Additive controlled, stereoselective benzylation of 2- thioxotetrahydropyrimidin-4(1H)-ones via chiral induction from a remote stereocenter

Article abstract of DOI:10.1016/j.tetasy.2012.04.002

Stereoselective alkylation reactions of 3-aryl-1-alkyl-2- thioxotetrahydropyrimidin-4(1H)-one derivatives were studied. The reaction conditions were optimized to obtain the monobenzylated adduct with improved diastereoselectivity by regulating the reaction kinetics using HMPA as the additive and chiral ethyl lactate as the quencher. The absolute configuration of the product was established by NMR experiments, computational calculations, and single crystal X-ray analysis.

Full text of DOI:10.1016/j.tetasy.2012.04.002

Tetrahedron: Asymmetry 23 (2012) 434–442
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Additive controlled, stereoselective benzylation
of 2-thioxotetrahydropyrimidin-4(1H)-ones via chiral induction
from a remote stereocenter
Varun Kumar a, Anang Pal a, Gopal L. Khatik a, Suman Bhattacharya b, Vipin A. Nair a,
⇑
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
b Department of Chemistry, Pondicherry University, Kalapet, Pondicherry 605 014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective alkylation reactions of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-one derivatives
were studied. The reaction conditions were optimized to obtain the monobenzylated adduct with
improved diastereoselectivity by regulating the reaction kinetics using HMPA as the additive and chiral
ethyl lactate as the quencher. The absolute configuration of the product was established by NMR exper-
iments, computational calculations, and single crystal X-ray analysis.
Received 17 January 2012
Revised 28 March 2012
Accepted 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
adduct with improved diastereoselectivity, and to establish the
absolute configuration at the newly generated stereocenter.
With the current surge in asymmetric synthesis, enolates have
demonstrated high versatility for stereoselective carbon–carbon
bond formation. This has facilitated the synthesis of various chiral
building blocks, drug intermediates, and natural products.1 The
geometry and aggregation of enolates have been controlled by
bases and additives, which influence the reactivity and selectivity
of these reactions.2 However, reactions of cyclic enolates are more
complex due to rigid conformations and geometrical constraints.
The stereoregulations are substrate specific with stereointegrity
originating from ring conformation, aggregation state, endo- and
exo-cyclic ring substituents, their position and relative orientation,
and hence represent a vibrant area of research.3 Our interests were
on the alkylation reactions of conformationally restricted enolates
of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-ones, which
are derivatives of dihydrothiouracil. Dihydrothiouracils have at-
tracted considerable attention because of their vast therapeutic po-
tential including anticancer, antibacterial, anticonvulsant, antiviral,
antimicrobial, antidiabetic, and antiatherosclerotic properties.4
Alkylation of these substrates suffer from serious drawbacks such
as low yields, poor diastereoselectivity, quantitative formation of
a dibenzylated adduct, and ambiguity in the determination of the
absolute configuration, and hence negates its synthetic applicabil-
ity.5g Therefore our efforts were focused on exploring the reaction
kinetics by employing different bases and additives so as to mod-
ulate the reactivity of the enolates in favor of the monobenzylated
2. Results and discussion
With an ever increasing aim to identify new pharmacologically
active heterocycles, our attention was mainly on synthesis and
functionalization.5 A one-pot synthesis of N-aryl-1-alkyl-2-thioxo-
tetrahydropyrimidin-4-ones5a from aryl isothiocyanates and b-
aminoesters afforded enantiomerically pure 3-aryl-1-(1-phenyl-
ethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones 5(a–e) and 50(a–
e) (Scheme 1). The reaction afforded the desired products with
excellent yields in short reaction time (Table 1) with ease of
purification.
The alkylation reaction was studied on a model substrate, 3-
cyano-4-chlorophenyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-one 5c by generating lithium enolates using dif-
ferent lithium bases (n-BuLi, LDA, and LHMDS) and then reacting
them with 4-chlorobenzyl bromide (Table 2, entries 1–6). The
reactions afforded low yields of the monobenzylated adduct with
poor diastereoselectivity (Scheme 2). When the reaction was
performed at an elevated temperature, the formation of dibenzy-
lated adduct 7(c)(iii) was favored. The poor selectivity indicates
that the stereo- and electronic factors remain equivalent, and
therefore have no
p-facial selectivity to the incoming electro-
phile. This prompted us to employ chiral lithium bases, which
are known to influence the stereochemical orientation of the
product by steric influences,6 however the starting material
was recovered as such, although the dibenzylated adduct was
observed in minute amounts at higher temperatures (Table 2,
entries 7–10).
⇑
Corresponding author.
E-mail address: vnair@niper.ac.in (V.A. Nair).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.002

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
435
R2
R2
R1
NCS
O
R1
O
S
LiClO4
neat
4(a-e)
H2N
R
O
R
MeO
+
N
N
R
1
2
Et3N, CH3CN
reflux
N
H
O
or
R=
Ph
Ph
3
5(a-e)
5'(a-e)
Scheme 1. One-pot synthesis of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-ones.
Cl
Cl
Cl
Cl
NC
NC
+
NC
S
S
S
NC
S
N
N
Ph
N
N
Ph
N
N
Ph
base, THF, -78oC
additive
N
N
Ph
+
O
O
O
O
Br
Cl
5(c)
Cl
Cl
Cl
6
7(c)(ii)
7(c)(i)
7(c)(iii) Cl
Scheme 2. Reaction conditions employed for the selective formation of 5-(4-chlorobenzyl)-3-(3-cyano-4-chlorophenyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydropyrimi-
din-4(1H)-ones.
were evaluated by employing different chelating agents (Table 2,
Table 1
entries 15–20) and the best result was obtained with HMPA.
The addition of HMPA at low temperature (ꢀ78 °C) greatly im-
proved the yields of monobenzylated product although the diaste-
reoselectivity was moderate (65:35). However the use of an excess
of base or alkylating agent under these conditions lowered the
yield of the monobenzylated product. The increased reactivity of
the enolate may be because of the coordination with HMPA. Since
HMPA is highly polar and aprotic, it coordinates strongly with the
lithium ion. This results in solvent metal dispersal allowing the
enolate to react even at lower temperatures with reasonable dia-
stereoselectivity. In order to improve the diastereoselectivity of
the reaction, the role of quenchers were examined, either by add-
ing them directly or by deprotonation followed by quenching. Var-
ious chiral and achiral reagents were screened (Table 3). Results
were modest in most cases while a significant enhancement in
Reactions of chiral b-aminoesters with aryl isothiocyanates
Entry
R1
R2
R
Time (h)
Yield (%)
Product
1
2
3
4
5
6
7
8
9
10
Cl
F
CN
Cl
CN
Cl
F
CN
Cl
H
Cl
Cl
CF3
CF3
H
Cl
Cl
(R)-
(R)-
(R)-
(R)-
(R)-
a
a
a
a
a
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
1.5
2.0
1.5
2.5
3.0
1.5
2.0
1.5
2.5
3.0
76
78
75
71
86
78
77
74
73
85
5(a)
5(b)
5(c)
5(d)
5(e)
50(a)
50(b)
50(c)
50(d)
50(e)
(S)-
(S)-
(S)-
(S)-
(S)-
a
a
a
a
a
CF3
CF3
CN
It could be assumed that at lower temperatures, lithium enolate
is strongly aggregated and thus may not be reactive enough to un-
dergo reaction with the electrophile. At a higher temperature,
aggregation was disrupted causing the formation of the dibenzy-
lated product. Therefore, it was necessary to modulate the reactiv-
ity of the enolates and consequently the reaction kinetics. Since the
reactivity of enolates is governed by the counter cation, the reac-
tion was next studied by generating different metal enolates. It
was observed that titanium and zirconium enolates were unreac-
tive, while the sodium and potassium enolates were highly reac-
tive to form only dibenzylated adducts (Table 2, entries 11–14).
Lithium enolates generated using LHMDS afforded better results
among the various bases employed and hence were considered
for further optimizations. Another attempt to improve the reactiv-
ity of lithium enolate was by changing the reaction medium. The
reaction was thus tried in the polar aprotic solvent DMF but only
the formation of the dibenzylated adduct was observed. The aggre-
gation of the enolate in the solvent can be altered by the addition
of chelating agents, such as tetramethyl ethylene diamine (TME-
DA), lithium chloride (LiCl), and hexamethyl phosphoramide
(HMPA), which can exert significant effects on the regio- and ste-
reochemical outcomes of the reaction.7 Therefore the reactions
diasteroselectivity (79:21) was observed with L-ethyl lactate. How-
ever, the diastereoselectivity was considerably reduced when
deprotonation with an additional equivalent of LHMDS followed
by quenching with chiral ethyl lactate, (Table 3, entry 8) was
attempted.
Reacting
3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-
ones with LHMDS and HMPA at ꢀ78 °C followed by the addition
of 4-chlorobenzylbromide and subsequent quenching with chiral
ethyl lactate turned out to be the best conditions to obtain the
monobenzylated product with good stereoselectivity (Scheme 3).
The scope of the reaction was then examined on substrates 5(a–
e) bearing different substituents on the aryl ring at N3; in all the
cases, the monobenzylated product was obtained in good yield
and with high diastereoselectivity (Table 4) in favor of diastereo-
mer 2. Similar reaction conditions were then employed for the
monobenzylation of the corresponding enantiomers 50(a–e).
The relative configuration of the diastereomers 7(e)(i) and
7(e)(ii) at C5 can be predicted on the basis of energy calculations
and NMR analysis 8. NMR spectra of the diastereomers were com-
pared and the structural assignments were made on the basis of
chemical shifts and the inferences drawn from COSY, NOESY, DEPT,

436
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
Table 2
Reaction conditions employed for selective monobenzylation
Entry
Base
Additive
Temp (°C)
5(c)a (%)
7(c)(i)+7(c)(ii)a (%)
7(c)(iii)a (%)
1
2
3
4
5
6
n-BuLi
n-BuLi
LDA
LDA
LHMDS
LHMDS
—
—
—
—
—
—
ꢀ78
0
—
—
—
—
—
—
15
10
25
18
39
23
34
35
30
32
25
35
ꢀ78
0
ꢀ78
0
7
—
—
—
—
ꢀ78
0
80
70
82
68
—
—
—
—
—
(S)
(S)
(S)
(S)
Ph
Ph
Ph
Ph
N
Ph
Ph
Ph
Ph
Li
8
10
—
N
Li
9
ꢀ78
0
(S)
(S)
N
Li
10
12
N
Li
11
12
13
14
15
16
17
18
19
20
DIPEA
n-BuLi
TiCl4
Zr(Cp)2Cl2
—
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
80
84
40
45
70
30
75
60
10
10
—
—
—
—
NHMDS
KHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
45
48
10
40
8
14
10
30
—
—
—
—
—
—
65
20
TMEDA
TMEDA
LiCl
LiCl
HMPA
HMPA
ꢀ78
0
ꢀ78
0
a
Isolated yields.
Table 3
Different quenching agents used for stereoselective monobenzylation
Entry
LHMDS equiv
Quenching agent
7(c)(i)+7(c)(ii)a (%)
7(c)(iii)a (%)
D2:D1b
1
2
3
4
5
6
7
8
0.99
0.99
0.99
0.99
0.99
0.99
0.99
2.1
NH4Cl
1 N HCl
N-Boc proline
Ethyl-3(R)-hydroxybutyrate
Ethyl-3(S)-hydroxybutyrate
Prolinol
(L)-Ethyl lactate
(L)-Ethyl lactate
65
64
63
60
62
60
67
50
10
9
10
12
10
9
65:35
68:32
75:25
70:30
70:30
70:31
79:21
60:40
8
15
a
Isolated yields.
b
Ratio determined from 1H NMR.
HMQC, and HMBC experiments. A comparison of the 1H NMR spec-
tra (Fig. 1) for the diastereomers 7(e)(i) and 7(e)(ii) indicated that
the C5 proton appeared as a multiplet at d values of 2.52 and 2.94,
respectively. In order to determine the exact geometry of both dia-
stereomers, energy optimizations were done by ab initio calcula-
tions performed using Gaussian B3LYP with basis set of 6–31G⁄
(d,p) for the different possible conformations of diastereomers
7(e)(i) and 7(e)(ii). The most stable conformations were identified
on the basis of the energy calculations (Fig. 2).9
A 3-dimensional structural representation of 7(e)(i) (diastereo-
mer 1), demonstrates that the proton at C5 is coplanar with respect
to the carbonyl group, which in turn exhibits its anisotropy result-
ing in a net upfield shift of the signal to 2.52 ppm; hence an (R)-
configuration can be assigned at C5 for diastereomer 1. However,
the corresponding proton at C5 resonated at 2.94 ppm for 7(e)(ii)
(diastereomer 2), indicating that it is free from the shielding effect
of the carbonyl group; hence an (S)-configuration can be assigned
at C5 in accordance with the NMR spectra. The configuration was
finally confirmed by single crystal X-ray analysis and an ORTEP
diagram of 7(e)(ii) is shown in Figure 3.
3. Conclusion
Benzylation reactions of enantiomerically pure 3-aryl-1-alkyl-
2-thioxotetrahydropyrimidin-4(1H)-ones were studied from the
perspective of the stereocontrol originating from the chiral substi-
tuent at N1, the additive, and the quenching agent. The absolute
configuration of the product was assigned by NMR experiments
based on the anisotropic effect exerted by the carbonyl group on
the adjacent proton at C5, and confirmed by single crystal XRD
analysis.
4. Experimental
4.1. General
The 1H and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively, on a Bruker Avance 400 (400 MHz) spec-
trometer in CDCl3 using TMS as an internal standard. The chemical
shifts (d) for 1H and 13C are given in ppm relative to residual signals
of the solvent. Coupling constants are given in Hz. The following

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
R2
437
R2
R2
R2
R1
R1
R1
R1
S
S
S
S
R
R
R
i)
LHMDS, HMPA, -78oC
Br
N
N
N
N
R
N
N
N
N
+
+
O
O
O
ii)
O
Cl
6
iii) L/D-ethyl lactate
Cl
Cl
Cl
5(a-e)
7(a-e)(i)
7'(a-e)(i)
7(a-e)(ii)
7'(a-e)(ii)
7(a-e)(iii)
7'(a-e)(iii)
5'(a-e)
Scheme 3. Syntheses of 5-(4-chlorobenzyl)-3-aryl-1-((R/S)-1-phenyl ethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.
Table 4
Alkylation reactions of 3-aryl-1-((R/S)-1-phenyl ethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones
Entry
R1
R2
R
Diastereomer 1 D1
Diastereomer 2 D2
Dibenzylated adduct
D2:D1c
1
2
3
4
5
6
7
8
9
10
Cl
F
CN
Cl
CN
Cl
F
CN
Cl
H
Cl
Cl
CF3
CF3
H
Cl
Cl
(R)-
(R)-
(R)-
(R)-
(R)-
a
a
a
a
a
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
-MeBn
7(a)(i), 13%
7(b)(i), 14%
7(c)(i), 14%
7(d)(i), 13%
7(e)(i), 14%
70(a)(i), 12%
70(b)(i), 14%
70(c)(i), 15%
70(d)(i), 13%
70(e)(i), 14%
7(a)(ii), 55%
7(b)(ii), 52%
7(c)(ii), 53%
7(d)(ii), 54%
7(e)(ii), 55%
70(a)(ii), 54%
70(b)(ii), 53%
70(c)(ii), 52%
70(d)(ii), 53%
70(e)(ii), 55%
7(a)(iii), 8%
7(b)(iii), 9%
7(c)(iii), 8%
7(d)(iii), 9%
7(e)(iii), 9%
70(a)(iii), 10%
70(b)(iii), 8%
70(c)(iii), 9%
70(d)(iii), 8%
70(e)(iii), 9%
81:19
79:21
79:21
80:20
79:21
82:18
79:21
78:12
81:19
79:21
(S)-
(S)-
(S)-
(S)-
(S)-
a
a
a
a
a
CF3
CF3
CN
c
Isolated yield.
Figure 1. Comparison of 1H NMR spectra for the diastereomers 7(e)(i) and 7(e)(ii).
abbreviations are used to indicate the multiplicity: s, singlet; d,
doublet; m, multiplet. Mass spectra were recorded on Finnigan
Mat LCQ LCMS and HRMS were recorded on a Bruker Maxis spec-
trometer. The reactions were monitored by TLC (Merck). Evapora-

438
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
4.3.1. (R)-3-(4-Chlorophenyl)-1-(1-phenylethyl)-2-thioxotetra-
hydropyrimidin-4(1H)-one 5(a) (Table 1, entry 1)
White solid; yield = 76%; mp = 202–204 °C; ½a D20
¼ þ240:60 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.66–1.69 (d, J = 7.0 Hz,
3H), 2.61–2.78 (m, 2H), 3.26–3.32 (m, 1H), 3.47–3.54 (m, 1H),
6.92–6.97 (q, J = 7.0 Hz, 1H), 7.13–7.16 (d, J = 8.4 Hz, 2H), 7.34–
7.45 (m, 7H); 13C NMR (100 MHz, CDCl3): d 14.56, 31.99, 39.19,
59.36, 127.11, 128.31, 128.95, 129.22, 130.78, 134.20, 138.21,
138.62, 166.36, 181.49; MS (APCI): [M+1]+ = 344.93.
4.3.2. (R)-3-(3-Chloro-4-fluorophenyl)-1-(1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-one 5(b) (Table 1, entry 2)
White solid: yield = 75%; mp =190–191 °C; ½a D20
¼ þ232:5 (c 1.0,
ꢂ
Figure 2. Most stable conformations for diastereomers 7(e)(i) and 7(e)(ii).
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.67–1.69 (d, J = 7.2 Hz, 3H),
2.61–2.78 (m, 2H), 3.26–3.33 (m, 1H), 3.47–3.54 (m, 1H), 6.90–
6.95 (q, J = 7.2 Hz, 1H), 7.07–7.11 (m, 1H), 7.22–7.28 (m, 2H),
7.33–7.44 (m, 5H); 13C NMR (100 MHz, CDCl3): d 14.55, 31.93,
39.17, 59.45, 116.56, 116.78, 121.22, 127.12, 128.38, 128.99,
129.49, 131.87, 135.88, 135.92, 138.5, 156.53, 159.02, 166.39,
181.27; MS (APCI): [M+1]+ = 362.93.
4.3.3. (R)-3-(3-Chloro-4-cyanophenyl)-1-(1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-one 5(c) (Table 1, entry 3)
White solid; yield = 78%; mp = 230–231 °C; ½a D20
¼ þ259:7 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.67–1.69 (d, J = 6.8 Hz,
3H), 2.62–2.79 (m, 2H), 3.28–3.35 (m, 1H), 3.52–3.57 (m, 1H),
6.84–6.89 (q, J = 6.8 Hz, 1H), 7.23–7.27 (m, 1H), 7.35–7.45 (m,
6H), 7.73–7.75 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
14.57, 31.90, 39.21, 59.33, 113.12, 115.63, 127.11, 128.51, 129.05,
131.65, 133.99, 137.13, 138.24, 144.31, 166.03, 180.32; MS (APCI):
[M+1]+ = 370.00.
Figure 3. ORTEP diagram for 7 (e)(ii).
4.3.4. (R)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(1-pheny-
lethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 5(d) (Table 1,
entry 4)
tion of solvents was performed under reduced pressure using a Bu-
chi rotary evaporator. Commercial grade reagents and solvents
were used without further purification.
White solid: yield = 71%; mp = 123–125 °C; ½a D20
¼ þ234:6 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.67–1.69 (d, J = 6.8 Hz,
3H), 2.62–2.79 (m, 2H), 3.29–3.35 (m, 1H), 3.50–3.56 (m, 1H),
6.87–6.93 (q, J = 6.8 Hz, 1H), 7.31–7.44 (m, 6H), 7.51–7.52 (d,
J = 2.4 Hz, 1H), 7.58–7.60 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 14.55, 31.91, 39.27, 59.44, 121.09, 123.81, 127.12,
128.43, 128.86, 129.00, 129.18, 131.93, 132.18, 134.15, 138.26,
138.42, 166.34, 180.92; MS (APCI): [M+1]+ = 413.00.
4.2. Single crystal X-ray analysis
A suitable crystal of 7(e)(ii) was subjected to X-ray diffraction
analysis. The intensity data were collected; and the lattice param-
eters and standard deviations were obtained. The data were cor-
rected for Lorentz and polarization factors. The structure was
solved by direct methods program SHELX–97 (Sheldrick, 1997)
package and also refined using the same. The final model was plot-
ted using the program ORTEP. Crystallographic data for the com-
pound have been deposited with the Cambridge Crystallographic
Data Centre, CCDC No. 857508. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
4.3.5. (R)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-1-(1-pheny-
lethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 5(e) (Table 1,
entry 5)
White solid; yield = 86%; mp = 180–182 °C; ½a D20
¼ þ240:05 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.68–1.70 (d, J = 7.2 Hz,
3H), 2.64–2.82 (m, 2H), 3.32–3.38 (m, 1H), 3.53–3.60 (m, 1H),
6.83–6.88 (q, J = 7.0 Hz, 1H), 7.36–7.48 (m, 5H), 7.52–7.54 (d,
J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.91–7.93 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 14.56, 31.83, 39.20, 59.40, 109.67, 115.13,
123.40, 126.12, 127.12, 128.55, 128.72, 129.07, 135.23, 138.18,
143.78, 166.14, 180.25; MS (APCI): [M+1]+ = 404.00.
4.3. General procedure for the synthesis of 3-(1-(1-phenylethyl)-
2-thioxotetrahydropyrimidin-4(1H)-ones
To a solution of aryl isothiocyanate (2.57 mmol) in 30 mL of
acetonitrile taken in a round-bottomed flask was added b-amino
ester (0.53 g, 2.57 mmol) followed by triethylamine (0.43 mL,
3.08 mmol) and LiClO4 (0.03 g, 0.26 mmol). The reaction mixture
was refluxed for 1.2 h and then concentrated at reduced pressure.
The residue was diluted with DCM, washed with water (2ꢁ 25 mL),
then with brine (1ꢁ 25 mL), and dried over anhydrous Na2SO4. It
was then concentrated and purified by column chromatography
on silica gel (60–120) using hexane–ethyl acetate mixture
(85:15) as the eluent and recrystallized from MeOH.
4.3.6. (S)-3-(4-Chlorophenyl)-1-(1-phenylethyl)-2-thioxotetra-
hydropyrimidin-4(1H)-one 50(a) (Table 1, entry 6)
White solid; yield = 78%; mp = 202–204°C; ½a D20
¼ ꢀ240:5 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.65–1.67 (d, J = 7.0 Hz, 3H),
2.60–2.77 (m, 2H), 3.25–3.31 (m, 1H), 3.46–3.53 (m, 1H), 6.90–6.95
(q, J = 7.0 Hz, 1H), 7.11–7.14 (d, J = 8.5 Hz, 2H), 7.32–7.43 (m, 7H);
13C NMR (100 MHz, CDCl3): d 14.56, 31.99, 39.19, 59.36, 127.11,
128.31, 128.95, 129.22, 130.78, 134.20, 138.21, 138.62, 166.36,
181.49; MS (APCI): [M+1]+ = 344.93

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
439
4.3.7. (S)-3-(3-Chloro-4-fluorophenyl)-1-(1-phenylethyl)-2-
4.4.1. (R)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((R)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 7(a)(i)
(Table 4, entry 1)
thioxotetrahydropyrimidin-4(1H)-one 50(b) (Table 1, entry 7)
White solid: yield = 74%; mp =190–191 °C; ½a D20
¼ ꢀ232:2 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.67–1.69 (d, J = 7.2 Hz, 3H),
2.61–2.78 (m, 2H), 3.27–3.32 (m, 1H), 3.46–3.54 (m, 1H), 6.90–
6.95 (q, J = 7.2 Hz, 1H), 7.07–7.11 (m, 1H), 7.21–7.28 (m, 2H), 7.33–
7.44 (m, 5H); 13C NMR (100 MHz, CDCl3): d 14.55, 31.93, 39.17,
59.45, 116.78, 121.22, 127.12, 128.99, 129.49, 131.87, 135.88,
138.5, 156.53, 159.02, 166.39, 181.27; MS (APCI): [M+1]+ = 362.93.
White solid; yield = 13%; mp = 130–132 °C; ½a D20
¼ þ266:75 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz,
3H), 2.48–2.54 (m, 1H), 2.62–2.67 (m, 1H), 3.09–3.26 (m, 3H),
6.73–6.75 (d, J = 8.3 Hz, 2H), 6.79–6.84 (q, J = 7.0 Hz, 1H), 7.03–
7.17 (m, 3H), 7.25–7.35 (m, 6H), 7.42–7.44 (d, J = 8.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3):
d 14.11, 31.99, 41.79, 42.72, 59.28,
127.07, 128.31, 128.52, 128.85, 129.26, 129.50, 130.68, 132.56,
134.25, 135.29, 138.27, 138.69, 168.66, 181.07; MS (APCI):
[M+1]+ = 468.94; HRMS (ESI): m/z [M+Na]+ Calcd for
4.3.8. (S)-3-(3-Chloro-4-cyanophenyl)-1-(1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-one 50(c) (Table 1, entry 8)
White solid; yield = 77%; mp = 230–231 °C; ½a D20
ꢂ
¼ ꢀ259:3 (c
C25H22Cl2N2OS: 491.0728. Found: 491.0738.
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.67–1.69 (d, J = 6.8 Hz,
3H), 2.62–2.79 (m, 2H), 3.29–3.35 (m, 1H), 3.50–3.57 (m, 1H),
6.84–6.89 (q, J = 6.8 Hz, 1H), 7.23–7.27 (m, 1H), 7.35–7.45 (m,
6H), 7.73–7.75 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
14.57, 31.85, 39.21, 59.33, 113.12, 115.63, 127.11, 128.51, 129.05,
131.65, 133.99, 137.13, 138.24, 144.31, 166.03, 180.32; MS (APCI):
[M+1]+ = 370.00.
4.4.2. (S)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((R)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 7(a)(ii)
(Table 4, entry 1)
White solid; yield = 55%; mp = 178–180 °C; ½a D20
¼ þ266:55 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 6.9 Hz,
3H), 2.40–2.46 (m, 1H), 2.81–2.92 (m, 1H), 2.99–3.04 (m, 1H),
3.09–3.13 (m, 1H), 3.36–3.40 (m, 1H), 6.67–6.69 (d, J = 7.4 Hz,
2H), 7.01–7.05 (q, J = 6.7 Hz, 1H), 7.09–7.11 (d, J = 7.6 Hz, 2H),
7.16–7.18 (d, J = 7.4 Hz, 2H), 7.35–7.44 (m, 7H); 13C NMR
(100 MHz, CDCl3): d 14.67, 33.01, 42.28, 42.72, 59.10, 127.70,
128.53, 128.85, 129.03, 129.31, 130.08, 130.65, 132.81, 134.25,
4.3.9. (S)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-1-(1-pheny-
lethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 50(d) (Table 1,
entry 9)
White solid; yield = 73%; mp = 123–125 °C; ½a D20
¼ ꢀ234:2 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.66–1.68 (d, J = 7.2 Hz,
3H), 2.61–2.77 (m, 2H), 3.27–3.34 (m, 1H), 3.48–3.56 (m, 1H),
6.84–6.89 (q, J = 7.0 Hz, 1H), 7.29–7.43 (m, 6H), 7.49–7.50 (d,
J = 2.3 Hz, 1H), 7.56–7.58 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 14.54, 31.93, 39.17, 59.40, 127.12, 128.41, 128.64,
128.86, 129.00, 129.18, 131.91, 132.18, 134.14, 138.28, 138.45,
166.30, 180.97; MS (APCI): [M+1]+ = 413.00.
135.66, 138.25, 138.39, 168.22, 181.09; MS
[M+1]+ = 468.94; HRMS (ESI): m/z [M+Na]+ Calcd for
25H22Cl2N2OS: 491.0728. Found: 491.0745.
(APCI):
C
4.4.3. (R)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-1-
((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
7(b)(i) (Table 4, entry 2)
White solid; yield = 14%; mp = 142–144 °C; ½a D20
¼ þ424:6 (c 1.0,
ꢂ
4.3.10. (S)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-1-(1-pheny-
lethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 50(e) (Table 1,
entry 10)
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz, 3H),
2.47–2.53 (m, 1H), 2.58–2.64 (m, 1H), 3.10–3.26 (m, 3H), 6.73–
6.75 (d, J = 8.4 Hz, 2H), 6.77–6.82 (q, J = 7.0 Hz, 1H), 7.11–7.14 (m,
3H), 7.19–7.34 (m, 7H); 13C NMR (100 MHz, CDCl3): d 14.10, 31.97,
41.82, 42.70, 59.37, 116.80, 121.26, 121.45, 127.06, 128.36, 128.88,
129.49, 132.61, 135.19, 135.98, 136.02, 138.59, 156.55, 159.04,
168.69, 180.88; MS (APCI): [M+1]+ = 486.94; HRMS (ESI): m/z
[M+Na]+ Calcd for C25H21Cl2FN2OS: 509.0634. Found: 509.0626.
White solid; yield = 85%; mp = 180–182 °C; ½a D20
¼ ꢀ239:9 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.66–1.68 (d, J = 7.2 Hz,
3H), 2.63–2.80 (m, 2H), 3.30–3.37 (m, 1H), 3.52–3.58 (m, 1H),
6.81–6.87 (q, J = 7.0 Hz, 1H), 7.35–7.47 (m, 5H), 7.50–7.53 (d,
J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.89–7.91 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 14.55, 31.84, 39.21, 59.40, 109.68, 115.09,
123.39, 127.12, 128.54, 128.72, 129.06, 133.70, 135.19, 138.21,
143.77, 166.09, 180.29; MS (APCI): [M+1]+ = 404.00.
4.4.4. (S)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-1-
((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
7(b)(ii) (Table 4, entry 2)
4.4. General procedure for the syntheses of 5-(4-chlorobenzyl)-
3-aryl-1-((R)/(S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-
4(1H)-ones
White solid; yield = 52%; mp = 155–158 °C; ½a D20
¼ þ224:2 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 6.8 Hz,
3H), 2.40–2.45 (m, 1H), 2.82–2.91 (m, 1H), 2.98–3.04 (m, 1H),
3.07–3.16 (m, 1H), 3.34–3.41 (m, 1H), 6.67–6.69 (d, J = 7.5 Hz,
2H), 6.99–7.05 (m, 2H), 7.12–7.25 (m, 4H), 7.36–7.45 (m, 5H);
13C NMR (100 MHz, CDCl3): d 14.66, 32.99, 41.28, 42.72, 59.20,
116.63, 116.85, 121.32, 121.51, 127.70, 128.58, 128.88, 129.06,
129.35, 130.06, 131.76, 132.86, 136.11, 138.14, 168.23, 180.91;
MS (APCI): [M+1]+ = 486.89; HRMS (ESI): m/z [M+Na]+ Calcd for
In a typical experiment, 3-aryl-1-((R)/(S)-1-phenylethyl)-2-thi-
oxotetrahydropyrimidin-4(1H)-one (0.25 g, 0.70 mmol) dissolved
in anhydrous THF (5 mL) and cooled to ꢀ78 °C, was treated with
LHMDS (0.70 mL, 0.70 mmol, 1.0 M solution in THF) under nitrogen
atmosphere and stirred for 30 min followed by the addition of
HMPA (0.13 g, 0.77 mmol). The reaction mixture was stirred for
1 h, and then 4-chlorobenzylbromide (0.15 g, 0.70 mmol) was
added, and stirred for another 2 h. It was then quenched with chi-
ral ethyl lactate and extracted into ethyl acetate. The organic layer
was dried and concentrated to provide a gummy compound, which
upon purification by column chromatography on silica gel (60–120
mesh) using hexane–ethyl acetate mixture (85:15) as the eluent
afforded the desired compound as a mixture of diastereomers.
The diastereomers were further separated by column chromatog-
raphy on silica gel (230–400 mesh) using hexane–ethyl acetate
mixture (90:10) as the eluent. The products were characterized
by analytical and spectroscopic methods.
C25H21Cl2FN2OS: 509.0633. Found: 509.0636.
4.4.5. (R)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-
((R)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
7(c)(i) (Table 4, entry 3)
White solid; yield 14%; mp 130–132 °C; ½a D20
¼ þ130:4 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.56–1.58 (d, J = 7.0 Hz, 3H),
2.49–2.56 (m, 1H), 2.64–2.67 (m, 1H), 3.14–3.27 (m, 3H), 6.74–
6.79 (m, 3H), 7.13–7.17 (m, 2H), 7.22–7.40 (m, 7H), 7.74–7.76 (d,
J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.13, 31.87, 41.84,
42.75, 59.29, 113.15, 115.60, 127.06, 128.48, 128.94, 129.48,
131.62, 132.72, 134.00, 134.97, 137.16, 138.35, 144.40, 168.36,

440
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
179.97; MS (APCI): [M+1]+ = 494.20; HRMS (ESI): m/z [M+Na]+
Calcd for C26H21Cl2N3OS: 516.0680. Found: 516.0674.
3.46 (m, 1H), 6.67–6.69 (d, J = 8.3 Hz, 2H), 6.91–6.96 (q,
J = 7.0 Hz, 1H), 7.16–7.20 (d, J = 8.3 Hz, 2H), 7.36–7.49 (m, 6H),
7.59 (s, 1H), 7.90–7.92 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz,
4.4.6. (S)-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-((R)-
1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 7(c)(ii)
(Table 4, entry 3)
CDCl3): d 14.68, 32.95, 42.34, 42.69, 59.14, 109.78, 115.05,
120.62, 127.72, 128.75, 128.96, 129.14, 130.03, 133.03, 133.48,
133.71, 133.81, 135.23, 135.28, 137.83, 143.89, 168.02, 179.89;
MS (APCI): [M+1]+ = 527.97; HRMS (ESI): m/z [M+Na]+ Calcd for
White solid; yield 52%; mp 135–137 °C; ½a D20
¼ þ139:4 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.56–1.58 (d, J = 7.0 Hz, 3H),
2.40–2.46 (m, 1H), 2.89–2.94 (m, 1H), 3.01–3.12 (m, 2H), 3.38–
3.43 (m, 1H), 6.67–6.69 (d, J = 8.0 Hz, 2H), 6.92–6.97 (q, J = 7.0 Hz,
1H), 7.12–7.21 (m, 3H), 7.33–7.45 (m, 6H), 7.73–7.75 (d,
J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.68, 32.95, 42.37,
42.67, 59.09, 113.17, 115.59, 127.69, 128.71, 128.94, 129.12,
130.05, 131.48, 131.56, 132.98, 134.05, 135.32, 137.20, 137.91,
144.48, 167.92, 179.96; MS (APCI): [M+1]+ = 494.27; HRMS (ESI):
m/z [M+Na]+ Calcd for C26H21Cl2N3OS: 516.0680. Found: 516.0672.
C27H21ClF3N3OS: 550.0944. Found: 550.0945.
4.4.11. (S)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 70(a)(i)
(Table 4, entry 6)
White solid; yield = 12%; mp = 130–132 °C; ½a D20
¼ ꢀ266:4 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz,
3H), 2.48–2.54 (m, 1H), 2.62–2.67 (m, 1H), 3.09–3.26 (m, 3H),
6.73–6.75 (d, J = 8.3 Hz, 2H), 6.79–6.84 (q, J = 7.0 Hz, 1H), 7.03–
7.17 (m, 3H), 7.25–7.35 (m, 6H), 7.42–7.44 (d, J = 8.8 Hz, 2H); 13C
4.4.7. (R)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 7(d)(i) (Table 4, entry 4)
NMR (100 MHz, CDCl3): d 14.11, 31.99, 41.79, 42.72, 59.28,
127.07, 128.31, 128.52, 128.85, 129.26, 129.50, 130.68, 132.56,
134.25, 135.29, 138.27, 138.69, 168.66, 181.07; MS (APCI):
[M+1]+ = 468.93; HRMS (ESI): m/z [M+Na]+ Calcd for
White solid; yield 13%; mp 160–163 °C; ½a D20
¼ þ228:6 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 7.0 Hz, 3H),
2.47–2.53 (m, 1H), 2.61–2.67 (m, 1H), 3.10–3.27 (m, 3H), 6.72–
6.80 (m, 3H), 7.11–7.13 (d, J = 8.0 Hz, 2H), 7.27–7.36 (m, 6H),
7.50 (s, 1H), 7.57–7.59 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
C25H22Cl2N2OS: 491.0728. Found: 491.0719.
4.4.12. (R)-3-(4-Chlorophenyl)-5-(4-chlorobenzyl)-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 70(a)(ii)
(Table 4, entry 6)
CDCl3):
d 14.10, 31.92, 41.85, 42.71, 59.37, 121.08, 123.80,
127.06, 128.40, 128.68, 128.91, 129.22, 129.47, 131.95, 132.23,
132.65, 135.11, 138.36, 138.51, 168.68, 180.53; MS (APCI):
[M+1]+ = 536.91; HRMS (ESI): m/z [M+Na]+ Calcd for
White solid; yield = 54%; mp = 178–180 °C; ½a D20
¼ ꢀ266:5 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 6.8 Hz,
3H), 2.41–2.47 (m, 1H), 2.86–2.93 (m, 1H), 3.00–3.06 (m, 1H),
3.10–3.15 (m, 1H), 3.37–3.42 (m, 1H), 6.69–6.71 (d, J = 8.4 Hz,
2H), 7.01–7.05 (q, J = 6.8 Hz, 1H), 7.10–7.12 (d, J = 8.0 Hz, 2H),
7.17–7.19 (d, J = 8.0 Hz, 2H), 7.31–7.45 (m, 7H); 13C NMR
(100 MHz, CDCl3): d 14.66, 33.01, 42.31, 42.73, 59.09, 127.68,
128.51, 128.85, 129.01, 129.28, 130.06, 130.64, 132.82, 134.25,
C26H21Cl2F3N2OS: 559.0602. Found: 559.0635.
4.4.8. (S)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 7(d)(ii) (Table 4, entry 4)
White solid; yield 13%; mp 152–154 °C; ½a D20
ꢂ
¼ þ439:5 (c 1.0,
135.67, 138.26, 138.39, 168.19, 181.12; MS
[M+1]+ = 469.00; HRMS (ESI): m/z [M+Na]+ Calcd for for
25H22Cl2N2OS: 491.0728. Found: 491.0713.
(APCI):
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz, 3H),
2.41–2.49 (m, 1H), 2.86–2.93 (m, 1H), 3.01–3.13 (m, 2H), 3.38–
3.43 (m, 1H), 6.67–6.69 (d, J = 8.2 Hz, 2H), 6.95–7.00 (q, J = 7.0 Hz,
1H), 7.11–7.19 (m, 2H), 7.25–7.36 (m, 1H), 7.37–7.45 (m, 5H),
7.47 (s, 1H), 7.57–7.59 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
C
4.4.13. (S)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
70(b)(i) (Table 4, entry 7)
CDCl3):
d 14.66, 32.99, 42.29, 42.73, 59.20, 121.06, 123.78,
127.72, 128.63, 128.90, 129.08, 129.26, 130.05, 131.99, 132.23,
132.91, 134.01, 135.46, 138.06, 138.45, 168.20, 180.56; MS (APCI):
[M+1]+ = 536.99; HRMS (ESI): m/z [M+Na]+ Calcd for
White solid; yield = 14%; mp = 142–144 °C; ½a D20
¼ ꢀ424:4 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 7.0 Hz,
3H), 2.49–2.55 (m, 1H), 2.60–2.65 (m, 1H), 3.14–3.28 (m, 3H),
6.74–6.76 (d, J = 8.4 Hz, 2H), 6.79–6.85 (q, J = 7.0 Hz, 1H), 7.12–
7.16 (m, 3H), 7.21–7.36 (m, 7H); 13C NMR (100 MHz, CDCl3): d
14.10, 31.96, 41.80, 42.69, 59.37, 116.80, 121.26, 121.45, 127.06,
128.36, 128.88, 129.49, 132.61, 135.19, 135.98, 136.02, 138.59,
156.55, 159.04, 168.69, 180.88; MS (APCI): [M+1]+ = 486.93. HRMS
(ESI): m/z [M+Na]+ Calcd for C25H21Cl2FN2OS: 509.0633. Found:
509.0623.
C26H21Cl2F3N2OS: 559.0602. Found: 559.0635.
4.4.9. (R)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 7(e)(i) (Table 4, entry 5)
White solid; yield 13%; mp 82–85 °C; ½a D20
¼ þ140:4 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.56–1.58 (d, J = 7.0 Hz, 3H),
2.48–2.54 (m, 1H), 2.62–2.70 (m, 1H), 3.13–3.26 (m, 3H), 6.69–
6.75 (m, 3H), 7.12–7.14 (d, J = 8.2 Hz, 2H), 7.23–7.34 (m, 5H),
7.50–7.52 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.90–7.92 (d, J = 8.1 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 14.13, 31.83, 41.86, 42.73,
59.35, 109.74, 115.07, 116.14, 120.64, 127.06, 128.52, 129.44,
130.28, 132.75, 133.43, 133.77, 134.48, 135.24, 138.27, 143.81;
168.50, 179.88; MS (APCI): [M+1]+ = 528.06; HRMS (ESI): m/z
[M+Na]+ Calcd for C27H21ClF3N3OS: 550.0944. Found: 550.0961.
4.4.14. (R)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
70(b)(ii) (Table 4, entry 7)
White solid; yield = 53%; mp = 155–158 °C; ½a D20
ꢂ
¼ ꢀ224:3 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d 1.54–1.56 (d,
J = 6.8 Hz, 3H), 2.40–2.45 (m, 1H), 2.82–2.91 (m, 1H), 2.98–3.04
(m, 1H), 3.07–3.16 (m, 1H), 3.34–3.41 (m, 1H), 6.67–6.69 (d,
J = 7.5 Hz, 2H), 6.99–7.05 (m, 2H), 7.12–7.25 (m, 4H), 7.36–7.45
(m, 5H); 13C NMR (100 MHz, CDCl3): d 14.66, 33.00, 42.28,
42.71, 59.20, 116.63, 116.85, 121.32, 121.51, 127.70, 128.59,
128.88, 129.06, 129.42, 130.06, 131.76, 132.86, 136.08, 138.14,
168.24, 180.91; MS (APCI): [M+1]+ = 486.92; HRMS (ESI): m/z
[M+Na]+ Calcd for for C25H21Cl2FN2OS: 509.0633. Found:
509.0626.
4.4.10. (S)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((R)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 7(e)(ii) (Table 4, entry 5)
White solid; yield 13%; mp 166–168 °C; ½a D20
¼ þ107:4 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 7.0 Hz, 3H),
2.42–2.48 (m, 1H), 2.89–2.96 (m, 1H), 3.04–3.13 (m, 2H), 3.41–

V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
441
4.4.15. (S)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
70(c)(i) (Table 4, entry 8)
59.35, 109.74, 115.07, 116.14, 120.64, 127.06, 128.52, 129.44,
130.28, 132.75, 133.43, 133.77, 134.48, 135.24, 138.27, 143.81;
168.50, 179.88; MS (APCI): [M+1]+ = 528.06; HRMS (ESI): m/z
[M+Na]+ Calcd for C27H21ClF3N3OS: 550.0944. Found: 550.0912.
White solid; yield 14%; mp 130–132 °C; ½a D20
¼ ꢀ130:4 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.56–1.58 (d, J = 7.0 Hz, 3H),
2.49–2.55 (m, 1H), 2.61–2.67 (m, 1H), 3.12–3.27 (m, 3H), 6.74–
6.79 (m, 3H), 7.13–7.17 (m, 2H), 7.22–7.40 (m, 7H), 7.74–7.76 (d,
J = 8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.12, 31.85, 41.82,
42.72, 59.28, 113.19, 115.60, 127.06, 128.49, 128.94, 129.46,
131.60, 132.72, 134.02, 134.93, 137.20, 138.34, 144.35, 168.37,
179.96; MS (APCI): [M+1]+ = 493.95; HRMS (ESI): m/z [M+Na]+
Calcd for C26H21Cl2N3OS: 516.0680. Found: 516.0672.
4.4.20. (R)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 70(e)(ii) (Table 4, entry 10)
White solid; yield 13%; mp 166–168 °C; ½a D20
¼ ꢀ107:6 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 7.0 Hz, 3H),
2.42–2.48 (m, 1H), 2.89–2.96 (m, 1H), 3.04–3.13 (m, 2H), 3.41–
3.47 (m, 1H), 6.67–6.69 (d, J = 8.3 Hz, 2H), 6.90–6.96 (q, J = 7.0 Hz,
1H), 7.17–7.19 (d, J = 8.3 Hz, 2H), 7.35–7.50 (m, 6H), 7.59 (s, 1H),
7.90–7.92 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.68,
32.95, 42.36, 42.69, 59.16, 109.72, 115.08, 120.64, 127.72, 128.76,
128.96, 129.14, 130.04, 133.02, 133.46, 133.74, 133.79, 135.24,
4.4.16. (R)-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-((S)-
1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 70(c)(ii)
(Table 4, entry 8)
White solid; yield 52%; mp 135–137 °C; ½a D20
ꢂ
¼ ꢀ139:5 (c 1.0,
135.29, 137.83, 143.93, 168.04, 179.88; MS
(APCI):
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz, 3H),
2.40–2.46 (m, 1H), 2.87–2.94 (m, 1H), 3.01–3.12 (m, 2H), 3.38–
3.43 (m, 1H), 6.67–6.69 (d, J = 8.3 Hz, 2H), 6.92–6.97 (q,
J = 7.0 Hz, 1H), 7.12–7.21 (m, 3H), 7.33–7.45 (m, 6H), 7.73–7.75
(d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.68, 32.95,
42.37, 42.67, 59.09, 113.17, 115.59, 127.69, 128.71, 128.94,
129.12, 130.05, 131.48, 131.56, 132.98, 134.05, 135.32, 137.20,
137.91, 144.48, 167.92, 179.96; MS (APCI): [M+1]+= 493.96; HRMS
(ESI): m/z [M+Na]+ Calcd for C26H21Cl2N3OS: 516.0680. Found:
516.0674.
[M+1]+ = 527.95; HRMS (ESI): m/z [M+Na]+ Calcd for
C27H21ClF3N3OS: 550.0944. Found: 550.0927.
Acknowledgments
We thank the Department of Science and Technology, Govern-
ment of India for the research funding and the University Grants
Commission for a research fellowship to V.K. The National Single
Crystal X-ray Diffractometer facility, and the support offered by
Dr. Binoy K. Saha, Department of Chemistry, Pondicherry Univer-
sity for solving the crystal structure are gratefully acknowledged.
4.4.17. (S)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 70(d)(i) (Table 4, entry 9)
References and notes
White solid; yield 13%; mp 160–163 °C; ½a D20
¼ ꢀ228:5 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.55–1.57 (d, J = 7.0 Hz, 3H),
2.47–2.53 (m, 1H), 2.61–2.67 (m, 1H), 3.11–3.27 (m, 3H), 6.73–
6.80 (m, 3H), 7.11–7.13 (d, J = 8.0 Hz, 2H), 7.27–7.36 (m, 6H),
7.49 (s, 1H), 7.57–7.59 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
1. Selected references include (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1,
2029; (b) Williams, D. R.; Heidebrecht, R. W. J. Am. Chem. Soc. 1843, 2003, 125;
(c) Kim, D.; Kim, I. H. Tetrahedron Lett. 1997, 38, 415; (d) Schetter, B.; Mahrwald,
R. Angew. Chem. Int. Ed. 2006, 45, 7506; (e) Jiang, Y.; Hong, J.; Burke, S. D. Org.
Lett. 2004, 61, 1445; (f) Crimmins, M. T.; Dechert, A.-M. R. Org. Lett. 2009, 11,
1635; (g) Evans, D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124,
5654; (h) Hassner, A. Advances in Asymmetric Synthesis Jai Press Inc: Connecticut
1995, 1, 75.
2. Selected references include: (a) Asymmetric Synthesis. Part B; Evans, D. A.,
Morrison, J. D., Eds.; Academic Press: New York, 1984. Vol. 3, p. 1; (b) Carey, F.
A.; Sundberg, R. J. In Advanced Organic Chemistry. Part B; Plenum Press: New York,
1990;Vol. 1, p. 21–41;(c) Gawley, R. E.; Aube, J. Principles ofAsymmetricSynthesis
In Tetrahedron Organic Chemistry Series; Baldwin, J. E., Ed.; Pergamon Press: Oxford,
1996; Vol. 14, pp 75–92; (d) Procter, G. Asymmetric Synthesis; Oxford: Oxford
University Press, 1996. p. 41–50;(e)Seebach, D.;Amstutz, R.; Dunitz,J. D. Helv. Chim.
Acta 1981, 64, 2622; (f) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624; (g)
Jackman, L. M.; Lange, B. C. J. Am. Chem. Soc. 1981, 103, 4494.
3. (a) Tomioka, K.; Yasuda, K.; Kawasaki, H.; Koga, K. Tetrahedron Lett. 1986, 27,
3247; (b) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462; (c) Maldaner,
A. O.; Pilli, R. A. Tetrahedron 1999, 55, 13321; (d) Still, W. C.; Galynker, I.
Tetrahedron 1981, 37, 3981; (e) Schöllkopf, U.; Hausberg, H.-H.; Segal, M.; Reiter,
U.; Hoppe, I.; Saenger, W.; Lindner, K. Liebigs. Ann. Chem. 1981, 439.
4. (a) Elokdah, H.; Sulkowski, T. S.; Abou-Gharbia, M.; Butera, J. A.; Chai, S.-Y.;
McFarlane, G. R.; McKean, M.-L.; Babiak, J. L.; Adelman, S. J.; Quinet, E. M. J. Med.
Chem. 2004, 47, 681; (b) Okawara, T.; Nakayama, K.; Furukawa, M. Chem. Pharm.
Bull. 1983, 31, 507; (c) Hakkou, H.; Eynde, J. J. V.; Hamelin, J.; Bazureau, J. P.
Tetrahedron 2004, 60, 3745; (d) Soliman, R.; Habib, N. S.; Ismail, K. A.; Moustafa,
M. T.; Fanaki, N. H. Boll. Chim. Farm. 2003, 142, 167; (e) Ojima, I.; Fuchikami, T.;
Fujita, M.T. US Patent 4581452, 1986.; (f) Glasser, A. C.; Doughty, R. M. J. Med.
Chem. 1966, 9, 351.
5. (a) Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966; (b) Khatik, G. L.; Pal, A.;
Apsunde, T. D.; Nair, V. A. J. Heterocycl. Chem. 2010, 47, 734; (c) Khatik, G. L.; Pal,
A.; Mobin, S. M.; Nair, V. A. Tetrahedron Lett. 2010, 51, 3654; (d) Khatik, G. L.;
Kaur, J.; Kumar, V.; Tikoo, K.; Venugopalan, P.; Nair, V. A. Eur. J. Med. Chem. 2011,
46, 3291; (e) Chouhan, M.; Senwar, K. R.; Sharma, R.; Grover, V.; Nair, V. A. Green
Chem. 2011, 30, 2553; (f) Khatik, G. L.; Khurana, R.; Kumar, V.; Nair, V. A.
Synthesis 2011, 3123; (g) Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org.
Biomol. Chem. 2010, 8, 4960; (h) Chouhan, M.; Sharma, R.; Nair, V. A. Appl.
Organomet. Chem. 2011, 25, 470; (i) Sharma, R.; Chouhan, M.; Sood, D.; Nair, V. A.
Appl. Organomet. Chem. 2011, 25, 305; (j) Randive, N. A.; Kumar, V.; Nair, V. A.
Monatsh. Chem. 2010, 141, 1329; (k) Kumar, V.; Khatik, G. L.; Nair, V. A. Synlett
2011, 2997; (l) Sharma, R.; Chouhan, M.; Nair, V. A. Tetrahedron Lett. 2010, 51,
2039; (m) Khatik, G. L.; Kaur, J.; Kumar, V.; Tikoo, K.; Nair, V. A. Bioorg. Med.
Chem. Lett. 1912, 2012, 22.
CDCl3):
d 14.11, 31.91, 41.84, 42.70, 59.37, 121.06, 123.80,
127.06, 128.41, 128.68, 128.91, 129.22, 129.46, 131.95, 132.23,
132.65, 135.09, 138.33, 138.50, 168.69, 180.53; MS (APCI):
[M+1]+ = 536.87; HRMS (ESI): m/z [M+Na]+ Calcd for
C26H21Cl2F3N2OS: 559.0602. Found: 559.0593.
4.4.18. (R)-3-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 70(d)(ii) (Table 4, entry 9)
White solid; yield 13%; mp 152–154 °C; ½a D20
¼ ꢀ439:65 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.54–1.56 (d, J = 7.0 Hz, 3H),
2.41–2.47 (m, 1H), 2.86–2.93 (m, 1H), 3.01–3.13 (m, 2H), 3.38–
3.43 (m, 1H), 6.67–6.69 (d, J = 8.2 Hz, 2H), 6.95–7.00 (q, J = 7.0 Hz,
1H), 7.11–7.19 (m, 2H), 7.25–7.36 (m, 1H), 7.37–7.45 (m, 5H),
7.47 (s, 1H), 7.57–7.59 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
d 14.67, 33.00, 42.29, 42.73, 59.21, 121.08, 123.80,
127.72, 128.64, 128.91, 129.09, 129.25, 130.06, 132.00, 132.24,
132.91, 134.02, 135.47, 138.06, 138.47, 168.21, 180.56; MS (APCI):
[M+1]+ = 536.87; HRMS (ESI): m/z [M+Na]+ Calcd for
C26H21Cl2F3N2OS: 559.0602. Found: 559.0597.
4.4.19. (S)-3-(4-Cyano-3-(trifluoromethyl)phenyl)-5-(4-chloro-
benzyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro pyrimidin-4
(1H)-one 70(e)(i) (Table 4, entry 10)
White solid; yield 13%; mp 82–85 °C; ½a D20
¼ ꢀ140:3 (c 1.0,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.56–1.58 (d, J = 7.0 Hz, 3H),
2.48–2.54 (m, 1H), 2.62–2.70 (m, 1H), 3.13–3.26 (m, 3H), 6.70–
6.75 (m, 3H), 7.12–7.14 (d, J = 8.2 Hz, 2H), 7.26–7.36 (m, 5H),
7.50–7.52 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.90–7.92 (d, J = 8.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): d 14.13, 31.83, 41.86, 42.73,

442
V. Kumar et al. / Tetrahedron: Asymmetry 23 (2012) 434–442
6. Selected references include (a) Cox, P. J.; Simpkins, N. S Tetrahedron: Asymmetry
1991, 2, 1; (b) Koga, K. J. Synth. Org. Chem., Jpn. 1990, 48, 463; (c) Koga, K. Pure
Appl. Chem. 1994, 66, 1487; (d) Koga, K.; Shindo, M. Synth. Org. Chem., Jpn. 1995,
52, 1021; (e) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552; (f) Hoppe, D. Angew. Chem., Int. Ed. 1997, 36, 2282; (g)
O0Brien, P. J. Chem. Soc., Perkin Trans. 1998, 1439.
7. (a) Romesberg, F. E.; Collum, B. D. J. Am. Chem. Soc. 1994, 116, 9198; (b)
Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385; (c) Juaristi, E.;
Madrigal, D. Tetrahedron 1989, 45, 629; (d) House, H. O. Modern Synthetic
Reactions, 2nd Ed.; Benjamin, W. A. Ed.: New York, 1972; p. 527.
8. Seco, J. M.; Quinñóa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
9. Energy calculations were performed using the Gaussian 03 program.