Abstract
Critical to advancing the uptake of olefin metathesis in leading contexts, including pharmaceutical manufacturing, is identification of highly active catalysts that resist decomposition. Amines constitute an aggressive challenge to ruthenium metathesis catalysts. Examined here is the impact of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), morpholine, n-butylamine, and triethylamine on Ru metathesis catalysts that represent the current state of the art, including cyclic alkyl amino carbene (CAAC) and N-heterocyclic carbene (NHC) complexes. Accordingly, the amine-tolerance of the nitro-Grela catalyst RuCl2(H2IMes)(=CHAr) (nG; Ar = C6H4-2-OiPr-5-NO2) is compared with that of its CAAC analogues nGC1 and nGC2, and the Hoveyda-class catalyst RuCl2(C2)(=CHAr′) HC2 (Ar′ = C6H4-2-OiPr). In C1, the carbene carbon is flanked by an N-2,6-Et2C6H3 group and a CMePh quaternary carbon; in C2, by an N-2-iPr-6-MeC6H3 group and a CMe2 quaternary carbon. The impact of 1 equiv amine per Ru on turnover numbers (TONs) in ring-closing metathesis of diethyl diallylmalonate was assessed at 9 ppm Ru, at RT and 70 °C. The deleterious impact of amines followed the trend NEt3 ∼ NH2nBu ≪ DBU ∼ morpholine. Morpholine is shown to decompose nGC1 by nucleophilic abstraction of the methylidene ligand; DBU, by proton abstraction from the metallacyclobutane. Decomposition was minimized at 70 °C, at which nGC1 enabled TONs of ca. 60 000 even in the presence of morpholine or DBU, vs ca. 80 000 in the absence of base. Unexpectedly, H2IMes catalyst nG delivered 70–90% of the performance of nGC1 at high temperatures, and underwent decomposition by Brønsted base at a similar rate. Density functional theory (DFT) analysis shows that this similarity is due to comparable net electron donation by the H2IMes and C1 ligands. Catalysts bearing the smaller C2 ligand were comparatively insensitive to amines, owing to rapid, preferential bimolecular decomposition.
Highlights
Olefin metathesis offers exceptionally versatile catalytic tools for the assembly of carbon−carbon bonds.[1]
Major Intrinsic Decomposition Pathways Established for Ru-H2IMes Metathesis Catalystsa aAn additional ring-expansion pathway has been established for olefins bearing an α-alkyl substituent.10a light of ambiguities concerning whether tertiary amines are innocuous.[18,22]
Catalysts surveyed are selected as representing the current state of the art: they include the cyclic alkyl amino carbene (CAAC) complexes nGC1, nGC2, and HC2, and the important, widely used Nheterocyclic carbene (NHC) analogue nitroGrela catalyst RuCl2(H2IMes)( CHAr) (nG)
Summary
Olefin metathesis offers exceptionally versatile catalytic tools for the assembly of carbon−carbon bonds.[1] Widely embraced in organic synthesis, metathesis methodologies have begun to emerge in pharmaceutical manufacturing, for the production of antiviral therapeutics.[2] Among the most important catalysts used in the latter context is the nitro-Grela complex nG (Chart 1),[3] which is stabilized by an Nheterocyclic carbene (NHC) ligand. Large-scale implementation, brings new demands for robustness, reliability, and mechanistic understanding (the latter encompassing both intended and unintended chemistries).4a From this perspective, olefin metathesis falls short of other catalytic methodologies, such as hydrogenation and cross-coupling, which are mainstays of pharmaceutical manufacturing.[4] Grubbs’ pioneering development of ruthenium metathesis catalysts,[5] with their dramatically improved tolerance for oxygen and water relative to their group 6 predecessors, was the development that put olefin metathesis into the hands of the practicing organic chemist. Like the majority of metathesis catalysts, the RuNHC catalysts readily degrade via β-elimination of the metallacyclobutane (MCB) ring from Ru-1 (Scheme 1a),[7] and bimolecular coupling of [Ru] CHR intermediates (Scheme 1b).[7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
