Quinoline, 4,7-dichloro

Quinoline, 4,7-dichloro-, 28, 38 Quinoline, 2,4-dimethyl-, 28, 49 Quinoline, 6-methoxy-8-nitro, 27, 48 Quinones, 22, 37... 

Reaction of 2,4,7-trichloroquinoline with sodium methoxide (65°, 30 min) yielded an equal mixture of 2,7-dichloro-4-methoxy- (40%) and 4,7-dichloro-2-methoxy-derivatives (31%). The activating effect of the chloro groups is evident from the inertness of 4-chloro-quinoUne to methoxide ion at 65°. Alteration of the relative reactivity by cationization of the azine ring is again noted here in the acid-catalyzed hydrolysis (dilute HCl, 100°, 1.5 hr) of the trichloro compound to give 72% of the 2-hydroxylation product.Similarly, acid-hydrolysis of the alkoxy group proceeds much more readily in 2-ethoxy-4-chloro- than in 4-ethoxy-2-chloro-quinoline. ... 

Finally, the quinoline ring can be methylated at the 3 position with retention of biologic activity. The starting quinoline is prepared by the same scheme as that used for the desmethyl compound by substituting the methylated oxosuccinate ester, S6, in the sequence. The initial quinoline carboxylate (87) is taken on to the dichloro compound (88) by the standard reactions. Condensation with the ubiquitous diamine (76) affords sontoquine (89)... 

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

The first attempted synthesis of a benzo[ ]thiepin derivative was the solvolysis of 7,7-dichloro-3,4-benzo-2-thiabicyclo[4.1,0]heptene (19)20). Unfortunately, the reaction of 19 in hot quinoline led to 2-chloronaphthalene which suggested the reaction mechanism as shown below. In the case of the reaction of l,l-dichloro-7b-ethoxy-... 

Among dichloro bis-electrophiles, malonyl chloride with enamine 183b affords pyridone 189, probably resulting from C-alkylation and cyclocondensation followed by aromatization (02T2821). Finally, o-chloro-benzoylchloride leads to C-benzoylation and subsequent intramolecular substitution of the isolable intermediate to yield quinoline 190 (03ARK (is.2)146). 

The direct metalation of 5-methylpyrimidine and 5,5 -bipyrimidinyl in the 4-position has been reported with LDA in low yield [74TL2373 75AG(E)713], but apart from that there are few other reports on the direct metalation of unactivated diazines. However, as with pyridine and quinoline, directed metalation can readily be achieved with all three of the diazine systems when the appropriate substituent groups are present [91AHC(52)187]. Thus, the direct lithiation of pyridazine in the 4-position has now been achieved with both the 3,6-dichloro and the... 

The aluminum chloride complex of quinoline is also brominated in a similar manner, except that less 8-bromoquinoline is formed, presumably reflecting steric hindrance by the aluminum chloride complexed at nitrogen. The 5,6- and 5,8-dibromoquinolines and 5,6,8-tribromo derivative can also be obtained by this procedure. Reaction of the complex with chlorine gives the 5,8-dichloro and 5,6,7,8-tetrachloro derivatives (67JHC410, 64JOC329). 

Chlorination of quinoline in the presence of silver sulfate in sulfuric acid gives 5-chloro, 8-chloro- and 5,8-dichloro-quinoline (63CI(L)1840, 66MI20601). Similarly, addition of iodine to quinoline and silver sulfate in sulfuric acid at 150-200 °C gives 5-iodo-, 8-iodo- and 5,8-diiodo-quinoline (Scheme 8). It is thought that I+ is the electrophile (64CI(L)1753, 66MI20602). 

The inclusion of aromatic rings as part of the side chains results in quite potent agents, possibly because the rigid rings better define the position of the basic nitrogen. Reaction of para-hydroxyacetanilide (19-1) with formaldehyde and diethylamine affords the corresponding Mannich product (19-2) hydrolysis of the acetamide then leads to the aniline (19-3). Treatment of that compound with dichloro-quinoline (17-6) leads to the displacement of chlorine on the heterocyclic ring and the formation of amodiaquine (19-4) [21]. 

Dichloro-diquinolino-palladium, [Pd(C9H7N)2Cl2], is prepared in the same way from quinoline, and separates as a jmllow precipitate which is readily soluble in aqueous ammonia. 

Treatment of 4-hydroxy-l-(2-pyridyl)quinolin-2-one (442) with sulfuryl chloride gave 3,3-dichloro-l-(2-pyridyl)quinoline-2, 4-dione (443) which, upon treatment with sodium carbonate, rearranged to pyrido[2,l- >]quinazolin-l 1-one (440) (79CB3424). 

Schiff base 293 with dichlorocarbene, prepared from chloroform and potassium hydroxide in situ, in the presence of benzyltriethylammonium chloride afforded 2-chloro-3-phenyl-l //-pyrimido[l, 2-a]quinolin-l-one (294), l-chloro-2-phenylimidazo[l,2-a]quinoline, and l-(l-quinolyl)-2,2-dichloro-3-phenylaziridine in 5%, 8%, and 6% yields, respectively (91KGS810). 

A nonconcerted pathway by which A-arylimines react with alkenes to give quinolines has been described (equation 192)690. The reaction takes place at room temperature, in acetonitrile, and is catalyzed by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) final processing involves bubbling ammonia into the reaction mixture. Yields are low (10-65%) but in many cases only a single product is formed, and purification from starting materials is a relatively simple matter. 

Step C Preparation of the (a-monoglyceride of 4-(2 -carboxyphenylamino)-7-chloro-quinoline - A mixture of 48 g of (2,3-isopropylidenedioxy)-propyl anthranilate, 36 g of 4.7-dichloro-quinoline, 36 cc of concentrated hydrochloric acid and 300 cc of water was agitated while heating to reflux for a period of two hours. The reaction mixture was filtered and the filtrate was allowed to stand at a temperature of 0°C for a period of three hours. The hydrochloride salt was then vacuum filtered and the salt was taken up in 600 cc 50% methanol at reflux. The solution was made alkaline by the addition of 120 cc of ammonia solution and iced for a period of one hour. The crystalline precipitate obtained was vacuum filtered, washed with water and dried to obtain 38.5 g (being a yield of 56%) of the a-monoglyceride of 4-(2 -carboxyphenylamino-7-chloro-quinoline having a melting point of 165°C. 

Oximes are good precursors to reductive cyclization. A reductive base-induced cyclization of O-aryl oxime 4 will yield the tetrahydroquinoline <1998CL437>. The reduction prevented the normal dihydro-cyclization product from disproportionating to the quinoline and tetrahydroquinoline <1998BCJ2945>. By adding 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) after cyclization, the quinoline is the sole product (Scheme 9). 

Compounds according to entries 1, nitrato-triphenyl-(pyridine-N-oxide)tin 2, (l,2-benzisothiazol-3(2//)-one-l,l-dioxide)-(quinoline-N-oxide)triphenyltin 3, chloro-(2,6-dimethylpyridine-N-oxide)trimethyltin 4, dichloro-(2,6-dimethylpyridine-N-oxide)diphenyltin 5, (coumarin-3-carboxylato)(quinoline-N-oxide)triphenyltin 6, isocyanato-(pyridine-N-oxide-O)-triphenyltin 7, bis(A,A)-dimethyldithiocarbamoylKacetato-0)(quinoline-N-oxide)tnphenyl-tin 8, (isopropylxanthato)(quinoline-N-oxide)triphenyltin. 

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