Electrochemical regioselective selenylation/oxidation of: N-alkylisoquinolinium salts via double C(sp2)-H bond functionalization

Article abstract of DOI:10.1039/d0cc06778d

An efficient, novel, and environmentally friendly electrochemical regioselective selenylation/oxidation of N-alkylisoquinolinium salts via double C(sp2)-H bond functionalization under undivided electrolytic conditions has been developed. A series of selenide isoquinolones were easily accessed through this sustainable and clean electrochemical system. The present protocol was further extended to afford selenide quinolones and 1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-ones. Furthermore, antiviral bioassays demonstrated that compound 3j exhibited excellent antiviral activity against tobacco mosaic virus (TMV), and its inhibition rate was up to 90%. This journal is

Full text of DOI:10.1039/d0cc06778d

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S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
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DOI: 10.1039/D0CC06778D
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Electrochemical Regioselective Selenylation/Oxidation of N-
Alkylisoquinolinium Salts via Double C(sp2)−H Bond
Functionalization
Received 00th January 20xx,
Accepted 00th January 20xx
a†
a†
a
a
a
DOI: 10.1039/x0xx00000x
Xiang Liu, Yajun Wang, Dan Song, Yuhan Wang, and Hua Cao*
Abstract: An efficient, novel, and environmentally friendly
electrochemical regioselective selenylation/oxidation of N-
OMe
Se
CO H (Me) N
2
2
OMe
MeO
MeO
MeO
N
alkylisoquinolinium
salts
via
double
C(sp2)−H
bond
functionalization under undivided electrolytic conditions has been
developed. A series of selenide isoquinolones were easily
accessed through this sustainable and clean electrochemical
system. The present protocol was further extended to afford
selenide quinolones and 1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-
ones. Furthermore, antiviral bioassays demonstrated that
compound 3j exhibited excellent antiviral activity against tobacco
mosaic virus (TMV), and its inhibition rate was up to 90%.
Se
N
MeO
N
Me
N
Me
N
Me
O
Me
O
CRTH2 antagonist
BRD9 inhibitor
Antiproliferative Antioxidant
Scheme 1 Biologically Active Natural Products and Drug Candidates
Indeed, organic electrochemistry is currently an increasingly
important issue. Owing to their replacement of oxidizing and
reducing agents with electric current, electrochemical
methods provide a reliable alternative to conventional
5
Isoquinolones are privileged building blocks and their
characteristic structural are widely present in natural products,
pharmaceuticals, and bioactive compounds. Also, isoquinolone
derivatives exhibit powerful physiological functions, including
antidepressant, antiulcer, antihypertensive agents, and in the
6
methods under mild conditions.
(
a) Oxidation of N-alkylisoquinolinium salts
1
-2
treatment of asthma and tumors (Scheme 1). Therefore,
tremendous efforts have been devoted to the construction of
isoquinolone derivatives. Direct oxidizing easily prepared
isoquinolinium salts utilizing terminal oxidant such as
traditional oxidation
√
R
R
X
R'
N
N
R'
Electroredox
H
C
Pt

O
K
3
Fe(CN)
6
was considered as an important synthetic
(
b) Electrochemical selenylation/oxidation of N-alkylisoquinolinium salts: This work
3
approach. But these methods usually need to use excess
expensive or hazardous oxidants, which makes the whole
process cumbersome. Later on, some elegant catalytic
oxidative functionalization of isoquinolines or isoquinolinium
H
SeR''
C
Pt
R
X
R'
undivided cell
R
N
+
R''SeSeR''
N
KI, base, O2
R'
H
O
salts for the synthesis of isoquinolone have been
documented. However, the electrochemical generation of Alkylisoquinolinium Salts
Scheme
2
Electrochemical Regioselective Selenylation/oxidation of N-
4
functionated isoquinolones through the anodic oxidation of N-
alkylisoquinolinium salts have not been reported to date
Scheme 2a). Though it was a potential alternative and
represented cleaned and more sustainable transformations.
Organoseleno compounds are of great significance in the
pharmaceutical industry, material sciences, and synthetic
chemistry. Particularly, recent studies have revealed that N-
(
7
heterocyclic molecules equipped with selenyl-substituents
show unique bioactivities and chemical properties (Scheme
8
a. School of Chemistry and Chemical Engineering and Guangdong Cosmetics
1).
Undoubtedly, it is highly desirable to expand green
Engineering
University, Zhongshan 528458, China.
E-mail: caohua@gdpu.edu.cn
&
Technology Research Center, Guangdong Pharmaceutical synthetic methods for the introduction of selenium groups to
9
the substituted heterocycles. Herein, we reported an
Electronic Supplementary Information (ESI) available: [details of any electrochemical regioselective selenylation/oxidation of N-
supplementary information available should be included here]. See
alkylisoquinolinium salts via double C(sp2)−H bond
DOI: 10.1039/x0xx00000x
†
These authors contributed equally to this work.
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functionalization under undivided electrolytic conditions to
yield selenide isoquinolones (Scheme 2b).
With the establishment of the optimal reaction conditions
(Table S1, entry 14), we turned our attention to investigate
View Article Online
DOI: 10.1039/D0CC06778D
H
SePh
electronic
and
steric
effects
on
electrochemical
C(+) | Pt(-), 10 mA
selenylation/oxidation with various N-alkylisoquinolinium
iodide salts (Scheme 3). The substrates 1 bearing both
electron-donating groups (-Me, -OMe, Ar, thienyl) and
electron-withdrawing groups (-Cl, -Br) at the C-6 position
provided good yields of the corresponding products 3b-3k. The
isoquinolinium salt with a substituent (−Ph, −Cl, −Br) at the C-7
position on the isoquinolin ring proceeded smoothly under the
optimal reaction conditions, leading to the 1,4-bisfunctional
products 3l-3n in 75-80% yields. The structure of 3l was
verified by X-ray diffraction (CCDC 2020934). Next, the effects
of C-5 and C-8 substituents on the isoquinolin ring were
examined. It was found that substrates 1o-1s all gave
satisfactory results. We have also attempted to use C-3
substituted isoquinolinium salts as substrate, but failed to
obtain the target product, which probably attributed to the
large steric hindrance of 1t.
R
R
I
PhSeSePh
N
+
N
O
MeCN: H O = 4: 1
Me
2
Me
KI, Cs CO , O
1
H
2a
2
3
2
3
SePh
3a, R = H, 83%
R
SePh
3
3
b, R = Me, 82%
c, R = Ph, 77%
3d, R = Cl, 75%
e, R = Br, 77%
3f, R = OMe, 72%
R
3g, R = OMe, 77%
N
O
3h, R = CF , 75%
3
Me
N
O
3
Me
SePh
SePh
N
SePh
S
O2N
N
O
N
O
3k, 60%
Br SePh
Me
Me
Me
O
3
i, 72%
3j, 64%
SePh
3l, R = Ph, 75%
3m, R = Cl, 78%
3n, R = Br, 80%
N
N
O
Me
R
Me
3l
O
CCDC: 2020934
NO2
SePh
3o, 73%
H
SePh
SePh
SePh
C(+) | Pt(-), 10 mA
N
Me
SePh
Me
X
R
PhSeSePh
N
+
N
O
MeCN: H O = 4: 1
N
O
N
O
2
R
Me
Me
KI, Cs CO , O
4
H
2a
2
3
2
5
N
O
R
O
Me
SePh
SePh
SePh
CO2CH3
3s, 70%
5a, X = I, R = Et, 79%
3q, R = Cl, 72%
3r, R = Br, 73%
3
t, 0%
5b, X = I, R = nPr, 77%
3
p, 63%
Ph
i
5
c, X = I, R = Pr, 75%
N
O
a
N
O
N
Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), KI (1.5 mmol), Cs
mmol), MeCN/H O = 4 mL/1 mL, O atmosphere, 10 mA, r.t., 10 h. Isolated yield.
Scheme 3 Substrate Scope of N-Methylisoquinolinium Salts
2
CO
3
(0.45
R
i
5
d, X = I, R = Bu, 72%
2
2
5e, X = I, R = nC7H15, 72%
O
a
5
f, X = Br, 72%
5g
, X = Br, 70%
SePh
SePh
SePh
To explore optimal reaction conditions, we commenced the
electrochemical selenylation/oxidation of isoquinolinium
iodide salts (1a) with diphenyl diselenide (2a) in an undivided
electrolytic cell under constant current (Tables S1 in the ESI).
Initially, no desired product 3a formation selecting KI as the
OH
CF3
N
O
N
N
O
O
Br
5
h, X = I, 65%
5i, X = I, 75%
5j, X = Br, 76%
SePh
SePh
Me
5
5
k, X = Br, R = F, 73%
l, X = Br, R = Me, 77%
R
electrolyte and MeCN/H
constant current (Table S1, entry 1). To our delight, the
reactions proceeded to achieve the selenylation/oxidation
2
O as the solvent under 10 mA
5m
,
5
X = Br, R = NO2, 68%
n, X = Br, R = Br, 72%
5o, X = Br, R =CF , 72%
N
O
N
O
3
5
p, X = Br, 73%
a
process when the bases such as Na
Cs CO were added (Table S1, entries 2-5). Cs
to be the most efficient base for this transformation. A series
of supporting electrolytes, such as KBr, NH I, n-Bu NI, n-
Bu NBF , and Et NPF , showed lower efficiency compared to KI
15−66% yields, Table S1, entries 6-10). Subsequently, different
kinds of solvents were screened with KI as the electrolyte and
Cs CO as the base under 10 mA constant current, and the
cosolvent of CH CN/H O (v/v = 4/1) provided the highest yield
compare Table S1, entries 11−13). On the contrary, the
cosolvent DMF/H O completely inhibited the transformation
2
CO
3 2 4
, KH PO , K
2
CO
3
, and
Reaction conditions: 4 (0.3 mmol), 2a (0.3 mmol), KI (1.5 mmol), Cs
mmol), MeCN/H O = 4 mL/1 mL, O atmosphere, 10 mA, r.t., 10 h. Isolated yield.
Scheme 4 Substrate Scope of N-Alkylisoquinolinium Salts
2 3
CO (0.45
2
2
2
3
2
CO
3
was found
a
4
4
Electrochemical selenylation/oxidation reaction was further
surveyed with different alkyl substituted N-alkylisoquinolinium
salts (Scheme 4). Substrates with linear and branched aliphatic
substituents (4a−4f) produced target molecules in reasonable
yields (72−79%). It is noteworthy that series of functional
groups including alkenyl, hydroxy, and trifluoromethyl could
be well tolerated (5g−5i). Subsequently, we turned our
attention to extend the substrates 4j-4p, in which the N-
substituent contained various benzyl groups. Corresponding
products 5j-5p were afforded in good yields (68−77%) under
the standard conditions.
The effects of different substituents of diselenides were
investigated (Scheme 5). We discovered that a variety of
functional groups on the aryl ring of the diphenyl diselenides
were suitable under this electrochemical protocol, and the
selenide isoquinolone derivatives could be generated in 67-74%
4
4
4
6
(
2
3
3
2
(
2
and no products were detected (Table S1, entry 12). To
improve the yield of 3a, the influence of atmosphere was
surveyed. We conducted this electrochemical transformation
at oxygen atmosphere instead of air atmosphere, resulting in
higher yield of 3a (Table S1, entry 14, 83%). Furthermore,
changing the operating current (5 mA) led to decrease the
product yield (Table S1, entry 15, 50%). Finally, control
experiment showed that no desired product was generated
without electricity (Table S1, entry 16).
2
| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
yields (6a−6g). Moreover, dibenzyl diselenide was also transformation. To probe redox potential of subsVtierwatAertsic,letOhnrleinee
tolerated under the conditions, the corresponding product 6h substrates (1a, 2a, and KI) in MeCN wDeOreI: 1o0p.1e0r3a9t/eDd0CiCn06c7y7c8liDc
was obtained in 74% yield.
voltammetry experiments (see ESI Figure S1). An oxidation
peak of 2-methylisoquinolin-2-ium iodide (1a) was observed at
0.94 V (vs Ag/Ag+), which was lower than the oxidation
potential of potassium iodide (at 1.13 V) and diphenyl
diselenide (2a, at 1.81 V). These results indicated that 1a and
KI are oxidized preferentially at the anode. Furthermore, when
isoquinolinium salt 1a was reacted under the electrocatalytic
conditions without diphenyl diselenide (2a), intermediate 2-
methylisoquinolin-1(2H)-one 9 was formed. The intermediate
H
SeR
C(+) | Pt(-), 10 mA
I
RSeSeR
N
+
N
O
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
CH3
CH3
1
a H
2
6
R = 4-Me, 6a, 70%
Ph
Se
R
R = 4-F, 6b, 71%
R = 4-CF3, 6c, 67%
R = 3-Cl, 6d, 69%
R = 2-Cl, 6e, 68%
Se
N
9
could further react with diphenyl diselenide (2a) to generate
Me
N
O
the final selenylation product (eq. 6). In order to illustrate the
Me R = 2-Ph, 6f, 72%
g, 74%
6
h, 74%
role of KI, we used I instead of KI as the iodine source without
R = 2-OMe,
6
2
O
electricity. No product 3a was obtained (eq. 7). The results
a
Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), KI (1.5 mmol), Cs
2
CO
3
(0.45
revealed that I
2
could not oxidize the isoquinolinium salts.
mmol), MeCN/H O = 4 mL/1 mL, O atmosphere, 10 mA, r.t., 10 h. Isolated yield.
2
2
Scheme 5 Substrate Scope of Diselenides a
SePh
C(+) | Pt(-), 10 mA
To prove the efficiency and practicability of electrochemical
selenylation/oxidation reaction, we performed large-scale
reaction using N-methylisoquinolinium salts 1a as the
substrate under the standard conditions. The selenide
isoquinolones could still be accessed in 78% yield (eq. 1). In
addition, this method could also be extended to prepare
selenide quinolones. N-methylquinolinium salts 7a underwent
the similar selenylation/oxidation process to produce 7b in
moderate yield (eq. 2). Finally, we tried to oxidize 1,3-
(4)
I
PhSeSePh
N
N
+
N
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
detected by HRMS (using 18O2 or H2O18)
Me
Me
3a'
O18
1
a
2a
SePh
C(+) | Pt(-), 10 mA
(5)
I
+
PhSeSePh
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
N
Me
Me
2a
1
a
3
a
O
additive: TEMPO, 35%; 1,1-diphenyl ethene, 40%
SePh
standard
conditions
electrolysis
N
(
6)
7)
I
N
N
Me PhSeSePh
N
dimethyl-1H-benzo[d]imidazol-3-ium
iodide
8a
via
Me
Me
O
1
a
9, detected
O
electrochemical synthesis. To our delight, the target product
3
a, detected
SePh
8
b was obtained in 94% yield (eq. 3).
H
SePh
without electrolysis
(
I
+
PhSeSePh
+
I2
MeCN: H2O = 4: 1
Cs2CO3, O2
N
C(+) | Pt(-), 10 mA
Me
Me
I
1a
2a
2 equiv.
(1)
N
+
PhSeSePh
O
N
O
Me
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
3a, n.d.
Me
1
a
H
2a
Scheme 7 Control Experiments
(
4 mmol, 1.08 g)
3
a (0.99 g, 78%)
Gram-scale synthesis
SePh
H
C(+) | Pt(-), 10 mA
Based on the above control experiments and the literature
reports,4,9
plausible reaction mechanism for the
electrochemical 1,4-difunctionalization of isoquinolinium salts
(
2)
3)
+
PhSeSePh
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
a
+
N
O
N
- H
I
2a
Me
b, 54%
7
a
Me
Me
7
Me
N
+
-
N I
C(+) | Pt(-), 10 mA
(
O
H
SePh
MeCN: H2O = 4: 1
KI, Cs2CO3, O2
N
N
Me
C
Pt
cathode
2H+
+ 2e-
8
a
Me
b, 94%
2I-
+
anode
N
8
Me
- 2e-
Scheme 6 Further Applications a
3a O
2 RSeI
H2
I2
PhSeSePh
To gain further insights into the mechanism of this
electrochemical 1,4-difunctionalization of isoquinolinium salts
with diselenides, several control experiments were executed
+
0.5 O2
H2O
Me
N
N
N
I
Me
Me
9
I
H
OH
1a
O
1
8
O2
(
Scheme 7). First, O-labeling experiments were carried out.
O
H2
1
8
The O-labeling product 3a' was detected by HRMS whether
O2
1
8
- H-
using
H
O
2
replaced common oxygen as atmosphere or using
N
.
N
N
Me
Me
Me
O
1
8
IV O+
.
2
O
replaced H O (eq. 4), which suggested that oxygen
2
II
III
.
OH
H
O
O
atoms in carbonyl group of 3a probably originated from
molecular oxygen and water. In addition, yield of 3a drop
decreased when 2 equiv. of radical scavenger TEMPO and 1,1-
diphenyl ethene was added to the electrocatalytic system (eq.
Scheme 8 Plausible Mechanistic Pathway
has been proposed in Scheme 8. First, nucleophilic addition of
2
H O to 1a produces the intermediate I, which was oxidized at
5
), which showed a radical process involved in the
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J. Name., 2013, 00, 1-3 | 3
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1
2
N. Kaila, B. Follows, L. Leung, J. Thomason, VAie.wHArutiaclne gO,nliAne.
the surface of anode to generate radical intermediate II.
Probably, oxidation of radical intermediate II to 9 involved two
pathways. First, the intermediate II was combined with
molecular oxygen to form alkperoxide III, which underwent a
proton loss to give oxygen-centered radical IV. Next, cleavage
of the O−O bond in IV at cathode, intermediate 9 was
obtained. Second, the intermediate II was directly oxidized by
Moretto, K. Janz, M. Lowe, T. S. Mansour, C. Hubeau, K.
DOI: 10.1039/D0CC06778D
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-
oxidation of I produced I
2
, which reacted with diselenide 3a to
3
4
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afford the product 3a and two protons. Cathodic reduction of
proton hydrogen render to the formation of hydrogen.
Finally, we also tested the antiviral activity of selenide
isoquinolones (Table S3 and Figure S3 in the ESI). A half-leaf
method was used to determine therapeutic effect against
tobacco mosaic virus (TMV). It is gratifying to note that some
compounds had shown good antiviral activity against TMV at a
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-1
concentration of 500 μg mL . Particularly, compound 3j
showed excellent inhibition effect on TMV, and its inhibition
rate was up to 90%, which even exceeded that of the positive
control (ningnanmycin, 64.1%). Further structural optimization
and structure-activity relationship studies are in progress.
5
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In conclusion, we have disclosed an efficient and
environmentally friendly electrochemical regioselective 1,4-
difunctionalization of isoquinolinium salts with diselenides. By
this protocol, various selenide isoquinolones were accessed
under undivided electrolytic conditions. In addition, the
electrocatalytic system was successfully extended to
synthesize selenide quinolones and 1,3-dimethyl-1H-
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benzo[d]imidazol-2(3H)-ones.
Importantly,
selenide
isoquinolones prepared by present method exhibited high
fluorescence absorption and emission intensity, and good
antiviral activity against tobacco mosaic virus. More in-depth
studies of biological activity are ongoing and will be reported
in near future.
6
48–651.
8
9
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (22001045), Outstanding Youth Project of
Guangdong Natural Science Foundation (2020B1515020026),
the Innovation and Strong School Project of Guangdong
Pharmaceutical University (2019KQNCX061), Special funds of
key disciplines construction from Guangdong and Zhongshan
cooperating.
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Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/D0CC06778D
TCE Graphic
Electrochemical Regioselective Selenylation/Oxidation of N-Alkylisoquinolinium
Salts via Double C(sp2)−H Bond Functionalization
†
†
Xiang Liu, Yajun Wang, Dan Song, Yuhan Wang, and Hua Cao *
An efficient and environmentally friendly electrochemical regioselective selenylation/oxidation of N-
alkylisoquinolinium salts via double C(sp2)−H bond functionalization has been developed.
H
SeR''
C
Pt
R
undivided cell
R
X
R'
N
+
R''SeSeR''
N
O
KI, base, O2
R'
H
Electrochemical redox
Good regioselectivity
Broad substrate scopes
Metal-free
4
5 examples
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