Challenging Metathesis Catalysts with Nucleophiles and Brønsted Base: Examining the Stability of State-of-the-Art Ruthenium Carbene Catalysts to Attack by Amines

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.

在包括制药工业在内的核心应用场景中推动烯烃复分解反应（olefin metathesis）规模化应用的关键，在于开发兼具高活性与抗分解性能的催化剂。胺类物质对钌基复分解催化剂具有极强的干扰破坏作用。本研究考察了1,8-二氮杂双环[5.4.0]十一碳-7-烯（1,8-diazabicyclo[5.4.0]undec-7-ene，简称DBU）、吗啉（morpholine）、正丁胺（n-butylamine）与三乙胺（triethylamine）四类胺类，对当前主流钌基复分解催化剂的影响，此类催化剂涵盖环烷基氨基卡宾（cyclic alkyl amino carbene，简称CAAC）与氮杂环卡宾（N-heterocyclic carbene，简称NHC）两类配合物。
据此，本研究对比了硝基-格雷拉催化剂（nitro-Grela catalyst）RuCl₂(H₂IMes)(=CHAr)（代号nG；其中Ar = C₆H₄-2-OiPr-5-NO₂）与其环烷基氨基卡宾类衍生物nGC1、nGC2，以及霍维达类催化剂（Hoveyda-class catalyst）RuCl₂(C₂)(=CHAr′) HC2（其中Ar′ = C₆H₄-2-OiPr）的胺耐受性。在配体C1中，卡宾碳两侧分别连接N-2,6-二乙基苯基（N-2,6-Et₂C₆H₃）与二苯甲基季碳（CMePh）；而在C2中，卡宾碳两侧则为N-2-异丙基-6-甲基苯基（N-2-iPr-6-MeC₆H₃）与二甲基季碳（CMe₂）。
本研究在9 ppm钌负载量、室温与70℃条件下，评估了每摩尔钌对应1摩尔胺时，对二烯丙基丙二酸二乙酯闭环复分解反应转化数（turnover number，简称TON）的影响。胺类的破坏作用遵循如下强弱趋势：三乙胺 ≈ 正丁胺 ≪ 1,8-二氮杂双环[5.4.0]十一碳-7-烯 ≈ 吗啉。实验表明，吗啉通过亲核攫取亚甲基配体的方式导致nGC1催化剂分解，而1,8-二氮杂双环[5.4.0]十一碳-7-烯则通过从金属环丁烷中间体中攫取质子引发催化剂降解。
在70℃条件下催化剂分解被显著抑制：即使在吗啉或1,8-二氮杂双环[5.4.0]十一碳-7-烯存在时，nGC1的转化数仍可达约60000，而无碱添加时其转化数约为80000。令人意外的是，在高温条件下，H₂IMes类催化剂nG的催化性能可达nGC1的70%~90%，且其被布朗斯特碱（Brønsted base）诱导分解的速率与nGC1相近。密度泛函理论（density functional theory，简称DFT）分析表明，这种性能相似性源于H₂IMes与C1两类配体提供的净电子效应相当。搭载体积更小的C2配体的催化剂对胺类的耐受性相对更强，这是因为其更易发生快速的双分子优先分解路径。