Phosphine Sequentially Catalyzed Domino 1,6-Addition/Annulation: Access to Functionalized Chromans and Tetrahydroquinolines with an Ethynyl-Substituted All-Carbon Quaternary Center

Abstract

A novel phosphine sequentially catalyzed domino 1, 6-addition/annulation process has been developed using p-quinone methides (p-QMs) and α-substituted allenoates which generates a series of chroman and tetrahydroquinoline derivatives containing an ethynyl-substituted all-carbon quaternary center with up to 97% yield and 20:1 dr. value. In this reaction, allenoates act as C2 synthons.

Enantioselective Catalytic [4+1]‐Cyclization of ortho‐Hydroxy‐para‐Quinone Methides with Allenoates

“…The outcome of this reaction is in sharp contrastt o other recently reported reactions between quinone methides 3 and allenoates. [12] Key to success was the use of the commercially availablec hiral phosphine B as ac atalystu nder carefully optimized reactionc onditions. This methodology allowed for the so far unprecedented synthesis of the chiral dihydrobenzofurans 5 as single diastereomers in yields up to 90 %a nd with enantiomeric ratios up to 95:5.…”

“…[6] Alternatively,t he hydroxy-containing para-quinone methides 3 have very recently emergeda sp owerful building blocks for formal (4 + n)-annulations as well. [7,[11][12][13] Interestingly however,t heir applicability for asymmetric[ 4 + +1]-cyclizations to access dihydrobenzofurans 1 has so far been ratherl imited,w ith highly asymmetric protocols still being rare (Scheme 1B). [7] Twoy ears ago we reported the first highly enantioselective synthesis of compounds 1 by reactingp reformed chiral ammonium ylides with in situ formed o-QMs 2.…”

“…Thus, we decided to investigate if this methodology may also be extended to the formal [4+ +1]-cyclization of the o-hydroxy-containing p-QMs 3 with allenoates 4. [12] We reasoned that this preformed and, compared to 2,m ore stable acceptorm olecule may be better suited to establish atruly catalytic as well as asymmetric protocol, whichw ould then allow for the first enantioselective [4+ +1]-annulation of p-QMs 3 to accesst he highly functionalized chiral dihydrobenzofurans 5 (Scheme 1D).…”

Theoretical investigation on the mechanism and enantioselectivity of organocatalytic asymmetric Povarov reactions of anilines and aldehydes

“…Until recent years some new methods emerge yielding a variety of substituted THQ. Zhu has obtained functionalized THQ derivatives containing an ethynyl‐substituted all‐carbon quaternary center using phosphine sequentially catalyzed domino 1,6‐addition/annulation process with 97% yield and 20:1 dr. value [15]. Zhang has realized the first enantioselective mode of phosphine‐catalyzed [4 + 2] annulation with β′‐acetoxy allenoates [16].…”

Phosphine‐Catalyzed β‐Selective Conjugate Addition of α‐Fluoro‐β‐ketoamides to Allenic Esters

“…Nucleophilic phosphine catalysis has emerged as one of the most reliable platforms for a variety of transformations involving activated allenes for the construction of synthetically valuable structural frameworks , . Since the pioneering work by Lu in the 1990s, the annulation reactions have been demonstrated to have tremendous potential, particularly in the construction of carbo‐ and heterocycles . Besides the extensively explored annulations of allenoates, the γ‐umpolung addition reactions of various nucleophiles to allenoates, first reported by Trost and Lu, have received considerable attention over the years .…”