Synthesis of 10-alkylsulfanyl-substituted pyrido-[4’,3’:4,5]thieno[3,2-d]pyrimidines annulated with pyran, cyclohexane, and cyclopentane rings

Article abstract of DOI:10.1007/s10593-016-1887-6

(Formula Presented) We propose a single-step procedure for the synthesis of 8-oxo-10-sulfanylpyrido[4’,3’:4,5]thieno[3,2-d]pyrimidines, annulated with pyran, cyclohexane, or cyclopentane rings. The alkylation of these compounds in aqueous DMF solution of KOH at room temperature was shown to proceed regioselectively and led to the formation of S-substituted products. Amino-and alkoxy-substituted derivatives of tetracyclic thieno[3,2-d]pyrimidines were synthesized. The antimicrobial activity of the obtained compounds was studied on Grampositive staphylococci and Gram-negative rods.

Full text of DOI:10.1007/s10593-016-1887-6

DOI 10.1007/s10593-016-1887-6
Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
Synthesis of 10-alkylsulfanyl-substituted pyrido-
[4',3':4,5]thieno[3,2-d]pyrimidines annulated with
pyran, cyclohexane, and cyclopentane rings
Ervand G. Paronikyan1, Shushanik Sh. Dashyan1*, Nune S. Minasyan2,
Grachya M. Stepanyan1, Evgene V. Babaev3
1
A. L. Mndzoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic
and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
26 Azatutyan Ave., Yerevan 0014, Armenia; e-mail: shdashyan@gmail.com
2
Molecular Structure Research Center, Scientific Technological Center of Organic
and Pharmaceutical Chemistry, National Academy of Sciences of Armenia, 26 Azatutyan Ave., Yerevan 0014, Armenia; e-mail:
nunemin@gmail.com
Moscow M. V. Lomonosov State University, 1 Leninskie Gory, Moscow 119991, Russia;
e-mail: babaev@org.chem.msu.ru
3
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(5), 337–345
Submitted March 3, 2016
Accepted after revision April 29, 2016
We propose a single-step procedure for the synthesis of 8-oxo-10-sulfanylpyrido[4',3':4,5]thieno[3,2-d]pyrimidines, annulated with
pyran, cyclohexane, or cyclopentane rings. The alkylation of these compounds in aqueous DMF solution of KOH at room temperature
was shown to proceed regioselectively and led to the formation of S-substituted products. Amino- and alkoxy-substituted derivatives of
tetracyclic thieno[3,2-d]pyrimidines were synthesized. The antimicrobial activity of the obtained compounds was studied on Gram-
positive staphylococci and Gram-negative rods.
Keywords: 10-alkylsulfanyl-8-oxothieno[3,2-d]pyrimidines, carbon disulfide, functionalized pyrimidines, antimicrobial activity,
regioselectivity.
The pyrimidine ring is a part of many natural and
synthetic compounds, while pyridine derivatives and
condensed systems containing pyridine rings have anti-
inflammatory, analgesic, and antibacterial properties.1–4
The preparation of tricyclic pyrido[4',3':4,5]thieno[3,2-d]-
pyrimidines from 3-amino-2-cyano(ethoxycarbonyl)thieno-
[2,3-b]pyridines has been described in the literature, and
these compounds show antitumor, antiviral, and anti-
microbial effects.5–12 The biological importance of condensed
pyrimidine derivatives has motivated significant interest
towards the synthesis of new pyrido[4',3':4,5]thieno[3,2-d]-
pyrimidine derivatives annulated with pyran, cyclohexane,
and cyclopentane rings.
methods for preparing derivatives of the respective
heterocycles. Previously we have reported a two-stage
method for the synthesis of 8-oxo-10-thioxothieno[3,2-d]-
pyrimidines 4a–e: in reactions of 1-amino-2-ethoxycarbonyl-
thieno[2,3-b]pyridines 1a–e with benzoylisothiocyanate,
involving the formation of N,N'-disubstituted thioureas 2a–e
as intermediates, which were subsequently cyclized in the
presence of alkali.13 We also described a more efficient one-
step procedure14 for the synthesis of compounds 4b,d by a
reaction of 1-amino-2-carbamoylthieno[2,3-b]pyridines 3b,d
with carbon disulfide in the presence of pyridine. In that case,
potassium hydroxide solution in ethanol was selected as
base for the synthesis of compounds 4а–е from aminoamides
3а–е,15 allowing to increase the yields of target products to
90–95% (Scheme 1).
In this work, we continued the synthetic studies of functio-
nalized tetracyclic thieno[3,2-d]pyrimidines by focusing on the
0009-3122/16/52(5)-0337©2016 Springer Science+Business Media New York
337

Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
Scheme 1
Scheme 2
We found that alkylation of 8-oxo-10-thioxothieno[3,2-d]-
appropriate alcohol gave the 8-alkoxy derivatives 8a–f
(Scheme 3). The signals of NH group in 1H NMR spectra of
compounds 7a,c,d,f,h were observed in the range of 7.30–
8.09 ppm, while the signals of OCH3, OCH2, and OCH
groups in spectra of compounds 8a–f were observed in the
range of 4.16–5.61 ppm.
The antimicrobial activity of compounds 5a–j, 7a–k, and
8a–f was studied by the agar diffusion assay.19 Experiments
were performed with Gram-positive staphylococci (Sta-
phylococcus aureus 209P, JC-1) and Gram-negative rods
(Shigella dysenteriae flexneri 6858, Escherichia coli 0-55).
The studies showed that compounds 5b,h, 7а,d,e,h, and
8c,d,f had weak activity against all tested microbial strains:
the diameters d of growth inhibition zones were 10–15 mm
(Table 1). The indicated compounds were significantly less
active than the reference drug furazolidone (d 24–25 mm).20
Thus, as a result of our studies, an efficient method has
been developed for the preparation of 8-oxo-10-sulfanyl-
pyrido[4',3':4,5]thieno[3,2-d]pyrimidines annulated with
saturated rings, and 90–95% yields were achieved.
pyrimidines 4а–е in aqueous DMF solution of KOH at 20–
22°С occurred regioselectively with the formation of
S-alkyl derivatives 5a–j. The regioselectivity of this
reaction was explained by the greater polarizability of
sulfur atom, compared to the nitrogen and oxygen atoms.16
The signals of S-methyl and S-methylene group protons
1
were observed in H NMR spectra of compounds 5a–j at
the ranges of 2.60–2.62 and 3.22–4.90 ppm, respectively,
while 13C NMR signals of these groups were at 13.0–
13.5 ppm (compounds 5а,f,g,j) and 31.1–38.5 ppm (com-
pounds 5b–e,h,i), confirming the formation of S-alkylated
products.17
The treatment of S-alkyl derivatives 5а,b,f,i,j with
phosphorus oxychloride further gave 10-alkylsulfanyl-
8-chlorothieno[3,2-d]pyrimidines 6a,c–f (Scheme 2). The
preparation of compound 6b was described previously.18
The reactions of compounds 6a–f with amines provided
5,8-diamino-substituted 10-alkylsulfanylthieno[3,2-d]pyrimi-
dines 7a–k, while treatment with sodium alkoxide in the
Scheme 3
338

Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
Table 1. The antimicrobial activity of compounds 5b,h, 7а,d,e,h,
δ, ppm: 1.35 (6H, s, 2CH3); 1.92–2.00 (4H, m, 3,4-CH2 pyrro-
lidine); 3.28 (2H, s, 1-CH2); 3.57–3.65 (4H, m, N(CH2)2
pyrrolidine); 4.75 (2H, s, 4-CH2); 11.04 (1H, br. s, NH);
12.44 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 25.0
(3,4-CH2 pyrrolidine); 26.1 (2CH3); 35.9 (1-CH2); 49.5
(2,5-CH2 pyrrolidine); 59.9 (4-CH2); 68.6 (C-2); 108.9;
112.5; 114.2; 140.0; 140.1; 156.0; 156.1; 160.2 (C-8);
174.6 (C-10). Found, %: С 55.72; Н 5.25; N 14.48;
S 16.47. C18H20N4O2S2. Calculated, %: С 55.65; Н 5.19;
N 14.42; S 16.51.
2,2-Dimethyl-5-(morpholin-4-yl)-10-thioxo-1,4,10,11-
tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-8(9H)-one (4b). Yield 3.84 g
(95%), light-yellow crystals, mp > 360°С. 1H NMR
spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 3.18–3.27 (4H, m,
N(CH2)2 morpholine); 3.37 (2H, s, 1-CH2); 3.72–3.81 (4H,
m, О(CH2)2 morpholine); 4.64 (2H, s, 4-CH2); 11.25 (1H,
br. s, NH); 12.59 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
26.1 (2CH3); 35.8 (1-CH2); 49.5 (3,5-CH2 morpholine);
59.2 (4-CH2); 66.0 (2,6-CH2 morpholine); 69.5 (C-2);
108.4; 113.5; 118.9; 140.7; 143.3; 156.9; 157.2; 159.4
(C-8); 175.6 (C-10). Found, %: С 53.52; Н 4.93; N 13.97;
S 15.72. C18H20N4O3S2. Calculated, %: С 53.45; Н 4.98;
N 13.85; S 15.85.
5-(Pyrrolidin-1-yl)-10-thioxo-1,2,3,4,10,11-hexahydro-
pyrimido[4',5':4,5]thieno[2,3-c]isoquinolin-8(9H)-one (4c).
Yield 3.26 g (91%), yellow crystals, mp > 360°С. 1H NMR
spectrum, δ, ppm (J, Hz): 1.66–1.77 (2H, m, 2-CH2); 1.86–
2.00 (6H, m, 3-CH2, 3,4-CH2 pyrrolidine); 2.71 (2H, br. t,
J = 5.8, 4-CH2); 3.35 (2H, br. t, J = 6.3, 1-CH2); 3.58–3.65
(4H, m, N(CH2)2 pyrrolidine); 10.48 (1H, br. s, NH); 12.43
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 20.9 (2-CH2);
22.0 (3-CH2); 25.2 (3,4-CH2 pyrrolidine); 26.0 (4-CH2);
27.1 (1-CH2); 49.8 (2,5-CH2 pyrrolidine); 108.3; 113.0;
117.7; 140.3; 143.1; 156.3; 159.4; 159.5 (C-8); 174.3 (C-10).
Found, %: С.88; Н 5.12; N 15.72; S 17.76. C17H18N4OS2.
Calculated, %: С 56.96; Н 5.06; N 15.63; S 17.89.
8c,d,f and furazolidone (diameter of growth inhibition zone, mm)
S. aureus
Com-
pound
S. dysenteriae
E. coli 0-55
flexneri 6858
209p
11
10
12
13
10
12
13
14
10
25
1
10
11
14
12
12
11
10
11
13
24
11
14
13
13
13
10
15
14
11
24
13
10
12
15
14
15
14
15
14
24
5b
5h
7a
7d
7e
7h
8c
8d
8f
Furazolidone
Reaction conditions were found for alkylation of the latter
compounds with various alkyl halides, enabling good
regioselectivity. Functionalized derivatives of condensed
pyrido[4',3':4,5]thieno[3,2-d]pyrimidines were synthesized
and biological activity of the obtained compounds was
evaluated, allowing to identify compounds with anti-
microbial effects on the bacterial strains Staphylococcus
aureus 209p, JC-1, Shigella dysenteriae flexneri 6858, and
Escherichia coli 0-55, opening possibilities for further search
of potential antimicrobial agents among this type of
compounds.
Experimental
IR spectra were recorded for Nujol mulls on a Nicolet
1
Avatar 330 FT-IR spectrometer. Н and 13С NMR spectra
were acquired on a Varian Mercury Vx 300 instrument
(300 and 75 MHz, respectively) in DMSO-d6, with TMS as
1
internal standard. The assignment of H and 13C NMR
signals was supported by DEPT, NOESY, and HMQC data
when needed (mixing time 1 s). Elemental analysis of the
C, Н, N, and S content was performed on a Euro EA 3000
Elemental Analyzer. The content of chlorine was
determined by the classic Pregl procedure. Melting points
were determined on a Boetius micro hot stage. The
aminoamides 3а–е were synthesized according to a
previously published procedure.15
Preparation of compounds 4a–e (General method).
Compound 3а–е (10 mmol) and carbon disulfide (20 ml,
0.33 mol) were added to a solution of KOH (1.68 g, 30 mmol)
in EtOH (50 ml). The mixture was refluxed on a water bath
at 60–70°С for 24 h. The solution was cooled, the excess of
carbon disulfide was removed by distillation and the
residue was acidified with dilute acetic acid solution. The
obtained precipitate was filtered off, washed with water,
and recrystallized from DMSO.
5-(Morpholin-4-yl)-10-thioxo-1,2,3,4,10,11-hexahydro-
pyrimido[4',5':4,5]thieno[2,3-c]isoquinolin-8(9H)-one
(4d). Yield 3.41 g (91%), white crystals, mp 313–315°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.68–1.79 (2H, m,
2-CH2); 1.87–2.00 (2H, m, 3-CH2); 2.68 (2H, br. t, J = 5.9,
4-CH2); 3.21–3.32 (4H, m, N(CH2)2 morpholine); 3.45
(2H, br. t, J = 6.7, 1-CH2); 3.72–3.81 (4H, m, О(CH2)2
morpholine); 10.70 (1H, br. s, NH); 12.59 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 21.4 (2-CH2); 22.0 (3-CH2);
26.2 (4-CH2); 26.8 (1-CH2); 49.8 (3,5-CH2 morpholine); 66.2
(2,6-CH2 morpholine); 108.3; 113.1; 118.1; 141.3; 145.1;
154.3; 157.8; 159.2 (C-8); 174.8 (C-10). Found, %: С.61;
Н 4.90; N 14.88; S 17.21. C17H18N4O2S2. Calculated, %:
С 54.52; Н 4.84; N 14.96; S 17.13.
4-(Morpholin-4-yl)-9-thioxo-2,3,9,10-tetrahydro-1H-
cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-
7-(8H)-one (4e). Yield 3.24 g (90%), gray crystals, mp >
360°С. 1H NMR spectrum, δ, ppm (J, Hz): 2.08–2.20 (2H, m,
2-CH2); 2.95 (2H, t, J = 7.2, 3-CH2); 3.43 (2H, t, J = 7.3,
1-CH2); 3.51–3.57 (4H, m, N(CH2)2 morpholine); 3.71–
3.77 (4H, m, О(CH2)2 morpholine); 11.49 (1H, br. s, NH).
12.43 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 25.2
2,2-Dimethyl-5-(pyrrolidin-1-yl)-10-thioxo-1,4,10,11-tetra-
hydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-
[3,2-d]pyrimidin-8(9H)-one (4a). Yield 5.41 g (92%),
light-yellow crystals, mp > 360°С. IR spectrum, ν, cm–1:
1
1260 (C=S), 1668 (CO), 3427 (2NH). H NMR spectrum,
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Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
(2-CH2); 29.2 (3-CH2); 34.1 (1-CH2); 47.9 (3,5-CH2
Found, %: С 57.46; Н 6.17; N 12.04; S 13.81.
C22H28N4O3S2. Calculated, %: С 57.37; Н 6.13; N 12.16;
S 13.92.
morpholine); 66.3 (2,6-CH2 morpholine); 108.6; 112.1;
115.2; 139.8; 140.0; 156.1; 156.3; 159.6 (C-7); 178.4
(C-9). Found, %: С 53.40; Н 4.53; N 15.46; S 17.68.
C16H16N4O2S2. Calculated, %: С 53.31; Н 4.47; N 15.54;
S 17.79.
2-{[2,2-Dimethyl-5-(morpholin-4-yl)-8-oxo-1,4,8,9-tetra-
hydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-
[3,2-d]pyrimidin-10-yl]sulfanyl}-N-phenylacetamide (5d).
Yield 2.58 g (96%), light-yellow crystals, mp > 360°С.
1H NMR spectrum, δ, ppm: 1.13 (6H, s, 2CH3); 3.12–3.20
(4H, m, N(CH2)2 morpholine); 3.67–3.76 (4H, m, О(CH2)2
morpholine); 3.31 (2H, s, 1-CH2); 4.23 (2H, s, SCH2); 4.60
(2H, s, 4-CH2); 6.99–7.06 (1H, m, H Ph); 7.24–7.32 (2H,
m, H Ph); 7.52–7.58 (2H, m, H Ph); 10.19 (1H, br. s, NH);
13.14 (1H, br. s, 9-NH). 13C NMR spectrum, δ, ppm: 26.5
(2CH3); 36.8 (SCH2); 38.7 (1-CH2); 49.8 (3,5-CH2
morpholine); 59.0 (4-CH2); 66.0 (2,6-CH2 morpholine);
69.5 (C-2); 119.1 (C-3,5 Ph); 119.5; 119.8; 123.3 (C-4 Ph);
128.7 (C-2,6 Ph); 138.8 (C-1 Ph); 138.9; 143.1; 152.0;
157.7; 158.8; 158.9 (C-8); 159.1 (C-10); 164.8 (CH2CO).
Found, %: С 58.16; Н 5.10; N 13.15; S 12.10.
C26H27N5O4S2. Calculated, %: С 58.08; Н 5.06; N 13.03;
S 11.93.
Preparation of compounds 5a–j (General method).
DMF (25 ml) and compound 4а–e (5 mmol) were added to
a solution of KOH (0.28 g, 5 mmol) in water (2.5 ml). The
mixture was treated by dropwise addition of the appropriate
alkyl halide (5 mmol) solution in ethanol (15 ml). The
mixture was stirred for 5 h at room temperature. The
obtained crystals were filtered off and recrystallized from
2:1 mixture of EtOH and DMF.
2,2-Dimethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-
1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido-[3',2':4,5]-
thieno[3,2-d]pyrimidin-8(9H)-one (5a). Yield 1.95 g (97%),
white crystals, mp > 360°С. IR spectrum, ν, cm–1: 1652 (CO),
3420 (NH). 1H NMR spectrum, δ, ppm: 1.30 (6H, s, 2CH3);
1.84–1.91 (4H, m, 3,4-CH2 pyrrolidine); 2.60 (3H, s,
SCH3); 3.35 (2H, s, 1-CH2); 3.56–3.62 (4H, m, N(CH2)2
pyrrolidine); 4.81 (2H, s, 4-CH2); 12.85 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 13.1 (SCH3); 25.1 (2CH3);
26.4 (3,4-CH2 pyrrolidine); 37.8 (1-CH2); 49.6 (2,5-CH2
pyrrolidine); 60.1 (4-CH2); 68.7 (C-2); 114.8; 116.4; 141.4;
152.4; 152.5; 156.3; 157.6; 158.2 (C-8); 160.0 (C-10).
Found, %: С 56.76; Н 5.56; N 13.83; S 15.81.
C19H22N4O2S2. Calculated, %: С 56.69; Н 5.51; N 13.92;
S 15.93.
10-Benzylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-
1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-thieno-
[3,2-d]pyrimidin-8(9H)-one (5b). Yield 2.25 g (98%),
white crystals, mp 314–315°С. 1H NMR spectrum, δ, ppm:
1.17 (6H, s, 2CH3); 3.15–3.21 (4H, m, N(CH2)2 mor-
pholine); 3.34 (2H, s, 1-CH2); 3.72–3.76 (4H, m, О(CH2)2
morpholine); 4.59 (2H, s, SCH2); 4.65 (2H, s, 4-CH2); 7.23–
7.36 (3H, m, H Ph); 7.43–7.47 (2H, m, H Ph); 13.10 (1H,
br. s, NH). 13C NMR spectrum, δ, ppm: 26.6 (2CH3); 33.8
(SCH2); 37.0 (1-CH2); 49.9 (3,5-CH2 morpholine); 59.2
(4-CH2); 66.1 (2,6-CH2 morpholine); 69.3 (C-2); 119.4;
119.8; 127.2 (C-4 Ph); 128.3 (C-3,5 Ph); 128.4 (C-2,6 Ph);
136.9 (C-1 Ph); 142.9; 151.8; 157.8; 157.9; 158.0; 158.9
(C-8); 159.1 (C-10). Found, %: С 60.62; Н 5.35; N 11.22;
S 13.10. C25H26N4O3S2. Calculated, %: С 60.71; Н 5.30;
N 11.33; S 12.97.
10-Allylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-di-
hydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-
[3,2-d]pyrimidin-8(9H)-one (5e). Yield 2.09 g (94%),
1
white crystals, mp 288–290°С. H NMR spectrum, δ, ppm
(J, Hz): 1.31 (6H, s, 2CH3); 3.17–3.25 (4H, m, N(CH2)2
morpholine); 3.43 (2H, s, 1-CH2); 3.74–3.81 (4H, m,
О(CH2)2 morpholine); 3.88 (2H, dt, J = 6.6, J = 1.2,
SCH2); 4.67 (2H, s, 4-CH2); 5.15 (1H, dq, J=.0, J = 1.2)
and 5.34 (1H, dq, J = 17.0, J = 1.2, CH=CH2); 6.04 (1H,
ddt, J = 17.0, J = 10.0, J = 6.6, CH=CH2); 12.75 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 26.4 (2CH3); 32.6 (SCH2);
37.0 (1-CH2); 49.9 (3,5-CH2 morpholine); 59.2 (4-CH2);
66.0 (2,6-CH2 morpholine); 69.0 (C-2); 117.2 (CH=CH2);
118.8; 120.2; 132.8 (CH=CH2); 141.2; 142.3; 151.4; 156.9;
157.8; 158.6 (C-8); 159.4 (C-10). Found, %: С 56.62;
Н 5.49; N 12.71; S 14.34. C21H24N4O3S2. Calculated, %:
С 56.73; Н 5.44; N 12.60; S 14.43.
10-Methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-tetra-
hydropyrimido[4',5':4,5]thieno[2,3-c]isoquinolin-8(9H)-one
(5f). Yield 1.73 g (93%), light-yellow crystals, mp > 360°С.
1H NMR spectrum, δ, ppm: 1.61–1.72 (2H, m, 2-CH2);
1.76–1.93 (6H, m, 3,4-CH2 pyrrolidine, 3-CH2); 2.60 (3H,
s, SCH3); 2.67–2.74 (2H, m, 4-CH2); 3.39–3.47 (2H, m,
1-CH2); 3.53–3.61 (4H, m, N(CH2)2 pyrrolidine); 12.81
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 13.0 (SCH3);
22.1 (2-CH2); 25.1 (3,4-CH2 pyrrolidine); 25.4 (3-CH2);
26.0 (4-CH2); 26.8 (1-CH2); 49.7 (2,5-CH2 pyrrolidine);
113.7; 115.4; 141.2; 151.8; 152.3; 155.6; 157.4; 158.5
(C-8); 161.0 (C-10). Found, %: С 58.13; Н 5.45; N 14.92;
S 17.14. C18H20N4OS2. Calculated, %: С 58.04; Н 5.41;
N 15.04; S 17.22.
10-Butylsulfanyl-2,2-dimethyl-5-(morpholin-4-yl)-1,4-
dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno-
[3,2-d]pyrimidin-8(9H)-one (5c). Yield 2.25 g (98%),
1
white crystals, mp > 360°С. H NMR spectrum, δ, ppm
(J, Hz): 0.92 (3H, t, J = 7.3, CH2CH3); 1.30 (6H, s, 2CH3);
1.39–1.51 (2H, m, SCH2CH2); 1.67–1.77 (2H, m,
CH2CH3); 3.16–3.21 (4H, m, N(CH2)2 morpholine); 3.22
(2H, t, J = 7.4, SCH2); 3.41 (2H, s, 1-CH2); 3.72–3.77 (4H,
m, О(CH2)2 morpholine); 4.68 (2H, s, 4-CH2); 12.99 (1H,
br. s, NH). 13C NMR spectrum, δ, ppm: 13.5 (CH2CH3);
21.6 (CH2); 26.8 (2CH3); 29.9 (CH2); 31.1 (SCH2); 37.0
(1-CH2); 49.9 (3,5-CH2 morpholine); 59.2 (4-CH2); 66.1
(2,6-CH2 morpholine); 69.4 (C-2); 115.0; 117.9; 119.4;
119.8; 142.8; 157.8; 158.3; 158.9 (C-8); 159.1 (C-10).
10-Methylsulfanyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydro-
pyrimido[4',5':4,5]thieno[2,3-c]isoquinolin-8(9H)-one (5g).
1
Yield 1.85 g (95%), white crystals, mp > 360°С. H NMR
spectrum, δ, ppm: 1.70–1.80 (2H, m, 2-CH2); 1.85–1.96
(2H, m, 3-CH2); 2.62 (3H, s, SCH3); 2.68–2.74 (2H, m,
4-CH2); 3.19–3.24 (4H, m, N(CH2)2 morpholine); 3.75–
3.80 (4H, m, О(CH2)2 morpholine); 3.51–3.57 (2H, m,
340

Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
1-CH2); 12.85 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
oxychloride was removed by distillation, the residue was
quenched with ice water (50 ml) and neutralized with
aqueous ammonia solution. The obtained crystals were
filtered off, washed with water, and recrystallized from a
4:1 mixture of CHCl3 and EtOH.
13.0 (SCH3); 20.8 (2-CH2); 21.9 (3-CH2); 26.0 (4-CH2);
26.7 (1-CH2); 49.6 (3,5-CH2 morpholine); 65.7 (2,6-CH2
morpholine); 113.2; 115.7; 141.4; 152.1; 153.5; 156.4;
157.6; 158.2 (C-8); 160.5 (C-10). Found, %: С 55.73;
Н 5.15; N 14.33; S 16.41. C18H20N4O2S2. Calculated, %:
С 55.65; Н 5.19; N 14.42; S 16.51.
8-Chloro-2,2-dimethyl-10-methylsulfanyl-5-(pyrro-
lidin-1-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine (6a). Yield 1.71 g
(81%), light-yellow crystals, mp 224–226°С. 1H NMR
spectrum, δ, ppm: 1.35 (6H, s, 2CH3); 1.96–2.02 (4H, m,
3,4-CH2 pyrrolidine); 2.60 (3H, s, SCH3); 3.36 (2H, s,
1-CH2); 3.66–3.73 (4H, m, N(CH2)2 pyrrolidine); 4.84 (2H,
s, 4-CH2). 13C NMR spectrum, δ, ppm: 13.8 (SCH3); 25.1
(3,4-CH2 pyrrolidine); 27.6 (2CH3); 36.5 (1-CH2); 50.1
(2,5-CH2 pyrrolidine); 60.3 (4-CH2); 68.6 (C-2); 115.6;
118.4; 121.5; 144.9; 151.7; 159.2; 160.5; 160.4 (C-8);
165.2 (C-10). Found, %: С 54.30; Н 5.09; N 13.15; S 15.33;
Cl 8.51. C19H21ClN4OS2. Calculated, %: С 54.21; Н 5.03;
N 13.31; S 15.23; Cl 8.42.
5-(Morpholin-4-yl)-10-[(2-oxo-2-phenylethyl)sulfa-
nyl]-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3-c]-
isoquinolin-8(9H)-one (5h). Yield 2.29 g (93%), white
crystals, mp 274–275°С. 1H NMR spectrum, δ, ppm
(J, Hz): 1.18–1.27 (2H, m, 2-CH2); 1.49–1.58 (2H, m,
3-CH2); 2.57 (2H, t, J = 5.9, 4-CH2); 3.09 (2H, t, J = 6.4,
1-CH2); 3.14–3.21 (4H, m, N(CH2)2 morpholine); 3.71–
3.78 (4H, m, О(CH2)2 morpholine); 4.90 (2H, s, SCH2);
7.52–7.58 (2H, m, H Ph); 7.61–7.68 (1H, m, H Ph); 8.05–
8.11 (2H, m, H Ph); 12.97 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 20.9 (2-CH2); 21.8 (3-CH2); 25.8 (4-CH2);
26.8 (1-CH2); 38.5 (SCH2); 49.5 (3,5-CH2 morpholine); 65.9
(2,6-CH2 morpholine); 115.6; 120.4; 121.4; 127.8 (C-3,5 Ph);
128.2 (C-2,6 Ph); 132.8 (C-4 Ph); 135.4 (C-1 Ph); 145.5;
151.7; 156.3; 157.6; 158.4 (C-8); 160.9 (C-10); 190.4
(CH2CO). Found, %: С 60.87; Н 4.96; N.49; S 13.10.
C25H24N4O3S2. Calculated, %: С 60.95; Н 4.91; N 11.37;
S 13.02.
10-Benzylsulfanyl-5-(morpholin-4-yl)-1,2,3,4-tetra-
hydropyrimido[4',5':4,5]thieno[2,3-c]isoquinolin-8(9H)-
one (5i). Yield 2.21 g (95%), white crystals, mp 325–327°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.61–1.84 (4H, m,
2,3-CH2); 2.67 (2H, t, J = 5.3, 4-CH2); 3.16–3.22 (4H, m,
N(CH2)2 morpholine); 3.40 (2H, t, J = 5.8, 1-CH2); 3.72–
3.79 (4H, m, О(CH2)2 morpholine); 4.55 (2H, s, SCH2);
7.23–7.38 (3H, m, H Ph); 7.43–7.47 (2H, m, H); 13.06
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 21.5 (2-CH2);
22.0 (3-CH2); 26.0 (4-CH2); 26.9 (1-CH2); 34.0 (SCH2);
49.7 (3,5-CH2 morpholine); 66.1 (2,6-CH2 morpholine);
120.3; 122.3; 127.2 (C-4 Ph); 128.4 (C-3,5 Ph); 128.5 (C-2,6
Ph); 136.7 (C-1 Ph); 146.2; 152.1; 155.5; 157.4; 157.8;
158.2 (C-8); 161.5 (C-10). Found, %: С 61.95; Н 5.26;
N 12.18; S 13.71. C24H24N4O2S2. Calculated, %: С 62.04;
Н 5.21; N 12.06; S 13.80.
8-Chloro-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (6b).18 White crystals, mp 261–
1
262°С. H NMR spectrum, δ, ppm: 1.34 (6H, s, 2CH3);
2.53 (3H, s, SCH3); 3.16–3.27 (4H, m, N(CH2)2
morpholine); 3.51 (2H, s, 1-CH2); 3.73–3.81 (4H, m, О(CH2)2
morpholine); 4.64 (2H, s, 4-CH2). 13C NMR spectrum, δ,
ppm: 13.6 (SCH3); 27.3 (2CH3); 36.9 (1-CH2); 48.4
(3,5-CH2 morpholine); 60.2 (4-CH2); 66.9 (2,6-CH2
morpholine); 68.4 (C-2); 115.7; 118.0; 121.7; 145.4; 151.7;
159.3; 160.6; 161.0 (C-8); 165.2 (C-10). Found, %: С 52.45;
Н 4.56; N 12.74; S 14.56. C19H21ClN4O2S2. Calculated, %:
С 52.23; Н 4.84; N 12.82; S 14.67.
10-Benzylsulfanyl-8-chloro-2,2-dimethyl-5-(morpholin-
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (6c). Yield 1.90 g (74%), white
1
crystals, mp 247–248°С. H NMR spectrum, δ, ppm: 1.27
(6H, s, 2CH3); 3.28–3.37 (4H, m, N(CH2)2 morpholine);
3.34 (2H, s, 1-CH2); 3.75–3.82 (4H, m, О(CH2)2
morpholine); 4.50 (2H, s, SCH2); 4.64 (2H, s, 4-CH2); 7.18–
7.32 (3H, m, H Ph); 7.40–7.46 (2H, m, H Ph). 13C NMR
spectrum, δ, ppm: 27.4 (2CH3); 34.1 (SCH2); 36.2 (1-CH2);
47.8 (3,5-CH2 morpholine); 60.1 (4-CH2); 66.8 (2,6-CH2
morpholine); 69.9 (C-2); 116.4; 119.7; 126.5 (C-4 Ph);
128.3 (C-3,5 Ph); 129.1 (C-2,6 Ph); 138.4 (C-1 Ph); 145.9;
151.4; 157.9; 158.2; 159.7; 160.4 (C-8); 165.1 (C-10).
Found, %: С 58.40; Н 4.96; N 10.84; S 12.58; Cl 6.83.
C25H25ClN4O2S2. Calculated, %: С 58.52; Н 4.91; N 10.92;
S 12.50; Cl 6.91.
9-Methylsulfanyl-4-(morpholin-4-yl)-2,3-dihydro-1H-
cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-
7(8H)-one (5j). Yield 1.80 g (96%), white crystals, mp
1
> 360°С. H NMR spectrum, δ, ppm (J,Hz): 2.06–2.16
(2H, m, 2-CH2); 2.60 (3H, s, SCH3); 2.95 (2H, t, J = 7.2,
3-CH2); 3.34 (2H, t, J = 7.5, 1-CH2); 3.47–3.53 (4H, m,
N(CH2)2 morpholine); 3.70–3.76 (4H, m, О(CH2)2
morpholine); 12.87 (1H, br. s, NH). 13C NMR spectrum, δ,
ppm: 13.5 (SCH3); 25.1 (2-CH2); 30.5 (3-CH2); 30.9
(1-CH2); 47.9 (3,5-CH2 morpholine); 66.1 (2,6-CH2
morpholine); 113.2; 117.5; 140.2; 151.9; 154.3; 155.6;
156.7; 158.6 (C-7); 163.6 (C-9). Found, %: С 54.61;
Н 4.79; N 14.87; S 17.02. C17H18N4O2S2. Calculated, %:
С 54.52; Н 4.84; N 14.96; S 17.13.
8-Chloro-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-
tetrahydropyrimido[4',5':4,5]thieno[2,3-c]isoquinoline
(6d). Yield 1.51 g (77%), yellow crystals, mp 216–217°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.71–1.79 (2H, m,
2-CH2); 1.86–1.94 (2H, m, 3-CH2); 1.95–2.01 (4H, m,
3,4-CH2 pyrrolidine); 2.61 (3H, s, SCH3); 2.77 (2H, br. t,
J = 5.9, 4-CH2); 3.48 (2H, br. t, J = 6.4, 1-CH2); 3.65–3.72
(4H, m, N(CH2)2 pyrrolidine). 13C NMR spectrum, δ, ppm:
13.9 (SCH3); 21.1 (2-CH2); 22.2 (3-CH2); 25.1 (3,4-CH2
pyrrolidine); 27.1 (4-CH2); 27.4 (1-CH2); 50.0 (2,5-CH2
pyrrolidine); 115.1; 117.6; 121.1; 145.9; 151.4; 158.9;
Preparation of compounds 6a,c–f (General method). A
mixture of compound 5а,b,f,i,j (5 mmol), phosphorus
oxychloride (25 ml, 0.268 mol), and pyridine (1.3 ml,
16 mmol) was refluxed for 6 h. The excess of phosphorus
341

Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
160.3; 160.7 (C-8); 167.0 (C-10). Found, %: С 55.38;
Н 4.96; N 14.22; S 16.52; Cl 9.16. C18H19ClN4S2.
Calculated, %: С 55.30; Н 4.90; N 14.33; S 16.40; Cl 9.07.
10-Benzylsulfanyl-8-chloro-5-(morpholin-4-yl)-1,2,3,4-
tetrahydropyrimido[4',5':4,5]thieno[2,3-c]isoquinoline
(6е). Yield 1.79 g (74%), light-yellow crystals, mp 246–
pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (7b). Yield 1.10 g
1
(78%), light-yellow crystals, mp 215–216°С. H NMR
spectrum, δ, ppm: 1.34 (6H, s, 2CH3); 1.91–2.03 (4H, m,
3,4-CH2 pyrrolidine); 2.53 (3H, s, SCH3); 3.46 (2H, s,
1-CH2); 3.59–3.64 (4H, m, N(CH2)2 pyrrolidine); 3.74–3.80
(4H, m, N(CH2)2 morpholine); 3.84–3.90 (4H, m, О(CH2)2
morpholine); 4.79 (2H, s, 4-CH2). 13C NMR spectrum, δ,
ppm: 13.5 (SCH3); 25.1 (3,4-CH2 pyrrolidine); 26.5
(2CH3); 37.0 (1-CH2); 48.6 (3,5-CH2 morpholine); 49.7
(2,5-CH2 pyrrolidine); 59.8 (4-CH2); 66.5 (2,6-CH2
morpholine); 68.9 (C-2); 107.8; 115.6; 118.4; 142.1; 154.7;
156.5; 157.2; 158.4 (C-8), 165.8 (C-10). Found, %:
С 58.64; Н 6.25; N 14.78; S 13.49. C23H29N5O2S2.
Calculated, %: С 58.57; Н 6.20; N 14.85; S 13.60.
2,2-Dimethyl-10-methylsulfanyl-5-(morpholin-4-yl)-
N-(2-phenylethyl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']-
pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8-amine (7c).
Yield 1.30 g (83 %), white crystals, mp 189–190°С. 1H NMR
spectrum, δ, ppm (J, Hz): 1.35 (6H, s, 2CH3); 2.56 (3H, s,
SCH3); 2.99 (2H, t, J = 7.5, NHCH2CH2); 3.17–3.24 (4H,
m, N(CH2)2 morpholine); 3.53 (2H, s, 1-CH2); 3.70–3.76
(2H, m, NHCH2); 3.76–3.82 (4H, m, О(CH2)2 morpholine);
4.68 (2H, s, 4-CH2); 7.11–7.20 (1H, m, H Ph); 7.21–7.28
(4H, m, H Ph); 7.47 (1H, br. t, J = 5.5, NH). 13C NMR
spectrum, δ, ppm: 13.5 (SCH3); 26.6 (2CH3); 34.9
(NHCH2); 37.0 (1-CH2); 41.9 (CH2Ph); 50.0 (3,5-CH2
morpholine); 59.1 (4-CH2); 66.0 (2,6-CH2 morpholine);
69.1 (C-2); 107.8; 118.5; 120.0; 125.4 (C-4 Ph); 127.7
(C-3,5 Ph); 128.3 (C-2,6 Ph); 139.2 (C-1 Ph); 142.8; 154.6;
155.7; 158.5; 158.6 (C-8); 166.6 (C-10). Found, %:
С 62.25; Н 6.05; N 13.54; S 12.37. C27H31N5O2S2.
Calculated, %: С 62.16; Н 5.99; N 13.42; S 12.29.
1
248°С. H NMR spectrum, δ, ppm (J, Hz): 1.72–1.78 (2H,
m, 2-CH2); 1.87–1.96 (2H, m, 3-CH2); 2.74 (2H, t, J = 5.8,
4-CH2); 3.25–3.34 (4H, m, N(CH2)2 morpholine); 3.51
(2H, t, J = 6.3, 1-CH2); 3.77–3.85 (4H, m, О(CH2)2
morpholine); 4.52 (2H, s, SCH2); 7.13–7.22 (3H, m, H Ph);
7.43–7.51 (2H, m, H Ph). 13C NMR spectrum.: 21.2
(2-CH2); 22.1 (3-CH2); 26.9 (4-CH2); 27.2 (1-CH2); 34.0
(SCH2); 47.9 (3,5-CH2 morpholine); 66.7 (2,6-CH2
morpholine); 121.6; 121.8; 126.8 (C-4 Ph); 128.5 (C-3,5
Ph); 128.8 (C-2,6 Ph); 138.2 (C-1 Ph); 145.6; 151.8; 158.0;
158.4; 159.5; 160.1 (C-8); 164.7 (C-10). Found, %: С 59.78;
Н 4.84; N 11.71; S 13.17; Cl 7.25. C24H23ClN4OS2.
Calculated, %: С 59.67; Н 4.80; N 11.60; S 13.28; Cl 7.34.
7-Chloro-9-methylsulfanyl-4-(morpholin-4-yl)-2,3-di-
hydro-1H-cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidine (6f). Yield 1.63 g (83%), white crystals, mp 250–
1
251°С. H NMR spectrum, δ, ppm (J, Hz): 2.16–2.26 (2H,
m, 2-CH2); 2.62 (3H, s, SCH3); 3.03 (2H, t, J = 7.3, 3-CH2);
3.43 (2H, t, J = 7.6, 1-CH2); 3.63–3.70 (4H, m, N(CH2)2
morpholine); 3.73–3.80 (4H, m, О(CH2)2 morpholine).
13C NMR spectrum, δ, ppm: 13.9 (SCH3); 24.6 (2-CH2);
27.8 (3-CH2); 28.9 (1-CH2); 47.8 (3,5-CH2 morpholine); 66.4
(2,6-CH2 morpholine); 114.6; 117.8; 125.3; 146.4; 151.6;
159.2; 160.5; 160.8 (C-7); 166.7 (C-9). Found, %: С 52.03;
Н 4.40; N 14.34; S 16.21; Cl 9.13. C17H17ClN4OS2.
Calculated, %: С 51.96; Н 4.36; N 14.26; S 16.32; Cl 9.02.
Preparation of compounds 7a–k (General method).
Compound 6a–f (3 mmol) in n-BuOH (40 ml) was treated
with the appropriate amine (12 mmol). The mixture was
refluxed for 8 h. The crystals that formed after cooling
were filtered off, washed with water, ethanol, and
recrystallized from a 1:1 mixture of CHCl3 and EtOH.
2,2-Dimethyl-10-methylsulfanyl-N-(pyridin-3-ylmethyl)-
5-(pyrrolidin-1-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']-
pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8-amine (7a).
Yield 1.20 g (81%), light-yellow crystals, mp 211–212°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.34 (6H, s, 2CH3);
1.93–2.01 (4H, m, 3,4-CH2 pyrrolidine); 2.49 (3H, s,
SCH3); 3.45 (2H, s, 1-CH2); 3.59–3.65 (4H, m, N(CH2)2
pyrrolidine); 4.73 (2H, d, J=.9, NHCH2); 4.77 (2H, s,
4-CH2); 7.25 (1H, dd, J = 7.7, J = 4.8, H-5 Py); 7.77 (1H,
ddd, J = 7.7, J = 1.9, J = 1.6, H-4 Py); 7.87 (1H, br. t,
J = 5.9, NH); 8.40 (1H, dd, J = 4.8, J = 1.6, H-6 Py); 8.58
(1H, d, J = 1.9, H-2 Py). 13C NMR spectrum, δ, ppm: 13.4
(SCH3); 25.0 (3,4-CH2 pyrrolidine); 26.3 (2CH3); 37.3
(1-CH2); 41.1 (NHCH2); 49.5 (2,5-CH2 pyrrolidine); 60.1
(4-CH2); 68.5 (C-2); 105.9; 113.9; 116.2; 122.8 (C-4(5) Py);
135.2 (C-3 Py); 135.6 (C-5(4) Py); 141.6; 146.7 and 148.3
(С-2,6 Py); 155.4; 155.5; 156.3; 159.3 (C-8), 166.1 (C-10).
Found, %: С60.83; Н 5.79; N 17.19; S 13.10. C25H28N6OS2.
Calculated, %: С 60.95; Н 5.73; N 17.06; S 13.02.
N-Hexyl-2,2-dimethyl-10-methylsulfanyl-5-(morpho-
lin-4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-8-amine (7d). Yield 1.20 g (80%),
1
white crystals, mp 231–232°С. H NMR spectrum, δ, ppm
(J, Hz): 0.91 (3H, t, J = 6.6, CH2CH3); 1.28–1.45 (6H, m,
CH3(CH2)3); 1.34 (6H, s, 2CH3); 1.61–1.71 (2H, m,
NHCH2CH2); 2.52 (3H, s, SCH3); 3.15–3.25 (4H, m, N(CH2)2
morpholine); 3.46–3.56 (4H, m, NHCH2, 1-CH2); 3.74–
3.84 (4H, m, О(CH2)2 morpholine); 4.68 (2H, s, 4-CH2);
7.30 (1H, br. t, J = 5.4, NH). 13C NMR spectrum, δ, ppm:
13.4 (CH2CH3); 13.6 (SCH3); 22.0 (CH2CH3); 26.1 (CH2);
28.7 (CH2); 31.0 (CH2); 26.6 (2CH3); 37.0 (1-CH2); 40.1
(NHCH2); 50.0 (3,5-CH2 morpholine); 59.1 (4-CH2); 66.0
(2,6-CH2 morpholine); 69.0 (C-2); 107.7; 118.5; 120.0;
142.8; 154.4; 155.8; 158.5 (С Ar, C-8); 166.5 (C-10).
Found, %: С 59.93; Н 6.98; N 13.81; S 12.67.
C25H35N5O2S2. Calculated, %: С 59.85; Н 7.03; N 13.96;
S 12.78.
10-Benzylsulfanyl-2,2-dimethyl-8-(4-methylpipera-
zin-1-yl)-5-(morpholin-4-yl)-1,4-dihydro-2H-pyrano-
[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (7e).
Yield 1.40 g (81%), white crystals, mp 206–207°С.
1H NMR spectrum, δ, ppm: 1.21 (6H, s, 2CH3); 2.30 (3H,
s, NCH3); 2.46–2.55 (4H, m, N(CH2)2 piperazine); 3.16–
3.22 (4H, m, N(CH2)2 morpholine); 3.41 (2H, s, 1-CH2);
3.75–3.80 (4H, m, О(CH2)2 morpholine); 3.89–3.96 (4H,
m, N(CH2)2 piperazine); 4.44 (2H, s, SCH2); 4.64 (2H, s,
2,2-Dimethyl-10-methylsulfanyl-8-(morpholin-4-yl)-
5-(pyrrolidin-1-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']-
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Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
4-CH2); 7.15–7.29 (3H, m, H Ph); 7.37–7.43 (2H, m, H Ph).
Found, %: С 61.25; Н 5.64; N 15.42; S 14.34. C23H25N5OS2.
Calculated, %: С 61.17; Н 5.58; N 15.51; S 14.20.
13C NMR spectrum, δ, ppm: 26.4 (2CH3); 34.3 (SCH2); 37.1
(1-CH2); 45.2 (NCH3, 3,5-CH2 piperazine); 49.8 (3,5-CH2
morpholine); 54.1 (2,6-CH2 piperazine); 59.0 (4-CH2); 65.9
(2,6-CH2 morpholine); 68.9 (С-2); 107.1; 118.7; 118.8; 126.2
(C-4 Ph); 127.7 (C-3,5 Ph); 127.8 (C-2,6 Ph); 137.8 (C-1 Ph);
143.1; 156.4 (C-10); 156.6; 156.9; 158.3; 159.1 (C-8).
Found, %: С 62.36; Н 6.25; N 14.69; S 11.03. C30H36N6O2S2.
Calculated, %: С 62.47; Н 6.29; N 14.57; S 11.12.
10-Benzylsulfanyl-5-(morpholin-4-yl)-8-(pyrrolidin-
1-yl)-1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3-c]iso-
quinoline (7i). Yield 1.29 g (83%), white crystals, mp 198–
1
200°С. H NMR spectrum, δ, ppm (J, Hz): 1.69–1.79 (2H,
m, 2-CH2); 1.81–1.91 (2H, m, 3-CH2); 2.01–2.10 (4H, m,
3,4-CH2 pyrrolidine); 2.70 (2H, t, J = 5.2, 4-CH2); 3.17–
3.24 (4H, m, N(CH2)2 morpholine); 3.53 (2H, t, J = 6.5,
1-CH2); 3.74–3.80 (4H, m, О(CH2)2 morpholine); 3.83–
3.91 (4H, m, N(CH2)2 pyrrolidine); 4.41 (2H, s, SCH2);
7.14–7.28 (3H, m, HPh); 7.37–7.42 (2H, m, H Ph).
13C NMR spectrum, δ, ppm: 21.8 (2-CH2); 22.3 (3-CH2);
24.6 (4-CH2); 25.1 (3,4-CH2 pyrrolidine); 26.8 (1-CH2);
34.5 (SCH2); 47.5 (2,5-CH2 pyrrolidine); 49.8 (3,5-CH2
morpholine); 66.0 (2,6-CH2 morpholine); 108.9; 117.8;
118.6; 126.7 (C-4 Ph); 127.5 (C-3,5 Ph); 127.9 (C-2,6 Ph);
137.8 (C-1 Ph); 143.6; 157.4; 158.3; 158.7; 159.2 (C-8);
166.1 (C-10). Found, %: С 65.08; Н 5.99; N 13.67;
S 12.28. C28H31N5OS2. Calculated, %: С 64.96; Н 6.04;
N 13.53; S 12.39.
N-Benzyl-10-benzylsulfanyl-2,2-dimethyl-5-(morpholin-
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-8-amine (7f). Yield 1.45 g (83%),
1
white crystals, mp 195–196°С. H NMR spectrum, δ, ppm
(J, Hz): 1.23 (6H, s, 2CH3); 3.17–3.22 (4H, m, N(CH2)2
morpholine); 3.42 (2H, s, 1-CH2); 3.75–3.81 (4H, m, О(CH2)2
morpholine); 4.40 (2H, s, SCH2); 4.66 (2H, s, 4-CH2); 4.76
(2H, d, J = 5.7, NHCH2); 7.14–7.31 (6H, m, H Ph); 7.33–
7.40 (4H, m, H Ph); 8.09 (1H, br. t, J = 5.7, NH). 13C NMR
spectrum, δ, ppm: 26.4 (2CH3), 34.2 (SCH2); 36.9 (1-CH2);
43.5 (NHCH2); 49.9 (3,5-CH2 morpholine); 59.0 (4-CH2);
65.9 (2,6-CH2 morpholine); 68.9 (С-2); 118.5; 119.8;
126.0; 127.6 (4CH Ph); 127.8 (2CH Ph); 127.9 (4CH Ph);
138.2 (C Ph); 139.2 (C); 142.8; 154.7; 155.8; 156.8; 158.6
(C-8); 158.7(C-10). Found, %: С 65.77; Н 5.76; N 11.91;
S 10.86. C32H33N5O2S2. Calculated, %: С 65.84; Н 5.70;
N 12.00; S 10.99.
9-Methylsulfanyl-4-(morpholin-4-yl)-7-(pyrrolidin-1-yl)-
2,3-dihydro-1H-cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidine (7j). Yield 1.03 g (80%), cream-colored
crystals, mp 241–242°С. 1H NMR spectrum, δ, ppm (J, Hz):
2.00–2.10 (4H, m, 3,4-CH2 pyrrolidine); 2.12–2.24 (2H, m,
2-CH2); 2.52 (3H, s, SCH3); 2.95 (2H, t, J = 7.2, 3-CH2);
3.47 (2H, t, J = 7.5, 1-CH2); 3.47–3.52 (4H, m, N(CH2)2
morpholine); 3.73–3.78 (4H, m, О(CH2)2 morpholine);
3.82–3.89 (4H, m, N(CH2)2 pyrrolidine). 13C NMR
spectrum, δ, ppm: 13.5 (SCH3); 25.1 (2-CH2); 25.2
(3,4-CH2 pyrrolidine), 31.4 (3-CH2); 31.7 (1-CH2); 49.4
(2,5-CH2 pyrrolidine); 49.8 (3,5-CH2 morpholine); 65.9
(2,6-CH2 morpholine); 106.8; 117.5; 123.6; 152.1; 156.4;
156.9; 157.3; 158.4 (C-7); 165.8 (C-9). Found, %: С 59.08;
Н 5.83; N 16.49; S 14.88. C21H25N5OS2. Calculated, %:
С 58.99; Н 5.89; N 16.38; S 15.00.
N-Butyl-N-ethyl-10-methylsulfanyl-5-(pyrrolidin-1-yl)-
1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3-c]isoquino-
lin-8-amine (7g). Yield 1.00 g (73%), light-yellow crystals,
1
mp 119–120°С. H NMR spectrum, δ, ppm (J, Hz): 1.01
(3H, t, J = 7.3, CH2CH3); 1.30 (3H, t, J = 7.0, NCH2CH3);
1.38–1.51 (2H, m, CH2CH3); 1.66–1.78 (4H, m, 2,3-CH2);
1.84–1.91 (2H, m, 4-CH2); 1.91–1.99 (4H, m, 3,4-CH2
pyrrolidine); 2.51 (3H, s, SCH3); 2.71 (2H, t, J = 5.9,
1-CH2); 3.52–3.62 (6H, m, NCH2CH2, N(CH2)2
pyrrolidine); 3.64–3.71 (2H, m, NCH2CH2); 3.76 (2H, q,
J = 7.0, NCH2CH3). 13C NMR spectrum, δ, ppm: 13.4
(NCH2CH3); 13.5 (SCH3); 19.5 (CH2CH3); 21.6 (2-CH2);
22.3 (3-CH2); 25.1 (3,4-CH2 pyrrolidine); 27.2 (4-CH2);
27.4 (1-CH2); 30.7 (CH2); 40.1 (CH2); 43.2 (CH2); 48.0
(CH2); 49.7 (2,5-CH2 pyrrolidine); 104.0; 116.5; 117.3;
145.3; 155.7; 157.4; 158.0; 159.8 (C-8); 165.1 (C-10).
Found, %: С 63.37; Н 7.26; N 15.24; S 14.17. C24H33N5S2.
Calculated, %: С 63.26; Н 7.30; N 15.37; S 14.07.
9-Methylsulfanyl-4,7-bis(morpholin-4-yl)-2,3-dihydro-
1H-cyclopenta[4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimi-
dine (7k). Yield 1.11 g (83%), light-pink crystals, mp 240–
1
241°С. H NMR spectrum, δ, ppm: 2.14–2.25 (2H, m,
2-CH2); 2.55 (3H, s, SCH3); 2.98 (2H, t, J = 7.2, 3-CH2);
3.48 (2H, t, J = 7.4, 1-CH2); 3.49–3.55 (4H, m, 4-N(CH2)2
morpholine); 3.73–3.81 (8H, m, 7-N(CH2)2 morpholine,
4-morpholine). 13C NMR spectrum, δ, ppm: 13.5 (SCH3);
25.1 (2-CH2); 31.5 (3-CH2); 31.9 (1-CH2); 45.5 (3,5-CH2
4-(morpholin-4-yl)); 47.4 (3,5-CH2 7-(morpholin-4-yl)); 65.8
(2,6-CH2 4-(morpholin-4-yl)); 65.9 (2,6-CH2 7-(morpholin-
4-yl)); 106.3; 117.0; 123.8; 152.6; 156.6; 156.7; 157.9; 158.6
(C-7); 166.1 (C-9). Found, %: С 56.98; Н 5.72; N 15.88;
S 14.32. C21H25N5O2S2. Calculated, %: С 56.86; Н 5.68;
N 15.79; S 14.46.
N-(2-Furylmethyl)-10-methylsulfanyl-5-(pyrrolidin-1-yl)-
1,2,3,4-tetrahydropyrimido[4',5':4,5]thieno[2,3-c]iso-
quinolin-8-amine (7h). Yield 1.00 g (74%), light-yellow
crystals, mp 159–160°С. 1H NMR spectrum, δ, ppm (J, Hz):
1.70–1.79 (2H, m, 2-CH2); 1.84–1.92 (2H, m, 3-CH2); 1.92–
1.99 (4H, m, 3,4-CH2 pyrrolidine); 2.53 (3H, s, SCH3); 2.71
(2H, t, J = 5.7, 4-CH2); 3.49–3.65 (6H, m, N(CH2)2 pyrro-
lidine, 1-CH2); 4.70 (2H, d, J = 5.6, NHCH2); 6.25–6.32
(2H, m, H-3,4 Fur); 7.39 (1H, dd, J = 1.7, J = 0.7, H-5
Fur); 7.66 (1H, br. t, J = 5.6, NH). 13C NMR spectrum, δ,
ppm: 13.5 (SCH3); 21.5 (2-CH2); 22.4 (3-CH2); 25.1
(3,4-CH2 pyrrolidine); 27.1 (4-CH2); 27.2 (1-CH2); 36.7
(NHCH2); 49.8 (2,5-CH2 pyrrolidine); 106.2; 106.6 (CH
Fur); 109.8 (CH Fur); 117.2 (2C); 140.7 (CH Fur); 145.2;
152.5; 155.4; 155.8; 158.4; 159.6 (C-8); 165.7 (C-10).
Preparation of compounds 8a–f (General method).
Compound 6a–e (2 mmol) was added to sodium ethoxide
solution obtained from sodium metal (46 mg, 2 mmol) and
anhydrous ethanol (15 ml). The mixture was refluxed for
10 h. The crystals that formed after cooling were filtered
off and washed with water, then recrystallized from a 1:2
mixture of CHCl3 and EtOH.
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Chemistry of Heterocyclic Compounds 2016, 52(5), 337–345
8-Ethoxy-2,2-dimethyl-10-methylsulfanyl-5-(pyrrolidin-
8-Ethoxy-10-methylsulfanyl-5-(pyrrolidin-1-yl)-1,2,3,4-
tetrahydropyrimido[4',5':4,5]thieno[2,3-c]isoquinoline (8e).
Yield 0.71 g (88%), yellow crystals, mp 206–207°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.49 (3H, t, J = 7.0,
OCH2CH3); 1.71–1.80 (2H, m, 2-CH2); 1.86–1.93 (2H, m,
3-CH2); 1.93–2.00 (4H, m, 3,4-CH2 pyrrolidine); 2.59 (3H,
s, SCH3); 2.74 (2H, t, J = 5.9, 4-CH2); 3.54 (2H, t, J = 6.3, 1-
CH2); 3.60–3.66 (4H, m, N(CH2)2 pyrrolidine); 4.60 (2H, q,
J = 7.0, OCH2CH3). 13C NMR spectrum, δ, ppm: 13.6
(SCH3); 14.0 (CH2CH3); 21.3 (2-CH2); 22.4 (3-CH2); 25.0
(3,4-CH2 pyrrolidine); 26.8 (4-CH2); 27.1 (1-CH2); 49.7
(2,5-CH2 pyrrolidine); 62.4 (CH2CH3); 113.7; 115.8; 119.4;
143.6; 152.8; 157.5; 159.4; 160.5 (C-8), 166.1 (C-10).
Found, %: С 59.90; Н 6.10; N 14.08; S 16.14. C20H24N4OS2.
Calculated, %: С 59.97; Н 6.04; N 13.99; S 16.01.
1-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (8a). Yield 0.66 g (77%),
1
light-yellow crystals, mp 188–189°С. H NMR spectrum, δ,
ppm (J, Hz): 1.35 (6H, s, 2CH3); 1.49 (3H, t, J = 7.1,
OCH2CH3); 1.95–2.00 (4H, m, 3,4-CH2 pyrrolidine); 2.58 (3H,
s, SCH3); 3.43 (2H, s, 1-CH2); 3.62–3.67 (4H, m, N(CH2)2
pyrrolidine); 4.61 (2H, q, J=.1, OCH2CH3); 4.80 (2H, s,
4-CH2). 13C NMR spectrum, δ, ppm: 13.5 (SCH3); 14.1
(CH2CH3); 25.0 (3,4-CH2 pyrrolidine); 26.5 (2CH3); 37.1
(1-CH2); 49.8 (2,5-CH2 pyrrolidine); 59.2 (4-CH2); 62.7
(CH2CH3); 68.8 (С-2); 108.7; 115.9; 116.1; 142.8; 156.6;
156.8; 158.5; 161.2 (C-8), 166.3 (C-10). Found, %:
С 58.49; Н 6.15; N.15; S 14.78. C21H26N4O2S2. Calculated,
%: С 58.58; Н 6.09; N 13.01; S 14.89.
8-Methoxy-2,2-dimethyl-10-methylsulfanyl-5-(morpholin-
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (8b). Yield 0.68 g (79%), white
10-Benzylsulfanyl-8-ethoxy-5-(morpholin-4-yl)-1,2,3,4-
tetrahydropyrimido[4',5':4,5]thieno[2,3-c]isoquinoline
(8f). Yield 0.78 g (79%), white crystals, mp 236–237°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.50 (3H, t, J = 7.1,
OCH2CH3); 1.71–1.81 (2H, m, 2-CH2); 1.84–1.95 (2H, m,
3-CH2); 2.66–2.74 (2H, m, 4-CH2); 3.22–3.30 (4H, m, N(CH2)2
morpholine); 3.45–3.54 (2H, m, 1-CH2); 3.74–3.83 (4H, m,
О(CH2)2 morpholine); 4.47 (2H, s, SCH2); 4.62 (2H, q,
J = 7.1, OCH2CH3); 7.17–7.32 (3H, m, H Ph); 7.38–7.46
(2H, m, H Ph). 13C NMR spectrum, δ, ppm: 14.0
(CH2CH3); 22.1 (2-CH2); 22.4 (3-CH2); 26.8 (4-CH2); 27.1
(1-CH2); 34.4 (SCH2); 49.7 (3,5-CH2 morpholine); 62.4
(CH2CH3); 65.8 (2,6-CH2 morpholine); 108.7; 118.5;
118.8; 126.4 (C-4 Ph); 127.7 (C-3,5 Ph); 127.8 (C-2,6 Ph);
137.4 (C-1 Ph); 142.7; 157.1; 159.4; 160.2; 162.8 (C-8);
166.5 (C-10). Found, %: С 63.46; Н 5.78; N 11.46;
S 13.14. C26H28N4O2S2. Calculated, %: С 63.39; Н 5.73;
N 11.37; S 13.02.
1
crystals, mp 209–210°С. H NMR spectrum, δ, ppm: 1.35
(6H, s, 2CH3); 2.61 (3H, s, SCH3); 3.22–3.28 (4H, m, N(CH2)2
morpholine); 3.49 (2H, s, 1-CH2); 3.76–3.81 (4H, m, О(CH2)2
morpholine); 4.16 (3H, s, OCH3); 4.70 (2H, s, 4-CH2).
13C NMR spectrum, δ, ppm: 13.7 (SCH3); 26.1 (2CH3); 37.0
(1-CH2); 49.7 (3,5-CH2 morpholine); 54.2 (OCH3); 59.4
(4-CH2); 66.1 (2,6-CH2 morpholine); 68.9 (С-2); 108.6; 119.5;
120.3; 143.7; 155.6; 156.4; 157.5; 158.8 (C-8); 166.1 (C-10).
Found, %: С 55.60; Н 5.64; N 12.83; S 14.97. C20H24N4O3S2.
Calculated, %: С 55.53; Н 5.59; N 12.95; S 14.83.
8-Isopropoxy-2,2-dimethyl-10-methylsulfanyl-5-(morpho-
lin-4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (8c). Yield 0.71 g (77%), white
1
crystals, mp 219–220°С. H NMR spectrum, δ, ppm (J, Hz):
1.35 (6H, s, 2CH3); 1.49 (6H, d, J = 6.2, CH(CH3)2); 2.59 (3H,
s, SCH3); 3.22–3.28 (4H, m, N(CH2)2 morpho-line); 3.49 (2H,
s, 1-CH2); 3.76–3.82 (4H, m, О(CH2)2 morpholine); 4.68 (2H,
s, 4-CH2); 5.61 (1H, sept, J = 6.2, OCH). 13C NMR spectrum, δ,
ppm: 13.5 (SCH3); 25.1 (CH(CH3)2); 26.7 (2CH3); 37.1
(1-CH2); 49.8 (3,5-CH2 morpholine); 59.3 (4-CH2); 66.0 (2,6-
CH2 morpholine); 65.7 (OCH); 69.0 (С-2); 108.4; 118.7; 121.4;
141.6; 153.8; 156.6; 158.2; 158.7 (C-8); 166.4 (C-10). Found,
%: С 57.45; Н 6.19; N 12.27; S 13.84. C22H28N4O3S2.
Calculated, %: С 57.37; Н 6.13; N 12.16; S 13.92.
Part of this study was performed with financial support
from the State Committee of Science at the Ministry of
Education and Science of the Republic of Armenia and
Russian Foundation for Basic Research within the
framework of joint scientific programs 15RF-027 and
15-53-05064/15, respectively.
References
10-Benzylsulfanyl-8-ethoxy-2,2-dimethyl-5-(morpholin-
4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (8d). Yield 0.84 g (80%), white
crystals, mp 178–179°С. 1H NMR spectrum, δ, ppm
(J, Hz): 1.25 (6H, s, 2CH3); 1.50 (3H, t, J = 7.0,
OCH2CH3); 3.21–3.26 (4H, m, N(CH2)2 morpholine); 3.38
(2H, s, 1-CH2); 3.75–3.80 (4H, m, О(CH2)2 morpholine);
4.48 (2H, s, SCH2); 4.63 (2H, q, J = 7.0, OCH2CH3); 4.65
(2H, s, 4-CH2). 7.17–7.30 (3H, m, H Ph); 7.39–7.45 (2H,
m, H Ph). 13C NMR spectrum, δ, ppm: 14.0 (CH2CH3);
26.4 (2CH3); 34.5 (SCH2); 37.0 (1-CH2); 49.8 (3,5-CH2
morpholine); 59.1 (4-CH2); 62.5 (CH2CH3); 65.9 (2,6-CH2
morpholine); 68.9 (С-2); 109.9; 118.6; 118.8; 126.3 (C-4
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142.9; 157.3; 159.1; 159.8; 162.4 (C-8); 166.1 (C-10).
Found, %: С 62.13; Н 5.72; N 10.63; S 12.35. C27H30N4O3S2.
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