Synthesis of 18F-labeled compounds from nitroso-substituted arenes

Abstract

The invention relates to a process for producing an organic compound comprising a group of general formula I, wherein A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; characterized in that an organic compound having a group of general formula II, wherein A, R1 and R2 have the meanings given above, is subjected to radiofluorination.

Description

[0001] The invention relates to a method for producing 18 F-labeled compounds made from nitroso-substituted arenes. It also concerns the use of nitroso-substituted arenes for the production of 18 F-labeled compounds.

[0002] Fluorine-18 is a widely used radionuclide for diagnostic imaging with positron emission tomography. The nuclide's physical properties are ideal. Its half-life of 109.7 minutes and the ability to produce large quantities, e.g., up to the terabecquerel level, using commercially available cyclotron devices, enable the production and delivery of radiopharmaceuticals in batches sufficient for more than 100 patients at once, and delivery over a relatively large area around the production site. Furthermore, the low energy (0.635 MeV) of the emitted β-rays makes it suitable for a wide range of applications. +Fluorine particles form the basis for high image resolution compared to other PET nuclides, such as gallium-68 or carbon-11. From a medicinal chemistry perspective, the incorporation of fluorine into a molecule is a widely used strategy for drug development. This is based on the fact that metabolic stabilization of the molecule can be achieved, and the replacement of, for example, hydrogen atoms or hydroxyl groups by fluorine is often tolerated with regard to binding affinity to the target enzyme, transporter, or receptor. Therefore, a large number of fluorinated compounds have been developed and tested for their biological properties. The radioactive labeling of molecules with fluorine-18 remains a challenge, based on the fact that radiofluorination of the molecule must be achieved at a late stage during the synthesis process. Currently, several radiofluorination techniques have been developed for this purpose.[1] used for aliphatic or aromatic organic compounds as well as for chelating agent-containing molecules that were initially developed for radiometallic complexation.

[0003] Within this body of techniques, strategies for radioactive labeling for accessing 18 F-labeled aromatic compounds are of major importance due to the widespread occurrence of fluoroarenes in pharmacologically active molecules. Nucleophilic aromatic substitution reactions are one of the most widely used reaction classes, with a wealth of methods described in the literature for their application, each with a specific scope of reaction. An overview of leaving groups used in the prior art is provided in Fig.The process is illustrated in Scheme 1, shown in Figure 5. Trimethylammonium or nitro groups were most commonly used as leaving groups for nucleophilic exchange. Recent developments include the radiofluorination of triarylsulfonium salts. [2,3] , Diaryliodonium salts [4,5] , spirocyclic hypervalent iodine(III)ylidenes [6] , N-arylsydnones [1] or oxidized iodarenes [7] as well as ruthenium-mediated deoxyfluorination of phenols [8] .

[0004] Nucleophilic aromatic substitution (SNAr) is a class of reactions widely used in pharmaceutical and chemical studies, providing a versatile framework for the modification of aromatic ring structures. [9]When applied to benzene derivatives, these reactions involve the exchange of a leaving group (LG) by a nucleophile on a ring that carries activating electron-withdrawing groups (Z) at the ortho and / or para positions of the leaving group. The generally accepted mechanism for SNAr reactions involves a two-phase addition-elimination sequence, often via a unique, non-aromatic Meisenheimer complex. Recent advances in mechanistic research have also revealed the involvement of concerted [10,11] and single electron transfer (SET)

[12] -Mechanisms proposed.

[0005] The diverse reactivity exhibited by nitrosoarenes makes them promising starting materials in organic chemistry. They can be considered effective nucleophiles and electrophiles and have demonstrated widespread application in recent decades for the efficient synthesis of a variety of CN bonds.[13,14] The ability of the nitroso group to adopt various conjugation states with an aromatic ring can influence the ring's electron deficiency. With regard to SNAr reactions, protonated nitrosoarenes can form stable cations due to the delocalization of p-electrons. Consequently, the nucleophilic reaction site undergoes a transition from the nitroso group to the aryl group. Based on this principle, diarylamines were synthesized via reactions between anilines and protonated p-nitrosophenyl ethers. [15,16] In these reactions, the nitroso group acts as the activating group (Z).

[0006] Therefore, in SNAr reactions, the leaving group (LG) plays a central role in influencing the reactivity of the substrate and consequently the overall efficiency of the reaction. Although several nitrogen-containing groups are known to be good leaving groups in SNAr reactions (e.g., diazonium salts, aryldiazonium derivatives, and A-ryltrialkylammonium salts),

[17] Nevertheless, it is desirable to find alternative leaving groups that exhibit at least equally good properties as the known leaving groups, but are suitable for reactions where the previously known leaving groups have disadvantages. This applies, for example, when reactions are to proceed without a transition metal.

[0007] It is particularly desirable to find a way that 18 F-labeled aromatic compounds are more easily and efficiently accessible via precursors with a suitable leaving group.

[0008] The object of the invention is to eliminate the disadvantages of the prior art. In particular, it aims to provide a method for manufacturing 18 F-labeled aromatic compounds are specified, which enables rapid and cost-effective radiofluorination with high radiochemical transformations and yields.

[0009] This problem is solved by the features of claims 1 and 12. Advantageous embodiments of the inventions result from the features of the dependent claims.

[0010] According to the invention, a method for producing an organic compound comprising a group of the general formula I is provided, wherein A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; characterized in that an organic compound comprising a group of general formula II The compound, wherein A, R1 and R2 have the meanings given above, is subjected to radiofluorination. The compounds of general formula II are also referred to as nitrosoarenes in the present invention. The terms arenes and aromatic hydrocarbon are used synonymously in the present invention.

[0011] This invention describes a method for manufacturing 18F-labeled arenes starting from nitrosoarenes under transition metal-free conditions, enabling faster and more cost-effective radiofluorination with high radiochemical transformations and yields.

[0012] The group of general formula I and the group of general formula II have a unit “ " on. This unit denotes a hydrocarbon residue bonded to the aryl or heteroaryl group A, or hydrogen bonded to the aryl or heteroaryl group A.

[0013] The group of general formula I is preferably a group of general formula IA.

[0014] The group of general formula IA is an independent organic compound that has a group of general formula I in which the unit “ "Hydrogen bonded to the aryl or heteroaryl group A. The group of general formula IA is therefore referred to below as the compound of general formula IA."

[0015] The group of general formula II is preferably a group of general formula IIA

[0016] The group of general formula IIA is an independent organic compound that includes a group of general formula II in which the unit “ "Hydrogen bonded to the aryl or heteroaryl group A. The group of general formula IIA is therefore referred to below as the compound of general formula IIA."

[0017] The aryl or heteroaryl group A is preferably a pyridinyl, indolyl, or biphenylyl group, or a 5- or 6-membered aromatic ring, optionally comprising a heteroatom selected from O, N, or S. More preferably, the aryl or heteroaryl group A is an indolyl group or a 5- or 6-membered aromatic ring, optionally comprising a nitrogen atom. Particularly preferably, the aryl or heteroaryl group A is a pyridinyl or phenyl group.

[0018] In one embodiment of the process according to the invention, R1 and R2 are independently selected from the group consisting of H, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, carboxymethyl, carboxyethyl, oxomethyl, nitro, or cyano. Preferably, R1 is in the ortho position with respect to the functional group and R2 is in the meta or para position with respect to R1.

[0019] In a preferred embodiment of the process according to the invention, R1 is H or cyano and R2 is selected from the group consisting of H, chlorine, methyl, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, methyl ketone, nitro or cyano.

[0020] In a further preferred embodiment of the process according to the invention, R1 H and R2 are selected from the group consisting of chlorine, trifluoromethyl, carboxyethyl, oxomethyl, nitro or cyano.

[0021] In a particularly preferred embodiment of the process according to the invention, R1 is cyano and R2 is selected from the group consisting of H, bromine, chlorine, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, nitro, or cyano. R2 is particularly preferred to be H, bromine, chlorine, or methoxy. Furthermore, R1 is preferably cyano in the ortho position with respect to the functional group, and R2 is preferably chlorine or methoxy in the para position with respect to R1.

[0022] Preferred examples of a compound of the general formula IA are: Nr. formula name 1 1-(Fluor- 18 F)-4-(trifluormethyl)benzol 2 4-(Fluor- 18 F)benzaldehyd 3 1-(Fluor- 18 F)-4-nitrobenzol 4 4-(Fluoro- 18 F)benzonitrile 5 Ethyl-4-(fluor- 18 F)benzoat 6 1-Chlor-4-(fluor- 18 F)benzol 7 2-(Fluoro- 18 F)benzonitrile 8 3-Chlor-2-(fluor- 18 F)benzonitril 9 4-Chlor-2-(fluor- 18 F)benzonitril 10 5-Chlor-2-(fluor- 18 F)benzonitril 11 2-(Fluor- 18 F)-5-methoxybenzonitril 12 2-(Fluor- 18 F)-4-(trifluormethyl)benzonitril 13 2-(Fluor- 18 F)-4-methoxybenzonitril 14 2-(Fluor- 18 F)-6-methylbenzonitril 15 4-(Fluor- 18 F)-3-chlorbenzonitril 16 5-Bromo-2-(fluoro- 18 F)benzonitrile 17 1-(4-(Fluor- 18 F)phenyl)(phenyl)methan-1-on 18 2-(Fluor- 18 F)pyridin

[0023] Compound 1 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is trifluoromethyl in the para position to 18 F is.

[0024] Compound 2 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is oxomethyl in the para position to . 18 F is.

[0025] Compound 3 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is nitro in the para position to 18 F is.

[0026] Compound 4 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is cyano in the para position to 18 F is.

[0027] Compound 5 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is carboxyethyl in the para position to 18 F is.

[0028] Compound 6 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is chloride in the para position to . 18 F is.

[0029] Compound 7 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 is H.

[0030] Compound 8 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 chlorine in ortho position to 18 F is.

[0031] Compound 9 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 Chlorine in meta-position to 18 F is.

[0032] Compound 10 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 chlorine in para position to 18 F is.

[0033] Compound 11 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 Methoxy is in the para position to 18 F is.

[0034] Compound 12 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 trifluoromethyl in the meta position to 18 F is.

[0035] Compound 13 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 Methoxy in meta-position to 18 F is.

[0036] Compound 14 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 Methyl in meta position to 18 F and ortho position to cyano is.

[0037] Compound 15 is a compound of the general formula IA, where A is phenyl, R1 is chloride, and R2 is cyano in the para position to 18 F is.

[0038] Compound 16 is a compound of the general formula IA, where A is phenyl, R1 is cyano in the ortho position to 18 F is and R2 bromine in para position to 18 F is.

[0039] Compound 17 is a compound of the general formula IA, where A is phenyl, R1 is H, and R2 is a phenyl ketone in the para position to . 18 F is.

[0040] Compound 18 is a compound of the general formula IA, where A is pyridine, R1 and R2 are H.

[0041] The process for the preparation of an organic compound having a group of general formula I is carried out according to Scheme 2.

[0042] The radiofluorination reaction shown in Scheme 2 is carried out in the exemplary embodiments by elution with a K2CO3-loaded quaternary methylammonium cartridge (QMA) using the phase transfer catalyst K 222 and reaction on a microliter scale in HPLC vials at a reaction temperature between 90°C and 130°C and solvents, MeCN, DMF, DMSO with [ 18 F]KF was carried out. The radiochemical reaction (RCC) was determined by radio-thinning chromatography and high-performance liquid chromatography. The radiochemical yield was determined by high-performance liquid chromatography after reaction and subsequent purification. The reaction conditions are described in more detail in the examples. Alternatively, other sources for [ 18 F]fluoride such as tetraethylammonium [ 18F]fluoride can be used, and the reaction can be carried out in other vessels and scales, such as in larger glass vessels or reaction vessels of synthesis machines.

[0043] Unless otherwise specified, the term "aryl" refers to a cyclic aromatic hydrocarbon group consisting of a mono-, bi-, or tricyclic aromatic ring system with 5 to 18 ring atoms, preferably 5 or 6 ring atoms. The aryl group may optionally be a substituted aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, naphthalenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzoopiperidinyl, benzoopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. A preferred example is phenyl.The term “substituted aryl group” refers in particular to an aryl group optionally independently modified with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, -COOR (where R is hydrogen or alkyl), -CN, -N3, -NO, -NO2, -SR (where R is hydrogen or alkyl), hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, monoarylamino, alkylarylamino, diarylamino, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R''). n -COOR (where n is an integer from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl) or -(CR'R'') n -CONR a' R b' (where n is an integer from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R a' and R b'is substituted independently of each other (hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

[0044] Unless otherwise specified, the term "heteroaryl" refers in particular to a monocyclic, bicyclic, or tricyclic group with 5 to 18 ring atoms, wherein at least one aromatic ring contains one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The heteroaryl group may optionally be a substituted heteroaryl group.Beispiele von Heteroaryl-Gruppen umfassen, sind aber nicht beschränkt auf Imidazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Isothiazolyl, Oxadiazolyl, Thiadiazolyl, Pyrazinyl, Pyridazinyl, Thiophenyl, Furanyl, Pyranyl, Pyridyl, Pyrrolyl, Pyrazolyl, Pyrimidyl, Chinolinyl, Isochinolinyl, Chinazolinyl, Benzofuranyl, Benzothiophenyl, Benzothiopyranyl, Benzimidazolyl, Benzoxazolyl, Benzooxadiazolyl, Benzothiazolyl, Benzothiadiazolyl, Benzopyranyl, Indolyl, Isoindolyl, Indazolyl, Triazolyl, Triazinyl, Chinoxalinyl, Purinyl, Chinazolinyl, Chinolizinyl, Naphthyridinyl, Pteridinyl, Carbazolyl, Azepinyl, Diazepinyl, Acridinyl und dergleichen. Ein bevorzugtes Beispiel ist Pyridinyl.The term “substituted heteroaryl group” refers in particular to a heteroaryl group which may be independently modified with one to four substituents, preferably one or two substituents, selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R''). n -COOR (where n is an integer from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl) or -(CR'R'') n -CONR a' R b' (where n is an integer from 0 to 5, R' and R'' are independently hydrogen or alkyl, and R a' and R b'is substituted independently of each other (hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

[0045] Unless otherwise specified, the term "alkyl" refers in particular to a saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. The alkyl group may optionally be substituted with one or more substituents, each substituent being independently alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0046] Unless otherwise specified, the term "alkoxy" refers in particular to a group of the formula -OR, where R is an alkyl group, as defined herein. Examples of alkoxy components include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The alkoxy group may optionally be substituted with one or more substituents, each substituent being independently alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0047] The term "acyl" refers to a group of the formula -C(=O)R, where R is alkyl as defined herein.

[0048] Unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine, iodine or astatine.

[0049] According to the invention, the use of an organic compound comprising a group of general formula II is further provided for, wherein A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; for the preparation of an organic compound having a group of the general formula I, wherein A, R1 and R2 have the meanings given above.

[0050] Details of the uses according to the invention can be found in the description of the method according to the invention.

[0051] The invention is explained in more detail below with reference to the drawing and exemplary embodiments which are not intended to limit the invention.

[0052] Fig. Figure 1 shows detailed results of a radiofluorination of compound 2 as an example of the analytical methods used in the optimization to determine the radiochemical conversion (RCC) for the 18 F-marked product according to Radio-DC ( Fig. 1A) and Radio-HPLC ( Fig. 1B). The RCC to 18 F-labeled by-products (NP), if any, are indicated in the corresponding row.

[0053] Fig. Figure 2 shows radio-DC chromatograms of optimization reactions with compound 2 as a precursor.

[0054] Fig. Figure 3 shows a radio-HPLC chromatogram of the crude reaction mixture from the radioactive labeling with [ 18 F]Fluoride was reacted using the base Normal for elution, DMF as the reaction solvent, and a temperature of 130°C for 15 min. The signals of the γ-detector are shown above and the signals of the UV detector at 254 nm are shown below.

[0055] Fig. Figure 4 shows on the left a radio-HPLC chromatogram of compound 2 and on the right a radio-HPLC chromatogram of compound 2 which was added to 4-fluorobenzaldehyde for product identification, obtained by radiolabeling with [ 18 F]Fluoride as above in Fig. The procedure described in section 3 was followed by semi-preparative HPLC. The signals from the gamma detector are shown above, and the signals from the UV detector, monitored at 254 nm, are shown below. The retention time difference between the UV and gamma detectors was 0.17 min under the applied analytical conditions.

[0056] Fig. Figure 5 shows in diagram 1 an overview of outlet groups used in the state of the art. Examples

[0057] The examples describe the production and characterization of nitrosoars according to the invention. General procedure for the synthesis of nitrosoarenes

[0058] A solution of oxone (2.51 g, 4.0 mmol) in water (20 ml) was slowly added to a stirred solution of the corresponding aniline (2.0 mmol) in CH₂Cl₂ (10 ml). The reaction mixture was stirred at room temperature until TLC analysis indicated complete consumption of the starting material. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 ml). The combined organic layers were washed successively with 1M HCl (20 ml), water (20 ml), 10% NaHCO₃ (20 ml), and saline solution (20 ml). The combined organic compounds were dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel, affording nitrosoarenes in 56–89% yield. Example 11-Nitroso-4-(trifluoromethyl)benzene (1)

[0059] Following the general procedure, starting from 4-(trifluoromethyl)aniline (322.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 1 was obtained as an orange solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (245.2 mg, 70 %).

[0060] 1 H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 164.2, 136.3, 135.4, 127.2, 127.1, 127.1, 127.0, 125.2, 121.6, 121.0 ppm. 19 F-NMR (282 MHz, CDCl3): δ -63.1 ppm. Anal. calculated for C7H4F3NO: C, 48.01; H, 2.30. Found: C, 48.09; H, 2.27. Example 2 Synthesis of 4-Nitrosobenzaldehyde (2)

[0061] Following the general procedure, starting from 4-aminobenzaldehyde (242.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 2 was obtained as a light yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (183.8 mg, 68%).

[0062] 1 H NMR (300 MHz, CDCb): δ 10.2 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDC13): δ 191.4, 163.9, 139.6, 131.2, 121.2 ppm. Anal. calculated for C7H5NO2: C, 62.22; H, 3.73. Found: C, 62.14; H, 3.76. Example 3 Synthesis of 1-Nitro-4-nitrosobenzene (3)

[0063] Following the general procedure, starting from 4-nitroaniline (276.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 3 was obtained as yellow platelets by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (182.5 mg, 60%).

[0064] 1 H NMR (300 MHz, CDCl3): δ 8.51 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 162.6, 150.5, 125.6, 121.4 ppm. Anal. calculated for C6H4N2O3: C, 47.38; H, 2.65. Found: C, 47.45; H, 2.63. Example 4 Synthesis of 4-Nitrosobenzonitrile (4)

[0065] Following the general procedure, starting from 4-aminobenzonitrile (236.3 mg) and stirring the reaction mixture for 1.5 h, nitrosobenzene 4 was obtained as a greenish-yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (235.2 mg, 89%).

[0066] 1 H NMR (300 MHz, CDCl3): δ 7.97 (s, 4H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 162.3, 134.1, 120.9, 118.5, 117.6 ppm. Anal. calculated for C7H4N2O: C, 63.64; H, 3.05. Found: C, 63.60; H, 3.07. Example 5 Synthesis of Ethyl 4-nitrosobenzoate(5)

[0067] Following the general procedure, starting from ethyl 4-ami-nobenzoate (330.4 mg) and stirring the reaction mixture for 4 h, nitrosobenzene 5 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (211.4 mg, 59%).

[0068] 1 H-NMR (300 MHz, CDC13): δ 8.30 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 165.2, 164.5, 135.6, 131.0, 120.4, 61.8, 14.2 ppm. Anal. calculated for C9H9NO3: C, 60.33; H, 5.06. Found: C, 60.40; H, 5.03. Example 6 Synthesis of 1-chloro-4-nitrosobenzene (6)

[0069] Following the general procedure, starting from 4-chloroaniline (255.1 mg) and stirring the reaction mixture overnight, nitrosobenzene 6 was obtained as a dark yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (252.0 mg, 89 %).

[0070] 1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 163.9, 142.6, 129.8, 122.3 ppm. Anal. calculated for C6H4ClNO: C, 50.91; H, 2.85. Found: C, 51.01; H, 2.83. Example 7 Synthesis of 2-Nitrosobenzonitrile (7)

[0071] Following the general procedure, starting from 2-aminobenzonitrile (236.3 mg) and stirring the reaction mixture for 3 h, nitrosobenzene 7 was obtained as a light yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (171.8 mg, 65 %).

[0072] 1 H-NMR (300 MHz, CDCl3): δ 8.06 (dd, J = 7.6, 1.2 Hz, 1H), 7.86 (td, J = 7.6, 1.2 Hz, 1H), 7.76 (td, J = 7.8, 1.3 Hz, 1H), 6.98 (dd, J = 7.8, 1.2Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 161.9, 135.4, 134.5, 133.6, 116.7, 114.1, 112.3 ppm. Anal. calculated for C7H4N2O: C, 63.64; H, 3.05. Found: C, 63.59; H, 3.02. Example 8 Synthesis of 3-chloro-2-nitrosobenzonitrile (8)

[0073] Following the general procedure, starting from 2-Amino-3-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene 8 was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (193.2 mg, 58%).

[0074] 1 H-NMR (300 MHz, CDCl3): δ 8.05 (dd, J = 8.1, 1.2 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.64 (dd, J = 7.6, 1.2 Hz, 1H) ppm. 13C-NMR (75 MHz, CDCl3): δ 158.4, 141.1, 137.1, 135.6, 133.0, 116.1, 96.0 ppm. Anal. calculated for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.52; H, 1.78. Example 9 Synthesis of 4-chloro-2-nitrosobenzonitrile (9)

[0075] Following the general procedure, starting from 2-amino-4-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, nitrosobenzene 9 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (219.5 mg, 66%).

[0076] 1 H-NMR (300 MHz, CDCl3): δ 8.03 (d, J = 8.2 Hz, 1H), 7.81(dd, J = 8.2, 2.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDC13): δ 161.0, 141.0, 135.5, 134.9, 115.9, 113.3, 111.9 ppm. Anal. calculated for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.55; H, 1.79. Example 10 Synthesis of 5-chloro-2-nitrosobenzonitrile (10)

[0077] Following the general procedure, starting from 2-Amino-5-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene 10 was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (229.8 mg, 69%).

[0078] 1 H-NMR (300 MHz, CDCl3): δ 8.02 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 160.0, 142.6, 134.1, 133.9, 115.8, 115.4, 113.3 ppm. Anal. calculated for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.40; H, 1.77. Example 11 Synthesis of 5-Methoxy-2-nitrosobenzonitrile (11)

[0079] Following the general procedure, starting from 2-amino-5-methoxybenzonitrile (296.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 11 was obtained as a green solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (217.3 mg, 67%).

[0080] 1 H-NMR (300 MHz, CDCl3): δ 7.42 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 9.1, 2.6 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 4.00 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 164.9, 160.2, 118.5, 118.4, 117.4, 116.6, 115.3, 56.8 ppm. Anal. calculated for C8H6N2O2: C, 59.26; H, 3.73. Found: C, 59.18; H, 3.78. Example 12 Synthesis of 2-Nitroso-4-(trifluoromethyl)benzonitrile (12)

[0081] Following the general procedure, starting from 2-Amino-4-(trifluoromethyl)benzonitrile (372.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 12 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (244.1 mg, 61%).

[0082] 1 H-NMR (300 MHz, CDCl3): δ 8.29 (d, J = 7.9 Hz, 1H), 8.12 (dd, J = 7.9, 0.7 Hz, 1H), 7.16 (d, J = 0.7 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDC13): δ 160.3, 135.5, 131.5, 131.4, 117.4, 115.4, 109.3, 109.2 ppm. Anal. calculated for C8H3F3N2O: C, 48.02; H, 1.51. Found: C, 47.95; H, 1.54. Example 13 Synthesis of 4-Methoxy-2-nitrosobenzonitrile (13)

[0083] Following the general procedure, starting from 2-Amino-4-methoxybenzonitrile (296.3 mg) and stirring the reaction mixture overnight, Nitrosobenzene 13 was obtained as a green solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (201.1 mg, 62%).

[0084] 1 H-NMR (300 MHz, CDCl3): δ 7.97 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5, 2.7 Hz, 1H), 6.27 (d, J = 2.7 Hz, 1H), 3.89 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 163.4, 135.6, 121.9, 117.0, 107.6, 95.2, 56.4 ppm. Anal. calculated for C8H6N2O2: C, 59.26; H, 3.73. Found: C, 59.19; H, 3.70. Example 14 Synthesis of 2-methyl-6-nitrosobenzonitrile (14)

[0085] Following the general procedure, starting from 2-Amino-6-methylbenzonitrile (264.3 mg) and stirring the reaction mixture overnight, Nitrosobenzene 14 was obtained as a green solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (207.5 mg, 71%).

[0086] 1 H-NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8, 1H), 6.73 (d, J = 7.8 Hz, 1H), 2.81(s, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 162.8, 144.8, 136.6, 132.7, 115.8, 115.1, 109.0, 20.4 ppm. Anal. calculated for C8H6N2O: C, 65.75; H, 4.14. Found: C, 65.70; H, 4.16. Example 15 Synthesis of 3-chloro-4-nitrosobenzonitrile (15)

[0087] Following the general procedure, starting from 4-Amino-3-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene 15 was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (196.5 mg, 59%).

[0088] 1 H-NMR (300 MHz, CDCl3): δ 8.14 (d, J = 1.5 Hz, 1H), 7.56 (dd, J = 8.3, 1.5 Hz, 1H), 6.23 (d, J = 8.3 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 157.8, 142.4, 136.6, 131.0, 120.0, 116.4, 109.4 ppm. Anal. calculated for C7H3ClN2O: C, 50.48; H, 1.82. Found: C, 50.53; H, 1.8. Example 16 Synthesis of 5-bromo-2-nitrosobenzonitrile (16)

[0089] Following the general procedure, starting from 2-amino-5-bromobenzonitrile (394.1 mg) and stirring the reaction mixture overnight, nitrosobenzene 16 was obtained as a yellow solid by column chromatography using a mixture of hexane:ethyl acetate 9:1 as eluent (240.6 mg, 57%).

[0090] 1 H NMR (300 MHz, CDCl3): δ 8.20 (d, J = 1.9 Hz, 1H), 7.89 (dd, J = 8.6, 1.9 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 191.4, 163.9, 139.6, 131.2, 121.2 ppm. Anal. calculated. For C7H3BrN2O: C, 39.84; H, 1.43. Found: C, 39.99; H, 1.39. Example 17 Synthesis of (4-Nitrosophenyl)phenylmethanone (17)

[0091] Following the general procedure, starting from (4-Aminophenyl)(phenyl)methanone (394.5 mg) and stirring the reaction mixture overnight, Nitrosobenzene 17 was obtained as a yellowish crystalline solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (280.1 mg, 71%).

[0092] 1 H NMR (300 MHz, CDCl3): δ 7.99-8.07 (m, 4H), 7.82-7.88 (m, 2H), 7.68 (tt, J= 7.5, 2.1 Hz, 1H), 7.55 (tm, J= 7.5 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCl3): 160.2, 137.1, 136.9, 131.3, 115.9, 115.3, 113.1 ppm. Anal. calculated for C 13 H9NO2: C, 73.92; H, 4.30. Found: C, 73.60; H, 4.1. Example 18

[0093] 2-Nitrosopyridine (18) is commercially available and has been used directly for radiolabeling. Comparative example 1: Synthesis of 1-chloro-2-nitrosobenzene (A)

[0094] Following the general procedure, starting from 2-chloroaniline (255.1 mg) and stirring the reaction mixture overnight, nitrosobenzene A was obtained as a dark green solid by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (172.7 mg, 61%).

[0095] 1 H-NMR (300 MHz, CDCl3): δ 7.79 (dd, J = 8.1, 1.1 Hz, 1H), 7.63 (td, J = 7.6, 1.7 Hz, 1H), 7.24 (td, J = 7.6, 1.1 Hz, 1H), 6.23 (dd, J = 8.1, 1.7Hz, 1) ppm. 13 C-NMR (75 MHz, CDCl3): δ 160.9, 142.8, 136.8, 132.2, 126.7, 108.7 ppm. Anal. calculated for C6H4CINO: C, 50.91; H, 2.85. Found: C, 50.99; H, 2.86. Comparative example 2 Synthesis of ethyl-3-nitrosobenzoate (B)

[0096] Following the general procedure, starting from ethyl 3-ami-nobenzoate (330.4 mg) and stirring the reaction mixture overnight, nitrosobenzene B was obtained as a brown solid by column chromatography using a mixture of hexane : CH2Cl2 1:1 as eluent (283.1 mg, 79%).

[0097] 1 H-NMR (300 MHz, CDCl3): δ 8.63 (t, J = 1.6 Hz, 1H), 8.38 (dt, J = 7.8, 1.6 Hz, 1H), 7.98 (dt, J = 7.8, 1.6 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 165.3, 165.0, 135.8, 132.2, 129.6, 123.7, 122.6, 61.9, 14.4 ppm. Anal. calculated for C9H9NO3: C, 60.33; H, 5.06. Found: C, 60.40; H, 5.03. Comparative example 3 Synthesis of 1-Methoxy-3-nitrosobenzene (C)

[0098] Following the general procedure, starting from 3-methoxyaniline (246.3 mg) and stirring the reaction mixture for 4 h, nitrosobenzene C was obtained as a white powder by column chromatography using a mixture of hexane:CH2Cl2 1:1 as eluent (219.5 mg, 80 %).

[0099] 1 H-NMR (300 MHz, CDCl3): δ 7.86 (dq, J = 7.9, 1.0 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.29 (ddd, J = 7.9, 2.6, 1.0 Hz, 1H), 6.90 (dd, J = 2.6, 1.0 Hz, 1H), 3.86 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 167.0, 160.5, 130.5, 122.9, 119.8, 99.8, 55.8 ppm. Anal. calculated for C7H7NO2: C, 61.31; H, 5.15. Found: C, 61.24; H, 5.13. Comparative example 4 Synthesis of 2-chloro-5-nitrosobenzonitrile (D)

[0100] Following the general procedure, starting from 5-Amino-2-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene D was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl2 1:1 as eluent (196.5 mg, 59%).

[0101] 1 H-NMR (300 MHz, CDCl3): δ 8.28 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.5, 2.2 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 161.1, 144.0, 131.6, 127.0, 124.4, 115.1, 114.7 ppm. Anal. calculated for C7H3ClN2O: C, 50.48; H, 1.82. Found: C, 50.44; H, 1.79. Example 16 Radiofluorination

[0102] The radiofluorination reactions were investigated using a microliter-scale radiofluorination approach in HPLC vials

[22] , taking into account the parameters K₂CO₃ concentration for QMA elution (29.4 mM (normal) vs. 7.3 mM (¼ base)), reaction temperature (90°C, 110°C, 130°C), and solvent (MeCN, DMF, DMSO). The radiochemical conversion (RCC) was determined by radio-TLC and radio-HPLC after dilution of the reaction mixture with acetonitrile / water 50 / 50 (v / v). Product identification was achieved by adding standards to the reaction mixture using authentic non-radioactive reference substances. For selected compounds, isolated radiochemical yields were determined by radiolabeling under optimized conditions and subsequent purification by semi-preparative HPLC. 18F-labeled products were then analyzed with or without standard addition of the authentic reference in a second analytical radio-HPLC system for product identification. Table 2

[0103] The table below lists the maximum radiochemical conversion, radiochemical yield, reaction conditions with respect to solvent used, temperature, and the amount of base used. Table 2 Maximum radiochemical conversion (RCC) in % and specification of the analytical method (TLC / HPLC) for determination Isolated radiochemical yield (RCY) in % solvent Temperature°C QuantityBase Verb. 1 19 (HPLC) 12, 13 DMF 130 Normal Verb. 2 41 (HPLC) 22, 19 DMF 130 Normal Verb. 3 35 (HPLC) 12, 14 DMSO 90 Normal Verb. 4 8 (HPLC) 2, 18 DMSO 130 Normal Verb. 5 14 (DC) 4, 10 (at 110°C) DMF 130 Normal Verb. 6 2 (DC) Not determined DMF 130 Normal Verb. 7 45 (DC) 34, 52 DMF 130 Normal Verb. 8 22 (DC) 23, 27 DMSO 190 Normal Verb. 9 78 (DC) 45, 17 DMSO 110 Normal Verb. 10 45 (DC) 40, 43 DMSO 130 Normal Verb 11 2 (DC) Not determined DMF 130 Normal Verb. 12 14 (DC) Not determined DMSO 130 ¼ Verb. 13 70 (DC) 54, 50 DMF 130 Normal Verb. 14 6 (DC) Not determined DMF 130 Normal Verb. 15 8 (DC) Not determined DMSO 110 Normal Verb. 16 18 (DC) 22,21 DMSO 130 Normal Verb. 17 29 (DC) 18,21 DMSO 130 Normal Verb. 18 62 (HPLC) 46,45 DMSO 130 Normal

[0104] For compounds 1 to 18 listed in Table 2, the formation of a 18 F-marked product by [ 18[F]Fluor-for-nitroso exchange was observed and verified by standard addition and analysis using radio-HPLC. The RCC as a measure of efficacy ranged from 2% for precursor compound 11 to 78% for precursor compound 9. It is advantageous for the reaction to use the normal K₂CO₃ concentration and to carry out the radioactive labeling at higher temperatures of 110°C or 130°C in DMSO or DMF. Selected 18 F-labeled compounds were isolated after radiolabeling by semi-preparative radio-HPLC to obtain isolated radiochemical yields calculated from the decay-corrected product activity of the collected product-containing HPLC fraction divided by the initial activity.

[0105] For nitroso compounds A to D, a reaction product was found that is solely due to [ 18 Fluorine-for-nitroso exchange does not occur, but the formation of 18F-labeled byproducts were observed in 2–8% RCC. These results suggest that the starting substrates should contain an electron-withdrawing group in the ortho- or para-position to the NO group. This is consistent with an SNAr mechanism, where the NO group acts as a leaving group. List of abbreviations used DMF Dimethylformamide DMSO Dimethyl sulfoxide MeCN Acetonitril Oxon potassium peroxymonosulfate RCC radiochemical conversion RCY radiochemical yield HPLC High-Performance Liquid Chromatography TLC thin-layer chromatography PET positron emission tomography QMA quaternary methyl ammonium LG Departure Group SNAr nucleophilic aromatic substitution literature 1. Narayanam, M.K.; Ma, G.; Champagne, P.A.; Houk, K.N.; Murphy, J.M. Synthesis of [(18) F]Fluoroarenes by Nucleophilic Radiofluorination of N-Arylsydnones. Angew Chem Int Ed Engl 2017, 56, 13006-13010, doi:10.1002 / anie.201707274. 2. Mu, L.; Fischer, C.R.; Holland, J.P.; Becaud, J.; Schubiger, P.A.; Schibli, R.; Ametamey, S.M.; Graham, K.; Stellfeld, T.; Dinkelborg, L.M .; et al. 18F-Radiolabeling of Aromatic Compounds Using Triarylsulfonium Salts. European J Org Chem 2012, 2012, 889-892, doi:10.1002 / ejoc.201101730. 3. Sander, K.; Gendron, T.; Yiannaki, E.; Cybulska, K.; Kalber, T.L.; Lythgoe, M.F.; Arstad, E. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18. Sei Rep 2015, 5, 9941, doi:10.1038 / srep09941. 4. Ross, TL; Ermert , J. ; Hocke, C.; Coenen, HH Nucleophilic 18F-Fluorination of Heteroaromatic Iodonium Salts with Non-Carrier-Added [18F]Fluoride. J Am Chem Soc 2007, 129, 8018–8025. 5. Pike, VW; Aigbirhio, FI Reactions of cyclotron-produced [18F]fluoride with diaryliodonium salts - a novel single-step route to no-carrier-added

[18] fluoroarenes. J Chem Soc, Chem Commun 1995, 2215–2216. 6. Rotstein, BH; Stephenson, NA; Vasdev, N.; Liang, SH Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat Commun 2014, 5, 4365, doi:10.1038 / ncomms5365. 7. Kwon, Y.-D.; Son, J.; Chun, J.-H. Catalyst-Free Aromatic Radiofluorination via Oxidized Iodoarene Precursors. Org Lett 2018, doi:10.1021 / acs.orglett.8b03450. 8. Neumann, C.N.; Hooker, J.M.; Ritter, T. Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-). Nature 2016, 534, 369-373, doi:10.1038 / nature17667. 9. Terrier, F. Modern Nucleophilic Aromatic Substitution. 2013. 10. Kwan, E.E.; Zeng, Y.; Besser, H.A.; Jacobsen, E.N. Concerted nucleophilic aromatic substitutions. Nat Chem 2018, 10, 917-923, doi:10.1038 / s41557-018-0079-7. 11. Rohrbach, S.; Smith, A.J.; Pang, J.H.; Poole, D.L.; Tuttle, T.; Chiba, S.; Murphy, J.A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew Chem Int Ed Engl 2019, 58, 16368-16388, doi:10.1002 / anie.201902216. 12. Makosza, M. Does Nucleophilic Substitution in Nitroarenes Proceed via Single Electron Transfer (SET)? European J Org Chem 2021, 2021, 6175-6179, doi:10.1002 / ejoc.202101017. 13. Gao, Y.; Yang, S.; Xiao, W.; Nie, J.; Hu, X.Q. Radical chemistry of nitrosoarenes: concepts, synthetic applications and directions. Chem Commun (Camb) 2020, 56, 13719-13730, doi:10.1039 / d0cc06023b. 14. Roscales, S.; Csaky, A.G. How to make C-N bonds using boronic acids and their derivatives without transition metals. Chem Soc Rev 2020, 49, 5159-5177, doi:10.1039 / c9cs00735k. 15. Hays, J.T.; Young, H.L.; Espy, H.H. p-Nitrosophenol chemistry. II. Amination of p-nitrosophenol ethers with primary aromatic amines. J Org Chem 1967, 32, 158-162, doi:10.1021 / jo01277a039. 16. Zou, S.; Zhang, V.; Wu, Q.; Zhao, T.; Li, V.; Liu, B.; Ma, X. Metal-Free, Hindered, Regioselective Access to Multifunctional Groups Diarylamines via S(N) Ar Substitution of P-Nitroso Aromatic Methyl Ether by Arylamines. Chemistry 2024, 30, e202303421, doi:10.1002 / chem.202303421. 17. Raviola, C.; Protti, S. Leaving Groups in Metal-Free Arylations: Make Your Choice! European J Org Chem 2020, 2020, 5292-5304, doi:10.1002 / ejoc.202000143. 18. Priewisch, B.; Rück-Braun, K. Efficient Preparation of Nitrosoarenes for the Synthesis of Azobenzenes. J Org Chem 2005, 70, 2350-2352, doi:10.1021 / jo048544x. 19. Garcia-Lacuna, J.; Baumann, M. Continuous Flow Synthesis of Nitrosoarenes via Photochemical Rearrangement of Aryl Imines. J Org Chem 2024, 89, 617-623, doi:10.1021 / acs.joc.3c02362. 20. Gooden, D.M.; Chakrapani, H.; Toone, E.J. C-nitroso compounds: synthesis, physicochemical properties and biological activities. Curr Top Med Chem 2005, 5, 687-705, doi:10.2174 / 1568026054679353. 21. van der Werf, A.; Selander, N. Para-Selective Halogenation ofNitrosoarenes with Copper(II) Halides. Org Lett 2015, 17, 6210-6213, doi:10.1021 / acs.orglett.5b03198. 22. Laube, M.; Wodtke, R.; Kopka, K.; Kniess, T.; Pietzsch, J. SP-050 - 18F-Chemistry in HPLC vials - a microliter scale radiofluorination approach. Nucl Med Biol 2021, 96-97, S61, doi:htt ps: / / doi.org / 10.1016 / S0969-8051(21)0 0367- X. 23. Pathuri, G.; Hedrick, A.F.; Awasthi, V.; Gali, H. Single-step radiosynthesis and in vivo evaluation of a novel fluorine-18 labeled hippurate for use as a PET renal agent. Nucl Med Biol 2012, 39, 1195-1201, doi:10.1016 / j.nucmedbio.2012.07.002. 24. Pascali, C.; Luthra, S.K.; Pike, V.W.; Price, G.W.; Ahier, R.G.; Hume, S.P.; Myers, R.; Manjil, L.; Cremer, J.E. The radiosynthesis of [18F]PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites. Int J Rad Appl Instrum A 1990, 41, 477-482, doi:10.1016 / 0883-2889(90)90008-5.

Claims

[1] Method for the preparation of an organic compound having a group of the general formula I, wherein A an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms, selected from O, N or S, is; R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or consists of an aryl group; characterized by that an organic compound belonging to a group of the general formula II exhibits, where A, R1 and R2 have the meanings given above, is subjected to radiofluorination. [2] Method according to claim 1, characterized by, that the aryl or heteroaryl group A is a pyridinyl, indolyl, biphenylyl group or a 5- or 6-membered aromatic ring, optionally comprising a heteroatom selected from O, N or S. [3] Method according to any of the preceding claims, characterized by , that the aryl or heteroaryl group A is a 5- or 6-membered aromatic ring, which may optionally have an N atom. [4] Method according to any of the preceding claims, characterized by that the aryl or heteroaryl group A is phenyl. [5] Method according to any of the foregoing claims, characterized by , that R1 and R2 are independently selected from the group consisting of H, Chlorine, Methyl, Ethyl, Methoxy, Ethoxy, Trifluoromethyl, Carboxymethyl, Carboxyethyl, Oxomethyl, Nitro or Cyano. [6] Method according to any of the foregoing claims, characterized by, that R1 is in ortho position with respect to the functional group and R2 is in meta or para position with respect to R1. [7] Method according to claim 6, characterized by , that R1 is H or cyano and R2 is selected from the group consisting of H, chlorine, methyl, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, methyl ketone, nitro or cyano. [8] Method according to one of claims 6 and 7, characterized by , that R1 is H and R2 is selected from the group consisting of chlorine, trifluoromethyl, carboxyethyl, oxomethyl, nitro or cyano. [9] Method according to one of claims 6 and 7, characterized by , that R1 is cyano and R2 is selected from the group consisting of H, Chlorine, Methoxy, Trifluoromethyl, Carboxyethyl, Oxomethyl, Nitro or Cyano. [10] Method according to claim 9, characterized by , that R1 is cyano and R2 is selected from the group consisting of H, chlorine and methoxy. [11] Method according to claim 9, characterized by , that R1 is cyano in the ortho position with respect to the functional group and R2 is chlorine or methoxy in the para position with respect to R1. [12] Use of an organic compound having a group of general formula II, wherein A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; for the preparation of an organic compound having a group of the general formula I, wherein A, R1 and R2 have the meanings given above.

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