Reactions heterofunctionalization

The fourth chapter gives a comprehensive review about catalyzed hydroamina-tions of carbon carbon multiple bond systems from the beginning of this century to the state-of-the-art today. As was mentioned above, the direct - and whenever possible stereoselective - addition of amines to unsaturated hydrocarbons is one of the shortest routes to produce (chiral) amines. Provided that a catalyst of sufficient activity and stabihty can be found, this heterofunctionalization reaction could compete with classical substitution chemistry and is of high industrial interest. As the authors J. J. Bmnet and D. Neibecker show in their contribution, almost any transition metal salt has been subjected to this reaction and numerous reaction conditions were tested. However, although considerable progress has been made and enantios-electivites of 95% could be reached, all catalytic systems known to date suffer from low activity (TOP < 500 h ) or/and low stability. The most effective systems are represented by some iridium phosphine or cyclopentadienyl samarium complexes. 

For some of the reactions described in this book, rather precise and detailed ideas about the reaction mechanism exist. However, for many catalytic reactions, the mechanistic understanding is very poor and further experimental studies are certainly needed. Calculations proved to be a highly valuable tool to gain a more precise picture of the reaction pathways. However, mostly only model systems can be studied due to the complexity of the problem. Anyway, it is the firm believe of the authors that for any reaction with an activation barrier a suitable catalyst can be found. This book shall give an insight into what has been achieved in this area concerning the synthesis of heterofunctionalized organic molecules. It is the hope of all contributors that future retro-synthetic schemes will include the catalytic approaches outlined in this book. 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

In related work, Sasai developed several bifunctional BINOL-derived catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction [111]. In early studies, careful optimization of the catalyst structure regarding the location of the Lewis base unit revealed 41 as an optimal catalyst for the aza-MBH reaction between acyclic a,P-unsaturated ketones and N-tosyl imines. Systematic protection or modification of each basic and acidic moiety of 41 revealed that all four heterofunctionalities were necessary to maintain both chemical and optical yields. As seen in Scheme 5.58, MO calculations suggest that one hydroxyl groups forms a... 

The presence of two substituents (generally both at the /3-carbon) still allows the reaction to occur in good yields [25,26], and the same is true when three substituents are present. Thus Verlhac et al. described the alkylation of stannylated silyl enol ethers and, after workup, obtained aryl ketones in moderate to good yields (Scheme 4-4) [27], Booth et al. [28] (Scheme 4-5) and Casson and Kocienski [29] reported couplings of heterofunctionalized vinyltins, Takeda et al. [30] prepared a series of highly substituted ajS-unsaturated ketones (Scheme 4-6) and Shi et al. [31] a number of /3-fluoro-a-keto acid derivatives. 

OrThiocyanato ketones. Oxidation of lead(II) thiocyanate in situ and reaction with silyl enol ethers accomplishes the heterofunctionalization of ketones. 

Scheme 1 Types of heterofunctionalization reactions of (shown here, but not restricted to ) terminal aUcenes and alkynes with oxygen nucleophiles...

Mechanistic hypotheses play an important role in developing new catalytic and selective heterofunctionalizations of alkenes. Two basic reaction cycles for metal-catalyzed hydroalkoxylation (and hydration, for R = H) of alkenes can be postulated (Scheme 2). One pathway leads to Markovnikov products via activation of the nucleophile, oxy-metallation, and protonolysis (hydro-de-metallation) (Scheme 2a). Alternatively to the inner sphere syn-oxymetallation depicted in Scheme 2a, external anti-attack of the nucleophUe to coordinated olefin is plausible. The oxidation state of the metal remains constant in this cycle. The alternative hydrometallation pathway (Scheme 2b) proceeds via oxidative addition of the H-OR bond, hydrometallation of the olefin, and reductive elimination to the anti-Markovnikov addition product [3,4]. 

The organocatalytic asymmetric conjugate addition of heteroatom nucleophiles to different electrophilic olefins has become a very popular reaction during the last few years. Different nitrogen, oxygen, sulfur, and selenium nucleophilic species have been successfully used leading to enantiomerically emiched heterofunctionalized derivatives. 

Conjugate additions of enamines to ot,p-unsaturated carbonyl or nitro compounds belong to the most commonly applied and useful organocatalytic C-C bondforming reactions (JS5,143-150). As already mentioned above, enamine-catalyzed conjugate additions are often used in combination with a-heterofunctionalizations. These combined examples will be described in more detail in Sect. 2.6. 

Conjugate additions Aldol and Mannich Friedel-Crafts Pericyclic reactions a-Heterofunctionalization Epoxidations... 

The methodology known as direct a-heterofunctionalization of carbonyl compounds was comprehensively reviewed in 2006 [1] and therefore only the most recent developments [2] in this research area since then are considered in this section. These will be presented by the reaction that led to the formation of the new carbon-heteroatom bond, excluding of those in which the hybridization of the previously functionalized carbonyl compound is modified. 

In addition, this reaction is also applicable for combinatorial chemistry. Thus, the heterofunctionalization of haloarenes on a solid support is a versatile method to create small-molecule libraries of high diversity. Starting with simple resins, aryl amines can be prepared in good to excellent yield by amination of polymer-bound aryl halides employing either the Hartwig or the Buchwald protocol (BINAP or P(o-Tol)j, /BuONa for a review, see refPrimary and secondary alkylamines and anilines can be employed in the case of cyclic amines, BINAP was found to be the optimal ligand for the arylation. ... 

Carboamination reactions of dienes lead to the efficient construction of heterocyclic ring systems. However, in all cases, nonstereoselective products were obtained. These reactions are also catalyzed by Pd complexes following a typical carboamination reaction mechanism. Initially, these reactions were called metal-catalyzed heteroannula-tions of diene. After the discovery of the carboamination reaction, these types of heterofunctionalization reactions are called 1,2-carboamination reactions. ... 

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