A Theoretical Investigation of the Co(CO) 4 - -Catalyzed Carbonylative Ring Expansion of N-Benzoyl-2-methylaziridine to -Lactams: Reaction Mechanism and Effect of Substituent at the Aziridine C r Atom Diego Ardura and Ramo ´n Lo ´pez* Departamento de Quı ´mica Fı ´sica y Analı ´tica, UniVersidad de OViedo, Julia ´ n ClaVerı ´a, 8; E-33006 OViedo, Spain rlopez@unioVi.es ReceiVed December 9, 2006 The reaction mechanism of the Co(CO) 4 - -catalyzed carbonylative ring expansion of N-benzoyl-2- methylaziridine to afford N-benzoyl-4-methyl-2-azetidinone and N-benzoyl-3-methyl-2-azetidinone was investigated by using the B3LYP density functional theory methodology in conjunction with the conductor polarizable continuum model/united atom Kohm-Sham method to take into account solvent effects. Computations predict that the most favorable reaction mechanism differs from the experimental proposals except for the nucleophilic ring-opening step, which is the rate-determining one. The regioselectivity and stereospecificity experimentally observed is explained in terms of the located reaction mechanism. The substitution of the methyl group at the carbon R of aziridine by the phenyl one gives rise to the obtaining of an only product that corresponds to the CO insertion into the C(substituted)-N bond in accordance with experimental findings. When the ethyl group replaces the methyl one the CO insertion occurs into the two C-N bonds, but the regioselectivity of the process is higher than that of the methyl substituent. Introduction Since the elucidation of the structure of penicillin by Crowfoot-Hodgkin et al. in 1945, 1 -lactams have become the center of attention for many synthetic, medicinal, and theoretical chemists and biologists due to their utility as synthetic inter- mediates and to their biological activity. 2-11 As a consequence, many chemical methods for the production of -lactams have been proposed. 8,9 One of these synthetic strategies is the * Corresponding author. Phone: +34 98 5 102 967. Fax: +34 98 5 103 1255. (1) Crowfoot, D.; Bunn, C. W.; Rogers-Low, B. W.; Turner-Jones, A. In The Chemistry of Penicillin; Clarke, H. T., Johnson, J. R., Robinson, R., Eds.; Princenton University Press: Princenton, New Jersey, 1949; Chapter 11, p 310. (2) Chemistry and Biology of -Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New York, 1982; Vols. 1-3. (3) Du ¨rkheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Ang. Chem., Int. Ed. Engl. 1985, 24, 180. (4) The Chemistry of -Lactams, Page, M. I., Ed.; Blackie Academic & Professional: London, 1992. (5) The Organic Chemistry of -Lactams, Georg, G. I., Ed.; VCH: Weinheim, 1992. (6) Southgate, R. Contemp. Org. Synth. 1994, 1, 417. 10.1021/jo0625249 CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 3259-3267 3259 Published on Web 03/24/2007