Synthesis of Ferrocene-Substituted 2-Azetidinones Miguel A. Sierra,* Marı ´a J. Manchen ˜ o, Rube ´n Vicente, and Mar Go ´mez-Gallego Departamento de Quı ´mica Orga ´ nica, Facultad de Quı ´mica, Universidad Complutense, 28040-Madrid, Spain sierraor@quim.ucm.es Received July 24, 2001 The photochemical reaction of alkoxychromium(0)carbene complexes and ferrocene mono- and disubstituted imines formed 2-azetidinones having one or two ferrocene moieties in good yields. Yields decrease when the carbene moiety bears an aminoferrocene moiety attached to the carbene carbon, while complex 9 having the ferrocene directly bonded to the carbene carbon was totally inert in these reactions. Access to -lactams with the ferrocene tethered to the C3 position through a methylene group was gained using the lithium enolate derived from ethyl 3-ferrocenylpropanoate. The reaction of this enolate produced two unexpected processes. Thus, 2-azetidinone 15 having an hydroxyl group at the C3 position was obtained together with the expected -lactam 14, by reaction of the lithium enolate of ethyl 3-ferrocenylpropenoate and imine 1. Additionally, unsaturated amide 17 was obtained by base-promoted Hoffmann-like breakage of the -lactam ring formed in the reaction of the same enolate and imine 2. Oxidation of the anion at the C3 of the 2-azetidinone ring on compound 14, as well as the sterically driven ring-breakage of the C3 anion derived from the nonisolated 2-azetidinone 18, should be responsible for this behavior. Introduction The search for -lactams having new structures or novel variations of well-known basic structures remains unabated. 1 This is mainly because of the increased worldwide awareness about bacterial-resistance 2 and the search for other biological properties of these compounds apart from their antibacterial action. These compounds are potent inhibitors of mammalian serine proteases, 3 such as human leukocyte elastase (HLE) 4 or thrombin, cholesterol absorption inhibitors, 5 and inhibitors of hu- man cytomegalovirus (HCMV, a -herpes virus). 6 More- over, development of synthetic methodology based on the 2-azetidinone nucleus has been steadily increased during the last 25 years meriting its own name: the -lactam synthon method, a term coined by Ojima almost 20 years ago. 7 Surprisingly, 2-azetidinones having organometallic- moieties attached to the four membered ring are scarce. 8 1,1′-Ferrocenyldicarboxiamidopenicillanic and cepha- losporanic acids and several derivatives having the penicillin and cephalosporin nuclei acylated with differ- ent ferrocene-carboxylic acids have been prepared. 9,10 To the best of our knowledge, only one example of a monolactam N-substituted with a ferrocenyl tethered chain has been prepared. 11 Finally, some 3-unsubstituted- 4-ferrocenyl--lactams have been reported while this work was in progress. 12 Taking apart their potential as antibacterial agents, one of the more attractive aspects of these ferrocenyl- substituted compounds is their foreseeable role as elec- trochemical markers in biological processes. 13 In fact, the (1) For a recent review, see (a) Go ´mez-Gallego, M.; Manchen ˜o, M. 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