Phenanthridine cyclization

Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene. 

The Morgan-Walls reaction is a variant of the Pictet-Hubert reaction where the phenanthridine cyclization was accomplished by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250—300 °C. 

The acyl residue controls the formation and stability of the carbonium ion. If the carbonium ion is destabilized (by electron withdrawing groups), then cyclization to the phenanthridine nucleus will be sluggish. The slower the rate of cyclization, the greater the chance of side reactions with the cyclization reagent. Therefore, the yield of the phenanthridine will depend on the relative rates of cyclization and side reactions, which is controlled by the stability of the carbonium ion. 

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin s results (118,119) and established the structure of the cyclized products 196 and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121) obtained the five-membered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 

Lead tetraacetate oxidation was applied to construct a benzo[c]-phenanthridine skeleton. The Hofmann degradation product 224 derived from the phenolic protoberberine 59a was oxidized with lead tetraacetate to afford the p-quinol acetate 225, which was cyclized to the benzo[c]-... 

The 2,3,7,8,10-pentaoxygenated benzo[c]phenanthridine alkaloid san-guilutine (248) was also conveniently synthesized according to the above method (Scheme 43) (138). The presence of the methoxyl group at C-5 peri to the cyclization position (C-4) was at first anticipated to retard cyclization however, the cyclization of the acetal 246 proceeded smoothly to give oxysanguilutine (247) in high yield. 

Reductive cyclization of 2-formyl-2 -nitrobiaryl compounds gives phenanthridine derivatives.136 The Stille coupling of nitroarylstannanes with 2-bromobenzaldehyde are used for the preparation of the requisite 2-formyl-2 -nitrobiaryls. Subsequent treatment of biphenyl derivatives with zinc dust in acetic acid gives the phenanthridine derivatives as shown in Eq. 10.80.137... 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

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... 

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

The direct anionic cyclization of 2-alkynylbenzonitriles 45 was applied to the synthesis of isoquinolinones <99T13193> and phenanthridines <990L767>. A bw-alkylation process of an amine with a hii-mesylate afforded the tetrahydroisoquinoline ring system <99SC645>. 

The reaction of vinyl isocyanates of type 123 with enamines gives intermediates containing the enaminoamide moiety, which subsequently undergoes an intramolecular cyclization and affords phenanthridine derivatives (84JOC4569). Numerous polyheterocycles were synthesized similarly (89JOC224). 

Certain aromatic imines undergo a similar cyclodehydrogenation to the phenanthridine. Benzylideneaniline (330) yields phenanthridine (331) only in sulfuric acid,355 whereas diphenylmethyleneaniline cyclizes in the presence of oxygen or iodine.356 Cyclizations have also been reported in Schiff s bases formed from a- and /J-naphthylamine357 and from 4-aminoquinoline,358 and in the mesomeric betaine 4,5-diphenyl-2-mercapto-l,3,4-thiadiazolium hydroxide.359 Irradiation of the anil of 2-aminonaphthalene (332) in ethanol, however, leads to incorporation of ethanol and the formation of 3-phenylbenzo[/]-quinoline (333).860 Additional photoproducts are obtained when the photolysis is carried out in w-hexanol.361... 

Badger and Sasse have described the preparation of 2-, 3-, and 8-bromophenanthridine by the cyclization of the appropriate bromo-formamidobiphenyl with polyphosphoric acid.25 In the case of 2-bromo-2 -formamidobiphenyl a higher concentration of phosphorus pentoxide in the acid was necessary to effect ring closure, and a simple steric effect was invoked.26 Nevertheless, the Morgan-Walls reaction has been used to obtain several overcrowded compounds in which unfavorable steric factors operate. Following the original report of the preparation of the 1,10-dimethylphenanthridine (5a) by this procedure,27 several other examples have been described, notably the synthesis of the related phenanthridine (5b),28 the l,2-(6)29 and 9,10-benzophenanthridines (7),30 and the 1,2 9,10-dibenzophenanthridine (8).29... 

Successful cyclizations involving attack on reduced rings have also been reported in the presence of polyphosphoric acid the originally formed hexahydrophenanthridines (15) all undergo spontaneous partial dehydrogenation to the corresponding 7,8,9,10-tetrahydro-phenanthridines (16).48... 

The Friedel-Crafts cyclization of the acid chloride (19a) occurs normally at — 70°, with the formation of the azacycloheptenone (20), but the sole product at 5° is 5,6-dihydro-5-tolylsulfonylphenanthridine (21). Similarly, the related acid (19b) gives phenanthridine when heated with polyphosphoric acid at 60°.53 Presumably a 5,6-dihydro-phenanthridine is formed which undergoes dehydrogenation in the reaction medium (cf. Das Gupta et aZ.48). 

In the simplest case, the conversion of benzylideneaniline to phenanthridine, ring closure occurs satisfactorily in sulfuric acid,151 and both 6-methyl- and 3,6-dimethylphenanthridine have been prepared in the same way, albeit in low yield, from the appropriate acetophenone anil.152 However, Mallory and Woods153 have shown that no phenanthridine is formed when benzylideneaniline is irradiated in either cyclohexane, benzene, or ethanol at 30°-40°, and have ascribed this to the short half-life (ca. 1 second at room temperature154, 155) of the cis isomer [although a successful cyclization has been reported in the case of the dimethylamino derivative (112b)156]. 

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