Synthesis of 2,3-Dimethoxy-7-methyl-7,12-dihydro-6H-[1]-benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione.

Treatment of 5,6-dimethoxy-2-(methylphenylcarbamoyl)-benzofuran-3-carboxylic acid with PPA yielded 2,3-dimethoxy-7-methyl-7,12-dihydro-6H-[1]-benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione. The analogous 2-[(5,6-dimethoxybenzo-furan-2-carbonyl)methylamino]benzoic acid was resistant to cyclization, whereas 2-[(6-methoxybenzofuran-2-carbonyl)-amino]benzoic acid underwent cyclization to the corresponding 3,1-benzoxazin-4-one.


Results and Discussion
The pathway shown in Scheme 1 was first explored. Rotenoids are often oxygenated at positions 2 and 3 [9]. Use of 3-bromo-7-methoxycoumarin (3) would result in only the monomethoxy rotenonoids, however this material was available in quantity and was seen as a useful prototype for our studies.

Scheme 2
Reagents: i) antranilic acid, Cu, CuBr, K 2 CO 3  Strong IR absorptions at 1635 and 1773 cm -1 , corresponding to the C=N and ester functionality, were observed. Compounds of this type are known to undergo base hydrolysis to produce the corresponding N-acyl anthranilic acids, which are then readily reconverted to benzoxazinones on treatment with NaOAc/Ac 2 O [12]. Our reaction product exhibited this reactivity, forming compound 6 on treatment with KOH. Subsequent treatment of compound 6 with NaOAc/Ac 2 O, caused reformation of benzoxazinone 7a.
We also obtained benzoxazinone 7a in 40% yield by treatment of acid 8a with PCl 5 and then reacting the resultant acid chloride with anthranilic acid (Scheme 3). It is clear that under Ullmann reaction conditions, 3-bromo-7-methoxycoumarin (3) underwent rearrangement to 6-methoxybenzofuran-2-carboxylic acid (8a). The rearrangement of such coumarins is known to occur in alkaline media [13,14]. We verified our observation by subjecting compound 3 to treatment with potassium carbonate in DMF at 140°C for 4 hours -conditions as obtained for the attempted Ullmann reaction but without copper and anthranilic acid. Quantitative conversion to compound 8a, identical in all respects with an authentic sample [15], was achieved.
Compounds of type 6, then, would cyclize to yield 3,1-benzoxazin-4-ones more readily than they would to give the desired benzazepines. (Compound 8b on treatment with PCl 5 followed by anthranilic acid gave 7b.) We considered that absence of the amide proton would disallow benzoxazinone formation, and could augur well for occurrence of the desired cyclization. With this in mind, compound 10a was prepared as shown in Scheme 4. Treatment of 10a with PPA, however, yielded none of the required 11a and as predicted, none of the corresponding benzoxazinone was formed. Even after heating 10a in PPA at 80-100°C for 24 hours, only starting material was recovered. Compound 10a was also unreactive to Friedel-Crafts conditions. Treatment with PCl 5 followed by SnCl 4 for 23 hours at 95°C afforded only starting material. Our work with the analogous 2-carbophenoxy-5,6-dimethoxybenzofuran-2'-carboxylic acid (10b, X = O) also shows that it is inert to Friedel-Crafts reaction conditions (using SnCl 4 as Lewis acid) [16].

Acknowledgements
This work was supported in part by a UWI/IDB research grant, which is gratefully acknowledged.

General
All melting points are uncorrected. IR spectra (KBr disks) were obtained on a Perkin Elmer 735B model or a Perkin Elmer 1600 FT-IR spectrometer. NMR spectra were recorded were determined in  (6) To a 25 mL round bottomed flask fitted with a reflux condenser and a calcium chloride guard tube, were added 7-methoxy 3-bromocoumarin (3) (0.50 g, 1.97 mmol) and N, N-dimethylformamide (10 mL). Anthranilic acid (0.27 g, 1.97 mmol), potassium carbonate (0.875 g, 6.30 mmol), copper powder (5.0 mg) and copper (I) bromide (8 mg) were added with stirring to this solution and the mixture was heated at 140°C for 4 hours. The mixture was then allowed to cool, diluted with water (40 mL), and treated with decolorizing carbon (0.12 g). After filtration the filtrate was acidified with hydrochloric acid (3N) and the resulting precipitate was collected and washed with water (25 mL).

2-(6'-Methoxybenzofuran)-3,1-benzoxazin-4-one (7a)
a) Compound 6 (2.0 g, 6.43 mmol) was added to well-stirred PPA (20 mL) which had been preheated to 90°C. This mixture was stirred at 110°C for 2 h, then poured onto ice (200 g), neutralized with 6N ammonia, and the resultant precipitate filtered and washed with saturated sodium bicarbonate. The solid was air-dried and purified by chromatography (neutral alumina, 4:1 hexane-EtOAc) to give 7a b) PCl 5 (0.63 g, 3.04 mmol) was added, with stirring, to a mixture of 6-methoxybenzofuran-2carboxylic acid (8a, 0.38 g, 1.99 mmol) [13] in benzene (5mL). This was heated at reflux for 2 h, after which time it was cooled to room temperature and then in an ice-bath. Anthranilic acid (0.28 g, 2.01 mmol was dissolved in pyridine (1 mL) and this solution was added dropwise to the reaction mixture with cooling and stirring. Upon completion of addition the ice-bath was removed and the reaction mixture was stirred at room temperature for 3 h. Benzene was then evaporated in vacuo and water added to the resultant crude brown precipitate. This was then collected by filtration and air dried. Recrystallisation from methanol yielded 7a as pale yellow crystals (0.235 g, 40%).

Alkaline hydrolysis of compound 7a.
Compound 7a (51.6 mg, 0.18 mmol) was added to ethanol (2 mL) with stirring. To this mixture potassium hydroxide (50 mg, 0.89 mmol) was added and the mixture heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo and the crude product dissolved in the minimum amount of water and acidified with conc. HCl. The product was collected by filtration, washed with cold water and dried at the pump, to yield 6 as a white powder (51.4 mg, 94%), mp 209-212 º C.

Conversion of 6 to 7a using sodium acetate and acetic anhydride.
A mixture of 6 (38.7 mg, 0.12 mmol), acetic anhydride (0.65 mL) and sodium acetate (204 mg) was heated to 140ºC with stirring for 1 h. The reaction mixture was then cooled in an ice-bath and immediately solidified to give a pale yellow precipitate. Water (5 mL) was added to this precipitate and the solution extracted with dichloromethane. The organic extract was then concentrated in vacuo and the crude product recrystallised from methanol to yield 7a as a pale yellow powder (20.3 mg, 56%), mp 210-213 º C.
To a mixture of the amide 13 (1.66 g, 5.10 mmol) in CCl 4 (100 mL), N-bromosuccinimide (NBS) (1.11 g, 6.24 mmol) was added with stirring. The reaction was then enclosed in a dark box and irradiated with a 100 W light bulb which allowed gentle reflux. After 24 h the mixture was filtered, the filtrate was concentrated in vacuo, and the resulting crude product was triturated with hot hexane to yield 14 as a tan powder (1.

5,6-Dimethoxy-2-(methyl phenylcarbamoyl)-benzofuran-3-carboxylic acid (16a).
Compound 15 (0.39 g, 1.15 mmol) was dissolved in CCl 4 (47 mL) and NBS (0.26 g, 1.46 mmol) was added with stirring. The reaction was enclosed in a dark box and irradiated with a 100 W light bulb for 24 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo. To this brown residue, water (20 mL) was added and the mixture was left to stand overnight. The water was decanted and the resultant brown solid was dissolved in ethyl acetate. The solution was dried (Na 2 SO 4 ) and concentrated in vacuo . The crude product was recrystallised from ethanol to yield 16a as a tan powder (0. To PPA (2 mL) which had been pre-heated to 90 0 C, compound 16a (0.100 g, 0.28 mmol) was added with stirring over 15 min. The reaction mixture was then heated at 90°C for 24 h, poured into water/crushed ice (100mL) and was extracted exhaustively with ethyl acetate. The organic extract was dried (Na 2 SO 4 ) and concentrated in vacuo and the crude product was chromatographed (SiO 2 , 2:1 dichloromethane-ethyl acetate) to yield 11a as bright yellow needles (0.024 g, 25%); mp 227-229°C;