Carbene C−H insertion

Carbene C−H insertion in organic chemistry concerns the insertion reaction of a carbene into a carbon–hydrogen bond. This organic reaction is of some importance in the synthesis of new organic compounds.[1] It is an example of C–H functionalization, and depending on authorial conventions may be considered a C−H activation reaction.

Simple carbenes such as the methylene and dichlorocarbene are not regioselective towards insertion, and prochiral substrates give racemic products. Metal-stabilized carbenes are much more selective. The first such reaction was reported in 1981,[2] and the general mechanism proposed by Doyle in 1993. In the transition state, the stabilizing metal partially dissociates, with concurrent Lewis-acid attack on the C−H bond. The resulting three-membered ring then collapses for a net proton transfer and carbon–carbon bond formation, and simultaneous expulsion of the metal:[3]

Carbene carbon hydrogen insertion

The copper catalysts used in this reaction historically have been superseded by rhodium. Other metals stabilize the carbene too much (e.g. molybdenum), giving Fischer carbenes; or too little (e.g. silver or gold, although modern ligands have enabled these metals). Dirhodium tetraacetate is a particularly effective achiral catalyst. In a typical reaction ethyl diazoacetate and dirhodium tetraacetate react with hexane; the insertion into a C−H bond occurs 1% on one of the methyl groups, 63% on the α methylene unit and 33% on the β unit. Rh2(methyloxy­carbonyl phenyl­propanoyl imidazolidine­oxido)4 is an effective asymmetric catalyst:

Chiral dirhodium catalysts. Only one ligand displayed for clarity; also one methylene bridge in MPPIM omitted between the phenyl group and the ureamide

The most successful reactions are intramolecular within geometrically rigid systems.[4][5]

References

  1. ↑ Catalytic Carbene Insertion into C−H Bonds Michael P. Doyle, Richard Duffy, Maxim Ratnikov and Lei Zhou Chem. Rev. 2009 Article ASAP doi:10.1021/cr900239n
  2. ↑ Transition-metal-catalysed reactions of diazoesters. Insertion into C−H bonds of paraffins by carbenoidsAlbert Demonceau, Alfred F. Noels, André J. Hubert and Philippe Teyssié, J. Chem. Soc., Chem. Commun., 1981, 688 doi:10.1039/C39810000688
  3. ↑ Electronic and steric control in carbon–hydrogen insertion reactions of diazoacetoacetates catalyzed by dirhodium(II) carboxylates and carboxamides Michael P. Doyle, Larry J. Westrum, Wendelmoed N. E. Wolthuis, Marjorie M. See, William P. Boone, Vahid Bagheri, Matthew M. Pearson J. Am. Chem. Soc., 1993, 115 (3), pp 958–964 doi:10.1021/ja00056a021
  4. ↑ Cyclopentanone synthesis by intramolecular carbon–hydrogen insertion of diazo ketones. A diterpene-to-steroid skeleton conversion Ernest Wenkert, Linda L. Davis, Banavara L. Mylari, Mary F. Solomon, Roberto R. Da Silva, Sol Shulman, Ronald J. Warnet, Paolo Ceccherelli, Massimo Curini, Roberto Pellicciari J. Org. Chem., 1982, 47 (17), pp 3242–3247 doi:10.1021/jo00138a008
  5. ↑ General route to highly functionalized cyclopentane derivatives by intramolecular C−H insertion Douglass F. Taber, Eric H. Petty J. Org. Chem., 1982, 47 (24), pp 4808–4809 doi:10.1021/jo00145a050
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