In this review, applications of the amide reductive functionalization methodology for the synthesis and modification of bioactive compounds are covered. A brief summary of the different protocols is presented in the introduction, followed by the synthetic application of these in late-stage functionalization, leading to known pharmaceuticals or to their derivatives, including bioisosteres, with potential higher activity as the main axis of the article. The synthetic approach to natural products based on amide reduction is also discussed; however, this is given in a condensed form focusing on recent or as yet unexplored applications due to a number of recently published excellent reviews covering this topic. The aim of this review is to illustrate the potential of reductive functionalization of amides as an elegant and useful tool in the synthesis of bioactive compounds and inspire further work in this field.

A direct protocol for the synthesis of functionalized amines from simple fluoroacetic acid-derived amides using Schwartz's reagent was presented.

The inexpensive and commercially available chlorosulfonyl isocyanate reacts readily with the variety of nucleophilic olefins to provide unstable [2+2]cycloadducts. The reaction proceeds via concerted mechanism rather than a stepwise process. The electron-donating substituent in the olefin component controls the regiochemistry of the reaction. The cycloaddition is stereospecific, leading from (Z)-olefin to the cis-adduct and from (E)-olefin to the trans-adduct. Increase of the reaction time or the presence of an acid contamination may result either in the epimerization at C(4) of the azetidin-2-one ring or in the rearrangement leading to the opening of the fourmembered ring. The N-deprotection of the [2+2]cycloadducts by reduction of the chlorosulfonyl group results in the formation of stable azetidin-2-ones, useful synthons in the synthesis of β-lactam antibiotics. The discussed reactions are sterically controlled and in many cases take place with a high asymmetric induction. Due to the observed exothermic nature of the cycloaddition, the conformation of the olefin in the transition state resembles, with a high probability, the low-energy ground-state conformation.