Imine formation methylbenzylamine

Enantiomerically pure neopentylamine derivatives have been prepared from the corresponding ketones by a four-step sequence involving imine formation with (R)-a-methylbenzylamine followed by a highly diastereoselective reduction with sodium borohydride62. 

When benzyl halide 1 is treated with HMTA, the first step was the straightforward formation of hexaminium salt 2. In the presence of water, an isomer of 2, iminium 7, is hydrolyzed to give hemiaminal 8. Fragmentation of 8 affords iminium 9, which collapses to benzylamine 4 and formaldehyde. Condensation of benzylamine 4 and formaldehyde provides another key intermediate, aldimine 5. The crucial key oxidation-reduction process takes place between 4 and 5 with the exchange of two equivalents of hydride, giving rise to methylbenzylamine 10 and imine 11, which is subsequently hydrolyzed to benzaldehyde 3. 

In early work, Lassaletta et al. described a DKR reaction coupled to the formation of primary amines [98], In a related process, an efficient ATH reaction was reported for the synthesis of an advanced intermediate to a drug for the treatment of human papillomavims infections (Fig. 28). This involves an interesting exo—C=N reduction in an in situ process. The formation of an imine followed by a reduction using a Ru(II)/BlNAP complex was also investigated, as was a diastereoselective method using alpha-methylbenzylamine as a directing group [99]. 

Subsequent experiments showed that piperidine with D-fructose gave D-glu-cose, and that morpholine, dicyclohexylamine as well as tertiary amines converted D-fructose into D-psicose without detectable formation of Heyns rearrangement products. Employing secondary amines such as pyrrolidine, the corresponding Heyns rearrangement products could be obtained very easily, contrasting results with other cyclic amines, for example, piperidine, hexame-thylene imine (azepane) and other open-chain amines such as dimethyl-, diethyl-, or methylbenzylamine, which did not react [105]. 

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