Deprotective Functionalization: A Direct Conversion of Nms-Amides to Carboxamides Using Carboxylic Acids

The nature of protecting group chemistry necessitates a deprotection step to restore the initially blocked functionality prior to further transformation. As this aspect of protecting group manipulation inevitably adds to the step count of any synthetic sequence, the development of methods enabling simultaneous deprotection and functionalization ("deprotective functionalization"-distinct from "deprotection followed by functionalization") is appealing, as it has the potential to improve efficiency and streamline synthetic routes. Herein, we report a deprotective functionalization of the newly introduced Nms-amides guided by density functional theory (DFT) analysis, which exploits the inherent Nms reactivity. Mechanistic studies further substantiate and help rationalize the exquisite reactivity of Nms-amides, as other commonly used protecting groups are shown not to exhibit the same reactivity patterns. The practicality of this approach was ultimately demonstrated in selected case studies. We present a concept termed "deprotective functionalization", which we have applied to the coupling of Nms-protected amines with carboxylic acids. Notably, this approach circumvents the need for a dedicated amine-deprotection step and obviates the use of additional reagents for carboxylate activation. The reaction was shown to be, in many cases, superior to deprotection followed by functionalization, both in terms of yield and atom economy. image