Hantzsch 1,4-dihydropyridine synthesis in aqueous ethanol by visible light

Article abstract of DOI:10.1016/j.tetlet.2012.10.079

A highly efficient environment-friendly Hantzsch 1,4-dihydropyridine synthesis under visible light in aqueous ethanol has been achieved in excellent yield via a one-pot three component reaction of various types of aliphatic and aromatic aldehydes with ethyl acetoacetate and ammonium hydroxide solution.

Full text of DOI:10.1016/j.tetlet.2012.10.079

Tetrahedron Letters 54 (2013) 58–62
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Hantzsch 1,4-dihydropyridine synthesis in aqueous ethanol by visible light
⇑
Somnath Ghosh , Forid Saikh, Jhantu Das, Arun Kumar Pramanik
Department of Chemistry, Jadavpur University, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient environment-friendly Hantzsch 1,4-dihydropyridine synthesis under visible light in
aqueous ethanol has been achieved in excellent yield via a one-pot three component reaction of various
types of aliphatic and aromatic aldehydes with ethyl acetoacetate and ammonium hydroxide solution.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 28 September 2012
Revised 17 October 2012
Accepted 20 October 2012
Available online 26 October 2012
Keywords:
Photochemical Hantzsch synthesis
One-pot three component reaction
Aqueous ethanol
1
,4-Dihydropyridines
9
10
1
,4-Dihydropyridines, first synthesized by Arthur Hantzsch in
irradiation, green solvents like ionic liquids or water or ethanol,
1
11
12
1
882, are an important class of heterocyclic compounds and exhi-
solid support, and Grignard reagent. It is noteworthy to observe
that all these protocols have been accomplished under thermal
reaction conditions and disposal of toxic solvents and catalysts of-
ten pose a problem.
bit a wide range of biological and pharmacological actions such as
calcium channel blockers, antitumor,3 anti-inflammatory, and
2
4
5
analgesic activities and more than 12 medicinally important drugs
viz. Diludine, Felodipine, Amlodipine, Nimodipin, and so forth are
An attractive area in organic synthesis involves photochemical
reactions particularly using visible light in environment-friendly
manufactured and used worldwide.6
Cl
Cl
NO2
Cl
O
O
O
CH3 O
O
O
CH3
C2H5O2C
H3C
CO2C2H5
CH3
C2H5O2C
CO2CH3
CH3
H3C
O
O
O
H3C
O
CH3
N
H
CH3
N
H
H3C
N
H
3
H C
N
H
CH3
H2N
Diludine
Felodipine
Amlodipine
Nimodipin
A large number of methods for the synthesis of the title com-
pounds have been reported using various processes based on
microwave assisted reaction,7 solar thermal energy,8 ultrasound
solvents like water or aqueous-ethanol and is generally considered
as a clean and green procedure. This type of photo-activation of
substrates very often minimizes the formation of byproducts and
requires much lesser time compared to thermal methods and for
this reason, photochemical reactions occupy an interesting posi-
1
3,14
⇑
Corresponding author. Tel./fax: +91 033 2414 6223.
E-mail address: ghoshsn@yahoo.com (S. Ghosh).
tion and excellent reviews
have been published.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.079

S. Ghosh et al. / Tetrahedron Letters 54 (2013) 58–62
59
Ar/R
EtO
2
C
CO
2
Et
CO
2
Et
aq. ethanol (1:1) / hν
-10 min
Ar/R CHO
NH
3
COMe
Me
N
H
Me
5
1
2
3
4
R
=
=
H
a
Me
b
MeO
MeO
Ar
OMe
NO2
MeO
c
d
h
l
e
f
O
O
2
O N
2
O N
g
i
j
OH
O
Cl
n
m
k
OHC
O
Scheme 1. Photochemical synthesis of Hantzsch 1,4-dihydropyridines.
In connection with our enduring interest for the synthesis of
heterocyclic compounds by photochemical reactions both by
employing ultraviolet radiation15 and visible light, we wish to re-
port here, for the first time, a highly efficient, rapid, and useful
Hantzsch reaction for the synthesis of 4-alkyl/aryl-1,4-dihydro-
pyridines stimulated by visible light (Scheme 1).
16
Table 1
Results of the photochemical Hantzsch reaction of aromatic aldehydes, ethyl acetoacetate, and ammonia
Entry
Substrate
Producta
Yieldb (%)
Mpc [lit. mp °C]
Time (min)
10
EtO C
CO Et
2
2
HCHO
182
1
Me
N
H
Me
92
21
1a
[183]
4
a
CH3
EtO C
CO Et
2
2
H
3
C–CHO
130
[130–31]
2
3
86
89
22
10
10
1b
Me
N
H
Me
4b
CHO
1
c
EtO C
CO Et
2
159
2
158–160]23
[
Me
N
H
Me
4
c
CHO
OMe
OMe
1
d
157
[
EtO C
CO Et
4
2
2
96
138–143]12
5
Me
N
H
Me
4d
(
continued on next page)

6
0
S. Ghosh et al. / Tetrahedron Letters 54 (2013) 58–62
Table 1 (continued)
Entry
Substrate
Producta
Yieldb (%)
Mpc [lit. mp °C]
Time (min)
CHO
OMe
MeO
1e
1
60
5
6
7
96
23
10
EtO C
CO Et
2
[158–160]
2
Me
N
H
Me
4e
MeO
MeO
CHO
OMe
OMe
1
f
91
147
5
EtO C
CO Et
2
2
Me
N
H
Me
4f
O
O
CHO
O
O
1
g
93
135
5
EtO C
CO Et
2
2
Me
N
H
Me
4
g
CHO
NO2
NO2
1
h
EtO C
CO Et
8
2
2
60
118
163
10
Me
N
H
Me
4h
O N
CHO
NO2
2
1
i
CO Et
9
EtO C
2
2
63
163]23
10
[
Me
N
Me
H
4i
CHO
NO2
O N
2
1
j
1
32
1
0
61
23
10
EtO C
CO Et
[136]
2
2
Me
N
H
Me
4j
CHO
Cl
Cl
1
k
1
50
1
1
EtO C
CO Et
93
23
5
2
2
[
144–146]
Me
N
H
Me
4k
HO
CHO
OH
1
l
EtO C
CO Et
180
[
2
2
1
2
65
180–182]10e
10
Me
N
H
Me
4l

S. Ghosh et al. / Tetrahedron Letters 54 (2013) 58–62
61
Table 1 (continued)
Entry
Substrate
Producta
Yieldb (%)
Mpc [lit. mp °C]
Time (min)
O
O
CHO
1
m
EtO C
CO Et
2
2
161
[
1
3
86
160–161]23
5
Me
N
H
Me
4
m
CHO
1
n
1
47
1
4
83
22
5
EtO C
CO Et
2
2
[147]
Me
N
H
Me
4
l
CHO
CHO
CHO
1
5
EtO C
CO
2
Et
59
136–38
15
2
1
o
Me
N
H
Me
4
o
a
b
c
All products were characterized by their satisfactory spectral data and also by comparison with the literature data (vide Supplementary data).
Yield refers to combined amounts of first and second crops of crystallized products obtained either directly or after chromatography.
Literature reference of melting point.
EtOOC
EtOOC
EtOOC
EtOOC
3
NH , hν
NH
OH
2
NH
3
O
NH2
O
I
II
I
hν
R
O
EtOOC
EtOOC
COOEt
EtOOC
COOEt
COOEt
RCHO
N
H
N
H
N
O
H
H
III
R
R
OH
COOEt
R
H
EtOOC
COOEt
EtOOC
EtOOC
cyclisation
-H
2
O
COOEt
N
H
N
N
H
IV
VI
V
Δ
R
electrocyclic
EtOOC
COOEt
N
H
4
Scheme 2. Plausible mechanistic pathway for the photochemical Hantzsch synthesis of 1,4-dihydropyridines.
The photochemical reactions were found to be very clean and
the products were obtained in extremely pure crystalline states
with an average yield of 59–96%. The reaction time varied on an
average from 5–10 min (monitored by TLC) and the products are
isolated from the reaction mixture in crystalline form by cooling
in an ice-bath and need no further crystallization. However, for

6
2
S. Ghosh et al. / Tetrahedron Letters 54 (2013) 58–62
entries 1 and 2 (Table 1), the dihydropyridines are obtained by
chromatographic separation over silica gel and the results of these
experiments are given in Table 1.
When the same reactions were performed under refluxing con-
ditions for 10 min, only ca. 5–10% of the corresponding dihydro-
pyridines were obtained; and the yield of the products increased
to 55–65% after 5 h. Thus, the present method, in comparison with
thermal ones, is encouragingly effectual and works smoothly both
for aromatic or aliphatic aldehydes free from any adhering byprod-
ucts or side reactions.
Cosconati, S.; Marinelli, L.; Lavecchia, A.; Novellino, E. J. Med. Chem. 2007, 50,
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1
296–1298; (d) Lee, Y. A.; Chan, K. S. J. Ind. Eng. Chem. 2011, 17,
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0. (a) Legeay, J.; Eyndeb, J. V.; Bazureau, J. P. Tetrahedron 2005, 61, 12386–12397;
b) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Green Chem. 2003, 5,
4
8
.
5
7
It is well-known that the formation of dihydropyridines by Han-
tzsch reaction under thermal conditions mechanistically involves
reactions of:
1
(
60–63; (c) Xia, J.; Wang, G. Synthesis 2005, 2379–2383; (d) Zonouz, A. M.;
Sahranavarde, N. E. J. Chem. 2010, 7, 372–376; (e) Tamaddon, F.; Razmi, Z.;
Jafari, A. A. Tetrahedron Lett. 2010, 51, 1187–1189; (f) Debache, A.; Ghalem, W.;
Boulcina, R.; Belfaitah, A.; Rhouati, Salah; Carboni, Bertrand. Tetrahedron Lett.
2009, 50, 5248–5250; (g) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8, 899–902.
a 1,5-dicarbonyl compound formed in situ from ethyl acetoace-
tate and aldehydes followed by reaction with ammonia,17
11. (a) Adharvana Chari, M.; Syamasundar, K. Catal. Commun. 2005, 6, 624–626; (b)
Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924–928.
an
a,b-unsaturated carbonyl compound and an enamino ester
derived from active methylene component, aldehydes, and
12. Love, B.; Goodman, M. M.; Snader, K. M.; Tedeschi, R.; Macko, E. J. Med. Chem.
1974, 17, 956–965.
1
8
ammonia,
a 1,5-dienamino-ammonium salt obtained from an imino ester
1
1
3. Hoffmann, N. Chem. Rev. 2008, 108, 1052–1103.
4. Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007, 107, 2725–2756.
1
9
and enamine,
Aza-Diels–Alder reaction of an aza-diene and a dienophile.
15. (a) Ghosh, S. N.; Das, T. K.; Datta, D. B.; Mehta, S. Tetrahedron Lett. 1987, 28,
611–4614; (b) Ghosh, S. N.; Datta, I.; Chakraborty, R.; Das, T. K.; Sengupta, J.;
2
0
4
Sarkar, D. C. Tetrahedron 1989, 45, 1441–1447; (c) Ghosh, S. N.; Datta, D. B.;
Datta, I.; Das, T. K. Tetrahedron 1989, 45, 3775–3786; (d) Datta, I.; Das, T. K.;
Ghosh, S. N. Tetrahedron Lett. 1989, 30, 4009–4012; (e) Datta, I.; Das, T. K.;
Ghosh, S. N. Tetrahedron 1990, 46, 6821–6830; (f) Ghosh, S. N.; Nandi, B.;
Saima, Y. Tetrahedron Lett. 1996, 37, 3169–3170; (g) Ghosh, S. N.; Baul, S.
Arkivoc 2003, 58–68.
In the present instance, we speculate that the reaction may
plausibly be initiated by an electron transfer from ammonia in
the presence of light to the carbonyl group of ethyl acetoacetate
to produce a radical anion (I) that subsequently transforms into
an enamino-ester (II). Further combination of the anion-radical
I) and enamino-ester (II) gives rise to bis-enamino-diester (III)
which on reaction with aldehydes produces the intermediate
IV). The product (4) is then obtained from IV through the interme-
1
1
6. (a) Ghosh, S.; Das, J. Tetrahedron Lett. 2011, 52, 1112–1116; (b) Ghosh, S.; Das,
J.; Chattopadhyay, S. Tetrahedron Lett. 2011, 52, 2869–2872; (c) Das, J.; Ghosh,
S. Tetrahedron Lett. 2011, 52, 7189–7194; (d) Ghosh, S.; Das, J.; Saikh, F.
Tetrahedron Lett. 2012, 53, 5883–5886; (e) Ghosh, S.; Baul, S. Synth. Commun.
(
2001, 31, 2783–2786.
(
7. Gilchrist, T. L. Heterocyclic Chemistry; Pitman Publishing Ltd: London, 1985.
diacy of either V or VI as depicted in Scheme 2.
Chapter 8, p. 241.
In conclusion, we have developed a potentially efficient, abso-
lutely clean, and very high yielding eco-friendly methodology
18. Collie, J. N. Justus Liebigs Ann. Chem. 1884, 226, 294.
19. Eynde, J.-J. V.; D’Orazio, P.; Mayence, A.; Maquestiau, A. Tetrahedron 1992, 48,
2
4
1263–1268.
for the Hantzsch synthesis of 4-alkyl/aryl-1,4-dihydropyridines in
aqueous ethanol in one-pot three component condensation and
cyclization of various types of aliphatic and aromatic aldehydes
with ethyl acetoacetate and ammonium hydroxide solution devoid
of any unwarranted side reactions such as Norrish Type I cleavage
and may be considered as an excellent improvement over the
existing methods.
2
0. Lee, Y. A.; Kim, S. C. J. Ind. Eng. Chem. 2011, 17, 401–403.
21. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G. Text book of Practical Organic
Chemistry, 5th ed.; Singapore: Longman Singapore, 1994. p. 1168.
2
2. Leov, B.; Snader, K. M. J. Org. Chem. 1965, 30, 1914–1916.
3. Jacques, J.; Eynde, V.; Delfaese, F.; Mayence, A.; Haverbeke, Y. V. Tetrahedron
1995, 51, 651l–6516.
4. Method: Different aliphatic or aromatic aldehydes (1a–o) (10 mmol), ethyl
acetoacetate (20 mmol), and ammonium hydroxide solution (25%) were taken
in aqueous-ethanol mixture (20 mL, 1:1 proportion) and irradiated with a
2
2
1
1
50 W tungsten lamp (Philips India Ltd). The reaction time varied from 5–
5 min (monitored by TLC after 5 min. interval). Upon completion of the
Acknowledgments
reaction, the reaction mixture was cooled and the crystalline product (4a–o) so
obtained was filtered, washed with water and dried in vacuo. The Hantzsch
dihydropyridines were isolated in high yields in essentially pure form.
This research was supported by the Council of Scientific and
Industrial Research and University Grants Commission, Govern-
ment of India to the authors (F.S. & J.D) and partly by the Centre
for Advance Studies, and DST-PURSE program of the Department
of Chemistry, Jadavpur University.
3
,5-diethoxycarbonyl-4-(3,4-dimethoxy)phenyl-2,6-dimethyl-1,4-dihy-dropyridine
(
4f): White needle shaped crystal, Yield: 3.55 g (91%), mp: 147 °C, IR (KBr):
À1 1
m
max 3343, 2982, 1651, 1483, 1209, 770 cm
3
H NMR (300 MHz, CDCl , 22 °C):
1.23 (t, 7.1 Hz), 2.32 (s, 6H), 3.81 (s, 3H), 3.83 (s, 3H), 4.09 (m, 4H), 4.94 (s, 1H)
5
1
1
.69 (s, 1H), 6.71 (d, 8.2 Hz, 1H), 6.79 (dd, 8.2 Hz, 2.0 Hz, 1H), 6.87 (d,1.6 Hz,
H) ppm. 13C NMR (300 MHz, CDCl
, 22 °C): d 167.7, 148.1, 147.2, 143.7, 140.7,
19.8, 111.8, 110.8, 104.1, 59.7, 55.9, 55.7, 38.98, 19.4, 14.3 ppm.
,5-Diethoxycarbonyl-4-(3,4-methylenedioxy)phenyl-2,6-dimethyl-1,4-dihydropy-
3
3
Supplementary data
ridine (4g): Off white flakes, Yield: 3.47 g (93%), mp: 135 °C. IR (KBr): mmax 3307,
À1 1
2
6
7
1
902, 1652, 1486, 799 cm . H NMR (300 MHz, CDCl3, 22 °C): d 1.23 (t, 7.2 Hz,
H), 2.30 (s, 6H), 4.10 (s, 4H), 4.91 (s, 1H), 5.77 (s, 1H), 5.87 (s, 2H), 6.64 (d,
.9 Hz, 1H), 6.75 (m, 2H) ppm.13C NMR (75 MHz, CDCl
, 22 °C): d 167.6, 147.1,
45.7, 143.6, 142.0, 120.9, 108.5, 107.5, 104.2, 100.6, 59.7, 39.3, 19.5, 14.2 ppm.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
3
0
79.
3,5-Diethoxycarbonyl-4-(2-nitro)phenyl-2,6-dimethyl-1,4-dihydropyridine (4h):
Yellow needle shaped crystal, Yield: 2.25 g (60%), mp: 118 °C. IR (KBr):
m
max
À1
1
3331, 1695, 1489, 1212, 716 cm
3
. H NMR (300 MHz, CDCl , 22 °C): d 1.15 (t,
References and notes
7.1 Hz, 6H), 2.32 (s, 6H), 4.06 (m, 4H), 5.68 (s, 1H), 5.84 (s, 1H), 7.48 (m, 4H)
ppm.
1
2
3
4
.
.
.
.
Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82.
David, J. T. Biochem. Pharmacol. 2007, 74, 1–9.
Boer, R.; Gekeler, V. Drugs Future 1995, 20, 499–509.
(a) Briukhanov, V. M. Exp. Clin. Pharmacol. 1994, 57, 47–49; (b) Bahekar, S.;
Shinde, D. Acta Pharm. (Zagreb) A 2002, 52, 281–287.
3,5-Diethoxycarbonyl-4-(4-formyl)phenyl-2,6-dimethyl-1,4-dihydropyri-dine
(4o):
Faint yellow needle shaped crystal, Yield: 210 mg. (59%), mp: 136–138 °C. 1H
1
NMR ( H NMR, CDCl3, 22 °C): d 9.93 (s, 1H), 7.74 (d, 8 Hz, 2H), 7.46, (d, 8 Hz,
2H), 5.95 (s, 1H), 5.06 (s, 1H), 4.08 (m, 4H), 2.34 (s, 6H), 1.20, (t, 7.1 Hz, 6H)
ppm. 13C NMR (75 MHz, CDCl3, 22 °C): d 192.2, 167.2, 154.8, 144.4, 134.6,
129.6, 128.8, 103.5, 59.9, 40.3, 19.6, 14.2 ppm. HRMS (ESI) m/z (%):
5
6
.
.
Gullapalli, S.; Ramarao, P. Neuropharmacology 2002, 42, 467–475.
(a) Bossert, F.; Mayer, H.; Wehinger, E. Angew. Chem., Int. Ed. Engl. 1981, 20,
+
7
62–769; (b) Gilpin, P. K.; Pachla, L. A. Anal. Chem. 1999, 71, 217–233; (c)
380.1473(M +Na).