Synthesis of Spiro- and Fused Heterocycles via (4+4) Annulation of Sulfonylphthalide with o-Hydroxystyrenyl Derivatives

Abstract

An expedient one-pot protocol for the synthesis of functionalized benzofuran containing fused and spiro-heterocycles has been accomplished by the modified Hauser–Kraus (HK) annulation of sulfonylphthalide with o-hydroxychalcones and o-hydroxynitrostyrylisoxazoles. The multicascade process involves Michael addition, Dieckmann cyclization, and a series of cyclizations, eliminations, and rearrangements to deliver the fused and spiro-heterocyclic products. An unusual transformation of fused indenofuran to naphthoquinone, the classical HK adduct, unraveled a novel pathway for the synthesis unsymmetrical naphthoquinones.

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2

“…Compounds containing sulfur, as sulfoxides and sulfones [98,99], selenium [100], iodine [47], amines, bromine, hydroxyls, alkenes, among other substituent groups [46,[101][102][103][104][105][106][107] were studied and evaluated according to their potential to act as anti-SARS-CoV-2. Imine derivatives were also targeted in our studies and were placed in group 6 [67].…”

Michael Addition‐Elimination and [4+1] Annulation of Sulfonylphthalide with Hydroxychalcones for the Synthesis of Alkylidenephthalides and Indanediones

“…Our recent efforts to treat 3‐sulfonylphthalide with various acceptors such as o ‐hydroxynitrostyrenes, [22] enones, nitrostyrylisoxazoles [23] and quinone methides [24] led to spiro‐ and fused heterocycles through an unusual [4+4] annulation followed by a cascade of rearrangements. We also demonstrated the reactivity of 3‐sulfonylphthalide with Rauhut‐Currier adducts of nitroalkenes, [25] 3‐olefinic oxindoles [26] and nitrobenzofurans [27] which resulted in the formation of [4+2] H−K annulation products.…”

“…Treatment of sulfonylphthalide with chalcones devoid of any ortho ‐hydroxy group delivers the expected naphthoquinones (Scheme 1a) or their precursor Michael adducts [17] . However, similar reaction with chalcones bearing a key hydroxy group on the styrenyl side leads to indenofurans and spirolactones (Scheme 1b) [22–24] . In this scenario, we intended to investigate the role, if any, of the ortho ‐hydroxyl group on the benzoyl side on the outcome of the reaction (Scheme 1c) and the results obtained are described herein.…”

“…[17][18][19][20] Hauser-Kraus (HÀ K) annulation is a widely employed synthetic method for the construction of naphthoquinones via [4 + 2] annulation of stabilized phthalides with Michael acceptors and thereby synthesis of a variety of bioactive molecules, including natural products (Scheme 1a). [21] Our recent efforts to treat 3-sulfonylphthalide with various acceptors such as o-hydroxynitrostyrenes, [22] enones, nitrostyrylisoxazoles [23] and quinone methides [24] led to spiroand fused heterocycles through an unusual [4 + 4] annulation followed by a cascade of rearrangements. We also demonstrated the reactivity of 3-sulfonylphthalide with Rauhut-Currier adducts of nitroalkenes, [25] 3-olefinic oxindoles [26] and nitrobenzofurans [27] which resulted in the formation of [4 + 2] HÀ K annulation products.…”

“…[17] However, similar reaction with chalcones bearing a key hydroxy group on the styrenyl side leads to indenofurans and spirolactones (Scheme 1b). [22][23][24] In this scenario, we intended to investigate the role, if any, of the ortho-hydroxyl group on the benzoyl side on the outcome of the reaction (Scheme 1c) and the results obtained are described herein.…”