Facile synthesis of imidazo[1,2-a]pyridines via a one-pot three-component reaction under solvent-free mechanochemical ball-milling conditions

Article abstract of DOI:10.1039/c3ra43221a

In this work, 3-aminoimidazo[1,2-a]pyridine derivatives have been synthesized by a one-pot three-component condensation reaction of 2-aminopridines, aldehydes and isocyanides under solvent-free mechanochemical ball-milling conditions in good to excellent yields at room temperature. This efficient protocol has many noticeable advantages such as mild reaction conditions, high yields, high atom economy, short reaction times and simple separation. the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra43221a

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Facile synthesis of imidazo[1,2-a]pyridines via a
one-pot three-component reaction under solvent-
free mechanochemical ball-milling conditions†
Cite this: RSC Adv., 2014, 4, 30229
*
Ali Maleki, Shahrzad Javanshir and Maryam Naimabadi
In this work, 3-aminoimidazo[1,2-a]pyridine derivatives have been synthesized by a one-pot three-
component condensation reaction of 2-aminopridines, aldehydes and isocyanides under solvent-free
mechanochemical ball-milling conditions in good to excellent yields at room temperature. This efficient
protocol has many noticeable advantages such as mild reaction conditions, high yields, high atom
economy, short reaction times and simple separation.
Received 26th June 2013
Accepted 27th June 2014
DOI: 10.1039/c3ra43221a
www.rsc.org/advances
Saripidem),8k,8l anti-HIV,9 and interesting uorescence proper-
ties (Fig. 1).10
Introduction
The rst synthesis of imidazo[1,2-a]azines through MCRs
was described in 1998.11 It can be classied as an extension of
the well-known Ugi-MCR12 including a reaction among an
aldehyde, an isocyanide, and a 2-aminoazine. Since then, in the
literature, this reaction has been reported in the presence of
various catalysts.13 However, some of these methods have de-
ciencies such as the requirement of expensive and excess
amounts of catalyst, using toxic solvents, difficulties in work-up
procedure, harsh reaction conditions and special instrumen-
tation. Therefore, the design and development of new
approaches for this reaction is of prime importance.
Nowadays, research in science and technology is focusing more
and more on clean, safe and inexpensive processes. In this
regard, the chemical industry and academics are developing
solvent-free reactions as one of the most important principals of
the “green chemistry” approach. They have several advantages
in comparison with traditional reactions using organic solvents,
like reduction of organic solvent disposal, enhanced reaction
rates, greater selectivity and the easy work-up procedures.1
Mechanochemical techniques like grindstone and ball-
milling could be used in various organic syntheses for the
grinding of materials into ne particles and the preparation or
modication of organic and inorganic solids. Recently, due to
this ability, some examples of using ball-mill in organic
synthesis have been reported.2–4
Multicomponent reactions (MCRs) are introduced as an
efficient strategy in synthetic organic chemistry because of their
valued features such as atom economy, straightforward reaction
design, simple purication of products, rapid generation of
molecular complexity, diversity-oriented synthesis, and
construction of chemical libraries of drug-like molecules with
target-oriented functionalities.5–7
Imidazo[1,2-a]azines have shown a broad range of pharma-
cological and biological activities such as antibacterial,8a anti-
diabetic,8b antifungal,8c anthelmintic,8d antiviral,8e anti-
protozoal,8f anti-inammatory,8g anticonvulsant,8h anxiolytic
(Alpidem) and hypnotic (Zolpidem),8i immunomodulatory
(Kifunensine),8j antiulcer agents (Zolmidine, Necopidem and
Fig. 1 The structure of some important drugs containing the imida-
zopyridine cores.
Department of Chemistry, Iran University of Science and Technology, Tehran
16846-13114, Iran. E-mail: maleki@iust.ac.ir; Fax: +98 21 73021584
† Electronic supplementary information (ESI) available: Melting points and CHN
analysis data of the products and copies of spectral analysis of
4-(6-bromo-3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol (4o).
See DOI: 10.1039/c3ra43221a
Scheme 1 One-pot synthesis of 3-aminoimidazo[1,2-a]pyridine.
RSC Adv., 2014, 4, 30229–30232 | 30229
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Table 1 Synthesis of 3-aminoimidazo[1,2-a]pyridines under ball-milling conditions
Isolated yield
(%)
Entry
1
R1
H
R2
R3
Product
Time (min)
20
C6H5
Cyclohexyl
90
90
2
3
4
H
H
H
p-ClC6H4
Cyclohexyl
Cyclohexyl
Cyclohexyl
15
20
15
p-MeC6H4
p-NO2C6H4
90
96
5
Br
o-ClC6H4
Cyclohexyl
20
96
6
7
Br
Br
C6H5
C6H5
Cyclohexyl
15
20
98
90
tert-Butyl
8
9
CH3
CH3
C6H5
tert-Butyl
25
20
90
95
m-NO2C6H4
Cyclohexyl
10
11
12
H
H
Br
p-FC6H4
p-BrC6H4
p-ClC6H4
Cyclohexyl
Cyclohexyl
Cyclohexyl
15
15
15
98
95
92
13
H
o-thienyl
Cyclohexyl
45
70
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Table 1 (Contd.)
Isolated yield
(%)
Entry
14
R1
R2
R3
Product
Time (min)
25
CH3
p-MeC6H4
tert-Butyl
80
86
15
Br
m-MeO-p-OH-C6H3
Cyclohexyl
25
In connection with our interest in MCRs,13c,13h–j,14 wish to
report the synthesis of 3-aminoimidazo[1,2-a]pyridines 4a–o by
a one-pot three-component reaction of 2-aminopyridines 1,
aldehydes 2 and isocyanides 3 under solvent-free ball-milling
conditions at room temperature (Scheme 1). To the best of our
knowledge, this work is the rst example of using mechano-
chemical activation as an easy-to-handle process for the
synthesis of variously substituted imidazo[1,2-a]pyridines
through an isocyanide-based MCR.
Experimental section
General
All chemicals were purchased from Merck, Aldrich or Fluka
chemical companies; and have been used as received. Ball mill
apparatus was Retsch MM2000 model having 20 mL iron cell
and two iron balls of 12 mm diameter at a frequency of 20 Hz
was used for protection reactions. Melting points were
measured on an Electrothermal 9200 apparatus and are
uncorrected. Mass spectra were recorded on a Finnigan-MAT
8430 mass spectrometer operating at an ionization potential of
70 eV. IR spectra were recorded on a Shimadzu FT-IR 8400s
Results and discussion
1
spectrometer. The H NMR spectra were recorded at 500 MHz
on Bruker DRX-500 Avance spectrometer. The 13C NMR spectra
were recorded at 125 MHz on Bruker DRX-500 Avance spec-
trometer; chemical shis (d scale) are reported in parts per
million (ppm). The elemental analyses were performed with an
In the rst step, to nd the best reaction conditions for the
synthesis of 3-aminoimidazo[1,2-a]pyridine derivatives, the one-
pot three-component condensation of 2-aminopyridine
1
(1 mmol), benzaldehyde 2 (1 mmol) and cyclohexyl isocyanide 3
(1 mmol) was examined under various reaction conditions. The
results showed that the efficiency and the yield of the reaction
under solvent-free conditions were higher than those obtained
in the presence of solvents.13
Elementar
Analysensysteme
GmbH VarioEL.
Known
compounds were characterized by elemental analyses and
comparison of the melting points with those of authentic
samples.
The scope and efficiency of the process was investigated
under optimized conditions and the results are summarized in
Table 1. For this purpose, a broad range of structurally diverse
General procedure for the preparation of (4a–o)
aldehydes bearing electron-releasing or electron-withdrawing A mixture of 2-aminopyridine (1 mmol), aldehyde (1 mmol),
substituents, 2-aminopyridines and isocyanides were success- isocyanide (1 mmol) and PTSA (15 mol%) were poured in a
fully condensed via a one-pot reaction.
10 mL stainless steel double-walled ball mill beaker for the
As shown in Table 1, all of the reactions proceeded efficiently appropriate time according to Table 1. Aer completion of
and the desired products were produced in good to excellent the reaction, as indicated by TLC (EtOAc–n-hexane, 2 : 1), the
yields in relatively short reaction times. Aromatic aldehydes reaction mixture was washed with H2O (2 Â 10 mL) and the
bearing electron-withdrawing groups (Entries 4 and 9) reacted solid product was ltered and then crystallized from hot water
at a faster rate in comparison to those substituted with electron- to obtain the pure product.
releasing groups such as CH3 or heteroaromatic thiophene
4-(6-Bromo-3-(cyclohexylamino)-2,3-difydroimidazo[1,2-a]-
moieties (Entries 3, 14, 15 and 13, respectively). Guaiacol as a pyridin-2ꢀ-yl)-2-methoxyphenol (4o). Cream powder (86%); mp:
specic aldehyde was also examined in this reaction and gave 234–236 C; IR (KBr): 3300 (OH), 3296 (NH), 3080, 2923, 2852,
1
good yield (Entry 15). Furthermore, halogen bearing aldehydes 1652. H NMR (500 MHz, DMSO-d6): dH (ppm) 1.01–1.65 (10H,
gave suitable reaction yields in reasonable times (Entries 2, 5, m, 5CH2 of cyclohexyl), 2.82 (1H, m, CH of cyclohexyl), 3.79 (3H,
10–12). In addition, diversity and scope of the other compo- s, OMe), 4.73 (1H, br s, NH), 6.78–7.60 (4H, m, H-Ar), 7.70 (1H, s,
nents of this reaction were examined. In this order, 2-amino-5- H-Ar), 8.40 (1H, s, H-Ar), 9.02 (1H, s, OH). 13C NMR (125 MHz,
bromopyridine (Entries 5–7, 12 and 15) and tert-butyl isocyanide DMSO-d6): 24.6, 25.4, 33.5, 55.5, 56.4, 105.3, 110.4, 115.4, 117.6,
(Entries 7, 8 and 14) were used and they gave excellent results, 119.5, 122.9, 125.1, 125.6, 126.0, 135.8, 138.6, 146.0, 147.4. MS,
as predicted.
m/z (%): 417 (M+ + 1, 81Br), 415 (M+ + 1, 79Br), 332, 305, 156, 55.
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1972, 15, 982; (e) A. Gueiffier, S. Mavel, M. Lhassani,
A. Elhakmaoui, R. Snoeck, G. Andrei, O. Chavignon,
J. C. Teulade, M. Witvrouw, J. Balzarini, E. De Clercq and
J. P. Chapat, J. Med. Chem., 1998, 41, 5108; (f) M. A. Ismail,
R. Brun, T. Wenzler, F. A. Tanious, W. D. Wilson and
D. W. Boykin, J. Med. Chem., 2004, 47, 3658; (g)
E. Abignente, Actual. Chim. Ther., 1991, 18, 193; (h)
S. Z. Langer, S. Arbilla, J. Benavides and B. Scatton, Adv.
Biochem. Psychopharmacol., 1990, 46, 61; (i) L. Almirante,
L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli,
A. Biancotti, A. Gamba and W. Murmann, J. Med. Chem.,
1965, 8, 305; (j) C. Hamdouchi, B. Zhong, J. Mendoza,
E. Collins, C. Jaramillo, J. E. De Diego, D. Robertson,
C. D. Spencer, B. D. Anderson, S. A. Watkins, F. Zhanga
and H. B. Brooks, Bioorg. Med. Chem. Lett., 2005, 15, 1943;
(k) A. N. Jain, J. Med. Chem., 2004, 47, 947; (l) N. Hsua,
S. K. Jha, T. Coleman and M. G. Frank, Behav. Brain Res.,
2009, 201, 233.
Conclusion
In summary, we have introduced an efficient and green
approach for the synthesis of 3-aminoimidazo[1,2-a]pyridines
via condensation reaction of 2-aminopyridines, aldehydes and
isocyanides under solvent-free mechanical ball-milling condi-
tions in good to excellent yields at room temperature. This
protocol for the preparation of synthetically, biologically and
pharmaceutically relevant imidazopyridine derivatives includes
some important aspects like the easy work-up procedure, high
atom economy, and mild reaction conditions. Furthermore, the
reaction has been shown to display good functional group
tolerance and product isolation is very straightforward and is
the rst introduction of ball-milling process in isocyanide-
based MCRs.
Acknowledgements
9 M. L. Bode, D. Gravestock, S. S. Moleele, C. W. van der
Westhuyzen, S. C. Pelly, P. A. Steenkamp, H. C. Hoppe,
T. Khan and L. A. Nkabinde, Bioorg. Med. Chem., 2011, 19,
4227.
10 A. T. Khan, R. Sidick Basha and M. Lal, Tetrahedron Lett.,
2012, 53, 2211.
The authors gratefully acknowledge nancial support from the
Iran National Science Foundation (INSF) and the Research
Council of Iran University of Science and Technology. The
authors would like to thank Dr M. R. Naimi-Jamal for Ball mill
apparatus.
11 (a) C. Blackburn, Tetrahedron Lett., 1998, 39, 5469; (b)
Notes and references
´
H. Bienayme and K. Bouzid, Angew. Chem., Int. Ed., 1998,
37, 2234; (c) K. Groebke, L. Weber and F. Mehlin, Synlett,
1998, 661.
1 M. S. Singh and S. Chowdhury, RSC Adv., 2012, 2, 4547.
2 Advanced Technologies Based on Self Propagating and
Mechanochemical Reactions for Environmental Protection, ed. 12 I. Ugi and R. Meyr, Chem. Ber., 1961, 94, 2229.
G. Cao, F. Delogu and R. Orru, Research Signpost: Kerala, 13 (a) M. Adib, M. Mahdavi, M. A. Noghani and P. Mirzaei,
India, 2003.
Tetrahedron Lett., 2007, 48, 7263; (b) M. Adib, E. Sheikhi
and N. Rezaei, Tetrahedron Lett., 2011, 52, 3191; (c)
A. Shaabani, E. Soleimani and A. Maleki, Tetrahedron Lett.,
2006, 47, 3031; (d) H. A. Oskooie, M. Amini, M. M. Heravi
and F. F. Bamoharram, Chin. J. Chem., 2010, 28, 299; (e)
A. Shaabani, F. Rezazadeh and E. Soleimani, Monatsh.
Chem., 2008, 139, 931; (f) S. K. Guchhait, C. Madaan and
B. S. Thakkar, Synthesis, 2009, 329; (g) M. Adib,
E. Sheibani, L.-G. Zhu and P. Mirzaei, Tetrahedron Lett.,
2008, 49, 5108; (h) A. Shaabani, E. Soleimani, A. Sarvary,
A. H. Rezayan and A. Maleki, Chin. J. Chem., 2009, 27, 369;
(i) A. Shaabani, E. Soleimani, A. Maleki and J. Moghimi-
Rad, Synth. Commun., 2008, 38, 1090; (j) A. Shaabani,
E. Soleimani and A. Maleki, Monatsh. Chem., 2007, 138, 73;
(k) T. Guntreddi, B. K. Allam and K. N. Singh, Synlett, 2012,
2635; (l) M. Adib, A. Mohamadi, E. Sheikhi, S. Ansari and
H. R. Bijanzadeh, Synlett, 2010, 1606; (m) B. Maiti,
K. Chanda, M. Selvaraju, C.-C. Tseng and C.-M. Sun, ACS
Comb. Sci., 2013, 15, 291.
3 G. Kaupp, M. R. Naimi-Jamal and V. A. Stepanenko, Chem.–
Eur. J., 2003, 9, 4156.
4 (a) Z. Zhang, J. Gao, J.-J. Xia and G.-W. Wang, Org. Biomol.
Chem., 2005, 3, 1617; (b) V. P. Balema, J. W. Wiench,
M. Pruski and V. K. Pecharsky, J. Am. Chem. Soc., 2002,
124, 6244; (c) B. Rodriguez, A. Bruckmann and C. Bolm,
Chem.–Eur. J, 2007, 13, 4710.
´
5 J. Zhu and H. Bienayme, Multicomponent Reactions, Wiley-
VCH, Weinheim, Germany, 1st edn,. 2005.
6 V. G. Nenajdenko, Isocyanide Chemistry: Applications in
Synthesis and Material Science, Wiley-VCH, Weinheim,
Germany, 2012.
¨
7 (a) A. Domling, Chem. Rev., 2006, 106, 17; (b) H. Bienayme,
C. Hulme, G. Oddon and P. Schmidt, Chem.–Eur. J, 2000, 6,
3321; (c) C. Hulme, M. M. Morrissette, F. A. Volz and
C. J. Burns, Tetrahedron Lett., 1998, 39, 1113; (d) C. Hulme
and V. Gore, Curr. Med. Chem., 2003, 10, 51; (e) M. Adib,
S. Ansari, S. Fatemi, H. R. Bijanzadeh and L.-G. Zhu,
Tetrahedron, 2010, 66, 2723.
8 (a) Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull.,
1992, 40, 1170; (b) T. Kercher, C. Rao, J. R. Bencsik and
J. A. Josey, J. Comb. Chem., 2007, 9, 1177; (c) Y. Rival,
G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med. Chem.,
1991, 26, 13; (d) M. H. Fisher and A. Lusi, J. Med. Chem.,
14 (a) A. Maleki, N. Ghamari and M. Kamalzare, RSC Adv., 2014,
4, 9416; (b) A. Maleki, Tetrahedron, 2012, 68, 7827; (c)
A. Maleki, Tetrahedron Lett., 2013, 54, 2055; (d) A. Maleki
and A. H. Rezayan, Tetrahedron Lett., 2014, 55, 1848; (e)
A. Maleki and M. Kamalzare, Catal. Commun., 2014, 53, 67;
(f) A. Maleki, Helv. Chim. Acta, 2014, 97, 587.
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