C-halogen bond formation

Abstract

Methods of halogenating a carbon containing compound having an sp3 C—H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond are provided. The halogenated products of the methods are provided.

What is claimed is: 
     
         1 . A method of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond to form an sp3 C-F bond, the method comprising:
 mixing a fluorinating catalyst, a fluorinating agent, and the carbon containing compound in an organic solvent to form a first mixture; 
 providing an inert gas over the first mixture; and 
 adding an oxidant to the first mixture to form a second mixture, 
 wherein the fluorinating agent is a fluoride ion source. 
 
     
     
         2 . The method of  claim 1 , wherein the carbon containing compound is a drug or drug candidate precursor. 
     
     
         3 . The method of  claim 1 , wherein the fluorinating agent is selected from the group consisting of silver (I) fluoride, silver (II) fluoride, tetrabutyl ammonium fluoride, sodium fluoride, potassium fluoride, silver fluoride and tetra alkyl ammonium fluoride, trialkyl amine trihydrofluoride R 3 N(HF) 3 , the ammonium salt [R 3 NH][H 2 F 3 ], and potassium crown ether fluoride. 
     
     
         4 . The method of  claim 1 , wherein the fluorinating catalyst is selected from the group consisting of Mn(TPP)Cl, Mn(TMP)Cl, Mn III (TPP)C, Mn III (TMP)Cl, Mn IV (TMP)F 2 , Mn(III) [tetra-2,6-dichlorophenyl porphyrin, Mn(III) [tetra-2-nitrophenyl porphyrin], Mn(III) [tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin, Mn(III) [tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin], Mn(III) [tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], and Mn(III)Retraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin. 
     
     
         5 . The method of  claim 1 , wherein the oxidant is selected from the group consisting of meta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, and peroxyacetic acid, peroxyphthalic acid, and peroxytungstic acid. 
     
     
         6 . A composition comprising at least one compound selected from the group consisting of 3-fluoro-5α-cholestane; 2- and 3-fluoro-sclareolide; 1, 3, 5(10)-estratrien-17-one; fluoro-(1R,4aS, 8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphthalenone; (1R, 4S, 6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one; fluoro-levomethorphan; fluoro-lupine; fluoro-20-methyl-5alpha(H)-pregnane; fluoro-isolongifolanone; fluoro-caryophyllene acetate; fluoro-N-acetylgabapentin methyl ester; fluoro-acetyl-amantidine; phthalimido-fluoro-amantadine; methylene-fluorinated methyloctanoate; methylene fluorinated saturated fatty acid esters; N-acetyl-fluoro-Lyrica methyl ester; fluoro-artemisinin, fluoro-adapalene; fluoro-finasteride; N-acetyl-methyl-fluoro-phenidate; fluoro-mecamylamine; N-acetyl-fluoro-mecamylamine; N-acetyl-fluoro-memantine; hthalimido-fluoro-memantine; N-acetyl-fluoro-enanapril precursor methyl ester; fluoro-progesterone; fluoro-dopamine derivative; fluoro-pregabalin; fluoro-cholestane; methyl-fluoro-phenidate derivative; fluoro-gabapentin; fluoro-memantine derivative; fluoro-rimantadine derivative; fluoro-tramadol; fluoro-enalapril precursor; fluoro-donepezil precursor; fluoro-amphetamine; fluoro-tocopherol form of vitamin E; fluoro-melatonin; homophenylalanine; DOPA; fluoro-ibuprofen methyl ester; fluoro-buspirone; fluoro-eticyclidine; fluoro-amantadine; fluoro-lubiprostone; fluoro-penridopril; fluoro-fosinopril; fluoro-2-adamantanone; fluoro-rimantadine analogue; fluoro-adapalene precursor; fluoro-perindopril precursor; protected fluoro-gabapentin; methyl fluoro-octanoate; methyl fluoro-nonanate; methyl fluoro-hexanoate; fluoro-cyclohexyl acetate; and fluoro-cyclohexane carboxylic acid methyl ester; or an analog of any of the foregoing. 
     
     
         7 . A method of visualization comprising:
 fluorinating a carbon containing compound having an sp3 C—H bond by the method of  claim 1 , where the fluorinating agent includes  18 F and a product produced by the method includes  18 F to create an imaging agent;   administering the imaging agent to a patient; and   performing positron emission tomography on the patient.   
     
     
         8 . A composition comprising a trans-difluoromanganese(IV) porphyrin Mn IV (TMP)F 2 . 
     
     
         9 . A composition comprising at least two or more of a carbon containing compound having an sp3 C—H bond, a fluorinating agent, a fluorinating catalyst, or an oxidant. 
     
     
         10 . The composition of  claim 9 , wherein the carbon containing compound includes a compound selected from the group consisting of neopentane; toluene; cyclohexane; norcarane; trans-decalin; 5α-cholestane; sclareolide; 1,3,5(10)-estratrien-17-one; (1R,4aS, 8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone; (1R, 4S, 6S, 10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one; levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone; caryophyllene acetate; N-acetyl-gabapentin methyl ester; acetyl-amantidine; phthalimido-amantadline; methyloctanoate; saturated fatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene; finasteride; N-acetyl-methylphenidate; mecamylamine; N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine; N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin; adapalene; dopamine derivative; pregabalin; cholestane; finasteride; methylphenidate derivative; mecamylamine; gabapentin; memantine derivative; gabapentin; rimantadine derivative; isoleucine derivative; leucine derivative; valine derivative; pregesterone; tramadol; enalapril precursor; (1R, 4aS, 8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one; phenylalanine; donepezil precursor; amphetamine; δ-tocopherol form of vitamin E; tyrosine; melatonin; tryptophan; estrone acetate; progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester; buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone; penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine; 2-adamantanone; rimantadine analogue; adapalene precursor; perindopril precursor; protected gabapentin; methyl octanoate; methyl nonanate; methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acid methyl ester; or an analog of any one of the foregoing. 
     
     
         11 . The composition of  claim 9 , wherein the fluorinating agent is selected from the group consisting of silver (I) fluoride, silver (II) fluoride, tetrabutyl ammonium fluoride, sodium fluoride, potassium fluoride, silver fluoride and tetra alkyl ammonium fluoride, trialkyl amine trihydrofluoride R 3 N(HF) 3 , the ammonium salt [R 3 NH][H 2 F 3 ] and potassium crown ether fluoride. 
     
     
         12 . The composition of  claim 9 , wherein the fluorinating catalyst includes a metal complexed with a ligand selected from the group consisting of a porphyrin, a phthalocyanine, a corrole, an N-pyridylmethyl-tri-aza-cycononane, an N,N-dipyridylmethyl cyclohexadiamine, a tetra-aza-cyclotetra-decane, an N,N-dipyridylmethyl 2,2′-dipyrrolidine, an N,N-dipyridylmethyl ethylenediamine, a tripyridyl amine (TPA), a salen, a salophen, a phthalocyanine, and a porphyrazine. 
     
     
         13 . The composition of  claim 12 , wherein the metal is selected from the group consisting of manganese, copper, vanadium, chromium, iron, cobalt and nickel. 
     
     
         14 . The composition of  claim 9 , wherein the fluorinating catalyst is a manganese porphyrin, a manganese salen, or a manganese salophen. 
     
     
         15 . The composition of  claim 14 , wherein the manganese porphyrin is selected from the group consisting of Mn(TPP)Cl, Mn(TMP)Cl, Mn III (TPP)C, Mn III (TMP)Cl, Mn IV (TMP)F 2 , Mn(III) [tetra-2,6-dichlorophenyl porphyrin, Mn(III) [tetra-2-nitrophenyl porphyrin], Mn(III) [tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin, Mn(III) [tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin], Mn(III) [tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], and Mn(III)Retraphenyl-2,3, 7,8,12,13,17,18-Octanitroporphyrin. 
     
     
         16 . The composition of  claim 9 , wherein the fluorinating catalyst is a manganese complex having at least one fluoride ligand bound to the manganese and the formula L 5 Mn(IV)-F, where L is selected from the group consisting of oxygen, nitrogen, and halide, and the manganese has octahedral coordination with six total ligands and a neutral overall charge. 
     
     
         17 . The composition of  claim 9 , wherein the fluorinating catalyst is a manganese complex having at least one fluoride ligand bound to the manganese and the formula L 5 Mn(V)-F, where L is selected from the group consisting of oxygen, nitrogen and halide, and the manganese has octahedral coordination with six total ligands and a neutral overall charge. 
     
     
         18 . The composition of  claim 9 , wherein the fluorinating catalyst is a manganese complex having one or two fluoride ligands bound to the manganese and the formula L 5 Mn(IV)-F or L 5 Mn(IV)-F 2 , where L is selected from the group consisting of oxygen, nitrogen and halide, and the manganese has octahedral coordination with six total ligands and a neutral overall charge. 
     
     
         19 . The composition of  claim 9 , wherein the oxidant is selected from the group consisting of meta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyacetic acid, peroxyphthalic acid, and peroxytungstic acid. 
     
     
         20 . The composition of  claim 9 , wherein the fluorinating agent includes  18 F.