Tungsten-Catalyzed Transamidation of Tertiary Alkyl Amides

Abstract

Transamidation has recently emerged as a straightforward and convenient means to diversify amides. However, the kinetically and thermodynamically demanding transamidation of notoriously robust, fully alkyl-substituted tertiary amides still remains a longstanding challenge. Here, we describe a method for the activation of tertiary alkyl amides to streamline transamidation using simple tungsten­(VI) chloride as a catalyst and chlorotrimethylsilane as an additive. The highly electrophilic and oxophilic tungsten catalyst enables the selective scission of a C–N bond of tertiary alkyl amides to effect transamidation of a myriad of structurally and electronically diverse tertiary alkyl amides and amines. Mechanistic study implies that the synergistic effect of the catalyst and the additive could pronouncedly induce the nucleophilic acyl substitution of tertiary alkyl amide with amine to realize transamidation.

Environmentally Benign Transamidation Protocol for Weakly Nucleophilic Aromatic Amines with N‐Acyl‐2‐piperidinones: Catalyst‐, Additive‐, Base‐ and Solvent‐Free Condition

“…[4,5] Nevertheless, amides are attractive feedstock for chemical transformation owing to high availability and versatility. [6] Mostly, amide CÀ N bond activation and cleavage are realized by a suitable catalytic system and/or by activation protocols. Among the existing methods, transamidation, a process in which a new amide is generated from an amide and amine, identified as a powerful synthetic tool for amide formation and diversification, offering a new and alternate retrosynthetic approach for chemical transformation.…”

“…Among the existing methods, transamidation, a process in which a new amide is generated from an amide and amine, identified as a powerful synthetic tool for amide formation and diversification, offering a new and alternate retrosynthetic approach for chemical transformation. [6] Typically, amides are generated by the condensation of activated carboxylic acids with amines. [7,8] In the recent past, transamidation has been developed as a viable alternate for amide bond formation.…”

“…Therefore, to achieve the task, harsh conditions such as high reaction temperature, long reaction time, or stoichiometric number of activating agents were employed to realize transamidation. [6] However, in the last two decades, various strategies have been adopted to effect transamidation with aromatic amines under relatively milder conditions. For example, N-activation by acylation/tosylation, [12,5] N-activation-metal catalyzation, [5,9,13,14] amide bond twist, [4,15] and amide bond twist-metal catalyzation.…”

A CO2-Catalyzed Transamidation Reaction

“…Amides are one of the most important organic functional groups constituting biological and artificial polymers and bioactive organic molecules. There is, therefore, a significant interest in amide-bond formation and functionalization beyond conventional peptide coupling reagents. − Recent developments in amide bond formation reactions have shown novel catalytic protocols and atom-economic activating reagents for carboxylic acid substrates to access carboxylic amides. , Alternatively, transamidation reactions, in principle, can offer straightforward methods to prepare various amides from a single amide donor and amine nucleophiles. ,− However, transamidation reactions are challenging due to the stability of the amide bonds in the starting materials, a potential reverse reaction governed by the thermodynamic stabilities of the reactants and products, and potential amidine formation reactions in the presence of an excess of amine nucleophiles and metal catalysts …”

“…Lewis acidic metals can activate amide bonds for transamidation reactions, as initially reported by Bertrand with AlCl 3 in overstoichiometric amounts (2.3 equiv) . Later, Lewis acidic transition metals − (i.e., Al, Ti, Zr, Sc, Ni, and WCl 6 /TMSCl) were proven to be efficient catalysts for amide activation (Figure a). A faster transamidation reaction was realized under equilibrium conditions, implying potential applications of transamidation in dynamic combinatorial chemistry of covalent amide bonds under catalytic conditions .…”