Iodine → (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-(2,4-dimethoxybenzyl)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoate

HRID 58862Notes

Reaction equation

HRID 58862 reaction equation
II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:19]1[CH:20]=[CH:21][C:22]2[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[CH2:25][CH2:24][C:23]=2[CH:41]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:16][C:19]1[CH:20]=[CH:21][C:22]2[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[CH2:25][CH2:24][C:23]=2[CH:41]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

8

Reactant 4

HCID 807Iodine2×HCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 1176082176-Bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide

Product 1

HCID 117690721(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-(2,4-dimethoxybenzyl)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoateYield 46%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

Iodine (0.11 g, 0.43 mmol) was added to a mixture of (R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (1.30 g, 3.58 mmol) and zinc (0.620 g, 9.75 mmol) in DMF (30 mL). The mixture was stirred for 10 min and another portion of iodine (0.11 g, 0.43 mmol) was added. The mixture was stirred for another 1 h. 6-Bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (1.34 g, 3.25 mmol), Pd2(dba)3 (0.08 g, 0.09 mmol) and S—Phos (0.070 g, 0.17 mmol) were added. The reaction mixture was stirred at 50° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtrate was poured into water (50 mL). The resulting mixture was extracted with EtOAc (100 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=15:1 to 3:1) to afford (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-(2,4-dimethoxybenzyl)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-6-yl)propanoate (0.8 g, 46% yield) as a yellow oil.

Workup

  1. stirringThe mixture was stirred for another 1 h
  2. stirringThe reaction mixture was stirred at 50° C. for 4 h
  3. filtrationThe mixture was filtered
  4. additionthe filtrate was poured into water (50 mL)
  5. extractionThe resulting mixture was extracted with EtOAc (100 mL×3)
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=15:1 to 3:1)

Sources & evidence

ORD record
ord-0d56489e19764a699e9a2b26bc10f6cb
Source dataset
uspto-grants-2016_09
Patent number
US09434761B2

Reaction notes

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