Directed metalation synthetic applications

The reduction of organic halides is of practical importance for the treatment of effluents containing toxic organic halides and also for valuable synthetic applications. Direct electroreduction of alkyl and aryl halides is a kinetically slow process that requires high overpotentials. Their electrochemical activation is best achieved by use of electrochemically generated low-valent transition metal catalysts. Electrocatalytic coupling reactions of organic halides were reviewed in 1997.202... 

However, because of the mostly very slow electron transfer rate between the redox active protein and the anode, mediators have to be introduced to shuttle the electrons between the enzyme and the electrode effectively (indirect electrochemical procedure). As published in many papers, the direct electron transfer between the protein and an electrode can be accelerated by the application of promoters which are adsorbed at the electrode surface [27], However, this type of electrode modification, which is quite useful for analytical studies of the enzymes or for sensor applications is in most cases not stable and effective enough for long-term synthetic application. Therefore, soluble redox mediators such as ferrocene derivatives, quinoid compounds or other transition metal complexes are more appropriate for this purpose. 

Oxazoline-directed aromatic substitution and addition reactions provide synthetic chemists with powerful tools for the construction of complex aromatic compounds. Since the last authoritative review by Meyers, these technologies have matured and found widespread applications in organic synthesis. While there has been somewhat limited methodological research in this area in the intervening years, one particularly exciting new development is the diastereoselective ortho-metalations directed by chiral oxazolines. Sections 8.3.9.1-8.3.9.3 will discuss these new developments as well as new synthetic applications of these reactions. 

These direct metallation-alkylation reactions of sulfolene and dihydrothiepin dioxide are incentives for future new synthetic applications of the associated cheletropic processes. 

Donor adducts of aluminum and gallium trihydride were the subject of considerable interest in the late 1960s and early 1970s.1 Thin-film deposition and microelectronic device fabrication has been the driving force for the recent resurgence of synthetic and theoretical interest in these adducts of alane and gallane.24 This is directly attributable to their utility as low-temperature, relatively stable precursors for both conventional and laser-assisted CVD,59 and has resulted in the commercial availability of at least one adduct of alane. The absence of direct metal-carbon bonds in adducts of metal hydrides can minimize the formation of deleterious carbonaceous material during applications of CVD techniques, in contrast to some metal alkyl species.10, 11... 

There are a number of useful synthetic applications of these reactions of chelated amino acid esters (Fig. 3-12). For example, if the attacking nucleophile is not a simple amine, but is another amino acid ester or an O-protected amino acid, then peptide or polypeptide esters are formed in excellent yields. This may be developed into a general methodology for the metal-directed assembly (and, in the reverse reaction, the hydrolysis) of polypeptides. 

The increasing application of direct metallation methods and the importance of primary amines as synthetic intermediates have created a need for new aminating reagents. In particular, reagents that could directly transfer an N-protected group rather than a free amino group. In this context several N.O-diprotected hydroxyl-amines have been recently reported (Scheme 2) terr-butyl and allyl iV-[(arylsul-fonyl)oxy]carbamate 6 [5] and the Af,0-bis(trimethylsilyl)hydroxylamine 7 [6]. 

Enantiopure 7 and 8 are of major importance because the sulfoxide moiety can act as an effective anchor group in a directed orf/jo-metalation. Thus, a variety of diastereomerically pure compounds has been synthesized and found synthetic application [17,18,19]. 

One of the most useful synthetic applications of the directed metalation reactions is in preparing heterocyclic systems. Of the available directing groups, those involving N-chelated intermediates have been by far the most useful. In several instances the route provided by ortho lithiation constitutes the only available method for preparing certain heterocycles. In other cases such syntheses, although not the only routes available, represent a considerable improvement over more conventional methods, especially considering the number of steps in the overall synthesis and yields. Furthermore many of the heterocyclic compounds produced via directed metalation procedures are of extreme interest in that they are natural products or derivatives thereof. 

The reaction of a metal-carbene complex with an olefin may lead to either cyclopropane or metathesis products, depending on the metal center and its ancillary ligands. In the case of olefin metathesis, the reaction may occur in variations that have enormous numbers of synthetic applications. Although these products are diverse in structure, they are all related by the same basic metal-carbene-mediated mechanism of formation. Because we provide only an overview of applications in this section and do not specify the particular catalyst used in each case, we direct the reader to the extensive reviews that are available for more information [32]. 

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