Palladium-Catalyzed Selective Synthesis of Dibenzo[c,e]azepin-5-ols and Benzo[c]pyrido[2,3-e]azepin-5-ols

Article abstract of DOI:10.1002/adsc.201900705

An efficient palladium-catalyzed tandem addition/cyclization of 2′-formyl-[1,1′-biaryl]-2-carbonitriles with arylboronic acids is reported. This reaction affords dibenzo[c,e]azepin-5-ols and benzo[c]pyrido[2,3-e]azepin-5-ols with excellent selectivity and wide functional group compatibility. The dibenzo[c,e]azepin-5-ols show good cell growth inhibitory activity against a triple-negative breast cancer cell line. Moreover, the proposed mechanistic rationale for this tandem process is supported by theoretical calculations. (Figure presented.).

Full text of DOI:10.1002/adsc.201900705

Title: Palladium-Catalyzed Selective Synthesis of
Dibenzo[c,e]azepin-5-ols and Benzo[c]pyrido[2,3-e]azepin-5-ols
Authors: Xinrongo Yao, Yinlin Shao, Maolin Hu, Maosheng Zhang,
Shaotong Li, Yuanzhi Xia, Tianxing Cheng, and Jiuxi Chen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900705
Link to VoR: http://dx.doi.org/10.1002/adsc.201900705

Advanced Synthesis & Catalysis
10.1002/adsc.201900705
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Selective Synthesis of Dibenzo[c,e]azepin-
-ols and Benzo[c]pyrido[2,3-e]azepin-5-ols
5
a
a
a
a
b
Xinrong Yao, Yinlin Shao, Maolin Hu, Maosheng Zhang, Shaotong Li, Yuanzhi
a
a
a,
Xia, Tianxing Cheng and Jiuxi Chen *
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China
Fax: (+86)-577-8668-9359; phone: (+86)-577-8668-9359; e-mail: jiuxichen@wzu.edu.cn
b
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient palladium-catalyzed tandem addition/cyclization of 2'-formyl-[1,1'-biaryl]-2-carbonitriles with
arylboronic acids is reported. This reaction affords dibenzo[c,e]azepin-5-ols and benzo[c]pyrido[2,3-e]azepin-5-ols with
excellent selectivity and wide functional group compatibility. The dibenzo[c,e]azepin-5-ols show good cell growth
inhibitory activity against a triple-negative breast cancer cell line. Moreover, the proposed mechanistic rationale for this
tandem process is supported by theoretical calculations.
Keywords: palladium-catalyzed; tandem reaction; dibenzo[c,e]azepin-5-ols; benzo[c]pyrido[2,3-e]azepin-5-ols; nitriles
Introduction
The development of transition-metal-catalyzed
addition of nitriles to organoboron reagents for
ketone and derivative synthesis has had remarkable
[1]
success over the past decade (Scheme 1a). However,
the nitrile’s nitrogen atom has not been used
effectively due to the hydrolysis of the ketamine
intermediate to limit the practicality of these types of
transformations for the synthesis of N-heterocycles.
Development of a new strategy for the selective
synthesis of N-heterocycles is a significant research
goal because of their importance in laboratory
synthesis and industrial applications. Our laboratory
recently demonstrated a palladium-catalyzed tandem
reaction of nitriles with organoboron reagents for the
synthesis of six-membered N-heterocycles with high
[2]
[3]
selectivity (Scheme 1b). In addition, Cheng and
Liu[ independently developed a cascade reaction of
formyl-substituted nitriles with arylboronic acids for
the synthesis of five-membered phthalides (Scheme
4]
1
c) or six-membered 9-amino-10-arylphenanthrenes
(
Scheme 1d).
Dibenz[c,e]azepine derivatives represent an
important class of unique seven-membered bridged
biaryl frameworks and have attracted increasing
attention because of their importance in synthesis and
medicinal chemistry.[5] Although the synthesis of
Scheme 1. Design for the construction of
dibenzo[c,e]azepin-5-ols and derivatives.
[6]
dibenzo[c,e]azepines has been well-established,
only few examples of the synthesis of
dibenzo[c,e]azepin-5-ols have been reported to date.
We envisioned that a palladium-catalyzed addition of
a
[7]
readily
available
2'-formyl-[1,1'-biaryl]-2-
carbonitriles or 2-(3-formylpyridin-2-yl)benzonitrile
to arylboronic acids would produce the imine
intermediate, followed by an intramolecular
cyclization with the formyl group to access a new
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201900705
class
of
dibenzo[c,e]azepin-5-ols
or
9). Replacement of 2,2'-bipyridine with different
nitrogen ligands or phosphine ligands, resulted in
lower yields (Table S1 in ESI). Among the different
additives examined (Table 1, entries 10−12),
benzo[c]pyrido[2,3-e]azepin-5-ols which are often
difficult to prepare using existing methods (Scheme
1
e). Moreover, the hydroxyl group in the products is
a useful handle for further synthetic manipulations,
thus broadening the diversity of the products with
high value to both synthetic and medicinal chemistry.
CH
3
SO H was found to be the best one, and the
3
desired product 3a was furnished in 73% yield (Table
1, entry 12). Temperature is also crucial for this
reaction, and it becomes sluggish if it is carried out at
room temperature (Table S1 in ESI). Further studies
revealed that 82% yield could be obtained by using
Results and Discussion
o
dry THF as solvent at 80 C (Table 1, entry
Initially, the readily available 2'-formyl-[1,1'-
13).Finally, we found that the yield of 3a improved to
86% when the model reaction was performed under
an atmosphere of nitrogen. Control experiments
indicated that both the catalyst and additive were
necessary to afford the desired product 3a in good
yield (Table 1, entries 14−15). Other reaction
parameters including the amount of catalyst, additive
biphenyl]-2-carbonitrile (1a) and phenylboronic acid
(
2a) were chosen as the model substrates in the
presence of Pd(OAc) as catalyst, 2,2'-bipyridine as
2
ligand, and trifluoroacetic acid as additive in 2-
methyltetrahydrofuran (2-MeTHF) at 90 °C under an
air atmosphere for 24 h, to afford the desired 7-
phenyl-5H-dibenzo[c,e]azepin-5-ol (3a) in 18% yield, and ligand were also examined (Table S1 in ESI).
along with a small amount of byproduct 2'-benzoyl-
The structure of new compound 3a was determined
1,1'-biphenyl]-2-carbaldehyde (3a’) from hydrolysis
[8a]
[
by its X-ray diffraction.
of the imine intermediate (Table 1, entry 1). With this
promising result, different solvents, catalysts, ligands,
and additives were screened sequentially. To our
delight, the yield of 3a could be improved to 58%
when THF was used as solvent (Table 1, entries 2−5).
It should be noted that the yield of byproduct 3a’
Table 2. Scope of arylboronic acids.[a]
could be improved to 82% using H
2
O as a solvent
(
Table 1, entry 6). An investigation into the effect of
catalysts showed that Pd(TFA)
2
was more efficient
for delivering a high yield of product (Table 1, entries
7
−
Table 1. Optimization of reaction conditions.[a]
[
a]
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(TFA)
mol%), bpy (12 mol%), CH SO H (10 equiv), dry THF (2
, isolated yield.
2
(6
3
3
o
mL), 80 C, 24 h, N
2
[
a]
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd catalyst (6
mol %), bpy (12 mol %), additive (10 equiv), solvent (2
We then investigated the scope of this tandem
reaction under the optimized reaction conditions.
Firstly, we examined the tandem reaction of 2'-
formyl-[1,1'-biphenyl]-2-carbonitrile (1a) with a
range of arylboronic acids. As shown in Table 2,
reaction of a variety of arylboronic acids with
substituents at the ortho-, meta- and para-positions
o
mL), 90 C, 24 h, air.
[
[
[
b]
c]
d]
Isolated yield.
At 80 C.
Under N atmosphere.
2
o
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201900705
proceeded smoothly to give the desired 7-aryl-5H-
dibenzo[c,e]azepin-5-ols in moderate to high yields
addition/hydrolysis byproducts (3t’–3u’). In addition,
the reaction was found to be affected by the
(
3b–3d). However, the presence of a substituent at
2
substituents (R ) on the aryl nitrile moiety. Both
the ortho-position on the arene ring reduced the
efficiency of the reaction, presumably due to the
enhanced steric hindrance (3d). This reaction
tolerates arylboronic acids with electron-donating
electron-donating groups such as methyl and
electron-withdrawing groups such as fluoro, chloro,
and trifluoromethyl, were tolerated, providing the
desired products in moderate to high yields (3v–4b).
Notably, treatment of 2-(2-formylthiophen-3-
yl)benzonitrile (1b) with o-tolylboronic acid (2b) as a
representative example is shown in Scheme 2,
providing 4c in 84% yield. The structure of 4c was
t
groups (e.g., Bu, OMe, OPh) to provide the
corresponding products in good yields (3e–3g),
however, reaction with a highly electron-rich
substrate afforded a low yield of the desired product
(
3h). Moreover, halogen-substituted (e.g. F, Cl, Br, I)
[8b]
substrates also reacted with 1a to produce the desired
products with high selectivity (3i–3l). Of note,
polycyclic boronic acids, such as biphenyl-4-
ylboronic acid, naphthalen-1-ylboronic acid, and
naphthalen-2-ylboronic acid were well tolerated in
this protocol, affording the corresponding products in
identified by X-ray diffraction.
7
8–84% yields (3m–3o).
Table 3. Scope of formyl-[1,1'-biaryl]-2-carbonitriles.[a]
Scheme 2. Reaction of 1b with o-tolylboronic acid.
Moreover, the scope of an N-heterocyclic
substrate was examined (Table 4). Pleasingly, the
desired product 4d was isolated in 83% yield from
the reaction of 2-(3-formylpyridin-2-yl)benzonitrile
(
1c) with phenylboronic acid. The compatibility of
this tandem reaction was confirmed by the
tolerance to methyl, fluoro, bromo, chloro, iodo,
and phenyl substituents (4e–4l). However,
substrate bearing a strongly electron-withdrawing
group (e.g., NO ) failed to provide the desired
2
product. Of note, naphthyl-substituted substrates
were also tolerated well and afforded the desired
products in 79–82% yields (4n–4o).
Table 4. Synthesis of benzo[c]pyrido[2,3-e]azepin-5-ols.[a]
[
a]
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(TFA)
mol%), bpy (12 mol%), CH SO H (10 equiv), dry THF (2
, isolated yield.
2
(6
3
3
o
mL), 80 C, 24 h, N
2
Next, the scope of formyl-[1,1'-biaryl]-2-
carbonitriles was evaluated as outlined in Table 3.
Firstly,
we
examined
formyl-[1,1'-biaryl]-2-
1
carbonitriles bearing substituents (R ) on the aryl
formaldehyde moiety. We found that treatment of 2'-
formyl-5'-methyl-[1,1'-biphenyl]-2-carbonitrile with
arylboronic acids delivered the desired products in
76–88% yields (3p–3r). The substrate bearing a
methoxy group was treated with phenylboronic acid
to afford 79% yield of 3s. However, highly electron-
rich substrates such as 2'-formyl-4',5'-dimethoxy-
[
1,1'-biphenyl]-2-carbonitrile failed to provide the
[
a]
desired products, only affording the
Conditions: 1c (0.2 mmol), 2 (0.4 mmol), Pd(TFA)
2
(6
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201900705
mol%), bpy (12 mol%), CH
3
SO
3
H (10 equiv), dry THF (2
We used the triple-negative breast cancer cell line
MDA-MB-468 to evaluate the cell growth inhibitory
activity of products using the Cell Counting Kit-8
o
mL), 80 C, 24 h, N
2
, isolated yield.
(
CCK-8) protocol, with BS-181 and LDC-3140 as
Further synthetic transformations of the as-
synthesized products were then explored, as outlined
in Scheme 3. For example, 3a could be easily
converted into the corresponding 5-(ethylthio)-7-
phenyl-5H-dibenzo[c,e]azepine (5a) and 7-phenyl-
positive controls (Table S2 in ESI). The tested
compounds (3a, 3d, 3n, 3v) displayed good
inhibitory activity, with IC50 values ranging from
8.52 to 45.12 M for the MDA-MB-468 cell line,
[9]
comparable to that of BS-181 and LDC-3140.
5
H-dibenzo[c,e]azepin-5-one (6a) in 71% and 72%
These results indicate that dibenzo[c,e]azepin-5-ols
show good cell growth inhibitory activity towards a
triple-negative breast cancer cell line and should be
investigated as potential inhibitors for other cancer
cell lines.
yield, via a substitution or oxidation reaction,
respectively. Thus, the hydroxyl group can be readily
transformed into useful carbonyl or ethylthio groups.
Conclusion
In summary, we have developed
a
novel
transformation to access dibenzo[c,e]azepin-5-ols and
benzo[c]pyrido[2,3-e]azepin-5-ols in moderate to
excellent yields through a Pd-catalyzed tandem
addition/cyclization of 2'-formyl-[1,1'-biaryl]-2-
carbonitriles with arylboronic acids. Control
experiments showed that this tandem process
involves sequential carbopalladation of the cyano
group generating an imine intermediate, followed by
an intramolecular cyclization with the formyl group.
DFT calculations were conducted to explain the
experimentally observed transformation.
Scheme 3. Synthetic applications.
To better understand the reaction, DFT calculations
were carried out to model the detailed transformation
of 1a and 2a to 3a (Figure 1). According to the
postulated mechanism, arylpalladium complex IN1
coordinates with 1a to form IN2, from which the
nitrile insertion occurs via TS1 with a barrier of 23.3
kcal/mol and forms arylated intermediate IN3
endergonically. In the next step, intramolecular
insertion of the formyl group into the Pd-N bond
occurs via TS2, which is slightly higher in energy Experimental Section
than TS1, and preferentially leads to alkoxide IN4.
1
The CH
3
SO
3
H is involved in the last step, forming
General Information. Melting points are uncorrected. H
NMR and 13C NMR spectra were measured on a 400 MHz
or 500 MHz spectrometer using DMSO-d or CDCl as the
product complex IN5 by protonation via TS3.
Dissociation of IN5 generates product 3a and
6
3
LPdSO
3
CH
3
. The latter complex then regenerates
solvent with tetramethylsilane (TMS) as an internal
standard at room temperature. Chemical shifts are given n
δ relative to TMS, and the coupling constants J are given
in hertz. High-resolution mass spectra were recorded on an
ESI-Q-TOF mass spectrometer. 2'-Formyl-[1,1'-biaryl]-2-
IN1 by reaction with 2a. A possible mechanism for
the formation of dibenzo[c,e]azepin-5-ols is proposed
(
Scheme S1 in ESI).
[
4,10]
carbonitriles (1),
method described
chromatography was performed using EM silica gel 60
300−400 mesh). X-ray crystallographic analysis was
was synthesized according to the
in the literature. Column
(
performed at the X-ray crystallography facility, Shanghai
Institute of Organic Chemistry (SIOC), Chinese Academy
of Sciences (CAS).
General Experimental Procedure for the Palladium-
Catalyzed Tandem Reaction
2
'-Formyl-[1,1'-biphenyl]-2-carbonitrile
formylpyridin-2-yl)benzonitrile (0.2 mmol), arylboronic
acid (0.4 mmol), Pd(TFA) (6 mol%), bpy (12 mol%), dry
THF (2 mL) and CH SO H (2 mmol) were successively
or
2-(3-
2
3
3
added to a full of nitrogen Schlenk reaction tube. The
reaction mixture was stirred vigorously at 80 °C for 24
hours. After the reaction mixture was cooled to room
temperature, washed with saturated NaHCO3, and
extracted with ethylacetate (3 × 10 ml). The combined
Figure 1. DFT results.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201900705
organic layers were dried over anhydrous Na
2
SO
4
and
Cooper, R. T. Cummings, H. Jayaram, S. Joshi, J. A.
Mertz, A. Neiss, E. Normant, M. O’Meara, E. Pardo, F.
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M. T. Larsen, S. Sinning, D. C. Williams, H. H. Jensen,
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evaporated under a vacuum. The residue was purified by
flash column chromatography with petroleum ether/ethyl
acetate (15:1) to afford the desired products 7-aryl-5H-
dibenzo[c,e]azepin-5-ol and 7-aryl-5H-benzo[c]pyrido[2,3-
e]azepin-5-ols.
Acknowledgements
We acknowledge financial support from the NSFC (No.
2
1572162), and the Natural Science Foundation of Zhejiang
Province (Nos. LY16B020012 and LQ18B020006).
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FULL PAPER
Palladium-Catalyzed Selective Synthesis of
Dibenzo[c,e]azepin-5-ols and Benzo[c]pyrido[2,3-
e]azepin-5-ols
Adv. Synth. Catal. Year, Volume, Page – Page
Xinrong Yao, Yinlin Shao, Maolin Hu, Maosheng
Zhang, Shaotong Li, Yuanzhi Xia, Tianxing Cheng
and Jiuxi Chen*
6
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