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

Abstract

We report two efficient and versatile alkenylative cyclization methods for the one-pot synthesis of substituted pyrrolidine, piperidine, indolizidine, and quinolizidine ring systems, and enimino carbocycles, respectively. The first method consists of amide activation (Tf 2 O) induced dehydrative coupling of halogenated secondary amides with alkenes and the NaBH 4 reduction triggered tandem cyclization reaction, while the second one features the Tf 2 O-promoted novel modes of extended Bischler-Napieralski cyclization reactions of olefinic secondary amides. Taking advantage of triflic anhydride (Tf 2 O) as the amide activating reagent, the hitherto failed two-step process for the construction of the quinolizidine ring system via intramolecular vinylogous Bischler-Napieralski cyclization has been realized in one pot. The first method was applied to the protecting-group-free one-pot synthesis of the cytotoxic natural product caulophyllumine B (5) and its bioactive derivatives, and to the synthesis of δ-coniceine and 6-styrylpiperidin-2-one. When ethyl vinyl ether and enamides were used as functionalized alkenes, saturated 1,3amino-ether/amido products 4A 1 -4A 3 were obtained in 73%-74% yields.Scheme 1 Designed tandem dehydrative coupling-reductive cyclization reaction of halogenated secondary amides. † In memory of the late Professor Zhi-Tang Huang. ‡ Electronic supplementary information (ESI) available: 1 H and 13 C NMR Spectra of all products. See

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

“…Possessing multiple functionalities and ambident reactivities, the enimines thus obtained constitute a class of versatile building blocks, which will find applications in both organic synthesis and medicinal chemistry. [17]…”

A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones

“…Inspired by the Diels-Alder [4+2] cycloaddition reaction (Scheme 1, eq 1) and the Robinson annulation (Scheme 1, eq 2), as well as a related work recently reported by the Davies group (Scheme 2, eq 1), [15] a three-step assembly of cyclic ketones 1 and -unsaturated amides 3 in a "*2+n+" manner was conceived (Scheme 2, eq 3). Our strategy relied on both the Suzuki coupling reaction [16] and the amide [17,18] reductive alkenylation reaction, a method disclosed recently in this laboratory [17a-c] (Scheme 2, eq 2). Whereas the formation of a 6-membered ring is quite promising, the construction of medium-sized rings has not yet been studied, which may be challenging due to the well-known unfavorable transannular interactions and entropic factors.…”

“…(E)-N-(2,6-Dimethylphenyl)-3,4,9,10-tetrahydrophenanthren-1(2H)-imine (16). Flash chromatography on silica gel (eluent: EtOAc/n-Hexane = 1 : 20) gave compound 16 as a yellow oil (152 mg, yield: 84%); IR (film) v max : 2916,1958,1712,1659,1650,1383,1196, 1076 cm 21.6,22.0,26.2,28.0,28.8,122.3,123.4,125.5 (2C),126.4,127.5,127.7 (2C),128.1,133.1,135.5,137.6,141.1,149.4,166.2;HRMS calcd for [C 22 H 24 N-(2,6-Dimethylphenyl)-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-imine (17). Flash chromatography on silica gel (eluent : EtOAc/n-Hexane = 1 : 20) gave compound 17 as a yellow oil (132 mg, yield: 87%); IR (film) v max : 2916,2848,2359,2340,1651,1504,1494,1384,1195,1131,1076,668 22.2,22.4,22.8,24.0,29.0,31.5,31.8,122.1,125.8 (2C),127.6 (2C),130.5,146.8,149.5,166.6;...…”

Enamines as Surrogates of Alkene Carbanions for the Reductive Alkenylation of Secondary Amides: An Approach to Allylamines

“…Compared with their utilization as synthetic modules, direct use of amides as versatile synthetic intermediates has been impeded by the low electrophilicity of amides. Until recently, considerable progress has been achieved for the direct conversion of amides into functional groups with lower oxidation states. − …”

“…As part of our long-term interest in developing amide based C–C bond-forming reactions, our group has developed one-pot methods for the synthesis of secondary carbinamines by the reductive alkylation of amides using trifluoromethanesulfonic anhydride (Tf 2 O) as the activation reagent and organometallic reagents as nucleophiles. However, attempted extension of these methods to the synthesis of allylamines with less reactive vinylmetallic reagents was unsuccessful. , More recently, we have disclosed an intermolecular alkenylation of secondary amides 1 with simple alkenes as C-nucleophiles for the preparation of α,β-unsaturated ketimines and α,β-enones 2 (Figure , eq 1) .…”