Heterocycles isoquinolines

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

The heterocyclic rings in quinoline (116) and isoquinoline are selectively reduced by Pd on carbon-catalyzed reaction of ammonium formatc[107]. Some benzene rings are also reduced. For example, nitrobenzene is reduced to cyclohexylamine (117) with formic acid. It is important to use a sevenfold excess of formic acid[108]. 

Heterocyclic aromatic compounds can be polycyclic as well A benzene ring and a pyridine ring for example can share a common side m two different ways One way gives a compound called quinoline the other gives isoquinoline... 

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). 

Various heterocyclic compounds have been used as substrates for the Conrad-Limpach reaction. Amino-isoquinoline 52 was converted into 54 in 36% overall yield. ... 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

The formation of quaternary salts from benzyl halides and related compounds occurs readily and has been known for many years. More recently, Krohnke and co-workers, who have studied the reactions of many heterocyclic quaternary salts, reported the formation of 5 from pyridine and benzylidene dibromide on heating the reactants together for 1 hr at 100°. The salt is sufficiently stable to be recrystallized from methanol containing a trace of hydrogen bromide. Isoquinoline gives a similar salt. 

Charton has recently examined substituent effects in the ortho position in benzene derivatives and in the a-position in pyridines, quinolines, and isoquinolines. He concludes that, in benzene derivatives, the effects in the ortho position are proportional to the effects in the para position op). However, he finds that effects of a-sub-stituents on reactions involving the sp lone pair of the nitrogen atoms in pyridine, quinoline, and isoquinoline are approximately proportional to CT -values, or possibly to inductive effects (Taft s a ). He also notes that the effects of substituents on proton-deuterium exchange in the ortho position of substituted benzenes are comparable to the effects of the same substituents in the a-position of the heterocycles. 

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 4-unsaturated-5-oxazolones provide convenient starting materials for the synthesis of other nitrogen-containing heterocyclic systems. The preparation of tetrazoles and isoquinolines is discussed in Sections II,B, 1 and II,B,2,b. 

Quinoxalines undergo facile addition reactions with nucleophilic reagents. The reaction of quinoxaline with allylmagnesium bromide gives, after hydrolysis of the initial adduct, 86% of 2,3-diallyl-l,2,3,4-tetrahydroquinoxaline. Quinoxaline is more reactive to this nucleophile than related aza-heterocyclic compounds, and the observed order of reactivity is pyridine < quinoline isoquinoline < phenan-thridine acridine < quinoxaline. ... 

Conformational studies of c/5-6,11/)-H- and /rnns-6,ll/)-H-6-methyl-2,3,4,6,7,1 l/)-hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones (136 and 137) by means of the MM2 method implemented in the HyperChem 4.5 suggested, that in the lowest-energy conformations heterocyclic moiety adopted trans-fu ed ring annotation in both cases, with a pseudo-equatorial and -axial methyl group, respectively (97LA1165). 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Just as there are heterocyclic analogs of benzene, there are also many heterocyclic analogs of naphthalene. Among the most common are quinoline, iso-quinoline, indole, and purine. Quinoline, isoquinoline, and purine all contain pyridine-like nitrogens that are part of a double bond and contribute one electron to the aromatic it system. Indole and purine both contain pyrrole-like nitrogens that contribute two - r electrons. 

The chemistry of these polycyclic heterocycles is just what you miglu expect from a knowledge of the simpler heterocycles pyridine and pyrrole Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms, anc both undergo electrophilic substitutions, although less easily than benzene Reaction occurs on the benzene ring rather than on the pyridine ring, and r mixture of substitution products is obtained. 

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. 

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... 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

As already discussed in Section 7.4, hexamethyidisiiane 857 (which is produced on a technical scale), in the presence of catalytic amounts of tetrabutylammonium fluoride di- or trihydrate in THF, reduces aromatic heterocyclic N-oxides such as pyridine N-oxide 860, quinoline N-oxide 877, or isoquinoline N-oxide 879 to the heterocycles [95] and nitrones to Schiff-bases. Aromatic nitro compounds such as nitrobenzene are reduced analogously to azo compounds such as azobenzene [96]. As mentioned in Section 7.5, secondary aliphatic nitro groups are reduced to oximes. 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

In recent years a number of new isoquinoline alkaloids of untypical structures, i.e., structures with open heterocyclic rings, have been isolated from natural sources. These bases were named secoisoquinoline alkaloids because they were believed to be produced in vivo from classic isoquinoline alkaloids as a result of various degradation processes causing oxidative cleavage of some bonds. 

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