page_title: Mizoroki-Heck vs. Reductive Heck
section_title: Reactions with Strained Alkenes
hierarchical_section_title: Mizoroki-Heck vs. Reductive Heck / Reductive Heck Reactions / Reactions with Strained Alkenes
caption_attribution_description: English: Reactions with Strained Alkenes. (A) Illustration of the diastereospecificity of migratory insertion and β-hydride elimination with norbornene substrates. (B) Seminal example of asymmetric coupling between a vinyl triflate and a norbornene substrate. (C) Illustrative example of the influence of the halide/pseudohalide used in the reductive Heck reaction of an oxanorbornene substrate. (D) Application of the reductive Heck reaction in the total synthesis of epibatidine from a protected azanorbornene.
context_page_description: The Mizoroki−Heck coupling of aryl halides and alkenes to form C–C bonds has become a staple transformation in organic synthesis, owing to its broad functional group compatibility and varied scope. In stark contrast, the palladium-catalyzed reductive Heck reaction has received considerably less attention, despite the fact that early reports of this reaction date back almost half a century. From the perspective of retrosynthetic logic, this transformation is highly enabling because it can forge alkyl–aryl linkages from widely available alkenes, rather than from the less accessible and/or more expensive alkyl halide or organometallic C synthons that are needed in a classical aryl/alkyl cross-coupling.
  In part due to the historical difficulties of developing a generally applicable palladium-catalyzed reductive Heck protocol that is compatible with diverse alkenes, various alternative strategies to achieve alkene hydroarylation have been developed. These include dual catalytic approaches, reactions involving other metals, and mechanistically distinct palladium-catalyzed methods.
context_section_description: In a seminal study in 1980, Catellani took advantage of the diastereospecificity of migratory insertion and β-hydride elimination with norbornene substrates, allowing interception of the alkylpalladium(II) intermediate 11. In these systems, ligand exchange of the halide with formate results in formation of the norbornyl palladium species (12), which undergoes decarboxylation (12 → 13) and reductive elimination to afford the corresponding product. Later work improved the efficiency of the reaction with piperidine and tetraalkylammonium salt additives.
  Asymmetric reductive Heck couplings of norbornene scaffolds were first reported in 1991 using (R,R)-NorPhos, albeit with moderate enantioselectivity. Subsequent reports found that enantioinduction could be improved through judicious choice of ligand (switching to P,N- or N,N- type ligands) and coupling partners (use of triflates over iodides). The latter observation has been posited to arise from a suppression of competing reduction of the C(sp²)–Pdᴵᴵ intermediate prior to alkene insertion.
  
  Following the successful development of asymmetric reductive Heck couplings on norbornene, this strategy was soon extended to oxanorbornene and azanorbornene substrates. Although the exact conditions and absolute configurations are not reported, Fiaud and coworkers reported an interesting observation regarding the reductive Heck arylation of 17. Enantioselectivity was strongly influenced by the nature of the halide/pseudohalide employed, with aryl triflates coupling partners giving moderate enantiomeric excess (ee) while aryl iodides demonstrated no enantioinduction. This supports hypotheses of both cationic and neutral pathways analogous to the classic Mizoroki–Heck reaction [7, 8]. The asymmetric coupling of azanorbornene scaffolds has also been successful. In particular, the reductive Heck coupling of azanorbornene 19 has allowed for short, enantioselective syntheses of the alkaloid epibatidine and structural analogues [35–38]. Further, a strategy to access the natural product ibogaine and analogues (5) involves an intramolecular reductive Heck reaction facilitated by a tether, a strategy that has also been extended to non-strained alkenyl systems.
caption: Reactions with Strained Alkenes. (A) Illustration of the diastereospecificity of migratory insertion and β-hydride elimination with norbornene substrates. (B) Seminal example of asymmetric coupling between a vinyl triflate and a norbornene substrate. (C) Illustrative example of the influence of the halide/pseudohalide used in the reductive Heck reaction of an oxanorbornene substrate. (D) Application of the reductive Heck reaction in the total synthesis of epibatidine from a protected azanorbornene.
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