Direct Aerobic α-Hydroxylation of Arylacetates for the Synthesis of Mandelates

Abstract

Aerobic α-hydroxylation of α-methylene esters has proven challenging due to overoxidation and hydrolysis of the materials. In this article, KO t Bu-promoted TBAB-catalyzed α-hydroxylation of α-methylene aryl esters using O2 as the oxygen source has been developed. Both low reaction temperature and catalyst TBAB are keys to success. This reaction provides an environmentally friendly and low-cost approach to mandelates, which are valuable building blocks and widely present in pharmaceuticals.

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

“…Recently, applications of SO 2 F 2 as a reagent in organic synthesis have been reviewed elsewhere. [70] In 2019, Qin and co-workers developed one SO 2 F 2 -mediated, clickable amidation of carboxylic acids (120) with amines under mild conditions (Scheme 22a). [71] This method exhibited good functional group tolerance (> 110 examples, > 90 % yield for most cases), high efficiency and good scalability.…”

“…Later, KOtBu was recognized as an efficient promoter in other reaction types, including synthesis of 3-hydroxyisoindolinones (206) from ipso-substituted benzamides (205) via CÀ C coupling/N-α-CÀ H hydroxylation cascades (Scheme 43b), [118] hydroxylation of C(sp 3 )À H bond at the benzylic position (207, Scheme 43c) [119] and aerobic oxidation of α-unsubstituted arylacetates (209) at the methylene position using TBAB as a co-catalyst (Scheme 43d). [120] In 2017, Jiang and co-workers identified a practical protocol for aerobic oxidative hydroxylation of pyrazol-5-ones (211) using K 2 CO 3 as a catalyst and O 2 as the oxygen source in the absence of transition metals (Scheme 44a). [121] A variety of 4-hydroxypyrazoles (212) were obtained in good to excellent yields.…”

“…However, the detailed mechanism was still unclear, while only a plausible reaction pathway including C−OO − (peroxide) bond formation and its cleavage by an in situ generated enolate was proposed. Later, KO t Bu was recognized as an efficient promoter in other reaction types, including synthesis of 3‐hydroxyisoindolinones ( 206 ) from ipso ‐substituted benzamides ( 205 ) via C−C coupling/N‐α‐C−H hydroxylation cascades (Scheme 43b), [118] hydroxylation of C(sp 3 )−H bond at the benzylic position ( 207 , Scheme 43c) [119] and aerobic oxidation of α‐unsubstituted arylacetates ( 209 ) at the methylene position using TBAB as a co‐catalyst (Scheme 43d) [120] …”

Cobalt Catalyzed α-Hydroxylation of Arylacetic Acid Equivalents with Dioxygen

“…In this context, the catalytic installation of a hydroxyl group selectively at the α-position of abundant arylacetic acid synthons arguably constitutes the most attractive strategy to access mandelic acid derivatives. Thus, the α-hydroxylation of arylacetic acid esters has been achieved by relying on enzymatic catalysis or base-mediated oxygenation approaches (Scheme C) . However, the inherent challenge in those methods, particularly for α-unsubstituted arylacetic acids, is the competitive formation of undesired α-keto acids via “over-oxidation”. , In the case of arylacetamides, the α-hydroxylation is accomplished via the α-oxyamination with 2,2,6,6-tetramethylpiperidine- N -oxyl (TEMPO) followed by N–O bond scission by employing (over)­stoichiometric reagents or through the formation and subsequent hydrogenation of α-keto acid amides. , Of note, reported benzylic C–H hydroxylation approaches do not apply to α-hydroxylation of arylacetic acids functionalized with several competing benzylic groups due to chemoselectivity issues .…”