Selective synthesis of cyclic peroxides from triketones and H 2O2

Article abstract of DOI:10.1021/jo202437r

A method for the assembly of tricyclic structures containing the peroxide, monoperoxyacetal, and acetal moieties was developed based on the acid-catalyzed reaction of β,δ-triketones with H₂O₂. Tricyclic compounds are formed selectively in yields from 39% to 90% by the reactions with the use of large amounts of strong acids, such as H₂SO ₄, HClO₄, or HBF₄, which act both as the catalyst and as the co-solvent. The reaction is unusual in that, despite the diversity of possible peroxidation pathways giving cyclic compounds and oligomers, the reaction proceeds with high selectivity and produces tricyclic peroxides via the monoperoxidation of the carbonyl groups in the β-positions and the transformation of the δ-carbonyl group into the acetal one. The syntheses are scaled up to tens of grams, and the resulting peroxides can be easily isolated from the reaction mixture.

Full text of DOI:10.1021/jo202437r

Article
pubs.acs.org/joc
Selective Synthesis of Cyclic Peroxides from Triketones and H2O2
Alexander O. Terent’ev,*,† Ivan A. Yaremenko,† Vladimir V. Chernyshev,‡,§ Valery M. Dembitsky,⊥
and Gennady I. Nikishin†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian
Federation
‡Department of Chemistry, Moscow State University, 119992 Moscow, Russian Federation
§A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, 31 Leninsky prosp., 119991 Moscow, Russian Federation
⊥Institute for Drug Research, P.O. Box 12065, Hebrew University, Jerusalem 91120, Israel
S
* Supporting Information
ABSTRACT: A method for the assembly of tricyclic structures containing
the peroxide, monoperoxyacetal, and acetal moieties was developed based on
the acid-catalyzed reaction of β,δ-triketones with H2O2. Tricyclic compounds
are formed selectively in yields from 39% to 90% by the reactions with the use
of large amounts of strong acids, such as H2SO4, HClO4, or HBF4, which act
both as the catalyst and as the co-solvent. The reaction is unusual in that,
despite the diversity of possible peroxidation pathways giving cyclic
compounds and oligomers, the reaction proceeds with high selectivity and
produces tricyclic peroxides via the monoperoxidation of the carbonyl groups
in the β-positions and the transformation of the δ-carbonyl group into the acetal one. The syntheses are scaled up to tens of
grams, and the resulting peroxides can be easily isolated from the reaction mixture.
In the present study, we show that the reactions of triketones
with H2O2 in the presence of acid catalysts result in the
selective assembly of tricyclic structures, peroxides, containing
only one O−O unit despite the use of more than an equimolar
amount of hydrogen peroxide. The resulting tricyclic
compounds are unusual in that they contain one acetal and
two monoperoxyacetal moieties, which are as a rule unstable
and can undergo peroxidation in the presence of water and
hydrogen peroxide under acidic conditions,8 and acetals are
susceptible to hydrolysis.9 The largest cycle in the tricyclic
structure is seven-membered 1,2,4,6-tetroxepane. Peroxides on
its base were prepared by ozonolysis of unsaturated compounds
and cyclocondensation of intermediate products with alde-
hydes.10
INTRODUCTION
■
The history of the chemistry of organic peroxides dates back
more than a century. During this period of time, ketones and
aldehydes have been recognized as the key reagents in the
synthesis of peroxides due to their availability and the ease of
the reaction of the carbonyl carbon atom with the highly
nucleophilic oxygen atom of the hydroperoxide group.
Peroxides prepared from ketones are produced on a multiton
scale and are widely used as initiators of the radical
polymerization of unsaturated monomers.1 In the past decades,
the chemistry of organic peroxides has attracted considerable
attention from physicians and pharmacologists because these
compounds were found to have antimalarial,2 antihelmintic,3
and antitumor activities.4 The interest in the synthesis of radical
polymerization initiators and drugs gave impetus to the
development of methods for the synthesis of peroxides with
the use of carbonyl compounds, their derivatives, and H2O2 as
the starting reagents.
The number of publications on the synthesis of peroxides by
the reactions of H2O2 with monoketones runs into the
hundreds,5 the corresponding reactions with diketones were
considered in about 10 publications,6 and only one example of
the synthesis with the use of triketones is known. Thus, a
tricyclic compound containing three peroxide groups was
synthesized in 18% yield from 3-acetylpentane-2,4-dione.7
There is an opinion that the number of reaction products
sharply increases with increasing number of carbonyl groups.
Hence, the selective synthesis of peroxides based on triketones
was regarded as an inherently difficult problem.
RESULTS AND DISCUSSION
■
The peroxidation of β,δ-triketones 1a−o with H2O2 in the
presence of acids selectively produces tricyclic compounds 2a−
o containing one peroxide group (Scheme 1).
Strong protic acids H2SO4, HClO4, and HBF4 were used as
the catalysts, which simultaneously acted as co-solvents.
The conditions of the preparation of tricyclic peroxides were
optimized using the synthesis of 9-benzyl-1,4,6-trimethyl-
2,3,5,10-tetraoxatricyclo[4.3.1.04,9]decane 2c from 3-acetyl-3-
benzylheptane-2,6-dione 1c as an example. We examined the
influence of the concentration and the nature of acid, the
Received: November 27, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of Tricyclic Peroxides 2a−o from β,δ-Triketones 1a−o and H2O2
amount of hydrogen peroxide, and the synthesis procedure on
the yield of tricyclic compound 2c (Table 1).
may be expected in the case of peroxides 2k−o containing the
Ar-C-O-O moiety. However, under the above-described
conditions, these reactions, if at all possible, do not influence
significantly on the synthesis of tricyclic peroxides.
Apparently, the formation of tricyclic compounds 2 occurs
via the peroxidation of one of the carbonyl groups in the β-
positions. The intermediates containing the OOH group
(which are susceptible to acid-catalyzed rearrangements due
to a high O−O bond polarization) rapidly undergo cyclization
to give dihydroxydioxolane followed by acetalyzation to form
tricyclic compounds 2 whose weakly polarized O−O bond is
less susceptible to acid-catalyzed transformations.
The reaction is unique in that, although it could give a
diversity of peroxides as a result of the reaction of three
carbonyl groups with binucleophilic H2O2, the product of
monoperoxidation at the β-carbonyl groups is selectively
formed. This result was unexpected considering that the
formation of bridged tetraoxanes via the diperoxidation of β-
carbonyl groups would be expected on the basis of the results
of our earlier study on the peroxidation of β-diketones.18
Evidently, the presence of three carbonyl groups strictly in
the β,δ-positions with respect to each other in molecule 1
determines the pathway of the peroxidation giving tricyclic
peroxide 2, which is not prone to undergo chemical
transformations in the reaction medium. Under the optimal
peroxidation conditions found for triketone 2c (run 3, Table 1),
the behavior of mono- and β-diketones differs from that of
triketones 1. We showed this fact with two examples (Scheme
2).
When performing the peroxidation of acetophenone 3, we
failed to achieve the complete conversion into geminal
bishydroperoxide 4 because the reaction in an acidic aqueous
medium is reversible.19 In the case of benzoylacetone 5, the
complete conversion was observed, but the reaction gave a
complex mixture of products. After the separation of resinous
substances on SiO2, the 13C NMR spectrum showed signals
characteristics of the carbonyl (δ 198), carboxy (δ 171−173),
and O−C−O (δ 105−110) groups.
Most experiments on the optimization were carried out in
the presence of sulfuric acid as the catalyst using an aqueous
solution of hydrogen peroxide in ethanol (runs 2−12); in the
absence of the acid (run 1), the conversion of triketone 1c was
virtually absent. The highest yield of the target peroxide 2c was
achieved when using an equivalent amount and a 1.5-fold molar
excess of H2O2 and a 8.7-fold molar excess of H2SO4 (81% and
74% in runs 4 and 7, respectively). It should be noted that the
influence of the amount of sulfuric acid on the yield of 2c
passes through a maximum. Thus, at a small excess of the acid
(runs 2 and 3), the reaction is not efficiently catalyzed (a
complex mixture of peroxides is formed); at a large excess of
the acid (run 6), the decomposition of peroxide occurs.
Isopropanol (run 13), tetrahydrofuran (run 14), and
acetonitrile (run 15) are less efficient solvents than ethanol.
As for other protic acids, tricyclic compound 2c is produced
in good yield only in the reactions catalyzed by HBF4 and
HClO4 (runs 16 and 17; yields 56% and 65%, respectively).
Weaker phosphoric acid is an inefficient catalyst for this
reaction (run 18).
In the case of the aprotic acids I2 (runs 19 and 20) and
SnCl2·2H2O (runs 21 and 22), which are used for the
peroxidation of carbonyl compounds,11 tricyclic compound 2c
was obtained in low yield (lower than 22%) only in the reaction
catalyzed by tin chloride.
The use of phosphomolybdic acid (runs 23−27), which
proved to be a good catalyst for the preparation of, for example,
vicinal hydroxyhydroperoxides,12 geminal bishydroperoxides,13
and tetraoxanes,14 enables the synthesis of 2c in good yield
(65%, run 25), but the complete conversion of 1c is not
achieved.
Based on the results of the optimization, it can be concluded
that a 1.5-fold molar excess of H2O2 and a 8−20-fold molar
excess of the acid H2SO4, HBF4, or HClO4 are the key
parameters determining good yields of tricyclic compound 2c.
Taking into account these conditions, we synthesized a series
of structurally related tricyclic compounds 2a,b,d−o containing
various functional groups and moieties: alkene 2e, alkyne 2j,
nitrile 2i, ester 2f, nitro 2h, and an aromatic core 2c, 2g, 2h,
and 2k−o (Table 2).
As can be seen from Table 2, the above-described method is
rather versatile and can be applied to the synthesis of tricyclic
peroxides containing various functionalized substituents.
The fact that a large amount of acids facilitates the
achievement of high yields of peroxides 2a−o was unexpected.
It is known that in an acidic medium peroxides tend to
decompose, in particular, via the Baeyer−Villiger,15 Criegee,16
and Hock reactions.17 The Hock and related decompositions
Therefore, the introduction of the third carbonyl group into
the diketone molecule, i.e., in the case under consideration
using 3-benzoylheptane-2,6-dione (1k) instead of benzoylace-
tone, provides the selectivity of the peroxidation and stability of
the resulting peroxide 2k.
Reactions of Tricyclic Peroxides 2c,e,f. To assess the
resistance of tricyclic peroxides to reagents used in organic
synthesis and to determine the structures, which are interesting
to test for biological activity, we performed the halogenation,
oxidation, alkaline hydrolysis, amidation, and reduction
(Scheme 3).
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Table 1. Results of the Optimization of the Conditions for the Synthesis of 9-Benzyl-1,4,6-trimethyl-2,3,5,10-
tetraoxatricyclo[4.3.1.04,9]decane 2c from 3-Acetyl-3-benzylheptane-2,6-dione 1c
acid
a
run
mole H2O2 per mole 1c
formula
H2SO4
mmole (mole per mole 1c)
solvent (procedure)
conv of 1c, %
yield 2c, % (based on NMR)
1
1.5
1.5
1.5
1.5
1.5
1.5
1
EtOH (A)
EtOH (A)
EtOH (A)
EtOH (A)
EtOH (A)
EtOH (A)
EtOH (A)
5
80
0
2
1 (0.9)
8
3
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
HBF4
5 (4.4)
95
31
b
4
10 (8.7)
100
100
100
90
81, 73
b
5
20 (17.4)
50 (43.5)
10 (8.7)
47, 40
6
35
b
7
74, 62
c
8
1
10 (8.7)
EtOH (A)
95
58
42
50
44
d
9
1
10 (8.7)
EtOH (A)
95
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2
10 (8.7)
EtOH (A)
EtOH (A)
EtOH (A)
i-PrOH (A)
THF (A)
100
100
100
95
3
10 (8.7)
b
7
10 (8.7)
42, 34
1.5
1.5
1.5
1.5
1.5
1.5
4.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
10 (8.7)
52
b
10 (8.7)
100
100
100
100
20
67, 60
10 (8.7)
CH3CN (A)
EtOH (B)
EtOH (B)
EtOH (B)
CH3CN (C)
CH3CN (C)
CH3CN (D)
CH3CN (D)
EtOH (E)
Et2O (E)
48
56
20 (17.4)
20 (17.4)
6 (5.2)
b
HClO4
H3PO4
I2
65, 58
traces
0
0.12 (0.1)
0.58 (0.5)
0.12 (0.1)
0.58 (0.5)
0.43 (0.37)
0.09 (0.074)
0.43 (0.37)
0.85 (0.74)
1.71 (1.49)
10
I2
90
0
SnCl2·2H2O
SnCl2·2H2O
PMA
43
13
22
13
42
60
16
PMA
50
b
PMA
Et2O (E)
80
65, 57
PMA
Et2O (E)
80
61
b
PMA
Et2O (E)
80
41, 35
a
General procedures A−E for the synthesis: (A) A 37% aqueous H2O2 solution (0.106−0.740 g, 1.15−8.05 mmol) and a solution of H2SO4 (0.10−
5.0 g, 1−50 mmol) (in run 1, in the absence of H2SO4) in EtOH (i-PrOH, THF, or CH3CN; 1 mL) were added with stirring to a solution of
triketone 1c (0.30 g, 1.15 mmol) in EtOH (i-PrOH, THF, or CH3CN; 4 mL) at 10−15 °C. The reaction mixture was stirred at 20−25 °C for 1 (3 or
20) h. (B) A 37% aqueous H2O2 solution (0.159 g, 1.73 mmol) and a solution of HBF4, HClO4, or H3PO4 (0.692−3.51 g, 6−20 mmol) in EtOH (1
mL) were added with stirring to a solution of triketone 1c (0.30 g, 1.15 mmol) in EtOH (4 mL) at 10−15 °C. The reaction mixture was stirred at
20−25 °C for 1 h. (C) Triketone 1c (0.30 g, 1.15 mmol) was added to a solution of I2 (0.03 or 0.147 g, 0.12 or 0.58 mmol) and a 37% aqueous
H2O2 solution (0.423 or 0.159 g, 4.6 or 1.73 mmol of H2O2) in CH3CN (10 mL). The reaction mixture was stirred at 20−25 °C for 24 h. (D) A
mixture of triketone 1c (0.30 g, 1.15 mmol), a 37% aqueous H2O2 solution (0.159 g, 1.73 mmol of H2O2), and SnCl2·2H2O (0.027 or 0.131 g, 0.12
and 0.58 mmol) in MeCN (5 mL) was stirred at 20−25 °C for 24 h. (E) A 37% aqueous H2O2 solution (0.159 g, 1.73 mmol) and phosphomolybdic
acid (PMA) (0.20−4.0 g, 0.09−1.71 mmol) were successively added with stirring to a solution of triketone 1c (0.30 g, 1.15 mmol) in Et2O or EtOH
b
c
(10 mL) at room temperature. The reaction mixture was stirred at 20−25 °C for 24 h. Yield based on the isolated product. Reaction time was 3 h.
d
Reaction time was 20 h.
The tricyclic peroxide moiety is resistant to m-chloroper-
benzoic acid, alkalies, ethyl chloroformate, and amines, which
enabled us to synthesize epoxide 6, acid 7, and amides 8 and 9
in high yields (76−95%). The course of the reaction of 2c with
triphenylphosphine was monitored by NMR spectroscopy. The
spectrum showed only signals of triketone 1c, which was
isolated in quantitative yield. The cyclic product of the insertion
of the phosphorus atom at the O−O bond, whose analogues
were observed, for example, in the studies,20 was not detected
by 31P NMR spectroscopy.
The resistance of tricyclic structures to heating was studied
using peroxide 2c as an example (see the Experimental
Section). Virtually no decomposition of the peroxide was
observed during refluxing for 1 h in EtOH. In the presence of
H2SO4, the peroxide was completely decomposed after
refluxing in EtOH to form a complex mixture of reaction
products.
Establishment of the Structures of Tricyclic Peroxides
2a−o and 6−9. All peroxides 2a−o and 6−9 are solids with
melting points from 43−44 °C (2e) to 159−160 °C (6). Their
1
The bromination of tricyclic peroxide 2e gave a complex
mixture of reaction products.
structures were established by H and 13C NMR spectroscopy,
ESI-HRMS mass spectrometry, and elemental analysis. In the
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a
Table 2. Structures and Yields of Tricyclic Peroxides 2a−o
a
General procedure: a 37% aqueous H2O2 solution (1.5 mol of H2O2 per mole of triketone 1a−o) and a solution of H2SO4 (1 g) in EtOH (1 mL)
were successively added to a solution of triketone 1a−o (0.30 g) in EtOH (4 mL) at 10−15 °C. The reaction mixture was stirred at 20−25 °C for 1
b
c
d
h. Yield based on the isolated product. Experiments were scaled up to 10 times larger initial amounts of the reagents. Reaction time was 2 h.
e
Because of the low solubility of 1h, a mixture of THF (3 mL) and EtOH (2 mL) was used as the solvent.
13C NMR spectra, the most informative signals are those for the
and 2l were studied by X-ray diffraction, which confirmed their
structures (see the Supporting Information).
carbon atoms of the monoperoxyacetal OOCO (δ 104.8−
107.5) and acetal OCO (δ 93.7−95.9) moieties, whose
chemical shifts are similar to those of known monoperox-
yacetals21 and acetals.22
Despite the NMR spectroscopic data, the establishment of
the structures of organic peroxides is always a difficult problem
because of the possible formation of peroxide oligomers or
rearrangements accompanied by changes in the carbon skeleton
and the formation of the ester group. Hence, compounds 2b
CONCLUSION
■
A selective method for the synthesis of the previously unknown
peroxide structures was developed based on the acid-catalyzed
reaction of β,δ-triketones with H2O2. The process is unusual in
that, despite the diversity of possible pathways in the presence
of a large excess of strong acids (H2SO4, HClO4, or HBF4) as
the catalyst, the reaction of β,δ-triketones with hydrogen
peroxide follows one pathway and produces tricyclic com-
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The tricyclic compounds are produced in 39−90% yields and
can be easily isolated from the reaction mixture. The reaction is
scaled up to several grams.
Scheme 2. Acid-Catalyzed Reactions of Acetophenone 3 and
Benzoylacetone 5 with H2O2
EXPERIMENTAL SECTION
■
Caution: Although we have encountered no difficulties in working
with peroxides, precautions such as the use of shields, fume hoods,
and the avoidance of transition metal salts, heating and shaking
should be taken whenever possible.
NMR spectra were recorded on a commercial instrument (300.13
1
MHz for H, 75.48 MHz for 13C) in CDCl3. High-resolution mass
spectra (HRMS) were measured in the electrospray ionization (ESI)
mode23 The measurements were taken in the positive ion mode (the
interface capillary voltage was 4500 V); the mass range was from m/z
50 to m/z 3000 Da; the external/internal calibration was done with
Electrospray Calibrant Solution. The syringe injection was used for
solutions in acetonitrile (flow rate was 3 μL/min). Nitrogen was used
as a dry gas; the 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
hot-stage apparatus. Chromatography was performed on silica gel
(63−200 mesh).
Acetone, EtOH, i-PrOH, CH2Cl2, Et2O, petroleum ether (PE) (40/
70), CH3CN, THF, ethyl acetate (EA), HClO4 (60% aqueous
solution), HBF4 (50% aqueous solution), H3PO4 (85% aqueous
solution), H2SO4, phosphomolybdic acid hydrate (ca. 78% phospho-
molybdic acid, PMA), 3-chloroperoxybenzoic acid (MCPBA, 70−75%
pounds via the monoperoxidation of the carbonyl groups in the
β-positions and the transformation of the δ-carbonyl group into
the acetal one. Apparently, due to the geometry of tricyclic
compounds, the monoperoxyacetal and acetal moieties are
stable even despite the presence of water, ethanol, and
hydrogen peroxide in the reaction mixture. Unlike many
compounds containing the O−O bond, which are rearranged in
acidic media, the resulting cyclic peroxides are quite stable
under the reaction conditions.
Scheme 3. Reactions of Tricyclic Peroxides 2c,e,f
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balance 3-chlorobenzoic acid and water), morpholine, Et3N, 1-
adamantanamine hydrochloride, acetylacetone, acetophenones, methyl
vinyl ketone, benzyl and alkyl bromides, allyl bromide, propargyl
bromide, ethyl acrylate, acrylonitrile, ethyl chloroformate, 1-phenyl-
butane-1,3-dione, Ph3P, H2O2 (37% aqueous solution), benzyltriethy-
lammonium chloride (98%), Na2SO4, K2CO3, NaHCO3, NaOH,
KOH, I2, FeCl3·6H2O, SnCl2·2H2O, NaI, and CeCl3·7H2O were
commercial products and were used as is.
NMR (300.13 MHz, CDCl3): δ 2.09 (s, 11H), 2.24−2.35 (m, 5H),
3.12 (s, 2H), 6.87 (d, 2H, J = 7.3 Hz), 7.03 (d, 2H, J = 7.3 Hz). 13C
NMR (75.48 MHz, CDCl3): δ 20.9, 24.2, 27.8, 30.0, 37.1, 38.0, 70.1,
129.2, 129.4, 132.2, 136.7, 206.9, 207.1. Anal. Calcd for C17H22O3: C,
74.42; H, 8.08. Found: C, 74.46; H, 8.09.
3-Acetyl-3-(4-nitrobenzyl)heptane-2,6-dione, 1h. Hazel crys-
1
tals. Mp = 113−114 °C. Rf = 0.31 (TLC, PE/EA, 2:1). H NMR
(300.13 MHz, CDCl3): δ 2.11 (s, 11H), 2.32 (t, 2H, J = 7.7 Hz), 3.24
(s, 2H), 7.19 (d, 2H, J = 8.8 Hz), 8.08 (d, 2H, J = 8.8 Hz). 13C NMR
(75.48 MHz, CDCl3): δ 24.5, 27.8, 30.0, 37.1, 37.7, 70.0, 123.6, 130.6,
143.6, 147.1, 206.1, 206.3. Anal. Calcd for C16H19NO5: C, 62.94; H,
6.27; N, 4.59. Found: C, 62.74; H, 6.37; N, 4.59.
Synthesis of β,δ-Triketones 1a−o. β,δ-Triketones 1a and 1b
were synthesized according to a known procedure.24
3-Acetylheptane-2,6-dione, 1a.24 Colorless oil. 1H NMR
(300.13 MHz, CDCl3): δ 1.97−2.16 (m, 11H), 2.40 (t, 2H, J = 7.0
Hz), 3.63 (t, 0.8H, J = 7.0 Hz), 16.64 (br.s, 0.2H).
4,4-Diacetyl-7-oxooctanenitrile, 1i. Hazel crystals. Mp = 74−75
°C. Rf = 0.27 (TLC, PE/EA, 2:1). 1H NMR (300.13 MHz, CDCl3): δ
2.05−2.31 (m). 13C NMR (75.48 MHz, CDCl3): δ 12.5, 24.1, 26.8,
26.9, 30.0, 37.4, 68.3, 118.7, 205.6, 206.1. Anal. Calcd for C12H17NO3:
C, 64.55; H, 7.67; N, 6.27. Found: C, 64.80; H, 8.00; N, 6.21.
3-Acetyl-3-(2-propynyl)-2,6-heptanedione, 1j. Yellow crystals.
3-Acetyl-3-methylheptane-2,6-dione, 1b.24 Colorless oil. 1H
NMR (300.13 MHz, CDCl3): δ 2.30 (s, 3H), 1.99−2.16 (m, 11H),
2.31 (t, 2H, J = 7.7 Hz).
Triketone 1c was synthesized according to a published procedure.24
Methyl vinyl ketone (4.91 g, 70 mmol) was added dropwise with
stirring to a solution of FeCl3·6H2O (0.865 g, 3.2 mmol) in 3-
benzylpentane-2,4-dione (12.00 g, 63 mmol) at 20−25 °C. The
mixture was stirred at 20−25 °C until it completely solidified, and the
solid was dissolved in CH2Cl2 (50 mL). The organic layer was washed
with a saturated NaHCO3 solution (4 × 10 mL), a 5% aqueous HCl
solution until the organic phase became colorless, and water (2 × 15
mL), dried over Na2SO4, and filtered. The solvent was removed in a
water jet vacuum. Triketone 1c was recrystallized from i-PrOH.
Compound 1c (10.93 g, 42 mmol), yield 67%.
1
Mp = 54−55 °C. Rf = 0.55 (TLC, PE/EA, 2:1). H NMR (300.13
MHz, CDCl3): δ 2.02 (t, 1H, J = 2.7 Hz), 2.09−2.16 (m, 9H), 2.25−
2.32 (m, 4H), 2.70 (d, 2H, J = 2.7 Hz). 13C NMR (75.48 MHz,
CDCl3): δ 21.3, 24.6, 26.9, 29.9, 37.8, 68.5, 72.2, 78.8, 204.9, 206.7.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.11; H, 7.83.
Triketones 1k−o were synthesized according to a known
procedure.26 Methyl vinyl ketone (1.45−2.16 g, 20.75−30.85 mmol)
was added with stirring to a solution of the corresponding β-diketone
(1.00 g, 4.15−6.17 mmol) in EtOH (10 mL). The mixture was
refluxed for 24 h and then cooled. Ethanol and methyl vinyl ketone
that remained unconsumed were removed in a water jet vacuum.
Products 1k−o were isolated by chromatography on SiO2 using a PE/
EA mixture as the eluent with a gradient of ethyl acetate from 30 to 90
vol %. Products 1k (1.22 g, 5.24 mmol), yield 85%; 1l (0.697 g, 2.24
mmol), yield 54%; 1m (1.01 g, 3.85 mmol), yield 74%; 1n (0.628 g,
2.55 mmol), yield 45%; 1o (0.707 g, 2.65 mmol), yield 52%.
3-Benzoylheptane-2,6-dione, 1k.26 Yellow oil. 1H NMR
(300.13 MHz, CDCl3): δ 1.95−2.28 (m, 8H), 2.35−2.61 (m, 2H),
4.53 (t, H, J = 6.6 Hz), 7.39−7.60 (m, 3H), 7.98 (d, 2H, J = 8.1 Hz).
13C NMR (75.48 MHz, CDCl3): δ 22.4, 28.5, 29.9, 40.4, 61.0, 128.6,
128.8, 133.8, 136.1, 196.5, 203.9, 207.8.
3-Acetyl-3-benzylheptane-2,6-dione, 1c. White crystals. Mp =
1
79−80 °C. Rf = 0.34 (TLC, PE/EA, 5:1). H NMR (300.13 MHz,
CDCl3): δ 2.09 (s, 11H), 2.26−2.34 (m, 2H), 3.16 (s, 2H), 6.97−7.06
(m, 2H), 7.16−7.27 (m, 3H). 13C NMR (75.48 MHz, CDCl3): δ 24.2,
27.7, 29.9, 37.5, 38.0, 70.0, 127.0, 128.5, 129.6, 135.5, 206.8, 206.9.
Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C, 73.79; H, 7.88.
Triketones 1d−j were synthesized according to a known
procedure.25 Methyl vinyl ketone (0.328−0.558 g, 4.68−7.96
mmol), CeCl3·7H2O (0.317−0.540 g, 0.85−1.45 mmol), and NaI
(0.064−0.109 g, 0.43−0.73 mmol) were successively added with
stirring to a solution of the corresponding β-diketone (1.00 g, 4.25−
7.24 mmol) in MeCN (1 mL) at 20−25 °C. The reaction mixture was
stirred at room temperature for 12 h. Then CH2Cl2 (20 mL) was
added, the catalyst was filtered off, and the precipitate was washed on
the filter with CH2Cl2 (20 mL). The solvents were removed in a water
jet vacuum. Products 1d−j were isolated by chromatography on SiO2
using a PE/EA mixture as the eluent with a gradient of ethyl acetate
from 40 to 90 vol %. Compounds 1d (1.01 g, 4.48 mmol), yield 70%;
1e (1.26 g, 5.99 mmol), yield 84%; 1f (1.05 g, 3.90 mmol), yield 78%;
1g (0.765 g, 2.79 mmol), yield 57%; 1h (1.08 g, 3.53 mmol), yield
83%; 1i (0.947 g, 4.24 mmol), yield 65%; 1j (1.24 g, 5.93 mol), yield
82%.
3-(4-Bromobenzoyl)heptane-2,6-dione, 1l. White crystals. Mp
1
= 70−71 °C. Rf = 0.45 (TLC, PE/EA, 2:1). H NMR (300.13 MHz,
CDCl3): δ 2.03−2.21 (m, 8H), 2.39−2.61 (m, 2H), 4.48 (t, H, J = 6.6
Hz), 7.61 (d, 2H, J = 8.1 Hz), 7.87 (d, 2H, J = 8.1 Hz). 13C NMR
(75.48 MHz, CDCl3): δ 22.3, 28.5, 29.9, 40.3, 61.1, 129.2, 130.2,
132.2, 134.8, 195.6, 203.7, 207.8. Anal. Calcd for C14H15BrO3: C,
54.04; H, 4.86; Br, 25.68. Found: C, 54.07; H, 5.01; Br, 25.62.
3-(4-Methoxybenzoyl)heptane-2,6-dione, 1m. Brown oil. Rf =
1
0.33 (TLC, PE/EA, 2:1). H NMR (300.13 MHz, CDCl3): δ 2.01−
2.23 (m, 8H), 2.35−2.60 (m, 2H), 3.83 (s, 3H), 4.46 (t, H, J = 7.0
Hz), 6.92 (d, 2H, J = 8.8 Hz), 7.98 (d, 2H, J = 8.8 Hz). 13C NMR
(75.48 MHz, CDCl3): δ 22.5, 28.3, 29.9, 40.5, 55.5, 60.8, 114.0, 129.1,
131.1, 164.1, 194.8, 204.2, 207.9. Anal. Calcd for C15H18O4: C, 68.68;
H, 6.92. Found: C, 68.43; H, 7.25.
3-Acetyl-3-butylheptane-2,6-dione, 1d. White crystals. Mp =
1
45−46 °C. Rf = 0.51 (TLC, PE/EA, 5:1). H NMR (300.13 MHz,
CDCl3): δ 0.85 (t, 3H, J = 7.0 Hz), 0.92−1.05 (m, 2H), 1.21−1.34 (m,
2H), 1.75−1.84 (m, 4H), 2.01−2.12 (m, 9H), 2.15−2.24 (m, 2H). 13C
NMR (75.48 MHz, CDCl3): δ 13.7, 23,1, 24,2, 25.9, 26.9, 29.9, 31.4,
38.1, 69.3, 207.2. Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found:
C, 69.28; H, 10.09.
3-(4-Methylbenzoyl)heptane-2,6-dione, 1n. Colorless oil. Rf =
1
0.56 (TLC, PE/EA, 2:1). H NMR (300.13 MHz, CDCl3): δ 2.05−
2.30 (m, 8H), 2.34−2.63 (m, 5H), 4.53 (t, 1H, J = 7.3 Hz), 7.29 (d,
2H, J = 8.3 Hz), 7.92 (d, 2H, J = 8.3 Hz). 13C NMR (75.48 MHz,
CDCl3): δ 21.6, 22.4, 28.5, 29.9, 40.5, 61.0, 128.9, 129.6, 133.8, 144.9,
196.1, 204.1, 207.9. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37.
Found: C, 73.03; H, 7.40.
3-Acetyl-3-allylheptane-2,6-dione, 1e. Yellow oil. Rf = 0.51
1
(TLC, PE/EA, 5:1). H NMR (300.13 MHz, CDCl3): δ 1.94−2.30
(m, 13H), 2.57 (d, 2H, J = 7.3 Hz), 4.98−5.15 (m, 2H), 5.38−5.56
(m, 1H). 13C NMR (75.48 MHz, CDCl3): δ 24.3, 27.1, 29.9, 35.9,
37.7, 69.1, 119.2, 131.6, 206.3, 207.0. Anal. Calcd for C12H18O3: C,
68.54; H, 8.63. Found: C, 68.54; H, 8.99.
3-(4-Chlorobenzoyl)heptane-2,6-dione, 1o. White crystals. Mp
1
= 56−57 °C. R = 0.56 (TLC, PE/EA, 2:1). H NMR (300.13 MHz,
f
Ethyl 4,4-Diacetyl-7-oxooctanoate, 1f. Colorless oil. Rf = 0.37
(TLC, PE/EA, 2:1). 1H NMR (300.13 MHz, CDCl3): δ 1.20 (t, 3H, J
= 7.0 Hz), 2.00−2.30 (m, 17H), 4.08 (q, 2H, J = 7.0 Hz). 13C NMR
(75.48 MHz, CDCl3): δ 14.1, 24.1, 26.1, 26.9, 28.8, 29.9, 37.7, 60.7,
68.4, 172.4, 206.5, 206.8. Anal. Calcd for C14H22O5: C, 62.20; H, 8.20.
Found: C, 62.44; H, 8.38.
CDCl3): δ 2.03−2.23 (m, 8H), 2.39−2.61 (m, 2H), 4.49 (t, H, J = 6.6
Hz), 7.45 (d, 2H, J = 8.1 Hz), 7.96 (d, 2H, J = 8.1 Hz). 13C NMR
(75.48 MHz, CDCl3): δ 22.4, 28.5, 30.0, 40.4, 61.2, 129.2, 130.2,
134.4, 140.5, 195.4, 203.7, 207.8. Anal. Calcd for C14H15ClO3: C,
63.04; H, 5.67; Cl, 13.29. Found: C, 63.07; H, 5.72; Cl, 13.18.
Synthesis of 9-Benzyl-1,4,6-trimethyl-2,3,5,10-
tetraoxatricyclo[4.3.1.04,9]decane 2c (Table 1, runs 1−
27). General Procedure for Peroxidation of 1c without
3-Acetyl-3-(4-methylbenzyl)heptane-2,6-dione, 1g. White
crystals. Mp = 125−126 °C. Rf = 0.56 (TLC, PE/EA, 2:1). 1H
1838
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(Table 1, experiment 1) and with the Use of H2SO4 (Table 1,
runs 2−15). A 37% aqueous H2O2 solution (0.106−0.740 g, 1.15−
8.05 mmol) and a solution of H2SO4 (0.1−5 g, 1−50 mmol) in EtOH
(i-PrOH, THF, or CH3CN; 1 mL) were added with stirring to a
solution of triketone 1c (0.30 g, 1.15 mmol) in EtOH (i-PrOH, THF,
or CH3CN; 4 mL) at 10−15 °C; in run 1, a solution of H2SO4 was not
added. The reaction mixture was stirred at 20−25 °C for 1 h, and a
mixture of CH2Cl2/PE = 1:1 (10 mL) was added. Then NaHCO3 was
added to the reaction mixture with stirring until the pH reached 7.0; in
run 1, NaHCO3 was not added. The precipitate was filtered off. The
filtrate was dried over Na2SO4, the precipitate was filtered off, and the
solvent was removed in a water jet vacuum. In runs 4, 5, 7, 12, and 14,
product 2c was isolated by chromatography on SiO2 using a PE/EA
mixture as the eluent with a gradient of ethyl acetate from 5 to 40 vol
%.
filtrate was dried over Na2SO4, the precipitate was filtered off, and the
solvent was removed in a water jet vacuum. Products 2a−o were
isolated by chromatography on SiO2 using a PE/EA mixture as the
eluent with a gradient of ethyl acetate from 5 to 50 vol %.
The scaled-up synthesis of 2e,f with an increase in the amounts of
the starting reagents and solvents by a factor of 10 was performed in
the same way.
3,6,7a-Trimethyltetrahydro-3H,4H-3,6-epoxy[1,2]dioxolo-
[3,4-b]pyran, 2a. White crystals. Mp = 73−74 °C. Rf = 0.24 (TLC,
PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 1.38 (s, 3H), 1.52 (s,
6H), 1.60−1.70 (m, 2H), 1.79−1.91 (m, 2H), 2.30−2.38 (m, H). 13C
NMR (75.48 MHz, CDCl3): δ 13.1, 17.7, 24.6, 29.2, 47.8, 95.3, 104.8.
Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.07; H, 7.62.
HRMS (ESI): m/z [M + NH4]+ calcd for [C9H18NO4]+ 204.1230;
found 204.1236.
General Procedure for Peroxidation of 1c with the Use of
HBF4 (50% aqueous solution), HClO4 (60% aqueous solution),
and H3PO4 (Table 1, runs 16−18). A 37% aqueous H2O2 solution
(0.159 g, 1.73 mmol) and a solution of HBF4, HClO4, or H3PO4
(0.69−3.51 g, 6−20 mmol) in EtOH (1 mL) were added with stirring
to a solution of triketone 1c (0.30 g, 1.15 mmol) in EtOH (4 mL) at
10−15 °C. The reaction mixture was stirred at 20−25 °C for 1 h.
Compound 2c was isolated, and the yield was calculated as described
in runs 1−15; in run 17, the yield was determined based on the
isolated 2c.
3,3a,6,7a-Tetramethyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran, 2b. White crystals. Mp = 94−95 °C. Rf = 0.49
1
(TLC, PE/EA, 5:1). H NMR (300.13 MHz, CDCl3): δ 1.0 (s, 3H),
1.39 (s, 3H), 1.43 (s, 6H), 1.64−1.73 (m, 4H). 13C NMR (75.48 MHz,
CDCl3): δ 15.3, 17.0, 21.2, 24.8, 31.2, 48.2, 94.3, 107.0. Anal. Calcd for
C10H16O4: C, 59.98; H, 8.05. Found: C, 60.26; H, 8.26. HRMS (ESI)
m/z [M + Na]+ calcd for [C10H16NaO4]+ 223.0941; found 223.0942.
3a-Benzyl-3,6,7a-trimethyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran, 2c. White crystals. Mp = 94−95 °C. Rf = 0.37
(TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 1.38 (s, 3H),
1.42 (s, 6H), 1.65−1.74 (m, 2H), 1.79−1.88 (m, 2H), 2.86 (s, 2H),
7.15−7.32 (m, 5H). 13C NMR (75.48 MHz, CDCl3): δ 16.1, 18.9,
24.7, 30.9, 36.8, 51.7, 93.7, 107.5, 126.8, 128.1, 131.2, 136.4. Anal.
Calcd for C16H20O4: C, 69.54; H, 7.30. Found: C, 69.64; H, 7.25.
HRMS (ESI): m/z [M + H]+ calcd for [C16H21O4]+ 277.1434; found
277.1433.
Procedure for Peroxidation of 1c with the Use of I2 (Table 1,
runs 19 and 20). Molecular iodine (0.03 or 0.147 g, 0.12 or 0.58
mmol) and a 37% aqueous H2O2 solution (0.423 or 0.159 g, 4.6 or
1.73 mmol) were dissolved in CH3CN (10 mL), and then triketone 1c
(0.30 g, 1.15 mmol) was added to the solution. The reaction mixture
was stirred at 20−25 °C for 24 h. Target peroxide 2c was not detected
by TLC in the course of the reaction and after the synthesis.
Procedure for Peroxidation of 1c with the Use of SnCl2·2H2O
(Table 1, runs 21 and 22). A mixture of triketone 1c (0.30 g, 1.15
mmol), a 37% aqueous H2O2 solution (0.159 g, 1.73 mmol), and
SnCl2·2H2O (0.027 or 0.131 g, 0.12 and 0.58 mmol) in CH3CN (5
mL) was stirred at 20−25 °C for 24 h. Then CH2Cl2 (40 mL) was
added. The organic layer was washed with water (10 mL), a 5%
aqueous NaHCO3 solution (2 × 10 mL), and again with water (10
mL). The organic layer was dried over Na2SO4 and filtered. The
solvent was removed in a water jet vacuum. Compound 2c was
isolated, and the yield was calculated as described in runs 1−15.
General Procedure for Peroxidation of 1c with the Use of
PMA (Table 1, runs 23−27). A 37% aqueous H2O2 solution (0.159
g, 1.73 mmol) and phosphomolybdic acid (PMA) (0.20−4.0 g, 0.09−
1.71 mmol) were successively added with stirring to a solution of
triketone 1c (0.30 g, 1.15 mmol) in Et2O or EtOH (10 mL) at room
temperature. The reaction mixture was stirred at 20−25 °C for 24 h,
and then CH2Cl2 (30 mL) was added. The organic layer was washed
with water (10 mL), a 5% aqueous NaHCO3 solution (2 × 10 mL),
and again with water (10 mL). The organic layer was dried over
Na2SO4 and filtered. The solvent was removed in a water jet vacuum.
Compound 2c was isolated, and the yield was calculated as described
in runs 1−15. In runs 25 and 27, the yield was determined based on
the isolated 2c.
In runs 1−27, the conversion of 1c (the characteristic signal is a
singlet of the CH2Carom group at δ 3.16) and the yield of 2c (the
characteristic signal is a singlet of the CH2Carom group at δ 2.86) were
determined from the 1H NMR spectroscopic data based on the
starting triketone 1c. 1,4-Dioxane was used as the internal standard
(the characteristic signal is a singlet of the CH2 group at δ 3.69).
General Procedure for the Synthesis of Tricyclic Peroxides
2a−o (Table 2). A 37% aqueous H2O2 solution (0.132−0.243 g,
1.44−2.64 mmol) and a solution of H2SO4 (1.0 g, 0.01 mol) in EtOH
(1 mL; THF/EtOH = 3:2 in the case of triketone 1h) were added with
stirring to a solution of triketone 1a−o (0.30 g, 0.96−1.76 mmol) in
EtOH (4 mL; THF/EtOH = 3:2 in the case of triketone 1h) at 10−15
°C. The reaction mixture was stirred at 20−25 °C for 1 h (in the case
of triketone 1g, for 2 h), and a mixture of CH2Cl2/PE = 1:1 (10 mL)
was added. Then NaHCO3 was added to the reaction mixture with
stirring until the pH reached 7.0. The precipitate was filtered off. The
3a-Butyl-3,6,7a-trimethyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran, 2d. White crystals. Mp = 60−61 °C. Rf = 0.39
(TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 0.89 (t, 3H, J
= 7.0 Hz), 1.20−1.52 (m, 15H), 1.67−1.71 (m, 4H). 13C NMR (75.48
MHz, CDCl3): δ 13.8, 16.1, 18.9, 23.6, 24.8, 26.3, 30.87, 30.94, 50.6,
94.0, 107.3. Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C,
64.33; H, 9.35. HRMS (ESI) m/z [M + H]+ calcd for [C13H23O4]+
243.1591; found 243.1591.
3a-Allyl-3,6,7a-trimethyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran, 2e. White crystals. Mp = 43−44 °C. Rf = 0.45
(TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 1.39 (s, 3H),
1.47 (s, 6H), 1.70−1.72 (m, 4H), 2.27 (d, 2H, J = 7.3 Hz), 5.04−5.15
(m, 2H), 5−79−5.95 (m, H). 13C NMR (75.48 MHz, CDCl3): δ 16.1,
19.0, 24.7, 30.8, 35.8, 50.7, 94.0, 107.1, 118.5, 133.2. Anal. Calcd for
C12H18O4: C, 63.70; H, 8.02. Found: C, 64.02; H, 7.95. HRMS (ESI):
m/z [M + H]+ calcd for [C12H19O4]+ 227.1279; found 227.1278.
Ethyl 3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran-3a-yl)propanoate, 2f. White crystals. Mp =
1
57−58 °C. Rf = 0.45 (TLC, PE/EA, 2:1). H NMR (300.13 MHz,
CDCl3): δ 1.23 (t, 3H, J = 7.1 Hz), 1.38 (s, 3H), 1.46 (s, 6H), 1.67−
1.70 (m, 4H), 1.76−1.83 (m, 2H), 2.47−2.54 (m, 2H), 4.1 (q, 2H, J =
7.1 Hz). 13C NMR (75.48 MHz, CDCl3): δ 14.2, 15.7, 20.0, 24.6, 26.5,
29.4, 30.7, 50.2, 60.6, 94.1, 106.8, 173.3. Anal. Calcd C14H22O6: C,
58.73; H, 7.74. Found: C, 58.75; H, 7.81. HRMS (ESI): m/z [M +
Na]+ calcd for [C14H22NaO6]+ 309.1309; found 309.1307.
3,6,7a-Trimethyl-3a-(4-methylbenzyl)tetrahydro-3H,4H-3,6-
epoxy[1,2]dioxolo[3,4-b]pyran, 2g. White crystals. Mp = 104−105
°C. Rf = 0.46 (TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ
1.38 (s, 3H), 1.42 (s, 6H), 1.65−1.75 (m, 2H), 1.77−1.87 (m, 2H),
2.31 (s, 3H), 2.82 (s, 2H), 7.07−7.10 (m, 4H). 13C NMR (75.48 MHz,
CDCl3): δ 16.6, 18.9, 21.0, 24.7, 30.9, 36.3, 51.7, 93.7, 107.5, 128.8,
131.1, 133.2, 136.4. Anal. Calcd C17H22O4: C, 70.32; H, 7.64. Found:
C, 70.14; H, 7.71. HRMS (ESI): m/z [M + NH4]+ calcd for
[C17H26NO4]+ 308.1856; found 308.1856.
3,6,7a-Trimethyl-3a-(4-nitrobenzyl)tetrahydro-3H,4H-3,6-
epoxy[1,2]dioxolo[3,4-b]pyran, 2h. White crystals. Mp = 149−150
°C. Rf = 0.20 (TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ
1.38 (s, 3H), 1.41 (s, 6H), 1.69−1.77 (m, 2H), 1.80−1.88 (m, 2H),
2.96 (c, 2H), 7.42 (d, 2H, J = 8.8 Hz), 8.15 (d, 2H, J = 8.8 Hz). 13C
NMR (75.48 MHz, CDCl3): δ 16.7, 19.0, 24.5, 30.7, 36.7, 51.8, 93.8,
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107.2, 123.3, 131.9, 144.4, 146.9. Anal. Calcd C16H19NO6: C, 59.81; H,
5.96; N, 4.36. Found: C, 59.74; H, 6.07; N, 4.33. HRMS (ESI): m/z
[M + H]+ calcd for [C16H20NO6]+ 322.1285; found 322.1284.
3-(3,6,7a-Trimethylhexahydro-3,6-epoxy[1,2]dioxolo[3,4-b]-
pyran-3a-yl)propanenitrile, 2i. White crystals. Mp = 114−115 °C.
Rf = 0.13 (TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 1.38
(s, 3H), 1.47 (s, 6H), 1.67−1.73 (m, 4H), 1.80−1.88 (m, 2H), 2.56−
2.64 (m, 2H). 13C NMR (75.48 MHz, CDCl3): δ 12.9, 15.6, 20.5, 24.5,
28.1, 30.5, 50.2, 94.3, 106.2, 119.5. Anal. Calcd C12H17NO4: C, 60.24;
H, 7.16; N, 5.85. Found: C, 60.36; H, 7.22; N, 5.87. HRMS (ESI): m/
z [M + H]+ calcd for [C12H18NO4]+ 240.1230; found 240.1231.
3,6,7a-Trimethyl-3a-(prop-2-yn-1-yl)hexahydro-3,6-epoxy-
[1,2]dioxolo[3,4-b]pyran, 2j. White crystals. Mp = 135−136 °C. Rf
the solvent was removed in a water jet vacuum. After the isolation with
the use of SiO2, peroxide 4 was obtained in 27% yield (0.115 g, 0.68
mmol).
(1,1-Dihydroperoxyethyl)benzene, 4.27 White crystals. Mp =
76−77 °C (Mp = 77−78 °C).27 1H NMR (300.13 MHz, CDCl3): δ
1.69 (s, 3H), 7.30−7.43 (m, 3H), 7.49 (d, 2H, J = 7.3 Hz), 8.85 (br.s,
2H). 13C NMR (75.48 MHz, CDCl3): δ 23.0, 111.3, 125.7, 128.5,
128.7, 138.1.
H2SO4-Catalyzed Reaction of 1-Phenylbutane-1,3-dione 5
with Hydrogen Peroxide (Scheme 2). A 37% aqueous H2O2
solution (0.256 g, 2.78 mmol H2O2) and a solution of H2SO4 (1.0
g, 10 mmol) in EtOH (1 mL) were added with stirring to a solution of
diketone 5 (0.30 g, 1.85 mmol) in EtOH (4 mL) at 10−15 °C. The
reaction mixture was stirred at 20−25 °C for 1 h, and a mixture of
CH2Cl2/PE = 2:1 (20 mL) was added. Then NaHCO3 was added to
the reaction mixture with stirring until the pH reached 7.0. The
precipitate was filtered off. The filtrate was dried over Na2SO4, the
precipitate was filtered off, and the solvent was removed in a water jet
vacuum. After the isolation with the use of SiO2, a complex mixture of
reaction products was obtained.
Synthesis of 3,6,7a-Trimethyl-3a-(oxiran-2-ylmethyl)-
tetrahydro-3H,4H-3,6-epoxy[1,2]dioxolo[3,4-b]pyran (6) from
3a-Allyl-3,6,7a-trimethyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran (2e). MCPBA (0.656 g, 2.66 mmol) was added
with stirring to a solution of 2e (0.30 g, 1.33 mmol) in anhydrous
CH2Cl2 (5 mL). The reaction mixture was kept at 20−25 °C for 24 h.
Then CH2Cl2 (20 mL) was added, the organic layer was washed with
water (2 × 10 mL), a 5% aqueous KOH solution (2 × 5 mL), and
again with water (2 × 10 mL), dried over Na2SO4, and filtered. Then
CH2Cl2 was removed in a water jet vacuum. The product was isolated
by chromatography on SiO2 using a PE/EA mixture as the eluent with
a gradient of ethyl acetate from 20 to 50 vol %. Product 6 (0.30 g, 1.24
mmol), yield 93%.
3,6,7a-Trimethyl-3a-(oxiran-2-ylmethyl)tetrahydro-3H,4H-
3,6-epoxy[1,2]dioxolo[3,4-b]pyran, 6. White crystals. Mp = 61−
62 °C. Rf = 0.46 (TLC, PE/EA, 1:1). 1H NMR (300.13 MHz, CDCl3):
δ 1.40 (s, 3H), 1.48 (s, 3H), 1.54 (s, 3H), 1.65−1.95 (m, 6H), 2.43
(m, 1H), 2.78 (t, 1H, J = 4.4 Hz), 3.04−3.15 (m, 1H). 13C NMR
(75.48 MHz, CDCl3): δ 16.0, 16.2, 19.2, 24.6, 30.7, 34.9, 47.2, 48.2,
50.7, 94.2, 106.9. Anal. Calcd C12H18O5: C, 59.49; H, 7.49. Found: C,
59.71; H, 7.28. HRMS (ESI): m/z [M + K]+ calcd for [C12H18KO5]+
281.0786; found 281.0783.
Synthesis of 3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy-
[1,2]dioxolo[3,4-b]pyran-3a-yl)propanoic Acid (7) from Ethyl
3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]dioxolo[3,4-
b]pyran-3a-yl)propanoate (2f). A solution of KOH (0.196 g, 3.50
mmol) in water (2 mL) was added with stirring to a solution of ester
2f (0.50 g, 1.75 mmol) in EtOH (5 mL) at 20−25 °C. The reaction
mixture was stirred at 20−25 °C for 1 h. Water (15 mL) was added to
the reaction mixture, the mixture was washed with CH2Cl2 (30 mL),
the aqueous layer was acidified with H2SO4 (0.35 g, 3.50 mmol), and
acid 7 was extracted with CH2Cl2 (3 × 30 mL). The combined organic
layers were washed with water (5 mL), dried over Na2SO4, and
filtered. The solvent was removed in a water jet vacuum. Product 7
was isolated by chromatography on SiO2 using a PE /EA mixture as
the eluent with a gradient of ethyl acetate from 40 to 70 vol %. Product
7 (0.429 g, 1.66 mmol), yield 95%.
1
= 0.50 (TLC, PE/EA, 5:1). H NMR (300.13 MHz, CDCl3): δ 1.39
(s, 3H), 1.50 (s, 6H), 1.71−1.79 (m, 2H), 1.92−2.00 (m, 2H) 2.04−
2.09 (m, H), 2.36−2.42 (m, 2H). 13C NMR (75.48 MHz, CDCl3): δ
16.0, 17.8, 20.7, 24.6, 30.7, 49.8, 72.2, 79.3, 94.5, 106.9. Anal. Calcd
C12H16O4: C, 64.27; H, 7.19. Found: C, 64.29; H, 6.83. HRMS (ESI):
m/z [M + Na]+ calcd for [C12H16NaO4]+ 247.0941; found 247.0940.
3,6-Dimethyl-7a-phenyltetrahydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran, 2k. White crystals. Mp = 75−76 °C. Rf = 0.5
1
(TLC, PE/EA, 2:1). H NMR (300.13 MHz, CDCl3): δ 1.47−1.86
(m, 10H), 2.65−2.69 (m, H), 7.32−7.45 (m, 3H), 7.52−7.62 (m, 2H).
13C NMR (75.48 MHz, CDCl3): δ 12.5, 17.8, 24.8, 29.3, 50.8, 95.8,
105.5, 106.4, 126.7, 128.5, 129.4, 133.0. Anal. Calcd C14H16O4: C,
67.73; H, 6.50. Found: C, 67.70; H, 6.60. HRMS (ESI) m/z [M + H]+
calcd for [C14H17O4]+ 249.1119; found 249.1121.
3-(4-Bromophenyl)-6,7a-dimethyltetrahydro-3H,4H-3,6-
epoxy[1,2]dioxolo[3,4-b]pyran, 2l. White crystals. Mp = 122−123
°C. Rf = 0.34 (TLC, PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ
1.55 (s, 3H), 1.61 (s, 3H), 1.71−1.80 (m, 4H), 2.61−2.65 (m, H),
7.45 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz). 13C NMR (75.48
MHz, CDCl3): δ 12.4, 17.7, 24.8, 29.3, 50.7, 95.9, 105.5, 106.1, 123.9,
128.6, 131.7, 132.3. Anal. Calcd C14H15BrO4: C, 51.40; H, 4.62; Br,
24.42. Found: C, 51.39; H, 4.63; Br, 24.29. HRMS (ESI) m/z [M +
H]+ calcd for [C14H16BrO4]+ 327.0219; found 327.0226.
3-(4-Methoxyphenyl)-6,7a-dimethyltetrahydro-3H,4H-3,6-
epoxy[1,2]dioxolo[3,4-b]pyran, 2m. White crystals. Mp = 89−90
1
°C. Rf =0.52 (TLC, PE/EA, 2:1). H NMR (300.13 MHz, CDCl3): δ
1.55 (s, 3H), 1.61 (s, 3H), 1.68−1.80 (m, 4H), 2.62−2.66 (m, H),
3.80 (s, 3H), 6.90 (d, 2H, J = 8.8 Hz), 7.49 (d, 2H, J = 8.8 Hz). 13C
NMR (75.48 MHz, CDCl3): δ 12.5, 17.9, 24.8, 29.3, 50.5, 55.3, 95.8,
105.6, 106.5, 113.9, 124.7, 128.1, 160.5. Anal. Calcd C15H18O5: C,
64.74; H, 6.52. Found: C, 64.73; H, 6.75. HRMS (ESI) m/z [M + H]+
calcd for [C15H19O5]+ 279.1227; found 279.1227.
3,6-Dimethyl-7a-(p-tolyl)hexahydro-3,6-epoxy[1,2]dioxolo-
[3,4-b]pyran, 2n. White crystals. Mp = 105−106 °C. Rf = 0.38 (TLC,
PE/EA, 5:1). 1H NMR (300.13 MHz, CDCl3): δ 1.47−1.87 (m, 10H),
2.35 (s, 3H), 2.64−2.67 (m, H), 7.20 (d, 2H, J = 8.1 Hz), 7.46 (d, 2H,
J = 8.1 Hz). 13C NMR (75.48 MHz, CDCl3): δ 12.5, 17.8, 21.2, 24.8,
29.3, 50.6, 95.8, 105.5, 106.5, 126.7, 129.2, 130.0, 139.8. Anal. Calcd
C15H18O4: C, 68.68; H, 6.92. Found: C, 68.55; H, 6.81. HRMS (ESI):
m/z [M + Na]+ calcd for [C15H18NaO4]+ 285.1097; found 285.1096.
3-(4-Chlorophenyl)-6,7a-dimethylhexahydro-3,6-epoxy-
[1,2]dioxolo[3,4-b]pyran, 2o. White crystals. Mp = 104−105 °C. Rf
1
= 0.29 (TLC, PE/EA, 5:1). H NMR (300.13 MHz, CDCl3): δ 1.55
(s, 3H), 1.61 (s, 3H), 1.70−1.84 (m, 4H), 2.61−2.65 (m, H), 7.36 (d,
2H, J = 8.8 Hz), 7.52 (d, 2H, J = 8.8 Hz). 13C NMR (75.48 MHz,
CDCl3): δ 12.4, 17.7, 24.8, 29.3, 50.7, 95.9, 105.5, 106.1, 128.3, 128.8,
131.7, 135.6. Anal. Calcd C14H15ClO4: C, 59.48; H, 5.35; Cl, 12.54.
Found: C, 59.47; H, 5.24; Cl, 12.55. HRMS (ESI): m/z [M + K]+
calcd for [C14H15ClKO4]+ 321.0290; found 321.0290.
H2SO4-Catalyzed Reaction of Acetophenone 3 with Hydro-
gen Peroxide (Scheme 2). A 37% aqueous H2O2 solution (0.345 g,
3.75 mmol H2O2) and a solution of H2SO4 (1.0 g, 10 mmol) in EtOH
(1 mL) were added with stirring to a solution of acetophenone 3 (0.30
g, 2.5 mmol) in EtOH (4 mL) at 10−15 °C. The reaction mixture was
stirred at 20−25 °C for 1 h, and a mixture of CH2Cl2/PE = 2:1 (20
mL) was added. Then NaHCO3 was added to the reaction mixture
with stirring until the pH reached 7.0. The precipitate was filtered off.
The filtrate was dried over Na2SO4, the precipitate was filtered off, and
3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]dioxolo-
[3,4-b]pyran-3a-yl)propanoic Acid, 7. White crystals. Mp = 146−
147 °C. Rf = 0.70 (TLC, methanol). 1H NMR (300.13 MHz, CDCl3):
δ 1.39 (s, 3H), 1.47 (s, 6H), 1.67−1.72 (m, 4H), 1.76−1.86 (m, 2H),
2.53−2.64 (M, 2H), 9.16 (br. s, H). 13C NMR (75.48 MHz, CDCl3): δ
15.7, 20.1, 24.6, 26.3, 29.2, 30.7, 50.2, 94.2, 106.8, 179.1. Anal. Calcd
C12H18O6: C, 55.81; H, 7.02. Found: C, 55.77; H, 6.90. HRMS (ESI):
m/z [M + K]+ calcd for [C12H18KO6]+ 297.0735; found 297.0734.
Synthesis of 4-[3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-
epoxy[1,2]dioxolo[3,4-b]pyran-3a-yl)propanoyl]morpholine
(8) from 3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran-3a-yl)propanoic Acid (7). Triethylamine
(0.157 g, 1.55 mmol) and ethyl chloroformate (0.168 g, 1.55 mmol)
were added with stirring to a solution of 7 (0.20 g, 0.78 mmol) in dry
1840
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The Journal of Organic Chemistry
Article
CH2Cl2 (20 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h.
Then morpholine (0.203 g, 2.33 mmol) was added. The reaction
mixture was stirred at 0 °C for 1 h, CH2Cl2 (20 mL) was added, and
the mixture was washed with water (10 mL), a 5% aqueous H2SO4
solution (2 × 10 mL), a 5% aqueous NaHCO3 solution (2 × 10 mL),
and water (1 × 10 mL). The organic layer was dried over Na2SO4 and
filtered. The solvent was removed in a water jet vacuum. Product 8
was isolated by chromatography on SiO2 using a PE/EA mixture as the
eluent with a gradient of ethyl acetate from 40 to 80 vol %. Product 8
(0.193 g, 0.59 mmol), yield 76%.
4-[3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]dioxolo-
[3,4-b]pyran-3a-yl)propanoyl]morpholine, 8. White crystals. Mp
= 117−118 °C. Rf = 0.37 (TLC, EA). 1H NMR (300.13 MHz,
CDCl3): δ 1.39 (s, 3H), 1.44 (s, 6H), 1.67−1.71 (m, 4H), 1.79−1.87
(m, 2H), 2.47−2.55 (m, 2H), 3.38−3.72 (m, 8H). 13C NMR (75.48
MHz, CDCl3): δ 15.6, 21.3, 24.6, 27.1, 27.4, 30.8, 42.0, 45.6, 50.4,
66.6, 66.8, 94.2, 106.7, 177.2. Anal. Calcd C16H25NO6: C, 58.70; H,
7.70; N, 4.28. Found: C, 58.71; H, 7.85; N, 4.29. HRMS (ESI): m/z
[M + K]+ calcd for [C16H25KNO6]+ 366.1313; found 366.1314.
Synthesis of N-(1-Adamantyl)-3-(3,6,7a-trimethyldihydro-
3H,4H-3,6-epoxy[1,2]dioxolo[3,4-b]pyran-3a-yl)propanamide
(9) from 3-(3,6,7a-Trimethyldihydro-3H,4H-3,6-epoxy[1,2]-
dioxolo[3,4-b]pyran-3a-yl)propanoic Acid (7). Triethylamine
(0.390 g, 3.85 mmol) and ethyl chloroformate (0.168 g, 1.55 mmol)
were added with stirring to a solution of 7 (0.20 g, 0.78 mmol) in
anhydrous CH2Cl2 (20 mL) at 0 °C. The reaction mixture was stirred
at 0 °C for 1 h, and then 1-adamantanamine hydrochloride (0.434 g,
2.31 mmol) was added. The mixture was stirred at 0 °C for 1 h. The
isolation was performed as described in the synthesis of 8. Product 9
(0.27 g, 0.69 mmol), yield 89%.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of β,δ-triketones 1; 1H and 13C NMR
spectra and mass spectra of tricycles 2, 7−9; and details of X-
ray data for 2b and 2l. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +7 (499) 1356428. Fax: +7 (499) 1355328. E-mail:
terentev@ioc.ac.ru.
ACKNOWLEDGMENTS
■
This work is supported by the Program for Support of Leading
Scientific Schools of the Russian Federation (Grant NSh
4659.2012.3), the Grant of the Russian Foundation for Basic
Research (Grant 11-03-00857-a), and the Ministry of education
and science of the Russian Federation (Grant 16.513.11.3108).
REFERENCES
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General Procedures for the Determination of Stability
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filtered. The solvent was removed in a water jet vacuum. According to
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