P. Vandervalk et Pg. Potvin, CHELATION-CONTROLLED REGIOSELECTIVITY IN THE SYNTHESIS OF SUBSTITUTEDPYRAZOLYLPYRIDINE LIGANDS .2. TRIDENTATES, Journal of organic chemistry, 59(7), 1994, pp. 1766-1770
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).