Phosphomolybdic acid catalyzed synthesis of 1,2,4,5-tetraoxanes

Article abstract of DOI:10.1055/s-0031-1289864

1,1-Dihydroperoxides were converted into 1,2,4,5-tetraoxanes through condensation with the corresponding ketones in 36-91% yields using phosphomolybdic acid as the catalyst and anhydrous MgSO₄ as the water scavenger. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289864

LETTER
2827
Phosphomolybdic Acid Catalyzed Synthesis of 1,2,4,5-Tetraoxanes
S
ynthesis of 1,2,4,
i
5-Tetra
n
oxane
s
g Yan, Jinglei Chen, Yun-Ting Zhu, Chunhua Qiao*
College of Pharmaceutical Science, Soochow University, 199 Ren Ai Road, Suzhou 215123, P. R. of China
Fax +86(512)65882092; E-mail: qiaochunhua@suda.edu.cn
Received 17 August 2011
bis(trimethylsilyl) peroxide catalyzed by the Lewis acid
TMSOTf.5c,8 Ozonolysis of alkenes,9 enol ethers,10 or
oximes11 can also provide symmetric 1,2,4,5-tetraoxanes.
Asymmetric 1,2,4,5-tetraoxanes are commonly prepared
by condensations of carbonyl compounds (or ketal and
acetal derivatives) with 1,1-dihydroperoxides [or bis-
(trimethylsilyl) derivatives] catalyzed by H2SO4,6d,e,12
MTO–HBF4,5l,13 Re2O7,14 I2–HBF4,15 BF3·OEt2,5k,16 or
TMSOTf.17 Among these catalysts, BF3·OEt2, TMSOTf,
and Re2O7 are highly moisture sensitive; MTO and Re2O7
are much expensive ($ 180/g and $ 150/g, respectively);
I2–HBF4 was limited to aromatic aldehyde substrates.5h,15
Furthermore, with the exception of Re2O7, condensation
yields catalyzed by other acids were much lower, espe-
cially in H2SO4 (23–34%).6d,e,12 Therefore, a more toler-
ant, inexpensive, and broadly applicable catalyst for the
preparation of 1,2,4,5-tetraoxanes is needed.
Abstract: 1,1-Dihydroperoxides were converted into 1,2,4,5-tet-
raoxanes through condensation with the corresponding ketones in
36–91% yields using phosphomolybdic acid as the catalyst and an-
hydrous MgSO4 as the water scavenger.
Key words: phosphomolybdic acid, catalysis, cyclic condensation,
1,2,4,5-tetraoxanes, peroxide
1,2,4,5-Tetraoxanes are a class of novel compounds con-
taining two peroxide groups.1 The peroxide group has
been proven as the pharmacophore of the noted antimalar-
ial drug artemisinin (1, Figure 1).2 Artemisinin deriva-
tives are the first-line treatments of Plasmodium
falciparum malaria.3 Since 1,2,4,5-tetraoxanes (e.g., 2)
were discovered as the promising alternatives to artemisi-
nin derivatives in the 1990s,4 numerous studies have been
carried out to search for 1,2,4,5-tetraoxanes as new anti-
malarial lead compounds.5 Compared with artemisinin
and its derivatives, 1,2,4,5-tetraoxanes were much easier
to be chemically synthesized. Moreover, some synthetic
1,2,4,5-tetraoxanes (e.g., 3) showed enhanced in vitro and
in vivo antimalarial activity.5i,m Recent researches have
revealed that 1,2,4,5-tetraoxanes possess a variety of im-
portant biological activities (e.g., antitumor,6 antitubercu-
losis,6b,d fasciocidal).7 The amazing structural motif and
exciting properties of 1,2,4,5-tetraoxanes provide broad
space to be fully investigated.
Phosphomolybdic acid (PMA, H3PMo12O40) was reported
as an efficient catalyst for the preparation of 1,1-
dihydroperoxides18 and the related b-hydroxyhydroperox-
ides.19 In the course of investigation the PMA hydrate cat-
alyzed preparation of 1,1-dihydroperoxides, we detected
the formation of symmetric 1,2,4,5-tetraoxanes as minor
byproducts. This accidental discovery inspired us to ex-
amine whether PMA could act as a catalyst in preparing
symmetric and the more important asymmetric 1,2,4,5-
tetraoxanes. PMA has numerous advantages including
water compatibility, lower price ($ 3.8/g), and functional
group tolerance of readily cleavable protecting groups
(Bn, TBS, MOM, and allyl).18,19 Herein, we report our in-
vestigation on PMA as an effective catalyst in preparing
1,2,4,5-tetraoxanes.
H
O
O
O
O
O
O
O
H
O
All 1,1-dihydroperoxides substrates (Figures 2, 5a–h)
were prepared through the reactions of the corresponding
ketones and aldehydes 4a–h with ethereal hydrogen per-
oxide, employing PMA hydrate as the catalyst.18
2
O
artemisinin (1)
O
N
N
O
O
O
O
N
Me
Our initial investigation used ketone 4h and 1,1-dihydro-
peroxide 5c as substrates, applying commercial available
PMA hydrate as a catalyst. The reaction afforded the de-
sired product 1,2,4,5-tetraoxane 6 in a low, but promising
yield (Table 1, entry 1). We speculated that the water of
crystallization in PMA hydrate might adversely influence
the condensation reaction by disturbing the substrates and
PMA coordination. Therefore, commercial PMA was de-
hydrated in a microwave oven till a constant weight was
observed. Employing the microwave-processed PMA; the
reaction yield was improved from 27% to 39% (Table 1,
entry 2). We subsequently pursued the optimization of the
reaction conditions using dehydrated PMA.
RKA182 (3)
Figure 1 Peroxides with potent antimalaria activity
Symmetric 1,2,4,5-tetraoxanes can be obtained from con-
densation of carbonyl compounds with hydrogen per-
oxide catalyzed by a Brønsted acid,4,5j or with
SYNLETT 2011, No. 19, pp 2827–2830
Advanced online publication: 09.11.2011
DOI: 10.1055/s-0031-1289864; Art ID: W18311ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2828
X. Yan et al.
LETTER
X
Schemes 1, 1,2,4,5-tetraoxanes 7 and 11 were afforded in
a moderate 70% yield, but yields of 9 and 10 were much
lower. Especially in the case of compound 8, it was very
difficult to isolate the desired product as the reaction was
very messy. Further examinations with aliphatic ketones
as substrates should be explored to improve the product
yield.
X
X
X
COOEt
X = O
4a
4b
5b
4c
5c
4d
5d
X = (OOH)2 5a
X
X
X
X
5 (1.0 equiv)
PMA (1 mol%)
H
1,2,4,5-tetraoxanes
+
n-Bu
n-Bu
CH2Cl2, r.t., 1–3 h
7–11
4 (1.5 equiv)
X = O
4e
4f
5f
4g
5g
4h
5h
O
O
O
X = (OOH)2 5e
COOEt
O
O
O
O
O
Figure 2 Ketones, aldehyde, and 1,1-dihydroperoxides used in this
work
n-Bu
n-Bu
7 (4h, 5d, 70%)
O
O
8 (4e, 5c, 0%)a
The catalyst loading was first optimized. As shown in
Table 1, different amount of PMA (0.1–5 mol%, entries
3–7) afforded 6 in 38–50% yields. The optimal yield was
achieved with a 1 mol% catalyst loading. Next, the sol-
vent system was investigated (Table 1, entries 8–10).
Both PMA (Table 1, entry 8) and PMA hydrate (Table 1,
entry 9) exhibited limited solubility in diethyl ether result-
ing in much longer reaction times (20–22 h) and very low
product yields (6–8%). In acetonitrile (Table 1, entry 10),
the reaction was much faster, but the yield was substan-
tially lower compared to CH2Cl2 (35% in MeCN vs. 50%
in CH2Cl2). According to the above observations, 1 mol%
PMA in CH2Cl2 was used as the optimal reaction condi-
tions.
O
O
Ph
9 (4h, 5b, 33%)
O
O
O
O
O
O
O
O
10 (4h, 5g, 31%)
11 (4c, 5b, 70%)
Scheme 1 Reaction details of 1,1-dihydroperoxides with carbonyl
compounds without anhydrous MgSO4 as desiccant. The reaction
a
mixture was too complex to purify.
In all cases, we observed that PMA was partially dis-
solved in CH2Cl2 in the beginning of the reaction. Howev-
er, it slowly became stuck to the sides of the reaction
vessel during the course of the reaction. We proposed that
the water produced during the condensation reactions re-
sulted in the conversion of PMA into its corresponding
hydrate form, which might be even less soluble in CH2Cl2.
It was reasonable to deduce that the reaction proceeded
more slowly as a result of PMA precipitation. Moreover,
the slow reaction resulted in the formation of undesired
and difficult-to-separate byproducts. Following this logic,
we hypothesized that addition of a desiccant to remove the
produced water should enhance the reaction yield.
To explore the substrate tolerance to these optimized reac-
tion conditions, a wide variety of 1,1-dihydroperoxides
and carbonyl compounds was examined. As shown in
Table 1 Conditions and Yields in Model Reaction
5c (1.0 equiv)
O
O
O
O
catalyst
+
solvent, r.t.
4h (1.5 equiv)
6
Entry Catalyst
Equiv
(mol%)
Solvent
Time
(h)
Yield
(%)a
We first applied 4 Å molecular sieves as a desiccant, but
hardly observed any yield improvement. Then anhydrous
MgSO4 was added due to its fast action, high capacity, and
weak acidity.20 Indeed, addition of 1.5 equivalents of an-
hydrous MgSO4 to the reaction improved the reaction
yields in most cases (Schemes 2, 7–10), and reduced the
formation of undesired byproducts. Highlighting the im-
pact of MgSO4 on the reaction, compound 8 could only be
obtained with the addition of MgSO4. Additionally, the
yields of 7, 9, and 10 were improved by 20–30%.
1
2
PMA hydrate
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
0.5
0.5
10
4
27
39
39
43
50
46
38
8
PMA
1
3
PMA
0.1
0.5
1
4
PMA
5
PMA
3
6
PMA
2
1
Employing PMA-catalyzed condensation of 1,1-dihydro-
peroxides with ketones and aldehydes afforded asymmet-
ric 1,2,4,5-tetraoxanes in moderate yields of 36–91%
(Schemes 2, 6–21), which were superior or comparable to
the most efficient Re2O7, according to the yields
reported14 or checked by ourselves. For example, in the
case that the substrate is possessing an ester group which
7
PMA
5
1
8
PMA
1
22
20
0.25
9
PMA hydrate
PMA
1
Et2O
6
10
1
MeCN
35
a Isolated yield.
Synlett 2011, No. 19, 2827–2830 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,2,4,5-Tetraoxanes
2829
could be functionalized to carbonyl acid and alcohol In conclusion, PMA offers a highly efficient and practical
(Scheme 2, entry 7), the reaction yield was significantly method to prepare biologically active 1,2,4,5-tetraoxanes,
higher in PMA (91%) vs. Re2O7 (72%). Another case with employing the condensation reaction between 1,1-dihy-
enhanced yield was with compound 10 (59% in PMA vs. droperoxides and carbonyl compounds. In comparison
49%14 in Re2O7). Other cases displayed a comparable with other reported catalysts, such as Re2O7 and MTO,
yield including compounds 6 (44% vs. 48%); 8 (41% vs. PMA is much less expensive; compared with the mois-
49%14); 9 (52% vs. 49%); 12 (57% vs. 66%14; yield in ture-sensitive acids, such as TMSOTf and BF3·OEt2. It is
PMA vs. yield in Re2O7). In addition, the catalyst load also substantially more stable in air and easy to handle.
dropped from 2–5 mol% in Re2O7 to 1 mol% in PMA. In Moreover, the reported tolerance of various protecting
addition, symmetric 1,2,4,5-tetraoxanes (15 and 18) could groups18,19 should promote its wider application.
also be prepared in good yields (64% and 59%, respec-
tively).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
PMA (1 mol%)
MgSO4 (1.5 equiv)
5 (1.0 equiv)
1,2,4,5-tetraoxanes
+
Acknowledgment
CH2Cl2, r.t., 4–5 h
4 (1.5 equiv)
6–21
O
O
O
This work was supported by Chinese National Science Foundation
(81072514) to Professor Chunhua Qiao at Soochow University.
O
O
O
O
COOEt
O
6 (4h, 5c, 44%)
7 (4h, 5d, 91%)a
References and Notes
O
O
O
O
n-Bu
n-Bu
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O
O
O
O
8 (4e, 5c, 41%)
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Ph
O
O
O
O
O
O
O
O
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(4c, 5b, 65%)
10 (4h, 5g, 59%)
11
O
O
O
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COOEt
O
O
O
O
12 (4h, 5c, 57%)
13 (4b, 5d, 73%)
O
O
O
O
O
O
COOEt
O
O
14 (4a, 5d, 38%)a–c
15 (4c, 5c, 64%)
O
O
O
O
COOEt
O
O
O
O
16 (4c, 5d, 59%)a,b
17 (4h, 5f, 37%)
O
O
O
O
n-Bu
n-Bu
EtOOC
COOEt
O
O
O
O
18 (4d, 5d, 52%)
19 (4e, 5b, 36%)
O
O
O
O
COOEt
O
O
O
O
21 (acetone, 5d, 70%)a,d
20 (4b, 5f, 50%)
Scheme 2 Reaction details of 1,1-dihydroperoxides with carbonyl
compounds employing anhydrous MgSO4 as desiccant.21 a New com-
pounds. b Yield was determined on 0.5 g scale of 1,1-dihydroperox-
ides. c 36% on 5.5 g scale of 5d. d Yield was determined in 7.4 g scale
of 5d.
Synlett 2011, No. 19, 2827–2830 © Thieme Stuttgart · New York

2830
X. Yan et al.
LETTER
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Adamantane-2-spiro-3¢-1¢,2¢,4¢,5¢-tetraoxane-6¢-spiro-4¢¢-
tert-butyl-1¢¢-cyclohexane (6)
A mixture of 4h (88 mg, 0.59 mmol, 1.5 equiv), PMA (7 mg,
3.9 mmol, 1 mol%), and anhyd MgSO4 (71 mg, 0.59 mmol,
1.5 equiv) in CH2Cl2 (3 mL) was stirred for 20 min at r.t. To
this solution was added 5c (80 mg, 0.39 mmol, 1.0 equiv) in
CH2Cl2 (3 mL) in 15 min. The mixture was stirred at r.t. and
monitored by TLC. When 5c was consumed completely,
H2O (10 mL) was added. The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic phase was dried by anhyd
Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatograph (PE–EtOAc = 400:1) to
afford 6 (58 mg, yield 44%) as white solid; mp 136–138 °C
(lit.14 134–136 °C). Rf = 0.79 (PE–EtOAc, 50:1). 1H NMR
(400 MHz, CDCl3): d = 3.17 (s, 2 H), 1.97 (s, 4 H), 1.86 (s,
2 H), 1.82–1.51 (m, 9 H), 1.50–1.35 (m, 2 H), 1.35–1.15
(s, 3 H), 1.08 (m, 1 H), 0.86 (s, 9 H). 13C NMR (400 MHz,
CDCl3): d = 110.4, 108.2, 47.6, 37.1, 34.5, 33.3, 32.6, 32.3,
29.8, 27.8, 27.2, 23.2.14
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Synlett 2011, No. 19, 2827–2830 © Thieme Stuttgart · New York

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