Quinolizinium ions

The quinolizinium ion is structurally derived from naphthalene by substituting one I—— C-atom for an azonia-nitrogen in the fused position (4a). In difference from the established nomenclature (cf. Chapter 2), the reduced systems 1, 2, and 3 are named as quinolizines and the perhydrosystem (4, 4a-azadecahydronaphfhalene) as quinolizidine  

The quinolizinium ion is considered to be aromatic from its spectroscopic data (for comparison, cf. quinoline/isoquinoline p. 387/407). The strong shielding of the protons in the 4- and 6-positions next to the azonia-nitrogen are characteristics in the and C-NMR spectra of the quinolizinium ion  

In its reactivity, the quinolizinium ion shows analogies to the pyridinium ion. As a deactivated heteroarene, the quinolizinium ion is resistant to electrophilic reactions. One of the few exceptions is bromination, which primarily leads to the perbromide 5, then under drastic SnAr conditions to the substitution product 6  

If halogen is present at the 4-position of the quinolizinium ion (e.g., 8), displacement reactions are possible. Thus, sodium malonic ester affords the methylene quinolizine 7 by nucleophilic substitution and subsequent deprotonation, whereas Pd-catalyzed 

Nucleophilic ring-opening reactions occur, for instance, with secondary amines to give aminodienes 11 or with aryl Grignard compounds to give aryl-1,3-dienes 10  

A number of pharmaceuticals are derived from isoquinoline. The long-known isoquinoline alkaloid papaverine 56 (synthesis on p 344) is still important as a spasmolytic. The antidepressant nomifensin 88 and the antibilharzia drug praziquantel 89 are derived from 1,2,3,4-tetrahydroisoquinoline. 

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Azonia substitution at a naphthalene bridgehead position gives the quinolizinium ion (16). Oxonia substitution, elsewhere, forms the 1- and 2-benzopyrylium ions (17) and (18). The two most well-known monoaza systems with three aromatie fused rings are aeridine (19), derived structurally from anthraeene, and phenanthridine (20), an azaphenanthrene. The better-known diaza systems inelude phenazine (21) and 1,10-phenanthroline (22), while systems with three linearly fused pyridine rings are ealled anthyridines, e.g. the 1,9,10-isomer (23). 

Quinolizinium iodide, 3,4-dihydro-dehydrogenation, 2, 547 Quinolizinium iodide, 2-methylthio-synthesis, 2, 544 Quinolizinium ions, 2, 525-578 aza analogues, 2, 525-578 charge transfer bands, 2, 527 MO calculations, 2, 527 nomenclature, 2, 526 structure, 2, 3 UV spectra, 2, 19, 526-527 Quinolizinium ions, hydroxydihydro-reactions, 2, 549... 

As suggested by the title the principal emphasis in this chapter will be on the quinolizinium ion and its benzo analogs, with quinolizine and quinolizidine derivatives being mentioned only if they are obtained from, or transformed to, the aromatic species. For a more comprehensive treatment of these non-cationic species, the earlier reviews by Thyagarajan <65AHC(5)291> and by Mosby <61HC(15-2)1001> should be consulted. 

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. 

Although not yet confirmed by single-crystal X-ray analysis, the quinolizinium ion has been assumed to have a planar structure resembling that of naphthalene. Consistent with such an assumption is the UV spectrum of the quinolizinium ion. This may be seen in comparison with naphthalene (54JA1832), where it is seen that introduction of the azonia nitrogen causes a general, but non-uniform, bathochromic shift accompanied by a pronounced... 

Molecular orbital methods have been applied with increasing success to the calculation of the UV spectra of the quinolizinium ion (71MI21000) and have been extended to the three benzoquinolizinium ions as well as to some tetracyclic systems having an azonia nitrogen (70G421). 

Evaluation of the UV-visible spectra has been used to demonstrate the formation of charge transfer complexes between the acridizinium (benzo[6]quinolizinium) ion and polycyclic aromatic hydrocarbons (78ZC33). Similar measurements have been employed to demonstrate the existence of an interaction between DNA and coralyne, a dibenzo[a,g]-quinolizinium salt (76JMC1261). 

The acridizinium (benzo[6]quinolizinium) ion, being isoelectronic with anthracene, is fluorescent (55JA4812). The fluorescent quantum yield for acridizinium perchlorate in methanol was reported to be 0.52 (80MI21000). The rate of quenching of this fluorescence by alkyl halides was found to be related to the ionization potential of the halide (78MI21001). Quenching by anions was also measured (79JPR420). 

Perhaps partly due to the difficulty of introducing solid salts into the ionization chamber, mass spectrometry has, to date, played an insignificant role in the study of quinolizinium compounds. It is of interest that a peak at m/e 130 which appears in the mass spectrum of 2-methylindolizine (11) (70OMS(3)1489) and in that of 6-(2-pyridyl)-3,6-dihydro-2i/-1,2-oxazine (12) (74BSB147) has been assigned to the quinolizinium ion (1). Evidence was presented that the ion next lost HCN to give a metastable ion of m/e 103 followed by loss of acetylene to afford a fragment of m/e 77. 

The symmetry of the quinolizinium ion is such that only four monosubstitution products are possible for any given substituent. On the basis of a computation using the Pariser-Parr-Pople method, including all singlet mono-excited electronic configurations, Galasso (68MI21000) concluded The carbon atoms at 3 and 7 are expected to be most reactive towards electrophilic substitution. ... 

While there does not appear to be any unequivocal case of the electrophilic substitution of the unactivated quinolizinium ion, such substitution does occur (Schemes 4 and 5) when strongly electron-releasing groups are present (63JCS2203, 64JCS2760). 

Another example of the effect of a substituent on the course of reaction may be seen in the halogenation of benzo[A]quinolizinium ion (3) in the presence of aluminum halides. As will be seen in Section 2.10.2.2, electrophilic attack on a benzoquinolizinium salt usually occurs in the side-chain ring but at 100 °C, in the presence of aluminum halides, the halogen enters the central nucleus (Scheme 7). Details of the mechanism, including whether it is indeed ionic, are unknown, but it has been suggested (67JOC1169) that in the chlorination reaction the 6,11-dichloroacridizinium ion (IS) may be formed first and subsequently converted into the chlorobenzoquinolizinone (16) on nucleophilic attack by water. 

The susceptibility of the quinolizinium ion to attack by nucleophiles varies with the nucleophile and the conditions. 

Stevens et al. (58JCS3067) found that when quinolizinium iodide was treated with silver oxide, or when it was warmed with ION NaOH, there was no evidence of the C-hydroxyla-tion (pseudobase formation) that is characteristic of the methiodides of the azanaphthalenes. Their suggestion that this resistance of the quinolizinium ion is understandable, in that C-hydroxylation would destroy the aromaticity of both rings, is probably correct. 

There are no reported examples of the reaction of the quinolizinium ion or its angular benzo derivatives with active methyl and methylene compounds. The linear benzo[6]quin-olizinium (3) bromide and some of its derivatives have been found to react with acetone, acetophenone and phenylacetonitrile in the presence of hydroxide ion (59JA1938). On the basis of 1HNMR data obtained later (67JOC733), it is clear that the reaction product of... 

The stereochemistry was presumed to be cis (69T397). Reduction of quinolizinium ion in ethanol with sodium borohydride gave a mixture of tetrahydro and hexahydro products. The reduction of the acridizinium ion (3) in water at 100 °C with sodium borohydride... 

Although there is no recorded example of the reduction of the parent quinolizinium ion to a quinolizine, it has been reported that certain 1,2,3,4-tetramethoxycar-bonylquinolizinium salts can be reduced to the corresponding 4//-quinolizines by the action of potassium borohydride (Scheme 22) or by dithionite (68JCS(C)351,64JCS3225). 

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). 

Since the quinolizinium nucleus is so inert to electrophilic attack (Section 2.10.2.1.2), it is predictable that the simple benzoquinolizinium derivatives will undergo electrophilic attack in the side-chain ring. Although this prediction has yet to be tested on the benzo[fl]quinolizinium ion, the behavior of the isomeric benzo[Z>]- and benzo[c]-quin-olizinium ions has been examined with some care. 

Nitration of benzo[c]quinolizinium ion (Scheme 33) has been shown <71JCS(C)3650) to occur at position 10 and it appears likely that the betaine obtained by sulfonation is substituted at the same position. 

Permanganate oxidation of the benzo[c]quinolizinium ion (Scheme 35) likewise involves attack of the quinolizinium nucleus to produce quinoline-2-carboxylic acid. Similar behavior is shown by the 10-nitrobenzo[c]quinolizinium ion (71JCS(C)3650). 

It appears that a carboxyl group (or ester) at the 4-position of the quinolizinium ion is easily removed by heating with aqueous acid. One example (Scheme 40) is the removal of... 

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