Tetrahydrofuran → 2-(4,6-Dichloropyridin-2-yl)-5-methylthiazole

HRID 523166

Reaction equation

HRID 523166 reaction equation
C1COCC1.Br[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1.C([Li])CCC.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21](Cl)[N:20]=1>CCOC(C)=O.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:23]1[CH:24]=[C:19]([Cl:18])[N:20]=[C:21]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][N:11]=2)[CH:22]=1

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 27665Pyridine, 2,4,6-trichloro-HCID 219061062-Bromo-5-methyl-1,3-thiazoleHCID 178418339Butyllithium

Product 1

HCID 901181852-(4,6-Dichloropyridin-2-yl)-5-methylthiazoleYield 9.8%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

A dry 25 mL schlenk flask equipped with a stir bar and placed under N2 atmosphere was charged with THF (7 mL) and 2-bromo-5-methylthiazole (610 mg, 3.43 mmol). The solution was cooled to −78° C. To the solution was added n-butyllithium in hexanes (1.37 mL, 3.43 mmol) upon which the solution immediately turned dark/golden. The solution was stirred for 5 minutes. To the solution was added zinc(II) chloride in THF (6.85 mL, 3.43 mmol) upon which the solution lightened to a golden color. The solution was immediately warmed to r.t. with a water bath, with stirring for 30 minutes. To the reaction solution was added 2,4,6-trichloropyridine (250 mg, 1.37 mmol) and Pd(dppf)Cl2 (100 mg, 0.137 mmol). The flask was sealed and then was placed in a 60° C. oil bath with stirring for 16 h. The reaction solution was transfered to a 500 mL reparatory funnel and was diluted with EtOAc (100 mL), then washed with brine (50 mL). The organic phase was dried over MgSO4; filtered; then concentrated in vacuo to afford a dark amber solid. This material was subjected to silica gel chromatography to afford 2-(4,6-dichloropyridin-2-yl)-5-methylthiazole as a white solid (33 mg, 8%): 1H-NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.7 Hz, 1H), 7.59 (d, J=1.1 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 2.55 (d, J=1.1 Hz, 3H); and 2,2′-(4-chloropyridine-2,6-diyl)bis(5-methylthiazole) as a white solid (160 mg, 48%): 1H-NMR (500 MHz, CDCl3) 8.10 (s, 2H), 7.60 (d, J=1.3 Hz, 2H), 2.59-2.55 (m, 6H).

Workup

  1. customA dry 25 mL schlenk flask equipped with a stir bar
  2. temperatureThe solution was immediately warmed to r.t. with a water bath
  3. stirringwith stirring for 30 minutes
  4. customThe flask was sealed
  5. customwas placed in a 60° C.
  6. stirringwith stirring for 16 h
  7. customThe reaction solution was transfered to a 500 mL reparatory funnel
  8. washwashed with brine (50 mL)
  9. dry with materialThe organic phase was dried over MgSO4
  10. filtrationfiltered
  11. concentrationthen concentrated in vacuo
  12. customto afford a dark amber solid

Sources & evidence

ORD record
ord-ca55644914624ef9b88c713e61c761be
Source dataset
uspto-grants-2016_05
Patent number
US09334279B2

Linked notes

Loading…