CuSO4-glucose for in situ generation of controlled Cu(I)-Cu(II) bicatalysts: Multicomponent reaction of heterocyclic azine and aldehyde with alkyne, and cycloisomerization toward synthesis of N-fused imidazoles

Article abstract of DOI:10.1021/jo3003024

The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO₄ with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A³-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco-friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process.

Full text of DOI:10.1021/jo3003024

Note
pubs.acs.org/joc
CuSO4−Glucose for in Situ Generation of Controlled Cu(I)−Cu(II)
Bicatalysts: Multicomponent Reaction of Heterocyclic Azine and
Aldehyde with Alkyne, and Cycloisomerization toward Synthesis of
N-Fused Imidazoles
Sankar K. Guchhait,*,† Ajay L. Chandgude,‡ and Garima Priyadarshani†
‡
†Department of Medicinal Chemistry, Department of Pharmaceutical Technology (Bulk Drugs), National Institute of
Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali), 160062, Punjab, India
S
* Supporting Information
ABSTRACT: The catalytic efficiency of mixed Cu(I)−Cu(II) system
in situ generated by partial reduction of CuSO4 with glucose in ethanol
(nonanhydrous) under open air has been explored. With this catalysis,
the multicomponent cascade reaction of A3-coupling of heterocyclic
amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and
prototropic shift has afforded an efficient and eco-friendly synthesis of
therapeutically important versatile N-fused imidazoles. Diverse
heterocyclic amidines, several of which are known to be poorly
reactive, and aldehydes are compatible in this catalytic process.
reported. However, these methods suffer from the requirements
he multicomponent reaction of aldehyde with amine and
3
Talkyne (A -coupling) toward synthesis of propargyl amine of a stringent anaerobic procedure and harsh conditions and
has gained importance in organic synthesis.1 Its incorporation
limited substrate scope.
The Cu(I)-catalyst in situ generated from Cu(II) and
reducing agents especially sodium ascorbate in water provides
excellent results for the modified Huisgen cycloaddition9,10 of
alkyne with azide to form triazole, the most efficient click
chemical reaction.11 The reduction of Cu(II) with reducing
sugar to Cu2O is used for the estimation of reducing sugar
(especially glucose) in analytical and clinical chemistry
(Fehling’s and Benedict’s tests). However, there is no report
for in situ generation and use of reduced metal [Cu(I)] as
catalyst in A3-coupling and its cascade process. We speculated
that Cu(I) in situ generated by reduction of CuSO4 with
reducing carbohydrates can be an efficient catalyst in A3-
coupling and cascade cycloisomerization toward synthesis of
imidazopyridine. Moreover, unlike reported procedures, this
approach could possibly facilitate the use of environment-
friendly solvent, avoidance of handling difficulty/hazards and or
costly σ/π-Lewis acid as catalyst, nonrequirement of anhydrous
conditions, and the reaction for versatile heterocyclic amidines
as well as other coupling components. It is noteworthy that like
imidazo[1,2-a]pyridine, other N-fused imidazoles12,13 and their
derivatives14 are also therapeutically important, yet their
syntheses were not explored in reported methodologies.
Here, we report a mixed Cu(I)−Cu(II) system in situ
generated from partial reduction of CuSO4 with glucose in
ethanol (nonanhydrous) under open air, that efficiently
catalyzes the cascade reaction of A3-coupling−cycloisomeriza-
in cascade processes of tethered cyclization with activation of
triple bond in propargyl amine affords access to versatile
molecular complex compounds.2 In these reaction sequences,
the group 11 metal (Cu, Ag, and Au) salts offer efficient
catalysis for alkyne C−H activation in alkynylation with σ-
activated imine and π-activation of triple bond toward
cyclization. The synthesis of many novel scaffolds/motifs
have been successfully accomplished with the use of a mixture
of catalytic species that are chemically compatible, such as
mixed copper salts [CuCl−Cu(OTf)2],3 Cu(I)−Au(III)
system,4 and CuBr−Wilkinson’s catalyst.5 Recently, a strategic
use of this approach with CuCl−Cu(OTf)2 catalysis6 has been
documented for the multicomponent synthesis of imidazo[1,2-
a]pyridine,7 a medicinally important scaffold, from 2-amino-
pyridine (a less reactive amine), aldehyde, and alkyne (Scheme
1). Several drugs such as zolpidem, necopidem, and saripidem
are accessible by this one-pot synthesis.6
For this cascade reaction, the subsequent modifications on
catalysis such as Cu(I)−p-TsOH,8a Cu(I)−NaHSO4−SiO2,8b
CuCl−ZnCl2,8c and InBr3 under basic conditions8d have been
Scheme 1. Approach of Cascade A3-Coupling−Cyclization−
Prototropic Shift toward Synthesis of Imidazopyridine
Received: February 16, 2012
Published: April 9, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
tion toward environment-friendly access to N-fused imidazoles.
In this catalytic process, various heterocyclic amidines, several
of which are poorly reactive amines, aldehydes, and alkynes
afforded versatile N-fused imidazoles in good to high yields
(Scheme 2).
Table 1. Evaluation of Cu(II)-Reducing Agents and
Conditions
a
Scheme 2. Cu(I)−Cu(II) Catalysis in A3-Coupling and
Cascade Cycloisomerization: Synthesis of Versatile N-Fused
Imidazoles
reducing
agent
temp
yield
c
b
entry Cu-catalyst (mol %)
(mol %)
solvent
EtOH
(°C)
(%)
1
2
3
4
5
6
CuSO4·5H2O (5)
CuSO4·5H2O (5)
CuSO4·5H2O (5)
CuSO4·5H2O (5)
CuSO4·5H2O (5)
CuSO4·5H2O (5)
Na-ascorbate
(10)
80
37
17
20
Na-ascorbate
(10)
H2O
80
80
80
80
80
Na-ascorbate
(10)
toluene
Na-ascorbate
(10)
EtOH−
22
H2O
d
Na-ascorbate
(10)
toluene−
NR
H2O
Our investigation centered on in situ generation of Cu(I) by
reduction of Cu(II) salt with reducing carbohydrates and its
function as π- and σ-electrophilic Lewis acid in cascade A3-
coupling and 5-exo-dig cycloisomerization. Accordingly, we
evaluated the efficiency of Cu(II) salts, reducing agents,
solvents, and conditions. 2-Aminopyridine, benzaldehyde, and
phenylacetylene were chosen as model substrates. The results
are summarized in Table 1. Initial experiments for the survey of
Cu(II) salts (CuSO4, Cu(OAc)2, CuCl2, and Cu(NO3)2),
reducing agents (sodium ascorbate, D-glucose, trisodium citrate,
lactose), and solvents (H2O, EtOH, PEG-400, toluene, EtOH−
H2O, PEG-400−H2O, toluene−H2O) revealed CuSO4−
glucose−EtOH to be most effective. The superior efficiency
of CuSO4−glucose−ethanol impelled us to investigate
isopropoanol as both reducing agent and solvent in place of
glucose−ethanol. However, it resulted in inferior yield of
product (data not shown in table). Use of water as solvent or its
mixture with other solvents (Table 1, entries 2 and 4−6)
promoted the oxidative dimerization of alkyne more. This
might be plausibly due to enhanced oxidation potential of
Cu(II) in these solvents. On the other hand, the presence of
Cu(II) was found to be necessary. The reaction conditions that
can promote enhanced formation of Cu(I) with reduced
possibility of regenerating back to Cu(II), such as the use of
higher quantity of glucose or anhydrous deoxygenated EtOH
under nitrogen, resulted in inferior yields of product (Table 1,
entries 13−16). The presence of Cu(II) in optimized
conditions under open air was confirmed by treating the
reaction mixture with aqueous ammonia or potassium
ferrocyanide solutions, which generated blue color or red
precipitates, respectively. These indicate that this A3-coupling−
cycloisomerization cascade requires the crucial optimum
conditions, which can provide controlled partial reduction of
Cu(II) to Cu(I) toward in situ generation of mixed Cu(I)−
Cu(II) catalysts system, but does not induce oxidation to
susceptible reactant such as alkyne by Cu(II). Increasing the
temperature from 80 to 100 °C enhanced the yield (Table 1,
entry 13 vs 15). Variation in equivalence revealed that CuSO4
(15 mol %)−glucose (30 mol %) (Table 1, entries 8 and 14 vs
13) was best. The reactions catalyzed by commercially received
CuCl, CuSO4, or CuCl−CuSO4 (Table 1, entries 17−19)
provided inferior results. These reveal the superior catalytic
efficiency of the mixed Cu(I)−Cu(II) system in situ generated
from CuSO4−glucose in EtOH under open air for this cascade
reaction. The experimental procedure is simple and straightfor-
ward.
Na-ascorbate
(10)
PEG−
15
H2O
7
8
9
CuSO4·5H2O (10)
CuSO4·5H2O (10)
CuSO4·5H2O (10)
lactose (20)
glucose (20)
EtOH
EtOH
80
80
80
32
50
35
trisod. citrate EtOH
(20)
10
11
Cu(OAc)2·H2O
(10)
glucose (20)
EtOH
80
80
43
12
Cu(NO3)2·3H2O
(10)
glucose (20)
EtOH
12
13
14
15
16
17
18
19
CuCI2 (10)
glucose (20)
glucose (30)
glucose (30)
glucose (30)
glucose (30)
glucose (30)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
80
80
17
56
26
79
68
56
12
63
CuSO4·5H2O (15)
CuSO4·5H2O (10)
CuSO4·5H2O (15)
CuSO4·5H2O (15)
CuCI (15)
80
100
100
100
100
100
e
CuSO4·5H2O (15)
CuCI(15) and
CuSO4·5H2O (5)
a
Reactants (mmol): 2-aminopyridine (1 mmol), benzaldehyde (1
mmol), phenylacetylene (1.5 mmol). Solvents were used as
commercially received without further distillation. Silicon oil bath
temperature. Isolated yields. No Reaction. Reaction was carried out
using anhydrous deoxygenated EtOH under N2.
b
c
d
e
With the optimized multicomponent protocol in hand, we
next set out to explore its scope. To our delight, versatile
heterocyclic amidines including 2-aminopyridine, 2-amino-
pyrazine, 2-aminopyrazole, 2-aminothiazole, and 2-amino-
benzimidazole underwent smooth reactions (Table 2). This
generalization of the present method is particularly interesting
because the heterocyclic amidines other than 2-aminopyridine
are known to be poorly reactive azines in multicomponent
reactions,13d,e,15 were not explored previously in this type of
cascade methodologies, and provide therapeutically important
compounds. Various aromatic aldehydes and alkynes afforded
good to high yields of products. However, aliphatic aldehydes
provided less yields because of fewer conversions, and aliphatic
alkynes (octyne and hexyne) resulted in formation of complex
mixture of products. Both electron-withdrawing and donating
functionalities on aldehydes were equally compatible.
The tolerance of functionalities such as chloro, bromo, nitro,
methoxy, and cyano in this protocol provides the opportunity
of their various further chemical manipulations in products.
Several therapeutically relevant moieties could be incorporated
at ease by this method into N-fused imidazoles.
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Note
a
Table 2. Synthesis of Versatile N-Fused Imidazoles
a
b
c
Reaction conditions: A (1 mmol), B (1 mmol), C (1 mmol), CuSO4·5H2O (15 mol %), D-glucose (30 mol %). Isolated yields. Isobutyraldehyde
(1.5 mmol).
mg, 1 mmol) was stirred for 15 min. Ethanol (2 mL) was added,
followed by phenylacetylene (153 mg, 1.5 mmol). Then, CuSO4·5H2O
(12.5 mg, 15 mol %) and D-glucose (54 mg, 30 mol %) were added,
and the resulting mixture was refluxed at 100 °C (silicon oil bath
temperature). After completion of reaction as indicated by TLC (10
h), the resultant mixture was directly adsorbed on neutral alumina
(without work up) and purified by column chromatography on neutral
alumina (60−325 mesh) eluting with ethyl acetate−hexane. It afforded
3-benzyl-2-phenylimidazo[1,2-a]pyridine (224 mg, 79% yield).
All reactions for the synthesis of N-fused imidazoles (Table 2) were
carried out following this representative procedure. For solid
aldehydes, ethanol (0.2 mL) was used for initial stirring with
heterocyclic azines.
In conclusion, we have explored catalytic efficiency of mixed
Cu(I)−Cu(II) system in situ generated by partial reduction of
CuSO4 with glucose in ethanol (nonanhydrous) under open air
for the multicomponent reaction of heterocyclic azine and
aldehyde with alkyne and cycloisomerization toward synthesis
of N-fused imidazoles. Unlike previous processes, the present
method avoids the requirement of an anaerobic procedure and
encompasses versatile heterocyclic amidines toward preparation
of diverse motifs in good to high yields. This approach is an
inexpensive, simple, general, and environmentally benign way
to synthesize N-fused imidazoles, which are of therapeutic
interests. This work reveals an inexpensive, eco-friendly, and
novel use of CuSO4−glucose as surrogate to efficient Cu(I)−
Cu(II) bicatalyst system in organic synthesis.
3-Benzyl-2-phenylimidazo[1,2-a]pyridine (Table 2, Entry
1).6,8 White crystalline solid: mp 118−120 °C; 224 mg, 79% yield;
EXPERIMENTAL SECTION
■
General Considerations. The starting materials and solvents were
used as received from commercial sources without further purification.
The 1H and 13C spectra were recorded in CDCl3/CD3OD solvents on
a 400 MHz spectrometer using TMS as internal standard. Melting
points determined are uncorrected.
IR (KBr) vmax 3073, 2924, 1652, 1602, 1491, 1447, 1352, 1254, 1073
cm−1; H NMR (400 MHz, CDCl3) δ = 7.80 −7.77 (m, 2H), 7.70−
1
7.68 (m, 2H), 7.43 (t, J = 6.6 Hz, 2H), 7.37 −7.34 (m, 1H), 7.33
−7.27 (m, 3H), 7.20 −7.16 (m, 1H), 7.15 (d, J = 6.9 Hz, 2H), 6.71 (t,
J = 6.8 Hz, 1H), 4.50 (s, 2H); 13C NMR (100 MHz, CDCl3) δ =
144.9, 144.2, 136.8, 134.5, 129.0, 128.6, 128.2, 127.74, 127.72, 126.9,
Representative Experimental Procedure for the Synthesis of
3-Benzyl-2-phenylimidazo[1,2-a]pyridine (Table 2, Entry 1). A
mixture of 2-aminopyridine (94 mg, 1 mmol) and benzaldehyde (106
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Note
124.2, 123.4, 117.7, 117.6, 112.2, 29.9; MS (APCI) m/z 285 (M +
H+).
3-Benzyl-7-methyl-2-phenylimidazo[1,2-a]pyridine (Table 2,
Entry 2).6,8b Light yellow crystals: mp 144−146 °C; 221 mg, 74%
2H), 4.53 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 143.5, 140.2,
135.7, 133.5, 129.4, 129.3, 128.9, 128.5, 128.4, 127.6, 127.3, 119.7,
116.5, 29.7; MS (APCI) m/z 286 (M + H+); HRMS (ESI) Calcd for
C19H16N3 [M + H]+ 286.1344, found m/z 286.1323.
Ethyl 3-Benzyl-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-car-
boxylate (Table 2, Entry 7). Yellow powder: mp 98−100 °C; 155
yield; IR (KBr) vmax 2956, 1646, 1494, 1453, 1360, 1259, 1028 cm−1;
1H NMR (400 MHz, CDCl3) δ = 7.78−7.76 (m, 2H), 7.56 (d, J = 6.9
Hz, 1H), 7.43−7.39 (m, 3H), 7.35−7.31 (m, 3H), 7.28−7.22 (m, 1H),
7.14 (d, J = 6.9 Hz, 2H) 6.52 (dd, J = 6.9 Hz, J = 1.6 Hz, 1H), 4.46 (s,
2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 145.3, 143.8,
137.1, 135.1, 134.7, 129.0, 128.6, 128.1, 127.7, 127.6, 126.9, 122.7,
117.0, 115.9, 114.8, 29.9, 21.3; MS (APCI) m/z 299 (M + H+).
3-Benzyl-6-chloro-2-phenylimidazo[1,2-a]pyridine (Table 2,
Entry 3). Off-white solid: mp 190−192 °C; 251 mg, 79% yield; IR
mg, 45% yield; IR (KBr) vmax 2956, 1698, 1610, 1491, 1463, 1224,
1
1055 cm−1; H NMR (400 MHz, CDCl3) δ = 8.6 (s, 1H), 8.29−8.27
(m, 2H), 8.04−8.02 (m, 2H), 7.62−7.61 (m, 3H), 7.55−7.53 (m, 5H),
7.41−7.39 (m, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ = 162.9, 159.1, 148.9, 147.94, 147.86,
136.6, 131.4, 131.2, 130.8, 129.5, 129.0, 128.9, 127.7, 106.4, 103.1,
60.3, 14.6; MS (APCI) m/z 345 (M+); HRMS (ESI) Calcd for
C21H20N3O2 [M + H]+ 346.1555, found m/z 346.1546 Calcd for
C21H19N3NaO2 [M + Na]+ 368.1375, found m/z 368.1371.
(KBr) vmax 3082, 2925, 1691, 1602, 1492, 1449, 1388, 1249, 1094
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.76 (d, J = 7.6 Hz, 2H), 7.74
(s, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.38−7.35
(m, 1H), 7.33−7.28 (m, 3H), 7.16−7.13 (m, 3H), 4.48 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ = 145.2, 143.2, 136.1, 133.9, 129.2, 128.7,
128.1, 128.0, 127.6, 127.2, 125.6, 121.2, 120.5, 117.9, 29.8; MS (APCI)
m/z 319 [M(35Cl) + H+], 321 [M(37Cl) + H+] in 3:1 ratio; HRMS
(ESI) Calcd for C20H16ClN2 [M + H]+ 319.1002, found m/z
319.0978; Calcd for C20H15ClN2Na [M + Na]+ 341.0822, found m/z
341.0787.
5-Benzyl-6-phenylimidazo[2,1-b]thiazole (Table 2, Entry 8).
Yellow powder: mp 106−108 °C; 133 mg, 46% yield; IR (KBr) vmax
2916, 2219, 1674, 1608, 1260, cm−1; 1H NMR (400 MHz, CDCl3) δ =
7.56−7.34 (m, 12H), 5.51 (d, J = 3.24 Hz, 1H), 5.42 (dd, J = 4.1 Hz, J
= 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 149.5, 140.8, 133.3,
131.1, 130.3, 129.5, 129.2, 129.1, 129.0, 126.6, 122.5, 113.0, 55.4; MS
(APCI) m/z 291 (MH+); HRMS (ESI) Calcd for C18H15N2S [M +
H]+ 291.0956, found m/z 291.0940 Calcd for C18H14N2SNa [M +
Na]+ 313.0776, found m/z 313.0776.
3-Benzyl-6-bromo-2-phenylimidazo[1,2-a]pyridine (Table 2,
Entry 4). Off-white crystals: mp > 200 °C; 290 mg, 80% yield; IR
1
(KBr) vmax 3076, 2924, 1602, 1491, 1448, 1324, 1249, 1074 cm−1; H
3-Benzyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole (Table
2, Entry 9). Yellow solid: mp > 200 °C; 202 mg, 63% yield; IR
NMR (400 MHz, CDCl3) δ = 7.82 (s, 1H); 7.76 (d, J = 7.2 Hz, 2H),
7.56 (d, J = 9.5 Hz, 1H), 7.44−7.40 (m, 2H), 7.37−7.26 (m, 4H), 7.22
(dd, J = 9.5 Hz, J = 1.5 Hz, 1H), 7.12 (d, J = 7.2 Hz, 2H), 4.46 (s, 2H);
13C NMR (100 MHz, CDCl3) δ = 145.0, 143.3, 136.2, 134.0, 129.2,
128.7, 128.1, 128.0, 127.65, 127.58, 127.1, 123.4, 118.24, 118.21,
106.9, 29.8 ; MS (APCI) m/z 363 [M(79Br) + H+], 365 [M(81Br) +
H+] in 1:1 ratio; HRMS (ESI) Calcd for C20H1679BrN2 [M + H]+
363.0497, found m/z 363.0485.
3-Benzyl-2-phenylimidazo[1,2-a]pyridine-6-carboxamide
(Table 2, Entry 5). Brown solid: mp > 200 °C; 249 mg, 76% yield; IR
(KBr) vmax 2955, 2372, 1466, 1275 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 8.32 (dd, J = 6.7 Hz, J = 3.2 Hz, 2H), 7.97 (d, J = 8.2 Hz,
1H), 7.74−7.63 (m, 5H), 7.54 (t, J = 3.2 Hz, 3H), 7.46 (t, J = 7.4 Hz,
1H), 7.26 (s, 2H), 7.03 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ = 153.5, 149.5, 136.7, 132.6, 131.3,
131.1, 129.4, 128.9, 128.4, 127.8, 125.9, 121.2, 120.3, 114.5, 105.3; MS
(APCI) m/z 322 (M − H+); HRMS (ESI) Calcd for C22H16N3 [M −
H]+ 322.1344, found m/z 322.1345.
3-Benzyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (Table 2,
Entry 10).8 White solid: mp 146−148 °C; 232 mg, 73% yield; IR
1
(KBr) vmax 2923, 2361, 1676, 1457, 1377, 1275 cm−1; H NMR (400
MHz, CD3OD) δ = 8.44 (s, 1H), 7.78 (d, J = 7.4 Hz, 2H), 7.70 (d, J =
9.1 Hz, 1H), 7.44−7.43 (m, 3H), 7.39−7.36 (m, 1H), 7.33−7.29 (m,
3H),7.13 (d, J = 7.2 Hz, 2H), 5.88 (bs, 2NH), 4.54 (s, 2H); 13C NMR
(100 MHz, CD3OD) δ = 170.8, 149.4, 148.8, 142.4, 139.3, 134.1,
133.9, 133.0, 132.72, 132.69, 131.9, 130.7, 128.6, 124.7, 124.5, 121.2,
33.8; MS (APCI) m/z 328 (M + H) +; HRMS (ESI) Calcd for
C21H18N3O [M + H]+ 328.145, found m/z 328.1435; Calcd for
C21H17N3ONa [M + Na]+ 350.1270, found m/z 350.1253.
3-Benzyl-2-phenylimidazo[1,2-a]pyrazine (Table 2, Entry 6).
Yellow crystals: mp 110−111 °C; 208 mg, 73% yield; IR (KBr) vmax
2924, 1701, 1629, 1534, 1428, 1260, 1065 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 9.14 (s, 1H); 7.81−7.79 (m, 3H), 7.66 (d, J = 4.2 Hz,
1H), 7.52−7.39 (m, 3H), 7.35 −7.28 (m, 3H), 7.11 (d, J = 6.8 Hz,
(KBr) vmax 3072, 2851, 1634, 1601, 1488, 1453, 1360, 1247, 1093
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.73−7.66 (m, 4H), 7.39 (d, J
= 8.6 Hz, 2H), 7.33−7.27 (m, 3H), 7.22−7.18 (m, 1H), 7.12 (d, J =
8.2 Hz, 2H), 6.73 (dt, J = 6.8 Hz, J = 1.1 Hz, 1H), 4.48(s, 2H); 13C
NMR (100 MHz, CDCl3) δ = 144.9, 143.0, 136.5, 133.7, 133.0, 129.4,
129.1, 128.9, 127.6, 127.0, 124.5, 123.4, 117.8, 117.6, 112.4, 29.8; MS
(APCI) m/z 319 (M + H+).
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Note
HRMS (ESI) Calcd for C21H19N2 O2 [M + H]+ 331.1446, found m/z
331.1428 Calcd for C21H18N2NaO2 [M + Na]+ 353.1266, found m/z
353.1244.
3-Benzyl-2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine
(Table 2, Entry 16). Brown solid: mp 86−88 °C; 288 mg, 77% yield;
3-Benzyl-2-(4-bromophenyl)imidazo[1,2-a]pyridine (Table
2, Entry 11).6,8b−d Yellow crystals: decomposes at 160 °C; 257
mg, 71% yield; IR (KBr) vmax 3032, 2928, 1632, 1492, 1445, 1358,
1
1256, 1070 cm−1; H NMR (400 MHz, CDCl3) δ = 7.71−7.69 (m,
2H), 7.66 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8 Hz, 2H), 7.32−7.28 (m,
3H), 7.20 (t, J = 8 Hz, 1H), 7.12 (d, J = 7.4 Hz, 2H), 6.73 (t, J = 6.7
Hz, 1H), 4.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 144.9, 143.0,
136.5, 133.5, 131.8, 129.7, 129.1, 127.6, 127.0, 124.5, 123.4, 121.9,
117.9, 117.6, 112.4, 29.8; MS (APCI) m/z 363 [M(79Br) + H+], m/z
365 [M(81Br) + H+] in 1:1 ratio.
1
IR (KBr) vmax 2925, 1605, 1502, 1462, 1363, 1242, 1126 cm−1; H
NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 6.4 Hz, 1H), 7.71 (d, J = 9.0
Hz, 1H), 7.32−7.29 (m, 2H), 7.24−7.19 (m, 2H), 7.13 (d, J = 7.2 Hz,
2H), 6.97 (s, 2H), 6.77 (t, J = 6.8 Hz, 1H), 4.51 (s, 2H), 3.87 (s, 3H),
3.75 (s, 6H); 13C NMR (100 MHz, CDCl3) δ = 153.4, 144.7, 144.0,
137.8, 136.9, 129.9, 129.1, 127.6, 126.9, 124.4, 123.2, 117.6, 117.5,
112.5, 105.2, 60.9, 56.0, 29.9; MS (APCI) m/z 375 (M + H+); HRMS
(ESI) Calcd for C23H23N2O3 [M + H]+ 375.1708, found m/z
375.1695; Calcd for C23H22N2NaO3 [M + Na]+ 397.1528, found m/z
397.1509.
3-Benzyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (Table 2,
Entry 12).6,8a−c Light yellow oil: 217 mg, 72% yield; IR (neat) vmax
1
2955, 1603, 1499, 1453, 1359, 1260, 750 cm−1; H NMR (400 MHz,
(E)-3-Benzyl-2-styrylimidazo[1,2-a]pyridine ((Table 2, Entry
17). Light orange solid: mp 185−186 °C; 217 mg, 70% yield; IR
CDCl3) δ = 7.75−7.67 (m, 4H), 7.33−7.27 (m, 3H), 7.20 (dt, J = 6.8
Hz, J = 1.2 Hz, 1H), 7.17−7.09 (m, 4H), 6.72 (dt, J = 7.2 Hz, J = 1.1
Hz, 1H), 4.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 162.6 (d,
JC−F = 245 Hz), 144.9, 143.3, 136.6, 130.6, 129.9 (d, JC−C−C−F = 8 Hz),
129.1, 127.7, 127.0, 123.9 (d, JC−C−F = 95 Hz), 117.5, 115.7, 115.5,
112.3, 29.8; MS (APCI) m/z 303 (M + H+).
4-(3-Benzylimidazo[1,2-a]pyridin-2-yl)benzonitrile (Table 2,
Entry 13).6,8b,c Light yellow solid: mp 134−136 °C; 253 mg, 82%
(KBr) vmax 3076, 2923, 1624, 1601, 1491, 1449, 1354, 1252, 1070
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 8.2 Hz, 1H), 7.68
(s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.35 (t, J =
7.4 Hz, 2H), 7.30−7.23 (m, 5H), 7.17−7.13 (m, 3H), 6.66 (t, J = 6.7
Hz, 1H) 4.40 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 145.2, 137.4,
136.5, 130.9, 128.9, 128.7, 128.0, 127.7, 127.0, 126.7, 126.5, 124.9,
123.3, 119.9, 118.0, 117.0, 112.1, 29.1; MS (APCI) m/z 311(M + H+);
HRMS (ESI) Calcd for C22H19N2 [M + H]+ 311.1548, found m/z
311.1521.
yield; IR (KBr) vmax 3043, 2223, 1676, 1610, 1494, 1450, 1356, 1258
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.90 (d, J = 6.7 Hz, 2H), 7.74
(d, J = 6.8 Hz, 1H), 7.71−7.68 (m, 3H), 7.35−7.28 (m, 3H), 7.24−
7.21 (m, 1H), 7.12 (d, J = 6.8 Hz, 2H), 6.77 (dt, J = 6.8 Hz, J = 1.0 Hz,
1H), 4.51 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 145.2, 142.0,
139.1, 136.0, 132.5, 129.2, 128.5, 127.6, 127.2, 125.1, 123.5, 119.0,
117.8, 112.8, 111.1, 29.8; MS (APCI) m/z 310 (M + H+).
3-Benzyl-2-isopropylimidazo[1,2-a]pyridine (Table 2, Entry
18).6,8a,b Yellow crystals: mp 84−86 °C; 50 mg, 20% yield; IR (KBr)
3-Benzyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (Table 2,
Entry 14).8b−d Yellow solid: mp 156−158 °C; 240 mg, 73% yield; IR
1
vmax 2925, 1219, 1069, 772 cm−1; H NMR (400 MHz, CDCl3) δ =
7.63−7.59 (m, 2H), 7.28−7.24 (m, 2H), 7.21 (d, J = 7.0 Hz, 1H),
7.09−7.05 (m, 3H), 6.61 (dt, J = 6.6 Hz, J = 1.2 Hz, 1H), 4.28 (s, 2H),
3.26−3.19 (m, 1H), 1.41 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ = 150.6, 144.6, 137.2, 128.8, 127.8, 126.7, 123.2, 123.1,
117.1, 116.2, 111.5, 28.9, 26.7, 23.1; MS (APCI) m/z 251 (M + H+).
3-Benzyl-2-(pyridin-4-yl)imidazo[1,2-a]pyridine (Table 2,
Entry 19). Off white solid: mp 124−125 °C; 199 mg, 70% yield; IR
(KBr) vmax 3071, 2925, 2434, 1632, 1598, 1506, 1454, 1336, 1252,
1111 cm−1; 1H NMR (400 MHz CDCl3) δ = 8.29 (d, J = 7.1 Hz, 2H),
7.96 (d, J = 7.3 Hz, 2H), 7.75−7.69 (m, 2H), 7.32−7.31 (m, 4H), 7.13
(s, 2H), 6.79−6.77 (m, 1H), 4.53 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ = 145.2, 141.3, 137.4, 136.5, 128.9, 128.7, 128.0, 127.7,
127.0, 126.7, 124.9, 123.3, 119.9, 118.0, 112.0, 29.1; MS (APCI) m/z
330 (M + H+).
5-(3-Benzylimidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol
(Table 2, Entry 15). Dark yellow solid: mp 102−103 °C; 264 mg,
1
(KBr) vmax 3029, 2925, 1605, 1494, 1362, 1275 cm−1; H NMR (400
MHz, CD3OD) δ = 8.61 (d, J = 4.6 Hz, 2H), 8.07 (d, J = 6.6 Hz, 1H),
7.80 (d, J = 4.7 Hz, 2H), 7.67 (d, J = 9 Hz, 1H), 7.42−7.38 (m, 1H),
7.32−7.29 (m, 2H), 7.26−7.24 (m, 1H), 7.12 (d, J = 7.1 Hz, 2H), 6.93
(t, J = 6.5 Hz, 1H), 4.63 (s, 2H); 13C NMR (100 MHz, CD3OD) δ =
150.5, 146.6, 144.1, 140.8, 137.7, 130.2, 128.7, 128.2, 127.6, 125.6,
124.0, 122.4, 117.8, 114.5, 30.1; MS (APCI) m/z 286 (M + H+);
HRMS (ESI) Calcd for C19H16N3 [M + H]+ 286.1344, found m/z
286.1338 Calcd for C19H15N3Na [M + Na]+ 308.1164, found m/z
308.1141.
80% yield; IR (KBr) vmax 2925, 1629, 1601, 1501, 1438, 1249, 1026
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.72 (d, J = 9.2 Hz, 1H), 7.69
(d, J = 6.8 Hz, 1H), 7.41 (s, 1H), 7.30−7.28 (m, 3H), 7.24−7.18 (m,
2H), 7.13 (d, J = 7.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.72 (t, J = 6.7
Hz, 1H), 4.49 (s, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
146.7, 145.9, 136.6, 129.0, 127.7, 126.9, 124.5, 123.4, 120.2, 117.2,
114.6, 112.4, 110.9, 55.9, 29.8; MS (APCI) m/z 331 (M + H+);
3-Benzyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (Table 2,
Entry 20).8d Greenish-yellow solid: mp 160−162 °C; 191 mg, 66%
4442
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The Journal of Organic Chemistry
Note
yield; IR (KBr) vmax 3076, 2925, 1601, 1493, 1454, 1375, 1241, 1094
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.74 (d, J = 1.1 Hz, 1H), 7.69
(d, J = 8.5 Hz, 2H), 7.61 (d, J = 9.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H),
7.35−7.27 (m, 3H), 7.16 (dd, J = 9.5 Hz, J = 1.8 Hz, 1H), 7.11 (d, J =
7.0 Hz, 2H), 4.44 (s, 2H); 13C NMR (100 MHz, CDCl3) δ = 144.0,
143.3, 135.9, 134.0, 132.5, 129.31, 129.27, 128.9, 127.6, 127.3, 125.8,
121.2, 120.7, 118.5, 117.9, 29.8; MS (APCI) m/z 353 (MH+); HRMS
(ESI) Calcd for C20H15Cl2N2 [M + H]+ 353.0612, found m/z
353.0588; Calcd for C20H14Cl2N2Na [M + Na]+, 375.0432, found m/z
375.0419.
1
yield; IR (KBr) vmax 2956, 1956, 1460, 1378, 1275, 1033 cm−1; H
NMR (400 MHz, CDCl3) δ = 7.73 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 9.1
Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.35 (dd, J = 5.1 Hz, J = 0.8 Hz,
1H), 7.30−7.23 (m, 3H), 7.19−7.15 (m, 3H), 7.09 (dd, J = 5.0 Hz, J =
3.6 Hz, 1H), 6.71 (t, J = 6.8 Hz, 1H), 4.55 (s, 2H); 13C NMR (100
MHz, CDCl3) δ = 144.7, 138.4, 137.4, 136.3, 129.0, 127.79, 127.77,
127.0, 125.6, 124.7, 124.6, 123.2, 117.4, 117.3, 112.5, 29.9; MS (APCI)
m/z 291 (M + H+); HRMS (ESI) Calcd for C18H15N2S [M + H]+
291.0956, found m/z 291.0935 Calcd for C18H14N2NaS [M + Na]+,
313.0776, found m/z 313.0754.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra of 1H for known compounds; spectra of 1H and 13C for
unknown compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
4-(3-(4-Methylbenzyl)imidazo[1,2-a]pyridin-2-yl)-
benzonitrile (Table 2, Entry 21).6 Off-white solid: mp 140−141 °C;
AUTHOR INFORMATION
Corresponding Author
*Fax: 91 (0)172 2214692. Tel: 91 (0)172 2214683. E-mail:
skguchhait@niper.ac.in.
■
233 mg, 72% yield; IR (KBr) vmax 3092, 2923, 2226, 1695, 1608, 1499,
1
1443, 1361, 1255, 1114 cm−1; H NMR (400 MHz, CDCl3) δ = 7.90
Notes
The authors declare no competing financial interest.
(d, J = 7.6 Hz, 2H), 7.75 (d, J = 6.4 Hz, 1H), 7.71−7.69 (m, 3H),
7.23−7.21 (m, 1H), 7.13 (d, J = 7.1 Hz, 2H), 7.0 (d, J = 7.0 Hz, 2H),
6.76 (t, J = 6.2 Hz, 1H), 4.46 (s, 2H), 2.33 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 145.1, 141.9, 139.2, 136.9, 132.9, 132.4, 129.9,
128.5, 127.4, 124.9, 123.6, 119.3, 119.0, 117.8, 112.7, 110.9, 29.4, 21.0;
MS (APCI) m/z 324 (M + H+).
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from DST, New
Delhi for this investigation.
4-(3-(Pyridin-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl)-
benzonitrile (Table 2, Entry 22). Brown solid: mp 166−168 °C;
REFERENCES
■
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214 mg, 69% yield; IR (KBr) vmax 2956, 2225, 1607, 1459, 1377, 1260,
1078 cm−1; 1H NMR (400 MHz, CDCl3) δ = 8.6 (dt, J = 4.0 Hz, J =
0.8 Hz, 1H), 7.99−7.95 (m, 3H), 7.73 (d, J = 6.7 Hz, 2H), 7.67 (d, J =
9.1 Hz, 1H), 7.60 (dt, J = 7.7 Hz,, J = 1.8 Hz, 1H), 7.24−7.19 (m, 2H),
7.98 (d, J = 7.9 Hz, 1H), 6.80 (dt, J = 6.8 Hz, J = 1.1 Hz, 1H), 4.64 (s,
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139.2, 137.3, 132.5, 128.7, 125.1, 123.8, 122.3, 121.9, 119.0, 118.5,
117.8, 112.8, 111.1, 33.0; MS (APCI) m/z 311 (M + H+); HRMS
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1
yield; IR (KBr) vmax 2924, 1696, 1604, 1446, 1247, 1070 cm−1; H
́
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NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 9.4
Hz, 1H), 7.70 (d, J = 6.9 Hz, 1H), 7.45−7.41 (m, 2H), 7.37−7.35 (m,
1H), 7.19 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.6
Hz, 2H), 6.72 (t, J = 6.7 Hz, 1H), 4.46 (s, 2H), 2.33 (s, 3H); 13C
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129.7, 128.6, 128.3, 127.8, 127.6, 124.3, 123.5, 117.9, 117.5, 112.3,
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