Catalytic Redox Chain Ring Opening of Lactones with Quinones to Synthesize Quinone-Containing Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.9b01672

Catalytic ring opening of five- to eight-membered lactones with quinones is achieved through a redox chain mechanism. With low loading of a simple metal triflate Lewis acid catalyst and a chain initiator, C-H bonds of many quinones were efficiently functionalized with carboxylic acid-containing side chains. This method also features 100% atom economy and wide substrate scope. A novel route to the anti-asthma drug Seratrodast was developed. Mechanism study suggests that the redox chain reaction likely undergoes a carbocation intermediate.

Full text of DOI:10.1021/acs.orglett.9b01672

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Redox Chain Ring Opening of Lactones with Quinones To
Synthesize Quinone-Containing Carboxylic Acids
Xiao-Long Xu†,‡ and Zhi Li*,†
†School of Physical Science and Technology, ShanghaiTech University, Shanghai, China 201210
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Catalytic ring opening of five- to eight-
membered lactones with quinones is achieved through a
redox chain mechanism. With low loading of a simple metal
triflate Lewis acid catalyst and a chain initiator, C−H bonds of
many quinones were efficiently functionalized with carboxylic
acid-containing side chains. This method also features 100%
atom economy and wide substrate scope. A novel route to the anti-asthma drug Seratrodast was developed. Mechanism study
suggests that the redox chain reaction likely undergoes a carbocation intermediate.
Scheme 1. Quinone-Containing Carboxylic Acid Derivatives
and Their Synthetic Strategies
uinone derivatives are an important class of organic
Q compounds that are uniquely oxidative. Some of them
are widely distributed in the nature as biological electron
transporters;1 some serve as potent pharmaceuticals and
nutritional supplements such as Idebenone,2 Seratrodast,3
and Coenzyme Q10;4 some are powerful oxidants for chemical
reactions (for example, 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ));5 and recently some of them exhibited new values as
battery materials.6 Great efforts have been devoted to the
synthesis of quinone derivatives.7 In particular, quinone-
containing carboxylic acid derivatives (QCAs) demonstrated
appealing activities as pharmaceuticals and material candidates
(Scheme 1a).8 However, synthetic strategies of QCAs are still
relying on traditional chemistry, generally involving two
steps:3,9 (1) Friedel−Crafts-type alkylation of phenols or aryl
ethers, which usually consumes stoichiometric Lewis acid
catalyst and acyl halide or anhydride electrophiles; and (2)
oxidation of the resulting intermediates to afford the QCAs,
which again usually requires stoichiometric oxidants (Scheme
1b). These processes were clearly not broad enough in scope
to sufficiently supply the diversity of compounds for activity
screening, nor economical or benign in the spirit of green
chemistry. Therefore, development of general and efficient new
synthetic methods to construct QCAs is essential to promote
their broader applications.
During our earlier study on the redox chain reaction
between quinones and benzyl esters, we attempted to
synthesize Seratrodast as a demonstration of synthetic utility.10
However, although the ethyl and methyl esters of Seratrodast
were constructed from the coupling between quinone and the
corresponding benzylic acetate, the final ester hydrolysis before
reaching the real drug failed after repeated trials, likely because
of the interaction between the quinone core and the base used
in hydrolysis (see Scheme S1 in the Supporting Information).
This failure naturally prompted us to consider the intriguing
possibility of taking benzylic lactones as the electrophile in the
redox chain reaction, which would allow formation of the C−C
bond and reveal the carboxylic acid-containing side chain at
the same time.
Lactones are the core structure of a large variety of natural
and bioactive compounds, and they are also widely available
through mild syntheses.11 Nevertheless, synthetic strategies
that use lactones as precursors are less common. Notable
recent advances include hydrogenation of lactones12 and the
ring opening of lactones to γ-amino acids.13 Our hypothesis is
Received: May 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that lactones, particularly those containing a labile benzylic C−
O bond, would also be able to participate in a redox chain
reaction as an electrophile. Herein, we report a very efficient,
atom-economical, and redox-economical14 synthesis of QCAs
by the redox chain reaction between quinones and activated
lactones. Under mild and simple catalytic conditions, a great
diversity of QCAs can be obtained in high yields and 100%
atom economy without adding any external oxidants.
solvent, but, at this temperature, the reaction gave no product
(Table 1, entry 16). The target product 3 could also be
obtained without addition of the initiator (Table 1, entry 18),
likely due to the production of trace reductive byproducts as in
situ initiators, for example, secondary benzylic alcohols
resulted from the hydrolytic ring opening of the lactones by
adventurous moisture.15 By adding a proper loading of
initiator, yields and reproducibility of the experiments were
improved (Table 1, entries 17−20). Lower temperatures
resulted in lower yields (Table 1, entries 21−23).
The optimized reaction conditions were then applied to
various γ-lactones using 1 as the representative quinone,
affording many γ-quinonyl carboxylic acids (see Scheme 2). A
conjugating group, such as phenyl (3, 5−21), heteroaryl (24−
30), or alkenyl (31, 32), is necessary at the γ-position of these
lactones. Simple γ-alkyl lactones do not undergo the ester C−
O cleavage reaction. Lactones containing electron-donating-
group-substituted (Me-, MeO-, MeS-) γ-aryls (5, 6, 11, 12)
performed better than those substituted with electron-with-
The reaction conditions were initially investigated by
studying the reaction between 2,6-dimethylquinone 1 and
lactone 2 (Table 1). Optimal yield was achieved using 4 mol %
a
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst
x
solvent
temperature, t (°C) yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Hf(OTf)4
Sc(OTf)3
Bi(OTf)3
Cu(OTf)2
Yb(OTf)3
SnCl2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
0
2
8
4
4
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PhCl
DMSO
DMF
dioxane
CH3CN
DCE
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
40
70
70
70
70
60
50
25
61
−
−
−
−
−
3
4
52
76
−
−
−
−
72
−
a
Scheme 2. Scope of γ-Lactones
Al(OTf)3
HfCl4
(Tf)2NH
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
Hf(OTf)4
DCM
d
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
77 (73)
60
70
74
46
27
−
a
Reaction conditions: 1 (0.25 mmol) and 2 (0.25 mmol) were mixed
with initiator 4 in 0.5 mL PhCF3 at room temperature (rt) for 0.5 h,
then Hf(OTf)4 (0.01 mmol, 4 mol %) was added, heated to specified
b
temperature and stirred for 6 h. Legend: DMSO, dimethylsulfoxide,
DMF, dimethylformamide; DCE, 1,2-dichloroethane; DCM, di-
c
chloromethane. Yields were determined by 1H NMR using
tetrachloroethane as an internal standard. Dash symbol (−) indicates
d
that no product was recovered. Parentheses refer to isolated yield
after column chromatography.
Hantzsch ester as the redox chain initiator, 4 mol % Hf(OTf)4
as the Lewis acid catalyst, and trifluorotoluene as the solvent at
70 °C (Table 1, entry 17). Other Lewis acids, such as
Sc(OTf)3 and Bi(OTf)3, were not as effective (Table 1, entries
2−8). Notably, strong Brønsted acid Tf2NH was capable of
catalyzing the reaction, providing a good yield (Table 1, entry
9). Polar solvents prohibited the reaction likely due to their
strong coordination to the Lewis acid (Table 1, entries 11−
14), while nonpolar solvents gave excellent yields (Table 1,
entries 1, 10, 15, 17). Note that the reaction in dichloro-
methane (DCM) was run at 40 °C to avoid boiling of the
a
Reaction conditions: 1 (0.25 mmol) and lactone (0.25 mmol) were
mixed with initiator 4 (4 mol %) in 0.5 mL PhCF3 at rt for 0.5 h, then
Hf(OTf)4 (4 mol %) was added and stirred at 50 °C for 2 h, unless
otherwise noted. Yields were all isolated after column chromatog-
b
c
raphy. NR = no product recovered. 70 °C for 6 h. A gram-scale
example: 5.0 mmol of 1 and 2 each, 70 °C for 6 h, 1.01 g of 3
d
e
obtained, 68% yield. 25 °C for 2 h. 70 °C for 16 h.
B
DOI: 10.1021/acs.orglett.9b01672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
drawing groups (7−9), even at lower temperatures and shorter
times. Lactones containing strong electron-withdrawing-group-
substituted γ-aryls (22, 23) are difficult substrates in the ring-
opening reaction. Also, nitrogen-containing heteroaryl γ-
substituents such as pyridyl completely inhibited the reaction,
likely due to high basicity. Alkyl (13, 14) and methylene (16−
21, 24, 25) substituents at the α- and β- positions of the
lactones could also afford good yields of corresponding QCAs.
Although in lower yield, an example using γ-(4-pinacolboryl)-
phenyl lactone is shown to be compatible with the redox chain
reaction conditions, allowing possibilities of further metal-
catalyzed cross-coupling reactions (21). Surprisingly, allylic
lactones also provided the QCA products with good yields (31,
32).
Scheme 4. Investigation of Ring Size of Lactones and
Synthesis of Seratrodast
Next, the scope of substituted quinones was examined (see
Scheme 3). Unfortunately, benzoquinone gave poor yield (33).
lactone 49 was obtained in 44% overall yield unoptimized.
In the second stage, as expected, Seratrodast (51) was
successfully accessed by using trimethyl-1,4-benzoquinone 50
and 49 in 67% yield in one catalytic step. In addition, 6-
membered (52) and 7-membered (53) lactones are also nice
substrates in these redox chain reactions.
a
Scheme 3. Scope of Substituted Quinones
Since ω-aryl-ω-lactones were mostly good examples, results
from lactones with ω-alkenyl substituents would also be
intriguing, because of the similarity between an aryl and an
alkenyl (Scheme 5). The reaction site shifted from the
Scheme 5. Redox Chain Reaction with γ-Vinyl-γ-lactones
congested ω-position of the lactone to the terminal position
of the vinyl, affording double bond-migrated ring-opening
product with high E-stereoselectivity, confirmed by NOE
experiments of the products (Figure S2 in the Supporting
Information). A particularly interesting case is that starting
from γ-vinyl-γ-methyl-γ-lactone (57), tocopheronolactone
(58) was obtained as the product, likely a result of an
intramolecular cyclization of the QCA. Reaction monitoring by
NMR indicated that the first substitution intermediate A could
slowly cyclize to 58 under the reaction condition. Higher yield
was obtained when BF3·Et2O was used as the catalyst (Table
S1 in the Supporting Information),17 along with a double
alkylation-cyclization minor product 59.
The mechanism of redox chain reaction has been
preliminarily illustrated in our previous study.10 In order to
further clarify the nature of the redox chain reaction, additional
mechanistic study was conducted. Alkylation of 1 with lactone
61 was performed with the addition of 0.5 equiv. oxidant Ag2O
instead of reductant initiator, and this reaction afforded no
target product. The result suggested that a strongly oxidative
environment may consume the true reactive intermediate, HQ,
a
Reaction conditions: quinones (0.25 mmol) and lactones (0.25
mmol) were mixed with initiator 4 (4 mol %) in 0.5 mL PhCF3 at rt
for 0.5 h, then Hf(OTf)4 (4 mol %) was added and stirred at 50 °C
for 2 h, unless otherwise noted. Yields were isolated after column
b
c
chromatography. 70 °C for 6 h. 30 °C for 2 h.
Most methyl- and methoxy-substituted benzoquinones gave
good yields when reacted with the different lactones that have
been tested (34−37, 41−44). Benzoquinones with one methyl
or one tertiary butyl substituent could be selectively
monofunctionalized at the 5-position (41, 42). Substituted
naphthoquinones are also good nucleophiles (38−40).
The utility of the method was demonstrated in a short total
synthesis of Seratrodast (51, Scheme 4). Several routes for its
synthesis have been developed to date, mostly from conven-
tional strategies for quinone synthesis.3,16 The first stage of our
approach started with preparation of the lactone precursor
from commercially available cycloheptanone. The desired
C
DOI: 10.1021/acs.orglett.9b01672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thus suppress the key C−C bond-forming Friedel−Crafts
alkylation. Meanwhile, the reaction between 1 and enantiomer-
enriched lactone samples (61, 79% ee and 2, 90% ee)18 under
standard conditions generated product mixtures with much
lower enantiomer excess. This result indicated that the lactone
was likely activated into a fully racemizing carbocation
transition state, excluding the possibility of SN2 pathway
(Scheme 6). The real pathway could be either a fully
21673141), “1000 Talents Plan for Young Professionals” start-
up funding, and ShanghaiTech University start-up funding. We
thank Analytical Instrumentation Center of ShanghaiTech for
facilities and services of characterization of compounds.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01672.
■
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Supplementary scheme, table and figure, reagent
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: lizhi@shanghaitech.edu.cn.
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Zhi Li: 0000-0003-2770-6364
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was generously provided by the
National Natural Science Foundation of China (Grant No.
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DOI: 10.1021/acs.orglett.9b01672
Org. Lett. XXXX, XXX, XXX−XXX