Hydrocyanation vinylarenes

Although several enzymes can enantioselectively catalyze the hydrocyanation of R2C=0 and R2C=NR bonds [7], (asymmetric) hydrocyanation of C=C double bonds has no precedents in biology. In homogeneous catalysis asymmetric hydrocyanation is still underdeveloped, as is apparent from the relatively few reports in the literature. In the following paragraphs a short overview will be given divided into the two major substrate classes investigated, cyclic (di)enes and vinylarenes. 

Figure 3. Ligands studied in the asymmetric hydrocyanation of vinylarenes.

Figure 5. The catalytic cycle of hydrocyanation of styrene as example of the vinylarenes.

In asymmetric hydrocyanation reactions the desired isomers are the chiral branched products only. Good regioselectivity toward the branched product (>98%) is limited to vinylarenes. Hydrocyanation of 1,3-dienes gives a variety of mixtures depending on the catalyst and conditions 1-alkenes give the linear nitrile as major product [34]. Both are seen in the adiponitrile process in which the unwanted branched 2M3BN (hydrocyanation product from 1,3-butadiene) is isomerized to the linear product 3-pentenenitrile, which is then hydrocyanated by in-situ isomerization to 4-pentenenitrile, resulting in the linear adiponitrile. Thus vinylarenes and cyclic alkenes (mainly norbomene) are usually the substrates of choice for the asymmetric hydrocyanation. Hopefully 1,3-dienes will become feasible substrates in the near future. 

The system was exploited by employing electronically unsymmetrical bis-(diaryl)phosphinites, giving excess of both enantiomers of naproxen nitrile in excellent yields (91 % S, 95 % R). Ligand tuning in the asymmetric hydrocyanation of vinylarenes is comprehensively surveyed by the same authors [57]. Figure 1 illustrates the tunable sites on a sugar-derived ligand. 

Keywords Asymmetric hydrocyanation. Hydrogen cyanide, Vinylarenes, 2-Arylpropanoic acids, Naproxen, Arylphosphinites, Carbohydrate ligands. Electronic effects. Electronic asymmetry... 

The highest enantioselectivities have been obtained for the asymmetric hydrocyanation of vinylarenes using carbohydrate-derived phosphinite-Ni catalysts. In the initial ligand scouting, carbohydrates appeared to show the most promise. 

In conclusion, until recently asymmetric hydrocyanation was limited to only a few substrates, mainly norbornene systems, giving only low to medium asymmetric inductions. The stereoselective syn hydrocyanation of alkynes and the new results with vinylarenes, however, offer... 

We describe the extension of this class of bisphosphite catalysts to asymmetric hydroformylation and hydrocyanation of vinylarenes.(3) These enantiose-lective catalytic transformations are employed for the asymmetric synthesis of S-Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID). Factors which influence regioselectivity and enantioselectivity, as well as characterization of the catalyst resting states, are discussed. 

One of the few available examples is represented by the synthesis of cilastatine by a chiral Cu complex promoted cyclopropanation reaction developed by Sumitomo Chemical Co. [78]. Another is the catalytic asymmetric hydrocyanation of vinylarenes developed at DuPont [79]. In this process (Fig. 27) sugar-derived phosphinites are used in combination with a Ni catalyst to prepare enantiomerically enriched precursors of the NSAID naproxen. 

The hydrocyanation of vinylarenes ° has been studied by a DuPont team using nickel catalysis. The hydrocyanation of 6-methoxy-2-vinylnaphthalene (2.219) affords the product (2.220), where the enantiomeric excess is strongly dependent upon the electronic nature of the bisphosphinite ligand (2.12). Hydrolysis of the nitrile (2.220) affords the nonsteroidal anti-inflammatory drug Naproxen. This nickel-catalysed procedure has also been applied with some success to the regiose-lective, asymmetric hydrocyanation of 1,3-dienes such as 1-phenyl-1,3-butadiene (2.221) to give the 1,2-adduct (2.222) with ees between 50 and 83%. ... 

The anti-inflammatory activities of 2-arylpropanoic acids (54) continue to stimulate new methods for their preparation. Hydrocyanation of styrenes and other vinylarenes can be catalysed... 

Nickel-catalyzed hydrocyanation of a-olefins t)q)ically produces the terminal nitrile as the more abundant, but not exclusive isomeric product. In contrast, nickel-catalyzed hydrocyanation of vinylarenes typically generates the branched product. This branched selectivity arises fijom the stability of -phenethyl complexes, as is shown in more detail in Section 16.2.5 on as)unmetric hydrocyanation. The relative rates for hydrocyanation follow the trend ethylene > styrene > propene 1-hexene > disubstituted olefins. Examples of these reactions and selectivities for formation of the linear and branched products are shown in Scheme 16.1. ... 

More success has been achieved with the enantioselective hydrocyanation of vinylar-enes. For reasons described below, the hydrocyanation of vinylarenes tends to generate the branched, chiral, a-aryl nitrile product, instead of the linear, achiral, P-aryl nitrile product. Much research has focused on the hydrocyanation of 6-methoxyvinylnaphtha-lene because hydrolysis of the nitrile product would lead to the profen drug Naproxen. As shown in Equation 16.9, the hydrocyanation of this vinylarene occurs with high enanti-oselectivity in the presence of a nickel catalyst containing a phosphinite derived from a... 

The asymmetric hydrocyanation of dienes with substantial enantioselectivities has also been reported (Equation 16.10). Like the reactions of vinylarenes, these reactions have been reported with catalysts containing carbohydrate-derived phosphinites. Reactions of aryl-substituted dienes occur to form the products from 1,2-hydrocyanation. In addition to the reactions of purely acyclic dienes, such as 1-phenyl-l,3-butadiene, dienes containing an exocyclic vinyl group have been studied. These are substrates for products possessing... 

The hydrocarboxylation of vinylarenes has also been studied extensively as a simple, clean route to the ot-aryl carboxylic acids that are common non-steroidal anti-inflamatory medicines, such as ibuprofen and naproxen. " By this process, a vinylarene undergoes hydrocarboxylation to form the branched a-aryl carboxylic acid. A series of patents and papers describe this hydrocarboxylation process " and the related hydroesteri-fication. Like the hydrosilylations and hydrocyanations presented in Qiapter 16 and the hydroformylations described in this chapter, the regioselectivity for reactions of vinylarenes contrasts with that for reactions of alkenes. The reactions of vinylarenes form branched hydrocarboxylation products. 

Chiral Catalysts Containing Group 10 Metals (Ni, Pd, and Pt). The catalyst formed in situ from Ni(acac)2 and bomane aminoalcohols (DAB or DAIB) catalyze the enantioselective addition of diethylzinc to chalcones (254) (Fig. 21). Nickel(II)-chiral Schiff-base (the ligand derived from 1,2-diaminocyclohexane or 1,2-diaminopropane with pyrone derivative) complexes were efficient in epoxida-tion of nonfunctionalized olefins (255). Bis-ferrocenyl-triphosphane (PIGIPHOS) formed catalytically active complex with Ni(II) (256). Nickel-catalyzed asymmetric hydrocyanation of vinylarenes using glucose-derived phosphinite ligands was observed (257). 

Hydrocyanation of vinylarenes provides an interesting access to antiinflammatory and pain killer drugs such as naproxen and dexibuprofen (the pharmacologically active enantiomer of ibuprofen, Scheme 8.3). However, the enantioselective hydrocyanation of these substrate types remains a challenge. In 1994, RajanBabu and Casalnuovo [14] reported the application of glucophosphinite ligands 1 for the hydrocyanation of P-vinylnaphathalene 3. 

A.L. Casalnuovo et al. - Ligand Electronic Effects in Asymmetric Catalysis Enhanced Enantioselectivity in the Asymmetric Hydrocyanation of Vinylarenes,... 

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