Aniline → N-[4-Ethoxy-2-(isobutylamino)phenyl]-3-phenylpropanamide

HRID 537328Notes

Reaction equation

HRID 537328 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:22](=O)[CH:23]([CH3:25])[CH3:24].[BH3-]C#N.[Na+].NC1C=CC=CC=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2].CO.C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:2]([NH:1][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:7]=1)[CH3:10]

Participants

10

Reactant 4

HCID 6115AnilineHCID 6561Isobutyraldehyde2×HCID 5003444Sodium cyanoborohydrideHCID 86689301N-(2-Amino-4-ethoxyphenyl)-3-phenylpropanamide

Product 1

HCID 86689300N-[4-Ethoxy-2-(isobutylamino)phenyl]-3-phenylpropanamideYield 89%

Reagents, catalysts & solvents 5

HCID 3007855ZincchlorideCatalystHCID 131717307ZINC chloride sodium cyanoborohydrideCatalystHCID 887MethanolSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 250 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 76 (3.30 g, 11.6 mmol), THF (35 mL), and MeOH (10 mL). To the resultant solution was added isobutyraldehyde (1.17 g, 1.48 mL, 16.2 mmol), and the mixture stirred 15 min at rt. Meanwhile, in a 100 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 16.2 mL, 16.2 mmol) was added to MeOH (10 mL). ZnCl2 (1M in Et2O, 8.1 mL, 8.1 mmol) was added next forming a cloudy mixture. After 15 min, this mixture was added to the above aniline solution. After stirring at rt 2.3 hr, another 0.3 mL isobutyraldehyde was added, followed by a second portion of 20% of the original amount of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred overnight at rt. The cloudy solution was diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (2×125 mL) and brine (100 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a yellow solid. The solid was triturated with hexanes:EtOAc 20:1 (20 mL), filtered, pressed with a rubber dam, and rinsed with hexanes (2×10 mL) to give 3.5 g of 77 as a yellow solid (89%). 1H NMR (Two isomers evident ˜3:2) (300 MHz, CDCl3): δ 7.38-7.18 (m, 5H), [6.87 (d, 0.6H), 6.78 (d, 0.4H)], [6.62 (s, 0.6H), 6.48 (s, 0.4H)], 6.24-6.12 (m, 2H), [4.02 (qt, 1.2H), 4.00 (qt, 0.8H)], [3.07 (t, 1.2H), 2.92 (t, 0.8H)], [2.86 (d, 1.2H), 2.84 (d, 0.8H)], [2.71 (t, 1.2H), 2.40 (t, 0.8H)], [1.85 (nonet, 0.4H), 1.84 (nonet, 0.6H)], [1.41 (t, 1.2H), 1.38 (t, 1.8H)], 0.94 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.5 min.

Workup

  1. customA 250 mL 3-neck flask fitted with a stir-bar, addition funnel
  2. customMeanwhile, in a 100 mL flask fitted with a stir-bar
  3. customnext forming a cloudy mixture
  4. waitAfter 15 min
  5. stirringAfter stirring at rt 2.3 hr
  6. stirringThe mixture stirred overnight at rt
  7. washwashed with saturated aqueous NaHCO3 (2×125 mL) and brine (100 mL)
  8. filtrationThe solution was filtered through phase separation paper
  9. concentrationconcentrated in vacuo to a yellow solid
  10. customThe solid was triturated with hexanes:EtOAc 20:1 (20 mL)
  11. filtrationfiltered
  12. washrinsed with hexanes (2×10 mL)

Sources & evidence

ORD record
ord-95f1fd84dd2248ad8a17e5471fd95bfc
Source dataset
uspto-grants-2014_10
Patent number
US08859780B2

Reaction notes

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