Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst

Abstract

Whilst allowing for easy access to synthetically versatile motifs and for modification of bioactive molecules, the chemoselective benzylic oxidation reactions of functionalized alkyl arenes remain challenging. Reported in this study is a new non-heme Mn catalyst stabilized by a bipiperidine-based tetradentate ligand, which enables methylene oxidation of benzylic compounds by H₂ O₂ , showing high activity and excellent chemoselectivity under mild conditions. The protocol tolerates an unprecedentedly wide range of functional groups, including carboxylic acid and derivatives, ketone, cyano, azide, acetate, sulfonate, alkyne, amino acid, and amine units, thus providing a low-cost, more sustainable and robust pathway for the facile synthesis of ketones, increase of complexity of organic molecules, and late-stage modification of drugs.

Keywords: Benzylic Oxidation; Cyclic Imines; Ketones; Manganese Catalysts; Selective Oxidation.

Figure 1

Catalytic benzylic methylene oxidation of alkyl chains bearing functional groups.

Figure 2

Formation of rac‐1 and meso‐1 and the X‐ray structures of rac‐1 and the cations [L¹ Mn(H₂O)₂]²⁺ of rac‐1 and meso‐1. Selected bond lengths [Å] for rac‐1: Mn1−N1 2.237(2), Mn1−N3 2.260(2), Mn1−N2 2.284(2), Mn1−N4 2.299(2), Mn1−O1 2.131(2), Mn1−O4 2.140(2); for [rac‐L¹ Mn(H₂O)₂]²⁺: Mn1−N1 2.2528(19), Mn1−N2 2.2979(18), Mn1−N3 2.2412(19), Mn1−N4 2.2999(18), Mn1−O1 2.1624(17), Mn1−O2 2.1644(18); for [meso‐L¹ Mn(H₂O)₂]²⁺: Mn1−N1 2.244(12), Mn1−N2 2.281(15), Mn1−N3 2.243(12), Mn1−N4 2.309(12), Mn1−O1 2.13(2), Mn1−O2 2.222(18). Hydrogen atoms have been omitted for clarity. See the Supporting Information for more details.

Figure 3

The time course of rac‐1 and meso‐1 catalyzed benzylic oxidation of ethyl benzene under the standard conditions.

Figure 4

Substrate scope of the rac‐1 catalyzed benzylic oxidation of alkylarenes. General reaction conditions: substrate (0.5 mmol), rac‐1 (2 mol %), and AcOH (2.5 mmol) were dissolved in MeCN (1.5 mL), and then H₂O₂ (2.5 mmol) in 1 mL of MeCN was introduced with a syringe pump over 1 h under stirring at room temperature without nitrogen protection. Isolated yield reported; [a] H₂O₂ (4 mmol); [b] ¹H NMR yield; [c] GC yield in parentheses; [d] 2 mol % of rac‐1 at the beginning followed by another 2 mol % 20 minutes later; H₂O₂ (4 mmol) in 1 mL of MeCN delivered with a syringe pump over 1 h; [e] AcOH (7.5 mmol, 15 equiv).

Figure 5

Kinetic follow of the oxidation of a chiral substrate with chiral catalysts. Reaction conditions were the same as the general conditions given in Figure 4; [a] (R,R)‐1 as catalyst, 1 h, with ee measured by chiral HPLC and isolated yield given. [b] ¹H NMR yield.

Figure 6

Substrate scope of rac‐1 catalyzed benzylic oxidation of alkylarenes containing primary amines. General reaction conditions: substrate (0.5 mmol) and rac‐1 (3 mol %) were dissolved in AcOH (1.5 mL), and then H₂O₂ (2.5 mmol) in 1.5 mL of MeCN was introduced with a syringe pump over 1 h under stirring at room temperature without nitrogen protection. Isolated yield reported.

Figure 7

Oxyfunctionalization of bioactive and drug molecules via rac‐1 catalyzed benzylic oxidation. General reaction conditions: substrate (0.25 mmol), rac‐1 (3 mol %), and ClCH₂COOH (2.5 mmol) were dissolved in MeCN (1.0 mL), and then H₂O₂ (1.25 mmol) in 1 mL of MeCN was introduced with a syringe pump over 1 h under stirring at room temperature without nitrogen protection. Isolated yield reported. [a] 2 mol % rac‐1 at the beginning followed by another 2 mol % 20 minutes later; H₂O₂ (2 mmol) in 1 mL of MeCN delivered with a syringe pump over 1 h; [b] 85 (3.1 mmol, 1.0 g); [c] reaction conditions were the same as the general conditions given in Figure 6.