WO2022084562A1 - Structurally rigid dianions for metal catalysis - Google Patents

Structurally rigid dianions for metal catalysis Download PDF

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WO2022084562A1
WO2022084562A1 PCT/EP2021/079582 EP2021079582W WO2022084562A1 WO 2022084562 A1 WO2022084562 A1 WO 2022084562A1 EP 2021079582 W EP2021079582 W EP 2021079582W WO 2022084562 A1 WO2022084562 A1 WO 2022084562A1
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alkyl
carbon atoms
cyclic hydrocarbon
hydrocarbon moiety
substituted
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PCT/EP2021/079582
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French (fr)
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Jyoti DHANKHAR
Elisa GONZÁLEZ-FERNÁNDEZ
Chao-chen DONG
Ilija Coric
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Universität Zürich
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    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
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    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/266—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of hydrocarbons and halogenated hydrocarbons
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    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
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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
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
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    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/337—Polycyclic acids with carboxyl groups bound to condensed ring systems
    • C07C63/34—Polycyclic acids with carboxyl groups bound to condensed ring systems containing two condensed rings
    • C07C63/38—Polycyclic acids with carboxyl groups bound to condensed ring systems containing two condensed rings containing two carboxyl groups both bound to carbon atoms of the condensed ring system
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    • C07C63/33—Polycyclic acids
    • C07C63/337—Polycyclic acids with carboxyl groups bound to condensed ring systems
    • C07C63/42—Polycyclic acids with carboxyl groups bound to condensed ring systems containing three or more condensed rings
    • C07C63/46—Polycyclic acids with carboxyl groups bound to condensed ring systems containing three or more condensed rings containing two carboxyl groups both bound to carbon atoms of the condensed ring system
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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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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    • C07D207/02—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
    • C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C07D207/10—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C—CHEMISTRY; METALLURGY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes

Definitions

  • the present invention relates to a method for accelerating a chemical transformation of a substrate, particularly C-H arylation and C-H alkylation. Furthermore, the invention relates to the compounds that are used in the method, namely a ligand suitable for forming a metal complex, a precatalyst that provides a metal, and a reagent that provides the moiety to be transferred to the substrate.
  • Catalytic activation of C-H bonds with transition metals can streamline multi-step organic syntheses and offer resource-efficient processes.
  • the direct arylation of C-H bonds in arenes represents an attractive alternative to C-C cross-coupling reactions, which usually require pre-functionalized substrates ( Figure 1a).
  • palladium catalysts are promising for direct transformation of C-H to C-C bonds.
  • high catalyst loading, control over regioselectivity, and application to complex molecules of pharmaceutical interest remain challenging.
  • Direct arylation of arenes requires excess arene, high temperatures, acidic, basic, or transition-metal additives, and is limited to certain classes of substrates.
  • a non-directed C-H activation followed by a direct arylation process remains a challenge, even for simple substrates. (Liu, L.-Y. et al. Angew. Chem. Int. Ed. 2020, 59, 13831.).
  • Palladium-based catalytic C-H activation reactions are often proposed to proceed through mechanisms such as concerted metalation-deprotonation (CMD) mechanism, where the metal and the coordinated anion help to cleave the C-H bond ( Figure 1b).
  • CMD metalation-deprotonation
  • Palladium(ll) acetate is usually used as precatalyst for C-H activation and the reactions without additives are inefficient, because the carboxylates block potential sites for C-H activation by incoordination and can form species of higher nuclearity, which might be inactive.
  • Neutral and anionic ligands have been used for non-directed, palladium-catalyzed C-H activation reactions.
  • silver(l) additives are often important for the reactivity.
  • the objective of the present invention is to provide means and methods to achieve catalytic activation of C-H bonds under mild conditions and at ambient temperature without the use of additives such as silver(l) salts.
  • This objective is attained by the subject-matter of the independent claims of the present specification, with further advantageous embodiments described in the dependent claims, examples, figures and general description of this specification.
  • a first aspect of the invention relates to a ligand of formula 1 , wherein
  • X 1 and X 2 are independently selected from -CO2H, -SO3H, -C(O)NHR NX , -SC>2NHR NX and anions thereof, with R NX being selected from -SC>2R s or aryl, wherein the aryl is substituted with one or more electron-withdrawing groups, wherein R s is selected from a C1.6 alkyl,
  • R 1 and R 2 are H or sterically demanding moieties
  • the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A
  • R 6 , R 7 , R 8 and R 9 are independently from each other selected from H, Ci-10-alkyl, -F, -Cl, -Br, -CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with
  • R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl and a cyclic or a hydrocarbon moiety comprising 3 to 14 carbon atoms, or two moieties of R 6 and R 7 and/or two moieties of R 8 and R 9 can be connected to each other to form an additional cycle fused to the naphthalene, and p and v are independently from each other 0, 1 or 2, q and w are independently from each other 0, 1 , 2 or 3.
  • the ligand according to the first aspect of the invention comprises two naphthyl moieties that form two side-arms.
  • Each side-arm comprises a moiety X 1 and X 2 , respectively.
  • X 1 and X 2 are suitable for coordinating a metal, e.g. two carboxylate moieties may coordinate palladium.
  • the two side-arms are connected by a spacer, e.g. a central aromatic spacer such as another naphthyl moiety.
  • the size and geometry of the spacer modulates the relative spatial arrangement of X 1 and X 2 , e.g. two carboxylate groups at X 1 and X 2 may be arranged approximately in a plane which is parallel to that of the arene spacer.
  • moieties at X 1 and X 2 tend to coordinate to more than one metal in a bridging mode, sterically demanding moieties at R 1 and R 2 may prevent such coordination.
  • mesityl moieties at R 1 and R 2 may prevent bridging of carboxylate moieties at X 1 and X 2 between two metal atoms.
  • the ligand When the ligand coordinates a metal, it can be used in a chemical transformation of a substrate such as the catalytic activation of a C-H bond and subsequent arylation at this site. If the substrate comprises more than one C-H bond that could be activated, control over regioselectivity of the C-H activation may be achieved by selecting a suitable substitution pattern at R 1 and R 2 . Different R 1 and R 2 may influence the site (alpha/beta) of arylation. Furthermore, a chiral enantioenriched reaction product may be obtained when a chiral enantioenriched ligand is used (enantioselectivity). Chirality of the ligand may also be achieved by selecting a suitable substitution pattern at R 1 and R 2 .
  • the ligand may further comprise linear, branched or cyclic substituents at the side-arms.
  • a second aspect of the invention relates to a metal complex comprising a ligand according to the first aspect of the invention and a metal.
  • the ligand according to the first aspect of the invention is suitable for coordinating a metal, e.g. palladium, by the moieties X 1 and X 2 .
  • the metal complex may be used in chemical transformations such as the catalytic activation of C-H bonds.
  • the geometric parameters of the X 1 /X 2 coordination on the metal namely the X 1 -metal-X 2 angles and X 1/2 -metal distances are important (see Fig. 1b).
  • simple metal carboxylate complexes such as Pd(C>2CCH3)2 are characterized by an angle a and an angle y. Both angles are formed between O-Pd-O, wherein one oxygen atom originates from one acetate group and the other oxygen atom originates from the other acetate group.
  • the angle a increases and the angle y decreases to allow formation of the transition state (see Fig. 1 b).
  • complexes according to the invention are characterized by two different angles a and y even in the absence of the substrate (see Fig. 1c).
  • the controlled spatial arrangement of X 1 and X 2 which is achieved by the side-arms and the spacer of the ligand according to the first aspect of the invention, leads to stabilization of the geometry required for the reaction transition state over, for example, / ⁇ -coordination in a metal complex comprising palladium and carboxylate groups at X 1 and X 2 .
  • the barrier for C-H activation is lowered and acceleration of a chemical transformation, e.g. C-H arylation or C-H alkylation, is achieved.
  • a third aspect of the invention relates to a reagent of formula 9, wherein
  • Z + is selected from l + and S + ,
  • Y is a Ci-20-alkyl, an aryl, a heteroaryl, or two Y form a ring structure, wherein
  • T is selected from Ci- 2 o-alkyl, an aryl, a heteroaryl, -CF 3 , -OR a , -F, -Br, alkenyl, alkynyl with R a being as defined above, wherein
  • A- is -O’ or -N(R 10 )-, with R 10 being a -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 substituents -OR a with R a being defined as above, the aryl is substituted with one or more electron withdrawing groups,
  • R 11 is a -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 substituents -OR a with R a being defined as above, the aryl is substituted with one or more electron withdrawing groups.
  • the reagent may be used in a C-H functionalization reaction as described above.
  • the reagent according to the third aspect of the invention is designed in such a way that the use of silver(l) compounds and any other potentially interfering additives or anions is avoided during the reaction.
  • the reagent provides a moiety T that is transferred to a substrate upon activation of a C-H bond of the substrate by the metal complex described above.
  • T is bound to l + or S + cation.
  • I + - reagents are useful particularly for C-H arylation reactions while and S + reagents are useful particularly for C- H alkylation reactions, e.g. for the transfer of -CF3.
  • I + reagents comprise one moiety Y and S + reagents comprise two moieties Y that remain at the cation.
  • the anion A'-R 11 is a bulky monodentate anion, which does not participate in the sixmembered CMD process.
  • the anion acts as a mild base to remove H + after the C-H activation step.
  • a fourth aspect of the invention relates to a precatalyst of formula 10, wherein
  • M is a metal
  • A’ is selected from -O-, -N(R 12a )-,
  • R 12 and R 12a are independently selected from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 -OR b with R b being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, the aryl is substituted with one or more electron withdrawing groups,
  • L is a neutral or anionic ligand x is equal to the charge of the metal M minus the number of L that are anionic, z is 0, 1 , 2, 3, or 4, wherein the sum of x and z equals the number of coordinating bonds that are formed by the metal M.
  • the precatalyst may be used in a C-H functionalization reaction as described above.
  • the precatalyst according to the fourth aspect of the invention is designed in such a way that the use of silver(l) compounds and any other potentially interfering additives or anions is avoided during the reaction.
  • the anions A'-R 12 and A'-R 5 are displaced from the metal and the metal is subsequently coordinated by the ligand according to the first aspect of the invention.
  • the moieties L of the precatalyst can also be displaced.
  • a ligand that comprises mesityl moieties at R 1 and R 2 may coordinate Pd(ll) without the moiety L of the precatalyst.
  • L-M-L is coordinated by the ligand according to the first aspect of the invention.
  • the moiety L functions as sterically demanding moiety that contributes to the spatial arrangement of the side-arms and the moieties X 1 and X 2 .
  • the anions A'-R 12 and A'-R 5 are a bulky monodentate anions, which do not participate in the six-membered CMD process.
  • the anions act as a mild base to remove H + after the C-H activation step.
  • a fifth aspect of the invention relates to a method for accelerating a chemical transformation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
  • the inventive method makes use of the ligand according to the first aspect of the invention. As described above, the ligand is suitable for coordinating a metal.
  • the metal is provided by a precatalyst.
  • a C-H bond of the substrate may be catalytically activated by a C-H activation process and subsequently a moiety from the reagent, e.g. an aryl or alkyl, may be transferred to the substrate to form a covalent bond with the activated C atom.
  • the inventive method may be performed without the use of silver(l) compounds or any other potentially interfering additives. Furthermore, the inventive method can be performed at mild conditions and at ambient temperature.
  • alkyl refers to a linear or branched hydrocarbon moiety.
  • a Cis-alkyl in the context of the present specification relates to a saturated linear or branched hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • a Ci-12-alkyl relates to a linear or branched hydrocarbon having up to 12 carbon atoms.
  • Ci-Ce alkyl examples include methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, terf-butyl, but-3-enyl, prop- 2-inyl, but-3-inyl, 3-methylbut-2-enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2- methylbutyl, 3-methylbutyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2-dimethylpropyl, pent-4- inyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl.
  • a Ci-e alkyl refers to methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), n-butyl (Bu), fertbutyl (tBu), n-pentyl and n- hexyl.
  • Ci-Ce alkyl examples include methyl, ethyl, propyl, n-butyl, 2-methylpropyl, terf-butyl, n-pentyl, 2-methyl butyl, 3-methylbutyl, 1 , 1-dimethylpropyl, 1 ,2- dimethylpropyl, 1 ,2-dimethylpropyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl.
  • a Ci-e alkyl refers to methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), n-butyl (Bu), terfbutyl (tBu), n-pentyl and n-hexyl.
  • cyclic hydrocarbon moiety relates to a mono- or polycyclic hydrocarbon moiety that comprises carbon-carbon single, double and/or triple bonds, particularly carbon-carbon single bonds and/or carbon-carbon double bonds.
  • the ring structures of a polycyclic hydrocarbon moiety may be bridged, fused or spirocyclic.
  • Non-limiting examples for cyclic hydrocarbon moieties are aryls, e.g. phenyl or naphthyl, and cycloalkyls, e.g. hexyl.
  • Cs-e-cycloalkyl in the context of the present specification relates to a saturated hydrocarbon ring having 5 or 6 carbon atoms.
  • Amberlyst® A26 hydroxide form resin relates to a strongly basic, macroreticular resin with quaternary ammonium functionality and containing hydroxide anions.
  • Amberlyst® (CF3)3CO ⁇ resin relates to a Amberlyst® A26 hydroxide form resin that has been modified by exchanging hydroxide with (CF3)3CO _ .
  • a first aspect of the invention relates to a ligand of formula 1 , particularly of formula 1a, wherein
  • X 1 and X 2 are independently, particularly X 1 and X 2 are both, selected from -CO2H, -SO3H, - C(O)NHR NX , -SC>2NHR NX and anions thereof, with R NX being selected from -SC>2R s or aryl, particularly phenyl or naphthyl, wherein the aryl is substituted with one or more electronwithdrawing groups, particularly -F, -CF3, -SF5, wherein R s is selected from a C1.6 alkyl, particularly -CH3,
  • aryl is particularly phenyl or naphthyl, substituted with one or more small substituents, particularly -F, -Cl, -CF3, -SF5, -CH3, isopropyl,
  • R 1 and R 2 are H or sterically demanding moieties, particularly R 1 and R 2 are H or sterically demanding moieties independently selected from a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
  • the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -SF5, -OR C1 , - C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the Ci-12-al kyl is optionally substituted by one or more-F atoms
  • the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl and a cyclic
  • R C1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs- 6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, or a C1-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, - CF 3 , -SF 5 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , - C(O)OR C1 , -
  • R 6 , R 7 , R 8 and R 9 are independently from each other selected from H, Ci-10-alkyl, particularly Ci-6-alkyl, more particularly Ci- 4 -alkyl, -F, -Cl, -Br, -CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , - SC>2NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or a C1 -12-alkyl and a cyclic or a hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly R
  • X 1 and X 2 are selected from anions of -CO2H, -SO3H, -C(O)NHR NX , - SC>2NHR NX with R NX being as defined above.
  • p, q, v and w are 0.
  • R 1 and R 2 are selected from a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or
  • branched Cs-12-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms wherein the branched Cs-12-al kyl or the Ci -4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -OR C1 , -C(O)NR N1 R N2 , - N(R N1 )C(O)H, -N(R N1 )C(O)R c1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , - N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with
  • R 1 and R 2 are selected from a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-io-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF 3 , - OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R
  • R 1 and R 2 are independently selected from
  • branched Cs-12-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms wherein the branched Cs-12-al kyl or the Ci-4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -OR C1 , -C(O)NR N1 R N2 , - N(R N1 )C(O)H, -N(R N1 )C(O)R c1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , - N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R
  • R 1 and R 2 are independently selected from
  • a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms wherein the branched Cs-i2-al kyl or the Ci -4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -OR C1 , -C(O)NR N1 R N2 , - N(R N1 )C(O)H, -N(R N1 )C(O)R c1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , - N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
  • R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl, particularly H or a Ci-e-alkyl, more particularly H, methyl, ethyl, hexyl, iso-propyl, tert-butyl.
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 6 to 14 carbon atoms, particularly 8 to 12 carbon atoms, more particularly 2-adamantyl, a Ci-e-alkyl, more particularly Ci-4-alkyl,
  • R N1 is H or Ci-2-alkyl, particularly H.
  • R C1 is a Ci-e-alkyl, particularly a Ci-4-alkyl, more particularly isopropyl or tert-butyl, even more particularly tert-butyl.
  • R 1 and R 2 are a phenyl optionally substituted with 1-5 substituents, particularly 1 to 3 substituents, selected from a linear or branched Ci-s-alkyl, particularly a linear or branched Ci-3-alkyl, and a Cs-s-cycloalkyl.
  • R 1 and R 2 are a phenyl substituted with two substituents in meta position (3 and 5 positions of the phenyl) or three substituents in ortho and para position (2,4,6-positions).
  • R 1 and R 2 are selected from 2,4,6-Me3CeH2, 2,4,6-iPr3CeH2, phenyl, 3,5-tBu3CeH3.
  • R 1 and R 2 are 2,4,6-Me3CeH2 (mesityl).
  • R 1 and R 2 are identical.
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
  • the substitution pattern at R 1 and R 2 may be chiral. If chiral enantioenriched ligands are used in a chemical transformation of a substrate such as the catalytic activation of a C-H bond and subsequent arylation at this site, a chiral enantioenriched reaction product may be obtained. Chirality of the ligand may be obtained by using a substitution pattern at R 1 and R 2 that comprises a linear alkyl, a saturated ring or an amino acid that comprises one or more stereocenter.
  • R 1 and R 2 are sterically demanding moieties as defined above, particularly R 1 and R 2 are a phenyl substituted by CF3, methyl, particularly
  • R 1 and R 2 each comprise at least one substituent selected from
  • R E1 being H or OH
  • R E2 and R E3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
  • o R N1 being H or Ci-4-alkyl
  • R 1 and R 2 are sterically demanding moieties as defined above, particularly R 1 and R 2 are a phenyl substituted by CF 3 , methyl, particularly
  • R 1 and R 2 each comprise at least one substituent selected from
  • R E1 being H or OH
  • R E2 and R E3 being Ci-4-alkyl, -F, -Cl, -Br, -CF 3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3.
  • R 1 and R 2 are sterically demanding moieties as defined above, particularly R 1 and R 2 are a phenyl substituted by CF3, methyl, particularly
  • R 1 and R 2 each comprise an additional substituent selected from
  • R E1 being H or OH
  • R E2 and R E3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3.
  • the cyclic hydrocarbon moiety at R 1 and/or R 2 , particularly R 1 and R 2 is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, - -F, -Cl, -Br, -CF 3 ,
  • R E1 being H or OH
  • R E2 and R E3 being Ci-4-alkyl, -F, -Cl, -Br, -CF 3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
  • o R N1 being H or Ci-4-alkyl
  • the ligand is a compound of formula 2, particularly of formula 2a, wherein X 1 , X 2 , R 1 and R 2 are defined as described above, and
  • R 6a , R 7a , R 7b , R 8a , R 9a , R 9b are defined as R 6 , R 7 , R 8 and R 9 , respectively.
  • R 6a , R 7a , R 7b , R 8a , R 9a , R 9b are H.
  • the spacer optionally comprises one or more substituents selected from F, Cl, Br, CF3, -OR C1 , Ci-10-alkyl, a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the alkyl and cyclic hydrocarbon moiety can be further substituted with one or more substituents selected from -F, -Cl, -Br, -CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, - N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , - SO 2 NR N1 R N2 with
  • R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
  • the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A.
  • the spacer is a planar cyclic moiety.
  • the cyclic moiety of the spacer may comprise substituents as described herein.
  • the spacer is a moiety of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a, wherein R 3 and R 4 are independently selected from
  • R C1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, ora Ci-12-alkyl and a cyclic hydrocarbon moiety, particularly an aryl, comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
  • the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -SF5, -OR C1 , - C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , -C(O)OR C1 , -OC(O)R C1 , - N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
  • the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly C1.4- alkyl, -F, -Cl, -Br, -CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, -N(R N1 )C(O)R C1 , - C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , -SO 2 NR N1 R N2 with R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6
  • the spacer is a moiety of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a, wherein R 3 and R 4 are independently selected from a Ci-12-al kyl and a cyclic hydrocarbon moiety, particularly an aryl, more particularly phenyl, comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
  • the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
  • the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-4-alkyl, -C(O)NR N1 R N2 , -N(R N1 )C(O)R c1 , - N(R N1 )C(O)NR N2 R N3 , with R N1 , R N2 , R N3 , R C1 being H, Ci- 6 -alkyl, or aryl, or two moieties of R 3 and R 4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle, n and m are independently from each other 0 or 1 , particularly n is 1 and and m is 0.
  • R 3 and R 4 are selected from F, Cl, Br, CF3, -OR C1 , a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly an aryl, more particularly phenyl, and Ci-10-alkyl, wherein the alkyl and cyclic hydrocarbon moiety can be further substituted with one or more substituents selected from -F, -Cl, -Br, -CF 3 , -OR C1 , -C(O)NR N1 R N2 , -N(R N1 )C(O)H, - N(R N1 )C(O)R c1 , -C(O)OR C1 , -OC(O)R C1 , -N(R N1 )C(O)NR N2 R N3 , -N(R N1 )C(S)NR N2 R N3 , - SO 2 NR N1 R N2 with
  • R N1 , R N2 , R N3 , R C1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
  • n is 1 and m is 0.
  • both n and m are 0.
  • the ligand is a compound of formula 2 having a spacer of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a. In certain embodiments, the ligand is a compound of formula 2a having a spacer of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a.
  • the ligand is a compound of formula 4 or 5, particularly of formula 4, (5), with R 1 and R 2 being as defined above.
  • the ligand is a compound of formula 6, 7, or 8, particularly of formula
  • the ligand is selected from a compound of formula 6, 7 or 8, and a compound of formula X1 to X17, and a compound of formula X18 to X29,
  • the ligand is selected from a compound of formula 6, and a compound of formula X1 to X17, and a compound of formula X18 to X21.
  • the ligand is a compound of formula 6, 7, 8, or X11, particularly of formula 6 and X11.
  • a second aspect of the invention relates to a metal complex comprising a ligand according to the first aspect of the invention and a metal.
  • the metal is selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt.
  • the metal is selected from Pd, Cu, Ir, Rh, Co, Au, Ru.
  • the metal is selected from Pd, Ir, Rh, Co, Ru.
  • the metal is Pd or Pt.
  • the metal is Pd.
  • a third aspect of the invention relates to a reagent of formula 9, (9), wherein
  • Z + is selected from l + and S + , particularly l + ,
  • A- is -O' or -N(R 10 )', particularly -0; with R 10 being a -Ci-6-alkyl or aryl, wherein - the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -OR a , particularly 0, with R a being defined as above,
  • the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)OR C with R c being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
  • R 11 is a -Ci-6-alkyl or aryl, wherein
  • the -C1.6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -OR a , particularly 0, with R a being defined as above,
  • the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)OR C with R c being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
  • R 11 is selected from -CH(CF3)2, -C(CF3)3.
  • R 11 is -C(CF3)3.
  • Z + is l + and r is 1.
  • Y and T are both an aryl, particularly phenyl, that is optionally substituted as described above.
  • Y is substituted by 1 or 2 substituents selected from -F, -Cl, -Br, -I, - CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, cyclopentyl, cyclohexyl and -CF3.
  • Y is substituted by 1 or 2 substituents selected from -F, -Cl, -Br, -I, - CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, and -CF3.
  • Y is substituted by 1 or 2 substituents selected from a Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, cyclopentyl, cyclohexyl.
  • Y is substituted by 1 or 2 substituents selected from a Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl.
  • T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a C1.4- alkyl, -CF3 and indole.
  • T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a C1.4- alkyl, and -CF3.
  • T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl.
  • substituents particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl.
  • A- is -O'.
  • R 11 is a Ci-6-alkyl or a fully or partly fluorinated Ci-e-alkyl, more particularly R 11 is -C-(CFs)3.
  • Z + is l + and r is 1 ,
  • Y and T are both an aryl that is optionally substituted as described above,
  • A' is -O
  • R 11 is defined as above, particularly R 11 is a Ci-6-alkyl or a fully or partly fluorinated Ci-e-alkyl, more particularly R 11 is -C-(CF3)3.
  • both moieties T and Y are based on an aryl such as phenyl
  • the respective substitution patterns determine which aryl remains at the cation (Y) and which aryl is transferred to a substrate (T).
  • the substitutions at phenyls that are at the ortho position in relation to the cation Z + are relevant. If both ortho positions of a phenyl (T) are unsubstituted, it will be transferred to a substrate.
  • the other phenyl (Y) needs to have one substituent in the ortho position to remain at the cation.
  • the left phenyl moiety of reagent RG1 remains bound to l + , while the right phenyl moiety may be transferred to a substrate.
  • Y and T are both an aryl, particularly a phenyl, wherein
  • - Y comprises one or more substituents as described above, wherein one substituent is at one ortho position in relation to Z + and the other ortho position in relation to Z + is unsubstituted, and
  • the reagent is a compound of formula (RG1), (RG1).
  • a fourth aspect of the invention relates to a precatalyst of formula 10, particularly of formula 10a, ⁇ wherein
  • M is a metal, particularly selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, particularly Pd,
  • A’ is selected from -O-, -N(R 12a )-, -N(R 5a )-, particularly -O-,
  • R 12 , R 12a , R 5 and R 5a are independently selected, particularly all are selected, from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 -OR b , particularly 0, with R b being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from -C(CF3)s, - CF3, -C(O)OR C with R c being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
  • L is a neutral or anionic ligand, particularly
  • L is in case of M being Pd, Cu, Au, Pt a weakly coordinated ligand selected from -NC-aryl, -NC-Ci-12-alkyl, -S(Ci -12-alkyl)2,
  • O(Ci-6-alkyl) 2 or an O-alkyl group, wherein the O-alkyl group is further attached to R 12 or R 5 ,
  • L is a coordinated neutral ligand, particularly a strongly coordinated neutral ligand, particularly cymene, in case of M being Ru,
  • L is a coordinated anionic ligand, particularly a strongly coordinated anionic ligand, particularly pentamethylcyclopentadienyl, in case of M being Rh or Ir x is equal to the charge of the metal M minus the number of L that are anionic, z is 0, 1 , 2, 3, or 4, wherein the sum of x and z equals the number of coordinating bonds that are formed by the metal M.
  • L is a neutral or anionic ligand suitable to form the metal complex 10 and 10a.
  • the precatalyst is a compound of formula 10, wherein
  • A’ is -O-
  • R 12 is a -Ci-6 alkyl is substituted by one or more -F, particularly -CH(CF3)2, -C(CF3)3, more particularly -C(CF3)3,
  • L is defined as above, particularly L is selected from -NC-phenyl, -NC-Ci-i 2 -alkyl, - S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, more particularly L is -NC-phenyl, x is 2 and z is 2.
  • the precatalyst is a compound of formula 10a, wherein
  • M is a metal, particularly selected from Pd, Pt, more particularly M is Pd,
  • A’ is selected from -O-, -N(R 12a )-, -N(R 5a )-, particularly -O-,
  • R 12 , R 12a , R 5 and R 5a are independently selected, particularly all are selected, from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 -OR b , particularly 0, with R b being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from -C(CF3)3, - CF3, -C(O)OR C with R c being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
  • L is a weakly coordinated ligand selected from -NC-aryl, -NC-Ci-i 2 -alkyl, -S(Ci-i2-alkyl)2, O(Ci-6-alkyl) 2 , or an O-alkyl group, wherein the O-alkyl group is further attached to R 12 or R 5 .
  • the precatalyst is a compound of formula 10a, wherein
  • A’ is -O-
  • R 12 and R 5 are a -Ci-e alkyl is substituted by one or more -F, particularly -CH(CF3)2, - C(CF 3 )3, more particularly -C(CF 3 )3,
  • L is defined as above, particularly L is selected from -NC-phenyl, -NC-Ci-i 2 -alkyl, - S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, more particularly L is -NC-phenyl.
  • the precatalyst is a compound of formula 10a with M being Pd.
  • R 12 and R 5 are selected from -CH(CF3)2, -C(CF3)3.
  • R 12 and R 5 are -C(CF3)3,
  • R 12 , R 12a , R 5 and R 5a are identical.
  • A’ is -O- and R 12 and R 5 are selected from -CH(CF3)2, -C(CF3)3, particularly R 12 and R 5 are -C(CF3)3,
  • L is a ligand selected from -NC-aryl, -NC-Ci-12-alkyl, -S(Ci-i2-alkyl)2, O(Ci-6-alkyl) 2 .
  • L is a ligand selected from -NC-phenyl, -NC-Ci-12-alkyl, -S(Ci-i2- alkyl) 2 , O(Ci-6-alkyl) 2 .
  • L is -NC-phenyl
  • A’ is -O- and R 12 and R 5 are selected from -CH(CF3)2, -C(CF3)3, particularly R 12 and R 5 are -C(CF3)3, and L is a ligand selected from -NC-phenyl, -NC-C1.12- alkyl, -S(Ci-i2-alkyl) 2 , O(Ci-6-alkyl) 2 .
  • A’ is -O- and R 12 and R 5 are selected from -CH(CF3)2, -C(CF3)3, particularly R 12 and R 5 are -C(CF3)3, and L is -NC-phenyl.
  • a fifth aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
  • the method for accelerating a chemical transformation comprises the steps of a. providing a substrate to be chemically transformed, a reagent according to the third aspect of the invention comprising at least one moiety to be transferred to the substrate, a precatalyst according to the fourth aspect of the invention comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
  • the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent comprising at least one aryl moiety Ar’ or alkyl moiety Aik’, a precatalyst comprising a coordinated metal, particularly a coordinated metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a compound comprising a moiety Ar-Ar’ or Ar-Alk’.
  • the reagent is a compound according to the third aspect of the invention.
  • the precatalyst is a compound according to the fourth aspect of the invention or a compound composed of a) Pd(ll), b) a weakly basic anion, particularly a basic anion having a p a of the corresponding acid ⁇ 2, particularly ⁇ 0.5, and c) optionally containing a weakly coordinating ligand, particularly a ligand selected from a nitrile, an ether, or thioether.
  • the precatalyst is a compound according to the fourth aspect of the invention. In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention with M being Pd.
  • the method is performed in a solvent.
  • the method is performed in an organic solvent, in particular selected from 1,4-dioxane, ethylacetate, dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl-methyl ether, 1,2-dimethoxyethane.
  • organic solvent in particular selected from 1,4-dioxane, ethylacetate, dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl-methyl ether, 1,2-dimethoxyethane.
  • the transformation step is performed at a temperature between 10 °C and 110 °C, particularly between 20 °C and 60 °C.
  • the transformation step is performed for 1 h to 72 h, particularly for 12 h to 72 h.
  • a sixth aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent according to the third aspect of the invention, a precatalyst comprising a coordinated metal, a ligand suitable to coordinate a metal, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
  • the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent according to the third aspect of the invention, a precatalyst comprising a coordinated metal, particularly a coordinated metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, a ligand suitable to coordinate a metal, particularly a metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c.
  • the ligand is a ligand according to the first aspect of the invention.
  • a seventh aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst according to the fourth aspect of the invention, a ligand suitable to coordinate a metal, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
  • the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent comprising at least one aryl moiety Ar’ or alkyl moiety Aik’, a precatalyst according to the fourth aspect of the invention, a ligand suitable to coordinate a metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a compound comprising a moiety Ar-Ar’ or Ar-Alk’.
  • the ligand is a ligand according to the first aspect of the invention.
  • An eighth aspect of the invention relates to a method for preparing a ligand according to the first aspect of the invention comprising the steps of preparing 1 ,8-dichloronaphthalene by treating 1 ,8-dichloronaphthalene with CuCI, preparing 1 ,8-Dichloro-2-arylnaphthalene by treating 1 ,8-dichloronaphthalene with lithium 2,2,6,6-tetramethylpiperidide and an aryl lithium reagent, palladium-catalysed cross-coupling reaction to connect the naphthalene-derived side arms to the central spacer moiety, and introduction of anionic moieties by a reaction involving a treatment of the precursor with lithium 4,4'-di-tert-butylbiphenylide.
  • a ninth aspect of the invention relates to a method for preparing a reagent according to the third aspect of the invention comprising the steps of preparing Amberlyst® (CFshCO- resin by treating Amberlyst® (CFs CO- resin with (CFs CO-, and treating a reagent salt containing a common anion of a strong acid (pKa ⁇ 1), particularly BF4; trifluorometanesulfonate, para- toluenesultfonate, methylsulfonate, with the Amberlyst® (CFshCO- resin in a solvent.
  • pKa ⁇ 1 strong acid
  • the method is especially suitable as it enables preparation of a clean product, is operationally simple, stirring in a solvent at room temperature for 1 min to few hours, and the resin can be easily separated from the product by filtration. Alternative methods do not give clean compounds easily.
  • a tenth aspect of the invention relates to a method for preparing a precatalyst according to the fourth aspect of the invention comprising the steps of treating a chloride or a bromide salt of a metal precursor with a silver, potassium, sodium, or tetralkyl ammonium salt of the anion -A’-R 12/5 .
  • Fig. 1 shows the spatial anion control concept for C-H activation, a) Increase of molecular scaffold complexity by direct C-H activation (left), compared to classical cross-coupling which need a prefunctionalized substrate (right) b) Relevance of anion coordination geometry for C-H activation, monomeric Pd(C>2CCH3)2 (left), C-H activation transition state (right) c) schematic influence of spatial anion control on O-M-O bond angles and M-0 distances, gray square represents a rigid backbone.
  • Fig. 2 shows the development of a catalytic system for mild C-H arylation.
  • Fig. 4 shows the molecular structure of isolated L a Pd(CH3CN)2.
  • Fig. 5 shows the influence of modifications to the catalytic system, a) Standard catalytic system with 1a, and a comparison using palladium precursor 1b and preformed complex 1c.
  • Fig. 6 shows the preparation of reaction components, a) H 2 L a . b) Palladium(ll) precatalysts, c) Arylation reagents. H atoms are not shown in the molecular structure diagrams.
  • Fig. 7 shows C-H Arylation reactions at ambient temperature. a H 2 L a (5 mol%), 1a (10 mol%), 24-72 h; b H 2 L a (10 mol%), 1a (20 mol%), 48-72 h. Combined yields of isolated products are given.
  • Fig. 8 shows site-selectivity in comparison with other methods for arene functionalization. Pd-catalyzed non-directed C-H arylation using the method from the current invention is given in the square. Conditions: a) Br 2 , DMF, r.t., 20 h, 46%; b) PhB(OH) 2 (2.5 equiv.), [RuCI 2 (p-cymene)] 2 (5 mol%), AgSbF 6 (20 mol%), Ag 2 O (1 equiv.), Cu(OTf) 2 (20 mol%), THF, 90 °C, 20 h, 85% (from J. Org. Chem.
  • Fig. 9 shows catalyst-controlled site selectivity in direct C-H activation reactions, a) Different substituents on the anion strongly influence the site selectivity of the arylation reaction, b) Catalyst control over the formation of the major regioisomer of the arylation product, c) Catalyst control over the formation of the major regioisomer of the olefination product.
  • Fig. 10 shows arylation next to small alkyl groups as predominant product using the ligand L1.
  • Fig. 11 shows a different or better selectivity for less sterically demanding sites with ligand L2 in comparison to the ligand L1.
  • L1 is as depicted in Fig. 10.
  • the inventor’s anion design for spatial anion control on palladium utilizes two 1 -naphthyl carboxylic acid-derived side-arms, which are structurally constrained by a central aromatic spacer group.
  • the size and geometry of the spacer modulates the relative spatial arrangement of the two carboxylate groups, while sterically demanding mesityl groups prevent the carboxylate groups from coordinating in a bridging mode.
  • Palladium precatalysts 1 and arylation reagents 2 which contain nonafluoro-terf-butoxide anions, were designed to avoid the use of silver additives and any other potentially interfering additives or anions (Figure 2a).
  • the bulky monodentate (CFshCO" can be displaced from palladium by carboxylates such as HaLa and act as a mild base to remove the proton after the C-H activation step.
  • the spatial anion control can enable challenging C-H functionalization reactions with palladium as shown with the non-directed arylation of arenes as limiting reactants.
  • Acid HaLa and palladium precatalyst 1a enabled catalytic C-H arylation of arene 3a with diaryl iodonium reagent 2a at ambient temperature, yielding 4a in 39% yield (Figure 2b).
  • Figure 2b With HaLd and simpler carboxylates, no product was observed (Figure 2b, see Figure 5 for additional screening experiments), which demonstrates the importance of spatial positioning of the two carboxylate groups for the catalytic reactivity.
  • Diaryl iodonium salts with BF4" and CF3SO3" anions have been used previously for C-H arylation of arene, but high temperature, an acid co-solvent, and an excess of arene were required.
  • the common diaryl iodonium salts are not suitable 1a was superior to other precatalysts, thereby demonstrating the importance of the (CFs CO" anion.
  • arylation reagents 2 are accessed from common diaryl iodonium salts by anion exchange on Amberlyst® (CFshCO" resin, whereas HaLa is available in five synthetic steps from commercial materials, and 1a is obtained in two steps from PdCl2(PhCN)2 ( Figure 6).
  • the constrained anion-enabled catalytic C-H arylation is applicable to a wide range of arenes 3 at 26 °C (Fig. 7).
  • Arenes with electron-fonating groups are excellent substrates (4c, 4d).
  • Aryl and bulky alkyl substituents can block ortho C-H activation (4e-g), although arylation next to smaller alkyl groups is possible (4h).
  • the use of bromo- and iodo-arenes and aryl triflates demonstrates complementary reactivity to common Pd-catalyzed crosscoupling processes (4l-o).
  • Fused (hetero)arenes are suitable substrates and yields of up to 86% could be obtained (4p-s).
  • Bis-functionalization can be achieved (4p, 4q, 4s), which demonstrates the potential for poly-arylation reactions.
  • Functional groups such as activated ketones and epoxides (4t, 4u) are compatible, and latestage functionalization of pharmaceutically relevant molecules can be accomplished (4v, 4w, 4x, 4y, 4z, 4aa, 4ab).
  • the catalytic C-H arylation enables the introduction of various aromatic groups with electron-withdrawing or -donating substituents (4ac-4ai).
  • Polybrominated polyaromatic hydrocarbons which are suitable for the preparation of extended aromatic systems, can be accessed (4aj).
  • inventive results demonstrate that structurally constrained carboxylates, especially together with novel precatalysts and reagents that avoid the use of silver salts or any interfering anions or additives, can enable difficult non-directed C-H functionalization of arenes at ambient temperature. Due to the mild reaction conditions late-stage functionalization of molecules of pharmaceutical interest is possible. Compared to traditional cross-coupling reactions, the method gives the products in one step, without requiring synthesis of modified substrates.
  • substitution pattern on R 1 and R 2 of the ligand control the site selectivity in C-H activation reactions.
  • the use of H 2 L a in an arylation or olefination reaction leads predominantly to the formation of an a-regioisomer, while the use of H 2 Lf leads predominantly to the formation of a p-regioisomer (see Fig. 9).
  • ligand L1 Using the ligand L1 , arylation is predominantly observed next to small alkyl groups (see Fig. 10), while the use of ligand L2 is suitable for the arylation at less sterically demanding sites (see Fig. 11).
  • reaction mixture was allowed to cool to room temperature, diluted with DCM (40 ml) and 10% aqueous HCI solution (70 ml, added slowly and in portions). The layers were separated and the aqueous layer was extracted with DCM (2 x 40 ml). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (35 g of silica gel, hexanes, the residue was dry loaded on silica gel) yielded the title compound as a colorless solid (1.8 g, 87% yield).
  • mesityl lithium (5.76 g, 5.00 equiv., 45.67 mmol) was loaded in a separate Schlenk flask.
  • the flask was sealed, taken to a fume hood, and connected to a Schlenk line.
  • the flask was cooled to 0 °C and THF (35 ml) was added slowly.
  • the mixture was briefly taken out of the cooling bath to ensure that most of the MesLi had dissolved, then returned to 0 °C.
  • the above-prepared solution of LiTMP was added at 0 °C to the solution of MesLi, followed by subsequent addition of a solution of S1 (1.8 g, 9.13 mmol) in THF (5 ml).
  • the reaction mixture was allowed to cool to room temperature and H2O (10 ml), 30 % aqueous H2O2 solution (10 ml), and DCM (10 ml) were added. The layers were separated and the aqueous layer was extracted with DCM (3 x 30 ml). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (100 g of silica gel, hexanes/DCM 9:1 , the residue was loaded as a suspension in the eluent) yielded the title compound as a colorless solid (1.15 g, 92% yield).
  • the combined organic extracts were filtered through DCM-soaked filter paper (without drying over MgSC ), and the solvent was removed under reduced pressure.
  • the residue was purified by column chromatography (10 g of silica gel, DCM then DCM/EtOAc 7:3, residue loaded as a suspension in DCM) and the combined fractions were acidified by washing with 20% aqueous HCI solution (before acidification different fractions containing the desired compound display different behavior by TLC analysis, likely due to presence of carboxylate salts after the silica gel column).
  • the organic solution was filtered and the solvent was removed under reduced pressure to give the title compound as a light yellow solid (190 mg, 62% yield).
  • Scheme 1 shows the synthesis of a ligand according to the invention.
  • the synthesis approach can also be applied to other ligands according to the invention.
  • Scheme 1 Synthesis of ligands according to the invention.
  • tert- butyl 8- bromo- 1 -naphthoate (S5) 1,8-Dibromonaphthalene (13.2 g, 46.2 mmol) was loaded in a Schlenk, dissolved with THF (120 mL) and cooled to -78 °C. After 10 min, n BuLi (2.5 M in hexanes, 18.5 mL, 46.2 mmol, 1 equiv.) was added dropwise over 10 min.
  • Amberlyst® A26 hydroxide form resin (ca. 45 ml) was placed in a 250 ml round-bottom flask and washed with distilled H2O (10 times, each time completely covering the surface of the resin, swirling, and then removing the H2O with a pipette). The flask was then attached to a Schlenk adapter equipped with a Teflon pin and dried under high vacuum at room temperature (the flask was kept immersed in a room temperature water bath) for 18 h. The flask was then placed under N2 gas and cooled in liquid N2.
  • the temperature of the flask can be estimated by hand, and if warming above room temperature is observed, the flask is quickly briefly cooled in liquid N2 with swirling of the resin.) After the flask reaches room temperature while being swirled and no temperature increase is observed during 2-3 min, the flask is sealed and left at room temperature for 10 h and then placed under high vacuum for 15 h. The above sequence of steps (addition of further (CFs ⁇ COH (3 ml), keeping the flask sealed for 10 h, and high vacuum for 15 h) was then repeated.
  • the flask was closed under vacuum and taken inside an N2-filled glovebox. Inside the glovebox, 1/3 of the amount of the resin was placed in a 20 ml vial, DCM (10 ml) was added, the vial was closed and gently shaken for 1-2 min. DCM was then removed using a pipette and replaced with DCM/(CF3)3COH 10:1 (11 ml, (CFs ⁇ COH was degassed prior to being placed inside the glovebox, but not dried on molecular sieves). The vial was closed, gently shaken, and kept at room temperature for 20 min. The solvent was removed using a pipette and the resin was then washed two more times with DCM (10 ml, 8 ml).
  • the sample of the resin was crushed into a fine powder before the measurement.
  • diaryl iodonium salts 0.84 g per 1 mmol of diaryl iodonium salt.
  • the mixture was stirred for 1 h at room temperature.
  • the solution was filtered through a small Celite plug, concentrated under vacuum to a minimal volume, and layered with pentane or hexane (1-2.5 ml).
  • the vial was closed and left at -35 °C for 1-48 h affording colorless crystals.
  • the supernatant was removed with a pipette and the crystals were washed with pentane (2 x 0.2-1 ml) and dried under vacuum for 4-5 h to give diaryl iodonium perfluoro-terf-butoxide salts 2a-j as colorless solids.
  • a further amount of product could be obtained from the supernatant solution by combination with the pentane washings followed by storing the solution at -35 °C, or by concentrating the solution, and repeating the crystallization process with reduced volumes
  • the compounds are stable as solids when stored at -35 °C under N2 atmosphere, but decompose slowly in solutions at room temperature.
  • reaction mixture was stirred at 26 °C in the dark for 24-72 h and then separated between DCM (10 ml) and H2O (5 ml).
  • the aqueous layer was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure.
  • the products were purified by column chromatography as specified for each case.
  • the c-isomer was obtained in a mixture with a second unassigned regioisomer (as observed in the 1 H and 19 F NMR spectra) and the starting material as minor impurities (29.7 mg, yellow solid, a’/second isomer/SM 1:0.08:0.04).
  • Overall yield of C-H arylation products 29 mg, 53%, a’/other 1:0.08.

Abstract

The present invention relates to a method for accelerating a chemical transformation of a substrate, particularly C-H arylation and C-H alkylation. Furthermore, the invention relates to the compounds that are used in the method, namely a ligand suitable for forming a metal complex, a precatalyst that provides a metal, and a reagent that provides the moiety to be transferred to the substrate.

Description

Structurally Rigid Dianions for Metal Catalysis
The present invention relates to a method for accelerating a chemical transformation of a substrate, particularly C-H arylation and C-H alkylation. Furthermore, the invention relates to the compounds that are used in the method, namely a ligand suitable for forming a metal complex, a precatalyst that provides a metal, and a reagent that provides the moiety to be transferred to the substrate.
Background of the Invention
Catalytic activation of C-H bonds with transition metals can streamline multi-step organic syntheses and offer resource-efficient processes. For example, the direct arylation of C-H bonds in arenes represents an attractive alternative to C-C cross-coupling reactions, which usually require pre-functionalized substrates (Figure 1a). In particular, palladium catalysts are promising for direct transformation of C-H to C-C bonds. However high catalyst loading, control over regioselectivity, and application to complex molecules of pharmaceutical interest remain challenging. Direct arylation of arenes requires excess arene, high temperatures, acidic, basic, or transition-metal additives, and is limited to certain classes of substrates. A non-directed C-H activation followed by a direct arylation process remains a challenge, even for simple substrates. (Liu, L.-Y. et al. Angew. Chem. Int. Ed. 2020, 59, 13831.).
Palladium-based catalytic C-H activation reactions are often proposed to proceed through mechanisms such as concerted metalation-deprotonation (CMD) mechanism, where the metal and the coordinated anion help to cleave the C-H bond (Figure 1b). Palladium(ll) acetate is usually used as precatalyst for C-H activation and the reactions without additives are inefficient, because the carboxylates block potential sites for C-H activation by incoordination and can form species of higher nuclearity, which might be inactive. Neutral and anionic ligands have been used for non-directed, palladium-catalyzed C-H activation reactions. However, silver(l) additives are often important for the reactivity. They act as terminal oxidants and halide scavengers, but could also assist the C-H functionalization process. Silver-free palladium systems for non-directed C-H activation enable reduced ligand loadings, mild reaction conditions, and challenging late-stage functionalizations of pharmaceutically important molecules With these goals in mind, the inventors describe herein a general strategy for the design of metal complexes containing palladium for C-H activation, particularly for C-H arylation and C-H alkylation of arenes as limiting reactants in mild conditions. Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods to achieve catalytic activation of C-H bonds under mild conditions and at ambient temperature without the use of additives such as silver(l) salts. This objective is attained by the subject-matter of the independent claims of the present specification, with further advantageous embodiments described in the dependent claims, examples, figures and general description of this specification.
Summary of the Invention
A first aspect of the invention relates to a ligand of formula 1 ,
Figure imgf000004_0001
wherein
X1 and X2 are independently selected from -CO2H, -SO3H, -C(O)NHRNX, -SC>2NHRNX and anions thereof, with RNX being selected from -SC>2Rs or aryl, wherein the aryl is substituted with one or more electron-withdrawing groups, wherein Rs is selected from a C1.6 alkyl,
- -CF3, and an aryl substituted with one or more small substituents,
R1 and R2 are H or sterically demanding moieties, the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A,
R6, R7, R8 and R9 are independently from each other selected from H, Ci-10-alkyl, -F, -Cl, -Br, -CF3, -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1, - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1RN2 with
RN1, RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic or a hydrocarbon moiety comprising 3 to 14 carbon atoms, or two moieties of R6 and R7 and/or two moieties of R8 and R9 can be connected to each other to form an additional cycle fused to the naphthalene, and p and v are independently from each other 0, 1 or 2, q and w are independently from each other 0, 1 , 2 or 3.
The ligand according to the first aspect of the invention comprises two naphthyl moieties that form two side-arms. Each side-arm comprises a moiety X1 and X2, respectively. X1 and X2 are suitable for coordinating a metal, e.g. two carboxylate moieties may coordinate palladium.
The two side-arms are connected by a spacer, e.g. a central aromatic spacer such as another naphthyl moiety. The size and geometry of the spacer modulates the relative spatial arrangement of X1 and X2, e.g. two carboxylate groups at X1 and X2 may be arranged approximately in a plane which is parallel to that of the arene spacer.
If the moieties at X1 and X2 tend to coordinate to more than one metal in a bridging mode, sterically demanding moieties at R1 and R2 may prevent such coordination. For example, mesityl moieties at R1 and R2 may prevent bridging of carboxylate moieties at X1 and X2 between two metal atoms.
When the ligand coordinates a metal, it can be used in a chemical transformation of a substrate such as the catalytic activation of a C-H bond and subsequent arylation at this site. If the substrate comprises more than one C-H bond that could be activated, control over regioselectivity of the C-H activation may be achieved by selecting a suitable substitution pattern at R1 and R2. Different R1 and R2 may influence the site (alpha/beta) of arylation. Furthermore, a chiral enantioenriched reaction product may be obtained when a chiral enantioenriched ligand is used (enantioselectivity). Chirality of the ligand may also be achieved by selecting a suitable substitution pattern at R1 and R2.
The ligand may further comprise linear, branched or cyclic substituents at the side-arms.
A second aspect of the invention relates to a metal complex comprising a ligand according to the first aspect of the invention and a metal.
As described above, the ligand according to the first aspect of the invention is suitable for coordinating a metal, e.g. palladium, by the moieties X1 and X2. The metal complex may be used in chemical transformations such as the catalytic activation of C-H bonds. When applied to a catalytic C-H functionalization reaction, the geometric parameters of the X1/X2 coordination on the metal, namely the X1-metal-X2 angles and X1/2-metal distances are important (see Fig. 1b).
For example, simple metal carboxylate complexes such as Pd(C>2CCH3)2 are characterized by an angle a and an angle y. Both angles are formed between O-Pd-O, wherein one oxygen atom originates from one acetate group and the other oxygen atom originates from the other acetate group. Upon contact with the substrate to be activated, the angle a increases and the angle y decreases to allow formation of the transition state (see Fig. 1 b).
In contrast to this, complexes according to the invention are characterized by two different angles a and y even in the absence of the substrate (see Fig. 1c). The controlled spatial arrangement of X1 and X2, which is achieved by the side-arms and the spacer of the ligand according to the first aspect of the invention, leads to stabilization of the geometry required for the reaction transition state over, for example, /^-coordination in a metal complex comprising palladium and carboxylate groups at X1 and X2. Hereby, the barrier for C-H activation is lowered and acceleration of a chemical transformation, e.g. C-H arylation or C-H alkylation, is achieved.
A third aspect of the invention relates to a reagent of formula 9,
Figure imgf000006_0001
wherein
Z+ is selected from l+ and S+,
Y is a Ci-20-alkyl, an aryl, a heteroaryl, or two Y form a ring structure, wherein
Y is optionally substituted by one or more substituents selected from -F, -Cl, -Br, -I, - CN, Ci-12-alkyl, -CF3, -C(=O)-Ra, -ORa, -(CH2)xORa, -SRa, -(CH2)xSRa or -NRa 2, with x being selected from 1 to 6 and with each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, r is 1 for Z+ = l+, and 2 for Z+ = S+,
T is selected from Ci-2o-alkyl, an aryl, a heteroaryl, -CF3, -ORa, -F, -Br, alkenyl, alkynyl with Ra being as defined above, wherein
T is optionally substituted by one or more substituents selected from -F, -Cl, -Br, -I, - CN, Ci-i2-alkyl, -CF3, -C(=O)-Ra, -ORa, -(CH2)xORa, -SRa, -(CH2)xSRa or -NRa 2, with x being selected from 1 to 6 and each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl,
A- is -O’ or -N(R10)-, with R10 being a -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 substituents -ORa with Ra being defined as above, the aryl is substituted with one or more electron withdrawing groups,
R11 is a -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 substituents -ORa with Ra being defined as above, the aryl is substituted with one or more electron withdrawing groups.
The reagent may be used in a C-H functionalization reaction as described above. The reagent according to the third aspect of the invention is designed in such a way that the use of silver(l) compounds and any other potentially interfering additives or anions is avoided during the reaction.
The reagent provides a moiety T that is transferred to a substrate upon activation of a C-H bond of the substrate by the metal complex described above. T is bound to l+ or S+ cation. I+- reagents are useful particularly for C-H arylation reactions while and S+ reagents are useful particularly for C- H alkylation reactions, e.g. for the transfer of -CF3.
I+ reagents comprise one moiety Y and S+ reagents comprise two moieties Y that remain at the cation.
In case both moieties T and Y are based on an aryl such as phenyl, the respective substitution patterns determine which aryl remains at the cation (Y) and which aryl is transferred to a substrate (T).
The anion A'-R11 is a bulky monodentate anion, which does not participate in the sixmembered CMD process. The anion acts as a mild base to remove H+ after the C-H activation step.
A fourth aspect of the invention relates to a precatalyst of formula 10,
Figure imgf000007_0001
wherein
M is a metal,
A’ is selected from -O-, -N(R12a)-,
R12 and R12a are independently selected from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, further optionally substituted by 1-2 -ORb with Rb being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, the aryl is substituted with one or more electron withdrawing groups,
L is a neutral or anionic ligand x is equal to the charge of the metal M minus the number of L that are anionic, z is 0, 1 , 2, 3, or 4, wherein the sum of x and z equals the number of coordinating bonds that are formed by the metal M.
The precatalyst may be used in a C-H functionalization reaction as described above. The precatalyst according to the fourth aspect of the invention is designed in such a way that the use of silver(l) compounds and any other potentially interfering additives or anions is avoided during the reaction.
When contacted with a ligand according to the first aspect of the invention, the anions A'-R12 and A'-R5 are displaced from the metal and the metal is subsequently coordinated by the ligand according to the first aspect of the invention.
With the ligand according to the first aspect of the invention the moieties L of the precatalyst can also be displaced. For example, a ligand that comprises mesityl moieties at R1 and R2 may coordinate Pd(ll) without the moiety L of the precatalyst.
In case the ligand according to the first aspect of the invention does not comprise sterically demanding moieties (R1 and R2 = -H), L-M-L is coordinated by the ligand according to the first aspect of the invention. In this case, the moiety L functions as sterically demanding moiety that contributes to the spatial arrangement of the side-arms and the moieties X1 and X2.
The anions A'-R12 and A'-R5 are a bulky monodentate anions, which do not participate in the six-membered CMD process. The anions act as a mild base to remove H+ after the C-H activation step.
A fifth aspect of the invention relates to a method for accelerating a chemical transformation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound. The inventive method makes use of the ligand according to the first aspect of the invention. As described above, the ligand is suitable for coordinating a metal. The metal is provided by a precatalyst. Upon formation of a metal complex comprising the ligand according to the first aspect of the invention and the metal, a C-H bond of the substrate may be catalytically activated by a C-H activation process and subsequently a moiety from the reagent, e.g. an aryl or alkyl, may be transferred to the substrate to form a covalent bond with the activated C atom.
The inventive method may be performed without the use of silver(l) compounds or any other potentially interfering additives. Furthermore, the inventive method can be performed at mild conditions and at ambient temperature.
Description of the Invention
Terms and definitions
For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated or cited herein by reference, the definition set forth shall control.
The terms “comprising,” “having,” “containing,” and “including,” and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of” or “consisting of.”
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictate otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
As used herein, including in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise. The term alkyl refers to a linear or branched hydrocarbon moiety. A Cis-alkyl in the context of the present specification relates to a saturated linear or branched hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms. Similarly, a Ci-12-alkyl relates to a linear or branched hydrocarbon having up to 12 carbon atoms. Non-limiting examples in a broader sense for a Ci-Ce alkyl include methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, terf-butyl, but-3-enyl, prop- 2-inyl, but-3-inyl, 3-methylbut-2-enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl, 2- methylbutyl, 3-methylbutyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 ,2-dimethylpropyl, pent-4- inyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl. In certain embodiments, a Ci-e alkyl refers to methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), n-butyl (Bu), fertbutyl (tBu), n-pentyl and n- hexyl. Particularly, non-limiting examples for a Ci-Ce alkyl include methyl, ethyl, propyl, n-butyl, 2-methylpropyl, terf-butyl, n-pentyl, 2-methyl butyl, 3-methylbutyl, 1 , 1-dimethylpropyl, 1 ,2- dimethylpropyl, 1 ,2-dimethylpropyl, 3-methyl-2-pentyl, and 4-methyl-2-pentyl. In certain embodiments, a Ci-e alkyl refers to methyl (Me), ethyl (Et), propyl (Pr), isopropyl (iPr), n-butyl (Bu), terfbutyl (tBu), n-pentyl and n-hexyl.
The term cyclic hydrocarbon moiety relates to a mono- or polycyclic hydrocarbon moiety that comprises carbon-carbon single, double and/or triple bonds, particularly carbon-carbon single bonds and/or carbon-carbon double bonds. The ring structures of a polycyclic hydrocarbon moiety may be bridged, fused or spirocyclic. Non-limiting examples for cyclic hydrocarbon moieties are aryls, e.g. phenyl or naphthyl, and cycloalkyls, e.g. hexyl.
The term Cs-e-cycloalkyl in the context of the present specification relates to a saturated hydrocarbon ring having 5 or 6 carbon atoms.
The term Amberlyst® A26 hydroxide form resin relates to a strongly basic, macroreticular resin with quaternary ammonium functionality and containing hydroxide anions.
The term Amberlyst® (CF3)3CO~ resin relates to a Amberlyst® A26 hydroxide form resin that has been modified by exchanging hydroxide with (CF3)3CO_.
Detailed description
A first aspect of the invention relates to a ligand of formula 1 , particularly of formula 1a,
Figure imgf000010_0001
Figure imgf000011_0001
wherein
X1 and X2 are independently, particularly X1 and X2 are both, selected from -CO2H, -SO3H, - C(O)NHRNX, -SC>2NHRNX and anions thereof, with RNX being selected from -SC>2Rs or aryl, particularly phenyl or naphthyl, wherein the aryl is substituted with one or more electronwithdrawing groups, particularly -F, -CF3, -SF5, wherein Rs is selected from a C1.6 alkyl, particularly -CH3,
-CF3, and an aryl, wherein the aryl is particularly phenyl or naphthyl, substituted with one or more small substituents, particularly -F, -Cl, -CF3, -SF5, -CH3, isopropyl,
R1 and R2 are H or sterically demanding moieties, particularly R1 and R2 are H or sterically demanding moieties independently selected from a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
- the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -SF5, -ORC1, - C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the Ci-12-al kyl is optionally substituted by one or more-F atoms,
- the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF3, -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1, -OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A, in particular the spacer is a mono- or polycyclic, particularly a planar mono- or polycyclic, hydrocarbon moiety, optionally comprising one or more heteroatoms selected from N, O and S, particularly N, having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A, wherein the spacer optionally comprises one or more substituents selected from
-F, -Cl, -Br,
-ORC1 with RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs- 6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, or a C1-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, - CF3, -SF5, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1, - C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , - SC>2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly C1.6- alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CFs, -ORC1 , - C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1, -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a Ci -12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, two moieties of R3 and R4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle,
R6, R7, R8 and R9 are independently from each other selected from H, Ci-10-alkyl, particularly Ci-6-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1, -C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , - SC>2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a C1 -12-alkyl and a cyclic or a hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly R6, R7, R8 and R9 are H, or two moieties of R6 and R7 and/or two moieties of R8 and R9 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle, and p and v are independently from each other 0, 1 or 2, q and w are independently from each other 0, 1 , 2 or 3.
Two moieties of R6 and R7 can be connected to each other means that in case of p=1 and q=1 , R6 and R7 together form an additional cycle. In case of p=2 (or q =2) two moieties R6 (or R7) form an additional cycle fused to naphthalene side-arm. The same applies to R8 and R9.
In certain embodiments X1 and X2 are selected from anions of -CO2H, -SO3H, -C(O)NHRNX, - SC>2NHRNX with RNX being as defined above.
In certain embodiments, p, q, v and w are 0.
In certain embodiments, R1 and R2 are selected from a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF3, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl,
- H, a branched Cs-12-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the branched Cs-12-al kyl or the Ci -4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , -C(O)NRN1 RN2, - N(RN1)C(O)H, -N(RN1)C(O)Rc1 , -C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, a monocyclic or bicyclic cycloalkyl comprising 5 to 14 carbon atoms, wherein the cycloalkyl optionally comprises one or more substituents, particularly 1 to 3 substituents, selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , - OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
In certain embodiments, R1 and R2 are selected from a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, - CF3, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, a branched C3.i2-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the branched C3.i2-alkyl or the Ci -4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , -C(O)NRN1 RN2, - N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, a monocyclic or bicyclic cycloalkyl comprising 5 to 14 carbon atoms, wherein the cycloalkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -Br, -CF3, -ORC1 , - C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-io-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, - ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, isopropyl, cyclopentyl, cyclohexyl.
In certain embodiments, R1 and R2 are independently selected from
- H, a branched Cs-12-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the branched Cs-12-al kyl or the Ci-4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , -C(O)NRN1 RN2, - N(RN1)C(O)H, -N(RN1)C(O)Rc1 , -C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, a monocyclic or bicyclic cycloalkyl comprising 5 to 14 carbon atoms, wherein the cycloalkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , - C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
In certain embodiments, R1 and R2 are independently selected from
- a branched Cs-12-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the branched Cs-i2-al kyl or the Ci -4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -ORC1 , -C(O)NRN1 RN2, - N(RN1)C(O)H, -N(RN1)C(O)Rc1 , -C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, a monocyclic or bicyclic cycloalkyl comprising 5 to 14 carbon atoms, wherein the cycloalkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CFs, -ORC1 , - C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms. In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
- -F, -Cl, -Br, -CF3,
- -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1, -OC(O)RC1, - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from H, Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, tert-butyl, cyclopentyl, cyclohexyl.
In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
- -F, -Cl, -Br, -CF3,
- -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)RC1, -C(O)ORC1, -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, with RN1, RN2, RN3, RC1 being H or a Ci-12-alkyl, particularly H or a Ci-e-alkyl, more particularly H, methyl, ethyl, hexyl, iso-propyl, tert-butyl.
In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 6 to 14 carbon atoms, particularly 8 to 12 carbon atoms, more particularly 2-adamantyl, a Ci-e-alkyl, more particularly Ci-4-alkyl,
- -F, -Cl, -Br, -CF3,
- -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)Rc1, particularly -ORC1 , -N(RN1)C(O)Rc1, with RN1, RN2, RC1 being H or a Ci-12-alkyl, particularly methyl, ethyl, hexyl, iso-propyl, tert-butyl.
In certain embodiments, RN1 is H or Ci-2-alkyl, particularly H.
In certain embodiments, RC1 is a Ci-e-alkyl, particularly a Ci-4-alkyl, more particularly isopropyl or tert-butyl, even more particularly tert-butyl. In certain embodiments, R1 and R2 are a phenyl optionally substituted with 1-5 substituents, particularly 1 to 3 substituents, selected from a linear or branched Ci-s-alkyl, particularly a linear or branched Ci-3-alkyl, and a Cs-s-cycloalkyl.
In certain embodiments, R1 and R2 are a phenyl substituted with two substituents in meta position (3 and 5 positions of the phenyl) or three substituents in ortho and para position (2,4,6-positions).
In certain embodiments, R1 and R2 are selected from 2,4,6-Me3CeH2, 2,4,6-iPr3CeH2, phenyl, 3,5-tBu3CeH3.
In certain embodiments, R1 and R2 are 2,4,6-Me3CeH2 (mesityl).
In certain embodiments, R1 and R2 are identical.
In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl,
Figure imgf000017_0001
a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
- -F, -Cl, -Br, -CF3,
- -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1, -OC(O)RC1, - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from H, Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, tert-butyl, cyclopentyl, cyclohexyl.
The substitution pattern at R1 and R2 may be chiral. If chiral enantioenriched ligands are used in a chemical transformation of a substrate such as the catalytic activation of a C-H bond and subsequent arylation at this site, a chiral enantioenriched reaction product may be obtained. Chirality of the ligand may be obtained by using a substitution pattern at R1 and R2 that comprises a linear alkyl, a saturated ring or an amino acid that comprises one or more stereocenter. In certain embodiments, R1 and R2 are sterically demanding moieties as defined above, particularly R1 and R2 are a phenyl substituted by CF3, methyl,
Figure imgf000018_0001
particularly
CF3 or methyl, wherein R1 and R2 each comprise at least one substituent selected from
- a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Ci-2-alkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by one or more, particularly 1 or 2, substituents selected from a Ci-4-alkyl, an unsubstituted phenyl, and a phenyl substituted by a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, a moiety Wv-B-Eq, wherein o W is -C(=O)-, -C(=O)NRN1-, -NRN1(C=O)- with RN1 being H or Ci-4-alkyl, o v is 0 or 1 , particularly v is 0 in case of B being a cycloalkyl and v is 1 in case of B being a 5- or 6-membered saturated heterocycle, o B is a 5- or 6-membered saturated heterocycle or a Cs-7-cycloalkyl, o E is Ci-e-alkyl, -C(=O)-O-R°, -C(=O)NRN1RN2, -NRN1(C=O)RC1 , with R°, RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E1),
Figure imgf000018_0002
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
- -C(=O)-NRN1-C(H)(RC2)-C(=O)-O-E, wherein o RN1 being H or Ci-4-alkyl, o RC2 is an unsubstituted Ci-4-alkyl or a Ci-4-alkyl substituted by -SH, -SCH3, OH, phenyl, phenyl-OH, indole, -C(=O)-NH2, -NH2, -NH-C(=NH)-NH2, -COOH, imidazole, particularly methyl, isopropyl, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-CH2-S- CH3, -CH2-phenyl, -CH2-phenyl-OH, -CH2-imidazole (particularly 1/7-imidazol-4- yl such as in histidine), -CH2-indole (particularly 1/7-indol-3-yl such as in tryptophan), -CH(OH)-CH3, -CH2-CH2-C(=O)-NH2, -CH2-C(=O)-NH2, -CH2-SH, - CH2-OH, -CH2-CH2-CH2-CH2-NH2, -CH2-CH2-CH2-NH-C(=NH)-NH2, -CH2-CH2- COOH, CH2-COOH, o E is H or Ci-4-alkyl, particularly Ci-4-alkyl, more particularly ethyl or methyl.
In certain embodiments, R1 and R2 are sterically demanding moieties as defined above, particularly R1 and R2 are a phenyl substituted by CF3, methyl,
Figure imgf000019_0001
particularly
CF3 or methyl, wherein R1 and R2 each comprise at least one substituent selected from
- a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Ci-2-alkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by one or more, particularly 1 or 2, substituents selected from a Ci-4-alkyl, an unsubstituted phenyl, and a phenyl substituted by a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, a moiety Wv-B-Eq, wherein o W is -C(=O)-, -C(=O)NRN1-, -NRN1(C=O)- with RN1 being H or Ci-4-alkyl, o v is 0 or 1 , o B is a 5- or 6-membered saturated heterocycle or a Cs-7-cycloalkyl, o E is Ci-e-alkyl, -C(=O)-O-R°, -C(=O)NRN1RN2, -NRN1(C=O)Rc1 , with R°, RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E1),
Figure imgf000019_0002
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3. In certain embodiments, R1 and R2 are sterically demanding moieties as defined above, particularly R1 and R2 are a phenyl substituted by CF3, methyl,
Figure imgf000020_0001
particularly
CF3 or methyl, wherein R1 and R2 each comprise an additional substituent selected from
- a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Ci-2-alkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by a Ci-4-alkyl and a phenyl that is substituted by a Ci-4-alkyl, a moiety Wv-B-Eq, wherein o W is -C(=O)-, o v is 0 or 1 , o B is pyrrolidinyl or cyclohexyl, o E is Ci-3-alkyl, -C(=O)-O-R°, -C(=O)NRN1RN2, -NRN1(C=O)Rc1 , with R°, RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E1),
Figure imgf000020_0002
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3.
In certain embodiments, the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl,
Figure imgf000020_0003
a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, - -F, -Cl, -Br, -CF3,
- -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from H, Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, tert-butyl, cyclopentyl, cyclohexyl, wherein the phenyl is optionally further substituted by at least one substituent selected from a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Coalkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by one or more, particularly 1 or 2, substituents selected from a Ci-4-alkyl, an unsubstituted phenyl, and a phenyl substituted by a Ci-io-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, a moiety Wv-B-Eq, wherein o W is -C(=O)-, -C(=O)NRN1-, -NRN1 (C=O)- with RN1 being H or Ci-4-alkyl, o v is 0 or 1 , o B is a 5- or 6-membered saturated heterocycle or a Cs-7-cycloalkyl, o E is Ci-e-alkyl, -C(=O)-O-R°, -C(=O)NRN1 RN2, -NRN1(C=O)RC1 , with R°, RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E1),
Figure imgf000021_0001
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
- -C(=O)-NRN1-C(H)(RC2)-C(=O)-O-E, wherein o RN1 being H or Ci-4-alkyl, o RC2 is an unsubstituted Ci-4-alkyl or a Ci-4-alkyl substituted by -SH, -SCH3, OH, phenyl, phenyl-OH, indole, -C(=O)-NH2, -NH2, -NH-C(=NH)-NH2, -COOH, imidazole, particularly methyl, isopropyl, -CH2-CH(CHs)2, -CH(CHs)-CH2-CH3, -CH2-CH2- S-CH3, -CH2-phenyl, -CH2-phenyl-OH, -CH2-imidazole (particularly 1/7- imidazol-4-yl such as in histidine), -CH2-indole (particularly 1/7-indol-3-yl such as in tryptophan), -CH(OH)-CH3, -CH2-CH2-C(=O)-NH2, -CH2-C(=O)-NH2, - CH2-SH, -CH2-OH, -CH2-CH2-CH2-CH2-NH2, -CH2-CH2-CH2-NH-C(=NH)-NH2, - CH2-CH2-COOH, CH2-COOH, o E is H or Ci-4-alkyl, particularly Ci-4-alkyl, more particularly ethyl or methyl.
In certain embodiments, the ligand is a compound of formula 2, particularly of formula 2a,
Figure imgf000022_0001
wherein X1, X2, R1 and R2 are defined as described above, and
R6a, R7a, R7b, R8a, R9a, R9b are defined as R6, R7, R8 and R9, respectively.
In certain embodiments, R6a, R7a, R7b, R8a, R9a, R9b are H.
In certain embodiments, the spacer optionally comprises one or more substituents selected from F, Cl, Br, CF3, -ORC1 , Ci-10-alkyl, a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the alkyl and cyclic hydrocarbon moiety can be further substituted with one or more substituents selected from -F, -Cl, -Br, -CF3, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, - N(RN1)C(O)RC1 , -C(O)ORC1, -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , - SO2NRN1RN2 with
RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms. In certain embodiments, the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A. In certain embodiments, the spacer is a planar cyclic moiety. The cyclic moiety of the spacer may comprise substituents as described herein.
In certain embodiments, the spacer is a moiety of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a,
Figure imgf000023_0001
wherein R3 and R4 are independently selected from
-F, -Cl, -Br, or
-ORC1 with RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, ora Ci-12-alkyl and a cyclic hydrocarbon moiety, particularly an aryl, comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
- the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CF3, -SF5, -ORC1, - C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
- the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly C1.4- alkyl, -F, -Cl, -Br, -CF3, -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1, - C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a C5-6- cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, two moieties of R3 and R4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle, n and m are independently from each other 0 or 1 , particularly n and m both are 0.
In certain embodiments, the spacer is a moiety of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a, wherein R3 and R4 are independently selected from a Ci-12-al kyl and a cyclic hydrocarbon moiety, particularly an aryl, more particularly phenyl, comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
- the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
- the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-4-alkyl, -C(O)NRN1RN2, -N(RN1)C(O)Rc1, - N(RN1)C(O)NRN2RN3, with RN1, RN2, RN3, RC1 being H, Ci-6-alkyl, or aryl, or two moieties of R3 and R4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle, n and m are independently from each other 0 or 1 , particularly n is 1 and and m is 0.
In certain embodiments, R3 and R4 are selected from F, Cl, Br, CF3, -ORC1 , a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly an aryl, more particularly phenyl, and Ci-10-alkyl, wherein the alkyl and cyclic hydrocarbon moiety can be further substituted with one or more substituents selected from -F, -Cl, -Br, -CF3, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, - N(RN1)C(O)Rc1 , -C(O)ORC1, -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , - SO2NRN1RN2 with
RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
In certain embodiments, n is 1 and m is 0.
In certain embodiments, both n and m are 0.
In certain embodiments, the ligand is a compound of formula 2 having a spacer of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a. In certain embodiments, the ligand is a compound of formula 2a having a spacer of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a.
In certain embodiments, the ligand is a compound of formula 4 or 5, particularly of formula 4,
Figure imgf000025_0001
(5), with R1 and R2 being as defined above.
In certain embodiments, the ligand is a compound of formula 6, 7, or 8, particularly of formula
6,
Figure imgf000025_0002
In certain embodiments, the ligand is selected from a compound of formula 6, 7 or 8, and a compound of formula X1 to X17, and a compound of formula X18 to X29,
Figure imgf000026_0001
Figure imgf000027_0001
RECTIFIED SHEET (RULE 91) ISA/EP
Figure imgf000028_0001
-NH-Piv is
In certain embodiments, the ligand is selected from a compound of formula 6, and a compound of formula X1 to X17, and a compound of formula X18 to X21. In certain embodiments, the ligand is a compound of formula 6, 7, 8, or X11, particularly of formula 6 and X11. A second aspect of the invention relates to a metal complex comprising a ligand according to the first aspect of the invention and a metal.
In certain embodiments, the metal is selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt.
In certain embodiments, the metal is selected from Pd, Cu, Ir, Rh, Co, Au, Ru.
In certain embodiments, the metal is selected from Pd, Ir, Rh, Co, Ru.
In certain embodiments, the metal is Pd or Pt.
In certain embodiments, the metal is Pd.
A third aspect of the invention relates to a reagent of formula 9,
Figure imgf000029_0001
(9), wherein
Z+ is selected from l+ and S+, particularly l+,
Y is a Ci-20-alkyl, an aryl, a heteroaryl, or two Y form a ring structure, particularly Y is an aryl when Z+ = l+, wherein
Y is optionally substituted by one or more substituents, particularly 1 or 2 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, -CF3, -C(=O)-Ra, -ORa, - (CH2)xORa, -SRa, -(CH2)xSRa or -NRa2, with x being selected from 1 to 6 and with each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, r is 1 for Z+ = l+, and 2 for Z+ = S+,
T is selected from Ci-20-alkyl, an aryl, a heteroaryl, -CF3, -ORa, -F, -Br, alkenyl, alkynyl, particularly T is an aryl when Z+ = l+, with Ra being as defined above, wherein
T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, more particularly 1 or 2 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, -CF3, -C(=O)-Ra, -ORa, -(CH2)xORa, -SRa, -(CH2)xSRa or -NRa 2, with x being selected from 1 to 6 and each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl,
A- is -O' or -N(R10)', particularly -0; with R10 being a -Ci-6-alkyl or aryl, wherein - the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -ORa, particularly 0, with Ra being defined as above,
- the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
R11 is a -Ci-6-alkyl or aryl, wherein
- the -C1.6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -ORa, particularly 0, with Ra being defined as above,
- the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms.
In certain embodiments, R11 is selected from -CH(CF3)2, -C(CF3)3.
In certain embodiments, R11 is -C(CF3)3.
In certain embodiments, Z+ is l+ and r is 1.
In certain embodiments, Y and T are both an aryl, particularly phenyl, that is optionally substituted as described above.
In certain embodiments, Y is substituted by 1 or 2 substituents selected from -F, -Cl, -Br, -I, - CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, cyclopentyl, cyclohexyl and -CF3.
In certain embodiments, Y is substituted by 1 or 2 substituents selected from -F, -Cl, -Br, -I, - CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, and -CF3.
In certain embodiments, Y is substituted by 1 or 2 substituents selected from a Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl, cyclopentyl, cyclohexyl.
In certain embodiments, Y is substituted by 1 or 2 substituents selected from a Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl.
T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a C1.4- alkyl, -CF3 and indole. T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a C1.4- alkyl, and -CF3.
T is optionally substituted by one or more substituents, particularly 1 , 2 or 3 substituents, selected from -F, -Cl, -Br, -I, Ci-12-alkyl, particularly a Ci-e-alkyl, more particularly a Ci-4-alkyl.
In certain embodiments, A- is -O'.
In certain embodiments, R11 is a Ci-6-alkyl or a fully or partly fluorinated Ci-e-alkyl, more particularly R11 is -C-(CFs)3.
In certain embodiments, Z+ is l+ and r is 1 ,
Y and T are both an aryl that is optionally substituted as described above,
A' is -O;
R11 is defined as above, particularly R11 is a Ci-6-alkyl or a fully or partly fluorinated Ci-e-alkyl, more particularly R11 is -C-(CF3)3.
In case both moieties T and Y are based on an aryl such as phenyl, the respective substitution patterns determine which aryl remains at the cation (Y) and which aryl is transferred to a substrate (T). Particularly the substitutions at phenyls that are at the ortho position in relation to the cation Z+ are relevant. If both ortho positions of a phenyl (T) are unsubstituted, it will be transferred to a substrate. The other phenyl (Y) needs to have one substituent in the ortho position to remain at the cation. For example, the left phenyl moiety of reagent RG1 (see below) remains bound to l+, while the right phenyl moiety may be transferred to a substrate.
In certain embodiments, Y and T are both an aryl, particularly a phenyl, wherein
- Y comprises one or more substituents as described above, wherein one substituent is at one ortho position in relation to Z+ and the other ortho position in relation to Z+ is unsubstituted, and
- T is optionally substituted as described above, wherein both ortho positions in relation to Z+ are unsubstituted.
Figure imgf000031_0001
In certain embodiments, the reagent is a compound of formula (RG1), (RG1). A fourth aspect of the invention relates to a precatalyst of formula 10, particularly of formula 10a, ■
Figure imgf000032_0001
wherein
M is a metal, particularly selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, particularly Pd,
A’ is selected from -O-, -N(R12a)-, -N(R5a)-, particularly -O-,
R12, R12a, R5 and R5a are independently selected, particularly all are selected, from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 -ORb, particularly 0, with Rb being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from -C(CF3)s, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
L is a neutral or anionic ligand, particularly
L is in case of M being Pd, Cu, Au, Pt a weakly coordinated ligand selected from -NC-aryl, -NC-Ci-12-alkyl, -S(Ci -12-alkyl)2,
O(Ci-6-alkyl)2, or an O-alkyl group, wherein the O-alkyl group is further attached to R12 or R5,
L is a coordinated neutral ligand, particularly a strongly coordinated neutral ligand, particularly cymene, in case of M being Ru,
L is a coordinated anionic ligand, particularly a strongly coordinated anionic ligand, particularly pentamethylcyclopentadienyl, in case of M being Rh or Ir x is equal to the charge of the metal M minus the number of L that are anionic, z is 0, 1 , 2, 3, or 4, wherein the sum of x and z equals the number of coordinating bonds that are formed by the metal M.
Neutral or anionic ligand are known to a skilled person. In certain embodiments, L is a neutral or anionic ligand suitable to form the metal complex 10 and 10a. In certain embodiments, the precatalyst is a compound of formula 10, wherein
M is Pd,
A’ is -O-,
R12 is a -Ci-6 alkyl is substituted by one or more -F, particularly -CH(CF3)2, -C(CF3)3, more particularly -C(CF3)3,
L is defined as above, particularly L is selected from -NC-phenyl, -NC-Ci-i2-alkyl, - S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, more particularly L is -NC-phenyl, x is 2 and z is 2.
In certain embodiments, the precatalyst is a compound of formula 10a, wherein
M is a metal, particularly selected from Pd, Pt, more particularly M is Pd,
A’ is selected from -O-, -N(R12a)-, -N(R5a)-, particularly -O-,
R12, R12a, R5 and R5a are independently selected, particularly all are selected, from -Ci-6-alkyl or aryl, wherein the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 -ORb, particularly 0, with Rb being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from -C(CF3)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
L is a weakly coordinated ligand selected from -NC-aryl, -NC-Ci-i2-alkyl, -S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, or an O-alkyl group, wherein the O-alkyl group is further attached to R12 or R5.
In certain embodiments, the precatalyst is a compound of formula 10a, wherein
M is Pd,
A’ is -O-,
R12 and R5 are a -Ci-e alkyl is substituted by one or more -F, particularly -CH(CF3)2, - C(CF3)3, more particularly -C(CF3)3,
L is defined as above, particularly L is selected from -NC-phenyl, -NC-Ci-i2-alkyl, - S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, more particularly L is -NC-phenyl.
In certain embodiments, the precatalyst is a compound of formula 10a with M being Pd. In certain embodiments, R12 and R5 are selected from -CH(CF3)2, -C(CF3)3.
In certain embodiments, R12 and R5 are -C(CF3)3,
In certain embodiments, R12, R12a, R5 and R5a are identical.
In certain embodiments, A’ is -O- and R12 and R5 are selected from -CH(CF3)2, -C(CF3)3, particularly R12 and R5 are -C(CF3)3,
In certain embodiments, L is a ligand selected from -NC-aryl, -NC-Ci-12-alkyl, -S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2.
In certain embodiments, L is a ligand selected from -NC-phenyl, -NC-Ci-12-alkyl, -S(Ci-i2- alkyl)2, O(Ci-6-alkyl)2.
In certain embodiments, L is -NC-phenyl.
In certain embodiments, A’ is -O- and R12 and R5 are selected from -CH(CF3)2, -C(CF3)3, particularly R12 and R5 are -C(CF3)3, and L is a ligand selected from -NC-phenyl, -NC-C1.12- alkyl, -S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2.
In certain embodiments, A’ is -O- and R12 and R5 are selected from -CH(CF3)2, -C(CF3)3, particularly R12 and R5 are -C(CF3)3, and L is -NC-phenyl.
A fifth aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
In certain embodiments, the method for accelerating a chemical transformation comprises the steps of a. providing a substrate to be chemically transformed, a reagent according to the third aspect of the invention comprising at least one moiety to be transferred to the substrate, a precatalyst according to the fourth aspect of the invention comprising a coordinated metal, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
In certain embodiments, the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent comprising at least one aryl moiety Ar’ or alkyl moiety Aik’, a precatalyst comprising a coordinated metal, particularly a coordinated metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, a ligand according to the first aspect of the invention, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a compound comprising a moiety Ar-Ar’ or Ar-Alk’.
In certain embodiments, the reagent is a compound according to the third aspect of the invention.
In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention or a compound composed of a) Pd(ll), b) a weakly basic anion, particularly a basic anion having a p a of the corresponding acid <2, particularly <0.5, and c) optionally containing a weakly coordinating ligand, particularly a ligand selected from a nitrile, an ether, or thioether.
In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention, Pd(-O-C(=O)-CF3)2, Pd(CH3CN)4(BF4)2, Pd(PhCN)4(BF4)2.
In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention with M being Pd, Pd(-O-C(=O)-CF3)2, Pd(CH3CN)4(BF4)2, Pd(PhCN)4(BF4)2.
In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention. In certain embodiments, the precatalyst is a compound according to the fourth aspect of the invention with M being Pd.
In certain embodiments, the method is performed in a solvent.
In certain embodiments, the method is performed in an organic solvent, in particular selected from 1,4-dioxane, ethylacetate, dichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl-methyl ether, 1,2-dimethoxyethane.
In certain embodiments, the transformation step is performed at a temperature between 10 °C and 110 °C, particularly between 20 °C and 60 °C.
In certain embodiments, the transformation step is performed for 1 h to 72 h, particularly for 12 h to 72 h.
A sixth aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent according to the third aspect of the invention, a precatalyst comprising a coordinated metal, a ligand suitable to coordinate a metal, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
In certain embodiments, the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent according to the third aspect of the invention, a precatalyst comprising a coordinated metal, particularly a coordinated metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, a ligand suitable to coordinate a metal, particularly a metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a compound comprising a moiety Ar-Ar’ or Ar-Alk’. With regard to the precatalyst, reference is made to the embodiments of the fourth and fifth aspect of the invention.
In certain embodiments, the ligand is a ligand according to the first aspect of the invention.
With regard to reaction conditions, reference is made to the embodiments of the fifth aspect of the invention.
A seventh aspect of the invention relates to a method for accelerating a chemical transformation, particularly for C-H arylation, C-H alkylation comprising the steps of a. providing a substrate to be chemically transformed, a reagent comprising at least one moiety to be transferred to the substrate, a precatalyst according to the fourth aspect of the invention, a ligand suitable to coordinate a metal, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound.
In certain embodiments, the method comprises the steps of a. providing a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent comprising at least one aryl moiety Ar’ or alkyl moiety Aik’, a precatalyst according to the fourth aspect of the invention, a ligand suitable to coordinate a metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a compound comprising a moiety Ar-Ar’ or Ar-Alk’.
With regard to the reagent, reference is made to the embodiments of the third and fifth aspect of the invention.
In certain embodiments, the ligand is a ligand according to the first aspect of the invention.
With regard to reaction conditions, reference is made to the embodiments of the fifth aspect of the invention. An eighth aspect of the invention relates to a method for preparing a ligand according to the first aspect of the invention comprising the steps of preparing 1 ,8-dichloronaphthalene by treating 1 ,8-dichloronaphthalene with CuCI, preparing 1 ,8-Dichloro-2-arylnaphthalene by treating 1 ,8-dichloronaphthalene with lithium 2,2,6,6-tetramethylpiperidide and an aryl lithium reagent, palladium-catalysed cross-coupling reaction to connect the naphthalene-derived side arms to the central spacer moiety, and introduction of anionic moieties by a reaction involving a treatment of the precursor with lithium 4,4'-di-tert-butylbiphenylide.
Further embodiments are shown in Figure 6a.
A ninth aspect of the invention relates to a method for preparing a reagent according to the third aspect of the invention comprising the steps of preparing Amberlyst® (CFshCO- resin by treating Amberlyst® (CFs CO- resin with (CFs CO-, and treating a reagent salt containing a common anion of a strong acid (pKa <1), particularly BF4; trifluorometanesulfonate, para- toluenesultfonate, methylsulfonate, with the Amberlyst® (CFshCO- resin in a solvent.
The method is especially suitable as it enables preparation of a clean product, is operationally simple, stirring in a solvent at room temperature for 1 min to few hours, and the resin can be easily separated from the product by filtration. Alternative methods do not give clean compounds easily.
A tenth aspect of the invention relates to a method for preparing a precatalyst according to the fourth aspect of the invention comprising the steps of treating a chloride or a bromide salt of a metal precursor with a silver, potassium, sodium, or tetralkyl ammonium salt of the anion -A’-R12/5.
Description of the Figures
Fig. 1 shows the spatial anion control concept for C-H activation, a) Increase of molecular scaffold complexity by direct C-H activation (left), compared to classical cross-coupling which need a prefunctionalized substrate (right) b) Relevance of anion coordination geometry for C-H activation, monomeric Pd(C>2CCH3)2 (left), C-H activation transition state (right) c) schematic influence of spatial anion control on O-M-O bond angles and M-0 distances, gray square represents a rigid backbone.
Fig. 2 shows the development of a catalytic system for mild C-H arylation. a) Design of the catalytic system, b) top: C-H arylation at ambient temperature, bottom: comparison with other carboxylates, Pd(ll) precursors, and l(lll) reagents.
Fig. 4 shows the molecular structure of isolated LaPd(CH3CN)2. Fig. 5 shows the influence of modifications to the catalytic system, a) Standard catalytic system with 1a, and a comparison using palladium precursor 1b and preformed complex 1c. b) Comparison of H2La with other carboxylic acids and the molecular structure of H2Lb (H atoms not shown), c) Comparison of 1a with other palladium precursors, d) Performance in other solvents, e) Effect of different catalyst loadings, f) Replacement of (CFs CO" in 2a with other anions, g) Control experiments.
Fig. 6 shows the preparation of reaction components, a) H2La. b) Palladium(ll) precatalysts, c) Arylation reagents. H atoms are not shown in the molecular structure diagrams.
Fig. 7 shows C-H Arylation reactions at ambient temperature. aH2La (5 mol%), 1a (10 mol%), 24-72 h; bH2La (10 mol%), 1a (20 mol%), 48-72 h. Combined yields of isolated products are given.
Fig. 8 shows site-selectivity in comparison with other methods for arene functionalization. Pd-catalyzed non-directed C-H arylation using the method from the current invention is given in the square. Conditions: a) Br2, DMF, r.t., 20 h, 46%; b) PhB(OH)2 (2.5 equiv.), [RuCI2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%), Ag2O (1 equiv.), Cu(OTf)2 (20 mol%), THF, 90 °C, 20 h, 85% (from J. Org. Chem. 2019, 84, 12893.); c) B2pin2 (0.72 equiv.), [lr(COD)OMe]2 (1 mol%), dtbbpy (2 mol%), THF, 50 °C, 2 h, 30%; d) 2a, 2i, or 2j (1.2 equiv.), H2La (10 mol%), 1a (20 mol%), 1 ,4-dioxane, 26 °C, 72 h.
Fig. 9 shows catalyst-controlled site selectivity in direct C-H activation reactions, a) Different substituents on the anion strongly influence the site selectivity of the arylation reaction, b) Catalyst control over the formation of the major regioisomer of the arylation product, c) Catalyst control over the formation of the major regioisomer of the olefination product.
Fig. 10 shows arylation next to small alkyl groups as predominant product using the ligand L1.
Fig. 11 shows a different or better selectivity for less sterically demanding sites with ligand L2 in comparison to the ligand L1. L1 is as depicted in Fig. 10.
Figure imgf000040_0001
During a concerted metal-carboxylate enabled C-H activation process, the geometric parameters of the carboxylate coordination on palladium, namely the O-Pd-O angles and Pd-0 distances, are different in the resting state of the catalyst and the transition state (Figure 1b). The inventors envisioned that the controlled spatial arrangement of constrained bis(anions) could influence the coordination parameters, as exemplified in Figure 1c. The spatial anion control could lead to stabilization of the geometry required for the C-H activation transition state over, for example, /^-coordination in the palladium-bis(carboxylate) catalyst, thus lowering the barrier for C-H activation.
Example 1: C-H arylation
The inventor’s anion design for spatial anion control on palladium, as shown in Figure 2a, utilizes two 1 -naphthyl carboxylic acid-derived side-arms, which are structurally constrained by a central aromatic spacer group. The size and geometry of the spacer modulates the relative spatial arrangement of the two carboxylate groups, while sterically demanding mesityl groups prevent the carboxylate groups from coordinating in a bridging mode. The crystal structure HaLa (spacer = 2,7-naphthyl) shows that the anionic groups are roughly in a plane which is almost parallel to the central arene spacer. Palladium precatalysts 1 and arylation reagents 2, which contain nonafluoro-terf-butoxide anions, were designed to avoid the use of silver additives and any other potentially interfering additives or anions (Figure 2a). The bulky monodentate (CFshCO", can be displaced from palladium by carboxylates such as HaLa and act as a mild base to remove the proton after the C-H activation step.
The spatial anion control can enable challenging C-H functionalization reactions with palladium as shown with the non-directed arylation of arenes as limiting reactants. Acid HaLa and palladium precatalyst 1a enabled catalytic C-H arylation of arene 3a with diaryl iodonium reagent 2a at ambient temperature, yielding 4a in 39% yield (Figure 2b). With HaLd and simpler carboxylates, no product was observed (Figure 2b, see Figure 5 for additional screening experiments), which demonstrates the importance of spatial positioning of the two carboxylate groups for the catalytic reactivity. Diaryl iodonium salts with BF4" and CF3SO3" anions have been used previously for C-H arylation of arene, but high temperature, an acid co-solvent, and an excess of arene were required. In the inventive system, the common diaryl iodonium salts are not suitable 1a was superior to other precatalysts, thereby demonstrating the importance of the (CFs CO" anion. The optimal reaction components for the arylation reaction can be prepared conveniently: arylation reagents 2 are accessed from common diaryl iodonium salts by anion exchange on Amberlyst® (CFshCO" resin, whereas HaLa is available in five synthetic steps from commercial materials, and 1a is obtained in two steps from PdCl2(PhCN)2 (Figure 6).
The constrained anion-enabled catalytic C-H arylation is applicable to a wide range of arenes 3 at 26 °C (Fig. 7). Arenes with electron-fonating groups are excellent substrates (4c, 4d). Aryl and bulky alkyl substituents can block ortho C-H activation (4e-g), although arylation next to smaller alkyl groups is possible (4h). The use of bromo- and iodo-arenes and aryl triflates demonstrates complementary reactivity to common Pd-catalyzed crosscoupling processes (4l-o). Fused (hetero)arenes are suitable substrates and yields of up to 86% could be obtained (4p-s). Bis-functionalization can be achieved (4p, 4q, 4s), which demonstrates the potential for poly-arylation reactions.
Functional groups, such as activated ketones and epoxides (4t, 4u) are compatible, and latestage functionalization of pharmaceutically relevant molecules can be accomplished (4v, 4w, 4x, 4y, 4z, 4aa, 4ab). The catalytic C-H arylation enables the introduction of various aromatic groups with electron-withdrawing or -donating substituents (4ac-4ai).
Polybrominated polyaromatic hydrocarbons, which are suitable for the preparation of extended aromatic systems, can be accessed (4aj).
The comparison of regioselectivity of the C-H arylation reaction with other common methods for arene functionalization is shown in Figure 8. Direct bromination with Br2 and the amide- directed C-H arylation result in the functionalization of the more electron-rich arene A. Iridium-catalyzed C-H borylation, a state-of-the-art method for non-directed C-H activation of arenes, functionalizes several positions on arene B. The reaction proceeds at the a’- position with good regioselectivity, thereby enabling direct C-H functionalization with electron-rich (4ak), electron-poor (4al), and fluorinated aromatic groups (4am).
Activation strain analysis (Bickelhaupt, F. et al. Angew. Chem. Int. Ed. 2017, 56, 10070.) shows that the lower catalyst strain in the transition stateis the main contributing factor when complex LaPd is used as catalyst, compared with that of mononuclear palladium^ I) acetate. Spatial orientation of the two constrained carboxylates, results in a distorted binding of La 2- to Pd, destabilizing the ground-state of LaPd, and lowering the barrier for CMD transition state. Additionally, the structure of complex LaPd(CH3CN)2 shows how La 2- can distort the geometry of the complex to enablebinding of weak ligands (Figure 4).
The inventive results demonstrate that structurally constrained carboxylates, especially together with novel precatalysts and reagents that avoid the use of silver salts or any interfering anions or additives, can enable difficult non-directed C-H functionalization of arenes at ambient temperature. Due to the mild reaction conditions late-stage functionalization of molecules of pharmaceutical interest is possible. Compared to traditional cross-coupling reactions, the method gives the products in one step, without requiring synthesis of modified substrates.
Example 2: Control over regioselectivity
The substitution pattern on R1 and R2 of the ligand control the site selectivity in C-H activation reactions. The use of H2La in an arylation or olefination reaction leads predominantly to the formation of an a-regioisomer, while the use of H2Lf leads predominantly to the formation of a p-regioisomer (see Fig. 9).
Using the ligand L1 , arylation is predominantly observed next to small alkyl groups (see Fig. 10), while the use of ligand L2 is suitable for the arylation at less sterically demanding sites (see Fig. 11).
Material and Methods
Figure imgf000042_0001
1, 8-Dichloronaphthalene (S1) ci ci A round-bottom flask was loaded with 1 ,8-dibromonaphthalene (3.0 g, 10.5 mmol), CuCI (3.12 g, 31.5 mmol), and pyridine (30 ml), and equipped with a
Figure imgf000042_0002
reflux condenser. The mixture was stirred at reflux temperature for 4 h under air.
The reaction mixture was allowed to cool to room temperature, diluted with DCM (40 ml) and 10% aqueous HCI solution (70 ml, added slowly and in portions). The layers were separated and the aqueous layer was extracted with DCM (2 x 40 ml). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (35 g of silica gel, hexanes, the residue was dry loaded on silica gel) yielded the title compound as a colorless solid (1.8 g, 87% yield).
HRMS (El) (m/z): [M+] calculated for CioH6CI2, 195.98411 ; found, 195.98422.
1, 8-Dichloro-2-mesitylnaphthalene (S2)
Preparation of LiTMP nBuLi (2.5 M in hexanes, 4.38 ml, 10.96 mmol, 1.20 equiv.) was added dropwise to a solution of 2, 2,6,6-
Figure imgf000042_0003
tetramethylpiperidine (1.31 ml, 7.69 mmol, 0.84 equiv.) in THF (10 ml) at -78 °C under an N2 atmosphere. After complete addition, the mixture was allowed to warm to 0 °C, and stirred for 1 h at the same temperature.
In a glovebox, mesityl lithium (5.76 g, 5.00 equiv., 45.67 mmol) was loaded in a separate Schlenk flask. The flask was sealed, taken to a fume hood, and connected to a Schlenk line. The flask was cooled to 0 °C and THF (35 ml) was added slowly. The mixture was briefly taken out of the cooling bath to ensure that most of the MesLi had dissolved, then returned to 0 °C. The above-prepared solution of LiTMP was added at 0 °C to the solution of MesLi, followed by subsequent addition of a solution of S1 (1.8 g, 9.13 mmol) in THF (5 ml). The resulting solution was stirred for 20 min at 0 °C. The dark brown solution was then cooled to -78 °C and a solution of hexachloroethane (8.65 g, 36.54 mmol, 4 equiv.) in THF (12 ml) was added dropwise over 2-3 min. The resulting yellow solution was stirred for 5 min at -78 °C and then allowed to warm to room temperature. To the mixture, H2O (40 ml) and DCM (40 ml) were added. The layers were separated, and the aqueous layer was extracted with DCM (2 x 40 ml). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (90 g of silica gel, hexanes, the residue was loaded as a suspension in hexanes) yielded the title compound as a colorless solid (2.24 g, 78% yield).
HRMS (El) (m/z): [M+] calculated for C H Ch, 314.06236; found, 314.06167.
Diisopropyl (8-chloro-7-mesitylnaphthalen-1-yl) boron ate (S3) 'BuLi (1.7 M in pentane, 6.4 ml, 7.33 mmol) was added dropwise to a solution of S2 (2.3 g, 4.89 mmol) in THF (20 ml) at -78 °C under an
Figure imgf000043_0001
N2 atmosphere. The reaction mixture was stirred at -78 °C for 2.5 h, which resulted in a dark brown solution. B(O'Pr)3 (3.39 ml, 9.77 mmol) was added dropwise and the reaction mixture was stirred for 10 min at -78 °C. Then, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 40 min, H2O (40 ml) and EtOAc (40 ml) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 40 ml). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (70 g of silica gel, hexanes/DCM 7:3 to 6:4, the residue was loaded as a suspension in the eluent) yielded the title compound as a colorless solid (2.49 g, 84% yield).
HRMS (El) (m/z): [M+] calculated for C25H30O2BCI, 408.20219; found, 408.20160.
8,8"-Dichloro-7, 7"-dimesityl-1,2':7', 1 ''-ternaphthalene (S4)
A Schlenk flask was loaded with 2,7-dibromonaphtahlene (0.52 g, 1.82 mmol), boronate ester S3 (1.64 g, 4.0 mmol), Pd(PPhs)4 (210
Figure imgf000043_0002
mg, 0.18 mmol) and Ba(OH)2'8H2O (2.4 g, 7.27 mmol), and was placed under an inert atmosphere with three vacuum/N2 cycles. Degassed 1,4-dioxane (7.2 ml) and degassed H2O (2.3 ml) were added and the resulting suspension was stirred at 80 °C (oil bath temperature) for 16 h. The reaction mixture was allowed to cool to room temperature and H2O (10 ml), 30 % aqueous H2O2 solution (10 ml), and DCM (10 ml) were added. The layers were separated and the aqueous layer was extracted with DCM (3 x 30 ml). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (100 g of silica gel, hexanes/DCM 9:1 , the residue was loaded as a suspension in the eluent) yielded the title compound as a colorless solid (1.15 g, 92% yield).
Two rotamers of the product in a 0.56:0.44 ratio are observed in the 1H and 13C NMR spectra.
1 H NMR (500 MHz, CDCI3) 6 7.95 - 7.91 (m, 4HmajOr + 4HminOr), 7.81 - 7.78 (m, 4HmajOr +
4H minor), 7.59 - 7.53 (m, 4H major + 4H minor), 7.46 (dt, J = 8.2, 2.2 Hz, 2HmajOr + 2H minor ) 7.28 (d, J = 8.3 Hz, 2H major + 2H minor), 6.92 (s, 2HmajOr), 6.91 (s, 2H minor), 6.90 (S, 2Hmajor), 6.88 (s,
2H minor), 2.31 (s, 6H major + 6H minor), 1.99 (s, 3HmajOr), 1.98 (s, 3H minor), 1.92 (s, 3HmajOr), 1.91 (s, 3H minor)-
7, 7"-Dimesityl-[1,2':7', 1"-ternaphthalene]-8,8''-dicarboxylic acid (H2l_a)
The reaction was performed under argon. In a Schlenk flask under argon, S4 (0.3 g, 0.437 mmol) was dissolved in THF (10 ml, stored under Ar) and cooled to -78 °C. Then, a freshly prepared LiDBB
Figure imgf000044_0001
solution2 (4.8 ml, 0.4 M in THF, 1.92 mmol, 4.4 equiv.) was added via syringe. The resulting brown-blue solution was stirred for 20 min at -78 °C. Afterwards, under vigorous stirring, the argon atmosphere was evacuated and the system was refilled with CO2 gas while being connected to an oil bubbler for gas release. The mixture was stirred at -78 °C for 40 min and then 40 min at -40 °C under a CO2 atmosphere. (CAUTION: a significant amount of CO2 dissolves in the reaction mixture at -78 °C, and gradual warming up and a connection to an oil bubbler for gas release are essential to avoid buildup of pressure). The flow of CO2 was then replaced with argon gas, the cooling bath was removed, and the light-brown solution was allowed to reach room temperature and then stirred for additional 1 h. To the reaction mixture, 20% aqueous HCI solution (40 ml) and DCM (40 ml) were added. The layers were separated and the aqueous layer was extracted with DCM (2 x 40 ml). The combined organic extracts were filtered through DCM-soaked filter paper (without drying over MgSC ), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (10 g of silica gel, DCM then DCM/EtOAc 7:3, residue loaded as a suspension in DCM) and the combined fractions were acidified by washing with 20% aqueous HCI solution (before acidification different fractions containing the desired compound display different behavior by TLC analysis, likely due to presence of carboxylate salts after the silica gel column). The organic solution was filtered and the solvent was removed under reduced pressure to give the title compound as a light yellow solid (190 mg, 62% yield). 1H NMR (400 MHz, CDCI3) 6 8.02 (d, J = 8.4 Hz, 2H), 7.96 (dd, J= 7.0, 2.6 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.82 (s, 2H), 7.63 - 7.59 (m, 4H), 7.53 (dd, J= 8.3, 1.6 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.81 (s, 2H), 6.76 (s, 2H), 2.32 (s, 6H), 1.97 (s, 6H), 1.76 (s, 6H).
General approach for the synthesis of ligands
Scheme 1 shows the synthesis of a ligand according to the invention. The synthesis approach can also be applied to other ligands according to the invention.
Figure imgf000045_0001
Scheme 1: Synthesis of ligands according to the invention. For representative conditions see representative examples below. tert- butyl 8- bromo- 1 -naphthoate (S5) 1,8-Dibromonaphthalene (13.2 g, 46.2 mmol) was loaded in a Schlenk, dissolved with THF (120 mL) and cooled to -78 °C. After 10 min, nBuLi (2.5
Figure imgf000045_0002
M in hexanes, 18.5 mL, 46.2 mmol, 1 equiv.) was added dropwise over 10 min. The resulting bright yellow solution was stirred at -78 °C for 30 min, when a solution of di-terf-butyldicarbonate (31.9 mL, 69.3 mmol, 3 equiv.) in dry THF (28 mL) was added dropwise in two portions over 4 min. The resulting dark brown mixture was stirred at -78 °C for 1 h, when the bath was removed and stirred 2 h further. The reaction was quenched with H2O (120 mL) and diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. To remove the excess of BOC2O, the resulting green oil was dissolved in DCM (120 mL) and, under stirring, /V-methylpiperazine (10 mL) was added dropwise. Once the gas evolution stops, the mixture was transferred to an extraction funnel and washed with aqueous 1 M HOI (50 mL). The layers were separated, the organic extract was collected, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography (silica gel, hexanes/EtOAc 9:1) yielded the title compound as a bright yellow solid (5.242 g, 38% yield). 1H NMR (400 MHz, CDCI3) 5 7.90 - 7.84 (m, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 7.2, 1.4 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 1.68 (s, 10H). di-tert-butyl [1 ,2':7', 1"-ternaphthalene]-8,8"-dicarboxylate (S6) 2 7-bis(4 4 5 5-tetrameth l-1 3 2-dioxaborolan-2- l)na hthalene
Figure imgf000046_0001
mg, 0.66 mmol, 10 mol%). Then, THF (25 mL) and H2O (12 mL) were added, and the mixture degassed through 10 consecutive N2/vacuum cycles. The Schlenk flask was sealed, and the reaction was stirred at 80 °C (oil bath temperature) for 24 h. The reaction mixture was then allowed to cool to room temperature and diluted with CH2CI2 (60 mL) and H2O (100 mL). The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 x 60 mL). The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. The crude was purified by column chromatography (silica gel, hexanes/EtOAc 9:1) to afford the desired compound as a pale purple foamy solid.
1H NMR (400 MHz, CDCI3) 5 7.98 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.91 - 7.85 (m, 2H), 7.80 (s, 2H), 7.72 - 7.64 (m, 4H), 7.64 - 7.57 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 0.88 (s, 18H).
(8,8"-bis(tert-butoxycarbonyl)-[ 1,2':7', 1 "-ternaphthalene]-7, 7"-diyl)diboronic acid (S7) was
Figure imgf000046_0002
2 . complete addition, the mixture was allowed to warm to 0 °C and stirred for 1 h at the same temperature. The resulting solution was cooled to -78 °C and triisopropylborate (1.6 mL, 6.93 mmol, 4 equiv.) was added the dropwise. After 5 min, a solution of S6 (981 mg, 1.69 mmol, 1 equiv.) in THF (5 ml) was added dropwise. The resulting yellow-greenish suspension was stirred at -78 °C for 2 h, and subsequently warmed slowly to room temperature over 2 h. Then, saturated aqueous NH4CI (10 mL) and EtOAc (25 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to afford an insoluble pale-yellow solid that was used in the next step without further purification. di-tert-butyl- 7, 7"-bis(4-bromo-3, 5-di-iso-propylphenyl) -[ 1, 2 ':7', 1 ”-ternaphthalene]-8, 8 dicarboxylate (S8)
Figure imgf000047_0001
10:2:1 (0.17 M solution of the aryl halide) and aryl halide were added. The Schlenk flask was sealed, and the reaction was stirred at 80 °C (oil bath temperature) until completion, as confirmed by TLC analysis. The reaction mixture was then allowed to cool to room temperature and diluted with EtOAcand H2O. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography. Prepared following general procedure from 2-bromo-5-iodo-1 ,3-diisopropylbenzene (1.1 mL, 4.68 mmol) and diboronic acid S7 (783 mg, 1.17 mmol), using K2CO3 (1.45 g, 10.5 mmol) and Pd(PPhs)4 (135 mg, 0.117 mmol). The reaction mixture was heated for 20 h. Purification by column chromatography (silica gel, hexanes/EtOAc) to afford the title compound as an off-white solid (583 mg, 47% yield over two steps).
1H NMR (500 MHz, CDCI3) 6 7.93 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.75 (s, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 9.3 Hz, 4H), 7.11 - 7.05 (br m, 4H), 3.49 (br q, J = 7.4 Hz, 4H), 1.19 (br d, J = 6.9 Hz, 24H), 0.33 (s, 18H). bis(4-bromo-3,5-di-iso-propylphenyl)-[1,2':7', '-ternaphthalene]-8,8"-dicarboxylic acid (L2) )
Figure imgf000047_0002
NMR analysis of an aliquot of the reaction mixture. The reaction mixture was then allowed to cool to room temperature and diluted with CH2CI2 and H2O. The layers were separated, and the organic layer was washed with H2O and 1M aqueous HCI solution. The organic layer was collected, filtered through CH2Cl2-soaked filter paper (without drying with MgSC ), and the solvent was removed under reduced pressure. Prepared following this general procedure from S8 (584 mg, 0.55 mmol), using TFA (0.82 mL, 11 mmol). The reaction mixture was heated for 2 h. After workup, the title compound was obtained as a pale-yellow solid (479 mg, 91% yield). 1H NMR (500 MHz, CDCI3) 6 8.00 (d, J = 8.5 Hz, 2H), 7.96 - 7.92 (m, 4H), 7.86 (br, 2H), 7.62
- 7.58 (m, 4H), 7.55 (dd, J = 8.4, 1.7 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.08 (s, 4H), 3.42 (hept, J = 6.9 Hz, 4H), 1.06 (d, J = 6.9 Hz, 12H), 1.04 (d, J = 6.8 Hz, 12H).
Synthesis of palladiumfl I) complexes
Pd(OC(CF3)3)2(PhCN)2 (1a) Inside an N2-filled glovebox, 1b (0.430 g, 0.652 mmol) was suspended in PhCN (5.5 ml). The resulting suspension was stirred
Figure imgf000048_0001
at room temperature under glovebox pressure for 1 h, then under vacuum for 10 min and further 1 h under glovebox pressure. The sequence of steps (vacuum, 10 min, then glovebox pressure, 1 h) was repeated four more times. The precipitate was then separated by filtration using a glass frit, and the solid was washed with hexane (2 x 2 ml) and dried under vacuum to give the title compound as a yellow solid (0.355 g, 69% yield).
1H NMR (500 MHz, CD2CI2) 6 7.75 (tt, J = 7.6, 1.3 Hz, 2H), 7.68 - 7.67 (m, 4H), 7.55 (t, J = 8.0 Hz, 4H).
Pd(OC(CF3)3)2(CH3CN)2 (1b)
F3C CF3 Inside an N2-filled glovebox, a solution of AgOC(CFs)3 (0.698 g,
F3( ?° P|D °T$CF3 2.04 mmol, 2.1 equiv.)56 in toluene (2.1 ml) and CH3CN (2.1 ml) CF3 NCCH3 CF3 was added to Pd(PhCN)2Ch (0.370 g, 0.965 mmol)7 in toluene (13 ml). The resulting suspension was stirred for 4 h in the dark at room temperature. Afterwards, the stirring was stopped and the precipitate was allowed to settle. The solution was filtered through a plug of Celite and the resulting dark yellow solution was kept in the glovebox freezer (-35 °C) overnight. The resulting bright orange crystals were separated from the mother liquor with a pipette, washed with pentane (2 x 2 ml), and dried under vacuum to give the title compound as a bright orange solid (0.368 g, 49% yield).
1H NMR (400 MHz, CD2CI2) 6 2.33 (s, 6H).
LaPd(CH3CN)2 (1c)
Inside an N2-filled glovebox, a 20 ml vial was loaded with HaLa (70.5 mg, 0.10 mmol), 1b (72.3 mg, 0.11 mmol), and CH3CN (2 ml). The mixture was heated at 75 °C in a closed vial for 75 min with
Figure imgf000048_0002
occasional gentle swirling. After being allowed to cool to room temperature, the solid was separated by filtration using a small glass frit, and the reaction vial and the solid were washed with CH3CN (3 x 0.4 ml). The obtained solid was dissolved in CH2CI2/CH3CN 10:1 (8 ml), the solution was filtered through a glass fiber filter and concentrated to give the title compound as a yellow solid, 62.8 mg, 70% yield. The product turns brownish after prolonged drying under high vacuum, potentially due to partial loss of the coordinated CH3CN.
1H-NMR (400 MHz, CD2CI2/CD3CN 3:1) 5 7.92 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.47 (t, J= 7.5 Hz, 2H), 7.40 (s, 2H), 7.36 (d, J = 7.4 Hz, 2H), 7.34 (s, 2H), 7.05 (d, J= 7.7 Hz, 2H), 6.65 (s, 2H), 2.42 (s, 6H), 2.33 (s, 6H), 1.93 (s), 1.55 (s, 6H).
Diaryl iodonium perfluoro-tert-butoxide salts
Preparation of Amberlyst® (CFs CCr resin
Amberlyst® A26 hydroxide form resin (ca. 45 ml) was placed in a 250 ml round-bottom flask and washed with distilled H2O (10 times, each time completely covering the surface of the resin, swirling, and then removing the H2O with a pipette). The flask was then attached to a Schlenk adapter equipped with a Teflon pin and dried under high vacuum at room temperature (the flask was kept immersed in a room temperature water bath) for 18 h. The flask was then placed under N2 gas and cooled in liquid N2. To the cooled flask, (CFs COH (3 ml) was added through the Schlenk adapter and the Teflon pin was attached leaving the system open to an N2 (1.5 atm) Schlenk line that was equipped with an oil bubbler for gas release. The flask was allowed to warm to room temperature with continuous swirling. (CAUTION: for safety reasons the connection to the N2 line has to be left open. After the flask is warmed up above 0 °C, as observed by melting of the water ice layer on the outside of the flask, the temperature of the flask can be estimated by hand, and if warming above room temperature is observed, the flask is quickly briefly cooled in liquid N2 with swirling of the resin.) After the flask reaches room temperature while being swirled and no temperature increase is observed during 2-3 min, the flask is sealed and left at room temperature for 10 h and then placed under high vacuum for 15 h. The above sequence of steps (addition of further (CFs^COH (3 ml), keeping the flask sealed for 10 h, and high vacuum for 15 h) was then repeated. Afterwards, the flask was closed under vacuum and taken inside an N2-filled glovebox. Inside the glovebox, 1/3 of the amount of the resin was placed in a 20 ml vial, DCM (10 ml) was added, the vial was closed and gently shaken for 1-2 min. DCM was then removed using a pipette and replaced with DCM/(CF3)3COH 10:1 (11 ml, (CFs^COH was degassed prior to being placed inside the glovebox, but not dried on molecular sieves). The vial was closed, gently shaken, and kept at room temperature for 20 min. The solvent was removed using a pipette and the resin was then washed two more times with DCM (10 ml, 8 ml). After removal of the second portion of DCM, the resin was dried under high vacuum overnight. The obtained Amberlyst® (CFshCO- resin has a pale yellow-brown color, while the untreated Amberlyst® A26 hydroxide form resin is pale pinkish gray. IR (cm"1): 3020 (br w), 2923 (br w), 1613 (w), 1490 (m), 1479 (m), 1460 (w, sh), 1423 (w), 1374 (w), 1257 (s, sh), 1241 (s), 1195 (s), 1133 (m, sh), 968 (s, sh), 947 (s), 886 (m), 855 (m), 825 (m), 764 (w), 721 (s), 686 (w, sh), 629 (br m), 565 (w), 532 (m), 482 (m). The sample of the resin was crushed into a fine powder before the measurement.
General procedure for the preparation of bis(aryl) iodonium perfluoro-tert-butoxide: In an N2-fi Hed glovebox, a 20 ml scintillation vial was charged with diaryl iodonium tetrafluoroborate or triflate salt, Amberlyst® (CFshCO- resin (ca. 0.84 g per 1 mmol of diaryl iodonium salt), and DCM. The mixture was stirred for 1 h at room temperature. The solution was then transferred with a pipette (additional 1.5 ml DCM used for washing the resin) into another 20 ml vial containing a second portion of the Amberlyst® (CFs CO- resin (ca. 0.84 g per 1 mmol of diaryl iodonium salt). The mixture was stirred for 1 h at room temperature. The solution was filtered through a small Celite plug, concentrated under vacuum to a minimal volume, and layered with pentane or hexane (1-2.5 ml). The vial was closed and left at -35 °C for 1-48 h affording colorless crystals. The supernatant was removed with a pipette and the crystals were washed with pentane (2 x 0.2-1 ml) and dried under vacuum for 4-5 h to give diaryl iodonium perfluoro-terf-butoxide salts 2a-j as colorless solids. A further amount of product could be obtained from the supernatant solution by combination with the pentane washings followed by storing the solution at -35 °C, or by concentrating the solution, and repeating the crystallization process with reduced volumes of the solvents.
The compounds are stable as solids when stored at -35 °C under N2 atmosphere, but decompose slowly in solutions at room temperature.
Bis(4-tert-butylphenyl) iodonium perfluoro-tert-butoxide (2a)
Bis(4-terf-butylphenenyl) iodonium triflate (1.355 g, 2.50 mmol), Amberlyst® (CFshCO- resin (2 x 2.11 g), and DCM (12 ml) were used. Yield 718 mg + 310 mg from a second crop, 65%, colorless solid.
1H-NMR (500 MHz, CD3CN) 5 8.59 - 8.56 (m, 4H), 8.13 - 8.11 (m, 4H), 1.94 (s, 18H).
Figure imgf000050_0001
13C-NMR (126 MHz, CD3CN) 5 156.0, 135.5, 129.5, 124.6 (q, JC-F = 298.9 Hz, further small splitting of the peaks is observed), 116.3, 85.1 (observed sext, JC-F = 27.5 Hz), 35.7, 31.2.
19F-NMR (471 MHz, CD3CN) 5 -75.55.
HRMS (ESI+) (m/z): [Ar2l+] calculated for C20H26l, 393.10737; found, 393.10715. HRMS (ESI- ) (m/z): [(CF3)3CO-] calculated for C4OF9, 234.98109; found 234.98120. Different batches of 2a were found to contain variable amounts of (CFs COH (which could be quantified by 1H NMR analysis in CeDe), especially if higher amounts of (CFs^COH are used during the preparation of the Amberlyst® (CFs CO- resin.
General procedure for C-H arylation of arenes
Inside an N2-filled glovebox, HaLa (5.6 mg, 0.008 mmol, 5 mol%), 1a (12.5 mg, 0.016 mmol, 10 mol%), and diaryl iodonium perfluoro-terf-butoxide salt 2 (0.112-0.240 mmol, 0.7-1.5 equiv.) were loaded into a 2 ml vial and 1 ,4-dioxane (0.60 ml) was added. Substrates 3 (0.160 mmol), if solids, were added to the vial prior to the addition of the solvent, or if liquids, were added immediately following the addition of the solvent. The reaction mixture was stirred at 26 °C in the dark for 24-72 h and then separated between DCM (10 ml) and H2O (5 ml). The aqueous layer was extracted with DCM (2 x 10 ml) and the combined organic extracts were dried over MgSC , filtered, and the solvent was removed under reduced pressure. The products were purified by column chromatography as specified for each case.
Modification for cases with increased catalyst loading (HaLa 10 mol%; 1a, 20 mol%) and when 2 was added in two portions: after 1 day, the second portions of HaLa (5.6 mg, 0.008 mmol, 5 mol%), 1a (12.5 mg, 0.016 mmol, 10 mol%), and 2 (0.080 mmol, 0.5 equiv.) were loaded into a new 2 ml vial. The initial reaction mixture was then added to the vial and 1 ,4-dioxane (0.1 ml) was used to wash the initial vial. The stirring was continued for 24-48 h.
4-Bromo-4'-(tert-butyl)-3,5-diisopropyl-1 , 1 '-biphenyl (4a) The reaction was performed on a 0.196 mmol scale using
2a ((CF3)3COH)o.7 (186.7 mg, 0.235 mmol, 1.2 equiv., added in two portions, 0.7 + 0.5 equiv.), HaLa (10 mol%, added in two portions, 5 + 5 mol%), 1a (20 mol%, added in two portions 10 + 10 mol%), and 1 ,4-dioxane
Figure imgf000051_0001
(0.75 + 0.1 ml). The second portions were added after 1 day, overall to. ■
25 reaction time 2 days, chromatography (silica gel 40 g, hexanes). Colorless solid, 40.6 mg, 55 % yield.
1H NMR (400 MHz, CDCI3) 5 7.55 - 7.53 (m, 2H), 7.51 - 7.49 (m, 2H), 7.34 (s, 2H), 3.57 (sept, J = 6.9 Hz, 2H), 1.39 (s, 9H), 1.32 (d, J = 6.9 Hz, 12H).
13C NMR (101 MHz, CDCI3) 5 150.6, 148.1 , 140.4, 138.4, 127.0, 125.9, 125.7, 123.2, 34.7, 33.8, 31.5, 23.3.
HRMS (El) (m/z): [M+] calculated for C22H29Br, 372.14472; found, 372.14534. Ethyl 2-(4-( 1-oxo-6-(4-(tnfluoromethyl)phenyl)isoindohn-2-yl)phenyl)propanoate (4am)
Figure imgf000052_0001
ay, overa reac on me ays, c romaograp y (s ca ge g, hexanes/EtOAc 8:2). The c-isomer was obtained in a mixture with a second unassigned regioisomer (as observed in the 1H and 19F NMR spectra) and the starting material as minor impurities (29.7 mg, yellow solid, a’/second isomer/SM 1:0.08:0.04). Overall yield of C-H arylation products, 29 mg, 53%, a’/other 1:0.08.
1H NMR (400 MHz, C6D6) 57.96 (dd, J=7.4, 1.2 Hz, 1H), 7.82-7.78 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.34-7.30 (m, 2H), 7.09 (t, J= 7.5 Hz, 1H), 7.03 (dd, J= 7.6, 1.2 Hz, 1H), 6.94 (d, J= 8.1 Hz, 2H), 4.97-3.88 (m, 4H), 3.59 (q, J= 7.1 Hz, 1H), 1.45 (d, J= 7.2 Hz, 3H), 0.89 (t, J= 7.1 Hz, 3H). The signals of the minor isomer are not listed.
13C NMR (101 MHz, C6D6) 5174.0, 166.7, 142.6, 139.1, 138.1, 137.2, 135.5, 134.9, 131.8, 130.2 (q, JC-F = 32.2 Hz), 129.2, 128.7, 128.4, 124.9 (q, JC.F = 272 Hz), 126.0 (q, JC.F = 3.6 Hz), 124.1, 119.6, 60.6,49.8,45.3, 18.9, 14.2. The signals of the minor isomer are not listed.
19F NMR (376 MHz, CDCh) 6 -62.61. The signal of the minor isomer appears at -62.54 ppm. HRMS (ESI) (m/z): [M+H+] calculated for C26H23O3NF3, 454.16245; found, 454.16275.

Claims

Claims
1. A ligand of formula 1, particularly of formula 1a,
Figure imgf000053_0001
wherein
X1 and X2 are independently, particularly are both, selected from -CO2H, -SO3H, - C(O)NHRNX, -SC>2NHRNX and anions thereof, with RNX being selected from -SC>2Rs or aryl, particularly phenyl or naphthyl, wherein the aryl is substituted with one or more electron-withdrawing groups, particularly -F, -CF3, -SF5, wherein Rs is selected from a Ci-6 alkyl, particularly -CH3,
- -CF3, and an aryl, wherein the aryl is particularly phenyl or naphthyl, substituted with one or more small substituents, particularly -F, -Cl, -CF3, -SF5, -CH3, isopropyl,
R1 and R2 are H or sterically demanding moieties, particularly R1 and R2 are H or sterically demanding moieties independently selected from a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein
- the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CFs, - SF5, -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , - OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1 , RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the C1-12-alkyl is optionally substituted by one or more-F atoms,
- the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1 , -C(O)NRN1RN2, - N(RN1)C(O)H, -N(RN1)C(O)Rc1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci.12-al kyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a C e-cyclalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, the spacer is a rigid cyclic moiety having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A, in particular the spacer is a mono- or polycyclic, particularly a planar mono- or polycyclic, hydrocarbon moiety, optionally comprising one or more heteroatoms selected from N, O and S, particularly N, having a length of 4.0 to 5.5 A, particularly 4.6 to 5.2 A, wherein the spacer optionally comprises one or more substituents selected from
-F, -Cl, -Br,
-ORC1 with RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a C5- 6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, or a C1-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, - CF3, -SF5, -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , - C(O)ORC1 , -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , - SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-io-alkyl, particularly Ci-e- alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1 , - C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci -12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, two moieties of R3 and R4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle,
R6, R7, R8 and R9 are independently from each other selected from H, Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1 , - C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic or a hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly R6, R7, R8 and R9 are H, or two moieties of R6 and R7 and/or two moieties of R8 and R9 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6- membered cycle, and p and v are independently from each other 0, 1 or 2, q and w are independently from each other 0, 1 , 2 or 3. The ligand according to claim 1 , wherein the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl,
Figure imgf000055_0001
a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
-F, -Cl, -Br, -CF3, - -ORC1 , -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , -OC(O)RC1 , - N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from H, Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, tert-butyl, cyclopentyl, cyclohexyl, wherein the phenyl is optionally further substituted by at least one substituent selected from a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Coalkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by one or more, particularly 1 or 2, substituents selected from a Ci-4-alkyl, an unsubstituted phenyl, and a phenyl substituted by a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, a moiety Wv-B-Eq, wherein o W is -C(=O)-, -C(=O)NRN1-, -NRN1 (C=O)- with RN1 being H or Ci-4-alkyl, o v is 0 or 1 , o B is a 5- or 6-membered saturated heterocycle or a Cs-7-cycloalkyl, o E is Ci-e-alkyl, -C(=O)-O-R°, -C(=O)NRN1 RN2, -NRN1(C=O)RC1 , with R°, RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E1),
Figure imgf000056_0001
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
- -C(=O)-NRN1-C(H)(RC2)-C(=O)-O-E, wherein o RN1 being H or Ci-4-alkyl, o RC2 is an unsubstituted Ci-4-alkyl or a Ci-4-alkyl substituted by -SH, -SCH3, OH, phenyl, phenyl-OH, indole, -C(=O)-NH2, -NH2, -NH-C(=NH)-NH2, -COOH, imidazole, particularly methyl, isopropyl, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-CH2- S-CH3, -CH2-phenyl, -CH2-phenyl-OH, -CH2-imidazole, -CH2-indole, -CH(OH)- CH3, -CH2-CH2-C(=O)-NH2, -CH2-C(=O)-NH2, -CH2-SH , -CH2-OH, -CH2-CH2- CH2-CH2-NH2, -CH2-CH2-CH2-NH-C(=NH)-NH2, -CH2-CH2-COOH, CH2-COOH, o E is H or Ci-4-alkyl, particularly Ci-4-alkyl, more particularly ethyl or methyl. The ligand according to any of the preceding claims, wherein the cyclic hydrocarbon moiety at R1 and/or R2, particularly R1 and R2, is phenyl, wherein the phenyl is unsubstituted or substituted by one or more, particularly 1 to 3, substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly 6 to 14 carbon atoms, more particularly 2-adamantyl, a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl,
- -F, -Cl, -Br, -CF3,
- -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1 , - OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3, -SO2NRN1RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from H, Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, tertbutyl, cyclopentyl, cyclohexyl. The ligand according to any of the preceding claims, wherein R1 and R2 are sterically demanding moieties as defined above, particularly R1 and R2 are a phenyl substituted by CF3, methyl,
Figure imgf000057_0001
particularly CF3 or methyl, wherein R1 and R2 each comprise at least one substituent selected from a substituted linear alkyl, particularly a linear Ci-e-alkyl, more particularly a Ci-2-alkyl, wherein the linear alkyl is substituted in such a way that a stereocenter is formed, wherein particularly the linear alkyl is substituted by one or more, particularly 1 or 2, substituents selected from a Ci-4-alkyl, an unsubstituted phenyl, and a phenyl substituted by a Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, a moiety Wv-B-Eq, wherein o W is -C(=O)-, -C(=O)NRN1-, -NRN1(C=O)- with RN1 being H or Ci-4-alkyl, o v is 0 or 1 , o B is a 5- or 6-membered saturated heterocycle or a Cs-7-cycloalkyl, o E is Ci-6-alkyl, -C(=O)-O-R°, -C(=O)NRN1RN2, -NRN1(C=O)RC1 , with R°,
RN1 , RN2, RC1 being H or Ci-4-alkyl, or a moiety of formula (E 1 ) ,
Figure imgf000058_0001
(E1), with
RE1 being H or OH,
RE2 and RE3 being Ci-4-alkyl, -F, -Cl, -Br, -CF3 wherein E is bound to B in such a way that a stereocenter is formed, o q is 1 , 2 or 3,
- -C(=O)-NRN1-C(H)(RC2)-C(=O)-O-E, wherein o RN1 being H or Ci-4-alkyl, o RC2 is an unsubstituted Ci-4-alkyl or a Ci-4-alkyl substituted by -SH, - SCH3, OH, phenyl, phenyl-OH, indole, -C(=O)-NH2, -NH2, -NH-C(=NH)- NH2, -COOH, imidazole, o E is H or Ci-4-alkyl, particularly Ci-4-alkyl, more particularly ethyl or methyl. The ligand according to claim 1 , wherein the cyclic hydrocarbon moiety at R1 and/or R2 is a monocyclic, bicyclic, or polycyclic aromatic moiety, wherein the cyclic aromatic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1 , -C(O)NRN1RN2, -N(RN1)C(O)H, - N(RN1)C(O)Rc1 , -C(O)ORC1, -OC(O)RC1 , -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1 RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2- alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl. The ligand according to claim 1 , wherein R1 and R2 are independently selected from H or a branched C3.i2-alkyl, a Ci-4-alkyl substituted by a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, wherein the branched C3.i2-al kyl or the Ci-4alkyl substituted by a cyclic hydrocarbon moiety optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, - CF3, -ORC1 , -C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1, -C(O)ORC1, - OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, a monocyclic or bicyclic cycloalkyl comprising 5 to 14 carbon atoms, wherein the cycloalkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, - CF3, -ORC1 , -C(O)NRN1RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1 , -C(O)ORC1, - OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1 , RN2, RN3, RC1 being H or a Ci-i2-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms. The ligand according to claims 5 and 6, wherein R1 and R2 are a phenyl optionally substituted with 1-5 substituents selected from a linear or branched Ci-s-alkyl, particularly a linear or branched Ci-3-alkyl, and a C3.8-cycloalkyl, particularly substituted with two substituents in meta position (3 and 5 positions of the phenyl) or three substituents in ortho and para position (2,4,6-positions), more particularly R1 and R2 are selected from 2,4,6-Me3CeH2, 2,4,6-iPr3CeH2, phenyl, 3,5-tBu3CeH3, even more particularly R1 and R2 are 2,4,6-Me3CeH2. The ligand according to any one of the preceding claims, wherein the ligand is a compound of formula 2, particularly of formula 2a,
Figure imgf000059_0001
Figure imgf000060_0001
wherein X1, X2, R1 and R2 are defined as described above, and
R6a, R7a, R7b, R8a, R9a, R9b are defined as R6, R7, R8 and R9, respectively, particularly H. The ligand according to any one of the preceding claims, wherein the spacer is a moiety of formula 3, particularly of formula 3’, more particularly of formula 3’a or 3’b, even more particularly of formula 3’a,
Figure imgf000060_0002
wherein R3 and R4 are independently selected from
-F, -Cl, -Br,
-ORC1 with RC1 being H or a Ci.12-al kyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-alkyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, or a Ci-12-al kyl and a cyclic hydrocarbon moiety comprising 3 to 30, particularly 3 to 20, carbon atoms, wherein the alkyl optionally comprises one or more substituents selected from a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, -F, -Cl, -CFs, -SFs, - ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, -N(RN1)C(O)RC1, -C(O)ORC1, -OC(O)RC1, -N(RN1)C(O)NRN2RN3, -N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a C1-12 alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, the cyclic hydrocarbon moiety optionally comprises one or more, particularly 1 to 3, substituents selected from Ci-10-alkyl, particularly Ci-e-alkyl, more particularly Ci-4-alkyl, -F, -Cl, -Br, -CF3, -ORC1, -C(O)NRN1 RN2, -N(RN1)C(O)H, - N(RN1)C(O)Rc1, -C(O)ORC1 , -OC(O)RC1, -N(RN1)C(O)NRN2RN3, - N(RN1)C(S)NRN2RN3 , -SO2NRN1RN2 with RN1, RN2, RN3, RC1 being H or a Ci-i2- alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly selected from Ci-6-al kyl and a Cs-6-cycloalkyl, more particularly methyl, ethyl, hexyl, iso-propyl, cyclopentyl, cyclohexyl, two moieties of R3 and R4 can be connected to each other to form an additional cycle fused to the naphthalene, particularly a 5- or 6-membered cycle, n and m are independently from each other 0 or 1 , particularly n and m both are 0. The ligand according to any one of the preceding claims, wherein the ligand is a compound of formula 4 or 5, particularly of formula 4,
Figure imgf000061_0001
(4), (5), with R1 and R2 being as defined above, wherein particularly the ligand is a compound of formula 6, 7, 8, or X11 , particularly of formula 6 and X11 ,
Figure imgf000062_0001
A metal complex comprising a ligand according to any one of claims 1 to 7 and a metal, particularly a metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt. A reagent of formula 9,
"A— R11
Figure imgf000062_0002
(9), wherein
Z+ is selected from l+ and S+, particularly l+,
Y is a Ci-20-alkyl, an aryl, a heteroaryl, or two Y form a ring structure, particularly Y is an aryl when Z+ = l+, wherein
Y is optionally substituted by one or more substituents, particularly 1 or 2 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, -CF3, -C(=O)-Ra, -ORa, - (CH2)xORa, -SRa, -(CH2)xSRa or -NRa2, with x being selected from 1 to 6 and with each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl, r is 1 for Z+ = l+, and 2 for Z+ = S+, T is selected from Ci-20-alkyl, an aryl, a heteroaryl, -CF3, -ORa, -F, -Br, alkenyl, alkynyl, particularly T is an aryl when Z+ = l+, with Ra being as defined above, wherein
T is optionally substituted by one or more substituents, particularly 1 or 2 substituents, selected from -F, -Cl, -Br, -I, -CN, Ci-12-alkyl, -CF3, -C(=O)-Ra, - ORa, -(CH2)xORa, -SRa, -(CH2)xSRa or -NRa2, with x being selected from 1 to 6 and each Ra being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl,
A' is -O' or -N(R10)', particularly -O', with R10 being a -Ci-6-alkyl or aryl, wherein
- the -C1.6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -ORa, particularly 0, with Ra being defined as above,
- the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CF3)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms,
R11 is a -Ci-6-alkyl or aryl, wherein
- the -C1.6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 substituents -ORa, particularly 0, with Ra being defined as above,
- the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly R11 is selected from -CH(CF3)2, -C(CF3)3, more particularly R11 is -C(CF3)3.
13. The reagent according to claim 12, wherein
Z+ is l+ and r is 1 ,
Y and T are both an aryl that is optionally substituted as described above,
A' is -O',
R11 is defined as above, particularly R11 is -C-(CF3)3.
61 The reagent according to any of claims 12 or 13, wherein Y and T are both an aryl, particularly a phenyl, wherein
- Y comprises one or more substituents as described above, wherein one substituent is at one ortho position in relation to Z+ and the other ortho position in relation to Z+ is unsubstituted, and
- T is optionally substituted as described above, wherein both ortho positions in relation to Z+ are unsubstituted. A precatalyst of formula 10, particularly of formula 10a,
Figure imgf000064_0001
wherein
M is a metal, particularly selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt,
A’ is selected from -O-, -N(R12a)-, -N(R5a)-, particularly -O-,
R12, R12a, R5 and R5a are independently selected, particularly all are selected, from - Ci-6-alkyl or aryl, wherein
- the -Ci-6 alkyl is substituted by one or more -F, particularly 6-12 -F, further optionally substituted by 1-2 -ORb, particularly 0, with Rb being selected independently from each other from H, a Ci-Cs alkyl, an aryl and a heteroaryl, in particular C1-C4 alkyl, an aryl or heteroaryl,
- the aryl is substituted with one or more electron withdrawing groups, particularly one or more electron withdrawing groups selected from - C(CFS)3, - CF3, -C(O)ORC with Rc being H or a Ci-12-alkyl and a cyclic hydrocarbon moiety comprising 3 to 14 carbon atoms, particularly R12 and R5 are selected from -CH(CF3)2, -C(CF3)3, more particularly R12 and R5 are -C(CF3)3,
L is a neutral or anionic ligand, particularly
L is in case of M being Pd, Cu, Au, Pt a weakly coordinated ligand selected from -NC-aryl, -NC-Ci-i2-alkyl, -S(Ci. i2-alkyl)2, O(Ci-6-alkyl)2, or an O-alkyl group, wherein the O-alkyl group is further attached to R12 or R5
L is a coordinated neutral ligand, particularly cymene, in case of M being Ru,
62 L is a coordinated anionic ligand, particularly pentamethylcyclopentadienyl, in case of M being Rh or Ir x is equal to the charge of the metal M minus the number of L that are anionic, z is 0, 1 , 2, 3, or 4, wherein the sum of x and z equals the number of coordinating bonds that are formed by the metal M. The precatalyst according to claim 15, wherein
M is Pd,
A’ is -O-,
R12 is a -Ci-6 alkyl is substituted by one or more -F, particularly -CH(CF3)2, -C(CF3)3, L is defined as above, particularly L is selected from -NC-phenyl, -NC-Ci-12-alkyl, - S(Ci-i2-alkyl)2, O(Ci-6-alkyl)2, more particularly L is -NC-phenyl, x is 2 and z is 2. A method for accelerating a chemical transformation, particularly for C-H arylation, C- H alkylation comprising the steps of a. providing a substrate to be chemically transformed, particularly a substrate comprising one or more aryl moieties Ar, wherein the ring structure forming the moiety Ar comprises at least one -CH- moiety, a reagent comprising at least one moiety to be transferred to the substrate, particularly at least one aryl moiety Ar’ or alkyl moiety Aik’, a precatalyst comprising a coordinated metal, particularly a coordinated metal selected from Pd, Cu, Ir, Rh, Co, Au, Ru, Pt, a ligand according to any one of claims 1 to 7, b. in a mixing step, mixing the substrate, the reagent, the precatalyst and the ligand yielding a reaction mixture, c. in a transformation step, incubating the reaction mixture yielding a chemically transformed compound, particularly a compound comprising a moiety Ar-Ar’ or Ar- Alk’. The method according to claim 17, wherein the reagent is a compound according to any one of claims 9 to 10. The method according to any one of claims 17 or 18, wherein the precatalyst is a compound according to any one of claims 11 to 12 or a compound composed of a) Pd(ll),
63 b) a weakly basic anion, particularly a basic anion having a p a of the corresponding acid <2, particularly <0.5, and c) optionally containing a weakly coordinating ligand, particularly a ligand selected from a nitrile, an ether, or thioether, particularly the precatalyst is selected from a compound according to claim, Pd(-O- C(=O)-CF3)2, Pd(CH3CN)4(BF4)2, Pd(PhCN)4(BF4)2, more particularly the precatalyst is a compound according to claim 11 or 12.
64
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