1,4-dichloro-2-methylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: In the next step, the obtained 2,5-dichloro-4-t-alkyltoluene or 2,5-dichloro-4-isopropyltoluene is brought into contact with toluene, thereby subjecting to transalkylation, disconnecting the t-alkyl group or the isopropyl group from the mother compound to obtain 2,5-dichlorotoluene.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (841 μl, 6 mmol) was added to 20 mL of THF under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5N n-butyllithium (55.5 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to -78° C. 2,5-Dichlorotoluene (642 μL, 5 mmol) was added and stirring was continued for 2 hours at -78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 mL THF. The reaction was stirred for 5 minutes at -78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 mL of saturated KH2PO4, removal of most of the THF on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1N HCl. The organic phase was washed twice with 1N HCl, once with 5% NaHCO3, dried over sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.80 minutes) of a water white oil The reaction was then cooled to -78° C stirring was continued for 2 hours at -78° C The reaction was stirred for 5 minutes at -78° C. to come to room temperature stirred overnight by adding 10 mL of saturated KH2PO4, removal of most of the THF on a rotary evaporator by partitioning of the aqueous residue between ethyl acetate and 1N HCl The organic phase was washed twice with 1N HCl, once with 5% NaHCO3 dried over sodium sulfate concentrated to a residue Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.80 minutes) of a water white oil

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

Procedure: The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5dichlorophenyl)pentanoate after hydrolytic work-up. Competitor 11 was prepared by LiOH hydrolysis of the methyl ester.

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

Procedure: Prepared by a modification of the method of H. D. Dakin and J. B. Cohen, J. Chem. Soc., 79, 1130 (1901). 2,5-Dichlorotoluene (18.7 g, 0.116 mol) was added in one portion to a 10° C. mixture of concentrated sulfuric acid (24 ml) and glacial acetic acid (10 ml). This was stirred at about 10° C. while a cold mixture of 70% nitric acid (8.2 ml) and concentrated sulfuric acid (8.2 ml) was added dropwise over 10 min. The reaction mixture was warmed slowly to room temperature and stirred for 2 hours. The reaction mixture was then recooled to 10° C. with an ice bath and quenched with ice and methylene chloride. The layers were separated and the aqueous layer extracted with methylene chloride. The combined organic layers were washed two times with water, two times with saturated sodium bicarbonate solution and one time with brine. After drying over magnesium sulfate, the solvent was evaporated in vacuo and the crude product crystallized from isopropanol (30 ml). The yield of light yellow solid was 13.4 g, 56%; NMR (CDCl3) δ 7.91 (s, 1), 7.42 (s, 1), 2.43 (s, 3). Prepared by a modification of the method of H was added dropwise over 10 min The reaction mixture was then recooled to 10° C. with an ice bath quenched with ice and methylene chloride The layers were separated the aqueous layer extracted with methylene chloride The combined organic layers were washed two times with water, two times with saturated sodium bicarbonate solution and one time with brine After drying over magnesium sulfate the solvent was evaporated in vacuo the crude product crystallized from isopropanol (30 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (841 ul, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5 N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to −78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at −78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at −78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1 N HCl. The organic phase was washed twice with 1 N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatogaphy (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, —COOCH3), 2.69 (t, J=7.8 Hz, Ar—CH2—), 2.35 (t, J=7.0 Hz, —CH2—COO—), 1.70-1.55 (m, —CH2—CH2—CH2—CH2—). The reaction was then cooled to −78° C stirring was continued for 2 hours at −78° C The reaction was stirred for 5 minutes at −78° C. to come to room temperature stirred overnight by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator by partitioning of the aqueous residue between ethyl acetate and 1 N HCl The organic phase was washed twice with 1 N HCl, once with 5% sodium bicarbonate dried over anhydrous sodium sulfate concentrated to a residue Flash chromatogaphy (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil

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

Procedure: The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5-dichlorophenyl)pentanoate after mild hydrolytic work-up. Competitor A was prepared by LiOH hydrolysis of the methyl ester.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (841 μl, 6 mmol) was added to 20 mL of THF under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5 N n-butyllithium (55.5 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to −78° C. 2,5-Dichlorotoluene (642 μL, 5 mmol) was added and stirring was continued for 2 hours at −78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 mL THF. The reaction was stirred for 5 minutes at −78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 mL of saturated KH2PO4, removal of most of the THF on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1 N HCl. The organic phase was washed twice with 1 N HCl, once with 5% NaHCO3, dried over sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.80 minutes) of a water white oil The reaction was then cooled to −78° C stirring was continued for 2 hours at −78° C The reaction was stirred for 5 minutes at −78° C. to come to room temperature stirred overnight by adding 10 mL of saturated KH2PO4, removal of most of the THF on a rotary evaporator by partitioning of the aqueous residue between ethyl acetate and 1 N HCl The organic phase was washed twice with 1 N HCl, once with 5% NaHCO3 dried over sodium sulfate concentrated to a residue Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.80 minutes) of a water white oil

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

Procedure: The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5-dichlorophenyl)pentanoate after hydrolytic work-up. Competitor 11 was prepared by LiOH hydrolysis of the methyl ester.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylamine (841 μl, 6 mmol) was added to 20 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° C. 5.5 ml of 2.5N n-butyllithium (13 mmol) was added and the reaction was stirred for 20 minutes. The reaction was then cooled to -78° C. 2,5-Dichlorotoluene (642 ul, 5 mmol) was added and stirring was continued for 2 hours at -78° C. Trimethyl 4-bromoorthobutyrate (1.14 g, 5 mmol) was added to the reaction mixture in 10 ml tetrahydrofuran. The reaction was stirred for 5 minutes at -78° C., allowed to come to room temperature and stirred overnight. The reaction was worked-up by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator followed by partitioning of the aqueous residue between ethyl acetate and 1N HCl. The organic phase was washed twice with 1N HCl, once with 5% sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil. 1H NMR (300 MHz, CDCl3) delta=7.24 (d, J=8.5 Hz, H3), 7.18 (d, J=2.5 Hz, H6), 7.09 (dd, J=2.5, 8.5 Hz, H4), 3.66 (s, --COOCH3), 2.69 (t, J=7.8 Hz, Ar--CH2 --), 2.35 (t, J=7.0 Hz, --CH2 --COO--), 1.70-1.55 (m, --CH2 --CH--CH2 --CH2 --). The reaction was then cooled to -78° C stirring was continued for 2 hours at -78° C The reaction was stirred for 5 minutes at -78° C. to come to room temperature stirred overnight by adding 10 ml of saturated KH2PO4, removal of most of the tetrahydrofuran on a rotary evaporator by partitioning of the aqueous residue between ethyl acetate and 1N HCl The organic phase was washed twice with 1N HCl, once with 5% sodium bicarbonate dried over anhydrous sodium sulfate concentrated to a residue Flash chromatography (silica gel; hexane/toluene (39/1)) of the residue gave 1.10 g (84%; GC retention time=15.8 minutes) of a water white oil

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

Procedure: The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5-dichlorophenyl)pentanoate after mild hydrolytic work-up. Competitor A was prepared by LiOH hydrolysis of the methyl ester.