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.
Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in ...academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.
Abstract
(Pentamethylcyclopentadienyl)rhodium (RhCp*)‐catalyzed CH transformations have emerged as a prosperous field in CH bond activation. Recent advances in this area have significantly focused ...on the development of new strategies for CC and Cheteroatom bond formation that are characterized by the novel reactivity of the RhCp* catalyst to undergo formal S
N
‐type reactions with electrophilic substrates. This review is intended to give an overview on this rather new class of RhCp*‐catalyzed CH transformations, covering recent CC and Cheteroatom bond‐forming reactions. The nature of the reaction partner in these CH functionalization reactions serves as a guideline throughout this article and, combined with selected descriptions of mechanistic proposals, should emphasize general characteristics of transformations within this novel reaction class.
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