Brønsted acid-catalysed regiodivergent phosphorylation of 2-indolylmethanols to synthesize benzylic site or C3-phosphorylated indole derivatives

Abstract

A Brønsted acid catalysed regiodivergent phosphorylation of 2-indolylmethanols with diarylphosphine oxides has been established, which provides a brand-new strategy for accessing highly functionalized phosphorus-containing indoles with structural diversity. Under the catalysis of HOTs·H2O, 2-indolylmethanols undergo regioselective benzylic phosphorylation at room temperature to afford benzylic site phosphorylated indoles in good to high yields (29 examples, up to 98% yield), while C3-phosphorylated indoles are obtained in the presence of HOTf under heating conditions (16 examples, up to 83% yield). Preliminary mechanistic studies suggest that C3-phosphorylated indoles are possibly obtained partially from direct C3-phosphorylation and dominantly from a tandem benzylic phosphorylation/[1,3]-P migration/isomerization sequence from 2-indolylmethanols. Furthermore, the acidity of the Brønsted acid and the reaction temperature play a vital role in the [1,3]-P migration of benzylic phosphorylated indoles to form C3-phosphorylated indoles. This protocol serves as a good example for regioselective benzylic functionalization of 2-indolylmethanols.

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

“…This behavior seems to be confirmed for a related process in which the same reactants are made to react in the presence of a catalytic amount of p ‐TolSO 3 H (Scheme ) . At 25 °C the kinetic products 108 are formed in usually high yields for a large variety of reactant combinations.…”

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

“…Our group has also investigated the same reaction, and identified that HOTf was effective for the formation of C‐3 phosphinoylated indoles 61 or 62 (Scheme ) …”

“…In detail, when R 1 and R 2 were aryl groups, the generation of carbocation I was preferential as it could be stabilized by these two aryl groups. In this case, carbocation I was attacked by 29a thus giving the normal 1,4‐addition products 69 that might be further converted to the 1,2‐addition adduct 68 via a reported 1,3‐P migration . In the case of 3‐indolylmethanols bearing an electron‐withdrawing group adjacent to the hydroxy moiety, the delocalized carbocation tended to form carbocation II , which was trapped by 29a thereby furnishing the direct 1,2‐addition products 68 .…”

Dehydrative Cross‐Coupling and Related Reactions between Alcohols (C−OH) and P(O)−H Compounds for C−P Bond Formation

“…Then Chen group has also investigated this reaction by utilizing the cheap and easily to handle HOTs⋅H 2 O as Brønsted acid (Scheme ) . Accordingly, in the presence of 10 mol% of HOTs⋅H 2 O, 2‐indolylmethanols with various substituents installed at the o ‐, m ‐ and p ‐positions of the phenyl ring reacted with diarylphosphine oxides in 15 min to 24 h, affording 61 or 62 in 28–98% yields (Scheme ).…”

“…In Chen's work, HOTf was identified as the best Brønsted acid to promote the formation of C‐3 phosphinoylated indoles 120 (Scheme ). Different from Wang and Kozllowski's mechanism, Chen's mechanistic studies suggest that C‐3 phosphinoylated indoles possibly arise partially from direct C‐3‐phosphinoylation and dominantly from a tandem benzylic phosphinoylation/[1,3]‐P migration/isomerization sequence from 2‐indolylmethanols.…”