Acridizinium derivatives

Table 9 Synthesis of Acridizinium Derivatives by Cyclodehydration of Quaternary Salts (Scheme 98)...

The salts (181) successfully cyclized include some bearing a ketone or ketone-derived functional group (181 Rn = alkyl or aryl) instead of an aldehyde function, providing a route to acridizinium derivatives substituted at position 11. 

The quaternization of 2-pyridinecarbaldehyde with 2,3,6-trimethoxy-9-phenanthryl-methyl bromide (183) yielded a salt (184) which, when cyclized, afforded a dibenz[/i,/]acridizinium derivative (185). Reduction of the quinolizinium ring of (185) afforded ( )-cryptopleurine (57JA3287). 

In the first cycloaddition reaction of the acridizinium ion, that with maleic anhydride, it had been observed that addition had occurred with great stereoselectivity, although it iVas not ascertained whether the product (4) was syn or anti with respect to the benzenoid ring. It was later demonstrated by use of NMR and IR evidence (derived from the... 

Not shown in Table I are several adducts obtained by cycloaddition of the acridizinium ion with 5,6-endo-substituted norbomene derivatives. These adducts each have two (imequally shielded) methylene hydrogen atoms which make simple the NMR analysis of mixtures of syn (8) and anti (9). When the 5,6-endo chain (R) was of the type... 

The three possible benzo derivatives of the quinolizinium ion are each well known (69ACR181), the benzo[a]- (2), benzo[6]- (acridizinium) (3) and benzo[c]-quinolizinium (4) ions. 

The simplest quinolizinium derivative which reacts with cyanide ion is the acridizinium ion (3) (58JCS3067,59JA1938) it gives an unstable product (Scheme 11) which was not isolated, but was dehydrogenated by bromine to afford what was believed to be the 6-cyanoacridizinium ion (23). 

Although the quinolizinium ion (1), like naphthalene, does not undergo photodimerization, its linear benzo derivative, the acridizinium ion, like anthracene, does so readily (Scheme 27) (57JOC1740). The photodimer dissociates when heated in ethanol. It has been reported that both the dimerization and dissociation in methanol are light-catalyzed and that the quantum yields for the two reactions are 0.23 and 0.49 respectively (78JPR739). 

It is now clear that acridizinium compounds and their benzo analogs are more susceptible to cycloaddition than are their quinolizinium counterparts. Fields et al. (68JOC390) showed that, even with the strong nucleophile 1,1-diethoxyethylene, 2,3-dimethylquinolizinium ion (35a) does not react. As yet the only quinolizinium derivative known to undergo cycloaddition is the anhydride (35b) of quinolizinium-2,3-dicarboxylic acid which, because of the increased electrophilicity provided by the electron-withdrawing substituents, undergoes cycloaddition even with the more moderately nucleophilic styrene to yield (36). 

Although no 4-aminoquinolizinium derivatives are known, a benzo derivative, 6-amino-acridizinium ion (72 Scheme 50), has been prepared (67JOC733). In the presence of hydroxide ion the amino group loses a proton to form a benzo[6 ]quinolizin-6-imine (73). Alkaline hydrolysis opens the ring to give the amide (74). 

An alcohol which is easily aromatized to a quinolizinium ion (albeit a benzo derivative) is (145 Scheme 87), an intermediate in an acridizinium synthesis (80JOC4248). In the preparation of 4-methylacridizinium bromide (146 R = Me) this route gave a better overall yield (34%) than had been obtained by other methods. 

The first synthesis of the benzo[6]quinolizinium ion (Scheme 98, Table 9, example 1) was by hydrobromic acid-catalyzed cyclization of the quaternary salt formed between 2-pyridinecarbaldehyde and benzyl bromide. Aromatic cyclodehydration has continued to the present as almost the only method used for the preparation of the acridizinium ion, its derivatives and benzo analogs. Because of its instability, 2-pyridinecarboxaldehyde has been replaced by more efficient derivatives. The first of these was the oxime (example 2) which not only gave a better overall yield, but also made possible the isolation of a crystalline intermediate (181 Z = NOH). The disadvantages are that it is not suitable for high temperature cyclizations involving polyphosphoric acid, and some products (182) (e.g. example 10, Table 10) may tend to form double salts with hydroxylamine hydrobromide. 

The preparation and properties of the charge transfer salt between azonia derivative (2 and 246) and tetracyanoquinodimethane (TCNQ) were reported (88MI2). Wang and Jones reported that acridizinium salt underwent single crystal — single crystal photodimerization (87T1273). 

Cationic additions of cyclopropenes are illustrated by the rapid and highly stereoselective addition of cyclopropene and its 1-methyl derivative to the 6,11-positions of the acridizinium cation. A marked preference (80-90 %) is shown for the regioisomer 168 (R = Me) which results from electrophilic attack of the cation on 1-methylcyclopropene such that charge separation is maximized. 

As in the earlier review1 this account will be restricted to the quinolizinium ion (1), the benzo[a]- (2), benzo [ft]- (3), and benzo[c]quinolizinium (4) ions, and to their derivatives. The quinolizones and compounds of similar structure (5) will be included, but the quinolizines (6 and 7) only where they appear as intermediates in synthesis or reaction. A number of trivial and unsystematic names have been used (pyridocolinium ion, dehydroquinolizinium ion for compound 1 acridizinium ion, 4u-azoniaanthracene for compound 3 phenanthridizinium ion for compounds 2 or 4), and numbering has also varied. Throughout this chapter the numbering will be as shown in formulas 1 to 4. 

Acridizinium salts. A soln. of l-benzyl-2-(l,3-dioxolan-2-yl)pyridinium bromide (prepn. s. 995) in 48%-HBr refluxed 11 hrs. acridizinium bromide. Y 95%.— The cyclic acetal was superior to any known picolinaldehyde derivative in both the yield and quality of the product. F. e. s. G. K. Bradsher and J. G. Parham, J. Org. Ghem. 28,83 (1963) 6a-azonianaphthacenequinones, compounds being quinolizinium salts as well as quinones, s. J. Org. Ghem. 28, 1669. 

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