Rhodium(I)-catalyzed addition of phenols to dienes. A new convergent synthesis of vitamin E

Article abstract of DOI:10.1016/S0040-4039(00)00381-6

A highly convergent and atom-economical synthesis of (dl)-[α]- tocopherol (vitamin E) is proposed, the realization of which was made possible by the discovery of the regioselective Rh(I)-catalyzed arylation of β-springene with trimethylhydroquinone. Other phenolic compounds and 2- substituted-1,3-dienes were shown to undergo this transformation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00381-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3339–3343
Rhodium(I)-catalyzed addition of phenols to dienes.
A new convergent synthesis of vitamin E
Hugues Bienaymé,a,∗ Jean-Erick Ancel,a,∗ Pierre Meilland a and Jean-Pierre Simonato b
aRhône-Poulenc Industrialisation, 69153 Décines, France
bRhodia Recherches, 69192 Saint Fons, France
Received 25 February 2000; accepted 2 March 2000
Abstract
A highly convergent and atom-economical synthesis of (dl)-[α]-tocopherol (vitamin E) is proposed, the realiza-
tion of which was made possible by the discovery of the regioselective Rh(I)-catalyzed arylation of β-springene
with trimethylhydroquinone. Other phenolic compounds and 2-substituted-1,3-dienes were shown to undergo this
transformation. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: vitamin E; homogeneous catalysis; rhodium; C-alkylation; phenol.
With a worldwide annual production over 10 000 tons, vitamin E [(dl)-[α]-tocopherol] is one of the
most important food and feed additives.1 Obviously, any shorter or more convergent synthesis of this
natural anti-oxidant is of great economical significance.
Industrial syntheses of this vitamin rely on a logical C20+C9 disconnection between the hydroquinone
ring and the phytyl side-chain: tocopherol is formed by the acid-catalyzed Friedel–Crafts alkylation of
trimethylhydroquinone (TMHQ) with isophytol, followed by the chromane ring closure (Scheme 1, route
a).2
If this disconnection remains unavoidable on chemical grounds, much can be done to improve the
phytyl side-chain synthesis, and thus to increase the overall economy of the process. For instance, the
common industrial phytyl side-chain synthon, isophytol, is prepared from petroleum bulk chemicals
(acetone, acetylene etc.), but in linear lengthy syntheses (6–9 steps).2 Our analysis of this problem led
us to consider β-springene as a viable alternative: not only this C20 fragment is easily prepared from
the convergent coupling of two myrcene units, but the direct addition between a 2-substituted diene and
TMHQ highlights one of the most important aspect of industrial synthesis: atom economy.3 Myrcene
itself originates from the thermal cracking of β-pinene, a cheap commodity from timber industry (Scheme
1, route b).4 However this choice was not devoid of chemical challenges, the most obvious being the
chemo- and regioselective coupling between TMHQ and β-springene.
∗
Corresponding authors. Tel: +(33) 4 72 93 61 19; fax: +(33) 4 72 93 62 10; e-mail: hugues.bienayme@crit.rhone-
poulenc.com (H. Bienaymé), jean-erick.ancel@crit.rhone-poulenc.com (J.-E. Ancel)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00381-6
tetl 16661

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Scheme 1. Routes to vitamin E
In this communication we disclose how a new rhodium(I)-catalyzed arylation of non-activated dienes
with phenols allowed us to perform one of the most efficient syntheses of vitamin E.5
As a prelude to our study, many Brönsted and/or Lewis acid catalysts were evaluated in an attempt to
promote the chemo- and regioselective Friedel–Crafts addition of β-springene to trimethylhydroquinone.
As anticipated, this seemingly simple transformation was hampered with several problems: protonation
of the weakly dissymmetric diene resulted in the formation of a mixture of benzopyran and benzofuran
isomers. Furthermore, trisubstituted olefins in the chain were often competitively protonated, resulting in
unwanted polycylic adducts.6
Direct functionalization of aromatics by transition metal catalysts through C–H bond activation was
recently shown to be a powerful tool for substitution under mild conditions.7 Though most examples
are reported with electron-poor (hetero)aromatics possessing ortho-directing groups (aromatic ketones,
pyridines, imidazoles etc.), we decided to investigate whether electron-rich phenols could be alkylated in
a similar fashion.8
Amongst numerous metal/ligand couples tested, we found that a combination of a catalytic amount of
a Rh(I) salt, a phosphine ligand and a base resulted in a high yielding, entirely regiocontrolled, arylation
of β-springene (or myrcene) with TMHQ under mild conditions (Scheme 2, step d).9
For the success of this transformation, bidentate diphosphine ligands were found superior, diphenyl-
phosphinobutane (dppb) being the best. As Rh(I) source, the cyclooctadienyl rhodium chloride dimer
[RhCl(COD)2] (0.5–1 mol%, Rh/P=1/3) was found convenient to use, though other weakly coordinated
rhodium salts were also efficient. In sharp contrast to Friedel–Crafts alkylation conditions, a weak
catalytic base was found necessary here: either potassium (sodium) phosphate, carbonate or bicarbonate
(suspended in the reaction medium).
The resulting vitamin E synthesis is shown in Scheme 2. The ene-type chlorination of myrcene resulted
in chloro-3-myrcene,10 whereas its hydrochlorination in the presence of copper(I) chloride gave a mixture
of geranyl/neryl chloride,11 both in excellent yields. Reductive coupling of both halves was realized by
successive Grignard formation on the latter followed by copper(I) chloride-mediated coupling with the
former. β-Springene thus formed can be condensed with TMHQ under Rh(I) catalysis in high yield and
selectivity (vide supra). The oxygen-sensitive adduct was directly cyclized to tocotrienol.
The chromane ring formation of tocotrienol rests on a non-trivial chemoselective acid-catalyzed pro-
tonation of the proximal olefin in the phytyl chain, followed by nucleophilic attack of the hydroquinone
alcohol function (step e). Working with a Brönsted or a Lewis acid catalyst (MeAlCl2) in an apolar
aprotic solvent (hexane), resulted in the generation of protons in the vicinity of the hydroquinone

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Scheme 2. A convergent vitamin E synthesis.a aReagents and conditions: (a) Cl2 (g), pentane, reflux; (b) CuCl (5 mol%), HCl
(g), CH2Cl2, 0°C; (c) Mg°, THF, −20°C then CuCl (5 mol%); (d) [RhCl(COD)]2 (0.5 mol%), dppb (0.7 mol%), K2CO3 (20
mol%), toluene, 110°C; (e) MeAlCl2 or pTSA (5 mol%), hexane, 100°C; (f) H2 (20 atm.), Pd/C (2 mol%), EtOH then Ac2O
(1.2 equiv.), Et3N (1.5 equiv.), 25°C
nucleus and thus ensured an entropically-favored proximal olefin protonation.12 Further hydrogenation
and acetylation was carried out under standard conditions, to give (dl)-[α]-tocopherol acetate.
Thus, high purity vitamin E could be obtained in six convergent steps with an overall 50% yield
from cheap industrially available starting materials. Key to the success of this synthesis is the new high
yielding Rh(I)-catalyzed addition of phenols to dienes. The potential of this method was thus rapidly
explored with other phenolic compounds (Table 1).
For instance, myrcene was condensed with electron-rich phenols in good yields, though regioselectiv-
ity with phenols possessing more than one ortho/para free position was not always high (however, meta
addition was never observed). In all cases, myrcene was functionalized on its terminal carbon atom only,
a behavior which is reminiscent of other Rh(I)-catalyzed hetero- and carbonucleophile additions to this
diene.13 Adducts with exo olefin configuration were formed predominantly (with exo/endo ratios ranging
from 75/25 to 98/2). Electron-poor phenols (m- and p-cyanophenol, hydroxy-4-pyridine) and aniline did
not react under these conditions.
Various dienes were also evaluated (cyclohexadiene, dimethyl-2,3-butadiene, 1-substituted butadienes
etc.) but only 2-substituted butadienes gave the expected adducts under these conditions.
Proposed mechanism: when the condensation of O-deuterated dimethyl-2,6-phenol with myrcene (in
a mixture of toluene/D2O to ensure the complete replacement of exchangeable protons by deuterium)
was carried out, no deuterium was incorporated in the adduct. Thus, it appears that it is the aromatic
hydrogen atom which is transferred to the myrcenyl chain, since no other hydrogen atoms are available.
This observation, when taken together with most of the experimental observations (e.g. regioselectivity)
argues for the putative mechanism depicted in Scheme 3.
First, because of the competitive para-substitution of unsubstituted phenols, a direct hydroxyl-directed
insertion of Rh(I) in the ortho C–H bond can be ruled out. Rather, in the presence of a base, a rhodium(I)
phenoxide is formed upon displacement of the weakly coordinated chloride ligand (KCl precipitates

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Table 1
Condensation of myrcene with various phenols.a aReagents and conditions: [RhCl(COD)]2 (1 mol%),
dppb (3 mol%), K2CO3 (1 equiv.), toluene, 110°C, 24 h. bUnoptimized yields, isolated products.
cMono- and bis-addition observed. dortho/para/bis addition ratio=59/23/18, determined by 1H NMR.
eDetermined by 1H NMR
Scheme 3. A possible mechanistic rationale
and can be recovered for quantitation by filtration). A keto–enolic equilibrium causes the rhodium
nucleus to migrate in the ortho/para positions, if available. Rearrangement of this intermediate with
1,2-H migration yields an aryl–hydrido–Rh(III) complex (which retains the aromatic proton). A simple
keto–enolic equilibrium at this stage would result in hydrogen scrambling, and is thus unlikely.
A perfectly regioselective carbo-rhodiation of the diene, followed by reductive elimination of the

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resulting hydrido–π-allyl rhodium(III) complex delivers the alkylated phenol as an endo/exo mixture,
and regenerates the Rh(I) phenoxide catalyst. We feel that the exact mechanism cannot be unambiguously
settled at this stage.
In conclusion, the vitamin E synthesis presented here was made possible by the use of a highly efficient
atom-economical transition metal-catalyzed addition. Such transformation, when selective, may be of
great value to improve existing multi-ton processes.
Acknowledgements
We thank our colleagues from the analytical department (M. Lanson, L. Godde, J. L. Dumoulin,
J. Guillaud-Saumur) for their skilled and dedicated contribution, and Aventis Animal Nutrition for
permission to publish these results.
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