Field of the invention

The present invention generally relates to improved methods and means for the preparation of metal carbene complexes via a continuous flow process or continuous flow system. Preferred carbene-metal complexes obtainable by such a method comprise heterocyclic carbene-metal complexes such as nitrogen-containing heterocyclic carbene (NHC)-metal complexes.

Background to the invention

The last few decades, heterocyclic carbene-metal complexes and in particular nitrogencontaining heterocyclic carbene (NHC)-metal complexes have gained considerable interest. They have been investigated as homogenous or heterogenous catalysts for polymerization reactions, cyclization reactions, crosscoupling reactions, etc. In addition, metal-NHC complexes also find use in medicinal chemistry and material sciences. Many protocols, primarily batch type protocols, for their synthesis have been developed.

The most common synthetic one-pot strategy to prepare heterocyclic carbene-metal complexes and in particular nitrogen-containing heterocyclic carbene (NHC)-metal complexes is based on the reaction of a free carbene with a metal source, wherein the free carbene is particularly obtained by deprotonation of the corresponding azolium salt with a strong base. The most important drawbacks of this so-called “free carbene” synthesis method lies in the need for strictly anhydrous conditions. The method is also highly sensitive to oxygen and thus requires working in an inert atmosphere. Furthermore, this method is not suitable for complexes requiring the use of metal precursors sensitive to strong bases. The method is expensive and has a high negative impact on the environment.

An alternative batch-type synthesis protocol which has been widely used involves the synthesis of Ag(l)- or Cu(l)-NHC species and the subsequent transfer of the carbene ligand to a different metal. This process is known as the “transmetallation” process. In a particular setup, the silver and copper carbene complexes are prepared by the reaction between the corresponding azolium salt and Ag2<D or CU2O. As the latter compounds act both as bases and as coordinating centers, these methods are referred to as so-called “built-in base” type protocols. Both the transmetallation and the built-in base preparation methods have as their main disadvantage a low atom economy. In addition, the use of Ag(l) species in the transmetallation methods, which are notoriously light-sensitive, also represents a resource depleting factor.

To overcome the severe limitations and disadvantages of the “free carbene”, transmetallation and “built in base” preparation methods described above, the so-called “weak-base” preparation protocol was developed. This synthesis protocol is a one-pot, batch type method for the preparation of NHC-metal complexes, wherein a weak base is mixed with an azolium salt and a metal precursor of interest in a suitable solvent. The “weak- base” preparation protocol allows to obtain NHC-metal complexes in a single step, with high atom efficiency at mild conditions. However, as a batch reaction, this process requires separation of the NHC-metal complex from the reaction mixture. This process further makes use of large solvent volumes and requires long reaction times of on average 6h or more. Also, the yield of the NHC-metal complex is limited by the reduced stability of the NHC- metal complex in the reaction mixture.

McQuade and co-workers discussed the possibility of obtaining copper-NHC complexes via continuous flow synthesis, comprising passing a solution containing an imidazolium salt through a bed comprising CU2O, and their subsequent and immediate use in downstream reactions (Opalka et al. Org. let. 2013, 15, 996-999). However, this synthesis approach suffers from poor atom efficiency and involves the use of environmentally deleterious solvents (5% MeOH/80% CH2Cl2/15% toluene) and high temperatures (110 °C) to ensure high conversion of the starting material. Furthermore, the efficiency of the reactor decreases significantly after less than 10 minutes of use.

There thus remains a need in the art for improved preparation methods for metal-carbene complexes.

Summary of the invention

The present inventors have developed improved methods and systems that address one or more of the above-mentioned problems in the art. The present invention envisages a continuous flow process for the preparation of metal-carbene complexes comprising the use of a continuous flow reactor containing a solid weak base, such as K2CO3, allowing to obtain highly pure metal carbene complexes in high yield and at mild reaction conditions. In particular, the inventors have surprisingly found that by passing a solution comprising an azolium salt, such as an imidazolium salt, and a metal precursor ML _n over a bed of a weak base, such as K2CO3, in a continuous flow reactor, NHC-metal complexes can be obtained in high yield, at short reaction times and with a high conversion ratio. Advantageously, the reaction proceeds under extremely mild conditions, even milder than in the batch-type “weak base” method discussed above and can be performed using technical grade acetone as solvent. As no free carbenes are generated, the reaction does not need to be performed under anhydrous conditions or inert gas atmosphere. In addition, the metal-carbene reaction products can be easily separated from the solvent, requiring no further purification steps, thus making it possible to completely recycle the solvent. Advantageously, the continuous flow process as envisaged herein is easily scalable, with a high level of control over the reaction conditions, such as residence time, temperature and pressure, and purity of the product. Advantageously, the continuous nature of the process and system envisaged herein allows establishing multi-step continuous flow synthesis procedures by sequentially interconnecting multiple reactor vessels or reaction zones and by introducing new reagents at set intervals between reactor vessels or reaction zones in the continuous flow sequence. The present continuous flow technology further offers the opportunity to perform in-line purification, extending ever more the potential of the process and methods envisaged herein.

A first aspect of the present invention relates to a continuous flow process for the preparation of a carbene-metal complex, said process comprising the steps of

(i) providing or contacting a salt of formula Z ⁺ -X' and a metal salt of formula ML _n , preferably a non-ionic metal salt of formula ML _n , in an organic solvent, thereby obtaining a reaction medium, wherein Z is a carbene; X' is an anion; M is a metal; L is an anion or an electron donor ligand; and

(ii) continuously passing said reaction medium through at least a first reaction zone comprising a packed bed of a weak base, thereby continuously obtaining a product flow comprising said carbene-metal complex in the organic solvent, wherein the weak base is not capable of deprotonating a protonated carbene Z ⁺ .

In certain embodiments, step (i) comprises continuously mixing a solution comprising a salt of formula Z ⁺ -X' with a solution comprising a metal salt of formula ML _n , preferably a nonionic metal salt of formula ML _n , thereby obtaining said reaction medium, particularly thereby obtaining a reaction medium comprising a metallate of formula Z ⁺ -ML _n X’ and the organic solvent. In certain embodiments, step (i) comprises the steps of

(ia) providing a solution of a salt of formula Z ⁺ -X' in the organic solvent; and

(ib) prior to step (ii), continuously passing said solution comprising said salt through a second reaction zone comprising a metal salt of formula ML _n , preferably a non-ionic metal salt of formula ML _n in solid form, thereby obtaining said reaction medium.

In particular embodiments, the continuous flow process according to the present invention further comprises the step of

(iv) separating the carbene-metal complex from the organic solvent, and, optionally, recycling the solvent.

In particular embodiments, the weak base is selected from the group consisting of carbonates, hydrogen carbonates, phosphates and amines, preferably is an alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal phosphate, more preferably is K2CO3 or Na ₂ CC>3.

In particular embodiments, the organic solvent is acetone, isopropyl acetate, ethyl acetate or ethanol.

In particular embodiments, Z is a nitrogen-containing heterocyclic carbene (NHC), preferably a substituted imidazoline-2-ylidene, a substituted 4,5-dihydroimidazol-2-ylidene, a substituted imidazoline-4-ylidene, a substituted 4,5-dihydroimidazol-4-ylidene, a substituted mesoionic carbene (MIC) or a cyclic(alkyl)(amino)carbene (CAAC), more preferably selected from the group consisting of IMes, SIMes, IPr, SIPr and ItBu, as specified elsewhere herein, and/or

X is selected from the group consisting of halides, carboxylates, alkoxy groups, aryloxy groups, alkylsulfonates, acetates, trifluoroacetates, tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates, cyanides, thiocyanates, isothiocyanates, cyanates, isocyanates, azides and selenocyanates.

In particular embodiments, M is a transition metal, preferably M is copper, iron, nickel, manganese, ruthenium, osmium, chromium, cobalt, silver, gold, palladium, platinum, iridium or rhodium; and/or L is selected from the group consisting of fluoride (F-), chloride (Cl"), bromide (Br), iodide (I-), triflate (trifluoromethane sulfonate) (OTf), acetate (OAc), trifluoroacetate (TFA-), tetrafluoroborate (BF4'), hexafluorophosphate (PFe’), hexafluoroantimonate (SbFe'), sulfate (SC>4 ² ') and phosphate (PCs ^2- ). In particular embodiments, step (ii) of the continuous flow process according to the present invention is conducted at a temperature between 20°C and 60°C, preferably between 30°C and 50°C, and with a contact time between reaction medium and the solid weak base of between 1 min and 10 min, preferably between 2 min and 5 min.

In certain embodiments, the continuous flow process as envisaged herein further comprises the step (iii) of continuously adding a further reactant to the product flow comprising a carbene-metal complex in an organic solvent obtained in step (ii), thereby obtaining a combined product flow, and continuously subjecting the combined product flow to conditions suitable for the reaction between the further reactant and the carbene-metal complex in the product flow.

More in particular, the continuous flow process as envisaged herein further comprises the step (iiia) of continuously adding a carbazole, a p-carboline, an alkyne, a heteroaromatic compound, a heterocycle or a thiol compound in an organic solvent to the product flow comprising a carbene-metal complex in an organic solvent obtained in step (ii), thereby obtained a combined product flow, and (iiib) continuously passing said combined product flow through a third reaction zone comprising a packed bed of a weak base as specified herein, thereby continuously obtaining a further product flow comprising a further metal- carbene complex in the organic solvent, said further metal-carbene complex comprising a ligand Y derived from a carbazole, a p-carboline, an alkyne, a heteroaromatic compound, a heterocycle or a thiol. In particular embodiments, step (iiib) is conducted at a temperature between 20°C and 70°C, preferably between 30°C and 60°C, and with a contact time between the combined product flow and the solid weak base of between 1 min and 10 min, preferably between 2 min and 5 min. In particular embodiments, the weak base of the third reaction zone is selected from the group consisting of carbonates, hydrogen carbonates, phosphates and amines, preferably is an alkali metal carbonate, alkali metal hydrogen carbonate or an alkali metal phosphate, more preferably is K2CO3 or Na2COs.

Another and related aspect of the present invention provides a system for the continuous preparation of a carbene-metal complex, comprising a reaction vessel, said reaction vessel comprising:

(a) at least one first reaction zone comprising a packed bed of a solid weak base, wherein the weak base is not capable of deprotonating a protonated carbene ligand, such as an azolium salt; (b) at least one inlet, in fluid communication with a first end of the at least one first reaction zone, for introducing a reaction medium in the reaction vessel; and

(c) at least one outlet, in fluid communication with a second end of the at least one first reaction zone, for removing a product flow from the reaction vessel.

In certain embodiments, the system according to the present invention further comprises a mixing means for the preparation of a reaction medium, said mixing means comprising at least an inlet for a solution of a salt of formula Z ⁺ -X' in an organic solvent, an inlet for a solution of a metal salt of formula ML _n , particularly a non-ionic metal salt of formula ML _n , in the organic solvent, and an outlet for the reaction medium, wherein the outlet of the mixing means is connected to the inlet of said reaction vessel.

In certain embodiments, the system according to the present invention further comprises at least a second reaction zone, comprising a metal salt of formula ML _n in solid form, particularly a non-ionic metal salt of formula ML _n in solid form, in fluid communication to and upstream of at least one first reaction zone, such as wherein the reaction vessel comprises multiple, alternating first and second reaction zones. Preferably, said at least one first reaction zone is separated from said at least one second reaction zone by an inert filler material, such as sand or SiC>2.

In certain embodiments, the system according to the present invention further comprises

(d) a third reaction zone, particularly in a separate reaction vessel, wherein the inlet of the third reaction zone is in fluid connection with the outlet of the first reaction zone or with the outlet of the reaction vessel comprising the first reaction zone, and (e) a means for introducing a reactant in the product flow between the outlet of the first reaction zone and the inlet of the third reaction zone. In particular, the third reaction zone comprises a packed bed of a solid weak base.

In particular embodiments, the system according to the present invention further comprises a product separation vessel, situated downstream of the reaction vessel via said at least one outlet, for separating the carbene metal complex reaction product from a solvent, and optionally comprising means for recycling the solvent.

In particular embodiments, the continuous flow process according to the present invention is performed with the system according to the present invention.

Figure Legends

Figure 1 represents a system according to an embodiment of the present invention. Figure 2 represents a system according to an embodiment of the present invention. Figure 3 represents a system according to an embodiment of the present invention.

Figure 4 represents the continuous flow synthesis of [M(IPr)(Cbz)] (M= Cu and Au, Cbz = carbazoyl), according to an embodiment of the present invention.

Detailed description of invention

Before the present system and method of the invention are described, it is to be understood that this invention is not limited to particular systems and methods or combinations described, since such systems and methods and combinations may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements, or method steps. It will be appreciated that the terms "comprising", "comprises" and "comprised of" as used herein comprise the terms "consisting of', "consists" and "consists of'.

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints.

The term "about" or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of +/-10% or less, preferably +/-5% or less, more preferably +/-1% or less, and still more preferably +/-0.1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" or “approximately” refers is itself also specifically, and preferably, disclosed.

Whereas the terms “one or more” or “at least one”, such as one or more or at least one member(s) of a group of members, is clear perse, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

The terms “first”, “second” and the like used in the description as well as in the claims, are used to distinguish between similar elements and not necessarily describe a sequence, either temporally, spatially, in ranking or in any other manner, unless specified otherwise. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

In the present description of the invention, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration only of specific embodiments in which the invention may be practiced. Parenthesized or emboldened reference numerals affixed to respective elements merely exemplify the elements by way of example, with which it is not intended to limit the respective elements. It is to be understood that other embodiments may be utilised, and structural or logical changes may be made without departing from the scope of the present invention. The following detailed description, therefore, is not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims.

The present invention envisages a continuous flow process and system for the preparation of metal-carbene complexes comprising the use of a continuous flow reactor containing a solid weak base, which allows to obtain highly pure metal carbene complexes in high yield, using short reaction times and at mild reaction conditions, and using technical grade organic solvents. The continuous flow process as envisaged herein is easily scalable, with a high level of control over the reaction conditions, such as residence time, temperature and pressure, and purity of the product.

A first aspect of the present invention provides a continuous flow process for the preparation of a carbene-metal complex, said process comprising the steps of

(i) providing or contacting a salt of formula Z ⁺ -X' and a non-ionic metal salt of formula ML _n in an organic solvent, thereby obtaining a reaction medium, wherein Z is a carbene; X' is an anion; M is a metal; L is an anion or an electron donor ligand; and

(ii) continuously passing said reaction medium through at least a first reaction zone comprising a packed bed of a weak base, thereby continuously obtaining a product flow comprising said carbene-metal complex in the organic solvent. As further specified below, said weak base cannot deprotonate a protonated carbene, such as an azolium salt.

As envisaged herein, a carbene-metal complex is an organometallic compound comprising a metal M and one or more two-electron donor carbene organic ligands Z _m , wherein m is an integer, in particular m is 1 or 2, with or without other ligands. The metal-carbene complex envisaged herein may thus comprise a single carbene ligand Z or may comprise multiple carbene ligands Zi, Z2, ... , wherein the multiple carbene ligands may be identical or different.

In the context of the different aspects and embodiments of the present invention, M is a metal, preferably a transition metal, i.e. an element from groups 3 to 12 of the Periodic Table. In preferred embodiments, M is a transition metal of any one of groups 6 to 11 of the Periodic Table, such as from groups 8 to 11 of the Periodic Table. Particularly preferred metals M include copper, iron, nickel, manganese, ruthenium, osmium, chromium, cobalt, silver, gold, palladium, platinum, iridium and rhodium. Particularly preferred metals M are copper, silver, gold, palladium, ruthenium and platinum. In the context of the different aspects and embodiments of the present invention, Z is a carbene ligand, particularly a N-heterocyclic carbene ligand. As such, the carbene carbon is a neutral species, having two single bonds to neighbouring atoms, i.e. nitrogen atoms in the N-heterocyclic carbene ligands, and a pair of non-bonding electrons. In its neutral state, the carbene carbon has only six electrons, and is stabilized by donation of adjacent nitrogen lone pair electron density to the empty carbon orbital to alleviate the electron deficiency. In the context of the different aspect and embodiments of the present invention, Z ⁺ is a protonated carbene ligand. Coordination of a proton to the nonbonding pair of electrons of the carbene results in the formation of an azolium salt that may possess any of numerous possible counter-anions X, e.g. halides, tetrafluoroborate, hexafluorophosphate, etc, as further discussed below. In particular embodiments, the carbene Z ⁺ is a protonated azolium compound.

Preferred heterocyclic carbene ligands comprise nitrogen-containing heterocyclic carbene ligands (NHC) having a ring of 4 to 8 members, for example 4 to 7 members. More preferably, the NHC has a ring of 5 or 6 members. The NHC may be saturated or unsaturated and may contain one or more nitrogen atoms. Optionally, the NHC may comprise other heteroatoms (such as O, B, P and S) in the ring.

In certain embodiments, Z is an NHC ligand according to formula (I)

Wherein: the groups R may be the same or different, the groups R1 may be the same or different; and the dashed line in the ring represents optional unsaturation, wherein it is understood that R1 and R2 are absent in case of unsaturation.

Each of the groups R and R1 may be, independently for each occurrence, selected from: H, a primary or secondary alkyl group that may be unsaturated and may be substituted or unsubstituted and may be cyclic, substituted or unsubstituted aryl, a substituted or unsubstituted heterocycle, or a functional group selected from the group consisting of halide, hydroxyl, sulfhydryl, cyano, cyanato, thiocyanato, amino, nitro, nitroso, sulfo, sulfonato, boryl, borono, phosphono, phosphinato, phosphinato, phospho, phosphino and siloxy. In particular, the groups R and R1 may be, independently for each occurrence unsaturated alkyl i.e. alkenyl (for example C2-C18 or C2-C14), that may be substituted or unsubstituted and may be cyclic.

One or more of the carbon atoms in the ring (apart from the carbene carbon) may be substituted with a heteroatom, for example O, B, P or S.

In preferred embodiments, Z is an NHC ligand bearing two nitrogen atoms in the ring, each nitrogen atom being adjacent to the carbene carbon. An NHC ligand of this type may be of the form according to formula (II):

Wherein: each of the groups R, R1 , R2, R3 and R4 may be the same or different; and the dashed line in the ring represents optional unsaturation, wherein it is understood that R1 and R2 are absent in case of unsaturation.

In addition, one or more of the carbon atoms in the ring (apart from the carbene carbon) may be substituted with a heteroatom, for example O, B, P or S.

Each of the groups R, R1, R2, R3 and R4 may be independently for each occurrence selected from: hydrogen, a primary, secondary or tertiary alkyl group (for example C1 -C18 or C1-C14) that may be unsaturated and may be substituted or unsubstituted and may be cyclic, substituted or unsubstituted aryl (for example substituted phenyl, naphthyl or anthracenyl), a substituted or unsubstituted heterocycle (for example pyridine), or a functional group selected from the group consisting of halide, hydroxyl, alkoxyl, aryloxyl, sulfhydryl, cyano, cyanate, thicyanato, amino, nitro, nitroso, sulfo, sulfonate, boryl, borono, phosphonato, phosphinato, phospho, phosphino and siloxy.

Preferably, the groups R3 and R4 may be a substituted or unsubstituted aromatic ring or heterocyclic aromatic rings.

Particular substituents R, R1 , R2, R3 and R4 of structures of formula (II) may include alkyl and unsaturated alkyl groups, aryl or heteroaryl groups that may be substituted. In particularly preferred embodiments, Z is a substituted imidazoline-2-ylidene, a substituted 4,5-dihydroimidazol-2-ylidene, a substituted imidazoline-4-ylidene, or a substituted 4,5- dihydroimidazol-4-ylidene. In certain embodiments, Z is a substituted mesoionic carbene (MIC) or a cyclic(alkyl)(amino)carbene (CAAC). Particularly preferred examples of an NHC ligand include any one of the carbenes listed in Table A.

TABLE A

In step (i) of the continuous flow process of the present invention, a salt of formula Z ⁺ -X' and a metal salt of formula ML _n , particularly a non-ionic metal salt of formula ML _n is contacted or provided in an organic solvent, thereby forming a reaction medium, and continuously passing this reaction medium over a fixed bed comprising a solid weak base, as further specified below. In particular embodiments, the reaction medium comprises a metallate of formula Z ⁺ -ML _n X’.

In particular embodiments, step (i) comprises continuously mixing a solution comprising a salt of formula Z ⁺ -X' with a solution comprising a metal salt of formula ML _n , thereby obtaining said reaction medium, in particular thereby obtaining a reaction medium comprising a metallate of formula Z ⁺ -ML _n X’ in the organic solvent. Preferably, the salt of formula Z ⁺ -X' and the metal salt of formula ML _n are mixed in a ratio corresponding to the ratio Z:M in the metallate of formula Z ⁺ -ML _n X. Alternatively, the reaction medium may be prepared by providing a metallate of formula Z ⁺ 'MLnX' and subsequently dissolving the metallate of formula Z ⁺ -ML _n X' in the organic solvent.

For the purpose of the present invention, a salt of formula Z ⁺ -X' comprises a protonated carbene ligand Z as envisaged herein, in particular an azolium, and an anion X. The term anion includes any type of negatively charged ions including anionic ligands. Preferably, X is selected from the group consisting of halides, carboxylates, alkoxy groups, aryloxy groups, alkylsulfonates, acetates, trifluoroacetates, tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates, cyanides, thiocyanates, isothiocyanates, cyanates, isocyanates, azides and selenocyanates.

In particular embodiments, a salt of formula Z ⁺ -X' is a N-heterocyclic carbene salt, in particular an azolium salt, such as an imidazolium salt, a 4,5-dihydro-imidazolium salt, a triazolium salt, or a pyrrolium salt. Suitable azolium salts include imidazolium, triazolium, tetrazolium, pyrazolium, benzimidazolium, oxazolium and thiazolium salts. More in particular, a salt of formula Z ⁺ -X' is a salt of a substituted imidazoline-2-ylidene, a salt of a substituted 4,5-dihydroimidazol-2-ylidene, a salt of a substituted imidazoline-4-ylidene, or a salt of a substituted 4,5-dihydroimidazol-4-ylidene, such as the hydrogen halide or acetic acid salt thereof. In certain embodiments, a salt of formula Z ⁺ -X' is a salt of a substituted mesoionic carbene (MIC) or a cyclic(alkyl)(amino)carbene (CAAC), such as the hydrogen halide or acetic acid salt thereof. Particular preferred examples are a salt of the NHC ligands listed in table A, more in particular a hydrogen halide salt, such as a HCI salt of the NHC ligands listed in table A.

In particular embodiments, a salt of formula Z ⁺ -X' is one of the salts listed in Table B.

Table B

For the purpose of the present invention, a metal salt of formula ML _n includes all salts comprising metal M and anion or electron donor ligand L. Preferably, the metal salt is a nonionic metal salt of formula ML _n , which includes all salts comprising metal M and electron donor ligand L, that are not ionic salts. Ionic salts refer to salts of formula M ^x+ L _n ^y ' whereby the metal and the anion are bonded by an ionic bond. Preferred non-ionic metal salts used in the method according to the present invention comprise compounds whereby the metal M and the anion L are bonded by a covalent or dative bond. M is a metal as envisaged herein. L comprises an anion or an electron donor ligand, such as a one-electron donor ligand or a two-electron donor ligand. Preferably, L comprises an anion selected from the group consisting of a halide, in particular fluoride (F-), chloride (Cl"), bromide (Br), iodide (I-), triflate (trifluoromethane sulfonate) (OTf-), acetate (OAc), trifluoroacetate (TFA-), tetrafluoroborate (BF4'), hexafluorophosphate (PFe’), hexafluoroantimonate (SbFe'), sulfate (SO ₄ ² ’) and phosphate (PCs ^2- ). Preferred non-ionic metal salts of formula ML _n are salts comprising a single metal M. Examples comprise CuCI, AgCI, AuCI, PdCh, NiCh, [RhL _n CI]2, [lrl_ _n CI]2, Ru(arene)Cl2]2.

For the purpose of the present invention, the organic solvent is an organic liquid or organic compound that dissolves at least the salt of formula Z ⁺ -X' or the metallate of formula Z ⁺ 'MLnX, and preferably also dissolves the metal salt ML _n , preferably the non-ionic metal salt ML _n . It is understood that the weak base as envisaged herein is not soluble in the organic liquid. Preferred organic solvents include acetone, isopropyl acetate, ethyl acetate, ethanol, isopropanol or t-butanol.

The concentration of the salt of formula Z ⁺ -X; or the metallate of formula Z ⁺ - ML _n X in the organic solvent is not essential to the present invention and inter alia depends on the solubility of these compounds in the organic solvent. In certain embodiments, the concentration of the salt of formula Z ⁺ -X; or the metallate of formula Z ⁺ -ML _n X in the organic solvent ranges from 1 mM and 1M, preferably from 1 mM to 100mM, such as between 10 mM and 50 mM.

In step (ii) of the continuous process of the present invention, the reaction medium is continuously passed through at least a first reaction zone comprising a packed bed of a weak base, thereby continuously obtaining a product flow comprising said carbene-metal complex in the organic solvent.

In particular embodiments, the continuous flow process comprises the steps of

(ia) providing a solution of a salt of formula Z ⁺ -X' as envisaged herein in the organic solvent;

(ib) prior to step (ii), continuously passing said solution comprising said salt through a second reaction zone comprising a metal salt of formula ML _n as envisaged herein in solid form, particularly a non-ionic metal salt of formula ML _n as envisaged herein in solid form, thereby obtaining said reaction medium, and

(ii) continuously passing said reaction medium through a first reaction zone comprising a packed bed of a weak base, thereby continuously obtaining a product flow comprising said carbene-metal complex in the organic solvent.

In the context of the different aspects and embodiments of the present invention, the weak base as envisaged herein is a base, particularly an inorganic base, which cannot, i.e. is incapable of, deprotonating the protonated carbene ligand Z ⁺ in the salt of formula Z ⁺ -X; particularly under the reaction conditions of the first reaction zone. Particularly, the weak base is a base, particularly an inorganic base, which cannot, i.e. is incapable of, deprotonating an azolium salt, particularly under the reaction conditions of the first reaction zone.

In this context, the skilled person understands that free carbenes, in particular free nitrogencontaining heterocyclic carbenes or NHCs are typically obtained via deprotonation of the corresponding azolium salts, such as imidazolium, triazolium, tetrazolium, pyrazolium, benzimidazolium, oxazolium, or thiazolium salts. Accordingly, in the different aspects and embodiments of the present invention, as the weak base cannot deprotonate such azolium salt, the corresponding free NHC will not be generated. Advantageously, and in contrast to the prior art methods, the “free carbene” methods as discussed above, the process as envisaged herein is thus not sensitive to water or oxygen, and thus does not need to be conducted in anhydrous conditions or under an inert atmosphere. The continuous flow process as envisaged herein can be performed using organic solvents, such as technical grade acetone, which comprise at least some traces of water, or in air. This contributes to the robustness of the process and system according to the present invention.

It is further understood by the skilled person that azolium salts typically have a pK _a value of 21-24. In this context, suitable weak bases as envisaged herein have a pKb value ranging between 4 and 8.5, preferably a pKb value between 5 and 8, more preferably a pKb value between 6 and 8, such as a pKb value between 7 and 8.

Advantageously, the weak base is not soluble in the organic solvent. In particular, the weak base is selected from the group consisting of carbonates, hydrogen carbonates, phosphates and amines, preferably is an alkali metal carbonate, alkali metal hydrogen carbonate or an alkali metal phosphate, more preferably is K2CO3 or Na2COs. In particular embodiments, the reaction zone comprising the weak base is contained in a suitable reaction vessel.

In particular embodiments, step (ii) of the continuous flow process as envisaged herein is conducted at a temperature between 20°C and 60°C, preferably between 30°C and 50°C.

It is understood that the flow rate of the reaction medium over the reaction zone comprising the weak base in solid form is selected to achieve a suitable residence time of the reaction medium in the reaction zone. In particular embodiments, the residence time of the reaction medium in the reaction zone comprising the weak base in solid form ranges between 1 min and 10 min, preferably between 2 min and 5 min.

In particular embodiments, the continuous flow process further comprises the step of separating the carbene-metal complex from the organic solvent, and, optionally, recycling the solvent. In particular embodiments, the carbene-metal complex and the organic solvent are separated by evaporating the organic solvent, particularly by evaporating under vacuum conditions.

In particular embodiments, the continuous flow process as envisaged herein is a multi-step continuous flow process comprising multiple sequential reaction zones, typically placed in series, wherein further reactants are continuously introduced between consecutive reaction zones, whereby a product flow exiting an earlier reaction zone is mixed with a further reactant and is subsequently converted in a subsequent reaction zone in a continuous manner.

In particular embodiments, the continuous flow process as envisaged herein further comprises the step (iii) of continuously adding a further reactant to the first product flow comprising a carbene-metal complex in an organic solvent, obtained in step (ii), thereby obtaining a combined product flow, and continuously subjecting the combined product flow to conditions suitable for the reaction between the further reactant and the carbene-metal complex in the product flow. In particular embodiments, said step (iii) comprises the step (iiia) of continuously adding a further reactant selected from the group consisting of a carbazole, a p-carboline, an alkyne, a heteroaromatic compound, a heterocycle and a thiol compound, in an organic solvent to the product flow comprising a carbene-metal complex, particularly an NHC-metal complex, in an organic solvent, obtained in step (ii), thereby obtained a combined product flow, and (iiib) continuously passing said combined product flow through a third reaction zone comprising a packed bed of a weak base, thereby continuously obtaining a further product flow comprising a further metal-carbene complex in an organic solvent, wherein the further metal-carbene complex further comprises a ligand Y derived from said carbazole, a p-carboline, an alkyne, a heteroaromatic compound, a heterocycle or a thiol. Examples of such further metal-carbene complex include a metal- carbene amido complex or a metal-carbene thiolato complex, in particular a metal-NHC amido complex or a metal-NHC thiolato complex. More in particular, the organic solvent in step (iiia) and the weak base in step (iiib) are as described elsewhere herein. In particular, in step (iiia) at least 1.1 equivalents, such as between 1.1 or 1.2 and 1.5 equivalents of carbazole or p-carboline, based on the amount of a carbene-metal complex, particularly an NHC-metal complex, in the first product flow, are introduced in the first product flow. In particular, about equimolar amounts, such as between 0.9 and 1.2 equivalents of a thiol compound, based on the amount of a carbene-metal complex, particularly an NHC-metal complex, in the first product flow, is introduced in the first product flow.

The term “heterocycle” refers to a compound comprising a ring stricture comprising carbon atoms and one or more heteroatom, preferably nitrogen, oxygen of sulfur.

The term “heteroaromatic compound” as used herein generally refers to but is not limited to a compound comprising 5 to 20 carbon-atom aromatic rings or ring systems, wherein each ring typically contains 5 to 6 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms, preferably by nitrogen atoms. Preferred heteroaromatic compounds include carbazole or p-carboline. As used herein, p-carboline represents a family of alkaloid compounds, particularly indole alkaloids sharing the basic chemical structure of Formula III.

(Formula III)

P-carbolines typically have different substituents on position 1 , 6 and 7. Examples of P-carboline compounds as envisaged herein include pinoline, harmane, harmine, harmaline or harmalol.

Thiol compounds as envisaged herein particularly include thiols with high reactivity towards coordination with Cu, Pd, Ag, Ru, Pt or Au metals, as known to the skilled person. Examples of thiol compounds include thiophenol or 1-thio-p-D-glucose tetraacetate.

In particular embodiments, the present invention relates to a continuous flow process for the preparation of a metal-NHC amido or metal-NHC thiolato complex, said process comprising the steps of

(i) providing or contacting an azolium salt and a metal salt of formula ML _n in an organic solvent, thereby obtaining a reaction medium, wherein M is a metal, particularly Cu, Ag or Au; L is an anion or an electron donor ligand;

(ii) continuously passing said reaction medium through at least a first reaction zone comprising a packed bed of a weak base as envisaged herein, thereby continuously obtaining a first product flow comprising a metal-NHC complex, particularly a Cu-NHC, Ag- NHC or Au-NHC complex, in the organic solvent,

(iiia) continuously introducing a reactant, particularly a carbazole, a p-carboline or a thiol compound in an organic solvent, in the first product flow comprising a metal-NHC complex, thereby obtaining a combined product flow; and

(iiib) continuously passing said combined product flow through a third reaction zone comprising a packed bed of a weak base as envisaged herein, thereby continuously obtaining a second product flow comprising a metal-NHC amido or metal-NHC thiolato complex in the organic solvent. In particular embodiments, said metal-NHC amido complex is a Ag(NHC)carbozoyl complex, a Cu(NHC)carbazoyl complex, a Au(NHC)carbazoyl complex, a Ag(NHC)(P-carboline) complex, Cu(NHC)(P-carboline) complex or a Au(NHC)(P-carboline) complex. In particular embodiments said thiolate complex is a Ag(NHC)(thiophenol) complex, a Cu(NHC)(thiophenol) complex, a Au(NHC)(thiophenol) complex, a Ag(NHC)(1-thio-p-D-glucose tetraacetate) complex, Cu(NHC)(1-thio-p-D- glucose tetraacetate) complex or a Au(NHC)(1-thio-p-D-glucose tetraacetate) complex. In particular embodiments, step (iiib) is conducted at a temperature between 20°C and 70°C, preferably between 30°C and 60°C, and with a contact time between the combined product flow and the solid weak base of between 1 min and 10 min, preferably between 2 min and 5 min. In certain embodiments, in step (iiia) at least 1.1 equivalents, such as between 1.1 or 1.2 and 1.5 equivalents of carbazole or p-carboline, based on the amount of a carbene-metal complex, particularly an NHC-metal complex, in the first product flow, are introduced in the first product flow. In particular, about equimolar amounts, such as between 0.9 and 1 .2 equivalents, of a thiol compound, based on the amount of a carbene- metal complex, particularly an NHC-metal complex, in the first product flow, is introduced in the first product flow.

As discussed above, it has been found that metal carbene metal complexes comprising a further ligand Y as specified above, in particular NHC metal amido and thiolato complexes, can be prepared via a continuous flow process in high yield at mild reaction conditions and short reaction times, with marked improvements over batch type versions of these processes, by passing a mixture of the corresponding NHC-metal complex and a suitable reactant, such as carbazole, p-carboline or thiol compound over a packed bed of a weak base. Advantageously, the reaction conditions for the continuous flow process for the synthesis of NHC metal amido and thiolato complexes are similar as the reaction conditions for the continuous flow process for the synthesis of the metal-NHC complexes from the corresponding azolium salt and metal source, as discussed elsewhere herein, thus contributing to the robustness of a multi-step continuous flow synthesis process for the synthesis of NHC metal amido and thiolato complexes, using, on the one hand, the corresponding azolium salt and metal source and a first reaction zone comprising a weak base, in particular K2CO3 or Na2COs, to obtain the metal-NHC complex and, using, on the other hand, carbazole, p-carboline or thiol compound and a separate reaction zone, placed in series with the first reaction zone, said separate reaction zone also comprising a weak base, in particular K2CO3 or Na2COs, to convert the metal-NHC complex to the corresponding metal-NHC amido or thiolato complex.

According to a second and related aspect of the present invention, a system for the continuous preparation of a metal-carbene complex is provided. The system according to the present invention comprises a reaction vessel, wherein the reaction vessel comprises: (a) at least one first reaction zone, said first reaction zone comprising or consisting of a packed bed of a solid weak base as specified elsewhere herein; (b) at least one inlet, in fluid communication with a first end of the at least one first reaction zone, for introducing an inlet flow, particularly for introducing a reaction medium as envisaged herein, in the reaction vessel; and

(c) at least one outlet, in fluid communication with a second end of the at least one first reaction zone, for removing a product flow comprising the metal-carbene complex from the reaction vessel.

Typically, the system further comprises suitable conduits connected to the at least one inlet and to the at least one outlet, for introducing an inlet flow to the reaction vessel and removing a product flow from the reactor vessel, respectively.

The inlet flow, particularly the reaction medium as envisaged herein, is typically introduced to the reaction zone by continuously pumping the inlet flow, via a pumping means, particularly the reaction medium to the reaction vessel and through a reaction zone of the reaction vessel.

The reaction vessel may be a flow channel or reactor, which may comprise one or a plurality of reaction zones.

In certain embodiments, the system as envisaged herein comprises a reaction vessel comprising one first reaction zone, although systems comprising more than one reaction zone, such as more than one first reaction zone, can be considered as well.

In certain embodiments, the system or reaction vessel further comprises at least a second reaction zone, different from the first reaction zone. In particular embodiments, said second reaction zone comprises or consists of a metal salt of formula ML _n in solid form as envisaged herein, particularly a non-ionic metal salt of formula ML _n in solid form, in fluid communication to an end of the at least one reaction zone. In particular embodiments, the reaction vessel comprises multiple, alternating first and second reaction zones.

In certain embodiments, the system according to the present invention may comprise a plurality of reaction vessels, wherein each reaction chamber comprises one or more first and, optionally, second reaction zones. More in particular, each of said first reaction zones is separated from each of said second reaction zones by an inert filler material, such as sand or SiC>2.

The inlet flow comprising the reaction medium as envisaged herein, may be obtained by mixing a first flow of a salt of formula Z ⁺ -X' as envisaged herein in an organic solvent and a second flow of a metal salt of formula ML _n as envisaged, particularly a non-ionic metal salt of formula ML _n . Accordingly, in certain embodiments, the system further comprises a mixing means upstream of the reaction vessel, and in fluid communication with the at least one inlet, for mixing a first flow of a salt of formula Z ⁺ -X' as envisaged herein in an organic solvent as envisaged herein and a second flow of a non-ionic metal salt of formula ML _n as envisaged herein in the solvent, thereby obtaining a flow of the reaction medium. Suitable mixing means are known in the art and include, but are not limited to, a static mixer.

In certain embodiments, the system further comprises (d) a third reaction zone, preferably located in a separate reaction vessel, wherein the inlet of the third reaction zone is in fluid connection with the outlet of the first reaction zone, and (e) a means for introducing a reactant in the product flow between the outlet of the first reaction zone and the inlet of the third reaction zone. In preferred embodiments, the third reaction zone comprises a packed bed of a solid weak base, as specified elsewhere herein.

In certain embodiments, the system further comprises a product separation vessel, situated downstream of the reaction vessel via said at least one outlet, for separating the carbene metal complex reaction product from the organic solvent, such as a means for vacuum evaporation of the organic solvent. Optionally, the system may further comprise means for recycling the organic solvent.

Figure 1 is an exemplary illustration of a system (100) for the continuous preparation of a metal-carbene complex according to an embodiment of the present invention. A flow of reactant A and a flow 102 of reactant B is provided via the respective conduits (101 , 102) to a mixer (103), for example a static mixer or any other mixing system, resulting in a combined flow comprising the reaction medium. Reactant A comprises a salt of formula Z ⁺ - X' as envisaged herein in an organic solvent as envisaged herein. Reactant B comprises for example a non-ionic metal salt of formula ML _n as envisaged herein in the solvent. The reaction medium flow is introduced by a conduit (104) to a reaction vessel (105) to flow through reaction zone (106). The reaction zone (106) comprises a packed bed of a solid weak base as envisaged herein, such as e.g. K2CO3. The temperature of the reaction chamber is thermostatically controlled (not shown). The product flow comprising the metal- carbene complex is removed from the reactor zone and the reactor vessel via conduit (107). Optionally, the system (100) further comprises a product separation vessel (108) to separate the metal-carbene complex product flow (110) from the organic solvent flow (109). Figure 2 is an exemplary illustration of a system (200) for the continuous preparation of a metal-carbene complex according to an embodiment of the present invention. A flow of a salt of formula Z ⁺ -X' as envisaged herein in an organic solvent is introduced in reaction vessel (202) via conduit (201). The flow of the salt of formula Z ⁺ -X' as envisaged herein is passed through different reaction zones, in particular a reaction zone comprising a nonionic metal salt of formula ML _n as envisaged herein (204) and a reaction zone comprising a packed bed of a solid weak base (203), such as K2CO3. The different reaction zones (203) and (204) are separated from each other by an inert filler (205). The temperature of the reaction chamber (202) is thermostatically controlled (not shown). The product flow comprising the metal-carbene complex is removed from the reactor zone and the reactor vessel via conduit (206). Optionally, the system (200) further comprises a product separation vessel (207) to separate the metal-carbene complex product flow (209) from the organic solvent flow (208).

Figure 3 is an exemplary illustration of a system (300) for the continuous preparation of a metal-carbene amido complex or a metal-carbene thiolato complex, according to an embodiment of the present invention. A flow of reactant A and a flow of reactant B is provided via the respective conduits (301 , 302) to a mixer (303), for example a static mixer or any other mixing system, resulting in a combined flow comprising the reaction medium. Reactant A comprises a salt of formula Z ⁺ -X' as envisaged herein in an organic solvent as envisaged herein. Reactant B comprises for example a non-ionic metal salt of formula ML _n as envisaged herein in the solvent. The reaction medium flow is introduced by a conduit (304) to a reaction vessel (305) to flow through a first reaction zone (306). The reaction zone (306) comprises a packed bed of a solid weak base as envisaged herein, such as e.g. K2CO3. The temperature of the reaction chamber is thermostatically controlled (not shown). The product flow comprising the metal-carbene complex is removed from the first reaction zone (306) and reaction vessel (305) via conduit (307) and introduced into another reaction vessel (308) comprising a third reaction zone (309), which comprises a packed bed of a solid weak base as envisaged herein, such as e.g. K2CO3. Reactant C, typically comprising a carbazole, a p-carboline or a thiol compound in an organic solvent as envisaged herein, is added to the product flow exiting the first reaction zone (306) prior to the product flow entering the third reaction zone (309) via conduit 311 , and, optionally a mixing unit (not shown). A product flow comprising a metal-carbene amido complex or a metal-carbene thiolato complex in an organic solvent leaves the third reaction zone (309) via conduit (310). Examples

Experimental setup for the comparative example and examples 1-4

All experiments were carried out using technical grade acetone as a solvent. K2CO3 was purchased from Honeywell Riedel-de-Haen™ and CuCI was commercially available from Acros Organics B.V.B.A. [AuCI(DMS)] was prepared from HAuCk n^O. [IPrHUCuCfe], [IPrH][AuCl2] and [IPrH][Pd(cin)Cl2] were prepared according to published procedures. All other reagents were purchased and used as received without further purification.

A ReaXus 601 OR Reciprocating Pump (Teledyne ISCO) was used to flow the substrate solution over the reactor plug. It can operate with accurate flow rate up to 10 mL/min and has a pressure capability up to 414 bar (6000 psi). T o heat the reactor quickly and accurately to the desired temperature, an empty GC-oven was used as a hot air heating chamber. This was done with an Agilent 6890 Series GC system, from which the GC column had been removed. The tubing used to create the reactor was obtained from Bohlender™ and consists of PTFE which guaranteed its temperature and chemical resistance. The internal and external diameter of these tubes is 2.4 and 3.2 mm respectively. A large-scale experiment was also performed, using a Buchi Sepacore C-690 Glass Column (I.D. = 15 mm). Apart from temperature and residence time, other variables were the length of the tubing inside the oven, the composition of the substrate solution and contents of the solid plug.

The 1 H NMR spectra were recorded at 400 MHz, on a Bruker AVANCE III spectrometer, equipped with 1 H/BB z-gradient probe (BBO, 5 mm). CDC was added as solvent for all analysis, and TMS was used as an internal chemical shift standard. All spectra were processed using TOPSPIN 3.6.2. In all cases, the measured spectral data were in accordance with literature.

In the experiments presented below, the reactor was filled with different plugs (or reactor beds) of solid material. In the comparative example, the reactor comprised a plug made up of a mixture of base (K2CO3) and metal source (CuCI). In the examples according to the present invention, the reactor contained either a (single) K2CO3 plug or a plug alternating between base (K2CO3) and metal source (CuCI), separated by a filler, SiO2 or sand.

Comparative example

A 0.01 M solution of IPr*HCI (1 ,3bis(diisopropylphenyl)imidazolium chloride) in technical grade acetone was injected into a microreactor, thermostated at 50 °C and filled CuCI and K2CO3 (1.5 g each, previously mixed), using 5 min as residence time. With this initial setup, no conversion to product was observed but instead the development of a deep purple colour in the reactor was evident. This is most likely due to the formation of copper (II) salts in the presence of K2CO3 under these specific conditions.

This was confirmed by carrying out the same reaction in a microreactor containing three reaction zones, a first reaction zone containing K2CO3, a second reaction zone containing CuCI and a third reaction zone containing the CUCI/K2CO3 mixture, with each reaction zone separated by a silica plug. Again, a strong colour change was observed in the K2CO3/CUCI layer. These observations show that the separation of the copper source from the weak base in the microreactor is required for converting the substrate into a NHC-metal complex via a continuous flow process. This is surprising as in the batch-type “weak-base” protocols, the azolium salt, the metal source and the weak base are present in a single reaction composition.

Example 1 : reactor comprising at least two reaction zones for preparing Cu-NHC complex

A/ In a first series of experiments, a 0.01 M solution of IPr*HCI (1 ,3bis(diisopropylphenyl)imidazolium chloride) in technical grade acetone was injected into a microreactor comprising a plug of K2CO3 (first reaction zone) and one of CuCI (second reaction zone), separated by silica. The reactor temperature was varied between 50 and 75°C, and the residence time between 5 and 25 min. The results are represented in table 1.

Table 1. Preparation of [Cu(IPr)CI]

Entry 1 , with similar reaction conditions as in the comparative example led to a 40% conversion to the desired product.

By increasing the residence time and/or temperature, the conversion of the imidazolium salt increased as well. However, this increased conversion went hand in hand with the formation of unwanted by-products, as confirmed by 1 H-NMR spectra. B/ An approach that allowed to significantly increase the efficiency of the reaction, involves an increase in the number of plugs (or packed beds) of K2CO3 and CuCI, separated by plugs of silica.

In a second series of experiments, four base/CuCI repeat units were created by alternating the base and CuCI segments, interspersed with plugs of silica or sand, resulting in conversions of 85 and 93%, respectively. The slight increase in conversion when using sand may be due to the slight acidity of the silica which counteracts the action of the base.

C/ In order to reduce the amount of solvent used, the concentration of the solution containing the imidazolium salt was increased. Using a 0.03 M solution and the setup containing the sand plugs, complete conversion of the starting imidazolium salt into [Cu(l Pr)CI] in a 82% isolated yield was obtained.

These series of experiments demonstrate the advantages of the continuous flow reaction for obtaining NHC-metal complexes according to the present invention, such as the use of an eco-friendly solvent (e.g. acetone) and performing the reaction under very mild operating conditions compared to the continuous flow process developed by McQuade and coworkers (discussed above).

Example 2: reactor comprising one reaction zone (base) for the preparation of Cu- NHC complex

A/ in a first series of experiments, a cuprate solution (0.03 M solution of [IPrH CuCh] in acetone) was prepared by mixing, such as by sonification, the corresponding imidazolium salt (IPr-HCI) and CuCI for 5 min at RT in green acetone (255 mg of IPr.HCI in 20 mL acetone + 59 mg CuCI (1.0 equiv)). Alternative, the cuprate may be obtained by a dry milling process according to WQ2020/048925, and can be dissolved directly in acetone (e.g. 3.14 mg in 20 mL acetone).

The cuprate solution was then continuously injected into a reactor comprising a solid base plug (1.5 g K2CO3 in a 55 cm long tubing), at a temperature of 50°C and with a residence time of 5 min. A clear product solution was recovered after the column, and upon evaporation of the solvent under vacuum, a final product powder was obtained.

Surprisingly, at these reaction conditions, the cuprate was completely converted into the corresponding NHC-copper complex, with a final yield of 90%.

Advantageously, by using a metallate solution in the continuous flow setup according to an embodiment of the present invention, a reagent is provided to the reactor which already contains the metal and azolium components in the correct ratio. It also allows to use a simple reactor design, only containing a reactor bed filled with the solid base.

B/ Next, the effect of varying reaction conditions on the cuprate conversion and NHC-copper complex yield was investigating by varying the reactor temperature between 50 and 75 °C, and by varying the residence time between 5 and 25 min. The results are represented in table 2.

Table 2. Preparation of [Cu(IPr)CI]

This data indicates that a shorter residence time and a lower temperature may lead to a better yield. In the conditions of the test, the optimal conditions guarantying a complete conversion of the substrate are 40 °C and 2 min as residence time.

C/ The continuous flow process based on a solid base reactor was further performed on a larger scale. The multigram synthesis of [Cu(IPr)CI] was performed using a Buchi Sepacore C-690 Glass Column (with I.D. 15 mm). The column was filled with 12 g of K2CO3, thus scaling up the test setup approximately ten-fold, whilst maintaining its operational simplicity. A 0.03 M cuprate solution was provided to the reactor and 2.6 g of product was made with an isolated yield of 89%.

Example 3: reactor comprising one reaction zone (base) for the preparation of Au- NHC complex

In order to obtain an [Au(IPr)CI] complex, a 0.01 M solution of [Au(DMS)CI] (with DMS = dimethylsulfide) and IPr*HCI was mixed (85 mg IPr*HCI and 59 mg [Au(DMS)CI] in 20 mL acetone) at room temperature for 5 min (thereby forming in situ the aurate species). The resulting solution was injected into the microreactor containing pure potassium carbonate (1 .5 g in 55 cm tubing) (T = 50 °C, t = 5 min). Unlike with the copper complex, a significant colour change of the column and a slightly lower conversion (84%) were noted. The same result was obtained by injecting into the reactor a solution of the aurate intermediate [IPrH AuCh] (prepared according to a protocol reported in the literature). This result is most likely due to the greater propensity of gold to form nanoparticles, which can also be seen in batch processes. This significantly alters the performance of the column.

Complete substrate conversion could be obtained, without altering the operating conditions of the system, by doubling the reactor size (110 cm column length vs 55 cm in the previous experiments), resulting in the complete conversion of the aurate species, with an AU-NHC yield of 94%. However, significant damage to the first half of the column containing the potassium carbonate was observed.

In an alternative setup, the decomposition processes inside the reactor were reduced while maintaining high substrate conversion by using a lower operating temperature and residence time for the process.

Table 3. Preparation of [Au(IPr)CI]

As can be seen in Table 3, using lower temperatures and/or residence time, it was possible to obtain high conversions and yields in the original reactor setup (55 cm column), without damaging the reactor column. Under the conditions of the experiment, the optimum conditions were to operate the column at 40 °C using 2 min as residence time.

Example 4: reactor comprising one reaction zone (base) for the preparation of a Pd- NHC complex

[Pd(IPr)CI(r|3-cinnamyl)] was prepared by passing a 0.03 M solution of [Pd(CI)(r|3- cinnamyl)]2 and IPr*HCI (in particular 255 mg IPr*HCI and 155 mg [Pd(cin)CI]2 in 20 mL acetone), pre-mixed for 5 min (allowing the formation of the palladate species in situ) through the reactor comprising pure K2CO3 (T = 50°C, t = 5 min). Similar as for the copper complex (example 2 above), complete conversion of the palladate was observed. An identical result is obtained if an acetone solution containing preformed palladate species (prepared separately following a published protocol) is injected in the microreactor. A slightly yellow product solution was obtained, which after evaporation of the solvent under vacuum, yielded the final product as a yellow oil.

An important observation here is the lack of significant signs of alteration of the reactor even after several passages of the substrate.

Similar as for the gold and copper derivatives, the yield and conversion were evaluated by varying the temperature and the residence time (see Table 4).

Table 4. Preparation of [Pd(l Pr)CI(cin)]

Similar as for the copper complex, shorter residence time and lower reactor temperature seem to promote the product yield. Under the test conditions, the optimal conditions to obtain the [Pd(IPr)CI(r|3-cinnamyl)] complex in good yields and purity are 40 °C and 2 min of residence time.

From examples 1-4, it can be concluded that a general continuous flow based method for the preparation of gold, copper and palladium-NHC complexes has been developed. For all complexes considered herein, a particularly advantageous setup consists of a microreactor filled with potassium carbonate, which is a weak and inexpensive base, into which is injected a technical grade acetone solution of an imidazolium salt (e.g. IPr HCI) and a metal precursor (e.g. CuCI, Au(DMS)CI or [Pd(CI)(r|3-cinnamyl)]2), particularly wherein these components are pre-mixed for a few minutes in order to obtain the corresponding metallate (e.g. cuprate, aurate or palladate) species.

In all cases, it was possible to completely convert the starting species into the corresponding NHC-complexes using very mild conditions (40 °C, 2 min) and without the need for further purification after solvent removal under vacuum. This solvent can be easily recycled. Noteworthy, the same reactions carried out in batch require more drastic conditions (60 °C for 1-24 h) and an additional purification step.

Experiments with the preparation of multigram quantities of the [Cu(IPr)CI] complex demonstrated that the present experimental setup is easily upscalable.

Example 5: Continuous Flow Synthesis of NHC metal amido and thiolato complexes

As shown in Examples 1-4 above, a major advantage to the use of continuous flow synthesis is the potential to access desired compounds at significantly higher reaction rates compared to batch synthesis. Another important advantage, mainly in terms of time management, is provided by performing one-pot or telescoping reactions. By simple adaptation of the flow setup, multiple reagent streams can be coupled in series. Therefore, multi-step procedures can be established by sequentially interconnecting reactor columns and by introducing new reagents at set intervals in the continuous flow sequence.

5.1/ In this context, the inventors have found that metal-carbene amido and thiolato complexes, such as M(NHC)(Cbz)] (Cbz = carbazolyl) and [M(NHC)(SPh)] (NHC = /V- heterocyclic carbene) complexes can be obtained via continuous flow synthesis, wherein the metal-carbene complex, in particular the M-NHC complex, is mixed with a suitable reactant, such as a carbazole or thiol solution, and passed over a catalyst bed comprising a weak base, such as K2CO3.

More in particular, initially, the continuous flow synthesis of [Cu(IPr)(Cbz)] in acetone was investigated. By providing Cu(IPr)CI and a carbazole solution (at least 1.1 equivalents) in acetone or ethanol to a coil PTFE reactor column filled with K2CO3, full conversion to the desired metal-carbene amido complex product was achieved with a residence time of 5 minutes and a temperature of 50 °C ([Cu(IPr)CI] 48.8 mg (0.10 mmol), carbazole (1.2 equiv.), 5 mL of solvent). Very short reaction times between 1 and 5 minutes, and low reaction temperatures between 30° and 50°C proved sufficient to reach full conversion to the desired product. Using a similar procedure, and with Au(IPr)CI in ethanol, a high yield of [Au(IPr)(Cbz)] was obtained with short residence times (2-5 min) and at mild temperature conditions (50°C-70°C). Similar results were also obtained when using a beta-carboline (harmine) instead of carbazole.

In a similar way, by adding a thiophenol or 1-thio-p-D-glucose tetraacetate instead of carbazole to the Cu(IPr)CI or Au(IPr)CI solution and passing it over the K2CO3 reactor bed, metal-carbene thiolato complexes were obtained in high yield, with short residence times (1-5 min) and at mild temperatures (50°C-70°C), 5.2/ As the reaction conditions in section 5.1 are very similar to those of examples 1-4, the combined continuous flow synthesis of NHC metal amido complexes, starting from an azolium salt, a metal salt and a carbazole solution was investigated. Initially, the continuous flow synthesis of [Cu(IPr)(Cbz)] (3) starting from IPr.HCI (1), CuCI and carbazole was performed, via the scheme set out in Figure 4 (with Cbz = carbazoyl).

A first reactor comprising a packed bed of K2CO3 was used for the synthesis of [Cu(l Pr)CI] (2), essentially as in example 2 above, using acetone as solvent, with a reaction temperature of 50°C or 60°C and a residence time of 2 min. The product flow of the first reactor, comprising [Cu(IPr)CI] dissolved in acetone, was in turn immediately fed into a second reactor comprising a packed bed of K2CO3 with concomitant introduction of a carbazole solution (with acetone or ethanol as solvent). Applying similar reaction conditions as in the first reactor, i.e. reaction temperature of 50 °C and a residence time of 2 minutes, allowed to obtain [Cu(IPr)(Cbz)] in high yield and in unprecedentedly short reaction times, without the need for wasteful intermediate purification steps.

Using a similar setup, the synthesis of [Au(IPr)(Cbz)] (7a) from imidazolium salt IPr HCI (1) and [Au(DMS)CI] (DMS = dimethyl sulfide) resulted in the desired AU-NHC amido complex, yet required a plug of silica to be added to the reactor column prior to the injection of the carbazole solution. The necessity for different solvents at the separate stages of the reaction presents no issues since the second reaction step is fully operational with one-to-one ethanol/acetone solvent mixtures.

Using a similar setup and reaction conditions, the continuous flow synthesis of [Au(IPr)(Hrm)] (Hrm = harmine) was performed. This metal-NHC amido complex was obtained by providing the product flow of the first reactor, comprising [AU(I Pr)CI] dissolved in acetone, immediately to the second reactor comprising a packed bed of K2CO3 with concomitant introduction of a harmine solution.

5.3/ Using a similar setup as in section 5.2, the combined continuous flow synthesis of NHC metal thiolato complexes, starting from an azolium salt, a metal salt and a thiol solution was investigated.

Initially, the continuous flow synthesis of [Cu(IPr)(SPh)] starting from IPr HCI, CuCI and thiophenol was performed.

A first reactor comprising a packed bed of K2CO3 was used for the synthesis of [Cu(l Pr)CI], essentially as in example 2 above, using acetone as solvent, with a reaction temperature of 50°C or60°C and a residence time of 2 min. The product flow of the first reactor, comprising [Cu(IPr)CI] dissolved in acetone, was in turn immediately fed into a second reactor comprising a packed bed of K2CO3 with concomitant introduction of a thiophenol solution (with acetone as solvent). Applying similar reaction conditions as in the first reactor, i.e. reaction temperature ranging between 30°C to 60°C and a residence time of 1 to 2 minutes, allowed to obtain [Cu(IPr)(SPh)] in high yield and in unprecedentedly short reaction times, without the need for wasteful intermediate purification steps. In addition, adding stoichiometric amounts of thiophenol to the product flow of the first reactor results in full conversion thus eliminating the need for additional workup to remove any additional/unreacted thiophenol.

Using a similar setup, the synthesis of the gold(l)thiolato complex [Au(IPr)(SPh)] from imidazolium salt IPr- HCI (1) and [Au(DMS)CI] (DMS = dimethyl sulfide) resulted in the desired AU-NHC thiolate. The product flow of the first reactor, comprising [Au(IPr)CI] dissolved in acetone, was mixed with equimolar amounts of a thiophenol solution and fed into a second reactor comprising a packed bed of K2CO3. Reaction conditions in the second bed included a reaction temperature ranging between 30°C to 60°C and a residence time of 1 to 2 minutes. Using a similar setup and reaction conditions, the biologically promising [Au(IPr)(1-thio-p-D-glucose tetraacetate)] complex, an auranofin-analogue and member of the Au(l)-thiolate glycoconjugate complex family, could be obtained, by providing the product flow of the first reactor, comprising [AU(IPr)CI] dissolved in acetone, immediately to the second reactor comprising a packed bed of K2CO3 with concomitant introduction of a 1- thio-p-D-glucose tetraacetate solution.