NHC-Catalyzed Dual Stetter Reaction: A Mild Cascade Annulation for the Syntheses of Naphthoquinones, Isoflavanones, and Sugar-Based Chiral Analogues

Abstract

The N-heterocycle carbene (NHC)-catalyzed dual Stetter cascade reaction is discovered through coupling of β-nitrostyrene with phthalaldehyde under mild conditions to furnish valuable aryl-naphthoquinones. The generality of the new reaction is validated through the development of a C–C and O–C bond forming Stetter cascade reaction using salicylaldehydes to obtain functionalized dihydroisoflavanones. The mild NHC organocatalysis is successfully employed for the construction of optically pure sugar-based naphthoquinones and dihydroisoflavanones. Herein, NHC is found as a unique and powerful organocatalyst to construct homoatomic C–C cross-coupling, heteroatomic O–C bond formation, and cascade cyclization utilizing NO2 as a leaving group at ambient temperature. A mechanistic pathway of the new metal-free catalysis is predicted on the basis of our ESI-MS study of the ongoing reaction and literature.

Recent Advances in Stetter Reaction and Related Chemistry: An update

“…Noticeably, NHC is known as a remarkable organocatalyst to generate homoatomic carbon-carbon cross-coupling, heteroatomic oxygen-carbon bond construction, and also cascade cyclization using nitro group (NO 2 ) as a leaving group at room temperature. [39] Worthy to mention that the construction of arylnaphthoquinones 90 was performed through dual Stetter reaction of various phthalaldehydes 87 and olefins 88 using NHC 89 (as catalyst) and cesium carbonate (as base) in CH 2 Cl 2 as solvent under a N 2 atmosphere at room temperature (Scheme 18). The generality of this reaction was examined with a series of nitroalkenes having electron-withdrawing groups at phenyl scaffolds for example 2-chloro, 4-fluoro, 3,5-difluoro, 4-trifluoromethyl, 3nitro and 3,5-dichloronitro to provide various substituted naphthoquinone derivatives 90 b, 90 c, 90 f-i.…”

“…Various electronrich aromatics such as naphthyl and biphenyl nitrostyrene were investigated, providing the relevant naphthoquinones in satisfactory yields (Scheme 18). [39] Asymmetric synthesis of a wide range of sugar-based naphthoquinones 92 was accomplished through dual Stetter reaction using phthalaldehyde 87 and pentose-based nitroalkenes or chiral olefins 91 at the presence of NHC-organocatalyst 89 and cesium carbonate in CH 2 Cl 2 under N 2 atmosphere at room temperature (Scheme 19). A collection of nitroalkenes were synthesized via nitro-aldol and dehydration reaction using sodium hydroxide.…”

“…Moreover, other two pentose-based nitroalkenes such as 91 b and 91 c yielded the relevant chiral centers-decorated naphthoquinones 92 b and 92 c, respectively with good yield, respectively (Scheme 19). [39] Different dihydroisoflavanones 94 were provided through Stetter cascade reaction of salicaldehyde 93 and nitrostyrenes 88 in the presence of NHC-organocatalyst 89 and (1 [39] Products 94 b-k were produced in satisfactory to very good yields at room temperature. Based on this method, electrondonating groups and electron-withdrawing groups were exam-ined.…”

“…dioxole 91 a and its methyl derivative 91 b were converted into the corresponding chirally modified dihydroisoflavanones 95 a and 95 b via NHC-catalyzed carboncarbon/oxygen-carbon coupled annulation reaction of salicylaldehydes 93 a and 93 b. [39] A possible mechanism was suggested for this dual Stetter and Stetter cascade reactions as shown in Scheme 22. "Breslow intermediate" 97 may be generated via coupling reaction of 87 a and NHC 89, that is treated with 88 a, providing [1,3m,6c,40] Eventually, intramolecular oxa-Michael addition produced the desired product 103 b.…”

“…Various electron‐rich aromatics such as naphthyl and biphenyl nitrostyrene were investigated, providing the relevant naphthoquinones in satisfactory yields (Scheme 18). [39] …”