Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones: Stereoregulations from endo- and exocyclic chiral centres

Article abstract of DOI:10.1016/j.tet.2012.12.020

The steric regulations imparted by the substituent at N1 in lithium mediated asymmetric aldol reactions of conformationally restricted 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones governed the formation of anti aldol adducts, by a kinetic reaction pathway. The preferential formation of the anti aldol diastereomers was also assisted by the steric effects of the electrophile through diastereofacial selection while the electronic effects of the aryl group at N3 remained subtle. Incorporation of an endocyclic methyl group at C6 witnessed the diastereoselective formation of an anti aldol adduct by regulation of π-facial selectivity. The absolute configurations of the aldol adducts were determined by computational calculations and NMR experiments, and confirmed by single crystal X-ray analysis.

Full text of DOI:10.1016/j.tet.2012.12.020

Tetrahedron 69 (2013) 1747e1754
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Aldol reactions of 2-thioxotetrahydropyrimidin-4(1H)-ones:
stereoregulations from endo- and exocyclic chiral centres
*
Varun Kumar, Kapil Kumar, Anang Pal, Gopal Lal Khatik, Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The steric regulations imparted by the substituent at N1 in lithium mediated asymmetric aldol reactions
of conformationally restricted 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones
governed the formation of anti aldol adducts, by a kinetic reaction pathway. The preferential formation of
the anti aldol diastereomers was also assisted by the steric effects of the electrophile through diaster-
eofacial selection while the electronic effects of the aryl group at N3 remained subtle. Incorporation of an
endocyclic methyl group at C6 witnessed the diastereoselective formation of an anti aldol adduct by
Received 4 September 2012
Received in revised form 4 December 2012
Accepted 10 December 2012
Available online 19 December 2012
Keywords:
Aldol
Cyclic enolate
2-Thioxotetrahydropyrimidin-4(1H)-one
Chiral induction
Diastereoselectivity
regulation of
p-facial selectivity. The absolute configurations of the aldol adducts were determined by
computational calculations and NMR experiments, and confirmed by single crystal X-ray analysis.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The origin of chirality in stereoselective carbonecarbon bond
forming reactions facilitated the synthesis of numerous natural
products and chiral building blocks in optically pure forms.1,2 The
aldol reactions of acyclic chiral enolates are well understood where
the stereochemical outcomes are often explained on the basis of
highly organized transition states.3 However the aldol reactions of
cyclic chiral enolates are rather complex due to stereoregulations
originating from the substrate conformation. To gain more insights
into the factors influencing the stereochemical outcome in aldol
reactions of cyclic enolates, a conformationally rigid heterocyclic
enolate of 2-thioxotetrahydropyrimidin-4(1H)-one was consid-
ered. The scaffold is associated with various applications and di-
verse biological properties (Fig. 1). The pyrimidinone core is an
integral part of many drugs, such as 5-fluorouracil, uramustine and
floxuridine (anticancer); zidovudine, stavudine and 1-
[(2-hydroxyethoxy)methyl]-6-(phenyl thio)thymine (antiHIV);
lamivudine and telbivudine (treatment of chronic hepatitis B);
sorivudine and trifluridine (antiviral); alogliptin (antidiabetic)
and aminometradine (diuretic).4 The present work discusses about
the asymmetric aldol reactions of 2-thioxotetrahydropyrimidin-
4(1H)-ones, and illustrates how the steric constraints and stereo-
regulations lead to diastereoselectivity. Our earlier studies in
Fig. 1. A few biologically active pyrimidinones.
this direction have demonstrated that the stereoselective
alkylation of 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-4(1H)-
one can be achieved by regulating the reaction kinetics using
HMPA as an additive and chiral ethyl lactate as a quencher.5a Ste-
reochemical outcome of the alkylation reactions can also be gov-
erned by incorporating suitably positioned exocyclic and
endocyclic groups, as illustrated in the case of 3-aryl-(S/R)-
6-methyl-1-[((S/R)-1-phenylethyl)]-2-thioxotetrahydropyrimidin-
4(1H)-ones.5b Similarly, in the aldol reactions of 3-aryl-1-alkyl-2-
thioxotetrahydropyrimidin-4(1H)-ones, the exocyclic group at N1,
* Corresponding author. Tel.: þ91 172 229 2045; fax: þ91 172 221 4692; e-mail
addresses: vn74nr@yahoo.com, vnair@niper.ac.in (V.A. Nair).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.020

1748
V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
electronic effects of the aryl substituent at N3 and steric demands
of the electrophile have been found to influence the
stereoselectivity.5c
2. Results and discussion
Based on our previous works on heterocyclic scaffolds,5 a one-pot
synthesis of optically pure 3-aryl-1-alkyl-2-thioxotetrahydropyrimidin-
4(1H)-ones was achieved by the condensation of aryl isothiocyanates
with chiral b
-aminoesters.5b As a model reaction, the lithium enolate
of 3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-one 1 was treated with 4-chlorobenzaldehyde.
Fig. 3. Ortep diagram of the acetate derivative of 5b.
Incorporation of a chiral
a-methyl benzyl group at N1 imparted
steric biasness and chiral features to the substrate leading to an
asymmetric aldol reaction. The reaction afforded diaster-
eoselectivity forming only two isomers 5a and 5b out of the four
possible aldol diastereomers (Scheme 1). The protons at C5 and C7
showed coupling constants of 8.8 and 8.0 Hz for 5a and 5b,
respectively, indicating an anti orientation for both of the aldol
diastereomers formed.5c The dihedral angles obtained by ab initio
calculations6 from the energy optimized structures of 5a and 5b
were also in agreement with the observed coupling constants.
1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones
gave
similar diastereoselectivity with 4-halo benzaldehydes (Table 1).
Further the steric effects of the electrophiles were explored in the
aldol reactions of 3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-ones by varying the aldehydes
(Scheme 2). Reactions with benzaldehydes containing electron
withdrawing substituents afforded good yields and moderate dia-
stereoselectivity whereas electron donating groups retarded the
reaction giving poor yields. The diastereoselectivity of the reaction
increased with increasing size of the electrophile, as observed
with furfural, N-benzyl-indole-3-carboxaldehyde and 2-
naphthaldehyde, while the reaction with 9-anthraldehyde affor-
ded only one anti aldol diastereomer (Table 2). Reactions with ali-
phatic aldehydes afforded inseparable mixture of diastereomers.
Table 1
Aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
ones: effect of substituents
Entry
R1
R2
R
Yield (%)
Product
anti:syn
b:aa
Scheme 1. Aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimdin-4(1H)-ones.
1
2
3
4
5
6
7
8
Cl
CN
F
Cl
Cl
CN
F
H
Cl
Cl
CF3
H
Cl
Cl
CF3
Cl
Cl
Cl
Cl
F
F
F
F
82
78
80
84
81
79
82
85
5a, 5b
6a, 6b
7a, 7b
8a, 8b
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
67:33
64:36
62:38
65:35
64:36
62:38
66:34
63:37
The energy minimized structure for the diastereomer 5b with R
configuration at C5 indicated that the proton at C5 has to be
shielded because of the anisotropy of the adjacent carbonyl carbon
9a, 9b
10a, 10b
11a, 11b
12a, 12b
(Fig. 2). 1H NMR spectra of 5b indicated a
d value of 2.78 ppm for the
Cl
C5 proton confirming that it was shielded while the corresponding
proton for 5a resonated at 3.12 ppm. Hence S and R configurations
can be fairly assigned at C5 for 5a and 5b, respectively. Since the
protons at C5 and C7 have an anti relation, R and S configurations
were assigned, respectively, for 5a and 5b, at C7. Thus an overall
a
Ratio determined from 1H NMR spectrum of the crude product.
configuration of SSR was assigned at Ca, C5 and C7 for the anti aldol
diastereomer 5a and an SRS configuration for the anti aldol di-
astereomer 5b. The configuration of 5b was finally confirmed by
single crystal X-ray diffraction analysis of the corresponding acetate
derivative 5b0 (Fig. 3). The aldol reactions of different 3-aryl-1-((S)-
Scheme
2. Aldol
reactions
of
3-(4-chlorophenyl)-1-((S)-1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-ones with different aldehydes.
Based on the conformation adopted by the 2-thioxotetra-
hydropyrimidin-4(1H)-one ring, the orientation of the substituents
and the stereoregulations posed by the electrophile, transition state
models were proposed (Scheme 3). The transition states TS-1 and TS-2
correspond to anti aldol diastereomers a and b, whereas the transition
states TS-3 and TS-4 correspond to the syn aldol diastereomers c and d,
respectively. A careful consideration of the stereoelectronic effects in-
dicate that the transition states TS-3 and TS-4 are highly unfavourable
because of the steric interactions between the aldehyde and the sub-
stituent at N1 and hence the reaction is anti specific. However, with
increasing steric constraints, the preferred formation of the anti aldol
diastereomer b can be explained on the basis of 1,2-interaction be-
tween the electrophile and the 2-thioxotetrahydropyrimidin-4(1H)-
Fig. 2. Configuration determination from the energy minimized structures of 5a and 5b.

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
1749
Table 2
Steric effects of electrophiles on aldol reactions of 3-(4-chlorophenyl)-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one
Entry
RCHO
Yield (%)
Product
anti:syn
b:aa
1
82
5a, 5b
100:0
65:35
2
81
9a, 9b
100:0
64:36
Scheme 4. Diastereoselective aldol reaction of 3-aryl-(S)-6-methyl-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.
3
4
80
78
13a, 13b
14a, 14b
100:0
100:0
65:35
58:42
coupling constant of 6.8 Hz was observed for the protons at C5 and C7
for 23b confirming an anti orientation. The decoupled spectra obtained
by irradiating the methyl protons at C6, revealed no interaction be-
tween the protons at C5 and C6, confirming an orthogonal relation.
Therefore with the configuration at C6 known, an R configuration can
be assigned at C5. Since the protons at C5 and C7 also have an anti
relation, configuration at C7 was assigned S, leading to an overall
5
6
7
72
84
86
70
15a, 15b
16a, 16b
17a, 17b
18a, 18b
100:0
100:0
100:0
100:0
82:18
85:15
>99
configuration of SRSS at Ca, C5, C6 and C7, respectively. This was further
confirmed by single crystal X-ray diffraction analysis of 23b (Fig. 4). The
transition state TS-6 is preferred over TS-5 (Scheme 5) because of the
steric constraints arising from an unfavourable coplanar relation be-
tween the C5eC6eMe and the aldehyde. Transition state TS-6 is free
from such an interaction as C5eC6eMe and the aldehyde are in op-
posite planes and this leads to the diastereoselective formation of anti
aldol diastereomers 23be30b (Table 3).
8
70:30
a
Ratio determined from 1H NMR spectra of the crude product.
Fig. 4. Ortep diagram of 23b.
Scheme 3. Transition state models for aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-
thioxotetrahydropyrimidin-4(1H)-ones.
Scheme 5. Transition state models for the diastereoselective aldol reaction of 3-aryl-
(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.
one ring. For the transition state TS-1 leading to the anti aldol di-
astereomer a, attack of the enolate occurs on the re face of the aldehyde
and this brings the electrophile and the heterocyclic ring in same plane.
Therefore with increasing size of the aldehyde substituent Rz, steric
interaction becomes prominent and hence the formation of anti aldol
diastereomer a is disfavoured. The transition state TS-2 is free-
from such interactions as the aldehyde and 2-thioxotetra-
hydropyrimidin-4(1H)-one ring are in opposite planes leading to the
preferential formation of anti aldol diastereomer b. From the transition
state models, we speculated that the approach of the electrophile can
be controlled by incorporating an endocyclic methyl group at the C6
position of 2-thioxotetrahydropyrimidin-4(1H)-ones. Thus the aldol
reaction of 3-(4-chlorophenyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-
thioxotetrahydropyrimdin-4(1H)-one 19, where the two methyl
Table 3
Aldol reactions of 3-aryl-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-ones
Entry
R1
R2
R
Yield (%)
Product
anti:syn
de
1
2
3
4
5
6
7
8
Cl
CN
F
Cl
Cl
CN
F
H
Cl
Cl
CF3
H
Cl
Cl
CF3
Cl
Cl
Cl
Cl
F
F
F
F
81
88
85
84
82
86
82
85
23b
24b
25b
26b
27b
28b
29b
30b
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
>99
>99
>99
>99
>99
>99
>99
>99
groups at Ca and C6 are in syn orientation (Scheme 4), led to the ster-
Cl
eoselective formation of the anti aldol diastereomer 23b. A vicinal

1750
V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
The aldol reaction of 3-(4-chlorophenyl)-(R)-6-methyl-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimdin-4(1H)-one 31, where
the two methyl groups at Ca and C6 are anti oriented (Scheme 6),
4. Experimental
4.1. General
also afforded only one anti aldol diastereomer 35a. The configura-
tion of the product 35a was concluded anti based on the vicinal
coupling constant of 8.2 Hz between the protons at C5 and C7. The
methyl group at C6 was irradiated to decouple and the decoupled
spectra showed that the protons at C5 and C6 are orthogonal to
each other. Thus with the configuration at C6 known, an S config-
uration was assigned at C5. Since the protons at C5 and C7 share an
anti relation, an R configuration was assigned at C7 with an overall
The 1H and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively, in CDCl3 using TMS as an internal stan-
dard. The chemical shifts (d
) for 1H and 13C are given in parts per
million relative to residual signals of the solvent. Coupling con-
stants are given in Hertz. The following abbreviations are used to
indicate the multiplicity: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br s, broad signal. HRMS were recorded
using TOF mass analyzer. All reactions were performed under
nitrogen atmosphere. THF was freshly distilled from sodium
benzophenone ketyl. Hexane was distilled before use for column
chromatography. The reactions were monitored by TLC. Com-
mercial grade reagents and solvents were used without further
purification.
configuration of SSRR at Ca, C5, C6 and C7, respectively. The steric
effects imparted by the methyl group at C6 disfavours the transition
state TS-8 (Scheme 7) and hence the only possibility left is the
formation of anti aldol diastereomers 35ae42a (Table 4) through
TS-7, resulting in a diastereoselective reaction.
4.2. General procedure for the aldol reaction
In
a
typical experiment, 1-alkyl-3-aryl-2-thioxotetrahyd
ropyrimidin-4(1H)-one (1.5 mmol), dissolved in anhydrous THF
(10 mL) and cooled to ꢀ78 ꢁC was treated with LHMDS (1.8 mL, 1 M
solution) under nitrogen atmosphere and stirred for 30 min. Al-
dehyde (1.65 mmol) was introduced into the reaction mixture,
stirred for another 30 min, then quenched with saturated aq NH4Cl
and extracted with ethyl acetate. The organic layer was dried and
concentrated to provide a gummy compound. The crude product
was purified by column chromatography on silica gel
(230e400 mesh) using ethyl acetate/hexane mixture (15:85) as the
eluent.
Scheme 6. Diastereoselective aldol reaction of 3-aryl-(R)-6-methyl-1-((S)-1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.
4.2.1. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 5a. Rf (30% EtOAc/Hexane) 0.32; white solid; mp 160e162 ꢁC;
yield 29% (0.21 g); 1H NMR (400 MHz, CDCl3):
d 1.47 (d, 3H,
J¼7.0 Hz), 2.56e2.69 (m, 2H), 3.12 (m, 1H), 4.29 (s, 1H), 4.75 (d, 1H,
Scheme 7. Transition state models for the diastereoselective aldol reaction of 3-aryl-
(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones.
J¼8.8 Hz), 6.72 (q, 1H, J¼7.0 Hz), 6.87 (d, 2H, J¼8.9 Hz), 7.15e7.47
(m, 11H); 13C NMR (100 MHz, CDCl3):
d 13.8, 40.8, 47.1, 59.5, 71.9,
127.0, 127.7, 128.4, 128.8, 129.0, 129.4, 134.4, 134.6, 136.9, 137.5,
138.4, 170.5, 180.3; HRMS (ESI): m/z [MþNa]þ calcd for
Table 4
C25H22Cl2N2NaO2S: 507.0677, found: 507.0674; [
a]
25 ꢀ117.18 (c 1.0,
Aldol reactions of 3-aryl-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-ones
D
CHCl3).
Entry
R1
R2
R
Yield (%)
Product
anti:syn
de
4.2.2. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 5b. Rf (30% EtOAc/Hexane) 0.22; white solid; mp 219e221 ꢁC;
1
2
3
4
5
6
7
8
Cl
CN
F
Cl
Cl
CN
F
H
Cl
Cl
CF3
H
Cl
Cl
CF3
Cl
Cl
Cl
Cl
F
F
F
F
83
81
84
82
86
80
80
85
35a
36a
37a
38a
39a
40a
41a
42a
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
>99
>99
>99
>99
>99
>99
>99
>99
yield 53% (0.38 g); 1H NMR (400 MHz, CDCl3):
d 1.43 (d, 3H,
J¼7.0 Hz), 2.78e2.82 (m,1H), 2.88e2.96 (m, 2H), 4.09 (s,1H), 4.76 (d,
1H, J¼8.4 Hz), 6.87 (q,1H, J¼7.0 Hz), 6.99e7.04 (m, 2H), 7.10e7.14 (m,
4H), 7.22e2.26 (m, 2H), 7.35e7.45 (m, 5H); 13C NMR (100 MHz,
Cl
CDCl3):
d 14.9, 41.1, 47.8, 59.2, 71.9, 115.7, 115.9, 127.3, 128.2, 128.3,
128.5, 128.9, 129.4, 130.6, 134.5, 135.2, 137.6, 169.5, 180.4; HRMS
(ESI): m/z [MþNa]þ calcd for C25H22Cl2N2NaO2S: 507.0677, found:
3. Conclusions
507.0672; [
a]
2D5 ꢀ253.74 (c 1.0, CHCl3).
Aldol reactions of 3-aryl-1-((S)-1-phenylethyl)-2-thioxotetra-
hydropyrimidin-4(1H)-ones afforded stereoselectivity towards
anti aldol diastereomers. Incorporation of a methyl group at
the C6 position of 2-thioxotetrahydropyrimidin-4(1H)-one dic-
tated the diastereoselectivity, forming one of the anti aldol di-
astereomers exclusively. The combined effects exerted by the
endo- and exocyclic groups at C6 and N1 provide convincing
evidence for the stereoelectronic influences of the cyclic sub-
strate and the substituents in governing the stereoselectivity of
aldol reactions.
4.2.3. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydro-
xy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 6b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 220e222 ꢁC;
yield 50% (0.38 g); 1H NMR (400 MHz, CDCl3):
d
1.49 (d, 3H, J¼7.0 Hz),
2.81e2.91 (m, 1H), 2.98e3.09 (m, 2H), 3.63 (s, 1H), 4.76 (d, 1H,
J¼7.4 Hz), 6.85 (q, 1H, J¼6.9 Hz), 7.03 (d, 2H, J¼8.4 Hz), 7.23e7.43 (m,
8H), 7.77 (d, 2H, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3):
d 14.9, 41.1,
47.7, 59.2, 71.7, 113.4, 115.5, 127.4, 127.8, 128.7, 128.8, 129.1, 131.5, 134.1,
134.7, 137.3, 137.4, 137.8, 143.9, 168.5, 179.3; HRMS (ESI): m/z [MþNa]þ

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
1751
calcd for C26H21Cl2N3NaO2S: 532.0629, found: 532.0628; [
(c 1.0, CHCl3).
a
]
2D5 ꢀ73.40
9b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 226e228 ꢁC; yield
52% (0.36 g); 1H NMR (400 MHz, CDCl3):
2.75e2.82 (m, 1H), 2.87e2.99 (m, 2H), 4.11 (s, 1H), 4.77 (d, 1H,
J¼8.3 Hz), 6.87 (q,1H, J¼7.2 Hz), 7.00e7.04 (m, 2H), 7.11e7.15 (m, 4H),
7.22e2.26 (m, 2H), 7.32e7.50 (m, 5H); 13C NMR (100 MHz, CDCl3):
d
1.45 (d, 3H, J¼7.1 Hz),
4.2.4. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydro-
xy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 7a. Rf (30% EtOAc/Hexane) 0.35; white solid; mp 166e168 ꢁC;
d
14.9, 41.1, 47.8, 59.2, 72.0, 115.7, 115.9, 127.3, 128.2, 128.3, 128.5,
128.9, 129.4, 130.6, 134.5, 135.2, 137.6, 169.5, 180.4; HRMS (ESI): m/z
[MþNa]þ calcd for C25H22ClFN2NaO2S: 491.0972, found: 491.0971;
yield 28% (0.20 g); 1H NMR (400 MHz, CDCl3):
d 1.47 (d, 3H,
J¼6.88 Hz), 2.60e2.71 (m, 2H), 3.01e3.14 (m, 1H), 4.23 (s, 1H), 4.76 (d,
[a]
2D5 ꢀ297.00 (c 1.0, CHCl3).
1H, J¼8.4 Hz), 6.73 (q, 1H, J¼6.8 Hz), 6.88e6.91 (m, 4H), 7.19e7.36 (m,
8H); 13C NMR (100 MHz, CDCl3):
d 13.8, 40.9, 47.1, 59.5, 71.9, 115.6,
4.2.10. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydro-
xy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 10b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 168e170 ꢁC;
115.9, 116.9, 127.0, 128.1, 128.2, 128.4, 128.9, 134.2, 138.4, 170.6, 180.2;
HRMS (ESI): m/z [MþNa]þ calcd for C25H21Cl2FN2NaO2S: 525.0583,
found: 525.0587; [
a]
2D5 þ114.11 (c 0.5, CHCl3).
yield 49% (0.36 g); 1H NMR (400 MHz, CDCl3):
d
1.46 (d, 3H, J¼7.0 Hz),
4.2.5. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 7b. Rf (30% EtOAc/Hexane) 0.25; white solid; mp 216e218 ꢁC;
2.80e2.87 (m, 1H), 2.96e3.03 (m, 2H), 3.68 (s, 1H), 4.76 (d, 1H,
J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.01e7.09 (m, 4H), 7.20e7.29 (m, 3H),
7.32e7.42 (m, 4H), 7.76 (d, 1H, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3):
yield 50% (0.37 g); 1H NMR (400 MHz, CDCl3):
d 1.45 (d, 3H,
d
14.9, 41.2, 47.9, 59.2, 71.8, 113.4, 115.5, 115.7, 127.4, 128.1, 128.7, 128.8,
J¼7.0 Hz), 2.77e2.84 (m, 1H), 2.93e3.00 (m, 2H), 3.89 (s, 1H), 4.76
129.0, 131.5, 134.1, 135.1, 137.3, 143.9, 161.6, 164.0, 168.7, 179.3; HRMS
(ESI): m/z [MþNa]þ calcd for C26H21ClFN3NaO2S: 516.0925, found:
(d, 1H, J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.05 (d, 2H, J¼8.4 Hz),
7.19e7.39 (m, 10H); 13C NMR (100 MHz, CDCl3):
d 14.9, 41.1, 47.7,
516.0921; [
a]
2D5 ꢀ289.20 (c 1.0, CHCl3).
59.3, 71.8, 113.4, 115.5, 127.4, 127.8, 128.7, 128.8, 129.1, 131.5,
134.1, 134.7, 137.3, 137.4, 137.8, 143.9, 168.5, 179.3; HRMS (ESI):
m/z [MþNa]þ calcd for C25H21Cl2FN2NaO2S: 525.0583, found:
4.2.11. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-fluorophenyl)hy-
droxy)methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-
4(1H)-one, 11a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp
525.0583; [
a]
2D5 ꢀ195.87 (c 1.0, CHCl3).
175e178 ꢁC; yield 28% (0.20 g); 1H NMR (400 MHz, CDCl3):
d 1.50 (d,
4.2.6. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-chlorophe-
nyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimi-
din-4(1H)-one, 8a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp
3H, J¼6.9 Hz), 2.63e2.74 (m, 2H), 3.01e3.17 (m, 1H), 4.26 (s, 1H),
4.78 (d, 1H, J¼8.2 Hz), 6.75 (q, 1H, J¼6.8 Hz), 6.89e6.94 (m, 4H),
7.22e7.28 (m, 4H), 7.33e7.39 (m, 4H); 13C NMR (100 MHz, CDCl3):
203e206 ꢁC; yield 34% (0.25 g); 1H NMR (400 MHz, CDCl3):
d 1.57 (d,
d
13.8, 28.2, 40.9, 47.1, 59.5, 71.9, 115.7, 115.9, 116.7, 116.9, 127.0, 128.1,
3H, J¼7.0 Hz), 2.58e2.65 (m, 2H), 2.96e3.00 (m, 1H), 3.55e3.62 (m,
1H), 5.43 (s, 1H), 6.74 (q, 1H, J¼7.0 Hz), 6.93 (d, 2H, J¼8.5 Hz),
7.18e7.24 (m, 5H), 7.26e7.40 (m, 3H), 7.54 (s, 1H), 7.62 (d, 1H,
128.2, 128.5, 129.0, 134.2, 138.4, 170.6, 180.2; HRMS (ESI): m/z
[MþNa]þ calcd for C25H21ClF2N2NaO2S: 509.0878, found: 509.0878;
[a]
2D5 þ139.88 (c 0.5, CHCl3).
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3):
d 13.9, 29.7, 31.9, 38.3, 47.9,
59.6, 68.1, 126.1, 127.0, 127.6, 128.4, 128.8, 128.8, 128.9, 129.1, 132.0,
132.4, 133.4, 134.0, 137.6, 138.0, 138.4, 168.3, 179.9; HRMS (ESI): m/z
[MþNa]þ calcd for C26H21Cl2F3N2NaO2S: 575.0551, found: 575.0551;
4.2.12. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-fluorophenyl)hydroxy)
methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one,
11b. Rf (30% EtOAc/Hexane) 0.28; white solid; mp 197e198 ꢁC; yield
[
a
]
2D5 þ75.54 (c 0.5, CHCl3).
54% (0.39 g); 1H NMR (400 MHz, CDCl3):
2.75e2.83 (m, 1H), 2.88e3.00 (m, 2H), 3.96 (s, 1H), 4.76 (d, 1H,
J¼8.2 Hz), 6.86 (q, 1H, J¼7.0 Hz), 6.99e7.04 (m, 2H), 7.08e7.13 (m, 3H),
7.15e7.25 (m, 4H), 7.30e7.42 (m, 3H); 13C NMR (100 MHz, CDCl3):
d
1.46 (d, 3H, J¼7.0 Hz),
4.2.7. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4-
chlorophenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahy-
dropyrimidin-4(1H)-one, 8b. Rf (30% EtOAc/Hexane) 0.31; white solid;
mp 202e204 ꢁC; yield 54% (0.45 g); 1H NMR (400 MHz, CDCl3):
d 1.48
d
14.9, 41.1, 47.8, 59.3, 71.9, 115.5, 116.7, 121.4, 127.0, 127.1, 128.2, 128.8,
135.2, 135.5, 137.6, 156.7, 159.2, 161.5, 164.0, 169.4, 180.2; HRMS (ESI): m/
z [MþNa]þ calcd for C25H21ClF2N2NaO2S: 509.0878, found: 509.0878;
(d, 3H, J¼7.0 Hz), 2.80e2.88 (m, 1H), 2.96e3.03 (m, 2H), 3.80 (s, 1H),
4.76 (d, 1H, J¼7.7 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.05 (d, 2H, J¼8.4 Hz),
7.25e7.35 (m, 5H), 7.37e7.44 (m, 3H), 7.49 (s, 1H), 7.59 (d, 1H,
[
a 25
]
D ꢀ280.02 (c 1.0, CHCl3).
J¼8.4 Hz); 13C NMR (100 MHz, CDCl3):
d 14.9, 41.1, 47.8, 59.3, 71.8,
121.0, 123.7, 127.4, 127.8, 128.6, 129.0, 129.3, 132.1, 132.5, 134.0, 134.7,
4.2.13. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-fluoro-
phenyl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-one, 12a. Rf (30% EtOAc/Hexane) 0.29; white solid;
137.5, 137.8, 137.9, 169.0, 179.9; HRMS (ESI): m/z [MþNa]þ calcd for
C26H21Cl2F3N2NaO2S: 575.0551, found: 575.0551; [
a]
2D5 ꢀ238.26 (c 1.0,
mp 210e213 ꢁC; yield 32% (0.25 g); 1H NMR (400 MHz, CDCl3):
d 1.58
CHCl3).
(d, 3H, J¼7.2 Hz), 2.60e2.66 (m, 2H), 2.99e3.04 (m,1H), 3.57e3.63 (m,
1H), 5.44 (s, 1H), 6.77 (q, 1H, J¼6.9 Hz), 6.90e7.00 (m, 4H), 7.24e7.37
(m, 6H), 7.54 (s,1H), 7.62 (d,1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3):
4.2.8. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one,
9a. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 186e189 ꢁC; yield
d
14.0, 38.5, 47.9, 59.5, 68.1,115.4,115.6,126.4,126.5,127.0,128.33,128.8,
29% (0.20 g); 1H NMR (400 MHz, CDCl3):
d
1.47 (d, 3H, J¼7.0 Hz),
132.1,132.0,134.7,138.0,138.5,168.4, 179.9; HRMS (ESI): m/z [MþNa]þ
25
2.57e2.69 (m, 2H), 3.08e3.16 (m, 1H), 4.29 (s, 1H), 4.74 (d, 1H,
J¼7.0 Hz), 6.72 (q,1H, J¼7.0 Hz), 6.87e6.90 (m, 2H), 7.13e7.20 (m, 5H),
7.29e7.38 (m, 4H), 7.46 (d, 2H, J¼4.3 Hz); 13C NMR (100 MHz, CDCl3):
calcd for C26H21ClF4N2NaO2S: 559.0846, found: 559.0840; [
a]
D
þ146.48 (c 1.0, CHCl3).
d
13.8, 40.8, 47.1, 59.5, 71.9,126.0,126.8,127.0,127.6,128.4,128.9,129.0,
4.2.14. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4-fluorophen-
yl)(hydroxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-
4(1H)-one, 12b. Rf (30% EtOAc/Hexane) 0.31; white solid; mp
129.4, 130.4, 136.9, 137.5, 138.4, 170.5, 180.3; HRMS (ESI): m/z
[MþNa]þ calcd for C25H22ClFN2NaO2S: 491.0972, found: 491.0972;
[
a
]
2D5 þ170.76 (c 1.0, CHCl3).
192e194 ꢁC; yield 53% (0.43 g); 1H NMR (400 MHz, CDCl3):
d 1.48 (d,
3H, J¼7.2 Hz), 2.79e2.86 (m, 1H), 2.94e3.02 (m, 2H), 3.87 (s, 1H), 4.76
(d,1H, J¼7.8 Hz), 6.85 (q, 1H, J¼7.0 Hz), 7.00e7.12 (m, 4H), 7.25e7.43 (m,
6H), 7.50 (s, 1H), 7.60 (d, 1H, J¼8.5 Hz); 13C NMR (100 MHz, CDCl3):
4.2.9. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one,

1752
V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
25
d
14.9, 41.2, 47.9, 59.3, 71.9, 115.7, 115.9, 127.4, 128.1, 128.2, 128.6, 129.0,
calcd for C34H30ClN3NaO2S: 602.1645, found: 602.1645; [a]
D
132.0, 132.5, 135.2, 137.5, 137.9, 161.6, 169.4, 179.9; HRMS (ESI): m/z
þ150.67 (c 1.0, CHCl3).
[MþNa]þ calcd for C26H21ClF4N2NaO2S: 559.0846, found: 559.0846;
[
a 25
]
D ꢀ284.02 (c 1.0, CHCl3).
4.2.20. 3-(4-Chlorophenyl)-(R)-5-(S)-(naphthalen-2-yl(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 16b. Rf (30% EtOAc/Hexane) 0.28; white solid; mp 209e211 ꢁC;
4.2.15. 3-(4-Chlorophenyl)-(S)-5-((R)-(hydroxy)(phenyl)methyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one,
13a. Rf
yield 72% (0.53 g); 1H NMR (400 MHz, CDCl3):
d 1.37 (d, 3H,
(30% EtOAc/Hexane) 0.26; white solid; mp 216e219 ꢁC; yield 28%
J¼7.0 Hz), 2.82e2.93 (m, 1H), 2.95e3.12 (m, 2H), 4.95 (d, 1H,
1
(0.17 g); H NMR (400 MHz, CDCl3):
d
1.43 (d, 3H, J¼7.0 Hz), 1.57 (s,
J¼8.4 Hz), 6.84 (q, 1H, J¼7.0 Hz), 7.12e7.15 (m, 4H), 7.22e7.54 (m,
1H), 2.78e2.85 (m,1H), 2.89e2.96 (m, 1H), 2.98e3.05 (m, 1H), 4.80 (d,
1H, J¼8.3 Hz), 6.89 (q, 1H, J¼7.0 Hz), 7.15e7.20 (m, 4H), 7.23e7.24 (m,
2H), 7.34e7.38 (m, 6H), 7.48 (d, 2H, J¼8.8 Hz); 13C NMR (100 MHz,
9H), 7.73e7.88 (m, 3H), 13C NMR (100 MHz, CDCl3):
d 15.0, 41.3, 47.6,
59.2, 72.7, 123.4, 126.1, 126.6, 127.4, 127.8, 128.1, 128.4, 128.8, 129.0,
129.4, 130.6, 133.0, 133.4, 134.5, 136.6, 137.6, 137.8, 169.6, 180.4;
HRMS (ESI): m/z [MþNa]þ calcd for C29H25ClN2NaO2S: 523.1223,
CDCl3):
d 15.0, 41.3, 47.8, 59.2, 72.7, 126.4, 127.3, 128.4, 128.9, 129.3,
129.3, 130.6, 134.5, 137.6, 137.8, 139.3, 169.8, 180.4; HRMS (ESI): m/z
found: 523.1223; [
a
]
2D5 ꢀ245.88 (c 1.0, CHCl3).
25
[MþNa]þ calcd for C25H23ClN2NaO2S: 473.1066, found: 473.1060; [
ꢀ153.82 (c 1.0, CHCl3).
a]
D
4.2.21. 3-(4-Chlorophenyl)-(R)-5-(S)-(anthracen-9-yl(hydroxy)
methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-
one, 17b. Rf (30% EtOAc/Hexane) 0.29; white solid; mp 162e164 ꢁC;
4.2.16. 3-(4-Chlorophenyl)-(R)-5-((S)-(hydroxy)(phenyl)methyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 13b. Rf
(30% EtOAc/Hexane) 0.35; white solid; mp 175e178 ꢁC; yield 52%
yield 86% (0.71 g); 1H NMR (400 MHz, CDCl3):
d 1.09 (d, 3H,
J¼7.2 Hz), 2.12e2.15 (m, 1H), 3.03e3.10 (m, 1H), 3.50e3.58 (m, 1H),
(0.32 g); 1H NMR (400 MHz, CDCl3):
d
1.48 (d, 3H, J¼7.0 Hz), 1.60
6.47e6.81 (m, 5H), 7.20e7.52 (m, 12H), 7.80e7.81 (m, 2H), 8.40 (s,
(s, 1H), 2.70e2.74 (m, 1H), 2.75e2.79 (m, 1H), 3.15 (m, 1H), 4.80
(d, 1H, J¼1.5 Hz), 6.78 (q, 1H, J¼7.0 Hz), 6.96e6.98 (m, 2H),
7.21e7.26 (m, 5H), 7.28e7.39 (m, 5H), 7.49 (d, 2H, J¼8.8 Hz); 13C
1H); 13C NMR (100 MHz, CDCl3):
d 13.7, 40.9, 45.9, 59.2, 68.0, 125.9,
126.6, 126.9, 127.2, 127.8, 128.0, 128.1, 128.4, 128.5, 129.3, 129.4,
129.5, 129.8, 134.5, 137.5, 137.8, 171.7, 180.2; HRMS (ESI): m/z
[MþNa]þ calcd for C33H27ClN2NaO2S: 573.1379, found: 573.1379;
NMR (100 MHz, CDCl3):
d 13.9, 41.0, 46.9, 59.4, 72.7, 126.4, 126.9,
128.3, 128.7, 128.9, 128.9, 129.4, 134.5, 137.7, 138.3, 138.5, 170.7,
[a
]
25 ꢀ167.35 (c 1.0, CHCl3).
D
180.4; HRMS (ESI): m/z [MþNa]þ calcd for C25H23ClN2NaO2S:
25
473.1066, found: 473.1061; [
a
]
ꢀ62.65 (c 0.5, CHCl3).
D
4.2.22. 3-(4-Chlorophenyl)-(S)-5-((E,R)-1-hydroxy-3-phenylallyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 18a. Rf
(30% EtOAc/Hexane) 0.16; white solid; mp 218e221 ꢁC; yield 49%
4.2.17. 3-(4-Chlorophenyl)-(S)-5-((R)-(furan-2-yl(hydroxy)methyl))-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 14a. Rf
(30% EtOAc/Hexane) 0.26; white solid; mp 148e151 ꢁC; yield 24%
(0.16 g); 1H NMR (400 MHz, CDCl3):
(0.23 g); 1H NMR (400 MHz, CDCl3):
d
1.68 (d, 3H, J¼7.0 Hz),
2.92e2.97 (m, 1H), 3.05 (d, 1H, J¼3.7 Hz), 3.14e3.20 (m, 1H),
3.50e3.55 (m, 1H), 4.48 (s, 1H), 5.99e6.05 (m, 1H), 6.38 (d, 1H,
J¼15.9 Hz), 7.03 (q, 1H, J¼7.0 Hz), 7.14 (d, 2H, J¼8.0 Hz), 7.28e7.34
d
1.56 (d, 3H, J¼7.0 Hz), 1.94 (d,
1H, J¼6.9 Hz), 2.94 (d,1H, J¼5.2 Hz), 3.02e3.09 (m, 1H), 3.19e3.26 (m,
1H), 4.90 (d, 1H, J¼8.6 Hz), 6.07 (d, 1H, J¼3.1 Hz), 6.24e6.25 (m, 1H),
6.85 (q, 1H, J¼6.9 Hz), 7.07e7.16 (m, 2H), 7.32e7.48 (m, 8H); 13C NMR
(m, 6H), 7.37e7.48 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 14.9, 41.0,
46.6, 59.3, 71.0, 126.7, 127.0, 127.5, 128.3, 128.5, 128.6, 129.0, 129.3,
130.7, 133.5, 134.4, 135.7, 137.9, 138.0, 168.3, 180.6; HRMS (ESI): m/z
[MþNa]þ calcd for C27H25ClN2NaO2S: 499.1226, found: 499.1226;
(100 MHz, CDCl3): d 14.0, 40.8, 45.0, 59.5, 65.8, 108.7, 110.1, 127.1, 128.3,
129.0, 129.3, 134.5, 137.7, 138.6, 142.9, 147.3, 151.1, 169.9, 180.5; HRMS
(ESI): m/z [MþNa]þ calcd for C23H21ClN2NaO3S: 463.0859, found:
[a
]
25 ꢀ93.54 (c 0.5, CHCl3).
D
463.0852; [
a]
2D5 ꢀ130.29 (c 0.5, CHCl3).
4.2.23. 3-(4-Chlorophenyl)-(R)-5-((E,S)-1-hydroxy-3-phenylallyl)-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 18b. Rf
(30% EtOAc/Hexane) 0.22; white solid; mp 185e189 ꢁC; yield 21%
4.2.18. 3-(4-Chlorophenyl)-(R)-5-((S)-(furan-2-yl(hydroxy)methyl))-1-
((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one, 14b. Rf
(30% EtOAc/Hexane) 0.16; white solid; mp 219e221 ꢁC; yield 44%
(0.30 g); 1H NMR (400 MHz, CDCl3):
(0.14 g); 1H NMR (400 MHz, CDCl3):
d
1.64 (d, 3H, J¼7.0 Hz),
d
1.60 (d, 3H, J¼7.0 Hz),
2.61e2.68 (m, 1H), 3.29e3.40 (m, 2H), 3.48e3.63 (m, 1H),
4.49e4.53 (s, 1H), 5.83 (q, 1H, J¼8.1 Hz), 6.56 (d, 1H, J¼15.9 Hz),
6.86e6.94 (m, 1H), 7.16 (s, 2H), 7.24e7.26 (m, 2H), 7.32e7.42 (m,
2.89e2.95 (m, 1H), 3.08e3.12 (m, 2H), 3.30e3.36 (m, 1H), 4.85 (d, 1H,
J¼8.3 Hz), 6.13 (d, 1H, J¼3.1 Hz), 6.34e6.35 (m, 1H), 6.95 (q, 1H,
J¼7.0 Hz), 7.14e7.16 (m, 2H), 7.32e7.48 (m, 8H); 13C NMR (100 MHz,
8H), 7.47 (d, 2H, J¼8.7 Hz); 13C NMR (100 MHz, CDCl3):
d 14.1, 40.9,
CDCl3):
d
15.0, 39.7, 46.0, 59.1, 64.7, 107.7, 110.6, 127.3, 127.4, 128.4,
46.0, 59.6, 71.2, 126.6, 126.7, 127.2, 128.4, 128.5, 128.6, 129.0, 129.3,
130.7, 134.0, 134.5, 135.6, 137.8, 138.7, 169.5, 180.6; HRMS (ESI): m/z
[MþNa]þ calcd for C27H25ClN2NaO2S: 499.1223, found: 499.1226;
129.0, 129.3, 130.7, 134.3, 138.1, 142.4, 152.6, 167.4, 180.6; HRMS (ESI):
m/z [MþNa]þ calcd for C23H21ClN2NaO3S: 463.0859, found: 463.0859;
[
a
]
2D5 ꢀ308.22 (c 1.0, CHCl3).
[a
]
25 ꢀ161.27 (c 1.0, CHCl3).
D
4.2.19. 3-(4-Chlorophenyl)-(R)-5-((S)-(1-benzyl-1H-indol-3-yl)(hyd-
roxy)methyl)-1-((S)-1-phenylethyl)-2-thioxotetrahydropyrimidin-
4(1H)-one, 15b. Rf (30% EtOAc/Hexane) 0.29; white solid; mp
4.2.24. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hydroxy)
methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyri-
midin-4(1H)-one, 23b. Rf (30% EtOAc/Hexane) 0.37; white solid;
mp 188e190 ꢁC; yield 81% (0.60 g); 1H NMR (400 MHz, CDCl3):
231e233 ꢁC; yield 51% (0.46 g); 1H NMR (400 MHz, CDCl3):
d 1.38
(d, 3H, J¼7.0 Hz), 2.86e2.93 (m, 1H), 3.15e3.21 (m, 1H), 3.47e3.50
(m, 1H), 3.63 (d, 1H, J¼2.8 Hz), 5.05 (m, 1H), 5.23 (m, 2H), 6.64 (s,
1H), 6.88 (q, 1H, J¼7.0 Hz), 7.04e7.32 (m, 15H), 7.44 (d, 2H,
d
1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.18 (d, 1H,
J¼4.9 Hz), 2.79 (d, 1H, J¼6.6 Hz), 3.60 (q, 1H, J¼6.6 Hz), 3.94 (dd,
1H, J¼5.0 Hz, J¼6.5 Hz), 6.50e6.53 (m, 2H), 7.08e7.16 (m, 3H),
7.29e7.35 (q, 1H, J¼7.3 Hz), 7.43e7.51 (m, 6H), 7.64 (m, 2H); 13C
J¼8.8 Hz), 7.66 (d, 1H, J¼8.0 Hz), 13C NMR (100 MHz, CDCl3):
d 14.9,
41.7, 47.0, 50.0, 59.1, 66.8, 110.2, 113.6, 119.7, 120.2, 122.6, 125.7,
126.7, 127.0, 127.5, 127.9, 128.2, 128.8, 128.9, 129.3, 130.7, 134.4,
137.0, 137.1, 138.0, 138.1, 169.6, 180.6; HRMS (ESI): m/z [MþNa]þ
NMR (100 MHz, CDCl3): d 16.1, 21.0, 49.3, 53.3, 59.2, 71.7, 127.7,
128.5, 128.8, 129.1, 129.2, 129.3, 134.1, 134.2, 138.8, 139.1, 140.1,
165.7, 180.5; HRMS (ESI): m/z [MþNa]þ calcd for

V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
1753
25
C26H24Cl2N2NaO2S: 521.0833, found: 521.0833; [
1.0, CHCl3).
a]
ꢀ186.51 (c
163.8, 165.3, 179.5; HRMS (ESI): m/z [MþNa]þ calcd for
D
C27H23ClFN3NaO2S: 530.1081, found: 530.1081; [
CHCl3).
a
]
2D5 ꢀ207.19 (c 1.0,
4.2.25. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-chlorophenyl)(hy-
droxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahyd-
ropyrimidin-4(1H)-one, 24b. Rf (30% EtOAc/Hexane) 0.32; white
solid; mp 192e193 ꢁC; yield 88% (0.69 g); 1H NMR (400 MHz,
4.2.30. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hy-
droxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahyd-
ropyrimidin-4(1H)-one, 29b. Rf (30% EtOAc/Hexane) 0.31; white
solid; mp 204e205 ꢁC; yield 82% (0.61 g); 1H NMR (400 MHz,
CDCl3):
d
1.50 (d, 3H, J¼6.3 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.01 (s, 1H),
2.79 (d, 1H, J¼5.8 Hz), 3.67 (q, 1H, J¼6.6 Hz), 3.87 (m, 1H), 6.57 (d,
2H, J¼8.4 Hz), 7.16 (d, 2H, J¼8.4 Hz), 7.22e7.27 (m, 1H), 7.37e7.50
(m, 4H), 7.63e7.66 (m, 2H). 7.75 (d, 2H, J¼8.2 Hz); 13C NMR
CDCl3):
d
1.48 (d, 3H, J¼6.7 Hz), 1.72 (d, 3H, J¼7.3 Hz), 2.00 (d, 1H,
J¼4.6 Hz), 2.79 (d, 1H, J¼6.2 Hz), 3.62 (q, 1H, J¼6.7 Hz), 3.87e3.90
(m, 1H), 6.57e6.61 (m, 2H), 6.83e6.88 (m, 2H), 7.09e7.38 (m, 4H),
7.46e7.48 (m, 3H), 7.62e7.65 (m, 2H); 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d 16.1, 21.0, 49.7, 55.1, 59.2, 72.0, 113.0, 115.7,
127.0, 127.5, 128.5, 129.0, 129.3, 129.4, 134.1, 134.4, 137.0, 138.5,
d 16.1, 21.0, 49.4, 55.2, 59.3, 71.9, 115.5, 115.7, 116.6, 116.9, 128.1,
140.0, 145.0, 165.0, 179.5; HRMS (ESI): m/z [MþNa]þ calcd for
128.2, 128.6, 129.1, 129.2, 136.6, 139.1, 161.3, 163.8, 165.6, 180.4;
25
C27H23Cl2N3NaO2S: 546.0786, found: 546.0781; [
a
]
ꢀ208.19 (c
HRMS (ESI): m/z [MþNa]þ calcd for C26H23ClF2N2NaO2S: 523.1035,
D
1.0, CHCl3).
found: 523.1033; [
a
]
25 ꢀ186.31 (c 1.0, CHCl3).
D
4.2.26. 3-(3-Chloro-4-fluorophenyl)-(R)-5-((S)-(4-chlorophenyl)(hy-
droxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahy-
dropyrimidin-4(1H)-one, 25b. Rf (30% EtOAc/Hexane) 0.32; white
solid; mp 225e226 ꢁC; yield 85% (0.65 g); 1H NMR (400 MHz,
4.2.31. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4-
fluorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-
2-thioxotetrahydropyrimidin-4(1H)-one, 30b. Rf (30% EtOAc/Hex-
ane) 0.31; white solid; mp 224e225 ꢁC; yield 85% (0.70 g); 1H NMR
CDCl3):
d
1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.08 (s, 1H),
(400 MHz, CDCl3):
d
1.51 (d, 3H, J¼6.6 Hz), 1.73 (d, 3H, J¼7.1 Hz),
2.79 (d, 1H, J¼6.3 Hz), 3.62 (q, 1H, J¼6.6 Hz), 3.90 (m, 1H), 6.54 (d,
2.05 (s, 1H), 2.82 (d, 1H, J¼6.0 Hz), 3.62 (q,1H, J¼6.4 Hz), 3.90 (d, 1H,
J¼5.5 Hz), 6.59e6.63 (m, 2H), 6.85e6.89 (m, 2H), 7.17e7.48 (m, 6H),
7.59 (d, 1H, J¼8.2 Hz), 7.64e7.66 (m, 2H); 13C NMR (100 MHz,
CDCl3): 14.1, 16.1, 49.5, 55.3, 59.3, 71.9, 115.5, 115.7, 127.0, 128.0,
128.1, 128.6, 129.0, 129.1, 129.2, 132.0, 137.5, 139.0, 161.3, 163.8,
2H, J¼8.4 Hz), 7.13e7.34 (m, 6H), 7.47e7.52 (m, 3H), 7.62e7.66 (m,
2H); 13C NMR (100 MHz, CDCl3):
d 16.1, 21.0, 49.4, 55.3, 59.3, 71.8,
116.6, 121.3, 127.6, 128.6, 128.9, 129.2, 129.2, 134.3, 136.5, 136.6,
139.1, 140.2, 156.5, 159.0, 165.3, 180.4; HRMS (ESI): m/z [MþNa]þ
25
calcd for C26H23Cl2FN2NaO2S: 539.0739, found: 539.0739; [
a]
165.6, 180.0; HRMS (ESI): m/z [MþNa]þ calcd for
D
25
ꢀ182.91 (c 1.0, CHCl3).
C27H23ClF4N2NaO2S: 573.1003, found: 573.1002; [
1.0, CHCl3).
a
]
ꢀ182.32 (c
D
4.2.27. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(R)-5-((S)-(4-
chlorophenyl)(hydroxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-
2-thioxotetrahydropyrimidin-4(1H)-one, 26b. Rf (30% EtOAc/Hex-
ane) 0.37; white solid; mp 118e120 ꢁC; yield 84% (0.71 g); 1H NMR
4.2.32. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hydroxy)
methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropy-
rimidin-4(1H)-one, 35a. Rf (30% EtOAc/Hexane) 0.29; white solid;
mp 203e204 ꢁC; yield 83% (0.62 g); 1H NMR (400 MHz, CDCl3):
(400 MHz, CDCl3):
2.07 (s, 1H), 2.79 (d, 1H, J¼6.2 Hz), 3.62 (q, 1H, J¼6.9 Hz), 3.89 (s,
1H), 6.52 (d, 2H, J¼8.4 Hz), 7.13e7.16 (m, 2H), 7.24e7.30 (m, 2H),
d
1.49 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz),
d
0.58 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.1 Hz), 2.75 (s, 1H), 2.79 (d,
1H, J¼7.9 Hz), 3.48 (q, 1H, J¼6.7 Hz), 4.85 (d, 1H, J¼5.0 Hz, J¼5.5 Hz),
7.42e7.65 (m, 7H); 13C NMR (100 MHz, CDCl3):
d 16.1, 21.1, 49.5,
7.09e7.15 (m, 2H), 7.25e7.40 (m, 8H), 7.41e7.43 (m, 4H); 13C NMR
55.2, 59.3, 71.9, 121.1, 123.8, 127.6, 128.6, 128.9, 129.2, 129.3, 132.0,
(100 MHz, CDCl3): d 15.6, 19.6, 49.3, 54.1, 59.0, 72.3, 128.4, 128.6,
134.4, 138.9, 139.0, 140.1, 165.5, 180.1; HRMS (ESI): m/z [MþNa]þ
128.9, 129.3, 129.5, 130.3, 134.2, 135.1, 137.9, 138.6, 139.0, 166.1,
25
calcd for C27H23Cl2F3N2NaO2S: 589.0707, found: 589.0708; [
a]
179.6; HRMS (ESI): m/z [MþNa]þ calcd for C26H24Cl2N2NaO2S:
D
ꢀ166.03 (c 1.0, CHCl3).
521.0833, found: 521.0833; [
a
]
25 ꢀ229.57 (c 1.0, CHCl3).
D
4.2.28. 3-(4-Chlorophenyl)-(R)-5-((S)-(4-fluorophenyl)(hydroxy)
methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropy-
rimidin-4(1H)-one, 27b. Rf (30% EtOAc/Hexane) 0.28; white solid;
mp 169e170 ꢁC; yield 82% (0.59 g); 1H NMR (400 MHz, CDCl3):
4.2.33. 3-(3-Chloro-4-cyanophenyl)-(S)-5-(R)-(4-chlorophenyl(hydr-
oxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydro-
pyrimidin-4(1H)-one, 36a. Rf (30% EtOAc/Hexane) 0.22; white
solid; mp 188e190 ꢁC; yield 81% (0.63 g); 1H NMR (400 MHz,
d
1.50 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.12 (d, 1H, J¼4.8 Hz),
CDCl3):
d
0.61 (d, 3H, J¼6.7 Hz), 1.61 (d, 3H, J¼7.1 Hz), 2.45 (s, 1H),
2.81 (d, 1H, J¼6.5 Hz), 3.60 (q, 1H, J¼6.6 Hz), 3.94 (m, 1H), 6.58 (m,
2H), 6.86 (m, 2H), 7.20e7.30 (m, 2H), 7.31 (q, 1H, J¼7.3 Hz),
7.43e7.51 (m, 5H), 7.63e7.65 (m, 2H); 13C NMR (100 MHz, CDCl3):
2.97 (d, 1H, J¼7.1 Hz), 3.44e3.49 (m, 1H), 3.59 (d, 1H, J¼6.7 Hz), 4.91
(d, 1H, J¼7.0 Hz), 7.09 (q, 1H, J¼7.0 Hz), 7.35e7.46 (m, 11H), 7.82 (d,
1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3):
d 15.5, 19.7, 49.8, 55.2,
d
16.1, 21.0, 49.3, 55.4, 59.3, 71.7, 115.5, 128.1, 128.2, 128.6, 129.1,
58.93, 72.8, 115.1, 115.7, 128.3, 128.4, 128.7, 129.0, 129.1, 129.3, 129.6,
134.1, 135.3, 137.2, 137.6, 139.0, 144.8, 165.6, 178.6; HRMS (ESI): m/z
[MþNa]þ calcd for C27H23Cl2N3NaO2S: 546.0786, found: 546.0786;
129.2, 129.9, 131.3, 134.1, 137.5, 138.8, 139.1, 161.3, 163.7, 165.7, 180.5;
HRMS (ESI): m/z [MþNa]þ calcd for C26H24ClFN2NaO2S: 505.1129,
found: 505.1129; [
a]
2D5 ꢀ185.31 (c 1.0, CHCl3).
[a
]
2D5 ꢀ217.88 (c 1.0, CHCl3).
4.2.29. 3-(3-Chloro-4-cyanophenyl)-(R)-5-((S)-(4-fluorophenyl)(hy-
droxy)methyl)-(S)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahyd-
ropyrimidin-4(1H)-one, 28b. Rf (30% EtOAc/Hexane) 0.19; white
solid; mp 177e178 ꢁC; yield 86% (0.65 g); 1H NMR (400 MHz,
4.2.34. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-chlorophenyl)(hy-
droxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahy-
dropyrimidin-4(1H)-one, 37a. Rf (30% EtOAc/Hexane) 0.32; white
solid; mp 179e180 ꢁC; yield 84% (0.62 g); 1H NMR (400 MHz,
CDCl3):
d
1.50 (d, 3H, J¼6.7 Hz), 1.75 (d, 3H, J¼7.3 Hz), 1.94 (d, 1H,
CDCl3):
d
0.61 (d, 3H, J¼6.7 Hz), 1.73 (d, 3H, J¼7.3 Hz), 2.08 (s, 1H),
J¼4.4 Hz), 2.81 (d, 1H, J¼5.8 Hz), 3.62 (q, 1H, J¼6.8 Hz), 3.86 (m, 1H),
6.61e6.65 (m, 2H), 6.88 (t, 2H, J¼8.6 Hz), 7.23e7.28 (m, 2H),
7.42e7.50 (m, 4H), 7.64e7.66 (m, 2H), 7.74e7.77 (m, 1H); 13C NMR
2.79 (d, 1H, J¼6.3 Hz), 3.62 (q, 1H, J¼6.6 Hz), 3.90 (m, 1H), 6.54 (d,
2H, J¼8.4 Hz), 7.13e7.34 (m, 6H), 7.47e7.52 (m, 3H), 7.62e7.66 (m,
2H); 13C NMR (100 MHz, CDCl3):
d 16.1, 21.0, 49.4, 55.3, 59.3, 71.8,
(100 MHz, CDCl3):
128.0, 128.1, 128.5, 129.2, 134.1, 137.2, 137.5, 137.6, 138.9, 145.0, 161.4,
d
16.1, 21.0, 49.7, 55.2, 59.2, 72.1, 113.1, 115.7,
116.6, 121.3, 127.6, 128.6, 128.9, 129.2, 129.3, 134.3, 136.5, 136.6,
139.1, 140.2, 156.5, 159.0, 165.3, 180.4; HRMS (ESI): m/z [MþNa]þ

1754
V. Kumar et al. / Tetrahedron 69 (2013) 1747e1754
25
calcd for C26H23Cl2FN2NaO2S: 539.0739, found: 539.0739; [
ꢀ206.89 (c 1.0, CHCl3).
a
]
128.4, 128.9, 129.0, 129.1, 132.0, 136.3, 136.4, 137.7, 138.7, 164.3, 166.1,
D
179.1; HRMS (ESI): m/z [MþNa]þ calcd for C27H23ClF4N2NaO2S:
573.1003, found: 573.1003; [
a]
2D5 ꢀ235.97 (c 1.0, CHCl3).
4.2.35. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-
chlorophenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-
2-thioxotetrahydropyrimidin-4(1H)-one, 38a. Rf (30% EtOAc/Hex-
ane) 0.35; white solid; mp 146e148 ꢁC; yield 82% (0.69 g); 1H NMR
Acknowledgements
The research funding from the Department of Science and
Technology, Government of India, and the National Single Crystal X-
ray Diffractometer facility at the Indian Institute of Technology
Bombay are gratefully acknowledged.
(400 MHz, CDCl3):
d
0.63 (d, 3H, J¼6.6 Hz), 1.61 (d, 3H, J¼7.1 Hz),
2.47 (d, 1H, J¼4.0 Hz), 3.00 (d, 1H, J¼7.4 Hz), 3.57 (q, 1H, J¼6.5 Hz),
4.90e4.93 (m,1H), 7.11 (q,1H, J¼7.0 Hz), 7.30e7.48 (m,11H), 7.59 (d,
1H, J¼8.4 Hz); 13C NMR (100 MHz, CDCl3):
d 15.6, 19.7, 49.5, 54.2,
59.1, 72.6, 128.1, 128.4, 128.9, 129.0, 129.2, 129.4, 129.6, 132.0, 132.2,
135.3, 135.5, 137.7, 138.7, 139.0, 166.0, 179.1; HRMS (ESI): m/z
[MþNa]þ calcd for C27H23Cl2F3N2NaO2S: 589.0707, found:
Supplementary data
25 ꢀ195.20 (c 1.0, CHCl3).
Crystallographic data for the compounds 5b0 and 23b have been
deposited with the Cambridge Crystallographic Data Centre, CCDC
No. 881433 and 881434, respectively. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk). Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2012.12.020.
589.0707; [
a
]
D
4.2.36. 3-(4-Chlorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hydroxy)
methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahydropyr-
imidin-4(1H)-one, 39a. Rf (30% EtOAc/Hexane) 0.32; white solid;
mp 175e176 ꢁC; yield 86% (0.62 g); 1H NMR (400 MHz, CDCl3):
d
0.60 (d, 3H, J¼6.7 Hz), 1.55 (d, 3H, J¼7.1 Hz), 2.52 (s, 1H), 2.99 (d,
1H, J¼8.1 Hz), 3.50 (q, 1H, J¼6.8 Hz), 4.88 (d, 1H, J¼8.0 Hz),
7.05e7.17 (m, 4H), 7.32e7.43 (m, 10H); 13C NMR (100 MHz, CDCl3):
References and notes
d
15.7, 19.6, 49.2, 54.2, 59.0, 72.3, 116.1, 128.4, 128.8, 129.0, 129.1,
129.3, 134.2, 136.3, 138.0, 138.6, 161.8, 164.3, 166.2, 179.5; HRMS
1. For a comprehensive discussion on aldol reactions see: (a) Heathcock, C. H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Elmsford, New York, 1991; Vol. 2, pp 133e238; (b) Kim, B. M.; Williams, S. F.;
Masamune, S. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Elmsford, New York, 1991; Vol. 2, pp 239e275.
(ESI): m/z [MþNa]þ calcd for C26H24ClFN2NaO2S: 505.1129, found:
505.1129; [
a]
2D5 ꢀ151.12 (c 1.0, CHCl3).
4.2.37. 3-(3-Chloro-4-cyanophenyl)-(S)-5-((R)-(4-fluorophenyl)(hy-
droxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahy-
dropyrimidin-4(1H)-one, 40a. Rf (30% EtOAc/Hexane) 0.19; white
solid; mp 134e135 ꢁC; yield 80% (0.61 g); 1H NMR (400 MHz,
2. Selected references (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127; (b) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc.
1989, 111, 5493; (c) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem.
Soc. 1990, 112, 2767; (d) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45,
7506.
3. (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117,
9073; (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991,
113, 1047; (c) Baldwin, S. W.; Chen, P.; Nikolic, N.; Weinseimer, D. C. Org. Lett.
2000, 2, 1193.
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) Mijasaka, T. H.; Tanaka, M.; Baba, H.; Hayakawa, R. T.;
Walker; Balzarini, J. E. J. Med. Chem. 1989, 32, 2507; (c) Mitsuya, H.; Yarchoan, R.;
Broder, S. Science 1990, 249, 1533; (d) Rahlan, R.; Kaur, J. Expert Opin. Ther. Pat.
2007, 17, 1061; (e) Baraldi, P. G.; Romagnoli, R.; Guadix, A. E.; de las Infantas, M. J.
P.; Gallo, M. A.; Espinosa, A.; Martinez, A.; Bingham, J. P.; Hartley, J. A. J. Med.
Chem. 2002, 45, 3630; (f) Yutaka, S.; Fujita, T.; Hiroi, S.; Hirayama, M.; Kaku, K.
Curr. Med. Res. Opin. 2012, 27, 1781.
5. (a) Kumar, V.; Pal, A.; Khatik, G. L.; Nair, V. A. Tetrahedron: Asymmetry 2012, 23,
434; (b) Kumar, V.; Raghavaiah, P.; Mobin, S. M.; Nair, V. A. Org. Biomol. Chem.
2010, 8, 4960; (c) Kumar, V.; Khatik, G. L.; Nair, V. A. Synlett 2011, 2997; (d)
Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966; (e) Khatik, G. L.; Pal, A.;
Mobin, S. M.; Nair, V. A. Tetrahedron Lett. 2010, 51, 3654; (f) Khatik, G. L.;
Khurana, R.; Kumar, V.; Nair, V. A. Synthesis 2011, 3123; (g) Kumar, V.; Khatik, G.
L.; Pal, A.; Praneeth, M. R.; Bhattarai, S.; Nair, V. A. Synlett 2012, 2357; (h) Khatik,
G. L.; Kumar, V.; Nair, V. A. Org. Lett. 2012, 14, 2442; (i) Chauhan, M.; Sharma, R.;
Nair, V. A. Org. Lett. 2012, 14, 5672.
CDCl3):
d
0.61 (d, 3H, J¼6.7 Hz), 1.60 (d, 3H, J¼7.3 Hz), 2.34 (s, 1H),
2.99 (d, 1H, J¼7.3 Hz), 3.58 (q, 1H, J¼6.7 Hz), 4.91 (d, 1H, J¼7.3 Hz),
7.07e7.18 (m, 4H), 7.35e7.45 (m, 8H), 7.74 (d, 1H, J¼8.3 Hz); 13C
NMR (100 MHz, CDCl3): d 15.5,19.7, 49.7, 54.3, 58.9, 72.7,113.1,115.7,
116.3, 116.5, 128.4, 128.8, 128.8, 128.9, 129.0, 134.1, 134.4, 137.2,
144.8, 161.8, 165.7, 178.6; HRMS (ESI): m/z [MþNa]þ calcd for
C27H23ClFN3NaO2S: 530.1081, found: 530.1081; [
CHCl3).
a
]
2D5 ꢀ253.44 (c 1.0,
4.2.38. 3-(3-Chloro-4-fluorophenyl)-(S)-5-((R)-(4-fluorophenyl)(hy-
droxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thioxotetrahy-
dropyrimidin-4(1H)-one, 41a. Rf (30% EtOAc/Hexane) 0.29; white
solid; mp 171e172 ꢁC; yield 80% (0.60 g); 1H NMR (400 MHz,
CDCl3):
d
0.62 (d, 3H, J¼6.7 Hz), 1.58 (d, 3H, J¼7.1 Hz), 2.39 (s, 1H),
3.01 (d, 1H, J¼7.7 Hz), 3.46e3.56 (m, 1H), 4.91 (d, 1H, J¼5.3 Hz),
7.11e7.25 (m, 5H), 7.30e7.45 (m, 8H); 13C NMR (100 MHz, CDCl3):
d
15.6, 19.7, 49.3, 54.3, 59.1, 72.4, 116.3, 116.4, 116.7, 116.9, 128.4,
6. Energy calculations were performed using the Gaussian 03 program package:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheese-
man, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J.
M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.;
Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J.
V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Re-
vision E.01; Gaussian: Wallingford CT, 2004.
128.9, 129.0, 129.1, 136.3, 136.4, 137.8, 166.1, 179.4; HRMS (ESI): m/z
[MþNa]þ calcd for C26H23ClF2N2NaO2S: 523.1035, found: 523.1035;
[
a]
2D5 ꢀ236.56 (c 1.0, CHCl3).
4.2.39. 3-(4-Chloro-3-(trifluoromethyl)phenyl)-(S)-5-((R)-(4-fluoro
phenyl)(hydroxy)methyl)-(R)-6-methyl-1-((S)-1-phenylethyl)-2-thio-
xotetrahydropyrimidin-4(1H)-one, 42a. Rf (30% EtOAc/Hexane) 0.32;
1
white solid; mp 174e175 ꢁC; yield 85% (0.66 g); H NMR (400 MHz,
CDCl3):
d
0.62 (d, 3H, J¼6.6 Hz),1.59 (d, 3H, J¼7.1 Hz), 2.35 (s, 1H), 2.99
(d, 1H, J¼7.6 Hz), 3.55 (q, 1H, J¼6.6 Hz), 4.91 (d, 1H, J¼7.6 Hz),
7.07e7.19 (m, 4H), 7.34e7.439 (m, 8H), 7.58 (d, 1H, J¼8.4 Hz); 13C NMR
(100 MHz, CDCl3):
d 15.6, 19.7, 49.5, 54.3, 59.1, 75.26, 116.3, 116.5,