Copper-catalyzed four-component synthesis of imidazo[1,2-a]pyridines via sequential reductive amination, condensation, and cyclization

Article abstract of DOI:10.1016/j.tetlet.2016.11.081

A novel and efficient four-component approach for the synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines is described. The copper-catalyzed reductive amination of 2-bromopyridine by sodium azide followed by sequential condensation and cyclization with aldehydes and isocyanides afforded the corresponding imidazo[1,2-a]pyridines in good yields.

Full text of DOI:10.1016/j.tetlet.2016.11.081

Accepted Manuscript
Copper-Catalyzed Four-component Synthesis of Imidazo[1,2-a]pyridines via
Sequential Reductive Amination, Condensation, and Cyclization
Emad Allahabadi, Sina Ebrahimi, Mehdi Soheilizad, Mehdi Khoshneviszadeh,
Mohammad Mahdavi
PII:
S0040-4039(16)31562-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.081
TETL 48367
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 August 2016
4 November 2016
18 November 2016
Please cite this article as: Allahabadi, E., Ebrahimi, S., Soheilizad, M., Khoshneviszadeh, M., Mahdavi, M., Copper-
Catalyzed Four-component Synthesis of Imidazo[1,2-a]pyridines via Sequential Reductive Amination,
Condensation, and Cyclization, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.081
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Graphical Abstract
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Copper-Catalyzed Four-component Synthesis of
Imidazo[1,2-a]pyridines via Sequential Reductive
Amination, Condensation and Cyclization
Emad Allahabadi, Sina Ebrahimi, Mehdi Soheilizad, Mehdi Khoshneviszadeh, Mohammad
Mahdavi
1

Copper-Catalyzed Four-component Synthesis of Imidazo[1,2-a]pyridines via Sequential
Reductive Amination, Condensation, and Cyclization
Emad Allahabadi,a Sina Ebrahimi,a Mehdi Soheilizad,b Mehdi Khoshneviszadeh,c Mohammad
Mahdavi*a
a Drug Design and Development Research Center, Tehran University of Medical Science, Tehran, Iran,
Tehran 14176, Iran
bSchool of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
cMedicinal & Natural Products Chemistry Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran
Abstract: A novel and efficient four-component approach for the synthesis of 2,3-disubstituted
imidazo[1,2-a]pyridines is described. The copper-catalyzed reductive amination of 2-
bromopyridine by sodium azide followed by sequential condensation and cyclization with
aldehydes and isocyanides afforded the corresponding imidazo[1,2-a]pyridines in good yields.
Keywords: Copper-catalyzed, Imidazo[1,2-a]pyridine, Reductive amination, 2-Bromopyridine,
Aldehyde, Isocyanide, Sodium azide.
*Corresponding author: Tel.: +98-21-66954708; fax: +98-21-66461178; e-mail:
Mahdavi_chem@yahoo.com
2

Introduction
The imidazo[1,2-a]pyridine core is an important biologically active, nitrogen-containing
heterocyclic scaffold due to its extensive applications in medicinal chemistry and material
science.1 Antibacterial,2 antifungal,3 antiviral,4 antineoplastic,5 antitumor6 and antiulcer7
properties have been reported for imidazo[1,2-a]pyridine derivatives. Additionally, the
imidazo[1,2-a]pyridine subunit has been widely used in medicinal chemistry. For example,
zolpidem, zolimidine, and alpidem are commercially available drugs based on the imidazo[1,2-
a]pyridine scaffold for use as sedative, anxiolytic and gastroprotective agents, respectively (Fig.
1).
Figure 1. Representative commercially available imidazo[1,2-a]pyridine-based drugs
Because of their pharmacological importance, the development of novel synthetic approaches
for the preparation of imidazo[1,2-a]pyridine derivatives has gained significant attention, and as
a result, many synthetic routes for this valuable scaffold have been reported in the literature.8
Typical approaches include the heterocyclization of 2-aminopyridine with α-haloketones,9 α,β-
unsaturated carbonyl compounds10 or α-diazoketones.11 Also, several three-component
condensation reactions have been reported including the coupling reaction of 2-aminopyridine
and aldehydes with isocyanides12 or alkynes,13 and the condensation between 2-aminopyridine,
isocyanides, and benzyl halides14 or benzyl alcohols15 (Scheme 1).
3

Scheme 1. General approaches for the synthesis of imidazo[1,2-a]pyridines
Recently, the synthesis of fused N-heterocycles using the copper-catalyzed reductive
amination of aryl halides by sodium azide as a convenient nitrogen source, has been widely
applied in organic synthesis.16 Due to the pharmacological value of imidazo[1,2-a]pyridines, and
in continuation of our research regarding the preparation of nitrogen-containing compounds,17
herein, we report a novel and efficient approach for the synthesis of imidazo[1,2-a]pyridines 5,
via the four-component condensation of 2-bromopyridine 1, sodium azide 2, aldehydes 3, and
isocyanides 4, in the present of CuI as a catalyst and L-proline as a ligand, in DMSO at 100 C
(Scheme 2). To the best of our knowledge, this is the first report on the synthesis of imidazo[1,2-
a]pyridines using 2-bromopyridine instead of 2-aminopyridine.
Scheme 2. Four-component synthesis of imidazo[1,2-a]pyridines
Result and Discussion
We began with the model reaction of 2-bromopyridine 1, sodium azide 2, benzaldehyde 3a,
and cyclohexyl isocyanide 4a, in the presence of CuI, in dry DMSO at 100 ºC, which led to the
isolation of product 5a in 33% yield (Table 1, entry 1). In order to improve the yield of 5a,
4

various experimental conditions were screened by varying the ligands, copper catalysts, solvents
and temperatures (Table 1). Firstly, screening the ligands 1,10-phenanthroline, pipecolic acid and
L-proline (Entries 2−4), revealed that the yield significantly increased in the presence of a ligand.
Among them, L-proline was found to be the most suitable ligand (Entry 4). Various copper salts
including CuBr, CuCl, CuCl2 and Cu2O (Entries 5−8), were screened and the highest yield was
obtained with CuI (compare entries 4 and 5−8). Several solvents including DMF, 1,4-dioxane
and toluene were tested (Entries 9−11), where DMSO proved to be the most effective (compare
entries 4 and 9−11). Finally, decreasing or increasing the reaction temperature did not lead to any
further improvement in yield (Entries 12 and 13).
Table 1. Optimization of conditions for the four-component synthesis of 5aa
Yield (%)b
Entry
Catalyst
CuI
Ligand
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Temp. (ºC)
100
1
33
58
64
78
70
66
62
52
60
10
5

2
CuI
1,10-Phenanthroline
Pipecolic acid
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
100
3
CuI
100
4
CuI
100
5
CuBr
CuCl
CuCl2
Cu2O
CuI
100
6
100
7
100
8
100
9
100
10
11
12
13
CuI
1,4-Dioxane
Toluene
DMSO
DMSO
100
CuI
100
CuI
80
63
CuI
120
69
a Reagents and conditions: 1 (1 mmol), 2 (2 mmol), 3a (1 mmol), 4a (1 mmol), Cu-source (0.05 mmol),
ligand (0.1 mmol), solvent (3 mL), 3 h.
b Isolated yield.
5

With the optimized conditions for the synthesis of imidazo[1,2-a]pyridines in hand, we then
investigated the substrates scope. Aromatic aldehydes with either electron-withdrawing or
electron-donating substituents, regardless of their position on the phenyl ring, provided the
corresponding products 5 in good yields (Table 2).18
Table 2. Substrate scope for the four-component synthesis of imidazo[1,2-a]pyridinesa
Entry Aldehyde
Isocyanide
4a
Product
Yield
(%)b
1
78
3a
2
3
4
5
81
79
82
76
3b
3c
3d
3e
4a
4a
4a
4a
6

6
7
81
88
3f
4a
4b
3a
8
9
84
84
85
3f
3b
3c
4b
4b
4b
10
a Reagents and conditions: 1 (1 mmol), 2 (2 mmol), 3 (1 mmol), 4 (1 mmol), CuI (0.05 mmol), L-proline
(0.1 mmol), DMSO (3 mL), 110 °C, 3 h.
b Isolated yield.
A plausible mechanism for the formation of imidazo[1,2-a]pyridines 5 is illustrated in
Scheme 3. Based on recent reports that sodium azide act as an ammonia surrogate to prepare
primary amines in the copper-catalyzed reductive amination of aryl halides,16 it is reasonable to
assume that, initially, reductive amination of 2-bromopyridine 1 using sodium azide in the
presence of the copper catalyst produced 2-aminopyridine 7. Subsequently, condensation of 2-
aminopyridine 7 with the aldehyde furnishes imine intermediate 8. Next, nucleophilic addition of
the isocyanide to imine 8, followed by intramolecular cyclization leads to the formation of
intermediate 10 which tautomerizes to afford the desired product 5 (Scheme 3).
7

Scheme 3. Plausible mechanism for the four-component synthesis of imidazo[1,2-a]pyridine 5.
Conclusion
In summary, we report a new and efficient, one-pot, four-component approach for the
synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines via the copper-catalyzed reductive
amination of 2-bromopyridine with sodium azide followed by sequential condensation-
cyclization with aldehydes and isocyanides. To date, this is the first report on the synthesis of
imidazo[1,2-a]pyridine using 2-bromopyridine instead of 2-aminopyridine.
Acknowledgement
This research was supported by a grant from Iran National Science Foundation (INSF).
References:
1. (a) Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J. Med. Chem. 2008, 51,
7243; (b) Wiegand, M. H. Drugs 2008, 68, 2411; (c) Rupert, K. C.; Henry, J. R.; Dodd, J. H.;
Wadsworth, S. A.; Cavender, D. E.; Olini, G. C.; Fahmy, B.; Siekierka. J. Bioorg. Med.
Chem. Lett. 2003, 13, 347; (d) Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H.
Chem. Pharm. Bull. 1992, 40, 371; (e) Smirnova, E. N.; Onschenskaya, T. V.; Zvolinskii, V.
P.; Nende, D. L. Fiz. Khim. Poverkhn. 1988, 65.
2. Rival, Y.; Grassy G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170.
8

3. (a) Fisher, M. H.; Lusi, A. J. Med. Chem. 1972, 15, 982; (b) Rival, Y.; Grassy, G.; Taudou
A.; Ecalle, R. Eur. J. Med. Chem. 1991, 26, 13.
4. (a) Lhassani, M.; Chavignon, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.;
Andrei, G.; Balzarini, J.; Clerc, E. D.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271; (b)
Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz B. A.; Vance, L. J. Med. Chem.
1999, 42, 50.
5. Badaway E.; Kappe, T. Eur. J. Med. Chem. 1995, 30, 327.
6. Hranjec, M.; Kralj, M.; Piantanida, I.; Sedi, M.; Suman, L.; Pavel K.; Karminski-Zamola, G.
J. Med. Chem. 2007, 50, 5696.
7. Kaminsky J. J.; Doweyko, A. M. J. Med. Chem. 1999, 40, 427.
8. Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun., 2015, 51, 1555
9. (a) Fisher, M. H.; Lusi, A. J. Med. Chem. 1972, 15, 982; (b) 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; (c) Ponnala, S.; Kumar, S. T.; Bhat, B. A.; Sahu, D. P.
Synthetic Commun. 2005, 35, 901.
10. (a) Yan, R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Huang, G. S.; Liang, Y. M. J. Org.
Chem. 2012, 77, 2024; (b) Guetzoyan, L.; Nikbin, N.; Baxendale, I. R.; Ley, S. V. Chem. Sci.
2013, 4, 764; (c) Monir, K.; Bagdi, A. K.; Mishra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal.
2014, 356, 1105.
11. Yadav, J. S.; Reddy, B. V. S.; Rao, Y. G.; Srinivas, M.; Narsaiah, A. V. Tetrahedron Lett.
2007, 48, 7717.
12. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 6, 661; (b) Rousseau, A. L.; Matlaba,
P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079; (c) Adib, M.; Mahdavi, M.; Noghani,
M. A.; Mirzaei, P. Tetrahedron Lett. 2007, 48, 7263; (d) Shaabani, A.; Soleimani, E.; Maleki,
A. Tetrahedron Lett. 2006, 47, 3031.
9

13. (a) Khan A, T.; Basha R.S.;Lai, M . Tetrahedron Lett. 2012, 53, 2211; (b) Chernyak, N.;
Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49, 2743; (c) Rassokhina, I. V.; Shirinian, V. Z.;
Zavarzin, I. V.; Gevorgyan, V.; Volkova Y. A. J. Org. Chem. 2015, 80, 11212.
14. Adib, M.; Sheikhi E.; Rezaei, N. Tetrahedron Lett. 2011, 52, 3191.
15. Ramesha, A. B.; Raghavendra, G. M.; Nandeesh, K. N.; Rangappa, K. S.; Mantelingu, K.
Tetrahedron Lett. 2013, 54, 95.
16. (a) Jia, F. C.; Xu, C.; Zhou, Z. W.; Cai, Q.; Li, D. K.; Wu A. X. Org. Lett., 2015, 17, 2820;
(b) Jia, F.C.; Zhou, Z. W.; Xu, C.; Cai, Q.; Li, D. K.; Wu, A. X. Org. Lett., 2015, 17,4236;
(c) Shindea, M. H.; Kshirsagar, U. A. RSC Adv., 2016, 6, 52884; (d) Dhiman, S.; Saini, H.
K.; Nandwana, N. K.; Kumar, D.; Kumar, A. RSC Adv., 2016, 6, 23987; (e) Goriya, Y.;
Ramana, C. V. Chem. Commun. 2014, 50, 7790; (f) Goriya, Y.; Ramana, C. V. Chem.
Commun. 2013, 49, 6376.
17. (a) Noushini, S.; Mahdavi, M.; Firoozpour, L.; Moghimi, S.; Shafiee, A.; Foroumadi, A.
Tetrahedron, 2015, 71, 6272; (b) Goli-Garmroodi, F.; Omidi, M.; Saeedi, M.; Sarrafzadeh,
F.; Rafinejad, A.; Mahdavi, M.; Bardajee, G. R.; Akbarzadeh, T.; Firoozpour, L.; Shafiee, A.;
Foroumadi, A. Tet. Lett., 2015, 56, 743; (c) Rahmani-Nezhad, S.; Safavi, M.; Pordeli, M.;
Ardestani, S. K; Khosravani, L.; Pourshojaei, Y.; Mahdavi, M.; Emami, S.; Foroumadi, A.;
Shafiee, A. Eur. J. Med. Chem. 2014, 86, 562; (d) Saeedi, M.; Mahdavi, M.; Foroumadi, A.;
Shafiee, A. Tetrahedron, 2013, 69, 3506; (e) Hosseini-Zare, M. S.; Mahdavi, M.; Saeedi, M.;
Asadi, M.; Javanshir, S.; Shafiee, A.; Foroumadi, A. Tet. Lett., 2012, 53, 3448; (f) Tahghighi,
A.; Razmi, S.; Mahdavi. M.; Foroumadi, P.; Ardestani, S. K.; Emami, S.; Kobarfard, F.;
Dastmalchi, S.; Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2012, 50, 124.
18. General procedure for the preparation of compounds 5a–j, exemplified with 5a: A mixture of
2-bromopyridine (1 mmol), NaN3 (1 mmol), benzaldehyde (1 mmol), cyclohexyl isocyanide
(1 mmol), CuI (0.05 mmol) and L-proline (0.1 mmol), in dry DMSO (3 mL) was stirred in a
sealed vessel under air for 3 hours at 100 °C. After reaction completion (TLC), the reaction
mixture was cooled, quenched with water (20 mL), and extracted with EtOAc (3 × 20 mL).
The extract was washed with 30% NaCl solution (V/V), dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by column chromatography using
10

petroleum ether/ethyl acetate (3:1) as eluent to afford the pure product 5a. N-cyclohexyl-2-
1
phenylimidazo[1,2-a]pyridin-3-amine (5a): m.p. 198–200 °C (lit.14 195–197 °C); H NMR
(DMSO-d6, 500 MHz): δ = 1.05-1.71 (10H, m), 2.82-2.87 (1H, m), 4.80 (1H, d, J = 6.0 Hz),
7.15 (3H, m), 7.20 (2H, d, J = 8.0 Hz), 7.44 (3H, m), 8.38 (1H, d, J = 7.0 Hz) ppm; 13C NMR
(DMSO-d6, 125 MHz): δ = 20.8, 28.36, 30.0, 55.6, 110.7, 116.3, 123.6, 123.8, 127.5,128.5,
129.2, 132.5, 136.0, 137.9, 140.9.
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Highlights
 A four component has been used to synthesis imidazo[1,2-a]pyridines
 The mechanism relies on sequential reductive amination, condensation, and cyclization
 Sodium azide acts as an ammonia surrogate to primary amines in a copper-catalyzed
reductive amination of aryl halides
12