A one-pot synthesis of pyrido[2,3.b][1,4]oxazin-2-ones

Article abstract of DOI:10.1021/jo034593i

Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.

Full text of DOI:10.1021/jo034593i

or 2-amino-3-hydroxypyridine. A similar approach, how-
ever, is not directly applicable to the pyrido[2,3-b][1,4]-
oxazine ring system. On the other hand, it was felt that
the Smiles rearrangement could be exploited to circum-
vent this limitation. Since the Smiles rearrangement
necessitates an electron-deficient center to proceed at a
reasonable rate, we selected 2-haloacetamide and 2-halo-
3-hydroxypyridine as the reaction partners.
In exploratory experiments, reaction of 2-bromo-3-
hydroxypyridine (2a ) with N-benzyl-2-chloroacetamide
(1a ) in the presence of potassium carbonate furnished
N-benzyl-2-(2-bromopyridin-3-yloxy)acetamide (3a ) as the
major product and bicyclic adduct 4a as only a minor
product (Scheme 1). Subsequent exposure of 3a to cesium
carbonate induced cyclization and gave 4a quantitatively.
Spectral and physical comparisons (IR, 1D/2D-NMR,
NOE, mp) of 4a cogently demonstrated it was different
from 4-benzyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (5), pre-
pared from commercial 2H-pyrido[3,2-b][1.4]oxazin-3-one
and benzyl chloride with potassium carbonate. X-ray
analysis unambiguously confirmed the structure of 4a
as 1-benzyl-1H-pyrido[2,3-b][1,4]oxazin-2-one.
A On e-P ot Syn th esis of
P yr id o[2,3-b][1,4]oxa zin -2-on es
Su-Dong Cho,† Yong-Dae Park,‡ J eum-J ong Kim,‡
Sang-Gyeong Lee,‡ Chen Ma,† Sang-Yong Song,†
Woo-Hong J oo,† J . R. Falck,§ Motoo Shiro,
Dong-Soo Shin,*,† and Yong-J in Yoon*,‡
Department of Chemistry and Research Institute of
Natural Sciences, Changwon National University,
Changwon 641-773, Korea, Department of Chemistry and
Research Institute of Natural Science, Gyeongsang National
University, Chinju 660-701, Korea, Department of
Biochemistry, University of Texas Southwestern Medical
Center, Dallas, Texas 75390, and Rigaku Corporation,
3-9-12 Matsubara-cho, Akishima-shi,
Tokyo 196-8666, J apan
yjyoon@nongae.gsnu.ac.kr
Received May 7, 2003
Abstr a ct: Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently
prepared in excellent yields by a one-pot annulation of
N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyr-
idines with use of cesium carbonate in refluxing acetonitrile.
The key transformation features a Smiles rearrangement
of the initial O-alkylation product and subsequent cycliza-
tion.
The overall annulation is best explained by a three-
step process (Scheme 2). Alkylation of 1 by 2 generates
adduct 3, which can be observed by TLC monitoring. Rate
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The wide occurrence of benzo-fused and heterocycle-
fused [1,4]oxazines in bioactive natural products and
pharmaceuticals has made them important synthetic
targets.1 For the most part, synthetic routes to benzo-
[1,4]oxazines,2 pyrido[3,2-b][1,4]oxazines,3 and pyrimido-
[5,4-b][1,4]oxazines4 are well established.5,6 In contrast,
pyrido[2,3-b][1,4]oxazines have received scant attention.7
As part of our continuing interest in the development of
economic syntheses of heterocyclic systems, we investi-
gated the utility of the Smiles rearrangement8 and report
herein its application to the synthesis of pyrido[2,3-b]-
[1,4]oxazin-2-ones using readily available, stable precur-
sors.
Typically, benzo[1,4]oxazines and pyrido[3,2-b][1,4]-
oxazines are made by the direct cyclization of 2-haloacetyl
halides or alkyl 2-halopropionates with 2-aminophenol
* Address correspondence to Yong-J in Yoon: Gyeongsang National
University. Phone: 082-055-751-6019. Fax: 082-055-761-0244.
† Department of Chemistry, Research Institute of Natural Sciences,
and Changwon National University.
‡ Gyeongsang National University.
§ University of Texas Southwestern Medical Center.
Rigaku Corporation.
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C.; Me´rour, J .-Y. Tetrahedron 2002, 58, 8145. (b) Kikelj, D.; Suhadolc,
E.; Urleb, U.; Zbontar, U. J . Heterocycl. Chem. 1993, 30, 597. (c)
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10.1021/jo034593i CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
7918
J . Org. Chem. 2003, 68, 7918-7920

SCHEME 1
TABLE 1. Effect of Ba se on th e Yield of 4a fr om 1a a n d
2 in Reflu xin g Aceton itr ile
SCHEME 2
entry
base
time
4a yield (%)a
1
2
3
4
5
6
7
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
SrCO3
7 days
7 days
7 days
3 h
3 h
7 days
48 h
trace
40
48
93
97
0
Ag2CO3
0
a
Isolated yield.
TABLE 2. Effect of Solven t on th e Yield of 4a fr om 1a
a n d 2, Usin g Cesiu m Ca r bon a te
determining Smiles rearrangement then sets the stage
for a rapid ring closure giving rise to 1-substituted-
pyrido[2,3-b][1,4]oxazin-2-one 4.
entry
reaction conditions
time (h)
4a yield (%)a
1
2
3
4
5
6
CH3CN, reflux
CH3CH2OH, reflux
THF, reflux
DMF, 90-100 °C
toluene, reflux
CH2Cl2, reflux
3
3
3
1
3
3
97
0
60
96
5
To study this reaction in more detail, we systematically
investigated the reaction parameters using 1a and 2
(Table 1). The common alkali carbonates Li2CO3, Na2-
CO3, and K2CO3 (entries 1-3, respectively) generated a
trace or very little of 4a even after prolonged heating in
refluxing acetonitrile; strontium and silver carbonate
(entries 6 and 7) proved disappointing as well. In sharp
contrast, cesium and rubidium carbonate afforded 4a in
excellent yields (entries 4 and 5) after just 3 h in refluxing
acetonitrile.
0
a
Isolated yield.
and 4), whereas a protic solvent, ethanol (Entry 2), and
the nonpolar solvents toluene and dichloromethane were
ineffective (entries 5 and 6). THF (entry 3) fell between
the two extremes. Consequently, all following Smiles
Polar, aprotic solvents such as N,N-dimethylformamide
and acetonitrile were quite effective (Table 2: entries 1
J . Org. Chem, Vol. 68, No. 20, 2003 7919

TABLE 3. P r ep a r a tion of 4 fr om 1 a n d 2
a
b
Method A: 1 + 2 f 4. Method B: 1 + 2 f 3 f 4. Isolated yield. c Yield of diastereomers: (S,S)-isomer (47%) and (S,R)-isomer
(45%).
tereoisomers of 4d could not be separated by SiO2 column
chromatography.
rearrangements/annulations were conducted with cesium
carbonate in refluxing acetonitrile.
Notably, cyclization of bromophenol instead of 3-hy-
droxy-2-chloropyridine with N-substituted chloroaceta-
mides under the same conditions did not form the
corresponding benzo[1,4]oxazin-3-ones.
In conclusion, we have developed an operationally
simple and economic synthesis of pyrido[2,3-b][1.4]oxazin-
2-ones based on the Smiles rearrangement. Its applica-
tion in the synthesis of natural compounds is underway
in our laboratory and will be reported in due course.
A variety of pyrido[2,3-b][1,4]oxazin-2-ones 4 were
synthesized with two related protocols (Table 3). Method
A involved direct cyclization of 1 with 2 in the presence
of cesium carbonate in refluxing acetonitrile without
isolation of 3. In Method B (Method A), intermediate 3
was preformed and then converted to 4 under the
standard conditions. Yields were excellent, ranging from
87 to 97%, even for acetamides with bulky N-substituents
(entries 5, 6, 15, 16, and 17). Cyclizations of 3d and 3n
yielded 4d and 4n as mixtures of diastereomers since the
precursor N-substituted R-methylacetamides were dis-
ateromeric by virtue of two different chiral centers. The
diastereomeric mixture 4n could be separated into its
(S,S)-isomer (4n -a , 47%) and (S,R)-isomer (4n -b, 45%)
by column chromatography. The absolute configurations
of 4n -a and 4n -b were established by using the proton
coupling constants of C2-H and N4-CR-H. The dias-
Ack n ow led gm en t. Supported by Korea Research
Foundation grant KRF-2002-C00008.
Su p p or tin g In for m a tion Ava ila ble: 1H/13C NMR and IR
spectral data, CHN analyses, melting points for 3 and 4; X-ray
analytical data for 4a and N-substituted-2-haloacetamides.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O034593I
7920 J . Org. Chem., Vol. 68, No. 20, 2003