Trimethyl borate → 4-[5-(5-Methoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol

HRID 1434910Notes

Reaction equation

HRID 1434910 reaction equation
[CH3:1][C:2]([OH:11])([CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].[Li+].CC([N-]C(C)C)C.COB(OC)OC.Cl[C:28]1[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:35][O:34][C:33]1[C:28]([C:8]2[S:7][C:6]([CH2:5][CH2:4][C:2]([CH3:1])([OH:11])[CH3:3])=[CH:10][CH:9]=2)=[N:29][C:30]([S:36][CH3:37])=[N:31][CH:32]=1

Participants

9

Reactant 5

HCID 8470Trimethyl borateHCID 2435114-Chloro-5-methoxy-2-(methylsulfanyl)pyrimidineHCID 516892Sodium BicarbonateHCID 2724682Lithium diisopropylamideHCID 326398272-Methyl-4-(thiophen-2-yl)butan-2-ol

Product 1

HCID 579361614-[5-(5-Methoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 80711,2-DimethoxyethaneSolvent2×

Conditions

Temperature
100 °C

Procedure

A solution of 2-methyl-4-thiophen-2-yl-butan-2-ol (340 mg, 2 mmol)—synthesis see Step A of Example 1—in 20 ml of THF was treated with LDA (2M in THF/heptane/ethylbenzene, 5 ml, 10 mmol) at −78° C. under nitrogen and the mixture was stirred for 5 minutes. Then, trimethylborate (1.1 ml, 10 mmol) was added in one portion and the cooling bath was removed. After 15 minutes, the mixture was quenched with 50 ml of saturated ammonium chloride solution and extracted twice with ether. The aqueous layer was then acidified with 2N-HCl and extracted once more with ether. The combined organic extracts were washed with brine and evaporated. This crude boronic acid was redissolved in 10 ml of DME and added to a stirred suspension 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (190 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 20 ml of DME and 3 ml of a 10% solution of sodium bicarbonate. This mixture was then kept at reflux (100° C. heat bath) for 90 minutes. After cooling, most of the DME was evaporated and the crude was partitioned between water and ether. The organic layer was separated, washed with 0.2N-HCl, water and brine, dried over sodium sulfate and evaporated. The crude was purified by chromatography on silicagel (EtOAc/hexane:1/1) to give 4-[5-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol. Yield: 275 mg (85%).

Workup

  1. customthe cooling bath was removed
  2. waitAfter 15 minutes
  3. customthe mixture was quenched with 50 ml of saturated ammonium chloride solution
  4. extractionextracted twice with ether
  5. extractionextracted once more with ether
  6. washThe combined organic extracts were washed with brine
  7. customevaporated
  8. dissolutionThis crude boronic acid was redissolved in 10 ml of DME
  9. temperatureat reflux
  10. customwas evaporated
  11. customthe crude was partitioned between water and ether
  12. customThe organic layer was separated
  13. washwashed with 0.2N-HCl, water and brine
  14. dry with materialdried over sodium sulfate
  15. customevaporated
  16. customThe crude was purified by chromatography on silicagel (EtOAc/hexane:1/1)

Sources & evidence

ORD record
ord-9bfaef46fd9641d69bfb7a83f9d0b927
Source dataset
uspto-grants-2009_11
Patent number
US07615562B2

Reaction notes

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