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

HRID 575108Notes

Reaction equation

HRID 575108 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[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].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:44][C:45]([OH:49])([C:47]#[CH:48])[CH3:46]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:48]#[C:47][C:45]([OH:49])([CH3:46])[CH3:44])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]

Participants

7

Reactant 3

HCID 82582-Methyl-3-butyn-2-olHCID 11776TriphenylphosphineHCID 866931389-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

Product 1

HCID 866931394-Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl esterYield 72%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred mixture of 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 0.27 mmol) in TEA (5 mL) and DMF (1 mL) were added Pd(OAc)2 (6.0 mg, 0.027 mmol), PPh3 (21.1 mg, 0.081 mmol), CuI (10.2 mg, 0.054 mmol) and 2-methylbut-3-yn-2-ol (113 mg, 1.34 mmol). The reaction mixture was degassed with N2 and heated in autoclave at 80° C. overnight. Then the mixture was cooled to room temperature, and EtOAc was added. The mixture was filtered though Celite, and the filtrate was washed with saturated brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 4-Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (80 mg, 72%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=2.1 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.51 (s, 1H), 4.44 (m, 1H), 4.3 (m, 1H), 3.95 (m, 1H), 3.22 (m, 1H), 2.14 (m, 2H), 1.7 (m, 2H), 1.52 (m, 2H), 1.48 (s, 6H); LC-MS (ESI & APCI): 413.7 (M+1).

Workup

  1. customThe reaction mixture was degassed with N2
  2. temperatureThen the mixture was cooled to room temperature
  3. additionEtOAc was added
  4. filtrationThe mixture was filtered though Celite
  5. washthe filtrate was washed with saturated brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. custompurified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%)

Sources & evidence

ORD record
ord-69e95188e9a043038626882ec73b9098
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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