Ceric ammonium nitrate promoted oxidation of oxazoles

Article abstract of DOI:10.1021/ol0624530

The ceric ammonium nitrate promoted oxidations of 4,5-diphenyloxazoles and oxazoles with various substitution patterns have been investigated. This transformation results in the formation of the corresponding imide in good yield and tolerates a wide variety of functional groups and substituents on the oxazole moiety.

Full text of DOI:10.1021/ol0624530

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5669-5671
Ceric Ammonium Nitrate Promoted
Oxidation of Oxazoles
David A. Evans,* Pavel Nagorny, and Risheng Xu
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received October 5, 2006
ABSTRACT
The ceric ammonium nitrate promoted oxidations of 4,5-diphenyloxazoles and oxazoles with various substitution patterns have been investigated.
This transformation results in the formation of the corresponding imide in good yield and tolerates a wide variety of functional groups and
substituents on the oxazole moiety.
The selection of an appropriate protecting group in the
context of a complex organic synthesis remains an ongoing
challenge due to constraints arising from compatibility issues.
In particular, finding a protecting group that is capable of
preserving the carboxylic acid oxidation state can be espe-
cialy difficult. Although there are a number of protecting
groups developed for alcohols, there are fewer options for
masking a carboxylic acid, with esters1 and amides1,2 usually
being the most common choices.
assembled or partially assembled subunits. The purpose of
this paper is to report that this heterocycle is also quite
sensitive to one-electron oxidants such as ceric ammonium
nitrate (CAN) or DDQ. Thus, when oxazole 1 was exposed
to these oxidants (Scheme 1), the corresponding lactones 3a
Scheme 1. Oxidation of the Oasomycin Aa,b C39-C46 Subunit
In our recent studies resulting in the total synthesis of
oasomycin A,3 we employed the “Wasserman option”4 for
this problem: the protection of the C46 lactone carboxylate
of oasomycin A as its derived 4,5-diphenyloxazole. The
singlet oxygen-mediated liberation of this carboxyl moiety
could, in principle, be executed at numerous points in the
synthesis due to the compatibility of this transformation with
the multitude of other oxygen-protecting groups in the
(1) Green, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999.
(2) For examples of amide protecting groups in organic synthesis, see:
(a) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Engl. 2002, 41, 4573-4576. (b) Evans, D. A.; Katz, J. L.; Peterson, G.
S.; Hintermann, T. J. Am. Chem. Soc. 2001, 123, 12411-12413. (c) Evans,
D. A.; Carter, P. H.; Carreirra, A. B.; Prunet, J. A.; Lautens, M. J. Am.
Chem. Soc. 1999, 121, 7540-7552 and references cited therein.
(3) Evans, D. A.; Nagorny, P.; Reynolds, D. J.; McRae, K. J. Angew.
Chem., Int. Ed. 2006, 45, in press.
(4) (a) Wasserman, H. H.; DeSimone, R. W.; Ho, W. B.; Spencer-Prowse,
K.; Spada, A. P. Tetrahedron Lett. 1992, 33, 7207-7210. (b) Wasserman,
H. H.; Gambale, R. J. J. Am. Chem. Soc. 1985, 107, 1423-1424 and
references cited therein.
and 3b were obtained. Acordingly, these reagents provide
an alternative to oxazole singlet oxygenation.
Examination of the CAN5-promoted oxidation leading to
3a revealed that lactone 3a is formed through the interme-
diacy of imide 2. Intrigued by the fact that the 4,5-
10.1021/ol0624530 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/02/2006

diphenyloxazole moiety is oxidized in preference to the
p-methoxybenzyl acetal, we decided to investigate the
generality of this reaction. Thus, a CAN-mediated oxidation
of a simple oxazole (entry 4) was executed under similar
conditions (Table 1). The formation of a corresponding imide
acid for a variety of substrates. The illustrated reaction is
tolerant of primary, secondary, and tertiary alkyl substitution
in the 2-position (entries 1-7)6 as well as to alkenyl
substitutents (entires 8-11).6 In general, even in the complex
cases (entries 11-13),3 the 4,5-diphenyloxazole moiety was
oxidized preferentially to the other functional groups.
However, in cases where the substituent is prone to oxidation
(entry 5) or the resulting imide can be isomerized (entries
10 and 11), an erosion of yield was observed. In the later
cases (entries 12 and 13), the intermediate imide can be
intercepted by a careful monitoring of the reaction progress.
Thus, depending on the oxidation time (entry 13, Table 1),
the transformation can afford either imide 2 or lactone 3a
(Scheme 1) in 76 and 77% yield, respectively.
Table 1. The Oxidation of Various 4,5-Diphenyloxazoles
Next, we decided to examine other one-electron oxidants
that mght be used as alternatives to CAN. The results of
this survey are outlined in Table 2. Potassium permanganate
Table 2. Survey of Different Oxidants
entry
oxidant
time (h) yield (%) side product (yield, %)
1
2
3
4
5
6
7
KMnO4
Mn(OAc)3
DDQ
2
336
336
336
48
57
0
0
0
40
0
benzil (24)
benzil (<5)
DDQa
Ce(OTf)4
Ce(SO4)2
CAN
benzil (<5)
benzil (42)
48
2
90
a Performed in CH2Cl2/H2O (9:1), rt.
was found to promote the oxidation of 4 to the corresponding
imide (entry 1); however, a lower yield as well as substantial
amounts of the benzil side product made this oxidant less
attractive. Manganese(III) acetate and DDQ (entries 2-4)
did not exhibit any reactivity such that starting material and
traces of benzil were the only detectable products. Interest-
ingly, the fact that sulfone 1 was slowly oxidized with DDQ
(Scheme 1) with the formation of lactone 3b and benzil
indicates that the C43 alcohol is essential for this transfor-
mation to take place. Finally, we decided to examine other
Ce(IV) sources (entries 5 and 6). Thus, we found a solution
of Ce(SO4)2 in sulfuric acid did not promote any reaction
besides the minor hydrolysis of oxazole followed by oxida-
tion of the formed benzoin to benzil. In contrast, Ce(OTf)4
slowly oxidized oxazole 4 to the corresponding imide 5.
a The reaction was carried out using 3.8 equiv of CAN in CH3CN/H2O
(8:1), rt. b Reaction was carried out using 2.7 equiv of CAN in CH3CN/
H2O (8:1), rt. c Reaction was carried out using 5.8 equiv of CAN in CH3CN/
H2O (8:1), rt (Bz ) benzoyl, PMP ) p-methoxyphenyl, PT ) 1-phenyl-
1H-tetrazole, Xc ) (S)-4-benzyloxazolidin-2-one).
(5) For the reviews of CAN-promoted oxidations, see: (a) Dhakshi-
namoorthy, A. Synlett 2005, 19, 3014-3015. (b) Nair, V.; Balagopal, L;
Rajan, R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21-30. (c) Nair, V.;
Panicker, S. B.; Nair, L. G.; George, T. G.; Augustine, A. Synlett 2003, 2,
156-165. (d) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. ReV. 1997,
26, 127-132. (e) Molander, G. Chem. ReV. 1992, 92, 29-68.
(6) (a) Meanwell, N. A.; Rosenfeld, M. J.; Trehan, A. K.; Wright, J. J.
K.; Brassard, C. L.; Buchanan, J. O.; Federici, M. E.; Fleming, J. S.;
Gamberdella, M.; Zavoico, G. B.; Seilert, S. M. J. Med. Chem. 1992, 35,
3483-3497. (b) Wasserman, H. H.; Gambale, R. J.; Pulmer, M. Tetrahedron
1981, 37, 4059-4067.
was also observed, and it was optimal when more than 3.0
equiv of CAN was used. Eleven other 4,5-diphenyloxazoles
have been evaluated (Table 1). The oxidation was found to
be general, affording the corresponding imide and benzoic
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Org. Lett., Vol. 8, No. 24, 2006

The CAN-promoted oxidation of other types of oxazoles
has also been addressed (Table 3). In general, a variety of
to be sensitive to the nature of the R3 substituent, and in
some cases, the oxidation was sluggish (entry 5) or resulted
in decomposition of the starting material (entry 7).
The balanced half-reaction for the oxazole transformation
requires a 4-electron oxidation (eq 1). While the electron
source could be exclusively Ce(IV), nitrate reduction cannot
be ruled out as an addiltional source of electrons.8
Table 3. Survey of Substituted Oxazole Oxidation
In conclusion, we have developed an efficient method of
oxidizing oxazoles to the corresponding imides. This oxida-
tion may serve as an alternative to the Wasserman singlet
oxygen conditions if other functionalities sensitive to singlet
oxygen are present. The fact that 4,5-diphenyloxazoles are
stable to a number of different oxidants (Table 2) while being
easily oxidized with CAN makes this functionality a useful
protecting group for imides and carboxylic acids. Also, we
believe that the awareness of such an oxidation is important
in realizing the total syntheses of complex oxazole-containing
natural products, as a number of modern oxidants are known
to act via a one-electron-transfer mechanism.
Acknowledgment. Financial support has been provided
by the National Institutes of Health (GM-33327-19).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
a The reaction was carried out using 3.8 equiv of CAN in CH3CN/H2O
(8:1). b Reaction was carried out using 3.3 equiv of CAN in CH3CN/H2O
(8:1) (PMP ) p-methoxyphenyl, PT ) 1-phenyl-1H-tetrazole) Xc )
(R)-4-benzyloxazolidin-2-one.
OL0624530
(7) For the syntheses of the substrated of entries 3-6, see: (a) Nagayoshi,
K.; Sato, T. Chem. Lett. 1983, 9, 1355-1356. (b) Panek, J. S.; Beresis, R.
T. J. Org. Chem. 1996, 61, 6496-6497. (c) Evans, D. A.; Fitch, D. M.;
Smith, T. E.; Cee, V. J.; Cho, P. S. J. Am. Chem. Soc. 2000, 122, 10033-
10046. (d) Boger, D. L.; Curran, T. T.; J. Org. Chem. 1992, 57, 2235-
2244.
(8) (a) Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Org. Lett.
2005, 7, 3303-3306. (b) Zhang, Y.; Jiao, J.; Flowers, R. A., II. J. Org.
Chem. 2006, 71, 4516-4520.
analogues (entries 1-5)7 may be readily oxidized to the
derived imides. Similar to 4,5-diphenyloxazoles, the corre-
sponding imide could be isomerized or cleaved under the
reaction conditions (entries 5-7). Also, the oxidation seems
Org. Lett., Vol. 8, No. 24, 2006
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