Phenanthridine reactivity

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

Phenanthridine (74) was converted by NBS into the 2-bromo derivative (40%) (55JA6379), but the bromine-sulfuric acid-silver sulfate reagent gave low yields of 1-, 4-, and 10-bromophenanthridines in the ratio (1 6.4 9.5), a reactivity order which contrasts with that found in nitration (1 > 10 > 4 > 2) (69AJC1105). Phosphoryl chloride converted phenanthridine 5-oxide into the 6-chloro derivative, but when that position was blocked by a phenyl substituent, the reductive chlorination process gave a 2-chloro compound (84MI2). 

Oxidative photocyclization of benzylideneaniline appears to proceed efficiently only in the presence of strong acid. The phenanthridine 31, however, has been prepared by irradiation of the imine 3228 few other examples of the photocyclization of arylimines have been reported.29 Strong acid is also required for successful photocyclization of azobenzenes to benzo-[c]cinnolines. Here, protonation is claimed to lower the reactive n, n excited state below the level of the unreactive n, it state. 2-Phenylazopyridine,... 

Whereas treatment of phenanthridine with AT-bromosuccinimide gives only 2-bromo-phenanthridine, use of bromine and silver sulfate in 92% sulfuric acid gives, in low yields, 10-, 4- and 1-bromo-phenanthridines in the ratio 9.5 6.4 1 together with some dibromo products (Scheme 11) (69AJC1105). This order of reactivity contrasts with that observed for nitration of phenanthridine (Section 2.06.2.1.2). 

Methyl substituents can have unusual effects on the reactivity of phenanthridine (21). In keeping with an electron-donating effect, the introduction of a methyl group at position 3 or 8 gives rise to a small, normal, rate acceleration in reactions with Mel. By contrast, a methyl group at position 1 or 10 produces a decrease in the rate constant for N-methylation, and methyl groups at both the 1 and 10 positions together... 

Although phenanthridine was discovered in the late nineteenth century1, 2 neither the parent base nor its derivatives attracted attention until useful therapeutic activity was established in certain quaternary phenanthridinium compounds.3 A substantial number of substituted phenanthridines (and many phenanthridinium salts) have now been described and lists of compounds appearing in the literature from 1884 until 1955 are available.4, 6 Phenanthridines have attracted surprisingly little systematic attention, although the system is of considerable theoretical interest and, with its nine nonequivalent carbon atoms, may be expected to provide a rigorous test of molecular orbital reactivity correlations. Naturally occurring derivatives include several Amaryllidaceae and Papaveraceae alkaloids, notably, lycorine, haemanthamine, and chelidonine the chemistry of the phenanthridine alkaloids has been reviewed.6... 

Calculated reactivity indices are at one with qualitative electronic theory in accounting for ready nucleophilic attack at C-6 in the phenanthridine molecule. However, the limited data available on positional reactivities in electrophilic substitutions is not accounted for satisfactorily by any of the available treatments (see later) and it has been pointed out that the simple Hiickel treatment used by some authors,223, 220 is generally inapplicable in heteroaromatic systems.228... 

Several acetylenic esters have been shown to react with phenan-thridine-5-oxide (or its 6-alkyl derivatives) forming adducts of the type (21 5).308 Under necessarily more vigorous conditions (in di-methylformamide at 100°) the less reactive methyl phenylpropiolate combined with 6-methylphenanthridine-5-oxide to form 2-phenyl-pyrrolo[l,2-/]phenanthridine-3-carboxylate (216) directly, presumably via an intermediate of type (215).285... 

Nitric acid alone is without effect on phenanthridine, but nitration occurs quite readily in sulfuric acid solution. The use of not more than one equivalent of nitric acid results in mononitration only, but a mixture of products is obtained and a quantitative recovery of the individual isomers has not been achieved. Valid assessments of reactivity are not possible from the available data, but the major products are certainly 1- and 10-nitrophenanthridine with smaller amounts of the 8-nitro isomers. To this extent the results are in agreement with localization energy calculations for the cation227 2-, 3-, and 4-nitrophenanthridine have also been isolated, but in minor amounts which could not be determined accurately.89... 

Although, predictably, C-6 of the phenanthridine ring is susceptible to nucleophilic attack, until recently only qualitative reactivity data were available. New examples of both direct substitutions (hydride ion extrusion) and nucleophilic replacements, notably of halogen atoms, have been reported since the last review.6... 

The known reactivity of phenanthridine towards lithium aryls extends to the hindered o-tolyllithium, where the stability of the 6-o-tolyl-5,6-dihydrophenanthridine allows its isolation.314 (6-Phenyl-phenanthridine forms 6,6-diphenyl-5,6-dihydrophenanthridine under similar conditions.62,314)p-Biphenylyllithium reacts smoothly to give the dihydro adduct oxidation in situ with boiling nitrobenzene gives the 6-biphenylylphenanthridine in good yield.327... 

The reactivity of the amide function of phenanthridine-6-carbox-amide differs somewhat from that in the corresponding A-oxide. Although the former compound is smoothly converted to the amine under Hofmann conditions and forms the acid on treatment with nitrous acid, the amide A-oxide is virtually inert under the conditions of both reactions.290... 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

Reports of bromination of phenanthridine (11.14) are contradictory, claiming (1) a 40% yield of 2-bromophenanthridine (55JA6379) and (2) a positional reactivity order of 10 > 4 > 2, the isomer yields being 6, 4, and 0.7%, respectively, with —1% of dibromo products (69AJCI105). These reports both contrast with nitration, in which positional order is I > 10 > 8 > 3. 

Heteroaromatic cations undergo reduction when treated with 1,4-dihydronicotinamide. An early study showed that the 10-methylacridinium ion (87) was rapidly reduced in a redox reaction to the 9,10-dihydro adduct by 1,4-dihydronicotinamides (M Scheme 18). A variety of systems including py-ridines, isoquinolines, quinolines and phenanthridines have been studied using this and related procedures. The selective reduction of pyridinium and quinolinium salts with 1-benzyl-1,2-dihydro-isonicotinamide (89) has been achieved. The selective conversion to the thermodynamically more stable 1,4-dihydro species (90 Scheme 18) is rationalized by the reversibility in the formation of the kinetic products (i.e. the 1,2-adducts) in the presence of pyridinium ions. In the pyridinium case 1,6-di-hydro adducts were also observed in some cases. Reactivity in such systems is sometimes hindered due to hydration of the dihydropyridine system. This is particularly so in aqueous systems designed to replicate biological activity. Dihydroazines derived from isoquinolines and 3,5-disubstituted pyridines have been reported to overcome some of these difficulties. ... 

Diels-Alder reaction. The diene is more reactive than phenylbutadiene. Braude and Fawcett used it for the interesting synthesis of phenanthridine (9) formulated. The overall yield from o-nitroaniline was about 15%. 

Further examples of the reactivity of a 6-chlorine atom in phenanthridine have been noted (M.S. Manhas and S.6. Amin, J. heterocyclic Chem., 1976, 903 D.F. Pipe and... 

Nicotine, conformational analysis, reactivity and models of 84H(22)165. Phenanthridine alkaloids from Amaryllidaceae, total synthesis of ... 

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