WO2019091898A1 - Process for the preparation of 5-substituted imidazole derivatives and manganese compounds useful therefor - Google Patents

Process for the preparation of 5-substituted imidazole derivatives and manganese compounds useful therefor Download PDF

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WO2019091898A1
WO2019091898A1 PCT/EP2018/080121 EP2018080121W WO2019091898A1 WO 2019091898 A1 WO2019091898 A1 WO 2019091898A1 EP 2018080121 W EP2018080121 W EP 2018080121W WO 2019091898 A1 WO2019091898 A1 WO 2019091898A1
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alkyl
cycloalkyl
formula
substituted
tri
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PCT/EP2018/080121
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French (fr)
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Christoph SÄMANN
Sergii Pazenok
Pierre-Yves Coqueron
David Bernier
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Bayer Aktiengesellschaft
Bayer Cropscience Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic System

Definitions

  • the present invention relates to a process for preparing 5-substituted imidazolylmethyl derivatives and to specific manganese compounds that can be used in this process.
  • Certain 5-substituted imidazolylmethyl derivatives are known to be useful in the field of crop protection, in particular as fungicides.
  • WO 2016/156290 Al discloses such 5-substituted imidazolylmethyl derivatives and several routes to synthesize those. One of said routes is referred to in WO 2016/156290 Al as process M and comprises reacting suitable 5-substituted imidazolylmethyl ketones and Grignard reagents. Such procedure provides access to the target 5-substituted imidazolylmethyl derivatives.
  • further improvement of the process e.g. in terms of yield and/or purity, is desirable.
  • object of the invention is providing an improved process for the synthesis of 5-substituted imidazolylmethyl derivatives as well as novel compounds that are particularly useful educts in such process.
  • 5-substituted imidazolylmethyl derivatives can be synthesized in high yield by reacting suitable 5-substituted imidazolylmethyl ketones with certain organomanganese compounds.
  • organomanganese compounds Generally, a wide variety of organomanganese compounds and their use in organic synthesis is known. P. Knochel et al.
  • subject of this invention is a process for preparing compounds of formula (I)
  • R represents hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-C8-alkenyl, Ci-Cs-haloalkenyl, Ci-Cs-alkynyl, C 2 -C 8 -haloalkynyl, phenyl-Ci-Cs-alkynyl, [tri(Ci-C 8 -alkyl)silyl]phenyl-C 2 -C 8 -alkynyl, C3-C7- cycloalkyl, bicycloalkyl, C3-C7-cycloalkyl-Ci-C4-alkyl, C3-C7-cycloalkyl-C3-C7-cycloalkyl, C3-C7- cycloalkenyl, tri(Ci-C8-alkyl)silyl-Ci-C4-alkyl, tri(Ci-C8-alkyl)silyl-Ci-C4-
  • R 2 represents hydrogen, d-Cs-alkyl, -Si(R 6a )(R 6b )(R 6c ), -P(0)(OH) 2 , -CH 2 -0-P(0)(OH) 2 , -C(0)-G-C 8 - alkyl, -C(0)-C 3 -C 7 -cycloalkyl, -C(0)NH-Ci-C 8 -alkyl, -C(0)N-di-Ci-C 8 -alkyl, or -C(0)0-G-C 8 - alkyl, wherein the -C(0)-Ci-C 8 -alkyl, -C(0)-C3-C 7 -cycloalkyl, -C(0)NH-Ci-C 8 -alkyl, -C(0)N-di- Ci-C 8 -alkyl and -C(0)0-Ci-C 8 -alkyl is non-substituted or substituted by one or more group(
  • R 6 , R 6b , R 6c represent independently from each other phenyl or Ci-C 8 -alkyl
  • R 3 represents halogen, hydroxyl, cyano, isocyano, amino, nitro, sulfanyl, pentafluoro- 6 -sulfanyl, carboxaldehyde, hydroxycarbonyl, Ci-C 8 -alkyl, Ci-C 8 -haloalkyl, Ci-C 8 -hydroxyalkyl, G-C 8 - cyanoalkyl, Ci-C 8 -alkyloxy, Ci-C 8 -haloalkyloxy, tri(Ci-C 8 -alkyl)silyl, tri(Ci-C 8 -alkyl)silyl-Ci-C 8 - alkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-C10- cycloalkylalkyl, C4-C10-
  • R 4 represents hydrogen or Ci-Cs-alkyl
  • R 5 represents hydrogen or Ci-Cs-alkyl; or R 4 and R 5 form together with the carbon atom to which they are attached a C3-C7-cycloalkyl, wherein the C3-C7-cycloalkyl ring is non-substituted or substituted by one or more Ci-C t-alkyl group(s); and represents a 6-membered aromatic cycle of formula (Q-I)
  • U represents CX or N
  • U 2 represents CX 2 or N
  • U 3 represents CX 3 or N
  • U 4 represents CX 4 or N
  • U 5 represents CX 5 or N; wherein X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6 -sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl having 1 to 5 halogen atoms, C3-C8-cycloalkyl, C3-C7-halocycloalkyl having 1 to 5 halogen atoms, Ci-Cs-haloalkyl- C3-C7-cycloalkyl, C3-C7-cycloalkenyl, Ci-Cs-alkenyl, Ci-Cs-alkynyl, C6-Ci2-bicycloalkyl, C3- C8-cycloalkyl-C2-C8-alkenyl, Cs-Cs-cycloalkyl-Ci-Cs-alky
  • U 1 and U 2 or U 2 and U 3 or U 3 and U 4 form together an additional saturated or unsaturated 4 to 6- membered halogen- or Ci-Cs-alkyl-substituted or non-substituted ring; by reacting a ketone of formula (II)
  • R 1 and R 3 are defined as in formula (I); and a manganese compound of formula (III),
  • each X, Y and Z represents independently from each other halogen
  • M represents Mg or Zn; n is 1 or 2; m is 0 or 1; n+m is 2; Q ⁇ z l ⁇ 10; 0 ⁇ z 2 ⁇ 10; and
  • R 4 , R 5 and Q are defined as in formula (I).
  • Formula (I) provides a general definition of the 5-substituted imidazolylmethyl derivatives obtainable by the process according to the invention. Preferred definitions of the symbols used in the formulae shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates, e.g. the ketones of formula (II) and the manganese compounds of formula ( ⁇ ).
  • R 1 preferably represents Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-C7-alkenyl, C2-C7-haloalkenyl, optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci-C t-haloaikoxy-, C1-C4- alkylthio- or Ci-C4-haloalkylthio-substituted C3-C7-cycloalkyl or optionally halogen-, cyano-, C1-C4- alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio- substituted C6-Ci4-aryl.
  • R 1 more preferably represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C7- cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, C1-C4- haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C6-Ci4-aryl.
  • R 1 more preferably represents Ci-C4-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-haloalkoxy-, Ci-C4-alkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C6- cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, C1-C4- haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted phenyl.
  • Ci-Cs-alkyl preferably represents H, Ci-Cs-alkyl, or halogen- or Ci-Cs-alkoxy-substituted or non-substituted - C(0)-Ci-C 8 -alkyl. More preferably represents H, Ci-C4-alkyl, or non-substituted -C(0)-Ci-C4-alkyl. most preferably represents H.
  • halogen cyano, nitro, carboxaldehyde, hydroxycarbonyl
  • R 5 more preferably represents hydrogen, methyl or ethyl.
  • R 5 most preferably represents hydrogen.
  • R 4 and R 5 may form together with the carbon atom to which they are attached an optionally Ci-C t-alkyl- substituted C 3 -C7-cycloalkyl ring.
  • R 4 and R 5 preferably form together with the carbon atom to which they are attached a non-substituted C3-C6-cycloalkyl ring, more preferably a non-substituted Cs-Cs-cycloalkyl ring, most preferably a cyclopropyl ring.
  • Q preferably represents a substituted 6-membered aromatic heterocycle containing one or two nitrogen atoms or a substituted 6-membered aromatic carbocycle. Substituted meaning that the cycle of the given formula comprises at least one of X 1 , X 2 , X 3 , X 4 or X 5 not being hydrogen.
  • Q also preferably represents a, preferably substituted, 6-membered aromatic cycle of formula (Q-I-l) to (Q-I-10)
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given for formula (I) above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • Q more preferably represents a, preferably substituted, phenyl, 3-pyridyl or 4-pyridyl of formula (Q-I- 1) to (Q-I-3) wherein X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given for formula (I) above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below. More preferably represents a, preferably substituted, phenyl or 3-pyridyl of formula (Q-I-1) or (Q-I-
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given for formula (I) above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • Q most preferably represents a, preferably substituted, phenyl of formula (Q-I-1)
  • X 1 , X 2 , X 3 , X 4 and X 5 have the same definition as given for formula (I) above. Preferred definitions of X 1 , X 2 , X 3 , X 4 and X 5 are given below.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6 -sulfanyl, Ci-Cs-alkyl, C i-C 8 -halo alky 1 having 1 to 5 halogen atoms, C3-C8- cycloalkyl, C3-C7-halocycloalkyl having 1 to 5 halogen atoms, Ci-C 8 -haloalkyl-C3-C7-cycloalkyl, C3-C7-cycloalkenyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C6-Ci 2 -bicycloalkyl, C3-C 8 -cycloalkyl-C 2 -C 8 - alkenyl, C3-C 8 -cycloalkyl
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6 -sulfanyl, Ci-Cs-alkyl, Cs-Cs-cycloalkyl, Ci-Cs-alkoxy, Ci-Cs- alkoxycarbonyl, Ci-C6-alkylsulfenyl, or C3-C6-cycloalkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, halogen, Ci-Cs- alkyl, C3-Cs-cycloalkyl or Ci-Cs-alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C4-alkyl, Cs-Cs-cycloalkyl or Ci-C4-alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, feri-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
  • X 1 most preferably represents hydrogen or fluorine.
  • X 2 most preferably represents hydrogen or chlorine.
  • X 3 most preferably represents hydrogen, fluorine or methoxy.
  • X 4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy.
  • X 5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
  • R 1 represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, O-C t-alkoxy-, Ci-C t-haloalkoxy-, Ci-C t-alkylfhio- or Ci-C4-haloalkylthio-substituted C3-C7-cycloalkyl or optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci-C t-haloalkoxy-, Ci- C t-alkylthio- or Ci-C4-haloalkylthio-substituted C6-Ci 4 -aryl,
  • R 3 represents fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-haloalkyl or carbamoyl, and
  • X 1 , X 2 , X 3 , X 4 and X 5 independently from each other represent hydrogen, halogen, Ci-Cs-alkyl, C3-C8- cycloalkyl or Ci-Cs-alkoxy.
  • R 1 preferably represents Ci-C4-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci- C4-haloalkoxy-, Ci-C4-alkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C6-cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted phenyl.
  • R 1 more preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ieri-butyl, 1- halocyclopropyl, l-(Ci-C 4 -alkyl)cyclopropyl, or optionally halogen-substituted phenyl.
  • R 1 most preferably represents isobutyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl, 1-methylcyclopropyl or 2,4-difluorophenyl.
  • R 3 preferably represents fluorine, cyano, nitro, CF 3 or carbamoyl.
  • R 3 most preferably represents fluorine or cyano.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C t-alkyl, Cs-Cs-cycloalkyl or Ci-C t-alkoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, feri-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
  • X 1 , X 2 , X 3 , X 4 , and X 5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
  • X 1 most preferably represents hydrogen or fluorine.
  • X 2 most preferably represents hydrogen or chlorine.
  • X 3 most preferably represents hydrogen, fluorine or methoxy.
  • X 4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy.
  • X 5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
  • R 1 , R 3 , R 4 , R 5 , and Q are defined as in formula (I).
  • the preferred, more preferred and most preferred definitions given with regard to formula (I) apply mutatis mutandis.
  • X, Y, and Z independently from each other preferably represent chlorine, bromine or iodine, more preferably chlorine or bromine.
  • n is either 1 or 2.
  • n is 1
  • m is 1, i.e. the manganese compound comprises one organic moiety per manganese atom.
  • the manganese compound comprises two organic moieties per manganese atom.
  • M 1 preferably represents Mg.
  • z 1 can be any number in the range of 0 to 10. If z 1 is greater than 0, M3 ⁇ 4 is present and can form a complex with the manganese moiety and optionally present LiZ. Preferably the following equation applies: 0 ⁇ z 1 ⁇ 5, preferably 0 ⁇ z 1 ⁇ 3, more preferred 0 ⁇ z 1 ⁇ 2.
  • z 2 can be any number in the range of 0 to 10. However, preferably z 2 is greater than 0, i.e. at least some LiZ is present. Preferably the following equation applies: 0 ⁇ z 2 ⁇ 5, preferably 0 ⁇ z 2 ⁇ 3, more preferred 0 ⁇ z 2 ⁇ 2.
  • Halogen fluorine, chlorine, bromine or iodine. Halogen-substitution is generally indicated by the prefix halo, halogen or halogeno.
  • Alkyl saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkyl such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylp
  • said group is a Ci- C t-alkyl group, e.g. a methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1-dimethylethyl (tert-butyl) group.
  • a Ci- C t-alkyl group e.g. a methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1-dimethylethyl (tert-butyl) group.
  • alkyl as part of a composite substituent, for example cycloalkylalkyl, hydroxyalkyl etc., unless defined elsewhere like, for example, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, haloalkyl or haloalkylsulfanyl.
  • Alkenyl unsaturated, straight-chain or branched hydrocarbyl radicals having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one double bond in any position, for example (but not limited to) C2-C6-alkenyl such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but- 2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2- methylprop-l-enyl, (E)-l-methylprop-l-enyl, (Z)-l-methylprop-l-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)- pent-3-enyl, (E)-pent-2-eny
  • Alkynyl straight-chain or branched hydrocarbyl groups having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one triple bond in any position, for example (but not limited to) C 2 -C6- alkynyl, such as ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, but-3-ynyl, l-methylprop-2- ynyl, pent-l-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1- methylbut-2-ynyl, 3-methylbut-l-ynyl, l-ethylprop-2-ynyl, hex- 1 -ynyl, hex-2-ynyl, hex-3-
  • said alkynyl group is ethynyl, prop-l-ynyl, or prop-2-ynyl.
  • This definition also applies to alkynyl as part of a composite substituent, for example haloalkynyl etc., unless defined elsewhere.
  • Alkoxy saturated, straight-chain or branched alkoxy radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1- methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1- dimethylpropoxy, 1,2-dimethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4- methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3- dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,
  • Alkylsulfanyl saturated, straight-chain or branched alkylsulfanyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfanyl such as methylsulfanyl, ethylsulfanyl, propylsulfanyl, 1-methylethylsulfanyl, butylsulfanyl, 1-methylpropyl- sulfanyl, 2-methylpropylsulfanyl, 1,1-dimethylethylsulfanyl, pentylsulfanyl, 1-methylbutylsulfanyl, 2- methylbutylsulfanyl, 3-methylbutylsulfanyl, 2,2-dimethylpropylsulfanyl, 1-ethylpropylsulfanyl, 1,1- dimethylpropylsulfanyl, 1,2-dimethylpropyl
  • Alkylsulfinyl saturated, straight-chain or branched alkylsulfinyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1-methylpropylsulfinyl,
  • Alkylsulfonyl saturated, straight-chain or branched alkylsulfonyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropyl- sulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2- methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, 1,1- dimethyl
  • Monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 carbon atoms attached to the nitrogen atom.
  • Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.
  • Dialkylamino represents an amino radical having two independently selected alkyl residues with 1 to 4 carbon atoms each attached to the nitrogen atom.
  • Non-limiting examples include -dimethylamino, -diefhylamino, A f /V-diisopropylamino, -ethyl- -mefhylamino, -mefhyl- -n-propylamino, N-iso- propyl-/V-n-propylamino and -tert-butyl- -mefhylamino.
  • Cycloalkyl monocyclic, saturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a composite substituent, for example cycloalkylalkyl etc., unless defined elsewhere.
  • Cycloalkenyl monocyclic, partially unsaturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as part of a composite substituent, for example cycloalkenyl alky 1 etc., unless defined elsewhere.
  • Cycloalkoxy monocyclic, saturated cycloalkyloxy radicals having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as part of a composite substituent, for example cycloalkoxyalkyl etc., unless defined elsewhere.
  • Haloalkyl straight-chain or branched alkyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C 3 -haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro methyl, chlorodifluoromethyl, 1-chloroethyl, 1- bromoethyl, l-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2- chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluor
  • Haloalkenyl and haloalkynyl are defined analogously to haloalkyl except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent.
  • Haloalkoxy straight-chain or branched alkoxy groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C3-haloalkoxy such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2- fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoro
  • Haloalkylsulfanyl straight-chain or branched alkylsulfanyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) O-C3- haloalkylsulfanyl such as chloromethylsulfanyl, bromomethylsulfanyl, dichloromethylsulfanyl, trichloromethylsulfanyl, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, chlorofluoromethylsulfanyl, dichlorofluoromethylsulfanyl, chlorodifluoromethylsulfanyl, 1-chloro- ethylsulfanyl, 1-bromoethylsulfanyl, 1-fluoroethyl
  • Aryl mono-, bi- or tricyclic aromatic or partially aromatic group having 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronapthyl, indenyl and indanyl.
  • the binding to the superordinate general structure can be carried out via any possible ring member of the aryl residue.
  • Aryl is preferably selected from phenyl, 1 -naphthyl and 2-naphthyl. Phenyl is particularly preferred.
  • Heteroaryl 5 or 6-membered cyclic aromatic group containing at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O, and which group can also be part of a bi- or tricyclic system having up to 14 ring members, wherein the ring system can be formed with one or two further cycloalkyl, cycloalkenyl, heterocyclyl, aryl and/or heteroaryl residues and wherein benzofused 5 or 6-membered heteroaryl groups are preferred.
  • the binding to the superordinate general structure can be carried out via any possible ring member of the heteroaryl residue.
  • Examples of 5-membered heteroaryl groups which are attached to the skeleton via one of the carbon ring members are fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl, pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-2-yl, imidazole-4-yl, l,2,4-oxadiazol-3-yl, l,2,4-
  • Examples of 5- membered heteroaryl groups which are attached to the skeleton via a nitrogen ring member are pyrrol-l-yl, pyrazol-l-yl, 1,2,4-triazol-l-yl, imidazol-l-yl, 1,2,3-triazol-l-yl and 1,3,4-triazol-l-yl.
  • 6-membered heteroaryl groups are pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3- yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazine-2-yl, l,3,5-triazin-2-yl, 1,2,4- triazin-3-yl and l,2,4,5-tetrazin-3-yl.
  • benzofused 5-membered heteroaryl groups are indol- 1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-l-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-l-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol- 6-yl, indazol-7-yl, indazol-2-yl, l-benzofuran-2-yl, l-benzofuran-3-yl, l-benzofuran-4-yl, l-benzofuran-5- yl, l-benzofuran-6-yl, l-benzofuran
  • Examples of benzofused 6-membered heteroaryl groups are quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5- yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl.
  • This definition also applies to heteroaryl as part of a composite substituent, for example heteroarylalkyl etc., unless defined elsewhere.
  • the binding to the superordinate general structure can be carried out via a ring carbon atom or, if possible, via a ring nitrogen atom of the heterocyclic group.
  • Saturated heterocyclic groups in this sense are for example (but not limited to) oxiranyl, aziridinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5- yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, oxazolidin-2-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-4-yl, thiazolidin-4-yl,
  • Partially unsaturated heterocyclic groups in this sense are for example (but not limited to) 2,3-dihydrofur-2-yl, 2,3-dihydrofur- 3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4- dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin- 4-yl, 2-isoxazolin-5-yl, 3-isoxa
  • benzofused heterocyclic groups are indolin-1- yl, indolin-2-yl, indolin-3-yl, isoindolin-l-yl, isoindolin-2-yl, 2,3-dihydrobenzofuran-2-yl and 2,3- dihydrobenzofuran-3-yl.
  • This definition also applies to heterocyclyl as part of a composite substituent, for example heterocyclylalkyl etc., unless defined elsewhere.
  • Oxo represents a doubly bonded oxygen atom.
  • Thiooxo represents a doubly bonded sulfur atom.
  • Optionally substituted groups may be mono- or polysubstituted, where the substituents in the case of polysubstitutions may be identical or different.
  • Ring structures having three or more adjacent oxygen atoms, for example, are excluded.
  • the ketone of formula ( ⁇ ) and the manganese compound of formula (III) are preferably reacted in a molar ratio of 1 : 0.4 to 1 : 5, more preferred 1 : 0.5 to 1 : 4, most preferred 1 : 0,55 to 1 : 3.
  • the manganese compound of formula ( ⁇ ) used is a manganese compound of formula ( ⁇ ), wherein n is 1 and m is 1, the molar ratio of ketone of formula (II) to manganese compound of formula ( ⁇ ) is preferably 1 : 1 to 1 : 5, more preferred 1 : 1.5 to 1 : 4, even more preferred 1 : 1.7 to 1 : 3, most preferred 1 : 2 to 1 : 2.5.
  • the manganese compound of formula ( ⁇ ) used is a manganese compound of formula ( ⁇ ), wherein n is 2 and m is 0, the molar ratio of ketone of formula (II) to manganese compound of formula ( ⁇ ) is preferably 1 : 0.4 to 1 : 3, more preferred 1 : 0.5 to 1 : 2, even more preferred 1 : 0.6 to 1 : 1, most preferred 1 : 0.7 to 1 : 0.8.
  • a solvent preferably in the presence of an aprotic solvent, more preferably a solvent selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, N-methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof, most preferably selected from diethyl ether, ieri-butyl methyl ether, tetrahydrofuran, toluene, and mixtures thereof.
  • a solvent preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, N-methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof,
  • the process is carried out at a temperature of -10°C to 50°C, more preferred -10°C to 30°C, and most preferred -5°C to 20°C.
  • the reaction time of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • the process according to the invention is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
  • the reaction mixture resulting from the process according to the invention is quenched with water or an aqueous ammonium halogenide solution, preferably an aqueous NH4CI solution, preferably a saturated aqueous NH4CI solution.
  • an aqueous ammonium halogenide solution preferably an aqueous NH4CI solution, preferably a saturated aqueous NH4CI solution.
  • R 2 represents hydrogen.
  • the reaction mixture resulting from the process according to the invention may be quenched with a suitable electrophile providing the R 2 group.
  • the reaction mixture can be quenched with an Ci-C 8 -alkylhalide, preferably Ci- C8-alkyliodide.
  • Ci-C 8 -alkylhalide preferably Ci- C8-alkyliodide.
  • suitable electrophiles providing different R 2 groups are for example dialkylsulfates, anhydrides, acid chlorides, phosphorylchloride, alkylisocyanates, carbamoyl chlorides, carbono chloridates and imidocarbonates.
  • R 2' represents G-C 8 -alkyl, -Si(R 6a )(R 6b )(R 6c ), -P(0)(OH) 2 , -CH 2 -0-P(0)(OH) 2 , -C(0)-C 1 -C 8 -alkyl, - C(0)-C3-C 7 -cycloalkyl, -C(0)NH-Ci-C 8 -alkyl, -C(0)N-di-Ci-C 8 -alkyl, or -C(0)0-Ci-C 8 -alkyl, wherein the -C(0)-Ci-C 8 -alkyl, -C(0)-C 3 -C 7 -cycloalkyl, -C(0)NH-Ci-C 8 -alkyl, -C(0)N-di-Ci-C 8 - alkyl and -C(0)0-Ci-C 8 -alkyl is non-substituted or substituted by one or
  • the compounds (lb) obtained according to the process of the invention can be converted in analogy to methods described in the literature to the corresponding compounds (Ic) (see e.g. DE-A 3202604, JP-A 02101067, EP-A 225 739, CN-A 101824002, FR-A 2802772, WO-A 2012/175119, Bioorganic & Medicinal Chemistry Letters, 7207-7213, 2012, Journal of the American Chemical Society, 19358-19361, 2012, Journal of Organic Chemistry, 9458-9472, 2012, Organic Letters, 554-557, 2013, Journal of the American Chemical Society, 15556, 2012).
  • compounds of the general structure (lb) are reacted with alkylhalides, dialkylsulfates, anhydrides, acid chlorides, phosphorylchloride, alkylisocyanate, carbamoyl chlorides, carbono chloridates or imidocarbonates, preferably in the presence of a base, to obtain compounds (Ic).
  • the reaction mixtures can be worked-up by procedures generally known in the art.
  • the reaction mixture is extracted with a suitable organic solvent, preferably ethyl acetate, ieri-butyl methyl ether or a mixture thereof.
  • a suitable organic solvent preferably ethyl acetate, ieri-butyl methyl ether or a mixture thereof.
  • the combined organic phases are preferably washed with water or a solution of a suitable salt, preferably with brine, and dried, preferably over sodium sulfate, calcium sulfate or magnesium sulfate.
  • the organic solvent is removed and the resulting crude product further purified by known techniques, for example recrystallization or chromatography.
  • Ketones of formula (II) are known from WO 2016/156290 Al and can be synthesized as disclosed therein.
  • Manganese compounds of formula ( ⁇ ) can be obtained as disclosed in P. Knochel et al., Synlett 2015, 26, 514-518 and WO 2007/113294 Al or in analogy to the methods described therein.
  • the manganese compounds of formula ( ⁇ ) are obtained by the reaction of a compound of formula (VI)
  • R 4 , R 5 , Q, X, Y, and Z apply mutatis mutandis.
  • the reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods. This reaction is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
  • the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof.
  • any solvent present in the reaction is dried before use.
  • the reaction is carried out in the presence of an activating agent selected from copper salts, nickel salts, iron compounds, cobalt compounds, I2, CiEUBri, Cl(CH2)2Br, ieri.-BuOLi, BCI3, BF3, L1BH4, L1AIH4, NaAlH t, Et 3 Al, DIBAL-H (diisobutyl aluminum hydride), Na[H 2 Al(OCH2CH 2 OCH3)], Me 3 SiCl, Et 2 Zn, IC1, SnCh and mixtures thereof, preferably selected from I 2 , C 2 H4Br2, Cl(CH 2 )2Br, ter - BuOLi, BCI3, BF 3 , LiBH 4 , L1AIH4, NaAlH 4 , Et 3 Al, DIBAL-H (diisobutyl aluminum hydride), Na[H 2 Al(OCH2CH 2 OCH3)], Me 3 SiCl, Et 2 Zn, IC1, SnCl 2 and
  • the reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
  • the compound of formula (VI) and the manganese halogenide of formula (VII) are reacted in a molar ratio of 1 : 0.4 to 1 : 1, more preferred 1 : 0.5 to 1 : 0.8, most preferred about 1 : 0.55 to 1 : 0.7.
  • the manganese halogenide of formula (VII) and LiZ are present in a molar ratio of 1 : 0.5 to 1 : 2, more preferred 1 : 0.7 to 1 : 1.5, most preferred about 1 : 0.8 to 1 : 1.2.
  • the compound of formula (VI) and magnesium are present in a molar ratio of 1 : 1 to 1 : 2, more preferred 1 : 1 to 1 : 1.5, most preferred about 1 : 1.1 to 1 : 1.3.
  • reaction mixture resulting from the reaction of the compound of formula (VI) and the manganese halogenide of formula (VII) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure.
  • the resulting manganese compounds of formula (III) may be further purified by known techniques, for example crystallisation.
  • the resulting reaction mixture comprising the manganese compound of formula (III) is directly used in the process according to the invention.
  • the manganese compounds of formula ( ⁇ ) are obtained by reacting a Grignard compound of formula (IV) wherein R 4 , R 5 , Q and X are defined as in formula (I), and a manganese lithium complex of formula (V)
  • Y and Z are defined as in formula (III); and z 3 is 0, 1, 2, 3, 4 or 5.
  • z 3 is preferably 1, 2 or 3, more preferably 1 or 2, and most preferably 2.
  • the reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods.
  • the Grignard compound of formula (IV) can be obtained by reacting the respective halogenide of formula (VI) and magnesium, preferably magnesium turnings, preferably in the presence of an activating reagent like copper salts, nickel salts, iron compounds, cobalt compounds, I2, C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, teri.-BuOLi, BC1 3 , BF 3 , L1BH4, L1AIH4, NaAlH 4 , Et 3 Al, DIBAL-H (diisobutyl aluminum hydride), Na[H 2 Al(OCH 2 CH 2 OCH3)], Me 3 SiCl, Et 2 Zn, IC1, SnCl 2 and mixtures thereof, preferably I 2 , C 2 H 4 Br 2 , Cl(CH 2 ) 2 Br, feri.-BuOLi, BC1 3 , BF 3 , L1BH4, L1AIH4, NaAlH 4 , Et 3 Al, DIBAL-H (diiso) activ
  • the reaction product resulting from the synthesis of the Grignard compound of formula (IV) for example in order to isolate, concentrate, dilute or purify the Grignard compound or a solution or suspension thereof.
  • the Grignard reagent is represented by formula (IV).
  • Grignard compounds undergo solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium.
  • the Schlenck equilibrium for the Grignard reagent according to formula (IV) can be schematically illustrated as follows:
  • formula (IV) encompasses not only the structures as depicted, but also the structures resulting from the Schleck equilibrium as well as the respective solvent adducts.
  • structures of Grignard reagents see also Milton Orchin, Journal of Chemical Education, Volume 66, Number 7, 1999, pp 586 to 588.
  • the reaction of the Grignard compound of formula (IV) and manganese lithium complex of formula (V) is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
  • the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof.
  • any solvent present is dried before use.
  • the reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
  • the Grignard compound of formula (IV) and the manganese lithium complex of formula (V) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, more preferred 1 : 0.9 to 1 : 1.4, more preferred about 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.2.
  • the Grignard reagent of formula (IV) is preferably used as solution in an aprotic solvent, in particular as solution in diethyl ether, tetrahydrofuran, toluene or a mixture thereof, particularly preferred as a 0.2 to 1.0 molar solution in diethyl ether or tetrahydrofuran.
  • the reaction mixture resulting from the reaction of the Grignard compound of formula (IV) and the manganese lithium complex of formula (V) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure. If desired, the resulting manganese compounds of formula (III) may be further purified by known techniques, for example crystallisation. However, preferably the resulting reaction mixture comprising the manganese compound of formula (III) is directly used in the process according to the invention.
  • reaction time of each of the steps of the processes outlined above varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
  • the invention further relates to novel compounds of formula (III-F), which are particularly useful in the process according to the invention and form part of the invention.
  • X, Y, Z, n, m, z 1 , z 2 , X 1 , X 2 , X 3 , and X 4 are defined as outlined above.
  • the manganese compounds of formula ( ⁇ -F) can be obtained in analogy to the two preferred processes for synthesizing compounds of formula (III) outlined above.
  • the invention is illustrated by the examples below. However, the invention is not limited to the examples.
  • the reaction mixture was quenched with saturated NH 4 CI solution (400 mL) at 0 °C and extracted with EtOAc (ethyl acetate) (3x250 mL). The combined organic phases were washed with brine (500 mL), dried over Na 2 SC>4 and concentrated in vacuo. The remaining oil was stirred in a mixture of w-heptane (250 mL) and water (250 mL) for 30 min. The formed precipitate was filtered and washed with water (150 mL) and w -heptane (150 mL). The obtained solid was again stirred in a mixture of w -heptane and water, filtered and again washed with water and w -heptane. The desired compound (1-01) was obtained as a white solid in 85% yield with 97% purity (45.45 g, 137.9 mmol).

Abstract

The present invention relates to a process for preparing 5-substituted imidazole compounds of formula (I), by reacting a ketone of formula (II) (II), and a manganese compound of formula (III), (III), wherein R1, R2, R3, R4, R5, Q, X, Y, Z, z1, M1, z2, n and m are defined as disclosed in the specification, as well as to specific manganese compounds useful in this process.

Description

Process for the preparation of 5-substituted imidazole derivatives and manganese compounds useful therefor
The present invention relates to a process for preparing 5-substituted imidazolylmethyl derivatives and to specific manganese compounds that can be used in this process. Certain 5-substituted imidazolylmethyl derivatives are known to be useful in the field of crop protection, in particular as fungicides. WO 2016/156290 Al discloses such 5-substituted imidazolylmethyl derivatives and several routes to synthesize those. One of said routes is referred to in WO 2016/156290 Al as process M and comprises reacting suitable 5-substituted imidazolylmethyl ketones and Grignard reagents. Such procedure provides access to the target 5-substituted imidazolylmethyl derivatives. However, to allow efficient synthesis in an industrial scale further improvement of the process, e.g. in terms of yield and/or purity, is desirable.
Hence, object of the invention is providing an improved process for the synthesis of 5-substituted imidazolylmethyl derivatives as well as novel compounds that are particularly useful educts in such process. Surprisingly, it has been found that 5-substituted imidazolylmethyl derivatives can be synthesized in high yield by reacting suitable 5-substituted imidazolylmethyl ketones with certain organomanganese compounds. Generally, a wide variety of organomanganese compounds and their use in organic synthesis is known. P. Knochel et al. disclose in Synlett 2015, 26, 514-518 the preparation of benzylic manganese chlorides by the direct insertion of magnesium into benzylic chlorides in the presence of MnCl2 '2LiCl and their reaction with a number of electrophiles. WO 2007/113294 Al discloses a process for synthesizing organoelemental compounds, including organomanganese compounds and their further reaction with various electrophiles. However, using organomanganese compounds in the preparation of funcicidal active compounds has not been disclosed hitherto.
Accordingly, subject of this invention is a process for preparing compounds of formula (I)
Figure imgf000003_0001
wherein
R represents hydrogen, Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-C8-alkenyl, Ci-Cs-haloalkenyl, Ci-Cs-alkynyl, C2-C8-haloalkynyl, phenyl-Ci-Cs-alkynyl, [tri(Ci-C8-alkyl)silyl]phenyl-C2-C8-alkynyl, C3-C7- cycloalkyl, bicycloalkyl, C3-C7-cycloalkyl-Ci-C4-alkyl, C3-C7-cycloalkyl-C3-C7-cycloalkyl, C3-C7- cycloalkenyl, tri(Ci-C8-alkyl)silyl-Ci-C4-alkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, or C6-Ci4-aryl, wherein the phenyl-C2-C8-alkynyl, [tri(Ci-C8-alkyl)silyl]phenyl-C2-C8-alkynyl, C3-C7-cycloalkyl, bicycloalkyl, C3-C7-cycloalkyl-Ci-C4-alkyl, C3-C7-cycloalkyl-C3-C7-cycloalkyl, C3-C7-cycloalkenyl, tri(Ci-C8-alkyl)silyl-Ci-C4-alkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, and C6-Ci4-aryl is non- substituted or substituted by one or more group(s) selected from halogen, cyano, Ci-C4-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, Ci-C4-alkylthio and Ci-C4-haloalkylthio;
R2 represents hydrogen, d-Cs-alkyl, -Si(R6a)(R6b)(R6c), -P(0)(OH)2, -CH2-0-P(0)(OH)2, -C(0)-G-C8- alkyl, -C(0)-C3-C7-cycloalkyl, -C(0)NH-Ci-C8-alkyl, -C(0)N-di-Ci-C8-alkyl, or -C(0)0-G-C8- alkyl, wherein the -C(0)-Ci-C8-alkyl, -C(0)-C3-C7-cycloalkyl, -C(0)NH-Ci-C8-alkyl, -C(0)N-di- Ci-C8-alkyl and -C(0)0-Ci-C8-alkyl is non-substituted or substituted by one or more group(s) selected from halogen and Ci-C8-alkoxy, wherein
R6 , R6b, R6c represent independently from each other phenyl or Ci-C8-alkyl;
R3 represents halogen, hydroxyl, cyano, isocyano, amino, nitro, sulfanyl, pentafluoro- 6-sulfanyl, carboxaldehyde, hydroxycarbonyl, Ci-C8-alkyl, Ci-C8-haloalkyl, Ci-C8-hydroxyalkyl, G-C8- cyanoalkyl, Ci-C8-alkyloxy, Ci-C8-haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8- alkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-C10- cycloalkylalkyl, C4-Cio-halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-C8-alkyl-C3-C7- cycloalkyl, Ci-C8-alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, C2-C8-alkenyloxy, C2-C8-haloalkenyloxy, C3-C8-alkynyloxy, C3-C8-haloalkynyloxy, Ci-C8-alkylamino, Ci-C8-haloalkylamino, Ci-C8-cyanoalkoxy, C4-C8-cycloalkylalkoxy, C3-C6- cycloalkoxy, Ci-C8-alkylsulfanyl, Ci-C8-haloalkylsulfanyl, Ci-C8-alkylcarbonyl, G-C8- haloalkylcarbonyl, arylcarbonyl, aryl-Ci-C6-alkylcarbonyl, C3-C8-cycloalkylcarbonyl, C3-C8- halocycloalkylcarbonyl, carbamoyl, Ci-C8-alkylcarbamoyl, di-Ci-C8-alkylcarbamoyl, N-G-C8- alkyloxycarbamoyl, Ci-C8-alkoxycarbamoyl, N-Ci-C8-alkyl-Ci-C8-alkoxycarbamoyl, aminothiocarbonyl, Ci-C8-alkoxycarbonyl, Ci-C8-haloalkoxycarbonyl, C3-C8-cycloalkoxycarbonyl, C2-C8-alkoxyalkylcarbonyl, C2-C8-haloalkoxyalkylcarbonyl, C3-Cio-cycloalkoxyalkylcarbonyl, G- C8-alkylaminocarbonyl, di-Ci-C8-alkylaminocarbonyl, C3-C8-cycloalkylaminocarbonyl, G-C8- alkylcarbonyloxy, Ci-C8-haloalkylcarbonyloxy, C3-C8-cycloalkylcarbonyloxy, G-C8- alkylcarbonylamino, Ci-C8-haloalkylcarbonylamino, Ci-C8-alkylaminocarbonyloxy, di-G-C8- alkylaminocarbonyloxy, Ci-C8-alkyloxycarbonyloxy, Ci-C8-alkylsulfinyl, Ci-C8-haloalkylsulfinyl, Ci-C8-alkylsulfonyl, Ci-C8-haloalkylsulfonyl, Ci-C8-alkylsulfonyloxy, Ci-C8-haloalkylsulfonyloxy, Ci-C8-alkylaminosulfamoyl, di-Ci-C8-alkylaminosulfamoyl, (Ci-C8-alkoxyimino)-Ci-C8-alkyl, (C3- C7-cycloalkoxyimino)-Ci-C8-alkyl, hydroxyimino-Ci-C8-alkyl, (Ci-C8-alkoxyimino)-C3-C7- cycloalkyl, hydroxyimino-C3-C7-cycloalkyl, (Ci-C8-alkylimino)-oxy, (Ci-C8-alkylimino)-oxy-Ci- C8-alkyl, (C3-C7-cycloalkylimino)-oxy-Ci-C8-alkyl, (Ci-C6-alkylimino)-oxy-C3-C7-cycloalkyl, (Ci- C8-alkenyloxyimino)-Ci-C8-alkyl, (Ci-C8-alkynyloxyimino)-Ci-C8-alkyl, (benzyloxyimino)-Ci-C8- alkyl, Ci-Cs-alkoxyalkyl, Ci-Cs-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs-haloalkoxyalkyl, benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy, phenyloxy, benzylsulfanyl, benzylamino, phenylsulfanyl, or phenylamino, wherein the benzyl, phenyl, 5- membered heteroaryl, 6-membered heteroaryl, benzyloxy or phenyloxy is non-substituted or substituted by one or more group(s) selected from halogen, hydroxyl, cyano, isocyano, amino, sulfanyl, pentafluoro- 6-sulfanyl, carboxaldehyde, hydroxycarbonyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-C8-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs-haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl- Ci-Cs-alkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-Cio-cycloalkylalkyl, C4-Cio-halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-Cs-alkyl-Cs- C7-cycloalkyl, Ci-C8-alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8- alkenyl, Ci-Cs-alkynyl, C2-C8-alkenyloxy, C2-Cs-haloalkenyloxy, Cs-Cs-alkynyloxy, C3-C8- haloalkynyloxy, Ci-Cs-alkylamino, Ci-Cs-haloalkylamino, Ci-Cs-cyanoaikoxy, Ct-Cs- cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs-alkylsulfanyl, Ci-Cs-haloalkylsulfanyl, Ci-Cs- alkylcarbonyl, Ci-Cs-haloalkylcarbonyl, arylcarbonyl, aryl-Ci-C6-alkylcarbonyl, C3-C8- cycloalkylcarbonyl, Cs-Cs-halocycloalkylcarbonyl, Ci-Cs-alkylcarbamoyl, di-Ci-Cs-alkylcarbamoyl, N-Ci-C8-alkyloxycarbamoyl, Ci-Cs-alkoxycarbamoyl, N-Ci-Cs-alkyl-Ci-Cs-alkoxycarbamoyl, aminothiocarbonyl, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, Cs-Cs-cycloalkoxycarbonyl, C2-C8-alkoxyalkylcarbonyl, C2-C8-haloalkoxyalkylcarbonyl, C3-Cio-cycloalkoxyalkylcarbonyl, Ci- C8-alkylaminocarbonyl, di-Ci-Cs-alkylaminocarbonyl, Cs-Cs-cycloalkylaminocarbonyl, Ci-Cs- alkylcarbonyloxy, Ci-Cs-haloalkylcarbonyloxy, Cs-Cs-cycloalkylcarbonyloxy, Ci-Cs- alkylcarbonylamino, Ci-Cs-haloalkylcarbonylamino, Ci-Cs-alkylaminocarbonyloxy, di-Ci-Cs- alkylaminocarbonyloxy, Ci-Cs-alkyloxycarbonyloxy, Ci-Cs-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-C8-alkylsulfonyl, Ci-Cs-haloalkylsulfonyl, Ci-Cs-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-C8-alkylaminosulfamoyl, di-Ci-Cs-alkylaminosulfamoyl, (Ci-C8-alkoxyimino)-Ci-C8-alkyl, (C3- C7-cycloalkoxyimino)-Ci-C8-alkyl, hydroxyimino-Ci-Cs-alkyl, (Ci-C8-alkoxyimino)-C3-C7- cycloalkyl, hydroxyimino-C3-C7-cycloalkyl, (Ci-C8-alkylimino)-oxy, (Ci-C8-alkylimino)-oxy-Ci- Ce-alkyl, (C3-C7-cycloalkylimino)-oxy-Ci-C8-alkyl, (Ci-C6-alkylimino)-oxy-C3-C7-cycloalkyl, (Ci- C8-alkenyloxyimino)-Ci-C8-alkyl, (Ci-C8-alkynyloxyimino)-Ci-C8-alkyl, (benzyloxyimino)-Ci-C8- alkyl, Ci-Cs-alkoxyalkyl, Ci-Cs-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs-haloalkoxyalkyl, benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy, phenyloxy, benzylsulfanyl, benzylamino, phenylsulfanyl, and phenylamino;
R4 represents hydrogen or Ci-Cs-alkyl;
R5 represents hydrogen or Ci-Cs-alkyl; or R4 and R5 form together with the carbon atom to which they are attached a C3-C7-cycloalkyl, wherein the C3-C7-cycloalkyl ring is non-substituted or substituted by one or more Ci-C t-alkyl group(s); and represents a 6-membered aromatic cycle of formula (Q-I)
Figure imgf000006_0001
wherein
U represents CX or N;
U2 represents CX2 or N;
U3 represents CX3 or N;
U4 represents CX4 or N;
U5 represents CX5 or N; wherein X1, X2, X3, X4, and X5 independently from each other represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl having 1 to 5 halogen atoms, C3-C8-cycloalkyl, C3-C7-halocycloalkyl having 1 to 5 halogen atoms, Ci-Cs-haloalkyl- C3-C7-cycloalkyl, C3-C7-cycloalkenyl, Ci-Cs-alkenyl, Ci-Cs-alkynyl, C6-Ci2-bicycloalkyl, C3- C8-cycloalkyl-C2-C8-alkenyl, Cs-Cs-cycloalkyl-Ci-Cs-alkynyl, Ci-Cs-alkoxy, Ci-Cs- haloalkoxy having 1 to 5 halogen atoms, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, Ci-C8-alkylsulfenyl, Ci-Cs-alkenyloxy, Cs-Cs-alkynyloxy, C3-C6-cycloalkoxy, Ci-Cs- alkylsulfinyl, Ci-Cs-alkylsulfonyl, tri(Ci-C8-alkyl)-silyloxy, tri(Ci-C8-alkyl)-silyl, tri(Ci-C8- alkyl)-silyl-C2-C8-alkynyl, tri(Ci-C8-alkyl)-silyl-C2-C8-alkynyloxy, aryl, aryloxy, arylsulfenyl, heteroaryl, heteroaryloxy, wherein the aryl, aryloxy, arylsulfenyl, heteroaryl, heteroaryloxy is non-substituted or substituted by one or more group(s) selected from halogen, cyanosulfanyl, pentafluoro-λ6- sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs- haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8-alkyl, C3-C7-cycloalkyl, C3-C7- halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-Cio-cycloalkylalkyl, C4-C10- halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-C8-alkyl-C3-C7-cycloalkyl, Ci-Cs- alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8-alkenyl, C2-C8- alkynyl, C2-C8-alkenyloxy, C2-C8-haloalkenyloxy, C3-Cs-alkynyloxy, Cs-Cs-haloalkynyloxy, Ci-Cs-cyanoalkoxy, C4-C8-cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs-alkylsulfanyl, Ci-Cs- haloalkylsulfanyl, Ci-Cs-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-Cs-aikylsulfonyl, Ci-Cs- haloalkylsulfonyl, Ci-Cs-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-Cs-alkoxyalkyl, Ci-C8-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs-haloalkoxyalkyl, benzyl, phenyl, 5- membered heteroaryl, 6-membered heteroaryl, 6-membered heteroaryloxy, benzyloxy, phenyloxy, benzylsulfanyl, and phenylsulfanyl, wherein the benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heteroaryloxy, benzyloxy, phenyloxy, benzylsulfanyl and phenylsulfanyl is non-substituted or substituted by one or more group(s) selected from halogen, CN, nitro, Ci-Cs-alkyl, C1-C4- haloalkyl, Ci-C t-alkoxy, Ci-C4-haloalkoxy and pentafluoro- 6-sulfanyl; and wherein at most two of U1, U2, U3, U4 and U5 represent N; or
U1 and U2 or U2 and U3 or U3 and U4 form together an additional saturated or unsaturated 4 to 6- membered halogen- or Ci-Cs-alkyl-substituted or non-substituted ring; by reacting a ketone of formula (II)
Figure imgf000007_0001
wherein
R1 and R3 are defined as in formula (I); and a manganese compound of formula (III),
Figure imgf000007_0002
wherein each X, Y and Z represents independently from each other halogen;
M represents Mg or Zn; n is 1 or 2; m is 0 or 1; n+m is 2; Q < zl < 10; 0 < z2 < 10; and
R4, R5 and Q are defined as in formula (I).
An arrow, as in formula (Q-I), depicts the bonding position of the shown moiety to the remainder of the molecule.
Formula (I) provides a general definition of the 5-substituted imidazolylmethyl derivatives obtainable by the process according to the invention. Preferred definitions of the symbols used in the formulae shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates, e.g. the ketones of formula (II) and the manganese compounds of formula (ΠΙ).
R1 preferably represents Ci-Cs-alkyl, Ci-Cs-haloalkyl, C2-C7-alkenyl, C2-C7-haloalkenyl, optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci-C t-haloaikoxy-, C1-C4- alkylthio- or Ci-C4-haloalkylthio-substituted C3-C7-cycloalkyl or optionally halogen-, cyano-, C1-C4- alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio- substituted C6-Ci4-aryl.
R1 more preferably represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C7- cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, C1-C4- haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C6-Ci4-aryl.
R1 more preferably represents Ci-C4-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-haloalkoxy-, Ci-C4-alkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C6- cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, C1-C4- haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted phenyl. more preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ieri-butyl, 1- halocyclopropyl, l-(Ci-C4-alkyl)cyclopropyl, or optionally halogen-substituted phenyl. most preferably represents isobutyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl, 1-methylcyclopropyl or 2,4-difluorophenyl. preferably represents H, Ci-Cs-alkyl, or halogen- or Ci-Cs-alkoxy-substituted or non-substituted - C(0)-Ci-C8-alkyl. more preferably represents H, Ci-C4-alkyl, or non-substituted -C(0)-Ci-C4-alkyl. most preferably represents H. preferably represents halogen, hydroxyl, cyano, isocyano, nitro, carboxaldehyde, hydroxycarbonyl, Ci-Ce-alkyl, Ci-Cs-haloalkyl, Ci-Cs-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs-haloalkyloxy, C3-C7- cycloalkyl, C3-C7-halocycloalkyl, Ci-Cs-alkenyl, Ci-Cs-alkynyl, C2-C8-alkenyloxy, C2-C8- haloalkenyloxy, Cs-Cs-alkynyloxy, Cs-Cs-halooalkynyloxy, Ci-Cs-alkylsulfanyl, Ci-Cs- haloalkylsulfanyl, Ci-Cs-alkylcarbonyl, Ci-Cs-haloalkylcarbonyl, C6-Ci4-arylcarbonyl, C6-Ci4-aryl- Ci-C6-alkylcarbonyl, Cs-Cs-cycloalkylcarbonyl, Cs-Cs-halocycloalkylcarbonyl, aminothiocarbonyl, carbamoyl, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, Cs-Cs-cycloalkoxycarbonyl, Ci-Cs- alkylcarbonyloxy, Ci-Cs-haloalkylcarbonyloxy, Cs-Cs-cycloalkylcarbonyloxy, benzyl, phenyl, 5- membered heteroaryl, 6-membered heteroaryl, benzyloxy, or phenyloxy, wherein the benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy and phenyloxy is optionally substituted by one or more group(s) selected from halogen, hydroxyl, cyano, isocyano, amino, sulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-alkyloxy, Ci-Cs-haloalkyloxy, tri(Ci-C8-alkyl)silyl, C3-C7-cycloalkyl, C2-C8-alkenyl, and C2-C8-alkynyl. more preferably represents halogen, cyano, nitro, carboxaldehyde, hydroxycarbonyl, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-cyanoalkyl, Ci-C4-alkyloxy, Ci-C4-haloalkyloxy, C3-C6-cycloalkyl, C3-C6- halocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-alkylsulfanyl, Ci-C4-haloalkylsulfanyl, C1-C4- alkylcarbonyl, Ci-C4-haloalkylcarbonyl, aminothiocarbonyl, carbamoyl, Ci-C4-alkoxycarbonyl or Ci-C4-halogenoalkoxycarbonyl. more preferably represents fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-haloalkyl or carbamoyl. more preferably represents fluorine, cyano, nitro, CF3 or carbamoyl. most preferably represents fluorine or cyano. preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or ferf -butyl. more preferably represents hydrogen, methyl or ethyl. most preferably represents hydrogen. preferably represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or ferf -butyl. R5 more preferably represents hydrogen, methyl or ethyl. R5 most preferably represents hydrogen.
R4 and R5 may form together with the carbon atom to which they are attached an optionally Ci-C t-alkyl- substituted C3-C7-cycloalkyl ring.
In such embodiment R4 and R5 preferably form together with the carbon atom to which they are attached a non-substituted C3-C6-cycloalkyl ring, more preferably a non-substituted Cs-Cs-cycloalkyl ring, most preferably a cyclopropyl ring.
Q preferably represents a substituted 6-membered aromatic heterocycle containing one or two nitrogen atoms or a substituted 6-membered aromatic carbocycle. Substituted meaning that the cycle of the given formula comprises at least one of X1, X2, X3, X4 or X5 not being hydrogen.
Q also preferably represents a, preferably substituted, 6-membered aromatic cycle of formula (Q-I-l) to (Q-I-10)
Figure imgf000010_0001
wherein X1, X2, X3, X4 and X5 have the same definition as given for formula (I) above. Preferred definitions of X1, X2, X3, X4 and X5 are given below.
Q more preferably represents a, preferably substituted, phenyl, 3-pyridyl or 4-pyridyl of formula (Q-I- 1) to (Q-I-3)
Figure imgf000011_0001
wherein X1, X2, X3, X4 and X5 have the same definition as given for formula (I) above. Preferred definitions of X1, X2, X3, X4 and X5 are given below. more preferably represents a, preferably substituted, phenyl or 3-pyridyl of formula (Q-I-1) or (Q-I-
2)
Figure imgf000011_0002
wherein X1, X2, X3, X4 and X5 have the same definition as given for formula (I) above. Preferred definitions of X1, X2, X3, X4 and X5 are given below.
Q most preferably represents a, preferably substituted, phenyl of formula (Q-I-1)
Figure imgf000011_0003
wherein X1, X2, X3, X4 and X5 have the same definition as given for formula (I) above. Preferred definitions of X1, X2, X3, X4 and X5 are given below.
X1, X2, X3, X4, and X5 independently from each other preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, C i-C8 -halo alky 1 having 1 to 5 halogen atoms, C3-C8- cycloalkyl, C3-C7-halocycloalkyl having 1 to 5 halogen atoms, Ci-C8-haloalkyl-C3-C7-cycloalkyl, C3-C7-cycloalkenyl, C2-C8-alkenyl, C2-C8-alkynyl, C6-Ci2-bicycloalkyl, C3-C8-cycloalkyl-C2-C8- alkenyl, C3-C8-cycloalkyl-C2-C8-alkynyl, Ci-Cs-alkoxy, Ci-Cs-haloalkoxy having 1 to 5 halogen atoms, Ci-C8-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, Ci-Cs-alkylsulfenyl, Ci-Cs-alkenyloxy, C3-C8-alkynyloxy, C3-C6-cycloalkoxy, Ci-Cs-alkylsulfinyl, Ci-Cs-alkylsulfonyl, tri(Ci-C8-alkyl)- silyloxy, tri(Ci-C8-alkyl)-silyl, tri(Ci-C8-alkyl)-silyl-C2-C8-alkynyl, tri(Ci-C8-alkyl)-silyl-C2-C8- alkynyloxy, C6-Ci4-aryl, C6-Ci4-aryloxy, C6-Ci4-arylsulfenyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroaryloxy, wherein the C6-Ci4-aryl, C6-Ci4-aryloxy, C6-Ci4-arylsulfenyl, 5- or 6-membered heteroaryl, and 5- or 6-membered heteroaryloxy is non-substituted or substituted by one or more group(s) selected from halogen, cyanosulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs-haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8-alkyl, C3-C7- cycloalkyl, C3-C7-halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-C10- cycloalkylalkyl, C4-Cio-halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-Cs-alkyl-Cs-C?- cycloalkyl, Ci-C8-alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, Ci-Cs-alkenyloxy, Ci-Cs-haloalkenyloxy, Cs-Cs-alkynyloxy, Cs-Cs-haloalkynyloxy, Ci-C8-cyanoalkoxy, C4-C8-cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs-alkylsulfanyl, Ci-Cs- haloalkylsulfanyl, Ci-Cs-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-Cs-alkylsulfonyl, Ci-Cs- haloalkylsulfonyl, Ci-Cs-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-Cs-alkoxyalkyl, Ci-Cs- alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs-haloalkoxyalkyl, benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heteroaryloxy, benzyloxy, phenyloxy, benzylsulfanyl, and phenylsulfanyl.
X1, X2, X3, X4, and X5 independently from each other more preferably represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, Cs-Cs-cycloalkyl, Ci-Cs-alkoxy, Ci-Cs- alkoxycarbonyl, Ci-C6-alkylsulfenyl, or C3-C6-cycloalkoxy.
X1, X2, X3, X4, and X5 independently from each other more preferably represent hydrogen, halogen, Ci-Cs- alkyl, C3-Cs-cycloalkyl or Ci-Cs-alkoxy.
X1, X2, X3, X4, and X5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C4-alkyl, Cs-Cs-cycloalkyl or Ci-C4-alkoxy.
X1, X2, X3, X4, and X5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, feri-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
X1, X2, X3, X4, and X5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
X1 most preferably represents hydrogen or fluorine.
X2 most preferably represents hydrogen or chlorine.
X3 most preferably represents hydrogen, fluorine or methoxy.
X4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy. X5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
The symbol definitions and explanations given above in general terms or stated within preferred ranges can be combined with one another as desired, i.e. including between the particular ranges and preferred ranges. They apply both to the end products and correspondingly to educts and intermediates. In addition, individual definitions may not apply.
Preference is given to those cases in which each of the symbols have the abovementioned preferred definitions.
Particular preference is given to those cases in which each of the symbols have the abovementioned more and/or most preferred definitions. Hence, particular preferred is a process for preparing a compound of formula (I), wherein the compound of formula (I) is represented by formula (la)
Figure imgf000013_0001
wherein
R1 represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, O-C t-alkoxy-, Ci-C t-haloalkoxy-, Ci-C t-alkylfhio- or Ci-C4-haloalkylthio-substituted C3-C7-cycloalkyl or optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci-C t-haloalkoxy-, Ci- C t-alkylthio- or Ci-C4-haloalkylthio-substituted C6-Ci4-aryl,
R3 represents fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-haloalkyl or carbamoyl, and
X1 , X2 , X3 , X4 and X5 independently from each other represent hydrogen, halogen, Ci-Cs-alkyl, C3-C8- cycloalkyl or Ci-Cs-alkoxy.
R1 preferably represents Ci-C4-alkyl, optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci- C4-haloalkoxy-, Ci-C4-alkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C3-C6-cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, Ci-C4-haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted phenyl. R1 more preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ieri-butyl, 1- halocyclopropyl, l-(Ci-C4-alkyl)cyclopropyl, or optionally halogen-substituted phenyl.
R1 most preferably represents isobutyl, 1-chlorocyclopropyl, 1-fluorocyclopropyl, 1-methylcyclopropyl or 2,4-difluorophenyl.
R3 preferably represents fluorine, cyano, nitro, CF3 or carbamoyl.
R3 most preferably represents fluorine or cyano.
X1 , X2 , X3 , X4 , and X5 independently from each other preferably represent hydrogen, fluorine, chlorine, bromine, Ci-C t-alkyl, Cs-Cs-cycloalkyl or Ci-C t-alkoxy.
X1 , X2 , X3 , X4 , and X5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, feri-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert- butoxy.
X1 , X2 , X3 , X4 , and X5 independently from each other more preferably represent hydrogen, fluorine, chlorine, bromine, methyl, cyclopropyl, or methoxy.
X1 most preferably represents hydrogen or fluorine.
X2 most preferably represents hydrogen or chlorine.
X3 most preferably represents hydrogen, fluorine or methoxy.
X4 most preferably represents hydrogen, fluorine, chlorine, methyl or methoxy.
X5 more preferably represents hydrogen, fluorine, bromine or cyclopropyl, most preferably fluorine.
In the process according to the invention compounds of formula (I) are prepared by reacting a ketone of formula (II)
Figure imgf000014_0001
and a manganese compound of formula (III)
Figure imgf000015_0001
As outlined above, R1, R3, R4, R5, and Q are defined as in formula (I). The preferred, more preferred and most preferred definitions given with regard to formula (I) apply mutatis mutandis.
X, Y, and Z independently from each other preferably represent chlorine, bromine or iodine, more preferably chlorine or bromine. n is either 1 or 2.
In case n is 1, m is 1, i.e. the manganese compound comprises one organic moiety per manganese atom.
In case n is 2, m is 0, i.e. the manganese compound comprises two organic moieties per manganese atom.
M1 preferably represents Mg. z1 can be any number in the range of 0 to 10. If z1 is greater than 0, M¾ is present and can form a complex with the manganese moiety and optionally present LiZ. Preferably the following equation applies: 0 < z1 < 5, preferably 0 < z1 < 3, more preferred 0 < z1 < 2.
Also z2 can be any number in the range of 0 to 10. However, preferably z2 is greater than 0, i.e. at least some LiZ is present. Preferably the following equation applies: 0 < z2 < 5, preferably 0 < z2 < 3, more preferred 0 < z2 < 2.
In the definitions of the symbols given in the above and below formulae, collective terms were used which are generally representative of the following substituents:
Halogen: fluorine, chlorine, bromine or iodine. Halogen-substitution is generally indicated by the prefix halo, halogen or halogeno. Alkyl: saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkyl such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1 -ethyl- 1-methylpropyl and l-ethyl-2-methylpropyl. Particularly, said group is a Ci- C t-alkyl group, e.g. a methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1-dimethylethyl (tert-butyl) group. This definition also applies to alkyl as part of a composite substituent, for example cycloalkylalkyl, hydroxyalkyl etc., unless defined elsewhere like, for example, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, haloalkyl or haloalkylsulfanyl.
Alkenyl: unsaturated, straight-chain or branched hydrocarbyl radicals having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one double bond in any position, for example (but not limited to) C2-C6-alkenyl such as vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but- 2-enyl, (Z)-but-2-enyl, (E)-but-l-enyl, (Z)-but-l-enyl, 2-methylprop-2-enyl, l-methylprop-2-enyl, 2- methylprop-l-enyl, (E)-l-methylprop-l-enyl, (Z)-l-methylprop-l-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)- pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-pent-l-enyl, 3- methylbut-3-enyl, 2- methylbut-3-enyl, l-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2- enyl, (E)-l-methylbut-2-enyl, (Z)-l- methylbut-2-enyl, (E)-3-methylbut-l-enyl, (Z)-3-methylbut-l-enyl, (E)-2- methylbut-l-enyl, (Z)-2-methylbut-l-enyl, (E)-l-methylbut-l-enyl, (Z)-l- methylbut-l-enyl, 1,1- dimethylprop-2-enyl, 1-ethylprop-l-enyl, 1 -propyl vinyl, 1- isopropylvinyl, (E)-3,3-dimethylprop-l-enyl, (Z)-3,3-dimethylprop-l-enyl, hex-5-enyl, (E)-hex-4- enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l-enyl, (Z)-hex-l-enyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1- methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3- methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-l- methylpent-3-enyl, (Z)-l - methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4- methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3- methylpent-2-enyl, (E)-2- methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-l -methylpent-2-enyl, (Z)-l- methylpent-2-enyl, (E)-4-methylpent-l-enyl, (Z)-4-methylpent-l-enyl, (E)-3- methylpent-l-enyl, (Z)-3- methylpent-1 -enyl, (E)-2-methylpent-l -enyl, (Z)-2- methylpent-l-enyl, (E)-l -methylpent-l-enyl, (Z)-l- methylpent-l-enyl, 3-ethylbut- 3-enyl, 2-ethylbut-3-enyl, l-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3- ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-l-ethylbut-2-enyl, (Z)-l-ethylbut-2-enyl, (E)-3-ethylbut-l-enyl, (Z)-3-ethylbut-l-enyl, 2-ethylbut-l-enyl, (E)-l-ethylbut-l-enyl, (Z)-l-ethylbut-l- enyl, 2-propylprop-2-enyl, l-propylprop-2- enyl, 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, (E)-2- propylprop-l-enyl, (Z)- 2-propylprop-l-enyl, (E)-l-propylprop-l-enyl, (Z)-l-propylprop-l-enyl, (E)-2- isopropylprop-l-enyl, (Z)-2-isopropylprop-l-enyl, (E)-l-isopropylprop-l-enyl, (Z)-l- isopropylprop-1- enyl, l-( 1,1 -dimethyl ethyl)ethenyl, buta-l,3-dienyl, penta-l,4-dienyl, hexa-l,5-dienyl or methylhexadienyl. Particularly, said group is vinyl or allyl. This definition also applies to alkenyl as part of a composite substituent, for example haloalkenyl etc., unless defined elsewhere.
Alkynyl: straight-chain or branched hydrocarbyl groups having 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms and one triple bond in any position, for example (but not limited to) C2-C6- alkynyl, such as ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, but-3-ynyl, l-methylprop-2- ynyl, pent-l-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1- methylbut-2-ynyl, 3-methylbut-l-ynyl, l-ethylprop-2-ynyl, hex- 1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4- ynyl, hex-5-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, l-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1- methylpent-3-ynyl, 4-methylpent-2-ynyl, l-methylpent-2-ynyl, 4-methylpent-l-ynyl, 3-methylpent-l- ynyl, 2-ethylbut-3-ynyl, l-ethylbut-3-ynyl, l-ethylbut-2-ynyl, l-propylprop-2-ynyl, l-isopropylprop-2- ynyl, 2,2-dimethylbut-3-ynyl, l,l-dimethylbut-3-ynyl, l,l-dimethylbut-2-ynyl, or 3,3-dimethylbut-l-ynyl group. Particularly, said alkynyl group is ethynyl, prop-l-ynyl, or prop-2-ynyl. This definition also applies to alkynyl as part of a composite substituent, for example haloalkynyl etc., unless defined elsewhere.
Alkoxy: saturated, straight-chain or branched alkoxy radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1- methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1- dimethylpropoxy, 1,2-dimethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4- methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3- dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2- trimethylpropoxy, 1 -ethyl- 1-methylpropoxy and l-ethyl-2-methylpropoxy. This definition also applies to alkoxy as part of a composite substituent, for example haloalkoxy, alkynylalkoxy, etc., unless defined elsewhere.
Alkoxy carbonyl: an alkoxy group which has 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above) and is bonded to the skeleton via a carbonyl group (-C(=0)-). This definition also applies to alkoxycarbonyl as part of a composite substituent, for example cycloalkylalkoxycarbonyl etc., unless defined elsewhere.
Alkylsulfanyl: saturated, straight-chain or branched alkylsulfanyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfanyl such as methylsulfanyl, ethylsulfanyl, propylsulfanyl, 1-methylethylsulfanyl, butylsulfanyl, 1-methylpropyl- sulfanyl, 2-methylpropylsulfanyl, 1,1-dimethylethylsulfanyl, pentylsulfanyl, 1-methylbutylsulfanyl, 2- methylbutylsulfanyl, 3-methylbutylsulfanyl, 2,2-dimethylpropylsulfanyl, 1-ethylpropylsulfanyl, 1,1- dimethylpropylsulfanyl, 1,2-dimethylpropylsulfanyl, hexylsulfanyl, 1-methylpentylsulfanyl, 2- methylpentylsulfanyl, 3-methylpentylsulfanyl, 4-methylpentylsulfanyl, 1,1-dimethylbutylsulfanyl, 1,2- dimethylbutylsulf anyl, 1 ,3-dimethylbutylsulfanyl, 2,2-dimethylbutylsulf anyl, 2,3-dimethylbutylsulfanyl, 3,3-dimethylbutylsulfanyl, 1-ethylbutylsulfanyl, 2-ethylbutylsulfanyl, 1,1,2-trimethylpropylsulfanyl, 1,2,2- trimethylpropylsulfanyl, 1 -ethyl- 1-methylpropylsulf anyl and l-ethyl-2-methylpropylsulfanyl. This definition also applies to alkylsulfanyl as part of a composite substituent, for example haloalkylsulfanyl etc., unless defined elsewhere.
Alkylsulfinyl: saturated, straight-chain or branched alkylsulfinyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1-methylpropylsulfinyl,
2- methylpropylsulfinyl, 1,1 -dimethyl ethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2- methylbutylsulfinyl, 3-methylbutylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, 1,1- dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-mefhylpentyl- sulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethyl- butylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3- dimefhyibutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2- trimethylpropylsulfinyl, 1 -ethyl- 1-methylpropylsulfinyl and l-ethyl-2-methylpropylsulfinyl. This definition also applies to alkylsulfinyl as part of a composite substituent, for example haloalkylsulfinyl etc., unless defined elsewhere.
Alkylsulfonyl: saturated, straight-chain or branched alkylsulfonyl radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropyl- sulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2- methylbutylsulfonyl, 3-methylbutylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, 1,1- dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methyl- pentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2- dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1 -ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1 , 1 ,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1 -ethyl- 1-methylpropylsulfonyl and l-ethyl-2-methylpropylsulfonyl. This definition also applies to alkylsulfonyl as part of a composite substituent, for example alkylsulfonylalkyl etc., unless defined elsewhere.
Monoalkylamino represents an amino radical having one alkyl residue with 1 to 4 carbon atoms attached to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.
Dialkylamino represents an amino radical having two independently selected alkyl residues with 1 to 4 carbon atoms each attached to the nitrogen atom. Non-limiting examples include -dimethylamino, -diefhylamino, Af /V-diisopropylamino, -ethyl- -mefhylamino, -mefhyl- -n-propylamino, N-iso- propyl-/V-n-propylamino and -tert-butyl- -mefhylamino.
Cycloalkyl: monocyclic, saturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies to cycloalkyl as part of a composite substituent, for example cycloalkylalkyl etc., unless defined elsewhere.
Cycloalkenyl: monocyclic, partially unsaturated hydrocarbyl groups having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropenyl, cyclopentenyl and cyclohexenyl. This definition also applies to cycloalkenyl as part of a composite substituent, for example cycloalkenyl alky 1 etc., unless defined elsewhere.
Cycloalkoxy: monocyclic, saturated cycloalkyloxy radicals having 3 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon ring members, for example (but not limited to) cyclopropyloxy, cyclopentyloxy and cyclohexyloxy. This definition also applies to cycloalkoxy as part of a composite substituent, for example cycloalkoxyalkyl etc., unless defined elsewhere.
Haloalkyl: straight-chain or branched alkyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C3-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro methyl, chlorodifluoromethyl, 1-chloroethyl, 1- bromoethyl, l-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2- chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1- trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a composite substituent, for example haloalkylaminoalkyl etc., unless defined elsewhere.
Haloalkenyl and haloalkynyl are defined analogously to haloalkyl except that, instead of alkyl groups, alkenyl and alkynyl groups are present as part of the substituent.
Haloalkoxy: straight-chain or branched alkoxy groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C3-haloalkoxy such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2- fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and l,l,l-trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a composite substituent, for example haloalkoxyalkyl etc., unless defined elsewhere.
Haloalkylsulfanyl: straight-chain or branched alkylsulfanyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) O-C3- haloalkylsulfanyl such as chloromethylsulfanyl, bromomethylsulfanyl, dichloromethylsulfanyl, trichloromethylsulfanyl, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, chlorofluoromethylsulfanyl, dichlorofluoromethylsulfanyl, chlorodifluoromethylsulfanyl, 1-chloro- ethylsulfanyl, 1-bromoethylsulfanyl, 1-fluoroethylsulfanyl, 2-fluoroethylsulfanyl, 2,2-difluoroethyl- sulfanyl, 2,2,2 -trifluoroethylsulfanyl, 2-chloro-2-fluoroethylsulfanyl, 2-chloro-2,2-difluoroethylsulfanyl, 2,2-dichloro-2-fluoroethylsulfanyl, 2,2,2-trichloroethylsulfanyl, pentafluoroethylsulfanyl and 1,1,1- trifluoroprop-2-ylsulfanyl. This definition also applies to haloalkylsulfanyl as part of a composite substituent, for example haloalkylsulfanylalkyl etc., unless defined elsewhere.
Aryl: mono-, bi- or tricyclic aromatic or partially aromatic group having 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronapthyl, indenyl and indanyl. The binding to the superordinate general structure can be carried out via any possible ring member of the aryl residue. Aryl is preferably selected from phenyl, 1 -naphthyl and 2-naphthyl. Phenyl is particularly preferred.
Heteroaryl: 5 or 6-membered cyclic aromatic group containing at least 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O, and which group can also be part of a bi- or tricyclic system having up to 14 ring members, wherein the ring system can be formed with one or two further cycloalkyl, cycloalkenyl, heterocyclyl, aryl and/or heteroaryl residues and wherein benzofused 5 or 6-membered heteroaryl groups are preferred. The binding to the superordinate general structure can be carried out via any possible ring member of the heteroaryl residue. Examples of 5-membered heteroaryl groups which are attached to the skeleton via one of the carbon ring members are fur-2-yl, fur-3-yl, thien-2-yl, thien-3-yl, pyrrol-2-yl, pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-2-yl, imidazole-4-yl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, l,2,4-triazol-3-yl, l,3,4-oxadiazol-2-yl, l,3,4-thiadiazol-2-yl and l,3,4-triazol-2-yl. Examples of 5- membered heteroaryl groups which are attached to the skeleton via a nitrogen ring member are pyrrol-l-yl, pyrazol-l-yl, 1,2,4-triazol-l-yl, imidazol-l-yl, 1,2,3-triazol-l-yl and 1,3,4-triazol-l-yl. Examples of 6-membered heteroaryl groups are pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3- yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazine-2-yl, l,3,5-triazin-2-yl, 1,2,4- triazin-3-yl and l,2,4,5-tetrazin-3-yl. Examples of benzofused 5-membered heteroaryl groups are indol- 1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzimidazol-l-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, indazol-l-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol- 6-yl, indazol-7-yl, indazol-2-yl, l-benzofuran-2-yl, l-benzofuran-3-yl, l-benzofuran-4-yl, l-benzofuran-5- yl, l-benzofuran-6-yl, l-benzofuran-7-yl, l-benzothiophen-2-yl, l-benzothiophen-3-yl, 1-benzothiophen- 4-yl, l-benzothiophen-5-yl, l-benzothiophen-6-yl, l-benzothiophen-7-yl, l,3-benzothiazol-2-yl, 1,3- benzothiazol-4-yl, l,3-benzothiazol-5-yl, l,3-benzothiazol-6-yl, l,3-benzothiazol-7-yl, l,3-benzoxazol-2- yl, l,3-benzoxazol-4-yl, l,3-benzoxazol-5-yl, l,3-benzoxazol-6-yl and l,3-benzoxazol-7-yl. Examples of benzofused 6-membered heteroaryl groups are quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5- yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. Further examples of 5- or 6- membered heteroaryls which are part of a bicyclic ring system are 1,2,3,4-tetrahydroquinolin-l-yl, 1,2,3,4- tetrahydroquinolin-2-yl, l,2,3,4-tetrahydroquinolin-7-yl, l,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4- tetrahydroisoquinolin-l-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, l,2,3,4-tetrahydroisoquinolin-5-yl, 1,2,3,4- tetrahydroisoquinolin-6-yl and l,2,3,4-tetrahydroisoquinolin-7-yl. This definition also applies to heteroaryl as part of a composite substituent, for example heteroarylalkyl etc., unless defined elsewhere.
Heterocyclyl: three- to seven-membered, saturated or partially unsaturated heterocyclic group containing at least one, if appropriate up to four heteroatoms and/or heterogroups independently selected from the group consisting of N, O, S, S(=0), S(=0)2 and di-(Ci-C4)alkylsilyl, which group can be benzofused. The binding to the superordinate general structure can be carried out via a ring carbon atom or, if possible, via a ring nitrogen atom of the heterocyclic group. Saturated heterocyclic groups in this sense are for example (but not limited to) oxiranyl, aziridinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5- yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, oxazolidin-2-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-4-yl, thiazolidin-5-yl, imidazolidin-2-yl, imidazolidin-4-yl, l,2,4-oxadiazolidin-3-yl, l,2,4-oxadiazolidin-5-yl, 1 ,3,4-oxadiazolidin-2-yl, 1 ,2,4-thiadiazolidin-3-yl, 1 ,2,4-thiadiazolidin-5-yl, 1 ,3,4-thiadiazolidin-2-yl, l,2,4-triazolidin-3-yl, l,3,4-triazolidin-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, l,3-dioxan-5-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl, tetrahydrothien-2-yl, hexahydropyridazin-3-yl, hexa- hydropyridazin-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-2-yl, l,3,5-hexahydrotriazin-2-yl and l,2,4-hexahydrotriazin-3-yl. Partially unsaturated heterocyclic groups in this sense are for example (but not limited to) 2,3-dihydrofur-2-yl, 2,3-dihydrofur- 3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4- dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin- 4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4- isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3- isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-l-yl, 2,3-dihydropyrazol-2-yl, 2,3- dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-l-yl, 3,4- dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5 -dihy drop yrazol-l-yl, 4,5- dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3- dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4- dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4- dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl. Examples of benzofused heterocyclic groups are indolin-1- yl, indolin-2-yl, indolin-3-yl, isoindolin-l-yl, isoindolin-2-yl, 2,3-dihydrobenzofuran-2-yl and 2,3- dihydrobenzofuran-3-yl. This definition also applies to heterocyclyl as part of a composite substituent, for example heterocyclylalkyl etc., unless defined elsewhere. Oxo represents a doubly bonded oxygen atom.
Thiooxo represents a doubly bonded sulfur atom. Optionally substituted groups may be mono- or polysubstituted, where the substituents in the case of polysubstitutions may be identical or different.
Not included are combinations which are against natural laws and which the person skilled in the art would therefore exclude based on his/her expert knowledge. Ring structures having three or more adjacent oxygen atoms, for example, are excluded.
In the process according to the invention the ketone of formula (Π) and the manganese compound of formula (III) are preferably reacted in a molar ratio of 1 : 0.4 to 1 : 5, more preferred 1 : 0.5 to 1 : 4, most preferred 1 : 0,55 to 1 : 3.
In case the manganese compound of formula (ΠΙ) used is a manganese compound of formula (ΙΠ), wherein n is 1 and m is 1, the molar ratio of ketone of formula (II) to manganese compound of formula (ΙΠ) is preferably 1 : 1 to 1 : 5, more preferred 1 : 1.5 to 1 : 4, even more preferred 1 : 1.7 to 1 : 3, most preferred 1 : 2 to 1 : 2.5.
In case the manganese compound of formula (ΠΙ) used is a manganese compound of formula (ΙΠ), wherein n is 2 and m is 0, the molar ratio of ketone of formula (II) to manganese compound of formula (ΙΠ) is preferably 1 : 0.4 to 1 : 3, more preferred 1 : 0.5 to 1 : 2, even more preferred 1 : 0.6 to 1 : 1, most preferred 1 : 0.7 to 1 : 0.8.
It is preferred to perform the process according to the invention in the presence of a solvent, preferably in the presence of an aprotic solvent, more preferably a solvent selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, N-methylpyridione (NMP), dimethylformamide (DMF) and mixtures thereof, most preferably selected from diethyl ether, ieri-butyl methyl ether, tetrahydrofuran, toluene, and mixtures thereof.
Preferably, the process is carried out at a temperature of -10°C to 50°C, more preferred -10°C to 30°C, and most preferred -5°C to 20°C. The reaction time of the process according to the invention varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
The process according to the invention is generally performed under standard pressure (1 atm). However, it is also possible to work under elevated or reduced pressure.
Preferably, the reaction mixture resulting from the process according to the invention is quenched with water or an aqueous ammonium halogenide solution, preferably an aqueous NH4CI solution, preferably a saturated aqueous NH4CI solution. Such procedure results in compounds of formula (I), wherein R2 represents hydrogen. In case compounds of formula (I) are desired, wherein R2 represents a group other than hydrogen, the reaction mixture resulting from the process according to the invention may be quenched with a suitable electrophile providing the R2 group. For example, if compounds of formula (I) are desired, wherein R2 represents Ci-C8-alkyl, the reaction mixture can be quenched with an Ci-C8-alkylhalide, preferably Ci- C8-alkyliodide. Further suitable electrophiles providing different R2 groups are for example dialkylsulfates, anhydrides, acid chlorides, phosphorylchloride, alkylisocyanates, carbamoyl chlorides, carbono chloridates and imidocarbonates.
It is also possible to first synthesize a compound of formula (I), wherein R2 represents hydrogen (in the following referred to as compound of formula (lb)) and to subsequently convert such compound to respective compounds of formula (I), wherein R2 represents a group other than hydrogen (in the following referred to as compound of formula (Ic)). Such procedure is schematically shown in scheme 1.
Scheme 1:
Scheme 1: Preparation of compounds (Ic).
Figure imgf000023_0001
(Ib) (Ic)
R2' represents G-C8-alkyl, -Si(R6a)(R6b)(R6c), -P(0)(OH)2, -CH2-0-P(0)(OH)2, -C(0)-C1-C8-alkyl, - C(0)-C3-C7-cycloalkyl, -C(0)NH-Ci-C8-alkyl, -C(0)N-di-Ci-C8-alkyl, or -C(0)0-Ci-C8-alkyl, wherein the -C(0)-Ci-C8-alkyl, -C(0)-C3-C7-cycloalkyl, -C(0)NH-Ci-C8-alkyl, -C(0)N-di-Ci-C8- alkyl and -C(0)0-Ci-C8-alkyl is non-substituted or substituted by one or more group(s) selected from halogen and Ci-C8-alkoxy, wherein R6 , R6b, R6c represent independently from each other phenyl or Ci-C8-alkyl.
The compounds (lb) obtained according to the process of the invention can be converted in analogy to methods described in the literature to the corresponding compounds (Ic) (see e.g. DE-A 3202604, JP-A 02101067, EP-A 225 739, CN-A 101824002, FR-A 2802772, WO-A 2012/175119, Bioorganic & Medicinal Chemistry Letters, 7207-7213, 2012, Journal of the American Chemical Society, 19358-19361, 2012, Journal of Organic Chemistry, 9458-9472, 2012, Organic Letters, 554-557, 2013, Journal of the American Chemical Society, 15556, 2012). Preferably, compounds of the general structure (lb) are reacted with alkylhalides, dialkylsulfates, anhydrides, acid chlorides, phosphorylchloride, alkylisocyanate, carbamoyl chlorides, carbono chloridates or imidocarbonates, preferably in the presence of a base, to obtain compounds (Ic). After quenching the reaction mixtures can be worked-up by procedures generally known in the art.
Preferably, the reaction mixture is extracted with a suitable organic solvent, preferably ethyl acetate, ieri-butyl methyl ether or a mixture thereof. The combined organic phases are preferably washed with water or a solution of a suitable salt, preferably with brine, and dried, preferably over sodium sulfate, calcium sulfate or magnesium sulfate. Preferably, the organic solvent is removed and the resulting crude product further purified by known techniques, for example recrystallization or chromatography.
Ketones of formula (II) are known from WO 2016/156290 Al and can be synthesized as disclosed therein.
Manganese compounds of formula (ΠΙ) can be obtained as disclosed in P. Knochel et al., Synlett 2015, 26, 514-518 and WO 2007/113294 Al or in analogy to the methods described therein.
In one preferred embodiment of the process according to the invention, the manganese compounds of formula (ΙΠ) are obtained by the reaction of a compound of formula (VI)
Figure imgf000024_0001
wherein R4, R5, Q and X are defined as in formula (I), and a manganese halogenide of formula (VII)
MnY2 (vn)> wherein each Y is defined as in formula (III), in the presence of magnesium and LiZ, wherein Z is defined as in formula (III).
The preferred, more preferred and most preferred definitions given above for R4, R5, Q, X, Y, and Z apply mutatis mutandis. The reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods. This reaction is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
Preferably, the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof. Preferably, any solvent present in the reaction is dried before use.
Preferably, the reaction is carried out in the presence of an activating agent selected from copper salts, nickel salts, iron compounds, cobalt compounds, I2, CiEUBri, Cl(CH2)2Br, ieri.-BuOLi, BCI3, BF3, L1BH4, L1AIH4, NaAlH t, Et3Al, DIBAL-H (diisobutyl aluminum hydride), Na[H2Al(OCH2CH2OCH3)], Me3SiCl, Et2Zn, IC1, SnCh and mixtures thereof, preferably selected from I2, C2H4Br2, Cl(CH2)2Br, ter - BuOLi, BCI3, BF3, LiBH4, L1AIH4, NaAlH4, Et3Al, DIBAL-H (diisobutyl aluminum hydride), Na[H2Al(OCH2CH2OCH3)], Me3SiCl, Et2Zn, IC1, SnCl2 and mixtures thereof. Particularly preferred the reaction is carried out in the presence of I2, C2H4Br2, diisobutyl aluminum hydride, or MesSiCl.
The reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
Preferably, the compound of formula (VI) and the manganese halogenide of formula (VII) are reacted in a molar ratio of 1 : 0.4 to 1 : 1, more preferred 1 : 0.5 to 1 : 0.8, most preferred about 1 : 0.55 to 1 : 0.7.
Preferably, the manganese halogenide of formula (VII) and LiZ are present in a molar ratio of 1 : 0.5 to 1 : 2, more preferred 1 : 0.7 to 1 : 1.5, most preferred about 1 : 0.8 to 1 : 1.2. Preferably, the compound of formula (VI) and magnesium are present in a molar ratio of 1 : 1 to 1 : 2, more preferred 1 : 1 to 1 : 1.5, most preferred about 1 : 1.1 to 1 : 1.3.
The reaction mixture resulting from the reaction of the compound of formula (VI) and the manganese halogenide of formula (VII) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure. If desired, the resulting manganese compounds of formula (III) may be further purified by known techniques, for example crystallisation. However, preferably the resulting reaction mixture comprising the manganese compound of formula (III) is directly used in the process according to the invention.
In another preferred embodiment of the process according to the invention, the manganese compounds of formula (ΙΠ) are obtained by reacting a Grignard compound of formula (IV)
Figure imgf000026_0001
wherein R4, R5, Q and X are defined as in formula (I), and a manganese lithium complex of formula (V)
MnY2 ■ z3 LiZ (V), wherein
Y and Z are defined as in formula (III); and z3 is 0, 1, 2, 3, 4 or 5.
The preferred, more preferred and most preferred definitions given above for R4, R5, Q, X, Y, and Z apply mutatis mutandis. z3 is preferably 1, 2 or 3, more preferably 1 or 2, and most preferably 2.
The reactants are known compounds that are readily available from commercial sources or can be prepared according to well established methods.
For example, the Grignard compound of formula (IV) can be obtained by reacting the respective halogenide of formula (VI) and magnesium, preferably magnesium turnings, preferably in the presence of an activating reagent like copper salts, nickel salts, iron compounds, cobalt compounds, I2, C2H4Br2, Cl(CH2)2Br, teri.-BuOLi, BC13, BF3, L1BH4, L1AIH4, NaAlH4, Et3Al, DIBAL-H (diisobutyl aluminum hydride), Na[H2Al(OCH2CH2OCH3)], Me3SiCl, Et2Zn, IC1, SnCl2 and mixtures thereof, preferably I2, C2H4Br2, Cl(CH2)2Br, feri.-BuOLi, BC13, BF3, L1BH4, L1AIH4, NaAlH4, Et3Al, DIBAL-H (diisobutyl aluminum hydride), Na[H2Al(OCH2CH2OCH3)], Me3SiCl, Et2Zn, IC1, SnCl2 and mixtures thereof, more preferred 1,2-dibromoethane, and an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof. Preferably, any solvent is dried before use.
Generally, one may work-up the reaction product resulting from the synthesis of the Grignard compound of formula (IV) for example in order to isolate, concentrate, dilute or purify the Grignard compound or a solution or suspension thereof. However, it is preferred to directly use the Grignard compound in the further reaction with the manganese lithium complex of formula (V) without any treatment like isolation or purification. The Grignard reagent is represented by formula (IV). However, as generally known to the skilled person, Grignard compounds undergo solvent-dependent equilibrium between different magnesium compounds that can be described by the so-called Schlenck equilibrium. The Schlenck equilibrium for the Grignard reagent according to formula (IV) can be schematically illustrated as follows:
Figure imgf000027_0001
Furthermore, it is known, that solvent molecules, in particular ethers such as diethylether or THF, which are commonly used for reactions with Grignard reagents, can add to the magnesium of the Grignard reagent thereby forming etherates. Hence, formula (IV) encompasses not only the structures as depicted, but also the structures resulting from the Schleck equilibrium as well as the respective solvent adducts. For general information regarding structures of Grignard reagents, see also Milton Orchin, Journal of Chemical Education, Volume 66, Number 7, 1999, pp 586 to 588.
The reaction of the Grignard compound of formula (IV) and manganese lithium complex of formula (V) is preferably conducted under a protective atmosphere, preferably nitrogen or argon atmosphere.
Preferably, the reaction is carried out in the presence of an aprotic solvent, preferably selected from tetrahydrofuran, methyltetrahydrofuran, in particular 2-methyltetrahydrofuran, diethylether, cyclopentyl methyl ether, ieri-butyl methyl ether, toluene, and mixtures thereof, most preferably selected from diethyl ether, tetrahydrofuran, toluene and mixtures thereof. Preferably, any solvent present is dried before use.
The reaction is preferably conducted at a temperature of from -10 to 30 °C, more preferred -5°C to 5 °C, and a pressure of from 0.5 to 2 bar.
Preferably, the Grignard compound of formula (IV) and the manganese lithium complex of formula (V) are reacted in a molar ratio of 1 : 0.8 to 1 : 1.5, more preferred 1 : 0.9 to 1 : 1.4, more preferred about 1 : 1 to 1 : 1.3, most preferred 1 : 1 to 1 : 1.2.
The Grignard reagent of formula (IV) is preferably used as solution in an aprotic solvent, in particular as solution in diethyl ether, tetrahydrofuran, toluene or a mixture thereof, particularly preferred as a 0.2 to 1.0 molar solution in diethyl ether or tetrahydrofuran.
The reaction mixture resulting from the reaction of the Grignard compound of formula (IV) and the manganese lithium complex of formula (V) can be worked-up by procedures generally known in the art, e.g. by evaporation of any organic solvent, preferably under reduced pressure. If desired, the resulting manganese compounds of formula (III) may be further purified by known techniques, for example crystallisation. However, preferably the resulting reaction mixture comprising the manganese compound of formula (III) is directly used in the process according to the invention.
The reaction time of each of the steps of the processes outlined above varies depending on the scale of the reaction and the reaction temperature, but is generally between a few, e.g. 5, minutes and 48 hours.
The invention further relates to novel compounds of formula (III-F), which are particularly useful in the process according to the invention and form part of the invention.
Accordingly, a further subject of this invention is manganese compounds of formula (ΠΙ-F)
Figure imgf000028_0001
wherein X, Y, Z, n, m, z1, z2, X1 , X2 , X3 , and X4 are defined as outlined above.
The preferred, more preferred and most preferred definitions of X, Y, Z, n, m, z1, z2, X1 , X2 , X3 , and X4 given above apply mutatis mutandis.
The manganese compounds of formula (ΠΙ-F) can be obtained in analogy to the two preferred processes for synthesizing compounds of formula (III) outlined above. The invention is illustrated by the examples below. However, the invention is not limited to the examples.
Examples
Example 1:
Synthesis of manganese compound (ffl-Ola)
Figure imgf000029_0001
Step 1:
Magnesium turnings (24.9 g, 1.02 mol, 2.5 equiv) were placed in a dry argon-flushed flask. After addition of anhydrous Et20 (400 mL), the magnesium was activated using 1,2-dibromoethane (2.2 mL). The reaction mixture was cooled down to 0 °C using an ice bath. Subsequently, a solution of 2-fluoro-benzyl bromide (77.4 g, 409.5 mmol, 1 equiv) in anhydrous Et20 was added so slowly that the temperature of the reaction mixture did not rise above 5-7 °C. After complete addition, the reaction mixture was stirred for 1 h at 0 °C.
Titration of the resulting Grignard reagent against L. showed the concentration to be 0.87M (M = molar). Step 2:
382.0 mL (332.3 mmol, 1 equiv) of the 0.87M Grignard reagent in Et20 resulting from step 1 was placed in a fresh dry argon-flushed flask and cooled down to 0 °C using an ice bath. A 0.5M MnCl2-2LiCl solution in THF (748.0 mL, 373.9 mmol, 1.12 equiv) was added dropwise and the resulting mixture was stirred for 10 min (min = minutes) at 0 °C. The resulting reaction mixture was used directly in the synthesis of compounds of formula (I).
Example 2: Synthesis of 3-[2-(l-chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile (I- 01) using manganese compound (ΠΙ-Ola)
Figure imgf000029_0002
3-[2-(l-chlorocyclopropyl)-2-oxo-ethyl]imidazole-4-carbonitrile (34.0 g, 162.2 mmol, 1 equiv) was dissolved in dry THF (300 mL) and added dropwise at 0 °C to the manganese compound (Ill-Ola) obtained in example 1 (2.05 equiv). After stirring for 30 min at 0 °C the ice bath was removed and the reaction mixture warmed up to room temperature (23 °C) within 1 h (h = hour). During this time, the colour of the reaction mixture turned yellow. The reaction mixture was quenched with saturated NH4CI solution (400 mL) at 0 °C and extracted with EtOAc (ethyl acetate) (3x250 mL). The combined organic phases were washed with brine (500 mL), dried over Na2SC>4 and concentrated in vacuo. The remaining oil was stirred in a mixture of w-heptane (250 mL) and water (250 mL) for 30 min. The formed precipitate was filtered and washed with water (150 mL) and w -heptane (150 mL). The obtained solid was again stirred in a mixture of w -heptane and water, filtered and again washed with water and w -heptane. The desired compound (1-01) was obtained as a white solid in 85% yield with 97% purity (45.45 g, 137.9 mmol).
The compounds of formula (I) listed in the following Table 1 have been prepared analogously to examples 1 and 2. Resulting yields and purities are given in this table. This shows that compounds of formula (I) can be obtained in good to very good yield and excellent purity by the process according to the invention.
Figure imgf000030_0001
Table 1
No. Q R1 R2 R3 R4 R5 Yield Purity
(1-01) 2-fluorophenyl 1 -chlorocyclopropyl H cyano H H 85% 97%
(1-02) phenyl 1 -chlorocyclopropyl H cyano H H 80% 98%
(1-03) phenyl 1 -chlorocyclopropyl H fluoro H H 71 % >99%
(1-04) 3-methylphenyl 1 -chlorocyclopropyl H cyano H H 73% 97%
(1-05) 2,3 -difluorophenyl 1 -chlorocyclopropyl H cyano H H 80% 98%
(1-06) 2,6-difluorophenyl 1 -chlorocyclopropyl H cyano H H 61% 98%
(1-07) 3-chloro-2-fluorophenyl 1 -chlorocyclopropyl H cyano H H 58% 95%
(1-08) 5-chloro-2-fluorophenyl 1 -chlorocyclopropyl H cyano H H 59% 95%
(1-09) phenyl 1 -fluorocyclopropyl H fluoro H H 73% >99%
(1-10) 2-cyclopropylphenyl 1 -fluorocyclopropyl H cyano H H 82% 98% (1-11) 2-fluorophenyl 1 -fluorocyclopropyl H cyano H H 83% 98%
(1-12) 2-fluorophenyl 1 -fluorocyclopropyl H fluoro H H 82% >99%
(1-13) 2,3 -difluorophenyl 1 -fluorocyclopropyl H cyano H H 83% 98%
(1-14) 2,3 -difluorophenyl 1 -fluorocyclopropyl H fluoro H H 62% >99%
(1-15) 2,4-difluorophenyl 1 -fluorocyclopropyl H cyano H H 83% 98%
(1-16) 2,4-difluorophenyl 1 -fluorocyclopropyl H fluoro H H 67% >99%
(1-17) 3-chloro-2-fluorophenyl 1 -fluorocyclopropyl H cyano H H 68% 98%
(1-18) 3-chloro-2-fluorophenyl 1 -fluorocyclopropyl H fluoro H H 74% >99%
(1-19) 5-chloro-2-fluorophenyl 1 -fluorocyclopropyl H cyano H H 79% >99%
2,4-difluoro-3-
(1-20) 1 -fluorocyclopropyl H cyano H H 66% 98% methoxyphenyl
2,3-difluoro^-
(1-21) 1 -fluorocyclopropyl H cyano H H 60% 97% methoxyphenyl
(1-22) 2-bromophenyl 1 -fluorocyclopropyl H cyano H H 87% 95%
(1-23) 4-fluorophenyl isopropyl H cyano H H 65% >99%
(1-24) 2,4-difluorophenyl isopropyl H cyano H H 66% >99%
(1-25) phenyl 2,4-difluorophenyl H cyano H H 89% 98%
(1-26) 2-fluorophenyl 2,4-difluorophenyl H cyano H H 62% 93%
2-fluoro-3-
(1-27) 2,4-difluorophenyl H cyano H H 58% 93% methylphenyl
(1-28) 3-chloro-2-fluorophenyl 2,4-difluorophenyl H cyano H H 59% 92%
(1-29) 2,4-difluorophenyl 2,4-difluorophenyl H cyano H H 79% >99%
(1-30) 2,3,4-trifluorophenyl 2,4-difluorophenyl H cyano H H 67% >99%
Example 3:
Synthesis of manganese compound (ΙΠ-Olb)
Figure imgf000031_0001
(III-01b) Magnesium turnings (3.95 g, 162.5 mmol, 1.2 equiv) and LiCl (3.45 g, 81.4 mmol, 0.6 equiv) were placed in a dry argon-flushed flask and dried at 450 °C for 10-15 min. After cooling to room temperature anhydrous MnCk (10.45 g, mmol, 81.4 mmol, 0.6 equiv), anhydrous THF (100 mL) and anhydrous toluene (50 mL) were added. Subsequently, 2-fluoro-benzyl chloride (1.0 g, 8.0 mmol, 0.05 equiv) and DIBAL-H (diisobutyl aluminum hydride) (0.48 g, 3.4 mmol, 0.025 equiv, 1M in THF) were added and the reaction mixture was stirred at room temperature for 15 min. After cooling to 0 °C 2-fluoro-benzyl chloride (19.0 g, 151.0 mmol, 0.95 equiv) was added via syringe pump within 90 min and the reaction mixture was stirred at 0 °C for 1 h. Titration against showed a concentration of 0.754M.
Example 4: Synthesis of 3-[2-(l-chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4-carbonitrile (I- 01) using manganese compound (ΠΙ-Olb)
Figure imgf000032_0001
3-[2-(l-chlorocyclopropyl)-2-oxo-ethyl]imidazole-4-carbonitrile (12.7 g, 60.6 mmol, 1 equiv) was dissolved in dry THF (30 mL) and added dropwise at 0 °C to the manganese compound (ΠΙ-Olb) (0.75 equiv) obtained in example 3. After stirring for 30 min at 0 °C the ice bath was removed and the reaction mixture warmed up to room temperature within 1.5 h. The reaction mixture was quenched with saturated NH4C1 solution (150 mL) at 0 °C and extracted with MTBE (feri-butyl methyl ether) (3x150 mL). The combined organic phases were dried over Na2S04 and concentrated in vacuo. The remaining oil was mixed with n-heptane (70 mL) and stirred at room temperature for 1 h. The resulting suspension was filtered and the obtained solid washed with « -heptane (2x 30 mL). The desired compound (T01) was obtained as an off-white solid in 80% yield with 88% purity (17.6 g, 48.5 mmol).
Comparative example:
Comparative synthesis of 3-[2-(l-chlorocyclopropyl)-3-(2-fluorophenyl)-2-hydroxy-propyl]imidazole-4- carbonitrile (T01) with classical Mg-Species according to process M disclosed in WO 2016/156290 Al At 0-5 °C (ice/NaCl bath) a solution of 2-fluoro-benzyl bromide (1.3 g, 6.9 mmol, 1.2 equiv) in Et20 (5 mL) was added dropwise to a suspension of magnesium turnings (417 mg, 17.1 mmol, 3.0 equiv; activated by stirring at room temperature under argon in the presence of a catalytic amount of iodine) in Ι¾0 (15 mL). The mixture was stirred 45 min at 5 °C. To this solution at 0-5 °C was added a solution of 3-[2-(l-chlorocyclopropyl)-2-oxo-ethyl]imidazole-4- carbonitrile (2.0 g, 60% purity, 3.7 mmol, 1.0 equiv) in Et20 (30 mL) dropwise over 5 min. The reaction mixture was further stirred while allowing warming up to room temperature over 1 h. The resulting solution was cooled down to 5 °C. Thereafter, saturated aqueous NH4CI was added. The resulting mixture was diluted with water, and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaHCCb, dried over MgSO and then concentrated to dryness in vacuo. The oily residue was purified by chromatography over silica gel, eluted with a mixture of n-heptane/ethyl acetate (100:0 to 60:40). The desired compound was obtained after evaporation of the solvent as yellow oil in 12% yield (218 mg, 0.68 mmol). This shows that the process according to the invention provides the target compound in much higher yield than the process known from WO 2016/156290 Al.

Claims

Claims
1 Process for preparing a compound of formula (I)
Figure imgf000034_0001
wherein
R represents hydrogen, Ci-C8-alkyl, Ci-C8-haloalkyl, C2-C8-alkenyl, C2-C8-haloalkenyl, C2-C8- alkynyl, C2-C8-haloalkynyl, phenyl-C2-C8-alkynyl, [tri(Ci-C8-alkyl)silyl]phenyl-C2-C8- alkynyl, C3-C7-cycloalkyl, bicycloalkyl, C3-C7-cycloalkyl-Ci-C4-alkyl, C3-C7-cycloalkyl-C3- Cv-cycloalkyl, C3-C7-cycloalkenyl, tri(Ci-C8-alkyl)silyl-Ci-C4-alkyl, tri(Ci-C8-alkyl)silyl-C3- C7-cycloalkyl, or C6-Ci4-aryl, wherein the phenyl-C2-C8-alkynyl, [tri(Ci-C8- alkyl)silyl]phenyl-C2-C8-alkynyl, C3-C7-cycloalkyl, bicycloalkyl, C3-C7-cycloalkyl-Ci-C4- alkyl, C3-C7-cycloalkyl-C3-C7-cycloalkyl, C3-C7-cycloalkenyl, tri(Ci-C8-alkyl)silyl-Ci-C4- alkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, and C6-Ci4-aryl is non- substituted or substituted by one or more group(s) selected from halogen, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl, C1-C4- alkoxy, Ci-C4-haloalkoxy, Ci-C4-alkylthio and Ci-C4-haloalkylthio;
R2 represents hydrogen, d-Cs-alkyl, -Si(R6a)(R6b)(R6c), -P(0)(OH)2, -CH2-0-P(0)(OH)2, -C(O)- Ci-C8-alkyl, -C(0)-C3-C7-cycloalkyl, -C(0)NH-Ci-C8-alkyl, -C(0)N-di-Ci-C8-alkyl, or - C(0)0-Ci-C8-alkyl, wherein the -C(0)-G-C8-alkyl, -C(0)-C3-C7-cycloalkyl, -C(0)NH-G- C8-alkyl, -C(0)N-di-Ci-C8-alkyl and -C(0)0-Ci-C8-alkyl is non- substituted or substituted by one or more group(s) selected from halogen and Ci-C8-alkoxy, wherein
R , R , R c represent independently from each other phenyl or Ci-C8-alkyl;
R3 represents halogen, hydroxyl, cyano, isocyano, amino, nitro, sulfanyl, pentafluoro-λ6- sulfanyl, carboxaldehyde, hydroxycarbonyl, Ci-C8-alkyl, Ci-C8-haloalkyl, G-C8- hydroxyalkyl, Ci-C8-cyanoalkyl, Ci-C8-alkyloxy, Ci-C8-haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8-alkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-Cio-cycloalkylalkyl, C4-Cio-halocycloalkylalkyl, C6-C12- cycloalkylcycloalkyl, Ci-C8-alkyl-C3-C7-cycloalkyl, Ci-C8-alkoxy-C3-C7-cycloalkyl, tri(Ci- C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8-alkenyl, C2-C8-alkynyl, C2-C8-alkenyloxy, C2-C8- haloalkenyloxy, Cs-Cs-alkynyloxy, Cs-Cs-haloalkynyloxy, Ci-Cs-alkylamino, Ci-Cs- haloalkylamino, Ci-Cs-cyanoalkoxy, C4-C8-cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs- alkylsulfanyl, Ci-Cs-haloalkylsulfanyl, Ci-Cs-alkylcarbonyl, Ci-Cs-haloalkylcarbonyl, arylcarbonyl, aryl-Ci-C6-alkylcarbonyl, Cs-Cs-cycloalkylcarbonyl, C3-C8- halocycloalkylcarbonyl, carbamoyl, Ci-Cs-alkylcarbamoyl, di-Ci-Cs-alkylcarbamoyl, N-Ci- C8-alkyloxycarbamoyl, Ci-Cs-alkoxycarbamoyl, N-Ci-Cs-alkyl-Ci-Cs-alkoxycarbamoyl, aminothiocarbonyl, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, C3-C8- cycloalkoxycarbonyl, Ci-Cs-alkoxyalkylcarbonyl, Ci-Cs-haloalkoxyaikylcarbonyl, C3-C10- cycloalkoxyalkylcarbonyl, Ci-Cs-alkylaminocarbonyl, di-Ci-Cs-alkylaminocarbonyl, C3-C8- cycloalkylaminocarbonyl, Ci-Cs-alkylcarbonyloxy, Ci-Cs-haloalkylcarbonyloxy, C3-C8- cycloalkylcarbonyloxy, Ci-Cs-alkylcarbonylamino, Ci-Cs-haloalkylcarbonylamino, Ci-Cs- alkylaminocarbonyloxy, di-Ci-Cs-alkylaminocarbonyloxy, Ci-Cs-alkyloxycarbonyloxy, Ci- C8-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-Cs-alkylsulfonyl, Ci-Cs-haloalkylsulfonyl, Ci- C8-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-Cs-alkylaminosulfamoyl, di-Ci-Cs- alkylaminosulfamoyl, (Ci-C8-alkoxyimino)-Ci-C8-alkyl, (C3-C7-cycloalkoxyimino)-Ci-C8- alkyl, hydroxyimino-Ci-Cs-alkyl, (Ci-C8-alkoxyimino)-C3-C7-cycloalkyl, hydroxyimino-C3- C7-cycloalkyl, (Ci-C8-alkylimino)-oxy, (Ci-C8-alkylimino)-oxy-Ci-C8-alkyl, (C3-C7- cycloalkylimino)-oxy-Ci-C8-alkyl, (Ci-C6-alkylimino)-oxy-C3-C7-cycloalkyl, (Ci-Cs- alkenyloxyimino)-Ci-C8-alkyl, (Ci-C8-alkynyloxyimino)-Ci-C8-alkyl, (benzyloxyimino)-Ci- Cs-alkyl, Ci-Cs-alkoxyalkyl, Ci-Cs-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs- haloalkoxyalkyl, benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy, phenyloxy, benzylsulfanyl, benzylamino, phenylsulfanyl, or phenylamino, wherein the benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy or phenyloxy is non-substituted or substituted by one or more group(s) selected from halogen, hydroxyl, cyano, isocyano, amino, sulfanyl, pentafluoro- 6-sulfanyl, carboxaldehyde, hydroxycarbonyl, Ci-C8-alkyl, Ci-Cs-haloalkyl, Ci-Cs-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs-haloalkyloxy, tri(Ci- C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8-alkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C3- C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-Cio-cycloalkylalkyl, C4-Cio-halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-C8-alkyl-C3-C7-cycloalkyl, Ci-C8-alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, Ci-Cs-alkenyl, Ci-Cs-alkynyl, Ci-Cs-alkenyloxy, C2- C8-haloalkenyloxy, Cs-Cs-alkynyloxy, C3-Cs-haloalkynyloxy, Ci-Cs-alkylamino, Ci-Cs- haloalkylamino, Ci-Cs-cyanoalkoxy, C4-C8-cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs- alkylsulfanyl, Ci-Cs-haloalkylsulfanyl, Ci-Cs-alkylcarbonyl, Ci-Cs-haloalkylcarbonyl, arylcarbonyl, aryl-Ci-C6-alkylcarbonyl, Cs-Cs-cycloalkylcarbonyl, C3-C8- halocycloalkylcarbonyl, Ci-Cs-alkylcarbamoyl, di-Ci-Cs-alkylcarbamoyl, N-Ci-Cs- alkyloxycarbamoyl, Ci-Cs-alkoxycarbamoyl, N-Ci-Cs-alkyl-Ci-Cs-alkoxycarbamoyl, aminothiocarbonyl, Ci-Cs-alkoxycarbonyl, Ci-Cs-haloalkoxycarbonyl, C3-C8- cycloalkoxycarbonyl, Ci-Cs-alkoxyalkylcarbonyl, Ci-Cs-haloalkoxyaikylcarbonyl, C3-C10- cycloalkoxyalkylcarbonyl, Ci-Cs-alkylaminocarbonyl, di-Ci-Cs-alkylaminocarbonyl, C3-C8- cycloalkylaminocarbonyl, Ci-Cs-alkylcarbonyloxy, Ci-Cs-haloalkylcarbonyloxy, C3-C8- cycloalkylcarbonyloxy, Ci-Cs-alkylcarbonylamino, Ci-Cs-haloalkylcarbonylamino, Ci-Cs- alkylaminocarboriyloxy, di-Ci-Cs-alkylaminocarbonyloxy, Ci-Cs-alkyloxycarbonyloxy, Ci- C8-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-Cs-alkylsulfonyl, Ci-Cs-haloalkylsulfonyl, Ci- C8-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-Cs-alkylaminosulfamoyl, di-Ci-Cs- alkylaminosulfamoyl, (Ci-C8-alkoxyimino)-Ci-C8-alkyl, (C3-C7-cycloalkoxyimino)-Ci-C8- alkyl, hydroxyimino-Ci-Cs-alkyl, (Ci-C8-alkoxyimino)-C3-C7-cycloalkyl, hydroxyimino-C3- C7-cycloalkyl, (Ci-C8-alkylimino)-oxy, (Ci-C8-alkylimino)-oxy-Ci-C8-alkyl, (C3-C7- cycloalkylimino)-oxy-Ci-C8-alkyl, (Ci-C6-alkylimino)-oxy-C3-C7-cycloalkyl, (Ci-Cs- alkenyloxyimino)-Ci-C8-alkyl, (Ci-C8-alkynyloxyimino)-Ci-C8-alkyl, (benzyloxyimino)-Ci- Ce-alkyl, Ci-Cs-alkoxyalkyl, Ci-Cs-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs- haloalkoxyalkyl, benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, benzyloxy, phenyloxy, benzylsulfanyl, benzylamino, phenylsulfanyl, and phenylamino;
R4 represents hydrogen or Ci-Cs-alkyl;
R5 represents hydrogen or Ci-Cs-alkyl; or R4 and R5 form together with the carbon atom to which they are attached a C3-C7-cycloalkyl, wherein the C3-C7-cycloalkyl ring is non-substituted or substituted by one or more C1-C4- alkyl group(s); and represents a 6-membered aromatic cycle of formula (Q-I)
Figure imgf000036_0001
wherein
U represents CX1 or N;
U2 represents CX2 or N;
U3 represents CX3 or N;
U4 represents CX4 or N;
U5 represents CX5 or N; wherein X1, X2, X3, X4, and X5 independently from each other represent hydrogen, halogen, nitro, cyano, sulfanyl, pentafluoro- 6-sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl having 1 to 5 halogen atoms, Cs-Cs-cycloalkyl, C3-C7-halocycloalkyl having 1 to 5 halogen atoms, Ci-Cs- haloalkyl-C3-C7-cycloalkyl, C3-C7-cycloalkenyl, Ci-Cs-alkenyl, C2-Cs-alkynyl, C6-C12- bicycloalkyl, Cs-Cs-cycloalkyl-Ci-Cs-alkenyl, Cs-Cs-cycloalkyl-Ci-Cs-alkynyl, Ci-Cs-alkoxy, Ci-C8-haloalkoxy having 1 to 5 halogen atoms, Ci-Cs-alkoxycarbonyl, Ci-Cs- haloalkoxycarbonyl, O-Cs-alkylsulfenyl, C2-C8-alkenyloxy, Cs-Cs-alkynyloxy, C3-C6- cycloalkoxy, Ci-Cs-alkylsulfinyl, Ci-Cs-alkylsulfonyl, tri(Ci-C8-alkyl)-silyloxy, tri(Ci-C8- alkyl)-silyl, tri(Ci-C8-alkyl)-silyl-C2-C8-alkynyl, tri(Ci-C8-alkyl)-silyl-C2-C8-alkynyloxy, aryl, aryloxy, arylsulfenyl, heteroaryl, heteroaryloxy, wherein the aryl, aryloxy, arylsulfenyl, heteroaryl, heteroaryloxy is non-substituted or substituted by one or more group(s) selected from halogen, cyanosulfanyl, pentafluoro-λ6- sulfanyl, Ci-Cs-alkyl, Ci-Cs-haloalkyl, Ci-Cs-cyanoalkyl, Ci-Cs-alkyloxy, Ci-Cs- haloalkyloxy, tri(Ci-C8-alkyl)silyl, tri(Ci-C8-alkyl)silyl-Ci-C8-alkyl, Cs-Cv-cycloalkyl, C3-C7- halocycloalkyl, C3-C7-cycloalkenyl, C3-C7-halocycloalkenyl, C4-Cio-cycloalkylalkyl, C4-C10- halocycloalkylalkyl, C6-Ci2-cycloalkylcycloalkyl, Ci-C8-alkyl-C3-C7-cycloalkyl, Ci-Cs- alkoxy-C3-C7-cycloalkyl, tri(Ci-C8-alkyl)silyl-C3-C7-cycloalkyl, C2-C8-alkenyl, C2-C8- alkynyl, C2-C8-alkenyloxy, C2-C8-haloalkenyloxy, C3-Cs-alkynyloxy, Cs-Cs-haloalkynyloxy, Ci-Cs-cyanoalkoxy, C t-Cs-cycloalkylalkoxy, C3-C6-cycloalkoxy, Ci-Cs-alkylsulfanyl, Ci-Cs- haloalkylsulfanyl, Ci-Cs-alkylsulfinyl, Ci-Cs-haloalkylsulfinyl, Ci-Cs-alkylsulfonyl, Ci-Cs- haloalkylsulfonyl, Ci-Cs-alkylsulfonyloxy, Ci-Cs-haloalkylsulfonyloxy, Ci-Cs-alkoxyalkyl, Ci-C8-alkylthioalkyl, Ci-Cs-alkoxyalkoxyalkyl, Ci-Cs-haloalkoxyalkyl, benzyl, phenyl, 5- membered heteroaryl, 6-membered heteroaryl, 6-membered heteroaryloxy, benzyloxy, phenyloxy, benzylsulfanyl, and phenylsulfanyl, wherein the benzyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heteroaryloxy, benzyloxy, phenyloxy, benzylsulfanyl and phenylsulfanyl is non-substituted or substituted by one or more group(s) selected from halogen, CN, nitro, Ci-Cs-alkyl, C1-C4- haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy and pentafluoro- 6-sulfanyl; and wherein at most two of U1, U2, U3, U4 and U5 represent N; or
U1 and U2 or U2 and U3 or U3 and U4 form together an additional saturated or unsaturated 4 to 6-membered halogen- or Ci-Cs-alkyl-substituted or non-substituted ring; by reacting a ketone of formula (II)
Figure imgf000038_0001
wherein
R1 and R3 are defined as in formula (I); and a manganese compound of formula (III),
Figure imgf000038_0002
wherein each X, Y and Z represents independently from each other halogen;
M represents Mg or Zn; n is 1 or 2; m is O or l; n+m is 2; Q < zl < 10; 0 < z2 < 10; and
R4, R5 and Q are defined as in formula (I). 2. Process according to claim 1, wherein R1 represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci- C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci-C t-haloalkoxy-, Ci-C4-alkylthio- or C1-C4- haloalkylthio-substituted C3-C7-cycloalkyl or optionally halogen-, cyano-, Ci-C4-alkyl-, C1-C4- haloalkyl-, Ci-C4-alkoxy-, Ci-C4-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted
3. Process according to at least one of claims 1 and 2, wherein R2 represents hydrogen. 4. Process according to at least one of claims 1 to 3, wherein R3 represents fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-haloalkyl or carbamoyl.
5. Process according to at least one of claims 1 to 4, wherein R4 and R5 each represent hydrogen.
6. Process according to at least one of claims 1 to 5, wherein
Q represents a 6-membered aromatic cycle of formula (Q-I-1)
Figure imgf000039_0001
wherein
X , X , X , X and X are defined as in claim 1.
Process according to at least one of claims 1 to 6, wherein X1, X2, X3, X4 and X5 independently from each other represent hydrogen, halogen, Ci-Cs-alkyl, Cs-Cs-cycloalkyl or Ci-Cs-alkoxy.
Process according to at least one of claims 1 to 7, wherein the compound of formula (I) is represented by formula (la)
Figure imgf000039_0002
wherein
R1 represents Ci-Cs-alkyl, optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, C1-C4- alkoxy-, Ci-C t-haloalkoxy-, Ci-C t-aikylthio- or Ci-C4-haloalkylthio-substituted C3-C7- cycloalkyl or optionally halogen-, cyano-, Ci-C t-alkyl-, Ci-C t-haloalkyl-, Ci-C t-alkoxy-, Ci- C t-haloalkoxy-, Ci-C4-alkylthio- or Ci-C4-haloalkylthio-substituted C6-Ci4-aryl,
R3 represents fluorine, chlorine, bromine, iodine, cyano, nitro, Ci-C4-haloalkyl or carbamoyl, and
X1 , X2 , X3 , X4 and X5 independently from each other represent hydrogen, halogen, Ci-Cs-alkyl, C3-C8-cycloalkyl or Ci-Cs-alkoxy. Process according to at least one of claims 1 to 8, wherein each X, Y and Z independently from each other represent fluorine, chlorine or bromine.
Process according to at least one of claims 1 to 9, wherein
0≤z1≤5, and/or
0 < z2 < 5.
11. Process according to at least one of claims 1 to 10, wherein the ketone of formula (II) and the manganese compound of formula (III) are reacted in a molar ratio of 1 : 0.4 to 1 : 5, preferably 1 : 0.5 to 1 : 4, more preferred 1 : 0,55 to 1 : 3. 12. Process according to at least one of claims 1 to 11, wherein the reaction is performed in the presence of a solvent selected from diethyl ether, ieri-butyl methyl ether, tetrahydrofuran, toluene, and mixtures thereof.
13. Process according to at least one of claims 1 to 12, wherein the reaction is performed at a temperature of from -10°C to +50°C. 14. Process according to at least one of claims 1 to 13, wherein the manganese compound of formula obtained by reacting a Grignard compound of formula (IV)
Figure imgf000040_0001
wherein R4, R5, Q and X are defined as in claim 1, and a manganese lithium complex of formula (V)
MnY2 ■ z3 LiZ (V), wherein
Y and Z are defined as in claim 1; and is 0, 1, 2, 3, 4 or 5; or by reacting a compound of formula (VI)
Figure imgf000041_0001
wherein R4, R5, Q and X are defined as in claim 1,
and a manganese halogenide of formula (VII)
MnY 2 (VII),
wherein
each Y is defined as in claim 1,
in the presence of magnesium and LiZ, wherein Z is defined as in claim 1.
15. Manganese compound of formula (III-F)
Figure imgf000041_0002
wherein X, Y, Z, n, m, z1, and z2 are defined as in claim 1 ; and
X , X , X , and X are defined as in claim 8.
PCT/EP2018/080121 2017-11-09 2018-11-05 Process for the preparation of 5-substituted imidazole derivatives and manganese compounds useful therefor WO2019091898A1 (en)

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