Facile ring-opening of oxiranes by H2O2 catalyzed by phosphomolybdic acid

Article abstract of DOI:10.1021/ol900811m

At ambient temperature, in the presence of catalytic amounts of phosphomolybdic acid (PMA), ethereal hydrogen peroxide reacted readily with a range of epoxides, giving corresponding β-hydroxyhydroperoxides in high yields.

Full text of DOI:10.1021/ol900811m

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2691-2694
Facile Ring-Opening of Oxiranes by
H2O2 Catalyzed by Phosphomolybdic
Acid
Yun Li, Hong-Dong Hao, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
yikangwu@mail.sioc.ac.cn
Received April 14, 2009
ABSTRACT
At ambient temperature, in the presence of catalytic amounts of phosphomolybdic acid (PMA), ethereal hydrogen peroxide reacted readily
with a range of epoxides, giving corresponding ꢀ-hydroxyhydroperoxides in high yields.
As a simple and readily accessible peroxy bond-containing
reagent hydrogen peroxide (H2O2) plays an important role
in construction of organic peroxides,1 a class of com-
pounds that in many cases possess significant antimalarial
activity as exemplified by qinghaosu2 (QHS, artemisinin,
1) and a plethora of derivatives as well as analogues. There
have been many different protocols in the literature for
incorporation of H2O2 into various organic molecular
frameworks, including Hg(II) ion3a or MeCONHBr3b
mediated additions to C-C double bonds, acid-catalyzed
dehydration of 2-furyl alcohols,3c,d alkylation with various
mesylates3e or a silyloxy group stabilized cation3f formed
in situ from a silyl enol ether, ring-opening perhydroly-
sis1a,b,3g of oxiranes (epoxides) or oxetanes, and perket-
-p
alization/ketal exchange1c,d,4 reactions. Among these, the last
two categories are of particular importance because the
products are related to antimalarial 1,2,4-trioxanes (Figure
1) and 1,2,4,5-tetraoxanes, respectively.
(1) See, for example: (a) Kerr, B.; McCullough, K. J. Chem. Commun.
1985, 590–591. (b) Subramanyam, V.; Brizulela, C. L.; Soloway, A. H.
Chem. Commun. 1976, 508–509. (c) Kovac, F. Tetrahedron Lett. 2001,
42, 5313–5314. (d) Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.;
Ogibin, Y. N.; Nikishin, G. I. Tetrahedron Lett. 2003, 44, 7359–7363. (e)
Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi, M.
Tetrahedron Lett. 2001, 42, 7281–7285. (f) Murakami, N.; Kawanishi, M.;
Itagaki, S.; Horii, T.; Kobayashi, M. Bioorg. Med. Chem. Lett. 2002, 12,
69–72. (g) Liu, H.-H.; Jin, H.-X.; Zhang, Q.; Wu, Y.-K.; Kim, H.-S.;
Wataya, Y. Chin. J. Chem. 2005, 23, 1469–1473. (h) Jin, H.-X.; Wu, Y.-
K. Tetrahedron Lett. 2005, 46, 6801–6803, Cf. also refs 4, 5 below.
(2) (a) Liu, J.-M.; Ni, M.-Y.; Fan, J.-F.; Tu, Y.-Y.; Wu, Z.-H.; Wu,
Y.-L.; Chou, W.-S. Acta Chim. Sin 1979, 37, 129–143. Chem. Abstr 1980,
92, 94594w. (b) Klayman, D. L. Science 1985, 228, 1049–1055. (c) Haynes,
R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73–79. (d) Vroman,
J. A.; Alvim-Gaston, M.; Avery, M. A. Curr. Pharm. Design 1999, 5, 101–
138. (e) Robert, A.; Dechy-Cabaret, O.; Cazalles, J. M.; Meunier, B. Acc.
Chem. Res. 2002, 35, 167–174. (f) Li, Y.; Wu, Y.-L. Curr. Med. Chem.
2003, 10, 2197–2230. (g) O’Neill, P. M.; Posner, G. H. J. Med. Chem.
2004, 47, 2945–2964. (h) Posner, G. H.; O’Neill, P. M. Acc. Chem. Res.
2004, 37, 397–404. (i) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Med. Res.
ReV. 2004, 24, 425–448. (j) Muraleedharan, K. M.; Avery, M. A.
ComprehensiVe Med. Chem. II 2006, 7, 765–814.
(3) (a) Bloodworth, A. J.; Bothwell, B. D.; Collins, A. N.; Maidwell,
N. L. Tetrahedron Lett. 1996, 37, 1885–1888. (b) Jefford, C. W.; Deheza,
M. F. Heterocycles 1999, 50, 1025–1031. (c) Lattanzi, A.; Iannece, P.;
Vicinanza, A.; Scettri, A. Chem. Comm. 2003, 1440–1441. (d) Massa, A.;
Palombi, L.; Scettri, A. Tetrahedron Lett. 2001, 42, 4577–4579. (e) Porter,
N. A.; Funk, M. O.; Gilmore, D.; Isaac, R.; Nixon, J. J. Am. Chem. Soc.
1976, 98, 6000–6005. (f) Saito, I.; Nagata, R.; Yuba, K.; Matsuura, T.
Tetrahedron Lett. 1983, 24, 1737–1740. (g) Payne, G. B.; Smith, C. W. J.
Org. Chem. 1957, 22, 1682–1685. (h) Mattucci, A. M.; Santambrogio, A.
Chem. Commun. 1970, 11987–1199. (i) Adam, W.; Rios, A. Chem.
Commun. 1971, 822–823. (j) Ogata, Y.; Sawaki, Y.; Shimizu, H. J. Org.
Chem. 1978, 43, 1760–1763. (k) Subramanyam, V.; Brizuela, C. L.;
Soloway, A. H. Chem. Commun. 1976, 508–509. (l) Antonelli, E.; D’Aloisio,
R.; Gambaro, M.; Fiorani, T.; Venturello, C. J. Org. Chem. 1998, 63, 7190–
7206. (m) Tang, Y.; Dong, Y.; Wang, X.; Sriraghavan, K.; Wood, J. K.;
Vennerstrom, J. L. J. Org. Chem. 2005, 70, 5103–5110. (n) Liu, Y.-H.;
Zhang, Z.-H.; Li, T.-S. Synthesis 2008, 3314–3318. (o) Dussault, P. H.;
Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591–4593 (ring-
opening of oxetanes). (q) Ramirez, A. P.; Thomas, A. M.; Woerpel, K. A
Org. Lett. 2009, 11, 507–510
.
10.1021/ol900811m CCC: $40.75
Published on Web 05/13/2009
 2009 American Chemical Society

tested, with the yield being 29 and 59%, respectively. The recent
SbCl3/SiO2/ethereal H2O2/sonication3n conditions of Zhang and
Li generally gave perhydrolysis products in higher yields
(72-85%) but are applicable only to the less-hindered 2-mono-
substituted oxiranes. Recently, we disclosed8 that phosphomo-
lybdic acid (PMA) is an excellent catalyst for converting
ketones/ketals into corresponding gem-hydroperoxides. Here in
this communication we wish to report that PMA is also an
excellent catalyst for perhydrolysis of oxiranes (epoxides).
Figure 1. Qinghaosu and some antimalarial 1,2,4-trioxanes.
Scheme 1
ꢀ-Hydroxyhydroperoxides are apparent precursors for 1,2,4-
trioxanes,3g-i,m,5 the well-known antimalarial core6 unit of
QHS (1) and many synthetic peroxide antimalarials. Such
hydroperoxides can also be used as protecting groups5a for
carbonyl groups, which are cleavable under neutral conditions
by, for instance, single-electron reduction and thus offer a
functionality compatibility profile different from those of
classic protecting groups for carbonyl groups. However, as
one of the straightforward accesses7 to the ꢀ-hydroxy-
hydroperoxides, the ring-opening reaction of oxiranes itself
still remain to be improved; mild yet effective protocols are
still to be developed.
Involvement of high concentration H2O2 appears to be one
of the main drawbacks. For instance, the conditions of Payne
and Smith3g and those of Adam and Rios3i all involved almost
neat (90 or 98%) H2O2, which is potentially hazardous and
strongly discourages broad application. In 2005 a distinct
improvement3m was made by Vennerstrom and co-workers,
who used 50% H2O2 with MoO2(acac)2 as the catalyst.
However, only two 2,2-disubstituted oxiranes (Vide infra) were
Our investigation on acid-catalyzed perhydrolysis of
oxiranes began with the reaction shown in Scheme 1, with
6a as the substrate. We first utilized urea-H2O2 complex
(UHP), a commercially available solid reagent with remark-
able convenience in storage and handling, as the source of
H2O2. However, the reaction using up to 10 mol equiv. (with
respect to the starting 6a) of UHP in MeO(CH2)2OMe (DME,
the best nonaqueous solvent for UHP according to our
experience) with a range of potential catalysts, including CSA
(camphor-10-sulfonic acid), SnCl2, Fe(acac)3, BF3·Et2O, Ti(i-
PrO)4, Cu(acac)2, Co(OAc)2, and MoO2(acac)2, all failed. In
most cases, essentially no desired 7a could be detected.
Table 1. Conversion of 6a to 7aa
(4) (a) Ledaal, T.; Solbjor, T. Acta Chem. Scand. 1967, 21, 1658–1659.
(b) Ramirez, A.; Woerpel, K. A. Org. Lett. 2005, 7, 4617–4620. (c)
Terent’ev, A. O.; Platonov, M. M.; Ogibin, Y. N.; Nikishin, G. I. Synth.
Commun. 2007, 37, 1281–1287. (d) Jefford, C. W.; Li, Y.; Jaber, A.;
Boukouvalas, J. Synth. Commun. 1990, 20, 2589–2596. (e) Das, B.;
Veeranjaneyulu, B.; Krishnaiah, M.; Balasubramanyam, P. J. Mol. Catal.
A 2008, 284, 116–119. (f) Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.;
Ogibin, Y. N.; Nikishin, G. I. Tetrahedron Lett. 2003, 44, 7359–7363. (g)
Bunge, A.; Hamann, H.-J.; Liebscher, J. Tetrahedron Lett. 2009, 50, 524–
526. (h) Das, B.; Krishnaiah, M.; Veeranjaneyulu, B.; Ravikanth, B.
Tetrahedron Lett. 2007, 48, 6286–6289. (i) Zmitek, K.; Zupan, M.; Stavber,
S.; Iskra, J. Org. Lett. 2006, 8, 2491–2494. (j) Iskra, J.; Bonnet-Delponb,
D.; Begue, J.-P. Tetrahedron Lett. 2003, 44, 6309–6312. (k) Ghorai, P.;
Dussault, P. H. Org. Lett. 2008, 10, 4577–4579. (l) Zmitek, K.; Zupana,
M.; Iskra, J. Org. Biomol. Chem 2007, 5, 3895–3908 (a review). (m) Ghorai,
P.; Dussault, P. H. Org. Lett. 2009, 11, 213–216.
entry
catalyst/reaction time (h)
yield of 7a (%)
1
2
3
4
5
6
7
8
LiClO4/12
CAN/24
Cu(acac)2/12
FeCl3-SiO2/24
SnCl4/12
TiCl4/8
Ce(OH)3OOH/12
ZrCl4/12
MoO2(acac)2/20
Salen Co(OAc)3/10min
Na2MoO4/12
Sc(OTf)3/12
PMA/6
0b
12%
0b c
,
21%
0d
0d
0b
0b c
,
9
62%
10
11
12
13
0e
0b
0b
(5) (a) Singh, C.; Malik, H. Org. Lett. 2005, 7, 5673–5676, but the
concept of using peroxy groups as protecting groups was first introduced
by Dussault using γ-hydroxyhydroperoxides. (b) Ahmed, A.; Dussault, P. H.
Org. Lett. 2004, 6, 3609–3611.
78%
a All runs were performed at ambient temperature in ethereal H2O2
containing 0.1 mol equiv (with respect to the added 6a) of indicated catalyst
with the substrate 6a and H2O2 concentration being 0.2 and 1.0 M,
respectively. b No reactions occurred. c A precipitate formed on addition
of the catalyst. d A complex mixture was formed. e On addition of the catalyst
H2O2 decomposed with violent gas evolving.
(6) For some synthetic antimalarial 1,2,4-trioxanes, see: (a) Singh, C.;
Gupta, N.; Puri, S. K. Biorg. Med. Chem. 2004, 12, 5553–5562. (b) Singh,
C.; Gupta, N.; Puri, S. K. Tetrahedron Lett. 2005, 46, 205–207. (c)
Haraldson, C. A.; Karle, J. M.; Freeman, S. G.; Duvadie, R. K.; Avery,
M. A. Biorg. Med. Chem. Lett. 1997, 7, 2357–2362. (d) Griesbeck, A. G.;
El-Idreesy, T. T.; Fiege, M.; Brun, R. Org. Lett. 2002, 4, 4193–4195. (e)
Jefford, C. W.; Rossier, J.-C.; Milhous, W. K. Heterocycles 2000, 52, 1345–
1352. (f) Posner, G. H.; Oh, C. H. Heteroatom Chem. 1995, 6, 105–116.
(g) Dechy-Canaret, O.; Benoit-Vical, F.; Rober, A.; Meunier, B. Chem-
Biochem 2000, 4, 283–284. (h) Jefford, C. W.; Kohmoto, S.; Jaggi, D.;
Timari, G.; Rossier, J.-C.; Rudaz, M.; Barbuzzi, O.; Gerard, D.; Burger,
U.; Kamalaprija, P.; Mareda, J.; Bernardinelli, G. HelV. Chim. Acta 1995,
78, 647–662. (i) Jefford, C. W.; Verarde, J. A.; Bernardinelli, G.; Bray,
D. H.; Warhurst, D. C. HelV. Chim. Acta 1993, 76, 2775–2788.
Then we switched to ethereal H2O2, because it worked very
well in our recently reported8 perketalization reactions. Some
of the outcomes in ethereal H2O2 are summarized in Table 1.
Again, in most cases no desired 7a could be detected (entries
1,3,5-8, 10-13). However, the reactions with Ce(NH4)2(NO3)6
2692
Org. Lett., Vol. 11, No. 12, 2009

(CAN) or FeCl3-SiO2 as the catalyst afforded the perhydrolysis
product in 12% and 21% yield, respectively (Table 1, entries 2
and 4). MoO2(acac)2 gave 7a after 20 h in a yield compatible
to that of Vennerstrom (entry 9).
carbocation. In the absence of such a stabilization effect, the
ring-opening occurred predominantly at the sterically less
crowded terminal carbon presumably via an SN2 mechanism
(Table 2, entry 13).
Even better result was found with PMA. Thus, with 0.1
mol equiv (with respect to 6a) of PMA as the catalyst stirring
of 6a at ambient temperature in ethereal H2O2 gave 7a in
9
Table 2. PMA Catalyzed Perhydrolysis of Various Epoxidesa
78% yield (entry 13) within 6 h, indicating for the first time
that PMA might also be an excellent catalyst for perhydroly-
sis of oxiranes.
Encouraged by the positive sign, we next examined
substrates3m (6b,c) of Vennerstrom for comparison. To our
delight, the anticipated 7b and 7c were formed in 47% and
80% yield (Table 2, entries 1-2), respectively, confirming
that PMA is indeed an excellent catalyst. An array of other
2,2-disubstituted oxiranes were then tested under the same
conditions (entries 3-10). In all cases the expected perhy-
drolysis products were obtained in satisfactory yields. The
regioselectivity was the same as under the Vennerstrom’s
conditions, including those substrates carrying a substituent
at the carbon next to the quaternary carbon in the oxirane
ring (entries 8-10).
The substrates containing TBS, MOM, or allyl groups
deserve particular mention. Although being placed in an
“unshielded” surrounding (i.e., on an unhindered primary
hydroxyl group), these protecting groups survived the
perhydrolysis (entries 5-7). To the best of our knowledge,
these results represent the first examples of using such readily
removable protecting groups in this type of reactions.
Apart from 2,2-disubstituted oxiranes, which are most
interesting to us because of their potential in malaria
chemotherapy, we also briefly examined a few epoxides of
other substitution patterns under the newly developed condi-
tions. In all cases, the expected perhydrolysis products were
obtained in good to excellent yields. The 2,3-disubstituted
oxirane 6l, for example, afforded the known 7l in 95% yield
within 6 h, substantially better than that (83%) under the
previous SbCl3/SiO2/ethereal H2O2/sonication3n conditions
(Table 2, entry 11).
The reactions with 2-monosubstituted epoxides (6m and
6n) were also high-yielding under the present conditions
(Table 2, entries 12-13). In contrast to 2,2-disubstituted
oxiranes, which underwent perhydrolysis exclusively at the
quaternary carbon, the regioselectivity with 2-monosubsti-
tuted epoxides depended critically on the substituent. When
one of the two epoxy carbons was at a benzylic position,
the predominant product carried the entering hydroperoxyl
group at that carbon (Table 2, entry 12) because of
stabilization effect of the phenyl group on the intermediate
(7) For an alternative access to ꢀ-hydroxyhydroperoxides using O2 as
the source of peroxy bonds, see, for example: (a) O’Neill, P. A.; Pugh, M.;
Davies, J.; Ward, S. A.; Park, K Tetrahedron Lett. 2001, 42, 4569–4571.
(b) Isayama, S. Bull. Chem. Soc. Jpn. 1990, 63, 1305–1310. (c) Isayama,
S.; Mukaiyama, T. Chem. Lett. 1989, 573–576.
a All runs were performed at ambient temperature in ethereal H2O2
containing 0.1 mol equiv (with respect to the starting 6) of PMA
(H3Mo12O40P·xH2O) with the substrate and H2O2 concentration being 0.2
and 1.0 M, respectively. b The starting 6 was a mixture of diastereomers,
but the resulting 7 appeared to be homogeneous in 1H and 13C NMR. c 0.15
Mol equiv of PMA was used. d 0.01 Mol equiv of PMA was used.
(8) Li, Y.; Hao, H.-D.; Zhang, Q.; Wu, Y.-K. Org. Lett. 2009, 11, 1615–
1618.
(9) Prepared by extracting the commercially available aqueous 30% H2O2
with Et2O. (a) Saito, I.; Nagata, R.; Yuba, K.; Matsuura, T. Tetrahedron
Lett. 1983, 24, 1737–1740. (b) Terent’ev, A. O.; Krylov, I. B.; Borisov,
D. A.; Nikishin, G. I. Synthesis 2007, 2979–2986, For a modified procedure,
see ref 8 above.
Org. Lett., Vol. 11, No. 12, 2009
2693

Similar regioselectivity had been reported3n previously.
However, no experimental evidence was provided therein.
This deficiency, along with a literature example10 of similar
ring-opening reaction that occurred with different regiose-
lectivity, urged us to check the identity of 7n more carefully.
Finally, with the assistance of DEPT, HMQC, and NOESY
experiments performed on the acetonide of 7n it was proven
beyond all doubt that the structure of 7n was indeed as
depicted (cf. Figure S in the Supporting Information).
The phenomenon observed with 6o also deserves a few
more words. When using the same amount of PMA (0.1 mol
equiv) as in other cases, a deep-blue color appeared im-
mediately and the reaction system became very complex as
shown by TLC. However, a clean reaction could be achieved
by reducing the amount of added PMA to 0.01 mol equiv.
Under such conditions, the desired 7o was isolated in 91%
yield after 2 h.
Scheme 2
the backside of the leaving epoxy group. Then, the hydro-
peroxyl group enters from the other face. Finally, a lacton-
ization occurs, leading to 6o/7o.
In brief, phosphomolybdic acid (PMA) is shown to be a
mild yet highly efficient catalyst for perhydrolysis of oxiranes
(epoxides). A range of ꢀ-hydroxyhydro-peroxides, immediate
precursors for 1,2,4-trioxanes, were readily prepared from
corresponding oxiranes using the newly developed protocol.
The reaction typically took ca. 10 h to complete at ambient
temperature in ethereal H2O2 with 0.1 mol equiv (with respect
to the substrate) of PMA as the catalyst. The regioselectivity
for 2,2-disubstituted oxiranes was very high, with the entering
hydroperoxyl group always attached to the quaternary carbon.
2,3-Disubstituted and 2-monosubstituted oxiranes also re-
acted well, but the regioselectivity depended significantly
on the nature of the substituents. Finally, the tolerance of
readily cleavable protecting groups in such reactions for the
first time observed in this work may open up new access to
a diverse of ꢀ-hydroxyhydroperoxides and consequently the
corresponding 1,2,4-trioxanes.
Figure 2. Key NOE’s observed in 2D NOESY spectrum, which
are compatible with 7o, but not 7o′ (boxed).
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20672129, 20621062,
20772143) and the Chinese Academy of Sciences (“Knowl-
edge Innovation”, KJCX2.YW.H08) is gratefully acknowl-
edged.
The relative configuration of 7o was established according
to the detected key NOE’s shown in Figure 2. This
unexpected stereochemistry along with the peculiar phe-
nomena observed during the reaction suggested that the 7o
was not formed via a simple SN1 mechanism.
A possible mechanism that may lead to the unexpected
stereochemical outcome with 6o/7o is shown in Scheme 2.
The ring-opening of the oxirane is greatly facilitated because
of stabilization of the carbocation by the carbonyl group from
Supporting Information Available: Experimental pro-
1
cedures, physical and spectroscopic data listing, H as well
as 13C NMR spectra for all new peroxides, and 1H NMR for
the known ꢀ-hydroxyperoxides 7b-d. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457.
OL900811M
2694
Org. Lett., Vol. 11, No. 12, 2009