Tag Archives: Heteroaromatics

Organocatalytic C−H Bond Arylation of Aldehydes to Bis-heteroaryl Ketones

Qiao Yan Toh, Andrew McNally, Silvia Vera, Nico Erdmann and Matthew Gaunt
J. Am. Chem. Soc.
DOI: 10.1021/ja400051d

The synthesis of ketones bearing a diverse range of aryl and heteroaryl functionality is of great importance to the medicinal chemistry industry as they can be readily converted into structural motifs commonly found in medicinal agents.

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A novel approach to these scaffolds has been developed by Gaunt et al who exploit the inherent electrophilicity of diaryliodonium salts by using them to trap carbogenic nucleophiles to form carbon–aryl bonds. The driving force for this research is the lack of known methods for the preparation of bis-heteroaryl ketones. The authors set themselves the challenge of developing an organocatalytic method for the regioselective diaryl ketone formation which is tolerant of a broad range of hetreoaromatic nuclei derived from diaryliodonium salts and carbogenic nucleophiles. This was achieved by using a commercially available NHC-organocatalyst with DMAP as the base to form a nucleophilic enolate from the heteroaromatic aldehyde substrate. Subsequent trapping of this enolate by the heteroaryl iodonium salt gave the bis-heteroaryl ketone products in up to 91% isolated yield.

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The broad scope of this transformation was illustrated with a variety of aryl and heteroaryl aldehydes. More interestingly, however, Gaunt and co-workers have shown that the use of a non-symmetrical diaryliodonium salts is tolerated in excellent selectivity.
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Non-symmetrical diaryliodonium salts are more economical as they are prepared with only one equivalent of the transferring group. Out of a number of non-symmetrical diaryliodonium salts screened, a uracil-pyridine salt displayed the best selectivity with the desired bis-heteroaryl ketone isolated with no evidence of the undesired ketone identifiable in the crude 1H NMR.

Finally, to further illustrate the utility of this methodology, the Gaunt research team demonstrated that a bis-heteroaryl ketone could be readily converted into enantioenriched amines by an Ellman imine formation and subsequent reaction with methylmagnesium bromide to give an α-tertiary amine in high yield and enantiopurity after cleavage of the chiral auxiliary.

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