Ethyl 2-chlorooxazole-4-carboxylate: A versatile intermediate for the synthesis of substituted oxazoles

Article abstract of DOI:10.1021/ol0262800

(formula presented) R¹ = Ar, Het, alkenyl R² = H, Ar, Het, alkenyl, alkynyl R³ = H, CO₂H, Ar, Het, alkenyl, alkynyl By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions,

Full text of DOI:10.1021/ol0262800

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2905-2907
Ethyl 2-Chlorooxazole-4-carboxylate: A
Versatile Intermediate for the Synthesis
of Substituted Oxazoles
Kevin J. Hodgetts* and Mark T. Kershaw
Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405
khodgetts@nrgn.com
Received June 2, 2002
ABSTRACT
By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles
from ethyl 2-chlorooxazole-4-carboxylate (2) was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted,
2,5-disubstituted, and 2,4,5-trisubstituted oxazoles.
The discovery of natural products containing one or more
oxazole units has stimulated interest in the chemistry and
synthesis of these heterocycles.1 The first naturally occurring
oxazoles to be isolated were relatively simple 2,5-disubsti-
tuted oxazoles such as annuloline2 and balsoxin.3 2,5-
Diaryloxazoles are also of considerable interest due to their
ability to scintillate or emit light in the presence of ionizing
radiation.4 In recent years, a wide variety of biologically
important 2,4-disubstituted oxazoles have been isolated
including the phorboxazoles,5 the ulapaulides,6 the virgin-
iamycins,7 and the calyculins.8 As a consequence a number
of contemporary strategies for the construction of 2,4-
disubstituted oxazoles have emerged.9 Trisubstituted oxazoles
are relatively rare but include diazonamide A, a secondary
metabolite of Diazona chinensis, which shows potent in vitro
activity against HCT-116 human colon carcinoma and B-16
murine melanoma cancer cell lines.10 As part of a medicinal
chemistry program, we required a flexible route that would
give high-yielding and rapid access to a series of substituted
oxazoles. A method involving a sequence of regiocontrolled
halogenation followed by palladium-catalyzed coupling,
based upon a readily available oxazole scaffold, was identi-
fied as an attractive possibility.11 There was limited literature
precedent for the elaboration of the oxazole nucleus with
palladium-catalyzed coupling reactions12 and the previously
(1) Turchi, I. J. In Oxazoles; John Wiley & Sons: New York, 1986;
and references therein.
(9) (a) Zhao, Z.; Scarlato, G. R.; Armstrong, R. W. Tetrahedron Lett.
1991, 32, 1609. (b) Shapiro. R. J. Org Chem. 1993, 53, 5759. (c) Connell,
R. D.; Tebbe, M.; Gangloff, A. R.; Helquist, P.; Akermark, B. Tetrahedron
1993, 49, 5445. (d) Cardwell, K. S.; Hermitage, S. A.; Sjolin, A. Tetrahedron
Lett. 2000, 41, 4239, (e) Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165, (f) Smith A. B., III; Minbiole, K.
P.; Freeze, S. Synlett 2001, 11, 1739.
(2) Axelrod, B.; Belzile, J. R. J. Org. Chem. 1958, 23, 919.
(3) Burke, B.; Parkins, H.; Talbot, A. M. Heterocycles 1979, 12, 349.
(4) Dyer, A. In An Introduction to Liquid Scintillation Counting;
Heyden: London, UK, 1974; p 12. For a recent study, see: Clapham, B.;
Richards, A. J.; Wood, M. L.; Sutherland, A. J. Tetrahedron Lett. 1997,
38, 9061.
(5) Searle, P. A.; Molinski, F. F. J. Am. Chem. Soc. 1995, 117, 8126.
(6) Roesener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986. 108, 846.
(7) Paris, J. M.; Barriere, J. C.; Smith, C.; Bost, P. E. Recent Progress
in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.;
Springer-Verlag: Berlin, 1990; pp 183-248.
(10) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1991, 113, 2303.
(11) (a) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363. For
recent reviews of this general strategy, see: (b) Collins, I. J. Chem. Soc.,
Perkin Trans. 1 2000, 2845. (c) Snieckus, V. Med. Res. ReV. 1999, 19, 342
and references therein.
(8) Matsumaga, S.; Fusetani, N. Tetrahedron Lett. 1991, 32, 5605.
10.1021/ol0262800 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002

unreported ethyl 2-chlorooxazole-4-carboxylate (2) and the
2-bromo analogue 3 were identified as potential precursors.
The synthesis of the halooxazoles 2 and 3 is outlined in
Scheme 1. Ethyl 2-aminooxazole-4-carboxylate (1) was
Table 1. Palladium-Catalyzed Coupling Reactions of 2a
Scheme 1a
entry
R
conditions time (h)
product yield (%)
1
2
3
4
Ph
vinyl
2-pyridyl
CtCPh
i
1
4
4
6
5a
5b
5c
5d
87
84
73
0
ii
iii
iv
a Reaction conditions: (i) Pd(Ph3P)4, PhB(OH)2, aq K2CO3, PhMe, 90
°C; (ii) Pd(Ph3P)2Cl2, CH2dCHSnBu3, dioxane, 100 °C; (iii) Pd(Ph3P)4,
2-pyridylzinc bromide, THF, 65 °C; (iv) Pd(Ph3P)2Cl2, CuI, phenylacetylene,
Et3N, 80 °C.
and 1 equiv of vinyltributyltin, coupling at the 2-position
afforded 5b in 84% isolated yield (entry 2). The Negishi
coupling reaction of 2 with 2-pyridylzinc bromide in THF
at reflux gave 5c in 73% yield (entry 3).17 Sonogashira
reaction of 2 with phenylacetylene gave a resinous material
and it was not possible to isolate the expected product, 5d,
from the mixture (entry 4).18 Low yields for the Sonogashira
reaction of 2-bromothiazoles11a,12b and 2-iodoimidazoles12b
have also been reported. In summary, Suzuki, Stille, and
Negishi reactions with the 2-chlorooxazole 2 all gave good
yields of the expected oxazoles 5a-c although a Sonogashira
reaction failed. In principle, the carboxylic functionality at
C-4 could now be exploited by a range of synthetic
maneuvers leading to a variety of 2,4-disubstituted oxazoles.
The synthesis of trisubstituted oxazoles via the installation
of substituents at the 5-position was investigated next. One
possibility was to utilize the 2,5-dibromooxazole 4. It was
anticipated that a palladium-catalyzed coupling reaction
would be selective for the more electron-deficient 2-position
and that the C-2 substituent could be introduced first. A
second coupling could then be used to install the C-5
substituent. Under standard Suzuki conditions, and 1 equiv
of phenylboronic acid, the dibromooxazole 4 gave a complex
mixture of products. Analysis of the crude reaction mixture
a Reaction conditions: (i) tBuONO (1.5 equiv), CuCl2 (1.5 equiv),
CH3CN, 80 °C (83%); (ii) tBuONO (1.5 equiv), CuBr2 (1.5 equiv),
CH3CN, 80 °C (3, 21%, 4, 16%).
prepared, on a 100-g scale, by the condensation of ethyl
bromopyruvate and urea at 100 °C.13 The 2-aminooxazole 1
was then treated with 1.5 equiv of tert-butyl nitrite and
copper(II) chloride in acetonitrile yielding 2-chlorooxazole
2 in 83% yield.14 Replacing the copper(II) chloride with
copper(II) bromide gave a low yield of a separable mixture
of 2-bromooxazole 3 and the 2,5-dibromooxazole 4. In an
attempt to improve the selectivity for the formation of either
3 or the potentially useful dibromide 4, the stoichiometry of
the reagents and temperature of the reaction were varied.
However, similar product distributions and low isolated
yields were the result. Under similar reaction conditions,
Doyle has observed that the reaction of anilines also gave
byproducts due to substitution of bromide either ortho or
para to the original amine substituent.14
With a large quantity of the chlorooxazole 2 in hand, its
palladium-catalyzed cross-coupling reactions with a variety
of organometallic reagents were examined. Under standard
Suzuki conditions15 and 1 equiv of phenylboronic acid,
coupling at the 2-position was observed, affording 5a in 87%
isolated yield (entry 1, Table 1). The Stille coupling reaction
was investigated next.12c,16 With use of standard conditions
1
by H NMR and LC-MS indicated the presence of mono-
and disubstituted coupled products and also products arising
from debromination of the coupled products and of the
starting material. It was decided not to pursue this approach
further but instead to utilize the 2,4-disubstituted oxazoles
5a-d prepared earlier.
The oxazole 5a was brominated at the 5-position by
treatment with N-bromosuccinimide in refluxing chloroform
and gave the bromide 6 in 86% yield. Under standard Suzuki
(12) (a) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry;
Pergamon Press: Elmsford, Oxford, UK, 2000; Chapter 8, pp 321-333.
(b) Sakamoto, T.; Nagata, H.; Kondo, Y.; Shiraiwa, M.; Yamanaka, H.
Chem. Pharm. Bull. 1987, 35, 823. (c) Barrett, A. G. M.; Kohrt, J. T. Synlett
1995, 415. (d) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4633. (e)
Jeong, S.; Chen. X.; Harran, P. G. J. Org. Chem. 1998, 63, 8640. (f) Boto,
A.; Ling, M.; Meek, G.; Pattenden G. Tetrahedron Lett. 1998, 39, 8167.
(g) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011. (h) Schaus,
J. V.; Panek, J. S. Org. Lett. 2000, 2, 469. (i) Smith, A. B., III; Minibiole,
K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942.
(j) Clapham, B.; Sutherland, A. J. J. Org. Chem. 2001, 66, 9033.
(13) Crank, G.; Foulis, M. J. J. Med. Chem. 1971, 14, 1075.
(14) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977, 42,
2426.
(16) (a) Stille, J. K. Angew. Chem. 1986, 98, 504. (b) Stille, J. K. Pure
Appl. 1985, 57, 1771.
(17) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821.
(18) (a) Cassar, L. J. Organomet. Chem. 1975, 93, 253. (b) Dieck, H.
A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259. (c) Sonogashira, K.;
Tohda, Y.; Nagihara, N. Tetrahedron Lett. 1975, 16, 4467. (d) Takahashi,
S.; Kuroyama, Y.; Sonogashira, K.; Nagihara, N. Synthesis 1980, 627.
(15) (a) Miyaura, N.; Suzuki, A. Chem ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
2906
Org. Lett., Vol. 4, No. 17, 2002

conditions and with phenylboronic acid, the 5-bromooxazole
6 proved to be reactive affording, after 4 h, 7a in 93% yield.
Similarly, 3,4-dimethoxyphenyl boronic acid gave an excel-
lent yield of the oxazole 7b. Standard Stille conditions and
vinyltributyltin gave 7c in 82% yield.12e,f Negishi coupling
with 2-pyridylzinc bromide gave 7d in 76% yield. The
Sonogashira reaction, which failed with the 2-chlorooxazole
2, gave a much cleaner reaction with 6, affording 7e in 77%
yield (Scheme 2).12b In general, the palladium-catalyzed
Scheme 3a
a Reaction conditions: (i) NaOH, EtOH, room temperature
(97%); (ii) KOH, AgNO3, H2O; (iii) Br2, CCl4, 75 °C (79%); (iv)
Pd(Ph3P)4, PhB(OH)2, aq K2CO3, PhMe, 80 °C, 4 h; (v) Pd(Ph3P)2Cl2,
CH2dCHSnBu3, dioxane, 100 °C, 8 h; (vi) Pd(Ph3P)4, 2-pyridylzinc
bromide, THF, 65 °C, 16 h; (vii) Pd(Ph3P)2Cl2, CuI, phenylacety-
lene, Et3N, 80 °C, 16 h.
Scheme 2a
(12), which has previously been isolated from the plant A.
plumieri (Scheme 4).3
Scheme 4a
a Reaction conditions: (i) NBS (4 equiv), CHCl3, reflux, 48 h
(86%); (ii) Pd(Ph3P)4, RB(OH)2, aq K2CO3, PhMe, 90 °C, 4 h; (iii)
Pd(Ph3P)2Cl2, CH2dCHSnBu3, dioxane, 100 °C, 8 h; (iv) Pd(Ph3P)4,
2-pyridylzinc bromide, THF, 65 °C, 18 h; (v) Pd(Ph3P)2Cl2, CuI,
phenylacetylene, Et3N, 80 °C, 18 h.
coupling reactions of the 5-bromooxazole 6 gave good yields
of the expected trisubstituted oxazoles 7a-e although slightly
longer reaction times were required for complete conversion.
The range of trisubstituted oxazoles available by this route
can be extended by manipulation of the carboxylic func-
tionality at C-4. For example, a Hunsdiecker19 reaction was
used to introduce a halogen at the C-4 position that proved
suitable for further functionalization via palladium-catalyzed
processes. Thus, hydrolysis of the ester 7a with sodium
hydroxide gave the acid 8, which was converted to the
corresponding silver salt by treatment with silver nitrate and
potassium hydroxide in water. Heating the silver salt in the
presence of 1 equiv of bromine gave the 4-bromooxazole 9
in 79% yield. Under standard Suzuki conditions and with
phenylboronic acid, the 4-bromooxazole proved to be reac-
tive affording, after 4 h, 10a in 89% yield. Standard Stille
conditions and vinyltributyltin gave 10b in 83% yield.12d,h,i,j
Negishi coupling with 2-pyridylzinc bromide gave 10c in
72% yield and Sonogashira reaction with phenylacetylene
gave 10d in 79% yield (Scheme 3). In summary, the
palladium-catalyzed couplings of the 4-bromooxazole 9 with
various organometallic reagents gave good yields of the
expected products.
a Reaction conditions: (i) NaOH, EtOH, room temperature
(95%); (ii) DMF-H2O (1:1), 150 °C, 60 h (74%).
The readily available ethyl 2-chlorooxazole-4-carboxylate
(2) proved to be a versatile scaffold for the synthesis of 2,4-
disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted ox-
azoles. Suzuki, Stille, and Negishi coupling reactions were
all successfully used to install substituents at the C-2 oxazole
position. Following bromination, a second palladium-
catalyzed coupling reaction was used to install substituents
at the C-5 position. The carboxylic functionality at C-4 could
then be exploited by a variety of synthetic transformations.
For example, decarboxylation directly gave the corresponding
2,5-disubstituted oxazole; alternatively, a Hunsdiecker reac-
tion was used to locate a bromide at the C-4 position, which
was then exploited in a third palladium-catalyzed coupling
reaction. The wide range of compatible organometallic
reagents and the synthetic versatility of the carboxylic
functionality at C-4 offers considerable flexibility for the
synthesis of substituted oxazoles from a single precursor.
The trisubstituted oxazoles 7a-e can also be exploited in
the synthesis of 2,5-disubstituted oxazoles. For example,
hydrolysis of the ester 7b with sodium hydroxide in ethanol
gave the acid 11 in 95% yield. Heating the acid 11 in wet
DMF resulted in clean decarboxylation and gave balsoxin
Supporting Information Available: Representative pro-
cedures for the preparation of 2, 5a, 5b, 5c, 6, 7e, 8, 9, 11,
and 12 and relevant spectroscopic data for compounds 2, 3,
4, 5a-c, 6, 7a-e, 8, 9, 10a-d, 11, and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) For a review see: Johnson, R. G.; Ingham, R. K. Chem ReV. 1956,
56, 219.
OL0262800
Org. Lett., Vol. 4, No. 17, 2002
2907