N,N,N',N'-Tetramethylethylenediamine → 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one

HRID 2183782Notes

Reaction equation

HRID 2183782 reaction equation
[Li]N1C(C)(C)CCCC1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:61][C:62]([F:68])([F:67])[C:63](OC)=[O:64]>C1COCC1>[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([C:63](=[O:64])[C:62]([F:68])([F:67])[F:61])[C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1

Participants

8

Reactant 6

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 9893Methyl trifluoroacetateHCID 187617721,2,2,3-TetramethylpiperidineHCID 219481862-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-oneHCID 178418339ButyllithiumHCID 178418821HCID 178418821, compound

Product 1

HCID 219482132-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-oneYield 56.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-40 °C

Procedure

A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (154 mg, 1.10 mmol), TMEDA (127.8 mg, 1.10 mmol) and n-BuLi (0.688 mL, 1.10 mmol)] in THF (5 mL) was added to a cooled (−40° C.) stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.273 mmol) in THF (10 mL). The reaction was stirred for 1 h and then cooled to −78° C. Methyl trifluoroacetate (350 mg, 2.74 mmol) was added and stirring was continued for 2 h. The reaction was quenched carefully with water (50 mL), warmed to room temperature and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 3:1 Hex:EtOAc gave 2-anilino-7-chloro-6-fluoro-1-phenyl-5-(trifluoroacetyl)-1,8-naphthyridin-4(1H)-one (71 mg, 56%) as a light yellow solid: LCMS RT: 3.43 min, MH+: 462.3. The anion generated from LTMP deprotonation can be quenched with other electrophiles including carbon dioxide and 4-nitrophenyl acetate.

Workup

  1. additionwas added to
  2. temperaturecooled to −78° C
  3. stirringstirring
  4. waitwas continued for 2 h
  5. customThe reaction was quenched carefully with water (50 mL)
  6. temperaturewarmed to room temperature
  7. extractionextracted with EtOAc
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-284c923b6b944162b7b2daf39725a621
Source dataset
uspto-grants-2005_05
Patent number
US06900205B2

Reaction notes

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