Friedel-Crafts allylation of 2-(benzyloxy)-3,4,5-trimethoxytoluene catalysed by a metal trifluoromethanesulfonic salt: Synthesis of coenzyme Q10

Article abstract of DOI:10.3184/030823407X270338

In the presence of a catalytic amount of scandium triflate, 2-benzyloxy-3,4,5-trimethoxytoluene reacted with allylic derivatives 4, giving the key intermediate 3 (R = benzyl) which was used for preparing coenzyme Q10, in moderate to high yields.

Full text of DOI:10.3184/030823407X270338

686 RESEARCH PAPER
DECEMBER, 686–688
JOURNAL OF CHEMICAL RESEARCH 2007
Friedel–Crafts allylation of 2-(benzyloxy)-3,4,5-trimethoxytoluene
catalysed by a metal trifluoromethanesulfonic salt: synthesis of
coenzyme Q10
Yun-Feng Zhenga, Jing-Du Lina, Cheng-Ping Lib and Jing-Hua Lia*
aCollege of Pharmaceutical Sciences, Zhejiang University of Technology, 310032, P. R. China
bCollege of Biology and Environmental Engineering, Zhejiang Shuren University, 310015, P. R. China
In the presence of a catalytic amount of scandium triflate, 2-benzyloxy-3,4,5-trimethoxytoluene reacted with allylic
derivatives 4, giving the key intermediate 3 (R = benzyl) which was used for preparing coenzyme Q10, in moderate
to high yields.
Keywords: 2-(benzyloxy)-3,4,5-trimethoxytoluene, metal triflate, Friedel–Crafts allylation, coenzyme Q10
Coenzyme Q10 (1, also called ubiquinone), was discovered in
1957,1 and shown to function in mitochondria in the formation
of ATP. It has been found to be beneficial for a variety of
conditions,2,3 such as heart disease and Parkinson’s disease.
Because of those important effects, there have been
extensive synthetic efforts directed at this natural product.4-12
The key issue was the coupling of the quinone core generally
derived from inexpensive trimethoxytoluene and the
polyprenyl side chain derived from expensive solanesol.
An ideal synthesis would seek to not only minimise the extent
to which intermediates based on solanesol are manipulated
en route to Coenzyme Q10 but also improve its overall
yield. Recently, a new process for preparing Q10 (Scheme 1,
R = Me) was reported.13 Although the final step, oxidation of
2 (R = Me) with (NH4)2Ce(NO3)6, gave Q10 in low yield, the
whole process is an improvement.
Scheme 1 shows that 3 is a key compound in the synthesis
of coenzyme Q-10 (1). Fujita14 reported a method for the
preparation of 3 (R = Me) via copper-mediated coupling
of (E)-4-Chloro-2-methyl-1-phenylsulfonyl-2-butene with
the Grignard reagent of 2,3,4,5-tetramethoxytolyl bromide.
Compared to Fujita’s method, Friedel–Crafts reaction of 5
(R = alkyl) with 4 might be a simpler and more economical
way to synthesise 3 (Scheme 2), because 5 (R = alkyl) is a
good electron-rich substrate for the Friedel–Crafts reaction.
The Friedel–Crafts reaction was achieved by Min et al.
recently.13 However, the low values of E/Z isomeric ratio of
3 (R = Me) were not desirable (E/Z = 10/1). Based on the
potential of its industrial application, we sought the optimal
process for synthesising Q10. According to Scheme 1 and
the literature,15,16 in which Q0 was prepared quantitatively
by oxidation of 2-hydroxy-3,4,5-trimethoxytoluene in air, we
deduced that 2 (R = H), easily obtained starting from 3 (R =
Bn) via intermediate 2 (R = Bn), might produce Q10 in similar
way to Q0 in good yield (Scheme 1). The search for a more
effective method for preparation of 3 (R = Bn) is necessary.
Recently, it is found that a metal triflate, as an all-purpose
Lewis acid, was generally useful as an effective catalyst in
organic synthesis,17 such as in Aldol reaction,18,19 Mannich-
type reaction,20–24 Diels–Alder reaction25–27 and Friedel–
Crafts reaction.28–30 To the best of our knowledge, however,
metal triflate catalysed Friedel–Crafts allylation of 5 has not
been reported. We now report our investigation using metal
triflate as a catalyst (Scheme 2, R = Bn) with improved
value of E/Z ratio. Compound 5 (R = Bn) and compound 5
(R = Me), both of which were derived from 2-hydroxy-
3,4,5-trimethoxytoluene, are useful starting materials for
synthesising Q10. The former is better compared to the latter,
because at the final step in synthesising Q10, 2 (R = Bn) is
more readily transformed into 2 (R = H) which leads to 1
quantitatively.
Results and discussion
As a Lewis acid, metal triflate can catalyse the Friedel–Crafts
allylation of 5 (R = Bn) with 4 (X =Cl, Br) (Scheme 2).
The results are summarised in Table 1.
OR
OR
MeO
SO2Ph
Br
MeO
SO2Ph
H
9
MeO
OMe
MeO
H
9
OMe
3
6
OR
O
O
MeO
MeO
MeO
H
10 H
MeO
10
OMe
1
2
Scheme 1 The synthetic route of Coenzyme Q10 (1) from the compound 3.
* Correspondent. E-mail: lijh571@163.com
PAPER: 07/4946

JOURNAL OF CHEMICAL RESEARCH 2007 687
OR
OR
MeO
MeO
SO2Ph
MeO
SO2Ph
X
catalyst
MeO
OMe
OMe
5
4
3
4a, X = Cl 4b, X = Br
Scheme 2 Preparation of the compound 3 (R = Me, Bn) catalysed by metal triflate.
Table 1 Allylation of 5 (R = Bn) in the presence of metal
75% methanol–water solution, λ = 254 nm) was observed
when 4 (X = Br) and 5 (R = Bn) were coupled using Sc(OTf)3
as catalyst under condition A, and a pure product E-3 (R = Bn)
can be readily obtained by recrystallisation from methyl tert-
butyl ether. It was easy to separate the E-isomer of 3 (R = Bn)
from its Z-isomer, which is important and useful for industrial
application.
In addition, the recovery and recycling of metal triflate
were also investigated, and the results show that the reaction
proceeded smoothly with recovered Yb(OTf)3 With the key
compound 3 (R = Bn) to hand, we attempted the total synthesis
of coenzyme Q10 (1) (Scheme 3). Q10 (1) was easily prepared
by similar methods to those described in the literatures:3,15
(a) condensing 3b with solanesyl bromide, (b) treating the
resultant product 6b with LiHBEt3/Pd(dppp)Cl2 followed by
debenzylation with K/EtOH and oxidation with air.
triflates
Entry Allylation
reagent
Catalyst
(equiv)
Condition
Yield% of
E-3 (R = Bn)
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
AgOTf (0.5)
Cu(OTf)2 (0.5)
Y(OTf)3(0.5)
Gd(OTf)3(0.5)
Ce(OTf)3(0.5)
La(OTf)3(0.5)
Yb(OTf)3(0.1)
Yb(OTf)3(0.2)
Yb(OTf)3(0.5)
Sc(OTf)3(0.5)
Yb(OTf)3(0.5)
Sc(OTf)3(0.5)
Aa
Aa
Aa
Aa
Aa
Aa
Bb
Bb
Aa
Aa
Aa
Aa
NDc
32
51
54
62
66
40
52
78
81
80
83
3
4
5
6
7
8
9
10
11
12
aA: THF at reflux temperature for 12 h. bB: THF at reflux temperature
for 18 h. cNot detected.
Conclusion
The condition of the Friedel–Crafts allylation with 0.5
equiv of metal triflate in THF at reflux temperature for 12 h
(condition A in Table 1) was established according to our
preliminary study. The reaction also proceeded with a less than
stoichiometric amount of metal triflate (condition B in Table 1),
however, it required a longer reaction time and produced a
lower yield of E-3 (R = Bn).
From Table 1, a different effect of each metal triflate on
the yield of the coupling product E-3 (R = Bn) was noticed.
AgOTf was not a good catalyst for this coupling reaction.
There was no product E-3 (R = Bn) detected in the case of
AgOTf. Cu(OTf)2, Y(OTf)3, and Gd(OTf)3 etc. generally
produced low yields of the product E-3 (R = Bn). A good yield
of the E-isomer of the compound 3 (R = Bn) was obtained
in the case of Yb(OTf)3 and Sc(OTf)3. Note that Sc(OTf)3
consistently produced high yields of E-3 (R = Bn), where
the E/Z ratio of 15:1 was maintained. The best result (83%;
E/Z = 15:1, determined by external standard method of HPLC:
column VP-ODS 150 L ¥ 4.6, flow rate 0.8 ml/min, eluent
In conclusion, an efficient and convenient procedure for
Friedel–Crafts allylation was carried out using a metal
triflate as a catalyst under mild conditions with a simple
methodology. It offered an important method for Friedel–
Crafts allylation of 4 (R = Bn) in order to synthesise compound
3b, a key intermediate for preparing coenzyme Q10 and an
economical method for preparation of Q10 from 3b was
achieved (Scheme 3).
Experimental
Melting points are uncorrected. 1H NMR spectra were determined on
a Varian Plus 400 instrument using TMS as an internal standard and
CDCl3 as a solvent. IR spectra were recorded on a Perkin-Elmer 683
instrument. Mass spectra were obtained on anAEI MS-902 instrument
and ESI-MS was obtained with a Finnigan TSQ 700 instrument.
Procedure for synthesis of 3b
A solution of 2-(benzyloxy)-3,4,5-trimethoxytoluene 5 (R = Bn)
(1.0 mmol) and (E)-4-chloro-2-methyl-1-phenylsulfonyl-2-butene
4a (1.0 mmol) and Sc(OTf)3 (0.50 mmol) in dry THF (10 ml) was
refluxed for 12 h. The solution was concentrated under reduced
OBn
MeO
OBn
H
MeO
Br
9
SO Ph
2
t-BuOK/THF
MeO
O
H
MeO
SO Ph
2
9
OMe
OMe
6b
3b
MeO
MeO
K / EtOH
O2
LiHBEt3
Pd(dppp)Cl2
H
10
O
1
Scheme 3 Preparation of the Q10 (1) from the compound 3b (3, R = Bn); dppp: 1,3-bi(diphenylphosphino)propane
PAPER: 07/4946

688 JOURNAL OF CHEMICAL RESEARCH 2007
pressure and the residue was extracted twice with 1,2-dichloroethane
(10 ml) and filtered. The filtrate was evaporated under reduced
pressure to give a solid. The solid residue was further purified by
recrystallisation from methyl tert-butyl ether to give 3b (E) in 81%
isolated yield.
Received 17 November 2007; accepted 13 December 2007
Paper 07/4946
doi: 10.3184/030823407X270338
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7
8
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Preparation of Q10 (1)
To a mixture of 808 mg 6b and Pd(dppp)Cl2 (20 mg) in THF (8 ml)
was added dropwise LiHBEt3 in THF (1.94 ml 1 mol/l) at –30°C.
After stirring for 6 h, the whole reaction mixture was quenched with
0.8 ml water and concentrated under reduced pressure to 30% of its
original volume. The concentrated residue was treated with water
(8 ml), extracted with petroleum ether (2 ¥ 2.5 ml), washed with
water (2 ml), dried over anhydrous MgSO4 and concentrated under
reduced pressure to give a sticky residue (700 mg). The residue was
mixed with ethanol (2 ml) and dry THF (25 ml) and K (450 mg)
at –40 ~ –20°C, and stirred at the same temperature for 4 h. Then
the reaction mixture was stirred with FeCl3•6H2O in air for 0.5 h.
The resulting mixture was partitioned with 1 mol/l HCl and isopropyl
ether. The organic layer was washed with water, dried over MgSO4,
and concentrated under reduced pressure to give an orange solid.
The solid residue was further purified by column chromatography
on silica gel with hexane/isopropyl ether (3:1 v/v) as an eluent, and
recrystallised from acetone to give 408 mg of an orange crystalline
powder 1 (yield 65%).
Q10 (1) m.p. 48–49°C (lit.32 47°C); 1H NMR (400 MHz, CDCl3):
δ 1.59 (36H, s), 1.97–2.06 (36H, m), 3.19 (2H, d, J = 6.0 Hz), 3.99,
6H,s 5.11 (10H, m); ESI-MS m/z (%) 885.6 (M + Na+, 85), 880.6
+
(M + NH4 , 100).
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PAPER: 07/4946