Recyclable NHC Catalyst for the Development of a Generalized Approach to Continuous Buchwald–Hartwig Reaction and Workup

Abstract

A generalized approach to the optimization and implementation of Buchwald-Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst; a universal approach for continuous work-up and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) pre-catalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η 3 -cinnamyl) is an excellent choice for continuous Buchwald-Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to 3 times in batch mode. A "right-firsttime" work-up methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald-Hartwig product into the aqueous stream as a salt, while retaining the aryl bromide starting material in the organic stream with the catalyst, thus negating the requirement for further purification. It is therefore envisaged that this approach will particularly amenable to exploitation in the Pharmaceutical industry. An optimized, scalable synthesis of [Pd(IPr*)(cin)Cl] is also reported on multi-hundred gram scale.

Synthesis and characterisation of an N-heterocyclic carbene with spatially-defined steric impact

“…24 Starting from cheap and commercially available 2,4-dimethylaniline, 25 the condensation reaction furnished the desired aniline in good yield and could be scaled up to gram quantities (Scheme 1). 24 Starting from cheap and commercially available 2,4-dimethylaniline, 25 the condensation reaction furnished the desired aniline in good yield and could be scaled up to gram quantities (Scheme 1).…”

Adjusting Ortho-Cycloalkyl Ring Size in a Cycloheptyl-Fused N,N,N-Iron Catalyst as Means to Control Catalytic Activity and Polyethylene Properties

“…1 H and 13 C NMR spectra of the polyethylenes were recorded using a Bruker DMX 300 MHz instrument at 100 • C in deuterated 1,1,2,2-tetrachloroethane with tetramethylsilane (TMS) as an internal standard. The compounds 2-acetyl-5,6,7,8-tetrahydrocyclohepta[b]pyridin-9-one [25] and the 2-cycloalkylanilines [26][27][28] have been prepared using the literature methods. pyridin -9-one (0.061 g, 0.30 mmol), 2-cyclopentyl-4,6-dibenzhydrylaniline (0.140 g, 0.66 mmol), and iron(II) chloride tetrahydrate (0.057 g, 0.29 mmol) in glacial acetic acid (20 mL) was stirred and heated under reflux for 3 h. Once cooled to ambient temperature, the solvent was partially removed under reduced pressure, and an excess of diethyl ether was added to induce precipitation.…”

Aluminum Amidinates: Insights into Alkyne Hydroboration

“…Pro-ligands L1 – L4 ( Figure 2 b) were synthesized in a modular fashion via modified literature procedures leading to a series of novel symmetric and asymmetric amidinates (for full experimental details, see the Supporting Information (SI) ). 32 …”