Quinolizine system

Table 1 Ab initio stabilities of the 4H- and 9a/-/-tautomers of a quinolizine system...

The C/C double bonds in the quinolizine system can be reduced by catalytic hydrogenation. One example, involving the transformation of an indolo[2,3- ]quinolizidine substrate 76 into compound 77, can be found in... 

Enamine fragments present in quinolizine systems show their expected behavior as nucleophiles. For example, reaction of the indoloquinolizine derivative 78 with formaldehyde at room temperature afforded the unstable hydroxymethyl derivative 79, while reflux of 78 with formaldehyde under acidic conditions led to indole deprotection and allowed the isolation of the pentacyclic derivative 80 (Scheme 4) <2001TL7237>. 

Opening of a cyclobutane ring fused to a quinolizine system under reductive conditions has been described. Thus, the previously mentioned compound 128 was obtained by treatment of 132 with samarium diiodide (Equation 8)... 

Another approach to a fused quinolizine system 363 through the generation of a,7-bonds in the key step is the reaction between 2-cyanomethylpyridine and 6-ary l-3-cy ano l-methy 1th io-2//-pyran-2-one 361 under basic conditions (Scheme 82). This process involves the initial displacement of the methylthio group by the 2-cyanomethylpyridine anion to give intermediate 362, followed by base-induced cyclization onto the nitrile group <1999S1884>. 

A radical cyclization controlled by sulfur yields the tetrahydroisoquinoline (Equation 49) <1997J(P1)2291>. In the absence of the sulfur groups, only the reduced product is isolated. Further reactions that utilize radical cyclizations with vinylsulfides show a cascade reaction eventually forming the benzo[ ]quinolizine system <1999TL1149> (Equation 50). 

There are three possible structures for the quinolizine system, namely 2//-quinolizine (1), 4/f-quinolizine (2), and 9a//-quinolizine (3). None has been isolated as a stable species, although (2) may have a transient existence <65TL905>. A number of derivatives of these structures are known and have been reviewed <79COC(4)233>. 

Fowler and co-workers have studied the participation of 1-acyl-l-azadienes in hetero Diels-Alder reactions, finding that vacuum pyrolysis of the O-acylhydroxamic acid (298) leads to a quinolizine system (300) through an intermediate A-acyl-l-azadiene (299) (Scheme 64), a method that was later applied to the synthesis of several quinolizine alkaloids <83JA7696, 85JOC27i9>. A similar result can be achieved by flash-vacuum pyrolysis of l-acyl-2-azetines <9UOC6729>. 

Protopine alkaloids. The structures of the P. a. are characterized by an iV-methyltetrahydroprotoberbe-rine structure in which the quinolizine system has been opened to give a 10-membered azecine ring they also usually possess a 14-oxo group and can be converted in a transannular reaction to protoberberine alkaloids. They are widely distributed in the plant families Ber-beridaceae, Fumariaceae, Papaveraceae, Ranuncula-ceae, and Rutaceae (see table). 

Several lupin alkaloids have been derived from the unsaturated quinalozidine 433, that was obtained in the treatment of amine 431 with ortho-quinone 432. This quinone behaves as a model of topaquinone, the cofactor of copper-containing amine oxidases. The cyclization step involved a nucleophilic attack of the piperidine nitrogen of 431 onto a side-chain aldehyde function that is unmasked by the oxidative deamination. Quinolizine 433, when treated with dehydropiperidine, gave the oxime ether 434 that, on ozonolysis followed by reduction, afforded sparteine 10, presumably via the bis(iminium) system 435 (Scheme 102) <1996JOC5581>. 

Two new zwitterionic alkaloids with a 5,6-dihydroindolo[2,3-a]quinolizine ring system have been isolated from Vinca major L. var. elegantissima Hort (13). The structures of vincarpine (4) and dihydrovincarpine (5) have been determined on the basis of their spectral data and via some derivatives obtained by either catalytic or hydride reduction. Interestingly, the H-NMR spectrum of vincarpine in TFA solution corresponds to structure 6 derived by lactonization of 4 in the presence of acid. 

A new route has been developed for the efficient formation of the variably substituted indolo[2,3-a]quinolizine ring system, starting from a properly substituted 2-piperidone (103, 104). For the preparation of octahydroindolo-quinolizine (1), the unsubstituted 2-piperidone 139 was treated with triethox-onium tetrafluoroborate. Then the corresponding lactim ether 140 was alkylated with 3-chloroacetylindole followed by a subsequent two-step reduction process and Bischler-Napieralski ring closure. Finally, reduction of the C=N bond afforded ( )-l (104). 

A vinylogous indole derivative like 264 reacts with DMAD to give a phenanthridone derivative (267) (Scheme 42). An interesting case of the reaction of an enamine system is observed in the case of the 2H-pyrrolizine (268), which gives a mixture of the azepino[2,l,7-crflpyrrolizine derivative (271) and the 1 1 adduct (275) (Scheme 43) 164,165 reaction of 3-ethoxycarbonylmethylene-3 -pyrrolizine, on the other hand, yields a pyrrolo[2,l,5-croom temperature, the primary adduct (278) is isolated and undergoes thermal cyclization to 281 (Scheme 44). ... 

The quinolizinium ion, the parent compound of the aromatic quinolizines, is a cationic aromatic system like the pyrylium or thia-pyrylium cation. It is isoelectronic with naphthalene. The parent... 

One of the significant developments in the chemistry of the quinolizines since 1954 was the synthesis of the parent aromatic system, the quinolizinium ion, which was unknown until then. This was achieved by Boekelheide and Gall2 by the condensation of 2-picolyllithium with /3-cthoxypropionaldehyde followed by the steps indicated in the sequence 2 - 3 -> 4 -> 1. 

Ring contraction to form the indolizine ring system is another side-reaction in the alkaline hydrolysis of a quinolizine ester. Acheson etal.30 have studied in detail the conversion of tetramethyl 4Zf-quinolizine-1,2,3,4-tetracarboxylate into the corresponding indolizine derivative. 

Indolizine is an important ring system in view of its similarity to indole. Like indole, it has a delocalized 10ir-electron system that confers aromaticity, in contrast to its analogs, pyrrolizine and quinolizine. Consequently, it has a theoretical and practical interest. 

No formation of the diazacycl[3,2,2]azine system (138) was reported. During attempts to prepare the cycl[4,3,2]azine system (139) by reaction of the enamine (140) with DMAD, the cyclopenta[c]quinolizine (141) was formed.165 Two intermediates of suggested structures 142... 

Another peculiarity appears in the case of replacement by an NR group it can be introduced into the carbon skeleton in such a way that it links both ring systems. Structures of this type, e.g., indolizine (23),43 quinolizine (24),44 and some azapentalenes3 (such as 25),45 are pseudoazulenes, also,... 

Thyagarajan, B. S., Aromatic Quinolizines, 5, 291 Claisen Rearrangements in Nitrogen Heterocyclic Systems, 8, 143. 

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