Reaction of ethyl 4-aryl-6-bromomethyl- 2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylates with n-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Article abstract of DOI:10.1007/s10593-012-1016-0

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6- tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4- tetrahydropyrimidine-5-carboxylates (10% KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6- tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylates in overall 30-58% yield. Under these conditions the N-methylmorpholinium 4-Ar¹-5-(N-Ar¹-carbamoyl)-3-cyano-6- methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar ¹-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3, 4-tetrahydropyrimidine-5-carboxylates (37-51%). In the absence of KOH, only the substituted pyridine-2(1H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.

Full text of DOI:10.1007/s10593-012-1016-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
REACTION OF ETHYL 4-ARYL-6-BROMOMETHYL-
2-OXO-1,2,3,4-TETRAHYDROPYRIMIDINE-5-CARBOXYLATES
WITH N-METHYLMORPHOLINIUM 3-CYANO-1,4-DIHYDRO-
AND 3-CYANO-1,4,5,6-TETRAHYDROPYRIDINE-2-THIOLATES
V. V. Dotsenko1*, I. A. Lebedeva2, S. G. Krivokolysko1, M. V. Povstyanoi2,
V. M. Povstyanoi2, and E. O. Kostyrko3
Alkylation of N-methylmorpholinium 4-Ar1-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using
ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10% KOH, DMF) gives
mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar1-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-
1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58% yield. Under these
conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar2-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-
2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar1-5-(N-Ar2-
carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
(37-51%). In the absence of KOH, only the substituted pyridine-2(1H)-thione is formed as a product of
oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained
possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and
Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.
Keywords: Biginelli dihydropyrimidines, N-methylmorpholinium 1,4-dihydropyridine-2-thiolates,
N-methylmorpholinium 1,4,5,6-tetrahydropyridine-2-thiolates, alkylation, biological activity, oxidation,
Thorpe-Ziegler reaction.
Over the last 20 years functionally substituted 3-cyanopyridine-2(1H)-thiones, tautomeric with 3-cyano-
2-mercaptopyridines, as well as their partially hydrogenated analogs have been recognised as promising and
reactive structural elements [1-5] thus opening up wide possibilities for constructing various fused heterocyclic
systems [6-9]. A large number of examples of pyridine-2-thiones and -thiolates reactions with 1,4-dielectro
philic alkylating agents have been reported and lead to derivatives of pyrido[3',2':4,5]thieno[3,2-d]pyrimidine,
_______
*To whom correspondence should be addressed, e-mail: Victor_Dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A/7 Molodyozhnyi Kv, Lugansk
91034, Ukraine.
2Kherson National Technical University, 24 Berislavsky Highway, Kherson 73008, Ukraine; e-mail:
ira_lebedeva2001@mail.ru.
3A. A. Bogomolets National Medical University, 13 T. Shevchenka Blvd., Kyiv 01601, Ukraine; e-mail:
lenakostirko@ukr.net.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 492-499, March, 2012. Original
article submitted February 21, 2011. Revision submitted November 28, 2011.
462
0009-3122/12/4803-0462©2012 Springer Science+Business Media, Inc.

pyrido[2',3':4,5]thieno[2,3-b]pyridine, and other polycondensed heterocyclic systems containing the thieno-
[2,3-b]pyridine structural fragment [6-8]. Our attention was drawn to the known Biginelli dihydropyrimidine
(DHPM) derivatives (namely, ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
1a-c) as 1,4-dielectrophilic agents which are readily prepared by bromination of the corresponding 6-methyl-
DHPM's using the Zigeuner method [10] (Scheme 1).
Scheme 1
Ar
Ar
N
O
O
NH
Br2, CHCl3
NH
EtO
Me
EtO
O
N
R
O
R
Br
1a–c
1 a R = Н, Ar = Ph; b R = Me, Ar = 4-MeOC6H4; c R = Me, Ar = 3-O2NC6H4
Continuing our study of the cyclocondensation reaction involving partially hydrogenated pyridine-
2-thiolates [11-17] we have now examined the reaction of the indicated alkylating agents 1a-c with the
N-methylmorpholinium 3-cyano-1,4-dihydropyridine-2-thiolates 2a,b and N-methylmorpholinium 3-cyano-
1,4,5,6-tetrahydropyridine-2-thiolates 3a-d (Scheme 2).
Scheme 2
Ar2
O
HN
Ar1
N
O
N
Ar1
S
Ar2
Me
10% KOH,
Me
N
4'
O
N1'
H
(from 2b)
NH
Me
DMF
DMF
S
N
H
Me
N
O
S
O
H
Me
+
N
NH
MeO
R
O
N1
OEt
4
O
N
H
5a,b
Ar
2a,b
4
Ar1
Ar1
N
N
OEt
O
EtOH, 
S
N
H
1'
O
Ar
NH
S
N
H
O
4
H
+ Me
N1
N
Me
O
O
3a–d
6a–d
2, 5 a Ar1 = Ar2 = Ph, b Ar1 = 5-methylfuran-2-yl, Ar2 = 2-MeOC6H4; 5 a R = Н, Ar = Ph;
b R = Me, Ar = 4-MeOC6H4; 3, 6 a Ar1 = Ph, b Ar1 = 2-EtOC6H4, c Ar1 = 2-furyl,
d Ar1 = 2,5-(MeO)2C6H3; 6 a–c Ar = 4-MeOC6H4, d Ar = 3-O2NC6H4
It was found that the result of the reaction of 1,4-dihydropyridine-2-thiolates 2a,b with 6-bromomethyl-
DHPM 1 depends on the reaction conditions. Hence attempts to alkylate the thiolate 2b with compounds 1b,c
under mild conditions in the absence of base led to oxidation of the dihydropyridine ring to form the N-aryl-
amide of the substituted pyridinecarboxylic acid 4 as the only reaction product isolated (yields 33% and 25%,
463

respectively). Reaction of thiolates 2a,b with 6-bromomethyl-DHPM 1a,b respectively in the presence of 1
equivalent of 10% KOH includes the stage of S-alkylation and also aromatization of the dihydropyridine
fragment to give compounds 5a,b (Scheme 2). Evidently the role of the KOH is to strengthen the
nucleophilicity of both the thiolates 2 and their potential intermediate oxidation products of type 4 and in result
in favoris the S-alkylation.
On the other hand, alkylation of the N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydro-
pyridine-2-thiolates 3a-c with compound 1b and also thiolate 3d with compound 1c occurs with retention of the
tetrahydropyridine system to give the expected substituted ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylates
6a-d respectively. In this case, the addition of 1 equivalent of 10% aqueous KOH does not significantly affect
the yields and reaction route. Both the alkylating agents 1 and the tetrahydropyridine-2-thiolates 3 are an equal
ratio mixture of (4R)- and (4S)-enantiomers hence their corresponding reaction products 6a-d are themselves a
1:1 mixture of two pairs of diastereomers (see Figure 1) according to the 1H NMR spectroscopic data.
We assumed that compounds 5 and 6 would be suitable subjects for a Thorpe-Ziegler type cascade
heterocyclization leading to the pyrido[3'',3'':4',5']thieno[2',3':5,6]pyrido[4,3-d]pyrimidines 7 (Scheme 3).
However, the action of 2 equivalents of 10% KOH or 2 equivalents of NaH in dry DMSO or DMF on sulfides 5
and 6 did not give the expected result. Treatment of the reaction mixture with water and acetic acid gave the
starting compounds.
Scheme 3
Ar1
Ar1
Ar1
KOH
or
NaH
N
R
NH2
H
OEt
Ar
O
N
N
O
CO2Et
NH
Ar
Ar
S
S
N
H
N
H
N
H
S
DMF
or
N
NH
N
NH
R
R
DMSO
O
O
7
O
Possibly the decisive factors in this case are the presence in the substrate molecule of NH- and CH-
acidic centers taking part in concurrent deprotonation reactions along with the SCH2 fragment together with
steric hindrances which prevent the cascade process initiation.
(4S)
(4R)
Ar1
Ar1
N
H
N
H
OEt
H
O
N
OEt
H
O
N
(4R)
Ar
(4S)
Ar
S
N
H
O
S
N
H
O
NH
NH
R
N
R
N
O
O
(4R)
(4S)
Ar1
Ar1
H
H
OEt
H
OEt
H
O
N
O
N
(4S)
Ar
(4R)
Ar
S
N
H
S
N
H
O
O
NH
NH
R
R
O
O
Fig. 1. Diastereomer pairs of compounds 6a-d.
464

TABLE 1. Results of the Antibacterial and Fungicidal Activity Assessment
of Compounds 5a, 6a,b,d
Diameter of inhibition zone, mm
Compound
E. coli
S. aureus
B. subtils
C. albicans
M-17
ATCC 25913
ATCC 6633
CCM 885
Clotrimazole
—
—
—
—
—
10
Nystatin
Azithromycin
Doxycycline
Streptomycin
Ciprofloxacin
5a
—
12
10
28
19
—
—
20
25
30
18
27
20
—
29
not sensitive
16
25
24
—
<10
<10
<10
<10
<10
10
not sensitive
<10
6a
15
10
not sensitive
not sensitive
6b
not sensitive
<10
6d
Compounds 5 and 6 are white or beige, finely crystalline powders which are insoluble in EtOH, poorly
soluble in acetone, and moderately soluble in DMSO and DMF. The signals of the H-4 and N(1)-H protons of
the 1,4-dihydropyridine system are absent in the 1H NMR spectra of compound 5.
Doubling of the set of virtually all of the 1H NMR signals for compounds 6 unambiguously points to the
formation of all four possible stereoisomers of these products in the course of the reaction (see Fig. 1).
The antimicrobial activity of the synthesized compounds 5a, 6a,b,d was studied in vitro towards the
cultures E. coli M-17, S. aureus ATCC 25913, B. subtilis ATCC 6633, and C. albicans CCM 885 using the
standard Kirby-Bauer disc diffusion method [18]. The fungicides clotrimazole and nystatin and antibacterials
azithromycin, doxycycline, streptomycin, and ciprofloxacin were used as reference standards. The results
obtained are given in Table 1.
From the data obtained, it was found that compounds 6a,b demonstrate a moderate antibacterial activity
towards the strains E. coli M-17 and B. subtilis ATCC 6633 but are inactive towards S. aureus. None of the
compounds tested showed clear fungicidal or fungistatic activity towards C. albicans.
EXPERIMENTAL
13
IR spectra were recorded on an IKS-29 spectrophotometer in nujol. The 1H and C NMR spectra were
recorded on a Bruker DRX-500 instrument (500 and 125 MHz respectively) using DMSO-d6 with TMS as
internal standard. The purity of the compounds prepared was monitored by TLC on Silufol UV-254 plates with
acetone–hexane(1:1) as eluent and were revealed using iodine vapor or UV radiation. Melting points were
determined on a Kofler hot bench and are not corrected. The starting N-methylmorpholinium thiolates 2a,b were
synthesized by the known general methods [19] and [20], respectively. The method of preparation and
spectroscopic parameters for the N-methylmorpholinium thiolates 3a,d have been reported in [12].
N-Methylmorpholinium (4RS)-3-Cyano-4-(2-ethoxyphenyl)-6-oxo- (3b) and (4RS)-3-Cyano-4-(2-
furyl)-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate (3c) (General Method). N-Methylmorpholine (10-15 drops)
was added with stirring to a mixture of 2-ethoxybenzaldehyde (14.0 ml, 0.10 mol) or furfural (8.3 ml, 0.10 mol),
cyanothioacetamide (10.0 g, 0.10 mol), and EtOH (150 ml). The reaction mixture was stirred for 1 h at 20ºC and
2,2-dimethyl-1,3-dioxane-4,6-dione (15 g, 0.10 mol) and N-methylmorpholine (16.5 ml, 0.15 mol) were added
to it. Stirring the solution obtained for 5-10 min gave a white precipitate of the Michael adduct, namely
N-methylmorpholinium 5-[3-amino-2-cyano-1-(2-ethoxyphenyl)-3-thioxopropyl]- or 5-[3-amino-2-cyano-1-(2-
furyl)-3-thioxopropyl]-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olate, respectively. The suspension obtained was
refluxed to full dissolution of the adduct and until evolution of CO2 ceased (1-3 h). The solution was evaporated
465

to a syrupy consistency and treated with acetone. The crystalline precipitate of product 3b,c formed upon
cooling and stirring was filtered off, washed with cold EtOH and then acetone, and used without further
purification.
Compound 3b. Yield 80%. Yellow-orange, finely crystalline powder, mp 140-145ºC (decomp.). IR
1
spectrum, , cm-1: 3140 (NH), 2180 (CN), 1670 (C=O). H NMR spectrum, , ppm (J, Hz): 9.62 (<1H*, br. s,
+NH); 8.67 (1H, br. s, NH); 7.19 (1H, dd, 3J = 7.5, 3J = 8.0, Н-4 Ar1); 7.05 (1H, br. d, 3J = 7.5, Н-6 Ar1); 6.95 (1H,
br. d, 3J = 8.0, H-3 Ar1); 6.87 (1H, dd, 3J = 7.5, 3J = 7.5, Н-5 Ar1); 4.06 (2Н, q, 3J = 7.0, СH2СН3); 3.93 (1H, dd,
3Jcis = 2.5, 3Jtrans = 7.8, H-4); 3.83-3.73 (4H, m, СН2ОСН2); 3.18-3.13 (4H, m, СН2N+CH2); 2.78 (3H, s, +NCH3);
2.71 (1H, dd, 2J = 16.1, 3Jtrans = 7.8, trans-H-5); 2.33 (1H, dd, 2J = 16.1, 3Jcis = 2.5, cis-H-5); 1.36 (3H, t, 3J = 7.0,
CH2CH3). Found, %: C 60.70; H 6.75; N 11.34. C19H25N3O3S. Calculated, %: C 60.78; H 6.71; N 11.19.
Compound 3c. Yield 55%. Light-brown crystals, mp 145-150ºC (decomp.). IR spectrum, , cm-1: 3170
1
(NH), 2189 (CN), 1695 (C=O). H NMR spectrum, , ppm (J, Hz): 9.70 (<1H*, br. s, N+H); 8.63 (1H, br. s,
NH); 7.54-7.52 (1H, m, H-5 Ar1); 6.35-6.33 (1H, m, H-4 Ar1); 5.98-6.01 (1H, m, H-3 Ar1); 3.85-3.70 (4H, m,
3
3
CH2OCH2); 3.66 (1H, pseudo-t, Jcis = 2.3, Jtrans = 7.5, H-4); 3.10-3.30 (4H, m, CH2N+CH2); 2.80 (3H, s,
N+CH3); 2.69 (1H, dd, 2J = 16.3, 3Jtrans = 7.5, trans-H-5); 2.44 (1H, dd, 2J = 16.3, 3Jcis = 2.3, cis-H-5). Found, %:
C 56.25; H 6.00; N 13.34. C15H19N3O3S. Calculated, %: C 56.06; H 5.96; N 13.07.
Reaction of Esters 1b,c with N-Methylmorpholinium Thiolate 2b in the Absence of KOH. A
mixture of thiolate 2b (300 mg, 0.063 mmol) and ester 1b,c (0.070 mmol) was heated in DMF (1.5 ml) to the
formation of a light-red solution which was held at 20ºC for two weeks. The precipitated crystals were filtered
off and washed with EtOH and petroleum ether to give in the case of ester 1b 77 mg (33%) and in the case of
ester 1c 59 mg (25%) of the [5-cyano-2-methyl-4-(5-methylfuran-2-yl)-6-thioxo-1,6-dihydropyridine-3]-[N-(2-
methoxyphenyl)]carboxamide 4. Beige crystals of globular form, mp 240-243ºC (decomp.) (mp 262-264ºC
1
[21]). IR spectrum, , cm-1: 3315 (NH), 2220 (C≡N), 1665 (C=O). H NMR spectrum, , ppm (J, Hz): 10.02
3
3
3
(1H, br. s, CONH); 7.89 1H, d, J = 7.5, H-6 Ar); 7.24 (1H, d, J = 2.5, H-3 Fur); 7.18 (1H, dd, J = 7.5,
3J = 8.5, H-4 Ar); 7.08 (1H, br. d, 3J = 8.5, H-3 Ar); 6.99 (1H, dd, 3J = 7.5, 3J = 7.5, H-5 Ar); 6.44-6.40 (1H, m,
H-4 Fur); 3.77 (3H, s, OCH3); 2.55 (3H, s) and 2.25 (3H, s, 2CH3). The signal for the endocyclic NH group is
not seen, evidently as a result of deuterium exchange. Found, %: C 63.06; H 4.55; N 11.24. C20H17N3O3S.
Calculated, %: C 63.31; H 4.52; N 11.07.
Reaction of Esters 1a,b with Thiolates 2a,b in the Presence of KOH (General Method). 10% KOH
(0.4 ml, 0.078 mmol) was added to a suspension of the thiolate 2a (0.065 mmol) in DMF (1.5 ml) and the
solution obtained was passed through a plaited filter into a solution of ester 1a (0.070 mmol) in DMF (1.0 ml).
The reaction mixture was held for 1-2 days at 20ºC, diluted with EtOH (5 ml), held for a further day, and the
precipitate was filtered off to give the product 5a in an analytically pure state. Thiolate 2b and ester 1b gave the
product 5b similarly.
Ethyl 6-[(3-Cyano-6-methyl-4-phenyl-5-phenylcarbamoylpyridin-2-ylthio)methyl]-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5a). Yield 37%. White finely crystalline powder, mp 185-187ºC. Rf
0.63 (acetone–hexane, 1:1). IR spectrum, , cm-1: 3345 (3NH), 2225 (C≡N), 1722 (COOEt), 1696, 1660
1
(2CONH), 1645 (C=C). H NMR spectrum, , ppm (J, Hz): 10.39 (1Н, br. s, CONHPh); 9.20 (1Н, s, 1-NH);
2
2
7.88 (1Н, br. s, 3-NH); 7.48-7.07 (15Н, m, H Ph); 5.21 (1Н, br. s, H-4); 4.68 (2Н, dd, J = 13.2, J = 13.2,
3
3
SСН2); 4.07 (2Н, q, J = 6.4, СH2CH3); 2.63 (3Н, s, 6'-СН3); 1.13 (3Н, t, J = 6.4, СН2CH3). Found, %:
C 67.96; H 4.82; N 11.73. C34H29N5O4S. Calculated, %: C 67.65; H 4.84; N 11.60
Ethyl 6-{[3-Cyano-6-methyl-5-(2-methoxyphenyl)carbamoyl-4-(5-methyl-furan-2-yl)pyridin-2-ylthio]-
methyl}-4-(4-methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5b). Yield
51%. Sandy colored crystals, mp 183-185ºC (decomp.). Rf 0.63 (acetone–hexane, 1:1). IR spectrum, , cm-1:
3270 (3NH), 2220 (C≡N), 1707 (COOEt), 1685, 1662 (2CONH), 1625 (C=C). 1H NMR spectrum, , ppm (J, Hz):
9.94 (1Н, br. s, CONHAr2); 8.07 (1Н, d, 3J = 3.9, 3-NH); 7.93 (1H, br. d, 3J = 7.1, H Ar2); 7.21-7.16 (4Н, m, 2H
______
* Integrated intensity of the signal lowered due to partial deuterium exchange.
466

Ar, H-3 Ar1, H Ar2); 7.16 (1H, d, 3J = 7.4, H Ar2); 7.09 (1H, dd, 3J = 7.8, 3J = 7.1, H Ar2); 6.92 (2H, d, 3J = 8.8,
3
3
2
H Ar); 6.39 (1H, d, J = 2.5, H-4 Ar1); 5.16 (1H, d, J = 3.9, H-4); 5.07 (1Н, d, J = 12.0) and 4.88 (1Н, d,
2J = 12.0, SСН2); 4.10 (2Н, q, 3J = 7.0, СH2CH3); 3.78 (3H, s, ОСН3); 3.74 (3H, s, ОСН3); 3.22 (3Н, s, 1-CH3);
2.60 (3H, s, 6'-CH3); 2.23 (3H, s, 5-CH3 Ar1); 1.16 (3Н, t, J = 7.0, СН2CH3). Found, %: C 63.26; H 5.20;
3
N 10.43. C36H35N5O7S. Calculated, %: C 63.42; H 5.17; N 10.27.
Reaction of Esters 1b,c with Thiolates 3a-d (General Method). A mixture of thiolate 3a-c
(2.0 mmol), ester 1b (2.1 mmol), and 90% EtOH (15 ml) was refluxed with stirring for 3-4 min, passed hot
through a plaited filter, and left for 10-12 days at room temperature. The precipitate was filtered off, washed
with EtOH, water, EtOH, and petroleum ether to give the products 6a-c in an analytically pure state. Thiolate 3d
and ester 1c gave the product 6d.
Ethyl
4-(4-Methoxyphenyl)-1-methyl-2-oxo-6-[(3-cyano-6-oxo-4-phenyl-1,4,5,6-tetrahydropyridin-
2-ylthio)-methyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6a). Yield 57%. White finely crystalline
powder, mMp 146-148ºC. Rf 0.50 (acetone–hexane, 1:1). IR spectrum, , cm-1: 3230 (NH), 2213 (C≡N), 1710
(COOEt), 1683 (2CONH), 1630 (C=C). 1H NMR spectrum, , ppm (J, Hz): 10.80 (0.5Н, br. s) and 10.74 (0.5Н,
br. s, 1'-NH); 7.98 (0.5Н, br. d, 3J = 3.2) and 7.93 (0.5Н, br. d, 3J = 3.2, 3-NН); 7.41-6.87 (9Н, m, Н Ph, H Ar);
3
3
5.17 (0.5Н, br. d, J = 3.2) and 5.15 (0.5Н, br. d, J = 4.2, H-4); 4.90-4.35 (2Н, m, SСН2); 4.01-3.90 (3H, m,
ОСH2CH3, H-4'); 3.74 (1.5Н, s) and 3.72 (1.5Н, s, ОСН3); 3.21 (1.5Н, s) and 3.19 (1.5Н s, 1-СН3); 2.84 (1Н,
3
2
3
2
3
dd, J = 7.3, J = 16.3, trans-H-5'); 2.59 (1Н, dd, J = 5.6, J = 16.3, cis-H-5') 1.12 (3Н, br t, J = 6.9,
2ОСН2CH3). Found, %: C 63.46; H 5.34; N 10.73. C28H28N4O5S. Calculated, %: C 63.14; H 5.30; N 10.52.
Ethyl 6-{[3-Cyano-4-(2-ethoxyphenyl)-6-oxo-1,4,5,6-tetra-hydropyridin-2-ylthio]methyl}-4-(4-meth-
oxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6b). Yield 51%. White finely
crystalline powder, mp 154-156ºC. Rf 0.53 (acetone–hexane, 1:1). IR spectrum, , cm-1: 3180 (NH), 2211
(C≡N), 1710 (COOEt), 1695 (CONH), 1610 (C=C). 1H NMR spectrum, , ppm (J, Hz): 10.75 (0.5Н, br. s) and
3
10.70 (0.5Н, br. s, 1'-NH); 8.00 (0.5Н, br. d, J = 2.5) and 7.92 (0.5Н, br. pseudo-s, 3-NH); 7.28-6.87 (8H, m,
H Ar); 5.18 (0.5Н, br. d, 3J = 2.4) and 5.08 (0.5Н, br. d, 3J = 2.0, H-4); 4.89-4.37 (2Н, m, SСН2); 4.18-3.97 (5H,
m, COОСH2CH3, Н-4', OCH2CH3 Ar); 3.74 (1.5Н, s) and 3.72 (1.5Н, s, OСН3); 3.25 (1.5Н, s) and 3.19 (1.5Н,
3
2
s, 1-СН3); 2.82 (1Н, dd, J = 7.8, J = 16.6, trans-H-5'); 2.55 (1Н, m, cis-H-5'); 1.34 (3Н, m, ОСН2CH3 Ar);
1.13 (3Н, m, COОСН2CH3). 13C NMR spectrum, , ppm: 168.9; 165.7; 159.2; 156.3; 153.4; 147.9; 145.6;
136.0; 129.5; 128.1; 127.9; 127.7; 127.5; 127.3; 120.9; 118.2; 118.0; 114.4; 114.3; 112.7; 106.3; 95.9; 95.7;
64.0; 60.7; 55.6; 55.5; 52.8; 52.6; 44.1; 36.2; 36.0; 35.5; 35.4; 30.5; 30.0; 14.9; 14.8; 14.4. Found, %: C 62.17;
H 5.61; N 9.88. C30H32N4O6S. Calculated, %: C 62.48; H 5.59; N 9.72.
Ethyl 6-{[3-Cyano-4-(2-furyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-ylthio]methyl}-4-(4-methoxyphenyl)-
1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6c). Yield 30%. Beige powder, mp 175-177ºC.
Rf 0.47 (acetone–hexane, 1:1). IR spectrum, , cm-1: 3230, 3120 (NH), 2204 (C≡N), 1715 (COOEt), 1695
(CONH), 1615 (C=C). 1H NMR spectrum, , ppm (J, Hz): 10.78 (1H, br. s, 1'-NH); 7.98 (0.5H, br. s) and 7.93
3
3
(0.5H, br. s, 3-NH); 7.64-7.62 (1H, m, H-5 Fur); 7.20 (1H, d, J = 8.3, H Ar); 7.15 (1H, d, J = 8.3, H Ar);
6.90-6.87 (2H, m, H Ar); 6.42-6.40 (1H, m, H-4 Fur); 6.21-6.19 (1Н, m, H-3 Fur); 5.17-5.15 (0.5Н, m) and
5.08-5.06 (0.5Н, m, H-4); 4.88-4.30 (2Н, m, SСН2); 4.13-3.99 (3H, m, ОСH2CH3, H-4'); 3.73 (1.5Н, s) and 3.72
(1.5Н, s, ОСН3); 3.18 (1.5Н, s) and 3.16 (1.5Н, s, 1-СН3); 2.84-2.82 (1Н, m) and 2.66-2.64 (1Н, m, 5'-CH2);
1.14-1.11 (3Н, m, ОCH2CH3). 13C NMR spectrum, , ppm: 168.5; 165.6; 159.2; 153.4; 152.5; 148.0; 146.4;
143.6; 136.5; 135.9; 128.0; 127.8; 118.0; 114.4; 114.3; 111.0; 106.9; 106.1; 93.7; 93.6; 60.6; 55.6; 52.6; 44.1;
35.0; 34.6; 34.0; 30.4; 30.2; 30.0; 14.3. Found, %: C 60.04; H 5.05; N 10.89. C26H26N4O6S. Calculated, %:
C 59.76; H 5.01; N 10.72.
Ethyl 6-{[3-Cyano-4-(2,5-dimethoxyphenyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-ylthio]methyl}-
1-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6d). Yield 58%. White
finely crystalline powder, mp 174-176ºC (EtOH). IR spectrum, , cm-1: 3220 (NH), 2209 (C≡N), 1715
(COOEt), 1685 (2CONH), 1615 (C=C). 1H NMR spectrum, , ppm (J, Hz): 10.78 (0.5Н, br. s) and 10.76 (0.5Н,
3
br. s, 1'-NH); 8.25-8.14 (3Н, m, 3-NH, Н Ar); 7.76-7.64 (2Н, m, Н Ar); 6.98 (0.5Н, br. d, J = 8.8) and 6.96
467

(0.5Н, br. d, 3J = 8.8, H Ar); 6.85-6.87 (1Н, m, H Ar); 6.57-6.60 (1Н, m, H Ar); 5.41 (0.5Н, br. d, 3J = 3.4) and
3
3
3
5.36 (0.5Н, br. d, J = 3.4, H-4); 4.94-4.37 (2Н, m, SСН2); 4.14 (1Н, pseudo-t, J = 5.3, J = 7.6, H-4');
4.06-4.00 (2H, m, ОCH2CH3); 3.73 (1.5Н, s), 3.72 (1.5Н, s), 3.70 (1.5Н, s), and 3.68 (1.5Н, s, 2OCH3); 3.23
3
2
3
(1.5Н, s) and 3.20 (1.5Н, s, 1-СН3); 2.75 (1Н, dd, J = 7.6, J = 16.4, trans-H-5'); 2.56 (1Н, dd, J = 5.3,
2J = 16.4, cis-H-5'); 1.14 (3Н, m, ОСH2CH3). Found, %: C 57.54; H 4.82; N 11.69. C29H29N5O8S. Calculated,
%: C 57.32; H 4.81; N 11.53.
Study of the Biological Activity of Compounds 5a, 6a,b,d. Standard sterile filter paper discs were
impregnated with solutions of the test samples in DMF at a concentration of 1.0 mg/ml (about 10 μg of the test
compound per disc). A standard Mueller-Hinton culture medium was poured into a Petri dishes to a layer
thickness of 4.0±0.5 mm, held to setting of the agar at room temperature, and dried before inoculation for 10-20
min at 35-37ºC. A standard 0.5 McF McFarland inoculum (1-2 ml) prepared directly before the experiment was
introduced by pipette onto the dried culture medium and spread uniformly along the surface over 10-15 min.
Sterile tweezers were used to place the paper discs with the test samples on the surface and incubated for 18-24
h at 35-37ºC. At the completion of the incubation period the diameter of the growth inhibition zone was
measured (in mm). A disc impregnated with pure DMF did not give a zone of growth inhibition. The results of
the experiments are given in Table 1.
The authors thank the Ukraine Ministry of Education and Science, Youth and Sport for financial
support (grant 0111U001128).
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