Hydrocyanation of Functionalized Olefins

1 Olefins with Heteroatoms and Aryl-Substituted Olefins 

Hydrocyanation of styrene 26 (eq. (7)) has been examined in some detail. With Ni[P(0-o-tolyl)3]4 27 the branched nitrile 29 is strongly favored over the linear one, which is explained by the intermediary formation of a detectable alkyl species 28. The stability of this intermediate is attributed to the donation of aromatic ring electrons to the coordinatively unsaturated metal center. Crystal structures of related compounds are reported in the literature [53, 54]. 

The features of homogeneously catalyzed hydrocyanations described above prompted attempts to prepare 2-aryl-2-propionitriles 32 (eq. (8)). The development of a synthesis for naproxen demonstrates the successful application of ligand tailoring , the adjustment of the catalyst ligand system to the demands of the reaction. In this case it is of particular importance to achieve a high stereoselectivity because the 7 -enantiomer has a number of undesirable health effects [55], 

6-Methoxy-2-vinylnaphthalene (MVN) 30 is hydrocyanated under the catalytic influence of Ni° complexes 31a-e of 1,2-diol phosphinites that are derived from readily available mono- and di-saccharides. The sugar backbone and substitution of the phosphorus-attached aryl groups have a pronounced effect on the reaction pathway. It is shown that electron-withdrawing groups on the aryl ligands dramatically increase the stereoselectivity. As much as 85% ee was obtained when 

Employing a tunable ligand system derived from a-methyl D-fructofuranoside, the enantioselective synthesis of (/ )-naproxen nitrile is described (94 %ee atO °C) [55]. 

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New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

The enantioselective hydrocyanation of alkenes has the potential to serve as an efficient method to generate optically active nitriles, as well as amides, esters, and amines after functional group interconversions of the nitrile group. As in asymmetric hydroformylation, asymmetric hydrocyanation requires control of both regiochemistry and stereochemistry because simple olefins tend to generate achiral terminal nitrile products. The hydrocyanation of norbomene will give a single constitutional isomer and was studied initially. However, modest enantioselectivities were obtained, and the synthetic value is limited. ... 

Although they are often considered as poorer ligands than diphosphines, they lead also to very efficient and attractive enantioselective catalytic systems as exemplified here. As recent examples, diphosphinites 19 and 20 have been involved successfully in hydrogenation of olefins (mostly itaconate derivatives and enamides, up to > 99.9 % ee) ([84-89] and functionalized ketones (21) (up to 86 % ee) [90], hydrocyanation (19) [91], standard Pd-mediated allylic alkylation (20) [92] (up to 86% ee) [93], and Diels-Alder reaction between a,/l-enals and dienes (eq. (4) 99 % ee) [94]. 

Addition reactions to olefins can be used both for the construction and for the functionalization of molecules. Accordingly, chiral catalysts have been developed for many different types of reactions, often with very high enantioselectiv-ity. Unfortunately, most either have a narrow synthetic scope or are not yet developed for immediate industrial application due to insufficient activities and/ or productivities. These reactions include hydrocarbonylation [Ilf], hydrosilyla-tion [12 i], hydroboration [12j], hydrocyanation [12 k], Michael addition [11 g, 121, 12 m], Diels-Alder reaction [11 h, 12n] and the insertion of carbenes in C-H bonds [Hi, 12p, 12q, 38], Cyclopropanation [Hi, 12p, 12q] and the isomerization of allylamines [12 s] are already used commercially for the manufacture of Cilastatin (one of the first industrial processes) [12 r], and citronellol and menthol (presently the second largest enantioselective process) [12t] respectively. 

There is currently a single example of olefin hydrocyanation under phase transfer catalytic conditions in the literature. Methacrylonitrile in acetonitrile reacts with potassium cyanide and acetone cyanohydrin in the presence of catalytic 18-crown-6 to yield 1,2-dicyanopropane (92%) according to equation 7.12. The cyanohydrin functions as both a proton donor and a source of cyanide ion [6]. 

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