One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones by a Smiles Rearrangement

Article abstract of DOI:10.1055/s-0037-1609338

A simple and convenient synthesis of indole-fused pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones is described. A range of 2-(1 H -indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in organic synthesis.

Full text of DOI:10.1055/s-0037-1609338

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
X. Jiang, F. Hu
Letter
Synlett
One-Pot Highly Regioselective Synthesis of Indole-Fused
Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-ones by a Smiles
Rearrangement
R3
Xiaolei Jiang
X
Fangdong Hu*
direct nucleophilic
substitution
O
N
X
R2
R3
School of Chemistry and Chemical Engineering, Linyi
University, Linyi, Shandong 276005, P. R. of China
hufangdong@lyu.edu.cn
R1
N
R2
O
N
H
N
HO
K2CO3
+
R3
Cl
Cl
DMF, 80 °C
N
N
X
R1
N
O
R2
Smiles rearrangement
X = CH, N
N
O
R1 = Et, n-Bu, n-pentyl, Bn, allyl, THP
R2 = Me, OMe, F, Cl, Br
R3 = Me, Br
N
R1
O
18 examples
52–92% yields
Received: 18.01.2018
Accepted after revision: 13.02.2018
Published online: 05.03.2018
DOI: 10.1055/s-0037-1609338; Art ID: st-2017-u0038-l
N
Abstract A simple and convenient synthesis of indole-fused pyridazi-
no[4,5-b][1,4]benzoxazepin-4(3H)-ones is described. A range of 2-(1H-
indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible
with this reaction. A Smiles rearrangement is proposed as a key step in
the highly regioselective construction of the products. The easy avail-
ability of the starting materials makes this an appealing method in
organic synthesis.
N
O
N
R
O
Figure 1 The structure of indole-fused pyridazino[4,5-b][1,4]benzox-
azepin-4(3H)-ones
Table 1 Optimization of the Reaction Conditionsa
Key words indoles, indolopyridazinobenzoxazepinones, regioselectivi-
ty, polycyclic heterocycles, Smiles rearrangement
N
H
Pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-one
ana-
OH
1a
logues are among the most attractive structural motifs to
the organic synthesis community, because these com-
pounds are valued for their diverse biological activities.1–6
In the recent decades, a great deal of effort has been devoted
toward their synthesis.7–10 However, heterocycle-fused pyr-
idazino[4,5-b][1,4]benzoxazepin-4(3H)-ones have attracted
surprisingly little attention. In this regard, indoles are im-
portant heterocyclic units that exhibit a wide range of bio-
logical activities.11–12 Fusion of an indole skeleton with a
pyridazino[4,5-b][1,4]benzoxazepin-4(3H)-one would lead
to a new heterocycle library (Figure 1). To the best of our
knowledge, no synthesis of this new fused heterocycle sys-
tem has been reported and, consequently, the development
of an economic and efficient method for their preparation
is in high demand.
N
base
+
solvent, temp
N
Cl
Cl
O
N
N
N
THP
O
THP
3a
O
2a
Entry
Temp (°C)
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
50
80
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMSO
81
90
87
71
82
71
100
80
80
80
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), base (2.5 equiv),
solvent, 3 h.
b Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
X. Jiang, F. Hu
Letter
Synlett
With the optimal reaction conditions in hand, we next
examined the substrate scope. Various alkyl-substituted
4,5-dichloropyridazin-3-ones 2a–f reacted smoothly with
2-(1H-indol-2-yl)phenol (1a) to give the corresponding
products 3a–f in good to excellent yields (Scheme 1). It was
noteworthy that the allyl-substituted 4,5-dichloropyridaz-
in-3-one 2f was also tolerated in this transformation, giving
the corresponding product 3f in 76% yield.
Cl
N
K2CO3 (2.5 equiv)
DMF, 80 °C
N
N
+
R1
N
N
H
Cl
O
HO
N
O
R1
O
1a
2a–f
3a–f
X
R3
N
O
N
N
N
H
R2
R3
HO
N
N
N
C2H5
N
N
nC4H9
O
O
O
X
1b–m
N
X = CH, N
N
THP
K2CO3 (2.5 equiv)
DMF, 80 °C
O
O
R2
+
3a 90%
3b 92%
3c 86%
N
Cl
Cl
O
N
N
N
C2H5
O
C2H5
3g–r
O
N
N
N
2b
N
N
N
O
O
O
N
N
N
nC5H11
Ph
O
O
O
Me
F
Cl
N
N
N
3d 83%
3e 90%
3f 76%
N
N
N
Scheme 1 The scope of 4,5-dichloropyridazin-3-ones. Reaction
conditions: 1a (0.3 mmol), 2a–f (0.3 mmol), K2CO3 (2.5 equiv), DMF
(2 mL), 80 °C, 3 h.
O
O
O
N
N
N
C2H5
C2H5
C2H5
O
O
O
3g 84%
3h 67%
3i 78%
The Smiles rearrangement is a powerful and important
tool for the construction of fused heterocycles.13–17 In com-
parison with stepwise transformations, one-pot syntheses
are much preferred due to their convenience. Consequently,
the Smiles rearrangement has been introduced into one-
pot syntheses of fused heterocycle systems.18–21 On the ba-
sis of this concept, many N- and O-containing fused hetero-
cycles have been conveniently produced with high efficien-
cies.8,22–24 Inspired by the reported works,9,10,25 we devel-
oped a one-pot, highly regioselective protocol for the
construction of indole-fused pyridazino[4,5-b][1,4]benzox-
azepin-4(3H)-ones through a Smiles rearrangement, using
readily available starting materials.
Br
MeO
N
N
N
N
N
F
N
O
O
O
N
N
N
C2H5
C2H5
C2H5
O
O
O
3j 81%
3k 75%
3l 63%
Me
Br
N
N
N
N
N
C2H5
MeO
O
N
N
O
O
N
N
O
C2H5
C2H5
O
O
We began our study by using 2-(1H-indol-2-yl)phenol
(1a) and 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyri-
dazin-3(2H)-one (2a) as model substrates. To our delight,
the desired product 3a was obtained in 81% yield under our
initial conditions (Table 1, entry 1). Raising the reaction
temperature slightly improved the yield (entries 2 and 3),
and the best result was achieved at 80 °C (entry 2). Next, a
screen of bases indicated that potassium carbonate was the
optimal base among those tested (entries 2, 4, and 5). The
use of dimethyl sulfoxide as solvent gave an inferior result
(entry 6). We therefore concluded that the best results were
obtained with potassium carbonate as base and N,N-di-
methylformamide as solvent at 80 °C, which gave the de-
sired product 3a in 90% yield.
3m 78%
3n 71%
3o 77%
Me
Me
N
N
N
N
N
N
N
N
N
C2H5
MeO
O
O
N
N
O
N
C2H5
O
O
C2H5
O
3p 52%
3q 69%
3r 53%
Scheme 2 The scope of 2-(1H-indol-2-yl)phenols. Reaction condition:
1b–m (0.3 mmol), 2b (0.3 mmol), K2CO3 (2.5 equiv), DMF (2 mL),
80 °C, 3 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
X. Jiang, F. Hu
Letter
Synlett
On the basis of these preliminary results, we then evalu-
ated the scope of the 2-(1H-indol-2-yl)phenols with vari-
ous substituents 1b–m in this transformation (Scheme 2).
To our satisfaction, all the tested 2-(1H-indol-2-yl)phenols
worked well in the reaction, delivering the corresponding
product 3g–o in 63–84% yield. Remarkably, the structure of
3n was unambiguously confirmed by X-ray crystallographic
analysis (Figure 2).26 The substrates were not limited to 2-
(1H-indol-2-yl)phenols; interestingly, this method could
also be extended to 2-(1H-benzimidazol-2-yl)phenols, and
under the same reaction conditions, the product 3p was
produced in 52% yield. Similarly, substituents on the 2-(1H-
benzimidazol-2-yl)phenol had no deleterious effect on the
outcome (3q, 3r).
To probe the reaction mechanism, two control experi-
ments were carried out (Scheme 3). When attempts were
Cl
N
N
K2CO3 (2.5 equiv)
+
+
no reaction
no reaction
Figure 2 The X-ray structure of compound 3n
N
DMF, 80 °C
standard conditions
Cl
THP
THP
H
MeO
O
80% recovery
2a
made to react 2-(2-methoxyphenyl)-1H-indole or 2-phenyl-
1H-indole with substrate 2a under the standard conditions,
no reaction occurred and the indole starting material was
recovered in 80% and 69% yield, respectively. These experi-
ments indicated that the indole nitrogen cannot serve as a
nucleophilic center under the optimal reaction conditions,
and that a hydroxy group in the substrate is indispensable
Cl
Cl
N
N
K2CO3 (2.5 equiv)
N
H
DMF, 80 °C
standard conditions
O
69% recovery
2a
Scheme 3 Control experiments
X
R3
R2
N
Cl
X
H
N
base
base
O
O
R3
+
N
R2
Cl
R1
N
H
N
Cl
HO
O
N
R1
A
X
X
X
N
R3
R3
R3
R2
R2
N
N
R2
path a
Cl
O
O
a
O
O
Smiles
rearrangement
O
b
Cl
Cl
N
N
N
N
N
R1
N
O
R1
R1
C
B
direct nucleophilic
substitution
path b
R3
R3
X
X
N
O
O
N
R2
R2
N
R1
N
O
O
N
N
R1
Scheme 4 Possible reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
X. Jiang, F. Hu
Letter
Synlett
for this transformation. We therefore deduced that a Smiles
rearrangement is involved in this reaction.
(10) Sapegin, A. V.; Kalinin, S. A.; Smirnov, A. V.; Dorogov, M. V.;
Krasavin, M. Synthesis 2012, 44, 2401.
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110, 4489.
Based on previous reports8,25 and on our preliminarily
mechanistic experiments, a possible reaction mechanism
was proposed (Scheme 4). Under basic conditions, the
intermediate A is initially formed through direct nucleo-
philic substitution of the phenolic oxygen anion with the
4,5-dichloropyridazin-3-one. The indole nitrogen anion B is
then generated under the same reaction conditions. Next, a
Smiles rearrangement occurs preferentially (path a), rather
than direct nucleophilic cyclization (path b), to give inter-
mediate C. Finally, the phenolic oxygen anion undergoes a
second nucleophilic substitution to afford the desired product.
In summary, we have successfully developed a highly
regioselective synthetic route for the construction of
indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-ones
through a Smiles rearrangement under transition-metal-
free conditions.27 A range of substrates with various func-
tional groups were compatible in this reaction and the cor-
responding products were obtained in good to high yields.
A probable involvement of a Smiles rearrangement in this
reaction was established by control experiments. Further
studies on applications of this reaction in synthesizing oth-
er fused heterocyclic compounds are currently in progress.
(12) Li, S.-M. Nat. Prod. Rep. 2010, 27, 57.
(13) Cho, S.-D.; Park, Y.-D.; Kim, J.-J.; Lee, S.-G.; Ma, C.; Song, S.-Y.;
Joo, W.-H.; Falck, J. R.; Shiro, M.; Shin, D.-S.; Yoon, Y.-J. J. Org.
Chem. 2003, 68, 7918.
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Chandrasekhar, S.; Reddy, C. R.; Shin, D.-S. Tetrahedron Lett.
2008, 49, 3827.
(18) Zhao, Y.; Wu, Y.; Jia, J.; Zhang, D.; Ma, C. J. Org. Chem. 2012, 77,
8501.
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Sci. 2013, 15, 130.
(20) Yang, B.; Tan, X.; Guo, R.; Chen, S.; Zhang, Z.; Chu, X.; Xie, C.;
Zhang, D.; Ma, C. J. Org. Chem. 2014, 79, 8040.
(21) Niu, X.; Yang, B.; Li, Y.; Fang, S.; Huang, Z.; Xie, C.; Ma, C. Org.
Biomol. Chem. 2013, 11, 4102.
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2012, 51, 2925.
Funding Information
(23) Zhou, Y.; Zhu, J.; Li, B.; Zhang, Y.; Feng, J.; Hall, A.; Shi, J.; Zhu, W.
Org. Lett. 2016, 18, 380.
We are grateful for financial support from Shandong Province Higher
Educational Science and Technology Program (Grant No. J17KA099),
Shandong Provincial Natural Science Foundation for Doctors Scholar
(Grant No. ZR2017BB016), and the Natural Science Foundation of
(24) Zhan, C.; Jia, J.; Yang, B.; Huang, A.; Liu, Y.; Ma, C. RSC Adv. 2012,
2, 7506.
(25) Sang, P.; Yu, M.; Tu, H.; Zou, J.; Zhang, Y. Chem. Commun. 2013,
49, 701.
(26) CCDC 1581528 contains the supplementary crystallographic
data for compound 3n. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
Linyi University (Grant No. LYDX2016BS092).
F
o
n
ds
der
ch
e
mscih
e
n
n
I
d
u
estri
)(
Supporting Information
(27) Indolo[1,2-d]pyridazino[4,5-b][1,4]benzoxazepin-9(8H)-
ones 3a–r; General Procedure
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609338.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
The appropriate 2-(1H-indol-2-yl)phenol 1 (0.30 mmol), 2-tetra-
hydropyranylpyridazin-3-one
2 (0.30 mmol), and K2CO3
(2.5 equiv.) were successively added to a 10 mL Schlenk tube.
DMF (2 mL) was then added from a dropper and the resulting
solution was stirred at 80 °C for 3 h. The mixture was cooled to
r.t. then extracted with EtOAc (×3). The combined organic phase
was washed with brine, dried (Na2SO4), and filtered. The solvent
was then removed in vacuoto give a crude mixture that was
purified by column chromatography (silica gel).
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b][1,4]benzoxazepin-9(8H)-one (3a)
Light-yellow solid; yield: 104 mg (90%); mp 122–124 °C. 1H
NMR (500 MHz, CDCl3): δ = 8.43 (s, 1 H), 7.72–7.70 (m, 2 H),
7.66 (d, J = 8.2 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.40–7.27 (m, 4 H),
6.98 (s, 1 H), 6.15–6.13 (m, 1 H), 4.17–4.14 (m, 1 H), 3.81–3.76
(m, 1 H), 2.23–2.15 (m, 1 H), 2.07–2.04 (m, 1 H), 1.80–1.71 (m, 3
H), 1.60–1.58 (m, 1 H). 13C NMR (125 MHz, CDCl3): δ = 157.55,
157.02, 144.65, 136.58, 135.94, 133.09, 131.39, 130.48, 129.45,
129.39, 126.36, 123.99, 123.54, 122.82, 122.15, 121.69, 111.56,
105.97, 83.32, 68.98, 28.99, 24.89, 22.83. HRMS (ESI): m/z [M +
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D