Increasing the Reactivity of Amides towards Organometallic Reagents: An Overview

Abstract

The nucleophilic addition of carbon nucleophiles to amides has traditionally been a difficult task, both due to reactivity and selectivity problems. When successful, these processes would represent straightforward routes towards carbonyl‐type or amine compounds, depending on the fate of the generated tetrahedral intermediate. The direct addition of nucleophiles to amides for the preparation of ketones has been studied and applied to the syntheses of several natural products. On the other hand, the addition of nucleophiles to amides to obtain substituted amines represented a major challenge, and only scattered applications on particular substrates have appeared. Initial improvements were based on the activation of amides by introduction of particular substituents, such as in N‐methoxy amides (Weinreb amides) or electron‐withdrawing groups able to increase the carbon nucleophilicity. Although these strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (i.e., carbonyls) are present, thus decreasing the versatility of the methods. In recent years, important advancements towards fully chemoselective methods have been realized. The capture of tetrahedral intermediates with acids generates highly electrophilic iminium species able to undergo chemoselective additions of various nucleophiles, thus accessing substituted amines. Alternatively, the in situ generation of an iminium triflate ion allows highly chemoselective additions of nucleophiles, yielding amines, ketones or ketimines. Also thioamides can be used as precursors of ketones or α‐substituted amines. The success of the above methodologies is further showcased by the application in various syntheses of natural products or biologically active molecules.

Amide Effects in C−H Activation: Noncovalent Interactions with L‐Shaped Ligand for meta Borylation of Aromatic Amides

“…In contrast, although aromatic amides and esters both are important chemical entities, [13] they behave differently in many common organic reactions,except in the metal coordi-nation chemistry, [14][15][16] and results from the different electronic delocalizations of the amide and ester (Scheme 1). Recently,w er eported [11] the para borylation of aromatic esters by an engineered L-shaped ligand (Scheme 2, TS-1).…”

Hydrozirconation of C=X Functionalities with Schwartz's Reagent

“…[18] In chemoselective nucleophilic addition to amides (Scheme 7), independently developed by Charette [19] and Huang, [20] this problem is overcome by the generation of a highly electrophilic imidoyl triflate 12. However, a key problem is the poor electrophilicity of both the amide carbonyl group and the imine species.…”

Telescoped, Divergent, Chemoselective C1 and C1‐C1 Homologation of Imine Surrogates: Access to Quaternary Chloro‐ and Halomethyl‐Trifluoromethyl Aziridines

“…Thep rotocol is highly versatile,c hemoselective,a nd of general applicability,a sd ocumented by the structural diversity of the synthesized compounds.T he following points underline the potential of the methodology: 1) neither the substituents electronic behavior nor their position across the aromatic ring influence the outcome;2)no concomitant halogen-lithium exchange occurs in systems featuring bromine,chlorine,and fluorine (2, 5-7). Nitrogenfeaturing substituents on the aromatic ring such as morpholine (21), ad iazo moiety (22), and al actam (23)f urther demonstrate the potential of the tactic. Taken together these examples showcase the formidable electrophilicity of TFAICs,e nabling the selective homologation exactly at the targeted carbon center.…”