Toluene → HCID 54505552, compound

HRID 636830

Reaction equation

HRID 636830 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1([CH2:50][C:49]2[CH:52]=[CH:53][C:46]([F:45])=[CH:47][CH:48]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]

Participants

7

Reactant 4

HCID 1140TolueneHCID 680214-Fluorobenzyl bromideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 44519651-Benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate

Product 1

HCID 54505552HCID 54505552, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (10.5 g, 27.8 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (200 mL) under a nitrogen atmosphere was added N,N-dimethylformamide (30 mL). The reaction was cooled to about −78° C., and a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (83 mL, 42 mmol) was added. The reaction was stirred at about −78° C. for about 1 hour, and then 4-fluorobenzyl bromide (5.2 mL, 42 mmol) was added. The reaction was stirred for about 1 hour more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product as a yellow oil. Purification by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (8.54 g, 63%) as a colorless oil: +APcI MS (M−Boc+H)+ 387; 1H NMR=400 MHz (CDCL3) δ: 7.45-7.30 (arom, br s, 5H), 7.00-6.80 (arom, br m, 4H), 5.35-5.05 (br m, 2H), 2.53 (br t, 1H), 1.40 (Boc, s, 9H).

Workup

  1. stirringThe reaction was stirred for about 1 hour more at about −78° C.
  2. temperaturewarmed to room temperature
  3. stirringstirred overnight
  4. customThe reaction was quenched with saturated sodium bicarbonate solution
  5. extractionthe mixture was extracted three times with ethyl acetate
  6. extractionThe combined organic layers were extracted twice with water, brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give the crude product as a yellow oil
  11. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-5e588bb12b574a7abf3ae99bcbf219f4
Source dataset
uspto-grants-2001_02
Patent number
US06194578B1

Linked notes

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