C-H Activation: Toward Sustainability and Applications

Abstract

Since the definition of the "12 Principles of Green Chemistry" more than 20 years ago, chemists have become increasingly mindful of the need to conserve natural resources and protect the environment through the judicious choice of synthetic routes and materials. The direct activation and functionalization of C-H bonds, bypassing intermediate functional group installation is, in abstracto, step and atom economic, but numerous factors still hinder the sustainability of large-scale applications. In this Outlook, we highlight the research areas seeking to overcome the sustainability challenges of C-H activation: the pursuit of abundant metal catalysts, the avoidance of static directing groups, the replacement of metal oxidants, and the introduction of bioderived solvents. We close by examining the progress made in the subfield of aryl C-H borylation from its origins, through highly efficient but precious Ir-based systems, to emerging 3d metal catalysts. The future growth of this field will depend on industrial uptake, and thus we urge researchers to strive toward sustainable C-H activation.

Figure 1

C–H Activation: sustainability trends.

Scheme 1. C–H Activation: Intrinsic Opportunities

Scheme 2. PDP-Mediated Alkane Oxidations

Scheme 3. Porphyrin/Phthalocyanine-Mediated Amination and Amidation

Scheme 4. Mn- and Co-Catalyzed C–H Functionalizations

Scheme 5. Ni-Catalyzed Undirected anti-Markovnikov Addition of Alkenes to Arenes

Scheme 6. Fujiwara–Moritani Reaction Catalyzed by Pd on Silica

Scheme 7. C–H Bromination Catalyzed by Pd Supported on a Salen-Based, Hyper-Cross-Linked Polymer

Scheme 8. Oxidative Coupling of Aminophenol Catalyzed by Heterogeneous Mn-Based K-OMS-2

Scheme 9. Directing Group Mode of Action

Scheme 10. Arylation of Bicyclic Amines with Removable DG

Scheme 11. Native Heteroatom Directed C(sp³)–H Arylation

Scheme 12. Co-Catalyzed C–H Methylation of Paclitaxel

Scheme 13. Regioselective C–H Hydroarylation with Internal Asymmetric Alkynes

Scheme 14. Regioselective Annulation Using a Carbonate TsDG

Scheme 15. Pd-Catalyzed CDC Using an Aniline TtDG

Scheme 16. C(sp³)–H Arylation Using a Carbamate TtDG

Scheme 17. Bidentate TtDG Mediated C(sp³)–H Arylation and Alkylation

Scheme 18. Atroposelective C–H Activation

Scheme 19. Transient Norbornene-Directed Amination

Scheme 20. Pd-Catalyzed Allylic Functionalization

Scheme 21. Rh-Catalyzed Allylic Functionalization

Scheme 22. Low-Loading Pd-Catalyzed Examples of Undirected C–H Activation

Scheme 23. Greener Alternatives to Static DGs

Scheme 24. General C–H Activation Mechanism Using Stoichiometric Oxidants

Scheme 25. General C–H Activation Mechanism Using a Preoxidized DG

Scheme 26. C–H Functionalizations Using Preoxidized DGs

Scheme 27. Indole Syntheses with Stoichiometric and Catalytic Cu Oxidant

Scheme 28. Rh-Catalyzed C–H Alkenylation with Air as the Terminal Oxidant

Scheme 29. General C–H Activation Involving Catalyst Photooxidation, with O₂ as Terminal Oxidant

Scheme 30. Photoredox Enabled C2-Acylation of Indoles

Scheme 31. Sequential C–C and C–N Bond Formation Catalyzed by a Co and a Photoredox Catalyst

Scheme 32. An Integrated Catalyst for C–H Activation and Photooxidation

Scheme 33. A Generalized Mechanism of C–H Activation Involving Anodic Oxidation

Scheme 34. Cobalta-Electrocatalyzed C–C/C–N Bond Formation

Figure 2

Pyramid of oxidation method sustainability.

Scheme 35. Iron-Catalyzed C–H Activation of Allenes in 2-MeTHF

Scheme 36. Direct C–H Arylation in Eucalyptol

Scheme 37. Ru-Catalyzed Annulation Reaction in PEG-400

Scheme 38. Intramolecular C–H Functionalization of 1,2,3-Triazoles in GVL

Scheme 39. Aqueous Tandem C–H/N–H Activation

Scheme 40. Evolution of Precious-Metal-Catalyzed Aryl Borylation

Scheme 41. PMP-Co Complex-Mediated Borylation