C-HALOGEN BOND FORMATION
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.
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:
combining a carbon containing compound having an sp3 C—H bond, a fluorinating agent, a fluorinating catalyst, and an oxidant, wherein the fluorinating agent is a fluoride ion source.
2 . The method of claim 1 , wherein the carbon containing compound is added in a concentration from 1 mM to 5 M, the fluorinating agent is added in a concentration from 1 mM to 5 M, the fluorinating catalyst is added in a concentration from 1 mol % to 20 mol %, and the oxidant is added in a concentration from 1 mM to 1 M in each addition.
3 . The method of claim 1 , further comprising allowing the combined carbon containing compound, fluorinating agent, fluorinating catalyst, and oxidant to react for 30 minutes to 12 hours.
4 . The method of claim 1 , further comprising maintaining the carbon containing compound, the fluorinating agent, the fluorinating catalyst, and the oxidant at a temperature from −20° C. to +100° C.
5 . The method of claim 1 , wherein combining further comprises:
mixing the fluorinating catalyst, the fluorinating agent, and the carbon containing compound in a solvent to form a first mixture;
providing an inert gas over the first mixture; and
adding the oxidant to the first mixture to form a second mixture.
6 . The method of claim 1 , 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-amantadine; 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; 6-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 of the foregoing.
7 . The method of claim 1 , wherein the carbon containing compound is a drug or drug candidate precursor.
8 . 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.
9 . The method of claim 1 , 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-cyclononane, 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, and (R,R)—Mn(salen)(F2): (R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(IV) trans-difluoride.
10 . The method of claim 5 , wherein the metal is selected from the group consisting of manganese, copper, vanadium, chromium, iron, cobalt and nickel.
11 . The method of claim 1 , wherein the fluorinating catalyst is a manganese porphyrin, a manganese salen, or a manganese salophen.
12 . The method of claim 11 , 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) [tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.
13 . The method of claim 1 , 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 including oxygen, nitrogen, and halide, and the manganese has octahedral coordination with six total ligands and a neutral overall charge.
14 . The method of claim 1 , 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.
15 . The method of claim 1 , 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 4 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.
16 . 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.
17 . The method of claim 1 , wherein the fluorinating agent includes 18 F and a product produced by the method includes 18 F.
18 . A composition comprising at least one compound selected from the group consisting of 3-fluoro-5a-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; phthalimido-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.
19 . A composition comprising the product of claim 17 .
20 . 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.
21 . A composition comprising at least two or more of a carbon containing compound, a fluorinating agent, a fluorinating catalyst and an oxidant.
22 . A composition comprising a trans-difluoromanganese(IV) porphyrin Mn IV (TMP)F 2 .
23 . A composition comprising 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 including oxygen, nitrogen, and halide, and the manganese has octahedral coordination with six total ligands and a neutral overall charge.
24 . A composition comprising 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.
25 . A composition comprising a manganese complex having one or two fluoride ligands bound to the manganese and the formula L 5 Mn(IV)—F or L 4 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.
26 . A composition comprising a fluoro-buspirone.
27 . 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.
28 . The composition of claim 27 , 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-amantadine; 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; 6-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.
29 . The composition of claim 27 , 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.
30 . The composition of claim 27 , 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-cyclononane, 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.
31 . The composition of claim 30 , wherein the metal is selected from the group consisting of manganese, copper, vanadium, chromium, iron, cobalt and nickel.
32 . The composition of claim 27 , wherein the fluorinating catalyst is a manganese porphyrin, a manganese salen, or a manganese salophen.
33 . The composition of claim 32 , 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) [tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.
34 . The composition of claim 27 , 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.
35 . The composition of claim 27 , 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.
36 . The composition of claim 27 , 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 4 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.
37 . The composition of claim 27 , 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.
38 . The composition of claim 27 , wherein the fluorinating agent includes 18 F.
39 . A kit comprising one or more container, wherein each container includes a composition having at least one reactant for a fluorination reaction selected from the group consisting of a carbon containing compound, a fluorinating agent, a fluorinating catalyst, and an oxidant, wherein the composition includes at least one fewer substance than required to make a fluorination reaction proceed.
40 . The kit of claim 39 , further comprising a container having a solvent.
41 . The kit of claim 39 , wherein the one or more containers in combination include all the substances required to make the fluorination reaction proceed.
42 . The kit of claim 39 , further comprising instructions for mixing the reactants from the at least one container.
43 . A composition comprising a product of a method of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond comprising combining the carbon containing compound, a fluorinating agent, a fluorinating catalyst, and an oxidant.
44 . The composition of claim 43 , wherein the carbon containing compound is 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-amantadine; 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; 6-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.