Copper-Catalyzed Regioselective and Diastereoselective Synthesis of Borylated 1-Benzo[ b]azepines

Article abstract of DOI:10.1021/acs.orglett.8b03286

A practical regioselective and diastereoselective synthesis of functionalized 1-benzo[b]azepines by copper-catalyzed intramolecular cyclization has been developed. The reaction involves borylcupration of a mixture of (E/Z)-1,3-dienes, followed by capture

Full text of DOI:10.1021/acs.orglett.8b03286

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Regioselective and Diastereoselective Synthesis
of Borylated 1‑Benzo[b]azepines
DingXi Li, Yeji Park, and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 440-746, Korea
S
* Supporting Information
ABSTRACT: A practical regioselective and diastereoselective synthesis
of functionalized 1-benzo[b]azepines by copper-catalyzed intramolecular
cyclization has been developed. The reaction involves borylcupration of
a mixture of (E/Z)-1,3-dienes, followed by capture of the generated (Z)-
allylcopper species with an imine to produce 7-membered N-hetero-
cycles as single diastereomers. The reaction is applicable to various (E/Z)-dienyl arenes with an imine moiety at the ortho-
position, including aryl, alkyl, and heterocyclic aldimines, and ketimines, affording borylated 2,3-cis-substituted 1-
benzo[b]azepines in good yields.
enzannulated nitrogen heterocycles are key structural
elements, frequently appearing in biologically active
homoallylic amines.12 Recently, Liao and co-workers have
developed an asymmetric allylation of imines by copper-
catalyzed borylative coupling of pure 1,3-dienes and aldimines
in an intermolecular process (Scheme 1a).12g More recently,
B
molecules, synthetic drugs, and drug candidates.1 In particular,
compounds bearing a 7-membered ring skeleton have been
incorporated into many commercial pharmaceuticals, such as a
drug against Gram-positive and Gram-negative bacteria
(ACHN-245),2 an anti-HIV-1 agent (orally active CCR5
antagonist),3 and a potential drug for the treatment of
pathological diseases related to hydroelectrolyte imbalances
(C9) (see Figure 1).4 As such, growing efforts have been
Scheme 1. Cu-Catalyzed Regioselective and
Diastereoselective Borylative Coupling of Dienyl Arenes
and Imines
Figure 1. Bioactive compounds containing 1-benzo[b]azepine
skeletons.
directed toward efficient preparation of the 1-benzo[b]azepine
backbone. Newly developed methods, including catalytic RCM
reactions,5 radical cyclization reactions,6 and catalytic [5 + 2]
cycloadditions,7 have worked well in the preparation of
valuable scaffolds, but the construction of two adjacent
stereocenters on the 1-benzp[b]azepine ring with high
stereoselectivity remains difficult. Other methods, such as Ir-
catalyzed allylic substitution via nucleophilic addition of
amine,8 carbene C−H or C−C insertions,9 ring expansion by
Beckmann rearrangement10a and Schmidt reaction,10b and
others,11 generally require specially functionalized substrates or
expensive catalysts and give low stereoselectivity. Therefore,
the development of reliable methods to construct the 1-
benzo[b]azepine backbones from readily available starting
materials is a highly desirable, yet challenging objective.
Over the past decades, the copper-catalyzed allylation of
imines has received much attention, as it is an efficient route to
our group and others have introduced copper-catalyzed
asymmetric borylative intramolecular cyclization of vinyl
arenes with tethered aldimines to produce cis-indolines, 5-
membered N-heterocycles (Scheme 1b).13,14 Based on this
success, we turned our attention to dienyl arenes (1)
containing tethered imines. When we applied Cu−Bpin
catalyst to 1, we found that a 7-membered ring unexpectedly
formed, instead of the vinyl indolines (Scheme 1c). Herein, we
report new developments in the copper-catalyzed borylative
Received: October 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03286
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coupling, whereby an NHC−Cu−Bpin complex added to a
mixture of (E/Z)-diene substrates combined with a tethered
imine in an intramolecular process to afford 2,3-substituted 1-
benzo[b]azepines with high efficiency and diastereoselectivity.
We used a mixture of (E/Z)-dienyl arenes 1a as our model
substrate without isolation of each individual isomer in the
presence of catalytic copper chloride, LiOt-Bu, B2pin2, and
various ligands (Table 1). Complete regioselectivity and
Scheme 2. Substrate Scope of the Copper-Catalyzed
Borylative Cyclization
a
Table 1. Optimization of Copper-Catalyzed Borylative
a
Cyclization
b
Yield (%)
b
entry
condition change
conversion (%)
cis-2a
64
74
69
85 (78)
82
trans-2a
c
d
1
CuCl, PPh3
CuCl, rac-Binap
CuCl, dppb
none
IPr−CuCl
SIMes−CuCl
0.2 equiv LiOt-Bu
100
93
−
c
2
17
5
−
−
−
−
c
3
100
100
100
100
54
4
5
6
7
54
38
a
b
Reactions were conducted on a 0.2 mmol scale. Conversions and
a
Reactions were conducted on a 0.2 mmol scale. Yields of isolated
1
yields were determined by H NMR analysis of the crude reaction
mixture, using dimethylformamide (DMF) as an internal standard.
b
products are shown. Gram scale (2.9 mmol) reaction of 1c was
c
performed to obtain 1.1 g of 2c; B2pin2 (1.65 equiv), IMesCuCl (2
Isolated yield of 2a is shown in parentheses. 5 mol % of copper salt
c
mol %), and LiOt-Bu (1.6 equiv) were used. Pure (E)-isomer was
d
and ligand were used. Not detected.
used.
stereoselectivity were observed with the triphenylphosphine
ligand (Table 1, entry 1). Unfortunately, the bisphosphine rac-
binap ligand gave low diastereoselectivity (Table 1, entry 2)
compared to the flexible bisphosphine ligand, dppb (Table 1,
entry 3). Gratifyingly, N-heterocyclic carbene copper(I)
complexes, IMesCuCl and bulky IPrCuCl were highly active,
giving full conversion and high yield of cis-2a15 with perfect
diastereoselectivity (Table 1, entries 4 and 5), while
SIMesCuCl resulted in an appreciably lower yield (Table 1,
entry 6). In particular, a decrease in the amount of base from a
stoichiometric quantity to a substoichiometric amount
considerably decreased the conversion and yield (Table 1,
entry 7), indicating a stoichiometric amount of base was
necessary for the catalytic cycle.
With the optimized conditions in hand, we examined the
substrate scope of this method using various dienyl arenes (see
Scheme 2). First, substituent effects on the aryl ring (R2) of the
imine moiety were investigated. Sterically bulky groups, such as
ortho-methyl (2b) and naphthyl (2c), were compatible with
this catalytic system and resulted in good to high yields, even
on a gram scale. However, an electron-withdrawing substituent
on the aromatic ring such as −CN at the meta-position (2d)
and −Br at the para-position (2e) resulted in slightly decreased
yields of the desired 1-benzo[b]azepines. The substrate with an
electron-donating methoxy group at the para-position of the
imine moiety gave the corresponding borylated 1-benzo[b]-
azepine (2f) in good yield. The reaction of imines containing
3-thiophene and 2-thiophene afforded the corresponding cis-1-
benzo[b]azepines (2g and 2h) in moderate to good yield. In
addition, the unstable 1-benzo[b]azepines (2i and 2j)
containing a vinyl and an alkyl substituent were oxidized to
the isolable corresponding alcohols with NaBO3·4H2O (3i and
3j) in moderate yield. Next, different substituents (R1) on the
phenyl ring of the dienyl arene were examined. Substrates with
an electron-donating substituent at the para-position, relative
to the imine moiety, produced 2k in moderate yield. A methyl
substituent at the para-position (1l) or ortho-position (1m) to
the dienyl group resulted in moderate yields as well.
Unfortunately, substrates with either a strong electron-
donating methoxy substituent or strong electron-withdrawing
fluorine atom at the para-position to the dienyl group exhibited
poor reactivity.16
In addition, less-reactive aryl ketimines were examined and
were found to produce trisubstituted 1-benzo[b]azepines in
good yields as single diastereoisomers under the optimized
catalytic conditions (see Scheme 3). Methyl phenyl ketimine
(4a), cyclic ketimine (4b), and ketimines containing an
electron-withdrawing (4c) or electron-donating substituent
(4d) resulted in moderate to good yields and excellent
diastereoselectivity. The reaction of ketimines containing 3-
thiophene and 2-thiophene afforded the corresponding 1-
B
DOI: 10.1021/acs.orglett.8b03286
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of the Copper-Catalyzed
Borylative Cyclization
Scheme 5. Proposed Catalytic Cycle
a
adds as a nucleophile to the imine intramolecularly to form a
cyclized 1-benzo[b]azepine D through a 6-membered ring
transition state C with its RL substituent in the favored
equatorial position. Finally, the catalytic cycle is completed by
ligand exchange with LiOt-Bu and B2pin2. The complexation of
copper to the imine in the allylcopper intermediate appears to
be responsible for 7-membered ring formation via a chairlike
transition state.12c,e,14
a
Reactions were conducted on a 0.2 mmol scale. Yields of isolated
products are shown.
benzo[b]azepines (5e and 5f) in good yields. The relative
configuration of 5a was ascertained by X-ray crystallographic
analysis and NOE analysis.
In summary, we have developed a mild and general copper-
catalyzed process for the facile construction of 2,3-substituted
cis-1-benzo[b]azepines with excellent diastereoselectivity via
NHC−Cu-catalyzed intramolecular borylative cyclization. This
process tolerates a broad range of functionalized aryl, alkyl,
heterocyclic aldimines, and various ketimines, providing rapid
access to 2,3-substituted cis-1-benzo[b]azepines. In this
diastereoselective protocol, a mixture of (E/Z)-dienyl arenes,
instead of pure dienyl arene could be used to deliver high
diastereoselectivity. Investigation of the asymmetric intra-
molecular cyclization is currently underway and will be
reported in due course.
Finally, asymmetric reactions were briefly investigated using
the Kundig-type NHC ligand, which previously has been
̈
reported to show high efficiency in copper-catalyzed
intermolecular allylations of imines (see Scheme 4).12d A 1:1
Scheme 4. Asymmetric Copper-Catalyzed Borylative
a
Cyclization
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03286.
a
Reactions were conducted on a 0.2 mmol scale. Yields of isolated
products are shown. The ee values were determined by HPLC
analysis.
Experimental procedures, characterization of products,
1
and copies of H and 13C NMR (PDF)
Accession Codes
mixture of (E/Z)-1a was converted to 2a in 85% yield and 20%
ee17 (eq 1 in Scheme 4). With pure (E)-1a, a similar yield was
obtained, but with an increased ee value (eq 2 in Scheme 4),
which indicated that the asymmetric cyclization was affected by
the E/Z ratio of dienyl arene, and the pure isomer could be
used for better chiral induction.
The proposed catalytic cycle is shown in Scheme 5. The
LCu−Bpin species (A) is generated from the reaction of
IMes−CuCl, base, and B2pin2. This species then undergoes
1,4-borylcupration with the mixture of (E/Z)-1,3-dienes 1 to
produce (Z)-σ-allylcopper intermediate B.18 The allylcopper B
CCDC 1863923 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jaesook@skku.edu.
C
DOI: 10.1021/acs.orglett.8b03286
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
H. Chem. - Eur. J. 2011, 17, 10081. (d) Liu, J.; Liu, Y. Org. Lett. 2012,
14, 4742. (e) Pagar, V. V.; Liu, R.-S. Angew. Chem., Int. Ed. 2015, 54,
4923. For Pd-catalyzed intramolecular cyclization, see: (f) Denis, J.
Jaesook Yun: 0000-0003-4380-7878
Notes
́
́
G.; Franci, G.; Altucci, L.; Aurrecoechea, J. M.; de Lera, A. R.; Alvarez,
R. Org. Biomol. Chem. 2015, 13, 2800.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by National Research Foundation
of Korea (NRF) grants (Nos. NRF-2016R1A2B4011719 and
NRF-2016R1A4A1011451), funded by the Korean govern-
ment (MEST). D.L. thanks the China Scholarship Council
(No. 201508260066).
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DOI: 10.1021/acs.orglett.8b03286
Org. Lett. XXXX, XXX, XXX−XXX