Oxidation of Mono-Phenols to para-Benzoquinones : a Comparative Study

A oxidação de mono-fenóis à para-benzoquinonas é assunto de interesse contínuo devido à existência de inúmeros produtos naturais contendo esta unidade estrutural. As para-benzoquinonas possuem reatividade química importante como agentes oxidantes e como dienófilos na reação de Diels-Alder. Usualmente nós preparamos as para-benzoquinonas pela reação de oxidação dos respectivos mono-fenóis com oxigênio molecular e catalisada por [Co(salen)]. Porém, foi necessário estudar estas oxidações utilizando-se outros oxidantes. Nós apresentamos aqui nossos resultados sobre esta importante reação de oxidação com uma variedade de oxidantes, utilizando onze mono-fenóis como substratos. Os oxidantes utilizados foram cobalto, níquel, cobre e vanádio derivados com alguns ligantes do tipo salen. Também foram estudados peróxido de hidrogênio, OXONE®, dimetil dioxirano e ácido iodoxibenzóico.


Introduction
Natural products frequently occur containing the parabenzoquinone sub-structural unit within the global structure, as can be exemplified by vitamins K 1 and K 2 , co-enzyme Q (ubiquinone), 1 and in many terpenes and alkaloids. 2These natural products [3][4][5][6][7][8][9][10][11][12][13] are associated with important biological properties, such as cardiovascular, anti-tumour, antibacterial, anti-germination and anti-protozoan among others.There is no doubt that the para-benzoquinone nucleus is an important charge transfer receptor and easily undergoes nucleophilic addition reactions. 1The redox relation with para-hydroquinones (para-quinols) is of importance in biological activity, and also makes many simple para-benzoquinones excellent oxidizing agents. 1 Synthetically, the para-benzoquinone structural unit is an excellent dienophile for the Diels-Alder reaction, among other relevant reactions. 1e usual and obvious manner to prepare parabenzoquinones 1,14,15 is from the corresponding parahydroquinones, which is however rather limited due to the lack of a wide range of commercially or synthetically available substrates.As a second choice, the simple monophenol is an ideal substrate due to the ready availability of an extremely wide range of such compounds.
A further point of interest is the large price differential between mono-phenols and the corresponding parabenzoquinones, being tens to over a hundred times more expensive when available. 16All this leads to a continuing interest in methodologies for the oxidation of mono-phenols to para-benzoquinones, with an acceptance of varied substitutions on the phenol ring.Historically, this oxidation has required reagents such as Fremy's salt, 17 heavy metal oxidants in large molar excess, 18 or chemical modification of the mono-phenol to introduce an amino group in the para-position. 19However these methods suffer from low yields, inconvenient reagents or multi-step sequences, Vol. 19, No. 8, 2008   and are not applicable to a wide range of substrates.Furthermore, the methodologies are not always susceptible to execution on multi-gram scales.
More recently new oxidants have been introduced, and we have routinely used molecular oxygen in the presence of [Co II (salen)] (or Salcomine) as catalyst, in DMF/H 2 O. 20 The catalyst is added in three portions over 12 h, and for certain substrates such as Thymol is an excellent choice (Scheme 1).This result is based upon a fairly extensive study of the [Co II (salen)] catalyst addition, where a certain deactivation is observed with time.Generally the yields fall quite substantially with addition in one portion, or the use of lower loadings of catalyst.As a general rule we use between 4% and 6% mol equivalents in three portions for a total catalyst loading of 12% to 18% mol.
In this paper we would like to present our results of a much more extensive study using eleven different phenol substrates, and varying the metal and ligand with respect to [Co II (salen)], and also the other oxidants hydrogen peroxide, OXONE®, dimethyldioxirane (DMD) and iodoxybenzoic acid (IBX).
The mechanism of this reaction is well accepted 21 as involving one electron oxidation of the phenolate anion to generate the phenoxy radical which then reacts with molecular oxygen to form the para-peroxycyclohexadienone.Finally, loss of water produces the parabenzoquinone.Competitive reaction of the phenoxy radical with molecular oxygen at the ortho position would lead to the ortho-benzoquinone.The usual side reactions also involve the phenoxy radical, and ortho-para and para-para carbon-carbon coupling leads to the bis-quinone-methides, the bis-phenol, and eventually to polymeric materials (Scheme 2; to simplify the Scheme we have omitted orthoortho and ortho-para couplings).
However some of our mono-phenol substrates gave sluggish reactions and lower yields, contamination with the starting mono-phenol and thus separation problems, and difficulties in scale-up, which has led us to study other oxidants.
We have examined the literature, and Table 1 provides some detailed information on published phenol substrates in oxidation with different oxidants.This Table is not meant to be exhaustive but illustrative of the wide variety of oxidants that have been evaluated.The mono-phenol substrates and para-benzoquinones products are shown in Figures 1 and 2 respectively.
Table 1 shows some interesting results with the varied oxidants, which are expensive, toxic, explosive or simply inconvenient, or used in large excess.This led us to the present study with some newer oxidants, which were chosen on the basis of availability (including price) or ease of preparation, easy reaction conditions, diminished toxicity problems, and use in more acceptable quantities.These oxidants have been compared with our original system of [Co II (salen)] and variations on this by exchanging the metal and or the ligand.

Results and Discussion
Our choice of phenol substrates (Figure 1) includes obviously phenol (1), three mono-alkyl-substituted phenols (2)-( 4), five di-alkyl-substituted phenols ( 5)-( 9), and α- (10)  and β-naphthol (11), giving a good coverage of possible substitution patterns.The possible para-benzoquinone products, (12) to (20), are shown in Figure 2. The study started with the standard O 2 and [Co II (salen)] experiments, followed by exchange of cobalt for nickel, copper and vanadium.The second exchange involves the ligand salen for other readily accessible ligands of the same type.Figure 3 shows our selection of metal salen type oxidants.
Table 2 shows our comparative study of the oxidation of the phenols (1) to (11) against the various metalligand catalysts.The para-benzoquinone products are all known compounds, and identification was performed by comparison of IR and NMR spectral data, as well as melting points determinations.The first conclusion is that cobalt is essential as the other metals (Ni, Cu and V) do not show any catalytic activity.The second conclusion is that the ligand salen is more efficient than the others ligands, and thus serendipity once again had led to the use of the commercially available complex.The substrates show structural variations on oxidation, and the more highly substituted phenols are more effective substrates.
These results suggested a study of other oxidants for the less substituted phenols.With this in mind we looked for simple and readily available oxidants, used in easy reaction conditions, and amenable to green chemistry requirements.The first oxidant which comes to mind is obviously hydrogen peroxide, followed by potassium peroxymonosulphate (OXONE®), and then dimethyldioxirane (DMD) and 2-iodoxybenzoic acid (IBX).Oxone is a very cheap oxidant, and furthermore is used in the simple preparations of DMD and IBX.These latter two oxidants were planned to be tested in the absence and the presence of molecular oxygen, in accordance with the proposed mechanism.The following Table shows our results.
Once again (Table 3), the di-substituted phenols are more reactive, while the other phenols were not affected by OXONE® and DMD.The best results were obtained in the absence of molecular oxygen.
The oxidants H 2 O 2 (30%) in the presence of molecular bromine, and IBX are demonstrated to be totally ineffective in the oxidation of all the eleven phenols.It is important to recognize that the statement of the lack of reactivity means recovery of the starting phenols.In the case of 30% H 2 O 2 with bromine, the substrate β-naphthol does react but the product is 1-bromo-2-naphthol. 38n conclusion, we have shown that several different oxidants, easily and cheaply available, can oxidize mono-   phenols in reasonable to excellent yields and in a highly regioselective manner.In none of the oxidations under study, have we observed the formation of the isomeric ortho-benzoquinone products, nor do we observe quininemethides or di-phenolic products that could be expected from the proposed mechanism (Scheme 2).

Experimental
General 1 H and 13 C NMR spectra were obtained on a Bruker DRX-400 spectrometer at 400 and 100 MHz, and on a Bruker ARX-200 spectrometer at 200 and 50 MHz respectively, with CDCl 3 as solvent.Chemical shifts are in ppm downfield from a tetramethylsilane internal standard.Infrared spectra were recorded on Bomen Michelson model 102 FTIR or Hartman & Braun MB, and the most intense or representative bands are reported (in cm -1 ).Melting points were determined on a Micro Química model APF 301 apparatus and are uncorrected.Gas liquid chromatographic analyses were performed on a Shimadzu GC-17A, equipped with a DB-1 capillary column (0.25 mm × 30 m) and using nitrogen as carrier gas.Solvents and reagents were used directly from the manufacturer, or purified when required by standard procedures.The eleven phenols and salen, [Co II (salen)] and [Ni II (salen)] are commercially available products (Aldrich) and used as obtained.0][41] The other complexes, [Co II (dmsalen)], [Co II (salpn)], [Co II (dmsalpn)], [Cu II (salen)], and [VO IV (salen)], were prepared as described in the cited references.Dimethyldioxirane 42 and iodoxybenzoic acid 43 were prepared according to published procedures.

General procedure for the metal complex catalyzed oxidations
The phenol (1.0 mmol), was dissolved in DMF (5 mL), and oxygen was bubbled into the reaction mixture for a few minutes, and then an oxygen atmosphere was maintained with a balloon.The catalyst (6% mol) was added, and stirred at room temperature for 3 h.Further catalyst (6% mol) was added and the reaction mixture stirred for 3 h at room temperature.The process was repeated once more, for a total addition of 18% mol catalyst, and a total reaction time of 24 h.Ether (20 mL) was added and the black mixture washed with 0.1 mol L -1 HCl (2 × 10 mL), water and brine.The ethereal solution was dried over anhydrous MgSO 4 and the solvent evaporated: the residue was purified by flash column chromatography using as eluent a mixture of 9:1 hexane:ethyl acetate to give the product.

General procedure for the OXONE® oxidations
An aqueous Na 2 .EDTA solution (20 mL, 4 × 10 -4 mol L -1 ) was added to a solution of the phenol (0.5 mmol) in CH 3 CN (30 mL), at room temperature.To this solution was added a mixture of OXONE® (2.5 mmol) and NaHCO 3 (7.75mmol).After stirring at room temperature for 24 h, the reaction mixture was poured into brine and extracted three times with EtOAc.The combined organic layers were dried over anhydrous MgSO 4 and concentrated.The pure product was obtained by flash column chromatography using as eluent a mixture of 9:1 hexane:ethyl acetate.

General procedure for the DMD oxidations
The phenol (2 mmol) was dissolved in acetone (4 mL) and distilled water (4 mL), and OXONE® (3 mmol) and NaHCO 3 (8 mmol) were added.The mixture was stirred at

Table 2 .
Mono-phenol oxidation with metal salen type complexes; numbers are isolated yields, and NR signifies no reaction

Table 3 .
Comparison of oxidations of phenols 1-11 with OXONE and DMD in the presence and absence of molecular oxigen

Table S1 .
NMR spectral data and melting points of the para-benzoquinone products