Iodine → (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate

HRID 716403Notes

Reaction equation

HRID 716403 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:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)[S:28][CH:29]=2)=[CH:21][CH:20]=1.C(Cl)Cl>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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:35]=3)[S:28][CH:29]=2)=[CH:23][CH:24]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

9

Reactant 4

HCID 807Iodine2×HCID 6344DichloromethaneHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 86689666HCID 86689666, compound

Product 1

HCID 86689667(S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoateYield 84%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
50 °C

Procedure

To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was added diiodine (35.4 mg, 0.14 mmol). When the color was discharged, further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol) were added. After 30 min, DMF (1 mL) was added and the mixture de-gassed by bubbling through N2. To the reaction mixture were added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg, 0.93 mmol), Pd2dba3 (21 mg, 0.02 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (19 mg, 0.05 mmol), the mixture was further de-gassed then heated to 50° C. for 3 h. The reaction mixture was cooled and purified by column chromatography (10-80% EA in iso-hexanes). The product obtained was taken into DCM (4 mL) and washed with water (20 mL) and dried through a hydrophobic frit. The organics were suspended in ACN (4 mL) and concentrated to afford 432 mg (83%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)phenyl)propanoate as a yellow foam. LCMS-ESI (m/z) calculated for C31H40N2O5S: 552.7; no ion observed, tR=3.36 min. (Method 4).

Workup

  1. customthe mixture de-gassed
  2. customby bubbling through N2
  3. customthe mixture was further de-gassed
  4. temperatureThe reaction mixture was cooled
  5. custompurified by column chromatography (10-80% EA in iso-hexanes)
  6. customThe product obtained
  7. washwashed with water (20 mL)
  8. customdried through a hydrophobic frit
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-d1b17b6a2c55445e98c70695e5f8280f
Source dataset
uspto-grants-2015_11
Patent number
US09187522B2

Reaction notes

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