New preparation of 1,2,4,5-tetraoxanes

Article abstract of DOI:10.1055/s-2004-831171

A convenient procedure was developed for the synthesis of 1,2,4,5-tetraoxanes based on the reaction of gem-bishydroper-oxycycloalkanes with ketals and acetals catalyzed by boron trifluoride etherate, which makes it possible to prepare the target products

Full text of DOI:10.1055/s-2004-831171

2
356
PAPER
New Preparation of 1,2,4,5-Tetraoxanes
a
a
b
b
a
a
N
A
ew
P
reparation
o
.
f
1, 2,4,5-Tet
O
raoxanes . Terent’ev, A. V. Kutkin, Z. A. Starikova, M. Yu. Antipin, Yu. N. Ogibin,* G. I. Nikishin
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 ul. Vavilova, 119991 Moscow, Russian
Federation
Fax +7(095)1355328; E-mail: ogibin@ioc.ac.ru
Received 3 June 2004
and O-ether oximes5,12,29 (Scheme 1). A number of other
Abstract: A convenient procedure was developed for the synthesis
of 1,2,4,5-tetraoxanes based on the reaction of gem-bishydroper-
oxycycloalkanes with ketals and acetals catalyzed by boron trifluo-
methods were also used for the synthesis of these com-
pounds.2
7,30–32
Only three preparative routes to unsymmet-
ride etherate, which makes it possible to prepare the target products rical tetraoxanes are known. These routes are based on
in yields from 13 to 93%.
catalytic cyclocondensation of ketones and aldehyde with
steroidal gem-bishydroperoxides (H SO as the cata-
Key words: tetraoxanes, heterocycles, peroxides, acetals, boron
2
4
11
lyst), aliphatic and alicyclic gem-dihydroperoxides (the
33
MeRhO –HBF system as the catalyst), and gem-bis(tri-
3
4
methylsilyldioxy)alkanes (TMSOTf as the catalyst) pre-
pared by treatment of bishydroperoxides with N,O-
bis(trimethylsilyl)acetamide (BSA).6
In the last 15 years, cyclic peroxides have attracted con-
siderable attention of chemists and pharmacologists be-
cause of their high antimalarial, antiproliferative, and
a
antimycobacterial activities, and the synthesis and phar- We developed a new convenient and simpler approach to
macological activities of this type of compounds, in par- tetraoxanes, which allows one to prepare these com-
ticular, of 1,2,4,5-tetraoxanes, have been subjects of pounds (in most cases, in higher yields) with the use of
1
–17
extensive research.
To date, more than 150 symmetrical and unsymmetrical
,2,4,5-tetraoxanes have been synthesized. Most symmet-
rical tetraoxanes were prepared by acid-catalyzed cyclo-
more readily accessible and inexpensive starting com-
pounds (Scheme 2). This approach is based on the reac-
tions of gem-bishydroperoxides with aldehyde or ketone
acetals catalyzed by boron trifluoride etherate.
1
condensation of hydrogen peroxide with ketones and We studied the cyclocondensation of cycloalkylidene
3
,7,13–15,18–25
benzaldehydes;
methylsilyl) peroxide with carbonyl compounds promot- ethyl acetals 2, aliphatic and alkylaromatic aldehydes and
ed by trimethylsilyl
trifluoromethanesulfonate ketones 3, and adamantanone dimethyl acetal 4. The main
ozonolysis of olefins,22,26 enol ethers,27,28 results of this investigation are given in Table 1.
TMSOTf);
cyclocondensation of bis(tri- bishydroperoxides 1 with cycloalkanone dimethyl and di-
2
,6b,11
(
Scheme 1
Scheme 2
SYNTHESIS 2004, No. 14, pp 2356–2366
x
x.
x
x
.
2
0
0
4
Advanced online publication: 19.08.2004
DOI: 10.1055/s-2004-831171; Art ID: P05504SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
New Preparation of 1,2,4,5-Tetraoxanes
2357
a
Table 1 BF ·OEt Catalyzed Cyclocondensation of Cycloalkylidene Bishydroperoxides 1– and Acetals 2–4
3
2
Procedureb Tetraoxanes, yield (%)
c
Ratiod
Entry Acetal
Solvent
BF ·OEt
t
3
2
(
equiv)
(min)
Cyclohexylidene-1,1-bishydroperoxide (1a)
1
Et O
0.3
40
A
4.3
2
2
a
5a, 52
5
b, 12
2
3
Et O
0.4
0.3
40
45
A
B
5b, 68
–
2
2
2
b
c
Et O
2.5
2
5c, 50
5
b, 20
4
5
Et O
0.3
0.3
50
60
B
A
3.1
2
2
d
5
5
d, 50
b, 16
Et O
–
2
2
2e
e
5e, 90
5e, 80
6
7
CH Cl
0.3
0.4
10
60
C
A
–
2
2
5
b, 3
n-C H CH(OMe)
Et O
2.8
8
17
2
2
3
a
6
5
a, 52
b, 18
8
9
PhCH(OMe)2
Et O
1.4
0.3
50
45
A
C
1.1
2.0
2
3
b
6
5
b, 22
b, 20
Et O
2
3
3
c
c
6c, 49
b, 24
6c, 35
b, 28
5
1
1
1
0
1
2
Et O
0.3
0.3
0.3
20
10
60
C
D
D
1.25
7.0
2
5
3c
3c
CH Cl
6c, 63
b, 9
2
2
5
CH Cl
6c, 20
b, 34
0.6
2
2
5
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

2
358
A. O. Terent’ev et al.
PAPER
a
Table 1 BF ·OEt Catalyzed Cyclocondensation of Cycloalkylidene Bishydroperoxides 1– and Acetals 2–4 (continued)
3
2
c
Ratiod
7.4
Entry Acetal
Solvent
BF ·OEt
t
Procedureb Tetraoxanes, yield (%)
3
2
(
equiv)
(min)
1
3
Et O
0.3
50
A
2
3
d
6
5
d, 67
b, 9
1
1
1
1
1
1
4
5
6
7
8
9
3d
3d
3d
3d
3d
CH Cl
0.3
0.3
0.3
0.3
0.3
1.4
10
60
60
60
60
60
C
C
D
A
B
A
6d, 77
b, 6
12.8
5.9
5.7
4.7
4.9
2.2
2
2
5
Et O
6d, 77
b, 10
2
5
Et O
6d, 74
b, 9
2
5
Et O
6d, 66
b, 14
2
5
Et O
6d, 64
2
5
b, 13
Et O
2
3
e
6
5
e, 35
b, 16
2
0
CH Cl
0.3
0.3
20
C
1
2
2
7
5
a, 29
b, 30
4
Cycloheptylidene-1,1-bishydroperoxide (1b)
2
1
Et O
50
A
4.1
2
2
f
8a, 49
9
, 12
2
2
2
3
PhCH(OMe)2
Et O
1.3
0.3
50
50
A
B
3
2
3
b
8
9
b, 30
, 10
Me CHCH C(OMe) Me
Et O
6.1
2
2
2
2
3
c
8
9
c, 61
, 10
2
2
4
5
3c
3c
CH Cl
0.03
0.03
20
60
C
C
8c, 51
, 8
6.4
5.3
2
2
9
Et O
8c, 48
, 9
2
9
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

PAPER
New Preparation of 1,2,4,5-Tetraoxanes
2359
a
Table 1 BF ·OEt Catalyzed Cyclocondensation of Cycloalkylidene Bishydroperoxides 1– and Acetals 2–4 (continued)
3
2
c
Ratiod
Entry Acetal
Solvent
CH Cl
BF ·OEt
t
Procedureb Tetraoxanes, yield (%)
3
2
(
equiv)
(min)
2
2
6
7
3c (80 mmol)
3c (10 mmol)
0.2
20
20
D
D
8c, 80
, 10
8
2
2
9
CH Cl
0.2
8c, 55
5.5
2
2
9
, 10
Cyclooctalidene-1,1-bishydroperoxide (1c)
2
8
Et O
0.3
60
B
5.9
2
2
a
1
1
0a, 46
1, 8
2
3
9
0
Me CHCH C(OMe) Me
Et O
0.3
0.3
60
60
A
C
5.7
3.2
2
2
2
2
3
c
1
1
0b, 40
1, 7
Et O
2
4
Cyclododecylidene-1,1-bishydroperoxide (1d)
7b, 32
1
1, 10
3
1
Et O
0.3
55
A
13
2
2
a
1
1
2a, 39
2e, 3
3
2
Et O
0.1
60
A
–
2
2
b
5e, 78
5e, 92
3
3
3
3
4
5
2b
2b
2b
Et O
0.3
0.5
0.3
60
60
10
B
A
D
–
–
2
Et O
5e, 93
5e, 89
2
CH Cl
22
2
2
1
2e, 4
3
6
2b
Et O
0.3
60
D
5e, 77
9.6
2
1
2e, 8
3
3
7
8
2b (0.9 mmol)
2b (15 mmol)
Et O
0.3
0.3
60
60
A
A
5e, 80
5e, 93
–
–
2
Et O
2
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

2
360
A. O. Terent’ev et al.
PAPER
a
Table 1 BF ·OEt Catalyzed Cyclocondensation of Cycloalkylidene Bishydroperoxides 1– and Acetals 2–4 (continued)
3
2
c
Ratiod
–
Entry Acetal
Solvent
BF ·OEt
t
Procedureb Tetraoxanes, yield (%)
3
2
(
equiv)
(min)
3
4
9
0
Et O
0.3
60
60
C
2
2
c
12c, 90
Et O
0.3
C
–
2
2
2
d
e
12d, 70
12e, 46
4
4
1
2
Et O
0.3
0.3
60
60
A
D
–
2
Et O
23
2
2
2
f
12f, 46
1
2e, 2
4
4
3
4
Et O
0.4
0.4
60
60
A
A
17.5
2.3
2
g
1
1
2g, 35
2e, 2
Et O
2
2
h
12h, 13
1
2e, 6
4
4
5
6
n-C8H CH(OMe)
Et O
0.3
1.3
60
60
A
A
11
1
17
2
2
3
a
1
1
3a, 44
2e, 4
Et O
2
3
e
1
1
3b, 41
2e, 19
Adamantylidene-1,1-bishydroperoxide (1e)
4
7
Et O
0.3
20
C
–
2
2
b
7
a, 61
a
b
c
In all experiments, temperature 20–25 °C, excluding entry 12 (0 °C).
The procedures A, B, C and D are described in the experimental part.
All yields were calculated on bishydroperoxides.
d
Ratio of unsymmetrical tetraoxanes to symmetrical ones.
Cyclocondensation was performed in diethyl ether or 3 min (at 0 °C, for ca. 20 min) and using of a 1.1-fold ex-
dichloromethane at 20–25 °C by adding either a solution cess of acetal and 0.03–1.4 equiv of the catalyst. Under
of acetal to a solution of bishydroperoxide and BF ·.OEt2 these conditions, bishydroperoxides underwent complete
3
(
methods A and B) or a solution of bishydroperoxide to a conversion (TLC control) within 10–60 min after comple-
solution of acetal and BF ·OEt (methods C and D) for 2– tion of the addition. Cross-cyclocondensation of bishy-
3
2
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

PAPER
New Preparation of 1,2,4,5-Tetraoxanes
2361
droperoxides with acetals afforded unsymmetrical for 12c and 12e are listed in Table 2. Of the tetraoxanes
,2,4,5-tetraoxanes. In all experiments with six-, seven-, synthesized, 23 have not been described earlier. Tetraox-
and eight-membered cycloalkylidene bishydroperoxides anes 5–13 are rather stable, do not decompose at room
a–c and in some experiments with dodecylidene bishy- temperature, and do not detonate in the course of purifica-
1
1
droperoxide (1d), this reaction was accompanied by com- tion and analysis. These compounds form stable complex-
petitive homocyclocondensation of bishydroperoxides es with boron trifluoride.
giving rise to symmetrical tetraoxanes. The total yield of
tetraoxanes varied from 19% in the reaction of 1d with 2-
nonylcyclododecanone acetal (entry 44) to 90–93% in the
reactions of bishydroperoxides 1b and 1d with acetals 3c
and 2b (entries 26 and 35, respectively). The ratio be-
tween unsymmetrical and symmetrical tetraoxanes varied
from 1:1 in the reaction of 1a with adamantanone acetal
(
entry 20) to 23:1 in the reaction of 1d with 2-methylcy-
clohexanone acetal (entry 42). The exceptions were the
reaction of bishydroperoxide 1a with cyclododecanone
acetal (entry 5) and the reactions of bishydroperoxide 1d
with acetals 2b–e. In these cases, only cross-cycloconden-
sation of bishydroperoxide and acetal occurred (entries
3
2–34 and 37–41). The use of a higher (eight-fold) excess
of acetal with respect to bishydroperoxide in the reaction
of cycloheptylidene bishydroperoxide with methyl isobu-
tyl ketone acetal led to an increase in the ratio between un-
symmetrical and symmetrical tetraoxanes 8c and 9 from
5
.5:1 to 8:1 (entries 27 and 26, respectively). The addition
of bishydroperoxide to acetal for 20 min resulted in a de-
crease in the yield of tetraoxanes due to partial acetal tar-
ring, as evidenced by the brown color of the reaction
mixture (cf. entries 8 and 9). In dichloromethane, cross-
cyclocondensation of bishydroperoxides and ketals pro-
ceeds more rapidly and more selectively than that in dieth-
yl ether (cf. entries 14 and 15, 24 and 25, 35 and 36). In
the absence of BF ·OEt , neither homocyclocondensation
Figure 1 Molecular structures of tetraoxanes 12c and 12
Previously, only symmetrical tetraoxanes with six-, sev-
34a
34b
en-, and eight-membered spiro rings (5b, 9,
and
34c
1
1, respectively) have been studied by X-ray diffraction
3
2
analysis, whereas the three-dimensional structures of un-
symmetrical tetraoxanes remained unknown. The confor-
mation and geometric parameters of the symmetrical
molecule with two 12-membered spiro rings (12) are sim-
ilar to those observed in other symmetrical molecules,
whereas the chair-like conformation of the heterocycle in
the unsymmetrical molecule with seven- and twelve-
membered spiro rings (12c) is distorted (the torsion angles
about the O–O bonds differ by 4º).
of bishydroperoxides nor their cross-cyclocondensation
with acetals occurs. The optimum amount of the catalyst
with respect to acetal is 0.3 equiv. Unsymmetrical tetraox-
anes are much more difficult to prepare by the reactions of
bishydroperoxides with benzaldehyde acetal (entries 8
and 22) or acetophenone acetal (entries 19 and 46), and
these reactions require the use of 1.3–1.4 equiv of
BF ·OEt . In the reactions with 0.3 equiv of the etherate,
3
2
the formation of aryl-substituted tetraoxanes was not ob-
served. The fact that homocyclocondensation and cross-
cyclocondensation are catalyzed by BF ·OEt provides
To summarize, we have developed a new practical and
convenient approach to symmetrical and unsymmetrical
3
2
1
,2,4,5-tetraoxanes using cycloalkylidene bishydroperox-
evidence that the catalyst activates both bishydroperox-
ides and acetals likely as the results of the formation of bo-
ron trifluoride complexes with these substrates.
Investigation aimed at confirming the involvement of bo-
ron trifluoride complexes with acetals and bishydroperox-
ides in the formation of 1,2,4,5-tetraoxanes, as well as a
study of boron trifluoride complexes with 1,2,4,5-tetraox-
anes are currently underway.
ides as the starting reagents in their BF ·OEt -catalyzed
3
2
cross-cyclocondensation with acetals. The reaction pro-
ceeds under mild conditions and makes a significant con-
tribution to the available methods for the preparation of
1
,2,4,5-tetraoxanes.
The NMR spectra were recorded on Bruker WM-250 (250.13 MHz
1
13
for H) and Bruker AM-300 (75.4 MHz for C) spectrometers in
The structures of tetraoxanes 5–13 (among which 6a,d,e,
CDCl . X-ray diffraction study of 12c and 12 was carried out on au-
3
8
c, 10b, and 13b were prepared as oils and all other com-
tomated diffractometers. The complete crystallographic data were
deposited with the Cambridge Crystallographic Data Centre [regis-
tration numbers CCDC 239946 (12c), 239947 (12e)]. The TLC
pounds were prepared as white powders) were determined
1
13
by H and C NMR spectroscopy. The molecular struc-
tures of 12c and 12e were established by X-ray diffraction analysis was carried out using Silufol UV-254 chromatographic
analysis (Figure 1). Crystal data and structure refinement plates. Flash chromatography was performed with the use of silica
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

2
362
A. O. Terent’ev et al.
PAPER
Table 2 Crystal Data and Structure Refinement for 12c and 12e
Compound
formula
12c
12e
C H O
C H O
4
19
34
4
24 44
mol. wt
326.46
396.59
crystal colour, habit
crystal size (mm)
crystal system
space group
cell constants
a (Å)
colorless prism
0.50 × 0.45 × 0.30
monoclinic
colorless plate
0.40 × 0.25 × 0.15
triclinic
P2 /n
P–1
1
5.964(3)
5.620(4)
b (Å)
16.728(6)
6.983(4)
c (Å)
14.928(6)
14.420(9)
a (deg)
90
85.43(1)
b (deg)
93.010(7)
88.71(1)
g (deg)
90
84.42(1)
V (Å3)
1886(2)
561.4(6)
Z
4
1
–
3
Dcalcd (g cm )
Diffractometer
Temp (K)
1.150
1.173
CAD4 Enraf-Nonius
Bruker SMART 1000 CCD
120
295
Radiation
MoKa (l = 0.71073)
MoKa (l = 0.71073)
Scan mode
q-5/3q
2
qmax (deg)
50
50
–
1
abs. coeff., m(MoKa) (cm )
Absorption correction
Tmax and Tmin
0.78
0.77
none
difabs
–
0.928 and 0.181
Structure solution
Refinement method
No. reflections collect
No. Independent reflections
No. observed reflections [I > 2s(I)]
No. of parameters
R1, wR2
direct method
direct method
full-matrix least-squares on F2
full-matrix least-squares on F2
3721
2577
3291 (Rint = 0.0221)
1503 (Rint = 0.0544)
1093
1002
208
127
0.0577, 0.1378
720
0.0628, 0.1401
220
F(000)
GOOF
0.966
0.988
–
3
Largest diff. peak and hole (eÅ )
0.375 and –0.208
0.194 and –0.202
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

PAPER
New Preparation of 1,2,4,5-Tetraoxanes
2363
gel L 40/100 m. Melting points were determined on a Kofler hot
plate.
Anal. Calcd for C H O : C, 61.66; H, 8.47. Found: C, 61.79; H,
8.50.
1
1
18
4
BF ·OEt was purchased from Acros. Bishydroperoxides were pre-
3
2
3
5,36
7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecane (5b)
pared according to a procedure described in the studies.
The
2
4
Mp 129–130 °C (CHCl ) (Lit. 131–132 °C); R = 0.85 (TLC,
3
f
starting acetals were synthesized by acetalization of the correspond-
ing carbonyl compounds.
Et O–petroleum ether, 1:4).
2
1
H NMR: d = 1.11–1.57 (m, 12 H, CH ), 2.36 (m, 8 H, CH ).
2
2
1
,1-Dimethoxynonane (3a)
13
C NMR: d = 22.8, 25.3, 30.5, 108.1.
Bp 87–88 °C (20 Torr).
1
H NMR: d = 0.86 (t, J = 6.6 Hz, 3 H, CH ), 1.20–1.38 (m, 12 H,
7,8,16,17-Tetraoxadispiro[5.2.6.2]heptadecane (5c)
Mp 68–70 °C (CHCl ); R = 0.78 (TLC, Et O–petroleum ether, 1:4).
3
CH ), 1.53–1.62 (m, 2 H, CH ), 3.29 (s, 6 H, OCH ), 4.33 (t, J = 5.9
2
2
3
3
f
2
Hz, 1 H, CH).
1
H NMR: d = 1.09–2.00 (m, 22 H, CH2).
1
3
C NMR: d = 22.0, 22.5, 25.4, 30.0, 30.7, 32.9, 107.6, 112.8.
5
,5-Dimethoxynonane (3d)
Bp 68–69 °C (20 Torr).
Anal. Calcd for C H O : C, 64.44; H, 9.15. Found: C, 64.70; H,
9.10.
1
3
22
4
1
H NMR: d = 0.87 (t, J = 6.6 Hz, 6 H, CH ,), 1.12–1.35 (m, 8 H,
2
3
CH ), 1.48–1.58 (m, 4 H, CH ), 3.10 (s, 6 H, CH ).
2
3
7
,8,17,18-Tetraoxadispiro[5.2.7.2]octadecane (5d)
1
3
C NMR: d = 13.9 (CH ), 22.9, 25.7, 32.1 (CH ), 47.5 (OCH ),
3
2
3
Mp 89–92 °C (CHCl ); R = 0.78 (TLC, Et O–petroleum ether, 1:4).
3
f
2
1
03.3 (C).
1
H NMR: d = 1.11–1.89 (m, 24 H, CH2).
Synthesis of Tetraoxanes 5–13; General Procedures
Procedure A
13
C NMR: d = 22.0, 24.5, 25.1, 25.3, 27.0, 29.7, 30.0, 104.2, 110.6.
Anal. Calcd for C H O : C, 65.60; H, 9.44. Found: C, 65.30; H,
1
4
24
4
A solution of acetal (10 mmol) in CH Cl or Et O (40 mL) was add-
2
2
2
9
.50.
ed to a stirred solution of bishydroperoxide (9 mmol) and BF ·OEt
3
2
(
0.1–1.4 equiv with respect to peroxide) in CH Cl or Et O (50 mL)
2 2 2
7
,8,21,22-Tetraoxadispiro[5.2.11.2]docosane (5)
at r.t. for ca. 2 min. The reaction mixture was stirred until the con-
version of bishydroperoxide was completed (10–60 min, TLC con-
trol) and then aq K CO (50 mL, 2 equiv) was added. The resulting
two-phase system was stirred for 30–60 min and the organic phase
was separated. The aq phase was extracted with CH Cl or Et O (3
×
(
[
Mp 103–104 °C (CHCl ); R = 0.75 (TLC, Et O–petroleum ether,
1
3
f
2
:4).
2
3
1
H NMR: d = 1.21–1.90 (m, 32 H, CH
).
C NMR: d = 19.3, 21.8, 22.0, 22.7, 25.3, 25.5, 25.8, 26.0, 31.7,
06.1, 113.4.
Anal. Calcd for C H O : C, 69.19; H, 10.32. Found: C, 68.98; H,
2
13
2
2
2
10 mL). The extracts were combined with the organic phase, dried
1
MgSO ), and concentrated. Column chromatography of the residue
4
gradient elution with a mixture of petroleum ether (bp 40–70 °C)
18 32
4
1
0.25.
and Et O with increasing concentration of the latter from 15% to
2
6
0%] afforded tetraoxanes 5–13 and other reaction products. Ana-
3
-Octyl-1,2,4,5-tetraoxaspiro[5.5]undecane (6a)
lytical samples of tetraoxanes were prepared by evacuation (0.1
Torr) at ca. 20 °C for 3–4 h.
Oil; R = 0.77 (TLC, Et O–petroleum ether, 1:4).
f
2
1
H NMR: d = 0.85 (t, J = 6.6 Hz, 3 H, CH ), 1.08–1.88 (m, 24 H,
3
Procedure B
CH ), 4.74 (t, J = 5.9 Hz, 1 H, CH).
2
An aq Et NH solution (20%) was added to the reaction mixture ob-
2
13
C NMR: d = 11.4, 22.6, 22.7, 24.9, 25.5, 28.6, 29.3, 29.4, 29.5,
0.4, 33.5, 107.8, 109.5.
tained according to procedure A until it reached pH 8–8.5. Then the
reaction mixture was stirred for 10–20 min. The aq and organic
phases were separated. The aqueous layer was extracted with petro-
leum ether (bp 40–70 °C) (2 × 15 mL). The extracts were combined
with the organic phase and worked up as described in procedure A.
3
Anal. Calcd for C15
10.29.
H O : C, 66.14; H, 10.36. Found: C, 66.00; H,
28 4
3
-Phenyl-1,2,4,5-tetraoxaspiro[5.5]undecane (6b)
6
a
Procedure C
Mp 103–104 °C (CHCl ) (Lit. 103–104 °C); R = 0.9 (TLC, Et O–
petroleum ether, 1:4).
3
f
2
A solution of bishydroperoxide (9 mmol) in CH Cl or Et O (40
2
2
2
mL) was added at r.t. for 2 min (in entry 10, for 20 min) to a stirred
solution of acetal (10 mmol) and BF ·OEt (0.03–0.3 equiv) in
1
H NMR: d = 1.41–1.72 (m, 10 H), 6.67 (s, 1 H), 7.40–7.52 (m, 5
3
2
H).
1
CH Cl or Et O (50 mL). The reaction mixture was stirred until the
2
2
2
3
C NMR: d = 19.6, 20.0, 23.1, 27.9, 29.6, 105.6, 106.5, 125.3,
conversion of bishydroperoxide was completed (10–60 min, TLC
control) and thereafter aq K CO was added. Then the reaction mix-
1
26.4, 128.8, 129.8.
2
3
ture was worked up as described in procedure A.
3
-Isobutyl-3-methyl-1,2,4,5-tetraoxaspiro[5.5]undecane (6c)
Mp 77–79 °C (CHCl ); R = 0.8 (TLC, Et O–petroleum ether, 1:4).
Procedure D
3
f
2
1
An aq Et NH solution (20%) was added to the reaction mixture ob-
H NMR: d = 0.96 (d, J = 6.6 Hz, 6 H, CH ), 1.32–1.91 (m, 16 H,
2
3
tained according to the procedure C until it reached pH 8–8.5. Then
the reaction mixture was worked up as described in the procedure B.
CH, CH , CH ).
2 3
1
3
C NMR: d = 18.1, 22.5, 22.7, 25.2, 25.5, 29.8, 31.6, 31.7, 106.1,
1
09.2.
6
,7,14,15-Tetraoxadispiro[4.2.5.2]pentadecane (5a)
Mp 95–97 °C (CHCl ); R = 0.80 (TLC, Et O–petroleum ether, 1:4).
Anal. Calcd for C12H O : C, 62.58; H, 9.63. Found: C, 62.40; H,
22 4
3
f
2
9
.51.
1
1
H NMR: d = 1.31–1.80 (m, 18 H, CH2).
3
C NMR: d = 22.6, 24.5, 25.5, 30.6, 33.4, 107.9, 118.8.
3,3-Dibutyl-1,2,4,5-tetraoxaspiro[5.5]undecane (6d)
Oil; R = 0.9 (TLC, Et O–petroleum ether, 1:4).
f
2
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

2
364
A. O. Terent’ev et al.
PAPER
1
1
H NMR: d = 0.81–0.95 (t, J = 6.6 Hz, 6 H, CH ), 1.26–1.90 (m, 22
H NMR: d = 1.22–2.29 (m, 24 H, CH2).
3
H, CH2).
1
13
C NMR: d = 22.8, 30.1, 32.8, 112.8.
3
C NMR: d = 13.7, 22.3, 22.6, 23.5, 25.4, 26.0, 30.6, 107.4, 110.4.
Anal. Calcd for C H O : C, 66.14; H, 10.36. Found: C, 65.99; H,
6
,7,16,17-Tetraoxadispiro[4.2.7.2]heptadecane (10a)
1
5
28
4
Mp 45–47 °C (CHCl ); R = 0.8 (TLC; Et O–petroleum ether, 1:4).
1
3
f
2
1
0.40.
H NMR: d = 1.20–1.85 (m, 22 H, CH2).
3
-Methyl-3-phenyl-1,2,4,5-tetraoxaspiro[5.5]undecane (6e)
13
C NMR: d = 24.6, 25.1, 28.1, 29.7, 33.2, 33.5, 106.6, 119.2.
Oil; R = 0.9 (TLC, Et O–petroleum ether, 1:3).
1
f
2
Anal. Calcd for C H O : C, 64.44; H, 9.15. Found: C, 64.70; H,
9
14 24
4
H NMR: d = 1.26–1.98 (m, 13 H, CH , CH ), 7.31–7.49 (m, 3 H,
2
3
.20.
CH), 7.54–7.68 (m, 2 H, CH).
1
3
C NMR: d = 22.2, 25.3, 25.5, 30.6, 108.0, 115.2, 127.9, 128.2,
3-Isobutyl-3-methyl-1,2,4,5-tetraoxaspiro[5.7]tridecane (10b)
1
29.4, 133.0.
Oil; R = 0.9 (TLC, Et O–petroleum ether, 1:4).
f
2
1
Anal. Calcd for C H O : C, 67.18; H, 7.25. Found: C, 66.93; H,
H NMR: d = 0.96 (d, J = 6.6 Hz, 6 H, CH ), 1.20–1.91 (m, 20 H,
3
14
18
4
7
.18.
CH, CH , CH ).
2 3
1
3
C NMR: d = 18.9, 22.0, 24.0, 24.6, 25.0, 26.7, 28.0, 28.1, 29.7,
3
-(1,1¢-Adamant-2-yl)-1,2,4,5-tetraoxaspiro[5.5]undecane (7a)
1
09.3, 111.7.
Mp 67–69 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether, 1:4).
3
f
2
Anal. Calcd for C H O : C, 65.09; H, 10.14. Found: C, 65.22; H,
1
14 26
4
H NMR: d = 1.21–2.48 (m, 22 H, CH, CH2).
1
0.17.
1
3
C NMR: d = 22.7, 25.0, 27.4, 29.7, 30.9, 36.2, 37.0, 37.3, 104.3,
1
07.9.
9,10,19,20-Tetraoxadispiro[7.2.7.2]eicosane (11)
1
5
Mp 100–102 °C (Lit. 98 °C); R = 0.9 (TLC, Et O–petroleum
f
2
Anal. Calcd for C H O : C, 68.54; H, 8.63. Found: C, 68.38; H,
8
16
24
4
ether, 1:2).
.50.
1
H NMR: d = 1.45–1.61 (m, 8 H, C–CH ), 1.79–1.83 (m, 20 H,
2
3
-(1,1¢-Adamant-2-yl)-1,2,4,5-tetraoxaspiro[5.7]tridecane (7b)
CH2).
Mp 85–87 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether, 1:3).
1
13
3
f
2
C NMR: d = 21.9, 25.8, 27.4, 28.0, 115.3.
H NMR: d = 1.16–2.25 (m, 28 H, CH, CH2).
Anal. Calcd for C H O : C, 67.57; H, 9.92. Found: C, 67.85; H,
1
6
28
4
1
3
C NMR: d = 22.7, 25.0, 27.4, 27.9, 28.9, 29.4, 29.7, 30.9, 33.5,
10.00.
3
7.3, 103.1, 104.0.
6
,7,20,21-Tetraoxadispiro[4.2.11.2]henicosane (12a)
Anal. Calcd for C H O : C, 70.10; H, 9.15. Found: C, 70.01; H,
18
28
4
Mp 57–59 °C (CHCl ); R = 0.82 (TLC, Et O–petroleum ether, 1:4).
3
f
2
9
.22.
1
H NMR: d = 1.08–1.73 (m, 30 H, CH2).
1
-Methyl-7,8,16,17-tetraoxadispiro[5.2.6.2]heptadecane (8a)
13
C NMR: d = 19.1, 22.2, 22.4, 24.6, 24.7, 25.1, 25.3, 33.2, 112.0,
18.9.
Mp 40–42 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether, 1:2).
3
f
2
1
1
H NMR: d = 0.75–2.00 (m, 24 H, CH, CH , CH ).
2
3
Anal. Calcd for C H O : C, 68.42; H, 10.13. Found: C, 68.32; H,
10.08.
1
7
30
4
1
3
C NMR: d = 22.1, 22.4, 22.6, 22.7, 29.8, 30.0, 31.7, 32.5, 32.8,
1
07.3, 112.5.
8
,9,22,23-Tetraoxadispiro[6.2.11.2]tricosane (12c)
Anal. Calcd for C H O : C, 65.60; H, 9.44. Found: C, 65.81; H,
14
24
4
Mp 68–72 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether, 1:4).
3
f
2
9
.40.
1
H NMR: d = 1.19–1.75 (m, 34 H, CH2).
3
-Phenyl-1,2,4,5-tetraoxaspiro[5.6]dodecane (8b)
13
C NMR: d = 19.3, 21.9, 22.2, 22.5, 24.6, 25.9, 26.4, 29.1, 30.0,
11.5, 112.6.
Mp 30–33 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether, 1:4).
3
f
2
1
1
H NMR: d = 1.33–1.89 (m, 12 H, CH ), 6.56 (s, 1 H, CH), 6.80–
2
Anal. Calcd for C H O : C, 69.90; H, 10.50. Found: C, 69.72; H,
1
1
9
34
4
6
.93 (m, 3 H, CH), 7.28–7.40 (m, 2 H, CH).
0.38.
1
3
C NMR: d = 22.6, 29.5, 32.5, 107.3, 113.8, 128.1, 129.0, 129.2,
1
31.5.
9,10,23,24-Tetraoxadispiro[7.2.11.2]tetracosane (12d)
Mp 148–151 °C (CHCl ); R = 0.9 (TLC, Et O–petroleum ether,
3
f
2
Anal. Calcd for C H O : C, 67.18; H, 7.25. Found: C, 66.98; H,
14
18
4
1
:4).
7
.50.
1
H NMR: d = 1.30–1.64 (m, 36 H, CH2).
3
-Isobutyl-3-methyl-1,2,4,5-tetraoxaspiro[5.6]dodecane (8c)
13
C NMR: d = 18.1, 19.4, 21.7, 22.2, 22.6, 24.3, 24.7, 25.5, 27.4,
9.7, 105.1, 112.6.
Oil; R = 0.92 (TLC, Et O–petroleum ether, 1:4).
f
2
2
1
H NMR: d = 0.96 (d, J = 6.6 Hz, 6 H, CH ), 1.32–1.91 (m, 18 H,
3
Anal. Calcd for C H O : C, 70.55; H, 10.66. Found: C, 70.43; H,
2
0
36
4
CH, CH , CH ).
2
3
1
0.58.
1
3
C NMR: d = 18.9, 22.6, 22.8, 24.1, 29.9, 30.1, 32.8, 32.9, 109.4,
1
12.7.
13,14,27,28-Tetraoxadispiro[11.2.11.2]octacosane (12)
1
5
Mp 200–201 °C (CHCl ) (Lit. 201 °C); R = 0.9 (TLC, Et O–pe-
3
f
2
Anal. Calcd for C H O : C, 63.91; H, 9.90. Found: C, 63.82; H,
13
24
4
troleum ether, 1:4).
9
.92.
1
H NMR: d = 1.18–1.93 (m, 44 H, CH2).
8
,9,17,18-Tetraoxadispiro[6.2.6.2]hexadecane (9)
13
C NMR: d = 22.0, 22.2, 23.0, 25.4, 26.0, 30.4, 108.1.
1
5
Mp 100–101 °C (CHCl ) (Lit. 103 °C); R = 0.85 (TLC, Et O–pe-
3
f
2
troleum ether, 1:4).
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

PAPER
New Preparation of 1,2,4,5-Tetraoxanes
2365
1
-Methyl-7,8,21,22-tetraoxadispiro[5.2.11.2]docosane (12f)
(3) (a) Vennerstrom, J. L.; Fu, H.-N.; Ellis, W. Y.; Ager, A. L.;
Wood, J. K.; Andersen, S. L.; Gerena, L.; Milhous, W. K. J.
Med. Chem. 1992, 35, 3023. (b) Dong, Y.; Matile, H.;
Chollet, J.; Kaminsky, R.; Wood, J. K.; Vennerstrom, J. L. J.
Med. Chem. 1999, 42, 1477.
Mp 105–106 °C (CHCl ); R = 0.85 (TLC, Et O–petroleum ether,
1
3
f
2
:2).
1
H NMR: d = 0.75–1.82 (m, 34 H, CH, CH , CH ).
2
3
1
3
C NMR: d = 19.3, 21.8, 22.0, 22.6, 24.2, 24.6, 24.7, 26.1, 26.3,
9.2, 30.9, 31.9, 108.0, 111.5.
(
4) Todovovic, N. M.; Stefanovic, M.; Tinant, B.; Declercq, J.-
P.; Makler, M. T.; Solaja, B. A. Steroids 1996, 61, 688.
5) Dong, Y.; Vennerstrom, J. L. J. Org. Chem. 1998, 63, 8582.
6) (a) Kim, H.-S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.;
Ushigoe, Y.; Masuyama, A.; Nojima, M.; McCullough, K. J.
Chem. Soc., Perkin Trans. 1 1999, 1867. (b) Kim, H.-S.;
Shibata, Y.; Wataya, Y.; Tsuchiya, K.; Masuyama, A.;
Nojima, M. J. Med. Chem. 1999, 42, 2604.
2
(
(
Anal. Calcd for C H O : C, 69.90; H, 10.50. Found: C, 70.73; H,
1
1
9
34
4
0.58.
1
3,14,28,29-Tetraoxadispiro[11.2.12.2]nonacosane (12g)
Mp 202–204 °C (CHCl ); R = 0.85 (TLC, Et O–petroleum ether,
1
3
f
2
:4).
(
7) Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.;
McCullough, K. J.; Kim, H.-S.; Shibata, Y.; Wataya, Y.
Tetrahedron Lett. 1999, 40, 4077.
1
H NMR: d = 1.18–1.78 (m, 46 H, CH2).
1
3
C NMR: d = 22.4, 23.8, 24.3, 24.6, 24.8, 25.3, 25.8, 25.9, 26.3,
7.2, 27.9, 31.9, 111.4, 111.9.
2
(8) (a) McCullough, K. J.; Nonami, Y.; Masuyama, A.; Nojima,
M.; Kim, H.-S.; Wataya, Y. Tetrahedron Lett. 1999, 40,
Anal. Calcd for C H O : C, 73.12; H, 11.29. Found: C, 72.93; H,
2
5
46
4
9151. (b) McCullough, K. J.; Wood, J. K.; Bhattacharjee, A.
1
1.19.
K.; Dong, Y.; Kyle, D. E.; Milhous, W. K.; Vennerstrom, J.
L. J. Med. Chem. 2000, 43, 1246.
1
-Nonyl-13,14,27,28-tetraoxadispiro[11.2.11.2]octacosane (12h)
(
9) Jefford, C. W.; Rossier, J.-C.; Milhous, W. K. Heterocycles
Mp 205 °C (CHCl ) with decomposition; R = 0.9 (TLC, Et O–pe-
3
f
2
2000, 52, 1245.
troleum ether, 1:1).
(
10) Vennerstrom, J. L.; Dong, Y.; Andersen, S. L.; Ager, A. L.;
Fu, H.-N. Jr.; Miller, R. E.; Wesche, D. L.; Kyle, D. L.;
Gerena, L.; Walters, S. M.; Wood, J. K.; Edwards, G.;
Holme, A. D.; McLean, W. G.; Milhous, W. K. J. Med.
Chem. 2000, 43, 2752.
11) Opsenica, D.; Pocsfalvi, G.; Juranic, Z.; Tinant, B.;
Declercq, J.-P.; Kule, D. E.; Milhous, W. K.; Solaj, B. A. J.
Med. Chem. 2000, 43, 3274.
1
H NMR: d = 0.84 (t, J = 6.6 Hz, 3 H, CH ), 1.14–1.78 (m, 59 H,
3
CH, CH ).
2
1
3
C NMR: d = 14.7 (CH ), 21.9–31.9 (30 C, CH, CH ), 105.0,
3
2
1
06.2.
(
Anal. Calcd for C H O : C, 75.81; H, 11.95. Found: C, 75.63; H,
3
3
62
4
1
1.80.
(
12) Dong, Y.; Vennerstrom, J. L. J. Heterocycl. Chem. 2001, 38,
3
-Octyl-1,2,4,5-tetraoxaspiro[5.11]heptadecane (13a)
463.
Mp 38–40 °C (CHCl ); R = 0.8 (TLC, Et O–petroleum ether, 1:4).
3
f
2
(
13) Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.;
Hamada, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.;
McCullough, K. J. Med. Chem. 2001, 44, 2357.
1
H NMR: d = 0.84 (t, J = 6.6 Hz, 3 H, CH ), 1.13–1.72 (m, 36 H,
3
CH ), 4.71 (t, J = 5.9 Hz, 1 H, CH).
2
1
3
(14) Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.;
C NMR: d = 14.0, 19.3, 21.8, 22.1, 22.4, 22.6, 24.1, 24.5, 24.7,
Kim, H.-S.; Ono, K.; Ogura, N.; Wataya, Y. J. Med. Chem.
2
4.8, 25.2, 26.6, 29.7, 34.0, 107.8, 113.5.
2002, 45, 1374.
Anal. Calcd for C H O : C, 70.74; H, 11.31. Found: C, 70.61; H,
1
2
1
40
4
(15) Solaj, B. A.; Terzic, N.; Pocsfalvi, G.; Genena, L.; Tinant,
1.30.
B.; Opsenica, D.; Milhous, W. K. J. Med. Chem. 2002, 45,
3
331.
3
-Methyl-3-phenyl-1,2,4,5-tetraoxaspiro[5.11]heptadecane
(
16) Kim, H.-S.; Begum, K.; Ogura, N.; Wataya, Y.; Nonami, Y.;
Ito, T.; Masuyama, A.; Nojima, M.; McCullough, K. J. J.
Med. Chem. 2003, 46, 1957.
(
13b)
Mp 95–97 °C (CHCl ); R = 0.83 (TLC, Et O–petroleum ether, 1:4).
3
f
2
1
H NMR: d = 1.21–1.84 (m, 25 H, CH , CH ), 7.33–7.45 (m, 3 H,
(17) Opsenica, D.; Angelovski, G.; Pocsfalvi, G.; Juranic, Z.;
2
3
CH), 7.52–7.59 (m, 2 H, CH).
Zisak, Z.; Kyle, D.; Milhous, W. K. Bioorg. Med. Chem.
2
003, 11, 2761.
18) (a) Sanderson, J. R.; Zeiler, A. G. Synthesis 1975, 125.
b) Sanderson, J. R.; Paul, K.; Story, P. R.; Denson, D. D.;
1
3
C NMR: d = 19.4, 21.8, 22.3, 25.9, 26.0, 26.2, 29.7, 112.3, 115.3,
(
(
1
26.1, 126.5, 128.1, 128.2.
(
Anal. Calcd for C H O : C, 71.82; H, 9.04. Found: C, 71.69; H,
9
20
30
4
Alford, J. A. Synthesis 1975, 159. (c) Sanderson, J. R.;
Zeiler, A. G.; Wilterdink, R. J. J. Org. Chem. 1975, 40,
.00.
2239. (d) Sanderson, J. R.; Wilterdink, R. J.; Zeiler, A. G.
Synthesis 1976, 479.
Acknowledgment
19) (a) Miles, N. A.; Norris, S. A.; Panagiotakos, P. C. J. Am.
Chem. Soc. 1939, 61, 2430. (b) Dilthey, W.; Inckel, M.;
Stephan, H. J. Prakt. Chem. 1940, 154. (c) Dilthey, W.;
Inckel, M.; Stephan, H. J. Prakt. Chem. 1940, 219.
This study was financially supported by the Federal Program for the
Support of Leading Scientific Schools of the Russian Federation
(
Grants No. 02121-2003-3, 01060-2003-3).
(
d) Kharash, M. S.; Sosnovsky, G. J. Org. Chem. 1958, 23,
322.
(20) Schulz, M.; Kirscke, K.; Höhne, E. Chem. Ber. 1967, 100,
242.
21) (a) Ledaal, T. Acta Chem. Scand. 1967, 21, 1656.
b) Dasnes, T.; Ledaal, T. Acta Chem. Scand. 1971, 25,
906.
22) Brune, H. A.; Wulz, K.; Hetz, W. Tetrahedron 1971, 27,
629.
1
References
2
(
1) (a) Magelli, O. L.; Shepard, C. S. In Organic Peroxides;
Swern, D., Ed.; Wiley: New York, 1972, 1. (b) Jefford, C.
W. Adv. Drug Res. 1997, 29, 271. (c) McCullough, K. J.;
Nojima, M. Curr. Org. Chem. 2000, 5, 583. (d) Dong, Y.
Mini-Reviews in Med. Chem. 2002, 2, 113.
(
(
(
1
3
(
2) Jefford, C. W.; Boukouvalas, A. J. J. Synthesis 1988, 391.
Synthesis 2004, No. 14, 2356–2366 © Thieme Stuttgart · New York

2
366
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