One-pot synthesis of imidazo[1,2-a]pyridines from benzyl halides or benzyl tosylates, 2-aminopyridines and isocyanides

Article abstract of DOI:10.1016/j.tetlet.2011.04.002

A one-pot synthesis of imidazo[1,2-a]pyridines is described. Benzyl halides or benzyl tosylates are oxidized to aldehydes under mild Kornblum conditions which then undergo a three-component reaction with various 2-aminopyridines and isocyanides to afford the imidazo[1,2-a]pyridines in excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.04.002

Tetrahedron Letters 52 (2011) 3191–3194
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Tetrahedron Letters
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One-pot synthesis of imidazo[1,2-a]pyridines from benzyl halides or benzyl
tosylates, 2-aminopyridines and isocyanides
⇑
Mehdi Adib , Ehsan Sheikhi, Narjes Rezaei
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of imidazo[1,2-a]pyridines is described. Benzyl halides or benzyl tosylates are oxi-
dized to aldehydes under mild Kornblum conditions which then undergo a three-component reaction
with various 2-aminopyridines and isocyanides to afford the imidazo[1,2-a]pyridines in excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 12 November 2010
Revised 16 March 2011
Accepted 1 April 2011
Available online 7 April 2011
Keywords:
Benzyl halides
Benzyl tosylates
Kornblum oxidation
Isocyanides
2-Aminopyridines
Imidazo[1,2-a]pyridines
Three-component reactions
Imidazo[1,2-a]pyridines are of interest because of the
occurrence of their saturated and partially saturated derivatives
in biologically active compounds. Compounds containing the
imidazo[1,2-a]pyridine ring system have been shown to possess
a broad range of useful pharmacological properties, including anti-
bacterial, antifungal, anthelmintic, antiviral, antiprotozoal, antiin-
flammatory, anticonvulsant, anxiolytic, hypnotic (e.g., zolpidem,
Fig. 1), gastrointestinal, antiulcer, and immunomodulatory
activities.1,2
N
Me
N
Me
CH2CONMe2
Figure 1. Zolpidem, a pharmacologically important imidazo[1,2-a]pyridine.
Multi-component reactions (MCRs) are useful for the construc-
tion of diverse chemical libraries of ‘drug-like’ molecules. The iso-
cyanide-based MCRs are especially important in this area.7 In 1998,
new variants of the Ugi MCR8 were described by Blackburn,9 Bien-
aymé,10 and Groebke11 which enabled simple syntheses of imi-
dazo[1,2-a]azines. Reactions of an aldehyde, an isocyanide and a
2-aminoazine in methanolic solution containing a catalyst such
as Sc(OTf)3,9 perchloric acid10 or glacial acetic acid11 were per-
formed at room temperature. However, these methods required
long reaction times and the work-ups were complicated. Imi-
dazo[1,2-a]azine syntheses have also been carried out under
microwave irradiation in the presence of a solid acid, Montmoril-
lonite K10,12 and Sc(OTf)3,13 and using a nonpolar solvent,14 or in
the presence of an ionic liquid.15 Improved conditions have been
reported in recent years.16
Several synthetic methods have been reported for the prepara-
tion of 2- or 3-substituted imidazo[1,2-a]pyridines with the
majority relying on the condensation of 2-aminopyridine with
a
-bromoketones to form the five-membered cyclic system.1,2
Particularly interesting are those structures that contain an amino
group at C-2 or C-3. There are well established methods for the
preparation of 3-aminoimidazo[1,2-a]pyridines; these include
nitration at C-3 of the already formed heterocycle and subsequent
reduction,3 preparation from pyridinium fluorides,4 Strecker-type
reaction between 2-aminopyridines, a cyanide and a limited num-
ber of aldehydes,5 or by use of benzotriazole as an auxiliary group.6
Most of these methods involve three or more sequential synthetic
steps, the use of harsh reaction conditions that give low yields, and
in some cases, the use of hazardous or expensive starting materials.
As part of our continuing efforts on the development of new
routes for the preparation of biologically active heterocyclic com-
pounds,17 we have reported syntheses of imidazo[1,2-a]pyridines
via microwave-assisted one-pot reaction of pyridines,
a-bromoke-
⇑
Corresponding author. Tel./fax: +98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
tones, and ammonium acetate,18 reaction between 2-aminopyri-
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.002

3192
M. Adib et al. / Tetrahedron Letters 52 (2011) 3191–3194
dines, benzaldehydes and imidazoline-2,4,5-trione under solvent-
O
free conditions,19 catalyst-free reaction between 2-aminopyri-
dines, aldehydes and isocyanides in water,20 and condensation of
2-aminopyridines and diaroylacetylenes.21 Herein, we describe a
novel and straightforward approach for the synthesis of imi-
dazo[1,2-a]pyridines which involves an in situ oxidation–cyclo-
condensation sequence starting from benzyl halides or benzyl
tosylates. This procedure develops the known reaction, while not
limiting one of the substrates to an aldehyde.
+
+
S
_
O
S
N
NH2
K2CO3
Ar
N
H
Ar
X
Ar
O
_
DMS
2
1
5
6
_
C
+
R
N
_
3
N
N
N
N
N
Ar
N
N
RN
Thus, under mild Kornblum oxidation conditions,22 benzylic
substrate 1 in DMSO in the presence of K2CO3 at 90 °C was con-
verted into the corresponding aldehyde (Scheme 1). Subsequently,
+
N
R
Ar
N
H
Ar
Ar
4
7
R
8
9
Scheme 1.
Table 1
One-pot synthesis of imidazo[1,2-a]pyridines 4
Y
Y
+
_
C
K2CO3, DMSO
+
N
+
R
N
Ar
X
N
90 °C, 6 h
N
NH2
R
N
Ar
H
2
3
1
4
Entry
1
ArCH2X
2-Aminopyridine
R
Yielda (%)
94
Mp (°C)
Cl
Cl
198–20016h
N
NH2
N
H3C
2
3
4
92
93
90
199–203 (dec)15
207–210 (dec)15
216–219 (dec)15
NH2
Cl
Br
N
NH2
Cl
H3C
H3C
H3C
Cl
N
NH2
Cl
5
6
7
95
90
90
208–210 (dec)15
15416e
N
NH2
Cl
CH3O
N
NH2
Cl
Cl
Br
206–208 (dec)15
N
NH2
H3C
H3C
8
95
216–219 (dec)15
N
NH2
NH2
Cl
H3C
9
93
94
92
211–21315
148–15016c
174–17624
N
Cl
Cl
Cl
10
11
N
NH2
Cl
Cl
Br
N
NH2
199–20124
12724
Cl
12
13
88
93
N
N
NH2
NH2
Cl
CH3O

M. Adib et al. / Tetrahedron Letters 52 (2011) 3191–3194
3193
Table 1 (continued)
Entry
ArCH2X
2-Aminopyridine
R
Yielda (%)
90
Mp (°C)
Br
14
15
16
17
18
198–20016h
N
N
N
N
NH2
NH2
NH2
NH2
NH2
Br
O2N
95
94
91
96
235–237
166–169
15416e
Br
H3C
Br
CH3O
OTs
OTs
198–20016h
N
H3C
19
20
94
95
216–219 (dec)15
166–169
N
NH2
OTs
H3C
N
NH2
a
Isolated yield.
2. Couty, F.; Evano, G. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier Science: Oxford,
2008. Vol 11, Chapter 10, 409–492, and references therein..
3. Roubaud, C.; Vanelle, P.; Maldonado, J.; Crozet, M. P. Tetrahedron 1995, 51,
9643–9656.
4. Kiselyov, A. Tetrahedron Lett. 2005, 46, 4487–4490.
5. Bristow, N. W.; Charlton, P. T.; Peak, D. A.; Short, W. F. J. Chem. Soc. 1954, 616–
629.
the in situ prepared aldehyde was condensed with the 2-amino-
pyridine 2 followed by treatment with isocyanide 3 at 90 °C to pro-
duce
the
corresponding
3-alkylamino-2-arylimidazo[1,2-
a]pyridine 4 in 88–96% yields (Table 1). All the reactions went to
completion within 6 h.23 1H NMR analysis of the reaction mixtures
clearly indicated the formation of the corresponding 3-aminoimi-
dazo[1,2-a]pyridines 4 in excellent yields. All the products were
characterized by melting point determination and from 1H and
13C NMR spectral data.
6. Katritzky, A. R.; Xu, Y. J.; Tu, H. B. J. Org. Chem. 2003, 68, 4935–4937.
7. (a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b) Dömling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168–3210.
8. Ugi, I.; Meyr, R. Chem. Ber. 1961, 94, 2229–2233.
Simple alkyl halides or alkyl tosylates were oxidized to the cor-
responding aldehydes in good yields, but these aldehydes, when
treated with 2-aminopyridines and isocyanides resulted in compli-
cated reaction mixtures.
9. Blackburn, C. Tetrahedron Lett. 1998, 39, 5469–5472.
10. Bienaymé, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234–2237.
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Tetrahedron Lett. 2006, 47, 947–951.
15. Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47, 3031–3034.
16. (a) Odell, L. R.; Nilsson, M. T.; Gising, J.; Lagerlund, O.; Muthas, D.; Nordqvist,
A.; Karlen, A.; Larhed, M. Bioorg. Med. Chem. Lett. 2009, 19, 4790–4793; (b)
Pirrung, M. C.; Ghorai, S.; Ibarra-Rivera, T. R. J. Org. Chem. 2009, 74, 4110–4117;
(c) Guchhait, S. K.; Madaan, C. Synlett 2009, 628–632; (d) Nayak, M.; Batra, S.;
Kanojiya, S. Synthesis 2009, 431–437; (e) Shaabani, A.; Soleimani, E.; Maleki, A.;
Moghimi-Rad, J. Synth. Commun. 2008, 38, 1090–1095; (f) Mert-Balci, F.;
Conrad, J.; Beifuss, U.; Meindl, K.; Schulz, T.; Stalke, D. Synthesis 2008, 3649–
3656; (g) Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48,
4079–4082; (h) Shaabani, A.; Maleki, A.; Moghimi Rad, J.; Soleimani, E. Chem.
Pharm. Bull. 2007, 55, 957–958; (i) Nenajdenko, V. G.; Reznichenko, A. L.;
Balenkova, E. S. Russ. Chem. Bull. 2007, 56, 560–562.
A mechanistic rationalization for this reaction is provided in
Scheme 1. Treatment of the benzylic substrate 1 with dimethyl
sulfoxide yields an alkoxysulfonium ion 5 which, in the presence
of K2CO3 undergoes elimination of dimethyl sulfide to form the
corresponding aldehyde 6. Next, the aldehyde undergoes conden-
sation with the 2-aminopyridine 2 to give the imine intermediate
7. This imine undergoes nucleophilic addition with the isocyanide
3 to form the isonitrilium intermediate 8, which cyclizes into the
imino intermediate 9. This intermediate tautomerizes under the
reaction conditions to afford the 3-alkylamino-2-arylimidazo[1,2-
a]pyridine 4.
17. (a) Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H. R. Tetrahedron 2010, 66,
9263–9269; (b) Adib, M.; Ansari, S.; Fatemi, S.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2010, 66, 2723–2727; (c) Adib, M.; Ansari, S.; Mohammadi, A.;
Bijanzadeh, H. R. Tetrahedron Lett. 2010, 51, 30–32; (d) Adib, M.; Mahdavi, M.;
Ansari, S.; Malihi, F.; Zhu, L. G.; Bijanzadeh, H. R. Tetrahedron Lett. 2009, 50,
7246–7248; (e) Adib, M.; Sheibani, E.; Zhu, L. G.; Bijanzadeh, H. R. Tetrahedron
Lett. 2009, 50, 4420–4422; (f) Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L. G.
Tetrahedron 2008, 64, 10681–10686; (g) Adib, M.; Sayahi, M. H.; Ziyadi, H.; Zhu,
L. G.; Bijanzadeh, H. R. Synthesis 2008, 3289–3294; (h) Adib, M.; Mohammadi,
B.; Bijanzadeh, H. R. Synlett 2008, 3180–3182; (i) Adib, M.; Mohammadi, B.;
Bijanzadeh, H. R. Synlett 2008, 177–180; (j) Adib, M.; Sayahi, M. H.; Ziyadi, H.;
Bijanzadeh, H. R.; Zhu, L. G. Tetrahedron 2007, 63, 11135–11140.
18. Adib, M.; Mohamadi, A.; Sheikhi, E.; Ansari, S.; Bijanzadeh, H. R. Synlett 2010,
1606–1608.
In conclusion, we have developed a new and straightforward
approach for the synthesis of imidazo[1,2-a]pyridines via a one-
pot, three-component condensation reaction between 2-amino-
pyridines, benzyl halides or benzyl tosylates and isocyanides. The
use of benzylic substrates in place of aldehydes and the excellent
yields of the products are the main advantages of this reaction.
Acknowledgment
This research was supported by the Research Council of the Uni-
versity of Tehran as research project (6102036/1/03).
19. Adib, M. E.; Sheibani, E.; Zhu, L. G.; Mirzaei, P. Tetrahedron Lett. 2008, 49, 5108–
5110.
20. Adib, M.; Mahdavi, M.; Alizadeh Noghani, M.; Mirzaei, P. Tetrahedron Lett. 2007,
48, 7263–7265.
References and notes
21. Adib, M.; Mahdavi, M.; Abbasi, A.; Haghighat Jahromi, A.; Bijanzadeh, H. R.
Tetrahedron Lett. 2007, 48, 3217–3220.
22. (a) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81, 4113–
4114; (b) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H.
1. Howard, A. S. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. V. F., Eds.; Pergamon Press: London, 1996. Vol. 8, Chapter 10,
pp 262–274, and references therein..

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M. Adib et al. / Tetrahedron Letters 52 (2011) 3191–3194
O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562; (c) Dave, P.;
Byun, H. S.; Engel, R. Synth. Commun. 1986, 16, 1343–1346.
[10H, m, CH(CH2)5], 2.90–2.94 [1H, m, NCH(CH2)5], 4.65 (1H, d, J = 5.6 Hz, NH),
6.89 (1H, t, J = 6.7 Hz, CH), 7.16–7.89 (7H, m, 7CH) 8.30 (1H, d, J = 6.8 Hz, CH).
13C NMR (125.8 MHz, CDCl3): d 24.6, 25.4, 33.6, 56.9, 109.3, 116.4, 123.2, 124.9,
126.8, 127.5, 128.4, 128.7, 133.2, 137.1, 142.2. 3-tert-Butylamino-2-(4-
chlorophenyl)imidazo[1,2-a]pyridine (Entry 10, Table 1): colorless crystals, mp
148–150 °C, yield: 0.282 g, 94%. 1H NMR (500.1 MHz, CDCl3): d 1.04 [9H, s,
C(CH3)3], 3.70 (1H, br s, NH), 6.82 (1H, t, J = 6.7 Hz, CH), 7.16 (1H, dd, J = 8.5,
7.1 Hz, CH), 7.42 (2H, d, J = 8.6 Hz, 2CH), 7.54 (1H, d, J = 7.2 Hz, CH), 7.92 (2H, d,
J = 8.6 Hz, 2CH), 8.26 (1H, d, J = 6.8 Hz, CH). 13C NMR (125.8 MHz, CDCl3): d
30.7, 56.4, 110.9, 116.6, 123.1, 123.6, 124.6, 127.3, 127.9, 132.3, 132.9, 138.4,
141.1.
23. The procedure for the preparation of 3-cyclohexylamino-2-phenylimidazo[1,2-
a]pyridine (entry 1, Table 1) is described as an example: a mixture of benzyl
chloride (0.126 g, 1 mmol) and K2CO3 (1.5 mmol) in DMSO (1 mL) was stirred
for 4 h at 90 °C. Next, 2-aminopyridine (0.094 g, 1 mmol) and cyclohexyl
isocyanide (0.120 g, 1.1 mmol) were added to the reaction mixture and stirring
was continued at 90 °C for 2 h. The reaction mixture was cooled to room
temperature and H2O (3 mL) was added. Stirring was continued for 1 h at
ambient temperature. The resulting white precipitate was filtered, washed
with H2O (2 Â 2 mL), dried, and recrystallized from n-hexane/EtOAc (3:1)25 to
give 3-cyclohexylamino-2-phenylimidazo[1,2-a]pyridine as colorless crystals,
mp 198–200 °C, yield: 0.274 g, 94%. 1H NMR (500.1 MHz, CDCl3): d 1.09–2.02
24. Guchhait, S. K.; Madaan, C.; Thakkar, B. S. Synthesis 2009, 3293–3300.
25. All reactions (Table 1) were carried out following this procedure.