Dicyclohexylcarbodiimide → Tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-2-carboxylate

HRID 1172978Notes

Reaction equation

HRID 1172978 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67])/[C:58](=[N:60]/O)/[NH2:59]>C(#N)C>[Cl:54][C:55]1[CH:56]=[C:57]([C:58]2[N:60]=[C:17]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16]4)[O:19][N:59]=2)[CH:62]=[CH:63][C:64]=1[O:65][CH:66]([CH3:68])[CH3:67]

Participants

7

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 164501432-(tert-Butoxycarbonyl)-2,3-dihydro-1H-isoindole-5-carboxylic acidHCID 595565653-chloro-N'-hydroxy-4-propan-2-yloxybenzenecarboximidamide

Product 1

HCID 59556543Tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-2-carboxylateYield 15.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (190 mg, 0.722 mmol) in acetonitrile (3 mL) in a 5 mL microwave vial was added HOBT (330 mg, 2.16 mmol), DCC (298 mg, 2.16 mmol), and DIEA (0.115 mL, 0.656 mmol). The mixture was stirred at room temperature for approximately 16 hours. Next, (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (150 mg, 0.656 mmol) (prepared by General procedure B) was added and the reaction was heated to 150° C. under microwave irradiation (max 300 W) for 20 minutes. After cooling, the reaction mixture was filtered, concentrated, and purified via Analogix system using RediSep 40 g column, with a gradient of 0-40% EtOAc/Heptane over 30 min. at a flow rate of 30 ml/min. Fractions containing product were combined, rotovapped, and dried in a vacuum oven to give tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-2-carboxylate (46.2 mg, 15.5%) LCMS (Table 1, Method c) Rt=3.40 min, m/z 456.22 (M+H)+; 1H NMR (400 MHz, DMSO) δ ppm 8.16 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.61 (m, 1H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.70 (d, 4H), 1.48 (s, 9H), 1.35 (d, 6H).

Workup

  1. temperaturethe reaction was heated to 150° C. under microwave irradiation (max 300 W) for 20 minutes
  2. temperatureAfter cooling
  3. filtrationthe reaction mixture was filtered
  4. concentrationconcentrated
  5. custompurified via Analogix system
  6. waitwith a gradient of 0-40% EtOAc/Heptane over 30 min. at a flow rate of 30 ml/min
  7. additionFractions containing product
  8. customdried in a vacuum oven

Sources & evidence

ORD record
ord-d5918a275ae24383bb8c3042358a2a3c
Source dataset
uspto-grants-2010_11
Patent number
US07834039B2

Reaction notes

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