meta C–H Alkylation under Ruthenium Catalysis

In 2011, Ackermann reported on the carboxylate-assisted direct C–H alkylations of ketimine derivatives with unactivated primary alkyl bromides.^[127c] However, the alkylation reaction af arylpyridine 117b provided 41% of the corresponding ortho-product 137 along with small amounts (up to 7%) of the meta C–H alkylated ortho-product 138 (Scheme 1.37). It is noteworthy that it is the first time that meta-selectivity under ruthenium catalysis was observed.

Inspired by the observation of the first meta-selective ruthenium catalyzed alkylation, Ackermann disclosed thereafter pyridyl- and azole-directed meta-selective C–H alkylations with secondary alkyl halides 139 with catalytic amounts of sterically demanding benzoic acid (MesCO₂H) (Scheme 1.38).^[166f] Detailed mechanistic studies on isotope labeling conclusively revealed an initial reversible cycloruthenation which was supportive of a subsequent electrophilic-type alkylation. In addition, by adding stoichiometric amounts of TEMPO no reaction was observed and the reaction of an enantiomerically enriched alkyl halide provided a racemic mixture of the corresponding product.

Scheme 1.38. Remote meta C–H alkylations with secondary alkyl halides 139.

In 2015, the groups of Ackermann^[166e] and Frost^[171] independently reported on methods for the meta-selective C–H alkylations with tertiary alkyl halides 139 (Scheme 1.39).

Notably, Ackermann’s protocol used monoprotected amino acids (MPAA) as the carboxylate ligand for the first time in ruthenium-catalyzed C–H activation and a removable auxiliary strategy to access meta-substituted anilines (Scheme 1.39a). Both methods showed efficient couplings with secondary and sterically congested tertiary alkyl halides. In this context, Frost’s protocol provided the desired products 140c with less reactive tertiary alkyl chlorids (Scheme 1.39b). Detailed experimental mechanistic studies provided strong evidence for a radical pathway rather than a S_EAr and supported a ruthenium-catalyzed homolytic C−Hal cleavage, reflected by an unusual second-order dependence on the ruthenium concentration.^[166e]

1.8. Remote C–H Activation by Ruthenium Catalysis

Scheme 1.39. meta C–H alkylations with tertiary alkyl halides 139.

Based on detailed mechanistic studies, such as radical clock experiments, racemization studies and kinetic analysis, Ackermann proposed a detailed catalytic cycle (Scheme 1.40).^[166e] Starting from ruthenium(II) complex 141, reversible ortho C–H metalation generates cyclometalated intermediate 142. Subsequent radical addition of 143, which is formed via single-electron transfer (SET) from ruthenium(II) to the alkyl halide, occurs at the para-position with respect to the ruthenium forming 144. Afterwards, redox rearomatization and hydrogen-atom abstraction lead to the formation of ruthenacycle 145.

Finally, proto-demetalation delivers the meta-alkylated compound 140d and regenerates the active ruthenium catalyst 141. Although Frost presented a catalytic cycle in less detail,^[171] both groups suggested a dual role of the ruthenium catalyst, which are cyclometalation and donation of an electron to the alkyl halide via SET and therefore facilitating homolytic C–X bond cleavage.[166e, 171]

Scheme 1.40. Proposed catalytic cycle for remote C–H alkylations via ortho-ruthenation.

Inspired by the removable auxiliary strategy, Ackermann thereafter disclosed a method for the efficient C–H alkylations of easily accessible ketimines 147 with exceptional positional selectivity (Scheme 1.41a). An operationally simple one-pot protocol delivered synthetically useful meta-functionalized benzyl amines or meta/ortho-substituted arenes and late-stage modified meta-substituted arenes, such as ketones, amines, indoles, acids and phenols.^[172] Inspired by these findings, transformable/removable directing groups for meta C–H alkylation were expanded to azobenzenes^[173] 49 and phenoxypyridines^[174] 150 by the groups of Li and Yang, as well as Li, thus providing an access to substituted anilines 149 and phenols 151 after removal of the directing groups (Scheme 1.41b-c).

1.8. Remote C–H Activation by Ruthenium Catalysis

Scheme 1.41. Remote C–H alkylations of a) ketimines 147, b) azobenzenes 49 and c) phenoxypyridines 150.

In 2017, Frost reported on the remote C–H alkylations of indole derivatives utilizing N-pyrimidyl indols with an ester at the C3-position to enable remote C6 alkylation on the benzenoid ring (Scheme 1.42).^[166c] This method benefited from computational chemistry, by means of calculated Fukui indices on organic and inorganic structures, which supported that cyclometalation at the C2-position of the indol increase electron density at the C6-position.

Scheme 1.42. Remote C–H alkylations of indole derivatives 152.

In the same year, Ackermann reported on the meta C–H functionalizations on purines 155 with α-mono/difluorobromoester 156 by assistance of an electron-deficient tertiary phosphine ligand in combination with a congested carboxylate ligand (Scheme 1.43a).^[175]

Inspired by this, Ackermann further disclosed the first remote C–H alkylation on purines with an arene-ligand-free ruthenium catalyst.^[176] The C–H alkylation proceeded with various alkyl halides 139 and enabled expedient C–H fluoromethylations (Scheme 1.43b).

These approaches highlight the importance of phosphine ligands for challenging meta C–H functionalizations, especially late-stage functionalizations of highly sensitive nucleosides.

Scheme 1.43. Remote C–H alkylations of purines 155.

Very recently, a breakthrough in meta C–H alkylations by integrating photoredox chemistry was reported by the groups of Ackermann^[177] and Greaney^[178] (Scheme 1.44).

Photochemical generation of the alkyl radical species resulted in a significant decrease in the reaction temperature, allowing meta-alkylations to proceed at ambient temperature.

Although considerably milder reaction conditions were employed and no additional photocatalyst was required, the use of energy-intensive blue LEDs proved to be necessary. Notably, Greaney’s system used small amounts of water as an additive, leading to an overall improved catalytic performance (Scheme 1.44b).^[178]

1.8. Remote C–H Activation by Ruthenium Catalysis

Scheme 1.44. Photochemical remote C–H alkylations of arenes 43.

Inspired by Ackermanns report on the meta C–H functionalizations on purines 155 with α-mono/difluorobromoester,^[175] Liang disclosed in 2019 a three-component ruthenium-catalyzed meta C–H functionalization of arenes 160 (Scheme 1.45).^[179] The mild reaction conditions allowed the introduction of styrenes (5), internal alkenes (67) and acrylates (161) together with (fluoro)alkyl halides 136 or 156, in a one-pot fashion, generating diversely decorated carbon frameworks 162. Detailed mechanistic and computational studies suggested a radical mechanism through initial SET from the (fluoro)alkyl radical, followed by the radical addition to the alkene. Subsequent, the newly formed radical undergoes C_Ar−H bond addition at the para-position to the carbon−ruthenium bond.

Scheme 1.45. Three-component ruthenium-catalyzed meta C–H functionalization of arenes 160.

Taking inspiration from these transformations numerous ruthenium-catalyzed remote C–H functionalizations were developed within the last deacde, such as benzylations,^[180]

carboxylations,^[181] brominations,[166d, 182]

and nitrations.^[183]