Five Roads That Converge at the Cyclic Peroxy-Criegee Intermediates: BF3-Catalyzed Synthesis of β-Hydroperoxy-β-peroxylactones

Article abstract of DOI:10.1021/acs.joc.8b02218

We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via BF₃-catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals, with H₂O₂. Strikingly, independent of the choice of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products, i.e., the peroxy analogues of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-peroxylactones indeed correspond to a deep energy minimum that connects a variety of the interconverting oxygen-rich species at this combined potential energy surface. The target β-hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl enol ethers, enol acetates, and cyclic acetals were obtained in 30-96% yields. These reactions proceed under mild conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are formed selectively even in those cases when alternative oxidation pathways can be expected. These β-peroxylactones are stable and can be useful for further synthetic transformations.

Full text of DOI:10.1021/acs.joc.8b02218

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Article
Five roads that converge at the cyclic peroxy-Criegee intermediates:
BF3-catalyzed synthesis of #-hydroperoxy- #-peroxylactones
Vera A. Vil’, Gabriel dos Passos Gomes, Maria V. Ekimova, Konstantin Lysenko, Mikhail A.
Syroeshkin, Gennady Ivanovich Nikishin, Igor V. Alabugin, and Alexander Olegovich Terent'ev
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02218 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 15, 2018
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Five roads that converge at the cyclic peroxy-Criegee intermediates:
BF -catalyzed synthesis of β-hydroperoxy- β-peroxylactones
3
a
b
a,c
d
Vera A. Vil’, Gabriel dos Passos Gomes, Maria V. Ekimova, Konstantin A. Lyssenko, Mikhail A.
1
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Syroeshkin, Gennady I. Nikishin, Igor V. Alabugin * and Alexander O. Terent’ev *
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
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, USA, 32309
[
alabugin@chem.fsu.edu]
c
D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, Moscow
1
25047, Russian Federation
d
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28
Vavilov st., Moscow 119991 Russian Federation
TABLE OF CONTENTS GRAPHIC
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O
O
R1
OR3
R1
R2
OTMS O
R2
O
O
R1
O
O O
R2
OR3
OR3
H O
2 2
HOO
R1
O
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BF Et O
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stable peroxy-Criegee
intermediates
OAc O
OAlk O
R1
OR3
R1
OR3
21 examples
0-96 % yields
3
R2
R2
ABSTRACT. We have discovered synthetic access to β-hydroperoxy-β-peroxylactones via
BF -catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters and their silyl enol ethers,
3
alkyl enol ethers, enol acetates, and cyclic acetals, with H O . Strikingly, independent on the choice
2
2
of starting material, these reactions converge at the same β-hydroperoxy-β-peroxylactone products,
i.e., the peroxy analogs of the previously elusive cyclic Criegee intermediate of the Baeyer-Villiger
reaction. Computed thermodynamic parameters for the formation of the β-hydroperoxy-β-
peroxylactones from silyl enol ethers, enol acetates, and cyclic acetals confirm that the β-
peroxylactones indeed correspond to a deep energy minimum that connects a variety of the
interconverting oxygen-rich species at this combined potential energy surface. The target β-
hydroperoxy-β-peroxylactones were synthesized from β-ketoesters, and their silyl enol ethers, alkyl
enol ethers, enol acetates, and cyclic acetals in 30-96% yields. These reactions proceed under mild
conditions and open synthetic access to a broad selection of β-hydroperoxy-β-peroxylactones that are
formed selectively even in those cases when alternative oxidation pathways can be expected. These β-
peroxylactones are stable and can be useful for further synthetic transformations.
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Keywords Baeyer-Villiger reaction, peroxides, dicarbonyl compounds, peroxidation, boron
trifluoride
INTRODUCTION
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The recent surge of research in the chemistry of cyclic organic peroxides stems from the
discovery of the potent antimalarial,1-3 anthihelmintic,4,5 cytotoxic, fungicide, and antiviral9,10
activities. The key role of natural peroxide artemisinin and its derivatives in the treatment of malaria
in the last decades was recognized by a Nobel Prize in Medicine in 2015.11-13 While searching for
synthetically available and affordable peroxides, it was shown that 5- and 6-membered cyclic
peroxides display a broad spectrum of biological activity.14-16 It is now apparent that cyclic organic
peroxides, that used to be considered exotic and dangerous compounds of minor importance, can lead
to breakthroughs in medicinal chemistry. Consequently, the development of selective synthetic
approaches to these compounds became an important problem for modern organic chemistry.
Currently, the reaction of ketones or aldehydes with H O and hydroperoxides serve as one of
6
7,8
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the main synthetic approaches to organic peroxides.17-21 Although many publications describe
reactions of hydrogen peroxide and monoketones,22-27 the problem of peroxidation selectivity in the
presence of several reactive centers has not found a general solution. For -dicarbonyl compounds,
this issue has been successfully addressed only in a small number of literature reports.28-31 It was
shown that -diketones can be transformed into 1,2,4,5-tetraoxanes 32,33 whereas δ-diketones can be
converted in 1,2,4-trioxolanes (ozonides) (Scheme 1).34,35 Peroxidation of malonic acids and their
esters yields malonyl peroxides (Scheme 1).36-39 In this context, peroxidation of β-ketoesters is
potentially challenging because of the large difference in the reactivity of ketone and ester groups
towards hydrogen peroxide. The only two earlier reports described the formation of β-hydroperoxy-β-
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peroxylactones from the simplest β-ketoesters, the acetoacetic ester, and two α,α-disubstituted β-
ketoesters40,41 by using the explosive concentrated hydrogen peroxide (87-90%) (Scheme 1).
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
-diketones and -diketones (ref.32-35)
H O
R1
2
2
O
O
O
(
37% aq. or 5% Et O)
2
O
R2
R1
H SO or PMA
2
4
O
R2
O
R1
O
O
O
5
% H O in Et O
2 2 2
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R1
R2
O
H SO or PMA or BF
3
O
2
4
R2
malonic acids and esters (ref. 36-39)
H O
O
O
2
2
O O
(
90% aq. or urea H O )
2 2
RO
OR
R = H, Et
O
O
CH SO H
3
3

-ketoesters (ref. 40,41)
O O
O
O
8
7-98% H O
HOO
R1
2
2
R1
OR3
O
H SO
2
4
R2
2
R
only three examples
O O
HOO
O O
O O
HOO
HOO
O
O
O
ref. 40
80%
ref. 41
84%
ref. 41
80%
~
synthesis of other types of peroxylactones
O
O O
1
1) O
2
R
O
R
OH
2
) H+
(ref. 42, 43)
O O
OH
O
R1
R1
30% H O
2
2
O
OEt
H SO
2
4
R2 R3
R2 R3
(ref. 45)
O
O
O
OH
O
n
O
1
) O3
O
O
O
n
2
) Ac O, Et N
2
3
(ref. 47)
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Scheme 1. Selection of known methods of peroxidation of dicarbonyl compounds and synthesis
of peroxylactones.
On the other hand, the related β-peroxylactones were obtained in several other ways (Scheme1)
that include photooxidation of α,β-unsaturated carboxylic acids with the subsequent acid-catalyzed
cyclization,42,43 photolysis of lactone with (diacetoxyiodo)-benzene (DIB) and iodine under oxygen
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atmosphere, and treatment of β-hydroxy esters with H O in the presence of H SO . α-Keto-β-
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2
2
4
peroxylactone is considered to be an intermediate in oxidation of p-methoxyphenylpyruvic acid by
46
oxygen. Ozonolysis of (alkenyldioxy)cyclododecyl hydroperoxides in CF CH OH with subsequent
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2
dehydration of the hydroperoxides 47 or reaction of epoxyketones with H O
48,49
are other possible
2
2
synthetic routes to peroxylactones. Although these approaches have synthetic value, they lack
simplicity and affordability associated with the use of dicarbonyl compounds and hydrogen peroxide
as starting materials.
We have recently reported50 that β-hydroxy-β-peroxylactones, the stable cyclic Criegee
intermediates51 constrained within a five-membered ring, can be prepared by mild reduction of
respective hydroperoxyl peroxyesters (β-hydroperoxy-β-peroxylactones). This discovery is based on
convenient and efficient BF -mediated synthesis of these bisperoxides from -ketoesters and H O . In
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this work, we disclose substantial study of discovered reaction, investigate scope of the new
transformation, and complement it with expanded computational analysis that compared energy
profiles for the alternative pathways. We also explored additional transformations of β-hydroperoxy-
β-peroxylactones with the goal to evaluate the stability of bisperoxide moiety and measured oxidative
properties of the new β-peroxylactones with cyclic voltammetry. An important fundamental finding
of the study is that the target peroxides can be also obtained from silyl enol ethers, alkyl enol ethers,
enol acetates, and cyclic acetals (Scheme 2). This finding substantially expands the choice of practical
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approaches to such cyclic peroxides. Remarkably, the β-hydroperoxy-β-peroxylactones are obtained
from enol ethers and acetals despite the presence of possible oxidative transformations.52-55
O
O
O
OX
O
O
3
R O OR3
O
O
R1
OR3 R1
OR3 R1
OR3
R1
R2
R1
R2
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X = TMS, Alk, Ac
O
H O
2
2
BF Et O
R
OOH
3
2
cyclic structure
linear structure
O O
HO O
O
R
HOO
O
R1
O
vs
R2
R2
R1
stable peroxy-Criegee
intermediates
unstable Criegee
intermediate in Baeyer-
Villiger rearrangement
Scheme 2. The stable and unstable peroxides from di- and monocarbonyl compounds,
respectively.
To the best of our knowledge, there are few reports describing peroxidation of silyl enol ethers,
alkyl enol ethers, enol acetates and acetals57-59. A literature search shows that only mono peroxy-
compounds were prepared from silyl enol ethers,60-65 but bisperoxide synthesis was not described
(Scheme 3). Peroxides from enol acetates were prepared exclusively by photooxygenation of α-
acetoxy diene compounds (Scheme 3).66-68 In this paper, we disclose bisperoxidation of silyl enol
ethers, alkyl enol ethers, enol acetates and acetals with additional ester group accompanied
intermolecular cyclization between hydroperoxyl fragment and ester group (Scheme 3).
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R Si
R Si
3
3
1O2
Adam, 1990
Abe, 1999
Watanabe, 2017
O
O
O
O
R2
R1
R1
R2
R Si
3
II
O OOSiEt3
O , Co
2
R2
Woerpel, 2014
R1
Et SiH
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R Si
3
H O
2
O OOH
2
R2
Saito, 1983
Gonzalez, 1988
R1
TFA
R Si
3
O O
O
O
H O
2
2
HOO
this work
O
R1
OR3 BF Et O
R1
3
2
R2
R2
first example of bisperoxide construction from silyl enol ether
OAc
OAc
1O2
Snider, 1992
Linker, 2015, 2017
R1
R2
R1
O
2 O
R
OAc O
O O
H O
2
2
HOO
this work
R1
OR3
O
R1
BF Et O
3
2
R2
R2
first example of peroxidation of enol acetate
Scheme 3. Peroxidation of silyl enol ethers and enol acetates.
RESULTS AND DISCUSSION
Our goal was to develop a convenient and selective single step access to β-hydroperoxy-β-
peroxylactones 6 via BF -catalyzed cyclizations of a variety of acyclic precursors, β-ketoesters 1 and
3
their silyl enol ethers 2, alkyl enol ethers 3, enol acetates 4, cyclic acetals 5, with H O (Scheme 4).
2
2
We have concentrated on the use of boron trifluoride as the peroxidation catalyst69 because this
5
8
catalyst was shown to work well in earlier synthesis of bishydroperoxides,
1,1′-
70
71,72
bishydroperoxydi(cycloalkyl) peroxides, and 1,2,4-trioxanes,
as well as various peroxides from
acetals and enol ethers.56
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O
O
R1
OR3
OR3
R2
1
OTMS O
R1
R2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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2
OAlk O
O O
H O
HOO
2
2
2
R1
OR3
OR3
OR3
O
R1
R2
Acid
R2
3
6
OAc O
1 examples
30-96 % yields
R1
R2
4
O
O
O
R1
R2
5
1
2
3
1
2
3
1
a, 3a: R = CH , R = H, R = CH CH , Alk = CH CH ; 1b, 2b: R = CH CH CH , R = H, R = CH CH ;
3
2
3
2
3
2
2
3
2
3
1
2
3
1
2
3
1c: R = CH(CH ) , R = H, R = CH CH ; 1d: R = CH CH(CH ) , R = H, R = CH CH ;
3
2
2
3
2
3 2
2
3
1
2
3
1
2
3
1e, 2e: R = CH C(O)OCH , R = H, R = CH ; 1f: R = CH C(O)OCH CH , R = H, R = CH CH ;
2
3
3
2
2
3
2
3
3
1
2
3
1
2
1
1
1
1
1
g, 3g, 4g: R = Ph, R = H, R = CH CH , Alk = 1,4-dioxan-2-yl; 1h: R = CH Ph, R = H, R = CH CH ;
2 3 2 2 3
1
2
3
1
2
3
i: R ,R = -(CH ) -, R = CH CH ; 1j, 5j: R ,R = -(CH ) -, R = CH CH ;
2
2
3
2
3
2 4
2
3
1
3
1
2
3
k: R = CH , R = Ad, R = CH CH ; 1l: R = CH , R = CH CCH, R = CH CH ;
3
2
3
3
2
2
3
1
2
3
m: R = CH , R = CH C(O)OCH CH R = CH CH ;
3
2
2
3,
2
3
3
1
2
n, 4n: R = CH , R = CH CH C(O)OCH CH R = CH CH ;
3
2
2
2
3,
2
1
3
1
2
3
2
3
1o, 5o: R = CH , R = CH CH CN, R = CH CH ; 1p: R = CH , R = CH CH C(O)CH R = CH CH ;
3
2
2
2
2
3
3
3
2
2
3,
2
3
1
1
1
1
q, 2q, 3q, 4q, 5q: R = CH , R = CH Ph, R = CH CH , Alk = 1,4-dioxan-2-yl;
3
2
2
3
1
2
3
1
2
3
r: R = CH , R = CH (4-(CH ) C-C H ), R = CH CH ; 1s: R = CH , R = CH (4-Cl-C H ), R = CH CH ;
3
2
3 3
6
4
2
3
3
2
6
3
4
2
3
1
2
3
1
2
t: R = CH , R = CH (4-Br-C H ), R = C(CH ) ; 1u: R = CH CH CH , R = CH Ph, R = CH CH ;
3
2
6
4
3 3
2
2
3
2
2
3
Scheme 4. Synthesis of β-hydroperoxy-β-peroxylactones 6a-u from β-ketoesters 1a-u, silyl enol
ethers 2b, 2e, 2q, alkyl enol ethers 3a, 3g, 3q, enol acetates 4g, 4n, 4q, cyclic acetals 5j, 5o, 5q, and
hydrogen peroxide.
The optimization of synthetic procedures for the preparation of β-hydroperoxy-β-
peroxylactones 6 was carried out for 4-benzyl-5-hydroperoxy-5-methyl-1,2-dioxolan-3-one 6q,
obtained from ethyl 2-benzyl-3-oxobutanoate 1q due to convenience of analysis of 6q. In particular,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
we determined the effect of acid type and concentration, as well as the amount of hydrogen peroxide
on the yield of β-peroxylactone 6q (Table 1).
Table 1. Optimization of 4-benzyl-5-hydroperoxy-5-methyl-1,2-dioxolan-3-one 6q synthesis
a
from ethyl 2-benzyl-3-oxobutanoate 1q and Н О .
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O O
H O
2
2
HOO
O
OEt
Acid
Ph
Ph
6q
1q
Time
b
Entry
H O (type, equiv.)
Acid (equiv.)
BF ·Et O (1)
Convn 1q, %
Yield 6q, %
2
2
(h)
1
2
Н О (A, 10)
12
12
12
12
12
12
12
3
18
86
trace
37
2
2
3
2
Н О (A, 10)
BF ·Et O (5)
3 2
2
2
Н О (A, 10)
BF ·Et O (10)
>95
>95
>95
>95
37
92
2
2
3
2
3
Н О (A, 5)
BF ·Et O (10)
81
2
2
3
2
4
5
Н О (A, 3)
BF ·Et O (10)
67
2
2
3
2
6
7
Н О (A, 2)
BF ·Et O (10)
32
2
2
3
2
Н О (A, 1)
BF ·Et O (10)
trace
83
2
2
3
2
8
Н О (A, 10)
BF ·Et O (10)
>95
91
2
2
3
2
9
Н О (A, 10)
BF ·Et O (10)
1
33
2
2
3
2
10
Н О (B, 3)
BF ·Et O (10)
24
12
12
12
12
12
91
43
2
2
3
2
c
1
1
1
1
1
2
3
4
Н О (C, 4)
H SO (0.24)
41
traces
traces
77
2
2
2
4
Н О (C, 4)
H SO (10)
54
2
2
2
4
Н О (A, 10)
H SO (10)
>95
92
2
2
2
4
Н О (A, 10)
HClO (10)
78
2
2
4
15
Н О (A, 10)
HBF (10)
87
67
2
2
4
H PMo O
3
12 40
1
6
Н О (A, 10)
24
84
66
2
2
·
xH O (1)
2
P O ·24WO ·44H O
2
5
3
2
17
Н О (A, 10)
24
24
90
57
-
2
2
(0.5)
Na MoO ·2H O (2)
1
8
Н О (A, 10)
no rxn
2
2
2
4
2
1
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Н О (A, 10)
I2 (5)
I2 (0.1)
24
no rxn
no rxn
>95
-
-
2
2
20
Н О (A, 10)
24
24
2
2
2
1
Н О (A, 10)
TBAI (2)
7, 27d
2
2
a
General procedure: An ethereal solution of H O (2.048 M, 0.488-4.882 mL, 1.0-10.0 mmol, 1-
2
2
1
0.0 equiv.) was added with stirring to 1q (220.3 mg, 1.00 mmol, 1.0 equiv.). The mixture was cooled
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to 0°C and acid was added dropwise with stirring. The reaction mixture was then stirred at 20-25 °С
b
for 1, 3, 12 or 24 h. type A – solution of H O in Et O, molar concentration 2.048 M, type B – urea
2
2
2
c
40 d
hydrogen peroxide, type C – 90% H O . literature procedure 4-phenylbutan-2-one (7)
2
2
The reaction does not proceed in the presence of an equimolar amount of boron trifluoride, even
despite the large excess of hydrogen peroxide (Table 1, entry 1). This observation suggests, that there
are unproductive coordination complexes for BF that effectively remove it from the reaction path
3
when only one equivalent of BF is available. On the other hand, raising the excess of BF ·Et O to 10
3
3
2
equivalents leads to an increase of the target cyclic peroxide yield to 92% (entries 1-3). Entries 4-7
illustrate the key role of the excess of H O on the product yield: the yield of 5-hydroperoxy-1,2-
2
2
dioxolan-3-one 6q decrease by 60% (entry 6), when 2 equivalents of peroxide were used. When one
equivalent of H O was used, only traces of desirable peroxide 6q were observed (entry 7). Using less
2
2
BF ·Et O (entry 2) results in the formation of a mixture of the desired peroxide 6q (37%) and the
3
2
acyclic geminal bisperoxide (ethyl 2-benzyl-3,3-dihydroperoxybutanoate, 32%). Shorter reaction
times (3 hrs and 1 h) lowered the yield by 9% and 59%, respectively (entries 8 and 9).
An attempt to use urea/H O complex instead of the ethereal solution of hydrogen peroxide
2
2
showed that use of the latter is essential for reaching the high product yields (entries 5 and 10).
Surprisingly, the application of the literature approach to β-hydroperoxy-β-peroxylactones, reported
4
0
by Cubbon and Hewlett, for synthesis of our target peroxide 6q did not lead to the formation of β-
peroxylactone with 0.24 equiv. of H SO (entry 11) or when an even larger amount of the acid was
2
4
used. Most likely, this result is associated with the instability of the keto group or benzyl moiety
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
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5
5
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5
5
5
5
5
5
5
6
7
3
under this conditions as well as the difficulties in applying heterogeneous reaction conditions of the
Cubbon and Hewlett method to the small amounts of the substrate. Substitution of the dangerous
concentrated Н О to an excess of ethereal Н О yields target peroxide 6q in good yields (67-78%,
2
2
2
2
entries 13-15) with use of a 10-fold excess of strong Bronsted acid (H SO , HClO , HBF ). Good
2
4
4
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
yields of peroxide 6q can be also obtained under catalysis by heteropolyacids such as
phosphomolybdic (entry 16) and phosphotungstic acids (entry 17) shown earlier to be excellent
peroxidation catalysts.59,74-76 Use of other common peroxidation catalysts such as sodium molybdate77
78
79
(
entry 18) and iodine (entries 19, 20) did not promote the reaction. In the case of TBAI, we
observed oxidative fragmentation with the formation of 4-phenylbutan-2-one in 27 % (entry 21).
As discussed earlier, the effect of acid equivalents on the formation of β-peroxylactones was
large and the cyclization proceeded efficiently only in the presence of a large excess boron trifluoride
10 equivalents). In the acidic media, peroxyesters are known to participate in the Baeyer-Villiger80-82
(
and Criegee83 reactions that involve the O-O bond scission. Under the present conditions, these
reactions do not occur.
β-Hydroperoxy-β-peroxylactones can be obtained from enol ethers and acetals despite the
presence of alternative oxidation pathways. Synthesis of β-hydroperoxy-β-peroxylactone 6q was
successfully carried out with silyl enol ether 2q, alkyl enol ether 3q, enol acetate 4q, cyclic acetal 5q
instead of β-ketoester 1q as substrate (Table 2).
Table 2. Synthesis of 4-benzyl-5-hydroperoxy-5-methyl-1,2-dioxolan-3-one 6q from silyl enol
ether 2q, alkyl enol ether 3q, enol acetate 4q, cyclic acetal 5q and Н О .
2
2
O O
H O
2
2
HOO
Starting
Compound
O
Acid
2q-5q
Ph
6q
№
Starting Compound
Yield of 6q, %
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H O /HClO /
Substrate
other order of
addition and HClO4
2
2
4
Substrate/ H O
H O / BF ·Et O/
2 2 3 2
2
2
(
10 equiv.) /
BF ·Et O
10 equiv.)
Substrate
other order of
3
2
a
b
(
addition
c
instead of BF ·Et O
3
2
TMSO
O
OEt
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
61
73
51
93
86
Ph
2q
O
O
O
O
55
OEt
Ph
3
q
OAc O
OEt
3
4
53
92
39
91
52
85
Ph
O
4q
O
O
OEt
Ph
5q
a
optimal reaction conditions for β-ketoesters: An ethereal solution of H O (2.048 M, 4.882
2
2
mL, 10.00 mmol, 10.0 equiv.) was added with stirring to starting compound 2q-5q (1.0 mmol, 1.0
equiv.). Later, BF ·Et O (10.0 mmol, 10.0 equiv.) was added dropwise with stirring to a solution at
3
2
0
°C.
b
other order of addition of reagents: BF ·Et O (10.0 mmol, 10.0 equiv.) was added dropwise
3
2
with stirring to ethereal solution of H O (2.048 M, 4.882 mL, 10.00 mmol, 10.0 equiv.) at 0°C. Later,
2
2
starting compound 2q-5q (1.0 mmol, 1.0 equiv.) was added dropwise with stirring to the mixture.
c
other order of addition of reagents and with HClO instead of BF ·Et O: HClO (10.0
4
3
2
4
mmol) was added dropwise with stirring to ethereal solution of H O (2.048 M, 4.882 mL, 10.00
2
2
mmol, 10.0 equiv.) at 0°C. Later, starting compound 2q-5q (1.0 mmol) was added dropwise with
stirring to the mixture.
The reaction mixture was stirred at 20-25 °С for 12 h.
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Surprisingly, only peroxide 6q was formed in the reaction of enol ethers 2q-4q and acetal 5q
with the H O /BF system. We have not observed α-oxylated products despite the literature reports
2
2
3
that this system acts as peracid in oxidation reactions,84,85 including the conversion of sulfides to
8
6
87
sulfones and aldehydes to carboxylic acids or esters. Furthermore, it is known that reactions of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
silyl enol ethers from β-ketoesters with MCPBA,88,89 p-nitrobenzenesulfonyl peroxide and DMDO
90
91
led to α-hydroxylated products. Enol acetates undergo anodic oxidation in the presence of acetic acid
to form conjugated enones, α-acetoxy carbonyl compounds, gem-diacetoxy compounds and triacetoxy
compounds,92,93 and in the presence of H O /NaOH system to α-hydroxylated products. Also α-
94
2
2
acetoxy carbonyl compounds can be prepared from enol acetates under action of lead tetraacetate via
9
5
96
rearrangement of epoxy acetate or under action of peracids.
Under the optimal conditions (Table 1, entry 3), the silyl enol ether 2q and alkyl enol ether 3q
were transformed into peroxide 6q in moderate yields 51-73% (Table 2, entries 1 and 2). High yields
(
93% and 86%) of 6q were achieved with use of HClO instead of BF ·Et O (Table 2, entries 1 and
4 3 2
2). Peroxidation of enol acetate 4q (Table 2, entry 3) was achieved only in moderate yields (39-53 %)
of 6q even with the other order of addition of reagents and with HClO instead of BF ·Et O due to the
4
3
2
low substrate conversion. With the use of acetal 5q, high yields (85-92 %) of 6q were achieved both
under the optimal conditions and with the other order of reagent addition (Table 2, entry 4).
Surprisingly, the easily oxidizable enol ethers 2q-4q and acetal 5q do not undergo observable
destructive oxidation. Even in the presence of large excesses of a strong oxidant and acid, enol ethers
2
q-4q and acetal 5q are selectively converted to cyclic peroxide 6q. It is possible that carbonyl
coordination with the Lewis acid decreases donor ability of the double bond.
The conditions identified as optimal for synthesis of β-hydroperoxy-β-peroxylactone 6q from
the corresponding β-ketoester (Table 1, entry 3) were utilized for the synthesis of β-hydroperoxy-β-
peroxylactones 6a-u with varying degrees of substitution (Table 3).
1
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a
Table 3. Scope of β-hydroperoxy-β-peroxylactones 6a-u synthesized from β-ketoesters 1a-u and
silyl enol ethers 2b, 2e, 2q, alkyl enol ethers 3a, 3g, 3q, enol acetates 4g, 4n, 4q, cyclic acetals 5j, 5o,
5q.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O O
1
0 equiv. H O (in Et O)
2 2 2
HOO
1-5
R1
O
1
0 equiv. BF3 Et O
2
R2
12 h, rt
6
O O
HOO
O O
O O
O
HOO
HOO
O
O
6
a, 88
(from 3a: 89)b
6b, 96
(from 2b: 88)c
6
c, 90
O O
HOO
O O
O O
HOO
O
HOO
EtO
O
O
O
OCH3
O
6e, 79
6
d, 64
6f, 78
(
from 2e: 61)d
HOO O O
O O
HOO
O
O O
O
HOO
HOO
HOO
O
O
6
g, 61
(from 3g: 73)e
(
6i, 87
from 4g: 86)f
6h, 77
O O
O O
O O
HOO
HOO
O
O
O
6
j, 57
from 5j: 75)g
6l, 64
(
6k, 80
O O
O O
O O
HOO
HOO
O
O
O
CN
EtO
O
OEt
6
o, 78
6n, 66
6
m, 73
(from 5o: 74)i
from 4n: 30)h
(
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O O
O O
O O
HOO
HOO
HOO
O
O
O
HOO
t-Bu
HOO
6
q, 92
6r, 76
6
p, 56
O O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O O
O O
HOO
HOO
HOO
O
O
O
Cl
Br
6u, 90
6
s, 93
6t, 81
a
General procedure: An ethereal solution of H O (2.048 M, 4.882 mL, 10.00 mmol, 10.0 equiv.)
was added with stirring to 1a-u (1.00 mmol, 1.0 equiv.). Later, BF ·Et O (1.419 g, 10.00 mmol, 10
equiv.) was added dropwise with stirring to the solution at 0 °C. The reaction mixture was stirred at
0-25 °С for 12 h. The values in parentheses – yield of 6 starting from 2-5.
from ethyl 3-ethoxybut-2-enoate 3a
from ethyl 3-((trimethylsilyl)oxy)hex-2-enoate 2b
from dimethyl 3-((trimethylsilyl)oxy)pent-2-enedioate 2e
from ethyl 3-((1,4-dioxan-2-yl)oxy)-3-phenylacrylate, 3g
from ethyl 3-acetoxy-3-phenylacrylate, 4g
from ethyl 1,4-dioxaspiro[4.5]decane-6-carboxylate 5j
from diethyl 2-(1-acetoxyethylidene)pentanedioate 4n
from ethyl 4-cyano-2-(2-methyl-1,3-dioxolan-2-yl)butanoate 5o
2
2
3
2
2
b
c
d
e
f
g
h
i
The α-unsubstituted β-hydroperoxy-β-peroxylactones 6а-h were obtained from β-ketoesters 1a-
h in good (61% for 6g) to excellent yields (96% for 6b). Fusion of the β-peroxylactone ring to a
cycloalkane provided bicyclic peroxides 6i, 6j in 87% and 57%, respectively. The preparation of β-
hydroperoxy-β-peroxylactones with bulky adamantyl (6k, 80%), propargyl (6l, 64%), ester (6m, 73%;
6
n, 66%) and nitrile (6o, 78%) functionalities, as well as the tetraperoxide that combined a β-
hydroperoxy-β-peroxylactone and a gem-dihydroxyperoxide moieties (6p, 56%) proceeded in good
yields. Presence of benzylic group increases the yields of β-hydroperoxy-β-peroxylactones - products
6
q-u were obtained in 76-93% yields. The flexibility of this approach in selection of starting materials
is illustrated by facile formation of β-hydroperoxy-β-peroxylactones from enols 2-4 and acetals 5, as
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well as the t-Bu esters of β-ketoesters (compound 6t). β-Hydroperoxy-β-peroxylactones 6b and 6e
were prepared from silyl enol ethers 2b and 2e (notes c and d) in good (61% for 6e) and high (88%
for 6b) yields. Use of the enol ethers 3a and 3g (notes b and e) instead of β-ketoesters 1a and 1g
increased the yields of 6a (89%) and 6g (73%). Synthesis of β-hydroperoxy-β-peroxylactone 6g from
enol acetate 4g (note f) led to the highest observed yield of 6g (86%). However, synthesis of 6n from
enol acetate 4n (note h) was less efficient (30%) than from β-ketoester 1n (66%). Peroxidation of
acetals 5j and 5o (notes g and i) provided good yield of the desirable β-hydroperoxy-β-peroxylactones
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
j (75%) and 6o (74%).
The oxidative properties of the synthesized β-hydroperoxy-β-peroxylactones were investigated
with cyclic voltammetry. It was shown that reduction potentials for the β-peroxylactones 6d and 6q (-
1091 mV and -1026 mV, respectively) are lower than the potentials for bridged 1,2,4,5-tetraoxane
(1,4-dimethyl-7-(1-(p-tolyl)ethyl)-2,3,5,6-tetraoxabicyclo[2.2.1] heptane, -1319 mV) but greater than
the potentials for cyclopropyl malonyl peroxide (-603 mV). These findings illustrate moderate
oxidative properties of β-hydroperoxy-β-peroxylactones (Scheme S1, Supplementary Information).
The nature of the second substrate at the α-position of β-ketoesters 8 greatly affects the
peroxidation process. Thus, α,α-dimethyl β-ketoester 8a formed desired β-hydroperoxy-β-
peroxylactone 9a with excellent (86%) yield in optimized condition (Table 1, entry 3), while α-
methyl, α-benzyl β-ketoester 8b was transformed into peroxide 9b in a slightly lower yield (74%) and
peroxidation of α,α-dibenzyl β-ketoester 8c did not lead to formation of 9c (Scheme 5).
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
R
O
R
O O
1
0 equiv. H O (in Et O)
2 2 2
HOO
HOO
O
O
OEt
O
1
0 equiv. BF3 Et O
2
R
R
12 h, rt
8
9
O O
O O
O O
HOO
O
HOO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
9b, 74 %
Ph Ph
9c, not observed
9a, 86 %
Scheme 5. Peroxidation of α,α-disubstituted β-ketoesters 8.
The unambiguous NMR determination of structure of organic peroxides can be challenging
because of the possibility of condensation of several molecular units via the peroxide bridges and
because of the possibility of acid-catalyzed skeletal rearrangements. To address this difficulty, we
have performed X-ray crystallographic analysis of several representatives (6q and 6s, Supplementary
Information) of this scarcely studied class of β-peroxylactones (Figure 1). In addition to confirming
the presence of two peroxide units, the X-ray data unambiguously determined the nature of the
1
13
diastereomeric product (formed as a single isomer according to H and C NMR spectra) for β-
hydroperoxy-β- peroxylactones 6q and 6s.
O O
HOO
O
6q
Figure 1. X-ray structure of β-hydroperoxy-β-peroxylactone 6q.
In order to gain first insights into the chemistry of this scarcely studied class of peroxides, we
have investigated further synthetic transformations of β-hydroperoxy-β-peroxylactones. As expected
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from the synthetic conditions used for their preparation, the β-hydroperoxy-β-peroxylactone
functionality is stable under the acidic conditions. We found that the hydroperoxide functionality in
6
q can be protected via installation of tetrahydropyranyl (THP), tetrahydrofuranyl (THF) and t-Bu
groups (Scheme 6).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O O
1
.1 equiv. DHP
TsOH cat.
O
O
O
CH Cl 2 h, rt
2
2,
Ph
10, 71%
O O
HOO
1.1 equiv. DHF
TsOH cat.
O
O
O
O O
O
O
CH Cl 2 h, rt
2
2,
Ph
6q
Ph
11, 70%
O
O
1
1
equiv. t-BuOH
O O
equiv. H SO4
2
O
CH Cl 96 h, rt
2
2,
Ph
2, 81%
1
Scheme 6. Transformations of hydroperoxy group in β-hydroperoxy-β-peroxylactone 6q.
Mechanistic studies:
Control experiments designed to provide an insight in the mechanism of the product formation
(Scheme 7), revealed that β-hydroperoxy-β-peroxylactone 6q does not equilibrate with β-hydroxy-β-
peroxylactone 13 under these conditions. On the other hand, acyclic bishydroperoxide 14 is converted
into the β-hydroperoxy-β-peroxylactone 6q readily and in an almost quantitative yield. The low
reactivity of these mono- and bisperoxides under the acidic conditions is likely to originate from the
“
inverse intramolecular 훼-effect” (the relatively inefficient stabilization of cationic center by an
adjacent peroxide in comparison to ethers, further exacerbated here by the presence of a carbonyl
substituent at the peroxide).97,98
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Because of this effect, peroxides are more reluctant to be converted into cationic intermediates
and may possess greater kinetic stability than the analogous ethers and alcohols that are readily
transformed into oxacarbenium ions.
O O
O O
HOO
10 eq. H O
HO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
O
O
1
0 eq. BF3 Et O
2
Ph
Et O, rt, 24 h
2
Ph
3, not observed
1
6q
O O
HO
1
0 eq. 5% H O in Et O
O
2 2 2
6q not observed
1
0 eq. BF3 Et O
2
Ph
13
rt, 12 h
O
O O
HOO OOH
HOO
O
OEt
10 eq. BF3 Et O
2
Ph
Et O, rt, 12 h
2
Ph
14
6q, 96%
Scheme 7. Experimental evaluation of stability of β-peroxylactones.
Computational analysis of reaction pathways
In order to understand the relative stabilities of the possible intermediates involved in the
formation of the new bisperoxides,63,99 we decided to chart the energy landscape for the interaction of
carbonyl compounds and H O by using quantum-mechanical calculations.
2
2
As the first step, we have evaluated thermodynamics for the interaction of key hydroxyl
containing functionalities with hydrogen peroxide. Interestingly, the transformation of carboxylic
acids into peroxyacids in reaction with H O is either weakly exergonic or thermoneutral. For the
2
2
ketones the situation is slightly different (Scheme 8). The addition of the first H O molecule to
2
2
acetone is slightly endergonic and the resulting unstable mixed monoperoxide are unlikely to be
persistent under the reaction conditions. On the other hand, the transformations of acetone and its
2
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hydrate into respective bishydroperoxy ketal are sufficiently exergonic to assure the preferential
formation of such bishydroperoxides at the equilibrium in the presence of sufficient amounts of
hydrogen peroxide.
H O H O
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
B
A
B
H
G
O
O
H
O
OH
-0.5 -0.7
O
O
O
O
O
O
H
OH -1.4 0.03
O
(SMD=H2O)/M06-2X(D3)/6-311++G(d,p), kcal/mol
H O
2
HO OOH
O
2

E = -14.9
+H O
2
2
H O
G = +0.8
E = -4.8
G = -4.2
2
-
H O
2

E = -8.8

G = +6.4
HOO OOH
HO OH
(SMD=H2O)/M06-2X/6-311++G(d,p), kcal/mol
Scheme 8. Calculated thermodynamic parameters for the interaction of H O with selected
2
2
carboxylic acids and acetone.
In the next stage, we have explored energy profiles for the interaction of β-ketoacids and esters
with hydrogen peroxide. From the two alternative pathways to the target cyclic structure, we favor the
one that start from peroxidation of the carbonyl functions. Furthermore, based on the experimental
observations reported in Scheme 7 and reiterated in Scheme 9 below, we suggest the ketoester is
transformed into a bishydroperoxide first and that it is the latter species that undergoes the cyclization
to form the β-peroxylactone. The cyclization of the mixed hydroxy/hydroperoxy ketal can be
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1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
discarded based on the observation that β-hydroxy-β-peroxylactone is not transformed into β-
hydroperoxy-β-peroxylactone under the reaction conditions. Apparently, the bisperoxide is formed
and cyclized quickly to provide the cyclic bisperoxide, the most stable species at this reaction
hypersurface.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
O
HOO OOH
HO OOH
H O
H O
2 2
2
2
OMe
OMe
OMe
fast
G = -3.8

G = +4.5
BF3 Et O
BF3 Et O
2
2

G = -4.6
G = -4.9
H O
2
3
3
-
R OH
- R OH
G energies, in kcal/mol
O O
at the (SMD=H O)/
O O
2
2
HOO
M06-2X(D3)/6-311++G(d,p)
level
HO
O
O
- H O
2
most stable

G = +3.5
Scheme 9. Suggested mechanism for synthesis of β-hydroperoxy-β-peroxylactones with the
calculated free energies for the formation of the intermediate structures.
We have also evaluated thermodynamics for the formation of the cyclic β-hydroperoxy-β-
peroxylactones from cyclic acetals, enol acetates and silyl enol ethers. Gratifying, all of these
transformations are exergonic, suggesting that the β-peroxylactones are indeed an energy minimum
that connects a variety of the interconverting oxygen-rich species at this combined potential energy
surface (Scheme 10). Especially noteworthy is the fact that β-peroxylactones can be formed
exergonically from cyclic acetal, a functional group that is strongly stabilized by anomeric effect.100
This observation provides another illustration of the increased thermodynamic stability of
bisperoxides where the anomeric effects (generally dormant in mono-peroxides) are
reactivated.34,35,97,101
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O
O O
OH
O


H = –2.7
G = –1.8
+
O
HOO
O
O
OH
+
MeOH
+
2 H O
2
2
TMS
O
HOO
TMS
2
HOOH
O
O
O


H = –15.8
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
G = –1.2
H O
2
H O
2 2
2
MeOH
+
H = +3.0
G = –8.8
MeOH
+
TMSOH
TMSOH
O O


H = –12.8
G = –10.0
HOO
O
Ac
Ac
HOOH
O
O
O
O
HOO


H = –12.2
O
O
G = +0.7
2 H O
H O
2 2
2
2

H = –8.1
MeOH
MeOH
+
+ AcOH G = –19.4
AcOH
O O


H = –20.3
G = –18.7
HOO
O
Scheme 10. Thermodynamical landscape for synthesis of β-hydroperoxy-β-peroxylactones from
cyclic acetals, enol acetates, and silyl enol ethers derived from β-ketoesters.
CONCLUSION
β-Hydroperoxy-β-peroxylactones can be prepared in moderate to excellent yields from five
different types of substrates: β-ketoesters and their silyl enol ethers, alkyl enol ethers, enol acetates,
and cyclic acetals. A broad scope of β-hydroperoxy-β-peroxylactones, both α-unsubstituted and α-
mono- and α,α-disubstituted, was synthesized. A large excess of BF ·Et O and H O is a key factor
3
2
2
2
determining the selectivity and efficiency of formation of β-hydroperoxy-β-peroxylactones that
allows to prepare the target cyclic peroxides in >90% yields.
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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6
The computationally evaluated thermodynamics for the formation of the β-hydroperoxy-β-
peroxylactones from β-ketoesters, silyl enol ethers, enol acetates, and cyclic acetals confirm that the
β-peroxylactone species correspond to an energy minimum that connects a variety of species at this
combined potential energy surface. Furthermore, the β-hydroperoxy-β-peroxylactones are stable in
acidic conditions and can be modified via hydroperoxyl group functionalization.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
Caution: Although we have encountered no difficulties in working with peroxides, precautions
such as the performance of reactions within a fume hood and behind a safety shield should be
taken. The use of redox-active transition-metal salts, heating and vigorous shaking should be
avoided!
1
NMR spectra were recorded on commercial instrument (300.13 MHz for Н, 75.48 MHz for
1
3
С) in СDCl . High resolution mass spectra (HRMS) were measured using electrospray ionization
3
(ESI-TOF).102 The measurements were done in a positive ion mode (interface capillary voltage –
500 V); mass range from m/z 50 to m/z 3000 Da; external/internal calibration was done with
4
Electrospray Calibrant Solution. A syringe injection was used for solutions in MeCN (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. The melting
points were determined on a Kofler hot-stage apparatus. Chromatography was performed on silica gel
(40-60 µm).
Ethyl acetoacetate (1a), ethyl butyrylacetate (1b), dimethyl 1,3-acetonedicarboxylate (1e), ethyl
benzoylacetate (1g, was distilled before use under reduced pressure (15-20 mmHg)), ethyl 2-
oxocyclopentanecarboxylate (1i), ethyl 2-oxocyclohexanecarboxylate (1j), diethyl acetylsuccinate
(1m), H O (37% solution in water), BF ·Et O, I , p-TsOH monohydrate, H SO , HClO (70%
2
2
3
2
2
2
4
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solution in water), HBF (48% solution in water), NaHCO , phosphomolybdic acid hydrate (formula
4
3
weight: 1,825.25 g/mol), phosphotungstic acid hydrate (formula weight: 2,880.05 g/mol),
Na MoO ·2H O, tetrabutylammonium iodide, urea hydrogen peroxide, 3,4-dihydro-2H-pyran, 2,3-
2
4
2
dihydrofuran, t-BuOH, Bu NClO , Et N, TMSCl, K CO , Na, NaH (60% in mineral oil), NaOH,
4
4
3
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TEBAC, triethyl orthoformate, Cu(OAc) ·H O, 1,4-dioxane, 5-6 M TBHP solution in decane,
2
2
pyridine, acetyl chloride, CuSO ·5H O, ethylene glycol, methyl iodide were purchased from
4
2
commercial sources and were used as is. All solvents were distilled before use using standard
procedures.
Distillation of the commercial ethyl benzoylacetate 1g was performed under medium vacuum
(10 mmHg). Fraction with bp = 129-134 °C was collected and used in peroxide synthesis.
A solution of H O in Et O (2.048 mol/L, ≈9.8% weight) was prepared by the extraction with
2
2
2
64,103
Et O (5 × 100 mL) from a 35% aqueous solution (100 mL) followed by drying over MgSO .
2
4
Solution of H O in Et O (90 % weight) prepared by evaporated of 9.8% solution of H O in Et O.
2
2
2
2
2
2
Synthesis of starting β-ketoesters 1
Procedure for the synthesis of ethyl 4-methyl-3-oxopentanoate (1c) 104
Isobutyric acid (2.91 g, 33.0 mmol, 1.0 equiv.) was dissolved in dry CH Cl (140 mL). Meldrum’s
2
2
acid (5.23 g, 36.3 mmol, 1.1 equiv.) and 4-(dimethylamino)-pyridine (6.11 g, 50.0 mmol, 1.5 equiv.)
were added and the mixture was stirred at 20-25 °C for 15 min. After cooling to 0 °C, a solution of
dicyclohexylcarbodiimide (8.26 g, 40.0 mmol, 1.2 equiv.) in dry CH Cl (10 mL) was added and the
2
2
reaction mixture stirred at 20-25 °C for 10 h. The precipitate containing dicyclohexylurea was filtered
off and the filtrate was washed with a 10% aqueous solution of citric acid (2×20 mL), brine (20 mL)
and dried over MgSO . The organic phase was concentrated under reduced pressure using a rotary
4
evaporator (15-20 mmHg), (bath temperature, ca. 20‒25 °C) and was applied to the next reaction step
without purification. The crude 5-(1-hydroxy-2-methylpropylidene)-2,2-dimethyl-1,3-dioxane-4,6-
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dione was refluxed in toluene (80mL) with EtOH (20 mL) for 3 h. Then reaction mixture was
concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca.
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0‒85 °C). The product 1c was isolated by column chromatography on SiO (PE:EtOAc = 10:1).
2
1
Yield 43 % (2.24 g, 14.2 mmol). Yellow oil. R = 0.67 (PE:EtOAc = 20:1). Keto/enol ratio = 9/1. H
f
0
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NMR (300.13 MHz, CDCl , δ): 12.12 (s, 0.1H), 4.96 (s, 0.1H), 4.17 (q, J = 7.1 Hz, 2H), 3.47 (s,
3
1
.8H), 2.70 (sept, J = 6.9 Hz, 0.9H), 2.45 – 2.31 (m, 0.1H), 1.25 (t, J = 7.1 Hz, 3H), 1.11 (d, J = 6.9
1
3
1
Hz, 6H). C{ H}NMR (75.48 MHz, CDCl , δ): 206.7, 167.5, 86.8, 61.4, 60.0, 47.2, 41.3, 19.8, 18.0,
3
4.2. The physical and spectral data were consistent with those previously reported.104
1
Procedure for the synthesis of ethyl 5-methyl-3-oxohexanoate (1d) 105
NaH (60% in mineral oil, 1.20 g, 30.0 mmol, 1.5 equiv.) was added to dry toluene (20 mL). The
diethyl carbonate (3.54 g, 30.0 mmol, 1.5 equiv.) was added to the stirred suspension. Then a solution
of 4-methylpentanone-2 (2.00 g, 20.0 mmol, 1.0 equiv.) in dry toluene (20 mL) was added dropwise.
In the middle of the process of addition one drop of absolute EtOH was added. The reaction mixture
was refluxed with stirring for 3 h. After cooling to 20‒25 °C the reaction was acidified to pH ~6 by
careful addition of 5% aq. HCl (50 mL). Organic layer was separated, aqua layer was extracted with
Et O (3×20 mL). The combined organic extracts were washed with brine, dried over Na SO , and
2
2
4
concentrated under reduced pressure (15-20 mmHg), (bath temperature, ca. 40‒45 °C). The product
1
d was isolated by column chromatography on SiO (PE:EtOAc = 15:1). Yield 47 % (1.62 g, 9.4
2
1
mmol). Yellow oil. R = 0.21 (PE:EtOAc = 20:1). Keto/enol ratio = 9/1. H NMR (300.13 MHz,
f
CDCl , δ): 12.06 (s, 0.1H), 4.93 (s, 0.1H), 4.18 (q, J = 7.1 Hz, 2H), 3.39 (s, 1.8H), 2.40 (d, J = 6.9 Hz,
3
1
3
1
2H), 2.24 – 2.05 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz, 6H). C{ H}NMR (75.48
MHz, CDCl , δ): 202.6, 167.3, 90.1, 61.4, 52.0, 49.8, 44.5, 24.4, 22.5, 22.5, 14.2. The physical and
3
spectral data were consistent with those previously reported.105
Procedure for the synthesis of diethyl 1,3-acetonedicarboxylate (1f) 106
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Citric acid monohydrate (2.10 g, 10.0 mmol, 1.0 equiv.) was added to chlorosulfonic acid (2.5 mL, 38
mmol, 3.8 equiv.) in CH Cl (3 mL) at 10 C. After 5 h the reaction mixture was cooled (0-5 C) and
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EtOH (5 mL) added carefully to ensure the temperature did not exceed 35 C. After stirring for 2 h at
5-40 C, the reaction was cooled, H O (10 mL) was added, and reaction was extracted with CH Cl
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(
3×20 mL). The organic phase was washed with 5 % solution of NaHCO (10 mL) and H O (10 mL),
3 2
dried over MgSO and concentrated under reduced pressure (15-20 mmHg), (bath temperature, ca.
4
3
0‒35 °C). The product 1f was isolated by column chromatography on SiO (PE:EtOAc = from 20:1
2
to 2:1). Yield 53 % (1.07 g, 5.3 mmol). Yellow oil. R = 0.76 (PE:EtOAc = 20:1). Keto/enol ratio =
f
1
5/1. H NMR (300.13 MHz, CDCl , δ): 12.08 (s, 0.17H), 5.11 (s, 0.17H), 4.18 (q, J = 7.1 Hz, 4H),
3
13
1
3
1
.59 (s, 3.3H), 3.20 (s, 0.35H), 1.26 (t, J = 7.1 Hz, 6H). C{ H}NMR (75.48 MHz, CDCl , δ): 195.5,
3
72.4, 170.0, 166.8, 92.1, 61.7, 61.5, 60.4, 49.1, 41.1, 14.3, 14.2, 14.1. The physical and spectral data
were consistent with those previously reported.106
Procedure for the synthesis of ethyl 3-oxo-4-phenylbutanoate (1h)107
4
Substrate 1h was synthesized according to the modified literature procedure. To a suspension of
phenylacetic acid (816.0 mg, 6.0 mmol, 1.0 equiv.) in dry CH Cl (10 mL), CDI (1.05 g, 6.5 mmol,
2
2
1.08 equiv.) was added. After stirring for 0.5 h, Meldrum's acid (1.081 g, 7.5 mmol, 1.25 equiv.) was
added and stirred for additional 12 h. Then the reaction mixture was poured into 5% HCl (30 mL) and
extracted with CH Cl (3×10 mL). The extract was washed with 5% HCl (25 mL) and with H O (25
2
2
2
mL) and concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath
temperature, ca. 30‒35 °C). To the residue, EtOH (10 mL) was added and the resulting mixture was
refluxed for 2 h. The obtained solution was concentrated and 5% NaHCO (30 mL) was added to the
3
residue. The obtained mixture was extracted with ethyl acetate (3×10 mL). The extract was washed
with H O (10 mL), filtered through thin layer of silica gel (2 cm) and concentrated under reduced
2
pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca. 30‒35 °C). The product 1h
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was isolated by column chromatography on SiO (PE:EtOAc = from 20:1 to 2:1). Yield 66 % (817.0
2
1
mg, 4.0 mmol). Yellow oil. R = 0.67 (PE:EtOAc = 20:1). Keto form: H NMR (300.13 MHz, CDCl ,
f
3
δ): 7.42 – 7.13 (m, 5H), 4.15 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.43 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H).
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C{ H}NMR (75.48 MHz, CDCl , δ): 200.5, 167.2, 133.3, 129.7, 128.9, 127.4, 61.5, 50.1, 48.4,
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4.2. The physical and spectral data were consistent with those previously reported.107
1
Procedure for the synthesis of ethyl 2-(adamantan-1-yl)-3-oxobutanoate (1k) 108
Cu(OTf) (90.4 mg, 0.25 mmol, 0.05 equiv.) was added to dry 1,2-dichloroethane (5 mL). Then a
2
solution of 1-adamantanol (761.2 mg, 5.00 mmol, 1 equiv.) and ethyl acetoacetate (650.7 mg, 5.00
mmol, 1 equiv.) in dry 1,2-dichloroethane (10 mL) was added. The reaction mixture was refluxed
with stirring for 2 h. After cooling to 20‒25 °C, 2 M HCl (10 mL) was added. The organic layer was
separated and the product was extracted from the aqueous phase with CHCl (3×10 mL). The
3
combined organic layers were washed with brine (10 mL), dried over MgSO , filtered and
4
concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca.
30‒35 °C). The product 1k was isolated by column chromatography on SiO (PE:EtOAc = 20:1).
2
1
Yield 74 % (978.2 mg, 3.7 mmol). Yellow oil. R = 0.57 (PE:EtOAc = 20:1). H NMR (300.13 MHz,
f
CDCl , δ): 4.15 (q, J = 7.1 Hz, 2H), 3.17 (s, 1H), 2.21 (s, 3H), 2.00 – 1.94 (m, 3H), 1.80 – 1.62 (m,
3
1
3
1
13H), 1.25 (t, J = 7.1 Hz, 3H). C{ H}NMR (75.48 MHz, CDCl , δ): 203.3, 168.8, 70.1, 60.8, 40.2,
3
3
7.1, 36.8, 32.1, 28.8, 14.3. The physical and spectral data were consistent with those previously
reported.108
Ethyl 2-acetylpent-4-ynoate (1l)
Product 1l was synthesized according to the literature procedure.109 Yield 67 % (2.53 g, 15.0 mmol)
1
Yellow oil. R = 0.63 (PE:EtOAc = 10:1). H NMR (300.13 MHz, CDCl , δ): 4.22 (q, J = 7.1 Hz, 2H),
f
3
3
.68 (t, J = 7.0 Hz, 1H), 2.70 (d, J = 7.0 Hz, 2H), 2.29 (s, 3H), 1.98 (t, J = 2.6 Hz, 1H), 1.27 (t, J = 7.1
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Hz, 3H). C{ H}NMR (75.48 MHz, CDCl , δ): 201.2, 168.2, 80.5, 70.4, 62.0, 58.4, 29.7, 17.5, 14.2.
3
The physical and spectral data were consistent with those previously reported.109
Procedure for the synthesis of diethyl 2-acetylpentanedioate (1n)
Na (0.69 g, 0.03 mol, 0.2 equiv.) was added to dry EtOH (5 mL). Resulting solution of EtONa was
cooled to room temperature and added to mixture ethyl acetoacetate (29.25 g, 0.225 mol, 1.5 equiv.)
and ethyl acrylate (15.02 g, 0.15 mol, 1.0 equiv.) with stirring. The reaction mixture was stirred over
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night at 20-25 C. Then CH Cl (100 mL) was added, mixture was washed with 5% solution of
2
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NaHCO (2×50 mL), brine (50 mL). The organic layer was dried over MgSO , filtered and
3
4
concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca.
0‒45 °C). Distillation of the remaining liquid under medium vacuum (8.00 mmHg) gave product 1n
4
as third fraction (bp = 165-175 °C). Yield 55 % (19.10 g, 83.0 mmol). Colorless oil. R = 0.65
f
1
(
PE:EtOAc = 20:1). H NMR (300.13 MHz, CDCl , δ): 4.18 (q, J = 7.2 Hz, 2H), 4.11 (q, J = 7.2 Hz,
3
2
H), 3.53 (t, J = 7.2 Hz, 1H), 2.36 – 2.29 (m, 2H), 2.23 (s, 3H), 2.17 – 2.08 (m, 2H), 1.29 – 1.20 (m,
1
3
1
6H). C{ H}NMR (75.48 MHz, CDCl , δ): 202.6, 172.7, 169.4, 61.6, 60.6, 58.5, 31.6, 29.2, 23.1,
3
4.3, 14.2. The physical and spectral data were consistent with those previously reported.110
1
Procedure for the synthesis of ethyl 2-acetyl-4-cyanobutanoate (1o)
Na (69.0 mg, 3.00 mmol, 2.0 equiv.) was added to dry EtOH (1 mL). Resulting solution of EtONa
was cooled to room temperature and added to mixture ethyl acetoacetate (292.8 mg, 2.25 mmol, 1.5
equiv.) and acrylonitrile (79.6 mg, 1.50 mmol, 1.0 equiv.) with stirring. The reaction mixture was
°
stirred over night at 20-25 C. Then CH Cl (10 mL) was added, mixture was washed with 5%
2
2
solution of NaHCO (2×3 mL), brine (3 mL). The organic layer was dried over MgSO , filtered and
3
4
concentrated under reduced pressure using a rotary evaporator (15-20 mmHg), (bath temperature, ca.
0‒45 °C). The product 1o was isolated by column chromatography on SiO (PE:EtOAc = 10:1).
4
2
Yield 80 % (220.0 mg, 1.20 mmol). Yellow oil. R = 0.58 (PE:EtOAc = 10:1). Keto/enol ratio = 4/1.
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