Highly efficient three-component synthesis of polysubstituted 2,5-dihydro-1,3-oxazin-6-ones under mild conditions

Article abstract of DOI:10.1055/s-2007-990909

But-2-ynedioic acid diethyl ester reacted with an amine and an aldehyde to afford polysubstituted ethyl 2,5-dihydro-2H-1,3-oxazine-6-one-4-carboxylate derivatives in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990909

3214
LETTER
Highly Efficient Three-Component Synthesis of Polysubstituted
2,5-Dihydro-1,3-oxazin-6-ones under Mild Conditions
T
hree-Component Syn
i
thesis
o
n
f
Polysubstitute
d
2
Z
,5-Dihydro-1,3
h
-oxazin-6-on
aes ng, Huanfeng Jiang,* Azhong Wang
The College of Chemistry, South China University of Technology, Guangzhou 510640, P. R. of China
Fax +86(20)87112906; E-mail: jianghf@scut.edu.cn
Received 3 September 2007
molecules from readily available starting materials. Here-
in, we report the first base-induced three-component syn-
thesis of 1,3-oxazin-6-ones containing a- and b-amino
acid units under mild conditions. Our approach comprises
the relay process of the following domino sequences
(Scheme 1): (1) two-component hydroamination; (2)
base-induced nucleophilic attack process, and (3) nucleo-
philic substitution cyclization process.
Abstract: But-2-ynedioic acid diethyl ester reacted with an amine
and an aldehyde to afford polysubstituted ethyl 2,5-dihydro-2H-1,3-
oxazine-6-one-4-carboxylate derivatives in good to excellent
yields.
Key words: three-component synthesis, but-2-ynedioic acid dieth-
yl ester, amines, aldehydes, dihydro-2H-1,3-oxazine-6-ones
But-2-ynedioic acid diethyl ester (1) reacts with aniline
(2a) and benzaldehyde (3a) to afford ethyl 2,3-diphenyl-
2,5-dihydro-2H-1,3-oxazine-6-one-4-carboxylate (4aa)
in good isolated yield (Tables 1, 78%). The hydroamina-
tion of 1 with 2a could rapidly afford the active interme-
diate 5,8 which would undergo nucleophilic attack to 3a
and then intramolecular nucleophilic substitution cycliza-
tion to give the target compound 4aa. Interestingly, no es-
ter amidation9 at the 4-position has been detected in this
MCR, and this reveals its excellent regioselectivity. To
the best of our knowledge, the use of simple inorganic
base to promote these different three-component reac-
tions, namely hydroamination, nucleophilic attack, and
nucleophilic substitution cyclization, has not been report-
ed previously.
The development of efficient and selective synthetic
transformations in one operation is a major challenge in
modern organic synthesis. Consequently, multicompo-
nent reactions (MCRs) including domino processes have
been used as a powerful tool to achieve this goal.1 1,3-Ox-
azinones and their analogues are an important class of
useful N,O-heterocyclic compounds, which have been
found to possess interesting and unique properties such as
nonsteroidal progesterone receptor agonist tanaproget and
melatonin receptor,2 as monomers for polymer synthesis,3
as photochromic agents,4 as detecting reagents of cya-
nide,5 and as synthetic intermediates.6 To our knowledge,
few general procedures are available for the preparation of
these compounds.7 We are interested in using this rapid
and elegant method for the preparation of these target
H
CO2Et
H
CO2Et
N–
CO2Et
H
OH–
EtO2C
NH2
N
EtO2C
2a
H
O
CO2Et
3a
hydroamination
1
5
6
O
O
OEt
–O
OEt
O
H
O
EtO2C
N
O–
EtO2C
EtO2C
N
4aa
8
7
Scheme 1 Proposed MCRs to synthesize 2,5-dihydro-1,3-oxazin-6-ones
SYNLETT 2007, No. 20, pp 3214–3218
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-990909; Art ID: W15907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Three-Component Synthesis of Polysubstituted 2,5-Dihydro-1,3-oxazin-6-ones
3215
Table 1 Optimization of Reaction Conditions for the Three-Component Reaction
O
O
CO2Et
base, r.t.
+
+
EtO2C
N
solvent
CHO
CO2Et
NH2
4aa
1
Entry
1
2a
3a
Solvent
–
Base
Time (min)
Yield (%)a
–
600
600
60
30
30
30
30
30
30
30
1
trace
trace
complex
61
2
toluene
Et3N
Na2CO3
Et3N
3
4
toluene
toluene
MeCN
Et2O
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
5
65
6
71
7
70
8
CH2Cl2
THF
67
9
56
10
11
EtOH
66
MeCN–H2O (1:1)
78
a Isolated yield.
A screening of the reaction conditions established the suit- solvent MeCN–H2O were suitable for the MCRs (Table 1,
able solvents and bases for the desired MCRs. As shown entries 4–10). The solvents MeCN–H2O (10:1) and KOH
in Table 1, it was necessary to employ solvent and inor- (1.2 equiv) were proved to be the best partners for the
ganic base in the reaction. Conventional solvents such as MCRs owing to the fact that they can provide a homoge-
toluene, MeCN, Et2O, CH2Cl2, THF, EtOH, and mixed nous reaction medium (Table 1, entry 6).
Table 2 Synthesis of Polysubstituted 2,5-Dihydro-1,3-oxazin-6-ones
O
O
CO2Et
KOH, r.t.
R1NH2
R2CHO
EtO2C
N
R1
R2
+
+
MeCN–H2O (10:1)
CO2Et
1
2
3
4
Entry
R1NH2
R2CHO
Time (min)
Product yield (%)a
O
O
EtO2C
N
1
30
NH2
CHO
3a
2a
4aa 78
Synlett 2007, No. 20, 3214–3218 © Thieme Stuttgart · New York

3216
M. Zhang et al.
LETTER
Table 2 Synthesis of Polysubstituted 2,5-Dihydro-1,3-oxazin-6-ones (continued)
O
O
CO2Et
KOH, r.t.
R1NH2
+
R2CHO
EtO2C
N
R1
R2
+
MeCN–H2O (10:1)
CO2Et
1
2
3
4
Entry
R1NH2
R2CHO
Time (min)
Product yield (%)a
O
O
EtO2C
4ab 63
EtO2C
N
2
30
NH2
NH2
NH2
NH2
NH2
CHO
3b
2a
2a
2a
2a
2a
O
N
O
Br
3
4
5
6
30
30
3
CHO
Br
3c
4ac 78
O
N
O
F
EtO2C
4ad 82
EtO2C
CHO
F
3d
O
N
O
CHO
3e
4ae 90
O
N
O
MeCHO
3f
EtO2C
1
4af 92
O
N
O
F
EtO2C
7
30
CHO
NH2
3a
2c
F
4ca 71
Synlett 2007, No. 20, 3214–3218 © Thieme Stuttgart · New York

LETTER
Three-Component Synthesis of Polysubstituted 2,5-Dihydro-1,3-oxazin-6-ones
3217
Table 2 Synthesis of Polysubstituted 2,5-Dihydro-1,3-oxazin-6-ones (continued)
O
O
CO2Et
KOH, r.t.
R1NH2
+
R2CHO
EtO2C
N
R1
R2
+
MeCN–H2O (10:1)
CO2Et
1
2
3
4
Entry
R1NH2
R2CHO
Time (min)
Product yield (%)a
O
O
EtO2C
N
8
30
NH2
CHO
3a
2b
4ba 73
O
N
O
EtO2C
MeCHO
3f
9
1
NH2
2b
4bf 93
EtO2C
4df 92
EtO2C
4ef 86
O
N
O
MeCHO
3f
10
1
NH2
2d
O
N
O
MeCHO
3f
11
1
NH2
2e
O
N
O
F
EtO2C
MeCHO
3f
12
1
NH2
2c
F
4cf 93
a Isolated yield.
With the optimized conditions in hand, we examined the products in good to excellent yields. Interestingly, when
scope of the three-component reactions (Table 2).10 All aliphatic aldehydes were employed, the reaction accom-
the reactions proceeded rapidly and afforded the desired plished in very short reaction time (less than 3 min), pro-
Synlett 2007, No. 20, 3214–3218 © Thieme Stuttgart · New York

3218
M. Zhang et al.
LETTER
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(Table 2, entries 5, 6, 9–12). It was also found that aro-
matic aldehydes could undergo smoothly within 30 min-
utes to give the products in good isolated yields (Table 2,
entries 1–4, 7, 8). These results indicated that both the ac-
tivity and bulkiness of aldehydes have significant influ-
ence on the reaction, but the electronic effects of the
substituents on aromatic rings only weakly influenced the
reaction.
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In conclusion, we have disclosed a highly efficient meth-
od for the synthesis of polysubstituted 2,5-dihydro-1,3-
oxazin-6-ones via the three-component reaction under ex-
ceedingly mild reaction conditions. This domino reaction
proceeded smoothly and rapidly in good to excellent
yields with simple experimental workup procedure. In ad-
dition, the obtained products in our experiments are inter-
esting N,O-heterocycles containing a- and b-amino acid
blocks. Further studies and applications on this domino
reaction are ongoing in our laboratory and will be pub-
lished in due course.
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Acknowledgment
We thank the National Natural Foundation of China (Nos.
20332020, 20572027, 20625205 and 20772034) and Guangdong
Natural Science Foundation (No. 07118070) for financial support.
References and Notes
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then react with benzaldehyde to afford product 4ab.
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(10) Experimental Procedure: To a stirring mixture of but-2-
ynedioic acid diethyl ester (1, 170 mg, 1 mmol) and aniline
(2a, 93 mg, 1 mmol), benzaldehyde (3a, 127 mg, 1.2 mmol),
solvent mixture (3 mL, MeCN–H2O, 10:1) and KOH (1.2
mmol, 67 mg) were added successively. The mixture was
stirred at r.t. for 30 min. After completion of the reaction
(monitored by TLC), the reaction mixture was diluted with
Et2O and dried with anhyd MgSO4. Then, the mixture was
filtered and washed with Et2O (5 × 5 mL). The combined
organic solvent was evaporated in vacuo and the crude
product was purified by preparative TLC with hexane–
EtOAc (10:1) as the eluent to afford the desired product 4aa
(252 mg, 78%) as a yellowish solid.
Synlett 2007, No. 20, 3214–3218 © Thieme Stuttgart · New York

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