Synthesis of C2‐Phosphorylated Indoles via Metal‐Free 1,2‐Phosphorylation of 3‐Indolylmethanols with P(O)‐H Species

Abstract

An efficient and practical method for synthesis of C2‐phosphorylated indoles has been disclosed via a metal‐free 1,2‐phosphorylation of 3‐indolylmethanols with H‐phosphine oxides or H‐phosphonates. This alternative protocol features a broad substrate scope with respect to both 3‐indolylmethanols derived from isatins, acyclic α‐keto amide, α‐keto ester, 1,2‐diketone and simple ketones and H‐phosphine oxides or H‐phosphonates, moderate to high yields and mild reaction conditions. Mechanistic studies indicate that this reaction proceeds via an unusual direct 1,2‐addition pathway, in which the existence of an electron‐withdrawing group adjacent to the hydroxyl group of 3‐indolylmethanols plays a decisive role.magnified image

Relay Cu(I)/Brønsted Base Catalysis for Phospha‐Michael Addition/5‐exo‐dig Cyclization/Isomerization of in situ Formed aza‐Alkynyl o‐quinone methides with P(O)−H compounds to C3‐Phosphorylated Indoles

“…In conjunction with our continuing interest in the chemistry of propargylic alcohols [4b,5a] and the design novel tandem reactions [14] based on the dehydrative couplings between P(O)‐H species and alcohols [14] for the synthesis of phosphorylated heterocycles, [9,15b–c,k–l] herein, we report a new approach for the assembly of C3‐phosphorylated indoles 3 via a relay Cu(I)/Et 3 N‐catalyzed one‐pot reaction of in situ generated aza ‐ o ‐AQMs and P(O)‐H compounds, involving a sequential phospha ‐Michael addition/5‐ exo ‐ dig cyclization/isomerization process (Scheme 2).…”

Synthesis of 2‐Phosphoryl‐3‐Monofluorovinylindoles under Catalyst‐ and Additive‐Free Conditions

“…Among various indole derivatives, 2‐phosphorylated indoles have attracted tremendous attention due to their unique structural motifs and broad applications in the fields of organic synthesis, pharmaceuticals, material science, and ligand chemistry [2–5] . Not surprisingly, numerous synthetic methods for accessing 2‐phosphorylindoles have been developed, including palladium‐catalyzed annulation of 1‐alkynylphosphine sulfides or oxides with 2‐iodoanilines (Scheme 1a), [6] transition metals‐catalyzed direct C−H phosphorylation of indoles, [7] photoredox phosphorylation/cyclization of 1‐isocyano‐2‐styrylbenzenes (Scheme 1b), [8] and acid‐catalyzed dehydrative coupling reactions (Scheme 1c) [9] . Very recently, an efficient TfOH‐catalyzed three‐component reaction of indoles, carbonyl compounds and H ‐phosphine oxides has also been successively realized (Scheme 1d) [10] .…”

“…[2][3][4][5] Not surprisingly, numerous synthetic methods for accessing 2-phosphorylindoles have been developed, including palladium-catalyzed annulation of 1-alkynylphosphine sulfides or oxides with 2-iodoanilines (Scheme 1a), [6] transition metalscatalyzed direct CÀ H phosphorylation of indoles, [7] photoredox phosphorylation/cyclization of 1-isocyano-2-styrylbenzenes (Scheme 1b), [8] and acid-catalyzed dehydrative coupling reactions (Scheme 1c). [9] Very recently, an efficient TfOH-catalyzed three-component reaction of indoles, carbonyl compounds and Hphosphine oxides has also been successively realized (Scheme 1d). [10] Despite notable advances, however, some of the reported methods still suffer from certain drawbacks such as the need for various noble metals or acid catalysts, poor C2/C3 site selectivity and, in some cases, harsh reaction conditions (e. g., strictly inert and anhydrous conditions).…”

Recent Advances in the Construction of Phosphorus‐Substituted Heterocycles, 2009–2019

“…As for a similar reaction, our group established a (±)‐CSA‐catalyzed 1,2‐phosphorylation of 3‐indolylmethanols, which provided an efficient and practical method for the preparation of C‐2 phosphorylated indoles . This protocol tolerated a broad scope with respect to both 3‐indolylmethanols derived from isatins, acyclic α‐keto amides, α‐keto esters, 1,2‐diketones and simple ketones, and nucleophilic P(O)−H compounds such as H ‐phosphine oxides and H ‐phosphonates, affording the desired products in moderate to high yields (Scheme ).…”