A facile and efficient Bi(III) catalyzed synthesis of 1,1-dihydroperoxides and 1,2,4,5-tetraoxanes

Article abstract of DOI:10.1016/j.tetlet.2012.07.001

Bismuth triflate is a remarkably efficient and mild catalyst for the synthesis of both 1,1-dihydroperoxides and 1,2,4,5-tetraoxanes. The successful application of this methodology for the synthesis of both symmetrical and unsymmetrical tetraoxanes is demonstrated.

Full text of DOI:10.1016/j.tetlet.2012.07.001

Tetrahedron Letters 53 (2012) 4880–4884
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A facile and efficient Bi(III) catalyzed synthesis of 1,1-dihydroperoxides and
1,2,4,5-tetraoxanes q
⇑
Koneni V. Sashidhara , Srinivasa Rao Avula, L. Ravithej Singh, Gopala Reddy Palnati
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Bismuth triflate is a remarkably efficient and mild catalyst for the synthesis of both 1,1-dihydroperoxides
and 1,2,4,5-tetraoxanes. The successful application of this methodology for the synthesis of both sym-
metrical and unsymmetrical tetraoxanes is demonstrated.
Received 8 May 2012
Revised 29 June 2012
Accepted 1 July 2012
Available online 7 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Dihydroperoxides
Tetraoxanes
Bi(III) catalyst
The discovery of artemisinin as the active principle of the Chi-
nese traditional drug Artemisia annua is a major step forward in
malaria chemotherapy. However, because of a limited availability
(natural plant sources),1 high cost,2 and poor bioavailability,3 there
is still a need for simple and efficient anti-malarial therapeutics.
Structure activity relationship studies conducted on artemisinin
and its semi-synthetic derivatives revealed that peroxide linkage
is the most crucial pharmacophore for its anti-malarial activity
(Fig. 1).4 Recently, several synthetic tetraoxane analogues have
been synthesized by incorporating this key peroxide bridge and
they have shown significant anti-malarial activity.5 However, the
diversity oriented synthesis of tetraoxanes through simple and
convenient way is still a challenging task.
reaction times, use of toxic and expensive metal catalysts, and are
usually associated with moderate yields. Therefore, convenient and
efficient protocols for the synthesis of gem-dihydroperoxides are
still needed.
As part of our enduring efforts on the development of useful
synthetic methodologies15 and to explore the catalytic activity of
environmentally friendly catalysts, we had the opportunity to look
into the use of bismuth compounds16 (which are low toxic, readily
available, and easy to handle) for the synthesis of dihydroperox-
ides. Most of Bi(III) compounds have proven their utility as catalyst
for a variety of chemical reactions.17
Initially, we investigated the hydroperoxidation of cyclohexa-
none with 30% aq H2O2 in the presence of Bi(NO3)3Á5H2O in aceto-
nitrile. Much to our delight, Bi(NO3)3Á5H2O was found to catalyze
the reaction. Encouraged by these results, a set of experiments
were performed using cyclohexanone as the starting material to
optimize the reaction conditions for the synthesis of dihydroperox-
ides, by taking into account various Bi(III) catalysts and solvents
(Table 1). Bismuth triflate was found to be the best catalyst among
the four Bi(III) catalysts used. Subsequently, the effect of catalyst
loading was investigated and we observed that 5 mol % was found
to be effective (Table 1). The effect of solvents was also investi-
gated, among the lot; CH3CN/CH2Cl2 (1:1) was found to be the best
solvent system at room temperature (Table 1). During the optimi-
zation process we carried out reactions with different equivalents
(2, 3, 4, and 5) of H2O2, however maximum yields were observed
at 4 equiv of H2O2 so all further reactions were carried out with
4 equiv of H2O2. With these standard protocols in hand, we conse-
quently set out to study the extent and limitation of this transfor-
mation in various types of carbonyl compounds.
On the other hand, 1,1-dihydroperoxides, have occupied size-
able significance in both synthetic and medicinal chemistry. These
are important building blocks in the various classes of peroxides
including tetraoxanes6 and are also useful in oxidation reactions,7
in the generation of singlet oxygen.8 In general, gem-dihydroperox-
ides can be synthesized by ozonolysis of ketone enol ethers or a-
9
olefins in the presence of H2O2 and also by the Brønsted or Lewis
acid mediated condensation of carbonyl compounds with hydro-
gen peroxide.10 Moreover, I2,11 Re2O7,12 PMA,13 and CAN14 were
also used as catalysts for these transformations. However, most
of these methods suffer from some noteworthy limitations such
as use of high concentration of H2O2, the need for excess acid, long
q
Part XI in the series, ‘Studies on novel synthetic methodologies’.
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2628493.
E-mail
addresses:
kv_sashidhara@cdri.res.in,
sashidhar123@gmail.com
(K.V. Sashidhara).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.001

K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 4880–4884
4881
(with 29% yield) because of the tendency of intermediate perhy-
drate to suffer from heterolytic fragmentation.12,20
Interestingly, during these studies, it was observed that bis-
muth triflate assisted the condensation of gem-dihydroperoxide
with unreacted carbonyl compounds to form tetraoxanes, when
the reaction mixtures were allowed to proceed for prolonged time.
To optimize the reaction conditions for the formation of 1,2,4,5-
tetraoxanes, initially we proceeded with the isolated dihydroper-
oxides of 4-methyl cyclohexanone and condensed with cyclohexa-
none in the presence of various Bi(III) salts and triflic acid as
catalysts (Table 3).
In all the cases, of the catalysts and solvent systems studied,
again bismuth triflate (5 mol %) in CH3CN/CH2Cl2 (1:1) was found
to be the optimum catalyst for the formation of tetraoxanes. Thus,
bismuth triflate was used as catalyst for the synthesis of symmet-
rical as well as unsymmetrical 1,2,4,5-tetraoxanes in good yields21
and the results are summarized in Table 4. All the compounds were
characterized using 1H NMR, 13C NMR, and 2D NMR. The purity of
these compounds was ascertained by TLC and spectral analysis.
Symmetric tetraoxanes were easily formed in good yields as
compared to unsymmetric tetraoxanes. The reaction conditions
worked well for the condensation of 1,1-dihydroperoxides of aro-
matic aldehydes including those bearing an electron-withdrawing
group (Cl) with cyclic as well as acyclic aliphatic ketones in good
yields.
We were also interested to verify the one-pot approach for the
synthesis of 1,2,4,5-tetraoxanes. Thus after the addition of
0.05 equiv of bismuth triflate to the solution of ketone (1.0 equiv)
and 30% aq H2O2 (4 equiv) in CH3CN/CH2Cl2 (1:1), the reaction
was monitored for complete consumption of the ketone (by TLC),
followed by addition of second ketone to this reaction mixture,
we observed the formation of 1,2,4,5-tetraoxane in very low yields
with relatively longer reaction time, as compared to the two-pot
method where hydroperoxides are first isolated and then con-
densed with second ketone.
Figure 1. Peroxy linkage containing natural and synthetic anti-malarial agents.
A variety of cyclic ketones, including 1-adamantanone, afforded
the desired gem-dihydroperoxides in very satisfactory yields18 and
in a short reaction time (10–30 min). Except for the use of iodine
and rhenium heptaoxide catalyst, the synthesis of gem-dihydroper-
oxide from acyclic ketones is difficult, whereas, with the use of bis-
muth triflate, acyclic ketones gave excellent yields within a few
minutes of reaction time. In some cases, we observed traces of
bishydroperoxyperoxide dimer along with gem-dihydroperoxides.
Since Bi(OTf)3 in aqueous solution is acidic,19 it may be possible
that the true catalyst is triflic acid which was released from the
hydrolysis of Bi(OTf)3. So we carried out reaction with triflic acid
and observed the formation of dihydroperoxides. However, it was
not efficient compared to Bi(OTf)3 in terms of both yield and time
(Table 1). Also, triflic acid is a corrosive liquid which makes it dif-
ficult to handle even in small amount.
Hydroperoxidation of aromatic aldehyde is quite complicated
by using the existing methodologies but in our case the reaction
was completed within 4–5 h up to 60% yield (Table 2). In the case
of aromatic ketones the reaction was found to be slow as expected
In general, the direct methods for the synthesis of symmetrical
1,2,4,5-tetraoxane involve the reaction of carbonyls with acidic
hydrogen peroxide,22 ozonolysis of O-alkyl oximes23 and enol
ether.24 While, the synthesis of unsymmetrical tetraoxanes
Table 1
Optimization of reaction conditions for Bi(III) salts and triflic acid catalyzed hydroperoxidation of cyclohexanone with 30% aq H2O2
O
HOO
OOH
catalyst / 30% aq. H2O2
solvent, r.t
2b
1b
Entry
Catalyst
Solvent
Catalyst loading (equiv)
H2O2 (equiv)
Time (min)
Yielda (%)
1
2
3
4
5
Bi(NO3)3Á5H2O
BiCl3
Bi(OTf)3
Bi5O(OH)9(NO3)4
Bi(OTf)3
CH3CN
CH3CN
CH3CN
CH3CN
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
4.0
4.0
4.0
4.0
4.0
5.0
3.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
60
60
35
>90
18
21
40
65
30
40
>120
>120
>60
17
25
65
71
69
73
65
78
72
35
23
62
59
—
CH3CN/CH2Cl2 (1:1)
6
7
8
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
TfOH
CH2Cl2
CHCl3
DMF
DMSO
1,4-Dioxane
CH3CN/CH2Cl2 (1:1)
CH3CN/CH2Cl2 (1:1)
CH3CN/CH2Cl2 (1:1)
9
—
10
11
12
13
53
80
57
38
0.025
0.05
a
Isolated yields.

4882
K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 4880–4884
Table 2
Application to the synthesis of cyclic, acyclic and aromatic 1,1-dihydroperoxides
Bi(OTf)3 (0.05 equiv)
carbonyl
1,1-Dihydroperoxides
compounds
30% aq.H2O2 (4.0 equiv)
CH3CN/CH2Cl2(1:1), r.t
(2a-2n)
(1a-1n)
Entry
1
Ketone
1,1-Dihydroperoxide
Time (h)
0.50
Yield (%)
79
O
HOO OOH
(2a)
(2b)
(1a)
(1b)
O
O
HOO OOH
HOO OOH
2
3
0.30
0.40
78
81
(2c)
(2d)
(1c)
(1d)
O
OOH
OOH
HOO
4
5
1.0
82
94
O
OOH
0.50
(2e)
(2f)
(1e)
(1f)
(1g)
HOO OOH
HOO OOH
HOO OOH
O
O
O
6
7
0.20
0.25
89
87
(2g)
8
0.20
85
(2h)
(2i)
(1h)
(1i)
HOO OOH
HOO OOH
HOO OOH
O
9
10
11
0.20
0.20
0.20
82
91
89
O
(2j)
(1j)
(1k)
O
(2k)
CHO
HOO
HOO
OOH
OOH
12
4.0
60
(1l)
(2l)
CHO
Cl
13
14
5.0
54
(1m)
(2m)
Cl
HOO
O
OOH
24.0
29a
(2n)
(1n)
a
More yield (48%) observed with bismuth nitrate pentahydrate compared to bismuth triflate.
involves the condensation of 1,1-dihydroperoxides with ketones/
aldehyde, catalyzed by H2SO4,25 Re2O7,26 BF3ÁOEt2,27 and TMSOTf.28
Excluding rhenium heptaoxide (however, their cost and moisture
sensitive nature of these catalyst often restricts their utilization),
all the other methods suffer from several drawbacks including
low yield and longer reaction times. Recently PMA (Phosphomo-

K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 4880–4884
4883
Table 3
Comparison of Bi(III) salts and triflic acid as catalysts for the synthesis of 1,2,4,5-tetraoxanes
O
OOH
HOO
catalyst (0.05 equiv)
O
O
O
O
+
CH3CN /CH2Cl2(1:1), r.t
1b
2c
8
Entry
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
Bi(NO3)3Á5H2O
BiCl3
Bi(OTf)3
Bi5O(OH)9(NO3)4
TfOH
60
90
15
>120
>90
51
32
61
Traces
27
Table 4
Application to the synthesis of symmetrical and unsymmetrical 1,2,4,5-tetraoxanes
Bi(OTf)3 (0.05 equiv)
Carbonyl
tetraoxanes (3-16)
(ketone, di-OOH, %, time)
+di-OOH
CH3CN/CH2Cl2(1:1) , rt
O O
O O
O O
O O
O
O
O
O
O O
O O
4
(1c, 2c, 75%, 12 min)
3 (1b, 2b, 72%, 15 min)
6 (1e, 2a, 57%, 30 min)
5
(1h, 2k, 59%, 10 min)
O
O
O O
O
O
O O
O
O
O
O
O
O
O O
8 (1b, 2c, 61%, 15 min)
7
9 (1e, 2c, 54%, 10 min)
(1e, 2b, 57%, 35 min)
10
(1f, 2c, 62%, 10 min)
O O
O O
O
O
O O
O O
O O
12 (1a, 2l, 72%, 30 min)
O O
O
O
O O
13 (1b, 2l, 69%, 30 min)
14
(1c, 2l, 69%, 30 min)
11 (1h, 2l, 65%, 30 min)
O O
Cl
Cl
O O
O O
16
15
(1c, 2m, 69%, 10 min)
(1b, 2m, 70%, 10 min)
lybdic acid) was also used as catalyst for these condensations,29
but this was not useful for the condensation of aliphatic acyclic ke-
tones with 1,1-dihydroperoxides. Our method appears of general
value, since methods reported in literature work just for certain
compounds, while Bi(OTf)3 reacted also with a variety of substrates
with or with no activated substituents.
for technical support, SAIF for NMR, IR, Mass spectral data. ASR,
LRS, GRP are thankful to the CSIR, New Delhi, for financial support.
This is CSIR-CDRI communication number 8274.
Supplementary data
In conclusion, we have developed a facile, highly efficient, and
common protocol for the synthesis of both 1,1-dihydroperoxides
and 1,2,4,5-tetraoxanes using Bi(OTf)3 catalyst. This method is
highly diversified in terms of its applicability to synthesize both
symmetrical and unsymmetrical tetraoxanes in quantitative yields.
Furthermore, the green chemistry eco-friendly approach and use of
cheaper catalyst make this method an attractive tool in the design-
ing of new functionalized tetraoxane chemotypes for their opti-
mum utilization in malaria chemotherapy.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 07.001.
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[5.2.5.2]hexadecane (3):
To a solution of 1,1-dihydroperoxycyclohexane (2b), (148 mg, 1 mmol) and
cyclohexanone (98 mg, 1 mmol) in 10 mL of CH3CN/CH2Cl2 (1:1), Bi(OTf)3
(5 mol %) was added and solution was stirred at room temperature, after
completion of reaction (monitored by TLC), the reaction mixture was
concentrated under reduced pressure and extracted with diethyl ether. The
organic layer was washed with water, dried over anhydrous Na2SO4 and the
solvent was removed under reduced pressure to obtain the crude product
which was further purified by using silica column chromatography (DCM/
hexane, (2:98)) to provide compounds (3) in good yields. White solid; yield:
72%; 1H NMR (CDCl3, 300 MHz) d: 2.27 (s, 3H), 1.59–1.57 (m, 11H), 1.46 (s, 5H),
1.24 (s, 1H); 13C NMR (CDCl3, 75 MHz) d: 108.2, 31.9, 29.8, 25.5, 22.1.
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18. Representative
procedure
for
synthesis
of
1,1-dihydroperoxy-4-
28. Jefford, C. W.; Jaber, A.; Boukouvalas, J. Synthesis 1988, 5, 391–393.
29. Yan, X.; Chen, J.; Zhu, Y.-T.; Qiao, C. Synlett 2011, 2827–2830.
methylcyclohexane (2c): To a solution of 4-methylcyclohexanone (112 mg,
1 mmol) and 30% aq H2O2 (136 mg, 4 mmol) in 10 mL of CH3CN/CH2Cl2 (1:1),