A practical method for oxazole synthesis by cycloisomerization of propargyl amides

Article abstract of DOI:10.1021/ol0485058

(Chemical Equation Presented) 2,5-Disubstituted and 2,4,5-trisubstituted oxazol-5-yl carbonyl compounds were prepared in good yields by a mild SiO ₂-mediated cycloisomerization of propargyl amides.

Full text of DOI:10.1021/ol0485058

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3593-3595
A Practical Method for Oxazole
Synthesis by Cycloisomerization of
Propargyl Amides
Peter Wipf,* Yasunori Aoyama, and Tyler E. Benedum
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf@pitt.edu
Received July 29, 2004
ABSTRACT
2,5-Disubstituted and 2,4,5-trisubstituted oxazol-5-yl carbonyl compounds were prepared in good yields by a mild SiO2-mediated cyclo-
isomerization of propargyl amides.
Oxazoles are common substructures in numerous biologically
active compounds, synthetic intermediates, and pharma-
ceuticals.1-3 Accordingly, many strategies have been devel-
oped for the preparation of oxazoles.1 In the classical and
widely used Robinson-Gabriel oxazole synthesis,4 harsh
dehydrating reagents (H2SO4, P2O5, SOCl2, etc.) are usually
required, which restricts the range of tolerated functional
groups. Milder protocols for cyclodehydration and oxazole
ring synthesis have recently become available.5 In addition,
alternatives to the cyclodehydration of hydroxy- or keto-
amides such as base-promoted or palladium-catalyzed cy-
cloisomerizations of alkynyl amides have recently been
reported by several groups.6 As part of our studies of oxazole-
containing natural products, we are interested in a general
approach toward oxazol-5-yl acetates. Agents containing this
core functionality possess diverse pharmacological properties,
including cardiovascular, antiinflammatory, and antihyper-
glycemic activities.7 C(5)-â-Carbonyl-substituted oxazoles
III are also valuable building blocks in organic synthesis.
Herein, we report a practical and mild method for the
syntheses of these 2,5-disubstituted and 2,4,5-trisubstituted
oxazoles by the silica gel mediated cycloisomerization of
alkynyl amides I.
Deprotonation of propargyl amides 1 with nBuLi or
LiHMDS, nucleophilic addition to benzaldehyde, and Dess-
Martin oxidation provided ready access to keto amides 3
(Scheme 1). In the course of a detailed investigation of the
cycloisomerization of alkynyl amide 3a, we found that
treatment with bases such as NaHMDS, Et3N, and K2CO3
provided no desired product (Table 1, entries 1, 2, and 3).
The instability of oxazole 4a under basic conditions led to
complex reaction mixtures. Neutral thermal conditions or the
presence of a palladium catalyst8 were similarly unsuccessful
(1) (a) Wipf, P. Chem. ReV. 1995, 95, 2115. (b) Jin, Z. Nat. Prod.
Rep. 2003, 20, 584. (c) Palmer, D. C., Ed. Oxazoles: Synthesis, reactions,
and spectroscopy, Part A; J. Wiley & Sons: Hoboken, NJ, 2003; Vol.
60.
(2) Palmer, D. C., Ed. Oxazoles: Synthesis, reactions, and spectroscopy,
Part B; J. Wiley & Sons: Hoboken, NJ, 2004; Vol. 60.
(3) See, for example: (a) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-
Bakht, S. C.; Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15,
269. (b) McGovern, S. L.; Caselli, E.; Grigorieff, N.; Shoichet, B. K. J.
Med. Chem. 2002, 45, 1712. (c) Murcia-Soler, M.; Perez-Gimenez, F.;
Garcia-March, F. J.; Salabert-Salvador, M. T.; Diaz-Villanueva, W.; Castro-
Bleda, M. J.; Villanueva-Pareja, A. J. Chem. Inf. Comput. Sci. 2004, 44,
1031.
(4) Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38, 2407.
(5) (a) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558. (b) Wipf,
P.; Miller. C. P. J Org. Chem. 1993, 58, 3604. (c) Wipf, P.; Yokokawa, F.
Tetrahedron Lett. 1998, 39, 2223. (d) Wipf, P.; Miller, C. P. Tetrahedron
Lett. 1992, 33, 907. (e) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165. (f) Wipf, P.; Methot, J.-L. Org.
Lett. 2001, 3, 1261.
(6) (a) Nilsson, B. M.; Hacksell, U. J. Heterocycl. Chem. 1989, 26, 269.
(b) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63, 7132.
(c) Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett.
2001, 3, 2501. (d) Coqueron, P.-Y.; Didier, C.; Ciufolini, M. A. Angew.
Chem., Int. Ed. 2003, 42, 1411.
(7) (a) Dow, R. L. J. Org. Chem. 1990, 55, 386. (b) Reck, S.;
Friedrichsen, W. J. Org. Chem. 1998, 63, 7680.
10.1021/ol0485058 CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/28/2004

Scheme 1. Silica Gel Mediated Conversion of Propargyl
Scheme 2. Selective Conversion of Alkyl and Alkenyl
Amides to 2,5-Disubstituted Oxazoles
Ketones to 2,5-Disubstituted Oxazoles
This methodology was readily extended to alkyl and
alkenyl carbonyl oxazoles, oxazol-5-yl acetates, and 2,4,5-
trisubstituted oxazoles (Schemes 2, 3, and 4, respectively).
Starting with amide 1a, the preparation of the isopropyl and
styryl ketones 7a and 7b followed a synthetic pathway
analogous to that of oxazoles 4 (Scheme 2). For the synthesis
of oxazol-5-yl acetate 11, propargylamine was converted to
the bis-TMS-protected amine 8 (Scheme 3). Treatment of
(entries 4 and 5). Acids such as pyridinium p-toluene-
sulfonate (PPTS), Cu(OTf)2, and Yb(OTf)3 were not effective
(entries 6, 7, and 9). However, Ag(I)-catalyzed cycloisomer-
ization9 proceeded to give 4a in a 57% yield (entry 8).
Moreover, a mild silica gel mediated reaction was found to
provide oxazolyl ketone 4a in excellent yield (entry 10).10,11
These reaction conditions proved general in scope with the
exception of ethyl carbamate 3e, which failed to undergo
the heterocyclization process (Scheme 1). In addition, the
C(2)-ethyl-substituted oxazole 4d was isolated in a modest
32% yield, but sterically hindered aliphatic and vinyl groups
at the C(2) position were well tolerated.
Scheme 3. Silica Gel Mediated Conversion of Propargyl
Amides to Oxazol-5-yl Acetates
Table 1. Preparation of oxazole 4a from alkynyl ketone 3a:
Reaction Optimization
yield
entry
1
conditions
product
[%]a
NaHMDS (1.0 equiv),
-78 °C, 30 min
Et3N (1.0 equiv), CH2Cl2,
complex mixture ND
complex mixture ND
complex mixture ND
2
rt, 4 h
the alkynyllithium derivative of 8 with ethyl chloroformate
gave ester 9. Fluoride-catalyzed amidation of (TMS)2-amine
9 with benzoyl chloride afforded alkynyl amide 10 in good
yield.12 Use of the fluoride-catalyzed amidation procedure
was crucial since alkynyl amide 10 as well as the desilylated
3
4
5
K2CO3 (6 equiv), DMF, rt, 4 h
toluene, reflux, 12 h
PdCl2 (10 mol %), MeCN,
rt, 24 h
no reaction
complex mixture ND
0
6
7
PPTS (1.0 equiv), CH2Cl2,
rt, 4 d
Cu(OTf)2 (0.2 equiv), CH2Cl2,
rt, 12 h
AgOTf (20 mol %), CH2Cl2,
rt, 12 h
Yb(OTf)3 (20 mol %), CH2Cl2,
rt, 24 h
no reaction
no reaction
4a
0
(8) Wipf, P.; Soth, M. J. Org. Lett. 2002, 4, 1787.
0
(9) For silver(I)-assisted heterocyclizations of acetylenic compounds,
see: (a) Pale, P.; Chuche, J. Tetrahedron Lett. 1987, 28, 6447. (b) Marshall,
J. A.; Sehon, C. A. Org. Synth. 1999, 76, 263. (c) Marshall, J. A.; Sehon,
C. A. J. Org. Chem. 1995, 60, 5966.
(10) A silica gel mediated furan synthesis has been reported by Marshall’s
group: (a) Marshall, J. A.; Zou, D. Tetrahedron Lett. 2000, 41, 1347. (b)
Marshall, J. M.; Van Devender, E. A. J. Org. Chem. 2001, 66, 8037.
(11) Care should be taken to use “dry” silica gel. Flash chromatography
grade silica gel (230-400 mesh) from several suppliers was used as received
and gave consistent results for 4a. However, if 10% w/w H2O was added
to the silica gel, the yield of 4a dropped by ca. 10% and some starting
material 3a remained after 24 h reaction time.
8
57
0
9
no reaction
10
silica gel (300%, w/w), CH2Cl2, 4a
99
rt, 24 h
a Yields of isolated 4a; ND ) not determined.
3594
Org. Lett., Vol. 6, No. 20, 2004

Scheme 4. Silica Gel Mediated Conversion of a Propargyl
Scheme 5. Chemoselective Heterocyclization To Give a
Amide to a 2,4,5-Trisubstituted Oxazole
2,4,5-Trisubstituted Polyunsaturated Oxazolyl Ketone
oxazol-5-yl ketones and esters. The use of silica gel, a cheap
and easily removable reagent, facilitates the cycloisomer-
ization process and allows for mild reaction conditions and
considerable functional group compatibility. Since ap-
propriately substituted cycloisomerization precursors can be
readily obtained from in situ prepared alkynyllithium re-
agents, this procedure is suitable for diversity-oriented
heterocycle synthesis15,16 as well as natural product synthesis.
derivative of 9 were unstable under basic conditions. The
silica gel mediated cycloisomerization of 10 led to oxazole
11 in 90% yield. As expected, a longer reaction time (72 h)
was necessary for the synthesis of oxazol-5-yl acetate 11
than for oxazoles 4a-d and 7a,b (24 h). The isomerization
of oxazoline II to oxazole III proved to be the rate-limiting
step in this conversion.
The addition of substituents at the 4-position of the oxazole
heterocycle required the synthesis of R-branched propargylic
amines (Scheme 4). Conversion of hydrocinnamaldehyde 12
to the propargylic alcohol, displacement of the corresponding
mesylate with azide, and reduction followed by deprotection
provided amine 13 in 61% overall yield. Amide formation
and subsequent nucleophilic addition to benzaldehyde pro-
vided alcohol 15. The Dess-Martin oxidation followed by
the silica gel mediated cycloisomerization led in good yield
to the 2,4,5-trisubstituted oxazole 16.13
Acknowledgment. This work has been supported by a
grant from the National Institutes of Health (GM-55433).
Y.A. gratefully acknowledges a Shionogi Postdoctoral Fel-
lowship.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0485058
As a further demonstration of the chemoselectivity and
functional group tolerance of this new oxazole synthesis,
TBS-protected diyne 19 was converted to the corresponding
trisubstituted oxazole 20 (Scheme 5). The dianion of crotyl
amide 17 was added to aldehyde 18 to give alcohol 19.
Subsequent Dess-Martin periodinane oxidation and silica
gel mediated cyclization led to the desired oxazolyl ketone
20 in 58% yield without significant interference of the
additional double and triple bonds in the substrate.14
In conclusion, we have developed a new, practical method
for the preparation of 2,5-disubstituted and 2,4,5-trisubstituted
(14) Interestingly, the structurally related TMS-protected diyne 21
underwent competitive double cycloisomerization to afford a 1:1 mixture
of oxazole 22 and benzindenone 23.
(12) (a) Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E.; Pataud-sat, M.
Tetrahedron Lett. 1982, 32, 3257. (b) Corriu, R. J. P.; Moreau, J. J. E.;
Pataud-Sat, M. J. Org. Chem. 1990, 55, 2878.
(13) The Dess-Martin oxidation of 15 afforded mixtures of alkynyl
ketones and oxazole 16. After the chromatographic removal of byproducts
derived from the Dess-Martin reagent, the mixture was treated with silica
gel to complete the conversion to 16.
(15) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46.
(16) Wipf, P.; Stephenson, C. R. J.; Walczak, M. A. A. Org. Lett. 2004,
6, 3009.
Org. Lett., Vol. 6, No. 20, 2004
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