Templated cyclization reactions

Fig. 3a,b. Template cyclization reactions of a crown ethers and b CPOs. The coordination bonds are illustrated by black arrows. In the crown ether synthesis, ethylene glycols coordinate toward the metal acting as the template (normal template reaction) however, the template coordinates to the incorporated metals of porphyrin In CPO synthesis (inverse-template reaction)... 

More direct attempts by Eschenmoser and his group to build up corrins at the desired oxidation level have unearthed a wealth of kinetic template cyclization processes. These have in turn developed into techniques which can now be applied to porphinoid compounds as well. A brief summary of the types of template cyclization reactions is relevant here. 

Other examples of template cyclization reactions leading to macrocycles with amine double bonds that can be reduced to the fully saturated systems will be discussed later. Often, without the template ion, small 1 1 cyclizations take place. In the case of the Curtis reaction, a seven-membered ring was formed without the template ion (Montecatini, 1968). Ethylenediamine condensed with mesityl oxide or with other a,/3-unsaturated ketones to give tetrahydro-l,4-diazepines without the template ion (Elguero et al., 1969 Guareshi, 1894 Mushkalo and Shokol, 1960). However, in the case of reactions of rigid arylideneacetone or benzylideneacetophenone with ethyl-... 

The tin template cyclization reaction is useful for the preparation of ma-crocyclic compounds from diols, dithiols, and diamines (Leygue et al., 1988). 

The kinetics of templated cyclization reactions can be considered in the same way as for the linear coupling described in Section 1.4.2.1. There is one significant difference cyclization reactions are intramolecular, so they have characteristic effective molarities even in the absence of a template. 

Several trithioether macrocyclic ligands have been produced in high yields as their complexes of the (rf-arene)Ru " fragment via template cyclization reactions based on [( 7 -arene)Ru S(CH2CH2S)2 ] and Br(CH2)nBr ( = 1-5). The crystal structures of three examples confirm... 

An approach to isobacteriochlorins1 ln-e makes use of Pd(II) or metal-free bilatrienes 1 as starting materials. Cyclization of the corresponding bilatriene derivatives is induced by base in the presence of palladium(II) or zinc(II) which exercise a template effect. Zinc can be readily removed from the cyclized macrotetracycles by acid whereas palladium forms very stable complexes which cannot be demetalated. Prior to the cyclization reaction, an enamine is formed by elimination of hydrogen cyanide from the 1-position. The nucleophilic enamine then attacks the electrophilic 19-position with loss of the leaving group present at the terminal pyrrole ring. 

The high-dilution and template methods are frequently used in the synthesis of cyclic compounds with the aim of increasing the yield. The former method is carried out at substrate concentrations lower than 1 mM [18-20]. This reaction condition decreases the contact of the substrate molecules in the solution. The linear intermediate produced prefers the intramolecular cyclization reaction rather than the intermolecular reaction. Therefore, this reaction condition is useful for the intramolecular reaction, method B (Fig. 2). 

Other template cyclizations. In another Schiff-base template reaction, 1,3-diaminopropane monohydrochloride was reacted with biacetyl in methanol in the presence of Ni(n) to yield the nickel complex of the corresponding cyclic tetraimine - see [2.16] (Jackels et al., 1972). The success of the procedure illustrated is quite dependent on the reaction conditions employed. Attempts to isolate the metal-free macrocycle were unsuccessful - this once again emphasizes the stabilizing role of the metal... 

Porphyrazines are typically synthesized by a templated cyclization of substituted dinitriles, Fig. 2 (2). The most common divalent metal used as the template for this reaction is Mg2+, usually as the butoxide or propoxide, although other group 1(1 A) and 2(IIA) metals have been reported (41). Mixed cyclizations, which utilize two different dinitriles, Fig. 3, in principal, would give a statistical mixture of six different products or isomers. The truly enabling synthetic foundation for modem pz chemistry is the development of strategies directed toward the synthesis... 

Since Pedersen s original work on the use of cations to template the formation of crown ethers [18-20], a large number of different templating agents for macro-cyclization reactions have been reported. While the initial work concentrated on the use of metal cations, further developments demonstrated that species with hydrogen bonding donor or acceptor properties could be equally useful to template the synthesis of macrocyclic molecules. 

Scheme 6.21 Synthesis of macrocycles with intraannular ester groups by the statistical and by the template-supported cyclization reaction.

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. 

Hoffman et al. have reported the synthesis of tetrakis-, tris-, and monothiacrown ethers containing a tetra-azaporphyrin unit 139-152. The first porphyradine crown ethers were prepared by the Mgz+ template cyclization of the appropriate crowned derivative of dithiomaleonitrile 32 and 33 to afford 139 and 143, respectively, in ca. 35% yields. Treatment of 139 and 143 with trifluoroacetic acid provided the metal-free porphyrazines 140 and 144, respectively. Subsequent reaction with Ni(OAc)2 or Cu(OAc)2 quantitatively produced 141, 142, 145, and 146 (Scheme 21). 

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