Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, via Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen

Abstract

From screening experimental parameters to scaling up, a safe approach is reported for the multidecagram scale preparation of methyl ester of 6,6-dibutyl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylic acid (7), a flexible common intermediate for the synthesis of a variety of anti-malarial and/or anti-leishmanial compounds. The critical feature of the reaction is the use of a pure oxygen flow under batch conditions using methyl acetoacetate and 2-butyl-1-hexene as reagents, and a mixture of Mn(II) and Mn(III) acetates as catalysts, in acetic acid. Once the best solvent, catalyst loading, temperature, and reaction time in the small-scale procedure (10 mL vial) were defined, the process was adapted up to a 3 L flask, eventually resulting in the production of about 70 g of 7. The developed reaction protocol gives a satisfactory result considering: (i) the inexpensive starting materials used, (ii) the 100% atom economy of the [2 + 2 + 2]-annulation reaction, (iii) the stoichiometric ratio of the two reagents (only oxygen is used in excess) coupled with low catalyst loading, and (iv) the mild conditions adopted. The calorimetric studies allow us to classify this reaction as an inherently safe process. On a larger scale, the possible formation of a flammable vapor mixture in the reactor headspace was minimized using two parallel continuous flows of oxygen and argon, thus ensuring a constant headspace vapor phase renewal.

Development of Lab-Scale Continuous Stirred-Tank Reactor as Flow Process Tool for Oxidation Reactions Using Molecular Oxygen

“…The Mn­(III)/Mn­(II)-catalyzed reaction of methyl acetoacetate ( 3 ), 1,1-diphenylethylene ( 4 ), and oxygen to form 3-hydroxy-3-methyl-6,6-diphenyl-1,2-dioxane-4-carboxylate methyl ester ( 5 ; Scheme ) was carried out using one to three mini-CSTR modules . The reaction mixture was intrinsically more complex compared with the aldehyde oxidation.…”

“…The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 8:2, v/v) to obtain 3-hydroxy-3-methyl-6,6-diphenyl-1,2-dioxane-4-carboxylate methyl ester ( 5 ) as a colorless solid. Spectral data are in accordance with the literature …”

“…57 The Mn(III)/Mn(II)-catalyzed reaction of methyl acetoacetate (3), 1,1-diphenylethylene (4), and oxygen to form 3-hydroxy-3-methyl-6,6-diphenyl-1,2-dioxane-4-carboxylate methyl ester (5; Scheme 2) was carried out using one to three mini-CSTR modules. 58 The reaction mixture was intrinsically more complex compared with the aldehyde oxidation. It consisted of three phases: a liquid phase (the acetic acid solution of the alkene and ketoester), a solid phase due to the partially soluble redox couple Mn(III)/Mn(II) in acetic acid, and the gas phase.…”

“…Spectral data are in accordance with the literature. 58 Additional details comprising setup illustration and product characterization can be found in the Supporting Information (Figures S5−S10).…”