Potassium Trinitromethanide as a 1,1-Ambiphilic Synthon Equivalent: Access to 2‑Nitroarenofurans Vitaly A. Osyanin,* Dmitry V. Osipov, Maxim R. Demidov, and Yuri N. Klimochkin Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya St., 443100 Samara, Russian Federation * S Supporting Information ABSTRACT: The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process. ■ INTRODUCTION Ambiphilic synthons, which contain both electrophilic and nucleophilic centers in the same molecule, are widely used in organic synthesis as useful building blocks. 1 The development of new synthetic methods using ambiphiles has great potential in the elaboration of new high-step-economy reactions. 2 Moreover, 1,1-ambiphiles with reaction centers on the same carbon atom are promising for the construction of cyclic molecules. 3 However, this reaction type remains undeveloped. The use of polynitromethane derivatives in the synthesis of heterocycles has generally been limited to isoxazole and isoxazolidine units. 4 In these transformations, polynitro- methanes react as 1,3-dipoles, and C, N, and O atoms are incorporated into the structures of the heterocycles. Potassium trinitromethanide (potassium nitroformate) is often used to introduce a trinitromethyl group in organic molecules. The reaction of potassium trinitromethanide as a 1,1-ambiphilic reagent, wherein only the carbon atom is included in the formed heterocyclic structure, is unprecedented. o-Quinone methides (o-QMs) are highly reactive and useful species that have been implicated as intermediates in the synthesis of natural products, usually as heterodynes, to form chromane systems. 5 They also react with nucleophiles as 1,4- Michael acceptors. 6 Reactions of o-QM precursors are excep- tionally facile compared with traditional Michael acceptors because aromatization energy provides additional product and transition-state stabilization in the case of the o-QM fragment. In addition, the initial products of Michael-type reactions with o-QM may undergo further intramolecular cyclization with phenolic hydroxyl groups to provide a pathway to oxygen- containing heterocycles. 7 However, such cascade protocols are rare and require further study. In the process of an overall synthetic program aimed at the development of new cascade transformations utilizing o-QMs, 7b we put our efforts on the study of the reaction of potassium trinitromethanide with o-QM precursors. We have found that this reaction affords 2-nitroarenofurans, which have drawn extensive attention because of their varied biological activities. For example, many of these compounds exhibit antibacterial, 8 antiparasitic, 9 radiosensitizing, 10 mutagenic properties 11 and can be used as regulators of the nuclear receptor HNF4α. 12 Besides, 2-nitrobenzofurans are useful intermediates for the preparation of 2-halogenobenzofurans, 13 dibenzofurans, 14 and benzofuro[2,3-c]pyrroles. 15 A number of methods for the synthesis of 2-nitrobenzofurans have been reported. These compounds are generally prepared by the condensation between o-hydroxybenzaldehydes and bromonitromethane. 12,16 Although this reaction has already been performed under miscellaneous conditions with a large variety of aldehydes, its applicability is not completely versatile and leads to rather unsatisfactory yields in certain cases. The direct nitration of benzofurans at the 2-position usually leads to low yields and unwanted nitration products. 17 3-Alkyl-2-nitrobenzofurans are also obtained by replacement of the acyl group in 2-acyl-3-alkylbenzofurans 18 and by treating 3-alkylbenzofurans successively with t-BuLi, trimethyltin chloride, and finally tetranitromethane in DMSO. 19 2-Nitro- benzofuran has been prepared by ipso-nitration of 2- benzofuranboronic acid using bismuth(III) nitrate 20 and by nitration of benzofuran using sodium nitrite in the presence of cerium(IV) ammonium nitrate. 21 Recently, 3-alkyl-2-nitro- benzofurans were synthesized from 2-(2-nitroethyl)phenols via a hypervalent-iodine-induced oxidative cyclization. 22 ■ RESULTS AND DISCUSSION Potassium trinitromethanide reacts with o-QMs through the carbon as a soft nucleophilic center and acts as a synthetic equivalent of a 1,1-dipole one-carbon synthon (A) or a dinitrocarbene (B) (Scheme 1). Received: November 26, 2013 Published: January 13, 2014 Article pubs.acs.org/joc © 2014 American Chemical Society 1192 dx.doi.org/10.1021/jo402543s | J. Org. Chem. 2014, 79, 1192-1198