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WO2025016888A1 - C-N COUPLING PROCESS WITH [CU 2(µ-SALBEN) 2] COMPLEXES - Google Patents

C-N COUPLING PROCESS WITH [CU 2(µ-SALBEN) 2] COMPLEXES Download PDF

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WO2025016888A1
WO2025016888A1 PCT/EP2024/069763 EP2024069763W WO2025016888A1 WO 2025016888 A1 WO2025016888 A1 WO 2025016888A1 EP 2024069763 W EP2024069763 W EP 2024069763W WO 2025016888 A1 WO2025016888 A1 WO 2025016888A1
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alkyl
halogen
mmol
hydrogen
same
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French (fr)
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Serena Maria FANTASIA
Lorenzo MARCHI
Luca RIGAMONTI
Markus Steiner
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
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    • C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages

Definitions

  • 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 wherein R 1 and R 2 are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl or hydrogen, and G 1 , G 2 , G 3 and G 4 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- C1-12-alkyl amino, carboxyl, C1-12 alkoxy carbonyl or nitro or G 1 , G 2 , G 3 and G 4 , independently of each other, together with the phenyl ring they are attached to form a fused
  • the inventions also relates to novel dinuclear copper(II) complexes bearing substituted salben-type ligands of the formula I, wherein R 1 and R 2 are the same and are substituents of the formula IIa, IIb or IIc wherein R 3 , R 4 , R 5 , R 6 and R 7 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 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 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 1 , X 2 , X 3 , X 4 and X 5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1; R 8 , R 9 and R 10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R 8 and R 9 together form a saturated carbocycle or a heterocycle or R 8 , R 9 and R 10 together form an unsaturated carbocycle, with the proviso that compounds with R 1 and R 2 being hydrogen, or R 1 and R 2 having the formula IIa and wherein R 3 , R 4 , R 6 and R 7 are hydrogen, while R 5 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 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.
  • 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.
  • 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.
  • 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.
  • halogen-C1-12-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.
  • aryl relates to an aromatic carbon ring such as to the phenyl, naphthyl ring anthracenyl or phenanthrenyl ring, preferably the phenyl ring.
  • 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, quinolinyl and isoquinolinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, thiazolyl or imidazolyl.
  • 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 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.
  • 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 can be defined with the formula III wherein X 6 , X 7 , X 8 , X 9 and X 10 are the same or different and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulphur; R 19 , R 20 , R 21 , R 22 and R 23 are the same or different and are hydrogen, C1-12-alkyl, C2-12- alkenyl, C2-12-alkynyl, C1-12-alkoxy, halogen, halogen-C1-12-alkyl, mono- or di- C1-12-alkyl amino 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 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- C
  • aryl halogenides X 6 , X 7 , X 8 , X 9 and X 10 are the same or different and represent carbon or one nitrogen atom; R 19 , R 20 , R 21 , R 22 and R 23 are the same or different and are hydrogen, methyl, methoxy or cyano; n is 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
  • R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 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 15 and R 16 together with the nitrogen they are attached to form a saturated 5-or 6- member heterocycle;
  • X 11 , X 12 , X 13 and X 14 are the same or different and represent a carbon atom optionally substituted with C1-12-alkyl, aryl-C1-12-alkyl, C1-12-alkoxy, halogen, halogen-C1-12-alkyl and at least one further heteroatom selected from nitrogen, oxygen or sulphur.
  • N-nucleophiles have the formula IVc, IVd, IVe, wherein R 15 , R 16 , R 17 and R 18 are the same or different and are hydrogen, C 15 1-6-alkyl, aryl, or R and R 16 together with the nitrogen they are attached to form a saturated heterocycle 5-or 6- member heterocycle; X 11 , X 12 , X 13 and X 14 are the same or different and represent a carbon atom optionally substituted with C1-12-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(II) complexes bearing substituted salben-type ligands having the formula I
  • R 1 and R 2 are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl, or hydrogen and G 1 , G 2 , G 3 and G 4 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- C1-12-alkyl amino, carboxyl, C1-12-alkoxy carbonyl or nitro or G 1 , G 2 , G 3 and G 4 , 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- C1-6-alkyl amino or nitro.
  • G 1 , G 2 , G 3 and G 4 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, N.N-dimethylamino, N.N-diethylamino, carboxyl, methoxy carbonyl, ethoxy carbonyl, i-propoxy carbonyl, n-butoxy carbonyl, t-butoxy carbonyl, nitro or G 1 , G 2 , G 3 and G 4 , independently of each other, together with the phenyl ring they are attached to form a fused aryl ring.
  • R 1 and R 2 are the same and are substituents of the formula IIa, IIb or IIc
  • Preferred substituents of formula IIa are those wherein R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, chlorine, bromine, trifluoromethyl, N.N-dimethylamino, N.N-diethylamino, 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 ring they are attached to form a fused aryl ring selected from 2-naphthalene, anthracene or phenanthrene
  • examples of formula IIa ⁇ R 3 to R 7 are hydrogen, or ⁇ R 3 is methyl, methoxy, chlorine or nitro and R 4 to R 7 are hydrogen, or ⁇ R 5 is methyl, t-butyl, methoxy, chlorine, nitro or N,N-dimethylamino and R 3 and R 4 and R 6 and
  • Preferred substituents of formula IIb can be selected from Particularly preferred substituents are of the formula IIb1, IIb2, IIb14, IIb17.
  • Preferred substituents of formula IIc are those wherein R 8 , R 9 and R 10 are the same or different and are hydrogen, hydroxy, hydroxy-C1-4-alkyl or R 8 and R 9 together form a heterocycle or R 8 , R 9 and R 10 together form an unsaturated carbocycle.
  • Particular examples of substituents of formulas IIc are:
  • catalysts IIa and IIc are most preferred.
  • Particularly preferred catalysts of the formula IIa are those wherein, R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, or R 3 is chlorine or methoxy and R 4 , R 5 , R 6 and R 7 are hydrogen, or R 5 is chlorine or methoxy and R 3 , R 4 , R 6 and R 7 are hydrogen, or R 3 and R 7 are methoxy and R 4 , R 5 and R 6 are hydrogen.
  • Particularly preferred catalysts of the formula IIc are those with the formula IIc1. The most preferred catalysts are listed below.
  • R 3 , R 4 , R 5 , R 6 and R 7 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 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 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 1 , X 2 , X 3 , X 4 and X 5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1; R 8 , R 9 and R 10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R 8 and R 9 together form a saturated carbocycle or a heterocycle or R 8 , R 9 and R 10 together form an unsaturated carbocycle, with the proviso that compounds with R 1 and R 2 being hydrogen, or R 1 and R 2 having the formula IIa and wherein R 3 , R 4 , R 6 and R 7 are hydrogen while R 5 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. With the exception for the known compounds, the preferences and particular examples as outlined before likewise apply for the novel dinuclear copper(II) complex bearing substituted salben-type ligands.
  • the preparation of the catalyst can be accomplished according to the scheme below:
  • the H2salben-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 °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 H2salben-type ligand of formula XII 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 1 ⁇ 2 h 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 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 a rule the base is applied in equivalents: from 1 to 5, preferably from 1.5 to 4.
  • an organic solvent which can be selected from aliphatic alcohols, such as methanol, ethanol, t-amylalcohol, N.N- dimethylformamide, tetrahydrofuran, acetonitrile, toluene or dimethylsulfoxide.
  • organic solvents are acetonitrile, tetrahydrofuran and dimethylsulfoxide.
  • the equivalent aryl halogenide in relation to1 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 %.
  • 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.
  • Hssalmp (0.30135 g, 0.870 mmol) was added to a solution of NH4OAC (0.20471 g, 2.66 mmol) in MeOH (10 mL).
  • (A)-Myrtenal (0.25308 g, 1.68 mmol) was added to the yellow suspension, and it was stirred at RT for 1 d, during which Hssalmp completely dissolved in 6 h and the desired product precipitated after 12 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: 0.29610 g (61%).
  • EtsN (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 H2O (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 ⁇ 2 mL) and dried under vacuum for several hours. Yield: 0.1882 g of a brown solid (83%).
  • EtsN (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), z'Pr2O (3 mL) and dried under vacuum for several hours, yielding 0.198 g of a brown solid (69% yield).
  • EtsN (0.156 g, 1.54 mmol) was added to a yellow suspension of H2sal(2-C1)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 overnight at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL), Et2O (2 x 2 mL) and dried under vacuum for several hours, yielding 0.285 g of a brown solid (96% yield).
  • EtsN (2.11 g, 20.8 mmol) was added to a yellow suspension of H2sal(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 x 10 mL) and /Pr2O (2 x 10 mL) and dried under vacuum for several hours, yielding 1.398 g of the title compound (70%).
  • EtsN (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 iPr2O (2 x 10 mL) and dried under vacuum for several hours, yielding 1.695 g of the title compound (84%).
  • EtsN (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 H2O (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%).
  • EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.2074 g of a brown solid (89%).
  • EtsN (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 H2O (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%).
  • EtsN (36.4 mg, 0.359 mmol) was added to a yellow suspension of H 2 (5-OMe)sal(2-Cl)ben (0.7146 g, 0.1685 mmol) in 3 mL of EtOH.
  • Solid Cu(OAc) 2 H 2 O (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%).
  • EtsN (98.0 mg, 0.969 mmol) was added to a yellow suspension of H 2 (5-OMe)sal(2- OMe)ben (0.2004 g, 0.4763 mmol) in 8 mL of EtOH.
  • Solid Cu(OAc) 2 H 2 O (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%).
  • EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.2123 g of a brown solid (93%).
  • EtsN (69.0 mg, 0.682 mmol) was added to a yellow suspension of H 2 (5-OMe)sal(2- NO 2 )ben (0.1435 g, 0.330 mmol) in 5.5 mL of EtOH.
  • Solid Cu(OAc) 2 H 2 O (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%).
  • EtsN (58.1 mg, 0.574 mmol) was added to a yellow suspension of H 2 sal(2-NO 2 )ben (0.100 g, 0.266 mmol) in 4 mL of EtOH.
  • Solid Cu(OAc) 2 H 2 O (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 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%).
  • iodobenzene (215 pL, 1.93 mmol, 1.5 equiv) and pyrrole (90 pL, 1.29 mmol, 1 equiv) were added to a suspension of CS2CO3 (839.2 mg, 2.58 mmol, 2 equiv) and [Cu2(p-salben)2] (5 mg, 6.45 x 10' 3 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.
  • iodobenzene (720 pL, 6.47 mmol, 1.5 equiv) and pyrrole (300 pL, 4.29 mmol. 1 equiv) were added to a suspension of K3PO4 (17.2 mmol, 3.65 g, 4 equiv) and [Cu2(p-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 external standard solution (1 mL of a 0.429 mol L“ 1 CDCI3 solution of dimethyl sulfone) was added, 150 pL of the so- obtained solution were diluted to 700 pL with CDCI3 in an NMR tube, and the 1 H NMR spectrum was registered to calculate the yield.
  • a screw-cap glass tube equipped with a stirring bar was charged with the base, the catalyst and the solvent.
  • 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 pm PTFE Syringe-Filter and the filter washed with MeCN (1-2 mL).
  • LC-MS sample was prepared from resulting solution.
  • the solvent was evaporated, and the crude product purified by chromatography for additional characterization.

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Abstract

The invention relates to a process for the coupling of an aryl halogenide with an N- nucleophile compound which is characterized in that the coupling takes place in the presence of a dinuclear copper(II) complex bearing substituted salben-type ligands having the formula (I). Also described are novel dinuclear copper(II) complex bearing substituted salben-type ligands within the scope of formula (I).

Description

C-N coupling process with [Cu2( ^-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
Figure imgf000002_0001
wherein R1 and R2 are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl or hydrogen, and G1, G2, G3 and G4 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- C1-12-alkyl amino, carboxyl, C1-12 alkoxy carbonyl or nitro or G1, G2, G3 and G4, 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- C1-6-alkyl amino or nitro. The inventions also relates to novel dinuclear copper(II) complexes bearing substituted salben-type ligands of the formula I, wherein R1 and R2 are the same and are substituents of the formula IIa, IIb or IIc
Figure imgf000003_0001
wherein R3, R4, R5, R6 and R7 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 R3 and R4 or R4 and R5 or R5 and R6 or R6 and R7 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. X1, X2, X3, X4 and X5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1; R8, R9 and R10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R8 and R9 together form a saturated carbocycle or a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle, with the proviso that compounds with R1 and R2 being hydrogen, or R1 and R2 having the formula IIa and wherein R3, R4, R6 and R7 are hydrogen, while R5 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 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, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-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-C1-12-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, 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
Figure imgf000005_0001
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 III
Figure imgf000005_0002
wherein X6, X7, X8, X9 and X10 are the same or different and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulphur; R19, R20, R21, R22 and R23 are the same or different and are hydrogen, C1-12-alkyl, C2-12- alkenyl, C2-12-alkynyl, C1-12-alkoxy, halogen, halogen-C1-12-alkyl, mono- or di- C1-12-alkyl amino or cyano, or R19 and R20 or R20 and R21 or R21 and R22 or R22 and R23 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- C1-6-alkyl amino or nitro; n is 0 or 1 and Z is a halogen atom. In preferred aryl halogenides X6, X7, X8, X9 and X10 are the same or different and represent carbon or one nitrogen atom; R19, R20, R21, R22 and R23 are the same or different and are hydrogen, methyl, methoxy or cyano; n is 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
Figure imgf000007_0001
wherein R11, R12, R13, R14, R15, R16, R17 and R18 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 R15 and R16 together with the nitrogen they are attached to form a saturated 5-or 6- member heterocycle; X11, X12, X13 and X14 are the same or different and represent a carbon atom optionally substituted with C1-12-alkyl, aryl-C1-12-alkyl, C1-12-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, IVe, wherein R15, R16, R17 and R18 are the same or different and are hydrogen, C 15 1-6-alkyl, aryl, or R and R16 together with the nitrogen they are attached to form a saturated heterocycle 5-or 6- member heterocycle; X11, X12, X13 and X14 are the same or different and represent a carbon atom optionally substituted with C1-12-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(II) complexes bearing substituted salben-type ligands having the formula I
Figure imgf000008_0001
wherein R1 and R2 are the same or different and are optionally substituted C1-12-alkyl, aryl or heteroaryl, or hydrogen and G1, G2, G3 and G4 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- C1-12-alkyl amino, carboxyl, C1-12-alkoxy carbonyl or nitro or G1, G2, G3 and G4, 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- C1-6-alkyl amino or nitro. In a preferred embodiment G1, G2, G3 and G4 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, N.N-dimethylamino, N.N-diethylamino, carboxyl, methoxy carbonyl, ethoxy carbonyl, i-propoxy carbonyl, n-butoxy carbonyl, t-butoxy carbonyl, nitro or G1, G2, G3 and G4, independently of each other, together with the phenyl ring they are attached to form a fused aryl ring. In a preferred embodiment R1 and R2 are the same and are substituents of the formula IIa, IIb or IIc
Figure imgf000009_0001
wherein R3, R4, R5, R6 and R7 are the same or different and are hydrogen, C1-12-alkyl, C1-12- alkoxy, halogen, halogen-C -alkyl, mono- or di- C -alkyl amino, nitro or R3 and R4 o 4 1-12 1-12 r R and R5 or R5 and R6 or R6 and R7 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, X1, X2, X3, X4 and X5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1; R8, R9 and R10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy-C1-12-alkyl, halogen or R8 and R9 together form a saturated carbocycle or a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle. Preferred substituents of formula IIa are those wherein R3, R4, R5, R6 and R7 are the same or different and are hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, chlorine, bromine, trifluoromethyl, N.N-dimethylamino, N.N-diethylamino, nitro or R3 and R4 or R4 and R5 or R5 and R6 or R6 and R7 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 IIa ● R3 to R7 are hydrogen, or ● R3 is methyl, methoxy, chlorine or nitro and R4 to R7 are hydrogen, or ● R5 is methyl, t-butyl, methoxy, chlorine, nitro or N,N-dimethylamino and R3 and R4 and R6 and R7 are hydrogen, or ● R3 and R5 are methoxy or chlorine and R4, R6 and R7are hydrogen, or ● R3 and R7 are methoxy or chlorine and R4 to R6 are hydrogen, or ● R3, R5 and R7 are methoxy and R4 to R6 are hydrogen. Preferred substituents of formula IIb can be selected from
Figure imgf000010_0001
Particularly preferred substituents are of the formula IIb1, IIb2, IIb14, IIb17. Preferred substituents of formula IIc are those wherein R8, R9 and R10 are the same or different and are hydrogen, hydroxy, hydroxy-C1-4-alkyl or R8 and R9 together form a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle. Particular examples of substituents of formulas IIc are:
Figure imgf000011_0001
Preferably they are selected from formula IIc1 and IIc2 The substituents IIa and IIc are most preferred. Particularly preferred catalysts of the formula IIa are those wherein, R3, R4, R5, R6 and R7 are hydrogen, or R3 is chlorine or methoxy and R4, R5, R6 and R7 are hydrogen, or R5 is chlorine or methoxy and R3, R4, R6 and R7 are hydrogen, or R3 and R7 are methoxy and R4, R5 and R6 are hydrogen. Particularly preferred catalysts of the formula IIc are those with the formula IIc1. The most preferred catalysts are listed below.
Figure imgf000012_0001
Figure imgf000013_0001
Dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I
Figure imgf000013_0002
wherein G1, G2, G3 and G4 are the same or different and stand for hydrogen or one or more substituents selected from C1-12-alkyl, C1126-alkoxy, halogen, halogen C1-12-alkyl, mono- or di- C1-12-alkyl amino, carboxyl, C1-12- alkoxy carbonyl or nitro or G1, G2, G3 and G4, 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- C1-6-alkyl amino or nitro; R1 and R2 are the same and are substituents of the formula IIa, IIb or IIc
Figure imgf000014_0001
R3, R4, R5, R6 and R7 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 R3 and R4 or R4 and R5 or R5 and R6 or R6 and R7 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. X1, X2, X3, X4 and X5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1; R8, R9 and R10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- C1-12-alkyl, halogen or R8 and R9 together form a saturated carbocycle or a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle, with the proviso that compounds with R1 and R2 being hydrogen, or R1 and R2 having the formula IIa and wherein R3, R4, R6 and R7 are hydrogen while R5 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. With the exception for the known compounds, the preferences and particular examples as outlined before likewise apply for the novel dinuclear copper(II) complex bearing substituted salben-type ligands. Preparation of catalysts: The preparation of the catalyst can be accomplished according to the scheme below:
Figure imgf000015_0001
The H2salben-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 H2salben-type ligand of formula XII 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 ½ h 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 I is 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 a rule 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, N.N- dimethylformamide, tetrahydrofuran, acetonitrile, toluene or dimethylsulfoxide. Preferred organic solvents are acetonitrile, tetrahydrofuran and dimethylsulfoxide, The equivalent aryl halogenide in relation to1 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. 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(μ-salben)2] catalyst in the presence of 2 equiv of Cs2CO3 in acetonitrile (MeCN) at 82°C. After 16 h full conversion is observed, and the product can be isolated in 83% yield.
Figure imgf000017_0001
1.2 Optimization studies Table 1. Optimization of temperature and catalyst loading.
Figure imgf000017_0002
Figure imgf000018_0001
General conditions: iodobenzene (215 µL, 1.93 mmol, 1.5 equiv), pyrrole (90 µL, 1.29 mmol, 1 equiv), Cs2CO3 (839.2 mg, 2.58 mmol, 2 equiv), [Cu2(μ-salben)2] in 1 mL of MeCN. [a] The catalyst loading refers to the amount of pyrrole. [b] 1H NMR yield, isolated yields in brackets. Table 2. Screening of bases in MeCN.
Figure imgf000018_0002
General conditions: iodobenzene (715 µL, 6.42 mmol, 1.5 equiv), pyrrole (300 µL, 4.29 mmol, 1 equiv), base (2 equiv) [Cu2(μ-salben)2] in 3.5 mL of MeCN. [a] The catalyst loading refers to the amount of pyrrole. [b] 1H NMR yield, isolated yields in brackets. [c] Tetrahydrofuran (THF) as solvent. [d] K3PO4 (3.64 g, 17.18 mmol, 4 equiv). Table 3. Screening of solvent and bases.
Figure imgf000019_0001
General conditions: iodobenzene (215 µL, 1.93 mmol, 1.5 equiv), pyrrole (90 µL, 1.29 mmol, 1 equiv), base (2.58 mmol, 2 equiv), [Cu2(μ-salben)2] (2.52 mg, 0.003 mmol, 0.0025 equiv) in 1 mL of solvent; T = 70-82°C, t = 16 h. [a] DMF = dimethylformamide, DMSO = dimethylsulfoxide, EtOH = ethanol. Table 4. Activity of the different copper (II) derivatives as catalysts. d
Figure imgf000019_0002
Figure imgf000020_0001
General conditions: iodobenzene (215 µL, 1.93 mmol, 1.5 equiv), pyrrole (90 µL, 1.29 mmol, 1 equiv), base (2.58 mmol, 2 equiv), 1 mL of MeCN; T = 82 °C, t = 16 h. [a] LC/MS yield (%). Table 5. Influence of various equivalents of base and iodobenzene. Entry Iodobenzene (equiv) Base (equiv) NMR yield
Figure imgf000020_0002
Figure imgf000021_0002
, , , , K3PO4, [Cu2(μ-salben)2] (0.006 mmol, 0.005 equiv) in 1 mL of MeCN; T = 82 °C, t = 16 h. 1.3. Substrate scope Table 6. Substrate scope with aryl iodides Aryl io
Figure imgf000021_0001
e - uceop e ro uct Yield % (LC/MS)
Figure imgf000021_0003
Figure imgf000022_0001
General conditions: aryl iodide (1.5 equiv), N-nucleophile (1 eq), Cs2CO3 (2 equiv), [Cu2(μ- salben)2] (0.5 mol %) in MeCN, c = 1 mol L–1; T = 82 °C, t = 16 h. Table 7. Substrate scope with aryl bromides t yield (LC/MS) O 66% N 55% N 51% N 20% N 48% N 54% O 63%
Figure imgf000023_0001
O 94%
Figure imgf000024_0002
General conditions: aryl bromide (1 equiv), N-nuclephile (n equiv as reported in the table), base, [Cu2(μ-salben)2] (2.5 mol%), base (n equiv as reported in the table), solvent, c = 0.5 mol L–1; T = 85 °C, t = 16 h. 2. Synthesis of the novel salben-type ligands 2.1 Synthesis of H2sal(2,6-diOMe)ben
Figure imgf000024_0001
H3salmp (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 × 2 mL) and diethyl ether (Et2O) (2 × 2 mL) and dried under vacuum for several hours, yielding 0.645 g of a bright yellow powdery solid (76% yield). Elemental analysis for C23H22N2O4, 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-1 (ATR): 3050-2830, 1628, 1585, 1493-1474, 1397, 1276, 1250, 1110- 1067, 758.1H NMR, 298 K, CDCl3, 400 MHz: δ (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 (3H, s).13C NMR, 298 K, CDCl3, 101 MHz: δ (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. 2.2 Synthesis of H2sal(2)thn
Figure imgf000025_0001
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 (iPr2O) and dried under vacuum for several hours, yielding 2.946 g of the title compound (67%). Elemental analysis for C19H16N2O2S, 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–1 (ATR): 3109, 2853, 1618, 1575, 1497, 1456, 1422, 1372, 1357, 1272, 1040, 1025, 975, 897, 753, 712, 598.1H NMR, 298 K, acetone-d6, 400 MHz: δ (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).13C NMR, 298 K, acetone-d6, 101 MHz: δ (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, m/z (intensity %): calculated for [M + H]+: 337.1011; found: 337.1000 (100). 2.3 Synthesis of H2sal(3)thn
Figure imgf000025_0002
H3salmp (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 title compound (75%). Elemental analysis for C19H16N2O2S, 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 1 (ATR): 3107, 3054, 3000, 2858, 1618, 1576, 1500, 1456, 1424, 1368, 1273, 1043, 976, 779, 752, 733, 635. ‘H NMR, 298 K, acetone^,, 400 MHz: 5 (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). 13C NMR, 298 K, acetone^,, 101 MHz: 5 (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).
Figure imgf000026_0001
Hssalmp (0.30135 g, 0.870 mmol) was added to a solution of NH4OAC (0.20471 g, 2.66 mmol) in MeOH (10 mL). (A)-Myrtenal (0.25308 g, 1.68 mmol) was added to the yellow suspension, and it was stirred at RT for 1 d, during which Hssalmp completely dissolved in 6 h and the desired product precipitated after 12 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: 0.29610 g (61%). Elemental analysis calcd (%) for C24H26N2O2 (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. 'HNMR (400 MHz, 298 K, acetone-de) in ppm: 5 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). 13C NMR (101 MHz, 298 K acetone-de) 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).
Figure imgf000027_0001
(/?)-Myrtenal (0.1352 g, 0.900 mmol) was added to a solution of NH3 (750 μL 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 iPr2O (3 x 3 mL) and dried under vacuum overnight. Yield: 0.2112 g (69%). Elemental analysis calcd (%) for C24H26N2O2 O.2 H2O (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, aceton e-t/r,) 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). 13C NMR (101 MHz, 298 K acetone-t/6) 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.
2.6 Synthesis of H2(4-OMe)salben
Figure imgf000028_0001
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 4 h. The formed pale-grey solid was filtered, washed with MeOH (3 ^ 3 mL) and dried under vacuum for 1 h. Yield 0.2615 g (49%). Elemental analysis calcd (%) for C23H22N2O4, (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-d6) in ppm: δ 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).13C NMR (151 MHz, 298 K, acetone- d6) δ 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−1): 1610, 1570, 1452, 1316, 1288, 1240, 1168, 764. Mass spectrum (ESI+) in MeCN, m/z (intensity %): calculated for [M + H]+: 391.1658; found: 391.1639 (100). 2.7 Synthesis of H2(5-OMe)salben
Figure imgf000028_0002
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 iPr2O (3 x 3 mL) and dried under vacuum for 1 h. Yield 0.1754 g (68%). Elemental analysis calcd (%) for C23H22N2O4, (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.1H NMR (600 MHz, 298 K, acetone-d6) in ppm: δ 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). 13C NMR (151 MHz, 298 K, acetone-d6) δ 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, m/z (intensity %): calculated for [M + H]+: 391.1658; found: 391.1655 (100). 2.8 Synthesis of H2(5-F)salben
Figure imgf000029_0001
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 ^ 3 mL) and iPr2O (3 ^ 3 mL) and dried under vacuum for 1h. Yield 0.2295 g (85%). Elemental analysis calcd (%) for C21H16F2N2O2, (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.1H NMR (600 MHz, 298 K, acetone-d6) δ 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).13C NMR (151 MHz, 298 K, acetone-d6) δ 166.1, 158.3, 156.3 (d, JC-F=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). 2.9 Synthesis of H2(5-Cl)salben
Figure imgf000030_0001
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 ^ 3 mL) and iPr2O (3 ^ 3 mL) and dried under vacuum for 1h. Yield 0.1567 g (61%). Elemental analysis calcd (%) for C21H16Cl2N2O2·0.3 H2O (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.1H NMR (600 MHz, 298 K acetone-d6) δ 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 (3H, m, 2 - 9 Hz), 6.95 (2H, d, 9 Hz), 6.21 (1H, s). 13C NMR (151 MHz, 298 K, acetone-d6) δ 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
Figure imgf000030_0002
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.2041 g (72%). Elemental analysis calcd (%) for C23H22N2O2·0.05 NH4OAc (362.29): C 76.58, H 6.22, N 7.93. Found: C 76.38, H 5.98, N 7.80. Melting Point: 125 - 130 °C. 1H NMR (400 MHz, 298 K, CDCl3) δ 12.72 (2H, s), 8.53 (2H, s), 7.49 – 7.29 (5H, 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
Figure imgf000031_0001
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.1431 g (51%). Elemental analysis calcd (%) for C23H21ClN2O4 (424.12): C 65.02, H 4.98, N 6.59. Found: C 64.56, H 4.91, N 6.54.1H NMR (400 MHz, 298 K, acetone-d6) δ 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).13C NMR (101 MHz, 298 K, acetone-d6) δ 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−1): 1613, 1600, 1459, 1317, 1252, 1171, 764, 728. Mass spectrum (ESI+) in MeCN, m/z (intensity %): calculated for [M + H]+: 425.1268; found: 425.1248 (60). 2.12 Synthesis of H2(5-OMe)sal(2-Cl)ben
Figure imgf000031_0002
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.1278 g (32%). Elemental analysis calcd (%) for C23H21ClN2O4 (424.12): C 65.02, H 4.98, N 6.59. Found: C 64.78, H 4.95, N 6.51.1H NMR (400 MHz, 298 K, acetone-d6) δ 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). 13C NMR (101 MHz, 298 K, acetone-d6) δ 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−1): 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
Figure imgf000032_0001
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.3028 g (76%). Elemental analysis calcd (%) for C24H24N2O5 (420.47): C 68.75, H 5.75, N 6.62. Found: C 69.07, H 5.83, N 6.68.1H NMR (400 MHz, 298 K, acetone-d6) δ 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-d6) δ 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−1): 1635, 1585, 1489, 1328, 1266, 1240, 1167, 760. Mass spectrum (ESI+) in MeCN,m/z (intensity %): calculated for [M + H]+: 421.1764; found: 421.2400 (40).
Figure imgf000033_0001
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.2996 g (76%). Elemental analysis calcd (%) for C22H18Cl2N2O3 (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 – 154.1H NMR (400 MHz, 298 K, acetone-d6) δ 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).13C NMR (101 MHz, 298 K, acetone-d6) δ 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−1): 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).
Figure imgf000033_0002
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 ^ 3 mL) and dried under vacuum for 1h. Yield 0.1957 g (49%). Elemental analysis calcd (%) for C23H21N3O6 (435.42): C 63.24, H (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). 13C NMR (101 MHz, 298 K, acetone-t/6) 8 166.9, 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-NOi)ben
Figure imgf000034_0001
2-NO2-benz H2(5-CI)sal(2-NO2)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 Ih. Yield 0.477 g (50%). Elemental analysis calcd (%) for C22Hi5C12N3O4 (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-t/e) 6 12.73 (2H, s), 8.80 (2H, s), 8.04 (IH, dd, 8 - 2 Hz), 7.99 (IH, dd, 7.8 - 1.3 Hz), 7.87 (IH, dd, 7 Hz), 7.69 (IH, dd, 8 Hz), 7.60 (2H, d, 3 Hz), 7.40 (2H, dd, 9 - 3 Hz), 6.95 (2H, d, 9 Hz), 6.73 (IH, s). 13C NMR (101 MHz, 298 K, aceton e-6/6) 6 167.7, 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, m/z (intensity %): calculated for [M + H]+: 444.0417; found: 444.0505 (40). 3. Synthesis of the new copper(II) dinuclear complexes
3.1 Synthesis of [Cu2(p-sal(4-tBu)ben)2]
Figure imgf000035_0001
2
[Cu2(p.-sal(4-tBu)ben)2]
EtsN (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 H2O (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 ^ 2 mL) and dried under vacuum for several hours. Yield: 0.1882 g of a brown solid (83%). Elemental analysis calcd (%) for C50H48CU2N4O4 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 -1): 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, DOI: : 10.3390/ijms21217882.
3.2 Synthesis of [Cu2(p-sal(2-OMe)ben)2]
Figure imgf000036_0001
EtsN (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 x 2 mL) and dried under vacuum for several hours, yielding 0.354 g of a brown solid (92% yield). Elemental analysis for C44H36CU2N4O6, 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’1 (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).
Figure imgf000036_0002
EtsN (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 several hours, yielding 0.285 g of a brown solid (85% yield). Elemental analysis for C46H40CU2N4O8, 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’1 (ATR): 3050-2840, 1604, 1528, 1470-1426, 1383, 1250, 1195, 1034-980, 758. Mass spectrum (ESI+), m/z (intensity %): 903 [Cu2(sal(2,6- diOMe)ben)2 + 1]+ (100).
3.4 Synthesis of [Cu2(p-sal(4-OMe)ben)2]
Figure imgf000038_0001
[Cu2(n-sal(4-OMe)ben)2]
EtsN (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), z'Pr2O (3 mL) and dried under vacuum for several hours, yielding 0.198 g of a brown solid (69% yield). Elemental analysis for C44H36CU2N4O6, 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’1 (ATR): 3050-2835, 1607, 1534, 1467-1440, 1395, 1243, 1196, 1176, 1148, 1051-979, 750, 736.
3.5 Synthesis of [Cu2(μ-sal(2-Cl)ben)2]
Figure imgf000038_0002
H2sal(2-CI)ben
[Cu2(n-sal(2-CI)ben)2]
EtsN (0.156 g, 1.54 mmol) was added to a yellow suspension of H2sal(2-C1)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 overnight at RT, and then the precipitate was isolated by filtration, washed with EtOH (2 x 2 mL), Et2O (2 x 2 mL) and dried under vacuum for several hours, yielding 0.285 g of a brown solid (96% yield). Elemental analysis for C42H30CI2CU2N4O4, 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’1 (ATR): 3058-2903, 1605, 1530, 1464-1430, 1319, 1270, 1194, 1149, 1035-978, 744.
3.6 Synthesis of [Cu2(p-sal(2)thn)i]
Figure imgf000039_0001
EtsN (2.11 g, 20.8 mmol) was added to a yellow suspension of H2sal(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 x 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 C38H28CU2N4O4S2, 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 1 (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, m/z (intensity %): calculated for [M + H]+: 795.0223; found: 795.0217 (100). 3.7 Synthesis of [Cu2(p-sal(3)thn)2]
Figure imgf000040_0001
EtsN (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 iPr2O (2 x 10 mL) and dried under vacuum for several hours, yielding 1.695 g of the title compound (84%). Elemental analysis for C38H28CU2N4O4S2, 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 1 (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(p,-(l?)-salClmyr)2]
Figure imgf000040_0002
Solid Cu(OAc)2 H2O (0.09931 g, 0.497 mmol) was added to a yellow suspension of (R )- H2salClmyr (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 filtered, washed with EtOH (3 x 3 mL) and /Pr2O (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 C48H48CU2N4O4 (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, m/z (intensity %): calculated for [M + H]+: 871.2346; found: 871.2319 (100).
3.8.2 Synthesis of [Cu2(p,-(l?)-salClmyr)2]
Solid Cu(OAc)2 H2O (0.0544 g, 0.273 mmol) was added to a yellow suspension of (/?)- EEsalClmyr (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 C48H48CU2N4O4 0.55H2O (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(p-(4-OMe)salben)2]
Figure imgf000041_0001
[Cu2(p.-(4-OMe)salben)2]
EtsN (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 H2O (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 C46H40CU2N4O8 (903.94): C 61.12, H 4.46, N 6.20. Found: C 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(p-(5-OMe)salben)2]
Figure imgf000042_0001
EtaN (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 H2O (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 C46H40CU2N4O8 (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, m/z (intensity %): calculated for [M + H]+: 903.1517; found: 903.1331 (100).
3.11 Synthesis of [Cu2(p-(5-F)salben)2]
Figure imgf000042_0002
EtsN (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 H2O (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 C42H28CU2F4N4O4 (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]
Figure imgf000043_0001
[Cu2(p.-(5-CI)salben)2]
EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.2074 g of a brown solid (89%). Elemental analysis calcd (%) for C42H28CU2CI4N4O4 (921.60): C 54.34, H 3.06, N 6.08. Found: C 54.37, H 3.03, N 5.99. IR-ATR (cm '): 3061, 2899, 1609, 1521, 1449, 1309, 1172, 1099, 976, 941, 876, 772. Mass spectrum (ESI+) in MeCN, m/z (intensity %): calculated for [M + H]+: 942.9325; found: 942.9382 (100). 3.13 Synthesis of [Cu2(p-(5-Me)salben)2]
Figure imgf000044_0001
[Cu2(p.-(5-Me)salben)2]
EtsN (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 H2O (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 C46H40CU2N4O4 (839.94): C 65.78, H 4.80, N 6.67. Found: C 65.78, H 4.75, N 6.64. IR-ATR (cm"1): 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(p-(4-OMe)sal(2-Cl)ben)2]
Figure imgf000044_0002
[Cu2(|4-(4-OMe)sal(2-CI)ben)2] EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.0672 g of a brown solid (52%). Elemental analysis calcd (%) for C46H38C12CU2N4O8 H2O (990.84): C 55.76, H 4.07, N 5.65. Found: C 55.85, H 3.85, 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(p-(5-OMe)sal(2-Cl)ben)2]
Figure imgf000045_0001
[Cu2(|4-(5-OMe)sal(2-CI)ben)2]
EtsN (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 H2O (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 C46H38C12CU2N4O8 (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. 3.16 Synthesis of [Cu2(p-(5-OMe)sal(2-OMe)ben)2]
Figure imgf000046_0001
[Cu2(n-(5-OMe)sal(2-OMe)ben)2]
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 H2O (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 C48H44CU2N4O10 (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(p-(5-Cl)sal(2-OMe)ben)2]
Figure imgf000046_0002
[Cu2(n-(5-CI)sal(2-OMe)ben)2] EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.2088 g of a brown solid (94%). Elemental analysis calcd (%) for C44H32CI4CU2N4O6 (981.65): C 53.84, H 3.29, N 5.71. Found: C 53.74, H 3.26, N 5.60. IR-ATR (cm"1): 2960, 2839, 1611, 1520, 1483, 1457, 1311, 1241, 1172, 1043, 982, 823, 740.
3.18 Synthesis of [Cu2(p-(5-Cl)sal(2-NO2)ben)2]
Figure imgf000047_0001
[Cu2(g-(5-CI)sal(2-NO2)ben)2]
EtsN (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 H2O (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 x 2 mL) and dried under vacuum for several hours. Yield: 0.2123 g of a brown solid (93%). Elemental analysis calcd (%) for C42H26CI4CU2N6O8 (1011.60): C 49.87, H 2.59, N 8.31. Found: C 49.63, H 2.55, N 8.00. IR-ATR (cm-1): 1610, 1520, 1384, 1311, 1175, 1036, 978, 829, 765. 3.19 Synthesis of [Cu2(p-(5-OMe)sal(2-NO2)ben)2]
Figure imgf000048_0001
[Cu2(n-(5-OMe)sal(2-NO2)ben)2]
EtsN (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 H2O (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 C46H38CU2N6OI2 EtOH (1040.00): C 55.44, H 4.29, N 8.08. Found: C 55.06, H 3.94, N 7.81. IR-ATR (cm"1): 2853, 1625, 1596, 1525, 1467, 1339, 1302, 1271, 1218, 1160, 1032, 954, 811, 766.
3.20 Synthesis of [Cu2(p-(sal(2-NO2)ben)2]
Figure imgf000048_0002
H2sal(2-NO2)ben
[Cu2(n-sal(2-NO2)ben)2]
EtsN (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 H2O (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 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 C42H30CU2N6O8 (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 (cm '): 3039, 3021, 2940, 2904, 1605, 1522, 1464, 1443, 1339, 1319, 1194, 1147, 1126, 1027, 979, 851, 751, 741, 713. Mass spectrum (ESI+) in MeCN, m/z (intensity %): calculated for [M + CH3CN + NH4 +]+: 931.1327; found: 931.1322 (100).
4. C-N coupling reactions
4.1 Coupling of iodobenzene with pyrazole with CS2CO3 as base
Under inert atmosphere, iodobenzene (215 pL, 1.93 mmol, 1.5 equiv) and pyrrole (90 pL, 1.29 mmol, 1 equiv) were added to a suspension of CS2CO3 (839.2 mg, 2.58 mmol, 2 equiv) and [Cu2(p-salben)2] (5 mg, 6.45 x 10'3 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 JH NMR spectrum with the commercially available sample. ‘H NMR, 298 K, CDCI3, 400 MHz: 5 (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 K3PO4 as base
Under inert atmosphere, iodobenzene (720 pL, 6.47 mmol, 1.5 equiv) and pyrrole (300 pL, 4.29 mmol. 1 equiv) were added to a suspension of K3PO4 (17.2 mmol, 3.65 g, 4 equiv) and [Cu2(p-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 x 5 mL). The organic phase was concentrated under reduced pressure to obtain the crude product as 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 1 H NMR spectrum with a commercially available sample. 1 H NMR, 298 K, CDC13, 400 MHz: 5 (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 pm 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“ 1 CDCI3 solution of dimethyl sulfone) was added, 150 pL of the so- obtained solution were diluted to 700 pL with CDCI3 in an NMR tube, and the 1 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 pm 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
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001

Claims

Claims
1. 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
Figure imgf000054_0001
wherein R1 and R2 are the same or different and are optionally substituted Ci-12-alkyl, aryl or heteroaryl, or hydrogen and
G1, G2, G3 and G4 are the same or different and hydrogen or one or more substituents selected from Ci-12-alkyl, Ci-12-alkoxy, halogen Ci-12-alkyl, halogen, mono- or di- Ci-12-alkyl amino, carboxyl, C1-12 alkoxy carbonyl or nitro or G1, G2, G3 and G4, 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 Ci-6-alkyl, Ci- 6-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro.
2. Process of claim 1, wherein R1 and R2 are the same and are substituents of the formula Ila, lib or lie
Figure imgf000054_0002
wherein
R3, R4, R5, R6 and R7 are the same or different and are hydrogen, Ci-12-alkyl, C1-12- alkoxy, halogen, halogen-Ci-12-alkyl, mono- or di- Ci-12-alkyl amino, nitro or R3 and R4 or R4 and R5 or R5 and R6 or R6 and R7 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 Ci-6-alkyl, Ci-6-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro,
X1, X2, X3, X4 and X5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1;
R8, R9 and R10 are the same or different and are hydrogen, Ci-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- Ci-12-alkyl, halogen or R8 and R9 together form a saturated carbocycle or a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle.
3. Process of claim 1 or 2, wherein the aryl halogenide has the formula III
Figure imgf000055_0001
wherein
X6, X7, X8, X9 and X10 are the same or different and represent carbon or at least one heteroatom selected from nitrogen, oxygen or sulphur;
R19, R20, R21, R22 and R23 are the same or different and are hydrogen, Ci-12-alkyl, C2-12- alkenyl, C2-i2-alkinyl, Ci-12-alkoxy, halogen, halogen-Ci-12-alkyl, mono- or di- Ci-12-alkyl amino or cyano, or R19and R20 or R20and R21 or R21 and R22 or R22 and R23 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 Ci-6-alkyl, Ci-6-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro; n is 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
Figure imgf000056_0001
wherein
R11, R12, R13, R14, R15, R16 R17 and R18 are the same or different and are hydrogen, C1-12- alkyl, Ci-12-alkoxy, aryl, halogen, halogen-Ci-12-alkyl, nitro, hydroxy, mono- or di- Ci-12-alkyl amino or R15 and R16 together with the nitrogen they are attached to, form a saturated heterocycle 5-or 6-member heterocycle;
X11, X12, X13 and X14 are the same or different and represent a carbon atom optionally substituted with Ci-12-alkyl, aryl-Ci-12-alkyl, Ci-6-alkoxy, halogen, halogen-Ci-12-alkyl and at least one further heteroatom selected from nitrogen, oxygen or sulphur.
5. Process of anyone of claims 1 to 4, wherein a base is present, which is selected from alkali salts of mineral acids or organic acids or from alkali alcoholates.
6. Process of anyone of claims 1 to 5, wherein the reaction takes place in the presence of an organic solvent at a reaction temperature between 20 °C and 200 °C.
7. Dinuclear copper(II) complex bearing substituted salben-type ligands having the formula I
Figure imgf000057_0001
wherein
R1 and R2 are the same or different and are optionally substituted Ci-12-alkyl, aryl or heteroaryl, or hydrogen and
G1, G2, G3 and G4 are the same or different and stand for hydrogen or one or more substituents selected from Ci-12-alkyl, Ci-12-alkoxy, halogen, halogen Ci-12-alkyl, mono- or di- Ci-12-alkyl amino, carboxyl, Ci-12-alkoxy carbonyl or nitro or G1, G2, G3 and G4, 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-6-alkoxy, halogen, mono- or di- Ci-6-alkyl amino or nitro;
R1 and R2 are the same and are substituents of the formula Ila, lib or lie
Figure imgf000057_0002
R3, R4, R5, R6 and R7 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 R3 and R4 or R4 and R5 or R5 and R6 or R6 and R7 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.
X1, X2, X3, X4 and X5 are the same or different and represent at least one heteroatom selected from nitrogen, oxygen or sulphur; n is 0 or 1;
R8, R9 and R10 are the same or different and are hydrogen, C1-12-alkyl, halogen C1-12- alkyl, hydroxy, hydroxy- Ci-12-alkyl, halogen or R8 and R9 together form a saturated carbocycle or a heterocycle or R8, R9 and R10 together form an unsaturated carbocycle, with the proviso that compounds with R1 and R2 being hydrogen, or R1 and R2 having the formula Ila and wherein R3, R4, R6 and R7 are hydrogen, while R5 is hydrogen, chlorine, methyl, or nitro, are excluded.
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