Phenanthridine alkylation

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 synthesis of selectively substituted benzoxepines from ortho-substituted aryl iodides and bromoenoates has been achieved by Lautens and coworkers by palladacycle alkylation followed by an intramolecular Heck reaction under the modified conditions reported in Eq. (8) for synthesis of l-(l-ethoxycarbonylmethy-lene)-9-methyl-4,5-dihydro-3-benzoxepine [8]. In the second example (Eq. 9) the palladium-bonded biphenylyl inserts diphenylacetylene to form 1,5-di-i-propyl-9,10-diphenylphenanthrene[9]. In the last case the synthesis of 4-methyl-5H-phenanthridin-6-one is achieved by palladium-catalyzed sequential C-C and C-N bond formation starting from o-iodotoluene and o-bromobenzamide [10]. 

The conversion of the phenanthridones obtained by both Beckmann and Schmidt procedures into the parent bases is described in Section II, D. Alternatively, phenanthridines (and their 6-alkyl derivatives) can be obtained directly by a variation of the Schmidt reaction... 

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... 

The suggestion5 that phenanthridine can probably be alkylated directly under suitably vigorous Friedel-Crafts conditions does not appear to have been tested experimentally. It receives support, however, from the successful conversion of the quaternary salts (220) (R1 = Me, R2 = H) and (220) (R1 = H, R2 = Ph) into the corresponding 221 by heating with polyphosphoric acid.287 Not surprisingly, however, the related salt (220) (R1 = H, R2 = m-methoxy-phenyl) forms 222 under similar conditions.17 Direct alkylation of phenanthridine has been achieved photochemically (see p. 400). 

Further examples of the reduction of the carbon-nitrogen link by means of lithium aluminum hydride have been reported,90, 332 and sodium borohydride has been used for the same purpose in the reduction of a number of 6-alkyl-l,2,3,4,4a,10b-hexahydrophenanthri-dines.42 Quaternary phenanthridinium salts form IV-alkyldihydro-phenanthridines on treatment with lithium aluminum hydride.333... 

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. 

On the route to benzo[c]phenanthridine alkaloids [37], naphthol 51 (Scheme 20) was 0-alkylated with 2-bromo-2-methylpropionoamide under forcing conditions to give 52 in 93% yield. The rearrangement of 52 was executed with sodium hydride in DMF-DMPU and the hydroxy-amide 53 was hydrolyzed to give the aminonaphthyl derivative 54. 

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]. 

In particular, the process has been employed in the construction of benzo[c]phenanthridines and benzo[c]phenanthridones,of 3-benzazepines and 3-benzoxep-ines, and of functionalized 6-alkylated purines. ... 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence.92 94 Thus, for example, the reaction of the isoquinoline Reissert anion (26) with polyfvinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave 37.92,93 A similar condensation takes place with quinoline, phenanthridine, and benzo-[/Jquinoline Reissert compounds.94 The Reissert anion 26 has also been alkylated with a mixture of m- and p-vinylbenzyl chloride and the product polymerized to a polymer of type 37.93 Copolymerization has also been studied.93... 

Reactions of dibenzopyridines show analogies with pyridine, quinoline and isoquinoline. Acridine and phenanthridine are A-protonated by strong protic acids, iV-alkylated by alkyl halides and A-oxidized by peroxy acids. Electrophilic substitutions of acridine often result in disubstitution at the 2- and 7-positions (e.g. nitration giving 3), whereas those of phenanthridine occur at different positions (e.g. nitration mainly at the 1- and 10-position yielding 4 and 5) ... 

The benzo[c]phenanthridines synthesized by Lete s group are not reported to possess any biological activity. Indeed, no 5-benzyl-substituted quaternary benzo[c]phenanthridines appear to be active. Their syntheses have been included because of the high overall yields (60%) and particularly their versatility, which allows for the synthesis of C-6 alkyl-substituted benzo[c]phenanthridines and the possibility of functionalization at C-11. Coupled with the facile removal of benzyl substituents from isoquinolines, it is envisaged that these routes will offer significant contributions to the structure-activity relationship profiles, which are being compiled for this class of compounds. 

Phenanthridines (and their 6-alkyl homologs) are oxidized to the corresponding phenanthridones by, for example, dichromate in acetic acid or acid permanganate. Under more... 

Intramolecular HAS induced by reducing reagents has been intensively applied to obtain a large number of compounds, where either alkyl, vinyl, aryl, or heteroaryl radicals successfully add onto arenes [31b, 40]. Different synthetic strategies, such as ring expansion [41], ipso substitution [42], 1,5-hydrogen translocation, and tandem cyclization [43], among others, have been applied to afford important cyclic compounds such as phenanthridines [44], polycyclic arenes [45], 6//-benzo[c] chromen-6-ones [13a], and strained helicenes [46]. 

A related approach used catalysis by FeCl, t-BuOOH (TBHP) as oxidant, and 1,8-diazabicycloundec-7-ene (DBU) as ligand. Several dialkyl ethers, sulfides, and amines have been used to generate alkyl radicals, which add to A-substituted A-phenylacrylamide [56]. This initiation methodology (M"+/ROOR) was also used in the synthesis of 6-arylated phenanthridines [57, 58], biaryls [59], fluorenones and xanthones [60], etc. 

Oxidation of RB(OH)2 with Mn(OAc)j also produces R that are subsequently added to aromatic rings to generate alkylated or arylated compounds [106], for example, in the synthesis of 6-alkyl- or 6-aryl-phenanthridines 129 from isonitriles 128 (Eq. 9.27) [107] ... 

Also, the intramolecular Sjjj l has proven to be highly efficient for the syntheses of heterocycles like carbazoles, carbolines, phenanthridines, etc. The Ar" radical intermediates can also be trapped by an appropriate double bond, and the resulting alkyl radical intermediates can react with a Nu to give substituted heterocycles. 

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