Staudinger ketene-imine cycloaddition experimental

The mechanism of the Staudinger ketene imine cycloaddition reaction has been the subject of much debate and has recently been reviewed. The mechanism has been studied both computationally and experimentally. Experimental evidence gathered on solution phase reactions supports a two-step mechanism, in which addition of the imine nitrogen to the ketene carbonyl group occurs to generate an intermediate zwitterion. Subsequent cyclization of the zwitterion results in formation of the key C3-C4 a-bond. 

Cycloaddition reactions are important in the synthesis of /3-lactams, since these compounds make up the penicillin and cephalosporin antibiotics. Amongst the many computational studies on these synthetic processes, a number have involved comprehensive calculations on the Staudinger reaction, the cycloaddition of ketenes and imines." Once again the solvent effect is found to be important and, although the reaction is shown to be a concerted cycloaddition in the gas phase, in solution the reaction is predicted to be a stepwise process (Figure 2). For substituted systems, the calculations predict that ring-closure in the second step occurs with conrotatory motion, in accordance with experimental observations. 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Two possible [2+2] cycloadditions can be envisaged for the synthesis of (3-lactams (Scheme 1). Interestingly, the same fragmentations have been observed in the mass spectra of these compounds [10, 11], One possibility consists of the [2+2] cycloaddition between ketenes (2) and imines (3) to yield (3-lactams (1). This reaction has been explored experimentally and it is also known as the Staudinger reaction between ketenes and imines [12-15]. In an alternative approach, the [2+2] cycloaddition between alkenes (5) and isocyanates (4) leads to (3-lactams (1). This reaction has been less extensively used, but it has proven to be useful in the chemical synthesis of interesting compounds [16-19]. 

Cossio, F. P., Lecea, B., Cuevas, C., Mielgo, A., Palomo, C. A novel entry for the asymmetric Staudinger reaction experimental and computational studies on the formation of P-lactams through [2+2] cycloaddition reaction of ketenes to imines. An. Quim. 1993, 89, 119-122. 

Ye applied his catalytic system to enantioselective p-lactam and p-lactone formations via Staudinger-like reactions with imines or ketones (Scheme 14.22). Furthermore, the reaction with benzoyldiazenes gave the corresponding oxadiazin-6-ones issue of a [4+2] cycloaddition reaction, instead of the reported [2+2] DMAP derivatives, as nucleophilic catalysts. The postulated formation of an azolium enolate upon reaction of the NHC with the ketene in these reactions was evidenced experimentally by the isolation and full characterization of such zwitterionic adducts in model reactions. ... 

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