Synthesis phenanthridine derivatives

A photochemical ring construction similar to that described in Scheme 5 was used in the synthesis of the aromatic lycorine alkaloid ungeremine (51) (Scheme 6). Photocyclization of the somewhat inaccessible imine (48) gave the phenanthridine derivative (49) in 21 % yield which upon metal hydride reduction and cyclization with phosphorus tribromide afforded the quaternary salt (50) which was shown to be identical with the methyl ether of ungeremine (51) obtained as shown. 

The synthesis of 6-amino-ll,12-dihydrobenzo[c]phenanthridine 133 and 6-amino-benzo[c]phenanthridine derivatives 134 was accomplished in a very straightforward approach by the condensation of 2-methylbenzonitrile 135 with aromatic aldehydes 136 resulting in the 6-amino-ll,12-dihydrobenzo[c]phenanthridine derivatives 133. Dehydrogenation of the dUiydro derivatives using DDQ yielded the 6-aminobenzo[c]phenanthridine derivatives 134 in Scheme 39 <0581052,05JMC2772, 05AG(1)635>. 

Linsenmeier AM, Williams CM, Brase S (2011) Synthesis of Phenanthridine Derivatives via Photolysis. J Org Chem 76 9127. 

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). 

G. Marandi, M. T. Maghsoodlou, N. Hazeri, S. M. Habibi-Khorassani, N. A. Torbati, F. Rostami-Charati, B. W. Skelton, M. Makha, Mol. Divers. 2011, 15, 197-201. Synthesis of cyano-2,3-dihydropyrrolo[l,2-/ phenanthridine derivatives via a domino-Knoevenagel-cyclization. 

Zhang L, Ang GY, Chiba S (2010) Copper-catalyzed synthesis of phenanthridine derivatives under an oxygen atmosphere starting from biaryl-2-carbomtriles and Grignard reagents. Oig Lett 12 3682-3685... 

Lu, T. Guo, C. Ni, P. Design, synthesis and evaluation of phenanthridine derivatives interacting with G-quadruplex as telomerase. Zhongguo Yaoke DaxueXuebao 2004,35,99-105 Chem. Abstr. 2005, 144, 31987. 

Chiba et al. developed an efficient copper -catalyzed synthesis of phenanthridine derivatives from biaryl-2-carbonitriles and Grignard reagents under an O2 atmosphere (Scheme 8.101). This Cu(OAc)2-catalyzed C-N bond formation involves an aromatic C-H bond activation process. This reaction proceeds via N-H imine formation by the nucleophiUc addition of a Grignard reagent to biaryl-2-carbonitrile and intramolecular aryl C(sp )-H functionaUzation with copper catalyst [174]. 

Scheme 8.101 Synthesis of phenanthridine derivatives from biaryl-2-carbonitriles and...

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromate afforded directly oxyche-lerythrine (232) instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient... 

The reaction of 6.36 with allyl and benzyl anions was examined with a view to develop an efficient method for the synthesis of phenanthridines and their benzo[/]-derivatives. The dithioacetal 6.36 when reacted with allyl anions yielded the corresponding... 

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... 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

This polycyclic 2-benzopyrylium salt was also obtained in good yield from the 2-benzopyrylium salt 56, through intramolecular acylation of the intermediate isochromene derivative 60. The same approach was used later by Elliott and co-workers (84CJC2435) in the synthesis of some benzofc]-phenanthridine analogs. 

Subsequently, Abramovitch et al. employed the Pschorr cyclisation of 100 in a synthesis of benzo[c]phenanthridine 102 <63CJC2265>. The key step involved addition of an aryl radical to C3 of an isoquinoline and proceeded in good yield (Scheme 33). Notably, no products derived from cyclisation to the pendent arene were observed [see also Scheme 56]. 

Dimethyl azodicarboxylate (164) has been reported to undergo a [ 4 + 2] photocycloaddition to the diene (165) to give the 2,3-diazabicyclo[2.2.2]octene (166). An analogous solid-state addition has been described in the ox-azolone (167) to give the photodimer (IbS), and oxidation of the photoadduct derived from 1-oxoanhydromethylberberine and nitrosobenzene has been used in a synthesis of ring C-substituted benzo[c]phenanthridines. ... 

ET-initiated alkylation of azines in the presence of alkyl halides has been found to occur under electrochemical conditions according to Scheme 43. Either alkylated dihydroheterocycles or the rearomatized products are obtained. As an example, electroreduction of quinoline in the presence of 1-bromoadamantane gives alkylated quinolines (10 % in position 2, 5 % in position 7) and 2-methyl- and 2-methoxyquinoline give the 7-adamantyl derivative in 20 and 23 % yield, respectively. 1,10-Phenanthroline gives bis(adamantyl) derivatives, whereas isoquinoline and phenanthridine give the 6-adamantyl-5,6-dihydro and the 9-adamantyl-9,10-dihydro derivatives, respectively [132]. Reaction with terr-butyl chloride also gives alkylated dihydroheterocycles [133]. Arylation has also been performed, e.g. in the synthesis of pyrazolophenanthridines (62, Scheme 44) [134]. 

The general synthesis of phenanthridines, which are benzoisoquinolines, are patterned on isoquinolines. The lithiation route is similar to the one, where, for an isoquinoline synthesis, a p-phenylethyl amine (75) is the starting compound. The starting compound now is a 2-amino biphenyl (79). Interestingly, it is no more necessary to convert the primary amine to its dimethyl derivative. 

Imidoyl radicals in organic synthesis, particularly, in construction of indoles, phenanthridines, pyrrolidines, quinolines, quinoxalines, and fused poly-cyclic N-containing derivatives 07COC1366. 

This methodology with some variations has been utilized in the synthesis of numerous heterocyclic systems, such as heterocycle-fused quinolinone derivatives [391], l,4-benzodiazepin-2-ones [392], benzo-, naphtho- and heterocycle-fused pyrrolo[2,l-c][l,4]diazepines [393], quinolinone or pyrrolidinone derivatives [394], dibenzo[fl,c]phenanthridines [395], thiazolo-fused quinolinones [396], isoindolinone and isoquinolin-2-one derivatives [397], indoline derivatives [398], 5-aroyl-pyrrolidinones [399,400], indazolone derivatives [401,402], substituted indolizidinones [403], 1-arylpyrrolopyrazinones [404], stmcturally diverse... 

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