New efficient synthesis of ubiquinones

Article abstract of DOI:10.1080/00397910701771066

A strategy for the ecofriendly and high-yielding synthesis of ubiquinones starting from simple materials and using mild conditions is reported. CoQ1, CoQ2, CoQ3, and CoQ9 were prepared. Copyright Taylor & Francis Group, LLC.

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New Efficient Synthesis of Ubiquinones
Paolo Bovicelli a , Giorgio Borioni a , Danilo Fabbrini a & Maurizio Barontini a
a CNR Institute of Biomolecular Chemistry–Rome Section, Sapienza
University of Rome, Department of Chemistry , Rome, Italy
Published online: 28 Jan 2008.
To cite this article: Paolo Bovicelli , Giorgio Borioni , Danilo Fabbrini & Maurizio Barontini (2008) New
Efficient Synthesis of Ubiquinones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:3, 391-400, DOI: 10.1080/00397910701771066
To link to this article: http://dx.doi.org/10.1080/00397910701771066
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Synthetic Communicationsw, 38: 391–400, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701771066
New Efficient Synthesis of Ubiquinones
Paolo Bovicelli, Giorgio Borioni, Danilo Fabbrini,
and Maurizio Barontini
CNR Institute of Biomolecular Chemistry–Rome Section, Department of
Chemistry, Sapienza University of Rome, Rome, Italy
Abstract: A strategy for the ecofriendly and high-yielding synthesis of ubiquinones
starting from simple materials and using mild conditions is reported. CoQ1, CoQ2,
CoQ3, and CoQ9 were prepared.
Keywords: coenzyme Q, halogenations, iridol, ubiquinones
The development of new antioxidant drugs is of primary importance to
improve the pharmacological treatment of diseases in which oxidative stress
plays a pathological role, such as asthma, rheumatoid arthritis, Alzheimer’s
disease, cataracts, and atherosclerosis.
A cofactor for all these diseases seems to be the lack of equilibrium
between oxidative processes and systems of defense in our organism. In this
case, the intake of hexogen antioxidants with the diet is essential to prevent
the development of pathologies.[1]
One of the most important classes of antioxidants is ubiquinones.[2]
These compounds, commercially known as coenzymes Qn (CoQn), are con-
stituted by a dimethoxy-benzoquinone structure carrying an all-trans poly-
prenyl chain.[3] They are present in almost all kinds of life[4] in which
mechanisms of electron transfer are involved.[5] Ubiquinones are powerful
antioxidants and as such are commonly used in diet integrators.[6] One of
Received in the U.K. May 3, 2007
Address correspondence to Paolo Bovicelli, CNR Institute of Biomolecular
Chemistry–Rome Section, Department of Chemistry, Sapienza University of Rome,
P.le A. Moro 5, Box 34, I-00185 Rome (Italy). E-mail: paolo.bovicelli@uniroma1.it
391

392
P. Bovicelli et al.
the most important ubiquinones is CoQ10, which is an endogen for the human
species[7] and is also as employed as anti-aging compound and nutrient in
creams to preserve the epithelium from damage due to aggressive environ-
mental oxidants.[8]
Because of these properties, the demand for ubiquinones, especially for
the natural CoQ10, is increasing daily, though all other ubiquinones have
powerful antioxidant properties as well and could be used as hexogen
species. The development of new, simple, and sustainable syntheses of such
compounds is highly attractive.
Recently, we described a new approach for the synthesis of ubiquinones,
exploiting a method for the oxyfunctionalization of aromatic compounds
developed in recent years.[9] In this synthesis, iridol is the compound we
use as a key intermediate, and a Lewis acid–promoted allyl rearrangement
on a suitable ether derived from iridol is the key step.[10]
In that procedure, BF3 etherate was used at 2208C, and the allyl shift
occurred either onto the ortho or the para positions with respect to the initial
position of the ethereal moiety. The main problem with this procedure is that
the regioselectivity of the isoprenyl chain rearrangement is low (Scheme 1).
To avoid the competitive para-rearrangement, we planned to block the
C-6 position of iridol, making use of the bromination–methanolysis
procedure, but under all the conditions we tried, the bromination reaction
was not selective, and thus a mixture of mono- and dibromo derivatives of
iridol was obtained.
Subsequently, we submitted 3,4,5-trimethoxytoluene to a formylation
reaction followed by an easy oxidation with hydrogen peroxide, which
led to a phenol derivative. This oxidation step, known as the Dakin
reaction,[11] is much more efficient and is easier to carry out than the
corresponding Baeyer–Villiger one; furthermore, it can be performed in a
one-pot procedure.
Scheme 1.

New Efficient Synthesis of Ubiquinones
393
The sodium salt of the obtained phenol was reacted with a suitable allyl
bromide to give the corresponding ether, and further treatment with BF3
etherate led to the expected product upon rearrangement of the allyl side
chain onto the vacant meta position (Scheme 2). This kind of rearrangement
is possible because the meta position is the only free one, and its
mechanism is not concerted.
By this method, good results were obtained for every allyl side chain we
used. In the case of the solanesyl group, yields were lower than those obtained
for shorter chains but still good. Worthy of note is that in no case was
isomerization of the allyl chain evidenced by our analytical methods.
Compounds 11a–d were prepared by etherification of sodium phenoxide,
8, with the suitable allyl bromide. Isopropyl and geranyl bromide are
commercially available. Farnesyl bromide was previously prepared by
treating farnesol with PBr3; solanesyl bromide was prepared by treating
solanesol with PBr3. Solanesol was extracted from a waste powder sample
Scheme 2.

394
P. Bovicelli et al.
obtained from a tobacco manufacturer.[12] The extraction was carried out by
shaking the powder with hexane for 2 h and filtering the mixture. A rapid
chromatography on silica gel, eluting with hexane, gave a sufficiently pure
product.
The corresponding ethers 11a–d were obtained in all cases in yields
higher than 90%. Rearrangement of aryl-allyl ethers were performed in
.
good yields (55–70%) in the presence of BF3 Et2O as the Lewis acid, and
the final oxidation step was carried out by treating 12a–d with FeCl3 (an
almost quantitative process). FeCl3 is the simplest oxidant we used, but a
number of other oxidants gave the same result.
Our research of convenient methods to prepare ubiquinones prompted us
to develop a synthetic scheme in which an allyl shift promoted by Lewis
acids is the key step. At first iridol was used as substrate, but the
rearrangement of the corresponding allyl ethers occurred satisfactorily only
in the case of short isoprenyl chains. The finding that the allyl shift can also
occur onto a vacant meta position led us to use 2-hydroxy-3,4,5-
trimethoxytoluene as the phenol to be etherified and rearranged. This
strategy worked well for every allyl chain we used, and CoQ1, CoQ2, CoQ3,
and CoQ9 were prepared in good to excellent yields. The only limitation
of this method, which in principle allows the preparation of every
ubiquinone, is the availability of the suitable allyl alcohol; however,
methods are known to extend isoprenyl chains. Thus the method can be
considered of general value for the synthesis of every ubiquinone, CoQ10
included.
EXPERIMENTAL
2,3,4-Trimethoxy-6-methylbenzaldehyde (6)
In a round-bottomed flask equipped with a dropping funnel, 256 mg
(1.4 mmol) of 3,4,5-trimethoxytoluene and 386 mg (2.9 mmol) of AlCl3
were vigorously stirred in 20 mL of anhydrous CH2Cl2 in an ice bath under
an inert atmosphere. Then 0.11 mL (138 mg, 1.2 mmol) of a,a-dichloro-
methyl methyl ether previously dissolved in 5 mL of anhydrous CH2Cl2
was added dropwise. The temperature was then allowed to raise to 258C,
and after an additional 2 h, the reaction as monitored by thin-layer chromato-
graphy (TLC) (9:1 hexane/EtOAc) was complete, leading to a unique product.
The reaction was then quenched with ice until its color turned light yellow.
The obtained mixture was concentrated, and the residue was extracted with
EtOAc. The organic solution was washed with brine until neutrality and
dried over Na2CO3, and the solvent was removed under a vacuum. The
product (280 mg, 95%), obtained as a colorless oil, was pure enough for
the next step. Physicochemical data were consistent with those reported in
the literature.[13]

New Efficient Synthesis of Ubiquinones
2,3,4-Trimethoxy-6-methylphenol (7)
395
Compound 7 (329 mg, 1.5 mmol) and 25 mg (0.2 mmol) of NaHSO4 were
mixed with 15 mL of MeOH. To the mixture, 0.22 mL (3.8 mmol) of a 50%
solution of hydrogen peroxide was added. After 30 min, the substrate was
completely converted into a single product. MeOH was removed under a
vacuum at room temperature, and the crude was extracted with EtOAc. The
organic solution was washed with brine until neutrality, then dried over
Na2SO4 and evaporated under reduced pressure to give phenol 7 (280 mg,
94%) as a practically pure compund. Physicochemical data agreed with
those of the literature.[14]
2,3,4-Trimethoxy-6-methylphenyl Prenyl Ether (11a)
To a solution of 7 (289 mg, 1.47 mmol) dissolved in THF (10 mL), NaH
(53 mg, 2.21 mmol) was added, and the mixture was stirred at room
temperature for 30 min. The solvent was removed under reduced pressure,
and a white power was obtained. A solution of prenyl bromide (0.20 mL,
1.76 mmol) in THF (5 mL) was added dropwise to a solution of the sodium
phenate 8 in 5 mL of anhydrous THF cooled in an ice bath. Then the tempera-
ture was allowed to raise to 258C, and the mixture was stirred for 12 h. The
mixture was quenched with a 5% solution of NH4Cl and diluted with
EtOAc (20 mL), and the two phases separated. The aqueous layer was
extracted twice with EtOAc (20-mL portions), and the combined organic
solutions were washed with brine until neutrality (10-mL portions). The
resulting solution was dried over anhydrous Na2SO4, and the solvent was
removed under a vacuum. The crude product was purified by flash chromato-
graphy (9:1 hexane/EtOAc). Compound 11a (370 mg, 95%) was obtained as a
light yellow oil. IR (CCl4, cm21): 1200, 1660. 1H NMR (CDCl3) d (ppm): 1.71
(3H, d, J ¼ 1 Hz), 1.78 (3H, d, J ¼ 0.9 Hz), 2.22 (3H, s), 3.81 (3H, s), 3.86
(3H, s), 3.92 (3H, s), 4.41 (2H, d, J ¼ 7.3 Hz), 5.55 (1H, t-sett, J ¼ 0.9,
7.3 Hz), 6.44 (1H, s). 13C NMR (CDCl3) d (ppm): 15.3, 25.6, 26.3, 39.6,
56.0, 61.0, 61.1, 69.5, 108.3, 120.2, 124.0, 131.8, 140.8, 141.2, 147.2. HR-
MS (ES Q-TOF) calcd. for C15H22O4 (M þ Na)þ: 289.1416. Found: 289.1710.
Geranyl 2,3,4-Trimethoxy-6-methylphenyl Ether (11b)
NaH (59 mg, 2.47 mmol) was added to a solution of 7 (325 mg, 1.65 mmol)
dissolved in THF (10 mL). The mixture was stirred at room temperature for
30 min. The solvent was removed under reduced pressure until a white
power was obtained. Anhydrous THF (5 mL) was added, the mixture was
cooled in an ice bath, and then a solution of geranyl bromide (0.54 mL,
2.48 mmol) in THF (5 mL) was added dropwise. The mixture was warmed

396
P. Bovicelli et al.
to room temperature and stirred for 12 h. The reaction was worked up as
described for 11a. Compound 11b (512 mg, 93%) was obtained as a light
1
yellow oil. IR (CCl4, cm21): 1220, 1460, 1660. H NMR (CDCl3) d (ppm):
1.59 (3H, s), 1.68 (3H, s), 2.07 (3H, s), 2.08 (4H, broad), 2.22 (3H, s), 3.80
(3H, s), 3.85 (3H, s), 3.92 (3H, s), 4.44 (2H, d, J ¼ 6.6 Hz), 5.09
(1H, m), 5.54 (1H, br t, J ¼ 6.6 Hz), 6.43 (1H, s). 13C NMR (CDCl3)
d (ppm): 15.5, 16.2, 17.6, 25.6, 26.3, 39.6, 56.1, 61.0, 61.1, 69.5, 108.3,
120.3, 123.9, 126.3, 131.6, 140.8, 141.2, 144.3, 147.2, 149.0. HR-MS (ES
Q-TOF) calcd. for C20H30O4 (M þ Na)þ: 357.2042. Found: 357.2226.
Farnesyl 2,3,4-Trimethoxy-6-methylphenyl Ether (11c)
NaH (47 mg, 1.95 mmol) was added to a solution of 7 (257 mg, 1.30 mmol)
dissolved in THF (10 mL). The mixture was stirred at room temperature for
30 min. The solvent was removed under reduced pressure until a white
power was obtained. Anhydrous THF (5 mL) was added, the mixture was
cooled in an ice bath, and then a solution of farnesyl bromide (0.49 mL,
1.70 mmol) in THF (5 mL) was added dropwise. The mixture was warmed
to room temperature and stirred for 12 h. The reaction was worked up as
described for 11a. Compound 11c (495 mg, 95%) was obtained as a light
1
yellow oil. IR (CCl4, cm21): 1215, 1470, 1660, 2910. H NMR (CDCl3) d
(ppm): 1.60 (3H, s), 1.68 (3H, s), 1.70 (3H, s), 2.10 (8H, m), 2.22
(3H, s), 3.81 (3H, s), 3.86 (3H, s), 3.92 (3H, s), 4.45 (2H, d, J ¼ 6.6 Hz),
5.09 (2H, m), 5.56 (1H, t, J ¼ 6.6 Hz), 6.43 (1H, s). 13C NMR (CDCl3) d
(ppm): 16.0, 16.2, 16.3, 17.6, 25.6, 26.3, 26.7, 39.6, 39.7, 56.1, 61.0,
61.1, 69.6, 108.4, 120.4, 123.9, 124.3, 126.3, 131.2, 135.3, 141.0, 141.2,
144.4, 147.3, 149.0. HR-MS (ES Q-TOF) calcd. for C25H38O4 (M þ Na)þ:
425.2668. Found: 425.2724.
2,3,4-Trimethoxy-6-methylphenyl Solanesyl Ether (11d)
Solanesol (0.83 mL, 1.18 mmol) in THF (1 mL) at 258C was treated with a
solution of PBr3 (0.38 mmol) in THF (1 mL). After 1 h, the mixture was
diluted with a 1:1 solution of hexane and diethyl ether (5 mL). The organic
layer was washed twice with a 5% solution of NaHCO3 (3 mL) and brine
(3 mL). The organic phase was then dried over Na2SO4, and the solvent
was removed under a vacuum. The residue was taken up in anhydrous THF
(5 mL) and added dropwise at 08C to a solution of 8 (278 mg, 0.79 mmol)
in THF (10 mL) prepared as for 11a–c. The mixture was stirred at room
temperature for 12 h and then treated with a 5% solution of NH4Cl. The
aqueous layer was extracted three times with EtOAc (10 mL portions); the
organic solutions were combined and washed with brine until neutrality
(3–4 ꢀ 5-mL portions). The final solution was dried over Na2CO3, and the

New Efficient Synthesis of Ubiquinones
397
solvent was removed under a vacuum. By flash chromatography (95:5
hexane/EtOAc), a pure product (575 mg, 90%) was obtained as a
1
yellow-brown oil. IR (neat, cm21): 1200, 1650. H NMR (CDCl3) d (ppm):
1.60 (24H, br s), 1.67 (3H, br s), 1.69 (3H, br s), 1.95–2.05 (32H, m), 2.22
(3H, s), 3.81 (3H, s), 3.86 (3H, s) 3.93 (3H, s), 4.44 (2H, d, J ¼ 6.6 Hz),
5.05–5.10 (8H, m), 5.56 (1H, t, J ¼ 6.6 Hz), 6.44 (1H, s). 13C NMR
(CDCl3) d (ppm): 16.0 (br), 16.26, 16.33, 17.6, 25.6, 26.3, 26.7 (br), 39.7
(br), 56.1, 61.05, 61.2, 69.6, 108.3, 120.3, 123.8, 124.2, 124.3 (br), 124.4,
126.3, 131.2, 134.9, 135 (br), 135.3, 140.9, 141.3, 144.3, 149.05. HR-MS
(ES Q-TOF) calcd. for C55H86O4 (M þ Na)þ: 833.6424. Found: 833.6518.
2,3,4-Trimethoxy-6-methyl-5-prenylphenol (12a)
The prenyl ether 11a (361 mg, 1.36 mmol) dissolved in 5 mL of Et2O was
.
treated with BF3 Et2O (1.72 mL, 13.6 mmol) at room temperature. After
30 min, a saturated solution of NaCl (10 mL) was added, and the mixture
was extracted three times with EtOAc (10 mL). The organic extracts were
washed with brine until neutrality, dried over anhydrous Na2SO4, and
brought to dryness under a vacuum. By flash chromatography (9:1 hexane/
EtOAc), the desired product (253 mg, 70%) was obtained as a light yellow
1
oil. IR (CCl4, cm21): 1200, 1650, 3470. H NMR (CDCl3) d (ppm): 1.69
(3H, d, J ¼ 1.5 Hz), 1.78 (3H, d, J ¼ 1.3 Hz), 2.14 (3H, s), 3.32 (2H, d,
J ¼ 6.6 Hz), 3.76 (3H, s), 3.92 (3H, s), 3.93 (3H, s), 5.05 (1H, m), 5.64
(1H, s). 13C NMR (CDCl3) d (ppm): 11.3, 17.9, 25.6 (2C), 60.7, 61.1, 61.2,
117.4, 123.0, 129.5, 131.3, 137.7, 143.3, 143.5, 144.3. HR-MS (ES Q-TOF)
calcd. for C15H22O4 (M þ Na)þ: 289.1416. Found: 289.1606.
5-Geranyl-2,3,4-trimethoxy-6-methylphenol (12b)
The geranyl ether 11b (424 mg, 1.27 mmol) dissolved in 5 mL of Et2O was
.
treated with BF3 Et2O (1.61 mL, 12.7 mmol) at room temperature. After
30 min, a saturated solution of NaCl (10 mL) was added, and the mixture
was extracted three times with EtOAc (10 mL). The organic extracts were
washed with brine until neutrality and dried over anhydrous Na2SO4, and
the solvent was stripped off under a vacuum. By flash chromatography (9:1
hexane/EtOAc), the desired product (318 mg, 75%) was obtained as a light
1
brown oil. IR (CCl4, cm21): 1205, 1650, 3465. H NMR (CDCl3) d (ppm):
1.58 (3H, s), 1.65 (3H, s), 1.76 (3H, s), 2.01 (4H, m), 2.13 (3H, s), 3.33
(2H, d, J ¼ 6.6 Hz), 3.76 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 5.00–5.10
(2H, br), 5.63 (1H, s). 13C NMR (CDCl3) d (ppm): 11.3, 16.1, 17.6, 25.5,
25.6, 26.6, 39.7, 60.7, 61.1, 61.2, 117.5, 123.0, 124.3, 129.7, 131.3, 134.9,
137.7, 143.3, 143.5, 144.3. HR-MS (ES Q-TOF) calcd. for C20H30O4
(M þ Na)þ: 357.2042. Found: 357.2226.

398
P. Bovicelli et al.
5-Farnesyl-2,3,4-trimethoxy-6-methylphenol (12c)
Farnesyl ether 11c (180 mg, 0.45 mmol) dissolved in 3 mL of Et2O was
.
treated with BF3 Et2O (0.56 mL, 4.50 mmol) at room temperature. After
30 min, a saturated solution of NaCl (6 mL) was added, and the mixture
was extracted three times with EtOAc (6 mL). The combined extracts were
washed with brine until neutrality, dried over anhydrous Na2SO4, and
brought to dryness under a vacuum. Upon flash chromatography (9:1
hexane/EtOAc), the desired product (126 mg, 70%) was obtained as a
1
brown oil. IR (CCl4, cm21): 1200, 1650. H NMR (CDCl3) d (ppm): 1.58
(6H, br s), 1.67 (3H, s), 1.77 (3H, s), 1.90–2.10 (8H, m), 2.14 (3H, s), 3.33
(2H, d, J ¼ 6.6 Hz), 3.76 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 5.05–5.12
(3H, m), 5.64 (1H, s). 13C NMR (CDCl3) d (ppm): 11.3, 16.0, 16.2, 17.6,
25.5, 25.6, 26.6, 26.7, 39.7 (2C), 60.7, 61.1, 61.2, 117.5, 123.0, 124.1,
124.4, 129.2, 129.6, 131.2, 135.0, 137.7, 143.3, 143.5, 144.4. HR-MS (ES
Q-TOF) calcd. for C25H38O4 (M þ Na)þ: 425.2668. Found: 425.2724.
2,3,4-Trimethoxy-6-methyl-5-solanesylphenol (12d)
The solanesyl ether 11d (272 mg, 0.30 mmol) dissolved in 5 mL of Et2O was
.
treated with BF3 Et2O (0.4 mL, 3 mmol) at room temperature. After 30 min,
a saturated solution of NaCl (10 mL) was added, and the mixture was
extracted three times with EtOAc (10 mL). The combined extracts were
washed with brine until neutrality, dried over anhydrous Na2SO4, and freed
from the solvent under a vacuum. Flash chromatography (9:1 hexane/
EtOAc), allowed us to obtain the desired product (149 mg, 55%) as a dark
1
brown oil. IR (CCl4, cm21): 1210, 1600. H NMR (CDCl3) d (ppm): 1.60
(24H, s), 1.68 (3H, s), 1.77 (3H, s), 1.90–2.10 (32H, m), 2.13 (3H, s), 3.33
(2H, d, J ¼ 6.6 Hz), 3.75 (3H, s), 3.90 (3H, s), 3.93 (3H, s), 5.05–5.20
(9H, m), 5.60 (1H, s). 13C NMR (CDCl3) d (ppm): 11.3, 16.0 (br), 16.2, 17.6,
25.5, 25.6, 26.7 (br), 39.7 (br), 60.7, 61.1, 61.2, 117.5, 123.0, 124.1, 124.3
(br), 124.4, 129.6, 131.2, 134.9 (br), 135.0, 137.7, 143.3, 143.4, 144.4. HR-
MS (ES Q-TOF) calcd. for C55H86O4 (M þ Na)þ: 833.6424. Found: 833.6520.
Ubiquinone Q1 (13a)
A solution of 12a (225 mg, 0.85 mmol) in EtOH (2 mL) was diluted with
water (10 mL), and an excess of FeCl3 (8.5 mmol) was added. The mixture
was stirred at room temperature for 2 h and then extracted with three
portions of EtOAc (10 mL). The organic extracts were pooled and washed
with three portions of brine (5 mL) to give CoQ1 as a pure product
(220 mg, .97%). Physicochemical data are in agreement with the
literature.[13]

New Efficient Synthesis of Ubiquinones
Ubiquinone Q2 (13b)
399
A solution of 12b (336 mg, 1 mmol) in EtOH (2 mL) was diluted with water
(10 mL), and an excess of FeCl3 (10 mmol) was added. The mixture was
stirred at room temperature for 2 h and then extracted with three portions of
EtOAc (10 mL). The organic extracts were combined and washed with
three portions of brine (5 mL) to give CoQ2 as a pure product (320 mg,
.95%). Physicochemical data are in agreement with the literature. (The
obtained compound was compared with an authentic sample purchased
from Sigma-Aldrich Co.).
Ubiquinone Q3 (13c)
A solution of 12c (272 mg, 0.68 mmol) in EtOH (1.5 mL) was diluted with
water (7 mL), and an excess of FeCl3 (6.8 mmol) was added. The mixture
was stirred at room temperature for 2 h and then extracted with three
portions of EtOAc (10 mL). The organic extracts were combined and
washed with three portions of brine (5 mL) to give CoQ3 as a pure product
(253 mg, 93%). Physicochemical data are in agreement with the literature.[15]
Ubiquinone Q9 (13d)
A solution of 12d (360 mg, 0.48 mmol) in a 1:1 mixture of EtOH and i-PrOH
(1 mL) was diluted with water (10 mL), and an excess of FeCl3 (4.8 mmol)
was added. The mixture was stirred at room temperature for 2 h, then
extracted with three portions of EtOAc (10 mL). The combined organic
extracts were washed with three portions of brine (5 mL) to give CoQ9 as a
pure product (325 mg, 90%). Physicochemical data are in agreement with
the literature.[16]
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