Further Studies on the Direct Synthesis of α,β‐Unsaturated Ketimines and α,β‐Enones by Chemoselective Dehydrative Addition of Functionalized Alkenes to Secondary Amides

Abstract

Described in this paper are the results of an investigation on the extension of the C‐H alkyliminylation and acylation of alkenes with secondary amides. The nucleophilic partner has been extended to cover a series of functionalized alkenes bearing functional groups including ester, α,β‐unsaturated ester, uncongested ketone groups, as well as enol derivatives of acetaldehyde such as enol ether and enamides. The electrophilic partner has been extended from N‐(2,6‐dimethylphenyl) and N‐methyl amides to N‐n‐butyl, and N‐cyclohexyl amides. The results demonstrated that the method can be used to synthesize a number of functionalized α,β‐unsaturated ketimines and α,β‐enones in an efficient, high yielding, and one‐pot manner. The method was applied to a concise synthesis of (E)‐6‐styryltetrahydro‐2H‐pyran‐2‐one (5), an immediate intermediate in the syntheses of a series of styryllactone natural products including (±)‐goniothalamine (6), (±)‐goniothalamine oxide (7), (±)‐goniodiol (8), (±)‐leiocarpin A (9), (±)‐9‐deoxygoniopypyrone (10), and (±)‐7‐epi‐goniodiol (11).

One-pot synthesis of N-heterocycles and enimino carbocycles by tandem dehydrative coupling–reductive cyclization of halo-sec-amides and dehydrative cyclization of olefinic sec-amides

“…Scheme 8 The synthesis of racemic δ-coniceine (7). Scheme 9 One-pot construction of indolizidine and quinolizidine ring systems.…”

“…3 In comparison, this chemistry has been less explored for secondary amides. 4 In connection with our endeavor to develop amidebased C-C bond forming reactions, [5][6][7] very recently, we have disclosed a highly chemoselective, intermolecular C-H alkyliminylation and acylation of alkenes with secondary amides, 7a-c which provides direct access to α,β-unsaturated ketimines (1-aza-1,3-dienes, enimines) and α,β-enones. As a continuation of this work, the tandem dehydrative alkenylation-reductive cyclization of secondary halogenated amides 1/2 to give 2-alkenylpyrrolidines 3 and 2-alkenylpiperidines 4 was envisioned (Scheme 1).…”

“…10c Alkaloid himbacine (9) is a potent and selective antagonist of the muscarinic M 2 receptor, which constitutes an attractive lead compound of a drug for the treatment of Alzheimer's disease. 10d In addition to their important biological profile, 2-substituted pyrrolidines and piperidines also serve as key intermediates for the synthesis of aza-bicyclic pyrrolizidine, 9a,11 indolizidine 9a,12 and quinolizidine 12 alkaloids such as δ-coniceine 13a (7) and epiquinamide, 13b,c (8). The latter was isolated from the skin of Ecuadorian frog Epipedobates tricolor.…”

Ketone Synthesis by Direct, Orthogonal Chemoselective Hydroacylation of Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl Carbanions

“…In those reactions, alkenes/ arenes serve as mild alternates of alkenyl/aryl carbanions A. [14] During one of those investigations, we discovered that upon activating with triflic anhydride (Tf 2 O), secondary amide 1B can couple with styrene (3A) and allyltrimethylsilane (3B) to yield saturated ketones 2A and 2B, respectively (Scheme 1d).…”

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

“…[17] This method was recently developed in our laboratory for the direct transformation of secondary amides. [18] To develop general and flexible access to 3,t he use of readily available potassium organotrifluoroborates (2)a sa lternative nucleophiles [19] was investigated. Thus,wehave established not only aprotocol for the synthesis of 3,but also the one-pot synthesis of 4 from 1 and 2 (see Scheme S1 in the Supporting Information).…”