One-pot synthesis of fused pyridazino[4,5- b ][1,4]oxazepine-diones via smiles rearrangement

Article abstract of DOI:10.1055/s-0031-1290073

Fused pyridazino[4,5-b][1,4]oxazepine-diones were easily obtained in moderate to excellent yields via Smiles rearrangement. The synthetic approach is supported by a one-pot coupling-Smiles rearrangement-cyclization process. This process has potential appl

Full text of DOI:10.1055/s-0031-1290073

LETTER
255
One-Pot Synthesis of Fused Pyridazino[4,5-b][1,4]oxazepine-diones via Smiles
Rearrangement
S
ynthesis of Fused
a
P
yridazino
n
[4,5-
b
][1,4]
o
l
xazepi
i
ne-diones Liu,a Ying Ma,a Chunjing Zhan,a Aiping Huang,a Chen Ma*a,b
a
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. of China
Fax +86(531)88564464; E-mail: chenma@sdu.edu.cn
b
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. of China
Received 6 September 2011
4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-
3(2H)-one (Scheme 1).
Abstract: Fused pyridazino[4,5-b][1,4]oxazepine-diones were eas-
ily obtained in moderate to excellent yields via Smiles rearrange-
ment. The synthetic approach is supported by a one-pot coupling–
Smiles rearrangement–cyclization process. This process has poten-
tial applications in the synthesis of biologically and medicinally rel-
evant compounds.
O
THP
N
O
N
R2
O
K2CO3
DMF
Cl
N
N
N
R1
R1
H
+
Key words: pyridazino[4,5-b][1,4]oxazepine-dione, one-pot, syn-
thesis, Smiles rearrangement, tandem reaction
80 °C
N
OH
Cl
THP
R2
O
2
O
1
3
Scheme 1 One-pot synthesis of fused pyridazino[4,5-b][1,4]oxaze-
pine-diones
Heterocyclic-fused oxazepinones have attracted consider-
able attention owing to their wide range of biological ac-
tivities, such as anti-ischemic,1a,b anticonvulsant,1c
antimicrobial,1d nonpeptidergic GPCR inhibitors,1e and
integrin antagonists.1f Pyridazinone derivatives have also
been widely studied because of their biological activities,
such as antimicrobial,2a antiarrhythmic,2b bioavailable in-
hibitors of Aurora A kinase,2d pesticides,2e,f and anticancer
activities.2g Nowadays, the combination of several func-
tional groups in one molecule seems as a useful tool to op-
timize properties of biological compounds. Fused
pyridazinooxazepines are valuable substrates with various
biological activities.3–8 Smiles rearrangement reactions of
pyridazines have been reported.2o,p However, to the best
of our knowledge, fused pyridazino[4,5-b][1,4]ox-
azepine-dione (Figure 1) has not been reported. In order to
study the activities and applications of these highly func-
tionalized compounds, we came upon a need for the syn-
thesis of fused pyridazino[4,5-b][1,4]oxazepine-diones.
Table 1 Optimization of the Reaction Conditions
O
THP
O
N
K2CO3
DMF
O
Cl
Cl
N
N
N
N
H
+
80 °C
THP
N
OH
O
O
1c
2
3c
Entry Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
THF
Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
K2CO3
r.t.
80
80
80
80
80
80
80
15
2
79
89
83
10
8
K2CO3
Cs2CO3
NaH
2
2
KOt-Bu
DBU
2
2
84
86
42
O
NH
K2CO3
K2CO3
2
O
N
2
NH
O
As can be seen from Table 1, N-propyl salicylamide 1c
and 2 were chosen as starting materials to optimize reac-
tion conditions. Firstly, temperature was examined by
treatment of 1c with 2 in dry DMF in the presence of
K2CO3 at room temperature and 80 °C, and the latter pro-
vided higher yield (Table 1, entries 1 and 2). Later on, the
reaction of 1c with 2 in DMF at 80 °C was conducted.
Owing to the possible side reaction, the yields of the de-
sired product decreased sharply when the reaction was
conducted in the presence of strong bases, such as NaH
and KOt-Bu (Table 1, entries 4 and 5), and K2CO3 was
Figure 1 Structure of fused pyridazino[4,5-b][1,4]oxazepine-dione
Herein, we report an effective and facile method for the
synthesis of fused pyridazino[4,5-b][1,4]oxazepine-
diones via Smiles rearrangement tandem reaction using
commercially available N-substituted salicylamide with
SYNLETT 2012, 23, 255–258
x
x.
x
x.
2
0
1
2
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290073; Art ID: W19511ST
© Georg Thieme Verlag Stuttgart · New York

256
Y. Liu et al.
LETTER
Table 2 Reaction of N-Substituted Salicylamides with 2a
proven to be the most effective base (Table 1, entries 2–
6). When DMF was replaced by MeCN and THF, the
yield decreased from 89% to 42% (Table 1, entries 7 and
8).
O
THP
O
N
O
Cl
Cl
R
N
K2CO3, DMF
N
N
N
H
+
With the optimal reaction conditions in hand, we contin-
ued our study to synthesize a variety of pyridazino[4,5-
b][1,4]oxazepine-diones. As shown in Table 2, both the
N-aryl and N-alkyl salicylamide produced the correspond-
ing products in good to excellent yields (Table 2, entries
1–12).
80 °C
THP
N
OH
R
O
2
O
3a–l
1a–l
Entry
1
R
Time (h) Product
Yield (%)b
1a Me
1b Et
1
3a
3b
3c
3d
3e
3f
87
95
89
95
85
88
75
81
80
83
89
85
To extend the substrate scope, 4a–f were treated with 2
under the optimal conditions, and the results are shown in
Table 3. Compound 2 reacted with N-benzyl salicylamide
possessing an electron-donating group, such as methyl
and phenyl, providing good yields of desired products
(Table 3, entries 1 and 5). N-Benzyl salicylamide with an
electron-withdrawing group was converted into the corre-
sponding compounds in 91% yield (Table 3, entry 3).
2
2
3
1c Pr
2
4
1d i-Pr
1e c-Hex
1f Bn
1.5
1
5
6
2
7
1g Ph
2
3g
3h
3i
Further, N-phenyl salicylamide with both electron-donat-
ing and electron-withdrawing groups were utilized to gen-
erate the desired products in moderate yields (Table 3,
entries 2, 4, 6).
8
1h 4-MeC6H4
1i 4-MeOC6H4
1j 4-FC6H4
4
9
5
A plausible mechanism is proposed in Scheme 2. Com-
pounds 1a–l were reacted with compound 2 to give 6a–l.
Compounds 6a–l could proceed in two paths (I and II).
Path I would afford the direct intramolecular nucleophilic
substituted products 10a–l. Path II would lead to com-
pounds 3a–l via Smiles rearrangement. However, 10a–l
were not observed. Therefore, the imido nitrogen in com-
pounds 7a–l underwent intramolecular nucleophilic at-
tack on the carbonium (meta position to the carbonyl
group) to give 8a–l.
10
11
12
5.5
5.5
6.5
3j
1k 4-ClC6H4
1l 4-BrC6H4
3k
3l
a Reaction conditions: 1.2 mmol 1a–l, 1 mmol 2, 3 mmol K2CO3, 10
mL DMF, 80 °C, 1-6.5 h.
b Isolated yield.
O
O
R
Cl
Cl
NHR
N
N
N
base
H
+
N
OH
N
O
THP
O
THP
O
Cl
6a–l
1a–l
2
O
O
O
R
R
N
N
R
O
base
path II
N
path II
N
O
N
N
N
N
path I
Cl
O
O
N
THP
Cl
THP
THP
Cl
O
O
7a–l
path I
9a–l
O
O
R
R
O
N
N
THP
N
N
O
O
N
N
THP
O
10a–l
3a–l
Scheme 2 Plausible reaction mechanism
Synlett 2012, 23, 255–258
© Thieme Stuttgart · New York

LETTER
Synthesis of Fused Pyridazino[4,5-b][1,4]oxazepine-dione
257
Secondly, migration of the spiro-oxygen, followed by an Additionally, H-H NOESY of product 3b was obtained
intramolecular nucleophilic substitution, afforded the de- (Figure 2). This spectrum contains a cross-peak in the re-
sired cyclization product 3a–l.
gion which characterizes the interaction of the protons in
the NCH2Me (d = 1.38–1.42 ppm) with an aromatic pro-
ton in the pyridazinone (the proton at C, d = 7.91 ppm). It
is important to note that the reaction was performed via
Smiles rearrangement.
In order to demonstrate the reaction occurred via Smiles
rearrangement, compound 11 was reacted with compound
2 in the presence of K2CO3 in DMF at 80 °C (Scheme 3),
but 12 was not found even when the temperature was in-
creased to 110 °C. Consequently, 13 was obtained as the In conclusion, we have developed an efficient and facile
sole product instead of 12. This result indicated that the method for the synthesis of fused pyridazino[4,5-
amide group in salicylamides 1a–l cannot serve as the nu- b][1,4]oxazepine-diones via Smiles rearrangement tan-
cleophilic reaction center under the reaction conditions.
dem reaction. The mechanism of fused pyridazino[4,5-
b][1,4]oxazepine-diones synthesis is assumed by a one-
pot coupling–Smiles rearrangement–cyclization process.
Table 3 Reaction of N-Substituted Salicylamide Derivatives with Compound 2a
O
THP
N
O
N
R2
O
Cl
Cl
K2CO3, DMF
80 °C
N
N
N
R1
H
R1
N
OH
THP
R2
5a–f
O
2
O
4a–f
Entry
1
4
Time (h)
7.5
Product
Yield (%)b
O
N
H
Bn
Ph
5a
75
OH
4a
O
N
H
2
14
5b
50
OH
4b
O
Cl
N
H
Bn
3
4
5
6
3
5c
5d
5e
5f
91
59
80
89
OH
4c
O
Cl
N
H
Ph
Bn
Ph
1.5
1.5
1.5
OH
4d
4e
4f
O
N
H
OH
O
N
H
OH
a Reaction conditions: 4a–f (1.2 mmol), 2 (1 mmol), K2CO3 (3 mmol), DMF (10 mL), 80 °C, 1.5–14 h.
b Isolated yield.
© Thieme Stuttgart · New York
Synlett 2012, 23, 255–258

258
Y. Liu et al.
LETTER
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O
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Ph
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NHPh
+
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Cl
THP
OMe
11
O
THP
Cl
12
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80–110 °C
Me
N
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Me
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THP
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Scheme 3 Reaction of 11 with 2
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Figure 2 H-H NOESY of product 3b
A wide range of N-aryl and N-alkyl salicylamides was
used to perform this reaction. Further studies on its appli-
cation in the synthesis of biologically relevant compounds
are currently in progress.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the National Science Foundation of China (No.
20872079), the Natural Science Foundation of Shandong Province
(2009ZRB019YA), IIFSDU (No. 2010TS052), and the State Key
Laboratory of Natural and Biomimetic Drugs of Peking University
(K20090205) for financial support of this research.
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