Nucleophilic co-catalysts

Rovis and coworkers used a-halo aldehydes to generate the formal redox ester products in the presence of an N-Ph triazolium salt [77]. This methodology was later extended to the enantioselective formation of phenyl a-chloroesters 96 [78] and a-chloro-carboxylic acids [79] from a,a-dichloro-aldehydes 94 using chiral triazolium salt 95 (Scheme 18.16). Consistent with the simultaneous observations by Bode and coworkers, a nucleophilic co-catalyst was necessary for the formation of amides [80]. An a-chloroamide could be synthesized in good enantioselectivity (80% ee) by the use of chiral triazolium salt 95. 

MBH reactions 899 nucleophilic catalysis 515 nucleophilic co-catalysts 1269 nucleophilic reactions 730... 

Eventually, the use of a catalytic amount of chiral amide-thiourea anion-receptor 116 in conjunction of with achiral nucleophilic co-catalyst 120 allowed for the resolution of several l,2-diaryl-l,2-diaminoethanes (Scheme 41.54) with useful levels... 

In sharp contrast, Bartoli showed that the (salen) Co catalyst system could be applied to the kinetic resolution of terminal epoxides with unprotected tert-butyl carbamate as nucleophile with extraordinarily high selectivity factors (Scheme 7.40) [72]. Excellent yields and selectivities are also obtained with use of ethyl, Cbz,... 

Rovis and Vora sought to expand the utility in alpha redox reactions to include the formation of amides [116]. While aniline was previously demonstrated as an efficient nucleophile in this reaction (Scheme 29), attempts to develop the scope to include non-aryl amines as various primary and secondary amines resulted in low yields. The discovery of a co-catalyst was the key to effecting amide formation (Table 15). Various co-catalysts, including HOBt, HOAt, DMAP, imidazole, and pentafluorophenol, are efficient and result in high yields of a variety of amides including those involving primary and secondary amines with additional functionality. 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

As previously explored by Bode, other a-reducible substrates, such as a,P-epoxy aldehyde and aziridinylaldehyde, are competent partners for redox reactions. (Scheme 33) [109], Various amines are compatible nucleophiles in this methodology in which P-hydroxy amides are furnished in good yield and excellent diastereose-lectivity. A similar reaction manifold was discovered concurrently by Bode and co-workers using imidazole as co-catalyst [117],... 

The proposed mechanism for allyhc acetoxylation of cyclohexene is illustrated in Scheme 15. Pd -mediated activation of the allyhc C - H bond generates a Jt-allyl Pd intermediate. Coordination of BQ to the Pd center promotes nucleophilic attack by acetate on the coordinated allyl ligand, which yields cyclohexenyl acetate and a Pd -BQ complex. The latter species reacts with two equivalents of acetic acid to complete the cycle, forming Pd(OAc)2 and hydroquinone. The HQ product can be recycled to BQ if a suitable CO catalyst and/or stoichiometric oxidant are present in the reaction. This mechanism reveals that BQ is more than a reoxidant for the Pd catalyst. Mechanistic studies reveal that BQ is required to promote nucleophilic attack on the Jt-allyl fragment [25,204-206]. 

The proposed catalytic cycle starts from the nucleophilic addition of carbene 17 to aldehyde 18 (Scheme 14.4) to afford acyl azolium intermediate 19, which takes part in an acyl transfer event with co-catalyst HOAt to deliver the activated car-... 

Recently, Taillefer et al. reported an Fe/Cu cooperative catalysis in the assembly of N-aryl heterocycles by C—N bond formation [90]. Similarly, Wakharkar and coworkers described the N-arylation of various amines with aryl halides in the presence of Cu—Fe hydrotalcite [91]. Interestingly, Correa and Bolm developed a novel and promising ligand-assisted iron-catalyzed N-arylation of nitrogen nucleophiles without any Cu co-catalysts (Scheme 6.19) [92]. Differently substituted aryl iodides and bromides react with various amides and N-heterocycles. The new catalyst system consists of a mixture of inexpensive FeCl3 and N,N -dimethylethylenediamine (dmeda). Clearly, this research established a useful starting point for numerous future applications of iron-catalyzed arylation reactions. 

Aromatic carboxylic acids, a,/f-unsaturated carboxylic acids, their esters, amides, aldehydes and ketones, are prepared by the carbonylation of aryl halides and alkenyl halides. Pd, Rh, Fe, Ni and Co catalysts are used under different conditions. Among them, the Pd-catalysed carbonylations proceed conveniently under mild conditions in the presence of bases such as K2CO3 and Et3N. The extremely high toxicity of Ni(CO)4 almost prohibits the use of Ni catalysts in laboratories. The Pd-catalysed carbonylations are summarized in Scheme 3.9 [215], The reaction is explained by the oxidative addition of halides, and insertion of CO to form acylpalladium halides 440. Acids, esters, and amides are formed by the nucleophilic attack of water, alcohols and amines to 440. Transmetallation with hydrides and reductive elimination afford aldehydes 441. Ketones 442 are produced by transmetallation with alkylmetal reagents and reductive elimination. 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

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. 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

Boron trifluoride (BF3) is an excellent catalyst for cationic polymerization because it leaves no good nucleophile that might attack a carbocation intermediate and end the polymerization. Boron trifluoride is electron-deficient and a strong Lewis acid. It usually contains a trace of water that acts as a co-catalyst by adding to BF3 and then protonating the monomer. Protonation occurs at the less substituted end of... 

The available evidence indicates a nonconcerted mechanism which is depicted in Scheme 14. Oxidation of a Pd(0) species by the carbon-nitrogen bond of the allyle-nammonium ion gives cleavage to the 7r-allylpalladium complex and an enamine. Nucleophilic reaction by the enamine on the Pd salt then forms resultant imines after a loss of a proton. The role of co-catalyst CF3C02H is to form the N-allylenammonium ion, which reacts readily with the Pd(0) species. 

The suggestion of direct nucleophilic attack of the nitrogen on the carbonyl carbon to form the initiating zwitter ion is in contrast to the earlier tmd more reasonable suggestion that protic impurities act as co-catalyst in the following manner... 

The essential feature of the catalyst systems is that they are formed by the combination of a palladium(II) species with a ligand containing a 2-pyridylphosphine moiety and a proton source containing anions weakly coordinating to palladium [8]. These catalysts are very efficient for the conversion of propyne (for example) as the alkyne and methanol as the nucleophilic co-reagent. 

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