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Sustainable Asymmetric Catalysis with Iron

Final Report Summary - ASYMM.FE.SUSCAT (Sustainable Asymmetric Catalysis with Iron)

The project Asymm.Fe.Sus.Cat aims at developing unprecedented well-defined iron complexes for asymmetric hydrogenation reactions. The transition from precious metals to iron is highly desirable due to the much higher abundancy of such a metal. its lower cost and higher compatibility of iron species with living organisms. Three novel classes of iron complexes have been designed for the asymmetric hydrogenation of C=O bonds: 1) complexes of general formula [Fe(P-P)(N-N)X2] (P-P: diphosphine ligand, N-N: diamine ligand; X: halide or hydride) inspired by the analogous Noyori ruthenium complexes (R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40); 2) half-sandwich cyclopentadienone iron complexes containing a carbene chiral ligand; 3) half-sadwich iron complexes containing a carbene chiral ligand with an –OH pending arm.
Complexes of general formula [Fe(P-P)(N-N)X2] (P-P: 1,2-Bis(diphenylphosphino)ethane or BINAP, N-N: N-N: ethylendiamine or DPEN; X: halide) with combinations of achiral with chiral C2-symmetric P-P and N-N ligands resulted in unstable species that slowly decompose in solution, even under inert atmosphere (scheme 1). Either hydrogenation of acetophenone with in-situ formed iron complexes (from [Fe(H2O)6](BF4)2, (S)-BINAP and ethylendiamine) under H2 pressure (20 bar) did not lead to any catalytic activity in the hydrogenation of acetophenone (or <5%).
A second class of complexes analogous to Knölker complex could be synthetically accessed (scheme 2) by replacement of one carbonyl ligand with an achiral carbene ligand (model inexpensive ligand) through oxidative CO activation with Me3NO. Also optimization of solvent, temperature and base (for imidazolium salt deprotonation and free carbene formation) was performed. Although the complex shows a promising stability that allows for purification and isolation, it is inert under hydrogenation conditions using benchmark acetophenone substrate at different reaction temperatures (no or negligible substrate conversion).

The most promising results of the Asymm.Fe.Sus.Cat project involved the application of the Knölker complex to the synthesis of chiral amines by borrowing hydrogen methodology. Using enantiopure amines and alcohols containing a stereogenic centre adjacent to the –OH or NH2 functional group may result either in chiral or racemic products depending on the operating mechanism.
A broad range of chiral amines (>20 examples) were alkylated by aliphatic alcohols with high yields (up to 90%) and no loss of enantiopurity in the final amine. Although thys methodology was already applied to the synthesis of amines (Yan et al., Nature Comm., 2014, 5, 5602), no examples with chiral substrates were reported so far and the retention of the absolute configuration represents an outstanding aspect due to the possible implication of biologically relevant amines. An extensive study of reaction conditions (solvent, temperature, time, catalyst loading and alcohol/amine ratio) was aimed at optimizing the product yields. When using chiral alcohols, partial racemization of the stereogenic centre has been observed due to the low configurational stability of the intermediate α-substituted chiral aldehyde, obtained by dehydrogenation of the chiral alcohol. However, the final enatiomeric ratio could be improved to excellent values (up to 95:5) by solvent and temperature optimization. The procedure was applied to the synthesis of N-heterocycles and enantiopure amine drugs that were previously synthesized by means of ruthenium or iridium catalysts.
Another important achievement was the use of Earth-abundant catalysts (namely copper) for sustainable processes aimed at obtaining value-added products. Two well studied processes involve the hydrogenation of platform chemical 5-hydroxymethylfurfural and the synthesis of benzimidazoles from aromatic 1,2 diamines or 1,2-nitroanilines in methanol as solvent and C1 carbon source.
Hydrogenation/hydrogenolysis of 5-hydroxymethylfurfural, a valuable biomass-derived platform chemical, selectively led to biofuels and useful building blocks (≥95% product yield), such as 2,5-furandimethanol (scheme 5). The selectivity of the process is temperature-dependant and the used catalyst only consists of copper and zinc in the structure of a nanosized alloy.
Simple copper-based mixed-oxide catalysts were also employed for the green synthesis of benzimidazoles from 1,2-diaminobenzenes/2-nitroanilines and methanol (scheme 6). The main advantage of this methodology resides in the use of methanol (and also other n-alcohols) as solvent and carbon source for the formation of benzimidazole heterocycles. Several benzimidazoles (about 30 examples) were synthesized in good yields (up to 80%) and mechanistic insights were provided..
Additionally, a minireview has been published on the use of homogeneous catalysts for the conversion of glycerol, a ´´waste´´ product of the biodiesel industry, into valuable lactic acid (G. Bottari, K. Barta, Recycl. Catal. 2015, 2, 70–77). The minireview provides a comprehensive collection of catalytic systems suitable for glycerol conversion, stressing the urge for the development of more sustainable alternatives to iridium and other precious metal-based catalysts.
The experimental work performed during the 2-years Asymm.Fe.Sus.Cat project will certainly contribute to reconsider the importance of more abundant and non-noble metals for more sustainable routes to fine chemicals. As an example, either chiral amines or chiral alcohols can be used to synthesize functionalized amines with retention of configuration by using an air-stable iron complex (Knölker complex) that operats through a green methodology (borrowing hydrogen), which only eliminates innocuous water as by-product (highly atom-economic) and is hydrogen-neutral. Such a study might lead to valuable synthetic applications (chiral compounds by sustainable iron catalysts) and paves the way to the applicability of such a methodology to the synthesis of a number of biologically relevant amines. Ultimately, the synthesis of many pharmacologically relevant amines might be redesigned leading to less expensive and more eco-compatible industrial processes, which the society would greatly benefit from in terms of waste generation and price of the final product.
In a second instance, the use of copper-based catalysts has proven a valid alternative to precious metals in the catalytic transformation of biomass-derived 5-HMF and benzimidazole synthesis. The market potential of 5-HMF is increasing exponentially and the development of sustainable catalysts for its conversion into value-added products is highly desirable. Additionally, the use of abundant and inexpensive n-alcohols as precursors for more reactive aldehydes by liberation of innocuous hydrogen will have a decisive impact on the sustainable design of N-heterocycles (such as benzimidazoles).