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.

For Abstract see ChemInform Abstract in Full Text.

The reduction of the nitro group represents a powerful and widely used transformation that allows to introducing an amino group in the molecule. New synthetic strategies for complex functionalized molecular architectures are deeply needed, including highly efficient and selective nitro reduction methods, tolerant of a diverse array of functional moieties and protecting groups. Since chiral amino groups are ubiquitous in a variety of bioactive molecules such as alkaloids, natural products, drugs, and medical agents, the development of reliable catalytic methodologies for the nitro group reduction is attracting an increasing interest also in the preparation of enantiomerically pure amines. In this context, the modern reduction methods should be chemoselective and respectful of the stereochemical integrity of the stereogenic elements of the molecule. The review will offer an overview of the different possible methodologies available for this fundamental transformation, with special attention on the most recent contributions in the field, especially in the last ten years: hydrogenations, metal dissolving and hydride transfer reductions, catalytic transfer hydrogenations, and metal-free reductions. The main advantages or limitations for the proposed methods will be briefly discussed, highlighting in some cases the most important features of the presented reduction methodologies from an industrial point of view. ■ CONTENTSAuthor Information 444 Corresponding Authors 444 Notes 444 Acknowledgments 444 References 444

The synthesis of amides remains one of the most important transformations and it is one of the more frequently performed reactions. In the pharmaceutical industry, building of the amide group is pivotal and among the more important transformations in the design of the synthetic plan. This review presents an overview of only very recent contributions, published in the last three years, to highlight the latest progresses in this "dateless" reaction, with a special focus on metal-free methodologies. New, more efficient and/or greener stoichiometric methods as well as catalytic strategies have been discussed, either for the "classical" coupling approach between an amine and a carboxylic acid (or its activated equivalent), and for more innovative approaches, mainly involving oxidation procedures to generate amides starting from amines.

A model for studying polar-pi interactions between arenes spaced at van der Waals distances is developed on the basis of peri-diarylbiphenylenes. A set of 1,8-diarylbiphenylenes is synthesized comprising two Hammett series, one with reference to mesityl ring interactions and the other with reference to pentafluorophenyl ring interactions. X-Ray crystal structures of several derivatives are determined. Barriers to rotation of the probe aryl ring are derived from dynamic NMR data and show a trend for the mesityl reference series (DeltaG(not equal) vs. sigma(0)). The model is also used as a test for comparison of modern density functional methods, including B3LYP, M06-2X and BMK functionals; dispersive effects are seen to be an important factor in the proper theoretical treatment of arene interactions.

Two series of conformationally restricted polycyclic compounds (1-3 and 4-7) have been synthesized as model systems for studying the through-space interactions between face-to-face, center-to-edge (parallel-offset) oriented arenes. These compounds feature different X substituents on one of the interacting rings. By monitoring the variation of the delta Gz for the rotation around the aryl-aryl bond in 1-7 as a function of X by 2D [1H,1H] EXSY NMR spectroscopy, it was found that the barriers increase on passing from electron-donating to electron-withdrawing substituted derivatives. Quantum mechanical calculations [MP2/DVZ (2d,p)//B3LYP/DVZ(2d,p)] gave barrier values and variations in agreement with the experimental data. The results are consistent with a repulsive arene-arene interaction dominated by electrostatic effects.

No abstract

No abstract