Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst: Asymmetric synthesis of dihydropyrimidines

Article abstract of DOI:10.1016/j.tet.2012.07.027

Several chiral primary amines were introduced as organocatalysts for the asymmetric Biginelli reaction. The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary amine-pyridine 5j and hydrochloric acid in a mixed

Full text of DOI:10.1016/j.tet.2012.07.027

Tetrahedron 68 (2012) 7867e7872
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journal homepage: www.elsevier.com/locate/tet
Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary
amine catalyst: asymmetric synthesis of dihydropyrimidines
*
Da-Zhen Xu, Hui Li, Yongmei Wang
Department of Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Several chiral primary amines were introduced as organocatalysts for the asymmetric Biginelli reaction.
The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary
amineepyridine 5j and hydrochloric acid in a mixed solvent of 1,4-dioxane/CHCl3 (8/2, v/v) at room
temperature. The corresponding dihydropyrimidines were obtained in moderate to high yields with up
to >99% ee under mild conditions.
Received 31 March 2012
Received in revised form 18 June 2012
Accepted 10 July 2012
Available online 15 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Biginelli reaction
Enantioselectivity
Multicomponent reactions
Primary amineepyridine catalyst
Pyrimidines
1. Introduction
decades, many improved procedures with new catalysts for Bigi-
nelli reaction have been reported.8 However, most of the reported
Functionalized 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) and
related heterocyclic compounds are very important pharmacolog-
ically active molecules and have found applications as calcium
channel blockers, a1-1-a-antagonists, antihypertensive agents, in-
hibitors of the fatty acid transporter, and mitotic kinesin inhibition.1
Several marine natural products containing the dihydropyr-
imidine-5-carboxylate core have been isolated were found to be
potent HIVgp-120-CD4 inhibitors.2 Compounds containing the
DHPM moiety are chiral molecules, and it has been discovered that
the configuration at the stereogenic carbon C(4) determines their
biological properties. The individual enantiomers have been found
to exhibit different or opposite pharmaceutical activities.3 For ex-
ample, only the enantiomer (R)-SQ 32 926 exhibits an antihyper-
tensive effect,4 and only (S)-Monastrol presents potential
anticancer activity.5 Therefore, an efficient method for the prepa-
ration of optically pure DHPMs is in a great demand.
methods only resulted in racemic DHPMs. The procedures for
manufacturing optically pure 3,4-dihydropyrimidin-2-(1H)-ones
mainly relied on resolution and chiral auxiliary-assisted asym-
metric synthesis.9 Procedures for the enantioselective synthesis of
DHPMs are rather limited,10 especially by the catalytic asymmetric
Biginelli reaction.11 The breakthrough in the catalytic asymmetric
Biginelli reaction was realized by Zhu and co-workers, who syn-
thesize of DHPMs by using a recyclable new chiral ytterbium cat-
alyst in 2005.11a The first organocatalytic highly enantioselective
Biginelli reaction was reported by Gong and co-workers using
a BINOL-derived phosphoric acids as catalyst.11b Some secondary
amines and Brønsted acids were also employed as catalyst to pro-
mote the Biginelli reaction with moderate to good enantioselecti-
vities.11d,12 Feng and co-workers11d reported an enantioselective
Biginelli reaction catalyzed by a trans-4-hydroxyproline-derived
secondary amine and a Brønsted acid as the combined catalyst.
Moorthy and Saha13 also reported a proline-derived secondary
amine as catalyst in the enantioselective Biginelli reaction. In
contrast, although primary amines are also known to participate as
catalysts in asymmetric synthesis reactions that involve enamine
intermediates, there were few examples on the use of chiral pri-
mary amines as catalysts in the asymmetric synthesis of DHPMs.14
Only Miao and co-workers15 reported an efficient catalytic system
of a chiral bifunctional primary amineethiourea and a Brønsted
acid as the combined catalyst for enantioselective Biginelli reaction.
The Biginelli reaction,6 one of the most useful multicomponent
reactions, offers straightforward access to multifunctionalized 3,4-
dihydropyrimidin-2-(1H)-ones (DHPMs) and related compounds7
through the simple condensation reaction of an aldehyde, a urea
or thiourea, and an easily enolizable carbonyl compound. In the last
* Corresponding author. Fax: þ86 22 2350 2654; e-mail address: wangym501@
yahoo.com.cn (Y. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.027

7868
D.-Z. Xu et al. / Tetrahedron 68 (2012) 7867e7872
Despite these elegant examples, it is still desirable to develop other
new organocatalysts for this important transformation. As a part of
our continuing interests in asymmetric small-molecule catalysis,16
here, we wish to disclose our study on the use of bifunctional pri-
mary amineepyridine as catalysts in the asymmetric synthesis of
DHPMs through the Biginelli reaction.
higher yield and enantioselectivity (Table 1, entry 3). The primary-
sulfamide conjugate 5d failed to catalyze the asymmetric Biginelli
reaction (Table 1, entry 4). Next, we explored sulfonamide 5e as
catalyst and found that this reaction can work effectively to provide
DHPM in 54% yield and 8% ee (Table 1, entry 5). When the similar
catalyst 5f was employed in the reaction, the corresponding
products obtained in higher enantioselectivity but with poor yield
2. Results and discussion
(Table 1, entry 6). The catalyst
a good yield of 56% (Table 1, entry 7). However, the catalyst pyr-
idinamides 5h and catalyst -prolinamides 5i failed to catalyze the
L
-prolinamides 5g gave DHPM in
Initially, we investigated the catalytic asymmetric Biginelli re-
action of benzaldehyde, urea, and ethyl acetoacetate with chiral
primary amine catalyst and HCl in THF at room temperature. Cat-
alyst 5a could catalyze this reaction to provide the desired product
DHPM 4a in a yield of 44% with 9% ee (Table 1, entry 1). Although
the enantioselectivity was low, this result encouraged us to further
optimize the catalyst scaffold. The efficacy of a series of primary
amines 5aek with a chiral 1,2-diphenylethane-1,2-diamine and
cyclohexane-1,2-diamine backbone was prepared and evaluated in
the asymmetric Biginelli reaction. Catalysts screening results are
listed in Table 1. As can be seen, the catalysts with a hydrophobic
long alkyl chain contributed a lot to ee (Table 1, entries 1e3). The
primary amine catalyst 5b promoted the asymmetric Biginelli re-
action with 14% enantioselectivity (Table 1, entry 2). Catalyst 5c was
superior to 5a and 5b, which promoted the Biginelli reaction with
L
asymmetric Biginelli reaction (Table 1, entries 8 and 9). The catalyst
pyridinamides 5j, with the backbone of cyclohexane-1,2-diamine,
could catalyze this reaction and produce the DHPM in excellent
enantioselectivity up to >99% (Table 1, entry 10). The catalyst 5k
could also catalyze this reaction to provide the desired product, but
the enantioselectivity was rather poor (Table 1, entry 11). Therefore,
this screening identified pyridinamides 5j as the best catalyst for
this reaction. Furthermore, increasing the loading amount of cata-
lyst from 10% to 20% did not affect the yield and enantioselectivity
(Table 1, entry 12). The absolute configuration of the major enan-
tiomer was determined to be (R) by comparing the reported
data.11e14
Then, we studied the solvent effects on this reaction by using
5j as the catalyst. When toluene was used as the solvent, the
Table 1
Screening catalysts for the asymmetric Biginelli reactiona
O
O
O
O
10 mol% cat.
NH
O
10 mol% HCl
+
∗
+
HN
H
H2N
NH2
OEt
THF, 25°C, 120h
CO2Et
2
3
1a
4a
5a R = CH3
Ph
Ph
5e R =
CH3
O
S
O
5b R = n-C4H9
5c R = n-C8H17
5d R = CF3
H2N HN
R
O
5f R =
5a-f
Ph
Ph
Ph
Ph
O
O
H2N HN
H2N HN
H2N HN
N
HN
5h
5g
5i
HN
O
O
S
H2N HN
H2N HN
CH3
O
5j
N
5k
Entry
Cat.
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
44
41
50
17
54
25
56
44
42
15
46
16
9
14
18
0
8
14
10
0
9
0
10
11
12d
5j
5k
5j
>99
<3
>99
a
The reaction was carried out on a 0.2 mmol scale and the ratio of 1/2/3 is 1/1.5/3.
Yield of isolated product.
Determined by HPLC (Chiralcel OD-H).
b
c
d
Catalyst 5j (20 mol %) was used.

D.-Z. Xu et al. / Tetrahedron 68 (2012) 7867e7872
7869
reaction proceeded in good enantioselectivity, but without any
improvement in terms of yield (Table 1, entry 2). When the re-
action was performed in polar solvents, such as H2O, DMSO,
C2H5OH, and i-PrOH, the product DHPM was formed in poor to
high enantioselectivities (Table 2, entries 3e6). The best result of
yield was observed when C2H5OH was used as the solvent, but
such as H2SO4 and H3PO4, could promote the reaction smoothly in
the yield from 14% to 17% with excellent enantioselectivities (Table
3, entries 2 and 3). We also screened organic acids. When TFA and
HOAc were used in the reaction, low enantioselectivities were
obtained (Table 3, entries 4 and 5). Different substituted benzoic
acids, which were favorable in terms of reactivity and enantiose-
Table 2
Optimization of solvent for the asymmetric Biginelli reactiona
O
O
10 mol% 5j
10 mol% HCl
solvent, 25°C
O
O
O
NH
+
+
HN
H
H2N
NH2
OEt
CO2Et
2
3
1a
4a
Entry
Solvent
T [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
THF
Toluene
H2O
DMSO
C2H5OH
i-PrOH
1,4-Dioxane
CHCl3
48
48
48
48
48
48
48
48
70
70
70
15
15
10
6
69
9
37
19
46
61
44
>99
91
77
0
81
96
98
>99
>99
>99
55
9
10
11
1,4-Dioxane/THF (8/2)
1,4-Dioxane/CHCl3 (8/2)
C2H5OH/CHCl3 (8/2)
a
The reaction was carried out on a 0.2 mmol scale and the ratio of 1/2/3 is 1/1.5/3.
Yield of isolated product.
Determined by HPLC (Chiralcel OD-H).
b
c
only 81% ee was obtained (Table 1, entry 5). When the reaction
was performed in 1,4-dioxane or CHCl3, moderate yields were
obtained and nearly without any loss of enantioselectivities (Table
2, entries 7 and 8). Therefore, mixed solvents were screened and
revealed that the best results were obtained in 1,4-dioxane/CHCl3
(8/2, v/v) as compared with other mixed solvents (Table 2, entries
9e11).
As we had obtained a good yield with >99% enantioselectivity of
the DHPM in 1,4-dioxane/CHCl3 (8/2, v/v) by using 10 mol % of 5j,
the effects of some Brønsted acids on the Biginelli reaction of
benzaldehyde, urea, and ethyl acetoacetate were examined in the
hope of improving the yield. Then various acids combined with 5j
were employed to catalyze this reaction (Table 3). Inorganic acids,
lectivity reported by Feng and Miao, were also employed as
Brønsted acids in the asymmetric Biginelli reaction.11d,15a Although
good to excellent enantioselectivities were obtained, they nearly
prevented the reaction (Table 3, entries 6e9). Both poor yield and
enantioselectivity were obtained when 4-hydroxybenzoic acid was
employed in the reaction (Table 3, entry 10).
Having established the most efficient Brønsted acids for Biginelli
reaction of benzaldehyde, urea, and ethyl acetoacetate, we then
examined the influence of the loading amount of HCl on the re-
action (Fig. 1). When no acid was added in the reaction, DHPM was
obtained in a poor yield of 4% with 55% ee. Good results were ob-
served when only 3 mol % HCl was added in the reaction. Then we
increase the loading amount of HCl from 3 mol % to 10 mol %, the
Table 3
Investigation of the Brønsted acid-catalyzed asymmetric Biginelli reactiona
O
O
10 mol% 5j
NH
O
O
O
10 mol% Acid
HN
+
+
H
H2N
NH2
OEt
1,4-dioxane/CHCl3 (8:2)
25°C, 72h
CO2Et
4a
2
3
1a
Entry
Acid
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
9
HCl
61
17
14
42
4
5
4
4
10
4
>99
96
98
36
33
83
90
97
86
10
H2SO4
H3PO4
TFA
HOAc
PhCOOH
4-NO2ePhCOOH
3,5-(NO2)2ePhCOOH
4-BrePhCOOH
4-HOePhCOOH
10
a
The reaction was carried out on a 0.2 mmol scale and the ratio of 1/2/3 is 1/1.5/3.
Yield of isolated product.
Determined by HPLC (Chiralcel OD-H).
b
c

7870
D.-Z. Xu et al. / Tetrahedron 68 (2012) 7867e7872
O
10 mol% 5j
HCl 10 mol%
NH
O
O
O
HN
+
Ph
N
NH2
O
1,4-dioxane/CHCl3 (8:2)
25°C, 72h
CO2Et
3
6
4a
21% yield
98% ee
Scheme 1. Benzylideneurea was used in the reaction.
moderate to good yields and with excellent enantioselectivities. As
shown in Table 4, the electronic and steric effects of the aromatic
ring substrate 1 have both influence on the yield and enantiose-
lectivity. The substrate of aromatic aldehydes with electron-
donating groups all afforded excellent enantioselectivities (98% to
>99% ee) (Table 4, entries 1e4). The aromatic aldehydes with weak
electron-withdrawing groups reduced both the reaction yields and
enantioselectivities slightly (Table 4, entries 5e7). When the sub-
strate with strong electron-withdrawing groups, such as nitro
groups, the substrate was found to be less reactive and afforded
a low of yield 5% with 7% ee (Table 4, entry 8). In the substrate with
electron-donating groups, because of the steric hindrance, the
yield and enantioselectivity of 1-naphthaldehyde reduced slightly
(Table 4, entry 4 vs, entries 1e3).
Fig. 1. The effect of HCl combined with 5j (10 mol %) in the asymmetric Biginelli re-
action of benzaldehyde, urea, and ethyl acetoacetate in 1,4-dioxane/CHCl3 (8/2, v/v).
reaction proceeded improvement in terms of both enantiose-
lectivity and yield. When the loading amount of HCl was added
more than 10 mol %, the reaction gave better yield but a decrease of
the ee value.
We found that benzaldehyde and urea formed benzylide-
neurea 6 in the first step, the yield was further improved if in-
crease the loading amount of urea. When 3 equiv urea was used,
product of DHPM (4a) could be obtained in a high yield of 91%
with >99% ee (Table 4, entry 1). Based on the above optimization
conditions, the benzylideneurea 6 used as substrate was also in-
vestigated. The reaction was carried out on a 0.2 mmol scale and
The possible mechanism for the reaction is shown in Fig. 2. Base
on the mechanism proposed for the secondary amine catalyzed
synthesis of DHPMs,11e13 a dual activation mechanism realized by
chiral primary amine catalyst 5j was proposed as shown in Fig. 2. In
the transition state I, chiral primary amine activates ethyl acetoa-
cetate 3 involving an enamine intermediate. At the same time, the
protonated picolinamide moiety of bifunctional catalyst 5j interacts
through hydrogen bonding with the acyl group of imine formed
between benzaldehyde and urea. Attack of the enamine onto the re-
face of the imine gives an intermediate, which, after condensation,
yields observed R-configured product 4.
Table 4
Three-component reaction of aldehydes, urea, and ethyl acetoacetate for the asymmetric synthesis of DHPMsa
O
10 mol% 5j
HCl 10 mol%
1,4-dioxane/CHCl3 (8:2)
1mL, 25°C
O
O
O
O
NH
+
+
HN
Ar
H2N
NH
2
Ar
H
OEt
CO2Et
2
1
3
4
Entry
4
Ar
Ph
T (h)
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
64
48
60
60
72
72
72
72
91
62
70
59
42
56
52
5
>99
>99
>99
98
76
93
4-MeeC6H4
4-MeOeC6H4
1-Naphthyl
4-CleC6H4
4-FeC6H4
4g
4h
4-BreC6H4
4-NO2eC6H4
91
7
a
The reaction was carried out on a 0.2 mmol scale and the ratio of 1/2/3 is 1/3/3.
Yield of isolated product.
Determined by HPLC (Chiralcel OD-H).
b
c
the ratio of benzylideneurea/ethyl acetoacetate is 1/3. The corre-
sponding DHPM 4a was obtained in low yield but with 98% ee
(Scheme 1).
Having established the optimal reaction conditions for asym-
metric Biginelli reaction, we then examined the scope of this re-
action in the solvent of 1,4-dioxane/CHCl3 catalyzed by 5j (10 mol %)
with co-catalyst HCl (10 mol %) at room temperature to establish the
general utility of this asymmetric transformation (Table 4). The
examined substrates could furnish the desired DHPM derivatives in
3. Conclusions
In summary, we have developed an enantioselective multi-
component Biginelli reaction catalyzed by a simple chiral primary
amine 5j and Brønsted acid HCl as the combined catalyst. Under the
optimal reaction conditions, a wide range of optically active dihy-
dropyrimidines was obtained in moderate to high yields with
excellent enantioselectivities (up to >99% ee). High enantiose-
lectivity was also obtained when intermediate benzylideneurea 6

D.-Z. Xu et al. / Tetrahedron 68 (2012) 7867e7872
10 mol% 5j
7871
O
O
O
O
NH
O
HCl 10 mol%
+
HN
Ar
+
H2N
NH2
OEt
Ar
H
1,4-dioxane/CHCl3 (8:2)
CO2Et
3
2
1
4
cat. 5j
HCl
O
O
NH
NH
Ar
N
N
H3C
H3C
H
H
N
N
H
N
H
O
EtOOC
EtOOC
N
H
H
O
Ar
NH2
ΙΙ
NH2
Ι
Fig. 2. Plausible reaction mechanism.
was used as substrate directly. Further investigations on the
enantioselective Biginelli reaction are in progress.
hexane¼8/92, 1.0 mL/min, 254 nm, tR (major)¼25.51 min, tR
(minor)¼38.90 min), >99% ee.
4. Experimental section
4.1.4. (R)-5-Ethoxycarbonyl-4-naphthalenyl-6-methyl-3,4-dihydropy-
rimidin-2(1H)-one (4d). White solid, yield 59%; mp 234e235 ꢀC; 1H
4.1. Typical procedure for the organocatalytic asymmetric
Biginelli reaction
NMR (300 MHz, DMSO):
d
(ppm) 0.81 (t, J¼6.9 Hz, 3H), 2.36 (s, 3H),
3.79 (dd, J1¼7.5 Hz, J2¼15 Hz, 2H), 6.05 (d, J¼2.4 Hz, 1H), 7.39e7.59
(m, 4H), 7.46 (s,1H), 7.84 (d, J¼7.8 Hz,1H), 7.94 (d, J¼7.5 Hz,1H), 8.30
After stirring
a
solution of benzaldehyde 1a (20.0
mL,
(d, J¼7.8 Hz, 1H), 9.25 (s, 1H); ½a D20
ꢂ36.4 (c 0.2, MeOH); The ee
ꢁ
0.20 mmol), urea 2 (36.0 mg, 0.6 mmol, 3.0 equiv), and hydro-
chloric acid (0.02 mmol) in 1,4-dioxane/CHCl3 (8/2, v/v, 1.0 mL) at
25 ꢀC for 1 h, the catalyst 5j (4.4 mg, 10 mol %, 0.02 mmol) and
was determined by HPLC analysis (Chiralpak AD-H, i-PrOH/
hexane¼8/92, 1.0 mL/min, 254 nm, tR (minor)¼27.36 min, tR
(major)¼45.48 min), 98% ee.
ethyl acetoacetate 3 (76.0 mL, 0.6 mmol, 3.0 equiv) were added
sequentially. The reaction mixture was stirred at room tempera-
ture for 48 h. Then, the crude product was purified by preparative
TLC (petroleum ether/ethyl acetate, 1/1) to afford 4a (48 mg, 91%
4.1.5. (R)-5-Ethoxycarbonyl-4-(4-chlorophenyl)-6-methyl-3,4-dihyd-
ropyrimidin-2(1H)-one (4e). White solid, yield 42%; mp
213e215 ꢀC; 1H NMR (300 MHz, DMSO):
d
(ppm) 1.09 (t, J¼7.2 Hz,
yield) as a white solid with >99% ee; ½a D20
ꢁ
ꢂ63.4 (c 0.21, CH3OH);
3H), 2.25 (s, 3H), 2.26 (s, 3H), 3.98 (dd, J1¼6.6 Hz, J2¼13.8 Hz, 2H),
5.15 (d, J¼2.4 Hz, 1H), 7.25 (d, J¼8.1 Hz, 2H), 7.39 (d, J¼8.1 Hz, 2H),
mp 200e202 ꢀC.
7.78 (s, 1H), 9.26 (s, 1H); ½a D20
ꢂ67.9 (c 0.2, MeOH); The ee was
ꢁ
4.1.1. (R)-5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
determined by HPLC analysis (Chiralpak OD-H, i-PrOH/hexane¼8/
92, 1.0 mL/min, 254 nm, tR (minor)¼16.72 min, tR (major)¼
24.90 min), 76% ee.
2(1H)-one (4a). White solid, yield 91%; mp 200e202 ꢀC; 1H NMR
(400 MHz, DMSO):
d
(ppm) 1.09 (t, J¼7.2 Hz, 3H), 2.25 (s, 3H), 3.98
(dd, J1¼7.2 Hz, J2¼14.4 Hz, 2H), 5.15 (d, J¼2.8 Hz, 1H), 7.23e7.34 (m,
5H), 7.74 (s, 1H), 9.19 (s, 1H); ½a D20
ꢁ
ꢂ63.4 (c 0.21, MeOH); The ee was
4.1.6. (R)-5-Ethoxycarbonyl-4-(4-fluorophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4f). White solid, yield 56%; mp
determined by HPLC analysis (Chiralpak OD-H, i-PrOH/hexane¼8/92,
1.0 mL/min, 254 nm, tR (minor)¼18.87 min, tR (major)¼23.24 min),
>99% ee.
183e185 ꢀC; 1H NMR (400 MHz, DMSO):
d
(ppm) 1.09 (t, J¼6.8 Hz,
3H), 2.25 (s, 3H), 3.98 (dd, J1¼6.8 Hz, J2¼13.6 Hz, 2H), 5.15 (d,
J¼2.8 Hz,1H), 7.13e7.17 (m, 2H), 7.25e7.29 (m, 2H), 7.76 (s,1H), 9.24
4.1.2. (R)-5-Ethoxycarbonyl-6-methyl-4-(p-tolyl)-3,4-dihydropyrim-
(s, 1H); ½a 2D0
ꢂ70.4 (c 0.2, MeOH); The ee was determined by HPLC
ꢁ
idin-2(1H)-one (4b). White solid, yield 62%; mp 233e236 ꢀC; 1H
analysis (Chiralpak OD-H, i-PrOH/hexane¼8/92, 1.0 mL/min,
254 nm, tR (minor)¼16.79 min, tR (major)¼25.39 min), 93% ee.
NMR (400 MHz, DMSO):
d
(ppm) 1.10 (t, J¼7.0 Hz, 3H), 2.25 (s, 3H),
2.26 (s, 3H), 3.99 (dd, J1¼7.2 Hz, J2¼14.4 Hz, 2H), 5.11 (d, J¼2.8 Hz,
1H), 7.12 (d, J¼8.4 Hz, 2H), 7.14 (d, J¼8.4 Hz, 2H), 7.70 (s, 1H),
4.1.7. (R)-5-Ethoxycarbonyl-4-(4-bromophenyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (4g). White solid, yield 52%; mp
a 20
9.17 (s, 1H); ½ ꢁD ꢂ66.4 (c 0.2, MeOH); The ee was determined
by HPLC analysis (Chiralpak OD-H, i-PrOH/hexane¼8/92, 1.0 mL/
min, 254 nm, tR (minor)¼16.57 min, tR (major)¼22.71 min),
>99% ee.
207e209 ꢀC; 1H NMR (300 MHz, DMSO):
d
(ppm) 1.09 (t, J¼6.6 Hz,
3H), 2.26 (s, 3H), 3.99 (dd, J1¼6.3 Hz, J2¼13.2 Hz, 2H), 5.14 (d,
J¼2.8 Hz, 1H), 7.20 (d, J¼8.1 Hz, 2H), 7.53 (d, J¼7.8 Hz, 2H), 7.77 (s,
1H), 9.25 (s, 1H); ½a D20
ꢂ73.4 (c 0.22, MeOH); The ee was de-
ꢁ
4.1.3. (R)-5-Ethoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,4-
termined by HPLC analysis (Chiralpak OD-H, i-PrOH/hexane¼8/92,
1.0 mL/min, 254 nm, tR (minor)¼17.58 min, tR (major)¼23.74 min),
91% ee.
dihydropyrimidin-2(1H)-one (4c). White solid, yield 70%; mp
204e205 ꢀC; 1H NMR (400 MHz, DMSO):
d
(ppm) 1.10 (t, J¼7.0 Hz,
3H), 2.24 (s, 3H), 3.71 (s, 3H), 3.98 (dd, J1¼6.4 Hz, J2¼13.2 Hz, 2H),
5.10 (d, J¼2.8 Hz, 1H), 6.87 (d, J¼8.0 Hz, 2H), 7.15 (d, J¼8.0 Hz, 2H),
4.1.8. (R)-5-Ethoxycarbonyl-4-(4-notrophenyl)-6-methyl-3,4-dihy-
7.68 (s, 1H), 9.17 (s, 1H); ½a D20
ꢁ
ꢂ58.5 (c 0.22, MeOH); The ee
dropyrimidin-2(1H)-one (4h). White solid, yield 5%; mp
was determined by HPLC analysis (Chiralpak OD-H, i-PrOH/
207e209 ꢀC; 1H NMR (400 MHz, DMSO):
d
(ppm) 1.11 (t, J¼7.2 Hz,

7872
D.-Z. Xu et al. / Tetrahedron 68 (2012) 7867e7872
4. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;
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3H), 2.29 (s, 3H), 4.00 (dd, J1¼7.2 Hz, J2¼14.4 Hz, 2H), 5.29
(d, J¼2.8 Hz, 1H), 7.52 (d, J¼8.8 Hz, 2H), 7.90 (s, 1H), 8.23 (d,
J¼8.8 Hz, 2H), 9.37 (s, 1H); The ee was determined by HPLC analysis
(Chiralpak OD-H, i-PrOH/hexane¼8/92, 1.0 mL/min, 254 nm, tR
(minor)¼39.76 min, tR (major)¼47.90 min), 7% ee.
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Dolling, U. H. J. Org. Chem. 1998, 63, 3454e3457; (c) Kappe, C. O. Acc. Chem. Res.
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (grant no. 20672061, China), National
Basic Research Program of China (973 Program) (no. 2010CB833301),
and the Fundamental Research Funds for the Central Universities.
We also thank the Nankai University State Key Laboratory of
Elemento-Organic Chemistry for support.
Supplementary data
10. (a) Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630e645; (b) Kappe, C. O. Eur. J. Med.
Chem. 2000, 35, 1043e1052; (c) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am.
Chem. Soc. 2005, 127, 11256e11257.
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.07.027.
11. (a) Huang, Y. J.; Yang, F. Y.; Zhu, C. J. J. Am. Chem. Soc. 2005, 127, 16386e16387;
(b) Chen, X. H.; Xu, X. Y.; Liu, H.; Cun, L. F.; Gong, L. Z. J. Am. Chem. Soc. 2006, 128,
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