Asymmetric Catalytic 1,6‐Conjugate Addition/Aromatization of para‐Quinone Methides: Enantioselective Introduction of Functionalized Diarylmethine Stereogenic Centers

Abstract

It′s just a phase: The title reaction sequence of para‐quinone methides (p‐QMs) has been developed with malonates under phase‐transfer catalysis. The reaction also offers an alternative route to asymmetric construction of diarylmethine stereocenters in excellent enantioselectivities and high yields.

Recent Advances in the Catalytic Enantioselective Reactions of para‐Quinone Methides

“…The first example of ag eneral organocatalytic enantioselective 1,6-addition reactiono fp-QMs was reported by Fan'sg roup in 2013. [5] They developed ap hase-transfer catalysis (PTC)-mediated asymmetric 1,6-conjugate addition of malonates to 2,6-disubstituted p-QMs. In the presence of an axially chiralb inaphthyl-modified ammonium bromide (C1;1mol %l oading), as eries of synthetically interesting, functionalized diarylalkanes were obtained in 29-96 %y ield with 9-99 % ee (Scheme1).…”

How Understanding the Role of an Additive Can Lead to an Improved Synthetic Protocol without an Additive: Organocatalytic Synthesis of Chiral Diarylmethyl Alkynes

“…The results indicate that the para-quinone methide intermediate QM is essential for the excellent enantioselectivity of the reduction step, presumably owning to key hydrogen bonding with the chiral acid catalyst. [9] Aseries of experiments were carried out to shed light on the exact role of the additive.F irst, we closely monitored the two steps by sequential addition of the reagents.I nt he absence of the additive and reductant 2b,t he reaction of substrate 1a proceeded smoothly to form the QM intermediate with complete conversion in 6h.S ubsequent addition of reductant 2b led to rapid formation of the desired product 3a with excellent conversion and enantioselectivity [Eq. (2)].…”

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

“…When the catalyst loading was decreased to 10 mol %a nd 5mol %, the yields slightly increased and the stereoselectivities remained excellent (entries 9a nd 10). No further improvements were observed when other solvents,s uch as DCM, DCE, Et 2 O, or PhCF 3 , were used (entries [11][12][13][14]. Theb est reaction conditions are those shown in entry 10, and gave 3a in 89 %y ield, 99 % ee, and 17:1 d.r.…”

“…First, thiourea catalyst A was used. No further improvements were observed when other solvents,s uch as DCM, DCE, Et 2 O, or PhCF 3 , were used (entries [11][12][13][14]. Thew idely used squaramide catalyst B delivered comparable results (entry 2).…”

“…Recently, para-quinone methides (p-QMs) have increasingly been investigated, [10] and 1,6-conjugate additions to p-QMs have emerged as am ost prevailing method for the synthesis of highly enantioenriched diarylmethine compounds. [11] Fore xample,t he groups of Fana nd Jørgensen have independently reported organocatalytic 1,6-addition reactions between p-QMs and malonates [11a] or aldehydes, [11b] respectively.S hortly after these reports,S un and co-workers developed an elegant strategy in which p-QMs were generated in situ and then trapped with pyrroles [11d] and naphthols. [11k] Furthermore,a ddition reactions of bis(pinacolato)diboron, [11c,f] thioacetic acid, [11e] 3-substituted oxindoles, [11h,i] glycine Schiff bases, [11g,l] and dicyanoolefins [11j] to p-QMs catalyzed by copper,c hiral phosphoric acids,c hiral ammonium salts,b ifunctional squaramides,a nd thioureas have also been developed (Scheme 1a).…”