Isabelle Cabanal-Duvillard, J. Berrien
1999
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0
Influential Citations
2
Citations
Journal
Heterocyclic Communications
Abstract
A wide variety of 2,5-disubstituted pyridines were synthetized in good yield, using 6-chloronicotinic acid 1 as starting material. These pyridines are useful in the field of the pesticide industry; as well as in medicinal chemistry. Introduction : Substituted pyridines can be considered as key building blocks because of their wide use in heterocyclic chemistry, complex chemistry and industrial chemistry. Furthermore. 2,5-disubstituted pyridines are useful precursors to pharmacological compounds (1,2) and recently retained much attention as taking part of natural products syntheses like epibatidine (3,4), nicotinic derivatives (5,6) or aritenoids (7). They can also be use in industrial chemistry (e.g. pesticides), as well as in the field of liquid crystals depending on their physicochemistry (8). We describe herein a simple access to many different 2,5-disubstituted pyridines. While many routes to 2,4or 2,6disubstituted pyridines are often described in the literature (9,10), syntheses of 2,5-disubstituted pyridines have been far less developed. Some 2,5-disubstituted pyridines have already been described in the literature (4,6,7,11,12,13,14). However most of these compounds require for their preparation many steps with no yields mentioned for some of them. We present now alternative routes with improved yields and very easy access. Results : Using 6-chloronicotinic acid i as starting material, we have been able to build many 2,5-disubstituted pyridines (compounds 2 16). which are potentially useful tools because of their diversity. We can classify the pyridine derivatives synthetized here into two categories, having either a chloro or a methoxy function at position 2. Position 5 encompasses many different functions like halogenomethyl, carbonyl, carboxyl and ethylenvl. For the 2-chloropyridine series (Scheme 1), 6-chloronicotinic acid 1 was efficiently transformed into the corresponding acylchloride with POCI3/PCI5 and then reduced with NaBH4 to give the methylalcohol 2 in 85% overall yield. Methylalcohol 2 was converted into the corresponding bromomethylpvridine 3 with PBr3 in CH2CI2 in 72% yield. It could also be made from chloromethylpyridine 4 (synthesized from alcohol 2 using SOCI2 in 8 5 % yield) by treating it with NaBr in acetone in 6 7 % yield. The iodomethyl analogue 5 was formed in good yield by treatment of either the bromomethyl derivate 3 (79%) or the chloromethyl 4 (87%) with Nal in acetone. lodomethylpyridine 5 has not been described in the literature so far while bromomethyipyridine 3 has been prepared in 5 steps from ß-picolin with no yield mentioned (13). Chloromethyl derivative 4 is of much interest and is used in the chemistry of pesticides. Its structure has been already described in two patents (15), but in more steps and lower yields. We propose here a very facile access to halogenomethyipyridines which are known to polymerize under other experimental conditions. We also have developed access to the tolvlsulfone building block 9 not described in the literature so far by treating chloromethylpyridine 4 with para-toluene sodium sulfmatc in DMF, in quantitative yield.