Condensed thienopyrimidines. 14. Synthesis of 10h-thiopyrano-[4″,3″: 4′,5′]thieno[2′,3′: 4,5]-pyrimido[2,3-c]-1,2,4-triazines

Article abstract of DOI:10.1023/A:1012752004506

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N′-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2- hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H -thiopyrano[4″,3″:4′,5′] thieno[2′,3′:4,5]pyrimido-[2,3-c]-1,2,4-triazines.

Full text of DOI:10.1023/A:1012752004506

Chemistry of Heterocyclic Compounds, Vol. 37, No. 8, 2001
CONDENSED THIENOPYRIMIDINES.
14*. SYNTHESIS OF 10H-THIOPYRANO-
[4'',3'': 4',5']THIENO[2',3': 4,5]-
c
PYRIMIDO[2,3- ]-1,2,4-TRIAZINES
A. Sh. Oganisyan, G. O. Grigoryan, and A. S. Noravyan
Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular
cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization
products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of
the latter with pyruvic acid gave the novel 10H-thiopyrano[4'',3'':4',5']thieno[2',3':4,5]pyrimido-
[2,3-c]-1,2,4-triazines.
Keywords: 10H-thiopyrano[4'',3'': 4',5']thieno[2',3': 4,5]pyrimido[2,3-c]-1,2,4-triazines.
Despite a systematic investigation carried out on a series of derivatives of condensed thieno[2,3-d]-
pyrimidines [2], compounds of the group indicated condensed with other heterocycles have been little studied.
In this regard, it is of current and of long term interest to develop convenient methods for the synthesis and
investigation of the biological activity of the novel, condensed thiopyranothienopyrimidotriazine derivatives
1a,b.
Treatment of 2-amino-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]thiopyran (2) [3] with
methyl or phenyl isothiocyanates gave the corresponding N'-methyl(phenyl)thioureido derivatives 3a,b. The
latter can then undergo an intramolecular cyclization in the presence of potassium hydroxide to form the
dihydrothiopyranothienopyrimidines 4a,b and also their 2-methylthio derivatives 5a,b. The heteryl hydrazines 6
were prepared by the reaction of compounds 4a,b with hydrazine hydrate in butanol. The target compounds 1a,b
were synthesized by two methods, the first being the reaction of the hydrazines 6a,b with pyruvic acid in
methanol and subsequent cyclization of the hydrazones formed 7a,b in acetic acid and the second method a one
stage reaction via refluxing the hydrazines 6a,b and pyruvic acid in ethanol in the presence of acetic acid
without separation of the intermediate hydrazones 7a,b.
_______
* For Communication 13 see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, Armenian Republic National Academy of Sciences,
Yerevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8,
pp. 1116-1119, August, 2001. Original article submitted June 16, 1999.
0009-3122/01/3708-1025$25.00©2001 Plenum Publishing Corporation
1025

COOEt
NH2
COOEt
NHC(S)NHR
O
RNCS
KOH
S
S
S
S
2
3a,b
O
N
R
S
R
MeI
N
S
S
N
H
N
SMe
S
S
5a,b
H2NNH2
4a,b
H2NNH2
O
N
R
N
S
S
NHNH2
MeC(O)COOH
6a,b
MeC(O)COOH
O
MeCOOH
O
N
R
R
N
MeCOOH
COOH
N
S
S
S
N
N
N
NHN
S
C
7a,b
O
Me
Me
1a,b
1, 3–7 a R = Me; b R = Ph
EXPERIMENTAL
1
IR spectra were taken on a UR-20 instrument using vaseline oil, H NMR spectra on a Varian T-60
spectrometer (60 MHz), and mass spectra on an MX-1303 instrument with an ionization energy of 70 eV. TLC
was carried out on Silufol UV-254 plates and revealed using iodine vapor.
c
3-Carbethoxy-5,5-dimethyl-2-(N'-methylthioureido)-4,5-dihydro-7H-thieno[2,3- ]thiopyran (3a).
A mixture of compound 2 (2.71 g, 0.01 mol), methyl isothiocyanate (0.73 g, 0.01 mol), and butanol (50 ml) was
refluxed for 10 h and held for about 16 h at room temperature. The precipitated crystals were filtered off and
washed with ether to give the product 3a (3.28 g, 76%); mp 173-175°C (ethanol), Rf 0.62 (CCl4–acetone, 2:1).
1
IR spectrum (thin film), , cm-1: 1450 (C=S), 1670 (C=O), 3300 (NH). H NMR spectrum (CDCl3), , ppm,
ν
δ
J (Hz): 12.06 (1H, s, NH); 6.90 (1H, d, J = 5, NH–CH3); 4.25 (2H, q, J = 7, OCH2); 3.62 (2H, s, 7,7-H2); 3.06
(3H, d, J = 5, NH–CH3); 2.89 (2H, s, 4,4-H2); 1.35 (3H, t, J = 7, CH2CH3); 0.98 (6H, s, 5,5-(CH3)2). Found, %:
C 47.42; H 5.53; N 8.38; S 27.61. C14H20N2O2S3. Calculated, %: C 47.80; H 5.85; N 8.13; S 27.92.
c
3-Carbethoxy-5,5-dimethyl-2-(N'-phenylthioureido)-4,5-dihydro-7H-thieno[2,3- ]thiopyran (3b).
From a mixture of compound 2 (2.71 g, 0.01 mol) and phenyl isothiocyanate (1.35 g, 0.01 mol) as described
above to give the product 3b (3.1 g, 77%); mp 181-182°C (ethanol), Rf 0.64 (hexane–acetone–ethyl acetate,
1:1:1). IR spectrum (thin film), , cm-1: 1470 (C=S), 1670 (C=O), 3200 (NH). H NMR spectrum (CDCl3),
1
ν
, ppm, J (Hz): 12.06 (1H, s, NH); 8.46 (1H, NH–C6H5); 7.40 (5H, s, Ph); 4.23 (2H, q, J = 7, CH2CH3); 3.50
δ
(2H, s, 7,7-H2); 2.86 (2H, s, 4,4-H2); 1.40 (3H, t, J = 7 , CH2CH3); 0.97 (6H, s, 5,5-(CH3)2). Found, %: C 56.30;
H 5.53; N 6.68; S 23.91. C19H22N2O2S3. Calculated, %: C 56.12; H 5.45; N 6.89; S 23.65.
1026

d
3,3,6-Trimethyl-4-oxo-2-thioxo-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidine (4a).
A mixture of compound 3a (3.44 g, 0.01 mol) and potassium hydroxide (1.12 g, 0.02 mol) in 50% ethanol
(50 ml) was refluxed for 3 h, cooled, and acidified with 10% hydrochloric acid to weakly acid reaction. The
precipitated crystals were filtered off, washed with water, and dried to give the product 4a (2.85 g, 96%);
mp 274-276°C (butanol), Rf 0.58 (acetone–CCl4, 1:1). IR spectrum (thin film), , cm-1: 1725 (C=O), 3400-3425
ν
(NH). Found, %: C 48.02; H 4.51; N 9.70; S 32.0. C12H14N2OS3. Calculated, %: C 48.29; H 4.72; N 9.38;
S 32.23.
d
6,6-Dimethyl-4-oxo-3-phenyl-2-thioxo-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidine
(4b). From a mixture of compound 3b (4.06 g, 0.01 mol) and potassium hydroxide (1.12 g, 0.02 mol) as
described above to give the product 4b (3.44 g, 95%); mp 286-288°C (butanol), Rf 0.65 (CHCl3–CCl4, 2:1).
Found, %: C 56.30; H 4.28; N 8.0; S 26.42. C17H16N2OS3. Calculated, %: C 56.63; H 4.47; N 7.77; S 26.68.
d
3,6,6-Trimethyl-2-methylthio-4-oxo-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidine (5a).
Methyl iodide (1.42 g, 0.01 mol) in 90% ethanol (5 ml) was added dropwise with stirring to a solution of
compound 4a (2.98 g, 0.01 mol) and potassium hydroxide (0.56 g, 0.01 mol) in ethanol (20 ml). Stirring was
continued for 2 h and the reaction mixture was then diluted with water (10 ml). The crystals formed were
filtered off, washed with ether, and dried to give the product 5a (2.85 g, 91%); mp 228-229°C (ethanol), Rf 0.56
(acetone–hexane, 1:1). 1H NMR spectrum (CDCl3), , ppm: 3.72 (2H, s, 8,8-H2); 3.50 (3H, s, NCH3); 2.98 (2H,
δ
s, 5,5-H2); 2.58 (3H, s, S–CH3); 1.20 (6H, s, 6,6-(CH3)2). Found, %: C 50.21; H 5.30; N 8.67; S 30.91.
C13H16N2OS3. Calculated, %: C 50.0; H 5.12; N 8.97; S 30.76.
d
6,6-Dimethyl-2-methylthio-4-oxo-3-phenyl-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]-
pyrimidine (5b). From a mixture of compound 4b (3.60 g, 0.01 mol), potassium hydroxide (0.56 g, 0.01 mol),
and methyl iodide (1.42 g, 0.01 mol) as described above to give the product 5b (3.38 g, 90%); mp 240-242°C
1
(ethanol), Rf 0.58 (CHCl3–ethyl acetate, 1:1). H NMR spectrum (CDCl3), , ppm: 7.24-7.80 (5H, m, Ph); 3.70
δ
(2H, s, 8,8-H2); 3.0 (2H, s, 5,5-H2); 2.63 (3H, s, S–CH3); 1.27 (6H, s, 6,6-(CH3)2). Found, %: C 57.61; H 4.66;
N 7.40; S 25.60. C18H18N2OS3. Calculated, %: C 57.72; H 4.84; N 7.48; S 25.68.
d
2-Hydrazino-3,6,6-trimethyl-4-oxo-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidine (6a).
A. Concentrated hydrazine hydrate (10 ml) was added to a solution of compound 4a (2.98 g, 0.01 mol) in
butanol (25 ml). The mixture was refluxed for 8 h and held for about 16 h at room temperature. The precipitated
crystals were filtered off, washed with water and then ether, and dried to give the product 6a (2.66 g, 89%);
mp 244-246°C (ethanol), Rf 0.61 (hexane–ethyl acetate, 1:3). IR spectrum (thin film), , cm-1: 1450 (arom.),
ν
1700 (C=O), 3200-3500 (NHNH2). Found, %: C 49.0; H 5.15; N 18.45; S 21.40. C12H16N4OS2. Calculated, %:
C 48.62; H 5.40; N 18.90; S 21.63.
B. Similarly from compound 5a (3.12 g, 0.01 mol) and concentrated hydrazine hydrate (5 ml) in butanol
(25 ml) to give the product 6a (2.37 g, 80%); mp 244-246°C (pyridine). A mixed sample of compound 6a
prepared using methods A and B did not show a depression of melting point.
d
2-Hydrazino-6,6-dimethyl-4-oxo-3-phenyl-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidine
(6b). A. From a mixture of compound 4b (3.60 g, 0.01 mol) and concentrated hydrazine hydrate (10 ml) in
butanol (25 ml) as described before in method A to give the product 6b (3.2 g, 89%); mp 256-258°C (pyridine),
Rf 0.60 (CHCl3–CCl4, 1:2). Mass spectrum, m/z (Irel, %): 358 (M+) (100), 325 (50), 315 (47), 295 (34), 285 (40),
284 (31), 269 (28), 254 (20), 192 (14), 152 (20). Found, %: C 56.77; H 4.78; N 15.91; S 17.80. C17H18N4OS2.
Calculated, %: C 56.95; H 5.0; N 15.63; N 17.88.
B. From compound 5b (3.74 g, 0.01 mol) and concentrated hydrazine hydrate (5 ml) in butanol (25 ml)
as described in method A to give the product 6b (3.02 g, 85%); mp 256-258°C (pyridine). A mixed sample of
compound 6b prepared using methods A and B did not show a depression of melting point.
d
2-(3,6,6-Trimethyl-4-oxo-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidyl) Hydrazone
of 2-Ketopropanoic Acid (7a). A mixture of compound 6a (2.90 g, 0.01 mol) and pyruvic acid (0.88 g,
0.01 mol) in methanol (80 ml) was refluxed for 3 h. The crystals produced on cooling were filtered off, washed
with water, and dried in air to give the product 7a (3.1 g, 83%); mp 211-213°C (pyridine), Rf 0.48
1027

(chloroform–pyridine–butanol–acetic acid, 3:3:3:1). IR spectrum (thin film), , cm-1: 1560 (arom), 1600, 1620
ν
(C=N), 1700 (C=O), 3220 (NH), 3380 (OH). Found, %: C 53.48; H 5.83; N 16.25; S 10.05. C15H18N4O3S2.
Calculated, %: C 53.87; H 5.42; N 16.75; S 9.59.
d
2-(6,6-Dimethyl-4-oxo-3-phenyl-5,6-dihydro-8H-thiopyrano[4',3':4,5]thieno[2,3- ]pyrimidyl)
Hydrazone of 2-Ketopropanoic Acid (7b). From compound 6b (3.58 g, 0.01 mol) and pyruvic acid (0.88 g,
0.01 mol) as described before to give the product 7b (3.77 g, 88%); mp 209-211°C (pyridine), Rf 0.60
(chloroform–pyridine–butanol–acetic acid, 3:3:3:1). IR spectrum (thin film), , cm-1: 1550 (arom.), 1600, 1640
ν
(C=N), 1685, 1740 (C=O), 3220 (NH), 3370 (OH). Found, %: C 56.71; H 4.97; N 12.70; S 14.50.
C20H20N4O3S2. Calculated, %: C 56.50; H 4.70; N 13.07; S 14.96.
2,5,8,8-Tetramethyl-1,6-dioxo-7,8-dihydro-10H-thiopyrano[4'',3'':4',5']thieno[2',3':4,5]pyrimido-
c
A. A mixture of the hydrazone
[2,3- ]-1,2,4-triazine (1a).
7a
(3.34 g, 0.01 mol) and acetic acid (40 ml) was
refluxed for 14 h. The crystals formed on cooling were filtered off, washed with water, and dried to give the
product 1a (2.5 g, 73%); mp 281-282°C (pyridine), Rf 0.62 (chloroform–pyridine–hexane, 1:1:2). IR spectrum
(thin film), , cm-1: 1550 (C=C), 1580 (C=N), 1680, 1700 (C=O). H NMR spectrum (pyridine), , ppm: 4.03
1
ν
δ
(2H, s, 10,10-H2); 3.76 (3H, s, NCH3); 3.38 (2H, s, 7,7-H2); 2.58 (3H, s, CH3); 1.40 (6H, s, 8,8-(CH3)2).
Found, %: C 51.46; H 4.50; N 15.89; S 17.92. C15H16N4O2S2. Calculated, %: C 51.70; H 4.63; N 16.08; S 18.40.
B. A mixture of compound 6a (2.96 g, 0.01 mol) and pyruvic acid (0.88 g, 0.01 mol) in acetic acid
(15 ml) and ethanol (50 ml) was refluxed for 10 h. The crystals formed on cooling were filtered off, washed
with water and then ether, and dried in air to give the product 1a (2.4 g, 69%); mp 281-282°C. A mixed sample
of compound 1a prepared using methods A and B did not show a depression of melting point.
2,8,8-Trimethyl-1,6-dioxo-5-phenyl-7,8-dihydro-10H-thiopyrano[4'',3'':4',5']thieno[2',3':4,5]-
c
pyrimido[2,3- ]-1,2,4-triazine (1b).
7
A. From the hydrazone (4.28 g, 0.01 mol) according to method A for the
synthesis of compound 1a to give the product 1b (3.7 g, 90%); mp 302-304°C (ethanol), Rf 0.60 (chloroform–
acetone–hexane, 3:3:1). IR spectrum (thin film), , cm-1: 1550 (C=C), 1580, 1600 (C=N), 1680, 1700 (C=O).
ν
1H NMR spectrum (CDCl3), , ppm: 7.76-7.20 (5H, m, Ph); 3.92 2H, s, 10,10-H2); 3.22 (2H, s, 7,7-H2); 2.57
δ
(3H, s, CH3); 1.22 (6H, s, 8,8-(CH3)2). Found, %: C 58.06; H 4.80; N 13.25; S 15.15. C20H18N4O2S2.
Calculated, %: C 58.51; H 4.42; N 13.65; S 15.62.
B. From compound 6b (3.58 g, 0.01 mol) according to method B for the synthesis of compound 1a to
give the product 1b (2.8 g, 68%); mp 301-304°C, identical in Rf and melting point to the sample synthesized by
method A.
REFERENCES
1.
2.
3.
A. Sh. Oganisyan, A. S. Noravyan, A. A. Karapetyan, M. S. Aleksanyan, and Yu. T. Struchkov, Khim.
Geterotsikl. Soedin., 681 (2001).
A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, A. A. Akopyan, N. E. Akopyan, and
S. A. Vartanyan, Khim.-Farm. Zh., 38 (1977).
A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, I. M. Nazaryan, N. E. Akopyan, and
S. A. Vartanyan, Khim.-Farm. Zh., 20 (1977).
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