Palladium-catalysed regioselective: N -arylation of anthranilamides: A tandem route for dibenzodiazepinone synthesis

Article abstract of DOI:10.1039/c9nj00539k

A palladium-catalyzed domino approach to the synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones from 2-aminobenzamides and 1,2-dihaloarenes has been developed. Our strategy integrating double N-arylations (inter- and intra-molecular) of 2-aminobenzamides with 1,2-dihaloarenes under palladium-catalyzed conditions is clearly distinct from the current literature available for the synthesis of dibenzodiazepinones. Unlike a previous report described for regioselective N-arylation of 2-aminobenzamide at the amine group, our mechanistic studies support the regioselective N-arylation of 2-aminobenzamide occurring first primarily at the amide group. The translational application of our protocol may be demonstrated in the synthesis of a marketed drug, clozapine.

Full text of DOI:10.1039/c9nj00539k

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The role of atropisomers on the photo-reactivity and fatigue of
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Palladium-catalysed regioselective N-arylation of
anthranilamides: A tandem route for dibenzodiazepinone
synthesis
Received 00th January 20xx,
Accepted 00th January 20xx
Joydev K. Laha,* Neelam Manral, and Mandeep Kaur Hunjan
DOI: 10.1039/x0xx00000x
www.rsc.org/
A palladium-catalyzed domino approach to the synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones from 2-
aminobenzamides and 1,2-dihaloarenes has been developed. Our strategy integrating double N-arylations (inter- and
intra-molecular) of 2-aminobenzamides with 1,2-dihaloarenes under palladium-catalyzed condition is clearly distinct from
the current literature available for the synthesis of dibenzodiazepinones. Unlike a previous report described for
regioselective N-arylation of 2-aminobenzamide at amine group, our mechanistic studies support regioselective N-
arylation of 2-aminobenzamide occurs first primarily at the amide group. The translational application of our protocol may
be
demonstrated
to
the
synthesis
of
a
marketed
drug,
clozapine.
the condensation and in situ cyclization of the reaction of o-
phenylenediamine and substituted isatoic anhydrides to give
diabenzodiazepinone.12 Remarkably, palladium catalyzed
reactions for the synthesis of diabenzodiazepinone remains
under developed.
Introduction
10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepinones
are
particularly an important class of nitrogen heterocycles
exhibiting considerable pharmaceutical applications as
antipsychotic, anti-anaphylatic, and anxiolytic agents.1
Dibenzodiazepinones have been known to act as histone
deacetylase inhibitor,2 and Chk1kinase inhibitor.3 The scaffold
has emerged as a key component of various antipsychotic
drugs, e.g.; clozapine, dibenzepin, pirenzepine, etc.4 In
particular, clozapine has gained attention over the years due
to lack of its extrapyramidal side effects, and for treating the
patients with drug resistant schizophrenia.5
In 2011, Buchwald et al. reported the reaction of 2-
aminobenzophenone and 2-bromochlorobenzene in the
Previous work:
Giani et al.
NH2
NH2
HOOC
+
O
X
X
NH2
NH2
Br
O2
NH2
EtO
Cu-catalyzed
+
+
O
N
COOH
Cu-catalyzed
Cu-catalyzed
NH
Yin et al.
Hanze et al.
Reported routes for dibenzodiazepinones largely rely on the
N
formation of a key lactam intermediate (Scheme 1).6,7 In 1963,
NH2
X
Cu-catalyzed
NH2
H
N
H
O
H
N
+
OH
O
Pd-catalyzed
Hanze et al. reported
a
multi-step synthesis of
NH2
+
O
O
EtO
O
dibenzodiazepinone from anthranilic acid and 2-
bromonitrobenzene in the presence of a copper-catalyst
leading to overall poor yield of dibenzodiazepinone.8 Giani et
al.9 and Yin et al.10 independently reported the synthesis of
dibenzodiazepinone from o-phenylenediamine and 2-
halobenzoates or o-halobenzoic acid in the presence of a
copper-catalyst. Yue et al. disclosed the synthesis of
diabenzodiazepinone from aniline and (2-halo-5-chlorophenyl)
amino acid using a copper-catalyst.11 Meshram et al. reported
Cl
H
Cl
Meshram et al.
Yue et al.
N
Buchwald et al.
Present work:
O
R2
O
O
NH
X
Y
NH2
Domino process
Pd-catalyzed
N
+
Y
R2
Y
H
NH2
X
R
X
N
R1
NH2
R1
H
R1
X = I, Br, Cl, F Y = CH, N
Scheme 1:- Approaches for the synthesis of dibenzodiazepinones
Department of Pharmaceutical Technology (Process Chemistry),
National Institute of Pharmaceutical Education and Research,
S. A. S. Nagar, Punjab 160062,
India
Email: jlaha@niper.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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presence of a palladium-catalyst to form diarylamine, which Reaction conditions: 2-aminobenzamide 1a (0.5 mmol), 1,2-dibromobenzene 2a (0.5 mmol),
upon further reaction gave dibenzodiazepinone.13 While some Pd(OAc)2 (10 mol%), ligand (20 mol%), base (3 equiv.), solvent (1 mL), 110 oC, 24 h
copper-catalyzed, especially tandem reactions have certain
advantages, a palladium-catalyzed domino reaction to the Heating 2-aminobenzamide and 1,2-dibromobenzene in the
synthesis of dibenzodiazepinones from readily available presence of Pd(OAc)2, rac-BINAP, and K2CO3 in toluene at 110
6
7
8
9
starting material is yet to be realized. While N-arylation of
℃ for 24 h did not result in the formation of any cyclized
anilines14 and benzamides15 using aryl halides have been product (Table 1, Entry 1). Likewise, a different ligand PPh3
studied well both under palladium-16 or copper-catalysis,17 and base NaOBu-t also proved to be ineffective (Entry 2).
regioselective N-arylation of 2-aminobenzamides that contain Changing the base from NaOBu-t to K2CO3 also did not result in
both the functional groups has been the subject of least the formation of the cyclized product (Entry 3). However,
investigation. Buchwald et al. has shown that regioselective N- another ligand PCy3
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arylation of 2-aminobenzamides with bromobenzene could
occur at amine group under palladium catalysis and at amide
group under copper-catalysis.18 Subsequently, Lui et al.
reported N-arylation at amine group (a reverse
regioselectivityto that observed in Buchwald’s reaction under
copper-catalysis) in the reaction of 2-aminobenzamide and
arylboronic acid under copper-catalysis.19 Inspired by these
two reports and our own interest in the domino reactions to
the synthesis of nitrogen heterocycles,20 we envisaged that
regioselective sequential double N-arylations of 2-
aminobenzamide with 1,2-dibromobenzene could give
dibenzodiazpinone.
O
O
Pd(OAc)2 (10 mol%)
S-Phos (20 mol%)
NH
Br
X
NH2
+
R1
R2
K2CO3 (3 equiv)
N
R2
NH2
H
R1
toluene, 110 C, 24 h
2a-2e
3a-3e
1a-1d
Entry
Substrates
Dihaloarene
Dibenzodiazepinone (%)
O
O
NH
Br
NH2
1
N
NH2
X
H
1a
3a
2a X = Br
2b X = Cl
2c X = F
2d X = I
X = Br: 68%
X = Cl: 65%
X = F: 62%
X = I : 60%
Our continued interest prompted us to develop a domino
O
O
approach
to
the
synthesis
of
10,11-dihydro-5H-
NH
2
Br
Br
X
NH2
Br
dibenzo[b,e][1,4]diazepinones by using 2-aminobenzamide
and 1,2-dibromobenzene under palladium-catalysis. The
reverse regioselectivity of N-arylation at amide group observed
in our study made this work distinct from the Buchwald’s
reaction under palladium-catalysis.
NH2
1b
N
H
3b
2a X = Br
2b X = Cl
2c X = F
2d X = I
X = Br: 57%
X = Cl: 54%
X = F: 52%
X = I : 50%
O
O
3
Cl
NH
Br
X
NH2
NH2
Cl
Results and discussion
Initially, a one-pot domino approach was explored that
involved 2-aminobenzamide and 1,2-dibromobenzene as the
two coupling partners to prepare dibenzodiazepinone.
N
H
1c
3c
2a X = Br
2b X = Cl
2c X = F
2d X = I
X = Br: 58%
X = Cl: 55%
X = F: 53%
X = I : 50%
O
O
NH
Br
X
4
Table
1.
Optimization study for the synthesis of
NH2
dibenzodiazepinone.
N
NH
CH3
CH3
3d
1d
2a X = Br
2b X = Cl
2c X = F
2d X = I
X = Br: 47%
X = Cl:
44%
X = F: 42%
X = I : 40%
O
O
5
Br
Br
NH
Cl
NH2
NH2
Cl
N
H
1a
2e
Ent
ry
Pd-
catalyst
3e
70%
Ligand
Base
Solvent
Temp.
%Yield
rac-
BINAP
PPh3
PPh3
PCy3
110o C
110o C
110o C
110o C
0
O
1
Pd(OAc)2
K2CO3
Toluene
O
NH
6
7
Br
Br
CF3
NH2
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaOBu-t
K2CO3
K2CO3
Toluene
Toluene
Toluene
0
0
30
N
NH2
N
N
H
CF3
1a
2f
3f
60%
rac-
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
K2CO3
DMF
110o C
110o C
110o C
110o C
140o C
110o C
110o C
110o C
20
65
55
O
O
BINAP
S-Phos
Xant-
Phos
S-Phos
S-Phos
S-Phos
S-Phos
S-Phos
NH
Br
Br
Toluene
Toluene
O
O
NH2
NH2
O
N
O
H
53%
2g
3g
8
9
10
11
12
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(TFA)2
Pd(acac)2
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
o-xylene
Toluene
Toluene
Toluene
60
35
20
0
1a
0
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Table 2. Synthesis of various substituted dibenzodiazepinones. Scheme 2: Synthesis of Clozapine
ARTICLE
1
2
3
4
5
6
7
produced dibenzodiazpinone in 30% yield (Entry 4). Reaction Next, we turned our attention to the development of metal-
of 1a and 2a in presence of Pd(OAc)2, rac-BINAP, and K2CO3 in catalyzed domino reaction that employs the use of 2-
DMF at 110
℃
for 24 h also produced the cyclized product only aminobenzamide and 2,3-dibromopyridine derivative. To our
1a and 2,3-dibromo-5-
in 20% yield (Entry 5). Further change of ligand from rac-BINAP delight, 2-aminobenzamide
(
)
8
9
to S-Phos resulted in an efficient conversion of the reaction trifluromethylpyridine (2f) were reacted successfully under the
yielding 65% yield of the product (Entry 6). The ligand Xant- standard condition to obtain the only cyclized product
Phos exhibits nearly a comparable effect delivering the benzopyridodiazepinone
(3f
)
in 60% yield (Entry 6).
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product 3a in 55% yield (Entry 7). Retaining the S-Phos as Furthermore, the substrate scope was also extended to the
ligand produced similar result in the presence of Cs2CO3 as a electron-donating dihaloarene. Reaction of 2-aminobenzamide
base (Entry 8). Finally, raising the temperature to 140
℃ did with 5,6-dibromobenzo[d][1,3]dioxole 2g yielded cyclized
not improve the yield (Entry 9). Changing the catalyst from product 3g in 53% yield.
Pd(OAc)2 to PdCl2, significantly decreases the formation of
Subsequently, the translation application our current protocol
cyclized product (Entry 10). Catalysts like Pd(TFA)2 and
Pd(acac)2 did not give the desired product (Entry 11-12).
Remarkably, the formation of N-monoarylated product in
some of these reactions proposes that the reaction follows a
domino reaction pathway.
was explored to the synthesis of an anti-psychotic drug,
clozapine (Scheme 2). Importantly, known synthesis of
dibenzodiazepinone moiety leading to the preparation of
clozapine invariably involves multi-steps.19 Reaction of 2-
aminobenzamide and 1,2-dibromo-4-chlorobenzene under the
optimized condition gave the desired dibenzodiazepinone 3e
regioselectivly in 70% yield.
Next, the scope of substituted 2-aminobenzamides (1a-d) and
various 1,2-dihaloarenes (2a-e) was investigated (Table 2).
Similar to 1,2-dibromobenzene, 1-bromo-2-chlorobenzene, 1-
bromo-2-iodobenzene and 1-bromo-2-fluorobenzene all
reacted with 2-aminobenzamide (1a) eventfully yielding 3a in
60-68% yield (Entry 1).
The installation of N-methylpiperzine onto dibenzodiazepinone
3e could be achieved using the known literature.21
It is likely that N-arylation of amine could occur with 1-bromo-
2-fluorobenzene via a nucleophilic substitution. However,
reaction of 2-amino-5-bromobenzamide
(1b
)
and 1,2-
dihaloarenes (2a-2d) under the optimized condition gave the
cyclized product (3b) in relatively reduced (50-57%) yield
(Entry 2). Notably, no debromination was observed under the
optimized condition demonstrating further synthetic utility of
the protocol. Similarly, 2-amino-5-chlorobenzamide
(1c)
Scheme 3: Possible domino route towards the synthesis of
dibenzodiazepinone.
reacted with different 1,2-dihaloarenes (2a-2d) under the
optimized condition delivering the cyclized product (3c) in 50-
58% yield (Entry 3). To further extend the substrate scope, the
reaction of N-methylbenzamide (1d) and 1,2-dihalobenzene
During optimization,
a product corresponding to the
regioselective N-arylation of amide group in 2-
(
2a-2d) was investigated, which upon isolation gave the
cyclized product 3d in 40-47% yield (Entry 4). 2-
aminobenzamide (1a) and 1,2-dibromo-4-chlorobenzene (2e
aminobenzamide was often obtained. Unlike the literature,18 a
(
)
control
experiment
using
2-aminobenzamide
and
)
bromobenzene under the optimized condition gave us 2-
amino-N-phenylbenzamide confirming that N-arylation takes
place at amide nitrogen. Based on this observation, the
following domino reaction was proposed (Scheme 3).
were reacted successfully under the standard condition to
obtain the cyclized product (3e) in 70% yield (Entry 5).
O
O
Pd(OAc)2 (10 mol%)
S-Phos (20 mol%)
NH
Br
Br
Cl
NH2
NH2
Cl
+
N
K2CO3 (3 equiv.)
toluene, 110 C, 24 h
H
2e
3e
1a
TiCl4,
N-methyl piperazine
H3C
N
N
N
Cl
N
H
4
Clozapine
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Scheme 4: Plausible mechanistic route for the synthesis of 2-amino-5-bromobenzamide (1b): In a screw capped reaction
dibenzodiazepione tube, solution of 2-aminobenzamide (0.5 mmol) in
acetonitrile (2 mL) and N-bromosuccinamide (0.6 mmol) was
a
Finally, a plausible reaction mechanism is proposed in Scheme added and the reaction was heated at 60 °C for 10 min. Upon
4. In the first catalytic cycle, an oxidative addition of Pd0 to the completion, the solution was diluted with EtOAc, and then
6
7
8
9
aryl halide would give
aminobenzamide in the presence of K2CO3 could give an Na2SO4, concentrated to afford the desired substrate. The data
intermediate
. In the second catalytic cycle, a palladium of the substrate was confirmed by literature report.22 White
catalyzed intramolecular N-arylation of
to give 3a is solid. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.73 (s, 1H),
proposed. In this cycle, an oxidative addition of Pd0 to the aryl 7.26 – 7.24 (dd, J = 2.0, 8.76 Hz, 1H), 7.21 (s, 1H), 6.71 (s, 1H),
halide would give followed by , which upon reductive 6.69 – 6.66 (d, 8.80 Hz, 2H).
5, which upon addition with 2- washed by brine. The organic layer was dried over anhydrous
6
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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50
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52
53
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56
57
58
59
60
7
8
elimination could yield 3a
.
2-(Methylamino)benzamide (1d): Synthesised according to
general method mentioned in literature:23 White solid. 1H NMR
(400 MHz, DMSO-d6): δ 8.01 – 8.00 (d, J = 4.84 Hz, 1H), 7.81 (s,
1H), 7.60 – 7.58 (dd, J = 1.24, 7.84 Hz, 1H), 7.30 – 7.26 (t, J =
7.32 Hz, 1H), 7.15 (s, 1H), 6.62 – 6.60 (d, J = 8.36 Hz, 1H), 6.54
– 6.50 (t, J = 7.32 Hz, 1H), 2.77 – 2.76 (d, J = 5.08 Hz, 3H).
Conclusion
In summary, we have developed domino reactions for the
synthesis of dibenzodiazepinone by employing palladium-
catalyzed double N-arylation reactions (inter and intra-
molecular) starting from readily available 2-aminobenzamide
and 1,2-dihaloarenes. This protocol was also extended to the
synthesis of benzopyridodiazepinone by utilizing 2-
aminobenzamide and 2,3-dihalopyridine derivatives. The
domino approach was further utilized to the synthesis of a
10,11-Dihydro-5H-dibenzo[b,e
][1,4]diazepinones (3a):24
1
White solid. H NMR (400 MHz, DMSOd6): δ 9.85 (s, 1H), 7.85
(s, 1H), 7.68 – 7.66 (dd, J = 1.04, 7.84 Hz, 1H), 7.35 – 7.31 (t, J =
7.04 Hz, 1H), 7.00 – 6.88 (m, 6H).
marketed anti-psychotic drug, clozapine.
A key to the
2-Bromo-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
successful development of our protocol includes regioselective
N-arylation of 2-aminobenzamide at amide nitrogen. Unlike
the literature, the explanation for reverse regioselectivity
observed in our case under palladium-catalysis requires
further investigation.
1
(3b):24 Yellow solid. H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1
H), 8.05 (s, 1H), 7.74 –7.73 (d, J = 2.52 Hz, 1H), 7.51 – 7.48 (dd,
2.56, 8.64 Hz, 1H), 6.97 – 6.93 (m, 5H).
2-Chloro-5, 10-dihydro-11H-dibenzo[b,e][1,4]diazepin- 11-
one (3c):24 Yellow solid. 1H NMR (400 MHz, DMSOd6): δ 10.00
(s, 1H), 8.05 (s, 1H), 7.62 – 7.61 (d, J = 2.6Hz, 1H), 7.40 – 7.37
(dd, J = 2.64, 8.64 Hz 1H), 7.02 – 6.94 (m, 5H).
Experimental Section
General Methods: All reagents and solvents were purchased
from commercial sources and used as received. 1,2-
Diamino(hetero)arenes and 1,2-dihalo(hetero)arenes were
purchased from commercial vendors. All palladium-catalyzed
domino reactions were degassed and performed in screw-
5-Methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
(3d): White solid. 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s,
1H), 7.64 – 7.62 (d, J = 7.68 Hz, 1H), 7.51 – 7.46 (t, J = 8.36 Hz,
1H), 7.19 – 7.17 (d, J = 7.84 Hz, 2H), 7.10 – 7.04 (m, 4H), 3.26
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 169.0, 153.4, 145.0,
133.2, 131.4, 129.2, 127.3, 125.1, 124.33, 123.0, 121.7, 119.5,
118.0, 29.8. HRMS: calcd for C14H12N2O [M+H]+ 225.1028,
found 225.1000.
1
capped vials under argon. The H and 13C NMR spectroscopic
data were recorded with a 400 MHz spectrometer and are
reported in δ units. The samples were dissolved in DMSO-d6,
and the coupling constants (J values) are reported in Hz.
Column chromatography was performed on silica gel (100–200
or 230–400 mesh).
8-Chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
(3e):25 Brown solid. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s,
1H), 7.99 (s, 1H), 7.69 – 7.67 (d, J = 7.48 Hz, 1H), 7.36-7.35 (d, J
= 5.32 Hz, 1H), 7.00 – 6.91 (m, 5H).
General Procedure for the Synthesis of Dibenzodiazepinones:
In a screw capped vial that was equipped with a rubber
septum, a mixture of 2-aminobenzamide (0.5 mmol), 1,2
dibromobenzene (0.5 mmol), Pd(OAc)2 (10 mol%), S-Phos (20
mol%), and K2CO3 (3 equiv) in toluene (1 mL) was purged with
argon for approximately 10 min and then heated at 110 °C for
24 h under argon. The reaction mixture was cooled to room
temperature and then diluted with an excess amount of ethyl
acetate. The obtained suspension was filtered through a celite
bed, and the filtrate was concentrated under reduced
pressure.
3-(Trifluoromethyl)-5,11-dihydro-6H-benzo[e]pyrido[3,2-b][1,
4]diazepin-6-one (3f): Yellow solid. 1H NMR (400 MHz,
DMSOd6): δ 10.03 (s, 1H), 9.21 (s, 1H), 8.23 (s, 1H), 7.77 – 7.75
(dd, J = 1.56, 7.92 Hz, 1H), 7.54 – 7.53 (s, J = 1.84 Hz, 1H), 7.42
– 7.38 (t, J = 8 Hz, 1H), 7.16 – 7.14 (d, J = 7.52 Hz, 1H), 6.97 –
6.94 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 170.0,
154.0, 145.6 140.0, 134.5, 132.8, 125.6, 124.47, 123.0, 122.0,
120.27, 119.71. HRMS: calcd for C13H8F3N3O [M+H]+ 280.0698,
found 280.0679.
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DOI: 10.1039/C9NJ00539K
Journal Name
ARTICLE
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9
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(a) R. A. Smits, H.D. Lim, B. R. Stegink, A. Bakker, I. J. de Esch
and R. Leurs, J. Med. Chem. 2006, 49, 4512; (b) J. Su, J. Tang,
B. A. McKittrick, D. A. Burnett, H. Zhang, A. Smith-Torhan, A.
5,11-dihydro-10H-[1,3]dioxolo[4',5':4,5]benzo[1,2-
b]benzo[e][1,4]diazepin-10-one (3g): Yellow solid. 1H NMR
(400 MHz, DMSO-d6): δ 9.65 (s, 1H), 7.64-7.62 (d, J = 7.72 Hz,
1H), 7.54 (s, 1H), 7.34 – 7.30 (m, 1H), 6.95 – 6.90 (m, 2H), 6.64
(s, 1H), 6.57 (s, 1H), 5.92 (s, 2H); 13C NMR (100 MHz, DMSO-
d6): δ 168.6, 151.8, 144.5, 143.5, 134.9, 133.4, 132.3, 123.8,
123.6, 121.4, 119.4, 102.7, 101.7, 101.4. HRMS: calcd for
C14H10N2O3 [M+H]+ 255.0770, found 255.0757.
Fawzi, and J. Lachowicz, Bioorg. Med. Chem. Lett. 2006, 16
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45; (c) A. V. Joshua, S. K. Sharma, A. Strelkov, J. R. Scott, M. T.
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McEwan, Bioorg. Med. Chem. Lett. 2007, 17, 4066; (d) Y.
Liao, B. J. Venhuis, N. Rodenhuis, W. Timmerman, H.
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Seyfried and S. Sundell, J. Med. Chem. 1999, 42, 2235; (e) L.
Wang, G. M. Sullivan, L. A. Hexamer, L. A. Hasvold, R. Thalji,
M. Przytulinska, Z. F. Tao, G. Li, Z. Chen, Z. Xiao, W. Z. Gu, J.
Xue, M. H. Bui, P. Merta, P. Kovar, J. J. Bouska, H. Zhang, C.
Park, K. D. Stewart, H. L. Sham, T. J. Sowin, S. H. Rosenberg
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2-amino-N
-phenylbenzamide (3h):23 White solid. 1H NMR (400
MHz, CDCl3): δ 7.80 (s, 1H), 7.60-7.58 (d, J = 7.84 Hz, 2H), 7.50
– 7.48 (dd, J = 1.24, 8.28 Hz, 1H), 7.41 – 7.37 (t, J = 8.08 Hz,
2H), 7.30 – 7.26 (m, 1H), 7.19 – 7.15 (t, J = 7.36 Hz, 1H), 6.75 –
6.72 (m, 2H), 5.51 (s, 1H).
2-Amino-N
-(2-bromophenyl)benzamide (6):17 White solid. 1H
7
8
9
X. Aniban, S. Mamidala, and A. J. Burke. Eur. J. Org. Chem.
2018, 47, 6743.
A. R. Hanze, R. E. Strube and M. E. Greig, J. Med. Chem. 1963,
NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 7.75 – 7.71 (m, 2H),
7.57 – 7.54 (dd, J = 1.36, 7.88 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.24
– 7.19 (m, 2H), 6.77 – 6.75 (d, J = 8.24 Hz, 1H), 6.61 – 6.57
(t,7.04 Hz, 1H), 6.46 (s, 2H).
6
, 767.
R. P. Giani, M. Borsa, E. Parini and G. C. Tonon,
Synthesis, 1985, , 550.
5
Conflicts of interest
“There are no conflicts to declare”.
10 Q. Y. Zhang, X. J. Wang, Y. L. Tian, J. G. Qi, C. Li and D. L. Yin,
Chin. Chem. Lett. 2013, 24, 825.
11 Key
clozapine intermediate
CN106220576A, 2016.
synthesis
method.
12 H. M. Meshram, P. R. Goud, B. C. Reddy and J. S. Yadav, One
step process for the preparation of substituted 5,10-
dihydrodibenzo[b,e][1,4]diazepine-11-onesUS8202989B2,
2009.
Acknowledgements
We greatly appreciate the financial support from the CSIR,
New Delhi. MKH thanks to the NIPER S.A.S. Nagar for a
research fellowship.
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Palladium-catalysed regioselective N-arylation of anthranilamides: A
tandem route for dibenzodiazepinone synthesis
Joydev K. Laha,* Neelam Manral, and Mandeep Kaur Hunjan
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H3C
N
Intermolecular arylation
Domino Process
O
O
N
NH
Pd(OAc)2
S-Phos
H
X
X
N
N
R2
H
+
R2
K2CO3, Toluene
110 oC, 24 h
N
NR
Cl
R1
R
R1
N
H
H
up to 70% yield
19 examples
Clozapine
Intramolecular arylation
A palladium-catalyzed tandem reaction of 2-aminobenzamide and 1,2-dihaloarenes for the synthesis
of dibenzodiazepinone via double N-arylations (inter and intra-molecular) has been achieved.