Structure Ligation Relationship of Amino Acids for the Selective Indole C−H Arylation Reaction: L‐Aspartic acid as Sustainable Alternative of Phosphine Ligands

Abstract

The Structure Ligation Relationship (SLR) of free amino acids (AAs) under Pd‐catalysis were examined for the chemo‐ and regio‐selective indole C−H arylation reactions. While the majority of AAs were minor or ineffective, the L‐aspartic acid (L‐Asp) stands out promising to deliver high‐value C3‐arylated indoles with excellent chemo‐ (C vs N) and regioselectivity (C3 vs C2) with high functional group tolerance. Thus, the protocol offers a cost‐effective and sustainable alternative of phosphine‐based ligands for the indole C3−H arylation reactions. Preliminary mechanistic investigations suggested the simultaneous involvement of −NH2, α‐CO2H, and β‐CO2H functionalities of L‐Asp and found critical for its ligation efficiency. The developed catalytic system was compatible with the tandem decarboxylation/arylation procedure for the chemoselective synthesis of 3‐aryl indoles.magnified image

Recent Progress Concerning the N-Arylation of Indoles

“…Similarly to the palladium-catalyzed arylation of pyrroles, the formation of 1, 2, and 3-arylated indoles can also be observed in the palladium-catalyzed arylation of indoles ( Scheme 13 ) [ 65 , 66 , 67 ]. The regioselectivity of palladium-catalyzed indole arylation can be influenced by the detailed optimization of the reaction conditions.…”

An integrative sustainability assessment of the Tsuji–Trost reaction simulating allylic amination under non-conventional (vs. conventional) conditions

“…Our lab is actively engaged in the development of sustainable organic reactions for diverse applications, including clean pharmaceutical synthesis. [60][61][62][63][64][65][66] In this context, we recently described an elegant Ni(cod) 2 -catalyzed 'in-water' allylic amination protocol with a diverse substrate scope. 61 To the best of our knowledge, there is no existing method that demonstrates a better diversity and adaptability of the substrate scope than this protocol in an aqueous environment, and hence we adopted this protocol as a model reaction and reference method (Method A) for this study.…”

Regioselective C3Alkylation of Indoles for the Synthesis of Bis(indolyl)methanes and 3-Styryl Indoles

“…There are many C 3 functionalization reactions of the indole nucleus being developed and such reactions are conventionally performed under acidic, neutral, or weak basic conditions (Scheme A) . For example, C 3 alkylation of indoles can be performed in the presence of boranes, , phosphoric acid, triflic acid, TFA, , Cu­(OTf) 2 , Co­(acac) 3 , aspartic acid, and TsOH . Lei and Rawal groups independently reported palladium-catalyzed regioselective C 3 –H functionalization of indoles under neutral conditions. In addition, weak bases such as morpholine, pyridine, K 2 CO 3, KOAc, and K 3 PO 4 have also been employed to catalyze direct C 3 alkylation of indoles.…”