The Mechanism of the Ketene−Imine (Staudinger) Reaction in Its Centennial: Still an Unsolved Problem?

Abstract

[Reaction: see text]. Although Staudinger reported the reaction between ketenes and imines 100 years ago (1907), this process is still the most general and useful method for the synthesis of beta-lactams and their derivatives. This reaction is a [2 + 2] thermal cycloaddition in which two chiral centers may be generated in one preparative step. Staudinger reactions involving alpha,beta-unsaturated imines or ketenes have issues concerning the [2 + 2] or [4 + 2] periselectivity of the reaction. This Account discusses how the main factors that determine the regiochemical and stereochemical outcomes of this reaction were elucidated with computational and experimental data. This fruitful interplay between theory and experiment has revealed that the [2 + 2] cycloaddition is actually a two-step process. The first step is a nucleophilic addition of the nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene. This attack forms a zwitterionic intermediate that evolves toward the final beta-lactam cycloadduct. The second step can be viewed as a four-electron conrotatory electrocyclization that is subject to torquoelectronic effects. When alpha,beta-unsaturated imines are used, the zwitterionic intermediates yield either the corresponding 4-vinyl-beta-lactams or the alternative 3,4-dihydropyridin-2(1 H)-ones. In this latter case, the cyclization step consists of a thermal disrotatory electrocyclization. In the context of stereoselectivity, it is usually assumed that the first step takes place through the less hindered side of the ketene. The cis-trans selectivity of the reaction depends on the geometry of the imine. As the general rule, ( E)-imines form cis-beta-lactams whereas ( Z)-imines yield trans-beta-lactams. Most of the experimental results point to the two-step model. The asymmetric torquoselectivity of the conrotatory ring closure of the second step accounts for the stereochemical discrimination in the reaction of chiral ketenes or chiral imines. Nevertheless, recent studies have revealed that isomerization paths in the imine or in the zwitterion may determine the stereochemistry of the reaction. Thus, if the rotation about the N1-C4 bond of the zwitterion intermediate is faster than the cyclization, the formation of trans-beta-lactams from ( E)-imines is biased. Alternatively, in some cases, the ( E)-( Z) isomerization of the starting imines prior to the cycloaddition steps also results in the formation of trans-cycloadducts. Although the main variables that govern the outcome of the reaction have been elucidated, there are still several aspects of the reaction yet to be disclosed. Finally, the discovery of the catalytic version of the reaction is a new and formidable mechanistic challenge and will be a nice playground for forthcoming theoretical-experimental discussions.

Metal‐Tuned Photochemistry of Metallocene‐Substituted Chromium(0)–Carbene Complexes

“…Detailed experimental procedures and characterization of compounds 10,11,12,14,15, and 16 are included as Supporting Information. …”

“…Thiazoline 15 was irradiated in the pres- www.chemeurj.org ence of complex 10 affording penicillinate 16 as a mixture of diastereomers in an overall 46 % yield (Scheme 4). Leaving aside the lack of stereochemical control (which was already predictable on the basis of the known mechanism of the Staudinger reaction) [10] this approach is the first reported entry to 6-ruthenocenyl-substituted penicillins.…”

Cycloaddition and Electrocyclic Reactions of Vinylketenes, Allenylketenes, and Alkynylketenes

“…1,3,32,37,[209][210][211] Although the previously discussed additions of vinylketenes to imines form a modest fraction of the many examples of these reactions, they do uniquely provide 3-alkenyl azetidinones, which are not available by most alternative routes. Other routes to β-lactams have involved ring closure by almost all of the possible bond-forming modes, by ring expansion, and by cycloaddition approaches A route to benzyl-protected ezetimibe, a potent inhibitor of cholesterol absorption, illustrates ring closure by formation of the N1-C2 amide bond (Scheme 189).…”

Heteroatom effect on potential energy topology. A novel reaction mechanism of stereospecific Staudinger synthesis

“…Moreover, the one step cycloaddition mechanism was also disapproved by QM methods, and by experimental studies and analytical investigations considering one or two intermediates in the reaction against only the one transition state. 5,6 The main research focused on the selectivity and the product distribution of the process. According to these studies a number of factors, such as the solvent, 9,10 the substituents, 5,10e12 the base 13 and the temperature 6,14 were analyzed in the last decades and found to influence the stereochemical outcome.…”