Derivatives of condensed thienopyrimidines. 22. Synthesis of 2-substituted 4-thioxopyrano[4′,3′:4,5]thieno[2,3-d]pyrimidines

Article abstract of DOI:10.1007/s10593-005-0133-4

A method has been developed for the synthesis of 4-thioxopyrano[4′3′:4,5]thieno[2,3-d]pyrimidines from the corresponding acyl derivatives of 2-amino-3-cyanothieno[2,3-c]pyran.

Full text of DOI:10.1007/s10593-005-0133-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 2, 2005
DERIVATIVES OF CONDENSED
THIENOPYRIMIDINES. 22*. SYNTHESIS
OF 2-SUBSTITUTED 4-THIOXOPYRANO-
[4',3':4,5]THIENO[2,3-d]PYRIMIDINES
A. P. Mkrtchyan, A. Sh. Oganisyan, Art. Sh. Oganisyan , and A. S. Noravyan
A method has been developed for the synthesis of 4-thioxopyrano[4',3':4,5]thieno[2,3-d]pyrimidines
from the corresponding acyl derivatives of 2-amino-3-cyanothieno[2,3-c]pyran.
Keywords: pyranothienopyrimidine, pyranothiophene, acylation, heterocyclization.
We have previously synthesized a series of 2-thioxothieno[2,3-d]pyrimidines by the heterocyclization of
thioureide derivatives of 2-amino-3-ethoxycarbonylthieno[2,3-c]pyrans [1,2].
In the present work a suitable method has been developed for the preparation of new derivatives of
thieno[2,3-d]pyrimidines containing reactive thio group in position 4 of the pyrimidine ring.
By acylation of 2-amino-3-cyanothienopyran (1) [3] with propionyl (2a), butyryl (2b), and phenylacetyl
(2c) chlorides the corresponding acyl derivatives 3a-c were obtained. On treatment of compounds 3a-c with
hydrogen sulfide in a mixture of triethylamine and pyridine intramolecular cyclization occurred to give the
required 2-substituted 4-thioxopyrano[4',3':4,5]thieno[2,3-d]pyrimidines 4a-c.
CN
CN
NH
RCOCl
2a–c
H2S
O
O
Et3N Py
NH2
S
R
S
C
O
1a
3a–c
S
NH
O
S
4a–c
N
R
2−4 a R = Et, b R = Bu, c R = CH2Ph
_______
* For part 21 see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences, Armenian
Republic, Erevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 2, 267-269, February, 2005. Original article submitted October 22, 2002; revision submitted February 17,
2004.
0009-3122/05/4102-0235©2005 Springer Science+Business Media, Inc.
235

The S-substituted compounds 6a-l were formed exclusively in all cases when compounds 4a-c were
treated with the chloroacetamides 5a-e in the presence of KOH.
S CH2 C NHR1
O
N
R1NHCCH2Cl
4a−c
+
KOH
O
S
R
N
O
6a−l
5a−e
5a, 6a R1 = H, 5b, 6b,e,i R1 = C6H4Me-4, 5c, 6c,f,j R1 = C6H4Br-4, 5d, 6d,g,k R1 = CHPh2,
5e, 6h,l R1 = C6H4Me-3, 6a-d R = Et, e-h R = Bu; i-l R = CH2Ph
TABLE 1. Characteristics of Compounds 3, 4, and 6
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Rf*
Yield, %
N
S
3а
3b
3c
4а
4b
4c
6а
6b
6c
6d
6e
6f
C13H16N2O2S
C15H20N2O2S
C18H18N2O2S
C13H16N2OS2
C15H20N2OS2
C18H18N2OS2
C15H19N3O2S2
C22H25N3O3S2
C21H22 BrN3O2S2
C28H29N3O2S2
C24H29N3O3S2
C23H26 BrN3O2S2
C30H33N3O2S2
C24H29N3O2S2
C27H27N3O3S2
C26H24 BrN3O2S2
C33H31N3O2S2
C27H27N3O2S2
10.28
10.60
9.42
9.60
8.68
8.59
9.88
10.00
9.01
9.09
8.38
8.19
12.30
12.46
9.20
9.48
8.18
8.53
8.21
8.35
8.81
8.92
8.24
8.07
7.81
7.91
9.34
9.23
12.01
12.12
10.68
10.96
9.70
9.81
22.95
22.86
20.85
20.78
18.48
18.71
18.68
18.99
14.70
14.45
13.31
13.01
12.48
12.78
13.62
13.59
12.40
12.31
12.18
12.05
14.01
14.06
12.50
12.67
11.38
11.55
162-163
158-159
167-169
238-240
235-237
250-252
218-220
225-226
225-227
232-233
212-214
228-230
220-221
208-210
240-242
200-201
233-235
218-220
0.61
0.58
0.56
0.52
0.53
0.50
0.49
0.52
0.61
0.54
0.53
0.61
0.58
0.62
0.59
0.48
0.57
0.63
80.2
78.4
82.1
79.8
80.2
83.1
75.5
77.7
84.5
74.3
78.8
83.6
75.6
72.3
77.5
84.5
72.2
75.8
6g
6h
6i
8.12
8.32
7.42
7.58
7.40
7.43
8.29
8.59
6j
6k
6l
11.53
11.33
13.23
13.09
_______
* Solvent systems: ethyl acetate–hexane, 1:2 (compounds 3a-c); ethyl
acetate–acetone, 1:2 (compounds 4a-c), acetone–hexane, 1:1 (compounds
6a-l).
236

EXPERIMENTAL
IR spectra of nujol mulls were recorded with UR-20 spectrometer, 1H NMR spectra were recorded with
Varian Mercury 300 machine (300 MHz) in CDCl3 (compounds 3a,3b) and DMSO-d6 (compounds 4a,b and
6a,d,j). TLC was carried out on Silufol UV-254 plates, developed with iodine.
The characteristics of the synthesized compounds 3, 4, and 6 are given in Table 1.
2-Acylamino-3-cyano-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyrans 3a-c. Freshly distilled acid
chloride 2a-c (0.1 mol) was added with stirring to compound 1 (20.8 g, 0.1 mol) in dry benzene (150 ml). The
mixture was boiled for 4h, cooled, the precipitate was filtered off, washed with ether, and dried to give products
1
3a-c. IR spectra (thin layer), ν, cm-1: 1675 (C=O), 2200 (C≡N), 3300 (NH). H NMR spectra, δ, ppm (J , Hz):
2
2
compound 3a – 11.30 (1H, s, NH); 4.58 (2H, t, J = 2.0, 2H-7); 3.00 (2H, t, J = 2.0, 2H-4); 2.55 (2H, q,
3J = 7.5, COCH2); 1.30 (6H, s, 2CH3-5); 1.22 (2H, t, 3J = 7.5, CH2CH3); compound 3b – 11.32 (1H, s , NH);
2
2
4.58 (2H, t, J = 2.0, 2H-7); 2.89 (2H, t, J = 2.0, 2H-4); 2.47 (2H, t, 3J = 7.5, COCH2); 1.62 (2H, tt, 3J1 = 7.5,
3J2 = 7.3, COCH2CH2); 1.37 (2H, tq, J1 = J2 = 7.3, CH2CH3); 1.27 (6H, s, 2CH3-5); 0.95 (3H, t, J = 7.3,
3
3
3
CH2CH3).
2-R-6,6-Dimethyl-4-thioxo-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidines
4a-c.
Hydrogen sulfide was passed through a solution of compounds 3a-c (0.1 mol) in triethylamine (100 ml) and
pyridine (50 ml) for 8 h at 80°C. The cooled mixture was poured into water (250 ml), the crystals of compounds
4a-c were filtered off, washed with water, and recrystallized from butanol. IR spectra (thin layers), ν, cm-1: 1430
(C=S), 1625 (C=N), 3200 (NH). 1H NMR spectra, δ, ppm (J, Hz): compound 4a – 13.36 (1H, s, NH); 4.71 (2H,
3
t, 2J = 2.0, 2H-8); 3.18 (2H, t, 2J = 2.0, 2H-5); 2.75 (2H, t, J = 7.5, CH2CH3); 1.30 (6H, s, 2CH3-6); 1.29 (3H, t,
3J = 7.5, CH2CH3); compound 4b – 13.23 (1H, s, NH); 4.58 (2H, t, 2J = 2.0, 2H-8); 2.98 (2H, t, 2J = 2.0, 2H-5);
2.48 (2H, t, 3J = 7.5, HetCH2) 1.64 (tt, 3J1 = 7.5, 3J2 = 7.3, HetCH2CH2); 1.40 (2H, tq, 3J1 = 3J2 = 7.3, CH2CH3);
1.30 (6H, s, 2CH3-6); 0.95 (3H, t, 3J = 7.3, CH2CH3).
2-R-6,6-Dimethyl-4-(thioxomethylamido)-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]-pyrimidines
6a-l. An N-substituted chloroacetamide 5a-e (0.01 mol) was added with stirring to a solution of compound 4a-c
(0.01 mol) and KOH (0.01 mol) in 80% ethanol (60 ml). The precipitated crystals of products 6a-l were filtered
1
off, washed with ether and dried. IR spectra (thin layers), ν, cm-1: 1620 (C=N), 1680 (C=O). H NMR spectra,
δ, ppm (J, Hz): compound 6a – 7.08 (2H, br. s, NH2); 4.77 (2H, t, 2J = 2.0, 2H-8); 3.93 (2H, s, S-CH2); 3.00 (2H,
t, 2J = 2.0, 2H-5); 2.93 (2H, q, 3J = 7.5, CH2CH3); 1.37 (3H, t, 3J = 7.5, CH2CH3); 1.34 (6H, s, 2CH3); compound
3
3
2
6d – 8.71 (1H, d, J = 8.5, NH); 7.17-7.30 (10H, m, 2C6H5); 6.14 (1H, d, J = 8.5, CH); 4.78 (2H, t, J = 2.0,
2
3
2H-8); 4.09 (2H, s, S-CH2); 3.01 (2H, t, J = 2.0, 2H-5); 2.75 (2H, q, J = 7.5, CH2CH3); 1.34 (6H, s, 2CH3-6);
3
3
1.25 (3H, t, J = 7.6, CH2CH3); compound 6j – 10.12 (1H, s, NH); 7.54 (2H, d, J = 8.9, C6H4); 7.36 (2H, d,
3J = 8.9, C6H4); 7.26 (2H, dd, J = 7.5, J = 2.2, C6H5); 7.05-7.15 (3H, m, C6H5); 4.77 (2H, t, J = 2.0, 2H-8);
3
4
2
4.14 (4H, s, S-CH2, CH2C6H5); 3.01 (2H, t, 2J = 2.0, 2H-5); 1.34 (6H, s, 2-CH3-6).
REFERENCES
1.
A. Sh. Oganisyan, A. S. Noravyan, I. A. Dzhagatspanyan, and G. T. Melikyan, Khim.-Farm. Zh., 37,
No. 1, 13 (2003).
2.
3.
A. Sh. Oganisyan and A. S. Noravyan, Khim. Geterotsikl. Soedin., 1388 (1998).
A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, R. A. Akopyan, N. E. Akopyan, and
S. A. Vartanyan, Khim.-Farm. Zh., 11, No. 9, 38 (1977).
237