New preparation of 1,2,4,5,7,8-hexaoxonanes

Article abstract of DOI:10.1021/jo071072c

(Chemical Equation Presented) A new versatile procedure was developed for the synthesis of 1,2,4,5,7,8-hexaoxonanes based on the Lewis acid catalyzed reaction of acetals with 1,1′-dihydroperoxydicycloalkyl peroxides. The procedure substantially extends the structural diversity of these compounds and, in most cases, allows the synthesis of these compounds in higher yields (to 96%) and with higher selectivity. Complexation of hexaoxonane with chloroform was documented for the first time. The structures of several triperoxides were established by X-ray diffraction.

Full text of DOI:10.1021/jo071072c

New Preparation of 1,2,4,5,7,8-Hexaoxonanes
Alexander O. Terent’ev,*,† Maxim M. Platonov,† Eduard J. Sonneveld,‡ Rene Peschar,‡
Vladimir V. Chernyshev,§,| Zoya A. Starikova, and Gennady I. Nikishin†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russian Federation, Laboratory for Crystallography, Van’t Hoff Institute for Molecular
Sciences, UniVersity of Amsterdam, Valckenierstrasse 65, Amsterdam 1018 XE, The Netherlands,
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, and A. N. NesmeyanoV Institute of Organoelement Compounds, Russian Academy of
Sciences, 28 ul. VaViloVa, 119991 Moscow, Russian Federation
terenteV@ioc.ac.ru
ReceiVed May 21, 2007
A new versatile procedure was developed for the synthesis of 1,2,4,5,7,8-hexaoxonanes based on the
Lewis acid catalyzed reaction of acetals with 1,1′-dihydroperoxydicycloalkyl peroxides. The procedure
substantially extends the structural diversity of these compounds and, in most cases, allows the synthesis
of these compounds in higher yields (to 96%) and with higher selectivity. Complexation of hexaoxonane
with chloroform was documented for the first time. The structures of several triperoxides were established
by X-ray diffraction.
Introduction
of interest to design antimalarial drugs. A number of studies5
were concerned with the properties of these cyclic peroxides
and methods of their analysis. Of particular interest is triper-
oxide-based explosives. For example, triacetone triperoxide is
one of the most sensitive explosives known, with power close
to trinitrotoluene.5a,b
Hexaoxonanes can be synthesized according to the following
three main methods: acid-catalyzed reactions of ketones with
hydrogen peroxide,6 ozonolysis of unsaturated compounds,7 and
condensation of 1,1′-dihydroperoxydicycloalkyl peroxides with
ketones.1e,8 The drawbacks of the first two methods are low
selectivity and difficulties in preparing hexaoxonanes containing
bulky substituents. The drawbacks of the third method are
moderate yields of the reaction products and a narrow range of
ketones suitable for condensation with 1,1′-dihydroperoxydi-
cycloalkyl peroxides. These compounds are limited to reactive
ketones, to which hydroperoxide groups are readily added. The
Triperoxides, 1,2,4,5,7,8-hexaoxonanes, have found applica-
tion in the synthesis of macrocyclic ketones and lactones
produced by thermolysis (Story reaction).1 Hexaoxonanes were
used in the synthesis of unsymmetrical tetraoxanes2 and as
polymerization initiators.3 Data on high antimalarial activity of
related peroxide compounds4 suggest that hexaoxonanes can be
† N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences.
‡ University of Amsterdam.
§ Moscow State University.
| A. N. Frumkin Institute of Physical Chemistry and Electrochemistry.
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences.
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Paul, K.; Story, P. R.; Denson, D. D.; Alford, J. A. Synthesis 1975, 159-
161. (c) Sanderson, J. R.; Paul, K.; Story, P. R. Synthesis 1975, 275-276.
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695. (e) Busch, P.; Story, P. B. Synthesis 1970, 181-183. (f) Starostin, E.
K.; Alexandrov, A. V.; Ignatenko, A. V.; Nikishin, G. I. Bull. Acad. Sci.
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10.1021/jo071072c CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/22/2007
J. Org. Chem. 2007, 72, 7237-7243
7237

Terent’ev et al.
SCHEME 1. General Scheme of the Synthesis of Hexaoxonanes 3-6
SCHEME 2. Synthesis of Peroxide 6f
syntheses of hexaoxonanes from less reactive ketones, which
are generally solids with high molecular weight, were documen-
ted,8c,d but these syntheses produced hexaoxonanes in lower
yields (10-42%).8d
study, which is a continuation of our ongoing research into
chemistry of geminal peroxide compounds,9 we developed a
new method for the synthesis of 1,2,4,5,7,8-hexaoxonanes
(3-6) based on the acid-catalyzed reaction of acetals (1) with
1,1′-dihydroperoxydicycloalkyl peroxides (2) in diethyl ether
or tetrahydrofuran (Scheme 1).
Results and Discussion
The advantage of the method is that it is not limited by the
reactivity of ketones, allows the use of nearly equimolar amounts
of reagents (acetals and peroxides), and, in most cases, gives
1,2,4,5,7,8-hexaoxonanes in high yield (80-96%).
Synthesis of Hexaoxonanes by Reaction of Acetals with
1,1′-Dihydroperoxydicycloalkyl Peroxides. In the present
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7238 J. Org. Chem., Vol. 72, No. 19, 2007

New Preparation of 1,2,4,5,7,8-Hexaoxonanes
TABLE 1. Optimization of the Conditions of the Synthesis of
Hexaoxonane 6fa
dihydroperoxide 2d. However, it should be noted that, in the
case of SnCl4, the preparative isolation of the reaction product
in pure form presents difficulties because of complications
associated with removal of the catalyst residues. Because of
low solubility of peroxide 6f in organic solvents, it is impossible
to use a convenient method of its purification from inorganic
impurities by filtration through SiO2; upon recrystallization,
SnCl4 residues are poorly removed. The rise of the temperature
from 20-25 °C (entries 4, 6, and 9) to 55-60 °C (entries 5,
7, and 10) leads to a decrease in the yield of the target peroxide
by 7-12%, but the reaction time is shortened. The reactions
with the use of Lewis acids TiCl4, AlCl3, or AlBr3 (entries 14-
16) or protic acids H2SO4 or TsOH‚H2O (entries 17-18) as
the catalyst produce peroxide 6f in lower yield.
mole of catalyst reaction conversion
yield
entry
catalyst
per mole of 2d
time, h
of 2d, %
of 6f, %
1b
2b
3b
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
BF3‚Et2O
SnCl4
H2SO4
0.5
0.5
0.5
0.05
0.05
0.2
0.2
0.5
0.6
0.6
0.6
0.2
0.5
0.5
0.5
0.5
0.5
0.5
15
15
16
38
15
18
6
6
5
2
20
1.5
1
9
3
10
7
23
10
15
5
60
100
90
100
100
100
100
100
100
100
90
6
9
1-2
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
SnCl4
SnCl4
TiCl4
AlCl3
AlBr3
44
37c
72
60c
84d
94
88c
88e
86
96
29
64
20
27
14
For the purpose of examining the scope of the procedure for
the synthesis of hexaoxonanes according to Scheme 1, we tested
a broad range of acetals containing a linear fragment, 1a and
1b, or a cyclic fragment, 1c-h, in condensation with 1,1′-
dihydroperoxydicycloalkyl peroxides 2a-d, which differ in the
ring size (C5, C6, C7, and C12; Table 2).
100
100
95
H2SO4
TsOH‚H2O
50
a Reaction conditions: a catalyst (0.05-0.6 mol of catalyst per mole of
2d) in THF or Et2O (0.5 mL) was added to a mixture of dihydroperoxide
2d (0.465 mmol, 0.2 g) and acetal 1f (0.604 mmol, 0.104 g) in THF or
Et2O (2 mL), and the reaction mixture was stirred at 20-25 °C; in entries
5, 7, and 10, at 55-60 °C. b The reaction with cyclooctanone. c The reaction
temperature was 55-60 °C. d The synthesis was scaled with increasing
amounts of the reagents by a factor of 10. e Et2O was used as the solvent.
We used diethyl ether as the solvent for peroxides 2a-c with
a ring size C5-C7, because these compounds are readily soluble
in this solvent; for dicyclododecyl peroxide 2d, we used THF.
The amount of the BF3‚Et2O catalyst was 0.2-0.5 mol per mole
of peroxide 2. The complete conversion of peroxides 2 was
achieved in a period of time from 3 to 8 h.
The best yields of hexaoxonanes were achieved in the
reactions of dihydroperoxides 2 with acetals 1a,b containing
the sterically unhindered reaction center; lower yields were
obtained for the reactions with acetals 1f and 1g, which were
prepared from cyclooctanone and cyclododecanone, respectively.
In the reactions of dihydroperoxides 2a and 2c with the same
acetals, the yields of hexaoxonanes were lower than those in
the reactions with dihydroperoxides 2b and 2d.
We performed condensation of 1,1′-dihydroperoxydicy-
clododecyl peroxide (2d) with 1,1-dimethoxycyclooctane (1f)
and studied the influence of the nature and the amount of the
catalyst, the nature of the solvent, and the reaction time on the
conversion of 2d and the yield of hexaoxonane 6f (Scheme 2,
Table 1). For comparison, Table 1 includes the results of the
reaction of cyclooctanone with peroxide 2d (entries 1-3).
The reactions were performed in two temperature modes, at
20-25 and 55-60 °C, by mixing reagents 1f and 2d in
tetrahydrofuran or diethyl ether in the presence of 0.05-0.6
mol of a catalyst per mole of 2d.
The longest time (6-8 h) for the complete conversion of
dihydroperoxides 2 was observed in the synthesis of hexaoxo-
nanes 6 from 1,1′-dihydroperoxydicyclododecyl peroxide 2d;
the reactions with dihydroperoxides 2a were completed in
shorter time (within 3-4 h).
Intermediate Formation in the Reaction of Acetal 1g with
Peroxide 2b. When performing the reaction of 1g and 2b for a
period of time insufficient for the complete conversion of
dihydroperoxide 2b, we succeeded in isolating the intermediate,
methoxyhydroperoxyperoxide 7, in 14% yield (Scheme 3).
We chose peroxide 6f for optimization, taking into account
that the synthesis of analogous peroxides from poorly active
cycloalkanones with a ring size >6 presents difficulties (earlier,
6f had been synthesized in 42% yield8d).
As can be seen from Table 1, peroxide 6f was generated from
dihydroperoxide 2d and cyclooctanone in THF in very low yield
(1-9%), which confirms that this reaction with ketones is
inefficient. The use of acetal instead of ketone in the acid-
catalyzed reaction enables the formation of an electrophilic
center that is more reactive with respect to the addition of the
hydroperoxide group. Subsequent syntheses of 6f were per-
formed with the use of acetal 1f in the presence of Lewis acids
BF3‚Et2O, SnCl4, TiCl4, AlCl3, or AlBr3 (entries 4-16), or protic
acids H2SO4 or TsOH‚H2O (entries 17 and 18) as the catalysts.
The best yield of peroxide 6f was obtained with BF3‚Et2O and
SnCl4 (entries 8-13) in an amount of 0.2-0.6 mol per mole of
This scheme illustrates a two-step formation of 1,2,4,5,7,8-
hexaoxonanes. At first, peroxide 7 is produced, which subse-
quently cyclizes intramolecularly into the nine-membered
cycle 4g. It is likely that peroxides 7 and 4g are being formed
with similar rates. Products of the bimolecular reaction of
peroxide 7 with the starting reagents 1g and 2b were not
obtained.
Synthesis of Hexaoxonanes by Reaction of Enol Ethers
with 1,1′-Dihydroperoxydicycloalkyl Peroxides. The reactions
of enol ethers 8d and 8g with dihydroperoxides 2b and 2d
showed that the corresponding hexaoxonanes 4d, 4g and 6d,
6g are produced in yields comparable with their yields from
acetals (Scheme 4). This approach extends the scope of the
synthesis of hexaoxonanes, because enol ethers derived, for
example, from vinyl halides or acetylenes can be used as the
starting reagents instead of acetals derived from ketones. An
attempt to synthesize hexaoxonanes from 1-trimethylsilyloxo-
(8) (a) Sanderson, J. R.; Zeiler, A. G. Synthesis 1975, 388-390. (b)
Criege, R.; Schnorrenberg, W.; Becke, J. Justus Liebigs Ann. Chem. 1949,
565, 7-21. (c) Research Corporation, Patent GB 1313372, 1970. (d) Paul,
K.; Story, P. R.; Busch, P.; Sanderson, J. R. J. Org. Chem. 1976, 41, 1283-
1285.
(9) (a) Terent’ev, A. O.; Kutkin, A. V.; Starikova, Z. A.; Antipin, M.
Yu.; Ogibin, Yu. N.; Nikishin, G. I. Synthesis 2004, 2356-2366. (b)
Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.; Ogibin, Yu. N.; Nikishin,
G. I. Tetrahedron Lett. 2003, 44, 7359-7363.
J. Org. Chem, Vol. 72, No. 19, 2007 7239

Terent’ev et al.
TABLE 2. Synthesis of Hexaoxonanes 3-6
7240 J. Org. Chem., Vol. 72, No. 19, 2007

New Preparation of 1,2,4,5,7,8-Hexaoxonanes
Table 2 (Continued)
cyclopentene (silyl enol ether) and dihydroperoxide 2b or 2d
failed, and the target triperoxides were obtained only in trace
amounts.
which the target peroxide precipitates from methanol. Method
C was used for isolation of MeOH-insoluble hexaoxonanes
6a-g (contain two C12 rings). It should be noted that hexaoxo-
nanes 6a-g are poorly soluble in THF, and major portions
precipitate during the synthesis.
Determination of 1,2,4,5,7,8-Hexaoxonane Structures. The
structures of the resulting compounds were established by NMR
spectroscopy, mass spectrometry, elemental analysis, and a
comparison of their melting points with those published in the
literature. The structures of peroxides 4d, 4h, 6a, and 6f were
additionally confirmed by X-ray diffraction.
Isolation of Hexaoxonanes. To isolate hexaoxonanes, we
used three procedures for the workup of the reaction mixture
depending on the structures of the starting dihydroperoxides and
acetals (see the Experimental Section). Method A was used for
isolation of hexaoxonanes 3a-e, 4a-e, and 5a,b,e, which were
prepared from dihydroperoxides having a medium-sized ring
and water-soluble ketone acetals. In the course of isolation,
byproducts, unconsumed acetal, and the hydrolysis product of
the latter (ketone) were washed out by water and aqueous
methanol. Method B was applied to hexaoxonanes 3g, 4f-h,
and 5f,g derived from water-insoluble ketone acetals. In essence,
method B is based on recrystallization of hexaoxonanes from
an Et2O-MeOH mixture with gradual removal of Et2O, after
As a rule, the 13C NMR spectra show two signals of different
intensity at δ: 105-120, which is typical of sp3-hybridized
carbon atoms bearing peroxide groups. The more intense signal
belongs to the quaternary carbon atoms (the residue of the
dihydroperoxide fragment).
J. Org. Chem, Vol. 72, No. 19, 2007 7241

Terent’ev et al.
SCHEME 3. Intermediate 7 in the Synthesis of Peroxide 4g
SCHEME 4. Synthesis of Hexaoxonanes with the Use of
Enol Ethers
of 1,1′-bis(hydroperoxy)dicycloalkyl peroxides with acetals
using Lewis acids as catalysts. The method substantially extends
the structural diversity of these compounds and, in most cases,
allows the synthesis of these compounds in higher yields (to
96%) and with higher selectivity. Complexation of hexaoxo-
nanes with chloroform was documented for the first time. The
structures of several triperoxides were established by X-ray
diffraction.
Experimental Section
Caution: Although we encountered no difficulties in working
with hexaoxonanes and dihydroperoxides, precautions such as the
use of shields and fume hoods, and avoidance of transition metal
salts, heating and shaking should be observed whenever possible.
6,7,13,14,21,22-Hexaoxatrispiro[4.2.48.2.515.25]docosane (3d).
1,1-Dimethoxycyclohexane 1d (0.374 g, 2.6 mmol) was added to
a solution of 1,1′-dihydroperoxydi(cyclopentyl)peroxide 2a (0.472
g, 2 mmol) in Et2O (1.5 mL). A solution of BF3‚Et2O (0.057 g, 0.4
mmol) in Et2O (0.5 mL) was added to the reaction mixture at 0-5
°C. Then the mixture was stirred at 20 °C for 4 h. Petroleum ether
(30 mL) was added to the reaction mixture. Then the mixture was
washed with a 2% NaOH solution (20 mL), water (2 × 20 mL) at
35-45 °C, and 50% aqueous methanol (3 × 20 mL) at 35-45 °C,
dried over Na2SO4, and filtered. The solvent was evaporated from
the filtrate, and analytically pure 3d (0.408 g, 13 mmol) was isolated
by column chromatography on SiO2 (petroleum ether-ethyl acetate,
20:1). Yield 65%. White crystals. Mp ) 53-55 °C (hexane) (Mp2
) 51-81 °C). Rf 0.41 (TLC, petroleum ether-ethyl acetate, 20:
Compounds 4c, 5g, 6c, 6d, and 6g were characterized by
informative mass spectra. Studies by electron impact mass
spectrometry revealed the Story reaction; the molecular ions of
macrocyclic alkanes and lactones corresponding to the molecular
formulas of cyclic triperoxides were obtained.
In the present study, it was important to perform X-ray
diffraction analysis. The fact is that the formation of diperoxides,
1,2,4,5-tetraoxanes, from peroxides 2, as well as macrocyclic
hexaperoxides from intermediate hydroperoxides (analogous to
hydroperoxide 7), which are produced according to Scheme 3,
cannot be a priori excluded in the synthesis of hexaoxonanes.
The results of X-ray diffraction experiments conclusively
confirmed the structure of 1,2,4,5,7,8-hexaoxonanes. As a result
of the single-crystal X-ray diffraction experiment for 4d grown
from CHCl3, we found the first example of complexation of
hexaoxonanes with CHCl3.
1
1). C NMR (250.13 MHz) δ: 1.45-1.88 (m, 22H), 2.11-2.32
(m, 4H). 13C NMR (50.32 MHz) δ: 22.6, 24.5, 25.4, 30.5, 33.4,
108.1, 118.8. Anal. Calcd for C16H26O6: C, 61.13; H, 8.34.
Found: C, 61.37; H, 8.58.
Compounds 6a, 6f, and 4h did not produce single crystals
suitable for the X-ray crystal structure determination and were
obtained only as crystalline powders. Therefore, their crystal
structures were determined by powder X-ray diffraction meth-
ods.10 Two polymorphic modifications were established for
compound 4h: triclinic (T) and monoclinic (M), respectively.
A similar phenomenon was observed for triacetone triperoxide
for which the existence of two conformers in the solid state
was obtained from the crystal structure.5c
7,8,15,16,29,30-Hexaoxatrispiro[5.2.5.2.11.2]triacontane (4g).
1-Methoxycyclododecene 8g (0.51 g, 2.6 mmol) was added to a
solution of 1,1′-dihydroperoxydi(cyclohexyl)peroxide 2b (0.524 g,
2 mmol) in Et2O (1.5 mL). A solution of boron trifluoride etherate
(0.142 g, 1 mmol) in diethyl ether (0.5 mL) was added to the
reaction mixture at 20-25 °C. The mixture was stirred at 20-25
°C for 6 h. Et2O (10 mL) and dry K2CO3 (0.5 g) were added to the
reaction mixture. The reaction mixture was stirred for 30 min and
filtered. The solvent was evaporated, methanol (10 mL) was added
to the residue (a sticky white precipitate was obtained), and Et2O
was added dropwise to the reaction mixture until the latter was
homogenized (∼10 mL). Then the mixture was stirred under
atmospheric pressure for 0.5 h, during which the major portion of
the ether was evaporated. The residue was cooled at 0 to -5 °C.
The crystals of 4g that precipitated were filtered off and washed
with MeOH (2 × 3 mL) at 0 °C. Analytically pure 4g (0.692 g,
16.2 mmol) was isolated by column chromatography on SiO2
(petroleum ether-ethyl acetate, 20:1). Yield 81%. Mp 57-59 °C
Conclusions
To summarize, we developed a new convenient procedure
for the synthesis of 1,2,4,5,7,8-hexaoxonanes by the reactions
(10) (a) Structure Determination from Powder Diffraction Data; David,
W. I. F., Shankland, K., McCusker, L. B., Baerlocher, C., Eds; Oxford
University Press: New York, 2002. (b) Baerlocher, C.; McCusker, L. B.
Z. Kristallogr. 2004, 219, 782. (c) Harris, K. D. M.; Cheung, E. Y. Chem.
Soc. ReV. 2004, 33, 526-538. (d) Chernyshev, V. V. Russ. Chem. Bull.
2001, 50, 2273-2292; IzV. Acad. Nauk, Ser. Khim. 2001, 2171-2190. (e)
Zhukov, S. G.; Chernyshev, V. V.; Babaev, E. V.; Sonneveld, E. J.; Schenk,
H. Z. Kristallogr. 2001, 216, 5-9.
1
(hexane). Rf 0.45 (TLC, petroleum ether-ethyl acetate, 20:1). C
NMR (250.13 MHz) δ: 1.17-1.93 (m, 42H). 13C NMR (62.9 MHz)
δ: 19.4, 22.1, 22.3, 22.8, 25.6, 26.0, 26.3, 26.8, 30.4, 107.6, 111.6.
Anal. Calcd for C24H42O6: C, 67.57; H, 9.92. Found: C, 67.31; H,
9.61.
7242 J. Org. Chem., Vol. 72, No. 19, 2007

New Preparation of 1,2,4,5,7,8-Hexaoxonanes
9,10,23,24,37,38-Hexaoxatrispiro[7.2.1111.2.1125.28]-
octatriacontane (6f). 1,1-Dimethoxycyclooctane 1f (0.447 g, 2.6
mmol) was added to a suspension of 1,1′-dihydroperoxydi-
(cyclododecyl)peroxide 2d (0.862 g, 2 mmol) in THF (8 mL). A
solution of BF3‚Et2O (0.17 g, 1.2 mmol) in THF (0.5 mL) was
added to the reaction mixture at 20 °C. Then the mixture was stirred
22.0, 22.2, 25.0, 26.0, 26.2, 26.7, 26.8, 28.1, 28.3, 111.5, 111.6.
Anal. Calcd for C32H58O6: C, 71.33; H, 10.85. Found: C, 71.57;
H, 10.46.
Acknowledgment. This work was supported by the Program
for Support of Leading Scientific Schools of the Russian
Federation (Grant NSh 5022.2006.3), the Grant of the President
of Russian Federation (No. MK-3515.2007.3), and the Russian
Science Support Foundation.
3
at 20-25 °C for 5 h. A major portion of solvent (∼ /4) was
evaporated from the reaction mixture, and cooled MeOH (15 mL)
was added. The white crystals that precipitated were filtered off
and washed with cooled MeOH (3 × 5 mL). The purity of the
compounds was ∼95%. Analytically pure 6f (1.01 g, 18.8 mmol)
was isolated by column chromatography on SiO2 (petroleum ether-
ethyl acetate, 20:1). Yield 94%. Mp ) 198-200 °C (MeOH). (Mp8d
Supporting Information Available: Experimental procedures,
1H and 13C NMR spectra, and details of X-ray data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
) 185-187 °C). Rf 0.86 (TLC, PE-EA, 20:1). H NMR (250.13
MHz) δ: 1.20-1.84 (m, 58H). 13C NMR (62.9 MHz) δ: 19.4,
JO071072C
J. Org. Chem, Vol. 72, No. 19, 2007 7243