2-azido-1,3-dichlorobenzene

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

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and 3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL) is heated to 120° C. for 23 h. The reaction mixture is allowed to cool to room temperature and is diluted with 100 mL methylene chloride. The solution is adsorbed onto diatomaceous earth and is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) to give [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g, 44%) as an off-white solid. is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80)

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and 4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) is heated to 120° C. overnight. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction is concentrated under reduced pressure and the residue is purified by flash chromatography, eluting with 5% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H), 1.46 (d, 6H), 1.15 (t, 3H).

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

Procedure: A solution of 2,6-dichloroaniline (100 g, 617 mmol) in MTBE (1 L) is added via addition funnel over 30 minutes to commercial hydrogen chloride (600 mL). The white suspension is stirred 15 minutes and is cooled to 0° C. A solution of sodium nitrite (42.5 g, 617 mmol) in water (150 mL) is added dropwise via addition funnel. After stirring at 0° C. for 30 minutes, a solution of sodium azide (40.1 g, 617 mmol) in water (150 mL) is added. After the addition is completed (45 minutes), the mixture is stirred at 5-10° C. for 30 minutes. The reaction mixture is basified (pH 12) with 50% aq. NaOH, and is stirred for 30 more minutes. The phases are separated and the aqueous layer is extracted three times with MTBE. The combined organic layers are dried over magnesium sulfate and filtered. Toluene (1 L) is added to the organic layer and the solution is concentrated under reduced pressure to a volume of 760 mL to yield the title compound (115 g, 100% conversion, 0.8M solution) as a toluene solution. ES/MS m/e 188 (M+1). After stirring at 0° C. for 30 minutes After the addition (45 minutes) the mixture is stirred at 5-10° C. for 30 minutes is stirred for 30 more minutes The phases are separated the aqueous layer is extracted three times with MTBE The combined organic layers are dried over magnesium sulfate filtered Toluene (1 L) is added to the organic layer the solution is concentrated under reduced pressure to a volume of 760 mL

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

Procedure: To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40 mL) is added concentrated hydrochloric acid (12 mL). The reaction is stirred for 10 min. To this solution is added a solution of sodium nitrite (2.55 g) in water (7.5 mL) over 3 min. Upon completion of the addition, the reaction is stirred for an additional 30 min. A solution of sodium azide (2.41 g) in water (8 mL) is added over 5 min. After 30 min, pH 7 buffer (50 mL) is added and the reaction is transferred to a separatory funnel. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.11 g). 1H NMR (400 MHz, CDCl3) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H) Upon completion of the addition the reaction is stirred for an additional 30 min After 30 min pH 7 buffer (50 mL) is added the reaction is transferred to a separatory funnel The layers are separated the aqueous layer is extracted with ethyl acetate washed with brine dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

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

Procedure: A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and 4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) in toluene (30 mL) are heated at 80° C. for 18 h. A large exotherm is observed at 25 minutes. The reaction is removed from heat until exotherm subsides. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction mixture is concentrated under reduced pressure to 51 g of crude material and purified via column chromatography using a gradient of 35-60% DCM in Hexanes to yield the title compound (28 g, 59%). ES/MS m/e 353.0 (M+1). The reaction is removed from heat until exotherm subsides The reaction mixture is concentrated under reduced pressure to 51 g of crude material purified via column chromatography

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and 3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL) is heated to 120° C. for 23 h. The reaction mixture is allowed to cool to room temperature and is diluted with 100 mL methylene chloride. The solution is adsorbed onto diatomaceous earth and is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) to give [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g, 44%) as an off-white solid. is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80)

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and 3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL) is heated to 120° C. for 23 h. The reaction mixture is allowed to cool to room temperature and is diluted with 100 mL methylene chloride. The solution is adsorbed onto diatomaceous earth and is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) to give [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g, 44%) as an off-white solid. is purified via flash chromatography eluting with hexanes/ethyl acetate (85:15 to 20:80)

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and 4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) is heated to 120° C. overnight. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction is concentrated under reduced pressure and the residue is purified by flash chromatography, eluting with 5% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H), 1.46 (d, 6H), 1.15 (t, 3H).

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

Procedure: A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and 4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) is heated to 120° C. overnight. Two regioisomers are observed in a range of 1:1 to 3:1 in favor of the desired product. The reaction is concentrated under reduced pressure and the residue is purified by flash chromatography, eluting with 5% ethyl acetate in hexanes. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H), 1.46 (d, 6H), 1.15 (t, 3H).

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

Procedure: A solution of 2,6-dichloroaniline (100 g, 617 mmol) in MTBE (1 L) is added via addition funnel over 30 minutes to commercial hydrogen chloride (600 mL). The white suspension is stirred 15 minutes and is cooled to 0° C. A solution of sodium nitrite (42.5 g, 617 mmol) in water (150 mL) is added dropwise via addition funnel. After stirring at 0° C. for 30 minutes, a solution of sodium azide (40.1 g, 617 mmol) in water (150 mL) is added. After the addition is completed (45 minutes), the mixture is stirred at 5-10° C. for 30 minutes. The reaction mixture is basified (pH 12) with 50% aq. NaOH, and is stirred for 30 more minutes. The phases are separated and the aqueous layer is extracted three times with MTBE. The combined organic layers are dried over magnesium sulfate and filtered. Toluene (1 L) is added to the organic layer and the solution is concentrated under reduced pressure to a volume of 760 mL to yield the title compound (115 g, 100% conversion, 0.8M solution) as a toluene solution. ES/MS m/e 188 (M+1). After stirring at 0° C. for 30 minutes After the addition (45 minutes) the mixture is stirred at 5-10° C. for 30 minutes is stirred for 30 more minutes The phases are separated the aqueous layer is extracted three times with MTBE The combined organic layers are dried over magnesium sulfate filtered Toluene (1 L) is added to the organic layer the solution is concentrated under reduced pressure to a volume of 760 mL