A Cascade of acid-promoted c-o bond cleavage and redox reactions: From oxa-bridged benzazepines to benzazepinones

Article abstract of DOI:10.1021/ol502971e

A sequence of C-O bond cleavage and redox reactions in oxa-bridged azepines was realized under acid promoted conditions. This protocol provides an atom-economical and straightforward approach to access benzo[b]azepin-5(2H)-ones in high yields. The formal synthesis of tolvaptan was achieved by exploiting this new transformation.

Full text of DOI:10.1021/ol502971e

Letter
pubs.acs.org/OrgLett
A Cascade of Acid-Promoted C−O Bond Cleavage and Redox
Reactions: From Oxa-Bridged Benzazepines to Benzazepinones
Yuewei Zhang, Fengzhi Yang, Lianyou Zheng, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The College of Chemistry and The School of
Pharmaceutical Sciences, Jilin University, 1266 Fujin Lu, Changchun, Jilin 130021, P. R. China
S
* Supporting Information
ABSTRACT: A sequence of C−O bond cleavage and redox reactions in oxa-bridged
azepines was realized under acid promoted conditions. This protocol provides an atom-
economical and straightforward approach to access benzo[b]azepin-5(2H)-ones in high
yields. The formal synthesis of tolvaptan was achieved by exploiting this new
transformation.
ecently, [1,5]-hydride transfer/cyclization processes,
namely, the “internal redox process”, have attracted
much attention for their unique features. They are synthetically
powerful strategies for the construction of various hetero-
cycles.1 As demonstrated in Scheme 1, this type of process
reported acid-promoted reductive ring openings of aza-bridged
azepines.8 We recognized the presence of the driving force of a
similar “internal redox process” in structure 3 and envisioned an
expeditious route to a benzo[b]azepin-5(2H)-one skeleton,
which is encountered in numerous biologically active
compounds,9 via a C−O bond cleavage/1,5-hydride transfer
sequence (Scheme 2). A cascade of three transformations (acid
R
Scheme 1. Typical Internal Redox Process
Scheme 2. Potential Cascade Reactions of C−O Bond
Cleavage/1,5-Hydride Transfer From Benzazepine 3 to
Benzazepinone 4
involves the cleavage of a C−H bond α to a heteroatom via a
1,5-hydride shift to give zwitterionic intermediate A, followed
by subsequent 6-endo cyclization to the cation species to yield
structurally diverse nitrogen- or oxygen-contained heterocycle
2.1p,2
promoted C−O bond cleavage, 1,5-hydride transfer, and loss of
a proton) in oxa-bridged benzazepines 3 would afford
benzo[b]azepin-5(2H)-one derivatives 4.
In most cases, an activated hydride acceptor, basically an
electronically deficient unsaturated bond, is required to be
located in an appropriate position to a hydride donor.
Moreover, the participation of benzylic C−H bonds3 without
an adjacent heteroatom and even of aliphatic nonbenzylic C−H
bonds4 in this type of reaction has been reported. These typical
“internal redox processes” are commonly activated either
thermally or by an acid catalysist.2c,d,3f,5 Furthermore, progress
has been made toward catalytic enantioselective variants as well
as finding applications in key disconnections of total
syntheses.5b,6 However, to the best of our knowledge, there is
no precedent of a cascade involving a C−O bond cleavage/
hydride-transfer process.
We speculated that the C−O bond of oxa-bridged azepines 3,
prepared by a carbonyl-ene type reaction, could cleave to form
iminium ion B in the presence of a Brønsted or Lewis acid. The
subsequent internal redox process in structure B should occur
via a 1,5-hydride transfer to give intermediate C. Intermediate
C would readily lose a proton to lead to benzazepinones 4. This
overall reaction is an intramolecular redox process and thus
may not require a stoichiometric oxidant. We thus decided to
investigate the acid-promoted transformation of 3 to 4. The
details of this successful investigation and the application to the
formal synthesis of tolvaptan are disclosed.
As part of the research program related to the development
Received: October 8, 2014
of synthetic methodologies for novel heterocycles,7 we recently
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502971e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We chose substrate 3a which was synthesized by a recently
reported procedure7h to examine an array of Brønsted and
Lewis acids to optimize the reaction conditions (Table 1).
Table 2. Scope of the Ring Opening/1,5-Hydride Transfer
Sequence
a
a
Table 1. Optimization of Reaction Conditions
entry
R1
R2
R3
4
time
2 h
yield (%)
1
2
3
4
5
Me
allyl
Bn
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
91
82
85
77
81
83
60
56
57
30
75
90
76
80
1.5 h
2.5 h
14 h
7.5 h
63 h
7 h
entry
acid/solvent
temp (°C) time (h) yield (%)
b
1
1 equiv of TiCl4/DCM
15 equiv of 3 N HCl/MeOH
15 equiv of TFA/(H2O/THF)
HCOOH
0−25
reflux
reflux
reflux
reflux
90
6
NR
64
73
70
87
90
88
NR
87
91
89
Ph
2
3
4-MeO-Ph
4-NO2-Ph
Me
3
5.5
1
b
6
4
7
4g
4h
4i
5
15% aq H2SO4
0.5
1.5
4
8
Me
4-MeO-Ph
12 h
8 h
6
15% aq H2SO4
9
Me
4-F-Ph
H
7
15% aq H2SO4
70
10
11
12
13
14
15
Me
8-MeO
7-MeO
7-Me
4j
10 min
6 h
b
8
15% aq H2SO4
50
2
Me
H
4k
4l
9
5% aq H2SO4
90
3
Me
H
1 h
10
11
10% aq H2SO4
90
2
Me
H
8-Cl
4m
4n
4o
2 h
20% aq H2SO4
90
1
Me
H
7-Cl
3 h
a
c
Unless indicated otherwise, the reaction was carried out on 0.5 mmol
Me
H
7-NO2
6 h
NR
b
scale in solvent (2 mL). Starting material 3a was recovered.
a
Unless indicated otherwise, the reaction was carried out on 0.5 mmol
b
c
scale in solvent (2 mL). 10% aq H2SO4 reflux. No reaction.
Treatment of 3a with TiCl4 in dried methylene dichloride
(DCM) yielded no expected product, and starting material 3a
was recovered (entry 1, Table 1). Various acids, such as 3 N
HCl, TFA, HCOOH, and H2SO4, were screened, and the
desired 4a was obtained in moderate to excellent yield (entries
2−5, Table 1). We found that 15% aq H2SO4 under reflux
conditions gave the best result (entry 5). Further screening of
other reaction parameters (such as reaction temperature and
acid concentration) revealed that a minimum temperature of 70
°C is necessary for the reaction to take place, and product 4a
was produced in a higher yield within a shorter time at 90 °C
(entries 6−11, Table 1). Eventually, optimum reaction
conditions of 10% aq H2SO4 at 90 °C led to 4a in 91% yield
(entry 10, Table 1).
With the optimized reaction conditions, the scope of this
reaction cascade was explored, and the results are listed in
Table 2. First, we tested the generality of this C−O bond
cleavage/1,5-hydride transfer process from oxa-bridged aze-
pines 3 with various substituents at the nitrogen atom.
Substrates 3a−f substituted at the nitrogen atom with an
alkyl or aromatic group proceeded smoothly to produce the
corresponding benzo[b]azepin-5(2H)-ones 4a−f in good to
excellent yields (entries 1−6, Table 2). It is worth noting that
when R1 is an aromatic group, the reaction rate decreased as the
electronic density of the phenyl ring decreased (entries 4−6,
Table 2).
Oxa-bridged azepines 3g−i with phenyl, p-methoxyphenyl,
and p-F-phenyl at C-4 reacted smoothly to yield the
corresponding products 4g−i in moderate yields at reduced
rates (entries 1, 7−9, Table 2). The substituent at the fused
benzene ring had strong effects on the reactivity. For instance,
substrate 3j with a methoxy group at the C-8 position
dramatically sped up the reaction (completed in 10 min)
(entry 10, Table 2). The faster reaction rate is likely due to the
increasing hydride shift ability by the electron-donor group;
thus, the reorganization is speeded up. The low yield may be
due to side reactions since substrate 3j is too electron-rich. In
contrast, substrate 3k with the methoxy group at the C-7
Recovered only starting material.
position was much less reactive and required a longer reaction
time to provide the corresponding product 4k in a good yield
(entry 11, Table 2). This observation can be rationalized by the
decrease of the hydridophilicity of the iminium ion by the
electron-donating resonance effect of the methoxy group (in
the para vs meta position with respect to iminium ion), as well
as by reducing the hydride donor ability of the hydroxy group
by the σ-effect of the methoxyl oxygen atom (Scheme 2).
Moreover, substrate 3l with the methyl group at the C-7 has no
significant effect on the reactivity (entry 12, Table 2). The
deactivating chloro substituent was well tolerated at the C-7 or
C-8 position, although it reduced the reactivity of substrate 3m
and 3n to require a longer reaction time (entries 13, 14, Table
2). However, NO2 at the C-7 position decreases the availability
of the N lone pair of 3 for assisting the ring opening of the oxa-
bridge, and prevents the 3 to 4 conversion (entry 15, Table 2).
The formal synthesis of tolvaptan10 was selected to showcase
the synthetic potential of the present transformation (Scheme
3). Substitution of 5-chloro-2-fluorobenzaldehyde 5 with
diallylamine gave product 6 in 85% yield. The carbonyl-ene
reaction of benzaldehyde 6 afforded epoxybenzo[b]azepine 7.
Compound 7 proceeded smoothly with the cascade reaction to
give desired product 8 in excellent chemical yield (88%).
Removal of the allyl group in benzo[b]azepin-5(2H)-one 8
with a palladium catalyst furnished amine 9, the key precursor
to tolvaptan 10 reported by Kondo.10a The NMR spectra of 9
coincided with those of the literature. Therefore, a formal
synthesis of tolvaptan (10) was achieved.
In summary, a new cascade reaction of C−O bond cleavage
and a 1,5-hydride transfer process was developed. Through this
internal redox reaction process, various benzazepines could be
readily transformed to the desired benzo[b]azepin-5(2H)-ones
in good to excellent chemical yields. The application of this
method to the formal synthesis of tolvaptan was also
B
dx.doi.org/10.1021/ol502971e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xbai@jlu.edu.cn.
Notes
The authors declare no competing financial interest.
(8) Zhang, Y.; Zheng, L.; Yang, F.; Zhang, Z.; Dang, Q.; Bai, X.
Unpublished results.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the National Natural
Science Foundation of China (No. 81072526) and a grant from
the sci-tech development project of Jilin Province in China
(No. 20140309010YY). Additional support was provided by
Changchun Discovery Sciences, Ltd.
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