A facile strategy for the one pot multicomponent synthesis of spiro dihydropyridines from amines and activated alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.09.119

An efficient preparation of a series of spiro dihydropyridines via one pot four-component reactions of mono/di/tri-ketones, malononitrile, primary amines, and acetylenic esters is reported. The reaction is atom-efficient, high yielding, and follows a simp

Full text of DOI:10.1016/j.tetlet.2011.09.119

Tetrahedron Letters 52 (2011) 6508–6511
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Tetrahedron Letters
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A facile strategy for the one pot multicomponent synthesis of spiro
dihydropyridines from amines and activated alkynes
⇑
Selvarangam E. Kiruthika, Neelakandan Vidhya Lakshmi, Babu Rasidha Banu, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient preparation of a series of spiro dihydropyridines via one pot four-component reactions of
mono/di/tri-ketones, malononitrile, primary amines, and acetylenic esters is reported. The reaction is
atom-efficient, high yielding, and follows a simple experimental procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 4 August 2011
Revised 23 September 2011
Accepted 26 September 2011
Available online 29 September 2011
Keywords:
Multi-component reactions
Spiro dihydropyridines
Monoketones
Diketones
Activated alkynes
Multi-component reactions (MCRs) are an important class of
chemical transformations for the efficient synthesis of natural
products and screening compounds for the discovery of biological
probes and drugs.1 Such reactions are able to create combinatorial
libraries of complex and diverse structures in a proficient fashion
by virtue of their convergent nature.2 A remarkable feature of
MCRs is their capability to generate multifunctionalized com-
pounds from simple monofunctional starting materials. One-pot,
multi-component reactions continue to be of interest in the
synthesis of poly-substituted nitrogen heterocycles owing to the
fast assembly of the same without the isolation of unstable inter-
mediates.3 Hence, a feasible method for the generation of biologi-
cally active nitrogen containing heterocycles through MCRs have
attracted great attention over the past decades.4
Literature reveals that Nair et al. and Yavari and co-workers
have reported several multi-component reactions involving nitro-
gen heterocycles, acetylenic esters, and electrophiles.5 In such
multi-component reactions replacing nucleophiles derived from
nitrogen heterocycles by several other nucleophiles like isocya-
nides, primary amines provide clean procedures for the synthesis
of polysubstituted N-heterocycles.6 Among N-heterocycles, 1,4-
dihydropyridines form a class with high biological activity.7 They
act as calcium antagonists,8 antitubercular agents,9 and possess
antidiabetic10 activities. Moreover reaction pathways leading to
spiro dihydropyridine products are of general interest to the
synthetic and medicinal chemistry communities.11,12 Hence we
are interested in developing a novel route for the synthesis of spiro
dihydropyridines through multi-component reactions.
In an exploratory experiment, isatin 1 (1 mmol) and malononit-
rile 2a (1 mmol) were stirred in ethanol in the presence of
MeO2C
N
NH2
CO2Me
NH2
O
MeO2C
NEt3
CN
+
+
+
CN
CN
O
EtOH
N
H
O
N
H
CO2Me
1
2a
3a
4a
5a
Scheme 1. Synthesis of 2-oxospiro-[indole-3,40-(10,40-dihydropyridine)] 5a.
Table 1
Screening of base catalysts
Entry
Base catalyst
Time (min)
Yielda (%)
1
2
3
4
K2CO3
NaHCO3
Sarcosine
60
75
100
50
59
60
45
70
L-Proline
5
Et3N
30
82
⇑
Corresponding author.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
a
Isolated yield after recrystallization.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.119

S. E. Kiruthika et al. / Tetrahedron Letters 52 (2011) 6508–6511
6509
NC
CN
O
CN
NEt3
O
O
+
N
H
N
H
CN
1
2a
1a
O
NC
NC
NH
MeO2C
NH
+
MeO2C
MeO2C
CO2Me
H
-
MeO2C
1a
..
-
CN
NH2
+
NH2
+
CN
O
CO2Me
N
H
3a
4a
1b
1c
MeO2C
MeO2C
MeO2C
MeO2C
N
MeO2C
MeO2C
N
:
HN
NH2
NH
N
CN
CN
CN
O
N
H
O
O
N
H
N
H
5a
1e
1d
Scheme 2. Plausible mechanism for the formation of spirodihydropyridine 5a.
1
Table 3
Synthesis of spirodihydropyridines 5a–p
R
RO2C
N
CO2R1
NH2
1
O
Entry Compounda
X
R
R1
Time
(min)
Yieldb
(%)
RO2C
CN
NEt3
R
NH2
X
O
+
+
+
EtOH
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
CN
CN
3-CH3C6H4
C6H5
Me 30
Me 30
Et
Et
Me 30
Me 30
82
80
83
80
79
82
CO2R1
N
X
O
N
H
H
CO2Et Cyclohexyl
35
30
1
2a-b
3a - j
4a-b
5a - p
CN
CN
CN
4-ClC6H4
4-BrC6H4
2,4-
R1 = 4a = Me,
X = 2a = CN,
X = 2b= CO2Et
R1 = 4b = Et
(CH3)2C6H4
C6H5
4-OCH3C6H4
Cyclohexyl
4-CH3C6H4
7
8
9
10
11
12
13
14
15
16
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
CN
CN
CN
CN
Et
30
85
82
80
82
79
78
75
76
81
77
Scheme 3. Synthesis of 2-oxospiro-[indole-3,40-(10,40-dihydropyridine)] derivatives
5a–p.
Me 30
Me 30
Me 35
CO2Et 3-CH3C6H4
CO2Et C6H5
CO2Et 4-OCH3C6H4
CO2Et 3-NO2C6H4
n-Propyl
CO2Et 4-CH3C6H4
Et
35
Me 40
Et
Et
Me 30
Et 35
Table 2
30
30
List of amine substrates 3a–j
Entry
Amine (3)
R
CN
1
2
3
4
5
3a
3b
3c
3d
3e
3f
3-CH3C6H4
C6H5
4-CH3C6H4
Cyclohexyl
4-ClC6H4
a
The products were characterized by IR, NMR, mass, and elemental analysis.
Isolated yield after recrystallization.
b
6
4-BrC6H4
7
8
9
10
3g
3h
3i
2,4-(CH3)2C6H4
4-OCH3C6H4
3-NO2C6H4
n-Propyl
Knoevenagel condensation with malononitrile 2a in the presence of
Et3N to give isatylidene malononitrile 1a. m-Toluidine 3a adds on to
DMAD 4a to afford the zwitterionic intermediate 1b which under-
goes Michael addition with 1a to form 1c and the latter through
the migration of hydrogen atom furnishes 1d. The intramolecular
addition of the amino group to the cyano triple bond provides 1e
which tautomerises to give 5a (Scheme 2).
With a view to explore the generality of the reaction, various
derivatives of amines and activated alkynes were exploited to
synthesize a library of spiro dihydropyridines under optimized
conditions (Scheme 3).
3j
equimolar quantities of base catalysts at room temperature. After
10 min m-toluidine 3a (1 mmol) and DMAD 4a (1 mmol) were
added and stirring was continued till the completion of the
reaction as evidenced by TLC (Scheme 1). Of all the bases screened,
the best results were obtained with triethylamine (Table 1, entry
5).
A plausible mechanism that could be accounted for the four-
component reaction is given in Scheme 2. Initially isatin 1 undergoes
The reaction proceeded smoothly with both aliphatic and
zaromatic amines 3a–j (Table 2) to produce spiro dihydropyridine

6510
S. E. Kiruthika et al. / Tetrahedron Letters 52 (2011) 6508–6511
Figure 1. ORTEP diagram of spirodihydropyridine 5h.
Table 4
MeO2C
R
Synthesis of spiro dihydropyridines 7a–j
N
MeO2C
O
Entry
Compounda
R
Time (min)
Yieldb (%)
O
O
NH2
CO2Me
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
3-CH3C6H4
C6H5
4-CH3C6H4
Cyclohexyl
4-ClC6H4
40
40
30
35
45
40
40
40
45
50
80
79
77
78
80
75
72
84
76
75
CN
CN
NEt3
R
NH2
CN
+
+
+
EtOH
CO2Me
6
2a
3a - j
4a
7a - j
4-BrC6H4
2,4-(CH3)2C6H4
4-OCH3C6H4
3-NO2C6H4
n-Propyl
Scheme 4. Synthesis of 2-oxospiro-[acenaphthyl-3,40-(10,40-dihydropyridine)]
derivatives 7a–j.
10
7j
a
The products were characterized by IR, NMR, mass, and elemental analysis.
Isolated yield after recrystallization.
derivatives 5a–p in good yields (75–85%). The results are summa-
rized as shown in Table 3.
b
The structures of compounds 5a–p were consistent with IR, 1H,
13C NMR, mass spectroscopy, and elemental analysis data.13,14 The
IR spectrum of 5a exhibit peaks at 3409, 2183, 1722, 1710 cmꢀ1 for
the –NH2, –CN, –CO2Me groups, respectively. The 1H NMR of 5a
showed a sharp singlet at d 5.70 ppm that indicated the presence
of –NH2 protons (D2O exchangeable) and a broad singlet appeared
at d 10.41 ppm due to the presence of –NH proton (D2O exchange-
able) of the oxindole ring. In the 13C NMR spectroscopy, the spiro
carbon displayed a signal at d 60.4 ppm and the ester carbonyl
carbon atoms resonated at d 163.0 and 163.1 ppm. The mass spec-
trum of compound 5a exhibited a distinguishing peak at m/z
445.14. The structure was further confirmed by the X-ray single
crystal analysis of 5h (Fig. 1).15 The relative stereochemistry of
compounds 5a–p was assigned by analogy of 5h.
O
O
OH
NH2
N
NC
O
OH
8
60 min
CO2Me
O
CO2Me
NH2
CO2Me
CN
9 (77%)
NEt3
O
+
+
EtOH
CN
N
CN
NH2
N
CO2Me
2a
3a
4a
10 N
75 min
N
CO2Me
N
CO2Me
11 (80%)
Scheme 5. Synthesis of spiro dihydropyridines from ninhydrin and indeno-[1,2-b] quinoxalin-11-one.

S. E. Kiruthika et al. / Tetrahedron Letters 52 (2011) 6508–6511
6511
Tetrahedron Lett. 2010, 66, 7995; (c) Ugi, I.; D€omling, A.; Werner, B. J.
Heterocycl. Chem. 2000, 37, 647; (d) Kappe, C. O. Eur. J. Med. Chem. 2000, 35,
1043.
Under identical conditions, the protocol was further extended
to synthesize spiro dihydropyridines employing acenaphthenequi-
none 6 (Scheme 4).
The Knoevenagel condensation of acenaphthenequinone 6 and
malononitrile 2a resulted in acenaphthylidene malononitrile
which reacts with the zwitter ionic intermediate generated
in situ from aryl amine 3a–j and DMAD 4a to provide spiro dihy-
dropyridines 7a–j in good yields (72–84%). The results obtained
are summarized in Table 4.
4. (a) Guarna, A.; Occhiato, E. G.; Macheeti, F.; Giacomelli, V. J. Org. Chem. 1999, 64,
4985; (b) Ling, Y. Z.; Li, J. S.; Liu, Y.; Kato, K.; Klus, G. T.; Brodie, A. J. Med. Chem.
1994, 40, 3297; (c) Kozyr, A. V.; Chenko, L. P.; Kolesnikow, A. V.; Zelenova, N. A.
Immunol. Lett. 2002, 80, 41.
5. (a) Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron 2008, 64, 3567; (b) Nair, V.;
Devipriya, S.; Suresh, E. Tetrahedron Lett. 2007, 48, 3667; (c) Yavari, I.; Mirzaei,
A.; Moradi, L.; Khalili, G. Tetrahedron Lett. 2010, 51, 396; (d) Yavari, I.;
Mokhtarporyani-Sanandaj, A.; Moradi, L.; Mirzaei, A. Tetrahedron 2008, 64,
5221.
The structures of compounds 7a–j were consistent with IR, 1H,
13C NMR, mass spectroscopy and elemental analysis data.16,17
The IR spectrum of compound 7a showed peaks at frequencies
3162, 2123, 1754, 1732, 1698 cmꢀ1 due to –NH2, –CN, –CO2Me
and keto groups, respectively. The 1H NMR of 7a displayed a sharp
singlet at d 3.92 ppm which marked the presence of –NH2 protons
(D2O exchangeable) of the spirodihydropyridine ring. In the 13C
6. (a) Liu, W. B.; Jiang, H. F.; Zhang, M.; Qi, C. R. J. Org. Chem. 2010, 75, 966; (b) Cao,
H.; Jiang, H. F.; Yao, W. J. Org. Lett. 2009, 11, 1931; (c) Liu, W. B.; Jiang, H. F.;
Qiao, C. L. Tetrahedron 2009, 65, 2110; (d) Jing, S.; Er-Yan, X.; Qun, W.; Chao-
Guo, Y. Org. Lett. 2010, 12, 3678.
7. (a) Sridharan, V.; Perumal, P. T.; Avendaño, C.; Carlos, J. M. Tetrahedron 2007,
63, 4407; (b) Adharvana, C. M.; Syamasundar, K. Catal. Commun. 2006, 6, 624;
(c) Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465; (d) Anniyappan, M.;
Muralidharan, D.; Perumal, P. T. Synth. Commun. 2002, 32, 659.
8. Zamponi, G. W.; Stotz, S. C.; Staples, R. J.; Andro, T. M.; Nelson, J. K.; Hulubei, V.;
Blumenfeld, A.; Natale, N. R. J. Med. Chem. 2003, 46, 87.
9. Peri, R.; Padmanabhan, S.; Rutledge, A.; Singh, S.; Triggle, D. J. J. Med. Chem.
2000, 43, 2906.
10. (a) Kharkar, P. S.; Desai, B.; Gaveria, H.; Varu, B.; Loriya, R.; Naliapara, Y.; Shah,
A.; Kulkarn, V. M. J. Med. Chem. 2002, 45, 4858; (b) McCormack, J. G.;
Westergaard, N.; Kristiansen, M.; Brand, C. L.; Lau, J. Curr. Pharm. Des. 2001, 7,
1457.
NMR spectroscopy the spiro carbon atom resonated at
d
79.4 ppm and the ester carbonyl carbons appeared at d 166.4 and
167.2 ppm. The keto carbon atom displayed at d 186.7 ppm. The
mass spectrum of compound 7a exhibited a distinct peak at m/z
480.23. The relative stereochemistry connectivity of compounds
7a–j was assigned by analogy to 5h.
In a similar fashion, the reaction of ninhydrin 8 and indeno-
[1,2-b] quinoxalin-11-one 10 with malononitrile 2a, m-toluidine
3a, and DMAD 4a yielded 9 and 11 in 77% and 80% yields, respec-
tively (Scheme 5).
In conclusion, in this Letter we have described a one pot multi-
component reaction for the synthesis of an array of spiro dihydro-
pyridines employing mono/di/tri-ketones, malononitrile, primary
amines, and acetylenic esters. The zwitterionic intermediate
formed in situ from amines and acetylenic esters play a key role
in the formation of spiro dihydropyridines. This protocol provides
a sustainable route for the synthesis of spiro dihydropyridines as
it is simple, high-yielding, and does not involve any purification
techniques like column chromatography. Further investigations
on this transformation are under study.
11. (a) Kotha, B. S.; Deb, C. A.; Lahiri, K. Synthesis 2009, 2, 0165; (b) Augustine, T.;
Kanakam, C. C.; Vithiya, S. M.; Ramkumar, V. Tetrahedron Lett. 2009, 50, 5906;
(c) Trost, B. M.; Brennan, M. K. Synthesis 2009, 18, 3003.
12. Sharavathi, G. P.; Christopher, F. P. Org. Lett. 2010, 15, 3434.
13. Experimental procedure for the synthesis of spirodihydropyridine 5a (Table 3,
entry 1): A mixture of isatin 1a (1 mmol), malononitrile 2a (1 mmol), and Et3N
(1 mmol) were stirred in ethanol for 10 min followed by the addition of 3-
methyl aniline 3a (1 mmol) and DMAD 4a (1 mmol) after 10 min. The reaction
mixture was stirred for another 20 min. After the completion of the reaction as
indicated by TLC, the solid formed in the reaction mixture was filtered, dried,
and recrystallized from ethanol to obtain the pure product 5a in good yield
(82%).
14. Spectral data for spirodihydropyridine 5a (Table 3, entry 1): white solid. Mp:
150–152 °C.
m
max (KBr): 3631, 3409, 2956, 2183, 1722, 1710, 1654, 1613, 1564,
1425, 979, 922, 755 cmꢀ1
.
1H NMR (DMSO-d6, 500 MHz): d 2.33 (s, 3H, –CH3),
3.28 (s, 3H, –OCH3), 3.30 (s, 3H, –OCH3), 5.70 (s, 2H, –NH2, D2O exchangeable),
6.80 (d, 1H, J = 7.7 Hz, Ar-H), 6.98 (t, 1H, J = 7.7 Hz, Ar-H), 7.17 (m, 3H, Ar-H),
7.21 (m, 1H), 7.30 (d, 1H, J = 7.7 Hz, Ar-H), 7.37 (t, 1H, J = 7.7 Hz, Ar-H), 10.41 (s,
1H, –NH, D2O exchangeable). 13C NMR (DMSO-d6, 125 MHz): d 21.2, 50.2, 52.3,
52.9, 60.4, 104.2, 109.9, 119.0, 122.7, 124.3, 127.5, 129.2, 129.9, 131.0, 131.3,
135.8, 136.2, 139.9, 143.9, 151.9, 163.0, 163.1 164.7, 179.4. MS (EI): m/z 445.14
[M+H]+; Anal. Calcd for C24H20N4O5: C, 64.86; H, 4.54; N, 12.61. Found: C,
64.23; H, 4.12; N, 12.03.
Acknowledgment
15. Crystallographic data for compound 5h in this Letter have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC-832875. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).
One of the authors, S.E.K. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship.
16. Experimental procedure for the synthesis of spirodihydropyridine 7a (Table 4,
entry 1): A mixture of acenaphthenequinone 6 (1 mmol), malononitrile 2a
(1 mmol), and Et3N (1 mmol) were stirred in ethanol for 10 min followed by
the addition of 3-methyl aniline 3a (1 mmol) and DMAD 4a (1 mmol) after
10 min. The reaction mixture was stirred for 40 min. After the completion of
the reaction as indicated by TLC, the solid formed in the reaction mixture was
filtered, dried, and recrystallized from ethanol to obtain the pure product 7a in
good yield (80%).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.119.
References and notes
17. Spectral data for the spirodihydropyridine 7a (Table 4, entry 1): white solid. Mp:
172–174 °C. mmax (KBr): 3162, 3003, 2986, 2123, 1754, 1732, 1698, 1563, 1423,
1. (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 332;
(b)Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005. p 468; (c) Jingqiang, W.; Jared, T. S. Org. Lett.
2007, 9, 4077.
2. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123; (b) D€omling, A. Chem. Rev. 2006, 106, 17; (c)
Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367; (d) Jing, S.; Er-
Yan, X.; Qun, W.; Chao-Guo, Y. ACS Comb. Sci. 2011, 13, 436.
789 cmꢀ1 1H NMR (DMSO-d6, 500 MHz): d 2.42 (s, 3H, –CH3), 3.61 (s, 3H, –
OCH3), 3.73 (s, 3H, –OCH3), 3.92 (s, 2H, –NH2, D2O exchangeable), 7.06 (d, 2H,
J = 8.4 Hz, Ar-H), 7.55 (d, 2H, J = 8.4 Hz, Ar-H), 7.69 (t, 2H, J = 7.7 Hz, Ar-H), 8.43
(d, 2H, J = 7.7 Hz, Ar-H), 9.13 (d, 2H, J = 8.4 Hz, Ar-H). 13C NMR (DMSO-d6,
125 MHz): d 21.7, 68.0, 68.6, 79.4, 101.1, 114.7, 117.6, 119.6, 120.1, 123.1,
125.8, 126.2, 127.0, 129.6, 130.3, 130.9, 131.6, 132.3, 134.1, 136.4, 139.6, 140.1,
141.6, 145.3, 153.1, 166.4, 167.2, 186.7. MS (EI): m/z 480.23 [M+H]+; Anal.
Calcd for C28H21N3O5: C, 70.14; H, 4.41; N, 8.76. Found: C, 69.69; H, 4.20; N,
8.12.
3. (a) Ana, G. N.; Delgado, J.; Cecilia, P.; Marcaccini, S.; Carlos, F. M. Tetrahedron
Lett. 2005, 46, 23; (b) Yavari, I.; Mohammad, J. B.; Mehdi, S.; Sanaz, S.