2.3.6- Trimethylhydroquinone reaction with

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. 

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). 

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... 

Trimethylhydroquinone in dichloromethane by reaction with acetaldehyde in dichloromethane saturated with hydrogen chloride at less than ambient temperature produced a 1,3-dioxan intermediate in 94% yield which upon vacuum pyrolysis at 460°C afforded 1,4-dihydroxy-2,3,5-trimethylvinylbenzene in 62% yield (ref.165). 

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). 

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>. 

Vitamin E, a-tocopherol, an effective antioxidant, is obtained as a diastereoisomeric mixture in the 2,3 (S),7 (R),11 (R), form and the natural 2,3 (R),7 (R), 11 (R), form (83) by the reaction of phytyl bromide with trimethylhydroquinone in the presence of zinc chloride (ref.86), the phytol required being obtained from chlorophyll. 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

The technical syntheses are based on the condensation of phytol or isophytol with trimethylhydroquinone, which can be prepared from 3,5-dimethylphenol by the Mannich reaction followed by a series of obvious steps. We prepared radioactive C -labelcd trimethylhydroquinone (specific activity 11.8 ic/mg), os shown in Fig. 2. 

E)-a-Tocopherol (vitamin E) was synthesized by the condensation reaction of trimethylhydroquinone with isoph34ol in supercritical CO2 (SCCO2) in the presence of (1) (eq 2). ... 

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