A novel and convenient synthesis of coenzyme Q1

Article abstract of DOI:10.1081/SCC-200036578

A convenient and efficient synthetic route to Coenzyme Q₁ (6) starting from 3,4,5-trimethoxytoluene (1) is described. The key features of this synthesis include the Diels-Alder reaction of 2,3-dimethoxy-1,4-benzoquinone (3) with cyclopentadiene and the introduction of a C₅ side chain to 4,5-dimethoxy-2-methyltricyclo[6.2.1.0^2,7]undeca-4,9-diene-3,6-dione (4) under mild conditions, (6) was obtained in overall 60% yield.

Full text of DOI:10.1081/SCC-200036578

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A Novel and Convenient
Synthesis of Coenzyme Q
1
a
a
Liang Lu & Fener Chen
a
Department of Chemistry , Fudan University ,
20 Handan Road, Shanghai, 200433, P.R. China
2
Published online: 10 Jan 2011.
To cite this article: Liang Lu & Fener Chen (2004) A Novel and Convenient Synthesis
of Coenzyme Q , Synthetic Communications: An International Journal for Rapid
1
Communication of Synthetic Organic Chemistry, 34:22, 4049-4053, DOI: 10.1081/
SCC-200036578
To link to this article: http://dx.doi.org/10.1081/SCC-200036578
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 22, pp. 4049–4053, 2004
A Novel and Convenient Synthesis of
Coenzyme Q1
*
Liang Lu and Fener Chen
Department of Chemistry, Fudan University, Shanghai, P.R. China
ABSTRACT
1
A convenient and efficient synthetic route to Coenzyme Q (6) starting
from 3,4,5-trimethoxytoluene (1) is described. The key features of this
synthesis include the Diels–Alder reaction of 2,3-dimethoxy-l,4-benzo-
quinone (3) with cyclopentadiene and the introduction of a C
5
side chain
to 4,5-dimethoxy-2-methyltricyclo[6.2.1.0 ]undeca-4,9-diene-3,6-dione
4) under mild conditions, (6) was obtained in overall 60% yield.
2
,7
(
Key Words: Coenzyme Q ; Diels–Alder reaction; Synthesis.
1
Coenzyme Q (6) is an important fragment of Coenzyme Q series which
1
function in the electron transport and oxidative phosphorylation processes in
[1]
mitochondria. Besides its bioactivities, it also acts as a key intermediate in
*
Correspondence: Fener Chen, Department of Chemistry, Fudan University, 220
Handan Road, Shanghai 200433, P.R. China; E-mail: rfchen@fudan.edu.cn.
4
049
DOI: 10.1081/SCC-200036578
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4
050
Lu and Chen
[2]
the synthesis of higher homologs. There have been several attempts to
[2–4]
prepare (6).
However, none of them is attractive enough for the large-
scale synthesis of (6) due to the drawbacks such as the use of some expensive,
severe reaction conditions, tedious chromatography separation, etc. Therefore,
a convenient and practical method for the synthesis of (6) is still in demand.
Herein we described a novel and practical synthesis of (6) which used a
Diels–Alder approach to activate the free quinoid position for alkylation
(Scheme 1).
Treatment of 3,4,5-trimethoxytoluene (1) with POCl in DMF at 808C for
3
[
.5 hr afforded aldehyde (2) in 96% yields. In the presence of p-TsOH, (2)
5]
1
was oxidized with 30% H O , without separation, and the resulting mixture
[
6]
2
2
was oxidized with Na Cr O at r.t. to afford benzoquinone (3) as red needle
2
2 7
crystals.
The Diels–Alder reaction of (3) with cyclopentadiene in CH Cl failed.
However the yield is almost quantitative when the above reaction performed
[7]
2
2
2
,7
in acetic acid. It is known that 4,5-dimethoxy-2-methyltricyclo[6.2.1.0 ]un-
deca-4,9-diene-3,6-dione (4) could be converted into enolate by potassium
tert-butoxide in Et O or THF at low temperatures. Then C 22 C bond for-
2
mations with various alkenyl bromides at the free bridgehead position could
[7]
proceed. Our attempts to obtain 2-(3-methyl-2-butenyl)-4,5-dimethoxy-7-
2
,7
methyltricyclo[6.2.1.0 ]undeca-4,9- diene-3,6-dione (5) via the similar con-
ditions resulted in moderate yield. After many trials, we established optimal
conditions for this condensation. Best yield (93%) of the desired product (5)
Scheme 1. Reagents and conditions: (a) POCl
i)30%H , p-TsOH, 308C., 2 hr. ii) Na Cr , r.t., 1 hr, 70%. (c) CH
pentadiene, r.t., 6 hr, 99%. (d) 60% NaH, 1-bromo-3-methyl-2-butene, THF, 08C, 6 hr,
3%. (e) 858C 3 hr, 98%.
3
, DMF, 808C, 1.5 hr, 96%. (b)
2
O
2
2
2
O
7
3
COOH, cyclo-
9

A Convenient Synthesis of Coenzyme Q1
4051
was obtained when NaH (1.2 eq) was used as the base (Table 1). After thermal
elimination of (5), Coenzyme Q was obtained in overall 60% yield.
1
In conclusion, this method has the advantages of mild conditions, easily
accessible starting materials and easiness of separation. It can be a promise
method for the industrial synthesis of Coenzyme Q and it should provide a
1
general method for synthesizing higher homologs.
EXPERIMENTAL
Melting points were measured on an WRS-1B digital melting point appar-
atus without correction. Infra red spectra (IR) were recorded on an Avvatar
1
60 FT-IR instrument. HNMR spectra were recorded with a Bruker
3
DMX500 (500 MHz). Chemical shifts (d) were expressed in ppm with the pro-
tonated solvent as reference. Mass spectra (MS) were recorded on MAT95 and
for the electronic impacts (EI) at 70 eV.
2
,3,4-Trimethoxy-6-methylbenylaldehyde (2)
To a stirred solution of 3,4,5-trimethoxytoluene (100 g, 0.549 mol) in
DMF (100 mL), POCl (94.5 g, 0.6 mol) was added dropwise at 40–508C
3
over a period of 1 hr. The reaction mixture was stirred at 808C for another
1
.5 hr. After being cooled to r.t., the reaction mixture was adjusted to
PH ¼ 7 with 10% aq. NaOH. The precipitate was collected by filtration,
dried to give (2) (110.7 g, 96%) as a white solid.
[
5]
21
1
m.p: 60–618C (lit. 61–61.58C). IR: 1686 cm
.
d, 3H), 3.89 (s, 9H), 7.20 (s, 2H), 9.90 (s, 1H). MS (m/z): 210 (M ).
HNMR: d 2.02
þ
(
Table 1. Summary of the results obtained from the condensation between (4) and
1-bromo-3-methyl-2-butene under the conditions indicated.
Reaction condition
Ratio of
4 : base
Yields of
products (%)
Base
Solvent
Et
Temp.
Time (hr)
t-BuOK
t-BuOK
t-BuOK
1 : 1.1
1 : 1.1
1 : 1.2
1 : 1.1
1 : 1.1
1 : 1.2
2
O
2708C–408C
2408C–208C
2408C–208C
08C
2
66
67
73
81
84
93
THF
THF
1.5
1.5
6
60%NaH
60%NaH
60%NaH
2
Et O
THF
THF
08C
08C
6
6

4
052
Lu and Chen
2
,3-Dimethoxy-l,4-benzoquinone (3)
To a stirred solution of (2) (40 g, 0.204 mol), p-TsOH (13.3 g, 0.08 mol) in
methanol (150 mL), 30% H O (19.2 mL, 0.245 mol) was added dropwise at
2
2
3
additional 2 hr. Then Na Cr O (26 g, 0.1 mol) in water (100 mL) was added
08C over a period of 45 min. The reaction mixture was stirred at 308C for
2
2 7
dropwise at r.t. over 30 min. After stirring for another 1 hr at r.t., the reaction
mixture was extracted with petroleum ether (50 mL ꢀ 3). The combined
organic phase was washed with brine (30 mL ꢀ 3) and dried over Na SO , fil-
2
4
tered, and evaporated to dryness in vacuo to give (3) (26 g, 70%) as red
needles.
[
8]
21
1
m.p: 56–588C (lit.
57–588C). IR: 1671, 1655 cm
500 MHz, CDCl ): d 2.04 (d, 3H), 3.99 (s, 3H), 4.00 (s, 3H), 6.40 (q, 1H);
,
HNMR
(
EI-MS (m/z): 182 (M ).
3
þ
2
,7
4
,5-Dimethoxy-2-methyltricyclo[6.2.1.0 ]undeca-4,
-diene-3,6-dione (4)
9
To a stirred solution of (3) (14.1 g, 0.077 mol) in AcOH (30 mL) was
added freshly distilled cyclopentadiene (7.2 g, 0.109 mol) and the reaction
mixture was stirred at r.t. for 6 hr until the red color has disappeared. The
resulting mixture was neutralized with 10% aq.NaOH, extracted with ethyl
acetate (50 mL ꢀ 3). The combined organic phase was washed with brine
(
30 mL ꢀ 3) and dried over Na SO , filtered, and evaporated to dryness in
2
4
vacuo to give (4) (19 g, 99%) as a yellow oil.
21 1
IR: 1665 cm . HNMR (500 MHz, CDCl ): d 1.48 (s, 3H), 1.54, 1.56,
3
1
.66, 1.67 (AB-System, 2H), 2.80 (d, 1H), 3.08 (m, 1H), 3.42 (m, 1H), 3.91
þ
(
s, 3H), 3.94 (s, 3H), 6.01 (dd, 1H), 6.16 (dd, 1H); EI-MS (m/z): 248 (M ).
2
-(3-Methyl-2-butenyl)-4,5-Dimethoxy-7-methyltricyclo
[
2
6.2.1.0 ]undeca-4,9-diene-3,6-dione (5)
,7
To a stirred solution of (4) (17.1 g, 0.069 mol) in dry THF (50 mL), at 08C,
0%NaH (4.13 g, 0.103 mol) was added in portions. Stirring was continued for
0 min at 08C, then 1-bromo-3-methyl-2-butene (12.32 g, 0.103 mol) in THF
6
3
(
10 mL) was added dropwise at 08C over 30 min. The reaction mixture was
stirred at 08C for another 6 hr and then poured into cooled water (100 mL),
extracted with ethyl acetate (50 mL ꢀ 3). The combined organic layer was
washed with brine (30 mL ꢀ 3) and dried over Na SO , filtered, and evaporated
2
4
to dryness in vacuo to give (5) (20.3 g) as a yellow oil in 93% yield.

A Convenient Synthesis of Coenzyme Q1
4053
21 1
IR: 2983, 1663 cm . HNMR (500 MHz, CDCl ): d 1.45–1.47 (d, 1H),
3
1
2
.50 (s, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.77–1.79 (d, 1H), 2.39–2.43 (m, 1H),
.72–2.77 (m, 1H), 3.01–3.09 (d, 2H), 3.87 (s, 3H), 3.91 (s, 3H), 5.07–5.10
þ
(t, 1H), 6.04–6.07 (t, 2H). EI-MS (m/z): 316 (M ).
Coenzyme Q (6)
1
(
0.01 bar) for 3 hr. The residue was chromatographed on silica gel using
5) (21.8 g, 0.069 mol) was heated with stirring at 858C in vacuo
(
hexane-ethyl acetate (6 : 1) to afford Coenzyme Q (17.2 g, 98%) as a red oil.
1
21 1
IR: 2946, 1655 cm . HNMR (500 MHz, CDCl ): d 1.67 (s, 3H), 1.74
3
(
s, 3H), 2.02 (s, 3H), 3.17 (d, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 4.89 (t, 1H).
þ
EI-MS (m/z): 250 (M ).
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1
. (a) Wolstenholme, G.E.W.; O’Connor, C.M. Ciba Foundation Symposium
on Quinones in Electron Transport; J. & E. Churchill: London, 1961;
b) Wagner, A.F.; Folkers, K. Vitamins and Coenzymes; Interscience:
(
New York, 1964; 435; (c) Morton, R.A. Biochemistry of Quinones;
Academic Press: New York, 1965.
2. Terao, S.; Kato, K.; Shiraishi, M.; Morimoto, H. Synthesis of ubiqui-
nones.2. An efficient preparation of ubiquinone-10. J. Org. Chem. 1979,
4
4 (5), 868.
3
. Sato, K.; Inoue, S.; Yamaguchi, R. A new synthesis of Coenzyme Q1.
J. Org. Chem. 1972, 37 (12), 1889.
4
. Shunk Clifford, H.; Linn Bruce, O.; Wong Emily, L.; Wittreich Paul, E.;
Robinson Franklin, M.; Folkers Karl. Synthesis of 6-farnesyl- and
6
-phytyl-derivatives of 2,3-dimethoxy-5-methylbenzoquinone and related
analogs. J. Amer. Chem. Soc. 1958, 80 (17), 4753.
. JP49080031, 1972.
5
6
. Baruah Robindra, N. Preparation of methoxyphenols by oxidation of meth-
oxybenzaldehydes with hydrogen peroxide in presence of p-toluenesulpho-
nicm. Ind. J. Chem. 1994, 33B, 1103.
7
. Merz Andreas; Rauschel Manfred. Synthesis of crown ethers related to
ubiquinones. Synthesis 1993, 797.
8
. Sato, K.; Inoue, S.; Sato, H. The synthesis of 2,3-dimethoxy-5-methyl-p-
benzoquinone. Bull Chem. Soc. Jpn. 1972, 45, 3455.
Received in Japan May 24, 2004