Aromatic heterocycle synthesis quinolines

This chapter describes in general terms the types of reactivity found in the typical six-and five-membered aromatic heterocycles. In addition to discussions of classical substitution chemistry, considerable space is devoted to radical substitution, metallation and palladium-catalysed reactions, since these areas have become very important in heterocyclic manipulations. In order to gain a proper appreciation of their importance in the heterocyclic context we provide an introduction to these topics, since they are only poorly covered in general organic text-books. Emphasis on the typical chemistry of individual heterocyclic systems is to be found in the summary/revision chapters (4, 7, 10, 12, 16, and 20) and a more detailed examination, of typical heterocyclic reactivity, and many more examples for particular heterocyclic systems are to be found in the chapters - Pyridines reactions and synthesis etc. For the advanced student, it is recommended that this present chapter should be read in its entirety before moving on to the later chapters, and that the introductory summary/revision chapters, like Typical reactivity of pyridines, quinolines and isoquinolines should be read before the more detailed discussions. 

SFs-anilines, aldehydes, and arylacetylenes (15EJ01415). This method was inspired by the Fe(III)-catalyzed aerobically oxidative synthesis of quinoHnes developed by Tu and coworkers (09CEJ6332). Both 3- and 4-SF5-anihnes (39 and 11), various aldehydes—aromatic, heterocyclic, formaldehyde, trifluoroacetaldehyde ethyl glyoxylate, and aromatic alkynes can serve as reaction components to provide access to a series of 2-aryl substituted 6(7)-SF5-quinolines 104a—s (Scheme 26). Flowever, cyclization products were not observed when aliphatic alkynes were used under the reported conditions. 

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],... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

In a report describing new syntheses of substituted quinolines, furo[2,3-g]quinolines (34) and (35) were prepared in high yield from the same 7-allylquinolinol (Scheme 1) <83JOC774>. Reductive desulfonylation of these tricyclics with LAH gave 2-methylfuro[2,3-g]quinoline (36) and the unsubstituted parent heterocycle (37), respectively. The latter could also be prepared in good yield by a simultaneous desulfurization-aromatization route from 5-(phenylsulfonyl)-6-oxo-5,6,7,8-tetra-hydroquinoline. The versatility of this second route is demonstrated by the synthesis of the isomeric furo[3,2- ]quinoline (38) shown in Scheme 2. 

The synthesis has been applied to a great variety of Mannich bases derived from aromatic compounds and from heterocycles, such as indole, pyridine, quinoline, coumar-in, etc.104 Compound 198, for instance, yields the pyranopyridine shown in equation 84104. 

Ferrocene derivatives coupled with heterocyclic systems have attracted special attention in recent years because of their interesting organic and inorganic properties. Recently, an efficient and rapid route for the synthesis of 4-aryl-2-ferrocenyl-quinolines 70 has been described by Tu and co-workers [116] through a microwave-assisted MCR of acetylferrocene with an aromatic aldehyde and dimedone in the presence of ammonium acetate in DMF. This novel procedure provides the target hetero-metallic compounds in excellent yields without the need of any purification (Scheme 54). 

A carboxyl group is removed from a heterocyclic nucleus in much the same way as from an aromatic nucleus (method 13), i.e., by thermal decomposition. The pyrolysis is catalyzed by copper or copper salts and is frequently carried out in quinoline solution. The reaction is important in the synthesis of various alkyl and halo furans. Furoic acid loses carbon dioxide at its boiling point (205°) to give furan (85%). A series of halo furans have been made in 20-97% yields by pyrolysis of the corresponding halofuroic acids. The 5-iodo acid decarboxylates at a temperature of 140°, whereas the 3- and 5-chloro acids requite copper-bronze catalyst at 250°. ... 

An alternative approach to the tetracyclic systan forms the heterocyclic ring by nucleophilic addition of an amine to a carbonyl group. Application of the Friedlander quinoline synthesis to various methoxy-1-tetralones yields the methoxy-5,6-dihydrobenz-[c]acridines, which are dehydrogenated to the aromatic compound by distillation from palladium-charcoal (M. Croisy-Delcey et al. J. med. Chem., 1983, 26, 303). 

We need to see some of these principles in action and a proper synthesis is overdue. The anti-malarial drug amopyroquine 25 might have been derived from quinine as it has a quinoline nucleus. It also has five functional groups - three amines (all different - one aromatic, one tertiary, and one secondary), a phenol and an aryl chloride. There are four rings, three aromatic and one saturated heterocyclic. 

Quinolinyl moiety has been applied in the Negishi reaction either as an electrophile or as nucleophile. 2- or 4-substituted quinolinyl triflates or bromides have been used extensively for introduction of aromatic rings at the C2 or C4 positions of the heterocycle. In a representative example, Murata et al. employed a Negishi reaction in his effort toward the formal synthesis of antitumor compound camptothecin. In accordance to that, 2-chloropyridine was allowed to react with lithium naphthalenide, followed by zinc chloride, to afford the corresponding zinc pyridine salt. Reaction of the resulting organozinc intermediate with 2-chloro-3-quinoline carboxylate provided the hetero biaryl core of camptothecin. ... 

Reductions of aromatic nitro compounds provide a simple and general access to various heterocyclic compounds through the domino process (Scheme 9.23). Quinolines are important skeletal moieties present in various natural products and biologically active compounds [58]. Most common methods of their preparation involve condensation of o-amino benzaldehydes with an enolizable carbonyl compound (Friedlander synthesis) [59]. Miller et al. [60] reported an efficient synthesis of quinolines 109, in which a reduction of o-nitroaryl carbaldehyde by SnCl2 followed by condensation with an enolizable carbonyl compound in the presence of ZnCl2 yielded 109 through a domino process. In 2001, Bunce et al. [61] reported a domino nitroarene reduction/reductive amination sequence for the preparation of tetrahydroquinoline-4-carboxylic ester 110 with excellent yields. 

The greatest progress in this area has been made in the reduction of bi-cyclic heterocyclic compounds which are presumably easier to hydrogenate than single aromatic rings as aromatic stabilisation of the heteroaryl ring is lowered in bicyclic systems. For example, a variety of catalytic systems have been developed for the synthesis of quinolines as illustrated in Scheme 14.23. Quinoline 63 can be reduced under either metal-catalysed pressure or transfer hydrogenation conditions, or Bronsted acid... 

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