Enantioselective remote meta-C-H arylation and alkylation via a chiral transient mediator

Abstract

Enantioselective carbon-hydrogen (C-H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules^1,2. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C-H bonds at positions remote to existing functional groups. Here we report enantioselective remote C-H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C-H activation to the meta position. This was used in the enantioselective meta-C-H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis^3,4.

Figure 1. Enantioselective C(sp²)–H activation

a, Enantioselective ortho-C–H activation. b, Enantioselective remote C–H activation (unsolved problem). c, Strategy for enantioselective remote C–H activation. d, Scope of enantioselective remote C–H activation.

Figure 2. Enantioselective meta-C–H arylation of diarylmethylamines

a, CTM and additive optimization. Reaction conditions: 10 mol% Pd(OAc)₂, 15 mol% pyridone-ligand, 50 mol% (+)-NBE-CO₂Me, 15 mol% additive, 3 equiv. methyl 4-iodobenzoate, 3 equiv. AgOAc, CHCl₃, 100 °C. For each entry number (in bold), data are reported as NMR yield. b, Scope of asymmetric arylation. Reaction conditions: 10 mol% Pd(OAc)₂, 15 mol% pyridone-ligand, 20 mol% (+)-NBE-CO₂Me, 15 mol% (R)-BNDHP, 3 equiv. Ar–I, 3 equiv. AgOAc, CHCl₃, 100 °C. ^*R¹ = Me. ^†15 mol% (PhO)₂PO₂H. ^‡1.5 equiv. Ar–I, 2 equiv. AgOAc. ^§80 °C. ^¶60 °C. ^**50 mol% (+)-NBE-CO₂Me. ^††R¹ = H. ^‡‡20 mol% Pd(OAc)₂, 30 mol% pyridone-ligand, 30 mol% (R)-BNDHP. ^§§15 mol% Pd(OAc)₂, 23 mol% pyridone-ligand. For each entry number (in bold), data are reported as isolated yield. The absolute configuration of 2ah was determined by X-ray crystallography. DG, directing group; Ar, aryl group; m-Tol, meta-tolyl group. Reducing the catalyst loading to 5 mol% produced comparable results for substrate 1a′ (see Table S6 in Supplementary Information).

Fig. 3. Enantioselective meta-C–H activation of homobenzylamines

a, Scope of desymmetrization. Reaction conditions: 10 mol% Pd(OAc)₂, 20 mol% 3-methyl-5-phenylpyridine, 20 mol% (+)-NBE-CO₂Me, 3 equiv. R–I, 3 equiv. AgOAc, TBME, 90 °C. ^*Methyl 2-bromobenzoate (as arylation reagent). ^†50 mol% (+)-NBE-CO₂Me. ^‡15 mol% Pd(OAc)₂, 30 mol% 3-methyl-5-phenylpyridine. ^§1.4 equiv. Ar–I. ^¶15 mol% Pd(OAc)₂, 30 mol% 4-acetylpyridine (as ligand). ^**1.5 equiv. (+)-NBE-CO₂Me, DCM (as solvent). b, Scope of kinetic resolution. Reaction conditions: 10 mol% Pd(OAc)₂, 20 mol% 3-methyl-5-phenylpyridine, 20 mol% (+)-NBE-CO₂Me, 0.5 equiv. R–X, 2 equiv. AgOAc, TBME, 80 °C. ^††1.5 equiv. R–X. ^‡‡1 equiv. R–X. ^§§3 equiv. R–X, 3 equiv. AgOAc. ^¶¶20 mol% 4-acetylpyridine, DCM. ^***50 mol% (+)-NBE-CO₂Me. For each entry number (in bold), data are reported as isolated yield. The absolute configurations of 4m and 4n were determined by X-ray crystallography. TBME, tert-butylmethylether; o-Tol, ortho-tolyl group; DCM, dichloromethane. Reducing the catalyst loading to 5 mol% produced comparable results for substrate 3a (see Table S10 in Supplementary Information).

Figure 4. Mechanistic studies

a, Reaction rate dependence on aryl iodide. b, Proposed catalytic cycle.