3
(CHCl3/reflux, 2h, 97%).8 The cyclization of the tricyclic esters
to provide the triaryloxazoles using ammonium acetate in acetic
acid is not without limitations and certain substitution patterns on
either the benzoin portion or the benzoyl ester portion may
nullify any yield of desired product. For example, the 2-azido-, 3-
azido- or 4-azidobenzoyl ester of 4, 4´-dibromobenzoin 15a-c
cyclized under normal conditions (NH4OAc/HOAc, 115ºC) to
afford the corresponding 2-azidopheny-(4,4'-dibromodiphenyl)
oxazoles 16a-c, but the 2-azido, 3-azido or 4-azidobenzoyl esters
of 2,2´-dibromobenzoin 17a-c do not cyclize to give the expected
azidophenyl-2,2'-(dibromodiphenyl) oxazoles. Another example
of steric influence resides in a comparison of the cyclization
reactions of the 4-iodobenzoyl ester 18 and 2-iodobenzoyl ester
20 of benzoin. Treatment of the 4-iodobenzoyl ester 18 under
normal cyclization conditions affords a clean yield (95%) of the
4-iodophenyloxazole 19, while under the same conditions, the
ortho-iodobenzoyl ester 20 gave none of the expected oxazole.
Spectrometry and Dr. Vanessa Santiago are acknowledged.
Financial support from the NIH/NIDCR through grant
1RO1DE023206 (DRD and FAL) is gratefully acknowledged.
Supplementary Information
The 1H, 13C, FTIR and HRMS data for 6a-i, 1a-i, 9a-c, 10a-c,
11a-c, 2a-c, 16a-c, 7, 12, 18 and 19 and experimental procedures
for compounds 4a-c, 5a-c, 6a-i, 1a-i, 9a-c, 10a-c, 2a-c, 11a-c, 7,
12, 13, 14 and 16a-c can be found in the online version at
References and notes
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Oxford, 2012; Vol. 24, pp 328-329.
Br
Br
Br
Br
O
O
N
O
O
N3
2. (a) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen,
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N3
15a: N3=2; Br=4,4'
15b: N3=3; Br=4,4'
15c: N3=4; Br=4,4'
16a: N3=2; Br=4,4'
16b: N3=3; Br=4,4'
16c: N3=4; Br=4,4'
17a: N3=2; Br=2,2'
17b: N3=3; Br=2,2'
17c: N3=4; Br=2,2'
No Cyclized Product
R1
R2
O
O
O
R1
R2
I
I
N
O
18: R1,R2=C6H5,
I=para
19: R1,R2=C6H5,
I=para
20: R1,R2=C6H5,
I=ortho
No Cyclized Product
In summary, we have detailed a synthetic route to 2, 4, 5-
trisubstituted oxazoles which are differentially substituted at the
4- and 5- positions with phenyl groups and alkyl groups
respectively. The route utilizes non-symmetrical acyloins as
starting materials and has the advantage of not involving
installation of an appendage on a pre-formed oxazole. In contrast
to cyclizing azidoalkyl esters to azidoalkyloxazoles, our newly-
developed strategy utilizes direct cyclization of haloalkyl esters
to haloalkyloxazoles so that they may be either transformed to
azides or further elaborated using other nucleophiles. We found
the chloromethyloxazoles to be a valuable intermediate for the
preparation of many more oxazole-based scaffolds and these
studies will be reported in due course.
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Acknowledgments
8. See Supplementary Information for general procedures.
The measurement of high resolution mass spectra by the
Texas A&M University Laboratory for Biological Mass