Synthesis of 5-Amino-oxazole-4-carboxylates from α-Chloroglycinates

Article abstract of DOI:10.1021/ol101704r

Aluminum-based Lewis acids are effective promoters of the condensation of α-chloroglycinates with isonitriles or with cyanide ion, leading to the formation of 5-amino-oxazoles.

Full text of DOI:10.1021/ol101704r

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3942-3945
Synthesis of 5-Amino-oxazole-4-carboxylates
from r-Chloroglycinates
Jianmin Zhang,† Pierre-Yves Coqueron,‡,§ Jean-Pierre Vors,‡ and
Marco A. Ciufolini*,†
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, BC V6T 1Z1, Canada, and Bayer CropScience SA, 14-20 Rue Pierre
Baizet, 69009 Lyon, France
ciufi@chem.ubc.ca
Received July 21, 2010
ABSTRACT
Aluminum-based Lewis acids are effective promoters of the condensation of r-chloroglycinates with isonitriles or with cyanide ion, leading
to the formation of 5-amino-oxazoles.
An oxazole-forming reaction devised in our laboratories1
proceeds through the condensation of an aluminum
Scheme 1. Oxazole Formation from R-Chloroglycinates
acetylide, 4, with an R-chloroglycinate 3, available in high
yield from a generic primary amide 1 by addition to a
glyoxylate ester2 and chlorination of the intermediate 2
with SOCl2 (Scheme 1). Applications have been demon-
strated in total syntheses of muscoride A1 and siphona-
zoles,3 as well as in the preparation of various oxazole
building blocks.4 In the latter connection, ongoing research
revealed a need for a family of 5-alkylamino derivatives
of 2-alkyloxazole-4-carboxylates. The work of Deyrup5
suggested that an avenue to 5-amino-oxazoles might
become available if the acetylenic nucleophile in the
chemistry of Scheme 1 were to be replaced with an
isonitrile or even with a cyanide ion (Scheme 2; cf. 3 f
12-13). Of course, the use of isonitriles as components
of oxazole syntheses is well documented. Noteworthy
examples of this chemistry are apparent from recent work
by Zhu. What may be rightfully described as the Zhu
oxazole synthesis involves the addition of isocyano-
acetamides to aldehydes or imines, leading to products 9
(Scheme 2).6 Enantioenriched products (cf. the starred C
atom in 9) emerge in the presence of chiral catalysts.6d-f
A variant of the Zhu reaction recently disclosed by Yu yields
5-amino-oxazoles 11 upon addition of cyanoacetamides to
in situ-generated carbalkoxyketenes 10.7 A somewhat related
transformation entails the addition of the anion of isocy-
† University of British Columbia.
‡ Bayer CropScience SA.
§ Portions of this work are taken from the Ph.D. dissertation of P.Y.C,
Universite´ Claude Bernard Lyon I, 2001.
(1) Coqueron, P. Y.; Didier, C.; Ciufolini, M. A. Angew. Chem. Int.
Ed. 2003, 42, 1411. This paper provides a bibliography of oxazole-forming
reactions through early 2003.
(2) (a) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863. (b) Ben-
Ishai, D.; Sataty, I.; Bernstein, Z. Tetrahedron 1976, 32, 1571. (c) Bernstein,
Z.; Ben-Ishai, D. Tetrahedron 1977, 33, 881.
(3) Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
(4) (a) Chau, J.; Zhang, J.; Ciufolini, M. A. Tetrahedon Lett. 2009, 50,
6163. (b) Zhang, J.; Polishchuk, E. A.; Chen, J.; Ciufolini, M. A. J. Org.
Chem. 2009, 74, 9140.
(5) Deyrup, J. A.; Killion, K. K. J. Heterocycl. Chem. 1972, 9, 1045.
10.1021/ol101704r  2010 American Chemical Society
Published on Web 08/10/2010

butylisonitrile leading to 12a (Table 1). In the absence of
promoters, the two components failed to combine, prompting
Scheme 2. Formation of Oxazoles from Isonitrile Educts
Table 1. Effect of the Lewis Acid Catalysts in the Reaction of
3a with tert-Butylisonitrile
entry
Lewis acid
temperature/°C
yieldb
a
b
c
d
e
f
AlCl3
ZnI2
0
0
0
–
27
48
66
49
55
69
ZnCl2
ZnCl2
ZnCl2
EtAlCl2
Me2AlCl
25
reflux
25
25
g
a Typical procedure: the Lewis acid (1-3 equiv) was added to a solution
of 3a (0.5 mmol) and of tert-butyl isonitrile (1.5 mmol) in THF. b After
column chromatography.
us to examine the effect of basic or acidic catalysts on the
reaction. Compounds 3 are sensitive to the action of bases.
Thus, exposure of 3a, with or without an isonitrile, to the
action of Et3N or K2CO3 at 0 °C in THF induced rapid
formation of intractable polymeric materials.
By contrast, particular halophilic Lewis acids were effec-
tive catalysts for the reaction (Table 1). No desired product
was obtained when the substrates were combined in the
presence of AlCl3, while ZnI2 afforded 12a in modest yield.
Better results were obtained with ZnCl2. The process became
more efficient at rt, while increasing the temperature to reflux
had an adverse effect. However, Me2AlCl at room temper-
ature proved to be superior to ZnCl2 in that it provided
cleaner products. Yields of the desired oxazole 12a were
highest when 3 equiv each of isonitrile and Lewis acid
promoter were employed.
This finding prompted us to examine the condensation
of various permutations of chloroglycinates and isonitriles.
Pertinent results are summarized in Table 2. It is apparent
that the reaction proceeds in uniformly satisfactory yield,
even though the yields of 2-methyloxazoles such as 12f
were consistently lower than those of its congeners.
Valine-derived chloroglycinate 3i provided the corre-
sponding oxazole 12i with no erosion of optical purity.
While at this time we favor (air-sensitive) Me2AlCl as
the promoter, the safer ZnCl2 enabled the conduct of
reactions that seemed to be amenable to automatization
using a system such as the Chemspeed robot. This
instrument, essentially a dispenser of liquids, would
combine THF solutions of ZnCl2, isonitriles, and chloro-
glycinates, and then perform an extractive workup and
purify the crude products by HPLC-MS.13
anoacetamide to an isocyanate.8 It is apparent from Scheme
2 that the hypothetical conversion of 3 into 12-13 differs
in outcome from other isonitrile-based avenues to 5-amino-
oxazoles. Accordingly, it would nicely complement such
alternative constructions. We also note that several other
methods for 5-amino-oxazole synthesis do not employ
isonitrile building blocks, relying instead on the cyclization
of R-amidonitriles9 and related reactions,10 on the cyclo-
dehydration of R-amido-amides,11 or upon Cornforth-type
rearrangements.12
The feasibility of the desired reaction was explored by
studying the condensation of chloroglycinate 3a with tert-
(6) (a) Sun, X.; Janvier, J.; Bienayme´, H.; Zhu, J. Org. Lett. 2001, 3,
877. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem. Soc.
2002, 124, 2560. (c) Janvier, P.; Bois-Choussy, M.; Bienayme´, H.; Zhu, J.
Angew. Chem. Int. Ed. 2003, 42, 811. (d) Wang, S.-X.; Wang, M.-X.; Wang,
D.-X.; Zhu, J. Org. Lett. 2007, 9, 3615. (e) Yue, T.; Wang, M. X.; Wang,
D. X.; Masson, G.; Zhu, J. Angew. Chem. Int. Ed. 2009, 48, 6717. (f) Yue,
T.; Wang, M. X.; Wang, D. X.; Masson, G.; Zhu, J. J. Org. Chem. 2009,
74, 8396. Related reactions: (g) Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett.
2006, 8, 4145. (h) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem. Int. Ed.
2007, 46, 2485.
(7) Wu, J.; Chen, W.; Hu, M.; Zou, H.; Yu, Y. Org. Lett. 2010, 11,
616.
(8) Daniel, M.; Rizvi, R. K.; Kaminski, J. J. Heterocycles 1987, 26,
651.
(9) (a) Cook, A. H.; Hunter, G. D. J. Chem. Soc. 1952, 3789. (b) Mandal,
S.; Li, W. T.; Bai, Y.; Shablykin, O. V.; Brovarets, V. S.; Drach, B. S.
Russ. J. Gen. Chem. 2007, 77, 1308. (c) Carreiras, M. C.; Eleuterio, A.;
Dias, C.; Brito, M. A.; Brites, D.; Marco-Contelles, J.; Gomez-Sanchez, E.
Heterocycles 2007, 71, 2249. (d) Robertus, J. D.; Kerwin, S. M. Beilst. J.
Org. Chem. 2008, 4. http://www.beilstein-journals.org/bjoc/content/provisional/
1860-5397-4-26.pdf.
(10) (a) Golovchenko, A. V.; Pilyo, S. G.; Brovarets, V. S.; Chernega,
A. N.; Drach, B. S. Russ. J. Gen. Chem. 2005, 75, 425. (b) Golovchenko,
A. V.; Pilyo, S. G.; Brovarets, V. S.; Chernega, A. N.; Drach, B. S. Synthesis
2003, 2851. (c) Drach, B. S.; Mis’kevich, G. N.; Martynyuk, A. P. Zh.
Org. Khim. 1978, 14, 508.
(11) (a) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Dettori, G. Eur. J.
Org. Chem. 2000, 3217. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.;
Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006,
128, 10589.
Two aspects of this effort merit comment. First, the size
of the library thus generated was of no import at this
juncture. Indeed, our objective was to demonstrate the
Org. Lett., Vol. 12, No. 17, 2010
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Table 2. 5-Alkylamino-oxazoles Obtained by the New Method
Table 3. Automated Preparation of a Library of
5-Amino-oxazoles (Chemspeed Robot)
Table 4. 5-Amino-oxazoles Obtained by the New Method
a General procedure: commercial Me2AlCl (1.0 M in hexanes, 1.5 mL,
1.5 mmol) was added to a stirred solution of 3 (0.5 mmol) and isonitrile
(1.5 mmol) in THF (1.5 mL), at rt. After 24 h, the mixture was quenched
with aqueous saturated NaHCO3 solution (5 mL) and extracted with EtOAc
(5 mL × 3). The combined extracts were washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash column
chromatography (30% EtOAc/hexanes in all cases). b After column chro-
matography.
feasibility of automating the new avenue to 5-amino-
oxazoles. Second, yields of end products were also of
marginal importance. The extractive workup performed
by the robot is nowhere near as efficient as that executed
by a human operator; but again, the goal here was to prove
a point. What mattered was purity.
We arbitrarily chose to count as successful those reactions
that afforded end products of a purity greater than 85%
(HPLC-MS) in yields greater than 10%. These criteria reflect
common boundary conditions applied during screening of
new synthetic compounds for possible biological activity.
The results of a parallel synthesis carried out with 5
chloroglycinates and 5 isonitriles are summarized in Table
3. Check marks indicate a successful reaction according to
the foregoing criteria. It is apparent that two-thirds of the
reactions were successful.
At this juncture, we turned to a study of the reaction of 3
with cyanide ion, in the interest of reaching amino-oxazoles
13 (cf. Table 4). Exposure of the chloroglycinates to KCN,
Zn(CN)2, ZnCl2/KCN, ZnCl2/TMSCN, and Et3N/KCN in
THF, at rt or reflux, failed to give any of the desired product.
However, efficient conversion of 3 into 13 was achieved upon
a General procedure: commercial Et2AlCN (1.0 M in toluene, 1.5 mL,
1.5 mmol) was added to a stirred solution of 3 (0.5 mmol) in THF (1.5
mL) at rt. After 24 h, the mixture was quenched with aqueous saturated
NaHCO3 solution (5 mL) and extracted with EtOAc (5 mL × 3). The
combined extracts were washed with brine, dried (MgSO4), and concentrated
in vacuo. The residue was purified by flash column chromatography (see
Supporting Information for details). b After column chromatography.
treatment with 3 equiv of Et2AlCN (Nagata reagent)14 in
THF at rt. Representative examples of this transformation
appear in Table 4. Once again, a diminshed yield was
recorded in the 2-methyloxazole series (cf. 13b).
Amino-oxazoles 13 are valuable building blocks for the
asssembly of bioactive agents. As a simple application of
the newly established route to these heterocycles, Scheme 3
details an avenue to oxazolylurea 18, which is a moderately
potent inhibitor of Raf kinase15 and consequently an interest-
ing starting point for the development of anticancer agents.
In summary, this work demonstrates a new construction
of 5-amino-oxazole-4-carboxylic esters that is amenable even
(12) (a) Turchi, I. J.; Maryanoff, C. A. Synthesis 1983, 837. (b) Nolt,
M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.;
Lindsley, C. W. Tetrahedron 2006, 62, 4698.
(13) In principle, the robot could also generate the chloroglycinates via
the reaction of an amide with a glyoxylic ester, followed by treatment of
the adduct with SOCl2. However, safety and corrosion issues associated
with the use of the latter reagent dissuaded us from carrying out this
sequence on the Chemspeed instrument.
(14) (a) Nagata, W.; Yoshioka, M. Tetrahedron Lett. 1966, 18, 1913.
(b) Nagata, W.; Yoshioka, M. Org. React. 1984, 25, 255.
3944
Org. Lett., Vol. 12, No. 17, 2010

methodology is likely to be of value both in synthetic organic
and medicinal chemistry research.
Scheme 3. Preparation of Kinase Inhibitor 18
Acknowledgment. We thank the University of British
Columbia, the Canada Research Chair Program, NSERC,
CIHR, and MerckFrosst Canada for financial support. A
portion of this work was carried out in France with financial
support by Bayer CropScience, the MRT, and the CNRS
(“BDI” Fellowship to P.Y.C.).
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds, plus
NMR (1H and 13C) spectra of several products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101704R
(15) Smith, R. A.; Barbosa, J.; Blum, C. L.; Bobko, M. A.; Caringal,
Y. V.; Dally, R.; Johnson, J. S.; Katz, M. E.; Kennure, N.; Kingery-Wood,
J.; Lee, W.; Lowinger, T. B.; Lyons, J.; Marsh, V.; Rogers, D. H.; Swartz,
S.; Walling, T.; Wild, H. Bioorg. Med. Chem. Lett. 2001, 11, 2775.
to automated parallel synthesis. The end products are
obtained in good yield and excellent purity. The new
Org. Lett., Vol. 12, No. 17, 2010
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