Synthesis of pyrano- and thiopyranopyrido-thienopyrimidines and pyrimidothienoiso-quinolines with a fused triazole or tetrazole ring at the pyrimidine ring

Article abstract of DOI:10.1007/s10593-012-1148-2

Cyclocondensation reactions gave 7,10-dihydro-8H-pyrano- and 7,10-dihydro-8H-thiopyranopyrido- thienopyrimidines and 7,8,9,10- tetrahydropyrimidothienoisoquinolines with a fused triazole or tetra- zole ring at the pyrimidine ring.

Full text of DOI:10.1007/s10593-012-1148-2

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
SYNTHESIS OF PYRANO- AND THIOPYRANOPYRIDO-
THIENOPYRIMIDINES AND PYRIMIDOTHIENOISO-
QUINOLINES WITH A FUSED TRIAZOLE OR TETRAZOLE
RING AT THE PYRIMIDINE RING
E. G. Paronikyan1, Sh. F. Hakobyan1, and A. S. Noravyan1*
Cyclocondensation reactions gave 7,10-dihydro-8H-pyrano- and 7,10-dihydro-8H-thiopyranopyrido-
thienopyrimidines and 7,8,9,10-tetrahydropyrimidothienoisoquinolines with a fused triazole or tetra-
zole ring at the pyrimidine ring.
Keywords: 7,10-dihydro-8H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[2,3-e]tetrazolo[1,5-c]pyrimidines,
7,10-dihydro-8H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[2,3-e][1,2,4]triazolo[1,5-c(4,3-c)]pyrimidines,
7,8,9,10-tetrahydrotetrazolo[1",5":1',6']pyrimido[4',5':4,5]thieno[2,3-c]isoquinolines, 7,8,9,10-tetrahydro-
[1,2,4]triazolo[1",5":1',6'(4",3":1',6')]pyrimido[4',5':4,5]thieno[2,3-c]isoquinolines, annelation, cyclo-
condensation.
It is known that many condensed compounds with a thienopyrimidine fragment possess biological
activity. Thus, amino-substituted derivatives of these compounds display antitumor [1], antimicrobial [2], and
antiviral activity [3], while their piperazino-substituted analogs are antidepressants [4]; thienopyrimidinones
display antihypertensive activity [5], while alkoxy-substituted derivatives may be used as fungicides [6].
The broad spectrum of biological activity of condensed thienopyrimidines and the possibility of further
modification of their cyclic structure makes these compounds extremely attractive for the synthesis of new
biologically active molecules.
The aim of the present work was to develop synthetic methods for 7,10-dihydro-8H-pyrano- and 7,10-di-
hydro-8H-thiopyranopyridothienopyrimidines and 7,8,9,10-tetrahydropyrimidothienoisoquinolines with a
triazole or tetrazole ring fused at the pyrimidine ring.
These compounds were synthesized starting with previously described condensed derivatives of
thieno[3,2-d]pyrimidine 1a-i [7], which after conversion to the 8-chloro derivatives 2a-i [8], were transformed
to the corresponding 8-hydrazino derivatives 3a-i [9-11]. Compounds 2b, 3b,f have been synthesized for the
first time (Table 1).
_______
*To whom correspondence should be addressed, e-mail: Noravyan@mail.ru.
1Scientific and Technological Center of Organic and Pharmacological Chemistry of National Academy of
Sciences of the Republic of Armenia, A. L. Mnjoyan Institute of Fine Organic Chemistry, 26 Azatutyan Ave.,
Yerevan 0014, Armenia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1491-1497, September, 2012.
Original article submitted April 7, 2011, revision submitted November 28, 2011.
1390
0009-3122/12/4809-1390©2012 Springer Science+Business Media New York

Heating hydrazino derivatives 3a-h at reflux in accord with the procedure A leads to 1,2,4-triazolo[4,3-c]py-
rimidines 4a-l, while heating 3a-c,e-h at reflux in accord with the procedure B leads to ambigouos results. Thus,
hydrazines 3b,h give triazolo[4,3-c]pyrimidines 4c,d,l in high yield, while hydrazines 3a,c,e-g give products
5a-f, which are [1,5-c]-isomers of compounds 4a,b,e,h,j,k. We should also note that maintaining the compound
3g in formic acid (procedure C) leads only to the triazolopyrimidine 4k.
These results suggest the initial formation of triazolopyrimidines 4, which upon the action of acid may
undergo Dimroth rearrangement with cleavage of the pyrimidine ring C–N bond, to give the isomers 5.
Triazolopyrimidines 4 display different stability relative to this rearrangement depending on the nature of
pyrimidine ring substitution, as well as the reaction temperature.
R2
R1
X
R1
X
R2
N
R4
N
O
R4
NH
POCl3
N2H4·H2O
, 2-PrOH
N
Py, 
R3
N
R3
N
S
S
Cl
2a–i
1a–i
R2
R2
R1
R1
X
X
R4
N
Method A
R4
N
N
R5
R5C(OEt)3
N
R3
S
N
R3
N

N
Method B
S
N
4a–l
NHNH2
3a–i
(from 3b,h)
R5CO2H
4c,d,l
R1
(from 3a,c,e–g)
R2

R5CO2H

X
R4
H+
N
[4a,b,e,h,j,k]
N
R3
S
N
N
N
R5
5a–f
1a–3a, 4a,b, 5a,b X = O, R1 = R2 = Me, R3 = morpholin-4-yl, R4 = H; 4a, 5a R5 = H; 4b, 5b R5 = Me;
1b–3b, 4c,d X = O, R1 = R2 = R4 = Me, R3 = morpholin-4-yl; 4c R5 = H; 4d R5 = Me;
1c–3c, 4e, 5c X = O, R1 = R2 = Me, R3 = morpholin-4-yl, R4 = SBn; 4e, 5c R5 = H;
1d–3d, 4f,g X = O, R1 = R2 = Me, R3 = pyrrolidin-1-yl, R4 = H; 4f R5 = H; 4g R5 = Me;
1e–3e, 4h,i, 5d X = O, R1 = R4 = H, R2 = i-Pr, R3 = morpholin-4-yl; 4h, 5d R5 = H; 4i R5 = Me;
1f–3f, 4j, 5e X = S, R1 = R2 = Me, R3 = morpholin-4-yl, R4 = H; 4j, 5e R5 = H;
1g–3g, 4k, 5f X = CH2, R1 = R2 = R4 = H, R3 = morpholin-4-yl, 4k, 5f R5 = H;
1h–3h, 4l X = CH2, R1 = R2 = H, R3 = morpholin-4-yl, R4 = SMe; 4l R5 = H;
1i–3i X = CH2, R1 = R2 = H, R3 = morpholin-4-yl, R4 = SBn
Thus, products 4c,d or 4l, which contain a methyl or methylthio group at the C-4 atom of the
pyrimidine ring, are stable upon heating at reflux in acid, while products 4a,b,h,j,k or 4e, which contain H or
benzylthio groups, are readily converted to the corresponding isomers 5a-f. Product 4k, which is unstable upon
heating at reflux, does not undergo rearrangement to isomer 5k at 50-60°C.
Isomers 4 and 5 with an unsubstituted triazole ring are readily distinguished by the position of the
1
proton signal of this ring in the H NMR spectra [12]: the H-3 proton signals in products 4 are found at
1391

9.23-9.44 ppm, which is downfield from the H-2 signal in products 5 at 8.42-8.57 ppm. This finding is probably
related to the magnetic anisotropy effect in the pyrimidine ring (Table 2). We also note that isomers 4 have
higher melting points than the isomers 5 (Table 1).
Treatment of 8-hydrazinopyrimidines 3b,d,e,i with aqueous sodium nitrite in acetic acid at room
temperature leads to the formation of products, which may exist as a mixture of tetrazolo[1,5-c]thieno-
[3,2-d]pyrimidines 6a-d and their azide tautomers 7a-d.
TABLE 1. Physicochemical Characteristics of Compounds 2-6
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
Mp,°C
Rf
C
H
N
S
2b
3b
3f
C19H21ClN4O2S
C19H24N6O2S
C18H22N6OS2
C19H20N6O2S
C20H22N6O2S
C20H22N6O2S
56.22
56.36
56.75
56.98
5.32
5.23
6.16
6.04
13.62
13.84
20.78
20.98
7.72
7.92
8.14
8.01
253-255
272-274
272-274
324-325
334-336
342-344
75
92
0.61
0.51
0.53
0.53
0.48
0.51
53.65
53.71
5.36
5.51
20.71
20.88
15.81
15.93
94
4A
4b
4c
57.75
57.56
5.16
5.08
21.48
21.20
8.15
8.09
87 (A)
70 (A)
58.41
58.52
5.48
5.40
20.63
20.47
7.65
7.81
58.78
58.52
5.66
5.40
20.33
20.47
7.56
7.81
66 (A)
72 (B)
4d
C21H24N6O2S
59.68
59.41
5.76
5.70
19.61
19.80
7.49
7.55
305-307
75 (A)
68 (B)
0.48
4e
4f
C26H26N6O2S2
C19H20N6OS
C20H22N6OS
C20H22N6O2S
C21H24N6O2S
C19H20N6OS2
C18H18N6OS
60.34
60.21
5.26
5.05
16.38
16.20
12.58
12.36
243-244
307-309
333-335
300-302
298-300
318-320
300-303
91 (A)
92 (A)
94 (A)
88 (A)
66 (A)
94 (A)
0.48
0.52
0.61
0.62
0.51
0.55
0.51
59.78
59.98
5.56
5.30
22.18
22.09
8.56
8.43
4g
4h
4i
60.78
60.89
5.43
5.62
21.54
21.30
8.28
8.13
58.32
58.52
5.46
5.40
20.63
20.47
7.56
7.81
59.32
59.41
5.41
5.70
19.63
19.80
7.32
7.55
4j
55.42
55.32
4.67
4.89
20.52
20.37
15.62
15.55
4k
59.35
59.00
4.77
4.95
22.80
22.93
8.92
8.75
55 (A)
48 (C)
4l
C19H20N6OS2
55.45
55.32
4.77
4.89
20.50
20.37
15.31
15.55
300-301
81 (A)
64 (B)
0.48
5A
5b
5c
5d
5e
5f
C19H20N6O2S
C20H22N6O2S
C26H26N6O2S2
C20H22N6O2S
C19H20N6OS2
C18H18N6OS
C19H21N7O2S
C18H19N7OS
C19H21N7O2S
C24H23N7OS2
57.18
57.56
5.26
5.08
21.31
21.20
8.18
8.09
271-272
248-250
236-238
243-245
253-255
219-221
258-260
214-216
227-229
231-233
75 (B)
72 (B)
83 (B)
61 (B)
75 (B)
71 (B)
97
0.53
0.53
0.51
0.48
0.58
0.53
0.46
0.62
0.64
0.44
58.41
58.52
5.52
5.40
20.31
20.47
7.76
7.81
60.41
60.21
5.14
5.05
16.45
16.20
12.63
12.36
58.32
58.52
5.45
5.40
20.61
20.47
7.64
7.81
55.52
55.32
4.74
4.89
20.52
20.37
15.32
15.55
59.23
59.00
4.78
4.95
22.74
22.93
8.56
8.75
6A
6b
6c
6d
55.62
55.46
5.24
5.14
23.52
23.83
7.62
7.79
56.78
56.68
5.16
5.02
25.58
25.70
8.22
8.41
76
55.62
55.46
5.35
5.14
23.64
23.83
7.81
7.79
97
58.74
58.87
4.56
4.73
20.16
20.03
13.26
13.10
98
1392

R1
X
R2
R1
X
R2
R4
R4
N
N
N
NaNO2
AcOH, H2O
b,d,e,i
3
N
N
R3
R3
S
N
S
N
N
N
7a–d
N3
6a–d
6,7 a X = O, R1 = R2 = R4 = Me, R3 = morpholin-4-yl; b X = O, R1 = R2 = Me,
R3 = pyrrolidin-1-yl, R4 = H; c X = O, R1 = R4 = H, R2 = i-Pr, R3 = morpholin-4-yl;
d X = CH2, R1 = R2 = H, R3 = morpholin-4-yl, R4 = SBn
The formation of such mixtures obtained from hydrazines 3d,e,i was confirmed by the 1H NMR spectra of
products 6a-d, in which a double signal is noted for some protons. The downfield signal of each pair was assigned to
the protons of tetrazole tautomer 6a-d, since they should be subjected to the effect of the aromatic tetrazole ring. The
ratio of tautomers 6 and 7 was determined from the ratio of the peak intensities of the double signals: 6b:7b = 55:45,
6c:7c = 60:40, 6d:7d = 83:17 (the fraction of 7a is insignificant). The azide form 7 probably exists only in DMSO-d6
1
solution during recording of the H NMR spectrum and is not formed during the reaction. The IR spectra of the
reaction products show signals at 1010-1100 cm-1 characteristic for the tetrazole ring, but lack bands at 2130-2150
cm-1 characteristic for the azide form. Similar azidotetrazole tautomerism is observed for tetrazolo[4,5-a]pyridines
[13].
Thus, derivatives of new pentacyclic heterocyclic systems, namely, triazolo[4,3-c]pyrimdines, tri-
azolo[1,5-c]pyrimidines and tetrazolo[1,5-c]pyrimidines, were synthesized in this study. The rearrangement of
condensed triazolo[4,3-c]pyrimidines to triazolo[1,5-c]pyrimidines was carried out. Azidotetrazole tautomerism
was established for condensed tetrazolo[1,5-c]pyrimidines.
EXPERIMENTAL
1
The IR spectra were recorded for vaseline mulls on a UR-20 spectrometer. The H NMR spectra were
recorded on a Mercury 300 spectrometer (300 MHz) in DMSO-d6 with TMS as internal standard. The electron
impact mass spectra were recorded on an MKh-1320 mass spectrometer with direct sample inlet into the ion
source at 50 eV. The elemental analysis was carried out on a Euro EA 3000 Elemental Analyzer. The melting
points were determined on a Boetius hot stage apparatus. The purity of the compounds was monitored by thin-
layer chromatography on Silufol UV-254 plates with eluent systems: 2:1 ethanol–chloroform (for compound
2b), 1:1 ethanol–chloroform (for compounds 3b,f), 3:1:1 1-butanol–pyridine–ethanol (for compounds 4a-l, 5a-f),
1:1 chloroform–benzene (for compounds 6a-d). Iodine vapor was used for visulization.
8-Chloro-2,2,10-trimethyl-5-(morpholin-4-yl)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine (2b). A mixture of compound 1b (3.86 g, 0.01 mol), POCl3 (40.0 ml), and pyridine
(0.5 ml) was heated at reflux for 2 h. Excess POCl3 was distilled off, the residue was cooled, diluted with ice
water (100 ml), and neutralized with NH3 aqueous solution. The crystals formed of compound 2b were washed
with water and recrystallized from 4:1 CHCl3–EtOH,
8-Hydrazino-2,2,10-trimethyl-5-(morpholin-4-yl)-1,4-dihydro-2H-pyrano- (3b) and 8-Hydrazino-
2,2-dimethyl-5-(morpholin-4-yl)-1,4-dihydro-2H-thiopyrano[4",3":4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine
(3f) (General Method). Hydrazine hydrate (2 g, 0.04 mol) was added to compound 2b or 2f (0.01 ml) in
absolute 2-propanol (40 ml), and the mixture was heated at reflux for 5 h. After cooling, the crystalline
precipitate of compound 3b or 3f was filtered off, washed with water and ethanol, and recrystallized from 2:1
chloroform–ethanol.
Thienopyrimidine 3f. IR spectrum, , cm-1: 1580-1600 (C=CAr), 3250-3300 (NHNH2).
1393

TABLE. 1H NMR Spectra of Compounds 2-7
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
1.37 (6H, s, 2-(CH3)2); 2.80 (3H, s, 10-CH3); 3.29-3.33 (4Н, m, N(CH2)2);
3.46 (2Н, s, 1-СН2); 3.77-3.82 (4Н, m, O(CH2)2); 4.68 (2H, s, 4-CH2)
2b
3b
1.34 (6H, s, 2-(CH3)2); 2.51 (3H, s, 10-CH3); 3.15-3.19 (4Н, m, N(CH2)2);
3.51 (2Н, s, 1-СН2); 3.76-3.80 (4Н, m, O(CH2)2); 4.53 (2Н, s, NH2);
4.68 (2H, s, 4-CH2); 8.48 (1H, s, NH)
1.23 (6H, s, 2-(CH3)2); 3.19-3.25 (4Н, m, N(CH2)2); 3.51 (2Н, s, 1-СН2);
3.79-3.84 (4Н, m, O(CH2)2); 3.95 (2H, s, SCH2); 4.51 (2Н, s, NH2);
8.29 (1H, s, NH); 8.41 (1H, s, H-10)
3f
1.38 (6H, s, 8-(CH3)2); 3.20-3.26 (4Н, m, N(CH2)2); 3.51 (2Н, s, 7-СН2);
3.77-3.83 (4Н, m, O(CH2)2); 4.72 (2H, s, 10-CH2); 9.44 (1H, s, H-3(5));
9.47 (1H, s, H-5(3))
4a
1.38 (6H, s, 8-(CH3)2); 2.81 (3H, s, 3-CH3); 3.15-3.23 (4Н, m, N(CH2)2);
3.41 (2Н, s, 7-СН2); 3.76-3.80 (4Н, m, O(CH2)2); 4.66 (2H, s, 10-CH2); 9.38 (1H, s, H-5)
4b
4c
4d
1.37 (6H, s, 8-(CH3)2); 3.01 (3H, s, 5-CH3); 3.19-3.24 (4Н, m, N(CH2)2);
3.50 (2Н, s, 7-СН2); 3.78-3.83 (4Н, m, O(CH2)2); 4.71 (2H, s, 10-CH2); 9.44 (1H, s, H-3)
1.37 (6H, s, 8-(CH3)2); 3.02 (3H, s, 3-CH3); 3.09 (3H, s, 5-CH3);
3.17-3.23 (4Н, m, N(CH2)2); 3.45 (2Н, s, 7-СН2); 3.78-3.82 (4Н, m, O(CH2)2);
4.69 (2H, s, 10-CH2)
1.21 (6H, s, 8-(CH3)2); 3.21-3.25 (4Н, m, N(CH2)2); 3.43 (2Н, s, 7-CH2);
3.78-3.83 (4Н, m, O(CH2)2); 4.71 (2Н, s, 10-CH2); 4.82 (2Н, s, SCH2); 7.23-7.53 (5Н, m, H Ph);
9.23 (1H, s, H-3)
1.38 (6H, s, 8-(CH3)2); 1.94-2.05 (4H, m, N(CH2CH2)2); 3.44 (2Н, s, 7-СН2);
3.58-3.69 (4Н, m, N(CH2)2); 4.80 (2H, s, 10-CH2); 9.35 (1H, s, H-3(5));
9.38 (1H, s, H-5(3))
4e
4f
1.39 (6H, s, 8-(CH3)2); 1.95-2.05 (4H, m, N(CH2CH2)2); 2.82 (3H, s, 3-CH3);
4g
4h
3.44 (2Н, s, 7-СН2); 3.59-3.69 (4Н, m, N(CH2)2); 4.81 (2H, s, 10-CH2); 9.18 (1H, s, H-5)
1.09 (3H, d, 3J = 6.7) and 1.11 (3H, d, 3J = 6.7, CH(CH3)2);
1.89 (1H, sept.d, 3J = 6.7, 3J = 6.3, CH(CH3)2); 3.10-3.18 (2H, m) and
3.26-3.34 (2H, m, N(CH2)2); 3.18-3.23 (1H, m, 7-CHA);
3.47 (1Н, ddd, 3J = 10.9, 3J = 6.3, 3J = 3.4, OCH); 3.69-3.78 (3H, m) and
3.81-3.89 (2H, m, O(CH2)2, 7-CHB); 4.68 (1H, d, 2J = 14.6) and 4.81
(1H, d, 2J = 14.6, 10-CH2); 9.43 (1H, s, H-3(5)); 9.44 (1H, s, H-5(3))
1.09 (3H, d, 3J = 6.7) and 1.10 (3H, d, 3J = 6.7, CH(CH3)2); 1.83-1.95 (1H, m, CH(CH3)2);
2.88 (3H, s, 3-CH3); 3.10-3.34 (5H, m, N(CH2)2 and 7-CHA); 3.44-3.52 (1Н, m, OCH);
3.71-3.78 (3H, m) and 3.80-3.89 (2H, m, O(CH2)2, 7-CHB); 4.68 (1H, d, 2J = 14.7) and
4.82 (1H, d, 2J = 14.7, 10-CH2); 9.27 (1H, s, H-5)
4i
1.41 (6H, s, 8-(CH3)2); 3.24-3.29 (4Н, m, N(CH2)2); 3.80-3.86 (8Н, m, O(CH2)2,
4j
7-CH2 and SCH2); 9.46 (1H, s, H-3(5)); 9.48 (1H, s, H-5(3))
1.77-1.86 (2H, m) and 1.93-2.02 (2H, m, 8,9-СН2); 2.76 (2H, t, 3J = 5.8, 10-СН2);
3.22-3.27 (4H, m, N(CH2)2); 3.62 (2H, t, 3J = 6.5, 7-СН2); 3.78-3.83 (4Н, m, O(CH2)2);
9.39 (1H, s, H-3(5)); 9.41 (1H, s, H-5(3))
4k
1.74-1.84 (2H, m) and 1.91-2.00 (2H, m, 8,9-СН2); 2.71-2.79 (2H, m) and
3.55-3.62 (2H, m, 7,10-CH2); 2.88 (3H, s, SCH3); 3.22-3.27 (4Н, m, N(CH2)2);
3.77-3.83 (4Н, m, O(CH2)2); 9.30 (1H, s, H-3)
4l
1.47 (6H, s, 8-(CH3)2); 3.23-3.29 (4Н, m, N(CH2)2); 3.63 (2Н, s, 7-СН2);
3.78-3.84 (4Н, m, O(CH2)2); 4.87 (2H, s, 10-СН2); 8.57 (1H, s, H-2); 9.45 (1H, s, H-5)
5a
5b
5c
1.39 (6H, s, 8-(CH3)2); 2.78 (3H, s, 2-CH3); 3.17-3.27 (4Н, m, N(CH2)2);
3.46 (2Н, s, 7-СН2); 3.75-3.85 (4Н, m, O(CH2)2); 4.68 (2H, s, 10-СН2); 9.39 (1H, s, H-5)
1.23 (6H, s, 8-(CH3)2); 3.20-3.25 (4Н, m, N(CH2)2); 3.43 (2Н, s, 7-СН2);
3.77-3.82 (4Н, m, O(CH2)2); 4.71 (2Н, s, 10-СН2); 4.82 (2Н, s, SCH2); 7.23-7.45 (5Н, m, H Ph);
8.45 (1H, s, H-2)
1.10 (3H, d, 3J = 6.7) and 1.12 (3H, d, 3J = 6.7, CH(CH3)2);
5d
5e
1.90 (1H, sept.d, 3J = 6.7, 3J = 6.3, CH(CH3)2); 3.12-3.36 (5H, m, N(CH2)2 and 7-CHA);
3.48 (1Н, ddd, 3J = 11.0, 3J = 6.3, 3J = 3.6, OCH); 3.71-3.89 (5H, m, O(CH2)2 and 7-CHB);
4.68 (1H, d, 2J = 14.6) and 4.80 (1H, d, 2J = 14.6, 10-CH2); 8.47 (1H, s, H-2);
9.53 (1H, s, H-5)
1.43 (6H, s, 8-(CH3)2); 3.26-3.31 (4Н, m, N(CH2)2); 3.81-3.86 (8Н, m, O(CH2)2,
7-CH2, and SCH2); 8.48 (1H, s, H-2); 9.58 (1H, s, H-5)
1394

TABLE 2 (continued)
1
2
5f
1.78-1.86 (2H, m) and 1.95-2.04 (2H, m, 8,9-CH2) 2.77 (2H, t, 3J = 5.8, 10-СН2 );
3.25-3.30 (4H, m, N(CH2)2); 3.65 (2H, t, 3J = 6.5, 7-СН2); 3.78-3.83 (4Н, m, O(CH2)2);
8.46 (1H, s, H-2); 9.55 (1H, s, H-5)
6a
1.40 (6H, s, 8-(CH3)2); 3.23 (3H, s, 5-CH3); 3.26-3.31 (4Н, m, N(CH2)2);
3.53 (2Н, s, 7-СН2); 3.79-3.83 (4Н, m, O(CH2)2); 4.71 (2H, s, 10-СН2)
6b, 7b 1.37 (2.7H, s) and 1.40 (3.3H, s, 8-(CH3)2); 1.95-2.05 (4H, m, N(CH2CH2)2);
3.42 (0.9Н, s) and 3.47 (1.1Н, s, 7-СН2); 3.63-3.72 (4Н, m, N(CH2)2);
4.83 (0.9H, s) and 4.85 (1.1Н, s, 10-СН2); 8.77 (0.45H, s) and 9.95 (0.55Н, s, H-5)
6s, 7c 1.07-1.14 (6H, m, CH(CH3)2); 1.82-1.97 (1H, m, CH(CH3)2); 3.11-3.41 (5H, m) and
3.42-3.53 (1H, m, 7-CH2, N(CH2)2); 3.66-3.90 (5H, m, H-8, O(CH2)2);
4.64-4.79 (2H, m, 10-СН2); 8.86 (0.4H, s) and 10.10 (0.6Н, s, H-5)
6d, 7d 1.71-1.82 (2H, m, 8-СН2); 1.84-1.96 (2H, m, 9-СН2); 2.69 (1.65H, t, 3J = 5.7) and
2.74 (0.35H, t, 3J = 5.7, 10-СН2); 3.26-3.32 (4H, m, N(CH2)2); 3.47 (1.65H, t, 3J = 6.5) and
3.52 (0.35H, t, 3J = 6.5, 7-СН2); 3.75-3.82 (4H, m, O(CH2)2); 4.48 (1.65H, s) and
4.81 (0.35H, s, SCH2); 7.17-7.54 (5H, m, H Ph)
7,10-Dihydro-8H-pyrano- and 7,10-Dihydro-8H-thiopyrano[4",3":4',5']pyrido[3',2':4,5]thieno-
[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 4a-j and 7,8,9,10-Tetrahydro[1,2,4]triazolo[4",3":1',6']pyrimido-
[4',5':4,5]thieno[2,3-c]isoquinolines 4k,j (General Method).
A. A mixture of hydrazine 3a-h (0.01 mol) and triethyl orthoformate or triethyl orthoacetate (0.70 mol)
was heated at reflux for 15 h. The crystalline precipitate of product 4a-l obtained upon cooling was filtered off,
washed with water, and recrystallized from 2:1 chloroform–ethanol.
B. Products 4c,d,l were synthesized similarly using compounds 3b,h (the description is given below for
the products 5) and were identical in their Rf and mp values to samples obtained according to procedure A.
C. A mixture of compounds 3g (3.56 g, 0.01 mol) and formic acid (10 ml) was maintained at 50-60°C
for 2 h. The cooled mixture was neutralized by adding 1 N aqueous potassium hydroxide. The crystalline
precipitate of compound 4k was filtered off, washed with water, and recrystallized from 2:1 chloroform–
ethanol. Product 4k was identical in its Rf and mp values to a sample prepared according to procedure A.
Compound 4a. Mass spectrum, m/z (Irel, %): 396 [M]+ (100), 372 (78), 356 (28), 326 (25), 302 (62).
Compound 4b. Mass spectrum, m/z (Irel, %): 410 [M]+ (100), 351 (51), 294 (46), 241 (20), 187 (63),
130 (12).
Compound 4f. Mass spectrum, m/z (Irel, %): 380 [M]+ (100), 365 (17), 351 (15), 325 (16), 310 (72), 296
(15).
Compound 4g. IR spectrum (neat), , cm-1: 1580 (C=Carom), 1600 (C=N). Mass spectrum, m/z (Irel, %):
412 [M]+ (100), 383 (7), 381 (36), 355 (52), 354 (27), 327 (21).
Compound 4j. Mass spectrum, m/z (Irel, %): 412 [M]+ (100), 381 (46), 379 (61), 355 (52), 353 (68), 321
(47).
7,10-Dihydro-8H-pyrano- and 7,10-Dihydro-8H-thiopyrano[4",3":4',5']pyrido[3',2':4,5]thieno-
[2,3-e][1,2,4]triazolo[1,5-c]pyrimidines 5a-e and 11-(Morpholin-4-yl)-7,8,9,10-tetrahydro[1,2,4]triazolo-
[1",5":1',6']pyrimido[4',5':4,5]thieno[2,3-c]isoquinoline (5f) (General Method). A mixture of compounds
3a,c,e-g (0.01 mol) and formic acid (68 ml, 1.80 mol) or acetic acid (69 ml, 1.20 mol) was heated for 5 h at
reflux in a flask equipped with a condenser. The excess acid was then distilled off and the residue was
neutralized by adding aqueous potassium hydroxide. The crystalline product 5a-f was filtered off, washed with
water, and recrystallized from 2:1 chloroform–ethanol.
7,10-Dihydro-8H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[2,3-e]tetrazolo[1,5-c]pyrimidines 6a-c
and
5-Benzylsulfanyl-11-(morpholin-4-yl)-7,8,9,10-tetrahydrotetrazolo[1",5":1',6']pyrimido[4',5':4,5]-
thieno[2,3-c]isoquinoline (6d) (General Method). A solution of sodium nitrite (5 g, 0.072 mol) in water
(25 ml) was added in portions to a suspension of compounds 3b,d,e,i (0.010 mol) in acetic acid (69 ml,
1395

1.200 mol). The reaction mixture was maintained at room temperature for 48 h with occasional stirring. The
crystalline precipitate was filtered off, washed with water, and recrystallized from DMSO.
Products 6a-d. IR spectrum, , cm-1: 1010-1100 (tetrazole), 1580-1600 (C=CAr), 1620-1630 (C=N).
REFERENCES
1.
2.
M. J. Munchhof and S. B. Sobolov-Jaynes, WO Pat. Appl. 9924440; Chem. Abstr., 131, 5266z (1999).
J. G. Buchanan, D. A. Craven, R. H. Wightman, and M. R. Harden, J. Chem. Soc., Perkin Trans. 1, 195
(1991).
3.
4.
L. G. Webber, African Pat. Appl. 7202648 (1979); Chem. Abstr., 92, 35997 (1980).
N. Kunihiro, N. Kazamasa, T. Akihiro, E. Mitsuo, and K. Kyoji, JP Pat. Appl. 6200427 (1987); Chem.
Abstr., 107, 59050 (1987).
5.
6.
7.
R. K. Russell, J. B. Prees, R. A. Rampulla, J. J. McNally, R. Falotico, J. A. Keiser, D. A. Bright, and
A. Tobia, J. Med. Chem., 31, 1786 (1988).
R. Preuss, G. Salbeck, W. Schaper, and P. Broun, EU Pat. Appl. 534341; Chem. Abstr., 120, 245136
(1994).
E. G. Paronikyan, Sh. F. Hakobyan, and A. S. Noravyan, Khim. Geterotsikl. Soedin., 1245 (2008)
[Chem. Heterocycl. Comp., 44, 1003 (2008)].
8.
9.
Sh. F. Hakobyan, Khim. Zh. Armenii, 59, 105 (2006).
E. G. Paronikyan, A. S. Noravyan, Sh. F. Hakobyan, I. A. Dzhagatspanyan, I. M. Nazaryan, and R. G.
Paronikyan, Khim.-Farm. Zh., 41, No. 9, 14 (2007) [Pharm. Chem. J., 41, 466 (2007)].
E. G. Paronikyan, Sh. F. Hakobyan, and A. S. Noravyan, Khim. Zh. Armenii, 62, 140 (2009).
E. G. Paronikyan, S. N. Sirakanyan, Sh. F. Hakobyan, and A. S. Noravyan, Fourth Eurasian Meeting on
Heterocyclic Chemistry, Thessaloniki, Greece (2006), p. 327.
10.
11.
12.
13.
C. J. Shishoo, M. B. Devani, G. V. Ullas, S. Anantham, and V. S. Bhadti, J. Heterocycl. Chem., 18, 43
(1981).
H. Ritter and H. H. Licht, J. Heterocycl. Chem., 32, 585 (1995).
1396