Synthesis of Spirolactones and Functionalized Benzofurans via Addition of 3-Sulfonylphthalides to 2-Formylaryl Triflates and Conversion to Benzofuroisocoumarins

Abstract

A convenient protocol for the synthesis of spirobenzofuran-isobenzofurans and substituted benzofurans via a modified Hauser–Kraus reaction of 3-sulfonylphthalide with 2-formylaryl triflates is reported here. The initial reaction involved 1,2-addition of phthalide to the formyl group and intramolecular cyclization via substitution of triflate followed by a cascade of rearrangements leading to spirolactone or benzofuran derivatives. The electronic nature of substituents on aryl triflates affected the course and outcome of the reaction. The mechanism was supported by successful characterization of one of the intermediates by mass spectrometry. A medicinally relevant influenza virus type B inhibitor, benzofuroisocoumarin, was synthesized in a single step from the spiro compound, thus demonstrating the synthetic utility of our methodology.

Synthesis of Natural Products, Carbocycles, and Heterocycles by Hauser–Kraus Annulation

“…Very recently, we have introduced a modified Hauser-Kraus reaction of sulfonylphthalide 9 with 2-formylaryl triflates 121 (Scheme 21). 38 This approach provides access to spirobenzofuran-isobenzofurans 123 and substituted benzofurans 122. The initial step involved 1,2-addition of phthalide 9 to the formyl group and intramolecular cyclization via substitution of triflate followed by a cascade of rearrangements leading to spirolactone 123 or benzofuran 122 (Scheme 22).…”

Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step

“…Due to having a wide profile of pharmaceutical activities, spirolactones attract considerable attention from scientists and advance both the development of simple and effective synthetic routes to such structures and the further study of their properties. Recently, numerous methods for the synthesis of spirolactones have been described in the literature [13][14][15][16]. Among a variety of known approaches, those that are based on mild, free-metal and stepeconomic reactions start from readily available materials and meet the requirements of modern and "advantageous" synthetic chemistry, and so deserve special attention.…”

Iodine-Catalyzed Cascade Annulation of 4-Hydroxycoumarins with Aurones: Access to Spirocyclic Benzofuran–Furocoumarins

“…The design and synthesis of biologically active spiro-heterocycles have attracted the attention of many pharmacologists and chemists [14,15]. In particular, the spiro-heterocycles that contain benzofuran have become one of the most interesting classes of molecules due to their notable biological activities [ [16][17][18]. For example, griseofulvin A is one of the earliest spirocyclic drugs to exhibit antifungal activity [19], while spiro-benzofuran B, with isobenzofuranone and benzofuranone motifs, has been found to be a core chemical skeleton for antivirals against influenza viruses [20].…”