Diethyl Malonate → Diethyl 2-(5-bromopyridin-2-yl)malonate

HRID 220168

Reaction equation

HRID 220168 reaction equation
BrC1C=CC(C(CCCCl)C(O)=O)=NC=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20](I)=[N:21][CH:22]=1.[CH2:24]([O:26][C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]>[Cu]>[CH2:24]([O:26][C:27](=[O:34])[CH:28]([C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][N:21]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:25]

Participants

5

Reactant 3

HCID 7761Diethyl MalonateHCID 5936905-Bromo-2-iodopyridineHCID 592382662-(5-Bromo-pyridin-2-yl)-5-chloro-pentanoic acid

Product 1

HCID 59238270Diethyl 2-(5-bromopyridin-2-yl)malonate

Reagents, catalysts & solvents 1

HCID 23978CopperCatalyst

Procedure

Key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII) can be prepared according to Scheme 8. Starting with commercially available 5-bromo-2-iodo-pyridine (XXXV), copper-catalyzed reaction with malonic acid diethyl ester furnishes 2-(5-bromo-pyridin-2-yl)-malonic acid diethyl ester (XXXVI). Hydrolysis and decarboxylation under basic conditions gives (5-bromo-pyridin-2-yl)-acetic acid (XXXVII), which subsequently can undergo nucleophilic acyl substitution with thionyl chloride in methanol to provide (5-bromo-pyridin-2-yl)-acetic acid methyl ester (XXXVIII). Deprotonation of XXXVIII with strong base followed by alkylation with 1-bromo-3-chloropropane gives 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (XXXIX), which can then be hydrolyzed under aqueous basic conditions to furnish key building block 2-(5-bromo-pyridin-2-yl)-5-chloro-pentanoic acid (XII).

Sources & evidence

ORD record
ord-d92c2f563d9b4e8c9c4fda92d65f3291
Source dataset
uspto-grants-2012_06
Patent number
US08202866B2

Linked notes

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