Cu(II)-catalyzed aerobic hydroperoxidation of Meldrum's acid derivatives and application in intramolecular oxidation: A conceptual blueprint for O 2/H2 dihydroxylation

Article abstract of DOI:10.1021/ol302848m

Aerobic hydroperoxidation of Meldrum's acid derivatives via a Cu(II)-catalyzed process is presented. The mild reaction conditions are tolerant to pendant unsaturation allowing the formation of endoperoxides via electrophilic activation. Cleavage of the O-

Full text of DOI:10.1021/ol302848m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Cu(II)-Catalyzed Aerobic
Hydroperoxidation of Meldrum’s Acid
Derivatives and Application in
Intramolecular Oxidation: A Conceptual
Blueprint for O2/H2 Dihydroxylation
Scott W. Krabbe, Dung T. Do, and Jeffrey S. Johnson*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599, United States
jsj@unc.edu
Received October 16, 2012
ABSTRACT
Aerobic hydroperoxidation of Meldrum’s acid derivatives via a Cu(II)-catalyzed process is presented. The mild reaction conditions are tolerant to
pendant unsaturation allowing the formation of endoperoxides via electrophilic activation. Cleavage of the OÀO bond provides 1,n-diols with
differentiation of the hydroxy groups.
Enolate oxidation is an important tool in organic
synthesis for the preparation of various R-functionalized
carbonyl compounds.1 This reaction is often achieved
through the application of oxygen-based electrophiles
such as oxaziridines, dioxiranes, and diacyl peroxides
(Scheme 1a); these reagents are useful for the installation
of a hydroxyl group or hydroxyl surrogate but their atom
economy is relatively poor.2 In the rarer cases where
hydroperoxides are generated during the course of enolate
functionalization (often as ROH/RO2H mixtures), it is
common practice to reduce the mixture to the hydroxyla-
tion (ROH) product upon workup. This reductive workup
in essence squanders one oxidation level conferred by the
oxidant. By contrast, an enolate oxidation that preserved
the elevated product oxidation state could in principle be
used to functionalize remote sites (Scheme 1b), so long as
the distal functionality was compatible with the oxidation
conditions. Initially providing an endoperoxide (3), hydro-
genolysis of the OÀO bond would provide formal dihy-
droxylation products (4) in a redox economical manner.3
Moreover, a catalytic enolate oxidation reaction that
used O2 would carry the inherent advantages of complete
atom economy and the use of a green oxidant. At issue in
translating this construct to practice is (1) the development
of a mild, functionalgroup-tolerant enolate oxidation using
O2 and (2) the development of tools for remote functional-
ization using the hydroperoxide products. The purpose of
this communication is to report efforts to this end in the
form of an efficient, operationally simple method for the
catalytic aerobic hydroperoxidation of Meldrum’s acid4
(1) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637–1656.
(2) (a) Bang-Chen, C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org.
React. (N.Y.) 2003, 62, 1–356. (b) For direct hydroxylation of active
methines using Pd(II)/O2, see: Chuang, G. J.; Wang, W.; Lee, E.; Ritter,
T. J. Am. Chem. Soc. 2011, 133, 1760–1762.
(3) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int.
Ed. 2009, 48, 2854–2867.
(4) For recent reviews of Meldrum’s acid in organic synthesis, see: (a)
Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43, 440–454. (b) Ivanov,
A. S. Chem. Soc. Rev. 2008, 37, 789–811.
r
10.1021/ol302848m
XXXX American Chemical Society

derivatives and the application of the products in intramo-
lecular πCtC and πCdC oxidation, including the first Au(I)-
catalyzed hydroperoxide/alkyne cyclization.
to 1,n-diols via OÀO bond cleavage by thiourea/MeOH14
or metal-catalyzed hydrogenolysis.15 The latter case is
especially attractive from a green chemistry perspective16
sincethe overall sequencecouldin principleprovide formal
dihydroxylation with O2 as the oxidant and H2 as the
reductant.
The projected intervention of intermediates such as 3 in
this strategy is significant since cyclic peroxides are pre-
valent in a number of natural products exhibiting anti-
malarial (artemisinin and its derivatives) and anticancer
(plakinic acids) activity.5À7 With this knowledge and the
findings that structurally simpler cyclic peroxides can still
exhibit useful biological activity,8 the short and efficient
synthesis of new cyclic peroxides has become a topic of
increased effort.9 Thus, the value of endoperoxides 3 is
twofold as theyare both biologically relevant and potential
precursors to ubiquitous 1,n-diols 4.
Our point of departure for this study was to examine
oxygenation of β-dicarbonyls with the expectation that the
appreciable CÀH acidity could translate to relatively mild
activation conditions. Extant methods for hydroperoxida-
tion of β-dicarbonyls are scant and often suffer from harsh
conditions and/or mixtures of hydroperoxide and alcohol.
The use of photosensitized 1O2 allows the formal addition
of O2 into an active methine,17 and endoperoxidic hemi-
ketals were formed in modest yield in the Ce(III)-catalyzed
peroxidation/cyclization of β-dicarbonyls with styrenes.18
The foremost methods for hydroperoxidation of active
CÀH bonds utilize aerobic oxidation of dimedone deriva-
tives19 or employ Mn(III)/O2 to peroxidize 1,2-diphenyl-
pyrazolidine-3,5-diones and barbituric acid derivatives.20
The aerobic oxidation conditions are quite specific to
dimedone derivatives,21 and Mn(III) is well-known to
give electrophilic radical intermediates with β-dicarbonyls,
rendering this method incompatible with pendant unsa-
turation due to competitive cyclization.22 A method
compatible with unsaturation is highly desirable as the
heightened oxidation state gained by hydroperoxidation
Scheme 1. Methods of Enolate Oxidation
Scheme 2. Cu(II)-Catalyzed Aerobic Oxidation of a Substituted
Meldrum’s Acid
A common strategy for the synthesis of endoperoxides is
the cyclization of hydroperoxides onto pendant alkenes.
This cyclization has been accomplished by peroxy radical
cyclization,10 attack onto in situ formed halonium or
mercuronium ions,11 conjugate addition into electron-
deficient alkenes,12 or olefin activation by electrophilic
transition metal catalysis.13 Endoperoxides provide access
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(21) In our hands, hydroperoxidation of Meldrum’s acid derivatives
was not observed under the reported conditions.
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Org. Lett., Vol. XX, No. XX, XXXX

can be effectively utilized. The use of substituted Meldrum’s
acids as flexible starting materials for CÀH hydroperox-
idation was attractive since asymmetric syntheses of these
compounds have been developed to a high level of sophis-
tication, simplicity, and scalability.23,24
Table 1. Hydroperoxidation of Meldrum’s Acid Derivatives
Reports on Cu(II)-catalyzed aerobic activation of
β-dicarbonyls prompted us to examine these reaction
conditions.25 Isopropyl Meldrum’s acid 5a was exposed
to Cu(II)/air (55 psig; standard Fisher-Porter bottle) in
acetonitrile at ambient temperature. The oxidative cleav-
age product 6 might nominally be expected based on
precedent, but the reduced electrophilicity of the ester
carbonyl led instead to a mixture of hydroperoxide 7a
and alcohol 8 (Scheme 2). Reducing the temperature to
0 °C minimized or eliminated reduction to alcohol 8 while
still providing good conversion to the hydroperoxide.
Operational simplicity was further achieved without detri-
ment to yield by using a balloon of O2, eliminating the need
for a pressure vessel.26
With optimized conditions realized,27 a variety of
Meldrum’s acids 5aÀj were subjected to the hydroperoxida-
tion (Table 1). The mild reaction conditions proved tolerant to
a variety of potentially vulnerable functional groups including
alkenes, terminal and internal alkynes, arenes, tertiary
benzylic CÀH bonds, and esters. In most cases, the hydro-
peroxide products 7aÀh were obtained in >90% purity
after a simple aqueous workup. Alkene substrates provided
modest to good yields of the desired hydroperoxides 7iÀj
following purification.28 In addition to providing hydroper-
oxy Meldrum’s acid derivatives in good yield, this metho-
dology also provided the barbituric acid derivative 9 with
pendant unsaturation in modest yield, a product presum-
ably unattainable in Mn(III)-catalyzed hydroperoxidations.
a Isolated yield without need for purification (except 7i, 7j, and 9).
b Yield following purification on SiO2. c 10:1 with alcohol. d 17:1 with
alcohol.
We next assayed the utility of unsaturated hydroper-
oxide products in intramolecular oxidation via endoper-
oxide formation. Au(I)-catalyzed cycloetherificationshave
been reported with a variety of gold catalysts,29 but to the
best of our knowledge, the corresponding endoper-
oxidation is unknown. Alkyl-substituted alkynyl hydro-
peroxides 7e,f undergo 6-endo cyclization catalyzed by
triphenylphosphinegold(I) triflimide30 in MeOH to give
mixed ketal endoperoxides in good yield (Scheme 3).31
Subsequent reductive cleavage of the OÀO bond of 10a
followed by hemiketalization of the transient ketone pro-
vided 11 in excellent yield with 3:1 dr. Ionic hydrogena-
tion32 of 11 affords tetrahydrofuran 12 in a highly diastereo-
convergent process.33
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products can be accessed from the same mixed ketal endo-
peroxide. Ionic hydrogenation of 10a provides endoper-
oxide 13 in modest yield with good diastereoselectivity as
(26) For representative thermogravimetric analyses of the peroxide
products, see the Supporting Information. While we encountered no
hazardous decomposition during the course of this work, anyone work-
ing with peroxides should be aware that spontaneous and exothermic
decomposition is possible. For some references on peroxide properties
and safety, see: (a) Zabicky, J. In The Chemistry of the Peroxide Group;
Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 2006; Part 2, Vol. 2,
pp 597À773. (b) Shanley, E. S. In Organic Peroxides; Swern, D., Ed.;
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also gave no reaction (TfOH, Cu(OTf)2, Ag(OTf), PtCl2, AuCl, AuCl3,
PPh3AuCl, and AuCl/AgPF6).
ꢀ
^
(27) (a) The Supporting Information describes additional optimiza-
tion studies. (b) Simple esters and branched malonates are not suitable
substrates for the Cu-catalyzed aerobic oxidation.25a
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the oxidative deacylation.25a
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Gold(I)-Catalyzed Endoperoxidation of Hydroper-
oxides and Endoperoxide Reactions
Scheme 4. Iodoendoperoxidation of Homoallylhydroperoxy-
Meldrum’s Acid and Barbituric Acid Derivatives
Scheme 5. Endoperoxide Cleavage in 1,2-Dioxolane System
In summary, we have developed a simple, mild and
efficient catalytic method for the hydroperoxidation of
Meldrum’s acid derivatives including those with unsatura-
tion. The hydroperoxide products can be used for intra-
molecular oxidation via electrophilic activation of the
pendant πCtC and πCdC functionality. Au(I)-catalyzed
endoperoxidations of hydroperoxyalkynes have been re-
ported for the first time. Reductive cleavage of the OÀO
bond yields 1,n-diol functionality with convenient differ-
entiation of the alcohols via lactonization, thereby provid-
ing the conceptual blueprint for the development of atom-
efficient O2/H2 dihydroxylations. Current efforts in our
laboratory are focused on expanding this methodology
to a wider range of Meldrum’s acid derivatives to provide
diverse endoperoxides and 1,n-diols.
predicted by standard half-chair analysis of the intermedi-
ate oxocarbenium ion. Reductive cleavage of the OÀO
bond with concomitant Meldrum’s acid opening and
decarboxylation gives the desired 1,4-diol functionality
as lactone 14 in good yield as a single diastereomer,
implying that the decarboxylation/protonation is com-
pletely stereoselective.
The complementary 5-exo cyclization mode was realized
through the remote oxidation of alkenyl hydroperoxy
Meldrum’s acid derivatives (Scheme 4). Homoallyl-
hydroperoxy 7i cyclized via electrophilic activation of the
alkene with 1,3-diiodo-5,5-dimethylhydantoin (DIH).34
This process was highly regio- and stereoselective providing
the 1,2-dioxolane 15a with pendant iodide in modest yield.
The N,N-dimethylbarbituric acid derivative 9 reacted
analogously giving the endoperoxide 15b in 49% yield.
Metal-catalyzed hydrogenolysis or thiourea/MeOH
provided smooth OÀO bond cleavage of 15a (Scheme 5).
Concomitant cyclization/ring-opening occurred on the
Meldrum’s acid with complete diastereotopic group dis-
crimination to provide the differentiated 1,3-diol function-
ality in the form of lactone 16, conveniently isolated as the
dicyclohexylamine salt in good yield as a single diastereo-
mer. The relative configuration of 16 was determined by
single-crystal X-ray diffraction.
Acknowledgment. The project described was supported
by Award No. R01 GM084927 from the National Institute
of General Medical Sciences. S.W.K. acknowledges a
National Science Foundation Graduate Research Fellow-
ship. D.T.D. acknowledges a Vietnam Education Founda-
tion Fellowship. The authors thank Dr. Peter White
(UNCÀCH) for X-ray diffraction analysis.
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and crystal-
lographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(34) (a) Reference 11. (b) Orazi, O. O.; Corral, R. A.; Bertorello, H. E.
J. Org. Chem. 1965, 30, 1101–1104.
The authors declare no competing financial interest.
D
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