Quinolines 4-aminoquinolines

Until recent years the only syntheses of 3-hydroxy quinoline involved multistep processes, the last step of which consisted of the conversion of 3-aminoquinoline to 3-hydroxyquinoline via the diazonium salt. " Small quantities of quinoline have been oxidized to 3-hydroxyquinoline in low yields by using oxygen in the presence of ascorbic acid, ethylenediaminetetraacetic acid, ferrous sulfate, and i)hosi)halc buffer. The decarboxylation of 3-hydroxycinchoninic, acid in boiling nitrobenzene has been re-... 

Trachelantamine, according to Syrneva, has a weak atropine-like action and also produces local anaesthesia. Its hydrolytic product, trache-lantamidine, which is structurally identical with tsoretronecanol, yields a p-aminobenzoyl derivative of -which the crystalline hydrochloride, m.p. 230-2°, is said to be as potent a local anaesthetic as cocaine hydrochloride. The chloro- -heliotridane (p. 606) formed by the aetion of thionyl ehloride on trachelantamidine reacts with 6-methoxy-8-aminoquinoline to form 6-methoxy-8-(pseMdoheliotridylamino)-quinoline,... 

The 8-hydroxy-7-aminoquinoline-5-sulfonic acid was used to clarify the role of intramolecular hydrogen bonding on the cyclization rate of hydroxy Schiff bases in the preparation of 2-aryloxazolo[4,5-/i]quinoline-5-sulfonic acids 13. Irradiation... 

Angularly annelated 2-trifluoromethylimidazo[4,5-/] and [4,5-/i]quinoline have been prepared from 5(6)-acetamido-2-trifluromethylbenzimidazole and 7,8-di-aminoquinoline, respectively. They undergo hydrolysis in dilute sodium hydroxide to give parent skeletons imidazo[4,5-/] and [4,5-/i]quinoline 113,114 (Scheme 35) (81JFC573). 

Triazolo[4,5-/i]quinoline 143 and triazolo[4,5-/i]quinoline-5-arsonic acid 144 were isolated from mother liquors after reduction and bis-diazotization of 5,7-dinitro-8-(4-toluenesulfone)aminoquinoline in the presence of cupric sulfate with trisodium arsenite (32JCS2196). 

Oxidation of 5-arylazo-6-aminoquinoline 146 with copper sulfate in pyridine gave the corresponding 2-aryltriazolo[4,5-/]quinolines 147. Condensation of halo-genated nitrobenzenes with triazolo[4,5-/]quinoline 145 yielded the appropriate 2H- and 3//-aryl derivatives. The nitration of 3-phenyl-3//-triazolo[4,5-/]quino-line 147 occurred at position 4 of the phenyl ring (Scheme 46) (73T221). 

Cyclocondenzation of 2-aminoquinoline and isopropylidene 2-(l-methylthioalkylidene)malonates on Si02 under microwave irradiations afforded 3-substituted (3-methylthio, 3-methyl, 3-ethyl, and 3-phenyl) l//-pyrimido[l, 2-n]quinolin-1-ones (00MI40). 

The 2-substituted quinoline 708 gave upon reaetion with mesitylenesulfo-nyl hydroxylamine the 1-aminoquinoline salt 709 whieh eould be eyclized with PPA to give 710 (75JHC481). Heating the 2-methylquinoline 711... 

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

Halogen exchange with metallic derivatives provides a powerful means of introducing iodine into specific quinoline sites. It has proved possible to prepare 2-, 3-, and 4-iodoquinolines from the trimethylstannyl [82H(19)168] or lithium derivatives [86S670]. Protected 2-aminoquinoline, lithiated at C-3, was quenched with iodine to give a 90% yield of the 3-iodo derivative (86S670). 

The identification of C8-guanyl and N6-adenyl adducts of 4-aminoquinoline-l-oxide (102,103) in DNA modified by the metaboli-cally-generated 0-seryl ester and the similarity of the adduct profile with that obtained on reaction of DNA with N-acetoxy-4-araino-quinoline-l-oxide suggest an electrophilic reaction mechanism similar to that for the N-acetoxy or N-sulfonyloxy arylamines (Figures 4 and 5). However, N-seryloxy or N-prolyloxy arylamines have not been synthesized and the decomposition products of the esters generated in vitro have not yet been studied. 

Pyrimido[l,2-a]quinoline-2-carboxylate (1055, R = Et, R2-R4 = H) was obtained in 50% yield when 2-aminoquinoline was reacted with EMME in boiling Dowtherm A for 20 min (74MIP1). The 6-hydroxy derivative of 1055 (R = Et, R2 = OH, R2 = R4 = H) was prepared in 20% yield when 2-amino-4-hydroxyquinoline and EMME were heated at 170°C for 8 hr (71IJC201). The angular pyrimido[l,2-a]quinoline-2-carboxylate (1055, R = Et, R2-R4 = H) could not be transformed into the linear isomer [77JCS(P1)780],... 

VI.a.2.1. AminoquinoUnes. The aminoquinolines currently used as antimalarials include the 4-amino-quinolines chloroquine and mefloquine and the 8-aminoquinoline primaquine. 

Aminoquinolines can increase plasma concentrations of penicillamine, hence the potential for serious hematological or renal toxicity. Similarly, aminoquinolines can increase digoxin levels. Gold and an amino-quinoline probably should not be administered concurrently because of the propensity of each to produce dermatitis. 

Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline-quinone metabolite that inhibits the coenzyme Q-mediated respiratory chain of the exoerythrocytic parasite. 

In a Chichibabin-type reaction (see Section 2.4.2), quinoline reacts with potassamide (KNH2) in liquid ammonia at -70 °C to give 2-amino-1,2-dihydroquinoline and this is oxidized by potassium permanganate [manganate(VII)] at the same temperature to yield 2-aminoquinoline (Scheme 3.6). If the temperature is allowed to increase to -45 °C the adduct rearranges into 4-amino-1,4-dihydroquinoline, and upon oxidation this product gives 4-aminoquinoline. 

The aromatic energy differences between the aminopyridine and pyridinone imine form (jE yridine -Epyridineimine) can be found as detailed previously (see Section 2.04.4.2) (72JCS(P2)1295). The pyridinone imine form retains much aromaticity, but less so than in the case of the oxygen compounds, as can be seen from the following figures for the above quantity 2-aminopyridine/pyridin-2-one imine, 42 4-aminopyridine/pyridin-4-one imine, 61 2-aminoquinoline/quinolin-2-one imine, 21 1-aminoisoquinolinone/isoquinolin-l-one imine, 26 kJ mol-1. 

Alkylpyridines are aminated preferentially at the 2-position, but reaction is slower than in the parent system. Quinoline is difficult to aminate and only a low yield of 2-aminoquinoline (32%) is obtained from reaction with sodamide in toluene. When dimethylaniline is employed as solvent, 2-amino-3,4-dihydroquinoline (24%) becomes the major product, and the yield of 2-aminoquinoline drops to 7%. The best yields of 2-aminoquinoline (53-69%) have been obtained by using barium or potassium amide in liquid ammonia. Use of the potassium salt also produces a 10% yield of the 4-amino isomer. The... 

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