Ruthenium carbene initiator Grubb

With the development of an analogous ruthenium benzylidene catalyst 17 by Grubbs and co-workers in 1995, a ruthenium carbene catalyst suitable for the cross-metathesis reaction was in place [34]. Benzylidene 17 exhibited the same impressive tolerance of air and moisture, and the same stability towards functional groups as its predecessor 4, but benefited from easier preparation [35,36] and much improved initiation rates. 

Ruthenium Carbene-Based Olefin Metathesis Initiators Catalyst Decomposition and Longevity M. Ulman, R.H. Grubbs,/. Org.Chem. 1999, 64, 7202— 7207. 

The short total synthesis of (+)-differolide based on a tandem enyne metathesis / [4+2] cycloaddition was accomplished by T.R. Hoye et al." The enyne metathesis was carried out on ally propynoate using Grubbs s first-generation metathesis catalyst. The catalyst was added to the substrate slowly to maintain high substrate and low ruthenium carbene concentrations. The initially formed 2-vinylbutenolide readily dimerized via a Diels-Alder cycloaddition in which the vinyl group participated as the dienophile to afford the natural product. 

A series of so-called Grubbs ruthenium—carbene complexes (Ru-12) can mediate living radical polymerization of MMA and styrene to afford controlled polymers with narrow MWDs (MJMn 1.2).63 66 The polymerization apparently proceeds via a radical mechanism, as suggested by the inhibition with galvinoxyl. For example, a novel ruthenium—carbene complex (Ru-13) carries a bromoisobutyrate group and can thus not only initiate but also catalyze living radical polymerization of MMA without an initiator.67... 

With the work by Grubbs et al. [27] and Herrmann et al. [28], the use of ruthenium carbene complexes as homogeneous catalysts for the ROMP (Ring-Opening Metathesis Polymerization) of olefins was estabhshed (see Section 2.4.4.3). The development of catalysts that can catalyze hving polymerization in water was an important goal to achieve, especially for applications in biomedicine. In this context, two water-soluble ruthenium carbene complexes (3 and 4) have been reported that act as initiators for the living polymerization of water-soluble monomers in a quick and quantitative manner [29]. 

Because the key to control of molecular weight distribution depends on the relative rates for initiation and propagation, studies to control these relative rates have been conducted. Studies with the Grubbs-type ruthenium carbene complexes have shown that the ruthenium benzylidene complexes undergo faster initiation than vinyl alkylidene... 

The Grubbs ruthenium-carbene complexes (2 and 3) exhibit high reactivity (albeit lower than the best molybdenum- and tungsten-based catalysts) in a variety of metathesis processes while showing a remarkable tolerance towards many different organic functionalities. These initiators are stable for weeks and reactions can be carried out in the presence of air and humidity or even in water. 

The Grubbs pyridine solvates are the fastest initiators of alkene metathesis and are valuable as synthetic intermediates to prepare other ruthenium carbene complexes. In particular, the 18-electron pyridine solvates 4a,b are very fast initiators that were developed to catalyze difficult alkene metatheses (e.g., the cross metathesis of acrylonitrile) [6]. The rates of initiation for several complexes are provided in Table 9.9. The pyridine solvate 4a has been found to initiate about 105 times faster than the parent Grubbs complex 2 and at least 100 times faster than the second-generation triphenylphosphine variant 26. When compared with the Hoveyda-Blechert complex 3a, 4a initiated about 100 times faster (c entry 3 vs. entry 5). The bromopyridine solvate 4b exceeded all of these in its initiation rate it was at least 20 times more reactive than 4a. 

Ulman, M., Grubbs, R.H., Ruthenium carbene-based olefin metathesis initiators catalyst decomposition and longevity, J. Org. Chem. 1999, 64 7202-7207. 

The basics and the synthetic potential of olefin metathesis has been recently presented in a comprehensive handbook and several reviews [58]. Thus, this chapter will be restricted to demonstrate the scope and flexibility of this type of reaction in the total synthesis of a complex natural product skeleton such as epothilone. The first total syntheses of these antitumor-active 16-membered macrolactones were based on a ringclosing metathesis (RCM) strategy (Scheme 11.36) [73]. Grubbs catalyst 143 has been used for the construction of the endocydic 1,2-disubstituted C12-C13 double bond in epothilone C 148 that, after epoxidation, affords epothilone A 150 [74]. In this approach, ruthenium carbene 143 is more efiident than Schrock molybdenum catalyst 142b [75a[. However, the RCM-route to epothilone D 149, the desoxy precursor of epothilone B 151 bearing a trisubstituted C=C bond, requires the molybdenum carbene catalyst 142b attempts to initiate ring-closure with 143 failed [75]. 

Despite the numerous reports concerning NHC-Ru olefin metathesis initiators, a complex incorporating a carbene that has only one exocyclic substituent adjacent to the carbenic centre was not reported until 2008. Studies by Grubbs and co-workers led to the development of ruthenium-based catalysts bearing such carbene ligands, in this case incorporating thiazole-2-ylidenes [63] (Fig. 3.19). 

By contrast, much of the work performed using ruthenium-based catalysts has employed well-defined complexes. These have mostly been studied in the ATRP of MMA, and include complexes (158)-(165).400-405 Recent studies with (158) have shown the importance of amine additives which afford faster, more controlled polymerization.406 A fast polymerization has also been reported with a dimethylaminoindenyl analog of (161).407 The Grubbs-type metathesis initiator (165) polymerizes MMA without the need for an organic initiator, and may therefore be used to prepare block copolymers of MMA and 1,5-cyclooctadiene.405 Hydrogenation of this product yields PE-b-PMMA. N-heterocyclic carbene analogs of (164) have also been used to catalyze the free radical polymerization of both MMA and styrene.408... 

Initial reports of cross-metathesis reactions using well-defined catalysts were limited to simple isolated examples the metathesis of ethyl or methyl oleate with dec-5-ene catalysed by tungsten alkylidenes [13,14] and the cross-metathesis of unsaturated ethers catalysed by a chromium carbene complex [15]. With the discovery of the well-defined molybdenum and ruthenium alkylidene catalysts 3 and 4,by Schrock [16] and Grubbs [17],respectively, the development of alkene metathesis as a tool for organic synthesis began in earnest. 

Ulman, M., Grubbs, R. H. Relative Reaction Rates of Olefin Substrates with Ruthenium(ll) Carbene Metathesis Initiators. Organometallics 1998, 17, 2484-2489. 

Better control of the reaction is achieved by using stable, isolable metal-carbene complexes, such as the Schrock initiators based on molybdenum and ffingsten (LXIV, Mt = W, Mo) and the Grubbs initiators based on ruthenium (LXV). The Schrock initiators... 

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