WO2011161451A1 - Complexes - Google Patents

Complexes Download PDF

Info

Publication number
WO2011161451A1
WO2011161451A1 PCT/GB2011/051171 GB2011051171W WO2011161451A1 WO 2011161451 A1 WO2011161451 A1 WO 2011161451A1 GB 2011051171 W GB2011051171 W GB 2011051171W WO 2011161451 A1 WO2011161451 A1 WO 2011161451A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
group
mmol
qphosci
Prior art date
Application number
PCT/GB2011/051171
Other languages
French (fr)
Inventor
Thomas John Colacot
Carin C. C. Johansson Seechurn
Sebastien Laurent Parisel
Original Assignee
Johnson Matthey Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Johnson Matthey Plc filed Critical Johnson Matthey Plc
Priority to EP19203075.7A priority Critical patent/EP3613504A1/en
Priority to DK11728654.2T priority patent/DK2585216T3/en
Priority to EP11728654.2A priority patent/EP2585216B1/en
Priority to ES11728654T priority patent/ES2769386T3/en
Priority to CN201180037387.2A priority patent/CN103037969B/en
Priority to PL11728654T priority patent/PL2585216T3/en
Priority to US13/806,575 priority patent/US10167305B2/en
Publication of WO2011161451A1 publication Critical patent/WO2011161451A1/en
Priority to US16/136,685 priority patent/US10597416B2/en

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2291—Olefins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2286—Alkynes, e.g. acetylides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/006—Palladium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/04—Nickel compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
    • B01J2231/4227—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group with Y= Cl
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4272—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type via enolates or aza-analogues, added as such or made in-situ, e.g. ArY + R2C=C(OM)Z -> ArR2C-C(O)Z, in which R is H or alkyl, M is Na, K or SiMe3, Y is the leaving group, Z is Ar or OR' and R' is alkyl
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0202—Polynuclearity
    • B01J2531/0205—Bi- or polynuclear complexes, i.e. comprising two or more metal coordination centres, without metal-metal bonds, e.g. Cp(Lx)Zr-imidazole-Zr(Lx)Cp
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0286—Complexes comprising ligands or other components characterized by their function
    • B01J2531/0288—Sterically demanding or shielding ligands
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/842—Iron
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/84—Metals of the iron group
    • B01J2531/847—Nickel

Definitions

  • the present invention relates to transition metal complexes and, in particular, to ⁇ -allyl complexes, such as ⁇ -allylpalladium and ⁇ -allylnickel complexes.
  • the invention also relates to the use of the transition metal complexes in coupling reactions.
  • the active catalyst is formed in situ by the additional of a transition metal precursor, such as Pd(OAc) 2 or Pd 2 (dba) 3 , and the ligand in question.
  • a transition metal precursor such as Pd(OAc) 2 or Pd 2 (dba) 3
  • an excess amount of ligand is usually required, which can be disadvantageous if the cost of the ligand is high, in addition to storage and handling difficulties if the ligand is air sensitive.
  • W099/47474 and WO01/16057 (both to Ciba Speciality Chemicals Holdings Inc.) describe various allylpalladium complexes containing tertiary phosphine ligands.
  • the ligands exemplified are trialkylphosphine ligands.
  • the inventors have discovered a class of ⁇ -allylpalladium and ⁇ -allylnickel complexes, which may be employed to effect a variety of reactions, such as C-N and C-C bond formation reactions.
  • the ⁇ -allyl complexes are highly active catalysts.
  • the ⁇ -allyl complexes are stable to air and moisture at ambient temperatures.
  • the present invention provides a complex of formula (1 )
  • M is palladium or nickel
  • R- ⁇ and R 2 are independently organic groups having 1-20 carbon atoms, or R-i and R 2 are linked to form a ring structure with the phosphorus atom
  • R 3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl,
  • R 4 is an organic group having 1-20 carbon atoms
  • n 0, 1 , 2, 3, 4 or 5
  • X is an anionic ligand.
  • the point of attachment of a moiety or substituent is represented by For example, -OH is attached through the oxygen atom.
  • Alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • the alkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms.
  • the alkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom.
  • the alkyl group may be unsubstituted or substituted.
  • Typical alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
  • cycloalkyl is used to denote a saturated carbocyclic hydrocarbon radical.
  • the cycloalkyl group may have from 3-15 carbon atoms, in certain embodiments, from 3-10 carbon atoms, in certain embodiments, from 3-8 carbon atoms.
  • the cycloalkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom.
  • the cycloalkyl group may unsubstituted or substituted.
  • Typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkoxy refers to an optionally substituted group of the formula alkyl-O- or cycloalkyl-O-, wherein alkyl and cycloalkyl are as defined above.
  • Alkoxyalkyl refers to an optionally substituted group of the formula alkoxy-alkyl-, wherein alkoxy and alkyl are as defined above.
  • Aryl refers to an aromatic carbocyclic group.
  • the aryl group may have a single ring or multiple condensed rings.
  • the aryl group can have from 6-20 carbon atoms, in certain embodiments from 6-15 carbon atoms, in certain embodiments, 6-12 carbon atoms.
  • the aryl group may be unsubstituted or substituted. Unless otherwise specified, the aryl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl and the like.
  • Arylalkyl refers to an optionally substituted group of the formula aryl-alkyl- where aryl and alkyl are as defined above.
  • Halo or “hal” refers to -F, -CI, -Br and -I.
  • Heteroalkyl refers to a straight-chain or branched saturated hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms).
  • the heteroalkyl group may be unsubstituted or substituted. Unless otherwise specified, the heteroalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom.
  • Examples of heteralkyi groups include but are not limited to ethers, thioethers, primary amines, secondary amines, tertiary amines and the like.
  • Heterocycloalkyl refers to a saturated cyclic hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms).
  • the heterocycloalkyl group may be unsubstituted or substituted. Unless otherwise specified, the heterocycloalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom.
  • heterocycloalkyl groups include but are not limited to epoxide, morpholinyl, piperadinyl, piperazinyl, thirranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, thiomorpholinyl and the like.
  • Heteroaryl refers to an aromatic carbocyclic group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms).
  • the heteroaryl group may be substituted or unsubstituted. Unless otherwise specified, the heteroaryl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom.
  • heteroaryl groups include but are not limited to thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, thiophenyl, oxadiazolyl, pyridinyl, pyrimidyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, indolyl, quinolinyl and the like.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with substituents (e.g. 1 , 2, 3 or more) which may be the same or different.
  • Metallocenyl refers to a transition metal complex group wherein a transition metal atom or ion is "sandwiched" between two rings of atoms.
  • the metallocenyl group may be substituted or unsubstituted. Unless otherwise specified, the metallocenyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom.
  • transition metal atoms or ions include but are not limited to chromium, manganese, cobalt nickel and iron.
  • An example of a suitable ring of atoms is a cyclopentadienyl ring.
  • metallocenyl group includes but is not limited to ferrocenyl, which comprises a Fe(ll) ion sandwiched between two cyclopentadienyl rings, wherein each cyclopentadienyl ring may be independently unsubstituted or substituted.
  • the present invention provides a complex of formula (1 )
  • M is palladium or nickel
  • R and R 2 are independently organic groups having 1-20 carbon atoms, or R and R 2 are linked to form a ring structure with the phosphorus atom,
  • R 3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl and substituted and unsubstituted metallocenyl,
  • R 4 is an organic group having 1-20 carbon atoms
  • n 0, 1 , 2, 3, 4 or 5
  • X is an anionic ligand.
  • the metal M is a precious metal selected from palladium or nickel.
  • M is palladium.
  • M may be Pd(ll).
  • M may be Ni(ll).
  • PR ⁇ Rs is a monodentate tertiary phosphine ligand.
  • R-i and R 2 are independently selected from the group consisting of substituted and unsubstituted straight- chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen.
  • R 2 may independently be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl.
  • alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl
  • the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy.
  • the aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. d-C 10 ), alkoxy (e.g. d-do alkoxy), straight- or branched-chain (dialkyl)amino (e.g.
  • C 1 -C 10 dialkyl)amino e.g. C 3 .i 0 heterocycloalkyl groups, such as morpholinyl and piperadinyl
  • Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl and 4-methoxy-3,5-dimethylphenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used.
  • R-i and R 2 are linked to form a ring structure with the phosphorus atom, preferably 4- to 7-membered rings.
  • R-i and R 2 are the same and are tert-butyl, cyclohexyl, phenyl or substituted phenyl groups. More preferably, and R 2 are both tert-butyl.
  • R 3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl.
  • R 3 is a substituted or unsubstituted aryl.
  • the aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C 1 -C 10 ), alkoxy (e.g. C 1 -C 10 alkoxy), substituted or unsubstituted aryl, straight- or branched-chain (dialkyl)amino (e.g. C 1 -C 10 dialkyl)amino), heterocycloalkyl (e.g. C 3 .
  • substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C 1 -C 10 ), alkoxy (e.g. C 1 -C 10 alkoxy), substituted or unsubstituted aryl, straight- or branched-
  • R 3 is preferably phenyl or 2-, 3- or 4- dimethylaminophenyl.
  • R 3 is a substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridinyl or quinolinyl.
  • R 3 is a substituted or unsubstituted metallocenyl group.
  • the metallocenyl group may have a structure of formula (2):
  • R-io and R-n are independently organic groups having 1-20 carbon atoms
  • p 0, 1 , 2, 3 or 4, and
  • q 0, 1 , 2, 3, 4 or 5.
  • Metallocenyl groups of formula (2) are described in WO02/1 1883 which is incorporated by reference in its entirety for all purposes.
  • R-io is an organic group having 1-20 carbon atoms, preferably 1-15 carbon atoms, more preferably 1-10 carbon atoms and even more preferably 1-8 carbon atoms.
  • the number of R-io groups range from 0 to 4 i.e. p is 0, 1 , 2, 3 or 4. In certain embodiments, p is 0. When p is 2, 3 or 4, each R 10 may be the same or different.
  • R-io may be substituted or unsubstituted alkyl, aryl, (alkyl)HN-, (dialkyl)N-, (dialkyl)amino-alkyl- or alkoxyalkyl.
  • the substituted or unsubstituted alkyl group may be a substituted or unsubstituted C ⁇ o alkyl group, preferably a substituted or unsubstituted C-i-C 10 alkyl and more preferably a substituted or unsubstituted C-
  • the aryl group may be substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C-
  • substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C-
  • Suitable aryl groups are phenyl, napthyl, 2-, 3- or 4-methoxyphenyl, or 2-, 3- or 4-halophenyl.
  • the substituted or unsubstituted (alkyl)HN- group may be substituted or unsubstituted methylamino, ethylamino or propylamino.
  • the substituted or unsubstituted (dialkyl)N- group may be dimethylamino, diethylamino or dipropylamino.
  • the substituted or unsubstituted (dialkyl)amino-alkyl- group may be 1-dialkylaminoethyl.
  • the substituted or unsubstituted alkoxyalkyl group may be methoxymethyl, or 1-alkoxyethyl, such as methoxyethyl or ethoxyethyl.
  • R-i-i is an organic group having 1-20 carbon atoms, preferably 1-10 carbon atoms and more preferably 1-8 carbon atoms.
  • the number of R-n groups ranges from 0 to 5 i.e. q is 0, 1 , 2, 3, 4 or 5. In certain embodiments, q is 4 or 5. When q is 2, 3, 4, or 5, each R-n may be the same or different.
  • R- ⁇ - ⁇ may be substituted or unsubstituted alkyl or aryl.
  • the substituted or unsubstituted alkyl group may be a substituted or unsubstituted C 1 -C 20 alkyl group, preferably a substituted or unsubstituted C 1 -C 10 alkyl and more preferably a substituted or unsubstituted Ci-C 8 alkyl, which may be branched or straight-chain, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl.
  • the aryl group may be unsubstituted or substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. d-C 10 ), alkoxy (e.g. C 1 -C 10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C 1 -C 10 dialkyl)amino), heterocycloalkyl (e.g. C 3 .i 0 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F 3 C-).
  • Suitable aryl groups are phenyl, napthyl, 2-, 3- or 4- methoxyphenyl, 2-, 3- or 4-halophenyl, 2- 3- or 4-methylphenyl or 2-, 3- or 4-F 3 C-phenyl.
  • the metallocenyl group has a structure of formula (3):
  • R-n and q are as defined above.
  • Rn is selected from the group consisting of phenyl, 2-, 3- or 4- methoxyphenyl, 2- 3- or 4-methylphenyl or 2-, 3- or 4-F 3 C-phenyl, and q is 4 or 5.
  • the metallocenyl group has a structure of formula
  • R 2 R 3 is:
  • R-i and R 2 are tert-butyl and R 3 is phenyl.
  • the M atom in the complex of formula (1 ) is coordinated to an optionally substituted allyl group.
  • R 4 is an organic group having 1-20 carbon atoms, preferably 1-10 carbon atoms and more preferably 1-8 carbon atoms.
  • the number of R 4 groups ranges from 0 to 5 i.e. n is 0, 1 , 2, 3, 4 or 5.
  • n is 2, 3, 4 or 5, each of R 4 may be the same or different.
  • n is 0 i.e. the allyl group is unsubstituted.
  • n is 1.
  • n is 2, wherein each R 4 is the same or different.
  • R 4 may be selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen.
  • R 4 is selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, and substituted and unsubstituted cycloalkyl.
  • R 4 is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen.
  • R 4 may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly or aryl groups such as phenyl, naphthyl or anthracyl.
  • the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I), alkoxy groups, e.g. methoxy, ethoxy or propoxy.
  • the aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C 1 -C 10 ), alkoxy (e.g. C 1 -C 10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g.
  • each R 4 is independently a methyl, phenyl or substituted phenyl group.
  • Suitable optionally substituted allyl groups as coordinated to the M atom are shown below:
  • X is an anionic ligand.
  • X is a halo group, preferably, CI, Br, I, and more preferably, CI.
  • the complex of formula (1 ) is a complex of formula (1a):
  • R and R 2 are independently organic groups having 1-20 carbon atoms, or R and R 2 are linked to form a ring structure with the phosphorus atom,
  • R 3 is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl,
  • R 4 is an organic group having 1-20 carbon atoms, preferably substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl wherein the heteroatoms are selected from sulphur, nitrogen and oxygen,
  • n 0, 1 , 2, 3, 4 or 5, preferably 1 , 2, 3, 4 or 5,
  • X is an anionic ligand.
  • R R 2 , n and X are as described above.
  • the complex of formula (1 ) is a complex of formula (1 b):
  • R and R 2 are independently organic groups having 1-20 carbon atoms, or R and R 2 are linked to form a ring structure with the phosphorus atom,
  • R 3 is selected from the group consisting of substituted and unsubstituted metallocenyl, preferably a metallocenyl of formula (2),
  • R 4 is an organic group having 1-20 carbon atoms
  • n O, 1 , 2, 3, 4 or 5
  • X is an anionic ligand.
  • R R 2 , R 3 , R 4 , n and X are as described above.
  • Preferred complexes of formula (1 ) are: QPhos
  • the present invention provides a method for the preparation of a complex of formula (1 ),
  • M is palladium or nickel
  • Ri and R 2 are independently organic groups having 1-20 carbon atoms, or R-i and R 2 are linked to form a ring structure with the phosphorus atom,
  • R 3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted metallocenyl,
  • R 4 is an organic group having 1-20 carbon atoms
  • n 0, 1 , 2, 3, 4 or 5
  • X is an anionic ligand.
  • the complex of formula (5) may be prepared according to known methods (see, for example, a) Marion, N.: Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. b) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2033. c) Dent, W. I.; Long, R.; Wilkinson, G. J. Chem. Soc. 1964, 1585.
  • the complexes of formula (5) include:
  • the complex of formula (5) and PR ⁇ F ⁇ may be combined in a solvent.
  • the solvent is any suitable aprotic solvent or combination of aprotic solvents.
  • aprotic solvents are toluene, benzene, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, acetone, acetonitrile, dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethylacetamide (DMAc), methyltertbutylether (MTBE), diethylether, hexane, heptane, pentane or ethylacetate.
  • Preferred solvents are THF, toluene, DCM or a combination thereof.
  • concentration of the complex of formula (5) in the solvent is preferably about 0.001 mol/L to about 0.25 mol/L and more preferably, about 0.03 mol/L to about 0.22 mol/L.
  • Any suitable quantity of PR-1R2R3 may be used, although it is preferred that the molar ratio of the complex of formula (5) : PR-
  • the reaction is preferably carried out under an inert atmosphere, such as nitrogen or argon.
  • the process of the invention may be carried out at a temperature in the range of about -10°C to about 60°C, preferably about 0°C to about 35°C and more preferably at about room temperature (i.e. about 20°C to about 30°C). It is preferred that the temperature is maintained below the decomposition temperature and so when the complexes of formula (5) or (1 ) are known to decompose within the temperature ranges given above, the temperature should be maintained below the decomposition temperature.
  • the reaction may be carried out for a period of from about several minutes to about 24 hours. Usually the reaction is complete in about 18 hours. On completion, a proportion of the solvent may be evaporated if desired prior to recovery of the complex.
  • an anti-solvent e.g. an alkane, such as hexane
  • an anti-solvent e.g. an alkane, such as hexane
  • the complex product may be recovered directly by filtering, decanting or centrifuging.
  • the separated complex may be washed and then dried. Drying may be performed using known methods, for example at temperatures in the range 10-60°C and preferably 20-40°C under 1-30 mbar vacuum for 1 hour to 5 days. If desired the complex may be recrystallised.
  • the catalysts of the present invention may be used for carbon-carbon coupling reactions.
  • Examples of carbon-carbon coupling reactions include the Heck or Suzuki reactions, ketone a-arylation reactions and aldehyde a-arylation reactions.
  • the catalysts of the present invention may also be used for carbon-nitrogen coupling reactions, such as the Hartwig- Buckwald reaction.
  • the ⁇ -allyl complexes are highly active catalysts. In certain embodiments, the ⁇ -allyl complexes are stable to air and moisture at ambient temperatures. In one preferred embodiment, the ⁇ -allyl complexes Pd ⁇ -allyl)QPhosCI and Pd(ji-1- crotyl)QPhosCI exhibit high activity and/or stability to air and moisture at ambient temperatures. In particular, Pd(7t-crotyl)QPhosCI has been identified as being a highly active, air-stable catalyst in Pd-catalysed C-N bond formations involving primary and secondary amines, with low catalyst loadings, short reaction times, using aryl and heteroaryl halides ranging from iodides to chlorides.
  • Figure 1 is an X-ray crystal structure of Pd(7t-cinnamyl)QPhosCI.
  • Figure 2 is an X-ray crystal structure of Pd(7t-crotyl)QPhosCI
  • Figure 3 is an X-ray crystal structure of Pd(jt-allyl)QPhosCI.
  • PdCI 2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); 1-chloride-3-methyl-2-butene (1.13 ml_, 9.99 mmol); H 2 0 (83 ml_).
  • the dimer was obtained as a yellow solid (606 mg, 87%).
  • rPdfa-prenyl)Cll PdCI 2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); 3-chloride-2-methyl-1-propene (0.98 ml_, 9.99 mmol); H 2 0 (83 ml_).
  • the dimer was obtained as a yellow solid (269 mg, 41 %).
  • the Pd(1-crotyl)QPhos complex showed a superior activity to the other catalytic systems with a 99% conversion at 0.5 mol% catalyst loading and a 95% conversion at 0.1 mol% loading.
  • the Pd(allyl)QPhosCI complex also provided the desired product with a good conversion.
  • Pd-113 showed good activity, however, the conversion in this case was lower than that of Pd(1-crotyl)QPhos and Pd(allyl)QPhosCI.
  • Pd-113 is air- and moisture sensitive and has to be stored under a nitrogen atmosphere.
  • Pd(n-crotyl)QPhosCI has been evaluated in several substrates for C-N coupling using a range of aryl halides with both primary and secondary amines (Table 5).
  • the inventors have also demonstrated a number of examples of a chemoselective amination reaction of an aryl bromide in the presence of a chloride functionality. This was achieved by virtue of the fact that the aryl bromides required lower reaction temperatures than the aryl chlorides.
  • Pd(ji-crotyl)QPhosCI effected the amination of an aryl iodide, a substrate which has been considered to be a problematic coupling partner in Pd catalysed C-N bond formation processes.
  • Methyl anthranilate (390 ⁇ _, 3.0 mmol); 5-bromo-1 ,2,3-trimethoxybenzene (594 mg, 2.3 mmol); NaOiBu (345 mg, 3.6 mmol); Pd(jr-crotyl)QPhosCI (43.5 mg, 0.06 mmol, 2.0 mol%); toluene (5.0 mL).
  • 2-aniline-pyridine 2-bromopyridine (153 ⁇ _, 1.6 mmol) or 2-chloropyridine (151 ⁇ _, 1.6 mmol); aniline (182 ⁇ _, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(7t-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 ml_).
  • 3-bromopyridine 154 ⁇ _, 1.6 mmol or 3-chloropyridine (152 ⁇ _, 1.6 mmol); aniline (182 ⁇ _, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(jt-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 ml_).
  • Table 12 Aryl Chlorides in Suzuki Coupling.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a complex of formula (1), wherein, M is palladium or nickel, R1 and R2 are independently organic groups having 1-20 carbon atoms, or R1 and R2 are linked to form a ring structure with the phosphorus atom, R3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl, R4 is an organic group having 1-20 carbon atoms, n is 0, 1, 2, 3, 4 or 5, X is an anionic ligand. The invention also provides a process for the preparation of the complex, and its use in carbon-carbon or carbon-nitrogen coupling reactions.

Description

Complexes
The present invention relates to transition metal complexes and, in particular, to π-allyl complexes, such as π-allylpalladium and π-allylnickel complexes. The invention also relates to the use of the transition metal complexes in coupling reactions.
In many transitions metal mediated reactions, the active catalyst is formed in situ by the additional of a transition metal precursor, such as Pd(OAc)2 or Pd2(dba)3, and the ligand in question. In these processes, an excess amount of ligand is usually required, which can be disadvantageous if the cost of the ligand is high, in addition to storage and handling difficulties if the ligand is air sensitive.
As an alternative to preparing the active catalyst in situ, it is possible to prepare pre-formed transition metal complexes which comprise a well-defined transition metal atom to ligand ratio.
W099/47474 and WO01/16057 (both to Ciba Speciality Chemicals Holdings Inc.) describe various allylpalladium complexes containing tertiary phosphine ligands. The ligands exemplified are trialkylphosphine ligands.
The present inventors have developed complexes which overcome problems associated with the prior art.
Summary of the invention
The inventors have discovered a class of π-allylpalladium and π-allylnickel complexes, which may be employed to effect a variety of reactions, such as C-N and C-C bond formation reactions. In certain embodiments, the π-allyl complexes are highly active catalysts. In certain embodiments, the π-allyl complexes are stable to air and moisture at ambient temperatures.
In one aspect, the present invention provides a complex of formula (1 )
Figure imgf000002_0001
wherein,
M is palladium or nickel, R-ι and R2 are independently organic groups having 1-20 carbon atoms, or R-i and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl,
R4 is an organic group having 1-20 carbon atoms,
n is 0, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
In addition, described more fully below is a process to prepare the π-allyl complexes, as well as processes that employ such complexes.
Definitions
The point of attachment of a moiety or substituent is represented by For example, -OH is attached through the oxygen atom.
"Alkyl" refers to a straight-chain or branched saturated hydrocarbon group. In certain embodiments, the alkyl group may have from 1-20 carbon atoms, in certain embodiments from 1-15 carbon atoms, in certain embodiments, 1-8 carbon atoms. Unless otherwise specified, the alkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. The alkyl group may be unsubstituted or substituted. Typical alkyl groups include but are not limited to methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
The term "cycloalkyl" is used to denote a saturated carbocyclic hydrocarbon radical. In certain embodiments, the cycloalkyl group may have from 3-15 carbon atoms, in certain embodiments, from 3-10 carbon atoms, in certain embodiments, from 3-8 carbon atoms. Unless other specified, the cycloalkyl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. The cycloalkyl group may unsubstituted or substituted. Typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkoxy" refers to an optionally substituted group of the formula alkyl-O- or cycloalkyl-O-, wherein alkyl and cycloalkyl are as defined above. "Alkoxyalkyl" refers to an optionally substituted group of the formula alkoxy-alkyl-, wherein alkoxy and alkyl are as defined above.
"Aryl" refers to an aromatic carbocyclic group. The aryl group may have a single ring or multiple condensed rings. In certain embodiments, the aryl group can have from 6-20 carbon atoms, in certain embodiments from 6-15 carbon atoms, in certain embodiments, 6-12 carbon atoms. The aryl group may be unsubstituted or substituted. Unless otherwise specified, the aryl group may be attached at any suitable carbon atom and, if substituted, may be substituted at any suitable atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl and the like.
"Arylalkyl" refers to an optionally substituted group of the formula aryl-alkyl- where aryl and alkyl are as defined above.
"Halo" or "hal" refers to -F, -CI, -Br and -I.
"Heteroalkyl" refers to a straight-chain or branched saturated hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). The heteroalkyl group may be unsubstituted or substituted. Unless otherwise specified, the heteroalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteralkyi groups include but are not limited to ethers, thioethers, primary amines, secondary amines, tertiary amines and the like.
"Heterocycloalkyl" refers to a saturated cyclic hydrocarbon group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). The heterocycloalkyl group may be unsubstituted or substituted. Unless otherwise specified, the heterocycloalkyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heterocycloalkyl groups include but are not limited to epoxide, morpholinyl, piperadinyl, piperazinyl, thirranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, thiomorpholinyl and the like.
"Heteroaryl" refers to an aromatic carbocyclic group wherein one or more carbon atoms are independently replaced with one or more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur atoms). The heteroaryl group may be substituted or unsubstituted. Unless otherwise specified, the heteroaryl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of heteroaryl groups include but are not limited to thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, thiophenyl, oxadiazolyl, pyridinyl, pyrimidyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, indolyl, quinolinyl and the like.
"Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with substituents (e.g. 1 , 2, 3 or more) which may be the same or different. Examples of substituents include but are not limited to -halo, -C(halo)3, -Ra, =0, =S, -0-Ra, - S-Ra, -NRaRb, =NRa, =N-ORa, -CN, -SCN, -NCS, -N02, -C(0)-Ra, -COORa, -C(S)-Ra, - C(S)ORa, -S(0)2OH, -S(0)2-Ra, -S(0)2NRaRb, -0-S(0)-Ra and -CONRaRb; wherein Ra and Rb are independently selected from the groups consisting of H, alkyl, aryl, arylalkyl, heteroalkyi, heteroaryl, or Ra and Rb together with the atom to which they are attached form a heterocycloalkyl group, and wherein Ra and Rb may be unsubstituted or further substituted as defined herein.
"Metallocenyl" refers to a transition metal complex group wherein a transition metal atom or ion is "sandwiched" between two rings of atoms. The metallocenyl group may be substituted or unsubstituted. Unless otherwise specified, the metallocenyl group may be attached at any suitable atom and, if substituted, may be substituted at any suitable atom. Examples of transition metal atoms or ions include but are not limited to chromium, manganese, cobalt nickel and iron. An example of a suitable ring of atoms is a cyclopentadienyl ring. An example of a metallocenyl group includes but is not limited to ferrocenyl, which comprises a Fe(ll) ion sandwiched between two cyclopentadienyl rings, wherein each cyclopentadienyl ring may be independently unsubstituted or substituted.
Detailed Description
In one aspect, the present invention provides a complex of formula (1 )
Figure imgf000005_0001
wherein,
M is palladium or nickel,
R and R2 are independently organic groups having 1-20 carbon atoms, or R and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl and substituted and unsubstituted metallocenyl,
R4 is an organic group having 1-20 carbon atoms,
n is 0, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
The metal M is a precious metal selected from palladium or nickel. In one particularly preferred embodiment, M is palladium. When M is palladium, M may be Pd(ll). When M is nickel, M may be Ni(ll). PR^Rs is a monodentate tertiary phosphine ligand. In one embodiment, R-i and R2 are independently selected from the group consisting of substituted and unsubstituted straight- chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen. and R2 may independently be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly, or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I) or alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. d-C10), alkoxy (e.g. d-do alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3.i0 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-). Suitable substituted aryl groups include but are not limited to 4-dimethylaminophenyl, 4-methylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl and 4-methoxy-3,5-dimethylphenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used. In an alternative embodiment, R-i and R2 are linked to form a ring structure with the phosphorus atom, preferably 4- to 7-membered rings. Preferably, R-i and R2 are the same and are tert-butyl, cyclohexyl, phenyl or substituted phenyl groups. More preferably, and R2 are both tert-butyl.
R3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl.
In one embodiment, R3 is a substituted or unsubstituted aryl. The aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), substituted or unsubstituted aryl, straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3.10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-). In one embodiment, R3 is preferably phenyl or 2-, 3- or 4- dimethylaminophenyl. In another embodiment, R3 is a substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted furanyl, thiophenyl, pyrrolyl, pyridinyl or quinolinyl.
In an alternative embodiment, R3 is a substituted or unsubstituted metallocenyl group. The metallocenyl group may have a structure of formula (2):
Figure imgf000007_0001
Fe (2)
(R1 l )q wherein,
R-io and R-n are independently organic groups having 1-20 carbon atoms,
p is 0, 1 , 2, 3 or 4, and
q is 0, 1 , 2, 3, 4 or 5.
Metallocenyl groups of formula (2) are described in WO02/1 1883 which is incorporated by reference in its entirety for all purposes.
R-io is an organic group having 1-20 carbon atoms, preferably 1-15 carbon atoms, more preferably 1-10 carbon atoms and even more preferably 1-8 carbon atoms. The number of R-io groups range from 0 to 4 i.e. p is 0, 1 , 2, 3 or 4. In certain embodiments, p is 0. When p is 2, 3 or 4, each R10 may be the same or different.
R-io may be substituted or unsubstituted alkyl, aryl, (alkyl)HN-, (dialkyl)N-, (dialkyl)amino-alkyl- or alkoxyalkyl. The substituted or unsubstituted alkyl group may be a substituted or unsubstituted C^^o alkyl group, preferably a substituted or unsubstituted C-i-C10 alkyl and more preferably a substituted or unsubstituted C-|-C8 alkyl, which may be branched or straight-chain, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl. The aryl group may be substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C-|-C10), alkoxy (e.g. C-|-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. (C-i-C-ιο dialkyl)amino), heterocycloalkyi (e.g. C3.-|0 heterocycloalkyi groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-). Suitable aryl groups are phenyl, napthyl, 2-, 3- or 4-methoxyphenyl, or 2-, 3- or 4-halophenyl. The substituted or unsubstituted (alkyl)HN- group may be substituted or unsubstituted methylamino, ethylamino or propylamino. The substituted or unsubstituted (dialkyl)N- group may be dimethylamino, diethylamino or dipropylamino. The substituted or unsubstituted (dialkyl)amino-alkyl- group may be 1-dialkylaminoethyl. The substituted or unsubstituted alkoxyalkyl group may be methoxymethyl, or 1-alkoxyethyl, such as methoxyethyl or ethoxyethyl.
R-i-i is an organic group having 1-20 carbon atoms, preferably 1-10 carbon atoms and more preferably 1-8 carbon atoms. The number of R-n groups ranges from 0 to 5 i.e. q is 0, 1 , 2, 3, 4 or 5. In certain embodiments, q is 4 or 5. When q is 2, 3, 4, or 5, each R-n may be the same or different. R-ι-ι may be substituted or unsubstituted alkyl or aryl. The substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C20 alkyl group, preferably a substituted or unsubstituted C1-C10 alkyl and more preferably a substituted or unsubstituted Ci-C8 alkyl, which may be branched or straight-chain, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl. The aryl group may be unsubstituted or substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. d-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C1-C10 dialkyl)amino), heterocycloalkyl (e.g. C3.i0 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-). Suitable aryl groups are phenyl, napthyl, 2-, 3- or 4- methoxyphenyl, 2-, 3- or 4-halophenyl, 2- 3- or 4-methylphenyl or 2-, 3- or 4-F3C-phenyl.
In one preferred embodiment, the metallocenyl group has a structure of formula (3):
Figure imgf000008_0001
wherein R-n and q are as defined above. In another preferred embodiment, is selected from the group consisting of phenyl, napthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4- halophenyl, 2- 3- or 4-methylphenyl or 2-, 3- or 4-F3C-phenyl, and q is 4 or 5. In yet another preferred embodiment, Rn is selected from the group consisting of phenyl, 2-, 3- or 4- methoxyphenyl, 2- 3- or 4-methylphenyl or 2-, 3- or 4-F3C-phenyl, and q is 4 or 5.
In one particularly preferred embodiment, the metallocenyl group has a structure of formula
Figure imgf000008_0002
In one especially preferred embodiment, PR-|R2R3 is:
(a) the sterically demanding electron rich QPhos ligand i.e. R-i and R2 are tert-butyl and R3 is a metallocenyl group of formula (4);
(b) Amphos i.e. R-i and R2 are tert-butyl and R3 is 4-dimethylaminophenyl; or
(c) P*Bu2Ph i.e. R-i and R2 are tert-butyl and R3 is phenyl. The M atom in the complex of formula (1 ) is coordinated to an optionally substituted allyl group. R4 is an organic group having 1-20 carbon atoms, preferably 1-10 carbon atoms and more preferably 1-8 carbon atoms. The number of R4 groups ranges from 0 to 5 i.e. n is 0, 1 , 2, 3, 4 or 5. When n is 2, 3, 4 or 5, each of R4 may be the same or different. In certain embodiments, when n is 2, 3, 4, or 5, each R4 is the same. In certain embodiments, n is 0 i.e. the allyl group is unsubstituted. In certain embodiments, n is 1. In certain embodiments, n is 2, wherein each R4 is the same or different.
R4 may be selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen. In one embodiment, R4 is selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, and substituted and unsubstituted cycloalkyl. In another embodiment, R4 is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen and oxygen. R4 may be substituted or unsubstituted branched- or straight-chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl or stearyl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantly or aryl groups such as phenyl, naphthyl or anthracyl. In one embodiment, the alkyl groups may be optionally substituted with one or more substituents such as halide (F, CI, Br or I), alkoxy groups, e.g. methoxy, ethoxy or propoxy. The aryl group may be optionally substituted with one or more (e.g. 1 , 2, 3, 4, or 5) substituents such as halide (F, CI, Br or I), straight- or branched-chain alkyl (e.g. C1-C10), alkoxy (e.g. C1-C10 alkoxy), straight- or branched-chain (dialkyl)amino (e.g. C^-Cw dialkyl)amino), heterocycloalkyl (e.g. C3.10 heterocycloalkyl groups, such as morpholinyl and piperadinyl) or tri(halo)methyl (e.g. F3C-). Suitable substituted aryl groups include but are not limited to 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4- methylphenyl, 2,3- or 3,5-dimethylphenyl, 2-, 3- or 4-methoxyphenyl and 4-methoxy-3,5- dimethylphenyl. Substituted or unsubstituted heteroaryl groups such as pyridyl may also be used. In one embodiment, each R4 is independently a methyl, phenyl or substituted phenyl group.
Suitable optionally substituted allyl groups as coordinated to the M atom are shown below:
Figure imgf000009_0001
In the complex of formula (1 ), X is an anionic ligand. In one embodiment, X is a halo group, preferably, CI, Br, I, and more preferably, CI.
In one embodiment, the complex of formula (1 ) is a complex of formula (1a):
Figure imgf000010_0001
wherein,
R and R2 are independently organic groups having 1-20 carbon atoms, or R and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl,
R4 is an organic group having 1-20 carbon atoms, preferably substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl wherein the heteroatoms are selected from sulphur, nitrogen and oxygen,
n is 0, 1 , 2, 3, 4 or 5, preferably 1 , 2, 3, 4 or 5,
X is an anionic ligand.
R R2, n and X are as described above.
In another embodiment, the complex of formula (1 ) is a complex of formula (1 b):
Figure imgf000010_0002
wherein,
R and R2 are independently organic groups having 1-20 carbon atoms, or R and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted and unsubstituted metallocenyl, preferably a metallocenyl of formula (2),
R4 is an organic group having 1-20 carbon atoms,
n is O, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
R R2, R3, R4, n and X are as described above. Preferred complexes of formula (1 ) are: QPhos
Q
Figure imgf000011_0001
In another aspect, the present invention provides a method for the preparation of a complex of formula (1 ),
Figure imgf000011_0002
comprising the step of reacting a complex of formula (5) with PR-|R2R3,
Figure imgf000011_0003
wherein,
M is palladium or nickel,
Ri and R2 are independently organic groups having 1-20 carbon atoms, or R-i and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted metallocenyl,
R4 is an organic group having 1-20 carbon atoms,
n is 0, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
M, R-i, R2, R3, R4, n and X are as described above. The complex of formula (5) may be prepared according to known methods (see, for example, a) Marion, N.: Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. b) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2033. c) Dent, W. I.; Long, R.; Wilkinson, G. J. Chem. Soc. 1964, 1585. d) Nicholson, J. K.; Powell, J.; Shaw, B. L. J. Chem. Soc; Chem. Commun. 1966, 174) each of which is incorporated herein by reference in its entirety for all purposes. Suitable complexes of formula (5) include:
Figure imgf000012_0001
In one embodiment, the complexes of formula (5) include:
Figure imgf000012_0002
The complex of formula (5) and PR^F^ may be combined in a solvent. In this case, the solvent is any suitable aprotic solvent or combination of aprotic solvents. Examples of aprotic solvents are toluene, benzene, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, acetone, acetonitrile, dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethylacetamide (DMAc), methyltertbutylether (MTBE), diethylether, hexane, heptane, pentane or ethylacetate. Preferred solvents are THF, toluene, DCM or a combination thereof. The concentration of the complex of formula (5) in the solvent is preferably about 0.001 mol/L to about 0.25 mol/L and more preferably, about 0.03 mol/L to about 0.22 mol/L. Any suitable quantity of PR-1R2R3 may be used, although it is preferred that the molar ratio of the complex of formula (5) : PR-|R2R3 is from about 1 :2.0 to about 1 :2.2. If desired PR-|R2R3 may be used in the form of a salt, for example, a tetrafluoroborate salt.
The reaction is preferably carried out under an inert atmosphere, such as nitrogen or argon.
The process of the invention may be carried out at a temperature in the range of about -10°C to about 60°C, preferably about 0°C to about 35°C and more preferably at about room temperature (i.e. about 20°C to about 30°C). It is preferred that the temperature is maintained below the decomposition temperature and so when the complexes of formula (5) or (1 ) are known to decompose within the temperature ranges given above, the temperature should be maintained below the decomposition temperature. The reaction may be carried out for a period of from about several minutes to about 24 hours. Usually the reaction is complete in about 18 hours. On completion, a proportion of the solvent may be evaporated if desired prior to recovery of the complex. Furthermore, if desired an anti-solvent (e.g. an alkane, such as hexane) may be used to precipitate the complex from the solvent. The complex product may be recovered directly by filtering, decanting or centrifuging.
Howsoever the complex is recovered, the separated complex may be washed and then dried. Drying may be performed using known methods, for example at temperatures in the range 10-60°C and preferably 20-40°C under 1-30 mbar vacuum for 1 hour to 5 days. If desired the complex may be recrystallised.
The catalysts of the present invention may be used for carbon-carbon coupling reactions. Examples of carbon-carbon coupling reactions include the Heck or Suzuki reactions, ketone a-arylation reactions and aldehyde a-arylation reactions. The catalysts of the present invention may also be used for carbon-nitrogen coupling reactions, such as the Hartwig- Buckwald reaction.
In certain embodiments, the π-allyl complexes are highly active catalysts. In certain embodiments, the π-allyl complexes are stable to air and moisture at ambient temperatures. In one preferred embodiment, the π-allyl complexes Pd^-allyl)QPhosCI and Pd(ji-1- crotyl)QPhosCI exhibit high activity and/or stability to air and moisture at ambient temperatures. In particular, Pd(7t-crotyl)QPhosCI has been identified as being a highly active, air-stable catalyst in Pd-catalysed C-N bond formations involving primary and secondary amines, with low catalyst loadings, short reaction times, using aryl and heteroaryl halides ranging from iodides to chlorides.
The invention will now be described by way of example only and with reference to the following drawings in which:
Figure 1 is an X-ray crystal structure of Pd(7t-cinnamyl)QPhosCI. Figure 2 is an X-ray crystal structure of Pd(7t-crotyl)QPhosCI Figure 3 is an X-ray crystal structure of Pd(jt-allyl)QPhosCI.
Examples
All solvents and reagents were purchased from commercial sources and used as received. All catalysts, ligands or precious metal precursors were obtained from Johnson Matthey Catalysis or Alfa Aesar. Flash chromatography was performed on a Flashmaster Personal (Biotage) using prepacked ISOLUTE silica gel cartridges. 1H and 3C NMR spectra were recorded on a Bruker 400 MHz spectrometer at ambient temperature in CDCI3 or CeDe (Sigma Aldrich). All reactions were carried out in individual Schlenk tubes under a nitrogen atmosphere. The purity of the isolated products was >95% as determined by 1H NMR, GC/MS or elemental analysis.
Example 1
General procedure for the preparation of fPdfoptionally substituted (RA,-allvD(X)lg complexes:
Distilled H20 in a three-necked roundbottom flask was purged with nitrogen for 30 minutes. PdCI2 and KCI were subsequently added to the flask and the solution was stirred at room temperature for 1 h. Then, optionally substituted (R4)n-allyl chloride was added and the resulting reaction mixture stirred at room temperature overnight (18-20 hrs). The reaction was extracted with chloroform, and the aqueous layer washed with chloroform three times. The organic layers were combined, dried over MgS04, filtered and concentrated in vacuo. The crude product was recrystallised from chloroform and methyl ierf-butyl ether, and the resulting solid was isolated by filtration and dried in vacuo. [Pdfa-cinnamvDCn?
Figure imgf000014_0001
PdCI2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); cinnamyl chloride (1.39 mL, 9.99 mmol); H20 (83 mL). The dimer was obtained as a yellow solid (494 mg, 58%).
[Pdfa-1-crotvnCll
PdCI2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); crotyl chloride (0.97 mL, 9.99 mmol); H20 (83 mL). The dimer was obtained as a yellow solid (636 mg, 97%). iPd(7i-prenyl)Cll2
Figure imgf000015_0001
PdCI2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); 1-chloride-3-methyl-2-butene (1.13 ml_, 9.99 mmol); H20 (83 ml_). The dimer was obtained as a yellow solid (606 mg, 87%). rPdfa-prenyl)Cll
Figure imgf000015_0002
PdCI2 (590 mg, 3.33 mmol); KCI (473 mg, 6.67 mmol); 3-chloride-2-methyl-1-propene (0.98 ml_, 9.99 mmol); H20 (83 ml_). The dimer was obtained as a yellow solid (269 mg, 41 %).
General procedure for the preparation of Pclfa-optionally substituted (RAi- allyl)(PRiR2R¾)(X) complexes:
The [Pd(n:-optionally substituted (R4)n-allyl)CI]2 and the PR!R2R3 Iigand were put in a Schlenk flask. The flask was evacuated and backfilled with nitrogen three times, then the solvent was added. The reaction mixture was stirred at room temperature for the indicated time and then the solvent was removed in vacuo. The resulting solid was triturated with anhydrous hexane and the solid isolated by filtration and dried in vacuo to give the desired palladium complex. The structures of the various complexes prepared in this manner may be represented as follows:
< -Pdlcl <?-Pd 'cl 4- 'Cl
QQPPhhooss ' " "-QQPPhooss ^Pd"QPhos Me— <f Pd-Cl
Me \ QPhos
Ph Me Me'
Figure imgf000015_0003
Pdfa-cinnamyl)(QPhos)CI
Figure imgf000016_0001
[Pd(;i-cinnamyl)CI]2 (74 mg, 0.14 mmol); QPhos (223 mg, 0.31 mmol); THF (2.8 ml_); 18 hrs. Product obtained as a pink solid (233 mg, 86%); 1H NMR (CDCI3, 400 MHz): δ 7.48-7.46 (m, 2H, CH2=CH-CH-C6AY5), 7.37-7.35 (m, 3H, CH2=CH-CH-C6H5), 7.14-7.03 (m, 25H, H-Ar), 5.68-5.60 (m, 1 H, CH2=CH-CH-C6H5), 5.20 (dd, J 13.2, 9.6, 1 H, CH2=CH-CH-C6H5), 5.08 (br s, 1 H, Cp-H), 4.84-4.81 (m, 1 H, Cp-H), 4.53 (app. s, 2H, Cp-H), 4.02 (br s, 1 H, CAY2=CH-CH- C6H5), 2.79 (br s, 1 H, Ctf^CH-CH-CeHs), 1.27-1.07 (m, 18H, PC(Ctf3)3); 13C (CDCI3, 100 MHz): δ 136.4, 135.1 , 132.6, 128.6, 128.3, 127.4, 126.5, 107.3, 87.7, 68.0, 53.9, 30.7; 3 P NMR (CDCI3, 162 MHz): δ 67.4. Elemental analysis, found: C 70.39, H 5.93, CI 3.52, P 3.18 (theoretical C 70.60, H 5.82, CI 3.66, P 3.19).
Single crystals of Pd(cinnamyl)QPhosCI were obtained by slow diffusion of 40-60 petroleum ether into a CH2CI2 solution, respectively, at -18°C (see Figure 1 ).
Pd(n-crotyl)(QPhos)CI
Figure imgf000016_0002
[Pd(ji-crotyl)CI]2 (200 mg, 0.51 mmol); QPhos (798 mg, 1.12 mmol); THF (10 ml_); 18 hrs. The complex was obtained as a pink solid (891 mg, 96%); 1H NMR (CDCI3, 400 MHz): δ 7.15-7.03 (m, 25H, H-Ar), 5.34 (br s, 1 H, Cp-H), 5.09-5.00 (m, 2H, CH2=CH-CH-CH3, Cp-H), 4.54-4.53 (m, 2H, Cp-H), 4.49-4.39 (m, 1 H, CH2=CH-CH-CH3), 3.77 (d, J 6.4, 1 H, CH2=CH-CH-CH3), 2.54 (d, J 1 1 .6, 1 H, Ctf2=CH-CH-CH3), 1.74 (dd, J 8.4, 6.8, 3H, CH2=CH-CH-CH3), 1.17 (t, J 13.2, 18H, PC(CH3)3); 13C (CDCI3, 100 MHz): δ 135.2, 132.6, 127.3, 126.5, 113.2, 103.0, 102.7, 87.7, 80.8, 80.1 , 52.2, 37.8, 30.6; 3 P NMR (CDCI3, 162 MHz): δ 65.0. Elemental analysis, found: C 68.90, H 6.16, CI 3.77, P 3.40 (theoretical: C 68.81 , H 6.00, CI 3.91 , P 3.41 ). Single crystals of Pd(jt-crotyl)QPhosCI were obtained by slow diffusion of 40-60 petroleum ether into an EtOAc solution at -18 °C (see Figure 2).
Pdfa-prenyl)(QPhos)CI
Figure imgf000017_0001
[Pd(ji-prenyl)CI]2 (200 mg, 0.48 mmol); QPhos (751 mg, 1.06 mmol); THF (10 mL); 18 hrs. Product obtained as a pink solid (867 mg, 98%); 1 H NMR (CDCI3, 400 MHz): δ 7.19-7.04 (m, 25H," C6H5), 5.44 (br s, 1 H, Cp-H), 4.94-4.81 (m , 2H, CH2=CH -(CH3)2, Cp-H), 4.51 (s, 2H, Cp-H), 3.52 (d, J 6.8, 1 H CA 2=CH -(CH3)2), 2.71 (d, J 12.0, CAY2=CH -(CH3)2), 1 .80 (d, J 8.4, 3H, CH2=CH -(CH3)2), 1 .62 (t, J 7.2, 3H, CH2=CH -(Ctf3)2), 1.24 (d, J 14.4, 9H, PC(CH3)3), 1.15 (d, J 14.4, 9H, PC(CH3)3); (CDCI3, 100 MHz): δ 135.2, 132.6, 127.3, 126.5, 121 .2, 106.8, 87.7, 80.3, 47.4, 37.8, 30.9, 30.6; 3 P NMR (CDCI3, 162 MHz): δ 68.3. Elemental analysis, found: C 68.81 , H 6.44, CI 4.57, P 3.25 (theoretical C 69.06, H 6.12, CI 3.85, P 3.36).
Pd(jr-2-crotyl)(QPhos)CI
Figure imgf000017_0002
[Pd(re-2-crotyl)CI]2 (200 mg, 0.51 mmol); QPhos (798 mg, 1.12 mmol); THF (5 mL); 18 hrs. The complex was obtained as a pink solid (788 mg, 85%); H NMR (CDCI3, 400 MHz): 5 7.19- 6.98 (m, 25H, H-Ar), 5.27 (br s, 1 H, Cp-H), 4.93 (br s, 1 H, Cp-H), 4.65 (dd, J 6.4, 2.8, 1 H, CH2=C(CH3)-CH2), 4.55 (br s, 2H, Cp-H), 3.84 (d, J 2.8, 1 H , CH2=C(CH3)-CH2), 3.77 (d, J 8.4, 1 H, CH2=C(CH3)-CH2), 2.68 (s, 1 H, CH2=C(CH3)-CH2), 1.94 (s, 3H, CH2=C(CH3)-CH2), 1 .18 (d, J 14.0, 9H, PC(CH3)3), 1 .13 (d, J 14.0, 9H, PC(CAY3)3); 13C (CDCI3, 100 MHz): δ 134.5, 131 .9, 128.6, 126.7, 126.6, 125.9, 87.1 , 79.4, 57.2, 30.0, 29.9, 29.6, 29.5, 21 .8; 3 P NMR (CDCI3, 162 MHz): δ 62.0. Elemental analysis, found: C 69.59, H 6.23, CI 3.41 , P 3.42 (theoretical C 68.81 , H 6.00, CI 3.91 , P 3.41 ). allvDQPhosCI
Figure imgf000018_0001
[Pd(ji-allyl)CI]2 (2.0 mmol); QPhos (4.4 mmol); THF (45 ml_); 18 hrs. The product was obtained as a pink solid (3.2 g, 90%); 1H NMR (CDCI3, 400 MHz): δ 7.17-7.01 (m, 25 C6H5), 5.46-5.36 (m, 1 H, CH2=CH-CH2), 5.33 (br s, 1 H, Fe-H), 5.08 (br s, 1 H, Fe-H), 4.83 (t, J 6.8, 1 H, CAY2=CH-CH2), 4.56 (br s, 1 H, Fe-H), 4.54 (br s, 1 H, Fe-H), 4.04 (d, J 4.8, 1 H, CAY2=CH- CH2), 3.87 (dd, J 13.6, 8.4, CH2=CH-CH2), 2.78 (d, J 12.4, 2H, CH2=CH-CH2), 1 .17 (d, J 14.0, PC(CH3)3); 13C (CDCI3, 100 MHz): δ 135.2, 132.7, 132.5, 132.1 , 127.3, 126.5, 114.2, 87.8, 83.5, 79.7, 67.1 , 57.5, 37.8, 30.5; 3 P NMR (CDCI3, 162 MHz): δ 61.8. Elemental analysis, found: C 68.40, H 6.00, CI 3.83, P 3.42 (theoretical C 68.54, H 5.87, CI 3.97, P 3.47).
Single crystals of Pd(n-allyl)QPhosCI were obtained by slow diffusion of diethyl ether into a CH2CI2 solution (see Figure 3).
The X-ray structures of Pd(^allyl)QPhosCI and Pd(^crotyl)QPhosCI (see Figure 2) are different in terms of the opposite orientation of the halide, presumably due to the steric effect of the Me group on the 3-position of the allyl in Pd(7t-crotyl)QPhosCI.
Pd(n-allyl)(Amphos)CI
,-CI
< -Pd
N e2
i-Bu i-Bu [Pd(7i-allyl)CI]2 (311 mg, 0.85 mmol); Amphos (496 mg, 1.87 mmol); THF (17 mL); 18 hrs. Product obtained as a yellow solid (727 mg, 96%); H NMR (CDCI3, 400 MHz): δ 7.50 (app. t, J 8.8, 2H, H-Ar), 6.65 (d, J 8.0, 2H, H-Ar), 5.50 (heptet, J 7.2, 1 H, CH2=CH-CH2), 4.63 (dt, J 6.8, 2.0, 1 H, CH2=CH-CH2), 3.69 (dd, J 13.2, 9.2, 1 H, CH2=CH-CH2), 3.39 (d, J 6.0, 1 H, CH2=CH-CH2), 3.01 (s, 6H, N(CH3)2), 2.68 (d, J 12.0, 1 H CH2=CH-CH2), 1.47 (d, J 14.0, 9H, PC(CH3)3), 1.39 (d, J 14.0, 9H, PC(CAY3)3); 3C (CDCI3, 100 MHz): δ 150.9, 136.7, 136.6, 116.9, 1 16.6, 115.2, 1 10.4, 110.3, 80.7, 80.4, 58.8, 39.9, 36.0, 30.6, 29.9; 31P NMR (CDCI3, 162 MHz): δ 61.9. Elemental analysis, found: C 51.44, H 7.51 , CI 7.54, P 6.94 (theoretical C 50.90, H 7.42, CI 7.91 , P 6.91 ). Pd(jr-crotvQ(Amphos)CI
Figure imgf000019_0001
[Pd(crotyl)CI]2 (132 mg, 0.34 mmol); P(i-Bu)2(p-NMe2C6H4) (180 mg, 0.68 mmol); THF (3.7 mL); 90 min. Product obtained as a yellow solid (263 mg, 85 %); 1H NMR (CDCI3, 400 MHz): δ 7.52 (t, J 8.8, 2H), 6.65 (d, J 8.0, 2H), 5.25-5.17 (m, 1 H), 4.40-4.29 (m, 1 H), 3.21-3.19 (m, 1 H), 3.00 (s, 3H), 2.47 (d, J 11.6, 1 H), 1.77 (dd, J 8.4, 6.4, 3H), 1 .44 (d, J 13.6, 9H), 1.38 (d, J 13.6, 9H); 3C (CDCI3, 100 MHz): δ 150.9, 149.6, 136.9, 136.7, 117.1 , 1 16.8, 114.1 , 1 10.3, 99.8, 99.6, 53.5, 40.0, 35.8, 30.6, 29.9, 17.4; 3 P NMR (CDCI3, 162 MHz): δ 65.5; Elemental analysis, found: C 51.93, H 7.54, N 2.84, P 6.58. (theoretical C 51.96, H 7.63, N 3.03, P 6.70).
Pd(jr-allvn(Pf-BuzPh)CI
Figure imgf000019_0002
[Pd(7i-allyl)CI]2 (100 mg , 0.27 mmol); Pi-Bu2Ph.HBF4 (169 mg , 0.55 mmol); toluene (1.5 mL), 18 hrs. The product was obtained as a yellow solid (217 mg, 98%); H NMR (CDCI3, 400 MHz): δ 7.90-7.68 (m, 5H, H-Ar), 5.51-5.42 (m, 1 H, CH2=CAY-CH2), 4.12 (d, J 6.4, 2H, CAY2=CH-CH2), 3.05 (d, J 12.0, 2H, CAY2=CH-CH2), 1.55 (d, J 16.8, PPh(CH3)2); 13C (CDCI3, 100 MHz): δ 135.0, 130.5, 127.4, 116.0, 1 15.3, 11 1.2, 63.0, 34.4, 28.0; 3 P NMR (CDCI3, 162 MHz): δ 44.4.
Example 2
General procedure for the Buchwald-Hartwiq coupling reaction:
A Schlenk flask was charged with the catalyst, NaOiBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent). The relative activities of Pd(jt-allyl)QPhosCI and Pd(7i-crotyl)QPhosCI were explored in a model C-N coupling reaction of 4-bromoanisole with N-methylaniline at room temperature (see Tables 1 and 2). Table 1. Optimization and Activities of Pd(jr-allyl)QPhosCI and Pd(jt-crotyl)QPhosCl.a
Me
Br Λ H catalyst, NaO'Bu fT^T ~Ph
Λ Me
MeO' toluene, 7 (°C) Me0'
catalyst toluene time conversion8 (%)
(mL) (hrs)
Pd(7i-allyl)QphosCI (1.0 mol%) 4.0 25 6 97
Pd(jt-crotyl)QPhosCI (1.0 mol%) 4.0 25 3 100
Pd(n-allyl)QPhosCI (0.5 mol%) 4.0 25 23 54
Pd(jt-crotyl)QPhosCI (0.5 mol%) 4.0 25 5 100
Pd(7t-allyl)QPhosCI (0.5 mol%) 2.0 25 7 93
Pd(ji-crotyl)QPhosCI (0.5 mol%) 2.0 25 1 100
4-bromoanisole (1.6 mmol), N-methylaniline (2.0 mmol), NaOi-Bu (2.4 mmol) GC/MS conversion.
Pd(allyl)QPhosCI on comparision with Pd(n-1-crotyl)QPhosCI at a lower concentration (0.5 mol%) gave 54% conversion after 23 hours vs 100% at 5 hours of reaction time. However, by keeping the catalyst loadings of Pd(allyl)QPhosCL at 0.5 mol% while increasing the concentration from 0.4 to 0.8M, 93% conversion was observed within 7 hours. The catalyst Pd(TT-1-crotyl)QPhosCI gave 100% conversion to the product after 1 hour, demonstrating its superiority. Table 2. Comparison of the Relative Activities of Pd(7t-allyl)QPhosCI and Pd(ji- crotyl)QPhosCl.a
Figure imgf000020_0001
Ar-X amine T (°C) catalyst conversion" (%)
/4 50 Pd(;i-allyl)QPhosCI 6.5 97
50 Pd(7t-crotyl)QPhosCI 2 100
Figure imgf000020_0002
Example 3
General procedure for the Buchwald-Hartwiq coupling reaction:
A Schlenk flask was charged with the catalyst, NaOfBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent).
Table 3: Reaction of 4-bromoanisole and N-methylaniline with various complexes
Me
catalyst, NaO'Bu Ph
Figure imgf000021_0001
solvent, T (°C) MeO
catalyst (mol%) 7 (°C) time (hrs) Conversion3 (%)
Pd(allyl)QPhosCI (1.0) 25 6 97 (96)
Pd(allyl)PfBu2PhCI (1.0) 25 22 8 (8)
Pd(allyl)AmPhosCI (1.0) 25 22 18
Pd(1-crotyl)AmP osCI (1.0) 25 22 95
Pd(prenyl)QPhosCI (1 .0) 25 6 100 (99)
Pd(prenyl)QPhosCI (0.5) 25 22 100
Pd(cinnamyl)QPhosCI (1.0) 25 22 81 (66)
Pd(1-crotyl)QPhosCI (1.0) 25 3 100 (99)
Pd(1-crotyl)QPhosCI (0.5) 25 18 99
Pd(1-crotyl)QPhosCI (0.1) 25 18 95
Pd(2-crotyl)QP osCI (1.0) 25 18 62
a GC/MS conversion. Isolated yield in parentheses
In order to get an idea of the relative activities of the present catalysts, a C-N coupling reaction of 4-bromoanisole with N-methylaniline at room temperature was carried out. At 1 mol% palladium loading, the Q-Phos based catalysts Pd(n-allyl)QPhosCI, Pd(n-1- crotyl)QPhosCI and Pd(n-prenyl)QPhosCI all provided the product with conversions greater than 90% within 3-18 hours. The Pd(crotyl)QPhosCI complex gave the desired product in the highest conversion even at 0.1 mol% palladium loading, while Pd(n-prenyl)QPhosCI gave the second highest activity. Pd(TT-1-crotyl)AmphosCI resulted in 95% conversion to the product with 22 hours of reaction time. Example 4
Comparison of In Situ and Commercially Available Catalysts in C-N coupling
A comparision of in situ and commercially available catalysts and catalytic systems in a C-N coupling reaction was carried out. In this reaction, N-methylaniline was coupled with 4- bromoanisole to give N-(4-bromophenyl)-N-methyl-phenylamine under the conditions set out in Table 4.
Table 4: Reaction of 4-bromoanisole and N-methylaniline substrates3 catalyst (mol%) T (°C) time (hrs) Conversion15 (%)
Pd - 1-crotyl)QPhosCI (1 .0) 25 3 1 00
Pd -1-crotyl)QPhosCI (0.5) 25 18 99c
Pd -1-crotyl)QPhosCI (0.1 ) 25 18 95
Br H Pd -allyl)QPhosCI (1.0) 25 6 97 f iTV^6 Pd2(dba)3 (0.25)
25 21 53
MeCT ^ Qp hos (0-5)
Pd- 1 1 3 (0.25) d 25 3 80
Pd- 1 1 6 (0.5) e 25 23 55
Nolan's cat. (0.5) 25 21 0
Pd(OAc)2 (0.5)
25 21 0
XPhos (0.5) f
Pd(OAc)2 (0.5)
QPhos (0.5) 25 23 0 a amine (1.0 mmol), aryl halide (0.8 mmol), NaOfBu (1 .2 mmol), toluene (2.0 mL) GC/MS conversions c Average of three reactions dPd-1 13 = [Ρά(μ-Βι-) '-Βυ3Ρ)2] e Pd-1 1 6 = tBu3P-Pd-PtBu3 f XPhos = 2',4'6'- triisopropylbiphenyl-2-dichlorohexylphosphine
Figure imgf000022_0001
The Pd(1-crotyl)QPhos complex showed a superior activity to the other catalytic systems with a 99% conversion at 0.5 mol% catalyst loading and a 95% conversion at 0.1 mol% loading. The Pd(allyl)QPhosCI complex also provided the desired product with a good conversion.
Pd-113 showed good activity, however, the conversion in this case was lower than that of Pd(1-crotyl)QPhos and Pd(allyl)QPhosCI. In addition, Pd-113 is air- and moisture sensitive and has to be stored under a nitrogen atmosphere.
Example 5
Substrate Scope of C-N Coupling
General procedure for the Buchwald-Hartwiq coupling reaction
A Schlenk flask was charged with the catalyst, NaOf-Bu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the amine in toluene was added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature and time (see Tables in communication). The crude mixture was absorbed onto silica gel (Merck Silica Gel 60 (0.040-0.063 mm)) and purified by flash column chromatography (MTBE/40-60 petroleum ether eluent). Table 5: C-N Bond Formation Mediated by 0.5 mol% Pd(crotyl)QPhosCla
Figure imgf000023_0001
toluene (2.0 mL)
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000023_0004
a aryl halide (1 .6 mmol), amine (2.0 mmol), NaOf-Bu (2.4 mmol), toluene (2.0 mL) " Using 2 mol% Pd(crotyl)QPhosCI 0 Using 1 mol% Pd(crotyl)QPhosCI " NMR yield of isolated mixture of excess diphenylamine and desired product θ Unoptimized reaction time ' GC/MS conversion 9 Using 0.05 mol% Pd -crotyl)QPhosCI h Using 0.1 mol% Pd -crotyl)QPhosCI.
Pd(n-crotyl)QPhosCI has been evaluated in several substrates for C-N coupling using a range of aryl halides with both primary and secondary amines (Table 5). The inventors have also demonstrated a number of examples of a chemoselective amination reaction of an aryl bromide in the presence of a chloride functionality. This was achieved by virtue of the fact that the aryl bromides required lower reaction temperatures than the aryl chlorides. In addition, Pd(ji-crotyl)QPhosCI effected the amination of an aryl iodide, a substrate which has been considered to be a problematic coupling partner in Pd catalysed C-N bond formation processes. The order of reactivity in aminations mediated by Pd(n-crotyl)QPhosCI appears to be the reverse to that observed in conventional Pd mediated coupling reactions. In this respect, electronrich aryl halides are aminated in higher yields at shorter reaction times than the electron-deficient electrophiles. Noteworthy is the amination of a very electron-rich tris- methoxybromobenzene in 65% yield.
As can be seen from Table 6, heterocyclic halides have also been successfully coupled.
Table 6: C-N Bond Formation using Heterocyclic Halides Mediated by 2 mol% Pd(crotyl)QPhosCr
Figure imgf000024_0001
toluene (2.0 mL)
T °C
Ar-X amine XX TT °°CC ttiimmee ((hh)) product yield(%)
Figure imgf000024_0002
Figure imgf000025_0001
8 aryl halide (1.6 mmol), amine (2.0 mmoij, iaOf-Bu (2.4 mmoi), toluene (2.0 mL)¾ isolated yieid using 1 mol% Pd(crotyl)QPhosCI. Unreacted aryl bromide could be detected by TLC before purification, indicating an incomplete reaction. Pyridine-, pyrimidine- and thiophene halides gave C-N coupled products in good yieds at 100°C. The reaction using 3-bromothiophene has been demonstrated at room temperature.
Experimental data for the products detailed in Tables 5 and 6
2-CO?lv1e-3',4',5'-trimethoxy-diphenylamine
Figure imgf000025_0002
Methyl anthranilate (390 μΙ_, 3.0 mmol); 5-bromo-1 ,2,3-trimethoxybenzene (594 mg, 2.3 mmol); NaOiBu (345 mg, 3.6 mmol); Pd(jr-crotyl)QPhosCI (43.5 mg, 0.06 mmol, 2.0 mol%); toluene (5.0 mL). The general procedure afforded the title compound as an off-white solid (462 mg, 65%); H NMR (CDCI3, 400 MHz): δ 9.39 (br s, 1 H), 7.96 (dd, J 4.4, 1.6, 1 H), 7.33 (dd, J 6.8, 1.6, 1 H), 7.21 (d, J 8.4, 1 H), 6.73 (dd, J 8.0, 0.8, 1 H), 6.49 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.83 (s, 6H); 13C (CDCI3, 100 MHz): δ 169.0, 153.8, 148.4, 136.6, 134.6, 134.2, 131.6, 1 16.9, 114.1 , 111.6, 100.7, 61.0, 56.1 , 51 .8; Elemental analysis, found: C 64.30, H 6.06, N 4.41 (theoretical: C 64.34, H 6.03, N 4.41 ).
N-(2,6-diisopropylphenyl)-N-(p-methoxy)amine
Figure imgf000025_0003
4-bromoanisole (200 μΙ_, 1.6 mmol) or 4-chloroanisole (196 μΙ_, 1.6 mmol); 2,6- diisopropylaniline (377 μί., 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(n-crotyl)QPhosCI (X = Br; 14.4 mg, 0.016 mmol, 1.0 mol%) or Pd(ji-crotyl)QPhosCI (X = CI; 7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 96 % yield (434 mg; X = Br) and 95% yield (429 mg; X = CI); H NMR (CDCI3, 400 MHz): δ 7.29-7.19 (m, 3H), 6.73 (d, J 6.8, 2H), 6.44 (d, J 6.8, 2H), 4.95 (br s, 1 H), 3.73 (s, 3H), 3.19 (heptet, J 6.8, 2H), 1.14 (d, J 7.2, 12H); 3C (CDCI3, 100 MHz): δ 152.2, 147.1 , 142.2, 136.0, 126.7, 123.8, 115.0, 114.2, 55.7, 28.0, 23.8; Elemental analysis, found: C 80.95, H 9.05, N 5.03 (theoretical: C 80.52, H 8.89, N 4.94).
/V-(4-methoxyphenv0morpholine
Figure imgf000026_0001
4-bromoanisole (200 μΙ_, 1.6 mmol) or 4-chloroanisole (196 μΙ_, 1.6 mmol); morpholine (175 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(7i-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 98 % yield (302 mg; X = Br) and 96% yield (297 mg; X = CI).
/V-(4-methoxyphenv0diphenylamine
Figure imgf000026_0002
4-bromoanisole (200 μΙ_, 1.6 mmol) or 4-chloroanisole (196 μΙ_, 1.6 mmol); diphenylaniline (338 mg, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(n-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 84 % yield (370 mg; X = Br) and 68% yield (298 mg; X = CI).
4- ethoxydiphenylamine
Figure imgf000026_0003
4-bromoanisole (200 μΐ, 1.6 mmol); aniline (182 μΐ, 2.0 mmol); NaOtBu (230 mg, 2.4 mmol); Pd(jr-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 91 % yield (288 mg). /V-(4-methoxyphenv0-/v-methylaniline
Figure imgf000027_0001
4-bromoanisole (200 μΙ_, 1.6 mmol), 4-chloroanisole (196 μL·, 1.6 mmol) or 4-iodoanisole (374 mg, 1.6 mmol); N-methylaniline (217 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(ji- crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 93 % yield (315 mg; X = Br), 98% yield (335 mg; X = CI) and 95% yield (325 mg; X = I).
4-chloro-2-methyldiphenyl-methylamine
Figure imgf000027_0002
2- bromo-5-chlorotoluene (213 μΙ_, 1.6 mmol); N-methylaniline (217 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(;i-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 88 % yield (324 mg); H NMR (CDCI3, 400 MHz): δ 7.27 (d, J 2.0, 1 H), 7.21-7.16 (m, 3H), 7.07 (d, J 8.4, 1 H), 6.73 (t, J 7.2, 1 H), 6.53 (d, J 8.0, 2H), 3.19 (s, 3H), 2.1 1 (s, 3H); 13C (CDCI3, 100 MHz) δ 146.5, 143.1 , 136.4, 129.1 , 128.9, 127.2, 126.7, 125.3, 114.9, 110.7, 36.8, 15.5; Elemental analysis, found: C 72.31 , H 6.13, N 6.05 (theoretical: C 72.57, H 6.09, N 6.04).
3- chloro-4-methyldiphenyl-methylamine
Figure imgf000027_0003
4-bromo-2-chlorotoluene (217 μΐ, 1.6 mmol); N-methylaniline (217 μΐ, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(;i-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 97 % yield (358 mg); H NMR (CDCI3, 400 MHz): δ 7.30-7.26 (m, 2H), 7.08 (d, J 8.4, 1 H), 7.02-6.96 (m, 4H), 6.79 (dd, J 8.4, 2.4, 1 H), 3.27 (s, 3H), 2.30 (s, 3H); 13C (CDCI3, 100 MHz): δ 148.7, 148.1 , 134.7, 131.2, 129.4, 128.2, 121 .9, 121.0, 120.3, 118.5, 40.4, 19.2; Elemental analysis, found: C 72.01 , H 6.04, N 5.98 (theoretical: C 72.57, H 6.09, N 6.04).
N-(2,6-diisopropylphenyl)-N-(o-tolyl)amine
Figure imgf000028_0001
2-bromotoluene (274 mg, 1.6 mmol) or 2-chlorotoluene (168 μΙ_, 1.6 mmol); 2,6- diisopropylaniline (377 L, 2.0 mmol); NaOfBu (230 mg, 2.4 mmol); Pd^-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 96 % yield (410 mg; X = Br) and 87% conversion (X = CI).
2- ethyldiphenylamine
Figure imgf000028_0002
2-bromotoluene (274 mg, 1.6 mmol) or 2-chlorotoluene (168 μΙ_, 1.6 mmol); aniline (182 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(jr-crotyl)QPhosCI (7.2 mg, 0.008 mmol, 0.5 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 91 % yield (267 mg; X = Br) and 83% yield (242 mg; X = CI).
3- ethoxydiphenylamine
Figure imgf000028_0003
3-chloroanisole (196 μί, 1.6 mmol); aniline (182 μL, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(jr-crotyl)QPhosCI (14.4 mg, 0.016 mmol, 1.0 mol%); toluene (2.0 mL). The general procedure afforded the title compound as a white solid in 91 % yield (290 mg).
4-Cvanodiphenylamine
Figure imgf000028_0004
4-bromobenzonitrile (292 mg, 1.6 mmol); aniline (182 μί, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(n-crotyl)QPhosCI (14.4 mg, 0.016 mmol, 1.0 mol%); toluene (2.0 mL). The general procedure afforded the title compound as an off-white solid (288 mg, 93%). 2-aniline-pyridine
Figure imgf000029_0001
2-bromopyridine (153 μΙ_, 1.6 mmol) or 2-chloropyridine (151 μΙ_, 1.6 mmol); aniline (182 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(7t-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 ml_). The general procedure afforded the title compound in 94 % yield (257 mg; X = Br) and 86% yield (235 mg; X = CI): 1H NMR (CDCI3, 400 MHz): δ 8.20 (d, J 4.0, 1 H), 7.50-7.46 (m, 1 H), 7.33 (d, J 4.0, 4H), 7.08-7.02 (m, 2H), 6.89 (d, J 8.4, 1 H), 6.74-6.71 (m, 1 H); 13C (CDCI3, 100 MHz): δ 156.1 , 148.4, 140.6, 137.7, 132.5, 129.3, 122.8, 120.7, 120.4, 1 15.0, 108.2; Elemental analysis, found: C 77.11 , H 5.99, N 16.20 (theoretical: C 77.62, H 5.92, N 16.46).
3-aniline-pyridine
Figure imgf000029_0002
3-bromopyridine (154 μΙ_, 1.6 mmol) or 3-chloropyridine (152 μΙ_, 1.6 mmol); aniline (182 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(jt-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 ml_). The general procedure afforded the title compound in 79 % yield (215 mg; X = Br) and 88% yield (239 mg; X = CI): H NMR (CDCI3, 400 MHz): 5 8.38 (d, J 2.0, 1 H), 8.15 (d, J 4.0, 1 H), 7.42 (d, J 7.2, 1 H), 7.30 (t, J 7.6, 2H), 7.16 (dd, J 8.0, 4.4, 1 H), 7.08 (d, J 8.0, 2H), 6.99 (t, J 7.2, 1 H), 6.01 (br s, 1 H); 13C (CDCI3, 100 MHz): δ 142.0, 141.8, 140.1 , 139.9, 129.6, 123.8, 123.4, 122.0, 1 18.3; Elemental analysis, found: C 77.19, H 6.02, N 15.96 (theoretical: C 77.62, H 5.92, N 16.46).
2-N-Methylaniline-pyrimidine
Figure imgf000029_0003
2-bromopyrimidine (127 mg, 0.8 mmol); N-methylaniline (109 μΙ_, 1.0 mmol); NaOiBu (115 mg, 1.2 mmol); Pd(ji-crotyl)QPhosCI (14.4 mg, 0.016 mmol, 2.0 mol%); toluene (1 .0 ml_). The general procedure afforded the title compound in 83 % yield (123 mg): 1H NMR (CDCI3, 400 MHz): δ 8.34 (d, J 4.4, 2H), 7.42 (t, J 8.0, 2H), 7.32 (d, J 7.6, 2H), 7.24-7.22 (m, 1 H), 6.57 (t, J 4.8, 1 H), 3.53 (s, 3H); 3C (CDCI3, 100 MHz): δ 162.0, 157.7, 145.5, 129.2, 126.6, 125.9, 110.8, 38.7; Elemental analysis, found: C 71.33, H 6.08, N 22.51 (theoretical: C 71.33, H 5.99, N 22.69).
2-(/V-Methyl-/V-phenylamino)thiophene
Figure imgf000030_0001
3-bromothiophene (150 μΙ_, 1.6 mmol) or 3-chlorothiophene (149 μΙ_, 1.6 mmol); N- methylaniline (217 μL, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(7i-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 mL). The general procedure afforded the title compound in 90 % yield (272 mg; X = Br) and 57% yield (172 mg; X = CI): H NMR (CDCI3, 400 MHz): δ 7.27-7.20 (m, 3H); 7.01 (d, J 7.6, 2H), 6.91 (t, J 7.6, 1 H), 6.87 (dd, J 5.2, 1.6, 1 H), 6.57 (dd, J 3.2, 1.2, 1 H), 3.29 (s, 3H); 3C (CDCI3, 100 MHz) δ 149.3, 148.4, 129.1 , 124.9, 123.3, 120.7, 1 18.8, 107.8, 41.0; Elemental analysis, found: C 70.13, H 5.84, N 7.32 (theoretical: C 69.80, H 5.86, N 7.40).
2-Chloro-5-/V-methylaniline-thiophene
Figure imgf000030_0002
2-bromo-5-chlorothiophene (175 μΙ_, 1.6 mmol); /V-methylaniline (217 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(7i-crotyl)QPhosCI (28.8 mg, 0.032 mmol, 2.0 mol%); toluene (2.0 mL); 25 °C; 20 hrs. The general procedure afforded the title compound as an off-white oil in 44% yield (155 mg): H NMR (CDCI3, 400 MHz): δ 7.26-7.23 (m, 2H), 6.94-6.88 (m, 3H), 6.70 (d, J 4.0, 1 H), 6.44 (d, J 4.0, 1 H), 3.28 (s, 3H); 3C (CDCI3, 100 MHz): δ 151.3, 148.8, 129.1 , 124.6, 123.3, 120.3, 1 19.1 , 116.1 , 41.8; Elemental analysis, found: C 59.28, H 4.54, N 6.29 (theoretical: C 59.05, H 4.51 , N 6.26).
4-methyldiphenyl-methylamine
Figure imgf000030_0003
4-bromotoluene (274 mg, 1.6 mmol); /V-methylaniline (217 μί, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd(ji-crotyl)QPhosCI (0.7 mg, 0.0008, 0.05 mol%); toluene (0.5 mL). The general procedure afforded the title compound in 83% yield (261 mg): 1H NMR (CDCI3, 400 MHz): δ 7.24-7.20 (m, 2H), 7.11 (d, J 8.4, 2H), 7.01-6.97 (m, 2H), 6.91 (app. d, J 7.6, 2H), 6.86 (app. t, J 7.6, 1 H), 3.28 (s, 3H), 2.31 (s, 3H); 3C (CDCI3, 100 MHz): δ 149.4, 146.6, 132.1 , 130.0, 129.1 , 122.6, 119.8, 118.2, 40.4, 20.8; Elemental analysis, found: C 85.25, H 7.75, N 7.29 (theoretical: C 85.24, H 7.66, N 7.10).
/v-4-toluene-2,6-diisopropylaniline
Figure imgf000031_0001
4-bromotoluene (274 mg, 1.6 mmol); 2,6-diisopropylaniline (377 μΙ_, 2.0 mmol); NaOiBu (230 mg, 2.4 mmol); Pd -crotyl)QPhosCI (0.7 mg, 0.0008, 0.05 mol%); toluene (0.5 mL). The general procedure afforded the title compound in 91 % yield (387 mg): 1H NMR (CDCI3, 400 MHz): δ 7.30-7.25 (m, 1 H), 7.22-7.19 (m, 2H), 6.94 (d, J 8.0, 2H), 6.39 (d, J 8.4, 2H), 5.02 (br s, 1 H), 3.19 (heptet, J 6.8, 2H), 2.23 (s, 3H), 1.13 (d, J 6.8, 12H); 3C (CDCI3, 100 MHz): δ 147.4, 145.9, 135.6, 129.8, 127.0, 126.9, 123.9, 1 13.1 , 28.2, 23.9, 20.5; Elemental analysis, found: C 85.22, H 9.45, N 5.29 (theoretical: C 85.34, H 9.42, N 5.24).
Example
N-Arylations at low catalyst loadings of Pdfa-crotvDQPhosCI
The arylation of amines at lower catalyst loadings were evaluated (Table 7) and, in this respect, reactions carried out with 0.05 or 0.1 mol% loading were successfully achieved.
Table 7: N- Arylations at Low Catalyst Loadings of Pd(n-crotyl)QPhosCI.
Figure imgf000031_0002
Figure imgf000031_0003
Figure imgf000031_0004
Figure imgf000032_0001
' aryl halide (1.6 mmol), amine (2.0 mmol), NaOi-Bu (2.4 mmol), toluene (0.5 ml_) GC/MS conversion.
See Example 5 for the experimental data for the products listed in Table 7 Example 7
Synthesis of the Toddaliopsin Framework
The synthesis of the toddaliopsin framework was realised by implementing a Pd -1- crotyl)QPhosCI catalysed aryl amination step incorporating a very electronrich aryl bromide. As can be seen, the C-N coupling reaction proceeded smoothly to provide the required product in 65% yield.
Figure imgf000032_0002
Toddaliopsin A R = H Toddaliopsin B R = Me
Toddaliopsin D R = CH2OMe Toddaliopsin C R = H
Figure imgf000032_0003
65% yield
Example 8
General procedure for the g-arylation reaction of aldehydes:
A Schlenk flask was charged with the catalyst, Cs2C03 and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, a solution of the aryl halide, if liquid, and the aldehyde in solvent were added. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for the indicated time, then the mixture was absorbed onto silica gel and purified by flash column chromatography (EtOAc/40-60 petroleum ether eluent).
Figure imgf000033_0001
81 % conversion 83% conversion 49% yield 42% conversion
55% yield 73% yield
Example 9
General procedure for the g-arylation of ketones:
A Schlenk flask was charged with the catalyst, NaOiBu and aryl halide, if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, the aryl halide (if liquid), followed by ketone and solvent were added via syringe. The resulting reaction mixture was stirred under nitrogen at the indicated temperature for 18 hours, then the mixture was absorbed onto silica gel and purified by flash column chromatography (MTBE/40-60 petroleum ether eluent).
Table 8: a-arylation of ketones
Figure imgf000033_0002
catalyst (mol%) solvent 7" (°C) time (hrs) Conversion8 (%)
Pd(allyl)QPhosCI (1.0) THF 60 1 7 76
Pd(1 -crotyl)QPhosCI (1.0) THF 60 1 7 99 (85)
Pd(1-crotyl)QP osCI (0.25) THF 60 17 (90)
Pd(dba)2 / QPhos (0.25) (Comparative) THF 60 17 (80)
Pd(OAc)2 / QPhos (0.25) (Comparative) THF 60 17 (85)
Pd-118 (0.25) (Comparative)0 THF 60 17 (64)
a Conversion using GC/MS. Isolated yield in parenthesis b All starting material consumed
c Pd-1 18 = dichloro[1, 1 '-bis(di-tert-butylphosphino)]ferrocene palladium (II)
It can be seen from the results in the above table that the Pd(n:-1-crotyl)QPhosCI precatalyst provided the best results in the a-arylation reaction. Moreover, in comparison with in situ generated QPhos based catalysts, the preformed complexes exhibited comparable or superior activities.
Example 10
Substrate scope for the g-arylation of ketones It was demonstrated that the mono-arylation of propiophenone proceeded smoothly using a range of electronrich and -neutral aryl halides and the Pd(7i-1-crotyl)QPhosCI catalyst. Substituents were tolerated in the ortho- and meta- as well as the para-position of the aryl moiety.
Table 9: Substrate scope for the a-arylation of ketones
Pd(1-crotyl)QPhosCI J
Ph NaOtBu ' J Ph
THF or dioxane, T °C Ar
Figure imgf000034_0001
x = Br 90% yield b ld3 63% yield3
(0.25 mol%, 60 °C)
Figure imgf000034_0002
βΟ ) (0.25 mol%, 60 °C)
Y _ r, 82% yield 61 % yield3 65% yield8
Λ Ul (1.0 mol%, 100 °C) (0.25 mol, 100 °C) (1 .0 mol%, 100 °C)
Figure imgf000034_0003
88% yield3 99% yield3
Γ (0.25 mol%, 60 °C) (1 .0 mol%, 60 °C)
3 Product co-running with propiophenone. Yield given is NMR yield from isolated mixture of product and propiophenone b Average yield from 3 reactions
Example 11
g-Arylation of 1-Tetralone
General Procedure
A Schlenk flask was charged with Pd(X)LCI (0.05 mol%, 0.001 mmol) and NaOi-Bu (365 mg, 3.8 mmol). The flask was evacuated and backfilled with nitrogen three times, then dioxane (2.0 ml), 4-chloroanisole (245 μΙ, 2.0 mmol) and a-tetralone (266 μΙ, 2.0 mmol) were added. The reaction mixture was stirred for 16 hours, then an aliquot was removed for analysis by GC/MS.
The activities of the π-allyl catalysts bearing the QPhos and P(i-Bu)2( -NMe2C6H4) ligands were evaluated in the π-arylation of cyclic ketone 1-tetralone. Pd(allyl)QPhosCI provided the product in 80 % conversion after 3 hours reaction time, whereas Pd(allyl)P(/-Bu)2(p- NMe2CeH4)CI gave 96 % conversion after the same time (Table 10, entries 1 and 2). The product was isolated in 91 % yield after an overnight reaction using catalyst loading as low as 0.05 mol % of Pd(allyl)P(f-Bu)2(p-NMe2C6H4)CI (entry 3). Table 10: α-Arylation of 1-Tetralone Using 0.05 mol % Pd Loading.3
Figure imgf000035_0001
1 Pd(allyl)QPhosCI 3 80
2 Pd(allyl)P(i-Bu)2(p-NMe2CeH4)CI 3 96
3 Pd(allyl)P(i-Bu)2(p-N e2C6H4)CI 22 100(91 )
Figure imgf000035_0002
Average of two runs. Isolated yield in parenthesis. Example 12
Suzuki Coupling Reactions
General procedure for the Suzuki reaction:
A Schlenk flask was charged with the catalyst, KOrBu (1.2 eq), boronic acid (1 .1 eq) and aryl halide (1.0 eq), if solid, and the flask was evacuated and backfilled with nitrogen three times. Subsequently, the aryl halide (if liquid) and solvent were added via syringe. The resulting reaction mixture was stirred under nitrogen at the indicated temperature, then the crude reaction mixture was analysed by GC/MS.
Table 11 : Suzuki coupling reactions
Figure imgf000035_0003
X solvent C (M) loading (mol%) time (h) T (°C) conversion (%f
Br toluene:H20 (4: 1) 0.8 0.01 20 100 100
Br toluene:H20 (4: 1) 0.8 1 .0 1 25 100
CI toluene 0.27 1.0 20 80 68 conversion into product, taking into account deboronated product formed.
The high activity of Pd(crotyl)Q-PhosCI was subsequently demonstrated in the sterically challenging Suzuki reaction of bromomesitylene and 1-naphthalene boronic acid. This coupling could be carried out at ambient temperature with 100 % GC conversion and 86 % isolated yield within 45 minutes of the reaction time.
Figure imgf000036_0001
Example 13
Aryl Chlorides in Suzuki Coupling
Extending the scope of the substrates to aryl chlorides, the coupling product of of 4- chloroanisole with 4-feri-butylbenzene boronic acid gave 90 % conversion (Table 12, entry 1 ) using the same reaction conditions as for the aryl bromides, but at 80 °C. The present inventors also decided to investigate the base effect and the use of heterocyclic chlorides employing the π-allyl catalysts in comparision with the use of PdCI2(P(f-Bu)2( -NMe2C6H4))2 as reported by Guram (Guram et al, Org. Lett., 2006, 8, 1787). Substituting K2C03for KOi-Bu in the case of 4-chloroanisole provided the coupling product in relatively low conversions, using both Pd(crotyl)QPhosCI and Pd(allyl)P(f-Bu)2(p-NMe2C6H4)CI (entries 2 and 3). However, employing 2-chlorothiophene in the Suzuki reaction, it was found that the yield of the product was comparable to the Guram conditions for PdCI2(P(f-Bu)2(p-N e2C6H4))2 and the new Pd(allyl) P(f-Bu)2(p-NMe2C6H4)CI (entries 4-5, 6-7, 8-9), demonstrating that a Pd:L ratio of 1 : 1 was sufficient for an efficient reaction. Using the reaction conditions developed for the aryl bromides, 2-chlorothiophene was coupled with 4-ieri-butyl-benzene boronic acid to obtain 52 % yield, with Pd(crotyl)QPhosCI catalyst (entry 10). The same reaction gave a lower yield (33 %) under the Guram conditions (entry 11 ). For chloropyridine substrate, Pd(n- allyl)AmphosCI gave 73 % yield (entry 13).
The described investigation of aryl chlorides in Suzuki coupling illustrates the importa careful choice of the catalyst and the reaction conditions to get the optimized yields.
Table 12: Aryl Chlorides in Suzuki Coupling.
Figure imgf000036_0002
Figure imgf000037_0001
In the Suzuki coupling reactions, the present inventors have been the first to demonstrate that K2C03 can be used as the base in conjunction with π-allyl precatalysts.

Claims

Claims
A complex of formula (1 ):
Figure imgf000038_0001
wherein,
M is palladium or nickel,
and R2 are independently organic groups having 1-20 carbon atoms, or and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl,
R4 is an organic group having 1-20 carbon atoms,
n is O, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
A complex according to claim 1 , wherein M is palladium.
A complex according to claim 1 or claim 2, wherein R-i and R2 are independently selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen and oxygen.
A complex according to any one of the preceding claims, wherein R3 is phenyl or dimethylaminophenyl.
A complex according to any one of claims 1 to 3, wherein the substituted or unsubstituted metallocenyl has a structure of formula (2):
Figure imgf000038_0002
Fe (2)
(R1 l )q wherein,
R10 and R-n are independently organic groups having 1-20 carbon atoms, p is 0, 1 , 2, 3 or 4, and
q is 0, 1 , 2, 3, 4 or 5.
Figure imgf000039_0001
A complex according to claim 5, wherein R10 is a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted (alkyl)HN-, substituted or unsubstituted (dialkyl)N-, substituted or unsubstituted (dialkyl)amino-alkyl or substituted or unsubstituted alkoxyalkyl.
Figure imgf000039_0002
R^ is a substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
A complex according to any one of claims 5 to 7, wherein the metallocenyl group has
Figure imgf000039_0003
a structure of formula (3):
Figure imgf000039_0004
wherein Rn is an organic group having 1-20 carbon atoms, and q is 0, 1 , 2, 3, 4 or 5. 9. A complex according to any one of claims 5 to 8, wherein R-n is selected from the group consisting of phenyl, napthyl, methoxyphenyl, halophenyl, methylphenyl and F3C-phenyl, and q is 4 or 5.
10. A complex according to any one of claims 5 to 9, wherein Rn is selected from the group consisting of phenyl, methoxyphenyl, methylphenyl and F3C-phenyl, and q is 4 or 5.
11. A complex according to any one of claims 5 to 10, wherein the metallocenyl group has a structure of formula (4):
Figure imgf000039_0005
A complex according to any one of the preceding claims, wherein R4 is selected from the group consisting of substituted and unsubstituted straight-chain alkyl, substituted and unsubstituted branched-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl wherein the heteroatoms are selected from the group consisting of sulfur, nitrogen and oxygen.
13. A complex according to any one of the preceding claims, wherein X is a halo group.
14. A complex according to any one of the preceding claims, wherein the complex of formula (1 ) is selected from the group consisting of:
Figure imgf000040_0001
15. A method for the preparation of a complex of formula (1 ),
Figure imgf000040_0002
comprising the step of reacting a complex of formula (5) with PR-1R2R3, n(R4)- ^~M^ /M— (5)
\ ^χ ^(R4)n wherein,
M is palladium or nickel,
Ri and R2 are independently organic groups having 1-20 carbon atoms, or and R2 are linked to form a ring structure with the phosphorus atom,
R3 is selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, and substituted and unsubstituted metallocenyl,
R4 is an organic group having 1-20 carbon atoms, n is 0, 1 , 2, 3, 4 or 5,
X is an anionic ligand.
The use of a complex of formula (1 ) according to any one of claims 1 to 14 as a catalyst for carbon-carbon coupling reactions or carbon-nitrogen coupling reactions.
A method for carrying out a carbon-carbon coupling reaction or a carbon-nitrogen coupling reaction in the presence of a catalyst, the method comprising using a complex of formula (1 ) according to any one of claims 1 to 14 as the catalyst.
PCT/GB2011/051171 2010-06-23 2011-06-22 Complexes WO2011161451A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP19203075.7A EP3613504A1 (en) 2010-06-23 2011-06-22 Pi-allylpalladium and pi-allylnickel complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions
DK11728654.2T DK2585216T3 (en) 2010-06-23 2011-06-22 PI-ALLYL PALLADIUM AND PI-ALLYLNICKEL COMPLEXES USED AS CATALYSTS IN CARBON-CARBON AND CARBON-NITROGEN COUPLING REACTIONS
EP11728654.2A EP2585216B1 (en) 2010-06-23 2011-06-22 Pi-allylpalladium and pi-allylnickel complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions
ES11728654T ES2769386T3 (en) 2010-06-23 2011-06-22 Pi-Allyl Palladium and Pi-Allyl Nickel Complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions
CN201180037387.2A CN103037969B (en) 2010-06-23 2011-06-22 Complex compound
PL11728654T PL2585216T3 (en) 2010-06-23 2011-06-22 Pi-allylpalladium and pi-allylnickel complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions
US13/806,575 US10167305B2 (en) 2010-06-23 2011-06-22 Allyl complexes for use in coupling reactions
US16/136,685 US10597416B2 (en) 2010-06-23 2018-09-20 Complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35774410P 2010-06-23 2010-06-23
US61/357,744 2010-06-23

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/806,575 A-371-Of-International US10167305B2 (en) 2010-06-23 2011-06-22 Allyl complexes for use in coupling reactions
US16/136,685 Division US10597416B2 (en) 2010-06-23 2018-09-20 Complexes

Publications (1)

Publication Number Publication Date
WO2011161451A1 true WO2011161451A1 (en) 2011-12-29

Family

ID=44532941

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/051171 WO2011161451A1 (en) 2010-06-23 2011-06-22 Complexes

Country Status (8)

Country Link
US (2) US10167305B2 (en)
EP (2) EP3613504A1 (en)
CN (1) CN103037969B (en)
DK (1) DK2585216T3 (en)
ES (1) ES2769386T3 (en)
PL (1) PL2585216T3 (en)
PT (1) PT2585216T (en)
WO (1) WO2011161451A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8933239B1 (en) 2013-07-16 2015-01-13 Dow Global Technologies Llc Bis(aryl)acetal compounds
US8962779B2 (en) 2013-07-16 2015-02-24 Dow Global Technologies Llc Method of forming polyaryl polymers
US9063420B2 (en) 2013-07-16 2015-06-23 Rohm And Haas Electronic Materials Llc Photoresist composition, coated substrate, and method of forming electronic device
WO2015189555A1 (en) * 2014-06-12 2015-12-17 Johnson Matthey Public Limited Company Complexes
US9410016B2 (en) 2013-07-16 2016-08-09 Dow Global Technologies Llc Aromatic polyacetals and articles comprising them
CN105944761A (en) * 2016-04-29 2016-09-21 宁波大学 Sulfaquinoxaline cobalt-nickel nano composite material and preparation method thereof
JP2017526621A (en) * 2014-06-12 2017-09-14 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ Complex
WO2018106337A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalyts, their synthesis and use in suzuki coupling
WO2018106338A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalysts, their synthesis and use in suzuki coupling
WO2018106336A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalyts, their synthesis and use in suzuki coupling
CN108368142A (en) * 2015-12-02 2018-08-03 住友化学株式会社 The manufacturing method and palladium complex of aromatic compound

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2585216T3 (en) * 2010-06-23 2020-06-01 Johnson Matthey Plc Pi-allylpalladium and pi-allylnickel complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions
CN104031005B (en) * 2014-05-30 2016-04-27 济南诚汇双达化工有限公司 A kind of preparation method of S-1574 intermediate
CN111116666B (en) * 2019-12-13 2020-12-29 中国科学院福建物质结构研究所 Preparation and application of triphenylphosphine allyl palladium halide compound and derivative thereof
CN111848453B (en) * 2020-07-22 2022-09-02 浙江金立源药业有限公司 Production process and production line of 4-methyl-2' -cyanobiphenyl
CN112250715A (en) * 2020-10-29 2021-01-22 西安凯立新材料股份有限公司 Preparation method of chloro (crotyl) (3-tert-butylphosphoryl) palladium (II)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047474A1 (en) 1998-03-18 1999-09-23 Ciba Specialty Chemicals Holding Inc. Coupling reactions with palladium catalysts
WO2001016057A1 (en) 1999-08-27 2001-03-08 Ciba Specialty Chemicals Holding Inc. Coupling reactions using palladium catalysts
WO2002011883A1 (en) 2000-08-07 2002-02-14 Yale University CATALYST FOR AROMATIC C-O, C-N, and C-C BOND FORMATION
WO2003000666A1 (en) * 2001-06-21 2003-01-03 Pfizer Products Inc. 5-ht receptor ligands and uses thereof
WO2007109355A2 (en) * 2006-03-21 2007-09-27 Janssen Pharmaceutica N.V. 6,7,8, 9 -tetrahydro- 5h- pyrimido [4, 5-d] azepin-4-yl] -amine derivatives as modulators of trpvl for the treatment of pain
WO2008016956A2 (en) * 2006-08-01 2008-02-07 Headwaters Technology Innovation Llc Methods for manufacturing ary-aryl coupled polymers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5892101A (en) * 1996-11-18 1999-04-06 E. I. Du Pont De Nemours And Company Cross-dimerization of olefins
PL2585216T3 (en) * 2010-06-23 2020-06-01 Johnson Matthey Plc Pi-allylpalladium and pi-allylnickel complexes for use as catalysts in carbon-carbon and carbon-nitrogen coupling reactions

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047474A1 (en) 1998-03-18 1999-09-23 Ciba Specialty Chemicals Holding Inc. Coupling reactions with palladium catalysts
WO2001016057A1 (en) 1999-08-27 2001-03-08 Ciba Specialty Chemicals Holding Inc. Coupling reactions using palladium catalysts
WO2002011883A1 (en) 2000-08-07 2002-02-14 Yale University CATALYST FOR AROMATIC C-O, C-N, and C-C BOND FORMATION
WO2003000666A1 (en) * 2001-06-21 2003-01-03 Pfizer Products Inc. 5-ht receptor ligands and uses thereof
WO2007109355A2 (en) * 2006-03-21 2007-09-27 Janssen Pharmaceutica N.V. 6,7,8, 9 -tetrahydro- 5h- pyrimido [4, 5-d] azepin-4-yl] -amine derivatives as modulators of trpvl for the treatment of pain
WO2008016956A2 (en) * 2006-08-01 2008-02-07 Headwaters Technology Innovation Llc Methods for manufacturing ary-aryl coupled polymers

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"Gmelin Handbuch der Anorganischen Chemie Ergänzungswerk zur 8. Auflage Band 17 Nickel-Organische Verbindungen Teil 2", 1974, SPRINGER VERLAG, ISBN: 3-540-93279-8, article "1.3.1.7.2 Verbindungen des Typs 3LNi(D)R - Compounds of the 3LNi(D)R Type", pages: 29 - 40, XP055008405 *
AKERMARK B ET AL: "Ligand effects and nucleophilic addition to (eta-3-allyl)palladium complexes. A carbon-13 nuclear magnetic resonance study", ORGANOMETALLICS, vol. 6, no. 1, March 1987 (1987-03-01), pages 620 - 628, XP002108717, ISSN: 0276-7333, DOI: 10.1021/OM00146A031 *
AUBURN, P. R., MACKENZIE, P. B., BOSNICH, B., J. AM. CHEM. SOC., vol. 107, 1985, pages 2033
CARTURAN G ET AL: "Activation of H2 with allylpalladium(II) derivatives. Selective catalytic hydrogenation of allene to propene", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 157, no. 4, 19 September 1978 (1978-09-19), pages 475 - 481, XP002125140, ISSN: 0022-328X, DOI: 10.1016/S0022-328X(00)94030-0 *
CHARTOIRE A ET AL: "Highly Active Well-Defined Palladium Precatalysts for the Efficient Amination of Aryl Chlorides", ORGANOMETALLICS, vol. 30, no. 16, 22 August 2011 (2011-08-22), pages 4432 - 4436, XP055008369, ISSN: 0276-7333, DOI: 10.1021/om2005222 *
DENT, W. I., LONG, R., WILKINSON, G., J. CHEM. SOC., 1964, pages 1585
DIETRICH S ET AL: "Amidoamine-based dendrimers with end-grafted Pd-Fe units: Synthesis, characterization and their use in the Heck reaction", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 696, no. 3, February 2011 (2011-02-01), pages 739 - 747, XP055008513, ISSN: 0022-328X, DOI: 10.1016/j.jorganchem.2010.09.063 *
DREHER S D ET AL: "Efficient Cross-Coupling of Secondary Alkyltrifluoroborates with Aryl Chlorides - Reaction Discovery Using Parallel Microscale Experimentation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 130, no. 29, July 2008 (2008-07-01), pages 9257 - 9259, XP055008960, ISSN: 0002-7863, DOI: 10.1021/ja8031423 *
GRABULOSA A ET AL: "Allylpalladium Complexes with P -Stereogenic Monodentate Phosphines. Application in the Asymmetric Hydrovinylation of Styrene", ORGANOMETALLICS, vol. 24, no. 21, October 2005 (2005-10-01), pages 4961 - 4973, XP055008518, ISSN: 0276-7333, DOI: 10.1021/om050421v *
GRABULOSA A ET AL: "Better Performance of Monodentate P-Stereogenic Phosphanes Compared to Bidentate Analogues in Pd-Catalyzed Asymmetric Allylic Alkylations", EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, vol. 2010, no. 21, July 2010 (2010-07-01), pages 3372 - 3383, XP055008521, ISSN: 1434-1948, DOI: 10.1002/ejic.201000308 *
GURAM ET AL., ORG. LETT., vol. 8, 2006, pages 1787
HE A ET AL: "Stereospecific Suzuki Cross-Coupling of Alkyl alpha-Cyanohydrin Triflates", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 132, no. 8, 3 March 2010 (2010-03-03), pages 2524 - 2525, XP055008938, ISSN: 0002-7863, DOI: 10.1021/ja910582n *
KISANGA P ET AL: "Development, synthetic scope, and mechanistic studies of the palladium-catalysed cycloisomerisation of functionalised 1,6-dienes in the presence of silane", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 122, no. 41, 18 October 2000 (2000-10-18), pages 10017 - 10026, XP002184755, ISSN: 0002-7863, DOI: 10.1021/JA001730+ *
KRASOVSKIY A ET AL: "Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature Without Prior Formation of Organozinc Reagents", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 43, 4 November 2009 (2009-11-04), pages 15592 - 15593, XP055008939, ISSN: 0002-7863, DOI: 10.1021/ja906803t *
LAMAC M ET AL: "Synthesis, Coordination and Catalytic Utility of Novel Phosphanyl-ferrocenecarboxylic Ligands Combining Planar and Central Chirality", EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, vol. 2007, no. 16, June 2007 (2007-06-01), pages 2274 - 2287, XP055008514, ISSN: 1434-1948, DOI: 10.1002/ejic.200700093 *
MARION, N., NAVARRO, 0., MEI, J., STEVENS, E. D., SCOTT, N. M., NOLAN, S. P., J. AM. CHEM. SOC., vol. 128, 2006, pages 4101
NICHOLSON, J. K., POWELL, J., SHAW, B. L., J. CHEM. SOC.; CHEM. COMMUN., 1966, pages 174
OHMURA T ET AL: "Switch of Regioselectivity in Palladium-Catalyzed Silaboration of Terminal Alkynes by Ligand-Dependent Control of Reductive Elimination", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 132, no. 35, 8 September 2010 (2010-09-08), pages 12194 - 12196, XP055008319, ISSN: 0002-7863, DOI: 10.1021/ja105096r *
OSLINGER M ET AL: "Further N.M.R. Studies of the Dynamic Stereochemistry of pi-Allylic Palladium(II) - Tertiary Phosphine Systems", CANADIAN JOURNAL OF CHEMISTRY, vol. 51, no. 2, 15 January 1973 (1973-01-15), pages 274 - 287, XP055008527, ISSN: 0008-4042, DOI: 10.1139/v73-040 *
REID S J ET AL: "Reactions of free radicals with eta3-allylpalladium(II) complexes: cyclohexyl radicals", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 689, no. 7, April 2004 (2004-04-01), pages 1257 - 1264, XP004496428, ISSN: 0022-328X, DOI: 10.1016/J.JORGANCHEM.2004.01.009 *
TOLKUNOVA V S ET AL: "Preparation of complexes of pi-allylpalladium chloride with ferrocenylphosphine ligands and investigation of retarded rotation around Pd-P bond", BULLETIN OF THE ACADEMY OF SCIENCES OF THE USSR, DIVISION OF CHEMICAL SCIENCES, vol. 30, no. 10, 1981, pages 1826 - 1830, XP055008376, ISSN: 0568-5230, DOI: 10.1007/BF00963401 *
VAN LEEUWEN P W M N ET AL: "Magnetic non-equivalence in substituted allylpalladium compounds in relation to molecular rearrangements", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 29, no. 3, 16 June 1971 (1971-06-16), pages 433 - 442, XP055008525, ISSN: 0022-328X, DOI: 10.1016/S0022-328X(00)85291-2 *

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9410016B2 (en) 2013-07-16 2016-08-09 Dow Global Technologies Llc Aromatic polyacetals and articles comprising them
US8962779B2 (en) 2013-07-16 2015-02-24 Dow Global Technologies Llc Method of forming polyaryl polymers
US9063420B2 (en) 2013-07-16 2015-06-23 Rohm And Haas Electronic Materials Llc Photoresist composition, coated substrate, and method of forming electronic device
US8933239B1 (en) 2013-07-16 2015-01-13 Dow Global Technologies Llc Bis(aryl)acetal compounds
US10858382B2 (en) 2014-06-12 2020-12-08 Johnson Matthey Public Limited Company Allyl phosphine complexes of palladium and their use in catalysis
EP3812040A1 (en) 2014-06-12 2021-04-28 Johnson Matthey Public Limited Company Complexes
US20170120231A1 (en) * 2014-06-12 2017-05-04 Johnson Matthey Public Limited Company Complexes
CN106661071A (en) * 2014-06-12 2017-05-10 庄信万丰股份有限公司 Complexes
JP2017526621A (en) * 2014-06-12 2017-09-14 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ Complex
JP2017527526A (en) * 2014-06-12 2017-09-21 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ Complex
US9777030B2 (en) 2014-06-12 2017-10-03 Johnson Matthey Public Limited Company Complexes
US11649258B2 (en) 2014-06-12 2023-05-16 Johnson Matthey Public Limited Company Complexes
JP7098673B2 (en) 2014-06-12 2022-07-11 ジョンソン、マッセイ、パブリック、リミテッド、カンパニー Complex
EP3845546A1 (en) 2014-06-12 2021-07-07 Johnson Matthey Public Limited Company Complexes
EP3842421A1 (en) 2014-06-12 2021-06-30 Johnson Matthey Public Limited Company Complexes
US10253056B2 (en) 2014-06-12 2019-04-09 Johnson Matthey Public Limited Company Complexes
RU2684934C2 (en) * 2014-06-12 2019-04-16 Джонсон Мэтти Паблик Лимитед Компани Complexes
JP2019116482A (en) * 2014-06-12 2019-07-18 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ Complexes
US10968244B2 (en) 2014-06-12 2021-04-06 Johnson Matthey Public Limited Company Syntheses of allyl phosphine complexes of palladium
CN106661071B (en) * 2014-06-12 2020-06-09 庄信万丰股份有限公司 Complex compounds
JP2020117508A (en) * 2014-06-12 2020-08-06 ジョンソン、マッセイ、パブリック、リミテッド、カンパニーＪｏｈｎｓｏｎ Ｍａｔｔｈｅｙ Ｐｕｂｌｉｃ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ Complexes
WO2015189555A1 (en) * 2014-06-12 2015-12-17 Johnson Matthey Public Limited Company Complexes
EP3385270A4 (en) * 2015-12-02 2020-01-22 Sumitomo Chemical Company, Ltd Method for producing aromatic compound, and palladium complex
US11045796B2 (en) 2015-12-02 2021-06-29 Sumitomo Chemical Company, Limited Process for producing aromatic compound, and palladium complex
CN108368142A (en) * 2015-12-02 2018-08-03 住友化学株式会社 The manufacturing method and palladium complex of aromatic compound
CN105944761A (en) * 2016-04-29 2016-09-21 宁波大学 Sulfaquinoxaline cobalt-nickel nano composite material and preparation method thereof
WO2018106336A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalyts, their synthesis and use in suzuki coupling
WO2018106338A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalysts, their synthesis and use in suzuki coupling
WO2018106337A1 (en) 2016-12-06 2018-06-14 Dow Global Technologies Llc Mono-ligated palladium catalyts, their synthesis and use in suzuki coupling

Also Published As

Publication number Publication date
US20130165660A1 (en) 2013-06-27
DK2585216T3 (en) 2020-02-03
CN103037969A (en) 2013-04-10
EP3613504A1 (en) 2020-02-26
PT2585216T (en) 2020-02-28
US20190016742A1 (en) 2019-01-17
EP2585216A1 (en) 2013-05-01
EP2585216B1 (en) 2019-11-20
ES2769386T3 (en) 2020-06-25
US10167305B2 (en) 2019-01-01
US10597416B2 (en) 2020-03-24
PL2585216T3 (en) 2020-06-01
CN103037969B (en) 2015-07-29

Similar Documents

Publication Publication Date Title
WO2011161451A1 (en) Complexes
EP1910253B1 (en) Stable cyclic (alkyl)(amino) carbenes as ligands for transition metal catalysts
CN101460513B (en) Organometallic ruthenium complexes and related methods for the preparation of tetra-substituted and other hindered olefins
AU2003271713A1 (en) Ruthenium complexes as (pre)catalysts for metathesis reactions
Xue et al. Iron (II) complexes with functionalized amine-pyrazolyl tripodal ligands in the cross-coupling of aryl Grignard with alkyl halides
EP3154689B1 (en) Complexes
US11649258B2 (en) Complexes
CN102432411A (en) Nitrogen-heterocyclic-cabbeen-palladium-iminazole complex for catalyzing application of aryl chloride in amination reaction
KR102616164B1 (en) Cross-coupling reaction catalyst, and methods of making and using the same
Boyarskiy et al. Palladium‐(Acyclic Diaminocarbene) Species as Alternative to Palladium‐(Nitrogen Heterocyclic Carbenes) in Cross‐Coupling Catalysis
JP2003183187A (en) N-heterocyclic carbene complex and its use
WO2007064869A2 (en) Catalysts for aryl sulfide synthesis and method of producing aryl sulfides
Li et al. Zinc‐Catalyzed Hydroamination Reactions
CA3024425A1 (en) Novel ionic half sandwich ruthenium complexes supported by n-heterocyclic carbene and/or phosphines, as efficient transfer hydrogenation catalysts
US6878850B2 (en) Catalysis using halophosphine compounds
WO2008102157A1 (en) Catalytic method

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180037387.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11728654

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2011728654

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13806575

Country of ref document: US