Synthesis of 3-Nitro-2-arylimidazo[1,2- a ]pyridines Using Sodium Dichloro?-iodide

Article abstract of DOI:10.1055/s-0034-1379185

Moderate to good yields of various 3-nitro-2-arylimidazo[1,2-a]pyridines have been easily achieved in the reaction of 2-aminopyridines and nitrostyrenes in the presence of sodium dichloriodide. The procedure is simple and various functional groups are tol

Full text of DOI:10.1055/s-0034-1379185

2636▌
LETTER
lSetyternthesis of 3-Nitro-2-arylimidazo[1,2-a]pyridines Using Sodium Dichloro-
iodide
3-Nitro-2-arylimidazo[1,2-a]pyridines
Prashant B. Jagadhane, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai – 400 019, India
Fax +91(22)33611020; E-mail: vikastelvekar@rediffmail.com
Received: 15.07.2014; Accepted after revision: 29.08.2014
in 1.5 hours, when 0.1 equivalent of aqueous sodium di-
Abstract: Moderate to good yields of various 3-nitro-2-arylimid-
chloroiodide was used.
azo[1,2-a]pyridines have been easily achieved in the reaction of 2-
aminopyridines and nitrostyrenes in the presence of sodium dichlo-
riodide. The procedure is simple and various functional groups are
tolerated in this reaction system.
Reactions were also carried out using different solvents
such as DMSO, MeOH, EtOH, and MeCN, but very low
yields were observed in each case. Thus DMF was
deemed the most suitable solvent for this reaction.
Keywords: 2-aminopyridine, nitrostyrene, iodine reagent, 3-nitro-
2-arylimidazo[1,2-a]pyridines
NO2
N
aq NaICl2
NH2
+
N
Nitrogen-containing heterocycles are widespread in na-
ture and many synthetic bioactive compounds are based
on nitrogen heterocycles;1 so heterocyclic synthesis con-
tinues to provide a focus for the development of novel
synthetic methodology.
N
NO2
Scheme 1 Synthesis of 3-nitro-2-arylimidazo[1,2-a]pyridine using
aqueous sodium dichloroiodide in DMF
Imidazopyridines are known to be one of the important
class of heterocycles in medicinal chemistry and, within
this group of heterocycles, imidazo[1,2-a]pyridines deriv-
atives have been widely exploited for as antitubercular,2
anti-inflammatory,3 anticancer,4 anti-HIV,5 and antimi-
crobial agents.6
The above method was applied successfully to synthesize
various 3-nitro-2-arylimidazo[1,2-a]pyridine derivatives,
and the results are summarized in Table 1.10 It was ob-
served that the nature of the substituent on the aromatic
rings of nitrostyrenes had little influence on the yields of
the products. All the nitrostyrenes with electron-donating
or electron-withdrawing groups gave moderate to good
yields of the corresponding 3-nitro-2-arylimidazo[1,2-
a]pyridines.
Our group is working on novel methodology using iodine
reagents7 and their applications in the synthesis of bioac-
tive compounds.8 During our studies, we needed to func-
tionalize 3-nitro-2-arylimidazo[1,2-a]pyridine as a key
compound. Very few examples of syntheses of 3-nitro-2-
arylimidazo[1,2-a]pyridine have been reported in the lit-
erature; these include condensation of 2-aminopyridines
with nitrostyrenes;9a three-component reactions of 2-ami-
nopyridines, aldehydes and nitromethane,9b and Suzuki–
Miyaura cross-coupling reactions of 2-chloro-3-nitroim-
idazo[1,2-a]pyridine.9c Thus our aim was to develop a
simple method for the synthesis of 3-nitro-2-arylimid-
azo[1,2-a]pyridine.
The substrate scope of 2-aminopyridines was further in-
vestigated and similar results were observed. It is interest-
ing to observe that 5-chloro-2-aminopyridine was found
to produce the desired product while 6-chloro-2-aminopy-
ridine proved to be inert (Table 1, 3m vs. 3n).
In summary, we have successfully developed a novel and
efficient system for the synthesis of 3-nitro-2-arylimid-
azo[1,2-a] pyridines. In this system, readily available ni-
trostyrenes and 2-aminopyridines were utilized in the
presence of aqueous sodium dichloroiodide. Various
functional groups are well tolerated in this reaction system
and gave moderate to good yields.
We proposed that this compound could be synthesized us-
ing iodine-based reagents. Thus in the initial experiment
we carried out the reaction between 2-aminopyridine and
nitrostyrene in the presence of aqueous NaICl2 at room
temperature in DMF (Scheme 1), but only a very low
yield of the desired 3-nitro-2-phenylimidazo[1,2-a]pyri-
dine was isolated after extended reaction time. However,
a higher yield of the desired product was obtained when
the reaction mixture was heated at 80 °C and, after optimi-
zation of reaction conditions, the best yield was obtained
Acknowledgment
V.N.T. thanks the University Grant Commission, New Delhi, India
for providing financial support under teh UGC-Major research
scheme and a Fellowship to P.B.J. under the Rajiv Gandhi National
Fellowship programme (UGC-RGNF).
References and Notes
SYNLETT 2014, 25, 2636–2638
Advanced online publication: 17.09.2014
DOI: 10.1055/s-0034-1379185; Art ID: st-2014-d0591-l
© Georg Thieme Verlag Stuttgart · New York
(1) Jansen, M.; Rabe, H.; Strehle, A.; Dieler, S.; Debus, F.;
Dannhardt, G.; Akabas, M.; Lüddens, H. J. Med. Chem.
2008, 51, 4430.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
3-Nitro-2-arylimidazo[1,2-a]pyridines
2637
Table 1 Synthesis of Various 3-Nitro-2-arylimidazo[1,2-a]pyridine Compounds Using Aqueous Sodium Dichloroiodidea
R1
NO2
N
aq NaICl2, DMF
80 °C, 1.5 h
R1
R2
R2
+
N
NH2
N
NO2
1a
2a
3a
N
N
OMe
N
N
NO2
NO2
85% 3a
82% 3b
N
N
Me
F
N
N
NO2
NO2
87% 3c
N
85% 3d
Cl
N
N
Cl
N
NO2
NO2
80% 3e
85% 3f
Me
N
N
NO2
N
N
NO2
NO2
75% 3g
83% 3h
Me
Me
N
N
Me
OMe
N
N
NO2
NO2
78% 3i
76% 3j
Me
N
N
N
F
N
NO2
Me
NO2
65% 3l
71% 3k
N
N
N
N
Cl
NO2
NO2
Cl
69% 3m
0% 3n
a Reaction conditions: nitrostyrene (1.2 mol), 2-aminopyridine (1 mol), aq NaICl2 (0.1 mol) in DMF at 80 °C.
b Isolated yields after column chromatography. Structures were confirmed by comparison of IR, 1H NMR and mp with literature reports.
(2) (a) Moraski, G.; Markley, L.; Chang, M.; Cho, S.;
Franzblau, S.; Hwang, C.; Boshoff, H.; Miller, M. Bioorg.
Med. Chem. 2012, 20, 2214. (b) Moraski, G.; Markley, L.;
Cramer, J.; Hipskind, P.; Boshoff, H.; Bailey, M.; Alling, T.;
Ollinger, J.; Parish, T.; Miller, M. ACS Med. Chem. Lett.
2013, 4, 675. (c) Hernández, P.; Rojas, R.; Gilman, R.;
Sauvain, M.; Lima, L.; Barreiro, E.; González, M.;
Cerecetto, H. Eur. J. Med. Chem. 2013, 59, 64.
Med. Chem. 1994, 29, 279. (b) Rupert, K.; Henry, J.; Dodd,
J.; Wadsworth, S.; Cavender, D.; Olini, G.; Fahmy, B.;
Siekierka, J. Bioorg. Med. Chem. Lett. 2003, 13, 347.
(4) (a) Baviskar, A.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain,
V.; Agarwal, A.; Guchhait, S.; Kundu, C.; Banerjee, U.;
Bharatam, P. J. Med. Chem. 2011, 54, 5013. (b) Gallud, A.;
Vaillant, O.; Maillard, L.; Arama, D.; Dubois, J.; Maynadier,
M.; Lisowski, V.; Garcia, M.; Martinez, J.; Masurier, N. Eur.
J. Med. Chem. 2014, 75, 382. (c) Fu, R.; You, Q.; Yang, L.;
(3) (a) Abignente, E.; Sacchi, A.; Laneri, S.; Rossi, F.;
D’Amico, M.; Berrino, L.; Calderaro, V.; Parrillo, C. Eur. J.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2636–2638

2638
P. B. Jagadhane, V. N. Telvekar
LETTER
Wu, W.; Jiang, C.; Xu, X. Bioorg. Med. Chem. 2010, 18,
8035.
2-(4-Methoxyphenyl)-3-nitroimidazo[1,2-a]pyridine (3b)
Yellow solid; mp 167–169 °C (lit.9a 168–170 °C). 1H NMR
(400 MHz, CDCl3): δ = 9.50 (d, J = 6.8 Hz, 1 H, H-5), 7.92
(d, J = 8.8 Hz, 2 H, H-2′ and 6′-Ph), 7.79 (d, J = 8.8 Hz, 1 H,
H-8), 7.63 (t, J = 8.0 Hz, 1 H, H-7), 7.24 (d, J = 6.8 Hz, 1 H,
H-6), 7.07 (d, J = 8.8 Hz, 2 H, H-3′ and 5′-Ph), 3.87 (s, 3 H,
OCH3). IR (KBr): 3016, 2922, 1608, 1541, 1481, 1369,
1211, 921, 758 cm–1.
(5) (a) Bode, M.; Gravestock, D.; Moleele, S.; van der
Westhuyzen, C.; Pelly, S.; Steenkamp, P.; Hoppe, H.; Khan,
T.; Nkabinde, L. Bioorg. Med. Chem. 2011, 19, 4227.
(b) Lam, P.; Jadhav, P.; Eyermann, C.; Hodge, C.; Ru, Y.;
Bacheler, L.; Meek, J.; Otto, M.; Rayner, M.; Wong, Y.
Science 1994, 263, 380.
(6) (a) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull.
1992, 40, 1170. (b) Al-Tel, T.; Al-Qawasmeh, R.; Zaarour,
R. Eur. J. Med. Chem. 2011, 46, 1874. (c) Shukla, N.;
Salunke, D.; Yoo, E.; Mutz, C.; Balakrishna, R.; David, S.
Bioorg. Med. Chem. 2012, 20, 5850.
(7) (a) Jadhav, N.; Jagadhane, P.; Patile, H.; Telvekar, V.
Tetrahedron Lett. 2013, 54, 3019. (b) Patel, K.; Jadhav, N.;
Jagadhane, P.; Telvekar, V. Synlett 2012, 23, 1970.
(c) Telvekar, V.; Bachhav, H.; Bairwa, V. Synlett 2012, 23,
2219.
(8) (a) Patel, K.; Telvekar, V. Eur. J. Med. Chem. 2014, 75, 43.
(b) Telvekar, V.; Bairwa, V.; Satardekar, K.; Bellubi, A.
Bioorg. Med. Chem. Lett. 2012, 22, 649. (c) Telvekar, V.;
Belubbi, A.; Bairwa, V.; Satardekar, K. Bioorg. Med. Chem.
Lett. 2012, 22, 2343.
2-(4-Fluorophenyl)-3-nitroimidazo[1,2-a]pyridine (3d)
Yellow solid; mp 224–226 °C (lit.9c 227–228 °C). 1H NMR
(400 MHz, CDCl3): δ = 9.52 (d, J = 6.8 Hz, 1 H, H-5), 7.88–
7.82 (m, 3 H), 7.69–7.65 (m, 3 H), 7.31–7.27 (m, 1 H). IR
(KBr): 3061, 3030, 1604, 1537, 1487, 1334, 1220, 837, 763
cm–1.
3-Nitro-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (3g)
Yellow solid, mp 216–218 °C. 1H NMR (400 MHz, CDCl3):
δ = 9.54 (d, J = 7.0 Hz, 1 H, H-5), 8.30 (d, J = 8.9 Hz, 2 H,
H-2′ and 6′-Ph), 8.13 (d, J = 8.9 Hz, 2 H, H-3′ and 5′-Ph),
7.73 (t, J = 8.2 Hz, 1 H, H-7), 7.66 (d, J = 9.2 Hz, 1 H, H-8),
7.37 (t, J = 7.0 Hz, 1 H, H-6). IR (KBr): 3074, 3032, 1635,
1599, 1514, 1481, 1334, 856, 758 cm–1.
2-(4-Methoxyphenyl)-8-methyl-3-nitroimidazo[1,2-
a]pyridine (3j)
(9) (a) Yan, R.; Yan, H.; Ma, C.; Ren, Z.; Gao, X.; Huang, G.;
Liang, Y. J. Org. Chem. 2012, 77, 2024. (b) Yan, H.; Yan,
R.; Yang, S.; Gao, X.; Wang, Y.; Huang, G.; Liang, Y.
Chem. Asian J. 2012, 7, 2028. (c) Bazin, M.; Marhadour, S.;
Tonnerre, A.; Marchand, P. Tetrahedron Lett. 2013, 54,
5378.
Yellow solid; mp 148–150 °C. 1H NMR (500 MHz, CDCl3):
δ = 9.37 (d, J = 7.2 Hz, 1 H, H-5), 7.94 (d, J = 8.8 Hz, 2 H,
H-2′ and 6′-Ph), 7.43 (d, J = 6.8 Hz, 1 H, H-7), 7.15 (t,
J = 6.8 Hz, 1 H, H-6), 7.03 (d, J = 8.8 Hz, 2 H, H-3′ and 5′-
Ph), 3.84 (s, 3 H, OCH3), 2.71 (s, 3 H, CH3). IR (KBr): 3030,
2922, 1610, 1611, 1580, 1472, 1369, 1238, 1149, 1031, 827,
754 cm–1.
(10) Typical Procedure
A mixture of nitrostyrene (1.2 equiv), 2-aminopyridine (1
equiv), and aq NaICl2 (0.1 equiv) in DMF was stirred at 80
°C for 1.5 h. After completion of reaction (monitored by
TLC), the reaction mixture was diluted with EtOAc and
washed with brine. The organic layer was separated, dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give the crude product. The product was
then purified using silica gel column chromatography
(EtOAc–hexane).
3-Nitro-2-phenylimidazo[1,2-a]pyridine (3a)
Yellow solid; mp 170–172 °C (lit.9a 172–174 °C). 1H NMR
(400 MHz, CDCl3): δ = 9.52 (d, J = 7.2 Hz, 1 H, H-5), 7.92–
7.89 (m, 2 H, H-2′ and H-6′-Ph), 7.84 (d, J = 8.8 Hz, 1 H, H-
8), 7.68–7.64 (m, 1 H, H-7), 7.52 (t, J = 2.0 Hz, 3 H, H-3′,
H-4′, and 5′-Ph), 7.28 (t, 1 H, H-6). IR (KBr): 3061, 3034,
1630, 1531, 1481, 1369, 1219, 929, 761, 694 cm–1.
2-(4-Fluorophenyl)-8-methyl-3-nitroimidazo[1,2-
a]pyridine (3k)
Yellow solid; mp 194–198 °C. 1H NMR (500 MHz, CDCl3):
δ = 9.37 (d, J = 6.95 Hz, 1 H, H-5), 7.96–7.92 (m, 2 H, H-2′
and 6′-Ph), 7.46 (d, J = 7.2 Hz, 1 H, H-7), 7.20 (t, J = 7.1 Hz,
3 H, H-6, H-3′, and 5′-Ph) 2.73 (s, 3 H, CH3). IR (KBr):
3053, 2918, 1607, 1539, 1479, 1366, 1238, 1157, 837, 746
cm–1.
5-Methyl-3-nitro-2-phenylimidazo[1,2-a]pyridine (3l)
Yellow viscous liquid. 1H NMR (400 MHz, CDCl3): δ = 7.99
(t, 2 H, H-2′ and 6′-Ph), 7.74 (s, 1 H, H-4′-Ph), 7.57 (d,
J = 8.8 Hz, 1 H, H-8), 7.44 (t, 2 H, H-3′ and 5′-Ph), 7.37 (t,
J = 7.4 Hz, 1 H, H-7), 7.15 (d, J = 6.8 Hz, 1 H, H-6), 2.61 (s,
3 H, CH3). IR (KBr): 3061, 3030, 2920, 1674, 1537, 1483,
1344, 1226, 1153, 947, 825, 775 cm–1.
Synlett 2014, 25, 2636–2638
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