Method for functionalization of an aromatic amino acid or a nucleobase

A method for functionalization of an aromatic amino acid or a nucleobase with a fluoroalkyl-containing moiety RF, wherein the aromatic amino acid or the nucleobase is reacted in the presence of at least one reductant with at least one hypervalent iodine fluoroalkyl reagent,

• wherein the hypervalent iodine fluoroalkyl reagent is of general formula 1
• wherein
• R1 is selected from H, C1-C4 alkyl, Me(OCH2CH2)nO, wherein n=1-10,
• X1 is not present or is selected from chloride, tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate, methanesulfonate, toluenesulfonate, fluoride, bromide, (F(CF2)sSO2)2N, wherein s=1 to 4, C1-C6 carboxylate, fluorinated C1-C6 carboxylate, hexafluoroantimonate;
• A1 is not present or is selected from
• carbonyl group (C═O),
• R2—C—R3, wherein R2 and R3 are independently selected from fluorine, chlorine, hydrogen, CF3, C1-C4 alkyl, phenyl, phenyl substituted by fluorine, chlorine and/or C1-C4 alkyl, omega-methoxy-(C1-C4)alkyl;
• or R2 and R3 together with the carbon atom to which they are bound form 1,1-cyclobutylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,1-(4-oxacyclohexylene);
• A2 is not present or is selected from
• hydroxyl group (OH),
• oxygen (—O—),
• C1-4 alkoxy,
• OSiR4R5R6, wherein R4,R5,R6 are independently selected from methyl, ethyl, n-propyl, i-propyl and phenyl;
• R7N, wherein R7 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, and 4-chlorophenyl-substituted C1-10 alkyl;
• R8CO—, wherein R8 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, CH3(OCH2CH2)o—, wherein o=1-10, Cl−Me3N+(CH2)p—, wherein p=1-10, —(CX2)mCOOQ, wherein m=2-3, —(CX2)mSO3Q, wherein m=2-3, -phenyl-SO3Q, -phenyl-COOQ, —(CX2)mCOO—, wherein m=2-3, —(CX2)mSO3—, wherein m=2-3, -phenyl-SO3—, -phenyl-COO—,
• X2═F or Cl,
• Q is selected from lithium, sodium, potassium, rubidium, cesium, tetra (C1-C4 alkyl, phenyl, benzyl) ammonium, tri (C1-C4 alkyl, phenyl, benzyl) pyridinium;
• R9C(O)O—, wherein R9 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, CH3(OCH2CH2)o—, wherein o=1-10, Cl−Me3N+(CH2)p—, wherein p=1-10, —(CX2)mCOOQ, wherein m=2-3, —(CX2)mSO3Q, wherein m=2-3, -phenyl-SO3Q, -phenyl-COOQ, —(CX2)mCOO—, wherein m=2-3, —(CX2)mSO3—, wherein m=2-3, -phenyl-SO3—, -phenyl-COO—,
• X2═F or Cl,
• Q is selected from lithium, sodium, potassium, rubidium, cesium, tetra (C1-C4 alkyl, phenyl, benzyl) ammonium, tri (C1-C4 alkyl, phenyl, benzyl) pyridinium;
• RF is-CF2-A3-A4, wherein
• A3 is not present and A4 is fluorine, or phenylsulfanyl (PhS) group, or
• A3 is CF2 and A4 is fluorine, C1-10 perfluoroalkyl, phenoxy, C1-10 alkoxy, phenylsulfanyl, N-imidazolyl, N-pyrazolyl, N-benzimidazolyl, N-triazoyl, N-(2-methyl) imidazolyl, CH3 (OCH2CH2)nO, where n=1-10, Cl−MeH2N+(CH2)r, wherein r=1-10, Cl−MeH2N+(CH2)2-phenyloxy, C1-10 alkyl, ethenyl, ethynyl, omega-azido C1-10 alkyl, omega-amino C1-10 alkyl, omega-ethynyl C1-10 alkyl, C1-10 alkylthio, phenyl, chloro, bromo, iodo, azido, nitro, C1-10 alkoxycarbonyl-substituted phenyl, C2-10 alkenyl, C2-10 alkyl omega substituted with SO2F, N-succinimide-O—C(O)—, methyldiaziridine, trifluoromethyldiaziridine, rhodamine, fluorescein or coumarin;
• aryl p-substituted with N-succinimide-O—C(O)—, rhodamine, fluorescein or coumarin, phenoxy p-substituted with N-succinimide-O—C(O)—, rhodamine, fluorescein or coumarin, and 2-(aryliodanyl)-1,1,2,2-tetrafluoroethyl;
• in alkyl chains, two neighboring carbon atoms may be replaced by a methylamido group (—N(Me)-C(O)—) and/or by a phenyl group;
• wherein the hypervalent iodine fluoroalkyl reagent is selected from the group consisting of the following reagents:

A hypervalent iodine fluoroalkyl reagent of general formula 1-1

• wherein
• R1 is selected from H, C1-C4 alkyl, Me(OCH2CH2)nO, wherein n=1-10,
• X1 is not present or is selected from chloride, tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate, methanesulfonate, toluenesulfonate, fluoride, bromide, (F(CF2)sSO2)2N−, wherein s=1 to 4, C1-C6 carboxylate, fluorinated C1-C6 carboxylate, hexafluoroantimonate;
• A1 is selected from
• R2—C—R3, where R2 and R3 are independently selected from chlorine, CF3, phenyl, phenyl substituted by fluorine, chlorine and/or C1-C4 alkyl, omega-methoxy-(C1-C4)alkyl;
• or R2 and R3 together with the carbon atom to which they are bound form 1,1-cyclobutylene, 1,1-cyclopentylene, 1,1-cyclohexylene, 1,1-(4-oxacyclohexylene);
• A2 is selected from
• hydroxyl group (OH),
• oxygen (—O—),
• C1-4 alkoxy,
• OSiR4R5R6, wherein R4,R5,R6 are independently selected from methyl, ethyl, n-propyl, i-propyl and phenyl;
• R7N, wherein R7 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, and 4-chlorophenyl-substituted C1-10 alkyl;
• R8CO—, wherein R8 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, CH3(OCH2CH2)o—, wherein o=1-10, Cl−Me3N+(CH2)p—, wherein p=1-10, —(CX2)mCOOQ, wherein m=2-3, —(CX2)mSO3Q, wherein m=2-3, -phenyl-SO3Q, -phenyl-COOQ, —(CX2)mCOO—, wherein m=2-3, —(CX2)mSO3—, wherein m=2-3, -phenyl-SO3—, -phenyl-COO—,
• X2═F or Cl,
• Q is selected from lithium, sodium, potassium, rubidium, cesium, tetra (C1-C4 alkyl, phenyl, benzyl) ammonium, tri (C1-C4 alkyl, phenyl, benzyl) pyridinium;
• R9C(O)O—, wherein R9 is selected from C1-10 alkyl, phenyl-substituted C1-10 alkyl, CH3(OCH2CH2)o—, wherein o=1-10, Cl−Me3N+(CH2)p—, wherein p=1-10, —(CX2)mCOOQ, wherein m=2-3, —(CX2)mSO3Q, wherein m=2-3, -phenyl-SO3Q, -phenyl-COOQ, —(CX2)mCOO—, wherein m=2-3, —(CX2)mSO3—, wherein m=2-3, -phenyl-SO3—, -phenyl-COO—,
• X2═F or Cl,
• Q is selected from lithium, sodium, potassium, rubidium, cesium, tetra (C1-C4 alkyl, phenyl, benzyl) ammonium, tri (C1-C4 alkyl, phenyl, benzyl) pyridinium;
• RF is —CF2-A3-A4, wherein
• A3 is not present and A4 is fluorine, or phenylsulfanyl (PhS) group, or
• A3 is CF2 and A4 is fluorine, C1-10 perfluoroalkyl, phenoxy, C1-10 alkoxy, phenylsulfanyl, N-imidazolyl, N-pyrazolyl, N-benzimidazolyl, N-triazoyl, N-(2-methyl) imidazolyl, CH3(OCH2CH2)nO, where n=1-10, Cl−MeH2N+(CH2)r, wherein r=1-10, Cl−MeH2N+(CH2)2-phenyloxy, C1-10 alkyl, ethenyl, ethynyl, omega-azido C1-10 alkyl, omega-amino C1-10 alkyl, omega-ethynyl C1-10 alkyl, C1-10 alkylthio, phenyl, chloro, bromo, iodo, azido, nitro, C1-10 alkoxycarbonyl-substituted phenyl, C2-10 alkenyl, C2-10 alkyl omega substituted with SO2F, N-succinimide-O—C(O)—, methyldiaziridine, trifluoromethyldiaziridine, rhodamine, fluorescein or coumarin;
• aryl p-substituted with N-succinimide-O—C(O)—, rhodamine, fluorescein or coumarin, phenoxy p-substituted with N-succinimide-O—C(O)—, rhodamine, fluorescein or coumarin, and 2-(aryliodanyl)-1,1,2,2-tetrafluoroethyl;
• in alkyl chains, two neighboring carbon atoms may be replaced by a methylamido group (—N(Me)-C(O)—) and/or by a phenyl group,
• provided that:
• A2 is not —O— or —OH, when:
• X1 is not present, RF is CF3 and A1 is R2—C—R3, wherein R2 and R3 are CF3 or wherein R2 and R3 together form 1,1-cyclohexylene.