PMGB

To chlorosulfonic acid (0.9 mol) at 0 ^oC was slowly added salicylic acid (0.09 mol) with constant stirring. After all the salicylic acid was dissolved, the mixture was heated at 75 ^oC for 1 h. The mixture was cooled to room temperature and then carefully added to 250 g of crushed ice. The white solid precipitated was filtered, dissolved in ethyl acetate, washed with water, dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding chlorosulfonylated product (47% yield).

Source Literature: Coburn R. A. US Patent 4,939,132.

Note: Recently chlorosulfonic acid has been used as a reagent for cyclization of electron-withdrawing arenes in the synthesis of haloindanones. Sharma, A. K.; Subramani, A. V.; Gorman, C. B. Tetrahedron 2007, 63, 389-395.

To a solution of the thiol (0.013 mol) in 140 mL ethanol was added sodium hydroxide (0.039 mol) slowly at room temperature over a period of 5 minutes. Sodium hydroxide was completely dissolved in 30 minutes. Then alkyl chloride (0.014 mol) was added slowly at 0 ^oC. The resulting mixture was stirred at room temperature for overnight (12 h). White solid precipitated out. The solvent was evaporated, the residue was dissolved in 50 mL water and 250 mL ethyl acetate, extracted, the organic layer was dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding S-alkylated product which was purified by triturating with ether (white solid, 90% yield).

To a stirred solution of the amine (0.005 mol) in 15 mL THF at 0 ^oC was added sodium hydride (60% in mineral oil, 0.0055 mol). A white solid precipitated and hydrogen gas was evolved. Chloromethyl methyl ether (0.0055 mol) (CAUTION: carcinogen) was added and the resulting mixture was stirred at room temperature for overnight (12 h). The solution turned yellow and then orange color. The reaction mixture was diluted with 50 mL ethyl acetate and 50 mL water. Some product precipitated out during extraction was filtered, washed (EtOAc) and dried under suction. The aqueous layer was extracted with dichloromethane, the organic layer was dried (Na₂SO₄) and evaporated to give the corresponding MOM ether of the amine in a total of 99% yield.   

Note: The same procedure also works in the preparation of MOM ethers of alcohols. Diisopropyl ethyl amine (DIPEA) can also be used for MOM protection of phenols: Scopton, A.; Kelly, T. R. Org. Lett. 2004, 6, 3869. 

A mixture of the benzyl alcohol (0.0006 mol) and 48% HBr in water (2 mL) (clear solution after 5 minutes) was stirred at room temperature for overnight (12 h). Solid precipitated out after 4 h. The reaction mixture was diluted with 50 mL ethyl acetate, washed with 50 mL aqueous saturated NaHCO₃ solution, dried (Na₂SO₄) and evaporated under reduced pressure to give the corresponding benzyl bromide which was purified by triturating with hexanes (white solid, 74% yield).

Note: Yield increased to 92% in 0.002 mol scale.

Reference: Cassady, J. M.; Howie, G. A.; Robinson, J. M.; Stamos, I. K. Org. Synth. 1990, Coll. vol 7, 319. 

To a stirred solution of the Grignard reagent (2M solution in ether, 0.0195 mol) under nitrogen atmosphere was added drop wise aliphatic nitrile (0.013 mol) in anhydrous THF at 40 ^oC (CAUTION exothermic!). Then the reaction mixture was slowly heated to reflux for 18 h. The reaction mixture was cooled to room temperature and then cooled in an ice-bath. The cooled mixture was decomposed with few pieces of ice and 25 mL conc. HCl solution. The solvent (THF) was removed in rotary evaporator and the residual acidic aqueous solution was heated at 100 ^oC for one hour to ensure the complete hydrolysis of ketimine. The solution was extracted with ethyl acetate, dried (MgSO₄) and evaporated under reduced pressure to give the corresponding ketone which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate, isolated as a colorless oil (25%).

Lead Reference: Hauser, C. R.; Humphelett, W. J.; Weiss, M. J. J. Am. Chem. Soc. 1948, 70, 426.

Mechanism: The reaction of Grignard reagent with the nitrile gives an imine salt intermediate which is then hydrolyzed to give the ketone. http://www.mhhe.com/physsci/chemistry/carey5e/Ch20/ch20-3-5-3.html