Directed C–H Functionalization of C3-Aldehyde, Ketone, and Acid/Ester-Substituted Free (NH) Indoles with Iodoarenes via a Palladium Catalyst System

Abstract

Pd(II)-catalyzed C−H arylations of free (NH) indoles including different carbonyl directing groups on C3-position with aryl iodides are demonstrated. Importantly, the reactions are carried out using the same catalyst system without any additional transient directing group (TDG). In this study, the formyl group as a directing group gave the C4-arylated indoles versus C2-arylation. Using this catalyst system, C−H functionalization of 3-acetylindoles provided domino C4-arylation/3,2-carbonyl migration products. This transformation involves the unusual migration of the acetyl group to the C2-position following C4-arylation in one pot. Meanwhile, migration of the acetyl group could be simply controlled and N-protected 3-acetylindoles afforded C4-arylation products without migration of the acetyl group. Functionalization of indole-3carboxylic acid (or methyl ester) with aryl iodides using the present Pd(II)-catalyst system resulted in decarboxylation followed by the formation of C2-arylated indoles. Based on the control experiments and the literature, plausible mechanisms are proposed. The synthetic utilities of these acetylindole derivatives have also been demonstrated. Remarkably, C4-arylated acetylindoles have allowed the construction of functionalized pityiacitrin (a natural product).

Acetoxy Group-Directed Regioselective C2 Alkenylation of Indoles via Pd–Ag Bimetallic Catalysis

“…The C3-acetoxy group has the ability to form a variety of metallocycles with Pd(II) as well as the other metal salts present in the reaction medium during the course of the C−H activation reaction, which ultimately governs the regioselectivity. 17 Again, such catalysis has been previously reported to proceed through the help of Pd−Ag cooperativity 27,28 via a bimetallic catalytic species. We mixed Pd(OAc) 2 and Ag 2 CO 3 in a 1:1 ratio at ambient temperature to explore this possibility.…”

Transition-Metal-Catalyzed Directing-Group-Assisted C4-H Carbon–Carbon Bond Formation of Indole

“…Further, a Pd(II)-catalyzed C4-arylation of NH-free indoles has been shown with aryl iodides employing formyl, acetyl, carboxylic acid, and ester functionalities at the C3-site as DG. 45 Using AgOAc as an oxidant and TFA as an additive, the desired arylation was achieved with excellent selectivity.…”

Engineering Saccharomyces cerevisiae for the de novo Production of Halogenated Tryptophan and Tryptamine Derivatives

“…[17] The addition of directing groups to the indole ring can also facilitate halogen-ation at the benzene ring, however, this strategy is associated with additional synthetic steps and reduced atom economy. [17][18] Therefore, catalyst-controlled methods employing enzymes that perform site-selective halogenations is emerging as a promising approach in synthetic chemistry, as they provide a means to overcome the electronic preference for substitution at the 2-and 3-positions. [19] Among multiple classes of halogenating enzymes found in nature, flavin-dependent halogenases (FDHs) stand out for their marked substrate specificity and regioselectivity.…”

“…Although multiple methods for the halogenation of indole heterocycles exist, these often involve the use of toxic reagents like transition metals, [15] generate significant amounts of by‐products, [16] and the regioselectivity is mostly achieved only at the 2‐ and 3‐positions on the indole ring [17] . The addition of directing groups to the indole ring can also facilitate halogenation at the benzene ring, however, this strategy is associated with additional synthetic steps and reduced atom economy [17–18] .…”

“…Although multiple methods for the halogenation of indole heterocycles exist, these often involve the use of toxic reagents like transition metals, [15] generate significant amounts of by‐products, [16] and the regioselectivity is mostly achieved only at the 2‐ and 3‐positions on the indole ring [17] . The addition of directing groups to the indole ring can also facilitate halogenation at the benzene ring, however, this strategy is associated with additional synthetic steps and reduced atom economy [17–18] . Therefore, catalyst‐controlled methods employing enzymes that perform site‐selective halogenations is emerging as a promising approach in synthetic chemistry, as they provide a means to overcome the electronic preference for substitution at the 2‐ and 3‐positions [19] .…”