2,6-diaryl-4,4-disubstituted 1,4-dihydropyridines: Source for spiro heterocycles

Article abstract of DOI:10.1002/hc.10183

Novel spiro heterocycles (5-12) were obtained by the cyclocondensation of 2,6-diaryl-4,4-dimethoxycarbonyl-/4-cyano-4-ethoxycarbonyl-1,4-dihydropyridines (3/4) with hydrazine hydrate, hydroxylamine hydrochloride, urea, and thiourea. All the compounds were

Full text of DOI:10.1002/hc.10183

Heteroatom Chemistry
Volume 14, Number 6, 2003
2,6-Diaryl-4,4-Disubstituted
1,4-Dihydropyridines:
Source for Spiro Heterocycles
V. Padmavathi,1 A. Balaiah,1 T. V. Ramana Reddy,2
B. Jagan Mohan Reddy,1 and D. Bhaskar Reddy1
1Department of Chemistry, S.V. University, Tirupati 517 502, India
2Chemical Lab, SPROB, SDC-SHAR Centre (ISRO), Sri Harikota 524124, Andhra Pradesh, India
Received 11 March 2003; revised 1 April 2003
[3,4]. On the basis of this, it was thought to de-
ABSTRACT: Novel spiro heterocycles (5–12) were
velop spiro heterocycles from 1,4-dihydropyridines.
In fact remarkable progress has been made by our
group during the last one decade in the synthe-
sis of spiro heterocycles [5], which was tradition-
ally associated with the presence of gem diester
or cyano ester functionality in the molecule and
this has become the basis for the present com-
munication. Thus, this report includes hitherto un-
known spiro heterocycles from 4,4-disubstituted 1,4-
dihydropyridines.
obtained by the cyclocondensation of 2,6-diaryl-
4,4-dimethoxycarbonyl-/4-cyano-4-ethoxycarbonyl-
1,4-dihydropyridines (3/4) with hydrazine hydrate,
hydroxylamine hydrochloride, urea, and thiourea. All
1
the compounds were characterized by IR, H NMR,
and 13C NMR spectral data.
2003 Wiley Periodicals,
ꢀ
C
Inc. Heteroatom Chem 14:513–517, 2003; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.10183
RESULTS AND DISCUSSION
INTRODUCTION
The synthesis involves the reaction of 1,5-diaryl-
3,3-dimethoxycarbonyl-1,5-pentanediones (1a–c)/
1,5-diaryl-3-cyano-3-ethoxycarbonyl-1,5-pentanedi-
ones (2a–c) with ammonium acetate in acetic
acid under reflux conditions to give 2,6-diaryl-4,4-
dimethoxycarbonyl-1,4-dihydropyridines (3a-c)/2,6-
diaryl-4-cyano-4-ethoxycarbonyl-1,4-dihydropyridi-
nes (4a–c) [6]. The gem-dicarboxylate or gem-cyano
ester on condensation with hydrazine hydrate,
hydroxylamine hydrochloride, urea, and thiourea
would furnish pyrazole, isoxazole, pyrimidine, and
thiopyrimidine derivartives. Accordingly, treatment
of 3a–c with these reagents in the presence of
NaOMe resulted in the formation of 7,9-diaryl-2,3,8-
triaza-spiro[4.5]deca-6,9-diene-1,4-diones (5a–c),
7,9-diaryl-2-oxo-3,8-diaza-spiro[4.5]deca-6,9-diene-
Doping of heteroatoms within the carbon framework
has been considered as a versatile method to design
new heterocycles. In this perspective attempts are
made to incorporate nitrogen into 3,3-disubstituted
1,5-diaryl-1,5-pentanediones [1] to furnish 4,4-
disubstituted 2,6-diaryl-1,4-dihydropyridines (3/4).
Indeed dihydropyridine and its derivatives were used
in the treatment of cardiovascular diseases such
as angina, hypertension, or arrhythmia [2]. On the
other hand 1,4-dihydropyridine fused to a carbo-
cyclic ring exhibited calcium modulatory properties
Correspondence to: V. Padmavathi; e-mail: vkpuram2001@
yahoo.com.
Contract grant sponsor: CSIR, New Delhi.
2003 Wiley Periodicals, Inc.
c
ꢀ
513

514 Padmavathi et al.
SCHEME 1
SCHEME 2

2,6-Diaryl-4,4-Disubstituted 1,4-Dihydropyridines: Source for Spiro Heterocycles 515
1,4-diones (6a–c), 8,10-diaryl-2,4,9-triaza-spiro-
singlet in the region δ = 4.85–5.63. The NH in 5–8
displayed a broad singlet at δ = 6.19–10.68. How-
ever, a broad singlet observed around δ = 6.89–10.14
in 9–12 accounts for NH and NH2. Apart from these,
11 showed a singlet for OH at δ = 6.89–6.97 while
12 for SH at δ = 1.37–1.43 (Table 2). The signals for
NH2, NH, and OH disappeared on deuteration. The
structure of 5–12 were also confirmed by 13C NMR
spectra (Table 2).
[5.5]undeca-7,10-diene-1,3,5-triones (7a–c), and 8,
10-diarly-3-thioxo-2,4,9-triaza-spiro[5.5]undeca-7,
10-diene-1,5-diones (8a–c), respectively (Scheme 1).
In a similar way, the reaction of 4a–c gave 4-
amino-7,9-diaryl-2,3,8-triaza-spiro[4.5]deca-3,6,-
9-trien-1-ones (9a–c), 4-amino-7,9-diaryl-2-oxo-3,8-
diaza-spiro[4.5] deca-3,6,9-trien-1-ones (10a–c),
5-amino-3-hydroxy-8,10-diaryl-2,4,9-triaza-spiro-
[5.5]undeca-2,4,7,10-tetraen-1-ones (11a–c), and
5-amino-3-mercapto-8,10-diaryl-2,4,9-triaza-spiro-
[5.5]undeca-2,4,7,10-tetraen-1-ones (12a–c), respe-
ctively (Scheme 2, Table 1).
EXPERIMENTAL
The IR spectra of 5–8 exhibited absorption bands
in the regions 1645–1682, 3200–3470, and 1495–
1510 cm−1 for CO, NH, and C S of pyrazolidine-
dione/isoxazolidinedione/pyrimidinetrione/thioxop-
yrimidinedione moiety. The compounds 9–12
showed absorption bands in the regions 1685–1710
and 3240–3470 cm−1 for CO, OH and NH2 and NH of
aminopyrazolone/aminoisoxazolone/aminopyrimid-
ine/thioxo-pyrimidine moiety. Apart from these, 6
and 10 exhibited bands around 1725–1735 cm−1 for
Melting points were determined on Mel-Temp ap-
paratus and are uncorrected. The IR spectra were
recorded on Perkin-Elmer 1600 FT-IR spectrome-
ter using KBr disc. The wave numbers are given in
cm−1. 1H NMR and 13C NMR spectra were recorded
in DMSO-d6 operating at 300 MHz and 75.45 MHz,
respectively, on a Bruker spectrospin spectrometer
with TMS as an internal standard. Purity of the
compounds was checked by TLC using silica gel
‘G’ (BDH) and hexane–ethyl acetate (3:1) as eluents.
The elemental analyses were obtained from Micro
Analytical Laboratory, University of Pune, Pune,
India.
1
CO O of isoxazole moiety. In the H NMR spectra
the methine protons C6 H and C10 H in 5, 6, 9, 10
and C7 H and C11 H in 7, 8, 11, 12 showed a sharp
TABLE 1 Physical Data of Compounds 5–12
Founda (%)
Mol. Formula
mp (◦C)
Yield (%)
(Mol. Wt.)
C
H
N
5a
237–239
233–235
224–226
194–196
202–204
183–184
275–277
284–285
270–271
280–282
276–277
269–271
207–209
225–227
199–201
189–191
195–197
176–177
263–265
281–283
273–274
260–262
256–258
277–279
72
64
66
62
68
73
69
57
60
68
62
63
61
58
65
70
66
69
62
68
71
60
59
62
C19H15N3O2 (317.35)
71.80 (71.91)
66.98 (66.83)
59.00 (59.09)
71.48 (71.69)
66.82 (66.66)
58.80 (58.94)
69.72 (69.56)
65.36 (65.18)
57.90 (57.99)
66.67 (66.47)
62.83 (62.69)
55.71 (55.82)
72.25 (72.14)
67.11 (67.01)
59.15 (59.24)
72.11 (71.91)
66.68 (66.83)
59.22 (59.09)
69.92 (69.76)
65.50 (65.34)
58.01 (58.13)
66.55 (66.65)
62.90 (62.84)
55.84 (55.95)
4.82 (4.76)
5.00 (5.07)
3.48 (3.39)
4.34 (4.43)
4.85 (4.79)
3.08 (3.12)
4.34 (4.38)
4.81 (4.72)
3.10 (3.16)
4.10 (4.18)
4.60 (4.54)
3.00 (3.05)
5.07 (5.10)
5.40 (5.36)
3.69 (3.66)
4.71 (4.76)
5.12 (5.07)
3.43 (3.39)
4.76 (4.68)
4.94 (4.98)
3.46 (3.41)
4.52 (4.47)
4.85 (4.79)
3.37 (3.29)
13.39 (13.24)
11.08 (11.13)
11.02 (10.88)
8.94 (8.80)
7.30 (7.40)
7.36 (7.23)
5b
C21H19N3O4 (377.40)
5c
C
C
C
19H13Cl2N3O2 (386.24)
C19H14N2O3 (318.34)
6a
6b
C
21H18N2O4 (378.39)
19H12Cl2N2O3 (387.23)
6c
7a
C
C
20H15N3O3 (345.36)
22H19N3O5 (405.41)
12.31 (12.17)
10.20 (10.36)
10.26 (10.14)
11.78 (11.63)
10.11 (9.97)
9.64 (9.76)
17.85 (17.71)
14.81 (14.88)
14.61 (14.54)
13.40 (13.24)
11.22 (11.13)
10.69 (10.88)
16.40 (16.27)
14.00 (13.85)
13.44 (13.56)
15.68 (15.54)
13.47 (13.32)
12.98 (13.05)
7b
7c
20H13Cl2N3O3 (414.25)
20H15N3O2S (361.43)
8a
C
8b
C22H19N3O4S (421.48)
20H13Cl2N3O2S (430.32)
C19H16N4O (316.37)
8c
C
9a
9b
C
21H20N4O3 (376.42)
9c
C19H14Cl2N4O (385.26)
10a
10b
10c
11a
11b
11c
12a
12b
12c
C
C
19H15N3O2 (317.35)
21H19N3O4 (377.40)
C
C
C
19H13Cl2N3O2 (386.24)
20H16N4O2 (344.38)
22H20N4O4 (404.43)
C
20H14Cl2N4O2 (413.27)
C20H16N4OS (360.44)
C22 20N4O3S (420.49)
20H14Cl2N4OS (429.33)
H
C
aValues in parentheses indicate calculated values.

516 Padmavathi et al.
TABLE 2 Spectroscopic Data of Compounds 5–12
δ
1H NMR
δ
13C NMR
5a
4.95 (s, 2H, C6 & C10 H), 7.22–7.78 (m, 10H, ArH), 8.24 (bs, 3H,
NH NH, NH).
45.12 (C5), 117.28 (C & C10), 137.95 (C7 &
C9), 175.80 (C1 & 6C4).
5b
3.65 (s, 6H, Ar OCH3), 4.92 (s, 2H, C6 & C10 H), 7.24–7.75 (m,
8H, ArH), 8.62 (bs, 3H, NH NH, NH).
–
5c
4.99 (s, 2H, C6 & C10 H), 7.21–7.77 (m, 8H, ArH), 8.76 (bs, 3H,
NH NH, NH).
45.06 (C5), 117.26 (C6 & C10), 137.11 (C7 &
C9), 175.70 (C1 & C4).
6a
5.11 (s, 2H, C6 & C10 H), 7.27–7.78 (m, 10H, ArH), 9.32 (bs, 2H,
NH O, NH).
3.63 (s, 6H, Ar OCH3), 5.19 (s, 2H, C6 & C10 H), 7.30–7.82 (m,
8H, ArH), 9.39 (bs, 2H, NH O, NH).
54.84 (C5), 114.78 (C6 & C10), 140.97 (C7 &
C9), 176.73, 175.93 (C1 & C4).
–
6b
6c
4.98 (s, 2H, C6 & C10 H), 7.29–7.80 (m, 8H, ArH), 9.25 (bs, 2H,
NH O, NH).
54.76 (C5), 114.28 (C6 & C10), 140.95 (C7 &
C9), 176.69, 175.94 (C1 & C4).
42.78 (C6), 118.23 (C7 & C11), 137.94 (C8 &
C10), 151.64 (C3), 164.35 (C1 & C5).
–
7a
4.98 (s, 2H, C7 & C
H), 6.32 (s, 1H, NH), 7.32–7.81 (m, 10H,
ArH), 10.11 (bs, 121H, NH CO NH ).
7b
3.62 (s, 6H, Ar OCH ), 4.95 (s, 2H, C7 & C
H), 6.36 (s, 1H,
NH) 7.34–7.85 (m,38H, ArH), 10.44 (bs, 21H1, NH CO NH).
7c
4.91 (s, 2H, C7 & C
H), 6.59 (s, 1H, NH), 7.33–7.84 (m, 8H,
–
ArH), 10.12 (bs, 121H, NH CO NH).
8a
4.85 (s, 2H, C7 & C
H), 6.24 (s, 1H, NH), 7.27–7.79 (m, 10H,
41.58 (C6), 113.48 (C7 & C11), 137.25 (C8 &
ArH), 10.59 (bs, 121H, NH CS NH).
C10), 159.92 (C1 & C5), 170.27 (C3).
8b
3.61 (s, 6H, Ar OCH ), 4.91 (s, 2H, C7 & C11 H), 6.19 (s, 1H,
–
NH), 7.23–7.79 (m3, 8H, ArH), 10.87 (bs, 2H, NH CS NH).
8c
5.11 (s, 2H, C7 & C
H), 6.27 (s, 1H, NH), 7.29–7.78 (m, 8H,
41.74 (C6), 113.92 (C7 & C11), 137.99 (C8 &
C10), 159.87 (C & C5), 170.31 (C3).
ArH), 10.68 (bs, 121H, NH CS NH).
9a
5.29 (s, 2H, C6 & C10 H), 7.25–7.78 (m, 10H, ArH), 8.64–8.66
(bs, 3H, NH2, NH), 10.02 (s, 1H, NH N).
39.12 (C5), 109.291(C & C ), 135.76 (C7 &
10
C9), 162.92 (C4), 1675.48 (C1).
9b
3.59 (s, 6H, Ar OCH3), 5.27 (s, 2H, C6 & C10 H), 7.26–7.77 (m,
8H, ArH), 8.59–8.61 (bs 3H, NH2, NH), 9.98 (s, 1H, NH N).
5.32 (s, 2H, C6 & C10 H), 7.24–7.80 (m, 8H, ArH), 8.61–8.63 (bs,
3H, NH2, NH), 10.14 (s, 1H, NH N).
5.63 (s, 2H, C6 & C10 H), 7.24–7.79 (m, 10H, ArH), 8.58–8.60
(bs, 3H, NH2, NH).
3.61 (s, 6H, Ar OCH3), 5.62 (s, 2H, C6 & C10 H), 7.25–7.80 (m,
8H, ArH), 8.46–8.48 (bs, 3H, NH2, NH).
5.58 (s, 2H, C6 & C10 H), 7.23–7.79 (m, 8H, ArH), 8.59–8.61 (bs,
3H, NH2, NH).
–
9c
41.29 (C5), 109.95 (C & C10), 137.98 (C7 &
C9), 163.29 (C4), 1675.82 (C1).
49.93 (C5), 108.27 (C & C10), 138.10 (C7 &
C9), 177.24 (C4), 1675.54 (C1).
–
10a
10b
10c
11a
11b
11c
12a
12b
12c
49.71 (C5), 108.88 (C & C10), 138.46 (C7 &
C9), 177.84 (C4), 1675.39 (C1).
37.24 (C6), 107.55 (C7 & C11), 135.41 (C8 &
C10), 163.02 (C3), 179.43 (C1), 185.18 (C5).
–
5.51 (s, 2H, C7 & C11 H), 6.89–6.91 (bs, 4H, NH, NH2, OH),
7.22–7.76 (m, 10H, ArH).
3.58 (s, 6H, Ar OCH ), 5.58 (s, 2H, C7 & C11 H), 6.92–6.93 (bs,
4H, NH, NH2, OH)3, 7.24–7.79 (m, 8H, ArH).
5.59 (s, 2H, C7 & C11 H), 6.95–6.97 (s, 4H, NH, NH2, OH),
7.23–7.77 (m, 8H, ArH).
1.39 (s, 1H, SH), 5.60 (s, 2H, C7 & C11 H), 7.23–7.75 (m, 10H,
ArH), 8.78–8.80 (bs, 3H, NH, NH2).
1.43 (s, 1H, SH), 3.60 (s, 6H, Ar OCH3), 5.57 (s, 2H, C7 &
C11 H), 7.24–7.78 (m, 8H, ArH), 8.69–8.71 (bs, 3H, NH, NH2).
1.37 (s, 1H, SH), 5.62 (s, 2H, C7 & C11 H), 7.23–7.78 (m, 8H,
ArH), 8.68–8.70 (bs, 3H, NH, NH2).
37.19 (C6), 107.14 (C7 & C11), 135.21 (C8 &
C10), 163.42 (C3), 179.01 (C ), 185.61 (C5).
37.27 (C ), 107.19 (C7 & C11), 1136.08 (C8 &
6
C10), 175.67 (C3), 176.29 (C1), 180.47 (C5).
–
38.05 (C6), 105.25 (C7 & C11), 143.20 (C8 &
C10), 175.39 (C3), 175.95 (C1), 180.45 (C5).
2,6-Diaryl-4,4-dimethoxycarbonyl-1,4-
dihydropyridine (3a–c)/2,6-Diaryl-4-cyano-
4-ethoxycarbonyl-1,4-dihydropyridine
(4a–c)
7,9-Diaryl-2,3,8-triaza-spiro[4.5]deca-6,9-diene-
1,4-dione (5a–c)/7,9-Diaryl-2-oxo-3,8-diaza-
spiro[4.5]deca-6,9-diene-1,4-dione (6a–c)/8,10-
Diaryl-2,4,9-triaza-spiro[5.5]undeca-7,10-diene-
1,3,5-trione (7a–c)/8,10-Diaryl-3-thioxo-2,4,9-
triaza-spiro[5.5]undeca-7,10-diene-1,5-dione
(8a–c)
Compound 1/2 (10 mmol), was dissolved in AcOH
(20 ml). To this NH4OAc (1.5 g) was added and
refluxed for 2 h. The reaction mixture was cooled
and poured onto crushed ice. The product obtained
was recrystallized from methanol.
A
mixture of
3 (10 mmol), 80% hydrazine
hydrate (15 mmol)/hydroxylamine hydrochloride

2,6-Diaryl-4,4-Disubstituted 1,4-Dihydropyridines: Source for Spiro Heterocycles 517
(10 mmol)/urea (10 mmol)/thiourea (10 mmol),
projects and AB for CSIR for providing Senior Re-
search Fellowship.
methanol (25 mL), and 10% NaOMe (5 ml) was re-
fluxed for 5–6 h, cooled, and poured onto crushed ice
containing HCl. The product obtained was recrystal-
lized from methanol.
REFERENCES
4-Amino-7,9-diaryl-2,3,8-triaza-spiro[4.5]deca-
3,6,9-trien-1-one (9a–c)/4-Amino-7,9-diaryl-
2-oxo-3,8-diaza-spiro[4.5]deca-3,6,9-trien-1-one
(10a–c)/5-Amino-3-hydroxy-8,10-diaryl-2,4,9-
triaza-spiro[5.5]undeca-2,4,7,10-tetraen-1-one
(11a–c)/5-Amino-3-mercapto-8,10-diaryl-2,4,9-
triaza-spiro[5.5]undeca-2,4,7,10-tetraen-1-one
(12a–c)
[1] Padmavathi, V.; Balaiah, A.; Bhaskar Reddy, D. Indian
J Chem (in press).
[2] (a) Triggle, D. J.; Langs, D. A.; Jamis, R. A. Med Res
Rev 1989, 9, 123; (b) Mehdi, S.; Ravikumar, K. Acta
Cryst 1992, C48, 1627; (c) Rowan, K. R.; Holt, M. E.
Acta Cryst 1996, C52, 2207.
[3] Rose, U. Arch Pharm 1990, 323, 281.
[4] Rose, U.; Drager, M.
2238.
J Med Chem 1992, 35,
[5] (a) Bhaskar Reddy, D.; Padmavathi, V.; Ramana Reddy,
P. V. Indian J Chem 1992, 31B, 774; (b) Bhaskar
Reddy, D.; Padmavathi, V.; Seenaiah, B.; Padmaja,
A. Heteroat Chem 1993, 4, 55; (c) Bhaskar Reddy,
D.; Ramana Reddy, M. V.; Padmavathi, V. Indian
J Chem 1998, 37B, 167; (d) Bhaskar Reddy, D.;
Ramana Reddy, M. V.; Padmavathi, V. Heteroat Chem
1999, 10, 17; (e) Bhaskar Reddy, D.; Chandrasekhar
Babu, N.; Padmavathi, V. Heteroat Chem 2001, 12,
113; (f) Bhaskar Reddy, D.; Chandrasekhar Babu, N.;
Padmavathi, V. J Heterocycl Chem 2001, 38, 769;
(g) Padmavathi, V.; Balaiah, A.; Venugopal Reddy, K.;
Padmaja, P.; Bhaskar Reddy, D. Indian J Chem 2002,
41B, 1670.
To a solution of 4 (10 mmol) in ethanol (25 mL),
80% hydrazine hydrate (15 mmol)/hydroxylamine
hydrochloride (10 mmol)/urea (10 mmol)/thiourea
(10 mmol), and 10% NaOEt (5 ml) was added. The
contents were refluxed for 5–8 h, cooled, and poured
onto crushed ice and acidified with acetic acid. The
separated solid was filtered and recrystallized from
ethanol.
ACKNOWLEDGEMENT
Two of the authors (VP & DBR) are thankful to CSIR,
New Delhi, India for the financial assistance to their
[6] Padmavathi, V.; Balaiah, A.; Bhaskar Reddy, D. J Het-
erocycl Chem 2002, 39, 649.