H-Phosphonate-Mediated Sulfonylation Of Heteroaromatic N-Oxide

The possibility of direct introduction of a new functionality via direct C-H bond transformation is a highly attractive strategy with high atom economy in covalent synthesis. Since carbon-heteroatom bond has an important role in the field of organic synthesis, substantial growth in carbon-heteroatom bond formation based on the transition-metal-catalyzed C-H bond activation has been observed. It is worth noticing that almost all of these reported catalysts contain metal, even toxic or noble metal and that building carbon-heteroatom bond by C-H activation with more green methods under metal free conditions were rarely reported. It is worth noting that the development of effective C-S bond formation reactions is less developed compared to C-N and C-O bond formation under metal catalytic conditions. It is well known that quinoline(or pyridine) is a highly important structural moiety that has been found in several natural products and a wide range of marketed drugs. Sulfones are not only versatile synthetic intermediates, but also exhibit a broad range of physical, chemical and biological activities. Therefore, a rapid, efficient, and practical access to those heteroaromatic sulfone compounds via C-H activation under metal free conditions is highly desired from a synthetic practicality viewpoint.According to the reported literatures, the synthesis of those heteroaromatic sulfone compounds mainly include:(1) oxidation of the corresponding sulfides;(2) alkylation or arylation of sulfinate salts;(3) copper-catalyzed sulfonylation of quinoline N-oxides. However, almost all of these methods suffer from disadvantages such as inaccessible sulfinate salts, long reaction time, requiring metal catalytic, or relatively harsh reaction conditions. Herein, we have developed a straight forward method by which a wide variety of N-heteroaromatic sulfones were synthesized via C-H bond activation, by a one-pot reaction of heteroaromatic N-oxides with widely available sulfonyl chlorides in the presence of diisopropyl H-phosphonate. Compared with literature methods, great advantages of this strategy include a wide range of reaction substrates, an efficient time-saving one-pot procedure, and extremely mild and metal-free reaction conditions. Finally, we comprehensively expound the mechanism of the reaction by using the 31 P NMR stacks and designed experiments.The main contents of this paper are as follows:1. The reaction conditions were optimized from the respects such as variety of H-phosphonates, ideal amount of H-phosphonate, the amount of reaction substrates, the influence of various bases, optimal amount of base and solvent with the template reaction of quinoline N-oxide and P-toluene sulfonyl chloride. t the best reaction conditions are as follows: diisopropyl H-phosphonate(1 equiv.), P-toluene sulfonyl chloride(2 equiv.), KOH(4 equiv.),THF(7 m L).2. Under the optimized conditions, the scope and regularity of this reaction were investigated. To our delight, the sulfonyl method could well be applied to both aryl and alkyl sulfonyl chlorides, the different substituent of quinoline N-oxides, pyridine N-oxides, isoquinoline N-oxides and quinoxaline. And 24 coupled compounds were synthesized with structural elucidation by 1H NMR、13C NMR and HRMS.3. We studied the mechanism of this reaction by using 31 P NMR stacks. Designed experiment:...