Diastereoselective syntheses of 3-aryl-5-(arylalkyl)-6-methyl-1-(1- phenylethyl)thioxotetrahydropyrimidin-4(1H)-ones: A stereochemical perspective from endo and exocyclic chiral centres

Article abstract of DOI:10.1039/c0ob00230e

Diastereoselective syntheses of 3-aryl-(S/R)-6-methyl-1-[(S/R)-1- phenylethyl)]-2-thioxotetrahydro pyrimidin-4(1H)-ones were achieved in good yields by the condensation of aryl isothiocyanates with ethyl 3-(1-phenylethylamino)butanoate in a one-pot reaction. Benzylation of these substrates illustrated that the orientations of the exocylic and endocylic groups determine the stereochemical outcome of the product formed.

Full text of DOI:10.1039/c0ob00230e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Diastereoselective syntheses of 3-aryl-5-(arylalkyl)-6-methyl-1-(1-
phenylethyl)thioxotetrahydropyrimidin-4(1H)-ones: A stereochemical
perspective from endo and exocyclic chiral centres†
Varun Kumar,a Pallepogu Raghavaiah,b Shaikh M. Mobinc and Vipin A. Nair*a
Received 8th June 2010, Accepted 4th August 2010
DOI: 10.1039/c0ob00230e
Diastereoselective syntheses of 3-aryl-(S/R)-6-methyl-1-[(S/R)-1-phenylethyl)]-2-thioxotetrahydro
pyrimidin-4(1H)-ones were achieved in good yields by the condensation of aryl isothiocyanates with
ethyl 3-(1-phenylethylamino)butanoate in a one-pot reaction. Benzylation of these substrates illustrated
that the orientations of the exocylic and endocylic groups determine the stereochemical outcome of the
product formed.
sen for benzylation reaction. Ethylacetoacetate 1, when reacted
with (S)-a-methyl benzyl amine 2a in presence of zirconium
Introduction
The importance of chirality in biological properties paved the
tetrachloride gave the corresponding enamines 3a and 3b,
path for continued interest and substantial efforts on asymmetric
which were subsequently reduced with sodium triacetoxyboro-
synthesis, particularly in the induction of organocatalysts, chiral
auxiliaries, heterogenous catalysts as well as metal and bio cata-
lysts, facilitating the syntheses of various chiral building blocks.1 3-
Aryl-2-thioxotetrahydropyrimidin-4-ones are well known hetero-
cyclic compounds which are extensively used in agrochemical and
hydride to afford the diastereomers, (S/R)-ethyl 3-[(S)-1-
phenylethylamino]butanoates7 4a and 4b, in quantitative yields
(Scheme 1). The mixture of b-aminoesters obtained from the
above step was treated with 2-chloro-4-isothiocyanatobenzonitrile
5a in presence of triethyl amine and lithium perchlorate under
reflux condition in acetonitrile8 to afford 3-(3-chloro-4-cyano-
phenyl)-(S/R)-6-methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahy-
dropyrimidin-4(1H)-ones 6a and 6b (Scheme 2) in a ratio of
2 : 1, with good yields (Table 1). Reaction with (R)-a-methyl
benzylamine 2b, also proceeded with the same diastereoselectivity
affording the isomers 6c and 6d. Our efforts were then directed
to determine the absolute configurations of the diastereomers.
Molecules containing stereogenic centres with fixed configurations
adjacent to a chiral centre with unknown stereochemistry facilitate
the prediction of absolute configuration by NMR studies with ease
and accuracy.9 The chiral centre Ca attached to N1 would serve
a similar purpose, assisting in the prediction of stereochemical
configuration at the chiral centre C6, provided the anisotropy
experienced by the methyl group and the proton at C6 from
the phenyl ring at Ca is different for the diastereomers. The
characterization of the diastereomers, 6a–6d was made on the basis
of chemical shifts and the inference drawn from COSY, DEPT-
135, HSQC and HMBC experiments. The methyl groups at the
chiral centre Ca and C6, distinguished on the basis of correlation
spectra, were identified at 1.75 and 1.47 ppm respectively for 6a
and at 1.67 and 0.74 ppm respectively for 6b. The proton at C6
resonated at d values of 3.76 and 3.96 ppm respectively for the
diastereomers 6a and 6b, which indicated that the proton at C6 is
in the ring current of the phenyl group for the diastereomer 6a.
Apparently, the methyl group at C6 for the diastereomer 6b
experienced an anisotropic effect from the phenyl ring with a
consequent upfield shift to 0.74 ppm from 1.47 ppm observed
for the diastereomer 6a (Fig. 1). Based on the spatial orientations
of groups at the chiral centre Ca, three different conformations
are possible for each of the diastereomers. The total energy
for each conformation of the diastereomer 6a was calculated
pharmaceutical research. They are found to be potent for treating
atherosclerotic conditions such as dyslipoproteinemias and coro-
nary heart disease.2 These compounds also exhibit anticancer, an-
tibacterial and insecticidal properties.3,4 3-aryl dihydrothiouracils
are proven for their herbicidal and anticonvulsant activities.5
Although various methods are known for the synthesis of 1-alkyl-
3-aryl-2-thioxotetrahydropyrimidin-4(1H)-ones,6 pharmaceutical
effects of its derivatives have not been explored yet. Our interests
were mainly focused to examine the influence of endocyclic and
exocylic groups in the stereoselective benzylation of 3-aryl-2-
thioxotetrahydropyrimidin-4-one derivatives.
Results and discussion
We herein report the diastereoselective benzylation of 3-aryl-
(S/R)-6-methyl-1-[(S/R)-1-phenylethyl]-2-thioxotetrahydropy-
rimidin-4(1H)-ones where the exocyclic chiral substituent at N1
and the endocyclic methyl group at C6 transmit a combined
effect to impose the stereochemical orientation of the electrophile
incorporated at position 5, adjacent to a carbonyl carbon.
As a model reaction, 3-(3-chloro-4-cyanophenyl)-6-methyl-1-(1-
phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-one 6 was cho-
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, Mohali, Punjab 160 062, India. E-mail:
vn74nr@yahoo.com; Tel: +91-172-2292045
bNational Single Crystal X-ray Diffractometer Facility, School of Chemistry,
University of Hyderabad, Hyderabad 500 046, India
cNational Single Crystal X-ray Diffraction Facility, Indian Institute of
Technology Bombay, Powai, Mumbai 400 076, India
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds. CCDC reference numbers 772207–772210. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00230e
using PM3 Hamiltonian after optimization by MM2 method.10
A
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Scheme 1 Syntheses of (S/R)-ethyl 3-[(S/R)-1-phenylethylamino]butanoates.
Scheme 2 Syntheses of 3-aryl-(S/R)-6-methyl-1-[(S/R)-1-phenylethyl)]-2-thioxotetrahydropyrimidin-4(1H)-ones.
3-dimensional structural representation corresponding to the most
stable conformation of the diastereomer 6a indicated that the
proton at C6 is in anisotropy with the phenyl ring at the chiral
centre Ca while the methyl group did not experience any such
effect (Fig. 2), which is in accordance with the NMR spectra,
and hence an SS configuration can be fairly assigned. A similar
computational study for the three possible conformations of the
diastereomer 6b revealed the most stable conformation and the
corresponding 3-dimensional structural representation showed
that the methyl group at C6 is in anisotropy with the phenyl
group at Ca, as concluded from the NMR studies, and hence
an SR configuration could be assigned for the diastereomer 6b.
Thus the chiral centre at Ca assisted not only in the separation of
the diastereomers but also in predicting the stereochemistry in an
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Fig. 1 Expanded 1H NMR spectra of the diastereomers 6a and 6b.
Table 1 Syntheses of 3-aryl-(S/R)-6-methyl-1-[(S)-1-phenylethyl)]-2-
thioxotetrahydropyrimidin-4(1H)-ones
Entry R1
R2
Time/h
Product
Yield (%)
Ratio (a:b)a
1
2
3
4
CN
F
Cl
H
Cl
Cl
H
NO2
3
3
3
3
6a,6b
7a,7b
8a,8b
9a,9b
73
78
80
77
2 : 1
2 : 1
2 : 1
2 : 1
a Ratio calculated from isolated yields.
Fig. 4 ORTEP diagram of the diastereomer 6d.
of an electrophile and the ensuing diastereoselectivity, 3-(3-
chloro-4-cyanophenyl)-6(S)-methyl-1-[(S)-1-phenylethyl]-2-thio-
xotetrahydropyrimidin-4(1H)-one 6a was enolized using the
lithium base LHMDS at -78 ◦C and subsequently treated with
4-chlorobenzylbromide to afford the corresponding benzylated
product (Scheme 3). The incorporation of the methyl group
led to diastereospecificity in the reaction; the chiral centre Ca
remaining fixed, the methyl group at C6 influenced the stereos-
electivity of the substitution at C5, forming the product 6ai ex-
clusively, whereas the substrate 3-(3-chloro-4-cyanophenyl)-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one 10 which
lacked the methyl group at C6 afforded the mixture of monoben-
zylated diastereomers 10b and 10c, along with the dibenzylated
product 10a. The DEPT-135 experiment for the diastereomer 6ai
displayed a signal at 30.37 ppm corresponding to the benzylic
carbon with the chemical shifts of the attached protons at 2.60 and
3.24 ppm, as revealed by the correlation obtained from HMQC
and COSY spectra.
Fig. 2 Most stable conformation of the diastereomers 6a and 6b.
unambiguous manner; the energy calculations and NMR analyses
corroborated the conclusions drawn.
Finally, the structural confirmation was made from the single
crystal X-ray structure of 6a (Fig. 3) which proved an SS
configuration with a conformation identical to that proposed.
Similar analyses set forth for the isomers 6c and 6d led to the
assignment of RR and RS configurations respectively and a
structural affirmation from single crystal X-ray analysis for the
isomer 6d (Fig. 4) substantiated our conclusion.
The absolute configuration at the newly generated chiral centre
C5 was deduced from the coupling constant. A mutiplet was
observed for the proton at C6, while the methyl group appeared
as a doublet for the diastereomer 6ai. Irradiation of the methyl
protons at C6 to decouple, displayed a coupling constant of
4.56 Hz; demonstrating a syn relation between the two vicinal
protons at C5 and C6 (Fig. 5). The absolute configuration at C5
can thus be fairly concluded as R, since the configurations at
Ca and C6 were already known from the established structure of
6a. Based on these assumptions, the overall configuration of the
molecule is expected to be SRS at the chiral centres Ca, C5 and
C6 respectively. The absolute configuration was finally confirmed
Fig. 3 ORTEP diagram of the diastereomer 6a.
To comprehend the influences collectively exerted by the
exocyclic chiral substituent and the endocyclic methyl group
in determining the p-facial selectivity during the approach
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Scheme 3 Syntheses of 10a–10c, 6ai–9ai and 6ci.
Fig. 5 Vicinal coupling of the protons at C5 and C6 for the diastereomer
6ai.
by single crystal X-ray analysis and the ORTEP diagram of
the product 6ai is shown in Fig. 6. The results of benzyla-
tion with various 2-thioxotetrahydropyrimidin-4-one analogues
(6a–9a) with SS configuration are listed in Table 2.
Fig. 6 ORTEP diagram of the diastereomer 6ai.
The diastereospecificity of the reaction can be explained on
the basis of a model proposed in Scheme 4. The lithium enolate
E1 has an E geometry due to the rigid skeleton and in this
conformationally locked position benzylation can occur either
from the re face (Path a) or from the si face (Path b) which can
afford the product A or B. The steric effects due to the methyl group
at C6 and the chiral substituent at N1 favoured the re approach of
the electrophile leading to the exclusive formation of the product
A. The proposed model justifies discrimination between the two
faces and the consequent perturbation in the approach of the
electrophile resulting in a diastereospecific reaction.
Table 2 Reactions
of
3-aryl-(S)-6-methyl-1-[(S)-1-phenylethyl)]-2-
thioxotetrahydropyrimidin-4(1H)-ones (6a–9a) with 4-chlorobenzyl
bromide
Entry
R1
R2
Base
Product/Yield(%)
de
1
2
3
4
CN
F
Cl
H
Cl
Cl
H
NO2
LHMDS
LHMDS
LHMDS
LHMDS
6ai/68
7ai/65
8ai/60
9ai/64
>99
>99
>99
>99
Benzylation of 6c, the enantiomer of 6a, at C5 using LHMDS
provided the corresponding enantiomeric product 6ci, as con-
firmed from the NMR studies and optical rotation. However
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Scheme 4 Proposed model for the diastereospecific formation of (5R,6S)-3-aryl-5-(4-chlorobenzyl)-6-methyl-1-[(S)-1-phenylethyl]-2-thioxotetra
hydropyrimidin-4(1H)-ones.
Table 3 Reactions
of
3-aryl-(R)-6-methyl-1-[(S)-1-phenylethyl)]-2-
benzylation of the isomer 6b with SR configuration exhibited
poor selectivity and a mixture of diastereomeric products 6bi
and 6bii was obtained in approximately equal amounts which is
indicative of the fact that the orientation of the methyl group
at C6 with respect to the chiral centre Ca plays a decisive role
in the product geometry (Scheme 5). For the diastereomers 6bi
and 6bii, the signals for the benzylic carbon were observed at
30.99 and 34.68 ppm respectively. To determine the absolute
configuration of the diastereomers 6bi and 6bii, methyl protons
at C6 were irradiated to decouple, and the relation between the
protons at C5 and C6 was deduced from the coupling constant;
the configurations at Ca and C6 were already known from the
structure of 6b. For the diastereomer 6bi decoupling of the
methyl protons showed a vicinal coupling constant of 4.56 Hz
indicative of the syn relation between the protons at C5 and C6
and hence the configuration at C5 can be fairly assigned as S
leading to an overall SSR configuration at the chiral centres Ca,
C5 and C6 respectively. For the diastereomer 6bii, the decoupling
of the methyl protons revealed lack of interaction between the
protons at C5 and C6, demonstrating an orthogonal relation
and hence an R configuration at the stereocentre C5 and an
SRR configuration for the molecule. The results of benzylation
on various 2-thioxotetrahydropyrimidin-4-one analogues (6b–9b)
with SR configuration are listed in Table 3.
thioxotetrahydropyrimidin-4(1H)-ones (6b–9b) with 4-chlorobenzyl
bromide
Entry R1 R2
Base
Product(bi+bii)/Yield (%) Ratio (bi:bii)a
1
2
3
4
CN Cl
LHMDS 6bi,6bii/66
LHMDS 7bi,7bii/68
LHMDS 8bi,8bii/70
40 : 60
40 : 60
40 : 60
40 : 60
F
Cl
H
Cl
H
NO2 LHMDS 9bi,9bii/65
a Ratio calculated from isolated yields.
The reaction of the diasteroemer 6d with LHMDS followed by
the treatment with 4-chlorobenzylbromide afforded two diastere-
omers 6di and 6dii which were found to be the enantiomers of
6bi and 6bii, as identified from the NMR spectra and specific
rotations. The absolute configuration of the diastereomer 6di was
convincingly proved by the crystal structure, and the ORTEP
diagram is shown in Fig. 7.
A model similar to that proposed in Scheme 3, illustrates that
the enolate E2 can afford the products C (Path a) and D (Path b)
depending on the approach of electrophile from the re and si faces
respectively (Scheme 6). The orientation of the substituents at the
chiral centre Ca and the methyl group at C6 would demonstrate
that the enolate E2 experiences almost the same kind of steric
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Scheme 5 Syntheses of 6bi–9bi, 6bii–9bii, 6di and 6dii.
spectra were recorded on Finnigan Mat LCQ LCMS spectrometer
and HRMS were recorded on Bruker Maxis spectrometer. The
reactions were monitored by TLC (Merck). Evaporation of
solvents was performed under reduced pressure using a Buchi
rotary evaporator. Commercial grade reagents and solvents were
used without further purification.
General procedure for the syntheses of ethyl 3-(1-phenylethyl-
amino)butanoates (4a–4d). To ethyl acetoacetate (8.0 g,
61.47 mmol) taken in a RB flask was added ZrCl4 (0.2 g,
0.95 mmol) followed by (S)-a-methyl benzylamine (6.0 mL,
61.47 mmol) in a dropwise manner. Reaction mixture was stirred
at room temperature for 2 h and monitored by TLC. After
completion of the reaction, the reaction mixture was diluted
with DCM, washed with water (2 ¥ 25 mL), then with brine
(1 ¥ 25 mL), dried over anhydrous Na2SO4 and concentrated to
give a mixture of E and Z ethyl 3-[(S)-1-phenylethylamino]but-
2-enoates 3a and 3b as a colourless liquid (12.1 g, 84%). A
solution of NaBH(OAc)3 was prepared by adding NaBH4 (4.3 g,
113.20 mmol) to 30 mL of glacial acetic acid maintained between
15 to 20 ◦C. After the evolution of H2 had ceased the above mixture
of ethyl 3-(1-phenylethylamino)but-2-enoates (8.8 g, 37.74 mmol)
was added to it and the reaction mixture was stirred for 4 h at
RT. Evaporation of acetic acid in vacuum followed by dissolution
of the residue in DCM and subsequent washing with sodium
carbonate provided (S/R)-ethyl 3-[(S)-1-phenylethylamino] bu-
tanoates 4a and 4b, as mixture of diastereomers (2 : 1) (7.2 g, 82%)
which was used in the next step without separation. Reaction
with (R)-a-methyl benzylamine afforded (S/R)-ethyl 3-[(R)-1-
phenylethylamino]butanoates 4c and 4d, as a diastereomeric
mixture in the ratio 2 : 1.
Fig. 7 ORTEP diagram of the diastereomer 6di.
effects on both the faces, making it impossible for the approaching
electrophile to distinguish between the two faces; thus resulting in
a poor diasteroselectivity.
Conclusions
Benzylation reactions of the diastereomers of 3-aryl-6-methyl-1-
(1-phenylethyl)-2-thioxotetrahydropyrimidin-4(1H)-ones with SS
and RR configurations afforded diastereospecificity but the di-
astereomers with SR and RS configurations gave poor selectivity.
The absence of the methyl substituent at C6 resulted in the
formation of a mixture of diastereomers, while its presence dictated
the selectivity of the substitution at C5. A trans relation between
the substituents at C6 and N1 gave no stereochemical control
over the substitution, whereas the syn orientation afforded the
specificity; which provides a convincing evidence for the combined
effect exerted by the endo and exocyclic groups.
General procedure for the syntheses of N-aryl-2-thioxotetra-
hydropyrimidin-4-one derivatives (6a–6d, 7a–9a, 7b–9b). To a
solution of aryl isothiocyanate (2.57 mmol) in 30 mL ace-
tonitrile taken in a RB flask was added (S/R)-ethyl 3-[(S)-
1-phenylethylamino]butanoate (0.6 g, 2.57 mmol) followed by
triethylamine (0.4 mL, 3.08 mmol) and LiClO4 (10 mol%,
30 mg, 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 (2 ¥ 25 mL),
then with brine (1 ¥ 25 mL) and dried over anhydrous
Experimental section
1
The H and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively on a Bruker Avance 400 (400 MHz)
spectrometer in CDCl3 using TMS as an internal standard. The
1
chemical shifts (d) for H and 13C are given in ppm relative to
residual signals of the solvent. Coupling constants are given in Hz.
The following abbreviations are used to indicate the multiplicity: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Mass
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Scheme 6 Proposed model for the formation of (5S,6R)/(5R,6R)-3-aryl-5-(4-chlorobenzyl)-6-methyl-1-[(S)-1-phenylethylthioxotetrahydropyrimidin-
4(1H)-ones.
Na2SO4. Reaction mixture was concentrated and the diastere-
omers were separated by column chromatography on silica gel
(230–400) using hexane–ethyl acetate mixture (85 : 15) as the
eluent to obtain 3-aryl-(S/R)-6-methyl-1-[(S)-1-phenylethyl)]-2-
thioxotetrahydropyrimidin-4(1H)-ones which were recrystalized
from MeOH.
6.68 Hz), 1.67 (d, 3H, J = 7.00 Hz), 2.69 (dd, 1H), 2.95 (dd, 1H),
3.95 (m, 1H), 7.03 (q, 1H, J = 7.00 Hz), 7.22 (d, 1H, J = 8.08 Hz),
7.35–7.54 (m, 6H), 7.75 (d, 1H, J = 8.28 Hz); 13C NMR (100 MHz,
CDCl3): d 15.33, 18.26, 39.08, 45.97, 59.26, 113.10, 115.62, 128.30,
128.89, 128.92, 131.43, 134.01, 137.17, 137.28, 144.18, 165.55,
178.87; MS (APCI): [M+1]+ = 384.20; HRMS (ESI): m/z [M+Na]+
Calculated for C20H18ClN3OS: 406.0757, Found: 406.0762.
3-(3-Chloro-4-cyanophenyl)-6(S)-methyl-1-[(S)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (6a). White solid; Yield
48%; mp 218–220 ◦C; Rf 0.50 (7 : 3 hexane–EtOAc); [a]D -195.87
3-(3-Chloro-4-cyanophenyl)-6(R)-methyl-1-[(R)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (6c). White solid; Yield
50%; mp 218–220 ◦C; Rf 0.50 (7 : 3 hexane–EtOAc); [a]D +195.57
1
(c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d 1.47 (d, 3H,
1
J = 6.80 Hz), 1.75 (d, 3H, J = 7.20 Hz), 2.44–2.59 (m, 2H),
3.76 (m, 1H), 6.91 (q, 1H, J = 7.20 Hz), 7.22–7.46 (m, 7H), 7.75
(d, 1H, J = 8.00 Hz); 13C NMR (100 MHz, CDCl3): d 15.35,
19.50, 38.62, 46.42, 59.72, 113.07, 115.64, 127.04, 128.61, 128.90,
129.06, 131.50, 134.02, 137.13, 138.91, 144.28, 165.53, 179.53; MS
(APCI): [M+1]+ = 384.20; HRMS (ESI): m/z [M+Na]+ Calculated
for C20H18ClN3OS: 406.0757, Found: 406.0757.
(c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d 1.97 (d, 3H,
J = 6.80 Hz), 1.76 (d, 3H, J = 7.20 Hz), 2.45–2.60 (m, 2H),
3.77 (m, 1H), 6.92 (q, 1H, J = 7.20 Hz), 7.23–7.47 (m, 7H), 7.75
(d, 1H, J = 8.00 Hz); 13C NMR (100 MHz, CDCl3): d 15.32,
19.46, 38.62, 46.38, 59.73, 113.10, 115.53, 127.03, 128.28, 128.86,
129.03, 131.52, 133.92, 137.08, 138.99, 144.29, 165.40, 179.64; MS
(APCI): [M+1]+ = 384.20; HRMS (ESI): m/z [M+Na]+ Calculated
for C20H18ClN3OS: 406.0757, Found: 406.0766.
3-(3-Chloro-4-cyanophenyl)-6(R)-methyl-1-[(S)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (6b). White solid; Yield
25%; mp 179–181 ◦C; Rf 0.39 (7 : 3 hexane–EtOAc); [a]D -510.18
(c 1.000, CHCl3);1H NMR (400 MHz, CDCl3): d 0.74 (d, 3H, J =
3-(3-Chloro-4-cyanophenyl)-6(S)-methyl-1-[(R)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (6d). White solid; Yield
24%; mp 179–181 ◦C; Rf 0.39 (7 : 3 hexane–EtOAc); [a]D +510.97
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(c 1.000, CHCl3); 1H NMR (400 MHz, CDCl3): d 0.76 (d, 3H, J =
6.68 Hz), 1.67 (d, 3H, J = 7.00 Hz), 2.69 (dd, 1H), 2.95 (dd, 1H),
3.96 (m, 1H), 7.00–7.05 (q, 1H, J = 7.00 Hz), 7.22 (d, 1H, J =
8.08 Hz), 7.33–7.55 (m, 6H), 7.75 (d, 1H, J = 8.28 Hz); 13C NMR
(100 MHz, CDCl3): d 15.26, 18.21, 39.13, 45.96, 59.25, 113.12,
115.51, 128.27, 128.85, 131.44, 133.90, 137.10, 137.39, 144.21,
165.41, 179.01; MS (APCI): [M+1]+ = 384.20; HRMS (ESI):
m/z [M+Na]+ Calculated for C20H18ClN3OS: 406.0757, Found:
406.0759.
51%; mp 156–158 ◦C; Rf 0.44 (7 : 3 hexane–EtOAc); [a]D -175.33
(c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d 1.50 (d, 3H,
1
J = 6.40 Hz), 1.75 (d, 3H, J = 7.20 Hz), 2.45–2.62 (m, 2H),
3.77 (m, 1H), 6.95 (q, 1H, J = 7.20 Hz), 7.25–7.64 (m, 7H), 8.06
(s, 1H), 8.27 (m, 1H); 13C NMR (100 MHz, CDCl3): d 15.35,
19.50, 38.68, 46.41, 59.83, 123.23, 125.13, 127.06, 128.52, 129.03,
129.50, 136.09, 139.08, 140.63, 148.56, 165.82, 180.11; MS (APCI):
[M+1]+ = 370.13; HRMS (ESI): m/z [M+Na]+ Calculated for
C19H19N3O3S: 392.1045, Found: 392.1049.
3-(3-Chloro-4-fluorophenyl)-6(S)-methyl-1-[(S)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (7a). White solid; Yield
54%; mp 170–171 ◦C; Rf 0.66 (7 : 3 hexane–EtOAc); [a]D -168.20
(R)-6-Methyl-3-(3-nitrophenyl)-1-[(S)-1-phenylethyl]-2-thioxo-
tetrahydropyrimidin-4(1H)-one (9b). Light yellow solid; Yield
26%; mp 95–97 ◦C; Rf 0.35 (7 : 3 hexane–EtOAc); [a]D -439.55
1
(c 1.000, CHCl3); H NMR; (400 MHz, CDCl3): d 1.46 (d, 3H,
1
(c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d 0.79 (d, 3H,
J = 6.80 Hz), 1.76 (d, 3H, J = 7.20 Hz), 2.42–2.57 (m, 2H),
3.75 (m, 1H), 6.98 (q, 1H, J = 7.20 Hz), 7.07 (m, 1H), 7.21–
7.27 (m, 1H), 7.35–7.54 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 15.33, 19.41, 38.70, 46.27, 59.80, 116.55, 121.25, 127.04, 128.46,
128.98, 131.64, 135.89, 139.20, 156.53, 165.80, 180.49; MS (APCI):
[M+1]+ = 377.13; HRMS (ESI): m/z [M+Na]+ Calculated for
C19H18ClFN2OS: 399.0710, Found: 399.0714.
J = 6.68 Hz), 1.70 (d, 3H, J = 7.04 Hz), 2.72 (dd, 1H), 2.40–
3.00 (dd, 1H), 3.98 (m, 1H), 7.08 (q, 1H, J = 6.96 Hz), 7.34–
7.59 (m, 3H), 7.54–7.66 (m, 3H), 7.62–7.66 (t, 1H, J = 8.00 Hz),
8.06 (s, 1H), 8.30 (m, 1H); 13C NMR (100 MHz, CDCl3): d
15.33, 18.27, 39.14, 45.95, 59.31, 123.29, 128.33, 128.86, 129.50,
137.42, 140.50, 148.57, 165.85, 179.42; MS (APCI): [M+1]+
=
370.20; HRMS (ESI): m/z [M+Na]+ Calculated for C19H19N3O3S:
392.1045, Found: 392.1045.
3-(3-Chloro-4-fluorophenyl)-6(R)-methyl-1-[(S)-1-phenylethyl]-
2-thioxotetrahydropyrimidin-4(1H)-one (7b). White solid; Yield
24%; mp 140–142 ◦C, Rf 0.45 (7 : 3 hexane–EtOAc); [a]D -459.59
General procedure for the syntheses of 3-aryl-5-(4-chloroben-
zyl)-6-methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-
4(1H)-ones (6ai–6dii, 7ai–9ai, 7bi–9bi, 7bii–9bii). In a typical
experiment, 3-aryl-(S)-6-methyl-1-[(S)-1-phenylethyl]-2-thioxo-
tetrahydropyrimidin-4(1H)-one (0.70 mmol) dissolved in
1
(c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d 0.72 (d, 3H,
J = 6.68 Hz), 1.67 (d, 3H, J = 7.04 Hz), 2.67 (dd, 1H), 2.93 (dd,
1H), 3.92 (m, 1H), 7.03–7.08 (q, 2H, J = 6.92 Hz), 7.19–7.25 (m,
2H), 7.35–7.43 (m, 3H), 7.54 (d, 2H, J = 7.80 Hz); 13C NMR
(100 MHz, CDCl3): d 15.32, 18.16, 39.13, 45.83, 59.34, 116.61,
116.83, 121.26, 121.45, 128.32, 128.81, 135.75, 137.52, 156.52,
159.01, 165.89, 179.76; MS (APCI): [M+1]+ = 377.13; HRMS
(ESI): m/z [M+Na]+ Calculated for C19H18ClFN2OS: 399.0710,
Found: 399.0714.
◦
anhydrous THF (5 mL) and cooled to -78 C, was treated with
LHMDS (0.76 mL, 0.77 mmol, 1.0 M solution in THF) under
nitrogen atmosphere and stirred for 30 min. 4-chlorobenzyl-
bromide (0.16 g, 0.77 mmol) was added to the reaction mixture,
stirred for another 2 h, then quenched with saturated aq.
NH4Cl 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 3-aryl-(R)-5-(4-chlorobenzyl)-(S)-6-methyl-1-
[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one. Re-
actions of 3-aryl-(R)-6-methyl-1-[(S)-1-phenylethyl]-2-thioxote-
trahydropyrimidin-4(1H)-one afforded diastereomers of the
desired product which were separated by column chromatography
on silica gel (230–400 mesh) using hexane–ethyl acetate mixture
(90 : 10) as the eluent. The products were characterized by
analytical and spectral methods.
3-(4-Chlorophenyl)-6(S)-methyl-1-[(S)-1-phenylethyl]-2-thi-
oxotetrahydropyrimidin-4(1H)-one (8a). White solid; Yield 53%;
mp 177–179 ◦C; Rf 0.66 (7 : 3 hexane–EtOAc); [a]D -173.62 (c
1
1.000, CHCl3); H NMR (400 MHz, CDCl3): d 1.46 (d, 3H, J =
6.80 Hz), 1.74 (d, 3H, J = 7.20 Hz), 2.41–2.58 (m, 2H), 3.72 (m,
1H), 6.99 (q, 1H, J = 7.20 Hz), 7.13 (s, 1H), 7.25–7.46 (m, 8H); 13
C
NMR (100 MHz, CDCl3): d 15.34, 19.36, 38.72, 46.28, 59.71,
127.06, 128.42, 128.97, 129.26, 129.73, 134.19, 138.14, 139.28,
165.85, 180.65; MS (APCI): [M+1]+ = 359.07; HRMS (ESI):
m/z [M+Na]+ Calculated for C19H19ClN2OS: 381.0805, Found:
381.0808.
3-(4-Chlorophenyl)-6(R)-methyl-1-[(S)-1-phenylethyl]-2-thi-
oxotetrahydropyrimidin-4(1H)-one (8b). White solid; Yield 27%;
mp 76–78 ◦C; Rf 0.55 (7 : 3 hexane–EtOAc); [a]D -472.85 (c 1.000,
CHCl3); 1H NMR (400 MHz, CDCl3): d 0.76 (d, 3H, J = 6.64 Hz),
1.69 (d, 3H, J = 7.04 Hz), 2.66 (dd, 1H), 2.94 (dd, 1H), 3.93 (m,
1H), 7.08–7.16 (m, 3H), 7.36–7.43 (m, 5H), 7.53 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 15.25, 18.06, 39.24, 45.80, 59.20,
128.28, 128.66, 128.73, 129.17, 130.15, 134.16, 137.77, 138.09,
165.71, 180.12; MS (APCI): [M+1]+ = 359.13; HRMS (ESI):
m/z [M+Na]+ Calculated for C19H19ClN2OS: 381.0805, Found:
381.0804.
(5R,6S)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6ai). White solid; Yield 68%; mp 193–195 ◦C; Rf 0.35
1
(8 : 2 hexane–EtOAc); [a]D -325.33 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 1.32 (d, 3H, J = 6.68 Hz), 1.62 (d, 3H,
J = 7.12 Hz), 2.36 (dd, 1H), 2.76 (m, 1H), 3.24 (dd, 1H), 3.35
(m, 1H), 6.55 (d, 2H, J = 8.16 Hz), 6.87 (q, 1H, J = 7.12 Hz),
7.08 (d, 2H, J = 8.20 Hz), 7.22–7.43 (m, 7H), 7.76 (d, J =
8.28 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 14.30, 14.86, 30.38,
46.59, 47.79, 59.58, 113.15, 115.56, 127.11, 128.53, 128.95, 129.01,
129.17, 131.41, 134.76, 137.20, 138.72, 144.28, 167.90, 179.33; MS
(APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+ Calculated
for C27H23Cl2N3OS: 530.0837, Found: 530.0843.
(S)-6-Methyl-3-(3-nitrophenyl)-1-[(S)-1-phenylethyl]-2-thioxo-
tetrahydropyrimidin-4(1H)-one (9a). Light yellow solid; Yield
This journal is
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Org. Biomol. Chem., 2010, 8, 4960–4970 | 4967
©

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(5S,6R)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6bi). White solid; Yield 26%; mp 179–181 ◦C; Rf 0.45
J = 7.08 Hz), 2.89–3.04 (m, 3H), 3.69 (q, 1H, J = 6.72 Hz), 7.05–
7.15 (m, 2H), 7.17–7.19 (d, 2H, J = 8.40 Hz), 7.25–7.27 (s, 1H),
7.33–7.46 (m, 7H), 7.71–7.74 (d, 1H, J = 8.28 Hz); 13C NMR
(100 MHz, CDCl3): d 15.68, 19.38, 34.69, 48.82, 50.16, 58.94,
113.15, 115.54, 128.42, 128.96, 129.07, 129.24, 129.86, 131.38,
133.42, 134.08, 134.46, 137.24, 137.56, 144.29, 167.20, 178.12; MS
(APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+ Calculated
for C27H23Cl2N3OS: 530.0837, Found: 530.0846.
1
(8 : 2 hexane–EtOAc); [a]D -105.37 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 0.65 (d, 3H, J = 6.64 Hz), 1.46 (d, 3H, J =
7.00 Hz), 2.48 (dd, 1H), 3.08 (m, 1H), 3.38 (dd, 1H), 3.55 (m, 1H),
6.92 (q, 1H, J = 6.88 Hz), 7.13 (d, 2H, J = 8.28 Hz), 7.28 (d, 1H,
J = 7.88 Hz), 7.37 (m, 8H), 7.75 (d, 1H, J = 8.28 Hz); 13C NMR
(100 MHz, CDCl3): d 13.14, 15.22, 30.99, 47.97, 48.12, 59.22,
113.12, 115.57, 116.15, 128.10, 128.76, 128.86, 129.18, 131.36,
133.05, 134.04, 135.87, 137.08, 137.20, 144.24, 167.84, 178.74; MS
(APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+ Calculated
for C27H23Cl2N3OS: 530.0837, Found: 530.0832.
(5R,6S)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (7ai). White solid; Yield 65%; mp 108–110 ◦C; Rf 0.54
1
(8 : 2 hexane–EtOAc); [a]D -303.96 (c 1.000, CHCl3).; H NMR
(400 MHz, CDCl3): d 1.33 (d, 3H, J = 6.72 Hz), 1.63 (d, 3H, J =
7.12 Hz), 2.37 (dd, 1H), 2.76 (m, 1H), 3.26 (dd, 1H), 3.35 (m, 1H),
6.54–6.58 (d, 2H, J = 8.32 Hz), 6.94 (q, 1H, J = 7.08 Hz), 7.07–7.09
(d, 2H, J = 9.04 Hz), 7.21–7.26 (m, 2H), 7.29–7.41 (m, 6H); 13C
NMR (100 MHz, CDCl3): d 14.21, 14.84, 30.49, 46.49, 47.64,
59.64, 116.60, 116.83, 121.31, 121.50, 127.12, 128.41, 128.89,
128.95, 129.20, 130.37, 132.32, 134.99, 135.89, 135.93, 138.96,
156.54, 168.22, 180.19; MS (APCI): [M+1]+ = 500.93; HRMS
(ESI): m/z [M+Na]+ Calculated for C26H23Cl2FN2OS: 523.0790,
Found: 523.0792.
(5R,6R)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6bii). White solid; Yield 32%; mp 132–134 ◦C; Rf 0.30
1
(8 : 2 hexane–EtOAc); [a]D -251.23 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 0.65 (d, 3H, J = 6.68 Hz), 1.63 (d, 3H,
J = 7.08 Hz), 2.89–3.04 (m, 3H), 3.69 (q, 1H, J = 6.72 Hz), 7.05–
7.13 (m, 2H), 7.17–7.19 (d, 2H, J = 8.40 Hz), 7.25–7.27 (s, 1H),
7.33–7.46 (m, 7H), 7.71–7.74 (d, 1H, J = 8.28 Hz); 13C NMR
(100 MHz, CDCl3): d 15.68, 19.38, 34.69, 48.82, 50.16, 58.94,
113.15, 115.54, 128.42, 128.96, 129.07, 129.24, 129.86, 131.38,
133.42, 134.08, 134.46, 137.24, 137.56, 144.29, 167.19, 178.12; MS
(APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+ Calculated
for C27H23Cl2N3OS: 530.0837, Found: 530.0841.
(5S,6R)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (7bi). White solid; Yield 30%; mp 138–140 ◦C; Rf 0.60
1
(8 : 2 hexane–EtOAc); [a]D -243.50 (c 1.000, CHCl3); H NMR
(5S,6R)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(R)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6ci). White solid; Yield 65%; mp 193–195 ◦C; Rf 0.35
(400 MHz, CDCl3): d 0.65 (d, 3H, J = 6.64 Hz), 1.47 (d, 3H, J =
7.00 Hz), 2.49 (dd, 1H), 3.07 (m, 1H), 3.40 (dd, 1H), 3.54 (m, 1H),
6.99 (q, 1H, J = 6.96 Hz), 7.15 (d, 2H, J = 8.36 Hz), 7.20–7.24
(t, 2H, J = 8.64 Hz), 7.25–7.40 (m, 8H); 13C NMR (100 MHz,
CDCl3): d 13.02, 15.19, 31.11, 47.81, 48.10, 59.24, 116.58, 116.80,
121.28, 121.47, 128.10, 128.71, 128.77, 129.11, 129.84, 132.94,
135.84, 135.88, 136.14, 137.36, 156.53, 159.02, 168.09, 179.64; MS
(APCI): [M+1]+ = 500.93; HRMS (ESI): m/z [M+Na]+ Calculated
for C26H23Cl2FN2OS: 523.0790, Found: 523.0790.
1
(8 : 2 hexane–EtOAc); [a]D +326.64 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 1.34 (d, 3H, J = 6.68 Hz), 1.64 (d, 3H, J =
7.12 Hz), 2.37 (dd, 1H), 2.77 (m, 1H), 3.25 (dd, 1H), 3.37 (m,
1H), 6.57 (d, 2H, J = 8.28 Hz), 6.83–6.88 (q, 1H, J = 7.08 Hz),
7.10 (d, 2H, J = 9.04 Hz), 7.23–7.42 (m, 7H), 7.77 (d, 1H, J =
8.28 Hz); 13C NMR (100 MHz, CDCl3): d 14.30, 14.86, 30.38,
46.59, 47.78, 59.58, 113.15, 115.57, 127.11, 128.53, 128.95, 129.01,
129.17, 131.43, 134.01, 134.76, 137.20, 138.72, 144.28, 167.90,
179.33; MS (APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+
Calculated for C27H23Cl2N3OS: 530.0837, Found: 530.0830.
(5R,6R)-3-(3-Chloro-4-fluorophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (7bii). White solid; Yield 36%; mp 172–174 ◦C; Rf 0.40
1
(8 : 2 hexane–EtOAc); [a]D -258.22 (c 1.000, CHCl3); H NMR
(5R,6S)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(R)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6di). White solid; Yield 27%; mp 179–181 ◦C; Rf 0.45
(400 MHz, CDCl3): d 0.66 (d, 3H, J = 6.68 Hz), 1.62–1.64
(d, 3H, J = 7.08 Hz), 2.91–3.05 (m, 3H), 3.64–3.68 (m, 1H),
7.00 (m, 1H), 7.13–7.24 (m, 5H), 7.35–7.42 (m, 5H), 7.44–7.48
(m, 2H); 13C NMR (100 MHz, CDCl3): d 15.67, 19.30, 34.68,
48.85, 49.99, 59.04, 116.65, 116.87, 121.34, 121.52, 128.44, 128.88,
129.16, 129.88, 132.28, 134.72, 135.91, 135.95, 137.82, 156.52,
159.01, 167.49, 179.05; MS (APCI): [M+1]+ = 500.93; HRMS
(ESI): m/z [M+Na]+ Calculated for C26H23Cl2FN2OS: 523.0790,
Found: 523.0790.
1
(8 : 2 hexane–EtOAc); [a]D +105.63 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 0.66 (d, 3H, J = 6.68 Hz), 1.47 (d, 3H, J =
7.00 Hz), 2.49 (dd, 1H), 3.10 (m, 1H), 3.39 (dd, 1H), 3.56 (m, 1H),
6.93 (q, 1H, J = 6.96 Hz), 7.15 (d, 2H, J = 8.36 Hz), 7.22 (d, 1H, J =
8.24 Hz), 7.33-7.41 (m, 8H), 7.76 (d, 1H, J = 8.28 Hz); 13C NMR
(100 MHz, CDCl3): d 13.13, 15.22, 30.99, 47.97, 48.13, 59.20,
113.13, 115.57, 116.15, 128.10, 128.76, 128.86, 129.18, 129.83,
131.36, 133.05, 134.03, 135.87, 137.08, 137.21, 144.23, 167.84,
178.74; MS (APCI): [M+1]+ = 508.40; HRMS (ESI): m/z [M+Na]+
Calculated for C27H23Cl2N3OS: 530.0837, Found: 530.0834.
(5R,6S)-5-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-methyl-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(8ai).
60%; White solid; Yield 60%; mp 193–195 ◦C; Rf 0.53 (8 : 2
hexane–EtOAc); [a]D -116.98 (c 1.000, CHCl3); 1H NMR
(400 MHz, CDCl3): d 1.33 (d, 3H, J = 6.76 Hz), 1.63 (d, 3H, J =
7.12 Hz), 2.37 (dd, 1H), 2.77 (m, 1H), 3.26 (dd, 1H), 3.33 (m, 1H),
6.57 (d, 2H, J = 8.28 Hz), 6.96 (q, 1H, J = 7.12 Hz), 7.06–7.15
(m, 4H), 7.28–7.41 (m, 7H); 13C NMR (100 MHz, CDCl3): d
14.15, 14.86, 30.51, 46.48, 47.63, 59.54, 127.14, 128.36, 128.86,
(5S,6S)-3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-6-
methyl-1-[(R)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-
one (6dii). White solid; Yield 32%; mp 132–134 ◦C; Rf 0.30
1
(8 : 2 hexane–EtOAc); [a]D +250.78 (c 1.000, CHCl3); H NMR
(400 MHz, CDCl3): d 0.65 (d, 3H, J = 6.68 Hz), 1.63 (d, 3H,
4968 | Org. Biomol. Chem., 2010, 8, 4960–4970
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128.92, 129.22, 129.26, 132.28, 134.21, 135.12, 138.20, 139.07,
168.16, 180.40; MS (APCI): [M+1]+ = 483.10; HRMS (ESI):
m/z [M+Na]+ Calculated for C26H24Cl2N2OS: 505.0884, Found:
505.0884.
(5R,6R)-5-(4-Chlorobenzyl)-6-methyl-3-(3-nitrophenyl)-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(9bii).
Light yellow solid; Yield 35%; mp 102–104 ◦C; Rf 0.33 (8 : 2
hexane–EtOAc); [a]D -242.59 (c 1.000, CHCl3); 1H NMR
(400 MHz, CDCl3): d 0.71 (d, 3H, J = 6.68 Hz), 1.66 (d, 3H, J =
7.08 Hz), 2.92–3.05 (m, 3H), 3.72 (q, 1H, J = 6.76 Hz), 7.16 (q,
1H, J = 7.08 Hz), 7.22 (d, 2H, J = 8.36 Hz), 7.29–7.54 (m, 8H),
7.61–7.65 (t, 1H, J = 8.80 Hz), 7.99 (s, 1H), 8.26–8.32 (m, 1H);
13C NMR (100 MHz, CDCl3): d 15.69, 19.39, 34.76, 48.88, 50.15,
59.06, 123.30, 128.34, 128.46, 128.95, 129.03, 129.23, 129.62,
129.91, 133.35, 134.60, 137.67, 140.64, 148.59, 167.51, 178.63;
MS (APCI): [M+1]+ = 494.33; HRMS (ESI): m/z [M+Na]+
Calculated for C26H24ClN3O3S: 516.1125, Found: 516.1129.
(5S,6R)-5-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-methyl-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(8bi).
White solid; Yield 30%; mp 112–115 ◦C; Rf 0.59 (8 : 2 hexane–
1
EtOAc); [a]D -343.32 (c 1.000, CHCl3); H NMR (400 MHz,
CDCl3): d 0.66 (d, 3H, J = 6.64 Hz), 1.47 (d, 3H, J = 7.04 Hz),
2.48 (dd, 1H), 3.09 (m, 1H), 3.41 (dd, 1H), 3.54 (m, 1H), 7.02
(q, 1H, J = 6.96 Hz), 7.13–7.15 (m, 4H), 7.31–7.37 (m, 7H),
7.41–7.45 (d, 2H, J = 7.64 Hz); 13C NMR (100 MHz, CDCl3): d
12.97, 15.21, 31.12, 47.78, 48.05, 59.12, 128.10, 128.33, 128.67,
128.75, 129.08, 129.29, 130.47, 132.87, 134.21, 136.22, 137.44,
138.12, 168.06, 179.81; MS (APCI): [M+1]+ = 483.17; HRMS
(ESI): m/z [M+Na]+ Calculated for C26H24Cl2N2OS: 505.0884,
Found: 505.0884.
3-(3-Chloro-4-cyanophenyl)-1-[(S)-1-phenylethyl]-2-thioxo-
tetrahydropyrimidin-4(1H)-one (10). White solid; Yield 75%; mp
230–231 ◦C; Rf 0.21 (7 : 3 hexane–EtOAc); [a]D -259.30 (c 1.000,
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.69 (d, 3H, J = 6.80 Hz),
2.62–2.79 (m, 2H), 3.28–3.35 (m, 1H), 3.52–3.57 (m, 1H), 6.84–
6.89 (q, 1H, J = 6.80 Hz), 7.23–7.27 (m, 1H), 7.35–7.45 (m,
6H), 7.75 (d, 1H, J = 8.00 Hz); 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; HRMS (ESI): m/z [M+Na]+ Calculated for
C19H16ClN3OS: 392.0601, Found: 392.0600.
(5R,6R)-5-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-methyl-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(8bii).
White solid; Yield 35%; mp 186–188 ◦C; Rf 0.47 (8 : 2 hexane–
1
EtOAc); [a]D -308.64 (c 1.000, CHCl3); H NMR (400 MHz,
CDCl3): d 0.66 (d, 3H, J = 6.64 Hz), 1.63 (d, 3H, J = 7.04 Hz),
2.89–3.08 (m, 3H), 3.67 (q, J = 6.60 Hz, 1H), 7.06 (d, 2H, J =
7.52 Hz), 7.14–7.19 (m, 3H), 7.35–7.48 (m, 9H); 13C NMR
(100 MHz, CDCl3): d 15.69, 19.25, 34.70, 48.86, 49.97, 58.92,
128.43, 128.86, 128.89, 129.14, 129.36, 133.20, 134.22, 134.81,
137.91, 138.19, 167.49, 179.20; MS (APCI): [M+1]+ = 483.20;
HRMS (ESI): m/z [M+Na]+ Calculated for C26H24Cl2N2OS:
505.0884, Found: 505.0884.
3-(3-Chloro-4-cyanophenyl)-5,5-bis(4-chlorobenzyl)-1-[(S)-1-
phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(10a).
White solid; Yield 30%; mp 130–132 ◦C; Rf 0.56 (8 : 2 hexane–
1
EtOAc); [a]D -167.22 (c 1.000, CHCl3); H NMR (400 MHz,
CDCl3): d 1.62 (d, 3H, J = 7.20 Hz), 2.38–2.42 (d, 2H, J =
13.98 Hz), 2.64–2.68 (d, 1H, J = 13.98 Hz), 3.08–3.15 (dd, 2H),
3.26–3.30 (d, 1H, J = 13.68 Hz), 6.57–6.59 (d, 2H, J = 8.36 Hz),
6.98–7.03 (m, 4H), 7.14–7.16 (d, 3H, J = 8.36 Hz), 7.25–7.27
(d, 2H, J = 8.16 Hz), 7.41–7.51 (m, 5H), 7.70–7.72 (d, 1H, J =
8.28 Hz); 13C NMR (100 MHz, CDCl3): d 14.32, 39.06, 39.55,
46.10, 46.77, 59.23, 113.60, 115.53, 128.10, 128.64, 128.82, 129.01,
129.15, 131.46, 131.58, 131.72, 132.74, 133.48, 133.52, 133.63,
134.02, 137.19, 137.89, 144.56, 168.42, 179.25; MS (APCI):
[M+1]+ = 619.93; HRMS (ESI): m/z [M+Na]+ Calculated for
C33H26Cl3N3OS: 640.0760, Found: 640.0760.
(5R,6S)-5-(4-Chlorobenzyl)-6-methyl-3-(3-nitrophenyl)-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(9ai).
Light yellow solid; Yield 64%; mp 110–112 ◦C; Rf 0.36 (8 : 2
hexane–EtOAc); [a]D -115.96 (c 1.000, CHCl3); 1H NMR
(400 MHz, CDCl3): d 1.38 (d, 3H, J = 6.76 Hz), 1.65 (d, 3H,
J = 7.16 Hz), 2.39 (dd, 1H), 2.81 (m, 1H), 3.27 (dd, 1H), 3.39
(m, 1H), 6.58 (d, 2H, J = 8.28 Hz), 6.92 (q, 1H, J = 7.1 Hz),
7.08–7.12 (m, 2H), 7.31–7.42 (m, 5H), 7.51–7.67 (m, 2H), 8.10
(s, 1H), 8.31 (m, 1H); 13C NMR (100 MHz, CDCl3): d 14.32,
14.87, 30.43, 46.55, 47.75, 59.67, 123.31, 127.14, 128.48, 128.93,
128.99, 129.20, 129.54, 132.38, 134.87, 138.86, 140.62, 148.57,
168.22, 179.83; MS (APCI): [M+1]+ = 494.47; HRMS (ESI):
m/z [M+Na]+ Calculated for C26H24ClN3O3S: 516.1125, Found:
516.1128.
3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-[(S)-1-phenyl-
ethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(10b). White
◦
solid; Yield 17%; mp 130–132 C; Rf 0.29 (8 : 2 hexane–EtOAc);
1
[a]D -130.36 (c 1.000, CHCl3); H NMR (400 MHz, CDCl3): d
1.56–1.58 (d, 3H, J = 7.04 Hz), 2.49–2.56 (dd, 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, 1H, J = 8.28 Hz); 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, 179.97; MS (APCI):
[M+1]+ = 494.20; HRMS (ESI): m/z [M+Na]+ Calculated for
C26H21Cl2N3OS: 516.0680, Found: 516.0680.
(5S,6R)-5-(4-Chlorobenzyl)-6-methyl-3-(3-nitrophenyl)-1-[(S)-
1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(9bi).
Light yellow solid; Yield 28%; mp 88–90 ◦C; Rf 0.45 (8 : 2 hexane–
1
EtOAc); [a]D -281.94 (c 1.000, CHCl3); H NMR (400 MHz,
CDCl3): d 0.70 (d, 3H, J = 6.68 Hz), 1.49 (d, 3H, J = 7.00 Hz), 2.51
(dd, 1H), 3.14 (m, 1H), 3.42 (dd, 1H), 3.58 (m, 1H), 6.97 (q, 1H,
J = 6.96 Hz), 7.12–7.18 (d, 2H, J = 9.12 Hz), 7.35–7.66 (m, 9H),
8.05 (s, 1H), 8.27–8.30 (m, 1H); 13C NMR (100 MHz, CDCl3): d
13.14, 15.24, 31.05, 47.93, 48.12, 59.27, 123.32, 128.13, 128.33,
128.81, 128.84, 129.16, 129.56, 129.85, 132.99, 136.00, 137.20,
140.56, 148.58, 168.14, 179.25; MS (APCI): [M+1]+ = 494.40;
HRMS (ESI): m/z [M+Na]+ Calculated for C26H24ClN3O3S:
516.1125, Found: 516.1133.
3-(3-Chloro-4-cyanophenyl)-5-(4-chlorobenzyl)-1-[(S)-1-phenyl-
ethyl]-2-thioxotetrahydropyrimidin-4(1H)-one
(10c). White
◦
solid; Yield 21%; mp 135–137 C; Rf 0.22 (8 : 2 hexane–EtOAc);
[a]D -139.48 (c 1.000, CHCl3); 1H NMR (400 MHz, CDCl3):
d 1.56 (d, 3H, J = 7.04 Hz), 2.40–2.46 (dd, 1H), 2.89–2.94 (m,
1H), 3.01–3.12 (m, 2H), 3.38–3.43 (dd, 1H), 6.67–6.69 (d, 2H,
This journal is
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Org. Biomol. Chem., 2010, 8, 4960–4970 | 4969
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Crystal data
Crystal
6a
6d
6ai
6di
Empirical formula
Formula mass
Color
C20H18ClN3OS
383.88
Colorless
Block
Orthorhombic
P212121
4
a 7.2935(2)
b 12.3730(3)
c 20.6291(5)
a 90.00
b 90.00
g 90.00
-8 £ h £ 7; -10 £ k £ 14;
-24 £ l £ 24
150(2)
1861.62(8)
Mo-Ka (l = 0.71073)
0.331
800
3.39–25.00
8067
3272 (Rint = 0.0208)
3272/0
C20H18ClN3OS
383.88
Colorless
Block
Orthorhombic
P212121
4
a 7.5879(2)
b 10.1912(2)
c 24.2981(4)
a 90.00
b 90.00
g 90.00
-9 £ h £ 8; -12 £ k £ 11;
-28 £ l £ 28
150(2)
1878.97(7)
Mo-Ka (l = 0.71073)
0.328
800
3.35–25.00
13418
3299 (Rint = 0.0210)
3299/0
C27H23Cl2N3OS
508.44
Colorless
Plate
Monoclinic
P21
2
a 9.7540(9)
b 9.3273(8)
c 13.3001(12)
a 90.00
b 89.90
g 90.00
-9 £ h £ 12; -11 £ k £ 11;
-16 £ l £ 15
100(2)
1210.02(19)
Mo-Ka (l = 0.71073)
0.381
528
1.53–25.94
6817
4421 (Rint = 0.0356)
4421/1
C27H23Cl2N3OS
508.44
Colorless
Block
Monoclinic
P21
2
a 10.8114(11)
b 10.9871(11)
c 11.0108(11)
a 90.00
b 107.048(2)
g 90.00
-12 £ h £ 13; -13 £ k £ 13;
-13 £ l £ 13
100(2)
1250.5(2)
Mo-Ka (l = 0.71073)
0.369
528
1.93–25.96
9363
4769 (Rint = 0.0244)
4769/1
Description
Symmetry
Space group
Z
˚
Length (A)
Angle (◦)
Collection ranges
Temperature (K)
3
˚
Volume (A )
Radiation
Absorption coefficient (mm-1)
F(000)
h range (◦)
Reflections Collected
Independent Reflections
Data/Restraints
Parameters
Maximum Shift
Goodness-of-fit on F2
Final R Indices I > 2r(I)
237
0.00
1.040
R1 = 0.0254
wR2 = 0.0643
R1 = 0.0283
wR2 = 0.0652
772207
237
0.00
1.073
R1 = 0.0211
wR2 = 0.0567
R1 = 0.0226
wR2 = 0.0571
772208
313
0.00
1.025
R1 = 0.0435
wR2 = 0.1125
R1 = 0.0443
wR2 = 0.1133
772209
309
0.00
1.033
R1 = 0.0282
wR2 = 0.0689
R1 = 0.0289
wR2 = 0.0694
772210
R indices (all data)
CCDC Number
J = 8.00 Hz), 6.92–6.97 (q, 1H, J = 7.00 Hz), 7.12–7.21 (m, 3H),
7.33–7.45 (m, 6H), 7.33–7.75 (d, 1H, J = 8.24 Hz); 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]+
Calculated for C26H21Cl2N3OS: 516.0680, Found: 516.0676.
Chem. Soc., 1997, 119, 6496–6511; (l) D. M. Fryzuk and B. Bosnich,
J. Am. Chem. Soc., 1977, 99, 6262–6267; (m) J. D. Cram and A. F.
Elhafez, J. Am. Chem. Soc., 1952, 74, 5828–5835; (n) D. A. Evans, M. J.
Dart, J. L. Duffy and M. G. Yang, J. Am. Chem. Soc., 1996, 118, 4322–
4343; (o) T. J. Leitereg and D. J. Cram, J. Am. Chem. Soc., 1968, 90,
4011–4018.
2 S.-Y. Chai, H. M. Elokdah and T. S. Sulkowaski, US Patent 5807864,
1998.
3 I. Ojima, T. Fuchikami and M. T. Fujita, US Patent 4581452, 1986.
4 G. W. Brouwer and E. E. Felauer, US Patent 4927451, 1990.
5 M. Teranishi, C. Murakata, I. Matsukama, M. Susono, K. Shuto and
S. Ischikawa, US Patent 4588729, 1986.
Acknowledgements
6 (a) H. Elokdah, T. S. Sulkowski, M. Abou-Gharbia, J. A. Butera, S.-Y.
Chai, G. R. McFarlane, M.-L. McKean, J. L. Babiak, S. J. Adelman
and E. M. Quinet, J. Med. Chem., 2004, 47, 681; (b) T. Okawara, K.
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Hakkou, J. J. V. Eynde, J. Hamelin and J. P. Bazureau, Tetrahedron, 2004,
60, 3745.
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 facilities at the Indian Institute
of Technology Bombay and the University of Hyderabad are
gratefully acknowledged.
7 G. Bartoli, C. Cimarelli, E. Marcantoni, G. Palmieri and M. Petrini,
J. Org. Chem., 1994, 59, 5328.
8 (a) V. Kumar and V. A. Nair, Tetrahedron Lett., 2010, 51, 966–969;
(b) G. L. Khatik, A. Pal, T. D. Apsunde and V. A. Nair, J. Heterocycl.
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V. A. Nair, Tetrahedron Lett., 2010, 51, 3654–3657.
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P. L. Polavarapu, T. Li, J. Drabowicz, K. M. Pietrusiewicz and K. Zygo,
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Polavarapu, A. Collet and L. D. Barron, Angew. Chem. Int. Ed. Engl.,
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A. Kawakami and K. Fuji, Tetrahedron Lett., 1999, 40, 9081–9084;
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6245–6248.
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10 Energy calculations were performed by the semi-emperical method
PM3 Hamiltonian on Chem3D Ultra 10.0 (CambridgeSoft).
4970 | Org. Biomol. Chem., 2010, 8, 4960–4970
This journal is
The Royal Society of Chemistry 2010
©