Continuous Electrochemical Synthesis of Iso-Coumarin Derivatives from o-(1-Alkynyl) Benzoates under Metal- and Oxidant-Free

Article abstract of DOI:10.1002/chem.202001766

A non-oxidant and metal-free strategy for synthesizing iso-coumarin by using a continuous electrochemical microreactor to initiate an oxidative cyclization reaction of o-(1-alkynyl) benzoate and radicals. This efficient and clean continuous electrosynthesis method not only avoids the complicated gas protection operation and production of by-products in the batch processes, but also help to overcome the difficulty that batch metal catalysis and electrocatalysis are difficult to scale up, and has the potential for pilot-scale experiment.

Full text of DOI:10.1002/chem.202001766

Accepted Article
Accepted Article
Title: Continuous Electrochemical Synthesis of Iso-coumarin
Derivatives from o‑(1-Alkynyl) benzoates under Metal- and
Oxidant-free
Authors: Xinxin Lin, Zheng Fang, Cuilian Zeng, Chenlong Zhu, Xinyan
Pang, Chengkou Liu, Wei He, Jindian Duan, Ning Qin, and
Kai Guo
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001766
Link to VoR: https://doi.org/10.1002/chem.202001766
01/2020

10.1002/chem.202001766
Chemistry - A European Journal
FULL PAPER
Continuous Electrochemical Synthesis of Iso-coumarin
Derivatives from o‑(1-Alkynyl) benzoates under Metal- and
Oxidant-free
Xinxin Lin,[a] Zheng Fang, [a] Cuilian Zeng,[a] Chenlong Zhu,[a] Xinyan Pang,[a] Chengkou Liu,[a] Wei He,[a]
Jindian Duan,[a] Ning Qin,[a] and Kai Guo *[a,b]
[a]
X. Lin, C. Zeng, C. Zhu, X Pang, C. Liu, W. He, J. Duan, N. Qin, Prof. Z. Fang, and Prof. K. Guo
Department: College of Biotechnology and Pharmaceutical Engineering
Institution: Nanjing Tech University
Address 1: 30 Puzhu Rd S., Nanjing 211816, China
E-mail: guok@njtech.edu.cn; fzcpu@163.com
[b]
K. Guo
Department; State Key Laboratory of Materials-Oriented Chemical Engineering
Institution: Nanjing Tech University
Address 2: 30 Puzhu Rd S., Nanjing 211816, China
Supporting information for this article is given via a link at the end of the document.
Abstract: A non-oxidant and metal-free strategy for synthesizing
iso-coumarin by using a continuous electrochemical microreactor to
initiate an oxidative cyclization reaction of o‑(1-Alkynyl) benzoate
and radicals. This efficient and clean continuous electrosynthesis
method not only avoids the complicated gas protection operation
and production of by-products in the batch processes, but also help
to overcome the difficulty that batch metal catalysis and
electrocatalysis are difficult to scale up, and has the potential for
pilotscale experiment.
(Scheme 1, method b). 9 Although these two reactions proposed
a method for the efficient synthesis of iso-coumarin, it is
regrettable that their applicability is limited due to the
participation of metals and the generation of halogen pollutants.
10
Thence, considering the possible environmental pollution
problems brought by the reaction and its application prospects, it
is still a significant challenge to develop an environmentally
friendly and inexpensive synthesis method to synthesize iso-
coumarin.
O
2Y)
R
FeCl
3, (R
O
Zeni's work
a
)
O
solvent
R1
Y=S,Se,Te
YR2
OMe
R1
Introduction
O
R2
PICl
2,MeCN,rt
O
R1
Many natural products and small organic molecules with
important biological activities contain iso-coumarin skeleton
structures. 1 Furthermore, most of iso-coumarin derivatives have
good biological activity, such as antibacterial,2 anti-inflammatory,
b) Du's work
R2
S(Se)R3
R3SSR3/PhSeSePh
This work
c)
O
O
O
Continuous flow
OMe
R2
R3
SeSeR3
or PhTeTePh
R1
3
anti-cancer,4 inhibiting protease and phytotoxic (Figure 1).5
R1
DC
R2
Se(Te)R3
These properties not only have potential medical application
value,6 but have also attract widespread attention in synthetic
research.
C(+) / Pt(-)
Scheme 1. Various strategies to synthesize iso-coumarin
Iso-coumarin can be formed by o‑(1-Alkynyl) benzoate that
undergo self-cyclization after radical initiation. Mechanistically,
the reaction involves electron transfer and oxidation processes.
Electrochemical oxidation provides a metal-free and oxidant-free
green cleaning method for the reaction.11 At the same time, with
the people's attention on electrochemistry,12 there have been
reports about the initiation of selenium radicals under
electrochemical conditions. Inspired by those work, we have
developed a method for the synthesis of iso-coumarin from o -
(1-alkynyl) benzoate and diorgano diselenide under
electrochemical conditions. However, through previous studies,
it was found that the reaction in batch yield can only reach 88%
at most, and there are also problems such as complicated
operations, easy side reactions and long reaction time. 13 The
literature investigation found that the electrochemical
O
OH
O
MeO
O
O
O
O
O
OMe
O
HO
O
Br
O
γ-Rubromycin
3-(4-bromophenyl)-1H-isochromen-1-one
antibacterial
antibacterial
O
OH
O
O
O
O
OH
Cl
H3CO
Ph
Cl
Cl
3-phenyl-1H-isochromen-1-one
3,4-dichloro-1H-isochromen-1-one
Cytogenin
antibacterial and weeding
inhibiting protease
anti-cancer
Figure 1. Biological activity of iso-coumarin derivatives
Therefore, many methods for synthesizing iso-coumarin
derivatives have been reported. 7 In 2011, Zeni and co-workers
achieved the FeCl3-mediated cyclization of o ‑ (1-Alkynyl)
benzoates to afford iso-coumarins in good yields (Scheme 1,
method a). 8 In 2019, Du’s group reported that PICl2 forms in-situ
formation of RSCl / ArSeCl and was applied to afford iso-
coumarins in good to excellent yields with alkynyl aryl esters
1
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10.1002/chem.202001766
Chemistry - A European Journal
FULL PAPER
microreactor can solve these problems well, and it also has the
advantages of small current gradient and effective use of
electrical energy. 14 Herein, we have developed a strategy for the
continuous synthesis of iso-coumarin derivatives from o-(1-
alkynyl) benzoate at room temperature using the
electrochemical microreactor (Scheme 1c).
cycloalkane, thiophene ring, and naphthalene ring substituents
attached to alkynes also proved to be well tolerated, providing
the corresponding products in relatively higher yields of 83% and
95%, respectively (Table 2, 3s-3v). In addition, substrates
containing n-butyl, n-hexyl, and t-butyl groups linked to alkynes
were also studied under optimal conditions. To our delight, these
substrates are stable under optimized conditions to produce the
desired product in good yields (84% to 86%) (Table 2, 3w–3y).
Furthermore, the substrate (1z) with a TMS group attached to
the alkyne moiety was also converted to the product 3z in 88%
yield, respectively (Table 2, 3z). When we explore the effect of
different substituents R2, substrates with either an electron-
donating methyl group or electron-withdrawing groups including
F, Cl substituted on the aromatic ring of o-alkynyl benzoate all
reacted stably with diphenyl diselenides under the optimized
conditions, and the desired product was obtained in good to
excellent yields (Table 2,3aa-3ad).Main Text Paragraph.
Results and Discussion
Table 1. Optimization of reaction conditions [a]
O
O
Continuous flow
O
O
PhSeSePh
DC
Ph
SePh
C(+) / Pt(-)
2a
3a
1a
Table 2. Substrate scope of electrochemical oxidative cyclization of o-(1-
Alkynyl) benzoate with diorganyl diselenides [a,b]
Entry
Deviation from standard conditions
none
3a [%] [b]
92%
0
O
O
1
2
Continuous flow
OMe
O
R2
R2
no electricity
DC
PhSeSePh
R1
SePh
3a
3
constant current: 5 mA
50
C(+) / Pt(-)
R1
1a
2a
4
constant current: 15 mA
80
O
R
R
R
3a, 1=2-H,92%
nBu4NBr instead of nBu4NBF4
nBu4NI instead of nBu4NBF4
nBu4NPF6 instead of nBu4NBF4
flow rate =450μL/min, resident time =0.5min
flow rate =225μL/min, resident time =1.0min
flow rate =125μL/min, resident time =2.0min
37
R1
R
3o, =4-OMe,90%
3f, 1=3-F,82%
3j, 1=4-F,85%
5
R
3b, R =2-F,72%
R1
O
3k, R =4-Cl,88%
=4-CF
1
=3-Cl,84%
3,82%
R
=4-CN,78%
3p,
3q,
R 1
3g,
R1
3c, 1=2-Cl,78%
3l, 1=4-Br,79%
3h, 1=3-Br,76%
R1
3d, R1=2-Br,68%
3e, R1=2-Me,83%
6
36
3m, R1=4-Me,89%
3n, R1=4-Et,87%
3r, =4-NO
3i
=3-Me,85%
R1
2,73%
,
1
R1
SePh
O
7
53
O
O
8
45
O
O
O
O
O
9
50
S
10
60
SePh
3s,95%
SePh
SePh
SePh
a Optimization of the reaction conditions. C (carbon filled PPS, 5.0 × 4.0 cm)
anode, Pt (platinum coated, 5.0 × 4.0 cm) cathode, flow volume (0.225 mL),
1a(0.2mmol), 2a(0.12mmol), nBu4NBF4(0.4mmol.), CH3CN=8mL, I=10mA,
resident time =5.0 min (5.5F/mol), room temperature. b isolated yield.
3u,83%
3t,93%
3v,87%
O
O
O
O
O
O
O
O
Si
SePh
SePh
SePh
86%
SePh
On the basis of electrochemical conditions in batch screening
(Table S2 in SI), the conditions of the reaction in the
electrochemical microreactor were screened. The optimal
conditions were: using acetonitrile as the solvent, adding 1a, 2a,
and two equivalents of nBu4NBF4 and mixing thoroughly. The
mixed solution was flowed into the electrochemical microreactor
for reaction which with a current set to 10 mA and the flow rate
is set to 45 μL/min. And the desired product can be obtained in a
yield of 92%. (Table 1, entry 1). When the current is set to 0 mA,
no desired product is produced, and then when the current is set
to 5 mA or 15 mA, the yield of the target product is reduced.
(Table 1, entries 2-4). Next, the electrolyte was simply screened.
When nBu4NBr, nBu4NI, and nBu4NPF6 were used as the
electrolyte, the yield was significantly reduced (Table 1, entries
5-7). Finally, the reaction flow rate, that is, the residence time, is
investigated. When the residence time is gradually shortened,
the yield decreases as it is shortened (Table 1, entries 8-10).
With the optimal reaction conditions established, the substrate
adaptability of this reaction was studied in the continuous flow
system. First, the reaction of different substituted o-(1- Alkynyl)
benzoate with diphenyl diselenide was studied to obtain different
3w,84%
3x,85%
3z,88%
3y,
O
O
O
O
F
Cl
O
O
O
O
Ph
Ph
Cl
Ph
Ph
SePh
SePh
SePh
SePh
70%
3ab,
3aa, 90%
3ac, 80%
3ad,80%
a Optimization of the reaction conditions. C (carbon filled PPS, 5.0 × 4.0 cm)
anode, Pt (platinum coated, 5.0 × 4.0 cm) cathode, flow volume (0.225 mL),
1a(0.2mmol), 2a(0.12mmol), nBu4NBF4(0.4mmol.), CH3CN=8mL, I=10mA,
resident time =5.0 min (5.5F/mol), room temperature. b isolated yield.
Next, the electrochemical oxidative cyclization in the continuous
flow system was further extended to the substrate adaptability of
diphenyl diselenides. In general, diphenyl diselenide reagents or
dithienyl diselenide reagents with electron-donating methyl
groups or electron-withdrawing chlorine or bromine substituents
on the aromatic ring are suitable for this conversion, and the
corresponding products can be obtained in moderate to good
yield (Table 3,4a-4f). However, it is worth noting that the yield
was significantly changed when dithiophene diselenide was
used instead of diphenyl diselenide, the corresponding product
was only obtained at a yield of 60%. In addition, dialkyl
diselenides are also suitable for this conversion, and the
corresponding products can be obtained in excellent yields
(Table 3,4g-4h). Surprisingly, the desired product can still be
obtained in a moderate yield when diphenyl ditelluride is used
instead of diphenyl diselenide (Table 3,4i).
iso-coumarin. As shown in table 2,
a series of o-(1-
Alkynyl)benzoate derived from ortho-, meta- and para-
substituted phenylacetylenes that bear electron-donating groups
(Me, Et, OMe) or electron-withdrawing groups (F, Cl, Br, CF3,
NO2, CN) showed great compatibility to give the corresponding
products(Table 2,3a-3r). Besides, substrates containing
2
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10.1002/chem.202001766
Chemistry - A European Journal
FULL PAPER
observed at 2.12 V, while the oxidation peak of diphenyl
diselenide 2a was observed at 1.74 V. And this result illustrated
that diphenyl diselenide 2a is more easily oxidized at the anode.
Table 3. Substrate scope of electrochemical oxidative cyclization of o-(1-
Alkynyl) benzoate with various diselenium reagents or ditelluride [a,b]
O
O
Continuous flow
OMe
O
R3SeSeR3
DC
e
e
Ph
Se(Te)R3
4a
PhTeTePh
Ph
C(+) / Pt(-)
1a
2a
O
O
O
O
O
O
O
O
O
O
Se
1/2PhSeSePh
+e
Se
Se
Cl
PhSeSePh
Se
Se
2a
Cl
Me
Br
4a,
78%
4b,
4c,
84%
70%
4d,
70%
4e,
80%
-e
O
O
O
O
O
O
O
O
Se
PhSe
PhSe
PhSeSePh
s
SeEt
TePh
4i,48%
SeMe
C
A
B
88%
Pt
4f,
4h,
89%
60%
4g,
C
a Optimization of the reaction conditions. C (carbon filled PPS, 5.0 × 4.0 cm)
anode, Pt (platinum coated, 5.0 × 4.0 cm) cathode, flow volume (0.225 mL),
1a(0.2mmol), 2a(0.12mmol), nBu4NBF4(0.4mmol.), CH3CN=8mL, I=10mA,
resident time =5.0 min (5.5F/mol), room temperature. b isolated yield.
Cathode
Anode
Ph
PhSe
1a
O
O
O
O
H+
+e
Continuous flow
OMe
O
D
DC
-e
PhSeSePh
0.936g
Ph
Ph
SePh
1.720g
C(+) / Pt(-)
1/2H2
-
1.180g
CH3
OH
Scheme 2. Gram scale synthesis in continuous flow
A scale-up reaction using 1 mmol and 5 mmol of 1a (1.18g) in
batch and continuous system was performed simultaneously in
order to verify the practical application of electrochemical
oxidation and the advantages of continuous flow (Scheme 2, for
more details about gram scale synthesis, see the ESI†).
Compared with the reaction in batch, the yield is greatly reduced
with the expansion of the scale, the reaction in a continuous
system can stably obtain the desired product in 91% yield even
if it is scaled up to 5 mol scale. It can be imagined the reaction in
flow can not only make the reaction simpler, greener, and more
efficient, but also has great potential in future industrial
applications.
CH3OH
3a
Scheme 4. Plausible reaction mechanism.
On the basis of above results and previous literature reports, 12
a
plausible reaction mechanism for electrochemical oxidative
cyclization is suggested in Scheme 4. Firstly, diphenyl selenide
is oxidized at the anode to a cationic radical intermediate A,
divided into phenyl-selenium radical B and phenyl-selenium
cation C, respectively. Phenyl-selenium cation C was reduced to
diphenyl-selenide at the cathode for the next cycle., while
phenyl-selenium radicals attack the C-C triple bond of o‑(1-
Alkynyl) benzoates 1a to provide vinyl radical D in high
regioselectivity. This in situ generated vinyl group then
undergoes intramolecular cyclization by reaction with OMe
moiety, resulting in the formation of the final product 3a and the
release of methyl positive ion, and then the methyl cation
captures the hydroxide anion in the solvent to generate CH3OH.
Ph
SePh
Ph
standard conditions
Tempo(2 equiv.)
(a)
PhSeSePh
OMe
O
O
O
2a
1a
3a,
0%
Ph
SePh
Ph
standard conditions
BHT(2 equiv.)
(b)
PhSeSePh
OMe
O
O
O
2a
1a
3a,
0%
Scheme 3. Control experiments.
For further investigation of the mechanism, some control
experiments were performed. When 2equiv of radical inhibitor
2,2,6,6-tertramethypiperidine oxide (TEMPO) or butylated
hydroxytoluene (BHT) was loaded, the reaction ceased and no
desired product 3a was obtained (Scheme 3a-b, for more control
experiment, see the ESI†), which indicated that the reaction is a
radical reaction. Furthermore, cyclic voltammetry (CV)
experiments were carried out to investigate the redox potential
of substrates (for more details about the cyclic voltammetry
experiments, see the ESI†). The oxidation peak of 1a was
Conclusion
In conclusion, we have successfully developed a green and
highly efficient continuous electrocatalytic strategy to synthesis
iso-coumarin derivatives via o ‑ (1-Alkynyl) benzoates under
oxidant-free and metal-free. This environmentally-friendly
strategy can efficiently use electrical energy, reduce post-
processing steps and emissions. And it shows broad substrate
adaptability and functional group tolerance, affording a series of
3
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10.1002/chem.202001766
Chemistry - A European Journal
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Experimental Section
General methods: o‑(1-Alkynyl)benzoates (0.2 mmol, 1equiv.), diphenyl
diselenide (0.12 mmol, 0.6 equiv.) and nBu4NBF4(0.4mmol, 2.0 equiv.)
were dissolved in CH3CN (8 mL). At ambient temperature, the reaction
mixtures were introduced into the electrochemical microreactor at 0.045
mL/min at a constant current of 10 mA. The reaction solution was
concentrated under reduced pressure. The reaction solution was
extracted with water (2 × 20 mL), and extracted with ethyl acetate (2 × 20
mL). The combined organic layers were dried over Na2SO4, filtered,
concentrated and purified by flash column chromatography using a
gradient of EtOAc/hexane (0-5%) as eluent to afford the
product.Experimental Details.
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Keywords: cyclization • electrochemistry • iso-coumarin •
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10.1002/chem.202001766
Chemistry - A European Journal
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Entry for the Table of Contents
O
O
Continuous flow
anode:carbon electrode
O
OMe
R2
R1
R1
R3XXR3
R2
XR3
Cathode:platinum electrode
nBu4NBF
4,I=10 mA,MeCN
40 examples
X=Se,Te
Up to 92% yield
Oxidant-free
Metal-free
Easy to handle
Broad scope
A novel method for the continuous synthesis of iso-coumarin derivatives by selenization and self-cyclization of alkynes through
electrochemical oxidation under metal-free and oxidant-free conditions has been developed.
5
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