An efficient one-pot microwave assisted synthesis of dibenzoazepinones

Article abstract of DOI:10.1016/j.tetlet.2013.03.065

Microwave assisted one-pot synthesis of substituted 5H-dibenzo[b,d]azepin- 6(7H)-ones from 2-(2-bromophenyl)acetic acid esters and 2-aminophenyl boronates has been described. This approach gives direct access to seven membered lactams with a shorter cycle time of synthesis and high yields.

Full text of DOI:10.1016/j.tetlet.2013.03.065

Tetrahedron Letters 54 (2013) 2916–2919
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Tetrahedron Letters
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An efficient one-pot microwave assisted synthesis of dibenzoazepinones
⇑
Prasant K. Deb, Somesh Sharma , Avinash Borude, Ravi P. Singh, Deepak Kumar, L. Krishnakanth Reddy
Jubilant Chemsys Limited, B-34, Sector-58, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted one-pot synthesis of substituted 5H-dibenzo[b,d]azepin-6(7H)-ones from 2-(2-
bromophenyl)acetic acid esters and 2-aminophenyl boronates has been described. This approach gives
direct access to seven membered lactams with a shorter cycle time of synthesis and high yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 February 2013
Revised 15 March 2013
Accepted 17 March 2013
Available online 27 March 2013
Keywords:
Methyl 2-(2-bromophenyl)acetate
Microwave synthesis
Dibenzoazepinone
Biaryl lactams have attracted the attention of researchers as
these are the privileged core, identified in many alkaloids and
pharmaceutically relevant organic molecules.1 This moiety is also
ence of Pd(PPh3)4 and Cs2CO3 in dimethoxyethane at 125–30 °C for
4 h (Scheme 1).
As expected, C–C coupling reaction was successful with greater
than 90% conversion by LCMS. However, intermediate 3 did not cy-
clize to the desired product, dibenzoazepinone 4 in this condition.
We even carried out this reaction in a microwave (BiotageÒ Initia-
tor) at 125 °C for 30 min and obtained similar results. The smooth
conversion to intermediate 3 under thermal and microwave condi-
tions encouraged us to investigate the optimum reaction conditions
for the cyclization to the product 4, with increased nucleophilicity
of amine. In order to facilitate the reaction, we added 3.0 equiv of
trimethylaluminium9 (1.0 M solution in toluene) and heated the
reaction mixture at 100 °C for 4 h. We observed the occurrence of
cyclization by LCMS with poor conversion (ꢀ10%).
very important due to it being
a core intermediate for
LY411575,2,3 an
c
-secretase inhibitor, a clinical candidate for Alz-
heimer’s disease. The synthesis of dibenzoazepinone has been pre-
viously reported by Stolle cyclization4 of N-([1,10-biphenyl]-2-yl)-
2-chloroacetamide and AlCl3 at elevated temperature in poor
yields (18–20%). Several other methods have also been reported
such as palladium-catalyzed borylation–Suzuki reaction,5 cycliza-
tion of hydroxylamides in neat trifluoromethanesulfonic acid,6a
intramolecular Staudinger–Aza-Wittig reaction of an azido penta-
fluorophenylester,6b and the hydrogenation of methyl 2-nitro-20-
biphenylacetate.6c These reported protocols result in low yields
of the desired product and involve multistep synthesis with te-
dious purification from byproducts. Recently, there is a report on
the synthesis of biologically active phenanthridinones and related
lactams from C–H arylation of the aniline ring using potassium
tert-butoxide,7 whereas, another report describes the one pot syn-
thesis of lactams utilizing N-methoxybenzamides and aryl iodide/
arene as coupling partners.8a,8b However, these methods were fo-
cused primarily on the synthesis of six-membered lactams.
Our current interest is to develop a robust, effective, and high
yielding methodology for the synthesis of dibenzoazepinones.
Herein, we report a synthetic approach which involves a palladium
catalyzed arylation, followed by intramolecular amide formation
for the synthesis of substituted 5H-dibenzo[b,d]azepin-6(7H)-ones.
A model reaction was carried out between 2-(2-bromophe-
nyl)acetic acid esters 1 and 2-aminophenyl boronate 2 in the pres-
O
B
Br
a
O
O
+
NH2
O
O
H2N
MeO
1
2
3
b
NH
O
Low conversion (10%)
4
Scheme 1. Reagents and conditions: (a) Pd(PPh3)4, Cs2CO3, 125 °C, DME, MW,
30 min or thermal, 4 h, 85%; (b) AlMe3, 100 °C, 4 h, 10%.
⇑
Corresponding author. Tel.: +91 120 409 3340; fax: +91 120 240 4336.
E-mail address: somesh_sharma@jchemsys.com (S. Sharma).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.065

P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919
2917
The cyclization of intermediate 3 with the addition of extra base
encouraged us to reiterate the thermal or microwave reaction for a
longer time to influence one-pot synthesis of dibenzoazepinone. To
our surprise, we observed poor conversion of the product after 36 h
of conventional heating at 125 °C. Similar results were obtained
under microwave heating at 125 °C for 4 h, along with several
impurities in the reaction mixture.
To optimize the reaction condition for one-pot formation of 5H-
dibenzo[b,d]azepin-6(7H)-ones, we investigated various catalysts,
bases, and solvents under MW condition as summarized in Table 1.
O
B
Br
O
O
NH
O
+
O
H2N
2
1
4
Yield 82%
Scheme 2. Reagents and conditions: Pd(PPh3)4, Cs2CO3, 125 °C, DME, MW, 30 min;
add KOtBu, 0 °C, 10 min.
We observed good one-pot conversion to product
4 with
Pd(PPh3)2/Cs2CO3 and DME:H2O as solvent system (entry 3). The
reaction was successful even with a milder base like Na2CO3, but
with comparatively lower yield (entry 4). The best one-pot conver-
sion was optimized with PdCl2(PPh3)2/Na2CO3 and DME:H2O as
solvent system in good yield (entry 7).
This extensive screening cascade gave us two best reaction con-
ditions 1 (entry 2) and 2 (entry 7).10 Their applicability was inves-
tigated further on various substrates as described in Table 2. In
general, we obtained better yield in condition 1, it might be due
to anhydrous environment of the reaction medium.
The influence of various groups on substrates (1 and 2, Table 2)
was studied for general applicability of these reaction conditions
leading to substituted 5H-dibenzo[b,d]azepin-6(7H)-ones. Yet
these results were not decisive to reflect the influence of substitu-
tions or reaction conditions on product yields.
Table 1
Optimization of reaction conditions in MW
Entry Catalyst
Base
Solvent
DME
Time (min) Yielda (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3/KOtBu DME
Cs2CO3
Na2CO3
30
30
–
82
53
42
45
42
80
60
26
DME:H2O 30
DME:H2O 30
DME
DME:H2O 30
DME:H2O 30
DME
PdCl2(PPh3)2 Cs2CO3
PdCl2(PPh3)2 Cs2CO3
PdCl2(PPh3)2 Na2CO3
30
PdCl2(dppf)
PdCl2(dppf)
Cs2CO3
Na2CO3
30
DME:H2O 30
a
Isolated yields obtained using 1–1.2 mmol of substrates,10 2–3.2 mmol of base,
and 21 mol % of catalyst, MW, 125 °C.
This result gave us further direction to use strong basic environ-
ment step-wise in the same reaction mixture to test the feasibility
of cyclization. In one of the reaction conditions, after completion of
C–C bond formation under microwave condition (30 min), we
added 1.5 equiv of potassium tert-butoxide to reaction mass at
0 °C and stirred the reaction mixture for 10 min. We observed com-
plete conversion of the reaction mixture to the desired product 4
(Scheme 2, Table 1, entry 2).
To extend the applicability of this methodology, we investi-
gated the synthesis of N-alkylated dibenzoazepinone. The reactions
were carried out with N-alkylated anilines (Substrate 2, Table 3)
under optimized reaction conditions. The prime objective of this
exploration was to make exclusively N-alkylated substrate, yet,
we observed a similar pattern of product yields. The results of
these experiments have been summarized in Table 3.
Table 2
Microwave mediated synthesis of substituted dibenzoazepinones10 (4a–4n)
Entry
Substrate 1
Substrate 2
Product
Isolated yield (%)-condition1/2
Br
O
O
O
B
O
O
O
O
1
60/50
NH
O
H2N
4a
Br
F
F
O
F
O
B
F
F
F
O
2
75/68
58/30
H2N
NH
O
4b
4c
Br
Br
O
O
O
B
O
O
3
4
O
NH
O
H2N
O
B
O
82/71
NH
O
H2N
4d
(continued on next page)

2918
P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919
Table 2 (continued)
Entry
Substrate 1
Substrate 2
Product
Cl
Isolated yield (%)-condition1/2
Br
O
O
B
Cl
O
O
O
5
6
80/73
NH
O
H2N
4e
NC
Br
O
O
B
CN
O
89/70
NH
O
H2N
4f
Br
O
F
O
B
O
O
O
F
7
8
9
71/82
78/71
64/80
O
NH
O
O
H2N
4g
4h
Br
O
B
O
O
NH
O
H2N
F
F
F
O
Br
O
F
F
O
B
F
O
NH
O
H2N
4i
O
O
Br
O
O
B
O
O
O
O
O
10
60/68
NH
O
H2N
4j
F
Cl
F
O
Br
F
F
B
Cl
F
O
11
12
68/26
81/75
O
F
NH
O
H2N
4k
Br
Br
O
F
O
O
O
B
O
O
O
O
NH
O
H2N
4l
F
F
F
O
F
F
F
B
O
13
84/47
F
F
H2N
NH
O
4m
F
O
F
O
Br
F
O
B
O
F
O
F
O
14
62/65
H2N
NH
O
4n

P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919
2919
Table 3
Formation of N-alkylated substituted dibenzoazepinones (5a–5d)
Entry
Substrate 1
Substrate 2
Product
Isolated yield (%)-condition1/2
Br
O
O
B
O
O
O
O
N
1
61/48
HN
5a
O
Br
Br
O
O
O
O
B
O
O
2
66/50
N
HN
5b
O
O
B
O
N
3
4
64/58
75/62
5c
HN
O
F
Br
O
O
F
B
O
O
N
HN
5d
O
5. Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67, 1199.
6. (a) Endo, Y.; Ohta, T.; Shudo, K.; Okamoto, T. Heterocycles 1977, 8, 367; (b)
Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.;
Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323; (c) Muth, C. W.;
Sung, W.-L.; Papanastassiou, Z. B. J. Am. Chem. Soc. 1955, 77, 3393.
7. Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org.
Lett. 2012, 14, 2838.
In summary, we have developed a robust, effective, and one-pot
high yielding microwave assisted methodology for the synthesis of
substituted dibenzoazepinones. This method has been also suc-
cessfully extended to synthesize N-alkylated dibenzoazepinones.
Further, exploratory experimentation is in progress in our labora-
tory to see the versatility of this strategy on substrates with substi-
8. (a) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. Angew. Chem. Int. Ed. 2011, 50, 1380; (b)
Karthikeyan, J.; Cheng, C.-H. Angew. Chem. Int. Ed. 2011, 50, 9880.
9. Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett.
2006, 47, 5767.
tutions on a-carbon of the carbonyl functionality.
Acknowledgment
10. Synthesis of 5H-dibenzo[b,d]azepin-6(7H)-one11 (4): Condition 1 (Table 1, entry
2) To
a 2–5 mL capacity microwave vial was charged methyl 2-(2-
bromophenyl)acetate (0.100 g, 0.43 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)aniline (0.115 g, 0.523 mmol) and cesium carbonate
(0.280 g, 0.86 mmol) in anhydrous 1,2-dimethoxy ethane (4 mL). The mixture
was stirred and degassed with argon for 5 min. To this mixture was added
Pd(PPh3)4 (25 mg, 0.021 mmol) under argon atmosphere, and purged for 2 min.
The tube was sealed and irradiated in microwave at 125 °C for 0.5 h. The vial
was cooled to 0 °C over a period of 15 min, followed by the addition of 1 M
potassium tert-butoxide (0.65 mL, 0.65 mmol) solution in THF. The resulting
mixture was stirred for 10 min and quenched with saturated ammonium
chloride solution. The mixture was diluted with ethyl acetate (30 mL) and
washed with water and brine. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated. The residue obtained was purified
by flash column chromatography by eluting with a gradient of 2–20% ethyl
acetate in hexane to afford the 5H-dibenzo[b,d]azepin-6(7H)-one (4) as off
white solid (0.075 g, 82%). 1H NMR (400 MHz, CDCl3) d 7.66ꢁ7.64 (d, 1H,
J = 8 Hz), 7.59ꢁ7.56 (m, 2H), 7.42ꢁ7.38 (m, 4H), 7.30 (t, 1H, J = 8 Hz), 7.09ꢁ7.07
(d, 1H, J = 8 Hz), 3.55ꢁ3.48 (m, 2H); LC–MS m/z 210.07 (M+H+); Purity: 99.69%
(AUC). Condition 2 (Table 1, entry 7) To a 2–5 mL capacity microwave vial was
charged methyl 2-(2-bromophenyl)acetate (0.100 g, 0.43 mmol), 2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.115 g, 0.523 mmol) and 2 M
aqueous sodium carbonate (0.5 mL, 0.86 mmol) in 1,2-dimethoxy ethane
(4 mL). The mixture was stirred and degassed with argon for 5 min. To this
mixture was added PdCl2(PPh3)2 (15 mg, 0.021 mmol) under argon
atmosphere, purging continued for another 2 min. The tube was sealed and
irradiated in microwave at 125 °C for 0.5 h. The vial was cooled to ambient
temperature in 15 min and diluted with ethyl acetate (30 mL) and washed with
water and brine. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue obtained was purified by flash column
chromatography by eluting with a gradient of 2–20% ethyl acetate in hexane to
afford 4 (0.073 g, 80%).
We are grateful to Jubilant Chemsys management for providing
financial support and analytical facilities for the execution of this
research work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
065.
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