2.3- Disubstituted quinolines

Combes Synthesis. When aniline reacts with a 1,3-diketone under acidic conditions a 2,4-disubstituted quinoline results, eg,... 

FrielA,nderSynthesis. The methods cited thus far all suffer from the mixtures which usually result with meta-substituted anilines. The use of an ortho-disubstituted benzene for the subsequent constmction of the quinoline avoids the problem. In the FrieWider synthesis (52) a starting material like 2-aminoben2aldehyde reacts with an CX-methyleneketone ia the presence of base. The difficulty of preparing the required anilines is a limitation ia this approach, but 2-nitrocarbonyl compounds and the subsequent reduction of the nitro group present a usehil modification (53). 

Diaminoquinoline also reacts with aldehydes in nitromethane. In a molar ratio of 1 1 it gave 2-substituted 106, and in a molar ratio of 1 2,1,2-disubstituted imidazo[4,5-/]quinolines 107 were formed (85IJC372, 82MI4). 

The low yields of 6,6 -disubstituted-2,2 -bipyridincs recorded in Table I are probably the result of steric retardation of the adsorption of 2-substituted pyridines. This view is supported by the observation that 2-methylpyridine is a much weaker poison for catalytic hydrogenations than pyridine. On the other hand, the quinolines so far examined (Table II) are more reactive but with these compounds the steric effect of the fused benzene ring could be partly compensated by the additional stabilization of the adsorbed species, since the loss of resonance energy accompanying the localization of one 71-electron would be smaller in a quinoline than in a pyridine derivative. 

It would be expected that the stabilization of the adsorbed species by an extended conjugated system should increase with the number of aromatic rings in the adsorbed azahydrocarbon. However, data suitable for comparison are available only for phenanthridine, benzo-[/]quinoline, and benzo[h] quinoline. The large difference in the yields of biaryl obtained from the last two bases could be caused by steric interaction of the 7,8-benz-ring with the catalyst, which would lower the concentration of the adsorbed species relative to that with benzo[/]quinoline. The failure of phenanthridine to yield any biaryl is also noteworthy since some 5,6-dihydrophenanthridine was formed. This suggests that adsorption on the catalyst via the nitrogen atom is possible, but that steric inhibition to the combination of the activated species is involved. The same effect could be responsible for the exclusive formation of 5,5 -disubstituted 2,2 -dipyridines from 3-substi-tuted pyridines, as well as for the low yields of 3,3, 5,5 -tetramethyl-2,2 -bipyridines obtained from 3,5-lutidine and of 3,3 -dimethyl-2,2 -... 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

The bicyclic system quinazoline undergoes intermolecular inverse cycloaddition reactions with enamines RRiNCR2=CHR3 (RRi=(CH2)3, R2 = Ph, R3 = H) yielding 2,3-disubstituted quinolines. 

A useful self-terminating catalyst system (77), employs a Pd catalyst [prepared from Pd(OAc)2, NaH, and r-AmOH in THF]. The solvent required for the hydrogenation depends on the acetylene structure monosubslituted acetylenes require solvents such as hexane or octane, whereas disubstituted acetylenes need ethanol, ethanol-hydrocarbon, or ethanol-THF mixtures. In all cases it was necessary to use quinoline as a catalyst modifier. The authors consider this system one of the best for achieving both high yield and stereoselectivity. 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

In another metal-catalyzed quinoline synthesis, NiBr2(dppe) was used to catalyze the reaction of 2-iodoanilines with aroylalkynes in acetonitrile at 80 °C <06JOC7079>. The resulting 2,4-disubstituted quinolines were synthesized in good yields and this method was reported to tolerate a broad range of functional groups. 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

Other nucleophile-electrophile pairs for which the pm-disubstituted naphthalene system has been used to monitor potential bonding interactions are illustrated in [35] and [36], The methoxynitrile [35], for example, shows the same sort of evidence for a bonding interaction, marked by a 7° distortion from linearity at the nitrile carbon, in plane, and exactly away from the methoxyl oxygen (Procter et al., 1981) so also does the bipyridyl dinitrile [37] (Baxter et al., 1991). In the unique case of the 8-diazonium quinoline-N-oxide [36] the proximity of a formally negatively charged oxygen induces a distortion from linearity of 10.4° in the diazonium group (Wallis and Dunitz, 1984). 

The thermal cyclization of )V-[2-(disubstituted amino)phenyl]amino-methylenemalonates (568, R1 + H,R2 + H) by heating in boiling diphenyl ether for 5-18 min afforded quinolines (569, R1 + H, R2 =h H) in 53-81% yields [75JCS(P 1)2409]. 7V-[2-(Substituted amino)phenyl]aminomethy-lenemalonates (568, R + H, R2 = H) failed to cyclize to the corresponding quinolines (569, R1 + H, R2 = H) when heated in diphenyl ether, but their JV-(p-tosyl) derivatives (568, R2 = 4-MePhS02) gave the expected products (569, R2 = 4-MePhS02) in 72-77% yields. 

N-(3,4-Disubstituted phenyl)aminomethylenemalonates (771) were cy-clized by heating in polyphosphate at 100- 120°C for 2 hr to give quinoline-3-carboxylates (772) in 42-72% yields (83ACH241). 

Another approach to the syntheses of quinazolines involves 3-(o-azido-phenyl)isoxazoles (210) which are accessible from a-chloro-Z-azido benzal-doximes (209) and /3-keto esters (R = Ph, = OEt). As shown in Scheme 78, the iminophosphorane resulting from the Staudinger reaction is transformed without isolation by an aza-Wittig reaction into 3,4-disubstituted isoxazolo[4,3-c]quinolines (211) (92MI1). 

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

Methoxy-3-isobutylpyrazine 176 (Structure 4.53) is found in galbanum oil obtained from Ferula galbaniflua. 2,4-disubstituted pyridines 177, N,N-dimeth-ylated amino compounds 178, alkyl pyrazines 179, quinoline 180 and methyl quinolines 181 were isolated from fig leaf absolute [64]. 

Disubstituted amino)-l//-pyrimido[l,2-a]quinolin-l-ones (149) were prepared in the reaction of 3-chloro derivative 148 with disubstituted amines and a cyclic amine in boiling ethanol or ethylene glycol (95MI1). 

Cyclization of malonamides (223) by treatment with phosphoryl chloride in boiling 1,2-dichloroethane gave l-(disubstituted amino)-3//-pyrim-ido[l,2-a]quinoline-3-ones (224) (95MI1). 

Cyclocondensation of 2-aminoquinoline and iminium derivatives 315 in boiling 1,2-dichloroethane yielded l-(disubstituted amino)-3//-pyrimido[l,2-a]quinolin-3-ones (224) containing traces of isomeric 3-(disubstituted amino)-l//-pyrimido[l,2-a]quinolin-l-ones (149) (95MI1). Similar reactions of 1-aminoisoquinoline with compounds 315 afforded 4-(disubstituted amino)-2//-pyrimido[2,l-a]isoquinolin-2-ones (33, R = Rj = Et, -(CH2)5-, -CH2CH2OCH2CH2-) (12-20%) together with a few percent (1.4-12%) of isomeric 2-(disubstituted amino)-4//-pyrimido[2,l-a]iso-quinolin-4-ones (34, R = R1 = Et, -(CH2)5-, -CH2CH2OCH2CH2-) (95MI1). 

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