Tetrahedron Letters 54 (2013) 2916–2919

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Tetrahedro n 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:Received 11 February 2013 Revised 15 March 2013 Accepted 17 March 2013 Available online 27 March 2013

Keywords:Methyl 2-(2-bromophenyl)acetateMicrowave synthesis Dibenzoazepinone

0040-4039/$ - see front matter � 2013 Elsevier Lthttp://dx.doi.org/10.1016/j.tetlet.2013.03.065

⇑ Corresponding author. Tel.: +91 120 409 3340; faE-mail address: somesh_sharma@jchemsys.com (S

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

� 2013 Elsevier Ltd. All rights reserved.

Br

O

O

H2N

BO

ONH2

OMeO

+

1 2 3

NH

OLow conversion (10%)

a

b

Biaryl lactams have attracted the attention of researchers asthese are the privileged core, identified in many alkaloids and pharmaceuti cally relevant organic molecules.1 This moiety is also 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 dibenzoazepi none has been pre- viously reported by Stolle cyclization 4 of N-([1,10-biphenyl ]-2-yl)-2-chloroacetam ide and AlCl 3 at elevated temperature in poor yields (18–20%). Several other methods have also been reported such as palladium-cata lyzed borylation–Suzuki reaction,5 cycliza-tion of hydroxylamide s in neat trifluoromethanesulfonic acid,6a

intramolecu lar Staudinger–Aza-Wittig reaction of an azido penta- fluorophenylester,6b and the hydrogenation of methyl 2-nitro-2 0-biphenylace tate.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 onthe synthesis of biologically active phenanthridin ones 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-methox ybenzamides 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 methodol ogy for the synthesis of dibenzoazepi nones.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-aminophe nyl boronate 2 in the pres-

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x: +91 120 240 4336.. Sharma).

ence of Pd(PPh3)4 and Cs2CO3 in dimethoxyetha ne 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, dibenzoazepi none 4 in this condition .We even carried out this reaction in a microwa ve (Biotage� Initia-tor) at 125 �C for 30 min and obtained similar results. The smooth conversio n to intermediate 3 under thermal and microwa ve condi- tions encourag ed us to investigate the optimum reaction condition sfor the cyclization to the product 4, with increased nucleophilici tyof amine. In order to facilitate the reaction, we added 3.0 equiv oftrimethyl aluminium 9 (1.0 M solution in toluene) and heated the reaction mixture at 100 �C for 4 h. We observed the occurrence ofcyclization by LCMS with poor 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) AlMe 3, 100 �C, 4 h, 10%.

Br

O

O

H2N

BO

O+ NH

O

Yield 82%1 2 4

Scheme 2. Reagents and conditions: Pd(PPh3)4, Cs2CO3, 125 �C, DME, MW, 30 min;add KOtBu, 0 �C, 10 min.

Table 1Optimization of reaction conditions in MW

Entry Catalyst Base Solvent Time (min) Yield a (%)

1 Pd(PPh3)4 Cs2CO3 DME 30 –2 Pd(PPh3)4 Cs2CO3/KOtBu DME 30 823 Pd(PPh3)4 Cs2CO3 DME:H2O 30 534 Pd(PPh3)4 Na2CO3 DME:H2O 30 425 PdCl 2(PPh3)2 Cs2CO3 DME 30 456 PdCl 2(PPh3)2 Cs2CO3 DME:H2O 30 427 PdCl 2(PPh3)2 Na2CO3 DME:H2O 30 808 PdCl 2(dppf) Cs2CO3 DME 30 609 PdCl 2(dppf) Na2CO3 DME:H2O 30 26

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.

P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919 2917

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 condition s, after completion ofC–C bond formatio n under microwa ve condition (30 min), weadded 1.5 equiv of potassium tert-butoxide to reaction mass at0 �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).

Table 2Microwave mediated synthesis of substituted dibe nzoazepinones 10 (4a–4n)

Entry Substrate 1 Substrate 2

1

Br

O

O

H2N

BO

O O

2

Br

O

O

H2N

BO

O

F

FF

3

Br

O

O

H2N

BO

O

4

Br

O

O

H2N

BO

O

The cyclization of intermedi ate 3 with the addition of extra base encourag ed us to reiterate the thermal or microwave reaction for alonger time to influence one-pot synthesis of dibenzoazepi none. Toour surprise, we observed poor conversio n of the product after 36 hof 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 formatio n of 5H-dibenzo[b,d]azepin-6(7H)-ones, we investigated various catalysts,bases, and solvents under MW condition as summari zed in Table 1.We observed good one-pot conversion to product 4 withPd(PPh3)2/Cs2CO3 and DME:H 2O 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 PdCl 2(PPh3)2/Na2CO3 and DME:H 2O assolvent 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. Ingeneral, we obtained better yield in condition 1, it might be due to anhydrou s environment of the reaction medium.

The influence of various groups on substrate s (1 and 2, Table 2)was studied for general applicability of these reaction condition sleading 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.

To extend the applicability of this methodol ogy, 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 explorati on was to make exclusively N-alkylated substrate , yet,we observed a similar pattern of product yields. The results ofthese experiments have been summarized in Table 3.

Product Isolated yield (%)-condition1/2

NH

O

O

4a

60/50

NH

O

FFF

4b

75/68

NH

O4c

58/30

NH

O4d

82/71

(continued on next page )

Table 2 (continued)

Entry Substrate 1 Substrate 2 Product Isolated yield (%)-condition1/2

5

Br

O

O

H2N

BO

O Cl

NH

O

Cl

4e

80/73

6

Br

O

O

H2N

BO

O CN

NH

O

NC

4f

89/70

7

Br

O

OO

H2N

BO

O NH

O

O

4g

71/82

8

Br

O

OF

H2N

BO

O NH

O

F

4h

78/71

9

Br

O

O

F

FF

H2N

BO

O NH

O

F

FF

4i

64/80

10

Br

O

OO

H2N

BO

O O

NH

O

O

O

4j

60/68

11

Br

O

O

F

FF

H2N

BO

O Cl

NH

O

F

Cl

FF

4k

68/26

12

Br

O

OO

H2N

BO

ONH

O

O

4l

81/75

13

Br

O

OF

H2N

BO

O

F

FF

NH

O

F

FFF

4m

84/47

14

Br

O

O

F

FF

H2N

BO

O O

NH

O

F

O

FF

4n

62/65

2918 P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919

Table 3Formation of N-alkylated substituted dibenzoazepinones (5a–5d)

Entry Substrate 1 Substrate 2 Product Isolated yield (%)-condition1/2

1

Br

O

O

HN

BO

O N

O5a61/48

2

Br

O

O

HN

BO

O O

N

O

O

5b

66/50

3

Br

O

O

HN

BO

O N

O5c

64/58

4

Br

O

OF

HN

BO

O N

O

F

5d

75/62

P. K. Deb et al. / Tetrahedron Letters 54 (2013) 2916–2919 2919

In summary, we have develope d a robust, effective, and one-pot high yielding microwave assisted methodol ogy for the synthesis ofsubstituted dibenzoazepinone s. This method has been also suc- cessfully extended to synthesize N-alkylated dibenzoazepi nones.Further, exploratory experimentation is in progress in our labora- tory to see the versatility of this strategy on substrates with substi- tutions on a-carbon of the carbonyl functionality .

Acknowled gment

We are grateful to Jubilant Chemsys management for providing financial support and analytical facilities for the execution of this research work.

Supplementa ry data

Supplement ary data associated with this article can be found, inthe online version, at http://dx .doi.org/10.1016/j .tetlet.2013.03.065.

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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 Mpotassium 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 purifiedby 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, CDCl 3) d 7.66�7.64 (d, 1H,J = 8 Hz), 7.59 �7.56 (m, 2H), 7.42 �7.38 (m, 4H), 7.30 (t, 1H, J = 8 Hz), 7.09 �7.07(d, 1H, J = 8 Hz), 3.55 �3.48 (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 Maqueous 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 PdCl 2(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 toafford 4 (0.073 g, 80%).