Ketene-imine reaction pathway

This effect has recently been explained by considering that under microwave irradiation the route involving direct reaction between the acyl chloride and the imine competes efficiently with the ketene-imine reaction pathway, a situation highlighted by theoretical calculations (Scheme 9.69) [42 a],... 

The existence of the zwitterionic intermediates has been inferred from the results of trapping experiments and by direct observation of zwitterionic intermediates that are unable to complete the cyclization to a P-lactam. Generation of the zwitterion 7 from ketene 5 and imine 6, followed by in situ trapping with sulfur dioxide, afforded the thiazolidine-4-one 1,1-dioxide 87 Similarly, reaction of the formamidate 10 with ketene 9 generated in situ by pyrolysis of the acylal afforded the formamide diethylacetal 12 upon trapping with ethanol, which suggests the intermediacy of the zwitterion 11 in this reaction pathway ... 

The reaction of a monosubstituted ketene with an aldimine produces two new stereocenters, C3 and C4, in the P-lactam ring. The substituents on these two carbon atoms may therefore be cis or trans to each other, and the reaction of any particular pair of ketene and imine may afford the cis P-lactam, the tra 5-P-lactam, or a mixture of the two. The importance of P-lactams as antibacterial agents has resulted in extensive effort to understand the diastereoselectivity of the Staudinger reaction. The two-step nature of the reaction pathway has made the interpretation of experimental results more difficult and increased the number of possible contributing factors. 

The lactam is an important class of heterocycles and has been investigated due to its potent anti-bacterial activity. Among the multiple synthetic approaches, a [2 -i- 2] cycloaddition of a ketene with an imine, is one method to provide quick access to cis P lactams. The typical prerequisite for these protocols involves the generation of the ketene from an activated carboxylic acid derivative (often an acyl chloride), which limits the scope of this pathway. Lee and coworkers developed a rhodium-catalyzed oxygenative addition reaction that furnishes the acyl chloride equivalent from a more stable terminal alkyne 41. An intermediate rhodium vinylidene then undergoes a [2 -i- 2] cyclization with imines (42) to provide the P-lactam 4. This reaction pathway enables more easily accessible alkynes to be employed as substrates for tran -P-lactam formation. 

Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cycloadditions have to be antarafacial on one component and the geometrical and orbital constraints thus imposed ensure that this process is encountered only in special circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise pathway involving diradical or zwitterionic intermediates [la]. Considerably fewer studies have been performed regarding the application of microwave irradiation in [2+2] cydoadditions than for other kinds of cydoaddition (vide supra). Such reactions have been commonly used to obtain /1-lactam derivatives by cycloaddition of ketenes with imines [18-20,117,118],... 

Very recently, an experimental study reported by Xu et al. [65] has highlighted the importance of the isomerization pathways in the reaction between ketenes and imines. According to this analysis, the cis/trans ratio is closely related to the rate constants of the direct ring closure (ki) and the isomerization of the zwitterionic intermediate (58) (k2), as indicated in (2) and Scheme 13. 

More recently, we have found that the role of the isomerization pathways in the reaction between ketenes and imines can be extended to the (E)/(Z) isomerization of imines themselves [68]. Thus, the stereocontrol observed in the reaction between methoxyketene 41 and (E)-imines (62a,b) was attributed to the competition between the energy barriers associated with the formation of intermediates (63a,b) and (65a,b) and the energies of activation corresponding to the isomerisation of (E)-imines (62a,b). Inclusion of isomerisation processes involving both imines (62a,b) and zwitterionic intermediates (63a,b) and (65a,b) led to a more complex kinetic analysis. As the final steps leading to (3-lactams (64) can be considered irreversible, the formation of both cis- and trans-(64) can be described by (3) and (4) ... 

There is a general agreement on the stepwise nature of the [2+2] cycloaddition between ketenes and imines. The first step consists of a nucleophilic attack of the iminic lone pair on the v/ -hybridized atom of the ketene to form a zwitterionic intermediate. The subsequent four-electron conrotatory electrocyclization leads to the corresponding (3-lactam. The final stereochemical outcome of the reaction depends on the combination of the following features (1) endo/exo attack of the imine on the ketene (2) inward outward disposition of the substituents at the conrotatory transition structure and (3) relevance of the isomerization pathways, including those of the starting imines. 

A general overview about advances in the catalytic, asymmetric synthesis of -lactams can be found in an article written by Thomas Lectka, 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 P-lactams and asymmetric induction from the ketene component. The influence of solvents and additives and the pathways of ketene generations and addition modes on the stereoselectivity. 

Tentative rationalizations of these stereochemical results have been offered on the basis of a mechanism involving a ketene intermediate reacting with an imine. However, it is by no means proven that all these reactions involve an intermediate ketene. Several pathways can lead from an acid chloride, an imine and triethylamine to a -lactam (Scheme 11). Thus the origin of the stereochemical selection in these multistep processes is not very well understood. 

The thermal [2-1-2] cycloaddition of cumulenes with alkenes, imines or carbonyl compounds is one of the most useful methods of four-membered ring formation. The cycloaddition of ketenes with alkenes to give cyclobutanones represents a reaction of general importance. According to Woodward and Hoffmann, these reactions proceed via a [ttIs+ttIi,] pathway [24]. Dihaloketenes are more reactive than simple ketenes and readily react with electron-rich olefins [25]. 

Photocyclization of NA -bisbenzylmethacrylamide (12) proceeds by cleavage of the biradical (13) to give dimethylketen and the imine, which recombine. A small amount of (14) results from the reaction of the keten with amine that is produced by hydrolysis of the imine. With di-isopropylmethacrylamide this photodealkylation is the major pathway, the alkylimine being less efficient in [2 + 2] addition to the keten.An unprecedented type II conversion is observed in the selective formation of jS-lactams in the solid-state irradiation of HN-dialkyl-a-oxoamides (15). In solution, other processes complicate the reaction. 

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