Tin(IV) chloride promoted reaction of oxiranes with hydrogen peroxide

Article abstract of DOI:10.1055/s-0032-1318213

A group of substituted oxiranes were readily transformed to the corresponding β-hydroxyhydroperoxides (HHP) in good yields in ethereal SnCl₄-H₂O₂ system in which SnCl₄ acts as catalyst. Alternatively, treating oxiranes with SnCl₄ first, followed by addition of ethereal H₂O₂ solution achieved primary gem-dihydroperoxides (DHP) in moderate yields. In the case of preparing DHP, SnCl₄ first promoted the rearrangement of oxiranes to aldehydes, followed by condensation with hydrogen peroxide to provide DHP as final products. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318213

502▌
LETTER
letter
Tin(IV) Chloride Promoted Reaction of Oxiranes with Hydrogen Peroxide
SnCl4-Promoted Reaction of Oxiranes with H2O2
Xing Yan,a Chunhua Qiao,*a Zhongwu Guob
a
College of Pharmaceutical Science, Soochow University, 199 Ren Ai Road, Suzhou 215123, P. R. of China
Fax +86(512)65882089; E-mail: qiaochunhua@suda.edu.cn
b
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA
Received: 11.12.2012; Accepted after revision: 22.01.2013
To prepare HHP, two general approaches were reported.
Abstract: A group of substituted oxiranes were readily transformed
One is the addition of singlet oxygen to allylic alcohols,8
to the corresponding β-hydroxyhydroperoxides (HHP) in good
which was restricted to an allylic specific alcohol skele-
yields in ethereal SnCl4–H2O2 system in which SnCl4 acts as cata-
lyst. Alternatively, treating oxiranes with SnCl4 first, followed by
ton. Alternatively, the ring-opening reaction of oxiranes
addition of ethereal H2O2 solution achieved primary gem-dihydro- by H2O2 can afford a variety of substitued HHP.7b,9 This
peroxides (DHP) in moderate yields. In the case of preparing DHP,
approach can also avoid the use of the oxygen gas tank.
SnCl4 first promoted the rearrangement of oxiranes to aldehydes,
However, a high concentration of H2O2 (>50%) as reac-
followed by condensation with hydrogen peroxide to provide DHP
tant is dangerous,7b,9d,e and the lack of efficient catalysts
as final products.
limited further application of this method. A few reported
catalysts include MoO2(acac)2,7b SbCl3/SiO2,9b and phos-
Key words: SnCl4, oxirane, β-hydroxyhydroperoxide, gem-dihy-
droperoxide
phomolybdic acid (PMA).9a MoO2(acac)2 was applied to
very few substrates. SbCl3/SiO2 was mainly used for the
ring opening of substituted styrene oxides. PMA was
Synthetic endoperoxides, 1,2,4-trioxanes and 1,2,4,5-te-
widely applicable, but the low reaction yield and pro-
traoxanes, have been discovered as novel antimalarial
longed reaction time can not satisfy the general demand.
drug candidates.1 Some of these endoperoxides, for exam-
Therefore, more efficient methods for preparing HHP are
required.
ple 12 and 23 (Figure 1), display activity against Plasmo-
dium falciparum malaria comparable to that of the first-
Ketone-derived DHP (secondary DHP) were readily
line antimalarial drug artemisinin (3). Besides antimalari-
formed in high yield by the reaction of ketones or ketals
al activity, recent studies also emphasized their other im-
with H2O2 using an acidic catalyst, such as PMA,10
portant biological activities, including antitumor,4
Re2O7,11 ceric ammonium nitrate,12 I2,13 SrCl2·6H2O,14
antituberculosis,4c,5 and fasciocidal.6
and SnCl2·2H2O,15 or sometimes even without catalyst.16
Some secondary DHP could also be obtained in low to
H
moderate yield by the reaction of ketones with molecular
O
O
oxygen and anthracene under light irradiation.17
N
O
O
O
O
O
Acid-catalyzed reactions of aromatic aldehydes with
H2O2 could provide aromatic primary DHP. However, un-
der the same conditions, aliphatic aldehydes would give
α-hydroxyhydroperoxides other than the corresponding
primary DHP.13b,14–17 Recently, a general method for pre-
paring aliphatic primary DHP was reported by reactions
of aliphatic aldehydes and hydrogen peroxide employing
camphorsulfonic acid (CSA) as catalyst.18 Some draw-
backs of this method include the use of highly concentrat-
ed H2O2 (70%), a long reaction time (16–40 h), and
undesirable yield (28–77%). Alternatively, ozonolysis of
enol ethers in ethereal H2O2 solution could prepare some
type of aliphatic primary DHP,19 but the use of ozone is
troublesome and the yield is not good (33–43%) either.
Considering aliphatic primary DHP were the key interme-
diates for the preparation of some biologically important
1,2,4,5-tetraoxanes,18,19 efficient synthetic methods for
this kind of DHP are valuable.
H
O
1
O
artemisinin (3)
O
N
O
O
N
N
O
RKA182 (2)
O
Figure 1 Endoperoxides with potent antimalarial activity
β-Hydroxyhydroperoxides (HHP) and gem-dihydroper-
oxides (DHP) are important reaction intermediates for
preparing 1,2,4-trioxanes and 1,2,4,5-tetraoxanes. These
hydroperoxides were conveniently converted into the cor-
responding 1,2,4-trioxanes and 1,2,4,5-tetraoxanes
through a condensation reaction with carbonyl com-
pounds (or ketals) under acidic conditions.7
SnCl4 is a strong Lewis acid and highly soluble in organic
solvents. It interacts preferentially with hard base like ox-
ygen. It has been reported that SnCl4 was involved in
many important organic reactions by activating the C–O
bond through coordinating with oxygen atom.20 Although
SYNLETT 2013, 24, 0502–0506
Advanced online publication: 06.02.2013
DOI: 10.1055/s-0032-1318213; Art ID: ST-2012-W1040-L
© Georg Thieme Verlag Stuttgart · New York
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3
6
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1
4
1
4
3
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2
0
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LETTER
SnCl4-Promoted Reaction of Oxiranes with H2O2
503
previous research found that SnCl4 could not catalyze the 3). Besides, addition of SnCl4 and H2O2 at low tempera-
formation of HHP at ambient temperature through the ture (lower than –30 °C) favored the formation of 6a.
ring-opening reaction of oxiranes in ethereal H2O2 solu-
tion,9a our present work show that HHP could be efficient-
Table 2 Yield of DHP under Various Conditions (Method B)
ly achieved under optimized conditions. Interestingly, we
demonstrated that the same reaction system could also af-
OH OH
O
O
O
1. SnCl4, CH2Cl2
ford the aliphatic primary DHP by changing reaction con-
ditions. Herein, we report our results about preparing
HHP by direct ring opening of oxiranes and the prepara-
tion of primary DHP by a tandem rearrangement–
condensation reaction.
2. H2O2, CH2Cl2–Et2O
4a
6a
Entry
SnCl4
H2O2
Temp
Yield
(%)c
(equiv)a
(equiv)b
(°C)
To prepare the HHP, our initial investigation started from
the reaction shown in Table 1 (entry 1). HHP 5a was read-
ily formed by adding a dichloromethane solution of 4a to
a mixture of SnCl4–CH2Cl2 and H2O2–Et2O solution,
which was prepared according to a literature procedure21
(method A). Next, we optimized the SnCl4 and H2O2 ratio,
reaction temperature, and time. We discovered that at
room to ice-bath temperature, a catalytic amount (0.1
equiv) of SnCl4 could efficiently promote the conversion
of oxirane into HHP by using 5.0 equivalents of H2O2 in
an ethereal solution (Table 1, entries 6 and 7).
1
2
3
4
5
6
2.0
1.0
0.1
1.0
1.0
1.0
3.0
3.0
3.0
5.0
5.0
5.0
0
31
38
0
0
0
0
21
71
70
–30 to r.t.
–70 to r.t.
a Conditions: 1.0 mol L–1 in CH2Cl2.
b Conditions: 1.4 mol L–1 in Et2O.
c Isolated yield.
Table 1 Yield of HHP 5a under Different Conditions (Method A)
OH OH
O
SnCl4, H2O2
CH2Cl2–Et2O
O
We then tested the substrate compatibility under these two
reaction conditions. As shown in Table 3, using method
A, all selected oxiranes 4b–l with different functional
groups could afford the corresponding HHP 5b–l in mod-
erate to good yields. Compared to reactions catalyzed by
PMA,9a the SnCl4-catalyzed reaction time was substan-
tially shortened (0.2–2 h vs. 2–12 h) without yield com-
promise. Moreover, the SnCl4–H2O2 system is broadly
applicable and can tolerate some commonly used protect-
ing groups (Bn, TBS) and functional group (COOEt).
4a
5a
Entry
SnCl4
H2O2
Temp
(°C)
Time
(h)
Yield
(%)c
(equiv)a
(equiv)b
1
2
3
4
5
6
7
1.1
1.1
1.0
1.0
2.0
0.1
0.1
3.0
3.0
3.0
5.0
5.0
5.0
5.0
0
–30
0
0.5
0.5
0.5
0.5
0.5
2.5
1.0
66
64
74
79
74
80
79
In terms of reaction regioselectivity of method A, the 2,2-
disubstituted oxiranes 4b–h (Table 3, entries 1–7, method
A) underwent perhydrolysis exclusively at the quarterna-
ry carbon, which is in agreement with the PMA-catalyzed
reaction.9a But 2-monosubstituted oxiranes 4i and 4j gave
HHP with different regioselectivity (Table 3, entries 8 and
9, method A). The electron-donating butyl group at the 2-
position of 4j may function to stabilize the intermediate
carbocation, giving the main products 5j–1 with the hy-
drogen peroxide group being added at the 2-position as
the major product (5j-1/5j-2 = 10:1 by 1H NMR analysis).
This result is different from that reported by another group
for the longer alkyl chain oxirane.9b This may be due to
the different reaction catalyst employed in the two sys-
tems. Accordingly, the electron-withdrawing oxygen
atom at the β-position in oxirane 4i would lose this stabi-
lizing effect, providing 5i as the main product with the hy-
drogen peroxide group being added at the less hindered
terminal carbon, which was consistent with published re-
port.9a To verify the regiochemistry, 5i was further trans-
formed to 1,2,4-trioxane 7 (Scheme 1) after reaction with
2,2-dimethoxypropane, the 1H NMR and 13C NMR spec-
tra of the product were consistent with the data reported in
0
0
0
r.t.
a Conditions: 1.0 mol L–1 in CH2Cl2.
b Conditions: 1.4 mol L–1 in Et2O.
c Isolated yield.
Interestingly, when 4a and a stoichiometric amount of
SnCl4 (1.0 equiv) were mixed first, followed by addition
of an ethereal H2O2 solution (method B), DHP 6a was ob-
tained as product rather than the expected HHP 5a (Table
2). Subsequent optimization of the reaction conditions
disclosed that the order of addition of the reaction compo-
nents, as well as the amount of SnCl4, was crucial to the
reaction outcome. While 1.0 equivalent or more than 1.0
equivalent of SnCl4 afforded 6a as the sole product, using
a substoichiometric amount of SnCl4 (0.9 equiv) resulted
in a mixture of 5a and 6a, and a catalytic amount (0.1
equiv) of SnCl4 could not afford 6a at all (Table 2, entry
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 502–506

504
X. Yan et al.
LETTER
the literature.9a Finally, symmetric 2,3-disubstituted oxi- HHP 5l with the hydrogen peroxide group being added to
rane 4k (Table 3, entry 10, method A) gave the trans- the benzyl position in moderate yield.
isomer 5k in good yield,20 the asymmetric 4l afforded the
Table 3 Products and Yield in Two Methods21
Entry
1
Oxiranes
Products of method A, yielda
Products of method B, yieldb
OH
O
O
OH
OH
O
O
OH
4b
5b 75%
6b 47%
O
O
OH
OH
O
2
3
OH
O
OH
4c
6c 54%
5c 81%
OH
OH
O
O
OH
OH
t-Bu
4d
t-Bu
t-Bu
O
O
6d 53%
6e 33%
5d 61%
5e 74%
O
OH
OH
O
O
OH
OH
4
O
O
4e
O
O
OH
OH
OH
OH
5
6
O
4f
5f 37%
6f 74%
Bu
OH
OH
Bu
O
O
OH
OH
O
Bu
Bu
Bu
O
Bu
4g
5g 49%
6g 80%
O
O
OH
OH
O
7
8
5h 55%c
EtO
EtO
O
4h
5h 66%
OH OH
O
O
BnO
BnO
5i 61%
4i
5i 60%
OH
O
OH
5j-1 major
O
5j-1 and 5j-2
20% total
9
OH OH
O
4j
5j-2 minor
54% total
OH
O
10
5k 30%
OOH
4k
5k 67%
Synlett 2013, 24, 502–506
© Georg Thieme Verlag Stuttgart · New York

LETTER
SnCl4-Promoted Reaction of Oxiranes with H2O2
505
Table 3 Products and Yield in Two Methods21 (continued)
Entry
11
Oxiranes
Products of method A, yielda
Products of method B, yieldb
OH
O
O
OTBS
OTBS
5l 17%
OH
4l
5l 55%
a Reaction conditions: 0.2–2 h, 0 °C to r.t., SnCl4 (0.1 equiv), H2O2 (5.0 equiv).
b Reaction conditions: 30 min, –70 °C to r.t., SnCl4 (1.2 equiv), H2O2 (5.0 equiv).
c 2.0 and 3.0 equiv of SnCl4 gave similar results.
reaction could not smoothly proceed for certain substrates
using method B. Consequently, the SnCl4-promoted hy-
droperoxidation of oxiranes would provide the same reac-
tion product as method A.
MeO
OMe
BnO
O
O
BnO
O
OH OH
5i
O
PTSA, CH2Cl2, r.t., 2 h
33%
7
In brief, we have disclosed an oxirane–SnCl4–H2O2 sys-
tem which could convert oxiranes into either HHP or pri-
mary DHP in moderate to good yields by adjusting the
order of addition, reaction temperature, and the amount of
SnCl4. SnCl4 acted as an efficient catalyst in the prepara-
tion of HHP. In the case of preparing primary DHP, SnCl4
first promoted the rearrangement of oxirane to aldehyde,
then catalyzed the condensation reaction of aldehyde with
hydrogen peroxide. This is the first report that primary
DHP could be efficiently prepared from the correspond-
ing oxirane via a two-step, one-pot tandem reaction, even
though the substrate scope is currently limited.
Scheme 1 Preparation of 1,2,4-trioxane 7 from 5i
Using method B, 2,2-disubstituted oxiranes 4a–g were
transformed to the corresponding DHPs 6a–g in good
yields. This reaction outcome could be explained by a
one-pot tandem rearrangement–condensation reaction:
the oxiranes that were primarily catalyzed by SnCl4 un-
derwent a Meinwald-type rearrangement to form the alde-
hyde 8,22 followed by condensation with two molecules of
hydrogen peroxide. Using 4a as substrate, the above pro-
posed two-step reaction process was confirmed. We first
isolated the corresponding first-step reaction product, al-
dehyde 8, which was further converted into DHP by treat-
ment with hydrogen peroxide in the presence of SnCl4
(Scheme 2). Obviously, the overall yield (32%) of two
separated steps was much lower than that from a tandem
reaction (71%), demonstrated the advantage of the one-
pot reaction.
Acknowledgment
This work was supported by the Chinese National Science Founda-
tion (81072514) to Professor Chunhua Qiao at Soochow University.
Foundation from the Priority Academic Program Development
(PAPD) of Jiangsu Higher Education Institutions and funding No.
CXZZ12_0851 are also acknowledged.
O
H
O
Supporting Information for this article is available online at
SnCl4 (1.2 equiv), CH2Cl2,
–70 °C, 5 min
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
70%
4a
8
References and Notes
OH OH
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6a
Scheme 2 Formation of DHP 6a from oxirane 4a in method B via an
intermediate aldehyde 8
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 502–506

506
X. Yan et al.
LETTER
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Hydroxyhydroperoxides (Method A, Conversion of 4a
into 5a)
To the ethereal H2O2 solution (1.4 mol·L–1, 2.2 mL, 3.08
mmol, 5.0 equiv) was added SnCl4–CH2Cl2 solution (1.0
mol·L–1, 0.062 mL, 62 μmol, 0.1 equiv) in an ice-bath. The
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stirred for about 1 h till the reaction was complete (TLC).
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mL), dried over anhyd Na2SO4, and concentrated. The crude
product was purified by column chromatography on silica
gel (PE–EtOAc = 5:1) to afford 5a as a white solid (95 mg,
79% yield). Rf = 0.2 (PE–EtOAc = 3:1). 1H NMR (300 MHz,
CDCl3): δ = 9.42 (br s, 1 H), 7.31–7.09 (m, 5 H), 3.70 (d,
J = 11.9 Hz, 1 H), 3.59 (d, J = 12.0 Hz, 1 H), 3.48 (br s, 1 H),
2.78–2.54 (m, 2 H), 2.00–1.84 (m, 1 H), 1.79–1.63 (m, 1 H),
1.21 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 142.1, 128.5
(2 C), 128.4 (2 C), 125.9, 84.67, 65.7, 35.6, 29.6, 18.3. ESI-
HRMS: m/z calcd for C11H16O3Na [M + Na]+: 219.0992;
found: 219.0994.
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Representative Procedure for Preparing Primary gem-
Dihydroperoxides (Method B, Conversion of 4a into 6a)
The solution of 4a (0.1 g, 0.62 mmol, 1.0 equiv) in CH2Cl2
(2 mL) was cooled to –70 °C. SnCl4–CH2Cl2 solution (1.0
mol·L–1, 0.62 mL, 0.62 mmol, 1.0 equiv) was added, and the
mixture was stirred for 5 min. Then ethereal H2O2 solution
(1.4 mol·L–1, 2.2 mL, 3.08 mmol, 5.0 equiv) was added
quickly. The mixture was stirred for 5 min at –70 °C. The
reaction vessel was warmed to r.t., and the reaction mixture
was stirred for 30 min and diluted with Et2O (30 mL),
washed with H2O (5 mL), sat. NaHCO3 solution (5 mL), and
brine (5 mL), dried over anhyd Na2SO4, and concentrated.
The crude product was purified by column chromatography
on silica gel (PE–EtOAc = 10:1) to afford 6a as a colorless
liquid (92 mg, 70% yield). Rf = 0.4 (PE–EtOAc = 3:1). 1H
NMR (400 MHz, CDCl3): δ = 9.38 (s, 2 H), 7.33–7.12 (m, 5
H), 5.08 (d, J = 7.2 Hz, 1 H), 2.76–2.66 (m, 1 H), 2.63–2.52
(m, 1 H), 2.05–1.86 (m, 2 H), 1.60–1.48 (m, 1 H), 1.06 (d,
J = 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 141.9,
128.4 (4 C), 125.9, 114.5, 33.9, 33.2, 32.8, 14.9. ESI-HRMS:
m/z calcd for C11H16O4Na [M + Na]+: 235.0941; found:
235.0943.
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Synlett 2013, 24, 502–506
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