2,3,6-Trimethylhydroquinone

Although all four tocopherols have been synthesized as their all-rac forms, the commercially significant form of tocopherol is i7//-n7i a-tocopheryl acetate. The commercial processes ia use are based on the work reported by several groups ia 1938 (15—17). These processes utilize a Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol (16), a phytyl haUde (7,16,17), or phytadiene (7). The principal synthesis (Fig. 3) ia current commercial use iavolves condensation of 2,3,5-trimethylhydroquiQone (13) with synthetic isophytol (14) ia an iaert solvent, such as benzene or hexane, with an acid catalyst, such as ziac chloride, boron trifluoride, or orthoboric acid/oxaUc acid (7,8,18) to give the all-rac-acetate ester (15b) by reaction with acetic anhydride. Purification of tocopheryl acetate is readily accompHshed by high vacuum molecular distillation and rectification (<1 mm Hg) to achieve the required USP standard. 

First, calculate the energy for the reaction of water and trimethylquinone (Q, R = Me) to give oxygen and trimethylhydroquinone (QH2, R = Me). (Energies for water and oxygen are given at right). 

Fig. 15. EPR spectra of the Rieske cluster in membranes of Paracoccus denitrificans in different redox states of the quinone pool and with inhibitors added. Q x, ascorbate reduced Qred) reduced with trimethylhydroquinone dissolved in dimethyl sulfoxide +EtOH, reduced with trimethylhydroquinone dissolved in 90% ethanol +Myxo, ascorbate reduced with myxothiazol added + Stigma, ascorbate reduced with stigmatellin added. Only the gy and signals are shown. The dotted line has been drawn at...

FUTAKUCHI M, HIROSE M, MIKI T, TANAKA H, OZAKI M and SHIRAI T (1998) Inhlhition of DMBA-initiated rat mammary tumour development hy l-O-hexyl-2,3,5-trimethylhydroquinone, phenylethyl isothiocyanate, and novel synthetic ascorbic acid derivatives , Eur J Cancer Prev, 7 153-9. 

An enantioselective hydrogenation of this type is also of interest in the production of a-tocopherol (vitamin E). Totally synthetic a-tocopherol can be made in racemic form from 2,3,5-trimethylhydroquinone and racemic isophytol. The product made in this way is a mixture of all eight possible stereoisomers. 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

Knowledge of the chemical structures of the major vitamins was acquired during the 30 years after 1920, and some were identified as known compounds. They were classified as fat-soluble and water-soluble vitamins. The only heterocyclic compounds in the former class are the tocopherols (vitamin E). They were discovered through their action in preventing sterility in rats, but they appear to play an important part in the metabolism of skeletal muscle. Vitamin E deficiency appears to occur rarely in man, but vitamin E therapy is tried in a number of clinical disorders. The tocopherols may be isolated from vegetable oils, and synthetic a-tocopherol (61) is made by condensing trimethylhydroquinone with phytol or phytyl halides (Scheme 2). For medicinal use they may be converted into their acetates or succinates. 

Much effort has been devoted to the synthesis of derivatives of chroman-6-ols as model compounds for studies of the chemistry of the tocopherols. Many routes concentrate on the acid-catalyzed alkylation of substituted benzene-1,4-diols by allyl alcohols or dienes. Trimethylhydroquinone and isoprene react in acetic acid in the presence of zinc chloride to give 2,2,5,7,8-pentamethylchroman-6-ol (39JOC311) isomer formation is not possible here and so the route is particularly attractive. 

The direct formation of racemic a-tocopherol from trimethylhydroquinone and isophytol occurs at low temperature in the presence of boron trifluoride or aluminum chloride (71JOC2910). It is important that the solvent should not be able to complex with the Lewis acid rather, it is the phenol-catalyst complex which is alkylated. 

A related transformation is the rearrangement-aromatization of ketoisophorone to trimethylhydroquinone diacetate, an intermediate in the industrial synthesis of (all-rac)-a-tocopherol. Of heterogeneous catalysts, Nafion-silica exhibited the best catalyst performance858 [Eq. (5.313)], but activities decreased with repeated use because of the leaching of Nafion resin. 

All three types of reactions can also be used for the production of substituted quinones and hydroquinones. For example, BASF has developed two laboratory processes for the synthesis of trimethyl-p-benzoquinone and trimethylhydroquinone. The latter is required for the synthesis of vitamin E. 

Since regeneration with acceptable turnover numbers has not been possible up to now, this synthesis has not assumed any industrial significance to date. Anic 126 127) and Mitsui128) describe syntheses of 2,4,6-trimethyl-4-hydroxycyclohexa-2,5-dien-4-one, which can undergo a rearrangement to give trimethylhydroquinone ... 

The synthesis of Vitamin E, that is, a-tocopherol (5,7,8-trimethyltocol) in the past has been accomplished primarily by reacting trimethylhydroquinone (TMHQ) with isophytol (3,7,ll,15-tetramethylhexadec-l-en-3-ol) or phytol (3,7,ll,15-tetramethylhexadec-2-en-l-ol) in a condensation reaction. The reaction is well known and has been practiced for many years (Stalla-Bourdillon, Ind. Chim. Belg., 35, 13 (1970) "The Vitamins" Vol. 5, pages 168-223, Academic Press, New York, 1967). 

The key features of a new total synthesis of vitamin E from 2,3,5-trimethylhydroquinone are an enantioselective Wacker cyclisation which generates the chroman ring system with the... 

A complex multistep synthesis of the 8-CD3 analogue of 5-tocopherol has been described <03EJ02840>. The super Lewis acid, Me3Si[C6FsCTf2], is an effective catalyst for the regioselective condensation between trimethylhydroquinone and isophytol that yields ( )-a-tocopherol <03AG(E)5731>. 

Reaction of trimethylhydroquinone with aldehydes yields 1,3-benzodioxins, oxa analogues of the tocopherol system, as a separable mixture of two diastereoisomers. The tra i-isomer is formed preferentially with bulky aldehydes <03T2687>. 

SYNS 1,4 -BENZENEDIOL, 2,3,5-TRIMETHYL- (9CI) V-CUMOHYDROQUINONE HYDROQUINONE, TRIMETHYL- TRIMETHYLHYDROQUINONE 2,3,5-TRIMETHYLHYDROQUINONE... 

Similarly, the stepwise electron transfer from 2 equiv. of trimethylhydroquinone (Me3QEl2) to Ceo occurs in the presence of Me4N+OH in benzonitrile (PhCN) to produce Ceo , which can be further converted into the corresponding dialkyl adduct (R2C60) by sequential electron transfer and 5 n2 reactions with alkyl halides... 

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