# Oxidation to allylic alcohols without stoichiometric metal reagents

Common methods of oxidation of alkenes to allylic alcohols in one step usually use stoichiometric metal oxidants, e.g., sodium dichromate. Without using this type of reagent, are the other methods typically peroxide forming, requiring further chemistry to adjust to the allylic alcohol, e.g., allylic hydroperoxides or t-butyl peroxides, or are there more "direct" methods?

Almost all allylic oxidation reactions have been using metal catalysts such as chromium, selenium, copper, etc. because it is relatively easy to abstract hydrogen radical from allylic position and metals are well known for doing so with or without single electron transfer (SET). This fact is well documented in the review published in 2013 (Ref.1), the abstract of which simply states that:

Although $$\ce{C–H}$$ oxidation of hydrocarbons is generally difficult, allylic $$\ce{C–H}$$ oxidation is relatively simple and predictable, even on a preparative scale, because active species generated at the allylic position are stabilized by the double bond. Therefore, allylic oxidation has been employed in natural product synthesis, and a variety of reagents and conditions for allylic oxidation have been reported...

Some of the specific catalysts the review referred are selenium Dioxide, diphenyldiselenide–Iodoxybenzene, chromium Trioxide–3,5-Dimethylpyrazole, pyridinium chlorochromate (PCC), chromic acid, etc., all of which are toxic to humans (e.g., selenium and chromium compounds) and fairly expensive (e.g., palladium and rhodium compounds). Recently, a paper published in Nature journal describes an electrochemical allylic $$\ce{C–H}$$ oxidation strategy that does not need toxic and expensive metal catalysts, but uses inexpensive and readily available materials. The method exhibits broad substrate scope, operational simplicity, and high chemoselectivity. The notable advantage of this electrochemical allylic $$\ce{C–H}$$ oxidation strategy is It represents a scalable allylic $$\ce{C–H}$$ oxidation (results have demonstrated on $$\pu{100 g}$$ scale reactions).

The General Procedure for electrochemical allylic oxidation is described as follows in the paper:

With no precautions to exclude air or moisture, a test tube is charged with a stir bar, $$\ce{Cl4NHPI}$$ $$(\pu{0.2 equiv})$$ and $$\ce{LiClO4}$$ ($$\pu{0.6 equiv}$$, $$\pu{0.1 M}$$). Acetone ($$\pu{6 mL/mmol}$$ substrate) is added, and the resulting suspension is stirred until most of the solids dissolve. Substrate ($$\pu{1 equiv}$$) is added, followed by pyridine ($$\pu{2 equiv}$$) and $$70\%$$ aqueous tert-butyl hydroperoxide ($$\pu{1.5 equiv}$$). The anode and cathode (RVC, separated by a glass slide) are placed in the solution, and the reaction mixture is electrolyzed at a current of $$\pu{10 mA/mmol}$$ substrate until the reaction is complete as judged by TLC or GCMS analysis. The reaction mixture is transferred to a separatory funnel, and the electrodes are washed thoroughly with hexanes, diethyl ether, or ethyl acetate. The organic layer is washed twice with $$\ce{H2O}$$, once with brine, dried, and concentrated. The resulting crude product was then purified on $$\ce{SiO2}$$ to furnish the desired enone product. Note: Pyridinium perchlorate can be added to the reaction ($$\pu{0.1–0.2 M}$$) to improve solubility of the reaction components. This co-electrolyte has negligible effect on product yields and may improve the reaction if the substrate contains any easily reduced functional groups since this increases the concentration of protons available to be reduced at the cathode.

Note that the mediator, $$\ce{Cl4NHPI}$$ is N-Hydroxytetrachlorophthalimide, which was synthesized from tetrachlorophthalic anhydride and $$\ce{H4N-OH/HCl}$$ in pyridine using thermal or microwave technique for this research. However, it was available in Sigma-Aldrich for $$\pu{62 USD}/\pu{10 g}$$.

The schematic diagram of the general procedure is depicted in above diagram (Figure A). The variety of mediators used during the progress of the process are listed in Figure B. Among them, N-Hydroxyphthalimide ($$\ce{NHPI}$$) and $$\ce{Cl4NHPI}$$ have given the best results (have given total yield of $$56\%$$ and $$77\%$$, respectively in otherwise optimized conditions). They are drastically efficient than others, e.g., next best has been TEMPO, which has given only $$26\%$$ total yield under identical conditions. Among the co-oxidants tried, $$\ce{t-Bu-OOH}$$ has given the optimal results ($$51\%$$). The next best is $$\ce{PhC(CH3)2-OOH}$$ with $$43\%$$ yield. Acetone ($$56\%$$) and $$\ce{CH3CN}$$ ($$51\%$$) have given equally impressive results as choice of solvent, and acetone was chosen for optimal conditions as the solvent for this research. Hence optimized electrochemical parameters were: $$(\pu{0.16 M})$$ of substrate with $$\ce{Cl4NHPI}$$ $$(\pu{0.2 equiv})$$, pyridine $$(\pu{2.2 equiv})$$, $$\ce{t-Bu-OOH}$$ $$(\pu{1.5 equiv})$$, $$\ce{LiClO4}$$ $$(\pu{0.6 equiv})$$ in acetone.

The tentative mechanism is illustrated in Figure C. The formation of tert-butyl-peroxy-intermediate (III) was confirmed. In a separated experiment, one of corresponding tert-butyl-peroxy-intermediate was synthesized in a different route and reacted in identical condition used in electrolytic procedure ($$\ce{Cl4NHPI/t-BuOOH/LiClO4/pyridine/acetone}/RT$$). The reaction has completed both with and without electrolysis within $$\pu{6 h}$$, confirming requirement of electrolysis during initial tert-butyl-peroxy-intermediate formation steps (Ref.2).

References:

1. Akihiko Nakamura, Masahisa Nakada, “Allylic Oxidations in Natural Product Synthesis,” Synthesis 2013, 45(11), 1421-1451 (DOI: 10.1055/s-0033-1338426).
2. Evan J. Horn, Brandon R. Rosen, Yong Chen, Jiaze Tang, Ke Chen, Martin D. Eastgate, Phil S. Baran, “Scalable and sustainable electrochemical allylic C–H oxidation,” Nature 2016, 533, 77–81 (https://doi.org/10.1038/nature17431).
• I really like the answer, but the question related to allylic alcohols, preferably in one step (albeit a step could occur during work-up). – Beerhunter May 27 '20 at 18:40

The oxidation of alkenes with t-butyl peroxybenzoate in acetonitrile or benzene in the presence of copper compounds has been reported by Levina and Mazart, Tetrahedron Asymmetry 6 147 (1995) e.g. cyclohexene to the allylic benzoate in 59% yield.

Similar oxidations of alkenes using t-butyl peroxybenzoate with catalytic amounts of bisoxazoline copper complexes have been reported by MB Andrus et al, Tetrahedron Letts. 36 2945 (1995).