Isoquinolines representative synthesis

The [4 + 2] cycloaddition of benzo-l-azadienes with electrophilic carbon—carbon double bonds has been implemented by de Meijere and coworkers (90CC574) in this case, the authors used N-unsubstituted benzo-phenone imine and cyclopropylideneacetates, and the reaction represents a new isoquinoline ring synthesis. 

Direct Sj UAr) substitution reactions allow syntheses of isoquinolines (Beugelmans et al. 1984), indoles (Beugelmans and Roussi 1979, Barolo et al. 2003), and derivatives of benzothiazole (Boujlel et al. 1982), benzothiazine (Layman et al. 2005), or benzofurane (Vaillard et al. 2002) by one-pot syntheses. The photoinitiated synthesis of 2-methylindole is a representative example depicted in Scheme 7.36. 

The 1.2.3.4-tetrahydroisoquinoline skeleton represents the framework found in many isoquinoline alkaloid derivatives and not only from plants. Some derivatives attracted much interest because of their anti-cancer activity [124], which has prompted many groups to invest in their chemical synthesis. The Pictet-Spengler reaction has become an important method in the preparation of this alkaloid type, and has often been described with phenylalanine derivatives and pyruvates as starting materials. Synthesis of appropriate tetrahydroisoquinoline-3 and the corresponding tetrahydroisoquinoline-1-carboxylic acid has been the key target [125]. 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

Preformed cyclic /V,A-dialkyliminium salts i.e. where a ring Joins the a-caibon and positively charged nitrogen) have been used in enolate condensation reactions. The number of examples, however, is rather limited, probably because of complications arising through abstraction of enolizable protons. A -Dehy-droindolizidinium salt (69) represents one of the few examples of an enolizable, cyclic A, -dialkylimi-nium salt known to react with an enolate (equation 8). The use of a soft zinc enolate in this reaction may be crucial. The relative stereochemistry of the resulting 3-amino ester (70) is undefined. /V-Alkyl-3,4-dihydroisoquinolinium salts e.g. 71), a class of nonenolizable, cyclic iminium salts, have had extensive applications in the total synthesis of protoberberine and phthalide isoquinoline alkaloids. A review by Pai and coworkers has covered much of this work. In a more recent application by Yamazaki and co-... 

For a preparation of alkaloids 35 configurated beyond all doubt, synthetic pathways from the ehiral pool were also elaborated (71). The C3N unit destined to represent the crucial chiral center at C-3 turned out to be the amino acid alanine, in its natural L-form 118, which should easily be incorporated into the isoquinoline framework by reductive amination with the acetophenone 119 and subsequent intramolecular acylation, as outlined in Scheme 29. The practical realization of such a non-biomimetic synthesis (see Scheme 30), however, differs from this very simple concept in three ways ... 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

An important variation of the Jones-Schmid indole synthesis is the base-mediated cyclization onto esters, which affords 3-hydroxyindoles (indoxyl tautomers) under mild conditions. Three case studies are shown in Scheme 2 (equations 1-3) [18-20]. This chemistry, like that in Table 1 (Entries 4-11), represents a powerful route to C-3 functionalized indoles. Kraus and coworkers use the steri-cally hindered phosphazine base, P -t-Bu, to prepare the 5,6-dihydroindolo[2,l-a]isoquinoline ring system (equation 4) [21]. Several derivatives display immunosuppressive activity. 

Although the intramolecular SrnI reaction has been studied to a lesser extent as compared to the intermolecular process, it has been shown to represent a highly useful route for the synthesis of various heterocyclic compounds. For example, the SrnI cyclization of N-alkyl-N-acyl-o-haloaniUnes and N-acyl-N-methyl-o-chlorobenzylamines (Equation 13.5) gives N-aUcylindol-2-one and 1,4-dihydro-2H-isoquinolin-3-ones in moderate to good yields [21]. lodoketone 1 reacts under SrnI conditions to provide the complex heterocyclic compound 2 with excellent yield (Equation 13.6) [22]. 

This stereoselective reaction proceeds through an exo transition state with a trans-oxazohydrindan bridge conformation. The stereocontrolled assembly of this compound in one step represents a direct route to functionalized isoquinoline derivatives, which may prove useful for alkaloid synthesis. 

Thiazolo-[4,5-)t]-, -[5,4-/l-, and -[5,4 h]-isoquinolines (C3NS-C5N-C6).—In their programme aiming at the synthesis of eight isomeric thiazolo-isoquinolines, Taurins and his co-workers have synthesized representatives... 

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