Preparation of key intermediates for the syntheses of coenzyme Q10 and derivatives by cross-metathesis reactions

Article abstract of DOI:10.3390/molecules25030448

An alternative catalytic strategy for the preparation of benzylmethacrylate esters, key intermediates in the synthesis of coenzyme Q10 and derivatives, was reported. This strategy avoided undesirable stoichiometric reduction/oxidation processes by utilizi

Full text of DOI:10.3390/molecules25030448

molecules
Article
Preparation of Key Intermediates for the Syntheses of
Coenzyme Q10 and Derivatives by
Cross-Metathesis Reactions
Trang Nguyen 1, Hung Mac 2,* and Phong Pham 1,
*
1
Laboratory of Catalysis at Faculty of Chemistry, VNU University of Science, Vietnam National University,
Hanoi 110403, Vietnam; nguyentrang2484@gmail.com
Laboratory of Medicinal Chemistry of Faculty of Chemistry, VNU University of Science,
Vietnam National University, Hanoi 110403, Vietnam
2
*
Correspondence: macdinhhung@gmail.com (H.M.); phvpham@hus.edu.vn (P.P.); Tel.: +84-963398889 (P.P.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 11 December 2019; Accepted: 21 January 2020; Published: 21 January 2020
Abstract: An alternative catalytic strategy for the preparation of benzylmethacrylate esters,
key intermediates in the synthesis of coenzyme Q10 and derivatives, was reported. This strategy
avoided undesirable stoichiometric reduction/oxidation processes by utilizing the catalytic formation
of allylarenes and then cross-metathesis to selectively form E-benzylmethacrylate esters with good
yields (58–64%) and complete E-selectivity. The ester intermediates were reduced to common key
benzylallylic alcohols (90–92% yield), which were subsequently used in the formal syntheses of
coenzyme Q10 and one derivative.
Keywords: coenzyme Q10; solanesol; claisen rearrangement; stille coupling; cross-metathesis.
1. Introduction
Coenzyme Q10
respiring eukaryotic cells [
syntheses of this compound [
(
1
), an isoprenylated quinone, is a critical electron-transfer compound found in all
]. The demand for commercial coenzyme Q10 calls for efficient artificial
11]. The frame of coenzyme Q10 can be viewed as a combination of
1–3
4–
terpenyl and aromatic fragments. Therefore, the simplest terpenyl moiety from solanesol, found in
tobacco leaves, and the common aromatic moiety benzylallyl alcohol (2c) were utilized to build up
coenzyme Q10 molecule [11]. In particular, previous studies [11] have utilized a Friedel–Craft allylation
of a quinol derivative with 2-methylbut-3-en-2-ol followed by a series of oxidation/reduction reactions
to achieve the desired target (2c). Alcohol (2c) was then used in transformations with the solanesyl
bromide obtained from the bromination of solanesol to achieve coenzyme Q10 (Scheme 1). This strategy
served as the framework for the synthesis of coenzyme Q10 based on the terpenyl chain from solanesol.
However, the preparation of the iso-pentenylated quinol in the reported work unexpectedly
required an additional reduction step. Re-examining the transformation, we found that quinone, the
oxidized form of the desired iso-pentenylated quinol, was in fact the major product in an inseparable
mixture of the two compounds. Indeed, upon exposure to air, all the amount of expected quinol was
oxidized to its corresponding quinone after 45 min. A similar unexpected oxidation was also observed
by the Hecht group [12]. This result led to an undesirable stoichiometric reduction step being added to
the synthesis. The iso-pentenylated quinol was stoichiometrically oxidized by SeO2 to aldehyde, not
alcohol, and therefore required an extra reduction step to obtain the benzylallyl alcohol (2c). The whole
procedure to prepare the aromatic moiety was, therefore, accompanied by unenviable stoichiometric
oxidation/reduction reactions. With the advantages of known catalytic processes, we anticipated that
suitable catalytic transformations such as Claisen rearrangement, Stille coupling, and cross-metathesis
could offer additional strategies and allow for catalytic access of coenzyme Q10 and derivatives.
Molecules 2020, 25, 448; doi:10.3390/molecules25030448
www.mdpi.com/journal/molecules

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Scheme 1. A previous stoichiometric approach to coenzyme Q10 through benzylallyl alcohol (2c).
Design Plan
We hypothesized that extra reduction/oxidation steps for preparing benzylallyl alcohol (2c) quinol
were required because the previous research used readily oxidizable quinol, and unfunctionalized
iso-pentenyl group. We envisioned that allyarene (
available aryl bromides ( ) by Stille coupling. This allylarene could then undergo a cross-metathesis
reaction with the methyl methacrylate to offer the desired E-cross-metathesis products [13 16], which
could be further reduced to the key synthetic intermediate benzyl alcohols ( ). This catalytic strategy
7) (Scheme 2) could be prepared from commercially
3
–
2
would allow for alternative access to common key intermediates in the syntheses of coenzyme Q10
and derivatives.
Scheme 2. Our catalytic approach to benzylallyl alcohols (2).
2. Results and Discussion
To examine the proposed idea, five allylated arenes (7a
synthesized either from commercially available aryl bromide
(path ) [20 24]. (Scheme 3) The Stille coupling of corresponding (MeO)2 aryl bromides with
allyltributylstannane directly afforded allylarenes 7b and 7e with high yields (75%–78%). Diacetate
allylarenes 7a and 7d were prepared from corresponding quinol derivatives ( ). First, quinols 4(a and d)
–
e) were prepared. These allylarenes were
3
(path ) [17 19] or monoacetylquinol
A
–
4
B
–
–c
4
were allylated to provide allyl ethers 5a (84%), and 5b (82%), which then participated in the Claisen
rearrangement to furnish allylated quinols 6a (78%) and 6d (55%). Allylated quinols 6a and 6d were
then acetylated with Ac2O to afford 7a (59% overall yield) and 7d (41% overall yield).
Next, the cross-metathesis of allylated arenes with methyl methacrylate was studied. The results
are shown in Table 1. Initially, the cross-metathesis reaction of 7a was carried out in neat methyl
methacrylate (Table 1, Entry 1). However, only a trace amount of the desired product was obtained.
The reaction was then conducted in dichloromethane with a ratio of one equivalent of allylarene 7a
and five equivalents of methyl methacrylate. In this case, we mostly obtained the homo-coupling of
allyarene (Table 1, Entry 2). Increasing the amount of methyl methacrylate to 20 equivalents, we were
able to isolate desired the product 8a with 56% yield and exclusive E-configuration based on NOESY
NMR spectroscopy analysis. This result was consistent with the previous studies [13
–16]. The reaction
condition was also applied to allylarenes 7b . All cross-metathesis reactions generated desired E
–
e

Molecules 2020, 25, 448
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isomers with moderate to good yields (8b
–e, 58–65% yields) providing the key intermediates for the
syntheses of coenzyme Q10 and derivatives (8a–e).
Scheme 3. Preparation of allylarenes.
Table 1. Cross-metathesis products.
Entries
Allylarene
Allyl Ester
Yields (%)
1
2
3
inseparable mixture a
Dimer b
7a
56% (all E) c
4
5
6
7
7b
61% (all E) c
58% (all E) c
64% (all E) c
64% (all E) c
7c
7d
7e
a
The reaction was conducted using methyl methacrylate as solvent at 50 ◦C; b methyl methacrylate, 5.0 equivalent,
CH2Cl2, refluxed; c methyl methacrylate, 20 equivalent, dichloromethane, refluxed.
We then reduced esters 8b,c,e by LiAlH4 to corresponding alcohols 2b,c,e with very good yields
(90%–92% yield) (Scheme 4). These alcohols could be used in well-established synthetic paths to
furnish coenzyme Q10 [25] (from 2c) and its derivatives.

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Scheme 4. Reduction of allylesters.
Synthesis of a Coenzyme Q10’s Derivative
Following a similar procedure for the formal synthesis of coenzyme Q10
[
25], we obtained
derivative 12 from the corresponding key alcohol (2b) (Scheme 5). First, the alcohol (2b) was converted
into allyl bromide ( ) (crude yield: 90%). The bromide ( , without purifying) was then treated with
9
9
PhSO2Na to obtain the phenylsulfinate (10: 62%). The sulfinate (10) was then subjected to an allylation
event with solanesyl bromide in the presence of tBuOK to form 11 with a moderate yield (58%). Finally,
0
the de-sulfination of 11 afforded the coenzyme Q10 s derivativate (12: 43%)
Scheme 5. Synthesis of coenzyme Q10 derivative (12).
3. Materials and Methods
3.1. General Information
Commercial reagents were purified prior to use following the guidelines of Perrin and
Armarego [26]. All solvents were redistilled before using. Reactions under N2 atmosphere were
performed with a Schlenk apparatus or simple dry-box (Laboratory build, Hanoi, Vietnam). Organic
solutions were concentrated under reduced pressure on a Büchi rotary evaporator using an ice-water
bath for volatile compounds. Chromatographic purification of products was accomplished by flash
chromatography on silica gel according to the method of Still [27]. Thin-layer chromatography (TLC)
was performed on Merk silica gel plates. Visualization of the developed chromatogram was performed
by fluorescence quenching, p–anisaldehyde, ceric ammonium molybdate, or potassium permanganate
stains. 1H and 13C NMR spectra were recorded on a Bruker Advance–III 500 (500 and 125 MHz)
instrument (Bruker Corp., Billerica, MA, USA) in the Faculty of Chemistry, VNU University of Science,
Vietnam National University, Hanoi, Vietnam, and were internally referenced to residual protic solvent
signals (note: CDCl3 referenced at d 7.27 and 77.0 ppm respectively). 13C NMR spectra were recorded
in J-MOD (J-modulated spin-echo) mode, which were the combination of 13C and DEPT without
1
losing quaternary 13C signals. Data for H NMR are reported as follows: chemical shift (
δ
ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, h = heptet, m = multiplet, b = broad),
integration, coupling constant (Hz), and assignment. Data for 13C NMR are reported in terms of
chemical shift and multiplicity; no special nomenclature has been used for equivalent carbons. The

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IR spectrum (Supplementary Materials) of alcohol
4
was recorded on the Shimadzu FTIR Affinity-1S
(Shimadzu Corp., Kyoto, Japan) in the Department of Inorganic Chemistry, Faculty of Chemistry, VNU
University of Science, Vietnam National University and has been reported in terms of frequency of
absorption. High-resolution mass spectra were obtained via ESI method on Agilent 6530 Accurate-Mass
Q-TOP LC/MS (Agilent Technonogy Inc., Santa Clara, CA, USA) in the Institute of Marine Biochemistry,
Vietnam Academy of Science and Technology Hanoi, Vietnam.
3.2. General Procedure for Allylation Reaction
NaH (0.78 g, 32.5 mmol) was slowly added to the solution of phenol (16 mmol) in DMF (60 mL) at
0 ◦C under an N2 atmosphere. The reaction mixture was stirred vigorously for 30 min to evaporate the
gas in solution. After that, allyl bromide (2.18 mL, 25.2 mmol) was slowly added to the reaction flask
and refluxed at 40 ◦C for 12 h. The mixture was poured into ice-water and extracted with ethyl acetate.
The organic layer was washed with brine, dried over Na2SO4, and evaporated under vacuum. The
residue was purified via flash column chromatography with silica gel as the stationary phase (0%–2%
ethyl acetate/n-hexane) to yield the titular allyl aryl ether.
4-(Allyloxy)-2,3,6-trimethylphenyl acetate (5a): clear oil, 84% yield. IR (film) 2976, 2918, 2864, 1759,
1744, 1599, 1584, 1404, 1357, 1211, 1161, 1111, 1084, 937, 895, 839, 768, 745 cm–1; 1H NMR (500 MHz,
CDCl3)
δ 6.58 (s, 1H), 6.14–6.02 (m, 1H), 5.44 (dq, J = 17.3, 1.7 Hz,1H), 5.28 (dq, J = 10.5, 1.5 Hz, 1H),
4.50 (dt, J = 5.0, 1.6 Hz, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz,
CDCl3)
δ 169.5, 154.2, 141.8, 133.8, 129.8, 127.1, 124.3, 116.9, 111.6, 69.4, 20.6, 16.7, 13.1, 12.1; HRMS
(ESI) exact mass calculated for [M + H]+ (C14H19O3) requires m/z 235.1334, found m/z 235.1329.
4-(allyloxy)-2-methylnaphthalen-1-yl acetate (5d): clear oil, 82% yield. IR (film) 3073, 2918, 2862, 1759,
1744, 1632, 1599, 1506, 1462, 1404, 1356, 1269, 1202, 1159, 1111, 1084, 937, 895, 839, 768, 745 cm–1; 1H
NMR (500 MHz, CDCl3)
m, 1H), 6.65 (s, 1H), 6.20–6.14 (m, 1H), 5.53 (dd, J = 17.3, 1.5 Hz, 1H), 5.34 (dd, J = 6.8, 1 Hz, 1H),
4.70 (d, J 5.1 Hz, 2H), 2.46 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, CDCl3)
169.6, 152.3, 137.8, 133.2,
δ 8.26 (d, J 8.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.52–7.48 (m, 1H), 7.45–7.42
(
δ
127.9, 127.2, 126.3, 124.9, 122.6, 120.6, 117.6, 107.7, 69.3, 20.7, 16.9; HRMS (ESI) exact mass calculated for
[M + H]+ (C16H17O3) requires m/z 257.1178, found m/z 257.1172.
3.3. General Procedure for Claisen Rearrangement
A solution of allyl aryl ether (11 mmol) in 1,2-dichlorobenzene (50 mL) was stirred for 24 h at
180 ◦C under an N2 atmosphere. The mixture was purified by column chromatography with silica gel
as the stationary phase (0%–5% ethyl acetate/n-hexane) to yield the titular allylphenol.
3-allyl-4-hydroxy-2,5,6-trimethylphenyl acetate (6a): yellow solid, 78% yield, mp = 119–120 ◦C. IR
1
3485, 2924, 1728, 1639, 1574, 1458, 1365, 1300, 1225, 1192, 1070, 993, 905 cm–1; H NMR (500 MHz,
CDCl3)
δ 6.01–5.88 (m, 1H), 5.11–5.02 (m, 2H), 4.79 (s, 1H), 3.41 (dt, J = 10.0, 3 Hz, 2H), 2.34, (d, J = 0.5 Hz,
2H), 2.15 (s, 5H), 2.05 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ
169.8, 150.1, 141.8, 135.5, 127.6, 126.4, 121.7,
121.4, 116.1, 31.5, 20.7, 13.3, 12.8, 12.3; HRMS (ESI) exact mass calculated for [M + H]+ (C14H19O3)
requires m/z 235.1334, found m/z 235.1329.
3-allyl-4-hydroxy-2-methylnaphthalen-1-yl acetate (6d):
mp = 117–118 ◦C. IR 3485, 3441, 3063, 2976, 2924, 1726, 1634, 1595, 1574, 1454, 1389, 1364, 1290,
1233, 1080, 1047, 1015, 982, 914, 768, 737 cm–1; 1H NMR (500 MHz, CDCl3)
8.11 (d, J = 7.5 Hz, 1H),
light yellow crystal, 55% yield,
δ
7.66 (d, J = 7.6 Hz, 1H), 7.49–7.43 (m, 2H), 6.07–6.00 (m, 1H), 5.36 (s, 1H), 5.17 (dq, J = 10.1, 1.6 Hz,
1H), 5.11 (dq, J = 18.9, 1.7 Hz, 1H), 3.59 (dt, J = 5.6, 1.7 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 3H); 13C NMR
(125 MHz, CDCl3)
δ 169.7, 147.7, 138.4, 135.0, 126.7, 126.5, 126.5, 125.3, 124.0, 121.7, 120.8, 118.2, 116.7,
31.4, 20.8, 13.5; HRMS (ESI) exact mass calculated for [M + H]+ (C16H17O3) requires m/z 257.1178,
found m/z 257.1172.

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3.4. General Procedure for Acetylation
Acetic anhydride (1 mL, 10 mmol) was added to the mixture of allylphenol (5 mmol) and pyridine
◦
(10 mL) at 0 C under an N2 atmosphere. After that, 4-dimethyl pyridine (0.15 g, 1 mmol) was
added as catalyst. The reaction mixture was stirred for 1 h at room temperature. After completion,
the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed
with water, saturate aqueous CuSO4 and brine, dried over Na2SO4, and evaporated under vacuum.
The residue was purified by column chromatography with silica gel as the stationary phase (0%–5%
ethyl acetate/n-hexane) to yield the titular allyl ester.
2-allyl-3,5,6-trimethyl-1,4-phenylene diacetate (7a): light yellow crystal, 90% yield, mp = 108–109 ◦C.
IR 3458, 3074, 2976, 2927, 1728, 1639, 1573, 1460, 1366, 1225, 1192, 1070, 993, 905, 860, 827, 706, 683 cm–1;
1H NMR (500 MHz, CDCl3)
(bd, J = 39.5 Hz, 2H), 2.34 (s, 3H), 2.31 (s, 3H), 2.06 (b, 6H, 2C
CDCl3)
δ
5.81–5.76 (m, 1H), 5.00 (dq, J = 10.1, 1.6, 1H), 4.94 (dd, J = 17.1, 1H), 3.27
3), 2.04 (s, 3H); 13C NMR (125 MHz,
H3CO),
H
δ
169.1 (b, 2 × C=O), 145.8, 145.6, 134.9, 128.4, 127.9, 127.7, 127.6, 127.4, 115.7, 31.8 (b, 2
C
20.5, 13.3, 12.7; HRMS (ESI) exact mass calculated for [M + Na]+ (C16H20NaO4) requires m/z 299.1259,
found m/z 299.1257.
Our above NMR data for prepared compound (7a) were comparable with the NMR data of
1
2-allyl-1,4-diacetoxy-3,5,6-trimethylbenzen in Reference [28]: H NMR (90 MHz, CDCl3)
δ 5.7–5.9
(
m, 1H), 5.0 (d, J = 11, 1 H), 4.94 (d, J = 18, 1H), 3.28 (br s, 2H), 2.32 and 2.34 (s, 6H), 2,04 and 2,06
(s, 9H) 168.90, 168.70, 145.97, 145.72, 134.97, 128.47, 127.92, 127.53, 127.36, 115.4, 31.78,
;
13C NMR
δ
20.42, 20.29, 13.07, 12.47.
2-allyl-3-methylnaphthalene-1,4-diyl diacetate (7d): brown solid, 90% yield, mp = 107–108 ◦C. IR
3069, 2982, 2928, 2870, 1753, 1639, 1599, 1427, 1354, 1198, 1169, 1092, 1049, 1011, 895, 773, 742 cm–1; 1H
NMR (500 MHz, CDCl3)
δ 7.72–7.71 (m, 1H), 7.67–7.65 (m, 1H), 7.48–7.46 (m, 2H), 5.91–5.86 (m, 1H),
5.06 (dq, J = 10.2, 1.6, 1H), 4.99 (dq, J = 17.1, 1.7, 1H), 3.48 (b, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H);
13C NMR (125 MHz, CDCl3)
δ
169.6 (2 × C=O) 142.9, 142.8, 134.7, 128.4, 127.1, 126.7, 126.6, 126.5, 126.3,
121.6, 121.4, 116.3, 32.1, 20.9, 20.8, 13.2. HRMS (ESI) exact mass calculated for [M + H]+ (C18H19O4)
requires m/z 299.1283, found m/z 299.1282.
3.5. General Procedure for Stille Coupling
Bromoaryl (1.0 mmol), (PPh3)2PdCl2 (0.025 mmol) allylSnBu3 (1.1 mmol), and PPh3 (0.1 mmol)
◦
were dissolved in DMF (10 mL), and then the mixture was heated at 110 C for 4 h under an N2
atmosphere. The reaction mixture was diluted with H2O, extracted five times with Et2O, and the
combined extracts were dried over Na2SO4 and evaporated under vacuum. The residue was purified
by column chromatography with silica gel as the stationary phase (10%–20% ethyl acetate/n-hexane) to
yield the titular allylated arene.
1-allyl-2,5-dimethoxy-3,4,6-trimethylbenzene (7b): clear oil, 75% yield. IR (film) 2994, 2936, 2845,
1638, 1558, 1454, 1383, 1223, 1084, 1038, 1002, 937, 837, 758 cm–1; 1H NMR (500 MHz, CDCl3)
δ
5.97–5.92
(m, 1H), 5.00 (dq, J = 10.0, 1.9 Hz, 1H), 4.90 (dq, J = 17.5, 2.0 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 3H), 3.43
(
dt, J = 4.0 Hz, 1.7 Hz, 2H), 2.19 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 153.2, 153.0, 136.9, 129.3, 128.9,
128.2, 128.1, 114.9, 61.2, 60.3, 31.4, 12.9, 12.8, 12.0; HRMS (ESI) exact mass calculated for [M + H]+
(C14H21O2) requires m/z 221.1542, found m/z 221.1537.
1-allyl-2,3,4,5-tetramethoxy-6-methylbenzene (7c): clear oil, 75% yield. IR (film) 2934, 2829, 1728,
1638, 1464, 1404, 1350, 1292, 1257, 1196, 1105, 1036, 1009, 978, 908, 871, 743 cm–1; 1H NMR (500 MHz,
CDCl3)
δ 5.93–5.86 (m, 1H), 5.00 (dd, J = 10.1, 1.4 Hz, 1H), 4.91 (dd, J = 17.1, 1.6 Hz, 1H), 3.91 (s, 3H),
3.90 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.38 (d, J = 5.8 Hz, 2H), 2.14 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ
147.9 (2 × C-OMe), 145.4, 144.8, 136.7 (–
CH=CH2), 127.0, 125.8, 114.9 (=CH2), 61.4, 61.3, 61.2, 60.8,
31.0, 11.7; HRMS (ESI) exact mass calculated for [M + H]+ (C14H21O4) requires m/z 253.1440, found
m/z 253.1436.
2-allyl-1,4-dimethoxy-3-methylnaphthalene (7e): off-white crystal, 78% yield, mp = 83–84 ◦C. 1H
NMR (500 MHz, CDCl3) δ 8.09–8.04 (m, 2H), 7.49–7.45 (m, 2H), 6.08–6.00 (m, 1H), 5.05 (dq, J = 10.2,

Molecules 2020, 25, 448
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1.8 Hz, 1H), 4.91 (dq, J = 17.2, 1.9 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.64 (dt, J = 5.5, 1.9 Hz, 2H), 2.39
(s, 3H); 13C NMR (125 MHz, CDCl3)
δ 150.3, 150.2, 136.7, 128.6, 127.9, 127.3, 125.7, 125.4, 122.5, 122.2,
115.2, 62.5, 61.5, 31.4, 12.4; HRMS (ESI) exact mass calculated for [M + H]+ (C16H19O2) requires m/z
243.1385, found m/z 243.1380.
Our above NMR data for prepared compound (7e) were comparable with the NMR data of
compound
5 δ 8.40–8.25 (m, 2H), 7.82–7.76 (m, 2H),
in Reference [29]: 1H NMR (80 MHz, CDCl3)
6.50–6.00 (m, 1H), 5.40–4.98 (m, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 3.85 (d, J = 6, 2H), 2.62 (s, 3H).
3.6. General Procedure for Key Cross Metathesis Reaction
Methyl methacrylate (200.0 mg, 2.0 mmol) and allylarene (0.1 mmol) were dissolvent in
dichloromethane (100 mL), and Grubbs 2nd (42.1 mg, 0.05 mmol) was added. The reaction mixture
was refluxed for 24 h at 40 ◦C under an N2 atmosphere. The mixture was then concentrated under
vacuum and the residue was purified by column chromatography with silica gel as the stationary
phase (5%–10% ethyl acetate/n-hexane) to yield the titular key ester intermediate. The E- configuration
of the cross-coupling products was determined by NOESY NMR spectroscopy analysis.
(E)-2-(4-methoxy-3-methyl-4-oxobut-2-en-1-yl)-3,5,6-trimethyl-1,4-phenylene diacetate (8a): clear oil,
56% yield. IR (film) 2927, 2926, 1740, 1639, 1495, 1445, 1373, 1238, 1045, 935, 878, 841, 731 cm–1; 1H
NMR (500 MHz, CDCl3)
(
δ
6.58 (td, J = 6.8, 1.4 Hz, 1H), 3.69 (s, 3H), 3.36 (b, 2H), 2.35 (s, 3H), 2.31
168.4, 168.2,
s, 3H), 2.06 (s, 3H), 2.04 (s, 6H), 1.96 (d, J = 1.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ
146.1, 145.7, 139.5, 128.7, 128.3, 127.9, 127.4, 112.9, 51.9, 27.6, 20.7, 20.6, 13.4 (d), 13.0, 12.8; HRMS (ESI)
exact mass calculated for [M + H]+ (C19H25O6) requires m/z 349.1651, found m/z 349.1646.
Methyl (E)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methylbut-2-enoate (8b): clear oil, 61% yield. IR
(film) 2916, 2849, 1719, 1649, 1458, 1402, 1300, 1259, 1244, 1206, 1132, 1080, 1059, 997, 802, 743 cm–1;
1H NMR (500 MHz, CDCl3)
d, J = 6.9 Hz, 2H), 2.19 (s, 6H), 2.17 (s, 3H), 2.01 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ
6.69 (td, J = 7.0, 1.0 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H), 3.53
168.7, 153.3,
(
δ
152.9, 141.3, 129.3, 129.1, 128.3, 127.9, 127.5, 61.0, 60.3, 51.8 27.1, 12.9, 12.8, 12.7, 12.5; HRMS (ESI) exact
mass calculated for [M + H]+ (C17H25O4) requires m/z 293.1753, found m/z 295.1750.
Methyl (E)-2-methyl-4-(2,3,4,5-tetramethoxy-6-methylphenyl)but-2-enoate (8c): clear oil, 58% yield. IR
(film) 2918, 2849, 1719, 1649, 1458, 1400, 1300, 1259, 1244, 1206, 1132, 1080, 1059, 999, 802, 741 cm–1; 1H
NMR (500 MHz, CDCl3)
δ
6.64 (t, J = 6.9 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.70
168.7, 148.1,
(s, 3H), 3.48 (d, J = 7.0 Hz, 2H), 2.13 (s, 2H), 2.00 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ
147.9, 145.8, 144.9, 140.8, 127.5, 126.5, 125.6, 61.3, 61.2, 61.1, 60.9, 51.9, 29.8, 12.7, 12.0; HRMS (ESI) exact
mass calculated for [M + H]+ (C17H25O6) requires m/z 325.1651, found m/z 325.1547.
(E)-2-(4-methoxy-3-methyl-4-oxobut-2-en-1-yl)-3-methylnaphthalene-1,4-diyl diacetate (8d): clear oil,
64% yield. IR (film) 2981, 2907, 1736, 1699, 1597, 1446, 1371, 1300, 1234, 1157, 1097, 1043, 937, 846,
785 cm–1; 1H NMR (500 MHz, CDCl3)
δ 7.73–7.71 (m, 1H), 7.69–7.67 (m, 1H), 7.51–7.47 (m, 2H), 6.67
(
td, J = 6.8, 1.4 Hz, 1H), 3.69 (s, 3H), 3.58 (b, 2H), 2.49 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H), 2.02 (d, J = 1.1 Hz,
3H); 13C NMR (125 MHz, CDCl3)
δ
169.4, 168.3 (2 × C=OCH3), 142.9, 142.8, 138.9, 128.6, 128.1, 126.9,
126.8, 126.7, 126.5, 126.3, 121.6, 121.4, 51.9, 27.8, 20.8, 20.7, 13.4, 12.9; HRMS (ESI) exact mass calculated
for [M + H]+ (C21H23O6) requires m/z 371.1495, found m/z 371.1489.
Methyl (E)-4-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-2-methylbut-2-enoate (8e): clear oil, 64% yield.
IR (film) 2982, 2939, 1736, 1699, 1597, 1447, 1371, 1300, 1234, 1098, 1043, 937, 847, 785 cm–1; 1H NMR
(500 MHz, CDCl3)
(
δ 8.07–8.03 (m, 2H), 7.50–7.46 (m, 2H), 6.74 (t, J = 6.8 Hz, 1H), 3.88 (s, 3H), 3.87
s, 3H), 3.73 (d, J = 6.9 Hz, 2H), 3.70 (s, 3H), 2.36 (s, 3H), 2.07 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ
168.6, 150.4, 150.3, 140.7, 128.4, 128.1, 128.0, 127.3, 126.5, 125.9, 125.7, 122.4, 122.3, 62.4, 61.6, 51.9, 27.7,
12.9, 12.8; HRMS (ESI) exact mass calculated for [M + H]+ (C19H23O4) requires m/z 315.1596, found
m/z 315.1592.

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3.7. General Procedure for the Reduction of Cross Metathesis Products
To a stirred solution of ester 6c (325.1 mg, 6.0 mmol) in anhydrous diethyl ether (10 mL) was
added dropwise a suspension of LiAlH4 in dry THF at 0 ◦C. The reaction was allowed to warm to room
temperature until completion as indicated by TLC (4 h). The reaction mixture was quenched at 0 ◦C by
addition of water (2 mL) and aq sodium hydroxide (20%, 1 mL). The workup was continued by the
further addition of water (10 mL) and aq sodium hydroxide (20%, 10 mL). The mixture was stirred for
30 min, after which the mineral solid precipitate was filtrated and washed with diethyl ether (40 mL).
The residue was purified by column chromatography with silica gel as the stationary phase (5–10%
ethyl acetate/n-hexane) to yield alcohol 4 (266.6 mg, 90% yield) as a clear and colorless viscous oil.
(E)-4-(2,5-dimethoxy-3,4,6-trimethylcyclohexa-1,5-dienyl)-2-methylbut-2-en-1-ol (2b): clear oil, 92%.
IR (film) 3435, 2954, 2927, 2870, 1724, 1641, 1456, 1400, 1375, 1248, 1148, 1082, 1006, 804, 765 cm–1;
1H NMR Spectrum (500 MHz, CDCl3): 5.36 (t, J = 6 Hz, 1H), 4.00 (s, 1H), 3.65 (s, 3H), 3.64 (s, 3H),
3.41 (d, J = 6 Hz, 2H), 2.19 (s, 3H), 2.18 (s, 6H); 13C NMR Spectrum (125 MHz, CDCl3): 153.29, 152.92,
134.92, 130.93, 128.79, 128.21, 127.79, 125.22, 69.10, 61.01, 60.30, 26,08, 14.10, 12.98, 12.89, 12.43; HRMS
(ESI) exact mass calculated for [M + H]+ (C16H25O3) requires m/z 265.1804, found m/z 265.1802.
(E)-2-methyl-4-(2,3,4,5-tetramethoxy-6-methylphenyl)but-2-en-1-ol (2c): clear oil, 90% yield. IR (film)
1
3414, 2931, 2860, 1463, 1406, 1350, 1257, 1193, 1103, 1050, 1005, 970, 871 cm–1; H NMR (500 MHz,
CDCl3)
(
δ
5.34 (t, J 6.7 Hz, 1H), 4.00 (s, 2H), 3.90 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.37
148.0, 147.8,
H3O), 60.7, 25.6, 14.0, 11.9; HRMS (ESI) exact
d, J = 6.7 Hz, 2H); 2.14 (s, 2H), 1.83 (d, J = 1.3 Hz, 3H). 13C NMR (125 MHz, CDCl3)
δ
145.3, 144.8, 134.8, 128.4, 125.2, 124.6, 69.0, 61.3, 61.2 (b, 2
mass calculated for [M + H]+ (C16H25O5) requires m/z 297.1702, found m/z 297.1701.
C
Our above IR and NMR data for prepared alcohol (2c) were comparable with the IR and NMR
data of alcohol
1013 cm–1; 1H NMR (400 MHz, CDCl3)
3.70 (3H, s), 3.29 (2H, dd, J = 6.8, 0.8 Hz), 2.07 (3H, s), 1.76 (3H, s), 13C NMR (100 MHz, CDCl3)
147.72, 145.19, 144.75, 134.68, 128.29, 125.23, 124.52, 68.83, 61.02, 60.99, 60.63, 25.51, 13.81, 11.76.
6
in Reference [25]: IR (CHCl3) 3432, 2935, 2862, 1466, 1407, 1351, 1219, 1105, 1067, 1039,
5.26 (1H, m), 3.93 (2H, s), 3.83 (3H, s), 3.82 (3H, s), 3.72 (3H, s),
147.93,
δ
δ
(E)-4-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-2-methylbut-2-en-1-ol (2e
)
:
clear oil, 91%. IR 3397,
1659, 1597, 1454, 1379, 1366, 1263, 1159, 1066, 1037, 1007, 899, 758, 739 cm–1; H NMR Spectrum
(500 MHz, CDCl3): 8.05 (m, 2H), 7.59–7.36 (m, 2H), 5.54–5.31 (m, 1H), 4.02 (d, J = 5.1 Hz, 2H), 3.89
(s, 3H), 3.87 (s, 3H), 3.61 (dd, J = 6.6, 2 Hz), 2.38 (s, 3H), 1.89 (d, J = 0.9 Hz, 3H); 13C NMR Spectrum
(125 MHz, CDCl3): 150.42, 150.10, 135.55, 130.21, 127.83, 127.45, 126.82, 125.73, 125.56, 124.61, 122.47,
1
122.36, 68.98, 62.35, 61.52, 26.22, 14.19, 12.69;
HRMS (ESI) exact mass calculated for [M + H]+ (C18H23O3)
requires m/z 287.1647, found m/z 287.1645.
Our above NMR data for prepared ancol (2e) were comparable with the NMR data of compound
1
21 in Reference [30]: H NMR (400 MHz, CDCl3)
δ 8.07–8.02 (m, 2H), 7.48–7.44 (m, 2H), 5.43–5.41
(m, 1H), 4.02 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.61 (d, J = 6.5, 2H), 2.38 (s, 3H), 1.90 (d, J = 1.0, 3H)
3.8. Bromination of 2b
Alcohol 2b (5 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran and PBr3 (2.5 mmol)
was slowly added to the reaction at
5 ◦C for 15 min under an N2 atmosphere. After 2 h, the reaction
−
mixture was poured into cold saturated sodium bicarbonate solution and then extracted with ethyl
acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum.
The crude bromide 9 was used for the next reaction without purification.
3.9. General Procedure for the Sulfination
Bromide (9) (4 mmol) and sodium benzene sulphinate were dissolved in 25 mL dimethyl
formamide. The reaction mixture was stirred at room temperature for 12 h under an N2 atmosphere.
The mixture was then poured into ice-cold water, acidified to pH ~4 with 2N HCl and extracted with
ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under

Molecules 2020, 25, 448
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vacuum. The residue was purified by column chromatography with silica gel as the stationary phase
(0%–10% ethyl acetate/n-hexane) to yield the titular sulfonyl compound (10).
(E)-1,4-dimethoxy-2,3,5-trimethyl-6-(3-methyl-4-(phenylsulfonyl)but-2-enyl)benzene (10): white solid,
90% yield, mp = 186–187 ◦C
. IR 3065, 2938, 2847, 1587, 1447, 1400, 1350, 1302, 1292, 1248, 1165, 1132,
1082, 1055, 1009, 955, 901, 768, 743 cm–1; 1H NMR Spectrum (500 MHz, CDCl3): 7.83–7.75 (m, 2H), 7.53
(t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 4.97 (t, J = 6.4 Hz, 1H), 3.71 (s, 2H), 3.61 (s, 3H), 3.54 (s, 3H),
3.27 (d, J = 6.6 Hz, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H); 13C NMR Spectrum (125 MHz,
CDCl3): 138.49, 138.46, 136.71, 135.36, 135.12, 133.50, 129.00, 128.54, 128.19, 127.85, 127.57, 123.44,
66.23, 60.93, 60.29, 26.78, 17.16, 12.96, 12.87, 12.37; HRMS (ESI) exact mass calculated for [M + H]+
(C22H29O4S) requires m/z 389.1787, found m/z 389.1784.
3.10. General Procedure for the Solanesylation:
Sulfonyl (10) (0.50 mmol) and solanesol bromide (0.75 mmol) were dissolved in 10 mL of anhydrous
tetrahydrofuran. Solution of potassium tert-butoxide (0.75 mmol) in 5 mL anhydrous tetrahydrofuran
was added dropwise to the above solution containing sulfonyl and solanesol bromide at
25 ◦C. After
−
2 h, the reaction was allowed to reach room temperature and the stirring was continued for 12 h
under an N2 atmosphere. After completion, the mixture was poured into ice-water, acidified to pH ~4
with 2N HCl, and extracted with ethyl acetate. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography with
silica gel as the stationary phase (0%–5% ethyl acetate/n-hexane) to yield the titular compound.
1-((2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyl-4-(phenylsulfonyl)
tetraconta-2,6,10,14,18,22,26,30,34,38-decaenyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (11): clear oil, 43%.
IR (film) 3296, 3233, 2914, 2849, 1728, 1468, 1418, 1290, 1217, 1194, 1177, 1101, 1047, 991, 943, 719 cm–1;
1H NMR Spectrum (500 MHz, CDCl3): 7.77 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),
5.13–5.10 (m, 7H), 5.05 (t, J = 6.6 Hz, 1H), 4.97 (t, J = 5.9 Hz, 1H), 4.87 (t, J = 6.8 Hz, 1H), 3.60 (s, 3H),
3.48 (m, 4H), 3.30 (dd, J = 15.7, 6.9 Hz, 1H), 3.17 (dd, J = 15.4, 5.3 Hz, 1H), 2.86–2.77 (m, 1H), 2.68–2.56
(m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10–2.04 (m, 16H), 2.02–1.92 (m, 19H), 1.84 (s, 3H), 1.68 (s, 3H),
1.64–1.50 (s, 32H), 1.26 (s, 6H); 13C NMR Spectrum (125 MHz, CDCl3): 153.16, 152.68, 135.53, 135.09,
131.41, 130.04, 128.93, 128.86, 128.86,128.13, 127.68, 126.97, 124.63, 124.50, 124.36, 123.96, 118.84, 74.07,
60.89, 60.26, 39.91, 29.89, 26.77, 26.59, 25.87, 17.84, 16.50, 16.22, 12.93, 12.87, 12.31; HRMS (ESI) exact
mass calculated for [M + H]+ (C27H37O4S) requires m/z 457.2413, found m/z 457.2413.
3.11. General Procedure for the De-Sulfination
To a solution of 11 (0.1 mmol) in 5 mL anhydrous tetrahydrofuran was added ethanol (0.005 mol).
Sodium (1.5 mmol) pieces ware slowly added to the reaction mixture under vigorous stirring at room
temperature for 12 h under an N2 atmosphere. The reaction was then poured into ice-water and
extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and
evaporated under vacuum. The residue was purified by column chromatography with silica gel as the
stationary phase (0%–2% ethyl acetate/n-hexane) to yield the titular compound.
1-((2E,6E,10E,14E,18E,22E,26E,30E,34E)-3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-2,6,10,14,18,
22,26,30,34,38-decaenyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (12): clear oil, 41%. IR (film) 3103, 2989,
2936, 2626, 1587, 1510, 1450, 1400, 1300, 1246, 1169, 1130, 1246, 1169, 1130, 1082, 1053, 1002, 903, 822,
741 cm–1; 1H NMR Spectrum (500 MHz, CDCl3): 5.28–5.00 (m, 10H), 3.64 (s, 6H), 3.36 (d, J = 6.3 Hz
,
2H), 2.69 (m, 3H), 2.18 (s, 12H), 2.08(m, 22H), 2.06(m, 24H), 1.78 (s, 3H), 1.68 (s, 6H), 2.63–1.56 (m, 38H);
13C NMR Spectrum (125 MHz, CDCl3): 153.25, 152.90, 135.27, 135.22, 135.13, 135.08, 131.84, 128.43,
128.07, 127.94, 124.62, 124.46, 124.33, 123.46, 123.36, 61.06, 60.29, 40.38, 39.94, 39.89, 27.21, 26.97,
26.92, 26.82, 26.37, 25.88, 16.50, 16.21, 12.96, 12.89, 12.34, 12.21; HRMS (ESI) exact mass calculated for
[M + H]+ (C21H33O2) requires m/z 317.2481, found m/z 317.2478.

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4. Conclusions
In conclusion, we devised an alternative synthesis route of benzylallyl ester intermediates for
the preparation of coenzyme Q10 and its derivatives. The key features of this strategy were the use of
catalytic formation of allylarenes and cross-metathesis reactions to selectively prepare E-benzylallyl
esters. The resultant esters were reduced to benzylallylic alcohols on the pathway toward coenzyme
Q10 and derivatives. One alcohol was utilized to synthesize a coenzyme Q10 derivative.
Supplementary Materials: The following Supplementary material including NMR and IR spectra of new synthetic
compounds are available online.
Author Contributions: Data curation, T.N.; Funding acquisition, P.P.; Investigation, T.N. and H.M.; Project
administration, P.P.; Supervision, H.M.; Validation, H.M.; Writing—original draft, H.M.; Writing—review &
editing, P.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research is funded by the Vietnam National University, Hanoi (VNU) under project number
QG.16.10.
Acknowledgments: The authors thank Dong M. Le, Duyen. Th. Duong, Giang T.N. Le, Luong Vu for their
preparation of some known starting materials, and Ky Nguyen for proof reading the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).