Synthetic route discovery and introductory optimization of a novel process to idebenone

Article abstract of DOI:10.1021/op200051v

An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1- methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.

Full text of DOI:10.1021/op200051v

ARTICLE
pubs.acs.org/OPRD
Synthetic Route Discovery and Introductory Optimization of a
Novel Process to Idebenone
Anna Tsoukala and Hans-Renꢀe Bjørsvik*
Department of Chemistry, University of Bergen, Allꢀegaten 41, N-5007 Bergen, Norway
S Supporting Information
b
ABSTRACT: An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed.
The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the
Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation,
and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is
composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.
Chart 1. Idebenone, Coenzyme Q0, Coenzyme Q10, Vitamin
E, and Trolox
’ INTRODUCTION
Idebenone was originally designed and synthesized as an
experimental drug intended for the treatment of various cogni-
tive defects such as Alzheimer’s1 and Parkinson’s diseases.2
Idebenone has also been investigated as an agent for the
treatment of ischemic stroke,3 inhibition of lipid peroxidation
in the brain4 and cardiac mitochondria,5 improvement of mito-
chondrial oxygen utilization,6 short-term memory and learning
disabilities,7 reduction of hepatocyte injury,8 and treatment of
oxidative eye diseases.9 In recent years, various clinical studies
involving idebenone for the treatment of neuromuscular diseases
such as Friedreich’s ataxia10 and Duchenne muscular dystrophy11
have also been concluded or are currently under way. A clinical
trial dedicated to investigation of idebenone’s effect on Leber’s
hereditary optic neuropathy was also recently concluded.12
Lately several other clinical trials using idebenon as a therapeutic
agent were initiated and include treatment of mitochondrial
encephalomyopathy, lactic acidosis, stroke-like episodes,13 and
primary progressive multiple sclerosis.14
Idebenone was also proved10e,15 to be a free radical scavenger
for a variety of reactive species such as the oxidant peroxynitrite.
The antioxidant efficiency of idebenone compared with vitamin
E and Trolox (Chart 1) revealed that the efficacy of idebenone
varies in the range 50ꢀ100% of that of the latter two. The much
shorter and much more carbon poor side chain of idebenone
(C10) compared to that of coenzyme Q10 (C40), see Chart 1,
provide idebenon with a minor hydrophobicity that facilitates it
to intercept free radicals both in hydrophobic and hydrophilic
environments.
The antioxidant properties of idebenone have also attracted
interest from the “beauty industry” and provided antiaging
remedies for topical applications for treatment of wrinkles.16
The recent renewed interest and the apparently large range of
application areas for idebenone 10 combined with our own long-
standing research activity related to oxidation processes in
organic synthesis and transition metal-catalyzed synthesis
spurred our curiosity to investigate previous syntheses of idebe-
none 10 and analogue compounds. Surprisingly few and in
general environmentally unfriendly synthetic processes17ꢀ24 to
idebenone 10 have been disclosed. The major divergence of
these processes and syntheses was found in the nature of the
substrate, in the type of oxidation processes that provided the
benzoquinone framework, and how the alkyl chain was con-
nected to the ring, whereof the most disclosures utilize some sort
of FriedelꢀCrafts reaction.
’ METHODS AND RESULTS
Our effort to design and realize a novel total synthesis leading
to idebenone was constrained by several requirements, namely
(1) it should be cost-effective and (2) preferably based on readily
Received: February 28, 2011
Published: March 21, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/op200051v Org. Process Res. Dev. 2011, 15, 673–680
|

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Scheme 1. A New Expedient High-Yielding Total Synthesis of Target Molecule Idebenone 10
Scheme 2. Bromination of 1,2,3-Trimethoxy-5-methylben-
zene 1 with KBr As the Only Bromine Sourcea
available reagents, (3) it should be scalable, (4) it should
preferably be usable for the operation in continuous flow fashion,
and (5) it should include as many environmentally friendly steps
and operations as possible.
One of the crucial steps of our outlined synthesis, see
Scheme 1, emerged to be a coupling of an aromatic moiety and
an alkyl chain that together constitute the entire Carbone
skeleton of our target molecule idebenone. In this context, we
assessed various transition metal catalysis coupling reactions,
whereof the Heck coupling25 appeared to be the most attractive
for the preparation of the target carbon skeleton.
For this purpose, we needed access to 2-bromo-3,4,5-tri-
methoxy-1-methylbenzene (2) and dec-9-en-1-ol (5), whereof
the bromobenzene 2 could be prepared from the readily available
1,2,3-trimethoxy-5-methylbenzene (1). A large number of bro-
minating protocols have previously been disclosed, unfortunately
most of them will not fulfill some of our important objectives,
namely low environmental impact and easy scalability. In this
context, we designed and realized recently26 a novel bromination
protocol where we utilized the two low-cost compounds 1,2,3-
trimethoxy-5-methylbenzene (1) as substrate and potassium bro-
mide as the only bromine source. KBr as bromine source is very
attractive since this compound has low toxicity and is easy to handle
even at large scale. The bromination proceeds in a one-pot process
where two distinct, but concurrent reactions proceed: (1) Molec-
ular bromine is produced from potassium bromide reacting with
nitric acid [see path a of Scheme 2], but at any time during the
bromination process, the quantity of bromine is very small. (2) The
minute quantities of molecular bromine that are produced are
concurrently consumed in an electrophilic substitution by means of
Brþ.27 The low molecular bromine concentration during the whole
course of the bromination give rise to high selectivity and excellent
yield (>95%). The bromination process operates excellently with
activated arenes and it appears that this process operates according
a Reaction a: Production of molecular bromine. Reaction b: Overall
bromination process.
to an electrophilic substitution by means of the Brþ ion. Since Br is
a deactivatinggroup (whenmonobrominationhastakenplace), the
monobrominated arenes turn out to be substantially less reactive
compared to the starting arene. This fact contributed also to the
high selectivity (>95% yield and quantitative conversion) of the
brominating protocol developed for the production of the brom-
benzene 2. Several more examples are given in our previous
disclosure.26
With the low cost and environmentally friendly process for the
production of the aromatic bromide 2 available, the next step
ought to be a coupling reaction. The Heck coupling involving the
bromobenzene 2 and the commercially available dec-9-en-1-ol
(5), Scheme 3, appeared to be a potential path to produce the
complete Carbone skeleton needed for the Idebenone.
For the outlined coupling reaction, three various palladium
catalysts were investigated: (1) palladium acetate [Pd(OAc)2],
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Organic Process Research & Development
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Scheme 3. Heck Coupling Reaction Conducted with Conventional Heating, Using an Oil Bath
(2) tetrakis(triphenylposphine)palladium(0) [Pd(PPh3)4], and
(3) [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloro-
pyridyl)palladium(II) dichloride (known as PEPPSI -IPr).28 The
three catalysts were selected due to their ligand variation, namely an
inorganic salt, a Pd catalyst with only phosphine ligands, and finally
a catalyst with NHC ligand. The Pd(OAc)2 catalyst provided the
highest substrate conversion (≈80%), using a reaction temperature
of 120 °C for a reaction period of 72 h with triethylamine as base
and triphenylphosphine as ligand for the palladium catalyst.
Three isomers 6a, 6b, and 12 were produced, whereof the two
most abundant and productive isomers 6a and 6b were isolated
in a yield of >60%. An undesired byproduct, the olefin 12, was
produced (≈15%) as a result of the coupling of the bromoben-
zene 2 at C2 of the olefine 5, a reaction that takes place with the
presence of either carbonyl or hydroxyl groups in the olefin.29
Even though the outcome of the Heck coupling was satisfac-
tory, this protocol had a serious drawback from an industrial scale
point of view, namely the requirement of a very long reaction
time (3 days). To optimize the Heck coupling with respect to two
concurrent goals, namely (1) minimizing the reaction time and
(2) increasing the reaction yield (and thus maximizing the
potential throughput), we investigated the Heck cross-coupling
reaction using microwave irradiation as the energy source as an
alternative to thermal heating. A selection of the experiments
involving microwave irradiation is given in Table 1.
Initially we utilized identical reaction conditions for the
procedure that used classical heating with an oil bath (that is
summarized in Scheme 3). The microwave irradiation driven
protocol is shown in Scheme 4. The five experimental variables
reaction time, solvent, reaction temperature, base, and catalyst
were investigated. This screening revealed that Pd(PPh3)4 as the
catalyst in combination with diisopropylethylamine as base and
N,N-dimethylfomamide (DMF) as solvent conducted at a reac-
tion temperature of 120 °C provided a higher outcome (giving an
isolated yield of 67%) compared with the experiment with
thermal heating (Scheme 3). Moreover, the microwave protocol
required a considerably shorter reaction time, namely only 30
min in the microwave reactor in contrast to 3 days (72 h) when
using conventional thermal heating. The selectivity with micro-
wave heating was also significantly improved, as only the desired
olefin isomers 6a and 6b were produced. Furthermore, when
Pd(OAc)2 was used as catalyst under similar microwave reactor
condition, a poor yield of 21% was achieved. The PEPPSI-IPr
catalyst also gave a low yield of 14%.
However, with an augmented quantity of the Pd(OAc)2
catalyst (from 2.6 mol % to 5.2 mol %), and increased reaction
temperature (from 120 to 160 °C, see Table 1, entry 16), a
similar yield as with Pd(PPh3)4 as catalyst was achieved (≈60%),
and the undesired isomer 12 was not produced. If the amine base
was substituted with K2CO3 (Table 1, entry 8), no improvement
was observed (affording a yield of ≈32%), but also under these
conditions only the desired isomers 6a and 6b were produced.
A two-step synthetic pathway leading to dec-9-en-1-ol (5) was
also investigated. This investigation was undertaken in order to
provide an extended process that hopefully resulted in an overall
reduced cost. The process leading to dec-9-en-1-ol (5) involves
decan-1,10-diol (3) as the basic substrate (pathways 7 and 8 of
Scheme 1) and includes a monobromination of the diol 3 to 10-
bromo-decan-1-ol (4) that in the subsequent step is subjected to
a dehydrohalogenation to produce dec-9-en-1-ol (5).
The bromoalkanol 4 was initially synthesized according to an
environmentally mild solvent free process disclosed by Goverd-
han and collaborators36 for the synthesis of bromoalkanols using
diols under microwave irradiation. The product was purified and
isolated from the disubstituted derivative in a medium yield of
45%, though the literature suggested a yield of 80%. By means of
statistical experimental design30 and multivariate regression31
techniques, we were able to improve both the yield and the
chemoselectivity to 64% and 90%, respectively. Moreover an
optimized procedure for industrial scale application was also
developed.32 A dehydrohalogenation method developed by Baugh-
man and collaborators37 was adopted for the preparation of the
alkenol 5, as the last step of the additional pathway utilizing
potassium tert-butoxide as the reagent for the dehydrohalogenation
reaction. Nevertheless, the alkenol 5was isolated only in a poor yield
(≈20%), which weakened the importance of this additional path-
way even with the efficiency of the first step 7 and the use of the
inexpensive decan-1,10-diol (3) as substrate. However, attempts to
optimize this step by means of multivariate design and modeling30,31
similar to step 732 of Scheme 1 has not yet been carried out.
A palladium on charcoal catalyzed hydrogenation was utilized
for the synthesis of 10-(2,3,4-trimethoxy-6-methylphenyl)decan-
1-ol (7). All fractions of the isomers from the Heck coupling (6a,
6b, 12) were subjected to hydrogenation conditions, and the
olefin 12 was not reactive probably due to stereic reasons. The
two reactive isomers 6a and 6b were successfully hydrogenated
to provide 10-(2,3,4-trimethoxy-6-methylphenyl)decan-1-ol (7)
in excellent yield (91%).
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Table 1. Heck Coupling Reaction Conducted under Microwave Irradiation Conditions
reaction conditionsa
measured responses
entry
catalyst
solvent
DMF
base
t [min]
T [°C]
y [%]g
ytotal [%]h
b
1
2
Pd(PPh3)4
PEPSSIb
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
30
30
30
30
15
30
10
10
10
10
30
30
60
30
30
45
120
120
120
100
135
120
100
90
67
14
21
48
26
43
55
32
67
14
23
48
29
47
55
32
DMF
c
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
4
DMF
5
DMSO
DMSO
DMSOd
H2O/EtOHe
H2O/TBAId
DMF
6
b
f
7
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
K2CO3
f
8
K2CO3
f
9
K2CO3
90
b
10
11
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Et3N
80
DMF
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
120
120
120
150
160
160
33
15
30
32
40
70
38
15
34
40
47
78
c
DMF
DMF
DMF
DMF
DMF
a General procedure: Substrate 2 (0.76 mmol, 0.2 g), 9-decen-1-ol 5 (1.25 mmol, 0.22 mL), catalyst (0.040 mmol, 9 mg), PPh3 (0.080 mmol, 21 mg),
base (1.25 mmol, 0.22 mL), and solvent (1 mL) were transferred to a thick walled Pyrex microwave vial that was closed with a silicon septum and
subjected to microwave irradiation. b 0.020 mmol. c 0.060 mmol. d 2 mL/0.5 mmol. e 1 mL/1 mL. f 2 mmol. g Measured yield of the productive fraction of
isomers. h Measured yield of all isomers (total sum of isomers).
Scheme 4. The Heck Coupling Reaction by Means of
Microwave Irradiation
Scheme 5. Alternative Pathway Leading to the Heck Product 13
Oxidation of compound 8 with the goal to produce the
benzoquinone framework 9 was another critical step of our
idebenone synthesis. Previously, our group33 have disclosed a green
high-yielding two-step telescoped oxidation process for the synth-
esis of coenzyme Q0 (CoQ0) using the aromatic compound 1 as
substrate and hydrogen peroxide and nitric acid as the oxidizing
agents in a two-step telescoped fashion. With this process, we
adapted a protocol that oxidized the sterically crowded aromatic
compound 8 to 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-
1,4-dienyl)decyl acetate (9) by using hydrogen peroxide as the only
oxidant (Scheme 6). The increased reactivity of the aromatic
compound 8 compared to that of trimethoxytoluene 1 (as is used
in the CoQ0 process)33 can be explained by the presence of the C10
alkyl side chain, which increases the electron density of the aromatic
ring by acting as an extra electron donor. As a result, the phenol 80
exhibits an increased reactivity towards oxidation that requires
milder conditions than those used for trimethoxytoluene 1.
The oxidation of the aromatic compound 8 proceeded with
high conversion (>70%). However, the workup and purification
of the target intermediate [10-(4,5-dimethoxy-2-methyl-3,6-di-
oxocyclohexa-1,4-dienyl)decyl acetate, 9] was challenging, but a
nonoptimized protocol resulted in a modest yield of 45%.
The next step of the synthetic path involves the oxidation
of the aromatic ring of compound 7 to the corresponding
benzoquinone framework 9. The existence of the free hydroxyl
group in the alkyl chain called for the introduction of a protecting
group in order to prevent oxidation of the hydroxyl group. A solvent-
free protocol previously disclosed by Phukan38 involving the con-
version of the free hydroxyl group to an O-acetyl group was utilized.
The hydroxyl protection proceeded smoothly to provide 10-(2,3,4-
trimethoxy-6-methylphenyl)decyl acetate (8) in a yield of 90%.
It is worth mentioning that an alternative path was also
attempted, a synthetic pathway that was based on the use of
Phukan protocol38 for O-acetylation of dec-9-en-1-ol (5) fol-
lowed by Heck coupling of dec-9-enyl acetate 11 with the aryl
bromide 2 in order to prepare compound 13 (Scheme 5).
Dec-9-enyl acetate 11 was produced in good yield (60%),
which, however, is slightly lower than in the step that compound
8 is produced, while product 13 was produced only in a moderate
yield of 47%. Thus this pathway was abandoned.
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Scheme 6. Oxidation Processa
a Reaction a: Peracetic acid is produced in situ. Reaction b: The aromatic ring of 10-(2,3,4-trimethoxy-6-methylphenyl)decyl acetate (8) is oxidized to
provide 10-(3-hydroxy-4,5,6-trimethoxy-2-methylphenyl)decyl acetate (80) that subsequently is oxidized to 10-(4,5-dimethoxy-2-methyl-3,6-dioxocy-
clohexa-1,4-dienyl)decyl acetate (9).
1
The final step of the synthetic path (step 6 of Scheme 1)
involves the deprotection of 9 by treatment with sodium car-
bonate in a methanolꢀwater mixture at room temperature,
which gave target molecule idebenone (10) in high yield (85%).
Additional studies related to the work described herein are
either completed or in progress, and include (1) organic solvent
nanofiltration for removal of trace quantities of palladium after
the Heck coupling reactions (completed), (2) investigation of
continuous flow processes for the bromation of the aromatic
compound 1 (step 1, Schme 1), and finally (3) optimization of
lowest yielding step 5 (oxidation) using a pre-experimental
design with the future goal of optimization by means of statistical
experimental design and multivariate regression, similar to the
optimization study previously reported by us for the bromination
of diol 3 (step 7 of Scheme 1).32
spectrometer operating at 400 MHz for H and 101 MHz for
13C. Chemical shifts were referred to the solvent peak of CDCl3/
CHCl3 (δH = 7.26 ppm, δC = 77.2 ppm). Starting materials and
reagents were purchased commercially and used without further
purification. The reaction products were analyzed by GC-MS.
Silica gel 60 (0.040ꢀ0.0063 mm) and alumina oxide (basic,
grade I) was used for the flash chromatography. F-254 TLC
plates were used in order to follow the progress of the reactions,
to determine the purity of substance, and to identify the various
fractions from the flash chromatography separation. The spots of
substances on the thin layer were visualized under UV light at λ =
254 nm. The elemental analysis was performed by an VarioEL
CHNS (by Elementar Analysensystem GmbH, serial no.
11053037). The experiments that were performed using
microwaves as the energy source were conducted by means of
a Biotage Initiator Sixty EXP Microwave System, that operates at
0ꢀ400 W at 2.45 GHz, in the temperature range of 40-250 °C, a
pressure range of 0ꢀ20 bar (2 MPa, 290 psi) with reactor vial
volumes of 0.2ꢀ20 mL.
’ CONCLUSIONS
A six-step total synthesis leading to idebenone (10) was
designed, developed, and partly optimized. Overall isolated yield
involving the reaction steps 1ꢀ6, Scheme 1, was 20%, which
corresponds to an average step yield of 76%. An additional two
steps pathway that lead to one of the starting reagents, were also
investigated but not included in the final process. Key steps
including a green brominating process (>95% yield), a palla-
dium-catalyzed Heck coupling reaction mediated by microwave
irradiation (67% yield), and an environmentally benign oxidation
process transferring an aromatic intermediate to the correspond-
ing benzoquinone framework (≈70% yield in reaction mixture)
have been designed and developed.
2-Bromo-3,4,5-trimethoxy-1-methylbenzene, 2 [72326-
72-8].34. Nitric acid (65%, 1.6 mmol, 0.11 mL) was added to
acetic anhydride (5.0 mL). This mixture was, by means of a
syringe-pump, added dropwise over a period of 30 min to a
mixture of 3,4,5-trimetoxytoluene (1, 1.5 mmol) and KBr
(2.0 mmol) in acetic anhydride (2.5 mL). After complete
addition of the oxidant, the reaction mixture was stirred for
another 45 min at 20 °C. Water (10 mL) was added to the
reaction mixture and mixed for 30ꢀ40 min at room temperature.
The quenched reaction mixture was then extracted with ethyl
ether (3 ꢁ 10 mL). The organics were combined and washed
with saturated brine solution, dried over sodium sulphate, and
filtered, and the solvent was then removed under reduced
pressure to achieve 2-bromo-3,4,5-trimethoxy-1-methylbenzene
(2) in a yield of >95% (colorless-yellowish oil). 1H NMR
(400 MHz, CDCl3, ppm): δ 2.36 [s, 3H], 3.83 [s, 3H], 3.85
[s, 3H], 3.88 [s, 3H], 6.60 [s, 1H]. 13C NMR (200 MHz): δ
22.43, 56.67, 61.52, 106.62, 134.22, 136.48, 153.68. MS m/z (%):
’ EXPERIMENTAL SECTION
General Methods. Mass spectra were acquired on a GC-MS
instrument using a gas chromatograph equipped with fused silica
column (L 30 m, 0.25 mm i.d., 0.25 μm film thickness) and He as
carrier gas. 1H NMR spectra were recorded on an NMR
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262 (100), 260 (99), 217 (25), 202 (40), 166 (20), 151 (25), 138
(47), 123 (38), 108 (12), 77(20), 63 (15), 51 (27). TLC system:
hexane:ethyl acetate = 11:1, Rf 0.45.
10-(2,3,4-Trimethoxy-6-methylphenyl)decan-1-ol, 7 [new].
A mixture of 10-(2,3,4-trimethoxy-6-methylphenyl)dec-9-en-1-ol
(6, 0.44 mmol, 0.148 g), ethanol (5 mL), and 10% palladium on
charcoal (15 mg) was added to a round-bottomed flask equipped
with a three-way valve. The reaction mixture was stirred at 25 °C
for 3 h under hydrogen atmosphere with the use of a balloon. After
the end of the reaction course the mixture was filtered through
Celite in order to remove the catalyst and the filter was washed
with diethyl ether (20 mL). The solvent form the organic phase
was removed under reduced pressure to give product 7 as a
10-Bromodecan-1-ol, 4 [53463-68-6].35. The same proce-
dure as used by Goverdhan et al.36 was followed. A mixture of
1,10-decanediol (3, 4.23 mmol, 0.736 g), 48% aq hydrobromic
acid (9.13 mmol, 0.74 g, 0.5 mL), and tetrabutylammonium
bromide (0.84 mmol, 0.27 g) was added in a heavy walled Pyrex
microwave vial (2ꢀ5 mL) covered with a silicon septum and
exposed to microwave irradiation for 5 min at 100 °C by means of
a MicroWell10 single-mode microwave cavity (Biotage). Then
the reaction mixture was cooled and extracted with dichloro-
methane (3 ꢁ 10 mL). The product 4 was purified from the
dibrominated derivative by using flash chromatography and
isolated in a yield of 45%. 1H NMR (400 MHz, CDCl3, ppm):
δ 1.26 [br s, 10H], 1.38 [qn, 2H], 1.52 [qn, 2H], 1.81 [qn, 2H],
1.89 [s, 1H, interchangeable with D2O], 3.36 [t, 2H], 3.58
[t, 2H]. 13C NMR (200 MHz): δ 26.13, 28.56, 29.14, 29.76,
29.83, 33.20, 33.23, 34.44, 63.48. MS m/z (%): 192 (6), 190 (7),
164 (14), 162 (16), 150 (46), 148 (48), 137 (22), 135 (23), 97
(80), 83 (86), 69 (100), 55 (94). IR (FT): ν 3327, 2923, 2852,
1463, 1371, 1256, 1054, 721, 644, 561. TLC system: hexane:ethyl
acetate = 8:2, Rf 0.40.
1
colorless oil in a yield of 91% (measured yield by means of H
NMR and 3,4-dimethoxyacetophenone as internal standard). 1H
NMR (400 MHz, CDCl3, ppm):δ 1.29[br s, 15H], 1.56[qn, 2H],
2.25 [s, 3H], 2.52 [t, 2H], 3.64 [t, 2H], 3.84 [t, 9H], 6.48 [s, 1H].
13C NMR (200 MHz): δ 20.15, 26.37, 27.37, 30.07, 30.12, 30.18,
30.24, 30.70, 31.02, 33.46, 56.58, 61.36, 61.68, 63.75, 109.97,
128.08, 132.07, 140.88, 151.52, 152.52. MS m/z (%): 338 (48),
195 (100), 180 (82), 165 (14), 150 (19), 137 (14), 91(13), 79
(10), 55 (20). IR (FT): ν 3403, 2923, 2852, 1737, 1676, 1597,
1493, 1463, 1403, 1331, 1269, 1236, 1196, 1121, 1071, 1027, 987,
922, 877, 829, 767, 723, 616, 568. Anal. Calcd for C20H34O4: C,
70.97; H, 10.12. Found: C, 69.82; H, 9.61. TLC system: hexane:
ethyl acetate = 7:3, Rf = 0.40.
10-(2,3,4-Trimethoxy-6-methylphenyl)decyl Acetate, 8
[new]. The same procedure as used by Phukan38 was followed. A
mixture of 10-(2,3,4-trimethoxy-6-methylphenyl)decan-1-ol
(7, 1 mmol, 0.338 g), acetic anhydride (5 mmol, 0.47 mL),
and iodine (0.1 mmol, 10.6 mg) was added to a round-bottomed
flask equipped with a reflux condenser. The reaction mixture was
stirred at 25 °C for 1 h. Water (10 mL) was then added and the
quenched reaction mixture was extracted with diethyl ether (3 ꢁ
10 mL). The organic phases were combined and washed first
with sodium thiosulphate (10 mL, 0.1 M), then with sodium
hydrogen carbonate (3 ꢁ 10 mL), and finally with saturated
brine solution, dried over sodium sulphate, and filtered and the
solvent was then removed under reduced pressure to achieve 8 as
a colorless oil in a yield of 90% (measured yield by means of
1H NMR and 3,4-dimethoxyacetophenone as internal standard).
1H NMR (400 MHz, CDCl3, ppm): δ 1.29 [br, s, 14H], 1.61 [qn,
2H], 2.04 [s, 3H], 2.25 [s, 3H], 2.52 [t, 3H], 3.84 [t, 9H], 4.05 [t,
2H], 6.48 [s, 1H]. 13C NMR (200 MHz): δ 19.91, 21.43, 26.32,
27.13, 29.01, 29.67, 29.88, 29.93, 30.47, 30.79, 56.34, 61.13,
61.43, 65.08, 109.73, 127.82, 131.83, 140.64, 151.28, 152.34,
171.72. MS m/z (%): 380 (84), 320 (25), 306 (40), 195 (100),
180 (98), 165 (51), 150 (76), 137 (42), 105 (39), 91 (36), 79
(32), 55 (41). IR (FT): ν 2924, 2853, 1738, 1600, 1494, 1464,
1404, 1364, 1332, 1235, 1196, 1123, 1033, 988, 923, 829, 722,
606, 561, 542. Anal. Calcd for C22H36O5: C, 69.44; H, 9.54.
Found: C, 68.64; H, 9.34. TLC system: hexane:ethyl acetate =
8:2, Rf 0.56. Bp 115ꢀ120 °C.
Dec-9-en-1-ol, 5 [13019-22-2]. The same procedure as used
by Baughman et al.37 was followed. A solution of 10-bromode-
can-1-ol (4, 4 mmol, 0.95 g) in 1:1 THF/toluene was prepared in
a round-bottomed flask. The flask was cooled to 0 °C and then
t-BuOK (6.51 mmol, 0.73 g) was added over a period of 30 min.
After the addition the reaction mixture was quenched with 1 M
HCl (50 mL). The organic phase was extracted with diethyl
ether (3 ꢁ 50 mL), washed with sodium hydrogen carbonate
(2 ꢁ 80 mL) then with saturated brine solution, dried over
sodium sulphate, and filtered and the solvent was then removed
under reduced pressure. The product 4 was purified by means of
flash chromatography and isolated in the scarce yield of 20%.
1H NMR (400 MHz, CDCl3, ppm): δ 1.29 [br, s, 11H], 1.55 [qn,
2H], 2.02 [q, 2H], 3.63 [t, 2H], 4.91 [dqn, 1H], 4.98 [dq, 1H],
5.80 [m, 1H]. MS m/z (%): 156 (7), 138 (32), 109 (76), 95 (86),
81(98), 67(100). TLC system:hexane:ethyl acetate =7:4, Rf 0.47.
10-(2,3,4-Trimethoxy-6-methylphenyl)dec-9-en-1-ol, 6a
[new] þ 10-(2,3,4-Trimethoxy-6-methylphenyl)dec-8-en-1-
ol, 6b [new]. A mixture of 2-bromo-3,4,5-trimethoxytoluene (2,
7.66 mmol), dec-9-en-1-ol (5, 12.5 mmol, 2.3 mL), triethylamine
(14.3 mmol, 2 mL), palladium acetate (0.20 mmol), and triphe-
nylphosphine (0.80 mmol) was added to a Shield Tube. The
mixture was flashed with nitrogen for 3 min, shield, and then heated
in an oil bath at 120 °C for 3 days.29a After the end of the reaction
course the cold reaction mixture was filtered through Celite, in
order to remove the catalyst, and the filter was washed with diethyl
ether (3 ꢁ 10 mL). The organic phase was washed with water and
dried with anhydrous sodium sulphate. Subsequently the solvent
was removed under vacuum and the product 6 was purified, by
means of flash chromatography, and isolated as a mixture of
position isomers regarding the double bond, in a yield of 60%
(measured yield by means of 1H NMR and 3,4-dimethoxyaceto-
phenone as internal standard). 1H NMR (400 MHz, CDCl3, ppm):
δ 1.28 [br, s, 9H], 1.54 [qn, 2H], 1.95 [q, 2H], 2.23 [s, 3H], 3.27
[d, 2H], 3.62 [t, 2H], 3.80 [t, 9H], 5.39 [m, 2H], 6.50 [s, 1H]. MS
m/z (%): 336 (75), 221 (56), 195 (100), 190 (80), 182 (95), 167
(25), 91 (22), 79 (12), 55 (34). Anal. Calcd for C20H32O4: C,
71.39; H, 9.59. Found: C, 70.88; H, 9.66. TLC system:hexane:ethyl
acetate = 8:2, Rf 0.32.
10-(4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-
dienyl)decyl Acetate, 9 [58186-28-0].39. A mixture of 10-
(2,3,4-trimethoxy-6-methylphenyl)decyl acetate (8, 3 mmol,
1.14 g), acetic acid (3 mL), hydrogen peroxide (35%, 9 mmol,
0.90 mL), and p-toluenesulfonic acid (0.11 mmol, 57 mg) was
added to a round-bottomed flask equipped with a reflux con-
denser and stirred at 75 °C for 25 min. Then the warm reaction
mixture was poured in ice-cold water (50 mL) and extracted
with ethyl acetate (3 ꢁ 50 mL). The organic phases were
combined, washed with water (4 ꢁ 100 mL), dried over sodium
sulphate, and filtered and the solvent was then removed under
reduced pressure to give crude product 9 as a light red oil in a
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Organic Process Research & Development
ARTICLE
yield of 70%. Product was further purified by means of flash
chromatography (Hex:EtOAc = 8:2) and isolated in a yield of
45%. H NMR (400 MHz, CDCl3, ppm): δ 1.27 [br, s, 14H],
1.61 [qn, 2H], 2.01 [s, 3H], 2.04 [s, 3H], 2.44 [t, 2H], 3.98
[s, 6H], 4.06 [t, 2H]. 13C NMR (200 MHz): δ 12.31, 21.42,
26.30, 26.80, 29.01, 29.13, 29.62, 29.74, 29.80, 29.86, 30.21,
61.54, 65.04, 139.07, 143.49, 144.72, 171.64, 184.56, 185.12. MS
m/z (%): 380 (20), 338 (30), 306 (12), 197 (100), 183 (76), 167
(17), 153 (24), 81 (17), 67 (23), 55 (37). TLC system: hexane:
ethyl acetate = 8:2, Rf 0.32.
’ AUTHOR INFORMATION
1
Corresponding Author
*E-mail: hans.bjorsvik@kj.uib.no. Phone: þ47 55 58 34 52. Fax:
þ47 55 58 94 90.
’ ACKNOWLEDGMENT
A financial grant is gratefully acknowledged from EC Marie
Curie Actions (The InSolEx project) and the Denomega com-
pany, Norway.
2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methylcyclohexa-
2,5-diene-1,4-dione (Idebenone), 10 [58186-27-9].39. So-
dium carbonate (0.095 mmol, 11 mg) was added to a solution
of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienyl)decyl
acetate (9, 0.2 mmol, 76.2 mg) in methanol (1.3 mL) and water
(0.32 mL) at 25 °C. The mixture was stirred at 25 °C for 20 h.
Water (10 mL) was then added and the quenched reaction
mixture was extracted with ethyl acetate (3 ꢁ 10 mL). The
organic phases were combined, washed with a saturated solution
of sodium chloride (2 ꢁ 10 mL), dried over sodium sulphate, and
filtered and the solvent was then removed under reduced
pressure to achieve product 10 as a yellow-red oil in a yield
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of 80% (85% measured yield by means of H NMR and 3,
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S
b
spectra (2, 4ꢀ11), 13C NMR spectra (2, 4, 7ꢀ11), IR spectra
(4, 7, 8, 10, 11), and DEPT-135 spectra (7, 8, 9, 10). This
material is available free of charge via the Internet at http://pubs.
acs.org.
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