Nickel-catalyzed electrochemical reductive decarboxylative coupling of: N -hydroxyphthalimide esters with quinoxalinones

Article abstract of DOI:10.1039/c9cc07840a

Herein the first example of electrochemically enabled, NiCl₂-catalyzed reductive decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with quinoxalinones is reported. A range of primary, secondary, tertiary aliphatic carboxylic acids and amino acid-derived esters were tolerated well. This decarboxylative coupling allows access to structurally diverse 3-alkylated quinoxalinones in up to 91% yields.

Full text of DOI:10.1039/c9cc07840a

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Nickel-catalyzed electrochemical reductive
decarboxylative coupling of N-hydroxyphthalimide
esters with quinoxalinones†
Cite this: Chem. Commun., 2019,
55, 14685
Received 6th October 2019,
Accepted 11th November 2019
ab
Fei Lian,a Kun Xu,
Chengchu Zeng
*
Wei Meng,a Haonan Zhang,a Zhoumei Tana and
a
*
DOI: 10.1039/c9cc07840a
rsc.li/chemcomm
Herein the first example of electrochemically enabled, NiCl2-catalyzed K2S2O8 are always needed. Besides, the functional group tolerance
reductive decarboxylative coupling of N-hydroxyphthalimide (NHP) for the alkyl radical precursors is not always good. NHP esters are
esters with quinoxalinones is reported. A range of primary, secondary, versatile Csp3 radical precursors with flexible functional group varia-
tertiary aliphatic carboxylic acids and amino acid-derived esters were tions.16 The electrochemical reductive decarboxylative coupling of
tolerated well. This decarboxylative coupling allows access to struc- NHP esters may provide diverse 3-alkylated quinoxalinones under
turally diverse 3-alkylated quinoxalinones in up to 91% yields.
mild conditions. Encouraged by previous studies on nickel-
catalyzed decarboxylative coupling of NHP esters with radical
Electrochemical metal catalysis significantly expanded the scope acceptors,17 and in continuation of our research interest in
of electrosynthesis by integrating sustainable electrosynthesis and electrochemical C–H functionalizations of quinoxalinones,18 we
powerful metal catalysis.1 This strategy arguably represents an herein report the first example of electrochemically enabled,
attractive means for enabling cross-coupling,2 C–H and CQC nickel-catalyzed reductive decarboxylative coupling of NHP esters
functionalization reactions.3 In contrast to precious 4d transition with quinoxalinones (Fig. 1b). The reaction tolerated a range
metals, nickel catalysis provides a unique single-electron-transfer of primary, secondary, and tertiary aliphatic carboxylic acids
catalytic cycle.4 The combination of electrosynthesis with a nickel and especially amino acid-derived NHP esters, providing
catalytic system would provide opportunities with great synthetic diverse 3-alkylated quinoxalinones in good to excellent yields.
potential. Indeed, some seminal studies have demonstrated the
Using 2-quinoxalinone 1a and NHP ester 2e as the model
synthetic utility of electrochemically driven nickel catalysis in substrates, we began our investigation into the optimal reaction
reductive cyclizations.5 In 2017, Baran and co-workers elegantly conditions (Table 1). When decarboxylative coupling of 1a and
established an electrochemical nickel-catalyzed amination 2e was performed in CH3CN with graphite felt as the anode and
reaction.6 Recently, groups of Hasen,7 Bio,8 Loren,9 Wang,10 nickel foam as the cathode under constant current electrolysis
Mei,11 Meggers,12 and Guo13 have independently broadened
the viable scope of electrochemical nickel catalysis in nonchiral
and chiral transformations. Despite these significant advances,
synthetic applications of electrochemical nickel catalysis are
still desired.
3-Alkylated quinoxalinones are unique structural motifs
existing widely in biologically active molecules (Fig. 1a).14 The
reported methodologies for the construction of 3-alkylated
quinoxalinones mainly relied on the oxidative coupling of alkyl
radical precursors with quinoxalinones.15 To achieve efficient
alkyl radical formation, chemical oxidants such as TBHP and
a Beijing Key Laboratory of Environmental and Viral Oncology, College of Life
Science & Bioengineering, Beijing University of Technology, Beijing 100124, China.
E-mail: kunxu@bjut.edu.cn, zengcc@bjut.edu.cn
b College of Chemistry and Pharmaceutical Engineering,
Nanyang Normal University, Henan 473061, China
Fig. 1 Electrochemically enabled, nickel-catalyzed 3-alkylated quinoxali-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
none synthesis.
c9cc07840a
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope with respect to NHP estersa
Entry
Catalyst
I/mA
Anode/cathode
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2ꢀglyme
NiBr2
4
4
6
8
8
8
8
8
8
8
8
8
8
8
8
8
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/C felt
C felt/Pt
Mg/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni foam
C felt/Ni plate
C felt/Ni foam
26
38
82
85
82
13
14
72
84
37
73
73
80
87
48
27
Ni(acac)2
NiCl2ꢀglyme
NiCl2(pph3)2
NiCl2(dppe)
NiCl2(Cy)2
NiCl2ꢀ6H2O
NiCl2ꢀ6H2O
—
a
Reaction conditions: 1a (0.3 mmol), 2e (0.6 mmol), LiClO4 (1.0 mmol),
nickel catalyst (0.06 mmol), 4,40-di-tert-butyl-2,20-bipyridine (dtbpy,
0.06 mmol), triethylamine (0.25 mL), anhydrous DMA (4 mL), graphite
felt (10 ꢁ 10 ꢁ 1 mm3) as the anode, nickel foam (10 ꢁ 10 ꢁ 1 mm3) as
b
the cathode, undivided cell, 8 mA, 60 1C, 3 h, Ar. Isolated yield.
c
CH3CN as the solvent.
(CCE) conditions, the desired product 3ae was isolated in 26%
yield (entry 1). When anhydrous N,N-dimethylacetamide (DMA)
was used as the solvent, the yield of 3ae increased to 38% (entry 2).
Further optimization showed that 3ae could be obtained in 85%
yield when the current was increased to 8 mA, while decreased
current density led to lower yields (entries 4 vs. 2 and 3). To
improve the chemical yield of 3ae, a series of electrode materials
were screened. The results showed that graphite felt and nickel
a
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), LiClO4 (1.0 mmol),
NiCl2ꢀ6H2O (0.06 mmol), dtbpy (0.06 mmol), triethylamine (0.25 mL),
anhydrous DMA (4 mL), graphite felt (10 ꢁ 10 ꢁ 1 mm3) as the anode,
nickel foam (10 ꢁ 10 ꢁ 1 mm3) as the cathode, undivided cell, 8 mA,
b
60 1C, 3 h, Ar; isolated yield. The yield in parentheses was the result
for a 3 mmol scale synthesis.
foam were the optimal electrode materials. Next, a series of nickel derived NHP esters were also tolerated well to give 3ak–3am in
catalysts were screened (entries 7–14). The results revealed that 40–74% yields. Moreover, amino acid derived NHP esters
readily available NiCl2ꢀ6H2O could give the best yield of 87% underwent the decarboxylative coupling with 2-quinoxalinone
(entry 14). The replacement of the Ni foam with a Ni plate 1a smoothly, affording the corresponding products 3an–3aq
decreased the yield to 48% (entry 15). Control experiments showed in 51–90% yields. To demonstrate the synthetic utility of this
that only 27% yield was obtained in the absence of a NiCl2 catalyst electrochemical protocol, a scale-up reaction of 1a with 2e was
(entry 16).
With the optimized reaction conditions identified, we began obtained in 68% yield (see the ESI† for details).
to survey the scope and the generality of the protocol by To further explore the synthetic potential of this electro-
carried out. To our delight, the desired product 3ae was
examining the reactions of 2-quinoxalinone 1a with a variety chemical methodology, the reaction of NHP ester 2e with a
of NHP esters 2. As shown in Table 2, redox active esters derived variety of 2-quinoxalinones 1 was investigated (Table 3). First,
from primary, secondary, tertiary carboxylic acids and also monosubstituted 2-quinoxalinones were investigated under the
amino acids with a broad scope are all suitable substrates, optimal conditions. Methyl, bromide, and cyano substituents
giving 3aa–3aq with up to 91% yield. First, a series of primary were well tolerated, giving the corresponding products 3ba–3da
carboxylic acid derived NHP esters were tested under the in 51–65% yields. When methyl substituted 2-quinoxalinones
optimal conditions. The results showed that the decarboxy- with a 1 : 1 regioisomer ratio were employed as the substrates,
lative coupling reactions underwent smoothly, giving the corres- the corresponding products 3ea and 3ea0 were obtained in 92%
ponding products 3aa–3ad with up to 89% yields. The secondary total yield. Similarly, with the regiomers of benzoyl substituted
carboxylic acid derived NHP esters were also suitable substrates, quinoxalinone (1 : 1 ratio) as the substrates, 3fa and 3fa0 were
yielding 3ae–3aj in 68–91% yields. It is noteworthy that tetrahydro- obtained in 32% and 29% yields, respectively. Then, disubstituted
2H-pyran-4-carboxylic acid derived NHP ester could give the corres- 2-quinoxalinones were tested under the standard conditions, and
ponding product 3ah in 68% yield. Next, the tertiary carboxylic acid the corresponding products 3ga–3ia were obtained in 61–92%
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Table 3 Substrate scope with respect to 2-quinoxalinonesa,b
Scheme 2 Proposed mechanism for the formation of 3ae.
at ꢂ1.3 V vs. Ag/AgNO3 (0.1 M in CH3CN) for substrate 2e. In
addition, the reductive potential of the complex of NiCl2ꢀ6H2O
with dtbpy was observed at ꢂ1.1 V vs. Ag/AgNO3 (0.1 M in
CH3CN). These results suggest that the Ni(II) complex is easier
to be reduced than substrate 2e.
Based on the above experimental studies and related litera-
ture reports,9 the reaction mechanism for the decarboxylative
coupling of quinoxalinone 1a with NHP ester 2e was proposed.
As depicted in Scheme 2, Ni(II) is first reduced to Ni(I) at the
cathode. The resulting Ni(I) species undergoes a single-electron-
transfer with NHP ester 2e to give Ni(II) species and a cyclohexyl
radical (path a). Meanwhile, the direct reduction of NHP ester 2e
at the cathode to generate a cyclohexyl radical can’t be ruled out
(path b).8 Then, the cyclohexyl radical undergoes an addition
reaction with complex 4 to give radical cation 5, which then loses
one molecule of H+ to afford radical 6. Finally, radical 6 undergoes
further oxidation and then loses one molecule of Ni(II)) to give the
desired product 3ae. Meanwhile, NEt3 is oxidized at the anode to
give a triethylamine radical cation.
In conclusion, we have developed the first example of NiCl2-
catalyzed electrochemical reductive coupling of NHP esters with
quinoxalinones. By integrating electrochemistry with nickel catalysis,
biologically important 3-alkylated quinoxalinones were obtained
in good to excellent yields. The present method features mild
conditions, cheap catalysts, a broad substrate scope, and excellent
functional group tolerance.
a
Reaction conditions: 1 (0.3 mmol), 2e (0.6 mmol), LiClO4 (1.0 mmol),
NiCl2ꢀ6H2O (0.06 mmol), dtbpy (0.06 mmol), triethylamine (0.25 mL),
anhydrous DMA (4 mL), graphite felt (10 ꢁ 10 ꢁ 1 mm3) as the anode,
nickel foam (10 ꢁ 10 ꢁ 1 mm3) as the cathode, undivided cell, 8 mA,
b
60 1C, 3 h, Ar. Isolated yield.
yields. The N-protected 2-quinoxalinones were also suitable
coupling partners, giving 3ja–3la in 57–74% yields. Notably, when
pyrido[3,4-b]pyrazin-2(1H)-one was employed as the substrate, the
coupling product 3ma was obtained in 30% yield.
To explore the mechanism for the decarboxylative coupling
of quinoxalinones with NHP esters, a series of control experi-
ments were performed. As shown in Scheme 1, the yield of
target product 3ae was reduced to 25% by including 3.0 equiv
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the standard
conditions. When 3.0 equiv. butylated hydroxytoluene (BHT)
was used as the radical inhibitor, no 3ae was observed. These
results indicate that this reaction involves radical species.
To gain more insight into the mechanism, cyclic voltammetry
(CV) experiments were carried out (see the ESI† for details).
The results showed that there is an obvious reduction peak
This work was supported by grants from the National Key
Technology R&D Program (2017YFB0307502), the National Natural
Science Foundation of China (No. 21871019), and the Project
funded by Beijing Postdoctoral Research Foundation.
Conflicts of interest
There are no conflicts to declare.
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