477-Quinolizines, formation

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). 

Lactam 299 was prepared from tryptamine and cyano diester 298 by reductive alkylation in about 12% yield. Phosphorus oxychloride cyclization of 299, followed by catalytic reduction, resulted in the corresponding trans disubstituted indolo[2,3-a]quinolizine 300. After transesterification, formylation and methyla-tion were carried out in two subsequent steps with ethyl formate in the presence of triphenylmethylsodium and with an excess of diazomethane to supply ( )-dihydrocorynantheine (163). 

The yields are high in this synthesis. However, the use of strong acids like sulfuric acid in the cyclization step causes much tar formation and lower yields. Acetylacetone, benzoylacetone, and acetoacetaldehyde have been successfully employed as starting j8-diketones and afford the corresponding 2,4-disubstituted quinolizines in 50-75% yield. The use of 2,6-lutidyllithium as starting component gave the corresponding 2,4,6-trisubstituted quinolizines. 

Formation of the imine and subsequent reduction can often be achieved in one pot . Thus, a microwave-assisted reductive amination-cyclisation domino reaction was used as the key step in the synthesis of perhydrocyclo-penta[ij]quinolizines from 1,5,9-triketones. This type of heterocycle is an important structural element in a series of alkaloids. The reaction of the triketone with ammonium formate in PEG-200 was performed within 1 min using microwave irradiation of370 W in a domestic microwave oven. Amixture oftwo ofthree possible stereoisomers was obtained in 87% overall yield (Scheme 4.29)52. 

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... 

Thermal addition of DMAD to 3-(T-dimethylaminovinyl)indolizine (49 R = Me or Ph) in toluene gave cyclopenta[c]quinolizine (53) via a cyclobutene601 and the diene 51 (Scheme 18). Formation of 53 involves a rearrangement apparently without precedent. By carrying out the addition in methanol, the zwitterion was intercepted by proton transfer to give 50, which was converted into the isomeric quinolizine 52 in boiling xylene.600... 

The photolysis of N(3- or 4-alkenyl)mono- or di-thioglutarimides seems to proceed in several steps involving initial intramolecular thietane formation between thiocarbonyl and N-substituted alkene. Photochemical cleavage of both C-S and C-C bonds of a thietane resulted in the formation of the corresponding indolizines or quinolizines (Equation 3) <2000H(53)2781>. 

In all cases one of the groups R2 or R3 in Eq. (19) has been an ester, and in most cases the ester group cyclizes on to the pyridine nitrogen atom. However, cyclization of a nitrile can give a quinolizine imine (Eq. 20). In an example where ethyl ethoxymethylene cyanoacetate was used32 the formation of imine was favored at —10° but not at higher temperatures where 4-quinolizone becomes the major product. Examples of the reaction (Eq. 20) have been reported where R1 was a nitrile,32,35 ester,32,35,36 or ketone... 

The scope of this process has been extended in a more detailed investigation to the synthesis of quinolizines [175] and the influence of alkyl substituents in various positions of the aminodialkene substrate on product diastereoselectivity was probed. Neodymium-based catalysts are particularly efficient for six-membered ring formation (40). The methodology has found further application in the synthesis of tri- and tetracyclic alkaloidal skeletons (41) [176]. 

Attempts to condense the quinolizine (73.4) with methyl propynoate in boiling tenzene or toluene containing palladium-charcoal failed, but when nitrobenzene was used, moderate-to-good yields of the pyridoquinolizine were obtained. Formation of a 4 oxo- or 4-chloro-pyridine ring from a carboxylic acid (or ester) or an acyl chloride respectively Is well documented (see pp. 378-381, and Section II.3 of this chapter) in this particular example, a fused... 

The use of 521 led to the synthesis of a number of natural products through the aza-annulation of this (i-imino sulfoxide (Scheme 42).117 118 Application of methyl acrylate in this aza-annulation process led to the formation of 522. The chiral auxiliary was then used to provide moderate stereochemical control in the reduction of the enamide alkene to 523 and 524 in a 1.9 1.0 ratio. Compound 523 was then reduced to remove both the sulfoxide and the lactam carbonyl to give (-)-l,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine (525). 117,118... 

Intramolecular amide formation is also a useful route to quinolizines. Thus, a very efficient synthesis of the phenanthroquinolizidine alkaloid cryptopleurine (189) described by Snieckus and... 

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