Benzo quinolizidine system

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

Ketone groups attached to quinolizidine systems also display the expected reactivity towards nucleophiles. This is illustrated in Scheme 23 with several reactions of benzo[a]quinolizidin-2-one systems (159). 

Hetero-Diels-Alder reactions have been succesfully employed for the synthesis of arenoquinolizine systems. For example, as shown in Equation 10, treatment of tetrahydroquinoline 319 with Danishefsky s diene 320 in the presence of a Lewis acid gave the benzo[c]quinolizidine derivative 321 <2000JME3718>. 

This chapter is organized in much the same manner as its predecessor, with some subsections expanded whenever warranted. Unless otherwise noted, the structural formulas of optically active compounds in this chapter represent their absolute configurations, and the numbering system employed for the benzo[n]quinolizidine alkaloids is identical with that used previously 1,12). 

Many other synthetic benzo a]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available a number of indole alkaloids carrying the indolo[2, 3 3,4]pyrido[l,2-b][2,7]-naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space. 

The most widely used procedure for the preparation of benzo[a]quinolizidin-2-ones and their 3-alkyl derivatives (270) consists of the reaction between 3,4-dihydroisoquinolines and a,/3-unsaturated ketones, with iminium salt (269) as an intermediate <62CB2135>. 4-Dimethylamino-2-butanone derivatives can play the same role as unsaturated ketones, and have the advantage of allowing the reaction to be conducted in aqueous solutions, which facilitates the isolation of the product <69JCS(C)85> (Scheme 56). The yields obtained in the latter case are usually quantitative for 3-substituted benzo[a]quinolizidin-2-ones, but are considerably lower for the unsubstituted system because of the formation of a secondary product (271). Fortunately, this problem may be overcome by modifying the pH and temperature of the reaction medium <88TH822-0l>. 

Recent work has shown that they, and the more reactive 2-hydroxytetrahydro-pyridines, can be obtained by photochemical addition of enamino-aldehydes (165) to olefins. The photochemical [2 + 2] cycloaddition proceeds with complete regiospecificity, presumably by the formation of a cyclobutane system, followed by a hetero-retro-aldol reaction and formation of a new enamino-aldehyde, which re-cyclizes to (166). Further treatment with acid provides a useful method for synthesis of benzo[a]quinolizidine alkaloids (167). The last two steps may be completed in one treatment of (166) with BFa EtjO on alumina. 

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