Enantioselective Michael addition of aldehydes to maleimides catalysed by surface-adsorbed natural amino acids

Asymmetric Michael addition of carbonyl compounds to N-substituted maleimides is an important method for obtaining optically pure succinimides, which are important chiral fine chemical intermediates. Environmentally friendly and sustainable procedures require the use of a heterogeneous, recyclable catalyst obtained from natural chirality sources and cheap auxiliaries. Here we report the application of in situ formed chiral inorganic-organic hybrid catalysts using amino acids such as l-phenylalanine and clay minerals or alumina, which were highly active and provided excellent enantioselectivities, up to 99%, in the addition of aldehydes to a large variety of N-substituted maleimides. Examinations indicated the occurrence of the asymmetric reaction on the surface of the recyclable solid hybrid materials. The catalytic materials were examined by thermogravimetry, XRD, FT-IR and Raman spectroscopy, SEM and adsorption experiments. Results of these methods showed that the amino acid is deposited as surface crystallites or intercalated in the layered cation exchangers, which both function as a supply of the chirality source, whereas the reactions are catalysed by the chiral compounds adsorbed on the surface. This catalytic system was used to conveniently prepare chiral succinimides at the gram scale, easily purified by crystallization. Accordingly, these chiral hybrid materials are convenient heterogeneous catalysts for obtaining valuable compounds in high optical purities using natural chirality sources, inorganic solids and ethyl acetate, a green organic solvent

Phosphoramide chiral catalysts for environmentally friendly asymmetric organocatalytic processes

Phosphoramides and thiophosphoramides were prepared from optically pure 1,2-diamines and were used as chiral organocatalysts in the asymmetric Michael additions of different Michaeldonors to N-substituted maleimides. The 1,2-diphenylethane-1,2-diamine derived thiophosphoramide, which could be prepared in good yield in a one-step procedure, was found to be excellent catalyst in the addition of aldehydes to various maleimide derivatives. Products resulted in reactions of ketones with maleimides were also obtained in high yields and enantioselectivities. The thiophosphoramide derivative was efficient in the asymmetric conjugate addition of other carbonyl compounds, such as -diketones and -keto esters, as well. Investigations of these reactions led to valuable conclusions as concerns the structural requirements of the catalyst and reactants needed for obtaining high activities and stereoselectivities. Due to the low catalyst amount and the solvent applied, these reactions could be carried out in a more environmentally benign way as with the previously used chiral organocatalysts

Natural chiral catalysts on solid surfaces used in Michael addition to maleimides

As the most important molecules in living organisms are chiral, the selective production of the optical isomers of substances designed to interact with them, such as drugs, is of paramount importance. In addition, from an environmental point of view, it is also desirable to carry out the asymmetric syntheses as efficiently as possible, thus minimising waste production. Asymmetric catalytic syntheses are one of the best methods for producing enantiomerically pure compounds, whereby the heterogenization of the chiral catalysts can allow their reuse. A simple method to heterogenize chiral catalysts is the adsorption of optically pure material on a solid surface. Some examples of the use of heterogeneous chiral catalysts that can be readily prepared by adsorption are known, however, solids of this type have not yet been used in reactions of maleimides. Based on these, we set out to explore the combined catalytic effect of natural amino acids and various inorganic oxides in Michael additions between maleimides and aldehydes. The investigation of a variety of starting materials provides an opportunity to study the activity, stereoselectivity and the applicability of these simple chiral catalysts. Our studies have shown that while natural amino acids have only negligible catalytic activity, adsorption on different oxide surfaces (alumina, bentonite or laponite) gave succinimide derivatives with excellent conversions and enantioselectivities. In conclusion, our research has led to the development of a novel chiral heterogeneous catalytic system that can be used to produce valuable optically pure intermediates for use in the pharmaceutical industry

The mechanochemical implementation of the environmentally friendly asymmetric transfer hydrogenation of ketones

Optically pure compounds are essential in the synthesis of pharmaceuticals, fragrances and pesticides. Asymmetric catalytic reactions are the most favorable methods to achieve high conversions and enantiomeric excesses in fast reactions, using only catalytic amount of the chirality sources. Hydrogenations and transfer hydrogenations are well-studied procedures to obtain optically pure chiral alcohols. The transfer hydrogenation is convenient, as it ensures the possibility to use a hydrogen donor compound instead of hydrogen gas to provide the necessary H atom. In the past few decades several synthetic chiral compounds were used as the ligand of the catalyst complex, however these days more environmentally friendly implementations are favored. The use of natural chiral compounds would provide great opportunities to carry out asymmetric catalytic reactions using less organic solvents and producing less hazardous waste. In our previous studies, we have developed an asymmetric catalytic system for the transfer hydrogenation of prochiral ketones using an in situ prepared Ru-chitosan complex in aqueous media. The catalyst prepared using the readily and easily available, biodegradable and inexpensive biopolymer provided good result in the transfer hydrogenation of various prochiral ketones in aqueous-phase reactions. In order to increase the preparative value of this method for preparing optically pure alcohols, we decided to use mechanical energy transmission instead of conventional thermally activated reactions carried out in magnetically stirred batch reactors. With the former method the reaction time can be reduced, as well as the volume of the used solvent and the produced waste. After the optimization of the reaction conditions in the transfer hydrogenation of 4-chromanone, we examined the reaction of various ketones and the obtained results were compared with those reached in reactions carried out conventionally. All the examined ketones were transformed in similar degrees and the chiral alcohols were obtained in high enantiomeric excesses (ee). The reactions were scaled up as well, to prepare the optically enriched compounds in mmol quantities

Environmentally benign asymmetric Michael addition to maleimides using mechanochemical activation

The preparation of chiral N-substituted succinimides is highly important since they are widely used intermediates in the pharmaceutical industry. Such compounds can be obtained by the Michael addition of nucleofiles to different maleimides. Since the environmental awareness is rising nowadays, there is a huge demand for sustainable synthetic methods that can be applied industrially. Carrying out reactions using efficient alternative activation is key to achieve environmentally friendly procedures. Asymmetric catalytic processes have been developed for Michael additions on maleimides using organocatalysts under batch conditions. Our aim was to carry out the implementation of mechanochemical activation in these reactions because of its huge benefits over the conventional methods, i.e. solvent-free conditions and significantly reduced reaction times. In the present study, we examined the impact of milling parameters through the test reaction of isobutyraldehyde and N-methylmaleimide. We set the goal to achieve similar conversion and enantioselectivity values as were obtained using thermal activation but without the addition of a solvent and under much less time. As a result of our studies, optimal conditions were determined to carry out the preparation of an N-substituted succinimide, which may be a significant step in the development of sustainable industrial synthetic methods of important pharmaceutical fine chemicals

Preparation of n-heterocyc compounds by environmentally benign cascade reactions

The N-heterocyclic compounds include various molecules with significant biological activity, such as the quinazolinone derivatives. The preparation, characterization and application of these molecules are in the focus of pharmaceutical chemistry. The mono- and disubstitued dihidroquinazolinone derivatives are potential anti-cancer and anti-inflammatory compounds, besides they can be used as other pharmaceutical and agrochemical ingredients [1]. Nowadays the demand for the protection of the environment is fortunately increasing, which places numerous expectation on the industries. In the fine chemical and pharmaceutical processes, it has become a basic requirement to take into account the 12 principles of green chemistry. Due to this, the catalytic and neat reactions along with the application of compound from sustainable sources, environmentally friendly solvents and alternative activation methods have a great importance. Among the alternative energy transmission methods, it is worth to highlight the implementation of the mechanochemistry, as the reactions carried out in ball mills, have many of the above-mentioned advantages. In this present study, we examined the cascade reaction of anthranilamide and acetone, in which one ring-closing step occurs, and then we expanded the system to a bifunctional compound, ethyl levulinate, which is a renewable reaction partner, to achieve a second ring-closing step. We examined the possibilities of neat reactions, the quality of the applied catalyst, reaction temperature and time. After the successful optimization of the magnetically stirred neat reactions, we turned our focus to the mechanochemical activation of the reactions. It is possible to carry out several reactions neat in a ball mill, however generally better result can be achieved by adding a small amount of solvent to improve the mixing and the energy transition in the system [2]. Under the optimized conditions, the reactions were carried out with outstanding selectivity, and the final products were obtained in good yields. The developed method provides essential experiences to synthesize optically pure Nheterocycles in a system that meets today’s environmental expectations. The initial experiment of the reaction between anthranilamide and other bifunctional compounds was also carried out. It is our ongoing future goal to optimize the conventional, then the mechanochemical synthesis of optically pure condensed ring systems