Tetrahydrofuran → 1-(2-Methylpyridin-4-yl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol

HRID 718823Notes

Reaction equation

HRID 718823 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=O)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O>O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:21](=[CH:44][C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=5)[CH2:20][CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 142732-PyridinecarboxaldehydeHCID 2733832Lithium HexamethyldisilazideHCID 867224321-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one

Product 1

HCID 867224331-(2-Methylpyridin-4-yl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
-77 °C

Procedure

A round bottom flask was charged with 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=2-methylpyridin-4-yl) (2.83 g, 9.71 mmol) and THF (43 mL). The solution was cooled to about −77° C. and then lithium bis(trimethylsilyl)amide (1.0 M in THF, 10.0 mL, 10.0 mmol) was added over about 30 min, keeping the internal temperature below about −75° C. After the addition was the mixture was stirred for about 5 min, the cold bath was removed and the mixture was allowed to warm to about 0° C. over about 1 h. The mixture was again cooled to about −75° C. then 2-pyridinecarboxaldehyde (3.2 mL, 34 mmol) was added. The mixture was allowed to warm to about −10° C. over about 1 h, and then water (40 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×40 mL) and then the combined organics were washed with brine (50 mL), dried over Na2SO4 and then concentrated under reduced pressure. The crude material was purified on silica gel (120 g, eluted with 0% to 2.5% MeOH in DCM). Collection and concentration of the appropriate fractions gave 1-(2-methylpyridin-4-yl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H-one (83, R1=2-methylpyridin-4-yl, R2′=pyridin-2-yl) (3.45 g, 93%) LC/MS, method 3, Rt=1.95 min, MS m/z 381 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.7 Hz, 1H), 8.61-8.53 (m, 1H), 8.11-8.08 (m, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.80-7.64 (m, 2H), 7.53 (s, 1H), 7.44-7.35 (m, 1H), 7.14-7.06 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 3.14-3.06 (m, 2H), 2.78 (s, 3H), 2.56-2.48 (m, 2H), 2.23-2.08 (m, 2H).

Workup

  1. customthe internal temperature below about −75° C
  2. additionAfter the addition
  3. customthe cold bath was removed
  4. temperatureto warm to about 0° C. over about 1 h
  5. temperatureThe mixture was again cooled to about −75° C.
  6. temperatureto warm to about −10° C. over about 1 h
  7. customthe layers were separated
  8. extractionThe aqueous layer was extracted with EtOAc (2×40 mL)
  9. washthe combined organics were washed with brine (50 mL)
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated under reduced pressure
  12. customThe crude material was purified on silica gel (120 g, eluted with 0% to 2.5% MeOH in DCM)
  13. customCollection and concentration of the appropriate fractions

Sources & evidence

ORD record
ord-37177e21982b4a31914f59e7962a6712
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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