Conspectus Reactions that convert carbon–hydrogen (C–H) bonds into carbon–carbon (C–C) or carbon–heteroatom (C–Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C–H bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C–H functionalization reactions become more widely utilized in organic synthesis. Research in the area of homogeneous transition metal–catalyzed C–H functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as “first functionalization.” Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C–H cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid over-functionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account. The second subfield of C–H functionalization involves substrates containing one or more pre-existing functional groups, termed “further functionalization.” One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C–H cleavage. Precoordination can overcome the paraffin nature of C–H bonds by increasing the effective concentration of the substrate so that it needn't be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs—the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs. In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C–H cle...

Controlling positional selectivity of C–H activation in molecules possessing multiple inequivalent C–H bonds is one of the most important challenges in developing synthetically useful C–H activation reactions. One widely used approach utilizes σ-chelating directing groups to achieve ortho-selectivity through conformational rigid five- or six-membered cyclic pre-transition states (TS).1–14 We envisioned that an “end-on” chelating template capable of delivering catalysts to previously inaccessible remote meta-C–H bonds via a macrocyclic cyclophane-like pre-TS could overcome the limitations imposed by traditional ortho-directing groups. Herein, we report a class of readily removable nitrile-containing templates that direct the activation of distal meta-C–H bonds (≥ 10 bonds away) of a tethered arene. We attribute this new mode of C–H activation to the weak “end-on” coordination of the linear nitrile group to metal center, as previously observed by Schwarz in the study of remote C–H activation of alkyl nitriles in gas phase.15, 16 The coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C–H activation event. Remarkably, this template overrides electronic and steric biases and ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids), thus constituting a fundamentally new mode of directed C–H activation that is anticipated to be widely adopted.

Reductive elimination from partially or completely oxidized metal centers is a vital step in a myriad of carbon–carbon and carbon–heteroatom bond–forming reactions. One strategy for promoting otherwise challenging reductive elimination reactions is to oxidize the metal center using a two-electron oxidant (i.e., from M(n) to M(n+2)). However, many of the commonly used oxidants for this type of transformation contain oxygen, nitrogen, or halogen moieties that are subsequently capable of participating in reductive elimination, leading to a mixture of products. This minireview examines an emerging solution to this widespread problem in organometallic chemistry, the use of bystanding F+ oxidants, and describes recent applications in Pd(II)/Pd(IV) and Au(I)/Au(III) catalysis. We then briefly discuss a rare example in which one-electron oxidants have been shown to promote selective reductive elimination in Pd(II)-catalyzed C–H functionalization, which we view as a promising future directing in the field.

Electrochemical transition metal catalysis is a powerful strategy for organic synthesis because it obviates the use of stoichiometric chemical oxidants and reductants. C–H bond functionalization offers a variety of useful conversions of simple and ubiquitous organic molecules into diverse functional groups in a single synthetic operation. This review summarizes recent progress in merging electrochemistry with transition metal-catalyzed C–H functionalization, specifically C–C, C–X (halogen), C–O, C–P, and C–N bond formation.

C-H amination of N-aryl benzamides with O-benzoyl hydroxylamines has been achieved with either Pd(II) or Pd(0) catalysts. Furthermore, we demonstrate that secondary amines can be directly used with benzoyl peroxide in a one-pot procedure that proceeds via the in situ generation of the appropriate O-benzoyl hydroxylamines. This catalytic reaction provides a new disconnection for the convergent synthesis of tertiary and secondary arylalkyl amines starting from benzoic acids.

Pd(OTf)(2) x 2 H(2)O-catalyzed ortho-fluorination of triflamide-protected benzylamines is reported. The use of N-fluoro-2,4,6-trimethylpyridinium triflate as the F(+) source and NMP as a promoter is crucial for this reaction. The conversion of triflamide into a wide range of synthetically useful functional groups makes this fluorination protocol broadly applicable in medicinal chemistry and synthesis.

Hand in hand: A versatile CH activation route for the synthesis of indolines, tetrahydroquinolines, and tetrahydroisoquinolines from simple arylethylamines relies on a one‐pot iodination and amination reaction (see scheme, Tf=trifluoromethanesulfonyl). The natural amino acids phenylalanine, tyrosine, and tryptophan can be converted into various heterocycles by using this technology.

Palladium-catalyzed C-H activation/C-O bond-forming reactions have emerged as attractive tools for organic synthesis. Typically, these reactions require strong chemical oxidants, which convert organopalladium(II) intermediates into the Pd or Pd oxidation state to promote otherwise challenging C-O reductive elimination. However, previously reported oxidants possess significant disadvantages, including poor atom economy, high cost, and the formation of undesired byproducts. To overcome these issues, we report an electrochemical strategy that takes advantage of anodic oxidation of Pd to induce selective C-O reductive elimination with a variety of oxyanion coupling partners.