Studies On The Stereoselectivity In The Staudinger Reactions Involving Monosubst Ituted Ketenes With Electron Acceptor Substituents

The Staudinger reaction (also called the Staudinger cycloaddition or the ketene-imine cycloaddition) is a versatile method to synthesize very importantβ-lactams, which are key structural elements in some antibiotics and synthetic intermediates as well. The mechanism of the Staudinger reaction includes two major steps, an imine attacks a ketene to generate a zwitterionic intermediate and the ring closure of the zwitterionic intermediate.Staudinger reactions involving monosubstituted ketenes with electron donor groups (EDGs) have been investigated thoroughly in both experiments and the theoretical calculation, in which the steric and torquoelectronic effects are consistent in the stereoselective control. Thus, torquoselectivity is applicable to the Staudinger reactions. However, the reactions involving monosubstituted ketenes with electron-acceptor groups (EAGs) have been seldom explored until now. To get a thorough understanding on the stereoselectivity and to summarize a general rule for the stereoselectivity in various monosubstituted ketene participating in Staudinger reactions, we studied the Staudinger reaction involving the monosubstituted ketenes with various electron-acceptor groups experimentally.The main achievements are as follows:1 After comparative analysis of the stereostructure of the products in the reactions involving ketenes with electron-acceptor substituents with cyclic and acyclic imines, the results suggest that imines attack ketenes from their exo-sides to generate zwitterionic intermediates, of which the imine moiety undergoes an isomerization for linear imines. The (isomerized) zwitterionic intermediates further undergo a conrotatory ring closure to afford the correspondingβ-lactams. The torquoelectronic effect does not affect the stereoselectivity in the practical monosubstituted ketene-participating in Staudinger reactions. The stereoselectivity of the Staudinger reactions involving monosubstituted ketenes is controlled by steric hindrance instead of the torquoelectronic effect. 2 A series of 2,3,6-trisubstituted 2H-1,3-oxazin-4(3H)-one derivatives were expeditiously synthesized in satisfactory to good yields from the reaction of imines and 2-diazo-3-oxoalkanals under the catalysis of tertiary amine during several seconds under mild condition. Different bases andα-diazo-β-dicarbonyl compounds were also evaluated, indicating that less steric tertiary amines are efficient catalysts and 2-diazo-3-oxoalkanals are suitable acylketene precursors. A reaction mechanism was proposed in which tertiary amines induce Wolff rearrangement of 2-diazo-3-oxoalkanals to generate acylketenes, which further undergo a heteroatom Diels-Alder reaction to yield 2,3,6-trisubstituted 2H-1,3-oxazin-3(4H)-ones. Compared with the corresponding thermal- and photo-induced reactions, the current method is a metal-free, mild, highly regioselective, and more efficient approach to synthesis of 2H-1,3-oxazin-4(3H)-one derivatives. 3 3-Alkoxy/aryloxy-β-lactams have been synthesized conveniently in satisfactory to good yields by the way of the photo-induced Staudinger reaction of imines and alkyl/aryl diazoacetates. Initially, the diazoacetates generated alkoxy/aryloxyketenes, via the photo-induced Wolff rearrangement, which underwent subsequent Staudinger reactions with various imines to give the desiredβ-lactam products. Compared with the corresponding thermal Staudinger reaction, in which the ketenes produced through base-mediated elimination of the corresponding alkoxy/aryloxyacetyl chlorides, or their equivalents, gave cis-β-lactams as the major or sole products, the current method provides in most cases, trans-β-lactams predominantly from linear imines. The formation of trans-β-lactams from linear imines is attributed to isomerization of the imines from their trans-isomers into their syn-isomers under UV irradiation. The present method represents a neutral approach to synthesize 3-alkoxy/aryloxy-β-lactams via the Staudinger reaction.