Metal template ring closure

Nickel(II) acetate Tefraazamacroheterocyclics by metal template ring closure... 

In generalizing the latter examples one may be tempted to assume that all metal-assisted cyclization and cross coupling reactions are templated processes. This viewpoint, however, not only sets an impractically wide scope for a review, it may even be incorrect. Therefore, the present article does not try to cover all potentially templated ring closure reactions [4], but presents just a very limited and personal selection of metal-assisted or metal-catalyzed cyclizations based on C-C coupling reactions. They are analyzed with the intention to deduce more accurately what the phenomenological effect of tern-plating refers to. 

The comparison of intramolecular carbopalladation reactions of allenes and alkenes outlined in Schemes 9-5 and 9-6 illustrates that not every transition metal catalyzed ring closure necessarily involves a template effect. Others, however, clearly benefit from it. A prototype example is the palladium catalyzed cycloisomerization of alkenyl epoxides carrying distal pre-nucleophiles [38, 39], representing one variant of the famous Tsuji-Trost allylation [40]. 

Chelation itself is sometimes useful in directing the course of synthesis. This is called the template effect (37). The presence of a suitable metal ion facihtates the preparation of the crown ethers, porphyrins, and similar heteroatom macrocycHc compounds. Coordination of the heteroatoms about the metal orients the end groups of the reactants for ring closure. The product is the chelate from which the metal may be removed by a suitable method. In other catalytic effects, reactive centers may be brought into close proximity, charge or bond strain effects may be created, or electron transfers may be made possible. 

The catalysed A/-alkylation of the potassium salt of sulphoximines in l, 2-dimethoxyethane produces yields in excess of 90% [48]. Similarly, azacrown ethers have been synthesized by alkylation of bis(tosyIamino)alkyl ethers under catalysed basic two-phase conditions [49] (Scheme 5.12). The yields of the cyclic products (Table 5.24) are influenced by the choice of the alkali metal hydroxide employed, suggesting that there is a degree of template control in the ring closure step. This is not the case in the analogous reaction of p-toluenesulphonamide with a, co-dihaloalkanes [50], which leads to the formation of a mixture of l l and 2 2 cyclic products... 

The success of these experiments provides a complete vindication of the suggestion that the coordination sphere of a metal ion represents the simplest and best understood chemical template, and that it may hold reactive groups in juxtaposition so that complicated multistep reactions may occur in a sterically highly selective manner. The specific examples cited provide a new principle of ring closure which has a counterpart in the synthesis of basketlike and cagelike structures. 

The most successful approach is to complete the macrocycle by A-D linkage formation (Scheme 69).239,240 The ring closure is effected by light or oxidants, and the presence of an appropriate metal template facilitates metallocorrole synthesis.239-242... 

The catenands are synthesized using the metal ion template effect, whereby a bis complex is formed from an a,a -disubstituted o-phenanthroline. This initial product is treated with a diiodoal-kane to effect the ring closures.34... 

Siegel and coworkers have recently applied a similar metal template approach with Ru(II), terpyridyl- (40) and pyridyl/phenanthroline-based (41) ligands using 20 equivalents of Cu(OAc)2/MeCN to enact a double ring closure (42-45) in the final step, with yields of [2]catenates (46, 47) ranging from 20 to 25% (Scheme 10.8) [37]. 

Principally, the same ring closure reactions as for tetraazacycles (Section 14.11.5.3) can be applied for preparation of larger polyazamacrocycles however, mostly tosylamide and peptide-like syntheses are employed. In addition, metal template or cyclization reactions between carbonyl compounds and amines (and reduction of intermediate Schiff base) are often utilized. 

The yV-alkyl-substituted azadiol was treated with an equimolar amount of tosyl chloride and excess alkali metal hydroxide in an aprotic solvent (powdered NaOH, dioxane, room temperature, 3 hr) to give a 60% yield of the monoaza-crown (Kuo et al., 1978). Template effects are important in this cyclization reaction, so sodium hydroxide was used for aza-15-crown-5 and potassium hydroxide for aza-18-crown-6. The intramolecular ring-closure process is the result of the initial formation of a tosylate by the reaction of one alkoxide anion with tosyl chloride followed by displacement of the tosylate leaving group by the second alkoxide anion. The pure monoaza-crowns were isolated from their metal ion complexes by thermolysis under reduced pressure (Kuo et al., 1980). 

In the beginning of the macrocycle chemistry era, thiaaza-crown macrocycles in the form of cyclic bis Schiff bases were prepared by template-assisted ring-closure reactions. In general, the imine double bonds were not reduced and the template metal ions were not removed (Thompson and Busch, 1964 Urbach and Busch, 1973). These macrocyclic imine complexes, which may be used as starting materials for the preparation of thiaaza-crowns, are not listed in the tables at the end of this chapter because this book describes only saturated macrocycles. The two general methods used to prepare the thiaaza-crown macrocycles are listed here. 

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