Bispidone,

The final step to 46 is cyclocondensation of 3,7-diazabicyclo[3.3.1]nonane (51), bispidine70, with formaldehyde. There are two different approaches to 51 (i) a pyridine is converted to a piperidine and (ii) the double Mannich or Robinson-Schopf condensation of ketone 52 with formaldehyde and primary amines affords 1,5-disubstituted 3,7-dazabicyclo[3.3.1]nonan-9-one (53), bispidone, from which 5,7-disubstituted l,3-diazaadamantan-6-one (61) is derived. Route (i) is adopted by Galinovsky and Langer,71 Stetter and... 

Caujolle. R., Castera, P and Lattes, A., Stdr-cochimic des formes enoliques de pipdridones prccurscurs dc bispidones. Bull. Soc. Chim. Fr.. 52. 1983. 

For copper(II) in particular, the tetradentate bispidone L has a high degree of preorganization and complementarity and therefore leads to very stable complexes with a range of interesting properties, in particular also due to the unique square pyramidal structure with an in-plane monodentate coligand 6... 

Figure 1. Structures of the tetradentate bispidone ligand L (left) and diamond (right).

B. BISPIDONE 3,7-DIMETHYL-9-OXO-2,4-BIS(2-PYRIDYL-3,7-DIAZABICY CLO[3.3.1]NON ANE-1,5-DICARBOXYLATE DIMETHYLESTER (L)... 

The piperidone pL and bispidone L are air-stable, colorless crystalline compounds. As for bispidones in general, the IR spectrum of L has characteristic Bohlmann bands (2795 and 2848 cm ), which disappear upon complexation. The blue crystalline copper(II) complex [Cu(L)(Cl)]+ is stable in air. In the UV-vis spectrum (aqueous solution), it shows a d-d transition at 2max = 656nm (15244cm x) with 656 = 90cm 1 M 1. The spin Hamiltonian parameters (obtained by simulation of a measured frozen solution EPR spectmm [116K, DMF/ CH3OH = 2 l]) are gz= 2.224, gx = gy = 2.Q5-, 175 x 10 4cm, Ay 22... 

The most common and versatile route to bispidines is a variant of the Mannich condensation (see Scheme 1). The reaction of a component with C H acidic hydrogen atoms, an aldehyde, and a primary amine or ammonia in the ratio 1 2 1 leads to a piperidone, which in some cases can be further condensed with an aldehyde (usually formaldehyde) and a primary amine to yield a bispidone. For symmetric bispidine derivatives, the preparation can be conducted in one step with the aldehyde, the C H acidic component, and the amine in a 4 1 2 ratio. 

In the case of highly symmetric bispidones, such as compounds 49-56 (Table II), as well as the comparable 1,5-dialkyl- or 1,5-unsubstituted derivatives, the Wolff-Kishner reaction with hydrazine hydrate (32, 88, 108-112) or tosyl... 

With 2,4-substituted, bispidones of lower symmetry and analoguous 1,5-dicarboxylic acid esters (e.g., compounds 10-48 in Table 1) the reduction under Wolff-Kishner conditions fails, but reaction with complex hydrides leads to the corresponding bispidoles. The treatment with LiAUTj yields a 1 1 mixture of the epimeric tris alcohols, whereas reduction with NaBELj at ambient temperature in various solvents leads to the epimeric mono-alcohols in different ratios up to epimerically pure compounds (see Scheme 9) (116, 117), which can be further reduced to the tris alcohols with LiAlH4. For example, the reduction of 14 with NaBH4 in dry methanol yields 65% syn- (84b) and 35% anri-product (84a), while the reaction in a mixture of dioxane-water leads exclusively to the anti-configuration of alcohol 84a (117). 

Substituents in 2,4-position generaly prefer equatorial orientations in a chair confonnation of the six-membered ring. Bis-axial orientation of these substituents would lead to strong repulsion, but in some examples an axial-equatorial confonnation is observed, as will be disscussed below. The X-ray analysis of the 2,4-diaryl-3,7-dimethyl-l,5-dimethoxycarbonylbispidin-9-one (3) reveals a flattened chair-chair conformation with the aryl substituents, as expected, in the equatorial position. From comparison of the IR-, H-, and NMR spectra with those of the analoguous p-methoxyphenyl- and p-chlorophenyl-substituted derivatives, it follows that these all adopt a double-chair conformation (56). The same behavior was also found for the bispidones 14 and 35 (70) 46-48 and 104 (see Chart 16) (160). The PM3 calculations for various bispidones with aromatic substituents have shown that the cc confonnation is slightly more stable than the cb form, and this is much more stable than the bb conformation in all cases (161). 

This leads to the conclusion that the formation of either epimeric stmcture can be controled by the conditions under which the reaction is carried out, and for most reactions it turns out that the endo-endo epimer is the thermodynamically controled product (see Chart 18). For p-nitrophenyl substituented bispidones, the free activation enthalphy for the isomerization, deduced from NMR experiments, was calculated to be 105kJmoP For phenyl- or m-nitrophenyl-substituted bispidinones, the endo-endo isomer is 8.4kJmoP ... 

Aromatic substituents at C2 and C4 are to some extent hindered in rotation. This leads to a third type of isomerism in bispidine chemistry (i.e., atropisomer-ism). The activation energy for the rotation around the C2/C4—aryl bond for bispidones with various meta-substituted phenyl groups was determined by various NMR methods and found to be 70-75 kJ mol (23). For a rotation of 180°, which is usually necessary for the coordination of bispidine ligands to metal ions (e.g., 14, see Scheme 14), two energy barriers have to be overcome. The higher is the result of an interaction of the ortho-disposed proton of the aromatic ring with the proton or the alkyl substituent at the N3 amine nitrogen atom. The... 

An interesting possible and stable isomer of the 2,4-bispyridine substituted ligand 14 is the corresponding 2,6-bispyridine-bispidone [shown in Fig. 2(c) is a plot of the X-ray molecular structure of its copper(II) complex] (205). There are two major differences between this structure and complexes of 14. (1.) In structure 2c, the two amine donors N3 and N7 are symmetry related, and therefore are identical in contrast to ligands and their complexes derived from... 

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