Selective Transannular Ring Transformations in Azirino‐Fused Eight‐Membered O,N‐ or S,N‐Heterocycles.

Abstract

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Fe(II)/Au(I) Relay Catalyzed Propargylisoxazole to Pyridine Isomerization: Access to 6-Halonicotinates

“…Recently, Gagosz et al discovered the effective gold-catalyzed transformation of alkyl 2-propargyl-2 H -azirine-2-carboxylates to functionalized pyridines . Isoxazoles under certain conditions can be transformed into 2-carbonyl-substituted 2 H -azirines, and this isomerization can serve as a reactivity switch that enables easier manipulation with substituents in an isoxazole, which is usually much less reactive than an azirine counterpart . Taking all this into account and based on our experience in the use of isoxazoles as synthetic equivalent of 2 H -azirines, we postulated that the use of propargyl-substituted isoxazoles in combination with an appropriate catalytic system could allow easy direct access to pyridine derivatives, and in particular, highly synthetically useful 2-halopyridines.…”

“…At first, we examined whether isoxazole 1a can undergo thermal conversion into pyridine 3a , but only the starting material was found in the reaction mixture even after heating at high temperature (Table , entry 1). We decided, therefore, to check the ability of some metal salts and complexes, which catalyze the isomerization of 5-alkoxy­isoxazole to 2 H -azirine-2-carbox­ylate, to induce the subsequent conversion of azirine 2a to nicotinate 3a . Iron­(II) chloride is well-known to promote the isoxazole-azirine transformation, − and it was, therefore, not unexpected to obtain azirine 2a in a nearly quantitative yield under reaction of isoxazole 1a at ambient temperature for 2 h (Table , entry 2).…”

“…We decided, therefore, to check the ability of some metal salts and complexes, which catalyze the isomerization of 5-alkoxy­isoxazole to 2 H -azirine-2-carbox­ylate, to induce the subsequent conversion of azirine 2a to nicotinate 3a . Iron­(II) chloride is well-known to promote the isoxazole-azirine transformation, − and it was, therefore, not unexpected to obtain azirine 2a in a nearly quantitative yield under reaction of isoxazole 1a at ambient temperature for 2 h (Table , entry 2). No other products were, however, detected in the reaction mixture even upon longer heating at elevated temperature (Table , entry 3).…”

“…No other products were, however, detected in the reaction mixture even upon longer heating at elevated temperature (Table , entry 3). The similar result was obtained with molybdenum hexacarbonyl, which was used as promoter of the 2 H -azirine–isoxazole interconversion (Table , entry 4). , Copper­(I) NHC complex (IPrCuCl), which was reported as catalyst for N–C (2) azirine bond cleavage, showed the ability to catalyze both the isomerization of isoxazole 1a to azirine 2a and the formation of nicotinate 3a , although to a lesser extent (Table , entry 5). We observed only a resignification of isoxazole 1a under the reaction conditions, which were used for transformation of 2-allyl-2 H -azirines to pyridines promoted by 1,8-diaza­bicyclo­[5.4.0]­undec-7-ene (DBU) (Table , entry 6).…”

“…A proposed mechanism for the formation of pyridines J , based on literature analysis of the transformations of 5-alkoxy­isoxa­zoles A under Fe­(II) catalysis − , and the transformations of 2-propargyl-2 H -azirines E under Au­(I) catalysis, , is presented in Scheme . It involves the isoxazole ring-opening in isoxazole complex B with the formation of Fe-nitrene complex C , the cyclization of C into Fe-azirine complex D , formation of Au-acetylene complex F , 5- endo -dig cyclization by nucleophilic attack into complex G , followed by the azirine ring expansion in G and proton transfer in H .…”