Acid catalyzed intramolecular attack of β-phenylthioureido group on amide function. Parallel formation of thiodihydrouracil and 4-iminothiodihydrouracil. Different pathways in the Edman degradation reaction in the formation of six- versus five-membered cy

Autor: Ivan G. Pojarlieff, Violina T. Angelova, Nikolay G. Vassilev, Ergun Atay, Maria M. Toteva, Iva B. Blagoeva, Asen H. Koedjikov
Rok vydání: 2007
Předmět:
Zdroj: Journal of Physical Organic Chemistry. 21:14-22
ISSN: 0894-3230
DOI: 10.1002/poc.1269
Popis: Contrary to the cleavage of a-phenylthioureido peptides 1 proceeding through intermediate 2-anilinothiazolinone 2, the b-analog cis-2-(3-phenylthioureido)cyclopentane-carboxamide 5 forms transiently 4-imino-2-thioxopyrimidine 6. Monitoring amide cyclization and hydrolysis of iminopyrimidine 6 in acid by UV showed that an equilibrium between 5 and 6 was reached followed by slower conversion of both compounds into 2-oxo-4-thioxopyrimidine 7. Both processes were characterized by isosbestic points, the first due to parallel conversion of 5 into 6 and 7 (or 6 into 5 and 7) at a constant ratio while the second identical for both reactants ‐ to conversion of equilibrated 5 and 6 into 7. The special isosbestic points allowed the determination of the individual constants of Scheme 2. Further confirmation was obtained from NMR product analysis and following the cyclization of amide 5 in DMSO:DCl. Product 2-oxo-4thioxopyrimidine 7 hydrolyzed reversibly to thioureido acid 8. The cyclization rate of 8 allowed the participation of 6-oxothiazine 10 formed by sulfur attack to be excluded. The absence of sulfur attack in the six-membered case is explained by the longer C—S bond bringing about greater bond angle strain at the tetrahedral ring atoms due to the geometrical characteristics of five- and six-membered rings with planar segments. The cyclizations of amide 5 to iminopyrimidine 6 and to thiodihydrouracil 7 are first order in [H þ ], while the reactions of protonated imine 6H þ are zero order to amide and � 1 to thiodihydrouracil. The reaction orders can be reconciled by assuming a rate determining proton transfer from the tetrahedral intermediate in amide cyclization. Copyright 2007 John Wiley & Sons, Ltd.
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