The formal [2+2]-cycloaddition of imines to ketenes forms β-lactams.
Mechanism of the Staudinger Synthesis
Both the ketene and the imine are molecules that can act as either nucleophiles or electrophiles. In the first step, the imine adds to the ketene as a nucleophile. The subsequent cycloaddition delivers the β-lactam:
The zwitterionic intermediate undergoes stepwise ring closure to give the β-lactam ring. The stereoselectivity is generated as a result of the competition between the direct ring closure and the isomerization of the imine moiety in the zwitterionic intermediate. The ring closure step is most likely an intramolecular nucleophilic addition of the enolate to the imine moiety, which is obviously affected by the electronic effect of the ketene and imine substituents. Electron-donating ketene substituents and electron-withdrawing imine substituents accelerate the direct ring closure, leading to a preference for cis-β-lactam formation, while electron-withdrawing ketene substituents and electron-donating imine substituents slow the direct ring closure, leading to a preference for trans-β-lactam formation (L. Jiao, X. Liang, J. X. Xu, J. Am. Chem. Soc. 2006, 128, 6060-6069, DOI):
At lower temperatures, a catalytic version involves the use of non-nucleophilic imines (for example tosylated imines) and the Umpolung of the ketene substrate using tertiary amines or other suitable nucleophiles, making the ketene nucleophilic:
This reversed reactivity mode allows the use of chiral nucleophilic catalysts for enantioselective induction (see recent literature below).
Diphenylketene is quite stable, but other ketenes readily polymerise and must be prepared immediately before the reaction. Ketenes can also be formed in situ in the presence of the imine by a light- or heat-induced Wolff-Rearrangement:
Using the reversed mode strategy, the reaction of acid chlorides with a tertiary amine in the presence of a proton sponge readily produces ketenes:
R3N could be an expensive chiral amine catalyst such as a chinchona alkaloid, whereas the proton sponge is used stoichiometrically. For achiral reactions, NEt3 can serve both functions. The subsequent reaction follows the pathway known from the reverse mode reactions, with the catalyst recovered unchanged:
A general overview about advances in the catalytic, asymmetric synthesis of β-lactams can be found in an article written by Thomas Lectka (Acc. Chem. Res. 2004, 37, 592-600. DOI), whereas a publication by Claudio Palomo discusses reactions of acyl chlorides with imines, including diastereoselectivites and mechanistic insights of the ring closure leading to cis or trans substituted β-lactams and asymmetric induction from the ketene component (Eur. J. Org. Chem. 1999, 3223-3235. DOI). The influence of solvents and additives and the pathways of ketene generations and addition modes on the stereoselectivity is described by Jiaxi Xu (J. Org. Chem. 2006, 71, 6983-6990. DOI).
Chiral N-Heterocyclic Carbene Catalyzed Staudinger Reaction of Ketenes with Imines: Highly Enantioselective Synthesis of N-Boc β-Lactams
Y.-R. Zhang, L. He, X. Wu, P.-L. Shao, S. Ye, Org. Lett., 2008, 10, 277-280.
Pd-Catalyzed Carbonylation of Diazo Compounds at Atmospheric Pressure: A Catalytic Approach to Ketenes
Z. Zhang, Y. Liu, L. Ling, Y. Li, Y. Dong, M. Gong, X. Zhao, Y. Zhang, J. Wang, J. Am. Chem. Soc., 2011, 133, 4330-4341.
The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of β-Lactams
A. E. Taggi, A. M. Hafez, H. Wack, B. Young, D. Ferraris, T. Lectka, J. Am. Chem. Soc., 2002, 124, 6626-6635.
Asymmetric Synthesis of 1-(2- and 3-Haloalkyl)azetidin-2-ones as Precursors for Novel Piperazine, Morpholine, and 1,4-Diazepane Annulated Beta-Lactams
W. Van Brabandt, M. Vanwalleghem, M. D'hooghe, N. De Kimpe, J. Org. Chem., 2006, 71, 7083-7086.