Synthesis of (S)-(+)-6-aryl-3-acetyl-6-trifluoromethyl-5,6-dihydropyridin- 2(1H)-ones

Article abstract of DOI:10.1134/S1070428010070183

(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-ones reacted with ethyl acetoacetate and ethyl trifluoroacetoacetate to give (S)-(+)-6-aryl-3-acetyl(or trifluoroacetyl)-6-trifluoromethyl-5,6-dihydropyridin-2(1H)-ones.

Full text of DOI:10.1134/S1070428010070183

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 1070–1073. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.M. Golovach, V.A. Sukach, M.V. Vovk, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 7, pp. 1071–1074.
Synthesis of (S)-(+)-6-Aryl-3-acetyl-6-trifluoromethyl-
5,6-dihydropyridin-2(1H)-ones
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 July 31, 2009
Abstract—(S)-(+)-4-Amino-4-aryl-5,5,5-trifluoropentan-2-ones reacted with ethyl acetoacetate and ethyl tri-
fluoroacetoacetate to give (S)-(+)-6-aryl-3-acetyl(or trifluoroacetyl)-6-trifluoromethyl-5,6-dihydropyridin-
2(1H)-ones.
DOI: 10.1134/S1070428010070183
Partly hydrogenated pyridine ring is a structural
fragment of molecules of a number of biologically
active natural compounds [1–4]; hydrogenated pyri-
dine derivatives are also widely used in agricultural
and pharmaceutical chemistry. In particular, some
compounds of the 5,6-dihydropyrimidin-2(1H)-one
series are effective herbicides [5], antiviral [6] and
antileukemic agents [7], and biological mediators
playing an important role in blood pressure regulation
processes [8]. Despite the existence of versatile meth-
ods for the synthesis of such compounds, the most
convenient procedures are based on intramolecular
cyclization of 2-substituted N-(3-oxoalkyl)acetamides
or their precursors generated in situ by the action of
bases [9–11]. Taking into account increased research-
ers’ interest [12, 13] in perfluoroalkyl-substituted ni-
trogen-containing heterocycles, compounds containing
a trifluoromethyl group in the α-position with respect
to the nitrogen atom [14–16], especially at a chiral
carbon center [17, 18] have attracted much attention.
Up to now, only a few 6-trifluoromethyl-5,6-dihydro-
pyridin-2(1H)-one derivatives have been synthesized
by cyclocondensation of “push–pull” enamines with
1-chloro-2,2,2-trifluoroethyl isocyanates [19]. There
are no published data on optically active trifluoro-
methyl-substituted 5,6-dihydropyridin-2(1H)-ones.
We have proposed a preparatively convenient
procedure for the synthesis of such compounds via
cyclization of accessible [20] highly optically pure
(S)-(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-ones
Іa–Id with ethyl acetoacetate (ІІa) and ethyl 4,4,4-tri-
fluoro-3-oxobutanoate (ІІb) under neutral conditions.
By heating the initial reactants in boiling toluene or
xylene we obtained the corresponding (S)-(+)-3-acetyl-
(or trifluoroacetyl)-6-aryl-4-methyl-6-trifluoromethyl-
5,6-dihydropyridin-2(1H)-ones ІIІa–IIIh in 63–91%
yield with an optical purity of 84–91%. `
We previously showed [21] that amines like І
undergo acylation only by the action of strong electro-
philes. Acetoacetic acid esters ІІa and IIb cannot be
regarded as such strong electrophiles; however, at
elevated temperature they are likely to be converted
into reactive α-keto ketenes [22], and the latter react
with compounds Іa–Id to produce N-(trifluoro)acetyl-
Scheme 1.
Ar
F3C
F3C
Ar
Me
Me
O
Ar
F3C
Me
R
OEt
+
R
NH
O
HN
R
–EtOH
–H2O
NH2
O
O
O
O
O
O
Ia–Id
IIa, IIb
A
IIIa–IIIh
І, Ar = Ph (a), 4-FC6H4 (b), 4-MeC6H4 (c), 4-MeOC6H4 (d); ІІ, R = Me (a), CF3 (b); ІІІ, R = Me, Ar = Ph (a), 4-FC6H4 (b),
4-MeC6H4 (c), 4-MeOC6H4 (d); R = CF3, Ar = Ph (e), 4-FC6H4 (f), 4-MeC6H4 (g), 4-MeOC6H4 (h).
1070

SYNTHESIS OF (S)-(+)-6-ARYL-3-ACETYL-6-TRIFLUOROMETHYL-5,6-DIHYDRO...
1071
acetamides A. Unlike N-(3-oxoalkyl)acetamides [9–11],
intermediate amides A undergo thermal intramolecular
cyclization in the absence of a base (Scheme 1). The
proposed scheme is confirmed by the fact that ethyl
cyanoacetate failed to react with amines I under analo-
gous conditions.
0.18 ml (1.6 mmol) of ethyl acetoacetate or 0.24 ml
(1.6 mmol) of ethyl 4,4,4-trifluoro-3-oxobutanoate,
respectively, was added, and the mixture was heated
for 4–6 h under reflux. The solvent was distilled off,
and the residue was recrystallized from 60% aqueous
ethanol (ІІІc, IIIe–IIIh) or purified by thin-layer chro-
matography on silica gel using ethyl acetate–hexane
(1:5) as eluent (ІІІa, IIIb, IIId).
The described reaction does not involve the chiral
carbon center (C6); therefore, its absolute configuration
remains the same as in the initial amine. The presence
of a β-dicarbonyl fragment in molecules ІІІ makes
these compounds promising as building blocks for the
synthesis of various chiral fused pyridine systems.
(S)-(+)-3-Acetyl-4-methyl-6-phenyl-6-trifluoro-
methyl-5,6-dihydropyridin-2(1H)-one (ІІІa). Yield
76%, mp 113–115°C, [α]D20 = +37.4° (c = 0.98,
MeOH). IR spectrum, ν, cm–1: 3210 (NH); 1705, 1685
1
(C=O). H NMR spectrum, δ, ppm: 1.98 s (3H, CH3),
The lactam fragment in compounds IIIa–IIIh gives
rise to IR absorption bands at 3200–3220 (N–H) and
1675–1690 cm–1 (C=O). Stretching vibrations of the
exocyclic acetyl carbonyl group are characterized by
absorption at 1705 cm–1, whereas the trifluoroacetyl
2.34 s (3H, CH3), 3.02 d (1H, CH2, J = 18.0 Hz),
3.20 d (1H, CH2, J = 18.0 Hz), 7.11 s (1H, NH), 7.42–
7.44 m (3H, Harom), 7.50–7.53 m (2H, Harom). 13C NMR
spectrum, δC, ppm: 21.06 (CH3), 31.39 (CH3), 36.93
(C5), 62.30 q (C6, J = 27.6 Hz), 124.93 q (CF3, J =
285.4 Hz), 126.15, 129.00, 129.38, 132.20 (Carom),
135.94 (C4), 149.08 (C3), 164.31 (C2), 200.64 (C=O).
19F NMR spectrum: δF –78.76 ppm. Mass spectrum:
m/z 298 [M]+. Found, %: C 60.58; H 4.77; N 4.73.
C15H14F3NO2. Calculated, %: C 60.60; H 4.75; N 4.71.
M 297.3.
1
group absorbs at 1680–1690 cm–1. In the H NMR
spectra of IIIa–IIIh we observed signals from the
NH and aromatic protons and two doublets in the
region δ 2.97–3.29 ppm due to AB spin system formed
by methylene protons on C5. The dihydropyridinone
structure of compounds ІIІa–IIIh is also reliably con-
firmed by the 13C NMR spectra which contained, apart
from the characteristic C2, C3, and C4 signals, a singlet
from C5 at δC 36–37 ppm and a quartet from C6 at
δC 62 ppm, the latter being coupled with fluorine atoms
in the trifluoromethyl group (2JCF = 27.6–28.9 Hz).
(S)-(+)-3-Acetyl-6-(4-fluorophenyl)-4-methyl-6-
trifluoromethyl-5,6-dihydropyridin-2(1H)-one
(ІІІb). Yield 63%, mp 110–113°C, [α]D20 = +23.2° (c =
1.0, MeOH). IR spectrum, ν, cm–1: 3200 (NH); 1705,
1
1675 (C=O). H NMR spectrum, δ, ppm: 1.98 s (3H,
CH3), 2.33 s (3H, CH3), 2.98 d (1H, CH2, J = 18.0 Hz),
3.19 d (1H, CH2, J = 18.0 Hz), 7.10–7.13 m (2H,
Harom), 7.46 s (1H, NH), 7.50–7.52 m (2H, Harom).
13C NMR spectrum, δC, ppm: 21.08 (CH3), 31.38
(CH3), 36.89 (C5), 62.02 q (C6, J = 27.6 Hz), 115.94,
116.11, 128.22, 128.29, 131.76 (Carom), 127.06 q (CF3,
J = 285.4 Hz), 132.24 (C4), 148.99 (C3), 164.09 d (C4′,
J = 248.9 Hz), 164.42 (C2), 200.50 (C=O). 19F NMR
spectrum, δF, ppm: –77.19, –78.95, –112.71. Mass
spectrum: m/z 316 [M]+. Found, %: C 57.13; H 4.14;
N 4.43. C15H13F4NO2. Calculated, %: C 57.15; H 4.16;
N 4.44. M 315.3.
EXPERIMENTAL
The H, 19F, and 13C NMR spectra were measured
1
on a Bruker Avance DRX-500 spectrometer at 500.13,
188.14, and 125.75 MHz, respectively, from solutions
in CDCl3 using tetramethylsilane (1H, 13C) and tri-
chlorofluoromethane (19F) as internal references. The
IR spectra were recorded from solutions in methylene
chloride on a UR-20 spectrometer. The mass spectra
were obtained on a PE SCIEX API 150 EX instrument
equipped with UV (λ 254 nm) and ELSD detectors.
The purity of the products was checked by thin-layer
chromatography on Silufol-254 plates using ethyl
acetate–hexane (1:5) as eluent. The optical rotations
were measured on a Perkin–Elmer 341 polarimeter.
The optical purity was determined by 19F NMR spec-
troscopy with the use of tris[3-(heptafluorobutyryl)-L-
camphorato]europium as lanthanide shift reagent.
(S)-(+)-3-Acetyl-4-methyl-6-(4-methylphenyl)-6-
trifluoromethyl-5,6-dihydropyridin-2(1H)-one
(ІІІc). Yield 90%, mp 145–147°C, [α]D20 = +2.0° (c =
1.0, MeOH). IR spectrum, ν, cm–1: 3210 (NH); 1705,
1
1690 (C=O). H NMR spectrum, δ, ppm: 1.94 s (3H,
CH3), 2.34 s (3H, CH3), 2.36 s (3H, CH3), 2.97 d (1H,
CH2, J = 17.5 Hz), 3.14 d (1H, CH2, J = 17.5 Hz),
6.54 s (1H, NH), 7.24 d (2H, Harom, J = 8.0 Hz), 7.38 d
(2Harom, J = 8.0 Hz). 13C NMR spectrum, δC, ppm:
20.99 (CH3), 21.08 (CH3), 31.39 (CH3), 36.80 (C5),
(S)-(+)-3-Acetyl-6-aryl-4-methyl-6-trifluoro-
methyl-5,6-dihydropyridin-2(1H)-ones ІІІa–IIIh
(general procedure). Amino ketone Іa–Id, 1.6 mmol,
was dissolved in 15 ml of anhydrous xylene or toluene,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

GOLOVACH et al.
1072
62.09 q (C6, J = 27.6 Hz), 124.78 q (CF3, J =
284.2 Hz), 126.20, 129.62, 132.18, 132.94 (Carom),
139.30 (C4), 149.28 (C3), 164.70 (C2), 200.79 (C=O).
19F NMR spectrum: δF –78.96 ppm. Mass spectrum:
m/z 312 [M]+. Found, %: C 61.70; H 5.23; N 4.48.
C16H16F3NO2. Calculated, %: C 61.73; H 5.18; N 4.50.
M 311.3.
162.08 d (C4′, J = 296.7 Hz), 169.75 (C2), 184.89 q
(C=O, J = 38.9 Hz). 19F NMR spectrum, δF, ppm:
–77.18, –78.98, –112.71. Mass spectrum: m/z 370 [M]+.
Found, %: C 48.82; H 2.70; N 3.81. C15H10F7NO2. Cal-
culated, %: C 48.79; H 2.73; N 3.79. M 369.2.
(S)-(+)-4-Methyl-6-(4-methylphenyl)-3-trifluoro-
acetyl-6-trifluoromethyl-5,6-dihydropyridin-2(1H)-
one (ІІІg). Yield 91%, mp 164–166°C, [α]D20 = +65.9°
(c = 1.39, MeOH). IR spectrum, ν, cm–1: 3220 (NH);
(S)-(+)-3-Acetyl-6-(4-methoxyphenyl)-4-methyl-
6-trifluoromethyl-5,6-dihydropyridin-2(1H)-one
(ІІІd). Yield 71%, mp 105–107°C, [α]D20 = +48.5° (c =
0.79, MeOH). IR spectrum, ν, cm–1: 3210 (NH); 1705,
1
1685, 1680 (C=O). H NMR spectrum, δ, ppm: 1.99 s
(3H, CH3), 2.37 s (3H, CH3), 3.04 d (1H, CH2, J =
18.0 Hz), 3.29 d (1H, CH2, J = 18.0 Hz), 7.25 d (2H,
Harom, J = 7.8 Hz), 7.38 d (2H, Harom, J = 7.8 Hz),
7.81 s (1H, NH). 13C NMR spectrum, δC, ppm: 20.96
(CH3), 37.06 (C5), 62.45 q (C6, J = 27.6 Hz), 115.05 q
(CF3, J = 291.1 Hz), 124.76 q (CF3, J = 284.1 Hz),
126.15, 126.97, 129.66, 132.12 (Carom), 139.55 (C3),
155.37 (C4), 163.71 (C2), 184.91 q (C=O, J = 38.9 Hz).
19F NMR spectrum, δF, ppm: –77.08, –79.01. Mass
spectrum: m/z 366 [M]+. Found, %: C 52.63; H 3.62;
N 3.87. C16H13F6NO2. Calculated, %: C 52.61; H 3.59;
N 3.83. M 365.3.
1
1695 (C=O). H NMR spectrum, δ, ppm: 1.97 s (3H,
CH3), 2.33 s (3H, CH3), 2.97 d (1H, CH2, J = 17.5 Hz),
3.16 d (1H, CH2, J = 17.5 Hz), 3.83 s (3H, CH3O),
6.94 d (2H, Harom, J = 7.5 Hz), 7.41 d (2Harom, J =
7.5 Hz), 7.41 s (1H, NH). 13C NMR spectrum, δC,
ppm: 21.08 (CH3), 31.40 (CH3), 36.88 (C5), 61.92 q
(C6, J = 27.6 Hz), 114.26, 127.52, 127.67, 160.15
(Carom), 124.80 q (CF3, J = 284.0 Hz), 132.18 (C4),
149.21 (C3), 164.53 (C2), 200.77 (C=O). 19F NMR spec-
trum: δF –79.08 ppm. Mass spectrum: m/z 328 [M]+.
Found, %: C 58.72; H 4.95; N 4.25. C16H16F3NO3. Cal-
culated, %: C 58.71; H 4.93; N 4.28. M 327.3.
(S)-(+)-6-(4-Methoxyphenyl)-4-methyl-3-tri-
fluoroacetyl-6-trifluoromethyl-5,6-dihydropyridin-
(S)-(+)-4-Methyl-6-phenyl-3-trifluoroacetyl-6-
trifluoromethyl-5,6-dihydropyridin-2(1H)-one
(ІІІe). Yield 87%, mp 115–117°C, [α]D20 = +37.7 (c =
1.15, MeOH). IR spectrum, ν, cm–1: 3210 (NH); 1680,
2(1H)-one (ІІІh). Yield 73%, mp 118–120°C, [α]D20
=
+16.5° (c = 1.0, MeOH). IR spectrum, ν, cm–1: 3210
1
(NH); 1690, 1680 (C=O). H NMR spectrum, δ, ppm:
1
2.02 s (3H, CH3), 3.10 d (1H, CH2, J = 17.5 Hz),
3.29 d (1H, CH2, J = 17.5 Hz), 3.84 s (3H, CH3O),
6.96 d (2H, Harom, J = 7.5 Hz), 7.46 d (2H, Harom, J =
7.5 Hz), 8.39 s (1H, NH). 13C NMR spectrum, δ, ppm:
21.00 (CH3), 37.07 (C5), 55.32 (CH3O), 62.25 q (C6,
J = 27.6 Hz), 114.18, 114.27, 126.91, 127.63 (Carom),
116.20 q (CF3, J = 291.7 Hz), 124.76 q (CF3, J =
284.1 Hz), 155.58 (C3), 160.28 (C4), 163.84 (C2),
184.91 q (C=O, J = 38.9 Hz). 19F NMR spectrum, δF,
ppm: –77.11, –79.13. Mass spectrum: m/z 382 [M]+.
Found, %: C 50.44; H 3.41; N 3.71. C16H13F6NO3. Cal-
culated, %: C 50.40; H 3.44; N 3.67. M 381.3.
1675 (C=O). H NMR spectrum, δ, ppm: 2.02 s (3H,
CH3), 3.15 d (1H, CH2, J = 18.0 Hz), 3.29 d (1H, CH2,
J = 18.0 Hz), 7.42–7.51 m (5H, Harom), 8.22 s (1H,
NH). 13C NMR spectrum, δC, ppm: 21.02 (CH3), 37.07
(C5), 62.63 q (C6, J = 28.9 Hz), 115.04 q (CF3, J =
291.7 Hz), 124.72 q (CF3, J = 284.2 Hz), 126.26,
126.98, 129.01, 129.55 (Carom), 135.10 (C3), 155.36
(C4), 163.69 (C2), 184.79 q (C=O, J = 38.9 Hz).
19F NMR spectrum, δF, ppm: –77.16, –78.77. Mass
spectrum: m/z 352 [M]+. Found, %: C 51.31; H 3.16;
N 3.99. M 351.2.
(S)-(+)-6-(4-Fluorophenyl)-4-methyl-3-trifluoro-
acetyl-6-trifluoromethyl-5,6-dihydropyridin-2(1H)-
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