C-n coupling process with [cu2(μ-salben)2] complexes

Abstract

The present invention relates to a method for coupling aryl halides with N-nucleophilic reagent compounds, characterized in that the coupling is carried out in the presence of a binuclear copper (II) complex with a substituted salbed-type ligand of formula (I). Also described are novel binuclear copper (II) complexes with a substituted salbed-type ligand within the scope of Formula (I).

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) 19) World Intellectual Propert = cee Organization , ANTM AA TA AOA A International Bureau —— (10) International Publication Number (43) International Publication Date =— WO 2025 / 016888 Al 23 January 2025 (23.01.2025) WIPOI|PCT (51) International Patent Classification: Modena (IT). STEINER, Markus; c / o F. Hoffmann-La CO7D 207 / 06 (2006.01) CO7D 498 / 04 (2006.01) Roche AG, Grenzacherstrasse 124, 4070 Basel (CH). BOTS 31 / 28 (2006.01) CO7F 1 / 08 (2006.01) (74) Agent: RAUBER, Mr. Beat; F. Hoffmann-La Roche AG, CO7C 209 / 10 (2006.01) CO7B 43 / 04 (2006.01) Patent Department, Grenzacherstrasse 124, 4070 Basel C07C 213 / 02 (2006.01) C07B 43 / 06 (2006.01) (CH) > > C07C 251 / 24 (2006.01) C07C 227 / 18 (2006.01) , C07D 207 / 323 (2006.01) CO07C 231 / 08 (2006.01) (81) Designated States (unless otherwise indicated, for every C07D 207 / 325 (2006.01) C07C 303 / 36 (2006.01) kind of national protection available); AE, AG, AL, AM,C07D 231 / 12 (2006.01) C07F 1 / 00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CO7D 233 / 58 (2006.01) CO7B 45 / 04 (2006.01) CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, CO7D 401 / 04 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, . oe . HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, (21) International Application aera T / EP2024 / 069763 KH. KN, KP. KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY. . MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, (22) International Filing Date: NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, 12 July 2024 (12.07.2024) RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, (25) Filing Language: English 7A IMZW. TT, TZ, UA, UG, US, UZ, VC, VN, WS, (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every ___ (30) Priority Data: kind of regional protection available): ARIPO (BW, CV, = 23185471.2 14 July 2023 (14.07.2023) EP GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST,— (71) Applicant (for all designated States except US): F. HOFF- Me Ee wy 2M, ZW), Eurasian (AM, AZ, BY, KG, KZ, , TJ, ), European (AL, AT, BE, BG, CH, CY, CZ, — MANN-LA ROCHE AG [CH / CH]; Grenzacherstrasse DE. DK, EE, ES, FI, FR, GB, GR, HR. HU, IE, IS, IT. LT. > 124, 4070 Basel (CH). LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, — (71) Applicant (for US only): HOFFMANN-LA ROCHE SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, => INC. [US / US], Overlook at Great Notch, 150 Clove Road, GQ, GW, KM, ML, MR, NE, SN, TD, TG). — 8th Floor, Suite 8 - Legal Department, Little Falls, New Jer- — sey 07424 (US). Published: — . — with international search report (Art. 21(3)) m= (72) Inventors: FANTASIA, Serena Maria; c / o F. Hoff- — mann-La Roche AG, Grenzacherstrasse 124, 4070 Basel = (CH). MARCHI, Lorenzo; c / o Universita degli Studi = di Modena e Reggio Emilia, Dipartimento di Scienze — Chimiche e Geologiche, via Giuseppe Campi, 103, 41125 —— Modena (IT). RIGAMONTI,Luca; c / o Universita degli — Studi di Modena e Reggio Emilia, Dipartimento di Scienze == Chimiche e Geologiche, via Giuseppe Campi, 103, 41125 =>} (54) Title: C-N COUPLING PROCESS WITH [CU 2(-SALBEN) 2] COMPLEXES — (57) Abstract: The invention relates to a process for the coupling of an aryl halogenide with an = G! —. .G? N-nucleophile compound which is characterized in that the coupling takes place in the presence _ ee O, -P \ 4 of a dinuclear copper(II) complex bearing substituted salben-type ligands having the formula m G _ mer (1). Also described are novel dinuclear copper(I) complex bearing substituted salben-type lig- N \n= ands within the scope of formula (1). oa) Rhum,R es = N= hand mare SON w rexie —T\o4 S a) | N © WO 2025 / 016888 PCT / EP2024 / 069763 -|- C-N coupling process with [Cu2(t1-salben)2] complexes The invention relates to a novel process for the coupling of aryl halogenides with an N- nucleophile compound in the presence of dinuclear copper(II) complexes bearing substituted salben-type ligands of the formula I 1 G2 — an \7 Nao y \ f Ww u NQ oN= R1 ties ~~ R2 i, N= Cu SPAN Gs — 74 I wherein R! and R? are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl or hydrogen, and G', G’, G’ and G* are the same or different and stand for hydrogen or one or more substituents selected from C1-12-alkyl, C1-12-alkoxy, halogen C1-12-alkyl, halogen, mono- or di- Cy-12-alkyl amino, carboxyl, C1-12 alkoxy carbonyl or nitro or G', G’, G? and G*, independently of each other, together with the phenyl ring they are attached to form a fused aryl ring with two or three rings,which are optionally substituted with one or more substituents selected from C1-6- alkyl, Ci-c-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -2- The inventions also relates to novel dinuclear copper(I]) complexes bearing substituted salben-type ligands of the formula I, wherein R! and R’ are the same and are substituents of the formula IIa, Ib or IIc Rs Ry x! , | BNL Rio x6 “wae? x3 R7 Rs l x4 Rg n lla IIb lic wherein R?, R*, R°, R° and R’ are the same or different and are hydrogen, C1-12-alkyl, C1-12- alkoxy, halogen, halogen-C.12-alkyl, mono- or di- C1-12-alkyl amino, nitro or R? and R* or R4 and R° or R° and R° or R° and R’ together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl, Ci-6-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro. X!, X?, X?,X* and X° are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; nis Oor 1; R® R? and R" are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R® and R’ together form a saturated carbocycle or a heterocycle or R°, R’ and R!° together form an unsaturated carbocycle, with the proviso that compounds with R! and R? being hydrogen, or R' and R? having the formula Ila and wherein R*, R*, R° and R’ are hydrogen, while R° is hydrogen, chlorine, methyl, or nitro, are excluded. The object of the present invention was to provide an alternative method for the C-N- coupling,i.e. the coupling of an aryl halogenide with an N-nucleophile with a dinuclear SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -3- copper(II) complex bearing substituted salben-type ligands of the formula I and to provide novel dinuclear copper(II) complex bearing substituted salben-type ligands of the formula I capable to catalyse the coupling. The object could be reached with the process as outlined below, which comprises the coupling of an aryl halogenide with an N-nucleophile compound in the presence of a dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I. The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. The term “C1-12-alkyl” relates to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twelve carbon atoms, preferably one to eight,more preferably one to four carbon atoms. This term is further exemplified by radicals as methyl, ethyl, 7-propyl, i-propyl, n-butyl, i-butyl, s-butyl or / -butyl, pentyl, or hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl and its isomers. The term “C1-12-alkoxy” refers to a C1-12-alkyl group as defined above to which an oxygen atom is attached. Typical representatives are methoxy or ethoxy. The term “mono- or di- C1-12-alkyl amino” refers to an amino group which is mono- or di-substituted by a C1-12-alkyl group as defined above. Typical examples are N-methylamino, N- ethylamino, N,N-dimethylamino or N,N-diethylamino. The term “halogen” refers to fluorine, chlorine, bromine or iodine, preferably to fluorine and chlorine, but in regard to the C-N coupling particularly to bromine and iodine. The term “halogen-C)-12-alkyl” refers to a C1-12-alkyl group as defined above which is substituted with one or more halogens, such as trichloromethyl, 1,1-dichloroethyl or 1,1-di- chlorooctyl. The term “aryl” relates to an aromatic carbon ring such as to the phenyl, naphthyl ring anthracenyl or phenanthrenyl ring, preferably the phenyl ring. The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and / or sulphur, such as pyridyl, pyridinyl, pyrazolyl, pyrimidinyl, benzoimidazolyl, SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -4- quinolinyl and isoquinolinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, thiazolyl or imidazolyl. The term “optionally substituted” refers to one or more substituents selected from C1-12- alkyl, C1-12-alkoxy, halogen, halogen C1-12-alkyl, mono- or di- C1-12-alkyl amino or nitro. The spiral bond a a . . . : : stands for “ > or for“ “ ” and thus indicating chirality of the molecule, but also for mixtures of the enantiomers. Whenever a chiral carbon is present in a chemical structure,it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof. Process: As outlined above the invention relates to a novel process for the coupling of aryl halogenides with an N-nucleophile compound in the presence of dinuclear copper(II) complexes bearing substituted salben-type ligands of the formula I. Aryl halogenide: Suitable aryl halogenides can be defined with the formula II R19 6 Z NES yI— R x10" at x8 7 R23 + al \ a R22 ll SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -5- wherein X°, X7, X®, X° and X!° are the same or different and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulphur; RR” R?!, R” and R* are the same or different and are hydrogen, C1-12-alkyl, C2-12- alkenyl, C2-12-alkynyl, C1-12-alkoxy, halogen, halogen-Cj-.12-alkyl, mono- or di- C1-12-alkyl amino or cyano,or R!? and R”° or R”° and R?! or R' and R” or R” and R® together with the ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-12-alkyl, C1-12-alkoxy, halogen, mono- or di- Cj.6-alkyl amino or nitro; nis 0 or 1 and Z is a halogen atom. In preferred aryl halogenides X°, X7, X®, X° and X!° are the same or different and represent carbon or one nitrogen atom; RR” R?! R” and Rare the same or different and are hydrogen, methyl, methoxy or cyano; nis 1 and Z is chlorine, bromine or iodine,preferably bromine or iodine. The aryl halogenides of the formula III are as a rule commercially available or they can be synthesized following procedures well known by the skilled in the art. N-nucleophile: Suitable N-nucleophile can be selected from compounds of the formulae SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -6- “as av Jt RB Sea Rip ON-OH HN® x"? H H H R17 N 14213 H IVa IVb IVc IVd Ve wherein R'E RY RE RM RE, RR!” and R' are the same or different and are hydrogen, C1-12- alkyl, C1-12-alkoxy, aryl, halogen, halogen-C1-12-alkyl, nitro, hydroxy, mono- or di- C1-12-alkyl amino or R!° and R'° together with the nitrogen they are attached to form a saturated 5-or 6- member heterocycle; X! XX} and X™ are the same or different and represent a carbon atom optionally substituted with C1-12-alkyl, aryl-C1-12-alkyl, Ci-12-alkoxy, halogen, halogen-C1-12-alkyl and at least one further heteroatom selected from nitrogen,oxygen or sulphur. Preferred N-nucleophiles have the formula IVc, IVd, [Ve, wherein RP, RR” and Rare the same or different and are hydrogen, C-6-alkyl, aryl, or R!° and R'° together with the nitrogen they are attached to form a saturated heterocycle 5-or 6- member heterocycle; X! XX} and X™ are the same or different and represent a carbon atom optionally substituted with Cy-12-alkyl, aryl-C1-12-alkyl, and at least one further heteroatom selected from nitrogen, oxygen or sulphur. Catalysts: The process of the present invention takes place in the presence of a dinuclear copper(I) complexes bearing substituted salben-type ligands having the formula I SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -7- G! — = ok ON Nao y \ f Ww u NU ‘y= R1 ties ~~ R2 =i, N= Cu CS PLN Gs — 74 I wherein R! and R’ are the same or different and are optionally substituted C1.12-alkyl, aryl or heteroaryl, or hydrogen and G', G’,G’ and G* are the same or different and stand for hydrogen or one or more substituents selected from C1-12-alkyl, C1-12-alkoxy, halogen, halogen C1.12-alkyl, mono- or di- Cy-12-alkyl amino, carboxyl, C1-12-alkoxy carbonyl or nitro or G!, G?, G? and G*, independently of each other, together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6- alkyl, Ci-c-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro. In a preferred embodiment G', G*, G* and G? are the same or different and stand for hydrogen or one or more substituents selected from methyl, ethyl, t-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, V.N-dimethylamino, V.N-diethylamino, carboxyl, methoxy carbonyl, ethoxy carbonyl, i-propoxy carbonyl, n-butoxy carbonyl, ¢-butoxy carbonyl, nitro or G', G’, G? and G*, independently of each other,together with the phenyl ring they are attached to form a fused aryl ring. In a preferred embodiment R! and R’ are the same and are substituents of the formula IIa, IIb or Hc SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -8- Rs 1 Ra XN 2 ae \ xX R Rg : | 8 Ne R, 0 x8 F--_ x3 vw Xx Rg n lla IIb lic wherein R?, R*, R°, R° and R’ are the same or different and are hydrogen, C1-12-alkyl, C1-12- alkoxy, halogen, halogen-C1.12-alkyl, mono- or di- C1-12-alkyl amino, nitro or R? and R* or R4 and R° or R° and R° or R° and R’ together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl, Ci-6-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro, X!, X?, X?, X* and X° are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; nis Oor 1; R® R? and R" are the same or different and are hydrogen, C1-12-alkyl,halogen C1-12- alkyl, hydroxy, hydroxy-C1-12-alkyl, halogen or R® and R? together form a saturated carbocycle or a heterocycle or R®, R’ and R!° together form an unsaturated carbocycle. Preferred substituents of formula Ia are those wherein R°, R*, R°, R° and R’ are the same or different and are hydrogen, methyl, ethyl, butyl, methoxy, ethoxy, chlorine, bromine, trifluoromethyl, N.N-dimethylamino, N.N-diethylamino, nitro or R? and R‘ or R* and R° or R° and R° or R° and R’ together with the phenyl ring they are attached to form a fused aryl ring selected from 2-naphthalene, anthracene or phenanthrene In particular, examples of formula Ia e R? to R’ are hydrogen, or e R?is methyl, methoxy, chlorine or nitro and R* to R’ are hydrogen, or SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 _9. e R° is methyl, ¢-butyl, methoxy, chlorine, nitro or N,N-dimethylamino and R? and R‘and R° and R’ are hydrogen, or e Rand R° are methoxy or chlorine and R*, R° and R’are hydrogen,or e Rand R’ are methoxy or chlorine and R* to R° are hydrogen, or e R?*,R°and R’ are methoxy and R‘ to R° are hydrogen. Preferred substituents of formula IIb can be selected from = f Ss = fi O = f NH —=N N—-NH Cs © Co © Nn L (CM A “T a i hd a aie IIb1 lIb2 IIb3 Ilb4 IIb5 Ilb6 Ilb7 Ilb8 / A L 3 op i 3 Nv 0 Nv 8 i Ne NH Cr Y Gone woo wos Wy Wy | | | “ey aed | aed f Ilb9 Ilb10 lIb14 IIb12 Ilb13 llb14 Ilb15 tlb16 N=\ ao o ~N ZN Ss Ch S a Ilb17 Ilb18 Ilb19 Ilb20 Particularly preferred substituents are of the formula IIb1, IIb2, IIb14, IIb17. Preferred substituents of formula IIc are those wherein R®, R? and R!° are the same or different and are hydrogen, hydroxy, hydroxy-C1.4-alkyl or R* and R’ together form a heterocycle or R®,R’ and R'° together form an unsaturated carbocycle. Particular examples of substituents of formulas IIc are: SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -10- ‘bo HO o> Ho.) “T ~“ aia a lIc1 IIe2 IIe3 llc4 Preferably they are selected from formula IIc] and Ic2 The substituents Ia and IIc are most preferred. Particularly preferred catalysts of the formula Ia are those wherein, R?, R*, R°, R° and R’ are hydrogen, or R? is chlorine or methoxy and R*, R°, R° and R’ are hydrogen, or R° is chlorine or methoxy and R?, R*, R° and R’ are hydrogen, or R? and R’ are methoxy and R*, R° and R° are hydrogen. Particularly preferred catalysts of the formula IIc are those with the formula IIc1. The most preferred catalysts are listed below. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -11- Z-%.,, O yO __ Doan _ vo NQ N= MeO *~ Ny —O =N, N= ore= OMe [Cuz(u-salben)>] [Cuz(u-sal(2-OMe)ben)>] pO, y-%,, __ on __ vo Cl N N= N N= —N,, N= Cl —N,,N= Cu y Cu y [Cus(p-sal(2-Cl)ben)>] [Cus(u-sal(4-OMe)ben)>] ny" \ MeO \=y” \___ / OMe = N= = N= —==N,, N,, “oh y MeO “ok y Me fe) re) O O [Cuy(p-sal(4-Cl)ben)s] [Cus(u-sal{2,6-diOMe)ben),] O,, 0 O, O NQ N= =NO N= =N, —N, N= Cu Wert o_o LY oS LY [Cug(u-(R)-salmyr)a] [Cup(y-sal(4-tBu)ben),] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -12- MeO OMe OMe MeQ O, 0) O,, O Oo CaN o, "oh o =n” S N Cl = N \n= =N, N= =N,, "\cl u MeO OMe OMe MeO [Cu2(u-(4-OMe)salben)a] [Cup(u-(3-OMe)sal(2-Cl)ben)z] Dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I 1 G? C. — Lo 7 Na ane NK N= Ri wn ~~ R2 —=N,, N= Cu CSN Gs —T\¢4 I wherein G', G’, G’ and G* are the same or different and stand for hydrogen or one or more substituents selected from C1-12-alkyl, Cii26-alkoxy, halogen, halogen C1-12-alkyl, mono- or di- C1-12-alkyl amino, carboxyl, C1-12- alkoxy carbonyl or nitro or G!, G?, G? and G*, independently of each other,together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6- alkyl, Ci-c-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro; R! and R’ are the same and are substituents of the formula IIa, Ib or IIc SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -13- R3 1 Ra XN 2 ae \ xX R Rg : | 8 Ne R, 0 R R xX wr 7 5 Y xf | Rg n lla IIb lic R?, R*, R°, R° and R’ are the same or different and are hydrogen, C1-12-alkyl, C1-12- alkoxy, halogen, halogen-C1.12-alkyl, mono- or di- C1-12-alkyl amino, nitro or R? and R* or R4 and R° or R° and R° or R° and R’ together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl, Ci-6-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro. X!, X?, X?,X* and X° are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; nis Oor 1; R® R? and R" are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R® and R’ together form a saturated carbocycle or a heterocycle or R*, R’ and R'° together form an unsaturated carbocycle, with the proviso that compounds with R! and R? being hydrogen, or R! and R” having the formula Ila and wherein R*, R*, R° and R’ are hydrogen while R° is hydrogen, chlorine, methyl, or nitro, are excluded. The excluded compounds have been disclosed by a) Alessandro Pasini, Francesco Demartin, Olivo Piovesana, Brunetto Chiari, Antonio Cinti and Ornella Crispu, J. Chem. Soc., Dalton Trans. 2000, 3467-3472,DOI: 10.1039 / b003825n The novel dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I are novel and therefore constitute a particular embodiment of the present invention. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -14- With the exception for the known compounds, the preferences and particular examples as outlined before likewise apply for the novel dinuclear copper(I] complex bearing substituted salben-type ligands. Preparation of catalysts: The preparation of the catalyst can be accomplished according to the scheme below: 1 / 213 / 4 G S A~onH RZ Rv2 ye ”, ~ TT “, ot WZ OH = HOT 4 MeOH / ELOH gis” Zon HOT N24 X XI XII Cux, MeOH / EtOH 1 G? o— , > VO on VF — Ko aN aon See = N= SN, Y Gs — Tos The Hosalben-type derivatives of formula XII can be prepared by reacting an N,N -bis- (salicylidene)-2-hydroxyphenylmethanediamine derivative of formula X with the appropriate aldehyde of formula XI in the presence of ammonium acetate a or ammonia and a polar protic solvent such as methanol or ethanol at temperatures from -10 °C to 40 °C under stirring for a period of time from 3 h to 120 h. The resulting ligand can be isolated by filtration, washing with polar protic solvent, and dried under vacuum. The formation of the dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I can then happen by adding a copper(II) salt CuX2, preferably the acetate monohydrate, to the suspended Hzsalben-type ligand of formula XT in a polar protic solvent, preferably methanol or ethanol, in the presence of tertiary amine,preferably triethylamine at temperatures from -10 °C to 40 °C under stirring for a period of time from %h SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -[5- to 24 h. The resulting complex can be isolated by filtration, washing with polar protic solvent, and dried under vacuum. C-N coupling process: The C-N coupling process i.e. the coupling of aryl halogenides with an N-nucleophile compound in the presence of dinuclear copper(II) complexes bearing substituted salben-type ligands of the formula Iis advantageously performed in the presence of a suitable base. The base can be selected from alkali salts of mineral acids or organic acids, such as caesium carbonate, potassium phosphate, potassium carbonate or sodium acetate, or from alkali alcoholates such as sodium- or potassium t-butylate. The preferred bases are caesium carbonate and potassium phosphate. As atule the base is applied in equivalents: from 1 to 5, preferably from 1.5 to 4. Furthermore,the reaction takes place in the presence of an organic solvent which can be selected from aliphatic alcohols, such as methanol, ethanol, t-amylalcohol, NV.N- dimethylformamide, tetrahydrofuran, acetonitrile, toluene or dimethylsulfoxide. Preferred organic solvents are acetonitrile, tetrahydrofuran and dimethylsulfoxide, The equivalent aryl halogenide in relation tol equivalent of the N-nucleophile, may vary dependent on the halogenide, but typically ranges from 0.2 to 3.0: 1.0., preferably 0.3 to 2.5:1.0. The reaction temperature is as rule held between 20 °C and 200 °C, preferably between 50 °C and 100 °C, more preferably between 70 °C and 90 °C. The catalyst loading in mol %, referred to the limiting reagent, which can be the N- nucleophile or the aryl halogenide, can vary between 0.1 mol % and 5.0 mol %, preferably between 0.25 mol % and 3.0 mol %. After a reaction time of 4 h to 24 h, preferably of 8 h to 18 h,the resulting aryl amine can be isolated by filtering off the catalyst and by evaporating the organic phase. The resulting crude aryl amine can further be purified via chromatography. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -16- Examples: Abbreviations: RT = room temperature MeOH = methanol Et2O = diethyl ether iPr2O = diisopropyl ether Et3N = triethylamine EtOH = ethanol MeCN = acetonitrile DMSO = dimethylsulfoxide THF = tetrahydrofuran DCM = dichloromethane 1. Activity of copper(II) complexes as catalysts in C-N coupling reactions 1.1 Optimized conditions The coupling of aryl iodide and pyrazole can be achieved by reaction with 0.5 mol% [Cu2(u-salben)2] catalyst in the presence of 2 equiv of Cs2COs in acetonitrile (MeCN) at 82°C. After 16 h full conversion is observed, and the product can be isolated in 83% yield. 4 0.5 mol% [Cu2(yu-salben)o] N CsoCOz3 (2 equiv) ~ CP CP =a OP'S MeCN, 82°C,16h 1.2 Optimization studies Table 1. Optimization of temperature and catalyst loading. Entry Cusource / | Cusource | 7 [°C| t Yield ligand loading [h] [%]!P [mol% |! 1 [Cur(p- 0.5 82 93 (83) salben)2] salben)2] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -17- 3 [Cu2(p- 0.25 82 16 salben)2] 4 [Cur(u- 0.25 70 16 46 salben)2] 5 [Cu2(p- 0.25 16 30 salben)2] [Cur(u- 0.25 50 16 16 salben)2] General conditions: iodobenzene (215 uL, 1.93 mmol, 1.5 equiv), pyrrole (90 uL, 1.29 mmol, 1 equiv), Cs2CO3 (839.2 mg, 2.58 mmol, 2 equiv), [Cu2(u-salben)2] in 1 mL of MeCN. ! The catalyst loading refers to the amount of pyrrole. '°! 'H NMR yield, isolated yields in brackets. Table 2. Screening of bases in MeCN. Entry | [(Cua(u-salben)2| | Base t[h] Yield [%]!?! | loading : [mol%|!! : rsSC«025~SSSSS=«*KKOOC(CH) 3S COs 96 (85 isl 75K POW to BH General conditions: iodobenzene (715 uL, 6.42 mmol, 1.5 equiv), pyrrole (300 uL, 4.29 mmol, 1 equiv),base (2 equiv) [Cu2(u-salben)2] in 3.5 mL of MeCN. !*! The catalyst loading refers to the amount of pyrrole. !°! 'H NMR yield, isolated yields in brackets. !*! Tetrahydrofuran (THF) as solvent. !! K3;PO, (3.64 g, 17.18 mmol, 4 equiv). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -18- Table 3. Screening of solvent and bases. ield [% 21 DMF CsCOn 220 DMP KP , [29 toluene | KOC(CH)s (31 tamylalcohol | NaOC(CHg)s_ 35000 | THF | NlOCKC 3600 THF KOC(CHS)s 37 PROM CCOn General conditions: iodobenzene (215 uL, 1.93 mmol, 1.5 equiv), pyrrole (90 uL, 1.29 mmol, 1 equiv), base (2.58 mmol, 2 equiv), [Cu2(u-salben)2] (2.52 mg, 0.003 mmol, 0.0025 equiv) in 1 mL of solvent; 7 = 70-82°C, t= 16h. ! DMF = dimethylformamide, DMSO = dimethylsulfoxide, EtOH = ethanol. Table 4. Activity of the different copper (ID) derivatives as catalysts. ——rrt—“a_OC—C—C—CC——C—CCTCTC—T—TC——CTC——TCT—CU—O.C'VT..CXiéC3CWS™—SCisCisC‘éisiYield~) | [Yo] [Cua(-sal(2-OMe)ben)r] [Cua(t-sal(2,6-diOMe)ben)2] [Cua(y-sal(2-Cl)ben)2] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -19- [Cua(t-sal(2,6-OMe)(2)-diOMe)ben [Water(u-salt(2-Cl)bene)] 19.50 mol% | 89 [Cua(u-sal(2)thn)2] 19.50 mol% (| 89 [58 | CsxCO3_| [Cuc(u-salt(3)thn)p] 0.50 mol% 96 ​​[Cua(u-salt(4-tBu)ben)2] 10.50_s99 C|x|x26 | [Cur(u-(S-Me)salben)p] | 0.50 mol% 174 [Cua(u-(4-OMe)salben)] 10.50mol% | 96 [Cua(u-(5-F)salben)] 165 | CsxCO3_| [Cua(u-(5-Cl)sal(2-OMe)ben)>] | 0.50 mol% 89 [66 |.Cua(u-(5-Cl)sal(2-NO2)ben),] 10.50mol% | 0.50 mol% 98 169 | Cs2xCOs_| [Aua(u-(5-OMe)sul(2-Cl)2] [Aua(-sul(2-NO2)sulfate)2] [Aua(u-(5-Me)salt)] [Aua(u-(5-Cl)salt),] 10.50mol% | 89 General conditions: iodobenzene (215 wb, 1.93 mmol, 1.5 equiv), pyrrole (90 nL, 1.29 mmol, 1 equiv), base (2.58 mmol, 2 equiv), 1 mL of MeCN; 7′ = 82 °C,t= 16h. |! LC / MS yield (%). Table 5. Influence of various equivalents of base and iodobenzene. : [%] so Sa SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -20- General conditions: iodobenzene, pyrrole (90 wL, 1.29 mmol, 1 equiv), K3PO4, [Cu2(u-salben)2] (0.006 mmol, 0.005 equiv) in 1 mL of MeCN; 7'= 82 °C, t= 16h. 1.3. Substrate scope Table 6. Substrate scope with aryl iodides ). : Yield % Aryl iodide | N-Nucleophile LC / MS | | = = N OMe HN] en oe) 81 —_ OMe | — = No HN OMe MeO | Cw te OMe | — a ~ ( an \ ‘N | = — — HN] yj Sn nN’ | C Ww fe ODN] 0 Il N SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -2]- l | “SN HN (\~— 81 Z N l [ wi) (9 aN N Nl | a — a N l Sromelare l / =N ( \ / =N do Po Oc fp | | N Nx ~~ CO [Se |Oxn |} l Nx Nex & we job fe | fe) Ch fe) oo [Mito ) H | Oh ro |! oO. C12 0 HN’? a 63 H SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -22- General conditions: aryl 1odide (1.5 equiv), N-nucleophile (1 eq), Cs2CO3 (2 equiv),[Cu2(p- salben)2] (0.5 mol %) in MeCN, c= 1 mol L'!; 7= 82 °C, ¢= 16h. Table 7. Substrate scope with aryl bromides base vee aryl bromide | N-nucleophile | product eu solvent | (LC / q MS Br a Ox LOH K3P04 0 Q NH, 15) (3 equiv) | PMSO | 09% 3 equiv H Br Le vet Vn O cauin) MeCN | 55% (1.5 equiv) 4 II N Br “OC N Cs2COs | MeCN | 51% . H (2 equiv) (1.5 equiv) Br MJD | Ca] Jeet | meen | 20% (1.5 equiv) 4 Br oF F HN] oF | es:C0s ; Q cr ¢ Vw (2 equiv) | MeCN | 48% 1.5 equiv Br HoN a. OC No N Cs2COs | MeCN | 54% -} Ni (2 equiv) fe) (1.5 equiv) Br H2N ° “OC Ch KsPOs | puso | 63%} N (3 equiv) (1.5 equiv) SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -23- H : 2 = K3P04 rT : Ho~ So N (3 equiv) NZ z DMSO | 94% R ‘ ° Hoo R yy £=20h cA . N O = ane (1.5 equiv) ae z O General conditions: aryl bromide (1 equiv), N-nuclephile (7 equiv as reported in the table), base, [Cu2(u-salben)2] (2.5 mol%), base (7 equiv as reported in the table), solvent, c = 0.5 mol L"!; 7= 85°C,= 16h. 2. Synthesis of the novel salben-type ligands 2.1 Synthesis of H2sal(2,6-diOMe)ben ho cA Pho SN NZ NH,OAc SN N~ Cr IO + MeO OMe ie) H3salmp Hysal(2,6-diOMe)ben Hssalmp (0.499 g, 1.44 mmol) and 2,6-dimethoxybenzaldehyde (0.478 g, 2.87 mmol) were added to a solution of ammonium acetate (0.113 g, 1.46 mmol) in 5 mL of methanol (MeOH), obtaining a yellow suspension that was left under magnetic stirring for 24 h at room temperature (RT). The yellow product was then recovered by filtration, washed with MeOH (2 x 2 mL) and diethyl ether (Et2O) (2 x 2 mL) and dried under vacuum for several hours, yielding 0.645 g of a bright yellow powdery solid (76% yield). Elemental analysis for C23H22N204, MW = 390.44 g / mol, calculated: C 70.75%; H 5.68%; N 7.17%. Found: C 70.54%; H 5.79%, N 7.24%. IR spectrum, cm’! (ATR): 3050-2830, 1628, 1585, 1493-1474, 1397, 1276, 1250, 1110- 1067, 758. 'H NMR, 298 K, CDCI3, 400 MHz: & (ppm) 13.62 (2H, s), 8.55 (2H, d), 7.32-7.28 (4H, m), 7.26 (1H, t), 6.95 (2H,dd), 6.87 (2H, td), 6.77 (1H, s), 6.58 (2H, d), 3.85 GH, s). BC NMR, 298 K, CDCl, 101 MHz: 5 (ppm) 163.4, 161.5, 158.5, 132.6, 132.0, 130.3, 119.1, 118.6, 117.3, 115.6, 104.7, 79.6, 56.0. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -24- 2.2 Synthesis of H2sal(2)thn S / S OH —_ a OH «HO ~ EtOH OH HO oO H3salmp Hsal(2)thn H3salmp (3.012 g, 8.695 mmol) was added to a solution of ammonium acetate (2.024 g, 26.26 mmol) in EtOH (50 mL). Thiophene-2-carboxaldehyde (1.70 mL, 18.5 mmol) was then added to the suspension, and the reaction mixture was stirred at RT for 4 days. The formed pale- yellow solid was filtered, washed with EtOH and diisopropyl ether ( / Pr2O) and dried under vacuum for several hours, yielding 2.946 g of the title compound (67%). Elemental analysis for CioHi6N2028, MW = 336.41, calculated: C 67.84%; H 4.79%; N 8.33%; S 9.53. Found: C 67.77%; H 4.84%; N 8.15%; S 10.05%. m.p.: 109-112 °C. IR spectrum, cm™! (ATR): 3109, 2853, 1618, 1575, 1497, 1456, 1422, 1372,1357, 1272, 1040, 1025, 975, 897, 753, 712, 598. 'H NMR, 298 K, acetone-ds, 400 MHz: & (ppm) 6.44 (s, 1H), 6.94 (dd, 2H), 7.08 (dd, 2H), 7.24 (dt, 2H), 7.40 (ddd, 2H), 7.51 (dd, 2H), 7.52 (dd, 2H), 8.85 (s, 2H), 12.82 (s, 2H). '3C NMR, 298 K, acetone-ds, 101 MHz: & (ppm) 86.2, 116.8, 118.7, 119.0, 125.2, 126.8, 127.2, 132.8, 133.4, 144.4, 161.1, 166.5. Mass spectrum (ESI") in MeOH, mz (intensity %): calculated for [M + H]’: 337.1011; found: 337.1000 (100). 2.3 Synthesis of H2sal(3)thn S) \ OH s ZA OH OHO ~ EtOH OH HO ie) H3salmp Hgsal(3)thn Hssalmp (3.011 g, 8.694 mmol) was added to a solution of ammonium acetate (2.017 g, 26.17 mmol) in EtOH (30 mL). Thiophene-3-carboxaldehyde (2.012 g, 17.94 mmol) was added to the suspension, and the reaction mixture was stirred at RT for 4 days. The formed pale-yellow solid was filtered, washed with EtOH and / Pr2O and dried under vacuum,yielding 3.268 g of the SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -25- title compound (75%). Elemental analysis for CipHisbN202S, MW = 336.41, calculated: C 67.84%, H 4.79%, N 8.33%, S 9.53%. Found: C 67.18%, H 4.76%, N 8.55%, S 10.50%. m.p.: 94-96 °C. IR spectrum, cm™! (ATR): 3107, 3054, 3000, 2858, 1618, 1576, 1500, 1456, 1424, 1368, 1273, 1043, 976, 779, 752, 733, 635. 'H NMR, 298 K, acetone-ds, 400 MHz: 6 (ppm) 6.26 (s, 1H), 6.94 (d, 2H), 6.96 (dd, 2H), 7.29 (dd, 2H), 7.39 (dd, 2H), 7.50 (dd, 2H), 7.54 (dd, 1H), 7.56 (m, 1H), 8.83 (s, 2H), 13.01 (s, 2H). &C NMR, 298 K, acetone-ds, 101 MHz: & (ppm) 87.5, 117.6, 119.6, 119.7, 123.4, 127.0, 127.8, 133.5, 133.9, 143.0, 162.0, 167.0. Mass spectrum (ESI’) in MeOH, m / z (intensity %): calculated for [M + H]": 337.1011; found: 337.1001 (100). 2.4.1 Synthesis of (R)-Hosalmyr ho OH HO So MeOH OH HO H3salmp Hesalmyr H3salmp (0.30135 g, 0.870 mmol) was added to a solution of NH4OAc (0.20471 g,2.66 mmol) in MeOH (10 mL). (X)-Myrtenal (0.25308 g, 1.68 mmol) was added to the yellow suspension, and it was stirred at RT for 1 d, during which H3salmp completely dissolved in 6h and the desired product precipitated after 12 h. The formed pale-yellow solid was filtered, washed with MeOH (3 x 3 mL) and 7Pr20 (3 x 3 mL) and dried under vacuum for | h. Yield: 0.29610 g (61%). Elemental analysis calcd (%) for C24H26N202 (374.48): C 76.98, H 7.00, N 7.48. Found: C 76.78, H 7.04, N 7.51. Melting point: 184-187 °C. 'H NMR (400 MHz, 298 K, acetone-de) in ppm: 6 0.86 (3H, s), 1.43 (3H, s), 1.85 (1H, d, 10 Hz), 2.00 (1H, dd, 2 —- 4 Hz), 2.14 —2.19 (1H, m), 2.57 — 2.66 (2H, m), 3.45 (1H, t, 5 Hz), 4.40 (1H, d, 8 Hz), 6.83 (1H, s), 6.86 — 6.94 (4H, m, 1 — 7 Hz), 7.30 — 7.34 (2H, m, 2 Hz), 7.37 (1H, dd, 2 — 8 Hz), 7.43 (1H, dd, 2 — 8 Hz), 8.40 (1H, s), 8.61 (1, s), 13.15 (1H, s), 13.20 (1H, s). 8 NMR (101 MHz, 298 K acetone-ds) in ppm: 5 22.3, 26.4, 27.5, 34.9, 41.5, 42.0, 45.9, 64.2, 117.4,117.4, 119.5, 119.8, 120.1, 120.4, 132.6, 132.7, 133.0, 133.3, 138.5, 144.8, 161.6, 161.9, 163.3, 164.2. IR-ATR (cm): 2993, 2969, 2949, 2865, 1645, 1620, 1596, 1563, 1495, 1456, 1413, 1300, 1278, 1244, 1148, 1079, 971, 844, 753. Mass spectrum (ESI°) in MeCN, m / z (intensity %): calculated for [M + H]’: 375.2073; found: 375.2060 (100). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -26- 2.4.2 Synthesis of (R)-HosalC1myr ® oe ote So , OH MeOH OH HO salH (R)-HzsalCimyr (R)-Myrtenal (0.1352 g, 0.900 mmol) was added to a solution of NH3 (750 wL of an aqueous solution 25% m / m, 10.0 mmol) in MeOH (2.5 mL). Salicylaldehyde (salH) (0.2001 g, 1.64 mmol) was added to the colourless solution, and the mixture was stirred at RT for 3 h with the formation of the desired product as precipitate. The formed pale-yellow solid was filtered,washed with MeOH (3 x 3 mL) and 7Pr20 (3 x 3 mL) and dried under vacuum overnight. Yield: 0.2112 g (69%). Elemental analysis caled (%) for C2s4H26N202:0.2 H20 (382.08): C 76.24, H 7.04, N 7.41. Found: C 76.04, H 6.68, N 7.38. Melting point: 135-139 °C. 'H NMR (400 MHz, 298 K, acetone-de) in ppm: 5 0.79 (3H, s), 1.28 (3H, s), 1.85 (1H, d, 10 Hz), 2.09-2.14 (1H, m), 2.27-2.42 (2H, m, 6 Hz), 2.45-2.48 (2H, m), 5.49 (1H, s), 5.76 (1H, s), 6.91-6.95 (4H, m), 7.35- 7.40 (2H, m), 7.48 (2H, dd, 1 — 8 Hz), 8.71 (1H, s), 8.73 (1H, s), 13.04 (1H, s), 13.06 (1H, s). ®C NMR (101 MHz, 298 K acetone-ds) in ppm: 5 21.6, 26.4, 32.0, 32.3, 38.6, 41.6, 43.1, 91.7, 117.6, 119.6, 121.4, 121.4, 133.3, 133.7, 148.2, 162.0, 166.6, 166.8. IR-ATR (cm): 2989, 2969, 2927, 2877, 1620, 1574, 1494, 1457, 1413, 1365, 1274, 1212, 1150, 1039, 976, 897, 836, 751. Mass spectrum (ESI+) in MeCN,m / z (intensity %): calculated for [M + H]+: 375.2073; found: 335.2067 (100. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -27- 2.6 Synthesis of H2(4-OMe)salben So MeO OH MeOH MeO OH HO OMe benz 4-OMe-salH H2(4-OMe)salben Benzaldehyde (0.1631 mg, 1.537 mmol) was added to a supersaturated solution of ammonium acetate (0.1631 g, 1.5368 mmol) in MeOH (2.5 mL) and stirred at RT for 5 min under inert atmosphere. 4-OMe-salH (0.4175 g, 2.734 mmol) was then added to the colourless solution, and the reaction mixture was stirred at RT for 4h. The formed pale-grey solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for 1 h. Yield 0.2615 g (49%). Elemental analysis calcd (%) for C23H22N20a, (390.44): C 70.76, H 5.68, N 7.16. Found: C 70.70, H 5.80, N 6.85. Melting Point: 111 - 112 °C. 1H NMR (400 MHz, 298 K, acetone-ds) in ppm: 5 13.44 (2H, s), 8.74 (2H, s), 7.56 (2H, d, 8 Hz), 7.47 — 7.43 (2H, m), 7.40 (2H, d, 8 Hz), 7.39 — 7.34 (1H, m), 6.51 (2H, dd, 8 — 2 Hz),6.46 (2H, d, 2 Hz), 6.03 (1H, s), 3.84 (6H, s). 'C NMR (151 MHz, 298 K, acetone- ds) 5 164.9, 163.9, 163.5, 141.8, 133.8, 128.8, 128.2, 127.0, 112.6, 106.4, 100.8, 90.4, 54.9. IR- ATR (cm): 1610, 1570, 1452, 1316, 1288, 1240, 1168, 764. Mass spectrum (ESI*) in MeCN, nvz (intensity %): calculated for [M + H]": 391.1658; found: 391.1639 (100). 2.7 Synthesis of H2(5-OMe)salben C moe NH,OAc a — + ——_—_—_——_ So OH MeOH OH HO benz H2(5-OMe)salben Benzaldehyde (84.2 mg, 0.794 mmol) was added to a supersaturated solution of ammonium acetate (0.9672 g, 15.81 mmol) in MeOH (2.5 mL) and stirred at RT for 5 min under inert atmosphere. 5-OMe-salH (201.3 mg, 1.332 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed pale-yellow solid was filtered,washed with MeOH (3 x 3 mL) and / Pr2O (3 x 3 mL) and dried under vacuum for 1 h. Yield 0.1754 g SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -28- (68%). Elemental analysis calcd (%) for C23H22N20,, (390.44): C 70.76, H 5.68, N 7.16. Found: C 71.04, H 5.71, N 7.26. Melting Point: 137-141 °C. 'H NMR (600 MHz, 298 K, acetone-ds) in ppm: 5 12.49 (2H, s), 8.82 (2H, s), 7.59 — 7.54 (2H, m), 7.47 — 7.42 (2H, m), 7.39 — 7.33 (1H, m), 7.08 (2H, d, 3 Hz), 7.00 (2H, dd, 9 —3 Hz), 6.86 (2H, d, 9 Hz), 6.14 (1H, s), 3.76 (6H, s). BC NMR (151 MHz, 298 K, acetone-ds) & 166.7, 156.1, 153.3, 129.8, 129.3, 127.8, 121.2, 119.3, 118.4, 116.3, 91.5, 56.1. Mass spectrum (ESI') in MeCN, mz (intensity %): calculated for [M + H]*: 391.1658; found: 391.1655 (100). 2.8 Synthesis of H2(5-F)salben G F. ~ NH,OAc F ~ & F Ae SE Or So OH MeOH OH HO benz H2(5-F)salben Benzaldehyde (83.2 mg, 0.784 mmol) was added to a supersaturated solution of ammonium acetate (0.8828 g,11.442 mmol) in MeOH (2.5 mL) and stirred at RT for 5 min. 5-F- salH (206.1 mg, 1.4708 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and iPr2O (3 x 3 mL) and dried under vacuum for lh. Yield 0.2295 g (85%). Elemental analysis calcd (%) for C21Hi6F2N202, (366.12): C 68.45, H 4.40, N 7.65. Found: C 68.19, H 4.32, N 7.54. Melting Point: 144 - 147 °C. 'H NMR (600 MHz, 298 K, acetone-de) 8 12.78 (2H, d, 4 Hz), 8.86 (2H, d, 3 Hz), 7.58 (2H, d, 8 Hz), 7.46 (2H, dd, 8 Hz), 7.43 — 7.35 (1H, m), 7.32 (2H, ddd, 9 — 3 — 2 Hz), 7.19 (2H, ddd, 9 —3 Hz), 6.94 (2H, ddd, 9-4-2 Hz), 6.20(, 2 Hz). 8C NMR (151 MHz, 298 K, acetone-ds) & 166.1, 158.3, 156.3 (d, Jo-r=233 Hz), 141.7, 129.8, 129.4, 127.9, 120.8 (d, 23 Hz), 119.6 (d, 8 Hz) 118.9 (d, 8 Hz), 118.3 (d, 23 Hz), 91.4. Mass spectrum (ESI’) in MeCN,m / z (intensity %): calculated for [M + H]*: 367.1258; found: 367.1254 (100). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -29- 2.9 Synthesis of H2(5-Cl)salben ¢ Cl ~ NH,OAc Cl SN NZ Cl So OH MeOH OH HO benz H2(5-Cl)salben Benzaldehyde (81.1 mg, 0.764 mmol) was added to a supersaturated solution of ammonium acetate (0.9869 g, 12.80 mmol) in MeOH (3 mL) and stirred at RT for 5 min. 5-Cl- salH (200.6 mg, 1.281 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and iPr2O (3 x 3 mL) and dried under vacuum for lh. Yield 0.1567 g (61%). Elemental analysis calcd (%) for C21HieClz2N202:0.3 H20 (405.28): C 62.33, H 4.13, N 6.92. Found: C 62.33, H 3.96, N 6.82. Melting Point: 128 - 131 °C. 'H NMR (600 MHz, 298 K acetone-ds) & 13.05 (2H, s), 8.86 (2H, s), 7.60 — 7.54 (4H, m, 2 — 7 Hz), 7.49 — 7.40 (2H, m(dd), 7 Hz), 7.40 — 7.34 GH, m, 2 - 9 Hz), 6.95 (2H, d, 9 Hz),6.21 (1H, s). 3C NMR (151 MHz, 298 K, acetone-ds) 5 166.1, 160.7, 141.6, 133.6, 132.5, 129.9, 129.5, 127.9, 123.8, 120.8, 119.5, 91.2. Mass spectrum (ESI*) in MECN, m / z (intensity %): calculated for [M + Na]: 399.0667; found: 399.0661 (100). 2.10 Synthesis of H2(5-Me)salben M NH4OAc Me ~ 7 Me So OH MeOH OH HO benz H2(5-Me)salben Benzaldehyde (84.2 mg, 0.8015 mmol) was added to a supersaturated solution of ammonium acetate (0.8636 g, 11.20 mmol) in MeOH (2.5 mL) and stirred at RT for 5 min. 5-Me- salH (214.5 mg, 1.5755 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.2041 g (72%). Elemental analysis calcd (%) for C23H22N202:0.05 NHsOAc (362.29): C 76.58, H 6.22, N 7.93. Found: C 76.38, H 5.98, N 7.80. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -30- Melting Point: 125 - 130 °C. 'H NMR (400 MHz, 298 K, CDCls) 8 12.72 (2H,s), 8.53 (2H, s), 7.49 — 7.29 (SH, m), 7.16 (2H, dd, 8 — 2 Hz), 7.11 (2H, d, 2 Hz), 6.89 (2H, d, 8 Hz), 5.99 (1H, s), 2.29 (6H, s). Mass spectrum (ESI') in MeCN, m / z (intensity %): calculated for [M + H]": 359.1758; found: 359.1747 (100). 2.11 Synthesis of H2(3-OMe)sal(2-Cl)ben NH,OA 7 ci~ ° . So vee. SN ~N So OH MeOH OH HO 2-Cl-benz OMe OMe OMe H»(3-OMe)sal(2-Cl)ben 2-Cl-benzaldehyde (92.2 mg, 0.657 mmol) was added to a solution of ammonium acetate (0.8808 g, 11.40 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 3-OMe-salH (0.2085 g, 1.370 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.1431 g (51%). Elemental analysis calcd (%) for C23H21CIN2O4 (424.12): C 65.02, H 4.98, N 6.59. Found: C 64.56, H 4.91, N 6.54. 'H NMR (400 MHz, 298 K, acetone-ds) 5 13.00 (2H, s), 8.91 (2H, s), 7.72 (1H, dd, 1 - 8 Hz), 7.53 (1H, dd, 1 - 8 Hz),7.49 (1H, dd, 1 - 7 Hz), 7.43 (1H, dd, 2 - 7 H) 7.15 (2H, d, 8Hz), 7.11 (2H, d, 8 Hz), 6.89 (2H, dd, 8 Hz), 6.55 (1H, s), 3.85 (6H, s). °C NMR (101 MHz, 298 K, acetone-de) 8 166.7, 151.5, 148.5, 138.1, 132.6, 130.0, 129.2, 127.2, 124.1, 118.8, 118.6, 118.5, 115.8, 86.3, 55.6. IR-ATR (cm): 1613, 1600, 1459, 1317, 1252, 1171, 764, 728. Mass spectrum (ESI') in MeCN, mz (intensity %): calculated for [M + H]’: 425.1268; found: 425.1248 (60). 2.12 Synthesis of H2(5-OMe)sal(2-Cl)ben cl’ ' NH,OA MeO Z OMe So OH MeOH OH HO 2-Cl-benz H,(5-OMe)sal(2-Cl)ben SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -31- 2-Cl-benzaldehyde (0.1322 g, 0.8689 mmol) was added to a solution of ammonium acetate (0.21665 g, 2.038 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 5-OMe-salH (0.2864 g, 2.038 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered,washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.1278 g (32%). Elemental analysis calcd (%) for C23H21CIN2O4 (424.12): C 65.02, H 4.98, N 6.59. Found: C 64.78, H 4.95, N 6.51. 'H NMR (400 MHz, 298 K, acetone-ds) 6 12.34 (2H, s), 8.85 (2H, s), 7.71 (1H, dd, 8 — 2 Hz), 7.51 (1H, dd, 8 — 2 Hz), 7.47 (1H, dd, 8 - 2 Hz), 7.41 (1H, dd, 8 — 2 Hz), 7.12 (2H, d, 3 Hz), 7.02 (2H, dd, 9 — 3 Hz), 6.86 (2H, d, 9 Hz), 6.54 (1H, s), 3.76 (6H, s). 8C NMR (101 MHz, 298 K, acetone-ds) 5 166.7, 155.2, 152.5, 138.1, 132.6, 130.0, 129.2, 127.9, 120.6, 118.4, 117.6, 115.5, 115.4, 86.5, 55.2. IR-ATR (cm”?): 1634, 1584, 1487, 1329, 1266, 1225, 1165, 770. Mass spectrum (ESI') in MeCN, m / z (intensity %): calculated for [M + H]": 425.1268; found: 425.1248 (60). 2.13 Synthesis of H2(5-OMe)sal(2-OMe)ben who wh + MeO ‘So __NMAOAG : moe oer So Ch MeOH OH HO 2-OMe-benz H2(5-OMe)sal(2-OMe)ben 2-OMe-benzaldehyde (0.1349 g, 0.9584 mmol) was added to a solution of ammonium acetate (0.2294 g,2.977 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 5-OMe-salH (0.2883 g, 1.895 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.3028 g (76%). Elemental analysis calcd (%) for C24H24N2Os (420.47): C 68.75, H 5.75, N 6.62. Found: C 69.07, H 5.83, N 6.68. 'H NMR (400 MHz, 298 K, acetone-ds) 5 12.60 (2H, s), 8.78 (2H, s), 7.49 (1H, dd, 8 — 2 Hz), 7.35 (1H, dd, 9 Hz), 7.10 — 7.07 (3H, m), 7.03 (1H, dd, 6 Hz), 7.00 (2H, dd, 9 — 3 Hz), 6.85 (2H, d, 9 Hz), 6.50 (1H, s), 3.96 (3H, s) 3.76 (6H, s). 13C NMR (101 MHz, 298 K, acetone-ds) 5 165.7, 156.8, 154.9, 153.2, 152.8, 129.6, 128.6, 127.5, 120.8, 120.0, 118.6, 117.5, 115.4, 111.4, 84.2, 55.2. IR-ATR (cm): 1635, 1585, 1489, 1328, 1266, 1240, 1167, 760. Mass spectrum (ESI') in MeCN,7 / z (intensity %): calculated for [M + H]": 421.1764; found: 421.2400 (40). 2.14 Synthesis of H2(5-Cl)sal(2-OMe)ben SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -32- MeO NH4OA\ Cl 7 cl So OH MeOH OH HO 2-OMe-benz H,(5-Cl)sal(2-OMe)ben 2-OMe-benzaldehyde (0.1287 g, 0.9449 mmol) was added to a solution of ammonium acetate (0.2173 g, 2.819 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 5-Cl-salH (0.2918 g, 1.864 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.2996 g (76%). Elemental analysis calcd (%) for C22HigCl2N2O3 (429.30): C 61.35, H 4.23, N 6.53. Found: C 61.05, H 4.26, N 6.55. Melting Point (°C): 152 — 154. 'H NMR (400 MHz, 298 K, acetone-ds) & 13.23 (2H, s), 8.90 (2H, s), 7.63 (2H, d, 3 Hz), 7.55 (1H, dd, 8 - 2 Hz), 7.36-7.30 (3H, m), 7.09 (1H, d, 9 Hz), 7.05 (1H, ddd, 8 — 1 Hz), 6.90 (2H, d, 9 Hz), 6.50 (1H,s), 3.90 (3H, s). 3C NMR (101 MHz, 298 K, acetone-ds) § 166.9, 162.2, 157.9, 133.8, 133.4, 130.7, 129.6, 128.5, 121.8, 119.9, 119.8, 117.7, 112.3, 85.2, 56.1. IR-ATR (cm): 1606, 1521, 1453, 1384, 1297, 1242, 1165, 748. Mass spectrum (ESI') in MeCN, m / z (intensity %): calculated for [M + H]*: 429.0773; found: 429.0660 (40). 2.15 Synthesis of H2(5-OMe)sal(2-NO2)ben OoN* r So OH MeOH OH HO 2-NO2-benz H2(5-OMe)sal(2-NOz)ben 2-NO2-benzaldehyde (0.1390 g, 0.9199 mmol) was added to a solution of ammonium acetate (0.2212 g, 2.869 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 5-OMe-salH (0.2796 g, 1.837 mmol) was added to the colourless solution, and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.1957 g (49%). Elemental analysis calcd (%) for C23H21N3O¢ (435.42): C 63.24, H 4.86, N 9.65. Found: C 62.98, H 4.90, N 9.25. Melting Point (°C): 159 — 160. 'H NMR (400 MHz, 298 K,acetone-ds) & 12.20 (2H, s), 8.82 (2H, s), 8.01 (1H, d, 8 Hz), 7.97 (1H, dd, 8 — 1 Hz), 7.86 SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -33- (1H, dd, 7 - 1 Hz), 7.66 (1H, dd, 8 - 1 Hz), 7.11 (2H, d, 3 Hz), 7.01 (2H, dd, 9 — 3 Hz), 6.85 (2H, dd, 9 Hz), 6.66 (1H, s), 3.77 (6H, s). 8C NMR (101 MHz, 298 K, acetone-ds) 5 166.9, 156.7, 154.8, 153.4, 134.7, 133.7, 129.7, 129.6, 124.5, 120.8, 118.3, 117.6, 115.6, 84.7, 55.9. IR-ATR (cm'): 1626, 1586, 1525, 1489, 1370, 1338, 1158, 767. Mass spectrum (ESI*) in MeCN, m / z (intensity %): calculated for [M + H]*: 436.1483; found: 436.1493 (60). 2.16 Synthesis of H2(5-Cl)sal(2-NOz)ben L ok? ‘ “Cre NH,OAc oe. soe So OH MeOH OH HO 2-NO2-benz H,(5-Cl)sal(2-NO.)ben 2-NO2-benzaldehyde (0.0976 g, 0.646 mmol) was added to a solution of ammonium acetate (0.1677 g, 2.175 mmol) in MeOH (10 mL) and stirred at RT for 5 min. 5-Cl-salH (0.2096 g, 1.339 mmol) was added to the colourless solution,and the reaction mixture was stirred at RT for 3 h. The formed yellow solid was filtered, washed with MeOH (3 x 3 mL) and dried under vacuum for lh. Yield 0.477 g (50%). Elemental analysis calcd (%) for C22HisCl2N3O4 (443.27): C 56.77, H 3.40, N 9.46. Found: C 57.26, H 3.42, N 9.61. Melting Point (°C): 148 - 151. 'H NMR (400 MHz, 298 K, acetone-ds) 5 12.73 (2H, s), 8.80 (2H, s), 8.04 (1H, dd, 8 — 2 Hz), 7.99 (1H, dd, 7.8 - 13 Hz), 7.87 (1H, dd, 7 Hz), 7.69 (1H, dd, 8 Hz), 7.60 (2H, d, 3 Hz), 7.40 (2H, dd, 9 — 3 Hz), 6.95 (2H, d, 9 Hz), 6.73 (1H, s). 3C NMR (101 MHz, 298 K, acetone-ds) 8 167.7, 160.4, 150.3, 135.0, 134.9, 133.3, 132.5, 130.4, 129.6, 124.9, 124.0 120.06, 119.6, 84.5. IR-ATR (cm): 1616, 1559, 1520, 1473, 1342, 1199, 792, 751. Mass spectrum (ESI') in MeCN,mz (intensity %): calculated for [M + H]": 444.0417; found: 444.0505 (40). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -34- 3. Synthesis of the new copper(II) dinuclear complexes 3.1 Synthesis of [Cu2(p-sal(4-7Bu)ben)2| J, _ vou NS SN= TO —=N,, N= OH HO Et3N, EtOH Cu Hsal(4-Bu)ben [Cus(u-sal(4-tBu)ben)>] Et3N (0.109 g, 1.08 mmol) was added to a yellow suspension of H2sal(4- / Bu)ben (0.2021 g, 0.5229 mmol) in 8 mL of EtOH. Solid Cu(OAc)2°H20 (0.1017 g, 0.5094 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.1882 g of a brown solid (83%). Elemental analysis calcd (%) for CsoHagCu2N404:0.8EtOH (932.91): C 66.43, H 5.70, N 6.01. Found: C 66.51, H 5.70, N 6.01. IR-ATR (cm): 3047, 2964, 1606, 1533, 1466, 1387, 1317, 1192, 1147, 1107, 981, 928,827. Mass spectrum (ESI') in MeCN, m / z (intensity %): calculated for [M + H]’: 895.2346; found: 895.2327 (100). The ligand structure has been published in Rigamonti, L et al, Int. J. Mol. Sci. 2020, 21, 7882, DOL: :10.3390 / ijms21217882. 3.2 Synthesis of [Cu2(p-sal(2-OMe)ben)2] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -35- Cy, eh) _ cu MeO N ‘w= OMe 2 we SN N7 Cu(OAc), : Et,N, EtOH SN) OMe OH HO 3N, Ss, y Hzsal(2-OMe)ben [Cuz(p-sal(2-OMe)ben)>] Et3N (0.185 g, 1.83 mmol) was added to a yellow suspension of H2sal(2-OMe)ben (0.329 g, 0.922 mmol) in 14 mL of EtOH. Copper acetate monohydrate (0.184 g, 0.912 mmol) was then added obtaining a colour change to brown / green in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL), Et2O (2 « 2 mL) and dried under vacuum for several hours,yielding 0.354 g of a brown solid (92% yield). Elemental analysis for Ca4H36Cu2N40c, MW = 843.9 g / mol calculated: C 62.62%; H 4.30%; N 6.64%. Found: C 61.85%; H 4.34%, N 6.74%. IR spectrum, cm”! (ATR): 3044-3010, 1601, 1586, 1531-1490, 1387, 1318, 1242, 1147-1026, 751. Mass spectrum (ESI'), m / z (intensity %): 843 [Cu2(sal(2-OMe)ben)2 + 1]* (100). 3.3 Synthesis of [Cu2(p-sal(2,6-diO Me)ben)2] MeO \—\7""\___ / OMe MeO OMe \ oN ——— —N, N= OH HO EtsN, MeOH MeO ou Me ow” 4 ce) Hsal(2,6-diOMe)ben [Cuz(u-sal(2,6-diOMe)ben)>] Et3N (0.150 g, 1.48 mmol) was added to a yellow suspension of H2sal(2,6-diOMe)ben (0.290 g, 0.743 mmol) in 7 mL of MeOH. Copper acetate monohydrate (0.148 g, 0.742 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 30 minutes at 0 °C, and then the precipitate was isolated by filtration, washed with cold MeOH (2 x 2 mL),Et2O (2 x 2 mL) and dried under vacuum for SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -36- several hours, yielding 0.285 g of a brown solid (85% yield). Elemental analysis for CaeH4oCu2N4Og, MW = 903.94 g / mol calculated: C 61.12%; H 4.46%; N 6.20%. Found: C 60.82%; H 4.57%, N 6.19%. IR spectrum, cm”! (ATR): 3050-2840, 1604, 1528, 1470-1426, 1383, 1250, 1195, 1034-980, 758. Mass spectrum (ESI’), m / z (intensity %): 903 [Cun(sal(2,6- diOMe)ben)2 + 1]* (100). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -37- 3.4 Synthesis of [Cu2(p-sal(4-OMe)ben)2] OMe 0 Cy. 7 _ cu N \n= Sy NZ Cu(OAc)> Hoo Vn SX )-om TO —N, = OH HO EtsN, EtOH Jerr y Oo” ‘No Hysal(4-OMe)ben [Cuo(u-sal(4-OMe)ben)>] Et3N (0.138 g, 1.36 mmol) was added to a yellow suspension of H2sal(4-OMe)ben (0.245 g, 0.680 mmol) in 10 mL of EtOH. Copper acetate monohydrate (0.138 g,0.690 mmol) was then added obtaining a colour change to green / brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (3 mL), iPr2O (3 mL) and dried under vacuum for several hours, yielding 0.198 g of a brown solid (69% yield). Elemental analysis for C4s4H36Cu2NsO6, MW = 843.89 g / mol calculated: C 62.62%; H 4.30%; N 6.64%. Found: C 63.02%; H 4.34%, N 6.83%. IR spectrum, cm‘! (ATR): 3050-2835, 1607, 1534, 1467-1440, 1395, 1243, 1196, 1176, 1148, 1051-979, 750, 736. 3.5 Synthesis of [Cu2(p-sal(2-Cl)ben)2] (y>, ch) _ Cu cl =NU \y= Cl as SN NZ Cu(OAc), - \ —_——- =N, yy \ Cl OH HO Et,N, EtOH So oh y Hzsal(2-Cl)ben [Cuz(u-sal(2-Cl)ben)>] Et3N (0.156 g, 1.54 mmol) was added to a yellow suspension of H2sal(2-Cl)ben (0.255 g, 0.699 mmol) in 10 mL of EtOH. Copper acetate monohydrate (0.154 g,0.774 mmol) was then added obtaining a colour change to green-brown in a few minutes. After 3 h under stirring, further 5 mL of EtOH were added and then the reaction mixture was left under magnetic stirring SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -38- overnight at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 = 2 mL), Et2O0 (2 x 2 mL) and dried under vacuum for several hours, yielding 0.285 g of a brown solid (96% yield). Elemental analysis for C42H30Cl2Cu2Ns4O4, MW = 852.72 g / mol calculated: C 59.16%; H 3.55%; N 6.57%. Found: C 59.23%; H 3.46%, N 6.80%. IR spectrum, cm"! (ATR): 3058-2903, 1605, 1530, 1464-1430, 1319, 1270, 1194, 1149, 1035-978, 744. 3.6 Synthesis of [Cu2(p-sal(2)thn)2| Cee 4D — yr WO) Ss oN Ce “OC Cu(OAc), = \\_'s —__~ SN, Y / Y OH HO EtsN, EtOH S-6 PLY Hesal(2)thn [Cup(u-sal(2)thn)2] Et3N (2.11 g, 20.8 mmol) was added to a yellow suspension of Hzsal(2)thn (1.699 g,5.051 mmol) in 75 mL of EtOH. Copper acetate monohydrate (1.012 g, 5.070 mmol) was then added obtaining a colour change to brown in a few minutes. After 3 h under stirring at RT, the obtained dark brown solid was filtered, washed with EtOH (2 < 10 mL) and / Pr2O (2 x 10 mL) and dried under vacuum for several hours, yielding 1.398 g of the title compound (70%). Elemental analysis for C3gsH2sCu2z2N40482, MW = 795.88, calculated: C 57.35%, H 3.55%, N 7.04%, S 8.06%. Found: C 57.25%, H 3.54%, N 7.03%, S 8.19%. IR spectrum, cm! (ATR): 3084, 3016, 2894, 1602, 1531, 1465, 1437, 1393, 1344, 1320, 1241, 1190, 1145, 1123, 1033, 973, 750, 735, 707. Mass spectrum (ESI) in MeCN, 7 (intensity %): calculated for [M + H]": 795.0223; found: 795.0217 (100). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -39- 3.7 Synthesis of [Cu2(p-sal(3)thn)2] Ss __ vou A oe $n SKY SN, Yo OH HO Et,N, EtOH CS. mY Hesal(3)thn [Cu(u-sal(3)thn)o] Et3N (1.81 g,17.9 mmol) was added to a yellow suspension of H2sal(2)thn (1.706 g, 5.073 mmol) in 75 mL of EtOH. Copper acetate monohydrate (1.012 g, 5.072 mmol) was then added obtaining a colour change to brown in a few minutes. After 3 h under stirring at RT, the obtained dark brown solid was filtered, washed with EtOH (2 x 10 mL) and 7Pr2O (2 « 10 mL) and dried under vacuum for several hours, yielding 1.695 g of the title compound (84%). Elemental analysis for C3gsH2sCu2N4O0482, MW = 795.88, calculated: C 57.35%, H 3.55%, N 7.04%, S 8.06%. Found: C 57.11%, H 3.52%, N 7.10%, S 8.06%. IR spectrum, cm! (ATR): 3088, 3017, 2898, 1604, 1532, 1465, 1439, 1393, 1343, 1320, 1192, 1145, 1123, 1033, 974, 845, 751, 732. Mass spectrum (ESI") in MeCN, m / z (intensity %): calculated for [M + H]*: 795.0223; found: 795.0200 (100). 3.8.1 Synthesis of [Cu2(u-(R)-salC1myr)2] y-%, 9 __ oo NQ N= SH NZ Cu(OAc), Gg Vrs OH HO EtgN, EtOH ‘Ca o” No (R)-H2salmyr [Cu2(u-(R)-salmyr)a] Solid Cu(OAc)2:H20 (0.09931 g,0.497 mmol) was added to a yellow suspension of (R)- HosalC lmyr (0.20174 g, 0.539 mmol) in EtOH (8 mL) and NEts (0.11112 g, 1.10 mmol) and the resulting dark green / brown mixture was stirred at RT for 3 h. The formed dark brown solid was SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -40- filtered, washed with EtOH (3 x 3 mL) and iPr2O (3 x 3 mL) and dried under vacuum for 2 h. Yield: 0.10927 g (50%). Further title compound was isolated upon storing the reaction mixture in the fridge for 4 d (0.06016 g, 28%). Elemental analysis calcd (%) for CagHagsCu2N4O4 (872.03): C 66.11, H 5.55, N 6.43. Found: C 66.22, H 5.90, N 6.30. IR-ATR (cm): 2970, 2918, 2864, 1600, 1532, 1464, 1445, 1325, 1194, 1145, 1051, 979, 917, 849, 752. Mass spectrum (ESI’) in MeCN, mz (intensity %): calculated for [M + H]": 871.2346; found: 871.2319 (100). 3.8.2 Synthesis of [Cu2(u-(R)-salC1myr)2] Solid Cu(OAc)2°H20 (0.0544 g, 0.273 mmol) was added to a yellow suspension of (R)- HysalC lmyr (0.1023 g,0.273 mmol) in EtOH (4 mL) and NEts (0.0566 g, 0.559 mmol) and the resulting dark green / brown mixture was stirred at RT for 3 h. The formed dark brown solid was filtered, washed with EtOH (3 x 3 mL) and / Pr2O (3 x 3 mL) and dried under vacuum for 2 h. Yield: 0.09696 g (82%). Elemental analysis calcd (%) for CagHasCu2N404 -0.55H20 (881.94): C 65.37, H 5.61, N 6.35. Found: C 65.32, H 5.56, N 6.35. IR-ATR (cm ‘‘): 3015, 2974, 2926, 2827, 1608, 1533, 1464, 1440, 1348, 1318, 1246, 1194, 1147, 971, 925, 750. 3.9 Synthesis of [Cu2(u-(4-OMe)salben)2] MeO OMe O Yo On N= Z Cu(OAc), e) a?) “N N Or Ni N= EtsN, EtOH mares i MeO OH HO OMe on” SY ie) H,(4-OMe)salben MeO OMe [Cuz(u-(4-OMe)salben)>] Et3N (0.109 g, 1.08 mmol) was added to a yellow suspension of H2(4-OMe)salben (0.2333 g, 0.5974 mmol) in 8 mL of EtOH. Solid Cu(OAc)2°H20 (0.1216 g, 0.6090 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT,and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.1198 g of a light brown solid (44%). Elemental analysis calcd (%) for C4aeHaoCu2NaOg (903.94): C 61.12, H 4.46, N 6.20. Found: C SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -4]- 61.15, H 4.57, N 5.86. IR-ATR (cm): 3002, 2936, 2839, 1592, 1520, 1485, 1439, 1314, 1217, 1117, 1025, 975, 832. 3.10 Synthesis of [Cu2(u-(5-OMe)salben)2] O OMe woo YO, / 4 id MeO > Z OMe Cu(OAc)e | eS) F \ o N N N N= EtsN, EtOH maar i y OH HO MeO Oo” No OMe H2(5-OMe)salben [Cuz(u-(5-OMe)salben)s] Etz3N (54.5 mg, 0.538 mmol) was added to a yellow suspension of H2(5-OMe)salben (0.1005 g, 0.2575 mmol) in 4 mL of EtOH. Solid Cu(OAc)2°H20 (0.05171 g, 0.2590 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration,washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.08951 g of a brown solid (77%). Elemental analysis calcd (%) for CasH4oCu2N4Ox (903.94): C 61.12, H 4.46, N 6.20. Found: C 60.97, H 4.43, N 6.13. IR-ATR (cm): 3062, 2928, 2827, 1623, 1592, 1532, 1456, 1307, 1215, 1157, 1026, 975, 813, 700. Mass spectrum (ESI") in MeCN, mz (intensity %): calculated for [M + H]*: 903.1517; found: 903.1331 (100). 3.11 Synthesis of [Cu2(u-(5-F)salben)2] O F ha N N= F C Z F Cu(OAc)z um SKY N N > N N= Et,N, EtOH mare if OH HO : Oo” \o% c H,(5-F)salben [Cua(u-(5-F)salben)s] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -42- Et3N (57.4 mg, 0.57 mmol) was added to a yellow suspension of H2(5-F)salben (0.1004 g, 0.2742 mmol) in 4 mL of EtOH. Solid Cu(OAc)2°H20 (0.0564 g, 0.282 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration,washed with EtOH (2 = 2 mL) and dried under vacuum for several hours. Yield: 0.0945 g of a brown solid (81%). Elemental analysis calcd (%) for Ca2H2gCu2F4N4O« (855.80): C 58.95, H 3.30, N 6.53. Found: C 58.91, H 3.17, N 6.53. IR-ATR (cm): 3053, 3004, 2897, 1607, 1538, 1457, 1393, 1310, 1241, 1209, 1141, 1002, 925, 865, 812. 3.12 Synthesis of [Cu2(p-(5-Cl)salben)2| O Cl —\11% N SN= cl Sy ey c) _CulOAc), CNovng i? oe Ser Et,N, EtOH We i OH HO cI o” No cI H2(5-Cl)salben [Cuz(u-(5-Cl)salben)s] Et3N (105.3 mg, 1.04 mmol) was added to a yellow suspension of H2(5-Cl)salben (0.2015 g, 0.5048 mmol) in 8 mL of EtOH. Solid Cu(OAc)2°H20 (0.10236 g, 0.5127 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration,washed with EtOH (2 = 2 mL) and dried under vacuum for several hours. Yield: 0.2074 g of a brown solid (89%). Elemental analysis caled (%) for C42H2sCu2Cl4N4O4 (921.60): C 54.34, H 3.06, N 6.08. Found: C 54.37, H3.03, N 5.99. IR-ATR (cm): 3061, 2899, 1609, 1521, 1449, 1309, 1172, 1099, 976, 941, 876, 772. Mass spectrum (ESI’) in MeCN, 7 / z (intensity %): calculated for [M + H]": 942.9325: found: 942.9382 (100). SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -43- 3.13 Synthesis of [Cu2(p-(5-Me)salben)2] __ vou NO N= Me SN NZ Me _CU(OAc)e OueN XD OH HO Me Oo” \o_% Me H2(5-Me)salben [Cus(u-(5-Me)salben)>] Et3N (61.7 mg, 0.609 mmol) was added to a yellow suspension of H2(5-Me)salben (0.1019 g, 0.2843 mmol) in 4 mL of EtOH. Solid Cu(OAc)2°H20 (0.0568 g, 0.284 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration,washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.1001 g of a brown solid (84%). Elemental analysis calcd (%) for CasHaoCu2N4Oa (839.94): C 65.78, H 4.80, N 6.67. Found: C 65.78, H 4.75, N 6.64. IR-ATR (cm): 3059, 3004, 2911, 2853, 1619, 1529, 1468, 1382, 1313, 1251, 1137, 1045, 974, 824, 759. Mass spectrum (ESI') in MeCN, m / z (intensity %): calculated for [M + H]": 839.1720; found: 839.1714 (100). 3.14 Synthesis of [Cu2(u-(4-OMe)sal(2-Cl)ben)2] MeO OMe 10) —_1 1% Cl =N N= Cl PTT Z Cu(OAc)> 5 “SN N TO N N= Cl Et,N, EtOH Oo MeO OH HO OMe ow” 4 oO H»(4-OMe)sal(2-Cl)ben 2 MeO OMe [Cuo(u-(4-OMe)sal(2-Cl)ben)>] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -44- Et3N (54.5 mg, 0.538 mmol) was added to a yellow suspension of H2(4-OMe)sal(2-Cl)ben (0.1099 g, 0.2587 mmol) in 4 mL of EtOH. Solid Cu(OAc)2°H20 (0.05256 g,0.2633 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 < 2 mL) and dried under vacuum for several hours. Yield: 0.0672 g of a brown solid (52%). Elemental analysis calcd (%) for CasH3gCl2Cu2N4Os'H20 (990.84): C 55.76, H 4.07, N 5.65. Found: C 55.85, H3.85, N 5.45. IR-ATR (cm): 3059, 3004, 2911, 2853, 1619, 1595, 1529, 1468, 1382, 1313, 1251, 1215, 1163,1137, 1045, 974, 824, 759. 3.15 Synthesis of [Cu2(u-(5-OMe)sal(2-Cl)ben)2] Wek JP, ohm AP CI=NZ \y= MeO SN N~ ome oe O a N= OH HO neo C90" wae H»(5-OMe)sal(2-Cl)ben [Cug(u-(5-OMe)sal(2-Cl)ben)>] Et3N (36.4 mg, 0.359 mmol) was added to a yellow suspension of H2(5-OMe)sal(2-Cl)ben (0.7146 g, 0.1685 mmol) in 3 mL of EtOH. Solid Cu(OAc)2:H20 (0.0330 g,0.165 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.07628 g of a brown solid (95%). Elemental analysis calcd (%) for CasH3sCl2Cu2N4Og (972.82): C 56.79, H 3.94, N 5.76. Found: C 56.85, H 4.00, N 5.73. IR-ATR (cm): 2831, 1624, 1594, 1532, 1470, 1307, 1218, 1159, 1031, 973, 952, 824, 755. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -45- 3.16 Synthesis of [Cu2(u-(5-OMe)sal(2-OMe)ben)2| MeO Vj O,,, YP OMe _ vo MeO N N= MeO TT MeO n Z OMe _CU(OAc)2 : N N Ni N= OM EtsN, EtOH —G a e OH HO Meo o” \o_% OMe H2(5-OMe)sal(2-OMe)ben [Cu(u-(5-OMe)sal(2-OMe)ben)s] EtsN (98.0 mg, 0.969 mmol) was added to a yellow suspension of H2(5-OMe)sal(2- OMe)ben (0.2004 g, 0.4763 mmol) in 8 mL of EtOH. Solid Cu(OAc)2°H20 (0.0951 g,0.0968 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 <x 2 mL) and dried under vacuum for several hours. Yield: 0.2091 g of a brown solid (91%). Elemental analysis calcd (%) for CagH44CuzNaO10 (963.99): C 59.81, H 4.60, N 5.81. Found: C 60.28, H 4.51, N 5.82. IR-ATR (cm): 3053, 2832, 1622, 1597, 1533, 1459, 1392, 1306, 1246, 1219, 1158, 1207, 953, 824, 754. Mass spectrum (ESI*) in MeCN, m / z (intensity %): calculated for [M + H]*: 963.1728; found: 963.1677 (100). 3.17 Synthesis of [Cu2(u-(5-Cl)sal(2-OMe)ben)2] O Cl Cl y, O., y Meo ‘=n \ N= MeO ATT OW eA A eo LulOAcde E N N Ni N= OM Et,;N, EtOH mare f e OH HO CI Oo” ‘ol cl H2(5-Cl)sal(2-OMe)ben [Cu(y-(5-Cl)sal(2-OMe)ben).] SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -46- Et3N (98.0 mg,0.969 mmol) was added to a yellow suspension of H2(5-Cl)sal(2-OMe)ben (0.1929 g, 0.1685 mmol) in 8 mL of EtOH. Solid Cu(OAc)2:H20 (0.0940 g, 0.471 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 = 2 mL) and dried under vacuum for several hours. Yield: 0.2088 g of a brown solid (94%). Elemental analysis calcd (%) for C44H32ClaCu2NaO0c (981.65): C 53.84, H 3.29, N 5.71. Found: C 53.74, H 3.26, N 5.60. IR-ATR (cm): 2960, 2839, 1611, 1520, 1483, 1457, 1311, 1241, 1172, 1043, 982, 823, 740. 3.18 Synthesis of [Cu2(u-(5-Cl)sal(2-NOz)ben)2| oY chy _ ou O2N SS “1 SN N~ a ue O é N= ioe Ser EtsN, EtOH muna tf NO2 OH HO oC So No i \ Ci H,(5-Cl)sal(2-NO>)ben [Cus(y-(5-Cl)sal(2-NO»)ben)s] Et3N (94.4 mg, 0.933 mmol) was added to a yellow suspension of H2(5-Cl)sal(2-NO2)ben (0.2046 g,0.460 mmol) in 8 mL of EtOH. Solid Cu(OAc)2:H20 (0.0898 g, 0.450 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 = 2 mL) and dried under vacuum for several hours. Yield: 0.2123 g of a brown solid (93%). Elemental analysis calcd (%) for C42H2eClaCu2NoOg (1011.60): C 49.87, H 2.59, N 8.31. Found: C 49.63, H 2.55, N 8.00. IR-ATR (cm): 1610, 1520, 1384, 1311, 1175, 1036, 978, 829, 765. SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -47- 3.19 Synthesis of [Cu2(p-(5-OMe)sal(2-NOz)ben)2| (0) OMe Meo YO / 4 NO-NO \y— O2N TTT \ MeO nw Z OMe CuOAc)2 : N N Ni N= No EtsN, EtOH Nef} 2 OH HO Meo 0” o oMe H2(5-OMe)sal(2-NO,)ben [Cus(y-(5-OMe)sal(2-NO)ben)o] Et3N (69.0 mg, 0.682 mmol) was added to a yellow suspension of H2(5-OMe)sal(2- NO2)ben (0.1435 g, 0.330 mmol) in 5.5 mL of EtOH. Solid Cu(OAc)2:H20 (0.0665 g,0.333 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL) and dried under vacuum for several hours. Yield: 0.141 g of a brown solid (82%). Elemental analysis calcd (%) for CasH3gCu2NeO12- EtOH (1040.00): C 55.44, H 4.29, N 8.08. Found: C 55.06, H3.94, N 7.81. IR-ATR (cm): 2853, 1625, 1596, 1525, 1467, 1339, 1302, 1271, 1218, 1160, 1032, 954, 811, 766. 3.20 Synthesis of [Cu2(u-(sal(2-NOz)ben)2] _ cu O2N nin \ Z Cu(OAc)> 5 “N N TO Ni N= No EtsN, EtOH eG i 2 OH HO o” No Hysal(2-NO»)ben [Cua(y-sal(2-NO})ben)>] Et3N (58.1 mg, 0.574 mmol) was added to a yellow suspension of H2sal(2-NO2)ben (0.100 g, 0.266 mmol) in 4 mL of EtOH. Solid Cu(OAc)2°H20 (0.050 g,0.275 mmol) was then added obtaining a colour change to brown in a few minutes. The reaction mixture was left under magnetic SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -48- stirring for 3 h at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL) and dried under vacuum for 1 h. Yield: 0.1022 g of a brown solid (43.9%). Elemental analysis calcd (%) for CazH30Cu2NoOs (873.82): C 57.73, H 3.46, N 9.62, O 14.65. Found: C 57.5, H 3.6, N 9.6, O 14.7. IR-ATR (cm7?): 3039, 3021, 2940, 2904, 1605, 1522, 1464, 1443, 1339, 1319, 1194, 1147, 1126, 1027, 979, 851, 751, 741, 713. Mass spectrum (ESI) in MeCN, mz (intensity %): calculated for [M + CH3CN + NHq‘]": 931.1327; found: 931.1322 (100). 4. C-N coupling reactions 4.1 Coupling of iodobenzene with pyrazole with Cs2CQs as base Under inert atmosphere, iodobenzene (215 uL, 1.93 mmol, 1.5 equiv) and pyrrole (90 uL, 1.29 mmol, 1 equiv) were added to a suspension of Cs2CO3 (839.2 mg, 2.58 mmol,2 equiv) and [Cu2(u-salben)2] (5 mg, 6.45 x 10° mmol, 0.005 equiv) in 1 mL of MeCN in a 10 mL tube with screw cap. The tube was closed and heated with an oil bath at 82°C and the reaction mixture was stirred for 16 h. The suspension was allowed to cool to RT and then the solvent was removed under reduced pressure. The obtained residue was treated with 10 mL of dichloromethane (DCM), the resulting suspension was filtered on a paper filter, and the remaining solid was washed with DCM (2 x 5 mL). The organic phase was concentrated under reduced pressure to obtain the crude product as a brown liquid that was purified via flash column chromatography on silica gel to afford 153 mg of the desired product (83% yield). The identity of the product was confirmed by comparison of the 'H NMR spectrum with the commercially available sample. 'H NMR, 298 K, CDCl3, 400 MHz: 6 (ppm) 7.45-7.38 (4H, m), 7.27-7.23 (1H, m), 7.09 (2H, t), 6.35 (2H,t). 4.2 Coupling of iodobenzene with pyrazole with K3POs as base Under inert atmosphere, 1iodobenzene (720 uL, 6.47 mmol, 1.5 equiv) and pyrrole (300 uL, 4.29 mmol. 1 equiv) were added to a suspension of K3POx4 (17.2 mmol, 3.65 g, 4 equiv) and [Cu2(u-salben)2] (0.0429 mmol, 33.6 mg, 0.010 equiv) in 3 mL of MeCN in a 50 mL tube with screw cap. The tube was closed and heated with an oil bath at 82°C and the reaction mixture was stirred for 16 h. The suspension was allowed to cool to RT and then the solvent was removed under reduced pressure. The obtained residue was treated with 10 mL of DCM, the obtained suspension was filtered on a paper filter,and the remaining solid was washed with DCM (2 =< 5 mL). The organic phase was concentrated under reduced pressure to obtain the crude product as SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -49- a brown liquid. The residual oil was purified via flash column chromatography on silica gel to afford 521 mg of the desired product (85% yield). The identity of the product was confirmed by comparison of the 'H NMR spectrum with a commercially available sample. 'H NMR, 298 K, CDCl3, 400 MHz: & (ppm) 7.45-7.38 (4H, m), 7.27-7.23 (1H, m), 7.09 (2H, t), 6.35 (2H, t). 4.3 General procedure for the screening of solvents and bases Under inert atmosphere, a 10 mL tube was charged with the base and the catalyst. The solvent was added (1 mL), and iodobenzene and pyrrole were added to the resulting suspension. The tube was closed and heated at the indicated temperature. After the indicated time,the tube was allowed to cool to RT. The suspension was filtered with a syringe on a 0.45 um PTFE filter. The solid on the filter was washed with the reaction solvent (3 x 3 mL). The filtrated was concentrated under reduced pressure to obtain the crude product. The external standard solution (1 mL of a 0.429 mol L~ ' CDCl; solution of dimethylsulfone) was added, 150 uL of the so- obtained solution were diluted to 700 wL with CDCl; in an NMR tube, and the 'H NMR spectrum was registered to calculate the yield. 4.4 General procedure for the coupling of aryl halides with N-nucleophiles Under inert atmosphere, a screw-cap glass tube equipped with a stirring bar was charged with the base, the catalyst and the solvent. To the suspension,the N-nucleophile and the aryl halide were added. The tube was closed and heated at the indicated temperature for the indicated time. The reaction mixture was filtered over 0.45 um PTFE Syringe-Filter and the filter washed with MeCN (1-2 mL). LC-MS sample was prepared from resulting solution. Optionally, the solvent was evaporated, and the crude product purified by chromatography for additional characterization. 4.5 Characterization data for product Arylhalide | _N-Nucleophile | = OMe HN ene MS (EI’): mz 174.1 a [M+1]° OMe | — ww (ro MS (EI'): mz 174.1 a [M+1]° OMe MeO SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -50- | = = | MS (EI): m / z 174.1 CO re neo) | Iver OMe | N No ZA ww) Zz MS (EI'): m / z 169.1 A [M+1]° \ N Nl = wd) NO MS (EI'): m / z 169.1 Z y [M+] Sn N | = _ = | MS (EI'): m / z 169.1 ¢ wn) n= VN] ate Il N | = — +\, kn ww) (Vo MS (EI’): m / z 145.1 | A =N [M+1] ZA | = VN ‘eo MS (EI*): mz 145.1 CO ne ()- Z [M+1]" ZN = i S MS (EI'): m / z 145.0 ~ e we ee Z [M+1]° eA,N | MS (EI'): m / z 148.1 OQ wn) ene [M+]° TH NMR, 298 K, CDCls, 400 MHz: 8 (ppm) 7.87 (s, 1 H), un CNS} | rar 736030 41 - 7.36 (m, , 4 2 7.30 (s, 1H), 7.22 (s, 1 H). MS (EI'): m / z 145.0 [M+1]" SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 5]- | N= N= MS (EI'): m / z 145.0 | N N N= Ns MS (EI'): m / z 146.1 HN N OQ 2 ()- - [M+1]' | f°) fe) MS (EI'): m / z 198.2 | H H2N N MS (EI'): m / z 170.1 oto ss | ame MS (EI'): m / z 184.1 oO [M+1]" | OQ, 0 Hanes C1 eye MS (EI'): m / z 234.1 mC) enenua Br Ox LOH ae L oO MS (EI’): m / z 164.2 + NH, N [M-1] "HNMR, 298 K, CDCls, 600 MHz: 8 Br (ppm) 7.73 - 7.75 (m, 1 H), 7.70 - 7.77 (m, 1 = _ =) | H), 7.48 - 7.54 (m, 2 re N= t \ ce H), 7.15 - 7.17 (m, 1 i H), 7.15 - 7.19 (m, 1 N H), 6.41 - 6.45 (m, 2H) MS (EI'): m / z 168.1 [M]" 'H NMR, 298 K, CDCls, 600 MHz: 8 Br ALN Ch (ppm) 7.43 - 7.48 (m, 1 2 26 N H), 7.36 - 7.38 (m, 3 H H), 7.29 - 7.33 (m, 1 H), 7.18 - 7.23 (m, 2 H), 6.75 (tt, J= 7.3,1.1 SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 -52- Hz, 1 H), 6.67 - 6.69 (m, 2 H), 4.36 (s, 2H), 3.91 - 4.19 (m, 1 H) MS (EI'): m / z 183.1 [M]* Br HN] (VW MS (EI'): m / z 148.0 [M+1]° Br we HN oF | MS (ET): m / z 166.0 cr ¢\- N] [M+1]* Br mo JL, MS (EI’): m / z 228.1 o” N ot Br i SN fo) Ise \NHa we NK MS ESI": m / z 409.1 NY : Lo | iar RM] HOT No R NO SUBSTITUTE SHEET (RULE 26) WO 2025 / 016888 PCT / EP2024 / 069763 52 Claims 1. Process for the coupling of aryl halogenides with an N-nucleophile compound in the presence of dinuclear copper(I) complexes bearing substituted salben-type ligands of the formula I 1 G2 e — = re) 0 Cg hI —_ Ww” u NU ‘y= R11 ties aw Sa R2 i, N= Cu CS \o 4 N Gs — 74 I wherein R! and R’ are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl, or hydrogen and G', G’, G? and G* are the same or different and hydrogen or one or more substituents selected from C1-12-alkyl, C1-12-alkoxy, halogen C1-12-alkyl, halogen,mono- or di- C1-12-alkyl amino, carboxyl, Cj-12 alkoxy carbonyl or nitro or G!, G?, G* and G*, independently of each other, together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl, C1- 6-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro. 2. Process of claim 1, wherein R'! and R’ are the same and are substituents of the formula Ila, Ib or Hc Rs 1 Ra XN 2 Q an xX R Rg A BNE R10 R R xp? we Rg n lla lib lic WO 2025 / 016888 PCT / EP2024 / 069763 53 wherein R?, R*, R°, R° and R’ are the same or different and are hydrogen, C1-12-alkyl, C1-12- alkoxy, halogen, halogen-C1-12-alkyl, mono- or di- C1-12-alkyl amino, nitro or R* and R‘ or R* and R° or R° and R° or R° and R’ together with the phenyl ring they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl,C1-6-alkoxy, halogen, mono- or di- C1-6-alkyl amino or nitro, X!, X?, X?, X* and X° are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; nis Oor 1; R*, R? and R"™ are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R® and R’ together form a saturated carbocycle or a heterocycle or R®, R’ and R" together form an unsaturated carbocycle. 3. Process of claim 1 or 2, wherein the aryl halogenide has the formula II R19 Zz xé mia x10" at x8 7 R23 bef \ a | n R22 Hh} wherein X°, X7, X®, X° and X!° are the same or different and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulphur; RR” R?! R” and R” are the same or different and are hydrogen, C1-12-alkyl, C2-12- alkenyl, C2-12-alkinyl, C1-12-alkoxy, halogen, halogen-C1-12-alkyl, mono- or di- C1-12-alkyl amino or cyano,or R’’and R”’ or R”’and R”! or R?! and R” or R” and R* together with the ring WO 2025 / 016888 PCT / EP2024 / 069763 54 they are attached to form a fused aryl ring with two or three rings, which are optionally substituted with one or more substituents selected from C1-6-alkyl, Ci-c-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro; nis 0 or 1 and Z is a halogen atom. 4. Process of any one of claims 1 to 3, wherein the N-nucleophile can be selected from compounds of the formulae “7s av Jt Re OS sa RIE RIE ON OF HN* x’?,

Claims

1. A method for coupling an aryl halide with an N-nucleophile compound in the presence of a dinuclear copper(II) complex of formula I with a substituted salben-type ligand. Where R 1 and R 2 For the same or different, and for C that is optionally substituted 1-12 -alkyl, aryl or heteroaryl, or hydrogen, and G 1 G 2 G 3 and G 4 Whether the same or different, and whether it is hydrogen or selected from C 1-12 -alkyl, C 1-12 -alkoxy group, halogen C 1-12 -alkyl, halogen, mono- or di-C 1-12 -alkylamino, carboxyl, C 1-12 One or more substituents of alkoxycarbonyl or nitro, or G 1 G 2 G 3 and G 4 Each ring independently forms a fused aryl ring with two or three rings together with the phenyl ring to which it is attached, wherein the two or three rings are optionally selected from C 1-6 -alkyl, C 1-6 -alkoxy, halogen, mono- or di-C 1-6 -One or more substituents of alkylamino or nitro groups.

2. The method according to claim 1, wherein R 1 and R 2 Substituents of the same type and of formula IIa, IIb or IIc in R 3 R 4 R 5 R 6 and R 7 For the same or different, and for hydrogen, C 1-12 -alkyl, C 1-12 -alkoxy groups, halogens, halogen-C 1-12 -alkyl, mono- or di-C 1-12 -alkylamino, nitro, or R 3 and R 4 Or R 4 and R 5 Or R 5 and R 6 Or R 6 and R 7 Together with the phenyl rings they are attached to, they form a fused aryl ring having two or three rings, said two or three rings optionally selected from C 1-6 -alkyl, C 1-6 -alkoxy, halogen, mono- or di-C 1-6 -One or more substituents of alkylamino or nitro groups are used for substitution. X 1 X 2 X 3 X 4 and X 5 They may be the same or different, and represent at least one heteroatom selected from nitrogen, oxygen or sulfur; n is 0 or 1; R 8 R 9 and R 10 For the same or different, and for hydrogen, C 1-12 -alkyl, halogen C 1-12 -alkyl, hydroxyl, hydroxy-C 1-12 -alkyl, halogen, or R 8 and R 9 Together they form saturated carbon rings or heterocycles, or R 8 R 9 and R 10 Together they form an unsaturated carbon ring.

3. The method according to claim 1 or 2, wherein the aryl halide has formula III in X 6 X 7 X 8 X 9 and X 10 They may be the same or different, and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulfur; R 19 R 20 R 21 R 22 and R 23 For the same or different, and for hydrogen, C 1-12 -alkyl, C 2-12 -Alkenyl, C 2-12 -Alynyl group, C 1-12 -alkoxy groups, halogens, halogen-C 1-12 -alkyl, mono- or di-C 1-12 -alkylamino or cyano, or R 19 and R 20 Or R 20 and R 21 Or R 21 and R 22 Or R 22 and R 23 Together with the rings they are connected to, they form a fused aryl ring having two or three rings, said two or three rings optionally selected from C 1-6 -alkyl, C 1-6 -alkoxy, halogen, mono- or di-C 1-6 -One or more substituents of alkylamino or nitro groups are used; n is 0 or 1, and Z represents a halogen atom.

4. The method according to any one of claims 1 to 3, wherein the N-nucleophile may be selected from compounds of the following formula: in R 11 R 12 R 13 R 14 R 15 R 16 R 17 and R 18 For the same or different, and for hydrogen, C 1-12 -alkyl, C 1-12 -alkoxy, aryl, halogen, halogen-C 1-12 -alkyl, nitro, hydroxyl, mono- or di-C 1-12 -alkylamino, or R 15 and R 16 Together with the nitrogen atoms they are attached to, they form saturated heterocyclic 5- or 6-membered heterocycles; X 11 X 12 X 13 and X 14 For the same or different, and indicating optional C 1-12 -alkyl, aryl-C 1-12 -alkyl, C 1-6 -alkoxy groups, halogens, halogen-C 1-12 - An alkyl-substituted carbon atom and at least one other heteroatom selected from nitrogen, oxygen or sulfur.

5. The method according to any one of claims 1 to 4, wherein a base is present, said base being selected from alkali metal salts of inorganic or organic acids or from alkali metal alkoxides.

6. The method according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of an organic solvent at a reaction temperature between 20°C and 200°C.

7. A binuclear copper(II) complex having a substituted salben-type ligand of Formula I in R 1 and R 2 For the same or different, and for C that is optionally substituted 1-12 -alkyl, aryl or heteroaryl, or hydrogen, and G 1 G 2 G 3 and G 4 For the same or different, and representing hydrogen or selected from C 1-12 -alkyl, C 1-12 -alkoxy groups, halogens, halogen C 1-12 -alkyl, mono- or di-C 1-12 -alkylamino, carboxyl, C 1-12 One or more substituents of -alkoxycarbonyl or nitro, or G 1 G 2 G 3 and G 4 Each ring independently forms a fused aryl ring with two or three rings together with the phenyl ring to which it is attached, wherein the two or three rings are optionally selected from C 1-6 -alkyl, C 1-6 -alkoxy, halogen, mono- or di-C 1-6 -One or more substituents of alkylamino or nitro groups are used; R 1 and R 2 For the same, and for substituents of formula IIa, IIb or IIc R 3 R 4 R 5 R 6 and R 7 For the same or different, and for hydrogen, C 1-12 -alkyl, C 1-12 -alkoxy groups, halogens, halogen-C 1-12 -alkyl, mono- or di-C 1-12 -alkylamino, nitro, or R 3 and R 4 Or R 4 and R 5 Or R 5 and R 6 Or R 6 and R 7 Together with the phenyl rings they are attached to, they form a fused aryl ring having two or three rings, said two or three rings optionally selected from C 1-6 -alkyl, C 1-6 -alkoxy, halogen, mono- or di-C 1-6 -One or more substituents of alkylamino or nitro groups are used; X 1 X 2 X 3 X 4 and X 5 They may be the same or different, and represent at least one heteroatom selected from nitrogen, oxygen or sulfur; n is 0 or 1; R 8 R 9 and R 10 For the same or different, and for hydrogen, C 1-12 -alkyl, halogen C 1-12 -alkyl, hydroxyl, hydroxy-C 1-12 -alkyl, halogen, or R 8 and R 9 Together they form saturated carbon rings or heterocycles, or R 8 R 9 and R 10 Together they form unsaturated carbon rings. The condition is to exclude R. 1 and R 2 It is hydrogen, or R 1 and R 2 Having the formula IIa and wherein R 3 R 4 R 6 and R 7 It is hydrogen, and R 5 Compounds that are hydrogen, chlorine, methyl, or nitro groups.