4-Hydroxybenzaldehyde → tert-Butyl (1S,4S)-5-(4-hydroxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

HRID 1807454Notes

Reaction equation

HRID 1807454 reaction equation
[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 1264-HydroxybenzaldehydeHCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 11521263(1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane

Product 1

HCID 57514842tert-Butyl (1S,4S)-5-(4-hydroxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 4-hydroxybenzaldehyde (20 g, 0.163 mol, 1 equiv.) in CH2Cl2 (340 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.7 g, 0.18 mol, 1.1 equiv.), acetic acid (2.8 mL, 0.05 mol, 0.3 equiv.) and sodium triacetoxyborohydride (41.4 g, 0.195 mol, 1.2 equiv.). The reaction was stirred at rt for 16 h. The reaction was quenched with satd. aq. NaHCO3 (3×150 mL) and 1 M NaOH (1×100 mL). The combined aqueous layers were reacidified with 1 M HCl and extracted with CH2Cl2 (2×300 mL). The organic layers were dried, filtered, and concentrated. Purification by column chromatography (5% MeOH/CH2Cl2) yielded product as a white powdery solid (24.4 g, 50%). 1H NMR (500 MHz, CDCl3): 7.16 (d, J=8.5, 2H), 6.74 (d, J=8.5, 2H), 4.37 (s, 0.5H), 4.25 (s, 0.5H), 3.65 (s, 2.5H), 3.52 (s, 0.5H), 3.47 (s, 1H), 3.16 (d, J=10.3, 1H), 2.92 (s, 0.5H), 2.82 (s, 0.5H), 2.72 (s, 0.5H), 2.57 (d, J=9.6, 0.5H), 1.85 (s, 1H), 1.74-1.62 (m, 1H), 1.47 (s, 9H). MS (ESI): mass calcd. for C17H24N2O3, 304.38; m/z found, 305.2 [M+H]+.

Workup

  1. customThe reaction was quenched with satd
  2. extractionextracted with CH2Cl2 (2×300 mL)
  3. customThe organic layers were dried
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by column chromatography (5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-4f58d28fbab2428a81583590fdf33fd5
Source dataset
uspto-grants-2013_01
Patent number
US08357684B2

Reaction notes

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