CHELATION-CONTROLLED REGIOSELECTIVITY IN THE SYNTHESIS OF SUBSTITUTEDPYRAZOLYLPYRIDINE LIGANDS .2. TRIDENTATES

A new, more reliable synthesis of tetraketone 4 was found. With (t)BuN HNH(2), PhNHNH(2), and 4-hydrazinobenzoic acid, it condensed to give m ostly in,in-disubstituted derivatives (7ii-9ii) of the parent, C-linke d 2,6-bis(pyrazol-3-yl)pyridine 5, along with some in,out materials. M eNHNH(2) also provided some out,out isomer (6oo). This same derivative was also produced by NaH-mediated methylation of 5 with CH3I, presuma bly via a Na+ chelate that disallowed access to the inner pyrazole nit rogens, and was able, as a tridentate, to solubilize solid sodium picr ate (NaPic) into CDCl3, with H-1-NMR detection of the complex. In cont rast, the bidentate in,out isomer did not solubilize NaPic. Similarly, ethyl bromoacetate produced 10oo and it also solubilized NaPic. Previ ously reported alkylations of 5 had also given out,out products that b ound alkali metal ions. 10oo was hydrolyzed to the disalt 13oo. In the presence of ZnCl2, 1 reacted with PhNHNH(2) to give the out,out deriv ative 8oo, presumably through a metal-mediated activation of the inner carbonyls of 1. Though 8oo also solubilized NaPic, a better NMR spect rum was obtained by treatment with CF3COOD, which indicated multidenta te binding of D+. The same phenomenon was also observed with the out,o ut diester 1 loo, which was obtained by the nucleophilic aromatic subs titution by 5 of ethyl 4-fluorobenzoate, presumably via a Kf chelate t hat also disallowed in substitution. A mono-out-substituted product 12 was also isolated from this reaction. Apart from mechanistic argument s and the ability or inability to dissolve NaPic, the aromatic H-1-NMR regions were diagnostic of the regiochemistries: In all cases, the py ridine H-3/5 doublet lay upfield of the H-4 triplet for in,in. isomers and downfield for out,out isomers, while in,out isomers showed one do ublet on either side of the triplet. The binding of Na+ or D+ by the o ut,out isomers resulted in shifts of the H-3/5 doublets to upfield pos itions. The deuteration of in,in isomers did not. This situation was a nalogous to that of the bidentates reported in the accompanying paper and was similarly interpreted in conformational terms, with support fr om MM2 calculations: Like terpyridine, the imino nitrogens of the out, out materials prefer anti orientations due to electronic and steric re pulsions (calculated Delta G(syn-anti) > 2.7 kcal/mol between rotamers about each pyridine-pyrazole bond in 6oo and 7oo and about the out-su bstituted pyrazole-pyridine bonds of 6io and 7io), but they are forced into syn orientations upon binding Na+ or D+. This induces a shieldin g interaction between the pyridine H-3/5 and neighboring CH2 groups. T his same shielding is present in any conformation of the in,in product s and of the in-substituted side of in,out isomers, which are much clo ser in energy (/Delta G(syn-anti)/ less than or equal to 0.4 kcal/mol for any ring-ring bond in 6ii and 7ii and for the in-substituted pyraz ole-pyridine bonds of 6io and 7io).