(4-fluorophenyl)hydrazine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenyl hydrazine.HCl, and the heterogeneous mixture brought to reflux at a bath temperature of 115° C. for 15 hours. During the course of reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23° C., a crystalline precipitate formed. The solution was poured into ice water (1000 mL) and stirred for 20 minutes. The yellow/brown crystals were filtered off, washed with additional cold water, and dried in vacuo to provide 5.8 g (86%) of product. (J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23,2603) 1H NMR (300 MHz, DMSO-d6) δ 7.31-7.41 (m, 2H), 7.57-7.57-7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347 (Br79Br79 M+H)+, m/z 349 (Br79Br81 M+H)+, m/z 364 (Br79Br79 M+NH4)+, and m/z 366 (Br79Br81 M+NH4)+. During the course of reaction upon cooling to 23° C. a crystalline precipitate formed The yellow/brown crystals were filtered off washed with additional cold water dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Plattner et al. and Harbert et al. also describe the earliest synthesis of flutroline: p-fluorophenylhydrazine is condensed with N-carbethoxy-4-piperidone to form 8-fluoro-2-carbethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. By the Ullman reaction the latter is arylated to form the 5-(p-fluorophenyl) derivative and then hydrolyzed under vigorous basic conditions to yield 8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (an intermediate common to the present processes). The earlier synthesis of flutroline is completed by 2-alkylation with 3-(p-fluorobenzoyl)propyl chloride and reduction of the ketone to an alcohol group with sodium borohydride.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Oxo-pentanoic acid ethyl ester (17.6 ml, 0.124 mol.) and conc. sulfuric acid (10 ml) were added to a solution of 4-fluorophenylhydrazine (20.2 g, 0.124 mol.) in abs. ethanol (90 ml), and the mixture was heated at reflux for 4 h. For working up, the mixture was filtered over silica gel and washed with ethanol (3×20 ml). The solution was poured into 500 ml of ice-water and extracted with ether (3×100 ml). The combined extracts were washed with 2M sodium hydrogen carbonate solution (50 ml), dried, filtered and concentrated. By recrystallisation from EE/cyclohexane (1:1) it was possible to obtain (5-fluoro-2-methyl-1H-indol-3-yl)acetic acid ethyl ester in a yield of 4.5 g (yellow solid, m.p. 61–62° C.). at reflux for 4 h the mixture was filtered over silica gel washed with ethanol (3×20 ml) The solution was poured into 500 ml of ice-water extracted with ether (3×100 ml) The combined extracts were washed with 2M sodium hydrogen carbonate solution (50 ml) dried filtered concentrated By recrystallisation from EE/cyclohexane (1:1) it

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir: