Quinolines coupling reactions

This coupling works best when the halogen at the 7-position is bromine rather than chlorine or fluorine. This represents the first appUcation of this coupling reaction to the intact quinoline nucleus and thus represents an important advance in quinolone chemistry. 

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. 

In summary, palladium-mediated reactions, especially cross-coupling reactions have found many applications in quinoline synthesis. It is noteworthy that due to the a and S activation for the C(2) and C(4) positions, even 2-chloro- and 4-chloro-quinolines are viable substrates for palladium-catalyzed reactions under standard conditions. With the advent of the palladium chemistry and more commercially available organometallic substrates, more palladium-mediated quinoline syntheses are to be added to the repertoire of quinoline chemistry. 

Kobayashi S, Ishitani H, Nagayama S (1995) Ln(OTf)3- or Sc(OTf)3-catalyzed three components coupling reactions between aldehydes, amines, and dienes or alkenes efficient synthesis of pyridine and quinoline derivatives. Chem Lett 423 f24... 

In the recent patent literature a procedure is given for coupling a diazonium salt with ethyl a-methylacetoacetate to afford an azo compound which could be used as an acetylating agent because its acetyl group was readily cleaved under mild conditions [26], In the coupling reaction, relatively weak bases such as pyridine, picolines, quinoline, and collidine are said to be effective. The example is given here for illustration only. It is to be noted that this is a composition of matter patent. 

Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions, which compete with the desired DoM process. 

In our attempt to extend the coupling reaction of arenes with alkenes to the coupling with alkynes, as shown in Scheme 4, it was found that the reaction of arenes with ethyl propiolate in TFA (trifluoroacetic acid) gave addition products instead of a coupling product [3]. This addition reaction has been extended to various alkynes and various arenes and also to intramolecular reactions for synthesis of heterocycles such as coumarins, quinolines, and thiocoumarins. 

Kobayashi and Nagayama [26] have reported the preparation of a library of quinoline derivatives using a novel polymer-supported scandium catalyst (Fig. 8) in a three-component coupling reaction. The scandium catalyst has the advantage of being partially soluble in the dichloromethane/acetonitrile mixtures but can be precipitated by the addition of hexanes and thus be removed quantitatively by filtration. 

Furo[2,3-c]quinolines have been synthesized by a coupling reaction of furanboronic acid with haloarenes. The reaction of 2-bromonitrobenzene (93) with 2-formylboronic acid (94) afforded... 

Thienoisoquinolines can be prepared in high yields by the palladium cross-coupling reaction of o-formylarylboronic acids with aryl halides. By this method, thieno[3,2-c]- (102), thieno[3,4-c]-(103), and thieno[2,3-c]isoquinolines (104) have been prepared in yields of 90%, 52%, and 75%, respectively (Scheme 48) <86CS3il, 89JHC865). This method was unsuccessful for the preparation of thieno[3,2-c]quinoline A-oxide and thieno[3,2-c]isoquinoline A-oxide. The former compounds were readily prepared via a modification of the reaction using a palladium-catalyzed coupling reaction between 2-tributylstannyl-3-thiophenecarboxaldehyde and o-bromonitrobenzene, while the isoquinoline A-oxide was prepared by mcpba oxidation of the parent compound <90JHC1127>. 

An organocopper intermediate was detected by Lewin and Cohen in the reaction of / -iodotoluene with copper in a good complexing solvent (184). Analysis of protonated aliquots from a reaction performed in quinoline indicated an accumulation of />-tolylcopper to a maximum of 43% after 95 hours, at which point the iodide was consumed, and then a slow decrease to by dimerization. Other experiments also indicate the formation of an arylcopper compound in Ullmann reactions (127,141, 210). The isolation of deuterated products, presumably from the decomposition of an intermediate organocopper species in deuterated benzene and cyclohexane, suggested decomposition to free radicals (127). Decompositions of certain o-haloarylcopper intermediates by a benzyne mechanism cannot be totally excluded. The formation of a dichlorobenzene and by-products such as dibenzofuran and triphenylene from only the ortho isomer of the chloroiodobenzenes in Ullmann coupling reactions (210)... 

Inhibitors binding at the Q site close to heme ba, e.g., antimycin A and hydroxy-quinoline-N-oxides. Qi site inhibitors prevent the reduction of quinone and the reoxidation of cytochrome b through the Qi site due to the coupled reaction at the Qo site, this will also inhibit the steady state reduction of cytochrome ci but not the presteady state reduction of oxidized bci complex. 

A microwave-assisted three-component coupling reaction of 5-amino-3-phenyl-pyrazole, a cychc 1,3-dicarbonyl compound and an aromatic aldehyde has been described by Chebanov and co-workers [121]. Depending on the apphed reaction conditions a series of 4-aryl-3-phenyl-l,4,6,7,8,9-hexahydro-l// pyrazolo[3,4-h] quinolin-5-ones 80, 9-p-tolyl-6,6-dimethyl-2-phenyl 5,6,7,9-tetrahydro-pyrazolo [5,l-h]quinazolin-8-ones 81, or 4-aryl-5a-hydroxy-4,5,5a,6,7,8-hexahydropyra-zolo[4,3-c]quinolizin-9-ones 82 can be formed (Scheme 61). 

An efficient, diverse synthesis of oxazolo[4,5-c]quinoline-4-ones and thiazolo[4,5-c]quinolines-4-ones is carried out in two steps from readily available starting materials <03OL2911>. The Suzuki-Miyaura coupling reaction was employed. 

Because the 2 -aminochalcones are known to form 2-aryl-4-quinolones, the authors undertook an investigation of possible reductive coupling reactions of 2 -hydroxy-2-nitrochalcones <03TL5893>. With a limited number of examples, the reactions were carried out via a one-pot synthesis. Quinoline-iV-oxides formed as side products are likely intermediates and can be carried on to the final material. 

Although beyond the scope of this section, some related approaches to these compounds are worth mentioning. 2-Substituted pyridines and quinolines can be obtained in two steps from the parent compounds following nucleophilic attack by an aryllithium (e.g. 2-thienyllithium) and then oxidiation. Intramolecular oxidative coupling reactions between the 2-positions of two indole nuclei can be achieved using DDQ, in the presence of a trace of tosic acid. A very efficient route to a variety of unsymmetri-... 

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