Direct Asymmetric α‐Allylation of Aldehydes with Simple Allylic Alcohols Enabled by the Concerted Action of Three Different Catalysts

Abstract

Tsuji-Trost allylations are Pd 0 -catalyzed reactions in which diverse nucleophiles are allylated with allylic alcohol derivatives such as allylic acetates.[1] Asymmetric catalysis of these reactions is commonly achieved by the use of chiral neutral ligands. [1,2] We have recently described a different approach that is based on the use of chiral counteranions, which are introduced to the reaction in catalytic amounts. [3,4] We discovered an asymmetric a-allylation of a-branched aldehydes using benzhydryl allyl amine as the allylating reagent and a combination of [Pd(PPh 3 ) 4 ] and the chiral Brønsted acid TRIP as catalysts.[4a] Herein, we report the first example of a highly enantioselective a-allylation of aldehydes with simple allylic alcohols [Eq. (1)]. This reaction is catalyzed by the concerted action of three different species, [Pd(PPh 3 ) 4 ], benzhydryl amine, and TRIP, and constitutes another example of asymmetric counteranion-directed catalysis (ACDC). [4] While great progress in the asymmetric catalysis of TsujiTrost-type allylations has been made in recent years, the direct use of allylic alcohols as allylating reagents is extremely rare [5] and even entirely unprecedented with carbonyl nucleophiles. [6,7] Continuing our studies on the use of chiral counteranions in asymmetric Pd catalysis, [4a] we recently became interested in further simplifying and potentially improving our previous protocol by directly utilizing simple allylic alcohols rather than benzhydryl allyl amines, which have to be synthesized individually in a separate step.In our previous allylation studies, we have suggested that our reaction involves the generation of the equivalent of a pallyl-Pd-TRIP ion pair as the critical intermediate, which reacts with an enamine generated from the released benzhydryl amine and the aldehyde. We reasoned that the same pallyl-Pd complex should also be generable from allylic alcohol and the combined action of TRIP and [Pd(PPh 3 ) 4 ]. Indeed, very recently we have shown that a simple achiral Brønsted acid and [Pd(PPh 3 ) 4 ] constitutes a powerful catalyst pair for nonasymmetric a-allylations of aldehydes, [8] suggesting that the concentration and nucleophilicity of the aldehyde-derived enol is sufficient for the reaction to occur. This transformation proceeds via a mass-spectrometrically detectable p-allyl-Pd intermediate and not through a Claisen mechanism, [6a,b] and no reaction occurs in the absence of Pd. However, while we were delighted to find that TRIP and [Pd(PPh 3 ) 4 ] indeed readily catalyze the a-allylation of hydratropic aldehyde (2-phenylpropanal, 1 a) with allylic alcohol (2 a), the enantiomeric ratio of product 3 a was disappointingly minuscule [Eq. (2)].We hypothesized that the low enantioselectivity can be attributed to the fact that both E-and Z-enol isomers are generated under our reaction conditions but lead to opposite enantiomeric products (Figure 1). In our previous and highly enantioselective variant, a benzhydryl amine derived enamine was invoked, of which we expect the ...

Transition metal-catalyzed allylic substitution reactions with unactivated allylic substrates

“…18 Pivotal to the success of this reaction was the introduction of a catalytic amount of the chiral Brønsted acid (S)-3,3 0 -bis(2,4,6-triisopropylphenyl)-2,2 0 -binaphtholate ((S)-TRIP, A2), which in combination with a Pd-catalyst and amine additive creates an effective tri-catalyst system (Table 1). 18 Pivotal to the success of this reaction was the introduction of a catalytic amount of the chiral Brønsted acid (S)-3,3 0 -bis(2,4,6-triisopropylphenyl)-2,2 0 -binaphtholate ((S)-TRIP, A2), which in combination with a Pd-catalyst and amine additive creates an effective tri-catalyst system (Table 1).…”

Catalytic Enantioselective Alkylations with Allylic Alcohols

“…13 In Scheme 6, the example of racemic 2-phenylpropanal (7a) is shown. The newly generated all-carbon quaternary stereocenter was obtained with high enantiomeric excess (94%).…”

Asymmetric Catalysis with CO2: The Direct α‐Allylation of Ketones

“…b-ketoesters,1 ,3-diketones,t etralones), [7,9] preformed enolates (e.g.e nol ethers or metal enolates), [10] and/or decarboxylative allylic alkylation conditions. [5,11] These indirect approaches are less atom-economic,r equire additional, sometimes low yielding synthetic steps for the substrate preparation, and often suffer from al ack of generality.H ence,d espite major advances in the field, ag eneral and direct catalytic enantioselective a-allylation of unsymmetrical ketones has never been achieved.We have recently developed ad irect a-allylation of branched aldehydes with allylic alcohols using an achiral amine/chiral Brønsted acid/Pd 0 catalytic system, [12] in which the enantioselectivity was controlled solely by the enantiopure counteranion.[13] Furthermore,the Carreira group developed an enantio-and diastereodivergent a-allylation of branched aldehydes,catalyzed by achiral amine in combination with ac hiral iridium p-complex. [14] Theu se of unsymmetrical cyclic ketones presents ac hallenging regioselectivity problem, as the more hindered enol needs to selectively react.…”