Synthesis of annulated heterocyclic systems based on 4-CF3-or 4-CHF2-3-cyano-(1H)-pyridine-2-thiones

Article abstract of DOI:10.1007/s11172-013-0321-9

A simple and convenient preparative method for the synthesis of 3-cyano-4-difluoro- and -trifluoromethylpyridine-2(1H)-thiones was developed. During studies of synthetic potential of these compounds, approaches to the synthesis of a number of annulated heterocyclic systems were suggested.

Full text of DOI:10.1007/s11172-013-0321-9

Russian Chemical Bulletin, International Edition, Vol. 62, No. 10, pp. 2214—2226, October, 2013
2214
Synthesis of annulated heterocyclic systems based
on 4ꢀCF3ꢀ or 4ꢀCHF2ꢀ3ꢀcyanoꢀ(1H)ꢀpyridineꢀ2ꢀthiones
L. A. Rodinovskaya, A. E. Fedorov, A. M. Shestopalov, P. A. Belyakov,† and K. G. Nikishin†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: alf@server.ioc.ac.ru
A simple and convenient preparative method for the synthesis of 3ꢀcyanoꢀ4ꢀdifluoroꢀ and
ꢀtrifluoromethylpyridineꢀ2(1H)ꢀthiones was developed. During studies of synthetic potential
of these compounds, approaches to the synthesis of a number of annulated heterocyclic systems
were suggested.
Key words: Claisen condensation, 3ꢀcyanoꢀ4ꢀdifluoromethylpyridineꢀ2(1H)ꢀthione, trifluꢀ
oromethylꢀ3ꢀcyclopyridineꢀ2(1H)ꢀthione, domino reactions, 3ꢀaminothieno[2,3ꢀb]pyridines,
1,4ꢀdiazepinediones, 4ꢀhydroxyꢀ1Hꢀthieno[2,3ꢀb;4,5ꢀb´]dipyridinꢀ2ꢀone, pyrido[3´,2´:4,5]ꢀ
thieno[3,2ꢀb]ꢀ4Hꢀpyrano[2,3ꢀd]pyridine.
In the last years, a considerable growth of interest to
groups.1,19—23 In the present study, we concentrated our
attention on the synthesis of the library of various heteroꢀ
cycles based on 3ꢀcyanopyridineꢀ2(1H)ꢀthiones obtained
from methylene(methine)methyl ketones, since their the
synthesis and properties are studied the least.
The synthesis of 3ꢀcyanoꢀ4ꢀdi(tri)fluoromethylpyridꢀ
ineꢀ2(1H)ꢀthiones containing methyl, methylene. or meꢀ
thine group at position 6 is of a separate interest from the
point of view of regioselectivity of the reaction of unsymꢀ
metric ketones. The reaction of methyl ketones 1a—e with
ethyl trifluoroꢀ or difluoroacetate 2a,b in the presence of
sodium ethoxide proceeds regioselectively with the formaꢀ
tion of the sodium salts of trifluoroꢀ or difluoroꢀ1,3ꢀdiꢀ
ketones 3a,b, respectively. The reaction of these salts with
cyanothioacetamide 4 leads to 6ꢀsubstituted 4ꢀCF3ꢀ and
4ꢀCHF2ꢀ3ꢀcyanopyridineꢀ2(1H)ꢀthiones 5 (Scheme 1).
the methods for the synthesis of pyridine derivatives conꢀ
taining di(tri)fluoromethyl groups is observed.1—6 First of
all, this is due to the fact that these compounds manifest
various types of biological activity.4—16 In particular, such
compounds were suggested as antiviral agents,6,13 selecꢀ
tive kinase Cdc7 inhibitors,4 tyrosine kinase EGFR inhibꢀ
itors,7 LIMK1,9 PDE4, and TNF5 inhibitors, endoꢀ
nuclease IRE1 inhibitors,16 modulators of microꢀRNAꢀ
activity,8,14 as well as a new outflow NorA inhibitor,
Staphylococcus aureus12. In addition, pyridines containꢀ
ing fluoromethyl groups can be used as dyes for the identiꢀ
fication of cell structures17 and monoazodyes.18
We continued our works on the development of simple
and convenient methods for the synthesis of new
polyannulated pyridines containing di(tri)fluoromethyl
Scheme 1
R = Bui, Pri, cycloꢀPr, Bn, 3,4ꢀ(MeO)2C6H3CH2, X = F, H
5
a
b
c
d
X
F
H
F
R
5
e
f
X
F
F
F
R
cycloꢀPr
CH2Pri
CH2Pri
Bn
Pri
g
3,4ꢀ(OMe)2C6H3CH2
H
Bn
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2214—2225, October, 2013.
1066ꢀ5285/13/6210ꢀ2214 © 2013 Springer Science+Business Media, Inc.

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2215
The modified by us synthetic method1 allows one to
carry out the synthesis without isolation and purification
of the corresponding fluorineꢀcontaining 1,3ꢀdiketones or
their salts. The yields of 3ꢀcyanoꢀ4ꢀdi(tri)fluoromethylꢀ
pyridineꢀ2(1H)ꢀthiones 5 were 50—80% and comparable
with those of compounds 5 obtained according to the proꢀ
cedure with isolation of the intermediate diketones.1
The structure of 3ꢀcyanoꢀ4ꢀdifluoro(trifluoro)methylꢀ
pyridineꢀ2(1H)ꢀthiones 5 was confirmed by IR spectrosꢀ
copy and 1H NMR spectroscopy. The IR spectra of these
compounds exhibit a strong absorption band of the CN
= 53.9—55.9 Hz.3,9 In the 19F NMR spectra, the difluoroꢀ
methyl group was found as a doublet centered at  –118.29
and the spinꢀspin coupling constant 2JH,F = 53 Hz, whereꢀ
as the trifluoromethyl group as a singlet at  –64.06.
It should be noted that no other isomers were ever
detected, pyridinethiones 5 were always exclusively formꢀ
ed. This indicates that both the Claisen reaction and the
Knoevenagel reaction proceeds regioselectively. There is
a basis to suggest that the regioselectivity of the Claisen
reaction is, in the first place, due to the steric factors,
rather that electron ones. The methylene group of benzyl
methyl ketones, undoubtedly, is more acidic than the meꢀ
thyl group and should have been involved in the condenꢀ
sation reaction first. However, the reaction proceeds exꢀ
clusively at the least sterically hindered methyl group.
Alkylation of pyridinethiones 5 with halides 6 furnished
a number of modified pyridines 7 (Scheme 2), which are
of undoubted practical interest. The alkylation was perꢀ
formed in DMF in the presence of an equimolar amount
1
group in the region 2216—2244 cm–1. In the H NMR
spectra, the signal for the 5ꢀH atom was found in the
region  6.60—8.06. The signal for the NH proton was
recorded as a singlet in the region  13.90—14.89 characꢀ
teristic of pyridineꢀ2(1H)ꢀthiones.4,7 In the 1H NMR specꢀ
tra of difluoromethylpyridineꢀ2(1H)ꢀthiones 5, the signal
for the proton of the CHF2 group was found in the region
2
 7.06—7.15 as a triplet with the constant J(19F—1H) =
Scheme 2
Hal = Cl, Br; X = H, F
Z = CN, CONHR´ (R´ = Alk, Ar, ArCH2, Het, CH2COOH); COR (R = Me, Ar), 4ꢀPy, 2ꢀPy
7
X
Z
R
8
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
X
F
F
F
H
H
H
F
F
F
F
F
F
F
F
F
Z
4ꢀMeC6H4CO
2ꢀPy
CONHCH2COOH
CONHCH2COOH
2ꢀPy
R
CH2Pri
CH2Pri
CH2Pri
Bn
CH2Pri
a
b
c
d
F
F
F
F
CN
CH2Pri
CONHꢀcycloꢀPr
CONH2
CH2Pri
CH2Pri
CON(Et)2
Bn
4ꢀPy
CONH2
CON(Et)2
CH2Pri
8
a
c
d
e
f
X
F
F
F
F
F
F
F
Z
CONHꢀcycloꢀPr
COOH
R
Bn
Bn
Bn
CH2Pri
CH2Pri
CH2Pri
CH2Pri
CH2Pri
CH2Pri
CH2Pri
CONHꢀ3,4ꢀ(MeO)2C6H3
CONHCH2(3,4ꢀOCH2O)C6H3
(3,4ꢀOCH2O)C6H3CO
4ꢀPy
MeCO
CONH2
CONH(3,4ꢀOCH2O)C6H3
(3,4ꢀOCH2O)C6H3CO
3,4ꢀ(MeO)2C6H3CH2
cycloꢀPr
cycloꢀPr
cycloꢀPr
g
h
CONH(2ꢀCOOMe)C6H4
CONH2
3,4ꢀ(MeO)2C6H3CH2
Pri

2216
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
of a 10% aq. solution of KOH. The reaction of pyridinethꢀ
iones 5 with alkyl halides 6, carried out upon reflux for
5—10 min in ethanol in the presence of a twofold excess of
KOH, afforded 3ꢀaminothieno[2,3ꢀb]pyridines 8. The
reaction was conducted in one step through the sequenꢀ
tially effected SN2 reaction and Thorpe—Ziegler reaction
(method A).
The corresponding 3ꢀaminothieno[2,3ꢀb]pyridines 8
were also obtained by the Thorpe—Ziegler cyclization of
some of compounds 7 containing an active methylene
group upon treatment with a base in ethanol (see Scheme 2,
method B).
ventꢀfree cyclization of these compounds upon heating at
220 C without exposure to air gave annulated diazepineꢀ
diones 9a,b (Scheme 3), analogs of natural compounds,
possessing high anticancer activity.25
Domino reactions (of the type SN2  Thorpe—Zieꢀ
gler  Thorpe—Guareschi) based on 3ꢀcyanoꢀ4ꢀdi(tri)ꢀ
fluoromethylpyridineꢀ2(1H)ꢀthiones 5a,b,f and ethyl
4ꢀchloroacetoacetate (10) using our procedure1,26—28
furnished the earlier undescribed 4ꢀhydroxyꢀ1Hꢀthienoꢀ
[2,3ꢀb;4,5ꢀb´]dipyridinꢀ2ꢀones 11. The reaction was carꢀ
ried out in one reaction vessel, without isolation of the
intermediate products (Scheme 4).
Nꢀ(Thieno[2,3ꢀb]pyridꢀ2ꢀylcarbonyl)ꢀꢀaminocarꢀ
boxylic acids 8k,l containing glycine moiety are conveꢀ
nient objects for further transformations.24 Thus, a solꢀ
Dipyridines 11 appeared to be convenient reagents for
the synthesis of annulated 2ꢀaminoꢀ4Hꢀpyrans 12. As
CHꢀacids,26,27 they were involved in the threeꢀcompoꢀ
nent reaction with malonoonitrile 13 and aromatic aldeꢀ
hydes 14 in the presence of triethylamine in ethanol with
the formation of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ5ꢀoxoꢀ5,6ꢀdiꢀ
hydroꢀ4Hꢀpyrano[2,3ꢀd]pyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ
pyridines 12a—f (Scheme 5). The process proceeded as
a oneꢀpot domino reaction: the Knoevenagel reaction 
 the Michael reaction  the hetero Thorpe—Ziegler
reaction. The presence of the di(tri)fluoromethyl group
and an alkyl substituent, considerably increasing solubiliꢀ
ty of the starting compounds, makes it possible to carry
out the reaction upon reflux in ethanol.
Scheme 3
The structure of obtained pyrans 12 was confirmed by
physicochemical analysis. The IR spectra, besides charꢀ
acteristic bands of carbonyl and amide groups, also exhibit
absorption bands of the nitrile and the amino group in the
regions 2191—2196 and 3408—3430 cm–1, respectively,
which are characteristic of 2ꢀaminoꢀ4Hꢀpyrans.29 In the
9: X = F (a), H (b)
Scheme 4
11: R = Bui, X = F (a), H (b); R = Pri, X = F (c)
Reagents and conditions: i. The Thorpe—Ziegler reaction; ii. The Thorpe—Guareschi reaction.

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2217
Scheme 5
12: X = F, Ar = 4ꢀClPh (a), 4ꢀBrPh (b), 4ꢀFPh (c); X = H, Ar = 4ꢀClPh (d), 4ꢀBrPh (e), 4ꢀFPh (f)
Reagents and conditions: i. The Knoevenagel reaction; ii. The Michael reaction; iii. The heteroꢀThorpe—Ziegler reaction.
1H NMR spectra, besides signals for the protons present
in the starting pyridothienopyridines 11, the signals for the
protons of the amino group were observed at  7.32—7.36,
as well as the signal for the proton at position 4 of the
pyran ring at  4.66—4.68.29 In the 19F NMR spectrum of
compounds 12a—c, there is present a singlet for the CF3
group at  –60.42. The 19F NMR spectrum of the CHF2
group in compounds 12d—f have some specific features.
Unlike the 19F NMR spectra of compounds 5b, 8l—n, 9b,
and 11b, which exhibit a doublet due to the spinꢀspin
plets; in the spectrum of compound 12f, the signals for the
F nuclei of the difluoromethyl group are overlapped with
the signal from the F nucleus at paraꢀposition of the
phenyl substituent, that makes the spectrum even more
complicated.
To simplify the spectrum and accurately determine
chemical shifts and spinꢀspin coupling constant 2J(19F—19F)
2
(the J(19F—1H) constant can be easily determined from
1
the H NMR spectrum), we recorded 19F—{1H} NMR
spectra. The obtained spectra of the difluoromethyl group
1
1
coupling of the 19F and H nuclei with the constant
exhibit the Hꢀpairs of doublets centered at  ~115 and
2J(19F—1H) = 53 Hz, the spectra of compounds 12d—f
are quite complicated. Compounds 12 are formed as an
enantiomeric pair, in the presence of the asymmetric
carbon atom the F nuclei of the difluoromethyl group
become diastereotopic and, therefore, not only magꢀ
netically, but also chemically nonequivalent. This
leads to the increase in the number of lines and comꢀ
plication of the spectrum because of the spinꢀspin couꢀ
pling of the F nuclei between each other. The 19F NMR
spectra of compounds 12d—f exhibit complicated multiꢀ
116, respectively (AB system) and very pronounced "roof
effect", the ratio of intensities is 1/10. For the analysis of
the spectrum of these systems (for the accurate determiꢀ
nation of chemical shifts and spinꢀspin coupling conꢀ
stants) we used the SpinWorks v.2.5 program based on
the NUMARIT algorithm (the author Kirk Marat,
kirk_marat@umanitoba.ca), which is available at ftp://
davinci.chem.umanitoba.ca/pub/marat/SpinWorks,
which.30 Results of the analysis of the spin systems are
given in Table 1.
Table 1. The NMR spectra and IR spectra of compounds obtained
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
5a
0.88 (d, 6 Н, (CH3)2CHCH2, 3J = 6);
98 (m, 1 Н, (CH3)2CHCH2); 2.63
(2 Н, (CH3)2CHCH2,3J = 7.1);
7.08 (s, 1 Н, С(5))
21.75, 28.026, 41.12,
109.09, 109.98, 113.70,
121.55 (q, 1J(13C—19F) =
= 2789, CF3); 141.03,
160.22, 179.06
–64.06 (s, CF3)
2232 (CN), 1610
(С=S), 1469, 1178,
1139
(to be continued)

2218
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
Table 1 (continued)
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
5b
0.88 (d, 6 Н, (CH3)2CHCH2, 3J = 6.1); 21.75, 28.76, 41.07,
1.97 (m, 1 Н, (CH3)2CHCH2); 108.91, 111.55 (t, CHF2,
2.62 (d, 2 Н, (CH3)2CHCH2, 3J = 6.9); 1J(13C—19F) = 242.1);
–118.29 (d,
2J(19F–1H) = 53.06)
2227 (CN),
1611 (СS), 1464,
1164, 1148
6.92 (s, 1 Н, H(5)); 7.09 (t, CHF2,
1J(19F—1H) = 53.6)
114.16, 115.13, 148.11,
154.77, 178.57
7a
7b
0.88 (d, 6 Н, (CH3)2CHCH2, 3J = 6.2); 16.16, 22.18, 28.01, 46.57,
–62.80 (s, CF3)
–62.91 (s, CF3)
2249 (CN), 2227
(CN), 1472, 1180,
1143
2.28 (m, 1 Н, (CH3)2CHCH2); 2.83
(2 Н, (CH3)2CHCH2, 3J = 6.8); 4.40
(s, 2 Н, CH2CN); 7.78 (s, 1 Н, С(5))
97.03, 102.19, 112.47, 121.95
(q, CF3, 1J(13C—19F) = 280.1);
117.21, 157.42, 161.10, 167.89
0.40 (m, 2 Н, CH2, cycloꢀPr); 0.61 (m,
2 Н, CH2, cycloꢀPr); 0.87 (d, 6 Н,
(CH3)2CHCH2, 3J = 6.0); 2.18
5.49, 22.10, 22.62, 27.93,
34.02, 45.53, 106.67, 112.82,
115.92, 119.56 (q, CF3,
3305 NH, 3050,
(cycloꢀPr), 2227
(CN), 1647, 1536
(СO), 1469, 1173,
1140
(m, 1 Н, (CH3)2CHCH2); 2.74 (d, 2 Н, 1J(13C—19F) = 280.1); 121.85,
(CH3)2CHCH2, 3J = 6.9); 2.60
(m, 1 Н, CH, cycloꢀPr); 3.96 (s, 2 Н,
CH2CО); 7.61 (s, 1 Н, С(5));
8.25 (br.s, NH)
145.02, 163.66, 167.21
7c
7d
4.03 (s, 2 H, S—CH2); 4.23 (s, 2 H,
CH2); 7.23—7.39 (m, 5 H, Ph); 7.60
(br.s, 2 H, CONH2); 7.65 (s, 1 H,
C(5))
34.07, 43.77, 99.18, 112.76,
115.41, 121.39 (q, CF3,
1J(13C—19F) = 279.8); 126.83
128.72, 129.24, 137.57, 140.31,
164.03, 166.31, 168.34
–63.75 (s, CF3)
–57.86 (s, CF3)
2226 (CN),
1645 (CO),1581
(NH), 1380, 1297
1178, 1137
1.03 (t, 3 H, CH3, J = 7.0); 1.19
(t, 3 H, CH3, J = 7.0); 3.29 (q,
2 H, CH2, J = 7.0); 3.40
(q, 2 H, CH2, J = 7.0); 4.23 (s, 2 H,
CH2); 4.30 (s, 2 H, S—CH2); 7.22—7.29 126.79, 128.61, 129.17, 137.55,
6.07, 13.00, 14.23, 33.98,
40.28, 41.87, 43.64, 99.05,
112.80, 115.51, 115.54, 121.41
(q, 1J(13C—19F) = 279.7);
3387, 3185 (NH2),
2227 (CN),
1657 (СO),
1620 (NH, "amide
band" II), 1397,
1304, 1246, 1142
(m, 5 H, Ph); 7.68 (s, 1 H, C(5))
164.30, 165.06, 166.21
8a
0.60 (m, 2 Н, CH2, cycloꢀPr); 0.68
(m, 2 Н, CH2, cycloꢀPr); 0.89 (d, 6 Н,
(CH3)2CHCH2, 3J = 6); 2.08 (m, 1 Н,
CH, cycloꢀPr); 2.12 (m, 1 Н,
(CH3)2CHCH2); 2.74 (d, 2 Н,
(CH3)2CHCH2, 3J = 6.9); 6.62
(br.s, 2 Н, NH2); 7.67 (s, 1 Н, С(5));
8.02 (br.s, NH)
5.79, 22.08, 22.98, 28.54,
46.05, 101.14, 116.65
(q, CF3, 1J(13C—19F) =
= 278.9); 130.99, 143.55,
149.64, 160.05, 162.34,
166.03
—57.44 (s, CF3)
3353 (NH2), 3302
(NH), 3090 (cycloꢀPr),
1600 (NH2), 1540
(СO), 1466, 1169,
1135
8b
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6);
2.15 (m, 1 Н, (CH3)2CHCH2); 2.40 (s,
3 Н, CH3); 2.83 (d, 2 Н, (CH3)2CHCH2, (q, CF3, 1J(13C—19F) =
3J = 6.9); 6.68 (s, 1 Н, H(4´));
6.86 (br.s, 2 Н, NH2); 7.72 (s, 1 Н,
H(5)); 10.83 (br.s, 1 Н, NH)
12.08, 22.12, 28.53, 46.14,
97.35, 99.06, 117.93, 120.87
–57.72 (s, CF3)
3523 (NH2), 3355
(NH), 1601 (NH2),
1624 (СO), 1471,
1165, 1124
= 278.9); 146.09, 158.32,
160.84, 163.83, 167.97,
169.17, 173.04
8c
8d
0.89 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.12, 28.53, 46.14, 114.07, 116.65, –57.75 (s, CF3)
3524 (NH2), 1601
(NH2), 1651 (СO),
1471, 1272 (ОН),
1165, 1124
2.13 (m, 1 Н, (CH3)2CHCH2); 2.83
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0); 7.68
(s, 1 Н, H(5))
122.67 (q, CF3, 1J(13C—19F) =
= 278.9); 135.28, 144.48,
144.60, 161.12, 162.81, 166.30
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.09, 28.59, 45.94, 116.94,
–57.72 (s, CF3)
3502, 1594 (NH2),
1469, 1161, 1123
2.14 (m, 1 Н, (CH3)2CHCH2); 2.82 (d, 119.15, 121.24 (q, CF3,
2 Н, (CH3)2CHCH2, 3J = 7.0); 5.04
(br.s, 2 Н, NH2); 7.68 (d, 2 Н, Py,
3J = 3.5); 7.70 (s, 1 Н, H(5));
8.68 (d, 2 Н, HРу, 3J = 3.5)
1J(13C—19F) = 278.8); 122.36
127.18, 129.61, 134.81, 140.65,
150.36, 154.78, 160.01
(to be continued)

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Table 1 (continued)
2219
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
8e
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.1); 22.07, 28.48, 29.24, 46.17,
2.14 (m, 1 Н, (CH3)2CHCH2); 2.42 (s, 106.30, 117.05, 122.35 (q, CF3,
–56.15 (s, CF3)
3502, 1594 (NH2),
1469, 1161, 1123
3 Н, Me); 2.83 (d, 2 H, (CH3)2CHCH2, 1J(13C—19F) = 278.5);
3J = 6.9); 7.35 (br.s, 2 H, NH2);
126.23, 143.22, 145.6,
161.20, 164.42, 192.40
7.73 (s, 1 Н, H(5))
8f
0.89 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.10, 28.52, 46.07, 107.41
–56.15 (s, CF3)
–57.49 (s, CF3)
3512, 3481, 1605
(СO), 1465, 1165,
1121
2.14 (m, 1 Н, (CH3)2CHCH2); 2.82 (d, 116.65, 119.32, 122.90 (q,
2 Н, (CH3)2CHCH2, 3J = 7.0); 6.65
(br.s, 2 Н, NH2); 7.43 (br.s, 2 Н,
NH2); 7.67 (s, 1 Н, H(5))
CF3, 1J(13C—19F) = 278.7);
133.34, 139.73, 143.93,
162.38, 166.69
8g
0.91 (d, 6 Н (CH3)2CHCH2, 3J = 6.0);
22.11, 28.57, 46.10, 100.49,
3526, 1608 (NH2),
3377 (NH), 1655,
1581 (СO), 1443,
1165, 1118
2.15 (m, 1 Н, (CH3)2CHCH2); 2.84 (d, 101.02, 103.73, 107.73,
2 Н, (CH3)2CHCH2, 3J = 7.0); 6.01 (s, 114.79, 116.95, 117.58, 122.7
2 Н, (ОCH2О)); 6.69 (br.s, 2 Н, NH2); (q, CF3, 1J(13C—19F) = 278.8);
6.88 (d, 1 Н, HAr, 3J = 8.1); 7.09 (d,
132.54, 143.5, 144.66, 146.88,
1 Н, HAr, 3J = 8.1); 7.29 (s, 1 Н, HAr); 151.99, 160.29, 162.83, 163.52
7.79 (s, H(5)); 9.62 (br.s, 1 Н, NH)
8h
0.89 (d, 6 Н, (CH3)2CHCH2, 3J = 6.1); 22.10, 28.47, 46.21, 101.86,
–57.49 (s, CF3)
3526, 1618 (NH2),
1589 (СO), 1450,
1153, 1130
2.14 (m, 1 Н, (CH3)2CHCH2); 2.83
107.80, 107.91, 110.21, 116.39,
(d, 2 Н, (CH3)2CHCH2, 3J = 8.1); 6.15 117.18, 122.64 (q, CF3,
(s, 2 Н, (ОCH2О)); 7.06 (d, 1 Н, HAr,
3J = 7.5); 7.30 (s, 1 H, HAr); 7.41 (d,
1 Н, HAr, 3J = 7.5); 7.64 (br.s, 2 Н,
NH2, 1 Н, HAr); 7.75 (s, 1 H, H(5))
1J(13C—19F) = 278.9); 122.97,
132.34, 134.49, 147.52,
147.84, 150.04, 162.41, 164.71
188.29
8i
8j
0.89 (d, 6 Н, (CH3)2CHCH2,3J = 6.0);
2.14 (m, 1 Н, (CH3)2CHCH2, 2.40 (s,
3 Н, СH3); 2.83 (d, 2 Н, (CH3)2CHCH2, (q, CF3, 1J(13C—19F) = 280.0);
3J = 7.0); 7.34 (d, 2 Н, HAr, 3J = 7.5);
7.71 (m, 4 Н, HAr, NH2); 7.75
(s, 1 H, H(5))
21.02, 22.09, 28.48, 46.21,
104.97, 116.34, 117.10, 122.73
–58.67 (s, CF3)
–56.58 (s, CF3)
3540 (NH2), 1593
(СO), 1446, 1157,
1130
127.56, 129.01, 132.18, 137.77,
141.57, 147.87, 162.50, 164.75,
184.09, 189.59
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.12, 28.56, 46.00, 108.59,
3507, 1606 (NH2),
1470, 1153, 1119
2.14 (m, 1 Н, (CH3)2CHCH2); 2.80
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0);
6.86 (br.s, 2 Н, NH2); 7.25 (d, 1 H,
3J = 8.1); 7.50 (m, 1 H HPy); 7.356
(1 H, H(5)); 7.86 (m, 1 H, HPy); 8.62
(d, 1 H, HPy, 3J = 7.5)
116.57, 116.64, 119.59, 120.66,
120.89, 122.90 (q, CF3,
1J(13C—19F) = 278.6); 129.71,
137.53, 138.50, 148.22, 153.96,
159.84, 160.63
8k
8l
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.1); 22.12, 28.56, 41.08, 46.09,
–57.52 (s, CF3)
3508 (NH2), 1605
(NH2), 1550 (СO),
1450, 1272 (ОН),
1167, 1132
2.13 (m, 1 Н , (CH3)2CHCH2); 2.83
(d, 2 Н, (CH3)2CHCH2); 3.87 (d, 2 Н,
NHCH2, 3J = 4.4); 6.62 (br.m, 2 Н,
NH2); 7.70 (s, 1 Н, H(5)); 8.31 (br.m,
1 Н, NH)
100.37, 116.82, 117.77, 121.33
(q, CF3, 1J(13C—19F) = 278.3);
126.00, 144.00, 160.09, 162.63,
164.99, 171.16
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.1); 22.16, 28.59, 41.03, 46.31,
2.12 (m, 1 Н, (CH3)2CHCH2); 2.78 (d, 99.86, 112.69 (t, 1J(13C—19F) =
2 Н, (CH3)2CHCH2, 3J = 7.1); 3.86 (d, = 239.9); 116.80, 119.88,
–111.07 (d, CHF2,
2J(19F–1H) = 53.9)
3362, (NH2), 1605,
NH2), 1623, 1552
(СO), 1443, 1276
(ОН), 1184, 1119
2 Н, NHCH2, 3J = 5.0); 6.70 (br.s,
2 Н, NH2); 7.50 (s, 1 Н, H(5)); 7.65
(t, CHF2,2J(19F—1H) = 53.9); 8.20
(br.m, 1 H, C(5))
137.13, 145.17, 159.32, 162.47,
165.08, 171.23
(to be continued)

2220
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
Table 1 (continued)
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
8m
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.25, 28.67, 46.31, 108.26,
2.12 (m, 1 Н, (CH3)2CHCH2); 2.77 (d, 111.29, 112.74 (t, 1J(13C—19F) =
–110.61 (d, CHF2,
2J(19F–1H) = 55.0)
3446, 1605 (NH2),
1473, 1159, 1110
2 Н, (CH3)2CHCH2, 3J = 7.0); 6.91
= 239.9); 116.61,120.57, 121.77,
136.16, 137.44, 139.59, 148.27,
(br.s, 2 Н, NH2); 7.23 (m, 1 Н, HPy);
7.46 (m, 2 Н, HPy, H(5)); 7.72 (t, CHF2, 154.18, 159.0, 160.50
2J(19F—1H) = 55.0); 7.85 (m, 1 H, HРy);
8.62 (m, 1 Н, HPy
)
8n
8o
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 7.0); 22.14, 28.61, 46.19, 107.34,
–109.82 (d, CHF2,
3346, 1596 (NH2),
1466, 1167, 1127
2.12 (m, 1 Н, (CH3)2CHCH2); 2.78 (d, 111.00, 112.91 (t, 1J(13C—19F) =
2J(19F–1H) = 55.0)
2 Н, (CH3)2CHCH2, 3J = 7.0); 5.24
(br.s, 2 Н, NH2); 7.51 (s, 1 Н, H(5));
7.60 (m, 2 Н, HPy); 7.75 (t, CHF2,
2J(19F—1H) = 55.0); 8.63 (m, 2 Н, HPy
= 239.8); 116.93, 122.19, 136.05,
140.86, 150.28, 154.02, 159.39,
160.03
)
4.33 (s, 2 H, CH2); 6.62 (br.s, 2 H,
NH2); 7.31—7.33 (m, 5 H, Ar); 7.41
(br.s, 2 H, NH2); 7.73 (s, 1 H, H(5))
43.18, 100.96, 116.38, 118.07,
122.67 (q, 1J(13C—19F) = 274.2);
126.55, 128.61, 129.02, 131.09,
138.52, 143.87, 160.15, 161.71,
166.64
–58.33 (s, CF3)
3523, 3346 (NH2),
3134 (NH2), 1656
(СО), 1596, 1534 (NH,
"amide band" II),
1497, 1353, 1278, 1169,
1131
8p
8q
1.19 (t, 6 2 H, CH3CH2, 3J = 7.0);
3.50 (q, 4 H, CH3CH2, 3J = 7.0); 4.32
(s, 2 H, CH2); 5.58 (br.s, 2 H, NH2);
7.22—7.34 (m, 5 H, Ar); 7.78
(s, 1 H, H(5))
13.69, 40.09, 41.51, 4319,
57.33 (s, CF3)
3526, 3362 (NH2),
1632 (СО), 1592,
1573, 1423, 1353,
1284, 1258, 1155,
1126
104.48, 116.57, 118.25, 122.83
(q, 1J(13C—19F) = 274.2); 126.59,
128.67, 129.10 ,130.78, 138.71
140.20, 160.41, 160.85, 164.47
3.76 (s, 3 H, OCH3); 3.77 (s, 3 H,
OCH3); 4.35 (s, 2 H, CH2); ); 6.70
(m, 1 H, Ar); 6.93 (m, 1 H, Ar);
7.24—7.35 (m, 8 H, NH2, Ar); 7.74
(s, 1 H, C(5)); 9.59 (br.s, 1 H, NH)
43.26, 55.50, 55.76, 106.80,
111.76, 113.74, 116.64, 120.42,
122.67 (q, 1J(13C—19F) = 274.2);
126.67, 128.72, 129.11,
131.87, 138.57, 142.73, 144.55,
145.53, 148.41, 150.71, 160.43,
162.14, 163.44
–58.29 (s, CF3)
3506, 3324 (NH2),
1644 (СО), 1600,
1608, 1536 (NH,
"amide band"
II), 1355, 1227,
1157, 1125
8r
3.72 (s, 6 H, 2 OCH3); 4.24 (s, 2 H,
CH2); 4.35 (d, 2 H, NH—CH2,
3J = 6.0); 5.97 (s, 2 H, O—CH2—O);
6.59 (br.s, 2 H, NH2); 6.79—6.97
(m, 6 H, Ph); 7.69 (s, 1 H, H(5));
8.48 (t, 1 H, NH, 3J = 6.0)
42.24, 42.77, 55.47, 100.76, 101.11, –58.31 (s, CF3)
107.95, 112.10, 112.99, 116.38,
118.04, 120.51, 121.04, 122.67
(q, 1J(13C—19F) = 274.2); 124.64,
130.78, 133.50, 143.79, 147.15,
3506, 3334, (NH2);
3311 (NH2); 1633
(СО); 1605, 1579 (NH,
"amide band" II);
1517, 1490, 1360, 1284,
1252, 1169, 1135,
1125
147.60, 148.77, 155.33, 160.05,
162.14, 164.54, 170.58, 180.05
8s
8t
1.14 (m, 4 H, CH2—CH2, cycloꢀPr);
2.45 (m, 1 H, CH, cycloꢀPr)*;
12.10, 17.39, 101.93, 104.52,
107.94, 113.89, 116.49, 120.08,
121.47 (q, 1J(13C—19F) = 274.1);
–59.29 (s, CF3)
–58.31 (s, CF3)
3529, 3300 (NH2),
3009, 2903
(cycloꢀPr);1591
(СО), 1548
(NH2), 1460, 1450,
1309 (CF3)
6.15 (s, 2 H, CH2); 7.05 (d, 1 H, Ar,
3J = 7.8); 7.28 (s, 1 H, Ar); 7.40 (d, 1 H, 123.00, 126.78, 138.71, 145.54,
Ar, 3J = 7.8); 7.63 (br.s, 2 H, NH2);
148.12, 150.07, 163.00,
7.83 (s, 1 H, H(5))
1.12 (d, 4 H, CH2CH2, cycloꢀPr, 3J = 8.1, 11.50, 17.09, 25.36, 40.09,
5.2); 2.42 (m, 1 H, CH, cycloꢀPr);** 2.97 100.61, 111.42, 111.84,
3536 (NH, indole);
3330, 3308 (NH2);
3012, 2954 (cycloꢀ
Pr), 1636
(СО); 1516
(NH, "amide
(t, 2 H, CH2, 3J = 8.1, 3J = 7.4); 3.54
(d, 2 H, CH2, J = 8.1, 3J = 7.4); 6.58
(br.s, 2 H, NH2); 6.99 (t, 1 H, Ar,
3J = 7.4); 7.08 (t, 1 H, Ar, 3J = 7.4);
115.41, 117.64, 118.29, 118.38,
120.98, 122.66, 123.65
(q, 1J(13C—19F) = 274.1);
127.32, 129.01, 136.30,
7.18 (d, 1 H, Ar, 3J = 2.2); 7.36 (d, 1 H, 143.68, 160.48, 164.21, 164.74
Ar, 3J = 8.1); 7.62 (d, 1 H, Ar, 3J = 8.1);
band" II); 1282
7.74 (s, 1 H, H(5)); 8.00 (t, H, NH,
3J = 5.9); 10.76 (m, 1 H, NH)
(to be continued)

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Table 1 (continued)
2221
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
8u
8v
1.18 (m, 4 H, cycloꢀPr); 2.43 (m, 1 H,
CH, cycloꢀPr)*; 3.97 (s, 3 Н, СООМе); 110.92, 117.28, 115.69, 120.34,
11.91, 17.17, 52.77, 98.88,
–58.54 (s, CF3)
3520, 3350 (NH2),
3012, 2954
6.77 (s, 2 H, NH2); 7.21 (t, 1 H, Ar,
3J = 7.7); 7.66 (t, 1 H, Ar, 3J = 7.7);
7.78 (s, 1 H, H(5)); 8.03 (d, 1 H, Ar,
3J = 8.1); 8.57 (d, 1 H, Ar, 3J = 8.8),
11.17 (s,1 H, NH)
122.63 (q, 1J(13C—19F) = 274.1);
122.99, 126.56, 130.80, 134.53,
140.69, 145.82, 160.54, 163.41,
165.54, 168.31
(cycloꢀPr), 1696
(СОOMe), 1651, 1608,
1588, (СОNH), 1538
(NH2), 1302 (СF3),
1264 (OMe)
3.72 (s, 6 H, OCH3); 4.24 (s, 2 H,
CH2); 6.59 (br.s, 2 H, NH2); 6.85
(m, 2 Н, Ar); 7.00 (s, 1 H, Ar); 7.48
(br.s, 2 H, NH2); 7.69 (s, 1 H, H(5))
42.87, 55.52, 101.12, 112.11,
113.00, 116.28, 118.04, 121.11,
121.18 (q, 1J(13C—19F) = 275.1);
121.68, 130.87, 131.16, 143.98,
147.64, 148.81, 160.15, 162.17,
166.73
–58.34 (s, CF3)
3516, 3399, 3336
(NH2), 3152 (NH2),
1658(СО), 1611,
1595, 1542, (NH,
"amide band" II),
1518, 1500, 1353,
1284, 1252, 1167, 1131
8w
1.33 (d, 6 H, 2 Me, 3J = 6.6);
22.05, 25.35, 35.65, 41.15,
101.44, 111.42, 111.84, 114.97,
–58.16 (s, CF3)
3508 (NHꢀindole),
3418, 3311 (NH2);
1633 (СО), 1546,
(NH, "amide
band" II), 1516,
1412, 1278, 1251,
1208, 1176
2.98 (t, 2 H, CH2, 3J = 8.1, 3J = 7.3);
3.29 (m, 1 H, CH); 3.55 (m, 2 H, CH2); 118.29, 118.38, 120.98, 121.71
6.60 (s, 2 H, NH2); 7.00 (t, 1 H, Ar,
3J = 7.3); 7.08 (t, 1 H, Ar, 3J = 7.3);
7.19 (d, 1 H, Ar, 3J = 2.2); 7.36 (d, 1 H, 160.98, 164.71, 167.78, 164.71
Ar, 3J = 8.1); 7.62 (d, 1 H, Ar, 3J = 8.1);
(q, 1J(13C—19F) = 275.1); 122.67,
127.32, 136.30, 143.57, 160.00,
7.71 (s, 1 H, H(5)); 8.05 (t, H, NH,
3J = 5.1); 10.76 (t, 1 H, NH)
9a
9b
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0,
22.09, 28.63, 44.83, 46.05,
–57.20 (s, CF3)
3443, 3219, 1643,
1689 (NH), 1590,
1555 (СO), 1463,
1162, 1137
3J = 7.3); 2.16 (m, 1 Н, (CH3)2CHCH2); 100.31, 116.78, 117.69, 121.60
2.87 (d, 2 Н, (CH3)2CHCH2, 3J = 7.0); (q, CF3, 1J(13C—19F) = 278.5);
3.84 (d, 2 Н, NHCH2); 7.84 (s, 1 Н,
H(5)); 8.99 (br.m, 2 H, NH, NH)
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.11, 28.64, 44.98, 46.27,
2.12 (m, 1 Н, (CH3)2CHCH2); 2.83 (d, 111.52, 114.68
2 Н, (CH3)2CHCH2, 3J = 7.0); 3.82 (d, (q, 1J(13C—19F) = 240.5);
2 Н, NHCH2, 3J = 4.4); 7.61 (s, 1 Н,
H(5)); 7.85 (t, CHF2, 2J(19F–1H) =
= 55.0); 8.84 (br.m, 1 H, NH); 10.17
(br.s, 1 Н, NH)
126.00, 144.00, 160.09, 162.69,
163.31, 168.57
–115.17 (CHF2,
2J (19F–1H) =
= 55.0)
3274, 2959, 1702,
1643 (NH), 1588,
1557 (СO), 1463,
1191
116.93, 121.01, 124.47, 130.04,
159.01, 162.51, 163.56, 168.95
11a
11b
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.12, 28.65, 46.19, 94.29,
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85 (d, 104.58, 113.85, 116.81, 123.10,
–60.18 (s, CF3)
3454, 1633 (NH),
1565, 1527 (СO);
1467, 1119
2 Н, (CH3)2CHCH2, 3J = 7.0); 6.34 (s,
1 Н, С(5)); 7.72 (s, 1 Н, H(11)); 10.58
(s, 1 H, ОH); 12.00 (br.s, 1 H, NH)
(q, CF3, 1J(13C—19F) = 274.5);
124.42, 147.27, 160.45, 160.87,
162.14, 163.90
0.90 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 2217, 28.72, 46.46, 93.89,
–115.17 (CF3,
2J (19F–1H)) =
3408, 1635 (NH),
1565, 1527 (СO),
1466, 1146, 1090
2.13 (m, 1 Н, (CH3)2CHCH2); 2.82
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0);
6.34 (s, 1 Н, H(11)); 7.60 (s, 1 Н,
H(5)); 8.39 (t, 1 Н, CF3, 2J(19F–1H) =
= 55.0); 10.77 (s, 1 Н, ОH);
100.56, 113.92 (t, 1J(13C—19F) =
= 239.0); 113.15, 115.47, 122.01, = 55.0)
137.97, 161.06, 161.34, 162.22,
164.27
11.73 (br.s, 1 H, NH)
11s
1.34 (d, 6 H, 2 CH3, 3J = 7.0);
3.31 (m, 1 H, CH); 6.35 (s, 1 H, H(11)); 115.06, 123.35 (t, CF3,
7.93 (s, 1 H, H(5)); 10.48 (br.s, 1 H,
OH); 11.68 (br.s, 1 H, NH)
22.23, 35.72, 94.50, 104.58,
–60.99 (s, CF3)
3408, 1635 (СO),
1565 (NH), 1533,
1462, 1161, 1127
1J(13C—19F) = 274.5); 124.42,
145.98, 123.95, 160.88, 162.30,
164.01, 167.72
(to be continued)

2222
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
Table 1 (continued)
Comꢀ
pound
NMR,  (J/Hz)
IR,
/cm–1
1Н
13С
19F
12a
12b
12c
0.92 (d, 6 Н, (CH3)2CHCH2, 3J = 7.0); 22.15, 28.75, 36.76, 46.51
–60.43 (s, CF3)
3428, 1596 (NH2),
3312, 1660 (NH),
2193 (CN), 1613,
1593 (CO), 1467
1173, 1142
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85
(d, 2 Н, (CH3)2CHCH2,3J = 7.0); 4.67
(s, 1 Н, H(4)); 7.23 (d, 2 Н, Ar,
3J = 8.2); 7.36 (m, 4 H, Ar, NH2);
7.79 (s, 1 Н, H(8)); 11.38 (br.s,
1 H, NH)
57.79, 90.25, 104.26, 106.04,
112.23, 117.26, 119.45, 119.64,
122.45, (q, CF3, 1J(13C—19F) =
= 271.6); 128.39, 129.45,
130.16, 131.39, 143.36, 151.13
151.34, 158.58, 163.00, 167.13
0.92 (d, 6 Н, (CH3)2CHCH2, 3J = 7.0); 22.15, 28.75, 36.33, 46.27,
–60.43 (s, CF3)
3428, 1596 (NH2),
3319, 1663 (NH),
2196 (CN), 1596
(СO), 1465, 1176,
1151
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0);
4.67 (s, 1 Н, H(4)); 7.11 (m, 2 H, Ar);
7.24 (m, 2 H, Ar); 7.34 (s, 2 Н, NH2);
7.79 (s, 1 Н, H(8)); 11.38 (br.s, 1 H,
NH)
57.79, 89.25, 104.14, 107.20,
116.40, 117.38, 119.52, 122.25
(q, CF3, 1J(13C—19F) = 272.6);
129.83, 131.31, 143.78, 151.12,
157.47, 158.56, 160.13, 162.17,
163.01, 167.26
0.91 (d, 6 Н, (CH3)2CHCH2, 3J = 7.0); 22.15, 28.75, 36.10, 46.22,
–60.43 (s, CF3);
–116.78 (s, F(4))
3430, 1603 (NH2),
3311, 1662 (NH),
2192 (CN), 1603,
1565 (СO), 1464,
1178
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0);
4.67 (s, 1 Н, H(4)); 7.23 (d, 2 Н, Ar,
3J = 7.0); 7.36 (m, 4 Н, Ar, NH2);
7.79 (s, 1 Н, H(8)); 11.35 (br.s,
1 Н, NH)
58.11, 88.03, 104.60, 107.97,
111.64, 115.14 (d, Ar—F,
2J(13C—19F) = 20.6); 117.35,
119.74, 122.47 (q, CF3,
1J(13C—19F) = 272.6); 129.45
(d, Ar—F, 3J(13C—19F) = 7.6);
130.16, 137.12, 140.60, 151.08,
158.59, 160.14, 162.45 (d, Ar—F,
1J(13C—19F) = 270.2); 162.97,
167.95
12d
12e
12f
0.92 (d, 6 Н, (CH3)2CHCH2, 3J = 7.0); 22.16, 28.80, 46.45, 57.73,
–115.51 (d, CFaFbH,
2J(19F–1H) = 55.9;
2J(19F–19F) = 304.4);
–116.26 (d, CFaFbH,
2J(19F–1H) = 55.9;
2J(19F–19F) = 304.4)**
3408, 1596 (NH2),
3140, 1660 (NH),
2193 (CN), 1613,
1593 (СO), 1467,
1173, 1142
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0);
4.67 (s, 1 Н, H(4)); 7.23 (d, 2 Н, Ar,
3J = 8.2); 7.36 (m, 4 H, Ar, NH2);
7.65 (s, 1 Н, H(8)); 8.26 (t, 1 Н,
2J(19F–1H) = 55); 11.58 (br.s, 1 H,
NH)
80.19, 103.73, 108.96, 111.79,
116.00, (t, Ar—F,
1J(13C—19F) = 238.5); 119.43,
122.13, 127.27, 128.38, 129.44,
131.38, 139.45, 143.33, 151.59,
158.57, 160.58, 162.30, 165.66,
169.62
0.91 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 22.17, 28.81, 36.26, 46.45,
2.16 (m, 1 Н, (CH3)2CHCH2); 2.86 57.65, 81.88, 104.15, 110.35,
(d, 2 Н, (CH3)2CHCH2, 3J = 7.0); 4.66 111.90, 116.23 (t,
–115.46 (d, CFaFbH,
2J(19F–1H) = 54.8;
2J(19F–19F) = 303.7);
–116.26 (d, CFaFbH,
2J(19F–1H) = 54.8;
2J(19F–19F) = 303.7)
3410, 1593 (NH2),
3144, 1666 (NH),
2193 (CN), 1613,
1593 (СO), 1467,
1173, 1142
(s, 1 Н, H(4)); 7.16 (d, 2 Н, Ar,
3J = 7.9); 7.36 (br.s, 2 Н, NH2); 7.49
(d, 2 Н, Ar, 3J = 7.9); 7.65 (s, 1 Н,
H(8)); 8.20 (t, 1 Н, 2J(19F–1H) = 55);
11.58 (br.s, 1 H, NH)
1J(13C—19F) = 240.0); 119.89,
121.42, 128.15, 129.82, 131.30,
143.78, 145.47,151.40, 158.56,
160.58,163.03, 165.22, 171.6
0.91 (d, 6 Н, (CH3)2CHCH2, 3J = 6.0); 2217, 28.81, 36.26, 46.45,
–115.46 (d, CFaFbH,
2J(19F–1H) = 54.8;
2J(19F–19F) = 303.7);
–116.26 (d, CFaFbH,
2J(19F–1H) = 54.8;
2J(19F–19F) = 303.7)
3415, 1601 (NH2),
3151, 1657 (NH),
2191 (CN), 1627,
1601 (СO), 1464,
1177, 1143
2.16 (m, 1 Н, (CH3)2CHCH2); 2.85 (d, 57.65, 81.49, 103.97, 110.17,
2 Н, (CH3)2CHCH2); 4.68 (s, 1 Н,
H(4)); 7.12 (m, 2 Н, Ar); 7.23 (m, 4 H, = 20.6); 116.23
115.14 (d, Ar—F, 2J(13C—19F) =
Ar, NH2); 7.66 (s, 1 Н, H(8)); 8.28
(t, 1 Н, 2J(19F–1H) = 55); 11.58 (br.s,
1 H, NH)
(t, 1J(13C—19F) = 240.0);
128.33, 128.51, 129.43, (d,
Ar—F, 3J(13C—19F) = 9.0);
138.01, 140.60, 146.92, 151.34,
158.57, 160.64, 160.94, 163.70,
163.81 (d, Ar—F, 1J(13C—19F) =
= 272.2); 169.356
* Partially overlapped with the solvent signal.
** The 19F—{1H} spectrum (recorded with the proton coupling).

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2223
a solution of pyridinethione 5 (2 mmol) in DMF (3 mL), the
solution was stirred on a magnetic stirrer for 5 min (if necessary,
the mixture was slightly heated) until it became homogeneous,
then, the corresponding halo derivative 6 (2.1 mmol) was added.
The stirring was continued for 10 min, followed by quenching
with water (3 mL), a precipitate formed was filtered off, washed
with minimum 50% aqueous ethanol and hexane and dried in
air. Compounds were obtained in the analytically pure form, if
necessary they were recrystallized from aq. ethanol.
3ꢀCyanoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylꢀ2ꢀ(cyanomethyl)merꢀ
captopyridine (7a), halo derivative ꢀchloroacetonitrile (6a). The
yield was 0.45 g (75%), colorless powder, m.p. 91 C. Found (%):
C, 52.13; H, 4.12; N, 10.38. C13H12F3N3S. Calculated (%):
C, 52.17; H, 4.04; F, 19.04; N, 14.04; S, 10.71.
2ꢀ{[3ꢀCyanoꢀ6ꢀisobutylꢀ4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl]ꢀ
thio}ꢀNꢀcyclopropylacetamide (7b), halo derivative ꢀchloroꢀNꢀ
cyclopropylacetamide (6b). The yield was 0.57 g (79%), colorless
powder, m.p. 165 C. Found (%): C, 53.63; H, 5.15; N, 11.38.
C16H18F3N3OS. Calculated (%): C, 53.77; H, 5.08; F, 15.95;
N, 11.76; S, 8.97.
2ꢀ{[6ꢀBenzylꢀ3ꢀcyanoꢀ4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl]thio}ꢀ
acetamide (7c), halo derivative ꢀchloroacetamide (6c). The yield
was 0.62 g (88%), colorless powder, m.p. 198 C. Found (%):
C, 54.63; H, 3.53; N, 11.88. C16H12F3N3OS. Calculated (%):
C, 54.70; H, 3.44; F, 16.22; N, 11.96; S, 9.13.
2ꢀ{[6ꢀBenzylꢀ3ꢀcyanoꢀ4ꢀ(trifluoromethyl)pyridinꢀ2ꢀyl]thio}ꢀ
N,Nꢀdiethylacetamide (7d), halo derivative ꢀchloroꢀN,Nꢀdiethylꢀ
acetamide (6d). The yield was 0.69 g (84%), colorless powder,
m.p. 98 C. Found (%): C, 60.01; H, 4.87; N, 10.28. C20H20F3N3OS.
Calculated (%): C, 59.95; H, 4.95; F, 13.99; N, 10.31; S, 7.87.
Synthesis of 6ꢀsubstituted 4ꢀtrifluoro(difluoromethyl)thienoꢀ
[2,3ꢀb]pyridines 8 (general procedure). Method A. Pyridine 7
(1 mmol) was dispersed in ethanol (15 mL), sodium ethoxide
(0.2 mmol) was added, and the mixture was refluxed for 15 min.
The solution was half concentrated at reduced pressure, folꢀ
lowed by addition of water (10 mL). A precipitate formed was
filtered off, washed with minimum cold ethanol and hexane
(5 mL), dried in air. Compounds were obtained in the analytically
pure form, if necessary they were recrystallized from ethanol.
Method B. Sodium ethoxide (2 mmol) was added to a soluꢀ
tion of pyridinethione 5 (2 mmol) in anhydrous ethanol (20 mL),
the solution was stirred on a magnetic stirrer for 5 min (if necesꢀ
sary, the mixture was slightly heated) until it became homogeꢀ
neous and then, the corresponding halo derivative 6 (2.1 mmol)
was added. The stirring was continued for 10 min, sodium ethꢀ
oxide (0.5 mmol) was added, and the mixture was refluxed for
15—20 min. The solution was half concentrated, water (10 mL)
was added (for compounds 8c,k,l containing a carboxy group, an
excess of sodium ethoxide was used calculated in order to neuꢀ
tralize the carboxy function). After dilution with water, the reacꢀ
tion mixture was acidified with dilute hydrochloric acid to рH 5,
a precipitate formed was filtered off, sequentially washed with
minimum cold 50% aq. ethanol and hexane (10 mL), dried in
air. Compounds were obtained in the analytically pure form, if
necessary they were recrystallized from 50% aq. ethanol.
3ꢀAminoꢀNꢀcyclopropylꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylthienoꢀ
[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8a). Method A, halo derivative
ꢀchloroꢀNꢀcyclopropylacetamide (6b). The yield was 0.29 g
(82%), yellow powder, m.p. 152 C. Found (%): C, 53.58;
H, 5.10; N, 11.32. C16H18F3N3OS. Calculated (%): C, 53.77;
H, 5.08; F, 15.95; N, 11.76; S, 8.97.
Experimental
IR spectra were recorded on a Brucker AlphaꢀT spectromeꢀ
ter (in KBr pellets). 1H, 13C and 19F NMR spectra were recordꢀ
ed on a Bruker Avance II 300 spectrometer (1H, 300 MHz; 13C,
75 MHz; 19F, 282 MHz) in solutions in DMSOꢀd6. Diethyl
ether was dehydrated by distillation over metallic sodium, other
solvents were used as purchased. Ketones, difluoroꢀ and trifluoroꢀ
acetic esters, chloroacetic amides, and other halo derivatives
used in the work were commercially available.
Synthesis of 6ꢀsubstituted 3ꢀcyanoꢀ4ꢀtrifluoro(difluoromethꢀ
yl)ꢀ2(1H)ꢀpyridinethiones 5 (general procedure). Anhydrous diꢀ
ethyl ether (100 mL) and sodium ethoxide (0.11 mol) were placed
into a threeꢀneck flask equipped with a reflux condenser, a tube
for the gas inlet, and a dropping funnel and preliminary purged
with argon. A mixture of the corresponding methyl ketone
(0.1 mol) and tri(di)fluoroethyl acetate (0.11 mol) was added
dropwise over 15 min with cooling (a water bath) and stirring on
a magnetic stirrer under argon. Then, the mixture was stirred for
15 min, the cooling was removed, and the stirring was continued
for 18 h at ~20 C. Then, the reaction mixture was concentrated
on a rotary evaporator to dryness in vacuo at the bath temperaꢀ
ture of <40 C. Ethanol (50 mL) and cyanothioacetamide
(0.11 mol) were added to the residue. The reaction mixture was
heated to boiling and dissolution of the components; then it was
cooled to 50 C, acetic acid (0.05 mol) was added, and the mixꢀ
ture was brought to reflux, then cooled to ~20 C, followed by
addition of acetic acid (0.06 mol) and water (50 mL). A precipiꢀ
tate formed was filtered off, washed with water, some ethanol,
and hexane and dried in air. Products, as a rule, were obtained in
the analytically pure form, if necessary, it was recrystallized from
acetic acid.
3ꢀCyanoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylꢀ2(1H)ꢀpyridinethione
(5a). The yield was 19.71 g (76%), orange powder, m.p. 178 C.
Found (%): C, 50.69; H, 4.30; N, 10.56. C11H11F3N2S. Calcuꢀ
lated (%): C, 50.76; H, 4.26; F, 21.90; N, 10.76; S, 12.32.
3ꢀCyanoꢀ4ꢀdifluoromethylꢀ6ꢀisobutylꢀ2(1H)ꢀpyridinethione
(5b). The yield was 19.36 g (80%), yellowish orange powder,
m.p. 158 C. Found (%): C, 54.51; H, 5.04; N, 10.48. C11H12F2N2S.
Calculated (%): C, 54.53; H, 4.99; F, 15.68; N, 11.56; S, 13.23.
6ꢀBenzylꢀ3ꢀcyanoꢀ4ꢀtrifluoromethylꢀ2(1H)ꢀpyridinethione (5c).
The yield was 19.31 g (65%), pale orange powder, m.p. 139—140 C.
Spectral characteristics were identical to those described earlier.1
6ꢀBenzylꢀ3ꢀcyanoꢀ4ꢀdifluoromethylꢀ2(1H)ꢀpyridinethione (5d).
The yield was 14.90 g (51%), pale orange powder, m.p. 171—172 C.
Spectral characteristics were identical to those described earlier.1
3ꢀCyanoꢀ6ꢀcyclopropylꢀ4ꢀtrifluoromethylꢀ2(1H)ꢀpyridinethꢀ
ione (5e). The yield was 17.34 g (71%), orange powder, m.p.
164—166 C. Spectral characteristics were identical to those deꢀ
scribed earlier.1
3ꢀCyanoꢀ6ꢀisopropylꢀ4ꢀtrifluoromethylꢀ2(1H)ꢀpyridinethione
(5f). The yield was 14.53 g (59%), pale orange powder, m.p.
110—112 C. Spectral characteristics were identical to those deꢀ
scribed earlier.1
3ꢀCyanoꢀ6ꢀ(3,4ꢀdimethoxybenzyl)ꢀ4ꢀtrifluoromethylꢀ2(1H)ꢀ
pyridinethione (5g). The yield was 25.51 g (72%), pale orange
powder, m.p. 175—177 C. Spectral characteristics were identiꢀ
cal to those described earlier.1
Synthesis of 6ꢀsubstituted 3ꢀcyanoꢀ2ꢀmercaptoꢀ4ꢀtrifluoroꢀ
(difluoromethyl)pyridines functionalized at the sulfur atom (7) (genꢀ
eral procedure). A 2 M solution of KOH (1 mL) was added to

2224
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
3ꢀAminoꢀ6ꢀisobutylꢀNꢀ[3ꢀ(5ꢀmethyl)isoxazolyl]ꢀ4ꢀtrifluoroꢀ
methylthieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8b). Method B, halo
derivative ꢀchloroꢀNꢀ(5ꢀmethylisoxazolꢀ3ꢀyl)acetamide (6e).
The yield was 0.69 g (86%), yellow powder, m.p. 187 C. Found (%):
C, 50.99; H, 4.17; N, 14.32. C17H17F3N4O2S. Calculated (%):
C, 51.25; H, 4.30; F, 14.31; N, 14.06; S, 8.05.
3ꢀAminoꢀ4ꢀdifluoromethylꢀ6ꢀisobutylꢀ2ꢀ(2ꢀpyridyl)thienoꢀ
[2,3ꢀb]pyridine (8m). Method B, halo derivative 2ꢀpicolyl chlorꢀ
ide (6l). The yield was 0.61 g (91.5%), yellow powder, m.p. 124 C.
Found (%): C, 59.99; H, 5.35; N, 12.13. C17H17F2N3S. Calcuꢀ
lated (%): C, 61.24; H, 5.14; F, 11.40; N, 12.60; S, 9.62.
3ꢀAminoꢀ4ꢀdifluoromethylꢀ6ꢀisobutylꢀ2ꢀ(4ꢀpyridyl)thienoꢀ
[2,3ꢀb]pyridine (8n). Method B, halo derivative 4ꢀpicolyl chloride
(6g). The yield was 0.59 g (88%), yellow powder, m.p. 120 C.
Found (%): C, 60.09; H, 5.29; N, 12.92. C17H17F2N2S. Calcuꢀ
lated (%): C, 61.24; H, 5.14; F, 11.40; N, 12.60; S, 9.62.
3ꢀAminoꢀ6ꢀbenzylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxamide (8o). Method A, halo derivative ꢀchloroacetamide
(6c). The yield was 0.63 g (90%), yellow powder, m.p. 218—219 C.
Found (%): C, 54.66; H, 3.49; N, 11.90. C16H12F3N3OS. Calcuꢀ
lated (%): C, 54.70; H, 3.44; F, 16.22; N, 11.96; S, 9.13.
3ꢀAminoꢀ6ꢀbenzylꢀN,Nꢀdiethylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]ꢀ
pyridineꢀ2ꢀcarboxamide (8p). Method A, halo derivative N,Nꢀ
diethylꢀꢀchloroacetamide (6d). The yield was 0.79 g (93%), yelꢀ
low powder, m.p. 77—78 C. Found (%): C, 59.87; H, 5.02;
N, 10.25. C20H20F3N3OS. Calculated (%): C, 59.95; H, 4.95;
F, 13.99; N, 10.31; S, 7.87.
3ꢀAminoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]pyridineꢀ
2ꢀcarboxylic acid (8c). Method B, halo derivative ꢀchloroacetic
acid (6f). The yield was 0.51 g (80%), yellow powder, m.p. 140 C.
Found (%): C, 49.99; H, 4.17; N, 9.12. C13H13F3N2O2S. Calcuꢀ
lated (%): C, 49.05; H, 4.12; F, 17.91; N, 8.80; S, 10.07.
3ꢀAminoꢀ6ꢀisobutylꢀ2ꢀ(4ꢀpyridyl)ꢀ4ꢀtrifluoromethylthienoꢀ
[2,3ꢀb]pyridine (8d). Method B, halo derivative 4ꢀpicolyl chloride
(6g). The yield was 0.63 g (89%), yellow powder, m.p. 154 C.
Found (%): C, 58.09; H, 4.67; N, 11.92. C17H16F3N2S. Calcuꢀ
lated (%): C, 58.11; H, 4.59; F, 16.22; N, 11.96; S, 9.13.
2ꢀAcetylꢀ3ꢀaminoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]ꢀ
pyridine (8e). Method B, halo derivative ꢀchloroacetone (6h).
The yield was 0.49 g (77%), yellow powder, m.p. 73 C. Found (%):
C, 53.09; H, 4.67; N, 8.52. C14H15F3N2OS. Calculated (%): C,
53.16; H, 4.78; F, 18.02; N, 8.86; S, 10.14.
3ꢀAminoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]pyridineꢀ
2ꢀcarboxamide (8f). Method B, halo derivative ꢀchloroacetamide
(6c). The yield was 0.56 g (87%), yellow powder, m.p. 157 C.
Found (%): C, 48.99; H, 4.56; N, 12.72. C13H14F3N3OS. Calcuꢀ
lated (%): C, 49.20; H, 4.45; F, 17.96; N, 13.24; S, 10.10.
3ꢀAminoꢀ6ꢀisobutylꢀNꢀ(3,4ꢀmethylenedioxyphenyl)ꢀ4ꢀtriꢀ
fluoromethylthieno[2,3b]pyridineꢀ2ꢀcarboxamide (8g). Method B,
halo derivative ꢀchloroꢀNꢀ(3,4ꢀmethylenedioxyphenyl)acetꢀ
amide (6i). The yield was 0.76 g (87%), yellow powder, m.p. 174 C.
Found (%): C, 54.79; H, 4.17; N, 9.52. C20H18F3N3O3S. Calcuꢀ
lated (%): C, 54.92; H, 4.15; F, 13.03; N, 9.61; S, 10.97.
3ꢀAminoꢀ6ꢀisobutylꢀ2ꢀ(3,4ꢀmethylenedioxy)benzoylꢀ4ꢀtriꢀ
fluoromethylthieno[2,3ꢀb]pyridine (8h). Method B, halo derivaꢀ
tive ꢀbromoꢀ(3,4ꢀmethylenedioxy)acetophenone (6j). The yield
was 0.72 g (85%), yellow powder, m.p. 106 C. Found (%):
C, 56.79; H, 4.10; N, 6.52. C20H17F3N2O3S. Calculated (%):
C, 56.87; H, 4.06; F, 13.49; N, 6.63; S, 7.59.
3ꢀAminoꢀ6ꢀisobutylꢀ2ꢀ(4ꢀmethylbenzoyl)ꢀ4ꢀtrifluoromethylꢀ
thieno[2,3ꢀb]pyridine (8i). Method B, halo derivative ꢀbromoꢀ
4ꢀmethylacetophenone (6k). The yield was 0.69 g (87%), yellow
powder, m.p. 117 C. Found (%): C, 60.99; H, 4.10; N, 7.45.
C20H19F3N2OS. Calculated (%): C, 61.21; H, 4.28; F, 14.52;
N, 7.14; S, 8.17.
3ꢀAminoꢀ6ꢀisobutylꢀ2ꢀ(2ꢀpyridyl)ꢀ4ꢀtrifluoromethylthienoꢀ
[2,3ꢀb]pyridine (8j). Method B, halo derivative 2ꢀpicolyl chloride
(6l). The yield was 0.66 g (90%), yellow powder, m.p. 102 C.
Found (%): C, 58.03; H, 4.65; N, 11.62. C17H16F3N2S. Calcuꢀ
lated (%): C, 58.11; H, 4.59; F, 16.22; N, 11.96; S, 9.13.
Nꢀ(3ꢀAminoꢀ6ꢀisobutylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]pyridꢀ
ineꢀ2ꢀcarbonyl)glycine (8k). Method B, halo derivative Nꢀ(ꢀ
chloroacetyl)glycine (6m). The yield was 0.68 g (90%), yellow
powder, m.p. 157 C. Found (%): C, 48.09; H, 4.27; N, 10.92.
C15H16F3N3O3S. Calculated (%): C, 48.00; H, 4.30; F, 15.18;
N, 11.19; S, 8.54.
3ꢀAminoꢀ6ꢀbenzylꢀNꢀ(3,4ꢀdimethoxyphenyl)ꢀ4ꢀtrifluoromethꢀ
ylthieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8q). Method B, halo deꢀ
rivative Nꢀ(3,4ꢀdimethoxyphenyl)ꢀꢀchloroacetamide (6n). The
yield was 0.86 g (88%), yellow powder, m.p. 182—183 C.
Found (%): C, 59.07; H, 4.19; N, 8.55. C24H20F3N3 O3S. Calꢀ
culated (%): C, 59.13; H, 4.14; F, 11.69; N, 8.62; S, 6.58.
3ꢀAminoꢀ6ꢀ(3,4ꢀdimethoxyphenyl)methylꢀNꢀ(3,4ꢀmethyleneꢀ
dioxyphenyl)methylꢀ4ꢀtrifluoromethylthieno[2,3ꢀb]pyridineꢀ2ꢀ
carboxamide (8r). Method B, halo derivative ꢀchloroacetic
Nꢀ(3,4ꢀmethylenedioxybenzyl)amide (6r). The yield was 0.96 g
(90%), yellow powder, m.p. 166—167 C. Found (%): C, 56.41;
H, 3.82; N, 8.05. C26H22F3N3O5S. Calculated (%): C, 56.49;
H, 3.79; F, 10.72; N, 7.91; S, 6.03.
3ꢀAminoꢀ2ꢀ(3,4ꢀmethylenedioxy)benzoylꢀ4ꢀtrifluoromethylꢀ
6ꢀcyclopropylthieno[2,3ꢀb]pyridine (8s). Method B, halo derivaꢀ
tive ꢀbromoꢀ(3,4ꢀmethylenedioxy)acetophenone (6j). The yield
was 0.96 g (90%), yellow powder, m.p. 152—153 C. Found (%):
C, 56.11; H, 3.32; N, 7.05. C19H13F3N2O3S. Calculated (%):
C, 56.16; H, 3.22; F, 14.03; N, 6.89; S, 7.89.
3ꢀAminoꢀ6ꢀcyclopropylꢀNꢀ[2ꢀ(1Hꢀindolꢀ3ꢀyl)ethyl]ꢀ4ꢀtriꢀ
fluoromethylthieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8t). Method
B, halo derivative ꢀchloroacetic Nꢀ[2ꢀ(1Hꢀindolꢀ3ꢀyl)ethyl]ꢀ
amide (6p). The yield was 0.84 g (95%), yellow powder, m.p. 193 C.
Found (%): C, 56.41; H, 3.82; N, 8.05. C22H19F3N4OS. Calcuꢀ
lated (%): C, 56.45; H, 4.31; F, 12.82; N, 12.61; S, 7.21.
3ꢀAminoꢀ6ꢀcyclopropylꢀNꢀ(2ꢀmethoxycarbonylphenyl)ꢀ4ꢀ
trifluoromethylthieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide
(8u).
Method B (to obtain this compound, methanol and sodium
methoxide were used instead of ethanol and sodium ethoxide),
halo derivative ꢀchloroacetic Nꢀ(2ꢀmethoxycarbonylphenyl)ꢀ
amide (6q). The yield was 0.69 g (79%), yellow powder,
m.p. 216—217 C. Found (%): C, 55.11; H, 3.82; N, 9.56.
C20H16F3N3O3S. Calculated (%): C, 55.17; H, 3.70; F, 13.09;
N, 9.65; S, 7.36.
Nꢀ(3ꢀAminoꢀ4ꢀdifluoromethylꢀ6ꢀisobutylthieno[2,3ꢀb]pyridꢀ
ineꢀ2ꢀcarbonyl)glycine (8l). Method B, halo derivative Nꢀ(ꢀ
chloroacetyl)glycine (6m). The yield was 0.62 g (86%), yellow
powder, m.p. 203 C. Found (%): C, 50.19; H, 4.93; N, 11.52.
C15H17F2N3O3S. Calculated (%): C, 50.41; H, 4.78; F, 10.63;
N, 11.76; S, 8.97.
3ꢀAminoꢀ6ꢀ(3,4ꢀdimethoxyphenyl)methylꢀ4ꢀtrifluoromethylꢀ
thieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8v). Method B, halo deꢀ
rivative ꢀchloroacetamide (6c). The yield was 0.72 g (87%),
yellow powder, m.p. 210—211 C. Found (%): C, 52.49; H, 3.98;
N, 10.15. C18H16F3N3O3S. Calculated (%): C, 52.55; H, 3.92;
F, 13.85; N, 10.21; S, 7.79.

Dif(tri)fluoromethyl condensed heterocyclic systems Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
2225
3ꢀAminoꢀNꢀ[2ꢀ(1Hꢀindolꢀ3ꢀyl)ethyl]ꢀ6ꢀisopropylꢀ4ꢀtrifluoroꢀ
methylthieno[2,3ꢀb]pyridineꢀ2ꢀcarboxamide (8w). Method B, halo
derivative ꢀchloroacetic Nꢀ[2ꢀ(1Hꢀindolꢀ3ꢀyl)ethyl]amide (6p).
The yield was 0.88 g (89%), yellow powder, m.p. 164—165 C.
Found (%): C, 59.13; H, 4.78; N, 12.48. C22H21F3N4OS. Calcuꢀ
lated (%): C, 59.18; H, 4.74; F, 12.77; N, 12.55; S, 7.18.
Synthesis of 3,4ꢀdihydroꢀ10ꢀtrifluoro(difluoro)methylꢀ1Hꢀ
pyrido[3´,2´:4,5]thieno[3,2ꢀe]ꢀ1,4ꢀdiazepineꢀ2,5ꢀdiones (generꢀ
al procedure). Thienopyridine 8k or 8l (1 mmol) was heated at
220 C for 35 min without exposure to air. The melt was cooled,
triturated, dispersed into a 10% aq. sodium bicarbonate (10 mL),
stirred for 10 min, filtered, sequentially washed with water,
ethanol, and hexane, and dried in air. Products were obtained in
the analytically pure form.
(1 mmol), and the corresponding aromatic aldehyde 14a—c
(1 mmol) was refluxed for 1 h under argon in ethanol (10 mL)
containing three drops of triethylamine. After cooling, the mixꢀ
ture was concentrated to dryness on a rotary evaporator and
recrystallized from ethanol.
2ꢀAminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5,6ꢀdihydroꢀ9ꢀisobutylꢀ5ꢀoxoꢀ
7ꢀtrifluoromethylpyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12a), aldehydeꢀpꢀchlorobenzꢀ
aldehyde (14a). The yield was 0.34 g (76%), white powder, m.p.
311 C (EtOH). Found (%): C, 56.59; H, 3.77; N, 10.79.
C25H18ClF3N4O2S. Calculated (%): C, 56.55; H, 3.42; Cl, 6.68;
F, 10.73; N, 10.55; S, 6.04.
2ꢀAminoꢀ4ꢀ(4ꢀbromophenyl)ꢀ5,6ꢀdihydroꢀ9ꢀisobutylꢀ5ꢀoxoꢀ
7ꢀtrifluoromethylpyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12b), aldehydeꢀpꢀbromobenzꢀ
aldehyde (14b). The yield was 0.47 g (82%), white powder,
m.p. 322 C (EtOH). Found (%): C, 51.89; H, 3.27; N, 9.59.
C25H18BrF3N4O2S. Calculated (%): C, 52.19; H, 3.15; Br, 13.89;
F, 9.91; N, 9.74; S, 5.57.
3,4ꢀDihydroꢀ8ꢀisobutylꢀ10ꢀtrifluoromethylꢀ1Hꢀpyridoꢀ
[3´,2´:4,5]thieno[3,2ꢀe]ꢀ1,4ꢀdiazepineꢀ2,5ꢀdione (9a). The yield
was 0.35 g (98%), cream powder, m.p. 189 C. Found (%):
C, 50.29; H, 4.07; N, 11.62. C15H14F3N3O3S. Calculated (%):
C, 50.42; H, 3.95; F, 15.95; N, 11.76; S, 8.97.
10ꢀDifluoromethylꢀ3,4ꢀdihydroꢀ8ꢀisobutylꢀ1Hꢀpyridoꢀ
[3´,2´:4,5]thieno[3,2ꢀe]ꢀ1,4ꢀdiazepineꢀ2,5ꢀdione (9b). The yield
was 0.33 g (97%), colorless powder, m.p. 210 C. Found (%):
C, 53.09; H, 4.47; N, 12.12. C15H15F2N3O2S. Calculated (%):
C, 53.07; H, 4.46; F, 11.20; N, 12.38; S, 9.45.
2ꢀAminoꢀ4ꢀ(4ꢀfluorophenyl)ꢀ5,6ꢀdihydroꢀ9ꢀisobutylꢀ5ꢀoxoꢀ
7ꢀtrifluoromethylpyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12c), aldehyde pꢀfluorobenzꢀ
aldehyde (14c). The yield was 0.33 g (65%), white powder, m.p.
296 C (EtOH). Found (%): C, 58.29; H, 3.57; N, 10.97.
C25H18F4N4O2S. Calculated (%): C, 58.36; H, 3.53; F, 14.77;
N, 10.89; S, 6.23.
2ꢀAminoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ7ꢀdifluoromethylꢀ5,6ꢀdihydroꢀ
9ꢀisobutylꢀ5ꢀoxopyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12d), aldehyde pꢀchlorobenzꢀ
aldehyde (14d). The yield was 0.40 g (78%), white powder, m.p.
294 C (EtOH). Found (%): C, 58.59; H, 3.79; N, 10.80.
C25H19ClF2N4O2S. Calculated (%): C, 58.54; H, 3.73; Cl, 6.91;
F, 7.41; N, 10.92; S, 6.25.
2ꢀAminoꢀ4ꢀ(4ꢀbromophenyl)ꢀ7ꢀdifluoromethylꢀ5,6ꢀdihydroꢀ
9ꢀisobutylꢀ5ꢀoxopyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12e), aldehyde pꢀbromobenzꢀ
aldehyde (14e). The yield was 0.44 g (80%), white powder,
m.p. 297 C (EtOH). Found (%): C, 53.79; H, 3.53; N, 9.89.
C25H19BrF2N4O2S. Calculated (%): C, 53.87; H, 3.44; Br, 14.33;
F, 6.82; N, 10.05; S, 5.75.
2ꢀAminoꢀ7ꢀdifluoromethylꢀ4ꢀ(4ꢀfluorophenyl)ꢀ5,6ꢀdihydroꢀ9ꢀ
isobutylꢀ5ꢀoxopyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyranoꢀ
[2,3ꢀd]pyridineꢀ3ꢀcarbonitrile (12f), aldehyde pꢀfluorobenzꢀ
aldehyde (14f). The yield was 0.36 g (72%), white powder, m.p.
279 C (EtOH). Found (%): C, 60.29; H, 3.95; N, 11.47.
C25H19F3N4O2S. Calculated (%): C, 60.48; H, 3.86; F, 11.48;
N, 11.28; S, 6.46.
Synthesis of 4ꢀhydroxyꢀ9ꢀtrifluoromethyl(difluoromethyl)ꢀ
1Hꢀthieno[2,3ꢀb:4,5ꢀb´]dipyridinꢀ2ꢀones 11a—c (general proceꢀ
dure). The reaction was carried out as a oneꢀpot process in one
reaction flask without isolation of the intermediate products.
A mixture of pyridinethione 5 (2 mmol) and sodium ethoxide
(2.2 mmol) in ethanol (20 mL) was stirred under inert atmoꢀ
sphere on a magnetic stirrer until the components were dissolved
(to accelerate the dissolution, the mixture was heated to 40—50 C).
Then, ethyl 4ꢀchloroacetate 10 (2.1 mmol) was added, the mixꢀ
ture was stirred for 10 min and heated to reflux. After this, the
reaction mixture was cooled to 30—40 C, sodium ethoxide
(2.2 mmol) in ethanol (10 mL) was added, and this was refluxed
for 1 h. After cooling, water (30 mL) was added, if necessary,
filtered through a folded filter, and acidified with a dilute hydroꢀ
chloric acid to рH 5. A precipitate formed was filtered off, seꢀ
quentially washed with water, ethanol, and hexane, and dried in
air. The compounds obtained, as a rule, did not required addiꢀ
tional purification.
4ꢀHydroxyꢀ7ꢀisobutylꢀ9ꢀtrifluoromethylpyridoꢀ1Hꢀthienoꢀ
[2,3ꢀb:4,5ꢀb´]dipyridinꢀ2ꢀone (11a). The yield was 0.61 g (89%),
brownish powder, m.p. 273 C. Found (%): C, 51.59; H, 34.07;
N, 12.79. C15H13F3N3O2S. Calculated (%): C, 52.63; H, 3.83;
F, 16.65; N, 8.18; S, 9.37.
9ꢀDifluoromethylꢀ4ꢀhydroxyꢀ7ꢀisobutylꢀpyridoꢀ1Hꢀthienoꢀ
[2,3ꢀb:4,5ꢀb´]dipyridinꢀ2ꢀone (11b). The yield was 0.60 g (78%),
pale yellow powder, m.p. 279 C. Found (%): C, 51.59; H, 34.07;
N, 12.79. C15H14F2N3O2S. Calculated (%): C, 55.55; H, 4.35;
F, 11.71; N, 8.64; S, 9.89.
4ꢀHydroxyꢀ7ꢀisopropylꢀ9ꢀtrifluoromethylpyridoꢀ1Hꢀthienoꢀ
[2,3ꢀb:4,5ꢀb´]dipyridinꢀ2ꢀone (11c). The yield was 0.57 g (87%),
cream powder, m.p. 306 C (decomp.). Found (%): C, 51.59;
H, 3.42; N, 8.59. C14H11F3N3O2S. Calculated (%): C, 51.22;
H, 3.38; F, 17.36; N, 8.53; S, 9.77.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 12ꢀ03ꢀ00429a).
References
1. L. A. Rodinovskaya, A. M. Shestopalov, A. V. Gromova,
A. A. Shestopalov, J. Comb. Chem., 2008, 10, 313.
2. N. M. Rateb, J. Sulfur Chem., 2011, 32, 611.
Synthesis of 2ꢀaminoꢀ5,6ꢀdihydroꢀ5ꢀoxoꢀ7ꢀtrifluoro(difluoro)ꢀ
methylpyrido[3´,2´:4,5]thieno[3,2ꢀb]ꢀ4Hꢀpyrano[2,3ꢀd]pyrꢀ
idineꢀ3ꢀcarbonitriles 12a—f (general procedure). A mixture
of pyridothienopyridine 11a,b (1 mmol), malonoodinitrile
3. V. O. Iaroshenko, Y. Wang, B. Zhang, D. Volochnyuk, V. Ya.
Sosnovskikh, Synthesis, 2009, 2393.
4. Ch. Zhao, C. Tovar, X. Yin, Q. Xu, I. T. Todorov, L. T.
Vassilev, Li Chen, Bioorg. Med. Chem. Lett., 2009, 19, 319.

2226
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 10, October, 2013
Rodinovskaya et al.
5. C. Reichelt, A. Ludwig, A. Schulze, M. Daghish, S. Leistꢀ
ner, A. Krodel, J. Heinicke, US Pat. Appl. Publ., 2008,
US 20080160028 A1 20080703.
20. V. P. Kislyi, K. G. Nikishin, E. Y. Kruglova, A. M. Shestoꢀ
palov, V. V. Semenov, A. A. Gakh, A. C. Buchanan, Tetraꢀ
hedron, 1996, 52, 10841.
6. N. Choi, J. J. Deadman, W. Issa, E. Jones, PCT Int. Appl.
(2007), WO 2007124544 A1 20071108.
7. S. Li, X. Sun, H. Zhao, Y. Tang, M. Lan, Bioorg. Med. Chem.
Lett., 2012, 22, 4004.
21. K. G. Nikishin, V. P. Kislyi, V. N. Nesterov, A. M. Shestoꢀ
palov, Yu. T. Struchkov, V. V. Semenov, Russ. Chem. Bull.
(Engl. Transl.), 1998, 47, 465 [Izv. Akad. Nauk, Ser. Khim.,
1998, 482].
8. Q. Huang, A. Deiters, K. Gumireddy, US Pat. Appl. Publ.
2012, US 20120010177 A1 20120112.
9. B. E. Sleebs, A. Levit, I. P. Street, H. Falk, T. Hammonds,
A. C. Wong, M. D. Charles, M. F. Olson, J. B. Baell, Medꢀ
ChemComm, 2011, 2, 977.
10. L. D. Walensky, M. L. Stewart, N. Cohen, PCT Int. Appl.
(2011), WO 2011094708 A2 20110804.
11. S. Ryder, PCT Int. Appl. 2010, WO 2010151799 A2
20101229.
22. K. G. Nikishin, V. N. Nesterov, V. P. Kislyi, A. M. Shestoꢀ
palov, V. V. Semenov, Russ. Chem. Bull. (Engl. Transl.), 1998,
47, 679 [Izv. Akad. Nauk, Ser. Khim., 1998, 701].
23. A. M. Shestopalov, V. P. Kislyi, E. Y. Kruglova, K. G. Niꢀ
kishin, V. V. Semenov, A. C. Buchanan, A. A. Gakh, J. Comb.
Chem., 2000, 2, 24.
24. A. E. Fedorov, A. M. Shestopalov, P. A. Belyakov, Russ.
Chem. Bull. (Int. Ed.), 2003, 52, 2063 [Izv. Akad. Nauk, Ser.
Khim., 2003, 2081].
12. J. P. Brincat, E. Carosati, S. Sabatini, G. Manfroni, A. Fravꢀ
olini, J. L. Raygada, D. Patel, G. W. Kaatz, G. Cruciani,
J. Med. Chem., 2011, 54, 354.
13. C. M. Byrd, D. Dai, R. Jordan, D. E. Hruby, PCT Int. Appl.
2010, WO 2010099166 A1 20100902.
25. D. E. Thurston, Mol. Aspects Anticancer DrugꢀDNA Interact.,
1993, 54.
26. L. A. Rodinovskaya, A. M. Shestopalov, A. V. Gromova,
Russ. Chem. Bull. (Int. Ed.), 2003, 52, 2185 [Izv. Akad. Nauk,
Ser. Khim., 2003, 2069].
14. Q. Huang, A. Deiters, K. Gumireddy, US Pat. Appl. Publ.
2010, US 20100196357 A1 2010080511.
27. L. Rodinovskaya, A. Shestopalov, A. Gromova, A. Shesꢀ
topalov, Synthesis, 2006, 2357.
15. A. C. Koong, D. E. Feldman, PCT Int. Appl. 2007, WO
2007101225 A2 20070907.
16. A. C. Koong, D. E. Feldman, PCT Int. Appl. 2007, WO
2007101224 A2 20070907.
17. Y. Kawazoe, H. Shimogawa, A. Sato, M. Uesugi, Angew.
Chem., Int. Ed., 2011, 50, 5478.
28. L. A. Rodinovskaya, A. M. Shestopalov, Russ. Chem. Bull.
(Int. Ed.), 2000, 49, 348 [Izv. Akad. Nauk, Ser. Khim.,
2000, 347].
29. Y. M. Litvinov, A. M. Shestopalov, Adv. Heterocycl. Chem.,
2011, 103,175.
30. J. S. Martin, A. R. Quirt, J. Magn. Reson., 1971, 5, 318.
18. Y. W. Ho, W. H. Yao, Dyes and Pigments, 2005, 70, 60.
19. L. A. Rodinovskaya, Yu. A. Sharanin, V. P. Litvinova, A. M.
Shestopalov, V. K. Promonenkov, V. K. Zolotarev, Yu. A.
Mortikov, J. Org. Chem. USSR (Engl. Transl.), 1985, 21, 2230
[Zh. Org. Khim., 1985, 21, 2439].
Received June 28, 2013;
in revised form August 12, 2013