Three-component condensation of trifluoromethyl-substituted cyanovinylphosphonates, arylamines, and ketones and cytotoxic activity of products thus obtained

Article abstract of DOI:10.1007/s11172-010-0057-8

A three-component condensation of trifluoromethyl-substituted cyanovinylphosphonates, arylamines, and ketones (acetone, cyclopentanone, or cyclohexanone) has been studied. A possibility of using trifluoromethyl- substituted cyanovinylphosphonates as precursors of 1,4-dihydropyridines, 4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridines, 1,4,5,6,7,8-hexahydroquinolines, and 1,4,4a,5,6,7-hexahydroquinolines, modified with both trifluoromethyl and diethoxyphosphoryl groups, has been demonstrated. Using X-ray diffraction analysis, it was found that in some cases of the three-component condensation under study a mixture of 1-aryl-2-amino-and 2-arylamino-substituted products was formed. Migration of the multiple bond onto the ring fused with the dihydropyridine ring has been inferred from the NMR spectra and X-ray diffraction data. Cytotoxic activity of some compounds synthesized has been studied in the US National Cancer Institute.

Full text of DOI:10.1007/s11172-010-0057-8

Russian Chemical Bulletin, International Edition, Vol. 59, No. 1, pp. 144—161, January, 2010
144
Threeꢀcomponent condensation
of trifluoromethylꢀsubstituted cyanovinylphosphonates, arylamines,
and ketones and cytotoxic activity of products thus obtained
A. F. Shidlovskii,a A. S. Peregudov,a B. B. Averkiev,a Yu. N. Bulychev,b M. Yu. Antipin,a and N. D. Chkanikova
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: nchkan@ineos.ac.ru
bResearch Institute for Tumor Experimental Diagnostics and Therapy,
N. N. Blokhin Russian Cancer Scientific Center, Russian Academy of Medical Sciences,
24 Kashirskoe shosse, 115478 Moscow, Russian Federation.
Eꢀmail: ybulychev@hotmail.com
A threeꢀcomponent condensation of trifluoromethylꢀsubstituted cyanovinylphosphonates,
arylamines, and ketones (acetone, cyclopentanone, or cyclohexanone) has been studied.
A possibility of using trifluoromethylꢀsubstituted cyanovinylphosphonates as precursors of
1,4ꢀdihydropyridines, 4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridines, 1,4,5,6,7,8ꢀhexahydroꢀ
quinolines, and 1,4,4a,5,6,7ꢀhexahydroquinolines, modified with both trifluoromethyl and diꢀ
ethoxyphosphoryl groups, has been demonstrated. Using Xꢀray diffraction analysis, it was found
that in some cases of the threeꢀcomponent condensation under study a mixture of 1ꢀarylꢀ2ꢀ
aminoꢀ and 2ꢀarylaminoꢀsubstituted products was formed. Migration of the multiple bond onto
the ring fused with the dihydropyridine ring has been inferred from the NMR spectra and Xꢀray
diffraction data. Cytotoxic activity of some compounds synthesized has been studied in the US
National Cancer Institute.
Key words: trifluoromethylꢀsubstituted cyanovinylphosphonates, arylamines, acetone, cyꢀ
clopentanone, cyclohexanone, 1,4ꢀdihydropyridines, 4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]ꢀ
pyridines, 1,4,5,6,7,8ꢀhexahydroquinolines, 1,4,4a,5,6,7ꢀhexahydroquinolines, threeꢀcompoꢀ
nent condensation, migration of multiple bond, Xꢀray diffraction analysis, cytotoxic activity.
1,1ꢀDicyanoꢀ2ꢀ(trifluoromethyl)ethylenes and 3,3ꢀdiꢀ
thylꢀsubstituted cyanovinylphosphonates 3—6 with aryꢀ
lamines and ketones and cytotoxic activity of the condenꢀ
sation products.
cyanoꢀ2ꢀ(trifluoromethyl)acrylic esters are convenient
precursors of various trifluoromethylꢀsubstituted nitrogenꢀ
containing heterocycles,1—8 in particular, 1,4ꢀdihydropyꢀ
ridines and 1,4ꢀdihydropyrimidines possessing high insecꢀ
ticide activity.1,6,8 Earlier, we have shown a possibility of
using 2ꢀchloroꢀ1ꢀcyanoꢀ1ꢀdiethoxyphosphorylꢀ2ꢀ(triꢀ
fluoromethyl)ethylene (1) and its chlorodifluoromethyl
analog 2 for the synthesis of fluoroꢀcontaining heterocyꢀ
clic phosphonates,9 developed a method for the syntheꢀ
sis10 and studied reactions of vinylphosphonates 3—6 with
some nitrogenꢀ11 and oxygenꢀcontaining10 binucleophiles.
We also studied cytotoxic activity in vitro of some fluoroꢀ
containing heterocyclic phosphonates synthesized against
the standard panel consisting of 60 human tumor cell
lines.11 Thus, fluoroꢀcontaining vinylphosphonates12,13 are
important class of reactants, which open a possibility for
the study of biological activity of fluoroꢀcontaining hetꢀ
erocycles8,14,15 and for the search of new biologically acꢀ
tive phosphonates.16—22 The present work is devoted to the
study of threeꢀcomponent condensation of trifluoromeꢀ
X = F (1), Cl (2); Z = CN (3), CO2Me (4); R = CF3 (5), CO2Et (6)
Results and Discussion
Fluorineꢀcontaining dicyanoethylenes react at room
temperature with enamines, obtained both in situ and preꢀ
synthesized from ketones and arylamines, leading to hetꢀ
erocyclic systems containing 1,4ꢀdihydropyridine ring.6,8
Trifluoromethylꢀsubstituted cyanovinylphosphonates 3—6
also react in this way, however, a number of specific feaꢀ
tures is observed in this case: the formation of stable interꢀ
mediate products of Cꢀalkylation of enamines, the migraꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 143—159, January, 2010.
1066ꢀ5285/10/5901ꢀ0144 © 2010 Springer Science+Business Media, Inc.

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
145
tion of the multiple bonds onto the ring fused with the
dihydropyridine cycle, and the formation of side 2ꢀaryꢀ
laminoꢀsubstituted 1,4ꢀdihydropyridines.
Alkene 3 reacts with enamines the most readily and
selectively, furnishing compounds 7—9 in from satisfactoꢀ
ry to good yields (Scheme 1, Tables 1 and 2).
Scheme 1
Ar = 2,6ꢀMe2C6H3 (7a, 8a), 4ꢀMeOC6H4 (7b, 8b), 4ꢀClC6H4 (7c, 8c, 9a), 2ꢀClC6H4 (7d, 8d), 2,5ꢀCl C6H3 (7e, 8e), 3ꢀCF3C6H4 (7f, 8f),
2
4ꢀCF3C6H4 (7g, 9f), 3,4ꢀMe2C6H3 (9b), 3ꢀClC6H4 (9c), 4ꢀPhOC6H4 (9d), 2,6ꢀCl C6H3 (9e), 2,5ꢀ(MeO)2C6H3 (9g)
2
Table 1. Physicoꢀchemical characteristics of compounds 7—9
Comꢀ
pound
Ar
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
P
C
H
N
F
Cl
—
7a
7b
7c
7d
7e
7f
2,6ꢀMe2C6H3
4ꢀMeOC6H4
4ꢀClC6H4
67
152—154*
139—141*
143—145*
182—184*
190—191*
126—128
114—116
128—130*
111—113*
118—120*
147—150*
157—160*
53.91
54.18
51.49
51.24
47.74
48.07
48.00
48.07
44.73
44.65
47.10
47.21
47.27
47.21
56.53
56.29
53.17
53.51
50.13
50.48
50.78
50.48
47.30
47.08
5.71
5.68
5.24
5.21
4.55
4.48
4.52
4.48
3.93
3.95
4.15
4.17
4.17
4.17
5.81
5.80
5.40
5.35
4.69
4.66
4.65
4.66
4.10
4.15
9.43
9.48
9.36
9.40
9.27
9.34
9.30
9.34
8.70
8.68
8.72
8.69
8.66
8.69
8.90
8.95
8.91
8.91
8.80
8.83
8.85
8.83
8.21
8.23
—
—
C20H25F3N3O3P
C19H23F3N3O4P
C18H20ClF3N3O3P
C18H20ClF3N3O3P
C18H19Cl2F3N3O3P
C19H20F6N3O3P
C19H20F6N3O3P
C22H27F3N3O3P
C21H25F3N3O4P
C20H22ClF3N3O3P
C20H22ClF3N3O3P
C20H21Cl2F3N3O3P
74
6.83
6.91
6.80
6.89
—
12.54
12.80
12.42
12.67
—
—
81
8.30
7.88
—
2ꢀClC6H4
72.5
67
2,5ꢀCl2C6H3
3ꢀCF3C6H4
4ꢀCF3C6H4
2,6ꢀMe2C6H3
4ꢀMeOC6H4
4ꢀClC6H4
—
—
—
—
—
—
—
54
6.43
6.41
—
23.50
23.58
—
7g
8а
8b
8c
8d
8e
76
56
—
—
—
—
62
39.5
44
6.55
6.51
—
11.73
11.98
—
7.53
7.45
—
2ꢀClC6H4
2,5ꢀCl2C6H3
68
—
—
—
(to be continued)

146
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Table 1 (continued)
Comꢀ
pound
Ar
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
P
C
H
N
F
Cl
—
8f
3ꢀCF3C6H4
4ꢀClC6H4
75
86—88
49.50
49.52
51.81
51.49
57.01
57.14
51.34
51.49
59.55
59.23
48.00
48.11
50.50
50.48
53.04
53.59
4.33
4.35
4.90
4.94
6.06
6.05
4.92
4.94
5.33
5.34
4.38
4.42
4.62
4.62
5.69
5.67
8.25
8.25
8.58
8.58
8.71
8.69
8.62
8.58
7.68
7.67
8.00
8.01
8.00
8.03
8.17
8.15
6.13
6.08
6.30
6.32
—
22.22
22.38
11.60
11.63
—
C21H22F6N3O3P
C21H24ClF3N3O3P
C23H29F3N3O3P
C21H24ClF3N3O3P
C27H29F3N3O4P
C21H23Cl2F3N3O3P
C22H24F6N3O3P
C23H29F3N3O5P
9a
9b
9с
9d
9e
9f
47
132—134
106—109*
154—156*
118—121*
145—156*
97—98
7.29
7.24
—
3,4ꢀMe2C6H3
3ꢀClC6H4
19
52
—
—
—
—
—
—
—
—
—
—
—
4ꢀPhOC6H4
2,6ꢀCl2C6H3
4ꢀCF3C6H4
47
35.5
54
5.96
5.92
—
21.83
21.78
—
9g
2,5ꢀ(MeO)2C6H3 36.5
116—128*
* Melts with decomposition.
1
Table 2. H, 19F, and 31P NMR spectra of compounds 7—9 (DMSOꢀd6, δ, J/Hz)
Comꢀ
pound
1H NMR
19F NMR
(3 F, CF3)
31P NMR
(1 P, P(O)(OEt)2)
7a
1.29 (m, 6 H, OCH2Me); 1.37 (br.s, 3 H, C(6)Me); 2.09,
8.72 (br.s)
8.16 (br.s)
9.70 (br.s)
15.40 (br.s)
16.00 (br.s)
15.83 (br.s)
2.16 (both s, 3 H each, Me); 4.15 (m, 4 H, OCH2Me); 4.77 (d, 1 H,
H(5), 3JH,P = 5.9); 5.34 (br.s, 2 H, NH2); 7.22 (m, 2 H, Ar);
7.31 (t, 1 H, Ar, J = 7.5)
7ba
1.39 (t, 6 H, OCH2Me, J = 7.1); 1.57 (d, 3 H, C(6)Me,
5JH,P = 2.5); 3.88 (s, 3 H, OMe); 4.25 (m, 4 H, OCH2Me);
4.80 (d, 1 H, H(5), 3JH,P = 5.3); 4.84 (br.s, 2 H, NH2);
7.08, 7.23 (both d, 2 H each, Ar, J = 8.7)
1.29 (t, 6 H, OCH2Me, J = 7.2); 1.49 (d, 3 H, C(6)Me, 5JH,P = 2.9);
4.16 (m, 4 H, OCH2Me); 4.75 (d, 1 H, H(5), 3JH,P = 5.2);
5.67 (s, 2 H, NH2); 7.28, 7.56 (both d, 2 H each, Ar, J = 8.4)
7c
7da,b
7ec
7f
1.39 (m, 6 H, OCH2Me);1.54 (d, 3 H, C(6)Me, 5JH,P = 2.2);
4.27 (m, 4 H, OCH2Me); 4.88 (m, 3 H, H(5), NH2);
7.44—7.68 (m, 4 H, Ar)
7.64, 8.23
(both br.s)
15.39, 15.75
(both br.s)
1.28 (m, 6 H, OCH2Me); 1.48 (m, 3 H, C(6)Me); 4.14 (m, 4 H,
OCH2Me); 4.77 (m, 1 H, H(5)); 5.82, 5.85 (both s, 2 H, NH2);
7.51—7.68 (m, 3 H, Ar)
1.29 (t, 6 H, OCH2Me, J = 7.2); 1.48 (d, 3 H, C(6)Me, 5JH,P = 3.1);
4.16 (m, 4 H, OCH2Me); 4.80 (d, 1 H, H(5), 3JH,P = 4.7);
5.88 (s, 2 H, NH2); 7.59, 7.86 (both d, 1 H each, Ar, J = 7.8);
7.63 (s, 1 H, Ar); 7.74 (t, 1 H, Ar, J = 7.8)
9.31, 9.52
(both br.s)
15.18, 15.57
(both br.s)
9.96 (br.s);
17.19 (s, 3 F,
CF3C6H4)
16.40 (q,
3JF,P = 1.3)
7g
8a
1.29 (t, 6 H, OCH2Me, J = 7.2); 1.49 (d, 3 H, C(6)Me, 5JH,P = 3.1);
4.16 (m, 4 H, OCH2Me); 4.79 (d, 1 H, H(5), 3JH,P = 5.0);
5.84 (s, 2 H, NH2); 7.50, 7.88 (both d, 2 H each, Ar, J = 8.4)
9.85 (br.s);
17.17 (s, 3 F,
CF3C6H4)
16.33 (br.s)
1.28 (m 6 H, OCH2Me); 1.74 (m, 4 H, (CH2)3);
2.07, 2.14 (both s, 3 H each, Me); 2.44, 2.71 (both m, 1 H each, (CH2)3);
4.13 (m 4 H, OCH2Me); 5.49 (s, 2 H, NH2); 7.20 (m, 2 H, Ar);
7.29 (t, 1 H, Ar, J = 7.5)
13.04 (br.s)
15.14 (q,
3JF,P = 1.5)
(to be continued)

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
147
Table 2 (continued)
Comꢀ
pound
1H NMR
19F NMR
(3 F, CF3)
31P NMR
(1 P, P(O)(OEt)2)
8ba
1.39 (m, 6 H, OCH2Me); 1.84 (m, 2 H, (CH2)3); 2.16, 2.82 (both m,
1 H each, (CH2)3); 2.43 (m, 2 H, (CH2)3, H2O); 3.87 (s, 3 H, OMe);
4.24 (m, 4 H, OCH2Me); 4.88 (br.s, 2 H, NH2); 7.07 (m, 2 H, Ar);
7.22 (br.s, 2 H, Ar)
12.88 (br.s)
15.72 (q,
3JF,P = 1.7)
8c
1.28 (m, 6 H, OCH2Me); 1.75 (m, 2 H, (CH2)3); 1.85, 2.14, 2.39,
2.70 (all m, 1 H each, (CH2)3); 4.17 (m, 4 H, OCH2Me);
5.81 (s, 2 H, NH2); 7.27, 7.55 (both d, 2 H each, Ar, J = 8.5)
14.14 (br.s)
15.49 (q,
3JF,P = 2.0)
8dd
8ee
8f
1.28 (m, 6 H, OCH2Me); 1.85 (m, 4 H, (CH2)3); 2.43, 2.74 (both m,
1 H each, (CH2)3); 4.14 (m, 4 H, OCH2Me); 5.63, 5.67 (both s, 2 H,
NH2); 7.45 (m, 3 H, Ar); 7.64 (d, 1 H, Ar, J = 7.5)
13.52, 13.74
(both br.s)
14.75, 15.15
(both br.s)
1.28 (m, 6 H, OCH2Me); 1.93 (m, 4 H, (CH2)3); 2.43, 2.73 (both m,
1 H each, (CH2)3); 4.14 (m, 4 H, OCH2Me); 5.87, 5.92 (both br.s,
2 H, NH2); 7.45—7.68 (m, 3 H, Ar)
13.69 (br.s)
14.85, 15.11
(both br.s)
1.29 (m, 6 H, OCH2Me); 1.78 (m, 3 H, (CH2)3); 2.18, 2.41,
2.69 (all m, 1 H each, (CH2)3); 4.10 (m, 4 H, OCH2Me);
5.95 (s, 2 H, NH2); 7.57 (m, 2 H, Ar); 7.73 (t, 1 H, Ar, J = 7.8);
7.84 (d, 1 H, Ar, J = 7.8)
14.30 (br.s);
17.18 (s, 3 F,
CF3C6H4)
15.96 (q,
3JF,P = 2.2)
9a
9b
9c
9d
1.30 (m, 6 H, OCH2Me); 1.39 (m, 2 H, (CH2)4); 1.55 (m, 3 H, (CH2)4);
1.72, 2.02, 2.59 (all m, 1 H each, (CH2)4); 4.13 (m, 4 H, OCH2Me);
5.41 (br.s, 2 H, NH2); 7.32, 7.56 (both d, 2 H each, Ar, J = 8.4)
17.11 (br.s)
16.72 (br.s)
17.27 (br.s)
16.96 (br.s)
16.82 (q,
3JF,P = 4.1)
1.29 (m, 6 H, OCH2Me); 1.37 (m, 2 H, (CH2)4); 1.55 (m, 3 H, (CH2)4);
1.71, 2.00, 2.60 (all m, 1 H each, (CH2)4); 4.13 (m, 4 H, OCH2Me);
5.20 (br.s, 2 H, NH2); 7.01 (m, 2 H, Ar); 7.26 (d, 1 H, Ar, J = 7.5)
16.65 (q,
3JF,P = 4.2)
1.30 (m, 6 H, OCH2Me); 1.41 (m, 2 H, (CH2)4); 1.57 (m, 3 H, (CH2)4);
1.77, 2.00, 2.58 (all m, 1 H each, (CH2)4); 4.14 (m, 4 H, OCH2Me);
5.50 (s, 2 H, NH2); 7.30—7.56 (m, 4 H, Ar)
16.90 (br.s)
1.30 (m, 6 H, OCH2Me); 1.40 (m, 2 H, (CH2)4); 1.57 (m, 3 H, (CH2)4);
1.75, 2.00, 2.60 (all m, 1 H each, (CH2)4); 4.14 (m, 4 H, OCH2Me);
5.39 (br.s, 2 H, NH2); 7.07, 7.27 (both d, 2 H each, Ar, J = 8.7);
7.11 (d, 2 H, Ar, J = 8.1); 7.20 (t, 1 H, Ar, J = 7.5);
16.82 (q,
3JF,P = 4.2)
7.44 (dd, 2 H, Ar, J = 7.5, 8.1)
9e
A: 58%; 1.27 (m, 6 H, OCH2Me); 1.35—2.25 (m, 7 H, (CH2)4);
2.70 (m, 1 H, (CH2)4); 4.12 (m, 4 H, OCH2Me); 5.61 (br.s, 2 H, NH2);
7.48—7.66 (m, 3 H, Ar)
B: 42%; 1.27 (m, 6 H, OCH2Me); 1.35—2.25 (m, 6 H, =CH(CH2)3);
3.03 (m, 1 H, H(4a)); 4.41 (m, 1H, H(8)); 4.12 (m, 4 H, OCH2Me);
5.61 (br.s, 2 H, NH2); 7.48—7.66 (m, 3 H, Ar)
15.66 (br.s)
15.73 (br.s)
15.82 (br.s)
17.74 (br.s)
9f
1.30 (m, 6 H, OCH2Me); 1.41 (m, 3 H, (CH2)4); 1.57 (m, 2 H, (CH2)4);
1.73, 2.01, 2.59 (all m, 1 H each, (CH2)4); 4.14 (m, 4 H, OCH2Me);
5.60 (br.s, 2 H, NH2); 7.55, 7.88 (both d, 2 H each, Ar, J = 8.4)
17.24 (s, 3 F,
CF3C6H4);
17.30
(d, 3JF,P = 3.7)
16.90 (q,
3JF,P = 3.7)
9gf
1.31(m, 6 H, OCH2Me); 1.40—1.72 (m, 6 H, (CH2)4);
2.00, 2.62 (both m, 1 H each, (CH2)4); 3.73, 3.76 (both s, 3 H each, OMe);
4.15 (m, 4 H, OCH2Me); 5.16, 5.24 (both br.s, 2 H, NH2);
6.72 (br.s, 1 H, Ar); 7.10 (m, 2 H, Ar)
14.97, 17.21
(both br.s)
15.59, 16.98
(both br.s)
a The spectrum was recorded in CD3CN.
b A mixture of atropoisomers 1.4 : 1.
c A mixture of atropoisomers 1.35 : 1.
d A mixture of atropoisomers 1.39 : 1.
e A mixture of atropoisomers 1.25 : 1.
f A mixture of atropoisomers 1.72 : 1.

148
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Scheme 3
Compounds 7d,e, 8d,e, and 9g containing a substituꢀ
ent at orthoꢀposition of the aromatic ring are formed as
a mixture of atropoisomers (the ratio is given in Table 2).
The isomerism in these substances is explained by the hinꢀ
drance of rotation around the N—Ar bond and the presꢀ
ence of asymmetric carbon atom C(4) in the dihydropyriꢀ
dine ring. In the case of compound 7d, individual isomers
were successfully isolated by preparative thinꢀlayer chroꢀ
matography, however, rather rapid interconversion of the
atropoisomers occurs in CD3CN.
In the 1H NMR spectrum of compound 9e recorded in
DMSOꢀd6 along with signals, which correspond to the
structure A, other signals are observed, from which two
characteristic signals at δ 3.03 and 4.41 could be separated.
These signals, apparently, correspond to the protons H(4a)
and H(8) in the structure В. The 19F and 31P NMR spectra
also contain double sets of signals for the trifluoromethyl
and diethoxyphosphoryl groups. It is possible that upon
dissolution of 9e, its equilibrium isomerization occurs
(Scheme 2). Integration of the corresponding signals of
two isomeric forms in the NMR spectra indicates a small
predominance of form A (58%) over form B (42%). Such
a phenomenon has been assumed earlier based on the NMR
spectral data, including twoꢀdimensional experiments
COSY and NOESY, for 4ꢀ(difluorodiethoxyphosphoryl)ꢀ
methylꢀsubstituted hexahydroquinolines.23
Scheme 2
It should be noted that a number of specific features is
observed for the threeꢀcomponent condensation of vinylꢀ
phosphonate 3 with trifluoromethylꢀsubstituted anilines
and ketones, depending on the structure of the latter. For
instance, the reaction with acetone, in addition to the maꢀ
jor 2ꢀaminodihydropyridines 7f,g, gives 11% and 4% (the
1H and 19F NMR spectral data of the reaction mixture) of
2ꢀarylaminoꢀsubstituted compounds 10a and 10b, respecꢀ
tively. The reaction of 3 with 4ꢀ(trifluoromethyl)aniline
and cyclohexanone also leads to 2ꢀarylaminohexahydroꢀ
quinoline 11, which was successfully isolated (6% yield)
and characterized (Scheme 3). At the same time, no forꢀ
mation of such side products was observed in the reaction
with cyclopentanone.
formation of a number of side compounds and the yields of
cyclization products at the nitrile group of compounds 12
and 13 do not exceed 60% (Scheme 4).
Alkene 4 reacts with arylamines and ketones considerꢀ
ably slower than 3, the reaction is always accompanied by

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
149
Scheme 4
F(2)
F(1)
F(3)
C(16)
C(5)
C(4)
C(4A)
C(6)
C(3)
N(2)
C(15)
C(7)
C(2)
C(7A)
N(1)
O(1)
C(8)
C(9)
Ar = 2,6ꢀMe2C6H3 (12a, 13b), 4ꢀMeOC6H4 (12b, 13a),
4ꢀCF3C6H4 (12c)
C(13)
C(10)
In the reaction of alkene 4 with pꢀanisidine and cycloꢀ
pentanone (Scheme 5), in addition to the target product
13a, compound 15 containing no diethoxyphosphoryl
group was isolated, the formation of which can be exꢀ
plained by intramolecular cyclization at the methoxycarꢀ
bonyl group and subsequent elimination of the phosꢀ
phonate group from the intermediate 14. The structure
of compound 15 was confirmed by the Xꢀray diffraction
data (Fig. 1).
C(12)
C(11)
O(2)
C(14)
Compound 5 under conditions of such threeꢀcompoꢀ
nent condensation very often forms stable intermediate
products of Cꢀalkylation of the enamine obtained in situ.
The reaction of 5 with substituted anilines and acetone in
CCl4 at 20 °C rapidly leads to compounds 16a—c, comꢀ
pounds 16a,b were isolated by preparative thinꢀlayer chroꢀ
matography and characterized (compound 16c was used
for the synthesis of 18c without chromatographic purificaꢀ
tion). No intramolecular cyclization to 1,4ꢀdihydropyriꢀ
dine derivatives was observed upon prolonged keeping of
the reaction mixtures at room temperature, rather a slow
Fig. 1. General view of the molecule 15 in representation of
atoms by ellipsoids of atomic displacements with 50% probability.
hydrolysis of compounds 16a—c (due to the water liberatꢀ
ing in the first step of the process) to the starting aryꢀ
lamines took place (confirmed by TLC data) and the prodꢀ
uct of acetone alkylation 17. The target 2ꢀaminoꢀ1ꢀarylꢀ
3ꢀdiethoxyphosphorylꢀ6ꢀmethylꢀ4,4ꢀbis(trifluoromethyl)ꢀ
1,4ꢀdihydropyridines 18a—c were obtained upon proꢀ
Scheme 5

150
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
longed reflux of compounds 16a—c in carbon tetrachloꢀ
ride (Scheme 6, Tables 3 and 4).
Similarly to the preceding transformation, the reaction
of alkene 5 with arylamines and cyclopentanone also leads
to the intermediate Cꢀalkylation products 19 (detected
by TLC), which undergo intramolecular cyclization to
4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridine derivatives
20a—d already at 20 °C (Scheme 7, see Tables 3 and 4).
Scheme 6
Scheme 7
i. 20 °C, 48—120 h.
Ar = 4ꢀMeOC6H4 (20a), 3ꢀCF3C6H4 (20b), 4ꢀCF3C6H4 (20c),
2ꢀClC6H4 (20d)
i. CCl4, reflux, 18 h; ii. 20 °C, 120 h.
Ar = 4ꢀMeOC6H4 (16a, 18a), 4ꢀClC6H4 (16b, 18b),
4ꢀPhOC6H4 (16c, 18c)
We also studied behavior of vinylphosphonate 5 in the
threeꢀcomponent condensation with arylamines and cyꢀ
Table 3. Physicoꢀchemical characteristics of compounds 18, 20, 21
Comꢀ
pound
Ar
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
P
C
H
N
F
Cl
—
18a
18b
18c
20a
20b
20c
20d
21a
21b
4ꢀMeOC6H4
4ꢀClC6H4
50
48
41
76
37
37
28
57
26
98—100
128—129
*
46.63
46.73
4.75
4.78
5.74
5.73
—
—
C19H23F6N2O4P
C18H20ClF6N2O3P
C24H25F6N2O4P
C21H25F6N2O4P
C21H22F9N2O3P
C21H22F9N2O3P
C20H22ClF6N2O3P
C22H27F6N2O4P
C22H24F9N2O3P
43.70
43.87
4.11
4.09
5.70
5.68
6.27
6.29
23.05
23.13
7.27
7.19
4ꢀPhOC6H4
4ꢀMeOC6H4
3ꢀCF3C6H4
4ꢀCF3C6H4
2ꢀClC6H4
52.45
52.37
4.58
4.59
5.07
5.09
—
—
—
—
—
—
—
—
—
—
—
—
—
147—148
164—165
188—189
113—115
134—135
164—165
49.00
49.03
4.91
4.90
5.45
5.45
22.00
22.16
45.68
45.66
4.01
4.01
5.07
5.07
30.90
30.95
45.41
45.66
4.01
4.03
5.07
5.02
—
46.15
46.30
4.29
4.27
5.43
5.40
—
4ꢀMeOC6H4
3ꢀCF3C6H4
50.06
50.01
5.14
5.15
5.32
5.30
5.89
5.86
21.43
21.57
46.78
46.65
4.29
4.27
4.94
4.95
—
29.89
30.19
* Amorphous substance.

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
151
Table 4. 1H, 19F, and 31P NMR spectra of compounds 18, 20, 21 (CDCl3, δ, J/Hz)
Comꢀ
pound
1H NMR
19F NMR
31P NMR
(1 P, P(O)(OEt)2)
18a
18b
18c
20a
1.31 (t, 6 H, OCH2Me, J = 7.1); 1.57 (s, 3 H, C(6)Me); 3.85 (s, 3 H,
OMe); 4.05 (m, 4 H, OCH2Me); 4.77 (d, 1 H, H(5), 4JH,P = 5.6);
6.40 (br.s, 2 H, NH2); 6.97, 7.12 (both d, 2 H each, Ar, J = 8.8)
7.73 (s,
6 F, 2 CF3)
26.59 s
1.32 (t, 6 H, OCH2Me, J = 7.2); 1.58 (s, 3 H, C(6)Me);
4.06 (m, 4 H, OCH2Me); 4.81 (d, 1 H, H(5), 4JH,P = 5.6);
6.38 (br.s, 2 H, NH2); 7.18, 7.47 (both d, 2 H each, Ar, J = 8.7)
7.77 (s,
6 F, 2 CF3)
26.06 s
26.37 s
27.51 s
1.32 (t, 6 H, OCH2Me, J = 7.2); 1.61 (s, 3 H, C(6)Me);
4.07 (m, 4 H, OCH2Me); 4.80 (d, 1 H, H(5), 4JH,P = 5.9);
6.44 (br.s, 2 H, NH2); 7.03—7.43 (m, 9 H, Ar)
7.73 (s,
6 F, 2 CF3)
1.32 (t, 6 H, OCH2Me, J = 7.1); 1.83 (quint, 2 H, CH2CH2CH2,
J = 7.3); 2.10, 2.67 (both m, 2 H each, CH2CH2CH2); 3.84 (s, 3 H, OMe);
4.05 (m, 4 H, OCH2Me); 6.55 (br.s, 2 H, NH2);
10.53 (s,
6 F, 2 CF3)
6.94, 7.13 (both d, 2 H each, Ar, J = 8.8)
20b
1.32 (t, 6 H, OCH2Me, J = 7.2); 1.87, 2.10, 2.69 (all br.m, 2 H each,
(CH2)3); 4.07 (m, 4 H, OCH2Me); 6.47 (br.s, 2 H, NH2); 7.45 (d, 1 H,
Ar, J = 7.5); 7.51 (br.s, 1 H, Ar); 7.63 (dd, 1 H, Ar, J = 7.5, 7.8);
7.73 (d, 1 H, Ar, J = 7.8)
10.59 (s,
6 F, 2 CF3);
15.02 (s,
26.55 s
3 F, CF3C6H4)
20c
20d
21a
1.32 (t, 6 H, OCH2Me, J = 7.2); 1.87 (m, 2 H, CH2CH2CH2);
2.11, 2.68 (both br.m, 2 H each, CH2CH2CH2); 4.06 (m, 4 H, OCH2Me);
6.47 (br.s, 2 H, NH2); 7.38, 7.75 (both d, 2 H each, Ar, J = 8.4)
10.58 (s, 6 F, 2 CF3);
15.00 (s,
3 F, CF3C6H4)
26.62 s
1.32 (br.m, 6 H, OCH2Me); 1.85 (br.s, 2 H, CH2CH2CH2);
1.96—2.20 (br.m, 2 H each, (CH2)3); 2.69 (br.s, 2 H, (CH2)3); 4.06 (br.m,
4 H, OCH2Me); 6.45 (br.s, 2 H, NH2); 7.30—7.56 (m, 4 H, Ar)
10.15, 11.99
(both q, 3 F each,
CF3, 4JF,F = 10.6)
27.33 br.s
27.34 s
1.30 (m, 6 H, OCH2Me); 1.38 (m, 1 H, =CH(CH2)3); 1.79—2.02 (m, 4 H,
=CH(CH2)3); 2.14 (br.s, 1 H, =CH(CH2)3); 3.32 (br.s, 1 H, H(4a));
3.85 (s, 3 H, OMe); 4.03 (m, 4 H, OCH2Me); 4.31 (br.m, 1H, H(8));
6.58 (br.s, 2 H, NH2); 6.94—7.08 (m, 4 H, Ar)
13.38 (q, 3 F, CF3,
4JF,F = 10.0);
16.51 (br.q, 3 F, CF3,
4JF,F = 10.0)
21b
1.31 (m, 6 H, OCH2Me); 1.40 (m, 1 H, =CH(CH2)3); 1.81—2.02 (br.m,
4 H, =CH(CH2)3); 2.16 (br.s, 1 H, =CH(CH2)3); 3.50 (br.s, 1 H,
H(4a)); 4.03 (br.m, 4 H, OCH2Me); 4.11 (br.m, 1 H, H(8));
6.49 (br.s, 2 H, NH2); 7.40 (d, 1 H, Ar, J = 7.6); 7.46 (br.s, 1 H, Ar);
7.65 (dd, 1 H, Ar, J = 7.6, 7.3); 7.71 (d, 1 H, Ar, J = 7.3)
13.45 (q, 3 F, CF3,
4JF,F = 10.1);
16.55 (br.q, 3 F, CF3,
4JF,F = 10.1);
26.52 s
15.08 (s, 3 F, CF3C6H4)
Scheme 8
clohexanone. It turned out that intermediate Cꢀalkylation
products of enamines fairly fast are converted to the subꢀ
stituted hexahydroquinolines 21a,b and, like compound
9e, there is observed migration of the multiple bond onto
the ring fused with the dihydropyridine cycle (Scheme 8,
see Tables 3 and 4). The structures of products 21a,b were
confirmed by NMR spectroscopy and Xꢀray diffraction
data for compound 21a (Fig. 2).
Vinylphosphonate 6 also reacts with anilines differentꢀ
ly depending on the ketone structure. For instance, in the
case of acetone, the reaction takes place only with aryꢀ
lamines containing electronꢀdonating substituents in the
aromatic ring, resulting in the low yields of mixtures of two
isomeric products 22 and 23 (Scheme 9, Tables 5 and 6). It
should be noted that both isomers 22b and 23b were isolatꢀ
ed only in the case of the reaction of alkene 6 with acetone
and pꢀanisidine.
i. 20 °C, 48 h.
Ar = 4ꢀMeOC6H4 (21a), 3ꢀCF3C6H4 (21b)

152
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Two products 24 and 25 were as well obtained in the
threeꢀcomponent condensation of vinylphosphonate 6
with cyclopentanone and most of the arylamines studied
by us. The overall yields were 60—70% and both isomers
24a—d and 25a—d can be isolated (see Scheme 9, Tables 5
and 6). However, in the case of 2,6ꢀdimethylaniline no
formation of noticeable amount of the side product was
observed in this transformation and only compound 24e
was successfully isolated. The structures of products 24
and 25 were confirmed by Xꢀray diffraction of compounds
24c (Fig. 3) and 25c (Fig. 4).
In the reaction of alkene 6 with cyclohexanone and
anilines, likewise in the case of alkene 5, migration of the
multiple bond and formation of hexahydroquinoline deꢀ
rivatives 26a—f were observed (see Scheme 9, Tables 5 and
6). It should be noted that compounds 26a—f are formed
as a mixture of diastereomers (the ratio is given in Table 6).
In conclusion, we studied the reaction of trifluoromeꢀ
thylꢀsubstituted cyanovinylphosphonates 3—6 with enamꢀ
ines obtained in situ from arylamines and ketones (aceꢀ
tone, cyclopentanone, and cyclohexanone). We demonꢀ
strated a possibility of using alkenes 3—6 as precursors
of 1,4ꢀdihydropyridines, 4,5,6,7ꢀtetrahydroꢀ1Hꢀcycloꢀ
penta[b]pyridines, 1,4,5,6,7,8ꢀhexahydroquinolines, and
1,4,4a,5,6,7ꢀhexahydroquinolines, modified with both triꢀ
fluoromethyl and diethoxyphosphoryl groups.
C(21)
F(2)
C(20)
F(3)
O(2)
O(1)
F(1)
C(16)
C(4)
C(5)
P(1)
C(6)
C(18)
C(19)
C(17)
O(3)
C(4A)
C(8A)
F(6)
C(2)
F(5)
C(7)
N(2)
N(1)
F(4)
C(9)
C(8)
C(14)
C(13)
C(12)
C(10)
C(11)
O(4)
C(15)
Cytotoxic activity of some compounds synthesized was
studied in vitro at the US National Cancer Institute against
Fig. 2. General view of the molecule 21a in representation of
atoms by ellipsoids of atomic displacements with 50% probability.
Scheme 9
Ar = 2,6ꢀMe2C6H3 (22a, 24e, 26b), 4ꢀMeOC6H4 (22b, 23b, 26c), 4ꢀPhOC6H4 (22c, 24a, 25a), Ph (23a, 26a), 2,5ꢀ(MeO)2C6H3 (23c),
4ꢀCF3C6H4 (24b, 25b, 26f), 4ꢀFC6H4 (24c, 25c), 3ꢀClC6H4 (24d, 25d, 26e), 3,5ꢀ(MeO)2C6H3 (26d)

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
153
Table 5. Physicoꢀchemical characteristics of compounds 22—26
Comꢀ
pound
Ar
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
P
C
H
N
F
Cl
—
22a
22b
22с
23a
23b
23c
24a
24b
24c
24d
24e
25a
25b
25c
25d
26a
26b
26c
26d
26e
26f
2,6ꢀMe2C6H3
4ꢀMeOC6H4
4ꢀPhOC6H4
Ph
35
9
*
53.90
53.88
6.19
6.17
5.75
5.71
6.31
6.32
11.45
11.62
C22H30F3N2O5P
C21H28F3N2O6P
C26H30F3N2O6P
C20H26F3N2O5P
C21H28F3N2O6P
C22H30F3N2O7P
C28H32F3N2O6P
C23H27F6N2O5P
C22H27F4N2O5P
C22H27ClF3N2O5P
C24H32F3N2O5P
C28H32F3N2O6P
C23H27F6N2O5P
C22H27F4N2O5P
C22H27ClF3N2O5P
C23H30F3N2O5P
C25H34F3N2O5P
C24H32F3N2O6P
C25H34F3N2O7P
C23H29ClF3N2O5P
C24H29F6N2O5P
121—123
168—170
*
51.11
51.22
5.72
5.73
5.73
5.69
—
—
—
—
—
—
—
—
—
—
9
56.12
56.32
5.46
5.45
5.02
5.05
—
—
14
4
52.10
51.95
5.66
5.67
6.05
6.06
6.75
6.70
12.21
12.33
4ꢀMeOC6H4
2,5ꢀ(MeO)2C6H3
4ꢀPhOC6H4
4ꢀCF3C6H4
4ꢀFC6H4
*
51.16
51.22
5.75
5.73
5.63
5.69
—
—
—
—
—
—
—
—
—
13
35
17
24
9
*
51.04
50.58
5.80
5.79
5.35
5.36
164—165
182—183
132—133
*
57.99
57.93
5.57
5.56
4.81
4.83
49.69
49.65
4.89
4.89
5.02
5.03
52.33
52.18
5.39
5.37
5.55
5.53
14.85
15.01
3ꢀClC6H4
50.51
50.54
5.22
5.20
5.35
5.36
5.95
5.92
11.00
10.90
6.69
6.78
2,6ꢀMe2C6H3
4ꢀPhOC6H4
4ꢀCF3C6H4
4ꢀFC6H4
23
32
43.5
47.5
46
41
19
55
50.5
49
38
*
55.99
55.81
6.26
6.24
5.39
5.42
—
—
—
—
—
—
—
—
—
—
117—118
158—159
178—180
183—185
135—137
93—95
156—158
144—146
133—135
209—210
57.98
57.93
5.55
5.56
4.83
4.83
49.49
49.65
4.88
4.89
5.06
5.03
52.10
52.18
5.37
5.37
5.54
5.53
6.10
6.12
14.95
15.01
3ꢀClC6H4
50.59
50.54
5.21
5.20
5.35
5.36
—
10.87
10.90
6.83
6.78
Ph
54.55
54.98
6.04
6.02
5.56
5.58
6.19
6.16
11.22
11.34
—
—
—
—
2,6ꢀMe2C6H3
4ꢀMeOC6H4
3,5ꢀ(MeO)2C6H3
3ꢀClC6H4
56.51
56.60
6.47
6.46
5.25
5.28
—
—
—
—
—
—
54.00
54.13
6.06
6.06
5.27
5.26
53.54
53.38
6.07
6.09
4.98
4.98
51.43
51.45
5.44
5.44
5.21
5.22
5.79
5.77
10.58
10.62
6.69
6.60
4ꢀCF3C6H4
50.40
50.53
5.14
5.12
4.91
4.91
—
19.75
19.98
—
* Amorphous substance.
a standard panel consisting of 60 human tumor cell
lines24 (Table 7). The data given should be considered as
the results of the first step in the study of compounds of
this series allowing us to find promising compounds for
further research.
Most of compounds studied possess moderate cytotoxꢀ
ic activity with the absence of clear selectivity of action
against the cell cultures belonging to various subpanels,
excluding absolutely inactive compound 25d. Compounds
of the dihydropyridine series 7c and 7е exhibited similar

154
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Table 6. 1H, 19F, and 31P NMR spectra of compounds 22—26 (DMSOꢀd6, δ, J/Hz)
Comꢀ
pound
1H NMR
19F NMR
(3 F, CF3)
31P NMR
(1 P, P(O)(OEt)2)
22a
1.15—1.23 (m, 9 H, OCH2Me); 1.34 (c, 3 H, C(6)Me);
2.09, 2.12 (both s, 3 H each, Me); 3.90 (m, 4 H, OCH2Me);
4.04, 4.14 (both m, 1 H each, OCH2Me); 4.66 (d, 1 H, H(5), 4JH,P = 5.9);
5.23 (s, 2 H, NH2); 7.21—7.31 (m, 3 H, Ar)
5.11 s
25.86 s
22ba
1.25—1.36 (m, 9 H, OCH2Me); 1.55 (s, 3 H, C(6)Me);
3.85 (s, 3 H, OMe); 4.07 (br.m, 4 H, OCH2Me); 4.27 (br.m, 2 H,
OCH2Me); 4.64 (d, 1 H, H(5), 4JH,P = 4.7); 5.11 (br.s, 2 H, NH2);
6.96 (d, 2 H, Ar, J = 8.7); 7.15 (br.m, 2 H, Ar)
3.38 s
25.74 s
22c
23a
1.15—1.24 (m, 9 H, OCH2Me); 1.53 (s, 3 H, C(6)Me); 3.90 (br.m, 4 H,
OCH2Me); 4.10 (br.m, 2 H, OCH2Me); 4.36 (br.d, 1 H, H(5),
4JH,P = 3.4); 5.35 (s, 2 H, NH2); 6.93—7.45 (m, 9 H, Ar)
3.83 s
3.51 s
25.03 s
25.59 s
0.94, 1.11, 1.20 (all t, 3 H each, OCH2Me, J = 7.2); 1.81 (s, 3 H,
C(6)Me); 3.81 (m, 4 H, OCH2Me); 4.04, 4.15 (both m, 1 H each,
OCH2Me); 4.38 (d, 1 H, H(5), 4JH,P = 5.0); 6.91—6.95 (m, 3 H, Ar);
7.28 (dd, 2 H, Ar, J = 7.5, 8.1); 7.40 (s, 1 H, NH);
9.16 (d, 1 H, NH, 4JH,P = 3.4)
23b
23c
1.04 (br.t, 3 H, OCH2Me, J = 7.1); 1.15, 1.21 (both br.t, 3 H each,
OCH2Me, J = 7.1); 1.78 (s, 3 H, C(6)Me); 3.72 (s, 3 H, OMe);
3.85 (br.m, 4 H, OCH2Me); 4.05, 4.13 (both br.m, 1 H each, OCH2Me);
4.34 (br.s, 1 H, H(5)); 6.91 (br.m, 4 H, Ar); 7.43 (s, 1 H, NH);
8.75 (br.s, 1 H, NH)
3.91 s
3.57 s
5.47 s
24.17 s
22.84 s
0.95 (t, 3 H, OCH2Me, J = 7.2); 1.19 (m, 6 H, OCH2Me);
1.83 (s, 3 H, C(6)Me); 3.67, 3.78 (both s, 3 H each, OMe);
3.80—4.18 (m, 6 H, OCH2Me); 4.39 (d, 1 H, H(5), 4JH,P = 4.7);
6.46—6.50 (m, 2 H, Ar); 6.93 (d, 1 H, Ar, J = 9.0); 7.32 (s, 1 H, NH);
9.22 (d, 1 H, NH, 4JH,P = 2.8)
24a
24b
24c
24e
25a
1.18—1.24 (m, 9 H, OCH2Me); 1.81 (br.m, 2 H, CH2CH2CH2);
1.93, 2.14, 2.31, 2.41 (br.m, 1 H each, CH2CH2CH2);
3.90 (m, 4 H, OCH2Me); 4.06, 4.16 (both m, 1 H each, OCH2Me);
5.34 (s, 2 H, NH2); 7.06—7.45 (m, 9 H, Ar)
25.42 s
24.97 s
23.99 s
28.25 s
23.98 s
1.18—1.25 (m, 9 H, OCH2Me); 1.83 (br.m, 3 H, (CH2)3);
2.17 (br.m, 1 H, (CH2)3); 2.39 (br.m, 2 H, (CH2)3); 3.92 (br.m, 4 H,
OCH2Me); 4.06, 4.19 (both m, 1 H each, OCH2Me); 5.42 (s, 2 H, NH2);
7.48, 7.87 (both d, 2 H each, Ar, J = 8.4)
5.46 s,
17.21 (s, 3 F,
CF3C6H4)
1.18—1.24 (m, 9 H, OCH2Me); 1.82 (br.m, 3 H, (CH2)3);
2.15, 2.31, 2.40 (all m, 1 H each, (CH2)3); 3.91 (br.m, 4 H, OCH2Me);
4.06, 4.17 (both m, 1 H each, OCH2Me); 5.33 (s, 2 H, NH2);
7.26—7.35 (m, 4 H, Ar)
–34.64
(s, 1 F, FC6H4);
5.43 s
1.17—1.24 (m, 9 H, OCH2Me); 1.79 (br.m, 3 H, (CH2)3);
1.92, 2.15, 2.43 (all br.m, 1 H each, (CH2)3); 2.09, 2.11 (both s,
3 H each, Me); 3.92 (m, 4 H, OCH2Me); 4.07, 4.18 (both m, 1 H each,
OCH2Me); 5.15 (s, 2 H, NH2); 7.20—7.31(m, 3 H, Ar)
6.83 s
5.79 s
1.01, 1.15, 1.21 (all t, 3 H each, OCH2Me, J = 7.2); 1.89 (br.m, 2 H,
CH2CH2CH2); 2.07, 2.34 (both br.m, 1 H each, CH2CH2CH2);
2.42 (br.m, 2 H, CH2CH2CH2); 3.77, 4.05, 4.18 (all m, 1 H each,
OCH2Me); 3.95 (m, 2 H, OCH2Me); 6.93—7.38 (m, 10 H, Ar, NH);
9.36 (d, 1 H, NH, 4JH,P = 3.1)
25b
0.91, 1.08, 1.23 (all t, 3 H each, OCH2Me, J = 7.2); 1.92 (br.m, 2 H,
CH2CH2CH2); 2.08, 2.36 (both br.m, 1 H each, CH2CH2CH2);
2.44 (br.m, 2 H, CH2CH2CH2); 3.72, 4.06, 4.19 (all m, 1 H each,
OCH2Me); 3.85 (m, 3 H, OCH2Me); 7.03, 7.58 (both d, 2 H each, Ar,
J = 8.7); 7.68 (s, 1 H, NH); 9.65 (d, 1 H, NH, 4JH,P = 3.7)
5.88 s,
18.55 (s, 3 F,
CF3C6H4)
22.14 s
(to be continued)

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
155
Table 6 (continued)
Comꢀ
pound
1H NMR
19F NMR
(3 F, CF3)
31P NMR
(1 P, P(O)(OEt)2)
25c
25d
0.99, 1.14, 1.21 (all t, 3 H each, OCH2Me, J = 7.2); 1.89 (br.m,
2 H, CH2CH2CH2); 2.07 (br.m, 1 H, CH2CH2CH2); 2.37 (br.m, 3 H,
CH2CH2CH2); 3.77, 4.05, 4.18 (all m, 1 H each, OCH2Me);
3.88 (m, 3 H, OCH2Me); 6.99, 7.13 (both m, 2 H each, Ar);
7.30 (s, 1 H, NH); 9.35 (d, 1 H, NH, 4JH,P = 3.1)
–43.86
(s, 1 F, FC6H4);
5.76 s
22.53 s
0.95, 1.10, 1.21 (all t, 3 H each, OCH2Me, J = 6.9); 1.91 (br.m,
2 H, CH2CH2CH2); 2.08, 2.33 (both br.m, 1 H each, CH2CH2CH2);
2.45 (br.m, 2 H, CH2CH2CH2); 3.75, 4.06, 4.18 (br.m, 1 H each,
OCH2Me); 3.87 (br.m, 3 H, OCH2Me); 6.85, 6.93 (both br.d, 1 H each,
Ar, J = 7.5, 7.8); 7.26 (dd, 1 H, Ar, J = 7.5, 7.8);
5.65 s
22.67 s
7.42 (br.s, 1 H, NH); 9.54 (br.d, 1 H, NH, 4JH,P = 3.4)
26aa,b
1.28 (m, 6 H, OCH2Me); 1.34 (t, 3 H, OCH2Me, J = 7.2); 1.47, 2.01
(both br.m, 1 H each, =CH(CH2)3); 1.72—1.91 (br.m, 4 H, =CH(CH2)3);
3.47 (br.m, 1 H, H(4a)); 4.06 (m, 4 H, OCH2Me); 4.15—4.45 (br.m,
3 H, OCH2Me, H(8)); 4.86 (br.s, 2 H, NH2); 7.16—7.51 (m, 5 H, Ar)
11.82, 13.84
both br.s
26.20 br.m
25.99 br.m
26ba,c
1.28 (m, 6 H, OCH2Me); 1.36 (t, 3 H, OCH2Me, J = 6.9);
1.44, 2.03 (both br.m, 1 H each, =CH(CH2)3); 1.71—1.96 (br.m, 4 H,
=CH(CH2)3); 2.12, 2.15 (both s, 3 H each, Me); 3.39 (br.m, 1 H, H(4a));
4.06 (m, 4 H, OCH2Me); 4.18—4.48 (br.m, 3 H, OCH2Me, H(8));
4.82 (br.s, 2 H, NH2); 7.15—7.27 (m, 3 H, Ar)
12.72, 14.48
both br.s
26sd,h
1.29 (m, 6 H, OCH2Me); 1.35 (t, 3 H, OCH2Me, J = 7.2);
1.45, 2.01 (both br.m, 1 H each, =CH(CH2)3); 1.73—1.92 (br.m, 4 H,
=CH(CH2)3); 3.48 (br.m, 1 H, H(4a)); 3.85 (s, 3 H, OMe); 4.07 (m, 4 H,
OCH2Me); 4.18—4.45 (br.m, 3 H, OCH2Me, H(8));
11.77, 13.80
both br.s
25.28 br.m
4.87, 4.90 (both br.s, 2 H, NH2); 6.93—7.14 (m, 4 H, Ar)
26de
1.14—1.25 (m, 9 H, OCH2Me); 1.34—2.11 (br.m, 6 H, =CH(CH2)3);
3.37 (br.m, 1 H, H(4a)); 3.76 (br.s, 6 H, OMe); 3.87 (br.m, 4 H,
OCH2Me); 3.95—4.25 (br.m, 3 H, OCH2Me, H(8));
13.35, 15.36
both br.s
23.99, 23.95
both br.s
5.21 (br.s, 2 H, NH2); 5.98—6.64 (br.m, 3 H, Ar)
26ea,f
1.30 (t, 6 H, OCH2Me, J = 7.2); 1.35 (t, 3 H, OCH2Me, J = 7.2);
1.46, 2.01 (both br.m, 1 H each, =CH(CH2)3); 1.70—1.95 (br.m, 4 H,
=CH(CH2)3); 3.48 (m, 1 H, H(4a)); 4.08 (m, 4 H, OCH2Me);
4.17—4.44 (br.m, 3 H, OCH2Me, H(8)); 4.85, 4.88 (both br.s,
2 H, NH2); 7.04—7.47 (br.m, 4 H, Ar)
11.85, 13.81
both br.s
25.71, 25.80
both br.s
26fa,g
1.30 (t, 6 H, OCH2Me, J = 7.2); 1.36 (t, 3 H, OCH2Me, J = 7.2);
1.41—2.05 (m, 6 H, =CH(CH2)3); 3.50 (br.m, 1 H, H(4a));
4.00—4.16 (br.m, 5 H, OCH2Me, H(8)); 4.20—4.40 (br.m, 2 H,
OCH2Me); 4.82, 4.85 (both br.s, 2 H, NH2); 7.37 (m, 2 H, Ar);
7.74, 7.77 (both d, 2 H, Ar, J = 8.4)
11.86, 13.96
both br.s;
15.01 (br.s, 3 F,
CF3C6H4)
25.55, 25.62
both br.s
a The spectrum was recorded in CDCl3.
b A mixture of diastereomers 3.3 : 1.
c A mixture of diastereomers 1.1 : 1.
d A mixture of diastereomers 2.7 : 1.
e A mixture of diastereomers 3.4 : 1.
f A mixture of diastereomers 1.77 : 1.
g A mixture of diastereomers 2.27 : 1.
h The 1H and 19F spectra were recorded in CDCl3.
moderate cytotoxicity independent of the substituent on
the nitrogen atom of the dihydropyridine ring. At the same
time, compound 18b has proved considerably less active
when two trifluoromethyl groups are present at position 4
and when cyano group is replaced with the diethoxyphosꢀ
phoryl residue. Compounds 8е, 8b, and 20a containing,
respectively, 2,5ꢀdichlorophenyl (8е) and 4ꢀmethoxypheꢀ
nyl (8b and 20a) substituents on the nitrogen atom of the

156
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
C(21)
C(20)
O(3)
C(17)
C(21)
O(3)
C(20)
C(16)
O(1)
C(19)
O(1)
O(5)
P(1)
O(2)
F(2)
O(2)
F(2)
C(3)
C(19)
F(3)
C(5)
C(6)
F(3)
C(15)
C(14)
O(4)
C(4)
C(4)
C(16)
O(5)
C(3)
C(2)
C(4A)
C(17)
C(18) F(1)
C(5)
C(6)
P(1)
C(18)
C(4A)
N(2)
C(7)
C(2)
N(2)
F(1)
C(14)
N(1)
C(8)
C(13)
C(7A)
N(1)
C(7A)
C(7)
C(15)
C(8)
C(13)
C(9)
C(10)
C(11)
C(9)
C(12)
C(12)
C(10)
C(11)
F(4)
F(4)
Fig. 3. General view of the molecule 24c in representation of
atoms by ellipsoids of atomic displacements with 50% probability
(the solvate molecule of diethyl ether is not shown).
Fig. 4. General view of the molecule 25c in representation
of atoms by ellipsoids of atomic displacements with 50% proꢀ
bability.
dihydropyridine ring exhibited noticeable cytotoxic activiꢀ
ty against the most tumor cells in contrast to the aforeꢀ
mentioned compound 25d containing no substituent at
this position. Compounds of hexahydroquinoline series 9g,
26c, and 26d displayed very similar moderate cytotoxic
properties having minimum structural differences. Apparꢀ
Table 7. Results of the study of cytotoxic activity of compounds
Cell
GI50/μmol L–1
cultures
7c
7e
8b
8e
9g
18b
20a
25d
26c
26d
Leukemia
CCRFꢀCEM
HLꢀ60(TB)
Kꢀ562
MOLTꢀ4
RPMIꢀ8226
SR
13.2
14.2
10.0
9.46
16.0
4.51
—
25.2
16.6
21.6
15.4
16.9
15.9
10.8
16.7
21.2
14.4
13.7
15.5
19.4
18.9
19.3
27.8
17.1
12.5
78.0
—
>100
1.35
20.2
10.3
17.1
6.53
14.8
15.5
>100
>100
>100
>100
>100
>100
25.5
13.8
23.9
14.9
14.7
24.4
20.6
25.2
20.0
9.88
19.8
17.6
5.76
>100
3.33
12.5
5.84
0.126
19.5
NonꢀSmall Cell Lung Cancer
A549/ATCC
EKVX
HOPꢀ62
51.3
23.8
>100
12.5
22.3
28.7
—
49.1
20.3
52.1
69.0
99.5
37.0
—
37.0
>100
40.3
33.2
94.6
13.7
42.6
34.7
38.5
31.0
17.4
31.0
22.2
17.3
16.7
23.1
33.6
28.6
15.7
17.4
36.7
30.0
47.1
22.8
45.2
38.3
37.0
18.9
19.1
>100
>100
>100
11.7
12.1
15.7
13.21
5.0
15.5
13.2
14.8
14.5
54.8
27.4
37.1
47.6
15.9
24.2
17.0
12.9
16.8
20.5
29.1
16.4
17.8
>100
>100
>100
>100
>100
>100
>100
HOPꢀ92
4.15
5.05
NCIꢀH226
NCIꢀH23
NCIꢀH322M
NCIꢀH460
NCIꢀH522
>100
>100
—
>100
66.2
57.0
43.2
53.5
27.2
32.0
49.4
27.4
47.7
(to be continued)

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
157
Table 7 (continued)
Cell
GI50/μmol L–1
cultures
7c
7e
8b
8e
9g
18b
20a
25d
26c
26d
Colon Cancer
COLO 205
HCCꢀ2998
HCTꢀ116
HCTꢀ15
HT 29
17.1
24.8
14.8
13.1
30.5
39.1
70.1
39.2
49.4
51.0
55.5
97.8
26.6
32.6
17.5
31.3
41.5
21.5
19.9
20.9
19.2
28.4
26.0
20.1
22.3
23.5
27.8
30.7
30.3
31.3
24.3
89.7
24.2
>100
>100
53.8
>100
>100
>100
>100
17.5
16.1
11.3
14.7
12.4
12.5
14.2
>100
>100
85.4
>100
>100
>100
>100
19.2
52.8
22.1
29.7
27.1
32.5
32.0
16.8
19.4
13.8
18.9
16.7
20.4
18.3
KM 12
SWꢀ620
1.21
14.6
CNS Cancer
SFꢀ268
SFꢀ295
SFꢀ539
SNBꢀ19
SNBꢀ75
U251
29.6
35.0
34.4
>100
21.3
56.1
—
96.8
66.3
59.8
73.5
30.8
21.9
30.2
71.7
26.5
32.0
15.7
18.3
17.0
18.8
24.5
18.3
17.1
17.2
17.0
35.9
20.0
38.9
>100
38.3
>100
>100
>100
>100
11.6
13.5
15.6
13.1
8.11
14.1
>100
>100
>100
>100
40.7
>100
33.6
24.6
27.5
44.3
24.13
4.9
16.7
16.5
17.4
16.3
13.4
18.1
26.6
Melanoma
LOX IMVI
MALMEꢀ3M
M14
SKꢀMELꢀ2
SKꢀMELꢀ28
SKꢀMELꢀ5
UACCꢀ257
UACCꢀ62
11.7
0.726
>100
27.0
40.4
34.8
18.7
26.9
15.8
51.7
22.9
17.1
23.2
18.5
20.6
21.7
15.7
—
20.4
30.0
23.8
3.92
31.2
25.1
15.1
32.1
>100
>100
>100
>100
>100
>100
>100
>100
13.6
13.2
13.5
13.9
14.4
12.0
12.3
10.0
>100
>100
>100
>100
>100
>100
>100
>100
20.5
23.5
33.2
24.6
50.8
14.6
24.6
28.7
16.1
21.2
15.8
18.5
17.9
14.4
16.5
15.9
37.7
38.9
39.9
60.7
31.4
65.4
37.5
30.4
89.4
16.3
18.6
34.6
20.8
17.6
Ovarian Cancer
IGROV1
6.51
6.12
15.8
18.5
27.1
68.4
38.7
99.6
13.3
16.0
34.5
28.1
31.7
24.5
22.0
88.8
>100
>100
>100
>100
>100
—
—
>100
>100
>100
>100
>100
25.4
25.0
26.3
26.9
33.2
44.6
—
OVCARꢀ3
OVCARꢀ4
OVCARꢀ5
OVCARꢀ8
SKꢀOVꢀ3
15.7
22.8
15.9
31.9
47.5
50.3
44.7
89.9
66.2
21.9
27.0
65.0
31.0
24.9
13.0
12.9
14.7
16.5
17.0
20.0
20.5
22.9
22.4
24.0
>100
Renal Cancer
768ꢀ0
A498
66.0
—
10.2
15.2
20.8
45.5
72.1
41.9
53.0
66.2
51.7
>100
>100
7.61
60.0
—
19.2
23.5
28.9
19.1
19.3
22.8
32.9
14.2
35.6
33.0
34.7
19.4
53.4
32.8
29.0
24.5
>100
—
14.5
11.2
14.8
>100
>100
>100
>100
52.0
25.8
25.8
23.8
37.6
37.0
40.1
23.3
62.1
29.0
ACHN
CAKIꢀ1
RXFꢀ393
SN12C
TKꢀ10
UOꢀ31
32.6
16.8
43.4
39.6
48.8
18.7
78.0
41.4
>100
>100
55.1
>100
>100
>100
32.1
40.6
>100
8.81
14.2
12.4
13.5
11.0
39.9
>100
>100
>100
3.04
20.6
35.4
Prostate Cancer
PCꢀ3
DUꢀ145
19.1
17.4
31.8
>100
19.8
20.3
15.9
20.4
24.8
25.2
4.27
>100
11.8
15.7
>100
>100
13.2
40.0
64.1
37.8
Breast Cancer
MCF7
NCI/ADRꢀRES 46.0
MDAꢀMBꢀ231/A 21.3
HS 578T
MDAꢀMBꢀ435 32.6
MDAꢀN
BTꢀ549
Tꢀ47D
25.3
37.6
32.7
35.7
13.3
13.4
27.5
—
16.6
28.6
16.9
21.2
18.9
—
10.2
26.1
25.2
22.1
—
—
12.8
25.9
>100
>100
>100
79.8
>100
—
14.2
12.6
12.4
10.0
12.6
—
>100
>100
51.7
70.7
>100
—
48.2
>100
26.8
27.2
25.2
26.8
32.8
—
54.1
59.7
28.8
49.3
40.9
—
41.4
46.0
41.8
63.3
—
2.26
—
15.1
11.3
44.8
31.3
17.7
46.4
16.0
18.6
>100
>100
15.4
12.4
35.8
33.4
33.1
53.6
Note. GI50 is the concentration of compound causing 50% retardation of the cell culture growth rates.

158
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Compounds 15, 21a, 24c, and 25c were studied by Xꢀray
diffraction analysis. The Xꢀray diffraction experiments of single
crystals of 15, 21a, 24c, and 25c were performed on a SMART
1000 CCD diffractometer (λ(MoꢀKα) = 0.71073 Å, a graphite
monochromator, ωꢀscanning). The main crystal and structural
parameters are given in Table 8. Analysis of measured intensities
was performed using the SAINT Plus25 and SADABS programs.26
The structures were solved by the direct method and refined by
the fullꢀmatrix least squares method in anisotropic approximation
ently, the presence of the methoxyphenyl and chloropheꢀ
nyl substituent on the nitrogen atom of the pyridine ring is
a necessary condition for the cytotoxic activity to be exꢀ
hibited by all the compounds represented in this series.
The results obtained give us substantiation of further search
for cytotoxic agents in the series under study, as well as
among other fluorineꢀcontaining heterocycles.
for nonhydrogen atoms against F2 using the SHELXTLꢀ97
hkl
Experimental
program package (see Ref. 27). Hydrogen atoms were placed in
the geometrically calculated positions and refined by the riding
model (Uiso(H) = nUeq(C), where n = 1.5 for the carbon atoms of
the methyl group, n = 1.2 for other C atoms). The disorder of the
ethyl group in compound 25c over two positions was an excepꢀ
tion, the both components of which were refined isotropically.
The hydrogen atoms of the amino groups were localized from the
differential synthesis of electron density and then the N—H disꢀ
tance was normalized by the value of 0.9 Å. Hydrogen atoms
were refined by the riding model (Uiso(H) = nUeq(N), where
n = 1.2). The independent part of the unit cell contains one
1
H, 13C{1H} and 31P{1H} NMR spectra of compounds synꢀ
thesized were recorded on a Bruker AMXꢀ400 spectrometer
(400.13, 100.61, and 160.62 MHz, respectively), 19F NMR specꢀ
tra were recorded on a Bruker WPꢀ200SY and Bruker AMXꢀ400
spectrometers (188.31 and 376.47 MHz, respectively). Chemical
shifts H and 13C were determined relatively to the residual sigꢀ
nal of the deuterated solvent and recalculated to SiMe4. Chemiꢀ
cal shifts of 19F and 31P were determined relatively to the exterꢀ
nal standards, CF3COOH and 85% aq. H3PO4, respectively.
1
Table 8. Crystallographic data and parameters of Xꢀray diffraction experiments for compounds 15, 21a, 24c, 25c
Parameter
15
21a
24c
25c
Molecular formula
Molecular weight
C17H13F3N2O2
334.29
C22H27F6N2O4P
528.43
C26H37F4N2O6P
580.55
C22H27F4N2O5P
506.43
T/K
110(2)
295(2)
110(2)
230(2)
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
Monoclinic
C2/c
23.390(5)
7.6033(16)
18.145(4)
90
111.081(5)
90
3011.0(11)
8
Triclinic
Pꢀ1
Orthorhombic
P212121
9.149(2)
13.981(4)
22.486(6)
90
Monoclinic
P21/n
12.548(3)
15.156(4)
12.548(3)
90
109.139(5)
90
2447.3(10)
4
9.918(5)
10.040(5)
13.247(7)
87.48(4)
68.34(4)
85.17(4)
1221.5(11)
2
90
90
γ/deg
V/Å3
2876.2(13)
4
0.163
1224
1.341
Z
Absorption coefficient μ/mm–1
F(000)
0.123
1376
1.475
0.190
548
1.437
0.178
1056
1.374
dcalc/g cm–3
Scanning range on θ/deg.
Number of reflections
measured
1.87—29.00
2.04—26.06
1.72—30.07
1.92—25.99
11234
3988
5094
4800
31466
8368
19802
4718
independent
(Rint
with I ≥ 2σ(I)
)
(0.0419)
2026
(0.0151)
3863
(0.0475)
5448
(0.0291)
3270
Number of parameters
Data completeness (%)
GOOF
218
99.2
1.011
0.0506
320
99.0
1.171
0.0469
357
99.3
0.993
0.0553
308
98.0
1.006
0.0649
Convergence of refinement
from reflections (R1(F)) with I > 2σ(I)a
Convergence of refinement
from all the reflections (wR2(F2))b
Residual electron
0.1089
0.1482
0.1151
0.1508
0.318/–0.241
0.347/–0.324
0.650/–0.316
0.985/–0.508
density (max/min), e/Å–3
a R1 = ∑|Fo – |Fc||/∑(Fo).
2 2
2 2 1/2
b wR2 = (∑[w(Fo2 – Fc ) ]/∑[w(Fo ) ]
.

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
159
molecule for all the compounds except 24c, which also includes
a solvate molecule of diethyl ether.
(CH2)4); 4.12 (m, 4 H, OCH2Me); 7.06 and 7.57 (both d, 2 H
each, Ar, J = 8.4 Hz); 8.90 and 9.08 (both s, 1 H each, NH).
13C NMR (DMSOꢀd6), δ: 21.4 and 21.6 (both d, OCH2Me,
3JC,P = 5 Hz); 26.2, 26.8, 30.3, and 31.7 (all s, C(5), C(6), C(7),
Compounds 3—6 were synthesized as described earlier.10
Diethyl [2ꢀaminoꢀ3ꢀcyanoꢀ1ꢀ(2,6ꢀdimethylphenyl)ꢀ6ꢀmethylꢀ
4ꢀ(trifluoromethyl)ꢀ1,4ꢀdihydropyridinꢀ4ꢀyl]phosphonate (7a).
A solution of alkene 3 (0.31 g, 1.1 mmol) in acetone (1.5 mL) was
added to a solution of 2,6ꢀdimethylaniline (0.12 g, 0.99 mmol) in
acetone (2.0 mL) at 20 °C with stirring. The reaction mixture was
stirred for 24 h at 20 °C. The solvent was evaporated in vacuo.
Carbon tetrachloride (7 mL) was added to the residue, a precipiꢀ
tate was filtered off and washed with pentane to obtain the prodꢀ
uct (0.29 g, 67%) (see Tables 1 and 2). 13C NMR (DMSOꢀd6), δ:
16.8 (m, OCH2Me); 17.2, 17.4, and 19.8 (all s, Me); 46.3
2
C(8)); 68.0, and 68.8 (both d, OCH2Me, JC,P = 7 Hz); 104.6
(d, C(4a), 2JC,P = 6 Hz); 121.5 (s, C(2´), C(6´)); 124.0 (s, CN);
125.3 (q, C(4´), 2JC,F = 32 Hz); 129.3 (dq, C(4)CF3, 1JC,F = 287 Hz
and 2JC,P = 12 Hz); 129.9 (q, C(4´)CF3, 1JC,F = 271 Hz); 131.5
3
3
(q, C(3´), C(5´), JC,F = 3 Hz); 139.2 (d, C(8a), JC,P = 7 Hz);
151.1 (s, C(1´)); 155.1 (s, C(2)).
The solvent from the filtrate was evaporated in vacuo. Comꢀ
pound 9f (0.35 g, 54%) was isolated by preparative TLC on silica
gel (eluent: ethyl acetate—light petroleum (6 : 1) (see Tables 1
and 2). 13C NMR (DMSOꢀd6), δ: 21.4 and 21.6 (both d,
OCH2Me, 3JC,P = 5 Hz); 27.0, 27.1, 30.8, and 33.4 (all s, C(5),
C(6), C(7), C(8)); 53.5 (m, C(3)); 56.6 (dq, C(4), 2JC,F = 25 Hz
and 1JC,P = 146 Hz); 68.1 and 68.5 (both d, OCH2Me, 2JC,P = 8 Hz);
108.3 (d, C(4a), 2JC,P = 7 Hz); 125.6 (s, CN); 129.1 (q, C(4´)CF3,
2
(m, C(3)); 63.6 (m, OCH2Me); 91.7 (d, C(5), JC,P = 8 Hz);
121.0 (s, CN); 122.4 (dq, CF3, 1JC,F = 283 Hz and 2JC,P = 15 Hz);
129.3 and 129.4 (both s, C(2´) and C(6´)); 130.1 (s, C(3´), C(5´));
134.1 (s, C(1´)); 138.1 (s, C(4´)); 138.3 (d, C(6), 3JC,P = 9 Hz);
155.0 (d, C(2), 3JC,P = 3 Hz).
Compounds 7b—g were synthesized similarly from alkene 3,
acetone, and corresponding arylamines (see Tables 1 and 2).
Diethyl [2ꢀaminoꢀ3ꢀcyanoꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(trifluoꢀ
romethyl)ꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridinꢀ4ꢀyl]phosꢀ
phonate (8b). A solution of alkene 3 (0.31 g, 1.1 mmol) in CCl4
(1.0 mL) was added to a solution of pꢀanisidine (0.12 g, 0.98 mmol)
and cyclopentanone (0.10 g, 1.2 mmol) in CCl4 (5.0 mL) at 20 °C
with stirring. The reaction mixture was stirred for 24 h at 20 °C, a
precipitate formed was filtered off and washed with pentane to
obtain the product (0.29 g, 62%) (see Tables 1 and 2).
1JC,F = 272 Hz); 129.7 (dq, C(4)CF3, 1JC,F = 287 Hz and 2JC,P
=
= 12 Hz); 132.0 (q, C(3´), C(5´), 3JC,F = 4 Hz); 134.7 (q, C(4´),
2JC,F = 32 Hz); 136.6 (s, C(2´), C(6´)); 139.9 (d, C(8a), 3JC,P
= 8 Hz); 146.3 (s, C(1´)); 160.6 (s, C(2)).
=
Methyl 2ꢀaminoꢀ4ꢀdiethoxyphosphorylꢀ1ꢀ(2,6ꢀdimethylpheꢀ
nyl)ꢀ6ꢀmethylꢀ4ꢀ(trifluoromethyl)ꢀ1,4ꢀdihydropyridineꢀ3ꢀcarboxꢀ
ylate (12a). A solution of alkene 4 (0.34 g, 1.09 mmol) in acetone
(1.0 mL) was added to a solution of 2,6ꢀdimethylaniline (0.12 g,
0.99 mmol) in acetone (1.0 mL) at 20 °C with stirring. The reacꢀ
tion mixture was kept for 72 h at 20 °C. The product (0.27 g, 57%)
was isolated by preparative TLC on silica gel (eluent: ethyl aceꢀ
tate—light petroleum (3 : 1)), m.p. 89—90 °C. Found (%):
C, 52.97; H, 5.94; F, 11.86; N, 5.89; P, 6.46. C21H28F3N2O5P.
Calculated (%): C, 52.94; H, 5.92; F, 11.96; N, 5.88; P, 6.50.
Compounds 8a,c—g were synthesized similarly from alkene
3, cyclopentanone, and corresponding arylamines (see Tables 1
and 2). In the case of compounds 8a,c,f,g, the products were
isolated by preparative TLC on silica gel using an ethyl aceꢀ
tate—light petroleum (3 : 1) solvent mixture as an eluent.
Diethyl 2ꢀaminoꢀ1ꢀ(4ꢀchlorophenyl)ꢀ3ꢀcyanoꢀ4ꢀtrifluoromeꢀ
thylꢀ1,4,5,6,7,8ꢀhexahydroquinolinꢀ4ꢀylphosphonate (9a). A soꢀ
lution of alkene 3 (0.31 g, 1.1 mmol) in CCl4 (1.0 mL) was added
to a solution of 4ꢀchloroaniline (0.13 g, 1.02 mmol) and cycloꢀ
hexanone (0.12 g, 1.2 mmol) in CCl4 (5.0 mL) at 20 °C with stiꢀ
rring. The reaction mixture was stirred for 48 h at 20 °C, the solvent
was evaporated in vacuo. The product (0.23 g, 47%) was isolated
by preparative TLC on silica gel using an ethyl acetate—light
petroleum (3 : 1) solvent mixture as an eluent (see Tables 1 and 2).
Compounds 9b—g were synthesized similarly from alkene 3,
cyclohexanone, and corresponding arylamines (see Tables 1 and 2).
Diethyl 3ꢀcyanoꢀ4ꢀtrifluoromethylꢀ2ꢀ(4ꢀtrifluoromethylpheꢀ
nylamino)ꢀ1,4,5,6,7,8ꢀhexahydroquinolinꢀ4ꢀyl]phosphonate (11)
and diethyl {2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀtrifluoromethylꢀ1ꢀ[4ꢀ(trifluoroꢀ
methyl)phenyl]ꢀ1,4,5,6,7,8ꢀhexahydroquinolinꢀ4ꢀyl} phosphonate
(9f). A solution of alkene 3 (0.30 g, 1.1 mmol) in CCl4 (0.5 mL)
was added to a solution of 4ꢀ(trifluoromethyl)aniline (0.16 g,
1.00 mmol) and cyclohexanone (0.12 g, 1.22 mmol) in CCl4
(3.5 mL) at 20 °C with stirring. The reaction mixture was stirred
for 16 h at 20 °C, a precipitate formed was filtered off and washed
with pentane to obtain compound 11 (0.06 g, 11.5%). Found (%):
C, 50.33; H, 4.68; F, 21.56; N, 8.10; P, 5.99. C22H24F6N3O3P.
Calculated (%): C, 50.48; H, 4.62; F, 21.78; N, 8.03; P, 5.92.
3
19F NMR (CDCl3), δ: 7.92 (d, 3 F, CF3, JF,P = 2.4 Hz).
1
31P NMR (CDCl3), δ: 20.57 (br.s, 1 P, P(O)(OEt)2). H NMR
(CDCl3), δ: 1.33 (m, 6 H, OCH2Me); 1.46 (br.s, 3 H, C(6)Me);
2.18 (s, 6 H, Me); 3.70 (s, 3 H, CO2Me); 4.19 (m, 4 H,
OCH2Me); 5.13 (d, 1 H, H(5), 3JH,P = 7.8 Hz); 6.76 (br.s, 2 H,
NH2); 7.17 (m, 2 H, Ar); 7.26 (m, 1 H, Ar).
Compounds 12b,c were synthesized similarly from alkene 4,
acetone, and corresponding arylamines.
Methyl 2ꢀaminoꢀ4ꢀdiethoxyphosphorylꢀ1ꢀ(4ꢀmethoxypheꢀ
nyl)ꢀ6ꢀmethylꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyridineꢀ3ꢀcarboxyꢀ
late (12b). The yield was 48%, m.p. 111—113 °C. Found (%):
C, 50.30; H, 5.49; F, 11.70; N, 5.86. C20H26F3N2O6P. Calculatꢀ
ed (%): C, 50.21; H, 5.48; F, 11.91; N, 5.86. 19F NMR (DMSOꢀd6),
δ: 10.20 (br.s, 3 F, CF3). 31P NMR (DMSOꢀd6), δ: 22.35 (q, 1 P,
P(O)(OEt)2, 3JF,P = 1.6 Hz). 1H NMR (DMSOꢀd6), δ: 1.24 (m, 6 H,
OCH2Me); 1.49 (d, 3 H, C(6)Me, 5JH,P = 1.9 Hz); 3.51 (s, 3 H,
CO2Me); 3.81 (s, 3 H, OMe); 4.05 (m, 4 H, OCH2Me); 4.87(d, 1 H,
H(5), 3JH,P = 8.1 Hz); 7.07(m, 4 H, Ar); 7.15 (br.s, 2 H, NH2).
Methyl 2ꢀaminoꢀ4ꢀdiethoxyphosphorylꢀ6ꢀmethylꢀ4ꢀtrifluoꢀ
romethylꢀ1ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1,4ꢀdihydropyridineꢀ3ꢀ
carboxylate (12c). The yield was 41%. Found (%): C, 46.40;
H, 4.58; F, 21.84; N, 5.44. C20H23F6N2O5P. Calculated (%):
C, 46.52; H, 4.49; F, 22.07; N, 5.42. 19F NMR (DMSOꢀd6), δ:
10.37 (br.s, 3 F, CF3); 17.16 (s, 3 F, CF3). 31P NMR (DMSOꢀd6),
δ: 19.92 (q, 1 P, P(O)(OEt)2, 3JF,P = 2.2 Hz). 1H NMR (DMSOꢀd6),
δ: 1.26 (t, 6 H, OCH2Me, J = 7.2 Hz); 1.50 (d, 3 H, C(6)Me,
5JH,P = 1.6 Hz); 3.54 (s, 3 H, CO2Me); 4.09 (m, 4 H, OCH2Me);
3
19F NMR (DMSOꢀd6), δ: 17.30 (d, 3 F, CF3, JF,P = 4.0 Hz);
18.51 (s, 3 F, CF3—C6H4). 31P NMR (DMSOꢀd6), δ: 17.80 (q, 1 P,
3
P(O)(OEt)2, JF,P = 4.0 Hz). 1H NMR (DMSOꢀd6), δ: 1.29
3
(m, 6 H, OCH2Me); 1.50 and 1.65 (both m, 2 H each, (CH2)4);
4.96 (d, 1 H, H(5), JH,P = 8.1 Hz); 7.36 (br.s, 2 H, NH2); 7.50
1.96 and 2.57 (both m, 1 H each, (CH2)4); 2.09 (br.s, 2 H,
and 7.90 (both d, 2 H each, Ar, J = 8.1 Hz).

160
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
Shidlovskii et al.
Methyl 2ꢀaminoꢀ4ꢀdiethoxyphosphorylꢀ1ꢀ(4ꢀmethoxypheꢀ
δ: 9.08 (q, 3 F, CF3, 4JF,F = 10.6 Hz); 13.56 (dq, 3 F, CF3, 4JF,F
=
nyl)ꢀ4ꢀtrifluoromethylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]ꢀ
pyridineꢀ3ꢀcarboxylate (13a) and 1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoꢀ4ꢀ
trifluoromethylꢀ2,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridineꢀ3ꢀ
carbonitrile (15). A solution of alkene 4 (0.34 g, 1.09 mmol) in
CCl4 (1.0 mL) was added to a solution of pꢀanisidine (0.06 g,
0.49 mmol) and cyclopentanone (0.06 g, 0.7 mmol) in CCl4
(1.0 mL) at 20 °C with stirring. The reaction mixture was kept for
72 h at 20 °C. The products were isolated by preparative TLC on
silica gel (eluent: ethyl acetate—light petroleum (3 : 1)). Comꢀ
pound 13a (0.05 g, 20%) was an amorphous substance. Found (%):
C, 51.69; H, 5.65; N, 5.53. C22H28F3N2O6P. Calculated (%):
C, 52.38; H, 5.59; N, 5.55. 19F NMR (CDCl3), δ: 14.99 (br.s, 3 F,
CF3). 31P NMR (DMSOꢀd6), δ: 19.80 (br.s, 1 P, P(O)(OEt)2).
1H NMR (DMSOꢀd6), δ: 1.24 (m, 6 H, OCH2Me); 1.65 (m, 2 H,
(CH2)3); 1.87, 2.03, 2.42, and 2.87 (all m, 1 H each, (CH2)3);
3.53 (s, 3 H, CO2Me); 3.81 (s, 3 H, OMe); 4.04 (m, 4 H,
OCH2Me); 7.04—7.16 (m, 6 H, Ar and NH2).
= 10.6 Hz, 4JF,P = 2.4 Hz). 1H NMR (CDCl3), δ: 1.31 and 1.41
(both t, 3 H each, OCH2Me, J = 7.1 Hz); 1.88 (m, 3 H, Me); 3.41
(AВꢀsystem, 2 H, CH2, 2JH = –16.9 Hz); 4.19 (br.m, 2 H,
OCH2Me); 4.31 (m, 2 H, OCH2Me); 6.07 (d, 1 H, CH, 2JH,P
=
28.7 Hz); 6.61 and 7.29 (both dd, 2 H each, Ar, J = 8.4 Hz
and 1.6 Hz).
Diethyl 1ꢀcyanoꢀ4ꢀoxoꢀ2,2ꢀbis(trifluoromethyl)pentylphosꢀ
phonate (17). A solution of alkene 5 (0.25 g, 0.77 mmol) in CCl4
(1.0 mL) was added to a solution of 4ꢀchloroaniline (0.085 g,
0.67 mmol) and acetone (0.1 g, 1.7 mmol) in CCl4 (1.0 mL) at
20 °C with stirring. The reaction mixture was kept for 120 h at
20 °C. The product (0.26 g, 90%) was isolated by preparative
TLC on silica gel (eluent: chloroform—acetone (15 : 1)), m.p.
92—93 °C. Found (%): C, 37.65; H, 4.21; F, 29.68; N, 3.66;
P, 8.02. C12H16F6NO4P. Calculated (%): C, 37.61; H, 4.21;
F, 29.74; N, 3.65; P, 8.08. 19F NMR (CDCl3), δ: 9.32 (q, 3 F,
4
4
CF3, JF,F = 10.6 Hz); 11.85 (dq, 3 F, CF3, JF,F = 10.6 Hz,
4JF,P = 2.4 Hz). 31P NMR (CDCl3), δ: 11.26 (q, 1 P, P(O)(OEt)2,
4JF,P = 2.4 Hz). 1H NMR (CDCl3), δ: 1.42 (m, 6 H, OCH2Me);
2.26 (s, 3 H, Me); 3.50 (AВꢀsystem, 2 H, CH2, 2JH = –18.1 Hz);
3.81 (s, 3 H, OMe); 4.28 (m, 4 H, OCH2Me); 5.19 (d, 1 H, CH,
2JH,P = 28.0 Hz).
Compound 15 (0.06 g, 37%), m.p. 151 °C. Found (%):
C, 61.00; H, 3.93; F, 16.98; N, 8.38. C17H13F3N2O2. Calculatꢀ
ed (%): C, 61.08; H, 3.92; F, 17.05; N, 8.38. 19F NMR (DMSOꢀd6),
1
δ: 15.32 (s, 3 F, CF3). H NMR (DMSOꢀd6), δ: 2.11, 2.66, and
3.03 (all m, 2 H each, (CH2)3); 3.87 (s, 3 H, OMe); 7.03 and 7.13
(both d, 2 H each, Ar, J = 8.7 Hz).
Compound 17 was isolated similarly from the reaction mixꢀ
tures obtained by the reaction of alkene 5, acetone, and pꢀanisiꢀ
dine and alkene 5, acetone, and 4ꢀphenoxyaniline. The yields
were 93% and 89%, respectively.
Diethyl 2ꢀaminoꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀmethylꢀ4,4ꢀbisꢀ
(trifluoromethyl)ꢀ1,4ꢀdihydropyridinꢀ3ꢀylphosphonate (18a). A soluꢀ
tion of compound 16a (0.09 g) in CCl4 (5 mL) was refluxed for 18 h.
The solvent was evaporated in vacuo. Compound 18a (0.045 g,
50%) was isolated by preparative TLC on silica gel (eluent: chloꢀ
roform—acetone (60 : 5)) (see Tables 3 and 4).
Methyl 2ꢀaminoꢀ1ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀdiethoxyphosphoꢀ
rylꢀ4ꢀtrifluoromethylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyꢀ
ridineꢀ3ꢀcarboxylate (13b) was obtained similarly to 13a from
2,6ꢀdimethylaniline, cyclopentanone, and alkene 4. The yield
was 51%, m.p. 83—85 °C. Found (%): C, 54.90; H, 6.03; F, 11.55;
N, 5.56. C23H30F3N2O5P. Calculated (%): C, 54.98; H, 6.02;
F, 11.34; N, 5.58. 19F NMR (DMSOꢀd6,), δ: 16.34 (br.s, 3 F,
CF3). 31P NMR (DMSOꢀd6), δ: 20.26 (q, 1 P, P(O)(OEt)2, 3JF,P
=
1
= 2.8 Hz). H NMR (DMSOꢀd6), δ: 1.22 (m, 6 H, OCH2Me);
1.75 (m, 4 H, (CH2)3); 2.07 and 2.11 (both s, 3 H each, Me); 2.42
and 2.91 (both m, 1 H each, (CH2)3); 3.52 (s, 3 H, CO2Me); 4.09
(m, 4 H, OCH2Me); 7.18—7.31 (m, 5 H, Ar and NH2).
Compound 18b was synthesized similarly from 16b. The yield
was 48% (see Tables 3 and 4).
Diethyl 2ꢀaminoꢀ6ꢀmethylꢀ1ꢀ(4ꢀphenoxyphenyl)ꢀ4,4ꢀbis(triꢀ
fluoromethyl)ꢀ1,4ꢀdihydropyridinꢀ3ꢀylphosphonate (18c). A soluꢀ
tion of alkene 5 (0.25 g, 0.76 mmol) in CCl4 (1.0 mL) was added
to a suspension of 4ꢀphenoxyaniline (0.13 g, 0.70 mmol), aceꢀ
tone (0.12 g, 2.07 mmol), and anhydrous sodium sulfate (1.5 g) in
CCl4 (1.0 mL) at 20 °C with stirring. The reaction mixture was
stirred for 2 h at 20 °C. The drying agent was filtered off and
washed with CCl4 (10 mL), the solvent was evaporated in vacuo.
The residue (16c) was dissolved in CCl4 (5 mL) and refluxed for
18 h. The solvent was evaporated in vacuo. Compound 18c (0.16 g,
41%) was isolated by preparative TLC on silica gel (eluent: chloꢀ
roform—acetone (60 : 5)) (see Tables 3 and 4).
Diethyl 2ꢀaminoꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4,4ꢀbis(trifluoromeꢀ
thyl)ꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridinꢀ3ꢀylphosphoꢀ
nate (20a). A solution of alkene 5 (0.21 g, 0.65 mmol) in CCl4
(1.0 mL) was added to a solution of pꢀanisidine (0.07 g, 0.57 mmol)
and cyclopentanone (0.09 g, 1.07 mmol) in CCl4 (1.0 mL) at 20 °C
with stirring. The reaction mixture was kept for 48 h at 20 °C. The
product (0.22 g, 76%) was isolated by preparative TLC on silica
gel (eluent: chloroform—acetone (10 : 1)) (see Tables 3 and 4).
Compounds 20b—d were synthesized similarly from alkene
5, cyclopentanone, and corresponding arylamines (the reaction
time was 120 h) (see Tables 3 and 4).
Diethyl 1ꢀcyanoꢀ4ꢀ(4ꢀmethoxyphenylimino)ꢀ2,2ꢀbis(trifluoroꢀ
methyl)pentylphosphonate (16a). A solution of alkene 5 (0.20 g,
0.62 mmol) in CCl4 (1.0 mL) was added to a suspension of
pꢀanisidine (0.07 g, 0.57 mmol), acetone (0.1 g, 1.7 mmol), and
anhydrous sodium sulfate in CCl4 (1.0 mL) at 20 °C with stirring.
The reaction mixture was stirred for 2 h at 20 °C. The drying
agent was filtered off and washed with CCl4 (10 mL), the solvent
was evaporated in vacuo. Compound 16a (0.27 g, 96%) was isoꢀ
lated by preparative TLC on silica gel (eluent: chloroform—aceꢀ
tone (15 : 1)) as light yellow oily substance. Found (%): C, 46.90;
H, 4.77; F, 23.16; N, 5.66; P, 6.30. C19H23F6N2O4P. Calculatꢀ
ed (%): C, 46.73; H, 4.75; F, 23.34; N, 5.74; P, 6.34. 19F NMR
(CDCl3), δ: 9.04 (q, 3 F, CF3, 4JF,F = 9.8 Hz); 13.58 (br.q, 3 F, CF3,
4JF,F = 9.8 Hz). 31P NMR (CDCl3), δ: 11.78 (br.s, 1 P, P(O)(OEt)2).
1H NMR (CDCl3), δ: 1.33 and 1.41 (both t, 3 H each, OCH2Me,
J = 7.1 Hz); 1.90 (s, 3 H, Me); 3.40 (AВꢀsystem, 2 H, CH2,
2JH = –16.5 Hz); 3.81 (s, 3 H, OMe); 4.18 (br.m, 2 H, OCH2Me);
4.30 (m, 2 H, OCH2Me); 6.25 (d, 1 H, CH, 2JH,P = 28.8 Hz); 6.62
and 6.87 (both d, 2 H each, Ar, J = 8.8 Hz).
Diethyl 4ꢀ(4ꢀchlorophenylimino)ꢀ1ꢀcyanoꢀ2,2ꢀbis(trifluoroꢀ
methyl)pentylphosphonate (16b) was obtained similarly to 16a
from alkene 5, acetone, and 4ꢀchloroaniline as light brown oily
substance. The yield was 93.5%. Found (%): C, 43.70; H, 4.12;
Cl, 7.26; F, 22.81; N, 5.71. C18H20ClF6N2O3P. Calculated (%):
C, 43.87; H, 4.09; Cl, 7.19; F, 23.13; N, 5.68. 19F NMR (CDCl3),
Diethyl 2ꢀaminoꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ4,4ꢀbis(trifluoromeꢀ
thyl)ꢀ1,4,4a,5,6,7ꢀhexahydroquinolinꢀ3ꢀylphosphonate (21a). A soꢀ
lution of alkene 5 (0.21 g, 0.65 mmol) in CCl4 (1.0 mL) was

Cyano(trifluoromethyl)vinylphosphonates
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 1, January, 2010
161
added to a solution of pꢀanisidine (0.07 g, 0.57 mmol) and cycloꢀ
hexanone (0.13 g, 1.3 mmol) in CCl4 (1.0 mL) at 20 °C with
stirring. The reaction mixture was kept for 48 h at 20 °C. The
product (0.17 g, 57%) was isolated by preparative TLC on silica
gel (eluent: CCl4—acetone (5 : 1)) (see Tables 3 and 4).
Compound 21b (26%) was obtained similarly from alkene 5,
cyclohexanone, and 3ꢀ(trifluoromethyl)aniline (the reaction time
was 120 h) (see Tables 3 and 4).
2. K. V. Komarov, N. D. Chkanikov, M. V. Galakhov, A. F.
Kolomiets, A. V. Fokin, J. Fluorine Chem., 1990, 47, 59.
3. V. Y. Tyutin, N. D. Chkanikov, A. F. Kolomiets, A. V. Fokin,
J. Fluorine Chem., 1991, 51, 323.
4. V. Yu. Tyutin, N. D. Chkanikov, V. S. Shklyaev, Yu. V. Shkꢀ
lyaev, A. F. Kolomiets, A. V. Fokin, Izv. Akad. Nauk, Ser.
Khim., 1992, 1474 [Bull. Russ. Acad. Sci., Div. Chem. Sci.,
1992, 41, 1474].
Ethyl 2ꢀaminoꢀ3ꢀdiethoxyphosphorylꢀ1ꢀ(2,6ꢀdimethylpheꢀ
nyl)ꢀ6ꢀmethylꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyridineꢀ4ꢀcarboxylate
(22a). A solution of alkene 6 (0.16 g, 0.48 mmol) in CCl4 (1.0 mL)
was added to a solution of 2,6ꢀdimethylaniline (0.05 g, 0.41 mmol)
and acetone (0.1 g, 1.7 mmol) in CCl4 (1.0 mL) at 20 °C with stiꢀ
rring. The reaction mixture was kept for 48 h at 20 °C. The proꢀ
duct (0.07 g, 35%) was isolated by preparative TLC on silica gel
(eluent: ethyl acetate—light petroleum (4 : 1)) (see Tables 5 and 6).
Compounds 22b,c were obtained similarly from alkene 6,
acetone, and corresponding arylamines (the reaction time was
72 h) (see Tables 5 and 6).
Ethyl 2ꢀaminoꢀ3ꢀdiethoxyphosphorylꢀ6ꢀmethylꢀ2ꢀphenylamiꢀ
noꢀ4ꢀtrifluoromethylꢀ1,4ꢀdihydropyridineꢀ4ꢀcarboxylate (23a).
A solution of alkene 6 (0.41 g, 1.25 mmol) in CCl4 (1.0 mL) was
added to a solution of aniline (0.1 g, 1.08 mmol) and acetone
(0.15 g, 2.59 mmol) in CCl4 (1.5 mL) at 20 °C with stirring. The
reaction mixture was kept for 72 h at 20 °C. The product (0.07 g,
14%) was isolated by preparative TLC on silica gel (eluent: ethyl
acetate—light petroleum (2 : 3)) (see Tables 5 and 6).
5. A. C. Golubev, V. Yu. Tyutin, N. D. Chkanikov, A. F. Koloꢀ
miets, A. V. Fokin, Izv. Akad. Nauk, Ser. Khim.., 1992, 2617
[Bull. Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 2068].
6. V. Yu. Tyutin, N. D. Chkanikov, V. N. Nesterov, M. Yu.
Antipin, Yu. T. Struchkov, A. F. Kolomiets, A. V. Fokin, Izv.
Akad. Nauk, Ser. Khim., 1993, 552 [Russ. Chem. Bull.
(Engl. Transl.), 1993, 42, 512].
7. A. Haas, M. Lieb, M. Schelvis, J. Fluorine Chem., 1997,
83, 133.
8. Pat. WO 97, 11057; Chem. Abstrs, 1997, 126, 305586f.
9. A. F. Shidlovskii, A. S. Peregudov, B. B. Averkiev, M. Yu.
Antipin, N. D. Chkanikov, Izv. Akad. Nauk, Ser. Khim., 2004,
1977 [Russ. Chem. Bull., Int. Ed., 2004, 53, 2060].
10. N. D. Chkanikov, A. F. Shidlovskii, V. I. Mukhanov, A. S.
Golubev, A. S. Peregudov, Mendeleev Commun., 2006, 16, 175.
11. A. F. Shidlovskii, A. S. Peregudov, Yu. N. Bulychev, N. D.
Chkanikov, Khim. Farm. Zh., 2009, 43, № 10, 77 [Pharm.
Chem. J. (Engl. Transl.), 2009, 43, No. 10].
12. T. Minami, J. Motoyoshiya, Synthesis, 1992, 333.
13. A. A. Kadyrov, E. M. Rokhlin, Usp. Khim., 1988, 57, 1488
[Russ. Chem. Rev. (Engl. Transl.), 1988, 57, 852].
14. R. Filler, J. Fluorine Chem., 1986, 33, 361.
Compounds 23b,c were obtained similarly from alkene 6,
acetone, and corresponding arylamines (the reaction time was
72 h) (see Tables 5 and 6).
Ethyl 2ꢀaminoꢀ3ꢀdiethoxyphosphorylꢀ1ꢀ(4ꢀphenoxyphenyl)ꢀ
4ꢀtrifluoromethylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀcyclopenta[b]pyridineꢀ
4ꢀcarboxylate (24a) and ethyl 3ꢀdiethoxyphosphorylꢀ2ꢀ(4ꢀpheꢀ
noxyphenylamino)ꢀ4ꢀtrifluoromethylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀ
cyclopenta[b]pyridineꢀ4ꢀcarboxylate (25a). A solution of alkene 6
(0.20 g, 0.61 mmol) in CCl4 (1.0 mL) was added to a solution of
4ꢀphenoxyaniline (0.1 g, 0.54 mmol) and cyclopentanone (0.09 g,
1.07 mmol) in CCl4 (1.5 mL) at 20 °C with stirring. The reaction
mixture was kept for 72 h at 20 °C. Compounds 24a (0.11 g) and
25a (0.10 g) were isolated by preparative TLC on silica gel (eluꢀ
ent: ethyl acetate—light petroleum (2 : 1)) (see Tables 5 and 6).
Compounds 24b—e and 25b—d were obtained similarly from
alkene 6, cyclopentanone, and corresponding arylamines (see
Tables 5 and 6).
Ethyl 2ꢀaminoꢀ3ꢀdiethoxyphosphorylꢀ1ꢀphenylꢀ4ꢀtrifluoroꢀ
methylꢀ1,4,4a,5,6,7ꢀhexahydroquinolineꢀ4ꢀcarboxylate (26a). A
solution of alkene 6 (0.36 g, 1.11 mmol) in CCl4 (1.0 mL) was
added to a solution of aniline (0.09 g, 0.97 mmol) and cyclohexꢀ
anone (0.19 g, 1.94 mmol) in CCl4 (1.0 mL) at 20 °C with stirring.
The reaction mixture was kept for 72 h at 20 °C. Compound 26a
(0.20 g, 41%) was isolated by preparative TLC on silica gel (eluent:
ethyl acetate—light petroleum (3 : 1)) (see Tables 5 and 6).
Compounds 26b—f were obtained similarly from alkene 6, cycꢀ
lohexanone, and corresponding arylamines (see Tables 5 and 6).
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18. M. R. Harnden, A. Parkin, M. J. Parrat, R. M. Perkins,
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19. Eur. Pat. 528,760; Chem. Abstr., 1993, 119, 72837b.
20. Ger. Pat 3,736,113; Chem. Abstrs., 1990, 112, 112068.
21. F. Palasios, A. Ochoa de Renata, J. Oyarzabal, Tetrahedron,
1999, 55, 5947.
22. A. A. Thomas, K. B. Sharpless, J. Org. Chem., 1999, 64, 8379.
23. P. V. Pasternak, B. B. Averkiev, M. Yu. Antipin, A. S.
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24. M. R. Boyd, Status of the NCI Preclinical Antitumor Drug
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26. G. M. Sheldrick, SADABS: A Program for Exploiting the Reꢀ
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Received October 14, 2009;
in revised form October 30, 2009