Catalyst-free electrochemical decarboxylative cross-coupling of: N -hydroxyphthalimide esters and N-heteroarenes towards C(sp3)-C(sp2) bond formation

Article abstract of DOI:10.1039/c9cc08528a

Cheap and widely available carboxylic acids are a class of ideal substrates to construct valuable compounds. As a candidate of decarboxylative reactions, the acid-based neutral N-hydroxyphthalimide ester undergoes a reductive decarboxylative process rather than a common oxidative decarboxylative process, which is a potential transformation mode for new reactions. In this work, we developed an electrochemical C(sp³)-C(sp²) coupling of N-hydroxyphthalimide esters and N-heteroarenes without any catalysts. Remarkably, this electrochemical protocol can not only be directly realised by carboxylic acids in a one-pot fashion, but also be scaled up using a continuous-flow reactor.

Full text of DOI:10.1039/c9cc08528a

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Catalyst-free electrochemical decarboxylative
cross-coupling of N-hydroxyphthalimide esters
and N-heteroarenes towards C(sp3)–C(sp2) bond
formation†
Cite this: Chem. Commun., 2019,
55, 14922
Received 1st November 2019,
Accepted 14th November 2019
Yichang Liu,a Liwei Xue,a Biyin Shi,a Faxiang Bu,a Dan Wang,a Lijun Lu,a Renyi Shi*a
DOI: 10.1039/c9cc08528a
ab
and Aiwen Lei
*
rsc.li/chemcomm
Cheap and widely available carboxylic acids are a class of ideal
substrates to construct valuable compounds. As a candidate of
decarboxylative reactions, the acid-based neutral N-hydroxy-
phthalimide ester undergoes a reductive decarboxylative process
rather than a common oxidative decarboxylative process, which is a
potential transformation mode for new reactions. In this work, we
developed an electrochemical C(sp3)–C(sp2) coupling of N-hydroxy-
phthalimide esters and N-heteroarenes without any catalysts.
Remarkably, this electrochemical protocol can not only be directly
realised by carboxylic acids in a one-pot fashion, but also be scaled
up using a continuous-flow reactor.
Scheme 1 Decarboxylative reaction.
Alkyl carboxylic acids are widely present in natural products,
pharmaceuticals and agrochemicals. The decarboxylative reaction
of alkyl carboxylic acids is an efficient method to produce alkyl carbon radical.8 During the past few years, NHP esters have been
radicals due to the good site selectivity with CO2 release.1 This widely applied in photochemical synthesis.9 For Minisci-type
13
process has been performed well in transition-metal catalysis,2 arylation, Fu,10 Wang,11 Opatz12 and Noel have achieved
¨
photochemistry3 and electrochemistry.4 The famous Kolbe reaction photo-induced C(sp3)–C(sp2) bond formation. In most reports,
is a classic case of electrochemical oxidative decarboxylative precious or complicated photosensitizers, such as iridium
reaction4c,5 (Scheme 1A). However, this type of reaction usually complexes10b or copper complexes,11 were generally essential
needs base, which can react with carboxylic acids to afford the (Scheme 1B).
corresponding carboxylates. The carboxylates could lose an
Recently, electrochemical synthesis has attracted more and
electron more easily at the anode. So, the Kolbe pathway might more attention, avoiding the use of catalysts and oxidants,
be inappropriate in some systems requiring strong acid, such as which meet with the requirement of green and sustainable
Minisci-type reactions.6 Moreover, strong proton acceptors are chemistry.14 However, reductive decarboxylation of NHP esters
not compatible with systems involving carboxylic acids.7
at the cathode remains less developed.15 As a complement of
In order to solve the above problems, chemists made many the Kolbe reaction, obtaining radicals at the cathode may
efforts towards exploring new strategies. For example, the acid– provide opportunities to achieve new reactions. In this work,
base neutral N-hydroxyphthalimide (NHP) ester can undergo a we introduced a simple and efficient electrochemical protocol
reductive decarboxylative protocol to generate the corresponding of NHP esters and quinoline derivatives to construct C–C bonds
without any catalysts (Scheme 1C).
We started our investigation by using the NHP ester (1d) and
a Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences,
4-methylquinoline (2a) as the model substrates. By using
p-toluenesulfonic acid (p-TsOH) as the additive, nBu4NBF4 as
Wuhan University, Wuhan 430072, Hubei, P. R. China.
E-mail: aiwenlei@whu.edu.cn
b National Research Center for Carbohydrate Synthesis, Jiangxi Normal University,
the electrolyte and dimethylacetamide (DMA) as the solvent, the
desired product could be obtained in 87% GC yield and 91% isolated
Nanchang 330022, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc08528a yield under 7.5 mA constant current for 150 min (Table 1, entry 1).
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Table 1 Effects of reaction parametersa
Entry
Variation(s) from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
87 (91)c
71
77
84
80
70
86
84
80
55
77
9
88
n.d.
n.d.
5 mA instead of 7.5 mA, 225 min
12.5 mA instead of 7.5 mA, 90 min
CH3SO2H instead of p-TsOH
TFA instead of p-TsOH
CF3SO2H instead of p-TsOH
DMSO instead of DMA
DMF instead of DMA
MeCN instead of DMA
(+) C rod|C rod (ꢀ)
9
10
11
12
13
14
15
(+) GF|C rod (ꢀ)
(+) GF|Pt (ꢀ)
In air
Without electric current
Cyclohexanecarboxylic acid instead of 1d
a
Reaction conditions: graphite felt anode (15 mm ꢁ 10 mm ꢁ 3 mm),
graphite felt cathode (15 mm ꢁ 10 mm ꢁ 3 mm), constant current =
7.5 mA, 1d (2 equiv., 0.4 mmol), 2a (1.0 equiv., 0.20 mmol), p-TsOH
(1.5 equiv., 0.3 mmol), nBu4NBF4 (0.05 M, 0.25 mmol), DMA (5 mL),
Scheme 2 Substrate scope of the reaction.a a Reaction conditions: graphite
felt anode (15 mm ꢁ 10 mm ꢁ 3 mm), graphite felt cathode (15 mm ꢁ 10 mm ꢁ
3 mm), constant current = 7.5 mA, 1 (2 equiv., 0.4 mmol), 2 (1.0 equiv.,
0.20 mmol), p-TsOH (1.5 equiv., 0.3 mmol), nBu4NBF4 (0.05 M, 0.25 mmol),
DMA (5 mL), room temperature, N2, 150 min (3.5 F), isolated yield. b NMR yield
with CH2Br2 as the internal standard. c 1 (4 equiv., 0.8 mmol) was used and the
time was extended to 300 min.
b
room temperature, N2, 150 min (3.5 F). The yields were determined
by GC analysis with biphenyl as the internal standard. Isolated yield.
c
n.d. = not detected.
When we decreased or increased the current, the yield decreased
(Table 1, entries 2 and 3). When other strong acids such as
methane sulfonic acid and trifluoroacetic acid (TFA) were used,
the yield decreased slightly (Table 1, entries 4 and 5). The trifluoro- On the other hand, other quinolines substituted with methyl
methanesulfonic acid seemed to be worse (Table 1, entry 6). For the could also afford good yields (3ab and 3ac). The chlorine atom
solvent, polar solvents such as N,N-dimethylformamide (DMF), was compatible with this system (3ad). The electron-rich
dimethyl sulfoxide (DMSO), and MeCN demonstrated similar 6-(morpholinyl)-2-methylquinoline led to a moderate isolated
reactivity to DMA (Table 1, entries 7–9). The variation of electrodes yield (3ae). When doubling the amount of ester and time, the
had the biggest influence on this reaction. Carbon-based materials unsubstituted quinoline could give the disubstituted product
showed good activity at both the anode and cathode. And graphite selectively (3af). For other N-heteroarenes, the phenanthridine
felt was better than carbon rods (Table 1, entries 10–12). This furnished the corresponding product in 97% yield (3ag). The
reaction could proceed smoothly in air (Table 1, entry 13). In isoquinoline only afforded 35% product due to the complicated
summary, multiple solvent/acid choices and air can provide more side reaction (3ah). But, with C4 being substituted with the
potential application opportunities. Finally, the product cannot be bromo atom, the yield improved to 65% (3ai) (Scheme 2).
detected without electric current (Table 1, entry 14). In addition,
cyclohexanecarboxylic acid cannot replace the NHP ester under achieve this transformation in a one-pot fashion. Without
these conditions (Table 1, entry 15). separation of the ester, the following electrochemical reaction
In order to make this protocol more convenient, we tried to
With the best optimized reaction conditions in hand, we would not be influenced (Scheme 3A). Remarkably, we scaled up
focused on exploring the substrate scope. Firstly, both chain this reaction on a gram-scale under a continuous-flow system (for
and cyclic tertiary carboxylic esters could afford the corres- more details please check the ESI,† S11). In this system, we tried
ponding products in moderate to good yield (3aa, 3ba and 3ca). to decrease the reaction time. The flow system had a higher
For secondary aliphatic carboxylic esters, the yields decreased faradaic efficiency and a good isolated yield (Scheme 3B). To our
to moderate values except for the cyclohexyl ester (3da, 3ea and delight, the Katritzky N-cyclohexylpyridinium salt (Scheme 3, 6)
3fa). Meanwhile, the alkenyl group can be retained under this can also be tolerated under the standard conditions (Scheme 3C).
system (3ga). A difluoro-substituted carboxylic ester could also This electrochemical approach can build C–C bonds through not
afford 50% yield (3ha). With regard to primary acids, high site only carboxylic acids, but also pyridinium salts, which came from
selectivity was shown and a moderate yield could be generated, aliphatic amines.
without rearrangement (3ia and 3ja). The benzyl product was isolated
Next, we tried to explore the mechanism of this system, and
in a low yield (3ka). And the terminal alkenyl groups were tolerated, did some control experiments. When removing the quinoline,
which provided a chance for further functionalization (3la). the bicyclohexyl can be detected by GC-MS, which may form by
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Scheme 5 Proposed mechanism.
Scheme 3 Other extensions of the reaction.a a Reaction conditions: (A) 4
(2 equiv., 0.4 mmol), 5 (0.44 equiv., 0.44 mmol), DMAP = 4-dimethylamino-
pyridine (0.2 equiv., 0.04 mmol), DIC = N,N0-diisopropylcarbodiimide (2.4 equiv.,
0.48 mmol), CH2Cl2 (1 mL), room temperature, air, 30 min. Then, adding 2a
(1.0 equiv., 0.20 mmol), p-TsOH (1.5 equiv., 0.3 mmol), nBu4NBF4 (0.05 M,
0.25 mmol), DMA (4 mL), graphite felt anode (15 mm ꢁ 10 mm ꢁ 3 mm),
graphite felt cathode (15 mm ꢁ 10 mm ꢁ 3 mm), constant current = 7.5 mA,
room temperature, N2, 150 min (3.5 F). (B) In a continuous-flow system, carbon
paper (93 mm ꢁ 93 mm ꢁ 0.2 mm), carbon paper (93 mm ꢁ 93 mm ꢁ
0.2 mm), constant current = 10 mA, 1d (2 equiv., 15 mmol), 2a (1.0 equiv.,
7.5 mmol), p-TsOH (1.5 equiv., 11.25 mmol), nBu4NBF4 (0.05 M, 5 mmol), DMA
(100 mL), room temperature, N2, 45 h (2.2 F). (C) Graphite felt anode (15 mm ꢁ
10 mm ꢁ 3 mm), graphite felt cathode (15 mm ꢁ 10 mm ꢁ 3 mm), constant
current = 7.5 mA, 6 (2 equiv., 0.4 mmol), 2a (1.0 equiv., 0.20 mmol), p-TsOH
(1.5 equiv., 0.3 mmol), nBu4NBF4 (0.05 M, 0.25 mmol), DMA (5 mL), room
temperature, N2, 150 min (3.5 F).
5,5-dimethyl-1-pyrroline N-oxide (DMPO) was detected (g =
2.0065, AN = 14.4 G, AH = 21.65 G). We proposed that the NHP
ester can lose one electron and produce a carbon radical after
the decarboxylation.
To further investigate the electrochemical properties of each
substrate, we performed cyclic voltammetry (CV) tests. We can
observe a reduction peak at ꢀ1.25 V (vs. AgCl/Ag, the same below),
which belonged to the ester (see the ESI,† S14). And, for the
quinoline, no extra significant reduction peak can be observed
relative to the blank control.
Based on the above experimental results, the possible mecha-
nism for the electrochemical decarboxylative cross-coupling reaction
is shown in Scheme 5. At first, the NHP ester (Scheme 5, I) could get
one electron from the cathode to give a radical anion (Scheme 5, II),
which further underwent decarboxylation to form the corres-
ponding alkyl radical (Scheme 5, III). Then, the alkyl radical could
attack protonated quinoline to form a new C–C bond (Scheme 5, IV).
Finally, the generated radical lost an electron on the anode, and
subsequently lost a proton to give the target product (Scheme 5, V).
In conclusion, we developed a catalyst-free electrochemical
protocol for the Minisci-type arylation by using NHP esters and
N-heteroarenes. This method used the cathode reduction process to
convert the ester into the corresponding carbon radical directly. Our
approach is a complement to the Kolbe oxidative decarboxylation
reaction and a promising strategy for finding more new reactions.
This work was supported by the National Natural Science
Foundation of China (21520102003, 21702152) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to Universities
of China (111 Program) is also acknowledged. The numerical
calculations in this paper were done on the supercomputing
system in the Supercomputing Center of Wuhan University.
the homo-coupling of cyclohexyl radicals (see the ESI,† S12).
Moreover, radical-trapping experiments were conducted. When
2,6-di-tert-butyl-4-methylphenol (BHT) was used as the radical-
trapping reagent, the coupling products with a cyclohexyl
radical and BHT were detected by GC-MS (see the ESI,† S13).
The above results indicated that the cyclohexyl radical was
probably involved in this transformation.
Besides, EPR results are shown in Scheme 4. In the absence
of quinoline and acid, a carbon centre radical trapped by
Conflicts of interest
There are no conflicts to declare.
Scheme 4 EPR results.a a Reaction conditions: graphite felt anode
(15 mm ꢁ 10 mm ꢁ 3 mm), graphite felt cathode (15 mm ꢁ 10 mm ꢁ
3 mm), constant current = 7.5 mA, 1d (0.4 mmol), nBu4NBF4 (0.05 M,
0.25 mmol), DMA (5 mL), room temperature, N2, 40 min. And then, DMPO
(0.3 mmol) was added in the system, for another 1 min electrolysis.
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