Phenanthridones, synthesis

Preparative routes to 5/7-dibenz[6,e]azepine-6,11 -diones (morphanthridinediones) are based mainly on the cyclization of 2-aminobenzophenone-2 -carboxylic acids and their derivatives (55LA(594)89). Studies on a-aminodiphenyImethane-2 -carboxylic acid reveal that cyclization to 5,11 -dibenz[6,e ]azepinone (188) is much slower at room temperature than the cyclizations of the analogous 2-aminobiphenyl-2 -carboxylic acid and the 2 -aminobiphenylacetic acid (189), which at room temperature cyclize spontaneously to phenanthridone and dibenz[f>,d]azepin-6-one (190) respectively (61JOC1329). The hydrogen bromide-induced cyclization of dinitriles (Scheme 16) is adaptable to the synthesis of 2-amino-7-bromo-3//-azepines and 5H-dibenz[c,e]azepin-7-ones (67JOC3325). Apparently, for unsymmetrical dinitriles cyclization is such as always to give the azepine with the bromo substituent attached to the carbon of the a,j8-unsaturated nitrile as exemplified in Scheme 16. 

Several syntheses of phenanthridone derivatives related to the aromatization products of narciclasine and lycoricidine and apparently designed to further support the structural revision have been completed. In a photochemical synthesis starting from 368 the compound 360 was obtained yielding on debenzylation narciprimine (356), whereas from 369 in an analogous way arolycoricidine (361) was prepared. Also, starting from the amide 370 through photocyclization to 362 via 363 a compound identical with natural permethylisonarciprimine (357) was obtained (81). 

More recently, a detailed paper discussed the synthetic problems presented by the syntheses of the substituted phenanthridones of the narciprimine-isonarciprimine series along with the synthesis of per-methylisonarciprimine 357 (79). The potential pharmacological interest of narciclasine and other Amaryllidaceae metabolites has been suggested (79a, 79b). 

Phenanthridone has been obtained by the action of carbon dioxide on 2-lithioaminobiphenyl49 and by cyelizing 2-biphenylyl isocyanate with aluminum chloride,50 the latter reaction appearing to be a general one. Thus, cyclization of 5-bromo-2-biphenylyl isocyanate gives 2-bromophenanthridone,51 while reaction of the isocyanate (17) with trifluoroacetic acid is a key stage in the synthesis of dihydroxy-crinene (18).52... 

Several reactions involving benzyne intermediates have been employed in the synthesis of phenanthridines. Benzyne itself reacts with phenyl isocyanate to give phenanthridone, probably via the Diels-Alder adduct (157). A second product is 6-phenoxyphenanthri-... 

An interesting new application of enaminone chemistry is ring closure involving benzyne intermediates. In this way an intramolecular arylation of enaminones is effected. The method is used for the synthesis of fused heterocyclic compounds and natural products119-121. Phenanthridone derivatives can be obtained in good yield119. 

Begley and Grimshaw (94) reported a modified synthesis of nitidine (77) by shortening the steps in Kessar s route (88) by using the A -methylbenza-mide (93) under photochemical conditions. However, they failed to obtain benzo[c]phenanthridone by electrochemical means (94) (Scheme 47). 

Earlier, a one-pot procedure based on consecutive Pd-catalyzed aryl-aryl coupling followed by N-C bond formation had been described for the synthesis of phenanthridones and their thiophene analogs <2004OL4759>. The starting materials were 2-iodotoluene and 3-bromothiophene-2-carboxamides or 3-bromobenzo[3]thiophene-2-carboxamides (Equations 40 and 41). The conditions were rather critical in order to prevent the nucleophilic amide group from coordinating with the palladium, tri-2-furylphosphine had to be added to the reaction mixture. Norbornene serves to form a palladacycle which then reacts with the bromoamide. 

Isoquinoline-1,3,4-triones are useful intermediates for the synthesis of benzo[c]phenanthridones in about a 30% yield in a three step sequence which utilises... 

The photocyclisation of A-phenyl-3-vinylquinolin-2( )-ones provides a facile route to benzo[k]phenanthridones. Under non-oxidative conditions, the tetrahydro derivative results, but photolysis in the presence of iodine gives the fully aromatic heterocycle. Introduction of a 2-chlorine substituent into the starting material results in the formation of 6-chloro-7,8-dihydrobenzophen-anthridones (K. Veeramani et al.. Synthesis, 1978, 855). 

Photolysis of styrylquinolones (130) affords benzo-[k]phenanthridones whilst the benzylidene lactones (131), from which the styrylquinolones may be prepared, give 6-oxobenzo[k]phenanthridine-7-carbo3 1ates on irradiation in methanol (V. Arisvaran et al,. Synthesis, 1981, 821). 

A. Padwa, H. Zhang, Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family, J. Org. Chem. T1 (2007) 2570. 

Coupling of amino cyclohexene derivative 100 with 6-bromopiperonylic acid (101) provides amide 102, which is a key intermediate for the synthesis of phenanthridone alkaloid lycoricidine (103).39... 

This reaction corresponds to the Bischler-Napieralski synthesis of isoquinoline (see p 343) and proceeds as an intramolecular S Ar process by way of nitrilium ions as intermediates. By an anlogous reaction, biphenyl-2-isocyanates 29, derived from 2-aminobiphenyl, on treatment with polyphosphoric acid, cyclize to yield phenanthridones 30. 

Cycloaddition reactions are not only used to construct quinoline derivatives, but also used to elaborate them. Phenanthridone derivatives were prepared by Diels-Alder reactions with 2(l )-quinolones and butadiene derivatives <01CPB407>. The synthesis of pyranoquinolines via a formal [3 + 3] cycloaddition was also reported. For example, aldehyde 66 was treated with piperidine and acetic anhydride to afford the corresponding iminum ion which undergoes a [3 + 3] cycloaddition with 4-hydroxyquinolone (67) to give pyranoquinoline 68. Intermediates such as pyranoquinoline 68 were used in the total syntheses of simulenoline and huajiaosimuline <01JOC1049>. 

Radicals can be generated from aromatic compounds by different methods and can be used for heterocycles synthesis. This is illustrated by the synthesis " in modest yield (45%) of benzoquinolones (phenan-thridones) starting with 2-aminobenzanilides (such as 4.43, Scheme 4.47). The amino group is converted to the stable (even when dry) dia-zonium fluoroborate (4.44) from which an aiyl radical is generated by action of metallic copper. The radical then adds to a double bond of the second benzene ring (Scheme 4.47) to form radical 4.45, which is resonance delocalized. An oxidative step (even just exposure to air) is then required to achieve the fully aromatic system of the phenanthridone (4.46). 

The phenanthridone alkaloid, lycoricidine 64 fScheme 12.32). is known to possess cytotoxic activity. Based on the retrosynthetic analysis as discussed in Section 12.3.2 f Scheme 12.18T the Chida group reported the total synthesis of lycoricidine starting from d-glucose in which the Ferrier carbocyclization reaction was enployed as the key reaction. For the preparation of the cyclohexene unit in lycoricidine, d-glucose was converted into 2-azido-d-altropyranoside derivative 122 via epoxide 121 fScheme 12.31T Protection of the diol moiety in 122 afforded 68, which was transformed into 5-enopyranoside 67 by the action of DBU. Ferrier carbocyclization of 67 with 1 mol% of Hg(OCOCF3)2, followed by p-elimination,... 

B.iv.e. Biaryl Synthesis by Arylation ofArenes. The intramolecular arylation of arenes on a polymer support to produce a library of phenanthridones has been described in a patent (Scheme 14). ... 

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