Enantioselective α-Arylation of Aldehydes via the Productive Merger of Iodonium Salts and Organocatalysis

Anna E. Allen and David W. C. MacMillan*

J. Am. Chem. Soc., ASAP

In the Buchwald lab here at MIT (of which I am a part), we use palladium catalysis to construct C-Z bonds, where X = C, O, N, halogen, etc.  One reaction developed in our lab a few years ago was the racemic and then enantioselective α-arylation of aldehydes (see references), a reaction limited to the construction of quartenary centers due to racemization of the product when an H was present (Figure 1).  Inspired by this effort and hoping to overcome its limitations, the MacMillan group at Princeton University set out to develop a method to catalytically construct enolizable stereocenters adjacent to aldehydes.

Figure 1

The MacMillan group approached the problem using organocatalysis, a rapidly growing field of organic chemistry in which catalytic amounts of organic molecules instead of transition metal complexes are used to effect reactions.  Thus, the author’s overarching goal was to use a catalytic amount of a chiral amine, namely 3, to transiently convert an aldehyde into the nucleophilic enamine, which could then stereoselectively attack an electrophilic aryl species to afford the α -aryl aldehyde.  A common choice in electrophilic aryl species are the non-toxic, easily generated diaryliodonium triflate salts used in this paper (Figure 2).  This approach is analogous to a traditional cross-coupling mechanism, in which the transition metal effectively makes the aryl halide “more electrophilic”, in that an enolate can attack the metal center and then reductively eliminate with the aryl group to afford the desired C-C bond.

Figure 2

In their initial studies, the authors found that transiently generated enamines were not nucleophilic enough to attack diaryliodonium salts directly.  Previous work has shown that Cu(I) species can greatly increase the electrophilicity of these species by oxidatively adding one of the aryl groups, generating ArI and a highly electron deficient Cu(III) aryl triflate species, which is more than willing to reductively elimination an aryl group to a nucleophile after displacement of OTf.  Thus, the authors found that adding a catalytic amount of CuBr, in addition to catalytic amounts of 3, enabled the catalytic cycle in Figure 3.  This interesting cycle involves a tandem organocatalytic-transition metal catalyzed sequence that effectively allows the desired reaction to occur without a strong base present, which prevents racemization of the sensitive stereocenter generated.  Indeed, the only necessary additive besides these two catalytic species is NaHCO3.

Figure 3

The reaction is quite general to aryl and heteroaryl species; the primary limitation seems to be sluggish reactions with bulky o-substituents on the aryl group.  Based on the electrophilic Cu(III) species the authors propose for the catalytic cycle, it seems that aryl triflates and perhaps even aryl halides could eventually be used instead of the more expensive diaryliodonium salts.  While one could argue all day about whether this reaction is organocatalytic, transition-metal catalyzed, or both, we can all agree that it will be interesting to see how the MacMillan group further develops this transformation and applies their combined organic-transition metal catalysis philosophy to new reactions.

References: Martín,R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236.

García-Fortanet, J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,47, 8108.


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