Dimethylformamide → 5-Chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)picolinaldehyde

HRID 706395Notes

Reaction equation

HRID 706395 reaction equation
Br[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Cl:10])=[CH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[Cl-].[Li+].C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>CC1OCCC1.S(=O)(=O)(O)O>[Cl:10][C:5]1[CH:6]=[C:7]([CH2:8][O:9][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:2]([CH:27]=[O:28])=[N:3][CH:4]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 80803,4-dihydro-2H-pyranHCID 71721408HCID 71721408, compoundHCID 178461733HCID 178461733, compound

Product 1

HCID 717382825-Chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)picolinaldehydeYield 74%

Reagents, catalysts & solvents 2

HCID 1118Sulfuric AcidCatalystHCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
-3 °C

Procedure

To a solution of 52 (5.0 g, 22.5 mmol) in 2-MeTHF (15 mL) was added 3,4-dihydro-2H-pyran (2.7 mL, 29.6 mmol) and concentrated sulfuric acid (125 mg) at room temperature. The solution was stirred for 10 min and was then cooled to −3° C. Isopropylmagnesium chloride lithium chloride solution (1.3 M, 30 ml, 39 mmol) was slowly added at −3 to 3° C. The resulting solution was stirred at −3° C. for 3 h until a HPLC showed the conversion was greater than 97%. DMF (5 ml) was added over 15 min below 5° C. The resulting solution was stirred for another 1 h at this temperature. The reaction mixture was quenched by addition of MTBE (50 mL), 15% aqueous citric acid (25 mL) and water (15 mL). The organic layer was separated and washed with 5% aqueous NaCl (50 mL) twice. The organic solution was concentrated under vacuum at 50° C. to give 53 as an oil (6.2 g, 68 wt %, 16.6 mmol, 74% yield). The crude product was used directly for the next step without further purification. The pure sample was isolated by flash chromatography on silica gel with 5% ethyl acetate in hexane as eluants. 1H NMR (CDCl3, 400 MHz): δ 10.13 (s, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 5.25 (d, J=16.6 Hz, 1H), 5.01 (d, J=16.6 Hz, 1H), 4.80 (m, 1H), 3.88 (m, 1H), 3.58 (m, 1H), 1.7 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 194.20, 147.06, 146.32, 138.98, 136.41, 134.87, 99.04, 64.42, 62.72, 30.53, 25.30, 19.66.

Workup

  1. stirringThe resulting solution was stirred at −3° C. for 3 h until a HPLC
  2. stirringThe resulting solution was stirred for another 1 h at this temperature
  3. customThe reaction mixture was quenched by addition of MTBE (50 mL), 15% aqueous citric acid (25 mL) and water (15 mL)
  4. customThe organic layer was separated
  5. washwashed with 5% aqueous NaCl (50 mL) twice
  6. concentrationThe organic solution was concentrated under vacuum at 50° C.

Sources & evidence

ORD record
ord-15f8123f3321473db47e86437b29c626
Source dataset
uspto-grants-2015_11
Patent number
US09174989B2

Reaction notes

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