Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Monday, September 17, 2007
Douglass F. Taber
University of Delaware

Selective C-H Functionalization

Direct conversion of an unactivated C-H bond to a C-O, C-N or C-C bond is a powerful way to add valuable complexity to a substrate. While this is by no means a new approach (Friedel-Crafts acylation converts a C-H bond to a C-C bond), there have been several useful new developments.

Biosynthetic C-H oxygenation is mediated by the several isozymes of Fe-centered cytochrome P-450. Debkumar Bandyopadhyay of the Indian Institute of Technology, New Delhi has developed (Chem. Comm. 2006, 4823. ) an Fe complex that catalyzed the oxidation of cyclohexane 1 to cyclohexanol 2, with about 20 turnovers. Shinobu Itoh of Osaka City University has devised (Chem. Comm. 2006, 4016. ) a Ni catalyst that effected the same conversion with about 600 turnovers, using MCPBA as the bulk oxidant.

More complex substrates are also interesting. Robert H. Crabtree and Gary W. Brudvig of Yale University have shown (Science 2006, 312, 1941. ) that a Mn-Mn complex catalyzed the oxidation of 3 to 4 with high selectivity.

David Crich, now at Wayne State University, has reported (J. Org. Chem. 2006, 71, 7106. ) a different approach to C-H functionalization. Exposure of phenylalanine derivatives such as 5 to NBS gave the bromide, presumably as a epimeric mixture. Solvolysis lead to the product 6 and thus to 7 as single diastereomers.

C-H bonds can also be converted to C-N bonds. Paul Müller of the University of Geneva and Robert H. Dodd and Philippe Dauban of Gif-sur-Yvette have reported (Angew. Chem. Int. Ed. 2006, 45, 4641. ) that oxidation of 9 in the presence of the prochiral 8 led to 10 in high de. David A. Powell of Merck Frosst Canada has also described (Org. Lett. 2006, 8, 6031. ) a protocol for the direct amidation of allylic and benzylic C-H bonds.

One of the most powerful of C-H functionalizations is the conversion to a C-C bond. E. J. Corey of Harvard University found (Org. Lett. 2006, 8, 3391. ) that oxidation of the amino acid derivative 11 with Pd salts led to the C-H activated product 12. If the palladation was run in the presence of an aryl iodide, intermediate 12 coupled to give 13, with high diastereocontrol.

Rh-mediated carbene transfer is also a powerful method for converting a C-H to a C-C bond. Andrew G. H. Wee of the University of Regina has described (Chem. Commun. 2006, 3732. ) the cyclization of the enantiomerically-pure diazo acetate 14. The C-H bond adjacent to the N is the more reactive, and is the site of insertion with racemic catalysts, leading to 15. With the enantiomerically-pure catalyst Rh2(4S-MPPIM)4, 15 was the only product observed. With the enantiomeric catalyst Rh2(4R-MPPIM)4, the chirality of the catalyst dominated, so the major product was 16. The Rh2(4R-MPPIM)4, and Rh2(4S-MPPIM)4 catalysts were developed by Michael P. Doyle of the University of Maryland.

D. F. Taber, Org. Chem. Highlights 2007, September 17.