Hydroalkylation of styrenes enabled by boryl radical mediated halogen atom transfer.

In this study, we present an inexpensive, stable, and easily available boryl radical source (BPh4Na) employed in a Halogen Atom Transfer (XAT) methodology. This mild and convenient strategy unlocks the use of not only alkyl iodides as radical precursors but also of the more challenging alkyl and aryl bromides to generate C-centered radicals. The generated radicals were further engaged in the anti-Markovnikov hydroalkylation of electronically diverse styrenes, therefore achieving the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. A series of experimental and computational studies revealed the prominent role of BPh4Na in the halogen abstraction step.

Going with the µFlow: Reinterpreting Energy Input in Organic Synthesis.

The popularity of microflow chemistry has skyrocketed in the last 20 years, more and more chemists are switching from macro-batch reactors to miniaturized flow devices. As a result, microfluidics is paving its way into the future by consolidating its position in organic chemistry not only as a trend but as a new, effective, and sustainable way of conducting chemistry, that clearly will continue to grow and evolve. This perspective highlights the most relevant examples of innovative enhancing technologies applied to microflow reactors aimed to improve and intensify chemical processes. The extensive applicability of microflow chemistry is further illustrated by briefly discussing examples of complex integrated microsystems and scale-up technologies, demonstrating ultimately that microflow chemistry has the potential to become the ideal technology for the future.

Light-Driven Four-Component Reaction with Boronic Acid Derivatives as Alkylating Agents: An Amine/Imine-Mediated Activation Approach.

Herein, we describe a one-pot aminoalkylation of styrene derivatives with boronic acids (BAs) and boronic acid pinacol esters as radical precursors for the synthesis of complex secondary amines in moderate to high yields through a mild and easily accessible organophotoredox-catalytic four-component reaction. Additionally, we report for the first time in a photoredox process the activation of alkyl boronic acid derivatives by imines, which play a dual role in the reaction as both substrate and Lewis base activator. The protocol applicability was greatly enhanced by its successful adaptation to photoflow reactors.

Visible-Light-Induced Cascade Difunctionalization of Indoles Enabled by the Synergy of Photoredox and Photoexcited Ketones: Direct Access to Alkylated Pyrrolophenanthridones.

Herein, we describe a methodology to construct polycyclic pyrrolophenanthridones with an (amino)alkyl side chain that involves visible-light-induced decarboxylative radical addition for the intermolecular dearomatization of indoles and subsequent photoinduced C(sp2)-X bond activation via photoexcited ketones for an intramolecular cyclization cascade. Carboxylic acids serve both as a radical source toward indole dearomatization and as reductants to initiate an electron transfer with photoexcited N-acylindole derivatives in the reaction toward pyrrolophenantridone skeletons, which occurs under mild reaction conditions with good functional group tolerance.

Multicomponent reactions and photo/electrochemistry join forces: atom economy meets energy efficiency.

Visible-light photoredox catalysis has been regarded as an extremely powerful tool in organic chemistry, bringing the spotlight back to radical processes. The versatility of photocatalyzed reactions has already been demonstrated to be effective in providing alternative routes for cross-coupling as well as multicomponent reactions. The photocatalyst allows the generation of high-energy intermediates through light irradiation rather than using highly reactive reagents or harsh reaction conditions. In a similar vein, organic electrochemistry has experienced a fruitful renaissance as a tool for generating reactive intermediates without the need for any catalyst. Such milder approaches pose the basis toward higher selectivity and broader applicability. In photocatalyzed and electrochemical multicomponent reactions, the generation of the radical species acts as a starter of the cascade of events. This allows for diverse reactivity and the use of reagents is usually not covered by classical methods. Owing to the availability of cheaper and more standardized photo- and electrochemical reactors, as well as easily scalable flow-setups, it is not surprising that these two fields have become areas of increased research interest. Keeping these in view, this review is aimed at providing an overview of the synthetic approaches in the design of MCRs involving photoredox catalysis and/or electrochemical activation as a crucial step with particular focus on the choice of the difunctionalized reagent.

Visible-Light-Driven Palladium-Catalyzed Radical Tandem Dearomatization of Indoles with Unactivated Alkenes.

A mild visible-light-driven palladium-catalyzed radical tandem dearomatization of indoles with unactivated alkenes is described with moderate to good yields and good to excellent diastereoselectivities. Under visible-light irradiation, the photoexcited state of the palladium complex was formed, which could transfer a single electron to N-(2-bromobenzoyl)indoles, leading to a hybrid palladium radical chemistry. This provides efficient and atom-economical access to diverse 2,3-disubstituted indoline derivatives.

Sequential and direct multicomponent reaction (MCR)-based dearomatization strategies.

Dearomatization strategies in a multicomponent fashion often result in complex heterocyclic frameworks, which have attracted the attention of chemists due to their natural product-like structures. The combination of these two processes can easily achieve extended molecular complexity and diversity from simple starting materials with high atom economy. Thus, this field has attracted extensive interest owing to its potential significance in both asymmetric catalysis and convenient build-up of libraries of molecules with novel three-dimensional scaffolds, which may find application in medicinal chemistry. Accordingly, a systematic review on this topic will provide the synthetic organic community with a conceptual overview and comprehensive understanding of the different multicomponent reaction (MCR) cascades involving dearomatization as the characteristic step. In addition, this review will help researchers to look at this promising area from a different perspective with respect to drug discovery, new MCR-based disconnections and often hidden opportunities.

Recent Developments in Transition-Metal Catalyzed Direct C-H Alkenylation, Alkylation, and Alkynylation of Azoles.

The transition metal-catalyzed C-H bond functionalization of azoles has emerged as one of the most important strategies to decorate these biologically important scaffolds. Despite significant progress in the C-H functionalization of various heteroarenes, the regioselective alkylation and alkenylation of azoles are still arduous transformations in many cases. This review covers recent advances in the direct C-H alkenylation, alkylation and alkynylation of azoles utilizing transition metal-catalysis. Moreover, the limitations of different strategies, chemoselectivity and regioselectivity issues will be discussed in this review.

Ligand-Enabled Palladium-Catalyzed Through-Space C-H Bond Activation via a Carbopalladation/1,4-Pd Migration/C-H Functionalization Sequence.

We report, herein, a palladium-catalyzed cascade comprising carbopalladation, 1,4-Pd-migration and C(sp2 )-C(sp2 ) bond formation to construct a variety of bis-heterocyclic frameworks in a single operational step. The methodology provides a direct approach to introduce an oxadiazole core at a remote location without any functional group obligation, with moderate to good yields.

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids.

An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacetylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the rhodium catalyst to promote C(sp2)-H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the isoquinolones is very wide and may be extended to the preparation of complex compounds having heterocyclic moieties such as pyridone, furan, thiophene and pyrrole, as well as the corresponding benzo-fused derivatives. The developed procedure is simple, reproducible and does not require inert conditions.

Metal-Free Dearomatization: Direct Access to Spiroindol(en)ines in Batch and Continuous-Flow.

A metal-free, phosphine-catalyzed intramolecular "umpolung Michael addition" on alkynes to form spiroindol(en)ines is reported. This nucleophilic catalysis enables the formation of a wide scope of five- and six-membered spiroindol(en)ines in moderate to excellent yields in batch as well as under continuous-flow conditions. Triphenylphosphine-catalyzed nucleophilic activation of alkynes allows the exclusive formation of exo-product under mild reaction conditions.

Gold-catalyzed post-MCR transformations towards complex (poly)heterocycles.

Post multicomponent reaction (MCR) transformations are one of the most successful methods leading to high structural diversity and molecular complexity. A well-known MCR, the Ugi reaction typically affords a linear peptide backbone, enabling post-Ugi transformations as an elegant solution to rigidify the Ugi adduct into more drug-like species. Not surprisingly, the development of such transformations leading to new structural frameworks has expanded rapidly over the last few years. These reactions have reached an impressive level of performance and versatility, particularly in amalgamation with gold catalysis. This review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects.

Facile synthesis of vanillin-based novel bischalcones identifies one that induces apoptosis and displays synergy with Artemisinin in killing chloroquine resistant Plasmodium falciparum.

The inherent affinity of natural compounds for biological receptors has been comprehensively exploited with great success for the development of many drugs, including antimalarials. Here the natural flavoring compound vanillin has been used as an economical precursor for the synthesis of a series of novel bischalcones whose in vitro antiplasmodial activities have been evaluated against erythrocytic stages of Plasmodium falciparum. Bischalcones 9, 11 and 13 showed promising antiplasmodial activity {Chloroquine (CQ) sensitive Pf3D7 IC50 (µM): 2.0, 1.5 and 2.5 respectively}but only 13 displayed potent activities also against CQ resistant PfDd2 and PfIndo strains exhibiting resistance indices of 1.4 and 1.5 respectively. IC90 (8 µM) of 13 showed killing activity against ring, trophozoite and schizont stages. Further, 13 initiated the cascade of reactions that culminates in programmed cell death of parasites including translocation of phosphatidylserine from inner to outer membrane leaflet, loss of mitochondrial membrane potential, activation of caspase like enzyme, DNA fragmentation and chromatin condensation. The combinations of 13 + Artemisinin (ART) exhibited strong synergy (ΣFIC50:0.46 to 0.58) while 13 + CQ exhibited mild synergy (ΣFIC50: 0.7 to 0.98) to mild antagonism (ΣFIC50: 1.08 to 1.23) against PfIndo. In contrast, both combinations showed marked antagonism against Pf3D7(ΣFIC50: 1.33 to 3.34). These features of apoptosis and strong synergy with Artemisinin suggest that bischalcones possess promising antimalarial drug-like properties and may also act as a good partner drugs for artemisinin based combination therapies (ACTs) against Chloroquine resistant P. falciparum.

A Lewis Base Catalysis Approach for the Photoredox Activation of Boronic Acids and Esters.

We report herein the use of a dual catalytic system comprising a Lewis base catalyst such as quinuclidin-3-ol or 4-dimethylaminopyridine and a photoredox catalyst to generate carbon radicals from either boronic acids or esters. This system enabled a wide range of alkyl boronic esters and aryl or alkyl boronic acids to react with electron-deficient olefins via radical addition to efficiently form C-C coupled products in a redox-neutral fashion. The Lewis base catalyst was shown to form a redox-active complex with either the boronic esters or the trimeric form of the boronic acids (boroxines) in solution.

Copper-catalyzed alkylarylation of activated alkenes using isocyanides as the alkyl source: an efficient radical access to 3,3-dialkylated oxindoles.

A novel and efficient protocol for the synthesis of 3,3-dialkylated oxindoles is described. The method involves a copper-catalyzed tandem radical addition/cyclization of N-arylacrylamides with the alkyl radicals generated from isocyanides. Two C-C bonds are formed in a single step.

Ligand-controlled product selectivity in palladium-catalyzed domino post-Ugi construction of (spiro)polyheterocycles.

A novel diversity-oriented access to (spiro)polyheterocycles possessing two adjacent quaternary carbon stereocenters is described. By combining an Ugi 4-CR with Pd-catalysis, the possible mode of cyclization is controlled by the appropriate choice of ligands. Using XantPhos, spirooxindoles are selectively generated, while with BINAP fused polycyclic cis-dihydrobenzofurans are obtained with high diastereoselectivity.

Microwave-Assisted Copper-Catalyzed Oxidative Cyclization of Acrylamides with Non-Activated Ketones.

An operationally simple and efficient microwave-assisted protocol for the oxidative cyclization of acrylamide derivatives with non-activated ketones to generate 3,3-disubstituted oxindoles is described. The reaction proceeds by a copper-catalyzed tandem radical addition/cyclization strategy and tolerates a series of functional groups with moderate to excellent yields.

Domino Carbopalladation/C-H Functionalization Sequence: An Expedient Synthesis of Bis-Heteroaryls through Transient Alkyl/Vinyl-Palladium Species Capture.

A microwave-assisted highly efficient intermolecular domino carbopalladation/C-H functionalization sequence has been developed to access bis-heteroaryl frameworks in a single operation. The reaction involves carbopalladation of the halogenated acrylamides or phenylpropiolamides by the Pd(0) catalysis, followed by the direct (hetero)arylation to give products with good to excellent yields. The synthetic utility of this method was also extended towards the application of the Ugi-adduct as the starting material.

Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds.

The Ugi-4CR is by far one of the most successful multicomponent reactions leading to high structural diversity and molecular complexity. However, the reaction mostly affords a linear peptide backbone, enabling post-Ugi transformations as the only solution to rigidify the Ugi-adduct into more drug like species. Not surprisingly, the development of these transformations, leading to new structural frameworks, has expanded rapidly over the last few years. As expected, palladium-catalyzed reactions have received the foremost attention, yet other metals, particularly gold complexes, are fast catching up. This tutorial review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects.

Pd-catalyzed Csp(2) -H functionalization of heteroarenes via isocyanide insertion: concise synthesis of di-(hetero)aryl ketones and di-(hetero)aryl alkylamines.

We report herein an efficient Pd-catalyzed direct C-H bond functionalization of heteroarenes via an isocyanide insertion strategy for the synthesis of di-(hetero)aryl ketones and di-(hetero)aryl alkylamines. The methodology involves a three component reaction between an azole, a haloarene and an isocyanide resulting in the formation of an imine, which in turn is either hydrolyzed or reduced to get the desired product.