3d metallaelectrocatalysis for resource economical syntheses

This review summarizes key developments in 3d metallaelectrocatalysis in the context of resource economy in molecular syntheses

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012−2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes

A Diversity-Oriented Synthesis Approach to Functionalized Azaheterocycles using Cyclic Alpha-Halo Eneformamides

Functionalized piperidines, azepanes, azamacrocycles, morpholines, and thiomorpholines are common structural motifs found in a wide range of pharmaceuticals such as carmegliptine, levofloxacin, thioridazine, claviciptic acid, and azithomycin. As a result, there is a strong desire to construct highly functionalized nitrogen-bearing ring scaffolds in order to construct a wide range of drug possibilities. There are several non-modular and step-uneconomical synthetic methods used in the construction of these aforementioned motifs such as ring closing metathesis, ring expansions, and intramolecular reductive amination. In this research, we present a step-economical, cost-effective, scalable, and diversity-oriented synthesis approach to highly functionalized N-heterocycles through the intermediacy of α-halo enamines/enamides. The synthetic utility of the method is exemplified through the construction of quaternary cyclic propargylic and homoallylic amines, polycyclic lactams, as well as chiral dihydro 1,4-oxazines and thiazines. Given the generality of the approach, we are confident that the synthesis and medicinal chemistry communities will undoubtedly embrace it, thus, endowing it with a practical advantage over existing methodologies

Cu Photoredox Catalysts Supported by a 4,6-Disubstituted 2,2 '-Bipyridine Ligand: Application in Chlorotrifluoromethylation of Alkenes

Interest in base metal catalysis motivates the development of Cu-based photoredox catalysts for organic synthesis. However, only a few Cu catalysts have been applied in photoredox reactions, the majority of which contain one or two 1,10-phenanthroline ligands. Here we design a 4,6-disubstituted 2,2'-bipyridine ligand for Cu. Two heteroleptic [Cu(NN)(PP)][PF6] complexes, where NN stands for the 2,2'-bipyridine ligand and PP stands for a bisphosphine ligand, have been synthesized and characterized. They exhibit longer excited state lifetimes and higher Cu(I) / Cu(II) potentials compared to the most widely used Cu catalyst, [Cu-(dap)(2)]Cl. The complex with Xantphos as the PP ligand is an efficient catalyst for chlorotrifluoromethylation of terminal alkenes, especially styrenes, which had been challenging substrates for previously reported photoredox reactions. This chlorotrifluoromethylation method enables the convenient introduction of a trifluoromethyl group into organic molecules under mild conditions, which is important for medicinal chemistry

Recent Progresses in the Preparation of Chlorinated Molecules: Electrocatalysis and Photoredox Catalysis in the Spotlight

Among halogenated molecules, those containing chlorine atoms are fundamental in many areas such as pharmaceuticals, polymers, agrochemicals and natural metabolites. Despite the fact that many reactions have been developed to install chlorine on organic molecules, most of them rely on toxic and hazardous chlorinating reagents as well as harsh conditions. In an attempt to move towards more sustainable approaches, photoredox catalysis and electrocatalysis have emerged as powerful alternatives to traditional methods. In this review, we collect the most recent and significant examples of visible-light- or current-mediated chlorination published in the last five years

Photoredox/nickel Dual Catalysis On Functionalization Of Unsaturated Systems

Alkene functional groups are ubiquitous, and development of olefin functionalization transformations provides a unique opportunity to install Csp3 centers with great atom- and step-efficiency. Many elegant strategies have been developed toward this goal, however, the selective functionalization of unactivated olefins still remains underdeveloped. By fulfilling single electron processes under mild conditions, the emergence of photoredox/Ni dual catalysis has significantly expanded the alkyl nucleophile repertoire in C-C bond constructions. Applying this concept in C=C and C=X functionalization thus possesses great potential. Both photoredox/Ni dual catalysis and reductive coupling transpire via single electron pathways. Although the reductive coupling requires a stoichiometric amount of reductant, photoredox/Ni dual catalysis may fulfill similar transformations in a redox-neutral form, potentially improving both atom economy and reproducibility. To take advantage of this concept, an amidation reaction using organic isocyanates and alkylsilicates was developed. Through a Csp2-Csp3 bond construction approach, various alkyl amides were synthesized with good functional group tolerance, and thanks to the mild conditions, the deleterious CO extrusion reactivity was avoided. Heterocarbofunctionalization of olefins has great potential of rapidly building molecular complexity, however, very few mild and selective approaches have been reported. Through a photoredox proton-coupled electron transfer (PCET) pathway, reactive amidyl radicals were generated mildly to facilitate a cascade amidoarylation/nickel-catalyzed cross-coupling of unactivated olefins. This new technology grants access to an array of complex molecules containing a privileged pyrrolidinone core from alkenyl amides and aryl- and heteroaryl bromides. Notably, not only amides, but carbamates and ureas were also used. Subsequently, carbonyl-type electrophiles, such as acyl (pseudo)halides and in situ-activated carboxylic acids, were incorporated in a highly diastereoselective amidoacylation reaction. Mechanistic studies, including hydrogen-bond affinity constants, cyclization rate measurements, quenching studies, cyclic voltammetry, isomerization experiments, as well as computational studies, were central to comprehend the subtleties contributing to the integration of the two catalytic cycles and the origin of the high diastereoselectivity. Finally, a method for Csp3-Csp3 and Csp3-X bond construction was developed by implementing photoredox/Ni dual catalysis into a Tsuji-Trost-type alkylation of allyl alcohol-derived partners. This transformation transpires with high linear and E-selectivity, avoiding the normal requirement for harsh conditions (e.g., strong base, elevated temperature). Additionally, using aryl sulfinate salts as radical precursors, allyl sulfones can also be obtained. Kinetic isotope effect experiments implicated oxidative addition of the nickel catalyst to the allylic electrophile as the turnover-limiting step, supporting previous computational studies. In summary, photoredox/Ni dual catalysis has proven enabling toward functionalization of unsaturated systems. Through different approaches, the unsaturated systems can be implemented as electrophiles (allyl alcohols, isocyanates) or radical precursors (pendant olefins). Various connections that are pivotal for synthetic chemistry have been demonstrated, such as Csp2-Csp3, Csp3-Csp3, Csp3-S and Csp3-N bonds, delivering a series of complex structures, such as functionalized monosaccharides, (hetero)arylated pyrrolidones, allyl sulfones, as well as highly functionalized amides

Forging sp3 Architectures via sp3 C−C Bond Cleavage and 1,2-Alkylboration Strategies

La creixent demanda d'estructures que contenen carbonis amb caràcter sp3 en el desenvolupament de fàrmacs, ha provocat que nous mètodes per construir enllaços entre carbonis sp3 hagin atret  un creixent interès per part del la química mèdica. En aquest context, les reaccions d'acoblament catalitzades per metalls de transició, han ofert solucions innovadores per sintetitzar estructures diverses amb presencia de carbonis amb naturalesa sp3. No obstant, la formació d'enllaços C–C mitjançant aquests tipus de processos, encara deixa espai per a noves millores. Així, mentre que la majoria de les reaccions d'acoblament creuat es centren en l'activació d’enllaços carboni-heteroàtom o enllaços C–H, les estratègies generals basades en la funcionalització d'enllaços C–C, particularment forts, segueixen essent un repte. Així mateix, malgrat els avenços realitzats en 1,2-carboboració en sistemes π, la construcció d’enllaços C(sp3)–C(sp3) catalitzada per metalls, utilitzant halurs d'alquil com a font de centres de carboni sp3, encara resulta desafiant. Per tant, s’han desenvolupat nous mètodes per a la síntesi d'estructures amb caràcter sp3; com el trencament d'enllaços C–C i la 1,2-alquilboració catalitzada per níquel. Oferint així, mètodes complementaris per preparar enllaços altament funcionalitzats, així com sintèticament versàtils, a partir de precursors simples i fàcilment accessibles.La creciente demanda de estructuras que contienen carbonos de tipo sp3, en el desarrollo de fármacos, ha provocado que nuevos métodos para construir enlaces entre carbonos sp3 estén atrayendo un interés cada vez mayor por parte de la química médica. En este contexto, las reacciones de acoplamiento cruzado, catalizadas por metales de la serie de transición, han ofrecido soluciones innovadoras para sintetizar estructuras diversas con carbonos de naturaleza sp3. No obstante, la formación de enlaces C–C mediante este tipo de procesos, aún deja espacio para mejoras. Así, mientras la mayoría de las reacciones de acoplamiento cruzado se centran en la activación de enlaces carbono-heteroátomo o enlaces C–H, las estrategias para llevar a cabo la funcionalización de enlaces C–C, particularmente fuertes, siguen siendo un reto. Asimismo, a pesar de los avances desarrollados en reacciones de 1,2-carboboración en sistemas de tipo pi, la construcción de enlaces C(sp3)–C(sp3) catalizada por metales, usando para ello haluros de alquilo como fuente de carbono sp3 aún resulta desafiante. Por lo tanto, se han desarrollado nuevos métodos para la síntesis de este tipo de estructuras; como la rotura de enlaces C–C y la 1,2-alquilboroación catalizada por níquel. Esto ofrece métodos complementarios para preparar enlaces altamente funcionalizados, así como sintéticamente versátiles, a partir de precursores simples y fácilmente accesibles.With the increasing demand for sp3 architectures in drug development, new methods to construct sp3-carbon linkages have attracted significant attention from medicinal chemists. Metal-catalyzed cross-coupling reactions have offered innovative solutions to synthesize structurally diverse sp3-carbon scaffolds. However, forging sp3 C–C bonds by transition metal-catalysis still leaves ample room for further improvements. On the one hand, while the majority of cross-coupling reactions focus on the activation of carbon-heteroatom bonds or C–H bonds, general strategies based on the functionalization of particularly strong C–C bonds still remain elusive. On the other hand, despite the advances realized in 1,2-carboboration of π‐systems, transition metal-catalyzed construction of C(sp3)–C(sp3) bonds with alkyl halides as the source of sp3-carbon centers is still challenging. To this end, we have developed new methods for the synthesis of sp3 architectures via C−C bond cleavage and Ni-catalyzed 1,2-alkylboration strategies, which offer a complementary new blueprint for preparing densely functionalized, yet synthetically versatile, sp3 C−C bonds from simple and readily accessible precursors.

C-H & C-O Functionalization by Silicon-Heteroatom Interelement Linkage

La química sintètica és gairebé inimaginable sense tres elements principals del grup, a saber, boro, silici i estany. Quan s'uneixen a un àtom de carboni de qualsevol hibridació, aquests grups funcionals serveixen de linchpins excepcionalment versàtils en síntesi, transformant-se selectivament en una enorme amplitud d'enllaços C-C i C-X, per tant, descobrir nous mètodes per forjar el valor afegit C-Si, Els enllaços C-B i C-Sn sempre tenen una gran demanda. D'acord amb l'interès de la investigació en el grup de Martín per activar enllaços o molècules inerts, aquesta tesi doctoral se centra en el desenvolupament de noves tècniques per fer ús de l'enllaç d'interrelació de silici-heteroatoma per funcionalitzar l'enllaç C-O i C-H inerts mitjançant una catàlisi de níquel o sistema lliure de transició de metalls. Hem desenvolupat tres nous mètodes per a la funcionalització d’enllaços C-O i C-H inerts mitjançant l’ús d’enllaços d’interrelació basats en silici. Totes les transformacions anteriors presenten un excel·lent perfil de quimioselectivitat en condicions suaus. Es duen a terme estudis i debats sobre mecanismes previs per entendre com i per què van continuar aquestes reaccions. Les transformacions realitzades contribueixen a la comprensió de l’ús més prolífic d’enllaços químics inerts en els compostos de valor afegit de síntesi. Creiem que aquests protocols contribuirienLa química sintética es casi inimaginable sin tres elementos principales del grupo, a saber, boro, silicio y estaño. Cuando se unen a un átomo de carbono de cualquier hibridación, estos grupos funcionales sirven como linchpins excepcionalmente versátiles en síntesis, transformándose selectivamente en una enorme variedad de enlaces C-C y C-X, por lo tanto, descubren nuevos métodos para forjar el valor agregado C-Si, Los bonos C-B y C-Sn siempre tienen una gran demanda. En línea con el interés de la investigación en el grupo de Martín de la activación de enlaces o moléculas inertes, esta tesis doctoral se centra en el desarrollo de nuevas técnicas para hacer uso del enlace de interelemento de silicio-heteroátomo para funcionalizar el enlace inerte C-O & C-H a través de catálisis de níquel o sistema sin transición de metal. Hemos desarrollado tres nuevos métodos para la funcionalización de enlaces inertes C-O y C-H mediante el uso de enlaces de interelemento basados ​​en silicio. Todas las transformaciones anteriores muestran un excelente perfil de quimioselectividad en condiciones suaves. Se realizan estudios y debates mecanicistas preliminares para comprender cómo y por qué se produjeron estas reacciones. Las transformaciones realizadas contribuyen a la comprensión del uso más prolífico de enlaces químicos inertes a los compuestos de valor agregado de síntesis.Synthetic chemistry is almost unimaginable without three main group elements, namely, boron, silicon, and tin. When attached to a carbon atom of any hybridization, these functional groups serve as exceptionally versatile linchpins in synthesis, selectively transforming into an enormous breadth of C-C and C-X bonds, thus, discover new methods to forge value added C-Si, C-B and C-Sn bonds are always in highly demand. In line with the research interest in Martín’s group of activating inert bonds or molecules, this doctoral thesis focuses on the development of novel techniques to make use of silicon-heteroatom interelement linkage to functionalize inert C-O & C-H bond via either nickel catalysis or transition metal free system. We have developed three new methods towards the functionalization of inert C-O & C-H bonds by using silicon-based interelement linkages. All the above transformations display excellent chemoselectivity profile under mild conditions. Preliminary mechanistic studies and discusses are carried out to understand how and why these reactions proceeded. The transformations realized contribute to the understanding of more prolific use of inert chemical bonds to the synthesis value added compounds. We believe these protocols would definitely contribute to a systematic utilization of silicon-heteroatom reagent in the arena of inert chemical bond functionalization