Quinolines Subject

Replacing one carbon atom of naphthalene with an a2omethene linkage creates the isomeric heterocycles 1- and 2-a2anaphthalene. Better known by their trivial names quinoline [91-22-5] (1) and isoquinoline [119-65-3] (2), these compounds have been the subject of extensive investigation since their extraction from coal tar in the nineteenth century. The variety of studies cover fields as diverse as molecular orbital theory and corrosion prevention. There is also a vast patent Hterature. The best assurance of continuing interest is the frequency with which quinoline and isoquinoline stmctures occur in alkaloids (qv) and pharmaceuticals (qv), for example, quinine [130-95-0] and morphine [57-27-2] (see Alkaloids). 

The Pfitzinger reaction describes the condensation of an o-aminophenylglyoxylic acid 16 (which can be generated in situ from an isatin IS) with 2 results in a quinoline-4-carboxylic acid (17), which is the subject of its own chapter in this book. ... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

The Skraup reaction is of wide scope for the synthesis of substituted quinolines. Certain primary amines, bearing a cyano, acetyl or methyl group, may however be subject to decomposition under the usual reaction conditions. 

Under N2, 6-chlorobcnzo[/]isoindolincdiiminc (5.04g, 21.9 mmol) was added to a refluxing mixture of SiCl (3.7 g, 2.5 mL, 22 mmol) and anhyd quinoline (40 mL) over 50 min. The resulting mixture was refluxed for 1.5 h, cooled, diluted with EtOH (75 mL), and the suspension was filtered. After the residue had been washed (MeOH), it was subjected to extraction (Soxhlet, pyridine) and then vacuum dried (90 C) to afford a blue-green solid yield 4.66 g (90%). 

Sometimes lateral chlorination can occur on a methyl or alkylthio substituent, especially when phosphorus pentachloride or its mixtures with phosphoryl chloride are used (91JHC1549). Reactions of 2-methyl-4(I//)-quinoline (67) exemplify this behavior (81CPB1069) (Scheme 31) 2-chloro-3- and -4-methyquinolines are also subject to methyl chlorinations by similar reagents (91JHC1549). Sulfuryl chloride and NCS are also likely to induce a proportion of lateral chlorination (83KFZ1055 86S835). 

Tu found that when aniline was used instead of the secondary amine under otherwise identical conditions 2,4-diphenyl-substituted quinoline was formed in 56% yield. Phenylacetylene and aniline were initially used as model substrates for exploring the aldehyde scope. With aromatic aldehydes the reactions proceeded smoothly to give the corresponding quinolines in moderate to good yields. A heteroaromatic aldehyde is also compatible with this transformation and the expected product was afforded in 83% yield. However, when ahphatic aldehydes were subjected to the reaction, the desired product was obtained in low yield (Scheme 19) [34]. 

The effect of hydrogen pressure in the reaction network and kinetics of quinoline hydrodenitrogenation has been matter of debate. Some controversial results and explanation were raised by the proposal of light hydrocarbons formation [78], The lack of observation of these hydrocarbons in previous experiments was explained by the low pressure employed and the deviations observed of the mass balances in these experiments were an evidence for the formation of lights HCs. The controversy is not clear yet and might be the subject for further investigations. 

The specific ortho functionalization of arylamines is obviously important in quinoline synthesis (cf. the rc-allyl procedure devised for the preparation of o-allylanilines used as indole and quinoline precursors).76 Recently acetanilides have been subjected to orthopalladation and the ensuing complexes converted into useful precursors of 2-substituted quinoline derivatives (Scheme 143).215... 

When the hydrochloride salt of 2,3,4,4a,5,6-hexahydro-l//-pyridazino [1,6-a]quinoline was subjected to catalytic hydrogenation in ethanol over Pt02, 3-[2-(l,2,3,4-tetrahydroquinolyl)]propylamine was obtained (66YZ608). Catalytic reduction of perhydropyrido[l,2-ft]pyridazine over a skeletal nickel catalyst in ethanol at 30 atm gave ring-opened 2-(3-aminopropyl)piperidine (66KGS91). 

As a rule, these compounds were obtained using phenols, hydroxy-quinolines, and other hydroxy-substituted heterocycles with UNs. In some cases aminochromenes were subjected to postsynthetic modifications (05BML4745, 07JME417) (Scheme 56). 

The alkylation of quinoline by decanoyl peroxide in acetic acid has been studied kineti-cally, and a radical chain mechanism has been proposed (Scheme 207) (72T2415). Decomposition of decanoyl peroxide yields a nonyl radical (and carbon dioxide) that attacks the quinolinium ion. Quinolinium is activated (compared with quinoline) towards attack by the nonyl radical, which has nucleophilic character. Conversely, the protonated centre has an unfavorable effect upon the propagation step, but this might be reduced by the equilibrium shown in equation (167). A kinetic study revealed that the reaction is subject to crosstermination (equation 168). The increase in the rate of decomposition of benzoyl peroxide in the phenylation of the quinolinium ion compared with quinoline is much less than for alkylation. This observation is consistent with the phenyl having less nucleophilic character than the nonyl radical, and so it is less selective. Rearomatization of the cr-complex formed by radicals generated from sources other than peroxides may take place by oxidation by metals, disproportionation, induced decomposition or hydrogen abstraction by radical intermediates. When oxidation is difficult, dimerization can take place (equation 169). 

Base-induced isomerization of propargyl amide 29a gives chiral ynamide 30a, which is subjected to ring-closure metathesis to afford cyclic enamide 31a. Diels-Alder reaction of 31a with dimethyl acetylene dicarboxylate (DMAD) gives quinoline derivative 32. In a similar manner, propargyl amide 29b is converted into ynamide 30b, RCM of which gives bicyclic compounds 31b and 31b in a ratio of 1 to 1 (Scheme 10). 

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

In the present article the primary chemical literature through July of 1997 has been surveyed. Chemical Abstracts Subject and Chemical Substance Indexes through and including Volume 126 have been searched for pyrim-ido[l,2-h]isoquinolines (1), pyrimido[l,2-a]quinolines (3), and pyrimido-[2,l-a]isoquinolines (5), and Volumes 101-126 for pyrido[2,l-6]quinazo-lines (2) and pyrido[l,2-a]quinazolines (4). Throughout this article the... 

---