Microwave-assisted metal-free synthesis of 2,8-diaryl-6-aminoimidazo-[1,2- a]pyridine via amine-triggered benzannulation

Article abstract of DOI:10.1055/s-0031-1290979

An efficient microwave-assisted metal-free amino benzannulation of aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)methanone with dialkylamines afforded a variety of 2,8-diaryl-6-aminoimidazo[1,2-a]pyridine in moderate to excellent yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290979

LETTER
▌1353
lMetteircrowave-Assisted Metal-Free Synthesis of 2,8-Diaryl-6-aminoimidazo-
[1,2-a]pyridine via Amine-Triggered Benzannulation
Aminobenzannulation Reactio
Muthupandi Nagaraj,a Muthusamy Boominathan,a Shanmugam Muthusubramanian,*a Nattamai Bhuvaneshb
a
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
Fax +91(452)2459845; E-mail: muthumanian2001@yahoo.com
b
X-ray Diffraction Lab, Department of Chemistry, Texas, A&M University, College Station, TX 77842, USA
Received: 16.02.2012; Accepted after revision: 22.03.2012
Besides the biological activities, the optical properties of
imidazo[1,2-a]pyridines are interesting, finding applica-
tions in organic white luminescent materials11 and
fluorescent responses to mercury ion.12 In the past few
years, usage of microwave energy to drive chemical reac-
tions has become increasingly popular in the medicinal
chemistry community. The short reaction times and ex-
panded reaction range offered by microwave-assisted or-
ganic synthesis are suited to the increased demands in
industry.
Abstract: An efficient microwave-assisted metal-free amino
benzannulation of aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-
yl)methanone with dialkylamines afforded a variety of 2,8-diaryl-6-
aminoimidazo[1,2-a]pyridine in moderate to excellent yield.
Key words: alkynes, amination, annulation, fused ring systems,
heterocycles, green chemistry
Imidazo[1,2-a]pyridine moieties represent important
building blocks in both natural and synthetic bioactive
compounds, which have been shown to possess diverse
therapeutic activities including antibacterial,1 antifungal,2
antiviral,3 and anti-inflammatory behaviors.4 They have
also been characterized as selective cyclin-dependent ki-
nase inhibitors,5 calcium channel blockers,6 β-amyloid
formation inhibitors.7 Several imidazo[1,2-a]pyridines al-
ready on the market include zolimidine (antiulcer drug),8
zolpidem (hypnotic drug), and alpidem (nonsedative an-
xiolytic).9 Necopidem and saripidem (Figure 1) are drugs
belonging to the imidazo[1,2-a]pyridine family. DS-1 is
the first drug developed that acts as a GABAA receptor ag-
onist selective for the α4β3δ subtype.10
A number of synthetic methods have been designed for
the preparation of imidazo[1,2-a]pyridine skeleton, a ma-
jority of them involving the formation of the imidazole
ring.13 However, a few methods are available based on the
formation of the pyridine ring.14 The coupling reaction of
2-aminopyridines with α-halocarbonyl compounds pro-
vides a practical method, which has found wide applica-
tions in medicinal chemistry and drug synthesis.15 Very
recently, Yu et al. has reported the oxidative coupling of
2-aminopyridines with β-keto esters or 1,3-diones leading
to imidazo[1,2-a]pyridines formation.16
A variety of benzannulation strategies involving Lewis
acid and transition-metal-catalyzed transformations, iodo-
cyclization, and thermal cyclization have been reported.17
Recently, the amine-triggered aminobenzannulation has
been considered as an attractive route for the construction
of useful amino-substituted aromatic rings and heterocy-
cles.18
N
N
Cl
N
N
Me
Me
N
N
O
O
In an attempt to synthesize imidazo[1,2-a]pyridines with
2,8-diaryl and 6-amino functionalities by an atom-eco-
nomical and environmentally friendly novel route, we de-
scribe a microwave-assisted, metal-free benzannulation
of the aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)-
methanone 3 with dialkylamines providing a variety of
2,8-diaryl-6-aminoimidazo[1,2-a]pyridine 5 in moderate
to excellent yield. To the best of our knowledge, amino-
benzannulation for the construction of the 2,8-diaryl-6-
aminoimidazo[1,2-a]pyridine has not been explored so
far.
Br
saripidem
necopidem
N
S
N
Br
NH
O
Cl
DS-1
Figure 1 Imidazo[1,2-a]pyridine-based drugs
Imidazole derivatives 2 were easily obtained by two sim-
ple and high-yielding steps from commercially available
acetophenones 1.19 These imidazoles could be converted
to a set of new N-propargyl derivatives 3 using propar-
gyl bromide.20 After optimization, it was found that
when phenyl(4-phenyl-1-(prop-2-ynyl)-1H-imidazol-2-yl)-
methanone (3a, 0.4 mmol) and pyrrolidine (4a, 2 mL)
SYNLETT 2012, 23, 1353–1357
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290979; Art ID: ST-2012-B0143-L
© Georg Thieme Verlag Stuttgart · New York

1354
M. Nagaraj et al.
LETTER
O
Br
1) SeO2
N
N
2) excess
NH4OAc
N
N
H
2a
O
O
1a
92%
3a
85%
N
MW, 4 Å MS
N
NH
N
80 ºC, 120 W, 10 min
N
4a
2.0 mL
O
N
3a
5a
94%
Scheme 1 Benzannulation of phenyl[4-phenyl-1-(prop-2-ynyl)-1H-imidazol-2-yl]methanone (3a) with pyrrolidine
were irradiated in the presence of MS 4 Å (200 mg) at reaction, confirming the formation of the intermediate X
80 °C and 120 W for 10 minutes, 2,8-diphenyl-6-amino- in the reaction (Scheme 2). Initially, nucleophilic attacks
imidazo[1,2-a]pyridine (5a) was obtained in excellent of the secondary amine on the terminal alkyne and car-
yield after recovering the excess pyrrolidine by distilla- bonyl carbon lead to the formation of intermediate X,
tion and subsequent purification by a short silica gel col- which undergoes subsequent cyclization.18b This is fol-
umn (Scheme 1).21 This protocol, which is similar to the lowed by the elimination of amine leading to the forma-
reported one,18b was then carried out with different acyclic tion of 6-aminoimidazo[1,2-a]pyridine 5.
and cyclic dialkylamines 4 to get a library of 5. The con-
ventional heating reaction requires more than an hour for
completion. The structure of 5 has been unambiguously
It was found that not only the substituted imidazoles, but
also the pyrrole derivatives can be subjected to benzannu-
assigned based on spectroscopic and analytical data. The
structures of 5b,c and 3a have been confirmed by single-
Ar
N
Ar
crystal X-ray analyses also (Figure 2; see also Supporting
N
Information).22
O
The reaction of 3a with pyrrolidine, when carried out in
the absence of molecular sieves, led to 5a in relatively
O
6
poor yield, less than 50%. Similarly when the reaction
was carried out in other solvents like CH2Cl2, MeCN, tol-
hydrolysis
uene, THF, and MeOH with 1.5 equivalents of pyrrolidine
with MS 4 Å resulted in poor yield of 5a (40–50%).
Ar
Ar
Ar
N
N
N
Ar
Ar
Ar
The benzannulation reactions of various 2 aryl(4-aryl-1-
(prop-2-ynyl)-1H-imidazol-2-yl)methanones 3 are sum-
marized in Table 1. Pyrrolidine has been found to be the
best secondary amine to trigger the cyclization, though
other secondary amines also resulted in an appreciable
yield of 5. However N-methylaniline and dicyclohexyl-
amine fail to participate in the reaction. Details of the tar-
geted 5 are provided in Table 1.
N
N
N
N
O
N
NH
N
3
X
••
N
H
Ar
Ar
N
N
Ar
Ar
N
A trace amount of another compound 6 was also formed
during the reaction of 3 with pyrrolidine in all the cases as
shown by TLC of the crude reaction mixture. In one case
(6g), it was successfully separated and shown to be 1-(2-
aroyl-4-aryl-1H-imidazol-1-yl)propan-2-one. The forma-
tion of 6 helps to understand the mechanism of the main
N
N
–
HN
H
N
N
5
Scheme 2 Proposed mechanism for the formation of 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1353–1357

LETTER
Aminobenzannulation Reactio
1355
lation, and the reaction of 723 with pyrrolidine proceeded
smoothly at 80 °C in 15 minutes giving the corresponding
6-(pyrrolidin-1-yl)indolizine (8) in high yield (Scheme 3).
H
O
N
MW, 4 Å MS
N
N
80 °C, 120 W, 15 min
H
The scope of this methodology has also been tested in the
acyclic 1,5-alkyne-carbonyl system. Accordingly, 9 was
allowed to react with pyrrolidine in the expectation of get-
ting 1,2-dihydropyridine derivative 10. The reaction did
not take place as anticipated even after 48 hours, and the
starting materials were recovered (Scheme 4).
N
4a
7
8
88%
Scheme 3 Synthesis of 6-(pyrrolidin-1-yl)indolizine
In summary, a microwave-assisted efficient synthesis of
2,8-diaryl-6-aminoimidazo[1,2-a]pyridine and 6-ami-
noindolizine through aminobenzannulation reaction has
been achieved, and the reaction proceeds under mild reac-
tion conditions without metal catalyst and additives.
Acknowledgment
The authors thank DST, New Delhi for assistance under the IRHPA
program for the NMR facility. Financial support from CSIR-JRF,
New Delhi is gratefully acknowledged.
Table 1 Benzannulation of Aryl[4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl]methanones 3 with Dialkylamines
R1
R1
N
N
R1
R2
R2
MW, 4 Å MS
80 °C, 120 W
R1
N
+ HN
N
O
4a–h
N
R2
R2
3a–h
5a–s
Entry
3
R1
Secondary amine 4
pyrrolidine
5
Time (min) Yield (%)a
1
2
3a
3b
3c
3d
3e
3f
Ph
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4c
4c
4c
4d
4e
4e
4f
5a
5b
5c
5d
5e
5f
10
10
10
10
15
15
12
10
20
20
20
20
25
40
30
30
20
20
20
94
92
94
90
92
89
89
90
72
68
66
61
58
15b
58c
56c
62d
56d
58d
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
2-thienyl
2-naphthyl
4-PhC6H4
Ph
pyrrolidine
3
pyrrolidine
4
pyrrolidine
5
pyrrolidine
6
pyrrolidine
7
3g
3h
3a
3f
pyrrolidine
5g
5h
5i
8
pyrrolidine
9
piperidine
10
11
12
13
14
15
16
17
18
19
2-thienyl
4-ClC6H4
4-BrC6H4
2-thienyl
Ph
piperidine
5j
3b
3c
3f
diethylamine
diethylamine
diethylamine
dimethylamine
morpholine
5k
5l
5m
5n
5o
5p
5q
5r
5s
3a
3a
3e
3a
3a
3a
Ph
4-MeOC6H4
Ph
morpholine
diisopropylamine
N-methylpiperazine
N-benzyl-N-methylamine
Ph
4g
4h
Ph
a Isolated yield.
b The yield was evaluated by the 1H NMR spectrum of the crude product and not isolated.
c The reaction was carried out at 120 °C.
d The reaction was carried out at 100 °C.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1353–1357

1356
M. Nagaraj et al.
LETTER
(6) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.;
Moore, J. B. J. Med. Chem. 1991, 34, 2060.
(7) Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J. M.;
Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis, R. T.;
Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S. M.;
Pike, A.; Brown, N.; Wafford, K. A.; Marshall, G.; Castro, J.
L.; Atack, J. R. J. Med. Chem. 2006, 49, 35.
(8) (a) Kaminsky, J. J.; Doweyko, A. M. J. Med. Chem. 1999,
40, 427. (b) Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.;
Rizvi, R. K.; Conn, D. J.; Elliot, A. J.; Lovey, R. G.; Guzik,
H.; Chui, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem.
1989, 32, 1686.
(9) Langer, S. Z.; Arbilla, S.; Benavides, J.; Scatton, B. Adv.
Biochem. Psychopharmacol. 1990, 46, 61.
(10) Wafford, K. A.; Niel, M. B.; Ma, Q. P.; Horridge, E.; Herd,
M. B.; Peden, D. R.; Belelli, D.; Lamber, J.
J. Neuropharmacology 2009, 56, 182.
(11) (a) Mutai, T.; Tomoda, H.; Ohkawa, T.; Yabe, Y.; Araki, K.
Angew. Chem. Int. Ed. 2008, 47, 9522. (b) Shono, H.;
Ohkawa, T.; Tomoda, H.; Mutai, T.; Araki, K. ACS Appl.
Mater. Interfaces 2011, 3, 654.
(12) Shao, N.; Pang, G. X.; Yan, C. X.; Shi, G. F.; Cheng, Y.
J. Org. Chem. 2011, 76, 7458.
(13) (a) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem. 2010,
8, 3631. (b) Rousseau, A. L.; Matlaba, P.; Parkinson, C. J.
Tetrahedron Lett. 2007, 48, 4079. (c) Dimauro, E. F.;
Kennedy, J. M. J. Org. Chem. 2007, 72, 1013.
(d) Aginagalde, M.; Vara, Y.; Arrieta, A.; Zangi, R.;
Cebolla, V. L.; Delgado-Camon, A.; Cossio, F. P. J. Org.
Chem. 2010, 75, 2776. (e) Adib, M.; Mohamadi, A.;
Sheikhi, E.; Ansari, S.; Bijanzadeh, H. Synlett 2010, 1606.
(f) Kiselyov, A. S. Tetrahedron Lett. 2006, 47, 2941.
(g) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4487.
(h) Dai, W.; Petersen, J. L.; Wang, K. K. J. Org. Chem.
2005, 70, 6647.
Figure 2 ORTEP diagram of 5b
MW, 4 Å MS
N
O
N
N
H
4a
(14) (a) Galons, H.; Bergerat, I.; Combet Farnoux, C.; Miocque,
M. Synthesis 1982, 1103. (b) Davey, D.; Erhardt, P. W.;
Lumma, W. C.; Wiggins, J.; Sullivan, M.; Pang, D.; Cantor,
E. J. Med. Chem. 1987, 30, 1337. (c) Basso, D.; Broggini,
G.; Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G.
Tetrahedron 2002, 58, 4445. (d) Dai, W.; Petersen, J. L.;
Wang, K. K. J. Org. Chem. 2005, 70, 6647. (e) Nadipuram,
A. K.; Kerwin, S. M. Tetrahedron 2006, 62, 3798. (f) Beebe,
X.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
3225. (g) Barluenga, J.; Rodriguez, J. G.; Martinez, S.;
Sobrino, A. S.; Tomas, M. Chem.–Eur. J. 2006, 12, 3201.
(15) (a) Ikemoto, T.; Wakimasu, M. Heterocycles 2001, 55, 99.
(b) Rydzkowski, R.; Blondeau, D.; Sliwa, H. Tetrahedron
Lett. 1985, 26, 2571. (c) Lober, S.; Hubner, H.; Gmeiner, P.
Bioorg. Med. Chem. Lett. 1999, 9, 97. (d) Hand, E. S.;
Paudler, W. W. J. Org. Chem. 1978, 43, 2900.
N
10
9
Scheme 4 Attempted synthesis of 1,2-dihydropyridine
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992,
40, 1170.
(2) (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, 13.
(16) (a) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem. Commun.
2011, 47, 11333. (b) Wang, X.; Ma, L.; Yu, W. Synthesis
2011, 2445.
(17) (a) Kotha, S.; Misra, S.; Halder, S. Tetrahedron 2008, 64,
10775. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
2901. (c) Dotz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999,
28, 187. (d) Lautens, M.; Klute, W.; Tam, W. Chem. Rev.
1996, 96, 49. (e) Trost, B. M. Science 1991, 254, 1471.
(18) (a) Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793. (b) Jin,
T.; Yang, F.; Yamamoto, Y. Org. Lett. 2010, 12, 388.
(19) Khalili, B.; Tondro, T.; Hashemi, M. M. Tetrahedron 2009,
65, 6882.
(3) (a) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.;
Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50.
(b) Lhassani, M.; Chavignon, O.; Chezal, J. M.; Teulade,
J. C.; Chapat, J. P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De
Clercq, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 271.
(4) 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.
(5) Hamdouchi, C.; Zhong, B.; Mendoza, J.; Collins, E.;
Jaramillo, C.; De Diego, J. E.; Robertson, D.; Spencer, C. D.;
Anderson, B. D.; Watkins, S. A.; Zhanga, F.; Brooks, H. B.
Bioorg. Med. Chem. Lett. 2005, 15, 1943.
(20) Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E.
Org. Lett. 2006, 8, 4839.
Synlett 2012, 23, 1353–1357
© Georg Thieme Verlag Stuttgart · New York

LETTER
Aminobenzannulation Reactio
1357
(21) General Procedure for the Preparation of 2,8-Diaryl-6-
aminoimidazo[1,2-a]pyridine (5)
1H NMR (300 MHz, CDCl3): δ = 2.02 (t, J = 6.3 Hz, 4 H),
3.27 (t, J = 6.3 Hz, 4 H), 6.98 (d, J = 1.8 Hz, 1 H), 7.23–7.28
(m, 2 H), 7.36–7.52 (m, 5 H), 7.77 (s, 1 H), 7.95 (dd, J = 7.8,
1.2 Hz, 2 H), 8.15 (dd, J = 7.8, 1.2 Hz, 2 H). 13C NMR (75
MHz, CDCl3): δ = 25.2, 48.3, 104.3, 108.5, 115.9, 125.8,
127.2, 127.9, 128.2, 128.4, 129.1, 129.5, 134.6, 136.9,
137.3, 140.7, 144.7. LC–MS [M + 1]: m/z = 340.42. Anal.
Calcd for C23H21N3: C, 81.38; H, 6.24; N, 12.38. Found: C,
81.18; H, 6.16; N, 12.24.
A mixture of 4-aryl-2-aryloyl-1-(prop-2-ynyl)-imidazole 3
(0.4 mmol), secondary amine 4 (2.0 mL), and 4 Å MS (200
mg) taken in a 10 mL closed microwave vial was subjected
to microwave irradiation power of 120 W 80 °C for 10 min.
Completion of the reaction was confirmed by TLC. After
removing the excess base, the residue was purified by
column chromatography using PE and EtOAc mixture
(90:10) to yield 5.
(22) CCDC No. 860197 (3a), 860199 (5b) and 860198 (5c).
(23) Loaiza, P. R.; Lober, S.; Hubner, H.; Gmeiner, P. Bioorg.
Med. Chem. 2007, 15, 7248.
Spectroscopic Data for Compound 5a
Compound 5a was isolated as pale green color solid; mp
140–142 °C. IR (KBr): 1626, 1477, 1392, 1240, 711 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1353–1357

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