Electrochemical synthesis of 1,2-diketones from alkynes under transition-metal-catalyst-free conditions

Article abstract of DOI:10.1039/c9cc03996a

We report an electrochemical protocol for the direct oxidation of internal alkynes in air to provide 1,2-diketones. A variety of functional groups and heterocycle-containing substrates can be tolerated well under mild conditions.

Full text of DOI:10.1039/c9cc03996a

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DOI: 10.1039/C9CC03996A
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Electrochemical synthesis of 1,2-diketones from alkynes under
transition-metal-catalyst-free conditions†
Jie Zhou,
and Hua-Jian Xu*
‡
Xiang-Zhang Tao,
‡
Jian-Jun Dai,* Chen-Guang Li, Jun Xu, Hong-Mei Xu
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report an electrochemical protocol for the direct oxidation of
internal alkynes with air to provide 1,2-diketones. A variety of
functional groups as well as heterocycle-containing substrates can
tolerate well with mild conditions.
1,2-Diketones are important structural motifs prevalent in a
variety of bioactive molecules1 and natural products, as well as
versatile intermediates for many valuable transformations.
Classical stoichiometric oxidation of internal alkynes usually
require the use of strong oxidants such as KMnO4,2 OsO4,3
H3PO5,4 dioxiranes,5 organic peracids.6 In the past decades, the
direct catalytic oxidation of internal alkynes using oxygen as the
mild oxidant has emerged as an efficient method for the rapid
synthesis of such diketones. Among them, transition-metal-
catalyzed (e.g., Pd,7 Cu,8 Au,9 Ru10) methods offer an important
alternative route to the production of 1,2-diketones (Scheme
1A). However, the above protocols uniformly suffer from
relatively harsh reaction conditions and limited functional
group tolerance. To overcome these limitations, recent
attention has been paid to the photocatalytic methods (Scheme
1B).11 For instance, Wang and Li reported a thiyl radical
catalyzed oxidation of diarylalkynes under visible-light
irradiation.11a Separately, Sun et al. demonstrated an aerobic
photooxidation of alkynes using eosin Y catalysis.11b In 2017, Liu
and co-workers also reported aerobic oxidation of alkynes to
1,2-diketones enabled by organic photoredox catalysis.11c
However, despite these significant achievements, the
development of practical and broadly applicable synthetic
methods for 1,2-diketones under green and sustainable
conditions is still highly desirable.12
Scheme 1 Approaches to 1,2-diketones via oxidation of internal alkynes.
Electrochemistry has been established as a powerful and
environmentally friendly tool for the radical-based organic
transformations at mild reaction conditions.13 In this context,
we reasoned that the electrochemical protocol would expand
the capacity of internal alkynes-oxidation-based strategies to
the synthesis of 1,2-diketones under transition-metal-catalyst-
free conditions (Scheme 1C). Moreover, the present
electrochemical synthesis is a complementary and alternative
method to the previous transition-metal-catalyzed and
School of Food and Biological Engineering, Key Laboratory of Metabolism and
Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei
University of Technology, Hefei 230009, China. E-mail: daijj@hfut.edu.cn;
hjxu@hfut.edu.cn
† Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/x0xx00000x
photocatalysis
approaches.
Remarkably,
heterocycle-
containing substrates can tolerate well with mild
electrochemical conditions.
‡
Jie Zhou and Xiang-Zhang Tao contributed equally to this work.
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Our studies commenced with the electrochemical
transformation of 1,2-diphenylethyne (1) with graphite and
platinum as anode and cathode, respectively. The optimized
conditions were shown in Table 1.14,15 The 1,2-diketone product
2 was obtained in 87% isolated yield with 20 mA constant
current, 1.0 equiv NaBF4 in a mixture of DMF and H2O at room
temperature (r.t.) for 8 h under air atmosphere (Table 1, entry
1). When other supporting electrolytes such as nBu4NPF6 and
LiClO4 were used, similar yields can be obtained (Table 1, entries
2 and 3). The yield was significantly reduced with the use of
MeOH, MeCN and DMSO as the solvents (Table 1, entries 4–6).
The yield was reduced to 23% in the absence of HCOOH (Table
1, entry 7), and 24% and 62% yields was observed when HCOOH
was replaced with HOAC and CF3COOH, respectively (Table 1,
entries 8 and 9). Interestingly, the reaction proceeded less
effectively under O2 atmosphere (Table 1, entry 10). This result
can be ascribed to the further oxidation of the 1,2-diketone.
Indeed, a certain amount of benzoic acid can be detected by GC-
MS analysis. It was found that the reaction was shut down
under N2 atmosphere (Table 1, entry 11). Other constant
current (i.e., 10 mA and 30 mA) can also cause the reaction, but
the yields were significantly diminished (Table 1, entries 12 and
13). The nature of the electrode materials exerted great effect
on the reaction.16 Using RVC and platinum as the anode, the
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DOI: 10.1039/C9CC03996A
Ar/Het/alkyl
Ar/Het
O
C
Pt
Ar/Het
Ar/Het/alkyl
“standard conditions”
O
A) scope of alkynes
F
Cl
CN
CF3
Br
O
O
O
O
O
O
O
O
2: 87% yield
(17%)
(20 mmol scale, 85%)
3: 80% yield
(16%)
4: 63% yield
5: 62% yield
(12%)
(13%)
t-Bu
OMe
Me
O
O
O
O
O
7: 86% yield
O
O
O
6: 70% yield
(14%)
8: 50% yield
(10%)
9: 67% yield
(13%)
(17%)
Me
Ph
OCF3
O
O
O
O
O
O
O
O
O
10: 73% yield
(15%)
11: 71% yield
12: 76% yield
13: 71% yield
(14%)
(14%)
(15%)
NO2
O
O
O
O
O
Me
O
Cl
O
O
O
OMe
14: 51% yield
(10%)
15: 76% yield
(15%)
16: 71% yield
(14%)
17: 72% yield
(14%)
MeO
O
Me
Me
O
O
O
F
O
O
O
O
Me
O
OMe
18: 36% yield
19: 70% yield
20: 69% yield
21: 64% yield
(7%)
(14%)
(14%)
(13%)
Table 1 Optimization of the reaction conditionsa
CF3
F
Me
O
O
O
O
F
O
O
O
O
O
F
MeO
F
Me
C
Pt
22: 82% yield
(16%)
23: 73% yield
(15%)
24: 89% yield
(18%)
25: 63% yield
(13%)
“standard conditions”
O
O
1
2
O
O
O
O
Me
Me
t-Bu
4
O
O
O
Entry
Variation from the standard conditions
Yield (%)b
O
26: 48% yielda
27: 42% yield
28: 50% yield
29: 56% yieldb
(31%)
(8%)
(10%)
(15%)
1
2
3
4
5
6
7
8
None
87
83
70
16
50
43
23
24
B) heterocycle-containing substrates
nBu4NPF6 instead of NaBF4
LiClO4 instead of NaBF4
MeOH instead of DMF
MeCN instead of DMF
DMSO instead of DMF
Without HCOOH
O
S
O
S
O
S
O
N
N
S
O
O
O
O
30: 46% yield
31: 40% yield
32: 53% yield
(11%)
33: 50% yield
(10%)
(9%)
(8%)
O
S
O
S
O
S
N
S
HOAc instead of HCOOH
O
O
O
MeO
N
9
CF3COOH instead of HCOOH
O2 atmosphere
62
77
trace
61
40
60
10
80
0
34: 51% yield
(10%)
35: 45% yield
36: 38% yield
10
11
12
13
14
15
16
17
(9%)
(8%)
C) bioactive or pharmceutical molecules-containing substrates
N2 atmosphere
O
Et
N
COOMe
NHBoc
10 mA instead of 20 mA, 16 h
30 mA instead of 20 mA, 5 h
RVC instead of graphite as anode
platinum instead of graphite as anode
graphite instead of platinum as cathode
No electric current
O
O
O
Et
Me
O
O
from Procaine
37: 43% yieldc
(35%)
from Tyrosine
38: 76% yield
(15%)
Scheme 2 Substrate scope. The values in the parentheses were the coulombic
efficiency. aI = 10.0 mA, the reaction time was 5 h (6.0 F mol-1). bI = 30.0 mA, the
reaction time was 10 h (37.0 F mol-1). cI = 10.0 mA, CH3CN instead of DMF
, LiClO4
instead of NaBF4, the reaction time was 4 h (5.0 F mol-1).
aStandard conditions: graphite plate anode: (10 mm × 15 mm), 1 (0.3 mmol),
NaBF4 (1.0 mmol), DMF (9.0 mL), H2O (1.0 mL), platinum plate cathode: (10 mm
× 10 mm), NaBF4 (1.0 mmol), H2O (9.0 mL), HCOOH (1.0 mL) in H-type divided
cell with an anion exchange membrane, constant current = 20.0 mA (janode = 13.3
mA cm-2), r.t., 8 h (20.0 F mol-1). bIsolated yield.
yields decreased to 60% and 10%, respectively (Table 1, entries
14 and 15). However, 80% yield was obtained when platinum
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was replaced by graphite as the cathode (Table 1, entry 16).
Finally, a control experiment demonstrated that electric current
is necessary for reactivity (Table 1, entry 17). the cathodic
reaction, H2 (65 mL, 2.9 mmol) could be obtained after 8 h.
With the optimized conditions in hand we began to evaluate
the scope of the electrochemical oxidation of a variety of
alkynes and the results were outlined in Scheme 2. It was found
that various alkyne substrates, bearing either electron-donating
or electron-withdrawing groups, could be smoothly converted
into the corresponding 1,2-diketones in moderate to good
yields (42–89%) under very mild conditions (Scheme 2A). Fluoro
(3, 19, 24, 25), chlorine (4, 17) and bromine (5) groups were well
compatible with the reaction, thus providing opportunities for
further conversions with cross-coupling reactions. Additionally,
the use of methyl-substituted (6, 16, 21, 23) or tert-butyl-
substituted (7) alkynes gave the desired product in good yields.
Furthermore, alkyne derivatives possessing cyano (8), methoxy
(9, 20, 23), phenyl (10), ketone (11), trifluoromethyl (12, 23),
trifluoromethoxy (13), nitro (14), ester (15, 20) and naphthyl (18)
are well tolerated. It was further demonstrated that olefin
group (26) can also survive well under current reaction
conditions. Notably, the present reaction could be scaled up to
20 mmol (3.56 g), and the desired product 2 was smoothly
furnished in 85% yield (3.57 g). Finally, the alkyl arylacetylenes
substrates, which were not effectively transformed under
previous photocatalytic conditions,11 were also examined to
evaluate compatibility of the present electrochemical protocol,
and the corresponding 1,2-diketones (27-29) were successfully
obtained in moderate yields.
A Competition experiment
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DOI: 10.1039/C9CC03996A
Ph
OMe
CF3
OMe
CF3
O
O
46: 0.15 mmol
C
Pt
+
+
Ph
Ph
“standard conditions”
O
O
Ph
12: 10% yield
9: 51% yield
47: 0.15 mmol
B CV analysis
Ph
OMe
CF3
a
Ph
b
Fig. 1 A) Competitive reaction between electron-rich alkyne (46) and electron-
deficient alkyne (47). B) Cyclic voltammograms studies: a) solutions of 46 (red line),
b) solutions of 47 (blue line) and c) the blank (black line); The cyclic voltammograms
were recorded at a scan rate of 100 mV s−1 at rt with two platinum electrodes.
applicability of this method for the late-stage modification of
complex molecules (Scheme 2C).
This reaction displays an interesting chemselectivity profile.
As shown in Scheme 3A, two triple bonds-containing internal
alkynes 39 can easily be converted to the corresponding 1,2-
diketone 40 under the standard reaction conditions.
Interestingly, 41 can be smoothly converted to 1,2-diketone 42
without the terminal alkyne group be oxidized (Scheme 3B).
Moreover, when 1,4-diphenylbuta-1,3-diyne (43) was subject
into the reaction a 1,4-diketone (45) was obtained as a major
product with a new triple bond formation (Scheme 3C).
We next conducted a competitive reaction between electron-
rich methoxy-derived alkyne (46) and electron-deficient
trifluoromethyl-derived alkyne (47) under standard conditions.
In this case, the major product was 9 (51% yield), arising from
reaction of the more electron-rich alkyne (Figure 1A). This result
was matched with the cyclic voltammetric (CV) studies. As
shown in Figure 1B, the oxidation potentials of 46 (electron-rich)
and 47 (electron-deficient) are 1.44 and 2.00 V vs. SCE,
respectively.
To understand the mechanism of the electrochemical
reaction, we conducted free-radical trapping experiments. The
formation of 1,2-diketone 2 was completely halted by using
radical scavengers such as TEMPO (tetramethylpiperidinoxyl),
BHT (2,6-di-tert-butyl-4-methylphenol) as well as PBN (N-tert-
butyl-α-phenylnitrone). Unfortunately, no radical-adduct could
be isolated at the current stage. These observations indicated
that the reaction should proceed with the intermediacy of
radical species.
The next investigation of the substrate scope was focused on
heterocycle-containing substrates (Scheme 2B). It was
demonstrated that triazole (30, 35), pyridine (31, 36) and
thiophene (32-36) derivatives gave the desired products in 38-
53% yields. In addition, the procaine and tyrosine-containing
alkyne derivatives are successfully transformed to the
corresponding 1,2-diketones (37, 38), thus highlighting the
Ph
O
Ph
O
C
Pt
(A)
O
Ph
“standard conditions”
Ph
O
40: 68% yield
39
O
O
Ph
O
O
Not detected
O
O
O
O
C
Pt
O
(B)
“standard conditions”
O
Ph
O
Ph
O
42: 52% yield
41
Ph
Not detected
O
O
Ph
Ph
C
Pt
Ph
(C)
Ph
+
Ph
“standard conditions”
O
Ph
O
43
44: 15% yield
45: 71% yield
1,2-diketone
1,4-diketone
To summarize, we have developed a green and efficient
electrochemical method for the conversion of internal alkynes
Scheme 3 Chemoselectivity in the presence of multiple triple bonds.
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12 For earlier examples, see: (a) K. J. Tan and U.VWiewilAlert,iclCe hOenlmine.
to 1,2-diketones under catalyst free conditions. This reaction
features mild reaction conditions, inexpensive reagents and
broad substrate scopes. A wide range of aryl alkynes as well as
hetero-containing alkynes are well tolerated, and the
corresponding 1,2-diketones can be achieved in moderate to
good yields. More studies on expanding the utility of
electrochemically-based radical reactions are ongoing in our
laboratory.
We are grateful to the National Natural Science Foundation
of China (No. 21871074, 21472033), CPSF (No. 2016M600478,
2017T100444) and the Fundamental Research Funds for the
Central Universities for financial support.
Commun., 2008, 6239; (b) U. Wille and J. Andropof, Aust. J.
DOI: 10.1039/C9CC03996A
Chem. 2007, 60, 420.
13 For selected recent examples, see: (a) Y. Kawamata, M. Yan,
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14 A 40% yield of 2 can be obtained using an undivided cell.
15 The cathodic reaction was the formation of hydrogen (H2),
which was identified by GC analysis, please see ESI for more
details.
Conflicts of interest
There are no conflicts to declare.
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