Diisopropylamine → 2-methyl-4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile

HRID 494852Notes

Reaction equation

HRID 494852 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][C:3]=1I.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C.[CH2:47]([N:51]1[CH2:55][CH2:54][CH2:53][C@H:52]1[CH3:56])[CH2:48][C:49]#[CH:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CC#N>[CH3:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:49]([CH2:48][CH2:47][N:51]4[CH2:55][CH2:54][CH2:53][C@H:52]4[CH3:56])=[CH:50][C:3]=3[CH:4]=2)[CH:13]=[CH:12][C:11]=1[C:14]#[N:15]

Participants

8

Reactant 4

HCID 7912DiisopropylamineHCID 80271Tri-o-tolylphosphineHCID 11367023(R)-1-(But-3-yn-1-yl)-2-methylpyrrolidineHCID 222746294'-Hydroxy-3'-iodo-3-methyl-1,1'-biphenyl-4-carbonitrile

Product 1

HCID 675334712-methyl-4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrileYield 55%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
55 °C

Procedure

The product from Example 106C (670 mg, 2.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), copper(I) iodide (114 mg, 0.60 mmol), and diisopropylamine (2.8 mL, 20 mmol) were dissolved into a 0.1M MeCN solution of (R)-1-but-3-ynyl-2-methylpyrrolidine (30 mL, 3.0 mmol) and heated at 55° C. overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and chromatographed through a short column of silica with a 10 to 100% gradient of EtOAc/CH2Cl2 to provide the impure title compound as an orange-brown foam (55% yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm×100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN/0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min.]. TFA salt: MS (AP) m/z 345 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.49(d, 3H), 1.68-1.82 (m, 1H), 1.99-2.23 (m, 2H), 2.30-2.44 (m, 1H), 2.60 (s, 3H), 3.22-3.90 (m, 7H) 6.82 (s, 1H), 7.55-7.87 (m, 6H).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. concentrationconcentrated under reduced pressure
  3. customchromatographed through a short column of silica with a 10 to 100% gradient of EtOAc/CH2Cl2

Sources & evidence

ORD record
ord-0507a6040ebd47ba94327be6c6798b33
Source dataset
uspto-grants-2009_05
Patent number
US07538138B2

Reaction notes

Loading…