Synthesis of the key intermediate of coenzyme Q10

Article abstract of DOI:10.3390/molecules16054097

(2′E)-1-(3-methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4, 5-tetramethoxybenzene (4) is the key intermediate in the synthesis of coenzyme Q10via a coupling reaction with solanesyl bromide. In this paper, we report a simple and effective synthesis of

Full text of DOI:10.3390/molecules16054097

Molecules 2011, 16, 4097-4103; doi:10.3390/molecules16054097
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of the Key Intermediate of Coenzyme Q10
Fan-Song Mu 1,2,†, Meng Luo 1,2,†,*, Yu-Jie Fu 1,2, Xuan Zhang 1,2, Ping Yu 1,2 and Yuan-Gang Zu 1,2,
*
1
Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University,
Harbin 150040, China; E-Mails: fansong2006@126.com (F.-S.M.);
fuyujie1967@yahoo.com.cn (Y.-J.F.); 350330842@163.com (X.Z.); yup2010@163.com (P.Y.)
2
Engineering Research Center of Forestry Bio-preparation, Ministry of Education,
Northeast Forestry University, Harbin 150040, China
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: wslm_5555@yahoo.com.cn (M.L.);
zygorl@vip.hl.cn (Y.-G.Z.); Tel.: +86-451-8219-0535; Fax: +86-451-8219-0535.
Received: 24 March 2011; in revised form: 9 May 2011 / Accepted: 9 May 2011 /
Published: 18 May 2011
Abstract: (2’E)-1-(3-methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4,5-tetramethoxybenzene
(4) is the key intermediate in the synthesis of coenzyme Q10 via a coupling reaction with
solanesyl bromide. In this paper, we report a simple and effective synthesis of compound 4,
starting with the readily available and inexpensive precursors p-toluenesulfonyl chloride
(TsCl) and isoprene to obtain (2E)-1-p-toluenesulfonyl-2-methyl-4-hydroxy-2-butene (3)
by addition, esterification and hydrolysis. Application of the Friedel-Crafts alkylation to
compound 3, followed by the addition of 2,3,4,5-tetramethoxytoluene (TeMT), assembled
the two parts into compound 4. The key parameters of each reaction were optimized at the
same time, and the four total operations needed to produced compound 4 had a 27.9%
overall yield under the optimized conditions. The structures of the compounds were
characterized by 1H-NMR, IR and MS. This alternative process has the potential to be used
for large-scale process.
Keywords:
p-toluenesulfonyl
chloride;
isoprene;
2,3,4,5-tetramethoxytoluene;
(2’E)-1-(3-methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4,5-tetramethoxybenzene

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1. Introduction
Coenzyme Q10 (CoQ10), consisting of a benzoquinone group and an isoprenoid chain, is a
fat-soluble quinonoid compound that plays a pivotal role in several metabolic sequences. It exists in
the mitochondria of every cell and participates in the electron transport process for respiration, thus
producing energy for living organisms. It has also been used to treat heart-related diseases and has
been used to enhance the immune system [1,2]. There is an increasing need for an efficient preparative
method for this substance because of its remarkable physiological and clinical activity. A great deal of
attention has been paid to CoQ10 since 1959. Over the years, researchers have put forward several
semisynthetic strategies, most of which employ the side-chain extending method [3-7]. Using
solanesol as a reagent for the synthesis of the all-trans isoprene side-chain of CoQ10 via coupling with
quinone derivatives is a potentially valuable production method. Solanesol can readily be obtained by
extraction from the leaves of tobacco or potato. However, its industrial application is still hampered by
the lack of an efficient method for the preparation of quinone derivatives, which are the key
intermediate of CoQ10. Therefore, a highly effective synthesis of quinone derivatives is important.
In particular, very promising key synthetic intermediates of CoQ10 have been developed. In 1979,
Terao and co-workers demonstrated an efficient route to CoQ10 using a sulfone-functionalized
prenylhydroquinone [8]. However, the stereoselective synthesis of the former component requires
multistep procedures. Fujita et al. reported a new method that produces the phenyl sulfone side-chain
via a Grignard reaction [9]. This multistep sequence forms the rather expensive key intermediate of
CoQ10; however, the process still needs to be improved for industrial applications. A better procedure
was proposed by Min et al. in 2003, who synthesized the key intermediate of CoQ10 via a
Friedel-Crafts alkylation reaction, which greatly simplified the synthetic route [10]. However, this
reaction required long reaction times and produced only low yields. New methods, such as those
involving chloromethylated CoQ0 and ionic liquid, have been introduced into the synthesis of the key
intermediate of CoQ10; however, these methods are still industrially inapplicable [11-13].
Here, we report a simple and effective synthesis of the key intermediate of CoQ10 (Scheme 1). The
synthesis begins with the readily available and inexpensive precursors p-toluenesulfonyl chloride
(TsCl) and isoprene to produce (2E)-1-p-toluenesulfonyl-2-methyl-4-hydroxy-2-butene (3) by addition,
esterification and hydrolysis. The Friedel-Crafts alkylation was then applied to compound 3, followed
by the addition of 2,3,4,5-tetramethoxytoluene (TeMT), which assembles the two parts into
(2’E)-1-(3-methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4,5-tetramethoxybenzene (4). Compound 4
is the key intermediate for the synthesis of CoQ10 via a coupling reaction with solanesyl bromide.
2. Results and Discussion
2.1. Synthesis of Compound 1
The reaction between isoprene and TsCl was catalyzed by copper (I) chloride-triethylamine
hydrochloride at 90 °C for 6 h. Isoprene should be added with acetonitrile under a nitrogen atmosphere
because it is highly volatile. The cocatalyst Et3N·HCl and the catalyst CuCl formed a CuCl alkyl amine
salt, which caused the mixture to be a homogenous solution and inhibited the formation of
dehydrochloride as a reaction product. After some exploratory experiments, we found suitable

Molecules 2011, 16
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conditions (TsCl and CuCl) for a successful reaction (Table 1). The highest yield of compound 1 was
achieved when the MTsCl:MCuCl ratio was 1:0.15. However, the subsequent separation of compound 1
became more difficult with increasing amounts of CuCl. The optimal conditions for the formation of
compound 1 were MTsCl:Misoprene:MCuCl:MEt3N·HCl = 1:1.8:0.15:0.15, heated at 90 °C for 6 h to produce
compound 1 with a 75.9% yield.
Scheme 1. Synthesis of the key intermediate of CoQ10.
O
S
O
S
a)
Cl
b)
Cl
O
O
1
O
S
O
S
O
CH3
OH
c)
O
O
O
3
2
OCH3
OCH3
H3CO
H3CO
CH3
H3CO
H3CO
d)
3
+
O
S
OCH3
OCH3
O
4
Reagents and conditions: (a): isoprene, copper (I) chloride (CuCl), triethylamine hydrochloride
(Et3N·HCl), 90 °C, 75.9%; (b): NaOAc, glacial acetic acid, 120 °C, 90.7%; (c): MeOH, 20% Na2CO3,
0 °C, 68.8%; (d): 2,3,4,5-tetramethoxytoluene (TeMT), 1,2-dichloroethane, boron trifluoride etherate
(BF3·OEt2), 80 °C, 58.8%.
Table 1. Effect of CuCl on the yield of compound 1.
Number
CuCl / g
Yield / %
1
0.052
-
2
3
4
5
6
0.105
58.6
0.157
75.9
0.209
75.0
0.313
70.4
0.522
68.8
2.2. Synthesis of Compound 2
Compound 1 and anhydrous sodium acetate were added to glacial acetic acid, and then the mixture
was heated to the selected temperature. It should be noted that this reaction is quite sensitive to
temperature. Five groups of experiments were carried out, and the results are summarized in Table 2.
The maximum yield of compound 2 was achieved when the reaction temperature reached 120 °C.
Dehydrochloride was formed when the temperature was increased to 125 °C and 130 °C. The
optimized conditions found were Mcompound 1:MNaOAc = 1:1.8, heated at 120 °C for 5 h, which produced
the desired compound 2 with a 90.7% yield. Furthermore, the product of this step can be used directly
in the next reaction without any purification.
Table 2. Effect of reaction temperature on the yield of compound 2.
Number
Temperature / °C
Yield / %
1
110
53.3
2
115
72.0
3
120
90.7
4
125
80.4
5
130
62.6

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2.3. Synthesis of Compound 3
Compound 2 was dissolved in methanol and cooled down to 0 °C, then 20% sodium carbonate
solution was added dropwise. Here, the addition time is an important factor in carrying out this step
successfully. Sodium carbonate solution (20% sodium carbonate) must be added dropwise over 2 h;
otherwise, the reaction will terminate if the addition time is too short. However, the yield of compound
3 did not change much when the addition time was within 2–3 h. Therefore, the optimal conditions
were Mcompound 2:MNa2CO3 = 1:1.6, 20% Na2CO3 added dropwise over 2 h at 0–5 °C, then reacted for 3 h
to produce compound 3 with a 68.8% yield.
Table 3. The effect of the addition time of 20% sodium carbonate solution on the yield of compound 3.
Number
Na2CO3 adding time / h
Yield / %
1
0.5
20.1
2
1
43.4
3
1.5
52.8
4
2
68.8
5
2.5
68.7
6
3
68.7
2.4. Synthesis of Compound 4
Compound 4 was prepared by coupling 2,3,4,5-tetramethoxytoluene with compound 3 via a Friedel-
Crafts reaction. The reaction of compound 3 with boron trifluoride etherate in 1,2-dichloroethane forms the
corrersponding carbocation, then it attacks benzene to form a δ-complex. Finally, it loses a proton to form
alkyl derivatives. Obviously, boron trifluoride etherate is an important factor for the synthesis of compound
4. The color of the reactants sequentially changed from a light yellow, clear liquid to an orange and maroon
color. From trial combinations of the precursor compound 3 and the catalyst boron trifluoride etherate
(Table 4), the best results were obtained in the case of MTeMT:Mcompound 3:MBF3·OEt2 = 1:1.2:0.3. With a slow
increase of temperature to 80 °C and continuous stirring for 8 h, the yield of compound 4 rose to 58.8%.
Table 4. Effect of boron trifluoride etherate on the yield of compound 4.
Number
BF3·OEt2 / mL
Yield / %
1
0.06
-
2
0.12
32.2
3
0.18
58.8
4
0.24
44.8
5
0.3
29.4
3. Experimental
3.1. General
All regents were analytical-grade chemicals and commercially available. The IR spectra were
1
recorded with KBr pellets on a Nicolet Magna-560 spectrophotometer. The H-NMR spectra were
recorded on a Bruker Avance-300 MHz instrument using CDCl3 as the deuterated solvent and TMS as
the internal standard. Mass spectra were measured on an API-3000 LC/MS-MS (ESI).
3.2. (2E)-1-p-Toluenesulfonyl-2-methyl-4-chloride-2-butene (1)
TsCl (2 g, 10.499 mmol), CuCl (0.1567 g, 1.575 mmol) and Et3N·HCl (0.2165 g, 1.575 mmol) were
mixed in four-neck round-bottom flask. A mixture of isoprene (1.89 mL, 18.9 mmol) and MeCN (4.2 mL)

Molecules 2011, 16
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was added, and the reactant was stirred at 90 °C under a nitrogen atmosphere for 6 h. After completion,
methanol (2 mL) was added to the mixture, which was cooled down to room temperature, then stirred
and cooled to 0 °C, recrystallized and filtered to yield a deep yellow power. It was then dissolved in
ethyl alcohol (1:2, m/v), cooled to 0 °C, filtered, dried under vacuum and recrystallized to produce
1
compound 1 as white crystals with a yield of 75.9%. H-NMR (CDCl3) δ (ppm): 1.87 (s, 3H, CH3),
2.45 (s, 3H, CH3–Ph), 3.74 (s, 2H, CH2–SO2), 3.98 (d, 2H, J = 7.9 Hz, CH2–Cl), 5.32 (t, 1H, J = 7.9 Hz,
=CH), 7.34 (d, 2H, J = 8.1 Hz, H–Ph), 7.73 (d, 2H, J = 8.1 Hz, H–Ph). IR (KBr), υ (cm−1): 2974, 2922,
1918, 1665, 1597, 1421, 1294, 1258, 1180, 1170, 1134, 1086, 890, 813, 752, 670, 629, 595, 543, 515,
483. MS (m / z): 281.3 [M + Na]+, 301.6 [M + MeOH]+.
3.3. (2E)-1-p-Toluenesulfonyl-2-methyl-4-acetoxy-2-butene (2)
Compound 1 (2 g, 7.737 mmol) and anhydrous sodium acetate (1.1424 g, 13.927 mmol) were added
into a three-neck round-bottom flask, and glacial acetic acid (22.5 mL) was added. The mixture was
then reacted at 120 °C for 5 h. After 5 h, the mixture was evaporated under reduced pressure to recycle
2/3 of the glacial acetic acid after the completion of the reaction. An appropriate amount of saturated
sodium bicarbonate was added to the mixture to adjust the pH to 4. The mixture was then extracted
with ethyl acetate (1:1, v/v) three times and evaporated under vacuum to obtain a faint yellow, oily
liquid which was subjected to column chromatography over silica gel eluting with petroleum ether and
1
ethyl acetate (5/1, v/v) to produce compound 2 in 90.7% yield as white crystals. H-NMR (CDCl3)
δ (ppm): 1.84 (s, 3H, CH3), 2.02 (s, 3H, CH3–OAc), 2.46 (s, 3H, CH3–Ph), 3.74 (s, 2H, CH2–SO2),
4.99 (d, 2H, J = 6.8 Hz, CH2–OAc), 5.26 (t, 1H, J = 6.8 Hz, =CH), 7.34 (d, 2H, J = 8.1 Hz, H–Ph),
7.73 (d, 2H, J = 8.1 Hz, H–Ph). IR (KBr), υ (cm−1): 2975, 2923, 1732, 1597, 1372, 1307, 1298, 1270,
1235, 1131, 1170, 1131, 1086, 1026, 817, 747, 595, 539, 514, 486. MS (m / z): 305.1 [M + Na]+, 321.4
[M + K]+, 587.4 [2M + Na]+.
3.4. (2E)-1-p-Toluenesulfonyl-2-methyl-4-hydroxy-2-butene (3)
Compound 2 (2 g, 7.080 mmol) was dissolved in MeOH (12 mL) in a three-neck round-bottom
flask, which was cooled down to 0 °C. Then, 20% Na2CO3 (6 mL, 11.327 mmol) was added dropwise
over 2 h at 0 °C and stirred continuously for 3 h. The reaction was filtered and concentrated under
reduced pressure after completion and extracted three times with ethyl acetate (1:1, v/v). The
combined organic extraction was washed with water, dried over anhydrous sodium sulfate and
evaporated under a reduced pressure to give an oily crude product. The crude was then dissolved in a
suitable amount of ether, stirred and recrystallized at room temperature to isolate a white powder. The
white powder was dissolved in petroleum ether by heating, then cooled to room temperature,
recrystallized and filtered. This process was repeated until no other products could be detected by TLC.
The product was dried under vacuum to produce compound 3 as a white solid with a yield of 68.8%.
1H-NMR (CDCl3) δ (ppm): 1.32 (s, 1H, OH), 1.82 (s, 3H, CH3), 2.45 (s, 3H, CH3–Ph), 3.73 (s, 2H,
CH2–SO2), 4.11 (d, 2H, J = 6.3 Hz, CH2–OH), 5.33 (t, 1H, J = 6.3 Hz, =CH), 7.35 (d, 2H, J = 8.1 Hz,
H–Ph), 7.74 (d, 2H, J = 8.1 Hz, H–Ph). IR (KBr), υ (cm−1): 3365, 2975, 2923, 1597, 1311, 1142, 1087,
1009, 817, 733, 677, 587, 537. MS (m / z): 263.4 [M + Na]+, 279.2 [M + K]+, 503.2 [2M + Na]+.

Molecules 2011, 16
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3.5. (2’E)-1-(3-Methyl-4-p-toluenesulfonyl-2-butene)-6-methyl-2,3,4,5-tetramethoxymethylbenzene (4)
2,3,4,5-Tetramethoxytoluene (TeMT, 1 g, 4.717 mmol) and compound 3 (1.3585 g, 5.660 mmol)
were dissolved in 1,2-dichloroethane (10 mL). BF3·OEt2 (0.18 mL, 1.415 mmol) was then added, and
the temperature was slowly increased to 80 °C. The reaction was allowed to proceed for 8 h. NH4Cl
solution was added to the mixture after the completion of the reaction, and the reaction product was left
standing to separate the organic phase and the water phase. The organic layers were washed with 5%
HCl, brine and distilled water in sequence, then dried over anhydrous sodium sulfate, filtered and
concentrated under a reduced pressure to reveal a yellow, oily product. The oily residue was purified by
silica gel column chromatography using petroleum ether and ethyl acetate (10/1, v/v) as the eluent to
afford compound 4 as a white solid in 58.8% yield. 1H-NMR (CDCl3) δ (ppm): 1.94 (s, 2H, CH2–SO2),
1.99 (s, 3H, CH3), 2.40 (s, 3H, CH3–Ph), 3.25 (d, 2H, J = 6.3 Hz, CH2–Ph), 3.69–3.91 (m, 15H,
OCH3 × 4–Ph, CH3–Ph), 4.92 (t, 1H, J = 6.3 Hz, =CH), 7.23 (d, 2H, J = 8.1 Hz, H–Ph), 7.66 (d, 2H,
J = 8.1 Hz, H–Ph). IR (KBr), υ (cm−1): 2976, 2933, 1597, 1470, 1406, 1352, 1312, 1162, 1132, 1109,
1087, 1069, 1040, 965, 892, 742, 623, 581, 532, 510. MS (m / z): 435.3 [M + H]+, 457.1 [M + Na]+, 452.4
[M + NH4]+, 891.5 [2M + Na]+.
4. Conclusions
In the present study, we have developed a simple and effective method for the synthesis of
compound 4, the key intermediate of CoQ10. The key parameters of each reaction were also optimized
and the overall yield of compound 4 was 27.9% under the optimized conditions (calculated based on
TsCl). The success of this approach is presumably due to the stabilization provided by a
p-phenylsulfonyl group in compound 3 in the presence of Lewis acids. The E-configuration of the C=C
bond was mostly retained in compound 4 after the Friedel-Crafts reaction. Furthermore, this method
produced the key intermediate of CoQ10 from the relatively inexpensive precursor isoprenol, which is
more economical than expanding the expensive natural nonaprenyl compound, solanesol, by an
isoprene unit before coupling it to the CoQ10 precursor. The present process has the potential to be
used for large-scale process.
Acknowledgments
The authors gratefully acknowledge the financial supports by Agricultural Science and Technology
Achievements Transformation Fund Program (2009GB23600514), Special Fund of Forestry Industrial
Research for Public Welfare of China (201004040), Project for Distinguished Teacher Abroad,
Chinese Ministry of Education (MS2010DBLY031), Heilongjiang Province Science Foundation for
Excellent Youths (JC200704), Natural Science Foundation of Heilongjiang Province (C200933), Key
Program for Science and Technology Development of Harbin (2009AA3BS083), Fundamental
Research Funds for the Central Universities (DL09BA30, DL09BB49, DL09EA04), and Northeast
Forestry University Fund for Young Scholars (No.07021).

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Sample Availability: Samples of the compounds are available from the authors.
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