Catalyst-free synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8- carboxylic acids via a three-component condensation

Article abstract of DOI:10.1016/j.tetlet.2014.03.121

The synthesis of a number of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8- carboxylic acids via a facile route involving the reaction between 2-amino-3-pyridinecarboxylic acid, benzaldehyde derivatives, and isonitriles is reported. The structures of the synthesized compounds are proved by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2014.03.121

Accepted Manuscript
Catalyst-free synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-car-
boxylic acids via a three-component condensation
Ghasem Marandi, Lotfali Saghatforoush, Rafael Mendoza-Meroño, Santiago
García-Granda
PII:
S0040-4039(14)00553-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.121
TETL 44443
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 November 2013
6 March 2014
27 March 2014
Please cite this article as: Marandi, G., Saghatforoush, L., Mendoza-Meroño, R., García-Granda, S., Catalyst-free
synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids via a three-component condensation,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.121
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2
Catalyst-free synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-
carboxylic acids via a three-component condensation
Ghasem Marandi,a,* Lotfali Saghatforoushb , Rafael Mendoza-Meroñoc, Santiago García-Grandac
a Shahid Bakeri High Education Center of Miandoab, Urmia University, Urmia, Iran
b Chemistry Department, Payame Noor University, 19395-4697, Tehran, Iran
c Faculty of Chemistry, Department of Physical and Analytical Chemistry, University Oviedo-CINN. C/ Julian
Claveria, 8, 33006, Oviedo (Asturias), Spain.
* Corresponding author: Tel: +984812265960; Fax: +984812245725; E-mail: marandi_gh@yahoo.com
Abstract
The synthesis of a number of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids via
a facile route involving the reaction between 2-amino-3-pyridinecarboxylic acid, benzaldehyde
derivatives and isonitriles is reported. The structures of the synthesized compounds are proved by
X-ray crystallography.
Keywords: 2-amino-3-pyridinecarboxylic acid, isocyanides, arylcarboxaldehydes, 3-(alkylamino)-
2-arylimidazo[1,2-a]pyridine-8-carboxylic acids

3
The synthesis of new compounds of high utility by known procedures is a very important goal for
organic chemists.1 The preparation of nitrogen-containing fused heterocycles such as imidazo[1,2-
a]pyridines is of importance to medicinal chemistry and materials science because of their
interesting properties.2-7 Zolpidem, olprinone and zolimidine are examples of such compounds
which possess an imidazopyridine scaffold. Pharmaceuticals containing the imidazo[1,2-
a]pyridine moiety have been shown to possess anticonvulsant, antipyretic, antiviral, anti-
inflammatory, antiprotozoal and anti-ulcer activities.8-14 Some of the synthetic methods for the
generation of compounds with an imidazo[1,2-a]pyridine core have gained increased interest,
among which, multicomponent reactions (MCRs) have a distinct place.15-17 Methods for the
synthesis of imidazo[1,2-a]pyridine derivatives have been reported using a catalyst or reflux
conditions.3,6,16-21 In continuation of our investigations on the synthesis of heterocyclic compounds
using isocyanides,22-25 we now report the catalyst-free synthesis of 3-(alkylamino)-2-
arylimidazo[1,2-a]pyridine-8-carboxylic acids.
We observed that the condensation reaction of 2-amino-3-pyridinecarboxylic acid (1) and
arylcarboxaldehydes 2 in the presence of alkyl isocyanides 3 afforded 3-(alkylamino)-2-
arylimidazo[1,2-a]pyridine-8-carboxylic acids 4 in excellent yields (Scheme 1).

4
CHO
CO2H
N
N
NH2
X
N
EtOH
50 °C
+
+
R N C
CO2H
X
N
R
3
2
1
4
H
4
R
X
Yield (%)
a
cyclohexyl 4-Me
4-Me
97
92
b
c
d
e
f
t-Bu
cyclohexyl 3-NO2 93
t-Bu
3-NO2
3-Cl
98
89
95
cyclohexyl
2-NO2
t-Bu
Scheme 1.
Compounds 4a-f are stable structures, which were fully characterized on the basis of 1H, 13C NMR
and IR spectroscopy, elemental analysis and mass spectrometry. Unambiguous structural
clarification was provided by single crystal X-ray diffraction of compounds 4a and 4d (Figures 1
and 2).
Figure 1. Molecular projection of 4a showing the numbering scheme. Atomic displacement ellipsoids have been
drawn at the 50% probability level.

5
Figure 2. Molecular projection of 4d showing the numbering scheme. Atomic displacement ellipsoids have been
drawn at the 50% probability level.
The IR spectrum of compound 4a showed distinct absorptions at 3302 cm-1, attributed to the NH
group at position 2 of the imidazole ring, and at 1733 cm-1 for the C=O of the carboxylic acid
functional group. The mass spectrum of compound 4a displayed the molecular ion peak at m/z =
349.
1
The H NMR spectrum of compound 4a exhibited multiplet signals arising from the cyclohexyl
(5×CH2) at 1.16–1.83 ppm and a multiplet signal due to the NCH of the cyclohexyl group at 3.00
ppm. A characteristic signal for the methyl group protons was observed at 2.42 ppm. In addition,
the NH signal was recorded at 3.17 ppm, which disappeared on D2O exchange. The resonances of
all seven protons of the aromatic cores of compound 4a were recorded between 7.00-8.31 ppm.
The resonance of the carboxylic acid proton was not observed.
1
13
The H decoupled C NMR spectrum of 4a showed five signals readily recognized as arising
from an ArMe group (20.4 ppm), the five methylenes of the cyclohexyl ring (23.7, 24.6 and 33.2
ppm) and the NCH carbon (56.1 ppm), respectively. The carbon of the carboxylic group was
recorded at 164.1 ppm, and all the other resonances were in agreement with the structure.

6
The proposed mechanism for the formation of products 4 is shown in Scheme 2. The first step
may involve an imine condensation of 2-amino-3-pyridinecarboxylic acid (1) and aldehyde 2a to
generate compound A, which was activated by the carboxylic acid toward attack of the isocyanide
3a, according to the Ugi reaction. This adduct undergoes intramolecular nucleophilic addition
involving the lone pair of the pyridyl nitrogen resulting in cyclization to give the five-membered
ring in intermediate C. Rearrangement and proton transfer gives the final compound 4a.
CH3
CH3
CH3
N
CHO
CH3
CH
HC
N
C N
3a
C
N
NH2
N
N
H
-H2O
N
+
H
N
N
CO2H
CO2H
H
1
CO2
CO2
A
2a
B
CO2
N
CO2
CH3
CO2H
NH
H
N
N
[1,3 H shift]
CH3
N
N
H
NH
CH3
N
N
4a
H
C
Scheme 2. Proposed mechanism for the generation of 3-(alkylimino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids
4
In summary, we have reported an efficient one-pot synthetic method for the preparation of 3-
(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-carboxylic acids via a three-component reaction

7
involving isocyanides. The products were obtained in excellent yields without addition of a
catalyst.
General procedure for synthesis of compounds 4 (exemplified by 4a)
To a magnetically stirred solution of 2-amino-3-pyridinecarboxylic acid (1) (1 mmol) and 4-
methylbenzaldehyde (2a) (1 mmol) in EtOH (10 mL) was added, dropwise, a mixture of
cyclohexyl isocyanide (1 mmol) in EtOH (5 mL) over 5 min at room temperature. The mixture
°
was heated at 50 C for 3 h to complete the reaction (monitored by TLC). The solvent was
removed by slow evaporation. The residue was washed with cold Et2O (2 × 3 mL), and the desired
product was then collected by filtration and recrystallized from EtOH (3 mL).
3-(cyclohexylamino)-2-(4-methylphenyl)imidazo[1,2-a]pyridine-8-carboxylic acid (4a)
◦
Light yellow crystals, (0.34 g), yield 97%; mp 198–201 C, IR (solid) (νmax, cm−1): 3302 (NH),
1733 (C=O). MS, m/z (%) = 350 (M+ + 1, 22), 349 (M+, 72), 305 (32), 266 (83), 239 (100), 223
(20), 147 (27), 119 (41), 94 (15), 55 (29). Anal. Calcd for C21H23N3O2 (349.43): C, 72.18; H, 6.63;
N, 12.03%. Found: C, 72.13; H, 6.57; N, 12.11%. 1H NMR (400.1 MHz, CDCl3): 1.16–1.83 (10H,
m, 5×CH2 of cyclohexyl), 2.42 (3H, s, ArCH3), 3.00 (1H, m, NCH of cyclohexyl), 3.17 (1H, br s,
NH), 7.00 (1H, t, J = 6.9 Hz, CHpyr), 7.30 (2H, d, J = 7.9 Hz, 2×CHaryl), 7.90 (2H, d, J = 7.9 Hz,
2×CHaryl), 8.09 (1H, d, J = 6.7 Hz, CHpyr), 8.31 (1H, d, J = 6.7 Hz, CHpyr). 13C NMR (100.6 MHz,
CDCl3): 20.4 (s, ArCH3), 23.7, 24.6 and 33.2 (3s, 5×CH2 of cyclohexyl), 56.1 (s, NCH of
cyclohexyl), 111.2 (s, Cpyr and CHpyr), 116.2 (s, NCNHimidazo), 124.3 (s, Caryl), 125.4 (s, CHpyr),
126.0 (s, 2×CHaryl), 128.1 (s, CHpyr), 128.5 (s, 2×CHaryl), 135.1 (s, Cimidazo), 137.3 (s, Caryl), 139.3
(s, Cfused), 164.1 (s, CO2H).

8
Single Crystal X-ray structure determination
The diffraction data from selected single crystals of compounds 4a and 4d were collected at room
temperature and 150 K with MoKα radiation (λ=0.7107 Å). The data were processed with
CrysAlis software, and empirical absorption correction using spherical harmonics were
implemented using the SCALE3 ABSPACK scaling algorithm.26 The crystallographic data and
the refinement parameters for these crystals are summarized in Table 1 in the Supporting
Information.
Crystal structures were solved by direct methods using Sir 200827 and refined by full-matrix least-
squares calculations against F2 using SHELXL.28 All non-hydrogen atoms were refined with
anisotropic displacement parameters. For both structures, aromatic C-H, -CH3 methyl and -CH2
cyclohexane hydrogen atoms were included in calculated positions and treated as riding atoms:
C—H = 0.93 Å for aromatic CH [U iso(H) = 1.2 × Ueq(C)], C—H = 0.96 Å for methyl group [U
iso(H) = 1.5 × Ueq(C)] and C—H = 0.97 Å for -CH2 [U iso(H) = 1.2 × Ueq(C)]. The Figures
were produced using ORTEP-3.29 Deposition numbers CCDC 965018 for 4a, and CCDC 965019
for 4d contain the supplementary crystallographic data for this paper. These data can be obtained
free
of
charge
from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Financial support was provided by the Research Council of Urmia University, Payame Noor
University, the Ministerio de Economía Competitividad de España (MAT2010-15094, Factoría de
Cristalización–Consolider Ingenio 2010) and ERDF.

9
References
1. Laszlo. P. Organic Reactions: Simplicity and Logic, Wiley: New York, 1995.
2. Falco, J. L.; Palomer, A.; Guglietta, A. US Patent 2006051063. Chem. Abstr. 2006, 144, 1080.
3. Ismail, M. A.; Brun, R.; Wenzler, T.; Tanious, F. A.; Wilson, W. D.; Boykin, D. W. J. Med.
Chem. 2004, 47, 3658-3664.
4. Kim, O.; Jeong, Y.; Lee, L.; Hong, S. S.; Hong, S. J. Med. Chem. 2011, 54, 2455-2466.
5. Jin, Y.; Rho, M. C.; Gajulapati, K.; Jung, H. Y.; Boovanahalli, S. K.; Lee, J. H.; Song, G. Y.;
Choi, J. H.; Kim, Y. K.; Lee, K.; Choi, Y. Bull. Korean Chem. Soc. 2009, 30, 1297-1304.
6. Anderson, M.; Beattie J. F.; Breault, G. A.; Breed, J.; Byth, K. F.; Culshaw, J. D.; Ellston, R. P.
A.; Green, S.; Minshull, C. A.; Norman, R. A.; Pauptit, R. A.; Stanway, J.; Thomas, A. P.;
Jewsbury, P. J. Bioorg. Med. Chem. Lett. 2003, 13, 3021–3026.
7. Katritzky, A. R.; Xu, Y. J.; Tu, H. J. Org. Chem. 2003, 68, 4935-4937.
8. Couty, F.; Evano, G. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden,
C. A., Scriven, E. V. F., Taylor, R. J. K., Eds.; Elsevier Science, Oxford, 2008, Vol. 11,
Chapter 10, pp 409–492.
9. Figueiredo, J. M.; Camara, C. A.; Amarante, E. G.; Miranda, A. L. P.; Santos, F. M.;
Rodrigues, C. R.; Fraga, C. A. M.; Berreiro, E. J. Bioorg. Med. Chem., 2000, 8, 2243–2248.
10. Cesur, N.; Cesur, Z. Farmaco 1994, 49, 679–681.
11. Chiacchio, A. D.; Rimoli, M. G.; Avallonea, L.; Arena, F.; Abignente, E.; Filippelli, W.;
Filippelli, A.; Falcone, G. Arch. Pharm. 1998, 331, 273-278.
12. Saxena, A. K.; Schaper, K. J. QSAR Comb. Sci. 2006, 25, 590-597.
13. Ozdemir, A.; Turan-Zitouni, G.; Asim Kaplancikli, Z.; Iscan, G.; Khan, S.; Demirci, F. Eur. J.
Med. Chem. 2010, 45, 2080-2084.

10
14. Kaminski, J. J.; Doweyko, A. M. J. Med. Chem. 1997, 40, 427-436.
15. Zhu, J.; Bienaymé, H. Multicomponent Reactions, 1st Ed., Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2005.
16. Rousseau, A. L.; Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079–4082.
17. Motevali, K.; Yaghoubi, Z.; Mirzazadeh, R. Eur. J. Chem. 2012, 9, 1047-1052.
18. Khan, A. T.; Basha, R. S.; Lal, M. Tetrahedron Lett. 2012, 53, 2211–2217.
19. Rostamnia, S.; Lamei, K.; Mohammadquli, M.; Sheykhan, M.; Heydari, A. Tetrahedron Lett.
2012, 53, 5257–5260.
20. Basilio-Lopes, A.; Mendonça de Aquino, T.; Mongeot, A.; Bourguignon, J. J.; Schmitt, M.
Tetrahedron Lett. 2012, 53, 2583–2587.
21. Ramesha, A. B.; Raghavendra, G. M.; Nandeesh, K. N.; Rangappa, K. S.; Mantelingu, K.
Tetrahedron Lett. 2013, 54, 95–100.
22. Maghsoodlou, M. T.; Marandi, G.; Hazeri, N.; Aminkhani, A.; Kabiri, R. Tetrahedron Lett.
2007, 48, 3197–3199.
23. Hazeri, N.; Marandi, G.; Maghsoodlou, M. T.; Habibi Khorassani, S. M. Lett. Org. Chem.
2011, 8, 12-15.
24. Maghsoodlou, M. T.; Marandi, G.; Hazeri, N.; Habibi Khorassani, S. M. Mirzaei, A. A. Mol.
Divers. 2011, 15, 227–231.
25. Marandi, G.; Maghsoodlou, M. T.; Hazeri, N.; Akbarzadeh Torbati, N.; Rostami-Charati, F.;
Skelton, B. W.; Makha, M. Mol. Divers. 2011, 15, 197–201.
26. Oxford Diffraction. CrysAlis PRO, CrysAlis CCD and CrysAlis RED. Oxford Diffraction Ltd,
Yarnton, Oxfordshire, United Kingdom, 2010.

11
27. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Cascarano, G. L.; De Caro, L.;
Giacovazzo, C.; Polidori, G.; Siliqi, D.; Spagna, R. J. Appl. Crystallogr. 2007, 40, 609-613.
28. Sheldrick, G. M. Acta Crystallogr. A 2008, 64, 112-122.
29. Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565-566.

1
Graphical abstract
Catalyst-free synthesis of 3-(alkylamino)-2-arylimidazo[1,2-a]pyridine-8-
carboxylic acids via a three-component condensation
Ghasem Marandi,* Lotfali Saghatforoush, Rafael Mendoza-Meroño, Santiago García-Granda
CHO
X
CO2H
N
N
NH2
X
N
EtOH
50 °C
+
+
R N C
CO2H
N
R
H
R: cyclohexyl, t-butyl
X: 4-methyl, 2-nitro, 3-nitro, 3-chloro