Copper-Catalyzed C-N Bond Formation via C-H Functionalization: Facile Synthesis of Multisubstituted Imidazo[1,2- a ]pyridines from N -(2-Pyridinyl)enaminones

Article abstract of DOI:10.1055/s-0037-1610071

An efficient, new copper-catalyzed approach to the construction of the multisubstituted imidazo[1,2- a ]pyridine skeleton from N -(2-pyridinyl)enaminones has been developed.

Full text of DOI:10.1055/s-0037-1610071

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
S. Cacchi et al.
Paper
Synthesis
Copper-Catalyzed C–N Bond Formation via C–H Functionalization:
Facile Synthesis of Multisubstituted Imidazo[1,2-a]pyridines from
N-(2-Pyridinyl)enaminones
Sandro Cacchia
Alessia Cioglia
Nicola Demitrib
O
R1
R1
R2
CuI, 1,10-phenanthroline
Li2CO3
O
Giancarlo Fabrizia
Francesca Ghirgac
Antonella Goggiamania
Antonia Iazzetti*a
Doriano Lambad
N
DMF, 100 °C
N
R3
R3
N
N
H
R2
46–96%
13 examples
a Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza,
Università di Roma, P.le A. Moro 5, 00185 Rome, Italy
antonella.goggiamani@uniroma1.it
antonia.iazzetti@uniroma1.it
b Elettra-Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science
Park, 34149 Basovizza, Trieste, Italy
c Center for Life Nano Science@Sapienza, Istituto Italiano di
Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
d Istituto di Cristallografia–CNR, S.S. 14 Km 163.5 in Area
Science Park, 34149 Basovizza, Trieste, Italy
Received: 01.03.2018
Accepted after revision: 03.05.2018
Published online: 28.06.2018
O
R1
R1
R2
O
N
Cu (cat.)
N
R3
R3
DOI: 10.1055/s-0037-1610071; Art ID: ss-2018-t0143-op
N
N
H
R2
Abstract An efficient, new copper-catalyzed approach to the con-
struction of the multisubstituted imidazo[1,2-a]pyridine skeleton from
N-(2-pyridinyl)enaminones has been developed.
1
2
Scheme 1 Copper-catalyzed cyclization of N-(2-pyridinyl)enaminones
1 to imidazo[1,2-a]pyridines 2: working hypothesis
Key words copper, enaminones, imidazo[1,2-a]pyridines, cyclization,
C–N bond formation, C–H functionalization
The imidazo[1,2-a]pyridine motif is a key structural
feature present in a wide variety of biologically active natu-
ral compounds and commercially available synthetic drugs5
such as zolpidem (a hypnotic drug),6 zolimidine (an antiul-
cer drug),7 alpidem (an anxiolytic agent),8 and loprinone (a
cardiotonic agent).9 The imidazo[1,2-a]pyridine moiety is
also present in drug candidates such as GSK812397 (candi-
date for the treatment of HIV infection).10 Thus, although
several approaches to its construction have been de-
scribed,11 the great potential of compounds featuring this
scaffold makes them valuable synthetic targets and justifies
the continuing efforts in the development of new general
and versatile methods for the synthesis of imidazo[1,2-
a]pyridine derivatives, particularly of methods that are
broad in scope and allow for the easy introduction of sever-
al points of diversity. Herein, we report just such a synthe-
sis involving the copper-catalyzed cyclization of N-(2-
pyridinyl)enaminones 1.
Because of their peculiar electronic properties (ambi-
dent nucleophilic character at the enamine moiety and am-
bident electrophilic character at the enone moiety) β-
enaminones are very useful synthetic intermediates.1 Thus,
they have been widely used to perform a variety of cycliza-
tions,2 including transition-metal-catalyzed processes.3 In
this context, as part of a program devoted to the develop-
ment of new syntheses of heterocycles based on their
chemistry,4 we have shown that N-(aryl)enaminones are
useful substrates for the construction of the multisubstitut-
ed indole skeleton through a copper-catalyzed C–C bond
formation via a C–H functionalization process.4d On this ba-
sis, we surmised that the readily available N-(2-pyr-
idinyl)enaminones 1 might be suitable precursors of multi-
substituted imidazo[1,2-a]pyridines 2 through a cyclization
involving a related copper-catalyzed direct amination of a
C–H bond (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
S. Cacchi et al.
Paper
Synthesis
N-(2-Pyridinyl)enaminones 1 were prepared through
Sonogashira cross-coupling of terminal alkynes with aroyl
chlorides,12 followed by the conjugate addition of 2-amino-
pyridines with the resultant α,β-ynones13 (Scheme 2).
mation of the copper–enaminone complex hampers the cy-
clization and that generating
a stable copper–ligand
complex preventing its formation is crucial for the success
of the reaction.
Using the optimized conditions shown in Table 1, entry
9, we next explored the substrate scope of our procedure.
As shown in Table 2, a wide variety of imidazo[1,2-a]pyri-
dines can be prepared in good to excellent yield and several
useful functionalities are tolerated, including ether, cyano,
keto, fluoro, trifluoromethyl, chloro, and bromo substitu-
ents.
With the N-(3-bromo-5-methyl-2-pyridinyl)enaminone
derivative, a remarkable selectivity was observed that fa-
vors the C–N bond formation leading to 2m (Table 2, entry
13) as opposed to C–C bond formation via C–Br functional-
ization that would lead to the corresponding azaindole de-
rivative.4b
O
PdCl2(PPh3)2
CuI, Et3N
R1
O
Cl
R1
THF, r.t., 1 h
R2
R2
O
N
R1
R3
NH2
MeOH, 120 °C, 24–48 h
N
R3
N
H
R2
1
Scheme 2 Synthesis of N-(2-pyridinyl)enaminones 1
We started our study by examining the conversion of 1a
into the corresponding imidazo[1,2-a]pyridine 2a using CuI
as the catalyst and Li2CO3 as the base at 100 °C, and explor-
ing the influence of solvents, ligands and bases on the reac-
tion outcome. Some of the results of our screening study
are shown in Table 1. As expected, no evidence of the de-
sired product was attained when omitting CuI and ligands
in DMF (Table 1, entry 1). Compound 2a was isolated in low
yield with 0.05 equivalents of CuI in DMF in the absence of
ligands (Table 1, entry 2). All other parameters being the
same, 2a was formed in trace amounts when switching to
dioxane as solvent (Table 1, entry 3) and no evidence of its
formation was obtained in MeCN (Table 1, entry 4). Low
yields were observed using ligands such as L-proline and
dppe (Table 1, entries 5 and 6). We were pleased to find that
2a could be isolated in 60% and 67% yield with PPh3 and
DMEDA, respectively (Table 1, entries 7 and 8). However,
the best result in terms of yield, cost, and reaction time was
achieved with 1,10-phenanthroline (Table 1, entry 9).14 In-
terestingly, the replacement of Li2CO3 with K2CO3 led to a
considerable decrease in the yield (Table 1, entry 10).
To shed some light on the role of ligands in this reaction,
we carried out a brief NMR study that investigated the be-
havior of copper iodide a) with the starting enaminone in
the absence of added ligands, b) with dppe and subsequent
addition of enaminone, and c) with 1,10-phenanthroline
and subsequent addition of enaminone. These experiments
revealed that: a) the starting enaminone exhibits a strong
tendency to coordinate copper; b) dppe generates a copper
complex whose stability is similar to that of copper with
enaminone; thus, a mixture of copper–dppe and copper–
enaminone complexes is observed; c) 1,10-phenanthroline
gives rise to a strong copper complexation that is unaffect-
ed by the addition of enaminone. On the basis of these re-
sults and our screening data, it may be argued that the for-
It is worth noting that the enaminone-based approach
described in the present paper allows for the conversion of
2-aminopyridines and α,β-ynones into imidazo[1,2-a]pyri-
dines that are regioisomeric with respect to those generat-
ed via the direct copper(II)/iron(III)-cocatalyzed oxidative
intermolecular diamination process11l (Scheme 3).
Table 1 Optimization of the Reaction Conditionsa
O
Ph
Ph
O
N
N
Ph
N
N
Ph
H
1a
2a
Entry
Ligand (equiv)
Solvent
Time (h)
Yield (%) 2ab,c
1d
2
–
DMF
24
24
24
24
24
24
24
24
2
– (79)
37 (12)
traces (62)
– (62)
–
DMF
3
–
dioxane
MeCN
DMF
4
–
5
L-proline (0.1)
dppe (0.05)
PPh3 (0.1)
DMEDAe (0.05)
22 (52)
33 (29)
60 (7)
6
DMF
7
DMF
8
DMF
67 (–)
9
1,10-phenf (0.05)
1,10-phenf (0.05)
DMF
84 (–)
10
DMF
24
54g (–)
a Reaction conditions (unless otherwise stated): 1a (0.25 mmol), CuI (0.05
equiv), Li2CO3 (2 equiv), solvent (2 mL), 100 °C.
b Yield of isolated product.
c Values in parentheses refer to recovered 1a.
d In the absence of CuI.
e N,N-Dimethylethylenediamine.
f 1,10-Phenanthroline.
g With K2CO3 (2 equiv) instead of Li2CO3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
S. Cacchi et al.
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Synthesis
Table 2 Synthesis of Imidazo[1,2-a]pyridines 2a
Table 2 (continued)
Entry
2
Time (h) Yield (%)b
Entry
2
Time (h) Yield (%)b
O
Ph
O
Ph
9
N
5.5
69
CN
N
N
N
N
1
2
2
84
66
Ph
N
N
2i
2a
2b
2c
2d
2e
2f
OMe
Cl
O
O
2
3
4
5
6
10
5
87
OMe
N
OMe
N
N
Br
2j
O
O
Ph
CF3
2
24
24
86
56
46
78
Ph
Ph
Ph
Br
11
12
N
9
4
96
71
N
Ph
N
2k
O
O
Ph
OMe
Cl
N
OMe
N
N
2l
F
O
O
Ph
Me
N
N
Ph
13
21
80
N
N
Br
2m
O
a Reaction conditions: 1 (0.25 mmol), CuI (0.05 equiv), 1,10-phenanthro-
line (0.05 equiv), Li2CO3 (2 equiv), DMF (2.5 mL), 100 °C.
b Yield of isolated product.
3.5
Me
N
Ph
N
As to the reaction mechanism, a possible rationale, anal-
ogous to the one proposed for the related copper-catalyzed
synthesis of multisubstituted indoles from N-(aryl)enami-
nones,4d considers the following basic steps (Scheme 4):
formation of complex A through the reaction of 1 with CuI
under basic conditions; intramolecular nucleophilic attack
of the pyridine nitrogen to copper promoted by extraction
of the hydrogen bound to the carbon α to the carbonyl
group (the chemoselectivity of this step, favoring formation
of the Npyridine–Cu bond over the Cortho–Cu bond, is most
probably due to the higher negative charge that concen-
trates on the pyridine nitrogen following removal of the hy-
drogen from the carbon adjacent to the carbonyl carbon);
conversion of the resultant ate complex B into C through a
protonation reaction followed by a rearomatization/tau-
tomerization process; formation of the imidazo[1,2-a]pyri-
dine product 2 via reductive elimination of CuH. Reaction of
the latter with the conjugate acid of the base regenerates
the active catalytic species.
Me
O
N
7
5
71
N
Me
O
2g
2h
Ph
O
N
8
2.5
91
N
Me
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
S. Cacchi et al.
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Synthesis
cording to the literature.12,13 Reaction products were purified on axi-
ally compressed columns, packed with silica gel 25–40 μm, connected
to a solvent delivery system and a refractive index detector, eluting
with n-hexane/EtOAc mixtures. 1H (400.13 MHz), 13C (100.6 MHz),
and 19F (376.5 MHz) NMR spectra were recorded on a Bruker Avance
400 spectrometer. Splitting patterns are designated as s (singlet), bs
(broad singlet), d (doublet), dd (doublet of doublets), t (triplet), td
(triplet of doublets), q (quartet), and m (multiplet). Mass spectra were
determined with a QP2010 gas chromatograph–mass spectrometer
(EI ion source). IR spectra were recorded on a Jasco FT/IR-430 spectro-
photometer. Melting points were determined with a Büchi B-545 ap-
paratus and are uncorrected.
O
R1
R2
N
R3
N
(a)
enaminone-based
route (present work)
O
R1
N
(b)
R3
Cu(II)/Fe(III) co-catalyzed
intermolecular diamination
NH2
R2
O
N
R3
3-Benzoyl-2-phenylimidazo[1,2-a]pyridine (2a); Typical Proce-
dure for the Preparation of Imidazo[1,2-a]pyridines 2
N
R1
R2
To a stirred solution of 1a (75.0 mg, 0.25 mmol) in DMF (2.5 mL), CuI
(2.4 mg, 0.0125 mmol), 1,10-phenanthroline (2.2 mg, 0.0125 mmol),
and Li2CO3 (37.0 mg, 0.50 mmol) were added. The reaction mixture
was warmed at 100 °C and stirred for 2 h. After this time, the mixture
was cooled to r.t., diluted with Et2O, and washed with brine. The or-
ganic layer was separated, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by chromatography on sil-
ica gel [n-hexane/EtOAc, 75:25 (v/v); Rf = 0.2] to afford 2a11m as a yel-
low solid; yield: 62.6 mg (84%); mp 129–130 °C.
Scheme 3 Synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines
and α,β-ynones: (a) via the enaminone-based route; (b) via direct cop-
per(II)/iron(III)-cocatalyzed intermolecular diamination
In conclusion, we have developed a straightforward, ef-
ficient new copper-catalyzed approach to the construction
of the multisubstituted imidazo[1,2-a]pyridine skeleton
from N-(2-pyridinyl)enaminones that may represent a use-
ful alternative to known procedures. Diversities can be
readily introduced at the acyl fragment, at C2, and in the
pyridine ring. The new method tolerates a variety of useful
functionalities including ether, cyano, keto, fluoro, trifluo-
romethyl, chloro, and bromo substituents. The experimen-
tal procedure is simple and the imidazo[1,2-a]pyridine
products are usually formed in good to excellent yield.
IR (KBr): 2933, 1601, 1573, 1464, 1419, 1387, 1253, 1220, 1024 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.44 (d, J = 6.8 Hz, 1 H), 7.70 (d, J =
8.8 Hz, 1 H), 7.43–7.40 (m, 3 H), 7.23 (d, J = 6.8 Hz, 2 H), 7.16 (t, J = 7.6
Hz, 1 H), 7.04–6.96 (m, 6 H).
13C NMR (100.6 MHz, CDCl3): δ = 187.3, 154.9, 147.4, 138.7, 134.0,
131.7, 130.2, 129.6, 129.2, 128.2, 127.7 (3 C), 119.8, 117.4, 114.6.
MS (EI): m/z (%) = 298 (100) [M+], 269 (60), 221 (48), 192 (25), 149
(16), 105 (19), 77 (83).
Anal. Calcd for C20H14N2O: C, 80.52; H, 4.73; N, 9.39. Found: C, 80.44;
H, 4.72; N, 9.38.
All the reagents, catalysts, bases, and solvents are commercially avail-
able and were used as purchased, without further purification. The
α,β-ynones and N-(2-pyridinyl)enaminones 1 were synthesized ac-
R1
O
H
N
N
R3
R2
1
H
H
B
H
B
R1
Cu
BH
Cu
O
BH
N
R3
R2
N
O
Cu
O
2
Cu
N
R1
N
R1
N
R3
R3
H
O
R2
N
R2
A
Cu
R1
N
R3
B
N
R2
B
O
C
BH
Cu
R1
N
R3
R2
BH
N
B
Scheme 4 Proposed reaction mechanism for the copper-catalyzed cyclization of N-(2-pyridinyl)enaminones 1 to imidazo[1,2-a]pyridines 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
S. Cacchi et al.
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Synthesis
3-(4-Chlorobenzoyl)-2-(4-methoxyphenyl)imidazo[1,2-a]pyri-
dine (2b)
13C NMR (100.6 MHz, CDCl3): δ = 187.2, 162.7 (d, JCF = 247 Hz), 153.6,
147.3, 138.5, 132.0, 131.9 (d, JCF = 3.7 Hz), 130.0 (d, JCF = 3.0 Hz), 129.5,
129.4, 128.3, 127.9, 120.0, 117.4, 114.8 (d, JCF = 21.5 Hz), 114.7.
19F NMR (376.5 MHz, CDCl3): δ = –112.8.
MS (EI): m/z (%) = 316 (100) [M+], 287 (56), 239 (47), 210 (19), 158
Pale yellow solid; yield: 59.7 mg (66%); mp 140–141 °C.
IR (KBr): 2923, 1601, 1569, 1459, 1419, 1387, 1257, 1232, 1085 cm–1
1H NMR (400.13 MHz, CDCl3): δ = 9.37 (d, J = 6.8 Hz, 1 H), 7.78 (d, J =
8.8 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.50–7.48 (m, 1 H), 7.33 (d, J = 8.4
Hz, 2 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.06 (td, J = 6.8, 0.8 Hz, 1 H), 6.65 (d, J
= 8.8 Hz, 2 H), 3.77 (s, 3 H).
.
(19), 105 (29), 77 (89).
Anal. Calcd for C20H13FN2O: C, 75.94; H, 4.14; N, 8.86. Found: C, 75.85;
H, 4.13; N, 8.89.
13C NMR (100.6 MHz, CDCl3): δ = 185.9, 163.0, 152.2, 147.2, 134.3,
132.7, 131.9, 131.4, 130.9, 128.9, 128.1, 128.0, 120.0, 117.4, 114.4,
113.3, 55.5.
MS (EI): m/z (%) = 364 (35) [M+, 37Cl], 362 (100) [M+, 35Cl], 333 (46),
255 (24), 192 (19), 135 (87), 107 (29), 77 (80).
2-Phenyl-3-(m-toluoyl)imidazo[1,2-a]pyridine (2f)
Yellow oil; yield: 61.6 mg (78%).
IR (neat): 2919, 1612, 1577, 1494, 1384, 1332, 1218 cm–1
1H NMR (400.13 MHz, CDCl3): δ = 9.47 (d, J = 6.8 Hz, 1 H), 7.71 (d, J =
8.8 Hz, 1 H), 7.44–7.40 (m, 3 H), 7.17 (t, J = 7.4 Hz, 1 H), 7.07–6.97 (m,
5 H), 6.89 (t, J = 7.4 Hz, 1 H), 6.85–6.83 (m, 1 H), 2.04 (s, 3 H).
.
Anal. Calcd for C21H15ClN2O2: C, 69.52; H, 4.17; N, 7.72. Found: C,
69.70; H, 4.16; N, 7.74.
13C NMR (100.6 MHz, CDCl3): δ = 187.4, 155.2, 147.4, 138.9, 137.3,
133.7, 131.6, 131.1, 129.4, 129.1, 129.0, 128.3, 127.7 (2 C), 127.3,
120.0, 117.4, 114.5, 21.0.
2-Phenyl-3-(3-(trifluoromethyl)benzoyl)imidazo[1,2-a]pyridine
(2c)
Yellow oil; yield: 78.7 mg (86%).
IR (neat): 2925, 1601, 1577, 1448, 1384, 1324, 1226, 1124, 1014 cm–1
1H NMR (400.13 MHz, CDCl3): δ = 9.49 (d, J = 6.8 Hz, 1 H), 7.75 (d, J =
8.8 Hz, 1 H), 7.52–7.39 (m, 5 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.22–7.14 (m,
2 H), 7.07 (td, J = 6.8, 1.0 Hz, 1 H), 7.02 (t, J = 7.6 Hz, 2 H).
MS (EI): m/z (%) = 312 (88) [M+], 283 (57), 207 (33), 105 (22), 77 (100).
.
Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.67;
H, 5.14; N, 8.95.
2-(3-Acetylphenyl)-3-(m-toluoyl)imidazo[1,2-a]pyridine (2g)
13C NMR (100.6 MHz, CDCl3): δ = 187.1, 153.2, 147.4, 138.4, 134.9,
133.1, 132.0, 130.2 (q, JCF = 32.6 Hz), 129.6, 129.4, 128.4, 128.3, 127.9,
127.2 (q, JCF = 4.0 Hz), 124.9 (q, JCF = 3.7 Hz), 123.7 (q, JCF = 272 Hz),
120.3, 117.6, 115.0.
19F NMR (376.5 MHz, CDCl3): δ = –62.7.
MS (EI): m/z (%) = 366 (81) [M+], 337 (39), 289 (43), 221 (20), 192 (19),
Yellow wax; yield: 62.8 mg (71%).
IR (KBr): 2921, 1685, 1616, 1457, 1384, 1332, 1207 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.53 (d, J = 6.8 Hz, 1 H), 7.80–7.72
(m, 4 H), 7.49–7.46 (m, 1 H), 7.22 (t, J = 7.7 Hz, 1 H), 7.06–6.98 (m, 3
H), 6.86–6.80 (m, 2 H), 2.28 (s, 3 H), 2.02 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 196.8, 186.0, 155.8, 147.6, 139.1,
137.5, 136.2, 133.6, 133.4, 131.0, 130.7, 129.9, 129.7, 129.2, 128.4,
128.3, 127.8, 127.4, 119.9, 117.5, 114.9, 26.3, 20.9.
105 (40), 77 (100).
Anal. Calcd for C21H13F3N2O: C, 68.85; H, 3.58; N, 7.65. Found: C,
68.97; H, 3.57; N, 7.67.
MS (EI): m/z (%) = 354 (100) [M+], 325 (38), 281 (22), 235 (25), 207
(70), 155 (15), 103 (18), 77 (35).
3-(3-Methoxybenzoyl)-2-phenylimidazo[1,2-a]pyridine (2d)
Anal. Calcd for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 78.10;
H, 5.13; N, 7.87.
Yellow oil; yield: 45.9 mg (56%).
IR (neat): 2935, 1612, 1577, 1448, 1384, 1332, 1222, 1041 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.46 (d, J = 6.8 Hz, 1 H), 7.73 (d, J =
8.8 Hz, 1 H), 7.47–7.42 (m, 3 H), 7.22–7.18 (m, 1 H), 7.06–6.99 (m, 3
H), 6.93 (t, J = 7.7 Hz, 1 H), 6.88–6.86 (m, 1 H), 6.76–6.75 (m, 1 H),
6.63–6.60 (m, 1 H), 3.54 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 187.3, 159.0, 154.7, 147.3, 138.8,
135.2, 131.8, 129.5, 129.2, 128.9, 128.2, 127.8, 122.9, 120.0, 117.5,
115.2, 114.8, 114.6, 55.2.
3-(4-Phenylbenzoyl)-2-(m-tolyl)imidazo[1,2-a]pyridine (2h)
Pale yellow solid; yield: 88.3 mg (91%); mp 81–83 °C.
IR (KBr): 2930, 1614, 1492, 1388, 1330, 1160 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.49 (d, J = 6.8 Hz, 1 H), 7.74 (d, J =
9.2 Hz, 1 H), 7.46–7.23 (m, 10 H), 7.19 (br s, 2 H), 7.01 (td, J = 6.8, 1.2
Hz, 1 H), 6.97–6.96 (m, 2 H), 1.99 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 187.5, 154.6, 147.4, 140.9, 140.7,
138.5, 137.5, 133.1, 132.4, 130.6, 130.5, 129.2, 128.8, 128.3, 127.9,
127.5, 127.0, 126.6, 126.4, 120.2, 117.4, 114.6, 20.9.
MS (EI): m/z (%) = 328 (100) [M+], 299 (68), 251 (17), 164 (19), 105
(24), 77 (78).
Anal. Calcd for C21H16N2O2: C, 76.81; H, 4.91; N, 8.53. Found: C, 76.73;
H, 4.92; N, 8.55.
MS (EI): m/z (%) = 388 (100) [M+], 281 (41), 207 (100), 73 (48).
Anal. Calcd for C27H20N2O: C, 83.48; H, 5.19; N, 7.21. Found: C, 83.56;
H, 5.20; N, 7.19.
3-(4-Fluorobenzoyl)-2-phenylimidazo[1,2-a]pyridine (2e)
Yellow solid; yield: 36.3 mg (46%); mp 126–127 °C.
IR (KBr): 2935, 1604, 1573, 1471, 1392, 1332, 1224 cm–1
1H NMR (400.13 MHz, CDCl3): δ = 9.46 (d, J = 6.8 Hz, 1 H), 7.72 (d, J =
8.8 Hz, 1 H), 7.48–7.41 (m, 3 H), 7.25–7.20 (m, 3 H), 7.07–7.01 (m 3
H), 6.70 (t, J = 8.4 Hz, 2 H).
3-Benzoyl-2-(4-cyanophenyl)imidazo[1,2-a]pyridine (2i)
.
Pale yellow solid; yield: 55.7 mg (69%); mp 177–178 °C.
IR (KBr): 2919, 2229, 1599, 1463, 1390, 1330, 1222 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.56 (d, J = 6.8 Hz, 1 H), 7.76 (d, J =
8.8 Hz, 1 H), 7.55–7.52 (m, 1 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4
Hz, 2 H), 7.11–7.05 (m, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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S. Cacchi et al.
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Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 185.0, 156.2, 147.9, 142.6, 133.6,
131.5, 130.2, 130.1, 129.7, 128.9, 128.5, 128.0, 119.8, 118.0, 117.6,
115.3, 114.5.
MS (EI): m/z (%) = 323 (100) [M+], 294 (70), 221 (40), 192 (27), 162
(20), 102 (42), 78 (25).
3-Benzoyl-8-bromo-6-methyl-2-phenylimidazo[1,2-a]pyridine
(2m)
Pale yellow solid; yield: 78.0 mg (80%); mp 174–175 °C.
IR (KBr): 2917, 1612, 1386, 1324, 1255, 1078 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.21 (br s, 1 H), 7.56 (d, J = 1.2 Hz, 1
H), 7.42 (d, J = 7.2 Hz, 2 H), 7.26 (d, J = 7.2 Hz, 2 H), 7.20–7.16 (m, 1 H),
7.04–6.96 (m, 5 H), 2.35 (s, 3 H).
Anal. Calcd for C21H13N3O: C, 78.00; H, 4.05; N, 13.00. Found: C, 78.13;
H, 4.06; N, 13.02.
13C NMR (100.6 MHz, CDCl3): δ = 187.6, 154.8, 144.3, 138.3, 134.1,
133.7, 132.0, 130.4, 129.6, 128.3, 127.8, 127.7, 125.3, 124.8, 121.1,
110.8, 18.3.
MS (EI): m/z (%) = 392 (11) [M+, 81Br], 390 (12) [M+, 79Br], 281 (7), 105
(29), 77 (100).
3-(3,5-dimethoxybenzoyl)-2-(3-bromophenyl)imidazo[1,2-a]pyri-
dine (2j)
Yellow solid; yield: 95.0 mg (87%); mp 55–56 °C.
IR (KBr): 2935, 1604, 1560, 1460, 1389, 1328, 1155, 1062 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.57 (d, J = 7.1 Hz, 1 H), 7.83 (d, J =
8.8 Hz, 1 H), 7.63–7.62 (m, 1 H), 7.59–7.55 (m, 1 H), 7.47 (d, J = 7.6 Hz,
1 H), 7.41 (d, J = 6.0 Hz, 1 H), 7.13 (td, J = 7.1, 0.8 Hz, 1 H), 7.04 (t, J =
8.0 Hz, 1 H), 6.47 (d, J = 2.4 Hz, 2 H), 6.30 (t, J = 2.4 Hz, 1 H), 3.66 (s, 6
H).
13C NMR (100.6 MHz, CDCl3): δ = 185.3, 160.3, 155.5, 147.4, 140.7,
135.6, 134.4, 132.3, 129.7, 129.3, 128.3, 127.5, 121.9, 119.9, 117.5,
115.0, 108.0, 102.0, 55.3.
Anal. Calcd for C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C,
64.67; H, 3.85; N, 7.18.
Acknowledgment
We gratefully acknowledge the University ‘La Sapienza’, Rome, for fi-
nancial support and the XRD-1 beamline staff at ELETTRA Trieste (Ita-
ly) for experimental assistance.
MS (EI): m/z (%) = 438 (18) [M+, 81Br], 436 (19) [M+, 79Br], 281 (12), 271
(25), 77 (100).
Anal. Calcd for C22H17BrN2O3: C, 60.43; H, 3.92; N, 6.41. Found: C,
60.29; H, 3.93; N, 6.39.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610071.
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3-Benzoyl-6-bromo-2-phenylimidazo[1,2-a]pyridine (2k)
Pale yellow solid; yield: 90.5 mg (96%); mp 128–130 °C.
IR (KBr): 2930, 1607, 1468, 1378, 1335, 1159, 1024 cm–1
.
References
1H NMR (400.13 MHz, CDCl3): δ = 9.62 (br s, 1 H), 7.60 (d, J = 9.2 Hz, 1
H), 7.50 (dd, J = 9.2, 1.8 Hz, 1 H), 7.42 (d, J = 7.2 Hz, 2 H), 7.23 (d, J = 7.2
Hz, 2 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.08–6.99 (m, 5 H).
13C NMR (100.6 MHz, CDCl3): δ = 187.3, 154.9, 145.7, 138.2, 133.5,
132.5, 132.1, 130.1, 129.6, 128.5, 128.3, 127.84, 127.83, 120.1, 118.0,
109.4.
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(7), 207 (100), 105 (17), 77 (56).
Anal. Calcd for C20H13BrN2O: C, 63.68; H, 3.47; N, 7.43. Found: C,
63.75; H, 3.46; N, 7.45.
3-Benzoyl-6-chloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine
(2l)
Pale yellow solid; yield: 64.2 mg (71%); mp 150–151 °C.
IR (KBr): 2923, 1618, 1592, 1382, 1335, 1026 cm–1
.
1H NMR (400.13 MHz, CDCl3): δ = 9.38 (dd, J = 2.0, 0.8 Hz, 1 H), 7.64
(dd, J = 9.6, 0.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.37 (dd, J = 9.6, 2.0
Hz, 1 H), 7.31–7.29 (m, 2 H), 7.13–7.05 (m, 3 H), 6.53 (d, J = 8.8 Hz, 2
H), 3.66 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 186.0, 163.0, 153.9, 145.4, 133.6,
132.0, 130.6, 130.1, 129.9, 128.4, 128.0, 126.0, 122.5, 120.7, 117.6,
113.2, 55.4.
MS (EI): m/z (%) = 364 (20) [M+, 37Cl], 362 (58) [M+, 35Cl], 333 (30), 281
(33), 207 (100), 191 (18), 135 (78), 107 (26), 77 (87).
Anal. Calcd for C21H15ClN2O2: C, 69.52; H, 4.17; N, 7.72. Found: C,
69.35; H, 4.16; N, 7.74.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
S. Cacchi et al.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G