ3-iodane-Mediated oxidative coupling of 2-aminopyridines with β-keto esters and 1,3-diones

Article abstract of DOI:10.1055/s-0030-1260106

Imidazo[1,2-a]pyridine-3-carboxylates can be prepared directly from 2-aminopyridines and β-keto esters by using bis(acetyloxy)(phenyl)- λ³-iodane as an oxidant and boron trifluoride etherate as a catalyst. The amount of catalyst plays a key rol

Full text of DOI:10.1055/s-0030-1260106

PAPER
2445
Synthesis of Imidazo[1,2-a]pyridines by the Bis(acetyloxy)(phenyl)-l3-iodane-
Mediated Oxidative Coupling of 2-Aminopyridines with b-Keto Esters
and 1,3-Diones
Xianpei Wang, Lijuan Ma, Wei Yu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
E-mail: yuwei@lzu.edu.cn
Received 25 April 2011; revised 23 May 2011
dure, which features the use of N-ethyl-N-methylimidazo-
Abstract: Imidazo[1,2-a]pyridine-3-carboxylates can be prepared
lium tosylate as the reaction medium with iodobenzene
directly from 2-aminopyridines and b-keto esters by using
bis(acetyloxy)(phenyl)-l3-iodane as an oxidant and boron trifluo-
and 4-chloroperbenzoic acid (MCPBA) as the oxidizing
system, has been developed to enable the synthesis to be
ride etherate as a catalyst. The amount of catalyst plays a key role
in determining the course of the reaction. Whereas the use of 0.2 performed in a one-pot manner.9 In an attempt to extend
equivalents of catalyst ensures the generation of imidazo[1,2-a]py-
ridines, raising the amount of catalyst to 1.0 equivalents results in
the synthetic utility of hypervalent iodine(III) reagents in
the synthesis of imidazo[1,2-a]pyridines, we hypothe-
exclusive a-acetoxylation of the b-keto esters. 2-Aminopyridines
sized that imidazo[1,2-a]pyridine-3-carboxylates 3 might
can also react with 1,3-diones to afford 3-acylimidazo[1,2-a]py-
be obtained from 2-aminopyridines and b-keto esters
ridines.
through a PIDA-mediated direct oxidative coupling
Key words: heterocycles, polycycles, cyclization, oxidation, cou-
(Scheme 1).10 Compounds 3 have been previously synthe-
pling
sized from 2-aminopyridines and a-bromo b-keto esters,
but the yields were not high.11 We hoped that our protocol
would not only help simplify the synthesis of imida-
Imidazo[1,2-a]pyridine is an important ring system that
zo[1,2-a]pyridine-3-carboxylates, but would also im-
forms the core structure of many pharmacologically im-
prove their yields.
portant compounds.1,2 Unsurprisingly, many efforts have
been made to gain access to imidazo[1,2-a]pyridine rings
with a range of substituents, and several approaches that
To achieve this goal, pyridin-2-amine (1a) and ethyl 2-
benzoylacetate (2a) were used as substrates, and the reac-
tion was performed by stirring a mixture of one equivalent
employ various strategies and precursors are now avail-
able.1,2 The condensation of 2-aminopyridines with a-ha-
each of 1a, 2a, and PIDA in dichloromethane at room
temperature (7 °C) for several hours. However, no reac-
locarbonyl compounds provides a conventional but
simple method.3 Recent studies have demonstrated that
the synthesis can also be achieved by a three-component
reaction.2,4 Although the latter strategy is attractive in
terms of its efficiency, the reaction of 2-aminopyridines
with a-halocarbonyl compounds offers a practical syn-
thetic route and is the method most frequently used in me-
dicinal chemistry.5
tion occurred. To effect the reaction, 1 equivalent of boron
trifluoride etherate (BF3·Et2O) was added to the mixture.
One hour later, the formation of a product was indicated
by thin-layer chromatography; this product was identified
as the keto ester 4a (Table 1, entry 2). This result was not
unexpected, as Lewis acids can catalyze the a-acetoxyla-
tion of carbonyl compounds.7a We speculated that the un-
wanted reaction might be restrained by reducing the
amount of BF3·Et2O. In our previous studies on the appli-
cations of hypervalent iodine in heterocycle synthesis,12
we found that a catalytic amount of BF3·Et2O was capable
of promoting hypervalent iodine-mediated coupling reac-
tions. We therefore adjusted the amount of BF3·Et2O in
the reaction system to examine whether the course of the
reaction could be changed (entries 2–6). To our delight,
when 0.2 equivalents of BF3·Et2O were used, the desired
ethyl 2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3a)
was obtained as the major product in 80% yield (entry 3).
The reaction was complete in one hour. The use of 0.5
equivalents or more of BF3·Et2O reduced the yield of 3a
and resulted in the formation of 4a (entries 5 and 6).
Hypervalent iodine(III) reagents such as bis(acetyl-
oxy)(phenyl)-l3-iodane (DIB or PIDA), bis(trifluoro-
acetyloxy)(phenyl)-l3-iodane (BTI or PIFA), and
hydroxy(phenyl)(tosyloxy)-l3-iodane (HTIB, Koser’s re-
agent) are very useful oxidants in organic synthesis.6 One
synthetic application of hypervalent iodine(III) reagents is
in effecting the a-functionalization of carbonyl groups. As
such, a-acetoxylation and a-tosylation of ketones have
been realized by using PIDA or HTIB, respectively, as the
oxidant.7 A reagent combination of iodosylbenzene and 4-
toluenesulfonic acid oxidizes alcohols to the correspond-
ing a-tosyloxy ketones. The products react with 2-ami-
nopyridines to afford imidazo[1,2-a]pyridines in
moderate-to-good yields.8 A modification of this proce-
The yield of 3a was also influenced by the reaction tem-
perature. When the reaction was performed at 25 °C, the
yield of 3a was reduced to 45% (entry 4).
SYNTHESIS 2011, No. 15, pp 2445–2453
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260106; Art ID: F43811SS
© Georg Thieme Verlag Stuttgart · New York

2446
X. Wang et al.
PAPER
1
N
NH2
OR2
O
O
O
O
O
O
PhI(OAc)2
R1
OR2
R1
AcO
R1
OR2
H2N
N
I
2
Ph
path a
N
R1
or
N
O
R2O
N
path b
NH2
N
N
H
3
1
HN
R1
PhI(OAc)2
OAc
HN
O
+
I
O
O
R1
OR2
Ph
CO2R2
OR2
R1
2
Scheme 1
Compound 4a could not react with 1a to generate 3a un-
der these conditions. This result is consistent with our ini-
tial hypothesis about the reaction process (Scheme 1), and
is different from that reported by Togo and co-workers.8
In their synthesis of imidazo[1,2-a]pyridines from ace-
tophenones and 2-aminopyridines, acetophenones were
initially converted into their a-tosylated counterparts by
the action of iodosylbenzene and 4-toluenesulfonic acid.
As a matter of fact, when ethyl 2-{[(4-methylphenyl)sul-
fonyl]oxy}-3-oxo-3-phenylpropanoate (4a¢) was treated
with 1a under the reported conditions,8 3a was not ob-
tained, and most of the starting materials decomposed.
Furthermore, a one-pot operation involving refluxing of a
mixture of 1a, 2a, iodosylbenzene, and 4-toluenesulfonic
acid in tetrahydrofuran failed to effect a reaction
(Scheme 2).
Table 1 Screening of the Reaction Conditions
N
Ph
O
N
N
O
NH2
EtO
3a
+
PhI(OAc)2
1a
BF3⋅Et2O
+
solvent
O
O
O
OEt
Ph
OEt
Ph
2a
OAc
4a
Entrya
Solvent
BF3·Et2O
(equiv)
Yield (%) Yield (%)
of 3ab
of 4ab
c
c
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
EtOH
0
–
–
1.0
0.2
0.2
0.5
1.5
0.2
0.2
0.2
0.2
0.2
0
80
45d
52
0
45
0
O
O
3
PhIO, TsOH
THF
1a, K2CO3
3a
2a
OEt
Ph
4
0d
21
75
0
MeCN
OTs
4a'
5
85%
TsOH
THF, reflux, 6 h
6
+
+
1a
2a
PhIO
no reaction
7
39
32
86
47
37
Scheme 2
8
0
9
THF
0
To gain more insight into the reaction mechanism, a con-
trol experiment was conducted by stirring a mixture of 1a,
2a, and BF3·Et2O in tetrahydrofuran in the absence of
PIDA. No reaction product was found after one day, and
no reaction occurred at an elevated temperature. This
showed that path b shown in Scheme 1 is unlikely to ac-
count for the formation of 3a. We therefore assumed that
the reaction probably proceeds by the mechanism shown
in path a.
10
11
toluene
MeCN
28
19
a 1a (1 mmol), 2a (1 mmol), PIDA (1 mmol), and BF3·Et2O in solvent
(5 mL). The temperature was 7 °C unless otherwise specified.
b Isolated yield.
c No reaction occurred.
d At 25 °C.
Synthesis 2011, No. 15, 2445–2453 © Thieme Stuttgart · New York

PAPER
Imidazo[1,2-a]pyridines
2447
It is interesting to note that whereas the PIDA-mediated Having determined the optimal reaction conditions
reaction of 1a and 2a is promoted by a catalytic amount of (Table 1, entry 8), we next examined the scope of the re-
BF3·Et2O, the use of 1.0 equiv. of BF3·Et2O prevents the action. As summarized in Table 2, a variety of substituted
reaction occurring. Acids have been frequently used to fa- imidazo[1,2-a]pyridine-3-carboxylates 3 could be pre-
cilitate reactions involving PIDA by enhancing its electro- pared by our new protocol. The results were generally
philic capacity and by promoting the elimination of good for 2-aryl substituted products. The reaction could
iodobenzene and acetic acid.6 The finding that the amount be carried out on a gram scale without an apparent de-
of acid determined the course of the reaction is an excep- crease in yield. Compared with the previously reported
tion to this general rule, and might be explained by the fact synthesis of 2-aryl imidazo[1,2-a]pyridine-3-carboxy-
that pyridin-2-amine (1a) is a base that can interact with lates from 2-aminopyridines and 2-benzoyl-2-bromoace-
the BF3·Et2O and the acetic acid generated during the re- tates,11 our new method not only eliminated the need for
action. The use of too much BF3·Et2O hampers the func- previous halogenation of the b-keto esters, but also gave
tion of 1a as a nucleophile, and this leads to the formation better yields. The method was also effective for the syn-
of 4a. The later process is disfavored compared with path thesis of 2-alkylimidazo[1,2-a]pyridine-3-carboxylates,
a in Scheme 1 when only 0.2 equivalents of BF3·Et2O are albeit in lower yields. In the case of 3s and 3t, the reaction
used.
proceeded poorly in tetrahydrofuran, but when refluxing
toluene was used as the solvent, complete conversion oc-
curred and the products were obtained in yields of 46%
and 66%, respectively (Table 2, entries 19 and 20).
The reaction was also performed with tetrahydrofuran,
methanol, methanol, acetonitrile, or toluene as a solvent
(Table 1 entries 6–10). Of these solvents, tetrahydrofuran
showed the best performance, giving 3a in a yield of 86%
(Table 1, entry 8). The results with the other solvents were
less satisfactory.
Table 2 Synthesis of Imidazo[1,2-a]pyridine-3-carboxylates
PhI(OAc)2 (1.0 equiv)
N
O
O
BF3⋅Et2O ( 0.2 equiv)
R1
+
R1
R2
N
OR3
R2
THF
N
NH2
1
2
O
R3O
3
Entrya
1
Time
2 h
Product
Yield (%)b
Entry
11
Time
Product
Yield (%)b
63
N
N
Ph
n-Pr
N
N
86
85
75
89
60
overnight
CO2Et
CO2Et
3k
3a
N
N
Ph
Ph
n-Pr
N
N
2
3
4
5
2 h
2 h
2 h
2 h
12
13
14
15
overnight
overnight
overnight
overnight
57
57
72
58
N
CO2Et
CO2Et
3b
3c
3l
N
N
n-Pr
N
N
Cl
CO2Et
CO2Et
3m
Cl
N
N
n-Pr
CO2Et
Ph
N
CO2Et
3n
3d
N
N
N
Ph
N
Cl
CO2Et
CO2Me
3o
3e
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2448
X. Wang et al.
PAPER
Table 2 Synthesis of Imidazo[1,2-a]pyridine-3-carboxylates (continued)
PhI(OAc)2 (1.0 equiv)
N
O
O
BF3⋅Et2O ( 0.2 equiv)
R1
+
R1
R2
N
OR3
R2
THF
N
NH2
1
2
O
R3O
3
Entrya
6
Time
2 h
Product
Yield (%)b
Entry
16
Time
Product
Yield (%)b
51
Cl
N
N
Ph
N
N
87
82
overnight
CO2Me
CO2Et
3p
3q
3f
N
N
4-ClC6H4
N
N
N
7
8
2 h
2 h
17
18
overnight
overnight
52
30
CO2Me
CO2Me
3g
3h
N
4-EtC6H4
N
83
N
CO2Et
CO2Me
3r
N
N
N
n-Pr
24 hc
24 hc
46
66
N
9
overnight
overnight
71
67
19
20
Cl
CO2Et
CO2Me
3s
3j
Cl
N
N
n-Pr
N
N
10
CO2Et
CO2Me
3j
3t
a The reaction was carried out in THF at 7 °C unless otherwise specified; 2 (1.2 equiv) and PIDA (1.2 equiv) were used for the synthesis of 3o–t.
b Isolated yield.
c The reaction was carried out in refluxing toluene.
Compounds 3 are useful intermediates for the synthesis of Compounds 5 are also useful in the synthesis of some an-
pharmaceutically important compounds. Reduction of tiviral agents.16
compounds 3 give the corresponding (imidazo[1,2-a]py-
The protocol could be extended to the reactions of 2-ami-
ridin-3-yl)methanols (5),13 which can be used as precur-
nopyridines with 1,3-diones such as 7 to give the corres-
sors for the synthesis of the N-methylcarboxamides 6
ponding 3-acylimidazo[1,2-a]pyridines 8 (Scheme 5).5a,17
(Scheme 3).14
When asymmetric 1,3-diones were used as the substrates,
the products were obtained as the mixture of two imida-
Carboxylates 3 can also be reduced by means of a recently
reported procedure using sodium borohydride.15 Thus, 3g
zo[1,2-a]pyridine isomers. For example, 1-phenylbutane-
and 3h were reduced to 5g and 5h, respectively, which can
1,3-dione (9) reacted with 2-aminopyridines 1 to afford
be converted into the anxiolytic drugs saripidem and
products 10 and 11, with the 2-methyl isomer 10 as the
major product (Scheme 6).
necopidem, respectively, in two more steps (Scheme 4).14
N
N
R1
R1
N
N
N
R2
NaH, MeI
R2
R1
1) R3CN, H2SO4
2) H2O
N
R2
HN
Me
N
OH
R3
R3
5
O
O
6
Scheme 3
Synthesis 2011, No. 15, 2445–2453 © Thieme Stuttgart · New York

PAPER
Imidazo[1,2-a]pyridines
2449
N
Cl
NaBH4
MeOH
N
N
N
Ref. 14
Cl
Cl
N
THF, reflux
84%
N
Me
N
CO2Me
i-Bu
OH
O
saripidem
3g
5g
N
Et
N
NaBH4
N
N
MeOH
THF, reflux
80%
Ref. 14
Et
Et
N
N
Me
N
CO2Et
3h
OH
n-Pr
necopidem
O
5h
Scheme 4
R
N
NH2
N
NH2
N
PhI(OAc)2 (1.2 equiv)
BF3⋅Et2O (0.2 equiv)
N
1 (1.0 equiv)
PhI(OAc)2 (1.2 equiv)
1a (1.0 equiv)
BF3⋅Et2O (0.2 equiv)
Ph
R
+
N
N
+
THF, 7 °C
O
O
O
COMe
CN
CN
Ph
12a
25%
8
7 (1.2 equiv)
(1.2 equiv)
Scheme 7
N
N
N
N
N
N
diones. The method is advantageous in terms of its high
efficiency and mild reaction conditions. We expect that
this new protocol will find synthetic applications in me-
dicinal chemistry.
COMe
COMe
COMe
8a (64%)
8b (63%)
8c (63%)
Cl
N
N
N
N
N
N
The 1H and 13C NMR spectra were recorded on a Bruker AM 400-
MHz spectrometer with TMS as the internal standard in CDCl3 or
DMSO-d6. The EI-MS spectra were recorded on an HP 5988A spec-
trometer by direct introduction at 70 eV. The high-resolution mass
spectra were recorded on a Bruker Daltonics APEX II 47e spec-
trometer. Melting points were measured on an XT-4 melting point
apparatus and are uncorrected.
Cl
COMe
COMe
8e (51%)
COMe
8f (63%)a
8d (63%)
Scheme 5 The reactions were performed in THF at 7 °C unless
otherwise specified. aThe reaction was performed in toluene at reflu-
xing temperature.
2-Substituted Imidazo[1,2-a]pyridine-3-carboxylates (3); Gen-
eral Procedure
On the other hand, PIDA was not as effective in promot-
ing the coupling/condensation of 1a with benzoylacetoni-
trile. The expected imidazo[1,2-a]pyridine product 12a
was obtained in only 25% yield (Scheme 7).
Keto ester 2 (1.0 mmol), PhI(OAc)2 (0.322 g, 1.0 mmol), and
BF3·Et2O (26 mL) were added successively to a 10-mL round-
bottomed flask containing THF (5 mL) and 2-aminopyridine 1 (1.0
mmol), and the mixture was stirred at 7 °C until the reaction was
complete (TLC). The mixture was then poured into sat. aq NaHCO3
(15 mL) and extracted with EtOAc (10 × 3 mL). The combined or-
ganic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
In summary, we have developed a new method for the
synthesis of imidazo[1,2-a]pyridines by bis(acetyl-
oxy)(phenyl)-l3-iodane-mediated direct oxidative cou-
pling of pyridine-2-amines and b-keto esters or 1,3-
R
R
R
PhI(OAc)2 (1.2 equiv)
N
N
O
O
BF3⋅Et2O (0.2 equiv)
Ph
+
+
N
N
THF, 7 °C
Ph
9 (1.2 equiv)
N
NH2
COPh
COMe
1 (1.0 equiv)
10
11
10a (48%)
10c (47%)
11a (26%)
11c (20%)
R = H
R = Me
Scheme 6
Synthesis 2011, No. 15, 2445–2453 © Thieme Stuttgart · New York

2450
X. Wang et al.
PAPER
chromatography (silica gel). For the synthesis of 3o–3t, 1.2 equiv
each of 2 and PIDA were used. The synthesis of compounds 3s and
3t was performed in refluxing toluene for 24 h.
13C NMR (CDCl3, 100 MHz): d = 51.2, 111.6, 114.2, 117.4, 127.8,
128.1, 128.3, 131.3, 132.8, 134.7, 147.1, 152.3, 161.1.
EI-MS: m/z (%) = 288 (37), 286 (100) [M+], 273 (17), 271 (60), 242
(18), 240 (42), 230 (23), 228 (73), 149 (59).
HRMS (ESI): [M + H]+ calcd for C15H12ClN2O2 : 287.0582; found:
287.0579.
Ethyl 7-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(3c)11b
White solid; mp 90–91 °C.
1H NMR (CDCl3, 400 MHz): d = 1.21 (t, 3 H, J = 7.2 Hz), 2.46 (s,
3 H), 4.29 (q, 2 H, J = 7.2 Hz), 6.86 (dd, 1 H, J = 6.8 Hz, J = 1.6
Hz), 7.40–7.44 (m, 3 H), 7.48 (s, 1 H), 7.75–7.77 (m, 2 H), 9.27 (d,
1 H, J = 6.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 13.9, 21.3, 60.2, 111.4, 116.0,
116.5, 127.3, 127.4, 128.5, 130.1, 134.5, 139.2, 147.5, 153.6, 161.1.
Ethyl 2-(4-Ethylphenyl)-6-methylimidazo[1,2-a]pyridine-3-
carboxylate (3h)
White solid; mp 60–62 °C.
1H NMR (CDCl3, 400 MHz): d = 1.24 (t, 3 H, J = 7.2 Hz), 1.27 (t,
3 H, J = 7.6 Hz), 2.41 (s, 3 H), 2.71 (q, 2 H, J = 7.6 Hz), 4.31 (q, 2
H, J = 7.2 Hz), 7.26 (d, 3 H, J = 8.4 Hz), 7.62 (d, 1 H, J = 8.8 Hz),
7.70 (d, 2 H, J = 8.0 Hz), 9.22 (s, 1 H).
EI-MS: m/z (%) = 280 (54) [M+], 208 (100).
HRMS (ESI): [M + H]+ calcd for C17H17N2O2: 281.1285; found:
281.1282.
13C NMR (CDCl3, 100 MHz): d = 14.0, 15.5, 18.4, 28.7, 60.2, 111.4,
116.6, 123.7, 126.2, 127.0, 130.1, 130.7, 131.8, 144.7, 146.1, 153.5,
161.3.
Ethyl 8-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
EI-MS: m/z (%) = 308 (71) [M+], 236 (100), 221 (47).
HRMS (ESI): [M + H]+ calcd for C19H21N2O2: 309.1598; found:
309.1591.
(3d)11b
White solid; mp 113–114 °C.
1H NMR (CDCl3, 400 MHz): d = 1.19 (t, 3 H, J = 7.2 Hz), 2.68 (s,
3 H), 4.28 (q, 2 H, J = 7.2 Hz), 6.94 (t, 1 H, J = 7.0 Hz), 7.22 (dd, 1
H, J = 6.8 Hz, J = 1.2 Hz) 7.40–7.45 (m, 3 H), 7.74–7.76 (m, 2 H),
9.27 (d, 1 H, J = 6.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 13.9, 17.1, 60.3, 112.3, 114.0,
126.0, 126.7, 127.4, 127.5, 128.4, 130.2, 134.9, 147.3, 153.2, 161.2.
Ethyl 2-Propylimidazo[1,2-a]pyridine-3-carboxylate (3i)
White solid; mp 24–26 °C.
1H NMR (CDCl3, 400 MHz): d = 1.00 (t, 3 H, J = 7.2 Hz), 1.42 (t,
3 H, J = 7.0 Hz), 1.75–1.84 (m, 2 H), 3.06 (t, 2 H, J = 7.6 Hz), 4.41
(q, 2 H, J = 7.2 Hz), 6.95 (t, 1 H, J = 6.8 Hz), 7.35 (t, 1 H, J = 8.4
Hz), 7.62 (d, 1 H, J = 9.2 Hz), 9.31 (d, 1 H, J = 7.2 Hz).
EI-MS: m/z (%) = 280 (53) [M+], 208 (100).
HRMS (ESI): [M + H]+ calcd for C17H17N2O2: 281.1285; found:
281.1286.
13C NMR (CDCl3, 100 MHz): d = 14.1, 14.3, 22.9, 32.2, 60.2, 112.2,
113.5, 116.8, 127.4, 128.0, 146.9, 156.9, 161.4.
EI-MS: m/z (%) = 232 (21) [M+], 204 (67), 132 (100), 78 (20).
HRMS (ESI): [M + H]+ calcd for C13H17N2O2 : 233.1285; found:
233.1280.
Ethyl 6-Chloro-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(3e)11b
White solid; mp 117–119 °C.
1H NMR (CDCl3, 400 MHz): d = 1.23 (t, 3 H, J = 7.2 Hz), 4.32 (q,
2 H, J = 7.2 Hz), 7.40–7.46 (m, 4 H), 7.68 (d, 1 H, J = 9.2 Hz),
7.74–7.76 (m, 2 H), 9.52 (d, 1 H, J = 1.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 13.9, 60.7, 112.3, 117.7, 122.4,
126.3, 127.6, 128.9, 129.2, 130.1, 134.0, 145.3, 154.0, 160.9.
EI-MS: m/z (%) = 302 (17), 300 (54) [M+], 230 (28), 228 (100), 174
(42), 159 (66), 149 (36).
Ethyl 6-Methyl-2-propylimidazo[1,2-a]pyridine-3-carboxylate
(3j)
Pale yellow solid; mp 31–33 °C.
1H NMR (CDCl3, 400 MHz): d = 1.01 (t, 3 H, J = 7.2 Hz), 1.44 (t,
3 H, J = 7.0 Hz), 1.74–1.84 (m, 2 H), 2.38 (s, 3 H), 3.05 (t, 2 H,
J = 7.6 Hz), 4.42 (q, 2 H, J = 7.2 Hz), 7.23 (dd, 1 H, J = 9.2 Hz,
J = 1.6 Hz), 7.54 (d, 1 H, J = 9.2 Hz), 9.15 (s, 1 H).
13C NMR (CDCl3, 100 MHz): d = 14.1, 14.4, 18.4, 22.9, 32.2, 60.1,
Ethyl 7-Chloro-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(3f)
White solid; mp 116–118 °C.
111.9, 116.0, 123.4, 126.0, 130.4, 145.9, 156.6, 161.5.
EI-MS: m/z (%) = 246 (20) [M+], 218 (61), 146 (100), 92 (14).
HRMS (ESI): [M + H]+ calcd for C14H19N2O2: 247.1441; found:
247.1449.
1H NMR (CDCl3, 400 MHz): d = 1.22 (t, 3 H, J = 7.2 Hz), 4.31 (q,
2 H, J = 7.2 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 7.43–7.47 (m, 3 H),
7.72–7.76 (m, 3 H), 9.36 (d, 1 H, J = 7.6 Hz).
13C NMR (CDCl3, 100 MHz): d = 13.9, 60.6, 112.0, 115.5, 116.4,
127.6, 128.6, 128.9, 130.1, 133.9, 134.5, 146.9, 154.2, 160.8.
EI-MS: m/z (%) = 302 (20), 300 (50) [M+], 230 (32), 228 (100), 149
(42), 57 (35).
HRMS (ESI): [M + H]+ calcd for C16H14ClN2O2: 301.0738; found:
301.0736.
Ethyl 7-Methyl-2-propylimidazo[1,2-a]pyridine-3-carboxylate
(3k)
White solid; mp 52–54 °C.
1H NMR (CDCl3, 400 MHz): d = 0.94 (t, 3 H, J = 7.2 Hz), 1.36 (t,
3 H, J = 7.0 Hz), 1.68–1.77 (m, 2 H), 2.34 (s, 3 H), 2.98 (t, 2 H,
J = 7.8 Hz), 4.42 (q, 2 H, J = 7.2 Hz), 6.70 (d, 1 H, J = 7.2 Hz), 7.30
(s, 1 H), 9.09 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 14.0, 14.2, 21.1, 22.8, 32.0, 59.9,
Methyl 2-(4-Chlorophenyl)imidazo[1,2-a]pyridine-3-carboxy-
late (3g)
White solid; mp 130–132 °C.
111.6, 115.3, 115.8, 127.0, 138.6, 147.2, 156.8, 161.2.
EI-MS: m/z (%) = 246 (21) [M+], 218 (61), 146 (100), 92 (16).
HRMS (ESI): [M + H]+ calcd for C14H19N2O2: 247.1441; found:
247.1436.
1H NMR (CDCl3, 400 MHz): d = 3.81 (s, 3 H), 7.02 (dt, 1 H, J = 6.8
Hz, J = 1.2 Hz), 7.39–7.44 (m, 3 H), 7.70 (d, 3 H, J = 8.4 Hz), 9.37
(dd, 1 H, J = 6.8 Hz, J = 1.2 Hz).
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Imidazo[1,2-a]pyridines
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Ethyl 6-Chloro-2-propylimidazo[1,2-a]pyridine-3-carboxylate
(3m)
EI-MS: m/z (%) = 204 (100) [M+], 173 (71), 146 (76), 145 (33), 104
(13).
Orange solid; mp 91–93 °C.
HRMS (ESI): [M + H]+ calcd for C11H13N2O2: 205.0972; found:
205.0979.
1H NMR (CDCl3, 400 MHz): d = 1.00 (t, 3 H, J = 7.2 Hz), 1.44 (t,
3 H, J = 7.2 Hz), 1.76–1.81 (m, 2 H), 3.05 (t, 2 H, J = 7.8 Hz), 4.43
(q, 2 H, J = 7.2 Hz), 7.33 (dd, 1 H, J = 9.2 Hz, J = 2.0 Hz), 7.56 (dd,
1 H, J = 9.2 Hz, J = 2.4 Hz), 9.41 (d, 1 H, J = 2.0 Hz).
Methyl 2,8-dimethylimidazo[1,2-a]pyridine-3-carboxylate (3r)
White solid; mp 99–100 °C.
13C NMR (CDCl3, 100 MHz): d = 14.1, 14.3, 22.8, 32.1, 60.5, 112.7,
1H NMR (CDCl3, 400 MHz): d = 2.62 (s, 3 H), 2.72 (s, 3 H), 3.95
(s, 3 H), 6.87 (t, 1 H, J = 7.0 Hz), 7.16 (d, 1 H, J = 6.8 Hz), 9.15 (d,
1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 16.5, 17.0, 51.2, 112.8, 113.6,
125.7, 126.4, 126.8, 147.0, 152.1, 161.9.
117.0, 121.8, 126.0, 128.7, 145.2, 157.3, 161.2.
EI-MS: m/z (%) = 268 (6), 266 (17) [M+], 240 (21), 238 (72), 168
(32), 166 (100).
HRMS (ESI): [M + H]+ calcd for C13H16ClN2O2: 267.0895; found:
267.0900.
EI-MS: m/z (%) = 204 (100) [M+], 173 (65), 146 (65), 145 (20).
HRMS (ESI): [M + H]+ calcd for C11H13N2O2: 205.0972; found:
205.0976.
Ethyl 7-Chloro-2-propylimidazo[1,2-a]pyridine-3-carboxylate
(3n)
White solid; mp 61–63 °C.
Methyl 6-Chloro-2-methylimidazo[1,2-a]pyridine-3-carboxy-
late (3s)
Khaki solid; mp 99–101 °C.
1H NMR (CDCl3, 400 MHz): d = 2.67 (s, 3 H), 3.95 (s, 3 H), 7.32
(dd, 1 H, J = 9.2 Hz, J = 2.0 Hz), 7.51 (d, 1 H, J = 9.2 Hz), 9.33 (d,
1 H, J = 1.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 16.5, 51.4, 112.9, 116.8, 121.9,
125.9, 128.8, 145.1, 153.2, 161.4.
1H NMR (CDCl3, 400 MHz): d = 1.00 (t, 3 H, J = 7.2 Hz), 1.43 (t,
3 H, J = 7.0 Hz), 1.73–1.82 (m, 2 H), 3.04 (t, 2 H, J = 7.8 Hz), 4.41
(q, 2 H, J = 7.2 Hz), 6.94 (dd, 1 H, J = 7.2 Hz, J = 2.0 Hz), 7.60 (d,
1 H, J = 2.0 Hz), 9.25 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 14.1, 14.3, 22.8, 32.1, 60.4, 112.4,
114.9, 115.8, 128.2, 134.1, 146.8, 157.6, 161.2.
EI-MS: m/z (%) = 268 (6), 266 (19) [M+], 240 (22), 238 (69),
168(33), 166 (100).
HRMS (ESI): [M + H]+ calcd for C13H16ClN2O2: 267.0895; found:
267.0893.
EI-MS: m/z (%) = 226 (31), 224 (100) [M+], 195 (30), 193 (91), 168
(23), 166 (71), 165 (20), 124 (28).
HRMS (ESI): [M + H]+ calcd for C10H10ClN2O2: 225.0425; found:
225.0433.
Methyl 2-Methylimidazo[1,2-a]pyridine-3-carboxylate (3o)
Pale yellow solid; mp 103–105 °C.
Methyl 7-Chloro-2-methylimidazo[1,2-a]pyridine-3-carboxy-
late (3t)
White solid; mp 141–143 °C.
1H NMR (CDCl3, 400 MHz): d = 2.69 (s, 3 H), 3.96 (s, 3 H,), 6.96
(dd, 1 H, J = 7.6 Hz, J = 2.0 Hz), 7.59 (d, 1 H, J = 2.0 Hz), 9.23 (d,
1 H, J = 7.6 Hz).
1H NMR (CDCl3, 400 MHz): d = 2.72 (s, 3 H), 3.97 (s, 3 H), 6.99
(t, 1 H, J = 6.8 Hz), 7.39 (t, 1 H, J = 7.2 Hz), 7.63 (d, 1 H, J = 9.2
Hz), 9.31 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 16.5, 51.3, 112.4, 113.7, 116.6,
127.7, 127.9, 146.9, 152.8, 161.8.
EI-MS: m/z (%) = 190 (100) [M+], 159 (83), 132 (68), 131 (24), 90
(28).
13C NMR (CDCl3, 100 MHz): d = 16.5, 51.5, 112.7, 115.1, 115.7,
128.1, 134.3, 146.8, 153.6, 161.6.
HRMS (ESI): [M + H]+ calcd for C10H11N2O2: 191.0815; found:
191.0817.
EI-MS: m/z (%) = 226 (13), 224 (100) [M+], 195 (27), 193 (80), 168
(25), 166 (77), 165 (29), 124 (25).
HRMS (ESI): [M + H]+ calcd for C10H10ClN2O2: 225.0425; found:
225.0422.
Methyl 2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylate (3p)
Pale yellow solid; mp 47–49 °C.
1H NMR (CDCl3, 400 MHz): d = 2.37 (s, 3 H), 2.67 (s, 3 H), 3.94
(s, 3 H), 7.21 (d, 1 H, J = 8.8 Hz), 7.49 (d, 1 H, J = 8.8 Hz), 9.09 (s,
1 H).
13C NMR (CDCl3, 100 MHz): d = 16.6, 18.3, 51.2, 112.1, 115.8,
123.4, 125.9, 130.5, 145.9, 152.6, 161.9.
EI-MS: m/z (%) = 204 (100) [M+], 173 (73), 146 (68), 145 (21), 104
(13).
HRMS (ESI): [M + H]+ calcd for C11H13N2O2: 205.0972; found:
205.0974.
2-Aryl-3-methoxymethylimidazo[1,2-a]pyridine; General
Procedure15
Finely powdered NaBH4 (96%, 0.74 g, 0.019 mol, 5.8 equiv) was
stirred in refluxing THF containing carboxylate 3g (0.92 g, 3.2
mmol) or 3h (0.99 g, 3.2 mmol) for 15 min. MeOH (6 mL) was then
added dropwise over 15 min, and the mixture was stirred and re-
fluxed for 1 h. At the end of reaction (TLC), the mixture was cooled
to rt and the reaction was quenched with sat. aq NH4Cl (10 mL) for
a further 1.5 h. The organic layer was then separated and the aque-
ous phase was extracted with EtOAc (70 × 3 mL). The combined or-
ganic extracts were dried (Na2SO4), and concentrated under reduced
pressure. The product was further purified by column chromatogra-
phy [silica gel, EtOAc–MeOH (10:1 to pure MeOH)]. Yield for 5h:
0.68 g, 80%.
Methyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate (3q)
White solid; mp 36–38 °C.
1H NMR (CDCl3, 400 MHz): d = 2.40 (s, 3 H), 2.65 (s, 3 H), 3.92
(s, 3 H), 6.77 (dd, 1 H, J = 6.8 Hz, J = 1.2 Hz), 7.32 (s, 1 H), 9.11
(d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 16.5, 21.3, 51.1, 111.9, 115.3,
116.0, 127.0, 139.0, 147.3, 152.9, 161.8.
[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methanol (5g)
White solid; yield: 0.69 g (84%); mp 204–206 °C.
1H NMR (DMSO, 400 MHz): d = 4.91 (d, 2 H, J = 5.2 Hz), 5.46 (t,
1 H, J = 5.2 Hz), 6.99 (dt, 1 H, J = 6.8 Hz, J = 1.2 Hz), 7.32 (ddd, 1
H, J = 9.2 Hz, J = 6.8 Hz, J = 1.2 Hz), 7.55 (dd, 2 H, J = 6.8 Hz,
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X. Wang et al.
PAPER
J = 2.0 Hz), 7.62 (d, 1 H, J = 9.2 Hz), 7.87 (dd, 2 H, J = 6.8 Hz,
J = 2.0 Hz), 8.46 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 18.3, 21.4, 30.0, 115.1, 116.8,
121.5, 128.2, 140.6, 147.2, 152.9, 187.2.
13C NMR (DMSO, 100 MHz): d = 52.0, 112.2, 116.7, 120.8, 125.2,
EI-MS: m/z (%) = 188 (67) [M+], 173 (100), 145 (17).
HRMS (ESI): [M + H]+ calcd for C11H13N2O: 189.1022; found:
189.1026.
128.6, 129.7, 132.4, 133.3, 141.6, 144.0.
EI-MS: m/z (%) = 260 (15), 258 (49) [M+], 243 (33), 242 (40), 241
(100), 206 (35), 205 (35), 57 (37), 44 (40).
1-(2,8-Dimethylimidazo[1,2-a]pyridin-3-yl)ethanone (8d)
White solid; mp 156–157 °C.
1H NMR (CDCl3, 400 MHz): d = 2.60 (s, 3 H), 2.62 (s, 3 H), 2.79
(s, 3 H), 6.90 (t, 1 H, J = 7.2 Hz), 7.23 (d, 1 H, J = 7.2 Hz), 9.58 (d,
1 H, J = 6.8 Hz).
HRMS (ESI): [M + H]+ calcd for C14H12ClN2O1: 259.0633; found:
259.0635.
[2-(4-Ethylphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]meth-
anol (5h)14
White solid; yield: 0.69 g (84%); mp 195–197 °C.
13C NMR (CDCl3, 100 MHz): d = 16.9, 18.4, 30.3, 114.4, 122.1,
1H NMR (DMSO, 400 MHz): d = 1.22 (t, 3 H, J = 7.6 Hz), 2.33 (s,
3 H), 2.65 (q, 2 H, J = 7.6 Hz), 4.88 (d, 2 H, J = 5.2 Hz), 5.38 (t, 1
H, J = 5.2 Hz), 7.14 (dd, 1 H, J = 9.2 Hz, J = 1.2 Hz), 7.31 (d, 2 H,
J = 8.0 Hz), 7.51 (d, 1 H, J = 9.2 Hz), 7.74 (d, 2 H, J = 8.4 Hz), 8.25
(s, 1 H).
126.1, 126.8, 128.1, 146.9, 152.1, 187.6.
EI-MS: m/z (%) = 188 (63) [M+], 173 (100), 104 (13).
HRMS (ESI): [M + H]+ calcd for C11H13N2O: 189.1022; found:
189.1024.
13C NMR (DMSO, 100 MHz): d = 15.6, 17.8, 27.9, 52.2, 116.0,
1-(6-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)ethanone
120.0, 121.0, 122.5, 127.7, 127.9, 128.1, 132.0, 142.8, 143.0, 143.1.
(8e)17c
EI-MS: m/z (%) = 266 (11) [M+], 149 (64), 57 (61), 44 (100).
White solid; mp 169–170 °C.
HRMS (ESI): [M + H]+ calcd for C17H19N2O1: 267.1492; found:
267.1494.
1H NMR (CDCl3, 400 MHz): d = 2.60 (s, 3 H), 2.76 (s, 3 H), 7.39
(dd, 1 H, J = 9.6 Hz, J = 2.0 Hz), 7.53 (d, 1 H, J = 9.6 Hz), 9.78 (d,
1 H, J = 1.6 Hz).
3-Acylimidazo[1,2-a]pyridines 8, 10, and 11; General Proce-
dure
13C NMR (CDCl3, 100 MHz): d = 18.3, 30.3, 116.6, 122.0, 122.7,
127.0, 130.1, 145.0, 153.0, 187.8.
Dione 7 or 9 (1.2 mmol), PhI(OAc)2 (0.386 g, 1.2 mmol), and
BF3·Et2O (26 mL) were added successively to a 10-mL round-bot-
tomed flask containing THF (5 mL) and 2-aminopyridine 1, and the
mixture was stirred at 7 °C overnight. When the reaction was com-
plete (TLC), the mixture was poured into sat. aq NaHCO3 (15 mL)
and the product was extracted with EtOAc (10 × 3 mL). The com-
bined organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was purified
by chromatography (silica gel). For the synthesis of 8f, the reaction
was performed in refluxing toluene for 24 h. Compound 12a was
prepared by a similar procedure.
EI-MS: m/z (%) = 210 (18), 208 (58) [M+], 195 (36), 193 (100), 124
(27).
1-(7-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)ethanone (8f)
Khaki solid; mp 157–159 °C.
1H NMR (CDCl3, 400 MHz): d = 2.60 (s, 3 H), 2.77 (s, 3 H), 6.97
(dd, 1 H, J = 7.6 Hz, J = 2.0 Hz), 7.59 (d, 1 H, J = 2.0 Hz), 9.64 (d,
1 H, J = 7.6 Hz).
13C NMR (CDCl3, 100 MHz): d = 18.2, 30.2, 115.5, 115.7, 121.8,
129.2, 135.5, 146.8, 153.4, 187.6.
EI-MS: m/z (%) = 210 (10), 208 (58) [M+], 195 (32), 193 (100), 124
(21).
1-(2-Methylimidazo[1,2-a]pyridin-3-yl)ethanone (8a)5a,17a
White solid; mp 105–106 °C.
HRMS (ESI): [M + H]+ calcd for C10H10ClN2O: 209.0476; found:
209.0479.
1H NMR (CDCl3, 400 MHz): d = 2.55 (s, 3 H), 2.72 (s, 3 H), 6.94
(t, 1 H, J = 7.2 Hz), 7.38 (t, 1 H, J = 7.6 Hz), 7.56 (d, 1 H, J = 8.0
Hz), 9.65 (dd, 1 H, J = 7.2 Hz, J = 0.8 Hz).
(2-Methylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone (10a)
White solid; mp 82–84 °C.
1H NMR (CDCl3, 400 MHz): d = 2.13 (s, 3 H), 7.00 (t, 1 H, J = 6.8
Hz), 7.42–7.48 (m, 3 H), 7.52–7.55 (m, 1 H), 7.62–7.64 (m, 3 H),
9.46 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 17.4, 114.2, 116.4, 121.2, 128.2,
128.4, 128.5, 129.1, 131.6, 140.2, 147.3, 153.3, 186.8.
EI-MS: m/z (%) = 236 (60) [M+], 235 (100), 159 (28), 90 (14),
77(13).
13C NMR (CDCl3, 100 MHz): d = 18.2, 30.1, 114.3, 116.2, 121.6,
128.8, 128.9, 146.7, 152.6, 187.4.
EI-MS: m/z (%) = 174 (69) [M+], 159 (100), 131 (17), 90 (33).
1-(2,6-Dimethylimidazo[1,2-a]pyridin-3-yl)ethanone (8b)
Pale yellow solid; mp 101–103 °C.
1H NMR (CDCl3, 400 MHz): d = 2.40 (s, 3 H), 2.61 (s, 3 H), 2.78
(s, 3 H), 7.31 (d, 1 H, J = 9.2 Hz), 7.53 (d, 1 H, J = 9.2 Hz), 9.55 (s,
1 H).
HRMS (ESI): [M + H]+ calcd for C15H13N2O: 237.1022; found:
237.1026.
13C NMR (CDCl3, 100 MHz): d = 18.3, 30.2, 115.5, 121.6, 124.3,
127.0, 131.8, 145.7, 152.5, 187.5.
EI-MS: m/z (%) = 188 (55) [M+], 173 (100), 104 (14).
HRMS (ESI): [M + H]+ calcd for C11H13N2O1: 189.1022; found:
189.1026.
(2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)(phenyl)methanone
(10c)
White solid; mp 149–151 °C.
1H NMR (CDCl3, 400 MHz): d = 2.12 (s, 3 H), 2.47 (s, 3 H), 6.87
(d, 1 H, J = 6.8 Hz), 7.40 (s, 1 H), 7.46–7.50 (m, 2 H), 7.54–7.58
(m, 1 H), 7.64 (d, 2 H, J = 7.6 Hz), 9.38 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 17.6, 21.6, 115.4, 116.8, 121.2,
127.9, 128.3, 128.6, 131.5, 140.6, 140.9, 148.1, 153.9, 186.7.
1-(2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)ethanone (8c)
White solid; mp 137–138 °C.
1H NMR (CDCl3, 400 MHz): d = 2.43 (s, 3 H), 2.57 (s, 3 H), 2.74
(s, 3 H), 6.82 (dd, 1 H, J = 6.8 Hz, J = 1.2 Hz), 7.36 (s, 1 H), 9.56
(d, 1 H, J = 6.8 Hz).
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Imidazo[1,2-a]pyridines
2453
EI-MS: m/z (%) = 250 (67) [M+], 249 (100), 173 (23), 77 (13).
HRMS (ESI): [M + H]+ calcd for C16H15N2O: 251.1179; found:
251.1176.
A, M. E.; Mendoza, P.; Jiménez, H.; Jiménez, R. J. Mol.
Struct. 2010, 979, 56.
(4) (a) Lyon, M. A.; Kercher, T. S. Org. Lett. 2004, 6, 4989.
(b) DiMauro, E. F.; Kennedy, J. M. J. Org. Chem. 2007, 72,
1013. (c) Liu, P.; Fang, L.; Lei, X.; Lin, G. Tetrahedron Lett.
2010, 51, 4605.
1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)ethanone (11a)
White solid; mp 110–112 °C.
(5) For recent examples, see: (a) Anderson, M.; Beattie, J. F.;
Breault, G. A.; Breed, J.; Byth, K. F.; Culshaw, J. D.;
Ellston, R. P. A.; Green, S.; Minshull, C. A.; Norman, R. A.;
Pauptit, R. A.; Stanway, J.; Thomas, A. P.; Jewsbury, P. J.
Bioorg. Med. Chem. Lett. 2003, 13, 3021. (b) Trapani, G.;
Laquintana, V.; Denora, N.; Trapani, A.; Lopedota, A.;
Latrofa, A.; Franco, M.; Serra, M.; Pisu, M. G.; Floris, I.;
Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 2005, 48, 292.
(c) Laquintana, V.; Denora, N.; Lopedota, A.; Suzuki, H.;
Sawada, M.; Serra, M.; Biggio, G.; Latrofa, A.; Trapani, G.;
Liso, G. Bioconjugate Chem. 2007, 18, 1397. (d) Denora,
N.; Laquintana, V.; Pisu, M. G.; Dore, R.; Murru, L.;
Latrofa, A.; Trapani, G.; Sanna, E. J. Med. Chem. 2008, 51,
6876. (e) Kishino, H.; Moriya, M.; Sakuraba, S.; Sakamoto,
T.; Takahashi, H.; Suzuki, T.; Moriya, R.; Ito, M.; Iwaasa,
H.; Takenaga, N.; Ishihara, A.; Kanatani, A.; Sato, N.;
Fukami, T. Bioorg. Med. Chem. Lett. 2009, 19, 4589.
(6) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008,
108, 5299.
1H NMR (CDCl3, 400 MHz): d = 2.19 (s, 3 H), 7.08 (dt, 1 H, J = 6.8
Hz, J = 1.2 Hz), 7.48–7.53 (m, 4 H), 7.57–7.60 (m, 2 H), 7.74 (d, 1
H, J = 8.8 Hz), 9.76 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 29.8, 114.8, 117.2, 121.3, 128.4,
129.0, 129.1, 129.3, 129.7, 135.2, 146.8, 155.3, 189.1.
EI-MS: m/z (%) = 236 (74) [M+], 235 (42), 221 (100), 192 (25).
HRMS (ESI): [M + H]+ calcd for C15H13N2O: 237.1022; found:
237.1024.
1-(7-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)ethanone
(11c)
White solid; mp 108–110 °C.
1H NMR (CDCl3, 400 MHz): d = 2.16 (s, 3 H), 2.48 (s, 3 H), 6.91
(dd, 1 H, J = 6.8 Hz, J = 1.6 Hz), 7.47–7.48 (m, 4 H), 7.56–7.58 (m,
2 H), 9.63 (d, 1 H, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): d = 21.5, 29.7, 115.8, 117.2, 121.1,
128.2, 128.3, 129.0, 129.7, 135.4, 140.9, 147.2, 155.5, 188.7.
EI-MS: m/z (%) = 250 (76) [M+], 249 (36), 235 (100).
HRMS (ESI): [M + H]+ calcd for C16H15N2O: 251.1179; found:
251.1174.
(7) (a) Moriarty, R. M.; Prakash, O. Org. React. (N. Y.) 1999,
54, 273. (b) Koser, G. Aldrichimica Acta 2001, 34, 89.
(8) Ueno, M.; Nabana, T.; Togo, H. J. Org. Chem. 2003, 68,
6424.
(9) Chang, Y.-L.; Wang, H.-M.; Hou, R.-S.; Kang, I.-J.; Chen,
L.-C. J. Chin. Chem. Soc. (Taipei) 2010, 57, 153.
(10) For an example of PIDA-mediated intramolecular oxidative
coupling of N-aryl enamines, see: Yu, W.; Du, Y.; Zhao, K.
Org. Lett. 2009, 11, 2417.
(11) (a) Abignente, E.; De Caprariis, P.; Fattorusso, E.; Mayol, L.
J. Heterocycl. Chem. 1989, 26, 1875. (b) Chiacchio, A. D.;
Rimoli, M. G.; Avallone, L.; Arena, F.; Abignente, E.;
Filippelli, W.; Filippelli, A.; Falcone, G. Arch. Pharm.
(Weinheim, Ger.) 1998, 331, 273.
(12) (a) Wang, J.-Y.; Liu, S.-P.; Yu, W. Synlett 2009, 2529.
(b) Wang, J.-Y.; Wang, X.-P.; Yu, Z.-S.; Yu, W. Adv. Synth.
Catal. 2009, 351, 2063. (c) Wang, X.; Han, B.; Wang, J.;
Yu, W. Org. Biomol. Chem. 2010, 8, 3865.
(13) Trapani, G.; Franco, M.; Ricciardi, L.; Latrofa, A.; Genchi,
G.; Sanna, E.; Tuveri, F.; Cagetti, E.; Biggio, G.; Liso, G.
J. Med. Chem. 1997, 40, 3109.
2-Phenylimidazo[1,2-a]pyridine-3-carbonitrile (12a)
White solid; mp 144–146 °C.
1H NMR (CDCl3, 400 MHz): d = 7.10 (dt, 1 H, J = 6.8 Hz, J = 0.8
Hz), 7.45–7.55 (m, 4 H), 7.77 (d, 1 H, J = 9.2 Hz), 8.18–8.21 (m, 2
H), 8.37 (d, 1 H, J = 6.8 Hz).
13C NMR (CDCl3, 100 MHz): d = 93.8, 112.8, 114.7, 118.2, 125.6,
127.3, 128.7, 129.0, 130.1, 131.2, 146.8, 153.4.
EI-MS: m/z (%) = 219 (100) [M+], 218 (20), 149 (11), 78 (16).
HRMS (ESI): [M + H]+ calcd for C14H10N3: 220.0869; found:
220.0863.
Supporting Information for this article is available online at
http://www.thiem-connect.com/ejournal/toc/synthesis.
(14) George, P.; Giron, C. US 4650796, 1987.
Acknowledgment
(15) da Costa, J. C. S.; Pais, K. C.; Fernandes, E. L.; de Oliveira,
P. S. M.; Mendonça, J. S.; de Souza, M. V. N.; Peralta, M.
A.; Vasconcelos, T. R. A. ARKIVOC 2006, (i), 128.
(16) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.;
Snoeck, R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.;
Witvrouw, M.; Balzarini, J.; De Clercq, E.; Chapat, J.-P.
J. Med. Chem. 1998, 41, 5108.
(17) For examples of syntheses of 3-acyl imidazo[1,2-
a]pyridines, see: (a) Starrett, J. E. Jr.; Montzka, T. A.;
Crosswell, A. R.; Cavanagh, R. L. J. Med. Chem. 1989, 32,
2204. (b) Byth, K. F.; Culshaw, J. D.; Green, S.; Oakes, S.
E.; Thomas, A. P. Bioorg. Med. Chem. Lett. 2004, 14, 2245.
(c) Hayakawa, M.; Kaizawa, H.; Kawaguchi, K.; Ishikawa,
N.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta,
M.; Tsukamoto, S.; Raynaud, F. I.; Waterfield, M. D.;
Parker, P.; Workman, P. Bioorg. Med. Chem. 2007, 15, 403.
The authors thank the National Natural Science Foundation of Chi-
na (No. 20772053) for financial support.
References
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Synthesis 2011, No. 15, 2445–2453 © Thieme Stuttgart · New York