Cobalt Catalyzed α-Hydroxylation of Arylacetic Acid Equivalents with Dioxygen.

A cobalt catalyst, under oxidative conditions, facilitates the single electron transfer process in N-pyridyl arylacetamides to form α-carbon-centered radicals that readily react with molecular oxygen, giving access to mandelic acid derivatives. In contrast to the known benzylic hydroxylation approaches, this approach enables chemo- and regioselective hydroxylation at a benzylic position adjacent to (N-pyridyl)amides. Mild conditions, broad scope, excellent selectivity, and wide synthetic practicality set up the merit of the reaction.

Cooperativity between the Substrate and Ligand in Palladium-Catalyzed Allylic Alkylation Using 1-Aryl-1-propynes.

A monoprotected amino acid Bz-Gly-OH assists in the allylic alkylation of a variety of ketones, ß-keto esters, aldehydes, etc., during enamine-palladium catalysis. Density functional theory calculations reveal that Bz-Gly-OH assists in the formation of an enamine that attacks the π-allylpalladium complex via an outer sphere mechanism. The preliminary result points to an asymmetric allylic alkylation under a new mode of bifunctional catalysis.

Enhancing the Extent of Enolization for α-C-H Bonds of Aliphatic Carboxylic Acid Equivalents via Ion Pair Catalysis: Application toward α-Chalcogenation.

In general, the α-functionalization of carboxylic acid derivatives requires either a transition metal catalyst or a stoichiometric activating agent/strong base/external additive. A transition metal free α-chalcogenation of aliphatic carboxylic acid equivalents is reported herein via ion pair formation using K3PO4 as a catalyst. Mild conditions, broad scope, scalability of the process, attaining bioactive glucokinase activators, and some synthetic intermediates establish merits of the strategy.

Catalytic Direct Cyanomethylenation of C(sp3)-H Bonds via a One-Step Double C-C Bond Formation.

An elegant and catalytic procedure for the one-step cyanomethylenation of C(sp3)-H bonds adjacent to benzazoles and ketones is described herein using DMF as a C-1 unit and TMSCN as the cyanide source. The copper-mediated reaction between DMF and TMSCN gives a cyanomethylene radical intermediate that reacts with 2-alkylbenzazoles or alkylketones to furnish desired cyanomethylenated compounds under palladium catalysis. Subsequent interconversion of cyanomethylenated products makes the protocol synthetically attractive.

Catalytic Direct α-Amination of Arylacetic Acid Synthons with Anilines.

A unique α-amination approach using various anilines has been developed for arylacetic acids via adaptation as benzazoles. The reaction proceeds through a single electron transfer mechanism utilizing an iron-based catalyst system to access α-(N-arylamino)acetic acid equivalents. Modification of approved drugs, facile cleavage of the benzazole auxiliary, and tolerance of amide linkage forming conditions constitute the potential applicability of this strategy.

Catalytic Approaches for the Direct Heterofunctionalization of Aliphatic Carboxylic Acids and Their Equivalents with Group 16 Elements.

In contrast to traditional multistep synthesis, modern organic synthesis extensively depends on the direct functionalization of unactivated C-H bonds for the construction of various C-C and C-heteroatom bonds in atom- and step-economic manner. Common aliphatic substrates, e. g. carboxylic acids and their synthetic equivalents, are regiospecifically functionalized based on either a directed approach, in which the polar directing group assists to functionalize a specific C-H bond positioned at ß- and γ-carbon centers, or a non-directed approach typically leading to α-functionalization. While numerous reviews on catalytic C-H functionalization have appeared, a concise review on the direct C(sp3 )-H heterofunctionalization of carboxylic acid synthons with Group 16 elements has been awaited. The recent advances on the direct oxy-functionalization and chalcogenation of aliphatic carboxylic acid synthons enabled by transition metal, organo- and photocatalysts are described herein.

PdII-Catalyzed methoxylation of C(sp3)-H bonds adjacent to benzoxazoles and benzothiazoles.

The Pd(OAc)2/PhI(OAc)2 catalyst system promotes the highly regioselective dehydrogenative methoxylation of a C(sp3)-H bond adjacent to benzoxazole and benzothiazole rings. The title transformation constitutes the first example of a Pd-catalyzed C(sp3)-H activating methoxylation at the proximal-selective α-position with regard to a directing auxiliary and provides expedient access to an important class of azole-decorated methyl ethers (up to 90% isolated yield). The synthetic practicality of the methodology was demonstrated by achieving α-methoxyacetic acids via the elimination of the benzoxazole auxiliaries and by obtaining the precursor of an O-methylated Breslow intermediate.

Chelation-assisted de-aryloxylative amination of 2-aryloxy quinolines: a new synthetic route to a key fragment of a bioactive PRMT5 inhibitor.

A highly regioselective de-aryloxylative amination of O- or N-chelating group-functionalized 2-aryloxy quinolines has been accomplished by means of a copper catalyst. The chelating functional groups of the substrate play a crucial role in directing the C-2-selective amination process, which proceeds through a novel aromatic nucleophilic substitution of the aryloxy group. The methodology provides expedient access to an important class of functionalized 2-aminoquinolines (up to 88% isolated yield) and was successfully applied for the synthesis of a key fragment of an important bioactive PRMT5 inhibitor.