AgNO3-catalyzed decarboxylative cross-coupling reaction: an approach to coenzyme Q

Article abstract of DOI:10.1039/d0nj01497d

An efficient and general method for the synthesis of coenzyme Q compounds through the activation of the 1,4-benzoquinone C_sp2-H bond has been developed. This C-C bond formation reaction proceeds readily in an open flask by the direct cross-coupling reaction of coenzyme Q₀with commercially available aliphatic carboxylic acids utilizing AgNO₃as a catalyst and K₂S₂O₈as an oxidant in aqueous solution. This radical reaction is operationally simple and amenable to gram-scale synthesis.

Full text of DOI:10.1039/d0nj01497d

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DOI: 10.1039/D0NJ01497D
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AgNO3-Catalyzed Decarboxylative Cross-coupling Reaction: An
Approach to Coenzyme Q
Wan-Yue Luoa#, Bin Lua#, Yong-Fu Qiua#, Rong-Ye Zhoua, Yong-Jing Hea, Jin Wanga,b*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
O
O
An efficient and general method for the synthesis of
O
O
O
O
Coenzyme
Q compounds through the activation of 1,4-
benzoquinone Csp2-H bond has been developed. This C-C bond
formation reaction proceeds readily in an open flask by direct
cross-coupling reaction of Coenzyme Q0 with commercially
available aliphatic carboxylic acids utilizing AgNO3 as catalyst and
K2S2O8 as oxidant in aqueous solution. This radical reaction is
operationally simple and amenable to gram-scale synthesis.
CH2
H
10
OH
10
O
CoQ10
Idebenone
O
O
O
O
O
O
R
Coenzyme Q (CoQn), also known as the ubiquinones, is a
vitamin-like 1,4-benzoquinone compound and functions as a
potent antioxidant that scavenges free radicals.1 CoQ molecules
are acting as mobile mediators for electron transfer and protein
translocation between redox enzymes in the electron transport
chain of mitochondria.2 The metabolites of CoQ homologues and
a number of synthetic CoQ compounds have been reported
possess antineoplastic, anti-inflammatory and antimicrobial
activities.3 CoQ10 and idebenone are the most known Coenzyme
Q drugs which is widely used in the treatment of Friedreich’s
ataxia,4 Alzheimer’s disease, Parkinson’s disease and
O
O
CoQ0
CoQ Compound
Figure 1. Structures of CoQ10, Idebenone, CoQ0 and CoQ compound
To date, the most general methods for the preparation of
7
CoQ compounds are starting from 3,4,5-trimethoxytoluene 1 or
8
2,3,4,5-tetramethoxytoluene
2
through multistep reactions
(Scheme 1a). These methods involved tedious reaction
conditions (Friedel-Crafts, hydrogenation, Heck reaction, etc.),
use of toxic reagents or low total yields.
Therefore, the
mitochondrial
disorders.5
2,3-Dimethoxy-5-methyl-1,4-
development of novel and practical methods for the
straightforward synthesis of CoQ compounds are highly desired.
benzoquinone, known as Coenzyme Q0 (CoQ0), can serve as a
key intermediate in the synthesis of coenzyme Q10, idebenone
and other CoQ Compounds (Figure 1.).6
a. School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road
No.2, Yancheng, 224007, Jiangsu Province, P. R. China
b. Université de Toulouse, Université Toulouse III – Paul Sabatier, 118 route de
Narbonne, 31062 Toulouse Cedex 9, France
# These authors contributed equally to this work
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Table Silver-catalyzed decarboxylative reaction under different
View Article Online
a) classical method for CoQ compound (previous work)
conditions
DOI: 10.1039/D0NJ01497D
O
O
O
O
O
multisteps
multisteps
low yield
not general
low yield
not convenient
O
O
O
R
O
O
O
O
O
O
O
O
O
catalyst, oxidant, air
HOOC CH2
CH3
CoQ compound
1
2
H
CH2 CH3
2
b) C-H Functionalization of Quinones with Boronic Acids ( Phil S.Baran et al and Xiao-Qi Yu et al)
2
O
O
O
O
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CoQ0
3
R
(HO)2B
R
+
O
O
Entr
y
Catalyst (%)
Oxidant (equiv.)
solvent
Yield (%)
c) Silver-Catalyzed Decarboxylative Cross-coupling of CoQ0 with Carboxylic Acids (this work)
O
O
O
O
O
O
O
1
2
none
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
(NH4)2S2O8(2)
Na2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(3)
K2S2O8(3)
CH3CN
CH3CN
THF
0
43
20
10
0
AgNO3/K2S2O8
CH3CN/H2O=1:1
Air
+
R
HO
R
AgNO3(10)
AgNO3(10)
AgNO3(10)
AgNO3(10)
AgNO3(10)
AgNO3(10)
AgNO3(10)
Ag2CO3(10)
AgOAc(10)
AgNO3(20)
AgNO3(20)
AgNO3(20)
AgNO3(30)
AgNO3(40)
AgNO3(50)
AgNO3(60)
O
O
CoQ0
CoQ, R = alkyl
3
Scheme 1. Various methods for CoQ compound
4
Acetone
MeOH
EtOH
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Arylboronic acids are widely used as cross-coupling reaction
partners in the formation of C–C bonds. Baran et al9 and Yu et al10
reported a direct arylation of quinones with boronic acids to afford
aryl substituted CoQ compounds (Scheme 1b). However, these
reactions are time comsuming, and the reagent arylboronic acids
are expensive and not easily available. Compared with the
boronic acids, the ready availability, high stability, and low cost of
aliphatic carboxylic acids are good reagents for the
decarboxylative reactions involving the cleavage of C(sp3)–
COOH bonds to form a new C-C bond.11 Following our previous
work on synthesis of Coenzyme Q analogues,12 herein, we report
the first direct decarboxylative cross-coupling reaction of CoQ0
with aliphatic carboxylic acids (Scheme 1c).
6
0
7
DMSO
DMF
Trace
0
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
20
32
57
Trace
50
64
75
70
60
10
11
12
13
14
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17
Our initial trial commenced with the reaction of CoQ0 and
butanoic acid (1.2 equiv) by catalytic AgNO3 (20%) in the
presence of K2S2O8 (2 equiv). Within 2 h, the reaction was
complete and delivered the alkylated CoQ 3 in 43% yield after
isolation. (entry 2, Table 1). This reaction is operationally simple,
is run under air, is clean and scalable. Without the catalyst silver
salt, the reaction can not proceed (entry 1, Table 1). Examination
of various solvents at 80 °C under open air for 2 h revealed that
the best reaction solvent is acetonitrile (entry 2, Table 1). Several
other silver catalysts were screened in the reaction, Ag2CO3 and
AgOAc catalyzed the reaction with moderate efficiency (entries 9-
10,Table 1), and AgNO3 was ultimately chosen as the catalyst
because it formed CoQ in the best yield. Oxidants K2S2O8,
Na2S2O8 and (NH4)2S2O8, were also examined in the reaction
(entries 11-13,Table 1), K2S2O8 can catalyze this reaction with a
best yield (57%, entry11, Table 1). The effect of the amount of
AgNO3 and K2S2O8 was examined, and the results showed that an
increase in the amount of AgNO3 and K2S2O8 lead to higher
conversion of Coenzyme Q0. (entries 14-17,Table 1). The optimal
condition was using AgNO3 (40%), and K2S2O8 (2 equiv) in
acetonitrile at 80 oC for 2 h (entry 15, Table 1).
Reaction Conditions: CoQ0 (0.02mol), butanoic acid (1.2 equiv), 80
oC, 2 hour under open air
With the optimum reaction conditions in hand, we explored
the substrate scope with regard to different carboxylic acid (Table
2). Delightfully, the substrate scope is quite general, comercial
availbale long-chain carboxylic acids can be applied to this
protocol, thus affording the corresponding CoQ compounds in
good to excellent yields (entry 1-3, Table 2). It was interesting to
note that a CoQ drug idebenone (6) was obtained in gram-scale
by the reaction of 11-Hydroxyundecanoic acid with CoQ0 in 75%
yield with no by-product (entry 3, Table 2). However, when use
the short carbon chains acetic acid or benzoic acid as coupling
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reaction partners to react with CoQ0 under the same conditions, silver-(I) nitrate in the presence of K2S2O8 as co-oxidants. This
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DOI: 10.1039/D0NJ01497D
low yield of CoQ product were observed (entry 4-5, Table 2).
decarboxylative C-C cross-coupling reaction between CoQ0 and
aliphatic carboxylic acids proceed well under open air conditions.
This method is easily operational, mild and efficient. It has been
applied to the gram-scale synthesis of CoQ drug idebenone (6)
with a yield of 75%, which makes the method highly applicable.
This chemistry provided a novel Csp2-H alkylation approach
leading to other alkylated CoQ compounds which are of high
synthetic value. Studies on the applications in natural CoQ
syntheses are ongoing in our laboratory.
Table 2. Cross-coupling of Coenzyme Q0 with carboxylic acids
O
O
O
O
O
O
AgNO3/K2S2O8
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Carboxylic acids
H
R
[open flask]
[gram-scale]
O
CoQ0
O
CoQ
Experimental Section
Entry
Carboxylic acids
R
CoQ Yield (%)
Synthesis of CoQ compounds
1
2
3
4
5
HOOC-(CH2)8-CH3
HOOC-(CH2)9-OH
HOOC-(CH2)10-OH
HOOC-CH3
(CH2)8-CH3
(CH2)9-OH
(CH2)10-OH
CH3
(4)
(5)
(6)
(7)
(8)
80
To a solution of Coenzyme Q0 (3.64 g, 0.02 mol) and carboxylic
acids (0.03mol) in acetonitrile 80 mL was added AgNO3 (1.35 g, 8
mmol). The mixture was heated to 80 oC and a solution of K2S2O8
(10.81 g, 0.04 mol) in distilled water 80 mL was added dropwise over
2 h, then the reaction mixture was stirred for another 2 h, with TLC
monitoring unitil the starting material was consumed. The resulting
mixture was cooled and extracted with CH2Cl2. The organic layer was
washed with water, then dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was purified by
column chromatograph on silica gel (PE/EtOAc= 5:1) to give CoQ
compounds.
70
75
trace
5
HOOC-Ph
Ph
Reaction Conditions: CoQ0 (0.02mol), carboxylic acid (1.5 equiv), AgNO3 (40%),
K2S2O8 (2 equiv)
Based on the experiment results,
decarboxylative decarboxylative Csp2-H cross-coupling reaction is
a
silver-catalyzed
We thank the National Natural Science Foundation of China
(No.81903427), the Natural Science Foundation of Jiangsu
Province (BK20160443), the Six Talent Peaks Project in Jiangsu
Province (SWYY-094) for financial support.
tentatively illustrated in Scheme 2. Initially, Ag(I) was oxidized into
2-
Ag(II) inermediate by S2O8 and the carboxylic acids (A)
underwent an SET process to generate the corresponding carbon
radical (B) and release CO2.13-14 The carbon radical (B) then
attack the Csp2-H of CoQ0 to afford intermediate (C), which can
2-
Notes and references
transfer to the product idebenone (D) by S2O8
.
1
A. Khattab, L. Hassanin, N. Zaki, AAPS PharmSciTech 2017,
18, 1657-1672.
CO2
2
3
J. Wang, X. Hu, J. Yang, Synthesis 2014, 46, 2371-2375.
Q. Fan, Y. Zhang, H. Yang, Q. Wu, C. Shi, C. Zhang, X. Xia, X.
Wang, Food Control 2018, 90, 274-281.
C. Tonon, R. Lodi, Expert Opinion on Pharmacotherapy 2008,
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Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M. Del
Bel, P. S. Baran, Journal of the American Chemical Society
2011, 133, 3292-3295.
CH2
R
HOOC CH2
(A)
R
n
n
(B)
4
5
6
7
8
9
O
O
O
Ag(II)
Ag(I)
2-
S2O8
O
H
CoQ0
O
O
O
O
2-
O
O
S2O8
CH2
R
O
CH2
R
n
n
H
(C)
O
(D)
10 W. Jian, W. Shan, W. Gao, Z. Ji, Y. Xiao-Qi, Chemical
Communications 2012, 48, 11769-11771.
11 C. Liu, X. Wang, Z. Li, L. Cui, C. Li, Journal of the American
Chemical Society 2015, 137, 9820-9823.
Scheme 2. Proposed reaction mechanism
12 J. Wang, S. Li, T. Yang, J. Yang, Tetrahedron 2014, 70, 9029-
9032.
13 Y. Zhu, X. Li, X. Wang, X. Huang, T. Shen, Y. Zhang, X. Sun, M.
Zou, S. Song, N. Jiao, Organic Letters 2015, 17, 4702-4705.
In conclusion, we have developed a practical and convenient
synthesis of Coenzyme Q compounds by the use of catalytic
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14 S. Mandal, T.Bera, G.Dubey, J.Saha, J. K. Laha, Acs Catalysis,
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Wan-Yue Luoa#, Bin Lua#, Yong-Fu
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Qiua#, Rong-Ye Zhoua, Yong-Jing Hea,
Jin Wanga,b*
O
O
O
O
O
AgNO3/K2S2O8
HOOC
AgNO3-Catalyzed Decarboxylative
Cross-coupling Reaction: An
Approach to Coenzyme Q
+
R
CH3CN/H2O=1:1
Air
O
R
H
9
O
O
CoQ0
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CoQ, R = alkyl
 high yields
 gram-scale synthesis
 Csp2-H functionalization
 Decarboxylative Cross-coupling