Triphenylphosphine → 3-(Bromomethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole

HRID 2222222Notes

Reaction equation

HRID 2222222 reaction equation
O[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:46]N1C(=O)CCC1=O>C(Cl)Cl>[Br:46][CH2:2][C:3]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:16][C:15]=2[Cl:26])[O:5][N:4]=1

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 200641365-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol

Product 1

HCID 693103283-(Bromomethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazoleYield 70%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

3-(Hydroxymethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (540 mg, 1.25 μmnol) in DCM (5 ml), prepared according to a literature procedure J. Med. Chem. (1990) 33, 1306-1311, was added rapidly to triphenylphosphine (410 mg, 1.56 mmol) and N-bromosuccinimide (278 mg, 1.56 mmol) in DCM (15 ml) at 0° C. The reaction was allowed to warm to room temperature, then after 3 hours the product was adsorbed onto silica gel and chromatographed on silica gel, eluent 1:1 ethyl acetate/hexane to give the brominated compound, 3-(bromomethyl)-5-[5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole as an off white solid (408 mg, 0.88 mmol) in 70% yield, Rf=0.25. 1H mm (D6 acetone): δ=8.01 (s, 2H); 6.46 (s, 1H); 4.69 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.00 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES):(M+H)+ 461,463,465. Neat 3,6,9-trioxa-11-azidoundecanol (237 mg, 1.08 mmol) prepared according to a literature procedure J Org. Chem. (1991) 56 4326, was added to a solution of sodium hydride (1.6 mmol) in DMF (3 ml) and stirred for 3 hours under argon. Tetrabutylammonium iodide (40 mg, 0.11 mmol) and a solution of the brominated compound (500 mg, 1.08 mmol) in DMF (3 ml) was added to the reaction. After 3 hours the reaction was quenched with water (1 ml) then partitioned between ethyl acetate (150 ml) and water (30 ml). The organic phase was washed with brine (30 ml), dried (Na2SO4) and concentrated to give a yellow brown oil. Chromatography of the crude residue twice on silica gel (50 g), eluent 2:1-3:1 ethyl acetate/hexane then 1:1 DCM/hexane gave 3-(1-azido-3,6,9,12-tetraoxamidecyl)-5-[5-[2,6-dichloro-4(4,5-dihydro-2-oxazolyl)phenoxy]-pentyl]-isoxazole (Compound 1) (400 mg, 0.67 mmol) in 62% yield. 1H nmr (D6 acetone): δ=8.01 (s, 2H); 6.34 (s, 1H); 4.70 (s, 2H); 4.61 (t, 2H); 4.26 (t, 2H); 4.16 (t, 2H); 3.8 (m, 14H); 3.52 (t, 2H); 2.95 (m, 2H); 2.2-1.7 ppm (m, 6H). MS (ES): (M+H)+ 600.

Workup

  1. customchromatographed on silica gel, eluent 1:1 ethyl acetate/hexane

Sources & evidence

ORD record
ord-3048727b2be84cce8f0788a9350eec38
Source dataset
uspto-grants-2008_05
Patent number
US07371755B1

Reaction notes

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