Site-Selective Difunctionalization of Arenes and Heteroarenes Enabled by Palladium/Norbornene Cooperative Catalysis

Poly-substituted aromatics are frequently found in pharmaceuticals and agrochemicals. During the past decades, cross-coupling reactions and nucleophilic aromatic substitutions (SNAr) have become indispensable tools for preparing functionalized arenes from readily available aryl halides. Recently, ortho metalation approaches, mediated by either stoichiometric organometallics or catalytic transition metals, enabled broadly useful ortho C−H functionalization. We were motivated by the merits of merging cross-coupling and ortho metalation, two powerful organic reactions, into a single palladium/norbornene (Pd/NBE)-catalyzed transformation. Pd/NBE catalysis, namely Catellani reaction, has recently emerged as a powerful approach for vicinal difunctionalization of arenes. Using simple aryl iodides as substrates, various nucleophiles and electrophiles have been installed at the ipso and ortho positions respectively through selective reactions with the aryl-norbornyl-palladacycle (ANP) intermediate. Some intrinsic challenges still exist in developing new Catellani-type transformation. First, the initially generated Pd(0) precatalyst must react with aryl iodide instead of the electrophile; thus, a fast/facile oxidative addition is necessary (Aryl Iodide Constraint). Second, the electrophile must selectively oxidize ANP instead of initially generated Pd(II) intermediate, which leads to a very limited electrophiles scope (Electrophile Constraint). Third, the NBE extrusion will only take place when two ortho positions of aryl iodide are blocked, otherwise undesired difunctionalization product or NBE-containing side products will be formed (Ortho Constraint). To address the aforementioned "Electrophile Constraint", we developed a direct annulation strategy between aryl iodides and epoxides, affording the desired 2,3-dihydrobenzofuran derivatives in decent yields and regioselectivity. Meanwhile, asymmetric annulation was also realized by using chiral NBE co-catalyst. Application of this method into a concise synthesis of insecticide fufenozide was then demonstrated. In addition, inspired by our previously reported ortho amination of aryl iodide, we developed an ortho thiolation strategy enabled by a new class of sulfenamide electrophile, derived from a seven-membered lactam. The arene ipso functionalization is simultaneously achieved through Heck, Suzuki or Sonogashira termination. To overcome the "Aryl Iodide Constraint", a redox-neutral ortho functionalization of aryl boroxines was developed. The reaction was initiated by a transmetalation of aryl boroxine to Pd(II) and terminated by a protodepalladation process, thereby avoiding stoichiometric amount of oxidant and reductant as well as tolerating a broader functional group including aryl iodide. In addition, a direct vicinal difunctionalization of thiophene was developed; this transformation was initiated by direct C−H palladation at C2 position of thiophene without aids of directing group, allowing for simultaneously installing two different functional groups at vicinal positions in a site-and regioselective manner. Then this difunctionalization method was successfully extended to other heteroarenes, including furans, pyrroles and indoles. Besides ortho arylation, ortho alkylation and ortho alkynylation were all realized with decent yields and regioselective. Meanwhile, a concise synthesis of Rhazinilam was realized to demonstrate the synthetic utility. Finally, a vicinal double C−H functionalization of five-membered heteroarenes with two different electrophiles in a site-selective and redox-neutral manner was realized by using aryl iodide as the first electrophile and alkynyl bromide as the second electrophile, enabling regioselective difunctionalization of a variety of five-membered heteroarenes at their C4 and C5 positions.