Mechanistic Understanding of KO^tBu‐Mediated Direct Amidation of Esters with Anilines: An Experimental Study and Computational Approach

Abstract

A sustainable and cost‐effective protocol has been reported for the synthesis of amide bonds from unactivated esters and non‐nucleophilic amines promoted by potassium tert‐butoxide under aerobic conditions. The reaction proceeds under relatively mild conditions, encompassing wide substrate scope. A combined experimental and quantum chemical study has been performed to shed light on the mechanism, which implied that a radical pathway is operating for the present protocol.

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

“…Finally, additional control experiments and DFT calculation results indicated a 1,3‐chelation of sodium ions with oxygen atoms from esters, while activation of amines by NaO t Bu were included in this process. Besides, KO t Bu‐promoted amidation of esters were reported by other researchers, including ball milling strategy, [90] mechanistic study [91] and phosphoramidates synthesis by direct amidation of triethylphosphate [92] …”

Cyclotrimetaphosphate-assisted ruthenium catalyst for the hydration of nitriles and oxidation of primary amines to amides under aerobic conditions in water

“…For instance, it is estimated that amide moieties are present in more than 25% of currently available drugs 2 and two-thirds of the drug candidates assessed in 2006. 1 f The traditional method for producing amides involves reacting amines with derivatives of carboxylic acids, 3 alcohols, 4 or aldehydes. 5 These techniques, however, are plagued by low atom efficiency, overuse of toxic substances, production of copious waste, and difficulties in separation and purification.…”

“…5 These techniques, however, are plagued by low atom efficiency, overuse of toxic substances, production of copious waste, and difficulties in separation and purification. 3–5 As a result, the ACS Green Chemistry Institute has identified the synthesis of amide bonds with good atom economy as one of the challenging topics in synthetic chemistry. 6 Moreover, the formation of the amide linkage has also been accomplished using several well-known reactions, such as Ugi, 7 Ritter, 8 Wolff, 9 Beckmann, 10 and Schmidt.…”