Synthesis of Unsymmetrical 5,5'-Disubstituted 2,2'-Bipyridines(1).

The preparation of unsymmetrical 6,6′-disubstituted 2,2′-bipyridines has generally occurred by the stepwise mono-N-oxidation,2 followed by a Boekelheide-type rearrangement3 or by a coupling of different pyridine precursors;4 both procedures are plagued with difficulties. It was, however, demonstrated5 that, in THF at -60 °C with 1 equiv of butyllithium, 6,6′-bis(hydroxymethyl)-2,2′bipyridine2 was transformed to the monoalkoxide, which was trapped as the monomesylate in an overall 96% yield. This procedure takes advantage of the different solubility characteristics of the intermediates vs the starting material; this monolithium alkoxide is insoluble under these specific reaction conditions. Application of this general procedure was used6 to afford 6-(bromomethyl)-6′-(hydroxymethyl)-2,2′-bipyridine, which was subsequently converted to functionalized oligobipyridines. In that we needed unsymmetrical 5,5′-disubstituted 2,2′-bipyridines for the synthesis of specifically located binding loci within dendrons, we herein describe the use of similar solubility differences of the intermediate(s) to prepare 5′-amino2,2′-bipyridine-5-carboxylic acid in excellent overall yield from the symmetrical diethyl 2,2′-bipyridine-5,5′-dicarboxylate. The synthesis of 5,5′-diamino-2,2′-bipyridine from diethyl 2,2′-bipyridine-5,5′-dicarboxylate (2) had been previously reported by Whittle.7 The desired diester 2 was prepared by refluxing neat ethyl nicotinate 1 with palladium on charcoal for 6 days under a partial vacuum; the catalyst and starting ester were removed and recycled (Scheme 1). Diester 2 was isolated in ca. 35% yield on the first cycle, and its simple NMR spectra supported the structure. By taking advantage of the low solubility of carbohydrazides, the exclusive formation of the monocarbohydrazide 3 was achieved by the use of approximately 1.5 equiv of hydrazine and by adjusting either the polarity of the solvent system (ethanol/toluene) or the reaction temperature (80 °C). The monocarbohydrazide 3 precipitated under these conditions and was obtained in 85% yield. Although 3 is nearly insoluble in many organic solvent, its 1H NMR spectrum in DMSO clearly showed two doublets (J ) 2 Hz) at δ 9.1 and 9.2 for the two different 6,6′-pyH, respectively, confirming the unsymmetrical substitution pattern. Treatment of 2 with excess hydrazine hydrate under more drastic conditions afforded (100%) the symmetrical dicarbohydrazide 4, which is insoluble in most common organic solvents. Reaction of monocarbohydrazide 3 with NaNO2 in concentrated HCl gave (ca. 100%) the corresponding carbazide 5, whose IR spectrum clearly demonstrates the presence of the characteristic carbazide stretch at 2181 and 2143 cm-1 as well as the shift (13C NMR) from δ 163.8 to 171.0 for the carbonyl groups supporting the conversion. Subsequent Curtius rearrangement of carbazide 5 provided (82%) urethane 6; the 13C NMR for 6 shows the expected upfield shift from δ 171.0 to 153.3 for the urethane moiety. Saponification of 6 afforded (89%) the desired 5′-amino-2,2′-bipyridine-5-carboxylic acid hydrochloride 7 supported by the carbonyl absorption at δ 176.0 and the disappearance of the peak for the urethane carbonyl. The bright yellow salt is soluble in aqueous base but shows only very low solubility in organic solvent other than DMSO. In order to enhance the solubility characteristics, the amino acid 7 was subjected to Fischer esterification conditions affording the ethyl ester 8, as a pale yellow solid. The enhanced organic solubility and the appearance of the typical ethyl absorption in the NMR spectra support the assigned structure. Application of the selective reactivity due to solubility differences has great potential in the preparation of unsymmetrical heterocycles8 and is being pursued in other N-heterocyclic functionalizations.