Iodane-mediated and electrochemical oxidative transformations of 2- methoxy-and 2-methylphenols

A series of 2-methoxy and 2-methylphenols have been submitted to oxygenative oxidation reactions using (1) the λ 3 -iodane DIB, (2) a non-explosive and non-moisture sensitive version of the λ 5 -iodane IBX, named SIBX for Stabilized IBX, and (3) anodic oxidation with the aim of identifying the best reaction conditions for preparing orthoquinonoid cyclohexadienone synthons. Both the use of DIB and anodic oxidation appeared equally valuable for making orthoquinone dimethyl ketals, but the λ 3 - and λ 5 -iodane reagents are more appropriate to induce ortho -oxygenation of 2-methylphenols. In particular, SIBX emerged as a useful reagent for mediating ortho -hydroxylation into dimerizing orthoquinols, a tactic that can be applied to the synthesis of natural bis(monoterpenoids) such as aquaticol.


Results and Discussion
The oxidative activation of 2-alkoxy-and 2-alkylarenols of type 1 is a valuable tactic for the synthesis of oxygenated carbo-and heterocyclic motifs of natural products. 15,16,24This activation can easily find expression in the displacement of two ring electrons through the aryloxyiodane intermediate of type 2a, which is generally thought to evolve into the arenoxenium ion of type 2b, with concomitant loss of the phenol hydrogen (Scheme 1). 15,16In the presence of a nucleophile (Nu), this electrophilic species can be trapped in an either concerted or stepwise fashion to give rise to synthetically useful cyclohexadienone derivatives of type 3, if the group at the 2-position of the starting arenol 1 can efficiently control the regiochemistry of the attack at that position (Scheme 1).

Scheme 2
We observed the same dimerization in 37% via DIB-mediated oxidative methoxylation of 1a 27 and improved the yield of this dimerization up to 92% by anodic oxidation at constant current under neutral conditions (Scheme 2).Under these conditions, electrooxidation of a phenol is expected to give rise to a phenoxenium ion intermediate of type 2b (Scheme 1).In contrast, the 4-bromo derivative 3b is stable enough to be isolated as such.Anodic oxidation of 4-bromoguaiacol (1b) furnished 3b in 64% yield, and DIB-mediated oxidative methoxylation of 1b at 0°C has been reported to furnish 3b in yields ranging from 90 to 98% (Scheme 2). 33ur current studies toward the total synthesis of (+)-aquaticol (4c), a novel bis-sesquiterpene isolated from the traditional Chinese medicine Veronica anagallis-aquatica, 34,35 led us to examine various oxidative ortho-oxygenations of 2,4-dialkylated phenols.It has been postulated that (+)-4c derives from a Diels-Alder dimerization of the naturally occurring sesquiterpenoid orthoquinol (6R)-3c, itself probably biosynthesized via a stereoselective oxidative hydroxylation of the (+)-cuparene-derived phenol 1c (Scheme 3). 34

Scheme 3
This sequence of transformations should be amenable to chemical synthesis, and 2-methyl-5tert-butylphenol 1e was selected as a model phenol to evaluate the potential of such a biomimetic approach to aquaticol.Initially, we planned to generate the stable orthoquinol acetate 3e that would subsequently be hydrolyzed to induce dimerization.A similar approach had already been followed by Carman and co-workers in their synthesis of the Callitris macleayana carvacrol (2methyl-5-iso-propylphenol)-derived diterpene 4d (Scheme 3). 36,37For both 4c and 4d, the Diels-Alder cyclodimerization follows an endo-selective back-to-back mutual approach of the face of the orthoquinol on which resides the hydroxy group with a regioselective participation of the 4,5double bond of the 2π partner, as it is the case for all reported cyclodimerizations of orthoquinols. 15More recently, K. C. Nicolaou's and E. J. Corey's groups exploited the relative stability of orthoquinol acetates and resolved sorbicillin-derived species by chromatographic separation.The appropriate acetate enantiomer was then hydrolyzed to induce dimerization into bisorbicillinoid natural products. 38,39We tried to implement the same various deacetylation procedures to our racemic acetate 3e, which was generated in quasi quantitative yield by oxidative acetoxylation of 1e using DIB in CH 2 Cl 2 /AcOH at -78°C (Scheme 4), but no clean dimerization was observed.

Scheme 4
We then decided to submit 1e to the DIB-mediated oxidative methoxylation conditions with the expectation that the orthoquinol methyl ether intermediate 3e' would spontaneously undergo the requisite [4+2] cycloaddition at room temperature.In fact, 3e' was isolated in 38% yield, together with the paraquinone dimethyl monoketal 5 in 30% yield (Scheme 4).This loss of regioselectivity in the trapping of a reaction intermediate of type 2 can be putatively attributed to the harder nucleophilic character of MeOH relatively to that of AcOH, and to the lack of differences in electrophilic reactivity between the methyl-substituted C-2 and the unsubstituted C-4 centers of 1e.An attempt to dimerize 3e' by heating it in a toluene solution was to no avail.The monoketal 5 was quantitatively converted into the paraquinone 6 upon standing in the fridge during a couple of weeks; this ketal hydrolysis was certainly engendered by residual H 2 O and traces of AcOH left after workup.Anodic oxidation of 1e in MeOH at constant current was totally inefficient in making 3e', and the only product isolated after an aqueous workup was the paraquinone 6 in 25% yield (Scheme 4).The anodic oxidation of 1e was then performed in the presence of H 2 O as the nucleophilic trapping agent instead of MeOH in the hope that an excess of H 2 O would help in forming a product mixture composed of both the paraquinone 6 and the orthoquinol-derived dimer 4e.The electrooxidation of 1e was this time carried out at controlled potential in order to minimize the concomitant oxidation of water that would occur during constant current electrolysis.The anode potential was set 100 mV anodic of the peak potential value for 1e (Ep = 1.411V vs. Ag/AgCl), as measured by cyclic voltammetry. 40The electrolysis was stopped after passage of 2.5 F/mol.Surprisingly, the only product generated under these conditions was the paraquinone 6 (Scheme 4).Notwithstanding this failure of the anodic oxidation reaction, a DIB-mediated oxidative hydroxylation was attempted using again a CH 3 CN/H 2 O solvent mixture.The desired endo-cyclodimer 4e was thus obtained in 27% yield, together with the paraquinone 6 (63%) and some recovered starting phenol 1e (8%).This result, which constitutes an almost four-fold yield improvement relatively to Carman's two-step dimerization of the iso-propyl analogue 1d (Scheme 3), was quite encouraging, even though the para-selectivity of the H 2 O attack and its electrochemical emphasis remain difficult to explain.In search of a solution to futher improve the dimerization yield, it appeared that a reagent capable of delivering an oxygen atom after being fixed on the phenolic oxygen would be ideal for ortho-selective oxygenation.The diphenylseleninic anhydride-mediated Barton oxidation 41,42 was an obvious method to try, but a recent report by Pettus and co-workers 43 on the use of IBX for regioselective ortho-oxygenation of phenols brought us to select this λ 5 -iodane reagent.These authors actually reported a yield of 51% for the conversion of 2,6-dimethylphenol 1f into the dimer 4f (Scheme 5). 43 We first repeated this reaction with a few modifications; the Stabilized IBX, or SIBX, 20 was used in THF at room temperature, and a final workup step with aqueous 1M NaOH instead of aqueous sodium dithionite furnished pure 4f in quasi quantitative yield (Scheme 5).The same reaction conditions were then applied to 1e to furnish a clean 1:1 mixture of the dimer 4e and the double-oxidized orthoquinone 7 (Scheme 6).Roughly, two thirds of the starting phenol 1e has thus reacted at its methylated C-2 position despite the higher steric impediment at that position relatively to the other ortho-position.The development of a partial positive charge at C-2, which would be stabilized by the attached methyl group, may be proposed as an explanation for this regioselectivity, assuming that the reaction follows an oxidative nucleophilic substitution pathway.Separation of the product mixture by silica gel chromatography gave pure 4e in 39% yield.2,5-Dimethylphenol (1g) also gave rise to an analogous 1:1 mixture composed of the orthoquinone 8 45 and the dimer 4g, which was this time isolated in 62% yield.This dimer has previously been synthesized by Adler and Holmberg 46

Scheme 6
Finally, the SIBX-mediated oxidation of 2,3,5-trimethylphenol (1h) was carried out to verify the fact that a small alkyl substituent at the C-5 position of the cyclohexa-2,4-dienone core is sufficient to block the [4+2] cyclodimerization. 15,28Indeed, no dimer was observed and a clean 1:1 mixture of the orthoquinol 3h 47 and the orthoquinone 9 was obtained in ca.83% yield.The orthoquinol 3h was separated from 9 by silica gel chromatography in a mere yield of 12%.Of particular note is the fact that, in contrast to the use of DIB (Scheme 2), SIBX-mediated oxygenation of guaiacol (1a) and 4-bromoguaiacol (1b) led to intractable mixtures, and 2methoxyphenols bearing an electron-withdrawing group such as vanillin and isovanillin failed to undergo any oxidation.The latter remark confirms observations already made by Pettus and coworkers. 43

Conclusions
This comparative study of iodane-mediated and electrochemical oxidations revealed the newly developed SIBX reagent, 20 an environmentally safe version of IBX, as an efficient λ 5 -iodane alternative for promoting ortho-oxygenation of 2-methylarenols.This regioselectivity is a consequence of the intramolecular delivery of an oxygen atom from the iodine(V) center of the aryloxyiodane intermediate (2c) to the carbon-2 center of the aryloxy unit with concomitant reduction into an orthoquinoxy-λ 3 -iodane species (3f).This one-pot synthesis of orthoquinols from 2-methylarenols will be applied to the synthesis of aquaticol (4c).This work and other synthetic applications of SIBX are currently in progress and will be reported in due course.

Experimental Section
General Procedures.Tetrahydrofuran (THF) and diethyl ether (Et 2 O) were purified by distillation from sodium/benzophenone under N 2 immediately before use.Dichloromethane (CH 2 Cl 2 ), acetonitrile (CH 3 CN), and methanol (MeOH) were distilled under N 2 prior to use from CaH 2 , P 2 O 5 , and CaCl 2 , respectively.Moisture and oxygen sensitive reactions were carried out in flame-dried glassware under N 2 .Evaporations were conducted under reduced pressure at temperatures less than 45 °C unless otherwise noted.Column chromatography was carried out under positive pressure using 40-63 µm silica gel (Merck) and the indicated solvents.Further drying of the residues was accomplished under high vacuum.Melting points are uncorrected.NMR spectra of samples in the indicated solvent were run at 200, 250, 300 or 400 MHz.Carbon multiplicities were determined by DEPT135 experiments.Electron impact (50-70 eV) and liquid secondary ion mass spectrometry low and high resolution (EIMS, and LSIMS, HRMS) were obtained from the mass spectrometry laboratory at the CESAMO, Université Bordeaux 1.

General procedure for SIBX-mediated oxidation
To a stirred solution of starting phenol (ca. 100 mg) in dry THF (ca.0.4 M) was added 1.1 equivalent of stabilized o-iodoxybenzoic acid (SIBX, Simafex, France) in one portion.After stirring at room temperature for 18 h, the reaction mixture was poured into a stirred ice-cold mixture of CH 2 Cl 2 (3 mL) and H 2 O (5 mL), treated dropwise with ice-cold 1 M NaOH until pH 8, and extracted with CH 2 Cl 2 (2 × 5 mL).The combined extracts were then washed with water (3 × 10 mL), dried over Na 2 SO 4 , filtered and evaporated to afford products of good to excellent purity.When deemed necessary, further purification and/or product separation were carried out by silica gel column chromatography.
in only 12% via the periodate-mediated Adler oxidation.