Phosphorus oxychloride → 6-Methylimidazo[1,5-A]pyridine

HRID 245841Notes

Reaction equation

P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][CH:15]=O)=[N:11][CH:12]=1>C1(C)C=CC=CC=1>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:15]=[N:14][CH:13]=2)[CH:12]=1

Participants

Conditions

Temperature: 100 °C

Procedure

In a round-bottomed flask, N-(5-methyl-pyridin-2-ylmethyl)-formamide (crude from step 2) was dissolved in toluene (30 ml) and phosphorus oxychloride (1.2 ml, 12.9 mmol) was added. The reaction mixture was stirred at 100° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-80% EtOAc) to give 386 mg (41%, 3 steps) of 6-methyl-imidazo[1,5-a]pyridine as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.09 (s, 1H), 7.74 (s, 1H), 7.32-7.43 (m, 2H), 6.60 (dd, J=9.4, 1.1 Hz, 1H), 2.25 (d, J=1.1 Hz, 3H).

Workup

temperaturethen cooled to 0° C.
customcarefully quenched with ice
additionAqueous 25% ammonium hydroxide was added until pH=˜9
additionThe mixture was diluted with water
extractionextracted with dichloromethane (2×)
dry with materialdried over sodium sulfate
filtrationfiltered
concentrationconcentrated
customThe residue was absorbed on silica gel
customchromatographed with EtOAc/hexanes (gradient 0-80% EtOAc)

Sources & evidence

ORD record: ord-a76a6aa1332c4b75aec1b29302a5f204
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658646B2

Reaction notes

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