Synthesis of 8-piperidino-5,6-dihydro-4H-thiazolo[5,4-c]azepines and 8-amino-5,6-dihydro-4H-bis[1,3]thiazolo-[3,2-a: 5',4'-c]azepin-7-ium chlorides

Full text of DOI:10.1134/S1070363206070334

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 7, pp. 1178 1180.
Pleiades Publishing, Inc., 2006.
Original Russian Text D.E. Stepanov, E.I. Ivanov, R.Yu. Ivanova, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 7, pp. 1226 1228.
LETTERS
TO THE EDITOR
Synthesis of 8-Piperidino-5,6-dihydro-4H-thiazolo[5,4-c]azepines
and 8-Amino-5,6-dihydro-4H-bis[1,3]thiazolo-
[3,2-a : 5 ,4 -c]azepin-7-ium Chlorides
D. E. Stepanov, E. I. Ivanov, and R. Yu. Ivanova
Bogatskii Physicochemical Institute, National Academy of Sciences of Ukraine,
Lyustdorfskaya doroga 86, Odessa, 65080 Ukraine
e-mail: physchem@paco.odessa.ua
Received June 23, 2005
DOI: 10.1134/S1070363206070334
Continuing our studies in the field of thiazo-
loazepine chemistry [1] we synthesized thiazoloaze-
pinethiones Ia and Ib by heating thiazoloazepinones
IIa and IIb with P4S10 in pyridine. The synthesis of
compounds IIa and IIb having no substituent in the
2-position via reduction of the corresponding 2-chlo-
rothiazoloazepinones was described previously [2].
Insofar as the yields of 2-chlorothiazoloazepinones [3]
were relatively poor, we obtained ketones IIIa and
IIIb by heating 2-chlorothiazolyl ketones IVa and
IVb with reduced iron in a boiling solution of acetic
acid in alcohol [3], and compounds IIIa and IIIb
were then converted into thiazoloazepines IIa and IIb
in 69 70% yield according to Schmidt under condi-
tions similar to those given in [3]. Amidines Va and
Vb were obtained by heating thiazoloazepinethiones
O
O
S
S
[H]
Cl
R
R
R
N
N
R
IIIa, IIIb
IVa, IVb
HN3
H
H
N
S
N
O
NH
HgCl2
S
S
S
N
P4S10
piridine
N
N
R
N
N
R
R
R
R
R
IIa, IIb
Ia, Ib
Va, Vb
ClCH2CN
S
NH2 Cl
+
N
S
N
R
R
VIa, VIb
R = CH3 (a), R = H (b).
1178

SYNTHESIS OF 8-PIPERIDINO-5,6-DIHYDRO-4H-THIAZOLO[5,4-c]AZEPINES
1179
Ia and Ib with piperidine in the presence of HgCl2 to
bind hydrogen sulfide liberated during the process.
By reaction of thiazoloazepinethiones Ia and Ib with
chloroacetonitrile were synthesized 8-amino-5,6-di-
hydro-4H-bis[1,3]thiazolo[3,2-a:5 ,4 -c]azepin-7-ium
chlorides VIa and VIb.
184 [M]+. C7H8N2S2. Calculated, %: C 45.62; H 4.38;
N 15.20; S 34.80. M 184.
5,5-Dimethyl-8-piperidino-5,6-dihydro-4H-thi-
azolo[5,4-c]azepine (Va). Compound Ia, 100 mg,
was dissolved in 2 ml of piperidine, 128 mg of HgCl2
was added, and the mixture was heated for 2 h under
reflux. It was then cooled and filtered, piperidine was
distilled off, the residue was dissolved in benzene, and
the solution was passed through a short column
charged with aluminum oxide, followed by elution
with benzene. The solvent was distilled off from the
eluate, and the residue was dissolved in chloroform
and purified by column chromatography on silica gel
using first chloroform and then chloroform ethanol as
eluent. Yield 77 mg (62%), mp 170 C (from benzene
5,5-Dimethyl-4,5,6,7-tetrahydrobenzothiazol-7-
one (IIIa). Chlorothiazoloazepinone IVa, 4.95 g, was
dissolved in 25 ml of ethanol, 5.2 g of reduced iron
and 12.5 ml of acetic acid were added, and the mix-
ture was heated for 40 h at the boiling point under
stirring. The mixture was cooled and filtered, the
solvent was distilled off from the filtrate, the residue
was dissolved in diethyl ether, and the organic solu-
tion was washed with an aqueous solution of NaHCO3
until neutral reaction and dried over Na2SO4. The
product was purified by column chromatography on
aluminum oxide using chloroform as eluent. Yield
3.62 g (87%). 1H NMR spectrum (DMSO-d6), , ppm:
1.19 s (6H, Me2C), 2.68 s (2H, 6-H), 3.01 s (2H, 4-H),
8.85 s (1H, 2-H). Found, %: C 59.66; H 6.14; N 7.71;
S 17.67. m/z 181 [M]+. C9H11NOS. Calculated, %:
C 59.64; H 6.12; N 7.73; S 17.69. M 181.
1
hexane). H NMR spectrum (DMSO-d6), , ppm (J,
Hz): 1.21 s (6H, Me2C), 1.64 m (6H, CH2, piperidine),
2.65 s (2H, 4-H), 3.40 s (2H, 6-H), 3.47 t (4H, NCH2,
piperidine, J = 6.3). Found, %: C 63.81; H 8.06;
N 1.93; S 12.17. m/z 263 [M]+. C14H21N3S. Calcu-
lated, %: C 63.84; H 8.04; N 1.95; S 12.17. M 263.
8-Piperidino-5,6-dihydro-4H-thiazolo[5,4-c]-
azepine (Vb) was synthesized in a similar way from
compound Ib. Yield 60%, mp 172 C (from benzene
4,5,6,7-Tetrahydrobenzothiazol-7-one (IIIb)
was synthesized in a similar way from compound IVb.
Yield 82%. 1H NMR spectrum (DMSO-d6), , ppm (J,
Hz): 2.06 m (2H, 5-H), 2.81 t (2H, 6-H, J = 6.5),
2.89 t (2H, 4-H, J = 6.2), 8.83 s (1H, 2-H). Found,
%: C 54.85; H 4.63; N 9.42; S 20.90. m/z 153 [M]+.
C7H7NOS. Calculated, %: C 54.88; H 4.61; N 9.41; S
20.93. M 153. Compounds IIIa and IIIb were iso-
lated as oily liquids.
1
hexane). H NMR spectrum (DMSO-d6), , ppm (J,
Hz): 1.64 m (6H, CH2, piperidine), 2.11 m (2H, 5-H),
2.88 t (2H, 4-H, J = 6.2), 3.48 t (4H, NCH2, piperi-
dine, J = 6.3), 3.51 t (2H, 6-H, J = 6.4). Found, %:
C 61.22; H 7.29; N 17.84; S 13.60. m/z 235 [M]+.
C12H17N3S. Calculated, %: C 61.24; H 7.28; N 17.85;
S 13.62. M 235.
5,5-Dimethyl-5,6-dihydro-4H-bis[1,3]thiazolo-
[3,2-a:5 ,4 -c]azepin-7-ium chloride (VIa). A mix-
ture of 143 mg of thiazoloazepinethione Ia (finely
powdered in a mortar) and 3 ml of chloroacetonitrile
was heated for 2 h on a boiling water bath. The mix-
ture was cooled and filtered, the precipitate was
washed on a filter with diethyl ether and mixed with
3 ml of isobutyl alcohol, and the mixture was heated
for 30 min under reflux, cooled, and filtered. The
precipitate was washed on a filter with isobutyl al-
cohol, dried in air, and recrystallized twice from
ethanol. Yield 140.62 mg (73%), mp 284 C (decomp.,
5,5-Dimethyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-
c]azepine-8-thione (Ia). Compound IIa, 1.96 g, was
dissolved in 20 ml of pyridine, 3.7 g of P4S10 was
added, and the mixture was heated for 9 h under re-
flux. The solvent was distilled off, the residue was
dissolved in chloroform, and the product was purified
by column chromatography on aluminum oxide using
chloroform as eluent. Yield 1.34 g (63%), mp 164C
(from toluene). 1H NMR spectrum (DMSO-d6),
,
ppm (J, Hz): 1.10 s (6H, Me2C), 2.94 s (2H, 4-H),
3.15 d (2H, 6-H, J = 6.7), 8.46 br.s (1H, 7-H), 8.77 s
(1H, 2-H). Found, %: C 50.90; H 5.71; N 13.18; S
30.18. m/z 212 [M]+. C9H12N2S2. Calculated, %: C
50.91; H 5.70; N 13.19; S 30.20. M 212.
from toluene). 1H NMR spectrum (DMSO-d6),
,
ppm: 1.02 s (6H, Me2C), 3.18 s (2H, 4-H), 4.25 s (2H,
6-H), 6.75 s (1H, thiazole), 6.98 br.s (2H, NH2), 9.36
s (1H, thiazole). Found, %: C 45.90; H 4.89; Cl
5,6,7,8-Tetrahydro-4H-thiazolo[5,4-c]azepine-8-
thione (Ib) was synthesized in a similar way from
compound IIb. Yield 61%, mp 167 C (from toluene).
1H NMR spectrum (DMSO-d6), , ppm (J, Hz):
1.97 m (2H, 5-H), 3.09 t (2H, 4-H, J = 6.0), 3.39 m
(2H, 6-H), 8.59 br.s (1H, 7-H), 8.79 s (1H, 2-H).
Found, %: C 45.60; H 4.39; N 15.18; S 34.77. m/z
12.33; N 14.63; S 22.23. m/z 252 [M
C11H13N3S2 HCl. Calculated, %: C 45.91; H 4.87;
Cl 12.35; N 14.61; S 22.26. [M HCl] 252.
HCl]+.
5,6-Dihydro-4H-bis[1,3]thiazolo[3,2-a :5 ,4 -c]-
azepin-7-ium chloride (VIb) was synthesized in a
similar way from thiazoloazepinethione Ib and chlo-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1180
STEPANOV et al.
roacetonitrile. Yield 75%, mp 280 C (decomp., from
toluene). H NMR spectrum (DMSO-d6), , ppm (J,
ion source. The progress of reactions and the purity
of products were monitored by TLC on Silufol
UV-254 plates.
1
Hz): 2.55 m (2H, 5-H), 3.21 t (2H, 4-H, J = 6.4),
4.30 t (2H, 6-H, J = 6.3), 6.79 s (1H, thiazole), 7.11
br.s (2H, NH2), 9.38 s (1H, thiazole). Found, %: C
41.60; H 3.87; Cl 13.63; N 16.17; S 24.68. m/z 224
REFERENCES
[M
HCl]+. C9H9N3S2 HCl. Calculated, %: C
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224.
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1
The H NMR spectra were recorded on a Varian-
2001, vol. 71, no. 9, p. 1499.
300 spectrometer (300 MHz). The mass spectra (elec-
tron impact, 70 eV) were obtained on an MKh-1321
spectrometer with direct sample admission into the
3. Stepanov, D.E., Ivanov, E.I., and Ivanova, R.Yu., Russ.
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006