The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation.

Cu-catalysed arylation reactions devoted to the formation of C-C and C-heteroatom bonds (Ullmann-type couplings) have acquired great importance in the last decade. This review discusses the history and development of coupling reactions between aryl halides and various classes of nucleophiles, focusing mostly on the different mechanisms proposed through the years. Selected mechanistic investigations are treated more in depth than others. For example, evidence in favour or against radical mechanisms is discussed. Cu(I) and Cu(III) complexes involved in the Ullmann reaction and N/O selectivity in aminoalcohol arylation are discussed. A separate section has been dedicated to the synthesis of heterocyclic rings through intramolecular couplings. Finally, recent developments in green chemistry for these reactions, such as reactions in aqueous media and heterogeneous catalysis, have also been reviewed.

Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. Microflow Technology and Photochemistry: A Perfect MatchThe use of light to promote chemical reactions has been exploited since the 18th century, but only recently a resurgence has been observed in synthetic organic chemistry, in particular due to the development of visible-light photoredox catalysis [1-5]. All transformations involving light (e.g., Figure 1A-D) must consider, besides classical chemical parameters (i.e., reaction conditions), the photophysical aspects of the sensitizer (see Glossary)/photocatalyst (when used), and the reactor design. The latter, although often neglected by chemists, is a critical aspect for the outcome of the studied chemical transformation. This includes, for example, the size, shape, and material of the reaction vessel, the characteristics and positioning of the light source(s), and heat-transfer properties, particularly when high-intensity lamps are used [6,7]. The engineering and technological aspects of photochemical processes are often at the basis of the irreproducibility and non-scalability of such transformations.According to the Beer-Lambert law, light transmittance decreases exponentially with the distance from the light source ( Figure 1F). For a standard batch reactor (diameter at least in the centimeter range), light intensity decreases considerably from the flask walls to the middle of the reaction mixture, resulting in slow reactions and nonhomogeneous irradiation of the reaction mixture. Performing photochemical reactions in microchannels (ID < 1 mm) allows a higher and more homogeneous photon flux, resulting in shorter reaction times and consequently less side-product formation due to over-irradiation, often observed in batch [8,9]. Another advantage of microflow chemistry, correlated with the large surface:volume ratio, is improved heat and mass transfer, with the possibility to perform mass-transfer-limited multiphasic reactions efficiently [10]. Reactive chemicals and intermediates can be handled more safely in flow than in batch, as no accumulation of dangerous components occurs within the confined reactor volume due to the continuous nature of the process. Together, these result in often faster, safer, and higher-yielding reactions, with the possibility to perform reactions under condition...

The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as Cu(II) complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry.

Ac ontinuous-flow, visible-light-promoted method has been developed to overcome the limitations of iron-catalyzedK umada-Corriu cross-coupling reactions.Avariety of strongly electron rich aryl chlorides,p reviously hardly reactive,c ould be efficiently coupled with aliphatic Grignard reagents at room temperature in high yields and within af ew minutes residence time,c onsiderably enhancing the applicability of this iron-catalyzedr eaction. The robustness of this protocol was demonstrated on amultigram scale,thus providing the potential for future pharmaceutical application. Scheme 1. C(sp 2)ÀC(sp 3)b ond formation through Kumada-Corriu cross-coupling reactions.

A copper-catalyzed aerobic oxidation of benzylpyridine N-oxides is reported. The N-oxide moiety acts as a built-in activator for the benzylic methylene oxidation, without requirement of additives. Reaction conditions were identified which suppress undesired benzoylpyridine formation via N-deoxygenation involving intermolecular oxygen transfer. The versatility of the Noxide group of the benzoylpyridine N-oxide reaction products for post-functionalization of the pyridine ring is demonstrated through efficient C-C, C-N, C-O and C-Cl bond forming procedures, with both nucleophiles and electrophiles. Finally, the applicability of the new synthetic methodology is demonstrated in an alternative route towards the anti-histaminic drug Acrivastine via three consecutive N-oxide activated C-H functionalization processes, starting from picoline N-oxide.

A new synthesis of 1,1,1-tris(pyrid-2-yl)ethane (L), and a survey of its coordination chemistry, are reported.

The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the residence time up to 16 times in comparison to the batch procedure, while achieving similar or higher yields. In addition, the use of inorganic bases was demonstrated to increase the reaction yield under batch conditions.