Utility of α-oxoketene and α-cyanoketene thioacetals in heterocyclic syntheses: Synthesis of some new benzothiazepine derivatives

Article abstract of DOI:10.1080/00397910903538644

Benzo[b][1,5]thiazepines 1a or 1b were prepared via reaction of o-aminothiophenol with 3-(bis(methylthio)methylene)-pentane-2,4-dione or 2-(bis(methylthio)methylene)-3-carbonitrile, respectively. Reaction of compound 1a with malononitrile afforded pyrano[

Full text of DOI:10.1080/00397910903538644

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Utility of α-Oxoketene and α-
Cyanoketene Thioacetals in Heterocyclic
Syntheses: Synthesis of Some New
Benzothiazepine Derivatives
Mounir A. A. Mohamed a
a Chemistry Department, Faculty of Science, Sohag University,
Sohag, Egypt
Published online: 13 Jan 2011.
To cite this article: Mounir A. A. Mohamed (2011) Utility of α-Oxoketene and α-Cyanoketene
Thioacetals in Heterocyclic Syntheses: Synthesis of Some New Benzothiazepine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:3, 331-340, DOI: 10.1080/00397910903538644
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Synthetic Communications1, 41: 331–340, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903538644
UTILITY OF a-OXOKETENE AND a-CYANOKETENE
THIOACETALS IN HETEROCYCLIC SYNTHESES:
SYNTHESIS OF SOME NEW BENZOTHIAZEPINE
DERIVATIVES
Mounir A. A. Mohamed
Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
Benzo[b][1,5]thiazepines 1a or 1b were prepared via reaction of o-aminothiophenol with
3-(bis(methylthio)methylene)-pentane-2,4-dione or 2-(bis(methylthio)methylene)-3-
carbonitrile, respectively. Reaction of compound 1a with malononitrile afforded
pyrano[4,3-b]benzothiazepine 2a, which underwent cyclization into pyrido[4,3-b][1,5]-
benzothiazepine 2b. Also, reaction of compound 1a with ethyl cyanoacetate afforded
pyrano[4,3-b][1,5]benzothiazepin-3-one 3. Reaction of compound 1a with hydrazine, phe-
nylhydrazine, or hydroxylamine afforded the corresponding azolobenzothiazepines, 4–6,
respectively. Reaction of compound 1a with ethylenediamine afforded 1,5-benzothiazepin-
ethanone 7, which underwent cyclization to [1,4]diazepino[5,6-b][1,5]benzothiazepine 8.
Also, compound 1b was reacted with acetylacetone or ethyl acetoacetate to afford
pyrano[4,3-b][1,5]benzothiazepines 9a or 9b, which reacted with ammonium acetate to
give pyrano[4,3-b][1,5]-benzothiazepine 10a or pyrido[4,3-b][1,5]-benzothiazepine 10b,
respectively. Compound 1b was allowed to react with hydrazine, phenylhydrazine,
or hydroxyl amine to afford pyrazolo or isoxazolo[3,4-b][1,5]benzothiazepines 11, 12,
or 13, respectively.
Keywords: Active methylene; benzothiazepines; a-oxoketene dithioacetals; piperidine
INTRODUCTION
Benzothiazepines exhibit antifungal, antibacterial, antifeedant, anti-
inflammatory, analgesic, and anticonvulsant properties.[1–4] Compounds possessing
a thiophene substructure also find applications as pharmaceuticals,[5,6] precursors
for natural products,[7] conjugated polymers,[8] and other materials.[9] Most literature
for the synthesis of benzothiazepines depends on the reaction of o-aminothiophenol
with an a,b-unsaturated carbonyl functionality via [4 þ 3]-annulation.[10–13]
Recently, new 3-benzyl-1,10-diaryl-4H,10H-thieno[3,4-c][1,5]benzothiazepines com-
prising both thiophene and benzothiazepine substructures were synthesized in a
one-pot, multistep tandem process from the reaction of 5-aryl-2,4-bis(arylmethylide-
ne)dihydro-3-thiophenones with o-aminothiophenol.[14] This prompted us to
Received August 10, 2009.
Address correspondence to Dr. Mounir A. A. Mohamed, Chemistry Department, Sohag
University, Nacer City, Sohag 82524, Egypt. E-mail: mounir_abbas@yahoo.com
331

332
M. A. A. MOHAMED
synthesize some fused benzothiazepines derivatives with a variety of nuclei include
pyrane, pyridine, and pyrazole oxazole pyrimidinone or 1,4-diazepine as biologically
active compounds.
RESULTS AND DISCUSSION
In continuation of our work on the chemistry of a-oxoketene S,S-acetals[15–17]
and diazepine derivatives,[18–21] we report here the synthesis of 1-((2E,4Z)-4-
methyl-2-(methylthio)benzo[b][1,5]thiazepin-3-yl)ethanone 1a or (Z)-2-(methylthio)-
4-oxo-4,5-dihydrobenzo[b][1,5]thiazepine-3-carbonitrile 1b via reaction of
3-(bis(methylthio)methylene)-pentane-2,4-dione or 2-(bis(methylthio)methylene)-3-
carbonitrile with o-aminothiophenol under reflux in ethanol in the presence of
triethylamine (TEA) as a catalyst (cf. Scheme 1).
Reaction of compound 1a with malononitrile in the presence of piperidine
as a base afforded the corresponding 1,11-dimethyl-3-oxo-3H-pyrano[4,3-b][1,5]-
benzothiazepine-4-carbonitrile 2a, which converted into 1,11-dimethyl-3-oxo-
2,3-dihydropyrido[4,3-b][1,5]benzothiazepine-4-carbonitrile 2b after refluxing with
ammonium acetate in acetic acid. Also, reaction of compound 1a with ethyl cyano-
acetate afforded 1,4,11-trimethyl-3H-pyrano[4,3-b][1,5]benzothiazepin-3-one
(Scheme 2).
3
The reaction mechanism was assumed to proceed via a nucleophilic addition of
an active methylene at the ethylenic bond of thiazepine ring with eliminatinon of the
MeSH molecule followed by enolization and cyclization to the desired pyrano-
benzthiazepine derivative.
Scheme 1.

NEW BENZOTHIAZEPINE DERIVATIVES
333
Scheme 2.
Compound 1a was reacted with hydrazine, phenylhydrazine, or hydroxylamine
to afford the corresponding azolobenzothiazepines, namely 3,4-dimethyl-2H-
pyrazolo[3,4-b][1,5]benzothiazepine 4, 3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-b]-
[1,5]benzothiazepine 5, or 3,4-di-methylisoxazolo[3,4-b][1,5]benzothiazepine 6,
respectively.
In the same manner, the reaction of compound 1a with ethylenediamine at
room temperature afforded 1-{2-[(2-aminoethyl)amino]-4-methyl-1,5-benzothiazepin-
3-yl}ethanone 7, which underwent cyclization in boiling ethanol to 5,6-dimethyl-2,3-
dihydro-1H-[1,4]diazepino[5,6-b][1,5]-benzothiazepine
8 (Scheme 3). The new
products were characterized using infrared (IR) and 1H NMR spectroscopy (Table 1).
On the other hand, compound 1b was allowed to react with acetylacetone or
ethyl acetoacetate to afford the corresponding 4-acetyl-1-imino-3-methyl-1H-
pyrano[4,3-b][1,5]benzothiazepin-11(10H)-one 9a or 4-acetyl-3-methylpyrido[4,3-
b][1,5]benzothiazepine-1,11(2H,10H)-dione 9b, which upon reaction with
ammonium acetate gave ethyl 1-imino-3-methyl-11-oxo-10,11-dihydro-1H-
pyrano[4,3-b][1,5]-benzothia-zepine-4-carboxylate 10a or 3-methyl-1,11-dioxo-1,2,
10,11-tetrahydro-pyrido[4,3-b][1,5]benzothiazepine-4-carboxylate 10b, respectively
(Scheme 4).
In continuation of the search for the synthesis of a new derivative of benzo-
thiazepine including tricyclic systems, compound 1b was reacted with hydrazine,
phenylhydrazine, or hydroxyl amine in ethanol to afford 3-amino-2H-
pyrazolo[3,4-b][1,5]benzothiazepin-4(5H)-one 11, 3-amino-2-phenyl-2H-pyrazolo-
[3,4-b][1,5]benzothiazepin-4(5H)-one
12,
or
benzothiazepin-4(5H)-one 13, respectively (Scheme 5).
3-aminoisoxazolo[3,4-b][1,5]-
EXPERIMENTAL
All melting points were determined on a Koffler melting-point apparatus and
1
are uncorrected. H NMR spectra were recorded on a Bruker Avance 300-MHz
spectrometer using tetramethylsilane (TMS) as internal reference (chemical shifts
in d, ppm), and IR spectra were obtained on a Bruker Fourier transform (FT)–IR
ISS 25 spectrophotometer (KBr, nmax in cmꢀ1).

334
M. A. A. MOHAMED
Scheme 3.
Synthesis of 1-[4-Methyl-2-(methylthio)-1,5-benzothiazepin-3-
yl]-ethanone (1a)
A mixture of o-aminothiophenol (3.13 g, 0.025 mol) and 3-[bis(methylthio)-
methylene]pentane-2,4-dione (5.1 g, 0.025 mol) in absolute ethanol (50 mL) was
treated with a catalytic amount of TEA, and the reaction mixture was heated
under reflux until the evolution of MeSH ceased (8 h). The solvent was evaporated
under reduced pressure, and the residual mass was triturated with petroleum ether

335

336
M. A. A. MOHAMED
Scheme 4.
(40–60 ꢁC). The formed solid was recrystallized from aq. ethanol into pale yellow
needles, mp 172–174 ꢁC.
Synthesis of 2-(Methylthio)-4-oxo-4,5-dihydro-1,5-benzothiazepine-
3-carbonitrile (1b)
A mixture of o-aminothiophenol (3.13 g, 0.025 mol) and ethyl 2-cyano-3,3-
bis(methylthio)acrylate (5.4 g, 0.025 mol) in absolute ethanol (50 mL) was treated
with a catalytic amount of TEA, and the reaction mixture was heated under reflux
until the evolution of MeSH ceased (6 h). The solvent was evaporated under reduced
Scheme 5.

NEW BENZOTHIAZEPINE DERIVATIVES
337
pressure, and the residual mass was triturated with petroleum ether (40–60 ꢁC). The
formed solid was recrystallized from aq. ethanol into pale yellow needles, mp
208–210 ꢁC.
Synthesis of 3-Imino-1,11-dimethyl-3H-pyrano[4,3-b][1,5]benzo-
thiazepine-4-carbonitrile 2a
A mixture of compound 1a (2.63 g, 0.01 mol), malononitrile (0.66 g, 0.01 mol) in
absolute ethanol (40 mL) and a catalytic amount of piperidine was heated under
reflux for 3 h. The solvent was evaporated, and the formed solid was collected by fil-
tration and recrystallized from MeOH into yellow needles, mp 214–216 ꢁC, yield 72%.
Synthesis of 1,11-Dimethyl-3-oxo-2,3-dihydropyrido[4,3-
b][1,5]benzo-thiazepine-4-carbonitrile 2b
Compound 2a (2.0 g, 0.076 mol) was dissolved in AcOH (25 mL) and then
treated with AcONH4 (1.0 g, 0.12 mol). The reaction mixture was heated under reflux
for 1 h, solvent was evaporated in vacuo, and then water (50 mL) was added. The
formed solid was filtered off and recrystallized from ethanol into white crystals,
mp 195–197 ꢁC, yield 65%.
Synthesis of 1,11-Dimethyl-3-oxo-3H-pyrano[4,3-b][1,5]benzo-
thiazepine-4-carbonitrile 3
A mixture of compound 1a (2.63 g, 0.01 mol), ethyl cyanoacetate (1.13 g,
0.01 mol) in absolute ethanol (40 mL), and two drops of piperidine was heated under
reflux for 3 h. Solvent was evaporated in vacuo, and the formed solid was collected
by filtration and recrystallized from EtOH into pale yellow needles, mp 243–245 ꢁC,
yield 78%.
Synthesis of 3,4-Dimethyl-2H-pyrazolo[3,4-b][1,5]benzothiazepine 4,
3,4-Dimethyl-2-phenyl-2H-pyrazolo[3,4-b][1,5]benzothiazepine 5,
and, 3,4-Dimethylisoxazolo[3,4-b][1,5]benzothiazepine 6
A mixture of compound 1a (2.63 g, 0.01 mol) and hydrazine, phenylhydrazine,
and=or hydroxylamine (0.012 mol) in absolute EtOH (40 mL) was heated under
reflux for 2 h. The solvent was evaporated under reduced pressure, and the formed
solid was collected by filtration (yields 85, 81, and 66%, respectively).
Synthesis of 1-{2-[(2-Aminoethyl)imino]-4-methyl-2,3-dihydro-1,5-
benzothiazepin-3-yl}ethanone 7
A mixture of compound 1a (2.63 g, 0.01 mol) and ethylenediamine (0.6 g,
0.01 mol) in ethanol (40 mL) was stirred at room temperature for 3 h. The solvent
was evaporated under reduced pressure, water (50 ml) was added, and the mixture
was left overnight. The formed solid was filtered off and recrystallized from EtOH
into light brown crystals, mp > 300 ꢁC, yield 88%.

338
M. A. A. MOHAMED
Synthesis of 5,6-Dimethyl-2,3-dihydro-1H-[1,4]diazepino[5,6-b][1,5]-
benzothiazepine 8
Compound 7 (2 g) was dissolved in ethanol (30 mL) and heated under reflux for
2 h. Solvent was evaporated, and the residual mass was then triturated with pet-
roleum ether (60–80). The formed solid was collected and recrystallized from ethanol
into pale yellow needles, mp 230–232 ꢁC, yield 62%.
Synthesis of 4-Acetyl-1-imino-3-methyl-1H-pyrano[4,3-
b][1,5]benzothiazepin-11(10H)-one 9a and Ethyl 1-Imino-3-methyl-
11-oxo-10,11-dihydro-1H-pyrano[4,3-b][1,5]-benzothiazepine-
4-carboxylate 10a
A mixture of compound 1a (2.63 g, 0.01 mol), acetylacetone or ethyl acetoace-
tate (0.01 mol) in absolute ethanol (40 mL), and a catalytic amount of piperidine was
heated under reflux for 3 h. The solvent was evaporated, and the formed solid was
collected by filtration and recrystallized from MeOH into 9a as a pale yellow solid,
mp 276–278 ꢁC, yield 75%, and 10a as brown crystals, mp 250–252 ꢁC, yield 68%.
Synthesis of 4-Acetyl-3-methylpyrido[4,3-
b][1,5]benzothiazepine-1,11(2H,10H)-dione 9b or 3-Methyl-1,11-
dioxo-1,2,10,11-tetrahydro-pyrido[4,3-b][1,5]benzothiazepine-
4-carboxylate 10b
Compound 9a or 10a (0.075 mol) was dissolved in AcOH (25 mL) and then
treated with AcONH4 (1.0 g, 0.12 mol). The reaction mixture was heated under reflux
for 1 h, solvent was evaporated in vacuo, and then water (50 mL) was added. The
residual mass was poored into cold ice water, and the formed solid was filtered off
and recrystallized from ethanol into 9b as white crystals, mp 223–225 ꢁC, yield
66%, and 10b as pale yellow crystals, mp 222–224 ꢁC, yield 62%.
Synthesis of 3-Amino-2H-pyrazolo[3,4-b][1,5]benzothiazepin-4(5H)-
one 11, 3-Amino-2-phenyl-2H-pyrazolo[3,4-b][1,5]benzothiazepin-
4(5H)-one 12, or 3-Aminoisoxazolo[3,4-b][1,5]-benzothiazepin-
4(5H)-one 13
A mixture of compound 1b (0.005 mol) and hydrazine, phenylhydrazine, and=
or hydroxylamine (0.01 mol) in absolute EtOH (40 mL) was heated under reflux for
2 h. The solvent was evaporated under reduced pressure, and the formed solid was
collected by filtration (yields 80, 75, and 65% respectively).
REFERENCES
1. (a) Mane, R. A.; Ingle, D. B. Synthesis and biological activity of some new 1,5-benzothia-
zepines containing thiazole moiety. Ind. J. Chem., Sect. B 1982, 21B, 973; (b) Attia, A.;
Abdel-salam, O. I.; Abo-Ghalia, M. H.; Amr, A. E. Chemical and biological reactivity of
newly synthesized 2-chloro-6-ethoxy-4-acetylpyridines. Egypt. J. Chem. 1995, 38, 543–553.

NEW BENZOTHIAZEPINE DERIVATIVES
339
2. Reddy, R. J.; Ashok, D.; Sarma, P. N. Synthesis of 4,6-bis(20-substituted-20,30-dihydro-
1,5-benzothiazepin-40-yl)resorcinols as potential antifeedants. Ind. J. Chem., Sect. B
1993, 32, 404–406.
3. Satyanarayana, K.; Rao, M. N. A. Synthesis of 3-[4-[2,3-dihydro-2-(substitutedaryl)-1,5-
benzothiazepin-4-yl]phenyl]sydnones as potential anti-inflammarory agents. Ind. J.
Pharm. Sci. 1993, 55, 230–234.
4. DeSarro, G.; Chimirri, A.; DeSarro, A.; Gitto, R.; Grasso, S.; Zappala, M. 5H-[1,2,4]-
Oxadiazolo[5,4-d]benzothiazepines as anticonvulsant agents in DBA=2 mice. Eur. J.
Med. Chem. 1995, 30(12), 925–929.
5. Gronowitz, S. The Chemistry of Heterocyclic Compounds: Thiophene and Its Derivatives;
Wiley: New York, 1991; vol. 44.
6. (a) Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. The synthesis of 5-alkoxy and 5-amino
substituted thiophenes. Tetrahedron Lett. 2000, 41(10), 1597–1600; (b) Luker, T. J.;
Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D. R. Palladium-catalysed amination
of electron-deficient halothiophenes. Tetrahedron Lett. 2000, 41(40), 7731–7735.
7. (a) Bohlmann, F.; Zdero, C.; Gronowitz, S. Thiophene and Its Derivatives; John Wiley &
Sons: New York, 1985; part 1, p. 261; (b) Koike, K.; Jia, Z.; Nikaido, T.; Liu, Y.; Zhao,
Y.; Guo, D. Echinothiophene, a novel benzothiophene glycoside from the roots of
Echinops grijissii. Org. Lett. 1999, 1(2), 197–198.
8. (a) Kiess, H. Conjugated Conducting Polymers; Springer: New York, 1992; vol. 102;
(b) Roncali, J. Conjugated poly(thiophenes): Synthesis, functionalization, and applica-
tions. Chem. Rev. 1992, 92(4), 711–738; (c) Schopf, G.; Kossmehl, G. Polythiophenes—
Electrically conductive polymers. Adv. Polym. Sci. 1997, 129, 1.
9. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Synthesis of novel (bis) (diarylamino)-
thiophenes via palladium-catalysed reaction of (di)bromothiophenes. Chem. Commun.
2000, 133–135.
10. Katritzky, A. R.; Odens, H. H.; Zhang, S. Novel synthesis of 2,3-dihydro-1,5-
benzothiazepin-4(5H)-ones and 2H-1,4-benzothiazin-3(4H)-ones. J. Org. Chem. 2001,
66, 6792.
11. Prakash, O.; Kumar, A.; Sadana, A.; Prakash, R.; Singh, S. P.; Claramunt, R. M.; Sanz,
D.; Alkorta, I.; Elguero, J. Study of the synthesis of chalcone analogs of dehydroacetic
acid and o-aminothiophenol: Synthesis and structure of 1,5-benzothiazepines and 1,4-
benzothiazines. Tetrahedron 2005, 61, 6642–4451.
12. Braun, R. U.; Muller, T. J. One-pot synthesis of dihydrobenzo[b][1,4]thiazepines and dia-
zepines via coupling isomerisation-cyclocondensation sequences. Tetrahedron 2004,
60(42), 9463–9469.
13. Levai, A. Oxazepines and thiazepines, 41: Synthesis of 4-aryl-2,3-dihydro-2-styryl-
1,5-benzothiazepines by the reaction of (E,E)-cinnamylidene-acetophenones with
2-aminothiophenol and their conversion into 2,2-disubstituted 3-acetyl-2,3-dihydrobe-
zothiazoles. J. Heterocycl. Chem. 2004, 41, 399403.
14. Karthikeyan, S. V.; Peruma, S. A facile tandem protocol for the synthesis of the
regioselective synthesis of novel thienobenzothiazepines. Tetrahedron Lett. 2007, 48(13),
2261–2265.
15. El-Shafei, A. K.; El-Saghier, A. M. M.; Ahmed, E. A. Synthesis of some new
spiro(pyrano-4,20-benzoxazole) derivatives. Synthesis 1994, 152.
16. Farhat, M. F.; El-Saghier, A. M. M.; Makhlouf, M. A.; Kreddan, K. M.; Elmezoughi,
A. B. Ketene-N,S-acetals in heterocyclic synthesis, part 1: Synthesis of N-phenyl-2-
ylidene and 2,5-diylidene thiazolidinone derivatives. J. Sulfur Chem. 2007, 28(6),
563–572.
17. El-Saraf, G. A.; El-Sayed, A. M.; El-Saghier, A. M. M. One-pot PTC synthesis of poly-
fused pyrazoles. Heteroatom 2003, 14(3), 211–217.

340
M. A. A. MOHAMED
18. Abdel-Ghany, H. A.; El-Saghier, A. M. M.; El-Sayed, A. M. A novel synthesis of hetero-
cyclic compounds from a-oxoketene-S,S-acetal. Synth. Commun. 1996, 26(22), 4289–4297.
19. El-Saghier, A. M. M.; Maihub, A. A.; Al-Shirayda, H. A. A novel synthesis of imida-
zo[2,1-d][1,2,4]triazine and imidazo[2,1-d][1,2,5]triazepine derivatives via ketene-N,S-
acetal. Synth. Commun. 1996, 27(14), 2433–2444.
20. El-Sayed, A. M.; Abdel-Ghany, H. A.; El-Saghier, A. M. M. A novel synthesis of pyra-
no(2,3-c)-, 1,3-oxazino(2,3-b)-, 1,2,4-triazolo(3,4-b)-, oxazolo(2,3-b)-, furano(2,3-c), and
3-substituted-(1,5)-benzodiazepin-2-ones. Synth. Commun. 1999, 29(20), 3561–3572.
21. El-Saghier, A. M. M.; Farhat, M. F.; Farhat, M. F. 1,4-Diazepines bearing thieno(2,3-
b)thiophene and cyclohexene carboxylate moieties. Phosphorus, Sulfur Silicon Relat. Elem.
2006, 181(7), 1569–1582.