Palladium-Catalyzed Cascade Reaction of o-Cyanobiaryls with Arylboronic Acids: Synthesis of 5-Arylidene-7-aryl-5 H-dibenzo[ c, e]azepines

Article abstract of DOI:10.1021/acs.orglett.9b02351

A palladium-catalyzed cascade reaction of 2′-acetyl-[1,1′-biphenyl]-2-carbonitriles with arylboronic acids is developed. This reaction affords a new class of seven-membered 5-arylidene-7-aryl-5H-dibenzo[c,e]azepines with good functional group compatibility and selectivity. Reaction mechanistic study suggests that this transformation involves carbopalladation of nitrile and subsequent intramolecular cyclization followed by oxidative Heck coupling.

Full text of DOI:10.1021/acs.orglett.9b02351

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Cascade Reaction of o‑Cyanobiaryls with
Arylboronic Acids: Synthesis of 5‑Arylidene-7-
aryl‑5H‑dibenzo[c,e]azepines
†
†
Xinrong Yao, Yinlin Shao, Maolin Hu, Yuanzhi Xia, Tianxing Cheng, and Jiuxi Chen*
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, P. R. China
*
S Supporting Information
ABSTRACT: A palladium-catalyzed cascade reaction of 2′-
acetyl-[1,1′-biphenyl]-2-carbonitriles with arylboronic acids is
developed. This reaction affords a new class of seven-
membered 5-arylidene-7-aryl-5H-dibenzo[c,e]azepines with
good functional group compatibility and selectivity. Reaction
mechanistic study suggests that this transformation involves
carbopalladation of nitrile and subsequent intramolecular
cyclization followed by oxidative Heck coupling.
ibenz[c,e]azepines are among the most important seven-
membered N-heterocycles with a biphenyl skeleton and
of a novel transformation for the synthesis of substituted
dibenz[c,e]azepines has been one of the prime targets in
organic synthesis.
D
have received great attention because of their pharmacological
1
2
properties and promising applications in organic synthesis.
Recently, treatment of o-cyanobiaryl derivatives with
arylboronic acids (or Grignard reagents/organic lithiums)
has received much attention. The Liu group reported reaction
of 2′-cyano-biaryl-2-aldehyde derivatives with arylboronic acids
for the preparation of functionalized 9-amino-10-arylphenan-
3
4
As shown in Scheme 1, Turner and Zhang independently
Scheme 1. Synthesis of Dibenzo[c,e]azepine Derivatives
10
threnes (Scheme 2a). Ji and Wang developed manganese-
mediated cascade cyclization of isocyano-substituted o-
cyanobiaryl derivatives with arylboronic acids via a radical
1
1
pathway for the synthesis of pyrrolopyridines (Scheme 2b).
12
As shown in Scheme 3c, reaction of biaryl-2-carbonitriles
with Grignard reagents under different reaction conditions
afforded phenanthridine derivatives and azaspirocyclohexadie-
none derivatives.
Inspired by the above-mentioned results and our studies of
13
transformation of nitriles, we envisioned that Pd-catalyzed
addition of arylboronic acids to [1,1′-biphenyl]-2-carbonitriles
and sequential intramolecular cyclization would provide a new
method for the tandem synthesis of phenanthridines (Scheme
described intramolecular cyclization of Boc-protected aryl-
bridged aminoketones A to afford dibenz[c,e]azepines
5
(
Scheme 1a). Sharp reported that dibenz[c,e]azepines were
1
d, proposed transformation). To our surprise, this reaction
generated from aryl-bridged imidoyl chlorides B via intra-
molecular cyclization of nitrile ylides (Scheme 1b). Gschwend
and Boyer reported the synthesis of 9-chloro-7-(o-fluorophen-
yl)-5H-dibenz[c,e]azepine by treatment of the substrate C with
a volatile and highly toxic CNBr and subsequent cyclization in
failed to give the anticipated six-membered N-heterocycle
phenanthridines. Instead, we observed unexpected seven-
membered ring products dibenzo[c,e]azepines (Scheme 1d,
observed transformation). Despite the remarkable success of
five- and six-membered N-heterocycles by transition-metal-
catalyzed reaction of organoborons with nitriles, the
construction of seven-membered N-heterocycles remains
underdeveloped. Herein, we report the unexpected discovery
of this novel procedure that combines three sequential
nucleophilic additions, intramolecular cyclization, and oxida-
tive Heck coupling in one pot to afford a new class of diverse
6
the presence of ethanolic ammonia (Scheme 1c). Blum
reported tandem reduction/intramolecular cyclization of the
7
substrate D with sodium in the boiling solution of 1-pentanol.
In 2014, Maestri and Malacria developed a palladium-/
norbornene-catalyzed three-component reaction of aryl iodide
and bromobenzylamine with olefin to provide a new strategy
8
for the synthesis of dibenzo[c,e]azepines.
The formation of a seven-membered dibenz[c,e]azepine
framework has been rarely reported to date, possibly due to its
Received: July 8, 2019
9
unfavorable transannular interactions. Thus, the development
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02351
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Reactions of o-Cyanobiaryls with ArB(OH) or
Scheme 3. Substrate Scope for Arylboronic Acids
2
RMgBr/RLi
seven-membered 5-benzylidene dibenzo[c,e]azepines that were
often difficult to access by classical routes. DFT calculations
were also conducted to explain the experimentally observed
transformation.
We begin our investigation with readily available 2′-acetyl-
[
(
1,1′-biphenyl]-2-carbonitrile (1a) and phenylboronic acid
2a) for the optimization of reaction conditions (Table 1).
Initially, various solvents including 2-methyltetrahydrofuran
2-MeTHF), toluene, DMSO, dioxane, THF, and DMF were
(
a
Conditions: 1a (0.2 mmol), 2 (0.6 mmol), Pd(TFA) (6 mol %), L
2
1
examined (entries 1−6). We found that a trace amount of
unexpected seven-membered product (Z)-5-benzylidene-7-
phenyl-5H-dibenzo[c,e]azepine (3a) was detected by GC-MS
analysis accompanied by a trace quantity of addition/
hydrolysis byproduct 1-(2′-benzoyl-[1,1′-biphenyl]-2-yl)-
ethan-1-one (3aa) in 2-MeTHF (entry 1). In the presence
of Pd(CF CO ) , 2,2′-bipyridine (L ), and trifluoroacetic acid,
(
12 mol %), MsOH (2 mmol), DMF (2 mL), air, 100 °C, 24 h.
Isolated yield.
addition, slightly increasing the temperature to 100 °C
improved the yield to 78% (entry 21). The reaction failed to
give 3a when HCl was used as an additive (entry 22).
Increasing the amount of 2a to 3 equiv, the yield of 3a could
be improved to 85% yield (entry 23).
3
2 2
1
the reaction afforded 3a in 42% yield in DMF (entry 6). Other
palladium catalysts, such as Pd(OAc) , Pd(acac) , and
2
2
Pd (dba) , gave 3a in 28%, 26%, and 38% yields, respectively
We next examined the substrate scope for arylboronic acids
(Scheme 3). Treatment of 1a with p- and m-tolylboronic acid
delivered 3b and 3c in 86% and 83% yields, respectively, while
o-tolylboronic acid gave the corresponding 3d in 76% yield.
2
3
(
entries 7−9). Pd(PPh ) as a representative Pd(0) catalyst
3
4
failed to afford any products (entry 10). An examination of
various bidentate N-donor ligands revealed that 4,4′-di-tert-
butyl-2,2′-bipyridine (L ) and 1,10-phenanthroline (L )
i
t
Moderately electron-rich substituents, such as Pr (3e), Bu
2
3
efficiently provided 3a in 39−40% yields (entries 11 and
(3f), and OCF (3g), were well-tolerated, achieving 86−88%
3
1
2). However, ligands including 6,6′-dimethyl-2,2′-bipyridine
yields. Moderately electron-deficient halogens, such as F (3h),
Cl (3i), Br (3j), and I (3k), were also compatible with this
protocol, although slightly lower yields were observed. Of note,
the halogens in the products (3h−3k) could be amenable to
further synthetic transformations. The structure of 3j was
identified by X-ray diffraction. The strongly electron-donating
groups (e.g., OMe and OPh) at the para position do not retard
the reaction to give 3l and 3m in 89% and 85% yields,
respectively, while the substrate with the p-trifluoromethyl
(
L ), 2,9-dimethyl-1,10-phenanthroline (L ), and 2,2′-biquino-
4
5
line (L ) resulted in a trace amount of 3a, presumably due to
6
the enhanced steric hindrance (entries 13−15). A variety of
additives including acetic acid, p-toluene sulfonic acid
(
TsOH), p-nitrobenzenesulfonic acid (PNSA), trifluorometha-
nesulfonic acid (TfOH), D-camphorsulfonic acid (CSA), and
methanesulfonic acid (MsOH) were evaluated, and MsOH
was found to be the best one, affording 3a in 61% yield. In
B
DOI: 10.1021/acs.orglett.9b02351
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 4. Substrate Scope for o-Cyanobiaryls
b
entry
Pd catalyst
ligand
solvent
additive
CF CO H
yield (%)
1
2
3
4
5
6
7
8
9
Pd(CF CO )
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L1
L1
L1
2-MeTHF
toluene
DMSO
dioxane
THE
trace
11
3
2
2
2
2
2
2
2
3
2
Pd(CF CO )
CF CO H
3 2
3
2
Pd(CF CO )
CF CO H
13
21
27
42
28
26
38
0
3
2
3
2
Pd(CF CO )
CF CO H
3
2
3
2
Pd(CF CO )
CF CO H
3
2
3
2
Pd(CF CO )
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CF CO H
3
2
3
2
Pd(OAc)2
Pd(acac)2
CF CO H
3
2
CF CO H
3
2
Pd (dba)3
CF CO H
2
3
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pd(PPh3)4
CF CO H
3
2
Pd(CF CO )
CF CO H
39
40
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
Pd(CF CO )
CF CO H
3
2
3
2
Pd(CF CO )
CF CO H
trace
trace
trace
15
3
2
3
2
Pd(CF CO )
CF CO H
3 2
3
2
Pd(CF CO )
CF CO H
3 2
3
2
Pd(CF CO )
CH CO H
3 2
3
2
Pd(CF CO )
TsOH H O
39
32
51
3
2
2
Pd(CF CO )
PNSA
TfOH
CSA
MsOH
HCI
3
2
Pd(CF CO )
3
2
Pd(CF CO )
49
3
2
c
Pd(CF CO )
61 (78 )
3
2
c
c
Pd(CF CO )
0
85
3
2
a
d
Conditions: 1 (0.2 mmol), 2 (0.6 mmol), Pd(TFA) (6 mol %), L
2 1
Pd(CF CO )
MsOH
3
2
(
12 mol %), MsOH (2 mmol), and DMF (2 mL), air, 100 °C, 24 h.
a
Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd catalyst (6 mol %),
Isolated yield.
ligand (12 mol %), additive (2 mmol), solvent (2 mL), 80 °C, 24 h,
air. Isolated yield. At 100 °C. 2a (0.6 mmol).
b
c
d
Scheme 5. Synthesis of 6-Aryl-4-styryl-4H-
benzo[c]thieno[3,2-e]azepines
group decreased the yield to 42% (3n). These transformations
were efficient with polycyclic substrates (e.g., biphenyl and
naphthyl), providing the desired products 3o−3q in 75−82%
yields. Notably, the substrate (9,9-dimethyl-9H-fluoren-2-
yl)boronic acid was also successfully reacted, albeit in slightly
lower yields (3r).
As shown in Scheme 4, a variety of o-cyanobiaryl substrates
are compatible with this transformation. Electron-rich groups
Scheme 6. Synthetic Applications
(
e.g., Me, OMe) and electron-deficient groups (e.g., F, Cl,
CF ) were all tolerated in this transformation. It is also
3
practically important that the phenyl nitrile moiety with an
ortho-substituent and the desired product 4d were obtained in
4
3% yield, which indicates that the steric hindrance around the
cyano group prevents nucleophilic addition. Pleasingly, treat-
ment of 2-(2-acetylthiophen-3-yl)benzonitrile, a representative
thienyl-containing substrate, with o-tolylboronic acid delivered
4
q in 83% yield (Scheme 5).
To showcase the potential synthetic applications of the as-
Scheme 7. Control Experiments
synthesized 5-arylidene-7-aryl-5H-dibenzo[c,e]azepines, we
performed Heck coupling reaction of 3a with bromobenzene
to deliver the corresponding product 5a in 61% yield (Scheme
6
3
a). In the presence of 3-chloroperoxybenzoic acid (m-CPBA),
a was oxidized to give 7-phenyl-5H-dibenzo[c,e]azepin-5-one
(
6a) in 94% yield (Scheme 6b).
In addition, several control experiments were examined
under the standard conditions (Scheme 7). The reaction of
phenylboronic acid with styrenes (e.g., styrene, 1-chloro-4-
C
DOI: 10.1021/acs.orglett.9b02351
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
vinylbenzene, 1-methyl-4-vinylbenzene) was conducted to
deliver oxidative Heck coupling products in good yield
AUTHOR INFORMATION
Corresponding Author
■
*
(
(
Scheme 7a). Our initial attempts to treat acetophenones
e.g., acetophenone, 1-(4-chlorophenyl)ethan-1-one, 1-(4-
E-mail: jiuxichen@wzu.edu.cn.
ORCID
methylphenyl)ethan-1-one) with phenylboronic acid did not
work (Scheme 7b).
A possible mechanism for the formation of 5-arylidene-7-
aryl-5H-dibenzo[c,e]azepines via Pd-catalyzed tandem addi-
tion/cyclization/oxidative Heck coupling reaction is shown in
Scheme 8. It involves the following key steps: (i) trans-
Yuanzhi Xia: 0000-0003-2459-3296
Jiuxi Chen: 0000-0001-6666-9813
Author Contributions
†
X.Y. and Y.S. contributed equally to this work
Notes
Scheme 8. Proposed Mechanistic Pathway
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
No. 21572162) and the Natural Science Foundation of
■
(
Zhejiang Province (Nos. LY16B020012 and LQ18B020006)
for financial support.
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