Sodium Carbonate → [4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]methanol

HRID 494860Notes

Reaction equation

HRID 494860 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])=[CH:7][C:6]=2[CH:18]=1.C1(P(C2CCCCC2)C2CCCCC2)C(C2C=CC=CC=2)=CC=CC=1.[OH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:49]3[CH:50]=[CH:51][C:46]([CH2:45][OH:44])=[CH:47][CH:48]=3)=[CH:18][C:6]=2[CH:7]=1

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 27347064-(Hydroxymethyl)benzeneboronic acidHCID 11220543(2R)-1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2-methylpyrrolidine

Product 1

HCID 11283135[4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]methanolYield 12%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 241BenzeneSolventHCID 702EthanolSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution (1.2 mL) of the product from Example 115A (350 mg, 1.1 mmol) in benzene (3.6 mL) was added to a mixture of palladium (II) acetate (11 mg, 0.05 mmol), and biphen-2-yl-dicyclohexylphosphine (28 mg, 0.08 mmol). The reaction mixture was then treated with 4-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol) in ethanol (500 μL) followed by 2M aqueous Na2CO3 (500 μL). The mixture was stirred thoroughly overnight. Additional ethanol (500 μL) was added and the mixture was stirred for four days, diluted with EtOAc, filtered, chromatographed through a short column of silica with a gradient of 0 to 2% MeOH/EtOAc, purified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min.], and then rechromatographed through a short column of silica with MeOH/CH2Cl2 to provide the title compound (12% yield). MS (ESI APCI) m/z 336 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.21 (d, 3H), 1.42-1.58 (m, 1H), 1.77-1.91 (m, 2H), 1.99-2.13 (m, 1H), 2.35-2.77 (m, 3H), 2.97-3.18 (m, 2H), 3.2-3.4 (m, 2H), 4.64 (s, 2H), 6.61 (s, 1H), 7.42 (d, 2H), 7.45-7.48 (m, 2H), 7.60 (d, 2H), 7.72 (dd, 1H).

Workup

  1. stirringthe mixture was stirred for four days
  2. filtrationfiltered
  3. customchromatographed through a short column of silica with a gradient of 0 to 2% MeOH/EtOAc
  4. custompurified by HPLC [Waters Nova-Pak HR C18 column (25 mm×100 mm, 6 μm particle size)
  5. customover 8 min
  6. custom(10 min run time)
  7. customthen rechromatographed through a short column of silica with MeOH/CH2Cl2

Sources & evidence

ORD record
ord-33de3ed78b4f419b841190ac9e83e9fb
Source dataset
uspto-grants-2009_05
Patent number
US07538138B2

Reaction notes

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