2-propylaniline

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

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

Procedure: 2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane.

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

Procedure: 2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane.

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10° C., then the mixture was allowed to stir at 10° C. for 30 min. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf0.43. This material was used in the next step without further purification. while maintaining the temp at 10° C. extracted with EtOAc (4×40 mL) The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) a saturated NaHCO3 solution (30 mL), dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10° C., then the mixture was allowed to stir at 10° C. for 30 min. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf0.43. This material was used in the next step without further purification. while maintaining the temp at 10° C. extracted with EtOAc (4×40 mL) The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) a saturated NaHCO3 solution (30 mL), dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of 2-n-propylaniline (8.91 g, 66 mmol) and Et3N (14 mL, 106 mmol) in CH2Cl2 (60 mL) was added acetic anhydride (10.9 mL, 99 mmol) dropwise. The resulting mixture was allowed to stir at room temp. overnight, then was treated with a 1N HCl solution (40 mL). The acidic mixture was extracted with CH2Cl2 (2×30 mL). The combined organic layers were sequentially washed with H2O (40 mL), a 1N NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting powder was purified by crystalization (EtOAc) to give 2-n-propylacetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc/hex) Rf0.37. The acidic mixture was extracted with CH2Cl2 (2×30 mL) The combined organic layers were sequentially washed with H2O (40 mL) a 1N NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4) concentrated under reduced pressure The resulting powder was purified by crystalization (EtOAc)

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

Procedure: To a solution of 2-n-propylaniline (8.91 g, 66 mmol) and Et3N (14 mL, 106 mmol) in CH2Cl2 (60 mL) was added acetic anhydride (10.9 mL, 99 mmol) dropwise. The resulting mixture was allowed to stir at room temp. overnight, then was treated with a 1N HCl solution (40 mL). The acidic mixture was extracted with CH2Cl2 (2×30 mL). The combined organic layers were sequentially washed with H2O (40 mL), a 1N NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The resulting powder was purified by crystalization (EtOAc) to give 2-n-propylacetanilide as white needles (7.85 g, 67%). TLC (30% EtOAc/hex) Rf0.37. The acidic mixture was extracted with CH2Cl2 (2×30 mL) The combined organic layers were sequentially washed with H2O (40 mL) a 1N NaOH solution (40 mL), H2O (40 mL) and a saturated NaCl solution (40 mL), dried (Na2SO4) concentrated under reduced pressure The resulting powder was purified by crystalization (EtOAc)

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

Procedure: Procedure as described for Amidine X using the following amounts: 6.00 mL of 2-n-propylaniline (42.6 mmol); 21.3 mL of 2.0 M butyllithium (42.6 mmol); 5.00 g of toluonitrile (42.6 mmol). Filtration of the final pentane solution yielded 9.53 g (89%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.76 (d, 2H), 7.22 (m, 3H), 7.15 (t, 1H), 6.99 (t, 1 H), 6.84 (d, 1 H), 4.69 (s, 2H), 2.51 (t, 2H), 2.39 (s, 3H), 1.58 (m, 2H), 0.90 (t, 3H). Filtration of the final pentane solution yielded 9.53 g (89%) of light yellow solid

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

Procedure: The hydrochloride salt of 2-propylaniline was prepared by dissolution of a commercial sample of 2-propylaniline in ethyl ether and addition of an ethereal solution of hydrogen chloride until no further precipitate formed. This precipitate was collected by filtration, washed with ether, and dried briefly in vacuo to provide 2-propylaniline hydrochloride, which was used immediately according to the following procedure. A suspension of this material (34.33 g) was prepared in a prechilled solvent mixture of acetic acid (120 ml), water (77 ml), and concentrated hydrochloric acid (43.4 ml), and was held at -12° with efficient stirring. Using strong external cooling as necessary to maintain an internal temperature between -15° and -10°, a solution of sodium nitrite (14.21 g) in water (67 ml) was added over a period of about 20 min. The mixture was then stirred at -18° for 15 min, and was then filtered into a waiting, prechilled (-7°) solution of 2-cyanoacetamide (50.44 g) in water (2.0 liters) containing sodium acetate (266.7 g). There was an immediate color change to deep yellow followed by the formation of a yellow precipitate. The reaction mixture was stirred in a -11° bath for two days. After warming to 10°, the precipitate was collected by filtration, and was washed alternately with hexanes and ice-cold water. After drying at 45° in vacuo over phosphorus pentoxide, there was obtained 42.12 grams (91% yield) of the title compound as a mixture of (E)- and (Z)-isomers. formed This precipitate was collected by filtration washed with ether dried briefly in vacuo

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

Procedure: The hydrochloride salt of 2-propylaniline was prepared by dissolution of a commercial sample of 2-propylaniline in ethyl ether and addition of an ethereal solution of hydrogen chloride until no further precipitate formed. This precipitate was collected by filtration, washed with ether, and dried briefly in vacuo to provide 2-propylaniline hydrochloride, which was used immediately according to the following procedure. A suspension of this material (34.33 g) was prepared in a prechilled solvent mixture of acetic acid (120 ml), water (77 ml), and concentrated hydrochloric acid (43.4 ml), and was held at -12° with efficient stirring. Using strong external cooling as necessary to maintain an internal temperature between -15° and -10°, a solution of sodium nitrite (14.21 g) in water (67 ml) was added over a period of about 20 min. The mixture was then stirred at -18° for 15 min, and was then filtered into a waiting, prechilled (-7°) solution of 2-cyanoacetamide (50.44 g) in water (2.0 liters) containing sodium acetate (266.7 g). There was an immediate color change to deep yellow followed by the formation of a yellow precipitate. The reaction mixture was stirred in a -11° bath for two days. After warming to 10°, the precipitate was collected by filtration, and was washed alternately with hexanes and ice-cold water. After drying at 45° in vacuo over phosphorus pentoxide, there was obtained 42.12 grams (91% yield) of the title compound as a mixture of (E)- and (Z)-isomers. formed This precipitate was collected by filtration washed with ether dried briefly in vacuo

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

Procedure: 2-n-Propylaniline was converted to 4-iodo-2-n-propylaniline according to Method A5a. The aniline was converted to 4-iodo-2-n-propylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-n-propylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-n-propylphenylimino)-1-thia-3-azaspiro[4.4]nonane.

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-n-propylaniline in MeOH (25 mL) was added a solution of NaHCO3 (5.0 g, 59.5 mmol) in H2O (25 mL). Iodine (8.4 g, 33.3 mmol) was added portionwise over 70 min. while maintaining the temp. at 10° C., then the mixture was allowed to stir at 10° C. for 30 min. The resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) and a saturated NaHCO3 solution (30 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-iodo-2-n-propylaniline (9.4 g, 98%): TLC (20% EtOAc/hex) Rf0.43. This material was used in the next step without further purification. while maintaining the temp at 10° C. extracted with EtOAc (4×40 mL) The combined organic layers were sequentially washed with a 5% Na2S2O3 solution (30 mL) a saturated NaHCO3 solution (30 mL), dried (Na2SO4) concentrated under reduced pressure