4-chloro-2-iodoaniline

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added □-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid. After the volatile was removed under reduced pressure the residue was dissolved in EtOAc washed with water (3×) and brine dried over MgSO4 Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added a-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3x) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid. After the volatile was removed under reduced pressure the residue was dissolved in EtOAc washed with water (3x) and brine dried over MgSO4 Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added α-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid. After the volatile was removed under reduced pressure the residue was dissolved in EtOAc washed with water (3×) and brine dried over MgSO4 Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes)

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

Procedure: To the mixture of the 2-iodo-4-chloroaniline (5.0 g, 20 mmol) and triethylamine (8.3 mL, 60 mmol) in methylene chloride (200 mL), the solution of methanesulfonyl chloride (3.4 mL, 44 mmol) was added slowly. The solution then was stirred at room temperature for 2 h. After being washed by HCl solution (0.5 N, 2×100 mL), NaOH solution (0.5 N, 2×100 mL), brine (100 mL), the organic layer was dried over Na2SO4 and concentrated providing the title compound (6.6 g). After being washed by HCl solution (0.5 N, 2×100 mL), NaOH solution (0.5 N, 2×100 mL), brine (100 mL) the organic layer was dried over Na2SO4 concentrated

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, 62B can be prepared as follows. To a cold suspension (0-5° C.) of 4-chloro-2-iodoaniline (10.0 g, 39.5 mmol) and sodium azide (7.95 g, 122 mmol) in trimethyl orthoformate (13.08 mL, 118 mmol) was added acetic acid (150 mL). The resulting clear, slightly brown solution was stirred vigorously at 0-5° C. for 30 min and then warmed to rt. A beige precipitate formed overtime and then redissolved to give a clear brown solution. After 22 h, water (400 mL) was added and the suspension was stirred vigorously for 1 h. The solid was collected by filtration, rinsed with water, air-dried, and dried under vacuum to give 11.16 g (92%) of 1-(4-chloro-2-iodo-phenyl)-1H-tetrazole as a beige solid. LCMS m/z 307.0. (M+H)+. A flame-dried sealed tube vessel containing this intermediate (0.250 g, 0.816 mmol) and palladium acetate (0.018 g, 0.082 mmol) was purged with argon for several minutes. Next degassed acetonitrile (3.26 mL) was added followed by the addition of ethyl acrylate (0.133 mL, 1.224 mmol) and triethylamine (0.171 mL, 1.224 mmol). The vessel was sealed and the orange brown solution was warmed to 85° C. to give a brown suspension. After 21 h, the reaction was stopped and cooled to rt. The reaction was filtered through a 0.45 micron Glass microfibre (GMF), rinsing with acetonitrile, and the filtrate was concentrated to give a brown residue. Flash chromatography gave 0.098 g (43%) of (E)-3-(5-chloro-2-tetrazol-1-yl-phenyl)-acrylic acid ethyl ester as a pale yellow solid. LCMS m/z 279.1 (M+H)+and 281 (M+2+H)+. Saponification as described above gave 62B. warmed to rt A beige precipitate formed overtime redissolved to give a clear brown solution After 22 h the suspension was stirred vigorously for 1 h The solid was collected by filtration rinsed with water air-dried dried under vacuum

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

Procedure: A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%). were heated to reflux for 2 h The reaction was cooled the organic phase was washed with water (20 mL) and brine (20 mL) dried over sodium sulfate filtered evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent

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

Procedure: A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%). were heated to reflux for 2 h The reaction was cooled the organic phase was washed with water (20 mL) and brine (20 mL) dried over sodium sulfate filtered evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent

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

Procedure: A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%). were heated to reflux for 2 h The reaction was cooled the organic phase was washed with water (20 mL) and brine (20 mL) dried over sodium sulfate filtered evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added □-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid. After the volatile was removed under reduced pressure the residue was dissolved in EtOAc washed with water (3×) and brine dried over MgSO4 Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes)

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

Procedure: 3-Ethynylpyridine and 4-chloro-6-iodoaniline are processed according to the method described in Example 86 to give 5-chloro-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 6.96 (s, 1H), 7.14 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.25 (dt, J=8.0, 1.9 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 9.02 (s, 1H). HRMS (ESI) m/z 229.0522 [(M+H)+ Calcd for C13H10ClN2: 229.0533].

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

Procedure: 3-Ethynylpyridine and 4-chloro-6-iodoaniline are processed according to the method described in Example 86 to give 5-chloro-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 6.96 (s, 1H), 7.14 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.25 (dt, J=8.0, 1.9 Hz, 1H), 8.50 (d, J=4.5 Hz, 1H), 9.02 (s, 1H). HRMS (ESI) m/z 229.0522 [(M+H)+ Calcd for C13H10ClN2: 229.0533].

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

Procedure: A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol), 1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acid monohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h. The reaction was cooled and EtOAc (50 mL) was added and the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent: EtOAc:hexane to give 3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55 g, 80%). were heated to reflux for 2 h The reaction was cooled the organic phase was washed with water (20 mL) and brine (20 mL) dried over sodium sulfate filtered evaporated to give a brown solid, which was purified by column chromatography [Silica, eluent