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      Practical and innate C–H functionalization of heterocycles

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          Abstract

          Nitrogen-rich heterocyclic compounds have had a profound impact on human health, as these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition metal-mediated cross-coupling have simplified the synthesis of such molecules; however, the development of practical and selective C–H functionalization methods that do not rely upon prefunctionalized starting materials is an underdeveloped area. 19 Paradoxically, the innate properties of heterocycles that make them so desirable for biological applications render them challenging substrates for direct chemical functionalization, such as limited solubility, functional group incompatibilities, and reagent/catalyst deactivation. Herein we report that zinc sulfinate salts 9 can be used to transfer alkyl radicals to heterocycles, allowing for a mild, direct and operationally simple formation of medicinally relevant C–C bonds while reacting in an orthogonal fashion to other innate C–H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition metal-mediated C–H insertion, C–H deprotonation). 27, 9 A toolkit of these reagents was prepared and reacted across a wide range of heterocycles (natural products, drugs, building blocks) without recourse to protecting group chemistry, and can even be employed in a tandem fashion in a single pot in the presence of water and air.

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          Most cited references31

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          Fluorine in medicinal chemistry.

          It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
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            Fluorine in pharmaceuticals: looking beyond intuition.

            Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.
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              Synopsis of some recent tactical application of bioisosteres in drug design.

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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                19 October 2012
                28 November 2012
                6 December 2012
                06 June 2013
                : 492
                : 7427
                : 95-99
                Affiliations
                Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
                [+ ]Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 1077 Science Center Drive, San Diego, California 92121
                Author notes
                [* ]Correspondence and requests for materials should be addressed to P. S. B pbaran@ 123456scripps.edu
                [†]

                These authors contributed equally to the manuscript

                Article
                NIHMS415404
                10.1038/nature11680
                3518649
                23201691
                884732dd-4ada-46b3-9d32-fb603fc03e25

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: R01 GM073949 || GM
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