Dimethylformamide → [(3S)-3-(hydroxymethyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetonitrile

HRID 1259450Notes

Reaction equation

HRID 1259450 reaction equation
CC(C)([O-])C.[K+].CN(C=O)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C@H:21]([CH2:24][OH:25])[O:20][C:19]=2[CH:26]=1)([O-:14])=[O:13].ClC1C=CC(O[CH2:33][C:34]#[N:35])=CC=1>CC(OC)(C)C>[OH:25][CH2:24][C@H:21]1[CH2:22][O:23][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[C:26]([CH2:33][C:34]#[N:35])[C:19]=2[O:20]1

Participants

6

Reactant 4

HCID 6228Dimethylformamide2×HCID 3064442-(4-Chlorophenoxy)acetonitrileHCID 23665647Potassium tert-butoxideHCID 25019919[(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol

Product 1

HCID 59168986[(3S)-3-(hydroxymethyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetonitrileYield 60%

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Procedure

A 5 L 3-necked flask equipped with a mechanical stirrer is charged with solid potassium t-butoxide (103.00 g, 0.918 mol) and DMF (1900 mL). The stirred solution is cooled until the internal temperature is 0° C., and a DMF (1100 mL) solution containing [(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (47.33 g, 0.224 mol) and (4-chlorophenoxy)acetonitrile (39.05 g, 0.233 mol) is added over 45 min. The reaction is quenched with 1 N HCl (1 L) and the volatiles are removed by rotary evaporation (˜3 L removed). The residue is dissolved in water (2 L) and extracted with EtOAc (3×600 mL). The combined extracts are washed with water (2×300 mL), 1 N NaOH (3×400 mL) and brine (300 mL), and evaporated to give an orange/brown solid. The solid is suspended with stirring in MTBE (300 mL) for 30 min. The solid is collected by vacuum filtration, washed with MTBE (50 mL) and then suction dried giving the title compound (33.60 g, 60%) as a tan solid. LCMS (Standard Method): 2.14 min, 251 (M+H)+. 1H NMR (300 MHz, CDCl2) δ 7.77 (d, J=9.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 4.48-4.37 (m, 2H). 4.28-3.91 (series of m, 5H), 2.32 (br s, 1H).

Workup

  1. customA 5 L 3-necked flask equipped with a mechanical stirrer
  2. temperatureThe stirred solution is cooled until the internal temperature
  3. customis 0° C.
  4. additionis added over 45 min
  5. customThe reaction is quenched with 1 N HCl (1 L)
  6. customthe volatiles are removed by rotary evaporation (˜3 L removed)
  7. dissolutionThe residue is dissolved in water (2 L)
  8. extractionextracted with EtOAc (3×600 mL)
  9. washThe combined extracts are washed with water (2×300 mL), 1 N NaOH (3×400 mL) and brine (300 mL)
  10. customevaporated
  11. customto give an orange/brown solid
  12. filtrationThe solid is collected by vacuum filtration
  13. washwashed with MTBE (50 mL)
  14. customsuction dried

Sources & evidence

ORD record
ord-e92b9e5151d541f6891c42bf74dc7314
Source dataset
uspto-grants-2013_06
Patent number
US08466296B2

Reaction notes

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