A simple one-pot synthesis of 2-aryl-5-alkyl-Substituted oxazoles byCs 2CO3-Mediated Reactions of aromatic primary amides with 2,3-dibromopropene

Article abstract of DOI:10.1055/s-0029-1217995

A simple and efficient method for the synthesis of 2-aryl-5-alkyl- substituted oxazoles has been developed. A series of 2,5-disubstituted oxazoles were synthesized in a single step by Cs2CO3-mediated reactions of aromatic primary amides with 2,3-dibromopr

Full text of DOI:10.1055/s-0029-1217995

LETTER
2825
A Simple One-Pot Synthesis of 2-Aryl-5-alkyl-Substituted Oxazoles by
Cs2CO3-Mediated Reactions of Aromatic Primary Amides with 2,3-Dibromo-
propene
S
ynthesis of 2-Ary
a
l-5-alkyl-S
s
ubstituted
i
O
xaz
o
m
les a Yasmin, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India
E-mail: jkray@chem.iitkgp.ernet.in
Received 29 May 2009
Our continued efforts14 to find out new methods for the
synthesis of heterocycles led us to anticipate that a suit-
able base might promote the synthesis of oxazoles with
primary aromatic amides and 2,3-dibromopropene.
Abstract: A simple and efficient method for the synthesis of 2-aryl-
5-alkyl-substituted oxazoles has been developed. A series of 2,5-
disubstituted oxazoles were synthesized in a single step by Cs2CO3-
mediated reactions of aromatic primary amides with 2,3-dibro-
mopropene.
Initially different organic and inorganic bases were
screened and benzamide (1a) was selected as a model sub-
strate (Table 1). Among the bases studied, Cs2CO3 was
found to be the best. When substrate 1a was treated with
3.3 equivalents of Cs2CO3 and 1.5 equivalents of 2,3-di-
bromopropene in DMSO at 110 °C for two hours, 5-me-
thyl-2-phenyloxazole (2a) was obtained in 83% yield
(Table 1, entry 8). It should be noted that in presence of
Na2CO3 and K2CO3, even after 24 hours, N-(2-bromo-
allyl)benzamide (3a) was obtained (entries 5 and 6) while
KOt-Bu afforded N-prop-2-ynyl-benzamide 4a (entry 7).
Key words: substituted oxazole, aromatic primary amide, 2,3-di-
bromopropene, cesium carbonate, dimethylsulfoxide
The substituted oxazole fragment is a fundamental struc-
tural motif found in many natural products,1 unnatural bi-
ologically active compounds,2 and molecular sensors.3 A
wide variety of marine natural products containing ox-
azole rings show significant biological activities such as
antitumor agents, antileukemia agents, antiviral agents,
antifungal agents, ichthyiotoxic agents, herpes simplex
virus type-1 (HSV-1) inhibitors, serine-threonine phos-
phatase inhibitors, antibacterials, antialgicidals, and pe-
ripheral analgesics.4 Oxazoles are also widely used as
intermediates for functional group transformations.5 Con-
sequently, substantial efforts have been expended by dif-
ferent groups4–12 to find a suitable method for oxazole
synthesis. But the development of new synthetic ap-
proaches still remains an active research area. While acid-,
base-, or metal-catalysed cyclizations of N-propargyl-
amides to afford oxazoles have been explored extensively,
comparatively little work has been done with primary
amides.13 Herein we report a novel, noncatalytic, one-pot
reaction of aromatic primary amides with 2,3-dibro-
mopropene (cheaper than so far widely used propargyl-
amine) for the synthesis of 2,5-disubstituted oxazoles
containing a methyl group that might provide a further av-
enue for structural elaboration (Scheme 1).
Table 1 Screening of Bases for the Synthesis of Oxazole from 1a
O
Br
base (3.3 equiv)
DMSO, 110 °C
+
Br
Ph
NH2
1a
O
O
O
+
Ph
+
Ph
N
Ph
N
H
H
N
Br
2a
3a
4a
Entry
Base
Time (h) Yield (%)a
2a
3a
0
4a
0
1
2
3
4
5
6
7
8
Et3N
24
24
24
24
24
24
8
0
pyridine
DMAP
DBU
0
0
0
0
0
0
0
0
0
O
Br
Na2CO3
K2CO3
KOt-Bu
Cs2CO3
0
35
85
0
0
O
Cs2CO3 (3.3 equiv)
Br
+
R
R
NH2
DMSO, 110 °C
2–3 h, N2 atm
0
0
N
R = aryl, cinnamyl
0
90
0
Scheme 1
2
83
0
a Isolated yield after column chromatography.
The formation of 2,5-disubstituted oxazoles may be ex-
plained by Hacksell model.8 Amide NH2 first substitutes
the allylic bromine of 2,3-dibromopropene to form a sec-
ondary amide intermediate I (Scheme 2). Elimination of
SYNLETT 2009, No. 17, pp 2825–2827
Advanced online publication: 30.09.2009
DOI: 10.1055/s-0029-1217995; Art ID: D14209ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2826
N. Yasmin, J. K. Ray
LETTER
Table 2 One-Pot Synthesis of Oxazoles 2 from Amides 1a
Br
O
R
Br
O
B:
+
Br
Entry Amide
Time Product
(h)
Yield
(%)b
NH2
R
N
H
I
CONH2
O
N
B:
1
2.5
78
73
2b
1b
O
•
CONH2
O
R
O
O
N
H
R
N
H
2
3
N
N
R
III
II
1c
2c
Scheme 2 Plausible mechanism of oxazole synthesis
Cl
CONH2
Cl
O
N
3
2.5
2.5
3
75
74
65
HBr from intermediate I forms a N-propa-1,2-dienyl-
amide intermediate II. It then undergoes 5-endo-dig cycli-
sation by amide oxygen (via enolization) to produce a
substituted oxazoline intermediate III that finally isomer-
ises at the exocyclic double bond to form 2,5-disubstituted
oxazoles.
1d
2d
Cl
CONH2
O
4
Cl
Cl
1e
Cl
N
2e
From our observation it is seen that a relatively stronger
base like Cs2CO3 can abstract a proton from the methylene
carbon of the intermediate I to form intermediate II which
then leads to formation of 2,5-disubstituted oxazoles.
However, a sterically hindered base like KOt-Bu abstracts
less hindered olefinic proton of intermediate I to afford 4a
(Table 1, entry 7). To study the scope of substrates, vari-
ous amides were subjected to the noncatalytic reaction
(Table 2). In all the cases oxazoles were obtained with
moderate to good yields. When a,b-unsaturated carboxy
amides, such as cinnamide and a-phenylcinnamide, were
subjected to the Cs2CO3-promoted reaction, 2-styrylox-
azoles were obtained with good yields (Table 2, entries 8
and 9).
OMe
CONH2
OMe
O
N
5
1f
2f
Br
CONH2
Br
O
N
6
2.5
2
70
82
1g
2g
CONH2
O
O2N
7
N
O2N
2h
1h
We then turned our attention to the application of this
methodology with substituted 2,3-dibromopropenes in or-
der to explore its scope. When benzamide (1a) was treated
with 1,2-dibromobut-2-ene (5) in the presence of Cs2CO3
in DMSO, 5-ethyl-2-phenyloxazole (2k) was obtained in
60% yield (Scheme 3). But (2,3-dibromopropenyl)ben-
zene (6) and 1,2-dibromooct-2-ene (7) produced N-(3-
phenylprop-2-ynyl)benzamide (6a) and N-oct-2-
ynylbenzamide (7a), respectively, when treated with
CONH2
O
N
8
3
3
80
78
1i
2i
CONH2
O
N
9
O
Br
O
Cs2CO3 (3.3 equiv)
NH2
1j
+
N
DMSO, 110 °C
12 h
2j
Br
2k
60%
1a
5
a All the reactions were carried out with 1 mmol of substrate, 1.5 equiv
of 2,3-dibromopropene, 3.3 equiv of Cs2CO3 in dry DMSO (5 mL) at
110 °C for 2–3 h under N2 atmosphere.
Scheme 3
b Isolated yield of pure 2 after column chromatography.
O
Br
O
Cs2CO3 (3.3 equiv)
NH2
+
R1
R1 = Ph (6)
C5H11 (7)
benzamide (1a) under similar reaction conditions
(Scheme 4).
Ph
N
H
DMSO, 110 °C
24 h
Br
R1
1a
6a: 85%
7a: 80%
In conclusion, we have developed a simple one-pot
Cs2CO3-mediated methodology for the synthesis of 2-aryl-
Scheme 4
Synlett 2009, No. 17, 2825–2827 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl-5-alkyl-Substituted Oxazoles
2827
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General Procedure
Amide (1 mmol), Cs2CO3 (3.3 equiv), 2,3-dibromopropene (1.5
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bottom flask. The solvent was degassed with N2, and then the mix-
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NH4Cl solution and extracted with Et2O (3 × 15 mL). The organic
layers were combined, washed with brine, dried over Na2SO4, and
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank DST, New Delhi for financial support. N.Y. thanks CSIR
for the fellowship.
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