Convenient preparation of 2,7,8-trimethyl-6-hydroxychroman-2-carboxylic acid (γ-trolox)

Article abstract of DOI:10.1080/00397910701648728

The title chroman is useful in synthesis and as a water-soluble analog of γ-tocopherol, a member of the vitamin E family. This new synthesis of γ-trolox proceeds via selective aromatic demethylation of Trolox, the more easily available 2,5,7,8-tetramethyl homolog compound. This route is shorter than the previous synthesis, avoids the use of cyanide and methoxybutadiene, and requires no chromatography. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701648728

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Convenient Preparation of
2,7,8‐Trimethyl‐6‐hydroxychroman‐2‐carboxylic
Acid (γ‐Trolox)
John A. Hyatt a b
a Department of Chemistry , East Tennessee State University , Johnson City,
Tennessee, USA
b Yasoo Health, Inc , Johnson City, Tennessee, USA
Published online: 25 Jan 2008.
To cite this article: John A. Hyatt (2007) Convenient Preparation of
2,7,8‐Trimethyl‐6‐hydroxychroman‐2‐carboxylic Acid (γ‐Trolox), Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:1, 8-14, DOI:
10.1080/00397910701648728
To link to this article: http://dx.doi.org/10.1080/00397910701648728
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Synthetic Communicationsw, 38: 8–14, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701648728
Convenient Preparation of 2,7,8-Trimethyl-
6-hydroxychroman-2-carboxylic Acid
(g-Trolox)
John A. Hyatt
Department of Chemistry, East Tennessee State University,
Johnson City, Tennessee, USA and Yasoo Health, Inc., Johnson City,
Tennessee, USA
Abstract: The title chroman is useful in synthesis and as a water-soluble analog of
g-tocopherol, a member of the vitamin E family. This new synthesis of g-trolox
proceeds via selective aromatic demethylation of Trolox, the more easily available
2,5,7,8-tetramethyl homolog compound. This route is shorter than the previous
synthesis, avoids the use of cyanide and methoxybutadiene, and requires no
chromatography.
Keywords: aromatic demethylation, decarbonylation, tocopherol, tocotrienol, tocol,
Trolox
In 1974, a group at Hoffman-LaRoche published the syntheses and antioxidant
activities of a series of carboxylic acid analogs of vitamin E (a-tocopherol, 1).[1]
Of some 30 homologous compounds, 2,5,7,8-tetramethyl-6-hydroxychroman-
2-carboxylic acid 2 (“Trolox”) showed the best combination of high antioxi-
dant activity and good water solubility and was produced commercially.
Trolox (available from Sigma-Aldrich) has subsequently been proven to
be a very useful starting material for the synthesis of a wide variety of
chromans. Such varied uses for Trolox derivatives as anti-inflammatories,[2]
Received in the USA June 1, 2007
Address correspondence to John A. Hyatt, Department of Chemistry, East
Tennessee State University, Box 70695, Johnson City, TN 37614-1710. E-mail:
hyatt@etsu.edu
8

2,7,8-Trimethyl-6-hydroxychroman-2-carboxylic Acid
9
nematic liquid crystals,[3] NO-releasing drug candidates,[4] and synthons in
natural product synthesis[5,6] have been published. A number of syntheses
of (S)-2 and its reduced analogs have also appeared.[5]
The existence of heretofore unsuspected nonantioxidant biological activi-
ties in g-tocopherol 3[7,8] and the related g-tocotrienol[9,10] have prompted
interest in the synthesis of these and related natural products.[11–13] As part
of an effort to synthesize tocotrienols, we required as a starting material
2,7,8-trimethyl-5-hydroxychroman-2-carboxylic acid 4, the g-homolog of
Trolox 2.
Compound 4 had been synthesized by the Roche group[1] using a seven-
step route which started with a difficult and inefficient monoprotection of 2,3-
dimethylhydroquinone and required large amounts of cyanide and the
expensive reagent 2-methoxybutadiene. Inspired by the chemistry of
Mazzini et al.[14] who demonstrated a selective demethylation of a-
tocopherol 1 to provide g-tocopherol 3, we decided to explore the conversion
of readily available Trolox 2 into the desired g-trolox 4. We were gratified to
find that the chemistry shown in Scheme 1 allowed preparation of 4 from the
methyl ester of 2 in a five-step sequence that required no chromatography and
involved only three isolated intermediates.
Scheme 1.

10
J. A. Hyatt
Although Trolox methyl ester (2 methyl ester) is readily prepared from
the commercial free acid via Fischer esterification,[3] we also provide
details of a one-step synthesis of this compound. Using the hetero-Diels–
Alder reaction of methacrylates with in situ–generated o-quinone methides
pioneered by Shitara et al.[3] and by Buyukkidan, Bilgic, and Bilgic,[15]
reaction of trimethylhydroquinone 8 with paraformaldehyde, dibutylamine,
acetic acid, and excess methyl methacrylate gave an acceptible yield of 2
methyl ester. This procedure avoids the use of the high-pressure conditions
used to prepare 2 methyl ester patented by Tanaka et al.[16] and is far
shorter than the route of Scott et al.[1]
Treatment of 2 methyl ester with bromine in a mixture of dichloro-
methane and carbon tetrachloride cleanly provided the 5-(bromomethyl)
compound, but this material was very sensitive toward elimination of HBr
to form an o-quinone methide that dimerized in situ. This problem was side-
stepped by O-acetylation after completion of the bromination; bromoacetate 5
was obtained in 78% yield after recrystallization. This unusually selective bro-
mination is well known in the case of vitamin E 1 and was studied mechanis-
tically by Rosenau and Habicher.[17] Oxidation of bromoacetate 5 with N-
methylmorpholine-N-oxide in acetonitrile afforded a 71% yield of crystalline
aldehyde 6.
Although Mazzini et al.[14] oxidized 5-formyl-a-tocopherol to the corre-
spoding carboxylic acid and obtained g-tocopherol by decarboxylation, it
appeared to us that decarbonylation of the aldehyde would provide direct
access to the g-series. We were therefore disappointed to find that attempts
to decarbonylate acetate 6 (or the corresponding phenol) using the preferred
rhodium complexes[18,19] in catalytic or stoichiometric quantities under a
variety of conditions gave only recovered starting material. Similarly,
attempted scandium triflate–catalyzed decarbonylation[20] gave very low con-
version to the desired product 7. We were therefore gratified to observe that,
upon heating at 210–2208C neat in the presence of 10% Pd/C catalyst,[21]
smooth decarbonylation of 6 occurred in acceptable yield (51% of 7 after
recrystallization). Ester hydrolysis of 7 under basic conditions then
completed the synthesis of g-trolox 4.
This synthesis of 4 proceeds in fewer steps than the previously published
route, involves only crystalline compounds, and requires no chromatography.
The conceptual approach of degrading a readily available higher homolog to
produce a desired product is seldom considered in lieu of de novo synthesis
but clearly deserves attention in certain circumstances.

2,7,8-Trimethyl-6-hydroxychroman-2-carboxylic Acid
EXPERIMENTAL
11
General Methods
1
All reactions were carried out under nitrogen or argon atmosphere. H NMR
spectra were recorded using a Jeol Eclipse 400 instrument (400 MHz).
Melting points are uncorrected. Elemental analyses were done by Atlantic
Microlabs, Inc., Norcross, GA.
Trolox Methyl Ester (2 Methyl Ester)
A 1-L, three-neck flask was equipped with heating mantle, reflux condenser,
and stirrer and charged with 159 ml (1.50 mol) of methyl methacrylate, 9 g
(0.30 mol) of paraformaldehyde, 4.8 g (0.036 mol) of dibutylamine, and
45 ml of acetic acid. This mixture was stirred at room temperature, and
45.6 g (0.30 mol) of trimethylhydroquinone were added. This mixture was
stirred under reflux for 20 h. The resulting dark mixture (solid was present)
was chilled to 0–58C and filtered (methanol wash) to give 30.7 g (39%
yield) of 2 methyl ester as a light tan solid. This material was suitable for
further use; a sample recrystallized from methanol [the hot solution being
filtered to remove traces of insoluble poly(methyl methactylate)] gave white
prisms of mp 160.5–162.58C lit.[22] 162–1648C. NMR (CDCl3): 5.65 (1H,
br S, OH), 3.67 (s, 3H), 2.65–2.72 (m, 1H), 2.41–2.55 (m, 2H), 2.18
(s, 3H), 2.16 (s, 3H), 2.06 (s, 3H), 1.82–1.90 (m, 1H), 1.59 (s, 3H).
Bromoacetate 5
A 1-L, three-neck flask was charged with 15.85 g (0.060 mol) of 2 methyl
ester, 240 ml of carbon tetrachloride, and 90 ml of dichloromethane. The
mixture was stirred at rt in the dark, and a solution of 3.30 ml (0.064 mol)
of bromine in 45 ml of carbon tetrachloride was added dropwise over
40 min. Stirring continued at rt for 2 h after completion of the bromine
addition; the resulting solution was dark, but no bromine color or vapor was
detectable. The mixture was purged with a stream of nitrogen for 30 min to
remove most of the HBr present, then stripped to dryness on the rotovap.
The resulting damp dark solid was treated with 130 ml of dichloromethane,
110 ml of glacial acetic acid, 30 ml of acetic anhydride, and 12 small drops
of conc. sulfuric acid. After stirring overnight at rt, the mixture was treated
with 600 ml of water and stirred for 1 h. The mixture was transferred to a
separatory funnel and the layers were separated. The aqueous layer was
extracted with ethyl acetate and the EtOAc layer was combined with the
dichloromethane layer. The combined organic layer was washed with brine,

12
J. A. Hyatt
dried (MgSO4), and stripped to dryness on the rotovap (considerable acetic
acid must be removed) to give a pale orange oil that crystallized on standing.
Recrystallization from methanol afforded 18.1 g (78%) of tan solid
product of mp 114–115.58C. NMR (CDCl3): 4.2–4.5 (broad, 2H, hindered
rotation); 3.68 (s, 3H); 2.8–2.9 (d of q, 1H), 2.56–2.68 (m, 1H), 2.24–2.48
(d of q, 1H), 2.37 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.85–
1.92 (m, 1H), 1.61 (s, 3H). Analysis: calcd. for C17H21BrO5: C, 52.99; H,
5.49. Found: C, 53.25; H, 5.66.
Aldehyde 6
A solution of 14.6 g (0.038 mol) of bromoacetate 5 in 120 ml of dry aceto-
nitrile was stirred at rt and treated with 13.23 g (0.114 mol, 3 eq.) of N-methyl-
morpholine-N-oxide. The resulting reaction mixture gave a mild exotherm
and progressed from a pale yellow color through green to dark orange-
brown when stirred 18 h at rt. Thin-layer chromatography (TLC) indicated
completion of the reaction, and the mixture was stripped to about 40 ml on
the rotovap. This concentrated solution was poured into about 600 ml of
water and extracted (3 ꢀ 100 ml) with ethyl acetate. The combined ethyl
acetate layers were washed with 5% HCl and with brine, dried (MgSO4),
and stripped to give 10.9 (89%) g of an orange syrup, which crystallized
when scratched. Trituration with ether–hexane gave 8.56 g (71%) aldehyde
as an off-white solid of mp 88–918C. NMR (CDCl3): 10.21 (s, 1H), 3.7
(s, 3H), 3.20–3.33 (m, 1H), 2.80–2.92 (m, 1H), 2.40–2.46 (m, 1H), 2.41
(s, 3H), 2.27 (s, 3H), 2.08 (s, 3H), 1.8–1.90 (m, 1H), 2.62
(s, 3H). Analysis: calcd. for C17H20O6: C, 63.74; H, 6.29. Found: C, 63.63;
H, 6.43.
g-Trolox Methyl Ester Acetate 7
A mixture of 2.20 g (0.0068 mol) of aldehyde 7 and 0.40 g of 10% Pd on
charcoal catalyst was placed in a 10-ml flask under a very slow stream of
argon and immersed in a 2108C oil bath with stirring for a total of 8 h, at
which time TLC analysis indicated complete consumption of the aldehyde
and formation of a single major and two very minor products (similar
results were obtained in about 4 h at 2208C, but poor results were obtained
with 5% Pd/C at any loading or temperature). The cooled reaction mixture
was dissolved in ethyl acetate, filtered (Celitew) to remove the catalyst, and
stripped of solvent on the rotovap to give 1.78 g of gamma-trolox methyl
ester acetate 7 as an orange oil, which crystallized when scratched. This
crude product (89% yield) appeared to be at least 90% pure by NMR. Recrys-
tallization from methanol afforded 1.02 g (51%) of pale yellow solid of mp
104–1058C. NMR (CDCl3): 6.52 (s, 1H), 3.69 (s, 3H), 2.6–2.7 (m, 2H),

2,7,8-Trimethyl-6-hydroxychroman-2-carboxylic Acid
13
2.3–2.4 (m, 1H), 2.28 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H), 1.8–1.9 (m, 1H), 1.60
(s, 3H). Analysis: calcd. for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.65;
H, 7.05.
g-Trolox 4
A mixture of 0.80 g (0.0027 mol) of methyl ester acetate 7, 20 ml of methanol,
and 1.60 g of 50% aq. NaOH solution (0.020 mol) was sparged with nitrogen
and stirred at reflux for 30 min. After cooling, the mixture was acidified with
5% HCl, extracted with chloroform, dried (MgSO4), and stripped of solvent in
vacuo, and the resulting solid was crystallized from ether–hexane to afford
0.49 g (89%) of 4, mp 166–1688C (lit.[1] 167.5–168.58C). NMR (DMSO-
d6): 6.28 (s, 1H), 2.56 (m, 2H), 2.22 (m, 1H), 2.04 (s, 3H), 1.99 (s, 3H),
1.74 (m, 1H), 1.47 (s, 3H).
ACKNOWLEDGMENT
The author is grateful to Elias Couladouros (Athens, Greece) for helpful
discussions regarding the preparation of chromans using the hetero-Diels–
Alder approach.
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