Heterocycles fused quinoline

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Syntheses of fused mesoionic heterocycles such as [l,2,3]triazolo[l,5-a]-quinoline, -quinazoline, -quinoxaline, and -benzotriazine derivatives have been described <02T3185>. Cyclizations of alkyl 2-benzoylamino-(4,5-dicyano-1 //-1,2,3-triazol-1 -yl)propenoates gave [1,2,3]triazolo[l, 5-a]pyrazines <02H(56)353>. Reaction of triethyl N-( 1 -ethy 1-2-methy 1-4-nitro-l//-imidazol-5-yl)phosphorimidate with aryl isocyanates provided a route to 2-aryI-2//,4//-imidazo[4,5-fif][l,2,3]triazoles <02JCS(P 1)1968>. 2-(A,A-Diphenylamino)-4-hydrazino-6-... 

Stannyl ketyl radicals were generated from an amide carbonyl group and when incorporated in cinnamic enamides, indolizidinone rings can be assembled [37]. Du and Curran have shown that a-thioaminoalkyl radicals such as 24 resulting from the addition of a tris(trimethylsilyl)radical onto N-aryl thiocarbamates, thioamides or thioureas 22, can be exploited in the context of the synthesis of carbocyclic and heterocyclic fused quinolines 23 (Scheme 8) [38]. 

The VNS process, as an attractive and convenient method for incorporation of alkyl-, amino-, or hydroxy groups in nitroarenes, was first reviewed in 1987 [12]. An interested reader may be referred to several reviews generalizing the data on the synthesis of fused nitrogen heterocycles (indoles, quinolines, purines, etc.) on the basis of VNS reactions [9, 20, 21]. 

Myriad examples are known of oxindoles reacting to form indoles without prior carbonyl activation. Given (he vast scope of this subject, only a few early examples will be cited in addition to recent studies. Several groups have annulated oxindoles to access fused-indole heterocycles. Ila, Junjappa, and coworkers prepared pyrido[2,3-( ]indoles [61, 62] and 67/-indolo[2,3-fc]quinolines [63] using this approach (Scheme 9, equation 1). Adib and colleagues reported a simple synthesis of 9/7-pyrimido[4,5-Z ]indoles from oxindoles (eqnation 2) [64], and Bazgir and coworkers described a four-component one-pot a-carboUne synthesis... 

Abass M (2005) Fused quinolines. Recent synthetic approaches to azoloquinolines-a review. Heterocycles 65 901-965. doi 10.3987/REV-04-592... 

Quinolines, heterocyclic compounds that contain a pyridine ring fused to a benzene ring, are commonly synthesized by a method known as the Skraup synthesis, in which aniline reacts with glycerol under acidic conditions. Nitrobenzene is added to the reaction mixture to serve as an oxidizing agent. The first step in the synthesis is the dehydration of glycerol to propenal. 

Synthesis of Substituted Heterocycles Cu-mediated intermolecular coupling reaction of zirconacycles with dihalogenated heteroaromatic compounds is applicable for the synthesis of fused aromatic heterocycles. Zirconacyclopentadi-ene reacted with 2-iodo-3-bromothiophene in the presence of 2 equiv of CuCl and DMPU at 50 °C to afford the corresponding benzothiophenes 71. When 2-chloro-3-iodopyridine and 4-chloro-3-iodopyridine were used, the corresponding substituted quinolines 72 and isoquinolines 73 were obtained in high yields, respectively (Scheme 11.28) [28],... 

Both of these approaches have been attempted, and both are substantially equivalent for heterocyclic (e.g. quinoline and isoquinoline) and homocyclic (naphthalene) systems. Consequently, in the subsequent discussion it is fruitful to include the available work on naphthalene derivatives. In the case of the fused six-membered rings, Eq. (3) is not applied because it does not permit treatment of the 5- and 8-positions, and the available series as a whole are too short to make this treatment useful. 

The fusion of four membered-heterocycles with two heteroatoms onto face a of the quinoline offers two isomeric combinations of the tricyclic ring system l,2-heterocyclo[2,3-a]quinoline and l,3-heterocyclo[3,2-a]quinoline. The later one of these two ring systems is the only one that examples of it namely, l,3-thiazeto[3,2-a]quinoline have been reported. Moreover, examples of those fused on faces ij or j are not known (Fig. 3). 

The site of dihydroxylation in heterocycles depends on the nature of the heteroaromatic system (Scheme 9.31) usually, electron-rich heterocycles like thiophene are readily biooxidized but give conformationally labile products, vhich may undergo concomitant sulfoxidation [241]. Electron deficient systems are not accepted only pyridone derivatives give corresponding cis-diols [242]. Such a differentiated behavior is also observed for benzo-fused compounds biotransformation of benzo[b] thiophene gives dihydroxylation at the heterocyclic core as major product, while quinoline and other electron-poor systems are oxidized at the homoaromatic core, predominantly [243,244]. 

For fused heterocyclic systems too, we can often make predictions based on the above principles, though many exceptions are known. Thus, indole is chiefly substituted in the pyrrole ring (at position 3) and reacts faster than benzene, while quinoline generally reacts in the benzene ring, at the 5 and 8 positions, and slower than benzene, though faster than pyridine. 

Naphthalene and other fused ring compounds are so reactive that they react with the catalyst, and therefore tend to give poor yields in Friedel-Crafts alkylation. Heterocyclic rings are also tend to be poor substrates for the reaction. Although some furans and thiophenes have been alkylated, a true alkylation of a pyridine or a quinoline has never been described.However, alkylation of pyridine and other nitrogen heterocycles can be accomplished by a free radical (14-23) and by a nucleophilic method (13-15). 

The latter reagent also methylates certain heterocyclic compounds (e.g., quinoline) and certain fused aromatic compounds (e.g., anthracene, phenanthrene). The reactions with the sulfur carbanions are especially useful, since none of these substrates can be methylated by the Friedel-Crafts procedure (11-12). It has been reported that aromatic nitro compounds can also be alkylated, not only with methyl but with other alkyl and substituted alkyl groups as well, in ortho and para positions, by treatment with an alkyllithium compound (or, with lower yields, a Grignard reagent), followed by an oxidizing agent such as Bra or DDQ (P- 1511). 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

This lead has been pursued extensively at Wyeth-Ayerst, resulting in several additional series of active compounds (reviewed in [340]). Activity was retained by replacement of the quinoline by other benzo-fused heterocycles such as benzothiazole and A -methylbenzimidazole, but the benzoxazoles were inactive no correlation was seen between in vitro and in vivo activities... 

A striking demonstration of the reduced activity towards electrophiles for the pyridine ring compared with the benzene ring will be seen later when we consider the fused heterocycles quinoline and isoquinoline (see Section 11.8.1). These contain a benzene ring fused to a pyridine ring electrophilic substitution occurs exclusively in the benzene ring. 

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