Transition metal catalyzed synthesis of N-aminoindoles

A process for preparing a compound of formula I

• and/or all stereoisomeric forms of the compound of formula I, and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of formula I, wherein
• A1, A2, A3 and A4 are independently from each other selected from a carbon or a nitrogen atom to form together with the two carbon atoms in formula I a stable aromatic or heteroaromatic ring;
• Q is selected from a covalent bond;
• —(C1-C6)-alkylene, wherein alkylene is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C3-C8)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• and
• —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• J is selected from a covalent bond;
• —(C1-C6)-alkylene, wherein alkylene is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C2-C6)-alkenylene, wherein alkenylene is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• —(C2-C6)-alkynylene, wherein alkynylene is unsubstituted or mono-, di- or trisubstituted independently of one another by R14,
• —(C3-C8)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• and
• —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• T is selected from a covalent bond;
• —(C1-C6)-alkylene, wherein alkylene is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C3-C8)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• and
• —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13;
• R0, R1, R2, R3, and R4 are identical or different, and are independently selected from:
• a) hydrogen atom,
• b) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13,
• c) halogen,
• d) phenyloxy-, wherein phenyloxy is unsubstituted or substituted one to three times by R13,
• e) —(C1-C3)-fluoroalkyl,
• f) —N(R10)-(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13,
• g) —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• h) —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• i) —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• j) a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulphur, and oxygen, wherein said cyclic residue is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• k) —O—CF3,
• l) —O—(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13,
• m) —NO2,
• n) —CN,
• o) —OH,
• p) —C(O)—R10,
• q) —C(O)—O—R11,
• r) —C(O)—N(R11)-R12,
• s) —N(R11)-R12,
• t) —N(R10)-SO2—R10,
• u) —S—R10,
• v) —SOn—R10, wherein n is 1 or 2,
• w) —SO2—N(R11)-R12, and
• x) —O—SO2—R13;
• wherein at least one of R1, R2, R3 or R4 is absent when at least one of A1, A2, A3 or A4 is a nitrogen atom, or
• R1 and R2, R2 and R3, or R3 and R4 form, together with the atoms with which they are attached, a 5- or 8-membered ring, containing up to 0, 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulphur or oxygen, wherein said ring is unsubstituted or substituted one, two, three or four times by R14;
• R5 and R6 are identical or different, and are independently selected from:
• a) —(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13,
• b) phenyloxy-, wherein phenyloxy is unsubstituted or substituted one to three times by R13,
• c) —(C1-C3)-fluoroalkyl,
• d) —N(R10)-(C1-C4)-alkyl, wherein alkyl is unsubstituted or substituted one to three times by R13,
• e) —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• f) —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• g) —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• h) a 3- to 7-membered cyclic residue, containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulphur, and oxygen, wherein said cyclic residue is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13,
• i) —C(O)—R10,
• j) —C(O)—O—R11,
• k) —C(O)—N(R11)-R12,
• l)—SOn—R10, wherein n is 1 or 2, and
• m) —SO2—N(R11)-R12;
• R10 is selected from hydrogen atom, —(C1-C3)-fluoroalkyl, and —(C1-C6)-alkyl;
• R11 and R12 are identical or different, and are independently selected from:
• a) hydrogen atom,
• b) —(C1-C6)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13,
• c) —(C6-C14)-aryl-, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, and
• d) —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13;
• R13 is selected from halogen, —NO2, —CN, ═O, —OH, —(C1-C8)-alkyl, —(C1-C8)-alkoxy, —CF3, phenyloxy-, —C(O)—R10, —C(O)—O—R17, —C(O)—N(R17)-R18, —N(R17)-R18, —N(R10)-SO2—R10, —S—R10, —SOn—R10, wherein n is 1 or 2, —SO2—N(R17)-R18, —(C6-C14)-aryl, wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, —(C4-C14)-heteroaryl, wherein heteroaryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, —(C3-C8)-cycloalkyl, wherein said cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, or a 3- to 7-membered cyclic residue, containing up to 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein said cyclic residue is unsubstituted or mono-, di- or trisubstituted independently of one another by R14;
• R14 is selected from halogen, —OH, ═O, —CN, —CF3, —(C1-C8)-alkyl, —(C1-C4)-alkoxy, —NO2, —C(O)—OH, —N(R11)-R12, —C(O)—O—(C1-C4)-alkyl, —(C1-C8)-alkylsulfonyl, —C(O)—NH—(C1-C8)-alkyl, —C(O)—N[(C1-C8)-alkyl]2, —C(O)—NH2, —S—R10, —N(R10)-C(O)—NH—(C1-C8)-alkyl, and —N(R10)-C(O)—N[(C1-C8)-alkyl]2;
• R17 and R18 are identical or different, and are independently selected from:
• a) hydrogen atom,
• b) —(C1-C6)-alkyl,
• c) —(C6-C14)-aryl-, and
• d) —(C4-C14)-heteroaryl,
• said process comprises reacting a compound of formula II
• wherein R0, R1, R2, R3, R4, A1, A2, A3, R4 and Q are as defined in formula I, and
• X is selected from Cl, Br, I, triflate, nonaflate, tosylate, alkyl sulfonate and aryl sulfonate, with a compound of formula III or any salts thereof,
• wherein J, T, R5 and R6 are as defined in formula I,
• in the presence of a transition metal compound selected from:
• palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, palladium (II) acetate, palladium (II) trifluoroacetate, tris(dibenzylideneacetone)di-palladium(0), tris(dibenzylideneacetone)di-palladium(0) chloroform adduct, bis(dibenzylideneacetone)palladium (0), bis(triphenyl-phosphine)palladium (II) chloride, and tetrakis(triphenylphosphine)palladium (0);
• in the presence of a phosphine ligand selected from:
• tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate salt, tricyclohexylphosphine, dicyclohexlphenylphosphine, methyldiphenylphosphine, dimethylphenyl-phosphine, trimethylphosphine, triethylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl, and 2,2′-bis(di-tert-butylphosphino)biphenyl;
• to give a compound of formula I and optionally, the compound of formula I is converted to its physiologically tolerated salt.