Efficient synthesis of Hantzsch esters and polyhydroquinoline derivatives in aqueous micelles

Article abstract of DOI:10.1055/s-2008-1042908

Hantzsch 1,4-dihydropyridine and polyhydroquinoline derivatives were synthesized in excellent yields in aqueous micelles. The reaction is catalyzed by PTSA and strongly accelerated by ultrasonic irradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042908

LETTER
883
Efficient Synthesis of Hantzsch Esters and Polyhydroquinoline Derivatives in
Aqueous Micelles
Synthesis of
H
antz
t
sch Est
u
ers and Poly
l
hydroquinoli
K
ne
D
erivative
s
umar,* Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
E-mail: dratulsax@gmail.com
Received 13 June 2007
R
Abstract: Hantzsch 1,4-dihydropyridine and polyhydroquinoline
R1OOC
COOR1
O
O
NH4OAc, PTSA
derivatives were synthesized in excellent yields in aqueous mi-
celles. The reaction is catalyzed by PTSA and strongly accelerated
by ultrasonic irradiation.
RCHO
+
COOR1
SDS, H2O
r.t. stirring
1a–k
N
H
2a–c
Key words: Hantzsch esters, polyhydroquinoline derivatives,
3a–m
aqueous micelles, PTSA
Scheme 1
micelles (SDS, 0.1 M) yielded 3a (65%) in four hours.
The same reaction without PTSA yielded 3a in 35% yield.
Thus the catalytic efficiency of PTSA was definitely iden-
tified. Using methane sulfonic acid instead of PTSA we
isolated 3a in 63% yield. In another experiment, camphor-
10-sulfonic acid was used and 3a was isolated in 62%
yield. In order to see the effect of temperature, we re-
fluxed the reaction mixture for three hours but there was
no significant improvement in the yield of the product. It
was observed that in neat water (absence of SDS) the re-
action gave poor yields.
Hantzsch 1,4-dihydropyridines (1,4-DHP) and their de-
rivatives are an important class of bioactive molecules in
the pharmaceutical field.1 These compounds are well
known as calcium channel modulators and have emerged
as one of the most important classes of drugs for the treat-
ment of hypertension.2 1,4-Dihydropyridine derivatives
possess a variety of biological activities such as vasodila-
tor, branchodilator, antitumor, hepatoprotactive, and
geroprotactive activity.3
Despite the potential importance of 1,4-dihydropyridyl
compounds from a pharmaceutical, industrial, and syn-
thetic point of view,4 comparatively few methods for their
preparation have been reported. The classical method for
the synthesis of 1,4-dihydropyridines is the one-pot con-
densation of aldehydes with ethyl acetoacetate and ammo-
nia either in acetic acid or by refluxing in alcohol.5 The
classical method, however, has several drawbacks such as
harsh reaction conditions, long reaction times, and gener-
ally low yields of products. Thus, improved synthetic pro-
cedures for the synthesis of Hantzsch esters6 and
polyhydroquinoline derivatives7 are in constant demand.
When the reaction mixture was irradiated with ultrasound,
almost quantitative conversion was observed (TLC) with-
in one hour and 3a was isolated in 96% yield. We also car-
ried out the reaction in various solvents. The ultrasonic
irradiation in aqueous micelles gave better yields than in
solvents such as methanol, ethanol, or THF (Table 1).
Table 1 Optimization of Reaction Conditions for 1,4-Dihydro-
pyridinesa
Entry
Catalyst
None
Solvent
H2O
Time (h) Yield (%)b
As a part of our continual efforts towards the development
of efficient synthetic procedures for multicomponent re-
actions, we turned our attention towards the synthesis of
1,4-dihydropyridines and polyhydroquinoline derivatives.
We report herein a practical synthesis of 1,4-dihydro-
pyridines and polyhydroquinoline derivatives in aqueous
micelles catalyzed by PTSA under ultrasonic irradiation.
1
2
3
4
5
6
7
7
8
12
6
16
28
65
63
62
96
62
74
78
PTSA
PTSA
MSA
H2O
SDS (aq)
SDS (aq)
SDS (aq)
SDS (aq)
THF
4
4
CSA
4
In order to optimize the reaction conditions for 1,4-dihy-
dropyridines, we took the reaction of benzaldehyde, ethyl
acetoacetate, and ammonium acetate as a model
(Scheme 1).
PTSAc
PTSAc
PTSAc
PTSAc
1
1
MeOH
EtOH
1
Our initial attempts to condense benzaldehyde, ethyl ace-
toacetate, and ammonium acetate using PTSA in aqueous
1
a Reaction conditions: benzaldehyde (1 mmol), ethyl acetoacetate (2
mmol), NH4OAc (1 mmol), catalyst (10 mol%).
b Isolated yield.
SYNLETT 2008, No. 6, pp 0883–0885
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042908; Art ID: D18307ST
x
x.
x
x.
2
0
0
8
c Ultrasonic irradiation.
© Georg Thieme Verlag Stuttgart · New York

884
A. Kumar, R. A. Maurya
LETTER
Using the optimized reaction conditions,8 we synthesized
a series of 1,4-dihydropyridine derivatives under ultrason-
ic irradiation (Table 2). 4-Aryl-1,4-dihydropyridines were
synthesized in excellent yields with a number of electron-
rich as well as electron-deficient aromatic aldehydes. A
heterocyclic aldehyde (entry 13, Table 2) also resulted to
good conversion into 1,4-dihydropyridines. Aliphatic al-
dehydes such as formaldehyde and acetaldehyde can also
be used for the synthesis of 1,4-dihydropyridines with
similar success.
Table 2 Ultrasound-Accelerated Synthesis of 1,4-Dihydropyri-
dinesa
Entry
1
R
R1
Product
3a
Yield (%)b
H
Me
Et
97
95
96
95
96
91
93
94
93
90
92
91
90
2
H
3b
3c
3
H
t-Bu
Et
4
Me
3d
3e
5
Ph
Et
After successfully synthesizing a series of Hantzsch esters
in excellent yields under ultrasonic irradiation, we turned
our attention towards the synthesis of polyhydroquinoline
derivatives via unsymmetrical Hantzsch reaction under
ultrasonic irradiation conditions (Scheme 2).
6
2-HOC6H4
2-O2NC6H4
4-MeC6H4
3-O2NC6H4
Me
Et
3f
7
Et
3g
8
Et
3h
3i
We carried out the four-component coupling reaction of a
cyclic 1,3-diketone, an aldehyde, an acetoacetatic ester,
and ammonium acetate in aqueous micelles. The reaction
was catalyzed by PTSA and was sonicated for 1–3 hours.
9
Et
10
11
12
13
Me
Me
Me
Me
3j
2-O2NC6H4
4-MeO2CC6H4
4-Pyridyl
3k
3l
RCHO
O
O
R
COR3
COR3
1
PTSA
3m
+
R1
R1
aq micelle
)))
O
O
a Reaction conditions: aldehyde (1 mmol), acetoacetate ester (2
mmol), NH4OAc (1 mmol), PTSA (10 mol%), ultrasound, 1 h.
b Isolated yield.
R2
2
N
H
R2
4
5
NH4OAc
Scheme 2
Table 3 Ultrasound-Accelerated Synthesis of Polyhydroquinoline Derivativesa
Entry
1
R
R1
R2
R3
Time (h)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
Product
5a
Yield (%)b
92
Ph
H
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
Ot-Bu
Ot-Bu
Me
2
4-ClC6H4
H
H
5b
5c
91
3
4-MeC6H4
4-MeOC6H4
Ph
H
H
93
4
H
H
5d
5e
90
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
89
6
3-O2NC6H4
4-HOC6H4
3-MeOC6H4
1-Naphthyl
4-O2NC6H4
4-HO-3-MeOC6H3
4-MeOC6H3CH=CH
4-MeC6H4
4-EtO-3-HOC6H3
4-HOC6H4
3-MeOC6H4
4-Me2NC6H4
5f
93
7
5g
91
8
5h
5i
90
9
92
10
11
12
13
14
15
16
17
5k
5l
92
90
5m
5n
5o
93
91
88
5p
5q
5r
89
75
Me
3
72
a Reaction conditions: aldehyde (1 mmol), acetoacetic ester/acetyl acetone (1 mmol), cyclic b-diketone (1 mmol), NH4OAc (1 mmol), PTSA
(10 mol%), ultrasound.
b Isolated yield.
Synlett 2008, No. 6, 883–885 © Thieme Stuttgart · New York

LETTER
Synthesis of Hantzsch Esters and Polyhydroquinoline Derivatives
885
Using the optimized reaction conditions,9 we synthesized
a number of polyhydroquinoline derivatives and the re-
sults are shown in Table 3.
(5) (a) Love, B.; Sander, K. M. J. Org. Chem. 1965, 30, 1914.
(b) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1888, 21, 942.
(6) (a) Chari, M. A.; Syamasundar, K. Catal. Commun. 2005, 6,
624. (b) Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org.
Chem. 1996, 61, 924. (c) Yadav, J. S.; Reddy, B. V. S.;
Basak, A. K.; Narasaiah, A. V. Green Chem. 2003, 5, 3.
(d) Maquestiau, A.; Maeyence, A.; Eynde, J. J. V.
The results of Table 3 clearly indicate the feasibility of
four-component unsymmetrical Hantzsch reaction in
aqueous micelles. The products were synthesized in ex-
cellent yield under ultrasonic irradiation. The method has
the ability to tolerate a variety of functional groups such
as hydroxy, chloro, nitro, methoxy, and unsaturation. We
observed that in the case of acetylacetone the reaction
took a longer time to complete and the isolated yields
were somewhat lower than corresponding acetoacetic es-
ter.
Tetrahedron Lett. 1991, 32, 3839. (e) Ohberg, L.; Westman,
J. Synlett 2001, 1296. (f) Anniyappan, M.; Muralidharan,
D.; Perumal, P. T. Synth. Commun. 2002, 32, 659.
(7) (a) Ko, S.; Yao, C.-F. Tetrahedron 2006, 62, 7293.
(b) Heravi, M. M.; Bakhtiari, K.; Javadi, N. M.;
Bamoharram, F. F.; Saeedi, M.; Oskooie, H. A. J. Mol.
Catal. A.: Chem. 2007, 264, 50. (c) Kumar, A.; Maurya, R.
A. Tetrahedron 2007, 63, 1946. (d) Wang, L.-M.; Sheng, J.;
Zhang, L.; Han, J.-W.; Fan, Z.-Y.; Tian, H.; Qian, C.-T.
Tetrahedron 2005, 61, 1539.
In conclusion, we have developed an efficient and versa-
tile method for the synthesis of symmetrical and unsym-
metrical Hantzsch esters. The reaction is catalyzed by
PTSA and has been carried out under ultrasonic irradia-
tion at room temperature. The process has several advan-
tages from economical and environmental points of view
such as short reaction time, high yields, and mild reaction
conditions.
(8) Typical Experimental Procedure for the Synthesis of 1,4-
Dihydropyridine Derivatives
In a 25 mL round-bottomed flask, benzaldehyde (1 mmol),
ethyl acetoacetate (2 mmol), NH4OAc (1 mmol), and PTSA
(0.1 mmol) was added. To this an aqueous solution of SDS
(3 mL, 0.1 M) was added. The reaction mixture was
immersed in an ultrasonic bath and irradiated for 1 h. Then,
the reaction mixture was diluted with brine and extracted
with EtOAc. The organic layer was dried over anhyd
Na2SO4 and concentrated to give a crude product. The pure
product was obtained by crystallization of the crude material
from MeOH; mp 158 °C. 1H NMR (200 MHz, CDCl3): d =
1.21 (t, J = 7.7 Hz, 6 H), 2.29 (s, 6 H), 4.08 (q, J = 7.7 Hz, 4
H), 4.98 (s, 1 H), 6.00 (s, 1 H), 7.01–7.26 (m, 5 H). IR (KBr):
3322, 1676, 1633 cm–1. MS: m/z = 330 [M + H]+. Anal.
Calcd for C19H23NO4: C, 69.28, H, 7.04, N, 4.25. Found: C,
69.12, H, 6.98, N, 4.14.
Acknowledgment
R.A.M. is thankful to CSIR, New Delhi for the award of a senior re-
search fellowship. The authors also acknowledge SAIF-CDRI for
providing the spectroscopic and analytical data.
References and Notes
(9) Typical Experimental Procedure for the Synthesis of
Polyhydroquinoline Derivatives
(1) (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int.
Ed. Engl. 1981, 20, 762. (b) Nakayama, H.; Kosoaka, Y.
Heterocycles 1996, 42, 901. (c) Godfraid, T.; Miller, R.;
Wibo, M. Pharmacol. Rev. 1986, 38, 321. (d) Mannhold,
R.; Jablonka, B.; Voigdt, W.; Schoenafinger, K.; Schravan,
K. Eur. J. Med. Chem. 1992, 229.
(2) (a) Buhler, F. R.; Kiowski, W. J. Hypertens. 1987, 5, S3.
(b) Reid, G. L.; Meredith, P. A.; Pasanisi, F. J. Cardiovasc.
Pharmacol. 1985, 7, S18.
(3) (a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 279.
(b) Mager, P. P.; Coburan, R. A.; Solo, A. J.; Trigle, D. J.;
Rothe, H. Drug Des. Discovery 1992, 8, 273. (c) Clusa, V.
Drugs Future 1995, 20, 135. (d) Boer, R.; Gekeler, V.
Drugs Future 1995, 20, 499.
(4) (a) Ruppert, R.; Jeandon, C.; Sgambati, A.; Callot, H. J.
Chem. Commun. 1999, 2123. (b) Menche, D.; Hassfeld, J.;
Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett. 2006,
8, 741. (c) Garden, S. J.; Guimarães, C. R. W.; Corréa, M.
B.; Oleveira, C. A. F. D.; Pinto, A. D. C.; Alencastro, R. B.
D. J. Org. Chem. 2003, 68, 8815. (d) Quellet, S. G.; Tuttle,
J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
(e) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128,
13368.
In a 25 mL round-bottomed flask, dimedone (1 mmol),
benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol),
NH4OAc (1 mmol), and PTSA (0.1 mmol) was added. To
this an aqueous solution of SDS (3 mL, 0.1 M) was added.
The reaction mixture was immersed in an ultrasonic bath and
irradiated until reaction was complete (TLC monitoring, 1–
3 h). The reaction mixture was diluted with brine and
extracted with EtOAc. The organic layer was dried over
anhyd Na2SO4 and concentrated to give a crude product. The
pure product was obtained by crystallization from MeOH;
mp 203–204 °C. 1H NMR (300 MHz, CDCl3): d = 0.94 (s, 3
H), 1.07 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 2.13–2.29 (m, 4
H), 2.35 (s, 3 H), 4.06 (q, J = 7.1 Hz, 2 H), 5.07 (s, 1 H), 6.64
(s, 1 H), 7.08–7.13 (m, 1 H), 7.18–7.23 (m, 2 H), 7.28–7.33
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 12.92, 17.96,
25.84, 28.15, 31.38, 35.33, 39.65, 49.50, 58.52, 104.72,
110.70, 124.74, 126.59, 126.72, 142.41, 145.82, 147.47,
166.24, 194.43. IR (KBr): 3287, 3078, 2963, 1697, 1611
cm–1. MS: m/z = 340 [M + H]+. Anal. Calcd for C21H25NO3:
C, 74.31, H, 7.42, N, 4.13. Found: C, 74.27, H, 7.39, N, 4.08.
Synlett 2008, No. 6, 883–885 © Thieme Stuttgart · New York