o-Quinodimethanes: Efficient Intermediates in Organic Synthesis.

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 β-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 α,β-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 β-lactam cycloadduct. The second step can be ...

The mechanism of the ketene-imine (staudinger) reaction in its centennial: still an unsolved problem?

Calculations using density functional theory (DFT, B3LYP/6-31G* level) provide an explanation for the stereodivergent outcome observed in the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (β-lactams). When the ketene is formed prior to the cycloaddition stages, preferential or exclusive formation of cis stereomers is predicted. When the imine reacts directly with the acyl chloride, the step that determines the stereochemical outcome of the reaction is an intramolecular SN2 displacement. Under these conditions, preferential or exclusive formation of trans stereomers is predicted, in good agreement with the experimental evidence available. It is found that both competitive processes are subjected to torquoelectronic effects. In addition, the reported calculations suggest that in both cases the polarity of the solvent enhances the diastereomeric excess of the reaction.

Origins of the Stereodivergent Outcome in the Staudinger Reaction between Acyl Chlorides and Imines.

The stereochemical outcomes observed in the thermal and microwave-assisted [3 + 2] cycloaddition between stabilized azomethine ylides and nitrostyrenes have been analyzed using experimental and computational approaches. It has been observed that, in the absence of solvent, three stereoisomers are formed, both under classical heating conditions and under microwave irradiation. This result contrasts with that observed in solution under classical thermal conditions. The 4-nitropyrrolidines obtained in this way can be aromatized under further microwave irradiation to yield mixtures of pyrroles and 4-nitropyrroles. It is found that ground state cycloadditions between imines and nitrostyrenes take place by three-step mechanisms. The first step involves enolization of the starting imine, and this is followed by a pseudopericyclic 10-electron [1.4]-hydrogen shift. Finally, the cycloaddition takes place by a relatively asynchronous aromatic six-electron supra-supra thermal mechanism.

Solvent-Free Thermal and Microwave-Assisted [3 + 2] Cycloadditions between Stabilized Azomethine Ylides and Nitrostyrenes. An Experimental and Theoretical Study

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.

Synthesis of Polycyclic Benzofused Nitrogen Heterocycles via a Tandem Ynamide Benzannulation/Ring Closing Metathesis Strategy. Application in a Formal Total Synthesis of (+)-FR900482

Substituent effects on the geometries and conrotatory electrocyclic ring openings of cyclobutenes were studied. This work extends the original investigations to many more substituents and provides a comprehensive theory of substituent effects on geometries and reaction rates. The effects of substitution at the 1 position are minimal; donor substituents raise the activation energy slightly, and powerful acceptor substituents slightly lower the activation energy. Substituents on C3 cause small distortions of the cyclobutene geometry, in the same direction as the favored stereochemistry of reaction. Donors prefer outward rotation, while strong acceptors prefer inward rotation. The activation energy changes and cyclobutene geometrical perturbations were found to correlate with Taft σR0 parameters. Amino, hydroxy, fluoro, chloro, methyl, cyano, formyl, and vinyl substituents were studied in the 1 position. Boryl, dimethylboryl, nitroso, formyl, nitro, carboxyl (neutral, protonated, and deprotonated), cyano, tr...

D. C. Spellmeyer

Papers

Substituent Effects on Rates and Stereoselectivities of Conrotatory Electrocyclic Reactions of Cyclobutenes. A Theoretical Study.