Access to different isomeric dibenzoxazepinones through copper-catalyzed C-H etherification and C-N bond construction with controllable smiles rearrangement

Article abstract of DOI:10.1021/acs.orglett.5b03378

An efficient new way to access two regio-isomeric dibenzoxazepinones is reported from 8-aminoquinoline benzamides and 2-bromophenols. Through choice of conditions, the reaction proceeds either through a sequential C-H etherification and subsequent Goldberg reaction, both controlled by the aminoquinoline group and Cu(I), or via a C-H etherification and subsequent Smiles rearrangement promoted by Cu(II) and t-BuOK. The 8-aminoquinoline moiety, e.g., 8-amino-5-methoxyquinoline, is readily removable from the structures of dibenzoxazepinones under moderate conditions.

Full text of DOI:10.1021/acs.orglett.5b03378

Letter
pubs.acs.org/OrgLett
Access to Different Isomeric Dibenzoxazepinones through Copper-
Catalyzed C−H Etherification and C−N Bond Construction with
Controllable Smiles Rearrangement
†
†
,†
†
†
‡
,‡,§
Yunfei Zhou, Jianming Zhu, Bo Li,* Yong Zhang, Jia Feng, Adrian Hall, Jiye Shi,*
,†
and Weiliang Zhu*
†CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, P. R. China
‡
UCB Biopharma SPRL, Chemin du Foriest, Braine-l’Alleud, Belgium
§
Kellogg College, University of Oxford, 60-62 Banbury Road, Oxford, OX2 6PN, United Kingdom
*
S Supporting Information
ABSTRACT: An efficient new way to access two regio-isomeric dibenzoxazepinones is reported from 8-aminoquinoline
benzamides and 2-bromophenols. Through choice of conditions, the reaction proceeds either through a sequential C−H
etherification and subsequent Goldberg reaction, both controlled by the aminoquinoline group and Cu(I), or via a C−H
etherification and subsequent Smiles rearrangement promoted by Cu(II) and t-BuOK. The 8-aminoquinoline moiety, e.g., 8-
amino-5-methoxyquinoline, is readily removable from the structures of dibenzoxazepinones under moderate conditions.
ver the past two decades, metal-catalyzed carbon−
(Scheme 1, eq 5), which is a further distinction to the work of
8c
O
hydrogen bond functionalization has attracted a lot of
Snieckus (eq 3). Thus, this new methodology allows access to
differently substituted dibenzoxazepinones from the same
starting materials, simply by modifying the reaction conditions.
We initiated our studies by screening the reaction of
benzamides containing different directing groups (Table 1, A,
B, C, D, and E) with 2-bromo-4-chlorophenol in the presence of
attention due to its ability to enable the direct introduction of
functionality to organic molecules, in an economical and efficient
1
manner. Recently, copperhas beenshown toplayanincreasingly
important role in this field, owing to its low-cost, abundance, and
2
environmentally benign nature. Combined with aromatic ortho-
3
C−H activation via a bidentate directing group strategy, copper
Cu (OH) CO as catalyst, K CO as base, and DMF as solvent.
2 2 3 2 3
has demonstrated a wide range of applications in the construction
To our surprise, the 8-aminoquinoline directing group gave not
only the expected Goldberg arylation product 7a but also the
rearrangedcompound8a,inwhichtheoxygenandchlorineatoms
have a meta-relationship (Table 1, entry 1). The structures of 7a
and 8a were unambiguously confirmed by X-ray crystallography
4
5
6
of C−O, C−S, and C−N bonds.
The dibenzoxazepinone scaffold is a promising bioactive
7
structure, and considerable effort has been expended on its
8
synthesis. One approach to construct the seven-membered ring
(
(
Supporting Information). However, alternative directing groups
substrates B, C, and D) gave unsatisfiedresults. No reaction took
of the dibenzoxazepinone employs the domino C−O coupling
and C−N bond formation via Smiles rearrangement (Scheme 1,
eqs 1−3). In addition, Du recently employed hypervalent
iodine(III)-mediated oxidative cyclization to access dibenzox-
place when naphthalene derivative (substrate E) was used,
indicating that coordination in an N,N′-fashion is essential to this
reaction. Cu(I) catalysts (Table 1, entries 3−5) showed exclusive
formation of7a, andCuI(entry5)gaveasuperior yieldoverother
Cu(I) catalysts (entries 3 and 4). Evaluation of the bases (entries
8
k
azepinone from 2-(aryloxy)benzamides (Scheme 1, eq 4).
2
However, allofthesestrategiesrequiretheβ-sp C−Hbondofthe
benzoic acid derivatives to be prefunctionalized with hydroxy or
8a
8
b,c,k
5
−8) revealed that K PO (entry 8) was optimal. Different
halide
(Scheme 1, eqs 1−4). Herein, we disclose a copper-
3
4
4a
solvents had an appreciable impact on reaction yield. Toluene
initiated aerobic oxidative C−H etherification assisted by the
removable directing group 8-aminoquinoline followed by C−N
bond formation to access different isomeric dibenzoxazepinones.
The formation of the different isomers, i.e., with or without a
Smiles rearrangement (Scheme 1, eqs 5 and 6), can be controlled
by choice of reaction conditions. The 8-aminoquinoline moiety
was found to be essential to enable the Goldberg reaction
(
(
entry 9), a nonpolar solvent, gave a poor yield, while acetonitrile
entry 12) gave a much higher yield (82%) than other polar
solvents (entry 8, 10, 11). Further attempts to improve the
Received: November 25, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Strategies for Dibenzoxazepinone
from binding to the 8-aminoquinoline directing group, thereby
interrupting the process of aerobic oxidative C−H etherification.
Thus, these results support the quinoline N atom of the 8-
aminoquinoline playing an essential role as a ligand to assist the
Goldberg amidation reaction. The optimal reaction conditions to
furnish the nonrearranged product 7a utilized 1 equiv of phenol
6
a and benzamide 5a, 3 equiv of K PO as base, and 20 mol % of
3 4
CuI catalyst in refluxing acetonitrile with air as oxidant.
Giventhereversalinselectivityhighlightedinentry2(Table1),
we deduced that a strong base should be necessary for the Smiles
rearrangementreactiontooccur(refertoSupportingInformation
for the optimization of the rearrangement reaction conditions).
Thus, at the end of the process of copper-catalyzed aerobic
oxidative C−H etherification (DMF as solvent, K CO as base,
2
3
copper acetate as catalyst, 74 °C), i.e., when the starting materials
were consumed, t-BuOK was added to facilitate the rearrange-
ment. These conditions led to exclusive formation of 8a in 73%
yield (Table 1, entry 13).
Returning to the nonrearranged product, to study the effect of
substitution on the benzamide moiety, we explored the
derivatives as shown in the Scheme 2. Introduction of electron-
Scheme 2. Copper-Catalyzed Nonrearrangement Reaction of
2
-Bromo-4-chlorophenol with 8-Aminoquinoline
a b
,
Benzamides
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
catalyst
base
solvent
DMF
7a
8a
1
2
3
4
5
6
7
8
9
Cu (OH) CO
K CO
10
5
15
25
0
2
2
3
2
3
Cu(OAc)2
K CO
DMF
2
3
3
3
3
Cu O
K CO
2
DMF
6
2
a
CuBr
CuI
K CO
2
DMF
9
0
Reaction conditions: 5 (0.2 mmol), 6a (0.2 mmol), copper iodide
(20 mol %), base (0.6 mmol), 74 °C for 0.5 h then reflux under 1 atm
K CO
2
DMF
25
28
4
0
b
CuI
Cs CO
2
DMF
0
for 4−8 h, open air. Isolated yield.
3
CuI
Na CO
2
DMF
0
3
CuI
K PO
DMF
55
10
40
35
82
0
0
donating groups (−Me, −OMe) made the yield of the target
products 7b−7d slightly lower than that of the derivatives 7f−7h
with election-withdrawing groups (−CF , −NO , −OCF ),
3
4
4
4
4
CuI
K PO
3
toluene
1,4-dioxane
DMSO
0
10
11
12
13
CuI
K PO
3
0
3
2
3
CuI
K PO
3
0
demonstratinggoodsubstratescope. Notably, anisonicotinamide
derivative was compatible with the reaction conditions, yielding
pyridyl amide derivative 7e. Substitution ortho to the benzamide
group, e.g., methyl, to give 7c was tolerated. Halides (fluorine,
chloride, and bromide) derivatives 7i−7k worked well. With
regard to the meta-substituted benzamides, cleavage of C−H
bond occurred para to the substituent to yield single regioisomers
c
CuI
K PO
3
CH CN
0
4
3
d
Cu(OAc)2
K CO
2
DMF
73
3
a
Reaction conditions: 5a (0.2 mmol), 6a (0.2 mmol), copper salts (20
b
mol %), base (0.6 mmol), 100 °C, 7−12 h, open air. Isolated yield.
c
d
7
4 °C for 0.5 h then reflux under 1 atm for 4−8 h. 74 °C for 5−10 h.
After 5a was consumed, t-BuOK was added.
7
f, 7g, and 7j. It is noteworthy that the 8-aminoquinoline group
reaction yield by adding ligands to chelate the copper failed
could be replaced by a 5-methoxy-8-amoinoquinoline, to afford
7la−7le in good yields (Schemes 2 and 3).
We also investigated the substrate scope with respect to 2-
bromophenols (Scheme 3). The reaction showed a broad scope,
electrondonating(Scheme3,7pand7q)andwithdrawinggroups
(Table S1, Supporting Information). It is noteworthy that
DMEDA (N,N′-dimethyl-1,2-ethanediamine) and picolinic acid,
the classic ligands in amidation, failed to yield any products. This
may be attributed to their ability to prevent the copper catalyst
B
DOI: 10.1021/acs.orglett.5b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Copper-Catalyzed Nonrearrangement Reaction of
N-(Quinolin-8-yl)benzamide with 2-Bromophenols
reaction conditions, potentially due to steric hindrance of the
phenol.
,
ab
To gain further insights into the mechanism of the reaction,
controlled experiments were performed (Scheme 5). We
Scheme 5. Controlled Experiments to Validate the Proposed
Mechanism
a
Reaction conditions: 5 (0.2 mmol), 6a (0.2 mmol), copper iodide
(
20 mol %), base (0.6 mmol), 74 °C for 0.5 h then reflux under 1 atm
b
for 4−8 h, open air. Isolated yield.
(
Scheme 3, 7r−7w) were both tolerated. In terms of
regiochemistry, substitution was acceptable in both the meta
and para positions relative to the phenolic oxygen. Notably 7v,
formed from 2-bromo-5-chlorophenol under nonrearrangement
reaction conditions, is identical tothe rearranged product 8afrom
successfully isolated and identified the postulated intermediate
M1 (Supporting Information). The assumption that M1 is an
intermediate was further supported by the fact that it could be
transformed into 7a in quantitative yield under the optimized
nonrearrangement reaction conditions (Scheme 5, eq 7).To
investigate the role of the 8-aminoquinoline moiety, we prepared
the ethylbenzamide analogue M2. Subjecting M2 to the optimal
nonrearrangement conditions failed to yield any nonrearranged
product (Scheme 5, eq 9). Under base-mediated copper-free
conditions (Scheme 5, eqs 8 and 10), M1 and M2 could be
transformed into the rearranged product respectively in
2
-bromo-4-chlorophenol (Scheme 1, eq 6), which further
confirms the regioselectivity of this reaction.
The scope of the rearrangement reaction was also studied, both
by varying the benzamide moiety, products 8b−8e, and the 2-
bromophenolmoiety,products8h−8k(Scheme4). Theseresults
further highlight the scope and utility of this methodology. Of
particular note is the naphthyl product 8i, the regioisomeric
derivative of which failed to be detected from nonrearrangement
8c
quantitative yield, which is consistent with Snieckus’s work.
Scheme 4. Copper-Catalyzed Rearrangement Reaction of 8-
Aminoquinoline Benzamides with 2-Bromophenols
,
a b
These results show that copper and 8-aminoquinoline are not
prerequisite for the rearrangement ring-closing reaction but are
essential to the nonrearrangement reaction. The ortho-blocked
benzamide 11 failed to generate Goldberg amidation product
(
Scheme 5, eq 11), supporting the hypothesis that the aerobic
oxidative C−H etherification should take place first in this
reaction.
Accordingly, the proposed mechanism of the reaction is
outlined in Scheme 6. The first step in both mechanisms is the
4a
aerobic oxidative C−H etherification to form intermediate M1.
Nonrearranged product 7a is then formed from M1 via a
Goldberg reaction assisted with 8-aminoquinoline chelating
Cu(I) at a higher temperature (82 °C). Alternatively, a moderate
temperature (74 °C) and Cu(II) guarantee the yield of M1 and
inhibit the cascade transformation of M1 into 7a. Then M1 is
converted to M3 through a base-mediated Smiles rearrangement
reaction, followed by cyclization to produce the rearranged
8c
a
product 8a.
Reaction conditions: 5 (0.2 mmol), 6 (0.2 mmol), copper acetate (20
Previous work has reported a modified 8-aminoquinoline
mol %), K CO base (0.4 mmol), open air, DMF solvent (5 mL), 74
2
3
°C. After 5 was consumed, t-BuOK (0.2 mmol) was added to the
auxiliary, 8-amino-5-methoxyquinoline, which can be easily
b
3e
mixture at room temperature. Isolated yield.
removed. Thus, we sought to ascertain if these derivatives
C
DOI: 10.1021/acs.orglett.5b03378
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 6. Plausible Reaction Mechanism
*E-mail: jiye.shi@ucb.com.
E-mail: wlzhu@simm.ac.cn.
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NNSF (81273435 and 81302699),
National Science & Technology Major Project (2013ZX0910-
■
3
0
001-001), Ministry of Science and Technology (2012AA-
1A305), Natural Science Foundation of Shanghai, China
(
14ZR1447800), and The State Key Laboratory of Natural and
Biomimetic Drugs (K20150205).
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3
1
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regioselective reaction that provides a general route to two
isomeric dibenzoxazepinones. The 8-aminoquinoline moiety is
found to actually play a double role to facilitate the reactions, not
only for C−H activation but also for the Goldberg coupling as a
ligand to ensure the nonrearrangement transformation. This
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ASSOCIATED CONTENT
Supporting Information
■
*
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.5b03378.
Experimental procedures, characterization data of new
compounds, and copiesof Hand CNMRspectra (PDF)
Crystallographic data (CIF)
1
13
1
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(j) Yang, Q.; Cao, H.; Robertson, A.; Alper, H. J. Org. Chem. 2010, 75,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: boli@simm.ac.cn.
D
DOI: 10.1021/acs.orglett.5b03378
Org. Lett. XXXX, XXX, XXX−XXX