Decarboxylative C(sp³)−O Cross‐Coupling

Abstract

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp )-O cross-coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp )-O cross-coupling and S 2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp )-O coupling of alkyl N-hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional-group tolerance to existing methods was demonstrated.

Photochemical Strategies for Carbon–Heteroatom Bond Formation

“…Combining photoredox and copper catalysis enabled carbon–heteroatom cross‐coupling reactions by generating alkyl radicals from redox‐active esters ( 108 , Scheme ) . Addition of 110 to a copper–amido complex and the following SET oxidation by PC ox triggers reductive elimination of the desired product ( 115 ).…”

“…Following this strategy, anilines, amides, and sulfonamides were coupled with alkyl radicals derived from the corresponding N ‐hydroxyphthalimide esters ( 116 , Scheme , A),[50a] or dialkyl iodomesitylene dicarboxylates. [50c] The use of benzophenone imines ( 120 ) as nucleophiles resulted in 121 which was subsequently hydrolyzed, furnishing primary amines ( 66 ) in good to excellent yields (Scheme , B). [50b] A similar mechanistic concept was reported for the formation of aryl alkyl ethers by coupling phenols with alkyl radicals generated from 116 (Scheme , C) …”

“…[50c] The use of benzophenone imines ( 120 ) as nucleophiles resulted in 121 which was subsequently hydrolyzed, furnishing primary amines ( 66 ) in good to excellent yields (Scheme , B). [50b] A similar mechanistic concept was reported for the formation of aryl alkyl ethers by coupling phenols with alkyl radicals generated from 116 (Scheme , C) …”

“…[50b] A similar mechanistic concept was reported for the formation of aryl alkyl ethers by coupling phenols with alkyl radicals generated from 116 (Scheme 21, C). [51] Scheme 21. Synthesis of amines (A), imines (B) and alkyl aryl ethers (C) by copper metallaphotoredox catalysis.…”

General Cyclopropane Assembly via Enantioselective Redox-Active Carbene Transfer to Aliphatic Olefins

“…However,l eaving-group-functionalizedc arbenes [M]-13 (Scheme 1c)a re known to be poorly reactive,n on-enantioselective,a nd their precursors tend to undergo substitution prior to the carbene transfer. [14] We envisioned that redoxactive carbenes [M]-13 a (Scheme 1c), containing an Nhydroxyphthalimide (NHPI) ester leaving group,c ould become equivalent to all the distinct carbenes 6-12,b ecause of the dual capacity of NHPI esters to act as acyl electrophiles [15] and radical precursors.T heir vividly expanding C À C, [16] C À N, [17] C À O, [18] and C À B [19] bond-forming reactions are well beyond the reach of current divergent strategies towards chiral cyclopropanes. [20, 21a] Despite their versatility,the orthogonality of NHPI esters to metal carbenes was unknown, and is reasonable concern when considering their facile irreversible fragmentation upon activation with various transition metals and/or visible light.…”