PROCESS

The present invention relates to a photocatalyst system and its use in a photochemical process for the preparation of a compound comprising one or more moieties of formula (I) as defined herein. In particular, the invention relates to a nickel containing photocatalyst system and its use in a

photochemical process for the functionalization of C-H bonds, which takes place without the use of a transition-metal based photosensitizer, using a diarylketone compound to trigger the reaction under light irradiation; preferably under visible light irradiation.

BACKGROUND ART The activation of relatively inert C-H bonds in chemical compounds is of wide interest as it allows preparing new compounds following a short and efficient procedure, which usually exhibits both atom and step economy. In that sense, organic chemists are constantly seeking new methodologies allowing for the preparation of highly functionalized compounds in a quick manner, in mild conditions of reaction and exhibiting a high tolerance to the presence of functional groups, therefore saving a large amount of time and effort in the preparation of complex molecules for several purposes (e.g. development of new crop protection agents, food ingredients, synthesis of natural products and analogues, bioactive ingredients, etc). Among the several approaches explored, nickel(ll) catalysis is currently gaining interest from scientists for its potential in the activation of C-H bonds for applications in cross-coupling procedures. Nickel is a non-toxic, cheap and abundant metal and is therefore attractive for the development of sustainable processes. For instance, in Nat. Commun. 2015, 6, 8404, You and co-workers have reported in 2015 a thermal process for the functionalization with benzylic radicals of a-aminoacids bearing a specific amine protecting group used as a directing group in the reaction. The reported procedure uses nickel(ll) acetylacetonate (Ni(acac)2) as catalyst as well as di-tert-butyl peroxide in stoichiometric amounts as radical initiator, in charge of oxidizing the Ni(ll) catalyst to a reactive nickel(lll) species and generating the reactive benzylic radical which couples with the amino-acid. Although useful in the preparation of aminoacids exhibiting quaternary carbon atoms, this procedure suffers from certain limitations with respect to substrate scope and requires the presence of a specific protecting group in the chosen substrate, as well as

stoichiometric amounts (actually four equivalents) of a radical initiator or oxidant.

On the other hand, photocatalysis has recently emerged as a promising source of methods for C-H bond activation reactions for the creation of C-C bonds. Most common photocatalytic procedures for C-H bond activation go through the formation of a carbon radical that can undergo cross-coupling with a reactive species, such as an organometallic compound. Such procedures typically require the use of a transition-metal based photosensitizer to allow the formation of the triplet excited state of said organometallic compound which reacts with the carbon radical. Typically, said photosensitizers are based on ruthenium(ll) or iridium(lll) coordination complexes. Upon light irradiation, such species get into a triplet excited state which is at a suitable energy level to allow for excitation of a reaction substrate or a catalyst through energy transfer in such a way that the coupling of a reagent onto the activated C-H bond can take place.

In this regard, Doyle and co-workers have described in J. Am. Chem. Soc. 2016, 138, 12719-12722 a photocatalytic process carried out under blue light irradiation and that allows for the arylation at the alpha position of alkyl ether substrates by cross-coupling between an aryl chloride compound and an alkyl ether substrate (used as a solvent or in large excess). The reported process is carried out under blue light irradiation and in the presence of a base, a nickel(0) catalyst formed in situ from a nickel(0) precursor and a 2,2’-bipyridine derivative as N,N bidentate ligand and a photocatalyst consisting of an iridium(lll) complex in charge of activating the release of a chlorine radical from the intermediate organometallic adduct and responsible for the C-H bond activation process. In a comparative experiment, the process appears to be poorly efficient in the reported conditions when aryl chloride substrates are replaced by aryl bromide substrates (yield is almost divided by 6). This procedure therefore requires the use of expensive and rare photosensitizers containing precious transition metals for the successful C-H bond activation process to take place, leading to the need for recycling such catalyst. It also suffers from a limited substrate scope, showing high efficiency for aryl chloride substrates only.

In a similar, yet different approach, Molander and co-workers have reported in J. Am. Chem. Soc. 2016, 138, 12715-12718 a photocatalytic process taking place under visible light irradiation for the arylation at the alpha position of alkyl ether substrates by cross-coupling between an aryl bromide compound and an alkyl ether substrate (used as a solvent or in large excess). The reported process is typically carried out under visible light irradiation and in the presence of a base, a nickel(O) catalyst formed in situ from a nickel(ll) precursor and a 2,2’-bipyridine derivative as N,N bidentate ligand, a

photosensitizer consisting of an iridium(lll) complex and a diarylketone compound used as a co-catalyst. The reaction goes through the release of a bromine radical that reacts with the ether to produce a radical that couples with the aryl radical through oxidative addition and reductive elimination at the nickel catalyst, thus forming the cross-coupling product. According to the authors, the diarylketone compound does not participate in the catalytic cycle of the reaction and is not essential for it to take place. In the reported conditions cyclohexane and other alkanes were found non-reactive. This procedure however therefore requires the use of expensive and rare photosensitizer containing precious transition metals for the successful C-H bond activation process to take place, leading to the need for recycling such catalyst. It also suffers from a poor substrate scope as alkanes, alkenes and the like were reported not to provide satisfactory results. Control experiments also suggest that the Ir(lll) based photosensitizer is essential for the C-H activation process to occur when visible light is used in the process (no reaction observed in such a case).

MacMillan and co-workers also reported in Science 2016, 352, 1304-1308 a photocatalytic procedure for the cross-coupling reaction at the carbon atom adjacent to a nitrogen atom in protected amines using alkyl or aryl bromides as electrophiles. Such cross-coupling reaction is triggered by an iridium(lll) based photosensitizer which activates a quinuclidine derivative that generates the reactive radical from the protected amine. The resulting radical reacts in turn with a nickel(0) catalyst formed in situ from a phenanthroline derivative and a nickel salt resulting in an intermediate organometallic species that undergoes oxidative addition with the electrophile followed by reductive elimination to yield the cross-coupling product. As in other cases, the iridium based photocatalyst is reported to be essential to trigger the cross-coupling process.

MacMillan and co-workers also reported in Science 2017, 355, 380-385, a photocatalyst composition consisting of a photosensitizer, being either

(lr(ppy)3) or benzophenone, and a nickel (0) complex (Ni(dtbbpy) cod) in a molar ratio of photosensitizer to nickel (0) complex of 1 :5. Such photocatalyst composition is used in the cross-coupling reaction of aromatic carboxylic acids and aryl bromides, which leads to the formation of aromatic esters through the coordination of the carboxylate (deprotonated carboxylic acid) to the nickel metal complex. In the reported transformation, both the aryl bromide and the carboxylate substrate coordinate to the nickel catalyst, and the

photosensitizer, when excited by light, promotes an energy transfer to the resulting nickel complex that triggers the reductive elimination leading to the formation of the aryl ester. The authors are however silent about the use of the catalytic composition in the activation of C-H bonds, such as those included in alkanes or ethers, which are known to be less labile than the O-H bond of carboxylic acids. Authors also report that the catalyst composition is more efficient when the photosensitizer is lr(ppy)3, allowing a yield of 85% after 18 hours of reaction. When the photosensitizer is benzophenone, the O- H activation reaction proceeds in 25% yield after 18 hours of reaction, while, in absence of a photosensitizer, a yield of 45% is reached after 120 hours of reaction, thus indicating a moderate photosensitizing activity for

benzophenone.

Finally, on a slightly different aspect and as reported in J. Am. Chem. Soc. 2013, 135, 17494-17500, Chen and co-workers used certain diarylketone compounds as photocatalysts in the fluorination of substrates containing benzylic C-H bonds. The reported diarylketones are there suggested as potential Hydrogen Atom Transfer agents for benzylic substrates under visible light irradiation.

From what is known in the state of the art, it derives that there is still the need for providing alternative photocatalyst system and process for the nickel mediated photocatalytic cross-coupling of C-H bond containing substrates that exhibits a broad scope of substrates, is carried out under light irradiation and can be carried out in the absence of a metallic photosensitizer. SUMMARY OF THE INVENTION

The inventors have developed a photocatalyst system and a process for the cross-coupling of a reaction substrate comprising a C-H bond with a bromide electrophile, said photocatalyst system comprising in the absence of a metal- based photosensitizer, a diaryl ketone compound, a nickel(ll) salt and, optionally a ligand. The process of the invention advantageously tolerates the presence of a broad range of functional groups onto the reaction substrate and can be carried out under irradiation of visible light. Remarkably, and unlike the processes described in the state of the art, the presence of iridium or ruthenium based photosensitizers in the photocatalyst system is not an essential feature of the catalyst system for the cross-coupling reaction to proceed. It is advantageous as such compounds are expensive and rare, and need to be separated from the reaction mixture and further recycled to be re- used. Such separation and recycling steps are no longer necessary thanks to the process of the invention, which also exhibits a broader substrate scope than the methods of the state of the art. Without wishing to be bound by theory, it is believed that, upon light irradiation, the diaryl ketone compound of formula (III) used in the process of the invention gets into a triplet excited state that undergoes a hydrogen atom transfer with the C-H bond containing substrate, thus generating a reactive radical. This reactive radical coordinates to the product of the oxidative addition of the bromide electrophile to the nickel(O) catalyst to provide an intermediate species that suffers a reductive elimination, therefore providing the cross-coupling product and regenerating the nickel(O) catalyst after an electron transfer process. The diaryl ketone compound of formula (III) described below is thus used to generate a radical species from a C-H bond comprised in a reaction substrate through hydrogen atom transfer and does not trigger the reductive elimination step in the catalytic cycle, as described in some processes of the state of the art.

Thus, in a first aspect, the invention relates to a photocatalyst system comprising, in the absence of a further photosensitizer other than the compound of formula (III) or a mixture thereof:

(i) a nickel(ll) salt, (ii) a compound of formula (III) or a mixture thereof,

wherein each of An and n independently represents a ring system

comprising from one to two six-membered aromatic hydrocarbon rings, the rings being isolated or fused and being further optionally substituted at any available position with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, halo and (Ci- C6)alkylcarbonyl;

(iii) optionally, a ligand selected from the group consisting of the compounds of formulae (IVa) and (IVb)

wherein Z is a diradical selected from the group consisting of the diradicals of formulae

wherein R _e and Rf are each independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)haloalkyl, nitrile, and benzyl;

Y is selected from the group consisting of N and the moieties of formula C- P(Ar3)2 wherein Ar3 is a phenyl group optionally substituted at any available position with a radical selected from the group consisting of halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl;

each of the pairs R _a and Rb, and R _c and Rd, together with the atoms to which they are attached independently form a known ring system comprising from 1 to 3 rings, the rings comprising from 5 to 6 members selected from the group consisting of C, CH, Chte, O, and N, the rings being aromatic or unsaturated, isolated or fused, and being further optionally substituted at any available position with a radical selected from the group consisting of phenyl, benzyl, (Ci-C6)alkyl, and (Ci-C6)haloalkyl; and wherein, Rb and Rd, together with the atoms to which they are attached further optionally form a phenyl ring optionally substituted at any available position with a radical selected from the group consisting of halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl. As found by the inventors, the photocatalyst system of the invention is useful as a catalyst system in photocatalytic cross-coupling reactions carried out under light irradiation.

Thus, a second aspect of the invention relates to the use of the photocatalyst system according to the first aspect of the invention in combination with an external light source; preferably with an external visible light source, in photocatalytic cross-coupling reactions.

The photocatalyst system of the invention can therefore be used in a process for the photocatalytic cross-coupling of substrates, carried out under light irradiation; preferably under visible light irradiation.

A third aspect of the invention therefore relates to a process for the preparation of a compound comprising one or more moieties of formula (I)

comprising the step of contacting under light irradiation, preferably under visible light irradiation, a compound comprising one or more moieties of formula (II)

with a compound of formula Ri-Br in the presence of a base and of a catalytically effective amount of the photocatalyst system defined in the first aspect of the invention

wherein Ri is a radical of formula wherein each of Gi and G3 is a radical independently selected from the group consisting of (Ci-C2o)alkyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; (C2-C2o)alkenyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy;

(C2-C2o)alkynyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; and

a known ring system comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, CH2, CO, N, NO, NH, O, SO, and S where chemically possible, said ring system being further optionally

substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci- C2o)alkyl optionally substistuted with one or more group selected from nitro, cyano, and hydroxy, (Ci-C2o)haloalkyl, (C2-C2o)alkenyl,

pinacolboryl, formyl, tris[(Ci-C6)alkyl]stannyl and (C2-C2o)alkynyl; and being G3 further selected from hydrogen, cyano, hydroxy, nitro, and halo, and being G3 further optionally substituted at any available position with one or more radicals selected from (Ci-C6)alkyloxy, (C1- C6)alkylcarbonyl, (Ci-C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, (C1- C6)alkyloxysulfonyl, (Ci-C6)alkylsulfonyloxy, (Ci-C6)alkylaminocarbonyl, (Ci-C6)alkylcarbonylamino, and a ring system comprising from one to two six-membered aromatic hydrocarbon rings, the rings being isolated or fused and being further optionally substituted at any available position with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl , nitro, halo, and (C1- C6)alkylcarbonyl;

G2 is a diradical selected from the group consisting of -Chte-, -O-, - NR2-, -S-, -COO-, -CO-, -OCO-, -NR2CO-, -CONR2-, -SO2-, -SO2NR2- and -SO3-; being R2 a hydrogen or a (Ci-C6)alkyl; and

m is an integer comprised from 0 to the number of carbon atoms comprised in G1, the groups of formula G2-G3 being attached to any available position in G1 ; and wherein the process converts at least one moiety of formula (II) comprised in the compound comprising one or more moieties of formula (II) in at least one moiety of formula (I) in the compound comprising one or more moieties of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

For the purposes of the invention, any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, and the like, should be considered approximate, unless specifically stated.

Unless specified otherwise, all amount indications are provided on a molar basis, with absolute indications being provided in the unit of moles and relative indications being provided as mol%. The term“mol%” is to be understood as the number of moles of a particular component with respect to the total number of moles of the compound of formula Ri-Br engaged in the process of the invention.

Unless specified otherwise, all indications of point values are intended to allow variation of ±10%, preferably of ±5% and most preferably ±0% of the specified value around the point value.

Unless specified otherwise, the term“comprising” is intended to permit the additional presence of unspecified further components or measures. It is however a preferred embodiment that no further components or measures are present, i.e. the term“comprising” encompasses also the meaning“consisting of” as a preferred embodiment.

Unless specified otherwise, the term“nickel(ll) salt” refers to a single inorganic or organic salt or to a mixture of inorganic or organic salts of nickel(ll). In one embodiment of the third aspect of the invention, the nickel(ll) salt is a salt with a halide anion or an oxoanion. In one embodiment of the third aspect of the invention, the nickel(ll) salt is selected from the group consisting of nickel(ll) halide, nickel(ll) sulphate, nickel(ll) perchlorate, nickel(ll) trifluoromethanesulfonate, nickel (II) hexafluoroacetylacetonate, nickel(ll) sulfamate, nickel(ll) carbonate, nickel(ll) acetylacetonate, nickel(ll) oxalate, a compound of formula Ni(OOCR)2 wherein R is (Ci-Ci2)alkyl, and solvates thereof.

In the context of the invention, the term“alkyl” refers to a linear or branched saturated hydrocarbon chain having the number of carbon atoms indicated in the description or claims. Examples of (Ci-C6)alkyl include, but are not limited to, methyl, ethyl, propyl, /so-propyl, tert- butyl, butyl, pentyl and hexyl.

In the context of the invention, the term“alkenyl” refers to an alkyl group as defined above comprising at least one carbon-carbon double bond. The term (C2-C2o)alkenyl therefore refers to linear or branched hydrocarbon chain, containing from 2 to 20 carbon atoms and comprising at least one carbon- carbon double bond. Similarly, the term“alkynyl” refers to an alkyl group as defined above comprising at least one carbon-carbon triple bond. The term (C2-C2o)alkynyl therefore refers to linear or branched hydrocarbon chain, containing from 2 to 20 carbon atoms and comprising at least one carbon- carbon triple bond.

In the context of the invention, the term“tris[(Ci-C6)alkyl]silanoxy” refers to a radical of formula -OS1G4G5G6 wherein each of G4, Gs and G6 are

independently selected from the (Ci-C6)alkyl groups as defined above.

In the context of the invention, the term“tris[(Ci-C6)alkyl]stannyl” refers to a radical of formula -SnG4GsG6 wherein each of G4, Gs and G6 are

independently selected from the (Ci-C6)alkyl groups as defined above.

In the context of the invention, the term“alkyloxy” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through an oxygen (O) atom.

In the context of the invention, the term“alkylcarbonyl” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through a carbonyl (C=0) group.

In the context of the invention, the term“halo” refers to a halogen group. Examples include fluoro, bromo, chloro, and iodo.

In the context of the invention, the term“haloalkyl” refers to an alkyl chain as defined above wherein at least one atom of hydrogen is substituted by a halogen group. In preferred embodiments, haloalkyl refers to an alkyl chain as defined above wherein at least one atom of hydrogen is substituted by fluorine, chlorine or iodine. In the context of the invention, the term“alkyloxycarbonyl” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through an oxycarbonyl (OCO-) group. For instance, a methyloxycarbonyl group is a group of formula CFbOCO-.

In the context of the invention, the term“alkylcarbonyloxy” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through a carbonyloxy (-COO) group. For instance, a methylcarbonyloxy group is a group of formula CFbCOO-.

In the context of the invention, the term“alkyloxysulfonyl” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through an oxysulfonyl (-OSO2) group. For instance, a methyloxysulfonyl group is a group of formula CFI3OSO2-.

In the context of the invention, the term“alkylsulfonyloxy” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through a sulfonyloxy (-SO3) group. For instance, a methylsulfonyloxy group is a group of formula CFI3SO3-.

In the context of the invention, the term“alkylaminocarbonyl” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through an aminocarbonyl (NFICO-) group. For instance, a

methylaminocarbonyl group is a group of formula CFI3NFICO-.

In the context of the invention, the term“alkylcarbonylamino” refers to an alkyl chain as defined above that is appended to the remainder of the molecule through a carbonylamino (CONFI-) group. For instance, a

methylcarbonylamino group is a group of formula CFI3CONFI-.

In the context of the invention, the term“light irradiation” refers to the fact that the reaction medium is submitted to some irradiation with light beams in a wavelength comprised from 300 to 800 nm; preferably from 350 to 800 nm. Suitable means allowing to carry out such light irradiation are known in the art and include LEDs, light bulbs, reactor inserts and photochemical reactors.

In the context of the invention, the term“visible light irradiation” refers to the fact that the reaction medium is submitted to some irradiation with light beams in a wavelength comprised from 400 to 800 nm.

In the context of the invention, the term“base” refers to a substance able to abstract a hydrogen atom from another substance.

In the context of the invention, the term“catalytically effective amount” refers to the fact that the amount of catalyst is much smaller than the stoichiometric amounts of either starting materials and is sufficient for the catalyzed process to take place at a reaction rate that is at least twice the rate of the non- catalyzed process. The amount is expressed as percentage calculated as the ratio of the number of moles of each catalyst component, namely, the nickel(ll) salt, the compound of formula (III) and, optionally, the ligand, in relation to the number of moles of the compound of formula Ri-Br.

In the context of the invention, the term“saturated carbon atom” refers to a carbon atom that is bonded to four adjacent atoms through single bonds.

In the context of the invention, when talking about a ring system comprising more than one ring, the term“isolated ring” refers to the fact that said ring is attached to the other ring(s) of the ring system by a single bond.

In the context of the invention, when talking about a ring system comprising more than one ring, the term“bridged ring” refers to a ring that shares two atoms with another ring, said shared atoms not being adjacent.

In the context of the invention, when talking about a ring system comprising more than one ring, the term“fused ring” refers to a ring that shares two atoms with another ring, said shared atoms being adjacent.

In the context of the invention, the term“ligand” refers to a compound having the ability to form coordination complexes with nickel. Typically, in the context of the invention, a ligand coordinates to a nickel metal atom through nitrogen or phosphorus atoms. Useful ligands in the invention consequently comprise at least one nitrogen or phosphorus atom in their molecular structure.

Bidentate ligands are particularly useful in the context of the invention, particularly those bidentate ligands that coordinate to the nickel atom through two nitrogen atoms or through one nitrogen atom and one phosphorus atom.

As described above, the invention relates to a photocatalyst system which is particularly useful in a process for the production of a compound comprising one or more moieties of formula (I) from a compound comprising one or more moieties of formula (II). In comparison with the photocatalyst systems, processes and methods described in the state of the art, the photocatalyst system of the invention does not comprise a metal-based photosensitizer, such as an Ir(lll) or Ru(ll) complex, and allows for the cross-coupling reaction of a broader range of substrates, including not only aryl bromides and the like but also alkyl bromides and the like. The efficiency of the method of the invention is measured by the yield of the method of the invention, expressed as a percentage, and corresponding to the ratio of the number of moles of the formed cross-coupling product to the number of moles of the compound of formula Ri-Br engaged in the reaction.

According to the first aspect of the invention, the invention relates to a photocatalyst system as defined above.

In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described below, the nickel(ll) salt is a salt with an halide anion or an oxoanion. Typically, suitable nickel(ll) salts of the catalyst system of the invention are commercially available. In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described below, the nickel(ll) salt is selected from the group consisting of nickel(ll) halide, nickel(ll) sulphate, nickel(ll) perchlorate, nickel(ll)

trifluoromethanesulfonate, nickel(ll) hexafluoroacetylacetonate, nickel(ll) sulfamate, nickel(ll) carbonate, nickel(ll) acetylacetonate, nickel (II) oxalate, a compound of formula Ni(OOCR)2 wherein R is (Ci-Ci2)alkyl, and solvates thereof.

In another particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described below, the nickel(ll) salt of the photocatalyst system is selected from the group consisting of nickel(ll) halide, nickel(ll) nitrate, nickel(ll) acetate, and nickel(ll)

acetyacetonate (Ni(acac)2).

In a more particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described below, the nickel(ll) salt of the photocatalyst system is nickel(ll) acetylacetonate.

The photocatalyst system of the invention comprises a compound of formula (III) as defined above. Suitable compounds of formula (III) are those forming under light irradiation a triplet state having an energetic level sufficient to allow for the formation of a radical resulting from the abstraction of the hydrogen atom from the reacting moiety of formula (II) comprised in the compound comprising one or more moieties of formula (II). Typically known in the art are diarylketone compounds of formula (III) as defined above. Such compounds are commercially available and can be prepared following methods known in the art, such as those described in Synthesis 2017, 49(16), 3602-3608. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound of formula (III) of the photocatalyst system is that wherein An and n are independently selected from a phenyl ring optionally substituted with a radical selected from the group consisting of (Ci-C6)alkyloxy and (Ci-C6)haloalkyl.

In a particular embodiment, optionally in combination with one or more of the embodiments described above and below, the compound of formula (III) of the photocatalyst system is selected from the group consisting of the compounds of formulae (Ilia), (lllb), (lllc) and (Mid)

(lllc) (Hid)

These diaryl ketones are commercially available. In a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound of formula (III) of the photocatalyst system is the compound of formula (Ilia) as defined above. The ligand comprised in the photocatalyst system used in the process of the invention is selected from the compounds of formulae (IVa) and (IVb) as defined above.

In an alternative embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the ligand comprised in the photocatalyst system is a compound of formula (IVa) wherein Y is N, and each of the pairs R _a and Rb, and R _c and Rd, together with the atoms to which they are attached form a 6-membered aromatic ring optionally substituted at any available position with a radical selected from the group consisting of halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl; and wherein, Rb and Rd, together with the atoms to which they are attached further optionally form a phenyl ring. More particularly, optionally in

combination with one or more of the embodiments described above and below, the ligand comprised in the photocatalyst system is a compound of formula (IVa) wherein Y is N, and each of the pairs R _a and Rb, and R _c and Rd, together with the atoms to which they are attached form a 6-membered aromatic ring optionally substituted at any available position with a (Ci-C6)alkyl group. Even more particularly, optionally in combination with one or more of the embodiments described above and below, the ligand comprised in the photocatalyst system is selected from the group consisting of 5,5’-dimethyl- 2,2’-bipyridine and 4,4’-di-te/f-butyl-2,2’-bipyridine. Even more particularly, optionally in combination with one or more of the embodiments described above and below, the ligand comprised in the photocatalyst system is 5,5’- dimethyl-2,2’-bipyridine. Typically, suitable ligands comprised in the

photocatalyst system are commercially available.

In an alternative embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the ligand comprised in the photocatalyst system is an enantiomerically enriched ligand selected from the enantiomerically enriched compounds of formulae (IVa) and (IVb) wherein:

Y is N or a moiety of formula C-P(Ar3)2 wherein Ar3 is a phenyl group optionally substituted at any available position with a (Ci-C6)alkyl group;

Rc and Rd, together with the carbon atoms to which they are attached form a phenyl ring;

R _a and Rb, together with the atoms to which they are attached form an oxazoline ring optionally substituted at any available position with one or more radicals selected from the group consisting of phenyl, benzyl, (Ci-C6)alkyl, and (Ci-C6)haloalkyl;

R9 and R9’ are selected from the group consisting of phenyl, benzyl, (C1- C6)alkyl, and (Ci-C6)haloalkyl;

each of R10, R10’, R11 and R11’ are selected from the group consisting of hydrogen and (Ci-C6)alkyl. Thus, in a particular embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the photocalyst system comprises a ligand selected from the group consisting of 5,5'-dimethyl-2,2'-bipyridine, 4,4’-di-te/t-butyl-2,2'-bipyridine and an enantiomerically enriched ligand selected from the enantiomerically enriched compounds of formulae (IVa) and (IVb) wherein:

Y is N or a moiety of formula C-P(Ar3)2 wherein Ar3 is a phenyl group optionally substituted at any available position with a (Ci-C6)alkyl group;

R _c and Rd, together with the carbon atoms to which they are attached form a phenyl ring;

R _a and Rb, together with the atoms to which they are attached form an oxazoline ring substituted at any available position with one or more radicals selected from the group consisting of phenyl, benzyl, (Ci-C6)alkyl, and (Ci- C6)haloalkyl;

R9 and R9’ are selected from the group consisting of phenyl, benzyl, (C1- C6)alkyl, and (Ci-C6)haloalkyl;

each of R10, R10’, R11 and R11’ are selected from the group consisting of hydrogen and (Ci-C6)alkyl.

When the photocatalyst system comprises a ligand, higher yields are obtained in the process described in the third aspect of the invention, if compared with a process wherein the photocatalyst system does not comprise a ligand. In particular, when the ligand is enantiomerically pure, an enantiomerically enriched product is obtained.

In a preferred embodiment of the first aspect of the invention, the

photocatalyst system comprises a ligand as defined in any embodiment described above and below.

In a more preferred embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the photocatalyst system is consisting of a nickel(ll) salt as defined in any of the embodiments above, the compound of formula (III) as defined in any of the embodiments above and a ligand as defined in any of the embodiments above.

In a preferred embodiment of the first aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the photocatalyst system is consisting of a nickel(ll) salt as defined in any of the embodiments above, the compound of formula (III) as defined in any of the embodiments above and a ligand as defined in any of the embodiments above wherein the molar ratio of the nickel (II) salt, the compound of formula (III) and, optionally, the ligand is 1 :1 :1 ; or, alternatively, wherein the molar ratio of the nickel (II) salt, the compound of formula (III) and, optionally, the ligand is 1 :2:1. When the photocatalyst system of the invention is used in a process according to the third aspect of the invention as detailed below wherein, in the compound of formula Ri-Br, the bromine atom is attached to a carbon atom comprised in an aromatic ring system or to an unsaturated carbon atom, the molar ratio of the nickel (II) salt, the compound of formula (III) and, optionally, the ligand is preferably 1 :1 :1. When the photocatalyst system of the invention is used in a process according to the third aspect of the invention as detailed below wherein, in the compound of formula Ri-Br, the bromine atom is attached to a saturated carbon atom, the molar ratio of the nickel (II) salt, the compound of formula (III) and, optionally, the ligand is preferably 1 :2:1.

As defined in the second aspect of the invention, the photocatalyst system of the first aspect of the invention may be used in combination with an external light source, preferably with an external visible light source, in photocatalytic cross-coupling reactions. In a more particular embodiment of the second aspect of the invention, the photocatalyst system of the first aspect of the invention may be used in combination with an external light source, preferably with an external visible light source, in a photocatalytic cross-coupling reaction wherein the cross-coupling reaction takes place between a bromide electrophile and a substrate comprising a bond between a saturated carbon atom and a hydrogen atom, and wherein said C-H bond reacts with the bromide electrophile.

A bromide electrophile is typically a substance comprising a carbon-bromide single bond. A saturated carbon atom is a carbon atom connected to four atoms, equal or different, through four single covalent bonds.

According to the process of the third aspect of the invention, a compound comprising one or more moieties a formula (II) is converted into a compound comprising one or more moieties of formula (I) when it is contacted with a compound of formula Ri-Br under light irradiation, preferably under visible light irradiation, and in the presence of a base and of a catalytically effective amount of the photocatalyst system described above.

The process of the third aspect of the invention may be carried out with any compound comprising one or more moieties of formula (II). Such compounds are either commercially available or can be prepared following methods known in the art, so that a skilled in the art person can easily identify and choose suitable compounds comprising one or more moieties of formula (II). The process of the third aspect of the invention is particularly selective and efficient when the carbon atom comprised in the moiety of formula (II) that is converted in the moiety of formula (I) is attached to at least one heteroatom or to at least one unsaturated carbon atom in the compound comprising one or more moieties of formula (II). When the compound comprising one or more moieties of formula (II) is such that it comprises one moiety of formula (II) wherein the carbon atom comprised in said moiety of formula (II) is attached to at least one heteroatom or to at least one unsaturated carbon atom, the cross-coupling reaction will preferably occur at this carbon atom. Without wishing to be bound by theory, it is believed that this specific selectivity is related to the electron withdrawing character of the appended group, namely the heteroatom or the unsaturated carbon atom, which makes the C-H bond in the moiety of formula (II) more reactive and prompt to generate a radical intermediate species. Such compounds are either commercially available or can be prepared following methods known in the art, so that a skilled in the art person can easily identify and choose suitable compounds comprising one or more moieties of formula (II). It is advantageous as it allows predicting the outcome of the process of the third aspect of the invention, especially when the compound comprising one or more moieties of formula (II) comprises more than one moiety of formula (II). Said heteroatom may in particular be selected from the group consisting of O, S, N, and P. Said unsaturated carbon atom may in particular be comprised in a double bond selected from the group consisting of a carbon-carbon double bond, a carbon-oxygen double bond, a carbon-nitrogen double bond and a carbon-sulphur double bond.

When the compound comprising one or more moieties of formula (II) does not comprise any moiety of formula (II) wherein the carbon atom is attached to a heteroatom or to an unsaturated carbon atom, the process of the third aspect of the invention is also particularly selective when the compound comprising one or more moieties of formula (II) is such that the carbon atoms comprised in the moieties of formula (II) have the same connectivity, which is particularly the case of cyclic compounds. This is particularly the case when the carbon atoms comprised in the moieties of formula (II) is an alkane or a cycloalkane, where the carbon atoms can be considered equivalent electronically. When the compound comprising one or more moieties of formula (II) is a

cycloalkane, the moieties of formula (II) have the same connectivity, which leads to the formation of one sole cross-coupling product. In a compound, two atoms are said to have the same connectivity when they are both connected to identical atoms or groups of atoms.

Thus, in a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described below, in the compound comprising one or more moieties of formula (II), the carbon atom comprised in the moiety of formula (II) that is converted in the moiety of formula (I) is attached to a heteroatom or to an unsaturated carbon atom in the compound comprising one or more moieties of formula (II); or,

alternatively, the carbon atoms comprised in the moieties of formula (II) have the same connectivity. When the carbon atom comprised in the moiety of formula (II) that is converted in the moiety of formula (I) is attached to a heteroatom, the heteroatom is selected from the group consisting of N, O, S and P; preferably, such heteroatom is selected from N and O. When the carbon atom comprised in the moiety of formula (II) that is converted in the moiety of formula (I) is attached to an unsaturated carbon atom, said unsaturated carbon atom is preferably comprised in a double bond selected from the group consisting of a carbon-carbon double bond, a carbon-oxygen double bond, a carbon-nitrogen double bond and a carbon-sulphur double bond; more preferably, it is comprised in a carbon-carbon double bond.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, when the compound comprising one or more moieties of formula (II) does not comprise any moiety of formula (II) wherein the carbon atom is attached to a heteroatom or to an unsaturated carbon atom, the carbon atoms comprised in the moieties of formula (II) have the same connectivity. In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the moiety of formula (I) is a moiety of formula (G)

and the moiety of formula (II) is a moiety of formula (IG)

wherein: R ₃ is selected from hydrogen and (Ci-C6)alkyl; and the carbon atom comprised in the moiety of formula (IG) is attached to a heteroatom or to an unsaturated carbon atom in the compound comprising one or more moieties of formula (II); or, alternatively, the compound comprising the moiety of formula (IG) comprises one or more moieties of formula (II) having the same

connectivity. Preferably, the heteroatom is selected from the group consisting of O, N, S and P; more preferably, it is O or N. Also, the unsaturated carbon atom is preferably comprised in a double bond selected from the group consisting of carbon-carbon double bond, carbon-oxygen double bond, carbon-nitrogen double bond and a carbon-sulphur double bond; more preferably, it is comprised in a carbon-carbon double bond.

In particular embodiments of the process of the third aspect of the invention, optionally in combination with one or more of the embodiments described below, in the compound comprising one or more moieties of formula (II), the carbon atom comprised in the moiety of formula (II) that is converted in the moiety of formula (I) is a secondary carbon atom.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the moiety of formula (I) is a moiety of formula (I”)

and the moiety of formula (II) is a moiety of formula (II”)

wherein: n is an integer from 0 to 1 ; and

when n is 1 , R3 is a hydrogen or a (Ci-C6)alkyl; or, alternatively, when n is 0; R3 is a known ring system comprising from 1 to 3 aromatic rings, each ring comprising 5 or 6 members selected from the group consisting of C, CH, O, N and S and being further optionally substituted at any available position with one or more radicals selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl , nitro, halo and (Ci-C6)alkylcarbonyl;

X is selected from the group consisting of O, NR4 and CHR2, being R4 selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkylcarbonyl, benzyloxycarbonyl and (Ci-C6)alkyloxycarbonyl and being R2 a hydrogen or a (Ci-C6)alkyl. In a preferred embodiment of the third aspect of the invention, when n is 1 and X is CHR2, the moieties of formula (II) in the compound comprising one or more moieties of formula (II) have the same connectivity as the moiety of formula (II”).

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the moiety of formula (II) is selected from the moieties of formulae wherein OAG represents a carbon atom comprised in an aromatic ring system comprising from 1 to three carbocyclic aromatic rings, each ring being optionally substituted with one or more radicals selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, halo, and (Ci-C6)alkylcarbonyl.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the compound comprising one or more moieties of formula (II) is a compound of formula (V)

wherein n, X and R3 are as defined above;

each of R12 and R13 is independently selected from the group consisting of hydrogen, (Ci-C2o)alkyl, (C2-C2o)alkenyl, (C2-C2o)alkynyl and a radical of formula -R14-X-R15 wherein R14 and R15 are each independently selected from the group consisting of (Ci-C2o)alkyl, (C2-C2o)alkenyl and (C2-C2o)alkynyl; or; alternatively,

R12 and R13, together with the atoms to which they are attached form a known ring system comprising from 1 to 5 rings, wherein:

each ring comprises from 3 to 8 members selected from the group consisting of C, CH, CH2, CO, O, S, SO, and SO2 where chemically possible;

each ring is saturated, unsaturated or aromatic,

the rings are isolated, bridged or fused; the rings are further optionally substituted at any available position with one or more radicals selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci-C2o)alkyl optionally substistuted with one or more group selected from nitro, cyano, and hydroxy, (C2- C2o)alkenyl, pinacolboryl, formyl, tris[(Ci-C6)alkyl]stannyl and (C2- C2o)alkynyl; and

the ring comprising X as a member when n is 1 is not aromatic; and with the proviso that when n is 1 , R12 is not hydrogen.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the compound comprising one or more moieties of formula (II) is a liquid in standard conditions of temperature and pressure. Standard conditions of temperature and pressure refer to a temperature of 25 °C and a pressure of 1.013 hPa (1 atm). In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the compound comprising one or more moieties of formula (II) comprises from one to twenty atoms other than hydrogen.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the moiety of formula (II) is selected from the moieties of formula -O-CH2-, -O- CH(CH ₃ )-, -CH2-CH2-, -O-CH2-O-, -(CO)NH-CH ₂ -, and -(CO)N(CH ₃ )-CH ₂ -.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above or below, the invention relates to a process as defined above wherein the compound comprising one or more moieties of formula (II) is selected from the group consisting of tetrahydrofurane, 1 ,4-dioxane, 1 ,3-dioxolane, 2,5- dimethyltetrahydrofurane, oxetane, 3,3-dimethyloxetane, 1 ,3- dihydroisobenzofuran, diethyl ether, 1 ,2-dimethoxyethane, 1 -methoxy-2-(2- methoxyethoxy)ethane, methyl-te/t-butyl ether, tert- butyl pyrrolidine-1 - carboxylate, toluene, mesitylene, cyclohexane, cyclopentane, cycloheptane, N-methylpyrrolidinone and ambroxide. The preferred and particular embodiments of the process of the third aspect of the invention related to the moiety of formula (II) shall also apply for the moiety of formula (I), the process of the third aspect of the invention allowing for the conversion of a moiety of formula (II) in a moiety of formula (I).

As defined above, the process of the third aspect of the invention allows for the cross-coupling reaction of a compoud of formula Ri-Br with a compound comprising one or more moieties of formula (II) as defined in the preferred and particular embodiments above. Compounds of formula Ri-Br are know in the art and are either commercially available or can be prepared following methods known in the art for the bromination of saturated and unstaurated hydrocarbons. The process of the third aspect of the invention is highly tolerant to the presence of functional groups on the compound of formula Ri- Br, which is advantageous as it allows for a fast functionalization of molecules. As mentioned above, Ri is a radical of formula -Gi (-G2-G3)m wherein m is an integer comprised from 0 to the number of carbon atoms in Gi .

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, Gi is a radical independently selected from the group consisting of (Ci-C2o)alkyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci- C6)alkyl]silanoxy; (C2-C2o)alkenyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; (C2- C2o)alkynyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; and a known ring system comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, CH2, CO, N, NO, NH, O, SO and S where chemically possible, said ring system being further optionally substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci- C2o)alkyl optionally substistuted with one or more group selected from nitro, cyano and hydroxy, (Ci-C2o)haloalkyl, (C2-C2o)alkenyl, pinacolboryl, formyl, tris[(Ci-C6)alkyl]stannyl and (C2-C2o)alkynyl, and

G3 is a radical independently selected from the group consisting of hydrogen, cyano, hydroxy, nitro, halo, (Ci-C2o)alkyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; (C2- C2o)alkenyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci-C6)alkyl]silanoxy; (C2-C2o)alkynyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, nitro, formyl, halo, cyano, phenyl and tris[(Ci- C6)alkyl]silanoxy; and a known ring system comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, CH2, CO, N, NO, NH, O, SO and S where chemically possible, said ring system being further optionally substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci-C2o)alkyl optionally substistuted with one or more group selected from nitro, cyano and hydroxy, (Ci-C2o)haloalkyl, (C2-C2o)alkenyl, pinacolboryl, formyl, tris[(Ci-C6)alkyl]stannyl and (C2-C2o)alkynyl, and being G3 further optionally substituted at any available position with one or more radicals selected from (Ci-C6)alkyloxy, (Ci-C6)alkylcarbonyl, (Ci-C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, (C1- C6)alkyloxysulfonyl, (Ci-C6)alkylsulfonyloxy, (Ci-C6)alkylaminocarbonyl, (C1- C6)alkylcarbonylamino, and a ring system comprising from one to two six- membered aromatic hydrocarbon rings, the rings being isolated or fused and being further optionally substituted at any available position with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl , nitro, halo and (Ci-C6)alkylcarbonyl.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, G1 is a radical

independently selected from the group consisting of (Ci-C2o)alkyl optionally substituted at any available position with one or more radicals selected from the group consisting of hydroxy, halo, phenyl, cyano and tris[(Ci- C6)alkyl]silanoxy; (C2-C2o)alkenyl optionally substituted at any available position with one or more phenyl groups; and a known ring system

comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, Chte, CO, N, NO, NH, O, SO and S, where chemically possible, said ring system being further optionally substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci- C2o)alkyl optionally substistuted with one or more group selected from nitro, cyano and hydroxy, (Ci-C2o)haloalkyl, (C2-C2o)alkenyl, pinacolboryl, formyl, tris[(Ci-C6)alkyl]stannyl and (C2-C2o)alkynyl.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, G2 is a diradical selected from the group consisting of -CH2-, -O-, -NR2-, -COO-, -CO-, -OCO-, -NR2CO- , -CONR2-, being R2 a hydrogen or a (Ci-C6)alkyl.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, m is an integer comprised of from 0 to 5. In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the

embodiments described above and below, in the compound of formula Ri-Br, m is an integer comprised of from 0 to 3. In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri- Br, m is an integer comprised of from 0 to 1.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, G3 is a radical independently selected from the group consisting of hydroxy, (Ci-C2o)alkyl, (C2-C2o)alkenyl, (C2-C2o)alkynyl and a known ring system comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, CH2, CO, N, NO, NH, O, SO and S, where chemically possible, said ring system being further optionally substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci-C2o)alkyl, (Ci- C2o)haloalkyl, (C2-C2o)alkenyl, pinacolboryl, and formyl, and being G3 further optionally substituted at any available position with one or more radicals selected from (Ci-C6)alkyloxy, (Ci-C6)alkylcarbonyl, (Ci-C6)alkyloxycarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxysulfonyl, (Ci-C6)alkylsulfonyloxy, (C1- C6)alkylaminocarbonyl, (Ci-C6)alkylcarbonylamino, and a phenyl ring.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, in the compound of formula Ri-Br, G3 is a radical independently selected from the group consisting of hydroxy, (Ci-C2o)alkyl optionally substituted at any available position with one or more radicals selected from (Ci-C6)alkyloxycarbonyl and a phenyl ring, (C2-C2o)alkenyl, (C2- C2o)alkynyl and a known ring system comprising from 1 to 5 saturated, unsaturated or aromatic rings, the rings being isolated, bridged or fused, each ring comprising from 3 to 8 members, the members being selected from the group consisting of C, CH, CH2, CO, N, NO, NH, O, SO and S, where chemically possible, said ring system being further optionally substituted at any available position with one or more radical selected from the group consisting of halo, hydroxy, amino, nitro, cyano, (Ci-C2o)alkyl, (Ci- C2o)haloalkyl, (C2-C2o)alkenyl, pinacolboryl, and formyl.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound of formula Ri-Br is selected from the group consisting of

It is advantageous since the process of the third aspect of the invention can be carried out with a broad range of compounds of formula Ri-Br and tolerates the presence of a broad range of functional groups and heteroatoms in the compound of formula Ri-Br.

In another particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the base is selected from the group consisting of alkaline and alkaline earth carbonate salts. More particularly, optionally in combination with one or more of the embodiments described above and below, the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate. Even more particularly, optionally in combination with one or more of the embodiments described above and below, the base is sodium carbonate. As mentioned above, the process of the third aspect of the invention can be carried out with a compound of formula Ri-Br wherein the bromine atom is attached to a saturated carbon atom. This is for instance the case when the compound of formula Ri-Br is an alkyl bromide as defined above. The process of the invention is particularly efficient when it is carried out in the presence of an additional base when the bromine atom in Ri -Br is attached to a saturated carbon atom of Gi in Ri. Thus, in a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the

embodiments described above and below, the process is carried out in the presence of an additional base when in the compound of formula Ri-Br, the carbon atom of Gi attached to the bromine atom is a saturated carbon atom. More particularly, said additional base is an alkaline salt of trifluoroacetate. Even more particularly, the additional base is sodium trifluoroacetate.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process of the invention is carried out at a temperature comprised from 0 °C to 50 °C. More particularly, optionally in combination with one or more of the embodiments described above and below, the process of the invention is carried out at a temperature comprised from 15 °C to 30 °C. Even more particularly, optionally in combination with one or more of the

embodiments described above and below, the process of the invention is carried out at room temperature. The term“room temperature” refers to a temperature comprised from 20 °C to 30 °C, more particularly of 25 °C.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the nickel (II) salt is used in an amount comprised from 0.01 mole to 0.2 mole per mole of compound of formula Ri-Br. More particularly, optionally in combination with one or more of the embodiments described above and below, the nickel (II) salt is used in an amount comprised from 0.05 mole to 0.15 mole per mole of compound of formula Ri-Br. Even more particularly, the nickel (II) salt is used in an amount of 0.1 mole per mole of compound of formula Ri-Br.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the ligand is used in an amount comprised from 0.01 mole to 0.2 mole per mole of compound of formula Ri-Br. More particularly, optionally in combination with one or more of the embodiments described above and below, the ligand is used in an amount comprised from 0.05 mole to 0.15 mole per mole of compound of formula Ri-Br. Even more particularly, the ligand is used in an amount of 0.1 mole per mole of compound of formula Ri-Br.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound of formula (III) is used in an amount comprised from 0.005 mole to 0.5 mole per mole of compound of formula Ri-Br. More particularly, optionally in combination with one or more of the embodiments described above and below, the compound of formula (III) is used in an amount comprised from 0.01 mole to 0.3 mole per mole of compound of formula Ri-Br. Even more particularly, the compound of formula (III) is used in an amount comprised from 0.05 mole to 0.25 mole per mole of compound of formula Ri-Br. Even more particularly, the compound of formula (III) is used in an amount comprised from 0.1 mole to 0.5 mole per mole of compound of formula Ri-Br. Even more particularly, the compound of formula (III) is used in an amount of 0.1 mole per mole of compound of formula Ri-Br.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound comprising one or more moieties of formula (II) is used in a an amount of at least twice the amount of compound of formula Ri-Br. More particularly, optionally in combination with one or more of the

embodiments described above and below, the compound comprising one or more moieties of formula (II) is used in a an amount of at least five times the amount of compound of formula Ri-Br. More particularly, optionally in combination with one or more of the embodiments described above and below, the compound comprising one or more moieties of formula (II) is used in a an amount of at least seven times the amount of compound of formula Ri- Br. More particularly, optionally in combination with one or more of the embodiments described above and below, the compound comprising one or more moieties of formula (II) is used in a an amount of at least ten times the amount of compound of formula Ri-Br. Alternatively, in a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound comprising one or more moieties of formula (II) is used as a solvent. The compound comprising one or more moieties of formula (II) is used as a solvent when it is a liquid in the conditions of the process; preferably, it is used as a solvent when it is a liquid in the conditions of the process and when it has a molecular weight inferior to 200 grams per mole of compound comprising one or more moieties of formula (II).

In other particular embodiments of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the compound comprising one or more moieties of formula (II) is used in a an amount of at least seven times the amount of compound of formula Ri- Br and the solvent does not comprise any moiety of formula (II), preferably, the solvent is benzene.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the base is used in an amount comprised from 0.5 mole to 2 moles per mole of compound of formula Ri-Br. More particularly, optionally in

combination with one or more of the embodiments described above and below, the base is used in an amount comprised from 0.7 mole to 1.5 mole per mole of compound of formula Ri-Br. Even more particularly, the base is used in an amount of 1 mole per mole of compound of formula Ri-Br.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process is carried out under light irradiation wherein the

wavelength of the irradiated light is comprised from 300 to 800 nm. In a more particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process is carried out under light irradiation wherein the

wavelength of the irradiated light is comprised from 350 to 800 nm. In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process is carried out under visible light irradiation wherein the wavelength of the irradiated light is comprised from 400 to 800 nm.

Alternatively, optionally in combination with one or more of the embodiments described above and below, the process is carried out under irradiation of light from a dark lamp, wherein the wavelength of the irradiated light is preferably comprised from 350 to 450 nm; more preferably, the wavelength of the irradiated light is 365 nm.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process is carried out under visible light irradiation and the visible light is irradiated at a power of at least 10 W; more particularly of at least 20 W and even more particularly of at least 30 W.

In a particular embodiment of the third aspect of the invention, optionally in combination with one or more of the embodiments described above and below, the process of the invention has at least one of the following features:

(i) the process is carried out at room temperature;

(ii) the nickel (II) salt and the ligand are used in an amount 0.1 mole per mole of compound of formula RiBr;

(iii) the compound of formula (III) is used in an amount comprised from 0.1 to 0.5 mole per mole of compound of formula Ri-Br;

(iv) the compound comprising one or more moieties of formula (II) is used in a an amount of at least twice the amount of compound of formula Ri-Br; or, alternatively, when it is a liquid, it is used as a solvent;

(v) the base is sodium carbonate;

(vi) the amount of base is of 1 mole of base per mole of compound of formula Ri-Br;

(vii) visible light is irradiated at a power of at least 30 W.

More particularly, the process of the third aspect of the invention has at least two of the features (i) to (vii) defined above. Even more particularly, the process of the third aspect of the invention has at least three of the features (i) to (vii) defined above. Even more particularly, the process of the third aspect of the invention has at least four of the features (i) to (vii) defined above. Even more particularly, the process of the third aspect of the invention has at least five of the features (i) to (vii) defined above. Even more particularly, the process of the third aspect of the invention has at least six of the features (i) to (vii) defined above. Even more particularly, the process of the third aspect of the invention has all the features (i) to (vii) defined above. EXAMPLES

General considerations

Reagents. All of the reactions were carried out in Schlenk tubes.

Commercially available aryl, alkyl halides and C-H precursors were used without further purification. Ni(acac)2 (95% purity) was purchased from Strem and Na2C03, 5,5'-dimethyl-2,2'-dipyridyl (L1 ), 4,4'-di-tert-butyl-2,2'-dipyridyl (L2) were purchased from Aldrich. Anhydrous benzene, tetrahydrofuran (THF) and other C-H precursors were purchased from Aldrich, Acros, TCI or Alfa Aesar, and used as received.

Analytical Methods. ¹ H NMR, ¹³ C NMR and ¹⁹ F NMR spectra were recorded for all compounds on a Bruker 300 MHz, a Bruker 400 MHz or a Bruker 500 MHz at 20 °C. All ¹ H NMR spectra were measured relative to the signals for CHCb (7.26 ppm). All ¹³ C NMR spectra were reported in ppm relative to residual CHCb (77.16 ppm) and were obtained with ¹ H decoupling. Melting points were also measured using open glass capillaries in a BOchi B540 apparatus. Mass spectra were recorded on a Waters LCT Premier

spectrometer. Specific optical rotation measurements were carried out on a Jasco P-1030 model polarimeter equipped with a PMT detector using the Sodium line at 589 nm. Gas chromatographic (GC) analyses were performed on Hewlett Packard 6890 gas chromatography instrument with a FID detector using 25m x 0.20 mm capillary column with cross-linked methyl siloxane as the stationary phase. Flash chromatography was performed with EM Science silica gel 60 (230-400 mesh) and using KMn04 TLC stain. UV-Vis

measurements were carried out on a Shimadzu UV-1700PC

spectrophotometer equipped with a photomultiplier detector, double beam optics and D2 and W light sources. Example 1. Control experiments and optimization of the reaction conditions

General procedure 1 : An oven-dried 12.0 mL Schlenk tube containing a stirring bar was charged with the compound of formula (III) indicated in Table 1 (10 mol%, 0.03 mmol), the ligand L1 or L2 as indicated in Table 1 (10 mol%, 0.03 mmol), and the aryl bromide (0.30 mmol, if solid). The Schlenk tube was then transferred to a nitrogen-filled glove-box where the Ni(acac)2 (10 mol%, 7.7 mg, 0.03 mmol), Na2C03 (1.0 eq, 32.0 mg, 0.30 mmol), aryl bromide (0.30 mmol, if liquid) and dry THF (0.075 M, 4ml_) were added. Then, the reaction mixture was stirred for 1 minute and taken out of the glovebox. The Schlenk tube was placed approximately ~3 cm away from two 32 W CFL and it was stirred for the time indicated in Table 1 facilitated by a fan to control the reaction temperature. The mixture was then analyzed by GC using decane as internal standard.

Table 1 summarizes the outcome of the control experiments.

Table 1

Table 1 shows that the process of the invention can advantageously be carried out in the absence of a metal-based photosensitizer, such as an iridium (III) or ruthenium (II) complex. It also shows that a nickel (II) salt, a compound of formula (III) and a base are essential features of the process of the invention. In addition, the reaction could be initiated by blue led; acceleration of the reaction was observed by dark lamp (Amax = 365 nm) with low selectivity.

Example 2: Cross-coupling of tetrahydrofuran (THF) with aryl bromides

Ni(Acac) ₂ (10 mol%)

CFL (32 W), RT General procedure 2: An oven-dried 12.0 ml_ Schlenk tube containing a stirring bar was charged with the compound of formula (Ilia) (10 mol%, 8.4 mg, 0.03 mmol), L1 (10 mol%, 5.6 mg, 0.03 mmol), aryl bromide (0.30 mmol, if solid). The schlenk tube was transferred to a nitrogen-filled glove-box where the Ni(acac)2 (10 mol%, 7.7 mg, 0.03 mmol), Na2C03 (1 .0 eq, 32.0 mg, 0.30 mmol), aryl bromide (0.30 mmol, if liquid) and anhydrous THF (0.075 M, 4ml_) were added. Then, the reaction mixture was stirred for 1 minute and taken out of the glovebox. The Schlenk tube was placed approximately ~3 cm away from two 32 W CFL and it was rigorously stirred for 24-96 h. After completion of the reaction, the crude material concentrated under reduced pressure. The desired product was directly purified by flash column chromatography in silica gel with pentane/EtOAc.

Table 2 summarizes the results obtained with various aryl bromide reagents in the formation of the compound of formula

LJ^ ^Ar

Table 2

^* deprotected amine was obtained as a product. ^† 10 mmol scale. ^# NaHC03 (1 .0 equiv) as base. ¹¹ Benzene as cosolvent (1 :1 , 0.05 M). ^§ C-H precursor (2.0-20 equiv) in benzene (0.075 M), (Ilia) (20 mol%) was used. Table 2 shows that the process of the invention can be carried out using a broad range of aryl bromides as reaction substrates, even when said reagent presents sensitive functional groups or heteroatoms.

Example 3: Scope of C-H precursor in photocatalytic cross-coupling procedure

Following general procedure 2 and replacing tetrahydrofuran by the C-H precursor specified in Table 3 and using the aryl bromide specified in Table 3, the cross coupling products were obtained as indicated in Table 3.

Table 3

_*

NaHC03 (1.0 equiv) as base. ¹¹ Benzene as cosolvent (1 :1 , 0.05 M). ^§ C-H precursor (2.0-20 equiv) in benzene (0.075 M), (Ilia) (20 mol%) was used.

Table 3 shows that the process of the invention can be carried out using a broad range of aryl bromides and precursors as reaction substrates, even when said reagent presents sensitive functional groups or heteroatoms.

Example 4: Cross-coupling reactions with alkyl bromides General Procedure 3: An oven-dried 12.0 ml_ Schlenk tube containing a stirring bar was charged with the compound of formula (Ilia) (20 mol%, 16.8 mg, 0.06 mmol), L2 (10 mol%, 8.1 mg, 0.03 mmol), alkyl bromide (0.30 mmol, if solid), CF3C02Na (1.0 eq, 40.8 mg, 0.3 mmol). The schlenk tube was transferred to a nitrogen-filled glove-box where the Ni(acac)2 (10 mol%, 7.7 mg, 0.03 mmol), Na2C03 (1.0 eq, 32.0 mg, 0.30 mmol), alkyl bromide of formula R”-Br (0.30 mmol, if liquid) and anhydrous THF (0.075 M, 4ml_) were added. Then, the mixture was stirred for 1 minute and taken out of the glovebox. The Schlenk tube was placed approximately ~3 cm away from two 32 W CFL and it was rigorously stirred for 36- 96 h. After completion of the reaction, the crude material concentrated under reduced pressure. The desired product was directly purified by flash column chromatography in silica gel with pentane/EtOAc.

Following general procedure 3, and replacing tetrahydrofuran by the C-H precursor specified in Table 4 and using the alkyl bromide R”-Br specified in Table 4, the cross coupling products were obtained as indicated in Table 4.

Table 4

^* Without CF3C02Na. ¹¹ Benzene as co-solvent (1 :1 , 0.05 M), compound (Ilia) (50 mol%) was used. ^# NaHC03 (1.0 equiv) as base.

Table 4 shows that the process of the invention can be carried out using a broad range of alkyl bromides and precursors as reaction substrates, even when said reagent presents sensitive functional groups or heteroatoms.

Example 5: Functionalization of Ambroxide

10 eq.

General Procedure 4: An oven-dried 12.0 ml_ Schlenk tube containing a stirring bar was charged with the compound of formula (Ilia) (20 mol%, 16.8 mg, 0.06 mmol), L1 (10 mol%, 5.6 mg, 0.03 mmol), aryl bromide (0.30 mmol, if solid). The schlenk tube was transferred to a nitrogen-filled glove-box where the Ni(acac)2 (10 mol%, 7.7 mg, 0.03 mmol), Na2C03 (1.0 eq, 32.0 mg, 0.30 mmol), aryl bromide (0.30 mmol, if liquid) and a solution of ambroxide (3 mmol) in benzene (5 ml_) were added. Then, the reaction mixture was stirred for 1 minute and taken out of the glovebox. The Schlenk tube was placed approximately ~3 cm away from two 32 W CFL and it was rigorously stirred for 96 h. After completion of the reaction, the crude material was concentrated under reduced pressure. The desired product was directly purified by flash column chromatography in silica gel with pentane/EtOAc.

Table 5 summarizes the observed results with different aryl bromide reagents. Table 5

Example 6: Preparation of cotinine and analogues thereof ( ),

10 eq.

Following general procedure 4 but replacing ambroxide by N- methylpyrrolidinone (NMP), the results of Table 6 were obtained using different aryl bromides.

Table 6

* ratio of arylation at the ring position to arylation product at the N-methyl position of NMP.

Example 7: Enantioselective photocatalytic cross-coupling of tetrahydrofuran with aryl bromides _{2 3} .

CFL (32W)

Following general procedure 3 using methyl-4-bromobenzoate as aryl bromide, the chiral ligand of Table 7 in an amount of 15 mol% (unless otherwise indicated) and 20 mol% of the compound of formula (Ilia), the results shown in Table 8 were obtained.

Table 8

^* 10 mol% of the chiral ligand were used; ^** 20 mol% of the chiral ligand were used

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