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European	Journal	of	Chemistry	5	(1)	(2014)	171‐175	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.1.171‐175.943	

	
	

	

	

European	Journal	of	Chemistry	
Journal	homepage:	www.eurjchem.com	

	 	 	

One‐pot,	multicomponent	synthesis	of	symmetrical	Hantzsch		
1,4‐dihydropyridine	derivatives	using	glycerol	as	clean	and	green	solvent	

Harvinder	Singh	Sohal	a,*,	Arun	Goyal	a,	Rajeev	Sharma	b	and	Rajshree	Khare	a	

a	Department	of	Chemistry,	Maharishi	Markandeshwar	University,	Mullana‐133	207,	Haryana,	India	
b	Department	of	Chemistry,	Multani	Mal	Modi	College,	Patiala‐147	001,	Punjab,	India	

*Corresponding	author	at:	Department	of	Chemistry,	Maharishi	Markandeshwar	University,	Mullana‐133	207,	Haryana,	India.		
Tel.:	+91.988.8857705.	Fax:	+91.1731.274375.	E‐mail	address:	luckysohal.singh@gmail.com	(H.	S.	Sohal).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.5.1.171‐175.943	

Received:	05	October	2013	
Received	in	revised	form:	21	November	2013	
Accepted:	27	November	2013	
Online:	31	March	2014	

KEYWORDS	

	 Multi	component,	one	pot	synthesis	of	symmetrical	1,4‐dihydropyridine	derivatives	from	the
condensation	 of	 ethyl/methyl	 acetoacetate,	 aromatic/aliphatic	 aldehyde	 and	 ammonium
acetate	has	been	described	using	glycerol,	as	economical,	easily	available	and	environmentally
benign	 reagent.	 The	 targeted	 molecules	 were	 obtained	 in	 high	 purity	 and	 excellent	 yield
without	 use	 of	 any	 additional	 catalyst	 and	 methodology	 from	 readily	 available	 starting
materials.	

One‐pot	
Glycerol	
Aldehydes	
Catalyst	free	
1,4‐Dihydropyridine	
Hantzsch	Condensation	

	
1.	Introduction	
	

The	 chemistry	 of	 1,4‐dihydropyridines	 (1,4‐DHP’s)	 found	
birth	 in	1882	with	Hantzsch	condensation	[1].	After	Hantzsch,	
multifarious	 new	 methods	 have	 been	 nurtured	 for	 the	
synthesis	 of	 original	 molecule.	 1,4‐DHP’s	 attracted	 more	
attention,	 thanks	 to	 its	 presence	 in	 the	 coenzyme,	 diphospho	
pyridine	nucleotide	(DPNH)	[2]	and	identification	as	bio‐active	
material.	 In	 the	 present	 scenario	 many	 representatives	 have	
been	 commercialised	 such	 as	 nifedipine	 [3],	 felodipine	 [4],	
nicardipine	[5],	amlodipine	[6]	and	even	more	have	made	their	
presence	felt	 in	 the	market	 [7]	 in	 the	 treatment	of	angina	and	
hypertension.	 The	 activity	 profiles	 of	 1,4‐DHP’s	 were	 further	
expanded	as	they	were	detected	to	possess	anti‐tumor	[8],	anti‐
inflammatory	 [9],	 anticonvulsant	 activity	 [10],	 antitubercular	
activity	 [11,12]	 cerebral	 antischemic	 activity	 in	 the	 treatment	
of	Alzheimer’s	disease,	PAF‐acether	antagonists	[13].	Invention	
and	execution	of	various	new	methodologies	have	engendered	
for	 the	 synthesis	 of	 symmetrical	 1,4‐DHP’s.	 Off	 late	 many	
supported	 catalysts	 have	been	brought	 into	use	 such	 as	 silica	
supported	 12‐tungstophosphoric	 acid	 [14].	 Organo	 catalyst	
[15],	[TBA]2[W6O19]	[16],	Y(OTf)3	[17]	and	use	of	nanoparticles	
also	provided	swiftness	 and	higher	degree	of	 efficiency	 to	 the	
reaction	such	as	Silicotungstic	acid	dispersed	in	the	micropores	
if	Cr‐pillared	clay	[18],	MgO	[19]	and	cobalt	[20]	nanoparticles	

with	 the	 use	 of	 many	 instruments	 like	 microwave	 [18,19,21‐
24],	sonicator	[25]	turn	out	to	exemplify.	The	above	mentioned	
protocols	 have	 advantages	 over	 one	 another	 as	 they	 improve	
the	Hantzsch	condensation	in	terms	of	reaction	time	and	yield	
[24].	However,	the	use	of	expensive	catalysts	and	solvents	does	
not	allow	the	process	to	stay	within	the	peripheries	of	a	limited	
budget.	In	addition	to	this	considering	environmental	and	time	
perspective	 the	 process	 of	 combining	 solvent	 and	 catalysts	
cannot	be	believed	 to	be	undoubtly	beneficial,	 the	recovery	of	
catalysts	requiring	a	lot	of	solvent,	time	and	purification	based	
upon	special	methods	could	be	termed	as	potent	reasons.	In	the	
recent	 past	 reactions	 mediated	 with	 glycerol	 astonishing	
attention	as	 glycerol	 is	 a	 solvent	which	 is	easily	available	and	
costs	virtually	nothing.	In	addition	to	this	it	does	not	distort	the	
environmental	processes.	Not	a	long	time	ago,	it	was	found	that	
glycerol	 has	been	used	 for	Heck	 and	 Suzuki	 coupling	 [26‐28],	
Michael	addition	[29],	Fridel‐Crafts	type	addition,	epoxide	ring	
opening	[30],	synthesis	of	xanthenes	[31]	and	very	recently	for	
the	 production	 of	 benzodiazepines	 and	 octahydroacridines	
[32,33].	Understanding	the	magnanimity	of	both	1,4‐DHP’s	and	
glycerol,	a	new	clean	and	green	protocol	has	been	discussed.	In	
this	 effort,	 we	 synthesize	 1,4‐DHP’s	 using	 glycerol	 as	 green	
solvent	 without	 amalgamatingany	 catalyst	 (Scheme	 1).	 The	
present	 protocol	 is	 found	 to	 be	 much	 efficient	 over	 other	
procedure.		



172	 Sohal	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	171‐175	
	
	
Table	1.	Effect	of	temperature	on	the	synthesis	of	compounds	4a.	
S.	No.	 Compound	 Temperature	(oC)	 Time	(minutes)	 Yield	a	(%)	
1	 4a	 70	 110 78	
2	 4a	 80	 85 83	
3	 4a	 90	 75	 94	
4	 4a	 100	 74	 94	
5	 4a	 110	 74	 93	
a	Yield	refer	to	combined	amounts	of	different	crops.	
	
	

	
	

Scheme	1
	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

Materials	 were	 obtained	 from	 commercial	 suppliers	 and	
were	 used	without	 further	 purifications.	 Melting	 points	 were	
recorded	in	open	end	capillaries	and	are	uncorrected.	1H	NMR	
spectra	were	recorded	 in	DMSO‐d6	on	a	Bruker	Avance	 II	400	
MHz	spectrometer;	chemical	shifts	(delta)	are	reported	in	ppm	
relative	to	TMS	as	internal	standard.	The	mass	spectrum	and	IR	
spectra	 were	 recorded	 at	 LC‐MS	 Spectrometer	 Model	 Q‐ToF	
Micro	 Waters	 and	 Perkin‐Elmer	 Spectrum	 II	 infra‐red	
spectrophotometer,	respectively.	Elemental	analyses	(C,	H,	and	
N)	 were	 performed	 using	 a	 Thermo	 Scientific	 elemental	
analyser.	
	
2.2.	Synthesis	

	
2.2.1.	Synthesis	of	diethyl	2,6‐dimethyl‐1,4‐dihydropyridine‐
3,5‐dicarboxylate	
	

In	 a	 conical	 flask	 benzaldehyde	 (0.01	 mol),	 ethyl	
acetoacetate	 (0.02	 mol)	 and	 ammonium	 acetate	 (0.02	 mol)	
were	taken	in	a	pre‐heated	glycerol	(10	mL)	and	stirred	at	90	
oC	 for	 the	 stipulated	 time	 Table	 1.	 After	 the	 completion	 of	
reaction	 (vide	 TLC),	 reaction	 mixture	 was	 cooled	 to	 room	
temperature	and	added	50	mL	 ice‐cold	water,	 solid	 separated	
out.	 Filtered	 and	 dried,	 recrystallized	 from	 ethanol	 to	 afford	
compound	4a,	94%	yield,	m.p.:	159‐160	oC	 (Entry	1,	Table	2).	
Similarly,	 other	 aldehydes	 2b‐k	 were	 reacted	 with	
ethyl/methyl	 acetoacetate	 and	 ammonium	 acetate	 to	 afford	
various	1,4‐dihydropyridines	derivatives	4b‐q	and	5a‐k	(Table	
2).	Data	obtained	using	advanced	spectral	techniques	for	some	
selected	compounds	have	been	summarized.	

Diethyl	 2,6‐dimethyl‐4‐phenyl‐1,4‐dihydropyridine‐3,5‐
dicarboxylate	(4a):	Yield:	94%.	M.p.:	159‐160	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3340	(N‐H	Str.),	 1695	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	 δ,	ppm):	1.21	 (t,	 6H,	2	x	CH3),	 2.36	 (s,	 6H,	2	x	CH3),	
4.11	(q,	4H,	2	x	CH2CH3),	4.98	(s,	1H,	C‐H),	6.01	(br	s,	1H,	N‐H),	
7.16‐7.33	(m,	5H,	Ar‐H).	MS	(EI,	m/z,	(%)):	330	(M+,	24).	Anal.	
calcd.	for	C19H23NO4:	C,	69.28;	H,	7.04;	N,	4.25.	Found:	C,	69.25;	
H,	7.00;	N,	4.24%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐methoxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4c):	 Yield:	 93%.	M.	 p.:	 158‐160	 oC.	
FT‐IR	(KBr,	ν,	cm‐1):3327	(N‐H	Str.),	1699	(C=O	Str.).	1H	NMR	
(400	MHz,	DMSO‐d6,	δ,	ppm):	1.23	(t,	6H,	2	x	CH3),	2.32	(s,	6H,	2	
x	CH3),	3.57	(s,	3H,	OCH3),	4.15	(q,	4H,	2	x	CH2CH3),	4.95	(s,	1H,	
C‐H),	6.11	(br	s,	1H,	N‐H),	7.01‐7.22	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	

(%)):	360	(M+,	25).	Anal.	calcd.	for	C20H25NO5:	C,	66.83;	H,	7.01;	
N,	3.90.	Found:	C,	66.81;	H,	6.99;	N,	3.89%.	

Diethyl	2,6‐dimethyl‐4‐(3,4‐dimethoxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4d):	 Yield:	 95%.	 M.p.:	 148‐150	 oC.	
FT‐IR	(KBr,	ν,	cm‐1):	3341(N‐H	Str.),	1689	(C=O	Str.).	1H	NMR	
(400	MHz,	DMSO‐d6,	δ,	ppm):	1.24	(t,	6H,	2	x	CH3),	2.31	(s,	6H,	2	
x	CH3),	3.79	(s,	3H,	OCH3),	3.85	(s,	3H,	OCH3)	 ,	4.12	(q,	4H,	2	x	
CH2CH3),	 4.90	 (s,	 1H,	C‐H),	5.80	 (br	 s,	 1H,	N‐H),	6.73‐6.89	 (m,	
3H,	 Ar‐H).	 MS	 (EI,	 m/z,	 (%)):	 390	 (M+,	 25).	 Anal.	 calcd.	 for	
C21H27NO6:	C,	64.77;	H,	6.99;	N,	3.60.	Found:	C,	64.75;	H,	6.97;	N,	
3.58%.	

Diethyl	 2,6‐dimethyl‐4‐(3,4,5‐trimethoxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4e):	 Yield:	 91%.	 M.p.:	 184‐186	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3356	 (N‐H	 Str.),	 1704	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	1.21	(t,	6H,	2	x	CH3),	2.30	(s,	
6H,	2	x	CH3),	3.78	(s,	3H,	OCH3),	3.82	(s,	6H,	2	x	OCH3)	4.11	(q,	
4H,	2	x	CH2CH3),	4.93	(s,	1H,	C‐H),	5.91	(br	s,	1H,	N‐H),	6.52	(s,	
2H,	 Ar‐H).	 MS	 (EI,	 m/z,	 (%)):	 420	 (M+,	 26).	 Anal.	 Calcd.	 for	
C22H29NO7:	C,	62.99;	H,	6.97;	N,	3.34.	Found:	C,	62.96;	H,	6.94;	N,	
3.31%.	

Diethyl	 2,6‐dimethyl‐4‐(3‐nitrophenyl)‐1,4‐dihydropyridine‐
3,5‐dicarboxylate	 (4g):	 	 Yield:	 93%.	 M.p.:	 155‐166	 oC.	 FT‐IR	
(KBr,	ν,	cm‐1):	3343	(N‐H	Str.),	1703	(C=O	Str.).	1H	NMR	(400	
MHz,	DMSO‐d6,	 δ,	 ppm):	1.25	 (t,	 6H,	2	x	CH3),	 2.36	 (s,	 6H,	 2	x	
CH3),	4.11	(q,	4H,	2	x	CH2CH3),	5.01	(s,	1H,	C‐H),	6.08	(br	s,	1H,	
N‐H),	7.10‐7.57	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	375	(M+,	26).	
Anal.	calcd.	for	C19H22N2O6:	C,	60.95;	H,	5.92;	N,	7.48.	Found:	C,	
60.93;	H,	5.90;	N,	7.47%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐nitrophenyl)‐1,4‐dihydropyridine‐
3,5‐dicarboxylate	 (4h):	 Yield:	 92%.	 M.p.:	 159‐160	 oC.	 FT‐IR	
(KBr,	ν,	cm‐1):	3350	(N‐H	Str.),	1699	(C=O	Str.).	1H	NMR	(400	
MHz,	DMSO‐d6,	 δ,	 ppm):1.27	 (t,	 6H,	 2	 x	 CH3),	 2.33	 (s,	 6H,	 2	 x	
CH3),	4.13	(q,	4H,	2	x	CH2CH3),	5.09	(s,	1H,	C‐H),	6.09	(br	s,	1H,	
N‐H),	7.16‐7.44	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	375	(M+,	25).	
Anal.	calcd.	for	C19H22N2O6:	C,	60.95;	H,	5.92;	N,	7.48.	Found:	C,	
60.92;	H,	5.91;	N,	7.44%.	

Diethyl	2,6‐dimethyl‐4‐(3‐chlorophenyl)‐1,4‐dihydropyridine‐
3,5‐dicarboxylate	(4i):	Yield:	90%.	M.p.:	138‐139	oC.	FT‐IR	(KBr,	
ν,	cm‐1):	3339	ν(N‐H	Str.),	1699	ν(C=O	Str.).	1H	NMR	(400	MHz,	
DMSO‐d6,	 δ,	 ppm):1.19	 (t,	 6H,	 2	 x	 CH3),	 2.31	 (s,	 6H,	 2	 x	 CH3),	
4.07	(q,	4H,	2	x	CH2CH3),	5.08	(s,	1H,	C‐H),	5.97	(br	s,	1H,	N‐H),	
7.29‐7.58	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	364	(M+,	23).	Anal.	
calcd.	 for	 C19H22ClNO4:	 C,	 62.72;	 H,	 6.09;	 N,	 3.85.	 Found:	 C,	
62.71;	H,	6.05;	N,	3.84%.	

Diethyl	2,6‐dimethyl‐4‐(4‐chlorophenyl)‐1,4‐dihydropyridine‐
3,5‐dicarboxylate	 (4j):	 Yield:	 93%.	M.p.:	 147	 oC.	 FT‐IR	 (KBr,	 ν,	
cm‐1):	3332	(N‐H	Str.),	1693	(C=O	Str.).		

	
	



Sohal	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	171‐175	 173	
 

	
Table	2.	Synthesis	of	symmetrical	1,4‐dihydropyridine	derivative.	
S.	No.	 Product	a	 R	 R1	 R2	 Yield	b	(%)	 Melting	point	(oC)	 Lit.	melting	point	(oC)	 Reference	
1	 4a	

	

C2H5	 C2H5	 94	 159‐160	 158‐160	 [37]	

2	 4b	

	

C2H5	 C2H5	 91	 139‐141	 138‐143	 [35]	

3	 4c	

	

C2H5	 C2H5	 93	 158‐160	 158‐160	 [37]	

4	 4d	

	

C2H5	 C2H5	 95	 148‐150	 147	 [38]	

5	 4e	

	

C2H5	 C2H5	 91	 184‐186	 182‐84	 [38]	

6	 4f	

	

C2H5	 C2H5	 85	 120‐123	 118	 [38]	

7	 4g	

	

C2H5	 C2H5	 93	 165‐166	 163	 [37]	

8	 4h	
O2N

	

C2H5	 C2H5	 92	 134‐135	 136	 [37]	

9	 4i	

	

C2H5	 C2H5	 90	 138‐139	 140‐142	 [37]	

10	 4j	

	

C2H5	 C2H5	 93	 147	 144‐146	 [37]	

11	 4k	

	

C2H5	 C2H5	 87	 181‐183	 180‐182	 [34]	

12	 4l	

	

C2H5	 C2H5	 89	 230‐231	 228‐230	 [34]	

13	 4m	

	

C2H5	 C2H5	 92	 155‐156	 160‐162	 [37]	

14	 4n	

	

C2H5	 C2H5	 91	 138‐139	 135‐137	 [36]	

15	 4o	

	

C2H5	 C2H5	 88	 162‐165	 160‐161	 [37]	

16	 4p	

	

C2H5	 C2H5	 89	 173‐175	 171‐173	 [37]	

17	 4q	

	

C2H5	 C2H5	 85	 137‐139	 136‐138	 [38]	

18	 4r	 	 C2H5	 C2H5	 94	 181‐182	 183	 [39]	
19	 4s	 	 C2H5	 C2H5	 89	 132‐133	 130‐131	 [36]	

20	 5a	

	

CH3	 CH3	 92	 199‐200	 197‐98	 [40]	

21	 5b	

	

CH3	 CH3	 87	 172‐174	 171‐172	 [40]	

22	 5c	

	

CH3	 CH3	 90	 157‐159	 155‐58	 [40]	

23	 5d	
O2N

	

CH3	 CH3	 93	 152‐153	 152‐154	 [40]	

24	 5e	

	

CH3	 CH3	 91	 191‐193	 195‐96	 [40]	

25	 5f	

	

CH3	 CH3	 89	 200‐201	 198‐199	 [40]	

26	 5g	

	

CH3	 CH3	 88	 172‐175	 173‐174	 [40]	

27	 5h	

	

CH3	 CH3	 90	 177‐180	 175‐176	 [40]	

28	 5i	

	

CH3	 CH3	 84	 147‐149	 148‐150	 [40]	

29	 5j	 	 CH3	 CH3	 85	 220‐222	 224‐25	 [40]	
a	Products	were	characterized	with	spectral	techniques	and	compared	with	authentic	samples.	
b	Yield	refer	to	combined	amounts	of	different	crops.	
	
	

	
	 	



174	 Sohal	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	171‐175	
	

1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	1.23	(t,	6H,	2	x	CH3),	
2.36	(s,	6H,	2	x	CH3),	4.13	(q,	4H,	2	x	CH2CH3),	5.11	(s,	1H,	C‐H),	
5.99	(br	s,	1H,	N‐H),	7.30‐7.57	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	
364	(M+,	24).	Anal.	calcd.	for	C19H22ClNO4:	C,	62.72;	H,	6.09;	N,	
3.85.	Found:	C,	62.71;	H,	6.08;	N,	3.82%.	

Diethyl	 2,6‐dimethyl‐4‐(3‐hydroxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4k):	 Yield:	 87%.	 M.p.:	 181‐183	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3430	(O‐H	Str.),	 3331	(N‐H	Str.),	 1690	
(C=O	Str.).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	1.27	(t,	6H,	2	
x	CH3),	2.21	(s,	6H,	2	x	CH3),	4.10	(q,	4H,	2	x	CH2CH3),	4.99	(s,	
1H,	C‐H),	5.98	(br	s,	1H,	N‐H),	7.10‐7.34	(m,	4H,	Ar‐H),	9.79	(br,	
s,	 1H,	 O‐H).	 MS	 (EI,	m/z,	 (%)):	 346	 (M+,	 19).	 Anal.	 calcd.	 for	
C19H23NO5:	C,	66.07;	H,	6.71;	N,	4.06.	Found:	C,	66.06;	H,	6.68;	N,	
4.03%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐hydroxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4l):	 Yield:	 89%.	 M.p.:	 181‐183	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3447	(O‐H	Str.),	 3338	(N‐H	Str.),	 1701	
(C=O	Str.).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):1.19	(t,	6H,	2	
x	CH3),	2.30	(s,	6H,	2	x	CH3),	4.07	(q,	4H,	2	x	CH2CH3),	5.01	(s,	
1H,	C‐H),	6.08	(br	s,	1H,	N‐H),	7.18‐7.54	(m,	4H,	Ar‐H),	9.81	(br,	
s,	 1H,	 O‐H).	 MS	 (EI,	m/z,	 (%)):	 346	 (M+,	 21).	 Anal.	 calcd.	 for	
C19H23NO5:	C,	66.07;	H,	6.71;	N,	4.06.	Found:	C,	66.02;	H,	6.71;	N,	
4.04%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐bromophenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4m):	 Yield:	 92%.	M.p.:	 155‐156	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3336	 (N‐H	 Str.),	 1703	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):1.21	(t,	6H,	2	x	CH3),	2.29	(s,	
6H,	2	x	CH3),	4.09	(q,	4H,	2	x	CH2CH3),	5.03	(s,	1H,	C‐H),	6.07	(br	
s,	1H,	N‐H),	7.13‐7.51	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	409	(M+,	
25).	 Anal.	 calcd.	 for	 C19H22BrNO4:	 C,	 55.89;	 H,	 5.43;	 N,	 3.43.	
Found:	C,	55.88;	H,	5.41;	N,	3.39%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐methylphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4n):	 Yield:	 91%.	 M.p.:	 138‐139	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3329	 (N‐H	 Str.),	 1695	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	1.20	(t,	6H,	2	x	CH3),	2.19	(s,	
3H,	CH3),	2.21	(s,	6H,	2	x	CH3),	4.03	(q,	4H,	2	x	CH2CH3),	5.07	(s,	
1H,	C‐H),	5.98	(br	s,	1H,	N‐H),	7.15‐7.53	(m,	4H,	Ar‐H).	MS	(EI,	
m/z,	(%)):	343	(M+,	20).	Anal.	calcd.	for	C20H25NO4:	C,	69.95;	H,	
7.34;	N,	4.08.	Found:	C,	69.88;	H,	7.31;	N,	4.02%.	

Diethyl	 2,6‐dimethyl‐4‐(2‐furyl)‐1,4‐dihydropyridine‐3,5‐
dicarboxylate	(4o):	Yield:	88%.	M.p.:	162‐165	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3335	(N‐H	Str.),	 1701	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	 δ,	 ppm):1.27	 (t,	 6H,	 2	 x	 CH3),	 2.31	 (s,	 6H,	 2	 x	 CH3),	
4.17	(q,	4H,	2	x	CH2CH3),	4.99	(s,	1H,	C‐H),	6.07	(br	s,	1H,	N‐H),	
6.33‐6.42	(m,	2H,	Furyl‐H),	7.17	(m,	1H,	Furyl‐H).	MS	(EI,	m/z,	
(%)):	320	(M+,	16).	Anal.	calcd.	for	C17H21NO5:	C,	63.94;	H,	6.63;	
N,	4.39.	Found:	C,	63.92;	H,	6.62;	N,	4.37%.	

Diethyl	 2,6‐dimethyl‐4‐(2‐theniyl)‐1,4‐dihydropyridine‐3,5‐
dicarboxylate	(4p):	Yield:	89%.	M.p.:	173‐175	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3345	(N‐H	Str.),	 1699	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	 δ,	ppm):	1.17	 (t,	 6H,	2	x	CH3),	 2.30	 (s,	 6H,	2	x	CH3),	
4.06	(q,	4H,	2	x	CH2CH3),	5.01	(s,	1H,	C‐H),	6.06	(br	s,	1H,	N‐H),	
6.09‐6.14	 (m,	2H,	Thienyl‐H),	6.89	 (m,	1H,	Thienyl‐H).	MS	 (EI,	
m/z,	(%)):	336	(M+,	18).	Anal.	calcd.	for	C17H21NO4S:	C,	60.87;	H,	
6.31;	N,	4.18.	Found:	C,	60.85;	H,	6.29;	N,	4.17%.	

Diethyl	 2,6‐dimethyl‐4‐(4‐formylphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (4q):	 Yield:	 85%.	 M.p.:	 137‐139	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3349	 (N‐H	 Str.),	 1706	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	1.19	(t,	6H,	2	x	CH3),	2.32	(s,	
6H,	2	x	CH3),	4.07	(q,	4H,	2	x	CH2CH3),	5.02	(s,	1H,	C‐H),	5.96	(br	
s,	1H,	N‐H),	7.49‐7.80	(m,	4H,	Ar‐H),	8.92	(s,	1H,	CHO).	MS	(EI,	
m/z,	(%)):	358	(M+,	23).	Anal.	calcd.	for	C20H23NO5:	C,	67.21;	H,	
6.49;	N,	3.92.	Found:	C,	67.20;	H,	6.47;	N,	3.89%.	

Dimethyl	 2,6‐dimethyl‐4‐phenyl‐1,4‐dihydropyridine‐3,5‐
dicarboxylate	(5a):	Yield:	92%.	M.p.:	199‐200	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3320	(N‐H	Str.),	 1690	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	 δ,	ppm):	2.25	 (s,	6H,	2	x	CH3),	3.68	 (s,	6H,	2	 x	CH3),	
4.99	(s,	1H,	C‐H),	6.04	(br	s,	1H,	N‐H),	6.94‐7.34	(m,	5H,	Ar‐H).	
MS	 (EI,	m/z,	 (%)):	 302	 (M+,	25).	Anal.	 calcd.	 for	C17H19NO4:	C,	
67.76;	H,	6.36;	N,	4.65.	Found:	C,	67.72;	H,	6.34;	N,	4.65%.	

Dimethyl	 2,6‐dimethyl‐4‐(4‐nitrophenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (5d):	 Yield:	 93%.	 M.p.:	 152‐153	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3342	 (N‐H	 Str.),	 1707	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.28	(s,	6H,	2	x	CH3),	3.74	(s,	
6H,	2	x	CH3),	5.03	 (s,	1H,	C‐H),	6.07	 (br	s,	1H,	N‐H),	7.12‐7.51	
(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	347	(M+,	24).	Anal.	calcd.	for	
C17H18N2O6:	C,	58.96;	H,	5.24;	N,	8.09.	Found:	C,	58.94;	H,	5.22;	
N,	8.08%.	

Dimethyl	 2,6‐dimethyl‐4‐(4‐chlorophenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (5e):	 Yield:	 91%.	 M.p.:	 191‐193	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3317	 (N‐H	 Str.),	 1700	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.26	(s,	6H,	2	x	CH3),	3.70	(s,	
6H,	2	x	CH3),	5.02	 (s,	1H,	C‐H),	6.01	 (br	s,	1H,	N‐H),	7.01‐7.37	
(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	336	(M+,	25).	Anal.	calcd.	for	
C17H18ClNO4:	C,	60.81;	H,	5.40;	N,	4.17.	Found:	C,	60.79;	H,	5.35;	
N,	4.15%.	

Dimethyl	 2,6‐dimethyl‐4‐(4‐methoxyphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	(5g):	M.p.:	172‐175	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3295	(N‐H	Str.),	 1691	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	δ,	ppm):	2.23	(s,	6H,	2	x	CH3),	3.68	(s,	6H,	2	x	OCH3),	
3.92	(s,	3H,	OCH3),	4.97	(s,	1H,	C‐H),	5.94	(br	s,	1H,	N‐H),	6.89‐
7.25	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	332	(M+,	24).	Anal.	calcd.	
for	 C18H21NO5:	 C,	 65.24;	 H,	 6.39;	 N,	 4.23.	 Found:	 C,	 65.22;	 H,	
6.38;	N,	4.20%.	

Dimethyl	 2,6‐dimethyl‐4‐(4‐methylphenyl)‐1,4‐dihydro	
pyridine‐3,5‐dicarboxylate	 (5h):	 Yield:	 90%.	 M.p.:	 177‐180	 oC.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3312	 (N‐H	 Str.),	 1689	 (C=O	 Str.).	 1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.18	(s,	3H,	CH3)2.24	(s,	6H,	
2	x	CH3),	3.66	(s,	6H,	2	x	CH3),	4.96	(s,	1H,	C‐H),	5.92	(br	s,	1H,	
N‐H),	6.90‐7.31	(m,	4H,	Ar‐H).	MS	(EI,	m/z,	(%)):	316	(M+,	23).	
Anal.	calcd.	 for	C18H21NO4:	C,	68.55;	H,	6.71;	N,	4.44.	Found:	C,	
68.54;	H,	6.69;	N,	4.41%.	

Dimethyl	 2,6‐dimethyl‐4‐(2‐furyl)‐1,4‐dihydropyridine‐3,5‐
dicarboxylate	(5i):	Yield:	84%.	M.p.:	147‐149	oC.	FT‐IR	(KBr,	ν,	
cm‐1):	 3317	(N‐H	Str.),	 1700	(C=O	Str.).	 1H	NMR	 (400	MHz,	
DMSO‐d6,	 δ,	ppm):	2.20	 (s,	6H,	2	x	CH3),	3.65	 (s,	6H,	2	x	CH3),	
4.98	(s,	1H,	C‐H),	6.05	(br	s,	1H,	N‐H),	6.33‐6.45	(m,	2H,	Furyl‐
H),	7.22	(m,	1H,	Furyl‐H).	MS	(EI,	m/z,	(%)):	292	(M+,	18).	Anal.	
calcd.	for	C15H17NO5:	C,	61.85;	H,	5.88;	N,	4.81.	Found:	C,	61.82;	
H,	5.87;	N,	4.78%.	
	
3.	Results	and	discussion	
	

Condensation	 of	 ethylacetoacetate	 (1),	 benzaldehyde	 (2a)	
and	 ammonium	 acetate	 (3)	 were	 carried	 out	 in	 glycerol	 at	
different	temperatures	(70‐110	oC).	It	was	observed	that	90	oC	
is	 the	 optimal	 temperature	 for	 the	 synthesis	 of	 1,4‐
dihydropyridines.	Further	rise	in	temperature	had	a	negligible	
impact	on	rate	and	yield	of	the	reaction	(Table	1)	

The	structure	of	the	compound	4a	was	confirmed	with	the	
use	of	spectral	 techniques.	 In	 IR	spectrum	absorption	at	3340	
cm‐1	represents	the	N‐H	stretching,	a	strong	absorption	for	C=O	
groups	was	observed	at	1695	cm‐1.	In	1H	NMR	spectra	peaks	for	
five	aromatic	protons	are	observed	at	δ	7.16‐7.33	ppm,	singlet	
at	 δ	 4.98	 ppm	 for	 ‐CH	 proton,	 singlet	 at	 δ	 6.01	 ppm	 for	 ‐NH	
proton	 and	 a	 singlet	 for	 two	 ‐CH3groups	 observed	 at	 δ	 2.36	
ppm,	a	triplet	for	two	‐CH3groups	observed	at	δ1.21	ppm	and	a	
quartet	 for	 two	 ‐CH2	 groups	 was	 observed	 at	 δ	 4.11	 ppm.	
Spectral	 data	 of	 compound	 4a	 fully	 supports	 the	 structure	
assigned	 to	 it.	 Similarly,	 other	 dialkyl‐2,6‐dimethyl‐4‐aryl‐1,4‐
dihydropyridine‐3,5‐dicarboxylate	 4b‐p	 and	 5a‐k	 have	 been	
synthesized	by	 the	 condensation	of	 ethyl/methyl	 acetoacetate	
(1),	 aldehyde	 (2)	 and	 ammonium	 acetate	 (3)	 in	 glycerol.	 The	
results	are	summarized	in	Table	2.	

In	 the	 proposed	 mechanism,	 for	 the	 synthesis	 of	
dihydropyridines	 follow	 the	addition	of	compound	1	 and	3	 to	
give	compound	6	by	the	removal	of	an	acetic	acid	molecule	and	
at	 the	 same	 time	 Knoevenagal	 condensation	 between	
compounds	1	 and	2	 to	give	compound	7,	which	upon	Michael	
addition	with	compound	6	produce	compound	8	them	followed		



Sohal	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	171‐175	 175	
 

	

	
	

Scheme	2	
	
	
by	cyclization	to	produce	9	and	rearrange	to	yield	the	1,4‐DHP	
molecule	(4a‐s	and	5a‐j)	(Scheme	2).	

Reactions	 proceeded	 smoothly	 with	 aldehydes	 carrying	
electron	withdrawing	as	well	as	electron	donating	substituents	
(Table	 2).	 This	 method	 endures	 various	 functionalities	 like	
nitro,	 ether,	 halogen	 etc.	 on	 the	 aldehydes.	 Efficacy	 of	 this	
method	 is	 fairly	 general	 and	 affords	 the	 resultant	products	 in	
excellent	yield	(85‐95%)	and	products	are	obtained	by	simple	
work	up.	
	
4.	Conclusion	
	

The	 present	 procedure	 is	 an	 effective	 method	 for	
production	 of	 tetra	 substituted	 1,4‐dihydropyridine	 from	
readily	 available	 starting	 materials	 in	 a	 single	 step	 with	
inherent	 flexibility	 and	diversity.	 This	method	was	 efficacious	
to	 reduce	 labor,	 cost,	 waste	 production	 and	 also	 devoid	 of	
harsh	 reaction	 conditions.	 The	 target	 compounds	 were	
obtained	in	an	acceptable	yield	with	simple	recrystallization	as	
a	purification	step.	
	
Acknowledgements	

	
The	 authors	 thank	 Maharishi	 Markandeshwar	 University,	

Mullana,	Ambala,	India	for	the	financial	support	and	Harvinder	
Singh	Sohal	and	Arun	Goyal	also	thank	Mr.	Vikas	Pahwa	for	the	
liberal	support.	
	
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