Issue 38, 2017

Enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation

Abstract

The highly enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl–β-amido allyl ester substituted oxindoles in good yields of 41–75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl–α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl–β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94–98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56–63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl–α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.

Graphical abstract: Enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation

Supplementary files

Article information

Article type
Paper
Submitted
29 Aug 2017
Accepted
09 Sep 2017
First published
18 Sep 2017

Org. Biomol. Chem., 2017,15, 8166-8178

Enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation

M. Jackson, C. Q. O'Broin, H. Müller-Bunz and P. J. Guiry, Org. Biomol. Chem., 2017, 15, 8166 DOI: 10.1039/C7OB02161E

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