Grubbs’ second-generation catalyst

Olefin metathesis is one of the most important reaction in organic synthesis [44], Complexes of Ru are extremely useful for this transformation, especially so-called Grubbs catalysts. The introduction of NHCs in Ru metathesis catalysts a decade ago ( second generation Grubbs catalysts) resulted in enhanced activity and lifetime, hence overall improved catalytic performance [45, 46]. However, compared to the archetypal phosphine-based Ru metathesis catalyst 24 (Fig. 13.3), Ru-NHC complexes such as 25 display specific reactivity patterns and as a consequence, are prone to additional decomposition pathways as well as non NHC-specific pathways [47]. 

The most commonly used catalyst is the benzylidene complex of RuC12[P(c — C6Hn)3]2, F, which is called the Grubbs catalyst, but several other catalysts are also reactive. Catalyst H, which is known as the second-generation Grubbs catalyst, is used extensively. 

Other monomeric precursors similar to 6-hexynyl-decaborane such as 6-norbornenyl-decaborane (129) and 6-cyclooctenyl-decaborane (131) (Fig. 75) underwent ROMP in the presence of either first- or second-generation Grubbs catalysts to produce the corresponding poly(norbornenyl-decaborane) (130) (Fig. 75) and poly(cyclooctenyl-decaborane) (132) (Fig. 75) with Mn > 30 kDa and polydis-persities between 1.1 and 1.8.152 Electrostatic spinning and pyrolysis of poly (norbomenyl-decaborane) was discovered to produce nanoscale, free-standing porous boron-carbide/carbon, ceramic fiber matrices.153... 

Polyether-type structures such as 6/3-38 are frequently found in bioactive compounds (e. g., maitansine). Nicolaou and coworkers [239] have developed a new, efficient approach to these compounds, which is based on a domino ROM/RCM using the second-generation Grubbs catalyst 6/3-15. Thus, the cyclobutene derivative 6/3-37 could be transformed into 6/3-38 in 80% yield (Scheme 6/3.10). 

In one example of application of the RCM strategy, summarized in Scheme 107, the key intermediate 454 was obtained from 451 by sequential Wittig methylenation to 452, reductive iV-deprotection to 453, and introduction of an alkenyl chain onto the secondary amine. The RCM reaction of 454 to 455 proceeded in quantitative yield in the presence of the second-generation Grubbs catalyst <20040L965>. 

A synthesis of 5//-pyrrolo[l,2-r] imidazole 105 has been developed via a chemoselective addition/dehydration of acetaldehyde on diiodo imidazole 103 giving the vinylic imidazole 104. This compound, treated under the metathesis condition in the presence of the second-generation Grubbs catalyst, gave the final product 105 (Scheme 11) <2003TL1379>. 

Figure 16.19. The first and second generation Grubbs catalysts and an asymmetric catalyst...

NHC) ligand, which is generated from a second-generation Grubbs catalyst [Ru] and vinyloxytrimethylsilane and the actual active species for these nonmetathetic reactions, isomerization of a terminal olefin (Scheme 10.6) [15],... 

Scheme 8.4 Grafting of isocyanate-telchelic poly(l, 3-di(l -mesityl)-4- [(bicyclo[2.2.1 ]hept-5-en-2-ylcarbonyl)oxy]methyl -4,5-dihydro-l H-imidazol-3-ium tetrafluoroborate) on silica and generation of the immobilized second generation Grubbs catalyst.

This silver salt was used for the halogen exchange with a broad variety of second generation Grubbs catalysts, leading to the catalytic species shown in Scheme 8.9. In the benchmark reaction with DEDAM, TONs up to 830 were achieved [88]. 

The use of the second-generation Grubbs catalyst or the Grubbs-Hoveyda catalyst (cat. Gr. H.) (Scheme 37) enables the synthesis of benzo-fused lactams 148 (09TA1154), 149 (05JOC5519), and a-amino-a, -unsaturated lactam 150a (08TL5141). 

The most straightforward application of the Grubbs reaction is to effect homologation of a terminal vinyl group. One concern with the use of the second generation Grubbs catalyst 3 is the cost, about 100/mmol. In conjunction with a total synthesis of the macrolide RK-397, Frank McDonald of Emory reported (J. Am. Chem. Soc. 126 2495, 2004) that the conversion of 1 to 2 required 10 mol % of 3, but that it proceeded efficiently with just 2 mol % of the Hoveyda Ru catalyst 4 (J. Am. Chem. Soc. 122 8168,2002). The alkene so prepared was cleanly trans. An advantage of 4 is that it avoids the use of the expensive PCy,. 

A simple yet powerful application of the Grubbs reaction is specific homologation of a terminal vinyl group. When there is more than one alkene in the molecule, suitably disposed, one would worry about competing cyclizalion. In studies directed toward the cryptophycins, Mark Lautcns of the University of Toronto has reported (Organic Lett. 2004,6, 1883) that the second generation Grubbs catalyst 2 smoothly converts 1 to 3. The alternative cyclization product 4 is produced only in trace amounts. 

The cyanthin diterpenes show physiological activity ranging from cytotoxicity to nerve-growth factor stimulation. Andrew J. Phillips of the University of Colorado recently described (J. Am. Client. Soc. 2005,127,5334) a concise cnantioselective synthesis of cyanthiwigin U 3, based on the metathesis conversion of 1 to 2, using the second generation Grubbs catalyst. 

The two-directional tandem metathesis of 1 to 2 proceeded smoothly using 20 mol % of the second generation Grubbs catalyst (now commercially available only from Aldrich and from Materia) under an atmosphere of ethylene. The conversion of 2 to 3 took advantage of the differing reactivity of the two ketones. Addition of hydride to 2 from the less hindered face of the less hindered ketone delivered 4. 

Enyne metathesis can also be used with highly substituted substrates. Catherine Lievre of the Univcrsite de Picardie reports (J. Org. Chem. 2004,69, 3400) that enynes such as 11, readily prepared from carbohydrate precursors, are cyclized by the second generation Grubbs catalyst 2 to the enantiomerically-pure cyclic dienes, exemplified by 12. 

The second generation Grubbs catalysts are even more stable and more active than the original versions. Some of these are depicted Activity 2 < lb < 4 < 5 i 1 ... 

Facile, regioselective ring opening-cross-metathesis reactions between unsymmet-rical norbornene derivatives and electron-rich alkenes in the presence of the second-generation Grubbs catalyst have been reported to generate highly substituted furans and pyrroles.114... 

Thiochromen 4-yl enol phosphates have been obtained from 2 -fluoroacetophenone through initial reaction with prop-2-enethiol followed by conversion to the enol phosphate. Ring closing metathesis (RCM) using a second generation Grubbs catalyst delivered the. V-hctcrocycle. Oxidation at sulfur prior to RCM provided access to the thiochromen-4-yl 1,1-dioxide enol phosphate (Scheme 120) <2003TL4275>. 

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