From Solution‐Phase to Solid‐Phase Enyne Metathesis: Crossover in the Relative Performance of Two Commonly Used Ruthenium Pre‐Catalysts

Abstract

A crossover in the ability of two distinct ruthenium-based metathesis pre-catalysts to effect the synthesis of dialkenylboronic esters in solution and on the solid-phase was observed. Specifically, while the Grubbs 2nd generation pre-catalyst 3 affords a greater degree of conversion to product than the Hoveyda-Grubbs pre-catalyst 2 in a solution-phase enyne-metathesis reaction, this trend is reversed in the solid-phase variant. Systematic investigation showed this trend to be general, regardless of variations in the homoallylic alcohol and alkynylboronic ester components of the reaction, as well as in the type of solid support employed. Experiments to determine a mechanistic hypothesis for this trend highlighted the significance of the ruthenium remaining bound to the substrate after metathetic rearrangement and found the presence of phosphine ligand to be detrimental to the success of the solid-phase reaction. Therefore, these results suggest an expanded role for phosphine-free pre-catalysts, such as 2, in challenging solid-phase metathesis reactions.

Solid-Phase Olefin Cross-Metathesis Promoted by a Linker

“…Also, no intrabead homodimerization was observed for each carbon chain length. We found that catalyst 1b consistently gave higher yields than catalyst 1a (entries 1−4; brackets), which is reminiscent of a report by the Schreiber group . Thus, we concluded that 1b was superior to 1a in solid-phase olefin cross-metathesis.…”

Prospect of Metal-Catalyzed C−C Forming Cross-Coupling Reactions in Modern Solid-Phase Organic Synthesis

“…Hoveyda−Grubbs ( 78a ) (Figure ) is also a very interesting precatalyst, but there are just a few reports of its use in solid-phase chemistry. The general trend is that this precatalyst improves the reaction conversion, particularly, in the case of α,β-unsaturated carbonyl compounds. – The use of microwave irradiation will be another tool for optimizing cross metathesis in solid phase; preliminary results show an increase in yields and a reduction in the reaction time comparing with conventional heating…”

“…46,47 In these reports, Hiyama and co-workers established the ideal conditions for the synthesis of a series of unsymmetrical biaryl compounds. A Wang resin-supported aryl iodide (66) reacted with arylhalosilanes (67a and b) in the presence of catalytic Pd(PPh 3 ) 4 and TBAF to give, after detaching from support, the desired products (68) in high yields in most of the cases (Scheme 17). As was corroborated in homogeneousphase synthesis, aryl(dichloro)-(67a) and aryl(difluoro)silanes (67b) were the best organosilicon substrates in order to increase activation of the silane.…”

Metathesis Reactions in Solid‐Phase Organic Synthesis

“…Analysis of a sample of the library showed that the final products were typically obtained in over 70% purity [86]. Schreiber et al further elaborated the potential of this reaction sequence in the context of diversity-oriented synthesis by using boronic esters in the ene-yne annulations, thus providing an extra handle to divergent reaction pathways [87,88]. In this case, it was observed that the efficacy of the reaction in solution could not be directly transferred to solid phase using highly loaded macrobeads.…”