Synthesis of polysubstituted 5-aminooxazoles from α- diazocarbonyl esters and α-isocyanoacetamides

Article abstract of DOI:10.1021/ol902850a

[Chemical equation presented] A novel and efficient reaction for the synthesis of 2-keto-5-aminooxazoles is developed. The entire sequence is realized by simply heating a xylene solution of α-diazocarbonyl esters and α-isocyanoacetamides without any promoters. A possible mechanism for the entire sequence is proposed.

Full text of DOI:10.1021/ol902850a

ORGANIC
LETTERS
2010
Vol. 12, No. 3
616-618
Synthesis of Polysubstituted
5-Aminooxazoles from r- Diazocarbonyl
Esters and r-Isocyanoacetamides
Jianwei Wu, Wenteng Chen, Miao Hu, Hongbin Zou, and Yongping Yu*
College of Pharmaceutical Sciences, Zhejiang UniVersity, Hangzhou 310058, P. R. China
yyu@zju.edu.cn
Received December 10, 2009
ABSTRACT
A novel and efficient reaction for the synthesis of 2-keto-5-aminooxazoles is developed. The entire sequence is realized by simply heating a
xylene solution of r-diazocarbonyl esters and r-isocyanoacetamides without any promoters. A possible mechanism for the entire sequence
is proposed.
The oxazole group is an important heterocyclic unit that is
widely present in medicinal, agrochemical, and natural
products.1,2 It is also present in applications for optical
materials such as scintillant molecules and fluorescent dyes.3
Thus, various synthetic methods of oxazole derivatives have
been developed. Currently, the main synthetic methods of
oxazoles include cyclodehydration reactions,4 oxidations of
oxazolines,5 direct derivation of the parent oxazole,6 and
metal-catalyzed cross-coupling reactions.7 The most common
method for the preparation of oxazoles is the cyclodehydra-
tion, but this method provides low yields of oxazoles.8
However, the lesser utilized methods of oxidations of
oxazolines, direct derivation of the parent oxazole, and metal-
catalyzed cross-coupling reactions are greatly limited by the
substrate.
Isocyanide-based multicomponent reactions (IMCRs) such
as the classic Passerini (P-3CR)9 and Ugi10 (U-4CR)
reactions have been widely used for generating molecular
complexity and molecular diversity.11 Zhu et al. reported a
novel multicomponent synthesis of polysubstituted 5-ami-
nooxazoles by the reaction of isocyanoacetamides with
aldehydes, amines in the presence of 1 equiv of ammonium
chloride as a promoter, and its subsequent use as a chemical
platform to generate new scaffolds.12 However, the multi-
component reaction cannot occur in the absence of promoters
(weak Brønsted and Lewis acids).13 Moreover, none of the
existing methods could satisfy the green-chemistry charac-
(1) Kean, W. F. Curr. Med. Res. Opin. 2004, 20, 1275–1277
(2) (a) Taylor, E. C.; Wipf, P. Oxazoles: Synthesis, Reactions, and
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Orru, V. A.; De Greef, M. Synthesis 2003, 10, 1471–1499. (c) Tempest, P.
Curr. Opin. Drug DiscoVery DeV. 2005, 8, 776–788. (d) Zhu, J. Eur. J.
Org. Chem. 2003, 7, 1133–1144. (e) Do¨mling, A. Chem. ReV. 2006, 106,
17–89.
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Ferrini, P. G.; Marxer, A. Angew. Chem., Int. Ed. 1963, 2, 99.
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Lett. 2001, 3, 877–880. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J.
J. Am. Chem. Soc. 2002, 124, 2560–2567. (c) Bonne, D.; Dekhane, M.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 2485–2488. (d) Yue, T.; Wang,
M. X.; Wang, D. X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48,
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10.1021/ol902850a  2010 American Chemical Society
Published on Web 01/05/2010

teristic of being ecologically benign as well as economical
in atom count.14 Thus developing a simple and effective
method to synthesize polysubstituted 5-aminooxazole from
simple and readily available starting materials is essential.
Furthermore, the 2-keto-5-aminooxazole compounds are
extraordinarily potent and selective inhibitors of fatty acid
amide hydrolase (FAAH) which is the primary catabolic
regulator of several bioactive lipid amides in vivo.15 Thus
we report herein a novel and efficient reaction for the
synthesis of 2-keto-5-aminooxazoles from R-isocyanoaceta-
mides and R-diazocarbonyl esters without the use of promot-
ers. The process is economical in atom count and ecologically
benign since only a molecule of nitrogen was lost in this
entire sequence.
Table 2. Synthesis of 2-Keto-5-aminooxazoles in the Optimal
Reaction Conditionsa
yield
product (%)b
entry
R1
R2
NR3R4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CH3
CH3
Ph
CH3
PhCH2
CH3(CH2)2 C2H5
p-ClC6H5 CH3
p-CH3C6H5 CH3
CH3
CH3
Ph
4-NO2PhCH2 morpholinyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
88
78
70
78
84
73
71
66
85
73
68
81
69
67
63
87
83
71
69
76
63
60
C2H5
C2H5
CH(CH3)3
C2H5
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
Scheme 1. Synthesis of 2-Keto-5-aminooxazoles
4-NO2PhCH2 piperidinyl
CH(CH3)3
C2H5
C2H5
piperidinyl
piperidinyl
piperidinyl
piperidinyl
piperidinyl
piperidinyl
3j
3k
3l
PhCH2
CH3(CH2)2 C2H5
p-ClC6H5 CH3
p-CH3C6H5 CH3
CH3
PhCH2
CH3(CH2)2 C2H5
Ph
CH3
p-ClC6H5
3m
3n
3o
3p
3q
3r
3s
3t
4-NO2PhCH2 pyrrolidinyl
Initially. the reaction conditions were optimized using
R-diazocarbonyl ester (1a) and R-isocyanoacetamide (2a) as
starting substrates (Scheme 1, Table 1). When the reaction
C2H5
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
C2H5
CH(CH3)3
CH3
3u
3v
p-CH3C6H5 CH3
Table 1. Optimization of the Reaction Conditions: Synthesis of
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), solvent (10 mL),
2-Keto-5-aminooxazolesa
N2. b The yield of the isolated product.
entry
solvent
additive
temp (°C)/time (h)
yield (%)b
1
2
3
4
5
6
7
8
toluene
toluene
xylene
xylene
xylene
xylene
xylene
xylene
none
none
none
none
NH4Cl
LiBr
CSA
Reflux/4
Reflux/12
140/4
Reflux/4
140/4
140/4
140/4
140/8
20
48
88
87
78
<5
<5
89
utilizing ammonium chloride (entry 5) slightly lowered the
product yield, while the addition of lithium bromide and
camphorsulfonic acid (CSA) was detrimental to the desired
transformation (entries 6 and 7). Prolonging the reaction time
to 8 h did not increase yields (entry 8). Thus, the optimal
reaction condition was obtained under the conditions outlined
in entry 3. This reaction occurred in xylene in the absence
of any promoters, which is intriguing, as most Passerini-
like reactions are sluggish and afford products in low yields
unless using an acidic promoter.16
none
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), additive (1.0
mmol), solvent (10 mL), N2. b The yield of the isolated product.
With the optimized conditions in hand, we next probed
the generality of this reaction. A variety of starting materials
including eight R-diazocarbonyl esters and three R-isocy-
anoacetamides were examined (Table 2). The R-diazocar-
bonyl esters were readily prepared from ꢀ-keto esters and
methanesulfonyl azide according to a previous report by
Taber.17 Aliphatic and aromatic substituents of R-diazocar-
bonyl esters with different steric and electronic properties
were tolerated in this reaction. They reacted with the
R-isocyanoacetamides to provide the corresponding 2-keto-
5-aminooxazoles in moderate to good isolated yields. Aro-
was carried out in toluene at reflux under nitrogen in the
absence of any promoters for 4 h, it gave relatively low yields
of 2-keto-5-aminooxazole (entry 1). Increasing the reaction
time to 12 h did not satisfactorily increase yields (entry 2).
When using xylene as solvent at 140 °C in the absence of
any promoters for 4 h, the yield was raised to 88% (entry
3). A further increase in the reaction temperature somewhat
decreased the yield (entry 4). We unexpectedly found that
(13) Cuny, G.; Ga´mez-Montan˜o, R.; Zhu, J. Tetrahedron 2004, 60,
4879–4885.
(14) Trost, B. M. Science 1991, 254, 1471–1477.
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B. F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 1423–1428. (b)
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Org. Lett., Vol. 12, No. 3, 2010
617

matic substitutive R-diazocarbonyl esters (R1 ) aryl) gave
a lower yield (entries 3, 7, 8, 11, 14, 15, 19, 21, and 22).
Aromatics containing an electron-withdrawing group pro-
vided higher yields than that with electron-donating groups
(entries 7, 8, 14, 15, 21, and 22). Lengthening the carbon
chain (R1 ) alkyl) decreased the yield (entries 6, 13, and
18). The benzyl group gave a good yield (entries 5, 12, and
17). The R2 group had a rare effect on yields even with
electronic and steric effects (entries 1, 2, and 4). The amine
part of the oxazole ring can be varied by simply changing
the structure of the isocyanoacetamides.18,19 Substituents such
as morpholinyl, piperidinyl, and pyrrolidinyl were success-
fully introduced into the C-5 position of the oxazole ring.
The amino group influenced the reaction efficiency and the
stability of products. 5-Piperidinyl-oxazoles are less stable
than the morpholinyl and pyrrolidinyl compounds. So
piperidinyl isocyanoacetamide gave lower yields than the
morpholinyl and pyrrolidinyl isocyanoacetamides (entries
9-15). To the best of our knowledge, this procedure
represents the first direct construction of 2-keto-5-aminoox-
azoles from simple and readily available starting materials.
Moreover, in this entire sequence only a molecule of nitrogen
was lost. After completing the reaction, the solvent was
removed under reduced pressure and could be collected.
Thus, the entire process is economical in atom count and
ecologically benign.
Scheme 2
.
Proposed Mechanism for the Synthesis of
2-Keto-5-aminooxazole
In conclusion, we have developed a novel and efficient
reaction for the synthesis of 2-keto-5-aminooxazoles from
R-isocyanoacetamides and R-diazocarbonyl esters. The entire
sequence was realized under very simple conditions without
the use of promoters. Moreover, the synthesis is economical
in atom count and ecologically benign since only a molecule
of nitrogen is lost in this entire sequence.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 30772652 and No. 90813026) and
National key Tech project for Major Creation of New Drugs
(No. 2009ZX09501-010).
On the basis of these results, we proposed the following
possible mechanism for this reaction, as shown in Scheme
2. First, R-diazocarbonyl ester 1 transforms to ketene A
through the Wolff rearrangement reaction.20 Then ketene A
reacts with isocyanoacetamide 2 to produce the nitrilium
intermediate B. This intermediate B after tautomerization will
cyclize to produce the desired 2-keto-5-aminooxazole 3.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902850A
(18) Coffin, A. R.; Roussell, M. A.; Tserlin, E.; Pelkey, E. T. J. Org.
Chem. 2006, 71, 6678–6681
.
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Med. Chem. Lett. 2007, 17, 4733–4736. (b) Zhao, G.; Bughin, C.; Bienayme´,
(20) (a) Ye, T.; Mckervey, M. A. Chem. ReV. 1994, 94, 1091–1160. (b)
Wolff, L. Liebigs Ann. Chem. 1912, 394, 23–36. (c) Yang, Y. Y.; Shou,
W. G.; Chen, Z. B.; Wang, Y. G. J. Org. Chem. 2008, 73, 3928–3930.
H.; Zhu, J Synlett 2003, 8, 1153–1154
.
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