LiBr as an Efficient Catalyst for One-pot Synthesis of Hantzsch 1,4-Dihydropyridines
hance the yields of the product but lack the simplicity of
the one-pot, one-step synthesis.16 Other procedures
comprise the use of microwaves,17 ionic liquids,18 bo-
ronic acids,10,19 metal triflates,20 TMSCl-NaI,21a
CeCl3•7H2O,21b molecular iodine,21c ceric ammonium
nitrate,21d iron(III) trifluoroacetate,21e in situ generated
HCl,22a and silica-supported acids,22b Na- and Cs-Norit
carbons,22c tetrabutylammonium hydrogen sulfate,13
fermenting Baker’s yeast22d and organocatalysts.23 Very
recently, Debache et al. have introduced triphenyl-
phosphine as a Lewis base catalyst for one-step synthe-
sis of Hantzsch 1,4-dihydropyridines.24
Although most of these processes offer distinct ad-
vantages, they suffer from certain drawbacks such as
high reaction temperatures, expensive metal precursors,
use of catalysts that are harmful to environment,
spending longer reaction times and unsatisfactory yields.
Thus, the development of a simple, efficient and versa-
tile method for the synthesis of 1,4-dihydropyridines
remains of interest and there is a scope for further
renovation toward milder reaction conditions and better
yields.
Considering the above valid points and in
continuation of our effort towards the development of
newer and ‘greener’ synthetic methodologies,25 we set
out to find out a simple and improved protocol for the
preparation of 1,4-dihydropyridines using a readily
available, cheap and non-toxic catalyst. Lithium bro-
mide is a stable, relatively safe and readily available low
cost reagent having unique mild Lewis acid properties.
It has a wide variety of utility in different chemical
transformations including Biginelli condensation, Kno-
evenagel condensation, Ehrlich-Sachs reaction, Friedel-
Crafts reaction, rearrangement of epoxides and prepara-
tion of acylals and xanthenes.26 In most of these re-
ported reactions, LiBr is almost neutral27 and also does
not form any corrosive or harsh by-products during
aqueous workup, unlike strong and expensive catalysts.
priate time (Table 2). After completion of the reaction,
as indicated by TLC, acetonitrile was removed and ethyl
acetate was added to the residue. The resulting suspen-
sion was washed with water followed by brine solution
and dried over Na2SO4. After evaporation of the solvent,
the crude yellow products were purified by crystalliza-
tion from ethanol to afford 1,4-dihydropyridines 4 in
81%—94%. The structure of the products was con-
1
firmed by comparison of their m.p., TLC, IR and H
NMR data with authentic samples prepared by the lit-
erature methods (Table 2).
Diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyri-
1
dine-3,5-dicarboxylate (4b) m.p. 157—159 ℃; H
NMR (CDCl3 300 MHz) δ: 1.30 (t, J=8.2 Hz, 6H),
2.22 (s, 6H), 4.09 (q, J=8.2 Hz, 4H), 5.02 (s, 1H), 5.90
(brs, 1H), 7.24—7.36 (m, 5H); IR (KBr) νmax:+3344,
-1
2958, 1705, 1652, 1497 cm ; EIMS m/z: 329 (M ).
Results and discussion
Herein, we report a mild and efficient protocol for
the preparation of 1,4-dihydropyridines derivatives by
three-component condensation of an aldehyde, a
β-ketoester and ammonium acetate at room temperature
using LiBr as catalyst (Eq. 1).
Our initial work commenced with screening of sol-
vent and catalyst loading so as to obtain optimal reac-
tion conditions for the synthesis of 1,4-dihydropyridines.
Compiled in Table 1 are the results of the model study
using benzaldehyde, methyl acetoacetate and ammo-
nium acetate as substrates under various reaction condi-
tions. The catalytic activity of LiBr was found to be the
best with 10 mol% catalyst loading in acetonitrile as the
solvent (Table 1, Entry 1) in terms of yield and reaction
time among all the other tested solvents, namely,
ethanol, THF, water (Table 1, Entries 3—5). There was
no improvement in the reaction rate and yield on in-
creasing the catalyst loading from 10 mol% to 20 mol%
(Table 1, Entries 1 and 7). In the absence of a catalyst,
the product 1,4-dihydropyridine 4a was obtained in only
25% yield after 16 h demonstrating the efficiency of our
catalyst (Table 1, Entry 8). Neat conditions furnished
the product 4a in 68% yield. Furthermore, the reaction
in the presence of other catalysts was also examined.
When LiClO4•3H2O and FeCl3•6H2O were used as the
catalyst, the reaction required longer time and afforded
the desired product in significantly lower yields than
Experimental
General procedure
Melting points were determined by open glass
capillary method and are uncorrected. IR spectra in KBr
were recorded on a Perkin-Elmer 993 IR spectropho-
1
tometer. H NMR spectra were recorded on a Bruker
WM-40 C (300 MHz) FT spectrometer in CDCl3 using
TMS as internal reference. Mass spectra (MS) were re-
corded under electron impact at 70 eV on an LC-MSD
instrument (Agilent Technologies). All chemicals used
were reagent grade and were used as received without
further purification. Silica gel-G was for TLC.
General procedure for the synthesis of Hantzsch
1,4-dihydropyridines
A mixture of an aldehyde (1 mmol), α,β-ketoester (2
mmol), NH4OAc (1.1 mmol), and LiBr (0.1 mmol) was
stirred at room temperature in acetonitrile for an appro-
Chin. J. Chem. 2011, 29, 118— 122
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
119