In-Situ Bromination Enables Formal Cross-Electrophile Coupling of Alcohols with Aryl and Alkenyl Halides

Abstract

Although alcohols are one of the largest pools of alkyl substrates, approaches to utilize them in cross-coupling and crosselectrophile coupling are limited. We report the use of 1°and 2°alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp 3 )− C(sp 2 ) bonds in a one-pot strategy utilizing a very fast (<1 min) bromination. The reaction's simple benchtop setup and broad scope (42 examples, 56% ± 15% average yield) facilitates use at all scales. The potential in parallel synthesis applications was demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate.

Control of Redox‐Active Ester Reactivity Enables a General Cross‐Electrophile Approach to Access Arylated Strained Rings**

“…We note that a broader ligand screen that includes low-performing ligands from Table 1 could be helpful. [32] Whereas N-cyano carboxamidine ligands like L7 have proven increasingly useful in cross-electrophile coupling, [23,24 ] no structural characterization of their nickel complexes has been reported. We were able to synthesize Ni(L7)(o-tol) by reaction of the free ligand with trans-(Ph 3 P) 2 Ni(o-tol)Br.…”

Radical Deoxyfunctionalisation Strategies**

“…One method involves the in situ conversion of the hydroxyl motif into the corresponding iodide or bromide, which subsequently reacts via metal‐catalysed coupling in a one‐pot cascade strategy. Inspired by this concept, Gong [47] and Weix [48] concurrently reported Ni‐catalysed methodologies for the formal cross‐coupling of alcohols with aryl halides (Gong) and aryl/alkenyl halides (Weix) (Scheme 29). The former employed 2‐chloro‐3‐ethylbenzo[ d ]‐oxazol‐3‐ium salts (CEBO) 61 as in situ halogenating reagents, while the latter utilised Hendrickson's POP reagent 62 [49] to achieve this goal.…”

Recent Progress on Transition-Metal-Mediated Reductive C(sp3)–O Bond Radical Addition and Coupling Reactions

“…Scheme 34 Cross-electrophile coupling of alcohols with aryl halides via hologenation by CEBO/TBAX Recently, Weix reported another method of in situ conversion of alcohols into alkyl bromides used in tandem crosselectrophile coupling with aryl and vinyl halides (Scheme 35). 72 The fast, homogeneous bromination system, POP/TBAB in MeCN and the employing of a new ligand, alone or with other ligand are key to provide high yields of products. They found that the mothed was effective for the coupling of a wide range of 1° and 2° alcohols with aryl, heteroaryl and vinyl bromides.…”