Perhydrolysis in Ethereal H2O2 Mediated by MoO2(acac)2: Distinct Chemoselectivity between Ketones, Ketals, and Epoxides

Article abstract of DOI:10.1021/acs.orglett.9b00425

Ketones, ketals, and epoxides were converted into corresponding hydroperoxides in high yields by reaction with ethereal H₂O₂ in the presence of a catalytic amount of MoO₂(acac)₂ with distinct (to date unattainable) chemoselectivity.

Full text of DOI:10.1021/acs.orglett.9b00425

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Perhydrolysis in Ethereal H2O2 Mediated by MoO2(acac)2: Distinct
Chemoselectivity between Ketones, Ketals, and Epoxides
Xiaosheng An, Qinghong Zha, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry and the University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Ketones, ketals, and epoxides were converted into
corresponding hydroperoxides in high yields by reaction with
ethereal H2O2 in the presence of a catalytic amount of MoO2(acac)2
with distinct (to date unattainable) chemoselectivity.
he potential of H2O2 as an inexpensive source of peroxy
bonds in the synthesis of organic peroxides has been long
currently is rarely a problem in the synthesis of nonperoxy
compounds, remains an unresolved challenge; differentiation
among those three major types of compounds/functional
groups in Figure 1 in perhydrolysis (often known as
peroxyacetalization when substrates are ketones), for example,
has been generally impossible.6
T
recognized. However, because of its relatively low reactivity,
incorporation of H2O2 into organic structures to date has not
been as straightforward as one might expect. In fact, despite
the continuing efforts over the decades since the late 1940s,1−3
mild, high-yielding, and generally applicable protocols1d−p,2
(catalyzed by Re2O7, PMA (phosphomolybdic acid), BF3·
Et2O, I2, etc.) were not available until the late 1990s/early
2000s.
The mild yet high-yielding perhydrolysis (including
peroxyacetalization) protocols developed in late 1990s/early
2000s, which fell into three main categories as shown in Figure
1 using ketones, ketals, or epoxides as the substrates, clearly
In continuation of our long-standing study on the synthesis
of organic peroxides, recently we found that MoO2(acac)2,
which to date was only known3b to be effective for
perhydrolysis of some spiro-epoxides (1,1-disubstituted
epoxides), could also promote conversion of a range of
ketones and ketals into corresponding gem-dihydroperoxides,
not only in good yields but also with previously unknown
chemoselectivity. The main results are detailed below.
Monofunctional linear or cyclic aliphatic ketones (1a−d,
Table 1, entries 1−5) could be smoothly transformed into
corresponding perketals in 83−93% yields. Ketone 1e and its
dimethyl ketal 1f also reacted satisfactorily (entries 5−6),
though more catalyst was required. It is noteworthy that, in the
case of ketal 1f, substantial amounts of corresponding free
ketone 1e was observed in the mixture soon after the
beginning of the reaction. However, aromatic ketone 1g
(entry 7) failed to give any satisfactory results (leading to a
complex mixture).
Figure 1. Three main/practical entries to organic hydroperoxides
Those ketones with nonconjugate C−C double bond(s) also
reacted well.7 As shown in Table 2, 1h and 1i both underwent
perhydrolysis smoothly under the giving conditions, delivering
gem-dihydroperoxides 2h and 2i, respectively, in high yields
(entries 1−2, Table 2). However, these two compounds
tended to decompose during chromatography. Therefore, the
crude bis-hydroperoxides were immediately treated with
TESCl/imidazole/CH2Cl2 and isolated as the corresponding
through reactions with H2O2 under mild conditions.
demonstrated that H2O2 could find much more utility in the
construction of organic peroxides than the early records
implied; many bioactive tetraoxanes4 and ozonides1p,3c thus
could be more readily accessed. Even trioxane qinghaosu
(artemisinin) could also be synthesized5 using H2O2 as the
source of the peroxy bond.
Nevertheless, it should not be overlooked that the chemistry
in this particular area still lags far behind its nonperoxide
counterparts in general. For instance, chemoselectivity, which
Received: January 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00425
Org. Lett. XXXX, XXX, XXX−XXX

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a
a
Table 1. MoO2(acac)2 Mediated Perhydrolysis (1)
Table 3. MoO2(acac)2 Mediated Perhydrolysis (3)
a
b
Performed in ethereal H2O2 at rt. Mol equiv with respect to the
substrate.
a
Table 2. MoO2(acac)2 Mediated Perhydrolysis (2)
a
b
Performed in ethereal H2O2 at rt. Mol equiv with respect to the
c
substrate; all compounds were racemic. The reaction mixture was
concentrated by bubbling N2 into the mixture for <2 h before timing
d
the reaction. Concentrated to ca. 1/2 of the initial volume.
e
f
Concentrated to ca. 1/5 of the initial volume. Concentrated to ca.
g
1/3 of the initial volume. The Et2O−H2O2 was used without drying
over MgSO4 as in other runs, along with 7% of recovered starting 1t
(cf. Supporting Information).
a
b
Performed in ethereal H2O2 at rt. Mol equiv with respect to the
c
substrate. The reaction mixture was concentrated to ca. 1/3 of the
initial volume by bubbling N2 into the mixture for <2 h before timing
the reaction. Yields for the corresponding bis-OOTES ketal (two-
observed with Na2MoO4-gly5 in our previous work. However,
the regioselectivity was dependent on the substitution pattern
and/or the relative configurations in structurally more complex
cases. In the case of 1o, the epoxy ring remained intact while
the ketel subunit fully reacted to afford the gem-dihydroper-
oxides 2o (entry 3, Table 3). The chemoselectivity in the case
of 1p, an epimer of 1o, was not clear because a multi-
component mixture was formed. However, it was revealed that
none of the components in the product mixture contained an
intact epoxy ring (entry 4).
1,2-Disubstituted epoxides were much less reactive under
the given conditions. Despite the prolonged reaction time, 1q
remained unchanged (entry 5). Under the same conditions,
the corresponding ketone 1r (racemic) reacted cleanly, but
only at the ketone carbonyl group rather than the epoxy ring
(entry 6). Monosubstituted epoxide 1s (racemic) gave similar
results, affording 2s as the major product (entry 7, Table 3).
d
step yield).
bis-OOTES ketals (with the yields shown being overall yields
for two steps). When using the di-MeO ketal of 1h as the
substrate, it was observed that a substantial amount of 1h was
generated before being converted into 2h (similar to what
occurred to 1f mentioned above). Ketones carrying a TBS or
an MOM group also reacted well; both protecting groups
survived (entries 3−5, Table 2).
Table 3 shows some representative results with bi- or
trifunctional substrates. 1,1-Disubstituted epoxy rings such as
those found in 1m and 1n (both racemic) were more reactive
than ethylene glycol ketals. In both cases, reaction occurred
predominantly at the epoxy moiety, similar to what was
B
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The presence of an additional alkyl group at the epoxy ring
remarkably increased the reactivity of the epoxide moiety in
the MoO2(acac)2 mediated perhydrolysis. The chemoselectiv-
ity was particularly obvious in the presence of traces of water.8
For instance, 1t (entry 8, Table 3) showed a reversed
chemoselectivity, affording 2t as the major product (along with
7% of unreacted 1t, 12% of 2t′, 2% of 2t′′, and 14% of 2t′′′,
Scheme 1). Until now most existing mild/high-yielding
in the same way (entry 2). This preference for free ketone
functionality was also clearly shown in the reaction of the
positional isomers of 1w (i.e., 1x, entry 3). Finally, switching
the location of the ketone and ketal groups (1y) did not lead to
any changes in chemoselectivity; the reaction still occurred
predominantly at the ketone carbonyl group (entry 6).
It may be noteworthy that some literature protocols,
including those in MeCN/aq. H2O2 (I2,1f Re2O7,1k,l or
CAN1g,j) or in ethereal H2O2 (BF3·Et2O1h or PMA1m),
which were already known to be effective for perhydrolysis
(including peroxyacetalization) of monofunctional substrates,
were also briefly tested on e.g. 1v, 1w, or 1t to examine the to
date unknown chemoselectivity. With I2 (0.1−0.3 equiv),1f
ReO7 (0.05 equiv),1k or CAN (0.05−0.1 equiv)1g as the
Scheme 1. Perhydrolysis of 1t
10
catalyst, the reaction of 1v in MeCN/aq. H2O2 led to a
complex mixture, while the reaction of 1w generated first the
corresponding diketone and then intramolecular ketal
exchange/cyclization products. In the reaction of 1t, all these
protocols led to mixtures (with 2t′ as the main component).
As for BF3·Et2O/ethereal H2O2,1h a main side reaction already
reported1h for monofunctional ketones was the partial
intermolecular ketal/perketal exchange. In the case of 1w,
the reaction suffered strong interference from intramolecular
ketal exchange/cyclization (resulting in nonpolar side products
exclusively). The reaction of 1t mediated by BF3·Et2O in
ethereal H2O2 also led to a complex mixture.11
We also tested I2, CAN, and Re2O7 (all of same equiv as
mentioned above), respectively, in ethereal H2O2 instead of
the original MeCN/aq. H2O2: With I2 as the catalyst, no
reactions occurred to either 1v or 1t. When CAN (insoluble)
was used, 1v gave a complex. The reaction of 1t catalyzed by
CAN also led to many minor side products (while most 1t
remained unchanged). ReO7 (0.05 equiv) converted 1v into 2v
in ca. 80% yield, but completely failed with 1w and 1t
(affording a complex mixture and mainly diol 2t′, respectively).
The results with PMA (0.0005 equiv)/ethereal H2O2 were
similar to those of Re2O7 (0.05 equiv) in the reaction of 1v
(giving ca. 80% of 2v) and 1w (affording a complex mixture).
However, in the perhydrolysis of 1t, the chemoselectivity
observed was comparable to that of MoO2(acac)2.
perhydrolysis protocols relying use of ketones as substrates.
Therefore, such to date unknown chemoselectivity is
particularly interesting and could be very useful. A tetrasub-
stituted epoxide (1u, racemic) was also tested. In this case, a
somewhat unexpected product 2u was obtained (Table 3,
entry 9).9
The reactivity differences between free ketone and ethylene
ketals shown in Table 3 suggested that under the H2O2−Et2O/
MoO2(acac)2 conditions it might be possible to achieve clean
conversion of free ketone carbonyl groups into gem-
dihydroperoxides without affecting coexisting ethylene ketals
in the same molecules, which is also an unattainable6
chemoselectivity to date.
For further insight into this possibility, we next examined
bifunctional substrates 1v−y. The results are listed in Table 4.
As expected, compound 1v indeed underwent perhydrolysis/
peroxyacetalization predominantly at the ketone group,
affording 2v in 89% yield (entry 1). Similarly, 1w also reacted
a
Table 4. MoO2(acac)2 Mediated Perhydrolysis (4)
In summary, ketones, ketals, and epoxides (three major
types of compounds to date known to be able to undergo
perhydrolysis to give high yields of hydroperoxides under mild
conditions) were examined in ethereal H2O2 in the presence of
a catalytic amount of MoO2(acac)2. The yields of the expected
peroxy products were generally high, while protecting groups
such as TBS and MOM were well tolerated. More importantly,
a distinct difference in reactivity (which is highly desirable yet
generally unattainable to date) was observed among the three
major types of substrates. The reactivity was found to be in
decreasing order as follows: Tri- or tetrasubstituted epoxides >
ketones > ethylene glycol ketals > monosubstituted or 1,2-
disubstituted epoxides. The distinct chemoselectivity between
ketones and ethylene glycol ketals is particularly noteworthy,
because under other known conditions ketals either were
equally reactive as ketones or underwent partial/incomplete
reactions and thus spoiled the synthesis.12
a
b
Performed in ethereal H2O2 at rt. Mol equiv with respect to the
c
d
substrate. 8% of 1v was recovered. The reaction mixture was
concentrated by bubbling N2 into the mixture for <2 h before timing
the reaction. Concentrated to ca. 1/3 of the initial volume.
e
C
DOI: 10.1021/acs.orglett.9b00425
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) For perhydrolysis of ketal, see (a) Murakami, N.; Kawanishi, M.;
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1m.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00425.
■
S
Scanned NMR and IR spectra, experimental procedures,
and X-ray structures (PDF)
Accession Codes
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PMA employed in refs 3e and 1m were only 1/12 of the reported
(calibrated for 1 equiv of molybdenum according to the formula
H3Mo12O40P·xH2O but by mistake not specified). For earlier reports
on perhydrolysis of epoxides, see: (f) Mattucci, A. M.; Perrotti, E.;
Santambrogio, A. J. Chem. Soc. D 1970, 1198−1199. (g) Adam, W.;
Rios, A. J. Chem. Soc. D 1971, 822−823. (h) Kerr, B.; McCullough, K.
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closely related perhydrolysis of oxytanes, see: (k) Dussault, P. H.;
Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591−4593.
(l) Han, W.-B.; Wu, Y.-K. Org. Lett. 2014, 16, 5706−5709.
(4) For example, see: (a) Kim, H. S.; Tsuchiya, K.; Shibata, Y.;
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7605−7619. For background of QHS (artemisinin), for example, see:
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(6) For the to date only existing known precedents of selective
perhydrolysis of epoxides in the presence of ethylene glycol ketals, see
ref 5a, b.
(7) The reaction of some substrates in the H2O2 “saturated” ethereal
solution was rather sluggish. Higher rates/better yields could be
attained through removing the solvent Et2O by bubbling N2 gas into
the reaction mixture.
(8) In this case, the ethereal H2O2 was employed without drying
over MgSO4. Use of MgSO4-dried ethereal H2O2 as in other runs led
to faster reaction but less satisfactory chemoselectivity.
(9) For the formation of 2u, compare see the Supporting
Information. Previously, 2u was also obtained in 77% yield from 1u
in 50% aq. H2O2−CH2Cl2 with HCO2H as the catalyst (where the
stereoselective addition of HOOH might be guided by the OH
through H-bonding). See: Ramirez, A. P.; Thomas, A. M.; Woerpel,
K. A. Org. Lett. 2009, 11, 507−510.
(10) Because of its potentially hazardous properties, 50% aq. H2O2
(used in some of the MeCN/aq. H2O based protocols) is a strictly
regulated reagent in China and thus not accessible to us.
(11) Also noteworthy is that use of t-BuOOH (commercially
available solution in decane) in reaction with ketone 1c instead of
ethereal H2O2 led to corresponding gem-di(t-BuOO) perketal in 90%
yield. Aldehydes could not be converted into corresponding gem-
CCDC 1870985−1870986 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yikangwu@sioc.ac.cn.
ORCID
Yikang Wu: 0000-0003-4501-5401
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672244, 21532002) and the Strategic
Priority Research Program of the Chinese Academy of
Sciences (XDB20020200).
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dihydroperoxides using MoO2(acac)2/ethereal H2O2 (affording
complex mixtures). Use of UHP (H2O2−urea, in soluble in Et2O or
DME) instead of ethereal H2O2 failed to result in any reactions.
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and long-term storage is not recommended. However, we did not
encounter any discernible problems in our preparation (on scales up
to 500 mL) and storage of the solution (in aluminum foil “sealed”
flasks, to prevent absorption of moisture and also to prevent
evaporation of the Et2O, at rt for 1−2 days in a well ventilated hood).
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E
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