N‐Heterocyclic‐Carbene‐Catalyzed Reaction of α‐Bromo‐α,β‐Unsaturated Aldehyde or α,β‐Dibromoaldehyde with Isatins: An Efficient Synthesis of Spirocyclic Oxindole–Dihydropyranones

Abstract

Smooth as isatin! A straightforward synthesis of spirocyclic oxindole–dihydropyranones through an N‐heterocyclic‐carbene‐catalyzed [4+2] annulation of α‐bromo‐α,β‐unsaturated aldehydes or α,β‐dibromoaldehyde bearing γ‐H with isatin derivatives under mild reaction conditions is disclosed (see scheme). The concise construction, ready availability of the starting materials, avoidance of external oxidants, and the potential utilization value of final products in molecular biology and pharmacy makes this approach particularly attractive.

Synthesis of α,β‐Unsaturated δ‐Lactones by Vinyl Acetate Mediated Asymmetric Cross‐Aldol Reaction of Acetaldehyde: Mechanistic Insights

“…In addition, α,β‐unsaturated δ‐lactones are a part of a wide variety of natural scaffolds, for example, fostriecin, callystatin, ( R )‐goniothalamin, asperlin, leptomycin B and kazusamycin A,20 or serve as intermediates in the synthesis of bioactive molecules, such as tetrahydrolipstatin21 and clavulactone 22. Owing to their importance, many methods have been developed for their synthesis, such as the hetero‐Diels–Alder (HDA) reactions of the Brassard diene with aldehydes or ketones,23–26 solid‐phase Diels–Alder cycloaddition,27 the annulation of open‐chain precursors,28 N‐heterocyclic‐carbene‐catalysed reactions of α‐bromo α,β‐unsaturated aldehydes,29 reactions of homoallylic alcohols with the lithium enolate of methyl acetate30 and enzymatic cyclisation31 (Figure 1). Intriguingly, most of these methods suffer from poor enantioselectivity and substrate scope, and often employ environmentally hazardous metal catalysts.…”

Enantioselective (4+2) Annulation of Donor–Acceptor Cyclobutanes by N‐Heterocyclic Carbene Catalysis

“…( Table 2, entry 1), while electron rich 2,4-(CH 3 O) 2 C 6 H 3 and 4-(CH 3 ) 2 NC 6 H 4 gave 6e and 6f in 99:1 e.r. [18] Va riation of the ester was examined with methyl, isopropyl, and allyl esters (6i, 6j and 6k)p repared with excellent enantiopurity (98:2, 94:6 and 99:1 e.r.) Ther eaction tolerated N-heterocycles with indole-containing b-lactone 6h prepared in 83 %y ield and 98:2 e.r.…”

“…Unfortunately, b-alkyl acyl fluorides were not compatible with the reaction, potentially due to acyl azolium dienolate formation as developed by Chi and others with related substrates. ( Table 1, entries [16][17][18]. [10][11][12].…”

“…(Table 1, entry 12). Finally a"salt" [17] and HMDS-free version of the reaction increased the yield to 93 %w ithout affecting enantioselectivity ( [18] Va riation of the ester was examined with methyl, isopropyl, and allyl esters (6i, 6j and 6k)p repared with excellent enantiopurity (98:2, 94:6 and 99:1 e.r.) [10][11][12].…”

Highly Enantioselective γ‐Amination by N‐Heterocyclic Carbene Catalyzed [4+2] Annulation of Oxidized Enals and Azodicarboxylates

“…[6] In 2012, Chi et al reported a pioneering oxidative NHCcatalyzed [4+2] annulation of enals with trifluoromethyl ketones by g addition (Scheme 1 a). [8] We envisioned that the addition of an NHC to enals having a g leaving group may generate a dienolate intermediate, which would then react with an azodicarboxylate to give the [4+2] annulation product (Scheme 1 c). [8] We envisioned that the addition of an NHC to enals having a g leaving group may generate a dienolate intermediate, which would then react with an azodicarboxylate to give the [4+2] annulation product (Scheme 1 c).…”