Synthesis of 6-thienyl-substituted 2-amino-3-cyanopyridines

Article abstract of DOI:10.1007/s11172-015-0920-8

An efficient method for the synthesis of 6-thienyl-substituted 2-amino-3-cyanopyridines by the ring transformation in the corresponding pyrimidines was developed. Further modification of the pyridines obtained under conditions of a room temperature aerobic Suzuki reaction in the presence of trans-bis(dicyclohexylamine)palladium(II) acetate as a catalyst was studied

Full text of DOI:10.1007/s11172-015-0920-8

Russian Chemical Bulletin, International Edition, Vol. 64, No. 3, pp. 689—694, March, 2015
689
Synthesis of 6ꢀthienylꢀsubstituted 2ꢀaminoꢀ3ꢀcyanopyridines*
E. V. Verbitskiy,a,b E. M. Cheprakova,a,b M. G. Pervova,a G. G. Danagulyan,c,d G. L. Rusinov,a,b
O. N. Chupakhin,a,b and V. N. Charushina,b
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Eꢀmail: Verbitsky@ios.uran.ru
bUral Federal University named after the first president of Russia B. N. Eltsin,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation
cRussianꢀArmenian (Slavonic) University,
123 ul. O. Emmina, 0051 Yerevan, Republic of Armenia
dScientificꢀTechnological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia,
26 prosp. Azatutyan, 0014 Yerevan, Republic of Armenia
An efficient method for the synthesis of 6ꢀthienylꢀsubstituted 2ꢀaminoꢀ3ꢀcyanopyridines by
the ring transformation in the corresponding pyrimidines was developed. Further modification
of the pyridines obtained under conditions of a room temperature aerobic Suzuki reaction in the
presence of transꢀbis(dicyclohexylamine)palladium(II) acetate as a catalyst was studied.
Key words: pyrimidines, pyridines, transformations of heterocycle, Suzuki crossꢀcoupling,
transꢀbis(dicyclohexylamine)palladium(II) acetate.
Scheme 1
Considerable attention to the synthesis of 2ꢀaminoꢀ3ꢀ
cyanopyridine derivatives is drawn by their interesting
photophysical properties, as well as by a wide range of
biological activity exhibited by this class of compounds. In
particular, compounds of this series are ligands of adenoꢀ
sine receptors,1—3 inhibitors of activated protein kinaseꢀ2
for treatment of diseases caused by the TNF tumor neꢀ
crosis factor,4,5 inhibitors of human cytomegalovirus,6
possess antibacterial activity,7—10 as well as are promising
in the development of agents for treatment of cardiovasꢀ
cular conditions.11
R1 = Ph, 4ꢀMeOC6H4, 4ꢀClC6H4, 4ꢀFC6H4, 2ꢀthienyl, 2ꢀfuranyl
R2 = H, Me, Ph
Scheme 2
Thus, the development of new methods for the syntheꢀ
sis of substituted 2ꢀaminoꢀ3ꢀcyanopyridines is an imporꢀ
tant synthetic problem. Various approaches to the syntheꢀ
sis of 2ꢀaminoꢀ3ꢀcyanopyridine derivatives described in
the literature,12,13 as a rule, are based on twoꢀ (Scheme 1)
and threeꢀcomponent (Scheme 2) reactions.
As to the photoactive molecules, here the 3ꢀcyanoꢀ
pyridine derivatives containing electronꢀdonating thienyl
moieties are of special interest. Recently,14 we have shown
a possibility of the preparation of 2ꢀaminoꢀ5ꢀ(het)arylꢀ
substituted 3ꢀcyanoꢀ6ꢀ(2ꢀthienyl)pyridines as photosenꢀ
sitizers for the dyeꢀsensitized solar cells starting from 4ꢀ(2ꢀ
thienyl)pyrimidine.
20 mol.% of CuI,
20 mol.% of piperidine
Piv is the pivaloyl.
The purpose of the present work is the development of
new methods for the synthesis of 6ꢀthienylꢀsubstituted
2ꢀaminoꢀ3ꢀcyanopyridines from the corresponding pyriꢀ
* Dedicated to Academician of the Russian Academy of Sciences
V. I. Minkin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0689—0694, March, 2015.
1066ꢀ5285/15/6403ꢀ0689 © 2015 Springer Science+Business Media, Inc.

690
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
Verbitskiy et al.
Scheme 3
Rearrangement
[4+2] Cycloaddition
Scheme 4
midine derivatives via the ring transformation according
to the scheme of [4+2] cycloaddition15,16 or the Kost—
Sagitullinꢀtype rearrangement17—20 (Scheme 3), as well
as the studies of a possibility of further modifications
of the obtained pyridines under the aerobic Suzuki
crossꢀcoupling reaction conditions, using a new cataꢀ
lyst transꢀbis(dicyclohexylamine)palladium(II) acetate
(DAPCy).21
Initially, we studied the transformation of 2ꢀthienylꢀ
substituted pyrimidines to the corresponding pyridine deꢀ
rivatives. It was facilitated by the quaternization of 6ꢀ(2ꢀthiꢀ
enyl)pyrimidine derivatives 1a—d with iodomethane. The
subsequent reaction of obtained salts 2a—d with malonoꢀ
dinitrile in the presence of triethylamine led to the correꢀ
sponding 2ꢀaminoꢀ6ꢀ(5ꢀRꢀthiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarboꢀ
nitriles 3a—d (Scheme 4). The structure of salts 2a—d was
unambiguously confirmed by Xꢀray diffraction studies,
using 4ꢀ([2,2´]bithiophenylꢀ5ꢀyl)ꢀ1ꢀmethylpyrimidinium
iodide (2c) as an example (Fig. 1).
Further bromination of 2ꢀaminoꢀ6ꢀ(thiophenꢀ2ꢀ
yl)pyridineꢀ3ꢀcarbonitrile (3a) with 1 and 3 equiv. of NBS
in DMF at room temperature gave 2ꢀaminoꢀ5ꢀbromoꢀ6ꢀ
(thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile (4) and 2ꢀaminoꢀ
5ꢀbromoꢀ6ꢀ(5ꢀbromothiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarboniꢀ
trile (5), respectively (Scheme 5).
1—3: R = H (a), Ph (b), 2ꢀthienyl (c), Br (d)
the influence of the negative side reactions, in this work
we studied the reactivity of bromoꢀsubstituted 2ꢀaminoꢀ
3ꢀcyanopyridines 3d, 4, and 5 toward phenylꢀ (6), 2ꢀthiꢀ
C(7)
C(5)
C(6)
C(1)
C(8)
S(2)
C(3)
N(1)
C(4)
N(3)
Earlier,14 we have shown that the Suzuki crossꢀcouꢀ
pling reaction of compound 4 with (het)arylboronic acids
under microwave activation at 160 C in a mixture of 1,4ꢀ
dioxane—H2O led to the target products, however, their
yields were moderate because of the formation of a conꢀ
siderable amounts of side compounds. In order to decrease
C(13)
C(12)
C(9)
C(10)
C(2)
S(1)
I(1)
C(11)
Fig. 1. Geometry of compound 2c in crystal.

2ꢀAminoꢀ3ꢀcyanopyridine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
691
Scheme 5
Table 1. The reaction mixture compositions in the reactions of
bromoꢀsubstituted 2ꢀaminoꢀ3ꢀcyanopyridines 3d, 4, and 5 with
phenylꢀ (6), 2ꢀthienylꢀ (7), 3ꢀthienylꢀ (8), and 2ꢀfuranylboronꢀ
ic (9) acids and yields of the corresponding crossꢀcoupling
products
Reaction
Reaction mixture
composition* (%)
Product
yield (%)
3d + 6
3d + 7
3d + 8
3d + 9
4 + 6
51.1 (3b), 26.6 (3d), 5.4 (3a),
2.1 (6), 9.5 (10), 5.3 (Cy2NH)
25.0 (3c), 69.6 (3d), 0.9 (3a),
4.5 (Cy2NH)
86.7 (3e), 0.8 (3d), 1.2 (3a),
3.9 (12), 7.4 (Cy2NH)
4.1 (3f), 89.3 (3d), 2.3 (3a),
4.3 (Cy2NH)
14.6 (14a), 74.5 (4),
10.9 (Cy2NH)
4.7 (14b), 82.9 (4),
12.4 (Cy2NH)
10.2 (14c), 83.2 (4),
6.6 (Cy2NH)
5.1 (14d), 94.9 (4)
0 (15a), 64.1 (5), 10.7 (6),
25.2 (Cy2NH)
0 (15b), 9.9 (4), 54.6 (5),
1.8 (11), 5.6 (14b), 7.9 (16b),
1.9 (17b), 18.3 (Cy2NH)
6.6 (15c), 13.8 (4), 15.3 (5),
9.0 (12), 10.4 (14c), 11.3 (16c),
3.1 (17c), 30.5 (Cy2NH)
1.6 (15d), 2.2 (3d), 2.2 (4),
68.9 (5), 0 (13), 0 (14d),
2.9 (16d), 2.1 (17d),
56 (3b), 17 (3d)
19 (3c), 65 (3d)
92 (3e), 0 (3d)
0 (3f), 85 (3d)
0 (14a), 69 (4)
0 (14b), 79 (4)
0 (14c), 81 (4)
enylꢀ (7), 3ꢀthienylꢀ (8), and 2ꢀfuranylboronic (9) acids
under mild Suzuki crossꢀcoupling reaction conditions
(a room temperature aerobic version).
2ꢀAminoꢀ6ꢀ(5ꢀRꢀthiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarboꢀ
nitriles 3b,c,e,f were obtained from 2ꢀaminoꢀ6ꢀ(5ꢀbromoꢀ
thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile (3d) and (het)ꢀ
arylboronic acids 6—9 at room temperature in air within
24 h, using 5 mol.% of DAPCy as a catalyst (Scheme 6;
Table 1, lines 1—8). The corresponding 6ꢀthienylꢀsubstiꢀ
tuted 2ꢀaminonicotinonitriles 3b,c,e were isolated by semiꢀ
preparative HPLC in moderate yields.
4 + 7
4 + 8
4 + 9
5 + 6
0 (14d), 89 (4)
0 (15a), 87 (5)
5 + 7
5 + 8
5 + 9
0 (15b), 35 (5)
0 (15c), 0 (5)
0 (15d), 48 (5)
Scheme 6
20.1 (Cy2NH)
* According to the GLC/MS data.
Scheme 7
Side products
Cy is the cyclohexyl.
Ar = Ph (3b, 6, 10), 2ꢀthienyl (3c, 7, 11), 3ꢀthienyl (3e, 8, 12),
2ꢀfuranyl (3f, 9, 13)
Ar = Ph (6, 14a), 2ꢀthienyl (7, 14b), 3ꢀthienyl (8, 14c),
2ꢀfuranyl (9, 14d)
i. DAPCy, K3PO4, ~20 C, 24 h, EtOH.
i. DAPCy, K3PO4, ~20 C, 24 h, EtOH.
The reactions of 2ꢀaminoꢀ5ꢀbromoꢀ6ꢀ(thiophenꢀ2ꢀ
yl)pyridineꢀ3ꢀcarbonitrile (4) with (het)arylboronic acids
6—9 were studied by GCꢀMS (Scheme 7; see Table 1,
lines 9—15). Unfortunately, in all the cases the isolation
of the reaction products failed even when semiꢀpreparaꢀ
tive HPLC was used.
The reactions of 2ꢀaminoꢀ5ꢀbromoꢀ6ꢀ(5ꢀbromothioꢀ
phenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile (5) with the same (het)ꢀ
arylboronic acids 6—9 were accompanied by the formaꢀ
tion of more complicated mixtures of side products with
different degrees of substitution by bromine (Scheme 8;
see Table 1, lines 16—27).
The analysis of the reaction mixtures showed that in
all the cases, independent of the bromo derivative used,
the yields of the crossꢀcoupling products progressively inꢀ
creased from 2ꢀfuranylꢀ (9) to 3ꢀthienylboronic (8) acid:
9 < 7 < 6  8. Such a sequence is confirmed by the literaꢀ
ture data21 on the very moderate yields of the crossꢀcouꢀ

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Verbitskiy et al.
Scheme 8
Side products
Ar = Ph (6, 10, 14a—17a), 2ꢀthienyl (7, 11, 14b—17b), 3ꢀthienyl (8, 12, 14c—17c), 2ꢀfuranyl (9, 13, 14d—17d)
i. DAPCy, K3PO4, ~20 C, 24 h, EtOH.
sampler (900 L), a diodeꢀarray detector (an analytical waveꢀ
length 280 nm) and a collector for fractions. A ZORBAX Eclipse
XDBꢀC18 PrepHT column (21.2 mm × 150 mm), the grain size
5 m, the temperature of the column ambient. A mixture of
acetonitrile—water in the ratio 6 : 4 was used as a mobile phase,
the phase flow rate 20 mL min–1, elution at an isocratic mode.
Flashꢀchromatography was carried out using Kieselgel 60
silica gel, 0.040—0.063 mm (230—400 mesh).
pling reaction products with electronꢀenriched arylboronꢀ
ic acids in the presence of DAPCy.
In conclusion, the rearrangement of 4ꢀthienylꢀsubstiꢀ
tuted pyrimidines is a convenient method for the synthesis
of 6ꢀthienylꢀsubstituted derivatives of 2ꢀaminoꢀ3ꢀcyanꢀ
opyridine. Besides, compound of this series can be easily
modified by subsequent bromination and involvement in
the Suzuki crossꢀcoupling reaction under mild conditions.
Reaction progress and purity of the products were monitored
by TLC on Sorbfil plates, visualization under UV light.
Xꢀray diffraction studies were performed on a Xcalibur 3
automated fourꢀcircle diffractometer with CCD detector accordꢀ
ing to a standard procedure ((MoꢀК), graphite monochromaꢀ
tor, /2 scan technique at 1 step, 295(2) К). The structure was
solved and refined using the SHELXTL software package24 by
the fullꢀmatrix least squares method on F2. Nonhydrogen atoms
are included in the model in anisotropic approximation. Hydroꢀ
gen atoms are localized on the peaks of the electron density
spatial distribution and included in the refinement in isotropic
approximation, using a riding model with depend thermal paraꢀ
meters. The results of the Xꢀray diffraction studies were depositꢀ
ed with the Cambridge Crystallographic Data Center as cifꢀfiles
(CCDC 1035843 for compound 2c). These materials are availꢀ
able free of charge upon request at www.ccdc.cam.ac.uk/
data_request/cifwww.ccdc.cam.ac.uk/data_request/cif.
4ꢀThienylꢀsubstituted 1ꢀmethylpyrimidinium iodides 2a—d
(general procedure). A solution of 4ꢀthienylꢀsubstituted pyrimiꢀ
dine 1a—d (5.0 mmol) in iodomethane (15 mL) was refluxed for
5 h. The solvent was evaporated. The residue was washed with
ethanol to obtain salts 2a—d.
1ꢀMethylꢀ4ꢀ(thiophenꢀ2ꢀyl)pyrimidinium iodide (2a).14 The
yield was 95%, a bright yellow powder. M.p. 264—265 C (decomp.).
1H NMR (DMSOꢀd6), : 4.18 (s, 3 H, CH3); 7.45 (dd, 1 H, H(4)
of thienyl, J = 3.8 Hz, J = 4.9 Hz); 8.28 (dd, 1 H, H(5) of
thienyl, J = 0.8 Hz, J = 4.9 Hz); 8.50 (d, 1 H, H(3) of thienyl,
J = 0.7 Hz, J = 3.8 Hz); 8.65 (d, 1 H, H(5), J = 6.9 Hz); 9.20 (dd,
1 H, H(6), J = 1.5 Hz, J = 6.9 Hz); 9.55 (s, 1 H, H(2)). 13C NMR
(DMSOꢀd6), : 43.88 (CH3), 115.83, 130.59, 135.20, 138.42,
138.77, 151.44, 154.22, 162.50. Found (%): C, 35.63; H, 2.93;
N, 9.40. C9H9IN2S. Calculated (%): C, 35.54; H, 2.98; N, 9.21.
Experimental
The starting compounds were synthesized according to the
known procedures.22,23
1H and 13C NMR spectra were recorded on a Bruker
AVANCEIIIꢀ500 spectrometer (500 and 126 MHz) in solutions
in CDCl3, using Me4Si as an internal standard. The signals in
the 1H and 13C NMR spectra were assigned using a combination
of 2D experiments 1H—1H COSY and 1H—13C HSQC/HMBC.
Elemental analysis was performed on a Perkin—Elmer PEꢀ2400
automated analyzer. Melting points were measured on a Boetius
heating stages and were not corrected.
GLC/MS analysis of all the samples was carried out using an
Agilent GC 7890A MS 5975C Inert XL EI/CI GLC/MS spectroꢀ
meter with a quadrupole mass spectrometric detector and an
HPꢀ5MS quartz capillary column (30 m × 0.25 mm), with
a 0.25ꢀm thick film. Electron impact ionization mass spectra
(70 eV) were recorded upon scanning on the total ion current in
the range m/z 20—1000. Carrier gas helium, separation of the
flow 1 : 50, the rate through the column 1.0 mL min–1; the
temperature regime of the column: first 40 C for 3 min, then,
a programmed increase to 290 C at the rate 10 C min–1, and
finally 290 C for 20 min; the injector temperature 250 C, the
temperature of the source of ions 230 C, of quadrupole 150 C,
of transfer chamber 280 C. The concentration of solutions of
samples in THF was 3—4 mg mL–1
.
Semiꢀpreparative HPLC was performed using an Agilent
1200 Series semiꢀpreparative liquid chromatograph (Agilent
Technologies, USA). The instrument was equipped with a autoꢀ

2ꢀAminoꢀ3ꢀcyanopyridine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
693
1ꢀMethylꢀ4ꢀ(5ꢀphenylthiophenꢀ2ꢀyl)pyrimidinium iodide (2b).
The yield was 90%, an orange powder. M.p. 206—208 C (deꢀ
comp.). 1H NMR (DMSOꢀd6), : 4.16 (s, 3 H, CH3); 7.43—7.50
(m, 3 H, Ph); 7.88 (d, 2 H, Ph, J = 7.3 Hz); 7.91 (d, 1 H, thienyl,
J = 4.1 Hz); 8.53 (d, 1 H, thienyl, J = 4.1 Hz); 8.62 (d, 1 H,
H(5), J = 6.8 Hz); 9.15 (dd, 1 H, H(6), J = 1.1 Hz, J = 6.8 Hz);
9.53 (s, 1 H, H(2)). 13C NMR (DMSOꢀd6), : 43.72 (CH3),
115.56, 126.18, 127.12, 129.23, 129.44, 129.90, 132.18, 136.71,
137.36, 151.03, 154.25, 154.74, 162.05. Found (%): C, 40.31;
H, 2.64; N, 7.21. C13H11IN2S2. Calculated (%): C, 40.42;
H, 2.87; N, 7.25.
4ꢀ([2,2´]Bithiophenylꢀ5ꢀyl)ꢀ1ꢀmethylpyrimidinium iodide
(2c). The yield was 75%, an orange powder. M.p. 206—208 C
(decomp.). 1H NMR (DMSOꢀd6), : 4.14 (s, 3 H, CH3); 7.22
(dd, 1 H, thienyl, J = 3.7 Hz, J = 5.0 Hz); 7.68—7.70 (m, 2 H,
thienyl); 8.47 (d, 2 H, thienyl, J = 4.2 Hz); 8.59 (d, 1 H, H(5),
J = 6.9 Hz); 9.11 (dd, 1 H, H(6), J = 1.5 Hz, J = 6.9 Hz); 9.50
(s, 1 H, H(2)). 13C NMR (DMSOꢀd6), : 43.72 (CH3), 115.56,
126.18, 127.12, 129.23, 129.44, 129.90, 132.18, 136.71, 137.36,
151.03, 154.25, 154.74, 162.05. Found (%): C, 40.31; H, 2.64;
N, 7.21. C13H11IN2S2. Calculated (%): C, 40.42; H, 2.87; N, 7.25.
4ꢀ(5ꢀBromothiophenꢀ2ꢀyl)ꢀ1ꢀmethylpyrimidinium iodide (2d).
The yield was 86%, a dark yellow powder. M.p. >300 C
(decomp.). 1H NMR (DMSOꢀd6), : 4.16 (s, 3 H, CH3); 7.63
(d, 1 H, thienyl, J = 4.2 Hz); 8.34 (d, 1 H, thienyl, J = 4.2 Hz);
8.64 (d, 1 H, H(5), J = 6.9 Hz); 9.23 (dd, 1 H, H(6), J = 1.4 Hz,
J = 6.9 Hz); 9.55 (s, 1 H, H(2)). 13C NMR (DMSOꢀd6), : 44.02
(CH3), 115.59, 124.98, 134.17, 135.89, 140.17, 151.84, 154.37,
161.28. Found (%): C, 28.25; H, 2.25; N, 7.20. C9H8BrIN2S.
Calculated (%): C, 28.22; H, 2.11; N, 7.31.
6ꢀThienylꢀsubstituted 2ꢀaminopyridineꢀ3ꢀcarbonitriles 3a—d
(general procedure). The salt 2a—d (2.0 mmol) was added to
a solution of malonodinitrile (159 mg, 2.4 mmol) and triethylꢀ
amine (697 L, 5.00 mmol) in ethanol (10 mL). The reaction
mixture was stirred for 48 h at room temperature, the solvent was
evaporated, the residue was subjected to chromatography, elutꢀ
ing with a mixture of ethyl acetate—hexane (1 : 2).
2ꢀAminoꢀ6ꢀ(thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile (3a).14,25
The yield was 66%, a light yellow powder. M.p. 126—129 C.
1H NMR (CDCl3), : 5.23 (br.s, 2 H, NH2); 7.05 (d, 1 H, H(5),
J = 8.1 Hz); 7.12 (dd, 1 H, H(4) of thienyl, J = 3.9 Hz, J = 4.9 Hz);
7.47 (dd, 1 H, H(5) of thienyl, J = 0.6 Hz, J = 4.9 Hz); 7.62 (d, 1 H,
H(3) of thienyl, J = 3.9 Hz); 7.66 (d, 1 H, H(4), J = 8.1 Hz).
13C NMR (CDCl3), : 88.65 (CN), 108.72, 116.94, 126.88,
128.28, 129.65, 141.67, 143.36, 155.11, 158.89. GLC: tR 22.05
min. MS (EI, 70 eV), m/z (Irel (%)): 201 [M+] (100). Found (%):
C, 59.67; H, 3.50; N, 20.84. C10H7N3S. Calculated (%): C, 59.68;
H, 3.51; N, 20.88.
Ar); 7.18 (d, 1 H, thienyl, J = 3.9 Hz); 7.26—7.31 (m, 2 H, Ar);
7.52 (d, 1 H, thienyl, J = 3.9 Hz); 7.66 (d, 1 H, H(4), J = 8.1 Hz).
13C NMR (CDCl3), : 88.55 (CN), 108.50, 116.99, 124.54,
124.63, 125.41, 127.62, 128.07, 137.03, 141.52, 141.58, 141.69,
154.86, 158.88. GLC: tR 29.36 min. MS (EI, 70 eV), m/z
(Irel (%)): 283 [M+] (100). Found (%): C, 59.11; H, 3.27;
N, 14.62. C14H9N3S2. Calculated (%): C, 59.34; H, 3.20; N, 14.83.
2ꢀAminoꢀ6ꢀ(5ꢀbromothiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile
(3d). The yield was 70%, a yellow powder. M.p. 206—207 C.
1H NMR (CDCl3), : 5.18 (br.s, 2 H, NH2); 6.98 (d, 1 H, H(5),
J = 8.1 Hz); 7.07 (d, 1 H, thienyl, J = 4.0 Hz); 7.34 (d, 1 H,
thienyl, J = 4.0 Hz); 7.67 (d, 1 H, H(4), J = 8.1 Hz). 13C NMR
(CDCl3), : 89.03 (CN), 108.02, 116.78, 117.62, 126.72, 131.21,
141.80, 144.87, 154.17, 158.83. GLC: tR 24.73 min. MS (EI,
70 eV), m/z (Irel (%)): 279 [M+] (100) (79Br), 281 [M+] (100)
(
81Br). Found (%): C, 42.90; H, 2.23; N, 14.79. C10H6BrN3S.
Calculated (%): C, 42.87; H, 2.16; N, 15.00.
Bromination of 2ꢀaminoꢀ6ꢀ(thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarboꢀ
nitrile (3a) (general procedure). NꢀBromosuccinimide (196 mg,
1.1 mmol (for the preparation of compound 4) or 544 mg,
3.0 mmol (for the preparation of compound 5)) was added to
a solution of 2ꢀaminoꢀ6ꢀ(thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile
(3a) (201 mg, 1.0 mmol) in DMF (5 mL). The reaction mixture
was stirred for 24 h at room temperature. Then, the mixture was
diluted with water, a precipitate formed was filtered off, washed
with water, dried in air, dissolved in chloroform, and subjected
to chromatography, eluting with a mixture of ethyl acetate—
hexane (1 : 2).
2ꢀAminoꢀ5ꢀbromoꢀ6ꢀ(thiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile
(4).14 The yield was 75%, a light brown powder. M.p. 158—159 C.
1H NMR (CDCl3), : 5.20 (br.s, 2 H, NH2); 7.14 (dd, 1 H, H(4)
of thienyl, J = 4.0 Hz, J = 5.0 Hz); 7.54 (dd, 1 H, H(5) of
thienyl, J = 0.8 Hz, J = 5.1 Hz); 7.89 (s, 1 H, H(4)); 8.25 (dd, 1 H,
H(3) of thienyl, J = 0.8 Hz, J = 3.9 Hz). 13C NMR (CDCl3),
: 90.55 (CN), 103.05, 115.33, 127.96, 130.90, 131.07, 141.99,
146.42, 152.70, 156.52. GLC: tR 24.38 min. MS (EI, 70 eV), m/z
(Irel (%)): 279 [M+] (100) (79Br), 281 [M+] (100) (81Br). Found (%):
C, 43.03; H, 2.32; N, 14.75. C10H6BrN3S. Calculated (%):
C, 42.87; H, 2.16; N, 15.00.
2ꢀAminoꢀ5ꢀbromoꢀ6ꢀ(5ꢀbromothiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarboꢀ
nitrile (5). The yield was 77%, a light brown powder. M.p.
1
218—223 C. H NMR (CDCl3), : 5.18 (br.s, 2 H, NH2); 7.09
(d, 1 H, thienyl, J = 4.2 Hz); 7.88 (s, 1 H, H(4)); 8.04 (d, 1 H,
thienyl, J = 4.2 Hz). 13C NMR (CDCl3), : 90.87 (CN), 102.48,
115.18, 119.48, 131.03, 131.38, 143.63, 146.55, 151.41, 156.40.
GLC: tR 26.80 min. MS (EI, 70 eV), m/z (Irel (%)): 359 [M+]
(100). Found (%): C, 33.33; H, 1.32; N, 11.86. C10H5Br2N3S.
Calculated (%): C, 33.45; H, 1.40; N, 11.70.
2ꢀAminoꢀ6ꢀ(5ꢀphenylthiophenꢀ2ꢀyl)pyridineꢀ3ꢀcarbonitrile
(3b). The yield was 51%, a yellow powder. M.p. 181—183 C.
1H NMR (CDCl3), : 5.19 (br.s, 2 H, NH2); 7.07 (d, 1 H, H(5),
J = 8.1 Hz); 7.30—7.36 (m, 2 H, Ar); 7.39—7.42 (m, 2 H, Ar);
7.59 (d, 1 H, thienyl, J = 3.9 Hz); 7.64—7.69 (m, 2 H, Ar, H(4)).
13C NMR (CDCl3), : 88.65 (CN), 108.72, 116.94, 126.88,
128.28, 129.65, 141.67, 143.36, 155.11, 158.89. GLC: tR 29.31
min. MS (EI, 70 eV), m/z (Irel (%)): 277 [M+] (100). Found (%):
C, 68.99; H, 3.80; N, 14.93. C16H11N3S. Calculated (%):
C, 69.29; H, 4.00; N, 15.15.
An aerobic Suzuki crossꢀcoupling reaction with bromoꢀsubstiꢀ
tuted 2ꢀaminoꢀ6ꢀthienylnicotinonitriles 3d, 4, 5 (general proceꢀ
dure). The salt K3PO4 (265 mg, 1.25 mmol (for the reaction with
compounds 3d, 4) or 531 mg, 2.5 mmol (for the reaction with
compound 5)) was added to a solution of bromoꢀsubstituted
2ꢀaminoꢀ6ꢀthienylnicotinonitrile 3d, 4, or 5 (0.5 mmol), (het)ꢀ
arylboronic acid 6—9 (0.75 mmol for the reaction with 3d, 4 or
1.0 mmol for the reaction with 5), and DAPCy (15 mg, 0.025 mmol
for the reaction with 3d, 4 or 30 mg, 0.05 mmol for the reaction
with 5) in EtOH (10—15 mL). A suspension obtained was stirred
for 24 h at room temperature. Then, the solvent was evaporated
in vacuo, the residue was extracted with CH2Cl2 (20 mL), inorꢀ
ganic impurities were filtered off, and the solvent was once more
2ꢀAminoꢀ6ꢀ([2,2´]bithiophenylꢀ5ꢀyl)pyridineꢀ3ꢀcarbonitrile
(3c). The yield was 55%, a yellow powder. M.p. 185—186 C.
1H NMR (CDCl3), : 5.18 (br.s, 2 H, NH2); 7.01—7.07 (m, 2 H,

694
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 3, March, 2015
Verbitskiy et al.
evaporated in vacuo. The thus obtained residue was analyzed by
GLCꢀMS and purified by semiꢀpreparative HPLC. The yields of
6ꢀthienylꢀsubstituted 2ꢀaminonicotinonitriles 3b,c,e are given
in Table 1.
8. M. M. Ghorab, A. Y. Hassan, Phosphorus, Sulfur, Silicon
Relat. Elem., 1998, 141, 251.
9. P. Verma, N. Kumar, S. Bhargava, A. K. Yadav, Indian J.
Heterocycl. Chem., 2007, 16, 387.
2ꢀAminoꢀ6ꢀ([2,3´]bithiophenylꢀ5ꢀyl)pyridineꢀ3ꢀcarbonitrile
(3e). The yield was 92%, a dark yellow powder. M.p. 192—195 C.
1H NMR (CDCl3), : 5.18 (br.s, 2 H, NH2); 7.06 (d, 1 H, H(5),
J = 8.1 Hz); 7.21 (d, 1 H, thienyl, J = 3.9 Hz); 7.34—7.39 (m, 2 H,
thienyl); 7.49 (dd, 1 H, thienyl, J = 1.3 Hz, J = 2.9 Hz); 7.55
(d, 1 H, thienyl, J = 3.9 Hz); 7.66 (d, 1 H, H(4), J = 8.1 Hz).
13C NMR (CDCl3), : 88.43 (CN), 108.51, 117.04, 120.71,
124.30, 125.87, 126.70, 127.69, 135.25, 141.32, 141.50, 143.23,
155.06, 158.90. GLC: tR 29.56 min. MS (EI, 70 eV), m/z
(Irel (%)): 283 [M+] (100). Found (%): C, 59.10; H, 3.54;
N, 14.71. C14H9N3S2. Calculated (%): C, 59.34; H, 3.20; N, 14.83.
10. D. C. Mungra, M. P. Patel, R. G. Patel, ARKIVOC, 2009,
XIV, 64.
11. DD Pat. 287260; Chem. Abstrs, 1991, 114, 207041g.
12. R. Troschutz, T. Dennstedt, Arch. Pharm. (Weinheim), 1994,
327, 33.
13. Q. Wu, Y. Zhang, S. Cui, Org. Lett., 2014, 16, 1350.
14. E. V. Verbitskiy, P. A. Slepukhin, Yu. O. Subbotina, M. S.
Valova, A. V. Shchepochkin, E. M. Cheprakova, G. L. Rusinov,
V. N. Charushin, Chem. Heterocycl. Compd. (Engl. Transl.),
2014, 50, 814 [Khim. Geterotsikl. Soedin., 2014, 883].
15. V. N. Charushin, H. C. van der Plas, Tetrahedron Lett., 1982,
23, 3965.
This work was financially supported by the Ural Branch
of the Russian Academy of Sciences (Program 13ꢀ3ꢀ019ꢀ
UMA), the Russian Foundation for Basic Research
(Project Nos 13ꢀ03ꢀ96049ꢀr_ural_a, 13ꢀ03ꢀ90606ꢀArm_a,
and 14ꢀ03ꢀ31040ꢀmol_a), the President of the Rusꢀ
sian Federation Council for Grants (Program of State Supꢀ
port for Young ScientistsꢀCandidates of Science, Grant
MKꢀ3939.2014.3), as well as within the Agreement beꢀ
tween the Skolkovo Institute of Science and Technologies
and the M. V. Lomonosov Moscow State University
(No. 182ꢀMRA).
16. V. N. Charushin, H. C. van der Plas, Recl. Trav. Chim. Paysꢀ
Bas, 1983, 102, 373.
17. E. A. Charushin, H. C. van der Plas, Recl. Trav. Chim. Paysꢀ
Bas, 1974, 102, 233.
18. G. G. Danagulyan, Chem. Heterocycl. Compd., 2005,
41, 1205.
19. R. S. Sagitullin, A. N. Kost, G. G. Danagulyan, Tetrahedron
Lett., 1978, 43, 4135.
20. G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky, S. N.
Denisenko, Heterocycles, 2000, 53, 419.
21. B. Tao, D. W. Boykin, J. Org. Chem., 2004, 69, 4330.
22. E. V. Verbitskiy, E. M. Cheprakova, P. A. Slepukhin, M. I.
Kodess, M. A. Ezhikova, M. G. Pervova, G. L. Rusinov,
O. N. Chupakhin, V. N. Charushin, Tetrahedron, 2012,
68, 5445.
References
23. E. V. Verbitskiy, E. M. Cheprakova, E. F. Zhilina, M. I.
Kodess, M. A. Ezhikova, M. G. Pervova, P. A. Slepukhin,
J. O. Subbotina, A. V. Schepochkin, G. L. Rusinov, O. N.
Chupakhin, V. N. Charushin, Tetrahedron, 2013, 69, 5164.
24. G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112.
25. WO 2011147038; Chem. Abstrs, 2011, 155, 683923.
1. M. W. Beukers, I. Meurs, A. P. Ijzerman, Med. Res. Rev.,
2006, 26, 667.
2. US Pat. 6030969; Chem. Abstrs, 2000, 132, 180592.
3. M. Mantri, O. de Graaf, J. van Veldhoven, A. Göblyös, J. K.
von Frijtag Drabbe Künzel, T. MulderꢀKrieger, R. Link,
H. de Vries, M. W. Beukers, J. Brussee, A. P. Ijzerman,
J. Med. Chem., 2008, 51, 4449.
4. WO 2004055015; Chem. Abstrs, 2004, 141, 89018n.
5. WO 2004054505; Chem. Abstrs, 2004, 141, 89013g.
6. DE Pat. 4117802; Chem. Abstrs, 1992, 118, 191550s.
7. K. M. Ghoneim, M. M. Badran, M. A. Shaaban, S. ElꢀMelꢀ
igie, Egypt. J. Pharm. Sci., 1988, 29, 553.
Received January 21, 2015;
in revised form January 27, 2015