leading

The use of metal catalysts in the decomposition of diazo compounds is well-documented¹. Rhodium catalysts, specifically, tend to proceed under mild conditions, making them a common choice in organic synthesis². The final reaction chosen by Lu et al uses rhodium acetate in dichloromethane to catalyze the C-H insertion reaction. The authors obtained the best yield for all catalysts using dichloromethane and the highest enantiomeric purity with rhodium acetate as a catalyst and pyrrolidine amides as chiral auxiliaries.

Regioselective Considerations: Rhodium acetate tends to selectively produce five-membered rings⁴. This phenomenon can be explained by the transition state (108) shown below, which involves a pseudo-ring. This trend holds true for our reaction; in non-rigid systems, “insertion of electrophilic rhodium carbene complexes into a C-H bond results in the preferential formation of five-membered rings⁵.”

Electronic Considerations: The main electronic effects with rhodium catalysts concern the rhodium carbenoid intermediate (107 in the above mechanism)⁷. The carbon atom double-bonded to the rhodium is highly electrophilic because of the resonance structure shown below, so electron-withdrawing ligands attached to rhodium are destabilizing⁸. In the presence of electron-withdrawing ligands, carbenoids react faster and less selectively due to their lower stability. Thus, rhodium acetate is a better catalyst because it is electron-donating and can therefore stabilize the carbenoid intermediate, allowing for a more selective reaction⁹.

Solvent Effects: Polar solvents have been empirically shown to improve the yield of rhodium-catalyzed C-H insertion reactions¹¹. This most likely because the reaction proceeds through several polar intermediates and transition states. When a polar solvent is used, the intermediates can be stabilized, allowing the reaction to proceed. This is consistent with the results of both our authors, who found that dichloromethane was a better solvent for this reaction than hexanes, and Padwa, who found that “nonpolar solvents did destabilize the transition state, and formation of the five-membered ring was totally suppressed¹²."

References:

1. Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797-1815.

2. Ibid.

3. TCI America. Rhodium (II) Acetate Dimer. http://www.tcichemicals.com/eshop/en/us/commodity/R0069/ (accessed March 30, 2015).

4. Taber, D. F.; Raman, K. J. Am. Chem. Soc. 1983, 105, 5935-5937.

5. Padwa, A. J. Organomet. Chem. 2000, 610, 88-101.

6. Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797-1815.

7. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 1998, 63, 3717-3721.

8. Padwa, A. J. Organomet. Chem. 2000, 610, 88-101.

9. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 1998, 63, 3717-3721.

10. Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797-1815.

11. Ibid.

12. Ibid.

13. Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814-825.

14. Evans, D. A.; Helmchen, G.; Rüping, M. Chiral Auxiliaries in Asymmetric Synthesis. In Asymmetric Synthesis: The Essentials; Christmann, M.; Brase, S.; Ed.; Wiley: New York, 2007. p 3.

15. McDougal, P. G. 2001. trans-2,5-Bis(methoxymethyl)pyrrolidine. e-EROS Encyclopedia of Reagents for Organic Synthesis.

Auxiliary Effects: In addition to stereoselective catalysts, auxiliaries are used to improve the stereoselectivity of C-H functionalization reactions¹³. Auxiliaries act primarily by making one stereoisomer sterically unfavorable¹⁴. Our reaction uses a pyrrolidine amide derivative as a chiral auxiliary. These auxiliaries are highly stereoselective and thus relatively simple to synthesize¹⁵.