Tetrahydrofuran → (R)-2-Acetamido-3-methoxy-N-(4-(3-methoxyprop-1-ynyl)benzyl)propanamide

HRID 1425701Notes

Reaction equation

HRID 1425701 reaction equation
[CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[C:6]([NH:9][C@H:10]([CH2:22][O:23][CH3:24])[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)=[O:12])(=[O:8])[CH3:7].C(N(CC)CC)C.COCC#C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CS(C)=O.CCOC(C)=O.CCOCC>[C:6]([NH:9][C@H:10]([CH2:22][O:23][CH3:24])[C:11]([NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]#[C:1][CH2:5][O:4][CH3:3])=[CH:19][CH:20]=1)=[O:12])(=[O:8])[CH3:7]

Participants

10

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 693933-MethoxypropyneHCID 45486399(R)-2-acetamido-3-methoxy-N-(4-iodobenzyl)propanamide

Product 1

HCID 44538056(R)-2-Acetamido-3-methoxy-N-(4-(3-methoxyprop-1-ynyl)benzyl)propanamide

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolvent

Procedure

To an anhydrous THF (10 mL) solution of (R)-2-acetamido-3-methoxy-N-(4-iodobenzyl)propanamide (376 mg, 1.0 mmol), triethylamine (280 μL, 2.0 mmol), 3-methoxyprop-1-yne (125 μl, 1.5 mmol), dichlorobis(triphenylphosphine)-palladium (II) (70 mg, 0.1 mmol), and CuI (38 mg, 0.2 mmol) were sequentially added under Ar. The mixture was stirred at room temperature (4 h), and then Et2O (10 mL) added and the precipitate filtered through a Celite pad. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel with EtOAc/MeOH (9/1) as the eluant to obtain (R)-6 (260 mg, 82%) as a beige solid: Rf=0.27 (EtOAc); mp 141-142° C.; [α]27D =+4.4° (c 1, DMSO); IR (nujol) 3278, 3096, 1640, 1554, 1458, 1370, 1304, 1257, 1192, 1099, 966, 903, 810, 732 cm−1; 1H NMR (CDCl3) δ 2.02 (s, CH3CO), 3.37 (s, OCH3), 3.45-3.47 (m, CHH′ and OCH3), 3.78 (dd, J=4.2, 9.0 Hz, CHH′), 4.32 (s, C≡CCH2OCH3) 4.38-4.52 (m, CH2N), 4.54-4.61 (m, NC(H)CO), 6.52 (d, J=6.6 Hz, CHNH), 6.91-6.99 (br t, CH2NH), 7.19 (d, J=7.9 Hz, 2 ArH), 7.41 (d, J=7.9 Hz, 2 ArH); 13C NMR (CDCl3) δ 23.2 (CH3CO), 43.2 (CH2N), 52.5 (CHCH2), 57.7 (C≡CCH2OCH3), 59.1 (OCH3), 60.4 (C≡CCH2OCH3), 71.7 (CH2OCH3), 85.2 (C≡C), 86.0 (C≡C), 121.8, 127.3, 132.1, 138.4 (C6H4), 170.4 (2 C(O)); HRMS (M+H+)(ESI+) 319.1652 [M+H+] (calcd for C17H22N2O4H+ 319.1658); Anal. Calcd. for C17H22N2O4.0.33H2O: C, 62.95; H, 7.04; N, 8.64. Found: C, 62.98; H, 6.78; N, 8.47.

Workup

  1. filtrationthe precipitate filtered through a Celite pad
  2. concentrationThe filtrate was concentrated in vacuo
  3. customthe residue was purified by flash chromatography on silica gel with EtOAc/MeOH (9/1) as the eluant
  4. customto obtain (R)-6 (260 mg, 82%) as a beige solid

Sources & evidence

ORD record
ord-7cbe9adcd50a4dfd9c6836afd2e4f2c8
Source dataset
uspto-grants-2015_01
Patent number
US08933065B2

Reaction notes

Loading…