CuI/l-proline-catalyzed intramolecular aryl amination: An efficient route for the synthesis of 1,4-benzodiazepinones

Article abstract of DOI:10.1055/s-0030-1260975

An effective protocol for the synthesis of potentially bioactive benzo[e]chromeno[6,5-b][1,4]diazepine-3,8(7H,13H)-dione and dibenzo[b,e][1,4] diazepin-11(10H)-one derivatives in good to excellent yields has been achieved by CuI/l-Proline catalyzed coupling reaction as the key step. The methodology offers clean reaction conditions and easy isolation of the products in 61-92% yields.

Full text of DOI:10.1055/s-0030-1260975

LETTER
1881
CuI/L-Proline-Catalyzed Intramolecular Aryl Amination: An Efficient Route
for the Synthesis of 1,4-Benzodiazepinones
S
ynthesis of 1,4-B
.
enzodiazepin
C
one
s
. Majumdar,* Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 23 February 2011
interest associated with the pharmacological activities of
Abstract: An effective protocol for the synthesis of potentially bio-
active benzo[e]chromeno[6,5-b][1,4]diazepine-3,8(7H,13H)-dione
and dibenzo[b,e][1,4]diazepin-11(10H)-one derivatives in good to
excellent yields has been achieved by CuI/L-Proline catalyzed cou-
dibenzodiazepinones and diazepinones bearing coumarin
and quinolone moieties justify further work on the devel-
opment of novel synthetic methodologies for these com-
pling reaction as the key step. The methodology offers clean reac- pounds. Several strategies to access 1,4-benzo-
diazepinones are known.14,15
tion conditions and easy isolation of the products in 61–92% yields.
Key words: CuI, L-proline, 1,4-benzodiazepinones, intramolecular
cyclization
The formation of carbon–heteroatom bonds by transition-
metal-catalyzed cross-coupling methodology has been the
subject of significant interest during the past few years.16
Buchwald reported17 a landmark development in the cop-
The 1,4-benzodiazepine moiety can be found in many
pharmaceutically important molecules that possess a wide
range of biological activities mostly based on their special
affinity for serotonin (5-HT2) and acetylcholine recep-
tors. These compounds play a vital role as anti-anxiety
and antihistaminic agents.1 These dibenzo[b,e][1,4]di-
azepin-11-ones are well-known antidepressants (1,
Figure 1),2 antihistaminics (2, Figure 1),3 anti-inflamma-
tories,4 anti-arhytmics,5 antitumors,6 and anticonvulsi-
vants.7 Additionally, pyrido[2,3-b]benzodiazepinones
have been examined as cardioselective muscarinic recep-
tor antagonists (3, Figure 1)8 and have displayed activity
as potential HIV-1 reverse transcriptase (RT) inhibitors as
isomeric structures of the potent RT inhibitor nevirapine,
a dipyridodiazepinone.
per-catalyzed reactions which are found to be very effec-
tive for the aryl amination reactions. Ma et al. have
introduced18 the synthesis of oxazepine ring system by
CuI/L-proline catalyzed C–N bond formation.19 Beccalli
and co-workers reported20 palladium-catalyzed synthesis
of dibenzo[b,e][1,4]diazepines. As a part of our continu-
ing efforts to synthesize potentially bioactive
heterocycles21 we have planned to develop a new protocol
for synthesizing 1,4-benzodiazepinones and heterocycle-
fused diazepinone derivatives by CuI/L-proline catalyzed
intramolecular aryl amination, and the results are reported
here.
The precursors 6a–i required for our present study were
synthesized in 80–91% yields by SnCl2 reduction of the
nitro compounds 5a–i. The compounds 5a–i were in turn
prepared by the treatment of 2-nitrobenzoyl chloride with
4a–i under phase-transfer-catalysis conditions using
TBAHS as a catalyst and potassium carbonate as a base
(Scheme 1).
Coumarin and quinolone moieties are found in a large
number of natural products, which possess a broad spec-
trum of biological activities, for example, antifungal, an-
tibacterial, antiviral, and antimicrobial properties.9–13 The
We have initiated our study with the compound 6a as a
model substrate. Initially the aryl amination reaction of 6a
with 10 mol% CuI, 20 mol% L-proline in the presence of
2 equivalents K2CO3 as base in DMSO at 120 °C for 15
hours afforded compound 8a in 51% yield (Scheme 2).
Cl
Me
H
N
N
N
N
O
O
The spectral analysis of the compound showed the forma-
tion of product 8a.22 However, to optimize the reaction
conditions to obtain the maximum yield of the cyclized
product, a set of experiments were carried out by changing
the parameters, viz., solvent, base, ligand, etc. Further in-
crease in the catalyst loading (10–20 mol% of CuI) did not
improve the yield of the cyclized product. However, when
the same reaction was conducted by changing the base,
that is, with Cs2CO3 in DMSO keeping the other parame-
ters unchanged, the reaction rate was accelerated (8 h), as
well as the yield of the cyclized product was increased
(51–72%, Table 1, entry 8).
NMe2
NMe2
1
2
N
O
N
N
Me
N
HN
O
3
Figure 1 Some biologically active benzodiazepinone derivatives
SYNLETT 2011, No. 13, pp 1881–1887
Advanced online publication: 25.07.2011
DOI: 10.1055/s-0030-1260975; Art ID: B04911ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

1882
K. C. Majumdar, S. Ganai
LETTER
O2N
H2N
O
X
O
O
NHR1
X
X
(ii)
(i)
+
Cl
O2N
NR1
NR1
R2
R2
R2
4a R1 = Me, R2 = Me, X = Br
4b R1 = H, R2 = Me, X = Br
4c R1 = H, R2 = H, X = Br
4d R1 = Et, R2 = Me, X = Br
4e R1 = H, R2 = H, X = Cl
5a R1 = Me, R2 = Me, X = Br
5b R1 = H, R2 = Me, X = Br
5c R1 = H, R2 = H, X = Br
5d R1 = Et, R2 = Me, X = Br
5e R1 = H, R2 = H, X = Cl
6a R1 = Me, R2 = Me, X = Br
6b R1 = H, R2 = Me, X = Br
6c R1 = H, R2 = H, X = Br
6d R1 = Et, R2 = Me, X = Br
6e R1 = H, R2 = H, X = Cl
O2N
H2N
O
Br
O
O
NHR1
+
Br
Br
(i)
(ii)
Cl
O2N
NR1
NR1
O
Y
O
Y
O
Y
4f Y = NMe, R1 = Et
4g Y = NMe, R1 = Me
4h Y = O, R1 = Me
5f Y = NMe, R1 = Et
5g Y = NMe, R1 = Me
5h Y = O, R1 = Me
6f Y = NMe, R1 = Et
6g Y = NMe, R1 = Me
6h Y = O, R1 = Me
O
NHMe
NO2
NH2
(i)
(ii)
Br
+
Cl
O2N
MeN
O
MeN
O
Br
Br
4i
5i
6i
Scheme 1 Reagents and conditions: (i) CH2Cl2–H2O, TBAHS, K2CO3, r.t., 8 h, (ii) SnCl2·2H2O, EtOAc, reflux, 2–3 h.
Table 1 Optimization of the CuI-Catalyzed Aryl Amination Reactionsa
Entry
1
Catalyst
CuI
Additive
Base
Solvent
DMSO
DMSO
DMF
Temp (°C) Time (h) Yield of 8a (%)b
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
–
K2CO3
100
120
120
reflux
reflux
120
120
120
120
120
120
120
120
13
13
15
15
15
13
15
8
44
51
16
0
2
CuI
K2CO3
3
CuI
K2CO3
4
CuI
Cs2CO3
Cs2CO3
Na2CO3
Et3N
toluene
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
5
CuI
0
6
CuI
37
<10c
72
32
0
7
CuI
8
CuI
Cs2CO3
DABCO·6H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
CuI
13
15
15
13
13
10
11
12
13
CuI
CuSO4
CuI
L-proline
N-methylglycine
1,10-phenanthroline
18
27
24
CuI
a Reaction conditions: 6a (0.5 mmol), CuI (0.05 mmol), L-proline (0.1 mmol), base (1 mmol), DMSO (5 mL).
b Isolated yield.
c 6 mmol of base were added.
Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Benzodiazepinones
1883
ducing a tosyl group. The desired starting material 7f for
this study was prepared by heating compound 6f in pyri-
dine with TsCl for 4 hours. The resulting compound 7f
was then subjected to the optimized conditions to give a
product in very low yield (Table 2, entry 1). The spectral
analysis of the compound showed the formation of the
product 8e.23 To increase the yield of the cyclized product,
a set of experiments, varying the solvent, base, and ligand
were performed (Table 2). Surprisingly, we observed that
the reaction with 7f using DABCO as base and L-proline
as ligand in DMSO gave a good yield of product 8e in 11
hours (Table 2, entry 4). When the reaction was conduct-
ed by adding 1 mL H2O in DMSO keeping the other pa-
rameters unchanged, the rate and yield of the cyclized
product was increased (from 62% to 88% in 9 h, Table 2,
entry 7). After performing a series of experiments, the op-
timized condition developed so far is to treat the tosylated
substrate with 10 mol% CuI, 20 mol% L-proline, 6 equiv-
alents DABCO in 4 mL DMSO and 1 mL H2O at 120 °C
(Table 2, entry 7).
H2N
O
(i)
Br
HN
O
NMe
NMe
Me
Me
6a
8a
Scheme 2 Reagents and conditions: (i) CuI, L-proline, K2CO3,
DMSO, 120 °C, 15 h.
The reaction was also studied in different solvents like
DMF, toluene, dioxane, etc., but DMSO was found to be
the best choice (Table 1, entry 3–5). Additive plays an im-
portant role in this reaction because in its absence the re-
action failed to occur (Table 1, entry 10). Among the
ligands used, L-proline was found to be most effective
(Table 1, entry 8). Therefore, the optimized condition for
the reaction is to treat the substrate with 10 mol% CuI, 20
mol% L-proline, 2 equivalents Cs2CO3 in 5 mL DMSO at
120 °C. These optimized reaction conditions were used
for the other substrates 6a,g,b,c to give the products 8a–d
in 61–72% yields (Table 3).
These optimized reaction conditions were used for the
other substrates 7g,h,a,d,i to give the products 8e–j in 77–
92% yield (Table 3).
To extend the scope of this reaction we have also investi-
gated this reaction using aromatic chloride as a substrate
(4e). The precursor 6e prepared accordingly, gave 58%
yield of cyclized product (8d) when treated with 10 mol%
CuI, 20 mol% L-proline, 2 equivalents Cs2CO3 in 5 mL
DMSO at 120 °C for 7 hours (Table 1, entry 8).
O
O
Et
N
Et
N
(i)
78%
Me
Me
N
N
H
Ts
8i
8k
As the yields of the products were not high (61–72%), we
have examined the effect of chelation owing to the pres-
ence of the free amine function in the substrate by intro-
Scheme 3 Reagents and conditions: (i) 8i (0.246 mmol), H2SO4 (2.3
mL), HCl (2.3 mL), AcOH (1.5 mL), heat, 4 h.
Table 2 Optimization of the CuI-Catalyzed Aryl Amination Reactionsa
Entry
1
Catalyst
CuI
Additive
Base
Solvent
Temp (°C) Time (h) Yield of 8e (%)b
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
–
Cs2CO3
DMSO
120
120
120
120
reflux
reflux
120
120
120
120
120
120
15
15
15
11
15
15
9
33
<25
16
2
CuI
K2CO3
DMSO
3
CuI
Na2CO3
DMSO
4
CuI
DABCO·6H2O
DABCO·6H2O
DABCO·6H2O
DABCO·6H2O
Et3N
DMSO
74
5
CuI
toluene
0
6
CuI
dioxane
0
7
CuI
DMSO–H2O
DMSO
88c
13d
0c
8
CuI
13
15
13
13
13
9
CuI
DABCO·6H2O
DABCO·6H2O
DABCO·6H2O
DABCO·6H2O
DMSO–H2O
DMSO–H2O
DMSO–H2O
DMSO–H2O
10
11
12
CuI
1,10-phenanthroline
N-methylglycine
L-proline
26c
28c
22c
CuI
CuSO4
a Reaction conditions: 7f (0.5 mmol), CuI (0.05 mmol), L-proline (0.1 mmol), base (3 mmol), DMSO (5 mL).
b Isolated yield.
c 1 mL H2O was added
d 6 mmol of base was added.
Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York

1884
K. C. Majumdar, S. Ganai
Table 3 Summarized Results of the Aryl Amination Reaction
Entry Precursors Time (h)
LETTER
Product
Yield (%)a
H2N
O
Me
N
O
Br
1
8
72
NMe
N
H
Me
Me
8a
6a
H2N
O
Br
HN
O
2
NMe
10
66
NMe
O
N
O
N
6g
8b
H2N
O
H
N
O
Br
3
4
5
7
7
7
61
67
58
NH
N
H
Me
Me
8c
6b
H2N
O
H
N
O
Br
NH
N
H
8d
8d
6c
6e
H2N
O
H
N
O
Cl
NH
N
H
TsHN
O
Br
TsN
O
NEt
6
9
88
NEt
O
N
O
N
7f
8e
TsHN
O
Br
TsN
O
NMe
7
10
81
NMe
O
N
O
N
7g
8f
Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,4-Benzodiazepinones
Product
Yield (%)a
1885
Table 3 Summarized Results of the Aryl Amination Reaction (continued)
Entry
Precursors
Time (h)
TsHN
O
Br
TsN
O
8
10
77
NMe
NMe
O
O
O
O
7h
8g
TsHN
O
O
Me
N
Br
9
7
7
91
92
NMe
Me
N
Ts
Me
8h
7a
TsHN
O
O
Et
N
Br
10
NEt
N
Me
Ts
Me
8i
7d
O
NHTs
MeN
11
8
86
MeN
O
Br
NTs
8j
7i
a Isolated yield of products.
The tosyl derivatives of the benzodiazepinones obtained, Supporting Information for this article is available online at
can also be detosylated for further substitution at the nitro- http://www.thieme-connect.com/ejournals/toc/synlett.
gen atom (Scheme 3).
Beccalli and co-workers synthesized [1,4]-diazepinones
using palladium-catalyzed reaction conditions. This
methodology may suffer from some limitations particu-
larly in the case of industrial application of the methodol-
ogy due to the air and moisture sensitivity of the
palladium catalyst24 as well as the higher costs of the Pd
catalyst. Our protocol involves the use of Cu catalyst and
L-proline ligand to afford benzodiazepinones and hetero-
cycle-annulated benzodiazepinone derivatives. The reac-
tion conditions offer advantages over palladium catalysis
as they required less expensive catalyst and ligand, and
they can also be applied to the large-scale synthesis of bi-
ologically important diazepinone derivatives.
Acknowledgment
We thank CSIR (New Delhi) for financial assistance. One of us
(S.G.) is grateful to the CSIR (New Delhi) for his research fel-
lowship. We also thank DST (New Delhi) for providing Bruker
NMR (400 MHz), Perkin-Elmer CHN Analyser, FT-IR, and UV-
Vis spectrometers under its FIST program.
References and Notes
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lated benzodiazepinone derivatives in 61–92% yields by
copper-catalyzed intramolecular aryl amination reaction.
Implementation of this strategy to the synthesis of other
biologically active heterocycles is currently under way
and will be reported in due course.
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Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York

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K. C. Majumdar, S. Ganai
LETTER
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(22) Procedure for the Synthesis of Compound 8a
To a solution of the compound 6a (160 mg, 0.50 mmol) in
DMSO (5 mL), CuI (9.5 mg, 0.05 mmol), L-proline (12 mg,
0.1 mmol), and Cs2CO3 (325.8 mg, 1 mmol) were added.
The reaction mixture was stirred at 120 °C for 8 h. The
reaction was monitored by TLC. After completion, the
reaction mixture was diluted with CH2Cl2 (3 × 15 mL) and
washed with H2O (3 × 15 mL). The combined organic layer
was filtered and dried over Na2SO4. The solvent was
distilled off, and the crude product was purified by column
chromatography over silica gel (60–120 mesh) using PE and
EtOAc (4:1) as eluent to give a white solid product 8a.
Analytical Data of Compound 8a
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III; Hirschmann, R. Org. Lett. 2001, 3, 1089. (e) Wang, T.;
Lui, A. S.; Cloudsdale, I. S. Org. Lett. 1999, 1, 1835.
(f) Ammadi, F.; Boukhris, S.; Souizi, A.; Coudert, G.
Tetrahedron Lett. 1999, 40, 6517. (g) Grunewald, G. L.;
Dahanukar, V. H.; Ching, P.; Criscione, K. R. J. Med. Chem.
1996, 39, 3539.
Yield 72%, solid; mp 156–158 °C. IR (KBr): nmax = 1609,
3328 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H),
3.51 (s, 3 H), 5.27 (s, 1 H), 6.72 (s, 1 H), 6.77 (d, 1 H, J = 7.6
Hz), 6.91 (s, 1 H), 7.01–7.07 (m, 2 H), 7.29 (d, 1 H, J = 8.8
Hz), 7.87 (d, 1 H, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3):
d = 20.61, 38.06, 118.39, 120.73, 122.59, 123.04, 124.85,
124.97, 132.45, 132.90, 135.76, 143.01, 150.60, 168.57.
HRMS: m/z calcd for C15H14N2O [M+ + Na]: 261.1004;
found: 261.1029.
(23) Procedure for the Synthesis of Compound 8e
To a solution of the compound 7f (0.50 mmol) in DMSO–
H2O (4:1; 5 mL), CuI (0.05 mmol), L-proline (0.1 mmol),
and DABCO (3 mmol) were added. The reaction mixture
was stirred at 120 °C for 9 h. After completion of the
reaction (monitored by TLC), the reaction mixture was
diluted with CH2Cl2 (3 × 15 mL) and washed with H2O
(3 × 15 mL). The combined organic layer was filtered and
dried over Na2SO4. The solvent was distilled off, and the
crude product was purified by column chromatography over
silica gel (60–120 mesh) using PE and EtOAc (1:1) as eluent
to give a white solid product 8e.
(16) (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(c) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(d) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727. (e) Klapars, A.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
(f) Jiang, L.; Job, G. E.; Klapars, A.; Stephen, L.; Buchwald,
S. L. Org. Lett. 2003, 5, 20. (g) Mallesham, B.; Rajesh, B.
M.; Reddy, P. R.; Srinivas, D.; Trehan, S. Org. Lett. 2003, 5,
7.
Analytical Data of Compound 8e
Yield 88%, white solid; mp 240–242 °C. IR (KBr):
n
max = 1162, 1600, 1644, 1659 cm–1. 1H NMR (400 MHz,
Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York

LETTER
CDCl3): d = 1.35 (t, 3 H, J = 6.4 Hz), 2.43 (s, 3 H), 3.28 (q,
Synthesis of 1,4-Benzodiazepinones
1887
129.29, 129.84, 132.22, 132.56, 132.83, 134.77, 135.74,
136.41, 138.52, 141.10, 144.42, 161.54, 165.17. HRMS:
m/z calcd for C26H23N3O4S [M+ + Na]: 496.1307; found:
496.1311.
1 H, J = 6.4 Hz), 3.46 (q, 1 H, J = 6.8 Hz), 3.71 (s, 3 H), 6.90
(d, 1 H, J = 10.0 Hz), 7.24 (s, 2 H), 7.35–7.50 (m, 5 H), 7.56–
7.61 (m, 2 H), 7.78 (d, 1 H, J = 7.6 Hz), 8.42 (d, 1 H, J = 9.6
Hz). 13C NMR (100 MHz, CDCl3): d = 14.14, 21.65, 29.79,
45.92, 115.58, 120.57, 123.65, 124.12, 127.39, 128.90,
(24) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
Synlett 2011, No. 13, 1881–1887 © Thieme Stuttgart · New York