Bronsted base-catalyzed one-pot three-component Biginelli-type reaction: An efficient synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-one and mechanistic study

Article abstract of DOI:10.1021/jo902394y

(Chemical Equation Presented) An efficient one-pot synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-ones via a three-component Biginelli-type condensation of aldehyde, 2-phenylacetophenone, and urea/thiourea in the presence of a catalytic amount of t-BuOK (20 mol %) is described. The reactions proceeded efficiently at 70 °C to afford the desired products in moderate to good yields. Detailed mechanistic study shows that the Biginelli-type reaction using urea and thiourea proceeds through two totally different pathways. Enone 5 and bis-urea 8 were highly suggested as respective reaction intermediates for reactions involving thiourea and urea as substrates.

Full text of DOI:10.1021/jo902394y

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Brønsted Base-Catalyzed One-Pot Three-Component Biginelli-Type
Reaction: An Efficient Synthesis of 4,5,6-Triaryl-3,4-dihydropyrimidin-
2(1H)-one and Mechanistic Study
Zhi-Liang Shen, Xiao-Ping Xu, and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, China
chemjsj@suda.edu.cn
Received November 9, 2009
An efficient one-pot synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-ones via a three-component
Biginelli-type condensation of aldehyde, 2-phenylacetophenone, and urea/thiourea in the presence of
a catalytic amount of t-BuOK (20 mol %) is described. The reactions proceeded efficiently at 70 °C to
afford the desired products in moderate to good yields. Detailed mechanistic study shows that the
Biginelli-type reaction using urea and thiourea proceeds through two totally different pathways.
Enone 5 and bis-urea 8 were highly suggested as respective reaction intermediates for reactions
involving thiourea and urea as substrates.
Introduction
compounds has permeated in organic transformations. This
is due to the fact that products can be prepared directly in a
single step and diversity can be achieved simply by varying
reaction substrates. Among them, the Biginelli reaction1a,2,3
involving a multicomponent condensation of aldehyde,
β-ketoester, and urea ranks as one of the most recognized
and widely employed MCCs for the preparation of dihydro-
pyrimidinones. Much effort was directed toward developing
highly efficient Biginelli reaction owing to the exhibition of a
wide range of biological activities4 in dihydropyrimidinones
such as antiviral, antitumor, antibacterial, and antiflamma-
tory properties as well as calcium channel modulating acti-
vity. To date, a wide variety of Lewis acids and protic acids
In recent decades, the utilization of multicomponent con-
densations1 (MCCs) to synthesize novel, drug-like scaffold
(1) For reviews concerning multicomponent reactions, see: (a) Multi-
component Reactions; Zhu, J. P., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Domling, A. Chem. Rev. 2006, 106, 17. (c) Bienayme, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem.;Eur. J. 2000, 6, 3321. (d) Posner,
G. H. Chem. Rev. 1986, 86, 831. (e) Ugi, I. Pure Appl. Chem. 2001, 73, 187.
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D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693. (h) Sunderhaus, J. D.;
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Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang,
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1162 J. Org. Chem. 2010, 75, 1162–1167
Published on Web 01/19/2010
DOI: 10.1021/jo902394y
r
2010 American Chemical Society

Shen et al.
JOCArticle
have been well-established to efficiently promote the
Biginelli reaction.5
SCHEME 1. Brønsted Base-Mediated Biginelli-Type Reaction
Recently, the use of other active methylene compounds in
addition to β-ketoester in classic Biginelli reaction has
emerged as one of the hot research areas in terms of the
preparation of various novel dihydropyrimidinones. Just as
the Biginelli reaction operates in the presence of Lewis acid
or protic acid,2,3,5 these MCC reactions for the preparation
of novel dihydropyrimidinones using various active methyl-
ene compounds, such as 5,5-dimethyl-1,3-cyclohexanedione,4b
1,3-cyclohexanedione,6 1-tetralone,6-8 acetophenone,8 cyclo-
pentanone,9 aliphatic aldehydes,10 and β-oxodithioesters,11
were also developed to be carried out using a Lewis or protic
acid such as HCl, TMSCl/NaI, FeCl3, ZnI2, YbCl3, BF3, and
SnCl2. More recently, a one-pot variant of Biginelli-type
reaction using enaminone12 promoted by TMSCl was also
reported.
However, despite extensive studies on the Biginelli-type
reactions reported in the literature, to the best of our know-
ledge, there is no report focusing on the development of one-
pot Biginelli-type reaction under basic conditions.13 We
envisioned that, if the Biginelli-type reaction can be deve-
loped under basic conditions using Brønsted bases14 rather
than Lewis acids, it will provide an important complement to
classic Biginelli reaction and help deepen our understanding
of Biginelli reaction. In continuation of our endeavors in
developing novel and practical multicomponent reactions to
synthesize useful heterocyclic compounds,14n,15 herein, we
describe a novel Brønsted base-promoted one-pot synthesis
of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-one via a three-
component condensation of aldehyde, 2-phenylacetophe-
none, and urea/thiourea. The reactions proceeded effici-
ently in the presence of a catalytic amount of Brønsted base
(20 mol % of t-BuOK) to afford dihydropyrimidinones in
moderate to good yields (Scheme 1). In addition, through
detailed mechanistic study, enone 5 and bis-urea 8 were
highly suggested as reaction intermediates for reactions
involving thiourea and urea as substrates, respectively.
(5) For selected examples, see: (a) Rodriguez-Dominguez, J. C.; Bernardi,
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and references cited therein. (c) Shi, F.; Jia, R. H.; Zhang, X. J.; Tu, S. J.; Yan, S.;
Zhang, Y.; Jiang, B.; Zhang, J. Y.; Yao, C. S. Synthesis 2007, 2782. (d) Tu, S. J.;
Fang, F.; Zhu, S. L.; Li, T. J.; Zhang, X. J.; Zhuang, Q. Y. Synlett 2004, 537.
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Results and Discussion
(6) Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Il Farmaco
Initial studies were focused on the one-pot three-component
condensation of 4-chlorobenzaldehyde, 2-phenylacetophe-
none, and thiourea at 70 °C for 12 h using different Lewis/
protic acids in ethanol. The results are summarized in Table 1.
As shown in Table 1, our attempt to perform the model
reaction using conventional Biginelli reaction conditions
in the presence of Lewis acids such as InCl3, FeCl3, ceric
ammonium nitrate (CAN), and I2 did not succeed; no desi-
red product was obtained after reacting at 70 °C for 12 h
(Table 1, entries 1-4). In comparison, moderate yields of 4a
2000, 55, 249.
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1989, 54, 5898. For selected typical examples of modifications of Biginelli
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Heterocycles 2005, 65, 767. (g) Valverde, M. G.; Dallinger, D.; Kappe, C. O.
Synlett 2001, 74. (h) Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49.
(i) Abdel-Fattah, A. A. A. Synthesis 2003, 2358. (j) Khodaei, M. M.;
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Vanden Eynde, J. J.; Toupet, L.; Bazureau, J. P. ARKIVOC 2007, iii, 13.
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48, 4899. (m) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819.
(n) Lusch, M. J.; Tallarico, J. A. Org. Lett. 2004, 6, 3237. (o) Hulme, R.;
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condensations, see: (a) Ranu, B. C.; Jana, R.; Sowmiah, S. J. Org. Chem.
2007, 72, 3152. (b) Wang, S. H.; Tu, Y. Q.; Chen, P.; Hu, X. D.; Zhang, F. M.;
Wang, A. X. J. Org. Chem. 2006, 71, 4343. (c) Volonterio, A.; Zanda, M.
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Lett. 2003, 5, 435. (e) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.;
Chernenko, V. N.; Shishkina, S. V.; Shishkin, O. V.; Kobzar, K. M.; Kappe,
C. O. Org. Lett. 2007, 9, 1691. (f) Baxendale, I. R.; Buckle, C. D.; Ley, S. V.;
Tamborini, L. Synthesis 2009, 1485. (g) Masquelina, T.; Obrecht, D. Tetra-
hedron 2001, 57, 153. (h) Yavari, I.; Kowsari, E. Synlett 2008, 897.
(i) Goswami, P.; Das, B. Tetrahedron Lett. 2009, 50, 2384. (j) Chetia, A.;
Saikia, C. J.; Lekhok, K. C.; Boruah, R. C. Tetrahedron Lett. 2004, 45, 2649.
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ꢀ
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TABLE 1. Optimization of Reaction Conditions Using Different Acidsa
TABLE 3. Optimization of Reaction Conditions with Different
Catalyst Loadings and Temperaturesa
entry
conditionsb
yield (%)c
0d
0
0
entry
conditions
yield (%)b
1
2
3
4
5
6
7
8
9
InCl3 (1 equiv), EtOH, 70 °C, 12 h
FeCl3 (1 equiv), EtOH, 70 °C, 12 h
CAN (1 equiv), EtOH, 70 °C, 12 h
I2 (1 equiv), EtOH, 70 °C, 12 h
HCl (1 equiv), EtOH, 70 °C, 12 h
PTSA (1 equiv), EtOH, 70 °C, 12 h
CSA (1 equiv), EtOH, 70 °C, 12 h
CSA (1 equiv), DMF, 100 °C, 12 h
CSA (1 equiv), toluene, 100 °C, 12 h
1
2
3
4
5
6
7
8
9
t-BuOK (1 equiv), EtOH, 70 °C, 12 h
t-BuOK (0.5 equiv), EtOH, 70 °C, 12 h
t-BuOK (0.2 equiv.), EtOH, 70 oC, 12 h
t-BuOK (0.2 equiv), EtOH, 70 °C, 8 h
t-BuOK (0.2 equiv), EtOH, 70 °C, 4 h
t-BuOK (1 equiv), EtOH, 23 oC, 12 h
t-BuOK (0.2 equiv), EtOH, 23 °C, 12 h
t-BuOK (0.2 equiv), EtOH, 23 °C, 24 h
t-BuOK (0.2 equiv), EtOH, 23 oC, 48 h
95
93
92
90
86
86
18
71
88
0
49
46
55 (72)e (59)f
13
8
aUnless otherwise noted, the reactions were carried out at 70 °C for
12 h using 4-chlorobenzaldehyde (1 mmol), 2-phenylacetophenone (1.1
mmol), thiourea (2 mmol), and Lewis/protic acid (1 mmol) in ethanol
(5 mL). bCAN = ceric ammonium nitrate, PTSA = p-toluenesulfonic
acid, CSA = D-(þ)-camphor-10-sulfonic acid, DMF = N,N-dimethyl-
formamide. cIsolated yield. dLess than 10% yield was obtained when the
reaction was carried out in THF. eReaction conditions: CSA (1 equiv),
EtOH, 70 °C, 24 h. fReaction conditions: CSA (0.2 equiv), EtOH, 70 °C,
48 h.
aThe reactions were carried out at 70 or 23 °C for 4-48 h using 4-chlo-
robenzaldehyde (1 mmol), 2-phenylacetophenone (1.1 mmol), thiourea
(2 mmol), and t-BuOK (0.2-1 mmol) in ethanol (5 mL). bIsolated yield.
TABLE 4. Optimization of Reaction Conditions Using Various
Solventsa
TABLE 2. Optimization of Reaction Conditions Using Various Basesa
entry
solvent
yield (%)b
1
2
3
4
5
6
7
8
EtOH
86
82
85
23
13
56
8
MeOH
i-PrOH
THF
CH2Cl2
CH3CN
n-hexane
toluene
entry
conditionsb
yield (%)c
1
2
3
4
5
6
7
8
K2CO3 (1 equiv), EtOH, 70 °C, 12 h
LiOH (1 equiv), EtOH, 70 °C, 12 h
NaOH (1 equiv), EtOH, 70 °C, 12 h
KOH (1 equiv), EtOH, 70 °C, 12 h
t-BuOK (1 equiv), EtOH, 70 oC, 12 h
pyridine (1 equiv), EtOH, 70 °C, 12 h
DABCO (1 equiv), EtOH, 70 °C, 12 h
DBU (1 equiv), EtOH, 70 °C, 12 h
77
84
88
90
95
3
15
aThe reactions were carried out at 23 °C for 12 h using 4-chloroben-
zaldehyde (1 mmol), 2-phenylacetophenone (1.1 mmol), thiourea (2 mmol),
and t-BuOK (1 mmol) in organic solvent (5 mL). bIsolated yield.
5
41
aThe reactions were carried out at 70 °C for 12 h using 4-chloroben-
zaldehyde (1 mmol), 2-phenylacetophenone (1.1 mmol), thiourea (2 mmol),
and base (1 mmol) in ethanol (5 mL). bDABCO=1,4-diazabicyclo[2.2.2]-
octane, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. cIsolated yield.
1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) resulted in poor to moderate
yields of the product (Table 2, entries 6-8).
Under the same reaction conditions, it was gratifying to
observe that similar high yields were obtained when the amount
of t-BuOK was decreased to 0.5 or 0.2 equiv (93 and 92%
yields, Table 3, entries 2 and 3). It indicates that the reaction
can also proceed well in a catalytic manner (20 mol % of
t-BuOK). When the reaction times were reduced to 8 or 4 h,
relatively low yields of 90 or 86% were obtained, respectively
(Table 3, entries 4 and 5 versus entry 1). Moreover, it was
noteworthy that the reaction also worked well at 23 °C after
reacting for 12 h using 1 equiv of t-BuOK or 48 h using
0.2 equiv of t-BuOK (86 and 88% yields, Table 3, entries
6-9).
Different organic solvents were also screened to see their
efficiency in the reaction. As shown in Table 4, it seems that
the reaction proceeds better in protic solvent than in aprotic
solvent. Good yields were obtained when the reactions
were operated in protic solvents such as EtOH, MeOH, and
were obtained when protic acids such as HCl, D-(þ)-cam-
phor-10-sulfonic acid (CSA), and p-toluenesulfonic acid
(PTSA) were employed (Table 1, entries 5-7). However,
operation of the reactions at higher temperature (100 °C)
using CSA in solvents such as DMF or toluene led to lower
yields (Table 1, entries 8 and 9).
After many trials with other additives, it was pleasing to
find that the one-pot reactions proceeded efficiently in the
presence of Brønsted bases such as K2CO3, LiOH, NaOH,
KOH, and t-BuOK, affording the desired product 4a in
77-95% yields after reacting at 70 °C for 12 h (Table 2,
entries 1-5). In addition, yield of the desired product 4a
increases with increasing basicity. It is important to note that
the best yield of 95% was obtained when t-BuOK was used as
reaction promoter (Table 2, entry 5). Furthermore, it was
found that the utilization of organic bases including pyridine,
1164 J. Org. Chem. Vol. 75, No. 4, 2010

Shen et al.
JOCArticle
TABLE 5. Substrate Scope Studiesa
of aldehyde, substituted 2-phenylacetophenone, and urea/
thiourea proceeded efficiently to furnish the corresponding
4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-ones in moderate
to good yields. It is noteworthy that the methodology
worked well even for heterocyclic aldehydes such as 2-pyri-
dinecarbaldehyde, 2-thiophenecarbaldehyde, and 2-furanecar-
baldehyde (Table 5, entries 17-22). Good to excellent yields
were also achieved for various substituted 2-phenylaceto-
phenones (Table 5, entries 23-34). However, poor yield
(5%) was obtained when the reaction was applied to alipha-
tic aldehyde such as hydrocinnamaldehyde due to the ease of
aldol-type self-condensation of the aldehyde under strong
basic conditions (Table 5, entry 35). In addition, we also
investigated the reaction using phenyl acetone as substrate.
However, the reaction involving 4-chlorobenzaldehyde,
phenyl acetone, and urea proceeded sluggishly under above
optimized reaction conditions to afford the desired product
only in 18% yield.
It is interesting to know that such a kind of three-component
condensation can proceed well under basic conditions. To
the best of our knowledge, this is the first Brønsted base-
mediated one-pot Biginelli-type reaction for the synthesis of
dihydropyrimidinones. Compared to other commonly emp-
loyed methods for the preparation of dihydropyrimidinones
using Lewis acids or protic acids,2,3,5 the methodology
presented herein also provided a novel, convenient, efficient,
and cheap access to a wide variety of dihydropyrimidinones
in a one-pot manner.
entry
R1
R2
R3
X time (h) yield (%)b
1
2
3
4
5
6
7
8
9
4-ClC6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
4-CNC6H4
4-CNC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
S
12
9
92
90
85
84
85
80
87
91
79
78
78
68
85
73
89
80
85
65
72
67
73
64
96
90
78
82
94
91
92
89
83
87
98
97
5
O
S
9
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
12
12
12
12
12
12
12
18
24
18
24
12
12
18
24
18
48
18
18
12
12
12
12
12
24
24
24
24
24
24
24
24
Ph
4-MeC6H4
10 4-MeC6H4
11 4-OMeC6H4
12 4-OMeC6H4
13 3,4-O2CH2C6H3 Ph
14 3,4-O2CH2C6H3 Ph
15 1-naphthyl
16 1-naphthyl
17 2-pyridyl
18 2-pyridyl
19 2-thienyl
20 2-thienyl
21 2-furyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
22 2-furyl
23 4-ClC6H4
24 4-ClC6H4
25 4-ClC6H4
26 4-ClC6H4
27 4-ClC6H4
28 4-ClC6H4
29 4-ClC6H4
30 4-ClC6H4
31 4-ClC6H4
32 4-ClC6H4
33 4-ClC6H4
34 4-ClC6H4
35 PhCH2CH2
4-ClC6H4
4-ClC6H4
Ph
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
In a previous report, Kappe proposed that Lewis acid or
protic acid-mediated Biginelli reaction proceeded via the
formation of an iminium ion (formed by acid-catalyzed
condensation of aldehyde with urea) as a key intermediate
rather than the carbenium ion intermediate (derived from
the acid-catalyzed aldol reaction of aldehyde and ethyl
acetoacetate).16 Considering the basic conditions involved
in the current methodology using t-BuOK, we envisaged that
the reaction may have proceeded in a different way.
Ph
4-MeC6H4 4-BrC6H4
4-MeC6H4 4-BrC6H4
4-MeC6H4 Ph
4-MeC6H4 Ph
4-ClC6H4
4-ClC6H4
Ph
Ph
4-OMeC6H4 Ph
4-OMeC6H4 Ph
Ph
Ph
To probe the mechanism of this Brønsted base-mediated
one-pot reaction, 3-(4-chlorophenyl)-1,2-diphenylprop-2-en-1-
one (E)-5 (derived from the condensation of 4-chlorobenzal-
dehyde and 2-phenylacetophenone)17,18 was preformed and
subsequently subjected to t-BuOK or CSA-mediated con-
densation with both urea and thiourea (Table 6). It was
gratifying to observe that the reaction of compound 5 with
thiourea proceeded efficiently at 70 °C in the presence of
t-BuOK to generate the desired product 4a in 96% yield
aThe reactions were carried out at 70 °C for a specific time using alde-
hyde (1 mmol), ketone (1.1 mmol), urea or thiourea (2 mmol), t-BuOK
(0.2 mmol), and ethanol (5 mL). bIsolated yield.
i-PrOH (Table 4, entries 1-3). However, only moderate to
poor yields (Table 4, entries 4-8) were observed when the
reactions were carried out in THF, CH2Cl2, CH3CN, n-hex-
ane, and toluene (1 equiv of t-BuOK, 23 °C, 12 h).
Thus, considering the overall effects of reaction time,
temperature, solvent, and catalyst loading, ensuing studies
on the exploration of substrate scopes were performed at
70 °C using a catalytic amount of t-BuOK (20 mol %) in
ethanol. It should be noted that, based on the relative acidity
of t-BuOH and EtOH, a metathesis reaction (double decom-
position reaction) between t-BuOK and EtOH may take
place to generate t-BuOH and EtOK. Therefore, what really
works in the reaction could be EtOK rather than t-BuOK.
However, in view of the lower price and ready availability of
t-BuOK as compared to EtOK, t-BuOK was chosen as the
catalyst in subsequent reactions.
(16) For a detailed mechanism study on Biginelli reaction by Kappe’s
group, see: (a) Kappe, C. O. J. Org. Chem. 1997, 62, 7201. For a recent
mechanistic study using mass spectrometry analysis, see: (b) De Souza,
R. O. M. A.; da Penha, E. T.; Milagre, H. M. S.; Garden, S. J.; Esteves, P. M.;
Eberlin, M. N.; Antunes, O. A. C. Chem.;Eur. J. 2009, 15, 9799.
(17) For the preparation of intermediate 5, see: (a) Mittal, S.; Durani, S.;
Kapil, R. S. J. Med. Chem. 1985, 28, 492. (b) Duke, P. J.; Boykin, D. W.
J. Org. Chem. 1972, 37, 1436.
(18) Compound 17 which derived from the condensation of 2-phenyl
acetophenone and thiourea/urea also might be an intermediate of the
reaction. However, we failed to preprepare it (reaction conditions: 1 equiv
of 2-phenylacetophenone, 2 equiv of thiourea, 0.2 equiv of PTSA (or 1 equiv
of KOH) in refluxing toluene or ethanol for 12 h).
With the optimized reaction conditions in hand, we con-
tinued to apply the approach to various aldehydes, substi-
tuted 2-phenylacetophenones, and urea/thiourea. As shown
in Table 5, the Brønsted base-mediated one-pot condensation
J. Org. Chem. Vol. 75, No. 4, 2010 1165

Shen et al.
JOCArticle
TABLE 6. Mechanistic Study Using Enone 5a
TABLE 7. Mechanistic Study Using Bis-urea 8a
R2
R3
yield (%)b
entry
catalyst
X
time (h)
yield (%)b
entry
catalyst
1
2
3
4
t-BuOK
t-BuOK
CSA
S
O
S
6
12
12
12
96
15
0
1
2
3
4
5
6
7
CSA
Ph
Ph
4-ClC6H4
Ph
4-MeC6H4
4-MeC6H4
4-ClC6H4
Ph
Ph
4-BrC6H4
4-BrC6H4
4-BrC6H4
Ph
0
98
89
93
87
87
81
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
CSA
O
0
aThe reactions were carried out at 70 °C for a specific time using enone
5 (1 mmol), urea or thiourea (2 mmol), t-BuOK or CSA (0.2 mmol), and
ethanol (5 mL). bIsolated yield.
Ph
aThe reactions were carried out at 70 °C for 12 h using bis-urea 8
(1 mmol), substituted 2-phenylacetophenone (1.1 mmol), t-BuOK or CSA
(0.2 mmol), and ethanol (5 mL). bIsolated yield.
within 6 h (Table 6, entry 1), and such a type of reaction is
well-documented in previous reports,19 whereas, under the
same conditions, it is important to note that the reaction of
enone 5 with urea proceeded sluggishly to give the target
product 4b in only 15% yield (Table 6, entry 2). In addition,
no reaction took place when CSA (20 mol %) was used. At
this stage, we think that the reaction using thiourea might
proceed via the formation of enone 5 as a key intermediate,
whereas the reaction using urea might proceed via a different
mechanism since very low yield was obtained.
occurred efficiently using t-BuOK (20 mol %) in ethanol,
generating the desired product 4b in 98% yield after reacting
at 70 °C for 12 h (Table 7, entry 2). Good to excellent yields
were also afforded using other substituted 2-phenylacetophe-
nones (Table 7, entries 3-7). Moreover, no desired product 4b
was obtained when CSA (20 mol %) was employed under the
same conditions (Table 7, entry 1). Thus, we hypothesize that
bis-urea compound 8 may be the key intermediate involved in
the Biginelli-type reaction using urea as substrate.
It was the first observation that the Biginelli-type reaction
using urea and thiourea proceeds through two totally diffe-
rent pathways. According to these observations, two plau-
sible reaction mechanisms were proposed for the Brønsted
base-mediated Biginelli-type reaction using urea and thiourea.
FIGURE 1. Possible reaction intermediates.
Compound 6, which is derived from the reaction of
4-chlorobenzaldehyde with urea/thiourea, might be an inter-
mediate which accounts for the mechanism of the reaction
(Figure 1).16,18 However, our attempt to synthesize inter-
mediate 6 failed (currently, there is no report on the success-
ful synthesis of compound 6 using aldehyde and urea/
thiourea as substrates). Only compound 7 was obtained
when 4-chlorobenzaldehyde (1 equiv), thiourea (2 equiv),
and PTSA (0.2 equiv) were condensed in refluxing toluene
for 24 h.20,21 In comparison, bis-urea 8 was easily obtained
when urea was reacted under the above reaction condi-
tions.16,21 When compound 7 was condensed with 2-phenyl-
acetophenone (20 mol % of t-BuOK or CSA, 70 °C, 12 h), no
desired product 4a was obtained. Therefore, we conclude
that the Biginelli-type reaction using thiourea as substrate
may proceed via enone 5 rather than intermediate 6 or 7.
It was interesting to find that the condensation of bis-urea
compound 8 (1 mmol) with 2-phenylacetophenone (1.1 mmol)
FIGURE 2. Proposed reaction mechanism using thiourea as sub-
strate.
As shown in Figure 2, the reaction using thiourea is initi-
ated via a Brønsted base-mediated aldol condensation of
aldehyde 1 with 2-phenylacetophenone (2), followed by eli-
mination of the resulting hydroxyl group to give enone 10.
Subsequent base-catalyzed aza-Michael addition of thiourea
to enone 10 leads to the formation of Michael adduct 11.
Finally, 1,2-addition of amino group (NH2) to the carbonyl
group followed by in situ elimination of the hydroxyl group
affords the desired product 4.
(19) For examples, see: (a) Simon, D.; Lafont, O.; Farnoux, C. C.;
Miocque, M. J. Heterocycl. Chem. 1985, 22, 1551. (b) Campbell, M. M.;
Jigajinni, V. B.; Wightman, R. H. Tetrahedron Lett. 1979, 26, 2455.
(20) Taylor, J. J. Chem. Soc. 1922, 115, 2267.
As for the reaction using urea as substrate, the reaction is
proposed to initiate via the formation of an equilibrium mix-
ture of intermediates 13 and 14 (Figure 3). When compound 2is
(21) See Supporting Information for detailed experimental procedures.
1166 J. Org. Chem. Vol. 75, No. 4, 2010

Shen et al.
JOCArticle
dihydropyrimidinones. In addition, enone 5 and bis-urea 8
were highly suggested as reaction intermediates for reac-
tions involving thiourea and urea as substrates, respectively.
Application of the methodology to other active methylene
compounds, development of an asymmetric version of this
reaction, and the use of bis-urea compound as substrate for
the synthesis of various dihydropyrimidinones are currently
in progress.
Experimental Section
General Procedure for the Three-Component Condensation of
Aldehyde, 2-Phenylacetophenone, and Urea/Thiourea: To a mix-
ture of aldehyde 1 (1 mmol), substituted 2-phenylacetophenone
2 (1.1 mmol), and urea or thiourea 3 (2 mmol) was added
absolute ethanol (5 mL), and it was stirred at room temperature
for 5 min. Then t-BuOK (0.2 mmol) was added, and the reaction
mixture was stirred vigorously at 70 °C for a certain time, as
shown in Table 5. After the completion of the reaction, solvent
was removed under vacuum. The residue was purified by silica
gel column chromatography using CH2Cl2 and MeOH as eluant
to afford the desired product of 4,5,6-triaryl-3,4-dihydropyri-
midin-2(1H)-one.
FIGURE 3. Proposed reaction mechanism using urea as substrate.
present, it reacts with either intermediate 13 or 14 to generate
compound 15. Compound 15 further cyclizes under base cata-
lysis and finally affords the desired product 4 upon elimination
of the hydroxyl group.
In the case of the CSA-mediated Biginelli-type reaction
(Table 1, entry 7), because it cannot proceed via the afore-
mentioned possible intermediates 5 and 8 (Table 6, entries 3
and 4 and Table 7, entry 6), we hypothesize that the reaction
may have occurred through the formation of intermediate
17.18 However, our attempt to synthesize the intermediate 17
proved futile.
Acknowledgment. The work was partially supported by
the National Natural Science Foundation of China (No.
20672079), Natural Science Foundation of Jiangsu Province
(No. BK2006048), Nature Science Key Basic Research of
Jiangsu Province for Higher Education (No. 06KJA15007),
and the Specialized Research Fund for the Doctoral Pro-
gram of Higher Education (No. 20060285001).
Conclusion
In conclusion, we have described a novel Brønsted base-
mediated one-pot procedure for the preparation of a wide
variety of novel 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-
ones via a three-component condensation of aldehyde, 2-phe-
nylacetophenone, and urea/thiourea. The method is simple,
convenient, efficient, and is expected to be a useful synthetic
protocol for the synthesis of a wide range of novel drug-like
Supporting Information Available: General experimental
procedures and spectral data for all reaction products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 4, 2010 1167