Electrochemically Induced Intermolecular Cross-Dehydrogenative C-O Coupling of β-Diketones and β-Ketoesters with Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.8b02791

The electrochemically induced cross-dehydrogenative C-O coupling of β-diketones and β-ketoesters (C-H reagents) with carboxylic acids (O-H reagents) was developed. An important feature of this reaction lies in the selective formation of intermolecular C-O

Full text of DOI:10.1021/acs.joc.8b02791

Subscriber access provided by Iowa State University | Library
Article
Electrochemically-induced intermolecular cross-dehydrogenative
#-O coupling of #-diketones and #-ketoesters with carboxylic acids
Oleg V. Bityukov, Olesya K. Matveeva, Vera A. Vil', Vladimir A. Kokorekin,
Gennady Ivanovich Nikishin, and Alexander Olegovich Terent'ev
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02791 • Publication Date (Web): 08 Jan 2019
Downloaded from http://pubs.acs.org on January 8, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 33
The Journal of Organic Chemistry
1
2
3
4
5
Electrochemically-induced intermolecular cross-dehydrogenative С-O
coupling of β-diketones and β-ketoesters with carboxylic acids
6
7
8
9
Oleg V. Bityukov, a Olesya K. Matveeva,a,b Vera A. Vil’, a Vladimir A. Kokorekin, a,c
Gennady I. Nikishin,a Alexander O. Terent’ev a,b
*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., 119991, Moscow, Russian Federation [phone +7 (499) 1356428; fax, +7 (499) 1355328,
e-mail, alterex@yandex.ru]
b D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square,
Moscow 125047, Russian Federation
c Sechenov First Moscow State Medical University, Trubetskaya st. 8-2, 119991, Moscow,
Russian Federation
TABLE OF CONTENTS GRAPHIC
O
O
O
O
R3COOH
R1
R2
O
R1
R2
KBr
DMSO/H2O
O
R3
CCE, undivided cell
air tolerable
yields up to 92%
Abstract
The electrochemically-induced cross-dehydrogenative С-O coupling of β-diketones and β-
ketoesters (C-H reagents) with carboxylic acids (O-H reagents) was developed. An important
feature of this reaction lies in the selective formation of intermolecular С-O coupling products in
high yields, up to 92 %, using DMSO as a solvent with a broad substrate scope in undivided cell
equipped with carbon and platinum electrodes at high current density. Electric current acts as a
stoichiometric oxidant.
Introduction
The oxidative cross-coupling (cross-dehydrogenative coupling) is promising and thriving
field of modern organic synthesis. The construction of the new bond occurs with high atom
efficiency and no functional groups are required.1-5 Among all types of oxidative coupling
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
reactions, the coupling to form the С–О bond between the partners is more difficult6, 7 for the
reason that it is generally accompanied by the oxidation of a C-partner into carbonyl products.8-10
The present study comprises two aspects of modern synthetic chemistry: the selective
oxyfunctionalization of carbonyl substrates and electrochemistry as an efficient tool in cross-
dehydrogenative coupling reactions.11-16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The α-oxy-β-dicarbonyl fragment is an important structural part of natural products and
pharmaceuticals.17-20 Series of naturally occurring α-acyloxy ketones exhibit antifungal,21-23
antimicrobial,24-27 antiviral28, 29 and others30 types of activity. Thus, the search of methods for the
efficient acyloxy-functionalization of the β-dicarbonyl group is a desirable and timely task.
Previously C-O functionalization of β-dicarbonyl compounds and their hetero analogs were
limited to hydroxylation,31-50 peroxidation,51-54 and the coupling of N–O fragments55, 56 and
phenols.57
In this paper, the attention is focused on electrochemically-induced intermolecular
acyloxylation of β-dicarbonyl compounds. Similar transformations with stoichiometric amounts
of chemical oxidants were performed using hypervalent iodine compounds,58-60 Bu4NI/t-
62
64
BuOOH,61,
manganese(III) acetate,63,
lead(IV) acetate,65 and iron(III) salts.66
Benzoyloxylation of the β-dicarbonyl compounds by benzoyl peroxide is based on their
preliminary transformation into enamines,67-70 copper complexes71 or enolates.72-74 Methods for
the intermolecular oxidative acyloxy-functionalization of β-dicarbonyl compounds by diacyl
peroxides have been discovered.75-77 Concerning electrochemical intermolecular acetoxylation, it
was found that anodic oxidation of enol acetates led to α-acetoxycarbonyl compounds.78, 79
One of the main ideas of our work lies in the replacement of chemical oxidants applied for
intermolecular oxidative C-O coupling of carbonyl compounds with carboxylic acids by electric
current mostly with involvement of anodic processes.
Electrolysis was implemented in many industries and synthetic applications.80-83 Last
years, more and more attention has been paid to the use of electrochemistry in redox processes of
organic synthesis by the following reasons: availability and low cost of electric current, variety
of electrochemical reaction mechanisms and decreasing of waste amounts.84-89 Electrolysis can
be carried out in a divided or undivided cell under controlled potential (CPE) or constant current
conditions (CCE).90 Using of undivided cell is more practical but at the same time more difficult
to implement because the active species electrogenerated at one electrode can undergo
undesirable reactions with species electrogenerated simultaneously at another electrode.91
Advances of constant current (CCE) conditions are high current density, electrodes with small
surface, and compact reaction vessels permitting to save a solvent.92
2
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Recently, more unambiguous due to monomolecular kinetic electrochemical processes of
intramolecular lactonization have been reported (Scheme 1, b).93 In the present work we decided
more challenging task on electrochemically-induced intermolecular cross-dehydrogenative С-O
coupling of β-dicarbonyl compounds with carboxylic acids with high yields at CCE in undivided
cell (Scheme 1, c). Despite the fact that many processes of anodic nature,83, 94-96 such as
hydroxylation,97-99 halogenation,100 dimerization101 and cathodic nature, for example carbonyl
group reduction,102-107 can take place in similar systems (Scheme 1, a), acyloxy-product is
selectively formed in our conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a) Possible transformation of carbonyl compounds in undivided cell
O
O
O
O
R2
R2
R1
R1
electrolysis
R2
R2
R2
R1
R1
R1
or
or
anodic
processes
Hal
ref. 100
OH
O
ref. 97-99
ref. 101
OH
O
electrolysis
R2
R2
R1
R1
cathodic
processes
ref. 102-107
b) Intramolecular C-O cross-coupling
O
O
electrolysis
R1
R1
ref. 93
O
HO
c) This work: Intermolecular C-O cross-coupling
O
O
O
O
R2
R2
electrolysis
+ R3COOH
R1
R1
O
O
R3
Scheme 1. Electrochemical oxidative transformation of carbonyl compounds.
Results and Discussion
To carry out the oxidative coupling, β-ketoesters 1a-e and β-diketones 1f-i were used as
the C-H reagents and carboxylic acids 2a-l were chosen as O-H reagents. As a result, coupling
products 3aa-ia, 3ab-al were obtained (Scheme 2).
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
6
7
8
9
O
O
O
O
CCE, undivided cell
R1
R2
O
R3COOH
R1
R2
supporting electrolyte
solvent
O
R3
1a-i
2a-l
3aa-ia, 3ab-al
3x,y (x = a-i, y = a-l)
1
2
3
3
R = Ph, R = OEt
R1 = Me, R2 = Me
R = Me
R = (CH2)2-cyclohexyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1a:
1b:
1c:
1d:
1e:
1f:
2a:
2g:
1
2
1
i
2
3
3
1g:
1h:
1i:
2b:
2c:
2d:
2e:
2f:
2h:
2i:
R = Me, R = OEt
R = Bu, R = Me
R = Et
R = (CH2)2Ph
1
i
2
1
2
3
3
R = Bu, R = OEt
R = Ph, R = Me
R = Ph
R = CH=CHPh
R3 = CH=CHCH=CHCH3
1
2
1
2
3
2j:
R = Ad, R = OEt
R = 2-Cl-Ph, R = Me
R = Pentyl
1
2
t
3
3
2k:
2l:
R = Me, R = OBu
R = CH2Ph
R3 = 2-I-Ph
R = CH2NHC(O)Ph
R3 = 2-Thienyl
Scheme 2. Intermolecular cross-dehydrogenative С-O coupling of β-dicarbonyl compounds 1a-i
with carboxylic acids 2a-l (in the codification of 3 the first letter index refers to the β-dicarbonyl
compound 1 moiety, the second letter index to the carboxylic acid 2 moiety).
Influence of supporting electrolyte and its amount, molar ratio of starting reagents, solvent
type, the amount of passed electric current and its density and also electrode materials were
investigated in the model of C-O coupling reaction of ethyl benzoylacetate 1a with acetic acid 2a
(Table 1).
Table 1. Optimization of the reaction conditions. a
O
O
O
O
CCE, undivided cell
CH3COOH
Ph
OEt
supporting electrolyte
solvent
Ph
OEt
OAc
2a
1a
3aa
Electrolyte
(molar ratio:
Molar
ratio 2a /
1a
Electricity
passed,
F/mol 1a
Entry
Solvent
Yield 3aa, %
mol per mol 1a)
1
2
10
10
10
10
10
10
10
10
10
10
10
180
10
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
50
76
80
KI (1)
NH4I (1)
NaBr (1)
KBr (1)
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
AcOH/H2O
THF/H2O c
3
4
81
67
5
NH4Br (1)
n-Bu4NBr (1)
HBr (1)
6
58
n.d.
7
8
KCl (1)
n.d.
27
9
KBrO3 (1)
LiClO4 (1)
NaBF4 (1)
KBr (1)
10
11
12
13
n.d.
n.d.
n.d.
KBr (1)
<5
4
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
14
15
10
10
10
10
10
10
10
10
2
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
2.0
9.0
0
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (0.5)
KBr (2)
CH3CN/H2O
EtOH/H2O
17
<5
36
72
65
59
35
63
46
62
83
33
29
n.d.
38
77
DMSO d
16
17 e
18 f
19g
20
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
22
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
KBr (1)
23
5
24
20
10
10
10
10
10
25
26
27
28h
29i
4.5
4.5
a
Reaction conditions: undivided cell, platinum plate cathode and anode (15 mm×20 mm×0.1 mm),
constant current = 0.1 A (j = 33.3 mA/cm2), 1a (1.0 mmol, 213.6 mg, 90% technical grade), DMSO (10.0
mL), H2O (1.0 mL), 35-40 °С, air atmosphere. Isolated yields, n.d. = not detected. THF (10.0 mL),
H2O (3.0 mL). without H2O. Copper plate cathode.
cathode. h 0-5 °C. i 60 °C
b
c
d
e
f
g
Graphite anode.
Graphite anode and iron
The nature of supporting electrolyte was demonstrated to play a crucial role in the
efficiency of C-O coupling reaction (Table 1, entries 1-11). Application of NaBr (entry 3) and
KBr (entry 4) as supporting electrolytes permits to achieve the best results. In the case of NH4Br
(entry 5) and n-Bu4NBr (entry 6) as supporting electrolytes product 3aa was obtained with 67 %
and 58 % yield, respectively. Iodides KI, NH4I (entries 1, 2) and KCl (entry 8) were less efficient
in this process. HBr, KBrO3, LiClO4 and NaBF4 were ineffective supporting electrolytes, the
yield of 3aa did not exceed 27 % (entries 7, 9-11).
A nature of solvent significantly influences on the yield of target compound 3aa (Table 1,
entries 12-16). When acetic acid is both as reagent and solvent, the desired product 3aa was not
formed (entry 12). THF/H2O (entry 13), CH3CN/H2O (entry 14) and EtOH/H2O (entry 15) were
not suitable solvent systems for the oxidative C-O coupling, product 3aa was prepared in low
amounts. Addition of H2O as a co-solvent was necessary for high yield of 3aa (entries 4 and 16).
Screening of electrode materials indicated that graphite or platinum anodes and copper,
platinum or iron cathodes gave comparable yields of 3aa (entries 17-19). The effect of the
amount of supporting electrolyte (KBr) was also investigated. The yield of 3aa decreased when
0.5 or 2 mol KBr per mol β-dicarbonyl compound 1a molar ratios were used (entries 20-21).
Entries 22-24 illustrate the influence of the amount of carboxylic acid on the product yield. In
comparison with 10-fold excess of acid 2a per mole β-dicarbonyl compound 1a (entry 4) the use
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
9
of the 2- or 5-fold excess of acid 2a results in decrease of 3aa yield to 46% and 62% (entries 22
and 23, respectively). Significant excess 20 equivalents of 2a did not lead to the pronounced
increase in the yield of 3aa (83%, entry 24). Decreasing (entry 25) or increasing (entry 26) of the
electric current amount passed through the reaction mixture did not give better results. Electric
current is obligatory condition for the development C-O coupling process, target product 3aa
was not formed in its absence (entry 27). Decreasing of the reaction temperature to 0-5 °C (entry
28) led to low yield of 3aa (38%), increasing up to 60 °C (entry 29) did not significantly affect
on product yield (77%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Under the optimized reaction conditions (Table 1, entry 4) the scope of this
electrochemical methodology for the intermolecular cross-dehydrogenative С-O coupling of β-
dicarbonyl compounds 1a-i with carboxylic acids 2a-l was tested (Table 2).
Table 2. Electrochemical synthesis of α-acyloxy-β-dicarbonyl compounds 3aa-ia, 3ab-al from
β-dicarbonyl compounds 1a-i and carboxylic acids 2a-l. a
O
O
CCE (0.1 A), undivided cell
Pt(+)-Pt(-) or C(+)-Fe(-)
O
O
R1
R2
O
R3COOH
O
R1
R2
KBr (1.0 equiv.)
DMSO/H2O = 10/1
R3
1a-i
2a-l
3aa-ia, 3ab-al
3x,y (x = a-i, y = a-l)
O
O
O
O
O
O
O
O
OEt
Ph
OEt
OEt
OEt
OAc
OAc
OAc
OAc
3aa, 76% (59%)
3ba, 70%
3ca, 81%
3da, 36%
O
O
O
O
O
O
O
O
OBut
Ph
OAc
OAc
OAc
OAc
3ea, 78%
3fa, 73% (62%)
3ga, 39%
3ha, 70%
O
O
O
O
O
O
Cl
O
O
Ph
OEt
O
Ph
OEt
Ph
OEt
O
O
O
O
O
OAc
Et
Ph
3ac, 85%
C5H11
3ia, 67%
3ab, 92% (51%)
3ad, 88%
6
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
Ph
OEt
O
Ph
OEt
O
Ph
OEt
O
O
Ph
OEt
O
O
O
O
I
9
Ph
3ae, 54%
Ph
3ah, 48%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3af, 29%
3ag, 83% (64%)
O
O
O
O
O
O
O
O
Ph
OEt
O
Ph
OEt
O
Ph
OEt
O
Ph
OEt
O
O
O
O
O
NH
S
Ph
3ai, 67%
O
Ph
3al, 38%
3ak, 56%
3aj, 58%
a General reaction conditions: The solution of β-dicarbonyl compounds 1a-i (1.0 mmol, 100.1-250.3
mg), carboxylic acids 2a-l (10.0 mmol, 601.0-1791.8 mg) and supporting electrolyte KBr (1.0 mmol,
119.0 mg) in 10 ml of DMSO and 1 ml of H2O (co-solvent) was electrolyzed using constant current
conditions (I = 0.1 A, j = 33.3 mA/cm2) at 35-40°C under magnetic stirring. Undivided cell, platinum
plate cathode and anode (15 mm×20 mm×0.1 mm). For values in brackets graphite anode and iron
cathode were used.
Various β-ketoesters 1a-e reacted with acetic acid (2a) to provide the desired products 3aa-
ea in good (3ba, 70%) to excellent (3ca, 81%) yields. The exception was ethyl 3-(adamantan-1-
yl)-3-oxopropanoate (1d), in the case of 1d, the yield of the desirable product 3da was 36%.
Easily oxidizable β-diketones 1f-i were also successfully introduced into the process, yields of
products 3fa-ia were 39-73%. The scope of the carboxylic acids (2a-l) was also tested. Nature of
carboxylic acid (2a-l) doesn’t strongly influence on yield of products (3ab-al). When cheaper
graphite anode and iron cathode were used instead of platinum electrodes α-acyloxy-β-
dicarbonyl compounds 3aa, 3fa, 3ab, 3ag were prepared with slightly lower yields.
The proposed mechanism of the intermolecular cross-dehydrogenative С-O coupling of
β-dicarbonyl compounds 1 with carboxylic acids 2 with formation of α-acyloxy-β-dicarbonyl
compounds 3 comprises electrochemical and chemical stages. Scheme 3 illustrates the
mechanism on the example of reaction of 1a with 2a.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
2 Br
Br2
H2O
OH
6
7
8
9
H2 + OH
Br
Br
O
O
O
O
Br3
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
Ph
OEt
OH
1a
2a
Br ,
Br
,
2
O
Br3
OEt
O
Br
A
O
O
Ph
OEt
O
O
3aa
Scheme 3. Proposed reaction mechanism on the example of ethyl benzoylacetate 1a
acyloxylation with formation of α-acyloxy-β-dicarbonyl compound 3aa
.
Molecular bromine is electrochemically generated at the surface of anode, then
itself, [Br]+ prepared from bromine and hydroxide anion
and [Br3]- formed from
108, 109
bromine and bromide anion110-112 react with ethyl benzoylacetate 1a resulting in α-
brominated ethyl benzoylacetate A. This mechanistic stage is supported by the results of entries
10 and 11 no yielding of 3aa (Table 1), in which LiClO4 and NaBF4 are supporting electrolytes
containing no bromide anion. Hydroxide anion is generated at the surface of cathode, then it
abstracts proton from acetic acid (2a) to give acetate anion, which substitutes bromine atom in α-
brominated ethyl benzoylacetate A with formation of target α-acyloxy-β-dicarbonyl
compound 3aa. Intermediate A can be transformed in accordance to various paths:
hydroxylation99 and dimerization,101 or reduction in the starting compound.113, 114 For these
reasons high concentration of carboxylate anion, prepared from carboxylic acid 2a, is required
for the fast formation of acyloxylated product 3aa and to prevent side-reactions with
participation of intermediate A. The property of media to be a base115, 116 helps to the cathode
reaction of base and then acetate anion formation. This conclusion is supported by entry 7 (Table
1) with use of acidic electrolyte HBr, in this case product 3aa was not detected.
The proposal about formation of bromine in anodic layer is supported by the CV
data (Figures 1-3), which demonstrate that from all possible oxidizable compounds in the
8
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
reaction mixture only bromide anion undergoes oxidation (Figure 1), ethyl benzoylacetate
1a and acetic acid (2a) are not oxidized in these conditions (Figures 2-3).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. CV curve for a 3.0 mmol/L solution of KBr in 0.1 M Et4NClO4 in DMSO/H2O (10/1
vv) on a working Pt electrode (d = 1 mm) under a scan rate of 0.1 V/s.
Figure 2. CV curve for a 3.0 mmol/L solution of AcOH in 0.1 M Et4NClO4 in DMSO/H2O
(10/1 vv) on a working Pt electrode (d = 1 mm) under a scan rate of 0.1 V/s.
Figure 3. CV curve for a 3.0 mmol/L solution of 1a in 0.1 M Et4NClO4 in DMSO/H2O (10/1
vv) on a working Pt electrode (d = 1 mm) under a scan rate of 0.1 V/s.
Additional evidences for supporting of proposed mechanism (Scheme 3) were
received from the experiments on acetoxylation of α-brominated ethyl benzoylacetate A
(Scheme 4).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
8
9
O
O
O
O
a-f
Conditions
10 CH3COOH
Ph
OEt
Ph
OEt
25 - 30 °C
Br
OAc
3aa
A
2a
a)
b)
c)
d)
A
2a
A
A
only and
DMSO / H2O
KBr (1 equiv.), DMSO/H2O
KOH (1 equiv.)
no conv. of
no conv. of
A
no conv.of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A
no conv. of
e) KOH (1 equiv.) DMSO/H O
f) AcOK (1 equiv.), DMSO/H2O
3aa
3aa
,
, 92%
, 86%
2
Scheme 4. Control experiments on the bromine substitution in brominated ethyl benzoylacetate
A in various conditions.
Reaction between acetic acid (2a) and α-brominated ethyl benzoylacetate A does not
occur in the cases of CH3COOH, mixtures of CH3COOH/DMSO/H2O, CH3COOH/DMSO/H2O
with combination of KBr, and CH3COOH with KOH (Scheme 4, a-d). Based on the proposed
mechanism (Scheme 3) we successfully carried out synthesis of α-acyloxy-β-dicarbonyl
compound 3aa (92 % and 86%, respectively) only in the system of solvents DMSO/H2O
with addition of KOH or AcOK (Scheme 4, e and f). It is important to note that in the
absence of DMSO nucleophilic substitution of bromine in A does not proceed (Scheme 4,
d). This fact can be explained by the formation of super base media in KOH/DMSO
system117-119 even in the presence of water.120, 121 Also DMSO, as is well known,
promotes nucleophilic substitution of halogen by nucleophile, through the formation of
intermediate sulfonium halides.122, 123 Thus, replacement of DMSO by THF or EtOH
(Table 1, entries 13 and 15, respectively) resulted in low conversion of 1a, formation of
the traces of α-brominated ethyl benzoylacetate A, and no observable amounts of product 3aa.
This suggests that super base media (KOH/DMSO) plays a key role in the substitution of
bromine atom by the acetate anion in α-brominated ethyl benzoylacetate A.
It should be noted that CH3CN as solvent (Table 1, entry 14) led to α-brominated ethyl
benzoylacetate A (69%) and C-O coupling product 3aa (17%) (Scheme 5). The observed result
also confirms the key role of super base media (KOH/DMSO) in the electrochemically-induced
cross-dehydrogenative С-O coupling of β-dicarbonyl compounds with carboxylic acids.
O
O
O
O
O
O
CCE (0.1 A), undivided cell
Pt(+)-Pt(-)
Ph
OEt
Ph
OEt
10 CH3COOH
Ph
OEt
KBr (1.0 equiv.)
Br
OAc
CH3CN/H2O = 10/1
1a
A
, 69%
2a
3aa
, 17%
Scheme 5. Control experiments on the influence of non-super base media.
10
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
Conclusion
4
5
6
7
8
9
We proposed an effective electrochemical strategy for the preparation of α-acyloxy-β-
dicarbonyl compounds via the intermolecular С-O coupling of β-dicarbonyl compounds with
carboxylic acids with the yields from moderate to high. The main feature of discovered
electrochemical intermolecular acyloxylation is the impressive selectivity. Despite of the
presence of possible oxidation and reduction ways, exclusively intermolecular С-O coupling is
observed. Developed oxidative coupling is characterized high efficiency and convenience of an
experimental technique in the undivided electrochemical cell, high current densities, high
concentration of starting reagents and complete conversion of starting substrates, which is
challenge for electrochemical reactions in undivided cells, where diversity of reactions at the
electrodes surface and in the media often prevent selective synthesis. In this context it should be
mentioned that in this work we did not observe by-products of anodic nature, such as
hydroxylation and dimerization, and cathodic nature, for example carbonyl group reduction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
13
1H and C NMR spectra were recorded on Bruker AVANCE II 300 spectrometer (300.13 and
75.48 MHz, respectively) in CDCl3. Chemical shifts were reported in parts per million (ppm),
1
13
and the residual solvent peak was used as an internal reference: H (СDCl3 δ=7.26 ppm), C
(СDCl3 δ=77.16 ppm). Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet).
High resolution mass spectra (HR-MS) were measured on a Bruker micrOTOF II instrument
using electrospray ionization (ESI).124 The measurements were performed in a positive ion mode
(interface capillary voltage – 4500 V); mass range from m/z 50 to m/z 3000 Da; external
calibration with Electrospray Calibrant Solution (Fluka). A syringe injection was used for all
acetonitrile solutions (flow rate 3 µL/min). Nitrogen was applied as a dry gas; interface
temperature was set at 180 °C.
The TLC analysis was carried out on standard silica gel chromatography plates (DC-Fertigfolien
ALUGRAMR Xtra SIL G/UV254). Column chromatography was performed using silica gel
(0.060-0.200 mm, 60 A, CAS 7631-86-9, Acros).
Ethyl benzoylacetate (1a) (90%, technical grade), ethyl acetoacetate (1b), tert-butyl acetoacetate
(1e), 2,4-pentanedione (1f), 1-phenyl-1,3-butanedione (1h), acetic acid (2a), propionic acid (2b),
benzoic acid (2c), hexanoic acid (2d), phenylacetic acid (2e), 2-iodobenzoic acid (2f), 3-
cyclohexanepropionic acid (2g), 3-phenylpropionic acid (2h), cinnamic acid (2i), sorbic acid
(2j), hippuric acid (2k), 2-thiophenecarboxylic acid (2l), KI, NH4I, NaBr, KBr, NH4Br, n-
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
Bu4NBr, HBr (48% aq), KCl, KBrO3, LiClO4, NaBF4, KOH, AcOK were purchased from
commercial sources and was used as is. All solvents were distilled before use using standard
procedures.
6
Starting β-dicarbonyl compounds 1c,125 1d,126 1g,127 1i128 were prepared accordingly literature
procedures.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Procedures for Table 1. Optimization of the reaction conditions.
Experimental Procedure for Table 1, entries 1-16.
An undivided cell was equipped with a platinum plate anode (3 cm2) and a platinum plate
cathode (3 cm2) and connected to a DC regulated power supply. The solution of ethyl
benzoylacetate 1a (1.0 mmol, 213.6 mg, 90% technical grade), acetic acid 2a (10.0 mmol, 601.0
mg) and supporting electrolyte KI, NH4I, NaBr, KBr, NH4Br, n-Bu4NBr, HBr, KCl, KBrO3,
LiClO4 or NaBF4 (74.6-322.4 mg, 1.0 mmol) in 11 mL of DMSO-H2O (10:1), AcOH-H2O
(10:1), CH3CN-H2O (10:1), EtOH-H2O (10:1), 11 mL DMSO or in 13 mL of THF-H2O (10:3)
was electrolyzed using constant current conditions (33.3 mA/cm2) at 35-40 °C under magnetic
stirring for 70 min with I = 100 mA. Then electrodes were washed with CH2Cl2 (2 × 20 mL).
The combined organic phases were washed with brine (10 mL), a 5% aqueous NaHCO3 solution
(2 × 10 mL), and again with brine (10 mL), dried over MgSO4, filtered and concentrated under
reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca. 20‒25 °C).
Product 3aa was isolated by chromatography on SiO2 (PE:EtOAc = from 20:1 to 2:1).
Experimental Procedure for Table 1, entries 17-19.
An undivided cell was equipped with a platinum plate or graphite anode (3 cm2) and a platinum
or copper or iron plate cathode (3 cm2) and connected to a DC regulated power supply. The
solution of ethyl benzoylacetate 1a (1.0 mmol, 213.6 mg, 90% technical grade), acetic acid 2a
(10.0 mmol, 601.0 mg) and supporting electrolyte KBr (119.0 mg, 1.0 mmol) in 11 mL of
DMSO-H2O (10:1) was electrolyzed using constant current conditions (33.3 mA/cm2) at 35-40
°C under magnetic stirring for 70 min with I = 100 mA. Then electrodes were washed with
CH2Cl2 (2 × 20 mL). The combined organic phases were washed with brine (10 mL), a 5%
aqueous NaHCO3 solution (2 × 10 mL), and again with brine (10 mL), dried over MgSO4,
filtered and concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath
temperature, ca. 20‒25 °C). Product 3aa was isolated as described above.
Experimental Procedure for Table 1, entries 20-26, 28, 29.
An undivided cell was equipped with a platinum plate anode (3 cm2) and a platinum plate
cathode (3 cm2) and connected to a DC regulated power supply. The solution of ethyl
benzoylacetate 1a (1.0 mmol, 213.6 mg, 90% technical grade), acetic acid 2a (2.0-20.0 mmol,
120.2-1202.0 mg) and supporting electrolyte KBr (59.5-238.0 mg, 0.5-2.0 mmol) in 11 mL of
12
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
DMSO-H2O (10:1) was electrolyzed using constant current conditions (33.3 mA/cm2) at 0-5 °C
or 35-40 °C or 60 °C under magnetic stirring for 35-140 min with I = 100 mA. Then electrodes
were washed with CH2Cl2 (2 × 20 mL). The combined organic phases were washed with brine
(10 mL), a 5% aqueous NaHCO3 solution (2 × 10 mL), and again with brine (10 mL), dried over
MgSO4, filtered and concentrated under reduced pressure using a rotary evaporator (15-20
mmHg), (bath temperature, ca. 20‒25 °C). Product 3aa was isolated as described above.
Experimental Procedure for Table 1, entry 27.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An undivided cell was equipped with a platinum plate anode (3 cm2) and a platinum plate
cathode (3 cm2). The solution of ethyl benzoylacetate 1a (1.0 mmol, 213.6 mg, 90% technical
grade), acetic acid 2a (10.0 mmol, 601.0 mg) and KBr (119.0 mg, 1.0 mmol) in 11 mL of
DMSO-H2O (10:1) was stirred at 35-40 °C under magnetic stirring for 70 min. Target product
3aa was not detected by TLC during the reaction and after the synthesis.
General Experimental Procedure for Table 2.
Electrochemical synthesis of α-acyloxy-β-dicarbonyl compounds 3 from different β-
dicarbonyl compounds 1 and carboxylic acids 2.
An undivided cell was equipped with a platinum plate or graphite anode (3 cm2) and a platinum
or iron plate cathode (3 cm2) and connected to a DC regulated power supply. The solution of β-
dicarbonyl compound 1a-i (1.0 mmol, 100.1-250.3 mg), carboxylic acid 2a-l (10.0 mmol, 601.0-
1791.8 mg) and supporting electrolyte KBr (119.0 mg, 1.0 mmol) in 11 mL of DMSO-H2O was
electrolyzed using constant current conditions (33.3 mA/cm2) at 35-40 °C under magnetic
stirring for 70 min with I = 100 mA. Then electrodes were washed with CH2Cl2 (2 × 20 mL).
The combined organic phases were washed with brine (10 mL), a 5% aqueous NaHCO3 solution
(2 × 10 mL), and again with brine (10 mL), dried over MgSO4, filtered and concentrated under
reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca. 20‒25 °C).
Product 3 was isolated by chromatography on SiO2 (PE:EtOAc = from 20:1 to 2:1).
Analytical data synthesized α-acyloxy-β-dicarbonyl compounds 3
Ethyl 2-acetoxy-3-oxo-3-phenylpropanoate, 3aa
O
O
Ph
OEt
OAc
Yield was 76% (0.76 mmol, 190.2 mg) in the case of Pt(+) – Pt(-) and 59% (0.59 mmol, 147.6
mg) in the case of C(+) – Fe(-). Yellow oil. Rf = 0.34 (PE:EtOAc =5:1); 1H NMR (300.13 MHz,
CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 2.20 (s, 3H), 4.22 (q, J = 7.0 Hz, 2H), 6.31 (s, 1H), 7.48 (t, J =
7.3 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.91-7.99 (d, J = 7.3 Hz, 2H); 13C{1H}NMR (75.48 MHz,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
CDCl3) δ 13.8, 20.5, 62.5, 74.4, 128.7, 129.1, 134.2, 165.1, 169.5, 189.6. The physical and
spectral data were consistent with those previously reported.59
Ethyl 2-acetoxy-3-oxobutanoate, 3ba
6
7
O
O
8
9
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OAc
1
Yield was 70% (0.70 mmol, 131.7 mg). Yellow oil. Rf = 0.25 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.30 (t, J = 7.3 Hz, 3H), 2.21 (s, 3H), 2.33 (s, 3H), 4.27 (q, J = 7.3 Hz),
5.48 (s, 1H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 14.0, 20.4, 27.2, 62.5, 77.9, 164.5, 169.4,
197.5. The physical and spectral data were consistent with those previously reported.59
Ethyl 2-acetoxy-5-methyl-3-oxohexanoate, 3ca
O
O
OEt
OAc
1
Yield was 81% (0.81 mmol, 186.5 mg). Colorless oil. Rf = 0,54 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 0.90 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.28 (t, J = 7.3 Hz,
3H), 2.13-2.17 (m, 1H), 2.20 (s, 3H), 2.51 (d, J = 6.6 Hz, 2H), 4.25 (q, J = 7.3 Hz, 2H), 5.45 (s,
13
1H); C{1H}NMR (75.48 MHz, CDCl3) δ 14.0, 20.4, 22.3, 22.4, 24.0, 48.5, 62.4, 77.8, 164.6,
169.4, 199.3. The physical and spectral data were consistent with those previously reported.129
Ethyl 2-acetoxy-3-(adamantan-1-yl)-3-oxopropanoate, 3da
O
O
OEt
OAc
1
Yield was 36% (0.36 mmol, 111.0 mg). Colorless oil. Rf = 0.6 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.25 (t, J = 7.3 Hz, 3H), 1.65-1.76 (m, 6H), 1.85-1.88 (m, 6H), 2.01-
2.08 (m, 3H), 2.16 (s, 3H), 4.22 (q, J = 7.3 Hz, 2H), 5.89 (s, 1H); C{1H}NMR (75.48 MHz,
13
CDCl3) δ 13.9, 20.4, 27.7, 36.3, 37.7, 46.9, 62.1, 71.4, 165.4, 169.4, 204.3. HRMS (ESI-TOF)
m/z [M + Na]+: Calcd for [C17H24NaO5]+: 331.1516. Found: 331.1511.
Tert-butyl 2-acetoxy-3-oxobutanoate, 3ea
O
O
OBut
OAc
1
Yield was 78% (0.78 mmol, 168.7 mg). Colorless oil. Rf = 0.38 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.47 (s, 9H), 2.19 (s, 3H), 2.30 (s, 3H), 5.37 (s, 1H); 13C{1H}NMR
(75.48 MHz, CDCl3) δ 20.4, 27.2, 27.8, 78.4, 84.0, 163.3, 169.5, 197.7. The physical and
spectral data were consistent with those previously reported.130
14
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
2,4-Dioxopentan-3-yl acetate, 3fa
exists as an equilibrating mixture of keto- and enol-tautomers (~3.2:1)
5
6
O
O
7
8
9
OAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield was 73% (0.73 mmol, 115.4 mg) in the case of Pt(+) – Pt(-) and 62% (0.62 mmol, 98.1
1
mg) in the case of C(+) – Fe(-). Colorless oil. Rf = 0.26 (PE:EtOAc = 5:1); H NMR (300.13
MHz, CDCl3) δ 2.00 (s, 6H, enol), 2.23 (s, 3H), 2.24 (s, 3H, enol), 2.28 (s, 6H), 5.47 (s, 1H),
14.41 (s, 1H, enol); 13C{1H}NMR (75.48 MHz, CDCl3) δ 20.3, 20.4, 20.7, 27.3, 85.1, 169.2,
184.7 (enol), 199.0. The physical and spectral data were consistent with those previously
reported.131
6-Methyl-2,4-dioxoheptan-3-yl acetate, 3ga
exists as an equilibrating mixture of keto- and enol-tautomers (~1.9:1)
O
O
OAc
Yield was 39% (0.39 mmol, 78.1 mg). Yellow oil. Rf = 0.53 (PE:EtOAc = 5:1); 1H NMR (300.13
MHz, CDCl3) δ 0.86-0.92 (m, 12H, keto + enol), 1.99 (s, 3H, enol), 2.11-2.17 (m, 4H, keto +
enol), 2.21 (s, 3H), 2.23 (s, 3H, enol), 2.25 (s, 3H), 2.47 (d, J = 6.6 Hz, 2H), 5.43 (s, 1H), 14.57
(s, 1H, enol); 13C{1H}NMR (75.48 MHz, CDCl3) δ 20.3, 20.4, 21.1, 22.2, 22.4, 22.6, 23.7, 25.4,
27.1, 41.4 (enol), 48.4, 85.2, 128.3 (enol), 169.2, 169.5, 185.4, 186.3, 199.1, 200.7. HRMS (ESI-
TOF) m/z [M + Na]+: Calcd for [C10H16NaO4]+: 223.0941. Found: 223.0938.
1,3-Dioxo-1-phenylbutan-2-yl acetate, 3ha
exists as an equilibrating mixture of keto- and enol-tautomers (~5.5:1)
O
O
Ph
OAc
1
Yield was 70% (0.70 mmol, 154.1 mg). Yellow oil. Rf = 0.30 (PE:EtOAc = 7:1); H NMR
(300.13 MHz, CDCl3) δ 2.11 (s, 3H, enol), 2.14 (s, 3H, enol), 2.22 (s, 3H), 2.28 (s, 3H), 6.25 (s,
1H), 7.40-7.44 (m, 3H, enol), 7.47 (t, J = 7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.73 (d, J = 8.0
13
Hz, 2H, enol), 7.99 (d, J = 7.5 Hz, 2H); C{1H}NMR (75.48 MHz, CDCl3) δ 20.5, 26.8, 82.2,
128.1 (enol), 128.3 (enol), 128.7, 129.5, 134.2, 134.3, 169.3, 190.9, 199.4. The physical and
spectral data were consistent with those previously reported.132
1-(2-Chlorophenyl)-1,3-dioxobutan-2-yl acetate, 3ia
exists as an equilibrating mixture of keto- and enol-tautomers (~1:1.5)
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
Cl
O
O
3
4
5
OAc
6
7
8
9
1
Yield was 67% (0.67 mmol, 170.6 mg). Yellow oil. Rf = 0.35 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.90 (s, 3H, enol), 2.13 (s, 3H, enol), 2.15 (s, 3H), 2.34 (s, 3H), 6.17 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H), 7.28-7.42 (m, 9H, keto+enol), 7.54 (d, J = 7.3 Hz, 1H), 14.37 (s, 1H, enol); C{1H}NMR
(75.48 MHz, CDCl3) δ 20.02, 20.03, 21.8, 27.5, 83.6, 126.5, 126.8, 127.8, 129.0, 129.8, 129.9,
130.5, 131.2, 131.7, 132.7, 133.1, 135.8, 169.30, 169.34, 177.5, 189.0, 193.4, 198.2. HRMS
(ESI-TOF) m/z [M + Na]+: Calcd for [C12H11NaClO4]+: 277.0238. Found: 277.0239.
Ethyl 3-oxo-3-phenyl-2-(propionyloxy)propanoate, 3ab
O
O
Ph
OEt
O
O
Et
Yield was 92% (0.92 mmol, 243.1 mg) in the case of Pt(+) – Pt(-) and 51% (0.51 mmol, 134.8
1
mg) in the case of C(+) – Fe(-). Colorless oil. Rf = 0.45 (PE:EtOAc = 5:1); H NMR (300.13
MHz, CDCl3) δ 1.17-1.24 (m, 6H), 2.49 (q, J = 7.3 Hz, 2H), 4.22 (q, J = 7.3 Hz, 2H), 6.30 (s,
13
1H), 7.47 (t, J = 7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H); C{1H}NMR
(75.48 MHz, CDCl3) δ 8.8, 13.8, 27.1, 62.3, 74.3, 128.7, 129.1, 134.1, 134.2, 165.2, 172.9,
189.8. HRMS (ESI-TOF) m/z [M + Na]+: Calcd for [C14H16NaO5]+: 287.0890. Found: 287.0886.
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl benzoate, 3ac
O
O
Ph
OEt
O
O
Ph
1
Yield was 85% (0.85 mmol, 265.5 mg). Colorless oil. Rf = 0.38 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.20 (t, J = 7.0 Hz, 3H), 4.26 (q, J = 7.0 Hz, 2H), 6.53 (s, 1H), 7.38 -
7.59 (m, 4H), 7.53 - 7.61 (m, 2H), 8.05-8.09 (m, 4H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.8,
62.3, 74.8, 128.34, 128.38, 128.7, 129.1, 130.0, 133.7, 134.08, 134.11, 164.9, 165.1, 189.6. The
physical and spectral data were consistent with those previously reported.133
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl hexanoate, 3ad
16
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
O
O
3
4
5
Ph
OEt
O
O
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Yield was 88% (0.88 mmol, 269.6 mg). Colorless oil. Rf = 0.55 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 0.83-0.87 (m, 3H), 1.17-1.29 (m, 7H), 1.62-1.67 (m, 2H), 2.45 (t, J = 7.2
Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 6.30 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H),
7.97 (d, J = 7.3 Hz, 2H); C{1H}NMR (75.48 MHz, CDCl3) δ 13.77, 13.84, 22.2, 24.3, 31.0,
13
33.7, 62.3, 74.3, 128.7, 129.1, 134.1, 134.2, 165.2, 172.3, 189.8. HRMS (ESI-TOF) m/z [M +
Na]+: Calcd for [C17H22NaO5]+: 329.1359. Found: 329.1361.
Ethyl 3-oxo-3-phenyl-2-(2-phenylacetoxy)propanoate, 3ae
O
O
Ph
OEt
O
O
Ph
1
Yield was 54% (0.54 mmol, 176.2 mg). Colorless oil. Rf = 0.51 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 3.79 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 6.29 (s,
1H), 7.26 - 7.33 (m, 5H), 7.43 (t, J = 7.7 Hz, 2H), 7.59 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 7.7 Hz,
2H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.8, 40.5, 62.4, 74.8, 127.3, 128.5, 128.6, 129.1,
129.3, 132.8, 134.1, 165.0, 170.1, 189.6. HRMS (ESI-TOF) m/z [M + Na]+: Calcd for
[C19H18NaO5]+: 349.1046. Found: 349.1046.
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl 2-iodobenzoate, 3af
O
O
Ph
OEt
O
O
I
1
Yield was 29% (0.29 mmol, 127.1 mg). Colorless oil. Rf = 0.44 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.24 (t, J = 7.3 Hz, 3H), 4.28 (q, J = 7.3 Hz, 2H), 6.57 (s, 1H), 7.18 (t, J
= 7.3 Hz, 1H), 7.42 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.3 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.99 -
8.07 (m, 4H); C{1H}NMR (75.48 MHz, CDCl3) δ 13.9, 62.6, 75.0, 94.7, 128.1, 128.8, 129.3,
13
132.0, 132.9, 133.4, 134.3, 141.6, 164.7, 164.9, 189.3. HRMS (ESI-TOF) m/z [M + Na]+: Calcd
for [C18H15INaO5]+: 460.9856. Found: 460.9837.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
Ethyl 2-((3-cyclohexylpropanoyl)oxy)-3-oxo-3-phenylpropanoate, 3ag
O
O
5
6
7
Ph
OEt
O
O
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield was 83% (0.83 mmol, 287.5 mg) in the case of Pt(+) – Pt(-) and 64% (0.64 mmol, 221.7
1
mg) in the case of C(+) – Fe(-). Colorless oil. Rf = 0.57 (PE:EtOAc = 5:1); H NMR (300.13
MHz, CDCl3) δ 0.81-0.95 (m, 3H), 1.16-1.24 (m, 7H), 1.53-1.68 (m, 6H), 2.48 (t, J = 8.0 Hz,
2H), 4.24 (q, J = 7.3 Hz, 2H), 6.30 (s, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.98
(t, J = 7.3 Hz, 2H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.9, 26.1, 26.5, 31.3, 32.0, 32.8, 37.0,
62.4, 74.3, 128.7, 129.2, 134.1, 134.3, 165.3, 172.7, 189.9. HRMS (ESI-TOF) m/z [M + Na]+:
Calcd for [C20H26NaO5]+: 369.1672. Found: 369.1658.
Ethyl 3-oxo-3-phenyl-2-((3-phenylpropanoyl)oxy)propanoate, 3ah
O
O
Ph
OEt
O
O
Ph
1
Yield was 48% (0.48 mmol, 163.4 mg). Colorless oil. Rf = 0.46 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.21 (t, J =7.0 Hz, 3H), 2.79-2.85 (m, 2H), 2.97-3.02 (m, 2H), 4.24 (q, J
= 7.0 Hz, 2H), 6.32 (s, 1H), 7.17-7.21 (m, 3H), 7.24-7.29 (m, 2H), 7.45-7.50 (m, 2H), 7.59-7.63
13
(m, 1H), 7.95-7.98 (m, 2H); C{1H}NMR (75.48 MHz, CDCl3) δ 13.9, 30.5, 35.2, 62.4, 74.4,
126.3, 128.2, 128.5, 128.7, 129.1, 134.13, 134.15, 139.9, 165.1, 171.4, 189.6; HRMS (ESI-TOF)
m/z [M + Na]+: Calcd for [C20H20NaO5]+: 363.1203. Found: 363.1206.
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl cinnamate, 3ai
O
O
Ph
OEt
O
O
Ph
1
Yield was 67% (0.67 mmol, 226.7 mg). Colorless oil. Rf = 0.51 (PE:EtOAc = 5:1); H NMR
(300.13 MHz, CDCl3) δ 1.23 (t, J = 7.3 Hz, 3H), 4.27 (q, J = 7.3 Hz, 2H), 6.46 (s, 1H), 6.57 (d, J
= 16.0 Hz, 1H), 7.36-7.40 (m, 3H), 7.50-7.53 (m, 4H), 7.60-7.65 (m, 1H), 7.79 (d, J = 16.0 Hz,
1H), 8.02-8.06 (m, 2H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.9, 62.4, 74.4, 116.1, 128.3,
18
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
128.8, 128.9, 129.2, 130.8, 133.9, 134.2, 134.3, 147.2, 165.2, 165.3, 189.8; HRMS (ESI-TOF)
m/z [M + Na]+: Calcd for [C20H18NaO5]+: 361.1046. Found: 361.1041. The physical and spectral
data were consistent with those previously reported.134
6
7
8
9
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl (2E,4E)-hexa-2,4-dienoate, 3aj
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
OEt
O
O
1
Yield was 58% (0.58 mmol, 175.4 mg). Colorless oil. Rf = 0.22 (PE:EtOAc = 10:1); H NMR
(300.13 MHz, CDCl3) δ 1.21 (t, J = 7.0 Hz, 3H), 1.84 (d, J = 4.8 Hz, 3H), 4.24 (q, J = 7.0 Hz,
2H), 5.89 (d, J = 15.4 Hz, 1H), 6.13-6.25 (m, 2H), 6.37 (s, 1H), 7.30-7.39 (m, 1H), 7.47 (t, J =
7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 8.01 (d, J = 7.3 Hz, 2H); 13C{1H}NMR (75.48 MHz,
CDCl3) δ 13.9, 18.7, 62.4, 74.3, 116.8, 128.7, 129.2, 129.6, 134.1, 134.3, 141.2, 147.5, 165.4,
165.6, 190.0; HRMS (ESI-TOF) m/z [M + Na]+: Calcd for [C17H18NaO5]+: 325.1046. Found:
325.1044.
Ethyl 2-((benzoylglycyl)oxy)-3-oxo-3-phenylpropanoate, 3ak
O
O
Ph
OEt
O
O
NH
O
Ph
Yield was 56% (0.56 mmol, 206.8 mg). White crystals, mp = 101-103 °C. Rf = 0.40 (PE:EtOAc
1
= 10:1); H NMR (300.13 MHz, CDCl3) δ 1.20 (t, J = 7.0 Hz, 3H), 4.24 (q, J = 7.0 Hz, 2H),
4.34-4.49 (m, 2H), 6.36 (s, 1H), 6.72 (broad s, 1H), 7.37-7.51 (m, 5H), 7.61 (t, J = 7.7 Hz, 1H),
7.76 (d, J = 7.7 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H); C{1H}NMR (75.48 MHz, CDCl3) δ 13.9,
13
41.6, 62.7, 75.1, 127.1, 128.6, 128.8, 129.2, 131.9, 133.4, 133.9, 134.4, 164.6, 167.5, 168.9,
189.0; HRMS (ESI-TOF) m/z [M + Na]+: Calcd for [C20H19NNaO6]+: 392.1105. Found:
392.1101.
1-Ethoxy-1,3-dioxo-3-phenylpropan-2-yl thiophene-2-carboxylate, 3al
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
O
O
3
4
5
Ph
OEt
O
O
6
7
8
S
9
1
Yield was 38% (0.38 mmol, 121.0 mg). Colorless oil. Rf = 0.28 (PE:EtOAc = 10:1); H NMR
(300.13 MHz, CDCl3) δ 1.23 (t, J = 7.0 Hz, 3H), 4.27 (q, J = 7.0 Hz, 2H), 6.45 (s, 1H), 7.10 (dd,
J = 3.8 Hz, J = 5.0 Hz, 1H), 7.46-7.52 (m, 2H), 7.59-7.64 (m, 2H), 7.88-7.89 (m, 1H), 8.03-8.06
(m, 2H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.9, 62.5, 75.0, 128.0, 128.8, 129.3, 131.6,
133.9, 134.2, 134.9, 160.5, 165.1, 189.5; HRMS (ESI-TOF) m/z [M + Na]+: Calcd for
[C16H14NaO5S]+: 341.0454. Found: 341.0455.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyclic voltammetry measurements
Cyclic voltammetry (CV) was performed on an Elins P-30JM computer-assisted potentiostat
manufactured by Elins (scan rate error 1.0%, potential setting 0.25 mV). The experiments were
performed in a 10-mL five-neck glass conic electrochemical cell with a water jacket for
thermostatting under a nitrogen atmosphere. CV curves were recorded using a three-electrode
scheme. The working electrode was a disc Pt electrode (d = 1 mm). A platinum plate (S = 3 cm2)
served as counter electrode. A saturated calomel electrode was used as the reference electrode
and was linked to the solution by a bridge with a porous ceramic diaphragm filled with
supporting electrolyte (0.1 M Et4NClO4 in DMSO/H2O 10/1 v/v). The tested solutions were
thermostatted at 25 ± 0.5 °C. In a typical case, 5 mL solution was utilized and the studied
compound concentration was 3 mmol/L. The working electrode was polished before recording
each CV curve.
Experimental Procedures for Scheme 4.
Ethyl 2-bromo-3-oxo-3-phenylpropanoate, A
O
O
Ph
OEt
Br
Ethyl 2-bromo-3-oxo-3-phenylpropanoate (A) was prepared according to literature procedure.135
Yield was 88% (4.41 mmol, 1.19 g). Yellow oil. Rf = 0.49 (PE:EtOAc = 10:1); 1H NMR (300.13
MHz, CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 4.23 (q, J = 7.0 Hz, 2H), 5.67 (s, 1H), 7.42-7.48 (m,
2H), 7.55-7.61 (m, 1H), 7.94-7.98 (m, 2H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 13.7, 46.3,
63.1, 128.8, 129.0, 133.2, 134.1, 165.0, 188.0. The physical and spectral data were consistent
with those previously reported.135
Experimental procedures for Scheme 4, a-f
20
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
a) Ethyl 2-bromo-3-oxo-3-phenylpropanoate (A) (271.1 mg, 1.0 mmol) was added to acetic acid
(601.0 mg, 10.0 mmol). The mixture was stirred for 70 min at 25-30 °C. Conversion of starting
compound A was not detected by TLC during the reaction and after the synthesis.
b) Acetic acid (601.0 mg, 10.0 mmol) was added to a solution of ethyl 2-bromo-3-oxo-3-
phenylpropanoate (A) (271.1 mg, 1.0 mmol) in 11 mL DMSO/H2O (10/1). The mixture was
stirred for 70 min at 25-30 °C. Conversion of starting compound A was not detected by TLC
during the reaction and after the synthesis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c) Acetic acid (601.0 mg, 10.0 mmol) was added to a solution of ethyl 2-bromo-3-oxo-3-
phenylpropanoate (A) (271.1 mg, 1.0 mmol) in 11 mL DMSO/H2O (10/1). Then KBr (119.0 mg,
1.0 mmol) was added. The mixture was stirred for 70 min at 25-30 °C. Conversion of starting
compound A was not detected by TLC during the reaction and after the synthesis.
d) Ethyl 2-bromo-3-oxo-3-phenylpropanoate (A) (271.1 mg, 1.0 mmol) was added to acetic acid
(601.0 mg, 10.0 mmol). Then KOH (56.1 mg, 1.0 mmol) was added. The mixture was stirred for
70 min at 25-30 °C. Conversion of starting compound A was not detected by TLC during the
reaction and after the synthesis.
e) Acetic acid (601.0 mg, 10.0 mmol) was added to a solution of ethyl 2-bromo-3-oxo-3-
phenylpropanoate (A) (271.1 mg, 1.0 mmol) in 11 mL DMSO/H2O (10/1). Then KOH (56.1 mg,
1.0 mmol) was added. The mixture was stirred for 70 min at 25-30 °C. After that time CH2Cl2
(40 mL) was added. The mixture was washed with brine (10 mL), a 5% aqueous NaHCO3
solution (2 × 10 mL), and again with brine (10 mL), dried over MgSO4, filtered and concentrated
under reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca. 20‒25
°C). Product 3aa was isolated as described above.
f) Acetic acid (601.0 mg, 10.0 mmol) was added to a solution of ethyl 2-bromo-3-oxo-3-
phenylpropanoate (A) (271.1 mg, 1.0 mmol) in 11 mL DMSO/H2O (10/1). Then AcOK (98.1
mg, 1.0 mmol) was added. The mixture was stirred for 70 min at 25-30 °C. After that time
CH2Cl2 (40 mL) was added. The mixture was washed with brine (10 mL), a 5% aqueous
NaHCO3 solution (2 × 10 mL), and again with brine (10 mL), dried over MgSO4, filtered and
concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath
temperature, ca. 20‒25 °C). Product 3aa was isolated as described above.
Experimental Procedure for Scheme 5.
An undivided cell was equipped with a platinum plate anode (3 cm2) and a platinum plate
cathode (3 cm2) and connected to a DC regulated power supply. The solution of ethyl
benzoylacetate 1a (1.0 mmol, 213.6 mg, 90% technical grade), acetic acid 2a (10.0 mmol, 601.0
mg) and supporting electrolyte KBr (119.0 mg, 1.0 mmol) in 11 mL of CH3CN-H2O (10:1) was
electrolyzed using constant current conditions (33.3 mA/cm2) at 35-40 °C under magnetic
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
8
9
stirring for 70 min with I = 100 mA. Then electrodes were washed with CH2Cl2 (2 × 20 mL).
The combined organic phases were washed with brine (10 mL), a 5% aqueous NaHCO3 solution
(2 × 10 mL), and again with brine (10 mL), dried over MgSO4, filtered and concentrated under
reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca. 20‒25 °C).
Products A and 3aa were isolated by chromatography on SiO2 (PE:EtOAc = from 20:1 to 2:1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgment
This work was supported by the Russian Science Foundation (Grant № 18-13-00027). Authors
are grateful to Department of Structural Studies, Zelinsky Institute of Organic Chemistry RAS
for HRMS analysis.
Supporting Information.
Photos of the used undivided electrochemical cell, calculation of the passed electric current,
copies of the 1H and 13C NMR spectra for all products (PDF).
References
1.
beyond Functional Group Transformations. Acc. Chem. Res. 2009, 42, 335-344.
2. Yeung, C. S.; Dong, V. M., Catalytic dehydrogenative cross-coupling: forming
Li, C.-J., Cross-Dehydrogenative Coupling (CDC): Exploring C−C Bond Formations
carbon−carbon bonds by oxidizing two carbon−hydrogen bonds. Chem. Rev. 2011, 111, 1215-
1292.
3.
a versatile strategy for C-C bond formations. Angew. Chem., Int. Ed. 2014, 53, 74-100.
4. Krylov, I. B.; Vil’, V. A.; Terent’ev, A. O., Cross-dehydrogenative coupling for the
intermolecular C–O bond formation. Beilstein J. Org. Chem. 2015, 11, 92-146.
5. Girard, S. A.; Knauber, T.; Li, C.-J., Chapter 1. The evolution of the concept of cross-
Girard, S. A.; Knauber, T.; Li, C.-J., The cross-dehydrogenative coupling of C-H bonds:
dehydrogenative-coupling reactions. In From C-H to C-C Bonds: Cross-Dehydrogenative-
Coupling, The Royal Society of Chemistry 2015; pp 1-32.
6.
Zhang, C.; Tang, C.; Jiao, N., Recent advances in copper-catalyzed dehydrogenative
functionalization via a single electron transfer (SET) process. Chem. Soc. Rev. 2012, 41, 3464-
3484.
7.
Samanta, R.; Matcha, K.; Antonchick, A. P., Metal-free oxidative carbon-heteroatom
bond formation through C–H bond functionalization. Eur. J. Org. Chem. 2013, 2013, 5769-5804.
22
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
8.
Han, B.; Liu, Q.; Liu, Z.; Mu, R.; Zhang, W.; Liu, Z.-L.; Yu, W., A metal-free catalytic
aerobic aromatization of Hantzsch 1,4-dihydro-pyridines by N-hydroxyphthalimide. Synlett
2005, 2005, 2333-2334.
6
7
8
9
9.
A concise review. Beilstein J. Org. Chem. 2013, 9, 1296-1310.
10. Yang, G.; Zhang, Q.; Miao, H.; Tong, X.; Xu, J., Selective organocatalytic oxygenation
Melone, L.; Punta, C., Metal-free aerobic oxidations mediated by N-hydroxyphthalimide.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of hydrocarbons by dioxygen using anthraquinones and N-hydroxyphthalimide. Org. Lett. 2005,
7, 263-266.
11.
Kirste, A.; Schnakenburg, G.; Stecker, F.; Fischer, A.; Waldvogel, S. R., Anodic phenol–
arene cross-coupling reaction on boron-doped diamond electrodes. Angew. Chem., Int. Ed. 2010,
49, 971-975.
12.
Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R., Insights into
the mechanism of anodic N–N bond formation by dehydrogenative coupling. J. Am. Chem. Soc.
2017, 139, 12317-12324.
13.
dehydrogenative coupling. Angew. Chem., Int. Ed. 2017, 56, 4734-4738.
14. Xiong, P.; Xu, H.-H.; Xu, H.-C., Metal- and reagent-free intramolecular oxidative
amination of tri- and tetrasubstituted alkenes. J. Am. Chem. Soc. 2017, 139, 2956-2959.
15. Wang, P.; Tang, S.; Lei, A., Electrochemical intramolecular dehydrogenative C–S bond
formation for the synthesis of benzothiazoles. Green Chem. 2017, 19, 2092-2095.
16. Wang, P.; Tang, S.; Huang, P.; Lei, A., Electrocatalytic oxidant-free dehydrogenative
C−H/S−H cross-coupling. Angew. Chem., Int. Ed. 2017, 56, 3009-3013.
17. Gao, J.-M.; Yang, S.-X.; Qin, J.-C., Azaphilones: chemistry and biology. Chem. Rev.
2013, 113, 4755-4811.
Wu, Z.-J.; Xu, H.-C., Synthesis of C3-fluorinated oxindoles through reagent-free cross-
18.
Sun, C.; Hunt, D. K.; Chen, C.-L.; Deng, Y.; He, M.; Clark, R. B.; Fyfe, C.; Grossman, T.
H.; Sutcliffe, J. A.; Xiao, X.-Y., Design, synthesis, and biological evaluation of hexacyclic
tetracyclines as potent, broad spectrum antibacterial agents. J. Med. Chem. 2015, 58, 4703-4712.
19.
Selected 5-substituted 5-(1-phenylethyl)barbituric acids. J. Med. Chem. 1974, 17, 1194-1197.
20. Vida, J. A.; Samour, C. M.; O'Dea, M. H.; Wang, T. S. T.; Wilber, W. R.; Reinhard, J. F.,
Vida, J. A.; Samour, C. M.; O'Dea, M. H.; Wang, T. S. T.; Reinhard, J. F., Analgesics. 2.
Analgesics. 1. Selected 5-substituted 5-propionoxybarbituric acids. J. Med. Chem. 1974, 17, 732-
736.
21.
Fukuda, T.; Matsumoto, A.; Takahashi, Y.; Tomoda, H.; Ōmura, S., Phenatic acids A and
B, new potentiators of antifungal miconazole activity produced by Streptomyces sp. K03-0132.
J. Antibiot. 2005, 58, 252.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
22.
Lin, L.; Mulholland, N.; Wu, Q.-Y.; Beattie, D.; Huang, S.-W.; Irwin, D.; Clough, J.; Gu,
Y.-C.; Yang, G.-F., Synthesis and antifungal activity of novel sclerotiorin analogues. J. Agric.
Food. Chem. 2012, 60, 4480-4491.
6
7
8
23.
Yamazaki, H.; mura, S.; Tomoda, H., 6'-Hydroxy-3'-methoxy-mitorubrin, a new
9
potentiator of antifungal miconazole activity, produced by Penicillium radicum FKI-3765-2.
Chem. Pharm. Bull. 2010, 58, 829-832.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
24.
Che, Y.; Gloer, J. B.; Koster, B.; Malloch, D., Decipinin A and Decipienolides A and B:ꢀ
New bioactive metabolites from the coprophilous fungus Podospora decipiens. J. Nat. Prod.
2002, 65, 916-919.
25.
Wang, X.; Sena Filho, J. G.; Hoover, A. R.; King, J. B.; Ellis, T. K.; Powell, D. R.;
Cichewicz, R. H., Chemical epigenetics alters the secondary metabolite composition of guttate
excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J. Nat. Prod. 2010, 73, 942-
948.
26.
Wang, P.; Kim, W.; Pickens, L. B.; Gao, X.; Tang, Y., Heterologous expression and
manipulation of three tetracycline biosynthetic pathways. Angew. Chem., Int. Ed. 2012, 51,
11136-11140.
27.
Wang, Z.; Sheng, Y.; Duan, H.; Yu, Q.; Shi, W.; Zhang, S., New haptens synthesis,
antibody production and comparative molecular field analysis for tetracyclines. RSC Adv. 2014,
4, 53788-53794.
28.
Wang, H.; Wang, Y.; Wang, W.; Fu, P.; Liu, P.; Zhu, W., Anti-influenza virus
polyketides from the acid-tolerant fungus Penicillium purpurogenum JS03-21. J. Nat. Prod.
2011, 74, 2014-2018.
29.
Xue-Long, S.; Hiroaki, T.; Keiichi, M.; Haruo, T.; Kimio, F.; Satoshi, O., Synthesis and
inhibitory activities of isochromophilone analogues against gp120-CD4 binding. J. Antibiot.
1996, 49, 689-692.
30.
Cignarella, G.; Barlocco, D.; Pocar, D.; Clerici, F.; Curzu, M. M.; Gessa, G. L.; Fadda,
F.; Serra, M.; Biggio, G., Synthesis and pharmacological evaluation of a new series of
substituted benzoyl-γ-butyrolactone derivatives. Eur. J. Med. Chem. 1995, 30, 721-726.
31.
molecular oxygen. J. Org. Chem. 1999, 64, 7668-7669.
32. Christoffers, J.; Werner, T.; Frey, W.; Baro, A., Cerium-catalyzed reaction of β-
Christoffers, J., Novel manganese-catalyzed α-oxidation of cyclic β-keto esters with
dicarbonyl compounds with styrene and atmospheric oxygen. Eur. J. Org. Chem. 2003, 2003,
4879-4886.
24
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
33.
Acocella, M. R.; Mancheño, O. G.; Bella, M.; Jørgensen, K. A., Organocatalytic
asymmetric hydroxylation of β-keto esters:ꢀ metal-free synthesis of optically active anti-diols. J.
Org. Chem. 2004, 69, 8165-8167.
6
7
8
34.
Christoffers, J.; Kauf, T.; Werner, T.; Rössle, M., Cerium-catalyzed α-hydroxylation
9
reactions of α-cyclopropyl β-dicarbonyl compounds with molecular oxygen. Eur. J. Org. Chem.
2006, 2006, 2601-2608.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
35.
Richardson, A. M.; Chen, C.-H.; Snider, B. B., Synthesis of methyl 1-hydroxy-6-oxo-2-
cyclohexenecarboxylate, a component of salicortin and tremulacin, and the monomer of
idesolide. J. Org. Chem. 2007, 72, 8099-8102.
36.
Gong, B.; Meng, Q.; Su, T.; Lian, M.; Wang, Q.; Gao, Z., Lappaconitine-catalyzed
asymmetric α-hydroxylation of β-keto esters: a Bronsted base organocatalyst developed from
terpenoid alkaloids. Synlett 2009, 2009, 2659-2662.
37.
Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G., Chiral Bronsted acid-
catalyzed enantioselective α-hydroxylation of β-dicarbonyl compounds. J. Am. Chem. Soc. 2009,
131, 4562-4563.
38.
hydroxylation of β-ketoesters. Chem. Commun. 2009, 3925-3927.
39. Smith, A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K. K., Delineating origins
Smith, A. M. R.; Billen, D.; Hii, K. K., Palladium-catalysed enantioselective α-
of stereocontrol in asymmetric Pd-catalyzed α-hydroxylation of 1,3-ketoesters. J. Org. Chem.
2010, 75, 3085-3096.
40.
hydroxylation of carbonyls with O2. J. Am. Chem. Soc. 2011, 133, 1760-1762.
41. Li, J.; Chen, G.; Wang, Z.; Zhang, R.; Zhang, X.; Ding, K., Spiro-2,2′-bichroman-based
Chuang, G. J.; Wang, W.; Lee, E.; Ritter, T., A dinuclear palladium catalyst for α-
bisoxazoline (SPANbox) ligands for ZnII-catalyzed enantioselective hydroxylation of β-keto
esters and 1,3-diester. Chem. Sci. 2011, 2, 1141-1144.
42.
Miyamura, H.; Kobayashi, S.; α-Hydroxylation of 1,3-dicarbonyl compounds catalyzed
by polymer-incarcerated gold nanoclusters with molecular oxygen. Chem. Lett. 2012, 41, 976-
978.
43.
Yao, H.; Lian, M.; Li, Z.; Wang, Y.; Meng, Q., Asymmetric direct α-hydroxylation of β-
oxo esters catalyzed by chiral quaternary ammonium salts derived from Cinchona alkaloids. J.
Org. Chem. 2012, 77, 9601-9608.
44.
De Fusco, C.; Meninno, S.; Tedesco, C.; Lattanzi, A., Enantioselective α-hydroxylation
of β-ketoamides. Org. Biomol. Chem. 2013, 11, 896-899.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
45.
Zou, L.; Wang, B.; Mu, H.; Zhang, H.; Song, Y.; Qu, J., Development of tartaric acid
derived chiral guanidines and their application to catalytic enantioselective α-hydroxylation of β-
dicarbonyl compounds. Org. Lett. 2013, 15, 3106-3109.
6
7
8
9
46.
and β-oxoamides. J. Org. Chem. 2014, 79, 11735-11739.
47. Gu, X.; Zhang, Y.; Xu, Z.-J.; Che, C.-M., Iron(III)–salan complexes catalysed highly
Asahara, H.; Nishiwaki, N., Metal-free α-hydroxylation of α-unsubstituted β-oxoesters
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
enantioselective fluorination and hydroxylation of β-keto esters and N-Boc oxindoles. Chem.
Commun. 2014, 50, 7870-7873.
48.
oxygen under mild conditions. Angew. Chem., Int. Ed. 2014, 53, 548-552.
49. Wang, Y.; Li, Z.; Xiong, T.; Zhao, J.; Meng, Q., Enantioselective α-hydroxylation of β-
keto esters catalyzed by Cinchona alkaloid derivatives. Synlett 2014, 25, 2155-2160.
50. Li, Z.; Li, T.; Li, J.; He, L.; Jia, X.; Yang, J., 2-Hydroxylation of 1,3-diketones with
atmospheric oxygen. Synlett 2015, 26, 2863-2865.
51. Rahman, M. T.; Nishino, H., Manganese(III)-catalyzed facile direct hydroperoxidation of
some heterocyclic 1,3-dicarbonyl compounds. Org. Lett. 2003, 5, 2887-2890.
52. Rahman, M. T.; Haque, M. A.; Igarashi, H.; Nishino, H., Mn(III)-initiated facile
oxygenation of heterocyclic 1,3-dicarbonyl compounds. Molecules 2011, 16, 9562-9581.
53. Haque, M. A.; Nishino, H., Facile access to 3-alkyl-substituted 3-hydroperoxy-2,4-
Liang, Y.-F.; Jiao, N., Highly Efficient C-H hydroxylation of carbonyl compounds with
pyrrolidinediones using manganese(III)-catalyzed aerobic oxidation. Synth. Commun. 2012, 42,
608-619.
54.
Terent´ev, A. O.; Vil´, V. A.; Bityukov, O. V.; Nikishin, G. I., Peroxidation of β-
diketones and β-keto esters with tert-butyl hydroperoxide in the presence of Cu(ClO4)2/SiO2.
Russ. Chem. Bull. 2014, 63, 2461-2466.
55.
Liu, Y.-Y.; Yang, X.-H.; Yang, J.; Song, R.-J.; Li, J.-H., Silver-mediated radical
cyclization: construction of Δ2-isoxazolines from α-halo ketoximes and 1,3-dicarbonyl
compounds. Chem. Commun. 2014, 50, 6906-6908.
56.
Krylov, I. B.; Paveliev, S. A.; Shelimov, B. N.; Lokshin, B. V.; Garbuzova, I. A.;
Tafeenko, V. A.; Chernyshev, V. V.; Budnikov, A. S.; Nikishin, G. I.; Terent'ev, A. O., Selective
cross-dehydrogenative C–O coupling of N-hydroxy compounds with pyrazolones. Introduction
of the diacetyliminoxyl radical into the practice of organic synthesis. Org. Chem. Front. 2017, 4,
1947-1957.
57.
Regev, A.; Shalit, H.; Pappo, D., Iron-catalyzed oxidative C–C and C–O coupling of
halophenols to α-substituted β-keto esters. Synthesis 2015, 47, 1716-1725.
26
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
58.
Moriarty, R. M.; Vaid, R. K.; Hopkins, T. E.; Vaid, B. K.; Prakash, O., Hypervalent
iodine oxidation of 5-keto acids and 4,6-diketo acids with [hydroxy(tosyloxy)iodo]benzene:
5
6
Synthesis of keto-γ-lactones and diketo-δ-lactones. Tetrahedron Lett. 1990, 31, 201-204.
7
8
59.
Yu, J.; Tian, J.; Zhang, C., Various α-Oxygen functionalizations of β-dicarbonyl
9
compounds mediated by the hypervalent iodine(III) reagent p-iodotoluene difluoride with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
different oxygen-containing nucleophiles. Adv. Synth. Catal. 2010, 352, 531-546.
60.
acetoxylation of 3-oxo-N-substituted butanamides. Beilstein J. Org. Chem. 2011, 7, 1436-1440.
61. Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K., Inꢀsitu generated (hypo)iodite catalysts
Liu, W.-B.; Chen, C.; Zhang, Q.; Zhu, Z.-B., Hypervalent iodine(III)-induced methylene
for the direct α-oxyacylation of carbonyl compounds with carboxylic acids. Angew. Chem., Int.
Ed. 2011, 50, 5331-5334.
62.
Xiaoqing, L.; Can, Z.; Xiangsheng, X., TBAI-catalyzed oxidative coupling of β-
ketoesters with carboxylic acid: synthesis of α-carboxylic-β-ketoesters. Arch. Org. Chem. 2012,
150-158.
63.
Citterio, A.; Santi, R.; Fiorani, T.; Strologo, S., Oxidation of malonic acid derivatives by
manganese(III) acetate. Aromatic malonylation reaction. Scope and limitations. J. Org. Chem.
1989, 54, 2703-2712.
64.
manganese(III)-based oxidative 1,2-radical rearrangement. J. Org. Chem. 2009, 74, 3978-3981.
65. Moloney, M. G.; Nettleton, E.; Smithies, K., Novel alkylation, lactonisation and cascade
Cong, Z.; Miki, T.; Urakawa, O.; Nishino, H., Synthesis of dibenz[b,f]oxepins via
coupling processes mediated by lead tetracarboxylates: the importance of ligands. Tetrahedron
Lett. 2002, 43, 907-909.
66.
carbonyl compounds by Fe(III) salts. Tetrahedron Lett. 1989, 30, 1289-1292.
67. Lee, J.; Oya, S.; Snyder, J. K., Asymmetric oxidation of β-ketoesters with benzoyl
Citterio, A.; Cerati, A.; Sebastiano, R.; Finzi, C.; Santi, R., Oxidative deprotonation of
peroxide; enantioselective formation of protected tertiary alcohols. Tetrahedron Lett. 1991, 32,
5899-5902.
68.
ketones. Angew. Chem., Int. Ed. 2011, 50, 9680-9683.
69. Jadhav, M. S.; Righi, P.; Marcantoni, E.; Bencivenni, G., Enantioselective α-
Lifchits, O.; Demoulin, N.; List, B., Direct Asymmetric α-benzoyloxylation of cyclic
benzoyloxylation of ketones promoted by primary amine catalyst. J. Org. Chem. 2012, 77, 2667-
2674.
70.
Wang, D.; Xu, C.; Zhang, L.; Luo, S., Asymmetric α-benzoyloxylation of β-
ketocarbonyls by a chiral primary amine catalyst. Org. Lett. 2015, 17, 576-579.
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
71.
Lloris, M. E.; Gálvez, N.; Marquet, J.; Moreno-Mañas, M., Reactions of copper(II) β-
diketonates under free radical conditions. Preparation of highly congested β-diketones.
Tetrahedron 1991, 47, 8031-8042.
6
7
8
72.
Salomon, R. G.; Salomon, M. F.; Zagorski, M. G.; Reuter, J. M.; Coughlin, D. J., Total
9
synthesis refutes the postulated structure of leucogenenol. J. Am. Chem. Soc. 1982, 104, 1008-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1013.
73.
19.
74.
Chmielewski, M.; Achmatowicz, O.; Zamojski, A., Bull. Pol. Acad. Sci. Chem. 1984, 32,
Zhang, Z.; Zheng, W.; Antilla, J. C., Highly enantioselective catalytic benzoyloxylation
of 3-aryloxindoles using chiral VAPOL calcium phosphate. Angew. Chem., Int. Ed. 2011, 50,
1135-1138.
75.
С–O coupling of 1,3-dicarbonyl compounds with diacyl peroxides. Synlett 2015, 26, 802-806.
76. Terent’ev, A. O.; Vil’, V. A.; Gorlov, E. S.; Nikishin, G. I.; Pivnitsky, K. K.; Adam, W.,
Terent’ev, A. O.; Vil’, V. A.; Nikishin, G. I.; Adam, W., Lanthanide-catalyzed oxidative
Lanthanide-catalyzed oxyfunctionalization of 1,3-diketones, acetoacetic esters, and malonates by
oxidative C–O coupling with malonyl peroxides. J. Org. Chem. 2016, 81, 810-823.
77.
Bityukov Oleg, V.; Vil’ Vera, A.; Merkulova Valentina, M.; Nikishin Gennady, I.;
Terent’ev Alexander, O., Silica gel mediated oxidative C–O coupling of β-dicarbonyl
compounds with malonyl peroxides in solvent-free conditions. In Pure Appl. Chem.2018; Vol.
90, p 7.
78.
oxidation of enol esters. J. Am. Chem. Soc. 1974, 96, 3532-3536.
79. Shono, T.; Okawa, M.; Nishiguchi, I., Electroorganic chemistry. XXI. Selective
Shono, T.; Matsumura, Y.; Nakagawa, Y., Electroorganic chemistry. XII. Anodic
formation of α.-acetoxy ketones and general synthesis of 2,3-disubstituted 2-cyclopentenones
through the anodic oxidation of enol acetates. J. Am. Chem. Soc. 1975, 97, 6144-6147.
80.
structures. Chem. Rev. 2018, 118, 4485-4540.
81. Waldvogel, S. R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C. J., Electrochemical arylation
reaction. Chem. Rev. 2018, 118, 6706-6765.
82. Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.; Waldvogel, S. R.,
Electrifying organic synthesis. Angew. Chem., Int. Ed. 2018, 57, 5594-5619.
83. Liang, S.; Xu, k.; Zeng, C.-C.; Tian, H.; Sun, B.-G., Recent advances in the
Jiang, Y.; Xu, K.; Zeng, C., Use of electrochemistry in the synthesis of heterocyclic
electrochemical α-C-H bonds functionalization of carbonyl compounds. Adv. Synth. Catal. 2018,
360, 4266-4292.
28
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
84.
Lund, H., A Century of organic electrochemistry. J. Electrochem. Soc. 2002, 149, S21-
S33.
85.
Sperry, J. B.; Wright, D. L., The application of cathodic reductions and anodic oxidations
6
7
8
9
in the synthesis of complex molecules. Chem. Soc. Rev. 2006, 35, 605-621.
86. Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R.,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Organic electrosynthesis: a promising green methodology in organic chemistry. Green Chem.
2010, 12, 2099-2119.
87.
electrochemical valorisation of CO2. Energy Environ. Sci. 2015, 8, 2574-2599.
88. Yan, M.; Kawamata, Y.; Baran, P. S., Synthetic organic electrochemical methods since
2000: on the verge of a renaissance. Chem. Rev. 2017, 117, 13230-13319.
89. Pletcher, D.; Green, R. A.; Brown, R. C. D., Flow electrolysis cells for the synthetic
organic chemistry laboratory. Chem. Rev. 2018, 118, 4573-4591.
90. Fuchigami, T., Methods for organic electrosynthesis. In Fundamentals and Applications
of Organic Electrochemistry,2014.
91. Grimshaw, J., Chapter 1 - Electrochemical oxidation and reduction of organic
Alvarez-Guerra, M.; Albo, J.; Alvarez-Guerra, E.; Irabien, A., Ionic liquids in the
compounds. In Electrochemical Reactions and Mechanisms in Organic Chemistry, Grimshaw, J.,
Ed. Elsevier Science B.V.: Amsterdam, 2000; pp 1-26.
92.
reactions. Chem. Rev. 2018, 118, 4817-4833.
93. Zhang, S.; Lian, F.; Xue, M.; Qin, T.; Li, L.; Zhang, X.; Xu, K., Electrocatalytic
Moeller, K. D., Using physical organic chemistry to shape the course of electrochemical
dehydrogenative esterification of aliphatic carboxylic acids: access to bioactive lactones. Org.
Lett. 2017, 19, 6622-6625.
94.
Ma, X.; Dewez, D. F.; Du, L.; Luo, X.; Markó, I. E.; Lam, K., Synthesis of diketones,
ketoesters, and tetraketones by electrochemical oxidative decarboxylation of malonic acid
derivatives: application to the synthesis of cis-jasmone. J. Org. Chem. 2018, 83, 12044-12055.
95.
Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.; Dorofeev, A. S.; Vereshchagin,
A. N.; Nikishin, G. I., Electrochemically induced Favorsky rearrangement: transformations of
dialkyl ketones into α,β-unsaturated carboxylic esters. Russ. Chem. Bull. 2003, 52, 998-1002.
96.
Selective C-alkylation of β-diketones. J. Org. Chem. 1988, 53, 907-910.
97. Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Nasybullin, R. F.; Litvin, E. F.;
Shono, T.; Kashimura, S.; Sawamura, M.; Soejima, T., Electroorganic chemistry. 103.
Kopyshev, M. V.; Nikishin, G. I., Indirect electrochemical oxidation of piperidin-4-ones
mediated by sodium halide-base system. Tetrahedron 2006, 62, 8021-8028.
29
ACS Paragon Plus Environment