The Grubbs Reaction in Organic Synthesis

Alkene metathesis (e.g. 1 + 2 — 3) has been known at least since the I950 s. Until Robert Grubbs of Caltech developed stable and versatile Ru catalysts for this transformation, however, this reaction was little used. 

Professor Grubbs recently publi.shed (J. Am. Chem. Soc. 125 10103, 2003 J. Am. Chem. Soc. 125 11360, 2003) two detailed articles on activation and selectivity in this reaction. The first article addresses variations on catalyst design. The second paper defines several types of alkenes, and lays out rules that allow one to predict which pairs of alkenes will dimerize efficiently. While it is not possible to summarize all of their results in this limited space, some highlights include  

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. 

Steve Martin of UT Austin has reported (J. Org. Chem. 68 8867, 2003) a detailed study of the synthesis of bridged azabicydic structures via ring-closing alkene metathesis. Some examples of his work include the conversion of 12 to 13, efficiently forming six, seven and eight membered rings. He also demonstrated five-membered ring formation with the conversion of 14 to 15, which has the cocaine skeleton. 

A real concern when attempting the Grubbs reaction with a complex substrate is the stability of other alkenes. J. Alberto Marco of the University of Valencia, Spain has shown (J. Org. Chem. 68 5672, 2003) that 16 is converted to 17 without isomerization of the Z alkene. Less congested alkenes might not be so resistant. 

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The Grubbs Reaction in Organic Synthesis Part One of Three... 

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]. 

In Section 24.12, we introduced alkene (olefin) metathesis, i.e. metal-catalysed reactions in which C=C bonds are redistributed. The importance of alkene and alkyne metathesis was recognized by the award of the 2005 Nobel Prize in Chemistry to Yves Chauvin, Robert H. Grubbs and Richard R. Schrock for the development of the metathesis method in organic synthesis . Examples of alkene metathesis are shown in Figure 27.3. The Chauvin mechanism for metal-catalysed alkene metathesis involves a metal alkyli-dene species and a series of [2 + 2]-cycloadditions and cycloreversions (Figure 27.4). Scheme 27.6 shows the mechanism for alkyne metathesis which involves a high oxidation state metal alkylidyne complex, L M=CR. 

Olefin metathesis ( metathesis from the Greek change of position, transposition ) [1] is a key reaction in organic synthesis because it allows preparation of molecules that are crucial to promote advances in medicine, biology and materials science. The importance of this reaction was demonstrated by the award of the 2005 Nobel Prize in chemistry to Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock for elucidation of the reaction mechanisms and discovery of various highly efficient and selective catalysts related to metathesis [2]. 

Olefin Metathesis. Olefin metathesis is one of the most important and powerful reactions in organic synthesis. Many of the catalysts used for the reaction contain at least one tricyclohexylphosphine ligand, the so-called Grubbs type 1(1) and Grubbs... 

Recently, ruthenium-carbene complexes have been developed as stable and highly reactive catalysts by Grubbs and others. Nowadays, the carbene complexes have become a series of innovative reagents for carbon-carbon bond formation reactions in organic synthesis [7]. 

Olefin-metathesis is a useful tool for the formation of unsaturated C-C bonds in organic synthesis.186 The most widely used catalysts for olefin metathesis include alkoxyl imido molybdenum complex (Schrock catalyst)187 and benzylidene ruthenium complex (Grubbs catalyst).188 The former is air- and moisture-sensitive and has some other drawbacks such as intolerance to many functional groups and impurities the latter has increased tolerance to water and many reactions have been used in aqueous solution without any loss of catalytic efficiency. 

Another broad class of compounds are the bridged carbene complexes. These compounds contain two identical or two different metal centers with the carbene centers bonded to both of the metal atoms in a bridging relationship. However, these binuclear complexes generally do not show classical carbene reactivity and will therefore not be discussed further, except to mention briefly the special case of the titanium-aluminum complex (3) developed by Tebbe and Grubbs and their coworkers.101 This, and related complexes, has proven to be particularly useful in organic synthesis, although its principal importance is in reactions other than cyclopropanations. 

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