Walker, Gordon N. published the artcileApplication of sodium borohydride reduction to synthesis of substituted aminopiperidines, aminopiperazines, aminopyridines, and hydrazines, Safety of 4-Amino-2-picoline, the publication is Journal of Organic Chemistry (1961), 2740-7, database is CAplus.
Quaternization of 4-aminopyridine (I) with alkyl and arylalkyl halides gave 4-aminopyridinium salts, which were reduced with NaBH4 to 1-(alkyl or arylalkyl)-4-aminopiperidines. Both 1-alkyl-4-aminopiperidines and 1-alkyl-4-aminopiperazines could be converted to Schiff bases, which were reduced with NaBH4 to the corresponding secondary amines. Similar reduction of appropriate Schiff bases as a means of preparing substituted 3-aminopiperidines, aminopyridines, and aminomethylpyridines, as well as reduction of dialkylhydrazones to the corresponding trisubstituted hydrazines were also described. Anhydrous HBr was passed through a cold solution of 33.6 g. veratryl alc. in 500 mL. C6H6 10 min., the lower layer separated, the C6H6 treated with Na2CO3, stirred, the solution of veratryl bromide (II) filtered, and used in the following step without purification To the C6H6 solution of II was added 19 g. I; the mixture refluxed 1.5 h., filtered, and the product crystallized gave 54 g. 1-(3,4-dimethoxybenzyl)-4-aminopyridinium bromide (IIa), m. 248-50° (decomposition), (alc.). A simple two-step synthesis was used in the preparation of the 1,2-diphenylethyl- and 3,4-dimethoxyphenacyl-substituted compounds The remaining substances were prepared from the com. available bromo (in one case, iodo) compounds by the same procedure with a few modifications in solvents used and reaction times. In reactions involving α,ω-dibromoalkanes, a mixture of the compound, 2 equivalents I, and a suitable amount of PhMe was refluxed. The product often settled as an oil. In this case the supernatant was decanted, and the oil crystallized 2-Methyl-4-aminopyridine (III) was most conveniently synthesized by a 2-step reduction of 4-nitro-2-picoline N-oxide as follows. (A) The oxide (45 g.) in 200 mL. alc. containing 4 g. 10% Pd-C shaken under H at 45 lb./sq. in. gave 33 g. 2-methyl-4-aminopyridine N-oxide (IV), yellow crystals, m. 181-3° (alc.). IV (30 g.) in 300 mL. 1:1 AcOH-H2O treated with excess Zn dust, the mixture warmed 1 h., cooled, covered with Et2O, treated with a 40% solution of 500 g. NaOH, and the Et2O solution evaporated gave 16.8 g. III, m. 95° (cyclohexane). The following (4-H2NC5H4N)RBr were obtained (R, solvent prepared in, reflux time in hrs., % yield, and m.p. given): EtO2CCH2, C6H6-alc., 1.5, 92, 197°; EtO2CCH2CH2, PhMe, 5, 73, 159°; HOCH2CH2, PhMe, 3.5, 80, 131°; PhCH2, C6H6, 0.5, 90, 196°; Ph2CH, PhMe, 3, 56, 263°; PhCH2CH2, PhMe, 2, 77, 260°; PhCH2CHPh, C6H6, 9, 53, 245°; PhOCH2CH2, PhMe, 4.5, 75, 184°; BzCH2, C6H6, 2, 96, 308°; 3,4-(MeO)2C6H3COCH2, C6H6-alc., 0.3, 64, 271°; p-O2NC6H4CH2, PhMe, 5.5, 66, 266°; 2,4-(O2N)2C6H3, PhMe, 1, 56, 294°. The following [4-H2NC5H4N(CH2)nNC5H4-4]Br2 were similarly obtained (n, solvent, reflux time, % yield, and m.p. of product given): 4, PhMe, 2, 87, 273°; 6, PhMe, 14, 91, 303°; 8, PhMe, 5.5, 84, 300°; 9, PhMe, 5, 14, 221°; 10, PhMe, 5, 88, 247°; 11, PhMe, 7.5, 48, 216°; 12, PhMe, 13, 29, 209°; 16, PhMe (prepared from alkyl iodide), 11, 94, 185°. The following [2,4-Me(H2N)C5H4N(CH2)nNC5H4(NH2)Me- 4,2]Br2 were obtained (n, solvent, reflux time in hrs., % yield, and m.p. given): 8, PhMe, 8, 60, 304°; 9, PhMe, 9, 17, 275°. IIa (30 g.) in 700 mL. MeOH treated in 1 h. with 250 g. NaBH4, the mixture heated on a steam bath, cooled, treated with 500 mL. H2O, covered with 2 l. Et2O, the 2 phases treated with anhydrous K2CO3 to convert the lower layer to a paste, the Et2O separated, evaporated, the 20 g. oil dissolved in 30 mL. alc., and treated with dry HCl gave 12.2 g. 1-(3,4-dimethoxybenzyl)-4-aminopiperidine-2HCl, m. 223-5° (decomposition) (MeOH-Et2O). Other 4-aminopiperidines were obtained from the resp. quaternary salts by the same procedure. The free bases were hygroscopic oils. The amines had to be salted out with NaCl. When 4-aminopiperidines, as free bases, were required for further work, they were used directly in the crude state. 1-Methyl-4-aminopiperidine and 1-(β-hydroxyethyl)-4-aminopiperidine, both formed hygroscopic salts with HCl. The following 4-(N-substituted-amino)piperidine-2HCl were thus obtained (R, % yield, and m.p. given): EtO2CCH2, 17, 169°; PhCH2, 41, 255°; PhCH2CH2, 88, 321°; PhCH2CHPh, 40, 237° (decomposition); PhOCH2CH2, 44, 220°; PhCH(OH)CH2, 90, 248° (decomposition); 3,4-(MeO)2C6H3CH(OH)CH2, 56, 220° (decomposition); p-O2NC6H4CH2, 10, 265° (decomposition). The following 4-H2NC5H4N(CH2)nNC5H4NH2-4.4HCl were similarly obtained (n, % yield, and m.p. given): 6, 22, 204°; 10, 16, 295°; 12, 34, 311°; 16, 20, 315°. 1,10-Bis(4-amino-1-piperidyl)decane was also characterized by preparation of the bis(dichloroacetate)-2HCl, m. 227-30° (decomposition) (alc.). 1-Methyl-4-aminopiperazine (8.1 g.) and 11.2 g. veratraldehyde in 200 mL. PhMe refluxed 1.5 h., evaporated, the residue dissolved in 150 mL. MeOH, the solution reduced with 40 g. NaBH4, heated 0.5 h. on the steam bath, and the 20.5 g. yellow oil treated with alc. HCl gave 10 g. 1-methyl-4-(3,4-dimethoxybenzylamine)piperazine, m. 199-202° (decomposition). Other secondary aminopiperidines and aminopiperazines were given in a table. Attempts to reduce imines derived from 1-phenyl-2-propanone and 1-substituted 4-aminopiperidines with NaBH4 did not lead to desired products, probably because of cleavage of the unstable imines. 3-Aminopyridine (16.8 g.) and 30 g. veratraldehyde in 500 mL. xylene refluxed 24 h. and the 45.5 g. residual oily imine in MeOH reduced with NaBH4 gave 33 g. 3-(3,4-dimethoxybenzylamino)pyridino (V), m. 123-5° (MeOH). The other pyridines were similarly prepared The following RNHR’ were thus obtained (R, R’, % yield, and m.p. given): 3,4- dimethoxybenzyl, 1-methyl-4-piperidyl, 60, 254-6° (decomposition); 3,4,5-trimethoxybenzyl, 1-methyl-4-piperidyl, 37, 264-5° (decomposition); 3,4-dimethoxybenzyl, 1-(β-hydroxyethyl)-4-piperidyl, 12, 255-6° (decomposition); 4-methoxybenzyl, 1-(3,4-dimethoxybenzyl)-4-piperidyl, 46, 274-5° (decomposition); 3,4,5-trimethoxybenzyl, 1-methyl-4-piperazyl, 56, 135-7°; p-dimethylaminobenzyl, 1-methyl-4-piperazyl, 40, 125-7° (157-60°); 3-pyridylmethyl, 1-methyl-4-piperazyl, 95, 201-2° (220-6° with 0.5H2O); 1-hydroxy-1-phenyl-2-Pr, 1-methyl-4-piperazyl, 25, 219-21° (decomposition); 3,4-dimethoxybenzyl, 2-pyridyl, 65, 102-3°; 3,4,5-trimethoxybenzyl, 2-pyridyl, 45, 167-8°; p-dimethylaminobenzyl, 2-pyridyl, 52, 125-6°; 3,4,5-trimethoxybenzyl, 3-pyridyl, 63, 109-10°; 3,4,5-trimethoxybenzyl, 3-pyridylmethyl, 90, 205-7°; p-dimethylaminobenzyl, 3-pyridylmethyl, 96, 185-6° (decomposition); 3,4-dimethoxybenzyl, 4-pyridylmethyl, 22, 200° (decomposition); 3,4,5-trimethoxyhenzyl, 4-pyridylmethyl, 43, 214-16°; p-dimethylaminobenzyl, 4-pyridylmethyl, 45, 195-6°; 1-phenyl-2-Pr, 3-pyridylmethyl, 55, 205-7°; 1-phenyl-2-Pr, 4-pyridylmethyl, 80, 181-3°; 3,4,5-trimethoxybenzyl, NMe2, 45, 81-3; p-dimethylaminobenzyl, NMe2, 7, 158-61° (decomposition); 1-phenyl-2-Pr, NMe2, 70, 123-5°; 1,2-diphenylethyl, NMe2, 23, 183-5°; PhCH:CHCHMe, NMe2, 5, 117-20° (decomposition). V (14.1 g.) converted rapidly to the MeI salt, evaporated, the crystals suspended in 200 mL. MeOH, reduced with 125 g. NaBH4, and the residual oil treated with HCl gave 14.6 g. 1-methyl-3-(3,4-dimethoxybenzylamino)piperidine-2HCl, m. 233-5° (decomposition). 3-Aminopiperidine (7.6 g.), 12.7 g. veratraldehyde, and 250 mL. PhMe refluxed 3.5 h., the crude imine reduced with NaBH4 in alc., and crystallized gave 20.6 g. V.2HCl, m. 229-31° (alc.). Reduction of p-dimethylaminobenzylidene derivative and isolation gave 76% 3-(4-dimethylaminobenzylamino)piperidine, no definite m.p. 3-(3-Pyridylmethylamino)piperidine was obtained in 79% yield by reduction of the 3-pyridylidene derivative and isolated as the tri-HCl salt. Veratraldehyde (16.3 g.) and 6.5 g. N,N-dimethylhydrazine mixed, the oil taken up in 200 mL. C6H6, the solution refluxed 4 h., evaporated, and the hydrazone reduced in MeOH with NaBH4 gave 13.9 g. N,N-dimethyl-N-(3,4-dimethoxybenzyl)hydrazine-HCl, m. 172-4.5°. The other hydrazine derivatives above were prepared by the same method.
Journal of Organic Chemistry published new progress about 18437-58-6. 18437-58-6 belongs to pyridine-derivatives, auxiliary class Pyridine,Amine, name is 4-Amino-2-picoline, and the molecular formula is C12H9NO, Safety of 4-Amino-2-picoline.
Referemce:
https://en.wikipedia.org/wiki/Pyridine,
Pyridine | C5H5N – PubChem