Citric Acid → 4-(2-Chloro-4-trifluoromethyl-phenyl)-4-cyano-but-3-enoic acid methyl ester

HRID 457416Notes

Reaction equation

HRID 457416 reaction equation
CC(C)([O-])C.[Na+].CO[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[CH2:26][C:27]#[N:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:9]=[C:26]([C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:16]=1[Cl:15])[C:27]#[N:28]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 2724617Methyl 3-methoxyprop-2-enoateHCID 219888322-Chloro-4-(trifluoromethyl)phenylacetonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 692570734-(2-Chloro-4-trifluoromethyl-phenyl)-4-cyano-but-3-enoic acid methyl esterYield 97.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of sodium tert-butoxide (3.28 g, 34.2 mmol) in tetrahydrofuran (20 mL) at 0° C. was added a solution of methyl 3-methoxyacrylate (2.65 g, 22.8 mmol) and (2-chloro-4-trifluoromethyl-phenyl)-acetonitrile (5.00 g, 22.8 mmol) in tetrahydrofuran (20 mL) dropwise over 45 minutes. The red solution was stirred at 0° C. for 3 hours and then allowed to warm to 10° C. over another 2 hours. The reaction was then treated with 0.2 M aqueous citric acid (50 mL) and extracted with a 2:1 mixture of methyl tert-butyl ether and hexanes (75 mL). The organic layer was washed with an aqueous saturated solution of sodium chloride (50 mL). The organic solution was passed through a short column of silica gel, washing the residual material through the pad with additional methyl tert-butyl ether. The filtrate was concentrated in vacuo to afford 4-(2-chloro-4-trifluoromethyl-phenyl)-4-cyano-but-3-enoic acid methyl ester as a red oil (6.74 g, 97%). Major olefin isomer: 1HNMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.58 (d, 1H, J=8.3), 7.49 (d, 1H, J=8.3), 6.89 (t, 1H, J=7.1), 3.78 (s, 3H), 3.69 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) δ 169.4, 145.9, 136.1, 133.7, 133.0 (q, J=33.5), 131.5, 127.6 (q, J=3.8), 124.5 (q, J=3.8), 123.2 (q, J=292), 115.4, 114.7, 52.7, 36.7; IR (ATR, neat) 2957, 2224, 1740, 1438, 1395, 1319, 1268, 1172, 1128, 1080, 1010, 963, 892, 831, 719, 655 cm−1. Minor olefin isomer: 1H-NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.61 (d, 1H, J=7.8), 7.43 (d, 1H, J=7.8), 7.02 (t, 1H, J=7.8), 3.71 (s, 3H), 3.11 (d, 2H, J=7.8).

Workup

  1. temperatureto warm to 10° C. over another 2 hours
  2. extractionextracted with a 2:1 mixture of methyl tert-butyl ether and hexanes (75 mL)
  3. washThe organic layer was washed with an aqueous saturated solution of sodium chloride (50 mL)
  4. washwashing the residual material through the pad with additional methyl tert-butyl ether
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-dc11229c0a2b465b9971e804c0aa979f
Source dataset
uspto-grants-2007_03
Patent number
US07186870B2

Reaction notes

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