8- methylquinoline

Quinaldine (or 2-methylquinoline) can be prepared by the Doebner.Miller Synthesis, which in some respects is closely similar to the Skraup Synthesis (p. 297) but has some significant differences. 

As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

By substituting paraldehyde for glycerol, 2-methylquinoline [27601-00-9] may be synthesized. The Skraup synthesis is regarded as an example of the broader Doebner-von Miller synthesis. In the case of the Skraup synthesis, the glycerol undergoes an acid-catalyzed dehydration to provide a small concentration of acrolein that is the reactive species. If acrolein itself is used as a reactant, it would polymerize. Crotonaldehyde is the reactive intermediate in the Doebner-von Miller synthesis (28). 

A 90% yield of isoquinoline (>95% pure) was reported by treating a cmde fraction with hydrochloric acid followed by addition of an alcohoHc solution of cupric chloride in a mole ratio of 1 2 CUCI2/isoquinoline (40). A slighdy lower yield of 2-methylquinoline [91-63-4] (97.5% pure) was obtained from bituminous coal using 30% aqueous urea to form a clathrate (41). 

A number of improvements have been made in these syntheses. For example, the use of ethanoHc ferric chloride and zinc chloride produces a good yield of 2-isopropylquinoline [17507-24-3] from isovaleraldehyde (46). The purification of 2-methylquinoline is facHitated through precipitation. A cmde quinaldine—hydrochloride and zinc chloride complex is prepared and then treated with aqueous base (47). 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

Polymers. Quinoline and its derivatives may be added to or incorporated in polymers to introduce ion-exchange properties (see Ion exchange). For example, phenol—formaldehyde polymers have been treated with quinoline, quinaldine, or lepidine (81) (see Phenolic resins). Resins with variable basic exchange capacities have been prepared by treating Amherlites with 2-methylquinoline (82). 

Quinoline Dyes. The reaction of 2-methylquinoline with phthahc anhydride produces a 2 1 mixture of 2-(2-quinolinyl)-l,3-indandione... 

In theory two carbanions, (189) and (190), can be formed by deprotonation of 3,5-dimethylisoxazole with a strong base. On the basis of MINDO/2 calculations for these two carbanions, the heat of formation of (189) is calculated to be about 33 kJ moF smaller than that of (190), and the carbanion (189) is thermodynamically more stable than the carbanion (190). The calculation is supported by the deuterium exchange reaction of 3,5-dimethylisoxazole with sodium methoxide in deuterated methanol. The rate of deuterium exchange of the 5-methyl protons is about 280 times faster than that of the 3-methyl protons (AAF = 13.0 kJ moF at room temperature) and its activation energy is about 121 kJ moF These results indicate that the methyl groups of 3,5-dimethylisoxazole are much less reactive than the methyl group of 2-methylpyridine and 2-methylquinoline, whose activation energies under the same reaction conditions were reported to be 105 and 88 kJ moF respectively (79H(12)1343). 

These early contradictions were eventually resolved and led to the correction by Knorr of his initially proposed structure. While Conrad and Limpach described the reaction of aniline 1 with ethyl acetoacetate 5 which ultimately yielded 4-hydroxy-2-methylquinoline (7) via initial reaction of the amine with the ketone, Knorr described... 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

In 1883, Bottinger described the reaction of aniline and pyruvic acid to yield a methylquinolinecarboxylic acid. He found that the compound decarboxylated and resulted in a methylquinoline, but made no effort to determine the position of either the carboxylic acid or methyl group. Four years later, Doebner established the first product as 2-methylquinoline-4-carboxylic acid (8) and the second product as 2- methylquinoline (9). Under the reaction conditions (refluxing ethanol), pyruvic acid partially decarboxylates to provide the required acetaldehyde in situ. By adding other aldehydes at the beginning of the reaction, Doebner found he was able to synthesize a variety of 2-substituted quinolines. While the Doebner reaction is most commonly associated with the preparation of 2-aryl quinolines, in this primary communication Doebner reported the successful use of several alkyl aldehydes in the quinoline synthesis. 

At a me thoxybu tenon e-aniline ratio of 1 2, dianyl is formed and further undergoes cyclization with elimination of the aniline to give 2-methylquinoline (229) in 20% yield (60MI1). 

The same pathway is traced in the reaction of o-aminobenzaldehyde, which with 4-methoxybut-3-en-2-one forms 2-methylquinoline-3-carbaldehyde dimethylac-etal (231) (80MI1). With 3-aminocyclohex-2-enone it gives tetrahydroquinolinone 232 in 72% yield (76BRP1432579). 

Treatment of quinoline with ethylene oxide gave oxazolo[3,2-u]quinoline 597 whereas 2-methylquinoline did not react with ethylene oxide (79JOC285). The oxazolidine 597 is labile as monitored by H NMR spectroscopy its colorless solution in CDCI3 became dark red within several hours (Scheme 100). 

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... 

Azido-2-methylquinoline (4, R - Me 0.500 g, 2.7 mmol) and NaOMc (4.0 g. large excess) in a mixture of MeOH (70 mL) and dioxane (70 mL) was irradiated for 30 min with a 400-W high pressure Hg lamp (Pyrex filter). The solvents were removed in vacuo and ice-water (20 mL) was added. The mixture was extracted with CH2C12 and the extract was washed with H20, dried and evaporated. The residue was chromatographed (silica gel, 1 % acetone/CH2Cl2) to give 5a yield 0.194 g (38%) pale-yellow prisms (acetone/hexanes) mp 78-79 C. 

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