1422
F. L. Zumpe et al. / Tetrahedron Letters 48 (2007) 1421–1423
time and possible solvents we found optimized condi-
tions for benzaldehyde. These conditions utilize a
1:1.2:1.2 ratio of aldehyde 1, b-ketoester 2 and urea 3
in a one-pot Biginelli reaction employing refluxing ethyl
acetate as solvent. One equivalent of ÒT3P with respect
to the aldehyde suffices for complete conversion of the
starting materials. After completion of the reaction
water is added to the reaction mixture in order to hydro-
lyze the residual ÒT3P and the reaction mixture is stirred
for another hour, before the precipitated product is iso-
lated by filtration.
relevant substitution patterns can be obtained using
ÒT3P in the Biginelli reaction. Aldehydes with electron-
withdrawing groups clearly gave the best results in terms
of yield and purity. In all cases studied, the crude
product was isolated in good to very good yield and
no further purification processes were required (Table
1, entries 3–5, 9–11). Aldehydes with electron-donating
groups behaved differently. Normally, they furnished
somewhat lower yields and products required chromato-
graphic workup for purification in some cases (Table 1,
entries 6, 8, 12). For both electron-deficient and elec-
tron-rich aromatic aldehydes the para substituted deriv-
atives led to a little lower yield than those bearing ortho
or meta substituents (Table 1, entries 3–8). Alkyl substi-
tuted aromatic aldehydes, heterocyclic aldehydes and
aliphatic aldehydes reacted smoothly and gave rise to
products with a high purity albeit in moderate yield only
(Table 1, entries 2, 16, 17). Nevertheless, this protocol
has its limitations. Employing acid sensitive aldehydes
such as furfural or aldehydes substituted with functional
groups that might participate in condensation reactions
was not suited for carrying out the Biginelli reaction
under these conditions. They only provided low to
moderate yields of the desired products. Moreover, the
products had to be purified by extractive or chromato-
graphic workup procedures (Table 1, entries 13–15).
Instead of ethyl acetoacetate, pentane-2,4-dione could
be used as the 1,3-dicarbonyl component without loss
of efficiency (Table 1, entries 18–20). Likewise, the
reaction was not negatively affected by replacing urea
by thiourea (Table 1, entries 20–21).
In a typical procedure benzaldehyde (0.53 g, 5 mmol),
ethyl acetoacetate (0.78 g, 6 mmol) and urea (0.36 g,
6 mmol) were dissolved in 8 ml of ethyl acetate. ÒT3P
(3.18 g, 5 mmol) as a 50% solution in ethyl acetate was
added and the mixture was heated to reflux for 6 h.
After cooling to room temperature, 10 ml of water were
added and the resulting mixture was stirred for 1 h. The
precipitated product was filtered, washed with water and
dried in vacuum. In most cases no further purification
was necessary.
All compounds obtained according to this protocol were
characterized and identified by their melting points,
mass spectra and NMR spectra in comparison to the
analytical data reported in the literature. To study the
generality of the process several aldehydes were reacted
with ethyl acetoacetate or pentane-2,4-dione and urea or
thiourea in the presence of ÒT3P (Table 1) under the
conditions mentioned above.
As can be seen from the data in Table 1 dihydropyrimid-
inones bearing aromatic rings with pharmacologically
In summary, ÒT3P has been shown to be a novel pro-
moter for the synthesis of DHPMs by the three-compo-
Table 1. ÒT3P Promoted formation of dihydropyrimidinones
Entry
Producta
R
R0
X
Yieldb (%)
Mpc (°C) found
Mp (°C) reported
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4a
4b
4c
4d
4e
4f
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
Ph–
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
77
69
69
86
86
59
81
86d (48)e
74
73
77
47
44f
16e
30e
69
53
60
64
72
206–207
215–216
212–213
195–197
216–219
203–204
220–221
257–258
212–213
177–178
223–224
177–178
209–220
246–248
201–202
210–211
238–239
242–243
269–270
219–222
205–207
206–2074b
214–2158
213–2159
192–19310
215–2184b
201–2039
207–20811
259–26012
208–2119
173–17513
222–22314
174–17614
225–22615
256–25816
206–20814
207–20814
237–23814
245–24617
284–28517
220–22211
206–2074b
4-(CH3)–C6H4–
4-(Cl)–C6H4–
3-(Cl)–C6H4–
2-(Cl)–C6H4–
4-(OCH3)–C6H4–
3-(OCH3)–C6H4–
2-(OCH3)–C6H4–
4-(NO2)–C6H4–
4-(CF3)–C6H4–
3,4-(Cl)2–C6H3–
3,4-(OCH3)2–C6H3–
4-(OH)–C6H4–
4-(NMe2)–C6H4–
2-Furyl–
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
2-Thienyl–
Hexyl–
3-(OCH3)–C6H4–
3-(Cl)–C6H4–
Ph–
Me
Me
OEt
4u
Ph–
S
80
a All compounds were characterized by 1H NMR, MS and mp.
b Isolated yields.
c Melting points are uncorrected.
d Yield of crude product.
e After chromatographic workup.
f After extractive workup.