Template cyclizations

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)... 

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 (pz), or tetraazaporphyrins, are compounds that can be viewed as porphyrin variants in which the meso carbon atoms are replaced with nitrogen atoms, as Fig. 1 shows (1). This difference intrinsically gives porphyrazines discrete physiochemical properties from the porphyrins. In addition, despite their similar molecular architecture, porphyrazines are prepared by an entirely different synthetic route than porphyrins—by template cyclization of maleonitrile derivatives, as in Fig. 2, where the open circle with the A in it represents the peripheral substituent of the pz—rather than by the condensation of pyrrole and aldehyde derivatives (1). The pz synthetic route allows for the preparation of macrocycles with chemical and physical properties not readily accessible to porphyrins. In particular, procedures have been developed for the synthesis of porphyrazines with S, N, or O heteroatom peripheral functionalization of the macrocycle core (2-11). It is difficult to impossible to attach the equivalent heteroatoms to the periphery of porphyrins (12). In addition, the preparation and purification of porphyrazines that bear two different kinds of substituents is readily achievable through the directed cocyclization of two different dinitriles, Fig. 3 (4, 5, 13). 

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... 

Porphyrin synthesis can be enhanced by metal template methods using several strategies, including tetramerization of pyrrole derivatives (equation 45),251 dimerization of dipyrrolomethenes (equation 46)252 and cyclization of 1,19-dideoxybiladiene-ac derivatives (equation 47).252 These derivatives can also be induced to undergo direct base-catalyzed template cyclization to octa-dehydrocorrins of different chromophores depending on the 1,19-substituents (Scheme 61).253-255 The cationic complex (99) can be transformed by thermal ring expansion processes to porphyrin derivatives (Scheme 62).253... 

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. 

Presumably the biosynthetic pathways of the porphyrins and corrins are related to some extent, and the direct template cyclization of a tetrapyrrole has now been described to give a mixture of 10 diastereoisomers of tetradehydrocorrin complexes (equation 54).271 In the pursuit of chemical and biosynthetic similarities and differences between corrins and porphyrins, it is necessary to... 

Oxa-crown porphyrazines (21) were synthesized by the Mg(II) template cyclization of crown ether derivatives of dithiomaleonitrile and shown to possess ligation of eight Ag(I) ions by utilizing both the crown ether and meso-pocket coordination sites [95AG(E)2020]. An improved preparation and the coordination chemistry with Ag(I) of oxa-crown derivatives of dithiomaleonitrile have been reported [95IC2300]. 

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). 

Sb(OEt)3 is highly effective for the metal-templated cyclization of tetramino esters to give macrocyclic spermine alkaloids such as buchnerine, verbacine, verbaskine, and verbascenine (Eq. 3) [9]. The accelerated rates and high regioselectivities suggest a mechanism in which the acyclic tetramino esters are covalently or coordinately attached to the antimony before the final cyclization step. In addition, Sb(OEt)3 is useful as an intermolecular amidation catalyst for reactions between esters or carboxylic acids and amines (Eq. 4) [9]. 

Metal-coordinated phosphines react similarly, as in the metal-templated cyclization of (CO)jMo(PH2CH2CH= 0113)3 in the presence of 2.2 -azobis(isobutyronitrile)(AIBN) ... 

As for phosphine macrocycles, arsine macrocycles involve very difficult synthetic chemistry. The reasons for the difficulties are essentially threefold (i) the volatility and well-known toxicity of the arsenic-containing precursors (ii) the instability of coordinated As—II functions, which renders template cyclizations of limited use for arsenic macrocycles (iii) the high energy barrier to inversion at arsenic (167.4kJmol 1),41 which means that high-dilution cyclizations of polydentate arsine macrocycles leads to mixtures of stereoisomers which are not at all trivial to separate. On the other hand, the macrocyclic (tertiary) arsines are less susceptible to oxidation than their phosphine analogs. 

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-... 

It is interesting to note that replacement of the sodium cations by tetra-methylammonium ion in the Richman-Atkins procedure did not inhibit the reaction as one might expect in a template cyclization but only decreased the yield of the tetraaza-crown to about 50%. Gokel and coworkers suggested that the increase in the yield from 50% to 80% when tetramethylammonium was replaced by sodium does indicate a small template effect by the sodium ion (Gokel et al., 1982). Bogatskii and coworkers used phase-transfer con-... 

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

Curtis and others showed that cyclic condensation also was possible in the absence of a metal template ion, but acid was necessary for those reactions. Possibly, the protonated amines formed an internal hydrogen-bonding network that acted as a template. Cyclization was observed in yields of up to 80% (Curtis and Hay, 1966 Kolinski and Korybut-Daszkiewicz, 1969 Tait and Busch, 1978a, 1978b). The isomers of the formed cyclic Schiff bases were difficult to separate. Reduction of the unsaturated macrocycles gave cyclic polyamines with up to six chiral centers and up to 20 diastereomeric isomers (Hay and Piplani, 1977 Kolinski and Korybut-Daszkiewicz, 1969). 

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. 

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