General methodology for the preparation of 2,5-disubstituted-1,3-oxazoles

Article abstract of DOI:10.1021/ol902833p

Chemical equation presented Deprotonation of 2-(phenylsulfonyl)-1,3-oxazole (1) readily provides a useful C-5 carbanion that is reactive with a variety of electrophiles. Aldehydes and ketones are useful substrates, and the formation of 5-iodo- and 5-tri-n-butylstannyl oxazoles affords access to cross-coupling reactions. Subsequent nucleophilic displacement of the 2-phenylsulfonyl group provides a general route for the synthesis of 2,5-disubstituted-1,3-oxazoles.

Full text of DOI:10.1021/ol902833p

ORGANIC
LETTERS
2010
Vol. 12, No. 4
808-811
General Methodology for the Preparation
of 2,5-Disubstituted-1,3-oxazoles
David R. Williams* and Liangfeng Fu
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received December 15, 2009
ABSTRACT
Deprotonation of 2-(phenylsulfonyl)-1,3-oxazole (1) readily provides a useful C-5 carbanion that is reactive with a variety of electrophiles.
Aldehydes and ketones are useful substrates, and the formation of 5-iodo- and 5-tri-n-butylstannyl oxazoles affords access to cross-coupling
reactions. Subsequent nucleophilic displacement of the 2-phenylsulfonyl group provides a general route for the synthesis of
2,5-disubstituted-1,3-oxazoles.
Oxazoles represent an important class of five-membered
heterocycles.1 Continuing interest in the chemistry of 1,3-
oxazoles has been undoubtedly stimulated by the incorpora-
tion of this ring system in a variety of biologically significant
secondary metabolites, such as hennoxazole A,2 telomesta-
tin,3 phorboxazoles A and B,4 the ulapualides,5 diazonamides
A and B,6 and rhizopodin.7 Depsipeptides often contain 1,3-
oxazoles as a result of oxidative cyclodehydrations of serine
or threonine residues resulting in 2,4-disubstitution of the
heterocycle.8 Additional examples of naturally occurring 1,3-
oxazoles feature 2,5-disubstitution and 5-monosubstitution,
and these substances may also exhibit significant biological
activity.9
The proliferation of interesting structures within this family
has inspired the development of methods to address the
synthesis of specific substitution patterns. Williams and Wipf
have devised oxidative cyclodehydration strategies to provide
a general route for the de novo preparation of 2,4-disubsti-
tuted oxazoles.10 Several laboratories have recently described
cross-coupling reactions for alkenylation and arylation at C-2
of the oxazole nucleus,11 as well as studies of Stille reactions
of 2-phenyl-1,3-oxazoles leading to C-4 and C-5 substitu-
(1) Taylor, E. C.; Wipf. P. Oxazoles: Synthesis, Reactions, and Spec-
troscopy; John Wiley & Sons: Hoboken, 2003.
(2) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.; Higa, T.; Gravalos, D. G.
J. Am. Chem. Soc. 1991, 113, 3173–3174.
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Furihata, K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123, 1262–
1263.
(4) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126–
8131.
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847. (b) Dalisay, D. S.; Rogers, E. W.; Edison, A. S.; Molinski, T. F. J.
Nat. Prod. 2009, 72, 732–738.
(9) (a) Giddens, A. C.; Boshoff, H. I. M.; Franzblau, S. G.; Barry, C. E.,
III; Copp, B. R. Tetrahedron Lett. 2005, 46, 7355–7357. (b) Fresneda, P. M.;
Castan˜eda, M.; Blug, M.; Molina, P. Synlett 2007, 324–326. (c) Shiomi,
K.; Arai, N.; Shinose, M.; Takahashi, Y.; Yoshida, H.; Iwabuchi, J.; Tanaka,
Y.; Omura, S. J. Antibiot. 1995, 48, 714–719.
(6) For structure revision of diazonamide A, see: Li, J.; Burgett,
A. W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew. Chem., Int. Ed.
2001, 40, 4770–4773.
(10) (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165–1168. (b) For initial application of this methodology
in the synthesis of hennoxazole A, see: Williams, D. R.; Brooks, D. A.;
Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 1303–1305.
(7) Hagelueken, G.; Albrecht, S. C.; Steinmetz, H.; Jansen, R.; Heinz,
D. W.; Kalesse, M.; Schubert, W.-D. Angew. Chem., Int. Ed. 2008, 48,
595–598.
(8) For examples, see: (a) Kanoh, K.; Matsuo, Y.; Adachi, K.; Imagawa,
H.; Nishizawa, M.; Shizuri, Y. J. Antibiot. 2005, 58, 289–292. (b) Perez,
L. J.; Faulkner, D. J. J. Nat. Prod. 2003, 66, 247–250. (c) Kohno, J.;
Kameda, N.; Nisho, M.; Kinumaki, A.; Komatsubara, S. J. Antibiot. 1996,
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M. F. Org. Lett. 2008, 10, 2717–2720. (c) Hodgetts, K. J.; Kershaw, M. T.
Org. Lett. 2002, 4, 2905–2907. (d) Smith, A. B., III; Minbiole, K. P.; Freeze,
S. Synlett 2001, 1739–1742.
10.1021/ol902833p  2010 American Chemical Society
Published on Web 01/19/2010

tion.12 Direct metalations via deprotonations of the 1,3-
oxazole ring have been studied in some cases.13 Removal
of the C-2 hydrogen leads to an equilibrium of the ring-
closed carbanion and the isomeric ring-opened isonitrile, and
acylation reactions produce 4,5-disubstituted oxazoles derived
from the Cornforth rearrangement.14 Examples of ring
metalations via complex-induced proximity effects15 (CIPE)
have been recorded in [2,4]bisoxazoles16 and for 2-methy-
loxazole-4-carboxylic acid.17 Very recently, Stambuli and
co-workers have described the selective C-5 deprotonation
of 2-methylthio-1,3-oxazole with tert-butyllithium leading
to the production of 2,5-disubstituted oxazoles.18 These
studies advance the earlier precedents of Shafer and Molinski
and reports of the regioselective copper-mediated allylation
of 2-(n-butylthio)-1,3-oxazole.19 In this letter, we disclose a
compilation of our findings for the site-selective deprotona-
tion and the synthetic utility of 2-(phenylsulfonyl)-1,3-
oxazole in processes of alkylation, alkenylation, and arylation
to afford a general pathway for the synthesis of 2,5-
disubstituted oxazoles.
Table 1. Reactions of 2-(Phenylsulfonyl)-1,3-oxazole 1
Direct incorporation of five-membered heterocycles into
complex molecules is an important and fundamental strategy
in medicinal chemsitry. Thus, we have explored the kinetic
deprotonation of 2-(phenylsulfonyl)-1,3-oxazole (1) and the
utility of carbanion 2. Reactions of 2 with a variety of
electrophiles and the subsequent replacement of the 2-phe-
nylsulfonyl group provide a general route for the preparation
of 2,5-disubstituted oxazoles 3 (Scheme 1). Our studies are
a Reaction conditions: a THF solution of sulfone 1 (1.0 equiv; 2.0 mmol)
was added into a solution of LDA (1.1 equiv) in THF at -78 °C. After
stirring under N2 for 1 h, electrophile in THF solution was added with
subsequent warming to 22 °C. b Products were purified by flash silica gel
chromatography. c Yields are reported for isolated and purified product.
Scheme 1. Site-Selective Substitutions of 1,3-Oxazole
The preparation of 1 began with the C-2 deprotonation of
oxazole using n-butyllithium at -78 °C (THF). Diphenyld-
isulfide was introduced, and reactions were allowed to stir
at room temperature (24 h) to give 2-phenylthio-1,3-oxazole
(91%) for oxidation with ammonium molybdate tetrahydrate
(2.2 equiv) in ethanol containing 30% aqueous H2O2 at 22
°C (98% yield).
The selective deprotonation of 2-(phenylsulfonyl)-1,3-
oxazole (1) with LDA (1.1 equiv) in THF at -78 °C afforded
a well-behaved C-5 carbanion 2 that reacted efficiently with
a number of electrophiles (Table 1). Under these reaction
conditions, alkylation of 2 with allyl bromide proceeded
poorly. This problem was overcome by transmetalation of 2
to give the corresponding organozinc species for a Negishi
cross-coupling to yield the desired alkylation product 14
(90%) (Scheme 3).
precedented by the selective (C-4) deprotonation of 1-[2′-
(trimethylsilyl)ethoxymethyl]-2-(phenylsulfonyl)imidazole
(4) and reactions with common electrophiles followed by
mild removal of SEM as illustrated in the preparation of 5
(Scheme 2).20 Reductive desulfonylation with 2% Na(Hg)
Scheme 2. Selective C-4 Deprotonation of Imidaxzole 4
Scheme 3. Negishi Coupling for C-5 Allylation of 1
in methanol leads to the introduction of the intact imidazole
nucleus.
(12) Ha¨mmerle, J.; Spina, M.; Schnu¨rch, M.; Mihovilovic, M. D.;
Stanetty, P. Synthesis 2008, 3099–3107.
Org. Lett., Vol. 12, No. 4, 2010
809

Table 2. Preparation of 2,5-Disubstituted-1,3-oxazoles 3 via Displacement of the 2-Phenylsulfonyl Substituent
a Reaction conditions: lithium reagents (1.2 or 2.2 equiv in entries 2 and 4) were added under N2 to a THF solution of sulfones (0.053 mmol) at 0 °C.
Reactions were generally complete within 5 min and warmed to 22 °C prior to addition of aq NH4Cl. b Products were purified by flash silica gel chromatography.
c All yields are reported for isolated and purified products. d Compound 18 was prepared via the Stille cross-coupling reaction as described for 17.
The efficient production of the iodide 6 (Table 1, entry 1)
facilitates studies of Suzuki cross-coupling reactions toward
the preparation of 2,5-disubstituted oxazoles. For example,
the arylation reaction of 6 with commercially available
4-methoxyphenyl boronic acid using 10 mol % Pd(PPh3)4
at 70 °C gave 15 in 94% isolated yield. Similarly, our
expectations that the 5-stannyl derivative 8 (Table 1, entry
3) would be useful for Stille processes have been confirmed
810
Org. Lett., Vol. 12, No. 4, 2010

by the effective cross-coupling with (Z)-iodide 1621 using
10 mol % Pd(PPh3)4 in the presence of LiCl (6 equiv) and
CuCl (5 equiv) in DMSO at 60 °C to yield oxazole 17 (90%
yield) (Scheme 4).
of the C-2 sulfonyl group. Examples are compiled in Table
2. To our knowledge, this preparation of 1,3-oxazoles
describes the first report for replacement of C-2 sulfonyl
functionality utilizing aryl, alkenyl, and alkyllithium reagents.
Small-scale reactions (0.1-0.05 millimolar scale) demon-
strate complete consumption of starting 2-phenylsulfonyl
oxazoles upon slow introduction of the organolithium species
(1.2 equiv) and warming from 0 °C to room temperature
over 5-10 min. We have briefly examined reactions of our
2-phenylsulfonyl oxazoles with the analogous cuprates and
have observed an expected lack of reactivity at low temper-
atures whereas warming to 22 °C led to uncharacterized
products that do not contain the 1,3-oxazole nucleus. Similar
results were observed in our limited attempts to use allyl-
magnesium chloride. Overall, the replacement of the 2-sul-
fonyl substituent upon treatment with reactive organolithium
reagents appears to be a general process that may be utilized
for the introduction of additional functionalization as evident
by reactions with acyl carbanion equivalents affording
oxazoles 22, 23, and 28 (Table 3, entries 4, 5, and 10).
In summary, an efficient preparation of 2-(phenylsulfonyl)-
1,3-oxazole facilitates a convenient, site-selective deproto-
nation to produce a reactive carbanion for halogenation,
stannylation, and alkylation reactions. Negishi, Suzuki, and
Stille cross-coupling processes are demonstrated to afford
high-yielding arylations and alkenylations leading to the
preparation of a variety of 2,5-disubstituted oxazoles. The
replacement of the 2-phenylsulfonyl substituent upon reaction
with aryl, alkenyl, and akyllithium reagents provides a
versatile pathway for the synthesis of a wide variety of
complex 2,5-disubstituted oxazoles.
Scheme 4. Stille Cross-Coupling Reactions
With the successful introduction of selective substitution
at the C-5 position of 1, our subsequent studies focused on
opportunities for the replacement of the 2-phenylsulfonyl
group as a general scheme for the synthesis of 2,5-
disubstituted-1,3-oxazoles. In this regard, we have found that
organolithium species react via an addition-elimination
pathway leading to the effective nucleophilic displacement
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Acknowledgment. We acknowledge the support of Indi-
ana University and partial support of the National Institutes
of Health (GM042897). We acknowledge the assistance of
Fese Mokube (Indiana University) for the preparation of
compound 18.
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Supporting Information Available: Experimental pro-
cedures and characterization data, including proton and
carbon NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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