Manganese(III) Acetate-mediated Oxidative Cyclization of α-Methylstyrene and trans-Stilbene with β-Ketosulfones

A convenient microwave irradiation protocol was utilized for the synthesis of β-ketosulfones 1–5 in good yields. These sulfones reacted with alkenes through a radical oxidative cyclization mediated by Mn(OAc)3. Dihydrofurans 6–10 were obtained in moderate to good yields starting from 1,1-disubstituted alkenes. Dihydrofurans 11–15 were synthesized in moderate yields and unexpected cyclopropanes 16–19 were obtained in low yields starting from 1,2-disubstituted alkenes. This protocol offers access to various dihydrofurans which could be tested for their antiparasitic potential.

a Yield of isolated product based on the corresponding ketone.
A suspension of manganese(III) acetate in glacial acetic acid was irradiated at 200 W in a microwave oven at 80 °C for 15 min until solubilization. -Ketosulfones 1-5 and the corresponding alkenes were added to this solution and the mixture was then irradiated at 200 W, 80 °C for 45 min.

16-19
From analysis of the 1 H-NMR spectra of synthesized products 11-19 and comparison with the previously reported results, we conclude that dihydrofuran and cyclopropane derivatives were obtained diastereoselectively from -ketosulfones 1-4 as the corresponding trans isomers.
Both protons of the dihydrofuran rings in 11-14 display two doublets at mean values of 5.50 and 4.50 ppm, with a vicinal coupling constant J between 5.0 and 5.6 Hz. For cis-2,3-dihydrofuran, the vicinal coupling constant of the two methine protons proved to be J = 7-10 Hz, while for trans-2,3dihydrofuran the vicinal coupling constant J = 4-7 Hz [38]. Moreover, these results agree with previous studies reporting trans-dihydrofuran diastereoselective synthesis via Mn(OAc) 3 mediated radical oxidative cyclizations starting from 1,2-disubstituted alkenes and -ketonitriles [39,40] or -ketoesters [41]. One of these studies [40] showed that the stereochemistry of Mn(OAc) 3 mediated oxidative cyclizations is not influenced by the stereochemistry of the starting alkene (cis or trans-stilbene).
To our knowledge, few studies have reported intramolecular cyclopropanation under Mn(OAc) 3 reactivity [42][43][44][45], and only one reported intermolecular reactions between oxabenzonorbornadiene and dimedone [46]. As Mn(OAc) 3 -mediated intermolecular cyclopropanation with trans-stilbene or a similar 1,2-disubstituted alkene has never been reported, the structure of cyclopropane 16 was established by X-ray diffraction analysis ( Figure 1). As specified in previous studies [44], Mn(OAc) 3 mediated cyclopropanation should come from the cation C (Schem 4), which reacted rapidly with the enolic form of -ketosulfone to close the cyclopropane ring. -ketosulfone 5 led to cis-dihydrofuran 15 with vicinal coupling constant J = 8.0 Hz. o-Nitro substitution appears to have reversed the diastereoselectivity and inhibited the cyclopropanation, probably through the stereoelectronic effects of the nitro group during the final cyclization step. Further research is in progress to explore this original mechanism.

General
Microwave-assisted reactions were performed in a multimode microwave oven (ETHOS Synth Lab Station, Ethos start, Milestone Inc., Rockford, IL, USA). Melting points were determined with a B-540 Büchi melting point apparatus. 1 H-NMR (200 MHz) and 13 C-NMR (50 MHz) spectra were recorded on a Bruker ARX 200 spectrometer in CDCl 3 or D 2 O at the Service Interuniversitaire de RMN de la Faculté de Pharmacie de Marseille. The 1 H chemical shifts were reported as parts per million downfield from tetramethylsilane (Me 4 Si), and the 13 C chemical shifts were referenced to the solvent peaks: CDCl 3 (76.9 ppm) or DMSO-d 6 (39.6 ppm). Absorptions were reported with the following notations: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, a more complex multiplet or overlapping multiplets. Elemental analysis and mass spectra, run on an API-QqToF mass spectrometer, were carried out at the Spectropole de la Faculté des Sciences site Saint-Jérôme. Mass spectra, run on a MicrOToF Q mass spectrometer, were carried out at the Plateforme Protéomique Innovation Technologique Timone (PIT2) UMR 911 Faculté de Pharmacie. The following adsorbent was used for flash column chromatography: silica gel 60 (Merck, particle size 0.040-0.063 nm, 70-230 mesh ASTM). TLC were performed on 5 cm × 10 cm aluminium plates coated with silica gel 60 F-254 (Merck) in an appropriate solvent.

General Procedure for the Synthesis of -Ketosulfones 1-5
Method A, starting from -bromoacetophenone: To a solution of sodium benzene sulfinate (4.1 mmol, 2 equiv.) in water (30 mL), an ethanolic solution of the corresponding acetophenone (2.05 mmol, 1 equiv.) was added. The reaction mixture was heated under reflux in a microwave oven under irradiation (500 W, 100 °C) during 45 min. The precipitate thus formed was filtered and crystallized from the appropriate solvent.

X-ray Structure Determination of Compounds 16
Crystal data for compound 16:

Conclusions
Thanks to the radical reactivity of Mn(OAc) 3 , we synthesized 10 new functionalized dihydrofurans, which could offer antiparasitic activities. Starting from trans-stilbene alkene, a diastereoselectivity reversion of dihydrofuran was observed with ortho-substituted -ketosulfones. Moreover, four original cyclopropanes were obtained in low yields. This original cyclopropanation reaction could be a very valuable tool in organic synthesis and additional research seeking to enhance yields is currently in progress.