Synthesis and Properties of 4,6-Dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile and 3-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines

Article abstract of DOI:10.1134/S1070363219080061

The reaction of 3-pentylpentane-2,4-dione with cyanothioacetamide afforded 4,6-dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile. Alkylation of the latter led to the formation of 2-alkylsulfanyl-4,6-dimethyl-5-pentylpyridine-3-carbonitriles or 3-amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines, depending on the alkylating agent and reaction conditions. The structures of the key compounds were proved by 2D NMR spectroscopy and X-ray analysis. Biological activity of the synthesized compounds was evaluated in silico. Some compounds were experimentally found to stimulate growth of sunflower seedlings.

Full text of DOI:10.1134/S1070363219080061

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 8, pp. 1575–1585. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 8, pp. 1182–1194.
Synthesis and Properties of 4,6-Dimethyl-
5
-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
and 3-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines
a
a–c
b
b
D. S. Buryi *, V. V. Dotsenko , N. A. Aksenov , I. V. Aksenova ,
c, d
e
S. G. Krivokolysko , and L. V. Dyadyuchenko
a
Kuban State University, Krasnodar, Russia
*
e-mail: victor_dotsenko_@mail.ru
b
North Caucasus Federal University, Stavropol, Russia
c
KhimEks Laboratory, Vladimir Dahl Lugansk National University, Lugansk, Ukraine
d
St. Luka Lugansk State Medical University, Lugansk, Ukraine
e
All-Russian Research Institute of Biological Plant Protection, Krasnodar, Russia
Received March 11, 2019; revised March 11, 2019; accepted March 14, 2019
Abstract—The reaction of 3-pentylpentane-2,4-dione with cyanothioacetamide afforded 4,6-dimethyl-5-pentyl-
-thioxo-1,2-dihydropyridine-3-carbonitrile. Alkylation of the latter led to the formation of 2-alkylsulfanyl-4,6-
2
dimethyl-5-pentylpyridine-3-carbonitriles or 3-amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines, depending
on the alkylating agent and reaction conditions. The structures of the key compounds were proved by 2D NMR
spectroscopy and X-ray analysis. Biological activity of the synthesized compounds was evaluated in silico. Some
compounds were experimentally found to stimulate growth of sunflower seedlings.
Keywords: cyanothioacetamide, Thorpe–Ziegler cyclization, thieno[2,3-b]pyridines, lipophilicity, in silico biologi-
5
cal activity, 1,3,2λ -diazaphosphinines
DOI: 10.1134/S1070363219080061
2
-Thioxo-1,2-dihydropyridine-3-carbonitriles [3-cy-
and cell membrane permeability [12, 13]. Therefore, the
synthesis of new derivatives of the 3-aminotieno[2,3-b]
pyridine series with controlled lipophilicity seems to be
an important problem.
anopyridin-2(1H)-thiones] is a class of readily accessible
compounds which attract interest due to their diverse pos-
sible applications in fine organic synthesis [1–5]. These
compounds are main precursors to 3-aminothieno[2,3-b]-
pyridines that are promising heterocyclic compounds
exhibiting a broad spectrum of biological activity
The traditional (and most popular) synthetic approach
to thieno[2,3-b]pyridines consists of base-catalyzed
Thorpe–Ziegler cyclization of 2-(R-methylsulfanyl)
pyridine-3-carbonitriles 1 prepared by alkylation of
[
6–11]. An important factor which is necessary to be
taken into account in the target-oriented synthesis of
bioactive 3-aminotieno[2,3-b]pyridine derivatives is
their lipophilicity; it characterizes their bioavailability
3
-cyanopyridine-2(1H)-thiones 2 (Scheme 1) [6–10]. In
this case, the resulting thieno[2,3-b]pyridine molecule
necessarily contains an amino group in the 3-position and
Scheme 1.
R3
R3
R3
NH2
4
R CH Hlg,
R2
R2
CN
S
2
R2
R1
base
CN
S
base
4
3
5
R4
2
R1
R4
R1
S
6
N
7
N
H
N
1
2
1
1
575

1576
BURYI et al.
Scheme 2.
CH3
CH
3
CH
3
NH2
R
R
C
CN
S
R
O
EWG
S
H C
O
H
3
N
H
H C
3
N
3
R = Me, Et, CO Me, CH Ar; EWG is an electron-withdrawing group.
2
2
4
a polar electron-withdrawing group (R ) in the 2-posi-
tion, and its lipophilicity can be controlled mainly by the
Leistner and Dumke [32] previously described an
original synthesis of bis(thieno[2,3-b]pyridin-2-yl) ke-
tones by reaction of 2-thioxopyridine-3-carbonitriles
with 1,3-dichloroacetone. We have found that the re-
action of 3 with 1,3-dichloroacetone in DMF even in
the presence of excess potassium hydroxide gives no
bis(thieno[2,3-b]pyridin-2-yl) ketone 6 and that the prod-
uct is 1,3-bis(pyridin-2-ylsulfanyl)acetone 7 (Scheme 3).
Inhibition of the cascade process and the formation of
compounds 5 and 7 as the major products are likely to
be related to the poor solubility of the latter in DMF, so
that they are removed from the reaction zone.
1
3
substituents R –R in positions 4, 5, and 6.
In continuation of a series of our studies in the field of
synthesis of functionalized thieno[2,3-b]pyridines [14–
0], herein we report the synthesis and some properties of
2
thienopyridines containing lipophilic alkyl substituents in
positions 4–6. We believed that the most rational approach
to the introduction of alkyl groups into those positions
is the classical pyridine ring construction by the Guare-
schi–Thorpe cyclization of cyanothioacetamide [21, 22]
with substituted 1,3-diketones, followed by alkylation
of 2-thioxo-1,2-dihydropyridine-3-carbonitriles 2 and
Thorpe–Ziegler cyclization of intermediates 1.
A few examples of phosphorylation of 3-amino-
thieno[2,3-b]pyridine-2-carboxamides with the forma-
5
The synthesis of thieno[2,3-b]pyridines with various
substituents in the 5-position starting from 3-substituted
acetylacetones has been demonstrated in [23–27] on a
limited number of examples (Scheme 2). This approach
is advantageous primarily due to preparative convenience
and accessibility of initial acetylacetone derivatives.
tion of fused 1,3,2λ -diazaphosphinine derivatives have
been reported in recent years [33, 34]. It should be noted
that 1,3,2-diazaphosphinines attract interest due to their
diverse biological activity [35–39]. By treatment of
thienopyridine 4a (EWG = CONH ) with an equimolar
2
amount of phosphorus(V) sulfide in boiling anhydrous
pyridine we obtained pyrido[3′,2′ : 4,5]thieno[3,2-d]-
Preliminary estimation of the c log P values (logarithm
of the octanol/water partition coefficient) for the expected
products using OSIRIS Property Explorer software [28]
showed that C –C is the limiting length of the alkyl chain
of the 5-substituent to meet Lipinski’s rule of five [29–31]
c log P ≤ 5.0) for peroral bioavailability. Therefore, it
[1,3,2]diazaphosphinine 8.
Compounds 4a–4f and 8 are finely crystalline
powders colored in various shades of yellow; they are
readily soluble in acetone, ethyl acetate, and benzene.
5
6
1
13
(
The product structure was proved by H and C NMR
seemed reasonable to confine the maximum alkyl chain
(DEPTQ), IR, and high-resolution mass spectra, as well
as by X-ray analysis. The 1H NMR spectra of all isolated
length to C (n-pentyl).
5
compounds characteristically showed upfield signals
due to pentyl and two methyl groups. The H NMR
By the condensation of 3-pentylpentane-2,4-dione
with cyanothioacetamide in the presence of morpho-
line we obtained previously unknown 4,6-dimethyl-
1
spectrum of 8 displayed no NH2 signal, and the most
1
3
5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (3)
downfield signal in its C NMR spectrum is that located
(Scheme 3). Compound 3 could be a convenient precur-
at δ 167.0 ppm (C=O), which indicates the absence of
C
sor to thieno[2,3-b]pyridine derivatives 4 with a pentyl
substituent on C . Treatment of 3 with alkylating agents
in DMF in the presence of excess potassium hydroxide
afforded thieno[2,3-b]pyridines 4a–4f, but in the reaction
of 3 with 2-chloro-N-(4-methylphenyl)acetanilide we
isolated only uncyclized S-alkylation product 5.
thioamide fragment in molecule 8. In the IR spectra of
3, 5, and 7 we observed an absorption band belonging
to stretching vibrations of the conjugated cyano group
(2216–2220 cm ), whereas no such band was present
in the spectra of 4a–4f. The structure of 4,6-dimethyl-
5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (3)
5
–
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

SYNTHESIS AND PROPERTIES OF 4,6-DIMETHYL-5-PENTYL-2-THIOXO-...
1577
Scheme 3.
CH3
CH3
CN
CN
S
CH3
CH3
morpholine,
EtOH,
H N
S
HlgCH EWG,
2
2
H C
N
5
EWG
EWG
CN
S
3
'
, 4
h
KOH, DMF
+
4
5%
CH3
O
O
H C
N
H
CH
3
3
NH2
H C
CH3
3
3
S
P
S
H C
N
4a–4f
3
CH3
SH
NH
CH3
HN
P S10, Py, '
4
CH3
EWG = CONH2
O
S
H C
N
3
8
CH3
H C
3
CH3
CH3
N
H N H N
2
2
u
CH3
CH3
Cl
KOH,
DMF
CN
S
H C
N
S
S
CH3
3
+
O
O
6
CH3
H C
H C
N
H
3
3
CH3
CH3
Cl
CN
S
NC
S
3
H C
3
N
N
CH3
O
7
4
, EWG = CONH (a), CO Et (b), CN (c), 3-O NC H NHCO (d), PhC(O) (e),
2 2 2 6 4
4
-BrC H C(O) (f); 5, EWG = 4-MeC H NHCO.
6 4 6 4
was confirmed by two-dimensional NMR spectroscopy
polar surface area (TPSA), toxicological parameters (i.e.,
risks of side effects such as mutagenic, carcinogenic, and
reproductive effects), drug likeness, and general pharma-
cological potential of a compound [28]. OSIRIS Property
Explorer provides the possibility of performing primary
analysis of a structure in terms of the Lipinski rule of
five (c log P ≤ 5.0, MW ≤ 500, TPSA ≤ 140, number of
hydrogen bond acceptors ≤ 10, number of hydrogen do-
nors ≤ 5) [29–31]. The results of calculations by OSIRIS
Property Explorer are given in Table 2.
1
13
1
13
1
15
(
H– C HSQC, H– C HMBC, H– N HMBC; Fig. 1,
Table 1), and the structures of 4c and 5 were determined
by X-ray analysis (Figs. 2, 3).
Compounds 3, 4a–4f, 5, 7, and 8 were evaluated in
silico for drug likeness byADMET (absorption, distribu-
tion, metabolism, excretion, toxicity) prediction using
OSIRIS Property Explorer [28] i admetSAR [40]. Their
biological activity was also predicted by PASS Online
[
[
41] and Molinspiration Property Calculation Service
42]. OSIRIS Property Explorer database covers the
As follows from the obtained data, the lipophilicity
of 3, 4a–4f, 5, 7, and 8 varies over a wide range, but
the c log P values for thienopyridines 4 mostly do not
exceed 5.0, which suggests possible good absorption
properties of 3300 drugs and 15 000 commercially avail-
able compounds (Fluka), which can be used to estimate
the lipophilicity c log P, solubility (log S), topological
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1578
BURYI et al.
1
13
1
15
Table 1. Principal correlations in the H– C and H– N HSQC and HMBC spectra of 4,6-dimethyl-5-pentyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (3)
a
1
15
1
15
H– N HSQC, δ , H– N HMBC, δ ,
1
13
1
13
N
N
δH, ppm
К H– C HSQC, δ , ppm
H– C HMBC, δ , ppm
C
C
ppm
ppm
0
.86 t (3Н, СН3)
14.0 (CH3)
21.9* (CН2)
–
–
3
1.3* (CН2)
1
.31–1.36 m
21.9* (CН ) 27.8* (CН )
14.0 (CH3)
–
–
2
2
[
6Н, (СН ) ]
31.3* (CН2)
21.9* (CН2)
2
3
2
2
3
7.1* (CН2)
7.8* (CН2)
1.3* (CН2)
2
.38 s
6
17.1 (CH3)
18.8 (CH3)
114.5* (С5)
155.6* (С6)
–
–
202.8 (NH)
–
(
3Н, С СН )
3
2
.39 s
4
114.5* (С5)
125.0* (С3)
(
3Н, С СН )
3
1
50.8* (С4)
2
(
.40–2.45 m
2Н, СН2)
27.1* (CН2)
27.8* (CН2)
114.5* (С5)
–
–
–
1
1
50.8* (С4)
55.6* (С6)
1
3.75 уш. с
1Н, NH)
–
114.5* (С5)
125.0* (С3)
202.8 (NH)
(
a
Opposite phase signals in the 13C DEPTQ spectrum (quaternary carbons and CH2).
and permeability [29–31]. The molecular weights of all
the examined compounds, except for 1,3-bis(pyridin-
bioavailability. It should be noted that the log S values
calculated by OSIRIS Property Explorer [28] for 80%
of commercially available drugs is higher than –4. The
parameter TPSA reflects surface area of polar parts of a
molecule.As a rule, increased TPSAis related to reduced
cell membrane permeability; therefore, lower TPSA
values are generally preferred from the viewpoint of
drug likeness. TPSA, molecular weight, and lipophilic-
ity are the key parameters responsible for transport of
molecules (in particular, low-molecular-weight kinase
2-ylsulfanyl)propan-2-one (7), are not higher than 430, in
keeping with the Lipinski rule of five. However, none of
the above compounds showed a positive drug likeness or
high drug score (>0.5). On the other hand, only compound
8
was predicted to have an appreciable toxicity due to the
presence of P=S and N–P=S fragments.
The parameter log S characterized the solubility; as
a rule, poor solubility implies low absorption and low
(a)
(b)
2
.402.45
H
1
.311.36
H
H
116.8
2
.39
31.3
27.8
1
8.8
C
150.8
CH3
14.0
N
0.86
H2 H2
27.1
14.5
17.1
N
H C
3
H C
C
C
3
1
125.0
C
H
C
2
02.8
H
21.9
2
2
H C
H
N
S
2
.38 H C
N
S
3
H
H
H 155.6
174.7
1
3.75
1
13
Fig. 1. Principal correlations in the H– C HMBC spectrum of 4,6-dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (3):
1
13
(
a) H and (b) C chemical shifts (δ, δ , ppm).
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

SYNTHESIS AND PROPERTIES OF 4,6-DIMETHYL-5-PENTYL-2-THIOXO-...
1579
Table 2. Toxicity risks and physicochemical parameters of compounds 3, 4a–4f, 5, 7, and 8, predicted by OSIRIS Property
Explorer
Toxicity riska
Physicochemical parameters
Compound no.
сLogP
logS
MW
TPSA drug likeness drug score
3
–
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
–
±
–
–
–
–
–
–
–
–
–
+
2.91
3.05
4.28
3.8
–3.9
–5.09
–5.44
–5.77
–6.97
–7.1
234.0
291.0
320.0
273.0
412.0
352.0
430.0
381.0
522.0
385.0
67.91
110.2
93.45
90.94
142.0
84.22
84.22
91.08
141.0
162.9
–13.08
–8.54
0.405
0.333
0.275
0.282
0.206
0.189
0.145
0.216
0.103
0.058
4
4
4
4
4
4
5
7
8
a
b
c
d
e
f
–12.53
–14.88
–12.32
–8.45
4.19
5.09
5.82
5.16
7.28
4.55
–7.93
–5.78
–7.86
–3.09
–10.97
–13.73
–14.26
–12.4
a
“+” denotes a high risk, “±” denotes a moderate risk, and “–” denotes the absence of toxicity.
inhibitors) through the blood–brain barrier [43]. Most of
the examined compounds, except for 4d, 7, and 8 meet
the condition TPSA ≤ 140.
and intestinal absorption upon peroral administration
HIA, human intestinal absorption). The examined com-
(
pounds are not cytochrome P450 (CYP450) substrates
but are CYP450 inhibitors to some extent, and they may
affect metabolism of other drugs. The Ames tests for
mutagenic activity were mainly negative. The predicted
LD values in rats were comparable with those of most
The results of ADMET prediction using admetSAR
[40] showed (Table 3) that all compounds are character-
ized by a good BBB (blood–brain barrier) permeability
5
0
Fig. 3. Structure of the molecule of 2-[(3-cyano-4,6-dimethyl-
-pentylpyridin-2-yl)sulfanyl]-N-(4-methylphenyl)acetamide
5) in crystal according to the X-ray diffraction data.
Fig. 2. Structure of the molecule of 3-amino-4,6-dimethyl-
5
(
5
-pentylthieno[2,3-b]pyridine-2-carbonitrile (4c) in crystal
according to the X-ray diffraction data.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1580
BURYI et al.
Table 3. ADMET parameters and possible biological activity of compounds 3, 4a–4f, 5, 7, and 8 predicted by admetSAR
Metabolism
LD50 in rats,
Compound no.
HIAa
BBBa
Ames’ toxicitya
CYP450
inhibitor
CYP450
substrate
mol/kg
3
+ (0.9280)
+ (0.9004)
+ (0.9755)
+ (0.9640)
+ (0.9860)
+ (0.9844)
+ (0.9809)
+ (0.9025)
+ (0.9434)
+ (0.5290)
+ (0.9622)
+ (0.9406)
+ (0.9679)
+ (0.9503)
+ (0.8080)
+ (0.9714)
+ (0.9479)
+ (0.9615)
+ (0.9686)
+ (0.8432)
+
+
+
+
+
+
+
+
+
+
–
–
–
–
–
–
–
–
–
–
– (0.7131)
– (0.6693)
– (0.6874)
+ (0.6247)
+ (0.6620)
+ (0.5440)
– (0.5242)
– (0.7356)
– (0.7494)
– (0.6342)
2.4633
2.6092
2.5456
2.7938
2.7431
2.7324
2.7086
2.4791
2.5677
2.7179
4a
4б
4в
4
г
4
д
4
е
5
7
8
a
“
+” denotes the occurrence of effect, and “–” denotes the absence of effect; the probability is given in parentheses in fractions of unity.
Table 4. Growth-regulating activity of compounds 4b and 4da
Concentration, %
Comp.
no.
Organ
Control (Lc)
10–2
10–3
10–4
10–5
Lt
75
A
Lt
71
A
Lt
77
A
Lt
80
A
4
b
d
Stem
Root
Stem
Root
67
102
67
112b
107
120b
110b
106
117b
122b
113b
115b
115b
105
120b
119b
122b
127b
120b
109
81
119
82
117
74
124
85
4
102
112
116
122
122
a
L is the length (mm) of an organ in the control group of seedlings; L is the length (mm) of an organ in the treated group of seedlings; A =
c
t
(
L /L )×100% is the growth-regulating effect.
t
c
b
The differences are reliable at p = 0.95.
drugs; compounds 3 and 5 were predicted to be most
toxic. According to the results of prediction of possible
biological activity using PASS Online software, com-
pound 3 is a Cyp2c12 substrate of cytochrome P450
with a probability of 0.814, and compound 8 is expected
to inhibit dihydroorotase with a probability of 0.964.
Molinspiration Property Calculation Service predicted
possible kinase inhibitory activity of thienopyridines 4a
and 4c–4f (Molinspiration bioactivity score 0.08, –0.05,
The prospects of using the synthesized compounds in
agrochemistry was studied at the All-Russian Research
Institute of Biological Plant Protection (Krasnodar). The
growth-regulating activity of compounds 4a–4f was
evaluated by laboratory experiments on Flagman sun-
flower seedlings (Table 4). Sunflower seeds were treated
with a solution of a test compound at different concen-
–
2
–5
trations (10 to 10 ). Each experiment was carried out
in triplicate with 100 seeds. The effect was evaluated by
the elongation of the stem and root of treated seedlings
in comparison to control (untreated seeds). The results
–0.09, –0.03, and –0.07, respectively; the higher the score,
the greater the probability of biological activity).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

SYNTHESIS AND PROPERTIES OF 4,6-DIMETHYL-5-PENTYL-2-THIOXO-...
1581
were statistically processed using Student’s t-test at p =
.95. Table 4 contains data for those compounds which
showed a growth-stimulating effect. Compounds 4b and
d favored stem elongation by 12–27% relative to control
and stimulated root growth by 10–20%, depending on
the concentration.
3-methylpentane-2,4-dione [45]. A mixture of 33.0 g
(0.33 mol) of freshly distilled acetylacetone, 49.5 mL
(60.4 g, 0.4 mol) of freshly distilled 1-bromopentane,
42.0 g (0.3 mol) of potassium carbonate, 6.6 g (0.04 mol)
of potassium iodide, and 70 mLof anhydrous acetone was
refluxed for 17 h (GC/MS monitoring). The precipitate
of potassium bromide was filtered off and washed with
0
4
In summary, we have proposed a procedure for
the synthesis of 4,6-dimethyl-5-pentyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile by the Guareschi–Thorpe
cyclization and used it as starting material to obtain a
number of new 5-pentylpyridine-3-carbonitrile, 3-ami-
no-4,6-dimethyl-5-pentylthieno[2,3-b]pyridine, and
pyrido[3′,2′ : 4,5]thieno[3,2-d][1,3,2]diazaphosphinine
derivatives. The structure of the obtained compounds was
confirmed by 2D NMR techniques and X-ray analysis.
The presence of a pentyl substituent in their molecules
endows them with high lipophilicity in comparison to
previously reported structural analogs. In silico analysis
of molecular parameters responsible for biological activ-
ity and pharmacological potential indicated prospects of
further studies in this line.Amoderate growth-stimulating
activity has been revealed for two 3-amino-4,6-dimethyl-
acetone. Additional amounts of K CO (8.4 g) and KI
2
3
(1.3 g) were added to the filtrate, and the mixture was re-
fluxed for 6.5 h more. The precipitate of KBr was filtered
off, acetone was distilled off under reduced pressure, and
the residue was distilled in a vacuum (10–12 mmHg) to
collect a fraction boiling in the range from 96 to 102°C.
The product was a colorless oil which was pure according
to the GC/MS data. Yield 73%.
4
,6-Dimethyl-5-pentyl-2-thioxo-1,2-dihydro-
pyridine-3-carbonitrile (3). A mixture of 8.4 g
(
(
0.049 mol) of 3-pentylpentane-2,4-dione, 5.01 g
0.05 mol) of cyanothioacetamide, 0.43 mL (0.005 mol)
of morpholine, and 20 mL of 96% ethanol was refluxed
for 4 h. The mixture was cooled, 30 drops of glacial ace-
tic acid were added, and the precipitate was filtered off,
washed with 50% aqueous propan-2-ol and petroleum
ether, and recrystallized from propan-2-ol. Yield 45%,
5
-pentylthieno[2,3-b]pyridines in laboratory tests on
sunflower seeds.
–1
yellow finely crystalline powder. IR spectrum, ν, cm :
EXPERIMENTAL
The NMR spectra were recorded on a Bruker Avance
3
180 (N–H), 3059, 2955, 2910, 2876, 2804 (C–H), 2218
1
(C≡N), 1610, 1572 (C=C), 1229 (C=S). H NMR spec-
trum, δ, ppm: 0.86 t (3H, CH , J = 6.8 Hz), 1.31–1.36
1
13
3
III HD 400 spectrometer at 400.17 ( H), 100.63 ( C),
3
1
5
and 40.55 MHz ( N) from solutions in DMSO-d ; the
m [6H, (CH ) ], 2.38 s (3H, 6-CH ), 2.39 s (3H, 4-CH ),
6
2 3
3
3
13
chemical shifts were measured relative to the residual
proton and carbon signals of the solvent ( H and 13C)
2.40–2.45 m (2H, CH ), 13.75 br.s (1H, NH). C NMR
2
1
spectrum (DEPTQ), δ , ppm: 14.0 (CH ), 17.1 (CH ),
C
3
3
1
5
or nitromethane (external standard, N). The IR spectra
were recorded on Bruker Vertex 70 spectrometer with
Fourier transform equipped with a diamond ATR acces-
18.8 (CH ), 21.9 (CH ), 27.1 (CH ), 27.8 (CH ), 31.3
3 2 2 2
5
3
4
(CH ), 114.5 (C ), 116.8 (C≡N), 125.0 (C ), 150.8 (C ),
2
6
155.6 (C ), 174.7 (C=S). Mass spectrum: m/z: 257.1083
–
1
+
sory; spectral resolution ±4 cm . The high-resolution
mass spectra were obtained on a Bruker maXis TOF
mass spectrometer (electrospray ionization) using aceto-
nitrile as solvent and HCO Na–HCO H calibration. The
[M + Na] ; calculated for C H N NaS: 257.1089.
1
3
18
2
3
-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]-
pyridines 4a–4f and pyridine-3-carbonitrile 5 (gen-
eral procedure). 4,6-Dimethyl-5-pentyl-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (3), 300 mg (1.28 mmol),
was dissolved in 2 mL of DMF, and 0.7 mL of 10% aque-
ous potassium hydroxide (d = 1.09 g/mL, 1.36 mmol)
was added with stirring on heating. The corresponding
alkylating agent (chloroacetamide, ethyl bromoacetate,
chloroacetonitrile, substituted chloroacetanilide, or bro-
moacetophenone), 1.3 mmol, was then added to the result-
ing solution of potassium pyridine-2-thiolate, the mixture
was stirred for 20 min at 50–60°C, an additional 0.7 mL
of 10% aqueous potassium hydroxide was added, and
2
2
elemental compositions (C, H, N) were determined with
a Carlo Erba 1106 analyzer. The purity of the isolated
compounds was checked by TLC on Sorbfil-A plates
(eluent acetone–hexane, 1 : 1); spots were visualized by
treatment with iodine vapor or under UV light.
Cyanothioacetamide was synthesized by passing gas-
eous hydrogen sulfide through a solution of malononitrile
in ethanol in the presence of triethylamine [44].
3
-Pentylpentane-2,4-dione was prepared by anal-
ogy with the patented procedure for the synthesis of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1582
BURYI et al.
the mixture was stirred for 10–15 min at room tempera-
ture. Aqueous ethanol (1 : 1), 5 mL, was added, and the
precipitate was filtered off, washed with water, aqueous
ethanol, and hexane, and dried in air at 60°C.
(CH ), 15.3 (CH ), 21.9 (CH ), 23.3 (CH ), 27.9 (CH ),
3 3 2 3 2
2
28.7 (CH ), 31.5 (CH ), 95.9 (C ), 114.9 (CHarom), 117.6
2
2
3
a
(CHarom), 123.2 (C ), 126.7 (CH ), 129.7 (CHarom),
arom
5
1′
3′
131.0 (C ), 140.4 (C ), 142.6, 147.8 (C ), 150.6, 156.3,
58.3, 164.7 (C=O). Found, %: C 61.17; H 5.97; N 13.54.
C H N O S. Calculated, %: C 61.14; H 5.86; N 13.58.
1
3
-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyri-
dine-2-carboxamide (4a). Yield 45%, yellow powder.
21 24
4
3
1
3
H NMR spectrum, δ, ppm: 0.88 t (3H, CH , J = 6.8 Hz),
(3-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]
pyridin-2-yl)(phenyl)methanone (4e). Yield 60%, yel-
3
1
.33–1.39 m [6N, (CH ) ], 2.53 s (3H, CH ), 2.64–2.67
2 3 3
–1
m (5H, CH , 5-CH ), 6.87 br.s (2H, NH ), 7.11 br.s [2H,
low crystals, mp 180–181°C. IR spectrum, ν, cm : 3499,
3
2
2
1
3
C(O)NH ]. C NMR spectrum (DEPTQ), δ , ppm: 14.0
3271 (N–H), 2960, 2949, 2920, 2895, 2864 (C–H), 1688
2
C
1
(
2
CH ), 15.1 (CH ), 22.0 (CH ), 23.3 (CH ), 27.9 (CH ),
(C=O). H NMR spectrum, δ, ppm: 0.89 t (3H, CH ,
3
3
2
3
2
3
2
3a
3
8.8 (CH ), 31.5 (CH ), 97.6 (C ), 123.9 (C ), 130.7
J = 6.8 Hz), 1.32–1.41 m [6H, (CH ) ], 2.55 s (3H, CH ),
2
2
2 3
3
5
(C ), 142.3, 148.5, 155.8, 157.4, 167.5 (C=O). Found,
2.66–2.69 m (3H, CH ), 2.71 s (3H, CH ), 7.50–7.58 m
2 3
3
%
: C 61.77; H 7.37; N 14.40. C H N OS. Calculated,
(3H, m-H, p-H), 7.72 d (2H, o-H, J = 7.8 Hz), 8.17 br.s
1
5
21
3
1
3
%
: C 61.82; H 7.26; N 14.42.
Ethyl 3-amino-4,6-dimethyl-5-pentylthieno[2,3-b]-
pyridine-2-carboxylate (4b). Yield 52%, yellow powder,
(2H, NH ). C NMR spectrum (DEPTQ), δ , ppm: 14.0
2
C
(
CH ), 15.7 (CH ), 21.9 (CH ), 23.5 (CH ), 27.9 (CH ),
8.7 (CH ), 31.5 (CH ), 102.6 (C ), 122.2 (C ), 127.3
2 2
3 3 2 3 2
2
3a
2
(CHarom), 128.4 (CHarom), 131.0 (CHarom), 131.1 (C5),
–
1
mp 170°C. IR spectrum, ν, cm : 3433, 3331 (N–H),
1
′
1
141.1 (C ), 143.8, 153.3, 158.8, 159.8, 189.0 (C=O).
Mass spectrum: m/z: 353.1684 [M + H] ; calculated for
2
972, 2953, 2922, 2872, 2854 (C–H), 1668 (C=O). H
+
3
NMR spectrum, δ, ppm: 0.88 t (3H, CH , J = 6.9 Hz),
.27 t (3H, OCH CH , J = 7.1 Hz), 1.32–1.43 m [6H,
3
3
C H N OS: 353.1692.
1
21 25 2
2
3
(
5
CH ) ], 2.55 s (3H, CH ), 2.65–2.71 m (5H, CH ,
(3-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyri-
din-2-yl)(4-bromophenyl)methanone (4f). Yield 54%,
2
3
3
3
3
-CH ), 4.24 q (2H, OCH , J = 7.1 Hz), 6.86 br.s (2H,
2 2
+
NH ). Mass spectrum: m/z 321.1637 [M + H] ; calculated
for C H N O S: 321.1631.
yellow–orange finely crystalline powder, mp 163–164°C.
IR spectrum, ν, cm–1: 3495, 3292 (N–H), 2954, 2926,
2
17
25
2
2
1
3
-Amino-4,6-dimethyl-5-pentylthieno[2,3-b]-
2870 (C–H), 1682 (C=O). H NMR spectrum, δ, ppm:
3
pyridine-2-carbonitrile (4c). Yield 67%, yellow crys-
tals. IR spectrum, ν, cm : 3344, 3230 (N–H), 2957,
2
0.89 t (3H, CH3, J = 6.8 Hz), 1.32–1.44 m [6H, (CH2)3],
–
1
2.55 s (3H, CH ), 2.66–2.75 m (5H, CH , CH ), 7.67 d
3 2 3
1
(2H, m-H, 3J = 7.8 Hz), 7.72 d (2H, o-H, 3J = 7.8 Hz),
8.22 br.s (2H, NH ). 13C NMR spectrum (DEPTQ), δ ,
924, 2872, 2858 (C–H), 2193 (C≡N). H NMR spec-
3
trum, δ, ppm: 0.87 t (3H, CH , J = 6.8 Hz), 1.32–1.40
2
C
3
m [6H, (CH ) ], 2.53 s (3H, CH ), 2.63–2.69 m (5H,
ppm: 13.9 (CH3), 15.7 (CH3), 21.9 (CH2), 23.5 (CH3),
2
3
3
1
3
2
CH , 5-CH ), 6.46 br.s (2H, NH ). C NMR spectrum
27.8 (CH ), 28.7 (CH ), 31.5 (CH ), 102.2 (C ), 122.1
3
2
2
2
2
2
3
a
4′
5
(
DEPTQ), δ , ppm: 13.9 (CH ), 15.3 (CH ), 21.9 (CH ),
(C ), 124.5 (C ), 129.4 (CH ), 131.2 (C ), 131.5
arom
(CHarom), 140.0 (C ), 143.9, 153.6, 158.8, 160.0, 187.6
(C=O). Found, %: C 58.45; H 5.50; N 6.44. C H Br-
C
3
3
2
1
′
2
3.3 (CH ), 27.8 (CH ), 28.6 (CH ), 31.5 (CH ), 72.9
3
2
2
2
2
3a
5
(
C ), 116.0 (C≡N), 121.7 (C ), 131.4 (C ), 142.8, 152.3,
57.2, 158.7. Mass spectrum: m/z 296.1193 [M + Na]+;
calculated for C H N NaS: 296.1192.
2
1
23
1
N OS. Calculated, %: C 58.47; H 5.37; N 6.49.
2
15
19
3
2-[(3-Cyano-4,6-dimethyl-5-pentylpyridin-2-yl)-
sulfanyl]-N-(4-methylphenyl)acetamide (5). Yield
3
-Amino-4,6-dimethyl-N-(3-nitrophenyl)-
–
1
5
-pentylthieno[2,3-b]pyridine-2-carboxamide (4d).
96%, beige powder. IR spectrum, ν, cm : 3280, 3254,
–
1
Yield 96%, yellow powder. IR spectrum, ν, cm : 3464,
3194, 3122 (N–H), 2957, 2914, 2868, 2845 (C–H), 2216
1
3
408, 3317 (N–H), 2955, 2927, 2870 (C–H), 1651 (C=O),
(C≡N), 1660 (C=O). H NMR spectrum, δ, ppm: 0.86 t
1
3
1524 (NO , asym.), 1342 (NO , sym.). H NMR spectrum,
(3H, CH , J = 6.7 Hz), 1.30–1.40 m [6H, (CH ) ], 2.23
2
2
3
2 3
3
δ, ppm: 0.86 t (3H, CH , J = 6.8 Hz), 1.29–1.38 m [6H,
s (3H, 4′-CH ), 2.41 s (3H, CH ), 2.45 s (3H, CH ),
3
3 3 3
(
CH ) ], 2.54 s (3H, CH ), 2.62–2.65 m (3H, CH ), 2.68 s
2.52–2.56 m (2H, CH ), 4.10 s (2H, SCH ), 7.09 d (2H,
2 2
2
3
3
2
Harom, J = 8.2 Hz), 7.44 d (2H, Harom, 3J = 8.2 Hz), 10.18
3
(3H, CH ), 7.15 br.s (2H, NH ), 7.55–7.59 m (1H, 5′-H),
3 2
3
4
13
7
.88 d.d (1H, 4′-H, J = 8.1, J = 2.0 Hz), 8.12 d (1H, 6′-
br.s (2H, NH). C NMR spectrum (DEPTQ), δ , ppm:
C
3
4
H, J = 8.3 Hz), 8.72 d (1H, 2′-H, J = 2.0 Hz), 9.79 br.s
13.9 (CH ), 17.5 (4-CH ), 20.5 (4′-CH ), 21.8 (CH ),
3
3
3
2
13
(CONH). C NMR spectrum (DEPTQ), δ , ppm: 13.9
22.8 (6-CH ), 27.8 (CH ), 27.9 (CH ), 31.5 (CH ), 34.7
3 2 2 2
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

SYNTHESIS AND PROPERTIES OF 4,6-DIMETHYL-5-PENTYL-2-THIOXO-...
1583
3
o
m
(
1
1
[
SCH ), 104.7 (C ), 115.5 (C≡N), 119.1 (C ), 129.1 (C ),
(CH ), 21.5 (CH ), 21.9 (CH ), 27.7 (CH ), 28.4 (CH ),
2
3
3
2
2
2
5
4′
1′
4
2
4a
9a
8
31.1 (C ), 132.2 (C ), 136.5 (C ), 150.1 (C ), 156.8 (C ),
59.9 (C ), 165.9 (C=O). Mass spectrum: m/z: 404.1770
M + Na] ; calculated for C H N NaOS: 404.1767.
31.4 (CH ), 98.4 (C ), 125.3 (C ), 131.7 (S ), 147.9
2
6
9b
9
7
(C ), 155.5 (C ), 157.6 (C ), 167.0 (C=O). Found, %: C
48.70; H 5.58; N 11.40. C H N PS . Calculated, %: C
+
2
2
27
3
15 20
3
3
4
8.76; H 5.46; N 11.37.
X-Ray analysis of a single crystal of compound 4c
(C H N S) was performed on an Agilent SuperNova
1
,3-Bis[(3-cyano-4,6-dimethyl-5-pentylpyridin-
2
3
1
1
-yl)sulfanyl]propan-2-one (7). Pyridine-2(1H)-thione
, 600 mg (2.56 mmol), was dissolved in 2 mL of DMF,
.3 mL of 10% aqueous potassium hydroxide (d =
.09 g/mL, 2.56 mmol) was added with stirring on heat-
1
5
19
3
automated four-circle diffractometer (Dual, Cu at zero,
Atlas S2 CCD detector) at 100.00(10) K. The structure
was solved by the direct method implemented in Olex2
ing, and 160 mg (1.26 mmol) of 1,3-dichloropropan-2-one
and 1.3 mL of 10% KOH were added. A beige solid pre-
cipitated. Aqueous ethanol (1 : 1), 5 mL, was added to
the resulting suspension, and the precipitate was filtered
off, washed with water, recrystallized from DMF, and
dried at 60°C. Yield 18%, beige powder, mp 110°C. IR
2
[46] and ShelXD [47] and was refined against F by the
full-matrix least-squares method in anisotropic approxi-
mation for non-hydrogen atoms using SHELXL [48].
Triclinic crystal system, space group P-1, M 273.39;
unit cell parameters: a = 7.7903(2), b = 12.1422(3), c =
15.2460(4) Å; α = 95.790(2)°, β = 92.145(2)°, γ =
–
1
spectrum, ν, cm : 2957, 2920, 2872, 2856 (C–H), 2220
1
102.757(2)°; V = 1396.71(6) Å ; Z = 4; d 1.300 g/cm3;
3
(C≡N), 1740 (C=O), 1548 (C=C). H NMR spectrum, δ,
calc
3
–1
ppm: 0.86 t (6H, CH , J = 6.7 Hz), 1.30–1.37 m [12H,
μ(Cu K ) = 1.962 mm ; F(000) = 584.0; 7.512° ≤ θ ≤
3
α
(
CH ) ], 2.40 s (6H, CH ), 2.43 s (6H, CH ), 2.52–2.55
152.492°; –9 ≤ h ≤ 9, –15 ≤ k ≤ 14, –19 ≤ l ≤ 19. Total
of 28 431 reflection intensities were measured, including
5803 independent reflections (R = 0.0399, R = 0.0242)
2
3
3
3
m (4H, CH ), 4.37 s (4H, SCH ). 13C NMR spectrum
2
2
(DEPTQ), δ , ppm: 13.9 (CH ), 17.5 (4-CH ), 21.8 (CH ),
C 3 3 2
int
σ
2
2.6 (6-CH ), 27.8 (CH ), 27.9 (CH ), 31.4 (CH ), 38.7
and 5803 reflections with I > 2σ(I); number of variables
365; final divergence factors: R = 0.0350, wR = 0.0963
3
2
2
2
3
5
4
(SCH ), 104.8 (C ), 115.4 (C≡N), 131.2 (C ), 150.2 (C ),
2
1
2
2
6
1
5
5
56.0 (C ), 159.9 (C ), 198.6 (C=O). Mass spectrum: m/z:
for reflections with I > 2σ(I); R = 0.0373, wR = 0.0985
1 2
+
45.2372 [M + Na] ; calculated for C H N NaOS :
for all independent reflections; goodness of fit with re-
2
9
38
4
2
2
–3
45.2379.
,9-Dimethyl-8-pentyl-2-mercapto-2-thi-
oxo-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2-d]-
spect to F 1.053; Δρmax/Δρmin = 0.32/–0.31 e Å . The
X-ray diffraction data for compound 4c were deposited
to the Cambridge Crystallographic Data Centre (CCDC
entry no. 1 900 576).
7
5
[
1,3,2λ ]diazaphosphinin-4(1H)-one (8). Crystalline
3
2
-amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridine-
-carboxamide (4a), 300 mg (1.03 mmol), was ground
Asingle crystal of 5 (C H N OS) for X-ray analysis
22
27
3
was obtained by recrystallization from DMSO; the X-ray
diffraction data were obtained using the same instru-
ment as for compound 4c at 99.98(15) K. The structure
was solved by the direct method implemented in Olex2
in a porcelain mortar to obtain a fine powder which was
dissolved on heating in 4 mL of anhydrous pyridine.
Diphosphorus decasulfide, 114 mg (0.257 mmol), was
added in one portion to the resulting solution, and the
mixture was refluxed for 1 h (TLC monitoring). The
mixture was cooled, poured into 15 mL of cold ethanol,
carefully acidified with aqueous HCl to pH 3, and stirred
for 3 h. The yellow solid was filtered off and washed with
ethanol and petroleum ether. Yield 65%, yellow powder,
2
[47] and ShelXD [48] and was refined against F by the
full-matrix least-squares method in anisotropic approxi-
mation for non-hydrogen atoms using SHELXL [49].
Monoclinic crystal system, space group P2 /n, M 381.52;
1
unit cell parameters: a = 9.1298(2), b = 19.3640(3), c =
3
23.3341(4); β = 95.378(2)°; V = 4107.06(13) Å ; Z = 8;
–
1
3
–1
mp 218–220°C. IR spectrum, ν, cm : 3396, 3325, 3256,
dcalc = 1.234 g/cm ; μ(Cu K ) = 1.517 mm ; F(000) =
α
3
211 (N–H), 2951, 2924, 2866, 2852 (C–H), 1661 (C=O).
1632.0, 7.61 ≤ θ ≤ 136.498°; –10 ≤ h ≤ 9, –23 ≤ k ≤ 23,
–28 ≤ l ≤ 28. Total of 117 536 reflection intensities were
1
3
H NMR spectrum, δ, ppm: 0.88 t (3H, CH , J = 6.8 Hz),
3
1
.31–1.44 m [6H, (CH ) ], 2.63 s (3H, CH ), 2.67–2.71
measured, including 7284 independent reflections (R =
2
3
3
int
m (2H, CH ), 2.75 s (3H, CH ), 7.20–7.32 br.s (1H, NH,
0.1391, R = 0.0411) and 7284 reflections with I >
2
3
σ
partially H–D exchangeable); no SH and C(O)NH signals
were observed; presumably, because of H–D exchange.
2σ(I); number of variables 499; final divergence factors:
R = 0.0732, wR = 0.1906 for reflections with I > 2σ(I);
1
2
13
C NMR spectrum (DEPTQ), δ , ppm: 13.9 (CH ), 15.7
R = 0.0857, wR = 0.2041 for all independent reflections;
C
3
1 2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 8 2019

1584
BURYI et al.
2
goodness of fit 1.027 (with respect to F ); Δρmax/Δρmin
1
5
=
11. Eurtivong, C., Semenov, V., Semenova, M., Konyushkin, L.,
Atamanenko, O., Reynisson, J., and Kiselyov, A., Bioorg.
Med. Chem., 2017, vol. 25, no. 2, p. 658. doi 10.1016/j.
bmc.2016.11.041
–3
.09/–0.44 e Å . The X-ray diffraction data for compound
were deposited to the Cambridge Crystallographic Data
Centre (CCDC entry no. 1 900 583).
1
2. Krauze, A., Grinberga, S., Krasnova, L., Adlere, I., So-
kolova, E., Domracheva, I., Shestakova, I., Andzans, Z.,
and Duburs, G., Bioorg. Med. Chem., 2014, vol. 22,
p. 5860. doi 10.1016/j.bmc.2014.09.023
3. Wang, N.Y., Zuo, W.Q., Xu, Y., Gao, C., Zeng, X.X.,
Zhang, L.D., You, X.Y,, Peng, C.T., Shen, Y., Yang, S.Y.,
and Wei, Y.Q., Bioorg. Med. Chem. Lett., 2014, vol. 24,
no. 6, p. 1581. doi 10.1016/j.bmcl.2014.01.075
FUNDING
This study was performed under financial support
by the Ministry of Science and Higher Education of
the Russian Federation (project no. 4.5547.2017/8.9,
V.V. Dotsenko, I.V.Aksenova; project no. 4.1196.2017/4.6,
N.A.Aksenov). Biological studies were performed in the
framework of state assignment of the Ministry of Sci-
ence and Higher Education of the Russian Federation
1
1
1
1
4. Dotsenko, V.V., Krivokolysko, S.G., Krivokolysko, B.S.,
and Frolov, K.A., Russ. J. Gen. Chem., 2018, vol. 88,
no. 4, p. 682. doi 10.1134/S1070363218040114
(
project no. 075-00376-19-00) and research project
no. 0686-2019-0013.
5. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov, V.P.,
Mendeleev Commun., 2003, vol. 13, no. 6, p. 267. doi
CONFLICT OF INTERESTS
1
0.1070/MC2003v013n06ABEH001851
No conflict of interest was declared by the authors.
6. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov, V.P.,
Mendeleev Commun., 2004, vol. 14, no. 1, p. 30. doi
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