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.

     

Copper‐Catalyzed or ‐Mediated C?H Bond Functionalizations Assisted by Bidentate Directing Groups

Copper salts, which are abundant, relatively inexpensive and possess low toxicity, have long been used as versatile catalysts for various reactions in organic synthesis. Recently, the development of Cu‐catalyzed or ‐mediated C H functionalization reactions has gained significant attention. Since the pioneering work of Daugulis on the introduction of 8‐aminoquinoline and picolinic acid auxiliaries as removable directing groups in transition metal‐catalyzed C H bond activations, the combination of copper salts with these bidentate directing groups has emerged as an innovative strategy for the construction of carbon‐carbon or carbon‐heteroatom bonds through C H bond cleavage. In addition to the 8‐aminoquinoline and picolinamide systems, several other bidentate directing groups including the 2‐aminophenyloxazoline group by Yu and Dai and the PIP system by Shi, have been developed as well. This review intends to cover most of the recent advances on copper‐catalyzed or ‐mediated direct sp² and sp³ C H bond functionalizations assisted by these bidentate directing groups. The major achievements in this area are discussed and catalogued by the type of bonds formed (C C, C O, C N, C S, C P etc.). Special attention is paid to the reaction mechanisms. Selected examples of substrates are listed as well. In addition, a personal outlook is given at the end.

     

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.     

Are DTTO and iso‐DTTO Worthwhile Targets for Synthesis?

Theoretical calculations were carried out for the isomeric di‐1,2,3,4‐tetrazine tetraoxides (DTTO and iso‐DTTO). The most important explosion performance parameters, the detonation pressure and detonation velocity, are dominated by the densities and not by the heats of formation of these compounds. Since DTTO and iso‐DTTO are unknown, reliable predictions of their crystal densities are crucial for an evaluation of the potential of these materials as explosives. In this study, the crystal densities were predicted using both Ammon’s Atom/Functional Group and Atom Code Volume Additivity Parameters and Quantum Mechanical molecular Volume methods, resulting in similar densities and explosion parameters. Although the likely uncertainties in our predicted density values are difficult to assess due to a lack of experimental data for closely related known compounds, our results demonstrate that Shechter’s originally proposed densities and performance parameters were grossly overestimated. Furthermore, it is shown that, based on our predicted density value ranges, DTTO and iso‐DTTO could match or substantially outperform the best state of the art explosives, such as CL‐20. Therefore, the synthesis of DTTO and iso‐DTTO should be further pursued.     

Phenyliodine Diacetate‐Mediated Intramolecular C(sp2)?H Amidation for 1,2‐Disubstituted Benzimidazole Synthesis under Metal‐Free Conditions

A transition metal‐free, hypervalent iodine(III) reagent [phenyliodine diacetate (PIDA)]‐mediated C(sp²) H amidation in trifluoroethanol (TFE) has been developed. The intramolecular coupling methodology presented here provides a direct access to 1,2‐disubstituted multifunctional benzimidazoles in good to excellent yields. The reactions were performed in the open air and at ambient temperature, and were found to be eco‐friendly and atom‐economical.

     

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.     

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.     

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.     

Copper‐Catalyzed Highly Regioselective Oxidative C?H Bond Amidation of 2‐Arylpyridine Derivatives and 1‐Methylindoles

Copper(I) bromide‐catalyzed amidation of 2‐arylpyridine derivatives and 1‐methylindoles with a variety of amides was achieved by employing tert‐butyl peroxide (TBP) as oxidant. Aryl halides could be tolerated under the reaction conditions. Neither a special ligand nor a base was required for this amidation process.     

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.

     

Copper‐Catalyzed C?NH2 Arylation of 2‐Aminobenzimidazoles and Related C‐Amino‐NH‐azoles

A copper(II)‐catalyzed selective C NH₂ arylation of 2‐aminobenzimidazoles and related C‐amino‐NH‐azoles was achieved in presence of 2,2′‐bipyridine and cesium carbonate at 60 °C under open air conditions and this is first method for the copper‐catalyzed selective C NH₂ arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the C NH₂ position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important C NH(aryl) derivatives of aminoazoles without any protection/deprotection of ring N H bonds. It is first example for the selective C NH₂ arylation of 5‐aminoindazole, 4‐aminopyrazole, 5‐aminopyrazole, 9H‐purine‐6‐amine, and 1H‐pyrazolo[3,4‐d]pyrimidin‐4‐amine derivatives.

     

The Nitrile‐Forming Enzyme 7‐Cyano‐7‐Deazaguanine Synthase from Geobacillus kaustophilus: A Reverse Nitrilase?

7‐Cyano‐7‐deazaguanine synthase (E.C. 6.3.4.20) is an enzyme that catalyzes the formation of a nitrile from a carboxylic acid and ammonia at the expense of ATP. The protein from G. kaustophilus was heterologously expressed, and its biochemical characteristics were explored by using a newly developed HPLC‐MS based assay, ³¹P NMR, and a fluorescence‐based thermal‐shift assay. The protein showed the expected high thermostability, had a pH optimum at pH 9.5, and an apparent temperature optimum at 60 °C. We observed strict substrate specificity of QueC for the natural substrate 7‐carboxy‐7‐deazaguanine, and determined AMP and pyrophosphate as co‐products of preQ₀.     

“On Water” Direct and Site‐Selective Pd‐Catalysed C?H Arylation of (NH)‐Indoles

This communication describes the development of a versatile catalytic system based on palladium(II) acetate/bis(diphenylphosphino)methane [Pd(OAc)₂/dppm] that works “on water” giving site‐selective C H arylation of (NH)‐indoles without protecting or directing groups. Remarkably, the control of regioselectivity was achieved by small changes in the “extra‐catalytic” base/halide partners. These innovative methodologies allow a high‐yielding access to both C2 and C3‐arylindoles, as well as 2,3‐diarylindoles, and display high chemo/regioselectivities and structural versatility with regard to either indole or aryl moieties.     

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.     

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.

     

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.     

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%.