The Baeyer‐Villiger oxidation versus aromatic ring hydroxylation: competing organic peracid oxidation mechanisms explored by multivariate modelling of designed multi‐response experiments

Abstract

Peroxy acids can be used as the terminal oxidant for the Baeyer–Villiger oxidation of acetophenones and for direct ring hydroxylation of methoxy-substituted benzenes. An oxidative system involving 3-chloroperbenzoic acid (mCPBA) and 2,6-\ud dimethoxyacetophenone as model substrate was investigated by means of statistical experimental design, multivariate modelling and response surface methodology. The outcome of the organic peracid oxidation experiments was portrayed\ud by a multi-response matrix consisting of the yields of three different compounds; 2,6-dimethoxyphenyl acetate, 1-(4-hydroxy-2,6-dimethoxy-phenyl)ethanone and 3-hydroxy-2,6-dimethoxy-phenyl acetate. The optimized reaction protocol was utilized to investigate a series of various substituted acetophenones. The overall investigation revealed that both the molecular structure of the acetophenone substrate and the experimental conditions exhibited a substantial impact on whether the oxidation reaction follows the oxygen insertion or direct ring hydroxylation mechanism. An improved protocol for the direct ring hydroxylation was also obtained from the experimental and modelling described herei

Regioselective Baeyer–Villiger oxidation of lignin model compounds with tin beta zeolite catalyst and hydrogen peroxide

“…Therefore, addition of an electron-donating group (EDG) was investigated to determine if it positively affects catalyst activity. 26,27 Indeed, when EDGs were present (i.e., methyl and methoxy groups, corresponding to 2 and 3, respectively), a higher yield of the corresponding phenyl acetate (2a, 3a) was observed. Due to an EDG inuenced increase in the basicity of the carbonyl oxygen, 27 3 was converted in 81% yield to 3a at 45 C aer 24 h. When the temperature was increased to 80 C selectivity decreased from 90% to 83%, and a notable darkening of the reaction mixture was observed, implying formation of phenolic resins.…”

“…Low yields of phenyl acetate (1a, 33%) were observed as a result of poor electron donation to the carbonyl oxygen, slowing nucleophilic addition of hydrogen peroxide. 26,27 Alkyl migration from the Criegee intermediate is considered to be the rate-limiting step, however, when using weak oxidants such as hydrogen peroxide, the rate-limiting step can become nucleophilic addition. 28 While this result is disappointing, angiosperm and gymnosperm lignins are the result of coniferyl (G) and sinapyl (S) alcohol polymerization, these monolignols containing one and two methoxy group(s), respectively.…”

“…Hydroxyl radicals can perform direct ring hydroxylation as well as many other side-reactions. 26 In competition with BVO, direct ring-hydroxylation reactions can involve both starting material and BVO products. Without the presence of an organic layer (i.e., using a single aqueous phase at 80 C), reactions resulted in the production of a dark insoluble phenolic resin or tar, as has been reported for similar reactions (i.e., hydrogen peroxide mediated oxidation of benzene to phenol).…”

Hit to Leads with Cytotoxic Effect in Leukemic Cells: Total Synthesis Intermediates as a Molecule Treasure Chest

“…A 12‐step total synthesis to carbazomycin G/H (Scheme ) was recently disclosed by our group, was used as a combined tool for 1) as a hit‐to‐lead screening library and 2) as an initial SAR investigation. The commercially available 2,6‐dimethoxytoluene ( 1 ) was used as the starting substrate for the synthesis of the indispensable intermediate phenol 2 by means of a high‐yielding direct hydroxylation method earlier developed and investigated in our laboratory. The attained phenol 2 was subsequently protected by treating with acetyl chloride, step ( b ), to obtain the O ‐ acetyl intermediate 3 .…”

Carbazomycin G: Method Development and Total Synthesis

“…This observation prompted us to undertake a thorough investigation of the byproduct formation, from which a high‐yielding direct hydroxylation method for methyl‐ and methoxy‐substituted benzenes, step (a) Scheme , was established by using H 2 O 2 in acetic acid with the presence of trifluoroacetic acid as an oxidizing system. The organic peracid oxidation mechanisms that clearly can follow either the Baeyer–Villiger oxidation mechanism or the direct aromatic‐ring hydroxylation were later explored in‐depth by means of multivariate modelling of designed multi‐response experiments …”