Regiodivergent C-H and Decarboxylative C-C Alkylation by Ruthenium Catalysis: ortho versus meta Position-Selectivity

Abstract

Ruthenium(II)biscarboxylate complexes enabled the selective alkylation of C-H and C-C bonds at the ortho- or meta-position. ortho-C-H Alkylations were achieved with 4-, 5- as well as 6-membered halocycloalkanes. Furthermore, the judicious choice of the directing group allowed for a full control of ortho-/meta-selectivities. Detailed mechanistic studies by experiment and computation were performed and provided strong support for an oxidative addition/reductive elimination process for ortho-alkylations, while a homolytic C-X cleavage was operative for the meta-selective transformations.

Keywords: C−C activation; C−H activation; alkylation; decarboxylation; ruthenium.

Scheme 1

Ruthenium‐catalyzed site‐selective alkylations.

Scheme 2

Site‐selective C−H alkylations.

Scheme 3

(a) Site‐selectivity of ruthenium‐catalyzed C−H alkylations of pyrazole 5 a with various bromocycloalkanes 2, (b) scope for C−H alkylation of pyrazoles 5. [a] The yield of meta‐alkylated product 7 is given in parentheses. [b] o‐Xylene was used as solvent.

Scheme 4

Electronic effect on the site‐selectivity of ruthenium‐catalyzed C−H alkylations of arylpyrazoles 5 with bromocyclohexane (2 a). [a] The yield of meta‐alkylated product 7 is given in parentheses. [b] Dialkylated product was obtained in 29 % yield.

Scheme 5

Ruthenium‐catalyzed C−H alkylation of phenylpyrazole 5 g. [a] The yield of di‐meta‐alkylated product is given in parentheses.

Scheme 6

Key mechanistic studies: (a) reaction in the presence of radical scavengers, (b) C−H alkylations with diastereomerically pure alkyl bromides 2.

Scheme 7

(a) Reactions with cyclometalated complex as catalysts, (b) detection of free p‐cymene. [a] The yield in parentheses was determined by ¹H‐NMR using 1,3,5‐trimethoxybenzene as the internal standard.

Figure 1

Relative Gibbs free energy profile for the oxidative addition/reductive elimination elementary step at the PW6B95‐D3(BJ)/def2‐TZVP+COSMO(o‐xylene)//TPSS‐D3(BJ)/def2‐TZVP level of theory.

Figure 2

Distortion energy (a) for reductive elimination with different heterocycles, (b) for radical addition with N‐heterocycles.

Scheme 8

Ruthenium‐catalyzed decarboxylative C−C alkylation. [a] [RuCl₂(p‐cymene)]₂ (5.0 mol %). [b] HCl adduct. [c] n‐Octane instead of o‐xylene as solvent. [d] PPh₃ (5.0 mol %), PhCMe₃ instead of o‐xylene.

Scheme 9

Product diversification by ozonolysis.

Scheme 10

Key mechanistic findings: (a) reaction in the presence of radical scavengers, (b) H/D scrambling experiments, (c) detection of free p‐cymene.

Scheme 11

Proposed catalytic cycle for ruthenium‐catalyzed ortho‐ or meta‐alkylation.