Y. Luo et Pg. Potvin, CHELATION-CONTROLLED REGIOSELECTIVITY IN THE SYNTHESIS OF SUBSTITUTEDPYRAZOLYLPYRIDINE LIGANDS .1. BIDENTATES, Journal of organic chemistry, 59(7), 1994, pp. 1761-1765
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.