A highly-efficient palladium-catalyzed aminocarbonylation/SNAr approach to dibenzoxazepinones

Article abstract of DOI:10.1039/c5gc00427f

A convenient procedure for the synthesis of dibenzoxazepinones has been developed. Utilizing the protocol of one-pot palladium-catalyzed aminocarbonylation/aromatic nucleophilic substitution (S_NAr) sequence, with 2-aminophenols and 2-bromofluorobenzenes as the substrates, the desired dibenzo[b,e][1,4]oxazepin-11(5H)-ones were prepared in moderate to excellent yields. The broad substrate scope and functional group tolerance of the reaction makes this approach a practical method for the synthesis of valuable dibenzoxazepinone and its derivatives. Mechanistic studies suggest that aminocarbonylation proceeds prior to S_NAr.

Full text of DOI:10.1039/c5gc00427f

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ARTICLE TYPE
Highly-Efficient Palladium-Catalyzed Aminocarbonylation/S Ar
N
Approach to Dibenzoxazepinones
[a]
Chaoren Shen, Helfried Neumann and Xiao-Feng Wu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A convenient procedure for the synthesis of dibenzoxazepinones has been developed. Utilizing the
protocol of one-pot palladium-catalyzed aminocarbonylation/aromatic nucleophilic substitution (S Ar)
N
sequence, with 2-aminophenols and 2-bromofluorobenzenes as the substrates, the desired
dibenzo[b,e][1,4]oxazepin-11(5H)-ones were prepared in moderate to excellent yields. The broad
substrate scope and functional group tolerance of the reaction makes this approach a practical method for
the synthesis of valuable dibenzoxazepinone and its derivatives. Mechanistic studies suggest that
1
0
aminocarbonylation proceeds prior to S Ar.
N
Introduction
Seven-membered heterocycles are receiving continuing attention
as their skeletons are widely present in numerous pharmaceuticals
1
2
2
3
3
4
4
5
0
5
0
5
0
5
[
1]
and natural products.
Among these seven-membered
heterocycles, dibenzo[b,e][1,4]oxazepin-11(5H)-one derivatives
represents a class of versatile compounds owing to their
promising pharmaceutical and biological activities, including
Figure 1. Selected antidepressant drugs with dibenzoxazepinone skeleton.
[
2]
[3]
In transition metal-catalyzed transformations, palladium-
catalyzed carbonylations have already become a true toolbox in
modern organic synthesis. Since the seminal work of Heck and
HIV-1 RT inhibition, H R agonist, antidepressant (Figure 1),
4
[
4]
[5]
[6]
5
5
6
6
7
7
0
5
0
5
0
5
anti-psychotic,
anti-tumor,
antioxidant
and anti-
[
7]
inflammatory activities. Motivated by the importance of these
compounds, many procedures have been developed for their
preparation. Since the first report on the synthesis of
dibenzoxazepinone derivatives in 1964, conventional routes to
dibenzoxazepinones and their derivatives usually involve
classical, several steps procedure through the intermolecular
cyclization of ortho-aminophenols with ortho-halogen benzonic
[
20]
co-workers in 1974, impressive progress has been achieved in
palladium-catalyzed carbonylation reactions after 40 years’
[
21]
[
8]
development.
Through palladium-catalyzed carbonylations,
carbon monoxide (CO), one of the cheapest C1 sources, can be
installed into the parent molecules. In this way, synthetically
important and valuable carbonyl-containing compounds are
readily accessible, which can be submitted for further
modifications. Based on our continual interest concerning
[
3,9]
[10]
acids
or ortho-nitro benzonic acids , or through reduction-
[
11]
lactamization sequence, Among these routes, the isolation of
intermediates and severe conditions (usually involving strong
inorganic bases and harsh reaction conditons) are two obstacles to
high efficiency and wide functionality tolerance. Although a
series of alternative protocols such as intramolecular Friedel–
[
22]
palladium-catalyzed carbonylative synthesis of heterocycles
and the fusion of carbonylation and nucleophilic substitution
[
23]
reactions,
we intended to develop a facile one-pot protocol
with mild conditions for the preparation of dibenzoxazepinones
from readily available reagents in virtue of palladium-catalyzed
aminocarbonylation and aromatic nucleophilic substitution
[
12]
[13]
[15]
[17]
Crafts acylation, oxidation of dibenzo(b,f)(1,4)-oxazepines,
[
14]
Beckmann rearrangement,
Smiles rearrangement,
palladium-catalyzed C-N cross coupling
Ugi four-component reaction,
Ru-catalyzed C-H hydroxylation,
(
SNAr).
[
16]
[
18]
and palladium-
Results and Discussion
[
19]
catalyzed intramolecular carbonylation have been described to
prepare dibenzoxazepinones, their substrates need to be prepared
beforehand. Thus it can be seen that developing general and
highly-efficient access to dibenzoxazepinones from commercially
available reagents still remains a challenge and interesting topic
for organic synthesis.
Initially, 2-bromofluorobenzene (1a) and 2-aminophenol (2a)
were selected as the model substrates to optimize the reaction
conditions (Table 1). A preliminary study was carried out on a
0
.5 mmol scale at 120 ⁰C in DMAc, using BuPAd as the ligand
2
and DBU as the base, affording 3a in 75% isolated yield (Table 1,
entry 1). Based on this preliminary result, further investigation on
solvents, bases, temperatures, reaction time, catalyst loading and
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CO pressure were conducted. Among the tested common polar
aprotic solvent (Table 1, entries 2, 3, 4, and 5), we found the best
yield was achieved in DMSO and the reaction time can be
shortened to 24 hours. Non-polar aprotic solvents such as 1,4-
dioxane and toluene are not suitable for this reaction (Table 1,
entries 6 and 7). This can be rationalized by the fact that
difluoromethyl or acetyl (all commercially available), which is
incompatible with strong basic conditions, at various positions
were tolerated and the desired dibenzoxazepinones were
obtained in moderate to good yields (3b-3j). It is noted that the
electron-withdrawing carbonyl group in the product 3h and 3i
has no activating effect to the fluorine and chlorine at para-
5
0
5
0
[
23]
intramolecular or intermolecular S 2 substitution is more
position.
antidepressant drug Loxapine and Amoxapine.
when this protocol was applied to
The reaction product 3d is the precursor of
N
23]
[
[3,8c]
favoured in the polar aprotic solvent. Then two other kinds of
organic tertiary amines were applied as bases (Table 1, entries 8
and 9), and no better performance was found than DBU. The
similar effect was observed when inorganic base K CO was used
However
3-bromo-4-
1
1
2
fluorobenzenesulfonamide, no corresponding product (3k) was
observed, although the substrate was consumed.
2
3
(Table 1, entry 10), which was probably due to the poor solubility
of K CO in DMSO. No dibenzo[b,e][1,4]oxazepin-11(5H)-one
[a]
2
3
Table 2. Substrate scope of 2-bromofluorobenzenes.
was observed when BuPAd was replaced with DPPP in MeCN
2
solution (detailed results in Table S1 of Supporting Information).
[
25]
This phenomena resembles
a
recent report.
Reducing
palladium catalyst loading or lowering CO pressure result in a
drop in yield; decreasing the reaction temperature also resulted in
the yield decline (detailed results in Table S1 of Supporting
Information).
3
b, 77%
3c, 74%
3f, 84%
3d, 90%
[a]
Table 1. Optimization of reaction conditions.
3
e, 92%
3g, 67%
[
b]
3h, 76%
3i, 75%
3j, 74%
Entry
CO (bar)
10
Base
DBU
Solvent
Yield
[
c]
1
2
3
4
5
6
7
8
9
DMAc
DMF
78 (75)
10
DBU
34
3k, 0%
a
10
DBU
NMP
58
All reactions were conducted under conditions: 1 (0.5 mmol), 2a (0.5
mmol), DBU (1.5 mmol), 2 mol% Pd(OAc) , 6 mol% BuPAd , DMSO
(2.0 mL), 10 bar CO, 120 ⁰C and 24 h. Yield of the isolated product.
2
2
10
DBU
DMSO
MeCN
86 (82)
25
2
3
3
5
0
5
10
DBU
Then the scope of substituted 2-aminophenols were
investigated (Table 3). Compared with the results of 4 or 5-
methyl substituted 2-aminophenol (3l, 3m), the yield of reaction
with 3-methyl substituted 2-aminophenol (3n) was lower, which
10
DBU
1,4-dioxane
toluene
DMSO
19
10
DBU
0
can be attributed to the steric hindrance that has been previously
10
DABCO
DIPEA
51
[27]
reported.
The 2-aminophenols bearing electron-withdrawing
groups are tolerated (3o, 3p). However when the secondary
aniline 2-(phenylamino)phenol was employed, no desired product
q was formed. This also can be explained by crowed
environment on the nitrogen atom and also the stability and
therefore lack of reactivity of the in situ formed N-Ph anion.
10
DMSO
70
10
10
K
2
CO
3
DMSO
43
3
[
a] Unless otherwise stated, the reaction was conducted on 0.50 mmol
scale (2mol% Pd(OAc) , 6 mol% BuPAd , 0.50 mmol of 1a, 0.50 mmol
of 2a, 1.5 mmol base) with 2.0 mL solvent. Reaction temperature was
20 ⁰C. Reaction time was 24 h. [b] Yields were determined by GC with
2
2
1
[a]
Table 3. Substrate scope of 2-aminophenols.
hexadecane as an internal standard; yields in parentheses are for the
isolated product. [c] Reaction time was 32 h. Ad = adamantyl, Bu = n-
butyl, DABCO =1,4-diazabicyclo[2.2.2]octane, DBU
=
1,8-
diazabicyclo[5.4.0]undec-7-ene, DIPEA = N,N’-diisopropylethylamine,
DMAc = N,N-dimethylacetamide, DMF = N,N-dimethylformamide,
DMSO = dimethyl sulfoxide, NMP = N-methyl-2-pyrrolidone.
With the optimized reaction conditions in hand, we further
investigated the substrates scope of this procedure. Several
substituted 2-bromofluorobenzenes were subjected to the
optimized conditions described above. As shown in Table 2, a
range of 2-bromofluorobenzene possessing methyl, halogen,
3l, 80%
3n, 71%
3m, 82%
2
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3au, 79%
3o, 77%
3p, 82%
3q, 0%
3as, 60%
3at, 0%
[
a] All reactions were conducted under conditions: 1 (0.5 mmol), 2 (0.5
mmol), DBU (1.5 mmol), 2 mol% Pd(OAc) , 6 mol% BuPAd , DMSO
2.0 mL), 10 bar CO, 120 ⁰C and 24 h. Yield of the isolated product.
2
2
(
3
av, 77%
ay, 75%
3ax, 69%
3
aw, 79%
5
0
5
To prove the broad-spectrum on substrates of this protocol,
combinatorial reactions of various substituted 2-aminophenols
with various substituted 2-bromofluorobenzenes were conducted
Table 4). As shown in Table 4, except two examples 3aj and
at, moderate to good yields were achieved for the other
substituted 2-aminophenols and substituted 2-
3
3
az, 80%
3ba, 80%
(
3
1
bromofluorobenzenes. It shows that the protocol has good
tolerance to diverse functional groups at different position of the
dibenzoxazepinone motif. Among these products, some of them
such as 3u, 3z, 3ao and 3at may potentially be applied as
3
bc, 72%
3bd, 71%
3
bb, 81%
[
3]
1
intermediates to prepare some analogues of Clozapine.
3bf, 78%
3
be, 73%
3bg, 80%
Table 4. Reaction of substituted 2-aminophenols with substituted 2-
[
a]
bromofluorobenzenes.
3bi, 71%
3bj, 68%
3bh, 69%
[
a] All reactions were conducted under conditions: 1 (0.5 mmol), 2 (0.5
mmol), DBU (1.5 mmol), 2 mol% Pd(OAc) , 6 mol% BuPAd , DMSO
2.0 mL), 10 bar CO, 120 ⁰C and 24 h. Yield of the isolated product.
20
2
2
(
Considering that to date, to the best of our knowledge, there
are only several reported examples involving Pd-catalyzed
aminocarbonylation of aryl halides with secondary amine for the
25
[
27,28]
preparation of tertiary amides
and only two examples for
3
r, 79%
u, 88%
3t, 69%
[28a]
aminocarbonylation of aryl bromide with N-methyl aniline,
3
s, 82%
aminocarbonylation of aryl bromide with N-alkyl aniline is still a
challenging issue. So we selected 2-(methylamino)phenol as
nucleophilic reagent to further extend the scope of reaction
substrates (Table 5). To our delight, the reactions between 2-
30
3
3v, 83%
3w, 81%
3z, 80%
(methylamino)phenol 4 and some electron-withdrawing group
substituted 2-bromofluorobenzenes 1 proceeded smoothly to give
the desired products in moderate yields (5a, 5b, 5c).
3y, 72%
3
x, 87%
35
Table 5. Reaction of substituted 2-aminophenols with 2-
[a]
(methylamino)phenol.
3
aa, 85%
3ab, 81%
3ae, 83%
3
ac, 77%
3
ad, 64%
ag, 77%
3af, 90%
3
3
ai, 63%
3ah, 81%
5a, 60%
5b, 54%
5c, 62%
[
a] All reactions were conducted under conditions: 1 (0.5 mmol), 4 (0.5
, 6 mol% BuPAd , DMSO
mmol), DBU (1.5 mmol), 2 mol% Pd(OAc)
2
2
3
aj, 0%
3al, 86%
3ao, 87%
40 (2.0 mL), 10 bar CO, 120 ⁰C and 24 h. Yield of the isolated product.
3
ak, 64%
Finally, in order to clarify the sequence of this palladium-
catalyzed aminocarbonylation and aromatic nucleophilic
substitution reactions and propose a plausible mechanism, some
3an, 64%
3
am, 80%
45
control experiments based on the model reaction were conducted
Scheme 1). Under the optimized conditions without Pd-catalyst,
(
no reaction product 7 or 8 was detected and no conversion of both
substrates was observed (Scheme 1a). It indicates that Pd-
3ap, 85%
3aq, 83%
3ar, 80%
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catalyzed aminocarbonylation occurs prior to the aromatic
nucleophilic substitution. Therefore we inferred that 2-fluoro-N-
2-hydroxyphenyl)benzamide should be the plausible
Acknowledgements
(
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF), and the
Deutsche Forschungsgemeinschaft for financial support. Thanks
also go to China Scholarship Council (CSC) for their financial
support to C. Shen (No. 201406230040). We also thank Dr. C.
Fischer, S. Schareina, and Dr. W. Baumann for their excellent
technical and analytical support. We also appreciate the general
support from Prof. Matthias Beller.
intermediate of reaction. Although some measures to obtain the
intermediate including reducing the catalyst loading, lowering
temperature, changing base and shortening reaction time were
taken for detecting the in-situ generated amide intermediate， the
amide intermediate was not observed by GC and GC-MS
analysis. Then the plausible amide 9 intermediate was prepared
5
0
5
4
5
[
3]
1
according to the literature method. As expected, the amide 9
was converted to the product under the conditions without the Pd-
catalyst (Scheme 1b), which not only indirectly confirms that the
amide 9 is the reaction intermediate, but also proves that DBU
50
General Considerations
NMR spectra were recorded on a 300 MHz spectrometer at 295 K
plays as base both in the aminocarbonylation and in the S Ar.
N
in CDCl or DMSO. Chemical shifts (parts per million) are given
3
1
1
relative to solvent. References for CDCl were 7.26 ppm ( H
3
1
3
55
NMR) and 77.00 ppm ( C NMR); references for [D ]DMSO
6
1
13
were 2.50 ppm ( H NMR) and 40.00 ppm ( C NMR). High-
resolution mass spectrometry (HRMS) was performed using an
ESI-TOF/MS instrument. The products were isolated from the
reaction mixture by column chromatography on silica gel 60
(0.063−0.2 mm, 70−230 mesh).
60
Scheme 1. Control experiments.
Based on the results of control experiments, a plausible
mechanism is given in Scheme 2. Firstly, acylpalladium species
is formed from 2-bromofluorobenzene through oxidative addition
with Pd(0). Subsequently, the amide intermediate is generated
from the reaction between 2-aminophenol and acylpalladium
complex. Finally, under the basic conditions, the fluorine atom
acts as a leaving group with the help of the carbonyl group at
Representative procedure for the synthesis of
dibenzoxazepinones
2
0
A vial (6 mL) was charged with Pd(OAc) (2 mol%), BuPAd (6
2
2
6
7
7
5
0
5
mol%), 2-aminophenol (0.5 mmol) and a magnetic stirring bar.
Then, 1-bromo-2-fluorobenzene (0.5 mmol), DBU (3.0 equiv),
and DMSO (2.0 mL) were injected under argon by syringe. The
vial (or several vials) was placed in an alloy plate, which was
transferred into a 300 mL autoclave of the 4560 series from Parr
Instruments under argon atmosphere. After flushing the autoclave
three times with CO, a pressure of 10 bar of CO was adjusted at
ambient temperature. Then, the reaction was performed for 24 h
at 120⁰C. After the reaction was complete, the autoclave was
cooled down with ice-water mixture to room temperature and the
pressure was released carefully. The solution was diluted with
ethyl acetate and then silica gel was added into the solution. After
evaporation of the organic solvent, the crude product was purified
by column chromatography using ethyl acetate/n-pentane.
2
5
ortho-position and the S 2 type aromatic nucleophilic
N
substitution occurs and the product is formed.
Notes and references
a
8
8
0
5
Leibniz-Institut für Katalyse an der Universität Rostock e.V. Albert-
Einstein-Str. 29a, 18059 Rostock (Germany);
E-mail: xiao-feng.wu@catalysis.de
†
3
0
Scheme 2. Proposed Reaction Mechanism.
Electronic Supplementary Information (ESI) available: [reaction
procedure and analytic data]. See DOI: 10.1039/b000000x/
Conclusions
[
[
1]
2]
J. H. Ryan, J. L. Green, C. Hyland, J. A. Smith, C. C. Williams.
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available starting materials has been developed. In the presence
of palladium catalyst and base, with 2-fluorobromobenzenes and
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N
4
0
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