untitled


European	Journal	of	Chemistry	5	(3)	(2014)	541‐544	

	

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.5.3.541‐544.1049	

	
	

	

	

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

	 	 	

Aqueous	phase	synthesis	of	polysubstituted	pyrimidines/pyrrolidines	
catalyzed	by	β‐cyclodextrin	

Jilla	Shankar,	Gaddam	Satish,	Katla	Ramesh	and	Nageswar	Yadavalli	Venkata	Durga	*	

Council	of	Scientific	and	Industrial	Research‐Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	Uppal	Road,												
Hyderabad	500‐007,	India	

*Corresponding	author	at:	Council	of	Scientific	and	Industrial	Research‐Medicinal	Chemistry	and	Pharmacology	Division,	Indian	Institute	of	Chemical	Technology,	
Uppal	Road,	Hyderabad	500‐007,	India.		
Tel.:	+91.040.27191654.	Fax:	+91.040.27193189.	E‐mail	address:	dryvdnageswar@gmail.com	(N.Y.V.	Durga).	

	
	

	 	

	 	 	
COMMUNICATION	INFORMATION	 	 ABSTRACT	

	
DOI:	10.5155/eurjchem.5.3.541‐544.1049	

Received:	13	March	2014	
Received	in	revised	form:	16	April	2014	
Accepted:	22	April	2014	
Online:	30	September	2014	

KEYWORDS	

	 Highly	 substituted	pyrimidine/pyrrolidine	derivatives	were	synthesized	 for	 the	 first	 time	 in
water	 under	 neutral	 conditions	 by	 the	 reaction	 of	 aromatic	 amines,	 dimethyl/diethyl
acetylene	 dicarboxylates,	 formaldehyde	 mediated	 by	 β‐cyclodextrin	 (β‐CD)	 in	 good	 to
excellent	 yields.	 β‐Cyclodextrin	 can	 be	 recovered	 and	 reused	 without	 any	 loss	 of	 catalytic
activity.	 The	 β‐Cyclodextrins	 employed	 were	 inexpensive	 and	 readily	 available	 when
compared	to	other	types	of	cyclodextrins	(α,	γ).	

Amines	
Formaldehyde	
β‐Cyclodextrin	
Pyrimidine	derivatives	
Pyrrolidine	derivatives	
Dimethyl/diethyl	acetylene	dicarboxylates	

	
1.	Introduction	
	

Pyrimidine	 derivatives	 are	 versatile	 building	 blocks	 in	
synthetic	organic	 chemistry	and	many	bioactive	molecules	 [1‐
4]	with	pyrimidine	skeleton	served	as	M1	muscarinic	receptor	
agonists	 for	 the	 treatment	 of	 Alzheimer’s	 disease	 [5,6]	 and	
human	 immune	deficiency	virus	 (HIV)	protease	 inhibitors	 [7].	
Pyrimidine	 moiety	 is	 an	 important	 class	 of	 N‐containing	
heterocyclic	 system	 [8,9],	 which	 exhibits	 wide	 spectrum	 of	
biological	 activities	 such	 as	 bactericidal	 [10],	 fungicidal	 [11],	
analgesic	 [12],	 anti‐hypertensive	 [13],	 antimicrobial	 [14]	 and	
anti‐infective	 properties	 [15].	 Research	 in	 potential	 poly‐
substituted	 pyrimidines	 prompted	 for	 the	 development	 of	 a	
variety	of	synthetic	strategies.	Vishwakarma	et.	al.	reported	the	
synthesis	 of	 poly‐substituted	 1,2,3,4‐tetrahydropyrimidines	
[16].	 Das	 et.	 al.	 reported	 the	 synthesis	 of	 poly	 substituted	
pyrrolidines	and	tetra‐hydropyrimidines	involving	indium	as	a	
catalyst	in	aqueous	medium	[17].	Zhu	et.	al.	described	a	one‐pot	
synthesis	 of	 poly‐substituted	 tetrahydropyrimidines	 via	 the	
proton‐promoted	MCRs	[18].	

In	 view	 of	 different	 biological	 activities	 associated	 with	
pyrimidine/pyrrolidine	derivatives	 and	 in	 continuation	of	 our	
interest	 in	 the	 use	 of	 cyclodextrins	 as	 mild	 and	 efficient	
biomimetic	 catalysts	 in	 promoting	 various	 organic	

transformations	 [19‐27],	 we	 here	 in	 report	 the	 synthesis	 of	
poly‐substituted	 tetra‐hydropyrimidine/pyrrolidine	 deriva‐
tives	 by	 the	 reaction	 of	 substituted	 anilines	 with	 but‐2‐
ynedioates	 and	 formaldehyde	 under	 neutral	 conditions	
involving	β‐cyclodextrin	in	water	medium.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

All	 chemicals	 were	 purchased	 from	 Fluka	 and	 S.	 D.	 Fine	
Chemicals	 and	 directly	 used	 for	 the	 synthesis.	 All	 reactions	
were	 carried	 out	 without	 any	 special	 precautions	 in	 an	
atmosphere	 of	 air.	 Analytical	 Thin	 Layer	 Chromatography	
(TLC)	 was	 carried	 out	 by	 using	 silica	 gel	 60F254	 pre‐coated	
plates.	 Visualization	 was	 accomplished	 with	 UV	 lamp	 or	 I2	
staining.	Melting	point	was	obtained	by	Fischer‐Johns	melting‐
point	 apparatus	 and	 uncorrected.	 All	 products	 were	
characterized	 by	 their	 NMR	 and	Mass	 spectra.	 1H	 NMR	were	
recorded	 on	 200	 MHz,	 in	 CDCl3	 using	 TMS	 as	 the	 internal	
standard	and	chemical	shifts	were	reported	in	parts	per	million	
(ppm,	 δ)	 downfield	 from	 the	 tetramethylsilane.	 NMR	 Spectra:	
Varian	 200	 spectrometer;	 in	 CDCl3;	 δ	 in	 ppm,	 J	 in	 Hz.	 Mass	
spectra:	VG	Autospec;	 in	m/z.	 IR	were	 recorded	 on	 a	 Thermo	
Nicolet	Nexus	670	FT‐IR	spectrometer.	



542	 Shankar	et	al.	/	European	Journal	of	Chemistry	5	(3)	(2014)	541‐544	
	
	
Table	1.	β‐CD	catalysed	synthesis	of	polysubstituted	pyrrolidines	a.	
Entry	 R	 R1	 Product	 Time	(h)	 Yield	(%)	b	
1	 4‐CF3‐C6H4	 CH3	 4a 4.5 75	
2	 4‐OH‐C6H4	 CH3	 4b 4.5 75	
3	 4‐CH3‐C6H4	 CH3	 4c	 4.5	 70	
4	 C6H5	 CH2‐CH3	 4d	 4.5	 75	
5	 3‐CH3‐C6H4	 CH2‐CH3	 4e	 4.5	 68	
a	Reaction	conditions:	Amine	(1.0	mmol),	DMAD/DEAD	(1.0	mmol),	Formaldehyde	(4.0	mmol),	β‐Cyclodextrin	(10	mol	%),	60	°C.	
b	Isolated	yield.	
	
	

COOR1

COOR1

2

O

HH
NH2R

-CD/H2O

60 oC

N
O

O
R1OOC

R1O

R1 3

Molar ratio of the reactants: 1:1:4

R= -C6H5, 4-CH3C6H4, 4-HOC6H4, 4-CF3C6H4, 3-CH3C6H4

R1= -CH3, -C2H5

68-75%

4

	
	

Scheme	1
	
	
2.2.	Synthesis	
	
2.2.1.	General	procedure	for	the	synthesis	of	poly‐
substituted	pyrrolidines	
	

β‐Cyclodextrin	 (1.135	 g,	 1	 mmol)	 was	 dissolved	 in	 water	
(15	 mL)	 by	 warming	 up	 to	 60	 °C	 until	 a	 clear	 solution	 was	
formed.	 To	 this	 clear	 solution,	 aniline	 (1.0	mmol)	 was	 added	
and	 stirred	 for	 10	 min,	 and	 then	 dimethylacetylene	
dicarboxylate	 (1.0	mmol)	was	added.	After	stirring	 for	half	an	
hour	4	equivalents	of	formaldehyde	(4.0	mmol)	was	added.	The	
reaction	mixture	was	stirred	until	completion	of	the	reaction	as	
indicated	 by	 TLC.	 The	 reaction	 mixture	 was	 cooled	 and	 β‐
Cyclodextrin	 was	 filtered.	 The	 aqueous	 phase	 was	 extracted	
with	 ethyl	 acetate	 (3	 ×	 10	 mL)	 and	 the	 organic	 layers	 were	
washed	 with	 water,	 saturated	 brine	 solution,	 and	 dried	 over	
anhydrous	 Na2SO4.	 The	 combined	 organic	 layers	 were	
evaporated	 under	 reduced	 pressure	 and	 the	 resulting	 crude	
product	was	purified	by	column	chromatography	by	using	ethyl	
acetate:	hexane	(2:8,	v:	v)	as	eluent	 to	give	 the	corresponding	
ethyl	 3‐(ethoxymethyl)‐4,5‐dioxo‐1‐phenylpyrrolidine‐3‐
carboxylate	as	pure	product	in	good	yield	(Scheme	1).	

Methyl	 1‐(4‐trifluoromethylphenyl)‐3(methoxy‐methyl)‐4,5‐
dioxopyrrolidine‐3	 carboxylate	 (Table	 1,	 Entry	 1):	 Yield:	 75%.	
Color:	Yellow	oil.	1H	NMR	(200	MHz,	CDCl3,	,	ppm):	8.05	(d,	2H,	
J	=	8.0	Hz,	Ar‐H),	7.74	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	4.55	(d,	1H,	J	=	
12.0	Hz,	CH2),	4.24	(d,	1H,	J	=	12.0	Hz,	CH2),	3.97	(d,	1H,	J	=	10.0	
Hz,	CH2),	3.87	(d,	1H,	J	=	10.0	Hz,	CH2),	3.81	(s,	3H,	OCH3),	3.36	
(s,3H,	OCH3).	FT‐IR	(KBr,	,	cm‐1):	1778,	1740,	1615,	1462.	MS	
(ESI,	m/z):	346	[M+H]	+.	

Methyl	 1‐(4‐hydroxyphenyl)‐3(methoxymethyl)‐4,5‐dioxo	
pyrrolidine‐3‐carboxylate	 (Table	1,	Entry	2):	Yield:	75%.	Color:	
Yellow	oil.	1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.67	(d,	2H,	J	=	8.0	
Hz,	Ar‐H),	6.89	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	4.49	(d,	1H,	J	=	12.0	Hz,	
CH2),	4.25	(d,	1H,	J	=	12.0	Hz,CH2),	4.00	(d,	1H,	J	=	10.0	Hz,	CH2),	
3.92	 (d,	 1H,	 J	 =	 10.0	 Hz,	 CH2),	 3.85	 (s,	 3H,	 OCH3),	 3.36(s,	 3H,	
OCH3),	2.86	(s,	1H,	OH).	FT‐IR	(KBr,	,	cm‐1):	3378,	1775	1695,	
1517,	1462.	MS	(ESI,	m/z):294	[M+H]	+.	

Methyl	3‐(methoxymethyl)‐4,	5‐dioxo‐1‐(p‐tolyl)	pyrrolidine‐
3‐carboxylate	 (Table	1,	Entry	3):	Yield:	70%.	Color:	Yellow	oil.	
1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.75	(s,	1H,	Ar‐H),	7.66	(d,	
1H,	J	=	8.0	Hz,	Ar‐H),	7.30	(t,	1H,	J	=	8.0	Hz,	Ar‐H),	7.12	(d,	1H,					
J	=	8.0	Hz,	Ar‐H),	4.55	(d,1H,	 J	=	12.0	Hz,	CH2),	4.26	(d,	1H,	J	=	
12.0	Hz,	CH2),	3.96	(d,	1H,	J	=	10.0	Hz,	CH2),	3.85	(d,	1H,	J	=	10.0	

Hz,	 CH2),	 3.78	 (s,	 3H,	OCH3	 ),	 3.32	 (s,	 3H,	OCH3	 ),	 2.46	 (s,	 3H,	
CH3).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1776,	 1714,	 1519,	 1265.	 MS	 (ESI,	
m/z):	292	[M+H]	+.	

Ethyl	 3‐(ethoxymethyl)‐4,5‐dioxo‐1‐phenylpyrrolidine‐3‐
carboxylate	(Table	1,	Entry	4):	Yield:	75%.	Color:	Yellow	oil.	1H	
NMR	(200	MHz,	CDCl3,	,	ppm):	7.88	(d,	2H,	J	=	8.0,	Ar‐H),	7.44	
(m,	2H,	 J	=	8.0	Hz,	Ar‐H),	7.28	(m,	1H,	 J	=	12.0	Hz,	Ar‐H),	4.25	
(m,	3H,	J	=	12.0	Hz,	CH2),	4.23	(d,	1H,	J	=	12.0	Hz,	CH2),	3.93	(q,	
2H,	J	=	10.0	Hz,	OCH2),	3.56	(q,	2H,	J	=	7.0	Hz,	OCH2),	1.27	(t,	3H,	
J	=	7.0	Hz,	CH3),	1.07	(t,	3H,	J	=	7.0	Hz,	CH3).	FT‐IR	(KBr,	,	cm‐1):	
1778,	1735,	1598,	1485.	MS	(ESI,	m/z):	306	[M+H]	+.	

Ethyl	 1‐(3‐methylphenyl)‐3(ethoxymethyl)‐4,5‐dioxopyrroli	
dine‐3‐carboxylate	(Table	1,	Entry	5):	Yield:	68%.	Color:	Yellow	
oil.	 1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.82	(s,	1H,	Ar‐H),	7.79	
(d,	1H,	J	=	8.0,	Ar‐H),	7.44	(t,	1H,	J	=	8.0	Hz,	Ar‐H),	7.19	(d,	1H,	J	
=	8.0,	aro	),	4.50	(1H,	d,	J	=	12.0	Hz,	CH2),	4.28	(3H,	m,	CH2),	3.97	
(2H,	q,	J	=	7.0	Hz,	CH2),	3.49	(2H,	q,	J	=	7.0	Hz,	CH2),	2.45	(3H,	s,	
CH3),	1.29	(t,	3H,	 J	=	7.0	Hz,	CH3),	1.11	(t,	3H,	J	=	7.0	Hz,	CH3).	
FT‐IR	 (KBr,	 ,	 cm‐1):	 1772,	 1710,	 1517,	 1255.	 MS	 (ESI,	m/z):	
320	[M+H]+.	
	
2.2.2.	General	procedure	for	the	synthesis	of	1,2,3,6‐tetra	
hydropyrimidines	
	

β‐Cyclodextrin	 (1.135	 g,	 1	mmol)	 was	 dissolved	 in	 water	
(15	 mL)	 by	 warming	 up	 to	 60	 °C	 until	 a	 clear	 solution	 was	
formed.	 To	 this	 clear	 solution,	 aniline	 (1.0	mmol)	 was	 added	
and	 stirred	 for	 10	 min,	 and	 then	 dimethylacetylene	
dicarboxylate	 (1.0	mmol)	was	added.	After	stirring	 for	half	 an	
hour	 another	 1	 equivalent	 of	 aniline	 (1.0	 mmol)	 was	 added	
followed	by	the	addition	of	4	equivalents	of	formaldehyde	(4.0	
mmol).	 The	 reaction	 mixture	 was	 stirred	 until	 completion	 of	
the	 reaction	 as	 indicated	 by	 TLC.	 The	 reaction	 mixture	 was	
cooled	and	β‐CD	was	filtered.	The	aqueous	phase	was	extracted	
with	 ethyl	 acetate	 (3	 ×	 10	 mL)	 and	 the	 organic	 layers	 were	
washed	 with	 water,	 saturated	 brine	 solution,	 and	 dried	 over	
anhydrous	 Na2SO4.	 The	 combined	 organic	 layers	 were	
evaporated	 under	 reduced	 pressure	 and	 the	 resulting	 crude	
product	was	purified	by	column	chromatography	by	using	ethyl	
acetate:	 hexane	 (2:8,	 v:v)	 as	 eluent	 to	 give	 the	 corresponding	
dimethyl	 1,3‐diphenyl‐1,2,3,6‐tetrahydropyrimidine‐4,5‐dicar‐
boxylate	as	pure	product	in	good	yield	(Scheme	2).	

Dimethyl	 1,3‐diphenyl‐1,2,3,6‐tetrahydropyrimidine‐4,5‐
dicarboxylate	(Table	2,	Entry	1):	Yield:	65%.	Color:	Yellow	oil.		



Shankar	et	al.	/	European	Journal	of	Chemistry	5	(3)	(2014)	541‐544	 543	
 

	 	
Table	2.	β‐CD	catalysed	synthesis	of	polysubstituted	tetrahydropyrimidines	a.	
Entry	 R	 R1	 Product	 Time	(h)	 Yield	(%)	b	
1	 C6H5	 CH3	 5a 4.5 65	
2	 4‐OCH3‐C6H4	 CH3	 5b 4.5 68	
3	 4‐CH3‐C6H4	 CH3	 5c 4.5 67	
4	 4‐CF3‐C6H4	 CH3	 5d 4.5 70	
5	 4‐CF3‐C6H4	 CH2‐CH3	 5e	 4.5	 70	
a	Reaction	conditions:	Amine	(2.0	mmol),	DMAD/DEAD	(1.0	mmol),	Formaldehyde	(4.0	mmol),	β‐Cyclodextrin	(10	mol	%),	60	°C.	
b	Isolated	yield.	
	
	

 
 

Scheme	2
	
	

1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.67	(d,	2H,	 J	=	8.0	Hz,	
Ar‐H),	7.51	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	7.44	(d,	2H,	J	=	8.0	Hz,	Ar‐
H),	6.84	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	6.65	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	
4.92	(s,	2H,	CH2),	4.35	(s,	2H,	CH2),	3.77	(s,	3H,	CH3),	3.65	(s,	3H,	
CH3).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1749,	 1715,	 1617,	 1336.	 MS	 (ESI,	
m/z):	353	[M+H]	+.	

Dimethyl	 1,3‐bis(4‐methoxyphenyl)‐1,2,3,6‐tetrahydro	
pyrimidine‐4,5‐dicarboxylate	 (Table	 2,	 Entry	 2):	 Yield:	 68%.	
Color:	Yellow	oil.	1H	NMR	(200	MHz,	CDCl3,	,	ppm):	6.85	(d,	2H,	
J	=	8.0	Hz,	Ar‐H),	6.77	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	6.72	(d,	2H,	J	=	
8.0	Hz,	Ar‐H),	6.69	 (d,	2H,	 J	=	8.0	Hz,	Ar‐H),	4.74	 (s,	2H,	CH2),	
4.12	(s,	2H,	CH2	),	3.74	(s,	6H,	OCH3),	3.69	(s,	3H,	CH3	),	3.56	(s,	
3H,	 CH3).	 FT‐IR	 (KBr,	,	 cm‐1):	 1743,	 1696,	 1583,	 1437,	 1250.	
MS	(ESI,	m/z):	435	[M+Na]	+.	

Dimethyl	 1,3‐di‐p‐tolyl‐1,2,3,6‐tetrahydropyrimidine‐4,5‐
dicarboxylate	 (Table	2,	Entry	3):	Yield:	67%.	Color:	Yellow	oil.	
1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.35	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	
7.22	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	6.75	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	6.65	
(d,	2H,	J	=	8.0	Hz,	Ar‐H),	4.85	(s,	2H,	CH2),	4.22	(s,	2H,	CH2),	3.79	
(s,	 3H,	 CH3),	 3.58	 (s,	 3H,	 CH3),	 2.35,	 (s,	 3H,	 CH3	 )	 2.25	 (s,	 3H,	
CH3).	 FT‐IR	 (KBr,	,	 cm‐1):	 1746,	 1697,	 1584,	 1438,	 1255.	MS	
(ESI,	m/z):	381	[M+H]	+.	

Dimethyl	 1,3‐bis(4‐(trifluoromethyl)phenyl)‐1,2,3,6‐tetra	
hydropyrimidine‐4,5	 dicarboxylate	 (Table	 2,	 Entry	 4):	 Yield:	
70%.	Color:	Yellow	oil.	1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.60	
(d,	2H,	J	=	8.0	Hz,	Ar‐H),	7.39	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	7.12	(d,	
2H,	J	=	8.0	Hz,	Ar‐H),	6.83	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	4.90	(s,	2H,	
CH2),	4.32	(s,	2H,	CH2	),	3.76	(s,	3H,	CH3),	3.63	(s,	3H,	CH3).	FT‐IR	
(KBr,	 ,	 cm‐1):	 1745,	 1710,	 1609,	 1440.	 MS	 (ESI,	 m/z):	 489	
[M+H]	+.	

Diethyl	 1,3‐bis(4‐(trifluoromethyl)phenyl)‐1,2,3,6‐tetrahydro	
pyrimidine‐4,5‐dicarboxylate	 (Table	 2,	 Entry	 5):	 Yield:	 70%.	
Color:	Yellow	oil.	1H	NMR	(200	MHz,	CDCl3,	,	ppm):	7.57	(d,	2H,	
J	=	8.0	Hz,	Ar‐H),	7.42	(d,	2H,	J	=	8.0	Hz,	Ar‐H),	7.15	(d,	2H,	J	=	
8.0	Hz,	Ar‐H),	6.79	 (d,	2H,	 J	=	8.0	Hz,	Ar‐H),	4.90	 (s,	2H,	CH2),	
4.33	(s,	2H,	CH2),	4.25	(q,	2H,	J	=	7.0	Hz,	OCH2),	4.10	(q,	2H,	J	=	
7.0	Hz,	OCH2),	1.33	(t,	3H,	J	=	7.0	Hz,	CH3),	1.09	(t,	3H,	J	=	7.0	Hz,	
CH3).	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1742,	 1711,	 1615,	 1330.	 MS	 (ESI,	
m/z):	517	[M+H]	+.	
	
3.	Results	and	discussion		

	
Cyclodextrins	 are	 cyclic	 oligosaccharides	 possessing	

hydrophobic	 cavities,	 which	 bind	 substrates	 selectively	 and	
catalyze	 different	 chemical	 reactions	 by	 supramolecular	
catalysis	 involving	 reversible	 formation	 of	 host‐guest	
complexes.	We	describe	herein,	the	aqueous	phase	synthesis	of	

poly‐substituted	 tetra	 hydro	 pyrimidine/pyrrolidine	 deriva‐
tives	 demonstrating	 the	 remarkable	 catalytic	 activity	 of	 β‐
cyclodextrin	 (Schemes	 1	 and	 2).	 In	 general,	 the	 reaction	 was	
carried	 out	 by	 the	 in	 situ	 formation	 of	 the	 β‐CD	 complex	 of	
aniline	 in	 water	 followed	 by	 the	 addition	 of	 but‐2‐ynedioate	
and	 formaldehyde.	 These	 reaction	 mixtures	 were	 stirred	 at						
60	 °C	 to	 give	 the	 corresponding	 poly‐substituted	 tetrahydro	
pyrimidines/pyrrolidines	at	high	yields	(65‐75%).	The	reaction	
goes	to	the	completion	in	4.5	h.	These	reactions	also	take	place	
with	α‐CD	and	γ‐CD,	but	with	lesser	yields.	However,	β‐CD	was	
selected	 as	 the	 mediator	 since	 it	 is	 inexpensive	 and	 easily	
accessible.	 Several	 examples	 illustrating	 this	 simple	 and	
practical	methodology	are	summarized	 in	 (Table	1	and	2).	No	
byproduct	 formation	 was	 observed.	 All	 the	 compounds	 were	
characterized	 by	 1H	 NMR,	 IR,	 and	 mass	 spectrometry.	 The	
catalytic	 activity	 of	 cyclodextrins	 in	 these	 reactions	 was	
established	 by	 the	 fact	 that	 no	 reaction	 was	 observed	 in	 the	
absence	 of	 cyclodextrin.	 Evidence	 for	 complexation	 between	
the	amine	and	cyclodextrin	 is	supported	by	 1H	NMR	spectros‐
copy.	 The	 complexation	with	 β‐CD	 increases	 the	 reactivity	 of	
amino	 group	 of	 aniline	 due	 to	 the	 intermolecular	 hydrogen	
bonding	with	 the	 CD‐hydroxyl	 groups	 facilitating	 the	 addition	
of	 but‐2‐ynedioates.	 Here,	 β‐CD	 not	 only	 forms	 the	 inclusion	
complex	with	aniline	but	is	also	involved	in	the	intermolecular	
hydrogen	bonding	with	the	guest	to	promote	the	reaction.	After	
the	completion	of	reaction,	the	reaction	mixture	was	cooled	to	
room	temperature	and	β‐CD	was	filtered	and	washed	with	ice‐
cold	 water	 and	 dried.	 The	 recovered	 β‐CD	 was	 further	 used	
with	 the	 same	 substrates	 as	 a	 catalyst	 and	 checked	 for	 the	
yields	and	catalytic	activity	of	recovered	catalyst.		
	
4.	Conclusion	

	
In	 conclusion,	 a	 neutral	 aqueous	 phase	 synthesis	 of	 poly‐

substituted	pyrimidine/pyrrolidine	derivatives	was	developed	
by	 the	 reaction	 of	 the	 corresponding	 aniline	 with	 but‐2‐
ynedioate	 and	 formaldehyde	 promoted	 by	 β‐cyclo‐dextrin.	
These	 cyclodextrin‐mediated	 aqueous	 phase	 reactions	 as	
environmentally	 benign	 methodology	 may	 find	 widespread	
application	in	organic	and	medicinal	chemistry.	
	
Acknowledgement	

	
We	thank	Council	of	Scientific	and	Industrial	Research,	New	

Delhi,	India,	for	fellowship	to	Jilla	Shankar,	Gaddam	Satish	and	
University	Grants	Commission	for	fellowship	to	Katla	Ramesh.	
	



544	 Shankar	et	al.	/	European	Journal	of	Chemistry	5	(3)	(2014)	541‐544	
	
References	
	
[1]. Sondhi,	 S.	 M.;	 Jain,	 S.;	 Dinodia,	 M.;	 Shuklab,	 R.;	 Raghubir,	 R.	 Bioorg.	

Med.	Chem.	2007,	15,	3334‐3344.		
[2]. Srivastav,	N.	C.;	Manning,	T.	D.;	Kunimoto,	Y.;	Kumar,	R.	Bioorg.	Med.	

Chem.	2007,	15,	2045‐2053.		
[3]. Gazivoda,	T.;	Plevnik,	M.;	Plavec,	 J.;	Kraljevic,	S.;	Kralj,	M.;	Pavelic,	K.;	

Balzarini,	 J.;	Clercq,	E.	D.;	Mintasa,	M.;	 Silvana,	R.	Bioorg.	Med.	Chem.	
2005,	13,	131‐139.		

[4]. Tozkoparan,	B.;	Yarim,	M.;	Sarac,	S.;	Ertan,	M.;	Kelicen,	P.;	Altinok,	G.;	
Demirdamar,	R.	Arch.	Pharm.	2000,	333,	415‐420.		

[5]. DeLucca,	G.	V.;	Liang,	J.;	De	Lucca,	I.	J.	Med.	Chem.	1999,	42,	135‐152.		
[6]. Dunbar,	P.	G.;	Durant,	G.	J.;	Rho,	T.;	Ojo,	B.;	Huzl,	J.	J.;	Smith,	D.	A.;	A	El‐

Assadi,	M.;	Sbeih,	S.;	Ngur,	D.	O.;	Periyasamy,	S.;	Hoss,	W.;	Messer,	W.	S.	
J.	Med.	Chem.	1994,	37,	2774‐2782.	

[7]. Muravyova,	 E.	 A.;	 Desenko,	 S.	 M.;	 Musatov,	 V.	 I.;	 Knyazeva,	 I.	 V.;	
Shishkina,	S.	V.;	Shishkin,	O.	V.;	Chebanov,	V.	A.	J.	Comb.	Chem.	2007,	9,	
797‐803.		

[8]. Swinbourne,	J.	F.;	Hunt,	H.	J.;	Klinkert,	G.	Adv.	Heterocycl.	Chem.	1987,	
23,	103‐170.		

[9]. Hermecz,	 I.;	 Vasvari‐Debreczy,	 L.;	 Matyus,	 P.	 In	 Comprehensive	
Heterocyclic	 Chemistry;	 Katritzky,	 A.	 R.;Rees,	 C.	W.;	 Scriven,	 E.	 V.	 F.	
Eds.;	Pergamon:	London,	1996;	Chapter	8.23,	pp.	563‐595.		

[10]. Nair,	A.	C.;	Jayatilleke,	P.;	Wang,	X.;	Miertus,	S.;	Welsh,	W.	J.	Med.	Chem.	
2002,	45,	973‐982.		

[11]. Zamri,	 A.;	 Sirockin,	 F.;	 Abdallah,	M.	 A.	Tetrahedron	1999,	 55,	 5157‐
5170.		

[12]. Shutalev,	 A.	 D.;	 Fesenko,	 A.	 A.;	 Cheshkov,	 D.	 A.;	 Goliguzov,	 D.	 V.	
Tetrahedron	Lett.	2008,	49,	4099‐4101.		

[13]. Mohrle,	H.;	Reinhardt,	H.	W.	Arch.	Pharm.	1981,	314,	767‐776.	
[14]. Cho,	H.;	Shima,	K.;	Hayashimatsu,	M.;	Ohnaka,	Y.;	Mizuno,	A.;	Takeuchi,	

Y.	J.	Org.	Chem.	1985,	50,	4227‐4230.		
[15]. Zhang,	M.;	Jiang,	H.	‐F.	J.;	Liu,	H.	L.;	Zhu,	Q.	H.	Org.	Lett.	2007,	9,	4111‐

4113.		
[16]. Chanda,	 K.;	 Dutta,	 Ch.	 M.;	 Karim,	 E.;	 Vishwakarma	 J.	 N.	 J.	

Heterocyclic.Chem.	2004,	41,	627‐631.		
[17]. Das,	 B.;	 Shinde,	 D.	 B.;	 ShashiKanth,	 B.;	 Satyalakshmi,	 G.	 Synthesis.	

2010,	16,	2823‐2825.		
[18]. Zhu,	Q.;	 Jiang,	H.;	Li,	 J.;	Zhang,	M.;	Wang,	X.;	Qi,	C.	Tetrahedron	2009,	

65,	4604‐4613.		
[19]. Shankar,	 J.;	Karnakar,	K.;	Srinivas,	B.;	Nageswar,	Y.	V.	D.	Tetrahedron	

Lett.	2010,	51,	3938‐3939.		
[20]. Ramesh,	K.;	Murthy,	S.	N.;	Nageswar,	Y.	V.	D.	Tetrahedron	Lett.	2011,	

52,	2362‐2366.		
[21]. Ramesh,	K.;	Murthy,	S.	N.;	Karnakar,	K.;	Nageswar,	Y.	V.	D.	Tetrahedron	

Lett.	2011,	52,	3937‐3941.		
[22]. Ramesh,	K.;	Murthy,	S.	N.;	Karnakar,	K.;	Nageswar,	Y.	V.	D.	Tetrahedron	

Lett.	2011,	52,	4734‐4737.		
[23]. Ramesh,	 K.;	 Murthy,	 S.	 N.;	 Karnakar,	 K.;	 Nageswar,	 Y.	 V.	 D.;	

Vijayalakhshmi,	 K.;	 Prabhavathi	 Devi,	 B.	 L.	 A.;	 Prasad,	 R.	 B.	 N.	
Tetrahedron	Lett.	2012,	44,	1126‐1129.		

[24]. Ramesh,	K.;	Karnakar,	K.;	Satish,	G.;	Reddy,	K.	H.	V.;	Nageswar,	Y.	V.	D.	
Tetrahedron	Lett.	2012,	53,	6095‐6099.		

[25]. Ramesh,	K.;	Karnakar,	K.;	Satish,	G.;	Anil	Kumar,	B.	S.	P.;	Nageswar,	Y.	
V.	D.	Tetrahedron	Lett.	2012,	53,	6936‐6939.		

[26]. Ramesh,	K.;	Karnakar,	K.;	Satish,	G.;	Nageswar,	Y.	V.	D.	Chin.	Chem.	Lett.	
2012,	23,	1331‐1334.		

[27]. Ramesh,	K.;	Narayana	Murthy,	S.;	Karnakar,	K.;	Nageswar,	Y.	V.	D.	Eur.	
J.	Chem.	2012,	3(1),	119‐124.