2,2-dimethylthiirane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) was dissolved in benzene (5 mL), and 2,2-dimethylthiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The volatiles were evaporated and the residue was dried under vacuum to afford 5.45 g (97%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 4.12 (q, J=7.1 Hz, 2H), 2.92-2.96 (d, J=11.9 Hz, 2H), 2.19-2.40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J=7.1 Hz, 2H). extracted several times with EtOAc The combined organic extracts were washed with brine dried over anhydrous sodium sulfate The volatiles were evaporated the residue was dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30. was added the resulting mixture was capped The reaction was then concentrated redissolved in dichloromethane filtered with neat ethyl acetate concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100 M%) and 12.46 g (1.42×10-1 mol, 100 M%) isobutylene sulfide (Synder et al, J. Am. Chem. Soc. 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silic in a 600 ml sintered glass funnel and eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C. The bomb was cooled to room temperature did not dissolve), washed with saturated aqueous NaCl solution the solvent was removed on the rotary evaporator The oily residue was placed on flash silic in a 600 ml sintered glass funnel eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether Evaporation of the first 50:50 hexane/ether fraction

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100 M%) and 12.46 g (1.42×10-1 mol, 100 M%) isobutylene sulfide (Synder et al, J. Am. Chem. Soc. 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silic in a 600 ml sintered glass funnel and eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C. The bomb was cooled to room temperature did not dissolve), washed with saturated aqueous NaCl solution the solvent was removed on the rotary evaporator The oily residue was placed on flash silic in a 600 ml sintered glass funnel eluted with 500 ml portion of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether Evaporation of the first 50:50 hexane/ether fraction

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Piperazine (7.72 g, 89.8 mmol) was dissolved in benzene (10 mL) and 2,2-dimethylthiirane (3.16 g, 35.9 mmol) was added. The reaction mixture was stirred at 80° C. for 1 hour, poured into the water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 3.9 g of the title compound. 1H NMR (CDCl3, 300 MHz): δ1.29 (s, 6H), 2.34 (s, 2H), 2.58 (t, 4H), 2.63 (s, 1H), 2.85 (t, 4H). extracted with ethyl acetate (3×100 mL) The combined organic extracts were washed with brine dried over anhydrous sodium sulfate Volatiles were evaporated the residue was dried on vacuum pump overnight

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Piperazine (7.72 g, 89.8 mmol) was dissolved in benzene (10 mL) and 2,2-dimethylthiirane (3.16 g, 35.9 mmol) was added. The reaction mixture was stirred at 80° C. for 1 hour, poured into the water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 3.9 g of the title compound. 1H NMR (CDCl3, 300 MHz): δ1.29 (s, 6H), 2.34 (s, 2H), 2.58 (t, 4H), 2.63 (s, 1H), 2.85 (t, 4H). extracted with ethyl acetate (3×100 mL) The combined organic extracts were washed with brine dried over anhydrous sodium sulfate Volatiles were evaporated the residue was dried on vacuum pump overnight

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL flask was equipped with a stir bar and a 150 mL addition funnel. The system was placed under an argon atmosphere, and charged with anhydrous tetrahydrofuran (150 mL) and 2.5 M n-BuLi (75 mL, 18.7 mmol) in hexanes (18.7 mmol). The solution was cooled to −78° C. using a dry ice/acetone bath. Acetonitrile (7.3 g, 9.4 mL, 18 mmol) was added drop-wise via a syringe over approximately 5 min. The reaction was stirred for 30 min, while white lithium-acetonitrile precipitate was formed. Isobutylene sulfide (12), (15 g, 17 mmol) was dissolved in 100 mL of anhydrous THF and added dropwise over approximately 30 min via the addition funnel. The cooling bath was removed and the reaction was allowed to stir for 3 hours. The flask was cooled in an ice/water bath as of 0.5 M HCl (38 mL) was added drop-wise. The THF layer was retained and the aqueous layer was washed twice with 75 mL of ethyl acetate. The THF and ethyl acetate layers were combined, dried over approximately 20 g of anhydrous sodium sulfate and transferred to a 250 mL flask. Solvent was removed by rotary evaporation under vacuum to give crude 13. Ethanol (30 mL) was added, and the contents were stirred as a solution of NaOH (8.0 g) in deionized water (30 mL) was slowly added. The flask was equipped with a reflux condenser and placed under an argon atmosphere. The reaction was refluxed overnight and then cooled to room temperature. Deionized water (60 mL) was added and the mixture was washed with 2:1 (v/v) ethyl acetate:hexanes (2×25 mL). The aqueous layer was acidified to pH 2 with concentrated HCl, and then extracted with ethyl acetate (3×75 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under vacuum to give 10 g of product 14 (39% yield). The product was used without further purification. 1H NMR (CDCl3): δ 1.38 (6H, s), 1.87-1.93 (2H, m), 2.08 (1H, s), 2.51-2.57 (2H, m). A 500 mL flask was equipped with a stir bar and a 150 mL addition funnel was formed added dropwise over approximately 30 min via the addition funnel The cooling bath was removed The flask was cooled in an ice/water bath as of 0.5 M HCl (38 mL) was added drop-wise the aqueous layer was washed twice with 75 mL of ethyl acetate dried over approximately 20 g of anhydrous sodium sulfate transferred to a 250 mL flask Solvent was removed by rotary evaporation under vacuum to give crude 13 was slowly added The flask was equipped with a reflux condenser The reaction was refluxed overnight cooled to room temperature the mixture was washed with 2:1 (v/v) ethyl acetate extracted with ethyl acetate (3×75 mL) The organic layers were dried over anhydrous sodium sulfate filtered the solvent was removed by rotary evaporation under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2-dimethyl-thiirane (TCI, 1.5 g, 17 mmol), N-butyl-cyanamide (1.7 g, 17 mmol) (prepared as described in Ross J. Med. Chem. 1979, 22; 412) and potassium carbonate (2.4 g, 17 mmol) in 2-butanone (15 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted twice with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford 2.11 g of the title compound. extracted twice with ethyl acetate The combined organic extracts were dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl piperidine-4-carboxylate (3.6 g, 22.9 mmol) was dissolved in benzene (5 mL), and 2,2-dimethylthiirane (5.04 g, 57.3 mmol) was added. The reaction mixture was stirred at 80° C. for 20 hours, poured into water and extracted several times with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The volatiles were evaporated and the residue was dried under vacuum to afford 5.45 g (97%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 4.12 (q, J=7.1 Hz, 2H), 2.92-2.96 (d, J=11.9 Hz, 2H), 2.19-2.40 (m, 6H), 1.61-1.86 (m, 4H), 1.29 (s, 6H), 1.25 (t, J=7.1 Hz, 2H). extracted several times with EtOAc The combined organic extracts were washed with brine dried over anhydrous sodium sulfate The volatiles were evaporated the residue was dried under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30. was added the resulting mixture was capped The reaction was then concentrated redissolved in dichloromethane filtered with neat ethyl acetate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30. was added the resulting mixture was capped The reaction was then concentrated redissolved in dichloromethane filtered with neat ethyl acetate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30. was added the resulting mixture was capped The reaction was then concentrated redissolved in dichloromethane filtered with neat ethyl acetate concentrated