Palladium-catalyzed tandem reaction of o-aminophenols, bromoalkynes and isocyanides to give 4-amine-benzo[b][1,4]oxazepines

Article abstract of DOI:10.1039/c2cc35802f

A robust route to 4-amine-benzo[b][1,4]oxazepines relying upon a palladium-catalyzed tandem reaction of o-aminophenols, bromoalkynes and isocyanides has been developed. This chemistry presumably proceeds through the migratory insertion of isocyanides into the vinyl-palladium intermediate as a key step.

Full text of DOI:10.1039/c2cc35802f

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COMMUNICATION
Palladium-catalyzed tandem reaction of o-aminophenols, bromoalkynes
and isocyanides to give 4-amine-benzo[b][1,4]oxazepinesw
Bifu Liu, Yibiao Li, Meizhou Yin, Wanqing Wu and Huanfeng Jiang*
Received 10th August 2012, Accepted 6th October 2012
DOI: 10.1039/c2cc35802f
A robust route to 4-amine-benzo[b][1,4]oxazepines relying upon
a palladium-catalyzed tandem reaction of o-aminophenols,
bromoalkynes and isocyanides has been developed. This chemistry
presumably proceeds through the migratory insertion of isocyanides
into the vinyl-palladium intermediate as a key step.
Scheme 1 Initial retrosynthetic analysis of 4-amine-benzo[b]-
N-Heterocycles represent a long sought after target because a
[1,4]oxazepines 1.
number of biological activities have been conferred to them
and they are common components of many natural products,
pharmaceuticals and agrochemical products.1 Among them,
building blocks in the construction of structurally appealing
N-containing heterocycles,8 however, transition metal-catalyzed
significant interest has been increased in seven-membered
multicomponent tandem reactions involving isocyanides are
heterocyclic rings, as these structural units widely exist in
relatively undervalued.9 Based on our previous studies in
bromoalkynes7a–d,10 and isocyanides,7d,11 we envisaged that a
palladium-catalyzed tandem reaction of o-aminophenols 2,
bromoalkynes 3, and isocyanides 4 would allow an efficient
access to 4-amine-benzo[b][1,4]-oxazepines 1 by selective C–O
and C–N bond-forming events (Scheme 1). To the best of our
knowledge, this catalytic version has not yet been reported.
Herein, we disclose a robust route to construct a series of
4-amine-benzo[b][1,4]oxazepines in a rapid and convenient manner
via a palladium-catalyzed tandem reaction of o-aminophenols,
bromoalkynes and isocyanides.
numerous natural products2 and various biologically interesting
molecules.3 Benzooxazepine derivatives are very important
kinds of the seven-membered rings and the core scaffolds in
medicinal chemistry with remarkable biological activities and
pharmaceutical interest.4 The fascinating biological profiles of
this group of compounds stimulated researchers to explore
efficient methods for the synthesis of benzooxazepines and their
structural analogues.5 Unfortunately, the major drawback of
the reported methods is their multistep synthesis, which usually
hinder them from constructing a large number of structural
derivatives of these heterocycles.5a Thus, the development of
new methodologies for the efficient synthesis of this type of
skeleton is highly desired.
To our delight, the palladium-catalyzed tandem reaction of
o-aminophenols, bromoalkynes and isocyanides afforded
good to excellent yields of functionalized 4-amine-benzo[b]-
[1,4]oxazepines (Scheme 2). For instance, 2-aminophenol (2a),
phenylethynyl bromide (3a) and tert-butylisocyanide (4a) were
allowed to react in the presence of Cs2CO3 (2.0 equiv.) in 1,
4-dioxane at 80 1C for 2 h, affording 86% yield of the desired
product 5 (Scheme 2, 5).12 With this result in hand, we next
investigated the scope of the reaction using different kinds of
bromoalkynes, o-aminophenols and isocyanides (Scheme 2).
Gratifyingly, aromatic alkynylbromides with either an electron-
donating (6–11) or electron-withdrawing (12–17) group on the
benzene ring could be smoothly transformed into the desired
products in good to excellent yields. Interestingly, halogen
atoms (–Cl, –Br) on the aromatic ring were inert in this reaction,
allowing them to be used for further transformation (13–16).
It is noteworthy that heteroaromatic alkynylbromide such as
2-(bromoethynyl)thiophene was also compatible with the reaction
conditions and generated the corresponding product 18 in 85%
yield. Alkynyl bromide such as 5-chloropentynyl bromide could
also undergo the same transformation but gave the desired product
Haloalkynes are attractive starting materials and important
intermediates in organic synthesis because they are highly
reactive and easily prepared from terminal alkynes.6 Recently,
we and other groups have revealed that certain nucleophiles,7 such
as halide ions (FÀ, IÀ),7a,b acetic anions (OAcÀ),7c isocyanides,7d
phenols,7e thiols,7f imidazoles,7g,h and sulfonamides7i,j could easily
undergo nucleophilic addition to haloalkynes, which generated
corresponding (Z)-2-bromoalkenes. More importantly, the (Z)-
2-bromoalkenes obtained by these reactions are important
precursors and have been explored in the synthesis of useful
heterocycles.7c–e,i,j Isocyanides have been recognized as powerful
School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou, 510640, China.
E-mail: jianghf@scut.edu.cn; Fax: +8620-87112906;
Tel: +8620-87112906
w Electronic supplementary information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
spectra for isolated compounds. See DOI: 10.1039/c2cc35802f
c
11446 Chem. Commun., 2012, 48, 11446–11448
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Scheme 3 Investigation of the reaction mechanism.
When 2a and 3a were treated in 1,4-dioxane using Cs2CO3
(2.0 equiv.) as base, only 10% of the desired nucleophilic
addition product (Z)-2-((2-bromo-1-phenylvinyl)oxy)aniline
(36) was obtained even the reaction time was prolonged to
12 h (Scheme 3, eqn (a)).13 However, when 36 and 4a were
carried out under the optimized reaction conditions, 91% of
the desired product 5 was obtained (Scheme 3, eqn (b)). These
experimental results revealed that this reaction proceeded
through the cis-nucleophilic addition of o-aminophenols to
bromoalkynes, and then the migratory insertion of isocyanides
into the vinyl-palladium intermediate. We presumed that, for
the palladium-catalyzed tandem reaction, the consumption of
36 in the second step obviously promoted the generation of the
36 in the first step.
On the basis of these preliminary results and the control
experiments conducted, a possible catalytic cycle involved in
the present process was outlined in Scheme 4. Initial nucleo-
philic addition of o-aminophenols (2) to bromoalkynes (3)
gave the intermediate A, which underwent oxidative addition
to Pd(0) species to generate a vinyl palladium species B.
Subsequent migratory insertion of isocyanide (4) would result
in the formation of intermediate C.14 With the aid of the base,
hydrogen bromide was extruded out of C to generate the eight-
membered azapalladacyclic intermediate D. Finally, reductive
elimination afforded E, regenerating the Pd(0) catalyst.
Immediately, the unstable product E isomerized to give the
final product F.
Scheme 2 Palladium-catalyzed tandem reaction of o-aminophenols 2,
bromoalkynes 3, and isocyanides 4.a
19 in 47% yield. Next, various substituted o-aminophenols were
also applied to this process under the optimized reaction
conditions (20–27). As can be seen from Scheme 2, the reactivity
of phenols with an electron-withdrawing group (23–27), such as
–F, –Cl, or –NO2, was much higher than that of the phenols
without a substituent or with an electron-donating group (20–22).
Additionally, 3-amino-2-naphthol (28) and 3-amino-2-pyridinol
(29) could be also employed in this transformation affording the
expected products in 88% and 91% yields, respectively. Unfortu-
nately, no reaction occurred when 2-amino-3-pyridinol (30) or
2-aminothiophenol (31) was employed in this transformation.
Finally, various alkyl, cycloalkyl, and aryl isocyanides were also
applied to probe the scope of the reaction substrates (32–35).
Generally, when alkyl and cycloalkyl isocyanides, even if sterically
bulky isocyanides such as 1,1,3,3-tetramethylbutyl isonitrile (32)
were used, the reaction gave the corresponding products in good
yields. However, when 2,6-dimethylphenyl isocyanide was applied
in this process under the optimized reaction conditions, the desired
product was detected by GC-MS, but was complicated and failed
to obtain the pure product (35).
To gain insight into the mechanism of the reaction, several
control experiments were conducted as shown in Scheme 3.
Scheme 4 A plausible reaction mechanism.
c
This journal is The Royal Society of Chemistry 2012
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In conclusion, we have demonstrated a novel and straight-
forward procedure for the synthesis of a new class of substituted
4-amine-benzo[b][1,4]oxazepines via palladium-catalyzed three-
component tandem reaction of bromoalkynes, o-aminophenols
and isocyanides. The reaction was successful with a variety of
bromoalkynes, o-aminophenols and smoothly converted to the
desired product in good to excellent yields. Most importantly,
this reaction may be applied to the construction of some
important benzo[b][1,4]oxazepine derivatives as effective pharma-
ceutical compounds with various biological activities.
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We thank the National Natural Science Foundation of
China (20932002 and 21172076), National Basic Research
Program of China (973 Program) (2011CB808600), Guang-
dong Natural Science Foundation (10351064101000000) and
the Fundamental Research Funds for the Central Universities
(2010ZP0003) for financial support.
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12 See ESIw for optimization of reaction conditions.
13 In order to perform the control experiments (Scheme 3, eqn (b))
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c
11448 Chem. Commun., 2012, 48, 11446–11448
This journal is The Royal Society of Chemistry 2012