Copper-Promoted Annulation of Terminal Alkynes with 2-Aminopyridines to Assemble 2-Halogenated Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/jhet.3660

Copper-promoted annulation reactions of terminal alkynes with 2-aminopyridines have been developed for the synthesis of 2-halogenated imidazo[1,2-a]pyridines using copper halide as the halogen source. A variety of substrates survived under the reaction conditions and gave the desired products in good yields. This reaction features advantages such as easily available starting materials, broad substrate scope, and mild reaction conditions.

Full text of DOI:10.1002/jhet.3660

Month 2019 Copper-Promoted Annulation of Terminal Alkynes with 2-Aminopyridines
to Assemble 2-Halogenated Imidazo[1,2-a]pyridines
a
a
b
*
*
Yuxuan Zhang, and Jinwei Sun
Yun Liu,
aSchool of Chemistry and Material Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, People’s Republic
of China
bJiangsu Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key
Laboratory of Atmospheric Environment Monitoring and Pollution Control, Nanjing University of Information Science &
Technology, Nanjing 210044, Jiangsu, People’s Republic of China
*E-mail: liu__yun3@sina.com; gysunjinwei@126.com
Received March 22, 2019
DOI 10.1002/jhet.3660
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Copper-promoted annulation reactions of terminal alkynes with 2-aminopyridines have been developed
for the synthesis of 2-halogenated imidazo[1,2-a]pyridines using copper halide as the halogen source. A va-
riety of substrates survived under the reaction conditions and gave the desired products in good yields. This
reaction features advantages such as easily available starting materials, broad substrate scope, and mild reac-
tion conditions.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
herein a convenient synthesis of 2-bromo and 2-
chloroimidazo[1,2-a]pyridines from terminal alkynes
using copper halide as both catalyst and halogen source
(Scheme 1e). In this reaction, haloalkynes were first
generated in situ via oxidative coupling of terminal
alkynes with copper halide and then reaction with
2-aminopyridines to form the target product 2-
haloimidazo[1,2-a]pyridines.
In the past decades, imidazo[1,2-a]pyridines have
exhibited significant biological activities [1–6] as well as
broad application in material field [7–9], and much
attention has been drawn to their syntheses [10,11].
Among these compounds, halogenated imidazo[1,2-a]
pyridines are important synthetic target molecules and
can be transformed into various functionalized
imidazo[1,2-a]pyridines via Heck coupling [12,13],
Sonogashira coupling [14,15], Suzuki coupling [16,17],
Stille coupling [18,19], and so on.
RESULT AND DISCUSSION
The annulation reactions of haloalkynes [20], alkynoic
acids [21], and terminal alkynes [22,23] with
2-aminopyridines are efficient synthetic strategies to 2-
haloimidazo[1,2-a]pyridines. Compared with haloalkynes
(Scheme 1a) and alkynoic acids (Scheme 1b), terminal
alkynes are more attractive substrates because they are
commercially available and do not need to be prepared
before use. However, up to now, only the synthesis of 2-
iodoimidazo[1,2-a]pyridines had been reported from
terminal alkynes with molecule iodine as the halogen
source (Scheme 1c and d). Hence, more general synthetic
protocols to transform alkynes to 2-haloimidazo[1,2-a]
pyridines are highly desired.
At the beginning of our work, we chose 2-
aminopyridine 1a and phenylacetylene 2a as the model
reactants to optimize the reaction conditions. Initially, we
heated 1a (1.5 mmol), 2a (0.5 mmol), and CuBr2
(0.5 mmol) in DCE at 90°C for 12 h, and we isolated
product 3a in 53% yield (Table 1, entry 1). Other
solvents were then tried, and acetonitrile performed the
best (Table 1, entries 2–5). With acetonitrile as solvent,
we employed CuBr in place of CuBr2 into this reaction
but only detected little amount of 3a (Table 1, entry 6).
Adding 1.5 equiv of CuBr2 also did not give better result
(Table 1, entry 7). In addition, carrying out the reaction
without CuBr2 or under Ar atmosphere, no 3a was formed
(Table 1, entries 8–9). On the basis of this, we investigated
the effect of different oxidants. The result showed that
under 1 atm of O2, 3a was formed only in 65% yield
(Table 1, entry 10). Other oxidants including TBHP,
DTBP, or K2S2O8 did not lead to 3a in high yield as well
Recently, copper-catalyzed oxidative coupling of
terminal alkynes with various nucleophilic reagents to
form carbon–carbon bond or carbon–heteroatom bond
has been developed rapidly for the preparation of organic
molecules [24–31]. Encouraged by this, we reported
© 2019 Wiley Periodicals, Inc.

Y. Liu, Y. Zhang, and J. Sun
Vol 000
Scheme 1. Synthesis of 2-haloimidazo[1,2-a]pyridines.
(Table 1, entries 11–13). Then we tried to use 1 equiv of
KBr as the bromine source in combination with catalytic
amount of Cu (OTf)2 or Cu (OAc)2 but found that the
yield decreased slightly (entries 14–15). Finally, we
changed the reaction temperature but did not get positive
result (Table 1, entries 16–17). Hence, the optimal
reaction conditions were heating 1.5 mmol of 1a,
0.5 mmol of 2a, and 1.0 equiv of CuBr2 in acetonitrile at
90°C for 12 h.
Table 1
Optimization of reaction conditions.a
Copper
(equiv)
Oxidant
(equiv)
Yield
(%)b
Entry
Solvent
On the basis of this, we then screened the scope of
reactants (Table 2). Initially, we investigate the kind of
terminal alkynes by employing 2-aminopyridine 1a as the
substrate. It was found that a variety of terminal alkynes
2 reacted with 1a well, giving 2-bromoimidazo[1,2-a]
pyridines 3 in good yields. For examples, alkynes 2b–2d
attached with phenyl and thienyl substituents formed
products 3b–3d in 76–85% yields, while alkynes 2e–2g
with aliphatic groups gave product 3e–3g in 52–82%
yields. Next, we examined the kind of substituted 2-
aminopyridines by reacting them with aromatic or
aliphatic alkynes. It showed that 2-aminopyridines 1b and
1c reacted with aromatic alkynes well under the optimal
conditions, affording products 3h–3i in high yields.
Similarly, the reaction of 2-aminopyridines 1c–1f with
aliphatic alkynes proceeded smoothly and resulted in
product 3j–3p in 73–87% yields. For annulated 2-
aminopyridine 1g, products 3q and 3r were isolated in
excellent yields as well. The structures of all products
were confirmed by NMR and HRMS, and the spectra
1
2
3
4
5
6
7
8
DCE
DMF
C6H6
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
CuBr (1)
CuBr2 (1.5)
None
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
CuBr2 (1)
Cu (OTf)2
Cu (OAc)2
CuBr2 (1)
CuBr2 (1)
Air
Air
Air
Air
Air
Air
Air
Air
None
O2
TBHP (2)
DTBP (2)
K2S2O8
Air
Air
Air
Air
53
48
62
51
78
Trace
78
0
0
65
62
25
Trace
72
68
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9c
10
11
12
13
14d
15d
16e
17f
53
75
aConditions: 1a (1.5 mmol), 2a (0.5 mmol), copper salt, oxidant, heating
in solvent (5 mL) at 90°C for 12 h.
bIsolated yield.
cUnder Ar.
dAdding 1 equiv of KBr.
eHeating at 70°C.
fHeating at 110°C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Annulation of Terminal Alkynes
Table 2
,
Synthesis of 2-bromoimidazo[1,2-a]pyridines.a b
aConditions: 1 (1.5 mmol), 2 (0.5 mmol), CuBr2 (0.5 mmol), heating in CH3CN (5 mL) at 90°C for 12 h in a sealed tube.
bIsolated yield.
data of known products are in accordance with our
previous report [13].
phenyl boronic acid (1.5 equiv) at 100°C under Ar
atmosphere with 2 mol% of PdCl2(PPh3)2 as catalyst and
2.0 equiv of K3PO4 as base, we obtained product 5 in
86% yield (Scheme 2).
Subsequently, we tried to prepare chlorinated products
by this protocol (Table 3). Pleasingly, by heating the
mixture of 2-aminopyridine 1a, aromatic or aliphatic
alkynes 2, and 1.0 equiv of CuCl2 in acetonitrile at 90°C
for 12 h, we obtained 2-chloroimidazo[1,2-a]pyridines
4a–4c in good yields. Additionally, substituted 2-
aminopyridines under the same conditions afforded
products 4d–4f in 52% to 61% yields.
For demonstrating the utility of these halogenated
imidazo[1,2-a]pyridines, we attempted to synthesize 2-
phenylimidazo[1,2-a]pyridine 5 from 3a via Suzuki
reaction (Scheme 2). As we expected, by heating 3a,
To shed light on the mechanism, several control
experiments were carried out. First, employing
bromoalkyne 6 as substrate to react with 1a under
optimal conditions, we obtained 3a in 66% yield
(Scheme 3a). In addition, exposing 2a with CuBr2 in
acetonitrile with base formed alkyne dimerization product
7 along with bromoalkyne 6 (Scheme 3b). These results
illustrated that bromoalkyne 6 was the possible reaction
intermediate. Second, no reaction occurred when
exposing C2-unsubstituted imidazo[1,2-a]pyridine 8 with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Liu, Y. Zhang, and J. Sun
Vol 000
Table 3
,
Synthesis of 2-chloroimidazo[1,2-a]pyridines.a b
aConditions: 1 (1.5 mmol), 2 (0.5 mmol), CuCl2 (0.5 mmol), heating in CH3CN (5 mL) at 90°C for 12 h in a sealed tube.
bIsolated yield.
Scheme 2. Synthesis of compound 5.
Scheme 4. Possible mechanism for the formation of 3a.
Scheme 3. Control experiments.
aminopyridine 1a, forming Cu(II) intermediate II. Finally,
intermediate II occurred tandem oxidation and reductive
elimination, dispelling CuBr and giving the final product
3a. In this reaction process, CuBr could be converted into
CuBr2 by the oxidation of molecular oxygen.
2-aminopyridine and CuBr2 (Scheme 3c). This illustrated
that the reaction should not proceed via bromination of
intermediate 8.
CONCLUSION
Based on our experimental results and previous
literatures [22,23], a possible mechanism was suggested
(Scheme 4). At first, oxidative coupling of alkyne 2a
with copper bromide led to bromoalkyne I in situ. Then,
intermediate I underwent oxidative cyclization with 2-
In conclusion, we have developed a copper bromide-
promoted annulation reaction of 2-aminopyridines with
terminal alkynes to assemble 2-halogenated imidazo[1,2-
a]pyridines. By this protocol, 2-brominated or 2-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Annulation of Terminal Alkynes
chlorinated products were generated in good yields. The
reaction features advantages such as easily available
starting materials, broad substrate scope, and mild
reaction conditions.
(m, 2H), 2.91 (t, J = 7.6 Hz, 2H), 6.84 (td, J = 6.8,
0.8 Hz, 1H), 7.16 (td, J = 8.0, 0.8 Hz, 1H), 7.35 (d,
J = 8.8 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 144.1, 123.8, 122.8,. 121.9, 117.2,
112.6, 31.5, 28.9, 27.1, 22.6, 14.1. HRMS (ESI) m/z calcd
for C13H18BrN2 [M + H]+ 281.0653, found 281.0642.
2-Bromo-3-cyclohexylimidazo[1,2-a]pyridine (3f).
White
EXPERIMENTAL
1
solid, mp 93–95°C. H NMR (400 MHz, CDCl3) δ 1.39–
1.46 (m, 3H), 1.81–2.02 (m, 7H), 3.00–3.06 (m, 1H),
6.81 (td, J = 6.8, 0.8 Hz, 1H), 7.14 (td, J = 6.8, 0.8 Hz,
1H), 7.52 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 144.1, 124.9, 123.7,
123.2, 120.1, 117.4, 112.3, 35.1, 29.6, 26.8, 25.9. HRMS
(ESI) m/z calcd for C13H16BrN2 [M + H]+ 279.0497,
General.
1H NMR spectra were measured on
400 MHz. 13C NMR spectra were measured on
100 MHz. HRMS (ESI) data were obtained in the
electron impact (EI) mode.
General preparation procedure of 3. 2-Aminopyridine
1a (1.5 mmol, 3 equiv), terminal alkynes 2 (0.5 mmol,
1 equiv), CuBr2 (0.5 mmol, 1 equiv), and CH3CN (5 mL)
were mixed into a sealed tube and heated at 90°C for
12 h. Then the reaction mixture was separated by flash
column chromatography on silica gel to give product 3.
found 279.0488.
2-Bromo-3-cyclopropylimidazo[1,2-a]pyridine (3g). White
1
solid, mp 69–71°C. H NMR (400 MHz, CDCl3) δ 0.77–
0.80 (m, 2H), 1.04–1.08 (m, 2H), 1.67–1.71 (m, 1H),
6.81 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.45
(d, J = 9.2 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 143.8, 124.4, 123.2, 122.4, 121.3,
116.8, 112.4, 5.57, 3.3. HRMS (ESI) m/z calcd for
2-Bromo-3-phenylimidazo[1,2-a]pyridine (3a).
White
solid, mp 150–151°C. 1H NMR (400 MHz, CDCl3) δ
6.78–6.81 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.45–7.49
(m, 1H), 7.53–7.60 (m, 5H), 8.11 (d, J = 6.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 144.6, 129.6, 129.2,
129.0, 127.6, 125.1, 123.2, 122.2, 117.3, 113.0. HRMS
(ESI) m/z calcd for C13H10BrN2 [M + H]+ 273.0027,
found 273.0022.
C10H10BrN2 [M + H]+ 237.0027, found 237.0038.
2-Bromo-8-fluoro-3-phenylimidazo[1,2-a]pyridine (3h).
White solid, mp 143–145°C. 1H NMR (400 MHz,
CDCl3) δ 6.72–6.77 (m, 1H), 6.92–6.97 (m, 1H), 7.49–
7.58 (m, 5H), 7.94 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 150.8 (d, J = 253 Hz), 137.2 (d,
J = 28 Hz), 129.7, 129.4, 129.3, 127.2, 124.0, 122.3,
119.6 (d, J = 5 Hz), 112.1 (d, J = 7 Hz), 107.9, 107.7.
2-Bromo-3-(4-chlorophenyl)imidazo[1,2-a]pyridine (3b).
White solid, mp 178–180°C. 1H NMR (400 MHz,
CDCl3) δ 6.81–6.83 (m, 1H), 7.48–7.51 (m, 1H), 7.54–
7.60 (m, 5H), 8.07 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 142.9, 134.6, 131.8, 129.6, 129.4,
129.3, 129.2, 126.7, 123.6, 120.1, 116.2, 114.7. HRMS
(ESI) m/z calcd for C13H9BrClN2 [M + H]+ 306.9638,
found 306.9646.
HRMS (ESI) m/z calcd for C13H9BrFN2 [M + H]+
290.9933, found 290.9928.
2-Bromo-7-chloro-3-phenylimidazo[1,2-a]pyridine (3i).
White solid, mp 127–129°C. 1H NMR (400 MHz,
CDCl3) δ 6.80 (dd, J = 7.2, 2.0 Hz, 1H), 7.48–7.60
(m, 6H), 8.03 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 144.2, 131.7, 129.6, 129.3, 129.2,
127.0, 123.5, 122.9, 122.6, 116.1, 114.6. HRMS (ESI)
m/z calcd for C13H9BrClN2 [M + H]+ 306.9638, found
2-Bromo-3-p-tolylimidazo[1,2-a]pyridine (3c).
Colorless
1
oil. H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 6.77–
7.80 (m, 1H), 7.19–7.23 (m, 1H), 7.36 (d, J = 7.6 Hz,
2H), 7.45 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 9.2 Hz,
1H), 8.09 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 144.5, 139.1, 129.9, 129.5, 125.0, 124.5,
123.2, 122.3, 122.1, 117.2, 112.9, 21.5. HRMS (ESI)
m/z calcd for C14H12BrN2 [M + H]+ 287.0184, found
287.0193.
306.9647.
2-Bromo-7-chloro-3-cyclopropylimidazo[1,2-a]pyridine
1
(3j). White solid, mp 166–167°C. H NMR (400 MHz,
CDCl3) δ 0.83–0.87 (m, 2H), 1.13–1.17 (m, 2H), 1.72–
1.76 (m, 1H), 6.87 (dd, J = 7.2, 2.0 Hz, 1H), 7.51 (d,
J = 1.2 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 143.4, 131.3, 123.5, 123.2, 121.8,
115.8, 114.2, 5.7, 3.2. HRMS (ESI) m/z calcd for
2-Bromo-3-(thiophen-2-yl)imidazo[1,2-a]pyridine (3d).
Colorless oil. H NMR (400 MHz, CDCl3) δ 6.86 (td,
1
J = 6.8, 1.2 Hz, 1H), 723–7.25 (m, 2H), 7.35 (dd,
J = 7.2, 0.8 Hz, 1H), 7.55–7.60 (m, 2H), 8.23 (d,
J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 145.0,
129.2, 127.9, 127.8, 127.6, 125.6, 124.1, 123.7, 117.2,
113.3. HRMS (ESI) m/z calcd for C11H8BrN2S [M + H]+
278.9592, found 278.9583.
C10H9BrClN2 [M + H]+ 270.9638, found 270.9647.
2-Bromo-7-chloro-3-hexylimidazo[1,2-a]pyridine (3k).
1
White solid, mp 78–79°C. H NMR (400 MHz, CDCl3) δ
0.87–0.90 (m, 3H), 1.29–1.38 (m, 6H), 1.60–1.66 (m,
2H), 2.87–2.91 (m, 2H), 6.87 (dd, J = 7.2, 2.0 Hz, 1H),
7.58 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 143.5, 131.1, 123.2, 122.5, 121.8,
115.8, 114.5, 31.5, 28.8, 27.0, 23.2, 22.5, 14.0. HRMS
2-Bromo-3-hexylimidazo[1,2-a]pyridine
(3e).
White
solid, mp 115–116°C. 1H NMR (400 MHz, CDCl3) δ
0.88 (t, J = 7.2 Hz, 3H), 1.26–1.39 (m, 6H), 1.59–1.67
Journal of Heterocyclic Chemistry
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Y. Liu, Y. Zhang, and J. Sun
Vol 000
White
(ESI) m/z calcd for C13H17BrClN2 [M + H]+ 315.0264,
2-Bromo-1-hexylimidazo[1,2-a]quinoline (3r).
1
found 315.0251.
solid, mp 57–58°C. H NMR (400 MHz, CDCl3) δ 0.88–
0.92 (t, J = 7.2 Hz, 3H), 1.32–1.36 (m, 4H), 1.47–1.49
(m, 2H), 1.71–1.78 (m, 2H), 3.26 (t, J = 7.6 Hz, 2H),
7.42–7.47 (m, 3H), 7.58–7.63 (m, 1H), 7.76 (dd, J = 8.0,
1.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 143.5, 133.8, 129.4, 128.5, 126.3,
126.0, 124.8, 124.4, 122.5, 116.9, 115.7, 31.5, 28.8,
28.2, 27.0, 22.6, 14.1. HRMS (ESI) m/z calcd for
C17H20BrN2 [M + H]+ 331.0810, found 331.0802.
2-Bromo-3-cyclopropyl-7-methylimidazo[1,2-a]pyridine
(3l). White solid, mp 160–161°C. H NMR (400 MHz,
1
CDCl3) δ 0.82–0.84 (m, 2H), 1.10–1.12 (m, 2H), 1.70–
1.75 (m, 1H), 2.40 (s, 3H), 6.70 (dd, J = 7.2, 1.6 Hz,
1H), 7.27 (s, 1H), 8.08 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 144.2, 135.6, 122.5, 121.9, 120.7,
115.3, 115.1, 21.3, 5.6, 3.3. HRMS (ESI) m/z calcd for
C11H12BrN2 [M + H]+ 251.0184, found 251.0171.
2-Bromo-3-hexyl-7-methylimidazo[1,2-a]pyridine (3m).
White solid, mp 57–59°C. H NMR (400 MHz, CDCl3)
General preparation procedure of 4. 2-Aminopyridine
1a (1.5 mmol, 3 equiv), terminal alkynes 2 (0.5 mmol,
1 equiv), CuCl2 (0.5 mmol, 1 equiv), and CH3CN (5 mL)
were mixed into a sealed tube and heated at 90°C for
12 h. Then the reaction mixture was separated by flash
column chromatography on silica gel to give product 4.
2-Chloro-3-phenylimidazo[1,2-a]pyridine (4a). Colorless
1
δ 0.88 (t, J = 7.2 Hz, 3H), 1.29–1.36 (m, 6H), 1.59–
1.63 (m, 2H), 2.39 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H),
6.67 (d, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.76 (d,
J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
144.5, 134.8, 122.0, 121.3, 121.1, 115.6, 115.1, 31.5,
28.8, 27.2, 23.3, 22.6, 21.2, 14.0. HRMS (ESI) m/z
1
oil. H NMR (400 MHz, CDCl3) δ 6.83 (t, J = 6.8 Hz,
calcd for C14H20BrN2 [M + H]+ 295.0810, found
295.0816.
1H), 7.23–7.27 (m, 1H), 7.47–7.49 (m, 1H), 7.54–7.61
(m, 5H), 8.16 (d, J = 7,2 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 143.2, 129.3, 129.2, 128.9, 128.8, 127.2,
125.2, 123.2, 117.3, 113.0. HRMS (ESI) m/z calcd for
C13H10ClN2 [M + H]+ 229.0533, found 229.0530.
2-Bromo-6-chloro-3-hexylimidazo[1,2-a]pyridine (3n).
White solid, mp 55–56°C. H NMR (400 MHz, CDCl3)
1
δ 0.88–0.91 (m, 3H), 1.31–1.40 (m, 6H), 1.61–1.65 (m,
2H), 2.87–2.91 (m, 2H), 7.15 (dd, J = 9.2 Hz, 1H),
7.50 (d, J = 9.6 Hz, 1H), 7.93 (s, 1H). 13C NMR
(100 MHz, CDCl3) δ 142.4, 125.4, 122.7, 122.5, 121.3,
120.7, 117.5, 31.5, 28.8, 26.9, 23.3, 22.6, 14.0. HRMS
(ESI) m/z calcd for C13H17BrClN2 [M + H]+ 315.0264,
2-Chloro-3-hexylimidazo[1,2-a]pyridine (4b).
Colorless
1
oil. H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz,
3H), 1.30–1.37 (m, 6H), 1.60–1.68 (m, 2H), 2.91 (t,
J = 7.6 Hz, 2H), 6.86 (td, J = 6.8, 0.8 Hz, 1H), 7.18 (td,
J = 6.8, 0.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.88 (d,
J = 6.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 142.8,
133.4, 123.9, 122.8, 119.2, 117.2, 112.6, 31.5, 28.9,
27.0, 22.7, 22.6, 14.1. HRMS (ESI) m/z calcd for
C13H18ClN2 [M + H]+ 237.1159, found 237.1159.
found 315.0276.
2-Bromo-3-hexyl-6-methylimidazo[1,2-a]pyridine (3o).
White solid, mp 77–78°C. H NMR (400 MHz, CDCl3) δ
1
0.87–0.91 (m, 3H), 1.30–1.40 (m, 6H), 1.61–1.64 (m,
2H), 2.35 (s, 3H), 2.85–2.89 (m, 2H), 7.01 (dd,
J = 9.2 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.65 (s, 1H).
13C NMR (100 MHz, CDCl3) δ 143.1, 127.0, 122.3,
121.5, 121.2, 120.5, 116.4, 31.5, 28.8, 27.0, 23.3, 22.6,
18.4, 14.1. HRMS (ESI) m/z calcd for C14H20BrN2
2-Chloro-3-cyclopropylimidazo[1,2-a]pyridine (4c). White
solid, mp 65–67°C. H NMR (400 MHz, CDCl3) δ 0.76–
1
0.80 (m, 2H), 1.03–1.07 (m, 2H), 1.68–1.71 (m, 1H),
6.83 (t, J = 7.2 Hz, 1H), 7.15 (td, J = 7.2, 0.8 Hz, 1H),
7.44 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 6.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 142.3, 134.0, 124.5, 123.3,
119.0, 116.8, 112.5, 5.3, 2.8. HRMS (ESI) m/z calcd for
C10H10ClN2 [M + H]+ 193.0533, found 193.0542.
2-Chloro-3-hexyl-7-methylimidazo[1,2-a]pyridine (4d).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.88 (t,
J = 7.2 Hz, 3H), 1.26–1.37 (m, 6H), 1.60–1.64 (m, 2H),
2.40 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H), 6.68 (d,
J = 6.8 Hz, 1H), 7.27 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 143.1, 135.0, 132.7,
122.1, 118.5, 115.6, 115.2, 31.5, 28.8, 27.1, 22.6, 22.5,
21.3, 14.0. HRMS (ESI) m/z calcd for C14H20ClN2
[M + H]+ 251.1315, found 251.1326.
[M + H]+ 295.0810, found 295.0803.
2-Bromo-3-cyclopropyl-6-methylimidazo[1,2-a]pyridine
(3p). White solid, mp 147–148°C. H NMR (400 MHz,
1
CDCl3) δ 0.84–0.85 (m, 2H), 1.12–1.14 (m, 2H), 1.69–
1.76 (m, 1H), 2.37 (s, 3H), 7.05 (d, J = 9.2 Hz, 1H), 7.42
(d, J = 9.2 Hz, 1H), 7.98 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 142.9, 127.6, 122.2, 121.9, 121.0, 116.2, 18.4,
5.6, 3.4. HRMS (ESI) m/z calcd for C11H12BrN2
[M + H]+ 251.0184, found 251.0177.
2-Bromo-1-cyclopropylimidazo[1,2-a]quinoline (3q).
White solid, mp 142–143°C. 1H NMR (400 MHz,
CDCl3) δ 1.02–1.05 (m, 2H), 1.29–1.32 (m, 2H), 2.13–
2.27 (m, 1H), 7.38–7.47 (m, 3H), 7.56–7.59 (m, 1H),
7.75 (dd, J = 8.0, 1.6 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 143.1, 134.2, 129.0,
128.0, 126.7, 125.8, 124.7, 124.4, 122.9, 117.4, 116.6,
10.3, 8.3. HRMS (ESI) m/z calcd for C14H12BrN2
[M + H]+ 287.0184, found 287.0172.
2-Chloro-3-cyclopropyl-7-methylimidazo[1,2-a]pyridine
(4e). White solid, mp 140–142°C. H NMR (400 MHz,
CDCl3) δ 0.82–0.83 (m, 2H), 1.09–1.11 (m, 2H), 1.73–
1.76 (m, 1H), 2.41 (s, 3H), 6.72 (d, J = 6.8 Hz, 1H), 7.28
(s, 1H), 8.06 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz,
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Annulation of Terminal Alkynes
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CDCl3) δ 142.7, 135.8, 133.6, 118.4, 115.3, 115.2, 21.3,
5.3, 2.8. HRMS (ESI) m/z calcd for C11H12ClN2
[M + H]+ 207.0689, found 207.0695.
2,7-Dichloro-3-cyclopropylimidazo[1,2-a]pyridine (4f).
White solid, mp 147–148°C. 1H NMR (400 MHz,
CDCl3) δ 0.83–0.85 (m, 2H), 1.12–1.14 (m, 2H), 1.73–
1.77 (m, 1H), 6.88 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 8.11
(d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
142.0, 134.8, 131.4, 123.6, 119.5, 115.7, 114.3, 5.4, 2.7.
HRMS (ESI) m/z calcd for C10H9Cl2N2 [M + H]+
227.0143, found 227.0155.
Procedure for the preparation of 5.
Imidazo[1,2-a]
pyridine 3a (0.2 mmol), phenyl boronic acid (0.3 mmol),
PdCl2(PPh3)2 (0.004 mmol), and K3PO4 (0.4 mmol) were
mixed in 2.0 mL of toluene and heated at 100°C under
Ar atmosphere for 12 h. After completion of the reaction,
the mixture was cooled and separated by flash column
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chromatography on silica gel to afford product 5.
2,3-Diphenylimidazo[1,2-a]pyridine (5). White solid, mp
151–152°C. 1H NMR (400 MHz, CDCl3) δ 6.68–6.72
(m, 1H), 7.15–7.29 (m, 4H), 7.43–7.52 (m, 5H), 7.66–
7.69 (m, 3H), 7.93 (dd, J = 7.2, 1.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 144.7, 142.3, 134.1, 130.6, 129.7,
129.4, 128.8, 128.2, 128.0, 127.4, 124.6, 123.2, 121.0,
117.4, 112.2. HRMS (ESI) m/z calcd for C19H15N2
[M + H]+ 271.1235, found 271.1247.
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Acknowledgments. This work was supported by the Natural
Science Foundation of the Jiangsu Higher Education Institutions
of China (17KJB150016) and the Natural Science Foundation
of Jiangsu Province (BK20170939).
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SUPPORTING INFORMATION
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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T. J Org Chem 2012, 77, 5552.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet