Electrochemical synthesis of enaminones: Via a decarboxylative coupling reaction

Article abstract of DOI:10.1039/c9gc01098j

An environmentally benign and efficient electrochemical synthesis of enaminones via a decarboxylative coupling reaction of α-keto acids using n-Bu₄NI as a redox catalyst and electrolyte under constant current electrolysis in an undivided cell is reported. A broad vinyl azide substrate scope and high functional group tolerance are observed. A gram-scale reaction further demonstrates the practicability of the protocol. The results of cyclic voltammetry and control experiments indicate that I₂ is likely the active species to initiate the oxidative decarboxylation via an acyl hypoiodite intermediate.

Full text of DOI:10.1039/c9gc01098j

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DOI: 10.1039/C9GC01098J
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Electrochemical Synthesis of Enaminones via a Decarboxylative
Coupling Reaction
Xianqiang Kong,† Yulong Liu†, Long Lin, Qianjin Chen,* Bo Xu*
Received 00th January 20xx,
Accepted 00th January 20xx
Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China.
DOI: 10.1039/x0xx00000x
www.rsc.org/
An environmentally benign and efficient electrochemical synthesis still highly desirable for their application in pharmaceutical
of enaminone via a decarboxylative coupling reaction of α-keto synthesis.
acids, using n-Bu4NI as a redox catalyst as well as the electrolyte The past decades have witnessed
a
renaissance in
under constant current electrolysis in an undivided cell was electrochemical organic synthesis33-43. The potential bias allows
reported. A broad vinyl azide substrate scope and high functional substrate molecules to lose or gain electrons at the electrode
group tolerance are observed. Gram-scale reaction further surface and produce highly reactive intermediates. The use of
demonstrates the practicability of the protocol. The results of cyclic redox mediator, which undergoes heterogeneous electron
voltammetry and control experiments indicate that the I2 is likely transfer with electrode surface to form
a stabilized
the active species to initiate the oxidative decarboxylation via an intermediate, can oxidize or reduce substrate molecules
acyl hypoiodite intermediate.
homogeneously in an indirect electrolytic process. Previously,
Zeng and coworkers demonstrated the electrochemically
decarboxylative Minisci acylation of electron-deficient N-
heteroarenes with α-keto acids44. Here, we report an
environmentally friendly electrocatalytic protocol of
electrochemically decarboxylative acylation of vinyl azide with
α-keto acids for the synthesis of enaminones (Scheme 1d). It
should be noted that the chemical oxidant, metal catalyst as
well as additional supporting electrolyte are not needed. Also,
the anode (graphite felt) we used, is relatively inexpensive and
could be reused.
Enaminones are important targets in natural products,
materials science, and pharmaceutical agents.1-5 They are also
used in the synthesis of heterocycles and pharmaceutical
compounds6-14 as well as the ligands for transition metal-
catalyzed catalysis15-17. Therefore, the development of efficient
transformations for the preparation of enaminones from readily
available starting materials has attracted considerable
attention. Although enaminones18-23 could be prepared from
the direct condensation reactions of 1,3-dicarbonyl compounds
with amines24-29, the regioselectivity was not easy to control.
Recently, two novel methods30,
31
for the synthesis of
enaminones were reported by using CuI catalyzed
decarboxylative coupling of α-keto acids with oxime acetates
(Scheme 1a) and vinyl azide (Scheme 1b). However, α-keto acids
are only limited to aromatic oxocarboxylic acids (Scheme 1a).
More recently, Wang and Hu32 reported a direct synthesis of
enaminones using a strong Lewis acid (BF3·OEt2) catalyzed
cyclization of 1-iodoalkyne and α-keto acid followed by amine-
mediated ring-opening (Scheme 1c). However, the synthesis of
functionalized enaminones at a metal-free and mild condition is
a.College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, 2999 North Renmin Lu, Shanghai 201620, China. Email:
qianjinchen@dhu.edu.cn or bo.xu@dhu.edu.cn
Scheme 1. Literature background.
† These authors contribute equally.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
In our initial studies, we took α-tolyl vinyl azide (1a) and α-keto
acid (2a) as a model substrate to optimize the reaction
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conditions in an undivided cell (see Table s1 for the details). We (Table 2). It was observed that substituents of different
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DOI: 10.1039/C9GC01098J
first evaluated different electrode materials using NH4I as the electronic properties (electron-withdrawing groups- Br, Cl, F,
o
mediator at 3.0 mA in MeCN at 50 C and found that C as the NC, CF3, Ph, CO2Me, MeCOO, and electron-donating groups-
anode and Pt as the cathode gave the 19% yield of the desired Me) at para-position give the corresponding enaminone
product (Table S1, entry 1). Further screening of mediators products in good yield (49-83%). The corresponding substitutes
suggested NH4I, NH4Br, NaI, NaBr, n-Bu4NBr, and n-Bu4NI can all at ortho position also give considerable yield while the 1-
catalyze the reaction but n-Bu4NI lead to a moderate yield of 35% naphthyl derivative shows the highest yield at 89%. The ortho-
(Table s1, entry 5-8). Reducing the amount of n-Bu4NI from 15 substituents were well tolerated under the standard conditions
to 5 mol% afforded nearly the same yield of 3a while lightly low
(3q−3r). A dichlorinated substrate was able to give the desired
yield (33%) was obtained using 4 mol% of n-Bu4NI. Subsequently, products at a yield of 77% (3r). Alcohol function group was well
different solvents such as MeOH, EtOH, DCE, dioxane, DMF and tolerated in the reaction, providing moderate to good yield (3t).
DMSO were also tested and MeCN was found the best choice Importantly, heterocyclic derivatives (pyridine, thiophene,
with a yield of only 36%. We further examined the solvent pyrimidine) could yield the corresponding products in good
mixture of MeCN and H2O45. To our delight, the yield was yields (3u-3w). On the other hand, an alkyl-vinyl azide did not
increased up to 73% with the solvent mixture of MeCN and H2O yield the desired product(3x).
Table 2. Scope for vinyl azides 1 a
.
at 10:1 ratio (Table s1, entry 20). To this point, the ratio of the
substrate between 1a and 2a was varied with 1:2 leading to the
highest yield (Table 1, entry 2-4). The various reaction
temperature was examined, and 40 oC is found to be the
optional one (Table 1, entry 3, 5, and 6). Increasing or
decreasing the current ended up with low yield (Table S1, entry
21-23). Finally, control experiments show that electric current,
as well as the redox mediator n-Bu4NI, are essential for this
reaction. To sum up, after above extensive optimization, we
found that 89% isolated yield of the desired product (3a) could
be obtained under constant current electrolysis at 3.0 mA in
solvent mixture of CH3CN and H2O at 10:1 ratio, with 5% n-Bu4NI
o
as redox mediator, at 40 C (Table 1, entry 5). It is noteworthy
that no additional supporting electrolyte was necessary to
achieve high yield, verifying the notion that electro-organic
synthesis is a green and sustainable process (Table s1, entry 26
- 27).46
Table 1. Optimization of reaction conditions.a
Entry
1
1a:
2a
1:3
J
(mA)
3
Temp/ oC
50
Solvent
Yields
[%]
50
MeCN/H2O (2:1)
2
3
4
5
1:3
1:2
1:1
1:2
3
3
3
3
50
50
50
40
MeCN/H2O (10:1)
MeCN/H2O (10:1)
MeCN/H2O (10:1)
MeCN/H2O (10:1)
73
74
36
89
(83b)
54
6
7
1:2
1:2
1:2
5
1
3
40
40
40
MeCN/H2O (10:1)
MeCN/H2O (10:1)
MeCN/H2O (10:1)
62
1
8c
a Standard conditions: C anode (10 mm × 10 mm × 0. 2 mm), Pt cathode (10 mm × 10
mm × 0.2 mm), constant current = 3mA, 1a (0.5 mmol), 2a (1.0 mmol), CH3CN: H2O
(1.82 mL : 0.18 mL), LiClO4 (0.1 mol/L), 40 oC . Yields of 3a were determined by GC
analysis. [b] Isolated yield. [c] n-Bu4NI (0 mol%).
With the optimal reaction conditions in hand, we first
examined the scope of vinyl azide in electrochemical acylation
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a Standard conditions: C anode (10 mm × 10 mm × 0. 2 mm), Pt cathode (10 mm
× 10 mm × 0.2 mm), constant current = 3 mA, 1a (0.5 mmol), 2a (1.0 mmol),
CH3CN: H2O (1.82 mL : 0.18 mL), LiClO4 (0.1 mol/L), 40 oC. b Constant voltage =
1.8 V.
and test scope of α-oxocarboxylic acids (Table 4). Satisfactorily,
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α-oxocarboxylic acids bearing electron-wDitOhId: r1a0w.10in39g/Csu9GbCst0it1u09te8Js
provide moderate to good yields. Generally, the addition of acyl
radical to biarylvinyl azides generates the corresponding iminyl
radicals, which subsequently cyclize with the intramolecular
arene moiety, furnishing aza-polycyclic aromatic hydrocarbons
Next, the scope of α-oxocarboxylic acids was investigated
(Table 3). In general, a variety of α-oxocarboxylic acids with
different substituents on the benzene ring were found to be
tolerable in this process. For example, the halogen group was
well tolerated when introduced at ortho-, meta- and poly-
skeletons having acyl function phenanthridine derivatives47-51
.
However, α-imine radical obtains iminyl radical by 1,3-H
transfer, and it did not get phenanthridine derivatives. α-
oxocarboxylic acids bearing electron-withdrawing substitutes
provide moderate to good yields (69%-82%). Their structures
were identified after comparing their 13C NMR data with that of
3aj, which was confirmed by single-crystal X-ray analysis.
Moreover, various functional groups such as ethers (Table 4,
substituted, delivering 3z–3b, 3ah-3ak in 65 to 80% yield. α-
oxocarboxylic acids with both the electron-donating (Me, MeO)
provided the desired enaminone in good yields (71%-80%). A
variety of electron-withdrawing groups such as trifluoromethyl
and cyano groups are well-tolerated under the standard
reactions (3ac−3ad). To our delight, naphthyl oxocarboxylic acid
3aj), trifluoromethyl group (Table 4, 3ai), halides (Table 4, 3ah
,
smoothly and produce the corresponding enaminones in
excellent yields 3ag. However, aliphatic α-keto acids bearing
linear and cyclic alkyl groups afforded the desired products in
lower chemical yields (3al-3an).
3al 3am), phenyl group (Table 4, 3ak) were well tolerated. And
,
the structure assignment of our obtained product was
confirmed by the single-crystal X-ray diffraction of a typical
product (see the ORTEP drawing of 3ar52 in Table 4).
Table 3. Substrate scope for α-oxocarboxylic acids 2.
Table 4. Substrate scope for reaction of biarylvinyl azide 1ag
with various α-oxocarboxylic acids 2.
[a] Reaction conditions: C anode (10 mm × 10 mm × 0. 2 mm), Pt cathode (10 mm ×
10 mm × 0.2 mm), constant current = 3mA, 1a (0.5 mmol), 1b (1.0 mmol), CH3CN:
H2O (1.82 mL : 0.18 mL), LiClO4 (0.1 mol/L), 40 o
C
To demonstrate the practical utility of this novel method, the
reaction of 1a and 2a was performed at the 10 mmol-scale and
a constant current of 5 mA without complication using a
commercial IKA ElectraSyn 2.0 apparatus. The 1.81 g final
product was obtained at a yield of 81% after isolation (Scheme
2).
[a] Reaction conditions: C anode (10 mm × 10 mm × 0. 2 mm), Pt cathode (10
mm × 10 mm × 0.2 mm), constant current = 3mA, 1a (0.5 mmol), 1b (1.0 mmol),
CH3CN: H2O (1.82 mL : 0.18 mL), LiClO4 (0.1 mol/L), 40 oC.
To further verify the generality of our electrochemical
approach, we used the α-(biaryl-2-yl)vinyl azide as the substrate
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DOI: 10.1039/C9GC01098J
Scheme 2. Gram scale synthesis of 3a.
We further demonstrated that enaminone products could be
converted to many biologically important skeletons (Scheme 3).
4a was obtained in a moderate yield with and Et3Nꢀ
dichloroethane.53 3aa reacted smoothly with PhIO gave the 2H
azirines 4b in a good yield.54 CuII-catalyzed one-pot cascade
reactions of phenylacetone with enaminone 3a gave pyridine
product 4c 55
Moreover, the reaction of 3a with hydroxylamine
⋅ꢀ3HF in 1,2-
‑
.
hydrochloride and phenylhydrazine hydrate gave the isoxazole 4d in
high yield.
Scheme 4. Control experiments.
On the other hand, cyclic voltammograms of related
compounds were investigated at the glassy carbon electrode.
As shown in Figure 1a using CH3CN/H2O (10:1) as the solvent,
relative to the background curve a, an oxidative peak was
observed at 1.42 V vs. Ag/AgCl in the presence of 5.0 mM 2-oxo-
2-phenylacetic acid (Figure 1a, curve II). Such an oxidative peak
was not observed in curve II of Figure 1b when CH3CN was used
as the solvent. This result shows a small addition of H2O to
CH3CN is necessary before benzoyl radical can be
electrochemically generated. The voltammogram of n-Bu4NI
gives two well-defined, transient-shaped oxidation peaks at Ep=
0.79 and 1.12 V vs Ag, along with two corresponding reduction
peaks at 0.30 and 0.98 V. The oxidation peaks correspond to the
Scheme 3. Further transformations of 3.
To gain insight into the reaction mechanism, TEMPO, a radical
scavenger, was added into the reaction of vinyl azide 1a with α-keto-
acid 2a under the standard electrochemical protocol, only trace
amount of 3a was detected while compound 4a was isolated as the
sole product (Scheme 4a). This result demonstrated the benzoyl
radical, which could be generated from the electrochemical
decarboxylation of α-keto acids, was involved in the reaction process
(Scheme 5). We found that iodine alone could not promote the
reaction (Scheme 4b). Also, α-keto-acid 2a did not react with I2
(Scheme 4c), but sodium salt of 2a (Na-2a) reacted with I2 to give the
oxidation of iodide to triiodide in an overall two-electron
-
homo-radical coupling product 6 (Scheme 4d). Both 2a and Na-2a process (I- to I3 ) and triiodide to iodine in an overall one-
-
electron process (I3 to I2). This quasi-reversible electron transfer
process in protic and aprotic solvents has been previously well
studied.56-58 The electrochemical behavior of iodide ion did not
significantly catalyze the oxidation of 2a in MeCN as shown in
Figure 1b (curve IV), However, when using MeCN:H2O (at 10:1)
as the solvent, the overall oxidation of 2a was enhanced at
potential of 1.9 V, which is consistent with the potential
observed during the constant current electrolysis during the
reaction. Since halogenation of carboxylates is reported to
generate acyl hypohalites,44, 59 it is reasonable to propose that
the oxidative catalytic current in curve IV in Figure 1a is due to
could be electrochemically oxidized to homo-radical coupling
product 6 in the presence of n-Bu4NI (Scheme 4e and Scheme 4f). We
also investigate the reaction of 1a with Na-2a without electricity, a
small amount of 3a was formed along with the formation of homo-
radical coupling product 6 (Scheme 4g). These results indicated that
the salt of 2a (Na-2a) was a key intermediate, and it could be
generated slowly in the cathode along with consuming of proton and
the formation of H2. The low yield of 3a in Scheme 4g may due to fact
that concentration of Na-2a was too high.
a
homogeneous chemical reaction of the in situ
-
electrogenerated I2 and I3 with anion of 2a to regenerate iodide.
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radical gives acyl radical C, which adds to vinyl azido to form the
DOI: 10.1039/C9GC01098J
intermediate D by releasing N2. Eventually, the protonation of
intermediate F results in the final compound 3a.
On the other hand, the unstable acyl hypoiodite undergoes
hemolytic dissociation to form aroyloxyl radical and iodine
radical.
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200
in CH3CN/H2O (10:1)
a
Conclusions
IV
150
In conclusion, we report an environmentally friendly, and
transition metal-free electrocatalytic protocol for the synthesis
of enaminones. The chemical oxidant, as well as additional
supporting electrolyte, is not necessary for the course of
electrolysis. We anticipate this electrochemical method will be
particularly useful in the rapid and straightforward synthesis of
relevant pharmacophores under mild condition.
100
II
III
50
I
0
in CH3CN
40
b
III
IV
20
0
II
I
ACKNOWLEDGMENT
We are grateful to the National Science Foundation of China
for financial support (NSFC-21672035 and NSFC-21804018).
QC is thankful to the National Science Foundation of China
(NSFC- 21804018). XK was also thankful to the “Fundamental
Research Funds for the Central Universities and Graduate
Student Innovation Fund of Donghua University”.
-20
0.5
1.0
1.5
2.0
Voltage vs Ag/AgCl
Figure 1. Cyclic voltammograms of n-Bu4NI and PhCOCOOH in 0.1 M LiClO4 in (a)
CH3CN/H2O (10:1), and (b) anhydrous CH3CN using 2 mm diameter glass carbon as
working electrode, Pt wire and Ag wire as counter and reference electrode at 100
mV/s: (I) background, (II) 5.0 mM PhCOCOOH, (III) 2.0 mM n-Bu4NI, and (IV) 5.0 mM
PhCOCOOH with 2.0 mM n-Bu4NI.
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Page 7 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C9GC01098J
N3
O
NH2
O
C(+) Pt(-)
HO
+
undivided cell
R1
R1
R2
R2
O
n-Bu4NI (5%)
MeCN/H2O (10:1)
metal free
oxidant free
43 examples
3 mA, 40 oC
Metal-free, oxidant-free, n-Bu4NI as the redox catalyst as well as the electrolyte.