Indium(III) chloride-catalyzed one-pot synthesis of dihydropyrimidinones by a three-component coupling of 1,3-dicarbonyl compounds, aldehydes, and urea: An improved procedure for the Biginelli reaction

Full text of DOI:10.1021/jo000711f

6270
J . Org. Chem. 2000, 65, 6270-6272
Sch em e 1
In d iu m (III) Ch lor id e-Ca ta lyzed On e-P ot
Syn th esis of Dih yd r op yr im id in on es by a
Th r ee-Com p on en t Cou p lin g of
1,3-Dica r bon yl Com p ou n d s, Ald eh yd es, a n d
Ur ea : An Im p r oved P r oced u r e for th e
Bigin elli Rea ction
such as HCl,7h AcOH7e and additives.7e Consequently,
there are scopes for further renovation toward milder
reaction conditions, variations of substituents in all three
components and better yields.
Recently, indium(III) chloride has emerged as a power-
ful Lewis catalyst imparting high regio- and chemose-
lectivity in various chemical transformations.8 Our own
work also found InCl3 to be a very efficient catalyst for
two and three component coupling reactions.9 We wish
to report here another remarkable catalytic activity of
InCl3 for the one-pot condensation of 1,3-dicarbonyl
compound, aldehyde and urea to dihydropyrimidin-2(1H)-
ones. (Scheme 1)
In a typical general experimental procedure, a solution
of â-dicarbonyl compound, an aldehyde and urea in THF
was heated under reflux in the presence of a catalytic
amount of indium(III) chloride (10 mol %) for a certain
period of time as required to complete the reaction (TLC).
The reaction mixture was then poured into crushed ice
and the solid product separated was filtered and recrys-
tallized.
A wide range of structurally varied â-dicarbonyl com-
pound, aldehyde and urea are coupled together by this
procedure to produce the corresponding dihydropyrimi-
dinones. The results are reported in Table 1. Both â-keto
ester and â-diketone participated in this reaction readily.
A wide variation in alkyl groups of â-dicarbonyl com-
pounds were tolerated in this procedure. A variety of
substituted aromatic, aliphatic, and heterocyclic alde-
hydes have been subjected to this condensation very
efficiently. Thiourea has been used with similar success
to provide the corresponding dihydropyrimidin-2(1H)-
thiones which are also of much interest with regard to
biological activity.3b Thus, variations in all three compo-
Brindaban C. Ranu,* Alakananda Hajra, and
Umasish J ana
Department of Organic Chemistry, Indian Association
for the Cultivation of Science,
J adavpur, Calcutta 700 032, India
ocbcr@mahendra.iacs.res.in
Received May 9, 2000
Dihydropyrimidinone derivatives have attracted con-
siderable interest in recent times because of their prom-
ising activities as calcium channel blockers, antihyper-
tensive agents and R-1a-antagonists.1 Moreover, several
alkaloids containing the dihydropyrimidine unit have
been isolated from marine sources, which also exhibit
interesting biological properties.2 Thus, synthesis of this
heterocyclic nucleus is of much current importance. The
most simple and straightforward procedure, reported by
Biginelli in 1893, involves one-pot condensation of ethyl
acetoacetate, benzaldehyde and urea under strongly
acidic conditions.3 However, one serious drawback of
Biginelli’s reaction is low yields in the case of substituted
aromatic and aliphatic aldehydes.4 This has led to the
development of multistep strategies that produce some-
what higher overall yields but lack the simplicity of the
one-pot, one-step synthesis.4,5
The art of performing efficient chemical transformation
coupling three or more components in a single operation
by a catalytic process avoiding stoichiometric toxic re-
agents, large amount of solvents and expensive purifica-
tion technique, represents a fundamental target of the
modern organic synthesis.6 Thus, Biginelli’s reaction for
the synthesis of dihydropyrimidinone has received re-
newed interest and several improved procedures have
recently been reported,3b,7 although some of these meth-
ods involve strong Lewis acids such as BF3,7e protic acids
(8) (a) Loh, T.-P.; Pei, J .; Lin, M. Chem. Commun. 1996, 2315. (b)
Loh, T.-P.; Pei, J .; Cao, G.-Q. Chem. Commun. 1996, 1819. (c) Babu,
G.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225. (d) Ranu, B. C.;
J ana, U. J . Org. Chem. 1998, 63, 8212. (e) Loh, T.-P.; Wei, L.-L.
Tetrahedron Lett. 1998, 39, 323. (f) Miyai, T.; Onishi, Y.; Baba, A.
Tetrahedron Lett. 1998, 39, 6291. (g) Hirashita, T.; Kamei, T.; Horie,
T.; Yamamura, H.; Kawai, M.; Araki, S. J . Org. Chem. 1999, 64, 172.
(h) Sengupta, S.; Mondal, S. Tetrahedron Lett. 1999, 40, 8685. (i) Inoue,
K.; Yasuda, M.; Shibata, I.; Babe, A. Tetrahedron Lett. 2000, 41, 113.
(9) (a) Ranu, B. C.; Hajra, A.; J ana, U. Org. Lett. 1999, 1, 1141. (b)
Ranu, B. C.; Hajra, A.; J ana, U. Tetrahedron Lett. 2000, 41, 531.
(10) After the reaction was over, the reaction mixture was poured
into crushed ice and extracted with ethyl acetate. Evaporation of
solvent furnished the crude product which was recrystallized from hot
ethanol.
(11) Folkers, K.; Harwood, H. J .; J ohnson, T. B. J . Am. Chem. Soc.
1932, 54, 3751.
(12) Eynde, J . J . V.; Audiart, N.; Canonne, V.; Michel, S.; Haverbeke,
Y. V.; Cappe, C. O. Heterocycles 1997, 45, 1967.
(13) Yarim, M.; Sarac, S.; Ertan, M.; Batu, O.; Erol, K. Farmaco
1999, 54, 359.
(14) Isobe, T.; Nagao, T.; Takashi, Y.; Miyagaki, M.; Ito, S.; Azuma,
H.; Ishikawa, M. J pn. Kokai Tokkyo Koho 1991; patent J P 3007265;
Chem. Abstr. 1991, 114, 228948.
(1) (a) 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. (b) Atwal, K. S.;
Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;
O’Reilly, B. C. J . Med. Chem. 1991, 34, 806 and references therein.
(2) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J . Am. Chem.
Soc. 1995, 117, 2657.
(3) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Kappe, C. O.
Tetrahedron 1993, 49, 6937.
(4) (a) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J . J .
Org. Chem. 1989, 54, 5898. (b) Barluenga, J .; Tomas, M.; Ballesteros,
A.; Lopez, L. A. Tetrahedron Lett. 1989, 30, 4573.
(5) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
(6) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(7) (a) Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. L Indian J .
Chem. 1995, 34B, 61. (b) Gupta, R.; Gupta, A.; Paul, S.; Kachroo, P.
Indian J . Chem. 1995, 34B, 151. (c) Wipf, P.; Cunningham, A.
Tetrahedron Lett. 1995, 36, 7819. (d) Studer, A.; J eger, P.; Wipf, P.;
Curran, D. P. J . Org. Chem. 1997, 62, 2917. (e) Hu, E. H.; Sidler, D.
R.; Dolling, U.-H. J . Org. Chem. 1998, 63, 3454. (f) Kappe, C. O.;
Falsone, S. F. Synlett 1998, 718. (g) Bigi, F.; Carloni, S.; Frullanti, B.;
Maggi, R.; Sartori, G. Tetrahedron Lett. 1999, 40, 3465. (h) Lu, J .; Ma,
H. R. Synlett 2000, 63.
(15) Chi, Wu Huaxue Xuebao 1956, 22, 184.
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10.1021/jo000711f CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/24/2000

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6271
Ta ble 1. In CI3-Ca ta lyzed Syn th esis of
Dih yd r op yr im id in on es
nents have been accommodated very comfortably. How-
ever, under the present reaction conditions â-keto alde-
hydes do not produce the corresponding dihydropyrimi-
dinones, instead leads to multiple products whose identi-
ties are yet to be established.
Use of just 10 mol % of InCl3 in refluxing THF (65-70
°C) is sufficient to push the reaction forward. Higher
amount of InCl3 did not improve the result to a great
extent. No additive or protic/Lewis acid is necessary in
this procedure. The yields are, in general, very high
regardless of the structural variations in dicarbonyl
compound, aldehyde or urea. The crude products obtained
are of high purity (>95% by 1H NMR). Another important
aspect of this procedure is survival of a variety of
functional groups such as NO2, Cl, OH, OMe, and
conjugated C-C double bond under the reaction condi-
tions. Presumably, the reaction proceeds by the usual
mechanism proposed using Lewis-acids.7
In conclusion, the present procedure of the synthesis
of dihydropyrimidin-2(1H)-ones by indium(III) chloride
catalyzed condensation of 1,3-dicarbonyl compound, al-
dehyde, and urea provides an efficient and much im-
proved modification of Biginelli’s reaction. In addition to
its simplicity and milder reaction conditions, this method
has the ability to tolerate a wide variety of substitutions
in all three components which is lacking in existing
procedures.7 Thus, this procedure will offer an easy access
to substituted dihydropyrimidin-2(1H)-ones and thiones
with varied substitution patterns in very high yields. We
believe, our procedure will find important applications
in the synthesis of dihydropyrimidinones to cater the
needs of academia as well as pharmaceutical industries.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
glass disk with an electrical bath and are uncorrected. 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were run in DMSO-
d6 solutions. IR spectra were taken as KBr plates. Tetrahydro-
furan (THF) was distilled over potassium-benzophenone im-
mediately before use. Indium(III) chloride was purchased from
Aldrich and was used as such. 1,3-Dicarbonyl compounds,
aldehydes urea and thiourea were all commercial materials. All
liquid reagents were distilled before use.
Gen er a l P r oced u r e for th e Syn th esis of Dih yd r op yr i-
m id ion es. Rep r esen ta tive P r oced u r e for 5-Eth oxyca r bo-
n yl-6-m et h yl-4-p h en yl-3,4-d ih yd r op yr im id in -2(1H )-on e
(En tr y 5). A solution of ethyl acetoacetate (260 mg, 2 mmol),
benzaldehyde (212 mg, 2 mmol) and urea (156 mg, 2.6 mmol) in
THF (5 mL) was heated under reflux (65-70 °C) in the presence
of indium(III) chloride (44 mg, 10 mol %) for 7 h (TLC) under
nitrogen. The reaction mixture, after being cooled to room
temperature was poured into crushed ice (20 g) and stirred for
5-10 min. The solid separated was filtered under suction (water
aspirator), washed with ice-cold water (20 mL) and then
recrystallized from hot ethanol to afford pure product (494 mg,
95%), mp 202-203 °C (lit.7e mp 202-204 °C).
This procedure was followed for the preparation of all the
dihydropyrimidinones and thiones listed in Table 1. The known
compounds have been identified by comparison of spectral data
(IR, 1H NMR, and 13C NMR) and mp with those reported. The
mp, spectral, and analytical data of the new compounds have
been presented below in order of their entries.
5-Eth oxyca r bon yl-4-(3-h yd r oxyp h en yl)-6-m eth yl-3,4-d i-
h yd r op yr im id in -2(1H)-on e (en tr y 11): mp 164-166 °C; IR
3348, 3247, 1728, 1704, 1681 cm-1; 1H NMR δ 9.33 (s, 1H), 9.14
(s, 1H), 7.67 (s, 1H), 7.07 (t, J ) 7.8 Hz, 1H), 6.63 (m, 3H), 5.05
(d, J ) 3 Hz, 1H), 4.01 (q, J ) 6.9 Hz, 2H), 2.22 (s, 3H), 1.09
(t, J ) 6.9 Hz, 3H); 13C NMR δ 165.7, 157.7, 152.9, 148.1, 146.6,
129.6, 117.2, 114.5, 113.4, 99.7, 59.5, 54.1, 18.1, 14.5. Anal. Calcd
a
Yields refer to pure solid products, properly characterized by
mp, spectral (IR, 1H, 13C NMR), and analytical data.

6272 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
for C14H16N2O4; C, 60.86; H, 5.84; N, 10.14. Found: C, 60.71; H,
5.69; N, 10.01.
5-Ben zoyl-4-(4-m eth oxyp h en yl)-6-m eth yl-3,4-d ih yd r op y-
r im id in -2(1H)-on e (en tr y 34): mp 218-219 °C; IR 3282, 1706,
1
1674, 1598 cm-1; H NMR δ 9.14 (s, 1H), 7.73 (s, 1H), 7.49 (m,
5-Eth oxyca r bon yl-4-(3-m eth oxyp h en yl)-6-m eth yl-3,4-d i-
h yd r op yr im id in -2(1H)-on e (en tr y 12): mp 207-208 °C; IR
5H), 7.12 (d, J ) 8.4 Hz, 2H), 6.86 (d, J ) 8.4 Hz, 2H), 5.26 (d,
J ) 2.4 Hz, 1H), 3.71 (s, 3H), 1.67 (s, 3H); 13C NMR δ 194.7,
158.7, 152.5, 145.3, 141.3, 136.7, 131.7, 128.9 (2), 128.0 (2),
127.7 (2), 114.1 (2), 110.0, 55.3, 55.0, 18.7. Anal. Calcd for
19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.58; H, 5.52;
N, 8.55.
5-Eth oxyca r bon yl-4-(3-m eth oxyp h en yl)-6-m eth yl-3,4-d i-
3242, 1701, 1651, 1598 cm-1 1H NMR δ 9.17 (s, 1H), 7.70 (s,
;
1H), 7.23 (t, J ) 7.8 Hz, 1H), 6.79 (m, 3H), 5.09 (d, J ) 2.7 Hz,
1H), 3.97 (q, J ) 6.9 Hz, 2H), 3.70 (s, 3H), 2.22 (s, 3H), 1.09 (t,
J ) 6.9 Hz, 3H); 13C NMR δ 165.7, 159.5, 152.5, 148.8, 146.6,
129.9, 118.5, 112.7, 102.6, 99.4, 59.5, 55.3, 54.6, 18.1, 14.4. Anal.
Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C,
61.89; H, 6.18; N, 9.49.
C
h yd r op yr im id in -2(1H)-th ion e (en tr y 36): mp 150-152 °C;
IR 3157, 3122, 1710, 1651, 1596 cm-1; 1H NMR δ 10.37 (s, 1H),
9.71 (s, 1H), 7.27 (t, J ) 9 Hz, 1H), 6.84 (m, 3H), 5.90 (s, 1H),
4.03 (q, J ) 6 Hz, 2H), 3.73 (s, 3H), 2.30 (s, 3H), 1.12 (t, J ) 6
Hz, 3H); 13C NMR δ 174.3, 165.4, 159.6, 145.3, 145.1, 130.1,
118.7, 112.8 (2), 101.1, 60.0, 55.3, 54.2, 17.5, 14.3. Anal. Calcd
for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14. Found: C, 58.62; H,
5.81; N, 9.05.
5-Acet yl-4-(4-m et h oxyp h en yl)-6-m et h yl-3,4-d ih yd r op y-
r im id in -2(1H)-on e (en tr y 29): mp 166-168 °C; IR 3230, 1714,
1
1699, 1596 cm-1; H NMR δ 9.1 (s, 1H), 7.76 (s, 1H), 7.16 (d, J
) 8.4 Hz, 2H), 6.87 (d, J ) 8.4 Hz, 2H), 5.20 (d, J ) 3 Hz, 1H),
3.70 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H); 13C NMR δ 194.7, 158.8,
152.5, 148.1, 136.7, 128.0 (2), 114.2 (2), 109.6, 55.4, 53.7, 30.5,
19.2. Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.39; H, 6.01; N, 10.67.
5-Acet yl-4-(3-m et h oxyp h en yl)-6-m et h yl-3,4-d ih yd r op y-
r im id in -2(1H)-on e (en tr y 30): mp 228-230 °C; IR 3340, 1714,
1678, 1598 cm-1; 1H NMR δ 9.16 (s, 1H), 7.80 (s, 1H), 7.22 (t, J
) 7.8 Hz, 1H), 6.81 (m, 3H), 5.22 (d, J ) 3.3 Hz, 1H), 3.70 (s,
3H), 2.26 (s, 3H), 2.07 (s, 3H); 13C NMR δ 194.6, 159.7, 152.6,
148.5, 146.0, 130.0, 118.7, 113.6, 112.5, 109.7, 55.3, 54.0, 30.6,
19.2. Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.42; H, 5.97; N, 10.68.
5-Acetyl-6-m eth yl-4-p h en yl-3,4-d ih yd r op yr im id in -2(1H)-
th ion e (en tr y 37): mp 220-222 °C; IR 3282, 1615, 1575 cm-1
;
1H NMR δ 10.06 (s, 1H), 9.53 (s, 1H), 7.04 (m, 5H), 5.07 (s, 1H),
2.01 (s, 3H), 1.92 (s, 3H); 13C NMR δ 195.1, 174.4, 144.9, 143.2,
129.0 (2), 128.0, 126.9 (2), 110.8, 54.1, 30.8, 18.6. Anal. Calcd
for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.18;
H, 5.61; N, 11.28.
5-Ben zoyl-6-m eth yl-4-ph en yl-3,4-dih ydr opyr im idin -2(1H)-
th ion e (en tr y 38): mp 228-230 °C; IR 3427, 1666, 1624, 1558
cm-1; 1H NMR δ 10.35 (s, 1H), 9.69 (s, 1H), 7.44 (m, 10H), 5.31
(d, J ) 3 Hz, 1H), 1.75 (s, 3H); 13C NMR δ 194.9, 174.6, 143.3,
141.9, 140.4, 132.2 (2), 129.0 (2), 128.9 (2), 128.0 (2), 126.6 (2),
110.0, 55.7, 18.2. Anal. Calcd for C18H16N2OS: C, 70.10; H, 5.23;
N, 9.08. Found: C, 69.89; H, 5.11; N, 8.91.
5-Acetyl-6-m eth yl-4(2-p yr id in yl)-3,4-d ih yd r op yr im id in -
2(1H)-on e (en tr y 31): mp 224-225 °C; IR 3290, 1712, 1679,
1
1587 cm-1; H NMR δ 9.13 (s, 1H), 8.47 (m, 1H), 7.71 (m, 2H),
7.23 (m, 2H), 5.31 (d, J ) 3.3 Hz, 1H), 2.21 (s, 3H), 2.17 (s, 3H);
13C NMR δ 194.7, 162.7, 152.8, 149.5, 148.3, 137.2, 122.9, 121.0,
109.4, 56.0, 30.7, 19.2. Anal. Calcd for C12H13N3O2: C, 62.33;
H, 5.67; N, 18.17. Found: C, 62.01; H, 5.59; N, 17.99.
5-Acetyl-4-(2-fu r fu r yl)-6-m eth yl-3,4-d ih yd r op yr im id in -
2(1H)-on e (en tr y 32): mp 210-212 °C; IR 3278, 1716, 1681,
Ack n ow led gm en t. We are pleased to acknowledge
the financial support from CSIR, New Delhi (Grant No.
01(1504)/98) for this investigation. A.H. and U.J . are
also thankful to CSIR for their fellowships.
1591 cm-1 1H NMR δ 9.21 (s, 1H), 7.82 (s, 1H), 7.53 (s, 1H),
;
6.33 (s, 1H), 6.10 (d, J ) 2.7 Hz, 1H), 5.30 (d, J ) 2.7 Hz, 1H),
2.22 (s, 3H), 2.14 (s, 3H); 13C NMR δ 194.1, 156.2, 152.8, 149.1,
142.6, 110.6, 107.5, 105.9, 48.1, 30.3, 19.2. Anal. Calcd for
C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C, 59.81; H,
5.38; N, 12.59.
J O000711F