Highly enantioselective Biginelli reaction catalyzed by double axially chiral bisphosphorylimides

Article abstract of DOI:10.1002/ejoc.201301560

Double axially chiral bisphosphorylimides have been used as catalysts in enantioselective Biginelli reactions. The three-component reaction of aromatic aldehydes, thiourea, and ethyl acetoacetate took place by using 5 mol-% catalyst in ethyl acetate at 50°C. A series of chiral dihydropyrimidinethiones (DHPMs) were obtained in high yields (up to 97 %) with good to high enantioselectivities (up to 96 % ee) in only 12 hours. The three-component Biginelli reaction was catalyzed by BINOL-derived double axially chiral bis-phosphorylimides. The catalyst with 3,3′-2-naphthyl substituents most effectively catalyzed the reaction and a series of chiral dihydropyrimidinethiones (DHPMs) were obtained in high yields up to 97 % with 90-96 % ee in only 12 hours. Copyright

Full text of DOI:10.1002/ejoc.201301560

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301560
Highly Enantioselective Biginelli Reaction Catalyzed by Double Axially Chiral
Bisphosphorylimides
Dong An,[a] Yan-Sen Fan,[a] Yang Gao,[a] Zi-Qian Zhu,[a] Liang-Yu Zheng,*[b] and
Suo-Qin Zhang*[a]
Keywords: Organocatalysis / Enantioselectivity / Asymmetric catalysis / Multicomponent reactions
Double axially chiral bisphosphorylimides have been used as
catalysts in enantioselective Biginelli reactions. The three-
component reaction of aromatic aldehydes, thiourea, and
ethyl acetoacetate took place by using 5 mol-% catalyst in
ethyl acetate at 50 °C. A series of chiral dihydropyrimid-
inethiones (DHPMs) were obtained in high yields (up to
97%) with good to high enantioselectivities (up to 96%ee)
in only 12 hours.
ingly, asymmetric catalytic Biginelli reactions have been the
subject of extensive research over the last decades. In 2005,
Zhu’s group developed a new chiral Ytterbium catalyst and
successfully used the catalyst in enantioselective Biginelli re-
action for the first time.[14] Not long after, H8-BINOL-
phosphoric acids were first applied in organocatalytic Bigi-
nelli reaction by Gong and co-workers.[15] Since then, vari-
ous organocatalytic enantioselective Biginelli reactions have
been reported,[16] including those catalyzed by using pri-
mary amines,[16b–16f] proline derivatives,[16g,16h] pyrrolidinyl
tetrazole,[16i] and ionic liquids.[16j] However, long reaction
times (from two days to a week) are necessary in most of
these reported methods. In addition, only a few examples
of chiral Brønsted acid catalysts have been reported for the
Biginelli reaction.[16k,16l] Herein, we wish to disclose the re-
sults of our research on the first double axially chiral bis-
phosphorylimides catalyzing the enantioselective Biginelli
reaction in the asymmetric synthesis of DHPMs.
Introduction
Chiral Brønsted acids that are derived from axially chiral
backbones such as BINOL and VAPOL have aroused in-
creasing interest since BINOL-phosphoric acids were ini-
tially used in an enantioselective Mannich type reaction in
2004.[1] The work of modifying the structure of BINOL-
derived Brønsted acids has been carried out by many
groups. In 2006, Yamamoto and co-workers developed a
new chiral N-triflyl phosphoramide that was successfully
used in enantioselective Diels–Alder reactions.[2] Before
long, N-phosphinyl phosphoramides[3] and N-pyridinyl
phosphoramides[4] were designed by the group of List. Re-
cently, BINOL-derived double axially chiral bisphosphoryl-
imides have also been recognized as a novel type of
Brønsted acid catalyst. In 2012, List and co-workers re-
ported the application of double axially chiral bisphosphor-
ylimides in asymmetric spiroacetalization,[5] sulfoxidation,[6]
and acetalization.[7] In the same year, our group also re-
ported the results of our work on double axially chiral bis-
phosphorylimides catalyzing asymmetric Mannich reac-
tion[8] and Friedel–Crafts reaction.[9]
Results and Discussion
As shown in Scheme 1, catalysts 1a–d were synthesized
according to our previous work[8] and screened in the three-
component Biginelli reaction of 4-nitrobenzaldehyde (2a),
thiourea (3), and ethyl acetoacetate (4; Table 1). The reac-
tion was performed at 25 °C in the presence of 5 mol-%
catalyst in toluene. We found that 1a, with small substituent
groups, afforded relative low yield and enantioselectivity
(Table 1, entry 1). Moreover, compared with catalysts 1b–d,
which afforded S-configured product, 1a provided R-con-
figured product in 17%ee.[16k] Upon increasing the size of
the substituents on one side of the catalyst (Table 1, en-
try 2), both the yield and enantioselectivity were signifi-
cantly improved. Encouraged by this result, catalyst 1c and
1d, with 3,3Ј-1-naphthyl and 3,3Ј-2-naphthyl substituents,
respectively, were subsequently used for the reaction
As one of the most available multicomponent reactions,
the Biginelli reaction[10] has attracted considerable atten-
tion.[11] It provides an important method for the straight-
forward synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
and -thiones (DHPMs), which are important components
of a range of drugs[12] and natural alkaloids.[13] Accord-
[a] College of Chemistry, Jilin University,
Changchun 130012, P. R. of China
E-mail: suoqin@jlu.edu.cn
lyzheng@jlu.edu.cn
http://chem.jlu.edu.cn/chemistry/teacher.php?tid=125&&id=3
[b] Key Laboratory for Molecular Enzymology and Engineering of
Ministry of Education, Jilin University,
Changchun 130012, P. R. of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301560.
Eur. J. Org. Chem. 2014, 301–306
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
301

D. An, Y.-S. Fan, Y. Gao, Z.-Q. Zhu, L.-Y. Zheng, S.-Q. Zhang
SHORT COMMUNICATION
(Table 1, entries 3 and 4). Among the catalysts examined, Table 2. Optimization of the reaction conditions with catalyst 1d.[a]
catalyst 1d was found to be most effective for the reaction,
affording 73% yield and 93%ee. Interestingly, in previous
work reported by Gong,[15] BINOL-derived phosphoric ac-
ids with 3,3Ј-phenyl substituents turned out to be highly
enantioselective. In contrast, phosphoric acids with 3,3Ј-2-
naphthyl substituents proved to have poor catalytic activity.
These differences between double axially chiral bisphospho-
rylimides and phosphoric acids suggest that different reac-
tion mechanisms and steric effects are in operation with the
two types of catalysts. The Brønsted acidic site and
Brønsted basic site of BINOL-phosphoric acids are linked
with the only phosphorus atom, which requires that the two
sites are close to each other. Two 3,3Ј-substituents are far
from the active site and give a relatively loose chiral envi-
ronment. On the other hand, double axially chiral bisphos-
phorylimides have two phosphorus atoms that link with the
Brønsted acidic site and Brønsted basic site separately. The
two sites stay away from each other and approach the 3,3Ј-
substituents on each side of catalyst. Moreover, the sur-
Entry 1d [mol-%] Solvent
T [°C] t [d] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
5
5
5
5
5
5
5
5
2
8
toluene
CH2Cl2
THF
CH3CN
EtOAc
Cl(CH2)2Cl
EtOAc
EtOAc
EtOAc
EtOAc
25
25
25
25
25
25
40
50
50
50
7
4
7
4
4
7
1
0.5
1
0.25
73
75
–
64
75
57
82
93
73
96
93
91
–
73
95
72
95
95
94
95
[a] Reaction conditions: 4-nitrobenzaldehyde (2a; 0.1 mmol,
1.0 equiv.), thiourea (3; 0.12 mmol, 1.2 equiv.), ethyl acetoacetate
(4; 0.3 mmol, 3 equiv.), catalyst (1d; 5 mol-%), solvent (1 mL).
[b] Isolated yield after flash chromatography. [c] Determined by
HPLC analysis by using a chiral column.
Scheme 1. BINOL- and H8-BINOL-based chiral bisphosphoryl-
imides.
Table 3. Scope of the enantioselective Biginelli reaction.[a]
Table 1. Screening of double axially chiral bisphosphorylimides.[a]
Entry
R1 (2)
Product Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4-NO2C6H4 2a
2-NO2C6H4 2b
5a
5b
5c
5d
5e
5f
93
90
87
94
89
93
83
92
88
94
97
92
95
95
95
93
92
93
91
93
90
90
90
93
93
96
3-BrC6H4
3-FC6H4
2c
2d
2e
2f
2g
2h
2i
2-ClC6H4
3-ClC6H4
2-BrC6H4
4-BrC6H4
2-MeC6H4
2-FC6H4
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
19
62
66
73
–17[d]
83
87
5g
5h
5i
9
93
10
11
12
13
2j
2k
5j
4-CNC6H4
4-CF3C6H4 2l
5k
5l
[a] Reaction conditions: 4-nitrobenzaldehyde (2a; 0.1 mmol,
1.0 equiv.), thiourea (3; 0.12 mmol, 1.2 equiv.), ethyl acetoacetate
(4; 0.3 mmol, 3 equiv.), catalyst (1; 5 mol-%), toluene (1 mL), 25 °C,
7 d. [b] Isolated yield after flash chromatography. [c] Determined
by HPLC analysis by using a chiral column. [d] The R-configured
product was produced in 17%ee. The absolute configuration of 5a
was determined by comparing the retention time of products by
HPLC with the published data.[16k]
2,4-Cl2C6H3 2m
5m
[a] Reaction conditions: benzaldehyde derivative (2; 0.1 mmol,
1.0 equiv.), thiourea (3; 0.12 mmol, 1.2 equiv.), ethyl acetoacetate
(4; 0.3 mmol, 3 equiv.), catalyst (1d; 5 mol-%), ethyl acetate (1 mL),
50 °C, 12 h. [b] Isolated yield after flash chromatography. [c] Deter-
mined by HPLC analysis by using a chiral column.
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High Enantioselective Biginelli Reaction
rounding two pairs of 3,3Ј-substituents further define the on the phenyl ring gave products with similar yields. How-
chiral environment and create an interlocking system.
ever, the electronic nature of the substituents of the phenyl
Having identified 1d as the optimal catalyst, we studied ring played an important role in controlling the enantio-
the solvent effects on this reaction. As summarized in selectivity. Most aromatic aldehydes with electron-with-
Table 2, good to high ee values of 72 to 95% were obtained drawing groups on the phenyl ring led to reactions with
in all solvents except tetrahydrofuran (Table 2, entries 1–6). higher enantioselectivities. For example, the use of ortho-
As the best solvent, ethyl acetate afforded 75% yield and and para-nitro-substituted benzaldehydes 2a and 2b re-
95% enantiomeric excess (Table 2, entry 5). In addition, sulted in excellent enantioselectivities (95%ee; Table 3, en-
temperature and catalyst loading were also surveyed tries 1 and 2). Other electron-withdrawing aromatic alde-
(Table 2, entries 7–10). To our surprise, performing the re- hydes also underwent the reaction with 90–93%ee (Table 3,
action at 50 °C with 5 mol-% 1d led to complete conversion entries 3–8 and 10–12). Furthermore, substrate 2m, with
in just 12 hours (Table 2, entry 8). Furthermore, the yield two electron-withdrawing groups, afforded the highest
improved to 93% and the enantioselectivity hardly changed enantioselectivity (96%ee; Table 3, entry 12). In contrast,
despite the temperature increase from 25 to 50 °C. We then electron-rich 2-methylbenzaldehyde (2i) underwent the reac-
reduced the catalyst loading of 1d to 2 mol-% (Table 2, en- tion with relatively low enantioselectivity (90%ee; Table 3,
try 9), but found a drop in both the yield and enantio- entry 9).
selectivity. Increasing the catalyst loading did not show a
Biginelli reactions of urea with aromatic aldehydes and
clear improvement in the catalytic performance (Table 2, ethyl acetoacetate were also tested on the basis of the opti-
entry 10). By screening a series of reaction conditions, op- mal conditions and with adjusted reaction conditions (sol-
erating with 5 mol-% 1d in ethyl acetate at 50 °C was found vent, temperature and feed ratio), but the corresponding
to be the most favorable.
products were not obtained.
With the optimal conditions established, the Biginelli re-
Base on relevant reports,[5,11d,16k] a plausible reaction
actions of a variety of aromatic aldehydes with thiourea and mechanism is shown in Scheme 2. Initially, the dehydration
ethyl acetoacetate were investigated with catalyst 1d. As can condensation of aldehyde with thiourea produces the corre-
be seen in Table 3, the reaction afforded DHPMs in high sponding imine, which interacts with chiral bisphosphoryli-
yields (83–97%) with excellent enantioselectivities (90– mide through a dual H-bond to the imine to give intermedi-
96%ee). Substrates with ortho-, meta- or para-substituents ate I. Subsequently, the enol form of ethyl acetoacetate is
Scheme 2. A plausible reaction mechanism for the Biginelli reaction catalyzed by double axially chiral bisphosphorylimides.
Eur. J. Org. Chem. 2014, 301–306
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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303

D. An, Y.-S. Fan, Y. Gao, Z.-Q. Zhu, L.-Y. Zheng, S.-Q. Zhang
SHORT COMMUNICATION
CDCl3): δ = 8.20 (d, J = 9.0 Hz, 2 H), 8.02 (s, 1 H), 7.59 (s, 1 H),
7.48 (d, J = 8.7 Hz, 2 H), 5.52 (d, J = 3.0 Hz, 1 H), 4.13 (q, J =
6.8 Hz, 2 H), 2.39 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 174.9, 165.3, 150.9, 147.4, 146.4, 128.3,
124.5, 100.2, 60.2, 54.2, 17.7, 14.5 ppm.
activated by a second P=O bond to form intermediate II.
The ethyl acetoacetate then attacked the imine to give chiral
intermediate III. Intramolecular cyclization takes place
through attack of the amino group on the C=O bond close
to the methyl group. Finally, intermediate IV is converted
into the product through dehydration, which also releases
the chiral bisphosphorylimide.
(S)-Ethyl
6-Methyl-4-(2-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5b): Yield 0.0288 g (90%); 95%ee [HPLC
with a Daicel Chiralpak AD-H; n-hexane/2-propanol, 90:10; flow
rate: 1.0 mL/min;
λ = 254 nm; tR = 19.58 (major), 29.68
(minor) min]; [α]2D5 = +242.1 (c = 0.5, EtOAc). 1H NMR (300 MHz,
CDCl3): δ = 8.12 (s, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.65 (t, J =
7.1 Hz, 1 H), 7.52 (s, 1 H), 7.48 (t, J = 8.4 Hz, 2 H), 5.85 (d, J =
2.7 Hz, 1 H), 3.99–3.91 (m, 2 H), 2.49 (s, 3 H), 0.96 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 174.6, 165.0, 147.8,
146.3, 138.6, 134.7, 130.0, 129.6, 124.7, 100.3, 60.0, 49.7, 17.6,
14.2 ppm.
Conclusions
Double axially chiral bisphosphorylimides have been
shown to be effective for the enantioselective Biginelli reac-
tion. Under the optimal reaction conditions, a variety of
chiral DHPMs were obtained in good yields (up to 97%)
with excellent enantioselectivities (up to 96%) in only 12
hours. Further exploration of the catalytic mechanism and
applications of the novel bisphosphorylimides in asymmet-
ric catalysis are in progress in our laboratory.
(S)-Ethyl 6-Methyl-4-(3-bromophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5c): Yield 0.0307 g (87%); 93%ee [HPLC
with a Daicel Chiralpak AS-H; n-hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min;
λ = 254 nm; tR = 9.60 (minor), 12.42
(major) min]; [α]2D5 = +87.3 (c = 0.5, EtOAc). H NMR (300 MHz,
CDCl3): δ = 7.91 (s, 1 H), 7.44–7.41 (m, 2 H), 7.39 (s, 1 H), 7.23
(t, J = 7.4 Hz, 2 H), 5.38 (s, 1 H), 4.16–4.07 (m, 2 H), 2.38 (s, 3 H),
1.20 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 174.8, 165.4, 146.5, 146.1, 131.5, 131.1, 129.8, 125.9, 122.2, 100.6,
60.2, 54.1, 17.7, 14.5 ppm.
1
Experimental Section
General Remarks: All reagents were used without purification. All
solvents were purified and dried according to standard methods.
The reaction products were purified by flash column chromatog-
raphy on 200–300 mesh silica gel. Optical rotations were measured
with a Jasco-P-2000 digital polarimeter at 25 °C and concentrations
(c) are given in gϫ(100 mL)–1. 1H and 13C NMR spectra were
recorded with Bruker 300 MHz spectrometers (300 MHz for 1H
NMR, 75 MHz for 13C NMR); chemical shifts (δ) are given in
ppm. Enantiomeric excess values were measured by analytical
HPLC with Daicel ChiralPak AD-H, Daicel ChiralPak AS-H or
Daicel Chiralcel OD-H columns.
(S)-Ethyl 6-Methyl-4-(3-fluorophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5d): Yield 0.0277 g (94%); 92%ee;
[HPLC with a Daicel Chiralpak AD-H; n-hexane/2-propanol,
80:20; flow rate: 1.0 mL/min; λ = 254 nm; tR = 9.23 (major), 10.23
(minor) min]; [α]2D5 = +61.7 (c = 0.5, EtOAc). H NMR (300 MHz,
1
CDCl3): δ = 7.87 (s, 1 H), 7.34–7.27 (m, 2 H), 7.09 (d, J = 8.1 Hz,
1 H), 6.99 (t, J = 8.0 Hz, 2 H), 5.41 (d, J = 2.7 Hz, 1 H), 4.17–4.06
(m, 2 H), 2.38 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 174.9, 165.5, 161.0, 146.7, 146.0, 131.2,
122.9, 115.1, 113.7, 100.7, 60.2, 54.0, 17.7, 14.5 ppm.
Synthesis of Catalyst 1d: The catalyst 1d was prepared according
to our previous work.[8]
Compound (R,R)-1d: White solid; m.p. 252–253 °C; [α]2D5 = –416.0
(c = 0.5, THF). H NMR (300 MHz, [D6]DMSO): δ = 8.28 (d, J
(R)-Ethyl 6-Methyl-4-(2-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5e): Yield 0.0276 g (89%); 93%ee [HPLC
with a Daicel Chiralpak AS-H; n-hexane/2-propanol, 80:20; flow
1
= 5.4 Hz, 4 H), 8.17–8.15 (m, 2 H), 8.02–8.00 (d, J = 7.8 Hz, 2 H),
7.86–7.75 (m, 7 H), 7.65–7.30 (m, 26 H), 7.21–7.14 (m, 4 H), 7.07–
7.04 (d, J = 8.7 Hz, 2 H), 7.00–6.95 (t, J = 7.5 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 145.34, 145.20, 134.61, 134.29,
134.10, 133.63, 132.97, 132.64, 132.31, 131.84, 131.39, 131.30,
130.65, 130.30, 128.76, 128.62, 128.38, 128.15, 127.97, 127.70,
127.08, 126.85, 126.55, 126.31, 125.76, 125.54, 123.45, 122.59 ppm.
rate: 1.0 mL/min;
λ = 254 nm; tR = 12.97 (minor), 17.83
(major) min]; [α]2D5 = +52.9 (c = 0.5, EtOAc). H NMR (300 MHz,
CDCl3): δ = 7.98 (s, 1 H), 7.40–7.37 (m, 1 H), 7.26–7.22 (m, 4 H),
5.90 (d, J = 2.4 Hz, 1 H), 4.03 (q, J = 7.0 Hz, 2 H), 2.46 (s, 3 H),
1.06 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
174.0, 164.8, 144.6, 138.5, 132.5, 129.8, 129.6, 128.5, 127.6, 100.7,
60.3, 52.6, 17.8, 13.8 ppm.
1
+
HRMS (ESI): calcd. for C80H50NO6P2 [M + H]+ 1182.3108;
found 1182.3108.
(S)-Ethyl 6-Methyl-4-(3-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5f): Yield 0.0289 g (93%); 91%ee [HPLC
with a Daicel Chiralpak AS-H; n-hexane/2-propanol, 70:30; flow
General Procedure for the Organocatalytic Biginelli Reaction: A
solution of aldehyde (0.1 mmol), thiourea (0.12 mmol), and catalyst
(5 mol-%, 0.005 mmol) in EtOAc (1 mL) was stirred at 25 °C for
2 h, then ethyl acetoacetate (0.3 mmol) was added. The reaction
mixture was stirred at 50 °C for 12 h (reaction progress monitored
by TLC). EtOAc and silica gel were added and, after removal of
the solvent, the residue was purified by flash column chromatog-
raphy on silica gel (ethyl acetate/petroleum ether, 1:5 to 1:2) to af-
ford the pure products.
rate: 1.0 mL/min;
λ = 254 nm; tR = 10.38 (minor), 13.53
(major) min; [α]2D5 = +82.5 (c = 0.5, EtOAc). H NMR (300 MHz,
CDCl3): δ = 8.08 (s, 1 H), 7.53 (s, 1 H), 7.28–7.26 (m, 3 H), 7.21–
7.16 (m, 1 H), 5.38 (d, J = 3.0 Hz, 1 H), 4.16–4.07 (m, 2 H), 2.38 (s,
3 H), 1.19 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 174.3, 165.0, 144.2, 143.4, 134.6, 130.2, 128.5, 127.0, 125.0, 102.3,
60.6, 55.6, 18.3, 14.1 ppm.
1
(S)-Ethyl
6-Methyl-4-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydro-
(R)-Ethyl 6-Methyl-4-(2-bromophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5g): Yield 0.0294 g (83%); 93%ee [HPLC
with a Daicel Chiralpak AD-H; n-hexane/2-propanol, 80:20; flow
pyrimidine-5-carboxylate (5a): Yield 0.0298 g (93%); 95%ee [HPLC
with a Daicel Chiralpak AS-H; n-hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min;
λ
=
254 nm; tR
=
18.08 (minor), 22.48 rate: 1.0 mL/min;
λ = 254 nm,; tR = 7.50 (major), 9.38
1
(major) min]; [α]2D5 = +202.1 (c = 0.5, EtOAc). 1H NMR (300 MHz,
(minor) min]; [α]2D5 = +21.7 (c = 0.5, EtOAc). H NMR (300 MHz,
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High Enantioselective Biginelli Reaction
CDCl3): δ = 7.89 (s, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.33–7.28 (m,
1 H), 7.24–7.14 (m, 3 H), 5.88 (s, 1 H), 4.02 (q, J = 7.1 Hz, 2 H),
2.46 (s, 3 H), 1.06 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 174.3, 165.2, 146.1, 142.9, 133.2, 130.2, 129.9,
129.0, 122.8, 100.6, 59.9, 54.6, 17.5, 14.5 ppm.
3 H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 174.2, 164.7, 144.7, 137.2, 134.8, 133.3, 129.7, 129.5, 128.0, 100.6,
60.5, 52.2, 17.9, 13.9 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra and HPLC chromatograms.
(S)-Ethyl 6-Methyl-4-(4-bromophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5h): Yield 0.0326 g (92%); 90%ee [HPLC
with a Daicel Chiralpak AD-H; n-hexane/2-propanol, 80:20; flow
Acknowledgments
rate: 1.0 mL/min;
λ = 254 nm; tR = 8.57 (minor), 11.27
(major) min]; [α]2D5 = +126.3 (c = 0.5, EtOAc). 1H NMR (300 MHz,
CDCl3): δ = 8.00 (s, 1 H), 7.52 (s, 1 H), 7.45 (d, J = 8.4 Hz, 2 H),
The authors are grateful for the financial support from the
National Natural Science Foundation of China (NSFC) (grant
7.17 (d, J = 8.4 Hz, 2 H), 5.36 (d, J = 2.4 Hz, 1 H), 4.10 (q, J = number 21372098) and the Jilin Province Science & Technology
7.1 Hz, 2 H), 2.36 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 175.0, 165.9, 146.2, 143.5, 132.3, 129.5,
121.7, 101.2, 60.6, 54.4, 18.0, 14.8 ppm.
Development Program (grant numbers 20100538, 20110436,
201215033, 20120315).
(S)-Ethyl 6-Methyl-2-thioxo-4-(o-tolyl)-1,2,3,4-tetrahydropyrimid-
ine-5-carboxylate (5i): Yield 0.0256 g (88%); 90%ee [HPLC with
a Daicel Chiralpak AD-H; n-hexane/2-propanol, 90:10; flow rate:
1.0 mL/min; λ = 254 nm; tR = 12.90 (major), 18.28 (minor) min];
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[α]2D5 = +146.9 (c = 0.5, EtOAc). H NMR (300 MHz, CDCl3): δ =
8.05 (s, 1 H), 7.21–7.11 (m, 5 H), 5.64 (s, 1 H), 4.00 (q, J = 7.1 Hz,
2 H), 2.44 (s, 3 H), 2.40 (s, 3 H), 1.06 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 173.0, 165.1, 143.1, 140.4, 134.8,
130.5, 128.0, 127.6, 126.8, 102.4, 60.1, 52.3, 19.1, 17.8, 13.9 ppm.
(R)-Ethyl 4-(2-Fluorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5j): Yield 0.0277 g (94%); 90%ee [HPLC
with a Daicel Chiralpak AS-H; n-hexane/2-propanol, 70:30; flow
rate: 1.0 mL/min;
λ = 254 nm; tR = 9.31 (minor), 11.10
(major) min]; [α]2D5 = +114.4 (c = 0.5, EtOAc). 1H NMR (300 MHz,
CDCl3): δ = 8.01 (s, 1 H), 7.32–7.27 (m, 1 H), 7.24–7.18 (m, 2 H),
7.13–7.03 (m, 2 H), 5.74 (s, 1 H), 4.06 (q, J = 7.2 Hz, 2 H), 2.42
(s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 174.6, 165.3, 145.8, 130.4, 130.3, 129.7, 125.1, 116.2,
115.9, 99.8, 60.0, 49.2, 17.5, 14.3 ppm.
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(S)-Ethyl 4-(4-Cyanophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5k): Yield 0.0291 g (97%); 93%ee
[HPLC with a Daicel Chiralpak AD-H; n-hexane/2-propanol,
80:20; flow rate: 1.0 mL/min; λ = 254 nm; tR = 12.77 (minor), 16.52
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1
CDCl3): δ = 8.09 (s, 1 H), 7.68–7.62 (m, 3 H), 7.42 (d, J = 8.4 Hz,
2 H), 5.47 (d, J = 3.0 Hz, 1 H), 4.17–4.07 (m, 2 H), 2.37 (s, 3 H),
1.19 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 175.0, 165.4, 149.0, 146.3, 133.2, 127.9, 119.1, 111.0, 100.3, 60.2,
54.3, 17.7, 14.5 ppm.
(S)-Ethyl 6-Methyl-2-thioxo-4-[4-(trifluoromethyl)phenyl]-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5l): Yield 0.0317 g (92%);
93%ee [HPLC with a Daicel Chiralpak AD-H; n-hexane/2-prop-
anol, 80:20; flow rate: 1.0 mL/min; λ = 254 nm; tR = 6.10 (minor),
7.30 (major) min; [α]2D5 = +109.9 (c = 0.5, EtOAc). 1H NMR
(300 MHz, CDCl3): δ = 7.83 (m, 1 H), 7.60 (d, J = 8.4 Hz, 2 H),
7.42 (d, J = 8.1 Hz, 2 H), 7.33 (m, 1 H), 5.48 (d, J = 3.0 Hz, 1 H),
4.16–4.08 (m, 2 H), 2.37 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 175.0, 165.4, 148.3, 146.2,
127.8, 126.1, 100.5, 60.2, 54.2, 17.7, 14.4 ppm.
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(R)-Ethyl
4-(2,4-Dichlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (5m): Yield 0.0327 g (95%); 96%ee
[HPLC with a Daicel Chiralpak OD-H; n-hexane/2-propanol,
90:10; flow rate: 1.0 mL/min; λ = 254 nm; tR = 8.02 (major), 10.27
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305

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Received: October 16, 2013
Published Online: November 19, 2013
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 301–306