Pyrrolo benzoxazepines

Benzopyrrolo[l,2]oxazepines 68 (X = O) can be obtained from the corresponding acids 67 by an intramolecular Friedel-Crafts acylation (Scheme 14, Section 2.1.1.5 (1996JMC3435, 2002JMC4276)). Similarly, pyrrolo-benzoxazepines 261 are accessible by intramolecular Friedel-Crafts cyclization of acids 260... 

N -(2-Hydroxymethylphenyl)pyrrole is prone to selective a-metalation with fj-BuLi-potassium ferf-butoxide. Trapping the formed anion with a variety of electrophiles and treatment of the crude products with silica gel in toluene results in pyrrolo-benzoxazepines 266 and pyrrolo-benzoxazepinone 267 (Scheme 57 (1994T2071)). 

Af-Phenylpyrrole generates a di-lithio derivative which after trapping with acetone and treatment with silica gel produces tetramethyl pyrrolo-benzoxazepine... 

Pyrrolo-benzoxazepines with other fusion modes. As with diazepine, benzoxazepine with the fused pyrrole ring 250a can be prepared by condensing ortho-amino phenol (X = O) with pyrrole carbaldehyde 249 in moderate yield (Equation (31), Section 3.1.1.4 (2006X6018)). 

The ester derivative of pyrrolo-benzoxazepine 403 (Scheme 84) has been transformed into ketone 404 with methyl lithium, while ester 406 was synthesized by esterification with acetyl bromide of alcohol 405, prepared by LAH reduction of 403 (1996JMC3435). 

Amino and imino groups. Amino thieno benzoxepine 163 (Scheme 32, Section 2.2.3) can be smoothly transformed into the corresponding amides and urea (1994JCS(P1)2191). The dimethylamino substituted pyrrolo-benzoxazepine... 

Pyrrolo-benzoxazepine 402 (Scheme 84, Section 5.2.1.1) gives ester 403 through the triflate intermediate by reaction with carbon monoxide and methanol in the presence of tetrakis(triphenylphosphine)palladium (1996JMC3435). 

The 5a-alkyl-l,2,5a,8,ll,lla-hexahydro-3/f,5//-pyrrolo[2,l-c][l,4]benzoxazepin-5-ones 1 and the l-[(l-alkyl-2-methoxy-2,5-cyclohcxadienyl)carbonyl]-2-(methoxymethoxymethyl)pyr-rolidines 2 can be rearranged and protected. The keto esters 3 thus obtained have been used as chiral synthetic intermediates28,32. 

Chemical Name 2H-Benzimidazol-2-one, l,3-dihydro-l-[l-[(4-methyl-4H,6H-pyrrolo[l,2-a][4,l]benzoxazepin-4-yl)methyl]-4-piperidinyl]-, maleate (1 1)... 

To a solution of 34.6 g of 2-(pyrrol-l-yl)benzyl alcohol in 300 ml of anhydrous tetrahydrofuran and 32 ml of tetramethylethylene diamine is added 183 ml of a 2.4 molar solution of n-butyl lithium in such a manner that the internal temperature of the reaction is maintained below 30°C. On completion of the addition, the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is then cooled to -70°C by means of a dry-ice/acetone bath, and 24 ml of ethyl pyruvate is added to the mixture over 1 minute. The reaction is then allowed to warm to room temperature and stirred overnight (18 hours). The reaction is then poured into an ice-water/ether mixture and the organic phase separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield ethyl-4-methyl-4H,6H-pyrrolo[l,2-a][4,l]benzoxazepine-4-carboxylate, MP 94°-96°C, which may be recrystallized from a mixture of ether-hexane (1 1). 

The mixture of 41 g thereof, 180 ml of 3 N sodium hydroxide and 150 ml of ethanol is heated at reflux temperature for 6 hours. The ethanol is then removed by evaporation under reduced pressure and the aqueous solution is acidified to pH 5 with 6 N HCI. The resulting product, 4-methyl-4H,6H-pyrrolo[l,2-a][4,l]benzoxazepine-4-carboxylic acid, MP 182°-183°C, is collected by filtration, and may be recrystallized from aqueous ethanol. 

To a solution of 7.5 g thereof, in 300 ml of tetrahydrofuran is added 5 g of l,l -carbonyldiimidazole and the resultant mixture stirred at room temperature for 1 hour. To this mixture is added 5 g of l,3-dihydro-l-(4-piperidyl)-2H-benzimidazol-2-one, and the reaction is heated at reflux temperature for 48 hours. After cooling to room temperature, the reaction mixture is poured into 150 ml of ice-water and extracted into 150 ml of methylene chloride. The organic extracts are washed successively with 150 ml of sodium carbonate solution, 150 ml of water and 150 ml of dilute hydrochloric acid, then dried over magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure to yield l,3-dihydro-l- l-[(4-methyl-4H,6H-pyrrolo[l,2-a][4,l]benzoxazepin-4-yl)carbonyl]-4-piperidinyl -2H-benzimidazol-2-one, m.p. 208°-210°C. 

The unsubstituted pyrrolo[l,2-a][4,l]benzoxazepine system (183) has been prepared from (182) by heating or by treatment with phosphorus pentoxide. The 6-oxo-derivative (184) was also prepared from (181), by selective reduction of the aldehyde and cyclization. ... 

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