An Indium(III)‐Catalyzed Synthesis of 4,4‐Dichloro‐1‐aryl‐N‐alkyl‐1‐yn‐3‐amines via an Intermolecular C(sp2)?C(sp) Bond Formation

This paper demonstrates an indium(III) triflate‐catalyzed reaction of electron‐deficient α,α‐dichloroaldimines with terminal alkynes leading to a rapid and selective access to highly functionalized propargylic amines in good to excellent yields. The dichloromethylene moiety of the aldimine acts as an activating group to accomplish this transformation under very mild conditions.     

Diruthenium(I,I) Catalysts for the Formation of β‐ and γ‐Lactams via Carbenoid C?H Insertion of α‐Diazoacetamides

Intramolecular carbenoid C H insertion of five α‐diazoacetamides [N₂CH CONR₂, NR₂=NEt₂ ( 3a ), NBu₂ ( 3b ), N(i‐Pr)₂ ( 3c ), N(CH₂Ph)₂ ( 3d ), N(i‐Pr)(CH₂Ph) ( 3e )], was investigated using as catalysts dinuclear Ru(I,I) complexes of the type [Ru₂(μ‐L¹)₂(CO)₄L²₂], where L¹ is a bidentate bridging acetate, calix[4]arenedicarboxylate, saccharinate, pyridin‐2‐olate, or triazenide ligand, as well as [RuCl₂(p‐cymene)]₂. The Ru(I,I) complexes were found to be suitable catalysts for the carbenoid cyclization reactions, except in the case of 3a . With diazoamides 3b–e , [Ru₂(μ‐sac)₂(CO)₅]₂ (sac=saccharinate) and [Ru₂(μ‐6‐chloropyridin‐2‐olate)₂(CH₃CN)₂(CO)₄] are as effective as Rh₂(OAc)₄ under the same conditions, although some differences in the regioselectivity and chemoselectivity of the cyclization are observed. The carbenoid cyclization reactions yield γ‐lactams from diazoamides 3a and 3b , both a β‐ and a γ‐lactam from 3c , and a β‐lactam as well as a 3‐azabicyclo[5.3.0]deca‐5,7,9‐trien‐2‐one from 3d . With 3e , formation of γ‐lactam 21 and of bicyclic lactam 23 prevails.     

Synthesis of 3‐Aryl‐1‐trifluoromethyltetrahydroisoquinolines by Brønsted Acid‐Catalyzed C(sp3)?H Bond Functionalization

A concise route to 3‐aryl‐1‐trifluoromethyltetrahydroisoquinolines by a benzylic [1,5]‐hydride shift‐mediated C H bond functionalization was developed. The [1,5]‐hydride shift of the benzylic C(sp³) H bond to the trifluoromethylketimine derived from para‐anisidine occurred smoothly to produce cis‐1‐trifluoromethyl‐3‐aryltetrahydroisoquinolines in good to excellent chemical yields with good diastereoselectivities. In contrast, use of the N H ketimine furnished N‐unprotected tetrahydroisoquinolines in good yields in favor of the trans‐isomer.

     

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

Copper binding to α‐synuclein (aS) and to amyloid‐β (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ? peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, β‐synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu^I ligand. We found that: 1) the peptides containing the Cu‐binding domains Ab1–16, aS1–15 and bS1–15 have similar affinities towards Cu^II and towards Cu^I, with Ab1–16 being slightly stronger, 2) in the case of Cu^I, the additional Met residue in bS1–15 increased the affinity slightly, 3) the exchange of Cu^I/II between the two peptides is rapid (≤ms), 4) a/bS1–15 and Ab1–16 form a heterodimeric complex with Cu^II, 5) Cu^I probably promotes a transient ternary complex, 6) the different Cu^I/II coordination of Ab1–16, aS1–15 and bS1–15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1–16, aS1–15 and Cu are present, the ROS production more closely resembles that by Ab1–16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.     

Cyclobutanone Analogues of β‐Lactam Antibiotics: β‐Lactamase Inhibitors with Untapped Potential?

β‐Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β‐lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β‐lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all‐carbon ring, the amide N is substituted by a tertiary C?H α to a ketone. Cyclobutanone analogues of various β‐lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the β‐lactamase enzymes that impart resistance to β‐lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of β‐lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of β‐lactamase; other compounds from this family inhibit Streptomyces R61 dd ‐carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising diversely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural diversity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.     

Design and Synthesis of 2‐Methyl‐7‐aminobenzoxazole as Auxiliary in the Palladium(II)‐Catalyzed Arylation of a beta‐Positioned C(sp3)?H Bond

A palladium(II)‐catalyzed direct arylation of methylene C(sp³) H bonds by 2‐methyl‐7‐aminobenzoxazole as an effective auxiliary is reported. This process exhibited high beta‐site selectivity, broad substrate scope, and compatibility with different functional groups with moderate to high yields up to 89%.

     

Should we be concerned about the dietary ω‐6:ω‐3 polyunsaturated fatty acid ratio?

Omega‐6 and ω‐3 polyunsaturated fatty acids compete at the active sites of enzymes responsible for Δ‐6 desaturation, incorporation into membrane phospholipids, release from membrane phospholipids and conversion into either prostaglandins or leukotrienes. Since prostaglandins are involved in the processes of platelet aggregation and inflammation then it has been suggested that ω‐6 and ω‐3 PUFA compete in vivo and that this has consequences for cell function and ultimately for health. It has been proposed that the dietary ω‐6: ω‐3 PUFA ratio should be used to measure this competition. Theoretical objections to the use of this ratio have recently been confirmed by hard scientific evidence showing that absolute amounts of ω‐6 and ω‐3 PUFA in the diet are more important than the ratio.     

Iridium(III)‐Catalyzed Direct C?H Sulfonamidation of 2‐Aryl‐1,2,3‐triazole N‐Oxides with Sulfonyl Azides

We have developed a method for the direct sulfonamidation of 2‐aryl‐1,2,3‐triazole N‐oxides using sulfonyl azides as the amino source to release molecular nitrogen as the sole by‐product. This protocol exhibits excellent functional group tolerance and proceeds efficiently under external oxidant‐free conditions. Various 2‐(2‐sulfonamidoaryl)‐1,2,3‐triazoles were prepared in up to 97% yields for 25 examples with excellent regioselectivity.

     

Palladium‐Catalyzed Decarboxylative Coupling of α‐ Oxocarboxylic Acids with C(sp2)?H of 2‐Aryloxypyridines

An efficient palladium‐catalyzed decarboxylative ortho‐acylation of 2‐aryloxypyridines with α‐oxocarboxylic acids is described. In this new transformation, the aromatic C(sp²) H bond was successfully acylated to give diverse aromatic ketones regioselectively in moderate to good yields. The pyridine group can be removed easily after the acylation to give the corresponding 2‐hydroxy aromatic ketones.     

Copper‐Catalyzed Direct C?H Arylation of Thieno[3,4‐c]pyrrole‐4,6‐dione (TPD): Toward Efficient and Low‐Cost Synthesis of π‐Functional Small Molecules

A series of thieno[3,4‐c]pyrrole‐4,6‐dione (TPD)‐based functional small molecules were efficiently synthesized through direct C H arylations using inexpensive copper salts. In this study, we examined all required reaction parameters including various copper complexes, ligands, bases, and (co)solvents. Under the optimum reaction conditions, the C H arylation proceeded smoothly and a variety of functional groups such as ester, nitrile, fluoride, chloride, triazene, and amine were tolerated. This method provides a step‐economical and relatively low‐cost synthetic alternative to presently used coupling reactions for the preparation of TPD‐containing π‐functional materials.

     

Transition Metal‐Free α‐C(sp3)?H Bond Functionalization of Amines by Oxidative Cross Dehydrogenative Coupling Reaction: Simple and Direct Access to C‐4‐Alkylated 3,4‐Dihydroquinazoline Derivatives

A transition metal‐free catalytic system has been developed for the cross dehydrogenative coupling of amines with nitroalkanes under mild condition employing potassium iodide/tert‐butyl hydrogen peroxide catalytic system. This methodology was further extended for the construction of biologically important N‐heterocycles, namely, 3,4‐dihydroquinazoline derivatives. This novel strategy provides a simple, efficient, and direct access to 4‐alkyl‐3,4‐dihydroquinazoline derivatives.     

Rhodium(II)‐Catalyzed Carbenoid Insertion of N‐Tosylhydrazones into Amide N?H Bonds: An Efficient Approach to N3‐Benzyl/Alkyl‐2‐arylquinazolinones

Dirhodium(II) acetate‐catalyzed reactions of N‐tosylhydrazones with dihydroquinazolinones bearing different types of N H bonds that give N³‐benzyl/alkyl‐2‐arylquinazolin‐4(3H)‐ones through Csp³ N bond formation by oxidative dehydrogenation and insertion of rhodium‐carbenoid into amide N H bond are reported for the first time. This method features good to excellent yields, good functional group tolerance, high regioselectivity and readily available starting materials.

     

Are 1,4‐ and 1,5‐Disubstituted 1,2,3‐Triazoles Good Pharmacophoric Groups?

Over the last decade, 1,2,3‐triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3‐dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3‐triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X‐ray crystal structures of complexes between 1,2,3‐triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3‐triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.     

Iron(III)/Iodine‐Catalyzed C(sp2)?H Activation of α,β‐Unsaturated Aldehydes/Ketones with Amidines: Synthesis of 1,2,4,5‐Tetrasubstituted Imidazoles

An efficient methodology to access a library of 1,2,4,5‐tetrasubstituted imidazoles from a broad range of amidines and α,β‐unsaturated aldehydes/ketones via a C(sp²) H amination has been developed. This method represents a new and simple way to prepare highly substituted imidazoles from easily available starting materials, inexpensive catalysts, and with good functional group tolerance in good to excellent yields.

     

Organocatalytic Asymmetric C?S Bond Formation: Synthesis of α‐Methylene‐β‐mercapto Esters with Simple Alkyl Thiols

A highly efficient organocatalytic enantioselective C S bond formation reaction between simple alkyl thiols and Morita–Baylis–Hillman (MBH) carbonates is described. The optically active α‐methylene β‐mercapto esters could be obtained under mild reaction conditions with excellent enantioselectivities (up to 97% ee). The broad scope and simple operation make this methodology very practical.     

Copper(II)‐Catalyzed Aerobic Oxidative Coupling between Chalcone and 2‐Aminopyridine via C?H Amination: An Expedient Synthesis of 3‐Aroylimidazo[1,2‐a]pyridines

A simple and efficient protocol has been developed for the synthesis of 3‐aroylimidazopyridines via copper(II) acetate‐catalyzed aerobic oxidative amination. A library of 3‐aroylimidazopyridines was synthesized from readily accessible chalcones and 2‐aminopyridines with high yields and regioselectivity. The reaction proceeds through a tandem Michael addition followed by an intramolecular oxidative amination. The successful application of this methodology for a gram‐scale reaction indicates its potential for bulk synthesis.

     

α,β‐Unsaturated Aldehydes as Substrates for Asymmetric C?C Bond Forming Reactions with Thiamin Diphosphate (ThDP)‐Dependent Enzymes

The enzymes benzaldehyde lyase (BAL) from Pseudomonas fluorescens, benzoylformate decarboxylase (BFD) from Pseudomonas putida and pyruvate decarboxylase (PDC) from Saccharomyces cerevisiae provide different C C bond forming possibilities of α,β‐unsaturated aldehydes with aliphatic and aromatic aldehydes. Structure elucidation and determination of the absolute configuration of the products, which were obtained with high regio‐ and stereoselectivity were carried out. Selective 1,2‐reactivity with yields of 75% and >98% ee, for one single isomer ( A ) were obtained, by choosing the suitable enzyme in combination with the appropriate substrates. By varying enzymes or substrates the regioisomeric hydroxy ketones C , with up to >99% ee, can be obtained. The application of these new chiral building blocks in the synthesis of natural products or biological active substances is considerably facilitated by applying the different ThDP‐dependent enzymes as catalysts. Abbreviations: BAL, benzaldehyde lyase; BFD, benzoylformate decarboxylase; PDC, pyruvate decarboxylase; His, hexahistidine; 2‐HPP, 2‐hydroxy‐1‐phenylpropan‐1‐one; PAC, phenylacetylcarbinol; NTA, nitrilotriacetic acid; ThDP, thiamin diphosphate; wt, wild‐type.     

Silver(I)‐Mediated C?H Amination of 2‐Alkenylanilines: Unique Solvent‐Dependent Migratory Aptitude

A highly effective silver(I)‐mediated C H amination of 2‐alkenylanilines has been developed to afford a diverse range of substituted indoles. High functional group tolerance, broad substrate scope, simple/fast/high‐yielding reaction, and recovery/reuse of the inexpensive silver oxidant are noteworthy. Furthermore, an uncommon migratory process of β‐monosubstituted 2‐alkenylanilines with solvent‐dependence was demonstrated.