Efficient access to (All-rac)-α-Tocopherol acetate by a crombie chromene synthesis

Article abstract of DOI:10.1246/bcsj.82.843

In contrast to reports in the literature, the pyridine-catalysed condensation of phenolic compounds and conjugated aldehydes to chromenes was found to be applicable to trimethylhydroquinone 2a with the result of complementary convergent approaches to the

Full text of DOI:10.1246/bcsj.82.843

© 2009 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 82, No. 7, 843–854 (2009)
843
Efficient Access to (All-rac)-¡-Tocopherol Acetate
by a Crombie Chromene Synthesis
Vincent Gembus, Nathalie Sala-Jung, and Daniel Uguen*,#
Laboratoire de Synthèse Organique (associé au CNRS), Ecole Européenne de Chimie, Polymères et Matériaux,
Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France
Received November 21, 2008; E-mail: uguen@chimie.u-strasbg.fr
In contrast to reports in the literature, the pyridine-catalysed condensation of phenolic compounds and conjugated
aldehydes to chromenes was found to be applicable to trimethylhydroquinone 2a with the result of complementary
convergent approaches to the title acetate using citral 3a and dihydromyrcene 9 as precursors of the phytyl residue.
(All-rac)-¡-tocopherol acetate 1aOAc, a substitute for
vitamin E in the feed industry, is produced by condensing
trimethylhydroquinone (TMHQ) 2a with isophytol, which is
synthesized from acetone by means of C3 and C2 homologation
processes.1 With the aim of designing a convergent access
to 1aOAc, we have previously studied the condensation of
TMHQ 2a and linalool, and shown that refluxing this C10
alcohol in 10:1 dodecane/CH2Cl2 with 2a and camphorsulfonic
acid mainly afforded the chromanols 1b and 1c, which were
subsequently converted to 1aOAc in few steps.2 However, this
new approach to 1aOAc suffers from incomplete selectivity
of the chromenisation reaction process: unlike isophytol, the
linalool molecule incorporates unsaturation at the ¦6 position,
protonation of which results in the formation of chromanol
by-products whose large-scale elimination would be problem-
atic. Keeping with a 2a-C10-C10 strategy, the condensation of
the quinol 2a and citral 3a was next examined (Scheme 1).
The reactivity of phenolic compounds with ¡,¢-unsaturated
aldehydes has previously been studied in relation to the
synthesis of such important compounds as flavonoids, rote-
noids, coumarins, and cannabinoids.3 Early investigations were
mainly concerned with the condensation of 5-pentylresorcinol
(olivetol) with 3a. With BF3¢Et2O as catalyst, isomeric
tetrahydrocannabinols were produced, a possible reaction
pathway being a cationic rearrangement of the initially-formed
hydroxygeranylolivetol to corresponding limonene derivatives,
which cyclize to the observed cannabinoids.4 A different
product distribution was observed under base catalysis. As
first reported by Crombie,5a-5c and almost simultaneously by
others,4c,5d,5e heating (ca. 130-150 °C) olivetol (or a related
m-diphenol) with 3a in pyridine afforded a mixture of mono-
and bis-chromenes, alongside polycyclic compounds formed
from these products by isomerization processes involving
either a [2 + 2], [2 + 4], or Diels-ene condensation reaction.3i,3j
Further investigation of this chromenisation process showed
that the use of citral dimethyl acetal 3b permitted shorter
reaction times, and thus a reduction in the formation of
polycyclic by-products, a result subsequently developed into a
preparative procedure.3f,6,7 Further refinement of this method-
ology has dealt with the catalyst conditions, good yields of
chromenes being achieved by using calcium hydroxide, or
ethylendiamine diacetate, as a catalyst,8,9 while in the case of
AcO
AcO
ref. 2
O
O
1bOAc/1cOAc
(All-rac)-α-tocopherol acetate 1aOAc
R
HO
HO
R
X
R
R
O
OH
R
4a, R=3-methyl-2-butenyl
4b, R=hexahydrofarnesyl
2a, R=Me
2b, R=H
Citral 3a, X=O; R=3-methyl-2-butenyl
3b, X=OMe, OMe; R=3-methyl-2-butenyl
Phytal 3c, X=O; R=hexahydrofarnesyl
3d, X=OMe, OMe; R=hexahydrofarnesyl
Scheme 1. Planned strategy.
Published on the web July 10, 2009; doi:10.1246/bcsj.82.843

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Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
¡-Tocopherol from Citral and Dihydromyrcene
N
N
H
H
Y
Y
X
R1
R1
R1
N
O
O
R3
O
R3
R2
R3
R2
R2
Y=OH or OMe
X=O or OMe, OMe
R1
R1
O
R3
O
R3
R2
R2
Scheme 2. Hypothetical mechanism of Crombie chromene synthesis.
monohydric phenols, better results were obtained by refluxing
metal phenoxides (TiIV, Al, and Mg) with ¡,¢-unsaturated
aldehyde dimethyl acetals in toluene.9 Independently, phenyl-
boronic acid, combined with a carboxylic acid was shown to be
an effective catalyst when a conjugated aldehyde was used.10
Crombie chromene synthesis strongly resembles the condensa-
tion of 1,3-dicarbonyl compounds and ¡,¢-unsaturated alde-
hydes to dihydropyrans.11 Mechanistically, it would proceed by
crotonization of the initially-formed aldol-like condensation
product to a vinyl o-quinone methide, which isomerizes to the
observed chromene (Scheme 2).7d Acid-assisted displacement
of the benzylic oxygen atom of the aldol-like intermediate by
the phenolic hydroxy might also be considered.10c,12 However,
as exemplified by the coenzyme Q/ubichromenol interconver-
sion,13a-13c prenylated quinones isomerize to chromenes in
basic conditions.13 Thus, it is likely that the indicated electro-
cyclic ring closure operates; indeed, this is a well-documented
process,14 occurring inter alia in the thermal rearrangement of
propargyl aryl ethers and o-butadienylphenols to chromenes,15
and its reversibility is exploited in various photochromic
systems.9c-9e
Chromenes being easily hydrogenated to chromanes,16 the
possibility of preparing tocopherol 1a from TMHQ 2a and
phytal 3c has previously been studied by Crombie, and
although his attempts to condense 2a and 3c in pyridine
proved unrewarding6f®“we never succeeded in condensing
this (i.e. 2a) or other simple hydroquinones with either phytal
(3c) or citral (3a)”®the goal was later achieved using the
conditions designed by Casiraghi in the case of weakly acidic
phenols.9b Thus, treating 2a with ethylmagnesium bromide
(two-fold excess), then refluxing the resulting phenoxide in
benzene with phytal dimethyl acetal 3d gave, after acetylation
followed by hydrogenation, the tocopherol acetate 1aOAc in
moderate yield (26%).17 As explained in the preceding paper,
recourse to expensive reagents to produce this acetate is
undesirable. The ready availability of pyridine, coupled with
the possibility of in situ acetylation of the chromene product
prompted us to re-evaluate the preceding Crombie experiments
with this base. The observed reluctance of 2a, compared with
less substituted phenolic compounds, to react with 3b (or 3d)
could result from a steric effect of its C-5 methyl group, and it
is possible that, due to the presence of trace air, a degradation
of 2a occurred. In the event, the prolonged heating of 2a in
pyridine with 3b under strictly oxygen-free conditions should
be beneficial, and proved to be the case.
Results and Discussion
First (Table 1, Entry 1), a mixture of TMHQ 2a, citral
dimethyl acetal 3b and pyridine (10 mmol each) was thor-
oughly degassed (three “freeze-pump-thaw” cycles), then
heated at ca. 165-175 °C under a static argon atmosphere.
After a few hours, only slow progress was noticed on TLC, but
after five days 3b was fully reacted and a new product had
formed. Still in absence of air, Ac2O and pyridine (both in
excess) were added and the resulting mixture was stirred
overnight to give, after acid hydrolysis and extraction, a brown
syrup from which the desired chromene acetate 4aOAc (59%;
NMR spectra identical to literature data)13h and the diacetate
of TMHQ 2a®i.e., 2aOAc®(22%) were isolated successively
by column chromatography. For the sake of comparison, citral
3a was reacted with 2a in the preceding conditions (Entry 2).
The reaction proceeded sluggishly and, after 6 days, 4aOAc
was obtained in low yield (8%), thus confirming the previously
observed greater reactivity of the acetal 3b under these
conditions. Next, attempts were made to improve the selec-
tivity of this condensation with regards to the quinol 2a
(expressed by the 4aOAc:reacted 2a ratio in Table 1). Varying
the reactants-to-pyridine ratio barely affected this selectivity,
except when pyridine was used in a two-fold excess (Entries 4-
6). When pyridine was omitted, only a trace amount of the
chromene 4aOAc was obtained (Entry 7), and this was not
improved by adding various rare-earth triflates (in acetonitrile).
Collidine and DMAP were also effective (Entries 8 and 9), but
without advantage compared with pyridine.
Next, with a view to speeding up this process, and as
recommended in a related case,3f an equimolar mixture of 2a,
3b, and pyridine was heated in a flask equipped with a Vigreux
column, the resulting volatiles being progressively eliminated

V. Gembus et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
845
Table 1. Effect of the Conditions on the Selectivity of the 2a/3b Condensation
3b (1 equiv), catalyst, ∆,
then Ac2O/pyridine,
then chromatography
AcO
AcO
2a
O
OAc
4aOAc
2aOAc
Entry
Catalyst (equiv)
Conditionsa)
Time
Reacted 2a/% 4aOAc/%e) 4aOAc:reacted 2a/%
1
2
3
4
5
6
7
8
9
Pyridine (1)
Pyridine (1)
Pyridine (1)
Pyridine (0.1)
Pyridine (0.5)
Pyridine (2)
®
Ab)
Ac)
Ad)
Ab)
Ab)
Ab)
Ab)
Ab)
Ab)
Bb)
Cb)
5 d
6 d
5 d
3 d
3 d
3 d
3 d
3 d
3 d
4 h
1 h
78
®
54
52
54
46
®
25
45
83
56
59
8
76
®
93
85
91
74
®
80
93
63
75
50
44
49
34
4
20
42
52
42
Collidine (1)
DMAP (1)
Pyridine (1)
Pyridine (1)
10
11
a) A: 10 mmol scale; 165-175 °C (bath), in a closed vessel. B: 10 mmol scale; 165-175 °C (bath) with progressive
elimination of the resulting volatiles. C: 20 mmol scale; slow addition of 3b diluted with pyridine to a heated (ca.
180-185 °C; bath) 2a/pyridine mixture with progressive elimination of the resulting volatiles. b) E-3b:Z-3b = 2:1.
c) With citral 3a. d) With Z-3b. e) Isolated.
AcO
a, b
MeO
MeO
O
Phytal dimethyl acetal 3d
1aOAc
Scheme 3. Reagents and conditions: a) 2a (1 equiv), pyridine (1 equiv), in conditions B of Table 1, then Ac2O/pyridine (33%; 70%
based on reacted 2a); b) 1 atm H2, 5% Pd/C, EtOAc, rt (96%).
by distillation (Entry 10). After a few hours the distillation
ceased, and TLC analysis indicated complete consumption of
the acetal 3b. Removing all volatiles in a vacuum then afforded
a brown slurry, which was reacted with Ac2O in pyridine as
above to give, after a purification by column chromatography,
the chromene 4aOAc in 52% yield (63% based on reacted 2a).
Altough the acetal 3b was fully reacted, we failed to identify
any decomposition product. Since 3b was a mixture of E and Z
isomers (E-3b:Z-3b µ 2:1), the observed limited selectivity
with regards to this reagent®i.e., the yield of 4aOAc in
Table 1®could result from a difference in the reactivity of
these stereomers. This was verified by reacting pure Z-3b with
2a under the conditions of Entry 1 to obtain 4aOAc in 50%
yield (Entry 3), to be compared to the 59% yield achieved
by using 3b under the same conditions. Another possibility
was a self-condensation reaction of these acetals. In the
event, lowering the concentration of 3b would be beneficial.
Accordingly, the acetal 3b diluted with a little pyridine was
progressively added to a heated (ca. 180-185 °C) mixture of
2a and pyridine, the resulting volatiles being progressively
distilled out as in the preceding experiment (Entry 11). After
one hour, TLC analysis indicated that 3b had fully reacted, but,
paradoxically, the chromene 4aOAc was then isolated in lower
yield and no more effort was expended in this direction.
Next, phytal dimethyl acetal 3d, prepared from commercial
phytone 5 as a 1:1 mixture of the E and Z isomers (see
experimental), was reacted with 2a under the conditions of
Entry 10 to give, after treatment with Ac2O/pyridine and
chromatography, the chromene acetate 4bOAc (33%; 70%
based on reacted 2a), as evidenced by NMR analysis.18 It is
noteworthy that some phytal 3c (ca. 25%) was recovered.
Hydrogenating this acetate afforded (all-rac)-¡-tocopherol
acetate 1aOAc in high yield (Scheme 3).
Interestingly, HPLC-MS analysis of this product showed it
not to contain the isomeric benzofuran derivative found as
a trace impurity in a commercial sample of 1aOAc. The
possibility of using hydroquinone 2b in these condensations
was also examined, since hydrogenating the chromene 4c
derived from 2b and 3d would deliver a chroman precursor of
1aOAc.19 Intriguingly, the reaction of 2b with 3d followed
by acetylation afforded in low yield the chromene 4cOAc,
alongside bis-chromene by-products (GC-MS). This was
exploited in a short synthesis of the racemic form of the
naturally-occurring antibiotic cordiachromene A 4d from 2b
and 3b (Scheme 4).20
The Isocitral Approach. Epoxidation of a benzochromene
having the same substitution pattern at C-2 as 4aOAc with a
manganese(III) catalyst has been shown to occur exclusively at
the C-3/C-4 unsaturation.8f Although it was later to prove
otherwise (vide infra), we surmised that the allylic oxygen-
ation/Wurtz coupling sequence that we had previously used for
homologating 1bOAc to 1aOAc would be inappropriate with

846
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
¡-Tocopherol from Citral and Dihydromyrcene
AcO
a
O
HO
4cOAc
b
OH
2b Hydroquinone
HO
O
4d (Rac)-Cordiachromene A
Scheme 4. Reagents and conditions: a) 3d (0.6 equiv), pyridine (1 equiv), 125 °C, 6 d, then Ac2O/pyridine (30%); b) 3b (1 equiv),
pyridine (1 equiv), 125 °C, 82 h (40%).
MeO
a, b
HO
MeO
O
7
3f
Geraniol
(ref. 2)
MeO
MeO
c
b
X
Citral 3a
O
O
Tetrahydrocitral 6a, X=O
6b, X=OAc, OAc
6c, X= OMe, OMe
Cl
3h
3g
Cl
d
e
3b, 3f
3a, 3e
AcO
OH
OH
O
O
AcO
g
f
h
4fOAc
4gOAc
1aOAc
2a/3f
O
AcO
4eOAc
Scheme 5. Reagents and conditions: a) TMSCHLiCH=NtBu, then aqueous HCO2H according to Ref. 23 (77%). b) MeOH,
CH(OMe)3, 1% PPTS (92%). c) Ca(OCl)2, CO2, H2O/CH2Cl2 (76%). d) Zn, AcOH, according to Ref. 24 (87%; 3a:3e = 1:1).
e) Zn, MeOH (59% overall from 3g; 3b:3f = 4:1). f) Conditions B of Table 1, then Ac2O/pyridine (52%; 88% based on reacted
2a). g) 6a, Me2AlCl (1.55 equiv), CH2Cl2 (58%; 4fOAc:4gOAc = 84:16). h) 1 atm H2, 5% Pd/C, EtOAc/HCl (overall 36% based
on reacted 2a).
4aOAc.2 Accordingly, the condensation of 2a and isocitral 3e
was studied. As shown by Snider21 and as previously illustrated
in the chroman series,2 2-methyl-1-alkenes ene-condense with
aliphatic aldehydes in the presence of an alkylaluminum
chloride much more readily than 2-alkenes. Hence, our hope
was that the chromene 4eOAc derived from 2a and isocitral
dimethyl acetal 3f would react with tetrahydrocitral 6a under
these conditions to give a ene-adduct potentially convertible to
1aOAc by hydrogenolysis.2 To this end, the preparation of
isocitral 3e was examined. One possibility was to condense
isomethylheptenone 7 and acetylene under basic conditions,22a
then to isomerize (Meyer-Schuster rearrangement) the resulting
propargylic alcohol to 3e.22a-22e However, it proved more
convenient to prepare 3e by means of a Peterson olefination of
the ketone 7 using the t-butylimine of trimethylsilylacetalde-
hyde, as described.23 Next, the reaction of 3e with methanol in
the presence of trimethyl orthoformate and pyridinium tosylate
(PPTS) afforded isocitral dimethyl acetal 3f in good yield
(92%) (Scheme 5).
Using the chlorination/reduction methodology designed
by Wolinsky to convert citral 3a to isocitral 3e was less
satisfactory.24 Reacting 3a with the Ca(OCl)2¢CO2 reagent
in a two-phase system, as described, did indeed afforded
chlorocitral 3g, but in contrast to the observations reported in
this otherwise valuable publication, treating this chloroalde-
hyde (10 g scale) with zinc in acetic acid furnished 3a and 3e as

V. Gembus et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
847
AcO
AcO
AcO
AcO
ref. 2
e
a
O
O
O
O
O
O
4aOAc
4hOAc
1dOAc
1bOAc
b, c
RO
ref. 2
O
ClMg
OR
8
Dihydromyrcene 9
4i, R=H
4jOAc, R=C(O)CH3
d
AcO
AcO
f
O
O
4kOAc
1aOAc
Scheme 6. Reagents and conditions: a) m-CPBA (1 equiv), Ca(OH)2, CH2Cl2 (93%). b) Al(O-i-Pr)3 (4 equiv), toluene (reflux) (95%).
c) Ac2O (excess), 1:1 CH2Cl2/pyridine, rt overnight (80% overall from 4hOAc). d) 8 (2 equiv), CuI (0.05 equiv), THF (84%).
e) 1 atm H2, 10% Pd/C, EtOAc (91%). f) 1 atm H2, 5% Pd/C, EtOAc (96%).
a 1:1 mixture (1H NMR), this ratio being essentially unaffected
by varying the dilution, the temperature or the zinc activation
conditions. Some improvement was gained, however, by first
reacting 3g with methanol in the presence of trimethyl
orthoformate and PPTS as above, then treating the resulting
chloroacetal 3h with zinc in MeOH to obtain a 4:1 mixture
of the acetals 3f and 3b respectively. Reacting TMHQ 2a
with 3f under conditions B of Table 1 afforded, after treatment
with Ac2O and column chromatography, the chromene acetate
4eOAc in fair yield (52%). Next, 4eOAc was reacted with
tetrahydocitral 6a in CH2Cl2 and added Me2AlCl (excess).
The reaction proceeded very slowly and additional 6a proved
reactivity could be steric in origin, another possibility being a
stereoelectronic effect: a hybridation change (from sp2 to sp3) at
C-3/C-4 might bring about an interaction of the C-5 methyl
group of 4bOAc with the hydrogen atom at C-4.28 Whatever
the validity of these hypotheses, the preceding observation was
encouraging. Accordingly, 4aOAc was reacted with m-CPBA
under standard conditions (CH2Cl2, 0 °C) to give in good yield
(93%) a single product (TLC) to which the structure 4hOAc
was assigned by NMR analysis (Scheme 6).
This was confirmed by hydrogenating this product (H2, 5%
Pd/C) to a chroman (91%) identified as 1dOAc (NMR, GC).2
Refluxing the epoxide 4hOAc in toluene with aluminum
isopropoxide afforded the chromenol 4i, which was converted
to the diacetate 4jOAc by treatment with Ac2O in pyridine
(overall 80%). CuI-catalysed Wurtz coupling of this diacetate
with citronellylmagnesium chloride 8 (two-fold excess) then
furnished the chromene acetate 4kOAc, which was hydro-
genated to 1aOAc in high yield (96%; 45% overall from 2a).
Encouraged by this result, the allylic chlorination of 4aOAc
was attempted. NMR features of the product (85%) obtained by
treating 4aOAc with the CaCl2¢CO2 reagent in a two-phase
system as above were consistent with the structure 4lOAc
(Scheme 7).
This sensitive product was immediately reacted with
citronellylmagnesium chloride 8 in THF and added CuI to
give 4kOAc (58%), which was subsequently hydrogenated
to 1aOAc (40% overall from 2a). In a converse manner,
the chloroacetal 3h was similarly reacted with 8. After only
a few minutes the reaction was completed, as evidenced
by TLC. NMR analysis of the product isolated after acid
hydrolysis showed it to be the aldehyde 3i (84%); no isomeric
coupling product was detected. Acetalizing this aldehyde with
methanol under the above conditions afforded quantitatively
the dehydrophytal acetal 3j. Reacting this acetal with 2a in
pyridine under the conditions C of the Table 1 afforded in fair
yield (49%; 82% based on reacted 2a) the chromene acetate
4kOAc, which was subsequently hydrogenated to 1aOAc
(96%).
1
necessary to observe a useful conversion. H NMR analysis of
the product then isolated indicated it to be an 84:16 mixture
of the isomeric chromenes 4fOAc and 4gOAc respectively.
Hydrogenating this product in acidic conditions (H2, Pd/C,
EtOAc/HCl) furnished, after purification by column chroma-
tography, (all-rac)-¡-tocopherol acetate 1aOAc with a purity
of 94.8% (HPLC-MS). Though our goal was achieved, the
use of 1.5 molar equivalents of Me2AlCl altered to some
extent the value of this approach. This led us to experiment
with the catalytic Diels-ene condensation conditions previously
designed by Aggarwal.25 Accordingly, the acylal 6b, conven-
iently prepared by treating tetrahydrocitral 6a with Ac2O in the
presence of a montmorillonite,26 was reacted with 4eOAc in
acetonitrile in the presence of scandium triflate (10%). No
reaction occurred and the addition of more catalyst after a few
days provoked decomposition. Reacting 4eOAc with tetrahy-
27
drocitral dimethyl acetal 6c in the presence of FeCl3 was no
more successful and this approach was abandoned.
The Citral Approach. Our interest then returned to the
elaboration of the chromene 4aOAc into 1aOAc. On electronic
grounds, and as illustrated with a parent naphthodihydropyran
(vide supra), the ¦3,4 unsaturation of 4aOAc should be the
most reactive with epoxidation reagents. Surprisingly however,
it has been observed that the chromene 4bOAc, prepared by
dehydrogenating tocopherol acetate 1aOAc with DDQ, epoxi-
dised only very slowly using Jacobsen’s catalyst.18 This low

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¡-Tocopherol from Citral and Dihydromyrcene
AcO
AcO
a
AcO
b
e
1aOAc
O
O
O
Cl
4aOAc
4lOAc
4kOAc
d
MeO
c
MeO
X
Cl
3i, X=O
3j, X=OMe, OMe
3h
Scheme 7. Reagents and conditions: a) Ca(OCl)2, CO2, H2O/CH2Cl2 (85%). b) 8 (1 equiv), CuI (0.05 equiv), THF (58%). c) 8 (1
equiv), CuI (0.05 equiv), THF, then 1 M HCl, then MeOH, CH(OMe)3, PPTS (88%). d) 2a (0.5 equiv) in conditions C (see
Table 1), then Ac2O/pyridine (49%; 82% based on reacted 2a). e) 1 atm H2, 5% Pd/C, EtOAc (94-96%).
(E,Z)-Phytal (3c).
1 M (in hexane) DIBA-H (23.4 mL,
Conclusion
23 mmol) was added dropwise to a cooled (dry ice/acetone bath)
solution of phytonitrile 10 (5.15 g, 17.7 mmol) in CH2Cl2 (55 mL)
with stirring. The resulting mixture was stirred at rt overnight, then
diluted with pH 2 tartaric buffer (210 mL). After 2 h stirring, the
aqueous layer was extracted with CH2Cl2 (2 © 50 mL) and the
pooled organic phases were washed with pH 2 tartaric buffer
(100 mL), saturated NaHCO3 (100 mL), brine (2 © 50 mL), and
dried (MgSO4). The residue left by evaporation of the solvents was
purified by column chromatography (hexane/CH2Cl2) to give
phytal 3c (E-3c:Z-3c µ 1.2:1; by 1H NMR) as a pale-yellow oil
In contrast to reports in the literature, the pyridine-catalysed
condensation of phenolic compounds and ¡,¢-unsaturated
aldehyde dimethyl acetals to chromenes®i.e., Crombie chro-
mene synthesis®was shown to be applicable to trimethylhy-
droquinone 2a, thereby providing short complementary routes
to (all-rac)-tocopherol 1aOAc either from citral 3a, isocitral 3e,
or phytal 3c. Of the various ways we have explored, that
starting from citral 3a, and leading by way of the chlorochro-
mene 1lOAc to the tocopherol acetate 1aOAc appears to be the
more efficient, allowing access to this important compound
in an acceptable 40% overall yield. However, given the ease
with which the chloroacetal 3h was prepared from 3a, the
complementary C10-C10-2a approach via the dehydrophytal
acetal 3j offers some advantages; besides being highly
convergent, the selectivity of the chromenisation step, both
with regards to the quinol 2a and the acetal 3j, is fairly good.
Alhough citronellylmagnesium chloride 8 is available by
hydrometalation of dihydromyrcene 9 (a commodity of the
timber industry), eliminating the associated metal wastes could
be a limitation. However, this is offset by the simplicity of the
conditions, no co-solvent being necessary for the chromenisa-
tion reaction process to proceed and all of the reagents used
being readily available, features which make these new routes
to 1aOAc attractive in comparison to the existing procedures.
1
(4.55 g, 86%). H NMR (200 MHz, CDCl3): ¤ 0.81-0.89 (m, 12H,
4 CH3), 0.95-1.65 (m, 19H), 1.97 (d, J = 1 Hz, ca. 1.5H, CH3C=
CHCHOsyn), 2.15 (d, J = 1 Hz, ca. 1.5H, CH3C=CHCHOanti), 2.18
(t, J = 7 Hz, ca. 1.5H, CH2C(CH3)=Canti), 2.55 (t, J = 7 Hz, ca.
1.5H, CH2C(CH3)=Csyn), 5.88 (dd, J = 8, 1 Hz, 1H, C=CH), 9.97
(d, J = 8 Hz, 1H, CHO).
(E,Z)-6-Chloro-3,7-dimethylocta-2,7-dienal (3g).
Since
being only briefly reported in the literature24 the chlorination of
citral 3a is described thereafter. In a 500-mL flask, a mixture of
Ca(OCl)2 (3.75 g, 1 equiv) and water (16.4 mL) was added to a
solution of citral 3a (5.02 g, 32.98 mmol) in CH2Cl2 (164 mL).
After 10 min stirring, the resulting mixture was warmed to ca.
35-40 °C (hot-water bath). With a vigorous stirring, finely ground
dry ice was progressively added until disappearance of 3a on
TLC (25-30 min). After cooling to rt, pH 7 phosphate buffer
(20 mL) was added. The aqueous layer was extracted with CH2Cl2
(3 © 30 mL) and the pooled organic phases were washed with
pH 7 phosphate buffer (40 mL), brine (40 mL), and dried (Na2SO4).
The oily residue left by evaporation of the solvents was purified
by distillation to give the chloroaldehyde 3g (4.71 g, 76%) as a
pale-yellow oil (bp 86 °C at 0.5 Torr). For sake of analysis, a
portion of this product was chromatographed on a thick layer of
silica gel (hexane/ether) to separate the E from the Z isomer
Experimental
General.
All general conditions were as described in the
1
preceding paper; except when otherwise stated H and 13C NMR
at 300 and 75 MHz, respectively. Citral 3a (purissim Fluka;
E-3a:Z-3a = 67:33), isomethylheptenone 7 (BASF), phytone 5
(Aventis Animal Nutrition), 65% calcium hypochlorite (Aldrich),
KSF montmorillonite (Fluka) and trimethyl orthoformate (Aldrich)
were used as received. Hydroquinone 2b (Fluka) was re-crystal-
lized from EtOAc and dried overnight in a desiccator prior to use.
Citral dimethyl acetal 3b (Fluka) was purified by distillation from
CaH2 (bp 50 °C at 0.2 Torr). Isocitral 3e (E-3e:Z-3e µ 1:1; by
1H NMR) was prepared from the ketone 7 by means of a Peterson
olefination using the t-butylimine of trimethylsilylacetaldehyde,
as described.23 Phytonitrile 10 (bp 158 °C at 0.01 Torr) was
prepared as a mixture of the E and Z isomers (E-10:Z-10 µ 3:2; by
1H NMR) from phytone 5 according to a reported procedure.29
Tetrahydrocitral 6a and citronellylmagnesium chloride 8 (in THF)
were prepared as described in the preceding paper.
1
(E-3g:Z-3g µ 3:1; by H NMR). E-3g: TLC (hexane:ether = 3:1)
1
Rf = 0.44; H NMR (CDCl3, 200 MHz): ¤ 1.8 (s, 3H, CH3), 1.96-
2.1 (m, 2H, CH2), 2.17 (s, 3H, CH3), 2.2-2.45 (m, 2H, CH2), 4.34
(t, J = 7 Hz, 1H, CHCl), 4.91 (m, 1H, H(H)C=), 5.02 (m, 1H,
H(H)C=), 5.89 (d, J = 7 Hz, 1H, CH), 10.01 (d, J = 7 Hz, 1H,
1
CH). Z-3g: TLC (hexane:ether = 3:1) Rf = 0.3; H NMR (CDCl3,
200 MHz): ¤ 1.8 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.01-2.12 (m,
2H, CH2), 2.63 (m, 2H, CH2), 4.34 (t, J = 7 Hz, 1H, CHCl), 4.91
(m, 1H, H(H)C=), 5.02 (m, 1H, H(H)C=), 5.92 (d, J = 7 Hz, 1H,
CH), 9.96 (d, J = 7 Hz, 1H, CH).
(2E/Z,6E/Z)-3,7,11,15-Tetramethylhexadeca-2,6,14-trienal
(3i). In a flask connected to an argon/vacuum line, CuI (203 mg,

V. Gembus et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
849
1.06 mmol, 0.049 equiv) was heated (hot-air gun) in a vacuum
(ca. 0.01 Torr). After cooling to rt, the flask was filled with argon
and a solution of the chloroacetal 3h (4.95 g, 21.48 mmol) in
THF (15 mL) was added with a syringe. The resulting mixture
was cooled to ¹5 °C (ice/methanol bath) and 1.05 M (in THF)
citronellylmagnesium chloride 8 (20.5 mL, 21.5 mmol) was added
dropwise with a syringe (10 min). After 5 min stirring, 1 M HCl
(20 mL) was slowly added and the resulting aqueous layer was
extracted with ether (3 © 10 mL). The pooled organic phases were
washed with saturated NH4Cl (15 mL), brine (2 © 15 mL), and
dried (MgSO4). The oily residue left by evaporation of the solvents
was purified by column chromatography (hexane/ether) to give
the dehydrophytal 3i (5.24 g, 84%) as a thick colorless oil. TLC
(hexane:ether = 2:1) Rf = 0.44; IR (neat, cm¹1): 2927, 2856, 2762,
1678, 1632, 1450, 1377; 1H NMR (CDCl3): ¤ 0.88 (d, J = 6.3 Hz,
3H, CH3), 1.03-1.19 (m, 2H, CH2), 1.24-1.49 (m, 5H, CH, 2
CH2), 1.62/1.69 (2 m, 9H, 3 CH3), 1.9-2.04 (m, 6H, 3 CH2), 2.16-
2.3 (m, 5H, CH, 2 CH2), 5.11 (m, 2H, 2 CH), 5.9 (m, 1H, CH),
9.99 (4 d, J = 7.9 Hz, 1H, CH); 13C NMR (CDCl3): ¤ 15.9 (CH3),
17.6 (CH3), 19.5 (CH3), 23.3 (CH3), 25.1 (CH3), 25.3 (CH2), 25.5
(CH2), 32 (CH2), 32.3 (CH), 36.9 (CH2), 37.1 (CH2), 39.9 (CH2),
40.6 (CH2), 121.8/122.9 (CH), 124.9/125 (CH), 127.4/128.6
(CH), 130.9/131 (C), 136.9/137.8 (C), 163.7/163.8 (C), 190.7/
191.2 (CH); MS (CI-NH3) m/z 308 (M + NH4+), 291 (M + H+),
273, 247, 217, 197, 179, 163, 149, 137, 121, 109, 95, 81.
3,7-Dimethyl-1-octylidene Diacetate (6b). Tetrahydrocitral
6a (0.41 g, 2.6 mmol) was diluted with Ac2O (0.8 mL, 8.2 mmol)
and KSF montmorillonite (54 mg) was added. The resulting
mixture was heated (ca. 125 °C, bath) for 1.5 h with stirring. After
cooling to rt, ether (40 mL) was added and the resulting mixture
was poured into brine (8 mL) diluted with water (16 mL). The
aqueous layer was extracted with ether (10 mL) and the pooled
organic phases were washed with saturated NaHCO3 (20 mL),
brine (10 mL), and dried (Na2SO4). The solvents were evaporated
in vacuo to give a colored residue, which was chromatographed on
silica gel (hexane/ether). Bulb-to-bulb distillation of the residue
left by evaporation of the solvents afforded the acylal 6b as a pale-
yellow oil (0.55 g, 81%). Bp 80-90 °C (bath) at 0.07 Torr; TLC
(hexane:ether = 9:1) Rf = 0.22; 1H NMR (200 MHz, CDCl3): ¤
0.86 (d, J = 7 Hz, 6H, 2 CH3), 0.93 (d, J = 6 Hz, 3H, CH3), 1.00-
1.88 (m, 10H), 2.06 (s, 3H, C(O)CH3), 2.07 (s, 3H, C(O)CH3),
6.84 (dd, J = 6, 4 Hz, 1H, CH(OAc)2); 13C NMR (50 MHz,
CDCl3): ¤ 19.8, 20.9, 22.6, 22.7, 24.5, 28.0, 28.5, 37.2, 39.1,
40.3, 89.8 (CH(OAc)2), 168.9 (C=O).
39.77, 40.12, 52.62, 52.70, 52.72, 100.54, 100.87, 121.73, 122.55,
142.99, 143.23; HRMS: found m/z 340.3347, calcd for C22H44O2
340.3341.
(E,Z)-3,7-Dimethylocta-2,7-dienal Dimethyl Acetal (3f):
From isocitral 3e (5 g, 32.8 mmol), the acetal 3f (E-3f:Z-3f =
1:1, by GC) was obtained as a colorless oil (5.99 g, 92%). Bp 73-
75 °C at 1.4 Torr; TLC (hexane:ether = 3:1) Rf = 0.29; 1H NMR
(CDCl3): ¤ 1.49-1.7 (m, 2H, CH2), 1.72 (s, 3H, CH3), 1.76 (s, 3H,
CH3), 1.96-2.18 (m, 4H, 2 CH2), 3.31 (s, 6H, 2 OCH3), 4.66-4.75
(m, 2H, C=CH2), 5.01/5.04 (d, J = 6.5 Hz, 1H, CH(OMe)2),
5.23-5.31 (m, 1H, C=CH); 13C NMR (CDCl3): ¤ 16.9 (CH3),
23.2/23.3 (CH3), 25.5/25.8 (CH2), 37.3/37.5 (CH2), 38.9 (CH2),
52.2/52.3 (OCH3), 100/100.4 (CH(OCH3)2), 110 (CH2=C),
121.7/122.5 (C=CH), 142.1/142.4 (C=CH), 145.56 (CH2=C);
Anal. Found: C, 72.55; H, 11.17%. Calcd for C12H22O2: C, 72.68;
H, 11.18%.
(E,Z)-6-Chloro-3,7-dimethylocta-2,7-dienal Dimethyl Acetal
(3h): From the chloroaldehyde 3g (15 g, 80.4 mmol), the acetal
3h was obtained as a colorless oil (14.65 g, 78.2%). Bp 67 °C
at 0.25 Torr; TLC (hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.8; IR
(neat, cm¹1): 3080, 2949, 2827, 1672, 1647, 1448, 1377, 1131,
1053, 963, 907; 1H NMR (CDCl3): ¤ 1.73 (s, 3H, CH3), 1.8 (s, 3H,
CH3), 1.86-2.05 (m, 2H, CH2), 2.0-2.26 (m, 2H, CH2), 3.31 (s,
6H, 2 OCH3), 4.35 (t, J = 7.5 Hz, 1H, CHCl), 4.9 (m, 1H,
CH-CH(OCH3)2), 5.03 (m, 2H, CH2=C), 5.31 (t, J = 7 Hz, 1H,
CH-CH(OCH3)2); 13C NMR (CDCl3): ¤ 17.1/17.6 (CH3), 23.1
(CH3C=CH2), 34.3/34.7 (CH2), 36.4/37.5 (CH2), 52.1/52.3
(2 OCH3), 66.1/66.2 (CHCl), 99.9/100.2 (CHO), 114.3
(CH2=C), 122.6/123.8 (C=CH), 140.5 (C=CH2), 144.1/144.2
(C=CH); Anal. Found: C, 62.01; H, 9.12; Cl, 15.01%. Calcd for
C12H21ClO2: C, 61.92; H, 9.09; Cl, 15.23%.
(2E/Z,6E/Z)-3,7,11,15-Tetramethylhexadeca-2,6,14-trienal
Dimethyl Acetal (3j): From the aldehyde 3i (1.44 g, 4.96 mmol),
the acetal 3j was obtained as a colorless oil (1.51 g, 100%). TLC
(hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.69; 1H NMR (CDCl3): ¤
0.84 (d, J = 6 Hz, 3H, CH3), 1.09-1.34 (2 m, 7H, CH, 3 CH2), 1.58
(s, 3H, CH3), 1.66 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.75 (s, 3H,
CH3), 1.90-2.15 (2 m, 8H, CH2), 3.31 (s, 6H, 2 OCH3), 4.09-4.95
(m, 3H, 3 CH), 5.23 (m, 1H, CHOCH3); 13C NMR (CDCl3): ¤ 16.9
(CH3), 17.6/19.6 (CH3), 23.4 (CH3), 25.3-26.2 (3 CH2), 25.7
(CH3), 32 (CH), 36.6-36.9 (2 CH2), 39.4 (CH2), 39.9 (CH2),
51.2/52.2 (2 OCH3), 100.1/100.2 (CH), 114.3 (CH), 121.6-125
(2 CH), 130.9 ((CH3)2C), 135.8/136.1 (CH2C(CH3)), 142/142.1
(CH2C(CH3)); HRMS found m/z 336.3041, calcd for C22H40O2
336.3028.
General Protocol for Preparing Dimethyl Acetals. In a flask
connected to an argon line, the aldehyde was diluted with tri-
methyl orthoformate (0.67 mL mmol¹1) and anhydrous MeOH (0.4
mL mmol¹1). Pyridinium tosylate (2.6 mg mmol¹1; 0.01 equiv)
was added and the resulting mixture was stirred 24 h at rt before
being diluted with aqueous 1 M NaOH (1.6 mL mmol¹1) and ether
(3.2 mL mmol¹1). After 15 min stirring, the aqueous layer was
extracted with ether (4 © 3.2 mL mmol¹1) and the pooled organic
phases were washed with 1 M NaOH (1.6 mL mmol¹1), brine
(2 © 6 mL mmol¹1), and dried (K2CO3). The residue left by
evaporation of the solvents was distilled from CaH2 in a vacuum.
General Protocols of Chromenisation Reaction Experiments
(Table 1).
Protocol A: A flask equipped with a condenser
connected to an argon/vacuum line was charged with the quinol,
the acetal and the base (10 mmol each). The resulting mixture was
thoroughly degassed (three freeze-pump-thaw cycles) and a static
atmosphere of argon was established. The flask was immersed in a
thermostated oil bath (ca. 165-175 °C) for the indicated time.
Protocol B: Similarly to protocol A in a flask equipped with a 10-
cm Vigreux column, a distillation head, and a receiver connected
to an argon/vacuum line, the heating being pursued until the
distillation of the resulting volatiles ceased (bp 35-65 °C).
Protocol C: A flask equipped with a Vigreux column, a distillation
head, and a receiver, as in protocol B, and an addition funnel
with a pressure-equalizing system was charged with the quinol
and pyridine (0.5 equiv). The resulting mixture was thoroughly
degassed and the flask was filled with argon. A degassed solution
of the acetal (1 equiv) in pyridine (0.5 equiv) was introduced into
Phytal Dimethyl Acetal (3d):
From phytal 3c (1.5 g,
0.5 mmol), the acetal 3d was obtained as a colorless oil (1.25 g,
72%) by bulb-to-bulb distillation. Bp 160 °C at 0.008 Torr; TLC
(hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.75; 13C NMR (100 MHz,
CDCl3): ¤ 17.35, 19.99, 20.07, 20.10, 20.14, 23.02, 23.12, 23.64,
24.86, 25.06, 25.19, 25.21, 25.42, 25.8, 28.38, 33.08, 33.1, 33.19,
33.25, 37.04, 37.14, 37.32, 37.4, 37.69, 37.71, 37.76, 37.79, 37.83,

850 Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
¡-Tocopherol from Citral and Dihydromyrcene
the funnel with a syringe and the flask was immersed in a
thermostated oil bath (ca. 180-185 °C). The acetal was added
dropwise (1 h) while the resulting volatiles were progressively
distilled out (bp 40-65 °C). Whatever the protocol used, after
cooling to ca. 0 °C (ice bath) pyridine (10 equiv) and Ac2O (7.5
equiv) were added sequentially with a syringe and the resulting
mixture was stirred at rt overnight before being diluted with ether
2-Methyl-2-(4,8,12-trimethyltridecyl)-2H-chromen-6-yl Ace-
tate (4cOAc): Protocol B (125 °C, 6 days): In pyridine (0.21 mL,
2.6 mmol). From hydroquinone 2b (0.279 g, 2.53 mmol, 1.5 equiv)
and phytal dimethyl acetal 3d (0.562 g, 1.65 mmol). Isolated:
hydroquinone diacetate 2bOAc (0.242 g, 49%), and the chromene
acetate 4cOAc as a pale-yellow oil (0.214 g, 30%). TLC (CH2Cl2)
Rf = 0.51; 1H NMR (200 MHz, CDCl3): ¤ 0.81-0.88 (m, 12H),
0.95-1.7 (m, in which s at 1.36, 24H), 2.26 (s, 3H, OC(O)CH3),
5.58 (d, J = 10 Hz, 1H, HC=C), 6.28 (d, J = 10 Hz, 1H, HC=C),
6.68-6.81 (m, 3H); 13C NMR (50 MHz, CDCl3): ¤ 19.69, 19.74,
19.8, 19.86, 21.16, 21.57, 22.75, 22.75, 22.84, 24.57, 24.92, 26.53,
28.07, 32.79, 32.86, 37.38, 37.43, 37.47, 37.52, 39.47, 41.66,
79.01, 116.66, 119.07, 121.62, 121.75, 122.33, 130.89, 144.02,
150.83, 169.92; HRMS found m/z 428.3292, calcd for C28H44O3
428.3290.
(10 mL mmol¹1) and 1 M HCl (10 mL mmol¹1). After 1 h stirring,
¹1
the aqueous layer was extracted with ether (4 © 3 mL mmol
)
and the pooled organic extracts were washed with 1 M HCl
(5 mL mmol¹1), brine (3 © 5 mL mmol¹1), and dried (MgSO4).
The residue left by evaporation of the solvents was dried overnight
in a vacuum (ca. 0.01 Torr), then chromatographed on silica gel
(hexane/CH2Cl2) to give, successively, the chromene acetate, and
the diacetate of the unreacted quinol.
2,5,7,8-Tetramethyl-2-(4-methylpent-3-enyl)-2H-chromen-6-
yl Acetate (4aOAc): Protocol B: In pyridine (0.81 mL, 10 mmol).
From TMHQ 2a (1.52 g, 10 mmol) and citral acetal 3b (1.98 g,
10 mmol). Isolated: the diacetate 2aOAc (0.397 g, 17%), and
the chromene acetate 4aOAc (1.7 g, 52%; 62% based on reacted
2a). Protocol C: In pyridine (1.7 mL, 21 mmol). From TMHQ
2a (3.12 g, 20.5 mmol) and citral dimethyl acetal 3b (4.07 g,
20.48 mmol). Isolated: 2.144 g (44%) of 2aOAc, and 2.795 g
(41.5%; 74% based on reacted 2a) of 4aOAc. TLC (CH2Cl2)
Rf = 0.62; IR (neat, cm¹1): 3046, 2968, 2925, 2860, 1759,
2-Methyl-2-(4-methylpent-3-enyl)-2H-chromen-6-ol: (rac)-
Cordiachromene A (4d): Protocol B (125 °C, 82 h): In pyridine
(0.2 mL, 2.48 mmol). From citral dimethyl acetal 3b (0.505 g,
2.54 mmol) and hydroquinone 2b (0.278 g, 2.52 mmol). Purifica-
tion by column chromatography (hexane/ether) of the crude
condensation product afforded, after evaporation of the solvents,
1
cordiachromene 4d as a pale-yellow oil (0.244 g, 40%). H NMR
(200 MHz, CDCl3): ¤ 1.37 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.6-
1.73 (m, in which s at 1.66, 5H, CH2, CH3), 2.04-2.16 (m, 2H,
CH2), 4.51 (s, 1H, OH), 5.09 (t, J = 7 Hz, HC=C(CH3)2), 5.6 (t,
J = 10 Hz, 1H, CH), 6.27 (d, J = 10 Hz, CH), 6.48 (d, J = 3 Hz,
1H, HCarom), 6.57 (dd, J = 8, 3 Hz, 1H, HCarom), 6.65 (d, J = 8 Hz,
1H, HCarom); 13C NMR (50 MHz, CDCl3): ¤ 17.75, 22.84, 25.81,
26.04, 40.89, 78.42, 113.19, 115.7, 116.87, 122.18, 122.8, 124.21,
131.02, 131.85, 146.86, 149.33.
1
1672, 1644, 1605, 1458, 1368, 1204, 1115, 1089, 1062; H NMR
(CDCl3): ¤ 1.37 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.66 (s, 3H, CH3),
1.6-1.73 (m, 2H, CH2), 2.02 (s, 3H, CH3), 2.04-2.16 (m, in
which s at 2.04 and 2.1, 8H, CH2, 2 CH3), 2.32 (s, 3H, C(O)CH3),
5.1 (t, J = 7 Hz, 1H, CH), 5.57 (d, J = 10.2 Hz, 1H, CH), 6.5
(d, J = 10.2 Hz, 1H, CH); 13C NMR (CDCl3): ¤ 11.5 (CH3), 11.8
(CH3), 13.2 (CH3), 17.7 (CH3), 19.6 (CH3), 22.8 (CH2), 25.8
(CH3), 26 (CH3), 40.8 (CH2), 78.4 (CO), 116.9 (Carom), 122.6
(Carom), 122.8 (CH), 124.2 (CH), 124.3 (Carom), 129.2 (Carom),
131 (CH), 131.8 (C(CH3)2), 146.8 (Carom), 149.3 (Carom), 169.4
(C(O)CH3)); MS (CI-NH3) m/z 346 (M + NH4+), 329 (M + H+),
313, 286, 273, 245, 203, 159, 105, 91. 2aOAc: 1H NMR (200
MHz, CDCl3): ¤ 2.05 (s, 3H), 2.07 (s, 3H), 2.11 (s, 3H), 2.31 (s,
3H), 2.34 (s, 3H), 6.75 (s, 1H).
2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltrideca-3,11-dienyl)-
2H-chromen-6-yl Acetate (4kOAc): Protocol C (180 °C, 2 h): In
pyridine (0.31 mL, 3.82 mmol). From TMHQ 2a (604 mg, 3.97
mmol) and the dehydrophytal dimethyl acetal 3j (1.34 g, 3.98
mmol). Isolated: 2aOAc (371 mg, 39.5%), and the chromene
acetate 4kOAc as a yellow viscous oil (914 mg, 49%, 82% based
on reacted 2a). TLC (hexane:CH2Cl2 = 1:1) Rf = 0.35; IR (neat,
cm¹1): 3045, 2966, 2927, 1760, 1672, 1455, 1368, 1206, 1113,
1080, 1063; 1H NMR (CDCl3): ¤ 0.9 (d, J = 7 Hz, 3H, CH3), 1.08-
1.47 (m, in which s at 1.39, 12H, CH, 4 CH2, CH3), 1.64 (s, 3H,
CH3), 1.69 (s, 3H, CH3), 1.70-2.22 (m, in which s at 1.72, 2.06,
2.08, 2.15, and 2.12, 21H, 3 CH2, 5 CH3), 5.15 (m, 2H, 2 CH),
5.62/5.64 (d, J = 10.2 Hz, 1H, CH), 6.54 (d, J = 10.2 Hz, 1H,
CH); 13C NMR (CDCl3): ¤ 11.5 (CH3), 11.6 (CH3), 13.2 (CH3),
15.8 (CH3), 17.6 (CH3), 19.6 (CH3), 20.5 (CH3), 22.5/22.6 (CH2),
23.4 (CH3), 25.3/25.4 (CH2), 25.7 (CH2), 25.7/25.8 (CH3), 32.3/
32.4 (CH), 36.6/36.8 (CH2), 37.1 (CH2), 40 (CH2), 40.9/41.2
(CH2), 77.2/77.3 (C), 117.6 (Carom), 120 (CH), 122.4 (Carom),
122.6 (Carom), 124.6 (C), 125 (C), 129 (Carom), 129.3 (CH), 130.9
(C), 135.6/135.8 (C), 141.3 (Carom), 148.5 (Carom), 169.4 (C); MS
(CI-NH3) m/z 484 (M + NH4+), 467 (M + H+), 385, 329, 272,
245, 230, 203, 174, 147, 95, 81, 69; HRMS found m/z 466.3458,
calcd for C31H46O3 466.3447.
2,5,7,8-Tetramethyl-2-(4-methylpent-4-enyl)-2H-chromen-6-
yl Acetate (4eOAc): Protocol B (165 °C, 1 day): In pyridine
(0.37 mL, 4.6 mmol). From TMHQ 2a (0.7 g, 4.6 mmol) and
isocitral dimethyl acetal 3f (0.9 g, 4.54 mmol). Isolated: the
diacetate 2aOAc (0.46 g, 42.3%), and the chromene acetate 4eOAc
1
as a clear oil (0.77 g, 52%; 88% based on reacted 2a). H NMR
(200 MHz, CDCl3): ¤ 1.35 (s, 3H, CH3), 1.55 (m, 4H, 2 CH2), 1.7
(s, 3H, CH3), 2.02 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.09 (s, 3H,
C
aromCH3), 1.97-2.03 (m, 2H, CH2), 2.34 (s, 3H, CH3), 4.68 (m,
1H, HHC=C), 4.71 (m, 1H, HHC=C), 5.59 (d, J = 10 Hz, 1H),
6.5 (d, J = 10 Hz, 1H). HRMS found m/z 328.2043, calcd for
C21H28O3 328.2038.
2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-chromen-
6-yl Acetate (4bOAc): Protocol B (165-175 °C, 6 h): In pyridine
(0.1 mL, 1.24 mmol). From TMHQ 2a (0.189 g, 1.24 mmol) and
phytal dimethyl acetal 3d (0.422 g, 1.24 mmol). Isolated: the
diacetate 2aOAc (0.155 g, 53%), impured (TLC) phytal 3c
(0.091 g, 25%), and the chromene acetate 4bOAc (0.192 g, 33%;
Ene-Condensation of the Chromene Acetate 4eOAc and
Tetrahydrocitral 6a: 2-(6-Hydroxy-8,12-dimethyl-4-methylene-
tridecyl)-2,5,7,8-tetramethyl-2H-chromen-6-yl Acetate (4fOAc)
and (E)-2-(6-Hydroxy-4,8,12-trimethyltridec-3-enyl)-2,5,7,8-
1
70% based on reacted 2a). H NMR (200 MHz, CDCl3): ¤ 0.82-
tetramethyl-2H-chromen-6-yl Acetate (4gOAc).
1 M (in
0.88 (m, 12H), 1.0-1.7 (m, in which s at 1.33, 24H), 2.02 (s, 3H,
CH3Carom), 2.05 (s, 3H, CH3Carom), 2.09 (s, 3H, CH3Carom), 2.32 (s,
3H, CH3C(O)), 5.59 (d, J = 10 Hz, 1H, CH), 6.48 (d, J = 10 Hz,
1H, CH).
hexane) Me2AlCl (1.7 mL, 1.7 mmol) was added dropwise to a
cooled (ice bath) solution of 4eOAc (0.361 g, 1.1 mmol) and
tetrahydrocitral 6a (0.26 g, 1.81 mmol) in CH2Cl2 (5.5 mL). The
resulting mixture was stirred overnight at rt. An excess of

V. Gembus et al.
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
851
tetrahydrocitral 6a (0.5 mL, 0.5 mmol) was added with a syringe
and the resulting mixture was further stirred (16 h), then diluted
with ether (10 mL), pH 7 phosphate buffer (4 mL) and 3 M HCl
(3 mL). After 30 min stirring the aqueous layer was extracted with
ether (2 © 5 mL) and the pooled organic extracts were washed with
saturated NaHCO3 (10 mL), brine (2 © 5 mL), and dried (MgSO4).
The solvents were evaporated and the residue (0.58 g) was
chromatographed on silica gel (hexane/CH2Cl2, then CH2Cl2/
ether) to give, successively, 4eOAc (78.8 mg, 22%), and a mixture
of 4fOAc and 4gOAc (4fOAc:4gOAc = 84:16; by 1H NMR) as
a pale-yellow oil (310 mg, 58%). 1H NMR (200 MHz, CDCl3):
¤ 0.85-0.92 (m, 9H, 3 CH3), 1-2.3 (m, ca. 31.5H), 2.33 (s, 3H,
C(O)CH3), 3.78 (m, 1H, CHOH), 4.84 (m, ca. 0.15H, HHC=C),
4.88 (m, ca. 0.15H, HHC=C), 5.25 (m, ca. 0.7H, HC=C), 5.57 (d,
J = 10 Hz, 1H), 6.57/6.6 (d, J = 1.6 Hz, 1H).
(All-rac)-Tocopherol Acetate (1aOAc): From the Ene-Adduct
4fOAc/4gOAc. A stream of HCl was passed into EtOAc (5 mL)
for 2 h with cooling (ice bath). The preceding 4fOAc/4gOAc
mixture was diluted with the HCl solution thus obtained and
5% Pd/C (100 mg) was added. The resulting mixture was stirred
overnight at rt in a H2 atmosphere. The solids were removed by
filtration on Celite (washings with ether) and the solvents were
evaporated. All these operations were repeated twice and the pale-
yellow oil finally obtained was purified by column chromatog-
raphy (hexane/CH2Cl2). The residue left by evaporation of the
solvents was dried overnight (30 °C, 10¹2 Torr) to give 1aOAc as a
thick colorless oil (170 mg, 36% overall, based on reacted 2a).
TLC (CH2Cl2) Rf = 0.73; IR (neat, cm¹1): 2924, 1760, 1455, 1372,
1209, 1078, 1011, 921; 1H NMR (CDCl3): ¤ 0.83-0.89 (m, 12H, 4
CH3), 1-1.65 (m, 24H, 3 CH, 9 CH2, CH3), 1.72-1.84 (m, 2H,
CH2), 1.98 (s, 3H, CaromCH3), 2.03 (s, 3H, CaromCH3), 2.09 (s, 3H,
for C21H28O4: C, 73.23; H, 8.19%.
2-[2-(3,3-Dimethyloxiran-2-yl)ethyl]-2,5,7,8-tetramethylchro-
man-6-yl Acetate (1dOAc). The epoxychromene 4hOAc
(867 mg, 2.52 mmol) was diluted with EtOAc (6 mL) and 10%
Pd/C (10 mg) was added. The resulting mixture was degassed, and
then stirred in a H2 atmosphere until the absorption ceased (1.5 h).
The solids were removed by filtration on a pad of Celite (washings
with ether). The oily residue left by evaporation of the solvents in a
vacuum was purified by column chromatography (hexane/CH2Cl2)
to give a thick colorless oil (794 mg, 91%) identified as 1dOAc
(NMR, GC).2
2-(3-Hydroxy-4-methylpent-4-enyl)-2,5,7,8-tetramethyl-2H-
chromen-6-ol (4i).
The epoxychromene 4hOAc (2.37 g,
6.92 mmol) was refluxed in toluene (36 mL) with aluminum
isopropoxide (5.66 g, 27.7 mmol) for 24 h with stirring. After
cooling to rt, the resulting mixture was slowly added to a stirred
mixture of ether (100 mL) and pH 2 tartaric buffer (100 mL). After
1 h stirring, the aqueous layer was extracted with ether (3 © 50 mL)
and the pooled organic phases were washed with pH 2 tartaric
buffer (50 mL), brine (2 © 50 mL), and dried (MgSO4). The
residue left by evaporation of the solvents was filtered on a short
column of silica gel (CH2Cl2/EtOAc) to give, after evaporation of
the solvents, the chromenol 4i as a colored oil (1.98 g, 95%). TLC
(hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.2; 1H NMR (CDCl3): ¤
1.33/1.34 (2 s, 3H, CH3), 1.6-1.79 (m, in which s at 1.7, 7H, 2
CH2, CH3), 2.11 (s, 3H, CaromCH3), 2.14 (s, 3H, CaromCH3), 2.17
(s, 3H, CaromCH3), 4.04-4.06 (m, 1H, CH), 4.5 (s, 1H, OH), 4.82-
4.93 (m, 2H, CH2), 5.58 (d, J = 10 Hz, 1H, CH), 6.51/6.52 (2 d,
J = 10 Hz, 1H, CH); 13C NMR (CDCl3): ¤ 10.8 (CH3), 11.6 (CH3),
12.4 (s, CH3), 17.5/17.6 (CH3), 25.2/25.5 (CH3), 29.2/29.3
(CH2), 36.3 (CH2), 75.8/76 (CH), 76.5/76.6 (C), 111.1/111.2
(CH2), 116.5 (Carom), 117.4/117.5 (Carom), 120.4/120.5 (CH),
122.2/123 (Carom), 129.3/129.6 (CH), 144.3/144.4 (Carom), 145.4
(Carom), 147.2/147.3 (Carom); MS (CI-NH3) m/z 303 (M + H+),
302 (M), 287, 269, 204, 203, 159.
2-(3-Acetyloxy-4-methylpent-4-enyl)-2,5,7,8-tetramethyl-2H-
chromen-6-yl Acetate (4jOAc). Ac2O (2.7 mL, 28.3 mmol) was
progressively added to a cooled (ice bath) solution of the
chromenol 4i (1.16 g, 3.83 mmol) in pyridine (6 mL, 76.6 mmol).
The resulting mixture was stirred at rt overnight, then diluted with
ether (50 mL) and 1 M HCl (30 mL). After 1 h stirring, the aqueous
layer was extracted with ether (4 © 15 mL) and the pooled organic
phases were washed with 1 M HCl (30 mL), brine (3 © 30 mL),
and dried (MgSO4). The solvents were evaporated in a vacuum
and the residue was filtered on a short column of silica gel
(hexane:CH2Cl2:EtOAc = 9:9:2) to give the diacetate 4jOAc as a
colorless oil (1.42 g, 96%). TLC (hexane:CH2Cl2:EtOAc = 9:9:2)
Rf = 0.55; 1H NMR (CDCl3): ¤ 1.33 (s, 3H, CH3), 1.58-1.85 (m, in
which s at 1.69, 7H, 2 CH2, CH3), 2.01 (s, 3H, CaromCH3), 2.02
(2 s, 6H, CH3, CaromCH3), 2.04 (s, 3H, CaromCH3), 2.32 (s, 3H,
CH3), 4.88-4.93 (m, 2H, CH2), 5.14-5.16 (m, 1H, CH), 5.54
(d, J = 10 Hz, 1H, CH), 6.51/6.52 (2 d, J = 10 Hz, 1H, CH);
13C NMR (CDCl3): ¤ 11.5 (CH3), 11.6 (CH3), 13.2 (CH3), 17.9/
18.1 (CH3), 20.5 (CH3), 21.1 (CH3), 25.9 (CH3), 26.9 (CH2), 36.2/
36.4 (CH2), 76.9 (C), 77.3/77.4 (CH), 112.9/113 (C=CH2),
117.3/117.4 (Carom), 120.3 (CH), 122.5 (Carom), 122.6 (Carom),
122.8 (Carom), 128.9/129.1 (CH), 141.4 (C), 142.7 (Carom), 148.2
(Carom), 169.5 (C=O), 170.3 (C=O); MS (CI-NH3) m/z 386 (M),
371, 327, 269, 246, 245, 204, 203, 159.
C
aromCH3), 2.33 (s, 3H, CH3), 2.59 (t, 2H, J = 6.7 Hz, CH2);
13C NMR (CDCl3): ¤ 11.8 (CH3), 12.1 (CH3), 12.9 (CH3), 19.6
(CH3), 19.8 (CH3), 20.5 (CH3), 21 (CH2), 22.6 (CH3), 22.7 (2
CH2), 24.5 (CH2), 24.8 (CH2), 28 (CH), 32.7 (CH), 32.9 (CH),
37.3-37.6 (4 CH2), 39.4 (CH2), 75 (C), 117.3 (Carom), 123 (Carom),
124.9 (Carom), 126.7 (Carom), 140.6 (Carom), 149.4 (Carom), 169.7
(C=O): MS (CI-NH3) m/z 491 (M + NH4+), 473 (M + H+), 472
(M), 430, 245, 207, 203, 165.
2-[2-(3,3-Dimethyloxiran-2-yl)ethyl]-2,5,7,8-tetramethylchro-
man-6-yl Acetate (4hOAc). With stirring, m-CPBA (341.3 mg, 1
equiv) was added progressively to a cooled (ice bath) solution of
the chromene acetate 4aOAc (500 mg, 1.52 mmol) in CH2Cl2
(25 mL). After 1 h stirring at ca. 0 °C, finely ground Ca(OH)2
(130 mg, 1.15 equiv) was added and the resulting mixture was
further stirred for 1 h before being filtered on a pad of Celite. The
solids were washed with CH2Cl2 (6 © 10 mL) and the pooled
organic extracts were dried (MgSO4). The residue left by evapo-
ration of the solvents was dried overnight (30 °C, 10¹2 Torr) to
give the epoxychromene 4hOAc as a colorless oil (485.5 mg,
1
93%). TLC (hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.61; H NMR
(CDCl3): ¤ 1.23/1.27/1.29 (3 s, 6H, 2 CH3), 1.36/1.37 (2 s, 3H,
CH3), 1.6-1.88 (m, 4H, 2 CH2), 2.01 (s, 3H, CaromCH3), 2.05 (s,
3H, CaromCH3), 2.09 (s, 3H, CaromCH3), 2.32 (s, 3H, C(O)CH3),
2.69-2.76 (m, 1H, CH), 5.56/5.59 (2 d, J = 10 Hz, 1H, CH), 6.52/
6.53 (2 d, J = 10 Hz, 1H, CH); 13C NMR (CDCl3): ¤ 11.5 (CH3),
11.6 (CH3), 13.2 (s, CH3), 18.5 (CH3), 18.6 (CH3), 20.5 (CH3),
23.7/24 (CH2), 24.8 (CH3), 37.3/37.6 (CH2), 58.4/58.5 (C), 64.2/
64.4 (CH), 76.8/77.1 (C), 111.6 (Carom), 117.3/117.5 (Carom),
120.3/120.4 (CH), 122.5 (Carom), 128.6/129 (CH), 141.4 (Carom),
144.2 (Carom), 148.2 (Carom), 169.4 (C(O)); MS (CI-NH3) m/z 344
(M), 329, 287, 246, 245, 203; Found: C, 72.91; H, 8.31%. Calcd
Wurtz Coupling of 4jOAc and Citronellylmagnesium Chlo-
ride 8: (E,Z)-2,5,7,8-Tetramethyl-2-(4,8,12-trimethyltrideca-
3,11-dienyl)-2H-chromen-6-yl Acetate (4kOAc).
In a flask

852
Bull. Chem. Soc. Jpn. Vol. 82, No. 7 (2009)
¡-Tocopherol from Citral and Dihydromyrcene
connected to an argon/vacuum line, CuI (3 mg, 0.05 equiv) was
flamed in a vacuum. After cooling to rt, the diacetate 4jOAc
(100 mg, 0.256 mmol) diluted with THF (350 ¯L) was added with
a syringe and the resulting mixture was cooled to ¹5 °C (ice/
methanol bath). A 0.82 M solution of the Grignard reagent 8 in
THF (0.65 mL, 0.54 mmol) was added dropwise followed, 10 min
later, by ether (2 mL) and saturated NH4Cl (1 mL). After 10 min
stirring, the aqueous phase was extracted with ether (3 © 1 mL)
and the pooled organic extracts were washed with saturated NH4Cl
(2 mL), brine (2 © 2 mL), and dried (MgSO4). The residue left by
evaporation of the solvents was purified by column chromatog-
raphy (hexane/ether) to give a thick colorless oil (102 mg, 84%)
identified as 4kOAc (TLC, NMR).
(All-rac)-Tocopherol Acetate (1aOAc): From 4kOAc. The
preceding acetate (87 mg, 0.186 mmol) was diluted with EtOAc
(2 mL) and 5% Pd/C (50 mg) was added. The resulting mixture
was stirred in a H2 atmosphere for 2 h to give, after filtration and
evaporation of the solvents, 1aOAc as a thick white oil (84 mg,
96%).
2-(3-Chloro-4-methylpent-4-enyl)-2,5,7,8-tetramethyl-2H-
chromen-6-yl Acetate (4lOAc). Ca(OCl)2 (173 mg, 0.78 mmol),
admixed with water (0.92 mL), was added to a solution of the
chromene 4aOAc (469 mg, 1.42 mmol) in CH2Cl2 (9.2 mL). The
resulting mixture was warmed to ca. 35-40 °C. With a vigorous
stirring, finely ground dry ice was progressively added until
disappearance of 4aOAc on TLC (30 min). pH 7 buffer (3 mL) was
then added and the mixture was worked-up as above (see the 3a
chlorination) to give, after drying (Na2SO4) and evaporation of
the solvents in a vacuum, the chloride 4lOAc as a colorless oil
(440 mg, 85%). TLC (hexane:CH2Cl2:EtOAc = 9:9:2) Rf = 0.71;
1H NMR (CDCl3): ¤ 1.35/1.36 (2 s, 3H, CH3), 1.5-1.73 (m, 4H, 2
CH2), 1.79/1.8 (2 s, 3H, CH3), 2.02 (s, 3H, CaromCH3), 2.05 (s, 3H,
Nathalie Sala-Jung (ULP, Strasbourg; 2002), and have been
presented in short at the VIIth ULP-Todai meeting (The
University of Tokyo; September 2006). This work was
supported by the “Ministère de la Recherche et de l’Education”
(France) and Aventis Animal Nutrition (grants to V. G. and
N. S.-J., respectively). Thanks are due to Dr. Jean-Eric Ancel
(Aventis Industrialisation) for analyses and discussions, and to
Dr. Tim Wallace (The University of Manchester, U.K.) for
helpful suggestions.
References
#
In memoriam, this paper is dedicated to Dr. Charles
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C
aromCH3), 2.09 (s, 3H, CaromCH3), 2.33 (s, 3H, CH3), 4.38 (t,
J = 7 Hz, 2H, CH2), 4.89-5.01 (m, 2H, CH2), 5.54/5.57 (2 d,
J = 10.2 Hz, 1H, CH), 6.51/6.54 (2 d, J = 10.2 Hz, 1H, CH);
13C NMR (CDCl3): ¤ 11.5 (CH3), 11.6 (CH3), 13.2 (CH3), 16.9
(CH3), 20.5 (CH3), 25.8/26.2 (CH3), 31.2/34.4 (CH2), 66.9 (CH),
76.8 (C), 114.4 (C=CH2), 117.3 (Carom), 120.4/120.5 (CH), 122.6
(Carom), 124.3 (Carom), 128.6/128.9 (CH), 141.4 (Carom), 144.2 (C),
148.2 (Carom), 169.5 (C=O); MS (CI-NH3) m/z 380 (M + NH4+),
363 (M + H+), 362 (M), 344, 327, 311, 269, 245, 203, 165, 121,
105, 91.
(All-rac)-Tocopherol Acetate (1aOAc): From the Chloride
4lOAc. CuI (3 mg, 0.05 equiv) was dried in a vacuum for a few
hours. After cooling to rt, the chloride 4lOAc (93 mg, 0.24 mmol)
diluted with THF (300 ¯L) was added with a syringe and the
resulting mixture was cooled to ¹5 °C (ice/methanol bath). A
0.44 M solution of the Grignard reagent 8 in THF (0.58 mL,
0.24 mmol) was added dropwise. The cooling bath was removed
and the reaction mixture was diluted with ether (2 mL) and
saturated NH4Cl (1 mL). After a few minutes stirring, the aqueous
phase was extracted with ether (3 © 1 mL) and the pooled organic
extracts were washed with saturated NH4Cl (2 mL), brine
(2 © 2 mL), and dried (MgSO4). The residue left by evaporation
of the solvents was purified by column chromatography (hexane/
ether) to give, after removal of the solvents in a vacuum, a thick
colorless oil (64.5 mg, 58%) identified as 4kOAc (TLC, NMR).
Hydrogenating this product (50 mg, 0.107 mmol) as above afford-
ed 1aOAc as a thick colorless oil (48 mg, 95%).
4
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