References
- Cochennec , C. , Rocca , P. , Marsais , F. , Godard , A. and Quéguiner , G. 1995 . Synthesis , : 321
- Rocca , P. , Cochennec , C. , Marsais , F. , Thomas-dit-Dumont , L. , Mallet , M. , Godard , A. and Quéguiner , G. 1993 . J. Org. Chem. , 58 : 7832
- Guillier , F. , Nivoliers , F. , Godard , A. , Marsais , F. , Quéguiner , G. , Siddiqui , M. A. and Snieckus , V. 1995 . J. Org. Chem. , 60 : 292
- Epsztajn , J. , Bieniek , A. and Kowalska , J. A. 1991 . Tetrahedron , 47 : 1697
- Lewis , N. and Mitchell , M. 1991 . Chem. Ind. , : 374
- Meyer , H. and Graf , R. 1928 . Chem. Ber. , 61 : 2202
- Mosher , H. S. and Look , M. 1955 . J. Org. Chem. , 20 : 283
- In Graf's3 synthesis, the reaction mixture was quenched with water and the free picolinic acid was obtained. It was shown by Mosher4 that isolation of the free ester was much more convenient and that it could be purified by distillation. Our synthesis is simpler because the ester hydrochloride salt is isolated and purified by crystallization and it does not need to be hydrolyzed before the halogen exchange reaction.
- When the methanol was added to the toluene solution of the acid chloride, the mixture separated in two phases with an oily residue. Inverse addition allowed the formation of fine and soft crystals.
- Graf , R. 1931 . Chem. Ber. , 64 : 21
- Titration with AgNO3 (19% HI), HClO4 (75.6% base) and NaOH (19.3% HI), as well as CHN-analysis, confirmed a salt structure of ½ HI per picolinic acid. 3 contained 5.8% H2O.
- 3 reacted sluggishly with methanol-H2SO4 and afforded only a moderate yield of ester. Transformation of the acid into its acid chloride with thionyl chloride was reported to replace the iodine atom by a chlorine in the pyridine nucleus3. We found that the use of oxalyl chloride at 0 °C gave the same side reaction to a lower extent (15% chloro-derivative for the preparation of N,N-diisopropyl 4-iodopicolinamide; the compound was obtained pure after recrystallization in hexanes).
- At that time, an aliquot of the solution was quenched with methanol and injected in G. The C. chromatogram revealed the presence of the product (79%), methyl picolinate (8.4%) and by-products (10.6%).