PEG-mediated catalyst-free synthesis of Hantzsch 1,4-dihydropyridines and polyhydroquinoline derivatives

Article abstract of DOI:10.1080/00397911.2010.528289

Hantzsch 1,4-dihydropyridines and polyhydroquinoline derivatives were synthesized in good yields by PEG-mediated, catalyst-free synthesis under solvent-free conditions. The products were directly recrystallized from hot methanol. The reaction gave excellent yields with low- as well as high-molecular-weight polyethylene glycols. Taylor & Francis Group, LLC.

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PEG-Mediated Catalyst-Free Synthesis
of Hantzsch 1,4-Dihydropyridines and
Polyhydroquinoline Derivatives
V. Siddaiah a , G. Mahaboob Basha a , G. Padma Rao a , U. Viplava
Prasad a & R. Suryachendra Rao b
a Department of Organic Chemistry, Food, Drugs and Water, Andhra
University, Visakhapatnam, India
b Department of Chemistry, Acharya Nagarjuna University, Guntur,
India
Available online: 10 Aug 2011
To cite this article: V. Siddaiah, G. Mahaboob Basha, G. Padma Rao, U. Viplava Prasad & R.
Suryachendra Rao (2012): PEG-Mediated Catalyst-Free Synthesis of Hantzsch 1,4-Dihydropyridines
and Polyhydroquinoline Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:5, 627-634
To link to this article: http://dx.doi.org/10.1080/00397911.2010.528289
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Synthetic Communications1, 42: 627–634, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.528289
PEG-MEDIATED CATALYST-FREE SYNTHESIS OF
HANTZSCH 1,4-DIHYDROPYRIDINES AND
POLYHYDROQUINOLINE DERIVATIVES
V. Siddaiah,1 G. Mahaboob Basha,1 G. Padma Rao,1
U. Viplava Prasad,1 and R. Suryachendra Rao2
1Department of Organic Chemistry, Food, Drugs and Water, Andhra
University, Visakhapatnam, India
2Department of Chemistry, Acharya Nagarjuna University, Guntur, India
GRAPHICAL ABSTRACT
Abstract Hantzsch 1,4-dihydropyridines and polyhydroquinoline derivatives were
synthesized in good yields by PEG-mediated, catalyst–free synthesis under solvent-free
conditions. The products were directly recrystallized from hot methanol. The reaction gave
excellent yields with low- as well as high-molecular-weight polyethylene glycols.
Keywords Catalyst-free; Hantzsch 1,4-dihydropyridines; polyethylene glycol; polyhydro-
quinoline derivatives; solvent-free conditions
INTRODUCTION
Over the past few decades, ecofriendly chemical processes have attracted much
attention both in the academic and industrial fields.[1] Hazardous, toxic, and volatile
organic solvents are being continuously replaced either by the use of solvent-free
techniques[2] or by using water,[3] phase-transfer catalysts,[4] or ionic liquids.[5] The
use of polyethylene glycol (PEG) as a reaction medium is highly beneficial as the sys-
tem remains neutral, which helps in maintaining a number of acid- and base-sensitive
functional groups unchanged.
Heterocycles containing the dihydropyridine ring are important targets in
synthetic and medicinal chemistry because this ring is the key moiety in numerous
Received June 22, 2010.
Address correspondence to V. Siddaiah, Department of Organic Chemistry, Food, Drugs and
Water, Andhra University, Visakhapatnam 530 003, India. E-mail: siddaiah_v@yahoo.com
627

628
V. SIDDAIAH ET AL.
biologically active compounds.[6] Some of them, such as amlodipine (1), felodipine
(2), isradipine (3), lacidipine (4), nifedipine (5), are prominent drugs in the treatment
of cardiovascular diseases and hypertension as effective calcium channel blockers.[7]
1,4-Dihydropyridines are also good precursors for the synthesis of the corresponding
substituted pyridine derivatives[8] and are useful as reducing agents for imines in the
presence of a catalytic amount of Lewis acid.[9] More than a century ago, 1,4-dihy-
dropyridines were prepared by Hantzsch for the first time.[10] This reaction involves a
one-pot condensation of an aldehyde with ethyl acetoacetate and ammonia
(ammonium acetate) either in acetic acid or refluxing in alcohol for a longer time.
However, the yields of 1,4-dihydropyridines obtained by the Hantzsch method are
generally poor. In recent years, several new methods have been reported for the syn-
thesis of 1,4-dihydropyridines.[11] Even though a number of modified methods under
improved conditions have been reported, many of them suffer from drawbacks such
as long reaction time, harsh reaction conditions, the use of a large quantity of sol-
vents, and generally poor yields. Therefore, it is necessary to develop an efficient
and versatile method for the preparation of 1,4-dihydropyridines.
PEG is commercially available, inexpensive, nontoxic medium that possesses
high thermal stability and helps in maintaining a neutral reaction. Organic synthesis
in PEG under solvent-free conditions is an area of significance in modern organic
synthesis.[12]
Considering these reports and in continuation of our previous efforts on the
development of new synthetic methodologies for biologically active compounds,[13]
herein we report the synthesis of Hantzsch 1,4-dihydropyridines and polyhydroqui-
noline derivatives in PEG-400 under solvent-free conditions at 75 ꢀC (Schemes 1
and 2).
Scheme 1. Synthesis of Hantzsch 1,4-dihydropyridines.

HANTZSCH 1,4-DIHYDROPYRIDINES
629
Scheme 2. Synthesis of polyhydroquinoline derivatives.
RESULTS AND DISCUSSION
To optimize the reaction conditions, we investigated the reaction with benzal-
dehyde (4 mmol), ethyl acetoacetate (7 mmol), and ammonium acetate (7 mmol) in
various solvents and under solvent-free classical heating conditions with different
quantities of PEG-400. The optimized results are summarized in Table 1. We found
that the reaction proceeded best under solvent-free conditions rather than using sol-
vents. The best result was obtained with 0.5 mL of PEG-400 for 4 mmol of benzal-
dehyde under solvent-free conditions at 75 ꢀC within 2 h (Table 1, entry 5). Using
more than 0.5 mL of PEG-400 did not improve the yield of the product, and at
the same time, very poor yield of the product was obtained in the absence of
PEG-400. Because only 0.5 mL of PEG-400 is used, it cannot act as a solvent, and
thus it is the promoter for the reaction without requiring any additional catalyst.
We investigated our protocol with various PEGs with molecular weights 200, 400,
600, 4000, and 6000 (0.05 mol% each) for our model reaction with benzaldehyde
(4 mmol), ethyl acetoacetate (7 mmol), and ammonium acetate (7 mmol). The
reaction occurred and gave excellent yields with low- as well as high-molecular-
weight PEGs.
With these results in hand, a variety of aldehydes, aromatic and heterocyclic,
possessing both electron-donating and electron-withdrawing groups, were employed
for 1,4-dihydropyridine formation. In all the cases, the yields were excellent (Table 2).
Two different esters were employed, and both reacted smoothly under the reaction
conditions. All the products were characterized by comparing their physical and
spectral data [infrared (IR), 1H NMR, 13C NMR] with those of the authentic
samples reported in the literature.[11] The data for previously unknown compounds
are reported in this article.
Table 1. Synthesis of Hantzsch 1,4-dihydropyridines under various conditions (entry 5 gives the optimum
conditions)
Entry PEG-400 (mL) Solvent (mL) Reaction medium temperature Time (h) Yield (%) isolated
1
2
3
4
5
6
7
8
9
–
–
EtOH (5)
100 ꢀC
Reflux
100 ꢀC
75 ꢀC
5
10
3
30
50
65
85
92
92
85
62
60
–
0.1
0.1
0.5
1.0
0.5
0.5
0.5
–
–
–
3
75 ꢀC
2
–
75 ꢀC
2
EtOH (5)
THF (5)
CH3CN (5)
Reflux
Reflux
Reflux
5
5
5

630
V. SIDDAIAH ET AL.
Table 2. Synthesis of Hantzsch 1,4-dihydropyridines with PEG-400 (0.5 mL) under solvent-free
conditions at 75 ꢀC
Entry
R
R1
R2
Time (h)
Product
Yield (%)
1
2
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
2
9a[11q]
9b[11q]
9c[11q]
9d[11i]
9e
9f[11q]
9g[11i]
9h[11q]
9i[11q]
9j[11i]
9k[11q]
9l[11q]
9m[11i]
9n
9o[11q]
9p[11r]
9q[11i]
9r[11r]
9s[11i]
9t[11i]
92
90
92
87
85
90
88
90
87
85
92
95
92
93
85
82
91
92
90
90
4-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2,3-(O-CH2-O)C6H3
4-OHC6H4
2-ClC6H4
2
3
2
4
2
5
3
6
2.5
3
7
8
4-ClC6H4
4-BrC6H4
2-BrC6H4
3
9
3
10
11
12
13
14
15
16
17
18
19
20
3
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
2-(Cl)-5-(NO2)-C6H3
2-Furyl
2.5
2.5
2.5
3
3
3-Pyridyl
Ph
3
2
2-O2NC6H4
4-MeC6H4
4-MeOC6H4
3
2.5
2.5
After successfully synthesizing a series of 1,4-dihydropyridines in excellent
yields under the optimized conditions, we turned our attention toward the synthesis
of polyhydroquinoline derivatives via unsymmetrical Hantzsch reaction. We carried
out the reaction with benzaldehyde (4 mmol), ethyl acetoacetate (4 mmol), cyclic
Table 3. Synthesis of polyhydroquinoline derivatives with PEG-400 (0.5 mL) under solvent-free
conditions at 75 ꢀC
Entry
R
R1
R2
Time (h)
Product
Yield (%)
1
2
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OEt
3
3
3
3
3
4
4
4
4
4
4
3
3
3
3
3
3
11a[11n]
11b[11n]
11c[11j]
11d[11s]
11e
11f[11j]
11g[11s]
11h[11n]
11i[11d]
11j[11d]
11k[11s]
11o[11d]
11p[11d]
11q[11n]
11r[11s]
11s[11n]
11u
93
92
93
90
86
90
90
90
88
87
92
85
82
91
92
91
83
4-MeC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2,3-(O-CH2-O) C6H3
4-OHC6H4
2-ClC6H4
3
4
5
6
7
8
4-ClC6H4
4-BrC6H4
2-BrC6H4
9
10
11
12
13
14
15
16
17
4-O2NC6H4
2-Furyl
3-Pyridyl
Ph
2-O2NC6H4
4-MeC6H4
5-Cl-2,3-(MeO)2-C6H2

HANTZSCH 1,4-DIHYDROPYRIDINES
631
1,3-diketone (4 mmol), and ammonium acetate (7 mmol) in the presence of PEG-400
(0.5 mL) under solvent-free conditions at 75 ꢀC. The reaction was completed within
3 h, and the product was obtained in excellent yields. Using the optimized reaction
conditions, we synthesized a number of polyhydroquinoline derivatives with a
variety of aromatic and heterocyclic aldehydes, and the results are summarized in
Table 3. The method has the ability to tolerate a variety of functional groups such
as chloro, bromo, methoxy, nitro, and hydroxy.
CONCLUSION
In conclusion, we have developed a simple, efficient, and catalyst-free synthesis
of Hantzsch 1,4-dihydropyridines and polyhydroquinoline derivatives in good yields
in the presence of PEG-400 under solvent-free conditions at 75 ꢀC. In this reaction,
PEG-400 act as a very efficient ‘‘green’’ promoter, and this methodology works
equally well with both low- and high-molecular-weight PEGs. Therefore, this is a
very general and environmentally benign procedure that would prove beneficial to
both academic and industrial fields.
EXPERIMENTAL
General Experimental Procedure for Hantzsch 1,4-Dihydropyridine
Formation
A mixture of an aldehyde (4 mmol), ethyl acetoacetate (7 mmol), ammonium
acetate (7 mmol), and PEG-400 (0.5 mL) was heated at 75 ꢀC for the specified time
(Table 2). The reaction mixture was monitored by thin-layer chromatography
(TLC) until the disappearance of the starting aldehyde. After cooling, the reaction
mixture was washed with water (15 mL), and the residue was recrystallized from
MeOH to afford the pure Hantzsch 1,4-dihydropyridines.
For the synthesis of polyhydroquinoline derivatives, a mixture of an aldehyde
(4 mmol), ethyl acetoacetate (4 mmol), cyclic 1,3-diketone (4 mmol), ammonium
acetate (7 mmol), and PEG-400 (0.5 mL) was heated at 75 ꢀC for the specified time
(Table 3). After completion of the reaction (TLC), the products were purified by
using the same procedure.
The data of the unknown Hantzsch 1,4-dihydropyridines (Table 2, entries 5
and 14) and polyhydroquinolines (Table 3, entries 5 and 17) are given.
Diethyl-4-(2,3-methylenedioxyphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-carboxylate (9e)
Mp: 156–158 ꢀC. FT-IR (KBr): 3345, 1705, 1645, 1528, 1487, 1216, 1123,
706 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d ¼ 1.2 (t, J ¼ 7.2 Hz, 6H), 2.2 (s, 6H),
4.03–4.13 (m, 4H), 5.1 (s, 1H), 5.88 (s, 1H), 5.89 (s, 2H) 6.59 (dd, J ¼ 7.6, 1.2 Hz),
6.71 (dd, J ¼ 7.6, 8.0 Hz), 6.76 (dd, J ¼ 8.0, 1.2 Hz). 13C NMR (22.5 MHz, CDCl3):
d ¼ 14.0, 19.1, 35.0, 59.5, 99.8, 102.1, 106.1, 120.7, 122.6, 129.6, 144.3, 144.53,
146.8, 167.6. LCMS: m=z ¼ 372 (M-H)ꢁ. Anal. Calcd. for C20H23NO6: C, 64.34;
H, 6.16; N, 3.75. Found: C, 64.30; H, 6.21; N, 3.72.

632
V. SIDDAIAH ET AL.
Diethyl-4-(2-chloro-5-nitrophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-carboxylate (9n)
Mp: 198–202 ꢀC. FT-IR (KBr): 3347, 1703, 1652, 1526, 1480, 1196, 1124,
1
716 cmꢁ1. H NMR (400 MHz, CDCl3): d ¼ 1.19 (t, J ¼ 7.0 Hz, 6H), 2.34 (s, 6H),
4.05 (q, J ¼ 7.0 Hz, 4H), 5.4 (s, 1H), 5.9 (s, 1H), 7.4 (d, J ¼ 8.8 Hz), 7.9 (dd,
J ¼ 8.8, 2.8 Hz), 8.2 (d, J ¼ 2.8 Hz). 13C NMR (22.5 MHz, CDCl3): d ¼ 13.9, 18.6,
38.0, 59.3, 101.7, 126.4, 129.7, 138.8, 145.9, 146.4, 147.7, 166.9. LCMS: m=z ¼ 393
(M-H)ꢁ. Anal. calcd. for C19H21NO6Cl: C, 57.86; H, 5.32; N, 3.55; Cl, 8.88. Found:
C, 57.82; H, 5.38; N, 3.59; Cl, 8.88.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(2,3-
methylenedioxyphenyl)-5(6H)-oxoquinolin-3-carboxylate (11e)
Mp: 265–267 ꢀC. FT-IR (KBr): 3340, 2957, 1695, 1644, 1609, 1488, 1379, 1217,
1
1027, 753 cmꢁ1. H NMR (400 MHz, CDCl3 þ DMSO-d6): d ¼ 0.95 (s, 3H), 1.07 (s,
3H), 1.208 (t, J ¼ 7.2 Hz, 3H), 2.15–2.33 (m, 4H), 2.35 (s, 3H), 4.02–4.07 (m, 2H),
5.11 (s, 1H), 5.84–5.95 (m, 3H), 6.58 (dd, J ¼ 7.6, 1.2 Hz, 1H), 6.66 (dd, J ¼ 7.6,
8.0 Hz, 1H), 6.80 (dd, J ¼ 8.0, 1.2 Hz, 1H).13C NMR (22.5 MHz, CDCl3 þ DMSO-
d6): d ¼ 14.0, 19.2, 26.5, 29.5, 32.2, 35.1, 50.2, 50.5, 59.5, 99.8, 103.8, 110.1, 113.1,
120.6, 122.6, 131.6, 144.2, 144.4, 146.8, 147.9, 166.9, 194.2. LCMS: m=z ¼ 382
(M-H)-. Anal. calcd. for C22H25NO5: C, 68.92; H, 6.52; N, 3.65; Cl, 8.08. Found:
C, 68.89; H, 6.55; N, 3.61.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(5-chloro-2,
3-dimethoxylphenyl)-5(6H)-oxoquinolin-3-carboxylate (11u)
Mp: 248–250 ꢀC. IR (KBr): 3297, 2956, 1703, 1648, 1606, 1496, 1381, 1215,
1
1031, 765 cmꢁ1. H NMR (400 MHz, CDCl3 þ DMSO-d6): d ¼ 1.00 (s, 3H), 1.068
(s, 3H), 1.214 (t, J ¼ 7.2 Hz, 3H), 2.15–2.26 (m, 4H), 2.29 (s, 3H) 3.77 (s, 3H), 3.86
(s, 3H), 4.05 (q, J ¼ 7.2 Hz, 2H), 5.11 (s, 1H), 6.0 (s, 1H), 6.5 (d, J ¼ 2.4, 1H), 6.9
(d, J ¼ 2.4, 1H). 13C NMR (22.5 MHz, CDCl3 þ DMSO-d6): d ¼ 14.5, 19.2, 26.7,
29.5, 32.1, 35.1, 49.2, 49.8, 55.2, 55.3, 59.5, 102.8, 110.1, 120.6, 126.6, 128.6, 134.6,
144.7, 145.4, 147.8, 149.9, 166.9, 194.3. LCMS: m=z ¼ 432 (M-H)-. Anal. Calcd.
for C23H28NO5Cl: C, 63.74; H, 6.46; N, 3.23; Cl, 8.08. Found: C, 63.71; H, 6.50;
N, 3.19; Cl, 8.03.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Department of
Science and Technology (DST), New Delhi.
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