(PPh3/toluene/heat) was the result of another heterocyclic
scaffold modification whereby the potential for carbon-carbon
bond formation and oxazole extension exists through Wittig
chemistry.11 The 2-(cyanomethyl)oxazole 16 was prepared by
cyanide (NaCN/DMF) substitution of 1.12 The nitrile group of 15
should offer excellent potential for carbon-carbon bond formation
at the 2-methylene position, through carbanion formation, as well
as providing a reactive acceptor for alkyllithiums toward gaining
carbonyl products. We demonstrate the usefulness of the 2-
halomethyloxazoles 1 and 2 in carbon-carbon bond formation by
a synthesis of the non-steroidal anti-inflammatory Oxaprozin
(Scheme 2).13 Chloromethyloxazole 1 is reacted with the anion of
diethylmalonate (NaH/THF) which affords the diester 17 in 40%
isolated yield. Under the same conditions, alkylation with the
more reactive bromomethyloxazole 2 provides the diester 17 in
90% isolated yield. Saponification of 17 (aq. NaOH) followed by
acidification (dil. HCl/reflux) then gives Oxaprozin in 47% yield.
synthesis of Oxaprozin using malonate alkylation as the key step.
A number of diverse amine nucleophiles may be used to prepare
2-methyloxazole-derived primary or secondary amines.
Similarly, the halomethyloxazoles react well with alkoxides or
phenoxides to give the corresponding ethers which have anti-
inflammatory or analgesic activity. Sulfur nucleophiles such as
thiocyanates and thiophenoxides react in high yield to give the
corresponding carbon-sulfur bond motif whereby the 2-
phenylthiomethyl analogue will show promise in further reaction
scenarios.
Acknowledgments
The measurement of high resolution mass spectra by the
Texas A&M University Laboratory for Biological Mass
Spectrometry is acknowledged. Financial support from the
NIH/NIDCR through grant 1RO1DE023206 is gratefully
acknowledged.
Scheme 2. Synthesis of Oxaprozin:
Supplementary Material
N
Supplementary data (1H NMR, FTIR) for compounds 2-18,
20; and additional 13C NMR data for new compounds 5, 9, 12-15,
17, 18, 20. HRMS data are included for compounds 9, 10-16, 20;
along with experimental procedures associated with this article
N
O
a
O
X
CH(COOEt)2
1, X=Cl
2, X=Br
17
b, c
References and notes
N
O
1.
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COOH
18, Oxaprozin
2.
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Reagents and conditions:(a) NaH/diethyl malonate/THF/
5oC to rt/16h (40%, X=Cl; 90%, X=Br). (b) 20% aq. NaOH/
rt/16h. (c) 10% aq. HCl, pH 3-5/reflux/3h (47% for b,c).
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experiments, our previously-reported 4,5-diphenyloxazole
aldehyde 195a,11 reacts as a convenient partner in a Schiff base
formation/reduction sequence to give secondary amines.
Therefore the employment of the oxazole aldehyde will provide a
useful alternative to the halomethyl intermediates in providing 2-
aminomethyl-substituted oxazole scaffolds.14 For example, the
reaction of 19 with (+)-R-α-methylbenzylamine (methanol/
reflux/16 h) gave the expected intermediate Schiff base (73%)
which was directly reduced with sodium borohydride
(methanol/rt/1h) to provide the chiral amine 20 (76%).
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H Ph
HN
Ph
Ph
O
H
Ph
Ph
N
N
O
CH3
O
19
20
In summary we have shown that 2-(chloromethyl)-4,5-
diphenyloxazoles, which are readily available from the
corresponding chloroacetyl esters of benzoin or substituted
benzoins, are excellent reactive scaffolds for synthetic
elaboration at the 2-(methylene) position. The 2-
(bromomethyl)oxazole analogue is best suited for a concise