Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1H- pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones

Article abstract of DOI:10.1007/s10593-011-0850-9

The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H- 1,2,4-triazepine-3-thiones and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of 7,8-dihydrothiazolo[3,2-b][1,2,4] triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-dihydro-1H- pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.

Full text of DOI:10.1007/s10593-011-0850-9

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
REACTION OF ACETYLENEDICARBOXYLIC ACIDS ESTERS
WITH 4,5-DIHYDRO-1H-PYRAZOLE-1-CARBOTHIOAMIDES
AND 3,4,5,6-TETRAHYDRO-2H-1,2,4-TRIAZEPINE-3-THIONES
N. A. Danilkina1*, L. E. Mikhaylov,1 and B. A. Ivin2*
The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones
and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of
7,8-dihydrothiazolo[3,2-b][1,2,4]triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-di-
hydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of
methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.
Keywords: 4,5-dihydro-1H-pyrazole-1-carbothioamides, 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thi-
ones, 1,3-thiazin-4-ones, 1,3-thiazol-4-ones, thiazolo[3,2-b][1,2,4]triazepin-3-ones, acetylenecarboxylic
acids esters, C–H coupling constants.
The reaction of thioamides with acetylenecarboxylic acids esters is a convenient method for the synthe-
sis of thiazoles and thiazines [1]. There have been no reports concerning reactions of pyrazolecarbothioamides
and triazepinethione with alkyl propynoates although such reactions should open a convenient approach to the
preparation of new derivatives of pyrazoline and triazepine containing thiazole and thiazine rings. Recently,
pyrazolinecarbothioamides have been attracting increasing attention since some of these compounds display
hypotensive [2], antidepressant [3], and anti-inflammatory activity [4], serve as inhibitors of cholinesterase
[6-8], monoamine oxidase A [3], and monoamine oxidase B [3, 5], and have antiamebic action [6-8]. Interest in
bicyclic compounds containing azepine rings has arisen upon finding immunosuppressant and antitumor activity
for such natural products as coformicine [12–15] and pentostatin [12–15] and their synthetic analogs [16–19].
Thus, there is current interest in the synthesis of new derivatives of pyrazoline and azepines.
In the present work, we studied the reactions of pyrazolecarbothioamides and triazepinethiones with
acetylenecarboxylic acid esters and developed methods for the synthesis of new derivatives of pyrazoline and
triazepine containing thiazole and thiazine rings.
_______
*To whom correspondence should be addressed, e-mail: danilkina.natalia@gmail.com.
1St. Petersburg State University, 26 Universitetskiy Pr., 198504 St. Petersburg, Russia
2St. Petersburg State Chemical-Pharmaceutical Academy, 14 Prof. Popova St., St. Petersburg 197022, Russia;
e-mail: boris.ivin@mail.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1079–1095, July, 2011. Original
article submitted January 28, 2011.
886
0009-3122/11/4707-0886©2011 Springer Science+Business Media, Inc.

2-(4,5-Dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones 3a–f* were isolated in the reaction of 4,5-di-
hydro-1H-pyrazole-1-carbothioamides 1a–c with acetylenecarboxylic acid esters 2a–c.
Me
Me
7
Me
8
7
8
7
8
R
O
9
R2
9
Me
R
R
N
9
O
O
R1
N
N
N
R1
R1
OMe
N
2
N
R
or
2
2a–c
MeO
OMe
N
2
R1
NH2
1a–c
S
N
2d
N
S
N
S
N
4
4
4
R2
O
AcOH, 118°C
O
10
6
6
O
CHCl3/Et3N
or AcOH
S
5
6
O
5
10
O
5
H
MeO
H
OMe
H
3a–f
4a–c
5a–c
1a, 3ac, 4a R = R1 = Me; 1b, 3d,e, 4b R = Ph, R1 = H; 1c, 3f, 4c R = 4-MeOC6H4, R1 = H;
2a, 3c,e,f R2 = H; 2b, 3a,d R2 = Ph; 2c, 3b R2 = 4-MeOC6H4
The structure of these compounds was supported by spectral methods (Tables 1–4) and by X-ray diffrac-
tion crystallographic analysis for compound 3d (Tables 5–7, Fig. 1).
Since a second ester group exists in dimethyl acetylenedicarboxylate (DMAD) (2d), we might have
expected that the reaction of this diester with thioamides 1a–c would lead not only to methyl esters of 2-(3-me-
thyl-4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-4H-1,3-thiazine-6-carboxylic acids 5a–c but also derivatives of 2-[2-
(3-methyl-4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acid 4a–c.
The method of Vögeli [20], based on analysis of the nJC–H coupling constants between H-5 and exocyclic
C(10) and endocyclic C(4) carbonyl carbon atoms, was used to establish the size of the ring formed. The 13C NMR
spectra of the compounds without proton broadband decoupling and with selective decoupling from H-5, 7-H3C,
C(8)H2, 9-(H3C)2, and H3CO (Table 3) were taken for an unequivocal assignment of the signals of the carbon
atoms of interest and determination of the scalar JC(4)–H(5) and JC(10)–H(5) constants. Since JC(4)–H(5) = 5.0 and
JC(10)-H(5) = 1.6 Hz for the compounds obtained (Table 3), the number of bonds separating atom H(5) from atom
C(4) is 3 and of atom H(5) from atom C(10) is 2. This finding is in accordance with the structure of thiazolidi-
nes 4a–c but not with the structure of 1,3-thiazines 5a–c [20]. Thus, this reaction proceeds to give only
3
pyrazolylthiazolidines 4a–c. Furthermore, the values of JC(4)–H(5) = 5.0 Hz indicates (Z)-configuration of the
exocyclic double bond in compounds 4a–c, which corresponds to the mechanism reported for the trans addition of
the SH group to the triple bond in DMAD [1].
It has been reported earlier that the reaction of 5,7-diaryl2,4,5,6-tetrahydro-3H-1,2,4-triazepine-
3-thiones with electrophilic agents such as -halo ketones [21] and ethyl bromoacetate [22] leads to
thiazolotriazepines. However, there have been no reports concerning the reactions of derivatives of
2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones with acetylenecarboxylic acid esters. On the other hand, we
might have expected that the reaction of triazepinethione 6a with ester 2b would be a convenient method for the
synthesis of previously unreported thiazinotriazepines 8 or 9. However, the reaction of 5,5,7-trimethyl-
2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione (6a) with methyl phenylpropynoate (2b) in the presence of
sodium methylate leads only to Michael adduct 7. The conversion of triazepinethione 6a is only 35%. Michael
adduct 7 does not cyclize to give thiazinotriazepines 8 or 9 upon heating in acetic acid at 118°C for 1 h, in
pyridine at 120°C for 3 h or in diglyme at 161°C for 1 h.
_______
*Here and henceforward, the numbering of the atoms was selected for convenience in discussion of the NMR
spectra and does not correspond to the IUPAC nomenclature numbering.
887

TABLE 1. Characteristics of compounds 3a–h, 4a–c, and 11a,b
Yield, %
Found,
Com-
pound
Empirical
formula
m/z [M+H]+
Calculated,
m/z [M+H]+
by method
Rf
Mp, °С*
(reaction time, h)
А
B
3a
3b
3c
C16H17N3OS
C17H19N3O2S
C10H13N3OS
C20H17N3OS
C14H13N3OS
C15H15N3O2S
C11H15N3OS
C17H19N3OS
C12H15N3O3S
C16H15N3O3S
C17H17N3O4S
C12H15N3O3S
C14H17N3O3S
300.1169
300.1171
0.34
0.29
0.24
0.31
0.20
0.16
0.25
0.36
0.39
0.33
0.36
0.47
0.56
172–174
159–161
160–162
182–184
250–252
225–228
184–186
194–196
173–176
187–190
198–200
183–185
82–85
43 (8)
40 (7)
55 (4)
39 (10)
83 (2)
53 (2)
29 (15)
330.1271
330.1276
447.1627*2
447.1637
3d
3e
348.1180
348.1171
272.0856
272.0858
3f
302.0961
302.0963
3g
3h
4а
4b
4c
238.1020
238.1014
27 (15)
33 (15)
314.1328
314.1327
282.0917
282.0912
63
40
38
40
38
330.0917
330.0912
360.1019
360.1018
45
11a
11b
282.0915
282.0912
308.1065
308.1069
_______
*Solvents: ~1:10 chloroform–hexane and then 1:5 benzene–hexane for
compounds 3a,c,e,f; ethanol for compounds 3d, 11a,b; ~1:10 methanol–water
and then ~1:5 benzene–hexane for compounds 3b, 4a; ~1:10 chloroform–
hexane for compounds 3g,h; ~1:5 benzene–hexane and then ethanol for
compound 4b; butan-1-ol for compound 4c.
*2Signal for [2M+H]+.
Me
O
Me
Me
Me
Me
Me
Me
H
N
Me
N
N
MeO
2b
N
or
Ph
S
S
S
O
S
MeONa/MeOH
Me
Ph
N
H
Me
N
O
N
N
Me
N
N
Me
N
H
N
Ph
6a
7
9
8
In an attempt to obtain derivatives of thiazinotriazepines by the reaction of triazepinethione 6a with es-
ters 2b,e,f in acetic acid at reflux, we were the first to find that opening of the triazepine ring and its recyclization
to a pyrazoline ring occurs under these conditions to give 2-(3,5,5-trimethyl-4,5-dihydro-1H-pyrazol-1-yl)-
4H-1,3-thiazin-4-ones 3a,g,h.
The finding that the product 3a obtained this way is identical to the product described above in the reac-
tion of pyrazolinecarbothioamide 1a with methyl phenylpropynoate 2b is evidence for the structure of the
products of this reaction.
888

889

890

891

TABLE 4. IR and UV Spectra of Compounds 3a–h, 4a–c, 11a,b
UV spectrum,

Com-
pound
IR spectrum, ν, cm–1
max, nm (ε10–4
l·mol–1·cm–1)
3a
3b
3c
3095, 2915, 1646, 1624, 1607, 1522, 1449, 1298, 857, 779
205 (1.4), 268 (2.6),
320 (0.8)
3060, 2970, 2918, 2838, 1620, 1602, 1524, 1507, 1447, 1314,
1302, 1254, 1181, 1032, 846
205 (1.5), 270 (2.8),
328 (1.5)
3024, 2968, 2933, 1620, 1593, 1493, 1350, 1315, 1284, 1245,
1155, 1106
258 (2.0), 302 (0.7)
3d
3e
3060, 3032, 1625, 1595, 1572, 1504, 1429, 1304, 1289, 860,
771, 757, 697
206 (2.1), 268 (2.6),
318 (0.8)
3033, 1624, 1594, 1492, 1420, 1358, 1296, 1211, 1115, 892
207 (0.7), 258 (2.4),
300 (0.8)
3f
3035, 2992, 2930, 1626, 1594, 1514, 1492, 1353, 1294, 1251,
1176, 1034, 893, 835
204 (0.7), 231 (0.9),
259 (1.8), 300 (0.6)
3g
3h
4a
4b
4c
3035, 3007, 1631, 1504, 1444, 1412, 1380, 1373, 1302, 1158,
1128, 1102, 1010, 932, 852, 753, 705
240 (2.91), 267 (1.2)
3025, 2979, 2916, 1628, 1598, 1516, 1502, 1412, 1379,1317,
1299,1283, 1256, 1238, 1198, 1160, 962
210 (1.7), 239 (1.2),
270 (2.9), 334 (0.9)
3064, 2988, 1945, 2921, 1691, 1637, 1556, 1366, 1327, 1269,
1241, 1184, 1155, 1005, 877, 770, 715, 576
207 (1.8), 222 (2.1),
256 (2.6), 319 (1.6)
2974, 2952, 2929, 1706, 1695, 1562, 1373,1318, 1234, 1197,
1175, 1004, 767
210 (1.0), 245 (0.3),
327 (1.8)
3070, 2997, 2951, 2840, 1693, 1555, 1515, 1368, 1324, 1246,
1232, 1203, 1170, 1031, 905, 771, 575
205 (0.9), 311 (1.7)
11a
11b
2959, 1738, 1706, 1648, 1603, 1424, 1379, 1325, 1294, 1260,
1198, 1177, 1131, 849, 752, 725, 703, 620
205 (0.7), 225 (0.7),
326 (1.4)
2965, 1730, 1702, 1640, 1613, 1424, 1421, 1305, 1291, 1288,
1173, 1101, 1053, 1020, 902, 843, 730, 710
208 (0.4), 227 (0.6),
334 (1.4)
Fig. 1. Molecular structure of 2-(3-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-
6-phenyl-4H-1,3-thiazin-4-one (3d) from X-ray diffraction crystallographic analysis.
892

TABLE 5. Bond Lengths (l) in Pyrazolylthiazinone 3d
Bond
l, Å
Bond
l, Å
S(1)–C(6)
1.7453(18)
1.7655(19)
1.293(2)
1.337(2)
1.384(2)
1.230(2)
1.463(3)
1.327(2)
1.477(2)
1.385(2)
1.386(2)
1.374(3)
1.364(3)
1.378(2)
C(65)–C(66)
N(7)–N(8)
1.380(2)
1.3977(18)
1.480(2)
1.2692(19)
1.486(2)
1.494(2)
1.537(2)
1.505(2)
1.367(2)
1.388(2)
1.379(2)
1.361(3)
1.382(2)
1.390(2)
S(1)–C(2)
C(2)–N(3)
C(2)–N(7)
N(3)–C(4)
C(4)–O(12)
C(4)–C(5)
N(7)–C(11)
N(8)–C(9)
C(9)–C(13)
C(9)–C(10)
C(10)–C(11)
C(11)–C(111)
C(111)–C(116)
C(111)–C(112)
C(112)–C(113)
C(113)–C(114)
C(114)–C(115)
C(115)–C(116)
C(5)–C(6)
C(6)–C(61)
C(61)–C(62)
C(61)–C(66)
C(62)–C(63)
C(63)–C(64)
C(64)–C(65)
TABLE 6. Valence Angles () in Pyrazolylthiazinone 3d
Angle
ω, deg
Angle
ω, deg
C(6)–S(1)–C(2)
N(3)–C(2)–N(7)
N(3)–C(2)–S(1)
99.80(11)
118.67(18)
129.11(16)
112.22(15)
121.98(19)
119.2(2)
C(2)–N(7)–N(8)
119.83(17)
124.81(17)
114.26(14)
106.91(16)
123.29(18)
115.08(18)
121.63(17)
103.59(15)
110.72(15)
99.95(14)
114.46(15)
118.98(19)
120.6(2)
C(2)–N(7)–C(11)
N(8)–N(7)–C(11)
N(7)–C(2)–S(1)
C(9)–N(8)–N(7)
C(2)–N(3)–C(4)
O(12)–C(4)–N(3)
O(12)–C(4)–C(5)
N(3)–C(4)–C(5)
C(6)–C(5)–C(4)
N(8)–C(9)–C(13)
N(8)–C(9)–C(10)
120.8(2)
C(13)–C(9)–C(10)
C(9)–C(10)–C(11)
N(7)–C(11)–C(111)
N(7)–C(11)–C(10)
C(111)–C(11)–C(10)
C(116)–C(111)–C(112)
C(116)–C(111)–C(11)
C(112)–C(111)–C(11)
C(113)–C(112)–C(111)
C(114)–C(113)–C(112)
C(113)–C(114)–C(115)
C(114)–C(115)–C(116)
C(111)–C(116)–C(115)
120.0(2)
127.5(2)
C(5)–C(6)–C(61)
C(5)–C(6)–S(1)
124.69(19)
121.43(18)
113.88(15)
117.2(2)
C(61)–C(6)–S(1)
C(62)–C(61)–C(66)
C(62)–C(61)–C(6)
C(66)–C(61)–C(6)
C(63)–C(62)–C(61)
C(64)–C(63)–C(62)
C(63)–C(64)–C(65)
C(64)–C(65)–C(66)
C(65)–C(66)–C(61)
120.1(2)
120.42(19)
120.5(2)
122.67(19)
120.8(2)
120.3(2)
121.4(2)
119.9(2)
119.2(2)
119.8(2)
119.5(2)
120.5(2)
122.0(2)
893

TABLE 7. Torsion Angles (in Pyrazolylthiazinone 3d
Angle
φ, deg
Angle
φ, deg
–3.0(3)
C(6)–S(1)–C(2)–N(3)
C(6)–S(1)–C(2)–N(7)
N(7)–C(2)–N(3)–C(4)
S(1)–C(2)–N(3)–C(4)
C(2)–N(3)–C(4)–O(12)
C(2)–N(3)–C(4)–C(5)
O(12)–C(4)–C(5)–C(6)
N(3)–C(4)–C(5)–C(6)
C(4)–C(5)–C(6)–C(61)
C(4)–C(5)–C(6)–S(1)
2.9(2)
N(3)–C(2)–N(7)–C(11)
–176.43(13)
179.91(17)
0.6(3)
S(1)–C(2)–N(7)–C(11)
176.37(13)
–163.93(17)
4.7(2)
C(2)–N(7)–N(8)–C(9)
C(11)–N(7)–N(8)–C(9)
174.7(2)
–4.0(3)
N(7)–N(8)–C(9)–C(13)
177.84(16)
–2.7(2)
N(7)–N(8)–C(9)–C(10)
–175.6(2)
3.1(3)
N(8)–C(9)–C(10)–C(11)
–0.1(2)
C(13)–C(9)–C(10)–C(11)
C(2)–N(7)–C(11)–C(111)
N(8)–N(7)–C(11)–C(111)
C(2)–N(7)–C(11)–C(10)
179.41(16)
–75.5(2)
116.58(17)
163.50(17)
–4.47(19)
2.58(18)
–115.74(18)
120.17(18)
–127.80(18)
–60.6(2)
51.4(2)
–178.97(18)
1.2(3)
C(2)–S(1)–C(6)–C(5)
–3.53(19)
176.62(13)
23.5(3)
C(2)–S(1)–C(6)–C(61)
C(5)–C(6)–C(61)–C(62)
S(1)–C(6)–C(61)–C(62)
C(5)–C(6)–C(61)–C(66)
S(1)–C(6)–C(61)–C(66)
C(66)–C(61)–C(62)–C(63)
C(6)–C(61)–C(62)–C(63)
C(61)–C(62)–C(63)–C(64)
C(62)–C(63)–C(64)–C(65)
C(63)–C(64)–C(65)–C(66)
C(64)–C(65)–C(66)–C(61)
C(62)–C(61)–C(66)–C(65)
C(6)–C(61)–C(66)–C(65)
N(3)–C(2)–N(7)–N(8)
S(1)–C(2)–N(7)–N(8)
N(8)–N(7)–C(11)–C(10)
C(9)–C(10)–C(11)–N(7)
–156.62(14)
–155.5(2)
24.4(2)
C(9)–C(10)–C(11)–C(111)
N(7)–C(11)–C(111)–C(116)
C(10)–C(11)–C(111)–C(116)
N(7)–C(11)–C(111)–C(112)
C(10)–C(11)–C(111)–C(112)
C(116)–C(111)–C(112)–C(113)
C(11)–C(111)–C(112)–C(113)
C(111)–C(112)–C(113)–C(114)
C(112)–C(113)–C(114)–C(115)
C(113)–C(114)–C(115)–C(116)
C(112)–C(111)–C(116)–C(115)
C(11)–C(111)–C(116)–C(115)
C(114)–C(115)–C(116)–C(111)
1.9(3)
–177.14(19)
–0.7(3)
–0.3(3)
–0.9(3)
–179.54(17)
0.6(3)
1.3(3)
–0.1(3)
–0.2(3)
–1.5(3)
–0.4(3)
177.53(17)
164.32(16)
–16.3(2)
–0.3(3)
178.93(16)
0.7(3)
8
MeB
B
8
Me
O
7
Me
9
7
9
Me
Me
R2
Me
Me
MeA
NH
MeA
N
N
OMe
N
2b
N
N
2b,e,f
or
2
6a
3a
2
AcOH, 118oC
Ph
AcOH, 100oC
N
S
S
6
NH
4
AcOH, 118oC
S
N
4
6
R2
O
O
Ph
O
5
5
10(B)
3a,g,h
10(A)
2b, 3a R2 = Ph; 2e, 3g R2 = Me; 2f, 3h R2 = 4-MeC6H4
894

H 8
H 8
CH3C
CH3B
7
CH3C
CH3B
7
8
8
9
9
A
N
CH3A
N
H3C
NH
2
HN
2
H
S
6
N
4
H
S
N
4
6
H
H
H
H
O
O
5
H5
5
H5
H
H
H
H
NOESY
COLOC
Fig. 2. Correlations in the NOESY and COLOC spectra of tautomeric form A of
compound 10. The correlations shown are identical for both tautomeric forms A and B.
Heating triazepinethione 6a with ester 2b in acetic acid at only 100°C permitted isolation of the intermedi-
ate product formed upon opening of the seven-membered ring, thiazinone 10, which exists in solution in one of
tautomeric forms A or B. Thin-layer chromatography indicated that heating intermediate 10 in acetic acid at reflux
leads to pyrazolylthiazinone 3a. The formation of thiazinone 10 suggests that opening of the triazepine ring occurs
at the N(4)–C(5) bond, and closing of the pyrazoline ring occurs by forming of N(2)–C(5) bond. On the other
hand, in the absence of ester 2b, opening of the ring in triazepinethione 6a in acetic acid at reflux does not occur.
1
The signals of the three methyl groups and H-8, and C(8) atoms are characteristic one in the H and
13C NMR spectra of thiazinone 10. The correlations found in its NOESY and COLOC spectra (Fig. 2) permit an
unequivocal assignment of the signals of all the protons and carbon atoms (the correlations between the benzene
ring atoms are not shown).
It should be noted that there is no cross peak for atoms H-5 and C(4) in the COLOC spectrum, which
may be the result of a low value of the 2JC(4)–H(5) coupling constant, characteristic for 1,3-thiazin-4-ones (Table 2
[23]). Thus, the signals for C(4) and C(2) atoms were assigned assuming that the signals for C(4) atom in
1,3-thiazin-4-one derivatives are always observed at lower field than the signals of C(2) atom (Table 2 [23]).
H
O
O
Me
O
Me
OMe
10 OMe
9
N
N
2
Me
R
N
S
S
Me
R
6
8
5
N
H5
N
4
R1
N
Me
7
R1
H
O
N 4
Me
R
S
11a,b
12a,b
2d
2
H
1
NH
O
CHCl3 / Et3N
O
N
N
R1
O
H
Me
Me
OMe
N
Me
R
S
Me
6a,b
S
OMe
R
N
N
N
R1
N
R1
O
14a,b
13a,b
6, 11–14 a R = H, R1 = Me; b R + R1 = (CH2)3
895

Since there are no correlations in the NOESY and COLOC spectra for the hydrogen atom of the NH
group, we cannot unequivocally determine which of the tautomeric forms (A or B) exists for thiazine 10 in
solution. Furthermore, these spectra do not shed light on the configuration of the exocyclic C=N bond. However,
we note that closure of the pyrazoline ring is possible only when it has (Z)-configuration, which is reflected in
the structure of 10.
On the other hand, by replacing the acetylenemonocarboxylic acid esters by DMAD 2d, we were able to
obtain bicyclic condensed systems containing the triazepine ring. Thus, the reaction of triazepinethiones 6a,b
with DMAD 2d proceeds at N(2) atom through 5-exo-dig cyclization. Only thiazolotriazepines 11a,b are formed
from the four possible products of this reaction 11–14.
This reaction course was confirmed by the X-ray crystallographic structural analysis of compound 11a
(Tables 8-10, Fig. 3).
It should be noted that the 1H and 13C NMR spectra of isomeric thiazolotriazepine 11a and
N-thiazolylpyrazolidine 4a are extremely similar. The only significant difference between the spectra of these
compounds is the position of the signal for C(2) atom in the 13C NMR spectra (Table 3). Thus, this signal is
found for thiazolotriazepine 11a at 141.4 ppm, while it is found for isomer 4a downfield by ~30 ppm at
172.3 ppm. Such a downfield shift for the signal of C(2) atom in pyrazoline derivatives 3a–h and 4a–c relative
to the signal of this atom in the spectra of triazepine derivatives 11 is a general phenomenon and may be used to
prove the structure of these heterocycles.
Fig. 3. Molecular structure of methyl (6,8,8-trimethyl-3-oxo-7,8-dihydro[1,3]thiazolo-
[3,2-b][1,2,4]triazepin-2-(3H)-ylidene)acetate (11a) according to X-ray crystallographic
structural analysis.
Thus, we are the first to observe that the condensation of 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-tri-
azepine-3-thione with methyl propynoates is accompanied by opening of the triazepine ring and its recyclization
to give a pyrazoline ring, leading to 2-pyrazolinyl-1,3-thiazines. The reaction of triazepinethiones with DMAD,
in contrast to the reactions with methyl propynoates, proceeds with retention of the seven-membered ring and
may serve as a method for the synthesis of new thiazolotriazepine derivatives. The reaction of pyrazolinecar-
bothioamides with esters of acetylenemonocarboxylic acids is a convenient method for the synthesis of
2-pyrazolinyl-1,3-thiazines, while the reaction with DMAD is a convenient method for the synthesis of
N-thiazolylpyrazolidines.
896

TABLE 8. Bond Lengths (l) in Thiazolotriazepine 11a
Bond
l, Å
Bond
l, Å
S(1)–C(2)
S(1)–C(9a)
C(2)–C(10)
C(2)–C(3)
C(3)–O(15)
C(3)–N(4)
N(4)–C(9a)
N(4)–N(5)
N(5)–C(6)
C(6)–C(6a)
1.715(5)
1.785(5)
1.334(7)
1.500(7)
1.190(6)
1.398(6)
1.395(7)
1.396(6)
1.243(7)
1.488(8)
C(6)–C(7)
1.552(5)
1.516(11)
1.469(7)
1.527(5)
1.539(5)
1.265(7)
1.507(9)
1.190(4)
1.318(7)
1.470(10)
C(7)–C(8)
C(8)–N(9)
C(8)–C(8b)
C(8)–C(8a)
N(9)–C(9a)
C(10)–C(11)
C(11)–O(12)
C(11)–O(13)
O(13)–C(14)
TABLE 9. Valence Angles () in Thiazolotriazepine 11a
Angle
ω, deg
Angle
ω, deg
C(2)–S(1)–C(9a)
C(10)–C(2)–C(3)
C(10)–C(2)–S(1)
C(3)–C(2)–S(1)
O(15)–C(3)–N(4)
O(15)–C(3)–C(2)
N(4)–C(3)–C(2)
C(9a)–N(4)–N(5)
C(9a)–N(4)–C(3)
N(5)–N(4)–C(3)
C(6)–N(5)–N(4)
N(5)–C(6)–C(6a)
N(5)–C(6)–C(7)
C(6a)–C(6)–C(7)
C(8)–C(7)–C(6)
92.4(2)
121.8(5)
126.7(4)
111.4(3)
125.5(5)
124.5(5)
109.9(4)
129.7(4)
116.0(4)
114.0(4)
122.5(5)
118.1(6)
121.3(7)
113.6(7)
108.4(7)
N(9)–C(8)–C(7)
111.8(6)
103.5(6)
117.6(11)
111.4(8)
111.6(7)
100.2(14)
122.4(5)
134.7(5)
114.9(4)
110.2(4)
118.3(5)
124.3(6)
123.5(5)
111.8(5)
111.6(6)
N(9)–C(8)–C(8b)
C(7)–C(8)–C(8b)
N(9)–C(8)–C(8a)
C(7)–C(8)–C(8a)
C(8b)–C(8)–C(8a)
C(9a)–N(9)–C(8)
N(9)–C(9a)–N(4)
N(9)–C(9a)–S(1)
N(4)–C(9a)–S(1)
C(2)–C(10)–C(11)
O(12)–C(11)–O(13)
O(12)–C(11)–C(10)
O(13)–C(11)–C(10)
C(11)–O(13)–C(14)
EXPERIMENTAL
The IR spectra were taken on an FSM 1201 spectrometer for KBr pellets. The electronic spectra were
1
taken on an SF-2000 spectrometer for solutions in ethanol. The H and 13C NMR spectra were taken on a
Bruker AM 500 spectrometer at 500 and 125 MHz, respectively, in DMSO-d6 (for compounds 6b and 7) or
CDCl3 (for compound 10). The chemical shifts are given relative to the signals of the residual protons ( 7.28
and 2.50 ppm) or carbon atoms ( 77.16 and 39.52 ppm, respectively) of the solvents. The COLOC spectrum
897

TABLE 10. Torsion Angles () in Thiazolotriazepine 11a
Angle
φ, deg
Angle
φ, deg
C(9a)–S(1)–C(2)–C(10)
C(9a)–S(1)–C(2)–C(3)
C(10)–C(2)–C(3)–O(15)
S(1)–C(2)–C(3)–O(15)
C(10)–C(2)–C(3)–N(4)
S(1)–C(2)–C(3)–N(4)
O(15)–C(3)–N(4)–C(9a)
C(2)–C(3)–N(4)–C(9a)
O(15)–C(3)–N(4)–N(5)
C(2)–C(3)–N(4)–N(5)
C(9a)–N(4)–N(5)–C(6)
C(3)–N(4)–N(5)–C(6)
N(4)–N(5)–C(6)–C(6a)
N(4)–N(5)–C(6)–C(7)
N(5)–C(6)–C(7)–C(8)
C(6a)–C(6)–C(7)–C(8)
C(6)–C(7)–C(8)–N(9)
C(6)–C(7)–C(8)–C(8b)
–176.9(12)
0.1(10)
C(6)–C(7)–C(8)–C(8a)
C(7)–C(8)–N(9)–C(9a)
C(8b)–C(8)–N(9)–C(9a)
C(8a)–C(8)–N(9)–C(9a)
C(8)–N(9)–C(9a)–N(4)
C(8)–N(9)–C(9a)–S(1)
N(5)–N(4)–C(9a)–N(9)
C(3)–N(4)–C(9a)–N(9)
N(5)–N(4)–C(9a)–S(1)
C(3)–N(4)–C(9a)–S(1)
C(2)–S(1)–C(9a)–N(9)
C(2)–S(1)–C(9a)–N(4)
C(3)–C(2)–C(10)–C(11)
S(1)–C(2)–C(10)–C(11)
C(2)–C(10)–C(11)–O(12)
C(2)–C(10)–C(11)–O(13)
O(12)–C(11)–O(13)–C(14)
C(10)–C(11)–O(13)–C(14)
–47.0(7)
–40.8(14)
–168.4(17)
84.8(13)
7(2)
–5(2)
178.1(13)
179.3(11)
2.1(14)
–179.2(8)
–9(2)
179.9(14)
–4.1(15)
6(2)
178.1(14)
177.4(9)
4.2(12)
–178.4(9)
9.6(19)
–177.6(10)
–2.3(8)
–177.1(12)
178.3(10)
29.3(18)
–78.3(12)
131.5(8)
78.4(8)
179.3(11)
–4(2)
9(2)
–177.7(12)
–10(2)
–162.0(11)
176.6(12)
optimized relative to the constant JC–H = 8 Hz of the solution of 1,3-thiazine 10 in CDCl3 and the NOESY
spectrum (mixing time 0.6 sec) of this solution was obtained on a Bruker DPX 300 spectrometer at 75 and
300 MHz, respectively. The high-resolution ESI mass spectra were taken on a Bruker MicrOTOF mass
spectrometer with recording of the positive ions. Methanol served as the solvent. The ionizing additive was
formic acid. The capillary voltage was 4500 V. The course of the reactions and purity of the products were
monitored by thin-layer chromatography on Sorbfil plates using 10:5:5:1 hexane–acetone–chloroform–ethanol
as the eluent.
3-Methyl-4,5-dihydro-1H-pyrazole-1-carbothiamides 1a–c [24, 25], methyl esters of propionic acids
2b,c,e,f [26], and 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione 6a [22] were obtained
according to reported procedures. Methyl propynoate 2a and DMAD 2d obtained from Sigma-Aldrich were
used without further purification.
X-ray diffraction crystallographic analysis of monocrystals 3d and 11a grown from solutions in
ethanol was carried out on a Bruker SMART 1000 CCD using MoK radiation. Unit cell parameters for
monoclinic crystals of compound 3d (C20H17N3OS): space group P21/n, a = 9.082(2), b = 10.811(2),
c = 17.789(4) Å,  = 104.58(3)°, Z = 4, Dx = 1.365 g/cm3, R1 = 0.0353 (I > 2I), wR2 = 0.0471, for 3712 nonzero
independent reflections. Unit cell parameters for orthorhombic crystals of compound 11a (C12H15N3O3S), space
group Pn21a, a = 15.012(3), b = 6.7740(10), c = 13.627(3), Z = 4, Dx =1.348 g/cm3, R1 = 0.0949, [I > 2(I)],
wR2 = 0.2273 for 2516 nonzero independent reflections, The full set of X-ray diffraction crystallographic data
for compounds 3d and 11a was deposited in the Cambridge Crystallographic Data Center (CCDC depos-
its 762050 and 762051, respectively).
2-(4,5-Dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones 3a–h. A. Ester 2a–c (3 mmol) was added to a
solution 4,5-dihydropyrazol-1-ylcarbothioamide 1a–c (3 mmol) in glacial acetic acid (15 ml). The mixture was
heated at reflux. Completion of the reaction was determined by thin-layer chromatography as indicated by
disappearance of the starting compounds. Acetic acid was removed at reduced pressure. The residue was
recrystallized twice to give products 3a–f.
898

B. Ester 2b,e,f (3 mmol) was added to a solution of compound 6a (513 mg, 3 mmol) in acetic acid
(15 ml). The mixture was heated at reflux for 15 h. Acetic acid was removed at reduced pressure. The residue
was subjected to chromatography on silica gel using 30:1 dichloromethane–methanol as the eluent. The isolated
products were recrystallized to give 3a,g,h.
Methyl Esters of (2Z)-[2-(3-Methyl-4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]-
acetic Acids 4a–c. A. A solution of DMAD 2d (284 mg, 2 mmol) in chloroform (5 ml) was added with stirring
to a solution of 4,5-dihydropyrazole-1-carbothioamide 1a–c (2 mmol) in a mixture of chloroform (20 ml) and
triethylamine (0.28 ml, 2 mmol). The reaction mixture was maintained for 48 h at room temperature. The
solvent was removed at reduced pressure. The residue was recrystallized.
B. A solution of ester 2d (284 mg, 2 mmol) in acetic acid (5 ml) was added with stirring to a solution of
4,5-dihydropyrazole-1-carbothioamide 1c (498 mg, 2 mmol) in acetic acid (20 ml). The reaction mixture was
maintained for 48 h at room temperature. The solvent was removed at reduced pressure. The precipitate obtained
was washed with ethanol (2x5 ml) and recrystallized from butan-1-ol.
5,5-Dimethyl-4,4,5a,6,7,8-hexahydrocyclopenta[f][1,2,4]triazepine-3(2H)-thione (6b). A solution of
concentrated sulfuric acid (0.50 g, 5 mmol, 0.27 ml) in water (1 ml) was added with stirring to
2-(1-methylethylidene)cyclopentanone (1.24 g, 10 mmol) [27] at 15°C. A solution of ammonium thiocyanate
(0.76 g, 10 mmol) in water (2 ml) was added to the mixture obtained. The reaction mixture was stirred for 2 h at
room temperature. The upper oily layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organic fractions were washed with water until the wash water was neutral and then dried over
sodium sulfate. The solvent was removed at reduced pressure to give 1.24 g (68%) 2-(1-isothiocyanato-
1-methylethyl)cyclopentanone, which was used without further purification.
10% Aqueous sodium hydroxide (2.5 ml) was added to
a vigorously-stirred mixture of
2-(1-isothiocyanato-1-methylethyl)cyclopentanone (1.24 g, 6.8 mmol) and hydrazine hydrate (0.34 g, 6.8 mmol,
0.33 ml) in water (10 ml). The reaction mixture was stirred for 10 h at room temperature. The precipitate formed
was filtered off and recrystallized from methanol to give 0.54 g (40%) previously unreported tri-
azepinethione 6b; mp 225–228°C; Rf 0.53. IR spectrum, , cm–1: 3222, 3183, 3139, 3099, 2989, 2957, 1688,
1566, 1545, 1477, 1384, 1367, 1288, 1238, 1198, 1147, 1116, 1007, 766, 677. 1H NMR spectrum, , ppm: 1.05
(3H, s, CH3); 1.20 (3H, s, CH3); 1.53 (2H, m, CH2); 1.77 (1H, m) and 1.97 (1H, m, CH2); 2.34 (2H, m, CH2);
2.72 (1H, m, CH); 8.29 (1H, s, NH); 10.26 (1H, s, NH). 13C NMR spectrum, , ppm: 23.1; 24.4; 27.5; 28.5;
34.5; 52.9; 57.7; 165.9; 175.3. Found: m/z 198.1069 [M+H]+. C9H16N3S. Calculated: m/z 198.1065.
Methyl Ester of (Z)-3-[(5,5,7-Trimethyl-5,6-dihydro-2H-1,2,4-triazepin-3-yl)sulfanyl]-3-phenyl-
acrylic Acid (7). Methyl phenylpropynoate (2b) (0.16 g, 1 mmol) was added to a suspension of
1,2,4-triazepine-3-thione 6a (171 mg, 1 mmol) in a mixture of methanol (20 ml) and 1 M solution of MeONa in
methanol (0.1 ml) and heated at reflux for 10 h. The solvent was removed at reduced pressure to half of the
initial volume. The precipitate formed was filtered off and recrystallized from ethanol to give 109 mg
(33%) ester 7; mp 167–170°C; Rf 0.59. IR spectrum, , cm–1: 3198, 3022, 2977, 2950, 1721, 1714, 1634, 1534,
1453, 1428, 1274, 1265, 1192, 1164, 942, 853, 769. UV spectrum, max, nm (10–4 l/mol·cm): 206 (1.0), 222
(0.6), 276 (1.3). 1H NMR spectrum, , ppm: 1.35 (6H, s, 2CH3); 2.02 (3H, s, CH3); 2.49 (2H, s, CH2); 3.67 (3H,
13
s, OCH3); 6.40 (1H, s, CH); 7.38 (3H, m, H Ar); 7.58 (2H, m, H Ar); 8.25 (1H, s, NH). C NMR spectrum, ,
ppm: 25.2; 29.2; 42.4; 51.1; 61.6; 113.6; 127.5; 128.1; 129.4; 135.2; 153.6; 163.9; 168.0; 177.9. Found:
m/z 332.1436 [M+H]+. C17H22N3O2S. Calculated: m/z 332.1433.
2-[2-(1,3-Dimethylbut-2-en-1-ylidene)hydrazine]-6-phenyl-4H-1,3-thiazin-4-one (10). Ester 2b
(1.76 g, 11 mmol) was added to 1,2,4-triazepine-3-thione 6a (1.71 g, 10 mmol) in acetic acid (50 ml). The
mixture was maintained for 8 h at 97–100°C. The solvent was removed at reduced pressure. The residue was
recrystallized from ethanol (5 ml) to give 0.9 g (30%) thiazinone 10; mp 158–159°C; Rf 0.65. IR spectrum, ,
cm-1: 3118, 3023, 2957, 2829, 1645, 1630, 1581, 1570, 1549, 1489, 1372, 1301, 1239, 1226, 841, 762, 700.
1H NMR spectrum, , ppm: 1.93 (3H, s, 9-CH3(B)); 2.12 (3H, s, 9-CH3(A)); 2.15 (3H, s, 7-CH3); 5.85 (1H, s,
H-8); 6.52 (1H, s, H-5); 7.47–7.61 (5H, m, Ph); 9.48 (1H, s, NH). 13C NMR spectrum, , ppm: 19.4 (7-CH3);
899

21.9 (9-CH3(B)); 28.4 (9-CH3(A)); 114.7 (C-5); 124.5 (C-8); 126.8 and 129.3 (C-o,m); 131.6 (C-p); 136.0 (C-i);
144.9 (C-9); 152.8 (C-6); 153.3 (C-2); 163.5 (C-4); 163.5 (C-7). Found: m/z 300.1173 [M+H]+. C16H18N3OS.
Calculated: m/z 300.1171.
Methyl Esters of (2Z)-(8,8-Dimethyl-3-oxo-7,8-dihydro[1,3]thiazolo[3,2-b][1,2,4]triazepin-
2(3H)-ylidene)acetic Acids 11a,b. A solution of DMAD 2d (0.284 g, 2 mmol) in chloroform (5 ml) was added
to a solution of 1,2,4-triazepine-3-thione 6a or 6b (2 mmol) in a mixture of chloroform (20 ml) and
triethylamine (0.28 ml, 2 mmol). The reaction mixture was maintained with vigorous stirring for 48 h at room
temperature. The solvent was removed at reduced pressure and the residue was recrystallized from ethanol.
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