Nucleophilic reactions bifunctional catalysts

The azinones and their reaction characteristics are discussed in some detail in Section II, E. Because of their dual electrophilic-nucleophilic nature, the azinones may be bifunctional catalysts in their own formation (cf. discussion of autocatalysis below) or act as catalysts for the desired reaction from which they arise as byproducts. The uniquely effective catalysis of nucleophilic substitution of azines has been noted for 2-pyridone. 

A bifunctional autocatalytic effect of azinones in general is possible in certain nucleophilic reactions such as amination. Zollinger has found that 2-pyridone is the best catalyst for anilino-dechlorination of various chloroazines. It seems likely that examples of autocatalysis will be found when the substrate contains an azinone moiety. The azinone hy-products of displacement reactions may also function in this way as catalysts for the main reaction. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

Chen and co-workers utilized the chiral bifunctional catalysts to directly access vinylogous carbon-carbon bonds via the asymmetric Michael addition of a,a-dicy-ano-olefms to nitro-olefms [102]. The scope of the reaction was explored with a variety of substituted a,a-dicyano-olefins and P-substituted nitro-olefms (Scheme 50). The authors propose the catalysf s tertiary amine functionality depro-tonates the cyano-olefm, activating the nucleophile to add to the -face of the pre-coordinated nitro-olefm. 

In contrast to monofunctional (thio)urea organocatalysts, bifunctional catalyst structures enable simultaneous coordination, activation, and suitable relative orientation of both reaction components (the electrophile and the nucleophile) resulting in high... 

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

Considerable effort has been devoted to the development of enantiocatalytic MBH reactions, either with purely organic catalysts, or with metal complexes. Paradoxically, metal complex-mediated reactions were usually found to be more efficient in terms of enantioselectivity, reaction rates and scope of the substrates, than their organocatalytic counterparts [36, 56]. However, this picture is actually changing, and during the past few years the considerable advances made in organocatalytic MBH reactions have allowed the use of viable alternatives to the metal complex-mediated reactions. Today, most of the organocatalysts developed are bifunctional catalysts in which the chiral N- and P-based Lewis base is tethered with a Bronsted acid, such as (thio)urea and phenol derivatives. Alternatively, these acid co-catalysts can be used as additives with the nucleophile base. 

Although dimeric Sharpless ligands as catalysts showed impressive results in related organocatalytic transformations, they provided only limited success in asymmetric MBH reactions (Scheme 5.12) [70]. These compounds are bifunctional catalysts in the presence of acid additives one of the two amine function of the dimers forms a salt and serves as an effective Bronsted acid, while another tertiary amine of the catalyst acts as a nucleophile. Whereas salts derived from (DHQD)2PYR, or (DHQD)2PHAL afforded trace amounts of products in the addition of methyl acrylate 8a and electron-deficient aromatic aldehydes such as 27, (DHQD)2AQN, 56, mediated the same transformation in ee up to 77%, albeit in low yield. It should be noted that, without acid, the reaction afforded the opposite enantiomer in a slow conversion. 

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Generally, the use of other heterocycles besides quinoline would be considered modifications of the original Reissert protocol. This reaction has been extended to convert an acyl chloride into an aldehyde through a one-pot process by adding the acyl chloride to a solution of quinoline and hydrocyanic acid, and subsequent steam distillation of the entire mixture with sulfuric acid. In addition, the formation of the Reissert compound has been modified to occur enantioselectively using TMSCN as the nucleophilic species in the presence of a Lewis acid-Lewis base bifunctional catalyst. Moreover, tri-n-butyltin cyanide and acetone cyanohydrin are also used for the preparation of the Reissert compounds. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

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