Reductive alkylation mechanism

Fig. 24 Reductive alkylation mechanism of interaction of kinamycin C with DNA as originally proposed [67], Nucleophilic (DNA) attack can occur on the Michael acceptor 32 through pathway a or b. The same mechanism should be applicable with the revised diazo structures...

Abstract Significant advances have been made in the study of catalytic reductive coupling of alkenes and alkynes over the past 10 years. This work will discuss the progress made in early transition metal and lanthanide series catalytic processes using alkyl metals or silanes as the stoichiometric reductants and the progress made in the use of late transition metals for the same reactions using silanes, stannanes and borohydrides as the reductant. The mechanisms for the reactions are discussed along with stereoselective variants of the reactions. 

Saturated Ketones and Ketol Acetates. Reductive Alkylation / 27 Mechanism of reduction / 27 Stereochemistry of reduction / 34 Side reactions in reductions / 37... 

Considering the reductive elimination mechanism that takes place within the coordination sphere of the palladium, one might expect the nucleophilic addition of unstabilized nucleophiles to be more enantioselective than that of stabilized nucleophiles because the nucleophile can directly interact with the chiral ligand. However, there are only a few examples in the literature that give high enantioselectivity. In the case of the alkylation with unstabilized carbanions, nickel catalysts have been more frequently used (see next section). 

The reductive alkylation of methyl pyruvate with and the t-butyl esters of amino acids using Pd/C catalyst leads to the formation of iminodicarboxylic acids such as 67 in selectivities of 29-75% d.e. depending on the amino acid and solvent used (hexane gave the best results). Hydrolysis of the t-butyl ester to the acid 68 followed by hypochlorite-promoted decarboxylation and imine hydrolysis leads to the formation of ( -alanine 69 in correspondingly high e.e.s278,281. The likely decarboxylation mechanism as far as the imine stage is shown in Scheme 65. 

The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2PhSi)2Zn and Cul has been shown to occur by an oxidative addition - reduction elimination mechanism rather than an SN2 mechanism.16... 

Our goal in this presentation is to evaluate the mechanism of reductive alkylation. The approach is more complicated than previously considered, with disruption of the coal structure occurring through many paths. Before going into the specific details of these complications, we brieflly outline the procedure of reductive alkylation. 

This question shows the purpose of making the furan in Problem 12 and revises material from Chapters 33 and 36. The above furan was used in the synthesis of the natural product hnderalactone by first alkylation and reduction. Give mechanisms for the reactions and comment on the stereochemistry of these... 

The essential parameters which determine the electrochemical process are the electron affinity of the neutral compound, which correlates with the energy of the LUMO, the energies of interaction with the solvent and counterions, the electron-electron repulsion energies and stereochemical factors. A precondition for an electrochemical study is that the chemical reaction which may occur, e.g. with the solvent, is much slower than the electron transfer process, and that the electrochemical reaction is reversible 66). Correlation of half-wave potentials with the energies of Huckel LUMO s has been one of the early successes of the Huckel model 8>2°.67-88>. The power of the electrochemical method in the study of polycyclic anions has been demonstrated recently 69a). Studies on reactions occurring during electrochemical reductions report reductive alkylations of polycyclic systems and their mechanism 70,69b). 

We have shown that heterogeneous catalysis can be applied to reductive alkylation with success in reactions such as ether synthesis or N-alkylation of amides and anilines. Concerning the mechanism, several pathways are in competition depending on the structure of the substrate and of the alkylating agent. The important point is that both the product of addition (the hemiacetal or hemiaminal) and the product of elimination (imine, enamine or enolether)... 

Cyclopentyl radicals substituted in the /1-position relative to the radical center are formed during the solvomercuration/reductive alkylation reaction of cyclopentene34. The organomer-curial produced in the first solvomercuration step is reduced by sodium borohydride and yields free cyclopentyl radicals in a radical chain mechanism. Addition of alkenes can then occur tram or cis to the / -alkoxy substituent introduced during the solvomercuration step. The adduct radical is finally trapped by hydrogen transfer from mercury hydrides to yield the tram- and ris-addition products, The transicis ratio depends markedly on the alkene employed and it appears that the addition of less reactive alkenes occurs with higher trans selectivity. In reactions of highly substituted alkenes, this reactivity control is compensated for by steric effects. Therefore, only the fnms-addition product is observed in reactions of tetraethyl ethenetetracarboxylate. The choice of alcohol employed in the solvomercuration step has, however, only a small influence on the stereoselectivity. 

A second and more plausible mechanism is the reductive alkylation of 2 by 1 to produce a 185 molecular weight intermediate 12, diat can cyclize to 13 and thermally rearrange to the two imines, 14 and 15 ( Thomas A. Johnson and Richard V. C. Carr, Air Products and Chemicals, Inc., private communication, 2002). 

The reduction is of course inherent in the hydrogen-chlorine exchange reaction which is the first step of the chain alkylation mechanism (Schmerling, 14). 

Halogenated Hydrocarbons - The destruction of cytochrome P-450 by CCl, first attributed to lipid peroxidation, has been shown to occur even under conditions where lipid peroxidation is not detectable.one possible explanation for this inactivation is that the trlchloromethyl radical or a related species obtained by reduction of the halocarbon reacts with the heme moiety or the apoprotein. The ill-defined radio-labeled porphyrins reported in Incubations of labeled CCI4 with hepatic microsomes would provide support for a heme alkylation mechanism were it not for the conflicting report that fluorescent N-alkylated porphyrins similar to those obtained with AIA are not isolated from CCl -incubated microsomes by procedures that result in isolation of the AIA adducts. ... 

The phenyl complex 12 of a similar structure is kinetically more resistant to C-O reductive elimination than the methyl analog 9 as different reductive elimination mechanisms are expected to be operational in these two cases, concerted three-center in the case of the aryl derivative and an Sn2 mechanism in the case of the alkyl complex. In particular, the symmetric phenyl complex (dpms)Pt Ph(OH)2, 12, in Fig. 6 is completely inert in acidic aqueous solutions at 100°C [25], whereas its methyl analog 9, (dpms)Pt Me(OH)2, eliminates methanol via an Sis/2 mechanism at room temperature [9]. 

On the basis of the analysis of the stereochemical outcome of oxidatively induced palladium-catalyzed C(sp )-0 forming reactions leading to substituted tetrahydrofurans, it was suggested that high valent alkyl palladium intermediates can react via a concerted three-center reductive elimination mechanism to form C (sp )-O bonds [31]. No characterization of these presumed high valent species or mechanistic studies of their reactions have been carried out. 

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