Cascade Synthesis of 3-Functionalized Indoles from Nitrones and Their Conversion to Cycloheptanone-Fused Indoles

Abstract

A cascade reaction of N-aryl-α,β-unsaturated nitrones and electron-deficient allenes has been discovered that allows single-step access to 3-functionalized indoles that usually require preformation and alkylation of an indole precursor. The heterocycles prepared through the hydrogen bond donor catalyzed cascade reaction are poised to undergo a McMurry coupling to form previously synthetically elusive cycloheptanone-fused indoles. The scope of these transformations is discussed as well as mechanistic experiments describing proposed intermediates of the cascade reaction and an initial catalytic asymmetric example that generates a carbon stereocenter during the cascade process.

Synthesis and Transformations of Nitrones for Organic Synthesis

“…The heterocycles prepared from the cascade synthesis undergo a McMurry coupling to form cycloheptanone-fused indoles (Scheme 24). 241 The reaction of fluorenylnitrones with electron-deficient allenes gives the corresponding 1,4-enamino ketones (eq 102). 242 The reaction proceeds through the [3.3]-rearrange- ment of dialkenylhydroxylamines generated from the addition of N-alkenylnitrones to electron-deficient allenes.…”

Highly Diastereo‐ and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral‐Phosphoric‐Acid‐Catalyzed (4+3) Cycloaddition

“…Other drying agents were evaluated, but 4 MS provided the best results in terms of both yield and enantioselectivity (entry 2v s. [5][6][7][8]. Lowering of the reaction temperature markedly decreased the yield of 3a and did not have as ignificant effect on the enantioselectivity (entry 3).…”

“…The reaction proceeded in lower yield in the absence of 4 MS, thus indicating the deleterious effect of water on the overall process (entry 4). Other drying agents were evaluated, but 4 MS provided the best results in terms of both yield and enantioselectivity (entry 2v s. [5][6][7][8]. Diversely substituted carbamates reacted with 1a,b ut the best results were obtained with Cbz-protected dienamines (entry 2v s. [10][11][12].…”

“…[4c] Even though the enantioselectivity was excellent (up to 99 % ee), this elegant approach is mainly limited to the formation of monosubstituted benzocyclohepta [b]indoles.T wo years later,H ong and co-workers described an enantioselective organocatalytic one-pot, two-step sequential process to synthesize trisubstituted cyclohepta [b]indoles with excellent enantioselectivity, albeit with moderate diastereoselectivity. [4d] In this context, the development of as traightforward procedure for the synthesis of enantiomerically pure cyclohepta [b]indoles is highly desirable.A mong the practicable strategies, [1,[3][4][5][6][7] (4+ +3) cycloaddition [8] appears the most efficient, direct, and economical approach. Surprisingly,o nly one asymmetric version has been disclosed, by Sun and coworkers,i nw hich the rhodium-catalyzed dearomative (4+ +3) cycloaddition of vinylindoles led to cyclohepta[b]indolines with high ee values.…”

Rhodium-Catalyzed Asymmetric Dearomative [4 + 3]-Cycloaddition of Vinylindoles with Vinyldiazoacetates: Access to Cyclohepta[b]indoles

“…Given their great importance, methods for the direct preparation of cyclohepta­[ b ]­indoles have attracted much attention, and a variety of protocols have been established . However, enantioselective syntheses of such tricyclic scaffolds are rare .…”