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.

Bioinspired Functionalization of Carbonyl Compounds Enabled by Metal Chelated Bifunctional Ligands.

In Nature, enzymatic reactions proceed through exceptionally ordered transition states giving rise to extraordinary levels of stereoselection. In those reactions, the active site of the enzyme plays crucial roles - through one position, it holds the substrate in the proximity to the reaction epicentre that facilitates both the reactivity and stereoselectivity of the chemical process. Inspired by this natural phenomenon, synthetic chemists have designed bifunctional ligands that not only coordinate to a metal centre but also preassociate with an organic substrate, for example aldehyde and ketone, and exerts stereodirecting influence to accelerate the attack of the incoming reacting partner from a particular enantiotopic face. The chief goal of the current review is to give an overview of the recently developed approaches enabled by privileged bio-inspired bifunctional ligands that not only bind to the metal catalyst but also activates carbonyl substrates via organocatalysis, thereby easing in the new bond forming step. As carbonyl α-functionalizations are dominated by enamine and enolate chemistry, the current review primarily focusses on enamine- and enolate-metal catalysis by bifunctional ligands. Thus, developments based on traditional cooperative catalysis occurring through two directly coupled but independent catalytic cycles of an organocatalyst and a metal catalyst are not covered.

Catalytic cascade synthesis of cyanohydrin esters via water/O2-induced cyanide transfer from K3Fe(CN)6.

The copper-catalyzed α-oxygenation of aryl benzyl ketones is merged with a unique water/O2-induced release of cyanide ions from K3Fe(CN)6 and a benzil-cyanide reaction. This strategy gives expedient access to cyanohydrin esters starting directly from broadly accessible aryl benzyl ketones. The cyanide release strategy was further integrated with a copper catalyzed oxygenation-decarbonylation sequence to produce cyanohydrin esters from 1,3-diketones.

Exploring amine-rich supramolecular silver(I) metallogels for autonomous self-healing and as catalysts for a three component coupling reaction.

A series of Ag(I) supramolecular organo-aqueous gels have been synthesized in the presence of an amine-rich triazole ligand as a gelator. Judicious choice of the triazole derivative and counter anion allows a desired spatial orientation of the pendant amine functionality to accentuate the gelation ability and autonomous self-healability via hydrogen bonding. In addition, the hydrogen bond donors, i.e. pendant -NH2 groups, offer a critical proximity of counter anions to the Lewis acidic Ag(I) and the reactants for promoting a three component coupling reaction of an aldehyde, a terminal alkyne and an amine, giving expedient access to propargyl amines, with remarkable functional group tolerance for both aromatic and aliphatic aldehydes, and aryl acetylenes. Experiments substantiate the pivotal role of counter anions and H-bonding interactions in the observed preference for propargylamines over the diacetylene by-product. Our catalyst is robust, bench-stable, and recyclable, and demonstrates a catalytic efficiency comparable to or better than those of reported systems. The catalyst was found equally effective for the gram-scale synthesis of propargylamines. Our approach lies at the intersection of metal-based, H-bond-mediated counter anion-tuned catalysis, evincing a potential for the development of purpose-built supramolecular gels for desired catalytic applications in the future.

Recent advances in catalytic decarboxylative transformations of carboxylic acid groups attached to a non-aromatic sp2 or sp carbon.

Chemists learn the most important transformations of the carboxylic acid functionality (COOH) from as early as the first semester of their studies. Carboxylic acids are not only safe to store and handle, but also broadly accessible with great structural diversity either from commercial sources or by means of a large variety of well-known synthesis routes. Consequently, carboxylic acids have long been recognized as a highly adaptable starting material in organic synthesis. A large body of reactions of carboxylic acids are based on catalytic decarboxylative conversions, in which the COOH group of carboxylic acids is catalytically replaced without trace by extrusion of CO2 chemo- and regioselectively. Within the last two decades, the area of catalytic decarboxylative transformations has expanded significantly by utilizing various classes of carboxylic acids as the substrate, including (hetero)aromatic acids, alkyl acids, α-keto acids, α,ß-unsaturated acids and alkynoic acids. A literature survey reveals that compared to aromatic acids, the number of original research papers on decarboxylative reactions of α-keto acids, α,ß-unsaturated acids and alkynoic acids has been rising every year lately, particularly within past five to six years. The prime aim of the current review is to give an overview of the decarboxylative transformations of α-keto acids, α,ß-unsaturated acids and alkynoic acids that have been developed since 2017. The article focuses on the decarboxylative functionalizations that occur in the presence or absence of transition metal catalysts and/or under photoredox catalysis.

Catalytic Methylene Insertion between Amines and Terminal Alkynes via C-N Bond Cleavage of N,N-Dimethylacetamide: A Unique Route to Propargylic Amines.

A copper-based system allows for the methylene insertion between an amine and a milder nucleophile, including a terminal alkyne counterpart, via C-N bond cleavage of N,N-dimethylacetamide. The method gives an expedient access to propargylic amines in good to excellent yields. A wide-ranging substrate scope and late-stage functionalization of complex molecules make the protocol practically valuable.

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.

Direct α-Chalcogenation of Aliphatic Carboxylic Acid Equivalents.

A novel approach to α-chalcogenation of aliphatic carboxylic acids has been developed by means of transforming them as the corresponding benzazoles. The catalyst system, consisting of CuI, DMSO, and a base, operates through a unique mechanism to access a range of practically significant thio- and selenoethers that are otherwise challenging to achieve. The applicative potentials have been exemplified by utilizing the resultant chalcogenated compounds as the precursor for the synthesis of biologically pertinent molecules and synthetic intermediates.

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.

Substrate Directed Asymmetric Reactions.

Historically, reagent controlled reactions (mechanism controlled reactions) have played a significant role in the asymmetric synthesis of complex structures. In contrast, today's asymmetric synthesis is greatly dependent on substrate directed approaches. In this approach, a polar functional group, namely, a "directing group", in the vicinity of the reactive site inside the substrate has been documented to preassociate with the chiral catalyst, which exerts stereodirecting influence by directing the reacting partner toward one of the enantiotopic faces of the reaction center. Those reactions usually proceed through exceptionally ordered transition states and result in extraordinary levels of stereoselection. Within the last four decades, the substrate directed approach has become an indispensible tool for the preparation of complex chiral frameworks starting directly from relatively simple achiral substrate molecules via asymmetric induction or various resolution techniques or both. Likewise, the substrate directed approach has been applied to functionalize enantiopure substrates bearing pre-exisiting stereocenters into complex structures as a single diastereomer. A classical example is Sharpless asymmetric epoxidation of allylic alcohols in which the free hydroxy function acts as an active anchor to a dimeric Ti-catalyst that controls the stereochemical outcome of the epoxidation process by transferring the oxidant enantioselectively. The principal aim of the present review is to give a general overview of substrate directed asymmetric transformations, a topic that has not yet been documented in the form of a concise review of recently developed approaches. Due to the large number of related applications, only recent advances that have been documented within the last two decades have been reviewed. Furthermore, in the current review, we have mainly highlighted asymmetric reactions that are controlled by abundant and frequently used directing groups such as hydroxy, amide, and sulfonamide groups. In addition, selected examples of a few important substrate-directed chemo-, regio-, and diastereoselective reactions have also been included in this review.

Catalytic Asymmetric Synthesis of N-Chiral Amine Oxides.

Direct asymmetric synthesis of N-chiral amine oxides was accomplished (up to 91:9 e.r.) by means of a bimetallic titanium catalyst. A hydroxy group situated at the γ-position of the N stereocenter enables the desired N-oxidation through dynamic kinetic resolution of the trivalent amine substrates. The method was further extended to the kinetic resolution of racemic γ-amino alcohols with a preexisting stereocenter, giving an important class of enantioenriched (up to 99.9:0.1 e.r.) building blocks that are otherwise difficult to synthesize.

Design of a New Bimetallic Catalyst for Asymmetric Epoxidation and Sulfoxidation.

A new chiral tethered 8-quinolinol-based ligand class is developed. The binuclear titanium complex of the ligand operates through a novel mechanism allowing for the regio- and stereoselective epoxidation of primary and tertiary homoallylic alcohols (up to 98% ee), as well as first examples of 2-allylic phenols (up to 92% ee). The new catalyst system also promotes the asymmetric oxidation of γ-hydroxypropyl sulfides giving an important class of chiral sulfoxides that have been inaccessible to date (up to 95% ee).

Heterogeneous Cu(II) -catalysed solvent-controlled selective N-arylation of cyclic amides and amines with bromo-iodoarenes.

A selective N-arylation of cyclic amides and amines in DMF and water, respectively, catalysed by Cu(II) /Al2 O3 has been achieved. This protocol has been employed for the synthesis of a library of arenes bearing a cyclic amide and an amine moiety at two ends, including a few scaffolds of therapeutic importance. The mechanism has been established based on detailed electron paramagnetic resonance (EPR) spectroscopy, X-ray photoelectron spectroscopy (XPS), UV diffuse reflectance spectroscopy (DRS) and inductively coupled plasma-mass spectrometry (ICP-MS) studies of the catalyst at different stages of the reaction. The Cu(II) /Al2 O3 catalyst was recovered and recycled for subsequent reactions.