Cesium carbonate → (S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate

HRID 625569Notes

Reaction equation

HRID 625569 reaction equation
[CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.Br[C:30]1[N:31]=[C:32]2[N:38]=[C:37]([C@@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:36]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:33]2=[N:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1.O>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[N:31]=[C:32]4[N:38]=[C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:36]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:33]4=[N:34][CH:35]=2)[CH:13]=[CH:12]3)[O:5]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 58498888(S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylateHCID 596108242,2'-(Naphthalene-2,6-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

Product 1

HCID 58498818(S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
120 °C

Procedure

In a microwave vial, 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (149 mg, 0.393 mmol), (S)-tert-butyl 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (294 mg, 0.590 mmol) (or a SEM regioisomer), cesium carbonate (384 mg, 1.18 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (32.3 mg, 0.079 mmol) were dissolved into THF (4 mL) and water (0.4 mL). An additional 1.5 mL of THF was added and the reaction was sparged with bubbling nitrogen until the 1.5 mL had evaporated away. To the clear solution was added palladium(II) acetate (8.83 mg, 0.039 mmol). The vial was flushed with nitrogen, sealed and then heated with microwave irradiation at 120° C. for 30 min. The reaction was diluted with EtOAc (˜3 mL) and washed with water (2 mL) and brine (2 mL). The reaction was dried (MgSO4), filtered and concentrated to a yellow oil which was purified by flash chromatography (12 g SiO2, 25-75% EtOAc/hexanes) to yield (2S,2′S)-tert-butyl 2,2′-(5,5′-(naphthalene-2,6-diyl)bis(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazine-5,2-diyl))dipyrrolidine-1-carboxylate (or a SEM regioisomer) (210 mg) as a yellow solidified foam and (S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-2-yl)pyrrolidine-1-carboxylate (or a SEM regioisomer) (53.5 mg) as a colorless oil.

Workup

  1. customthe reaction was sparged with bubbling nitrogen until the 1.5 mL
  2. customhad evaporated away
  3. customThe vial was flushed with nitrogen
  4. customsealed
  5. additionThe reaction was diluted with EtOAc (˜3 mL)
  6. washwashed with water (2 mL) and brine (2 mL)
  7. dry with materialThe reaction was dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated to a yellow oil which
  10. customwas purified by flash chromatography (12 g SiO2, 25-75% EtOAc/hexanes)

Sources & evidence

ORD record
ord-7e9b5f0c7ebb406a95ab7ec567b701ec
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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