Reductive Deuteration of Aromatic Esters for the Synthesis of α,α-Dideuterio Benzyl Alcohols Using D2O as Deuterium Source

Abstract

Abstractα,α-Dideuterio benzyl alcohols are important building blocks for the synthesis of deuterium-labeled medicines and agrochemicals. We have developed the first general single-electron transfer reductive deuteration of readily commercially available aromatic esters for the synthesis of α,α-dideuterio benzyl alcohols using benign D2O and a mild single-electron donor SmI2. This operationally convenient method features very good functional group tolerance and high deuterium incorporations (>95% D2). The potential impact has been exemplified by the synthesis of numerous deuterium labeled building blocks of important bioactive compounds. Most crucially, the method represents the first example of selective reductive deuteration of benzylic-type ketyl radicals using mild and highly chemoselective lanthanide(II) reagents.

Single Electron Transfer Reductive Deuteration of Acyl Chlorides for the Synthesis of Deuterated Alcohols with a High Deuterium Atom Economy

“…Additionally, this method frequently encounters harsh reaction conditions, poor deuterium incorporation, and uncontrolled regioselectivity (Figure A) . (2) Reductive deuteration of carboxylic acids and their derivatives: , α,α-Dideuterio alcohols are typically produced through the reductive deuteration of esters and amides, using costly and pyrophoric metal deuterides, like LiAlD 4 and NaBD 4 . − In our prior research, we have developed a series of single electron transfer (SET) reductive deuteration reactions to synthesize deuterated alcohols from carboxylic acid derivatives, employing mild SmI 2 as the electron donor. − Although these reactions achieved high deuterium incorporation and regioselectivity, the deuterium atom economy was still unsatisfactory. For instance, the reductive deuteration of acyl chloride with SmI 2 –D 2 O demonstrated a deuterium atom economy of less than 4% as a result of the necessity of using excess D 2 O as the ligand of SmI 2 .…”

Multielectron Reduction of Esters by a Diazabenzacenaphthenium Photoredox Catalyst

“…Compared with photoinduced radical reactions, the development of photocatalytic molecular transformations via ionic (anion/cation) species generated through a multielectron-transfer process has received scant attention . We recently achieved the generation of α-hydroxy carbanion (carbinol anion) species from aldehydes and ketones through a successive double SET, thereby realizing an umpoled electrophilic substitution of the carbonyl group. , However, the photocatalytic reduction of esters to form carbinol anions is a formidable challenge because it requires an unprecedented successive quadruple SET process; as a result, this reaction remains undeveloped . Here, we report the first photocatalytic four-electron reduction of esters by using a novel diazabenzacenaphthenium photocatalyst in which the resulting carbinol anions react with water and a second carbonyl compound, thereby providing a protonative reduction (Scheme A) and a cross-pinacol coupling (Scheme B).…”

Precision Deuteration Using Cu-Catalyzed Transfer Hydrodeuteration to Access Small Molecules Deuterated at the Benzylic Position

“…Direct access is commonly achieved via a deoxygenative deuteration of aryl carbonyl compounds, where relatively forcing conditions are sometimes required, thereby limiting reaction scope. − Even modern and more mild protocols for deoxygenative deuteration can lead to significant levels of inseparable isotopic impurities and remain deficient for N-heterocycle or amine-containing substrates (Scheme a) . Alternatively, highly selective single-electron-transfer carbonyl reductive deuterations exist for accessing compounds deuterated at the benzylic position, but only for the synthesis of α,α-dideuteriobenzyl alcohols (Scheme b). − Recognizing the importance of complete deuteration at only the target site for pharmaceutical applications, we sought to develop a mild and general reaction for the selective synthesis of molecules precisely deuterated at the benzylic position. Importantly, the reaction must be compatible with functionality commonly found in small-molecule drugs such as amines, O-, S-, or N-containing heterocycles, esters, and halogens. , …”