Benzyl Bromide → HCID 76413181, compound

HRID 376021Notes

Reaction equation

HRID 376021 reaction equation
[Cl-].[Li+].C(NC(C)C)(C)C.C([Li])CCC.[OH:15][CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])[CH3:18].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:15][CH:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH2:22][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[CH3:18]

Participants

7

Reactant 5

HCID 7498Benzyl BromideHCID 7912DiisopropylamineHCID 433294Lithium ChlorideHCID 3376357HCID 3376357, compoundHCID 178418339Butyllithium

Product 1

HCID 76413181HCID 76413181, compoundYield 90%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A dry 2 L 3-necked round-bottomed flask was equipped with a mechanical stirrer, and charged with lithium chloride (25.0 g, 596 mmol, 6.0 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv), and tetrahydrofuran (120 mL). The suspension was cooled to -78° C., and n-butyllithium (2.43M in hexanes, 85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. After a brief warming to 0° C., it was recooled to -78° C. [S-[R*,R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl propionamide (22.0 g, 99.41 mmol, 1.0 equiv) was added as a 0° C. solution in tetrahydrofuran (300 mL). The resulting solution was stirred at -78° C. for 1 hour, warmed to 0° C. for 15 minutes, warmed to 23° C. for 5 minutes, and cooled to 0° C. Benzyl bromide (17.74 mL, 149 mmol, 1.5 equiv) was added, and the reaction was stirred at 0° C. The reaction was quenched after 15 minutes with saturated ammonium chloride, and the amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (500 mL, 150 mL, 150 mL). The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a yellow solid was obtained. Recrystallization from toluene (100 mL) yielded the desired product as a white powder (27.77 g, 90% yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 99% de: mp 136°-137° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 10 H), 4.45 (m, 1H), 4.25 (br, 1H), 3.96 (m, 1H), 3.80 (m, 1H), 3.36 (dd, 2H, J=13.1 Hz, 6.92 Hz), 3.01 (m, 1H), 2.75 (m, 1H), 2.70 (s, 3H), 2.45-2.59 (m, 3H), 2.08 (s, 3H), 1.05 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.5 Hz), 0.83 (d, 3H, J=7.0 Hz), 0.59 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ178.2, 177.2, 142.3, 141.1, 140.5, 139.9, 129.2, 128.9, 128.6, 128.31, 128.26, 127.5, 126.8, 126.4, 126.2, 76.4, 75.2, 58.0, 40.3, 40.0, 38.9, 38.1, 32.3, 27.1, 17.7, 17.4, 15.5, 14.3; FTIR (neat film) cm-1 3384 (br, m), 3027 (m), 2973 (m), 2932 (m), 1617 (s), 1493 (m), 1453 (m), 1409 (m), 1080 (m), 1050 (m), 701 (s); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312.1965. Found: 312.1972; Anal. Calcd for C20H25NO2: C, 77.14, H, 8.09, N, 4.50. Found: C, 76.87, H, 8.06, N, 4.50.

Workup

  1. customA dry 2 L 3-necked round-bottomed flask was equipped with a mechanical stirrer
  2. temperatureAfter a brief warming to 0° C.
  3. customwas recooled to -78° C.
  4. temperaturewarmed to 0° C. for 15 minutes
  5. temperaturewarmed to 23° C. for 5 minutes
  6. temperaturecooled to 0° C
  7. stirringthe reaction was stirred at 0° C
  8. customThe reaction was quenched after 15 minutes with saturated ammonium chloride
  9. extractionthe amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (500 mL, 150 mL, 150 mL)
  10. dry with materialThe combined organic extracts were dried over sodium sulfate
  11. customafter removal of the solvent under reduced pressure
  12. customa yellow solid was obtained
  13. customRecrystallization from toluene (100 mL)

Sources & evidence

ORD record
ord-323d7dca1f95477dadeed61c46b2d709
Source dataset
uspto-grants-1996_01
Patent number
US05488131

Reaction notes

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