Amines macrocyclic, reaction with

The hexahydropyrimidine (58), formed from l-phenylpropane-l,2-dione and propane-1,3-diamine, is an excellent precursor for the a-diimine macrocyclic complexes (60), presumably via the amino ketone (59) (Scheme 36).126 In this case, intramolecular cyclization of (59) to (58) is reversible, so that the metal ion can exert a thermodynamic template effect in formation of the complex (60). This represents a further example of a long-known phenomenon in which a metal ion can stabilize an a-diimine structure by virtue of the formation of stable five-membered chelate rings. Many 2-hydroxy- or 2-mercapto-amines undergo reaction with a-dicarbonyl compounds to yield heterocyclic compounds rather than a-diimines. However, in the presence of suitable metal... 

By judicious choice of reaction conditions an acyclic Ni11 complex (784) could be isolated, which serves as a valuable starting material for the preparation of unsymmetrical and mixed metal complexes by subsequent reaction with various amines. Also, a symmetrical Schiff base macrocycle of larger size has been obtained as a minor byproduct upon condensation of (784) with 1,3-diaminopropane. The resulting Ni11 complex (785) is again bimetallic, although room to bind four metal ions is in principle available.1367... 

These aquation reactions follow the same general mechanism as for non-cyclic amines, even though the rates can be many orders of magnitude less.35 The rate expression can show acid independent (solvolytic) and/or acid dependent pathways. For secondary amine/imine macrocycles with less than 16 members, reactions with Ni2+ are usually first order in [H+] (cleavage of first M—N bond rate-determining), while for Cu2+ they are second order in [H+] (cleavage of second... 

X-ray photoelectron spectroscopy, 139 Diazo ligands, 100 Dicarbonyl compounds reaction with amines aza macrocycles from, 902... 

Simple a-diimines are hydrolytically unstable, but can be stabilized as metal complexes by virtue of the formation of stable five-membered chelate rings.68 69 a-Diketones and glyoxal undergo metal template reactions with amines to yield complexes of multidentate ligands such as (34),70 (35)71 and (36).72>73 In the last case, the metal exerts its stabilizing influence on the a-diimine partner in an equilibrium process (Scheme 5). The same phenomenon occurs with amino alcohols74 75 in addition to amino thiols. The thiolate complexes (37) can be converted to macrocyclic complexes by alkylation in a kinetic template reaction (Scheme 5).76 77... 

Sometimes this deactivation is so great that co-ordinated amines are non-nucleophilic. This is particularly likely when the ligand is co-ordinated to a non-labile metal centre. However, even in these cases, all is not lost. We may also use the enhanced acidity of ligands co-ordinated to a metal centre to generate reactive nucleophiles which would not otherwise be readily accessible. For example, nickel(n) complexes of deprotonated diamines may be prepared, and react with dialkylating agents to yield macrocyclic complexes (Fig. 6-10). To clarify this, consider the reaction in Fig. 6-10 in a little more detail. The amine 6.14 is reactive and unselective, and does not give the desired macrocycle upon reaction with the ditosylate. Deprotonation of the amine under mild conditions is not pos-... 

Figure 6-14. The reduction of co-ordinated macrocyclic imines provides a method for the preparation of macrocyclic amines. The reaction above illustrates one of the standard methods for the preparation of cyclam. The metal ion may be removed from the nickel(n) complex by prolonged reaction with cyanide.

In addition to their thermodynamic stability, complexes of macrocyclic ligands are also kinetically stable with respect to the loss of metal ion. It is often very difficult (if not impossible) to remove a metal from a macrocyclic complex. Conversely, the principle of microscopic reversibility means that it is equally difficult to form the macrocyclic complexes from a metal ion and the free macrocycle. We saw earlier that it was possible to reduce co-ordinated imine macrocycles to amine macrocyclic complexes in order to remove the nickel from the cyclam complex that is formed, prolonged reaction with hot potassium cyanide solution is needed (Fig. 6-24). 

The nature of the additional nucleophile may be varied. For example, the reaction of the nickel(n) complex 6.56 with formaldehyde and methylamine gives the macrocyclic complex 6.57 (Fig. 6-46). Again, it is not clear whether the first steps of the reaction involve reaction with formaldehyde, followed by attack of amine upon the imine, or initial formation of an electrophile such as H2C=NMe, which attacks 6.56. 

It was converted to the phthalimide via a Mitsunobu reaction, reduced to the amine, and the amine was coupled with />-nitrophenylacetic acid to give the precursor to the macrocycle. Macrocylization was done via Troger s base formation using Johnson s method, which resulted in two isomers of the amide macrocycle. These were separated and reduced to give the cyclophane host. This was the first time two diastereomers were observed in these syntheses and the separation of these diastereomers was very difficult. 

Most of the template syntheses of nonbenzenoid macrocycles originated with Curtis (39) and involve the condensation of metal-amine complexes with aliphatic carbonyl compounds, e.g., the reaction of acetone with tris(diaminoethane)nickel(II) perchlorate at ambient temperature leads to the isolation of three products, two of which may be represented as cts-XLIX and trans-L and the other is formed by a further interconversion of complex L in solution (39,143). With Cu(II) diaminoperchlorates, a mixture of cis and trans complexes analogous to XLIX and L is formed, but with Co(II) only the trans analog of L has been isolated. When ketones containing bulky groups are used, the reaction is much slower, e.g., there is only a small yield of LI from... 

The most common template syntheses have been for macrocycles containing the donor atoms in the ratio of 2 2, e.g., reaction of the Ni(II) complexes (LXXXV), formed by condensation of oc-diketones with /i-mercaptoamines in the presence of Ni(II) ions, with a,a -dibromo-o-xylene affords LXXXVI through a kinetic template effect (see Section II,A) (136-138). Reaction with acetone links the coordinated amine groups of dithiodiamine to form the macrocycle complex LXXXVII (23). 

A closely related synthesis of symmetrically substituted bispidinones 19a-w is provided by the Mannich reaction with acetone derivatives 319, paraformaldehyde, and the acetate salts of various amines. Such a reaction is formally a C2N + C2N + 2C synthesis but is reported here because of its relationship to the above bispidinone synthesis. In this case the intermediate piperidinone cannot be isolated but once formed, it reacted with the primary amine and formaldehyde to give the eight-membered ring <1995T2055, 19970M1167>. Similarly, the diamine 320 reacted with dibenzyl ketone and formaldehyde to give the macrocycle 321 in 48% yield <1995T4819>. 

If nonprotected cycles are used in the reaction, a number of substituents, and a place of reaction, are often controlled by conditions (mainly by stoichiometry and solvent used). Direct reaction with amines is simple to run but may lead to inseparable reaction mixture. Selective protection adds several extra synthetic steps. Overall yields of both ways can be, therefore, comparable as well as time consumption. Isomers can be prepared with two or more substituents, (depending on the symmetry of the macrocycle). For cyclen and cyclam, they are commonly called trans ... 

Although the preparation of macrocycles often involves improved methods, several efforts have been made particularly to improve synthetic approaches. In an unusual approach, 4,13-diaza-l 8-crown-6 was converted to its bis(methyl) aminal. The CH3OCH2N< side-chain residues are labile and permitted a Mannich-type reaction with various bis(phenols) under acid catalysis <1995JOC4912>. Two of the resulting structures are shown as 20 and 21 in Figure 21. Not all phenols proved to be successful substrates for this reaction but compound 20 was formed in 25% yield. 

Again, these reactions, depending on the structure of monomer, may be reversible or irreversible. If resulting branched or macrocyclic onium ions are not reactive, i.e., they can not re-form the original active species either by intramolecular cyclization or by reaction with the next monomer molecule, then these reactions lead to termination (such a situation exists in the polymerization of cyclic sulfides or amines cf., Section 1II.D.E.). 

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