Double C-alkylation

To a suspension of NaH (17.6 g, 60%) in DMF (150 mL) at ice-bath temperature with mechanical stirring was added over a one hour period a mixture of 4-chlorobenzyl cyanide (30.3 g) and 1,3-dibromopropane (22.3 mL, 44.5 g). The reaction mixture was stirred for an additional 1 hour, and isopropyl alcohol (10 mL) was added slowly to quench excess NaH. Water (150 mL) was added. The reaction mixture was extracted with MTBE (2 × 200 mL), and the combined extracts were washed with water (3 × 200 mL), brine, and dried over MgSO₄. The solvent was removed in rotavapor and the final product was purified by column chromatography to give 1-(4-chlorophenyl)cyclobutanecarbonitrile (32.6 g, 85%) as a pale yellow oil. NMR complies.

Note: 1. The procedure was taken from US patent 6,974,838 B2. But we found anhydrous DMF (stored over molecular sieves) is a better solvent than DMSO in this case. 2. The reaction is very exothermic when the starting materials were added to NaH in DMF at 0 oC. The addition should be very slow in order to avoid foaming and overflow.

DIBAL Reduction of Ester to Alcohol

 

(E)-Ethyl 3-(2-chlorophenyl)acrylate (1.5 g, 0.007 mol) was dissolved in 15 mL of anhydrous dichloromethane, cooled to -78 ^oC and treated with a solution of di-iso-butylaluminum hydride (1.0 M solution in hexane, 21.4 mL, 0.021 mol) over a period of 20 minutes (the solution turned yellow in color). After 1.5 hours total at -78 ^oC, the reaction was quenched with methanol (15 mL) at -78 ^oC (the solution became colorless and then a white solid precipitated out), warmed to 23 ^oC (over 9 hrs) and treated with a saturated aqueous solution of NH₄Cl (60 mL). The resulting mixture was extracted with dichloromethane (2 × 100 mL) (emulsion formed was filtered over Celite to remove white gummy precipitate). The combined extracts were dried (Na₂SO₄) and concentrated under vacuum to give (E)-3-(2-chlorophenyl)prop-2-en-1-ol which was purified by column chromatography (silica gel, 0-50% ethyl acetate in hexanes) as a pale brown oil (0.45 g, 37% yield, NMR complies). 0.8 g of starting ester was also recovered. Ref: WO2005/097744

 

Bromination

A mixture of 1-phenylethanol (1.21 mL) and 48% HBr in water (12 mL) was stirred at room temperature for overnight (12 h). The reaction mixture was diluted with 50 mL ethyl acetate, washed with 50 mL aqueous saturated NaHCO₃ solution, dried over Na₂SO₄ and evaporated under reduced pressure to give (1-bromoethyl)benzene as a light brown oil (1.5 g, 83% yield). NMR complies.

This material was prepared to protect the N atom of an amide so that after a sequence of reactions it can be cleaved off easily using MsOH. [06TL1813]

C-Alkylation

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.

Phenol

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%).

 

Dialkyl ether

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.

Chlorosulfonylation

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.

S-alkylation of thiols

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).

MOM protection of amine

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. 

Benzyl bromide

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.