PMGB

A 1.6 M solution of n-butyllithium in hexane (9.36 mL) was added to a stirred solution of diisopropylamine (2.22 mL) in THF (15 mL) at -5 to 0 ^oC. After being stirred at -5 to 0 ^oC for 30 min, the reaction mixture was cooled to -78 ^oC and ethyl isobutyrate (1.9 mL) was added. Stirring was continued at -78 ^oC for 45 min. A solution of 1-bromo-2-chloroethane (1.19 mL) in THF (1 mL) was then added dropwise to the mixture. The whole was further stirred at -78 ^oC for 1 h and at room temperature for 2 h, then poured into an excess of aqueous NH₄Cl solution and extracted with ethyl acetate, the extract was washed with brine, dried over MgSO₄, and evaporated in vacuum to give a residue, which was distilled to give ethyl 4-chloro-2,2-dimethylbutanoate isolated as a colorless oil, 2.1 g. NMR complies.

Ref: Chem. Pharm. Bull. 1997, 45, 1447-1457.

To a suspension of compound containing an acetyl (-COCH₃) group (0.01 mol) in 50 mL of dichloromethane was added m-chloroperbenzoic acid (0.03 mL) in three small portions at room temperature. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with 50 mL dichloromethane and washed successively with 2% aqueous sodium thiosulfate (50 mL), saturated aqueous NaHCO₃ solution (2 × 50 mL) and brine (50 mL), dried over MgSO₄ and evaporated to give the corresponding Baeyer-Villager oxidation product (-OCOCH₃) which was purified by triturating with ether. White solid (60%).

Reference: Baeyer-Villager Oxidation

Sosnowski, J. J.; Danaher, E. B.; Murray, R. K. J. Org. Chem. 1985, 50, 2759-2763.

To a suspension of the acetate obtained in the previous step (0.0024 mol) in 4 mL ethanol was added 2 mL 2N aq. NaOH solution. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated on rotavapor under reduced pressure and the residue was cooled in ice bath. A few pieces of crushed ice were introduced into the flask and then acidified with 1N HCl solution. The precipitate formed was filtered and washed with water and air dried to give the corresponding phenol. Brown solid (73%).

To a suspension of sodium hydride (0.0004 mol) and alkyl methanesulfonate (0.0004 mol) in 5 mL THF at ice-bath temperature was added benzyl alcohol (0.0004 mol) in 5 mL THF dropwise. After the addition was complete, the resulting reaction mixture was allowed to warm to room temperature and then heated at 50 ^oC for 12 h. The reaction mixture was evaporated, diluted with 50 mL ethyl acetate, washed with saturated aq. NaHCO₃ solution and brine, dried (Na₂SO₄) and evaporated to give the corresponding benzyl alkyl ether  which was purified by silica gel column chromatography using ethyl acetate (75% yield, NMR and MS complies).

Procedure was taken from Bhatia S. K.; Hajdu, J. J. Org. Chem. 1988, 53, 5034-5039.

Note: This procedure worked in the presence of lactam and piperazine moieties.

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

Here are some tips from my experience.

Filtration: Kimberly-Clark Professional Single-Fold paper Towels can be used as the filter paper (probably cheapest) to filter out sodium sulfate. Filtration is generally faster than normal filter paper.

Column Chromatography: Rubber bulb set for pumping air (available from VWR, Catalog No. 56335-003) in flash column chromatography is much safer to operate. Accidents due to high air pressure in the column when using in-house nitrogen gas can easily be avoided by using this technique. Properly cut round filter paper can be used in place of sand to cover the silica gel or alumina in the column. 

Reflux Condenser cooling: In-house air can be used in the condenser at night for avoiding water flooding problem. Alternatively house vacuum (in the outlet of the condenser) can be used to pass the air through the condenser (keeping the inlet open for sucking atmospheric air).

Thiol smell: Commercial bleach is used to prewash the glassware used in the reaction invoving ethanethiol inside the hood to prevent the smell going out.  

Nitrogen Balloon: Insert one balloon (12” round helium quality) in another (double balloon).  Insert the double balloon in one inch tubing (5/16’’ ID, VWR Cat. No. 60985-536) and then insert to a T-joint (so you don’t need to tie the balloon to the T joint) and then fill the balloon with nitrogen. The erectile dysfunction of the balloon can be solved by putting its neck inside a cut-out 24 mL syringe.

Case 1: Amidation using DCC and DMAP: 

A mixture of aromatic carboxylic acid (0.025 mol), amine (0.025 mol), dicyclohexylcarbodiimide (DCC) (0.025 mmol), 4-(dimethylamino) pyridine (DMAP) (0.025 mmol) in 200 mL dichloromethane was stirred at room temperature for 1 h. The clear solution became turbid after 5 minutes. The solid (dicyclohexyl urea) precipitated was filtered and washed with dichloromethane; the combined filtrate and washings was washed with saturated aqueous citric acid solution (to remove amine and DMAP) and water, dried (MgSO₄) and evaporated to give the corresponding amide which was purified by triturating with ethyl acetate (white solid, 76%).

Case 2: Amidation using NHS/DCC:

To a solution of the aliphatic carboxylic acid (0.012 mol) and N-hydroxysuccinimide (NHS) (0.013 mol) in 20 mL THF was added dicyclohexylcarbodiimide (DCC) (0.013 mol) and stirred at room temperature for overnight (12 h). The clear solution became turbid after 10 minutes. The reaction mixture was filtered to remove the white precipitate (dicyclohexylurea), washed the precipitate with 50 mL THF. To the combined filtrate and washings was added the amine HCl salt (0.01 mol) followed by sodium bicarbonate (0.07 mol). Then 20 mL of water was added and the heterogeneous mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was concentrated, the residue was diluted with dichloromethane, washed with water and dried (MgSO₄) to give the corresponding amide which was purified by silica gel column chromatography using a gradient of hexanes and ethyl acetate (oil, 85%).

Case 3: Carboxamide

A mixture of the aromatic ethyl ester (0.05 mol) and ammonia (7N solution in methanol, 0.25 mol) in a sealed tube was heated to 50 ^oC for overnight (12 h). The solvent was evaporated to give the corresponding carboxamide which was purified by triturating with ether (orange solid, 84%).

Case 4: from acid chlorides

To a stirred suspension of the aliphatic amine hydrochloride salt (0.02 mol) in 25 mL DCM cooled by ice bath was added aliphatic acid chloride (0.02 mol) followed by triethylamine (0.03 mol) drop wise. The resulting mixture was stirred at room temperature for overnight (12 h). The reaction mixture was diluted with 50 mL water, extracted with 50 mL dichloromethane, washed with saturated NaHCO₃ solution, dried (MgSO₄) and evaporated to give the corresponding amide which was purified by silica gel column chromatography using a  gradient of hexane and ethyl acetate (colorless oil, 22%).