Unprecedented synthesis of hantzsch 1,4-dihydropyridines under biginelli reaction conditions

Article abstract of DOI:10.1081/SCC-100000534

Hantzsch 1,4-dihydropyridines are synthesized in high yields by a one-pot cyclocondensation of aldehyde, β-ketoester, and urea on the surface of silica gel under microwave irradiation in solvent-free conditions.

Full text of DOI:10.1081/SCC-100000534

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UNPRECEDENTED SYNTHESIS OF HANTZSCH 1,4-
DIHYDROPYRIDINES UNDER BIGINELLI REACTION
*
CONDITIONS
a
a
a
Jhillu S. Yadav , Basi V. Subba Reddy & Polepally Thirupathi Reddy
a
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Published online: 09 Nov 2006.
To cite this article: Jhillu S. Yadav , Basi V. Subba Reddy & Polepally Thirupathi Reddy (2001): UNPRECEDENTED
*
SYNTHESIS OF HANTZSCH 1,4-DIHYDROPYRIDINES UNDER BIGINELLI REACTION CONDITIONS , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:3, 425-430
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SYNTHETIC COMMUNICATIONS, 31(3), 425–430 (2001)
UNPRECEDENTED SYNTHESIS OF
HANTZSCH 1,4-DIHYDROPYRIDINES
UNDER BIGINELLI REACTION
∗
CONDITIONS
†
Jhillu S. Yadav, Basi V. Subba Reddy,
and Polepally Thirupathi Reddy
Organic Division-I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
ABSTRACT
Hantzsch 1,4-dihydropyridines are synthesized in high yields
by a one-pot cyclocondensation of aldehyde, β-ketoester, and urea
on the surface of silica gel under microwave irradiation in solvent-
free conditions.
Hantzsch 1,4-DHPs are biologically active compounds that include vari-
ous vasodilator, antihypertensive, branchodilator, antiatherosclerotic, hepatopro-
tective, antitumor, antimutagenic, geroprotective, and antidiabetic agents (1–3).
DHPs have found commercial utility as calcium channel blockers (4–6) such as
Nifedipine, Nitrendipine, and Nimodipine. A number of DHP calcium antagonists
have been introduced as potential drugs for the treatment of congestive heart failure
(
7,8). Among DHPs with other types of bioactivity, cerebrocrast (9) has been intro-
duced as a neuroprotectant and cognition enhancer. In addition, a number of DHPs
∗
IICT Communication No. 4425.
†
Corresponding author.
4
25
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
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4
26
YADAV, REDDY, AND REDDY
with platelet antiaggregatory activity have also been discovered (10). However, a
number of methods have been reported for the synthesis of DHPs, which suffer
from drawbacks like longer reaction times, low to moderate yields, and require
highly acidic reaction conditions. Organic reactions on solid supports and those
that are associated with microwaves, especially under solvent-free conditions, have
attracted much attention. The advantage of these methods over conventional re-
actions is that they provide greater selectivity, enhanced reaction rates, cleaner
reaction products, and operational simplicity, and are eco-friendly. Due to a wide
range of biological significance of DHPs, we describe a new and rapid method for
the synthesis of DHPs by the cyclocondensation of aldehyde, β-ketoester and urea
mediated by silica gel (11,12) under microwaves in dry media (Sch. 1).
O
R
O
O
O
Silica gel
EtO
Me
OEt
R CHO
+
OEt
Urea, M.W
N
H
Me
R = aryl, benzyl, alkyl and heterocyclic
Scheme 1.
Generally, 1,4-dihydropyridines (13–18) were synthesized by Hantzsch
method, which involves cyclocondensation of 1 mol of aldehyde, 2 mol of
β-ketoester, and 1 mol of ammonia either in acetic acid at room temperature or
refluxing in alcohol for a long time. Surprisingly, under the Biginelli reaction con-
ditions comprising three-component condensation among aldehyde, β-ketoester,
and urea, 1,4-dihydropyridines are formed rapidly in high yields on the surface
of silica gel under microwave irradiation. However, when KSF clay was used as
the catalyst instead of silica gel, pyrimidines were obtained in good yields under
present reaction conditions (19).
Several substituted dihydropyridines such as aryl, alkyl, benzyl, and het-
erocyclic moieties at 4 position are synthesized by the condensation of 1 mol
of aldehyde, 2 mol of ethyl acetoacetate, and 1 mol of urea when subjected to
microwave irradiation in the presence of silica gel for 3–5 min.
All the reactions were carried out under solvent-free conditions in a open
pyrex test tube and were rapid, clean, and high-yielding when compared to those
obtained by conventional methods. The results are summarized in Table 1. The
reaction procedure is very simple, it involves mixing the reactant on the sur-
face of SiO2 and subjecting it to microwaves to afford exclusively good yields of
dihydropyridines without the formation of pyrimidines.
In conclusion, we have described a rapid and high-yielding protocol for
the synthesis of DHPs in the presence of silica gel under microwave irradiation.

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HANTZSCH 1,4-DIHYDROPYRIDINES
427
Table 1. Microwave-Assisted Synthesis of Hantzsch 1,4-Dihydropyridines
Microwave Conventional
Irradiation
b
Heatingc
◦
m.p. ( C)/b.p./tarr
Time Yield Time Yield
Reportedd
(13–18)
Ra
Phenyl
α-Naphthyl
2-Thienyl
2-Furyl
(min) (%)
d
(h)
(%)
Found
Entry
a
b
c
d
e
f
g
h
i
j
k
l
m
n
3
5
2
2
4
4
3
5
4
5
5
6
4
5
90
87
93
90
85
88
89
78
75
70
73
80
78
82
12
12
12
12
12
12
12
12
12
12
12
–
50
55
77
47
39
47
15
50
61
61
26
–
158–159
196–198
167–168
163–165
144–145
200–202
142–143
128–129
116–118
96–98
156–157
195–198
167–169
164
145–146
203
138–143
129–130
115–117
97–99
4-ClC
4-Me
2-MeOC
4-NO
Benzyl
6
H
4
2
NC
6
H
4
6
H
4
2
6 4
C H
Isopropyl
n-Hexyl
n-Decyl
188–190/0.1 mm 189–190/0.1 mm
Liquid
148–150
162–163
–
C
6
H
4
CH == CH
12
12
50
50
148–149
162–164
3-NO
2
6 4
C H
a
1
All products were characterized by IR, H NMR, mass spectra, and by comparison of
physical characteristics with authentic samples.
b
Pulsed irradiation (1 min with 20-s interval) operating at 2450 MHz.
Refluxed in ethanol in the presence of concentrated NH
Isolated yields after column chromatography are reported.
c
4
OH.
d
The new procedure is simple, inexpensive, solvent-free reaction condition and
eco-friendly, making it a useful alternative to the existing methods.
EXPERIMENTAL
Aldehyde (10 mmol), ethylacetoacetate (20 mmol), and urea (10 mmol)
were thoroughly admixed with silica gel (5 g, Aldrich 200–300 mesh) in solid
state using pestle and mortar. The resulting powder was transferred to a 25-mL
Erlenmeyer flask and subjected to microwave irradiation (BPL, BMO-700T) for
2–5 min at 650 W. After complete conversion, as shown by TLC, the reaction mass
was charged directly on a small silica gel column (60–120 mesh), and eluted with
ethyl acetate–hexane (3:7) to afford pure product.
1
Entry a. H NMR (CDCl3): δ 1.30 (t, 6H, J = 8.2 Hz), 2.55 (s, 6H),
4
.10 (q, 4H, J = 8.2 Hz), 5.05 (s, 1H), 5.75 (br, s, 1H), 7.25–7.35 (m, 5H). CHN

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28
YADAV, REDDY, AND REDDY
analysis calcd. for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found C, 69.15; H,
.95; N, 4.14.
6
1
Entry b. H NMR (CDCl3): δ 0.95 (t, 6H, J = 8.2 Hz), 2.30 (s, 6H), 3.95
(
q, 4H, J = 8.2 Hz), 5.55 (br, s, 1H), 5.75 (s, 1H), 7.25–7.50 (m, 4H), 7.60 (d, 1H,
J = 8.6 Hz), 7.70 (d, 1H, J = 8.6 Hz), 8.55 (d, 1H, J = 8.6 Hz). CHN analysis
calcd. for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found C, 72.41; H, 6.41; N,
3
.55.
1
Entry c. H NMR (CDCl3): δ 1.25 (t, 6H, J = 8.2 Hz), 2.30 (s, 6H), 2.35
(
s, 6H), 4.25 (q, 4H, J = 8.2 Hz), 5.25 (s, 1H), 5.75 (brs, 1H), 6.75–7.05 (m, 3H).
CHN analysis calcd. for C17H21NO4S: C, 60.88; H, 6.31; N, 4.18. Found C, 60.47;
H, 6.23; N, 4.06.
1
Entry d. H NMR (CDCl3): δ 1.30 (t, 6H, J = 8.2 Hz), 2.40 (s, 6H), 4.30
(
q, 4H, J = 8.2 Hz), 5.30 (s, 1H), 5.80 (brs, 1H), 6.80–7.05 (m, 3H). CHN analysis
calcd. for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found C, 63.68; H, 6.42; N,
.18.
4
1
Entry e. H NMR (CDCl3): δ 1.25 (t, 6H, J = 8.2 Hz), 2.35 (s, 6 H), 4.15
(
q, 4H, J = 8.2 Hz), 5.00 (s, 1H), 5.70 (brs, 1H), 7.15–7.25 (m, 4H). CHN analysis
calcd. for C19H22CINO4: C, 62.72; H, 6.09; N, 3.85. Found C, 62.41; H, 5.93;
N, 3.53.
1
Entry f. H NMR (CDCl3): δ 1.25 (t, 6H, J = 8.2 Hz), 2.35 (s, 6H), 3.10
(
s, 6H), 4.15 (q, 4H J = 8.2 Hz), 5.10 (s, 1H), 5.6 (brs, 1H), 7.15–7.75 (m, 4H).
CHN analysis calcd. for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52. Found C, 67.41;
H, 7.51; N, 7.26.
1
Entry g. H NMR (CDCl3): δ 1.25 (t, 6H, J = 8.2 Hz), 2.30 (s, 6H),
3
.90 (s, 3H), 4.10 (q, 4H, J = 8.2 Hz), 5.10 (s, 1H), 5.80 (brs, 1H), 6.80 (d, 2H,
J = 8.7 Hz), 7.4 (d, 2H, J = 8.7 Hz). CHN analysis calcd. for C20H25NO5: C,
6
6.84; H, 7.01; N, 3.90. Found C, 66.42; H, 6.89; N, 3.55.
1
Entry h. H NMR (CDCl3): δ 1.20 (t, 6H, J = 8.2 Hz), 2.25 (s, 6H), 4.10
(
(
7
q, 4H, J = 8.2 Hz), 5.05 (s, 1H), 5.70 (brs, 1H), 7.40 (d, 2H, J = 8.7 Hz), 8.10
d, 1H, J = 8.7 Hz). CHN analysis calcd. for C19H22N2O6: C, 69.95; H, 5.92; N,
.48. Found C, 60.78; H, 5.79; N, 7.26.
1
Entry i. H NMR (CDCl3): δ 1.30 (t, 6H, J = 8.2 Hz), 2.55 (d, 2H, J =
7
.2 Hz), 4.05 (q, 4H, J = 8.2 Hz), 4.20 (t, 1H), 5.25 (brs, 1H), 6.95–7.35 (m, 5H).

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HANTZSCH 1,4-DIHYDROPYRIDINES
429
CHN analysis calcd. fo C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found C, 69.59;
H, 7.16; N, 3.93.
1
Entry j. H NMR (CDCl3): δ 0.80 (d, 6Hm, J = 7.0 Hz), 1.25 (t, 6H,
J = 8.2 Hz), 1.5 (m, 1H), 3.90 (d, 1H, J = 7.2 Hz), 4.15 (q, 4H, J = 8.2 Hz), 5.6
(
brs, 1H). CHN analysis calcd. for C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found
C, 64.93; H, 8.37; N, 4.54.
1
Entryk. HNMR(CDCl3):δ 0.90(t, 3H, 8.2Hz), 1.15(t, 6H, J = 8.2Hz),
1
(
.25 (t, 6H, J = 8.2 Hz), 1.45 (m, 2H), 2.30 (s, 6H), 3.85 (t, 1H, J = 8.2 Hz), 4.15
q, 4H, 8.2 Hz), 5.65 (brs, 1H). CHN analysis calcd. for C19H31NO4: C, 67.63; H,
9.26; N, 4.15. Found C, 67.42; H, 9.06; N, 4.03.
1
Entry l. H NMR (CDCl3): δ 0.90 (t, 3H, J = 8.4 Hz), 1.15 (m, 16H),
1
.25 (t, 6H, J = 8.4 Hz), 1.45 (m, 2H), 2.30 (s, 6H), 3.85 (t, 1H), 4.15 (q, 4H,
J = 8.6 Hz), 5.65 (brs, 1H). CHN analysis calcd. for C23H39NO4: C, 72.04; H,
7
.62; N, 3.65. Found C, 71.86; H, 7.39; N, 3.42.
1
Entry m. H NMR (CDCl3): δ 1.20 (T, 6H, J = 8.2 Hz), 2.45 (s, 6H),
4
.15 (q, 4H, J = 8.2 Hz), 5.15 (d, 1H, J = 5.4 Hz), 5.75 (brs, 1H), 6.19 (t, 1H,
J = 6.0 Hz), 7.20 (d, 1H, J = 16.6 Hz), 7.25 (m, 5H). CHN analysis calcd. for
C21H24NO4: C, 71.17; H, 6.83; N, 3.95. Found C, 70.98; H, 6.56; N, 3.74.
1
Entry n. H NMR (CDCl3): δ 1.25 (t, 6H, J = 8.2 Hz), 2.4 (s, 6H), 4.10
(
(
q, 4H, J = 8.2 Hz), 5.15 (s, 1H), 5.75 (brs, 1H), 7.35 (t, 1H, J = 8.8 Hz), 7.60
d, 1H, J = 8.8 Hz), 8.0 (d, 1H, J = 8.8 Hz), 8.1 (s, 1H). CHN analysis calcd.
for C19H22N2O6: C, 60.94; H, 5.93; N, 7.49. Found C, 60.56; H, 5.76; N, 7.31.
ACKNOWLEDGMENT
BVS and PTK thank CSIR, New Delhi, for the award of fellowship.
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Received in Japan January 14, 2000

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