Carbene reactions industrial application

Carbene species can be stabilized by complexation to metals and transferred to olefinic substrates in catalytic reactions. Although the main industrial application of carbenes is in metathesis (Chapter 6), an important application in the area of fine chemicals is to asymmetric cyclopropanation. 

Much work is still in progress to improve the Ru-carbene complexes. Considerable attention has recently also been directed at efforts to immobilize a Ru-based metathesis catalyst on solid supports, which could make the metathesis reaction even more attractive for industrial applications. 

Addition reactions to olefins can be used both for the construction and for the functionalization of molecules. Accordingly, chiral catalysts have been developed for many different types of reactions, often with very high enantioselectiv-ity. Unfortunately, most either have a narrow synthetic scope or are not yet developed for immediate industrial application due to insufficient activities and/ or productivities. These reactions include hydrocarbonylation [Ilf], hydrosilyla-tion [12 i], hydroboration [12j], hydrocyanation [12 k], Michael addition [11 g, 121, 12 m], Diels-Alder reaction [11 h, 12n] and the insertion of carbenes in C-H bonds [Hi, 12p, 12q, 38], Cyclopropanation [Hi, 12p, 12q] and the isomerization of allylamines [12 s] are already used commercially for the manufacture of Cilastatin (one of the first industrial processes) [12 r], and citronellol and menthol (presently the second largest enantioselective process) [12t] respectively. 

It is clear that the construction of appropriately substituted monocyclic P-lactams has attracted great attention not only in the monobactam field, but also in the penem and carbapenem area of antibiotics. Since methods for the construction of the -lactam ring are now abundant, the main difficulties involved are primarily the stereocontrol and the instability of the final product. Although the carbene insertion reaction developed by the Merck group seems to be the most efficient route for the construction of the bicyclic ring system, the development of new procedures, specially for industrial applications, is desirable. It is beyond the scope of this article to provide a comprehensive account of all types of P-lactams appeared in the literature which, perhaps, in some cases could be used as carbapenem building blocks. On the other hand, it has been the purpose of this work to deal with those monocyclic P-lactams, which upon further elaboration, lead to PS-5 and PS-6 carbapenems and related compounds by established protocols. Less emphasis has been put on thienamycin because an excellent review on this subject has recently been published. I wish to apologise... 

Although olefin metathesis had soon after its discovery attracted considerable interest in industrial chemistry, polymer chemistry and, due to the fact that transition metal carbene species are involved, organometallic chemistry, the reaction was hardly used in organic synthesis for many years. This situation changed when the first structurally defined and stable carbene complexes with high activity in olefin metathesis reactions were described in the late 1980s and early 1990s. A selection of precatalysts discovered in this period and representative applications are summarized in Table 1. 

Among typical carbon-carbon bond (C-C) formation reactions with carbenes, the cyclopropanation reaction with olefins has been well studied including its application to industrial processes. The second typical reaction of carbenes is the insertion reaction into the carbon-hydrogen bond (C-H) which seems to be a direct and efficient C-C bond forming reaction. However, its use for synthetic purpose has often been limited due to low selectivity of the reactions.3... 

The preparation of different (NHC) - Pd°(dvds) complexes allowed the authors to make a systematic comparison of structure/activity for the telomerization reaction [228]. This study showed that electron-withdrawing substituents on the carbene backbone destabilizes the catalyst and therefore enhance its reactivity. These catalysts are applicable to primary and secondary alcohol as well as phenols and represent the first industrially viable catalyst system for palladium-catalyzed telomerization of butadiene with alcohol. 

The most versatile carbene precursors are a-diazocarbonyl compounds such as diazoacetic acid esters because they are readily prepared, easy to handle and much more stable than ordinary diazoalkanes [10,38]. Nevertheless, one should always be aware of the potential hazards of diazo compounds in general [39],but if the necessary precautions are taken, they can be safely handled even on an industrial scale [18]. The most frequently used reagent is commercially available ethyl diazoacetate. Besides a-diazocarbonyl reagents, diazomethane [40,41 ] and a y-diazoacrylate derivative [42] have been used in enantioselective Cu-cata-lyzed cyclopropanations but the scope of these reactions has not been studied systematically. It has been shown in certain cases that diazo compounds can be replaced by other carbene precursors such as iodonium ylides, sulfonium yUdes, or lithiated sulfones [8,43],but successful applications of these reagents in enantioselective Cu-catalyzed reactions have not been reported yet. 

A review gives an overview over the contribution of organometalllc catalysis to Industry, another In the series on transition metals In organic synthesis covers CO reactions, hydrogenations and oxidations. The role of zirconium catalysts In hydro- and carboalumination of alkenes and alkynes, cyclopropanatlons and diene oligomerisations has been dlscussed, and an account deals with the role of electrophilic metal carbenes In cyclopropanatlons and other synthetic applications. 

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