Iron-Catalyzed Hydromagnesiation: Synthesis and Characterization of Benzylic Grignard Reagent Intermediate and Application in the Synthesis of Ibuprofen

Mark D. Greenhalgh, Adam Kolodziej, Fern Sinclair, Stephen P. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

Iron-catalyzed hydromagnesiation of styrene derivatives using ethylmagnesium bromide has been investigated for the synthesis of benzylic Grignard reagents. The benzylic Grignard reagent formed in the reaction was observed directly and its conformation in solution characterized by multinuclear and variable-temperature NMR spectroscopy. The Grignard reagent could be stored for at least 2 weeks without significant loss in activity. Hydromagnesiation of styrene in tetrahydrofuran gave a mixture of monoalkyl- and dialkylmagnesium species, (1-phenylethyl)magnesium bromide (2; RMgBr) and bis(1-phenylethyl)magnesium (3; R2Mg), with the equilibrium between these species lying in favor of the dialkylmagnesium species. The thermodynamic parameters of alkyl exchange for the reaction MgBr2 + R2Mg (3) ⇌ 2RMgBr (2) were quantified, with the enthalpy and entropy of formation of 2 from MgBr2 and 3 calculated as 32 ± 7 and 0.10 ± 0.03 kJ mol–1, respectively. This methodology was applied, on a 10 mmol scale, as the key step in the synthesis of ibuprofen, using sequential iron-catalyzed alkyl–aryl and aryl–vinyl cross-coupling reactions to give 4-isobutylstyrene, which following hydromagnesiation and reaction with CO2 gave ibuprofen. Each step proceeded in excellent yield, at temperatures between 0 °C and room temperature, at atmospheric pressure. Inexpensive, nontoxic, and air- and moisture-stable iron(III) acetylacetonate was used as the precatalyst in each step in combination with inexpensive amine ligands.
Original languageEnglish
Pages (from-to)5811-5819
JournalOrganometallics
Volume33
Issue number20
Early online date5 Jun 2014
DOIs
Publication statusPublished - 27 Oct 2014

Fingerprint Dive into the research topics of 'Iron-Catalyzed Hydromagnesiation: Synthesis and Characterization of Benzylic Grignard Reagent Intermediate and Application in the Synthesis of Ibuprofen'. Together they form a unique fingerprint.

Cite this