ChemInform Abstract: (PhIO)n Mediated Annulations of Aromatic Aldehyde N‐Acylhydrazones for the Synthesis of 1,3,4‐Oxadiazoles.

Abstract

Oxadiazole as a class of five-membered heterocycles has been reported to be biologically versatile compounds due to their metabolic profile. Amongst these heterocycles, 1,3,4oxadiazole has become an important construction motif for the development of new drugs, furamizole as antibiotics, tiodazosin as antihypertensive agent and raltegravir as antiretroviral agent have been on market. In addition, 2,5-disubstituted-1,3,4-oxadiazole derivatives have also been used as electron conducting and hole blocking (ECHB) materials for electron deficient and good electron transport properties of oxadiazole rings. The most common synthetic approach to 1,3,4-oxadiazoles involves cyclodehydration of 1,2-diacylhydrazines 3 (Scheme 1). Typically, this reaction is carried out by using SOCl2, 5 POCl3, 6 as well as others. Although these methods are very useful for the preparation of large quantities of materials due to the ready availability of diacylhydrazines, hydrazides, and hydrazones as starting materials, the reaction conditions tend to be harsh and long reaction times are generally needed. An alternative route to 1,3,4-oxadiazoles 2 by oxidative cyclization from the corresponding aldehyde N-acylhydrazones 1 proceeds (a) with transition metal oxidants such as Pb, Mn, Fe, Ce or Cu et al.; (b) with chloramine T, Trichloroisocyanuric Acid, iodobenzene diacetate (IBD), Dess–Martin reagent (DMP) or other oxidants; (c) electrochemical methods (Scheme 1). To the best of our knowledge, preparation of 1,3,4-oxadiazoles utilizing iodosobenzene as the oxidizing agent has not been reported yet. In our continuous research program of the oxidation of hypervalent iodine, we were interested in the development of robust and general method to access functionalized 2,5-disubstituted-1,3,4-oxadiazoles. It was found that aromatic aldehyde N-acylhydrazones 1 reacted with (PhIO)n/BF3·Et2O at room temperature to efficiently afford 2,5-disubstituted-1,3,4-oxadiazoles 2 in mild to good yields (Scheme 2). The polymeric character of iodosobenzene makes it less suitable as oxidant than other hypervalent reagents, mainly because of its insolubility in ordinary solvents. Its utility is, however, greatly enhanced when it is used with catalysts, notably boron trifluoride. The electrophilic character of iodine in iodosobenzene is greatly increased by the addition of boron trifluoride, probably because of the in-situ formation of the monomeric dipole PhI+-OBF3 −. N'-Benzylidenefuran-2-carbohydrazide (1a) was chosen as the substrate in initial studies (Table 1). When the substrate