Hydrogenation of plant polyalkoxybenzene derivatives: convenient access to coenzyme Q0 analogues

Article abstract of DOI:10.1016/j.mencom.2020.09.015

A technologically advanced protocol has been developed for converting plant allyl(polyalkoxy)benzenes to methyl- and propyl(polyalkoxy)benzenes being intermediates in the syntheses of coenzyme Q₀ analogues. The key stage of allyl and benzaldehyde moieties hydrogenation was carried out in a periodical autoclave mode on highly porous ceramic block Pd-catalysts. These catalysts possess large surface area, low hydraulic resistance, significant thermal and mechanical stabililty, multiple cycling and easy regeneration, which can dramatically reduce Pd consumption.

Full text of DOI:10.1016/j.mencom.2020.09.015

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 599–601
Hydrogenation of plant polyalkoxybenzene derivatives:
convenient access to coenzyme Q0 analogues
Alexander E. Varakutin,*a Egor A. Muravsky,b Ilia Yu. Shinkarev,b
Victor N. Khrustaleva,c and Victor V. Semenova
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: vs@zelinsky.ru
b D. I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation
c Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2020.09.015
A technologically advanced protocol has been developed for
converting plant allyl(polyalkoxy)benzenes to methyl- and
propyl(polyalkoxy)benzenes being intermediates in the
syntheses of coenzyme Q0 analogues. The key stage of allyl
and benzaldehyde moieties hydrogenation was carried out in
a periodical autoclave mode on highly porous ceramic block
Pd-catalysts. These catalysts possess large surface area, low
hydraulic resistance, significant thermal and mechanical
stabililty, multiple cycling and easy regeneration, which can
dramatically reduce Pd consumption.
ꢀAlkOꢁn
ꢀAlkOꢁn
Me
Cꢂ2
n ꢃ ꢄꢅ ꢆ
Coenꢉyme ꢊ0
analogues
Parsley
Ceramic highly
Me
ꢇorous Pdꢈcatalyst
O
ꢀAlkOꢁn
ꢀAlkOꢁn
Dill
Keywords: coenzyme Q0, antioxidants, ceramic block catalysts, palladium catalysts, hydrogenation, alkyl(polyalkoxy)benzenes.
R1
R1
The family of coenzymes in the organisms of mammals and
plants is part of the mitochondrial respiratory chain. They have
strong antioxidant activity and regulate the permeability of
mitochondrial membranes. The synthesis of numerous analogues
of coenzymes Q0–Q15 with various lengths of the isoprenoid
chain (n = 0–15) and alkoxy/alkyl substituents in the quinonoid
ring (Scheme 1) has been the subject of several thousand
R2
R3
R2
R3
Me
CH2
i
85–95%
R5
R5
R4
1a–e
R4
5a–d
a R1 = R4 = OMe, R2 + R3 = OCH2O, R5 = H
b R1 = H, R2 + R3 = OCH2O, R4 = R5 = OMe
c R1 = R2 = R3 = R4 = OMe, R5 = H
publications.
2,3-Dimethoxy-5-methyl-1,4-benzoquinone
(coenzyme Q0)1,2 is the main synthon for their preparation.
Recently, compound Q0 was found to possess antitumor
properties, in particular, it inhibits the metastasis of breast,3 skin
(melanoma)4 and ovarian5 cancer in mice. The original synthesis
of Q0 comprised a multistage scheme starting from gallic acid.6
More efficient schemes involved the oxidation and demethylation
of 1-methyl-2,3,4,5-tetramethoxytoluene 4c (Scheme 2)7 or
1-methyl-3,4,5-trimethoxytoluene 4e,8 which were in turn
85–94%
(ref. 12)
ii
d R1 = R5 = H, R2 + R3 = OCH2O, R4 = OMe
e R1 = R5 = H, R2 = R3 = R4 = OMe
R1
R1
R2
R3
Me
R2
R3
CHO
R5
iii
80–85%
(ref. 13)
R5
R4
R4
OMe
O
2a–e
3a–e
MeO
MeO
MeO
MeO
trans:cis = (4–5.7):1
R1
R2
R3
Me
R5
Me
Me
i
R
O
85–95%
R = H, MeO
Coenzyme Q0
R4
4a–e
O
O
n = 0
MeO
MeO
Me
Scheme 2 Reagents and conditions: i, H2 (20 atm), 5% Pd/6% a-Al2O3/
g-Al2O3, MeOH, 20 °C, 2–6 h; ii, KOH, 100 °C, 40 min; iii, O3,
CHCl3–MeOH–pyridine (80:20:3 v/v), –15 °C, 1–2 h.
H
Me
n
Coenzyme Q10
obtained by selective hydrogenation of the corresponding
benzaldehydes on 10% Pd/C.9 However, the majority of
alkylbenzenes and benzaldehydes with four alkoxy substituents
n = 10 (Ubiquinone)
Scheme 1
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 599–601
had previously to be obtained from trimethoxybenzene
reaction mixture, benzyl methyl ether, which further turned to
methylbenzene 4a, was detected by mass spectrometry. These
observations agree with the published data on the hydrogenation
of aldehydes on Pd/C.9 It was found that compounds without
substituents at the ortho position relative to the hydrogenated
group (1d, 3d, 3e) react faster than those containing an ortho
methoxy group (for example, 1d is consumed within 2 h while
1b within 4 h). The application of catalysts with different Pd
concentrations (0.6–5%) did not affect the purity of the final
product, however, the reaction time decreased significantly with
a decrease in the catalyst concentration (for example, 4–8 h at
5% Pd and 20 h at 0.6% Pd for benzaldehydes 3).† According to
the reported data,9 the hydrogenation of benzaldehydes on Pd/C
often results in product mixtures (the corresponding alcohols
and methyl ethers9). The selective formation of methylbenzenes
(Pd/C, 5 wt%) is observed upon addition of strong acids such as
HCl or CF3COOH, which complicates the further purification of
the products.9 In our experiments, only trace amount of impurities
were found after hydrogenation on block Pd-catalyst in the
absence of acids in pure methanol.
derivatives, while direct oxidation of 4e to coenzyme Q0 was
complicated by side processes.8
In this work, we suggest a facile source for synthesizing the
intermediates of Q0 and its analogues with methoxy,
methylenedioxy, methyl and alkyl substituents in the ring based
on allylpolymethoxybenzenes 1a–e (see Scheme 2) that are
easily isolated in large quantities from CO2 extracts of parsley
and dill seeds.11 The isomerization of allylbenzenes to
propenylbenzenes 2a–e in alkaline media and the consequent
ozonolysis to aldehydes 3a–e that we developed earlier12,13
occur in high yields even in large (50–100 g) scale.
It is important to note that the starting allylbenzenes 1 and
their methyl- (4) and propyl-containing (5) analogues have an
antitumor effect as well. In fact, methyl derivative of apiole (4a,
referred to as SY-1 in the literature) and coenzyme Q0 were
isolated from the Chinese parasite fungus Antrodia camphorata.
They are the main components responsible for the antitumor
activity.14 The extracts of mycelium and spores of this fungus
have long been used in the traditional Chinese medicine.15
Compound 4a not only inhibits the growth of various cancer
lines (breast, prostate, liver), but also has a synergistic effect –
namely, it enhances the effect of taxol on prostate cancer.14
Rather recently, data on the inhibition of colon cancer cells
COLO 205 appeared for apiole 1a, dihydroapiole 5a, and a
number of other derivatives.17,18 The chemico-prophylactic
anticancer properties of myristicin 1d and dihydromyristicin 5d
were described.19
After unloading the reaction solution, the block catalyst can
be used up to 40 times in the next syntheses after regeneration,
while hydrogenation can be carried out at a 2.5 times higher
concentration of aldehydes (5 wt%) than in the case of Pd/C.9
For this reason, the production and isolation of products are
faster and cheaper, while the consumption of palladium per
1 mol of the product becomes many times smaller because
nothing of fresh catalyst should be added.
The key stage of the synthesis (see Scheme 2) involves the
hydrogenation of allylbenzenes and benzaldehydes on highly
porous ceramic block palladium catalysts in a periodical
autoclave mode. Previously, catalysts of this type were
successfully used for the hydrogenation of nitrobenzenes,20
benzaldoximes,21 and Schiff bases.21 Such catalysts have a
number of advantages, namely, a wide range of block designs
and sizes, large surface area, low hydraulic resistance, high
thermal and mechanical resistance. The possibility of repeated
regeneration (30–40 times)20 without activity loss reduces the
consumption of the Pd-catalyst. Moreover, the reaction mixture
can be removed without the need for filtering devices, which
greatly simplifies the procedure. In our hands, the reaction was
well reproducible at various concentrations and loads of the
starting compounds 1 and 3 (2–5%, 1–5 g). Varying the hydrogen
pressure did not affect the composition of the final product but
affected the reaction time (6–8 h at 2 atm and 2–4 h at 20 atm for
allylbenzenes; 24–28 h at 5 atm and 4–6 h at 20 atm for
aldehydes). In the hydrogenation of compound 3a as the example
of benzaldehydes 3, the formation of the intermediate benzylic
alcohol was detected by TLC, HPLC, and mass spectrometry. If
an equimolar amount of hydrochloric acid was added to the
The spatial structure of natural compound 4a (SY-1) that is
necessary for further studies of the antitumor and antioxidant
properties of its analogues was confirmed by single-crystal
X-ray analysis (Figure 1).‡
Except for the hydrogen and C(8) atoms, the molecule of 4a
is almost planar (the rms deviation is 0.037 Å). The methoxy
group at the C(3) carbon atom is slightly twisted by 3.18(19)°
relative to the bicyclic plane, apparently due to steric reasons.
Cꢀꢃ0ꢂ
Oꢀꢁꢂ
Cꢀꢅꢂ
Cꢀꢆꢂ
Oꢀꢃꢂ
Oꢀ2ꢂ
Cꢀꢇꢂ
Cꢀꢃꢂ
Cꢀꢁꢂ
Cꢀ2ꢂ
Cꢀꢄꢂ
Cꢀꢈꢂ
Oꢀꢈꢂ
Cꢀꢉꢂ
Figure 1 Molecular structure of 4a (50% ellipsoids).
†
F(000) = 416, μ = 0.112 mm–1. X-ray diffraction data were collected on a
three-circle Bruker D8 QUEST PHOTON-III CCD diffractometer
[l(MoKa)-radiation, T = 100 K, graphite monochromator, j and w scan
mode] and corrected for absorption using the SADABS program.27 The
data were indexed and integrated using the SAINT program.28 For details,
see Online Supplementary Materials, Table S1. The structure was
determined by direct methods and refined by full-matrix least squares
technique on F2 with anisotropic displacement parameters for non-
hydrogen atoms. The hydrogen atoms were placed in calculated positions
and refined within the riding model with fixed isotropic displacement
parameters [Uiso(H) = 1.5Ueq(C) for the Me groups and 1.2Ueq(C) for the
other groups]. All calculations were carried out using the SHELXTL
program suite.29
General procedure for the hydrogenation of allylbenzenes 1a–d
and benzaldehydes 3a–e. A solution of allylbenzene 1a–d or
benzaldehyde 3a–e (23 mmol) in methanol (100 ml) was loaded into
a stainless steel autoclave with fluoroplastic insert, and a regenerated
block highly porous ceramic catalyst cylinder was fixed.
Hydrogenation was carried out at 20 bar at room temperature for
2–4 h (for allylbenzenes) or 4–8 h (for benzaldehydes) with HPLC
and/or TLC monitoring. After the starting reactant disappeared, the
reaction solution was poured out of the autoclave, the block catalyst
was washed with methanol (3 × 30 ml), and the combined solutions
were filtered from mechanical impurities. The solvent was
evaporated to afford analytically pure aromatic alkyl(polyalkoxy)-
benzenes 4a–e or 5a–d.
‡
Crystal data for 4a. The crystal of 4a (C10H12O4, M = 196.20) is
CCDC 1997755 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
hexagonal, space group P21/c, at T = 100 K: a = 6.9251(7), b = 18.0537(17)
and c = 7.2902(7) Å, V = 902.79(15) Å3, Z = 4, dcalc = 1.444 g cm–3
,
– 600 –

Mendeleev Commun., 2020, 30, 599–601
13 A. V. Samet, O. G. Shevchenko, V. V. Rusak, E. M. Chartov,
The two methoxy groups are arranged trans relative to each
other [the C(8)–O(3)···O(4)–C(10) torsion angle is 166.45(12)°].
The molecules of 4a in a crystal are packed in stacks along the
crystallographic axis a and arranged at Van der Waals distances.
A. B. Myshlyavtsev, D.A. Rusanov, M. N. Semenova andV.V. Semenov,
J. Nat. Prod., 2019, 82, 1451.
14 M. Geethangili and Y.-M. Tzeng, J. Evidence-Based Complementary
Altern. Med., 2011, 212641.
15 H.-M. Lien, H.-W. Lin, Y.-J. Wang, L.-C. Chen, D.-Y. Yang, Y.-Y. Lai
and Y.-S. Ho, J. Evidence-Based Complementary Altern. Med., 2009, 6,
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16 S. Liu, D. Township, W. Wen, W. Tsou and M. Kuo, Patent US
2008/0103195, 2008.
17 H.-M. Lien, P. Kuo, C. Huang, J. Kao, H.-W. Lin, D.-Y. Yang and
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18 L.-S. Shi, C.-H. Chao, D.-Y. Shen, H.-H. Chan, C.-H. Chen, Y.-R. Liao,
S.-J. Wu, Y.-L. Leu, Y.-C. Shen, Y.-H. Kuo, E.-J. Lee, K. Qian, T.-S. Wu
and K.-H. Lee, Bioorg. Med. Chem., 2011, 19, 677.
19 G. Q. Zheng, P. M. Kenney and L. K. T. Lam, J. Agric. Food Chem.,
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20 I. B. Karmanova, S. I. Firgang, L. D. Konyushkin, V. N. Khrustalev,
A. V. Ignatov, L. A. Kuznetsov, Yu. A. Pinchuk, I. A. Kozlov and
V. V. Semenov, Mendeleev Commun., 2016, 26, 66.
21 A. V. Ignatov, A. E. Varakutin, I. N. Solovieva, I. B. Karmanova,
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This work was carried out with financial support of Scientific
Schools Development Program at N. D. Zelinsky Institute of
Organic Chemistry. Crystal structure determination was
performed in the Department of Structural Studies of
N. D. Zelinsky Institute of Organic Chemistry, Moscow, Russia.
X-Ray structure determination was supported by the RUDN
University Program ‘5-100’.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.09.015.
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Received: 28th April 2020; Com. 20/6207
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