Procedure:  250 mL 1-neck flask, stirbar, condenser, septum, N₂ inlet

                  Dissolved 5.811 g of I in 50 mL of THF.  Added 1.430 g of LiOH-H₂O and stirred at rt for 1h.  Then 3.55 mL of Me₂SO₄ was added and the reaction mixture was refluxed overnight.  After 17 h, TLC showed product spot at Rf 0.50 (1:9 EtOAc-hexanes, UV).  The mixture was cooled to rt and quenched with 30 mL of NH₄OH and 30 mL of water. The mixture was stirred for 30 min and the THF was removed by rotary evaporation.  The mixture brown mixture was diluted with water and extracted with EtOAc.  The organic layer was dried over MgSO₄, filtered and the solvent was removed by rotary evaporation.  The product was isolated by flash chromatography on silica gel using 1:9 EtOAc-hexanes as eluant.  The product was a clear, yellow oil.

 

¹H NMR (CDCl₃, 300 MHz)  7.23 (m, 2H), 7.11 (m, 1H), 3.95 (s, 3H), 2.33 (s, 3H).

 

notes

 

This method is particularly good for esterification of sterically hindered carboxylic acids (see Chakraborti, A.K.; Basak, A.; Grover, V.  J. Org. Chem.  1999, 64, 8014).  In this case, several attempts to esterify the acid using HCl, MeOH or treatment with (COCl)₂ followed by addition of MeOH were unsuccessful.  The difficulty with these methods is probably due to the flanking chloro and methyl groups which preclude attack of a nucleophile to the carbonyl to form the tetrahedral intermediate.  This procedure avoids this problem by using the lithium carboxylate as the attacking nucleophile.  The procedure works well despite the poor nucleophilicity of the carboxylate anion due to the six-membered transition state made possible by the use of the lithium counterion.