Quinolines, methyl-, amination

Methyl-A -(3-methoxyphenyl)-l//-l,2,3-triazolo[5,4-/]quinoline-9-amine was prepared and tested as an immunostimulant (93MI2). 

Doebner-von Miller reaction Condensation of an aromatic amine with an aldehyde or ketone in the presence of hydrochloric acid to form a quinoline derivative. A general method, thus aniline and ethanal give 2-methyl-quinoline (quinaldine) and p-phenetidine. 

B) Methiodi s. Members of Classes (i), (ii) and (iv) combine wdth methyl iodide (some very vigorously) to form quaternary methiodides. It is best to add the amine to an excess of methyl iodide dissolved in about twice its volume of methanol, allow any spontaneous reaction to subside, and then boil under reflux for 30 minutes (extend to 1 hour for Class (iv) except pyridine and quinoline). The methiodide may crystallise when the reaction-mixture cools if not, evaporate the latter to small bulk or to dryness, and recrystallise, (M.ps., pp. 553-554 )... 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

The Skraup reaction is of wide scope for the synthesis of substituted quinolines. Certain primary amines, bearing a cyano, acetyl or methyl group, may however be subject to decomposition under the usual reaction conditions. 

Kuroda and Suzuki used reaction of 267a with 2-bromoaniline leading to anilide 312 as the first step of their sequence in the preparation of 1H-imidazo[4,5-c]quinolin-4(5//)-ones (Scheme 77) (91TL6915). Reaction of 267a with amines usually does not require any catalyst and/or base, but in this case use of sodium hydride was reported. The anilide 312 was sequentially alkylated, first with methyl iodide in ethanol with potassium hydroxide at room temperature and then with different alkyl iodides in acetone at reflux to provide intermediate 313. This compound was then cyclized via palladium catalyzed reaction leading to product 314. This reaction provides a new entry to l//-imidazo[4,5-c]quinolin-4(5//)-ones that are of current interest as antiasthmatic agents. 

Pyridine (and quinoline) which in so many respects are aromatic and comparable to benzene, lose this character completely on hydrogenation to piperidine (and hydroquinoline), which are entirely of the same nature as secondary aliphatic amines. The completely hydrogenated heterocyclic bases undergo degradation reactions which have become important particularly in the investigation of the constitution of alkaloids. A. W. Hofmann s method of opening rings by means of exhaustive methylation may be illustrated with piperidine. By thermal decomposition of the quaternary ammonium base a C—N-link-age is broken and at the same time water is eliminated. 

Figure 13.8 Mutagenic and carcinogenic heterocyclic amines (a) IQ (2-amino-3-methylimidazo[4,5-/ quinoline), (b) IQx (2-amino-3-methylimidazo[4,5-/ quinoxaline), (c) PhIP, (2-amino-l-methyl-6-phenylimidazo[4,5- ] pyridine), (d) 1,5,6-TMIP (2-amino-l,5,6-trimethylimidazo[4,5-6] p5ridine).

---