One-pot synthesis of functionalized tetrahydro-1,4-thiazepines

Article abstract of DOI:10.1080/00397911003797908

One-pot synthesis of (5Z,7Z)-5-amino-7-(ethyl or arylimino)-2,3,4,7- tetrahydro-1,4-thiazepine-6-carbonitriles from cyclocondensation of 2-((ethyl or arylamino)(mercapto)methylene)malononitrile potassium salts or their methylated derivatives with 2-chloro

Full text of DOI:10.1080/00397911003797908

Synthetic Communications1, 41: 1181–1185, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003797908
ONE-POT SYNTHESIS OF FUNCTIONALIZED
TETRAHYDRO-1,4-THIAZEPINES
M. Bakavoli, H. Beyzaei, M. Rahimizadeh, and H. Eshghi
Department of Chemistry, School of Sciences, Ferdowsi University of
Mashhad, Mashhad, Iran
GRAPHICAL ABSTRACT
Abstract One-pot synthesis of (5Z,7Z)-5-amino-7-(ethyl or arylimino)-2,3,4,7-
tetrahydro-1,4-thiazepine-6-carbonitriles from cyclocondensation of 2-((ethyl or arylami-
no)(mercapto)methylene)malononitrile potassium salts or their methylated derivatives
with 2-chloroethylamine hydrochloride or cysteamine in dimethylformamide via two routes
but a single intermediate is described.
Keywords Heterocyclization; isothiocyanates; malononitrile; 1,4-thiazepine
INTRODUCTION
In connection with our interest in the synthesis of novel polyfunctionalized
1,4-thiazepines as potential precursors for the synthesis of biologically important
fused 1,4-thiazepines, we previously described the reaction of sodium
2,2-dicyanoethene-1,1-bis(thiolate) and ethyl-2-cyano-3,3-dimercaptoacrylate dipo-
tassium salts with 2-chloroethylamine hydrochloride in water to prepare the novel
5-amino-1,4-thiazepines[1,2] (Scheme 1).
To extend the scope of this reaction, we have explored the reaction of other
substituted (methylene)malononitrile potassium salts with 2-chloroethylamine
hydrochloride to synthesize the new (5Z,7Z)-5-amino-7-(ethyl or arylimino)-2,3,4,7-
tetrahydro-1,4-thiazepine-6-carbonitriles 8a–f via two different routes.
Received January 21, 2010.
Address correspondence to M. Bakavoli, Department of Chemistry, School of Sciences, Ferdowsi
University of Mashhad, Mashhad, Iran. E-mail: mbakavoli@yahoo.com
1181

1182
M. BAKAVOLI ET AL.
Scheme 1. Synthesis of 5-amino-1,4-thiazepines.
RESULTS AND DISCUSSION
The functionalized tetrahydro-1,4-thiazepines 8a–f were obtained via two
routes. In route A, a mixture of 2-((ethyl or arylamino)(mercapto)methylene)malo-
nonitrile potassium salts 3a–f (which were prepared as intermediates from malono-
nitrile 1 and isothiocyanates 2a–f) and 2-chloroethylamine hydrochloride 4 in
dimethylformamide (DMF) was first stirred at room temperature for 3 h, then heated
at 60 ꢀC for 12 h to afford the solid products 8a–f (Scheme 2). In route B, similar
treatment of the methylated salts 5a–f with cysteamine 6 afforded the desired
products 8a–f. The yields of the products obtained are depicted in Table 1.
Scheme 2. Synthetic routes to (5Z,7Z)-5-amino-7-(ethyl or arylimino)-2,3,4,7-tetrahydro-1,4-thiazepine-6-
carbonitriles 8a–f.
Table 1. Comparing yields of compounds 8a–f obtained by routes A and B
Yield (%)
Entry
R
Substrate
Method A
Method B
1
2
3
4
5
6
C2H5
C6H5
8a
8b
8c
8d
8e
8f
32
35
38
40
44
33
48
50
55
58
61
50
p-ClC6H4
p-BrC6H4
p-NO2C6H4
m-MeC6H4

TETRAHYDRO-1,4-THIAZEPINES
1183
A comparison between the results obtained from both routes leads us to the
conclusion that route A is 66% to 72% as efficient as route B. While route B has
greater yields, it also requires use of toxic methyl iodide and cysteamine, which
has an unpleasant odor. This probably makes it less advantageous from an oper-
ational standpoint. It is worth noting that both routes share the same intermediate,
2-((2-aminoethylthio)(ethyl or arylamino)methylene)malononitriles 7a–f. The multi-
step reactions can account for the poor yields of the final products.
The structures of compounds 8a–f were confirmed from their spectral and
1
micro analytical data. Their H NMR spectra in acetone-d6 showed triplet signals
due to S-CH2 groups at 2.88–3.03 ppm (J ꢁ 6.8 Hz) and doublet triplet signals due
to N-CH2 at 3.64–3.78 ppm (J ꢁ 6.0 Hz). After adding D2O, the latter signals
appeared as triplets with the same coupling constants as their neighboring methylen
groups. Two broad signals at 6.61–7.39 and 8.62–9.13 ppm are attributed to NH2
and NH groups respectively. The infrared (IR) spectra of the products showed
two different absorption bands at 3270–3432 cmꢂ1 and 3215–3282 cmꢂ1 assignable
to NH and NH2 groups, bands at 2183–2208 cmꢂ1 belonging to CꢃN groups, and
absorption bands at 1579–1648 cmꢂ1 belonging to C N imine groups.
=
EXPERIMENTAL
Materials
All the reactions were carried out without any special precautions in an atmo-
sphere of air. Chemicals were purchased from Merck and used as received. Melting
points were recorded on an Electrothermal type 9100 melting-point apparatus and
1
are uncorrected. The H NMR spectra were recorded on a Bruker AC 100 spec-
trometer. Chemical shifts are reported in parts per million (ppm) downfield from
tetramethylsilane (TMS) as internal standard. The IR spectra were obtained on a
4300 Shimadzu spectrometer, and only noteworthy absorptions are listed. The mass
spectra were observed on a Varian Mat CH-7 at 70 ev. Elemental analyses (C, H,
N, S) were performed on a Thermo Finnigan Flash EA microanalyzer.
General Procedure for the Synthesis of Functionalized
Tetrahydro-1,4-thiazepines 8a–f
Method A. A suspension of 1 (10 mmol, 0.66 g), isothiocyanates 2a–f
(10 mmol), and potassium carbonate (10 mmol, 1.4 g) in DMF (20 ml) was stirred
for 3 h at 25 ꢀC before 2-chloroethylamine hydrochloride (10 mmol, 1.16 g) was
added to it all at once. Then it was stirred for another 2 h before it was heated at
60 ꢀC for 12 h. The mixture was neutralized with acetic acid (0.3 ml), and the solvent
was removed at room temperature. The residue was dissolved in ethanol (10 ml)
and added dropwise to brine 20% (30 ml). The solid was filtered off, washed with
water (2 ꢄ 10 ml), and recrystallized from acetonitrile (12–23 ml) as white needles
to give 8a–f.
Method B. A suspension of 1 (10 mmol, 0.66 g), isothiocyanates 2a–f
(10 mmol), and potassium carbonate (10 mmol, 1.4 g) in DMF (20 ml) was stirred
for 3 h at 25 ꢀC before methyl iodide (10 mmol, 0.6 ml) was added dropwise on

1184
M. BAKAVOLI ET AL.
stirring for 1 h. Then cysteamine 6 (10 mmol, 0.77 g) was added at once, and the mix-
ture was heated at 60 ꢀC for 12 h. The products were purified as in method A.
Data
(5Z,7Z)-5-Amino-7-(ethylimino)-2,3,4,7-tetrahydro-1,4-thiazepꢂin1e-6-
;
1H
carbonitrile (8a). Mp 197–198 ꢀC; IR (KBr) 3300, 3282, 2183, 1586 cm
NMR (acetone-d6, 100 MHz) d: 1.23 (t, J ¼ 7.1 Hz, 3H, CH3), 3.03 (t, J ¼ 7.3 Hz,
2H, S-CH2), 3.45 (q, J ¼ 7.1 Hz, 2H, N-CH2CH3), 3.76 (dt, J ꢁ 6.1 Hz, 2H,
N-CH2), 6.61 (s, 3H, NH, NH2); mass (70 eV) 196 m=z. Anal. calcd. for
C8H12N4S (196.27): C, 48.96; H, 6.16; N, 28.55; S, 16.33. Found: C, 48.88; H,
6.24; N, 28.67; S, 16.21.
(5Z,7Z)-5-Amino-2,3,4,7-tetrahydro-7-(phenylimino)-1,4-thiazepꢂin1 e-6-
;
1H
carbonitrile (8b). Mp 127–128 ꢀC; IR (KBr) 3312, 3279, 2192, 1579 cm
NMR (acetone-d6, 100 MHz) d: 2.93 (t, J ¼ 6.8 Hz, 2H, S-CH2), 3.64 (dt, J ꢁ 6.3 Hz,
2H, N-CH2), 6.90 (s, 2H, NH2), 7.25 (m, 5H, Ph), 8.62 (s, 1H, NH); mass (70 eV) 244
m=z. Anal. calcd. for C12H12N4S (244.32): C, 58.99; H, 4.95; N, 22.93; S, 13.13.
Found: C, 59.12; H, 4.88; N, 22.79; S, 13.21.
(5Z,7Z)-7-(4-Chlorophenylimino)-5-amino-2,3,4,7-tetrahydro-1,4-
thiazepine-6-carbonitrile (8c). Mp 251–252 ꢀC; IR (KBr) 3300, 3231, 2197,
1602 cmꢂ1
;
1H NMR (acetone-d6, 100 MHz) d: 3.00 (t, J ¼ 6.6 Hz, 2H, S-CH2),
3.72 (dt, J ꢁ 5.9 Hz, 2H, N-CH2), 7.04 (s, 2H, NH2), 7.19, 7.34 (dd, 4H, Ph), 8.71
(s, 1H, NH); mass (70 eV) 278 m=z. Anal. calcd. for C12H11ClN4S (278.76): C,
51.70; H, 3.98; N, 20.10; S, 11.50. Found: C, 51.56; H, 3.89; N, 20.21; S, 11.40.
(5Z,7Z)-7-(4-Bromophenylimino)-5-amino-2,3,4,7-tetrahydro-1,4-thiaze-
pine-6-carbonitrile (8d). Mp 264–265 ꢀC; IR (KBr) 3270, 3247, 2189, 1595 cmꢂ1
;
1H NMR (acetone-d6, 100 MHz) d: 3.00 (t, J ¼ 6.7 Hz, 2H, S-CH2), 3.72 (dt,
J ꢁ 6.1 Hz, 2H, N-CH2), 7.02 (s, 2H, NH2), 7.22, 7.54 (dd, 4H, Ph), 8.74 (s, 1H,
NH); mass (70 eV) 323 m=z. Anal. calcd. for C12H11BrN4S (323.21): C, 44.59; H,
3.43; N, 17.33; S, 9.92. Found: C, 44.64; H, 3.47; N, 17.47; S, 9.79.
(5Z,7Z)-7-(4-Nitrophenylimino)-5-amino-2,3,4,7-tetrahydro-1,4-thiazepine-
6-carbonitrile (8e). Decomp. 243–244 ꢀC; IR (KBr) 3324, 3215, 2208, 1648 cmꢂ1
;
1H NMR (acetone-d6, 100 MHz) d: 3.02 (t, J ¼ 6.4 Hz, 2H, S-CH2), 3.78 (dt,
J ꢁ 5.6 Hz, 2H, N-CH2), 7.39 (s, 2H, NH2), 7.45, 7.24 (dd, 4H, Ph), 9.13 (s, 1H,
NH); mass (70 eV) 289 m=z. Anal. calcd. for C12H11N5O2S (289.31): C, 49.82; H,
3.83; N, 24.21; S, 11.08. Found: C, 49.94; H, 3.75; N, 24.18; S, 11.08.
(5Z,7Z)-7-(m-Tolylimino)-5-amino-2,3,4,7-tetrahydro-1,4-thiazepine-6-
carbonitrile (8f). Mp 144–145 ꢀC; IR (KBr) 3432, 3263, 2190, 1594 cmꢂ1; 1H NMR
(acetone-d6, 100 MHz) d: 2.34 (s, 3H, CH3), 2.88 (t, J ¼ 6.5 Hz, 2H, S-CH2), 3.74 (dt,
J ꢁ 5.8 Hz, 2H, N-CH2), 6.93 (s, 2H, NH2), 7.08 (m, 4H, Ph), 8.65 (s, 1H, NH); mass
(70 eV) 258 m=z. Anal. calcd. for C13H14N4S (258.34): C, 60.44; H, 5.46; N, 21.69; S,
12.41. Found: C, 60.54; H, 5.38; N, 21.56; S, 12.52.

TETRAHYDRO-1,4-THIAZEPINES
1185
REFERENCES
1. Bakavoli, M.; Beyzaei, H.; Rahimizadeh, M.; Tajabadi, J. Green synthesis of a novel func-
tionalized tetrahydro-1,4-thiazepine and computational studies of its tautomeric structures.
Synth. Commun. 2009, 39, 1324–1331.
2. Bakavoli, M.; Rahimizadeh, M.; Raissi, H.; Beyzaei, H.; Tajabadi, J. Synthesis of a func-
tionalized tetrahydro-1,4-thiazepine in water as the solvent and theoretical investigation of
its tautomeric structures. Monatsh. Chem. 2008, 139, 1211–1215.

Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.