Ketene aminals 2 molecules

The amination of ketenes to produce amides (see Scheme 1) has been subjected to a variety of computational methods, including several treatments of the solvent, with explicit roles for actively participating amine and water molecules. All the results favour a two-step process with initial addition to the C=0 bond, rather than a concerted reaction involving the C=C bond. The former involves a 1-amino-1-hydroxy ene intermediate (6), formally the enol of the amide. Inclusion of a second amine molecule lowers the barrier to the two-step reaction. Replacing the second amine with a water molecule lowers it even further, an effect which should be even greater when water is the bulk solvent. Some experimental evidence is presented for the highly hindered substrates, bis(mesityl)ketene and bis(pentamethylphenyl)ketene. Addition of primary or secondary amines clearly shows, from IR and UV spectra, the build-up and subsequent tautomerization of the intermediate enols. The kinetics of these more hindered substrates are first order in amine this is not inconsistent with the theoretical results, as such hindered ketenes may only react rather slowly with amine dimer, which is also in low concentration under the conditions used. 

The preparation of optically active /Mactams by asymmetric synthesis is also a topic of major interest, because of the pharmaceutical and biochemical importance of those molecules [44]. A typical and economical route consists of a [2+2]-cycloaddition of a ketene to an imine. Many diastereoselective versions of this reaction type are known [45] as well as catalytic processes involving chiral (metal) catalysts [46, 47] or biocatalysts [48]. A [2+2]-cycloaddition of a ketene to an imine, however, can also be performed very efficiently when applying nucleophilic amines as chiral catalysts [49-60]. Planar-chiral DMAP derivatives have also been found to be suitable catalysts [61]. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

The product of the elimination is a substituted ketene—a highly reactive species whose parent structure is the molecule CH2=C=0 that you will meet in the next chapter. It is the ketene that reacts with the amine to form the amide. 

Although this reaction is still at an early stage of development, a few modifications have been exploited. These modifications include the extension of the Bellus-Claisen rearrangement to ring strain molecules (such as 2-vinyloxetane, 2-vinyloxirane, and 2-vinylaziridines ) and to tertiary allyl amines, the application of chiral Lewis acid derived from Mgl2 and bis(oxazolinyl)aryl ligands, and the implementation of electron-rich ketene equivalents (e.g., alkoxyketenes, aminoketenes) by the photolysis of chromium carbene complexes. 

A pyrone 32 can be obtained from the reaction of two molecules of ketene and one of enamine 31 and loss of amine (Scheme 13) (1965JOC2642). 

What is the mechanism of the coupling reaction of Rgure 23.47 Remember that other cumulated double bonds (p. 512) such as ketenes (p. 515), isocyanates (p. 918), and isothiocyanates (p. 1198) all react rapidly with nucleophiles. The related DCC is no exception, and it is attacked by amines to give molecules called guanidines. Carboxylates are nucleophiles too, and will also add to DCC (Fig. 23.48). 

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