Nickel solves a long-lasting challenge; An efficient asymmetric hydrogenation of oximes to produce chiral hydroxylamines

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By Valentinos Mouarrawis and Sander Kluwer

The pool of chiral molecules is of great value across the chemical and pharmaceutical industry as it presents a starting point for the preparation of chiral compounds. A missing member for the generation of chiral centers is the direct asymmetric synthesis of hydroxylamines, a functional group often found in numerous pharmaceuticals. Typically, an organometallic complex bearing a chiral ligand is involved where the chiral information is selectively transferred to produce one of the desired enantiomers. The success of this methodology is well established for the hydrogenation of alkenes (C=C), carbonyls (C=O), and imines (C=N) bonds, increasing the availability of chiral compounds, which are found at key positions in API synthesis.

However, a long-lasting challenge is the efficient asymmetric hydrogenation of oximes for the preparation of chiral hydroxylamines from unsubstituted oximes without the cleavage of the N–O bond. This is evidenced by the challenges and limitations found in the only two previously reported studies involving the reduction of O-substituted oximes to hydroxylamines. First, in a study published in 2014, a non-chiral B(C6F5)3-catalysed hydrogenation of oxime ethers was reported, not tolerating unsubstituted oximes. Second, a study published in 2020, using an iridium complex as the catalyst generated chiral hydroxylamines from oximes with e.e.’s up to 95%. However, this method was not widely applicable for unsubstituted oximes as only one unsubstituted substrate was tested generating the desired product in 92% yield and 80% e.e.  

The article by Wanbin Zhang et al. in Nature Chemistry ( opens new possibilities as it describes the use of a readily available bisphosphine nickel complex as catalyst for the asymmetric hydrogenation of both substituted and unsubstituted oximes, yielding the formation of optically pure hydroxylamines with yields up to 99% and 99% e.e.  Interestingly, it is suggested by the authors that the selectivity of this reaction to the desired hydroxylamine is controlled by supramolecular interactions between the catalyst and oximes particularly the C-H/π∙∙H-C/π interactions between the ligand and the substrate. By performing computational studies the authors showed that these weak interactions significantly contribute to improving the reaction efficiency in terms of the observed enantioselectivity. In addition, the authors addressed the use of TFE being an undesirable solvent for industrial applications in terms of cost and toxicity, and screened the use of alternative solvents. The use of methanol for the transformation of a model substrate led to the formation of the corresponding product in a good yield of 80 % and excellent enantioselectivity of 94 %.

An important aspect when employing a newly developed catalytic strategy is scalability, a factor that can demotivate the chemical industry to use new technologies in their manufacturing schemes. What stands out when we look at the general procedure of this catalytic step is the need to use a nitrogen-filled glovebox and degassed and anhydrous solvents to avoid catalyst deactivation (i.e. oxidation) or hydrolysis of the substrate. Furthermore, although the authors showed the use of alternative solvents, TFE is yet the best-performing solvent (94% yield, 97% e.e). The catalytic performance in methanol is only demonstrated for the model substrate (80 %, 94% e.e) and further optimization is needed to expand the substrate scope in more environmentally friendly solvents.

 Overall, we believe this newly reported methodology has several advantages over previously reported catalytic examples. As mentioned, it tolerates the use of both substituted and unsubstituted oximes which further expands the applicability of this method to a larger substrate scope. Furthermore, the use of nickel represents a great alternative to metals such as iridium, rhodium, or ruthenium typically used in these types of transformations. The lower cost of Ni ($22.46 per kg) over other precious metals allows the use of larger amounts of catalyst and in turn, leads to better scalability of a chemical process. In our previous blog ( in which we showcase the opportunities and challenges regarding the use of palladium and nickel catalysts in industry, it is clear that is important to shift our focus from scarce precious metals (Ir, Rh, Ru, etc.) to more abundant ones (Fe, Ni, Mn, etc.). This, however, requires extensive research in order to find new catalysts and optimal reaction conditions for efficient non-precious metal-based catalytic systems that can be widely used in commercial scale.

About InCatT ( InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical, and bulk chemical industry to solve their most challenging projects.

Article: “Nickel-catalysed asymmetric hydrogenation  of oximes”

By Bowen Li, Jianzhong Chen, Dan Liu, Ilya D. Gridnev & Wanbin Zhang.

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