New environmentally friendly solvent free synthesis of dihydropyrimidinones catalysed by N-butyl-N,N-dimethyl-α -phenylethylammonium bromide

Article abstract of DOI:10.1016/j.tetlet.2003.09.030

N-Butyl-N,N-dimethyl-α-phenylethylammonium bromide catalyzes efficiently the three component condensation reaction of an aromatic aldehyde, a β-keto ester and urea/thiourea under solvent free conditions at 100°C to afford the corresponding dihydropyrimidi

Full text of DOI:10.1016/j.tetlet.2003.09.030

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8173–8175
New environmentally friendly solvent free synthesis of
dihydropyrimidinones catalysed by
N-butyl-N,N-dimethyl-a-phenylethylammonium bromide
ꢀ
K. Rosi Reddy, Ch. Venkateshwar Reddy, M. Mahesh, P. V. K. Raju and V. V. Narayana Reddy*
Organic Chemistry Division II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 26 June 2003; revised 21 August 2003; accepted 1 September 2003
Abstract—N-Butyl-N,N-dimethyl-a-phenylethylammonium bromide catalyzes efficiently the three component condensation reac-
tion of an aromatic aldehyde, a b-keto ester and urea/thiourea under solvent free conditions at 100°C to afford the corresponding
dihydropyrimidinone in high yield.
©
2003 Elsevier Ltd. All rights reserved.
Dihydropyrimidinones and their derivatives have
attracted great attention recently in synthetic organic
chemistry due to their pharmacological and therapeutic
properties such as antibacterial and antihypertensive
activity as well as behaving as calcium channel blockers,
catalyst for this transformation under solvent-free con-
ditions. Despite being described as a catalyst, ammo-
nium chloride is used in molar equivalents with respect
to the reactant (0.5:1.0). This prompted us to seek an
alternative and solvent-free method of synthesis of these
biologically significant compounds. Our efforts in evalu-
ating a new class of trialkylammonium halides as phase
transfer catalysts for the synthesis of homochiral syn-
thetic pyrethroids, culminated in the identification of a
new catalyst, N-butyl-N,N-dimethyl-a-phenylethyl-
ammonium bromide I, as an efficient PTC for alkyla-
1
a-1a-antagonists and neuropeptide Y (NPY) antago-
2
nists. The biological activity of some alkaloids isolated
recently has been attributed to a dihydropyrimidinone
3
moiety. The first procedure to these compounds
4
reported by Biginelli more than a century ago makes
use of the three component, one-pot condensation of a
b-ketoester, an aldehyde and urea under strongly acidic
17
tion, esterification, etc.
5
conditions. However this method suffers from low
yields in the case of substituted aromatic and aliphatic
aldehydes. Owing to the versatile biological activity of
dihydropyrimidinones, development of an alternative
synthetic methodology is of paramount importance.
Herein we wish to report the utilization of I as a catalyst
in the one-pot, three-component Biginelli’s reaction
under solvent-free conditions. This method (Scheme 1)
not only preserved the simplicity of Biginelli’s one-pot
procedure but also remarkably improved the yields
6
This has led to the development of several new synthetic
strategies involving combinations of Lewis acids and
(
>86%) of dihydropyrimidinones in shorter reaction
times (20–60 min) as against the longer reaction times
required for other catalysts.
7
transition metal salts, e.g. BF –OEt , montmorillonite
3
2
8
9
10
14
(
KSF) polyphosphate esters and reagents like InCl ,
3
11 12 13
LiBr,
TMSCl/NaI,
LaCl ·7H O,
CeCl ·7H O,
3 2
3
2
Three sets of experiments were conducted simulta-
neously using salt I or ammonium bromide as the
catalyst, or neat, with no catalyst, at the same tempera-
ture and time. The results obtained are summarized in
Table 1.
1
5
Mn(OAc) ·2H O, which give better yields of dihy-
3
2
dropyrimidinones.
Most of these reagents are expensive. More recently
16
Ahmad Shabani et al. reported ammonium chloride as
Keywords: N-butyl-N,N-dimethyl-a-phenylethylammonium bromide;
b-ketoesters; Biginelli reaction; dihydropyrimidinones.
ꢀ
IICT Communication No. 030610.
*
Corresponding author. Fax: +91-40-27160387; e-mail: vaddu@
iict.res.in
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.030

8
174
K. Rosi Reddy et al. / Tetrahedron Letters 44 (2003) 8173–8175
Scheme 1.
The three-component, cyclocondensation reaction may
be performed under relatively simple reaction condi-
tions by heating together the three components, an
aldehyde, b-ketoester and urea/thiourea, in the ratio of
Most of the catalysts used for preparation of dihy-
dropyrimidinones are halogen containing Lewis acids.
The present results indicate that the halide present in
the catalyst may be playing a crucial role in these
transformations and may assume significance in the
wake of the large number of publications which have
appeared recently for the synthesis of dihydropyrimidi-
nones by modified Biginelli reactions using heavy metal
halide catalysts. Maybe there is some doubt as to
whether the reaction is catalyzed by Lewis acids via
metal ion coordination or simply by the halide ions.
Moreover, the reaction proceeds neat on prolonged
reaction times without using solvents.
1
:1:3 and the catalyst (0.35–0.50 mol%), to 100°C with
18
stirring. After the completion of the reaction, as indi-
cated by TLC, the reaction mixture was poured onto
crushed ice from which the dihydropyrimidinones were
isolated by filtration and recrystallised from methanol/
ethanol as indicated in Table 1.
The results presented in the Table indicate the scope
and generality of the method, which is efficient, not
only for urea or thiourea, but also for aliphatic as well
as aromatic aldehydes. An important feature of this
method is that electron releasing or withdrawing groups
give excellent yields in high purity. It is pertinent to
note that catalyst I gave consistently higher yields with
aliphatic aldehydes, cf. entry 4u as against the moderate
In conclusion, N-butyl-N,N-dimethyl-a-phenylethylam-
monium bromide has proved to be a catalyst for the
synthesis of dihydropyrimidinones in excellent yields,
with short reaction times, under solvent-free reaction
conditions.
1
9
yields reported earlier.
Table 1. N-Butyl-N,N-dimethyl-a-phenylethylammonium bromide-catalyzed formation of dihydropyrimidinones
a
R1
R2
Yield (%)b
Product (4)
X
Time (min)
Melting point (°C)
Foundc
Reported
A
B
C
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
C H
4-CH C H
4-HOC H
4-CH OC H
4-ClC H
2,5-(CH O) C H
C H
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
S
0
0
0
0
20
61
55
45
25
35
60
45
65
35
35
60
30
60
40
45
53
55
65
65
25
96
97
98
96
87
93
97
98
99
96
97
92
98
98
97
99
93
93
92
91
86
81
86
86
88
81
84
92
89
85
91
93
87
87
85
86
90
77
86
79
78
64
73
85
77
75
72
84
84
83
82
73
72
75
81
80
79
80
75
75
66
68
52
201
170
228
202
210
212
192
208
210
233
177
197
210
203
205
230
209
152
154
170
170
202.47
6
5
2
5
5
5
5
5
5
5
5
5
5
5
5
7
C H
172
3
6
4
2
227–2292
2
C H
6
4
2
7
C H
201–202
3
6
4
2
C H
213–2157
6
4
2
C H
–
194
3
2
6
3
2
23
3-(C H O)C H
C H
6
5
6
4
2
207–2082
206–2081
2
5
4-NO C H
2-NO C H
4-HO, 3-CH OC H
3,4-(CH O) C H
C H
2
6
4
4
2
C H
2
6
2
4
C H
232–233
3
6
3
2
C H
17820
3
3
6
3
2
4-BrC H
C H
–
6
4
2
7
C H
CH3
CH3
CH3
CH3
209–212
6
5
2
1
4-CH C H
4-ClC H
4-HOC H
204
3
6
4
204–2077
–
6
4
6
4
208–2102
1
0
C H
C H
6
5
2
5
5
5
5
5
2
CH -(CH )
C H
151–152
3
2 5
2
s
t
u
CH -(CH )
C H
152–15424
–
3
2 4
2
CH -(CH )
C H
3
2 8
2
CH-(CH3)2
C H
170–17222
2
A: New catalyst (100°C).
B: NH Br (100°C).
4
C: Neat (100°C).
a
All products were characterized by 1H NMR, IR and mass spectroscopy
Isolated and unoptimised yields
Compounds 4a–l recrystallised in ethanol. Compounds 4m–u recrystallised in methanol and melting points were determined on a EDMUND
b
c
BUHLER instrument and are uncorrected.

K. Rosi Reddy et al. / Tetrahedron Letters 44 (2003) 8173–8175
8175
Acknowledgements
18. General procedure for the preparation of N-butyl-N,N-
dimethyl-a-phenylethylammonium bromide-catalyzed syn-
thesis of dihydropyrimidinones 4: A mixture containing the
b-ketoester (10 mmol), aldehyde (10 mmol), urea or
thiourea (30 mmol) and quaternary ammonium bromide
salt (0.35 mol%) was heated at 100°C for the appropriate
time as mentioned in Table 1. After completion of the
reaction, as indicated by TLC, the reaction mixture was
poured onto crushed ice, filtered and recrystallized from
K.R.R. is thankful to the Director, IICT, for financial
support. M.M. and Ch.V.R. thank the CSIR, New
Delhi, for the award of fellowships.
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