One-pot carbonylative coupling reaction and hydrogenation reaction using a multifunctional catalyst

Abstract

The present invention is directed towards catalysts comprising metal nanoparticles and a N-heterocyclic carbene comprising palladium or nickel, their use in carbonylative coupling reactions and hydrogenation reactions, and their use in one-pot carbonylative coupling and hydrogenation reaction. A method employing such catalysts to access ynone and chalcone derivatives is also claimed. The catalysts and methods of the present invention improve upon the disadvantages associated with literature reactions.

Description

[0001] Title of Invention

[0002] One-Pot Carbonylative Coupling Reaction and Hydrogenation Reaction Using a Multifunctional Catalyst

[0003] Field of the Invention

[0004] The present invention is directed towards a catalyst, its use in carbonylative coupling reactions and / or hydrogenation reactions and its use in a one-pot carbonylative coupling and hydrogenation reaction.

[0005] Background of the Invention

[0006] Chaicones are highly valuable a, 3-unsaturated ketones from the flavonoid family and are key compounds for the preparation of pharmaceuticals ( e. g., anticancer, antimicrobial, anti-inflammatory, antidiabetic, antipyretic, antiallergic, analgesic and antimalarial agents ), fluorescent probes, anti-corrosion agents, pesticides, liquid crystals, and various organic molecules ( e. g., flavones, isoxazole, pyrazole, pyrazoline, pyrimidine, thiazine and imidazoline derivatives ). Chaicones are typically prepared by Claisen-Schmidt condensation of aromatic ketones and aldehydes catalysed by strong bases or acids ( e. g., A. Rayar, M. S. Veitia and C. Ferroud, Springerpl us, 2015, 4, 221 ). Alternative synthetic routes include Suzuki-Miyaura coupling ( e. g., K. R. Bus zek and N. Brown, Org. Let t., 2007, 9, 707-710 ), Stille coupling ( e. g., R. D. Maz zola, Jr., S. Giese, C. L. Benson and F. G. West, J. Org. Chem., 2004, 69, 220-22 ), decarboxylative cross coupling ( e. g., N. Zhang, D. Yang, W. Wei, L. Yuan, F. Nie, L. Tian and H. Wang, J. Org. Chem., 2015, 80, 3258-3263 ), Sonogashira isomeri zation coupling ( e. g., T. J. J. Muller, M. Ansorge and D. Aktah, Angew. Chem. Int. Ed., 2000, 39, 1253- 1256 ), Photo- fries rearrangement ( e. g., P. Subramanian, D. Creed, A. C. Gri f fin, C. E. Hoyle and K. Venkataram, J. Photochem. Photobi ol. A, 1991, 61, 317- 327 ), and carbonylative Heck coupling ( e. g., X. F. Wu, H. J. Jiao, H. Neumann and M. Beller, Chemcatchem, 2011, 3, 726-733; X. F. Wu, H. Neumann and M. Beller, Angew. Chem. Int. Ed., 2010, 49, 5284-5288; X. F. Wu, H. Neumann, A. Spannenberg, T. Schulz, H. Jiao and M. Beller, J. Am. Chem. Soc., 2010, 132, 14596-14602 ).

[0007] However, these methods suffer from various limitations including low functional group tolerance, low availability of substrates, low reaction rates, unwanted side reactions, and use of excess reagents, ligands and additives.

[0008] Therefore, alternative methods to synthesise chaicone derivatives are sought-after.

[0009] To avoid the disadvantages associated with past methods, the present inventors have designed a new one-pot synthetic route providing access to E-chalcones via carbonylative coupling of aryl iodides, phenylacetylenes, and CO integrated with subsequent selective hydrogenation of the corresponding ynones. The inventors have furthermore accessed ynones through a carbonylative coupling of aryl iodide derivatives with phenylacetylene derivatives and CO. In addition, the inventors have accessed chaicone derivates through a chemoselective and stereoselective hydrogenation reaction of the corresponding ynone derivatives.

[0010] It is an obj ect of the present invention to access ynone derivates and chaicone derivatives and to improve upon the disadvantages associated with conventional methods. In particular, the present invention allows for the production of ynone and chaicone derivatives with good yields, good selectivity and good substrate scope, whilst the catalyst according to the present invention is stable and recyclable. The catalyst and methods according to the present invention, also allow for the one-pot synthesis of valuable compounds. This has the advantage that there is no need to isolate intermediate compounds.

[0011] Furthermore, the catalyst according to the present invention is very active, selective and versatile, and provides access to a large variety of E-chalcones. In addition, the catalyst and methods of the present invention allow for improvements in practicability, scalability and sustainability as compared to state-of-the-art synthetic approaches.

[0012] In addition, the catalysts described herein allow for the chemo- and stereoselective hydrogenation of ynone derivatives to produce the corresponding E-chalcone derivatives.

[0013] Summary of the Invention

[0014] The above obj ect is solved by a catalyst comprising supported N-heterocyclic carbenes comprising palladium or nickel and metal nanoparticles (NPs); processes incorporating such a catalyst to access ynone and chaicone derivatives; and a catalyst for use in carbonylative coupling and / or hydrogenation and / or one-pot carbonylative coupling and hydrogenation reactions as defined in claims 1, 5, 6, 8, and 11. Preferred embodiments are the subj ect of the dependent claims.

[0015] Catalysts containing N-heterocyclic carbenes comprising palladium have been previously reported in WO 2015 / 197890 Al and by Gtirbuz et al. (N. Gtirbuz, S. Vural, S. Yagar, I. Ozdemir and T. Segkin; J Inorg Organomet Polym, 2010, 20, 19-25). However, such catalysts have not been reported in the context of carbonylative coupling reactions, nor in the context of stereoselective hydrogenation reactions. Furthermore, these catalysts do not contain supported metal nanoparticles. In addition, these catalysts are simple heterogenized Pd complexes that do not have multifunctionality. Moreover, the characterisation of these catalyst is superficial ( e. g., no demonstration of the attachment of the complexes to the supports, no demonstration of the nature of the Pd species, etc. ).

[0016] It is noted that in the context of coupling and hydrogenation reactions, to the best of the inventors' knowledge, multifunctional catalysts comprising metal-NHC complexes and metal nanoparticles have only been described on one occasion:

[0017] D. Kalsi, S. J. L. Anandaraj, M. Durai, C. Weidenthaler, M. Emondts, S. P. Nolan, A. Bordet and W. Leitner; ACS Catalysis 2022, 12, 14902-14910: " One-Pot Multicomponent Synthesis of Allyl and Alkylamines Using a Catalytic System Composed of Ruthenium Nanoparticles on Copper N-Heterocyclic Carbene-Modified Silica".

[0018] However, such catalysts have not been reported in the context of carbonylative coupling reactions, nor in the context of chemo- / stereoselective hydrogenation reactions. Utilising such catalysts in carbonylative coupling reactions would likely result in no activity and in degradation of the Cu-NHC complex.

[0019] By employing a catalyst according to the present invention, the inventors have improved upon the drawbacks associated with traditional methods of coupling and hydrogenation reactions, particularly traditional methods of synthesising chaicones.

[0020] Brief Description of the Drawings

[0021] Figure 1: Overview of methods for covalent attachment of a linker group to a support. Silanization (Fig. 1A), amidation (Fig. IB) and C-C coupling (Fig. IB and Fig. 1C).

[0022] Figure 2: Overview of catalysts according to the present invention. Figure 3: Overview of method of carbonylative coupling reaction according to the invention.

[0023] Figure 4: Overview of method of hydrogenation reaction according to the invention.

[0024] Figure 5: Overview of method of one-pot carbonylative coupling reaction and hydrogenation reaction according to the invention.

[0025] Figure 6: Overview of method of synthesising a catalyst according to the invention. Overview of two-step process (Figure 6A); first step of process (Figure 6B); second step of process (Figure 60).

[0026] Figure 7:1H NMR (500 MHz, THF-d8 ) spectrum of complex 11.

[0027] Figure 8: (a) 1H- 29Si CP-MAS NMR spectrum of Ru-SiO2- [Pd- NHC] before catalysis recorded at 11.7 T and 17.0 kHz MAS. Dashed lines show the decomposition of the spectrum to individual resonances. (b-c) 1H-13C CP-MAS NMR spectra recorded at 11.7 T and 17.0 kHz MAS.

[0028] Figure 9:1H-29Si CP-MAS NMR spectrum of non-grafted NHC. Br recorded at 16.4 T and 17.0 kHz MAS.

[0029] Figure 10:1H-13C CP-MAS NMR spectra recorded at 11.7 T and 17.0 kHz MAS. a) SiO2- [Pd-NHC], b) Pd-NHC, c) non-grafted NHC. Br. Peak splittings in c are caused by different chemical environments in the asymmetric unit.

[0030] Figure 11: Transmission FT-IR spectra of [Pd-NHC] (solid line) and Ru-SiO2- [Pd-NHC] (dashed line). Figure 12: Characteri zation of Ru-Si02- [ Pd-NHC ] and [ Pd-NHC ] by X-ray photoelectron spectroscopy. High resolution XPS spectra of ( a ) Pd3d and (b ) Ru3p.

[0031] Figure 13: Characteri zation of Ru-Si02- [ Pd-NHC ] before catalysis by XPS. High resolution XPS spectra of ( a ) Ci s & Ru3d, (b ) Nl s.

[0032] Figure 14: XPS high resolution scans showing the Pd3d region from the first and last 3 scans o f Ru-Si02- [ Pd-NHC ] catalyst. The binding energy positions of 3ds / 2 and 3d3 / 2 in metallic Pd is marked for reference.

[0033] Figure 15: Schematic depiction a ), and electron microscopy b-f ) of Ru-Si02- [ Pd-NHC ]. b ) STEM-HAADF, and c- f ) EDX elemental mapping of c ) Si-Ka; d) Br-Ka; e ) Pd-La; f ) Ru-Ka.

[0034] Figure 16: Si ze distribution of Ru nanoparticles in Ru-SiO2- [Pd-NHC]. Average diameter = 1. 8 ± 0. 4 nm.

[0035] Figure 17: NPs formation via beam damage during the characteri zation of reference Pd-NHC-SiO2 by STEM-HAADF. Average diameter = 1. 3 ± 0. 3 nm.

[0036] Figure 18: Time profile of carbonylative sonogashira coupling under optimi zed reaction conditions: Ru-SiO2- [ Pd-NHC ] ( 30 mg; 0. 006 mmol of Pd / Ru, 2 mol% ), iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to [ Pd-NHC ] ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), PC ( 1. 5 mL ), CO ( 2 bar ), 100 °C; Yield was determined by GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta- l, 3-diyne and benzene. Data points are average of three experiments and error bars represent standard deviations.

[0037] Figure 19: Recycling experiments for the one-pot synthesis of chaicones 4 using Ru-SiO2- [ Pd-NHC ]. Figure 20: Solid state1H-13C CPMAS NMR spectra of Ru-SiO2- [Pd-NHC] (a) before and (b) after catalysis recorded at 11.7 T and 17.0 kHz MAS. * labels signal from left-over product and solvent.

[0038] Figure 21: Transmission FT-IR spectra of Ru-SiO2- [Pd-NHC] before (solid line) and after catalysis (dashed line).

[0039] Figure 22: Characterization of Ru-SiO2- [Pd-NHC] after catalysis by XPS. High resolution XPS spectra of (a) Pd3d, (b) Nls, and (c) Cis & Ru3d.

[0040] Figure 23: Characterization of the spent Ru-SiO2- [Pd-NHC] catalyst after four catalytic cycles by electron microscopy a) STEM-HAADF b) STEM-BF images; c-f ) EDX elemental mapping of Si-Ka, I-La, Pd-La, Ru-Ka.

[0041] Figure 24: Size distribution of Ru-nanoparticles in Ru-SiO2- [Pd-NHC] after catalysis (4 runs) of average diameter = 2.4 ± 0.7 nm.

[0042] Figure 25: Evaluation of the synthesis of (E) -3-phenyl-l- (thien-2-yl) prop-2-en-l-one (4r) by a conventional route ( carbonylative Heck coupling), and by the one-pot carbonylative Sonogashira coupling + selective hydrogenation approach according to an embodiment of the present invention. Area proportional to the green chemistry metrics (large area = good metrics).

[0043] Figure 26: Transmission FTIR spectrum of different catalyst material with chemisorbed CO and silica as reference.

[0044] Figure 27:1H-29Si CP-MAS NMR spectrum of Ru-SiO2- [Pd-NHC] after catalysis, recorded at 11.7 T and 17.0 kHz MAS. Dashed lines show the decomposition of the spectrum to individual resonances.

[0045] Figures 28- 67: NMR characterisation associated to isolated products.

[0046] Figure 28:1H NMR ( 500 MHz, THF-d8 ) spectrum of ligand 8.

[0047] Figure 29:13C NMR ( 126 MHz, THF-d8) spectrum of ligand 8.

[0048] Figure 30:29Si NMR ( 79 MHz, THF-d8) spectrum of ligand 8.

[0049] Figure 31:1H NMR ( 500 MHz, THF-d8 ) spectrum of complex 9.

[0050] Figure 32:13C NMR ( 126 MHz, THF-d8) spectrum of complex 9.

[0051] Figure 33:29Si NMR ( 79 MHz, THF-d8) spectrum of complex 9.

[0052] Figure 34:1H,1H-COSY NMR ( 500 MHz, THF-d8) spectrum of complex 9.

[0053] Figure 35:1H,13C-HSQC NMR ( 500, 126 MHz, THF-d8) spectrum of complex 9.

[0054] Figure 36:1H,13C-HMBC NMR ( 500, 126 MHz, THF-d8) spectrum of complex 9.

[0055] Figure 37:1H,1H-NOESY NMR ( 500 MHz, THF-d8) spectrum of complex 9.

[0056] Figure 38:1H NMR ( 400 MHz, CDCI3 ) spectrum of product 4b.

[0057] Figure 39:13C NMR ( 101 MHz, CDCI3 ) spectrum of product 4b.

[0058] Figure 40:1H NMR ( 400 MHz, CDCI3 ) spectrum of product 4f.

[0059] Figure 41:13C NMR ( 101 MHz, CDCI3 ) spectrum of product 4f. Figure 42:1H NMR (400 MHz, CDCI3) spectrum of product 4 j. Figure 43:13C NMR ( 101 MHz, CDCI3) spectrum of product 4 j.

[0060] Figure 44:1H NMR (400 MHz, CDCI3) spectrum of product 4k.

[0061] Figure 45:13C NMR ( 101 MHz, CDCI3) spectrum of product 4k.

[0062] Figure 46:19F NMR (376 MHz, CDCI3) spectrum of product 4k.

[0063] Figure 47:1H NMR (400 MHz, CDCI3) spectrum of product 4m.

[0064] Figure 48:13C NMR ( 101 MHz, CDCI3) spectrum of product 4m.

[0065] Figure 49:19F NMR (376 MHz, CDCI3) spectrum of product 4m.

[0066] Figure 50:1H NMR (400 MHz, CDCI3) spectrum of product 4n.

[0067] Figure 51:13C NMR ( 101 MHz, CDCI3) spectrum of product 4n.

[0068] Figure 52:1H NMR (400 MHz, CDCI3) spectrum of product 4o.

[0069] Figure 53:13C NMR ( 101 MHz, CDCI3) spectrum of product 4o.

[0070] Figure 54:1H NMR (400 MHz, CDCI3) spectrum of product 4r.

[0071] Figure 55:13C NMR ( 101 MHz, CDCI3) spectrum of product 4r.

[0072] Figure 56:1H NMR (400 MHz, CDCI3) spectrum of product 4u.

[0073] Figure 57:13C NMR ( 101 MHz, CDCI3) spectrum of product 4u.

[0074] Figure 58:1H NMR (400 MHz, CDCI3) spectrum of product 4y.

[0075] Figure 59:13C NMR ( 101 MHz, CDCI3) spectrum of product 4y.

[0076] Figure 60:1H NMR (400 MHz, CDCI3) spectrum of product 4ag. Figure 61:13C NMR ( 101 MHz, CDCI3) spectrum of product 4ag.

[0077] Figure 62:1H NMR (400 MHz, CDCI3) spectrum of product 4ah.

[0078] Figure 63:13C NMR ( 101 MHz, CDCI3) spectrum of product 4ah.

[0079] Figure 64:1H NMR (400 MHz, CDCI3) spectrum of product 4ai.

[0080] Figure 65:13C NMR ( 101 MHz, CDCI3) spectrum of product 4ai.

[0081] Figure 66:1H NMR (400 MHz, CDCI3) spectrum of product 4ak.

[0082] Figure 67:13C NMR ( 101 MHz, CDCI3) spectrum of product 4ak.

[0083] Detailed Description

[0084] Embodiments according to the present invention will now be described in more detail.

[0085] As used herein, the term " N-heterocyclic carbene" (NHC) refers to a cyclic carbene species with two neighbouring nitrogen atoms.

[0086] As used herein, the term "ynone" refers to a compound having a ketone functional group and a C-C triple bond. The general formula of an ynone can be described as R-C=C-C (=0) -R'.

[0087] As used herein, an "ionic liquid" ( IL) is a salt in the liquid state at or below 100 °C at atmospheric pressure, i. e., the pure IL is a liquid and contains a mixture of cations and anions in these conditions.

[0088] As used herein, the term "support" (Su) refers to a solid material on which the components of the catalyst are immobilised. As used herein, the term "linker group" (L) refers to a molecular functionality that is responsible for the attachment of the N-heterocyclic carbene to the support.

[0089] As used herein, the term "spacer group" (Sp) refers to a molecular group that provides separation and connection between the linker and the N-heterocyclic carbene.

[0090] As used herein, the term "monometallic nanoparticles" refers to nanoparticles comprised of one metal, and "bimetallic nanoparticles" refers to nanoparticles comprised of two different metals.

[0091] As used herein, the term "3d transition metal" refers to metals from the first transition series or 3d series, including Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu and Zn.

[0092] As used herein, the term "noble metal" refers to metals that have outstanding resistance to oxidation, including Rh, Ru, Rd, Pt, Ag, Re, Os, Ir and Au.

[0093] As used herein, the term "neat conditions" refers to a reaction that is carried out without the presence of any additional solvents.

[0094] As used herein, the term "one-pot" refers to a process where multiple reactions occur sequentially in the same reaction vessel without the need for isolation of intermediates.

[0095] As used herein, the term "coupling reaction" refers to a reaction in which two reactant compounds are bonded together.

[0096] As used herein, the term "carbonylative coupling reaction" refers to a coupling reaction that includes the incorporation of carbon monoxide. An example of a carbonylative coupling reaction is the reaction of an aryl iodide derivative with a phenylacetylene derivative and carbon monoxide, to form a ynone. For example:

[0097] CO

[0098] R

[0099]

[0100] According to an embodiment of the present invention, the catalyst comprises a support, metal nanoparticles and a N-heterocyclic carbene comprising palladium or nickel, preferably palladium. The metal nanoparticles are immobilised on the support and the N-heterocyclic carbene comprising palladium or nickel is covalently bound to the support, preferably via a spacer and / or a linker.

[0101] The metal nanoparticles according to the present invention are immobilised on the support. A preferred method of immobilising the nanoparticles on the support is outlined in the examples of the present invention.

[0102] The covalent attachment of the N-heterocyclic carbene (NHC) comprising Pd or Ni, can proceed through different methods. Examples of such methods include silanization (Fig. 1A), amidation (Fig. IB) and C-C coupling (Fig. IB and Fig. 1C).

[0103] Silanization is the preferred method for metal oxide supports. For the attachment to carbon-based support materials, amidation or C-C coupling ( e. g., via diazotisation) are preferred methods. The carbon-based support can be activated by generation of -COOH functionalities on the surface and then reacted with amines to form amide bonds. Alternatively, direct C-C coupling can be achieved using diazonium chemistry. In this latter case, the linker can be an arene group.

[0104] When the NHC is attached on the support via silanization, the linker group is an -Si-0- group. When the NHC is attached on the support via C-C coupling, the linker group is a C-C linkage, wherein the C-C linkage is preferably an alkylene or arylene group. When the NHC is attached on the support via amidation, the linker group is an amide group.

[0105] According to an embodiment of the present invention (Figure 2A), a catalyst comprises the following structure:

[0106]

[0107] and metal nanoparticles immobilised on the support, wherein:

[0108] Su is a support;

[0109] L is a linker group;

[0110] Sp is a spacer group;

[0111] M is Pd or Ni, preferably Pd;

[0112] Z is Br2, I2, Cl2, F2, OTf2, preferably Z is Br2;

[0113] Ri and R2 are either i) each independently selected from the group consisting of a saturated or unsaturated carbocyclic group with 5-6 carbon atoms, a saturated or unsaturated 5- to 6-membered heterocyclic group, or an alkyl group with 1-10 carbon atoms, preferably with 1-6 carbon atoms; or ii) Ri and R2 form with the nitrogen atoms to which each of Ri and R2 are attached, the two carbon atoms attached to the M, and the M, a 6- to 8-membered ring, preferably a 6-membered ring.

[0114] Preferably, Ri and R2 are either i) each independently an alkyl group with 1-6 carbon atoms; or ii) Rx and R2 form with the nitrogen atoms to which each of Ri and R2 are attached, the two carbon atoms attached to the M, and the M, a 6-membered ring. The definitions of the following embodiments equally apply to the above.

[0115] In a preferred embodiment, the metal nanoparticles are monometallic or bimetallic nanoparticles, wherein the metal or metals are selected from the group consisting of the 3d transition metals and / or the noble metals. When the nanoparticles are bimetallic nanoparticles, they can be represented by:

[0116] M1xM2100-x

[0117] wherein:

[0118] M1is a 3d transition metal or a noble metal;

[0119] M2is a 3d transition metal or a noble metal; and x is a number between 1 and 99, preferably between 5 and 80.

[0120] According to a preferred embodiment, M1is a 3d transition metal and M2is a noble metal, wherein x is a number between 5 and 80.

[0121] Preferred 3d transitional metals are Mn, Ni, Co, Cu, and Fe, and preferred noble metals are Ru, Pd, Rh, and Pt. In a more preferred embodiment, x is a number between 5 and 70. More preferably, x is a number between 10 and 50.

[0122] According to a more preferred embodiment, the metal nanoparticles are monometallic metal nanoparticles. Most preferred are monometallic Ru nanoparticles.

[0123] As will be appreciated, the subscript x as used herein in the definition of the bimetallic nanoparticles denotes the relative, preferably average, atomic proportions of M1and M2in the bimetallic nanoparticles.

[0124] According to a preferred embodiment, the metal nanoparticle loading on the support is from 0.2-10 weight-%, preferably 0.5-7 weight-%, more preferably 1-5 weight-%, even more preferably 1.5-3 weight-%. According to a most preferred embodiment, the metal nanoparticle loading on the support is 2 weight-%.

[0125] The spacer (Sp) can be an alkylene group with 1-30 carbon atoms, optionally containing one or more groups selected from ether, ester, amido or arylene groups. Preferably, the spacer Sp is an alkylene group with 2-10 carbon atoms, most preferably with 2-4 carbon atoms.

[0126] The support (Su) can be selected from SiO2, A12O3, TiO2, ZrO2, CaO2, ZnO2, MgO2, CeO2, graphene, graphitic material, activated charcoal or carbon nanotubes. Preferably, the support is SiO2.

[0127] The support can serve to immobilise the NHC comprising palladium or nickel, as well as the metal nanoparticles. This has the advantage that it improves the recyclability of the catalyst. In addition, the support has the advantage that it can help to control the poisoning of the catalyst with carbon monoxide. This is further outlined below. The metal nanoparticles are immobilised on the same support to which the N-heterocyclic carbene comprising palladium or nickel is covalently bound.

[0128] The linker (L) can be an -Si-O- group, a C-C linkage or an amido group connected to the support. Preferably, the linker is a -Si-O- group connected to the support. When the linker is an -Si-O- group, the spacer is preferably an alkylene group with 1-30 carbon atoms, more preferably an alkylene group with 2-10 carbon atoms, most preferably an alkylene group with 2-4 carbon atoms. A C-C linkage can be an alkylene or an arylene group.

[0129] M is nickel or palladium, preferably palladium. Preferably, the metal loading M on the support is from 0.2-10 weight-%, preferably 0.5-7 weight-%, more preferably 1-5 weight-%, even more preferably 1.5-3 weight-%. According to a most preferred embodiment, the metal loading M on the support is 2 weight-%.

[0130] Z is Br2, I2, Cl2, F2, OTf2, preferably Br2.

[0131] R2and R2are either i) each independently selected from the group consisting of a saturated or unsaturated carbocyclic group with 5-6 carbon atoms, a saturated or unsaturated 5- to 6-membered heterocyclic group, or an alkyl group with 1-10 carbon atoms, preferably with 1-6 carbon atoms; or ii) R2and R2form with the nitrogen atoms to which each of R2and R2are attached, the two carbon atoms attached to the M, and the M, a 6- to 8-membered ring, preferably a 6-membered ring.

[0132] Preferably, R2and R2are either i) each independently selected from an alkyl group with 1-10 carbon atoms, preferably with 1-6 carbon atoms; or ii) R2and R2form with the nitrogen atoms to which each of R2and R2are attached, the two carbon atoms attached to the M, and the M, a 6-membered ring.

[0133] According to an embodiment of the invention, the total metal loading (metal nanoparticles and metal M) on the support is from 0.5-20 weight-%, preferably 1-8 weight-%, most preferably 2-4 weight-%.

[0134] According to a preferred embodiment, the catalyst is poisoned by carbon monoxide.

[0135] The inventors unexpectedly found that the poisoning of the catalyst had the advantage of improving the chemo- and stereoselectivity of hydrogenation reactions, particularly hydrogenation reactions of ynones to the corresponding E-chalcones. It is more preferred, that the catalyst is only partially poisoned. Preferably, the metal nanoparticles of the catalyst are partially poisoned by carbon monoxide. Partially poisoned means, that the metal nanoparticles are not completely poisoned (i. e., deactivated) by the carbon monoxide.

[0136] According to a preferred embodiment, the metal nanoparticles of the catalyst have active sites which are partially blocked by adsorbed carbon monoxide. More preferably, the metal nanoparticles of the catalyst have active sites which are blocked by adsorbed carbon monoxide to the extent that the nanoparticles are inactive for alkene, aromatic and ketone hydrogenation, but are active for the hydrogenation of an alkyne to an alkene, preferably to an E-alkene.

[0137] The poisoning of the catalyst with carbon monoxide can be achieved by (i. e., the poisoned catalyst is obtainable by) heating the catalyst in the presence of carbon monoxide.

[0138] Preferably the catalyst is heated in the presence of carbon monoxide at a temperature of 21-110 °C and under a carbon monoxide pressure of 1-10 bar. More preferably the catalyst is heated in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-5 bar. Even more preferably the catalyst is heated in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-3 bar for 1-3 hours. Most preferably the catalyst is heated in the presence of propylene carbonate and carbon monoxide at a temperature of 100 °C and under a carbon monoxide pressure of 2 bar for 2 hours.

[0139] For example, the poisoning of the catalyst with carbon monoxide can be achieved by the following protocol (i. e., the poisoned catalyst is obtainable by): The catalyst to be treated ( 0.006 mmol) is pressurised with CO (2 bar) in the presence of 1.5 mL propylene carbonate as a solvent and heated at 100 °C for 2 hours.

[0140] Without wishing to be bound by theory, it is believed that the poisoning of the catalyst with carbon monoxide allows for the chemo- and stereoselective hydrogenation of ynones to the corresponding E-chalcones. It is further believed that the interaction of the metal nanoparticles with the NHC comprising Pd or Ni, is important in controlling the strength of the poisoning and avoiding complete deactivation of the metal nanoparticles. Due to this interaction, the immobilisation of the metal nanoparticles on the support and the attachment of the NHC comprising Pd or Ni to the support, is advantageous.

[0141] The above definitions and explanations equally apply to the catalysts described in the following sections.

[0142] According to a preferred embodiment, the catalyst comprises the following structure:

[0143]

[0144] and metal nanoparticles immobilised on the support, wherein:

[0145] Su is a support, wherein the support Su is selected from SiO2, A12O3, TiO2, ZrO2, CaO2, ZnO2, MgO2, CeO2, graphene, graphitic material, activated charcoal or carbon nanotubes, preferably the support is SiO2;

[0146] L is a linker group, wherein the linker L is an -Si-O-group, a C-C linkage or an amido group connected to the support; preferably, the linker is a -Si-0- group connected to the support;

[0147] Sp is a spacer group, wherein the spacer Sp is an alkylene group with 1-30 carbon atoms, preferably 2-10 carbon atoms;

[0148] M is Pd or Ni, preferably Pd;

[0149] Z is Br2, I2, Cl2, F2, OTf2, preferably Z is Br2;

[0150] Ri and R2are either i) each independently selected from an alkyl group with 1-10 carbon atoms, preferably with 1-6 carbon atoms; or ii) Ri and R2form with the nitrogen atoms to which each of Ri and R2are attached, the two carbon atoms attached to the M, and the M, a 6-membered ring; and

[0151] the metal nanoparticles are selected from Ru, Pd, Mn, Ni, Co, Cu, Rh, Pt and Fe, preferably the metal nanoparticles are Ru;

[0152] preferably wherein the catalyst is poisoned by carbon monoxide.

[0153] In a further preferred embodiment according to the present invention (Figure 2B), a catalyst comprises the following structure:

[0154]

[0155] and metal nanoparticles immobilised on the support, wherein:

[0156] Su is a support, preferably wherein the support is SiO2; L is a linker group, preferably wherein the linker is an -Si-O- group;

[0157] Sp is a spacer group, preferably wherein the spacer is an alkylene group with 2-4 carbon atoms, more preferably 3 carbon atoms; preferably wherein the metal nanoparticles are Ru nanoparticles and / or wherein the catalyst is poisoned by carbon monoxide.

[0158] Advantages of the catalysts described herein include their recyclability and re-usability.

[0159] In another embodiment according to the present invention, the catalysts described above can be used in a carbonylative coupling reaction and / or a hydrogenation reaction.

[0160] In yet another embodiment according to the present invention, the catalysts described above can be used in a chemo- and stereoselective hydrogenation reaction.

[0161] In a further embodiment, the catalysts described above can be used in a one-pot carbonylative coupling reaction and hydrogenation reaction.

[0162] According to another embodiment, the catalysts described above can be used in the synthesis of ynone derivatives and / or chaicone derivatives. Specifically, the catalysts described above can be used in the chemo- and stereoselective synthesis of E-chalcone derivatives.

[0163] In the following embodiments, methods of carbonylative coupling reactions are described (Figure 3). These methods can for example be used to synthesise ynone derivatives.

[0164] According to an embodiment of the invention, a method is disclosed of coupling a substrate 1 having one of the following general formulas 1A or IB, with a substrate 2 having one of the following general formulas 2A or 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst as described above, and heating in the presence of carbon monoxide and a base,

[0165]

[0166] R8 Ry R8

[0167] 2A 2B

[0168] wherein:

[0169] Y is I, Br or OTf, preferably I;

[0170] X2-X5are each independently C, N, 0, or S, provided that at most one of X2-X5is N, 0, or S;

[0171] X6-X10are each independently C, N, 0, or S, provided that at most one of X6-X10is N, O, or S;

[0172] R1-R5 are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent R1-R5 form a 5- to 8-membered ring with the X2-X5to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -NO2, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group;

[0173] R6-R10are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent R6-RIO form a 5- to 8-membered ring with the X6-X10to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -NO2, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group.

[0174] According to a preferred embodiment,

[0175] R1-R5 are each independently H, F, Cl, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, CN, phenyl, or morpholyl; or two adj acent R1-R5 form a 6-membered ring with the X2-X5to which they are attached;

[0176] R6-RIO are each independently H, F, Cl, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, or phenyl; or two adj acent R6-RIO form a 6-membered ring with the X6-X10to which they are attached;

[0177] X2-X5are either: i) each independently C, or ii) each independently C, provided that one of X2-X5is N, or S; and X6-X10are either: i) each independently C, or ii) each independently C, provided that one of X6-X10is S.

[0178] These preferred definitions of R2-RIO and X2-X10equally apply to all other embodiments of the invention.

[0179] In a preferred embodiment according to the invention, the coupling of substrate 1 with substrate 2 produces a compound having one of the following general formulas 3A, 3B, 3C or 3D

[0180]

[0181] wherein R!-R10and X!-X10are as defined in the above embodiments.

[0182] According to a preferred embodiment, the catalyst loading (reflected by Pd loading in moll) is 0.5-4 moll, more preferably 1-3.5 moll, most preferably 2-3 mo 11.

[0183] The above preferred embodiments equally apply to the following methods.

[0184] In the following embodiments, methods of hydrogenation reactions are described (Figure 4 ). These methods can, for example, be used to synthesise chaicone derivatives. The methods can be used specifically for the chemo- and stereoselective synthesis of E-chalcone derivatives.

[0185] An embodiment of the present invention, includes a method of hydrogenating a substrate 3 having one of the general formulas 3A, 3B, 3C or 3D, wherein the method comprises bringing substrate 3 into contact with a catalyst as described above, and heating in the presence of hydrogen,

[0186]

[0187] wherein:

[0188] Ri-Rio and Xi-Xi0are as defined above.

[0189] According to a preferred embodiment, the catalyst is treated with carbon monoxide before it is brought into contact with substrate 3 (i. e., the catalyst is pre-treated with carbon monoxide). This has the advantage of allowing for a chemo-and stereoselective hydrogenation of substrate 3. Without wishing to be bound by theory, it is believed that the pretreatment of the catalyst with carbon monoxide leads to a partial poisoning of the catalyst. It is believed that carbon monoxide partially poisons the active sites of the metal nanoparticles. This means for example that the active sites of the nanoparticles are poisoned to the extent where they become inactive for alkene, aromatic and ketone hydrogenation, but remain active for the selective hydrogenation of alkynes to E-alkenes. It is further believed that the interaction of the metal nanoparticles with the NHC containing Pd or Ni plays a role in controlling the strength of the poisoning and in avoiding the complete deactivation of the metal nanoparticles. The treatment of the catalyst with carbon monoxide before it is brought into contact with a substrate, can for example be achieved as follows:

[0190] The catalyst to be treated ( 0.006 mmol) is pressurised with CO (2 bar) in the presence of propylene carbonate as a solvent and heated at 100 °C for 2 hours.

[0191] According to an embodiment of the present invention, the hydrogenation of substrate 3 produces a compound having one of the following general formulas 4A, 4B, 4C or 4D:

[0192] 4A

[0193]

[0194] wherein R -Rio and Xi-Xio are as defined above.

[0195] The above preferred embodiments equally apply to the following methods.

[0196] In the following embodiments, methods of one-pot carbonylative coupling and hydrogenation reactions are described (Figure 5). These methods can for example be used to synthesise chaicone derivatives. The methods can be used specifically for the stereoselective synthesis of E-chalcone derivatives. An embodiment of the present invention includes a method of a one-pot coupling and hydrogenation reaction of a substrate 1 having one of the following general formulas 1A or IB, and a substrate 2 having one of the following general formulas 2A and 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst as described in the above embodiments, and heating in the presence of carbon monoxide, hydrogen, and a base,

[0197] Y

[0198] 1A 1B

[0199]

[0200] R8 RJ R8

[0201] 2A 2B

[0202] wherein Y, R!-R10and X!-X10are as defined above.

[0203] According to an embodiment of the present invention, the one-pot coupling reaction and hydrogenation of substrates 1 and 2 produces a compound having one of the following general formulas 4A, 4B, 4C or 4D, 4A

[0204]

[0205] wherein R!-R10and X!-X10are as defined above.

[0206] According to a preferred embodiment of the invention, in the one-pot coupling reaction, in a first step, substrate 1 is brought into contact with substrate 2 and the catalyst, and is heated in the presence of carbon monoxide and a base under a pressure of 1-10 bar of carbon monoxide, to form a reaction mixture; and in a second step, an excess pressure of carbon monoxide is removed and the reaction mixture is heated in the presence of hydrogen under a pressure of 1-3 bar of hydrogen.

[0207] If the above-described reaction is completed in a solvent, in the second step there can remain some carbon monoxide dissolved in the solvent (solution phase), after removal of the excess pressure left in the gas phase after carrying out the first step.

[0208] According to a further embodiment, substrate 1, substrate 2, the base, and the catalyst are heated in the presence of both carbon monoxide and hydrogen, preferably wherein substrate 1, substrate 2, the base, and the catalyst are heated under a pressure of 2-10 bar of carbon monoxide and hydrogen. In any of the above-described methods, the reaction is completed under neat conditions or in a solvent. The reactions are preferably completed in a solvent.

[0209] It is preferred that the solvent is a polar solvent or an ionic liquid. Examples of such solvents include but are not limited to propylene carbonate, dimethyl carbonate, 1, 4 dioxane and l-Butyl-3-methylimiadozoliumhexaf luorophosphate ( [Bmim] PF6).

[0210] It is more preferred, that the solvent is propylene carbonate, dimethyl carbonate, ethylene carbonate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, tetrahydrofuran, 1, 4-dioxane, anisole, or toluene.

[0211] Most preferably, the solvent is dimethylformamide or propylene carbonate.

[0212] In any of the above-described methods, the base is preferably an amine, a carbonate or a hydroxide. It is preferred that the base is triethylamine, diethylamine, potassium carbonate, caesium carbonate, sodium carbonate, N, N-di isopropyl ethyl amine, 1, 8-Diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [ 2. 2. 2 ] octane, piperidine, sodium hydroxide, potassium hydroxide, or caesium hydroxide. Most preferably, the base is triethylamine.

[0213] In any of the above-described methods, heating is completed at a temperature of 50 °C - 150 °C, preferably between 80 °C - 130 °C, most preferably between 100 °C - 120 °C. Heating at or above a temperature of 80 °C, preferably 100 °C, has the advantage that reaction times can be improved. Heating at or below a temperature of 130 °C, preferably 120 °C, has the advantage that decomposition of the NHC comprising palladium or nickel can be prevented. In any of the above-described methods, it is preferred that the carbon monoxide is under a pressure of 1-10 bar.

[0214] In any of the above-described methods, it is preferred that the hydrogen is under a pressure of 1-3 bar.

[0215] In any of the above-described methods, when carbon monoxide and hydrogen are simultaneously utilised ( e. g., as syngas) it is preferred that the carbon monoxide and hydrogen are under a pressure of 2-10 bar.

[0216] According to a more preferred embodiment of the present invention, a method of a one-pot coupling and hydrogenation reaction of a substrate 1 having one of the following general formulas 1A or IB, and a substrate 2 having one of the following general formulas 2A and 2B, comprises in a first step bringing substrate 1 into contact with substrate 2 and a catalyst, and heating under pressure in the presence of a solvent, carbon monoxide, and a base under a pressure of 1-10 bar of carbon monoxide, to form a reaction mixture, and in a second step, removing an excess pressure of carbon monoxide and heating the reaction mixture in the presence of hydrogen under a pressure of 1-3 bar of hydrogen,

[0217] Y

[0218] R- ± ^Rg Y

[0219] Xf ^<x,, I

[0220] x! X,R1 "

[0221] R2 R4k=x3

[0222]

[0223] R3 R2R3

[0224] 1 A 1B 2D

[0225]

[0226] Er

[0227] wherein:

[0228] heating is completed at a temperature of 50 °C - 150 °C, preferably between 80 °C - 130 °C, most preferably between 100 °C - 120 °C;

[0229] the solvent is a polar protic or a polar aprotic solvent, preferably the solvent is propylene carbonate, dimethyl carbonate, ethylene carbonate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, tetrahydrofuran, 1, 4-dioxane, anisole, or toluene, more preferably the solvent is dimethylformamide or propylene carbonate;

[0230] the base is triethylamine, diethylamine, potassium carbonate, caesium carbonate, sodium carbonate, N, N-di isopropyl ethyl amine, 1, 8-Diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [ 2. 2. 2 ] octane, piperidine, sodium hydroxide, potassium hydroxide, or caesium hydroxide, preferably triethylamine; and

[0231] the catalyst comprises the following structure:

[0232]

[0233] and metal nanoparticles immobilised on the support, wherein: Su is a support, preferably wherein Su is selected from SiO2, A12O3, TiO2, ZrO2, CaO2, ZnO2, MgO2, CeO2, graphene, graphitic material, activated charcoal or carbon nanotubes, more preferably the support is SiO2;

[0234] L is a linker group, preferably wherein the linker L is an -Si-0- group, a C-C linkage or an amido group connected to the support, most preferably, the linker is a -Si-0- group connected to the support;

[0235] Sp is a spacer group, preferably wherein the spacer Sp is an alkylene group with 1-30 carbon atoms, optionally containing one or more groups selected from ether, ester, amido or arylene groups, more preferably wherein the spacer Sp is an alkylene group with 2-10 carbon atoms, most preferably 2-4 carbon atoms;

[0236] M is Pd or Ni, preferably Pd;

[0237] Z is Br2, I2, Cl2, F2, OTf2, preferably Br2;

[0238] R2and R2are either i) each independently selected from the group consisting of a saturated or unsaturated 5- to 6-membered carbocyclic group; a saturated or unsaturated 5- to 6-membered heterocyclic group; or an alkyl group with 1-10 carbon atoms, preferably with 1-6 carbon atoms; or ii) R2and R2form with the nitrogen atoms to which each of R2and R2are attached, the two carbon atoms attached to M, and the M, a 6-to 8-membered ring, preferably a 6-membered ring; and

[0239] the metal nanoparticles are ruthenium nanoparticles, wherein the ruthenium nanoparticles are poisoned by carbon monoxide. Preferably, the Ru nanoparticles are partially poisoned by carbon monoxide.

[0240] Preferably, the catalyst described above comprises the following structure:

[0241]

[0242] wherein Su, L and Sp are defined as in any of the above embodiments.

[0243] The invention includes:

[0244] Item 1

[0245] A catalyst comprising:

[0246] a support;

[0247] metal nanoparticles; and

[0248] a N-heterocyclic carbene comprising palladium or nickel, preferably palladium;

[0249] wherein:

[0250] the metal nanoparticles are immobilised on the support; and

[0251] the N-heterocyclic carbene comprising palladium or nickel is covalently bound to the support, preferably via a spacer and a linker.

[0252] Item 2

[0253] A catalyst according to item 1, wherein the catalyst comprises the following structure:

[0254]

[0255] and metal nanoparticles immobilised on the support, wherein:

[0256] Su is a support;

[0257] L is a linker group;

[0258] Sp is a spacer group;

[0259] M is Pd or Ni;

[0260] Z is Br2, I2, Cl2, F2, OTf2, preferably Z is Br2;

[0261] Ri and R2are either i) each independently selected from the group consisting of a saturated or unsaturated 5- to 6-membered carbocyclic group; a saturated or unsaturated 5- to 6-membered heterocyclic group; or an alkyl group with 1-10 carbon atoms, preferably an alkyl group with 1-6 carbon atoms; or ii) Ri and R2form with the nitrogen atoms to which each of Ri and R2are attached, the two carbon atoms attached to M, and the M, a 6- to 8-membered ring, preferably a 6-membered ring.

[0262] Item 3

[0263] Catalyst according to any preceding item, wherein the metal nanoparticles are monometallic or bimetallic nanoparticles, wherein the metal or metals are selected from the group consisting of the 3d transition metals and / or the noble metals; preferably the metal or metals are selected from Ru, Pd, Mn, Ni, Co, Cu, Rh, Pt and Fe; most preferably the metal nanoparticles are monometallic Ru nanoparticles.

[0264] Item 4

[0265] Catalyst according to any preceding item, wherein the spacer Sp is an alkylene group with 1-30 carbon atoms, optionally containing one or more groups selected from ether, ester, amido or arylene groups;

[0266] preferably the spacer Sp is an alkylene group with 2-10 carbon atoms.

[0267] Item 5

[0268] Catalyst according to any preceding item, wherein the support Su is selected from SiO2, A12O3, TiO2, ZrO2, CaO2, ZnO2, MgO2, CeO2, graphene, graphitic material, activated charcoal or carbon nanotubes; preferably wherein the support is SiO2.

[0269] Item 6

[0270] Catalyst according to any preceding item, wherein the linker L is an -Si-O- group, a C-C linkage or an amido group connected to the support; preferably, the linker is a -Si-O-group connected to the support.

[0271] Item 7

[0272] Catalyst according to any preceding item, wherein the catalyst is poisoned by carbon monoxide.

[0273] Item 8

[0274] Catalyst according to any preceding item, wherein the catalyst is partially poisoned by carbon monoxide.

[0275] Item 9

[0276] Catalyst according to any preceding item, wherein the metal nanoparticles of the catalyst are partially poisoned by carbon monoxide.

[0277] I tern 10

[0278] Catalyst according to any preceding item, wherein the nanoparticles of the catalyst have active sites which are partially blocked by adsorbed carbon monoxide.

[0279] I tern 10 Catalyst according to any one of items 7-9, wherein the poisoned catalyst is obtainable by heating the catalyst in the presence of carbon monoxide,

[0280] preferably heating the catalyst in the presence of carbon monoxide at a temperature of 21-110 °C and under a carbon monoxide pressure of 1-10 bar,

[0281] more preferably heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-5 bar,

[0282] even more preferably heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-3 bar for 1-3 hours,

[0283] most preferably heating the catalyst in the presence of propylene carbonate and carbon monoxide at a temperature of 100 °C and under a carbon monoxide pressure of 2 bar for 2 hours.

[0284] I tem 11

[0285] Catalyst according to any preceding item, wherein the nanoparticles of the catalyst have active sites which are blocked by adsorbed carbon monoxide to the extent that the nanoparticles are inactive for alkene, aromatic and ketone hydrogenation, but are active for the hydrogenation of an alkyne to an alkene, preferably to an E-alkene.

[0286] Item 12

[0287] Use of a catalyst according to any preceding item in a carbonylative coupling reaction and / or a hydrogenation reaction.

[0288] I tem 13

[0289] Use of a catalyst according to any preceding item in a one-pot carbonylative coupling reaction and hydrogenation reaction.

[0290] I tem 14 Use of a catalyst according to any preceding item in the synthesis of a chaicone or an ynone, preferably a chaicone, more preferably an E-chalcone.

[0291] I tem 15

[0292] Use of a catalyst according to any preceding item in the selective hydrogenation of an alkyne to the corresponding E-alkene.

[0293] I tem 16

[0294] Method of coupling a substrate 1 having one of the following general formulas 1A or IB, with a substrate 2 having one of the following general formulas 2A or 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst according to any one of items 1-11, and heating in the presence of carbon monoxide and a base,

[0295] R6" X6<5^S‘X9'R9

[0296] X? Xg

[0297] R7R8

[0298]

[0299] 2B

[0300] wherein:

[0301] Y is I, Br or OTf, preferably I;

[0302] Xi-X5are each independently C, N, 0, or S, provided that at most one of Xi-X5is N, 0, or S; X6-X10are each independently C, N, 0, or S, provided that at most one of X6-X10is N, O, or S;

[0303] R1-R5 are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent R1-R5 form a 5- to 8-membered ring with the X2-X5to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -N02, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group;

[0304] Rg-Rio are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=0) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent Rg-Rio form a 5- to 8-membered ring with the X6-X10to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -NO2, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group.

[0305] I tem 17

[0306] Method according to item 16, wherein the coupling of substrate 1 with substrate 2 produces a compound having one of the following general formulas 3A, 3B, 3C or 3D

[0307]

[0308] Xi-Xio and Ri-Rio are as defined above.

[0309] I tem 18

[0310] Method of hydrogenating a substrate 3 having one of the general formulas 3A, 3B, 3C or 3D, wherein the method comprises bringing substrate 3 into contact with a catalyst according to any one of items 1-11, and heating in the presence of hydrogen,

[0311]

[0312]

[0313] wherein:

[0314] Xi-Xio and R1-R10 are as defined above.

[0315] I tem 19

[0316] Method according to item 18, wherein the catalyst is treated with carbon monoxide before it is brought into contact with substrate 3,

[0317] preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of carbon monoxide,

[0318] more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of carbon monoxide at a temperature of 21-110 °C and under a carbon monoxide pressure of 1-10 bar,

[0319] even more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-5 bar,

[0320] even more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-3 bar for 1-3 hours,

[0321] most preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of propylene carbonate and carbon monoxide at a temperature of 100 °C and under a carbon monoxide pressure of 2 bar for 2 hours. Item 20

[0322] Method according to item 18 or 19, wherein the hydrogenation of substrate 3 produces a compound having one of the

[0323]

[0324] Xi-Xio and Ri-Rio are as defined above.

[0325] Item 21

[0326] Method of a one-pot coupling and hydrogenation reaction of a substrate 1 having one of the following general formulas 1A or IB, and a substrate 2 having one of the following general formulas 2A and 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst according to any one of items 1-11, and heating in the presence of carbon monoxide, hydrogen, and a base,

[0327] Y

[0328]

[0329] 1 A 1 B

[0330]

[0331] wherein:

[0332] Y, X1-X10and R1-R10are as defined above.

[0333] Item 22

[0334] Method according to item 21, wherein the one-pot coupling reaction and hydrogenation of substrates 1 and 2 produces a compound having one of the following general formulas 4A, 4B,

[0335]

[0336] wherein:

[0337] Xi-Xio and Ri-Rio are as defined above.

[0338] Item 23

[0339] Method according to any one of items 21-22, wherein:

[0340] in a first step, substrate 1 is brought into contact with substrate 2 and a catalyst according to any one of items 1-11, and is heated in the presence of carbon monoxide and a base under a pressure of 1-10 bar of carbon monoxide, to form a reaction mixture; and

[0341] in a second step, an excess pressure of carbon monoxide is removed and the reaction mixture is heated in the presence of hydrogen under a pressure of 1-3 bar of hydrogen.

[0342] Item 24

[0343] Method according to any one of items 21-23, wherein substrate 1, substrate 2, the base, and the catalyst are heated in the presence of both carbon monoxide and hydrogen, preferably wherein substrate 1, substrate 2, the base, and the catalyst are heated under a pressure of 2-10 bar of carbon monoxide and hydrogen.

[0344] Item 25

[0345] Method according to any one of items 16-24, wherein the reaction is completed in a solvent;

[0346] preferably wherein the solvent is a polar solvent or an ionic liquid;

[0347] more preferably wherein the solvent is a polar protic or a polar aprotic solvent;

[0348] even more preferably wherein the solvent is propylene carbonate, dimethyl carbonate, ethylene carbonate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, tetrahydrofuran, 1, 4-dioxane, anisole, or toluene; most preferably wherein the solvent is dimethylformamide or propylene carbonate.

[0349] Item 26

[0350] Method according to any one of items 16-25, wherein the base is an amine, a carbonate or a hydroxide;

[0351] preferably wherein the base is triethylamine, diethylamine, potassium carbonate, caesium carbonate, sodium carbonate, N, N-diisopropylethylamine, 1, 8-Diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2. 2. 2 ] octane, piperidine, sodium hydroxide, potassium hydroxide, or caesium hydroxide; most preferably wherein the base is triethylamine.

[0352] Item 27

[0353] Method according to any one of items 16-26, wherein heating is completed at a temperature of 50 °C - 150 °C, preferably between 80 °C - 130 °C, most preferably between 100 °C - 120 °C.

[0354] Item 28

[0355] Method according to any one of items 16-27, wherein the heating in the presence of carbon monoxide is under a pressure of 1-10 bar of carbon monoxide.

[0356] Item 29

[0357] Method according to any one of items 16-28, wherein the heating in the presence of hydrogen is under a pressure of 1-3 bar of hydrogen.

[0358] Item 30

[0359] Method according to any one of items 16-29, wherein the heating in the presence of carbon monoxide and hydrogen, is under a pressure of 2-10 bar of carbon monoxide and hydrogen.

[0360] Examples

[0361] Examples according to the present invention will be presented.

[0362] Terminology:

[0363] The notation M-NHC refers to a N-heterocyclic carbene comprising a metal (such as Pd). The notation Ru-SiCy is utilised to define Ru nanoparticles that are immobilised on the support SiCy. Similarly, the notation Ru-SiCy- [M-NHC] is utilised to define Ru nanoparticles that are immobilised on the support SiCy, and a NHC comprising a metal that is bonded to the same SiO2support. Safety Warning:

[0364] High-pressure experiments with compressed CO or H2were carried out with 10 mL stainless steel autoclaves following safety precautions. To protect the autoclaves and avoid cross-contaminations, all the reactions were performed in glass inlets using a magnetic stirrer and an aluminum-heating block. Low pressure reactions (< 5 bar) were carried out in Fisher-Porter bottles placed behind a protective blast shield. The catalytic tests were repeated at least two times to ensure reproducibility.

[0365] General methods:

[0366] If not otherwise stated, the synthesis of [Pd-NHC], Ru-SiO2, and Ru-SiO2- [Pd-NHC] were carried out under an argon atmosphere using standard Schlenk techniques or in a glovebox, as previously reported or with modified protocols. Solvents for air- and moisture-sensitive experiments were used from a solvent purification system (MBraun-SPS-7 ) and stored directly in the glovebox over molecular sieves (3 and 4 A). All synthesized complexes and catalysts were stored under an argon atmosphere. Silica from Merck (Grade 10184, pore size 100 A, 63-200 pm) was dehydroxylated under vacuum at 500 °C for 16 h. [Ru ( 2-Me-allyl )2( cod) ] was obtained from Alfa Aesar. All other chemicals and solvents were purchased from commercial sources and used without purification.

[0367] Analytics:

[0368] Solution-state NMR

[0369] All solution-state NMR spectra were recorded on a Bruker Ascend 400 MHz and 500 MHz spectrometer at room temperature. The coupling constants (J) are given in Hertz (Hz), and the chemical shifts ( 5) are expressed in ppm, relative to TMS at 25 °C. The peak multiplicities were designated as follows: s = singlet; d = doublet; t = triplet, dd = doublet of doublet, ddd = doublet of doublets of doublets, dt = doublet of triplet, m = multiplet. Solid-state NMR

[0370] 1H-13C solid-state cross-polarization magic-angle spinning (CP-MAS) NMR spectra were recorded on a wide-bore Bruker 500 MHz ( 11.7 T) spectrometer (13C Larmor frequency of 125.7 MHz).1H-29Si CPMAS spectra were recorded on wide-bore Bruker 500 MHz ( 11.7 T) or 700 MHz ( 16.4 T) spectrometers (29Si Larmor frequency of 99.3 and 139.1 MHz, respectively). All spectra were recorded with Bruker 3.2 mm triple-resonance probes in double-resonance mode at 17.0 kHz magic-angle spinning (MAS). The probe was cooled with an active cooling gas to 270 or 280 K to maintain the sample temperature at around 290 K. The spectra were processed with the software Topspin version 4.1.4 (Bruker Biospin).2H-13C cross-polarization parameters were optimized on a13C-labelled glycine ethyl ester standard sample.2H-29Si cross-polarization parameters were optimized on a29Si-labelled octakis (trimethylsiloxy) silsesquioxane standard sample. All CP-MAS NMR spectra were acquired using a2H 90° pulse length of 2.5 ps, a CP contact time of 4.5 or 5.0 ms, and a relaxation delay between 1.0 and 12.5 s. More experimental parameters are summarized in Table 1 and Table 2.

[0371] Table 1. Overview of representative experimental parameters of1H-13C CP MAS NMR measurements.

[0372] Ru-SiO2- [ Pd- Ru-SiO2- [ Pd- SiO2- [ Pd- Pd-NHC NHC] before NHC] after NHC] catalysis catalysis

[0373] MAS frequency / kHz 17. 0 17. 0 17. 0 17. 0

[0374] Bo / T 11.7 11.7 11.7 11.7

[0375] v1(1H) excitation / 100 100 100 100 kHz

[0376] CP contact power 60 60 60 60 v2(1H) / kHz CP contact power 43 43 43 43 v2(13C ) / kHz

[0377] CP contact time / ms 5. 0 5. 0 5. 0 5. 0

[0378] FID acquisition time 19. 7 14. 7 15. 4 15. 4

[0379] / ms

[0380] InterS can delay / s 1. 95 2. 50 1. 95 12. 5

[0381] Number of s cans 27000 27000 30720 2048

[0382] Probe target 280 270 270 270 temperature / K

[0383] Total acquisition 14. 8 18. 9 16. 9 7. 2 time / h

[0384] Table 2. Overview of experimental parameters of1H-29Si CP-MAS NMR measurements.

[0385] Ru-SiO2- [ Pd-NHC] Ru-SiO2- [ Pd- NHC. Br before catalysis NHC] after

[0386] catalysis

[0387] MAS frequency / kHz 17. 0 17. 0 17. 0

[0388] Bo / T 16. 4 11. 7 11. 7

[0389] v1(1H ) excitation / 100 100 100 kHz

[0390] CP contact power v260 60 60 ( iH ) / kHz

[0391] CP contact power 43 43 43 v2(29Si ) / kHz

[0392] CP contact time / ms 5. 0 4. 5 4. 5

[0393] FID acquisition time 14. 7 15. 4 41. 5 / ms

[0394] InterScan delay / s 1. 69 1. 04 3.25

[0395] Number of scans 40000 72000 256

[0396] Probe target 280 270 270 temperature / K

[0397] Total acquisition 19. 0 21.3 0.25 time / h

[0398] Adiabatic CP transfer under the Hartmann-Hahn condition was achieved by a ramped-amplitude CP pulse1, with vRF(1H) being swept from 48 to 72 kHz. All spectra were acquired under 90 kHz SPINAL-64 proton decoupling using a pulse length of 5.56 ps during data acquisition. Chemical shifts were referenced indirectly to (CH3)4Si using secondary standards adamantane for13C (CH25 = 38.56 ppm) and octakis (trimethylsiloxy) silsesquioxane for29Si (OSi (CH3)35 = 11.5 ppm). The spectrum decomposition analysis were performed with the software DMFit.

[0399] Gas Chromatography

[0400] Gas chromatography (GC) was performed on a Shimadzu GC-2030 equipped with an FID-detector and a Rtx-1701 column from Restek.

[0401] Scanning Transmission Electron Microscopy with Energy Dispersive X-ray Spectroscopy

[0402] STEM / EDX was performed on a Thermo Scientific Tales F200X operated at 200 kV acceleration voltage. STEM imaging was performed using a camera length of 98 mm and a beam current of 99 pA (measured on the screen). EDX data was acquired using the SuperX EDX system, incorporating four SDDs with a total of 0.9sr collection angle. Samples for electron microscopy were prepared by depositing the colloidal powder onto a copper TEM grid with an amorphous carbon support film. All samples were handled under inert conditions from preparation to insertion into the TEM. To determine the NP size, the particles were analyzed using ImageJ with a count of at least 150-200 NPs.

[0403] High Resolution Mass Spectrometry

[0404] HRMS were carried out using Bruker APEX III FT-MS (7 T magnet), MAT 95 (Finnigan), Thermo Scientific LTQ-FT or Thermo Scientific Exactive.

[0405] N2Adsorption and Brunauer-Emmett-Teller Surface Area Determination

[0406] N2adsorption measurements were performed on a Quadrasorb SI from Quantachrom Instruments. BET surface areas were determined using a QuadraSorb station (7.01 ).

[0407] Transmission Fourier Transform Infrared Spectroscopy

[0408] FT-IR was performed using a Thermo Scientific Nicolet™ iS5 Spectrometer equipped with a transmission cell. Sample preparation was performed in a glovebox, where a small amount of [Pd-NHC] complex / catalyst was sandwiched between two layers of dry KBr and pressed into a thin disc.

[0409] X-ray Fluorescence

[0410] XRF was performed using a spectro Xepos C with a prolene foil of 12 pm at 3keV to 19 keV.

[0411] X-ray Photoelectron Spectroscopy

[0412] XPS measurements were performed on Ru-SiO2- [Pd-NHC] to identify the electronic structure of the material. [Pd-NHC] and Ru-SiO2- [Pd-NHC] after catalysis were also analyzed in a similar manner for comparison. In all cases, the corresponding powder samples were spread onto a carbon tape on the sample holder in a compact manner. XPS measurements were conducted employing a near ambient pressure (NAP) XPS (SPECS GmbH) at ultra-high vacuum conditions (~10-8mbar). The system was equipped with an Al-Ka source which produces monochromated X-rays of energy 1486. 6 eV, and a NAP hemispherical energy analyzer with an inbuilt double delay line detector. All high-resolution spectra were recorded using a pass energy of 20 eV and a resolution of 0.05 eV whereas the survey scans were recorded using 100 eV pass energy. In each case, at least 10 consecutive scans were performed. However, a greater number of scans in the Ru-SiO2- [Pd-NHC] led to the decomposition of the complex and thus detecting metallic Pd. Hence, only the first 3 scans were considered to obtain the high-resolution spectra of Pd3d, Nls and Cis & Ru3d, and the integrated data is presented. Data analysis was performed using the CasaXPS software after a binding energy calibration using the Cis at 484. 6 eV. Inductively Coupled Plasma Optical Emission Spectroscopy ( ICP-OES) was carried out by Mikroanalytisches Labor Kolbe on an ICP-OES Spectro Arcos from Spectro. The sample preparation was performed using a CEM-Mars 6 microwave.

[0413] Example 1: Synthesis of the [Pd-NHC] complex ( [ (3,3 ' ~ methylene bis (1- (3-triethoxysilyl) propyl) -2,2 ' -3,3 ' -tetrahydro- lH-imidazol -2 -yl) palladium (II) dibromide] )

[0414] [ (3, 3 ' -methylene bis ( 1- (3-triethoxysilyl ) propyl ) -2, 2 '-3, 3 '-tetrahydro-lH-imidazol-2-yl ) palladium ( I I ) dibromide ] is abbreviated as Pd-NHC.

[0415] Synthesis of Pd-NHC complex:

[0416] a) Synthesis of NHC. Br ligand [ ( 3, 3 ' -methylene bis ( l- (3- triethoxysilyl ) propyl) -lH-imidazol-3-ium) dibromide] (8) 2Br

[0417]

[0418] Compound 8 was synthesised using a literature procedure ( Gardiner, M. G.; Herrmann, W. A.; Reisinger, C. -P.; Schwarz, J.; Spiegler, M., Dicationic chelating N-heterocyclic carbene complexes of palladium: new catalysts for the copolymerisation of C2H4 and CO. J. Organomet. Chem. 1999, 572, 239-247 ).

[0419] In a schlenk flask, a mixture of 7 [ l— ( 3— triethoxysilylpropyl ) - IH-imidazole ] ( 2. 179 g, 8 mmol ) and dibromomethane ( 730 mg, 4. 2 mmol ) in toluene ( 10 mL ) was refluxed at 150 ° C for 48 h. The resulting white precipitate was washed with THF / Toluene ( 1: 10 ) and dried under vacuum to yield NHC. Br ( 8 ) as a white powder ( 4. 99 g, 87 % isolated yield).

[0420] 1H NMR (500 MHz, THF-d8): 5 (ppm) = 11. 06 ( s, 2H), 9. 11 ( s, 2H), 8. 07 ( s, 2H), 7. 54 ( s, 2H), 4. 40 ( t, J = 7. 3 Hz, 4H), 3. 83 ( q, J = 7. 0 Hz, 12H), 2. 08 - 2. 02 (m, 4H), 1. 18 ( t, J = 7. 0 Hz, 18H), 0. 71 - 0. 67 (m, 4H).

[0421] 13C NMR ( 126 MHz, THF-cfe): 5 (ppm) = 140. 13 ( s, 2C ), 124. 02 ( s, 2C ), 123. 58 ( s, 2C ), 59. 32 ( s, 6C ), 58. 20 ( s, 1C ), 53. 26 ( s, 2C ), 24. 83 ( s, 2C ), 19. 07 ( s, 6C ), 8. 25 ( s, 2C ).

[0422] 29Si NMR (79 MHz, THF-cfe): 5 (ppm) = -46. 90 ( s, 2Si ).

[0423] b ) Synthesis of Pd-NHC complex ( 9 ) Pd(acac)2(1 equiv.)

[0424] THF, 60 °C, 5 h 110 °C, 1 h Si (EtO)3\OEt)3

[0425]

[0426] [Pd-NHC] was prepared by adapting the procedure reported by Gardiner, M. G.; Herrmann, W. A.; Reisinger, C. -P.; Schwarz, J.; and Spiegler, M. (Dicationic chelating N-heterocyclic carbene complexes of palladium: new catalysts for the copolymerisation of C2H4 and CO. J. Organomet. Chem. 1999, 572, 239-247 ).

[0427] In the glovebox, a schlenk tube was loaded with NHC. Br (8, 1.44 g, 2 mmol) and [Pd facach] (0. 61 g, 2 mmol) in THF ( 10 mL). The clear solution was heated at 60 °C for 5 h, and then 110 °C for 1 h. After completion, the resulting solution was filtered through a pad of celite and concentrated under vacuum. To the crude product, pentane (3*10 mL) was added in a dropwise manner while stirring to obtain the complex 9 as a pale-yellow solid ( 1.38 g, 83% isolated yield). Notably, diastereotopic protons are generated in complex 9 upon coordination of Pd to the symmetrical ligand 8 as shown in Figure 7. HRMS results showed that 9 exist as an ionic complex with one bromine ligand in the outer coordination sphere.

[0428] 1H NMR (500 MHz, THF-d8) 5 (ppm) = 7.74 (d, J = 2. 0 Hz, 2H), 7.08 (d, J = 2.0 Hz, 2H), 6.70 (d, J = 13.2 Hz, 1H), 6.33 (d, J = 13.1 Hz, 1H), 4.58 (ddd, J = 13.0, 9.5, 6.0 Hz, 2H), 4.37 (ddd, J = 13.0, 9.7, 5.7 Hz, 2H), 3.81 (q, J = 7.0 Hz, 12H), 2.07 - 1.92 (m, 4H), 1.18 (t, J = 7.0 Hz, 18H), 0. 67 (ddd, J = 14.9, 11.0, 5.3 Hz, 2H), 0.54 (ddd, J = 14.9, 11.2, 5. 6 Hz, 2H).13C NMR (126 MHz, THF-d8) δ (ppm) = 162.48 (s, 2C), 122.36 (s, 2C), 121. 67 (s, 2C), 64.38 (s, 1C), 59.16 (s, 6C), 54.31 (s, 2C), 25.98 (s, 2C), 19.00 (s, 6C), 8.12 (s, 2C).

[0429] 29Si NMR (79 MHz, THF-d8): δ (ppm) = -46.56 (s, 2Si).

[0430] HRMS / ESI ( + ) (CH3CN): m / z = [C25H48BrN4O6PdSi2]1= 741.1327 and [Br] “ = 80

[0431] Example 2: Synthesis of the catalyst Ru-SiO2~ [Pd-NHC] (Figure 6A)

[0432] The synthesis of the Ru-SiO2- [Pd-NHC] catalyst was accomplished in two main steps (Figure 6A). These involve the immobilization of Ru NPs on SiO2, followed by covalently grafting the prepared [Pd-NHC] onto Ru-SiO2 by silanisation. In detail:

[0433] 1 ) Synthesis of Ru NPs on silica (Ru-SiCy) (Figure 6B)

[0434] [Ru ( 2-methylallyl ) 2 ( cod) ] ( 64 mg, 0.2 mmol) in THF (5 mL) was added to a suspension of partially dehydroxylated (500 °C under vacuum for 16 h) SiCy ( 1.0 g) in THF ( 10 mL) and stirred for 1 h at room temperature. After removal of solvent under vacuum, the impregnated SiCy was transferred to a 10 mL high-pressure autoclave containing a glass inlet and heated at 100 °C under an atmosphere of H2(50 bar) for 18 h. The autoclave was then cooled and Ru-SiCL was obtained as a black powder with a theoretical Ru loading of 0.2 mmol. g-1(2 wt%).

[0435] 2 ) Synthesis of Ru-SiO2- [Pd-NHC] (Figure 6C)

[0436] In a 250 mL schlenk flask, a solution of [Pd-NHC] (11, 165 mg, 0.2 mmol) was added to a suspension of Ru-SiCy ( 1 g) in THF ( 10 mL) and refluxed at 120 °C under argon atmosphere for 48 h. After cooling down, the clear supernatant was removed and the solid catalyst was washed with THF (3*10 mL) under vigorous stirring (700 rpm) to remove the loosely bound or physisorbed complex from the surface. Finally, the catalyst was dried and collected as a black powder with a theoretical Pd loading of 0.2 mmol. g-1(2 wt%). Example 3: Characterisation of the catalyst Ru-Si02~ [Pd-NHC] Ru and Rd loadings (Table 3) were determined by inductively coupled plasma-optical emission spectrometry ( ICP-OES) to 0.19 mmol. g-1( 1.86 wt%) and 0.19 mmol. g-1( 1.97 wt%) for Ru and Pd respectively, which is well in agreement with theoretical values (2 wt%).

[0437] Table 3. Characterization of different materials by N2physisorption and ICP-OES.

[0438] Entry Material BET surface Metal loading ( ICP-OES ) (wt% ) area (m2. g-1)

[0439] Ru Pd

[0440] 1 SiO2332

[0441] 2 Ru-SiO2325 1. 89

[0442] 3 Ru-SiO2- [ Pd-NHC] 289 1. 86 1. 97

[0443] 4 After catalysis 297 1.72 1. 89

[0444] The Brunauer-Emmett-Teller (BET) surface area of the support (SiO2, 332 m2. g-1) obtained from N2physisorption experiments did not change upon Ru loading (Ru-SiO2, 325 m2. g-1). A substantial decrease was observed after silanization of the [Pd-NHC] complex (Ru-SiO2- [Pd-NHC], 289 m2. g-1), as expected (Table 3).2H-29Si cross-polarization (CP) spectra recorded under magic-angle spinning (MAS ) conditions (Table 1 and Table 2 ) of Ru-SiO2- [Pd-NHC] (Figure 8a) show Si species which can be assigned to different chemical environments according to their chemical-shift values. Firstly, silanol groups on the surface of the silica support are detected, which can be described by using the " Qn-nomenclature" (with Q referring to [SiO tetrahedra and n being the number of bridging Si-O-Si groups). Spectral deconvolution of the29Si CP-MAS NMR spectrum as given in Figure 8a reveals resonances at -110 ppm (Q2), -101 ppm (Q3) and -95 ppm (Q2). Secondly, silicon atoms of the ethoxysilane-functionalized [Pd-NHC] complex covalently grafted on the silica support are present that can be described by using the " Tn-nomenclature" (with T referring to [RSiO2] tetrahedra and n being the number of C-Si-Osurfacegroups).29Si resonances at -58 ppm (T2), -53 ppm (Ti) and -47 ppm (To) have been detected (Table 4 ).

[0445] Table 4. Assignment of decomposed signals in Figures 8a and 9 to different silicate species.

[0446] <5iSO(ppm) Assignment Structure

[0447] -47 ToCH3

[0448] Si -OR

[0449] ROZOR

[0450] -53 T2CH3

[0451] ^Si — O — Si-OR

[0452] ZOR

[0453] -58 T2H3C O

[0454] -hsi-O — Si-O-Si

[0455] -95 Q2OH

[0456] zSH

[0457] u0

[0458] - 101 Q3OH

[0459] zSU0

[0460] 0o

[0461] -110 Q4O

[0462] Z®'" O

[0463] 0

[0464] The T2and T2signals corresponds to the Si atoms of [Pd-NHC] covalently bound to the SiO2surface and thus provide clear evidence for the successful grafting of the complex to the silica support. The assignment of the resonance at -47ppm to Tounits is further supported by comparing the spectrum to one of the non-grafted NHC. Br where one of the two29Si resonances is observed at -46 ppm (Figure 9). This suggests that part of the triethoxysilane functionalities did however not react with the SiO2surface during the silanisation reaction and the [Pd-NHC] catalyst is only immobilized via one of the two organic linkers. Note that the discussed29Si spectra are not quantitative due to the CP-polarization transfer employed.2H-13C CP-MAS NMR spectra revealed the Pd-C resonance at a chemical-shift value of ~162 ppm characteristic for the Pd-coordinated NHC carbene, indicating that the structure of the Pd11complex was preserved upon grafting (Figure 8b).

[0465] This is further supported by comparing the13C CP-MAS spectra of the immobilized [Pd-NHC] catalyst with the one of SiO2- [NHC. Br] in the absence of Pd2+, where the same13C resonance is more shielded ( 140 ppm, Figure 8c). Pd-coordination to the immobilized NHC. Br thus leads to a13C high-frequency shift of about 22 ppm, which is of similar magnitude than the chemical-shift change observed for the non-immobilized NHC. Br upon [Pd-NHC] complex-formation (see Figure lOb-c). The13C NMR chemical-shift values between the "free" [Pd-NHC] complex and the immobilized one are very similar, both in the presence and absence of Ru nanoparticles (Figures 8b and 10a-b).

[0466] Transmission Fourier transform infrared spectroscopy (FT-IR) of the [Pd-NHC] complex (Figure 11 ) showed signals characteristic of C-H stretching in imidazole cycles and N-alkyl chains (2884-3092 cm-1region), as well as C=N stretches ( 1714 cm-1) and symmetric ring stretches ( 1563 and 1521 cm-1), in agreement with literature reports (G. Li, H. Q. Yang, W. Li and G. L. Zhang, Green Chemistry, 2011, 13, 2939-2947; G. Borj a, A. Monge-Marcet, R. Pleixats, T. Parella, X. Cattoen and M. W. C. Man, Eur. J. Org. Chem., 2012, 2012, 3625-3635; B. Karimi and D. Enders, Org. Lett., 2006, 8, 1237-1240). The same signals can be observed in the spectrum of Ru-SiO2- [Pd-NHC] (Figure 11 ), confirming that the structure of the [Pd-NHC] complex was preserved upon chemisorption on Ru-SiO2.

[0467] X-ray photoelectron spectroscopy (XPS) measurements were carried out to study the electronic structure of Ru-SiO2- [Pd-NHC] using the "free" [Pd-NHC] complex as a reference. The high resolution XPS spectra of Pd3d (Figure 12a) showed that Pd species in [Pd-NHC] and Ru-SiO2- [Pd-NHC] are in (+2 ) oxidation state, with binding energy values (3ds / 2 at ~337.1 eV and 3d3 / 2 at ~342.5 eV) and at Nls ~400.0 eV (Figure 13a) matching well with literature data on Pd-NHC species (G. Buscemi, M. Basato, A. Biffis, A. Gennaro, A. A. Isse, M. M. Natile and C. Tubaro, J. Organomet. Chem., 2010, 695, 2359-2365). Interestingly, prolonged exposure to the X-Ray beam led to a partial reduction of the Rd species, giving a mixture of Pd11and Pd°, evidencing the beam-sensitivity of the chemisorbed [Pd-NHC] complex (Figure 14 ). The Ru3d3 / 2 (BE ~280.0 eV) (Figure 13b) and Ru3p3 / 2(BE ~461.0 eV) (Figure 12b) signals revealed the presence of Ru° on Ru-SiO2- [Pd-NHC].

[0468] Characterization of Ru-SiO2- [Pd-NHC] by scanning transmission electron microscopy using the high-angle annular dark-field detector (STEM-HAADF) showed small and well dispersed Ru NPs ( 1.8 ± 0.4 nm, Figure 15 and Figure 16) on the support. Elemental mapping using energy-dispersive X-ray spectroscopy (EDX) confirmed that Ru NPs and [Pd-NHC] are homogeneously present on the SiO2 support (Figure 15c-f ). Notably, exposure to the electron beam also damaged the [Pd-NHC] complex, with the formation of Pd NPs over time, as shown for a Pd-NHC-SiO2 reference ( 1.3 ± 0.4 nm, Figure 17 ). Taken together, these results demonstrate the co-existence of Ru NPs and [Pd-NHC] species at the surface of the same SiO2 support material.

[0469] Example 4: Catalytic Study using the catalyst Ru-SiC>2- [Pd-NHC] in the one-pot synthesis of chaicones

[0470] Ru-SiO2- [Pd-NHC] was applied to the one-pot synthesis of chaicones. The reaction sequence consists of two consecutive steps: a) carbonylative Sonogashira coupling of aryl iodides and phenylacetylenes in presence of CO to form ynones (3), followed by b) selective hydrogenation of 3 to chaicones using molecular H2. The one-pot two step synthesis of 4 from iodobenzene and phenylacetylene was selected as a model reaction. Step 1 Step 2

[0471] O O

[0472] Ru-SiO2-[Pd-NHC] CO, T, t

[0473]

[0474] 1 2

[0475] 1 ) Carbonylative Sonogashira coupling

[0476] Step 1 was first investigated separately to identify suitable reaction conditions. The carbonylative Sonogashira coupling of phenyl iodide ( 0.3 mmol) and phenyl acetylene ( 1 equiv. ) with Ru-SiO2- [Pd-NHC] (2 mol% Pd) and reference catalysts was tested using Fischer-Porter bottles under conditions adapted from literature (P. Gautam, N. J. Tiwari and B. M. Bhanage, ACS Omega, 2019, 4, 1560-1574 ): triethyl amine as a base, toluene as a solvent, at 100 °C, with 4 bar CO, for 4 h (Table 5 ).

[0477] Table 5. Testing of catalysts and reaction parameters for the carbonylative Sonogashira coupling of iodobenzene (1) and phenylacetylene (2) in presence of CO.

[0478] I O

[0479] Catalyst (2 mol%) NEt3(2 equiv.) CO (x bar), T °C, t Solvent (1.5 mL)

[0480]

[0481] 1 2 (0.3 mmol) (1 equiv.)

[0482] Conv Yield CO Temp Time

[0483] Entry Catalyst Solvent % 3 % bar °C h

[0484] [ a ] [ a ] 1 [Pd-NHC] Toluene 4 100 4 74 72 2 5% Pd / C Toluene 4 100 4 12 11 3 Ru-SiO2 Toluene 4 100 4 2 2 4 Ru-SiO2- [Pd- Toluene 4 100 4 29 27 NHC]

[0485] 5 Ru-SiO2- [Pd- DMF 4 100 4 86 79 NHC]

[0486] 6 Ru-SiO2- [Pd- PC 4 100 4 81 78 NHC]

[0487] 7 Ru-SiO2- [Pd- PC 10 100 4 98 87 NHC]

[0488] 8 Ru-SiO2- [Pd- PC 2 100 4 83 80 NHC]

[0489] 9 Ru-SiO2- [Pd- PC 2 100 4 70 68 NHC]

[0490] 1 mol%Pd

[0491] 10 Ru-SiO2- [Pd- PC 2 100 4 84 80 NHC]

[0492] 3 mol%Pd

[0493] 11 Ru-SiO2- [Pd- PC 2 80 4 50 47 NHC]

[0494] 12 Ru-SiO2- [Pd- PC 2 120 4 87 81 NHC]

[0495] 13 Ru-SiO2- [Pd- PC 2 100 12 87 83 NHC]

[0496] 14 Ru-S102- [Pd- PC 2 100 16 93 88

[0497]

[0498] NHC] 2 mol% catalyst was used unless otherwise mentioned.[alConv. and yields were determined by GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta-l, 3-diyne and benzene. 'PC' is propylene carbonate. 'DMF' is dimethyl formamide.

[0499] The free [Pd-NHC] complex was tested first, delivering promising activity and selectivity (72% of 3, Entry 1 ). In contrast, Pd / C (5 wt% Pd, 3.5 nm Pd NPs) and Ru-SiO2(2 wt% Ru, 1. 6 ± 0.4 nm Ru NPs) gave low yields of 3 ( 11% and 2%, respectively, Entry 2-3), indicating that Pd and Ru NPs are poorly active under these conditions. Using Ru-SiO2- [Pd-NHC], moderate conversion (29%) and yield of 3 (27%) were observed (Entry 4 ), demonstrating that the immobilized [Pd-NHC] complex is still active, although its performance is reduced as compared to the free complex in toluene. The detailed testing / optimization of the different reaction parameters is summarised in Tables 6-12 below.

[0500] Table 6. Testing of catalysts. Entry Catalyst Conv. ( % )[ a ]Yield 3 ( % )[ a]

[0501] 1 [ Pd-NHC ] 74 72

[0502] 2 5% Pd / C 12 11

[0503] 3 Ru-SiO22 2

[0504] 4 Ru-SiO2- [ Pd-NHC ] 29 27

[0505] 5 Pd ( acac )268 66 Reaction conditions: ( Catalyst: 0. 006 mmol of Pd / Ru ), iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to catalyst ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), toluene ( 1. 5 mL ), CO ( 4 bar ), 100 °C, 4 h;[a]Conv. and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta- l, 3-diyne and benzene.

[0506] Table 7. Testing of bases using Ru-SiO2- [ Pd-NHC ].

[0507] Entry Base Conv. ( % )[ a ]Yield 3 ( % )[ a]

[0508] 1 NEt329 27

[0509] 2 K2CO38 7

[0510] 3 DIPEA 13 12

[0511] Reaction conditions: ( Ru-SiO2- [ Pd-NHC]: 30 mg; 0. 006 mmol of Pd / Ru ), iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to [ Pd-NHC] ), phenylacetylene ( 0. 3 mmol ), Base ( 0. 6 mmol ), toluene ( 1. 5 mL ), CO ( 4 bar ), 100 °C, 4 h;

[0512] [a]Conv. and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta-1, 3-diyne and benzene.

[0513] Table 8. Testing of solvents using Ru-SiO2- [ Pd-NHC ].

[0514] Entry Solvent Conv. ( % )[ a ]Yield 3 ( % )[ a]

[0515] 1 Toluene 29 27

[0516] 2 DMC 33 32

[0517] 3 Propylene 74 72

[0518] carbonate

[0519] 4 DMF 86 79

[0520] 5 1, 4-Dioxane 50 49 Reaction conditions: ( Ru-SiO2- [ Pd-NHC]: 30 mg; 0. 006 mmol of Pd / Ru ), iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to [ Pd-NHC] ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), solvent ( 1. 5 mL ), CO ( 4 bar ), 100 °C, 4 h;

[0521] [a]Conv. and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta-1, 3-diyne and benzene.

[0522] Table 9. Testing of CO pressures using Ru-SiO2- [ Pd-NHC ].

[0523] Entry CO Pressure Conv. ( 1 )[ a ]Yield 3 ( 1 )

[0524]

[0525] 1 1 bar 79 76

[0526] 2 2 bar 83 80

[0527] 3 4 bar 74 72

[0528] 4 10 bar 98 87 Reaction conditions: ( Ru-SiO2- [ Pd-NHC]: 30 mg; 0. 006 mmol of Pd / Ru ), iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to [ Pd-NHC] ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), PC ( 1. 5 mL ), 100 °C, 4 h;[a]Conversion and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta- l, 3-diyne and benzene.

[0529] Table 10. Testing of catalyst loadings ( reflected by Pd loading in moll ) using Ru-SiO2- [ Pd-NHC ].

[0530] Entry Catalyst loading Conv. ( l )[ a]Yield 3 ( l )[ a]

[0531] 1 0. 5 moll 68 65

[0532] 2 1 moll 70 68

[0533] 3 2 mo 11 83 80

[0534] 4 3 moll 84 80 Reaction conditions: ( Ru-SiO2- [ Pd-NHC]: x mg; x mmol of Pd / Ru ), iodobenzene ( 0. 3 mmol; x equiv. w. r. t to [ Pd-NHC] ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), PC ( 1. 5 mL ), CO ( 2 bar ), 100 °C, 4 h;[a]Conversion and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta- l, 3-diyne and benzene. Table 11. Testing of reaction temperatures using Ru-SiO2- [ Pd-NHC ].

[0535] Entry Temperature Conv. ( % )[ a ]Yield 3 ( % )[ a ]

[0536] 1 80 °C 50 47

[0537] 2 100 °C 83 80

[0538] 3 120 °C 87 81 Reaction conditions: ( Ru-SiO2- [ Pd-NHC]: 30 mg; 0. 006 mmol of Pd / Ru, 2 mol% ) iodobenzene ( 0. 3 mmol; 50 equiv. w. r. t to [ Pd-NHC] ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), PC ( 1. 5 mL ), CO ( 2 bar ), 4 h;[a]Conv. and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta-1, 3-diyne and benzene.

[0539] Table 12. Testing of reaction scale and substrate concentrations using Ru-SiO2- [ Pd-NHC ].

[0540] 1: Pd

[0541]

[0001] Conv. Yield 3 Entry Time (h) molar

[0542] (mmol ) ( % )[ a ]( % )[ a ]

[0543] ratio

[0544] 1 0. 3 1 50 51 49 2 0. 3 4 50 75 73 3 1 1 50 71 69 4 1 4 50 92 89 5 1 1 333 52 50 6 1 1 500 58 56 7 1 4 500 83 81 Reaction conditions: ( Ru-SiO2- [ Pd-NHC], iodobenzene ( x mmol ), phenylacetylene ( 1 equiv. ), NEt3( 2 equiv. ), PC ( 1. 5 mL ), CO ( 2 bar );

[0545] [a]Conversion and yield were determined through GC-FID using mesitylene as internal standard. Byproducts are 1, 2-diphenylethyne, 1, 4-diphenylbuta- 1, 3-diyne and benzene.

[0546] Interestingly, changing the solvent from toluene to dimethyl formamide ( DMF) or propylene carbonate ( PC ) enhanced catalytic performances ( Table 5, Entries 5- 6 ), with yields reaching 79% and 72 %, respectively. This ef fect is rationali zed by a better dispersion of the Ru-SiO2- [ Pd-NHC ] catalyst in these more polar solvents. In accordance with principles of "green chemistry", PC was selected as the reaction solvent for future reactions.

[0547] Raising the CO pressure to 10 bars in a steel autoclave resulted in higher conversion ( 98%), albeit at slight expense of selectivity ( 87% yield of 3, 89% selectivity, Entry 7 ). Good yield of 3 ( 83%) at excellent selectivity ( 96%) was observed when using lower CO pressure (2 bar, Entry 8 ), which was thus used as standard pressure for the rest of the study as it allowed using simple glass reactors (Fischer-Porter bottles) instead of steel autoclaves.

[0548] Lowering the catalyst loading and temperature from the standard conditions gave lower conversions, while an increase in these parameters did not result in better performance (Entries 9-12 ). Replacing NEt3by other bases such as K2CO3 or DIPEA resulted in lower conversions (Table 7 ). Recording a time profile under optimized conditions (Table 5, Entry 14 ) revealed an expected apparent first order kinetic with a yield of 3 reaching 90% after 16 h (Figure 18 ).

[0549] A hot filtration test was performed separating the Ru-SiO2- [Pd-NHC] catalyst under optimized conditions after 30 mins from the reaction mixture by cannula filtration (Table 13). The negligible change in yield of 3 after filtration of the solid catalyst demonstrates that the reaction is catalyzed by the surface-bound Pd-complex and not due to any leached Pd-species.

[0550] Table 13. Hot-filtration experiment using Ru-SiO2- [Pd-NHC].

[0551] Ru-SiO2-[Pd-NHC] (2%) NEt3(2 equiv ) CO (2 bar), 100 °C, 30 mins propylene carbonate (1 3 ml_) without solid catalyst CO (2 bar), 100 °C, 30 mins

[0552]

[0553] 3 3

[0554] Entry Time (mins) Conversion (%)[a]Yield (%)[a] 1 30 29 27

[0555] 2 30 ( after hot 32 30

[0556] filtration)

[0557] Reaction conditions: Ru-SiO2- [ Pd-NHC] ( 100 mg; 0. 02 mmol of Pd / Ru, 2 mol% ) Iodobenzene ( 1 mmol; 50 equiv. w. r. t to Pd-NHC ), Phenylacetylene ( 1 mmol ), NEt3( 2 mmol ), PC ( 1. 3 mL ), CO ( 2 bar ), 100 °C, 30 mins; After 30 mins, the hot solution was filtered through a pad of celite and analysed. The filtered crude solution was then performed with CO ( 2 bar ) at 100 °C for 30 mins without solid catalyst.[a]Conversion and Yield was determined through GC-FID using mesitylene as internal standard.

[0558] 2 ) Hydrogenation

[0559] The hydrogenation step in a one-pot two-step sequence was investigated. This involved releasing the CO pressure after 16 h and pressuri zing with H2without any intermediate workup or isolation. Treating the reaction mixture containing the intermediate ynone- under 2 bar o f H2at 100 ° C for 3 h gave 71 % yield of E- l, 3-Diphenylprop-2-en- l-one (4 ), along with 20% of the intermediate 3 remaining unreacted ( Table 14, Entry 1 ).

[0560] Table 14. One-pot two-step synthesis of chaicone 4 - Study of the hydrogenation step

[0561] Ru-SiO2-[Pd-NHC] (2 mol%) _ NEt3(2 equiv.) _ H2(X bar) CO (2 bar), 100 °C, 16 h 100 °C, t Propylene carbonate

[0562]

[0563] 2 4

[0564] Yield Yield

[0565] P (H2) Time Conv.

[0566] Entry 3 4

[0567] bar (h) ( % )[ a ]

[0568] ( % ) [ a j ( % )[ a ]

[0569] 1 2 3 98 20 71 2 2 8 99 9 86 3 3 8 >99 0 95 4 4 8 >99 0 93 5 5 8 >99 0 94 6[b]3 2 98 69 25

[0570] 7[ c]3 3 >99 0 96 8[ c]3 2 >99 0 96 Reaction conditions: Step 1: Ru-SiO2- [ Pd-NHC] ( 30 mg, 0. 006 mmol Pd / Ru ), iodobenzene ( 0. 3 mmol, 50 equiv. w. r. t. Pd-NHC ), phenylacetylene ( 0. 3 mmol ), NEt3( 0. 6 mmol ), PC ( 1. 5 mL ), CO ( 2 bar ), 100 °C, 16 h. Step 2: H2( 2-3 bar ), 100 °C, 2- 8 h.[ aIConversion and yield were determined through GC-FID using mesitylene as internal standard.[b]Pd-NHC-SiO2was used as reference catalyst.[c]Step 1: Ru-SiO2- [ Pd-NHC] ( 100 mg, 0. 02 mmol Pd / Ru ), iodobenzene ( 1 mmol, 50 equiv. w. r. t. Pd-NHC ), phenylacetylene ( 1 mmol ), NEt3( 2 mmol ), PC ( 1. 3 mL ), CO ( 2 bar ), 100 ° C, 4 h. Step 2: H2( 3 bar ), 100 ° C, 2 h.

[0571] Extending the reaction time to 8 h (Entry 2 ) and raising the H2pressure to 3 bar (Entry 3 ) allowed reaching 95% yield of 4. The same reaction using the reference SiO2- [ Pd-NHC ] catalyst without Ru NPs af forded poor hydrogenation of 3 to 4 ( 25%, Entry 6 ), indicating that the hydrogenation activity of Ru-SiO2- [ Pd-NHC ] is dominated by Ru NPs. Increasing the scale of the reaction ( 1 mmol, x3 ) and substrates concentrations resulted in a faster reaction ( Table 12 ) and 4 was obtained in 96% yield within 6 h instead of 24 h (Entries 6-7 ).

[0572] Interestingly, the hydrogenation of 3 was chemo- and stereoselective towards the E-chalcone 4 even after 8 h and increasing H2pressures (Entries 4-5 ). To gain more insights into this surprising selectivity for Ru NPs under these conditions, control experiments for the direct hydrogenation of 3 were performed,

[0573] o Catalyst (2 mol%) Catalyst (2 mol%) H2(3 bar), 100 °C, 2 h J H2(3 bar), 100 °C, 2 h Propylene carbonate 3 Propylene carbonate 5 CO Pre-treatment

[0574]

[0575] 95% Pristine Ru-SiO2- [ Pd-NHC ] under previously optimi zed hydrogenation conditions led to a quantitative yield ( 95% ) of the saturated alcohol 1, 3-diphenylpropan- l-ol ( 5 ), evidencing the expected C=C and C=O hydrogenation activity of the immobilized Ru NPs. In contrast, pre-treating Ru-SiO2- [Pd- NHC] under an atmosphere of CO prior to hydrogenation resulted in a selectivity switch, with 4 being obtained as the product in 99% yield. These results indicate that the chemo- and stereo-selectivity observed in the one-pot reaction sequence originates from the partial poisoning of the catalyst surface by CO adsorption.

[0576] Since the hydrogenation activity of the Ru NPs were modulated significantly upon exposure to CO, the direct one-step conversion of the aryl iodide 1 and the alkyne 2 in simultaneous presence of CO and H2to form the E-chalcone 4 was attempted.

[0577] i O Ru-SiO2-[Pd-NHC] (2 mol%) NEt3(2 equiv.) CO / H2(4 bar), 100 °C, 18 h' Propylene carbonate 1 2 4 1a 2a 9

[0578]

[0579] conversion: 99% 1% 59% 6% 27% 5%

[0580] In addition to integrating the two reactions into one single operation, the use of the 1: 1 mixture of the two gases known as synthesis gas would be significantly more cost effective than the two gases individually.

[0581] Interestingly, the one-pot / one-step tandem reaction performed by pressurizing the reactor directly with 4 bar of syngas gave a promising yield of 4 reaching 59% after 18 h. The competing hydrogenation of phenylacetylene to unreactive styrene was found to be the major limitation in the reaction yield. Besides, benzene and benzaldehyde were observed in low yields. This preliminary result opens promising perspective for continuous-flow operation of the concept.

[0582] Example 5: Further example studies using the catalyst Ru- SiO2~ [Pd-NHC] in the one-pot synthesis of chaicones (synthetic scope experiments)

[0583] The optimized conditions were then applied to assess the synthetic applicability of this tandem catalytic approach to synthesize a variety of stereo-defined E-chalcones: o

[0584] Variation of lodobenzene derivatives

[0585] Variation of Phenylacetylene derivatives

[0586] Potential drug molecules >

[0587]

[0588] Reaction conditions: Step 1: Ru-SiO2- [ Pd-NHC] ( 100 mg, 0. 02 mmol Pd / Ru ), iodobenzene ( 1 mmol, 50 equiv. w. r. t. Pd-NHC ), phenylacetylene ( 1 mmol ), NEt3( 2 mmol ), PC ( 1. 3 mL ), CO ( 2 bar ), 100 °C, 4 h. Step 2: H2( 3 bar ), 100 °C, 2 h. Yields were determined through GC-FID using mesitylene as internal standard. Isolated product yield in parentheses.

[0589] Hence, iodobenzene derivatives with diverse functionalities reacted effectively with phenylacetylene in presence of Ru-SiO2- [Pd-NHC] to give the corresponding E-chalcones in moderate to excellent yields (4a-4u, 48-98%). Moderate yield was observed for o-dimethyl-iodobenzene (4g, 48%), presumably due to steric hindrance. 4q was also obtained in moderate yield (54%) due to the reaction of 3-iodopyridine in the competing non-carbonylative Sonogashira coupling (35% yield of 3- (phenylethynyl ) pyridine ). Very little competing formation of non-carbonylative Sonogashira products was observed in most other cases, indicating that Ru-SiO2- [Pd-NHC] is very selective toward the formation of intermediate ynones. Cyclohexyl iodide (4v) was found unreactive as expected for an alkyl iodide substrate.

[0590] Notably, functionalities like halo (4k-4m), morpholine (4n) and cyano (4s) were well tolerated in this protocol. Furthermore, electron-rich and electron-deficient phenylacetylene derivatives were examined under optimized conditions and yielded the corresponding E-chalcones (4w-4ah) in high to excellent yields (71-92%). Satisf yingly, valuable H-chalcones finding application in the treatment of cancers (4r, 87%), infections (4ab, 92%), inflammations (4ai, 80%), Parkinson' s disease (4aj, 61%), as well as in bioimaging (4ak, 70%) and herbicides (4k, 81%) were isolated in high yields. To further outline the practicability of this approach, the potential anti-inflammatory compound 4ai (market value of approximately 620 € / g) was prepared and isolated in analytically pure form on gram-scale ( 1.13 g, 69% isolated yield), as outlined below.

[0591] General procedure for synthesis of chaicones Ru-SiO2-[Pd-NHC] (2%) NEts (2 equiv.) H2(3 bar) propylene carbonate(1.3 mL) 100 °C, 2 h CO (2 bar), 100 °C, 4 h

[0592]

[0593] In a glovebox, Ru-SiO2- [Pd-NHC] (100 mg, 0.02 mmol Pd / Ru, 2 mol% w. r. t 1), aryl iodide ( 1 mmol, 50 equiv. w. r. t. Pd), arylalkyne ( 1 mmol), NEt3(2 mmol), propylene carbonate ( 1.3 mL) were added to a Fisher-Porter (FP) bottle equipped with a stirring bar. The reaction vessel was sealed and taken out of the glovebox. The reaction mixture was cooled using liquid nitrogen, evacuated and pressurized with 2 bar of CO gas. The FP bottle was then placed behind a protective blast shield and heated at 100 °C for 4 h. Upon cooling to room temperature, the excess pressure was vented under quick vacuum. In case of volatile compounds, the reaction mixture was frozen using liquid nitrogen before depressurizing under vacuum. The FP bottle was then pressurized with 3 bar of H2gas and heated at 100 °C for 2 h while kept behind a protective blast shield. After reaction completion, the bottle was cooled down and excess pressure was released carefully. The reaction mixture was separated by filtration, rinsed with ethyl acetate (EtOAc) and washed with brine. The organic layer was collected, dried over MgSO4and concentrated by rotary evaporation. The resulting crude product was purified by flash column chromatography on silica gel using EtOAc / pentane as eluent to obtain pure chaicones 4a-4ak.

[0594] Gram-scale synthesis of 4ai Ru-SiO2-[Pd-NHC] (0.5%) Cl H2(3 bar) propylene carbonate(3 mL) 100 °C, 4 h CO (3 bar), 100 °C, 12 h 4a i

[0595]

[0596] 75% (69) In a glovebox, Ru-SiO2- [Pd-NHC] ( 150 mg, 0.03 mmol Pd / Ru, 0.5 mol% w. r. t. 1ai), 4-iodoanisole ( 6 mmol, 200 equiv. w. r. t. Pd), l-chloro-2-ethynylbenzene ( 6 mmol), NEt3( 12 mmol), propylene carbonate (3 mL) were added to a Fisher-Porter (FP) bottle with a stirring bar. The reaction vessel was sealed and taken out of the glovebox. The reaction mixture was cooled using liquid nitrogen, evacuated and pressurized with 2 bar of CO gas. The FP bottle was then placed behind a protective blast shield and heated at 100 °C for 12 h. After 1 h, there was a pressure drop from 2 to 1 bar, so repressurized the bottle to 2 bar. Upon cooling to room temperature, the excess pressure was vented under quick vacuum. The reactor was then pressurized with 3 bar of H2gas and heated at 100 °C for 6 h kept behind a protective blast shield. After reaction completion, the bottle was cooled down and excess pressure was released carefully. Conversion and yield were determined by GC-FID using mesitylene as internal standard. The reaction mixture was separated by filtration, rinsed with ethyl acetate (EtOAc) and washed with brine. The organic layer was collected, dried over MgSO4 and concentrated by rotary evaporation. The resulting crude product was purified by flash column chromatography on silica gel using EtOAc / pentane as eluent to obtain pure target compound 4ai in 69% isolated yield ( 1.13 g).

[0597] 1H NMR (400 MHz, Chloroform-d) δ (ppm) = 8.16 (d, J = 15.7 Hz, 1H), 8.05 - 8.02 (m, 2H), 7.75 - 7.73 (m, 1H), 7.49 (d, J = 15.7 Hz, 1H), 7.45 - 7.42 (m, 1H), 7.34 - 7.30 (m, 2H), 7.00 - 6.97 (m, 2H), 3.91 (s, 3H).

[0598] 13C NMR (101 MHz, Chloroform-d) δ (ppm) = 188.72, 163. 65, 139.88, 135.49, 133.56, 131.09, 131.07, 130.92, 130.38, 127.87, 127.16, 124.80, 114.00, 55. 62.

[0599] XRF analysis: I (53 ppm), Ru (< 0.2 ppm), Pd (< 1.4 ppm).

[0600] Analytical Data for Isolated Chaicones

[0601] (E) -1- (4 -methoxyphenyl) -3-phenylprop-2-en-l-one (4b)

[0602] 4b was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90) as an off-white solid. Yield: 205 mg, 86%. NMR data of the compound is in good agreement with the literature data.1H NMR (400 MHz, Chloroform-d) δ (ppm) = 8. 05 ( d, J = 8. 9 Hz, 2H), 7. 81 ( d, J = 15. 7 Hz, 1H), 7. 66 - 7. 64 (m, 2H), 7. 55 ( d, J = 15. 7 Hz, 1H), 7. 42 ( dd, J = 5. 2, 1. 9 Hz, 3H), 6. 99 ( d, J = 8. 9 Hz, 2H), 3. 89 ( s, 3H).

[0603] 13C NMR ( 101 MHz, Chloroform-d) δ (ppm) = 188. 86, 163. 57, 144. 11, 135. 22, 131. 23, 130. 96, 130. 47, 129. 06, 128. 50, 122. 01, 113. 98, 55. 64.

[0604] XRF analysis: I ( 20 ppm), Ru ( 0. 2 ppm), Pd ( 0. 6 ppm).

[0605] (E) -1- (3, 5 -dimethylphenyl ) -3-phenylprop-2-en-l-one (4f)

[0606] 4f was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 30: 70 ) as an yellow oil. Yield: 208 mg, 88 %. NMR data of the compound is in good agreement with the literature data.

[0607] 1H NMR (400 MHz, Chloroform-d) δ (ppm) = 7. 81 ( d, J = 15. 7 Hz, 1H), 7. 68 - 7. 64 (m, 4H), 7. 53 ( d, J = 15. 7 Hz, 1H), 7. 45 - 7. 39 (m, 3H), 7. 22 ( s, 1H), 2. 41 ( s, 6H).

[0608] 13C NMR ( 101 MHz, Chloroform-d) δ (ppm) = 190. 89, 144. 50, 138. 38, 138. 34, 135. 05, 134. 57, 130. 52, 129. 01, 128. 52, 126. 37, 122. 43, 21. 37.

[0609] (E) -1- (4 -acetylphenyl ) -3-phenylprop-2-en-l-one (4j )

[0610] 4j was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 20: 80 ) as a white solid. Yield: 225 mg, 90%. NMR data of the compound is in good agreement with the literature data.

[0611] 1H NMR (400 MHz, Chloroform-d) δ (ppm) = 8. 07 ( s, 4H), 7. 82 ( d, J = 15. 7 Hz, 1H), 7. 67 - 7. 64 (m, 2H), 7. 51 ( d, J = 15. 7 Hz, 1H), 7. 44 - 7. 43 (m, 3H), 2. 66 ( s, 3H).

[0612] 13C NMR ( 101 MHz, Chloroform-d) δ (ppm) = 197. 67, 190. 16, 146. 00, 141. 74, 139. 96, 134. 69, 131. 04, 129. 17, 128. 79, 128. 72, 128. 65, 121. 91, 27. 04.

[0613] (E) -1- (4 -Fluorophenyl ) -3-phenylprop-2-en-l-one (4k) 4k was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90 ) as a white solid. Yield: 183 mg, 81 %. NMR data of the compound is in good agreement with the literature data.

[0614] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8. 08 - 8. 05 (m, 2H), 7. 82 ( d, J = 15. 7 Hz, 1H), 7. 67-7. 63 (m, 2H), 7. 51 ( d, J = 15. 7 Hz, 1H), 7. 43 ( t, J = 3. 3 Hz, 3H), 7. 18 ( t, J = 8. 6 Hz, 2H).

[0615] 13C NMR ( 101 MHz, Chloroform-d) 5 (ppm) = 188. 99, 165. 75 ( d, J = 254. 4 Hz ), 145. 21, 134. 90, 134. 67 ( d, J = 3. 0 Hz ), 131. 24 ( d, J = 9. 2 Hz ), 130. 81, 129. 14, 128. 62, 121. 71, 115. 90 ( d, J = 21. 8 Hz ).

[0616] 19F NMR (376 MHz, Chloroform-d) 5 (ppm) = - 105. 51.

[0617] XRF analysis: I ( 16 ppm), Ru ( 0. 1 ppm), Rd ( 1. 5 ppm).

[0618] (E ) -3-phenyl-l- (4 - (trifluoromethyl ) phenyl ) prop-2-en-l-one (4m)

[0619] 4m was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90 ) as a white solid. Yield: 218 mg, 79%. NMR data of the compound is in good agreement with the literature data.

[0620] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8. 10 ( d, J = 8. 0 Hz, 2H), 7. 84 ( d, J = 15. 7 Hz, 1H), 7. 77 ( d, J = 8. 1 Hz, 2H), 7. 66 ( dd, J = 6. 6, 2. 9 Hz, 2H), 7. 49 ( d, J = 15. 7 Hz, 1H), 7. 47 - 7. 44 (m, 3H).

[0621] 13C NMR ( 101 MHz, Chloroform-d) 5 (ppm) = 189. 83, 146. 28, 141. 18, 134. 63, 134. 33, 134. 00, 131. 13, 129. 20, 128. 91, 128. 75, 125. 87, 125. 84, 125. 80, 125. 76, 121. 70.

[0622] 19F NMR (376 MHz, Chloroform-d) 5 (ppm) = - 63. 21.

[0623] (E ) -1- (4 -morpholinophenyl ) -3-phenylprop-2-en-l-one (4n)

[0624] 4n was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane =20: 80 ) as an of f-white solid. Yield: 202 mg, 69%. NMR data of the compound is in good agreement with the literature data.

[0625] ^■H NMR (400 MHz, Chloroform-d) 5 8.02 (d, J = 8. 6 Hz, 2H), 7.80 (d, J = 15. 6 Hz, 1H), 7. 65 (dd, J = 7. 3, 2. 3 Hz, 2H), 7.56 (d, J = 15. 6 Hz, 1H), 7.43 - 7.40 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H), 3.87 (t, J = 4.8 Hz, 4H), 3.34 (t, J = 4. 9 Hz, 4H).

[0626] 13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 188.32, 154.33, 143.49, 135.42, 130.79, 130.31, 129.04, 128.97, 128.45, 122.09, 113.57, 66.73, 47. 65.

[0627] methyl 4-cinnamoylbenzoate (4o)

[0628] 4o was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane =10: 90) as an off-white solid. Yield: 210 mg, 79%. NMR data of the compound is in good agreement with the literature data.

[0629] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8.17 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 15.7 Hz, 1H), 7. 67 - 7. 65 (m, 2H), 7.51 (d, J = 15.7 Hz, 1H), 7. 45 - 7.42 (m, 3H), 3. 97 (s, 3H).

[0630] 13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 190.29, 166.47, 145.98, 141.80, 134.75, 133. 68, 131.03, 130.01, 129.19, 128.74, 128.53, 121.97, 52. 63.

[0631] (E) -3-phenyl-l- (thiophen-2-yl) prop-2 -en-1 -one (4r)

[0632] 4r was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90) as an off-white solid. Yield: 186 mg, 87%. NMR data of the compound is in good agreement with the literature data.

[0633] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 7.88 (s, 1H), 7.86 (d, J = 12. 1 Hz, 1H), 7. 69 (d, J = 4.9 Hz, 1H), 7. 65 (dd, J = 6.5, 2.9 Hz, 2H), 7.45 - 7.41 (m, 4H), 7.19 (t, J = 4.4 Hz, 1H).13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 182.19, 145. 67, 144.24, 134.85, 134.05, 131.95, 130.75, 129.12, 128. 64, 128.40, 121.76.

[0634] (E) -1- ( [1, 1 ’ -biphenyl] -4-yl) -3-phenylprop-2-en-l-one (4u) 4u was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90) as an pale yellow solid. Yield: 236 mg, 83%. NMR data of the compound is in good agreement with the literature data.

[0635] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8.13 - 8.11 (m, 2H), 7.86 (d, J = 15.7 Hz, 1H), 7.75 - 7.73 (m, 2H), 7. 69 - 7. 65 (m, 4H), 7.59 (d, J = 15.7 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.46 - 7.39 (m, 4H).

[0636] 13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 190.13, 145.70, 144.93, 140.10, 137.05, 135.08, 130.71, 129.28, 129.13, 129.12, 128. 63, 128.37, 127.45, 122.16.

[0637] (E) -3- (4- (tert-butyl) phenyl) -l-phenylprop-2-en-l-one (4y) 4y was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90) as a off-white solid. Yield: 219 mg, 83%. NMR data of the compound is in good agreement with the literature data.

[0638] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8.08 - 8.02 (m, 2H), 7.82 (d, J = 15.7 Hz, 1H), 7. 61 - 7.44 (m, 8H), 1.35 (s, 9H).

[0639] 13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 190.48, 154.01, 144. 65, 138.15, 132.47, 131.92, 128.39, 128.28, 128.14, 125.74, 121.08, 34.74, 30.95.

[0640] (E) -3- (Naphthalen-2-yl) -l-phenylprop-2-en-l-one (4ag)

[0641] 4ag was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90) as a yellow solid. Yield: 207 mg, 80%. NMR data of the compound is in good agreement with the literature data. ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8. 08 - 8. 04 (m, 3H), 7. 99 ( d, J = 15. 8 Hz, 1H), 7. 90 - 7. 80 (m, 4H), 7. 66 ( d, J = 15. 7 Hz, 1H), 7. 60 ( d, J = 7. 3 Hz, 1H), 7. 55 - 7. 51 (m, 4H).

[0642] 13C NMR ( 101 MHz, Chloroform-d) 5 (ppm) = 190. 68, 145. 09, 138. 42, 134. 52, 133. 49, 132. 94, 132. 51, 130. 82, 128. 88, 128. 79, 128. 67, 127. 94, 127. 53, 126. 92, 123. 79, 122. 32.

[0643] XRF analysis: I ( 16 ppm), Ru ( 0. 2 ppm), Rd ( 1. 7 ppm).

[0644] (E) -3- ( [ 1, 1 ’ -biphenyl ] -4 -yl ) -l-phenylprop-2-en-l-one (4ah) 4 ah was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 10: 90 ) as a yellow solid. Yield: 202 mg, 71 %. NMR data of the compound is in good agreement with the literature data.

[0645] 1H NMR (400 MHz, Chloroform-d) δ (ppm) = 8. 05 ( d, J = 7. 4 Hz, 2H), 7. 87 ( d, J = 15. 7 Hz, 1H), 7. 73 ( d, J = 8. 0 Hz, 2H), 7. 68 - 7. 58 (m, 6H), 7. 51 ( dt, J = 28. 0, 7. 6 Hz, 4H), 7. 39 ( t, J = 7. 3 Hz, 1H).

[0646] 13C NMR ( 101 MHz, Chloroform-d) 5 (ppm) = 190. 66, 144. 56, 143. 46, 140. 26, 138. 40, 133. 97, 132. 94, 129. 13, 129. 07, 128. 79, 128. 65, 128. 05, 127. 75, 127. 20, 122. 03.

[0647] XRF analysis: I ( 13 ppm), Ru ( 0. 2 ppm), Pd ( 0. 2 ppm).

[0648] (E) -3- (2 -chlorophenyl ) -1- (4 -methoxyphenyl ) prop-2-en-l-one ( 4ai )

[0649] 4ai was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 30: 70 ) as a white solid. Yield: 218 mg, 80%. NMR data of the compound is in good agreement with the literature data.

[0650] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8. 16 ( d, J = 15. 7 Hz, 1H), 8. 05 - 8. 02 (m, 2H), 7. 75 - 7. 73 (m, 1H), 7. 49 ( d, J = 15. 7 Hz, 1H), 7. 45 - 7. 42 (m, 1H), 7. 34 - 7. 30 (m, 2H), 7. 00 - 6. 97 (m, 2H), 3. 91 ( s, 3H).

[0651] 13C NMR ( 101 MHz, Chloroform-d) 5 (ppm) = 188. 72, 163. 65, 139. 88, 135. 49, 133. 56, 131. 09, 131. 07, 130. 92, 130. 38, 127. 87, 127. 16, 124. 80, 114. 00, 55. 62. (E) -3- (4- (dimethyl ami no) phenyl) -l-phenylprop-2-en-l-one (4ak) 4ak was obtained by following the general procedure on a 1 mmol scale and isolated by flash column chromatography (EtOAc: pentane = 1: 10) as a reddish solid. Yield: 176 mg, 70%. NMR data of the compound is in good agreement with the literature data.

[0652] ^■H NMR (400 MHz, Chloroform-d) 5 (ppm) = 8.01 (d, J = 7.5 Hz, 2H), 7.80 (d, J = 15.4 Hz, 1H), 7. 61 - 7.42 (m, 5H), 7.34 (d, J = 15.4 Hz, 1H), 6. 69 (d, J = 8.4 Hz, 2H), 3.03 (s, 6H).13C NMR (101 MHz, Chloroform-d) 5 (ppm) = 190.74, 152.10, 145.95, 139.15, 132.23, 130.51, 128.53, 128.39, 122. 68, 116.94, 111.90, 40.20.

[0653] Example 7: Catalyst Recycling

[0654] The stability and reusability of Ru-SiO2- [Pd-NHC] was explored through recycling experiments (Figure 19) for the one pot synthesis of 4 under adapted conditions (2 bar CO, 100 °C, 4 h followed by 1 bar H2, 100 °C, 1 h). Satisf yingly, catalytic performances remained fairly constant for 4 cycles, with only slight decreases in yield for the hydrogenated coupling product from 95% to 91%. While the chemo-selectivity of the hydrogenation of the triple bond to the double bond remained almost perfect, the E: Z selectivity was found to be somewhat less robust changing from 96: 4 to 86: 14 ratio in favour of the E-isomer

[0655] After four cycles, the used catalyst was washed with propylene carbonate and acetonitrile, dried and characterized. Elemental analysis by ICP-OES revealed minimal metal leaching with a total loss of 4% Pd and 7% Ru detected after four cycles (Table SI ).1H-29Si CP-MAS NMR spectra confirmed the robustness of the [Pd-NHC] covalent linkage on SiO2, and even revealed an improved grafting under catalytic conditions, as shown by a more prominent T2-signal for the material after catalysis (Figure 68 ). The1H-13C CP-MAS NMR spectrum of the used catalyst reveals broader resonances pointing to a more heterogenous sample after catalysis. The Pd-C resonance (~170 ppm) is slightly high-frequency shifted compared to the initial catalyst suggesting a change in the Pd coordination environment. Several additional resonances appear in the spectrum of the used catalyst compared to the catalyst before reaction, for instance the resonance at ~140 ppm (Figure 20b), which has also been observed in the spectrum of SiO2-NHC. Br (Figure 10c) and assigned to theNCNimidazolium carbon atom. This suggests a partial degradation of the complex. FT-IR spectra of the used Ru-SiO2- [Pd-NHC] catalyst did not show any significant changes (Figure 21 ). XPS measurements showed no significant change in the oxidation state of Pd and Ru (Figure 22 ), although detection of the potential presence of free NHC and Pd° in the spent catalyst was challenging due to the relatively high noise levels and X-ray beam damage. A slight increase in Ru NPs size (2.4 nm) was observed using STEM-HAADF-EDX and STEM bright-field (STEM-BF) images, although without any noticeable agglomeration (Figures 23 and 24 ).

[0656] Experimental details for a recycling experiment:

[0657] In a glovebox, Ru-SiO2- [Pd-NHC] (100 mg, 0.02 mmol Pd / Ru, 2 moll), aryl iodide ( 1 mmol, 50 equiv. w. r. t. Pd), arylalkyne ( 1 mmol), NEta (2 mmol), propylene carbonate ( 1.3 mL) were added to a Fisher-Porter (FP) bottle with a stirring bar. The reaction vessel was sealed and taken out of the glovebox. The reaction mixture was cooled using liquid nitrogen, evacuated and pressurized with 2 bar of CO gas. The FP bottle was then placed behind a protective blast shield and heated at 100 °C for 4 h. Upon cooling to room temperature, the excess pressure was vented through quick vacuum. The FP bottle was then pressurized with 1 bar of H2gas and heated at 100 °C for 1 h kept behind a protective blast shield. After reaction completion, the bottle was cooled down and excess pressure was released under vacuum. The bottle was taken inside the glovebox and the supernatant was removed to prepare a GC sample. The solid catalyst was washed with propylene carbonate ( 1.5 mL). New substrates and solvent were added to the washed catalyst to proceed the next cycle.

[0658] Example 8: Evaluation of Synthetic Approach

[0659] A systematic comparison of the new one-pot tandem synthetic approach of the present invention to standard state-of-the-art carbonylative Heck coupling method for the synthesis of (E) -3-Phenyl-l- (thien-2-yl) prop-2-en-l-one (4r, anti-cancer properties) showed the superiority of the method of the present invention, especially in terms of atom economy, safety, and yield (Figure 26).

[0660] (E) -3-Phenyl-l- (thien-2-yl) prop-2-en-l-one (4r) was chosen as the target product for this evaluation considering the anticancer properties of its derivatives. The one-pot approach of the present invention was systematically compared to carbonylative heck coupling (Figure 26 - area proportional to the green chemistry metrics, i. e., large area = good metrics).

[0661] The carbonylative Heck coupling pathway for the preparation of (E) -3-Phenyl-l- (thien-2-yl) prop-2-en-l-one is illustrated as follows (showing product yield and number of steps):

[0662] Steps: 1 [(cinnamyl)PdCI]2(2 mol% Pd)

[0663] ligand (4 mol%) Eco: 5 NEt3(1.4 mL), CO (5 bar) _ Safety: 2 / 5 Dioxane (0.5 mL) AE: 12% (1 mmol) 100 °C, 20 h Y: 75

[0664]

[0665] (6 mmol) %

[0666]

[0667] The synthetic pathway according to the present invention for the preparation of (E) -3-Phenyl-l- (thien-2-yl) prop-2-en-l-one is illustrated as follows (showing product yield and number of steps ):

[0668] Steps: 1 Ru-SiO2-[Pd-NHC]-2 mol%

[0669] NEt3(2 mmol), CO (2 bar) Eco: 4.5 Propylene carbonate (1.3 mL) Safety: 3 / 5 100 °C, 4 h then H2(3 bar), 2 h AE: 42% (1 mmol) (1 mmol) Y: 87%

[0670]

[0671] In both synthetic approaches, since the starting material is a commercially available compound, its preparation was not included in the evaluation. Five parameters based on green chemistry principles were selected to rank the pathways: the number of steps (Steps), atom economy (AE), overall reaction yield (Y), hazardous nature of the reagents (Safety), and the economic aspect (Eco).

[0672] The AE was determined using the following formula:

[0673] total molecular weight of desired product

[0674] AE = - tota;l — mo;l —ecu;l -ar weigh —t o nf all - rea -ct -antsx100

[0675] The Safety parameter was evaluated qualitatively by ranking the different chemicals on a scale from one (= most hazardous) to five (= least hazardous) based on their hazardous nature (Table 15). The parameter Eco is based on the difference in price between the starting materials and the desired product. The carbonylative Heck coupling provides a better difference and the Eco parameter is set arbitrarily to 5. For the approach of the present invention, the addition of value is slightly high, and Eco was thus set to 4.5 (see Figure 25).

[0676] Table 15. GHS ranking of chemicals.

[0677] GHS ranking

[0678] 1 explosive, oxidizing, toxic, health hazard harmful, flammable, environmental, corrosive 2

[0679] (combination of 3 hazards)

[0680] harmful, flammable, environmental, corrosive 3

[0681] (combination of 2 hazards)

[0682] harmful, flammable, environmental, corrosive 4

[0683] ( 1 hazard)

[0684] 5 -

[0685]

[0686] Chemical CAS MW Price GHS hazard (g / mol) (€ / g)

[0687] 2 -iodo thiophene 3437-95-4 210. 03 3. 9 Harmful + corrosive (3) Styrene 100-42-5 104. 15 0. 4 Toxic +

[0688] Flammable ( 1 ) Phenylacetylene 536-74-3 102. 13 1. 6 Toxic +

[0689] Flammable ( 1 ) Dioxane 123-91-1 88.11 0. 15 Toxic +

[0690] Flammable + Harmful ( 1 ) Tri ethyl amine 121-44-8 101.19 0. 4 Toxic +

[0691] Corrosive ( 1 ) Propylene 108-32-7 102. 09 0.199 Harmful (4 ) carbonate

[0692] (E) -3-Phenyl-l- 3988-77-0 214.29 70.80 Product (5) ( thien-2-yl ) prop- 2-en-l-one

[0693]

[0694] Example 9: Control Experiments Investigating the Catalytic Poisoning with Carbon Monoxide

[0695] The catalytic poisoning and its role in the hydrogenation reaction of 3 was further investigated.

[0696]

[0697] 8

[0698] # Catalyst CO pre- Yield 4 Yield Yield Yield Yield treatment (%) 5 (%) 6 (%) 7 (%) 8 (%) 1 Ru-SiO2- 99 (Z: E

[0699] yes _ _ _ _ [Pd-NHC] =13: 87 )

[0700] 2 Ru-SiO2- no - - 95 1 1 [Pd-NHC]

[0701] 3 Ru-SiO2yes 1 Ru-SiO262 (Z: E =

[0702] no 23 1 9 3

[0703] 3: 97 )

[0704] Ru-SILP yes_ _ _ _ _ Ru-SILPno_ 97 - 2 - Pd-NHC-SiO218 (Z: E =

[0705] Yes _ _ _ _

[0706] 94: 6)

[0707] Pd-NHC-SiO2 No_100

[0708] Pd-SiO2

[0709] Yes 78 22

[0710] 0 Pd-SiO2 Nq_10 Q_ _ _ 1 Ru-SiO2+ 63 (Z: E =

[0711] Ys s _ _ _ _ Pd-NHC-SiO24: 16)

[0712] 2 Ru-SiO2+

[0713] no - 48 52 - - Pd-NHC-SiO2

[0714] Reaction conditions: Catalyst ( 30 mg, 0.006 mmol Pd / Ru), 3 ( 0.3 mmol, 50 equiv. w. r. t. Pd / Ru), PC ( 1.5 mL), H2( 3 bar), 100 °C, 2 h. Pretreated with CO (2 bar), 100 °C, 2 h and depressurized. Conversion and yield were determined through GC-FID using mesitylene as internal standard.

[0715] Control experiments were conducted using various catalyst materials, with and without CO exposure, to investigate the selective hydrogenation of compound 3 to the target product 4. The developed Ru-SiO₂-[Pd-NHC] gave 4 when pre-treated with CO and 6 under H2pressure (entry 1 and 2 ). This result suggests that the observed chemoselectivity in the one-pot reaction sequence originates from the partial poisoning of the Ru NPs surface by CO adsorption. In contrast, both pretreated Ru-SiO2and Ru-SILP catalysts showed no hydrogenation activity (entry 3 and 5) which implies that the Ru active sites are completely blocked by adsorbed CO unlike the bimetallic catalyst (entry 1 ). Pd-NHC-SiO2and Pd nanoparticles (NPs) on silica were also tested in the hydrogenation of 3 (entries 7-10). Only 18% of chaicone product 3 was observed using pre-treated Pd-NHC-SiO2indicating that the hydrogenation activity of Ru-SiO2- [Pd- NHC] is dominated by Ru NPs. However, Pd NPs on SiO2showed better hydrogenation activity even with CO exposure, consistent with their known activity in reductive carbonylation reactions under CO / H2pressure, such as converting aryl halides and nitrobenzenes to aromatic aldehydes and N-aryl formamide respectively. A physical mixture of poisoned Ru-SiO2and Pd-NHC-SiO2gave product 3 in 63% yield (entry 11 ).

[0716] To gain more insights, FTIR spectra were recorded for different catalyst materials using CO as probe molecule (Figure 26). CO is a frequently used IR probe molecule in the characterization of metal surfaces used in catalytic hydrogenation. For the measurement, 15 mg of each catalyst was taken in a fisher porter bottle and pressurized with CO (3 bar) for 18 h. Then, CO was evacuated under vacuum and FTIR was recorded by preparing KBr pellets of the samples (IDl transmission mode). Ru-SiO2(long dash; " Ru@SiO2"; Figure 26) displays characteristic peaks at 2064, 1998 and 1877 cm-1corresponding to gem-terminal (Ru- (CO)2), two or three-fold bridged CO ( (Ru)n-CO) species respectively. Pd-SiO2(short dot; " Pd@SiO2"; Figure 26) shows characteristic peaks at 1947 and 1697 cm-1corresponding to two-fold bridged Pd2-CO and four-fold bridged Pd4-CO species respectively. Notably, the bridged Ru-CO bands at 1988 or 1697 cm-1and bridged Pd-CO bands at 1947 cm-1are absent in the developed bimetallic catalyst (Ru-SiO2- [Pd-NHC], dot; " Ru@SiO2- [ Pd-NHC] "; Figure 26). This clearly indicates the absence of Pd NPs or isolated Ru NPs (i. e., Ru NPs not interacting with Pd-NHC species) at the surface of Ru-SiO2- [Pd-NHC].

[0717] A key finding from this measurement is the appearance of new band at 2122 cm-1in the dot spectrum (also visible at 2128 cm-1with lower intensity for the physical mixture, dash-dot spectrum). This new band is characteristic of Pd+-CO species arising from the interaction between the Ru NPs and Pd-NHC complex. This Ru-Pd electronic interaction renders Pd more electron rich, creating partially positively charged Pd species which are absent in the reference materials. In addition, the band of CO adsorbed on Ru shifted to lower wavenumbers ( from 2064 to 2056 cm-1), as expected for a Pd-Ru interaction.

[0718] These results show a strong interaction between the Ru NPs and the neighboring surface-attached Pd-NHC molecules (RuPd alloying can be excluded under these conditions). This interaction is thought to control the absorption mode and strength of CO at the surface of the Ru NPs, which could be why they are not fully poisoned and chemoselective to E-chalcone products.

Claims

1. Claims2.Claim 13.A catalyst comprising:4.a support;5.metal nanoparticles; and6.a N-heterocyclic carbene comprising palladium or nickel, preferably palladium;7.wherein:8.the metal nanoparticles are immobilised on the support; and9.the N-heterocyclic carbene comprising palladium or nickel is covalently bound to the support, preferably via a spacer and a linker.10.Claim 211.A catalyst according to claim 1, wherein the catalyst comprises the following structure:12.>14. 16.and metal nanoparticles immobilised on the support, wherein:17.Su is a support;18.L is a linker group;19.Sp is a spacer group;20.M is Pd or Ni;21.Z is Br2, I2, Cl2, F2, OTf2, preferably Z is Br2;22.Ri and R2 are either i) each independently selected from the group consisting of a saturated or unsaturated 5- to 6- membered carbocyclic group; a saturated or unsaturated 5- to 6-membered heterocyclic group; or an alkyl group with 1-10 carbon atoms, preferably an alkyl group with 1-6 carbon atoms; or ii) Rx and R2 form with the nitrogen atoms to which each of Ri and R2 are attached, the two carbon atoms attached to M, and the M, a 6- to 8-membered ring, preferably a 6-membered ring.23.Claim 324.Catalyst according to any preceding claim, wherein:25.the metal nanoparticles are monometallic or bimetallic nanoparticles, wherein the metal or metals are selected from the group consisting of the 3d transition metals and / or the noble metals; preferably the metal or metals are selected from Ru, Pd, Mn, Ni, Co, Cu, Rh, Pt and Fe; most preferably the metal nanoparticles are monometallic Ru nanoparticles; and / or26.the spacer Sp is an alkylene group with 1-30 carbon atoms, optionally containing one or more groups selected from ether, ester, amido or arylene groups; preferably the spacer Sp is an alkylene group with 2-10 carbon atoms; and / or27.the support Su is selected from SiO2, AI2O3, TiO2, ZrO2, CaO2, ZnO2, MgO2, CeO2, graphene, graphitic material, activated charcoal or carbon nanotubes; preferably wherein the support is SiO2; and / or28.the linker L is an -Si-O- group, a C-C linkage or an amido group connected to the support; preferably, the linker is a -Si-O- group connected to the support.29.Claim 430.Catalyst according to any preceding claim, wherein the catalyst is poisoned by carbon monoxide.31.Claim 532.Use of a catalyst according to any preceding claim in:33.a carbonylative coupling reaction and / or a hydrogenation reaction; a one-pot carbonylative coupling reaction and hydrogenation reaction;34.the synthesis of a chaicone or an ynone, preferably a chaicone, more preferably an E-chalcone; and / or35.the selective hydrogenation of an alkyne to the corresponding E-alkene.36.Claim 637.Method of coupling a substrate 1 having one of the following general formulas 1A or IB, with a substrate 2 having one of the following general formulas 2A or 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst according to any one of claims 1-4, and heating in the presence of carbon monoxide and a base,38.1B39.R6" X6<5^S‘X9'R940.X? Xg41.R7R843.

44. 2B45.wherein:46.Y is I, Br or OTf, preferably I;47.Xi-X5are each independently C, N, 0, or S, provided that at most one of Xi-X5is N, 0, or S;48.X6-X10are each independently C, N, 0, or S, provided that at most one of X6-X10is N, O, or S; R2-R5are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=O) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent R1-R5 form a 5- to 8-membered ring with the X2-X5to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -NO2, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group;49.R6-R10are each independently H, a halogen, OCH3, C (CH3)3, C (=O) CH3, CH3, CF3, C (=O) OCH3, C (=O) OCH2CH3, CN, phenyl, naphthyl, morpholyl, a saturated or unsaturated heterocyclic group, a linear or branched alkyl group, or wherein two adj acent R6-R10form a 5- to 8-membered ring with the X6-X10to which they are attached; wherein the linear or branched alkyl group is optionally substituted with at least one substituent selected from the group consisting of -OMe, -Me, -F, -NH2, -Cl, -Br, -I, -CF3, -CHO, -NO2, -CN, -OH, and / or the linear or branched alkyl group optionally contains at least one group selected from C-C double bond, C-C triple bond, keto group, ester group, ether group or amido group.50.Claim 751.Method according to claim 6, wherein the coupling of substrate 1 with substrate 2 produces a compound having one of the following general formulas 3A, 3B, 3C or 3D Xi-Xio and Ri-Rio are as defined above.52.Claim 853.Method of hydrogenating a substrate 3 having one of the general formulas 3A, 3B, 3C or 3D, wherein the method comprises bringing substrate 3 into contact with a catalyst according to any one of claims 1-4, and heating in the presence of hydrogen,55.

57.

58. 3C wherein:59.Xi-Xio and Ri-Rio are as defined above.60.Claim 961.Method according to claim 8, wherein the catalyst is treated with carbon monoxide before it is brought into contact with substrate 3,62.preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of carbon monoxide,63.more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of carbon monoxide at a temperature of 21-110 °C and under a carbon monoxide pressure of 1-10 bar,64.even more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-5 bar,65.even more preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of a solvent and carbon monoxide at a temperature of 50-100 °C and under a carbon monoxide pressure of 1-3 bar for 1-3 hours, most preferably wherein the treatment with carbon monoxide involves heating the catalyst in the presence of propylene carbonate and carbon monoxide at a temperature of 100 °C and under a carbon monoxide pressure of 2 bar for 2 hours. Claim 1066.Method according to claim 8 or 9, wherein the hydrogenation of substrate 3 produces a compound having one of the following general formulas 4A, 4B, 4C or 4D,68.

69. wherein:70.Xi-Xio and Ri-Rio are as defined above.71.Claim 1172.Method of a one-pot coupling and hydrogenation reaction of a substrate 1 having one of the following general formulas 1A or IB, and a substrate 2 having one of the following general formulas 2A and 2B, wherein the method comprises bringing substrate 1 into contact with substrate 2 and a catalyst according to any one of claims 1-4, and heating in the presence of carbon monoxide, hydrogen, and a base,73.Y75. 77.1 A 1 B78. 80.wherein:81.Y, X1-X10and R1-R10are as defined above.82.Claim 1283.Method according to claim 11, wherein the one-pot coupling reaction and hydrogenation of substrates 1 and 2 produces a compound having one of the following general formulas 4A, 4B, 4C or 4D,85.

86. wherein:87.Xi-Xio and Ri-Rio are as defined above.88.Claim 1389.Method according to claim 11 or 12, wherein:90.in a first step, substrate 1 is brought into contact with substrate 2 and a catalyst according to any one of claims 1-4, and is heated in the presence of carbon monoxide and a base under a pressure of 1-10 bar of carbon monoxide, to form a reaction mixture; and91.in a second step, an excess pressure of carbon monoxide is removed and the reaction mixture is heated in the presence of hydrogen under a pressure of 1-3 bar of hydrogen.92.Claim 1493.Method according to claim 11 or 12, wherein substrate 1, substrate 2, the base, and the catalyst are heated in the presence of both carbon monoxide and hydrogen, preferably wherein substrate 1, substrate 2, the base, and the catalyst are heated under a pressure of 2-10 bar of carbon monoxide and hydrogen.94.Claim 1595.Method according to any one of claims 6-14, wherein:96.the reaction is completed in a solvent; preferably wherein the solvent is a polar solvent or an ionic liquid; more preferably wherein the solvent is a polar protic or a polar aprotic solvent; even more preferably wherein the solvent is propylene carbonate, dimethyl carbonate, ethylene carbonate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, tetrahydrofuran, 1, 4-dioxane, anisole, or toluene; most preferably wherein the solvent is dimethylformamide or propylene carbonate; and / or97.the base is an amine, a carbonate or a hydroxide; preferably wherein the base is triethylamine, diethylamine, potassium carbonate, caesium carbonate, sodium carbonate, N, N-di isopropyl ethyl amine, 1, 8-Diazabicyclo [5.4.0] undec- 7-ene, 1, 4-diazabicyclo [ 2.

2. 2 ] octane, piperidine, sodium hydroxide, potassium hydroxide, or caesium hydroxide; most preferably wherein the base is triethylamine; and / or heating is completed at a temperature of 50 °C - 150 °C, preferably between 80 °C - 130 °C, most preferably between 100 °C - 120 °C; and / or98.the heating in the presence of carbon monoxide is under a pressure of 1-10 bar of carbon monoxide; and / or the heating in the presence of hydrogen is under a pressure of 1-3 bar of hydrogen; and / or99.the heating in the presence of carbon monoxide and hydrogen is under a pressure of 2-10 bar of carbon monoxide and hydrogen.

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