Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives

Article abstract of DOI:10.1016/j.tet.2020.131341

N-(2,2-Diethoxyethyl)isoindolin-1-ones were readily obtained via the reaction of o-lithiated aromatic imines with carbon monoxide under mild conditions in gram-scale, and they were double-deprotonated by two equivalents of potassium bis(trimethylsilyl)ami

Full text of DOI:10.1016/j.tet.2020.131341

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of benzazepinoisoindolinone and bridged tricyclic
isoindolinone derivatives
*
Xiao-Yu Liu, Xi-Meng Luo, Liang-Fu Tang
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2020
Received in revised form
N-(2,2-Diethoxyethyl)isoindolin-1-ones were readily obtained via the reaction of o-lithiated aromatic
imines with carbon monoxide under mild conditions in gram-scale, and they were double-deprotonated
by two equivalents of potassium bis(trimethylsilyl)amide at the 3-position and subsequently reacted
4
June 2020
with ArCH
2
Br to give 3,3-dibenzyl-N-(2,2-diethoxyethyl)isoindolin-1-ones. Treatment of 3-benzyl-N-
CO H or AlCl led to an intramolecular cyclization reaction
Accepted 12 June 2020
Available online xxx
(
2,2-diethoxyethyl)isoindolin-1-ones with CF
3
2
3
to afford benzazepinoisoindolinones, while bridged tricyclic isoindolinone derivatives were successfully
obtained using 3,3-dibenzyl-N-(2,2-diethoxyethyl)isoindolin-1-ones as the substrates. Preliminary
in vitro tests for fungicidal activity indicate that some bridged tricyclic isoindolinones exhibit good
fungicidal activities.
Keywords:
Polycyclic isoindolinone
Benzazepinoisoindolinone
PomeranzeFritsch cyclization
Bridged ring
© 2020 Elsevier Ltd. All rights reserved.
Fungicidal activity
1. Introduction
alkylation of phthalimide derivatives [14], the annulation re-
actions of thioalkynes with phthalimide-substituted donor-
The isoindolinone skeleton is an important structural motif
which is commonly found in numerous synthetic pharmaceuticals
and natural products with a wide range of biological activities
acceptor cyclopropanes [15], and the cascade Michael addition/
cyclization of 3-carboxylate-substituted isoindolinones with ortho-
hydroxychalcones [16]. In consideration of the structural diversity
and the structure-activity relationship of isoindolinone derivatives,
more efficient synthetic methods for the bridged polycyclic iso-
indolinones from simple and readily available starting materials are
in great demand. Our previous investigations demonstrated that
the reaction of o-lithiated aromatic imines with carbon monoxide,
subsequently with various electrophiles under mild conditions
easily gave isoindolinone derivatives [17], which inspired us to
explore further application of this method for the synthesis of
polycyclic isoindolinones especially the scare bridged iso-
indolinone derivatives. We herein report the convenient synthesis
of benzazepinoisoindolinones and bridged tricyclic isoindolinones
employing this strategy.
(Fig. 1) [1]. Moreover, simple isoindolinone derivatives have been
extensively used as building blocks for the synthesis of various
important drugs and natural products [2]. As a consequence, many
synthetic methods for the construction of the isoindolinone skel-
eton have been reported in literature [3]. Among isoindolinone
derivatives, fused polycyclic isoindolinones have been attracting
considerable attention in recent years because of their novel
structural characteristics and extensive bioactivities [4]. A variety of
synthetic approaches have also been explored to construct the
fused isoindolinones with multiple functional groups, such as N-
acyliminium cyclization [5], dearomatization of indole derivatives
[
6], coupling reactions [7], condensation reactions [8], photo-
chemical reactions [9], Diels-Alder reactions [10], cascade Michael/
aldol-like cyclization [11], multicomponent cascade reactions [12],
and others [13]. Comparing with these rich approaches to the
fused isoindolinones, the synthetic methods of the bridged
polycyclic isoindolinones are few. These involve the Friedel-Crafts
2
. Results and discussion
2.1. Synthesis of N-acetal-substituted isoindolinones
The N-acetal-substituted isoindolinones were reported in liter-
ature [12b,18], though the starting materials were usually obtained
by multistep reactions. We herein find that the N-acetal-
substituted isoindolinones (1ae1f) are easily obtained through the
*
Corresponding author.
E-mail address: lftang@nankai.edu.cn (L.-F. Tang).
https://doi.org/10.1016/j.tet.2020.131341
040-4020/© 2020 Elsevier Ltd. All rights reserved.
0
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2
X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
attributes to the activation of the methoxy group in 1f. It is note-
worthy that compound 4b can be directly obtained in reasonable
yield from aromatic imine, in other words, without isolation of the
crude 1f. It is known that further hydrogenation of benzazepinones
with the core of 4a and 4b easily produces analogs of lennoxamine
[18]. Thus we provide here a convenient approach to analogs of
lennoxamine. The NMR spectra of 4a and 4b are in agreement with
their structures, and the structure of 4b has been confirmed by X-
ray single crystal diffraction, which is shown in Fig. 2.
2.3. Synthesis of bridged tricyclic isoindolinone derivatives
Fig. 1. Examples of pharmaceuticals (Indoprofen and Pagoclone) and natural products
(
Lennoxamine and Magallanesine) with the isoindolinone scaffold.
Compounds 2 contain two benzyl groups attached to the 3-
position of isoindolinone ring, so double intramolecular electro-
philic aromatic substitution reactions are expected for these com-
pounds. Indeed, bridged tricyclic isoindolinones (5ae5t) were
obtained in moderate to good yields via double intramolecular
cyclization reaction of o-lithiated aromatic imines with carbon
monoxide under mild conditions according to our previous work
(Scheme 1) [17]. The deprotonation at the methylene group of
cyclization reactions upon treatment of 2ae2t with AlCl
3
(Scheme
isoindolinone ring by various organic strong bases has been used to
synthesize various 3-monosubstituted isoindolinones [19]. We
found that the double-deprotonation of the methylene group of 3-
position in 1ae1d was successful in one-pot. 3,3-Dibenzyl-N-(2,2-
diethoxyethyl)isoindolin-1-ones (2ae2r and 2u) can be conve-
niently obtained in moderate to excellent yields upon direct
treatment of 1ae1d with two equivalents of potassium bis(-
4). The position of bromine on the benzyl group rarely affects this
cyclization reaction. For example, all these ortho, meta and para-
bromo substituted benzyl substrates (2be2d) gave bridged tricy-
clic isoindolinones (5be5d) in good yields. In addition, there were
no other regioisomers obtained in the cyclization process even for
meta-substituted benzyl substrates, such as 2c and 2f. Furthermore,
the unsymmetric substrates 2s and 2t were cyclized successfully to
bridged derivatives 5s and 5t. Halogen and methoxy are tolerable
on the benzyl groups and isoindolinone ring. Compound 2u only
afforded the hydrolysis product 6 (Scheme 5), showing that the
electron-withdrawing ester group is incompatible in this cycliza-
tion reaction. Taking into account that these functional groups
show great potential for other organic transformations, such as the
CeC coupling reactions of bromine, the amplification experiment
has been done. The yield of 5c barely reduced when 2c was used as
the substrate and the reaction was amplified to gram scale. More-
trimethylsilyl)amide (KHMDS) subsequently with ArCH
2
Br
(Scheme 2). Both electron-withdrawing fluorine and electron-
donating methoxy are tolerable on the substrates (2le2r). The
ester functional groups are compatible in the preparation of 3,3-
dibenzyl derivative (2u). In addition, unsymmetric 3,3-dibenzyl
derivatives (2s and 2t) can be similarly obtained through equiva-
lent amounts of KHMDS and 1e. Moreover, compounds
1
a and 2c were synthesized successfully in gram-scale. All these
newly synthesized compounds 1 and 2 have been characterized by
1
13
H and C NMR spectra as well as HRMS. The most remarkable
1
3
over, the demethylation of 5g with BBr is achieved (Scheme 6),
change in H NMR spectra is that the methylene protons of iso-
which affords compound 7 in almost quantitative yield. These
multifunctional compounds can probably be exploited as important
intermediates in future work.
indolinone ring in 1 disappeared after reaction.
Compounds 5e7 were fully identified by 1H and 13C NMR
spectra as well as HRMS, and the structure of 5a was further
confirmed by the X-ray crystal structure determination, which is
depicted in Fig. 3.
2.2. Synthesis of benzazepinoisoindolinones
Compounds 1e and 1f are excellent precursors for the
PomeranzeFritsch cyclization [18]. However, treatment of 1e with
CF CO H or CH CO H/H SO did not induce the PomeranzeFritsch
cyclization (Scheme 3), instead it only gave the hydrolysis product
, which has been obtained by multistep reactions [20]. When
strong Lewis acid AlCl was introduced as the catalyst, the cycli-
zation reaction took place to give benzazepinoisoindolinone de-
rivative of 4a. With 1f as the substrate, CF CO H could smoothly
3
2
3
2
2
4
3
2.4. Fungicidal activity
3
The preliminary in vitro antifungal activities of 5 and 7 were
assessed at 50 mg/mL, and results are listed in Table 1. Most of
3
2
induce the intramolecular cyclization to afford 4b, which obviously
bridged isoindolinone derivatives, especially compounds 5e and 5s,
showed good fungicidal activities against Sclerotinia sclerotiorum,
which causes serious diseases in a wide range of plants [21]. This is
similar to previously reported results of 3-substituted iso-
indolinones [17b]. Compounds 5o, 5q and 5r also showed good
activities against Rhizoctonia cerealis. Their inhibition percentages
are close to that of boscalid, a positive control drug.
In summary, a concise synthetic approach to polycyclic iso-
indolinones especially bridged polycyclic derivatives has been
developed through N-acetal-substituted isoindolinones that are
easily obtained from readily available starting materials under mild
reaction conditions. This method is simple and efficient, and the
gram-scale synthesis is achieved. Preliminary in vitro tests for
fungicidal activity indicate that most of bridged isoindolinone de-
rivatives exhibit good fungicidal activity against Sclerotinia
sclerotiorum.
Scheme 1. Synthesis of 1a-1f.
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X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
3
Scheme 2. Synthesis of 2a-2u.
Fig. 2. The molecular structure of 4b.
Scheme 3. Reaction of 1e and 1f.
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
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4
X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
Scheme 4. Synthesis of 5a-5t.
3
Scheme 5. Reaction of 2u with AlCl .
Fig. 3. The molecular structure of 5a.
3
Scheme 6. Reaction of 5g with BBr .
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
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X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
5
Table 1
Antifungal activity of 5 and 7 (Percent inhibition, 50 mg/mL in DMF).
Comp.
Sclerotinia sclerotiorum
Botrytis cinerea
Cercospora arachidicola
Alternaria solani
Rhizoctonia cerealis
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
0
0
70
10
75
0
17
22
22
12
32
24
37
27
66
37
24
29
27
29
49
7
0
72
0
0
0
0
0
0
0
0
0
0
0
0
58
0
0
21
0
0
15
0
0
0
0
0
0
36
27
27
30
21
6
20
2
0
0
53
18
0
45
49
0
6
0
0
59
71
59
69
73
57
59
45
73
0
65
58
47
56
61
47
56
72
53
69
61
75
61
50
100
0
40
24
32
28
8
0
24
100
20
41
49
54
12
100
s
t
24
91
boscalid
3
. Experimental
123.4, 128.9, 130.0, 141.9, 142.3, 168.8; HRMS (ESI) calcd for
þ
C
15
H
22NO
3
[MþH] : 264.1600, found: 264.1595.
1
3.1. General
Data of 1c. Yellow oil. H NMR
m, 2H), 3.69 (d, J ¼ 5.4 Hz, 2H), 3.73e3.79 (m, 2H), 3.87 (s, 3H), 4.49
(s, 2H), 4.68 (t, J ¼ 5.4 Hz, 1H), 6.93 (s, 1H), 6.97 (d, J ¼ 8.4 Hz, 1H),
d
1.21 (t, J ¼ 7.0 Hz, 6H), 3.52e3.60
(
Solvents were dried by standard methods and freshly distilled
prior to use. All reactions were carried out under an argon atmo-
sphere. NMR ( H and C) were recorded on a Bruker 400 spec-
trometer using CDCl as the solvent unless otherwise noted, and
the chemical shifts were reported in ppm with respect to the
13
7.75 (d, J ¼ 8.4 Hz, 1H); C NMR
d 15.4, 45.4, 51.6, 55.6, 63.1, 101.4,
1
13
107.5, 114.5, 124.9, 125.2, 144.1, 162.6, 168.6; HRMS (ESI) calcd for
þ
3
C
15
H22NO
4
[MþH] : 280.1549, found: 280.1541.
1
Data of 1d. Yellow oil. H NMR
d
1.21 (t, J ¼ 7.0 Hz, 6H), 3.53e3.61
1
13
4
reference (internal SiMe for H and C NMR spectra). HR mass
(m, 2H), 3.71 (d, J ¼ 5.4 Hz, 2H), 3.74e3.80 (m, 2H), 4.53 (s, 2H), 4.69
13
spectra were obtained on a Varian QFT-ESI spectrometer. Pre-
liminary in vitro tests for fungicidal activity of compounds have
been carried out by the fungi growth inhibition method [22]. The
synthesis of aromatic imines is provided in the supporting
information.
(t, J ¼ 5.4 Hz,1H), 7.13e7.17 (m, 2H), 7.82 (dd, J ¼ 8.0, 5.4 Hz,1H);
C
NMR
d
15.4, 45.4, 51.4, 63.2, 101.2, 110.0 (d, JF-C ¼ 24.2 Hz), 115.6 (d,
J
F-C ¼ 23.5 Hz),125.4 (d, JF-C ¼ 9.8 Hz),128.6,144.2 (d, JF-C ¼ 10.1 Hz),
165.0 (d, JF-C ¼ 250.8 Hz), 167.7; HRMS (ESI) calcd for C14
H18FNNaO
3
þ
[MþNa] : 290.1168, found: 290.1160.
1
Data of 1e. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 3H), 1.26 (t,
J ¼ 7.0 Hz, 3H), 2.74 (dd, J ¼ 13.6, 8.5 Hz, 1H), 3.32 (dd, J ¼ 14.4,
3.2. Typical procedure for the synthesis of 1ae1f
6
2
.9 Hz, 1H), 3.44e3.54 (m, 2H), 3.62e3.69 (m, 1H), 3.73e3.82 (m,
H), 4.27 (dd, J ¼ 14.4, 3.5 Hz, 1H), 4.71 (dd, J ¼ 6.8, 3.5 Hz, 1H), 5.06
A hexane solution of n-BuLi (1.6 M, 1.25 mL, 2 mmol) was slowly
(
dd, J ¼ 8.5, 4.1 Hz, 1H), 6.86e6.89 (m, 1H), 7.03e7.05 (m, 2H),
added to the stirred solution of aromatic imine (2 mmol) in THF
13
ꢁ
7.21e7.25 (m, 3H), 7.37e7.40 (m, 2H), 7.76e7.79 (m, 1H); C NMR
(
30 mL) at ꢀ78 C. After continuously stirring for half an hour,
d
15.4 (2 C), 37.7, 40.1, 61.5, 63.3, 63.9, 101.5, 123.0, 123.5, 126.9,
28.0, 128.4, 129.6, 130.9, 131.9, 136.1, 145.5, 168.5; HRMS (ESI) calcd
carbon monoxide was bubbled into the solution. The carbon
monoxide atmosphere was kept with a balloon at the exit. The
reaction mixture was continuously stirred at low temperature for
1
þ
for C21
H
25NNaO
3
[MþNa] : 362.1732, found: 362.1726.
1
Data of 1f. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 3H), 1.26 (t,
1
h, then water (0.2 mL) or benzyl bromide (2 mmol) was slowly
J ¼ 7.0 Hz, 3H), 2.71 (dd, J ¼ 13.6, 8.5 Hz, 1H), 3.31 (dd, J ¼ 14.4,
added dropwise with syringe. The reaction mixture was allowed to
reach room temperature slowly and stirred for 2 h. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica with ethyl acetate/petroleum
ether (V/V ¼ 2:5) as the eluent to afford products 1ae1f.
6
3
3
.8 Hz, 1H), 3.46e3.52 (m, 2H), 3.61e3.67 (m, 1H), 3.69 (s, 3H),
.74e3.81 (m, 2H), 4.27 (dd, J ¼ 14.4, 3.5 Hz, 1H), 4.71 (dd, J ¼ 6.8,
.5 Hz,1H), 5.06 (dd, J ¼ 8.5, 4.0 Hz, 1H), 6.56 (d, J ¼ 1.8 Hz, 1H), 6.65
(
7
d, J ¼ 7.6 Hz, 1H), 6.75 (dd, J ¼ 8.2, 2.3 Hz, 1H), 6.93e6.96 (m, 1H),
13
.15 (t, J ¼ 7.9 Hz, 1H), 7.38e7.42 (m, 2H), 7.77e7.80 (m, 1H);
C
Data of 1a [23]. Yellow oil. This compound was also obtained in
1
NMR d 15.4 (2 C), 37.7, 43.0, 55.1, 61.3, 63.2, 63.8, 101.4, 112.4, 115.0,
47% (1.19 g) yield in 10 mmol scale. H NMR
d
1.21 (t, J ¼ 7.0 Hz, 6H),
1
21.9, 123.1, 123.5, 128.0, 129.4, 131.0, 131.9, 137.6, 145.5, 159.5,
3
.53e3.60 (m, 2H), 3.73 (d, J ¼ 5.6 Hz, 2H), 3.75e3.80 (m, 2H), 4.55
þ
168.5; HRMS (ESI) calcd for C22
H
27NNaO
4
[MþNa] : 392.1838,
(
s, 2H), 4.70 (t, J ¼ 5.4 Hz, 1H), 7.46 (t, J ¼ 7.3 Hz, 2H), 7.54 (t,
1
3
found: 392.1829.
J ¼ 7.2 Hz, 1H), 7.85 (d, J ¼ 7.2 Hz, 1H); C NMR
d 15.4, 45.5, 51.8,
6
3.2, 101.3, 122.7, 123.6, 127.9, 131.3, 132.5, 141.9, 168.8; HRMS (ESI)
þ
calcd for C14
H19NNaO
3
[MþNa] : 272.1263, found: 272.1261.
3.3. Typical procedure for the synthesis of 2ae2u
1
Data of 1b. Yellow oil. H NMR
d
1.20 (t, J ¼ 7.0 Hz, 6H), 2.45 (s,
3
4
H), 3.52e3.59 (m, 2H), 3.70 (d, J ¼ 5.4 Hz, 2H), 3.73e3.79 (m, 2H),
.49 (s, 2H), 4.69 (t, J ¼ 5.4 Hz, 1H), 7.24e7.26 (m, 2H), 7.72 (d,
A THF solution of KHMDS (1.0 M, 2.2 mL, 2.2 mmol) was slowly
added to the stirred solution of 1ae1d (1 mmol) or 1e (2 mmol) in
THF (20 mL) at room temperature. After continuously stirring for
13
J ¼ 7.8 Hz, 1H); C NMR
d 15.4, 21.9, 45.4, 51.6, 63.1, 101.3, 123.2,
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X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
half an hour, ArCH
2
Br (2 mmol) was added. The reaction mixture
2H), 7.58 (d, J ¼ 7.2 Hz, 1H); 13C NMR
d 15.4, 42.6, 46.0, 55.1, 64.3,
was stirred at room temperature overnight. The solvent was
removed in vacuo, and the residue was purified by column chro-
matography on silica with ethyl acetate/petroleum ether (V/
69.9, 100.9, 113.3, 123.0, 124.0, 127.5, 127.9, 130.3, 131.2, 132.1, 147.2,
þ
158.4, 169.1; HRMS (ESI) calcd for C30
H35NO
5
[MþH] : 490.2593,
found: 490.2580.
1
V ¼ 1:3) as the eluent to afford products 2ae2u.
Data of 2i. Yellow oil. H NMR
d
1.10 (t, J ¼ 7.0 Hz, 6H), 2.24 (s,
1
Data of 2a. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.16 (d,
3H), 3.06 (d, J ¼ 14.1 Hz, 2H), 3.39 (d, J ¼ 14.1 Hz, 2H), 3.53e3.56 (m,
2H), 3.57 (d, J ¼ 5.0 Hz, 2H), 3.70e3.78 (m, 2H), 5.01 (t, J ¼ 5.1 Hz,
1H), 6.48 (s, 1H), 6.73 (dd, J ¼ 7.4, 1.7 Hz, 4H), 7.00e7.05 (m, 7H),
J ¼ 14.1 Hz, 2H), 3.48 (d, J ¼ 14.1 Hz, 2H), 3.58e3.65 (m, 2H), 3.69 (d,
J ¼ 5.1 Hz, 2H), 3.79e3.86 (m, 2H), 5.11 (t, J ¼ 5.0 Hz, 1H), 6.79e6.81
1
3
(
1
m, 5H), 7.08e7.14 (m, 6H), 7.28e7.36 (m, 2H), 7.57 (d, J ¼ 7.0 Hz,
7.38 (d, J ¼ 7.7 Hz, 1H); C NMR
d 15.4, 22.0, 43.7, 46.0, 64.3, 69.4,
1
3
H); C NMR
d
15.4, 43.6, 46.0, 64.4, 69.8, 100.8, 123.0, 124.1, 126.8,
100.9, 122.8, 124.6, 126.8, 127.8, 128.9, 129.5, 130.3, 135.7, 140.8,
þ
127.9,128.0,130.3,130.4,132.0,135.5,146.9,169.0; HRMS (ESI) calcd
147.2, 169.1; HRMS (ESI) calcd for C29
H34NO
3
[MþH] : 444.2539,
þ
for C28
H
32NO
3
[MþH] : 430.2382, found: 430.2372.
found: 444.2525.
1
1
Data of 2b. Yellow oil. H NMR
d
1.17 (t, J ¼ 7.0 Hz, 6H), 3.51 (d,
Data of 2j. Yellow oil. H NMR
d
1.17 (t, J ¼ 7.0 Hz, 6H), 2.21 (s,
J ¼ 14.8 Hz, 2H), 3.56e3.64 (m, 2H), 3.73 (d, J ¼ 5.1 Hz, 2H),
.77e3.85 (m, 4H), 5.17 (t, J ¼ 5.1 Hz, 1H), 6.77e6.81 (m, 3H), 6.95
td, J ¼ 7.6, 1.5 Hz, 2H), 7.02 (t, J ¼ 7.0 Hz, 2H), 7.22 (t, J ¼ 7.4 Hz, 1H),
.27 (t, J ¼ 7.2 Hz,1H), 7.40 (d, J ¼ 7.2 Hz, 2H), 7.63 (d, J ¼ 7.3 Hz,1H);
3H), 3.49 (d, J ¼ 14.8 Hz, 2H), 3.54e3.62 (m, 2H), 3.70 (d, J ¼ 5.0 Hz,
2H), 3.74 (d, J ¼ 14.8 Hz, 2H), 3.76e3.84 (m, 2H), 5.14 (t, J ¼ 5.0 Hz,
1H), 6.57 (s, 1H), 6.80 (d, J ¼ 7.6 Hz, 2H), 6.96 (t, J ¼ 7.6 Hz, 2H),
3
(
7
13
7.01e7.08 (m, 3H), 7.41 (d, J ¼ 7.9 Hz, 2H), 7.50 (d, J ¼ 7.7 Hz,1H);
C
13
C NMR
d
15.3, 41.8, 45.9, 63.9, 69.7, 100.5, 122.9, 123.7, 126.3, 127.0,
NMR d 15.3, 21.8, 41.9, 45.8, 63.9, 69.4, 100.6, 122.6, 124.3, 126.3,
1
28.1,128.4,130.7,130.8,131.8,132.9,135.5,146.3,169.3; HRMS (ESI)
127.0, 128.3, 129.0, 129.2, 130.7, 132.8, 135.6, 141.2, 146.5, 169.5;
þ
þ
calcd for C28
H
29Br
2
NNaO
3
[MþNa] : 610.0391, found: 610.0378.
HRMS (ESI) calcd for C29
H
32Br
2
NO
3
[MþH] : 602.0728, found:
1
Data of 2c. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.8 Hz, 6H), 3.17 (d,
602.0717.
1
J ¼ 14.2 Hz, 2H), 3.39 (d, J ¼ 14.1 Hz, 2H), 3.58e3.66 (m, 4H),
Data of 2k. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 6H), 2.34 (s,
3
6
.79e3.87 (m, 2H), 5.08 (t, J ¼ 4.2 Hz, 1H), 6.75 (d, J ¼ 7.6 Hz, 2H),
.87 (d, J ¼ 7.5 Hz, 1H), 6.93 (s, 2H), 6.97 (td, J ¼ 7.9, 1.4 Hz, 2H), 7.26
3H), 3.11 (d, J ¼ 14.1 Hz, 2H), 3.45 (d, J ¼ 14.1 Hz, 2H), 3.59 (s, 6H),
3.60e3.64 (m, 2H), 3.77e3.85 (m, 2H), 5.07 (t, J ¼ 5.0 Hz, 1H), 6.28
(
(
1
d, J ¼ 8.1 Hz, 2H), 7.36 (t, J ¼ 7.5 Hz, 1H), 7.44 (t, J ¼ 7.5 Hz, 1H), 7.62
(s, 2H), 6.47 (d, J ¼ 7.5 Hz, 2H), 6.67e6.69 (m, 3H), 7.04 (t, J ¼ 7.9 Hz,
13
13
d, J ¼ 7.4 Hz, 1H); C NMR
d
15.3, 43.0, 46.0, 64.3, 69.4, 100.7, 121.9,
2H), 7.15 (d, J ¼ 7.7 Hz, 1H), 7.50 (d, J ¼ 7.7 Hz, 1H); C NMR
d 15.4,
23.4, 123.6, 128.5, 128.7, 129.5, 130.0, 130.8, 131.9, 133.2, 137.6,
21.9, 43.7, 45.9, 55.0, 64.3, 69.4, 100.9, 112.7, 115.5, 122.8, 122.9,
þ
146.2, 168.9; HRMS (ESI) calcd for
C
28
H
30Br
2
NO
3
[MþH] :
124.6, 128.8, 128.9, 129.7, 137.1, 140.7, 147.5, 159.0, 169.0; HRMS (ESI)
þ
5
88.0572, found: 588.0560.
calcd for C31
H
38NO
5
[MþH] : 504.2750, found: 504.2743.
1
1
Data of 2d. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 6H), 3.14 (d,
Data of 2l. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.18 (d,
J ¼ 14.2 Hz, 2H), 3.38 (d, J ¼ 14.2 Hz, 2H), 3.57e3.64 (m, 4H),
J ¼ 14.1 Hz, 2H), 3.45 (d, J ¼ 14.1 Hz, 2H), 3.61e3.67 (m, 2H), 3.68 (d,
J ¼ 5.1 Hz, 2H), 3.79e3.86 (m, 2H), 5.08 (t, J ¼ 5.1 Hz, 1H), 6.45 (dd,
J ¼ 8.7, 2.1 Hz, 1H), 6.83 (dd, J ¼ 7.2, 2.2 Hz, 4H), 6.99 (td, J ¼ 8.8,
3
6
.79e3.86 (m, 2H), 5.09 (t, J ¼ 4.8 Hz, 1H), 6.67 (d, J ¼ 7.7 Hz, 4H),
.85 (d, J ¼ 7.3 Hz, 1H), 7.22 (d, J ¼ 7.4 Hz, 4H), 7.32e7.41 (m, 2H),
13
13
7
.60 (d, J ¼ 7.4 Hz, 1H); C NMR
d
15.3, 42.9, 46.0, 64.4, 69.3, 100.7,
2.2 Hz, 1H), 7.10e7.15 (m, 6H), 7.53 (dd, J ¼ 8.3, 5.1 Hz, 1H); C NMR
121.0,123.4,123.6,128.4,130.7,131.1,131.8,131.9,134.3,146.3,168.9;
d
15.4, 43.4, 46.1, 64.3, 69.5, 100.7, 111.4 (d, JF-C ¼ 24.4 Hz), 115.6,
þ
HRMS (ESI) calcd for C28
5
H30Br
2
NO
3
[MþH] : 588.0572, found:
115.8, 125.0 (d, JF-C ¼ 9.7 Hz), 127.0, 128.0, 130.2, 135.1, 149.4 (d, JF-
88.0551.
Data of 2e. Yellow oil. H NMR
C
¼ 9.1 Hz), 164.1 (d, JF-C ¼ 250.6 Hz), 167.9; HRMS (ESI) calcd for
1
þ
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.17 (d,
C
28
H31FNO
3
[MþH] : 448.2288, found: 448.2280.
1
J ¼ 14.2 Hz, 2H), 3.41 (d, J ¼ 14.2 Hz, 2H), 3.61e3.64 (m, 2H), 3.65 (d,
Data of 2m. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 6H), 3.49 (d,
J ¼ 5.0 Hz, 2H), 3.79e3.87 (m, 2H), 5.10 (t, J ¼ 5.1 Hz, 1H), 6.76e6.84
J ¼ 14.7 Hz, 2H), 3.57e3.65 (m, 2H), 3.73 (d, J ¼ 5.1 Hz, 2H), 3.76 (d,
J ¼ 14.7 Hz, 2H), 3.80e3.86 (m, 2H), 5.16 (t, J ¼ 5.1 Hz, 1H), 6.42 (dd,
J ¼ 8.8, 2.1 Hz, 1H), 6.88 (dd, J ¼ 7.7, 1.5 Hz, 2H), 6.93e7.02 (m, 3H),
7.08 (t, J ¼ 7.5 Hz, 2H), 7.43 (dd, J ¼ 7.9, 1.2 Hz, 2H), 7.58 (dd, J ¼ 8.3,
13
(
4
m, 9H), 7.31e7.40 (m, 2H), 7.59 (d, J ¼ 7.2 Hz, 1H); C NMR
d 15.3,
2.6, 46.0, 64.4, 69.6, 100.7, 114.8 (d, JF-C ¼ 21.1 Hz), 123.3, 123.7,
1
28.2, 130.6, 131.1 (d, JF-C ¼ 3.3 Hz), 131.6 (d, JF-C ¼ 7.9 Hz), 132.0,
1
3
146.5, 161.8 (d, JF-C ¼ 245.6 Hz), 169.0; HRMS (ESI) calcd for
5.1 Hz, 1H); C NMR d 15.3, 41.6, 45.9, 64.0, 69.3, 100.4, 111.3 (d, JF-
þ
C
H
28 30
F
2
NO
3
[MþH] : 466.2194, found: 466.2179.
C
¼ 24.9 Hz), 115.8 (d, JF-C ¼ 23.4 Hz), 124.8 (d, JF-C ¼ 9.6 Hz), 126.3,
1
Data of 2f. Yellow oil. H NMR
d
1.20 (t, J ¼ 7.9 Hz, 6H), 2.17 (s,
127.2, 127.7,128.7, 130.7, 133.1,135.1, 148.6 (d, JF-C ¼ 9.8 Hz),164.3 (d,
6
4
6
H), 3.09 (d, J ¼ 14.0 Hz, 2H), 3.45 (d, J ¼ 14.0 Hz, 2H), 3.62e3.66 (m,
H), 3.79e3.86 (m, 2H), 5.10 (t, J ¼ 4.0 Hz, 1H), 6.60e6.62 (m, 4H),
.81 (d, J ¼ 7.3 Hz,1H), 6.93 (d, J ¼ 7.3 Hz, 2H), 6.99 (t, J ¼ 7.3 Hz, 2H),
J
F-C ¼ 250.9 Hz), 168.3; HRMS (ESI) calcd for C28
2 3
H28Br FNNaO
þ
[MþNa] : 628.0297, found: 628.0322.
1
Data of 2n. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.14 (d,
13
7
4
.32e7.37 (m, 2H), 7.59 (d, J ¼ 7.0 Hz, 1H); C NMR
d
15.4, 21.3, 43.6,
J ¼ 14.1 Hz, 2H), 3.43 (d, J ¼ 14.1 Hz, 2H), 3.57e3.66 (m, 10H),
3.78e3.86 (m, 2H), 5.07 (t, J ¼ 5.1 Hz, 1H), 6.32 (s, 2H), 6.46 (d,
6.0, 64.3, 69.8, 100.9, 122.9, 124.3, 127.3, 127.5, 127.7, 127.9, 130.1,
131.2, 132.1, 135.5, 137.3, 147.1, 169.0; HRMS (ESI) calcd for
J ¼ 7.5 Hz, 2H), 6.56 (dd, J ¼ 8.7, 2.0 Hz, 1H), 6.69 (dd, J ¼ 8.2, 2.0 Hz,
þ
13
C
30
H
36NO
3
[MþH] : 458.2695, found: 458.2676.
2H), 7.00e7.08 (m, 3H), 7.57 (dd, J ¼ 8.3, 5.1 Hz, 1H); C NMR
d 15.4,
1
Data of 2g. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.13 (d,
43.5, 46.0, 55.1, 64.3, 69.4, 100.7, 111.4 (d, JF-C ¼ 24.4 Hz), 112.7,
115.68, 115.7 (d, JF-C ¼ 23.4 Hz), 122.7, 125.1 (d, JF-C ¼ 9.6 Hz), 128.2,
J ¼ 14.1 Hz, 2H), 3.48 (d, J ¼ 14.1 Hz, 2H), 3.58 (s, 6H), 3.60e3.66 (m,
H), 3.78e3.84 (m, 2H), 5.09 (t, J ¼ 5.0 Hz, 1H), 6.27 (s, 2H), 6.47 (d,
J ¼ 7.5 Hz, 2H), 6.67 (d, J ¼ 8.2 Hz, 2H), 6.90 (d, J ¼ 7.4 Hz,1H), 7.04 (t,
4
129.0, 136.6, 149.6 (d, JF-C ¼ 9.3 Hz), 159.1, 164.1 (d, JF-C ¼ 252.2 Hz),
þ
167.9; HRMS (ESI) calcd for C30
H
34FNNaO
5
[MþNa] : 530.2319,
13
J ¼ 7.9 Hz, 2H), 7.34e7.39 (m, 2H), 7.61 (d, J ¼ 7.2 Hz, 1H); C NMR
found: 530.2307.
1
d
15.4, 43.7, 46.0, 55.0, 64.3, 69.7, 100.8, 112.6, 115.6, 122.8, 123.1,
24.1, 128.1, 128.8, 130.3, 132.2, 137.0, 147.1, 159.0, 168.9; HRMS (ESI)
Data of 2o. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.14 (d,
1
J ¼ 14.1 Hz, 2H), 3.47 (d, J ¼ 14.1 Hz, 2H), 3.63e3.65 (m, 4H), 3.67 (s,
3H), 3.78e3.86 (m, 2H), 5.08 (t, J ¼ 5.1 Hz, 1H), 6.21 (d, J ¼ 2.1 Hz,
1H), 6.82e6.86 (m, 5H), 7.09e7.13 (m, 6H), 7.49 (d, J ¼ 8.4 Hz, 1H);
þ
calcd for C30
H
35NNaO
5
[MþNa] : 512.2413, found: 512.2408.
1
Data of 2h. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.07 (d,
1
3
J ¼ 14.2 Hz, 2H), 3.41 (d, J ¼ 14.2 Hz, 2H), 3.58e3.66 (m, 4H), 3.70 (s,
C NMR d 15.4, 43.7, 46.0, 55.4, 64.4, 69.2, 100.9, 108.5, 115.1, 124.3,
6
4
H), 3.79e3.86 (m, 2H), 5.10 (t, J ¼ 5.0 Hz, 1H), 6.63 (d, J ¼ 8.4 Hz,
H), 6.72 (d, J ¼ 8.5 Hz, 4H), 6.83 (d, J ¼ 7.2 Hz, 1H), 7.29e7.37 (m,
124.7, 126.9, 127.9, 130.3, 135.6, 149.1, 161.6, 168.8; HRMS (ESI) calcd
þ
for C29
H
34NO
4
[MþH] : 460.2488, found: 460.2478.
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131341

X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
7
1
Data of 2p. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 6H), 3.48 (d,
and the residue was purified by column chromatography on silica
with ethyl acetate/petroleum ether (V/V ¼ 1:3) as the eluent to
afford 1.54 g (55%) of 2c.
J ¼ 14.7 Hz, 2H), 3.59 (s, 3H), 3.60e3.66 (m, 2H), 3.71 (d, J ¼ 5.1 Hz,
2
1
H), 3.77 (d, J ¼ 14.7 Hz, 2H), 3.80e3.86 (m, 2H), 5.17 (t, J ¼ 5.1 Hz,
H), 6.23 (d, J ¼ 2.1 Hz, 1H), 6.76 (dd, J ¼ 8.4, 2.2 Hz, 1H), 6.90 (dd,
J ¼ 7.7, 1.6 Hz, 2H), 6.97 (td, J ¼ 7.8, 1.6 Hz, 2H), 7.06 (td, J ¼ 7.5,
3 2
3.5. Reaction of 1e with CF CO H
13
1
.2 Hz, 2H), 7.42 (dd, J ¼ 8.0, 1.1 Hz, 2H), 7.50 (d, J ¼ 8.4 Hz, 1H);
C
NMR
d
15.3, 41.7, 45.8, 55.3, 64.0, 69.2, 100.7, 107.4, 116.0, 124.1,
Trifluoroacetic acid (0.14 mL, 1.9 mmol) was added the solution
of 1e (325 mg, 0.96 mmol) in CH Cl (30 mL). The reaction mixture
1
24.3, 126.5, 127.1, 128.4, 130.9, 132.9, 135.6, 148.5, 161.8, 169.3;
HRMS (ESI) calcd for C29
2
2
þ
H32Br
2
NO
4
[MþH] : 618.0678, found:
was stirred overnight at room temperature, and quenched with
saturated aqueous sodium carbonate solution (10 mL). The aqueous
layer was extracted with ethyl acetate (10 mL ꢂ 3), and the com-
6
18.0698.
1
Data of 2q. Yellow oil. H NMR
d
1.19 (t, J ¼ 7.0 Hz, 6H), 2.19 (s,
6
4
H), 3.08 (d, J ¼ 14.0 Hz, 2H), 3.44 (d, J ¼ 14.0 Hz, 2H), 3.57e3.63 (m,
H), 3.67 (s, 3H), 3.78e3.86 (m, 2H), 5.07 (t, J ¼ 5.0 Hz, 1H), 6.24 (d,
2 4
bined extracts were dried over anhydrous Na SO . The solvent was
removed in vacuo and the residue was purified by column chro-
matography on silica with ethyl acetate/petroleum ether (V/
J ¼ 2.1 Hz, 1H), 6.63e6.65 (m, 4H), 6.85 (dd, J ¼ 8.4, 2.2 Hz, 1H), 6.94
13
(
d, J ¼ 7.5 Hz, 2H), 7.01 (t, J ¼ 7.4 Hz, 2H), 7.50 (d, J ¼ 8.4 Hz, 1H);
C
V ¼ 3:2) as the eluent to afford 207 mg (82%) of 3 as yellow oil. [20]
1
NMR
d
15.4, 21.3, 43.7, 45.9, 55.4, 64.3, 69.2, 101.0, 108.6, 115.2,
H NMR
d
3.00 (dd, J ¼ 14.0, 7.0 Hz, 1H), 3.14 (dd, J ¼ 14.0, 6.4 Hz,
1
24.2,124.8,127.4,127.6,127.7,131.2,135.5,137.3,149.3,161.6,168.8;
1H), 3.99 (d, J ¼ 18.9 Hz, 1H), 4.63 (d, J ¼ 18.9 Hz, 1H), 4.98 (t,
J ¼ 6.7 Hz, 1H), 7.06e7.11 (m, 3H), 7.25e7.30 (m, 3H), 7.42e7.50 (m,
þ
HRMS (ESI) calcd for C31
88.2802.
Data of 2r. Yellow oil. H NMR
H38NO
4
[MþH] : 488.2801, found:
1
3
4
2H), 7.83 (dd, J ¼ 6.4, 1.5 Hz, 1H), 9.54 (s, 1H); C NMR
d 39.2, 51.3,
1
d
1.19 (t, J ¼ 7.0 Hz, 6H), 3.10 (d,
61.4, 122.9, 123.9, 127.3, 128.4, 128.8, 129.3, 131.1, 131.7, 136.0, 145.5,
169.0, 196.9.
J ¼ 14.1 Hz, 2H), 3.45 (d, J ¼ 14.1 Hz, 2H), 3.57e3.64 (m,10H), 3.69 (s,
3
1
2
H), 3.79e3.83 (m, 2H), 5.06 (t, J ¼ 5.1 Hz, 1H), 6.30 (d, J ¼ 2.1 Hz,
H), 6.33 (s, 2H), 6.49 (d, J ¼ 7.6 Hz, 2H), 6.68 (dd, J ¼ 8.2, 2.2 Hz,
H), 6.86 (dd, J ¼ 8.4, 2.2 Hz, 1H), 7.05 (t, J ¼ 7.9 Hz, 2H), 7.52 (d,
3.6. Synthesis of 4a
13
J ¼ 8.4 Hz, 1H); C NMR
d
15.4, 43.8, 45.9, 55.0, 55.4, 64.3, 69.1,
Powdery AlCl
1e (41 mg, 0.12 mmol) in CH
3
(72 mg, 0.54 mmol) was added to the solution of
Cl (3 mL) at room temperature. The
1
1
5
00.9, 108.6, 112.5, 115.2, 115.8, 122.8, 124.4, 124.8, 128.8, 137.0,
2
2
þ
49.3, 159.0, 161.7, 168.7; HRMS (ESI) calcd for C31
H38NO
6
[MþH] :
reaction mixture was stirred for 12 h, and quenched with aqueous
sodium hydroxide solution (40%, 10 mL). The aqueous layer was
extracted with ethyl acetate (10 mL ꢂ 3), and the combined extracts
20.2699, found: 520.2685.
Data of 2s. Yellow oil. 1H NMR
d 1.16e1.21 (m, 6H), 3.15 (d,
J ¼ 14.1 Hz, 2H), 3.44e3.51 (m, 2H), 3.57 (s, 3H), 3.59e3.64 (m, 2H),
2 4
were dried over anhydrous Na SO . The solvent was removed in
3
6
6
7
4
1
1
4
.67 (d, J ¼ 5.1 Hz, 2H), 3.78e3.86 (m, 2H), 5.10 (t, J ¼ 5.0 Hz, 1H),
.25 (s, 1H), 6.46 (d, J ¼ 7.5 Hz, 1H), 6.66 (d, J ¼ 9.9 Hz, 1H),
.61e6.68 (m, 3H), 7.03 (t, J ¼ 7.9 Hz, 1H), 7.09e7.12 (m, 3H),
vacuo and the residue was purified by column chromatography on
silica with ethyl acetate/petroleum ether (V/V ¼ 1:6) as the eluent
to afford 21 mg (71%) of 4a as yellow oil [20], which solidifies
13
1
.32e7.38 (m, 2H), 7.59 (d, J ¼ 7.3 Hz, 1H); C NMR
d
15.35, 15.37,
during storage. H NMR
d
3.09 (dd, J ¼ 15.4, 9.8 Hz, 1H), 3.53 (d,
3.6, 43.7, 46.0, 55.0, 64.3, 69.7, 100.8, 112.6, 115.6, 122.8, 123.1,
J ¼ 15.3 Hz, 1H), 4.82 (d, J ¼ 9.8 Hz, 1H), 5.84 (d, J ¼ 10.3 Hz, 1H),
24.1, 126.8, 127.9, 128.0, 128.8, 130.29, 130.34, 132.1, 135.6, 137.0,
47.0, 159.0, 168.9; HRMS (ESI) calcd for C29
7.18e7.26 (m, 5H), 7.52 (t, J ¼ 7.4 Hz,1H), 7.59 (d, J ¼ 7.6 Hz,1H), 7.66
þ
13
H
33NNaO
4
[MþNa] :
(td, J ¼ 7.5, 1.1 Hz, 1H), 7.89 (d, J ¼ 7.6 Hz, 1H); C NMR
d 42.0, 60.5,
82.2307, found: 482.2305.
109.8, 121.3, 122.3, 124.2, 126.9, 127.3, 128.9, 129.8, 130.7, 131.1,
Data of 2t. Yellow oil. 1H NMR
d
1.16e1.22 (m, 6H), 3.09 (d,
132.9, 135.3, 135.8, 144.4, 165.7. HRMS (ESI) calcd for C17
[MþH] : 248.1075, found: 248.1073.
H14NO
þ
J ¼ 14.2 Hz, 1H), 3.14 (d, J ¼ 14.1 Hz, 1H), 3.42 (d, J ¼ 14.2 Hz, 1H),
.47 (d, J ¼ 14.1 Hz, 1H), 3.58e3.68 (m, 4H), 3.72 (s, 3H), 3.78e3.86
m, 2H), 5.10 (t, J ¼ 5.1 Hz, 1H), 6.63 (d, J ¼ 8.7 Hz, 2H), 6.71 (d,
J ¼ 8.7 Hz, 2H), 6.81 (d, J ¼ 7.7 Hz, 3H), 7.08e7.12 (m, 3H), 7.30e7.38
3
(
3.7. Synthesis of 4b
13
(
4
1
(
m, 2H), 7.58 (d, J ¼ 6.7 Hz, 1H); C NMR
d
15.34, 15.38, 42.7, 43.5,
When 1f was used as the substrate instead of 1e as described
above for 3, compound 4b was obtained as a white solid in 63%
yield. This compound has also been directly obtained from aromatic
imine as follows. A hexane solution of n-BuLi (1.6 M, 1.25 mL,
2 mmol) was slowly added to the stirred solution of N-(2-
bromobenzylidene)-2,2-diethoxyethanamine (0.6 g, 2 mmol) in
6.0, 55.1, 64.3, 69.8, 100.8, 113.3, 123.0, 124.0, 126.8, 127.4, 127.86,
27.94, 130.26, 130.33, 131.2, 132.0, 135.7, 147.0, 158.4, 169.0; HRMS
þ
ESI) calcd for C29
H
33NNaO
4
[MþNa] : 482.2307, found: 482.2294.
1
Data of 2u. Yellow oil. H NMR
d
1.18 (t, J ¼ 7.0 Hz, 6H), 1.35 (t,
J ¼ 7.1 Hz, 6H), 3.31 (d, J ¼ 14.0 Hz, 2H), 3.51 (d, J ¼ 14.0 Hz, 2H),
ꢁ
3
(
(
.58e3.65 (m, 2H), 3.68 (d, J ¼ 5.0 Hz, 2H), 3.80e3.87 (m, 2H), 4.32
THF (30 mL) at ꢀ78 C. After continuously stirring for half an hour,
q, J ¼ 7.1 Hz, 4H), 5.09 (t, J ¼ 5.0 Hz,1H), 6.85 (d, J ¼ 7.5 Hz,1H), 6.89
carbon monoxide was bubbled into the solution. The carbon
monoxide atmosphere was kept with a balloon at the exit. The
reaction mixture was continuously stirred at low temperature for
1 h, 3-methoxybenzyl bromide (0.28 mL, 2 mmol) was slowly
added dropwise with syringe. The reaction mixture was warmed to
room temperature slowly and stirred for 5 h. The solvent was
d, J ¼ 8.2 Hz, 4H), 7.30e7.40 (m, 2H), 7.58 (d, J ¼ 7.2 Hz, 1H), 7.79 (d,
13
J ¼ 8.2 Hz, 4H); C NMR
d 14.3, 15.3, 43.5, 46.0, 60.9, 64.4, 69.4,
1
1
5
00.7, 123.3, 123.6, 128.4, 129.08, 129.13, 130.1, 130.8, 131.8, 140.6,
þ
46.2, 166.3, 168.8; HRMS (ESI) calcd for C34
96.2624, found: 596.2624.
H
39NNaO
7
[MþNa] :
2 2
removed in vacuo, and the residual was redissolved in CH Cl
3
.4. Gram-scale synthesis of 2c
(30 mL). Trifluoroacetic acid (2.6 mL, 4 mmol) was added. The re-
action mixture was stirred overnight at room temperature, and
quenched with saturated aqueous sodium carbonate solution
(30 mL). The aqueous layer was extracted with ethyl acetate
(20 mL ꢂ 3), and the combined extracts were dried over anhydrous
A THF solution of KHMDS (1.0 M,10.5 mL,10.5 mmol) was slowly
added to the stirred solution of 1a (1.18 g, 4.75 mmol) in THF
30 mL) at room temperature. After continuously stirring for half an
(
hour, the solution of 3-bromobenzyl bromide (2.62 g, 10.5 mmol) in
THF (5 mL) was slowly added. The reaction mixture was stirred at
room temperature overnight. The solvent was removed in vacuo,
2 4
Na SO . The solvent was removed in vacuo and the residue was
purified by column chromatography on silica with ethyl acetate/
petroleum ether (V/V ¼ 1:5) as the eluent to afford 4b (262 mg,
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131341

8
X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
1
5
1
6
7
7
0%). H NMR
d
3.08 (dd, J ¼ 15.4, 9.9 Hz, 1H), 3.46 (d, J ¼ 15.4 Hz,
120.8, 123.5, 128.1, 128.2, 130.2, 130.8, 131.6, 132.4, 135.6, 136.5,
þ
H), 3.84 (s, 3H), 4.80 (d, J ¼ 9.8 Hz, 1H), 5.79 (d, J ¼ 10.3 Hz, 1H),
136.6, 153.8, 169.0; HRMS (ESI) calcd for C26
366.1858, found: 366.1849.
H
24NO [MþH] :
.78e6.81 (m, 2H), 7.11 (d, J ¼ 10.2 Hz, 1H), 7.17 (d, J ¼ 9.2 Hz, 1H),
1
.51 (t, J ¼ 7.4 Hz, 1H), 7.58 (d, J ¼ 7.4 Hz, 1H), 7.64 (t, J ¼ 7.1 Hz, 1H),
Data of 5g. White solid. H NMR
d
3.24 (d, J ¼ 16.7 Hz, 2H), 3.55
13
.88 (d, J ¼ 7.5 Hz, 1H); C NMR
d
42.1, 55.4, 60.3, 109.7, 112.2, 115.7,
(d, J ¼ 16.7 Hz, 2H), 3.73 (s, 6H), 4.14 (d, J ¼ 3.3 Hz, 2H), 4.38 (t,
J ¼ 3.4 Hz, 1H), 6.57 (s, 2H), 6.73 (dd, J ¼ 8.4, 2.5 Hz, 2H), 7.20 (d,
J ¼ 8.4 Hz, 2H), 7.47 (t, J ¼ 7.4 Hz, 1H), 7.58 (d, J ¼ 7.5 Hz, 1H), 7.65 (t,
1
1
19.3, 122.2, 124.1, 128.0, 128.8, 130.9, 132.5, 132.7, 137.3, 144.2,
þ
58.5, 165.5. HRMS (ESI) calcd for C18
found: 278.1176.
H16NO
2
[MþH] : 278.1181,
1
3
J ¼ 7.4 Hz, 1H), 7.79 (d, J ¼ 7.5 Hz, 1H); C NMR
d 45.4, 46.2, 48.5,
5
5.3, 65.0, 112.6, 116.2, 120.8, 123.6, 128.2, 130.8, 131.2, 132.2, 132.4,
þ
3
.8. Typical procedure for the synthesis of 5ae5t and 6
136.9, 153.6, 158.3, 169.0; HRMS (ESI) calcd for C26
H
24NO
3
[MþH] :
3
98.1756, found: 398.1753.
Data of 5h. Yellow oil. H NMR
1
Powdery AlCl
1 mmol) in CH
3
(3.5 mmol) was added to the solution of 2ae2u
Cl (40 mL) at room temperature. The reaction
d
3.20 (d, J ¼ 16.5 Hz, 2H), 3.51 (d,
(
2
2
J ¼ 16.5 Hz, 2H), 3.78 (s, 6H), 4.18 (d, J ¼ 3.5 Hz, 2H), 4.34 (t,
J ¼ 3.4 Hz, 1H), 6.68 (dd, J ¼ 8.4, 2.7 Hz, 2H), 6.85 (d, J ¼ 2.6 Hz, 2H),
6.95 (d, J ¼ 8.4 Hz, 2H), 7.46 (t, J ¼ 7.4 Hz,1H), 7.56 (d, J ¼ 7.6 Hz,1H),
mixture was stirred overnight, and quenched with aqueous sodium
hydroxide solution (40%, 10 mL). Then, the mixture was extracted
with CH
13
2
Cl
2
(20 mL ꢂ 3). The extracts were combined and dried
7.64 (t, J ¼ 7.9 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz, 1H); C NMR
d 44.4, 45.5,
over anhydrous Na
2
SO . The solvent was removed in vacuo and the
4
50.6, 55.3, 65.2, 112.2, 115.8, 120.7, 123.5, 128.0, 128.1, 130.8, 132.0,
residue was purified by column chromatography on silica with
ethyl acetate/petroleum ether (V/V ¼ 1:2) as the eluent to afford
132.4, 140.2, 153.7, 158.7, 169.0; HRMS (ESI) calcd for C26
H
24NO
3
þ
[MþH] : 398.1756, found: 398.1746.
1
products 5ae5t and 6.
Data of 5i. White solid. H NMR
d
2.53 (s, 3H), 3.27 (d, J ¼ 16.7 Hz,
1
Data of 5a. White solid. H NMR
d
3.29 (d, J ¼ 16.7 Hz, 2H), 3.58
2H), 3.55 (d, J ¼ 16.7 Hz, 2H), 4.17 (d, J ¼ 3.5 Hz, 2H), 4.45 (t,
J ¼ 3.5 Hz, 1H), 7.03 (d, J ¼ 7.2 Hz, 2H), 7.11 (td, J ¼ 7.4, 1.4 Hz, 2H),
7.18 (td, J ¼ 7.4, 1.2 Hz, 2H), 7.27 (d, J ¼ 7.8 Hz, 1H), 7.30 (d, J ¼ 7.5 Hz,
(
7
7
7
5
1
3
d, J ¼ 16.7 Hz, 2H), 4.20 (d, J ¼ 2.9 Hz, 2H), 4.48 (t, J ¼ 2.9 Hz, 1H),
.04 (d, J ¼ 7.4 Hz, 2H), 7.13 (t, J ¼ 7.4 Hz, 2H), 7.20 (t, J ¼ 7.3 Hz, 2H),
.32 (d, J ¼ 7.4 Hz, 2H), 7.48 (t, J ¼ 7.3 Hz, 1H), 7.59 (d, J ¼ 7.5 Hz, 1H),
1
3
2H), 7.39 (s, 1H), 7.66 (d, J ¼ 7.7 Hz, 1H); C NMR
d 22.2, 45.3, 45.7,
13
.66 (t, J ¼ 7.5 Hz, 1H), 7.79 (d, J ¼ 7.4 Hz, 1H); C NMR
d
45.3, 45.7,
50.3, 64.9, 121.4, 123.3, 127.0, 127.4, 128.2, 129.2, 130.4, 130.9, 136.0,
þ
0.2, 65.1, 120.8, 123.6, 127.0, 127.4, 128.3, 130.4, 130.8, 130.9, 132.5,
139.3, 143.2, 154.1, 169.1; HRMS (ESI) calcd for C25
352.1701, found: 352.1700.
H
22NO [MþH] :
þ
35.9, 139.2, 153.6, 169.0; HRMS (ESI) calcd for C24
H
20NO [MþH] :
1
38.1545, found: 338.1543.
Data of 5j. Yellow oil. H NMR
d
2.57 (s, 3H), 3.38 (d, J ¼ 17.6 Hz,
1
Data of 5b. Yellow solid. H NMR
d
3.38 (d, J ¼ 17.7 Hz, 2H), 3.71
2H), 3.69 (d, J ¼ 17.6 Hz, 2H), 4.21 (d, J ¼ 3.6 Hz, 2H), 4.51 (t,
(
7
7
6
1
4
d, J ¼ 17.7 Hz, 2H), 4.21 (s, 2H), 4.50 (s, 1H), 6.99 (d, J ¼ 7.5 Hz, 2H),
J ¼ 3.6 Hz, 1H), 7.04 (t, J ¼ 7.8 Hz, 2H), 7.24 (t, J ¼ 7.0 Hz, 2H), 7.31 (d,
.23 (d, J ¼ 7.3 Hz, 2H), 7.42 (d, J ¼ 7.7 Hz, 2H), 7.45e7.53 (m, 1H),
J ¼ 7.8 Hz, 1H), 7.45 (d, J ¼ 1.2 Hz, 1H), 7.47 (s, 2H), 7.69 (d, J ¼ 7.8 Hz,
13
13
.65e7.69 (m, 2H), 7.81 (d, J ¼ 7.1 Hz, 1H); C NMR
d
45.5, 45.6, 51.1,
1H); C NMR
d
22.3, 45.5 (2 C), 51.3, 64.4, 121.3, 123.5, 126.9, 127.5,
4.6, 120.9, 123.7, 126.9, 128.5, 128.6, 130.0, 130.1, 132.1, 132.9, 135.0,
128.4, 129.6, 129.9, 132.1, 135.1, 141.4, 143.7, 154.0, 169.0; HRMS (ESI)
þ
þ
1
41.4, 153.6, 168.9; HRMS (ESI) calcd for C24
95.9735, found: 495.9739.
Data of 5c. Yellow oil. H NMR
H18Br
2
NO [MþH] :
calcd for C25
H20Br
2
NO [MþH] : 509.9891, found: 509.9885.
Data of 5k. White solid. H NMR d 2.53 (s, 3H), 3.22 (d,
1
d
3.24 (d, J ¼ 16.8 Hz, 2H), 3.51 (d,
J ¼ 16.7 Hz, 2H), 3.53 (d, J ¼ 16.7 Hz, 2H), 3.71 (s, 6H), 4.12 (d,
J ¼ 3.5 Hz, 2H), 4.36 (t, J ¼ 3.5 Hz, 1H), 6.57 (d, J ¼ 2.6 Hz, 2H), 6.72
(dd, J ¼ 8.4, 2.7 Hz, 2H), 7.19 (d, J ¼ 8.4 Hz, 2H), 7.27 (d, J ¼ 8.1 Hz,
J ¼ 16.9 Hz, 2H), 4.14 (d, J ¼ 3.4 Hz, 2H), 4.40 (t, J ¼ 3.4 Hz, 1H), 7.16
d, J ¼ 8.1 Hz, 2H), 7.21 (s, 2H), 7.32 (dd, J ¼ 8.1, 1.9 Hz, 2H), 7.49 (t,
J ¼ 7.4 Hz, 1H), 7.55 (d, J ¼ 7.6 Hz, 1H), 7.67 (t, J ¼ 7.5 Hz, 1H), 7.80 (d,
(
1
3
1H), 7.38 (s, 1H), 7.67 (d, J ¼ 7.7 Hz, 1H); C NMR
d 22.1, 45.5, 46.1,
13
J ¼ 7.5 Hz, 1H); C NMR
d
44.8, 45.2, 49.1, 64.6, 120.7, 120.9, 123.8,
48.5, 55.2, 64.8, 112.6, 116.2, 121.3, 123.3, 128.2, 129.2, 131.2, 132.3,
1
27.7, 128.6, 130.5, 131.9, 132.8, 133.6, 137.7, 138.0, 152.9, 168.9;
137.0, 143.1, 154.0, 158.2, 169.1; HRMS (ESI) calcd for C27
H
26NO
3
þ
þ
HRMS (ESI) calcd for C24
95.9724.
Data of 5d. Yellow oil. H NMR
J ¼ 16.8 Hz, 2H), 4.16 (d, J ¼ 3.4 Hz, 2H), 4.35 (t, J ¼ 3.4 Hz, 1H), 6.93
d, J ¼ 8.1 Hz, 2H), 7.26e7.32 (m, 2H), 7.46 (d, J ¼ 1.8 Hz, 2H), 7.49 (t,
J ¼ 7.5 Hz, 1H), 7.56 (d, J ¼ 7.6 Hz, 1H), 7.66 (t, J ¼ 7.5 Hz, 1H), 7.79 (d,
H
18Br
2
NO [MþH] : 495.9735, found:
[MþH] : 412.1913, found: 412.1912.
1
4
Data of 5l. Yellow solid. H NMR
d
3.27 (d, J ¼ 16.7 Hz, 2H), 3.54
1
d
3.22 (d, J ¼ 16.8 Hz, 2H), 3.49 (d,
(d, J ¼ 16.7 Hz, 2H), 4.17 (d, J ¼ 3.2 Hz, 2H), 4.47 (t, J ¼ 3.2 Hz, 1H),
7.04 (t, J ¼ 7.48 Hz, 2H), 7.11e7.16 (m, 3H), 7.20e7.25 (m, 2H),
13
(
7.28e7.32 (m, 3H), 7.75e7.78 (m, 1H); C NMR d 45.1, 45.8, 50.2,
64.9, 108.4 (d, JF-C ¼ 24.1 Hz), 116.0 (d, JF-C ¼ 23.5 Hz), 125.7 (d, JF-
13
J ¼ 7.5 Hz, 1H); C NMR
d
44.7, 45.3, 49.5, 64.6, 120.7, 121.1, 123.8,
28.5, 130.3, 130.5, 132.6, 132.7, 133.1, 134.9, 140.5, 153.1, 168.9;
C
¼ 9.5 Hz), 126.8, 127.1, 127.5, 130.4, 130.9, 135.5, 139.1, 155.9 (d, JF-
1
C
C
¼ 8.8 Hz), 165.8 (d, JF-C ¼ 252.4 Hz), 167.9; HRMS (ESI) calcd for
þ
þ
HRMS (ESI) calcd for C24
95.9724.
Data of 5e. Yellow oil. H NMR
J ¼ 16.6 Hz, 2H), 4.18 (d, J ¼ 3.5 Hz, 2H), 4.36 (t, J ¼ 3.5 Hz, 1H), 6.85
H
18Br
2
NO [MþH] : 495.9735, found:
24
H
19FNO [MþH] : 356.1451, found: 356.1445.
1
4
Data of 5m. Yellow oil. H NMR
d
3.40 (d, J ¼ 17.6 Hz, 2H), 3.67 (d,
1
d
3.25 (d, J ¼ 16.7 Hz, 2H), 3.52 (d,
J ¼ 17.6 Hz, 2H), 4.19 (d, J ¼ 3.5 Hz, 2H), 4.52 (t, J ¼ 3.5 Hz, 1H), 7.04
(t, J ¼ 7.8, 2H), 7.19 (td, J ¼ 8.8, 2.2 Hz, 1H), 7.25 (d, J ¼ 7.1 Hz, 2H),
7.39 (dd, J ¼ 8.1, 2.1 Hz, 1H), 7.46 (dd, J ¼ 8.0, 1.1 Hz, 2H), 7.79 (dd,
(
7
1
(
1
J
3
td, J ¼ 8.3, 2.6 Hz, 2H), 7.00e7.03 (m, 4H), 7.49 (t, J ¼ 7.4 Hz, 1H),
13
.57 (d, J ¼ 7.6 Hz,1H), 7.66 (td, J ¼ 7.6, 0.9 Hz,1H), 7.79 (d, J ¼ 7.5 Hz,
J ¼ 8.3, 5.0 Hz, 1H); C NMR
d 45.3, 45.6, 51.1, 64.3, 108.5 (d, JF-
1
3
H); C NMR
d
44.4, 45.2, 49.9, 64.8, 114.1 (d, JF-C ¼ 20.8 Hz), 116.9
C
¼ 24.3 Hz), 116.4 (d, JF-C ¼ 23.4 Hz), 125.9 (d, JF-C ¼ 9.8 Hz), 126.2
d, JF-C ¼ 21.2 Hz), 120.7, 123.7, 128.4, 130.6, 131.6 (d, JF-C ¼ 3.1 Hz),
(d, JF-C ¼ 1.8 Hz), 126.9, 128.6, 129.9, 132.1, 134.7, 141.3, 155.9 (d, JF-
32.5 (d, JF-C ¼ 7.9 Hz), 132.7, 140.4 (d, JF-C ¼ 6.9 Hz), 153.3, 161.9 (d,
C
¼ 8.9 Hz), 165.9 (d, JF-C ¼ 253.2 Hz), 167.8; HRMS (ESI) calcd for
þ
þ
F-C ¼ 248.8 Hz), 168.9; HRMS (ESI) calcd for C24
H F
18 2
NO [MþH] :
C
24
H17Br
2
FNO [MþH] : 513.9640, found: 513.9632.
1
74.1356, found: 374.1349.
Data of 5n. White solid. H NMR
d
3.23 (d, J ¼ 16.7 Hz, 2H), 3.51
1
Data of 5f. Yellow oil. H NMR
d
2.23 (s, 6H), 3.22 (d, J ¼ 16.7 Hz,
(d, J ¼ 16.7 Hz, 2H), 3.72 (s, 6H), 4.11 (d, J ¼ 3.5 Hz, 2H), 4.37 (t,
J ¼ 3.5 Hz, 1H), 6.57 (d, J ¼ 2.6 Hz, 2H), 6.73 (dd, J ¼ 8.4, 2.7 Hz, 2H),
7.13e7.18 (m, 1H), 7.20 (d, J ¼ 8.4 Hz, 2H), 7.25e7.27 (m, 1H), 7.77
2
H), 3.53 (d, J ¼ 16.7 Hz, 2H), 4.15 (d, J ¼ 3.3 Hz, 2H), 4.39 (t,
J ¼ 3.3 Hz,1H), 6.84 (s, 2H), 6.98 (d, J ¼ 7.4 Hz, 2H), 7.18 (d, J ¼ 7.7 Hz,
13
2
H), 7.45 (d, J ¼ 7.3 Hz, 1H), 7.56 (d, J ¼ 7.5 Hz, 1H), 7.63 (t, J ¼ 7.4 Hz,
(dd, J ¼ 8.3, 5.0 Hz, 1H); C NMR
d 45.3, 46.3, 48.4, 55.3, 64.8, 108.4
13
1
H), 7.78 (d, J ¼ 7.4 Hz, 1H); C NMR
d
20.8, 45.2, 46.0, 49.4, 65.2,
(d, JF-C ¼ 24.2 Hz), 112.7, 116.0 (d, JF-C ¼ 23.4 Hz), 116.2, 125.7 (d, JF-
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131341

X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
9
C
C
¼ 9.7 Hz), 126.8 (d, JF-C ¼ 1.7 Hz), 131.3, 132.1, 136.5, 155.9 (d, JF-
stirred solution of 2c (1.54 g, 2.63 mmol) in CH
temperature. The reaction mixture was stirred overnight, and
quenched with aqueous sodium hydroxide solution (40%, 25 mL).
2
Cl
2
(80 mL) at room
¼ 9.0 Hz), 158.3, 165.7 (d, JF-C ¼ 252.2 Hz), 167.9; HRMS (ESI) calcd
þ
for C26
H23FNO
3
[MþH] : 416.1662, found: 416.1656.
1
Data of 5o. White solid. H NMR
d
3.28 (d, J ¼ 16.7 Hz, 2H), 3.53
The mixture was extracted with CH
were combined and dried over anhydrous Na
2
Cl
2
(30 mL ꢂ 3). The extracts
(
d, J ¼ 16.7 Hz, 2H), 3.94 (s, 3H), 4.16 (d, J ¼ 3.5 Hz, 2H), 4.46 (t,
2
SO . The solvent was
4
J ¼ 3.5 Hz, 1H), 6.98 (dd, J ¼ 8.4, 2.2 Hz, 1H), 7.03e7.05 (m, 3H), 7.12
removed in vacuo and the residue was purified by column chro-
matography on silica with ethyl acetate/petroleum ether (V/
V ¼ 2:3) as the eluent to afford 0.911 g (70%) of 5c as yellow oil.
(
0
6
1
3
td, J ¼ 7.4, 1.4 Hz, 2H), 7.19 (td, J ¼ 7.4, 1.2 Hz, 2H), 7.30 (dd, J ¼ 7.5,
13
.9 Hz, 2H), 7.70 (d, J ¼ 8.3 Hz, 1H); C NMR
d 45.4, 45.7, 50.3, 55.8,
4.8, 106.0, 114.4, 123.4, 125.0, 127.0, 127.4, 130.4, 130.9, 135.9, 139.3,
þ
55.9, 163.6, 168.9; HRMS (ESI) calcd for C25
68.1651, found: 368.1648.
Data of 5p. Yellow oil. H NMR
H22NO
2
[MþH] :
3.10. Reaction of 5g with BBr3
1
d
3.31 (d, J ¼ 17.6 Hz, 2H), 3.58 (d,
BBr (0.12 mL,1.26 mmol) was added to the stirred solution of 5g
3
ꢁ
J ¼ 17.6 Hz, 2H), 3.88 (s, 3H), 4.10 (d, J ¼ 3.5 Hz, 2H), 4.42 (t,
J ¼ 3.5 Hz, 1H), 6.92e6.96 (m, 3H), 7.06 (d, J ¼ 2.1 Hz, 1H), 7.12e7.17
(125 mg, 0.31 mmol) in CH Cl (25 mL) at ꢀ78 C. The reaction
2
2
mixture was warmed to room temperature, stirred overnight, and
13
(
m, 2H), 7.36 (dd, J ¼ 8.0, 1.1 Hz, 2H), 7.65 (d, J ¼ 8.4 Hz, 1H);
C
quenched with H O (10 mL). The mixture was transferred to a
2
NMR
d
45.48, 45.53, 51.3, 55.9, 64.3, 106.3, 114.5, 122.7, 125.2, 126.9,
separatory funnel and extracted with ethyl acetate (20 mL ꢂ 3). The
1
28.4,129.9,132.0,135.0,141.4, 155.8,163.8,168.8; HRMS (ESI) calcd
combined organic extracts were dried over anhydrous Na SO . The
2
4
þ
1
for C25
H20Br
2
NO
2
[MþH] : 525.9840, found: 525.9841.
solvent was removed in vacuo and the residue was purified by
column chromatography on silica with ethyl acetate/petroleum
Data of 5q. Yellow oil. H NMR
d
2.21 (s, 6H), 3.21 (d, J ¼ 16.7 Hz,
2
4
H), 3.48 (d, J ¼ 16.7 Hz, 2H), 3.91 (s, 3H), 4.11 (d, J ¼ 3.4 Hz, 2H),
ether (V/V ¼ 3:2) as the eluent to afford 113 mg (98%) of 7 as a white
1
.36 (t, J ¼ 3.4 Hz, 1H), 6.83 (s, 2H), 6.95e6.97 (m, 3H), 7.04 (d,
solid. H NMR (DMSO‑d )
d
3.07 (d, J ¼ 16.9 Hz, 2H), 3.51 (d,
6
1
3
J ¼ 2.1 Hz, 1H), 7.16 (d, J ¼ 7.7 Hz, 2H), 7.69 (d, J ¼ 8.4 Hz, 1H);
C
J ¼ 16.9 Hz, 2H), 3.92 (d, J ¼ 2.4 Hz, 2H), 4.38 (s, 1H), 6.48 (s, 2H),
NMR
d 20.8, 45.4, 46.0, 49.4, 55.8, 64.9, 106.0, 114.5, 123.5, 124.9,
6.57 (dd, J ¼ 8.1, 1.8 Hz, 2H), 7.12 (d, J ¼ 8.2 Hz, 2H), 7.51 (t, J ¼ 7.4 Hz,
1
28.0,130.2,131.6,135.6,136.4,136.7,156.1,163.6,168.9; HRMS (ESI)
1H), 7.62 (d, J ¼ 7.4 Hz, 1H), 7.72 (t, J ¼ 7.4 Hz, 1H), 7.87 (d, J ¼ 7.6 Hz,
þ
1
13
calcd for C27
H26NO
2
[MþH] : 396.1964, found: 396.1966.
1H), 9.22 (s, 2H); C NMR (DMSO‑d )
d
44.4, 45.9, 47.0, 64.5, 113.6,
6
Data of 5r. White solid. H NMR
d
3.21 (d, J ¼ 16.8 Hz, 2H), 3.50
117.1, 121.8, 122.4, 128.1, 130.1, 130.8, 131.0, 132.6, 137.0, 153.9, 155.6,
þ
(
4
2
(
5
1
[
d, J ¼ 16.8 Hz, 2H), 3.68 (s, 6H), 3.91 (s, 3H), 4.08 (d, J ¼ 3.4 Hz, 2H),
167.8. HRMS (ESI) calcd for C24H20NO [MþH] : 370.1443, found:
3
.33 (t, J ¼ 3.4 Hz, 1H), 6.56 (d, J ¼ 2.5 Hz, 2H), 6.70 (dd, J ¼ 8.4,
.6 Hz, 2H), 6.96 (dd, J ¼ 8.4, 2.1 Hz, 1H), 7.04 (d, J ¼ 1.9 Hz, 1H), 7.17
370.1438.
CCDC 1998409e1998410 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif. Crystal structure determinations
of 4b and 5a along with their data and the synthesis of aromatic
1
3
d, J ¼ 8.4 Hz, 2H), 7.69 (d, J ¼ 8.4 Hz, 1H); C NMR
d 45.5, 46.1, 48.5,
5.2, 55.8, 64.7, 106.0, 112.6, 114.5, 116.2, 123.4, 124.9, 131.3, 132.3,
36.9, 155.9, 158.2, 163.6, 168.8; HRMS (ESI) calcd for C27
H
26NO
4
þ
MþH] : 428.1862, found: 428.1851.
1
1
13
Data of 5s. Yellow oil. H NMR
d
3.26 (dd, J ¼ 16.7, 11.1 Hz, 2H),
imines as well as H and C NMR spectra of all compounds are
provided.
3
2
2
.56 (dd, J ¼ 16.7, 13.7 Hz, 2H), 3.72 (s, 3H), 4.17 (dd, J ¼ 3.5, 1.5 Hz,
H), 4.42 (t, J ¼ 3.5 Hz, 1H), 6.58 (d, J ¼ 2.6 Hz, 1H), 6.73 (dd, J ¼ 8.4,
.7 Hz,1H), 7.02 (d, J ¼ 7.4 Hz,1H), 7.11 (td, J ¼ 7.4, 1.4 Hz,1H), 7.18 (t,
Declaration of competing interest
J ¼ 6.8 Hz, 1H), 7.22 (d, J ¼ 8.4 Hz, 1H), 7.29 (d, J ¼ 6.5 Hz, 1H), 7.47
(
1
6
1
td, J ¼ 7.4, 0.9 Hz,1H), 7.58 (d, J ¼ 7.6 Hz,1H), 7.65 (td, J ¼ 7.5, 1.1 Hz,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
13
H), 7.79 (d, J ¼ 7.5 Hz, 1H); C NMR
d 45.2, 45.5, 45.9, 49.4, 55.3,
5.1, 112.6, 116.2, 120.8, 123.6, 126.9, 127.4, 128.3, 130.2, 130.8, 130.9,
31.4, 131.7, 132.5, 135.7, 137.1, 139.7, 153.6, 158.3, 169.0; HRMS (ESI)
þ
calcd for C25
H
22NO
2
[MþH] : 368.1651, found: 368.1649.
Acknowledgments
1
Data of 5t. Yellow oil. H NMR
d
3.21 (d, J ¼ 16.6 Hz, 1H), 3.27 (d,
J ¼ 16.8 Hz, 1H), 3.51 (d, J ¼ 16.5 Hz, 1H), 3.58 (d, J ¼ 16.7 Hz, 1H),
.77 (s, 3H), 4.19 (dd, J ¼ 6.1, 3.6 Hz, 2H), 4.41 (t, J ¼ 3.5 Hz, 1H), 6.68
dd, J ¼ 8.4, 2.7 Hz, 1H), 6.84 (d, J ¼ 2.7 Hz, 1H), 6.96 (d, J ¼ 8.4 Hz,
H), 7.02 (d, J ¼ 7.4 Hz, 1H), 7.12 (td, J ¼ 7.4, 1.4 Hz, 1H), 7.19 (t,
This work is supported by the National Key Research and
Development Plan of China (2017YFD0200900).
3
(
1
Appendix A. Supplementary data
J ¼ 7.4 Hz, 1H), 7.31 (d, J ¼ 8.6 Hz, 1H), 7.46 (td, J ¼ 7.4, 0.9 Hz, 1H),
7
1
1
.57 (d, J ¼ 7.6 Hz, 1H), 7.64 (td, J ¼ 7.5, 1.1 Hz, 1H), 7.78 (d, J ¼ 7.5 Hz,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131341.
1
3
H); C NMR
d 44.5, 45.1, 45.6, 50.4, 55.3, 65.2, 112.3, 115.8, 120.8,
23.5, 127.1, 127.4, 127.9, 128.2, 130.3, 130.75, 130.82, 132.0, 132.4,
1
C
36.0, 139.1, 140.3, 153.7, 158.7, 169.0; HRMS (ESI) calcd for
References
þ
25
H
22NO
2
[MþH] : 368.1651, found: 368.1645.
1
Data of 6. Yellow oil. H NMR
d
1.28 (t, J ¼ 7.1 Hz, 6H), 3.18 (d,
[1] (a) K. Speck, T. Magauer, Beilstein J. Org. Chem. 9 (2013) 2048e2078;
(b) M.S. Leonard, ARKIVOC (i) (2013) 1e65.
J ¼ 14.0 Hz, 2H), 3.43 (d, J ¼ 14.0 Hz, 2H), 4.09 (s, 1H), 4.25 (q,
J ¼ 7.1 Hz, 4H), 6.71 (d, J ¼ 8.2 Hz, 4H), 7.18 (d, J ¼ 7.7 Hz,1H), 7.38 (d,
J ¼ 7.5 Hz, 1H), 7.50e7.56 (m, 2H), 7.70 (d, J ¼ 8.2 Hz, 4H), 9.15 (s,
[
2] (a) F. Scorzelli, A.D. Mola, G. Croce, L. Palombi, A. Massa, Tetrahedron Lett. 56
2015) 2787e2790;
(b) J. Wu, W. Zhang, C. Wang, Synthesis (2009) 1821e1828.
[3] G. Stajer, F. Csende, Curr. Org. Chem. 9 (2005) 1277e1286.
(
13
1
H); C NMR d 14.3, 43.8, 49.9, 61.0, 69.2, 123.1, 124.1, 129.0, 129.5,
[
4] (a) F. Csende, F. Mikl oꢀ s, G. St ꢀa jer, Curr. Org. Chem. 16 (2012) 1005e1050;
b) F. Csende, G. Stajer, Curr. Org. Chem. 9 (2005) 1261e1276.
5] (a) J. Li, S. Bai, Y. Li, Z. Wang, X. Huo, L. Liu, J. Org. Chem. 83 (2018) 8780e8785;
b) M. Berthet, A. Beauseigneur, C. Moine, C. Taillier, M. Othman, V. Dalla,
Chem. Eur. J. 24 (2018) 1278e1282;
129.6, 129.8, 131.4, 131.7, 139.2, 146.5, 166.1, 168.7, 197.6; HRMS (ESI)
(
þ
calcd for C30
H30NO
6
[MþH] : 500.2073, found: 500.2070.
[
(
3.9. Gram-scale synthesis of 5c
(c) V.K. Pandey, P. Anbarasan, J. Org. Chem. 79 (2014) 4154e4160;
(d) K.K.S. Sai, M.J. O’Connor, D.A. Klumpp, Tetrahedron Lett. 52 (2011)
Powdery AlCl (1.23 g, 9.21 mmol) was slowly added to the
3
2195e2198.
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131341

1
0
X.-Y. Liu et al. / Tetrahedron xxx (xxxx) xxx
R. G ꢀa mez-Monta n~ o, E. Gonz aꢀ lez-Zamora, Org. Biomol. Chem. 15 (2017)
[
6] (a) M.S. Joshi, F.C. Pigge, Synthesis 50 (2018) 4837e4845;
b) R.R. Liu, Y.G. Wang, Y.L. Li, B.B. Huang, R.X. Liang, Y.X. Jia, Angew. Chem. Int.
Ed. 56 (2017) 7475e7478;
c) X.R. Qin, M.W. Lee, J.R. Zhou, Angew. Chem. Int. Ed. 56 (2017)
2723e12726;
d) S. Chen, X.X. Wu, J. Wang, X.H. Hao, Y. Xia, Y. Shen, H.W. Jing, Y.M. Liang,
(
2363e2369;
(c) Z. Al-Jaroudi, P.P. Mohapatra, T.S. Cameron, A. Jha, Synthesis 48 (2016)
4477e4488;
(d) M. Ghandi, N. Zarezadeh, A. Abbasi, Org. Biomol. Chem. 13 (2015)
8211e8220.
(
1
(
Org. Lett. 18 (2016) 4016e4019.
[13] (a) W. Zhang, P. Chen, G. Liu, Angew. Chem. Int. Ed. 56 (2017) 5336e5340;
(b) D.Y. Kim, P.D.Q. Dao, N.S. Yoon, C.S. Cho, Asian J. Org. Chem. 8 (2019)
1726e1731.
[
7] (a) M.C. García-Gonz aꢀ lez, E. Hern aꢀ ndez-V aꢀ zquez, R.E. Gordillo-Cruz,
L.D. Miranda, Chem. Commun. 51 (2015) 11669e11672;
(
b) V. Mamane, Y. Fort, Tetrahedron Lett. 47 (2006) 2337e2340.
8] (a) A. Kundu, A. Pramanik, Tetrahedron Lett. 55 (2014) 4466e4474;
b) Y. Zhou, L. Qian, W. Zhang, Synlett (2009) 843e847.
9] (a) N. Cindro, I. Halasz, K. Mlinari ꢀc -Majerski, N. Basari ꢀc , Eur. J. Org. Chem.
[14] J.E. Aaseng, O.R. Gautun, Tetrahedron 70 (2014) 5057e5063.
[15] S. Racine, B. Hegedìs, R. Scopelliti, J. Waser, Chem. Eur. J. 22 (2016)
11997e12001.
[16] S. Jin, J. Guo, D. Fang, Y. Huang, Q. Wang, Z. Bu, Adv. Synth. Catal. 361 (2019)
456e461.
[17] (a) H.J. Li, Y.Q. Zhang, L.F. Tang, Tetrahedron 71 (2015) 7681e7686;
(b) Y. Xu, X.Y. Liu, Z.H. Wang, L.F. Tang, Tetrahedron 73 (2017) 7245e7253;
(c) X.Y. Liu, Y. Xu, L.F. Tang, Chem. J. Chin. Univ. 39 (2018) 2433e2437.
[18] (a) S. Couty, B. Liegault, C. Meyer, J. Cossy, Tetrahedron 62 (2006) 3882e3895;
(b) A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau, Tetrahedron 56 (2000)
1491e1499.
[
[
(
(
(
2013) 929e938;
b) O. Shvydkiv, S. Gallagher, K. Nolan, M. Oelgem o€ ler, Org. Lett. 12 (2010)
5
170e5173.
[
10] (a) J. Huang, X. Du, K.V. Hecke, E.V. Van der Eycken, O.P. Pereshivko,
V.A. Peshkov, Eur. J. Org. Chem. (2017) 4379e4388;
(
6
b) C. Alonso, M. Gonz ꢀa lez, F. Palacios, G. Rubiales, J. Org. Chem. 82 (2017)
379e6387.
[
11] (a) O. S aꢀ nchez-Antonio, R. Gonz aꢀ lez-Olvera, A. Aguilera-Cruz, A. Reyes-Ram-
[19] (a) R.A. Hemming, M. Bell, L.J. Duffy, J. Bristow, J.D. Wallis, S.M. Allin,
P.C.B. Page, Tetrahedron 75 (2019) 121e127;
írez, E. Juaristi, Tetrahedron 75 (2019) 130594;
(
1
b) L. Zhang, B. Zhang, T. Jiang, T. Lu, Q. Zhou, Org. Chem. Front. 4 (2017)
19e123;
(b) A. J oꢀ ꢀz wiak, P.M. Zagorski, M.W. Płotka, D. Cal, Tetrahedron Lett. 55 (2014)
2420e2422;
(
(
(
c) F. Scorzelli, A.D. Mola, G. Croce, L. Palombi, A. Massa, Tetrahedron Lett. 56
2015) 2787e2790;
d) M. Włostowski, D. Ja nꢀ czewski, S. Czarnocka, L. Synoradzki, Synlett (2008)
(c) D.L. Comins, S. Schilling, Y. Zhang, Org. Lett. 7 (2005) 95e98.
[20] T. Bousquet, J.F. Fleury, A. Daïch, P. Netchitaïlo, Tetrahedron 62 (2006)
706e715.
3
198e3202.
[21] M.D. Bolton, B.P.H.J. Thomma, B.D. Nelson, Mol. Plant Pathol. 7 (2006) 1e16.
[22] Y.F. Xie, Y. Yu, Z.J. Fan, L. Ma, N. Mi, L.F. Tang, Appl. Organomet. Chem. 24
(2010) 1e7.
[
12] (a) M. Kurva, M.D. Kerim, R. G ꢁa mez-Monta n~ o, L.E. Kaim, Org. Biomol. Chem. 17
(
(
2019) 9655e9659;
b) O. V aꢀ zquez-Vera, J.S. S aꢀ nchez-Badillo, A. Islas-J aꢀ come, M.A. Rentería-
[23] S. Das, D. Addis, L.R. Kn o€ pke, U. Bentrup, K. Junge, A. Brückner, M. Beller,
G oꢀ mez, S.G. Pharande, C.J. Cortes-García, M.A. Rinc oꢀ n-Guevara, I.A. Ibarra,
Angew. Chem. Int. Ed. 50 (2011) 9180e9184.
Please cite this article as: X.-Y. Liu et al., Synthesis of benzazepinoisoindolinone and bridged tricyclic isoindolinone derivatives, Tetrahedron,
https://doi.org/10.1016/j.tet.2020.131341