InCl3-catalyzed four-component reaction: A novel synthesis of N-carbazolyl dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2011.10.044

We have developed a simple, efficient, and environmentally benign microwave-assisted InCl₃-catalyzed synthesis of N- carbazolyldihydropyridines via a four-component reaction of 3-amino-9- ethylcarbazole, malononitrile, aromatic aldehydes, and a

Full text of DOI:10.1016/j.tetlet.2011.10.044

Tetrahedron Letters 52 (2011) 6805–6808
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
InCl3-catalyzed four-component reaction: a novel synthesis of N-carbazolyl
dihydropyridines
Ezhumalai Yamuna a, Matthias Zeller b, Karnam Jayarampillai Rajendra Prasad a,
⇑
a Department of Chemistry, Bharathiar University, Coimbatore 641 046, India
b Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a simple, efficient, and environmentally benign microwave-assisted InCl3-catalyzed
synthesis of N-carbazolyldihydropyridines via a four-component reaction of 3-amino-9-ethylcarbazole,
malononitrile, aromatic aldehydes, and acetylenic esters. The use of microwave heating allowed for
reduced reaction times and resulted in higher yields. This four-component reaction is atom-efficient,
high-yielding, and applicable to a wide variety of four-component reactions.
Received 3 June 2011
Revised 7 October 2011
Accepted 9 October 2011
Available online 15 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-Carbazolyldihydropyridines
1,4-Dipolar addition
InCl3
Four-component reaction
Multi-component, one-pot syntheses have received considerable
attention because of their wide range of applications in pharmaceu-
tical chemistry for the creation of structural diversity and combina-
torial libraries for drug discovery.1 DHPs (dihydropyridines) are an
important class of compounds in the field of pharmaceuticals due
to the high level of biological activity including vasodilation, bron-
chodilation, hepatoprotection, geroprotection, and as antiathero-
sclerosis, antidiabetes, antitumor, antimutagenic, antioxidant,
anticonvulsant, and antiradical agents.2 Also, 1,4-DHPs are the most
potent calcium antagonists or calcium channel blockers.3 Carbaz-
oles and related compounds, on the other hand, also display a range
of biological activities which have made them attractive compounds
for both synthetic as well as medicinal chemists.4,5 It is with that
background in mind that we decided to extend the preparative scope
of our synthesis of DHPs to include heterocyclic compounds such as
carbazoles with DHP’s building blocks in order to modify and poten-
tially enhance their biological activities.
In the Huisgen 1,4-dipolar addition, a reactive intermediate is
formed in situ by the addition of nitrogen heterocycles to electron
deficient alkynes, and the reaction with different dipolarophilic re-
agents leads to a considerable number of heterocyclic compounds.6
In the past years, extensive interest has been given to these 1,4-di-
poles, and a number of carbon–carbon bond formation reactions
and heterocyclic constructions have been established.7 Recently,
these potential 1,4-dipoles have been also widely used in multi-
component reactions to develop more atom-economic and envi-
ronmentally synthetic methods. A series of three-component and
four-component reactions involving nitrogen heterocycles, acti-
vated acetylenes, and electrophiles or dipolarophiles have been
developed by several research groups.8–11 Recently, this protocol
has been broadened to employ primary and secondary amines to
replace nitrogen heterocycles to generate the 1,4-dipolar interme-
diates.12 Multi-component reactions containing a primary amine,
acetylenedicarboxylate, and a third component as well as others
provide new elegant procedures for the clean synthesis of polysub-
stituted heterocycles.13
Recently, indium trichloride has evolved as a mild and water-tol-
erant Lewis acid imparting high regio-, chemo-, and diastereoselec-
tivity in various organic transformations.14 Compared to conven
tional Lewis acids, indium trichloride in particular has the advantages
of low catalyst loading, moisture stability, and catalyst recycling. Fur-
thermore, it is highly efficient to activate nitrogen-containing com-
pounds, such as imines and hydrazones, etc.15 In this Letter, we
wish to report an efficient and versatile method for the InCl3-cata-
lyzed synthesis of polysubstituted N-carbazolyl-1,4-dihydropyri-
dines via a four-component reaction of aminocarbazoles, aromatic
aldehydes, malononitrile, and acetylenic esters.
In our initial approach, we investigated the reaction of 3-amino-
9-ethylcarbazole 1,4-methoxy benzaldehyde, and malononitrile
with dimethyl acetylene dicarboxylate (DMAD) in the presence
of various catalysts using same solvent system at varying temper-
atures in a Biotage microwave oven to yield N-carbazolyl dihydro-
pyridine (5).16 Using as the catalyst either triethyl amine (1 mmol),
piperidine (1 mmol), tin(II) chloride (1 mmol), zinc chloride
(1 mmol), or ceric ammonium nitrate (1 mmol) (Table 1, entries
⇑
Corresponding author. Tel.: +91 422 2422311; fax: +91 422 2422387.
E-mail address: prasad_125@yahoo.com (K.J. Rajendra Prasad).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.044

6806
E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6805–6808
1–6) gave only low to moderate yields. Ytterbium triflate (1 mmol),
-proline (1 mmol), or indium(III) chloride, (entries 7–12), on the
other hand, showed promising results. Ytterbium triflate or -pro-
To extend the utility of this domino reaction, the reactivity of
methyl propiolate (instead of DMAD) was also explored. Under
similar reaction conditions, the four-component reaction of 3-ami-
no-9-ethylcarbazole 1, aromatic aldehydes, malononitrile, and
methyl propiolate proceeded smoothly and regioselectively to give
another series of polysubstituted N-carbazolyl-dihydropyridines
6a–g in good yield as shown in Scheme 1. For compound 6a the
IR spectrum showed an unusually low frequency for the ester car-
bonyl group of 1701 cmꢀ1. The other IR frequencies of 6a at 3452,
3365 cmꢀ1 for NH2 and at 2189 cmꢀ1 for the cyano group were
again as expected. In particular, the regiochemistry proposed for
the product 6a was decided on the basis of its 1H NMR spectrum
exhibiting singlets at d 4.43 and 7.34 due to the 4- and 6-position
protons of the dihydropyridine ring system. The 2-amino protons
of dihydropyridine show a broad singlet at d 5.59. This result
showed that a domino reaction for the efficient synthesis of the
versatile functionalized N-carbazolyl dihydropyridines has been
successfully established. Based on specific rotation of DHP deriva-
tives, all the compounds were found to be racemic mixtures.
To explain the mechanism of this multicomponent reaction, we
propose the following reaction course (Scheme 2). InCl3-assisted
Knoevenagel condensation of the aldehyde with malononitrile
yields arylidene malononitrile (A). Arylamine added to acetylene-
dicarboxylate to furnish the 1,4-dipole intermediate (B). Then, Mi-
chael addition of B to arylidene malononitrile A yielded the adduct
C, which transformed to intermediate D through the migration of
the hydrogen atom. In intermediate D, the intramolecular addition
of the amino group facilitated by InCl3 to the C–N triple bond gives
the cyclic intermediate (E). In the final step, N-carbazolyl dihydro-
pyridine 5 or 6 is formed by tautomerization of the imino group to
form the amino group as shown in Scheme 2.
L
L
line as the catalysts facilitated the formation of dihydropyridine (5)
in good yields (around 60%). With InCl3 as the catalyst the reac-
tions proceeded smoothly in an even shorter reaction time with
similar good yields, thus indicating InCl3 as the most efficient cat-
alyst of those tested (Table 1). In order to optimize the reaction
conditions we evaluated the most appropriate catalyst loading.
With the use of 10, 15, 20, and 25 mol % of InCl3 at 70 °C the yields
steadily increased with loading until it reached a maximum of
>90% at 25 mol % catalyst. No additional increase in yield was ob-
served upon further increasing the load of InCl3. As seen in entries
2 and 3 (base condition), and entry 8 (amino acid), although these
additives are not Lewis acids, yet the reaction proceeded smoothly
to generate 1,4-dipolar intermediates. Hence, the products have
been obtained in reasonable yield.
With the optimized conditions in hand, we turned our attention
to examine the scope of the reaction. At first, various aromatic
aldehydes were employed, and the reaction proceeded very well
to give the corresponding polysubstituted N-carbazolyl-dihydro-
pyridines 5a–g in good yields as shown in Scheme 1. Dimethyl
acetylenedicarboxylate also showed very high reactivity. These
results indicated that this four-component reaction is quite general
and has very broad substrate scopes. All compounds were isolated
by crystallization only and no chromatographic work-up was
required to obtain pure products. The structures of the product
N-carbazolyl dihydropyridines 5a–g were deduced from their ele-
mental analysis data, and from their IR, mass, 1H NMR, 13C NMR
spectra and one of the products was also confirmed by single crys-
tal X-ray diffraction study. The IR spectrum of 5a, for example,
shows absorption peaks at 3442, 3317, 2184, 1745, and 1711 cm
ꢀ1, which attest to the presence of amino, cyano, and ester groups,
respectively. 1H NMR spectrum of 5a exhibited a 2-amino group
singlet d 5.61 and the proton at the 4-position of the dihydropyri-
dine appears at d 4.48. Finally, the structure of one of the members
of the series, 5e, was confirmed by single crystal X-ray analysis (
Fig. 1).
In conclusion we have developed a novel domino four-compo-
nent synthesis of dihydropyridines from the simple synthons
aminocarbazole, aromatic aldehydes, malononitrile, and acetylenic
esters. The remarkable catalytic activity of InCl3 is superior to the
other reported catalysts with respect to improved yields and re-
duced reaction times. The higher yields, mild reaction conditions,
the ease of purification, and economic availability of the synthons
Table 1
Reaction of 3-amino-9-ethylcarbazole with p-methoxybenzaldehyde, malononitrile, and acetylenic esters under various conditions
Entry
Additive
Solvent
Temperature (°C)
Time (min)
Yield
5a
6a
1
2
3
4
5
6
7
8
—
Et3N
Piperidine
SnCl2ꢁH2O
ZnCl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
70
70
70
70
70
70
70
75
40
40
25
30
25
20
25
20
45
40
56
54
55
62
66
15
26
29
35
38
52
53
62
CAN
Yb(OTf)3
L-Proline
9
InCl3 (10 mol %)
InCl3 (15 mol %)
InCl3 (20 mol %)
InCl3 (25 mol %)
CH3CN
CH3CN
CH3CN
CH3CN
70
75
70
70
15
15
15
10
80
80
85
93
79
79
81
91
10
11
12

E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6805–6808
6807
Scheme 1. Synthesis of N-carbazolyldihydropyridines catalyzed by InCl3
employing 1,4-dipole intermediates to design other similar
multi-component reactions. Further expansion of the reaction
scope and synthetic applications of this methodology are in pro-
gress in our laboratory.
Acknowledgements
Our sincere thanks go to the Director, ISO Quality Assurance
Cell, IICT, Hyderabad, SAIF, IIT Madras, Chennai, IISc, Bangalore
and the Madurai Kamaraj University, Madurai for providing access
to their Mass, NMR spectral facilities, optical rotations measure-
ments. The diffractometer was funded by NSF grant 0087210, by
the Ohio Board of Regents grantCAP-491, and by Youngstown State
University.
Supplementary data
Figure 1. X-ray crystal structure of compound 5e.
A complete cif file for compound 5e has been deposited with the
Cambridge Crystallographic Data Centre, CCDC Deposit # 819925.
Copies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2011.10.044.
and catalyst make this an ecologically friendly procedure for the
synthesis of dihydropyridines. This protocol does not only provide
a novel and effective methodology for the preparation of function-
alized dihydropyridines but also opens up a new pathway for
Scheme 2. Mechanism for the formation of N-carbazolyldihydropyridines.

6808
E. Yamuna et al. / Tetrahedron Letters 52 (2011) 6805–6808
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16. General procedure for the preparation of N-carbazolyl-1,4-dihydropyridines (5 and
6): A mixture of 3-amino-9-ethylcarbazole (1, 1 mmol), aromatic aldehyde (2,
1 mmol), malononitrile (3, 1 mmol), acetylenic ester (dimethyl acetylene
dicarboxylate or methyl propiolate) (4, 1 mmol), and InCl3 (25 mol %) was
dissolved in CH3CN and subjected to microwave irradiation (Biotage
microwave oven, 70 °C, 2 bar pressure) for 10 min. The progress of the
reaction was monitored by thin-layer chromatography. Upon cooling, the
product precipitated from the reaction mixture, which was filtered, dried, and
recrystallized from ethanol.
3. (a) Glossmann, H.; Ferry, D. R.; Goll, A.; Striessnig, J.; Zernig, G.
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5221.
Dimethyl 6-amino-5-cyano-1-(9-ethyl-9H-carbazol-3-yl)-4-(4-methoxyphenyl)-
1,4-dihydro pyridine-2,3-dicarboxylate (5a): Yellow solid (0.498 g, 93%); mp:
289 °C; ½a 2D5 = 0.400° (CHCl3); IR (KBr) 3442, 3317, 2184, 1745, 1711 cmꢀ1 1H
;
ꢂ
NMR (500 MHz, DMSO): d (ppm) 1.35 (t, 3H, J = 7.0 Hz, N9-CH2CH3), 3.25 (s,
3H, 60-OCH3), 3.54 (s, 3H, 50-OCH3), 3.79 (s, 3H, 400-OCH3), 4.48 (s,1H, 40-H), 4.50
(q, 2H, J = 7.0 Hz, N9-CH2), 5.61 (s, 2H, 20-NH2), 7.02 (d, 2H, J = 8.5 Hz, 300-H &
500-H), 7.27 (t, 1H, J = 7.5 Hz, 6-H), 7.31 (d, 2H, J = 8.5 Hz, 200-H & 600-H), 7.32 (dd,
1H, Jo = 7.5 Hz, Jm = 2.0 Hz, 2-H), 7.53 (t, 1H, J = 7.5 Hz, 7-H), 7.68 (d, 1H,
J = 7.5 Hz, 1-H), 7.72 (d, 1H, J = 7.5 Hz, 8-H), 8.15 (d, 1H, J = 2.0 Hz, 4-H), 8.28 (d,
1H, J = 7.5 Hz, 5-H); 13C NMR (125 MHz, DMSO) d (ppm) 14.22, 37.70, 38.40,
52.28, 52.66, 55.55, 59.99, 104.58, 109.99, 110.13, 114.63, 119.82, 121.45,
121.71, 122.33, 122.89, 122.93, 126.57, 127.00, 127.51, 128.41, 138.47, 140.02,
140.69, 142.76, 151.77, 158.74, 163.58, 165.76; MS, m/z (%): 536 (M+, 100), 505
(38), 477 (81), 474 (21), 418 (78), 312 (18); Anal. Calcd for C31H28N4O5: C,
69.39; H, 5.26; N, 10.44. Found: C, 69.43; H, 5.31; N, 10.49.
Methyl 6-amino-5-cyano-1-(9-ethyl-9H-carbazol-3-yl)-4-(4-methoxyphenyl)-1,4-
dihydro pyridine-3-carboxylate (6a): Yellow solid (0.434 g, 91%); mp: 280 °C;
½ ꢂ ;
a 2D5 = 0.600° (CHCl3); IR (KBr) 3452, 3365, 2936, 2189, 1701 cmꢀ1 1H NMR
(500 MHz, DMSO): d (ppm) 1.35 (t, 3H, J = 7.0 Hz, N9-CH2CH3), 3.52 (s, 3H, 50-
OCH3), 3.77 (s, 3H, 400-OCH3), 4.43 (s,1H, 40-H), 4.51 (q, 2H, J = 7.0 Hz, N9-CH2),
5.59 (s, 2H, 20-NH2), 6.94 (d, 2H, J = 8.0 Hz, 300-H & 500-H), 7.26 (t, 1H, J = 7.5 Hz,
6-H), 7.28 (d, 2H, J = 8.0 Hz, 200-H & 600-H), 7.34 (s, 1H, 60-H), 7.47 (dd, 1H,
Jo = 7.5 Hz, Jm = 2.0 Hz, 2-H), 7.52 (t, 1H, J = 7.5 Hz, 7-H), 7.68 (d, 1H, J = 7.5 Hz,
1-H), 7.76 (d, 1H, J = 7.5 Hz, 8-H), 8.29 (d, 1H, J = 7.5 Hz, 5-H), 8.31 (d, 1H,
J = 2.0 Hz, 4-H); 13C NMR (125 MHz, DMSO) d (ppm) 14.23, 37.65, 39.03, 51.57,
55.50, 60.13, 106.42, 109.92, 110.68, 114.30, 119.67, 120.63, 121.49, 122.18,
122.42, 123.38, 125.54, 126.93, 128.64, 130.90, 139.17, 139.62, 139.92, 140.71,
151.43, 158.50, 166.61; MS, m/z (%): 478 (M+, 100), 447 (35), 419 (88), 371
(15); Anal. Calcd for C29H26N4O3: C, 72.79; H, 5.48; N, 11.71 Found: C, 72.74; H,
5.42; N, 11.75.
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