Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero)alkoxides

Abstract

An efficient strategy for N/O-(deutero)­alkylation of indoles and phenols with alkoxides/alcohols as the alkylation reagents is described. The consecutive detosylation/alkylation transformations feature mild reaction conditions, high ipso-selectivity, and good functional group tolerance (>50 examples). A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized. The application of this method is demonstrated by the introduction of isotope-labeled (CD3 and 13CH3) groups using the readily accessible labeled alcohols and the synthesis of pharmaceuticals.

Broadening of horizons in the synthesis of CD3-labeled molecules

“…In 2019, Liu and co-workers reported the in-situ generation of CD3OTs in ipso-detosylative Ntrideuteromethylation of N-tosylindoles using KOCD3 (Scheme 56). 99 CD3OTs is generated from the nucleophilic attack of CD3Oon the sulfonamide, followed by the cleavage of the indole N-S bond. A subsequent SN2 attack of the N anion on CD3OTs affords the Ntrideuteromethylation product.…”

“…In the previous section, we have discussed KOCD3 as the CD3 source for detosylative Ntrideuteromethylation of N-tosylindoles (Scheme 56). 99 This reaction system is also suitable for the ipso-detosylative O-trideuteromethylation of O-tosylphenols using either commercially available or in-situ generated KOCD3 as the trideuteromethylating reagent (Scheme 65). 99…”

“…99 This reaction system is also suitable for the ipso-detosylative O-trideuteromethylation of O-tosylphenols using either commercially available or in-situ generated KOCD3 as the trideuteromethylating reagent (Scheme 65). 99…”

Semiconductor photocatalysis to engineering deuterated N-alkyl pharmaceuticals enabled by synergistic activation of water and alkanols

“…The substitution is of interest as these alkylation reagents are highly toxic, carcinogenic, and volatile 25 – 28 , which generally cause high costs and waste production. In addition, these reactions often suffered from excess methylation leading to ammonium salts 29 , 30 . Reduction of N -CO 2 R moieties with LiAlD 4 is another effective approach that has good potential for the introduction of N -CD 3 group without formation of ammonium salts 20 .…”

Metal-Free Hydroxymethylation of Indole Derivatives with Formic Acid as an Alternative Way to Indirect Utilization of CO2

“…Besides, the nucleophilic reactions with alkylation reagents, such as alkyl halides, imines, hydrazones, and carbonates, are always assisted by bases or basic catalysts (Scheme B). Through the “hydrogen borrowing” process, alcohols could also achieve the N-alkylation of indoles (Scheme C) . In addition, boronic acid, bismuth reagent, carbene precusor, diacyl peroxides, and alkenes are used for the N-alkylation of indoles as well.…”