2-Methyl-3-butyn-2-ol → 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

HRID 575120Notes

Reaction equation

[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:21])([CH3:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([OH:21])([CH3:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:26]#[C:25][C:23]([OH:27])([CH3:24])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]

Participants

Conditions

Temperature: 80 °C

Procedure

A mixture of 9-Bromo-4-hydroxy-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (387 mg, 1.04 mmol), 2-methyl-3-butyn-2-ol (699 mg, 8.32 mmol), Pd(OAc)2 (23 mg, 0.104 mmol), CuI (39 mg, 0.208 mmol) and PPh3 (82 mg, 0.312 mmol) in Et3N (15 mL) was degassed with N2, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as a yellow solid (312 mg, 80%). LC-MS (ESI & APCI): 374.3 (M+1).

Workup

customwas degassed with N2
temperatureThe reaction mixture was cooled to room temperature
concentrationconcentrated
custompurified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%)

Sources & evidence

ORD record: ord-506bd4db4a4d4515b62656af6a0bea2e
Source dataset: uspto-grants-2015_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09034866B2

Reaction notes

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