Small-Scale One-Pot Reductive Alkylation of Unprotected Aminocyclitols with Supported Reagents

Abstract

A protocol for the reductive alkylation of unprotected aminocyclitols with supported reagents and scavengers is described. The method is operatively simple and provides the corresponding secondary amines in high yields and purities.

Key words

alkylations - aldehydes - supported reagents - aminocyclitols

References

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1

On leave from IOCB (Institute of Organic Chemistry and Biochemistry, Prague, Czech Republic).

19

Although the starting aminocyclitol 1 could be removed from the reaction mixture by simple precipitation from MeOH, this was not the case with aminocyclitol 2.

21

The use of supported reagents and scavengers in combinatorial chemistry protocols facilitates workup procedures, allows the use of excess reagents, the reduction of the reaction scale, and avoids the hazards associated to the handling of toxic reagents, such as NaBH₃CN.

22

Several reaction systems were tried. Aminocyclitol 1 is only slightly soluble in MeOH, MeCN, THF, i-PrOH, and dioxane. In our reductive alkylation protocol with PSCBH, addition of H₂O increases the solubility of 1 at the expense of the reaction rate, which became too slow for practical purposes.

24

Despite formation of a putative intermediate oxazolidine, arising from reaction of the initially formed imine with a vicinal hydroxyl group cannot be ruled out,⁷ this did not hamper the reactivity of our DMSO-AcOH system, since aldehyde consumption was complete after 16 hours reaction at r.t.

25

Aldehydes 2a-c and 2j are benzaldehyde derivatives with different electronic properties; 2e,f are α-branched aliphatic aldehydes; 2g and 2h are β-branched (aliphatic or aromatic) aldehydes; and 2i is an example of an heteroaromatic aldehyde.