Catalytic utilization of converter gas – an industrial waste for the synthesis of pharmaceuticals

Catalytic utilization of converter gas –an industrial waste for the synthesis of pharmaceuticals† Sofiya A. Runikhina, a Oleg I. Afanasyev, ab Ekaterina A. Kuchuk, a Dmitry S. Perekalin, ac Rajenahally V. Jagadeesh, * de Matthias Beller * d and Denis Chusov* ac Converter gas is a large scale waste product that is usually burned to carbon dioxide and contributes to the world emission of greenhouse gases. Herein we demonstrate that instead of burning the converter gas can be used as a reducing agent in organic reactions to produce valuable pharmaceuticals and agrochemicals. In particular, amide-based selected drug molecules have been synthesized by a reaction of aromatic nitro compounds and carboxylic acids in the presence of converter gas. In addition, we showed that this gas can also be conveniently utilized to carryout classical reductive amination reaction. Introduction Converter gas is one of the largest waste products of the steel industry. 1 Each year millions of tons of converter gas is formed. 2 Typically this gas is burned to carbon dioxide which is then released to the atmosphere and makes a signicant contribution to the world emission of greenhouse gases (Fig. 1). 3,4 While the emission of greenhouse gases from burning fossil fuels can be reduced by using other energy sources (such as electricity from solar, hydro, or nuclear plants), emissions from steel production are currently unavoidable. Therefore, it is highly desirable not to burn converter gas but rather to apply it in the chemical industry for the synthesis of valuable products. Herein, we address this challenge and demonstrate that converter gas can be used as a reducing agent for the production of a variety of organic chemicals including pharmaceuticals. The composition of converter gas depends on the temperature of the steel-making process, but typically it contains 60– 95% of CO, as well as N 2 and CO 2 as the main components. 5 During the traditional burning process, the converter gas acts essentially as a reducing agent for atmospheric oxygen. Therefore, it may be also possible to use it in a similar manner for reduction of organic compounds. Recently we and others have used CO as a reducing agent in various transformations. 6–9 In the course of these studies, we found that converter gas can be used for the direct amidation of nitroarenes and carboxylic acids without any additives or coupling agents (Scheme 1). This atomand step-economic process converts the industrial starting materials into valuable amide derivatives. The amide bond is one of the most important bonding motifs in organic chemistry and provides the basis for the unique physical and biological properties of many high-performance materials, natural products and biology related molecules. 10–12 Consequently, amides are found in numerous pharmaceutical drugs 13–15 and Fig. 1 The formation and possible applications of converter gas for production of pharmaceuticals, polymers, and other chemicals. a A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilova St. 28, Moscow, 119991, Russian Federation. E-mail: chusov@ ineos.ac.ru b Plekhanov Russian University of Economics, Stremyanny per. 36, Moscow, 117997, Russian Federation c Faculty of Chemistry of the National Research University Higher School of Economics, Miasnitskaya Str. 20, Moscow, 101000, Russian Federation d Department of Applied Homogeneous Catalysis Leibniz-Institut für Katalyse e. V., Albert-Einstein-Straße 29A, Rostock, 18059, Germany. E-mail: jagadeesh. [email protected]; [email protected] e Nanotechnology Centre, Centre of Energy and Environmental Technologies, V ˇ SB Technical University of Ostrava, Ostrava-Poruba, Czech Republic †Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3sc00257h Cite this: Chem. Sci.,2023,14,4346 All publication charges for this article have been paid for by the Royal Society of Chemistry Received 13th January 2023 Accepted 12th March 2023 DOI: 10.1039/d3sc00257h rsc.li/chemical-science 4346 |Chem. Sci.,2023,14,4346–4350 © 2023 The Author(s). Published by the Royal Society of Chemistry Chemical Science EDGE ARTICLE Open Access Article. Published on 31 March 2023. Downloaded on 1/9/2024 1:22:36 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue agrochemicals. To show the practical potential of the amidation reaction using converter gas, we applied it for the synthesis of various pharmaceuticals. Results and discussion First, we studied the reaction of 4-nitrophenol with acetic acid in the presence of converter gas to produce paracetamol (3a). In accordance with previous reports on related processes, 7,16–19 we found that ruthenium complexes are efficient catalysts for this transformation. Under optimal conditions, the commercially available ruthenium catalyst [(cymene)RuCl 2 ] 2 (at 1 mol% loading) allowed us to obtain paracetamol (3a) in 99% yield (Table 1, entry 1). Noteworthy, other ruthenium complexes can be used as catalysts but reaction did not proceed at all in the absence of the ruthenium source or in the absence of the converter gas (Table 1, entry 7; full details of conditions optimization are provided in the ESI†). Both Ru(acac) 3 and RuCl 3 can be used as catalysts indicating that the nature of ligands is not crucial for the process (Table 1, entries 2 and 3). Water can be used as a solvent for the reaction, which makes the reaction attractable for the industrial chemistry (Table 1, entry 4). The optimal conditions are 140 °C and 30 bar; reactions at lower temperature or pressure gave lower yields (Table 1, entries 5 and 6). In a similar manner, other important pharmaceuticals such as phenacetin (3b), propanil (3c), acedoben (3d), neracetam (3e), and actarit (3f) were produced in 65–85% yields (Scheme 1). It is important to note that this amidation reaction is compatible with various functional groups including hydroxyl (in paracetamol), chloride (in propanil), amide (in neracetam), and carboxylic acid (in actarit and acedoben). In addition, vorinostat (4), one of the main drugs against T cell lymphoma, 20 was synthesized in two steps from suberic acid, nitrobenzene, and hydroxylamine in almost quantitative yield. The function of converter gas in these syntheses is essential to capture and remove the excessive oxygen atoms from the nitroand carboxylic groups of the reagents. Since the industrial converter gas may contain sulfur-based impurities, 21 we tested the catalytic amidation in the presence of thiophene. Fortunately, this did not lead to poisoning of the catalyst (see ESI, Table S7†). Scheme 1 Synthesis of selected pharmaceuticals by catalytic amidation of nitroarenes and carboxylic acids with the aid of converter gas. Reaction conditions (detailed reaction conditions are provided in the ESI†): a 1 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 10 equiv. of 1, 30 bar of converter gas, 140 °C, 20 h; b 0.5 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 10 equiv. of 1, 50 bar of converter gas, 180 °C, 20 h; c 0.5 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 10 equiv. of 1, 30 bar of converter gas, 160 °C, 20 h; ] 0.5 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 10 equiv. of 1,30 bar of converter gas, 170 °C, 20 h; e 0.5 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 5 equiv. of 1, 30 bar of converter gas, 170 °C, 20 h; f 0.75 mol% of [(cymene)RuCl 2 ] 2 , 1 equiv. of 2, 10 equiv. of 1, 30 bar of converter gas, 140 °C, 20 h; g for preparation of 3g: 0.75 mol% of [(cymene)RuCl 2 ] 2 ,1 equiv. of 2, 5 equiv. of 1, 30 bar of converter gas, 170 °C, 20 h. NHOH group highlighted by green color was introduced in a second step. Table 1 Selected optimization results Entry Deviation from the optimal conditions Yield of 3a 1 None 99% 2 Ru(acac) 3 instead of [(cymene)RuCl 2 ] 2 84% 3 RuCl 3 instead of [(cymene)RuCl 2 ] 2 31% 4 Water instead of THF 85% 5 20 bar of converter gas 47% 6 130 °C instead of 140 °C 56% 7 No catalyst or CO 2 instead of converter gas 0% 8 CO instead of converter gas 86% © 2023 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2023,14,4346–4350 | 4347 Edge Article Chemical Science Open Access Article. Published on 31 March 2023. Downloaded on 1/9/2024 1:22:36 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online The exact mechanism of the catalytic amidation is not clear, but we can propose a possible sequence based on experimental observations and previous literature reports 7,22–24 (Scheme 2). First the nitro compounds are reduced by CO in the presence of ruthenium carbonyl species 25 Ru x (CO) y to give isocyanates or amines. 26 Then isocyanates or amines can react with carboxylic acid to give the desired amide similar to the known organic transformation. The detailed discussion of the possible mechanism is provided in the ESI.† In order to prove that converter gas can be used in a general manner for other reductive transformations, we explored another important reaction involving the formation of C–N bonds, namely, the reductive amination (Scheme 3). 27–32 Indeed, it was found that this reaction between readily available carbonyl compounds and amines proceeded in the presence of converter gas and was catalysed by a simple rhodium acetate without any additional expensive ligands. This way we synthesized antifungal agent butenane (7a) directly from formaline, naphthaldehyde, and 4-tert-butylbenzylamine. Further expansion of this method provided other drugs such as fendiline (7b), trimetazidine (7c), rivastigmine (7d), piribedil (7e), bromantane (7f), cyclizine (7g), and chlorocyclizine (7h) (detailed reaction conditions are provided in the ESI†). Once again, the reaction displayed excellent selectivity and was not inhibited by various functional groups. Scheme 2 Possible mechanism of the catalytic amidation reaction. Scheme 3 Catalytic reductive aminations using converter gas: synthesis of selected pharmaceuticals. Reaction conditions (detailed reaction conditions are provided in the ESI†): a 0.5 mol% of Rh 2 (OAc) 4 , 1.5 equiv. 6, 1 equiv. of 5, 30 bar of converter gas, 120 °C, 22 h. After 22 h 2.20 equiv. of formaline were added for an additional 22 h to achieve methylation (highlighted by green color); b 0.5 mol% of Rh 2 (OAc) 4 , 1.1 equiv. of % 6,1 equiv. of 5, 30 bar of converter gas, 140 °C, 22 h; c 1 mol% of [(h 4 -cyclooctadiene)Rh(h 6 -2,3,6,7-tetramethoxy-9,10-dimethylanthracene)]BF 4 ,10 equiv. of 6, 1 equiv. of 5, 30 bar of converter gas, 120 °C, 22 h; d reductive amination step: 0.5 mol% of Rh 2 (OAc) 4 , 5 equiv. of 6, 1 equiv. of 5, 30 bar of converter gas, 120 °C, 48 h. C(O)NMeEt group highlighted by green color was introduced in the next step; e 0.5 mol% of Rh 2 (OAc) 4 , 1 equiv. of 6, 1 equiv. of 5, 30 bar of converter gas, 120 °C, 22 h; f 0.5 mol% of Rh 2 (OAc) 4 , 1 equiv. of 6, 2 equiv. of 5, 42 bar of converter gas, 120 °C, 22 h; g 2 mol% of Rh 2 (OAc) 4 , 5 equiv. of 6, 1 equiv. of 5, 45 bar of converter gas, 130 °C, 48 h. 4348 |Chem. Sci.,2023,14,4346–4350 © 2023 The Author(s). Published by the Royal Society of Chemistry Chemical Science Edge Article Open Access Article. Published on 31 March 2023. Downloaded on 1/9/2024 1:22:36 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online As in the previous case, the main role of converter gas is to remove the oxygen atoms from the carbonyl molecules. We assume that rhodium species rst coordinate with CO, which is then attacked by the OH group of the hemiaminal intermediate to give the Rh–COOH group. Its further decarboxylation gives rhodium hydride species, which immediately reduce the iminium cation similar to previous reports 33,34 (Scheme 4). Experimental Preparation of converter gas The model converter gas was prepared in a 40 liter gas cylinder at room temperature. The gas cylinder was lled with 29 bar of carbon monoxide, followed by 10 bar of carbon dioxide and 11 bar of nitrogen. 35 General procedure for the reductive amidation The ruthenium catalyst [(p-cymene)RuCl 2 ] 2 (0.5–1 mol%), nitroarene, acetic acid, THF, and a magnetic stirring bar were placed into an autoclave. The autoclave was sealed, ushed three times with 10 bar of converter gas, and then charged with 30 bar of converter gas. The autoclave was placed into an oil bath preheated to the required temperature (140–180 °C). Aer the indicated time (typically 20 h), the autoclave was cooled to room temperature and depressurized. The reaction mixture was transferred into a ask and the autoclave was additionally washed with dichloromethane (2 ×1 mL). The solvents were removed using a rotary evaporator, and the residue was analyzed by NMR. General procedure for the reductive amination Rhodium(II) acetate (0.5–2 mol%), amine, and the carbonyl compound were placed into an autoclave. The autoclave was sealed, ushed three times with 10 bar of converter gas, and then charged with 45 bar of converter gas. The reactor was placed into an oil bath preheated to the required temperature (120–140 °C). Aer the indicated time (20–48 h), the autoclave was cooled to room temperature and depressurized. The reaction mixture was transferred into a ask and the autoclave was additionally washed with dichloromethane (2 ×1 mL). The solvents were removed using a rotary evaporator, and the residue was analyzed by NMR. Conclusions To conclude, we have demonstrated that, instead of burning converter gas, it can be conveniently used to synthesize valuable organic life science products. The generality of this approach is showcased in the preparation of several current pharmaceuticals via the reductive amidation protocol as well as via more classical reductive amination. We believe that converter gas can be used for many other atomand step-economical reduction transformations in the near future. In particular, converter gas from steel plants might replace natural gas sources in well-known large-scale industrial processes involving CO such as synthesis of acetic acid, 36–38 hydroformylation, 39–41 urea synthesis, 8,42–44 etc. Hopefully, this discovery will attract other researchers to develop chemical processes involving converter gas. Data availability All data associated with this report may be found in the ESI.† Author contributions S. A. R., O. I. A., E. A. K. carried out all experiments, D. S. P. carried out quantum chemical modelling. D. C. generated an idea of the paper and coordinated all project. R. V. J. and M. B. involved in the development of this project. O. I. A., D. S. P., R. V. J., M. B., D. C. wrote the manuscript. Conflicts of interest There are no conicts to declare. Acknowledgements This work was supported by the Russian Science Foundation (Grant No. 22-73-10020). The NMR data were collected using the equipment of the Center for molecular composition studies of INEOS RAS with nancial support from the Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-03-2023-642). Notes and references 1 K. He and L. Wang, Renewable Sustainable Energy Rev., 2017, 70, 1022–1039. 2 T. A. Napp, A. Gambhir, T. P. Hills, N. Florin and P. S. Fennell, Renewable Sustainable Energy Rev., 2014, 30, 616–640. Scheme 4 Possible mechanism for reductive amination by CO in the presence of a rhodium catalyst. © 2023 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2023,14,4346–4350 | 4349 Edge Article Chemical Science Open Access Article. Published on 31 March 2023. Downloaded on 1/9/2024 1:22:36 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online 3 A. 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