Hexane → HCID 70558534, compound

HRID 707703Notes

Reaction equation

HRID 707703 reaction equation
C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20].[C:21]([O:40][CH2:41][C@@H:42]1[C@@H:49]2[C:45](=[N:46][O:47][CH2:48]2)[CH2:44][O:43]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1.COC(C)(C)C.O>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C@:45]12[CH2:44][O:43][C@H:42]([CH2:41][O:40][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:49]1[CH2:48][O:47][NH:46]2

Participants

10

Reactant 5

HCID 8058HexaneHCID 25517Ammonium ChlorideHCID 27332601-Bromo-2,3-difluorobenzeneHCID 57827729HCID 57827729, compoundHCID 178418339Butyllithium

Product 1

HCID 70558534HCID 70558534, compoundYield 67.6%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolventHCID 22635083Tetrahydrofuran tolueneSolvent

Conditions

Temperature
-75 °C

Procedure

A 2.50 M solution of n-butyllithium in hexane (197 mL, 0.493 mol, 1.90 equiv.) was added dropwise to a solution containing 1-bromo-2,3-difluorobenzene (95.1 g, 0.493 mol, 1.90 equiv.) in THF/toluene (100 mL/1000 mL) under a nitrogen atmosphere at −75 to −69° C. After 10 min, boron trifluoride-diethyl etherate complex (62.5 mL, 0.493 mol) was added dropwise while maintaining temperature below −71° C. A previously prepared solution of (3aR*,4S*)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (100 g, 0.259 mol, 1.0 equiv.) in THF (400 mL) was added while maintaining the temperature below −70° C. After stirring at the −75° C. for 1.5 h, saturated aq. NH4Cl (300 mL) and water (100 mL) were slowly added (over 5 min) to the reaction solution. 2-methoxy-2-methylpropane (300 mL) was added and the reaction was allowed to warm up to 0° C. The organic phase was isolated and washed with 27% aq NaCl solution (200 mL). The organic layer concentrated under reduced pressure and recrystallised from THF (200 mL)/isopropyl alcohol (700 mL). Title compound (87.5 g) was isolated. 1H NMR (500 MHz, DMSO) δ ppm 7.42-7.33 (m, 8H), 7.31 (t, J=7.6 Hz, 6H), 7.28-7.21 (m, 3H), 7.20-7.12 (m, 1H), 6.39 (s, 1H), 4.13 (d, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.97 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.70 (m, 1H), 3.36-3.29 (m, 1H), 3.26 (dd, J=10.1, 6.0 Hz, 1H), 3.15 (dd, J=10.0, 3.5 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 150.74 (dd, JCF=246.4, 14.4 Hz), 148.66 (dd, JCF=248.3, 13.5 Hz), 144.09, 130.58, 128.67, 128.32, 127.48, 124.75, 124.45, 117.18 (d, JCF=17.0 Hz), 86.57, 84.91, 78.16, 76.81, 64.82, 56.46.

Workup

  1. temperaturewhile maintaining temperature below −71° C
  2. temperaturewhile maintaining the temperature below −70° C
  3. temperatureto warm up to 0° C
  4. customThe organic phase was isolated
  5. washwashed with 27% aq NaCl solution (200 mL)
  6. concentrationThe organic layer concentrated under reduced pressure
  7. customrecrystallised from THF (200 mL)/isopropyl alcohol (700 mL)

Sources & evidence

ORD record
ord-14d72e3c3b0343b5b090b4a3ae7c4e31
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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