Substitution 6- substituted phenanthridines

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... 

The products are described,192 apparently incorrectly, as 4-substituted rather than 3-substituted phenanthridines. 

The same authors reported the synthesis of 6-substituted phenanthridines 360 via intramolecular trapping of imine anions 359179b. They speculated that these two observations could lead to the pentacyclic systems 361a-c from 358a-c via the cascade process indicated in Scheme 109. They also reported that compounds 358 could be converted into pentacyclic 13-azadibenzo[a, [Pg.130]

The iminyls (191), generated by oxidation of imino-oxyacetic acid derivatives of type (190) with persulphate, undergo intramolecular cyclization to 6-substituted phenanthridines (192) in yields of up to 78% (Scheme 78) N-methoxybiaryl-2-carboxamides undergo analogous cyclization to phenan-thridones, and triarylvinyliminyls similarly yield 2,3,4-triaryl-quinolines. 

This reaction is useful for the preparation of phenanthridine derivatives, especially for 6-substituted phenanthridines. ... 

An interesting Csp -Csp coupling via an aryl radical cyclization has been used as the key step in a unified strategy to synthesize vasconine (22), assoanine (20), oxoassoanine (21), and pratosine. Tin hydride cyclization of an A-(o-bromobenzyl)-aniline yielded a substituted phenanthridine which was subsequently transformed into vasconine (22), from which the remaining natural products were prepared (269) (Scheme 9). 

The 6-substituted phenanthridines 98 have been prepared by a one-pot coupling of fluoroarenes with nitriles (Scheme 12.29) [57]. Ortho-lithiation of fluorobenzene with t-BuLi led to o-fluorophenyllithium (96), and benzyne was subsequently generated from 96 by the loss of liF. A nucleophiUc addition of 96 to benzyne led to the formation of biaryl lithium species 97, while product 98 was generated after nucleophihc addition of 97 to a nitrile and subsequent intramolecular SnAt reaction. 

In 2012, a palladium-catalyzed ring opening of aminocyclopropyl Ugi adducts was presented. Dihydropyridine and benzoazepinone derivatives were produced in moderate yields (Scheme 3.35a). Catellani and co-workers reported a palladium-catalyzed synthesis of substituted phenanthridine derivatives in 2008. Selectively substituted phenanthridine derivatives were obtained by a facile reaction of o-allqrlated aiyl iodides, o-bromoar-enesulfonylanilines and activated olefins in the presence of palladium and norbornene as catalysts. The reaction takes place under mild conditions to give the products in satisfactory yields using readily available starting materials (Scheme 3.35b). 

This procedure was employed for the synthesis of 6-substituted phenanthridine 43 from isonitriles 41 (Eq. 9.10). In this example, thermolysis of dibenzoyl peroxide (BPO) was used to generate two benzoyloxy radicals (PhCOO ), which abstracted the a-H of dioxane (Z = 0) [24] or from cyclohexane (Z=CH2) [25]. The radical 42 is produced and then intramolecular radical cyclization took place from it to finally form the 6- substituted phenanthridine 43 in good yields ... 

Reuter DC, Flippin LA, McIntosh J, Caroon JM, Hammaker J (1994) SnAr reactions of benzaldimines a concise synthesis of substituted phenanthridines. Tetrahedron Lett 35 4899-4902... 

Taylor, E.C. and Spence, G.G., Group migration in the photolysis of 6-substituted phenanthridine N-oxides, /. Chem. Soc., Chem. Commun., 767, 1966. 

Azonia substitution at a naphthalene bridgehead position gives the quinolizinium ion (16). Oxonia substitution, elsewhere, forms the 1- and 2-benzopyrylium ions (17) and (18). The two most well-known monoaza systems with three aromatie fused rings are aeridine (19), derived structurally from anthraeene, and phenanthridine (20), an azaphenanthrene. The better-known diaza systems inelude phenazine (21) and 1,10-phenanthroline (22), while systems with three linearly fused pyridine rings are ealled anthyridines, e.g. the 1,9,10-isomer (23). 

Demethylvasconine (85) (9-methoxy-5-methyl-phenanthridin-8-olate) presented in Scheme 31 was found in Crinum kirkii (95P1291) (Amaryllidaceae). Although published as cation, no information about the anion of this alkaloid is given. Its relationship to other alkaloids of this class, however, makes a betainic structure more than likely and this is confirmed by a comparison of the NMR data of 85 with the cationic and betainic alkaloids presented in Table III. This betaine is isoconjugate with the 2-methylphenanthrene anion and thus defined the alkaloid as a member of class 1 (odd alternant hydrocarbon anions). Whereas substitution of the isoconjugate phenanthridinium moiety at the 1-position with an anionic fragment results in zwitterions (cf. Section III.D), the phenanthridinium-2-olate is a mesomeric betaine. 

Thus, the phenanthridine-fused benzaldehyde triazinylhydrazone 229 was cyclized by using thionyl chloride to the phenyl substituted pentacyclic product 230 <1998NN1385>. The corresponding methyl-substituted fused system... 

Quinoline, isoquinoline, and phenanthridine resemble pyridine in reacting comparably, and diketene may he substituted for ketene. 

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