Cesium carbonate → 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine

HRID 1889971Notes

Reaction equation

HRID 1889971 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([Cl:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:18][PH:19]([CH3:21])=[O:20].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:17][C:15]1[N:16]=[C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([P:19]([CH3:21])([CH3:18])=[O:20])=[CH:3][CH:4]=3)=[CH:13][CH:12]=[CH:11][N:10]2[N:14]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 674814248-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridineHCID 178503022methylphosphonoylmethane

Product 1

HCID 674814912-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

198 a) 8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+. 198 b) To an oven dried tube was added 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.90 g, 2.9 mmol), methylphosphinoylmethane (0.24 g, 3.1 mmol)(prepared as described in WO2005/009348), palladium acetate (13.5 mg, 0.0601 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36.0 mg, 0.0622 mmol), cesium carbonate (1422.0 mg, 4.3644 mmol) and 1,4-dioxane (9 mL). The tube was evacuated, carefully, and backflushed with nitrogen. The tube was sealed and heated at 90° C. for 24 hours then cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol). 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.303 g, 34%). MP=220-223° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.94-7.86 (m, 2H), 7.77 (t, J=7.4 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H). MS=306, 308 (MH)+. 198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.

Workup

  1. custom198 b) To an oven dried tube
  2. customThe tube was evacuated
  3. customThe tube was sealed
  4. temperaturethen cooled to room temperature
  5. additiondiluted with dichloromethane (30 mL)
  6. filtrationfiltered through a plug of diatomaceous earth
  7. customevaporated
  8. customThe residue was purified via chromatography
  9. custompurification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol)

Sources & evidence

ORD record
ord-b32923ad24c445c79191e640ac39ad06
Source dataset
uspto-grants-2013_08
Patent number
US08501936B2

Reaction notes

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