2-Chloroaniline → HCID 66926929, compound

HRID 81047Notes

Reaction equation

HRID 81047 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[C:13]([Cl:28])=[C:14]([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[CH:18][N:19]=1)[C:15]#[N:16].[Cl:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>C1COCC1>[Cl:28][C:13]1[C:12]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[Cl:29])=[N:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[C:14]=1[C:15]#[N:16]

Participants

5

Reactant 3

HCID 72402-ChloroanilineHCID 2733832Lithium HexamethyldisilazideHCID 86665690HCID 86665690, compound

Product 1

HCID 66926929HCID 66926929, compoundYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 1 M solution of lithium bis(trimethylsilyl)amide (0.573 mL, 0.573 mmol) was added to a solution of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (40 mg, 0.143 mmol, from Step 3 of Example 128) and 2-chloroaniline (36.6 mg, 0.287 mmol) in THF (2 mL) at room temperature. After 1 h at room temperature, LCMS and HPLC analysis indicated that a 1:2 mixture of two products were formed. The reaction mixture was quenched with saturated sodium bicarbonate (5 mL) and diluted with ethyl acetate (60 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5-20% ethyl acetate in hexanes, gave 3-chloro-2-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile as yellow solid (11 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.51-8.63 (1H, m), 8.35 (1H, s), 7.87 (1H, s), 7.38-7.51 (2H, m), 7.29-7.37 (1H, m), 6.97-7.16 (4H, m), 3.88 (3H, s); MS (ES+) m/z: 370 (M+H); LC retention time: 4.28 min (analytical HPLC Method A). The minor product was found to be 2-chloro-3-(2-chlorophenylamino)-5-(3-methoxyphenyl)isonicotinonitrile.

Workup

  1. additionLCMS and HPLC analysis indicated that a 1:2 mixture of two products
  2. customwere formed
  3. customThe reaction mixture was quenched with saturated sodium bicarbonate (5 mL)
  4. additiondiluted with ethyl acetate (60 mL)
  5. washwashed with water (5 mL), brine (5 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. washeluting with 5-20% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-e0e5339caf6f40d6b96a39d3e9029878
Source dataset
uspto-grants-2014_09
Patent number
US08846673B2

Reaction notes

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