Experimental:Reaction of 5-Cyanoindole with:A. Acid Chlorides and Stannic Chloride.
The following preparation of 3-acetyl-5-cyanoindole (II) is representative of the procedure used to prepare the related ketones listed in Table I. To an ice cold suspension of 25.0 g. (0.176 mole) of 5-cyanoindole in 400 ml. of benzene containing 21.5 ml. (0.302 mole) of acetyl chloride was added, dropwise with stirring, a solution of 35.5 ml. (0.305 mole) of anhydrous stannic chloride in 100 ml. of benzene. An orange-red complex precipitated and the mixture was stirred at 0-5° for 1 hour and mixed with 1250 ml. of ice cold water. The resulting mixture was stirred for 30 minutes at 0-5° and the solid collected by filtration, washed thoroughly with water and dried. The crude material was treated with 800 ml. of hot acetone and allowed to stand for a few hours. The product was collected and dried to yield 20.0 g. of off-white crystals, m. p.>300°. A second crop of 2.8 g., m. p. >300°, was obtained by concentration of the mother liquors to 300 ml. The total yield of 3-acetyl-5-cyanoindole was 22.8 g. or 70%.B. Acid Anhydride and Stannic Chloride.
This reaction was conducted as above with 3.90 g. (27 mmoles) of 5-cyanoindole, 4.3 ml. (43 mmoles) of acetic anhydride and 9.7 ml. (80 mmoles) of stannic chloride to give a crude yield of 4.67 g. (93%), of II, m. p. 230-300°. This material was dark colored and required a recrystallization from 75 ml. of acetonitrile to yield 3.26 g. (65%), m.p. 300-305°. The purified material was still of inferior quality as compared with that obtained by the acid chloride procedure. Runs with propionic anhydride gave similar results.C. Trifluoroacetic Anhydride.
To 12 ml. of ice cold trifluoroacetic anhydride was added slowly 2.00 g. of 5-cyanoindole and the mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness in vacuo and the residue was stirred between 10 ml. of ether and 10 ml. of saturated aqueous sodium bicarbonate solution. The solid was collected, washed thoroughly with water and ether and dried to leave 2.91 g. (88%) of the trifluoroketone (VII). An analytical sample was obtained by recrystallization from ethanol.Reduction of Ketones with:A. Sodium borohydride in Ethanol.
Ethanolic solutions of equal weights of the ketones and sodium borohydride were refluxed for 1 hour. The solvents were removed in vacuo and the residues diluted with water. Solid products at this stage were collected by filtration and liquid ones extracted into chloroform. The crude products were either extracted with hot benzene and recrystallized from the solvent or were chromatographed on silica gel. The methyl ketone (II) gave only an unstable syrup when reduced at 0-5°, room temperature or at reflux. Its infrared spectrum showed no carbonyl absorption at 6.10u. The phenyl ketone (V) gave mostly 3-benzyl-5-cyanoindole (XV) when run at reflux as shown by infrared comparison with analytically pure material. When the reaction was conducted at room temperature a crystalline solid, m.p. 129-131.5°, was obtained whose analysis indicated it to be mostly the alcohol.B. Sodium Borohydride in 1-Propanol.
Solutions of the ketones (1 g.) and sodium borohydride (2 g.) in 2,55 ml. of 1-propanol were stirred at reflux for 15 hours. The solvent was evaporated in vacuo and the residues were partitioned between chloroform and water. Evaporation of the chloroform gave 70-90% yields of crude products, which showed the presence of two spots (Rf, 0.5 and 0.6-0.75) on silica gel thin layer plates when developed with chloroform and detected with iodine vapor. The spot at Rf, 0.5 was identical with that of 5-cyanoindole and the faster moving spots were the 3-alkyl-5-cyanoindoles (XII-XVI). No spots corresponding to the previously described ketones or alcohols (Rf, 0-0.2) were detected. The alkylindoles were obtained in low yield either by repeated recrystallization from benzene or cyclohexane or by column chromatography on silica gel. From the reduction of the isobutylketone (IV), 5-cyanoindole was isolated by column chromatography and identified by its infrared spectrum. The trifluoroketone (VII) was not investigated under these reduction conditions. Exposure of the alcohol (X) to the above reduction conditions afforded 5-cyanoindole and 5-cyano-3-phenethylindole (XVI) as shown by thin layer chromatography. 3-Bromoacetyl-5-cyanoindole (XVII).
To a solution of 5.00 g. (27.2 mmoles) of 3-acetyl-5-cyanoindole (II) in 50 ml. of dimethylformamide at 50° was added slowly a solution of 2.5 ml. (45.8 mmoles) of bromine in 75 ml. of methanol. The mixture was stirred for one hour at 50° and allowed to stand at room temperature for 15 hours. The white precipitate that formed was collected, washed with water, and dried to leave 5.45 g. (76%) of product, m. p. 278-284° (dec.). An analytical sample, m. p. 288-292°, was obtained by recrystallization from acetonitrile.3-(2-Bromopropionyl)-5-cyanoindole (XVIII).
A mixture of 2.01 g. (10.3 mmoles) of 5-cyano-3-propionylindole (III), 3.6 g. (9.6 mmoles) of trimethylphenylammonium tribromide (10) and 75 ml. of tetrahydrofuran was stirred at 35-40° for 27 hours. The solvent was removed in vacuo and the residue stirred with 100 ml. of water. The insoluble product was collected, washed thoroughly with water, and dried to leave 2.81 g. (99%), of XVIII, M.P. 259-262° (dec.). Recrystallization from acetone of material from another run provided an analytical sample, m.p. 244-246°. Considerable variation in melting points was observed for different runs, although the infrared spectra were essentially the same.3-Bromoacetyl-5-nitroindole (XIX).
This bromoketone was prepared by the same procedure for 3-bromoacetyl-5-cyanoindole (XVII). The product, m.p. >300°, was obtained in 46% yield after recrystallization from ethanol-dimethylformamide. alpha-Azido-3-indolylketones.
A mixture of the appropriate 5-cyano-alpha
-bromoketone (1 g.), sodium azide (2 g.) and 83% dimethylformamide (60 ml.) was stirred at 40° for 15 hours. The mixture was diluted with 30 ml. of water and the precipitate was collected, washed with water and dried. The crude products were recrystallized from aqueous dimethylformamide. 3-azidoacetylindole (XXVIII) was similarly prepared from 3-bromoacetylindole  but in 83% methanol and the product was recrystallized from ethanol. The azido ketones exhibited prominent bands at 4.7 microns in the infrared. The data for these compounds appear in Table II.alpha-Dialkylamino-3-indolylketones.
The various alpha
-bromoketones were allowed to react with a 3-4 mole excess of an appropriate secondary amine in refluxing 2-propanol, according to the general procedure of Bodendorf and Walk . The data for these compounds are presented in Table II.Substituted Tryptamines.
The appropriate dialkylaminoketone or azidoketone was refluxed with twice its weight of sodium borohydride in 1-propanol for 15 hours. The solvent was evaporated in vacuo and the residue was partitioned between water and chloroform. The chloroform extract was extracted with 3N-hydrochloric acid to separate the tryptamines from accompanying 3-unsubstituted indoles. 5-Cyanoindole (identified by infrared analysis and mixed melting point determination) was obtained from the reduction of XXI and indole (identified by infrared spectrum) was obtained from XXIX. The acid extracts were alkalized with 10% sodium hydroxide and the liberated bases extracted into chloroform. The tryptamines were isolated either as the free base or picrate salt. The data for the tryptamines appear in Table III.3-(2-Azido-1-hydroxyethyl)-5-cyanoindole (XXXVII).
A mixture of 0.50 g. (13.3 mmoles) of sodium borohydride, 0.50 g, (2.2 mmoles) of 3-azidoacetyl-5-cyanoindole (XX) and 10 ml. of ethanol was stirred at room temperature for one hour. The ethanol was evaporated in vacuo and the residue was taken up in 30 ml. of water. The aqueous solution was extracted with four 15-ml. portions of chloroform. The chloroform extract was dried over magnesium sulfate and evaporated in vacuo to leave 0.43 g. (84%) of a syrup, which later solidified to give pale green plates, m. p. 121-123°3-(2-Azido-1-hydroxyethyl)indole (XXXVIII).
To a stirred suspension of 0.70 g. of 3-azidoacetylindole (XXVIII) in 28 ml. of methanol was slowly added 0,70 g, of sodium borohydride. The mixture was stirred at ambient temperature for 1 hour and evaporated in vacuo. The residue was partitioned between 30 ml. of water and 30 ml. of ether. The ether extract was washed with 10 ml. of water, dried over magnesium sulfate and evaporated in vacuo to leave 0.53 g. of a clear syrup3-(2-Amino-1-hydroxyethyl)indole Picrate (XXXIX).
A mixture of 0.53 g. of the azido alcohol (XXXVIII), 50 mg. of platinum oxide and 10 ml. of ethanol was stirred under an atmosphere of hydrogen for 5 hours. Only uptake for the catalyst was observed. The catalyst was removed by filtration and the filtrate was evaporated in vacuo
to leave a viscous syrup. The infrared spectrum showed complete loss of the azide band and stronq OH, NH absorption with association typical of amino alcohols. The syrup was dissolved in 5 ml. of ethanol and added to 0.65 g. of picric acid in 50 ml. of warm water. The resulting yellow, crystalline precipitate was collected, washed with water and dried to leave 0.80 g., m.p. 146-150° (dec. ). A 200 mg. portion was recrystallized from 5 ml. of ethanol to yield 55 mg. of picrate, m.p. 148-150° (dec. ). Ames, et al. had previously obtained this material by reduction of 3-N-carbobenzoxy-glycylindole; picrate, m.p. 100° (dec.).References:
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