Synthetic toolbox: Carbonylation

CHEM21 Case Study: Carbonylative α-Arylation of β Ketonitriles

Carbonylative α-arylations have seen a lot of interest over the years; however, initial methods were limited to the use of malonate derivatives as starting materials.[1][2][3] Catalytic systems for the intermolecular carbonylative α-arylation of ketones have been developed although these reactions were limited to the use of C-nucleophiles furnished with a carbonyl group.[4][5][6][7] Thus, extending carbonylative α-arylation towards nitriles as readily available coupling partners represents an attractive goal for further development.  The resultant β-ketonitrile products from such methods are useful bifunctional intermediates for the synthesis of pharmaceutically relevant compounds.[8][9][10][11]  As important optically active intermediates, the diversity of available β-ketonitriles has a significant impact on the range of structures that can be accessed.[12][13][14][15][16][17] As such, the conventional methods for the synthesis of β-ketonitriles through acylation of acetonitriles or carbonylative coupling of trimethylsilylacetonitrile (Scheme 1) are limited to the formation of β-ketones that are unsubstituted at the α-position.[18]

Scheme 1: β-ketonitrile formation from carbonylative coupling of trimethylsilylacetonitrile ([18])

Although recent approaches have been reported that enable access to α-substituted β-ketonitriles, these protocols do not allow for the generation of a quaternary α-carbon centre.[19][20] As a result, the development of protocol that allows access to β-ketonitriles from aryl halides, carbon monoxide and uses nitriles as a simple abundant feedstock represents an advantageous achievement.  CHEM21 researchers have developed the first example of such a transformation using a commercially available catalyst system that allows for the selective formation of α-disubstituted β-ketonitriles under low CO pressures with the use of unactivated nitriles (Scheme 2).[21]

Scheme 2: CHEM21 Approach and first example of the synthesis of α-disubstituted β-ketonitriles from unactivated nitriles([21])

The method is applicable to the synthesis of 24 α-disubstituted β-ketonitriles in good to excellent yields, which were achieved in a straightforward appraoch. The approach allows for the selective carbonylative α-arylation in an atom economical manner using CO gas.

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