Derivatives of condensed thieno[2,3-d]-pyrimidines. 20. Synthesis of 2-substituted 5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2,3-d] pyrimidin-4(3H)-ones and 5,6,7,8-tetrahydrobenzo-[b]thieno[2,3-d]pyrimidin-4- ones

Article abstract of DOI:10.1007/s10593-006-0098-y

We have developed a method for obtaining 2-substituted 3-amino-6,6- dimethyl-5,6-dihydro-8H-pyrano[4′,3′:4,5]-and 5,6,7,8- tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones, converted by deamination to the corresponding dihydropyranothieno-3H-pyrimidino

Full text of DOI:10.1007/s10593-006-0098-y

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
DERIVATIVES OF CONDENSED THIENO[2,3-d]-
PYRIMIDINES. 20*. SYNTHESIS OF 2-SUBSTITUTED
5,6-DIHYDRO-8H-PYRANO[4',3':4,5]THIENO[2,3-d]PYRIMIDIN-
4(3H)-ONES AND 5,6,7,8-TETRAHYDROBENZO-
[b]THIENO[2,3-d]PYRIMIDIN-4-ONES
A. P. Mkrtchyan and A. S. Noravyan
We have developed a method for obtaining 2-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-
pyrano[4',3':4,5]- and 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones, converted by
deamination to the corresponding dihydropyranothieno-3H-pyrimidinones.
Keywords: substituted 5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones, 5,6,7,8-tetra-
hydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones, acylation, deamination.
Continuing our research on synthesis of condensed thieno[2,3-d]pyrimidin-4-ones [2], we have
developed
a
convenient method for obtaining 2-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-
pyrano[4',3':4,5]- and 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones 3a-g and 4a-e respectively,
without separating the intermediate N-acylated 2-amino-3-ethoxycarbonylthiophenes, by treatment of the
reaction mixture after acylation of compounds 1, 2 with hydrazine hydrate. The method is convenient, and
ensures a good yield of the end products 3a-g, 4a-e.
O
O
O
R
R
R
R
R
R
NaNO2/AcOH
C
NH
1. R1COCl
NNH2
R1
OEt
X
X
X
S
R1
N
2. NH2–NH2
NH2
S
S
N
5a,b, 6a,b
3a–g, 4a–e
1, 2
1, 3a-g, 5a,b X = O, R = Me, 2, 4a-e, 6a,b X = CH2, R = H; 3a, 4a, 6a R1 = –(CH2)6Me,
3b, 4b, 5a, 6b R1 = –(CH2)7Me, 3c, 4c R1 = –CH2CHMe2, 3d, 4d R1 = –CH2C6H4OMe-4,
3e, 4e, 5b R1 = –(CH2)2Ph, 3f R1 = –CH2C6H3Cl2-2,6, 3g R1= –CH2C6H3(OMe)2-3,4
_______
* For Communication 19, see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic of
Armenia, Yerevan 375014; e-mail: amartirosyam@web.am. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 441-444, March, 2006. Original article submitted September 20, 2000.
392
0009-3122/06/4203-0392©2006 Springer Science+Business Media, Inc.

Earlier [3] we developed a method for deamination of 2-substituted 3-aminothieno[2,3-d]pyrimidin-
4(3H)-ones to form 2-substituted 3H-thieno[2,3-d]pyrimidin-4(3H)-ones by treatment with a mixture of nitrous
and acetic acids. We used this method to obtain the corresponding 2-R1-3H-pyrimidin-4-ones 5a,b, 6a,b in high
yields from compounds 3b,e, 4a,b.
TABLE 1. Characteristics of Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield %
N
S
3a
3b
3c
3d
3e
3f
C18H27N3O2S
12.11
12.02
11.60
11.56
13.70
13.66
11.45
11.31
11.93
11.82
10.36
10.25
10.55
10.47
13.46
13.15
12.64
12.59
15.37
15.14
12.53
12.30
13.02
12.91
8.15
8.03
8.39
8.22
9.36
9.20
8.93
8.80
9.25
9.20
8.90
8.82
10.52
10.43
8.70
8.63
9.22
9.02
7.94
7.81
8.19
7.99
10.26
10.03
9.87
9.61
11.77
11.56
9.62
9.40
9.98
9.85
9.34
9.20
9.42
9.41
10.60
10.53
10.18
10.06
143-145
186-188
162-163
199-200
178-179
227-228
194-195
120-121
126-128
149-152
156-158
200-202
186-188
226-227
170-172
157-158
64.7
88.8
C19H29N3O2S
C15H21N3O2S
C19H21N3O3S
C19H21N3O2S
C18H17Cl2N3O2S
C20H23N3O4S
C17H25N3OS
C18H27N3OS
C14H19N3OS
C18H19N3O2S
C18H19N3OS
C19H28N2O2S
C19H20N2O2S
C17H24N2OS
C18H26N2OS
83.3
78.5
62.5
61.0
3g
4a
4b
4c
4d
4e
5a
5b
6a
6b
75.6
70.0
67.2
85.08
68.40
73.15
88.80
80.00
89.70
98.50
TABLE 2. IR Spectra and 1H NMR Spectra of Synthesized Compounds
IR spectrum,
Com-
pound
1H NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
1
2
3
3a
1665-1670 (CO),
4.84 (2Н, s, NH2); 4.80 (2H, t, J = 1.8, H2-8,8);
3170-3345 (NH2) 3.01 (2H, t, J = 1.8, H2-5,5); 2.99 (2H, t, J = 8.0, 2-CH2–);
1.80 (2H, m, 2-CH2CH2–); 1.50-1.25 (8H, m, 2-CH2CH2(CH2)4–);
1.35 (6H, s, 6,6-(CH3)2); 0.90 (3H, t, J = 6.8, 2-(CH2)6CH3)
3b
3c
1665-1672 (CO),
4.83 (2Н, br. s, NH2); 4.80 (2H, t, J = 1.8, H2-8,8);
3173-3325 (NH2) 3.00 (2H, t, J = 1.8, H2-5,5); 2.99 (2H, t, J = 8.0, 2-CH2–);
1.80 (2H, m, 2-CH2CH2–); 1.25-1.50 (10H, m, 2-CH2CH2(CH2)5–);
1.35 (6H, s, 6,6-(CH3)2); 0.90 (3H, t, J = 6.8, 2-(CH2)7CH3)
1660-1675 (CO),
4.83 (2Н, s, NH2); 4.79 (2H, t, J = 1.7, H2-8,8); 3.00 (2H, t,
3140-3340 (NH2) J = 1.7, H2-5,5); 2.90 (2H, d, J = 7.2, 2-CH2); 2.29 (1H, d,
J = 6.6, 2-CH2CH); 1.34 (6H, s, 6,6-(CH3)2); 1.03 (6H, d,
J = 6.6, 2-CH2CH(CH3)2)
393

TABLE 2 (continued)
1
2
3
3d
1680-1700 (CO),
7.28 (2H, d, J = 8.7, HAr); 6.86 (2H, d, J = 8.7, HAr); 4.82 (2H, s,
3125-3335 (NH2) NH2); 4.81 (2H, t, J = 1.9, H2-8,8); 4.29 (2H, s, 2-CH2); 3.79 (3H, s,
OCH3); 2.99 (2H, t, J = 1.9, H2-5,5)
3e
3f
1675-1680 (CO),
7.20-7.35 (5H, m, HAr); 4.67 (2H, br. s, NH2); 4.81 (2H, br. s,
3155-3320 (NH2) H2-8,8); 3.32-3.15 (4H, m, 2-CH2CH2Ph); 3.01 (2H, br. s, H2-5,5);
1.35 (6H, s, 6,6-(СH3)2)
7.38 (2H, m, HAr); 7.27 (1H, m, HAr); 5.79 (2H, br. s, NH2);
1685-1660 (CO),
3200-3395 (NH2) 4.67 (2H, t, J = 1.9, H2-8,8); 4.64 (2H, s, 2-CH2);
3.90 (2H, t, J = 1.9, Н2-5,5); 1.30 (6H, s, 6,6-(СH3)2)
3g
1660-1680 (CO),
6.92 (1H, d, J = 1.8, HAr); 6.89 (1H, dd, J1 = 8.1, J2 = 1.8, HAr);
3170-3380 (NH2) 6.81 (1H, d, J = 8.1, HAr); 4.87 (2H, br. s, NH2); 4.81 (2H, t, J = 1.8,
H2-8,8); 4.29 (2H, s, 2-CH2); 3.00 (2H, t, J = 1.8, H2-5,5);
3.86 (6H, s, (OCH3)2); 1.35 (6H, s, 6,6-(СH3)2)
4a
4b
1660-1680 (CO),
4.83 (2Н, br. s, NH2); 2.99 (2H, m, H2-5,5); 2.76 (2H, m, H2-8,8);
3160-3380 (NH2) 2.97 (2H, t, J = 8.0, 2-CH2–); 1.78 (2H, m, 2-CH2CH2–); 1.86 (4H,
m, H2-6,6, Н2-7,7); 1.25-1.50 (8H, m, 2-CH2–CH2(CH2)4);
0.89 (3H, t, J = 6.6, 2-(CH2)6CH3)
1670-1680 (CO),
4.82 (2Н, br. s, NH2); 2.77 (2H, t, J = 7.0, 2-СH2–);
3165-3390 (NH2) 2.75 (2H, m, H2-5,5); 2.96 (2H, m, Н2-8,8);
1.87 (4H, m, H2-6,6, Н2-7,7); 1.80 (2Н, m, 2-CH2CH2–);
1.20-1.50 (10H, m, 2-CH2CH2(CH2)5); 0.97 (3H, t,
J = 6.7, 2-(CH2)7CH3)
4c
1660-1690 (CO),
4.82 (2Н, br. s, NH2); 2.77 (2H, m, H2-5,5); 3.00 (2H, m, H2-8,8);
3170-3355 (NH2) 1.87 (4H, m, H2-6,6, Н2-7,7); 2.89 (2H, d, J = 7.2, 2-CH2СН);
2.29 (1H, sеpt, J = 6.6, 2-CH2CH); 1.02 (6H, d, J = 6.6,
2-CH2CH(CH3)2)
4d
1680-1690 (CO),
3175-3385 (NH2) 4.81 (2H, br. s, NH2); 4.26 (2H, s, 2-CH2);
3.79 (3Н, s, OCH3); 2.79 (2Н, m, H2-8,8); 2.99 (2Н, m, Н2-5,5);
7.26 (2H, d, J = 8.7, HAr); 6.85 (2H, d, J = 8.7, HAr);
1.87 (4Н, m, H2-6,6, H2-7,7)
4e
5a
1665-1685 (CO),
7.20–7.35 (5H, m, HPh); 3.12 (2Н, t, J = 8.0, 2-СН2); 3.35 (2Н, t,
3175-3390 (NH2) J = 8.0, СН2С6Н5); 4.70 (2H, br. s, NH2); 2.78 (2Н, m, Н2-5,5);
3.00 (2Н, m, Н2-8,8)
1665-1670 (CO),
3170 (NH)
11.72 (1H, br. s, NH); 4.83 (2Н, br. s, Н2-8,8); 3.02 (2Н,
br. s, Н2-5,5); 2.73 (2Н, t, J = 7.1, 2-СН2); 1.85 (2Н, q,
J = 7, 2-СН2СН2); 1.20-1.50 (10Н, m, 2-СН2СН2(СН2)5);
0.89 (3Н, t, J = 6.7, 2-(СН2)7СН3); 1.38 (6Н, s, 6,6-(СН3)2)
5b
6a
1670-1675 (CO),
3170 (NH)
12.54 (1H, br. s, NH); 7.18-7.30 (5Н, m, НPh); 4.84 (2Н, t,
J = 1.7, Н2-8,8); 3.03 (2Н, t, J = 1.7, Н2-5,5);
3.05-3.20 (4Н, m, 2-СН2СН2С6Н5); 1.35 (6Н, s, 6,6-(СН3)2)
1670-1673 (CO),
3185 (NH)
11.91 (1H, s, NH); 3.02 (2Н, m, Н2-8,8); 2.79 (2Н, m, Н2-5,5);
1.88 (4H, m, Н2-6,6, H2-7,7); 2.73 (2Н, t, J = 7.8, 2-СН2);
1.83 (2Н, m, 2-СН2СН2); 1.24-1.46 (8Н, m, 2-СН2СН2(СН2)4);
0.88 (3Н, t, J = 6.6, 2-(СН2)6СН3)
6b
1661-1675 (CO),
3180 (NH)
11.90 (1H, br. s, NH); 3.00 (2Н, br. s, Н2-5,5); 2.80 (2Н, br. s,
Н2-8,8); 1.84 (4H, m, Н2-6,6, H2-7,7); 2.73 (2Н, t, J = 6.2, 2-СН2);
1.80 (2Н, m, 2-СН2СН2); 1.20-1.50 (10Н, m, 2-СН2СН2(СН2)5);
0.90 (3Н, t, J = 7.0, 2-(СН2)7СН3)
EXPERIMENTAL
The 1H NMR spectra were obtained on a Varian Mercury-300 spectrometer (300 MHz), provided under
a grant within the US CRDF RESC 17-S program. The solvent was CDCl3 or DMSO-d6 (in the case of
compound 2f). The IR spectra were taken on a UR-20 in nujol. The purity of the compounds obtained was
monitored by TLC on Silufol UV-254 plates in the system 1:1:1 chloroform–ethyl acetate–acetone or 2:1 ethyl
alcohol–chloroform.
The characteristics of the synthesized compounds are given in Tables 1 and 2.
394

2-R1-3-Amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones
3a-e and -5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones 4a-e. Dry triethylamine (0.01 mol)
was added to a solution of compounds 1 and 2 (0.01 mol) in dry benzene (30 ml), and then the corresponding
acid chloride (0.01 mol) in benzene (5 ml) was added dropwise. The mixture obtained was boiled for 4 h, then
water (30 ml) was added and the benzene was evaporated off. The precipitate formed was filtered out, washed
with water, and boiled for 8 h with hydrazine hydrate (5 ml) and n-butanol (15 ml). The crystals of products 3
and 4 precipitating out upon cooling were filtered out, washed with alcohol and then water, and then dried at
50°C and recrystallized from alcohol.
2-R1-3H-6,6-Dimethyl-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones
5a,b
and -5,6,7,8-tetrahydrobenzo[b]thieno]2,3-d]pyrimidin-4(3H)-ones 6a,b. A solution of sodium nitrite (1.0 g,
0.015 mol) in water (3 ml) was added dropwise to a solution of compounds 3b,e and 4a,b (0.01 mol) in acetic
acid (15 ml) at room temperature. After 5 h, the mixture was diluted with water and recrystallized from a 10:1
n-butanol–DMF mixture. The crystals of product 5 and 6 were filtered out and dried.
REFERENCES
1.
2.
3.
A. Sh. Oganisyan, A. S. Noravyan, A. A. Karapetyan, M. S. Aleksanyan, and Yu. T. Struchkov, Khim.
Geterotsikl. Soedin. 85 (2004).
A. P. Mkrtchyan, S. G. Kazaryan, A. S. Noravyan, R. A. Akopyan, I. A. Dzhagatspanyan,
N. E. Akopyan, and A. G. Akopyan, Khim.-Farm. Zh., 19, 557 (1985).
S. G. Kazaryan, A. S. Noravyan, and G. A. Gevorgyan, Khim. Geterotsikl. Soedin., 941 (1999).
395