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

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, (1phenylethyl)magnesium bromide (2; RMgBr) and bis(1-phenylethyl)magnesium (3; R 2 Mg), with the equilibrium between these species lying in favor of the dialkylmagnesium species. The thermodynamic parameters of alkyl exchange for the reaction MgBr 2 + R 2 Mg (3) ⇌ 2RMgBr (2) were quantified, with the enthalpy and entropy of formation of 2 from MgBr 2 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 4isobutylstyrene, which following hydromagnesiation and reaction with CO 2 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.

Catalytic Isofunctional Reactions—Expanding the Repertoire of Shuttle and Metathesis Reactions

“…Following mechanistic investigations (Scheme 10 B), [52] the authors proposed that the reaction proceeds by transmetalation between the Grignard reagent and the catalyst to give complex 30 followed by b-hydride elimination. Hydrometalation of the styrene ligand in 32 and subsequent transmetalation affords the Grignard product, which is trapped by reaction with CO 2 .I nc ontrast to the work by the groups of Shirakawa and Hayashi, this reaction displays selectivity for the formation of the secondary, a-aryl Grignard intermediate rather than the primary, b-aryl Grignard intermediate.T he authors suggest that this likely arises from preferential formation of am ore stable benzylic anion.…”

Katalytische, isofunktionelle Reaktionen – Erweiterung des Repertoires an Shuttle‐ und Metathesereaktionen

“…[52] Hydrometallierung des Styrolliganden in 32 mit anschließender Tr ansmetallierung ergibt das Grignard-Produkt, das durch Reaktion mit CO 2 abgefangen wird. [52] Hydrometallierung des Styrolliganden in 32 mit anschließender Tr ansmetallierung ergibt das Grignard-Produkt, das durch Reaktion mit CO 2 abgefangen wird.…”

Iron‐Catalysed Hydrofunctionalisation of Alkenes and Alkynes

“…[151] The developed methodology was applied as the key step in the synthesis of ibuprofen using only iron-catalysed processes. An alternative catalyst system of Fe(acac) 3 and N,N,N,N-tetramethylethylene (TMEDA) was used.…”