N,O-Acetals are a relevant functional group because of their i) presence in numerous bioactive natural products, ii) role as pro-drugs in medicinal chemistry, and iii) utility as imine surrogates in organic synthesis. We have previously shown that a number of N,O-acetals can be prepared by C–N bond insertion of aldehydes into electronically-activated imides and amides. The conditions required to mediate this reaction involved use of a combination of sodium iodide and a nitrogen base dissolved in a co-solvent system. To avoid the cumbersome nature of these conditions, we have identified alternative conditions that rely on a nucleophilic organocatalyst. The revised protocol is much easier to carry out, and lends itself to use of chiral catalysts to impose stereoselectivity during product formation. Furthermore, the scope of amenable catalysts is quite large, including analogues of DMAP and tetramisole. This presentation will describe experiments related to reaction discovery and optimization. The scope of amenable aldehydes, electronically-activated amides, and catalysts will be also be discussed. Additionally, our working mechanistic hypothesis will be presented along with relevant experimental details.

Organocatalytic synthesis of N,O-acetals by C–N bond insertion of aldehydes into electronically-activated amides

255th National Meeting (2018)

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