Pyridine 1-oxide ring expansion

The JV-amino derivatives 269 underwent oxidative ring expansion to tri-azine 270. Analogous pyrazolo[3,4-c]pyridines, however, gave only intractable products. The latter system lacked the peri interaction necessary for repulsion of nucleophilic attack at the 4-position of the triazine ring.157... 

Synthesis From Other Ring Systems. These syntheses are further classified based on the number of atoms in the starting ring. Ring expansion of dichlorocyclopropane carbaldimine (53), where R = H and R = ryl, on pyrolysis gives 2-arylpyridines. Thermal rearrangement to substituted pyridines occurs in the presence of tungsten(VI) oxide. In most instances the nonchlorinated product is the primary product obtained (63). 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

Examples treated in this book are summarized in Table 9. One frequently found type consists of ring expansions of cyclic conjugated systems with an exocyclic ylide function, such as pyridine /V-oxides or /V-imides incorporation of the exocyclic half of the ylide function expands the ring by one member. 

Buchardt, O., Pedersen, C.L. and Harrit, N. (1972) Photochemical studies. XVIII. Light-induced ring expansion of pyridine N-oxides. Journal of Organic Chemistry, 37 (23), 3592-3595. 

About a decade ago 6-APA and 7-ADCA were mainly produced by chemical deacylation of penicillin G, penicillin V or phenylacetyl 7-ADCA, the last of which was derived from chemical ring expansion of oxidized penicillin G. As a result of the fact that these processes were rather complex and employed hazardous reagents, for example pyridine, phosphorus pentachloride, nitrosyl chloride and dichlorome-thane, alternative processes have been developed. Penicillin amidases (E. C. 3.5.1.11) catalyze the hydrolysis of the linear amide bond in penicillin molecules producing both the P-lactam nucleus, 6-APA and the corresponding side chain without affecting the P-lactam amide bond in the four-membered ring. Based on their substrate specificity the penicillin amidases are grouped into three classes[591 ... 

Alkoxy radicals for ring expansion can be generated from alcohols by oxidative methods such as hypohalite thermolysis/photolysis [19a] and lead tetraacetate oxidation [19b], or peroxide reduction [19c]. The recent development of the hyper-valent organoiodine reagent (diacetoxyiodo)benzene (DIB) provides another way for efficient generation of alkoxy radicals (Scheme 11) [19d]. Additional oxidative methods to prepare cyclopropyloxy radicals include reaction of tertiary cyclopropanols or their silyl ether derivatives with various reagents such as manganese(III) tris(pyridine-2-carboxylate) [Mn(pic)3] [20a], Fe(III) salts [20b], and vanadyl ace-tylacetate [20c] (Scheme 12). 

Recently, two methodologies have been published that use very unique approaches to synthesize 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, a key thiophene-containing intermediate en route to clopidogrel. One such approach is the copper-catalyzed ring expansion of vinyl thiiranes followed by oxidation and subsequent removal of the amine protecting group. ... 

Davies and coworkers discovered that pyridines can be produced by rhodium-catalyzed cyclization of carbenoids and isoxazoles as well [74], Highly functionalized pyridines and 1,4-dihydropyridines could be produced by this procedure in good yields (Scheme 3.35). For the reaction mechanism, the reaction proceeds through an initial carbenoid induced ring expansion of isoxazoles and then followed by a rearrange-ment/tautomerization/oxidation sequence. 

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