Efficient route to 6-CF3-substituted nicotinic acid derivatives

Article abstract of DOI:10.1016/j.jfluchem.2006.03.007

A novel synthetic sequence for preparation of CF₃-pyridines is presented. Reaction of α,β-unsaturated trifluoromethylketones with α-cyanoketones leads to α-hydroxydihydropyranes 1 containing CF₃-group. α-Hydroxydihydropyranes can be

Full text of DOI:10.1016/j.jfluchem.2006.03.007

Journal of Fluorine Chemistry 127 (2006) 865–873
www.elsevier.com/locate/fluor
Efficient route to 6-CF3-substituted nicotinic acid derivatives
*
Valentine G. Nenajdenko , Sergey V. Druzhinin, Elizabeth S. Balenkova
Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
Received 18 January 2006; received in revised form 10 March 2006; accepted 18 March 2006
Available online 28 March 2006
Abstract
A novel synthetic sequence for preparation of CF3-pyridines is presented. Reaction of a,b-unsaturated trifluoromethylketones with
a-cyanoketones leads to a-hydroxydihydropyranes 1 containing CF3-group. a-Hydroxydihydropyranes can be easily transformed to
a-hydroxytetrahydropyridines, 1,4-dihydropyridines and CF3-pyridines. All CF3-pyridine derivatives were obtained in good yields. This route
can be applied for preparation of CF3-pyridines containing various substituents with further possible modification on cyano-group.
# 2006 Elsevier B.V. All rights reserved.
Keywords: a,b-Unsaturated trifluoromethylketones; a-Hydroxydihydropyranes; a-Hydroxytetrahydropyridines; 1,4-Dihydropyridines; CF3-pyridines
1. Introduction
ADMA level [8]. So the approaches for preparation of various
6-CF3-nicotinic acid derivatives, including hydrogenated com-
pounds, using simple, available and inexpensive reagents – a,b-
unsaturated trifluoromethylketones – may be very useful.
1.1. On importance of CF3-pyridine derivatives
Substituted pyridines and their hydrogenated derivatives are
very important compounds as candidates in drug research. For
example, 1,4-dihydropyridines possess high biological activity
as NO-donor and calcium channel agonist properties [1], anti-
hypoxic, anti-ischemic, acaricidal, insecticidal, bactericidal
and herbicidal activities [2,3].
2. Results an discussion
2.1. Synthesis of starting CF3-dihydropyranes 1
In spite of the fact that there are a lot of well-known,
widely used methods for synthesis of pyridine cycle, such as
Hantzsch synthesis and related condensation of 1,5-dicarbo-
nyl compounds with ammonia, methods for producing
pyridines containing trifluoromethyl group are not widely
described. Existing methods have some disadvantages such
as formation of mixture of isomers [9,10], low yields [11],
use of complex and hardly available reagents [12]. Synthesis
of CF3-tetrahydropyridones using reaction of a,b-unsatu-
rated CF3-ketones was described in work [13]. Also 4-
arylsubstituted 1,4-dihydro 2,6-di-CF3-pyridines were pre-
pared in low yields by modified Hantzsch synthesis from
corresponding arylaldehyde, trifluoroacetoacetic acid ethyl
ester and ammonia [14] Rare examples of preparation of 6-
trifluoromethylnicotinonitryles are known [15,16]. Now we
present new general method for synthesis of substituted
CF3-nicotinic acid and their hydrogenated derivatives.
Recently we have found that a-hydroxydihydropyranes 1
containing cyano- and trifluoromethyl group can be readily
obtained in the form of single diastereomer in good yields by
Introduction of fluorine into organic compounds is well-
known methodology to enhance their physiological activity
[4,5]. In this aspect methods for synthesis of trifluoromethyl
derivatives of pyridine can serve as very useful tool for
modification of existing drugs and for obtaining novel drug
candidates. One of the useful methods for synthesis of CF3-
derivatives of heterocyclic compounds is application of a,b-
unsaturated trifluoromethylketones as building blocks [6].
Nicotinic acid (Vitamin B3) and its derivatives such as
nicotinoamide (Vitamin PP, niacine) play very important role in
biochemical processes in life processes. Also nicotinic acid is
very important structural fragment of coenzymes (NAD and
NADH). Nicotinic acid by itself is a hypolipidemic agent
appears unique due to its potential to increase HDL cholesterol
levels to a greater extent than other drugs [7] and lowers
* Corresponding author. Fax: +7 095 932 88 46.
E-mail address: nen@acylium.chem.msu.ru (V.G. Nenajdenko).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.03.007

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V.G. Nenajdenko et al. / Journal of Fluorine Chemistry 127 (2006) 865–873
Scheme 1. Synthesis of a-hydroxydihydropyranes 1.
of tar as the by-product was formed. As the result yields of
tetrahydropyridines containing 4-NO2C6H4 group were lower
(Table 1).
According to spectral data reaction proceeds 100%
stereoselectively. a-Hydroxytetrahydropyridines 2 are formed
as a single diastereomer. The spectral NMR data for 2 are very
similar with structural analogues 1 and some other six-
membered having CF3–C–OH fragment. The structure of
compounds 2 was determined by comparison of spectral data
with literature [13,17] and starting a-hydroxydihydropyranes 1,
the structure of those was determined using X-ray analysis [18].
Equatorial orientation of R2 and trifluoromethyl groups and
axial orientation of hydroxyl-group in compounds 2 witness of
more stable diastereomer formation. Therefore, we believe that
the reaction proceeds under thermodynamic control. a-
Hydroxytetrahydropyridines 2 were obtained as stable crystal-
line compounds with relatively high melting points. It is
very typical for cyclic CF3-compounds containing semi-ketal
(like in the starting hydroxydihydropyranes 1 [17]), semi-
aminal [19,20] or even semi-amidal [21] fragment because of
strong electron-withdrawing properties of CF3-group.
Scheme 2. Reaction of a-hydroxydihydropyranes 1 with ammonium acetate.
reaction of a,b-unsaturated trifluoromethylketones with a-
substituted cyanoketones in the presence of potassium fluoride
as a base [17] (Scheme 1). More bulky trifluoromethyl and aryl
groups in these compounds are arranged in more energy
favorable equatorial position while hydroxy-group is arranged
in axial position. a-Hydroxydihydropyranes 1 present the
hidden cyclic form of 1,5-diketone. Therefore, we proposed
that they can be used in Hantzsch pyridine synthesis as
analogues of 1,5-dicarbonyl compounds.
2.2. Synthesis of CF3-a-hydroxytetrahydropyridines 2
We found that reflux of a-hydroxydihydropyranes 1 with
ammonium acetate in ethanolic solution leads to formation
of the corresponding a-hydroxytetrahydropyridines 2 instead
of 1,4-dihydropyridines, which are formed usually in Hantzsch
synthesis. The products are formed mainly in up to quantit-
ative yields (Scheme 2). Only in the case of compounds with
R1 = 4-NO2C6H4 the reaction proceeds much slower and a lot
2.3. Dehydration reaction for a-
hydroxytetrahydropyridines 2: synthesis of 1,4-
dihydropyridines 3
The dehydration reaction for 2 also has been studied [21,13].
Contrary to starting hydroxydihydropyranes 1 a-hydroxyte-
Table 1
Synthesis of CF3-derivatives 2, 3 and 4
R1
Ph
R2
Tetrahydropyridine
Yield, %
Dihydropyridine
Yield, %
Pyridine
Yield, %
Ph
2a
2b
2c
2d
2e
90
87
87
84
88
3a
3b
3c
3d
3e
90
87
87
84
88
4a
4b
4c
4d
4e
93
95
87
99
97
4-MeC6H4
3-MeC6H4
3-MeOC6H4
2-Th
4-MeOC6H4
Ph
2f
2g
2h
2i
95
91
92
88
93
3f
3g
3h
3i
95
91
92
88
–
4f
4g
4h
4i
96
92
99
99
–
4-MeC6H4
3-MeC6H4
3-MeOC6H4
2-Th
2j
5
–
b
4-NO2C6H4
Ph
2k
2l
2m
46
38
38
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
b
4-MeC6H4
3-MeC6H4
3-MeOC6H4
2-Th
–
b
–
a
b
–
–
b
2n
34
–
a
No target product was isolated.
b
The reaction has no been carried out.

V.G. Nenajdenko et al. / Journal of Fluorine Chemistry 127 (2006) 865–873
867
Scheme 5. Oxidation of 1,4-dihydropyridines 3 to pyridines 4.
Scheme 3. Dehydration of a-hydroxytetrahydropyridines 2.
trahydropyridines 2 smoothly eliminate water to form
corresponding 1,4-dihydropyridines 3. The reaction was
accomplished by refluxing toluene solution of 2 with catalytic
amounts of p-toluenesulfonic acid (Scheme 3) during 5–6 h.
1,4-Dihydropyridines 3 were obtained as white or slightly
yellow solids in nearly quantitative yields (Table 1).
3. Experimental
3.1. Materials and physical methods
NMR spectra were recorded on Varian VXR-400 and Bruker
AM 400C spectrometers in CDCl3 with TMS as an internal
standard and Me2SO-d6. The IR spectra were obtained with
UR-20 spectrometer. Chromatography was performed on silica
gel (63–200 mesh, Merck). All solvents used were dried and
distilled according to the standard procedures.
A very unusual result was obtained for the transformation of
the hydroxytetrahydropyridine 2j. Instead of the formation of
compound 3j the reaction did not stop on the stage of
dehydration. Elimination of thiophene from the corresponding
dihydropyridine 3j takes place (Scheme 4). This reaction
presents a rare example of dihydropyridine transformation with
C–C bond cleavage. Several similar examples are described in
literature [22]. The driving force for these reactions is the
formation of aromatic pyridine ring.
3.2. Experimental procedures
3.2.1. Typical procedure for preparation of a-
hydroxytetrahydropyridines (2)
The solution of 3 mmol of a-hydroxydihydropyrane (1) and
30 mmol of ammonium acetate in 30 ml of ethanol was
refluxed for several hours until complete of reaction (TLC
monitoring, hexane–ethylacetate 3:1). The solvent was
evaporated and the mixture was taken up in 30 ml of water.
The product was extracted with methylene chloride
(2 Â 20 ml). Combined organic layers were passed through
thin silica gel layer and evaporated to result the product as light
solid.
2.4. Oxidation of 1,4-dihydropyridines 3 to pyridines 4
There are a lot of methods for aromatization of 1,4-
dihydropyridines to pyridines [25,26], including 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) [27] and sodium per-
sulfate/cobalt(II) nitrate mixture [28]. The attempts to use the
air oxygen for oxidizing 1,4-dihydropyridines 3 failed. Trial
reaction for oxidizing compounds 3 with sodium persulfate/
cobalt nitrate mixture showed comparatively lower yields
(ꢀ60%) and proceeds with noticeable formation of by-product.
The application of DDQ for oxidizing 1,4-dihydropyridines 3
showed excellent results. The oxidation reaction proceeded in
methylene chloride for several minutes at room temperature
and desired trifluoromethylpyridines 4 were obtained with
nearly to quantitative yields (Scheme 5).
3.2.1.1. 6-Hydroxy-2,4-diphenyl-6-(trifluoromethyl)-1,4,5,6-
tetrahydropyridine-3-carbonitrile (2a). Yield 930 mg (90%),
white solid: m.p. 190–191 8C; IR (nujol): n 1620 (C C–N),
1
2215 (CN), 3365 (–NH); H NMR (400 MHz, Me2SO-d6): d
1.83 (b.d.d, 1H, –CH2–, J = 12.7 Hz, J = 12.5 Hz); 2.13 (d.d,
1H, –CH2–, J = 12.7 Hz, J = 5.1 Hz); 3.86 (d.d, 1H, –CH–,
J = 12.5 Hz, J = 5.1 Hz); 7.21 (b.s, 1H, NH); 7.24–7.33 (m, 1H,
Ph); 7.33–7.42 (m, 4H, Ph); 7.43–7.50 (m, 3H, Ph); 7.51–7.58
(m, 2H, Ph); 8.05 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 35.5 (CH); 36.3 (CH2);
78.8 (q, C–OH, J = 31.5 Hz); 80.6 (C–CN); 120.5 (CN); 124.0
(q, CF3, J = 286.0 Hz); 127.2, 128.0, 128.1, 128.7, 128.8,
128.9, 134.7, 141.8 (Ph, Ph); 155.0 (C C–N).
So the presented sequence of three reactions severs as an
efficient and simple synthetic route to substituted 6-trifluor-
omethyl derivatives of nicotinic acid nitriles, which are very
interesting for medicinal chemistry. The advantage of the
presented method is the possibility to isolate intermediate di-
and tetrahydropyridines 2 and 3. Cyano-group in these
compounds can be involved into further transformations.
Scheme 4. Formation of compound 5.

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Anal. calcd. for C19H15F3N2O: C, 66.27; H, 4.39. Found: C,
66.51; H, 4.57.
1H NMR (400 MHz, Me2SO-d6): d 1.93 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.29 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 5.0 Hz); 4.24 (d.d, 1H, –CH–, J = 12.5 Hz, J = 5.0 Hz);
6.93–7.08 (m, 2H, C4H3S); 7.09–7.18 (m, 1H, C4H3S); 7.28
(b.s, NH); 7.40–7.57 (m, 5H, Ph); 8.15 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 31.5 (CH); 36.0 (CH2);
78.8 (q, C–OH, J = 31.5 Hz); 80.1 (C–CN); 120.0 (CN); 123.8
(q, CF3, J = 286.0 Hz); 124.8, 126.0, 126.9, 128.1, 128.7,
130.0, 134.4, 144.5 (C4H3S, Ph); 154.4 (C C–N).
Anal. calcd. for C17H13F3N2OS: C, 58.28; H, 3.74. Found:
C, 58.02; H, 3.66.
3.2.1.2. 6-Hydroxy-4-(4-methylphenyl)-2-phenyl-6-(trifluoro-
methyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile (2b). Yield
940 mg (88%), white solid: m.p. 118–119 8C; IR (nujol): n
1615 (C C–N), 2220 (CN), 3375 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.85 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.9 Hz); 2.14 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 5.1 Hz); 2.31 (s, CH3); 3.86 (d.d, 1H, –CH–, J = 12.9 Hz,
J = 5.1 Hz); 7.15–7.31 (m, 4H, 4-MeC6H4, Ph, NH); 7.44–7.60
(m, 6H, 4-MeC6H4, Ph); 8.02 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 20.6 (CH3); 35.5 (CH);
35.8 (CH2); 78.8 (q, C–OH, J = 30.7 Hz); 80.9 (C–CN); 120.4
(CN); 124.1 (q, CF3, J = 286.0 Hz); 127.9, 128.0, 128.7, 129.2,
129.8, 134.8, 136.2, 138.7 (4-MeC6H4, Ph); 154.7 (C C–N).
Anal. calcd. for C20H17F3N2O: C, 67.03; H, 4.78. Found: C,
66.90; H, 4.90.
3.2.1.6. 6-Hydroxy-2-(4-methoxyphenyl)-4-phenyl-6-(trifluor-
omethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2f). Yield 1060 mg (94%), light-yellow solid: m.p. 168–
169 8C; IR (nujol): n 1620 (C C–N), 2220 (CN), 3330 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.84 (b.d.d, 1H, –CH2–,
J = 12.9 Hz, J = 12.7 Hz); 2.15 (d.d, 1H, –CH2–, J = 12.9 Hz,
J = 5.0 Hz); 3.8 (s, OCH3); 3.87 (d.d, 1H, –CH–, J = 12.7 Hz,
J = 5.0 Hz); 7.02 (d, 2H, 4-MeOC6H4, J = 8.6 Hz); 7.14 (b.s,
1H, NH); 7.24–7.43 (m, 5H, Ph); 7.51 (d, 2H, 4-MeOC6H4,
J = 8.6 Hz); 7.86 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 35.5 (CH); 36.3 (CH2);
55.3 (OCH3); 78.8 (q, C-OH, J = 30.7 Hz); 80.1 (C-CN); 113.4,
126.9, 127.1, 128.0, 128.6, 130.2, 141.9, 160.5 (4-MeOC6H4,
Ph); 120.7 (CN); 123.9 (q, CF3, J = 286.0 Hz); 154.5 (C C–N).
Anal. calcd. for C20H17F3N2O2: C, 64.17; H, 4.58. Found: C,
64.38; H, 4.37.
3.2.1.3. 6-Hydroxy-4-(3-methylphenyl)-2-phenyl-6-(trifluoro-
methyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile (2c). Yield
930 mg (87%), white solid: m.p. 188–189 8C; IR (nujol): n
1615 (C C–N), 2215 (CN), 3320 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.85 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.14 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.5 Hz); 2.33 (s, CH3); 3.86 (d.d, 1H, –CH–, J = 12.5 Hz,
J = 4.5 Hz); 7.05–7.30 (m, 4H, 3-MeC6H4, Ph, NH); 7.40–7.62
(m, 6H, 3-MeC6H4, Ph); 8.02 (b.s, 1H, OH).
13CNMR(100 MHz,Me2SO-d6):d21.0(CH3);35.5(CH);36.2
(CH2); 78.8 (q, C–OH, J = 30.7 Hz); 80.7 (C–CN); 120.4 (CN);
124.0 (q, CF3, J = 286.0 Hz); 127.8, 128.0, 128.4, 128.5, 128.7,
129.8, 134.7, 137.7, 141.7 (3-MeC6H4, Ph); 154.8 (C C–N).
Anal. calcd. for C20H17F3N2O: C, 67.03; H 4.78. Found: C,
67.27, H, 4.79.
3.2.1.7. 6-Hydroxy-2-(4-methoxyphenyl)-4-(4-methylphenyl)-
6-(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2g). Yield 1060 mg (91%), white solid: m.p. 140–141 8C; IR
(nujol): n 1615 (C C–N), 2215 (CN), 3330 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.83 (b.d.d, 1H, –CH2–,
J = 12.9 Hz, J = 12.7 Hz); 2.12 (d.d, 1H, –CH2–, J = 12.9 Hz,
J = 4.8 Hz); 2.30 (s, 3H, CH3); 3.80 (s, 3H, OCH3); 3.81 (d.d,
1H, –CH–, J = 12.7 Hz, J = 5.0 Hz); 7.02 (d, 2H, 4-MeOC6H4,
J = 8.6 Hz); 7.13 (b.s, 1H, NH); 7.17 (d, 2H, 4-MeC6H4,
J = 7.8 Hz); 7.26 (d, 2H, 4-MeC6H4, J = 7.8 Hz); 7.51 (d, 2H,
4-MeOC6H4, J = 8.6 Hz); 7.82 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 20.2 (s, CH3), 35.6
(CH); 35.9 (CH2); 55.3 (OCH3); 78.8 (q, C–OH, J = 30.7 Hz);
80.1 (C–CN); 113.4, 126.9, 127.9, 129.2, 130.2, 136.1, 138.8,
160.5 (4-MeOC6H4, 4-MeC6H4); 120.7 (CN); 123.8 (q, CF3,
J = 286.0 Hz); 154.4 (C C–N).
3.2.1.4. 6-Hydroxy-4-(3-methoxyphenyl)-2-phenyl-6-(trifluor-
omethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2d). Yield 940 mg (84%), white solid: m.p. 186–187 8C; IR
(nujol): n 1615 (C C–N), 2215 (CN), 3300 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.86 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.16 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.5 Hz); 3.77 (s, OCH3); 3.86 (d.d, 1H, –CH–, J = 12.5 Hz,
J = 4.5 Hz); 7.05–7.30 (m, 3H, 3-MeOC6H4); 7.20 (b.s, NH);
7.29 (t, 1H, 3-MeOC6H4, J = 7.6 Hz); 7.40–7.62 (m, 5H, Ph);
8.02 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 35.3 (CH); 36.3 (CH2);
55.0 (OCH3); 78.8 (q, C–OH, J = 30.7 Hz); 80.5 (C–CN);
112.5, 113.9, 128.3, 128.5, 128.8, 129.7, 129.9, 134.7, 143.4,
159.4 (3-MeOC6H4, Ph); 120.2 (CN); 124.0 (q, CF3,
J = 286.0 Hz); 154.9 (C C–N).
Anal. calcd. for C21H19F3N2O2: C, 64.94; H, 4.93. Found: C,
64.84; H, 5.17.
3.2.1.8. 6-Hydroxy-2-(4-methoxyphenyl)-4-(3-methylphenyl)-
6-(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2h). Yield 1070 mg (92%), light-yellow solid: m.p. 102–
103 8C; IR (nujol): n 1615 (C C–N), 2220 (CN), 3280 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.82 (b.d.d, 1H, –CH2–,
J = 12.9 Hz, J = 12.7 Hz); 2.12 (d.d, 1H, –CH2–, J = 12.9 Hz,
J = 5.0 Hz); 2.32 (s, 3H, CH3); 3.80 (s, 3H, OCH3); 3.81 (d.d,
1H, –CH–, J = 12.7 Hz, J = 5.0 Hz); 7.02 (d, 2H, 4-MeOC6H4,
J = 8.6 Hz); 7.17 (d, 1H, 3-MeC6H4, J = 7.4 Hz); 7.14 (b.s, 1H,
Anal. calcd. for C20H17F3N2O2: C, 64.17; H, 4.58. Found: C,
64.28; H, 4.80.
3.2.1.5. 6-Hydroxy-2-phenyl-4-(2-thienyl)-6-(trifluoromethyl)-
1,4,5,6-tetrahydropyridine-3-carbonitrile (2e). Yield 940 mg
(87%), white solid, m.p. 138–139 8C; IR (nujol): n 1620 (C C–
N); 2220 (CN); 3320 (–NH);

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869
NH); 7.14–7.21 (m, 2H, 3-MeC6H4); 7.25 (t, 1H, 3-MeC6H4,
J = 7.4 Hz); 7.51 (d, 2H, 4-MeOC6H4, J = 8.6 Hz); 7.86 (b.s,
1H, OH).
7.15–7.50 (m, 6H, Ph, NH); 7.84 (d, 2H, 4-NO2C6H4,
J = 8.6 Hz); 8.29 (b.s, 1H, OH); 8.33 (d, 2H, 4-NO2C6H4,
J = 8.6 Hz).
13C NMR (100 MHz, Me2SO-d6): d 35.1 (CH); 36.2 (CH2);
78.8 (q, C–OH, J = 31.5 Hz); 82.1 (C–CN); 119.8 (CN); 124.0
(q, CF3, J = 286.9 Hz); 123.2, 127.2, 128.1, 128.6, 130.5,
140.9, 141.3, 148.2 (4-NO2C6H4, Ph); 153.0 (C C–N).
Anal. calcd. for C19H14F3N3O3: C, 58.61; H, 3.62. Found: C,
58.73; H, 3.64.
13C NMR (100 MHz, Me2SO-d6): d 21.1 (s, CH3), 35.6
(CH); 36.3 (CH2); 55.3 (OCH3); 78.8 (q, C–OH, J = 30.7 Hz);
80.1 (C–CN); 113.4, 125.9, 126.9, 127.8, 128.5, 129.6, 130.3,
137.7, 141.8, 160.5 (4-MeOC6H4, 3-MeC6H4); 120.7 (CN);
123.8 (q, CF3, J = 286.0 Hz); 154.5 (C C–N).
Anal. calcd. for C21H19F3N2O2: C, 64.94; H, 4.93. Found: C,
64.83; H, 4.84.
3.2.1.12. 6-Hydroxy-4-(4-methylphenyl)-2-(4-nitrophenyl)-6-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2l). Yield 460 mg (38%), yellow solid: m.p. 114–115 8C; IR
(nujol): n 1360, 1530 (NO2), 1590 (C C–N), 2215 (CN), 3360
(–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.87 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.18 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.8 Hz); 2.30 (s, 3H, CH3); 3.86 (d.d, 1H, –CH–,
J = 12.5 Hz, J = 4.8 Hz); 7.18 (d, 2H, 4-MeC6H5); 7.22–7.35
(m, 3H, 4-MeC6H5, NH); 7.82 (d, 2H, 4-NO2C6H4, J = 8.6 Hz);
8.25 (b.s, 1H, OH); 8.32 (d, 2H, 4-NO2C6H4, J = 8.6 Hz).
13C NMR (100 MHz, Me2SO-d6): d 20.6 (CH3); 35.1 (CH);
35.8 (CH2); 78.8 (q, C–OH, J = 31.5 Hz); 82.3 (C–CN); 119.8
(CN); 124.0 (q, CF3, J = 286.0 Hz); 123.2, 127.9, 129.2, 130.5,
136.3, 138.2, 140.9, 148.2 (4-NO2C6H4, 4-MeC6H4); 152.8
(C C–N).
3.2.1.9. 6-Hydroxy-2-(4-methoxyphenyl)-4-(3-methoxyphe-
nyl)-6-(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carboni-
trile (2i). Yield 1070 mg (88%), light-yellow solid: m.p. 102–
103 8C; IR (nujol): n 1620 (C C–N); 2210 (CN); 3310 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.84 (b.d.d, 1H, –CH2–,
J = 12.9 Hz, J = 12.7 Hz); 2.14 (d.d, 1H, –CH2–, J = 12.9 Hz,
J = 5.0 Hz); 3.77 (s, 3H, 3-MeOC6H4); 3.80 (s, 3H, 4-
MeOC6H4); 3.84 (d.d, 1H, –CH–, J = 12.7 Hz, J = 5.0 Hz);
6.82 (d.d, 1H, 3-MeOC6H4, J = 7.8 Hz, J = 1.8 Hz); 6.90–6.98
(m, 2H, 3-MeOC6H4); 7.02 (d, 2H, 4-MeOC6H4, J = 8.6 Hz);
7.14 (b.s, 1H, NH); 7.29 (t, 1H, 3-MeOC6H4, J = 7.8 Hz); 7.51
(d, 2H, 4-MeOC6H4, J = 8.6 Hz); 7.88 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 35.4 (CH); 36.4 (CH2);
55.0 (s, 3-MeOC6H4), 55.3 (s, 4-MeOC6H4); 78.8 (q, C–OH,
J = 30.7 Hz); 80.0 (C–CN); 112.5, 113.4, 113.8, 120.2, 126.9,
129.7, 130.3, 143.5, 159.4, 160.5 (4-MeOC6H4, 3-MeC6H4);
120.8 (CN); 123.9 (q, CF3, J = 286.0 Hz); 154.5 (C C–N).
Anal. calcd. for C21H19F3N2O3: C, 62.37; H, 4.74. Found: C,
62.40; H, 4.80.
Anal. calcd. for C20H16F3N3O3: C, 59.55; H, 4.00. Found: C,
59.30; H, 4.04.
3.2.1.13. 6-Hydroxy-4-(3-methylphenyl)-2-(4-nitrophenyl)-6-
(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2m). Yield 460 mg (38%), yellow solid: m.p. 158–159 8C; IR
(nujol): n 1360, 1530 (NO2),1590 (C C–N), 2215 (CN), 3360
(–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.88 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.15 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.8 Hz); 2.32 (s, 3H, CH3); 3.86 (d.d, 1H, –CH–,
J = 12.5 Hz, J = 4.8 Hz); 7.05–7.31 (m, 5H, 3-MeC6H4, NH);
7.83 (d, 2H, 4-NO2C6H4, J = 8.6 Hz); 8.25 (b.s, 1H, OH); 8.33
(d, 2H, 4-NO2C6H4, J = 8.6 Hz).
13C NMR (100 MHz, Me2SO-d6): d 21.0 (CH3); 35.2 (CH);
36.1 (CH2); 78.8 (q, C–OH, J = 30.7 Hz); 82.2 (C–CN); 119.8
(CN); 124.0 (q, CF3, J = 286.0 Hz); 123.2, 125.2, 127.9, 128.5,
128.6, 130.5, 137.8, 140.9, 141.2, 148.2 (4-NO2C6H4, 3-
MeC6H4); 152.9 (C C–N).
3.2.1.10. 6-Hydroxy-2-(4-methoxyphenyl)-4-(2-thienyl)-6-(tri-
fluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2j). Yield 1060 mg (93%), light-yellow solid: m.p. 141–
142 8C; IR (nujol): n 1615 (C C–N), 2220 (CN), 3350 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.91 (b.d.d, 1H, –CH2–,
J = 12.9 Hz, J = 12.7 Hz); 2.27 (d.d, 1H, –CH2–, J = 12.9 Hz,
J = 4.9 Hz); 3.80 (s, 3H, 4-MeOC6H4); 4.22 (d.d, 1H, –CH–,
J = 12.7 Hz, J = 4.9 Hz); 6.95–7.01 (m, 1H, C4H3S); 7.02 (d,
2H, 4-MeOC6H4, J = 8.4 Hz); 7.13 (d, 1H, C4H3S, J = 2.7 Hz);
7.22 (b.s, 1H, NH); 7.44 (d, 1H, C4H3S, J = 4.9 Hz); 7.47 (d,
2H, 4-MeOC6H4, J = 8.4 Hz); 7.98 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 31.6 (CH); 36.1 (CH2);
55.3 (4-MeOC6H4), 78.8 (q, C–OH, J = 30.7 Hz); 80.5 (C–
CN); 113.5, 126.0, 126.6, 126.9, 130.3, 144.8, 159.4, 160.6 (4-
MeOC6H4, C4H3S); 120.3 (CN); 123.9 (q, CF3, J = 286.0 Hz);
154.1 (C C–N).
Anal. calcd. for C20H16F3N3O3: C, 59.55; H, 4.00. Found: C,
60.13; H, 4.20.
Anal. calcd. for C18H15F3N2O2S: C, 56.84; H, 3.97. Found:
C, 56.80; H, 4.26.
3.2.1.14. 6-Hydroxy-2-(4-nitrophenyl)-4-(2-thienyl)-6-(tri-
fluoromethyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile
(2n). Yield 480 mg (40%), yellow solid: m.p. 201–202 8C; IR
(nujol): n 1360, 1530 (NO2), 1620 (C C–N), 2220 (CN), 3380
(–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.97 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.4 Hz); 2.31 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.5 Hz); 2.32 (s, 3H, CH3); 3.86 (d.d, 1H, –CH–,
J = 12.4 Hz, J = 4.5 Hz); 6.96–7.06 (m, 1H, C4H3S); 7.15 (d,
3.2.1.11. 6-Hydroxy-2-(4-nitrophenyl)-4-phenyl-6-(trifluoro-
methyl)-1,4,5,6-tetrahydropyridine-3-carbonitrile (2k). Yield
540 mg (46%), yellow solid: m.p. 187–188 8C; IR (nujol): n
1350, 1530 (NO2), 1620 (C C–N), 2220 (CN), 3350 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 1.89 (b.d.d, 1H, –CH2–,
J = 12.7 Hz, J = 12.5 Hz); 2.18 (d.d, 1H, –CH2–, J = 12.7 Hz,
J = 4.8 Hz); 3.91 (d.d, 1H, –CH–, J = 12.5 Hz, J = 4.8 Hz);

870
V.G. Nenajdenko et al. / Journal of Fluorine Chemistry 127 (2006) 865–873
1H, C4H3S, J = 9.6 Hz); 7.36 (b.s, 1H, NH); 7.45 (d, 1H,
C4H3S, J = 4.3 Hz); 7.79 (d, 2H, 4-NO2C6H4, J = 8.3 Hz); 8.32
(d, 2H, 4-NO2C6H4, J = 8.3 Hz); 8.37 (b.s, 1H, OH).
13C NMR (100 MHz, Me2SO-d6): d 31.5 (CH); 35.6 (CH2);
78.8 (q, C–OH, J = 31.5 Hz); 82.5 (C–CN); 119.3 (CN); 123.9
(q, CF3, J = 286.0 Hz); 123.3, 124.9, 126.2, 127.0, 130.5,
140.6, 143.9, 148.3 (4-NO2C6H4, C4H3S); 152.5 (C C–N).
Anal. calcd. for C17H12F3N3O3S: C, 51.64; H, 3.06. Found:
C, 51.72; H, 3.24.
7.11–7.18 (m, 3H, 3-MeC6H4); 7.32 (t, 1H, 3-MeC6H4,
J = 7.6 Hz); 7.46–7.57 (m, 5H, Ph); 9.66 (b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 21.1 (CH3); 40.1 (CH);
80.4 (C–CN); 106.1 (q, C C–CF3, J = 3.7 Hz); 120.3 (CN);
120.5 (q, CF3, J = 272.3 Hz); 126.0 (q, C C–CF3,
J = 36.6 Hz); 124.8, 126.2, 128.5, 128.6, 128.9, 129.4, 130.4,
133.0, 138.1 (Ph, 3-MeC6H4); 150.3 (C C–N).
Anal. calcd. for C20H15F3N2: C 70.58, H 4.44. Found, %C,
70.36; H, 4.32.
3.2.2. Typical procedure for preparation of 1,4-
dihydropyridines (3)
3.2.2.4. 4-(3-Methoxyphenyl)-2-phenyl-6-(trifluoromethyl)-
1,4-dihydropyridine-3-carbonitrile (3d). Yield 700 mg (98%),
white solid: m.p. 82–83 8C; IR (nujol): n 2200 (CN), 3250 (–
NH);
1H NMR (400 MHz, Me2SO-d6): d 3.77 (s, 3H, –OMe); 4.55
(d, 1H, –CH–, J = 3.7 Hz); 5.51 (d, 1H, –C CH–, J = 4.7 Hz);
6.86–6.92 (m, 1H, 3-MeOC6H4); 6.95 (d, 1H, 3-MeOC6H4,
J = 7.2 Hz); 7.33–7.39 (m, 1H, 3-MeOC6H4); 7.46–7.56 (m,
5H, Ph); 9.66 (b.s., 1H, NH).
The solution of 2 mmol of a-hydroxytetrahydropyridine (2)
and catalytic amount of p-TsOH in 20 ml of toluene was
refluxed for several hours until complete of reaction (TLC
monitoring, hexane–ethylacetate 3:1). The mixture was diluted
with methylene chloride (1:1) and the solution was passed
through thin silica gel layer and evaporated to result the product
as light solid.
13C NMR (100 MHz, Me2SO-d6): d 55.0 (OCH3); 40.2
(CH); 80.4 (C-CN); 106.1 (q, C C-CF3, J = 4.4 Hz); 120.3
(CN); 120.5 (q, CF3, J = 272.3 Hz); 126.0 (q, C C–CF3,
J = 36.6 Hz); 124.8, 126.2, 128.4, 128.5, 128.9, 129.3, 130.4,
133.0, 146.3, 159.7 (Ph, 3-MeOC6H4); 150.3 (C C–N).
Anal. calcd. for C20H15F3N2O: C, 67.41; H, 4.24; Found: C,
67.02; H, 4.13.
3.2.2.1. 2,4-Diphenyl-6-(trifluoromethyl)-1,4-dihydropyri-
dine-3-carbonitrile (3a). Yield 523 mg (76%), white solid:
m.p. 143–144 8C; IR (nujol): n 2200 (CN), 3220 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 4.58 (d, 1H, –CH–,
J = 3.2 Hz); 5.51 (d, 1H, –C CH–, J = 4.4 Hz); 7.28–7.39 (m,
3H, Ph); 7.39–7.46 (m, 2H, Ph); 7.47–7.57 (m, 5H, Ph); 9.68
(b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 40.3 (CH); 80.3 (C–
CN); 106.0 (q, C C–CF3, J = 4.3 Hz); 120.3 (CN); 120.5 (q,
CF3, J = 272.3 Hz); 126.1 (q, C C–CF3, J = 33.7 Hz); 127.5,
127.6, 128.5, 128.6, 129.0, 130.5, 133.0, 144.7 (Ph, Ph); 150.6
(C C–N).
3.2.2.5. 2-Phenyl-4-(2-thienyl)-6-(trifluoromethyl)-1,4-dihy-
dropyridine-3-carbonitrile (3e). Yield 630 mg (95%), white
solid: m.p. 105–106 8C; IR (nujol): n 2190 (CN), 3270 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 4.90 (d, 1H, –CH–,
J = 4.5 Hz); 5.61 (d, 1H, –C CH–, J = 4.5 Hz); 6.99–7.08 (m,
2H, Ph); 7.44–7.69 (m, 6H, Ph, 2-Th); 9.86 (b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 35.3 (CH); 80.6 (C–
CN); 105.5 (q, C C–CF3, J = 4.4 Hz); 120.1 (CN); 120.5 (q,
CF3, J = 275.5 Hz); 124.2, 126.1, 127.3, 128.5, 128.6, 129.3,
130.5, 132.7 (Ph, 2-Th); 126.2 (q, C C–CF3, J = 34.4 Hz);
150.1 (C C–N).
Anal. calcd. for C19H13F3N2: C, 69.93; H, 4.02. Found: C,
69.70; H, 3.84.
3.2.2.2. 4-(4-Methylphenyl)-2-phenyl-6-(trifluoromethyl)-1,4-
dihydropyridine-3-carbonitrile (3b). Yield 670 mg (99%),
white solid: m.p. 120–121 8C; IR (nujol): n 2200 (CN), 3260
(–NH);
1H NMR (400 MHz, Me2SO-d6): d 2.31 (s, 3H, –Me); 4.52
(d, 1H, –CH–, J = 3.5 Hz); 5.47 (d, 1H, –C CH–, J = 4.5 Hz);
7.19–7.29 (m, 4H, Ph, 4-MeC6H4); 7.46–7.57 (m, 5H, Ph, 4-
MeC6H4); 9.64 (b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 20.6 (CH3); 39.9 (CH);
80.6 (C–CN); 106.1 (q, C C–CF3, J = 4.4 Hz); 120.3 (CN);
120.5 (q, CF3, J = 272.3 Hz); 126.1 (q, C C–CF3,
J = 34.4 Hz); 127.4, 128.4, 128.5, 129.5, 130.4, 133.0, 136.7,
141.9 (Ph, 4-MeC6H4); 150.3 (C C–N).
Anal. calcd. for C17H11F3N2S: C, 61.44; H, 3.34. Found: C,
61.09; H, 3.16.
3.2.2.6. 2-(4-Methoxyphenyl)-4-phenyl-6-(trifluoromethyl)-
1,4-dihydropyridine-3-carbonitrile (3f). Yield 585 mg (85%),
white solid: m.p. 106–107 8C; IR (nujol): n 2220 (CN), 3260 (–
NH);
1H NMR (400 MHz, Me2SO-d6): d 3.8 (s, 3H, OMe); 4.54
(d, 1H, –CH–, J = 4.5 Hz); 5.61 (d, 1H, –C CH–, J = 4.5 Hz);
7.04 (d, 2H, 4-MeOC6H4, J = 8.8 Hz); 7.15 (d, 2H, Ph, J = 8.8);
7.27–7.37 (m, 3H, Ph); 7.48 (d, 2H, 4-MeOC6H4, J = 8.8 Hz);
9.58 (b.s., 1H, NH).
Anal. calcd. for C20H15F3N2: C, 70.58; H, 4.44. Found: C,
70.24; H, 4.20.
3.2.2.3. 4-(3-Methylphenyl)-2-phenyl-6-(trifluoromethyl)-1,4-
dihydropyridine-3-carbonitrile (3c). Yield 670 mg (99%),
white solid: m.p. 92–93 8C; IR (nujol): n 2200 (CN); 3230
(–NH);
1H NMR (400 MHz, Me2SO-d6): d 2.33 (s, 3H, –Me); 4.53
(d, 1H, –CH–, J = 4.7 Hz); 5.48 (d. 1H, –C CH–, J = 4.9 Hz);
13C NMR (100 MHz, Me2SO–d6): d 40.3 (CH); 55.3 (–
OMe); 79.5 (C–CN); 106.0 (q, C C–CF3, J = 4.4 Hz); 120.7
(CN); 114.0 (4-MeOC6H4); 120.8 (q, CF3, J = 275.2 Hz); 125.0
(4-MeOC6H4); 125.8 (q, C C–CF3, J = 34.4 Hz); 127.5, 128.9,
129.1, 135.3 (Ph); 144.8 (4-MeOC6H4); 150.2 (C C–N); 160.9
(4-MeOC6H4).

V.G. Nenajdenko et al. / Journal of Fluorine Chemistry 127 (2006) 865–873
871
Anal. calcd. for C20H15F3N2O: C, 67.41; H, 4.24. Found: C,
67.12; H, 4.17.
J = 34.4 Hz); 146.4 (4-MeOC6H4); 150.2 (C C–N); 160.9
(4-MeOC6H4).
Anal. calcd. for C21H17F3N2O2: C, 65.28; H, 4.43. Found: C,
64.97; H, 4.28.
3.2.2.7. 2-(4-Methoxyphenyl)-4-(4-methylphenyl)-6-(trifluoro-
methyl)-1,4-dihydropyridine-3-carbonitrile (3g). Yield 670
mg (91%), white solid: m.p. 128–129 8C; IR (nujol): n 2190
(CN), 3270 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 2.30 (s, 3H, –Me); 3.80
(s, 3H, –OMe); 4.49 (d, 1H, –CH–, J = 4.5 Hz); 5.46 (d. 1H, –
C CH–, J = 4.5 Hz); 7.05 (d, 2H, 4-MeOC6H4, J = 8.5 Hz);
7.23 (b.s., 4H, 4-MeC6H4); 7.48 (d, 2H, 4-MeOC6H4,
J = 8.5 Hz); 9.56 (b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 20.6 (–Me); 40.0 (CH);
55.3 (–OMe); 79.8 (C–CN); 106.1 (q, C C–CF3, J = 4.4 Hz);
120.7 (CN); 113.8 (4-MeOC6H4); 120.5 (q, CF3, J = 272.3 Hz);
125.0 (4-MeOC6H4); 126.0 (q, C C–CF3, J = 34.4 Hz); 127.7
(4-MeC6H4); 129.5 (4-MeC6H4); 136.6 (4-MeC6H4); 137.7 (4-
MeC6H4); 144.8 (4-MeOC6H4); 150.0 (C C–N); 160.9 (4-
MeOC6H4).
3.2.2.10. 2-(4-Methoxyphenyl)-6-(trifluoromethyl)nicotinoni-
trile (5). Yield 510 mg (92%), white solid: m.p. 91–92 8C; IR
(nujol): n 2235 (CN);
1H NMR (400 MHz, CDCl3): d 3.88 (s, 3H, OCH3); 7.04 (d,
2H, 4-MeOC6H4, J = 8.8 Hz); 7.65 (d, 1H, H–C C–CF3,
J = 8.1 Hz); 8.02 (d, 2H, 4-MeOC6H4, J = 8.8 Hz); 8.20 (d, 1H,
H–C C–CN, J = 8.1 Hz).
13C NMR (100 MHz, CDCl3): d 55.4 (OCH3); 109.0 (C–
CN); 114.3, 128.1, 130.7, 160.5 (4-MeOC6H4); 117.0 (CN);
117.2 (d, H–C C–CF3, 2.2 Hz); 120.9 (q, CF3, J = 275.2 Hz);
143.9 (H–C C–CN); 150.5 (q, C C–CF3, J = 35.9 Hz); 162.0
(4-MeOC6H4–C–N).
Anal. calcd. for C14H9F3N2O2: C, 60.44; H, 3.26. Found: C,
60.17; H, 3.12.
Anal. calcd. for C21H17F3N2O: C, 68.10; H, 4.63. Found: C,
67.97; H, 4.46.
3.2.3. Typical procedure for preparation of CF3-pyridines
(4)
To a solution of 0.5 mmol of 1,4-dihydropyridine (3) in 3 ml
of anhydrous methylene chloride 0.5 mmol of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) was added. The mixture
immediately warmed up and 2,3-dichloro-5,6-dicyanohydro-
quinone precipitated. Solvent was evaporated and the residue
was taken up in hexanes–ethylacetate mixture (15:1) and
passed through thin silica gel layer. The solvent was evaporated
to result the product as light solid.
3.2.2.8. 2-(4-Methoxyphenyl)-4-(3-methylphenyl)-6-(trifluoro-
methyl)-1,4-dihydropyridine-3-carbonitrile (3h). Yield 670
mg (91%), white solid: m.p. 153–154 8C; IR (nujol): n 2200
(CN), 3250 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 2.33 (s, 3H, –Me); 3.81
(s, 3H, –OMe); 4.50 (d, 1H, –CH–, J = 4.5 Hz); 5.48 (d. 1H, –
C CH–, J = 4.5 Hz); 7.05 (d, 2H, 4-MeOC6H4, J = 8.6 Hz);
7.10–7.20 (m, 3H, 3-MeC6H4); 7.32 (t, 1H, 3-MeC6H4,
J = 7.7 Hz); 7.49 (d, 2H, 4-MeOC6H4, J = 8.6 Hz); 9.57
(b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 21.1 (–Me); 40.3 (CH);
55.4 (–OMe); 79.6 (C–CN); 106.1 (q, C C–CF3, J = 4.4 Hz);
113.8 (4-MeOC6H4); 120.4 (q, CF3, J = 272.3 Hz); 120.7 (CN);
124.8, 128.0, 128.1, 128.9, 130.2, 138.1 (3-MeC6H4); 125.0 (4-
MeOC6H4); 125.9 (q, C C–CF3, J = 34.4 Hz); 144.8 (4-
MeOC6H4); 150.2 (C C–N); 160.9 (4-MeOC6H4).
Anal. calcd. for C21H17F3N2O: C, 68.10; H, 4.63. Found: C,
67.93; H, 4.41.
3.2.3.1. 2,4-Diphenyl-6-(trifluoromethyl)nicotinonitrile
(4a). Yield 150 mg (93%), white solid: m.p. 140–141 8C; IR
(nujol): n 2245 (CN);
1H NMR (400 MHz, CDCl3): d 7.52–7.61 (m, 6H, Ph); 7.63–
7.69 (m, 2H, C–H, Ph); 7.96–8.03 (m, 2H, Ph).
13C NMR (100 MHz, CDCl3): 108.8 (C–CN) 116.3 (CN);
118.9 (q, H–C C–CF3, J = 2.9 Hz); 120.8 (q, CF3,
J = 275.2 Hz); 128.6, 128.7, 129.2, 129.4, 130.7, 130.8,
135.3, 136.3 (2 Ph); 150.0 (q, C C–CF3, J = 35.9 Hz); 157.0
(Ph–C); 163.0 (Ph–C–N).
Anal. calcd. for C19H11F3N2: C, 70.37; H, 3.42. Found: C,
70.28; H, 3.21.
3.2.2.9. 4-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-6-(tri-
fluoromethyl)-1,4-dihydropyridine-3-carbonitrile (3i). Yield
670 mg (91%), white solid: m.p. 105–106 8C; IR (nujol): n
2200 (CN), 3250 (–NH);
1H NMR (400 MHz, Me2SO-d6): d 3.76 (s, 3H, –OMe); 3.81
(s, 3H, –OMe); 4.51 (d, 1H, –CH–, J = 4.5 Hz); 5.51 (d. 1H, –
C CH–, J = 4.5 Hz); 6.85–6.91 (m, 2H, 3-MeOC6H4); 6.93 (d,
1H, 3-MeOC6H4, J = 7.7 Hz); 7.05 (d, 2H, 4-MeOPh,
J = 8.8 Hz); 7.35 (d, 1H, 3-MeOC6H4, J = 7.7 Hz); 7.48 (d,
2H, 4-MeOPh, J = 8.8 Hz); 9.58 (b.s., 1H, NH).
13C NMR (100 MHz, Me2SO-d6): d 40.3 (CH); 55.0 (–
OMe); 55.4 (–OMe); 79.4 (C–CN); 106.1 (q, C C–CF3,
J = 4.4 Hz); 112.5, 113.4, 125.0, 146.4, 150.3, 159.7 (3-
MeOC6H4); 113.8 (4-MeOC6H4); 120.4 (q, CF3, J = 272.3 Hz);
120.7 (CN); 125.0 (4-MeOC6H4); 125.9 (q, C C–CF3,
3.2.3.2. 4-(3-Methylphenyl)-2-phenyl-6-(trifluoromethyl)nico-
tinonitrile (4b). Yield 160 mg (95%), white solid: m.p. 123–
124 8C; IR (nujol): n 2235 (CN);
1H NMR (400 MHz, CDCl3): d 7.36–7.42 (m, 1H, 3-
MeC6H4); 7.43–7.51 (m, 3H, 3-MeC6H4); 7.53–7.60 (m, 3H,
Ph); 7.75 (s, 1H, C–H); 7.94–8.04 (m, 2H, Ph).
13C NMR (100 MHz, CDCl3): 21.4 (CH3); 108.8 (C–CN);
116.3 (CN); 118.8 (q, H–C C–CF3, J = 2.9 Hz); 120.8 (q, CF3,
J = 275.2 Hz); 125.8, 128.7, 129.1, 129.2, 129.4, 130.8, 131.4,
135.3, 136.4 (3-MeC6H4, Ph); 149.9 (q, C C–CF3,
J = 35.1 Hz); 157.2 (3-MeC6H4–C); 163.0 (Ph–C–N).
Anal. calcd. for C20H13F3N2: C, 71.00; H, 3.87. Found: C,
70.78; H, 3.80.

872
V.G. Nenajdenko et al. / Journal of Fluorine Chemistry 127 (2006) 865–873
3.2.3.3. 4-(4-Methylphenyl)-2-phenyl-6-(trifluoromethyl)nico-
tinonitrile (4c). Yield 160 mg (95%), white solid: m.p. 143–
144 8C; IR (nujol): n 2235 (CN);
Anal. calcd. for C20H13F3N2O: C, 67.79; H, 3.70. Found: C,
67.57; H, 3.93.
1H NMR (400 MHz, CDCl3): d 2.46 (s, 3H, CH3); 7.39 (d,
2H, 4-MeC6H4, J = 7.8 Hz) 7.53–7.61 (m, 5H, 4-MeC6H4, Ph);
7.75 (s, 1H, C–H); 7.97–8.01 (m, 2H, Ph).
3.2.3.7. 2-(4-Methoxyphenyl)-4-(4-methylphenyl)-6-(trifluoro-
methyl)nicotinonitrile (4g). Yield 170 mg (92%), white solid:
m.p. 142–143 8C; IR (nujol): n 2235 (CN);
13C NMR (100 MHz, CDCl3): d 21.3 (CH3); 108.6 (C–CN);
116.5 (CN); 118.7 (q, H–C C–CF3, J = 2.9 Hz); 120.8 (q, CF3,
J = 275.2 Hz); 128.5, 128.6, 128.7, 129.4, 129.9, 130.7, 132.4,
136.4, 141.2 (4-MeC6H4, Ph); 149.8 (q, C C–CF3,
J = 35.1 Hz); 157.0 (4-MeC6H4–C); 163.1 (Ph–C–N).
Anal. calcd. for C20H13F3N2: C, 71.00; H, 3.87. Found: C,
69.92; H, 3.77.
1H NMR (400 MHz, CDCl3): d 2.45 (s, 3H, CH3); 3.88 (s,
3H, OCH3); 7.05 (d, 2H, 4-MeOC6H4, J = 8.6 Hz); 7.37 (d, 2H,
4-MeC6H4, J = 7.6 Hz); 7.56 (d, 2H, 4-MeC6H4, J = 7.6 Hz);
7.67 (s, 1H, C–H); 8.00 (d, 2H, 4-MeOC6H4, J = 8.6 Hz).
13C NMR (100 MHz, CDCl3): d 21.4 (CH3); 55.4 (OCH3);
107.8 (C–CN); 114.2, 118.0, 128.6, 129.9, 131.1, 132.6, 141.1,
161.7 (4-MeOC6H4, 4-MeC6H4); 116.9 (CN); 118.0 (q, H–
C C–CF3, J = 2.9 Hz); 120.9 (q, CF3, J = 275.9 Hz); 149.8 (q,
J = 35.1 Hz, C C–CF3); 157.1 (4-MeC6H4–C); 162.8 (4-
MeOC6H4–C–N).
3.2.3.4. 4-(3-Methoxyphenyl)-2-phenyl-6-(trifluoromethyl)ni-
cotinonitrile (4d). Yield 175 mg (99%), white solid, m.p. 103–
104 8C; IR (nujol): n 2240 (CN);
Anal. calcd. for C21H15F3N2O: C, 68.47; H, 4.10. Found: C,
68.09; H, 4.29.
1H NMR (400 MHz, CDCl3): d 7.10 (d.d, 1H, 3-MeOC6H4,
J = 8.2 Hz, J = 1.8 Hz); 7.16 (t, 1H, 3-MeOC6H4, J = 1.8 Hz);
7.22 (d, 1H, 3-MeOC6H4, J = 8.2 Hz); 7.48 (t, 1H, 3-
MeOC6H4, J = 8.0 Hz); 7.53–7.60 (m, 3H, Ph); 7.75 (s, 1H,
C–H); 7.94–8.03 (m, 2H, Ph).
3.2.3.8. 2-(4-Methoxyphenyl)-4-(3-methylphenyl)-6-(trifluoro-
methyl)nicotinonitrile (4h). Yield 180 mg (99%), white solid:
m.p. 156–157 8C; IR (nujol): n 2235 (CN);
13C NMR (100 MHz, CDCl3): d 55.5 (OCH3); 108.8 (C–
CN); 114.2, 116.4, 120.9, 128.7, 129.4, 130.4, 130.8, 136.3,
136.5, 160.0 (3-MeOC6H4, Ph); 116.3 (CN); 118.8 (q, H–C C–
CF3, J = 2.9 Hz); 120.7 (q, CF3, J = 275.9 Hz); 149.9 (q, C C–
CF3, J = 35.1 Hz); 156.9 (3-MeOC6H4–C); 163.0 (Ph–C–N).
Anal. calcd. for C20H13F3N2O: C, 67.79; H, 3.70. Found: C,
67.74; H, 3.75.
1H NMR (400 MHz, CDCl3): d 2.47 (s, 3H, CH3); 3.88 (s,
3H, OCH3); 7.05 (d, 2H, 4-MeOC6H4, J = 9.1 Hz); 7.35–7.40
(m, 1H, 3-MeC6H4,); 7.42–7.47 (m, 3H, 3-MeC6H4,); 7.67 (s,
1H, C–H); 8.00 (d, 2H, 4-MeOC6H4, J = 9.1 Hz).
13C NMR (100 MHz, CDCl3): d 21.4 (CH3); 55.4 (OCH3);
108.0 (C–CN); 114.1, 118.0, 128.6, 129.9, 131.1, 132.6, 135.4,
139.0, 141.1, 161.8 (4-MeOC6H4, 3-MeC6H4); 116.8 (CN);
118.0 (q, H–C C–CF3, J = 2.4Hz); 120.9 (q, CF3, J = 275.9
Hz); 149.8 (q, C C–CF3, J = 35.1 Hz,); 157.2 (3-MeC6H4–C);
162.4 (4-MeOC6H4–C–N).
3.2.3.5. 2-Phenyl-4-(2-thienyl)-6-(trifluoromethyl)nicotinoni-
trile (4e). Yield 160 mg (97%), white solid: m.p. 107–108 8C;
IR (nujol): n 2235 (CN);
1H NMR (400 MHz, CDCl3): d 3.89 (s, 3H, OCH3); 7.39
(d.d, 1H, 2-Th, J = 5.0 Hz; J = 4.0 Hz); 7.53–7.58 (m, 3H, Ph);
7.66 (d.d, 1H, 2-Th, J = 5.0 Hz; J = 1.0 Hz); 7.83 (s, 1H, C–H);
7.91–7.96 (m, 2H, Ph); 8.00 (d.d, 1H, 2-Th, J = 4.0 Hz;
J = 1.0 Hz).
13C NMR (100 MHz, CDCl3): d 106.4 (C–CN); 116.9 (CN);
118.7 (q, H–C C–CF3, J = 2.5 Hz); 120.3 (q, CF3,
J = 275.2 Hz); 128.7, 129.1, 129.4, 130.8 (b), 136.2, 136.3,
148.4 (2-Th, Ph); 150.1 (q, C C–CF3, J = 35.1 Hz); 156.5 (2-
Th–C); 164.0 (Ph–C–N).
Anal. calcd. for C21H15F3N2O: C, 68.47; H, 4.10. Found: C,
68.17; H, 4.33.
3.2.3.9. 2-(4-Methoxyphenyl)-4-(3-methoxyphenyl)-6-(tri-
fluoromethyl)nicotinonitrile (4i). Yield 180 mg (99%), white
solid: m.p. 120–121 8C; IR (nujol): n 2240 (CN);
1H NMR (400 MHz, CDCl3): d 3.88 (s, 6H, OCH3, OCH3);
7.05 (d, 2H, 4-MeOC6H4, J = 9.1 Hz); 7.07–7.11 (m, 1H, 3-
MeOC6H4,); 7.15 (t, 1H, 3-MeC6H4, J = 1.8 Hz); 7.18–7.22 (m,
1H, 3-MeOC6H4); 7.47 (t, 1H, 3-MeC6H4, J = 7.8 Hz); 7.68 (s,
1H, CH); 8.00 (d, 2H, 4-MeOC6H4, J = 9.1 Hz).
13C NMR (100 MHz, CDCl3): d 55.4 (OCH3); 55.5 (OCH3);
108.0 (C–CN); 114.1, 116.2, 120.8, 128.7, 130.3, 131.1, 136.7,
159.9, 161.8 (4-MeOC6H4, 3-MeOC6H4); 116.7 (CN); 118.0
(b, H–C C–CF3); 120.9 (q, CF3, J = 275.9 Hz); 149.9 (q,
C C–CF3, J = 35.9 Hz); 156.9 (3-MeOC6H4–C); 162.4 (4-
MeOC6H4–C–N).
Anal. calcd. for C17H19F3N2S: C, 61.81; H, 2.75. Found: C,
62.06; H, 2.57.
3.2.3.6. 2-(4-Methoxyphenyl)-4-phenyl-6-(trifluoromethyl)ni-
cotinonitrile (4f). Yield 170 mg (96%), white solid: m.p. 121–
122 8C; IR (nujol): n 2235 (CN);
1H NMR (400 MHz, CDCl3): d 7.22 (d, 2H, 4-MeOC6H4,
J = 7.6 Hz); 7.48–7.76 (m, 6H, Ph, C–H); 8.01 (d, 2H, 4-
MeOC6H4, J = 7.6 Hz).
Anal. calcd. for C21H15F3N2O2: C, 65.62; H, 3.93. Found: C,
65.48; H, 3.98.
13C NMR (100 MHz, CDCl3): d 55.4 (OCH3); 107.9 (C–
CN); 114.1, 128.6, 128.7, 129.2, 130.6, 131.1, 135.4, 161.8 (4-
MeOC6H4, Ph); 116.7 (CN); 118.1 (b, H–C C–CF3); 120.7 (q,
CF3, J = 275.2 Hz); 149.8 (q, C C–CF3, J = 35.1 Hz); 157.0
(Ph–C); 162.4 (4-MeOC6H4–C–N).
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