Gold‐Catalyzed Highly Chemo‐ and Regioselective C‐H Bond Functionalization of Phenols with Haloalkynes

Abstract

A highly chemo‐ and stereoselective addition of unprotected phenols to haloalkynes was developed. A ligand and counterion controlled process enabled the highly site‐selective and chemoselective C‐H bond functionalization of phenol derivatives with haloalkynes in moderate to excellent yield at room temperature. The simple availability of the starting materials in combination with the preferred para‐C‐H functionalization over a competing O‐H insertion makes this an attractive protocol. The stereoselectivity of the products depends on the choice of the catalyst. From a synthetic prospective, this method offers an efficient route towards vinyl chlorides, which are valuable precursors for the synthesis of pharmaceutical drugs.

Catalytic Gold Chemistry: From Simple Salts to Complexes for Regioselective C−H Bond Functionalization

“…( 4)). [151] According to the proposed mechanism, the [IPrAu(I)] + species coordinated with chloroalkyne 98 to form a stable chloro-vinyl cation 96 b. The highly electrophilic nature of this intermediate coupled with the absence of base, drives a chemoselective nucleophilic attack by a carbon nucleophile (vs. oxygen nucleophile) of phenol to form a Wheland complex 99.…”

“…Hashmi et al., recently succeeded in a chemo‐ and regioselective hydroarylation of phenols 95 onto Au(I)‐activated chloroalkynes 96 a to prepare ( Z )‐chloro‐vinylated phenols 97 (Scheme 14, Eq. (4)) [151] . According to the proposed mechanism, the [IPrAu(I)] + species coordinated with chloroalkyne 98 to form a stable chloro‐vinyl cation 96 b .…”

AuI-Catalyzed Hydroalkynylation of Haloalkynes

“…When the same reaction was performed without exclusion of water the yield dropped to 73% (entry 11), suggesting that hydrolysis of the terminal alkyne (particularly facilitated by the triflate counteranion) 22 or the bromoalkyne 23 may compete in some extent under these conditions. Reaction performed with this catalyst in combination with AgOTs resulted very low yield (entry 12), while the introduction of more basic counteranions, using AgOAc or AgTFA as scavengers, totally inhibited the reaction (entries 13,14). Bulky phosphine ligands were also tested, but both reactivity and selectivity were disappointing.…”

Advances and Prospects in Gold‐Catalyzed C−H Activation

“…Hashmi et al developed a new protocol for the chemo-and regio-selective CÀ H functionalization of phenols 198 with haloalkynes 199 through Au-catalysis (Scheme 47). [44] This new protocol has a wide variety of applications especially in pharmaceuticals for synthesising precursors for drug manufacture like vinyl chloride in comparatively easy manner with easily available starting materials. They have applied this protocol in a variety of molecules under optimized conditions (199 (0.24 mmol), 198 (0.2 mmol), IPrAuCl (2 mol%), NaBARF (3 mol%), DCE (1 mL), RT, 3-12 hrs.)…”

“…Hashmi et al . developed a new protocol for the chemo‐ and regio‐selective C−H functionalization of phenols 198 with haloalkynes 199 through Au‐catalysis (Scheme ) . This new protocol has a wide variety of applications especially in pharmaceuticals for synthesising precursors for drug manufacture like vinyl chloride in comparatively easy manner with easily available starting materials.…”