Synthesis of Easy-modified and Useful Dibenzo-[ b,d ]azepines by Palladium(II)-Catalyzed Cyclization/Addition with a Green Solvent.

A novel strategy in which palladium(II)-catalyzed tandem cyclization is used to obtain N-heterocyclic architectures containing a seven-membered ring has been developed and used to synthesize a series of derivatives. The reaction uses an eco-friendly mixed solvent (water : EtOH = 2 : 1) instead of DMSO and maintains a high yield (91%). Its potential application value and reaction mechanism have also been explored.


General
All raw reagents were bought from commercial sources and used as received.All reagents were purchased from Sigma Aldrich or Fluorochem and used as received.All reactions apart from where noted were carried out in air.All flash column chromatography was carried out using silica purchased from Fluorochem using the solvent system noted. 1H NMR spectra were recorded at 400 MHz using a Bruker Avance III spectrometer. 13C NMR spectra were recorded at 600 MHz using a Bruker Avance III spectrometer.All coupling constants are reported in Hertz (Hz).In cases where it was required 2D NMR techniques were used to confirm compound identity.Chemical shifts are reported in ppm and are referenced to residual solvent peaks; CHCl 3 ( 1 H 7.26 ppm, 13 C 77.0 ppm).(cyanomethyl)phenyl)-4,5,5-trimethyl-1,3,2-dioxaborolan-4-yl)methylium (1.5 eq) (prepared according to the procedures reported in the patent US 2017/0158704 A1), K 2 CO 3 (2 eq) in the solvent (THF : H 2 O = 5:1) was added Pd(dppf)Cl 2 (0.1 eq).Then the mixture was stirred at 80 o C for 5 h under N 2 atmosphere.The reaction was then cooled to room temperature and diluted with H 2 O, extracted three times with EA, dried by Na 2 SO 4 and evaporated under a vacuum.The crude material was purified by column chromatography to give the desired product.

N 3a 6-phenyl-7H-dibenzo[b,d]azepine
Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and phenylboronic acid (73 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 91% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (dd, J = 6.7, 2.9 Hz, 2H), 7.74 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (dq, J = 7.0, 2.2 Hz, 1H), 7.54 (dd, J = 8.1, 1.5 Hz, 1H), 7.49 (dd, J = 7. Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and ptolylboronic acid (82 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 89% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 6.0 Hz, 2H), 7.71 (dd, J = 10.6, 5.  Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and mtolylboronic acid (82 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 90% yield.Synthesised according to the general method , after addition of the 1a (100 mg, 0.4 mmol) and 4methoxyphenylboronic acid (91 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 30:1) to give the desired product as a yellow liquid in 75% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 3methoxyphenylboronic acid (91 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 30:1) to give the desired product as a yellow liquid in 80% yield.

N
Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 4tert-butylbenzeneboronic acid (107 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 91% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 4-(trifluoromethyl)phenylboronic acid (114 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 45% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 3-(trifluoromethyl)phenylboronic acid (114 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 40% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 3chlorophenylboronic acid (94 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 66% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 3,4dichlorophenylboronic acid (114 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 68% yield.Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 4bromophenylboronic acid (120 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 89% yield. 1   Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 3,4dimethoxyphenylboronic acid (109 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 25:1) to give the desired product as a yellow liquid in 80% yield. 1   Synthesised according to the general method, after addition of the 4a (122 mg, 0.4 mmol) and phenylboronic acid (73 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 89% yield. 1

Cl 5b 3-chloro-6-(p-tolyl)-7H-dibenzo[b,d]azepine
Synthesised according to the general method, after addition of the 4a (122 mg, 0.4 mmol) and ptolylboronic acid (82 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 90% yield.

Cl 5c 6-(m-tolyl)-7H-dibenzo[b,d]azepine
Synthesised according to the general method, after addition of the 4a (122 mg, 0.4 mmol) and m-tolylboronic acid (82 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 87% yield.2.39 (s, 3H). 13

Characterization Data of Products 6a and 7a
(17.9 mg, 0.21 mmol, 1.5 eq) and the mixture was stirred overnight at 100 °C under nitrogen atmosphere.The reaction mixture was then cooled to room temperature and quenched with water, extracted three times with EA, dried over Na 2 SO 4 and concentrated in vacuo.The residue was purified by column chromatography (PE : EA = 30:1 ) to give the desired product as a yellow oil in 86% yield.Synthesised according to the general method same as 8a.The crude material was purified by column chromatography (PE : EA = 30:1 )to give the desired product as a yellow oil in 47% yield.

+
Fig. S1The product of large-scale experiment
Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and naphthalen-2-ylboronic acid (103 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 74% yield.
Synthesised according to the general method, after addition of the 1a (100 mg, 0.4 mmol) and 4chlorophenylboronic acid (94 mg, 0.6 mmol) with other reagents, the reaction mixture was heated to 100 °C in a sealed tube using a hotplate.The crude material was purified by column chromatography (PE : EA = 40:1) to give the desired product as a yellow liquid in 85% yield.