Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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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
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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.
T
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 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). 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
he potential of H2O2 as an inexpensive source of peroxy bonds in the synthesis of organic peroxides has been long 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
Figure 1. Three main/practical entries to organic hydroperoxides 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 © XXXX American Chemical Society
Received: January 31, 2019
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DOI: 10.1021/acs.orglett.9b00425 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. MoO2(acac)2 Mediated Perhydrolysis (1)a
Table 3. MoO2(acac)2 Mediated Perhydrolysis (3)a
a
Performed in ethereal H2O2 at rt. bMol equiv with respect to the substrate.
Table 2. MoO2(acac)2 Mediated Perhydrolysis (2)a
a
Performed in ethereal H2O2 at rt. bMol equiv with respect to the substrate; all compounds were racemic. cThe reaction mixture was concentrated by bubbling N2 into the mixture for ethylene glycol ketals > monosubstituted or 1,2disubstituted 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
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 chemoselectivity 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 Scheme 1. Perhydrolysis of 1t
perhydrolysis protocols relying use of ketones as substrates. Therefore, such to date unknown chemoselectivity is particularly interesting and could be very useful. A tetrasubstituted 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 gemdihydroperoxides 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 Table 4. MoO2(acac)2 Mediated Perhydrolysis (4)a
a Performed in ethereal H2O2 at rt. bMol equiv with respect to the substrate. c8% of 1v was recovered. dThe reaction mixture was concentrated by bubbling N2 into the mixture for
