CHELATION-CONTROLLED REGIOSELECTIVITY IN THE SYNTHESIS OF SUBSTITUTEDPYRAZOLYLPYRIDINE LIGANDS .1. BIDENTATES

En route to novel C-linked pyrazole-pyridine bidentate ligands for tra nsition metals, a new, higher-yielding synthesis of diketone 1 was fou nd. It was quantitatively converted to the parent, C-linked 3-(pyridin -2-yl)pyrazole 2. Condensations of 1 with five aromatic hydrazines led to in-substituted derivatives of 2 (4i-8i). With CH3NHNH2, both in an d out isomers formed, but 3o could be isolated pure. In the presence o f ZnCl2, CH3NHNH2 and methyl 4-hydrazinobenzoate formed the isolable 1 :1 complexes (3o)ZnCl2 and (6o)ZnCl2, respectively, which were charact erized by NMR and elemental analysis. The bidentate, out-substituted 3 o and 6o were freed from the complexes with NH4OH. Without isolation o f complexes, PhNHNH(2) and 4-hydrazinobenzoic acid were similarly used to prepare the out-substituted derivatives 4o and 5o, respectively. N ucleophilic aromatic substitution by 2 of a-bromopyridine and ethyl 4- fluorobenzoate led to the out products 8o (a novel tridentate) and 9o, respectively. Both esters 6o and 9o could be hydrolyzed to the acid 5 o in higher overall yield than the direct condensation of 4-hydrazinob enzoic acid. The regiochemistries were assigned by several arguments: Only bidentate out-substituted materials were expected to form stable ZnCl2 complexes. It was also shown that 4o reacted with TiCl4. The for mation of out materials in the presence of ZnCl2 could be rationalized by a preferred attack of the metal-activated, inner carbonyl of 1 by the more nucleophilic NH2 ends of the aromatic hydrazines, whereas the outer carbonyl is more reactive in the absence of ZnCl2. The formatio n of out materials by nucleophilic aromatic substitutions of 2 could b e rationalized as proceeding through a K+ chelate intermediate that di sallows access to the inner pyrazole nitrogen. These two mechanistic a rguments were tied through the conversion of a product of nucleophilic aromatic substitution (9o) into a product of ZnCl2-mediated condensat ion (5o). The aromatic H-1-NMR signals were also diagnostic of the reg iochemistries: in all cases, the pyridine H-3 doublets lay upfield of the H-4 signals for in isomers and downfield for out isomers but, in t he latter case, the H-3 signals shifted upfield in the Zn complexes (a nd in the TiCl4 adduct of 4o). This pattern was interpreted in conform ational terms and the interpretation found support in MM2 calculations : The out products, like bipyridine, prefer anti orientations of the i mino nitrogens due to electronic and steric effects (calculated Delta G(syn-anti) > 3.3 kcal/mol for 3o-7o). Complexation forces a syn orien tation which produces a shielding of the pyridine H-3 by a nearby CH2 group. This same shielding effect is present in either conformation of the in isomers, which are much closer in energy (calculated /Delta G( syn-anti)/ < 0.5 kcal/mol for 3i-7i). Finally, the mass spectral fragm entations could be related to the regiochemistry.