title: Thermal Ring Contraction Reactions of 9-Aryl-5H,7H-[1,2,5]thiadiazolo[3,4-h][2,3,4]benzothiadiazepine 6,6-Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations.
abstract: When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e. 9-aryl-5H,7H-[1,2,5]thiadiazolo[3,4-h][2,3,4]benzothiadiazepine 6,6-dioxides, resulted in a substantially different product mixture: formation of sultines and benzocyclobutenes was observed, while only small amounts of the sulfones were formed, if any. Density functional theory calculations support the mechanism proposed for the transformations involving a zwitterionic intermediate formed by the tautomerization of the thiadiazepine ring followed by dinitrogen extrusion. When starting from 7-chloro-substituted 2,3,4-benzothiadiazepine 2,2-dioxide, the formation of sulfone via o-quinodimethane is the preferred pathway from the zwitterion. However, in the case of thiadiazolobenzothiadiazepine 6,6-dioxides it has been found that the ring closure of the zwitterion leading to the formation of sultines was kinetically preferred over the loss of sulfur dioxide leading to o-quinodimethane, which is the key intermediate to benzocyclobutene-type products. The calculations explain the differences observed between the product distributions of the chloro-substituted and the thiadiazolo-fused derivatives.
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Bertha
authors.affiliation: Department of Inorganic Chemistry, University of Pécs and MTA-PTE Research Group for Selective Chemical Syntheses , 6 Ifjúság útja, H-7624 Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kégl
authors.affiliation: Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , P.O. Box 91, H-1521 Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Fetter
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Molnár
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Dancsó
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Németh
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Gyula
authors.initials: G
authors.lastname: Simig
authors.affiliation: Directorate of Drug Substance Development, Egis Pharmaceuticals Plc. , P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Balázs
authors.identifier: 0000-0002-2019-1874
authors.initials: B
authors.lastname: Volk