N-bromosuccinimide as an almost neutral catalyst for efficient synthesis of dihydropyrimidinones under microwave irradiation

Article abstract of DOI:10.1055/s-2004-822348

NBS has been used as a mild, efficient and almost neutral catalyst for the preparation of dihydropyrimidinones (DHPMs) and the corresponding thio-derivatives under microwave irradiation. By this method, a wide variety of DHPMs were synthesized in good to

Full text of DOI:10.1055/s-2004-822348

PAPER
1239
N-Bromosuccinimide as an Almost Neutral Catalyst for Efficient Synthesis of
Dihydropyrimidinones Under Microwave Irradiation
N
-Bromosuccinim
a
ide as Neut
s
ral Cataly
s
st for Synt
a
hesis of
D
i
n
hydropyrimidinone
H
s
azarkhani, Babak Karimi*
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P.O.Box 45195-159, Gava Zang, Zanjan, Iran
Fax +98(241)4249023; E-mail: karimi@iasbs.ac.ir
Received 20 January 2004; revised 23 February 2004
catalysts and also need prolonged reaction times. Further-
Abstract: NBS has been used as a mild, efficient and almost neutral
more, the yields of the corresponding DHPMs are not
always satisfactory. On the other hand, N-bromo-
catalyst for the preparation of dihydropyrimidinones (DHPMs) and
the corresponding thio-derivatives under microwave irradiation. By
succinimide (NBS) is a very cheap and safe reagent that
has extensively been used as oxidizing and brominating
agent in organic synthesis.15 However, the catalytic be-
havior of NBS as Lewis acid has been firstly studied in our
laboratories during a research program in order to find a
mild procedure for the acetalization of carbonyl com-
pounds.16 It was shown that NBS catalyzes selective ace-
talization of aldehydes in the presence of ketones under
mild and neutral reaction conditions. Subsequently, NBS
has exponentially been utilized as a mild and almost neu-
tral either a Lewis acid or a reagent for different types of
functional group transformations. For example, acetyla-
tion of alcohols,17 preparation of acylals,18 cleavage of
oxathiacetals,19 interchange of thioacetals and oxathio-
acetals into their acetals,19 transesterification, oxathio-
acetalization, thio-acetalization and trans-thioacetal-
ization of carbonyl compounds20 have also been achieved
using NBS under mild reaction conditions. In continua-
tion of this study, herein, we wish to report a facile and
improved protocol for preparation of DHPMs under near-
ly neutral reaction conditions using NBS as catalyst
(Scheme 1).
this method, a wide variety of DHPMs were synthesized in good to
high yields.
Key words: N-bromosuccinimide, dihydropyrimidinones, micro-
wave irradiation
Dihydropyrimidinones (DHPMs) derivatives have attract-
ed considerable interest in recent years due to their prom-
ising activities as calcium channel blockers,1
antihypertensive, antibacterial, antitumor and anti-inflam-
matory agents.2 Moreover, several alkaloids containing
the dihydropyrimidine target have been isolated from ma-
rine sources, which also exhibited interesting biological
properties.3 For example, batzelladine alkaloids have been
utilized as potent HIV gp-120-CD4 inhibitors.4 Therefore,
the synthesis of these heterocyclic compounds has gained
special attention. A literature search shows that the prep-
aration of dihydropyrimidinones contains a three compo-
nent condensation reaction of aldehydes, b-keto esters and
urea in acidic solution of EtOH as shown by the pioneer
work of Biginelli.5 The major drawback of this protocol is
the low yields in the case of both substituted aromatic and
aliphatic aldehydes. Therefore, the search for finding
milder and more convenient methods for the preparation
of dihydropyrimidinones continued to attract attention.
Recently, many improved procedures have been reported
for the preparation of DHPMs using InBr3,6 InCl3,7
LiClO4,8 FeCl3·6H2O or NiCl2·6H2O,9 p-TsOH,10
When a mixture of benzaldehyde and ethyl acetoacetate
was allowed to react with urea in the presence of NBS (20
mol%) in refluxing EtOH for 10 hours, 5-ethoxycarbonyl-
6-methyl-4-phenyl-3,4-dihydropyrimidine-2-1H-one was
obtained in 94% yield (Table 1, entry 1). In a similar way,
various types of aromatic aldehydes containing either
electron-withdrawing or electron-donating substituents as
well as cinnamaldehyde successfully react with both urea
and thiourea to afford the corresponding 5-ethoxycarbon-
yl-6-methyl-4-aryl-3,4-dihydropyrimidine-2-1H-one and
their corresponding sulfur analogs, respectively, in good
13
LaCl3·7H2O,11 Bi(OTf)3,12 BF3·OEt2 as catalyst. Poly-
phosphate ester (PPE)14 has also been used as a reaction
mediator for Biginelli condensation under microwave ir-
radiation. However, many of these protocols suffer from
drawbacks such as the use of expensive and highly acidic
Scheme 1
SYNTHESIS 2004, No. 8, pp 1239–1242
x
x
.
x
x
.2
0
0
4
Advanced online publication: 04.05.2004
DOI: 10.1055/s-2004-822348; Art ID: Z01104SS
© Georg Thieme Verlag Stuttgart · New York

1240
H. Hazarkhani, B. Karimi
PAPER
to excellent yields (Table 1, entries 2–14). Furthermore, cess is that NBS probably generates small quantities of
under similar reaction conditions, both butanal and hepta- HBr or Br2, which may be the actual catalyst for the reac-
nal as a model for aliphatic and enolizable aldehydes gave tion. Since the generation of HBr in protic solvent such as
the corresponding 5-ethoxycarbonyl-6-methyl-4-alkyl- aqueous EtOH is more probable and causes the reaction
3,4-dihydropyrimidine-2-1H-one in high yields (entries conditions to became slightly acidic, we have selected
15 and 16). Moreover, application of microwave irradia- N,N-dimethylacetamide (DMAC). Moreover, owing to
tion has opened a new perspective in synthetic organic the higher solubility of the substrates, and the excellent
chemistry, not only in terms of high yield and selectivity, energy transfer property, it seems that DMAC is a superi-
but also ease of the reaction conditions and rate accelera- or solvent than EtOH for this transformation. Under these
tion.11 Hence, microwaves have been applied to accelerate conditions NBS acts as an almost neutral catalyst through
reaction rates for a variety of chemical transformations which either Br+ or Br2 may be considered as the actual
and improve the yields of products in most cases. Along catalyst. Therefore we have chosen DMAC as the reaction
this line we observed that, when a mixture of ethyl ace- solvent in all of the subsequent reactions. In this regard,
toacetate, benzaldehyde and urea in EtOH (95%) was ir- several types of 5-ethoxycarbonyl-6-methyl-4-aryl-3,4-
radiated with microwave (600 W power) in the presence dihydropyrimidine-2-1H-ones have been effectively pre-
of a catalytic amount of NBS (20 mol%), the reaction was pared under mild reaction conditions (Table 1). Similarly,
almost completed within 3 minutes. Work-up of the reac- 4-alkyl substituted DHPMs were successfully prepared
tion mixture shows that 5-ethoxycarbonyl-6-methyl-4- from the reaction of ethyl acetoacetate, urea and aliphatic
phenyl-3,4-dihydropyrimidine-2-1H-one was prepared in aldehydes under the same reaction conditions in good
92% after recrystallization from 95% EtOH (entry 3). The yields (entries 15 and 16). Further, the usefulness of this
actual role of NBS is not clear so far, as we have men- methodology has also been extended to the synthesis of 5-
tioned in our previous reports.16–18 However, a plausible ethoxycarbonyl-6-methyl-4-aryl-3,4-dihydropyrimidine-
explanation is that NBS might act as a source of Br+ ions 2-1H-thiones using thiourea. When NBS (20 mol%) was
which in turn activates the aldehyde for further reaction added to a solution of ethyl acetoacetate, 4-tolylaldehyde
with ethyl acetoacetate. Another explanation for this pro- and thiourea in DMAC, and the reaction mixture was irra-
Table 1 Synthesis of DHPMs Using NBS as Catalyst Under Microwave Irradiation
Entry
RCHO
X
Time (h)
Refluxing in EtOH
Yield (%)a,b
Time (min)
Irradiated in DMAC
Yield (%)a,b
1
2
PhCHO
O
S
10
15
3
94
88
92c
91d
90
90
89
90
88
75
85
78
90
85
88
85
3
5
–
–
4
6
4
4
6
6
6
6
6
5
4
5
92
80
–
PhCHO
3
PhCHO
O
O
O
S
4
4-MeC6H4CHO
4-MeC6H4CHO
4-MeC6H4CHO
4-MeOC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-NO2C6H4CHO
4-NO2C6H4CHO
Cinnamaldehyde
Cuminaldehyde
CH3CH2CH2CHO
CH3CH2CH2CH2CH2CHO
4
–
5
10
16
12
1
94
89
91
92
89
80
88
80
89
80
84
82
6
7
O
S
8
9
O
S
15
20
25
25
20
20
10
11
10
11
12
13
14
15
16
O
S
O
O
O
O
a Isolated yield.
b Products were identified by the comparison of their mp (bp), IR, and 1H NMR data with those of the authentic samples.
c The reactions were carried out under microwave irradiation for 3 min.
d 4 min under microwave irradiation.
Synthesis 2004, No. 8, 1239–1242 © Thieme Stuttgart · New York

PAPER
N-Bromosuccinimide as Neutral Catalyst for Efficient Synthesis of Dihydropyrimidinones
1241
(EtOAc–n-hexane, 10:1) pure product was obtained as white crys-
tals; yield: 2.4 g (80%), mp: 157–159 °C.
hydropyrimidine-2-1H-thione was obtained in 87% yield. 1H NMR (500 MHz, DMSO-d6): d = 9.15 (s, 1 H), 7.67 (s, 1 H),
diated (600 W), the reaction was completed within 3
minutes and 5-ethoxycarbonyl-6-methyl-4-tolyl-3,4-di-
7.18–7.13 (dd, J = 8.15 Hz, 4 H), 5.11 (s, 1 H), 4.00–3.96 (q, J = 7
Hz, 2 H), 2.84–2.82 (sep., J = 6.8 Hz, 1 H), 2.23 (s, 3 H), 1.17–1.15
(d, J = 6.8 Hz, 6 H), 1.11–1.08 (t, J = 7 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 165.91, 152.77, 148.66,
147.91, 142.89, 126.77, 126.70, 99.99, 59.70, 54.13, 33.62, 24.42,
24.37, 18.31, 14.61.
By this procedure different types of structurally diverse 5-
ethoxycarbonyl-6-methyl-4-aryl-3,4-dihydropyrimidine-
2-1H-thiones were prepared from the condensation reac-
tions of various aromatic aldehydes, bearing either elec-
tron-withdrawing or electron-releasing substitutents, with
thiourea and ethyl acetoacetate under microwave irradia-
tion (entries 2, 6, 8, 10 and 12).
Preparation of 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihy-
dropyrimidine-2-1H-thione using NBS in DMAC under Micro-
wave Irradiation; Typical procedure
A mixture of ethyl acetoacetate (1.30 g, 10 mmol), benzaldehyde
(1.10 g, 10 mmol), thiourea (1.06 g, 14 mmol) and NBS (0.36 g, 2
In summary we have introduced a new application for
NBS. High yields of the products, short reaction times in
the case of microwave irradiation and also mild reaction
conditions make this protocol complementary to the exist-
ing methods. Further applications of NBS in organic
transformation are currently being studied in our laborato-
ries.
mmol) in DMAC (2 mL), contained in a tall beaker, was placed in
the microwave oven. The beaker was covered with a watch glass
and irradiated at 600 W power for 5 min (Table 1, entry 2). To con-
trol the evolution of EtOH from the reaction mixture and to prevent
splashing, irradiation sequences reaction was interrupted after every
20 s. Then the reaction mixture was allowed to cool to r.t., and H2O
(5 mL) was added. The precipitate was filtered off and washed with
H2O. After column chromatography on silica gel (EtOAc–n-hex-
ane, 10:1) pure product was obtained as yellow-white crystals;
yield: 2.15 g (80%); mp 215–217 °C (lit.7 220–222 °C).
1H NMR and 13C NMR spectra were recorded on a Bruker 250 or
500 MHz spectrometer in CDCl3 as solvent and with TMS as an in-
ternal standard. All of the products are known and gave satisfactory
IR and NMR spectra.
Preparation of 5-Ethoxycarbonyl-6-methyl-4-toluyl-3,4-dihy-
dropyrimidine-2-1H-one using NBS in Refluxing EtOH (95%);
Typical Procedure
Acknowledgments
The authors are thankful to Institute for Advanced Studies in Basic
Sciences (IASBS) for the partial support of this work.
A solution of ethyl acetoacetate (1.30 g, 10 mmol), 4-tolylaldehyde
(1.2 g, 10 mmol), urea (0.84 g, 14 mmol) and NBS (0.36 g, 2 mmol)
in 95% EtOH was heated under reflux for 10 h (Table 1, entry 5).
Then the volume of the solvent was reduced to one half and the so-
lution was allowed to cool to r.t. The precipitate was filtered off,
washed with H2O and recrystallized from 95% EtOH to afford pure
DHPM as a white solid; yield: 2.5 g (90%); mp 172–174 °C (lit.13
172 °C).
References
(1) (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.;
Hayashimatsu, M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi,
M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.;
Ishihara, T.; Funahashi, K.; Satah, F.; Morita, M.; Noguchi,
T. J. Med. Chem. 1989, 32, 2399. (b) Atwal, K. S.;
Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K.
M.; Malley, M. F. J. Med. Chem. 1990, 33, 2629.
(c) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
Dimarco, J. D.; Gougoutas, J.; Hedberg, A. Ó.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
1995, 38, 119.
(2) (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A. Ó.; Reilly, B. C. J. Med. Chem.
1991, 34, 806. (b) Grover, G. J.; Dzwonczyk, S.; McMullen,
D. M.; Normadinam, C. S.; Sleph, P. G.; Moreland, S. J. J.
Cardiovasc. Pharmacol. 1995, 26, 289.
(3) Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3823.
(4) (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner,
D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R.
K.; Westly, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60,
1182. (b) Rama Rao, A. V.; Gujar, M. K.; Vasudevan, J. J.
Chem. Soc., Chem. Commun. 1995, 1369. (c) Snider, B. B.;
Chen, J.; Patil, A. D.; Freyer, A. Tetrahedron Lett. 1996, 37,
6977.
(5) (a) Biginelli, P. Gazz. Chem. Ital. 1893, 23, 360. (b) For a
review see also: Kappe, C. O. Tetrahedron 1993, 49, 6937.
(6) Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.;
Peppe, C. Tetrahedron 2002, 58, 4801.
Preparation of 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihy-
dropyrimidine-2-1H-one using NBS in EtOH (95%) under Mi-
crowave Irradiation; Typical Procedure
A mixture of ethyl acetoacetate (1.30 g, 10 mmol), benzaldehyde
(1.1 g, 10 mmol), urea (0.84 g, 14 mmol) and NBS (0.36 g, 2 mmol)
in 95% EtOH (3 mL), contained in a tall beaker, was placed in the
microwave oven. The beaker was covered with a watch glass and ir-
radiated at 600 W power for 3 min (Table 1, entry 1). To control the
evolution of EtOH from the reaction mixture and to prevent splash-
ing, irradiation sequences reaction was interrupted after every 20 s.
Then the reaction mixture was allowed to cool to r.t., and 95%
EtOH (5 mL) was added. The precipitate was filtered off and
washed with H2O. After drying the almost pure product was ob-
tained as a yellow-white solid; yield: 2.4 g (92%); mp 203–205 °C
(lit.13 202–204 °C).
Preparation of 5-Ethoxycarbonyl-6-methyl-4-cuminyl-3,4-di-
hydropyrimidine-2-1H-one using NBS in DMAC under Micro-
wave Irradiation; Typical Procedure
A mixture of ethyl acetoacetate (1.30 g, 10 mmol), cuminaldehyde
(1.48 g, 10 mmol), urea (0.84 g, 14 mmol) and NBS (0.36 g, 2
mmol) in DMAC (2 mL), contained in a tall beaker, was placed in
the microwave oven. The beaker was covered with a watch glass
and irradiated at 600 W power for 5 min (Table 1, entry 14). To con-
trol the evolution of EtOH from the reaction mixture and to prevent
splashing or frothing, irradiation sequences reaction was interrupted
after every 20 s. Then the reaction mixture was allowed to cool to
r.t., and H2O (5 mL) was added. The precipitate was filtered off and
washed with H2O. After column chromatography on silica gel
(7) Ranu, B.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270.
(8) Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341.
Synthesis 2004, No. 8, 1239–1242 © Thieme Stuttgart · New York

1242
H. Hazarkhani, B. Karimi
PAPER
(9) (a) Lu, J.; Ma, H. Synlett 2000, 63. (b) Lu, J.; Bai, Y.
Synthesis 2002, 466.
(16) Karimi, B.; Ebrahimian, G. R.; Seradj, H. Org. Lett. 1999, 1,
1737.
(10) Jin, T.; Zhang, S.; Li, T. Synth. Commun. 2002, 32, 1847.
(11) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett. 2000, 41, 9075.
(12) Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 67.
(13) Hu, E. H.; Slider, D. R.; Dolling, U.-H. J. Org. Chem. 1998,
63, 3454.
(17) Karimi, B.; Seradj, H.; Ebrahimian, G. R. Synlett 2000, 623.
(18) Karimi, B.; Seradj, H.; Tabaei, M. H. Synlett 2000, 1798.
(19) Karimi, B.; Seradj, H.; Maleki, J. Tetrahedron 2002, 58,
4513.
(20) (a) Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. Synlett
2001, 11. (b) Kamal, A.; Chouhan, G. Synlett 2002, 474.
(c) Kamal, A.; Chouhan, G.; Ahmed, K. Tetrahedron Lett.
2002, 43, 6947.
(14) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799.
(15) Hudlicky, M. Oxidations in Organic Chemistry; ACS
Monograph 186; American Chemical Society: Washington,
DC, 1990.
Synthesis 2004, No. 8, 1239–1242 © Thieme Stuttgart · New York