2 alkyl substituted quinolines

A variety of 2-aryl-substituted tetrahydroquinolines were already synthesized with excellent enantioselectivities under the conditions developed by Rueping s group, but 2-alkyl-substituted tetrahydroquinolines in lower enantioselectivities (87-91% ee). With the use of this new phosphoric acid, Du reported that a low catalyst loading (0.2 mol%) was sufficient to obtain excellent enantioselectivities of up to 98% ee for 2-aryl- and 2-alkyl-substituted quinolines. Best results were obtained with i-Pr and cyclohexyl derivatives, likely due to the increased steric effects. 

Molecular ion Strong, except when braizylic-type cleavage is possible. Odd mass for odd number of N atoms in the molecule. No tendency to protonate. [M-l]+ is usually present and is strong in alkyl-substituted quinolines. 

The Lewis acid-catalyzed cyclization of 3-anaino-2-alkerLirnines (21) leads to a wide variety of alkyl- and aryl-substituted quinolines (59). The high regiospecificity and the excellent yields obtained make this process promising. 

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. 

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

IrCl2H(cod)]2 catalyzed the synthesis of substituted quinolines, where the reachon of aniline derivahves, aromatic and alkyl aldehydes efficiently proceeds under an oxygen atmosphere (Scheme 11.34) [46]. The plausible mechanism consists of a Mannich reaction, a Friedel-Craft-type aromahc substituhon, dehydration, and dehydrogenation. This can be recognized as a formal [4+2] cycloaddition of N-aryl imine and enol (Scheme 11.35). 

A large number of 5-deazaflavins (32 R1, R2 = H, alkyl, aryl R3, R4 = H, Cl, NO2, OH 48 examples in all), have been prepared in good yields via condensation of 6-substituted aminouracils with o-halo-benzaldehydes in DMF under reflux. The mechanism shown in Scheme 14 was proposed for this reaction.138 Several bis(5-deazaflavin-10-yl)alkanes (33 n = 6, 8, 10, 12) have also been prepared via the same route using bis(uracil-6-ylamino)alkanes.138 By an analogous reaction the substituted quinolines (34a) and (34b) were obtained in 87% and 50% yield, respectively, from enaminones (35a X = Y = NMe Z = O) and (35b X = Y = CH2 Z = Me2) and pentafluorobenzaldehyde in glacial acetic acid at reflux.139... 

A-Acylpyridinium salts are more reactive than the A-alkyl derivatives and afford more stable dihydropyridine products on addition of nucleophiles. Organocuprates are utilized for entry into 2-alkynyl-substituted quinoline systems (Equation 53) <2005TL8905>. They have the advantage of superior selectivity over Grignard reagents, which yield a mixture of the 2- and 4-substituted products. The reaction has been expanded to include isoquinolines and pyridines. 

The Brpnsted acid catalyzed enantioselective hydrogenation of the corresponding readily available 2-substituted quinolines (for an interesting approach to 2-alkyl tetrahydroquinolines by an aza-xylene Diels-Alder reaction, see Steinhagen and Corey 1999 Avemaria et al. 2003), which we prepared by simple alkylation of 2-methylquinoline, generated the tetrahydroquinoline derivatives in excellent enantioselectivities and subsequent A-methylation gave the desired natural products in good overall yields (Fig. 5). 

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either 77-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include AI2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig-Homer chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, sUyl substituents have been introduced into A-acylated pyridines by using silylcuprates [72]. 

A solventless synthesis of substituted quinolines occurs when anilines are reacted with alkyl vinyl ketones in the presence of indium(III) chloride on silica gel and with microwave radiation <03T813>. The mechanism proposed involves Michael addition of aniline to the vinyl ketone followed by cyclization and aromatization under the catalysis of InClj/SiOj. The reactions are fast, clean, and high-yielding. 

The PNA fraction of the shale oil was smaller (6%) than that fraction in the coal liquids (10- 29%). In shale oil, a larger fraction of the PNA compounds are alkylated than in coal-derived liquids. For example, C5 or higher-substituted aromatics were seen in shale oil but C3 substitution was rare in coal liquid. This characteristic difference in alkyl substitution was repeated also when the N-heterocyclic compounds were similarly compared. Few alkylated species were seen in the coal liquids but Ce and higher-substituted pyridines, quinolines, acridines, indoles, and carbazoles were detected in shale oil. For example, the PNA fraction of shale oil contained many indoles which can be seen in the gas chromatogram of this fraction see Figure 7). The different alkyl substitution patterns found in these two syncrude materials may well reflect the underlying structural differences in coal and kerogen. 

The quinolines, isoquinolines, and pyridines are structurally diverse with a large number of alkyl-substituted isomers. Direct isotopic measurements have not been made on nitrogen heterocycles. 

---