Cu(I)-catalysed oxidative coupling of 2-aminopyridines with β-keto esters: Synthesis of imidazo[1,2-a]pyridine-3-carboxylates

Article abstract of DOI:10.3184/174751912X13415906694258

A simple, economical, and environmentally friendly copper-catalysed direct oxidative C-N coupling of 2-aminopyridines with β-keto esters using air as oxidation agent for the creation of imidazo[1,2-a]pyridine-3-carboxylates is demonstrated. Imidazo[1,2-a]pyridine is the basic skeleton for a wide range of biological and pharmacological compounds.

Full text of DOI:10.3184/174751912X13415906694258

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 525
SEPTEMBER, 525–527
Cu(I)-catalysed oxidative coupling of 2-aminopyridines with β-keto esters:
synthesis of imidazo[1,2-a]pyridine-3-carboxylates
Xiaoqing Li*
College of Chemical Engineering and Materials Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
A simple, economical, and environmentally friendly copper-catalysed direct oxidative C–N coupling of 2-aminopyri-
dines with β-keto esters using air as oxidation agent for the creation of imidazo[1,2-a]pyridine-3-carboxylates is
demonstrated. Imidazo[1,2-a]pyridine is the basic skeleton for a wide range of biological and pharmacological
compounds.
Keywords: imidazo[1,2-a]pyridine-3- carboxylates, 2-aminopyridines, β-keto esters, copper, oxidative coupling, green synthesis
The imidazo[1,2-a]pyridine moieties appear as basic skeletons
in a wide range of biologically interesting and pharmacologi-
cally important compounds.1–4 In addition, imidazo[1,2-a]
pyridine derivatives have been widely used as fluorescent
dyes.5–8 Thus, considerable effort had been devoted towards
the development of an efficient and green methodology for
the synthesis of imidazo[1,2-a]pyridines.9–18 Recently, it was
reported that TBAI could catalyse the direct oxidative C–N
coupling of 2-aminopyridines with β-keto esters and 1,3-diones
to afford imidazo[1,2-a]pyridines using tert-butyl hydroperox-
ide (TBHP) as the oxidant [Scheme 1, Eqn (1)].19 Although the
TBAI/TBHP oxidising system was used instead of stoichio-
metric amounts of hypervalent iodine reagent,18 the process
still suffers from the use of moisture sensitive BF3·Et2O as
the co-catalyst and TBHP as the oxidant, which could result
in t-BuOH as a byproduct. On the other hand, Yan and
co-workers20 have developed an efficient method for the
direct synthesis of 3-nitro-imidazo[1,2-a]pyridines from
aminopyridines and nitro-olefins based on copper-catalysed
single electron transfer (SET) processes using air as the
oxidant [Scheme 1, Eqn (2)]. This method is excellent because
air is the ideal oxidant due to its abundance, low cost, and lack
of toxic byproducts and the copper-catalysts are inexpensive,
readily available and easily handled. However, imidazo[1,2-a]
pyridine-3-carboxylates, which are useful intermediates for
the synthesis of pharmaceutically important compounds21 were
not synthesised using this appealing method. Here we report
a green and facile synthesis of imidazo[1,2-a]pyridine-3-
carboxylates via copper-catalysed SET processes using air as
the oxidant [Scheme 1, Eqn (3)].
Initially, the oxidative coupling of 2-aminopyridine (1a)
with ethyl 2-benzoylacetate (2a) was chosen as a model reac-
tion and several copper (I) salts, such as CuCl, CuBr and CuI,
(Table 1, entries 1–3) and copper (II) salts, such as Cu(OAc)2,
Cu(OTf)2 and CuCl2(Table 1, entries 4 and 5) were tested using
DMF as solvent at 70 °C. CuI showed the highest activity for
this reaction and resulted in 49% yield (Table 1, entries 3).
Although the reaction time could be significantly shortened
to 30 h when O2 was employed as oxidant, the yield was
not increased. Thus, air was chosen as the oxidant for its
abundance, low cost, and convenience. Other solvents, such as
CH3CN, MeNO2, dioxane and DMA proved to be less effective
for the reaction (Table 1, entries 9−12). Furthermore, the yield
decreased when the temperature was changed to 80 or 60 °C
(Table 1, entries 13 and 14).
Various substituted 2-aminopyridines and β-keto esters
were investigated using CuI as a catalyst in DMF. The results
are listed in Table 2. 2-Phenyl-imidazo[1,2-a]pyridine-3-
carboxylates were prepared in moderate yield when 3-, 4- and
5-methyl substituted 2-aminopyridines were used as substrates.
In contrast, when 4-chloro-2-aminopyridine was used as sub-
strate, only 10% of the desired product was obtained (Table 2,
entry 5). On the other hand, methyl, chloro and methoxyl
groups in the para position of β-keto esters have no significant
influence on the reaction.
On the basis of Yan’s study20 and the above experimental
results, a mechanism for the reaction is proposed (Scheme 2).
Enamination of β-keto esters 2 with 2-aminopyridines 1 affords
Table 1 Optimisation of the reaction conditionsa
Entry Catalyst Oxidant Solvent Temp./°C Time/h Yield/%b
1
2
CuCl
CuBr
CuI
Air
Air
Air
Air
Air
Air
O2
Air
Air
Air
Air
Air
Air
DMF
DMF
70
70
70
70
70
70
70
70
70
70
70
80
60
60
60
60
60
60
60
30
60
60
60
60
60
60
11
18
3
DMF
49
4
Cu(OTf)2
Cu(OAc)2
CuCl2
CuI
DMF
6
5
DMF
13
6
DMF
15
7
DMF
48
9
CuI
MeCN
MeNO2
dioxane
DMA
DMF
27
10
11
12
13
14
CuI
Trace
22
CuI
CuI
Trace
40
30
CuI
CuI
DMF
a Reaction conditions: 1a (0.60 mmol), 2a (0.50 mmol), catalysts
(0.05 mmol), 2 mL of solvent, in an open tube. b Isolated yield
based on 2a.
Scheme 1
* Correspondent. E-mail: xqli@zjut.edu.cn

526 JOURNAL OF CHEMICAL RESEARCH 2012
Table 2 Synthesis of imidazo[1,2-a]pyridinesa
After the mixture was cooled to room temperature, the resulting
mixture was diluted with ethyl acetate (15 mL) and filtered through
celite. The filtrate was washed with brine (10mL) and dried over anhy-
drous Na2SO4. After evaporation of the solvent under vacuum, the
residues were purified by column chromatography, eluting with
petroleum ether/EtOAc to give pure 3.
Ethyl 2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3a): White
Product Yield/%b
1
solid, m.p. 65–66 °C (lit.19 66–67 °C); H NMR (500 MHz, CDCl3)
Entry
R1
R2
R3
δ 9.42 (d, J = 7.0 Hz, 1H), 7.87–7.65 (m, 3H), 7.54–7.34 (m, 4H), 7.04
(td, J = 6.9, 1.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 161.1, 153.6, 147.1, 134.5, 130.2,
128.7, 128.4, 127.9, 127.5, 117.5, 114.1, 112.0, 60.4, 14.0.
Ethyl 8-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3b):
White solid, m.p. 110–111 °C (lit.19 113–114 °C); 1H NMR (500 MHz,
CDCl3) δ 9.27 (d, J = 6.9 Hz, 1H), 8.11–7.70 (m, 2H), 7.57–7.34 (m,
3H), 7.29–7.16 (m, 1H), 6.93 (t, J = 7.0 Hz, 1H), 4.28 (q, J = 7.1 Hz,
2H), 2.68 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 161.2, 153.1, 147.3, 134.9, 130.2, 128.5, 127.5, 126.7,
126.0, 114.0, 112.4, 60.3, 17.1, 13.9.
1
2
1a, H
1b, 3-Me
1c, 4-Me
1d, 5-Me
1e, 4-Cl
1a, H
1b, 3-Me 2b, MeO
1d, 5-Me 2b, MeO
1a, H
1d, 5-Me
1a, H
2a, H
2a, H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
49
32
28
38
10
41
34
34
53
42
45
3
2a, H
4
2a, H
2a, H
2b, MeO
5
6
7
8
9
2c, Me
2c, Me
2d, Cl
10
11
3j
3k
Ethyl 7-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3c):
a Reaction conditions: 1 (0.60 mmol), 2 (0.50 mmol), CuI (0.05
mmol), 2 mL of DMF, in an open tube at 70 °C for 60 h. b Isolated
yield based on 2.
1
White solid, m.p. 89–90 °C (lit.19 90–91 °C); H NMR (500 MHz,
CDCl3) δ 9.28 (d, J = 7.1 Hz, 1H), 7.76 (dd, J = 7.5, 1.8 Hz, 2H),
7.50 (s, 1H), 7.42 (d, J = 6.6 Hz, 3H), 7.26 (s, 1H), 6.87 (dd, J = 7.1,
1.3 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.22 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 161.2, 153.6, 147.5, 139.4, 134.6,
130.2, 128.6, 127.5, 116.6, 116.1, 111.5, 60.3, 21.4, 14.0.
β-enamino esters I, which undergo one-electron oxidation
with a copper catalyst to form intermediate II. Then hydride
abstraction with oxidation forms intermediate III. Finally,
intramolecular nucleophilic addition of intermediate III to
intermediate IV and the subsequent proton elimination gives
product 3.
In conclusion, we have developed a direct Cu(I)-catalysed
one-pot method for the synthesis of imidazo[1,2-a]pyridine-3-
carboxylates with aminopyridines and β-keto esters under air.
The procedure, using air as the oxidative agent, is a simple,
economical and environmentally friendly protocol for the
synthesis of imidazo-[1,2-a]pyridines-carboxylates.
Ethyl 6-methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3d):
1
White solid, m.p. 71–72 °C (lit.19 72–74 °C); H NMR (500 MHz,
CDCl3) δ 9.24 (s, 1H), 7.75 (dd, J = 7.5, 1.9 Hz, 2H), 7.65 (d, J =
9.0 Hz, 1H), 7.46–7.38 (m, 3H), 7.29 (dd, J = 9.1, 1.5 Hz, 1H), 4.30
(q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.3, 153.3, 146.1, 134.6, 130.9, 130.2, 128.6,
127.5, 126.2, 124.0, 116.7, 111.7, 60.4, 18.5, 14.0.
Ethyl 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-carboxylate (3e):
White solid, m.p. 116–117 °C (lit.19 117–119 °C); 1H NMR (500 MHz,
CDCl3) δ 9.51 (d, 1H, J = 1.1 Hz), 7.75–7.73 (m, 2H), 7.67 (d, 1H,
J = 9.3 Hz), 7.45–7.39 (m, 4H), 4.31 (q, 2H, J = 7.1 Hz), 1.22 (t, 3H,
J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 161.0, 154.1, 145.4, 134.1,
130.2, 129.3, 129.0, 127.7, 126.4, 122.5, 117.8, 112.4, 60.8, 14.0.
Ethyl 2-(4-methoxyl-phenyl)imidazo[1,2-a]pyridine-3-carboxylate
(3f): White solid, m.p. 78–79 °C; 1H NMR (500 MHz, CDCl3) δ 9.42
(d, J = 7.0 Hz, 1H), 7.76 (dd, J = 12.1, 5.4 Hz, 3H), 7.47–7.41 (m, 1H),
7.03 (td, J = 6.9, 1.0 Hz, 1H), 7.00–6.94 (m, 2H), 4.34 (q, J = 7.1 Hz,
2H), 3.88 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 161.2, 160.1, 153.4, 147, 1, 131.6, 128.4, 127.8, 126.8,
117.3, 113.8, 113.0, 111.6, 60.4, 55.3, 14.1. HRMS Calcd for
C17H16N2O3 [M+H]+: 297.1239. Found: 297.1232.
Experimental
Melting points were measured on a Büchi B-545. H NMR and 13C
1
NMR spectra were obtained on a Bruker AVANCE III 500 (500 MHz)
instrument in CDCl3 using tetramethylsilane (TMS) as internal stan-
dard. Chemical shifts (δ) were reported in ppm and coupling constants
J are given in Hz. ESI–MS spectra were determined on a LCQ Deca
XP Plus ion-trap mass spectrometer, Commercially obtained reagents
were used without further purification.
Ethyl 8-methyl-2-(4-methoxyl-phenyl)imidazo[1,2-a]pyridine-3-
1
carboxylate (3g): White solid, m.p. 88–90 °C; H NMR (500 MHz,
Synthesis of imidazo[1,2-a]pyridines (3); typical procedure
A mixture of 1 (0.60 mmol), 2 (0.50 mmol), and CuI (9.5 mg,
0.05 mmol) in DMF (2 mL) was stirred at 70 °C under air for 60 h.
CDCl3) δ 9.25 (d, J = 6.9 Hz, 1H), 7.76–7.71 (m, 2H), 7.20 (d, J =
7.0 Hz, 1H), 7.00–6.94 (m, 2H), 6.91 (t, J = 7.0 Hz, 1H), 4.31 (q, J =
7.1 Hz, 2H), 3.86 (s, 3H), 2.67 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C
Scheme 2 Plausible reaction mechanism.

JOURNAL OF CHEMICAL RESEARCH 2012 527
NMR (125 MHz, CDCl3) δ 161.3, 160.0, 152.9, 147.3, 131.6, 127.2,
126.7, 126.1, 113.8, 113.0, 112.0, 60.3, 55.3, 17.0, 14.1. HRMS Calcd
for C18H18N2O3 [M+H]+: 311.1396. Found: 311.1387.
Received 13 May 2012; accepted 19 June 2012
Paper 1201311 doi: 10.3184/174751912X13415906694258
Published online: 28 August 2012
Ethyl 6-methyl-2-(4-methoxyl-phenyl)imidazo[1,2-a]pyridine-3-carb-
1
oxylate (3h): White solid, m.p. 128–130 °C; H NMR (500 MHz,
References
CDCl3) δ 9.23 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 9.0 Hz,
1H), 7.29 (d, J = 0.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.32 (q, J =
7.1 Hz, 2H), 3.87 (s, 3H), 2.42 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 161.3, 160.1, 153.1, 146.1, 131.6, 130.8,
127.0, 126.3, 123.8, 116.5, 113.0, 111.3, 60.3, 55.3, 18.5, 14.1. HRMS
Calcd for C18H18N2O3 [M+H]+: 311.1396. Found: 311.1386.
1
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White solid, m.p. 86–88 °C (lit.21 90–93 °C); H NMR (500 MHz,
CDCl3) δ 9.40 (d, J = 7.0 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.69 (d,
J = 8.1 Hz, 2H), 7.44 – 7.39 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.01
(td, J = 6.9, 1.0 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.26
(t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 161.2, 153.8, 147.1,
138.6, 131.5, 130.1, 128.3, 128.2, 127.8, 60.4, 21.4, 14.1. HRMS
Calcd for C17H16N2O2 [M+H]+: 281.1290. Found: 281.1286.
Ethyl 6-methyl-2-(4-methyl-phenyl)imidazo[1,2-a]pyridine-3-carb-
oxylate (3j): Lxq110: White solid, m.p. 84–86 °C (lit.21 73–75 °C); 1H
NMR (500 MHz, CDCl3) δ 9.22 (d, J = 0.6 Hz, 1H), 7.67 (d,
J = 8.1 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H), 7.27 (dd, J = 8.6, 1.9 Hz,
1H), 7.23 (d, J = 8.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.41 (s, 6H),
1.25 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 161.3, 153.5,
146.1, 138.4, 131.7, 130.8, 130.1, 128.2, 126.2, 123.8, 116.6, 111.5,
60.3, 21.4, 18.5, 14.1. HRMS Calcd for C18H18N2O2 [M+H]+: 295.1447.
Found: 295.1434.
7
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Methyl 2-(4-chloro-phenyl)imidazo[1,2-a]pyridine-3-carboxylate (3k):
White solid, m.p. 129–130 °C (lit.19 130–132 °C); 1H NMR (500 MHz,
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We thank the National Natural Science Foundation of China
(21102130) for financial support.

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