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The reaction of an aromatic heterocycle with a proton is called a protonation. One of articles about this theory is 《Aminoalkylphenols as antimalarials. II. (Heterocyclic amino)-α-amino-ο-cresols. The synthesis of camoquin》. Authors are Burckhalter, J. H.; Tendick, F. H.; Jones, Eldon M.; Jones, Patricia A.; Holcomb, W. F.; Rawlins, A. L..The article about the compound:4-Chloro-8-methylquinolinecas:18436-73-2,SMILESS:CC1=C2N=CC=C(Cl)C2=CC=C1).Application In Synthesis of 4-Chloro-8-methylquinoline. Through the article, more information about this compound (cas:18436-73-2) is conveyed.

In view of the high antimalarial activity of certain substituted α-amino-ο-cresols, earlier work (C.A. 41, 414d) has been extended to analogs containing heterocyclic nuclei. This reports the preparation of a group of 122 (heterocyclic amino)-α-amino-ο-cresols and a related group of 12 (heterocyclic amino)benzylamines, as well as the new intermediates used therein. This work has resulted in the preparation of a promising antimalarial (SN 10,751) named camoquin, as well as other compounds which are the most active 4-aminoquinoline derivatives heretofore reported in trophozoite-induced Plasmodium gallinaceum infection in the chick. Catalytic reduction of the appropriate nitrophenol in the presence of Ac2O gave these 4-acetamidophenols: 2-Cl, m. 144°, 55% yield; 2-Ph, m. 160°, 60%; and 2-acetamidophenols: 4-Cl, m. 186°, 52%; 4-Ph, m. 165°, 89%; and 4-tert-Bu, m. 170°, 79%. 2-Allyl-4-acetamidophenol, m. 93-4°, was obtained in 83% yield from the rearrangement of 4-CH2:CHCH2OC6H4NHAc. The Mannich reaction on the substituted acetamidophenols gave these 4-acetamido-α-substituted-ο-cresols: diethylamino (I), m. 135°, 82%; dibutylamino, m. 73°, 87% (picrate, m. 183-5°); dibenzylamino, m. 230°, 75%; (2-methyl-1-piperidyl) (HCl.H2O, m. 175°, 65%); 4-morpholinyl, m. 133°, 27%; [methyl(2-hydroxyethyl)amino] (HCl, m. 198°, 50%); (2-butylamino), m. 156°, 37%; (2-hydroxyethylamino) (HCl, m. 230°, 31%); the 6-allyl derivative of I, m. 86°, 58%: the 5-acetamido isomer of I (HCl, m. 210°, 33%); and these 6-acetamido-α-diethylamino-4-substituted-ο-cresols: Cl (HCl, m. 212°, 66%); tert-Bu (HCl, m. 158°, 53%); and Ph (HCl, m. 183°). Acid hydrolysis of the appropriate 4-acetamido compound gave these 4-amino-α-substituted-ο-cresols (di-HCl salts) (all m. with decomposition); diethylamino, SN 12,458, m. 218-20°, 96%; 1-piperidyl, m. 153-5°, 91%; and 4-morpholinyl, m. 259-60°, 45%. The Mannich reaction on 4-nitrophenol (A) and the reaction of the amine on 2-(chloromethyl)-4-nitrophenol (B) were used to prepare these α-substituted-4-nitro-ο-cresol HCl salts (all m. with decomposition): diethylamino, A, m. 224°, 40%; diisopropylamino, B, m. 193°, 19%; dibutylamino, B, m. 176°, 75%; diisobutylamino (free base), B, m. 113°, 43%; diisoamylamino, B, m. 132°, 32%; isopropylamino, B, m. 238°, 38%; isobutylamino, B, m. 247°, 29%; tertbutylamino, B, m. 275°, 20%; 1-piperidyl, A, m. 260°, 68%; and α-diethylamino-4-nitro-6-phenyl-ο-cresol, A, m. 125°, 21%; and 4-tert-butyl-α-diethylamino-6-nitro-ο-cresol, A, m. 103°, 50%. The method of Price and Roberts (C.A. 40, 5739.5) was used to prepare these substituted 4-chloroquinolines: 6-Me, m. 55°, 50%; 6-anilino, m. 148°, 6%; 7-EtO, m. 76°, 53%; 7-hexyloxy, a high-boiling liquid, 41%; 8-Me, m. 99°, 71%; 5,7-di-Me, m. 59°, 51%; 5,8-di-Me, m. 51°, 59%; 5-chloro-8-methoxy, m. 127°, 6%; 5-methyl-8-methoxy, m. 78°, 45%; 6,8-di-Me, m. 90°, 82%; and 6,7,8-trichloro, m. 156°, 39%. The (heterocyclic amino)-α-alkylamino-ο-cresols were prepared by minor variations of the general procedure of heating the chloroheterocycle with the amino-α-alkylamino-ο-cresols in aqueous or alc. solution on the steam bath. The latter were obtained either by acid hydrolysis of the acetamido derivatives or by catalytic reduction of the nitro derivatives and were usually condensed without isolation. The products are isolated either as the free bases or HCl salts. All the quinine equivalents (Q) reported here are based on the B4 test using P. gallinaceum in the chick. Nearly all the HCl salts m. with decomposition and are colored yellow to orange. 4-(4-Quinolylamino)-α-diethylamino-ο-cresol (II) di-HCl, SN 12,452, m. above 300°, was obtained in 48% yield and had a quinine equivalent of 3 (designated hereafter in the form Q 3). Analogs of II, substituted on the quinoline nucleus: 2-Cl (2HCl, SN 11,986, m. 248°, 30%, Q <0.07); 3-Ph, SN 11,631, m. 155°, 31%, Q 0.4; 6-MeO (2HCl, SN 10,274, m. 270°, 75%, Q 8); 6-Cl (HCl.0.5H2O, SN 11,597, m. 220°, 60%, Q 3.0); 6-Me, SN 11,559, m. 172° (2HCl, m. 238°, 56%, Q 4); 6-anilino (2HCl.H2O, SN 12,361, m. 196°, 63%, Q 0.2); 6-dimethylamino (3HCl.0.5H2O, SN 11,984, m. 235°, 73%, Q 2.5); 6-nitro (2HCl.1.5H2O, m. 210°, 63%, Q 0.8); 7-MeO (2HCl.0.5H2O, SN 11,554, m. 210°, 43%, Q 7); 7-EtO (2HCl.2H2O, SN 11,281, m. 136°, 44%, Q 7); (7-hexyloxy, SN 11,634, m. 153°, 35%, Q 0.5; Q 7); 7-Me (2HCl, SN 12,699, m. 245°, 93%, Q 9); 7-Cl (camoquin) SN 10,751, m. 208°, 86%, Q 25 (2HCl.0.5H2O, m. 243°); 2HCl.H2O, m. 183°; (2HCl.2H2O, m. 160°, 90%); 8-Cl, SN 11,551, m. 212° (2HCl.0.5H2O, m. 253°, 79%, Q 0.5); 8-MeO (2HCl.1.5H2O, SN 11,594, m. 241°, 50%, Q 0.8); 8-Me (2HCl.H2O, SN 11,601, m. 253°, 66%, Q 0.7); 5-chloro-3-Me (2HCl, SN 11,985, m. 258°, 48%, Q 0.3); 5,7-di-Cl (2HCl, SN 12,700, m. 200°, 65%, Q 3); 5,7-di-Me (2HCl, SN 11,561, m. 242°, 67%, Q 10); 5,8-di-Cl (2HCl.H2O, SN 11,596, m. 235°, 60%, Q 0.25); 5,8-di-Me (2HCl, SN 11,560, m. 249°, 80%, Q 0.6); 5-chloro-8-methoxy [2HCl, SN 12,162,(incorrectly given as 12,161 in original), m. 231°, 80%, Q 0.4]; 6-methoxy-2-Me (2HCl, SN 9223, m. 278°, 45%, Q 1.2); 6-methoxy-2-Ph (2HCl.1.75H2O, SN 11,592, m. 198°, 61%, Q 0.25); 6,7-di-Cl (2HCl, SN 12,161, m. 257°, 71.5%, Q 5); 6,7-di-MeO (2HCl, SN 13,395, m. 258°, 68%, Q 2.5); 6,7-di-Me, SN 11,990, m. 215°, 49%, Q 6; 6,8-di-Me (2HCl.H2O, SN 11,558, m. 264°, 54%, Q 0.6); 7-chloro-2-Ph (2HCl, SN 11,232, m. 260°, 41%, Q 0.3); 7-chloro-3-Ph, SN 12,228, m. 165°, Q 1; 7-chloro-3-Me (2HCl, SN 10,492, m. 260°, 64%, Q 6); 8-methoxy-5-Me (2HCl, SN 11,632, m. 210°, 90%, Q 0.6); 6,7,8-tri-Cl (2HCl, SN 11,633, m. 277°, 40%, Q <0.3); and 6-HO (2HCl, SN 11,563, m. 262°, 64%, Q 0.2) (prepared by HBr demethylation of the 6-MeO derivative). 4-(6-Methoxy-4-quinolylamino)-α-dibutylamino-ο-cresol (III) (2HCl.1.25H2O, m. 193°, 10%, Q 9); the (7-chloro-3-methyl-4-quinolylamino) analog of III (2HCl.1.5H2O, m. 177°, 43%, Q 10). 4-(6-Methoxy-4-quinolylamino)-α-1-piperidyl-ο-cresol (IV) (2HCl.0.5H2O, SN 12,038, m. 270°, 80%, Q 8); analogs of IV: (6,7-dimethoxy-4-quinolylamino) (2HCl, SN 13,413, m. 230°, 40%, Q 4); (7-chloro-3-methyl-4-quinolylamino) (2HCl, SN 12,360, m. 270°, 47%, Q 2); (6-methyl-4-quinolylamino) (2HCl, SN 12,456, m. 240°, 41%, Q 2.5). 4-(6-Methoxy-4-quinolylamino)-α-4-morpholinyl-ο-cresol (V) (2HCl, SN 11,989, m. 265°, 57%, Q 1); analogs of V: (7-chloro-3-methyl-4-quinolylamino) (2HCl, SN 12,362, m. 242°, 33%, Q 0.15); (6-methyl-4-quinolylamino), SN 12,457, m. 239°, 50%, Q 0.8. 5-(7-Chloro-4-quinolylamino)-α-diethylamino-ο-cresol, SN 13,730, m. 173°, Q 9; 6-(7-chloro-4-quinolylamino)-α-diethylamino-4-(diethylaminomethyl)-ο-cresol-1.5H2O, m. 145°, Q 5; 4-chloro-α-diethylamino-6-(6-methoxy-4-quinolylamino)-ο-cresol (2HCl, SN 12,885, m 205°, 50%, Q 0.5). 6-Chloro-4-(7-chloro-4-quinolylamino)-α-diethylamino-ο-cresol (VI), SN 13,729, m. 225°, Q 12; analogs of VI: 6-Ph (0.5H2O, m. 235°, 25%); 6-allyl, SN 11,991, m. 148°, 44%, Q 10; 6-allyl-α-1-piperidyl, SN 12,697, m. 190°, 32%, Q 4; 6-allyl-α-diallylamino, SN 13,394, m. 131°, 25%, Q 0.7. 6-Allyl-α-diethylamino-4-(6-methoxy-4-quinolylamino)-ο-cresol, SN 12,039, m. 161°, 33%, Q 7. Variations of the alkylamino group on the cresol portion of camoquin were studied: α-amino-4-(7-chloro-4-quinolylamino)-ο-cresol (VII) (2HCl.0.5H2O, SN 1603, m. 325°, 80%, Q 6); analogs of VII (substituents on the α-amino group): benzoyl (HCl, SN. 11,557, m. 289°, 80%, Q 0.15); Et (2HCl, m. 280°, Q 40, 4% conversion, prepared by the Mannich reaction of EtNH2, (HCHO)x, and 7-chloro-4-(4-hydroxyanilino)quinoline (HCl, m. above 320°, 94%)); Pr(2HCl.0.5H2O, m. 244°, 24%, Q 30); iso-Pr (2HCl, m. 287° 50%, Q 40); Bu (2HCl, m. 254°, 6%, Q 30); sec-Bu (2HCl.H2O, m. 252°, 3%, Q 50); iso-Bu (2HCl, m. 256°, 65%, Q 75); tert-Bu (2HCl, m. 285°, 36%, Q 40); Am (2HCl, m. 266°, 15%, Q 50); (1-methylbutyl 2HCl, m. 231°, 22%, Q 40); iso-Am (2HCl, m. 279°, 20%, Q 50); hexyl (2HCl, m. 280°, 56%, Q 25); (2-ethylbutyl (2HCl, m. 263°, 15%, Q 50)); heptyl (2HCl, m. 278°, 29%, Q 15); octyl, m. 150°, 15%, Q 2.5; allyl (2HCl, m. 257°, 3%, Q 20); 1-methylallyl (2HCl.1.75H2O, m. 95°); cyclohexyl (2HCl.0.25H2O, m. 252°, 30%, Q 30); 2-hydroxyethyl (2HCl.H2O, m. 182°, 15%, Q 3); 2-methoxyethyl (2HCl, m. 271°, Q 25); benzyl (2HCl, m. 270°, Q 16); (α-methylphenethyl) (2HCl.0.25H2O, m. 243°, 31%, Q 25); di-Me (2HCl, m. 290°, 85%, Q 6); N-ethyl-N-butyl(2HCl, m. 240°, 65%, Q 30); di-Pr, SN 13,835, m. 181°, 11%, Q 25; di-Bu, SN 14,105, m. 164°, 20%, Q 35; diiso-Bu (0.5H2O, m. 166°, 38%); diiso-Am (0.5H2O, m. 135°); dihexyl (2HCl, m. 220°, 40%, Q 0.5); diheptyl (2HCl, m. 203°, 52%, Q 1); dioctyl (2HCl, m. 192°, 46%, Q 0.2); bis(2-ethylhexyl) (2HCl.H2O, m. 154°, 1%, Q 3); methyl(2-hydroxyethyl) (2HCl, SN 12,363, m. 250°, 63%, Q 3); butyl(2-hydroxyethyl), SN 14,824, m. 149°, 22%, Q 12; bis(2-hydroxyethyl), m. 193°, 25%, Q 0.6; dibenzyl (2HCl, m. 235°, 74%, Q 2.5); N-methyl-N-Ph (H2O, m. 140°, 39%, Q 0.07); N-ethyl-N-Ph, m. 131°, 54%, Q <0.05. Further analogs of VII: α-1-piperidyl (2HCl.2.5H2O, SN 11,636, m. 302°, 77.5%, Q 25); α-(2-methyl-1-piperidyl) (2HCl, SN 12,357, m. 288°, 66%, Q 20); α-4-morpholinyl (2HCl, SN 11,987, m. 292°, 60-5%, Q 4). Compounds containing heterocyclic nuclei other than the 4-quinolyl include the following 4-(heterocyclic amino)-α-diethylamino-ο-cresols: 9-acridyl (2HCl, SN 12,356, m. 265°, 45%, Q 1.5); (3-chloro-9-acridyl) (2HCl, SN 12,355, m. 267°, 52%, Q 3); (4-methoxy-9-acridyl) (2HCl, SN 12,164, m. 245°, 50%, Q 0.15); (3-chloro-5-methyl-9-acridyl) (2HCl, SN 11,988, m. 275°, 40%, Q 0.25); 2-quinolyl (2HCl, SN 9559, m. 230°, 48%, Q 0.12); (6-methoxy-2-quinolyl) (2HCl, SN 11,537, m. 237°, 20.5%, Q 0.7); (5-nitro-2-quinolyl) (2HCl, SN 9307, m. 245°, 33%, Q <0.07); (2-amino-4-pyrimidyl) (2HCl, SN 9591, m. 258°, 41%, Q 1.1); [2-(1-piperidyl)-4-pyrimidyl], SN 10,177, m. 156°, 31%, Q 0.4; (2-amino-6-methyl-4-pyrimidyl) (2HCl, m. 245°, 55%); (4-methoxy-2-benzothiazolyl) (2HCl, SN 11,189, m. 163°, 47%, Q <0.07); (6-chloro-2-methoxy-9-acridyl) (VIII), SN 8617, m. 175°, 50% (H2O, m. 117°; 2HCl, m. 280°, 76%, Q 4; 2HCl.2H2O, m. 180°); analogs of VIII: α-(ethylbutylamino) (2HCl, m. 252°, 36%, Q 5); α-dibutylamino (2HCl, SN 11,599, m. 246°, 69%, Q 2.5); α-diallylamino, SN 13,163, m. 158°, 16%, Q 0.5; α-dihexylamino (2HCl, m. 254°, 23%, Q 0.4); α-dioctylamino (2HCl, m. 285°, 20%, Q <0.06); α-1-piperidylamino (2HCl, SN 11,536, m. 287°, Q 0.6); α-hexylamino (2HCl.H2O, m. 226°, 7%, Q 1); α-(2-hydroxyethylamino) (2HCl.H2O, SN 11,233, m. 284°, 90%, Q 0.2); α-benzamido (HCl.0.5H2O, SN 11,589, m. 294°, 95%, Q <0.04). 5-(6-Chloro-2-methoxy-9-acridylamino)-α-diethylamino-ο-cresol (2HCl.0.5H2O, SN 9614, m. 237°, 50%, Q 1); 4-tert-butyl-6-(6-chloro-2-methoxy-9-acridylamino)-α-diethylamino-ο-cresol (IX) (2HCl, SN 11,544, m. 271°, 98%, Q 0.6); 4-Ph analog of IX (2HCl, SN 11,553, m. 274°, 84%, Q 0.5); 4-diethylaminomethyl analog of IX (3HCl.H2O, SN 11,550, m. 257°, 73%, Q 2); 6-allyl-4-(6-chloro-2-methoxy-9-acridylamino)-α-diethylaminο-ο-cresol (X) (2HCl, SN 11,234, m. 233°, 65%, Q 3); α-diallylamino analog of X (2HCl.H2O, SN 13,399, m. 188°, 12%, Q 0.3); and α-1-piperidyl analog of X, SN 12,701, m. 164°, 44%, Q 2. A series of nitrobenzylamines was prepared by condensation of the nitrobenzyl chloride with the amine in absolute EtOH. During the course of this work, 2-(chloromethyl)-4-nitrophenetole,m. 72-5°, was obtained in 75% yield from the chloromethylation of 4-nitrophenetole. The nitrobenzylamines were reduced catalytically in absolute EtOH and the resulting aminobenzylamines without isolation were condensed with the chloroheterocycle. Thus were obtained: N,N-diethyl-3-nitrobenzylamine, b6 145-8°, 60%; 4-nitro isomer (XI) (HCl, m. 162°, 45%); analogs of XI: N,N-di-Pr (HCl, m. 138°, 68%); N-monoisopropyl (HCl, m. 232°, 82%); N-monoisobutyl (HCl, m. 214°, 64%). N,N-Diethyl-5-nitro-2-methoxybenzylamine (XII) (HCl, m. 178°, 72%); analogs of XII: N-monoisobutyl (HCl, m. 176°, 63%); N-monoamyl (HCl salt could not be separated from an impurity of AmNH2.HCl). N,N-Diethyl-5-nitro-2-ethoxybenzylamine (HCl, m. 182°, 56%). 3-(7-Chloro-4-quinolylamino)-N,N-diethylbenzylamine (2HCl.2H2O, SN 11,590, m. 128° (all these HCl salts m. with decomposition), 85%, Q 1); 4-(7-chloro-4-quinolylamino)-N,N-diethylbenzylamine (XIII) (2HCl, SN 12,455, m. 261°, Q 4); N,N-di-Pr analog of XIII (2HCl, m. 255°, 60%, Q 4); the N-monoisopropyl analog of XIII (2HCl salt, m. 303°, 23%, Q 10); N-monoisobutyl analog of XIII (2HCl.H2O, m. 288°, 76%); 5-(7-chloro-4-quinolylamino)-N,N-diethyl-2-methoxybenzylamine (XIV), m. 203°, 64%, Q 25; N-monoisobutyl analog of XIV (2HCl.0.25H2O, m. 194°, 76%, Q 17); N-monoamyl analog of XIV (2HCl, m. 288°, 42%, Q 15); 2-ethoxy analog of XIV (2HCl.2H2O, m. 247°, 73%, Q 8); 3-(6-chloro-2-methoxy-9-acridylamino)-N,N-diethylbenzylamine (XV) (2HCl.0.75H2O, SN 10,984, m. 278°, 55%, Q 0.5); the 4-substituted benzyl isomer of XV (2HCl.0.5H2O, SN 10,028, m. 260°, 92%, Q 0.4); and 5-(6-chloro-2-methoxy-9-acridylamino)-2-methoxy-N,N-diethylbenzylamine (2HCl.0.5H2O, m. 212°, 67%, Q 3). 6-Chloro-9-(4-hydroxyanilino)-2-methoxyacridine, m. 266° (decomposition) (HCl, orange, m. above 300°, prepared in 98% yield from p-NH2C6H4OH and 6,9-dichloro-2-methoxyacridine on the steam bath), failed to undergo the usual Mannich reaction. Failure of this reaction led to the development of the method of synthesis used for all of the heterocyclic derivatives reported in this paper. Compounds in my other articles are similar to this one(4-Chloro-8-methylquinoline)Application In Synthesis of 4-Chloro-8-methylquinoline, you can compare them to see their pros and cons in some ways,such as convenient, effective and so on.

Reference:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia