Synthesis of (S)-(-)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4- dihydropyrimidine-2(1H)-thiones

Article abstract of DOI:10.1134/S1070428012030165

(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-one reacted with aryl isothiocyanates containing electron-withdrawing substituents to give (S)-(-)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4-dihydropyrimidine-2(1H) -thiones. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012030165

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 430–433. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.M. Golovach, V.A. Sukach, M.V. Vovk, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 3, pp. 432–434.
Synthesis of (S)-(–)-1,4-Diaryl-6-methyl-4-trifluoromethyl-
3,4-dihydropyrimidine-2(1H)-thiones
N. M. Golovach, V. A. Sukach, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: mvovk@i.com.ua
Received June 3, 2011
Abstract—(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-one reacted with aryl isothiocyanates containing
electron-withdrawing substituents to give (S)-(–)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4-dihydropyrimidine-
2(1H)-thiones.
DOI: 10.1134/S1070428012030165
3,4-Dihydropyrimidine-2(1H)-thiones are biologi-
cally important pyrimidine derivatives. For example,
monastrol [ethyl 4-(3-hydroxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] is
an effective allosteric inhibitor of the mitotic kinesin
Eg5 [1, 2]. Most partly hydrogenated pyrimidine-2-
thiones synthesized so far are 4-monosubstituted deriv-
atives. Their 4,4-disubstituted analogs have been
studied to a much lesser extent, though some of these
were found to exhibit strong anti-inflammatory and
analgesic activity [2–5]. Unlike 4-monosubstituted
3,4-dihydropyrimidine-2(1H)-thiones which are gen-
erally synthesized by the Biginelli reaction [6], 4,4-di-
substituted derivatives are obtained by condensation of
α,β-unsaturated ketones with ammonium thiocyanate
[7, 8] or of β-isothiocyanato carbonyl compounds with
amines [9–12]. The reaction of β-amino ketones with
aryl isothiocyanates was less successful, for it was
accompanied by side formation of 6-hydroxy-3,4,5,6-
tetrahydropyrimidine-2(1H)-thiones [13].
qualitatively new chemical and biological properties
[14, 15]; of particular interest are structures in which
trifluoromethyl group is attached to an asymmetric
carbon atom [16, 17]. We previously synthesized
optically active 4-aryl-4-trifluoromethyl-3,4-dihydro-
pyrimidine-2(1H)-thiones having no substituent on N1
by condensation of chiral β-trifluoromethyl-β-amino
ketones with potassium thiocyanate or acyl isothio-
cyanates [18]. Our attempts to involve in analogous
reaction ethyl or phenyl isothiocyanate as electrophile
were unsuccessful.
We succeeded in synthesizing the target compounds
with the use of more electrophilic aromatic isothiocy-
anates. Preparatively accessible [19] (S)-(+)-4-amino-
4-aryl-5,5,5-trifluoropentan-2-ones Іa–Id with high
optical purity reacted with aryl isothiocyanates IIa–IIe
having electron-withdrawing substituents in the ben-
zene ring to give (S)-(–)-1,4-diaryl-6-methyl-4-tri-
fluoromethyl-3,4-dihydropyrimidine-2(1H)-thiones
ІІІa–IIIg in 58–87% yield with an optical purity of
88–96% (Scheme 1). Most probably, the reaction
involves intermediate formation of thioureas A which,
Introduction of a trifluoromethyl group into mole-
cules of organic compounds endows them with
Scheme 1.
Ar
CF3
NH
S
Ar'
NH
NH2
O
+
Ar'NCS
IIa–IIe
HN
F3C
O
F3C
–H2O
Me
Me
N
S
Ar
Me
Ar
Ar'
Ia–Ic
A
IIIa–IIIg
І, Ar = Ph (a), 4-MeC6H4 (b), 4-FC6H4 (c); ІІ, Ar′ = 2-FC6H4 (a), 2-F3CC6H4 (b), 4-O2NC6H4 (c), 2-Cl-5-F3CC6H3 (d),
3,5-(F3C)2C6H3 (e); ІІІ, Ar = Ph, Ar′ = 2-F3CC6H4 (a), 4-O2NC6H4 (b); Ar = 4-MeC6H4, Ar′ = 2-FC6H4 (c), 4-O2NC6H4 (d),
2-Cl-5-F3CC6H3 (e), 3,5-(F3C)2C6H3 (f); Ar = 4-FC6H4, Ar′ = 4-O2NC6H4 (g).
430

SYNTHESIS OF (S)-(–)-1,4-DIARYL-6-METHYL-4-TRIFLUOROMETHYL-...
431
unlike analogous ureas [18], undergo intramolecular
cyclization under neutral rather than acid conditions.
Stepwise transformation of β-amino ketones Іa–Id
does not affect the chiral center, and its absolute con-
figuration is retained in the cyclization products.
amino ketone Іa–Ic in 1 ml of anhydrous acetonitrile,
and the mixture was heated for 10 h under reflux. In
the synthesis of compounds ІІІb and IIId, the precip-
itate was filtered off and washed with hexane. In the
other cases, the mixture was evaporated, the oily resi-
due was dissolved in 15 ml of methylene chloride, the
solution was washed with a solution of sodium carbon-
ate, and the organic phase was separated, dried over
anhydrous sodium sulfate, and evaporated. The prod-
ucts were recrystallized from 60% aqueous methanol.
The H, 13C, and 19F NMR spectra of compounds
1
ІІІa–IIIg unambiguously indicate their dihydropyrimi-
dinethione structure. Pyrimidinethiones ІІІa, IIIc, and
IIIe having an ortho-substituted phenyl ring on N1
displayed in almost all NMR spectra a double set of
signals with an intensity ratio of ~0.6:0.4. Presumably,
this is the result of atropisomerism arising from
restricted rotation of the ortho-substituted benzene ring
about the C–N bond due to the presence of methyl
group in position 6 of the pyrimidine ring (Scheme 2).
(S)-(–)-6-Methyl-4-trifluoromethyl-1-[2-(tri-
fluoromethyl)phenyl]-4-phenyl-3,4-dihydropyrimi-
dine-2(1H)-thione (IIIa). Yield 65%, mp 157–158°C,
ee 93%, [α]D20 = –10.91° (c = 1.0, MeOH). IR spectrum
1
(KBr), ν, cm–1: 3165 (NH), 1705 [NHC(S)]. H NMR
spectrum, δ, ppm: 1.63 s and 1.65 s (3H, CH3), 5.17 s
and 5.34 s (1H, 5-H), 7.19–7.81 m (10H, Harom, NH).
13C NMR spectrum, δC, ppm: 20.64, 20.82 (CH3);
63.08 q, 63.16 q (C4, J = 28.9 Hz); 98.93, 99.18 (C5);
124.60 q, 126.71 q (CF3, J = 286.5 Hz); 125.99,
126.01, 126.08, 127.36, 127.40, 127.44, 127.48,
128.94, 129.05, 129.09, 129.18, 129.46, 132.60,
132.63, 132.67, 132.75, 136.54, 136.71, 137.71,
137.82, 137.93, 138.14 (Carom, C6); 178.29, 178.55
(C=C). 19F NMR spectrum, δF, ppm: –78.56 s (CF3),
–63.07 s and –62.66 s (CF3). Mass spectrum: m/z 417
[M]+. Found, %: C 54.83; H 3.37; N 6.72; S 7.69.
C19H14F6N2S. Calculated, %: C 54.81; H 3.39; N 6.73;
S 7.70. M 416.4.
Scheme 2.
S
S
R'
R'
HN
HN
F3C
Ar
F3C
Ar
N
N
R
R
Me
Me
IIIa, IIIc, IIIe
R = F3C, R′ = H (a); R = F, R′ = H (c); R = Cl, R′ = F3C (e).
The presence in the 19F NMR spectra of ІІІc and
IIIe of two nearby signals from the CF3 group made it
difficult to perform NMR experiments with the use of
shift reagents; so that we failed to determine optical
purity of these compounds.
(S)-(–)-6-Methyl-1-(4-nitrophenyl)-4-phenyl-
4-trifluoromethyl-3,4-dihydropyrimidine-2(1H)-
thione (IIIb). Yield 70%, mp 171–172°C, ee 96%,
[α]D20 = –2.99° (c = 1.0, MeOH). IR spectrum (KBr), ν,
EXPERIMENTAL
The IR spectra were recorded in KBr on a UR-20
1
cm–1: 3175 (NH), 1700 [NHC(S)]. H NMR spectrum,
spectrometer. The H, 19F, and 13C NMR spectra were
1
δ, ppm: 1.65 s (3H, CH3), 5.27 s (1H, 5-H), 7.16 s (1H,
NH), 7.27–7.55 m (7H, Harom), 8.29 d (2H, Harom, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 21.05 (CH3),
63.07 q (C4, J = 28.9 Hz), 100.23 (C5), 124.45 q (CF3,
J = 286.5 Hz); 124.56, 125.96, 129.26, 129.32, 131.00,
135.93, 137.19, 145.92, 147.66 (Carom, C6); 178.12
(C=S). 19F NMR spectrum: δF –78.78 ppm, s (CF3).
Mass spectrum: m/z 394 [M]+. Found, %: C 54.98;
H 3.57; N 10.69; S 8.14 C18H14F3N3O2S. Calculated,
%: C 54.96; H 3.59; N 10.68; S 8.15. M 393.4.
measured on a Bruker Avance DRX-500 instrument at
500.13, 470.59, and 125.75 MHz, respectively, using
CDCl3 as solvent and tetramethylsilane (1H, 13C) or
C6F6 (19F) as internal reference. The mass spectra were
obtained on a PE Sciex API 150EX LC–MS system
(Perkin Elmer) equipped with UV (λ 254 nm) and
ELSD detectors. The optical rotations were measured
on an Anton Paar polarimeter. The optical purity of
compounds ІІІa, IIIb, IIId, IIIf, and IIIg was deter-
mined by 19F NMR spectroscopy using tris[3-(hepta-
fluorobutyryl)-L-camphorato]europium(III) as lan-
thanide shift reagent.
(S)-(–)-1-(2-Fluorophenyl)-6-methyl-4-(4-methyl-
phenyl)-4-trifluoromethyl-3,4-dihydropyrimidine-
2(1H)-thione (IIIc). Yield 77%, mp 118–119°C,
[α]D20 = –30.51° (c = 1.00, MeOH). IR spectrum (KBr),
(S)-(–)-1,4-Diaryl-6-methyl-4-trifluoromethyl-
3,4-dihydropyrimidine-2(1H)-thiones IIIa–IIIg
(general procedure). Aryl isothiocyanate ІІa–IIe,
3.6 mmol, was added to a solution of 3.3 mmol of
1
ν, cm–1: 3198 (NH), 1695 [NHC(S)]. H NMR spec-
trum, δ, ppm: 1.62 s and 1.66 s (3H, CH3), 2.36 s and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

GOLOVACH et al.
432
2.38 s (3H, CH3), 5.14 s and 5.22 s (1H, 5-H), 7.19–
7.67 m (9H, Harom, NH). 13C NMR spectrum, δC, ppm:
20.30, 20.47 (CH3); 21.06 (CH3); 62.92 q, 62.97 q (C4,
J = 28.9 Hz); 99.31, 99.39 (C5); 125.83 q, 125.91 q
(CF3, J = 286.4 Hz); 116.37, 116.52, 124.37, 124.40,
124.68, 124.72, 125.85, 125.95, 128.03, 128.17,
128.27, 129.01, 129.23, 129.51, 129.80, 130.90,
131.44, 131.52, 134.66, 136.52, 139.14, 158.40 d (J =
251.5 Hz), 158.53 d (J = 251.5 Hz), 159.53 d (J =
16.3 Hz) (Carom, C6); 178.31, 178.46 (C=S). 19F NMR
spectrum, δF, ppm: –120.99 s, 121.84 s (2′-F);
–78.67 s, –79.05 s (CF3). Mass spectrum: m/z 381
[M]+. Found, %: C 59.97; H 4.25; N 7.38; S 8.45.
C19H16F4N2S. Calculated, %: C 59.99; H 4.24; N 7.36;
S 8.43. M 380.4.
(CF3); –63.60 s, –63.64 s (CF3). Mass spectrum: m/z
465 [M]+. Found, %: C 51.65; H 3.27; N 6.05; S 6.89.
C20H15ClF6N2S. Calculated, %: C 51.67; H 3.25;
N 6.03; S 6.90. M 464.9.
(S)-(–)-1-[3,5-Bis(trifluoromethyl)phenyl]-6-
methyl-4-(4-methylphenyl)-4-trifluoromethyl-3,4-
dihydropyrimidine-2(1H)-thione (IIIf). Yield 80%,
mp 151–152°C, ee 96%, [α]D20 = –15.26° (c = 1.00,
MeOH). IR spectrum (KBr), ν, cm–1: 3195 (NH), 1695
1
[NHC(S)]. H NMR spectrum, δ, ppm: 1.64 s (3H,
CH3), 2.39 s (3H, CH3), 5.27 s (1H, 5-H), 7.18–7.49 m
(5H, Harom, NH), 7.64–7.70 m (2H, Harom), 7.91 s (1H,
Harom). 13C NMR spectrum, δC, ppm: 21.04 (CH3),
21.27 (CH3), 62.91 q (C4, J = 28.9 Hz), 100.64 (C5),
122.70 q (CF3, J = 285.8 Hz); 125.84, 126.32, 129.91,
130.38, 132.62, 134.15, 135.53, 139.43, 141.83 (Carom
,
(S)-(–)-6-Methyl-4-(4-methylphenyl)-1-(4-nitro-
phenyl)-4-trifluoromethyl-3,4-dihydropyrimidine-
2(1H)-thione (IIId). Yield 87%, mp 177–178°C,
ee 95%, [α]D20 = –20.93° (c = 1.00, MeOH). IR spec-
trum (KBr), ν, cm–1: 3200 (NH), 1695 [NHC(S)].
1H NMR spectrum, δ, ppm: 1.65 s (3H, CH3), 2.39 s
(3H, CH3), 5.25 s (1H, 5-H), 7.16 s (1H, NH), 7.25–
7.46 m (6H, Harom), 8.29 d (2H, Harom, J = 8.4 Hz).
13C NMR spectrum, δC, ppm: 20.31 (CH3), 21.06
(CH3), 63.09 q (C4, J = 28.9 Hz), 100.37 (C5), 124.36 q
(CF3, J = 285.4 Hz); 124.54, 125.80, 129.91, 131.00,
134.26, 135.76, 139.41, 145.96, 147.64 (Carom, C6);
178.08 (C=S). 19F NMR spectrum: δF –78.99 ppm, s
(CF3). Mass spectrum: m/z 408 [M]+. Found, %:
C 55.98; H 3.95; N 10.33; S 7.85. C19H16F3N3O2S.
Calculated, %: C 56.01; H 3.96; N 10.31; S 7.87.
M 407.4.
C6); 178.23 (C=S). 19F NMR spectrum, δF, ppm:
–78.94 s, –64.00 s (CF3). Mass spectrum: m/z 499
[M]+. Found, %: C 50.59; H 3.06; N 5.59; S 6.45.
C21H15F9N2S. Calculated, %: C 50.61; H 3.03; N 5.62;
S 6.43. M 498.4.
(S)-(–)-4-(4-Fluorophenyl)-6-methyl-1-(4-nitro-
phenyl)-4-trifluoromethyl-3,4-dihydropyrimidine-
2(1H)-thione (IIIg). Yield 67%, oily substance,
ee 88%, [α]D20 = –130.90° (c = 1.0, MeOH). IR spec-
trum (KBr), ν, cm–1: 3170 (NH), 1695 [NHC(S)].
1H NMR spectrum, δ, ppm: 1.68 s (3H, CH3), 5.26 s
(3H, 5-H), 6.23 s (1H, Harom), 7.17–7.43 m (4H, Harom
,
NH), 7.55–7.57 m (2H, Harom), 8.31 d (2H, Harom, J =
8.4 Hz). 13C NMR spectrum, δC, ppm: 20.31 (CH3),
63.05 q (C4, J = 28.9 Hz), 99.31 (C5), 126.34 q (CF3,
J = 285.4 Hz); 124.41, 126.58, 128.21, 130.94, 131.42,
136.54, 139.02, 157.46, 159.46, 158.40 d (J =
251.5 Hz) (Carom, C6); 178.40 (C=S). 19F NMR spec-
trum, δF, ppm: –112.88 s (4′-F), –78.96 s (CF3). Mass
spectrum: m/z 412 [M]+. Found, %: C 52.53; H 3.21;
N 10.19; S 7.77. C18H13F4N3O2S. Calculated, %:
C 52.55; H 3.19; N 10.21; S 7.79. M 411.4.
(S)-(–)-1-[2-Chloro-5-(trifluoromethyl)phenyl]-
6-methyl-4-(4-methylphenyl)-4-trifluoromethyl-3,4-
dihydropyrimidine-2(1H)-thione (IIIe). Yield 58%,
oily substance, [α]D20 = –43.78° (c = 1.00, MeOH). IR
spectrum (KBr), ν, cm–1: 3168 (NH), 1700 [NHC(S)].
1H NMR spectrum, δ, ppm: 1.65 s and 1.67 s (3H,
CH3), 2.32 s and 2.34 s (3H, CH3), 5.25 s (1H, 5-H),
6.99–7.02 m (1H, Harom), 7.18–7.27 m (1H, Harom),
7.28–7.32 m (2H, Harom), 7.44–7.47 m (2H, Harom),
7.59–7.66 m (2H, Harom, NH). 13C NMR spectrum, δC,
ppm: 20.30, 20.54 (CH3); 21.05, 21.39 (CH3); 63.17 q,
63.21 q (C4, J = 28.9 Hz); 99.98, 100.23 (C5);
124.61 q, 124.77 q (CF3, J = 285.4 Hz); 125.77,
125.78, 125.95, 125.96, 126.97, 127.00, 128.15,
128.97, 129.89, 129.90, 130.81, 130.96, 134.63,
134.70, 135.40, 135.52, 137.79, 137.99, 138.53,
138.60, 139.22, 139.29 (Carom, C6); 177.45, 177.51
(C=S). 19F NMR spectrum, δF, ppm: –78.48 s, –78.64 s
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