Derivatives of condensed thieno[2,3-d]pyrimidines. 15*. Synthesis of 2-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4′,3′:4,5]-thieno[2, 3-d]pyrimidin-4-ones

Article abstract of DOI:10.1023/A:1015355729220

A method has been developed for the preparation of 2-R-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2, 3-d]pyrimidin-4-ones based on 2-R-amino-3-ethoxycarbonylpyrano-[2,3-c]thiophenes. It has been established that their cyclization with hydrazine hydrate requires vigorous conditions.

Full text of DOI:10.1023/A:1015355729220

Chemistry of Heterocyclic Compounds, Vol. 38, No. 2, 2002
DERIVATIVES OF CONDENSED
d
THIENO[2,3- ]PYRIMIDINES. 15*. SYNTHESIS
OF 2-SUBSTITUTED 3-AMINO-6,6-DIMETHYL-
5,6-DIHYDRO-8H-PYRANO[4',3':4,5]-
d
THIENO[2,3- ]PYRIMIDIN-4-ONES
A. P. Mkrtchyan, A. S. Noravyan, and V. M. Petrosyan
A method has been developed for the preparation of 2-R-substituted 3-amino-6,6-dimethyl-5,6-dihydro-
8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-ones based on 2-R-amino-3-ethoxycarbonylpyrano-
[2,3-c]thiophenes. It has been established that their cyclization with hydrazine hydrate requires
vigorous conditions.
Keywords: pyranone, pyranothienopyrimidine, pyranothiophene, thienopyrimidine, thiophene.
The readily obtainable 2-acylamino-3-ethoxycarbonylthiophenes [2,3] are frequently used as starting
materials for the synthesis of condensed thieno[2,3-d]pyrimidin-4-ones.
This paper reports a suitable method for the synthesis of new 2-R-3-aminothieno[2,3-d]pyrimidin-4-ones
1a-h from 2-R-amido-3-ethoxycarbonylthiophenes 2a-i. We developed this method to prepare
2-alkyl-substituted 3-aminothienopyrimidin-4-ones [4].
Compounds 2a-i were synthesized by acylation of 2-amino-3-ethoxycarbonylthiophene with the
corresponding acid chloride. The amido esters 2a-h were converted into the thieno[2,3-d]pyrimidines 1a-i by
treatment with hydrazine hydrate. Compounds 2 appeared to be less reactive than the corresponding
2-alkyl-substituted compounds [4].
O
NH2
R
CO2Et
NHCOR
CO2Et
NH2
Me
Me
Me
Me
Me
Me
N
N2H4
RCOCl
O
O
O
S
N
S
S
3
2a–i
1a–h
1, 2 a R = Ph; b R = CH2Ph; c R = C6H4OMe-4; d R = C6H4OBu-4; e R = C6H4Cl-2;
f R = -pyridyl; g R = C H (OMe) -3,4; h R = C H OMe-3; i R = CHPh
γ
6
3
2
6
4
2
_______
* For paper 14, see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, Armenian National Academy of Sciences, Erevan
375014, Republic of Armenia; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 2, 261-264, February, 2002. Original article submitted June 16, 1999; revision submitted May 19, 2000.
238
0009-3122/02/3802-0238$27.00©2002 Plenum Publishing Corporation

TABLE 1. Characteristics of 2-R-Amido-3-ethoxycarbonylthiophenes 2a-1 and 2-R-3-Aminothieno[2,3-d]pyrimidin-4-
ones 1a-h
Found, %
——————
Com-
IR spectrum
Empirical
formula
Yield,
%
Calculated, %
mp, °С
1H NMR spectrum, δ, ppm, coupling constant (J), Hz
ν, cm-1
pound
N
3
S
4
1
2
5
6
7
8
C19H21NO4S
3.93
3.88
8.99
8.92
156-157 1680 (NCO);
1700 (COO);
12.61 (1H, s, NH); 8.96-7.46 (5H, m, HPh); 4.70 (2H, s, 7,7-H2);
4.42 (2H, q, J = 7.0, CH2); 3.48 (2H, s, 4,4-H2); 1.33 (3H, t, J = 7, CH2CH3);
1.20 (6H, s, 5,5-(CH3)2)
73.5
2a
3280 (NH)
C20H23NO4S
C20H23NO5S
C23H29NO5S
3.76
3.72
8.65
8.58
98-99
1678 (NCO);
1705 (COO);
3282 (NH)
12.46 (1H, s, NH); 7.35 (5H, s, HPh); 4.65 (2H, s, 7,7-H2); 4.25 (2H, q, J = 7.1, OCH2);
3.80 (2H, s, CH2Ph); 2.70 (2H, s, 4,4-H2); 1.41 (3H, t, J = 7.1, CH2CH3);
1.30 (6H, s, 5,5-(CH3)2)
80.5
78.0
65.1
2b
2c
2d
3.60
3.59
8.52
8.48
160-161 1683 (NCO);
12.25 (1H, s, NH); 8.00 (2H, d, J = 6.0, HAr); 7.01 (2H, d, J = 6.0, HAr);
4.80 (2H, s, 7,7-H2); 4.40 (2H, t, J = 6.0, OCH2); 3.90 (3H, s, OCH3);
3.10 (2H, s, 4,4-H2); 1.41 (3H, t, J = 6.0, CH2CH3); 1.35 (6H, s, 5,5-(CH3)2)
1700 (COO);
3279 (NH)
3.32
3.24
7.33
7.42
128-130 1678 (NCO);
12.20 (1H, s, NH); 8.00 (2H, d, J = 7.5, HAr); 7.01 (2H, d, J = 7.5, HAr);
1700 (COO);
4.78 (2H, s, 7,7-H2); 4.40 (2H, q, J = 7.5, OCH2); 4.10 (2H, t, J = 7.5, O-CH 2CH3);
2.80 (2H, s, 4,4-H2); 1.81 (2H, t, J = 7.5, OCH2CH2); 1.62-1.42 (2H, m, CH2CH3);
1.41 (3H, t, J = 7.5, OCH2CH3); 1.26 (6H, s, 5,5-(CH3)2); 1.00 (3H, t, J = 7.5, CH3)
3275 (NH)
C19H20ClNO4S
C18H20N2O4S
C21H25NO6S
C20H23NO5S
3.87
3.90
8.86
8.94
139-140 1680 (NCO);
1710 (COO);
12.20 (1H, s, NH); 7.60–7.40 (4H, m, HAr); 4.82 (2H, s, 7,7-H2);
4.65 (2H, q, J = 7.2, OCH2); 3.10 (2H, s, 4,4-H2); 1.45 (3H, t, J = 7.2, CH2CH3);
1.40 (6H, s, 5,5-(CH3)2)
61.0
52.0
76.5
78.9
2e
2f
3275 (NH)
7.80
7.77
8.75
8.89
170-171 1685 (NCO);
12.45 (1H, s, NH); 8.85 (2H, d, J = 6.1, HAr); 7.85 (2H, d, J = 6.1, HAr);
4.80 (2H, s, 7,7-H2); 4.40 (2H, q, J = 7, OCH2); 2.80 (2H, s, 4,4-H2);
1.41 (3H, t, J = 7, CH2CH3); 1.30 (6H, s, 5,5-(CH3)2)
1715 (COO);
3283 (NH)
3.12
3.33
7.75
7.62
142-144 1680 (NCO);
12.30 (1H, s, NH); 7.90 (1H, d, J = 8.5, HAr); 7.79 (1H, s, HAr);
2g
2h
1710 (COO);
6.99 (1H, d, J = 8.5, HAr); 4.81 (2H, s, 7,7-H2); 4.25 (2H, q, J = 7.1, OCH2);
3275 (NH)
4.00 (6H, s, 2-OCH3); 2.95 (2H, s, 7,7-H2); 1.40 (3H, t, OCH2); 1.30 (6H, s, 5,5-(CH3)2)
3.64
3.50
8.13
8.02
134-136 1670 (NCO);
12.20 (1H, s, NH); 7.61(2H, s, J = 7.8, HAr); 7.41 (1H, t, J = 7.8, HAr);
7.18 (1H, d, J = 7.8, HAr); 4.78 (2H, s, 7,7-H2); 4.40 (2H, t, J = 7.26, OCH2);
3.90 (3H, s, OCH3); 2.80 (2H, s, 4,4-H2); 1.41 (3H, t, J = 7.2, CH2CH3);
1.38 (6H, s, 5,5-(CH3)2)
1715 (COO);
3275 (NH)

TABLE 1 (continued)
1
2
3
4
5
6
7
8
C26H27NO4S
3.20
3.11
7.09
7.13
118-119 1675 (NCO);
1705 (COO);
11.30 (1H, s, NH); 7.35 (10H, s, HPh); 5.19 (1H, s, СН); 4.70 (2H, s, 7,7-H2);
4.20 (2H, q, J = 7.1, OCH2); 2.70 (2H, s, 4,4-H2); 1.36 (3H, t, J = 7.1, CH2-CH3);
1.30 (6H, s, 5,5-(CH3)2)
2i
53.2
3276 (NH)
C17H17N3O2S
C18H19N3O2S
C18H19N3O2S
C21H25N3O3S
12.76
12.83
9.71
9.79
224-225 1665-1670 (CO);
7.80-7.50 (5H, m, HPh); 5.10 (2H, s, NH2); 4.82 (2H, s, 8,8-H2); 3.08 (2H, s, 5,5-H2);
51.0
47.05
50.0
1a
1b
1c
1d
3180-3250 (NH2)
1.28 (6H, s, 6,6-(CH3)2)
12.36
9.44
212-214 1665-1675 (CO);
3185-3300 (NH2)
7.30 (5H, br. s, HAr); 5.70 (2H, s, NH2); 4.70 (2H, s, 8,8-H2); 4.30 (2H, s, CH2Ph);
2.85 (2H, s, 5,5-H2); 1.25 (6H, s, 6,6-(CH3)2)
12.30
9.39
11.82
11.75
9.03
8.96
230-232 1660-1675 (CO);
7.85 (2H, d, J = 6,HAr); 7.00 (2H, d, J = 6,HAr); 5.10 (2H, s, NH2); 4.85 (2H, s, 8,8-H2);
3190-3310 (NH2)
3.90 (3H, s, OCH3); 3.06 (2H, s, 5,5-H2); 1.38 (6H, s, 6,6-(CH3)2)
10.58
8.12
198-200 1665-1670 (CO);
3150-3300 (NH2)
7.85 (2H, d, J = 6, HAr); 6.91 (2H, d, J = 6, HAr); 5.60 (2H, s, NH2); 4.72 (2H, s, 8,8-H2); 45.4
4.05 (2H, t, J = 6.05, OCH2); 2.92 (2H, s, 5,5-H2); 1.75-1.81 (2H, m, CH2CH3);
1.45-1.60 (2H, m, OCH2CH2); 1.32 (6H, s, 6,6-(CH3)2); 1.00 (3H, t, J = 6,CH3)
10.51
8.02
C17H16ClN3O2S
C16H16N4O2S
C19H21N3O4S
11.65
11.59
8.93
8.84
212-214 1670-1675 (CO);
3185-3320 (NH2)
7.50 (4H, m, HAr); 5.00 (2H, s, NH2); 4.85 (2H, s, 8,8-H2); 3.10 (2H, s, 5,5-H2);
61.1
48.5
50.0
1e
1f
1.40 (6H, s, 6,6-(CH3)2)
17.21
9.68
217-218 1660-1675 (CO);
8.80 (2H, d, J = 6.3, HHet); 7.75 (2H, d, J = 6.3, HHet); 4.95 (2H, s, NH2);
17.11
9.76
3180-3335 (NH2)
4.82 (2H, s, 8,8-H2); 3.10 (2H, s, 5,5-H2); 1.40 (6H, s, 6,6-(CH3)2)
10.93
10.84
8.33
8.27
176-177 1665-1670 (CO);
3150-3300 (NH2)
7.90 (1H, d, J = 8.5, HAr); 7.78 (1H, s, HAr); 6.98 (1H, d, J = 8.5, HAr);
5.10 (2H, s, NH2); 4.82 (2H, s, 8,8-H2); 4.00 (6H, d, J = 8.5, OCH3);
2.95 (2H, s, 5,5-H2); 1.38 (6H, s, 6,6-(CH3)2)
1g
C18H19N3O3S
11.62
11.75
8.88
8.96
218-220 1665-1675 (CO);
3180-3335 (NH2)
7.66 (2H, t, J = 7.9, HAr); 7.45 (1H, t, J = 7.8, HAr); 7.20 (1H, d, J = 7.8, HAr);
5.00 (2H, s, NH2); 4.80 (2H, s, 8,8-H2); 3.85 (3H, s, OCH3); 2.80 (2H, s, 5,5-H2);
1.30 (6H, s, 6,6-(CH3)2)
52.0
1h

It was found by varying the reaction conditions (time, temperature, and medium) that to obtain the best
yields the process should be carried out in boiling n-butanol for a long time (15-20 h). The decreased activity is
probably explained by steric hindrance caused by the substituent R, consequently the diphenylmethylamide 2i
did not cyclize to the desired thienopyrimidine under these reaction conditions.
EXPERIMENTAL
1
IR spectra of nujol mulls were recorded with a UR-20 spectrometer. H NMR spectra were recorded
with a Varian Mercury 300 spectrometer (working frequency 300 MHz) using US CRDF RESC 17-S programs.
The solvents were CDCl3 (compounds 1a,b,e,f,h, 2a-i) and DMSO-d6 (compounds 1b,d,g). Purity of the
compounds synthesized was monitored by TLC on Silufol UV-254 plates with the eluent chloroform–ethyl
acetate–ether (0.5:1.0:0.5), and development with UV light.
2-N-Acylamino-3-ethoxycarbonyl-5,5-dimethyl-4,5-dihydro-7-thieno[2,3-c]pyrans (2a-i). Dry
triethylamine (0.01 mol) was added to a solution of compound 3 (0.01 mol) in dry benzene (30 ml), and then the
corresponding acid chloride (0.01 mol) was added dropwise. The mixture was boiled (4 h) and then cold water
(30 ml) was added, and the benzene was evaporated. The precipitate was filtered off, washed with water and
methanol, and recrystallized from ethanol to give compounds 2a-i.
2-R-3-Amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-ones (1a-h).
Hydrazine hydrate (10 ml, 85%) was added to a suspension of an amido ester 2 (0.01 mol) in n-butanol (15 ml)
and the mixture was boiled for 15-20 h. The crystals which formed on cooling were filtered off, washed with
ethanol and water, dried at 50 C, and recrystallized from ethanol to give 1.
°
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241