Synthesis of New dihydropyrimidinones catalysed by dicationic ionic Liquid

Article abstract of DOI:10.1007/s12039-011-0127-y

A convenient multi step synthetic protocol for new dihydropyrimidinones bearing quinolynyl methoxy phenyl moiety has been developed from 2-chloro-3-formyl quinolines. The last step is one-pot Biginelli reaction of multicomponents, 4-((2-chloroquinolin-3-yl) methoxy) benzaldehydes, ethyl acetoacetate and urea mediated and catalysed by dicationic ionic liquid (3-methyl-1-[3-(methyl-1H-imidazolium-1-yl) propyl]- 1H-imidazolium dibromide (C₃ [min]2 2 [Br^-] )). Simple work-up procedures and moderate to good yields of the pyrimidinones and the intermediates are the merits of the route. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0127-y

c
J. Chem. Sci. Vol. 123, No. 5, September 2011, pp. 645–655. ꢀ Indian Academy of Sciences.
Synthesis of New dihydropyrimidinones catalysed by dicationic ionic
liquid
DHANAJI V JAWALE, UMESH R PRATAP, APARNA A MULAY, JYOTIRLING R MALI
and RAMRAO A MANE∗
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
e-mail: manera2011@gmail.com
MS received 21 December 2010; accepted 17 May 2011
Abstract. A convenient multi step synthetic protocol for new dihydropyrimidinones bearing quinolynyl
methoxy phenyl moiety has been developed from 2-chloro-3-formyl quinolines. The last step is one-pot Big-
inelli reaction of multicomponents, 4-((2-chloroquinolin-3-yl) methoxy) benzaldehydes, ethyl acetoacetate and
urea mediated and catalysed by dicationic ionic liquid (3-methyl-1-[3-(methyl-1H-imidazolium-1-yl) propyl]-
1H-imidazolium dibromide (C3 [min]2 2 [Br−] )). Simple work-up procedures and moderate to good yields of
the pyrimidinones and the intermediates are the merits of the route.
Keywords. Dihydropyrimidinones; quinoline; dicationic ionic liquid; ethereal linkage; Biginelli reaction.
1. Introduction
reported. Many of these reported methods employ
catalysts such as H2SO4,13 BF3OEt2,14 polyphosphate
esters,15 montmorillonite KSF,16 zeolites,17 FeCl3.6H2O,18
Yb (OTf)3,19 bismuth triflate,20 cupric chloride,21 zir-
conium chloride,22 heteropoly acids,23 ion exchange
resins,24 polymer-based solid acids,25 chiral phosphoric
acids,26 TaBr5,27 propane phosphoric acid anhydride,28
TMSCl,29 Cu(NO3)2H2O,30 InCl3,31 CeCl3.7H2O,32
chiral yetterbium33 and ionic liquids.34
Recently Biginelli reaction has been catalysed by
using t-BuOK.35 The Biginelli one-pot condensation
has also found to be accelerated by microwave,36 ultra-
sonication37 and solid fluorous phase.38
Dihydropyrimidinones (DHPMs) occupy special place
in the realm of natural and synthetic organic chem-
istry, because of their therapeutic and pharmacological
properties.1 Dihydropyrimidinones scaffold emerged as
an integral backbone of several drugs used as cal-
cium channel blockers,2 antihypertensive3 and anti-
cancer agents.4 DHPMs also elicit antidiabetic activi-
tiy.5 Recently isolated marine alkaloids6 concomitant
with dihydropyrimidine-5-carboxylate core. Most note-
worthy among the isolated marine alkaloids is batzella-
dine, a potent HIVgp-120- CD4 inhibitor.7
Quinolines are gaining importance in medicinal
chemistry due to their elegant pharmacological proper-
ties like antibacterial,8 antidepressant,9 antimalerial10
and hypoglycemic.11 The ethereal linkage and 2,4-
thiazoldinedione are essential in the molecular frame-
work of various antidiabetic drugs12 like, pioglitazone,
troglitazone and rosiglitazone.
The above methods need expensive catalysts, strong
acidic conditions, higher temperatures and prolonged
reaction time. Most of the routes require costly re-
agents, toxic/hazardous organic solvents and tedious
work-up. Hence chemists are putting more efforts to
modify reaction conditions of the Biginelli protocol by
employing some green tools.
The most simple and straight forward procedure for
the synthesis of DHPMs was reported by Biginelli1c in
1893. This involves one-pot condensation of ethylace-
toacetate, aryl aldehydes and urea under strongly acidic
conditions. One of the drawbacks of this method is
low yields. Synthesis of DHPMs has attracted renewed
attention and many improved procedures have been
Ionic liquids are emerging as a set of new green sol-
vents to replace the volatile organic solvents.39 The use
of non-volatile organic solvents for chemical reactions
is of ecological and economic concern. Ambient tem-
perature of ionic liquids encompassing 1,3-dialkyl imi-
dazolium cations are alternative to conventional organic
solvents.40 The important properties of these ionic liq-
uids are low volatility, negligible vapour pressure, ease
of handling, potential for recycling, and compatibil-
ity with various organic compounds and organometallic
∗For correspondence
645

646
Dhanaji V Jawale et al.
catalysts.41 Ionic liquids have been found to be use- Shimanzu GCMS and on JEOL – Accu TOF DART-
ful in various organic transformations.42 The ionic liq- MS- T 100 Lc. Elemental analyses were performed
uids with wide range of combinations of cations and on Perkin Elmer elemental auto analyzer. The melt-
anions are well-explored as media and catalysts. The ing points were taken in open capillary and are uncor-
ionic components can be easily modified by specific rected. Dicationic ionic liquid used here was prepared
functional groups to produce ionic liquids of useful by reported methods.44,51
applications.43
It has been reported that dicationic ionic liquids
2.2 Experimental procedure for the synthesis of
Dihydropyrimidinone 5a
linked by alkyl chains show much higher thermal
stability than that of most common ionic liquids.44
Armstrong et al have synthesized dicationic ionic liq-
A mixture of benzaldehyde (10 mmol), ethyl acetoac-
etate (10 mmol) and urea (12 mmol) were heated in
uids containing dicationic imidazolium with halides
possessing high thermal stability.44 Literature sur-
dicationic ionic liquid, C3 [min] 2Br− (10 mmol) at
vey reveals that there is scanty information on the
80◦C. The progress of the reaction was monitored by
use of such dicationic ionic liquids in the organic
thin layer chromatography. After 2 h of the reaction,
the reaction mass was allowed to cool to rt. and it
was poured on ice cold water. Thus obtained solid
mass was filtered, washed with water and dried. Sim-
transformations.
Multicomponent reactions (MCRs) are of increas-
ing importance in organic and medicinal chemistry.45
Multicomponent strategies offer significant advantages
ilarly the other compounds, (5 b–f) of the series were
over conventional linear type syntheses.45 The most
synthesized.
useful MCRs have additional advantages of selectivity,
synthetic convergancy and atom-economy.45,46
Considering the pharmacological importance of 2.3 Experimental procedure for the synthesis of
DHPMs, quinolines and ethereal linkage and the draw- (2-chloroquinolin-3-yl) methanol 8a
backs of existing routes for the synthesis of DHPMs,
To the solution of 2-chloro-3-formyl quinoline (10 g,
52 mmol) in methanol (100 mL), NaBH4 (1.98 g,
52 mmol) was added portion-wise and then the mass
was stirred at rt. The progress of the reaction was mon-
itored by thin layer chromatography. After 30 min of
stirring, solvent was removed from the reaction mass
under vacuum and the residue was added in ice cold
water. The obtained solid was filtered and washed with
water and dried. Similarly the other compounds, (8 b–
h) were synthesized by following the above procedure.
here it was thought worthwhile to bring DHPMs, quino-
line and ethereal linkage in one molecular framework
using multicomponent one-pot safer route to obtain the
new molecules with the hope that they may display
intensified bioactivities.
In continuation of our earlier work, carried to
develop convenient synthetic protocols for the syn-
thesis of bioactive heterocycles47 by employing green
tools and considering the above urgent need to pro-
vide convenient rapid route for the DHPMs, here we
report for the first time the Biginelli reaction by sub-
jecting substituted quinoline methoxy benzaldehydes,
ethyl acetoacetate and urea in dicationic ionic liquid
(3-methyl-1-[3-(methyl-1H-imidazolium-1-yl) propyl]-
1H-imidazolium dibromide (C3 [min]2 2 [Br−] )), as
medium and catalyst for obtaining new DHPMs.
2.3a (2-Chloroquinolin-3-yl) methanol 8a: White
solid; m.p. 148–149◦C; yield: 87%.; 1H–NMR
(300 MHz, DMSO−d6): δ = 8.29 (s, 1H, quinoline),
8.04 (d, 1H, J = 8.4 Hz, Ar–H quinoline), 7.84 (d, 1H,
J = 6.0 Hz, quinoline Ar–H), 7.76 (t, 1H, J = 6.0 Hz,
quinoline Ar–H), 7.55 (t, 1H, J = 9.0 Hz, quinoline
Ar–H), 3.49 (s, 1H, OH, exchangeable with D2O),
2.08 (s, 2H, CH2)ppm; DART-MS: (ESI+, m/z) = 194
(M+), 196 (M++2).
2. Experimental
2.1 General
2.3b (2-Chloro-8-methylquinolin-3-yl) methanol 8b:
Chemicals and solvents required were from Merck, White solid; m.p. 137–138◦C; yield: 84%; H–NMR
Spectorchem and SD fine meck. 1H–NMR spectra were (300 MHz, DMSO−d6): δ = 8.22 (s, 1H, quinoline),
recorded at 400 MHz on Jeol and at 300 MHz on 7.66 (d, 2H, J = 6.0 Hz, quinoline Ar–H), 7.55 (t, 1H,
Bruker DRX-300. The mass spectra were recorded on J = 6.0 Hz, quinoline Ar–H), 7.45 (t, 1H, J = 6.0 Hz,
1

Synthesis of New dihydropyrimidinones catalysed by dicationic ionic liquid
647
quinoline Ar–H), 4.91 (s, 2H, CH2), 3.49 (s, 1H, OH, 2.3h (2,7-Dichloroquinolin-3-yl)methanol 8h: White
exchangeable with D2O), 2.76 (s, 3H, CH3); DART- solid; m.p. 105–106◦C; yield: 88%; 1H–NMR
MS: (ESI+, m/z) = 208 (M+), 210 (M++2).
(400 MHz, DMSO−d6): δ = 8.5 (s, 1H, quinoline
Ar–H), 8.3 (s, 1H, quinoline Ar–H), 7.80 ( d, 1H, J =
8.10 Hz), 7.6 (d, 1H, J = 7.60 Hz, quinoline Ar–H),
5.10 (s, 2H, CH2), 3.80 (s, 1H, OH, exchangeable with
D2O) ppm; GCMS: (ESI+, m/z) = 228 (M+), 230
(M++2), 232 (M++4).
2.3c (2-Chloro-7-methylquinolin-3-yl) methanol 8c:
White solid; m.p. 144–145◦C; yield: 87%; H–NMR
1
(300 MHz, DMSO−d6): δ = 8.15 (s, 1H, quinoline
Ar–H), 7.8 (d, 1H, J = 8.3 Hz, quinoline Ar–H),
7.58 (s, 1H, quinoline Ar–H), 7.41(d, 1H, J = 8.1 Hz,
quinoline Ar–H), 4.92 (s, 2H, CH2), 3.48 (s, 1H, OH,
exchangeable with D2O), 2.76 (s, 3H, CH3); DART-
MS: (ESI+, m/z) = 208 (M+), 210 (M++2).
2.4 Experimental procedure for the synthesis
of (2-chloroquinolin-3-yl) methyl
4-methylbenzenesulfonate 9a
(2-Chloroquinolin-3-yl) methanol (7.0 g, 36 mmol) and
triethyl amine (5.4 g, 51 mmol) were dissolved in DCM
(100 mL) and the solution was stirred for 30 min. To
this stirred solution p-toluene sulphonyl chloride (7.6
gm, 39 mmol) was added in portions at 0◦C. Then
the reaction mass was further stirred for 5–6 h at rt.
The progress of reaction was monitored by thin layer
chromatography. After the 6 h of the reaction, the sol-
vent was removed from the mass under vacuum. The
residue was then poured in ice cold water. The solid was
obtained filtered, washed water and dried. It was used
for the further reaction without any purification. Simi-
larly the other compounds, (9 b–h) of the series were
synthesized by following the above same procedure.
2.3d (2-Chloro-6-methylquinolin-3-yl) methanol 8d:
1
White solid; m.p. 124–125◦C; yield: 86%; H–NMR
(300 MHz, DMSO−d6): δ = 8.10 (s, 1H, quinoline Ar–
H), 7.60 (d, 1H, J = 7.50 Hz, quinoline Ar–H), 7.58
(s, 1H, quinoline Ar–H), 7.40 (d, 1H, J = 7.30 Hz,
quinoline Ar–H), 4.93(s, 2H, CH2), 3.51(s, 1H, OH,
exchangeable with D2O), 2.77 (s, 3H, CH3); DART-
MS: (ESI+, m/z) = 208 (M+), 210 (M++2).
2.3e (2-Chloro-7-methoxyquinolin-3-yl) methanol 8e:
1
White solid; m.p. 197–198◦C; yield: 85%; H–NMR
(400 MHz, DMSO−d6): δ = 8.01 (s, 1H, quinoline Ar–
H), 7.26 (d, 1H, J = 8.50 Hz, quinoline Ar–H), 7.19
(d, 1H, J = 7.0 Hz, quinoline Ar–H), 7.02 (s, 1H,
quinoline Ar–H), 5.03 (s, 2H, CH2), 3.46 (s, 1H, OH,
exchangeable with D2O); GCMS: (ESI+, m/z) = 224
(M+), 226 (M++2).
2.4a (2-Chloroquinolin-3-yl) methyl 4-methyl benzene-
sulfonates 9a: White solid; m.p. 98–99◦C; Yield:
1
82%; H–NMR (300 MHz, DMSO−d6): δ = 8.29 (s,
1H, quinoline), 8.03 (d, 1 H, J = 6.0 Hz, quinoline Ar–
H), 8.03 (d, 1H, J = 9.0 Hz, quinoline Ar–H),7.90 (d,
2H, J = 7.50 Hz, Ar–H), 7.85 (d, 1 H, J = 6.0 Hz,
quinoline Ar–H), 7.77 (t, 1 H, J = 6.0 Hz, quinoline
Ar–H), 7.75 (d, 2 H, J = 7.50 Hz, Ar–H), 7.58 (t, 1 H,
J = 9.0 Hz, quinoline Ar–H), 4.85 (s, 2H, CH2), 1.56
(s, 3H, CH3) ppm; DART-MS: (ESI+, m/z) = 348 (M+),
350 (M++2).
2.3f (2-Chloro-6-methoxyquinolin-3-yl) methanol 8f:
1
White solid; m.p. 145–146◦C; yield: 87%; H–NMR
(400 MHz, DMSO−d6): δ = 7.80 (s, 1H, quinoline Ar–
H), 7.25 (d, 1H, J = 8.50 Hz, quinoline Ar–H), 7.20 (d,
1H, J = 7.0 Hz, quinoline Ar–H), 7.03 (s, 1H, quino-
line Ar–H), 4.80 (s, 2H, CH2), 3.80 (s, 3H, OCH3),
3.47 (s, 1H, OH, exchangeable with D2O) ppm; GCMS:
(ESI+, m/z) = 224 (M+), 226 (M++2).
2.3g (2-Chloro-6-ethoxyquinolin-3-yl) methanol) 8g: 2.4b (2-Chloro-8-methylquinolin-3-yl) methyl 4-methyl
1
White solid; m.p. 121–123◦C; yield: 86%; H–NMR benzenesulfonate 9b: White solid; m.p. 78–79◦C;
(400 MHz, DMSO−d6): δ = 7.74 (s, 1H, quinoline yield: 76%; 1H–NMR (300 MHz, DMSO−d6): δ = 8.23
Ar–H), 7.42 (s, 1H, quinoline Ar–H), 7.26 (d, 1H, (s, 1H, quinoline Ar–H), 7.80 (d, 2H, J = 7.1 Hz, Ar–
J = 7.50 Hz, quinoline Ar–H), 7.20 (d, 1H, J = H), 7.67 (d, 1H, J = 9.0 Hz, quinoline Ar–H), 7.60
7.20 Hz, quinoline Ar–H), 4.85 (s, 2H, CH2), 4.11 (m, (d, 2H, J = 7.60 Hz, Ar–H), 7.59 (d, 1H, J = 6.0 Hz,
2H, −OCH2CH3), 3.70 (s, 1H, OH, exchangeable with quinoline Ar–H), 7.48 (t, 1H, J = 12.0 Hz, quino-
D2O), 1.76 ( t, 3H, J = 7.10 Hz, −OCH2CH3)ppm; line Ar–H), 4.92 (s, 2H, CH2), 2.77 (s, 3H, CH3) ppm;
GCMS: (ESI+, m/z) = 238 (M+), 240 (M++2).
DART-MS: (ESI+, m/z) = 362 (M+), 364 (M++2).

648
Dhanaji V Jawale et al.
2.4c (2-Chloro-8-methylquinolin-3-yl) methyl 4-methyl (s, 2H, −CH2-), 4.10 (q, 2H, J = 7.60 Hz, CH2CH3),
benzenesulfonate 9c: White solid; m.p. 121–122◦C; 2.53 (s, 3H, CH3), 1.37 (t, 3H, J = 7.11 Hz, CH2CH3)
yield: 75%; 1H–NMR (300 MHz, DMSO−d6): δ = 8.15 ppm; GCMS: (ESI+, m/z) = 392 (M+), 394 (M++2).
(s, 1H, quinoline Ar–H), 7.81 (d, 2H, J = 7.72 Hz, Ar–
H), 7.70 (d, 1H, J = 8.1 Hz, quinoline Ar–H), 7.51 (d,
2.4h (2,7-dichloroquinolin-3-yl)methyl 4-methyl ben-
1H, J = 7.90 Hz, quinoline Ar–H), 7.67 (s, 1H, quino-
line Ar–H), 7.51 (d, 1H, J = 7.90 Hz, quinoline Ar–
H), 4.92 (s, 2H, CH2), 2.76 (s, 3H, CH3), 2.61 (s, 3H,
CH3) ppm; DART-MS: (ESI+, m/z) = 362 (M+), 364
(M++2).
zene sulfonate 9h: White solid; m.p. 97–98◦C; yield:
1
80%; H–NMR (400 MHz, DMSO−d6): δ = 8.40 (s,
1 H, quinoline Ar–H), 8.1 (s, 1H, quinoline Ar–H), 7.90
(d, 2H, J = 8.50 Hz, Ar–H), 7.70 (d, 1H, J = 8.10 Hz,
quinoline Ar–H), 7.50 (d, 1H, J = 7.90 Hz, quinoline
Ar–H), 7.20 (d, 2H, J = 8.0 Hz, quinoline Ar–H), 4.91
( s, 2H, CH2), 2.61 (s, 3H, CH3) ppm; GCMS: (ESI+,
m/z) = 382 (M+), 384 (M++2), 386 (M++4).
2.4d (2-Chloro-6-methylquinolin-3-yl) methyl 4-
methylbenzenesulfonate 9d: White solid; m.p. 101–
1
102◦C; yield: 87%; H–NMR (300 MHz, DMSO−d6):
δ = 8.11 (s, 1H, quinoline Ar–H), 7.80 (d, 2 H, J =
7.70 Hz, Ar–H), 7.69 (d, 1H, J = 7.90 Hz, quinoline
Ar–H), 7.55 (s, 1H, quinoline Ar–H), 7.51 (d, 2H, J =
7.58 Hz, Ar–H), 7.41 (d, 1H, J = 7.80 Hz, quinoline
Ar–H), 4.94 (s, 2H, CH2), 2.77 (s, 3H, CH3), 2.60 (s,
3H, CH3) ppm; DART-MS: (ESI+, m/z) = 362 (M+),
364 (M++2).
2.5 Experimental procedure for the synthesis
of 4-((2-chloroquinolin-3-yl) methoxy)
benzaldehyde 10a
A mixture of 4-hydroxybenzaldehyde (1.82 g, 15 mmol)
and potassium carbonate (2.71 g, 20 mmol) was stirred
in DMF (60 mL) for 20 min. at 80 ◦C. To this, (2-
chloroquinolin-3-yl) methyl 4-methylbenzenesulfonate
(9a) (5 g, 14 mmol) was added and further the mass
stirred for 3 h at 80◦C. The progress of the reaction was
observed by thin layer chromatography. After 3 h of the
reaction, the reaction mass was allowed to cool at rt. and
poured on crushed ice. The obtained solid crude was
filtered, washed with water and crystallized by using
ethanol. Similarly the other compounds, (10 b–h) of the
series were synthesized by following the same synthetic
procedure.
2.4e (2-Chloro-7-methoxyquinolin-3-yl) methyl 4-
methyl benzenesulfonate 9e: White solid; m.p. 124–
1
125◦C; yield: 83%; H–NMR (400 MHz, DMSO−d6):
δ = 7.80 (s, 1H, quinoline Ar–H), 7.73 (d, 2H, J =
7.65 Hz, Ar–H), 7.50 (d, 2H, J = 7.65 Hz, Ar–H), 7.24
(d, 1H, J = 8.40 Hz, quinoline Ar–H), 7.19 (d, 1H,
J = 7.60 Hz, quinoline Ar–H), 7.03 (s, 1H, quinoline
Ar–H), 4.60 (s, 2H, −CH2-), 3.76 (s, 3H, OCH3), 2.52
(s, 3H, CH3) ppm; GCMS: (MS+, m/z) = 378 (M+),
380 (M++2).
2.5a 4-((2-Chloroquinolin-3-yl) methoxy) benzaldehy-
des 10a: White solid; m.p. 118–119◦C; yield: 83%;
1H–NMR (300 MHz, DMSO−d6): δ = 9.90 (s, 1H,
CHO), 8.64 (s, 1H, quinoline Ar–H), 8.08 (d, 1H, J =
6.0 Hz, quinoline Ar–H), 7.99 (d, 2H, J = 9.0 Hz, Ar–
H), 7.92 (d, 1H, J = 9.0 Hz, quinoline Ar–H), 7.85 (t,
1H, J = 6.0 Hz, quinoline Ar–H), 7.69 (t, 1H, J =
9.0 Hz, quinoline Ar–H), 7.32 (t, 1H, J = 9.0 Hz,
quinoline Ar–H), 5.43 (s, 2H, CH2) ppm; DART-MS:
(ESI+, m/z) = 298 (M+), 300 (M++2).
2.4f (2-Chloro-6-methoxyquinolin-3-yl)methyl 4-methyl
benzenesulfonate 9f: White solid; m.p. 131–132◦C;
yield: 84%; 1H–NMR (400 MHz, DMSO−d6): δ = 7.81
(s, 1H, quinoline Ar–H), 7.7 (d, 2H, J = 7.65 Hz, Ar–
H), 7.40 (d, 2H, J = 7.65 Hz, Ar–H), 7.24 (d, 1H,
J = 8.5 Hz, quinoline Ar–H), 7.21 (d, 1H, J = 7.0 Hz,
quinoline Ar–H), 7.01 (s, 1H, quinoline Ar–H), 4.70 (s,
2H, −CH2-), 3.80 (s, 3H, OCH3), 2.53 (s, 3H, CH3)
ppm; GCMS = (ESI+, m/z): 378 (M+), 380 (M++2).
2.4g (2-Chloro-6-ethoxyquinolin-3-yl)methyl-4-methyl
benzenesulfonate 9g: White solid; m.p. 110–111◦C;
yield: 83%; 1H–NMR (400 MHz, DMSO−d6): δ = 7.77
(s, 1H, quinoline Ar–H), 7.60 (d, 2H, J = 7.68 Hz, Ar–
H), 7.41 (s, 1H, quinoline Ar–H), 7.30 (d, 2H, J =
7.40 Hz, Ar–H), 7.25 (d, 1H, J = 7.40 Hz, quinoline
Ar–H), 7.19 (d, 1H, J = 7.60 Hz, quinoline Ar–H), 4.80
2.5b 4-((2-Chloro-8-methylquinolin-3-yl) methoxy)
benzaldehyde 10b: White solid; m.p. 135–136◦C;
1
yield: 87%; H–NMR (300 MHz, DMSO−d6): δ =
9.89 (s, 1H, CHO), 8.59 (s, 1H, quinoline Ar–H), 7.90
(t, 2H, J = 9.0 Hz, quinoline Ar–H), 7.69 (d, 2H, J =
6.0 Hz, Ar–H), 7.56 (t, 1H, J = 6.0 Hz, quinoline Ar–
H), 7.32 (d, 2H, J = 9.0 Hz, Ar–H), 5.42 (s, 2H, CH2),

Synthesis of New dihydropyrimidinones catalysed by dicationic ionic liquid
649
2.67 (s, 3H, CH3) ppm; DART-MS: (ESI+, m/z) = 312 (d, 2H, J = 7.80 Hz, Ar–H), 7.42 (s, 1H, quinoline Ar–
(M+), 314 (M++2).
H), 7.28 (d, 1H, J = 7.50 Hz, quinoline Ar–H), 7.20
(d, 1H, J = 7.60 Hz, quinoline Ar–H), 7.15 (d, 2H,
J = 7.10 Hz, Ar–H), 5.10 (s, 2H, −CH2O), 4.10(m,
2H, OCH2CH3), 1.37 (t, 3H, J = 7.10 Hz, OCH2CH3)
ppm; GCMS: (ESI+, m/z) = 342 (M+), 344 (M++2).
2.5c 4-((2-Chloro-7-methylquinolin-3-yl) methoxy)
benzaldehyde 10c: White solid; m.p. 138–139◦C;
1
yield: 82%; H–NMR (300 MHz, DMSO−d6): δ =
9.83 (s, 1H, CHO), 8.61 (s, 1H, quinoline Ar–H), 7.92
(d, 2H, J = 8.6 Hz, Ar–H), 7.63 (d, 1H, J = 8.0 Hz,
quinoline Ar–H), 7.51 (d, 1H, J = 7.9 Hz, quinoline
Ar–H), 7.11 (d, 2H, J = 6.8 Hz, Ar–H), 5.13 (s, 2H,
CH2), 2.77 (s, 3H, CH3) ppm; DART-MS: (ESI+, m/z)
= 312 (M+), 314(M++2).
2.5h
4-((2,7-Dichloroquinolin-3-yl)methoxy)
benzaldehyde 10h: White solid; m.p. 132–133◦C;
1
yield: 81%; H–NMR (400 MHz, DMSO−d6): δ =
9.93 (s, 1H, CHO), 8.50 (s, 1H, quinoline Ar–H), 7.93
(d, 2 H, J = 8.40 Hz, Ar–H), 7.80 (d, 1H, J = 8.10 Hz,
quinoline Ar–H), 7.50 (d, 1H, J = 7.60 Hz, quinoline
Ar–H), 7.30 (d, 2H, J = 8.10 Hz, Ar–H), 5.05 (s,
2H, CH2) ppm; GCMS :(ESI+, m/z) = 332 (M+), 334
(M++2), 336 (M++4).
2.5d 4-((2-Chloro-6-methylquinolin-3-yl) methoxy)
benzaldehyde 10d: White solid; m.p. 140–141◦C;
1
yield: 87%; H–NMR (300 MHz, DMSO−d6): δ =
9.85 (s, 1H, CHO), 8.30 (s, 1H, quinoline Ar–H), 7.90
(d, 2H, J = 8.60 Hz, Ar–H), 7.60 (d, 1H, J = 8.10 Hz,
quinoline Ar–H), 7.60 (s, 1H, quinoline Ar–H), 7.48
(d, 1H, J = 7.80 Hz, quinoline Ar–H), 7.20 (d, 2H,
J = 7.20 Hz, Ar–H), 5.10 (s, 2H, CH2), 2.76 (s, 3H,
CH3) ppm; DART-MS :(ESI+, m/z) = 312 (M+),
314(M++2).
2.6 Experimental procedure for the synthesis
of ethyl 4-(4-((2-chloroquinolin-3-yl) methoxy)
phenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-
5-carboxylate 11a
Multicomponent 4-((2-chloroquinolin-3-yl) methoxy)
benzaldehyde (1 g, 3.4 mmol), ethyl acetoacetate (
0.4 g, 3.7 mmol) and urea (0.27 g, 4.40 mmol) was
heated in dicationic ionic liquid C3[min] 2Br− (1.26 g,
3.4 mmol) at 80◦C. The progress of reaction was mon-
itored by thin layer chromatography. After heating the
reaction mass for 2 h, it was allowed to cool to rt.
and poured on ice cold water. Thus solid mass was
obtained filtered, washed with water and dried. Simi-
larly the other compounds (11 b–h) of the series were
synthesized.
2.5e 4-((2-Chloro-7-methoxyquinolin-3-yl) methoxy)
benzaldehyde 10e: White solid; m.p. 128–129◦C;
yield: 86%; 1H–NMR (400 MHz, DMSO−d6): δ = 9.89
(s, 1H, CHO), 7.81 (s, 1H, quinoline Ar–H), 7.77 (d,
2H, J = 8.20 Hz, Ar–H), 7.28 (d, 1H, J = 8.60 Hz,
quinoline A–H), 7.23 (d, 1H, J = 8.20 Hz, quinoline
Ar–H), 7.12 (d, 2H, J = 6.9 Hz, Ar–H), 5.17 (s, 2H,
CH2), 3.78 (s, 3H, OCH3) ppm; GCMS: (ESI+, m/z) =
328 (M+), 330 (M++2).
2.5f 4-((2-Chloro-6-methoxyquinolin-3-yl)methoxy)
2.6a Ethyl 4-(4-((2-chloroquinolin-3-yl) methoxy)
phenyl)-1, 2, 3, 4-tetrahydro-6-methyl-2-oxopyrimidine-
5-carboxylates 11a: White solid; m.p. 230–231◦C;
yield: 83%; H–NMR (300 MHz, DMSO−d6): δ =
benzaldehyde 10f: White solid; m.p. 126–127◦C;
1
yield: 83%; H–NMR (400 MHz, DMSO−d6): δ =
9.88 (s, 1H, CHO), 7.80 (s, 1H, quinoline Ar–H), 7.75
(d, 2H, J = 8.20 Hz, Ar–H), 7.26 (d, 1H, J = 8.50 Hz,
quinoline Ar–H), 7.22 (d, 1H, J = 7.10 Hz, quinoline
Ar–H), 7.10 (d, 2H, J = 6.80 Hz, Ar–H), 7.02 (s,
1H, quinoline Ar–H), 5.14 (s, 2H, −CH2O), 3.70 (s,
3H, OCH3) ppm; GCMS: (ESI+, m/z) 328 (M+), 330
(M++2).
1
11.95 (s, 1 H, NH, exchangeable with D2O), 9.13 (s,
1H, NH, exchangeable with D2O), 7.97 (s, 1H, quino-
line Ar–H), 7.69 (t, 1H, J = 7.8 Hz, Ar–H quinoline),
7.49 (t, 1H, J = 6.0 Hz, quinoline Ar–H), 7.19 (d, 2H,
J = 6.0 Hz, Ar–H), 7.15 (d, 1H, J = 6.0 Hz, quinoline
Ar–H), 5.10 (s, 1H, −CH-), 5.02 (s, 2H, CH2), 3.97 (q,
2H, J = 6 Hz, −CO CH2 CH3), 2.67 (s, 3H, CH3), 1.09
(t, 3H, J = 9.0 Hz, −CO CH2 CH3) ppm; Anal. Cald
for C24H22ClN3O4: C 63.79, H 4.91, N 9.30, Found: C
62.18, H 4.77, N 9.18. GCMS: (ESI+, m/z) = 452 (M+),
454 (M++2).
2.5g 4-((2-Chloro-6-ethoxyquinolin-3yl)methoxy)
benzaldehyde 10g: White solid; m.p. 120–121◦C;
1
yield: 84%; H–NMR (400 MHz, DMSO−d6): δ =
9.83 (s, 1H, CHO), 7.80 (s, 1H, quinoline Ar–H), 7.70

650
Dhanaji V Jawale et al.
2.6b Ethyl 4-(4-((2-chloro-8-methylquinolin-3-yl) 2.6e Ethyl 4-(4-((2-chloro-7-methoxyquinolin-3-yl)
methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2- methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2-
oxopyrimidine-5-carboxylate 11b: White solid; m.p. oxopyrimidine-5-carboxylate 11e: White solid;
1
237–238◦C; yield: 82%; 1H–NMR (400 MHz, m.p. 225–226◦C; yield: 87 %; H–NMR (400 MHz,
DMSO−d6): δ = 11.21 (s, 1H, -NH exchangeable with DMSO−d6): δ = 11.80 (s, 1H, -NH exchangeable with
D2O), 9.14 (s, 1H, exchangeable with D2O), 8.62 (s, D2O), 8.93 (s, 1H exchangeable with D2O), 7.81 (s, 1H,
1H, quinoline Ar–H), 7.90 (t, 1H, J = 9.0 Hz, quino- quinoline Ar–H), 7.28 (d, 1H, J = 8.60 Hz, quinoline
line Ar–H), 7.70 (d, 1H, J = 8.10 Hz, quinoline Ar–H), Ar–H), 7.20 (d, 1H, J = 7.20 Hz, quinoline Ar–H), 7.01
7.28 (d, 1H, J = 9.0 Hz, quinoline Ar–H), 6.99 (d, (s, 1H, quinoline Ar–H), 6.91 (d, 2H, J = 8.90 Hz, Ar–
2H, J = 7.30 Hz, Ar–H), 5.13 (s, 2H, −CH2O), 5.0 (s, H), 5.18 (s, 1H, −CH-), 5.01 (s, 2H, CH2O), 4.06 (m,
1H, −CH-), 3.96 (q, 2H, J = 7.10 Hz, −COCH2CH3), 2H, −CO CH2 CH3), 3.79 (s, 3H, OCH3), 2.29 (s, 3H,
2.78 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.06 (t, 3H, CH3), 1.14 (t, 3H, J = 7.52 Hz, −CO CH2CH3) ppm;
J = 7.10 Hz, −COCH2CH3) ppm; Anal. Cald for Anal. Cald. for C25H24ClN3O5, : C 62.31, H 5.02, N
C25H24ClN3O4: C 64.44, H 5.19, N 9.02, Found: C 8.72, Found: C 62.27, H 4.98, N 8.68. GCMS: (ESI+,
63.98, H 5.13, N 8.96. GCMS: (ESI+, m/z) = 466 m/z) = 482 (M+), 484 (M++2).
(M+), 468 (M++2).
2.6f Ethyl 4-(4-((2-chloro-6-methoxyquinolin-3-yl)
methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2-
2.6c
Ethyl 4-(4-((2-chloro-7-methylquinolin-3-yl)
oxopyrimidine-5-carboxylate
11f: White
solid;
methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2-
oxopyrimidine-5-carboxylate 11c: White solid; m.p.
228–229◦C; yield: 85%; 1H–NMR (400 MHz,
DMSO−d6): δ = 11.12 (s, 1H, -NH exchangeable
with D2O), 9.13 (s, 1H exchangeable with D2O), 8.06
(s, 1H, quinoline Ar–H), 7.62 (d, 1H, J = 8.0 Hz,
quinoline Ar–H), 7.52 (d, 1H, J = 7.90 Hz, quinoline
Ar–H), 7.00 (d, 2H, J = 8.40 Hz, Ar–H), 5.05 (s,
1H, −CH-), 5.14 (s, 2H, CH2O), 3.99 (q, 2H, J =
7.1 Hz, −COCH2CH3), 2.77 (s, 3H, CH3), 2.77 (s, 3H,
CH3), 2.24 (s, 3H, CH3), 1.08 (t, 3H, J = 7.20 Hz,
−COCH2CH3) ppm; Anal. Cald for C25H24ClN3O4,: C
64.44, H 5.19, N 9.02, Found: C 63.98, H 5.13, N 8.96.
GCMS: (ESI+, m/z) = 466 (M+), 468 (M++2).
1
m.p. 215–216◦C; yield: 85%; H–NMR (400 MHz,
DMSO−d6): δ = 11.82 (s, 1H, -NH exchangeable
with D2O), 8.92 ( s, 1H exchangeable with D2O), 7.80
(s, 1H, quinoline Ar–H), 7.26 (d, 1H, J = 8.50 Hz,
quinoline Ar–H ), 7.21 (d, 1H, J = 7.10 Hz, quinoline
Ar–H), 7.02 (s, 1H, quinoline Ar–H), 6.91 (d, 2H, J =
8.50 Hz, Ar–H), 6.80 (d, 2H, J = 8.50 Hz, Ar–H), 5.18
(s, 2H, −CH2-), 4.99 (s, 1H, −CH-), 4.05-3.98 (m, 2H,
−COCH2CH3), 3.8 (s, 3H, CH3), 2.28 (s, 3H, CH3),
1.15 (t, 3H, J = 7.50 Hz, −COCH2CH3) ppm; Anal.
Cald for C25H24ClN3O5, : C 62.31, H 5.02, N 8.72,
Found: C 62.27, H 4.98, N 8.68. GCMS: (ESI+, m/z)
= 482 (M+), 484 (M++2).
2.6g
2.6d Ethyl 4-(4-((2-chloro-6-methylquinolin-3-yl) methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2-
methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2- oxopyrimidine-5-carboxylate 11g: White solid;
oxopyrimidine-5-carboxylate 11d: White
solid; m.p. 218–219◦C; yield: 83%; H–NMR (400 MHz,
Ethyl 4-(4-((2-chloro-6-ethoxyquinolin-3-yl)
1
1
m.p. 211–212◦C; yield: 84%; H–NMR (400 MHz, DMSO−d6): δ = 11.78 (s, 1H, -NH exchangeable with
DMSO−d6): δ = 11.13 (s, 1H, -NH exchangeable with D2O), 8.92 (s, 1H exchangeable with D2O), 7.76 (s,
D2O), 9.14 (s, 1H exchangeable with D2O), 7.67 (s, 1H, quinoline Ar–H), 7.40 (s, 1H, quinoline Ar–H),
1H, quinoline Ar–H), 7.54 (d, 1H, J = 7.70 Hz, quino- 7.26 (d, 1H, J = 7.50 Hz, quinoline Ar–H ), 7.20 (d,
line Ar–H), 7.34 (d, 1H, J = 7.0 Hz, quinoline Ar–H), 1H, J = 7.50 Hz, quinoline Ar–H), 6.90 (d, 2H, J =
7.17 (d, 2H, J = 8.40 Hz, Ar–H), 7.00 (d, 1H, J = 7.90 Hz, Ar–H), 6.83 (d, 2H, J = 7.60 Hz, Ar–H),
8.40 Hz, Ar–H), 5.10 (s, 2H, CH2), 5.0 (s, 1H, −CH-), 5.19 (s, 1H, −CH-), 4.90 (s, 2H, −CH2-), 4.11 (m, 2H,
3.98 (q, 2H, J = 7.10 Hz, −COCH2CH3), 2.44 (s, 3H, −OCH2CH3), 4.10 (m, 2H, −OCOCH2CH3), 2.23 (s,
CH3), 2.24 (s, 3H, CH3), 1.09 (t, 3H, J = 7.10 Hz, 3H, CH3), 1.37 (t, 3H, J = 7.1 Hz, −OCH2 CH3), 1.16
−COCH2CH3) ppm; Anal. Cald. for C25H24ClN3O4, (t, 3H, J = 7.1 Hz, −O CO CH2CH3) ppm; Anal. Cald
Calculated: C 64.44, H 5.19, N 9.02, Found: C 63.98, for C26H26ClN3O5, : C 62.97, H 5.28, N 8.47, Found:
H 5.13, N 8.96. GCMS: (ESI+, m/z) = 466 (M+), 468 C 62.93, H 5.27, N 8.43. GCMS: (ESI+, m/z) = 496
(M++1).
(M+), 498 (M++2).

Synthesis of New dihydropyrimidinones catalysed by dicationic ionic liquid
651
O
R
HN
O
Br
N
R
Br
N
O
O
O
NH
N
N
4
H2N
NH2
O
O
CHO
1a-f
80OC, 2 h
5a-f
2
3
Scheme 1. Synthesis of dihydropyrimidinones catalysed by dicationic ionic liquid.
2.6h
Ethyl 4-(4-((2,7-dichloroquinolin-3-yl) catalyst and diluent. It was noted that after heating,
methoxy) phenyl)-1,2,3,4-tetrahydro-6-methyl-2- the product yield obtained was relatively low. Then the
oxopyrimidine-5-carboxylate 11h: White solid; above model reaction was carried under neat condi-
1
m.p. 232–233◦C; yield: 85%; H–NMR (400 MHz, tion in the presence of various catalysts like p-toluene
DMSO−d6): δ = 11.90 (s, 1H, -NH exchangeable sulphonyl chloride (PTSA), acetic acid, boric acid and
with D2O), 9.01 (s, 1H exchangeable with D2O), 8.4 SiO2Cl at 80◦C for 2 h. The yields of DHPM (5b) are
(s, 1H, quinoline Ar–H), 7.90 (d, 1H, J = 8.0 Hz, recorded in table 1. Keeping these results in mind, w−e
quinoline Ar–H), 7.50 (d, 1H, J = 7.60 Hz, quinoline then performed the model reaction in [C4 min] Br
Ar–H), 7.30 (d, 2H, J = 8.10 Hz, Ar–H), 7.01 (d, 2H, (1-Butyl-3-methyl-1H-imidazolium bromide) ionic liq-
J = 8.30 Hz, Ar–H), 5.18 (s, 1H, −CH-), 5.10 (s, 2H, uid, and observed yield enhancement. Encouraged by
CH2O), 4.10 (m, 2H, −CO CH2 CH3), 2.32 (s, 3H, these results, we focused our attention on the use of C3
CH3), 1.16 (t, 3H, J = 7.60 Hz, −COCH2CH3) ppm; [min]2 2 [Br−] (dicationic ionic liquids) as a catalyst
Anal. Cald. for C24H21Cl2N2O4 : C 59.27, H 4.35, N and medium to perform the cyclocondensation of afore-
8.64, Found: C 59.25, H 4.33, N 8.64. GCMS: (ESI+, mentioned model reaction at 80◦C. It was found that
m/z) = 486(M+), 488 (M++2). 490 (M++4).
the dicationic ionic liquid worked well and the conden-
sation was found to take place rapidly giving excellent
yield of DHPM (5b) (table 1).
3. Results and discussion
With all the above optimized conditions in hand, we
then applied this approach to various aromatic alde-
hydes, ethylacetoacetate and urea using the dicationic
ionic liquid and obtained DHPMs with excellent yields
(table 2). It is noteworthy to mention that the method-
ology worked-well to both electron donating and with-
drawing substituent on aldehydes. To the best our
knowledge, we have been reporting first time the use of
dicationic ionic liquid mediated and catalysed one-pot
Biginelli reaction for DHPMs (table 2).
We have developed an environmentally benign and eco-
sustainabale one-pot synthetic protocol for the synthe-
sis of known DHPMs (5 a–f) by allowing the interac-
tions of aryl aldehydes (1 a–f), ethyl acetoacetate (2)
and urea (3) in presence of freshly prepared dicationic
ionic liquid, 3-methyl-1-[3-(methyl-1H-imidazolium-
1-yl) propyl]-1H-imidazolium dibromide (C3 [min]2 2
[Br−] ) (4) at 80◦C for 2 h (scheme 1).
To investigate the choice of catalysts, we have
attempted the Biginelli reaction of multicomponents,
4-methoxy benzaldehyde (1b), ethyl acetoacetate (2)
and urea (3) as a model reaction to afford the DHPM
(5b). Initially the reaction was run in the absence of
The developed synthetic strategies for DHPMs have
been found to be economic as the dicationic ionic liquid
can be recovered and reused.
Table 2. Synthesis of known dihydropyrimidinones
(scheme 2).
Table 1. Optimization of catalysts.
Sl. No. Catalystsa
Time (h)b Isolated yieldsc
Entry
R
Productsa b
Yieldb (%)
1
2
3
4
5
6
7
None
PTSA
AcOH
Boric acid
SiO2Cl
2
2
2
2
2
2
2
61
65
68
73
75
80
89
1
2
3
4
5
6
H
5a
5b
5c
5d
5e
5f
85
89
84
87
88
86
4-OCH3
4-Cl
4-OH
4-NO2
3-NO2
[C4 min] Br
C3 [min]2 2 [Br−]
a All compounds are known and their spectroscopic data and
aAmount of catalyst required 100 mole %; bReaction carried melting point are in good agreement with literature48
at 80◦C; cIsolated yield bIsolated yields of products

652
Dhanaji V Jawale et al.
H
R
R
N
DMF, POCl3
80-90OC
R
CHO
NaBH4, CH3OH,
rt. 30 min,
OH
O
N
Cl
N
8 a-h
Cl
6 a-h
7 a
-h
DCM, TEA, p-toluene
sulphonyl chloride
5-6h, 0OC
R
R
TsO
P-hydroxy benzaldehyde
80OC, 5h
O
CHO
Cl
N
N
Cl
9 a-h
10 a-h
Scheme 2. Synthesis of new 4-((2-chloroquinolin-3-yl) methoxy) benzaldehydes.
R
O
Br
N
Br
N
O
CHO
R
N
HN
O
N
4
O
N
Cl
O
NH
O
10 a-h
80OC, 2 h
N
Cl
11a
O
H2N
NH2
O
O
-h
3
2
Scheme 3. Synthesis of new DHPMs using dicationic ionic liquid.
Keeping these results in mind, we then paid our atten-
The dicationic ionic liquid encompasses two imida-
tion to synthesize new dihydropyrimidinones bearing zole cations and two bromide ions. The ions might
quinolines, catalysed by dicationic ionic liquid using be useful for strong H-bondining with the substrate as
new aldehydes and the details are given below.
compared with the traditional ionic liquids. It was also
New 4-((2-chloroquinolin-3-yl) methoxy) benzalde- noted that dicationic ionic liquid has dual nature and
hydes (10 a–h), required precursors for the one-pot the plausible mechanism for the formation of DHPMs
synthesis were freshly prepared by following the reac- using C3 [min]2 2Br− has been depicted in (scheme 4).
tion sequence presented in (scheme 2). 2-Chloro- The electrophilic character of carbonyl carbon of the
3-formyl quinolines (7 a–h), prepared by literature aldehydes (1) might be increased by forming inter-
procedure49 were first reduced50 using sodium boro- molecular H- bonding between H atoms of imidazoles
hydride for getting corresponding (2-chloroquinolin- cations and carbonyl oxygen of the aldehydes and the
3-yl) methanols (8 a–h). The compounds, (8 a–h) nucleophilicity of N atom of urea (3) might be enhanced
when tosylated using p-toluene sulphonyl chloride and by forming the H bonding between H atom of urea
triethylamine gave (2-chloroquinolin-3-yl) methyl 4- and bromide ions of C3[min]2 2Br− (4). Therefore, the
methylbenzenesulfonates, (9 a–h). The sulphonates, (9
Table 3. Synthesis of new dihydropyrimidinones
(scheme 3).
a–h) on condensation with p-hydroxy benzaldehyde
in DMF in presence of potassium carbonate yielded
the required 4-((2-chloroquinolin-3-yl) methoxy) ben-
zaldehydes, (10 a–h) with good yields.
Entry
R
Productsa
Yieldb (%)
1
2t
3
4
5
6
7
8
H
11a
11b
11c
11d
11e
11f
11g
11h
83
82
85
84
87
85
83
85
We have applied the above developed environmen-
tally benign, ecosustaibale one-pot synthetic protocol
for the synthesis of new DHPMs, (11 a–h) by carrying
out the cyclocondensation of 4-((2-chloroquinolin-3-yl)
methoxy) benzaldehydes (10 a–h), ethyl acetoacetate
(2) and urea (3) in dicationic ionic liquid, ([C3 min]2
2 Br − ) (4) at 80◦C for 2 h (scheme 3). The cyclocon-
densation gave excellent yields of DHPMs (11 a–h),
(table 3). This modified protocol was found to be better
than any other reported for Biginelli reaction.
8-CH3
7-CH3
6-CH3
7-OCH3
6-OCH3
6-OCH2CH3
7-Cl
aAll products were characterized by 1H–NMR, Mass spectral
and Elemental analyses
b Isolated yields of products

Synthesis of New dihydropyrimidinones catalysed by dicationic ionic liquid
653
2Br-
4
N
2 Br-
( )3
2Br-
H
N
O
N
O
( )
N
N
O
N
N
3N
N
N
O
H
N
N
O
O
O
O
H
N
R
1
H
R
H2N
N
NH2
O
3
5
2Br-
N
O
R
O
H
R
O
R
O
O
NH
O
NH
O
NH
N
HO
O
N
H
O
N
H
O
H20
H2N
N
N
8
7
6
Scheme 4. Plausible mechanism for the synthesis of DHPMs using dicationic ionic liquid.
nucleophic addition of nitrogen atom of urea on the Acknowledgements
electrophilic carbonyl carbon might be enhanced and
Authors are thankful to Professor D B Ingle for
his invaluable discussions and guidance. One of the
authors, D V Jawale is also grateful to University Grants
Commission (UGC), New Delhi, India for Research
Fellowship in ‘Sciences for meritorious students’.
thus rate of acceleration of Mannich reaction was found
to be increased to give intermediate N-acyliminium
species (5). Further, the successive nucleophilic addi-
tion of enolic ethyl acetoacetate (3) on N-acylinium
species would have occurred leading to intermediates
(6). Thus obtained intermediates are being unstable
which on successive dehydration would have helped to
yield DHPMs (8). Thus, dicationic ionic liquid plays
triple role other than as medium for obtaining DHPMs
such as, (i) it might be enhancing the rate accelera-
tion of Mannich addition of urea on aldehydes, (ii) it
might be enhancing the nucleophilic addition of eno-
lic ethylacetoacetate on N-acyliminium species and (iii)
it would be useful for the successive dehydration of the
intermediates for obtaining DHPMs.
References
1. (a) Kappe C O, 2000 Acc. Chem. Res. 49 879; (b) Kappe
C O 1993 Tetrahedron 49 37; (c) Biginelli, P. 1893 Ber.
26 447
2. (a) Rovnyak G C, Atwal K S, Hedberg A, Kimball
S D, Moreland S, Gougoutas J Z, OReilly B C,
and Malley M F 1992 J. Med. Chem. 35 3254;
(b) Cho H, Ueda M, Shima K, Mizuno A, Ohnaka
M, Takeuchi Y, Hamaguchi Y, Aisaka M K, Hidaka T,
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2399
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D M, Normandin D E, Parham C S, Sleph P G, and
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(b) Haggarty S J, Mayer T U, Miyamoto D T, Fathi R,
King R W, Mitchson T J and Schreiber S L 2000 Chem.
Biol. 7 268
4. Conclusion
We have developed safer, economic and one-pot
synthetic protocol for the synthesis of DHPMs.
Dicationic ionic liquid circumvents the problems asso-
ciated with the organic solvents and also it mini-
mizes the use of acetic acid and mineral acids. The
synthetic strategy made more economic by recover-
ing and recycling of dicationic ionic liquid. We have
synthesized new DHPMs encompassing quinolines
through ethereal link in four steps from known formyl
quinolines. The fascinating scope of this synthetic strat-
egy is that the products and intermediates obtained were
from readily available materials and are unambiguous.
The synthesized compounds are well-characterized by
the spectral and elemental analyses.
5. Tewari N, Tiwari V K, Mishra R C, Tripathi R P A,
Srivastava K, Ahmad R R, Srivastava B. S. 2003 Bioorg.
Med. Lett. 11 2911
6. Snider B B and Shi Z 1993 J. Org. Chem. 58 3828, and
refs cited therein

654
Dhanaji V Jawale et al.
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