Vinylarenes asymmetric hydrocyanation

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.

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... 

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 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... 

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). 

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

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. 

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