A Novel Route to 1,2,3-Thiadiazole, 1,3,4-Thiadiazine, and 1,2, 5-Triazepine Derivatives

Article abstract of DOI:10.1055/s-2003-42414

New convenient methods for the synthesis of 1,2,3-thiadiazole, 1,3,4-thiadiazine, and 1,2,5-triazepine derivatives are reported. In the heterocyclization process, the reactivity of 1-thia-4-aza-1,3-butadiene system of syn-2-phenylhydrazono-3-oxothiobutanoic acid anilides was exploited.

Full text of DOI:10.1055/s-2003-42414

PAPER
2559
A Novel Route to 1,2,3-Thiadiazole, 1,3,4-Thiadiazine, and 1,2,5-Triazepine
Derivatives
A
N
ovel Route to
a
1,2, 3-Thia
r
diazole,
b
1,3,4-Thiadi
a
a
zine, and
1
,2,5-Tri
a
a
zepine
D
erivativ
Z
es aleska,*a Bartosz Trzewik,a Jacek Grochowski,b Paweł Serdab
a
Department of Organic Chemistry, Jagiellonian University, ul. Romana Ingardena 3, 30–060 Kraków, Poland
Fax 48(12)6340515; E-mail: zaleska@chemia.uj.edu.pl
b
Regional Laboratory of Physicochemical Analyses and Structural Research, ul. Romana Ingardena 3, 30–060 Kraków, Poland
Received 3 July 2003; revised 1 August 2003
cleophilic attack of the nitrogen atoms of aliphatic 1,3- or
1,4-diamines on C-2 of compounds 1, followed by a novel
sigmatropic rearrangement. On the other hand, the reac-
tions of 1 with aliphatic 1,2-diamines lead to 1,4-diazines
by ring expansion of the intermediate 1,3-diazines.12
Abstract: New convenient methods for the synthesis of 1,2,3-thia-
diazole, 1,3,4-thiadiazine, and 1,2,5-triazepine derivatives are re-
ported. In the heterocyclization process, the reactivity of 1-thia-4-
aza-1,3-butadiene system of syn-2-phenylhydrazono-3-oxothiobu-
tanoic acid anilides was exploited.
Key words: ring closure, heterocycles, cyclizations, thiadiazole,
thiadiazine, triazepine
In order to develop synthetic applications of thioanilides
1a–c in closing heterocyclic rings we have transformed
them into phenylhydrazones 2a–c by treatment with phe-
nylhydrazine (Scheme 1). The nucleophilic attack of the
amino group of phenylhydrazine took place exclusively
on the C-2 position of 2-anilino-2-methoxy-3-oxothiobu-
tanoic acid anilides 1a–c.
The structure and chemistry of the 1,2,3-thiadiazole sys-
tem have been under active investigation for years.1–3 Its
derivatives are useful in the treatment of hyperprolifera-
tive disorders including tumor growth and angiogenesis,
and lymphoproliferative symptoms.4 Moreover, deriva-
tives of this system are applied in the treatment and/or pre-
vention of morbid states mediated by oxytocin, including
premature labour and dysmenorhea.5 The 1,2,3-thiadia-
zole moiety is crucial for the antibacterial activity of new
carbapenems6 as well as for the efficacy of some pesti-
cides.7 The biological activity of 1,2,5-triazepines8 has re-
ceived less attention than the corresponding benzofused
system.
Recently, we have reported9,10 the synthesis of 1,3- and
1,4-diazines which used the C-2 disubstituted thioanilides
of 3-oxobutanoic acid 1 (X = S)11 in heterocyclization re-
actions with various diamines. We have found that good
leaving groups at C-2 of compound 1 offer an entry to for-
mation of six- and seven-membered rings by treatment
with binucleophiles. The reaction includes the initial nu-
In contrast, the reaction of 2-anilino-2-methoxy-3-oxobu-
tanoic acid anilide 3a (X = O), under similar conditions,
exclusively provided osazone 4a (Scheme 1).
Compounds 2a–c can appear in two isomeric forms corre-
sponding to Z or E configuration of the 1-thia-4-aza-1,3-
butadiene system. In solution, spectral data confirm the
structure of the molecules of 2a–c as shown in Scheme 1
as the unique reaction product. X-ray analysis of 2a was
carried out to prove the configuration in the solid state and
precisely determine the molecular geometry.14
A perspective view of molecule of 2a with the crystallo-
graphic atom numbering is presented in Figure 1. The
central framework of the molecule, consisting of hetero-
atoms (S1, O1, N1–N3) and carbon atoms C1–C4, is quite
flat. None of these atoms deviates from the least-squares
plane passing through the heteroatoms by more than 0.1
Scheme 1
SYNTHESIS 2003, No. 16, pp 2559–2563
x
x.
x
x
.
2
0
0
3
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42414; Art ID: Z09703SS
© Georg Thieme Verlag Stuttgart · New York

2560
B. Zaleska et al.
PAPER
Å. This flat configuration is a result of the strong coupling The Z configuration of the 1-thia-4-aza-1,3-butadiene sys-
within the 1-thia-4-aza-1,3-butadiene system, as predicted tem presented in compounds 2a–c, as well as the syn-con-
from NMR evidence. The relative position of C1–S1 and figuration of the hydrazone, incorporate the structural
C2–N2 double bonds is Z. Consequently, the central moi- requirements for the construction of heterocyclic rings.
ety forms two fused rings, which involve two rather strong
As an extension of our previous work,12,13 we have envis-
hydrogen bonds N1–H13–S1 and N3–H10–O1 (Table 2)
aged that both oxidation and electrophilic attack should
enhancing the coupling.
take place on the sulfur and nitrogen atoms of compounds
2a–c.
Oxidative heterocyclisation of hydrazones 2a–c, by treat-
ment with H2O2, exclusively produced the 1,2,3-thiadia-
zole derivatives 5a–c (Scheme 2), which was favoured by
intramolecular interaction between the sulphur atom and
the nitrogen of the =NNH– fragment. The structure of the
1,2,3-thiadiazoles 5a–c was supported by spectroscopic
data and the microanalyses. Both, 1H and 13C NMR spec-
tra of derivatives 5a–c show that the acetyl group and the
arylimine groups are substituents. Moreover, signals char-
acteristic for hydrazones 2a–c have disappeared. They
were those of the =NNH– fragment at d = 16.8–16.7 and
Figure 1
of the –CSNH– fragment at d = 13.6–13.4 in the 1H NMR
spectra, and the signal of the carbon of the C=S group at
It is also manifested by slight shifts in the relevant bond
lengths: C1=S1 is somewhat shorter, as is N1–N2, where-
d = 184 ppm in the 13C NMR spectra.
as C2=N2 is slightly longer than a typical C=N double
bond (Table 1). Since all possible hydrogen donors are in-
volved in intramolecular hydrogen bonds, it is no surprise
that there are practically no intermolecular close contacts
in the crystal. The flat phenyl groups are nearly coplanar
with the plane of the 1-thia-4-aza-1,3-butadiene moiety.
The reaction of compounds 2a,b with thiophosgene led to
formation of the six-membered ring of 1,3,4-thiadiazine
derivatives 6a,b.
Spectral evidences such as NMR, IR, and MS spectra con-
firm the structure of products 6a,b. When a 4-chlorophe-
nyl substituent was present in the thioamide moiety of
hydrazone 2c, the expected 1,3,4-thiadiazine derivative 6c
was not isolated. The probably reason is the electron-
withdrawing effect of the chlorine atom.
Table 1 Selected Bond Lengths and Bond Angles for 2a
Bond
Bond length
(pm)
Bond
Bond angle (º)
Diacylation of 2a–c with oxalyl chloride at room temper-
ature in toluene afforded products 8a–c with high to ex-
cellent yields (Scheme 2). The structures of the
compounds obtained were established on the basis of
spectral evidences. All spectral data confirm that reaction
of 2a–c with oxalyl chloride yielded exclusively the 1,2,5-
triazepine derivatives 8a–c (Scheme 2).
The 13C NMR spectra display the characteristic signals of
the C=S group at d = 180.4–179.6, while signals of NH
groups significant for the starting compounds 2a–c are not
observed. Probably, as the first step, the mechanism of the
S- and N-acylation took place with formation of the ex-
pected 1,4,5-thiadiazepine derivatives 7a–c, but in a sec-
ond step the 1,4,5-thiadiazepine system undergoes the
Dimroth rearrangement immediately to the thermody-
namically more stable 1,2,5-triazepine system.
S1–C1
O1–C3
N1–N2
N1–C5
N2–C2
N3–C1
N3–C11
C1–C2
C2–C3
C3–C4
168.0(2)
123.2(3)
129.4(3)
141.2(3)
131.7(3)
133.5(3)
140.5(3)
149.0(3)
148.7(3)
149.8(4)
N1–N2–C
C1–N3–C11
N3–C1–C2
N3–C1–S1
C2–C1–S1
N2–C2–C3
N2–C2–C1
C3–C2–C1
O1–C3–C2
124.7(2)
133.6(2)
113.2(2)
124.0(2)
122.7(2)
110.2(2)
127.1(2)
122.7(2)
122.9(2)
C12–C11–N3 126.2(2)
The high efficiency of the proposed facile syntheses can
be explained by the unique Z configuration of the 1-thia-
4-aza-1,3-butadiene system presented in hydrazones 2a–
c, which was confirmed by X-ray analysis. Hydrazones
2a–c are, therefore, excellent building-blocks for con-
structing heterocyclic systems of 1,2,3-thiadiazole, 1,3,4-
thiadiazine, and 1,2,5-triazepine. In all syntheses de-
scribed, (2Z)-3-oxo-2-phenylhydrazonothiobutanoic acid
Table 2 Intramolecular Hydrogen Bonds in 2a
D–H–A
D–A (pm) H–A (pm) D–H (pm) Angle
D–H–A (°)
N1–H13–S1 292.7(2)
N3–H10–O1 258.3(2)
215(4)
182(3)
92(4)
85(3)
143(3)
150(3)
Synthesis 2003, No. 16, 2559–2563 © Thieme Stuttgart · New York

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A Novel Route to 1,2,3-Thiadiazole, 1,3,4-Thiadiazine, and 1,2,5-Triazepine Derivatives
2561
Scheme 2
solution was stirred for 24 h. Yellow crystals of the product were
separated and crystallized from toluene.
anilides 2a–c can be used except for 2c (4-chloroanilide)
in reaction with thiophosgene.
4-Thioxo-4,5-dihydro-1H-1,2,5-triazepin-6,7-dione Derivatives
8; General Procedure
Mps were determined on an electrothermal IA9000 digital mp ap-
paratus and are uncorrected. The IR spectra were obtained on a
Bruker IFS 48 spectrometer. 1H and 13C NMR spectra were record-
ed with a Bruker AMX 500 NMR spectrometer at r.t. Chemical
shifts are given in ppm. Spectral data for compounds 1a–c and 3a
are described in our previous work.11 Yields are given for pure prod-
ucts.
The corresponding hydrazone 2 (1 mmol) was dissolved in toluene
(5 mL) at r.t. and oxalyl chloride (1 mmol, 0.13 g) was added to the
stirred solution. Red or orange crystals of the products were filtered
off under reduced pressure after 10 min and purified by crystalliza-
tion from toluene.
(2Z)-3-Oxo-2-phenylhydrazonothiobutanoic Acid Anilide (2a)
Yield: 7.85 g (88%); orange needles; mp 103–104 °C.
IR (KBr): 1662, 1532, 1462, 1284, 1105 cm–1.
1H NMR (CDCl3): d = 16.76 (s, 1 H, NNH), 13.53 (s, 1 H, CONH),
7.60–7.20 (m, 10 H, 2 Ph), 2.64 (s, 3 H, CH3).
13C NMR (CDCl3): d = 201.3 (C=O), 184.4 (C=S), 141.6 (C=N),
137.6, 129.7, 128.9, 127.1, 126.2, 125.9, 125.0, 116.6 (2 Ph), 27.1
(CH3).
(2Z)-3-Oxo-2-phenylhydrazonothiobutanoic Acid Anilides 2;
General Procedure
The corresponding 2-anilino-2-methoxy-3-oxothiobutanoic acid
anilide 1 (30 mmol) and phenylhydrazine (30 mmol, 3.24 g) were
heated in the presence of a catalytic amount of 4-methylsulphonic
acid in MeOH (50 mL) under reflux for 1 h. Cooling the mixture
yielded orange crystals, which were purified by crystallization from
EtOH.
MS (EI): m/z (%) = 297 (55, M+), 254 (7, M+ – CH3CO+), 205 (38,
M+ – C6H6N), 173 (27, M+ – C6H6N – S), 136 (11, PhNHCS), 105
(22, PhNN), 93 (83, C6H7N), 77 (100, Ph), 43 (72, CH3CO+).
2,3-Bisphenylhydrazonobutanoic Acid Anilide 4a
The corresponding 2-anilino-2-methoxy-3-oxobutanoic acid anilide
3a (3.4 mmol, 1.00 g) and phenylhydrazine (6.8 mmol, 0.74 g) were
heated in presence of a catalytic amount of 4-methylsulphonic acid
in MeOH (10 mL) under reflux for 2 h. Cooling the mixture yielded
yellow crystals, which were crystallized from EtOH.
Anal. Calcd for C16H15N3OS: C, 64.62; H, 5.08; N, 14.13. Found:
C, 64.56; H, 4.96; N, 14.05.
X-Ray Crystal Structure of 2a
2,5-Dihydro-1,2,3-thiadiazole Derivatives 5; General Procedure
The corresponding hydrazone 2 (2 mmol) was dissolved in MeOH
(10 mL) and hydrogen peroxide (30%; 6 mmol) solution in H2O
(0.68 g) was added. The mixture was heated under reflux for 2 h and
the solvent was evaporated. The brownish residue was purified
twice by rotary chromatography (SiO2; CHCl3–MeOH, 20:1, then
30:1) to give a red powder, which was crystallized from MeOH.
Compound 2a with formula C16H15N3OS crystallizes in the mono-
clinic system, space group C2/c, with unit cell parameters
a = 27.250(1), b = 7.1912(4), c = 15.392(1) Å, b = 90.028(3)º,
V = 3016.2(3) Å3, Z = 8. A total of 2697 independent reflections
[R(int) = 0.0213] were collected on a sample (size 0.35 × 0.3 × 0.2
mm) using a KappaCCD diffractometer and MoKa radiation. The
structure was solved by direct methods and refined by the full-ma-
trix least squares method on F2 using the SHELX97 program sys-
tem. All hydrogen atoms were located on a difference Fourier map
of electron density. Final R indices for I > 2s(I) were equal
R1 = 0.0588, wR2 = 0.1484, and R1 = 0.0788, wR2 = 0.1741 for all
data. The extinction coefficient was refined and converged to
2-Thioxo-3,6-dihydro-2H-1,3,4-thiadiazine Derivatives 6; Gen-
eral Procedure
The corresponding hydrazone 2 (1.47 mmol) was dissolved in tolu-
ene (10 mL) at r.t. and CSCl2 (0.17 g, 1.47 mmol) was added. The
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2562
B. Zaleska et al.
PAPER
0.055(6). The final difference Fourier map of electron density was
featureless with the largest peak and hole at 0.280 and –0.251 eÅ–3,
respectively.
MS (EI): m/z (%) = 295 (84, M+), 190 (3, M+ – PhNN), 135 (18,
PhNCS), 123 (13, PhNS), 91 (5, C6H5N), 77 (11, Ph), 43 (5,
CH3CO+).
Anal. Calcd for C16H13N3OS: C, 65.06; H, 4.44; N, 14.23. Found:
C, 65.17; H, 4.51; N, 14.37.
(2Z)-3-Oxo-2-phenylhydrazonothiobutanoic Acid (4-Methoxy)
Anilide (2b)
Yield: 7.30 g (76%); orange needles; mp 109–110 °C.
IR (KBr): 1652, 1459, 1277, 1105 cm–1.
4-Acetyl-2-phenyl-5-(4-methoxy)phenylimino-2,5-dihydro-
1,2,3-thiadiazole (5b)
Yield: 0.34 g (52%); orange powder; mp 113–114 °C.
IR (KBr): 1696, 1590, 1478, 1276, 1103 cm–1.
1H NMR (CDCl3): d = 7.46–6.94 (m, 9 H, Ph, MeOPh), 3.83 (s, 3
H, OCH3) 2.72 (s, 3 H, CH3).
13C NMR (CDCl3): d = 190.5 (C=O), 156.7 (N=CS), 147.9 (C=N),
157.4, 142.3, 141.4, 129.7, 126.3, 120.6, 117.9, 115.0 (Ph, MeOPh),
55.4 (OCH3), 29.0 (CH3).
1H NMR (CDCl3): d = 16.73 (s, 1 H, NNH), 13.38 (s, 1 H, CONH),
7.52–6.94 (m, 9 H, Ph, MeOPh), 3.84 (s, 3 H, OCH3), 2.63 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 201.2 (C=O), 184.1 (C=S), 141.6 (C=N),
158.3, 130.5, 129.6, 126.3, 126.2, 125.7, 116.5, 114.1 (Ph, MeOPh),
55.4 (OCH3), 27.0 (CH3).
MS (EI): m/z (%) = 327 (100, M+), 284 (8, M+ – CH3CO+), 235 (25,
M+ – C6H6N), 203 (29, M+ – C6H6N – S), 166 (9, MeO – PhNCS),
134 (59, MeO – PhNC), 107 (9, MeO – Ph), 105 (12, PhNN), 92
(55, C6H6N), 77 (62, Ph), 43 (43, CH3CO+).
MS (EI): m/z (%) = 325 (100, M+), 123 (21, PhNS), 107 (5,
MeOPh), 43 (20, CH3CO+).
Anal. Calcd for C17H15N3O2S: C, 62.75; H, 4.65; N, 12.91. Found:
C, 62.51; H, 4.70; N, 12.78.
Anal. Calcd for C17H17N3O2S: C, 62.37; H, 5.23; N, 12.83. Found:
C, 62.19; H, 5.20; N, 12.90.
4-Acetyl-2-phenyl-5-(4-chloro)phenylimino-2,5-dihydro-1,2,3-
thiadiazole (5c)
Yield: 0.27 g (42%); orange powder; mp 130–131 °C.
IR (KBr): 1698, 1571, 1473, 1277, 1092 cm–1.
1H NMR (CDCl3): d = 7.44–7.03 (m, 9 H, Ph, ClPh), 2.73 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 190.3 (C=O), 158.5 (N=CS), 153.2 (C=N),
142.1, 141.1, 130.7, 130.1, 129.8, 126.7, 120.6, 118.0 (Ph, ClPh),
29.0 (CH3).
(2Z)-3-Oxo-2-phenylhydrazonothiobutanoic Acid (4-Chloro)
Anilide (2c)
Yield: 8.76 g (88%); orange needles; mp 132–133 °C.
IR (KBr): 1650, 1533, 1457, 1284, 1093 cm–1.
1H NMR (CDCl3): d = 16.73 (s, 1 H, NNH), 13.58 (s, 1 H, CONH),
7.58–7.21 (m, 9 H, Ph, ClPh), 2.63 (s, 3 H, CH3).
13C NMR (CDCl3): d = 201.3 (C=O), 184.5 (C=S), 141.5 (C=N),
136.0, 132.3, 129.6, 129.0, 126.1, 126.1, 126.0, 116.6 (Ph, ClPh),
27.0 (CH3).
MS (EI): m/z (%) = 331 (87, M+), 298 (17, M+ – HS), 288 (6, M+ –
CH3CO+), 239 (20, M+ – C6H6N), 207 (19, M+ – C6H6N – S), 138
(37, Cl PhNC), 111 (24, ClPh), 105 (24, PhNN), 93 (100, C6H7N),
77 (96, Ph), 43 (71, CH3CO+).
MS (EI): m/z (%) = 329 (47, M+), 123 (23, PhNS), 111 (11, ClPh),
43 (27, CH3CO+).
Anal. Calcd for C16H12ClN3OS: C, 58.27; H, 3.67; N, 12.74. Found:
C, 58.42; H, 3.68; N, 12.70.
Anal. Calcd for C16H14ClN3OS: C, 57.92; H, 4.25; N, 12.66. Found:
C, 57.75; H, 4.28; N, 12.62.
5-Acetyl-3-phenyl-6-phenylimino-2-thioxo-3,6-dihydro-2H-
1,3,4-thiadiazine (6a)
Yield: 0.36 g (73%); yellow needles; mp 214–215 °C.
IR (KBr): 1718, 1558, 1453, 1334, 1079 cm–1.
1H NMR (CDCl3): d = 7.53–6.97 (m, 10 H, 2 Ph), 2.58 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 194.6 (C=O), 184.2 (C=S), 147.0 (N=CS),
143.4 (C=N), 144.6, 144.2, 129.6, 129.4, 129.2, 126.9, 126.9, 119.6
(2 Ph), 28.8 (CH3).
2,3-Bisphenylhydrazonobutanoic Acid Anilide (4a)
Yield: 0.81 g (65%); yellow needles; mp 172–174 °C.
IR (KBr): 3331, 3205, 3168, 1640, 1513, 1240 cm–1.
1H NMR (CDCl3): d = 13.95 (s, 1 H, C-2 NNH), 12.07 (s, 1 H,
CONH), 7.40 (s, 1 H, C-3 NNH), 7.68–6.95 (m, 15 H, 3 Ph), 2.34
(s, 3 H, CH3).
13C NMR (CDCl3): d = 163.3 (C=O), 146.4, 144.5 (2 C=N), 143.3,
137.7, 129.6, 129.4, 129.1, 125.6, 124.6, 122.6, 121.0, 120.9, 114.3,
113.5 (3 Ph), 11.5 (CH3).
MS (EI): m/z (%) = 339 (32, M+), 296 (12, M+ – CH3CO+), 236 (80,
M+ – PhNC), 135 (10, PhNCS).
MS (EI): m/z (%) = 371 (46, M+), 278 (96, M+ – PhNH2), 105 (14,
PhNN), 93 (100, PhNH2).
Anal. Calcd for C17H13N3OS2: C, 60.16; H, 3.86; N, 12.38. Found:
C, 60.13; H, 4.02; N, 12.45.
Anal. Calcd for C22H21N5O: C, 71.14; H, 5.70; N, 18.86. Found: C,
70.80; H, 5.71; N, 18.74.
5-Acetyl-6-(4-methoxy)phenylimino-3-phenyl-2-thioxo-3,6-di-
hydro-2H-1,3,4-thiadiazine (6b)
Yield: 0.16 g (30%); yellow needles; mp 160–161 °C.
IR (KBr): 1716, 1329, 1077 cm–1.
1H NMR (CDCl3): d = 7.52–6.94 (m, 9 H, Ph, MeOPh), 3.84 (s, 3
H, OCH3), 2.56 (s, 3 H, CH3).
4-Acetyl-2-phenyl-5-phenylimino-2,5-dihydro-1,2,3-thiadia-
zole (5a)
Yield 0.37 g (63%); dark orange powder; mp 107–108 °C.
IR (KBr): 1690, 1580, 1436, 1304, 1064 cm–1.
13C NMR (CDCl3): d = 195.0 (C=O), 184.1 (C=S), 145.1 (N=CS),
143.5 (C=N), 158.8, 144.8, 139.7, 129.4, 126.9, 122.5, 115.8, 114.6
(Ph, MeOPh), 55.5 (OCH3), 28.9 (CH3).
1H NMR (CDCl3): d = 7.43–7.09 (m, 10 H, 2 Ph), 2.73 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 190.4 (C=O), 158.0 (N=CS), 154.9 (C=N),
142.1, 141.2, 130.0, 129.7, 126.5, 125.6, 119.1, 117.9 (2 Ph), 29.0
(CH3).
MS (EI): m/z (%) = 369 (92, M+), 326 (39, M+ – CH3CO+), 236
(100, M+ – MeOPhNC), 165 (39, MeOPhNCS), 43 (37, CH3CO+).
Synthesis 2003, No. 16, 2559–2563 © Thieme Stuttgart · New York

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A Novel Route to 1,2,3-Thiadiazole, 1,3,4-Thiadiazine, and 1,2,5-Triazepine Derivatives
2563
Anal. Calcd for C18H15N3O2S2: C, 58.52; H, 4.09; N, 11.37. Found:
C, 58.51; H, 4.17; N, 11.72.
Anal. Calcd for C18H12ClN3O3S: C, 56.04; H, 3.14; N, 10.89.
Found: C, 56.00; H, 3.19; N, 10.65.
3-Acetyl-1,5-diphenyl-4-thioxo-4,5-dihydro-1H-1,2,5-triazepin-
6,7-dione (8a)
References
Yield: 0.34g (97%); red plates; mp 211–212 °C.
IR (KBr): 1717, 1698, 1650, 1458, 1124 cm–1.
1H NMR (CDCl3): d = 7.70–7.33 (m, 10 H, 2 Ph), 1.87 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 198.4 (C=O), 180.4 (C=S), 156.1, 152.4
(COCO), 143.2 (C=N), 137.5, 135.2, 132.2, 131.2, 130.3, 129.5,
128.6, 123.0 (2 Ph), 31.8 (CH3).
MS (EI): m/z (%) = 351 (8, M+), 323 (8, M+ – CO), 295 (100, M+ –
2 CO), 218 (19, M+ – Ph), 135 (8, PhNCS), 91 (15, C6H5N), 77 (61,
Ph), 43 (18, CH3CO+).
(1) (a) Cyraski, M. K.; Krygowski, T. M.; Katritzky, A. R.; von
Schleyer, P. J. Org. Chem. 2002, 67, 1333. (b) Glossman-
Mitnik, D. THEOCHEM 2001, 549, 285.
(2) (a) Shafiee, A.; Jalilian, A. R.; Rezaei, M. J. Heterocycl.
Chem. 2000, 37, 1325. (b) Naidu, A. V.; Dave, M. A. Asian.
J. Chem. 2000, 687.
(3) (a) Abramov, M. A.; Dehaen, W.; D’hooge, B.; Petrov, M.
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3933. (b) Hameurlaine, A.; Abramov, M. A.; Dehaen, W.
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(4) Zhang, Z.; Yan, J.; Leung, D.; Wang, S.; Costello, P. C.;
Sanghera, J. US 6420400, 2002; Chem. Abstr. 2002, 137,
93758p.
Anal. Calcd for C18H13N3O3S: C, 61.53; H, 3.73; N, 11.96. Found:
C, 61.56; H, 3.82; N, 11.80.
(5) Schwarz, M.; Page, P.; Pomel, V.; Quattropani, A.; Thomas,
R. J. PCT Int. Appl. WO 02102799, 2002; Chem. Abstr.
2003, 138, 55968v.
3-Acetyl-5-(4-methoxy)phenyl-1-phenyl-4-thioxo-4,5-dihydro-
1H-1,2,5-triazepin-6,7-dione (8b)
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Y.; Tawara, S. Bioorg. Med. Chem. 2001, 9, 465.
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Koho JP 2001 335570, 2001; Chem. Abstr. 2002, 136,
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T.; Yamaguchi, R.; Imano, T. Jpn. Kokai Tokkyo Koho JP
2002 114612, 2002; Chem. Abstr. 2002, 136, 305521n.
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3233. (b) Bianchi, M.; Butti, A.; Rossi, S. Tetrahedron
1974, 30, 2765.
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Grochowski, J.; Serda, P. J. Org. Chem. 2002, 67, 4526.
(10) Zaleska, B.; Socha, R. Monatsh. Chem. 2000, 131, 1151.
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Pilati, T. Monatsh. Chem. 2000, 131, 1158.
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J. Org. Chem. 2003, 68, 2334.
(13) Zaleska, B.; Cież, D.; Haas, A. Synth. Commun. 1996, 26,
4165.
Yield: 0.33 g (86%); orange needles; mp 229–230 °C.
IR (KBr): 1736, 1702, 1130 cm–1.
1H NMR (CDCl3): d = 7.71–7.01 (m, 9 H, Ph, MeOPh), 3.88 (s, 3
H, OCH3), 1.90 (s, 3 H, CH3).
13C NMR (CDCl3): d = 198.3 (C=O), 180.2 (C=S), 156.1, 152.2
(COCO), 143.2 (C=N), 161.3, 137.4, 131.9, 129.7, 129.2, 127.2,
122.8, 115.2 (Ph, MeOPh), 55.7 (OCH3), 31.7 (CH3).
MS (EI): m/z (%) = 381 (11, M+), 353 (13, M+ – CO), 325 (100, M+
– 2 CO), 107 (18, MeO – Ph), 105 (10, PhNN), 77 (71, Ph), 43 (33,
CH3CO+).
Anal. Calcd for C19H15N3O4S: C, 59.83; H, 3.96; N, 11.02. Found:
C, 59.97; H, 3.91; N, 11.01.
3-Acetyl-5-(4-chloro)phenyl-1-phenyl-4-thioxo-4,5-dihydro-
1H-1,2,5-triazepin-6,7-dione (8c)
Yield: 0.25 g (65%); light red plates; mp 220–221 °C.
IR (KBr): 1735, 1698, 1650, 1132 cm–1.
1H NMR (CDCl3): d = 7.69–7.28 (m, 9 H, Ph, ClPh), 1.95 (s, 3 H,
CH3).
13C NMR (CDCl3): d = 198.0 (C=O), 179.6 (C=S), 155.6, 152.1
(COCO), 142.6 (C=N), 137.2, 137.2, 133.3, 132.0, 130.3, 129.5,
129.2, 122.8 (Ph, ClPh), 31.6 (CH3).
MS (EI): m/z (%) = 385 (6, M+), 357 (6, M+ – CO), 329 (100, M+ –
2 CO), 111 (18, ClPh), 105 (8, PhNN), 77 (73, Ph), 43 (36,
CH3CO+).
(14) Compound 2a crystallizes in the monoclinic system. See
experimental for details of X-ray structure determination.
The structural data have been deposited at the Cambridge
Crystallographic Data Centre under the reference number
CCDC 209483.
Synthesis 2003, No. 16, 2559–2563 © Thieme Stuttgart · New York