Synthesis of 2-substituted-4-methyl-5,13-dihydropyrimido[4′,5′:5,6][1,4]thiazepino[2,3-b]quinoxaline as a new heterocyclic system

Article abstract of DOI:10.1080/10426507.2018.1455199

2-Substituted-4-methyl-5,13-dihydropyrimido[4′,5′:5,6][1,4]thiazepino[2,3-b]quinoxalines (7a-g), derivatives of a new heterocyclic system were synthesized through cyclocondensation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine (3) with 3-aminoquinoxaline-2-thiol (4) and subsequent substitution by various secondary amines. Regioselective heterocyclization was confirmed by X-ray crystallographic analysis for 4-methyl-2-(pyrrolidin-1-yl)-5,13-dihydropyrimido[4′,5′:5,6] [1,4]thiazepino[2,3-b]quinoxaline (7a).

Full text of DOI:10.1080/10426507.2018.1455199

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Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis of 2-substituted-4-methyl-5,13-
dihydropyrimido[4',5':5,6][1,4]thiazepino[2,3-
b]quinoxaline as a new heterocyclic system
Marzieh Akbarzadeh, Mehdi Bakavoli, Hossein Eshghi, Ali Shiri, Hamid
Azizollahi & Joel T. Mague
To cite this article: Marzieh Akbarzadeh, Mehdi Bakavoli, Hossein Eshghi, Ali Shiri,
Hamid Azizollahi & Joel T. Mague (2018): Synthesis of 2-substituted-4-methyl-5,13-
dihydropyrimido[4',5':5,6][1,4]thiazepino[2,3-b]quinoxaline as a new heterocyclic system,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1455199
To link to this article: https://doi.org/10.1080/10426507.2018.1455199
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Publisher: Taylor & Francis
Journal: Phosphorus, Sulfur, and Silicon and the Related Elements
DOI: https://doi.org/10.1080/10426507.2018.1455199
Synthesis of 2-substituted-4-methyl-5,13-dihydropyrimido[4',5':5,6][1,4]thiazepino[2,3-
b]quinoxaline as a new heterocyclic system
Marzieh Akbarzadeha, Mehdi Bakavoli a*, Hossein Eshghia, Ali Shiria,
Hamid Azizollahia, Joel T. Magueb
a Department of Chemistry, Faculty of Science, Ferdowsi University of
Mashhad, 91775-1436 Mashhad, Iran.
b Department of Chemistry, Tulane University, New Orleans, LA 70118, USA.
*E-mail: mbakavoli@um.ac.ir, mbakavoli@yahoo.com
Abstract
2-Substituted-4-methyl-5,13-dihydropyrimido[4',5':5,6][1,4]thiazepino[2,3-b]quinoxalines
(7a-g), derivatives of a new heterocyclic system were synthesized through
cyclocondensation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine (3) with 3-
aminoquinoxaline-2-thiol (4) and subsequent substitution by various secondary amines.
Regioselective heterocyclization was confirmed by X-ray crystallographic analysis for 4-

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methyl-2-(pyrrolidin-1-yl)-5,13-dihydropyrimido[4',5':5,6] [1,4]thiazepino[2,3-b]quinoxaline
(7a).
Keywords 1,4-thiazepine, pyrimidothiazepine, quinoxaline-2,3-dithiol, intramolecular SNAr
reaction.
Introduction
2

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The 1,4-thiazepine-containing aryl- and heteroaryl-fused structures play a vital role in
natural and synthetic biologically active compounds 1-2. They are recognized as antiviral 3,
antitumor 4, and antiulcer agents 5 as well as inhibitors of HIV-1 integrase and reverse
transcriptase 6. Some of these compounds also show interesting pharmacological properties
such as angiogenic 7 antispasmodic 8 and antiarrhythmic 9 activities.
Examples of synthetic methods to prepare 1,4-thiazepine-containing compounds include the
condensation of dichloropyrimidine with 3,4-dimethoxythiophenol under basic conditions
followed by cyclization in the presence of paraformaldehyde 10, cyclization of N-acyl
derivatives of 2-arylthioethylbenzamide under Bischler-Napieralski conditions 11, reductive
cyclization of 2-((3-nitropyrid in-4-yl)thio)benzaldehyde under catalytic hydrogen conditions
12 and Sonogashira coupling of electron poor (hetero)aryl halides and 1-phenyl propynol in
the presence of 2-amino thiophenols 13.
A literature survey revealed that various methods are reported for the synthesis of fused
thiazepines including cyclocondensation of 5-amino-6-methylpyrimidine-4-thiols and 2-
chloroquinoline-3-carbaldehydes in the presence of K2CO3 in DMF 14, reaction of 6-methyl-
4-phenyl-N-(pyridin-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide with 2-
(benzo[d]thiazol-2-yl)-4-chloro-3-oxobutannitrile 15, treatment of 6-chloro-1-methyluracil
with 2-aminothiophenol followed by heating with appropriate aromatic aldehydes 16 and
treatment of 4-methoxy-5-amino-6-mercaptopyrimidine with 4,6-dichloro-5-
formylpyrimidine in methanolic KOH medium 17.
Prompted by these findings and as part of our ongoing studies towards the synthesis of
various fused pyrimidines 18-24, herein, we wish to report the synthesis of 2-substituted-4-
methyl-5,13-dihydropyrimido[4',5':5,6][1,4]thiazepino[2,3-b]quinoxalines (7a-g) as a new
3