Electrochemical decarboxylative C3 alkylation of quinoxalin-2(1: H)-ones with N -hydroxyphthalimide esters

Article abstract of DOI:10.1039/d0cc05391k

We have developed a protocol for electrochemical decarboxylative C3 alkylation of a wide range of quinoxalin-2(1H)-ones under metal- and additive-free conditions. N-Hydroxyphthalimide esters derived from chain, cyclic, primary, secondary, and tertiary carboxylic acids with a broad scope proved to be suitable substrates. This operationally simple protocol performed in an undivided cell under constant-current conditions is suitable for late-stage functionalization of quinoxalin-2(1H)-ones. The reactions can even be carried out with a 3 V battery as a power source, which demonstrates that organic electrosynthesis can be accomplished without the need for specialized equipment.

Full text of DOI:10.1039/d0cc05391k

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DOI: 10.1039/D0CC05391K
COMMUNICATION
Electrochemical Decarboxylative C3 Alkylation of Quinoxalin-
2(1H)-ones with N-Hydroxyphthalimide Esters
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Kaikai Niu, a Lingyun Song, a Yanke Hao, a Yuxiu Liu a and Qingmin Wang*a,b
We have developed a protocol for electrochemical decarboxylative C3
alkylation of a wide range of quinoxalin-2(1H)-ones under metal- and
additive-free conditions. N-Hydroxyphthalimide esters derived from chain,
cyclic, primary, secondary, and tertiary carboxylic acids with a broad scope
proved to be suitable substrates. This operationally simple protocol
performed in an undivided cell under constant-current conditions is
suitable for late-stage functionalization of quinoxalin-2(1H)-ones. The
reactions can even be carried out with a 3 V battery as a power source,
which demonstrates that organic electrosynthesis can be accomplished
without the need for specialized equipment.
organic electrosynthesis, and various electrochemical reactions that
form C–C,11 C–N,12 C–O,13 and C–S14 bonds under mild conditions
have been reported. Inspired by this elegant work, we have now
developed an electrochemical protocol for decarboxylative C3
alkylation of quinoxalin-2(1H)-ones with N-hydroxyphthalimide
(NHP) esters, which are prepared in one step from the
corresponding carboxylic acids and served as excellent alkyl radical
precursors (Scheme 1).15
previous work
R2
R2
New methods and strategies for the direct functionalization of
N
O
H
Peroxide, Transition-Metal
N
O
R1
Alkyl
radical source
quinoxalin-2(1H)-ones1 and other N-heterocycles2 can greatly fulfill
the demand of high-throughput drug screening.3 The direct C3
alkylation of quinoxalin-2(1H)-ones has played a prominent role in
this context owing to the utility of C3 alkylated quinoxalin-2(1H)-
ones as versatile drug candidates.4 Quinoxalin-2(1H)-ones alkylated
at C3 have traditionally been synthesized by reactions of 1,2-
diaminobenzene derivatives with alkyl-substituted keto esters or
acids.5 In recent years, substantial effort has been devoted to
developing methods for direct C3 alkylation of quinoxalin-2(1H)-
ones6. Most of these methods involve addition reactions of alkyl
radicals generated from their precursors by means of radical
initiators (Scheme 1). However, despite many attempts to improve
the practicality and efficiency of these methods, most of them
require stoichiometric amounts of oxidants,7 metal catalysts,8 or
photocatalysts.9 Therefore, greener and more sustainable methods
for direct C3 alkylation of quinoxalin-2(1H)-ones would be desirable.
We speculated that electrochemistry could serve this purpose.
Electrochemistry, which is a powerful and economical way of
forging new chemical bonds, uses electrons as a clean, renewable
reagent.10 The past few years have witnessed booming interest in
R1
Homogenous or Heterogeneous PC/hv
N
Alkyl
N
this work
A
R2
N
R2
N
O
O
H
O
DC power or battery
O
R1
R1
N
rt, air, undivided cell
Alkyl
O
N
Alkyl
N
O
mild conditions
simple scale-up and operation
additive free
open flask
Scheme 1. Strategies for direct C3 alkylation of quinoxalin-2(1H)-
ones by means of a radical intermediate.
We commenced our investigation by using 1-methylquinoxalin-
2(1H)-one (1a) and NHP ester 2a as model substrates to optimize
the reaction conditions (Table 1). We were pleased to find that
when we used graphite plates as electrodes, dimethylacetamide
(DMA) as the solvent, nBu4NBF4 as the electrolyte, and a current
density of 5 mA/cm2, desired product 3aa could be obtained in 85%
yield by 1H NMR spectroscopy and 92% isolated yield after 12 h
under an air atmosphere (entry 1). When we shortened the
reaction time, the yield decreased (entries 2 and 3). Decreasing or
increasing the current density also lowered the yield (entries 4–7).
Evaluation of different solvents revealed that DMA was the best
choice (entries 8–10). In addition, control experiments indicated
that the current and the electrolyte were essential for this reaction
and that it was unaffected by air (entries 11–13). The structure of
3aa was unambiguously confirmed by X-ray analysis (Scheme 2).
a. State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People’s Republic of China. E-mail: wangqm@nankai.edu.cn
b. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300071, People’s Republic of China
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
J. Name., 2013, 00, 1-3 | 1
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a
Table 1. Optimization of the reaction conditionsa
Scheme 2. Substrate scope with respect to the NHP ester
DOI: 10.1039/D0CC05391K
C/
C
C/
C
nBu4NBF4
nBu4NBF4
O
O
N
N
O
N
N
O
R
DMA, r.t.
N
O
O
O
N
N
O
DMA, r.t.
N
O
undivided cell
5 mA/cm2, 12 h
R
N
O
O
undivided cell
5 mA/cm2, 12 h
N
1a
O
2
3
O
3aa
1a
2a
N
N
N
N
O
N
O
Entry
Variation from standard
Yieldb (%)
N
conditions
none
3ab, 66%
3ac, 70%
3aa, 92%
CCDC 2009783
1
85 (92c)
13
31
62
74
72
15
34
43
53
0
N
N
O
N
N
O
N
N
O
N
N
O
O
2
3
1.5 h
8
4
O
3ad, 71%
4.5 h
3 mA/cm2
8 mA/cm2
3ae, 54%
3af, 70%
3ag, 82%
4
N
N
O
N
N
O
N
N
O
N
N
O
5
F
O
F
6
10 mA/cm2
15 mA/cm2
MeCN as solvent
DMSO as solvent
DMF as solvent
No electricity
No electrolyte
Under Air
3ah, 76%
3ai, 70%
3aj, 85%
3ak, 81%
7
N
N
O
N
N
O
N
N
O
N
N
O
8
9
3am, 52%
3an, 40%
3ao, 57%
3al, 75%
10
11
12
13
N
N
O
N
N
O
O
H
H
NHBoc
H
H
O
O
0
3ap, 72%
From valine
3aq, 43%
From dehydrocholic acid
87
n
aReaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Bu4NBF4
(2.0 equiv), DMA (5 mL), undivided cell with two graphite
electrodes (each 1.0 × 1.0 cm2), room temperature (r.t.), 5 mA/cm2,
12 h. bYields were determined by 1H NMR spectroscopy with CH2Br2
as an internal standard. cIsolated yield.
aReaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), nBu4NBF4
(2.0 equiv), DMA (5 mL), undivided cell with two graphite
electrodes (each 1.0 × 1.0 cm2), room temperature (r.t.), 5 mA/cm2,
12 h. Isolated yields are provided.
Scheme 3. Substrate scope with respect to the quinolin-2(1H)-
onea
Having optimized the conditions, we investigated the scope of
the reaction with respect to the NHP ester (Scheme 2). To our
delight, a wide range of chain, cyclic, primary, secondary, and
tertiary NHP esters proved to be suitable substrates (3aa–3ao).
Included were some heterocyclic substrates, which gave products
3aj and 3ak. Furthermore, NHP esters derived from valine and
dehydrocholic acid were also acceptable, affording 3ap and 3aq and
suggesting that this method is applicable to other amino acids and
natural products.
R2
C/
C
O
nBu4NBF4
DMA, r.t.
R2
N
O
N
O
O
R1
N
O
R1
undivided cell
5 mA/cm2, 12 h
N
O
N
1
2a
3
N
N
O
N
O
N
N
O
Cl
N
N
O
R3
F
N
Cl
R3 6-Me 3ba
=
R3 7-Me 3ba'
3ba:3ba'=1:1, 70%
=
3ca, 64%
3da, 46%
3ea, 53%
We also investigated the scope with respect to the quinoxalin-
2(1H)-one (Scheme 3). Substrates 1 bearing various substituents on
the aromatic ring (methyl, chloro, fluoro, cyano, methoxy, and
trifluoromethyl) reacted smoothly with 2a under the optimal
conditions to produce the corresponding products (3ba–3ka) in
moderate to good yields. Furthermore, in addition to 1-
methylquinoxalin-2(1H)-ones, quinoxalin-2(1H)-ones bearing an
npropyl, benzyl, or ethoxycarbonylmethylene group on the nitrogen
were also suitable substrates, providing 3la–3na, respectively. It is
worth noting that sensitive allyl and alkyne groups were also
retained under the reaction conditions (3oa and 3pa). In addition,
3qa could be synthesized from the corresponding substrate with an
unprotected nitrogen atom on the quinoxalin-2(1H)-one moiety.
N
N
O
N
N
O
N
N
O
N
N
O
NC
MeO
F3
C
3ha, 54%
3ia, 76%
3fa, 75%
3ga, 55%
F
N
N
O
Cl
Cl
N
N
O
N
N
O
N
N
O
F
3ma, 56%
3ja, 50%
O
3ka, 43%
3la, 67%
O
H
N
N
O
N
N
O
N
N
O
N
N
O
N
Boc
3qa, 83%
3pa, 63%
3oa, 65%
3na, 86%
aReaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), Bu4NBF4 (2.0
equiv), DMA (5 mL), undivided cell with two graphite electrodes
(each 1.0 × 1.0 cm2), room temperature (r.t.), 5 mA/cm2, 12 h.
Isolated yields are provided.
n
2 | J. Name., 2012, 00, 1-3
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Having explored the substrate scope, we turned our attention undergoes N–O bond cleavage followed by decarboxylation to give
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DOI: 10.1039/D0CC05391K
to the mechanism (Scheme 4). First, when 2.0 equiv of a radical corresponding alkyl radical B. This reactive species adds to the
inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidinooxy) or BHT (2,6-di- quinoxalinone to furnish nitrogen-centered radical C. Next, a 1,2-H
tert-butyl-4-methylphenol), was added to the standard reaction shift gives carbon-centered radical D, which undergoes single-
mixture (Scheme 4A), alkylation was completely suppressed. When electron oxidation at the anode, followed by deprotonation, to give
N-phenylmethacrylamide (1r) was subjected to electrolysis with product 3aa.
NHP esters 2a and 2o under the standard conditions, radical
addition products 3ra and 3ro were detected by high-resolution
mass spectrometry16 (Scheme 4B, 4C). These results indicate that
Scheme 5. Proposed mechanism
this reaction probably proceeded via
a radical pathway.
O
O
N
N
O
N
O
Furthermore, cyclic voltammetry showed that the reduction
potentials of substrates 1a and 2a were −1.67 and −1.23 V (vs. SCE),
respectively; that is, 2a was more easily reduced than 1a at the
surface of the cathode (Figure 1).1a The reduction peak of 2a
indicates a reductive pathway for alkyl radical generation.
H
N
O
N
H
O
2a
3aa
+e-
oxidation -e-
reduction
N
O
O
,

2 H Shift
N
O
N
N
O
N
1
O
CO2
N
O
NPhth
N
H
Scheme 4. Mechanistic studies
O
radical addition
A
A
B
C
D
C/
C
anode
cathode
nBu4NBF4
O
O
N
N
O
N
N
O
DMA, r.t.
N
O
undivided cell
5 mA/cm2, 12 h
O
To verify the practicality of this protocol, we carried out a
scaled-up reaction. Specifically, when 6.0 mmol of 1-
methylquinoxalin-2(1H)-one (1a) was allowed to react with NHP
ester 2a under the standard condition, 3aa was isolated in 88%
yield, indicating no loss in efficiency (Scheme 6A). In addition, the
reaction could be carried out in one pot, without separation of the
NHP ester (Scheme 6B). Finally, in a further test of the robustness of
this electrochemical reaction, we performed it using a 3 V battery
and obtained a 90% yield of 3aa (Scheme 6C).
3aa
NR
NR
1a
2a
2 eq TEMPO
2 eq BHT
B
O
C/
C
O
nBu4NBF4
N
N
DMA, r.t.
O
N
O
undivided cell
5 mA/cm2, 12 h
O
O
2a
3ra
1r
Detected by HRMS
[M+H]+: 260.2014
found: 260.2014
C/
C
C
nBu4NBF4
O
Scheme 6. Practicality of the electrochemical method
DMA, r.t.
N
O
N
N
O
undivided cell
5 mA/cm2, 12 h
O
O
O
A. Gram scale synthesis
C/
C
nBu4NBF4
O
2o
3ro
1r
O
Detected by HRMS
[M+H]+: 312.2327
found: 312.2327
N
N
O
DMA, r.t.
3aa
N
O
undivided cell
15 mA, 40 h
O
1a, 6 mmol
2a
1.28g, 88%
-8
-6
-4
-2
0
1a
2a
B. One-pot synthesis
O
N
N
O
O
N
N
O
DIC, DMAP
DCM
OH
HO
N
C/
C
undivided cell
5 mA/cm2, 12 h
O
2
4
3aa, 87%
6
8
C. Use of 3-V battery as a readily available power source
10
C/
C
nBu4NBF4
DMA, r.t.
O
O
-2.5
-2.0
-1.5
-1.0
-0.5
N
N
O
E (V) vs Fc/Fc+
3aa
N
O
two 1.5 V NANFU battery
connection in series
O
undivided cell, 12 h
Figure 1. Cyclic voltammograms of 1a and 2a in 0.1 M
nBu4NPF6/MeCN at a scan rate of 100 mV/s. The reduction
potentials versus an aqueous SCE (E1a/1a- = −1.67 V; E2a/2a- = −1.23 V)
were calibrated by the addition of ferrocene (Fc) as an internal
standard; E(Fc/Fc+)0 = 0.424 V vs SCE.17
On the basis of literature reports, a proposed mechanistic
pathway for this electrochemical decarboxylative C3 alkylation is
depicted in Scheme 5. Initially, single-electron reduction of NHP
ester 2a at the cathode generates radical anion A, which then
90%
1a
2a
Conclusions
In conclusion, we have developed a protocol for metal- and
additive-free electrochemical decarboxylative C3 alkylation of
quinoxalin-2(1H)-ones with NHP esters, and we demonstrated its
practicality, scalability, and operational simplicity. We believe that
this protocol has potential utility for pharmaceutical derivatization
and other industrial applications.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the National Natural Science Foundation of China
(21732002, 21672117) for financial support for our programs.
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05391K
Table of Contents (TOC)
A
R2
R2
O
DC power or battery
rt, air, undivided cell
N
O
H
N
O
O
R1
R1
N
Alkyl
O
N
Alkyl
N
O
mild conditions
simple scale-up and operation
additive free
open flask
Electrochemical decarboxylative C3 alkylation of
a
wide range of
quinoxalin-2(1H)-ones under metal- and additive-free conditions was reported.