Catalytic Methodology Research Articles

Silver-catalyzed carboxylative cyclization of alkynic hydrazones with carbon dioxide

The development of new catalytic methodologies to synthesize heterocyclic fine chemicals using carbon dioxide as a synthon has attracted considerable attention. Herein, we report the silver(I)-catalyzed carboxylative cyclization of a variety of alkynic hydrazones with carbon dioxide to produce the corresponding 1,3,4-oxadiazin-2-ones under mild reaction conditions. In this reaction, silver(I) salts play a π-Lewis acid role for the highly efficient activation of the alkyne moiety in the hydrazone substrates. Single-crystal X-ray analysis and NOE experiments confirm that the newly formed oxadiazinone products exhibit Z configuration. Based on control experiments and NMR studies, a mechanism including the formation of a reactive carbazate intermediate, electrophilic cyclization, and subsequent protonation is proposed. This study offers an efficient and atom-economical method for the synthesis of biologically important 1,3,4-oxadiazin-2-ones.

Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical Cascade Reactions

The monoterpene indole alkaloids, containing over 3000 known members and more than 40 structural types, represent one of the largest natural product families that have proven to be an important drug source. Their complex chemical structures and significant biological activities have rendered these alkaloids attractive targets in the synthetic community for decades. While chemists have developed many synthetic methodologies and tactics toward this end, general strategies allowing divergent access to a large variety of structural types and members of monoterpene indole alkaloids are still limited and highly desirable. Photoredox catalysis has emerged in recent years as a powerful tool to realize chemical transformations via single electron transfer (SET) processes that would otherwise be inaccessible. In particular, when the radical species generated by the visible light photoinduced approach is involved in well-designed cascade reactions, the formation of multiple chemical bonds and the assembly of structurally complex molecules would be secured in a green and economic manner. This protocol might serve to remodel the way of thinking for the preparation of useful pharmaceuticals and complex natural products. Due to a long-standing interest in the synthesis of diverse indole alkaloids, our group previously developed a cyclopropanation strategy ( Qin , Y. Acc. Chem. Res. 2011 , 44 , 447 ) that was versatile to access several intriguing indole alkaloid molecules. With an idea of developing more general synthetic approaches to as many members of various indole alkaloids as possible, we recently disclosed new radical cascade reactions enabled by photoredox catalysis, leading to the collective asymmetric total synthesis of 42 monoterpene indole alkaloids belonging to 7 structural types. Several important discoveries deserve to be highlighted. First, the use of photocatalytic technology allowed us to achieve an unusual reaction pathway that reversed the conventional reactivity between two nucleophilic amine and enamine groups. Second, a crucial nitrogen-centered radical, directly generated from a sulfonamide N-H bond, triggered three types of cascade reactions to deliver indole alkaloid cores with manifold functionalities and controllable diastereoselectivities. Moreover, expansion of this catalytic, scalable, and general methodology permitted the total synthesis of a large collection of indole alkaloids. In this Account, we wish to provide a complete picture of our studies concerning the original synthetic design, method development, and applications in total synthesis. It is anticipated that the visible-light-driven cascade strategy will find further utility in the realm of natural product synthesis.

Primary Benzylamines by Efficient N-Alkylation of Benzyl Alcohols Using Commercial Ni Catalysts and Easy-to-Handle Ammonia Sources

Primary benzylamines are highly important building blocks in the pharmaceutical and polymer industry. An attractive catalytic approach to access these compounds is the direct coupling of benzyl alcohols with ammonia via the borrowing hydrogen methodology. However, this approach is usually hampered by a series of side-reactions, one of the most prominent being the overalkylation of the formed primary amine. Herein, we describe a robust catalytic methodology, which utilizes commercially available heterogeneous Ni catalysts and easy-to-handle ammonia sources, such as aqueous ammonia or ammonium salts, for the formation of primary benzylamines with good selectivity and scope. Notably, our method enables the conversion of potentially lignin-derived vanillyl alcohol to vanillylamine, which can be used to produce emerging biobased polymers or as pharma building blocks. Important sugar derived platform alcohols as well as long chain aliphatic primary alcohols can be successfully aminated. Moreover, we provide an alternative, sustainable route to p-xylylenediamine and m-xylylenediamine, important components of heat resistant polyamides such as Kevlar.

Stereodivergent Synthesis of Chiral Paraconic Acids via Dynamic Kinetic Resolution of 3-Acylsuccinimides.

A direct N-heterocyclic carbene (NHC) catalysis of maleimides with alkyl aldehydes is established for the synthesis of 3-acylsuccinimides. The first dynamic kinetic resolution of 3-acylsuccinimides is accomplished through asymmetric transfer hydrogenation. These two catalytic methodologies are utilized for the synthesis of each enantiomer of trans-paraconic acids in three steps and cis-paraconic acids in four steps with good yields and high stereoselectivities. This stereodivergent synthetic methodology is applied for the synthesis of seven bioactive paraconic acid natural products.

Advances in The Catalytic Synthesis of Triarylmethanes (TRAMs)

The last couple of decades has witnessed an incredible development in the progress of catalytic creation of triarylmethane (TRAM) motif. The broad‐spectrum applications of TRAMs in domains like medicinal chemistry, pharmacology, dyes, and functional materials has urged scientists to invent their efficient synthetic strategies. Herein, we have attempted to comprehensively document the catalytic methodologies for the synthesis of triarylmethanes which will satiate the anticipations of the readers who are looking for an update and stimulate the researches for further development.

Concise Total Synthesis of (-)-Vermiculine through a Rhodium-Catalyzed C2 -Symmetric Dimerization Strategy.

A short and efficient synthesis of the C2 -symmetric antibiotic (-)-vermiculine by utilizing an enantioselective catalytic one-step dimerization methodology as key-step to construct the core structure is reported. The late-stage modifications feature a double metathesis homologation followed by a double Wacker-type oxidation. These key-steps allowed the synthesis of vermiculine in only seven steps, starting from commercially available building blocks.

Direct hydroxyethylation of amines by carbohydrates via ruthenium catalysis

A halogen-free catalytic methodology for the synthesis of β-amino alcohols from aromatic amines and biomass-related carbohydrates is demonstrated for the first time.

Phenol-Directed C–H Functionalization

Phenols are important starting materials, intermediates, and functional elements of a very broad range of chemicals and materials. They are large-volume products of benzene oxidation and are increasingly available from biomass. Investment in methodologies that improve the efficiency of their use can have both immediate and future impacts on chemical upgrading. This review summarizes recent phenol-directed C–H functionalization reactions, which provide efficient increases in molecular complexity. Catalytic methodologies play an increasingly important role in addressing long-standing challenges of chemo- and regioselectivity, setting the stage for increased use of phenols in fine-chemical synthesis. We discuss these advances while underscoring persistent challenges, with the goal of motivating increased interest in this versatile functional group.

Application of Silver Nanoparticles in the Multicomponent Reaction Domain: A Combined Catalytic Reduction Methodology to Efficiently Access Potential Hypertension or Inflammation Inhibitors.

The catalytic efficacy of silver nanoparticles was investigated toward the chemoselective reduction of nitro-tetrazole or amino acid-substituted derivatives into the corresponding amines in high isolated yields. This highly efficient protocol was thereafter applied toward the multicomponent reaction synthesis of heterocyclic dihydroquinoxalin-2-ones with high isolated yields. The reaction proceeds with low catalyst loading (0.8–1.4 mol %) and under mild catalytic conditions, a very good functional-group tolerance, and high yields and can be easily scaled up to more than 1 mmol of product. Thus, the present catalytic methodology highlights a useful synthetic application. Different molecules are designed and accordingly synthesized with the current protocol that could play the role of inhibitors of the soluble epoxide hydrolase, an important target for therapies against hypertension or inflammation.

PPh3AuTFA Catalyzed in the Dearomatization of 2-Naphthols with Allenamides.

A new catalytic methodology for the direct dearomatization of substituted 2-naphthols via intermolecular condensation with allenamides is presented. PPh3AuTFA (5 mol %) promotes the formal allylating dearomative protocol under mild conditions, large scope (24 examples), and high regioselectivity and stereoselectivity. The synergistic catalytic role played by the [PPh3Au]+ (π-acid) and TFA- (Lewis base) is highlighted.

Martín Fañanás‐Mastral

Martín Fañanás‐Mastral

3 + 2] Cycloaddition of Isocyanides with Aryl Diazonium Salts: Catalyst-Dependent Regioselective Synthesis of 1,3- and 1,5-Disubstituted 1,2,4-Triazoles

An unprecedented catalyst-dependent regioselective [3 + 2] cycloaddition of isocyanides with aryl diazonium salts is reported. 1,3-Disubstituted 1,2,4-triazoles were selectively obtained in high yield under Ag(I) catalysis, whereas 1,5-disubstituted 1,2,4-triazoles were formed by Cu(II) catalysis. These catalytic methodologies provide a controlled, modular, and facile access to 1,2,4-triazole scaffolds with high efficiency, broad substrate scope, and excellent functional group compatibility.

Scalable and Highly Diastereo- and Enantioselective Catalytic Diels-Alder Reaction of α,β-Unsaturated Methyl Esters.

Despite tremendous advances in enantioselective catalysis of the Diels-Alder reaction, the use of simple α,β-unsaturated esters, one of the most abundant and useful class of dienophiles, is still severely limited in scope due to their low reactivity. We report here a catalytic asymmetric Diels-Alder methodology for a large variety of α,β-unsaturated methyl esters and different dienes based on extremely reactive silylium imidodiphosphorimidate (IDPi) Lewis acids. Mechanistic insights from accurate domain-based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) calculations rationalize the catalyst control and stereochemical outcome.

Rh-Catalyzed Asymmetric Hydrogenation of β-Substituted-β-thio-α,β-unsaturated Esters: Expeditious Access to Chiral Organic Sulfides.

Rh/bifunctional bisphosphine-thiourea ligand (ZhaoPhos)-catalyzed asymmetric hydorgenation of both ( Z)- and ( E)-isomers of β-substituted-β-thio-α,β-unsaturated esters was successfully developed. This new asymmetric catalytic methodology provided highly efficient access to two enantiomers of chiral organic sulfides ethyl β-substituted-β-thio-propanoates with excellent results (up to 99% yield and >99% ee for ( Z)-substrates, up to 99% yield and 98% ee for ( E)-substrates, TON up to 5000), which are important intermediates in organic synthesis.

Comparative Nitrene-Transfer Chemistry to Olefinic Substrates Mediated by a Library of Anionic Mn(II) Triphenylamido-Amine Reagents and M(II) Congeners (M = Fe, Co, Ni) Favoring Aromatic over Aliphatic Alkenes

Selective amination of σ and π entities such as C–H and C═C bonds of substrates remains a challenging endeavor for current catalytic methodologies devoted to the synthesis of abundant nitrogen-containing chemicals. The present work addresses an approach toward discriminating aromatic over aliphatic alkenes in aziridination reactions, relying on the use of anionic metal reagents (M = Mn, Fe, Co, Ni) to attenuate reactivity in a metal-dependent manner. A family of MnII reagents bearing a triphenylamido-amine scaffold and various pendant arms has been synthesized and characterized by various techniques, including cyclic voltammetry. Aziridination of styrene by PhI═NTs in the presence of each MnII catalyst establishes a trend of increasing yield with increasing MnII/III anodic potential. The FeII, CoII, and NiII congeners of the highest-yielding MnII catalyst have been synthesized and explored in the aziridination of aromatic and aliphatic alkenes, exhibiting good to high yields with para-substituted styrenes...

Synergistic Catalysis: Highly Enantioselective Acetyl Aza-arene Addition to Enals.

A novel catalytic enantioselective methodology based on synergistic catalysis for the synthesis of chiral 2-acyl pyridines and pyrazines is reported. The strategy involves the metal-Lewis acid activation of acetyl aza-arenes and the secondary-amine activation of enals. The proposed mechanism is supported by DFT calculations.

The Quest for Selectivity in Hydrogen Atom Transfer Based Aliphatic C-H Bond Oxygenation.

Aliphatic C-H bond functionalization is at the frontline of research because it can provide straightforward access to simplified and cost-effective synthetic procedures. A number of these methodologies are based on hydrogen atom transfer (HAT), which, as a consequence of the inert character of C-H bonds, often represents the most challenging step of the overall process. Because the majority of organic molecules contain multiple nonequivalent C-H bonds that display similar chemical properties, differentiating between these bonds with high levels of selectivity represents one of the most challenging issues. Clarification of the factors that govern the relative reactivity of C-H bonds toward HAT reagents is thus of primary importance in order to develop selective functionalization procedures. In this Account we describe, through the combination of kinetic studies employing a genuine HAT reagent such as the cumyloxyl radical, along with oxidations performed with H2O2 and iron or manganese catalysts, our contribution toward the development of selective C-H functionalization methodologies. Despite the different nature of these reagents, an oxygen-centered radical and a metal-oxo species, congruent reactivity and selectivity patterns have emerged, providing strong evidence that both reactions proceed via HAT. Consequently, selectivity in this class of metal catalyzed C-H oxidations can be reasonably predicted and synthetically exploited. Amides have been identified as preferential functional groups for governing selectivity on the basis of electronic, steric, and stereoelectronic effects. Torsional effects have proven moreover to be particularly important C-H directing factors in the oxidation of cyclohexane scaffolds where a delicate balance of these effects, in synergistic combination with catalyst design, enables highly chemoselective and enantioselective oxidations. Medium effects have been also shown to govern the relative HAT reactivity of C-H bonds in proximity to polar, hydrogen bond acceptor (HBA) functional groups. By engaging in hydrogen bonding with these groups, fluorinated alcohols strongly deactivate proximal C-H bonds toward HAT-based oxidation. As a result, alcohols, ethers, amines, and amides, which are electron rich and effective proximal C-H activating groups toward HAT reagents in conventional solvents, become oxidatively robust deactivating functionalities that direct C-H oxidation toward remote positions. These deactivating effects enable moreover the accomplishment of product chemoselective methylenic hydroxylations. Overall, clarification of the factors that govern HAT-based reactions has served to provide unique examples of catalytic methodologies for chemoselective and enantioselective oxidation of nonactivated aliphatic C-H bonds of potential utility in organic synthesis.

Green and Convenient One-Pot Access to Polyfunctionalized Piperidine Scaffolds via Glutamic Acid Catalyzed Knoevenagel- Intramolecular [4+2] aza-Diels-Alder Imin-Based Multi-Component Reaction Under Ambient Temperature

ABSTRACTA catalytic methodology is reported that enables the green, operationally simple and convenient synthesis of corresponding polyfunctionalized piperidine scaffolds via one-pot Knoevenagel- intramolecular [4+2] aza-Diels-Alder imin-based multi-component reaction of between β-ketoesters, aromatic aldehydes and various amines, including some relevant drugs and pharmacologically active derivatives in the presence of biologically active α-amino acid, glutamic acid as a green and biodegradable catalyst. Remarkable E factors, green, readily and inexpensive catalyst, short reaction times, high to excellent yields, mild reaction conditions, high atom-economy and easy isolation procedures are key features of this methodology.

Synthesis of Alpha‐trifluoromethylthio Carbonyl Compounds: A Survey of the Methods for the Direct Introduction of the SCF3 Group on to Organic Molecules

AbstractThe role of fluorine atoms in drug discovery has become of fundamental importance, due to their ability to confer unprecedented therapeutic profiles on a molecule. In this framework, the trifluoromethylthio group (SCF3) is attracting an increasing attention in pharmaceutical, agrochemical and material chemistry and it is commonly used to modulate lipophilicity, bioavailability and metabolic stability of newly designed molecules. Actually, several drugs whose biological activity is strictly related to the presence of a SCF3 residue in the molecular scaffold are already on the market. Despite trifluoromethylthiolated carbonyl derivatives present a high potential of application in medicinal chemistry, synthetic approaches to α‐SCF3‐substituted carbonyl compounds are still limited, and catalytic strategies to access optically active functionalized carbonyl compounds are almost unexplored. The present review will discuss the use of radical, nucleophilic and electrophilic trifluoromethylthiolating reagents, to synthesize decorated trifluoromethylthio carbonyl derivatives, with a particular attention on catalytic methodologies and stereoselective methods affording enantiomerically enriched molecules.

Catalytic Aza-Wacker Annulation: Tuning Mechanism by the Activation Mode of Amide and Enantioselective Syntheses of Melinonine-E and Strychnoxanthine

An unprecedented N-substituent of the amide was found to be crucial for the successful annulation to establish 2-azabicyclo[3.3.1]nonane and other ring skeletons in good yield. The novel catalytic aza-Wacker annulation methodology was further illustrated in the concise syntheses and the absolute configuration determinations of melinonine-E and strychnoxanthine.