Methylation of quinoline

Scheme 83 Microwave induced activation of benzylic methyl of quinolines.

Pschorr ring closure 15, 561 Pseudoacids s. Hydroxylactones Pseudoaromatic rings s. Di-thiylium salts. Metal complex compounds, ar., Tropenium salts Pseudoazulenes 15, 468 N-Pseudoazulenes 14, 791 0-Pseudoazulenes 14, 338 Pseudobase adducts and their reactions 13, 584 —, dehydrogenation 14, 769 —, p-methylation of quinolines via — 14, 769 Pseudobases 11, 323 Pseudobases, N-heterocyclic (s. a. 0-Alkylpseudobases, N-heterocyclic) 15, 304... 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

Affinities toward other alkyl radicals have also been measured by Szwarc and his co-workers using techniques similar to those described above, It is interesting to compare the affinities of naphthalene with those of quinoline toward methyl, ethyl, and n-propyl radicals (Table X). 

Most of the reactions with quinolines and degassed Raney nickels have been carried out at the atmospheric boiling point (above 230 C), a condition which is known to favor the formation of by-products. With quinoline and 4-methylquinoline (lepidine), however, the yields of the 2,2 -biquinolines were increased three to four times by heating in vacuo at 150° C, and it seems probable that other quinolines will behave similarly. Table II also shows that the yields of 2,2 -biquino-lines obtained under comparable conditions vary with the position of the methyl group in a fashion reminiscent of the trends observed with the pyridines (Table I). This similarity extends to the behavior of the two 2-methyl substituted quinolines studied, which undergo loss of the 2-methyl group to some extent and form traces of 2,2 -biquinolines. 

An interesting reaction of dimsyl anion 88 is the methylation of polyaromatic compounds. Thus naphthalene, anthracene, phenanthrene, acridine, quinoline, isoquinoline and phenanthridine were regiospecifically methylated upon treatment with potassium t-butoxide and DMSO in digyme or with sodium hydride in DMSO123-125. Since ca. 50% of D was found to remain in the monomethyl derivative 93 derived from 9-deuteriophenanthrene 92, the mechanistic route shown in Scheme 2 was suggested125. 

Cyanations of quinoline 877 and isoquinoline N-oxide 879 in DMF or N-methyl-pyrrolidone provides the cyano compounds 878 and 880 in 90 and 79% yield, respectively (Scheme 7.4) it was expected, e.g., that pyrimidine N-oxides would react analogously [6]. 

The zinc alkoxide of 2-methyl-l-(3-quinolyl)propan-l-ol was used in a catalytic amount to give ee up to 94% in the enantioselective alkylation of quinoline-3-carbaldehyde by diisopropyl-... 

In general, symmetrical oxo-squaraines having the same end-groups are synthesized by reacting squaric acid with two equivalents of quatemized indolenine, 2-methyl-substituted benzothiazole, benzoselenazole, pyridine, quinoline [39, 45, 46] (Fig. 4) in a mixture of 1-butanol - toluene or 1-butanol - benzene with azeotropic removal of water in presence [39, 45] or absence [47] of quinoline as a catalyst. Other reported solvent systems include 1-butanol - pyridine [48], 1-propanol - chlorobenzene, or a mixture of acetic acid with pyridine and acetic anhydride [49]. Low CH-acidic, heterocyclic compounds such as quatemized aryl-azoles and benzoxazole do not react, and the corresponding oxo-squaraines cannot be obtained using this method [23, 50]. 

Bromo-3(6)-methyl-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- 5 ]-l,4-benzoxazine-6-carboxylate 380 (R= H, R1 =Br) was obtained by cyclization of quinoline-3-carboxylate 379 (R = H, R1 Br) (Scheme 33) <2000WO00/046223>. (l,4-Benzoxazin-4-yl)methylenemalonate 381 was cyclized using PPA <1998MI828, 1998MIP1181381,... 

The proposed pathways for methyl-substituted quinolines differ from those shown in Fig. 23, even for the same culture, and most particularly, the fact that no C—N bond cleavage has been observed in most of the strains. A limited number of methylquinolines can be hydroxylated due to the inhibiting and blocking effect of the methyl group, particularly at position 2. So, neither P. aeruginosa QP nor P. putida QP could metabolize 2-methylquinoline however, a new strain of Pseudomonas (MQP) isolated by Grant and Al-Najjar [328] was reported to be able to transform 2-methylquinoline, yielding... 

Johansen, S. S. Licht, D., and Arvin, E., Metabolic Pathways of Quinoline, Indole and Their Methylated Analogs by Desulfobacterium Indolicum (DSM 3383). Appl Microbiol Biot, 1997. 47(3) pp. 292-300. 

US patent 6,734,308, Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-l-methyl-lH-quinolin-2-one, 2,3,-dihydroxy-butanedioate salts and method of production [108]. The invention relates to crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-meth-yl]-4-(3-ethynyl-phenyl)-1 -methyl-lH-quinolin-2-one, 2,3-dihydroxy butanedioate salts, and to pharmaceutical compositions containing the above compound, methods of treating hyperproliferative diseases, such as cancers, in mammals, especially humans by administering the above compound, and to methods of preparing the crystal forms of the above compound and related compounds. 

A number of heteroaromatic monothiocarboxylic acids are formed by Pseudomonas sp. From P. putida, there was isolated pyridine-2,6-di-(mon-othiocarboxylic acid) 46 (Scheme 16). Of interest is the fact that in P. stutzeri KC, a copper complex of 46 is the active agent for a one electron transfer in the bacterial biodegradation of CCI4. Methylation of P. putida extracts provides a number of related structures such as 47. In addition, a P. fluorescens sp. contains 8-hydroxy-4-methoxy-quinoline-2-monothiocarboxylic acid 48.98... 

Synthetic a-carbolines have also attracted interest as antitumor agents. For example, Chen and coworkers [97] prepared a series of indolo[2,3-fr] quinoline derivatives, the most active of which was 154, which had a mean GI50 value against three cancer cell lines of 0.78 iM. This compound was prepared by methylation of 153 with dimethyl sulfate (Fig. 43), and was isolated in 12% yield, along with isomeric 155, which was isolated in 40% yield, but had significantly lower cytotoxicity. Precursor 153 itself was found to be inactive. 

The beneficial effect of the change of the flow rate of the mobile phase has also been exploited for the improvement of CCC purification of the components of the dye Quinoline yellow (Colour Index No. 47005). The chemical structures of the components of Quinoline yellow are shown in Fig. 3.121. The two-phase system used for the purification consisted of tm-butyl methyl ether-l-butanol-ACN-0.1 M TFA (1 3 1 5 v/v). The column... 

Chan and coworkers developed a new diphosphine 9, related to MeO-BiPhep 5 (Fig. 10) [21]. [lr(p-Cl)(COD)]2/9/l2 catalytic system provided similar enantios-electivities than [lr(p-Cl)(COD)]2/5/l2 in the Ir-catalyzed hydrogenation of quinolines but higher enantioselectivitites in the reduction of 2-methyl-quinoxaline and 2,3,3-trimethylindolenine (Fig. 10). 

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