Reactions of quinolines

The synthesis of (V-heterocyclic isothiocyanates has been a difficult challenge due to their propensity to oligomerize by autocatalysis. In an attempt to alleviate this issue, silver thiocyanate was used in a novel synthesis of 4-quinolyl isothiocyantes 06TL2161 . Reaction of 4-chloroquinoline with silver thiocyanate in refluxing anhydrous toluene for 12 h results in the desired product in quantitative yields and excellent purity. 

The asymmetric hydrogenation of quinoline continues to be of interest. Li et al. reported the asymmetric hydrogenation of a variety of 2-substituted-quinolines to the corresponding tetrahydroquinolines using an Ir-catalyst with a BINOL-derived diphosphonite ligand 

A one-pot synthesis of pyrano[3,2-c]quinolin-2,5( 5/7)-dione 107 was reported through the condensation reaction of chlorocarbonyl ketenes 108 with 4-hydroxyquinolin-2(l//)-ones 109. This simple procedure was shown to be a convenient synthesis of pharmacologically active compounds in high yields 06S435 . 

Kappe and co-workers developed two general microwave methods for the synthesis of symmetrical (hetero)-biaryls 110 from 4-chloroquinolin-2(177)-one 111 06JOC1707 . The two methods include either a Pd(0)- or Ni(0)-mediated homocoupling, as exemplified below. 

A novel catalytic enantioselective variant of the Petasis transformation of quinolines was reported using a newly designed thiourea catalyst 112 to generate the desired 1,2-dihydroquinolines 113 in good yields and high enantioselectivity 07JA6686 . 

An interesting and novel rearrangement of quinoline N-oxides was recently discovered. In synthesizing 2-heptyl-l-hydroxy-4(l//)-quinolone, Hammerschmidt et al. observed an unexpected rearrangement of 4-(alkoxycarbonyloxy)quinoline A+oxidcs 116 to 1-(alkoxycarbonyloxy)-2-heptyl-4(l//)-quinolones 117 07S1517 . 

Selvero and co-workers 05SL2755 presented an interesting synthesis of 2,4-dialkoxyquinolines. Using an operationally simple mild and efficient one-pot process that employed silver carbonate as the base, they were able to synthesize a series of 2,4-dialkoxyquinolines in good yield at room temperature. 

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Hydroxyquinolines (Quinolinols). A number of methods have been employed for their preparation. A modified Chichibabia reaction of quinoline ia fused KOH—NaOH at 240°C produces 70% of 2-hydroxyquiQoline [59-31-4] (121). Alternative names based on the facile keto—enol tautomerism of two of these compounds are 2(1H) and 4(lJd)-quiQolinone none of the other quinolinols show this property. The treatment of... 

Fused benzene rings are treated as substituents. Thus quinoline, for example, is considered as a substituted pyridine, albeit a very special and important one, and treated alongside other substituted pyridines in the discussion of its structure, reactivity and synthesis. Reactions of quinoline at positions 1-4 are considered as reactions at ring atoms, whilst reactions at positions 5-8 are regarded as reactions of the substituent . 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

Sufficient data are not yet available to allow evaluation of the relative merits of palladium-on-carbon and degassed Raney nickel catalysts. Comparable yields of 2,2 -biquinolines have been obtained by both methods under suitable conditions but the percentage conversions with degassed Raney nickel have been found to be much lower, reflecting the extent of side reactions with this catalyst. However, work in this laboratory has shown that the reaction of quinoline with palladium-on-carbon is not free from complications for example, at least three products in addition to 2,2 -biquinoline have been detected by paper chromatography. 

Hydroxy-3-(4-biphenyl)perhydropyrido[l,2-c][l,4]oxazine was obtained in the reaction of 2-piperidinemethanol and 4-bromoacetylbiphenyl in a mixture of acetone and Et20 at room temperature (00JMC609, 00MIP13). Perhydropyrido[l,2-c][l,4]oxazin-l-one 298 was obtained in the reaction of quinoline derivative 297 and chloroacetyl chloride (OOMIPl). 

In the Meisenheimer reaction of quinoline 1-oxides chlorine atoms usually enter the 2-and 4-positions, but not exclusively. 2,4-Dibromoquinoline 1-oxide was 6-chlorinated (57MI1), and the 5- and 6-nitroquinoline 1-oxides were 3-chlorinated to some extent (44JOC302). This reaction with phosphoryl chloride-phosphorus pentachloride has also been used in the preparation of chlorinated phenanthrolines (88YZ1148). 

Strong effects of the catalyst on the regioselectivity have been observed in the cycloadditions of a variety of heterocyclic dienophiles. Some results of the BF3-catalyzed reactions of quinoline-5,8-dione (21) and isoquinoline-5,8-dione (22) with isoprene (2) and (E)-piperylene (3) [25], and of the cycloadditions of 4-quinolones (23a, 23b) as well as 4-benzothiopyranone (23c) with 2-piperidino-butadienes, are reported [26] in Scheme 3.8 and Equation 3.2. The most marked... 

Six-Membered Ring Systems Pyridine 6.1.3.2 Reactions of Quinolines... 

Analogously, reaction of quinoline N-oxide 877 with ben2yltrimethylsilane 83 affords 65% 2-benzylquinoUne 951 and HMDSO 7 and toluene (Scheme 7.17) [60]. 

The synthesis of 1,4-dithiines from arenes and heteroarenes has been known for more than 100 years. The reaction of quinoline and sulfur monochloride gave dithiodiquinoline 152 (R = R = H) (1896JPR340). The structure of such compounds has been correctly identified only recently (1976PJC785, 1997JCR(S)435 Scheme 80). 

The selective addition reactions of quinolines are important to the preparation of more complex products. Tetrahydroquinoline undergoes anodic oxidation with incorporation of cyanide in the 2-position to prepare the 2-cyanoquinolines <99EJOC2645>. 

Benzoylation constitutes the first step of the Reissert and Reissert-Henze reactions of quinoline and quinoline 1-oxides respectively, but as the benzoyl intermediates are rarely isolated this topic will be dealt with in Section 2.05.4.7. Pyridine and quinoline N-oxides react easily with p-toluenesulfonyl chloride in pyridine solution to give a variety of products which closely resemble those from the last two reactions discussed (equations 22 and 23). These belong to a family of reactions that have considerable synthetic potential and much mechanistic interest (B-67MI20501) which will be discussed collectively in Section 2.05.4.5. 

A hydrogen attached to a pyridine or pyridine 1-oxide nucleus cannot be replaced directly by cyanide however, addition of cyanide to various quaternary salts constitutes an important class of reactions of synthetic importance. Before surveying these reactions in detail, the four main classes are outlined. In 1905, Reissert reported the first example, the reaction of quinoline with benzoyl chloride in aqueous potassium cyanide (Scheme 111) (05CB1603). This yielded a crystalline product, C17H12N2O, a Reissert compound (176) which afforded benzaldehyde and quinaldinic acid on acid hydrolysis (Scheme 111). Kaufmann (09CB3776) treated a 1 -methylquinolinium salt with aqueous potassium cyanide and observed 1,4-rather than 1,2-addition (Scheme 112), the Reissert-Kaufmann reaction. Reissert compounds are well known in the quinoline and isoquinoline series, but only rarely have even small yields been found in the pyridine series. On the other hand, cyanide ions add 1,4 with ease to pyridinium salts that have an electron withdrawing substituent at C-3. 

Attack by alkoxycarbonyl radicals, which are isoelectronic with but less nucleophilic than carbamoyl radicals, has been less well studied than acylation and amidation. An example is provided by the reaction of quinoline with ethyl pyruvate, hydrogen peroxide and an iron(II) salt (Scheme 213) (73TL645). 

Problem 20.39 Give structures for the products of reaction of quinoline with (n) HNO,. H,SO (b) NaNH ... 

Another example is the reaction of indoles with nitrosoarenes in the presence of acids. The redox potentials of the reactants cannot justify an outer-sphere ET process, thus the formation of the phenylaminoxyl detected for the reaction carried out in the ESR cavity, could be more likely justified by an inner-sphere ET mechanism95. In fact the reaction of quinoline N-oxide with primary alkyl Grignards for which an outer-sphere mechanism was earlier proposed, takes place through classical nucleophilic addition96. 

On the basis of considerable documentation regarding the reactions of quinolines with organometallics, the aminoquinolines were expected to... 

Reactions of quinoline Reissert compounds were less satisfactory than those of the corresponding isoquinolines. The hydrochloride of 64 with DMAD gave 65 in only 7% yield in methylene chloride ethanol, and 10% in DMF. From a study of the mechanism of the 1,3-dipolar addition of Reissert salts to arylpropiolate esters, McEwen et a/.499 concluded that a concerted cyclization was more probable than a two-step process. 

Including Reissert-type reaction of quinolines and isoquinolines... 

Although there are several studies of the reactions of quinolines, there is a paucity of data on electrophilic substitutions. In the case of quinoline, with the exception of the 5-position, all of the others are deactivated relative to benzene, but only by a slight amount [71JCS(B)4, 71JCS(B)2382], The partial rate factors for quinoline have also been determined [71JCS(B)1254],... 

R. Ring opening reactions of quinoline-substituted epoxides. Tetrahedron Lett. 2003, 44, 9299-9302. 

Monomeric metallochelates can also be immobilized on the polymer surface via a valent metal-carbon bonding. For example, the interaction of a copolymer of St and chloromethylstyrene with cobaloxime in a benzene-pyridine mixture gives PCMU with a Co—C bond [109]. N202-Metallochelates such as Co(II) complex with V,lV -bis(salicylaldehyde)ethylenediamine react with poly (chloromethylstyrene) (PCMSt) in THF at 193 K in a similar fashion [110], The same is true of reactions of quinoline (HQ) V(V) complexes with hydroxyl-containing polymers [111] ... 

The reaction of quinoline with [( 5-Cp )Rh(AN)3]2+ gives the rjl(N)-coordinated complex 121 (88OM2250). If this reaction occurs in acetone or acetonitrile containing traces of water, the product is [( 75-Cp )Rh (quinoline)(/x-OH)]2(BF4)2. The reaction of isoquinoline with [( 5-Cp ) Rh(AN)3]2+ or [( 5-Cp )Rh(/ -xylene)]2+ gives complex 122. 2-Methyl quinoline gives a mixture of products 123 and 124. In 124 coordination is fulfilled via the benzene ring. 

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