Methyltrioxorhenium-catalysed oxidation of pseudocumene in the presence of amphiphiles for the synthesis of vitamin E

Abstract

Vitamin E is an essential food component and antioxidant of major economic relevance. 2,3,5-Trimethyl-1,4-benzoquinone is a key intermediate in the production of vitamin E, which can now be selectively achieved through MTO-catalysed oxidation of simple and inexpensive pseudocumene (1,2,4-trimethylbenzene), in the presence of hydrogen peroxide and an appropriate amphiphile.

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Vitamins are essential organic compounds, which are either not synthesised in the human or animal organism, or not formed in sufficient amounts. Vitamin E and especially its most active component α-tocopherol is of particular biological relevance and industrial interest because of its antioxidant properties.^1–4 One of the key intermediates in the synthesis of α-tocopherol is 2,3,5-trimethyl-1,4-benzoquinone (3), which is usually prepared from 2,3,6-trimethylphenol.^5–20 Industrially more interesting, but more difficult to achieve, is the oxidation of cheap pseudocumene under mild conditions via hydroquinone 2.^21–26 Improving the selective oxidation of pseudocumene, as shown in Scheme 1, compared to existing methods would be an important step towards industrial application. Vitamin E is actually prepared from 2. 3 as the main product of the reaction—due to reaction conditions—can easily be reduced to 2. Previous research by our group on MTO-catalysed oxidation of pseudocumene showed that water is a very influential component, having two major effects. One is the well known but slow decomposition of MTO in the presence of water.^8,26–29 The other effect is a reduction of the energy barrier through nitromethane and water as proton transfer agent during the first oxidation step to a phenolic intermediate 3.²⁶ A possible approach to improve the activity of the catalytic system—likely hampered by the presence of two liquid phases—could be the use of amphiphiles with their known beneficial effects in catalysis.^30–33 Furthermore, the use of an imidazole-functionalised amphiphilic copolymer linked to MTO has been recently reported as a recyclable catalyst for epoxidation, setting a precedent in its field.³⁴

Scheme 1 Oxidation of 1 for the synthesis of vitamin E.

Hence, given the high importance of benzoquinone 3 as an intermediate in the synthesis of vitamin E, we report herein the MTO-catalysed selective oxidation of pseudocumene in the presence of different amphiphiles as an appealing alternative to the existing methods and to improve product selectivity of 3.

First, a number of commercially available neutral, anionic and cationic amphiphiles, shown in Fig. 1, were probed in the target oxidation of pseudocumene, at 50 °C, using MTO as a catalyst and hydrogen peroxide (30% aqueous solution) as an oxidant.† The results are summarised in Table 1. Side-products of the reaction are usually trimethylphenol, acting as an intermediate on the way to 3,²⁶ or derivatives of 1 with oxidised methyl groups. These by-products were observed with GC/MS techniques. As it can be seen from Table 1, the use of certain amphiphiles can have a positive effect on the conversion of the reaction while maintaining a high selectivity. Indeed, the best results are obtained when using the inexpensive, neutral amphiphile Brij 30. When this additive is used in the presence of aqueous H₂O₂ solution as only solvent, the product selectivity is 67% (Table 1, entry 3). A reduction of the amount of amphiphile leads to a slightly increased conversion, but is accompanied by a significantly lower selectivity (Table 1, entry 3 vs. 4). Interestingly, the use of an additional solvent, such as nitromethane, affords a selectivity of 80%, which is the highest from all experiments with amphiphiles shown in this work (Table 1, entry 5). A water-miscible solvent such as methanol has no particular effect (Table 1, entry 3 vs. 6).

Fig. 1 Amphiphilic additives used in this work.

Table 1 MTO-catalysed oxidations of 1 in the presence of various amphiphiles

Entry	Reaction conditions^a	Time/h	Temp./°C	Conv. 1 [%]	Sel. 3 [%]
a Reaction conditions: 1 (1.44 mmol; 1 equiv.), MTO (2 mol%), H2O2 (30% in H2O, 4 equiv.), H2O2 (aq. solution) : Brij 30 = 12 (v/v, when indicated in the table), conversion of starting material and formation of 3 were quantified by GC-MS using an internal standard, selectivity of 3 refers to the amount of converted starting material that turned into target product 3, salox = salicylaldoxime. b H2O2 (30%) : Brij 30 = 30 (v/v). c 0.35 mL of solvent per mmol of 1. d 0.14 mL of solvent per mmol of 1. e 0.7 mL of solvent per mmol of 1.
1		20	50	13	100
2	Brij 30/without MTO	20	50	0	0
3	Brij 30	20	50	27	67
4^b	Brij 30	20	50	38	47
5^c	Brij 30, MeNO2	20	50	28	80
6^c	Brij 30, MeOH	20	50	31	52
7^c	4 mol% salox, Brij 30, MeNO2	22	50	29	72
8^c	2 mol% salox, Brij 30, MeNO2	72	50	39	62
9^c	2 mol% salox, Brij 30, H2O2 (50%), MeNO2	72	50	50	60
10^d	4 mol% salox, Brij 30, MeNO2	72	50	37	57
11^e	4 mol% salox, Brij 30, MeNO2	72	50	35	63
12	4 mol% (Bu4N)Br, Brij 30	22	50	21	0
13	4 mol% (Bu4N)PF6, Brij 30	19	50	28	46
14	4 mol% (Bu4N)HSO4, Brij 30	22	50	24	54
15^e	4 mol% salox, 10 mol% (Bu4N)HSO4, Brij 30, MeNO2	72	50	21	24
16	1 mol% CTAS	72	50	36	44
17	50 mol% CTAT	72	50	55	11
18^c	4 mol% N(Dodec)3, 2 mol% CTAT, CHCl3	72	40	30	27
19	2 mol% SDS	72	40	31	55

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We have shown that the use of salicylaldoxime as a ligand in combination with MTO improved the yield and selectivity of the oxidation of pseudocumene in comparison with the ligand-free analogue oxidation.²⁶ Hence, salicylaldoxime was tested as a ligand for the target oxidation in the presence of Brij 30, yielding benzoquinone 3 with a selectivity of 72% (Table 1, entry 7). Interestingly, the amount of nitromethane added to the system seems to have two contrary effects reflected by different selectivities (Table 1, entries 7, 10, and 11).

Higher diluted systems (Table 1, entry 11) probably lack amphiphile/salox coordination to MTO, while too concentrated systems (Table 1, entry 10) lose the beneficial effect nitromethane seems to induce during the first oxidation step.²⁶ In both cases, the selectivity is lower than in the medium diluted case (Table 1, entry 7). The addition of ammonium salts as phase transfer catalysts (PTC) to the Brij 30-containing reaction mixture does not improve the conversion or product yield. Nevertheless, the anion of a PTC seems to have an effect on the reaction. For instance, (Bu₄N)Br inhibits the reaction, whereas (Bu₄N)PF₆, and (Bu₄N)HSO₄ afford selectivities of around 50% (Table 1, entries 12–14). Common cetyltrimethyl derived cationic amphiphiles lead to low selectivities (Table 1, entries 16–18), while anionic sodium dodecyl sulfate (SDS) affords moderate selectivity values (Table 1, entry 19). Generally, the use of ionic additives to the reaction lowers the selectivity significantly. Non-ionic amphiphile Brij 30 alone provides much better selectivities and the probing of similar amphiphiles appears reasonable. Amphiphiles could possibly be improved by additional functionalities like Lewis basic moieties. Such a combination might allow the combination of the positive effects of Lewis bases in MTO catalysed oxidations (higher catalyst stability and improved selectivity) and the positive effect of amphiphiles shown in this work. Amphiphile and Lewis base combined to one molecule could lead to a superior behaviour compared to adding the two separate substances to the reaction mixture (Table 1, entries 7–11 and 15).

Conclusion

In summary, a mild procedure for the MTO-catalysed oxidation of pseudocumene based on the use of amphiphiles to improve the selectivity of the product distribution is presented. The applied strategy leads to a good selectivity of up to 80% and generally improved results when compared to the same reaction conditions in the absence of amphiphiles.²⁶ The use of sustainable hydrogen peroxide and the economic relevance of benzoquinone 3 in the production of vitamin E render the presented procedure very appealing from an industrial point of view. Further, the design of amphiphilic ligands that could also coordinate to MTO and decrease its Lewis acid character is also an object of our ongoing studies.

Notes and references

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Footnote

† General procedure for the MTO-catalysed oxidation of 1 using amphiphiles: to a solution of MTO (2 mol%), 1 (1.4 mmol, 1 equiv.), the amphiphile of choice (see Table 1) and solvent (when indicated, see Table 1) H₂O₂ 30% (4 equiv.) was added to start the reaction. The reaction mixture was stirred at 40–50 °C temperature for 20–72 h. After the reaction was stopped, the crude mixture was extracted with diethyl ether. Subsequently, a catalytic amount of MnO₂ was added to destroy traces of peroxide if necessary, and the resulting solution was dried over anhydrous sodium sulfate, filtered and analysed by GC-MS using 4-methylbiphenyl and n-decane as internal standard. For characterisation, 2,3,5-trimethyl-1,4-benzoquinone (3), was purified through flash chromatography (dichloromethane/pentane 4 : 6) after work-up and obtained as a pale orange solid. Spectroscopic data are in accordance with literature data.¹⁰

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