Highly Enantioselective C−H Oxidation of Arylalkanes with H₂O₂ in the Presence of Chiral Mn‐Aminopyridine Complexes

Abstract

Bioinspired chiral Mn‐aminopyridine complexes [(S,S)‐LMnII(OTf)2] and [(R,R)‐LMnII(OTf)2] (where (S,S)‐L=(2S,2′S)‐1,1′‐bis((3‐methyl‐4‐(2,2,2‐trifluoroethoxy)pyridin‐2‐yl)methyl)‐2,2′‐bipyrrolidine, and (R,R)‐L=(2R,2′R)‐1,1′‐bis((3‐methyl‐4‐(2,2,2‐trifluoroethoxy)pyridin‐2‐yl)methyl)‐2,2′‐bipyrrolidine) have been shown to efficiently catalyze the benzylic C−H oxidation of arylalkanes with hydrogen peroxide in the presence of carboxylic acid additives, affording enantiomerically enriched 1‐arylalkanols and the corresponding ketones. Optically pure additive N‐Boc‐(L)‐proline, in combination with [(R,R)‐LMnII(OTf)2] complex, affords 1‐arylalkanols in up to 86 % ee, which is the highest reported enantioselectivity for direct benzylic hydroxylations with H2O2 in the presence of transition‐metal catalysts. Oxidative kinetic resolution only slightly contributes to the increase of the observed enantiomeric excess over the reaction course. The observed kH/kD values (3.5–3.6 for the oxidation of ethylbenzene/d10‐ethylbenzene) and competitive oxidation data are consistent with either a hydrogen‐atom transfer/oxygen rebound or hydride transfer/oxygen rebound asymmetric hydroxylation mechanism.

Enantioselective Benzylic Hydroxylation of Arylalkanes with H2O2 in Fluorinated Alcohols in the Presence of Chiral Mn Aminopyridine Complexes

“…Recently, we developed the catalytic protocol for the asymmetric benzylic hydroxylation of arylalkanes with H 2 O 2 in acetonitrile in the presence of bipyrrolidine derived manganese complexes ( S , S )‐1 and ( R , R )‐1 (Figure ), affording the desired chiral 1‐arylalkanols with up to 86 % ee ,. The catalysts (0.1 mol.…”

“…First of all, the oxidation of substituted ethylbenzenes shows rather high slope ρ of −2.74. This is higher than the values of −1 to −2, typically observed in electrophilic transition‐metal mediated C−H oxidations,, reflecting substantially higher sensitivity of the Mn‐catalyzed oxidation in TFE to electronic effects. On the contrary, the oxidation of substituted alcohols in TFE exhibits the slope ρ + of −0.60, which is smaller than typical values of −0.8 to −2.0 ,…”

“…In trifluoroethanol, the observed primary k H / k D value of 3.2 has been observed for the oxidation of ethylbenzene/d 10 ‐ethylbenzene by the system ( R , R )‐1 /EHA/H 2 O 2 in TFE (0.2 mL) at 0 °C, which is somewhat lower than KIE for the same process in CH 3 CN (3.5…3.6) . For the oxidation of 1‐phenylethanol/ α ‐D‐1‐phenylethanol, such difference is negligible: 2.3 in TFE vs. 2.2 in CH 3 CN, respectively.…”

“…Further, following the approach previously developed for the C−H oxidations in CH 3 CN, we have attempted the use of chiral catalytic additives, derived from enantiomerically pure proline (Table ). In order to analyze the product yield and ee at different conversions, the experiments were conducted as follows: to a solution of the substrate (0.1 mmol), the Mn complex (0.2 μ mol), and the additive in TFE or DFE (0.2 mL), 30 % H 2 O 2 was added portionwise (in 15–20 μ mol portions), the mixture was stirred for 0.5 h after each addition, followed by taking 2 μ mol aliquots, that were subject to chiral HPLC analysis .…”

“…% loading) were able to perform several hundreds of turnovers; however, owing to the facile overoxidation to ketone, the reaction procedure required that high substrate excess conditions be used, and the reaction be stopped at low conversion levels (∼10 %), the yield of the target chiral alcohol typically not exceeding 5–6 %. It was a serious practical drawback, unsolvable at the time of publication of our reports ,. Encouragingly, very recently, Company, Bietti, and Costas introduced the replacement of CH 3 CN with 2,2,2‐trifluoroethanol (TFE) as reaction solvent, which improvement substantially enhanced the aliphatic hydroxylation selectivity in the presence of manganese based catalysts, further ketonization step being dramatically suppressed …”