Tri-o-tolylphosphine → tert-Butyl (3R)-4-(5-amino-2-methyl-phenyl)-3-(tert-butoxycarbonylamino)-butanoate

HRID 1053658Notes

Reaction equation

HRID 1053658 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18]I)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:24][C:23]1[CH:22]=[CH:21][C:27]([CH3:28])=[C:26]([CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:25]=1

Participants

5

Reactant 3

HCID 80271Tri-o-tolylphosphineHCID 1188893-Iodo-p-toluidineHCID 86222841tert-Butyl (S)-3-(Boc-amino)-4-iodobutanoate

Product 1

HCID 118276609tert-Butyl (3R)-4-(5-amino-2-methyl-phenyl)-3-(tert-butoxycarbonylamino)-butanoateYield 61%

Reagents, catalysts & solvents 1

HCID 23994ZincCatalyst

Procedure

Following the General Procedure of Description 15 (Part B), The zinc insertion product of (6c) was used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (1.21 g, 5.2 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (119 mg, 0.13 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (158 mg, 0.52 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with an ethyl acetate (EtOAc)/hexane mixture (EtOAc/hexane=7:3, v/v) furnished 1.15 g (61% yield) of the title compound (6d) as a yellow viscous oil. Rf˜0.28 (EtOAc/hexane=1:1, v/v). 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=8.1 Hz, 1H), 6.50-6.46 (m, 2H), 5.20-5.10 (br. m, 1H), 4.18-4.00 (m, 1H), 3.24 (br. s, 2H), 2.88-2.78 (br. dd, 1H), 2.70 (dd, 1H), 2.44 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.36 (dd, J=15.4 Hz, 5.4 Hz, 1H), 2.22 (s, 3H), 1.45 (s, 9H), 1.40 (s, 9H) ppm. LC/MS: Rt=1.433 min; ESI (pos.) m/z=365.20 (M+H+)+.

Workup

  1. customin anhydrous degassed DMF (6 mL)
  2. filtrationFiltration, aqueous work-up, and purification by silica gel column chromatography with an ethyl acetate (EtOAc)/hexane mixture (EtOAc/hexane=7:3

Sources & evidence

ORD record
ord-692c1e18a2914c2e83b83c0e67838111
Source dataset
uspto-grants-2016_07
Patent number
US09394237B2

Reaction notes

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