Decarboxylative Triazolation Enables Direct Construction of Triazoles from Carboxylic Acids

Abstract

Triazoles have major roles in chemistry, medicine, and materials science, as centrally important heterocyclic motifs and bioisosteric replacements for amides, carboxylic acids, and other carbonyl groups, as well as some of the most widely used linkers in click chemistry. Yet, the chemical space and molecular diversity of triazoles remains limited by the accessibility of synthetically challenging organoazides, thereby requiring preinstallation of the azide precursors and restricting triazole applications. We report herein a photocatalytic, tricomponent decarboxylative triazolation reaction that for the first time enables direct conversion of carboxylic acids to triazoles in a single-step, triple catalytic coupling with alkynes and a simple azide reagent. Data-guided inquiry of the accessible chemical space of decarboxylative triazolation indicates that the transformation can improve access to the structural diversity and molecular complexity of triazoles. Experimental studies demonstrate a broad scope of the synthetic method that includes a variety of carboxylic acid, polymer, and peptide substrates. When performed in the absence of alkynes, the reaction can also be used to access organoazides, thereby obviating preactivation and specialized azide reagents and providing a two-pronged approach to C–N bond-forming decarboxylative functional group interconversions.

Photocatalytic Hydrodecarboxylation of Fatty Acids for Drop‐in Biofuels Production

“…Acridines are inexpensive reagents and have been previously proved to be efficient for the decarboxylation of carboxylic acids, generating alkyl radicals that can further engage in a series of organic transformations. Moreover, acridines are known to afford alkyl radicals directly from carboxylic acids via a proton‐coupling electron transfer (PCET) mechanism not requiring the preformation of carboxylates, thus avoiding the addition of base in the reaction [22–29] . Under the initial conditions, we were pleased to observe the hydrodecarboxylation of 1 a affording n‐undecane ( 2 a ), an alkane in the range of biofuels such as green diesel and biojet fuel, albeit in only 16 % yield.…”

“…Moreover, acridines are known to afford alkyl radicals directly from carboxylic acids via a proton-coupling electron transfer (PCET) mechanism not requiring the preformation of carboxylates, thus avoiding the addition of base in the reaction. [22][23][24][25][26][27][28][29] Under the initial conditions, we were pleased to observe the hydrodecarboxylation of 1 a affording n-undecane (2 a), an alkane in the range of biofuels such as green diesel and biojet fuel, albeit in only 16 % yield. Solvent optimization (See SI) revealed that a mixture of CH 2 Cl 2 /H 2 O (9 : 1) was the optimal solvent system and 2 a was obtained in 37 % yield (Table 1, entry 2).…”

“…Our proposed mechanism for this transformation is based on previously reported work for photocatalytic hydrodecarboxylation of carboxylic acids as depicted in Scheme 2 [20,22,28,29] . First, a complex between the carboxylic acid and acridine via hydrogen bonding is formed ( 3 ).…”

“…Our proposed mechanism for this transformation is based on previously reported work for photocatalytic hydrodecarboxylation of carboxylic acids as depicted in Scheme 2. [20,22,28,29] First, a complex between the carboxylic acid and acridine via hydrogen bonding is formed (3). This complex (3) is then photoexcited and promotes a PCET, giving Acr-II * (4) and an alkyl radical (9) after decarboxylation of (8).…”

Visible‐Light Photoredox Catalysis in the Late‐Stage Functionalization of Anticancer Agents

“…O. V. Larionov and co‐workers [83] reported a decarboxylative triazolation reaction that allows for the direct conversion of carboxylic acids to triazoles by using a tricomponent coupling with alkynes and a straightforward azide reagent. This synthetic protocol includes the chemical reaction between carboxylic acid 71 , alkyne 72 and potassium azide 73 , catalyzed by acridine and a copper(I) salt in the presence of mixture of acetonitrile and trifuorotoluene and tert‐butyl perbenzoate (TBPB) as an oxidant under 400 nm LED light to give the desired product 74 with excellent yield (Scheme 17).…”