Benzoyl chloride → 3,6-dihydro-2H-pyridin-1-yl(phenyl)methanone

HRID 244282Notes

Reaction equation

[NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[N:1]1([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1

Participants

Reactant 2

HCID 7412Benzoyl chloride

HCID 127501,2,3,6-Tetrahydropyridine

Product 1

HCID 5700373,6-dihydro-2H-pyridin-1-yl(phenyl)methanone

Procedure

The target compounds were synthesized as depicted in Schemes 1-3. The synthesis started with 1,2,3,6-tetrahydropyridine, in which the secondary amine was first protected by reacting with benzoyl chloride to form benzamide 10. The alkenyl double bond of compound 10 was oxidized by meta-chloroperoxybenzoic acid (m-CPBA) to form epoxide 11. The epoxide 11 was refluxed with substituted 4-benzoylpiperidine hydrochloride salts, namely (4-(4′-fluorobenzoyl)piperidine hydrochloride or 4-(4′-methoxybenzoyl)piperidine hydrochloride), in ethanol with triethylamine as the base to afford tertiary amino alcohol intermediates. To improve the yield, commercially available 4′-substituted 4-benzoylpiperidine hydrochloride salts were used in excess and the reaction temperature was kept below 75° C. This reaction afforded (3′-hydroxy-1,4′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates and their regioisomers, (4′-hydroxy-1,3′-bipiperidin-4-yl)(4-substituted phenyl)methanone intermediates. The separation of these regioisomers by silica gel chromatography was difficult. The mixture of corresponding regioisomers was reacted with acetic anhydride to convert the free hydroxyl group to the corresponding acetates 12a-d. Subsequently, 12a and 12b were separated easily by silica gel chromatography. To confirm the structures of the regioisomers (12a(c) and 12b(d)), in addition to 1D NMR, 2D NMR was performed for regioisomers, 12c and 12d. The 1H, 13C NMR and HMQC spectra showed δH=5.31/2.68, 3.79/3.12, 2.06/1.47, 3.70, 2.48 and δH=4.89/2.66, 4.09/2.82, 1.95/1.41, 3.43 and 2.41 belong to the CH2-a, CH2-c, CH-d and CH-e (FIG. 2). The exact regioisomer (12a(c) or 12b(d)) were further verified by 1H-1H COSY. For regioisomer 12c, the correlations were observed between δH=5.31 (CH-a)/δH=2.68 (CH-a′) and δH=2.48 (CH-e); δH=3.79 (CH-b)/δH=3.12 (CH-b′) and δH=2.06 (CH-c)/δH=1.47 (CH-c′). In contrast, for regioisomer 12d, δH=4.89 (CH-a)/δH=2.66 (CH-a′) has no correlation with δH=2.41 (CH-e), and δH=4.09 (CH-b)/δH=2.82 (CH-b′) and has no correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′), but it has correlation with δH=1.95 (CH-c)/δH=1.41 (CH-c′) and δH=1.4I(CH-d).

Workup

customThe target compounds were synthesized

Sources & evidence

ORD record: ord-e9931814cd094d35a24325e56abb8e07
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658131B2

Reaction notes

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