The Grubbs Catalyst

Americans Robert H. Grubbs and Richard R. Schrock and Frenchman Yves Chauvin shared the 2005 Nobel Prize in Chemistry for this reaction a synthetic and mechanistic tour de force. 

The Grubbs catalyst is an organoruthe-nium complex. The n bond between carbon and ruthenium is the center at which the catalytic reaction occurs. 

The above reactant contains two terminal alkenyl groups. They can assume a conformation that brings them together in a Grubbs metathesis reaction. One of the products is a seven-membered ring the other is ethene. 

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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. 

Figure 5.2 The use of hollow PDMS thimbles to achieve site separation ofGrubbs catalyst and an osmium dihydroxylation catalyst [34], The solution of the Grubbs catalyst was placed on the interior of the PDMS thimble in which a metathesis reaction was then performed. After...

Moreover, in this example, the solvent systems used are also incompatible. The Grubbs catalyst is used in a relatively dry, nonpolar solvent to dissolve the substrates, whereas the AD-mix is placed in various alcohol-water mixtures. 

Thus, by using a mixture of the Grubbs catalyst 6/3-13 and Pd(OAc)2/PPh3, 6/3-84a was transformed into 6/3-85a in 65% yield. With the polystyrene-bound palladium catalyst 71 % yield was obtained in contrast, the use of a biphasic system... 

Although the metathesis of ene-ynes is a valuable method for the preparation of 1,3-butadienes, and may be used for Diels-Alder reactions, a problem arises from the need to employ either a high temperature or a Lewis add to accelerate the cycloaddition, which is usually not feasible with the Grubbs catalyst Therefore, the combination of metathesis and cycloaddition is usually performed in sequential fashion (as just shown, and highlighted earlier) [264]. However, Laschat and coworkers [265] have shown the Lewis acid BC13 to be compatible with the Grubbs I catalyst (6/3-13). Reaction of 6/3-92 and ethyl acrylate using a mixture of 2.5 equiv. of the Lewis acid and 10 mol% of 6/3-13 led to 6/3-93 in 60% yield (Scheme 6/3.27). 

Recently Cavaleiro et al. described an easy synthetic approach to glycoporphyrins from zinc(n) protoporphyrin-IX dimethyl ester 4 and O-allyl carbohydrate acetonides 5A-E (D-ribose (A), D-galactose (B), D-glucose (C), and two isomeric derivatives (D) and (E) of D-fructose) by cross-metathesis (Scheme 2).12 Two equivalents of each carbohydrate and the Grubbs catalyst were used, giving the carbohydrate derivatives 6 in a range of 74% to 93% yields. 

These reactions involve metallate rearrangements , migratory insertion and transition metal-catalysed vinylic substitution reactions. They also perform well in applications in natural product synthesis . Many useful synthetic possibilities arise from application of ring-closing olefin metathesis (RCM) to unsaturated homoaldol products and their derivatives by means of the Grubbs catalyst 3942 4-286 Equation 105 presents some examples. ... 

Scheme 8.7 Synthesis of allenylidene and indenylidene complexes with the Grubbs catalyst structure.

Presumably, the complex IX is expected to generate the same intermediate RuCl2(=CH2)(PCy3)2 as the Grubbs catalysts after the first cycle of a terminal diene RCM reaction. 

Other closely related ruthenium-allenylidene were made and evaluated in alkene metathesis [32]. Werner et al. [49] also produced allenylidene complexes of analogous structure to that of the Grubbs catalyst, but containing hemilabile phosphine such as complex X (Scheme 8.9). However, the Ru—O bond may be too stable to initiate the rearrangement into indenylidene, the coordination of alkene and to become a catalyst. 

Figure 4 Routes to the Grubbs catalyst 22b and related alkylidene species. Routes based on ring opening (yellow dot), alkylidene transfer (green), alkyne reagents (red), chloroalkanes (blue) are shown in the figure.

It is also not possible to even partially review all the many applications in synthesis that have already been demonstrated for the Grubbs reaction. I have chosen to focus on three papers. For those desiring to deploy the Grubbs catalyst only from time to time, storage and handling become serious issues. We have found (J. Org. Chem. 68 6047,2003) that the commercial catalyst dissolved in paraffin wax can be stored exposed to the laboratory atmosphere for many months and still retain full activity. The example above of 1 + 2 - 3 is taken from that paper. 

Because of the functional group tolerance of the Grubbs catalyst 3, it will operate even with complex substrates. In the course of a total synthesis of (-)-cylisine, Giordano Lesma and Alessandra Silvani of the University of Milan reported (Organic Lett. 6 493,2004) that 5, with a free N-H, could be cyclized efficiently to 6. 

Kevin J. Quinn of the College of the Holy Cross chose (Organic Lett. 2005, 7, 1243) a complementary approach in his synthesis of rollicosin. The symmetrical diol 4 is also available from carbohydrate precursors. Monosilylation followed by esterification with acryloyl chloride gave 5. Exposure of 5 to the Grubbs catalyst in the presence of 6 led, by ring-closing metathesis and cross metathesis, to the y-lactonc 7. Note that 5-lactone formation did not compete ... 

The use of the Grubbs catalyst is largely restricted to terminal dienes. In these cases the by-product is ethylene. Since this is an equilibrium process, the ethylene diffuses out of solution, which helps drive the reaction to completion. Neverdieless the catalyst is highly tolerant of functional groups and generally gives good yields. 

The Schrock catalysts are more active and are useful in the conversion of sterically demanding substrates, while the Grubbs catalysts tolerate a wide variety of functional groups. 

Fig. 43 Tandem RCM/ATRC and tandem RCM/ATRC/ATRA reactions catalyzed by the Grubbs catalysts...

Intramolecular [2+2+2] cyclotrimerizations of diynes and triynes possessing heteroatom tethers furnish benzoheterocycles. The cyclization of triynes 88 using the Grubbs catalyst 76 proceeds via cascade metathesis as shown in Eq. (35) to yield a tricyclic product 89 [88]. This novel type of catalytic alkyne cyclotrimerization can be applied to the cycloaddition of 1,6-diynes with monoalkynes [89]. 

In line with our previous experiences, diene 56 readily cyclized to the desired 19-membered ring 57 on reaction with the ruthenium carbene 2 (5 mol%) in refluxing CH2C12. The fact that neither the free hydroxyl group nor any other functionality in the substrate interfere with RCM illustrates the excellent compatibility and selectivity of the Grubbs catalyst (7). Hydrogenation of the crude cycloalkene ( -mixture) thus obtained afforded the desired disaccharide 57 in 77% yield. The elaboration of this compound into tricolorin A 46 can be achieved according to literature procedures (25). 

Ring-closing metathesis of the readily accessible doubly unsaturated sulfonamide 64 proceeded in the presence of the Grubbs catalyst in 53% yield to produce azocine 65 (Scheme 23 <1999JA8126>). 

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