Electrochemical synthesis of pyrazolines and pyrazoles

Abstract

The present invention relates to an electrochemical process for the synthesis of pyrazolines and pyrazoles of formula (I). The method can be used in particular for the synthesis of the herbicide safener mefenpyr-diethyl. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an electrochemical method for synthesizing pyrazoline and pyrazole, and the method can be particularly used for synthesizing the herbicide safener mefenpyr-butyl. Background Art

[0002] Pyrazolines and pyrazoles are basic building blocks of complex agrochemical or pharmaceutical compounds and are therefore highly relevant for industrial applications.

[0003] Various methods for synthesizing pyrazoline and pyrazole are described in the prior art. For example, it is known to prepare pyrazoline and pyrazole by [3+2] cycloaddition starting from the corresponding hydrazonium halide using a base. However, the hydrazonium halide required for this method must be prepared in a complex manner, sometimes using toxic and expensive halogenating agents (WO 2010 / 127855). In addition, α, β-unsaturated ketones can be organically catalyzed with hydrazine to generate the corresponding pyrazoline, but the reaction must be carried out in anhydrous conditions and using complex catalyst systems and toxic halogenated solvents. In addition, some methods are also known to be able to prepare pyrazoline enantioselectively from alkyne components. These methods use expensive transition metal catalysts based on palladium, titanium, copper and iridium, some of which have complex ligand systems.

[0004] The known processes are generally characterized by the use of expensive transition metals, superstoichiometric amounts of (auxiliary) reagents, complex substrate synthesis or multi-stage synthesis sequences, and chemical halogenating agents, which are often used as excess components. The increased material input and the use of toxic solvents lead to increased reagent waste, which must be disposed of in a complex and expensive manner and is an obstacle to the economic efficiency of the process.

[0005] Therefore, there is a need for a less costly or less material intensive and less time consuming method for synthesizing pyrazoles and pyrazolines. It is therefore an object of the present invention to provide a new method for synthesizing which does not have the above mentioned disadvantages. Summary of the invention

[0006] This object is achieved at least in part by a process for preparing compounds of general formula (I)

[0007]

[0008] in is a single bond or a double bond;

[0009] R 1 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted;

[0010] R 2is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted;

[0011] R 3 is alkyl, -C(O)O-alkyl, -C(O)O-aryl, -C(O)N-(alkyl)2, -CN, -P(O)(O-alkyl)2, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0012] R 4 if is a single bond, then it exists, and R 4 is alkyl, -C(O)O-alkyl, C(O)O-aryl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0013] or R 3 and R 4 Connected to R in the compound of formula (I) 3 and R 4 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0014] R 5 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0015] or R 4 and R 5 Connected to R in the compound of formula (I) 4 and R 5 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0016] or R 1 and R 5 Connected to R in the compound of formula (I) 1 and R 5 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0017] It is characterized in that the compound of general formula (II)

[0018]

[0019] Where R 1 and R 2 The definition is the same as that of general formula (I), and an electrochemical reaction occurs with a compound of formula (III) or (IV) in the presence of an iodide source.

[0020]

[0021] Where R 3, R 4 and R 5 The definition of is the same as in the general formula (I).

[0022] Here, represents the cis or trans isomer of the compound of formula (III), that is, R 3 and R 5 They can be in cis or trans configurations, or R 4 and R 5 They can be in cis or trans configuration relative to each other.

[0023] In particular, the present invention relates to a method for preparing a compound of general formula (Ia)

[0024]

[0025] in

[0026] R 1 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted;

[0027] R 2 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted;

[0028] R 3 is alkyl, -C(O)O-alkyl, -C(O)O-aryl, -C(O)N-(alkyl)2, -CN, -P(O)(O-alkyl)2, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0029] R 4 is alkyl, -C(O)O-alkyl, -C(O)O-aryl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0030] or R 3 and R 4 Connected to R in the compound of formula (I) 3 and R 4 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0031] R 5 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H;

[0032] or R 4 and R 5 Connected to R in the compound of formula (I) 4 and R 5The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0033] or R 1 and R 5 Connected to R in the compound of formula (I) 1 and R 5 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group;

[0034] It is characterized in that the compound of general formula (II)

[0035]

[0036] Where R 1 and R 2 The definition is the same as that of general formula (Ia), and an electrochemical reaction occurs with a compound of formula (III) in the presence of an iodide source.

[0037]

[0038] Where R 3 , R 4 and R 5 The definition of is the same as in the general formula (I).

[0039] R 1 To R 5 The groups alkyl, -C(O)O-alkyl, -C(O)N-(alkyl)2, -C(O)O-aryl, cycloalkyl, aryl or heterocyclyl in the group may each be independently substituted by different substituents.

[0040] The present invention provides an electrochemical method for directly synthesizing pyrazoline and pyrazole from hydrazone and olefin or alkyne. The substrates required for the reaction can be constructed from common chemicals through simple condensation reactions, thus creating a value-added chain that makes it possible to abandon environmentally harmful transition metals and halogenating agents as well as toxic solvents.

[0041] In the present method, the iodide source plays a dual role as a conductive salt and a mediator, and is efficiently utilized, so that almost no expensive reagent waste is generated. The product is easy to purify, and the reagents used in superstoichiometric amounts can be recycled, which further improves the economic efficiency and sustainability of the method. Therefore, the present invention enables a simple, efficient and sustainable electrochemical synthesis of a library of related pyrazolines and pyrazoles.

[0042] Preferably, alone or in combination,

[0043] R 1 is unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted C3-C12 - cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl.

[0044] Preferably, alone or in combination,

[0045] R 2 is unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl.

[0046] Preferably, alone or in combination,

[0047] R 3 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted -C(O)O-phenyl, unsubstituted or substituted -C(O)O-benzyl, unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl.

[0048] Preferably, if is a single bond, either alone or in combination,

[0049] R 4 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted -C(O)O-phenyl, unsubstituted or substituted -C(O)O-benzyl, unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl.

[0050] Or, R 3 and R 4 Connected to R in the compound of formula (I) 3 and R 4 The carbon atoms of 12 - a cycloalkyl group or a heterocyclic group.

[0051] Preferably, alone or in combination,

[0052] R 5 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl.

[0053] Or, R 1 and R 5Connected to R in the compound of formula (I) 3 and R 5 The carbon atoms of 12 - a cycloalkyl group or a heterocyclic group.

[0054] Or, R 4 and R 5 Connect with R 4 and R 5 The carbon atoms of 12 - a cycloalkyl group or a heterocyclic group.

[0055] If R 1 and R 5 To form a ring system, preferably R 3 and R 4 No ring system is formed and vice versa.

[0056] Further preferably, alone or in combination,

[0057] R 1 C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or poly-substituted by C1-C4-alkyl, phenyl mono- or poly-substituted by halogen, phenyl mono- or poly-substituted by nitro, phenyl mono- or poly-substituted by cyano,

[0058] -C(O)O(C 1-4 -alkyl) mono- or poly-substituted phenyl or naphthyl.

[0059] In particular, R 1 It can be -C(O)OCH2CH3.

[0060] Further preferably, alone or in combination,

[0061] R 2 C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or poly-substituted by C1-C4-alkyl, phenyl mono- or poly-substituted by halogen, phenyl mono- or poly-substituted by nitro, phenyl mono- or poly-substituted by cyano,

[0062] -C(O)O(C 1-4 -alkyl) mono- or poly-substituted phenyl, mono- or poly-sulfo-substituted phenyl or naphthyl.

[0063] In particular, R 2 It may be dichlorophenyl.

[0064] Further preferably, alone or in combination,

[0065] R 3 C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or poly-substituted by C1-C4-alkyl, phenyl mono- or poly-substituted by halogen, phenyl mono- or poly-substituted by nitro, phenyl mono- or poly-substituted by cyano,

[0066] -C(O)O(C 1-4 -alkyl) mono- or poly-substituted phenyl or naphthyl.

[0067] In particular, R 3 It can be CH3.

[0068] More preferably, if is a single bond, either alone or in combination,

[0069] R 4 H, C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), -C(O)O-benzyl mono- or poly-substituted by C1-C4-alkyl, C(O)O-phenyl mono- or poly-substituted by C1-C4-alkyl, C3-C8-cycloalkyl, phenyl, phenyl mono- or poly-substituted by C1-C4-alkyl, phenyl mono- or poly-substituted by halogen, phenyl mono- or poly-substituted by nitro, phenyl mono- or poly-substituted by cyano, or -C(O)O(C 1-4 -alkyl) mono- or poly-substituted phenyl.

[0070] In particular, R 4 It can be -C(O)O(C 1-4 -alkyl), C(O)O-benzyl which is mono- or poly-substituted by C1-C4-alkyl, or C(O)O-phenyl which is mono- or poly-substituted by C1-C4-alkyl.

[0071] More preferably, R 4 It can be -C(O)OCH2CH3.

[0072] Further preferably, alone or in combination,

[0073] R 5 H, C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C 10 -cycloalkyl, phenyl, phenyl mono- or poly-substituted by C1-C4-alkyl, phenyl mono- or poly-substituted by halogen, phenyl mono- or poly-substituted by nitro, phenyl mono- or poly-substituted by cyano or -C(O)O(C 1-4 -alkyl) mono- or poly-substituted phenyl.

[0074] In particular, R 5 It can be H.

[0075] The iodide source is preferably used in the form of sodium iodide, lithium iodide or potassium iodide or a mixture thereof.

[0076] The use of sodium iodide, lithium iodide or potassium iodide to play the dual role of mediator and conductive salt saves resources and achieves efficient and simple recycling. In contrast, the electrochemical methods known in the prior art require high material inputs due to the separate roles of electrochemical mediator and conductive salt, which is an obstacle to the economic efficiency of the known methods.

[0077] Sodium iodide is particularly preferred.

[0078] The iodide source can be in an aqueous solution, in an organic solvent, in a solvent mixture of two or more organic solvents, or in a biphasic mixture of an aqueous solution and an organic solvent or a solvent mixture of two or more organic solvents.

[0079] In one embodiment of the invention, the iodide source is present in a biphasic mixture of an aqueous solution and an organic solvent or a solvent mixture of two or more organic solvents. Here, the iodide source is used in a concentration of 0.2 to 2.0 M, based on the aqueous solution; more preferably, the concentration is 0.5 to 1.4 M, based on the aqueous solution; in particular, the concentration is 0.8 to 1.4 M, based on the aqueous solution. The organic solvent is preferably selected from ethyl acetate, tert-butyl methyl ether, dichloromethane, chlorobenzene, 1,2-dichloroethane or a mixture thereof. Ethyl acetate and / or tert-butyl methyl ether are particularly preferred as organic solvents.

[0080] In an alternative embodiment, the iodide source is only in aqueous solution without adding organic solvent. Here, the iodide source is used in a concentration of 0.2 to 2.0 M, based on the aqueous solution; more preferably, the concentration is 0.5 to 1.4 M, based on the aqueous solution; in particular, the concentration is 0.8 to 1.4 M, based on the aqueous solution.

[0081] In another alternative embodiment, the iodide source is present in an organic solvent or a solvent mixture of two or more organic solvents, without adding water. Here, the iodide source is used at a concentration of 0.2 to 4.0 M, based on an organic solvent or solvent mixture; more preferably, the concentration is 0.5 to 3.5 M, based on an organic solvent or solvent mixture; in particular, when the concentration is 0.8 to 3.0 M, based on an organic solvent or solvent mixture. The organic solvent is preferably selected from ethanol, acetonitrile, ethyl acetate, tert-butyl methyl ether, dichloromethane, chlorobenzene, 1,2-dichloroethane or a mixture thereof. A mixture of ethanol and acetonitrile is particularly preferred as an organic solvent mixture, preferably in a mixing ratio of 1:10 to 10:1, more preferably 1:5 to 5:1, and particularly preferably 1:2 to 2:1 (vol / vol).

[0082] The amount of compound (III) or (IV) used is preferably 1.0 to 6.0 equivalents, more preferably 2.0 to 5.0 equivalents, based on the total amount of the compound of formula (II) used.

[0083] The reaction is preferably carried out in an undivided electrolytic cell.

[0084] Graphite electrodes are preferably used as anode and cathode.

[0085] Therefore, the method of the present invention is cost-effective in terms of electrode materials and the construction of a simple electrolytic cell.

[0086] Preference is given to using isostatic graphite.

[0087] The method is preferably carried out at 20 to 50 mA / cm 2 The current density is preferably 30 to 40 mA / cm 2 .

[0088] The method is preferably carried out until the amount of charge applied reaches 1 to 10F, preferably 2 to 6F.

[0089] The reaction is preferably carried out at a temperature of 10 to 50°C, more preferably 20 to 40°C.

[0090] These reaction conditions increase the yield of pyrazole or pyrazoline.

[0091] Preferably, if an aqueous phase is used, it is separated and freeze-dried to recover the iodide source. Alternatively, the aqueous phase may be separated and used without further treatment to carry out another reaction step or process according to the invention.

[0092] The recycling of the iodide source or of the aqueous phase makes it possible to produce the compounds in a particularly environmentally friendly manner.

[0093] Compound (I) or (Ia) is preferably diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (pyrazoline-butyl), compound (II) is ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate; compound (III) is ethyl methacrylate, wherein

[0094] R 1 is -C(O)O-ethyl;

[0095] R 2 It is 2,4-dichlorophenyl;

[0096] R 3 is CH3;

[0097] R 4 is -C(O)O-ethyl;

[0098] R 5 For H.

[0099] The compounds of formula (II) may generally exist as racemates or (E) or (Z) isomers, i.e.

[0100]

[0101] in indicates cis or trans isomers.

[0102] One of the isomers can preferably react in the process of the invention. In this respect, in other configurations of the invention, the yield of the synthesis can be increased by using one of the possible isomers of the general formula (II-a).

[0103] Compound (I) or (Ia) is particularly preferably diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (pyrazoline-methylenediamine), compound (II) is (Z)-ethyl glyoxylate 2,5-dichlorophenylhydrazone; compound (III) is ethyl methacrylate, wherein

[0104] R 1 is -C(O)O-ethyl;

[0105] R 2 It is 2,4-dichlorophenyl;

[0106] R 3 is CH3;

[0107] R 4 is -C(O)O-ethyl;

[0108] R 5 For H. DETAILED DESCRIPTION

[0109] The method of the present invention makes it possible to efficiently carry out the reaction in a two-phase solvent system consisting of water and an organic solvent. Here, an iodide source, preferably sodium iodide, is used as a conductive salt on the one hand and as an electrochemical mediator on the other hand.

[0110] Carrying out the reaction in an undivided electrolysis cell with a simple cell structure (two-electrode arrangement) under galvanostatic operation enables scalable reaction conditions. The possibility of recycling the mediator and the unreacted excess dipolephile contributes to the sustainability and economic viability of the process.

[0111] In particular, a high yield of 73% of the herbicide safener mefenpyr-butyl can be obtained using the method of the present invention.

[0112] The terms used herein are known to those skilled in the art. Otherwise, the following definitions apply:

[0113] In the context of the present invention, the term "alkyl" includes saturated hydrocarbon groups, which may be branched or straight-chain and unsubstituted or at least monosubstituted. Examples of suitable alkyl groups (which may be unsubstituted or monosubstituted or polysubstituted) are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, n-octyl, -C(H)(C2H5)2, -C(H)(n-C3H7)2 and -CH2-CH2-C(H)(CH3)-(CH2)3-CH3.

[0114] The term "cycloalkyl" refers to an optionally substituted carbocyclic saturated ring system preferably having 3-12, more preferably 3-8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In the case of an optionally substituted cycloalkyl, a ring system with a substituent is included, and a substituent with a double bond on the cycloalkyl group is also included, such as an alkylidene group, such as a methylene group. In the case of an optionally substituted cycloalkyl, a polycyclic aliphatic system is also included, such as bicyclo [1.1.0] butyl -1- base, bicyclo [1.1.0] butyl -2- base, bicyclo [2.1.0] pentyl -1- base, bicyclo [2.1.0] pentyl -2- base, bicyclo [2.1.0] pentyl -5- base, bicyclo [2.2.1] heptyl -2- base (norbornyl), bicyclo [2.2.2] octyl -2- base, adamantane -1- base and adamantane -2- base.

[0115] In the case of substituted cycloalkyl groups, spirocycloaliphatic systems are also included, for example spiro[2.2]pent-1-yl, spiro[2.3]hex-1-yl, spiro[2.3]hex-4-yl, 3-spiro[2.3]hex-5-yl.

[0116] In the context of the present invention, the term "aryl" refers to a monocyclic or polycyclic, preferably monocyclic or bicyclic aromatic hydrocarbon group preferably having 6, 10 or 14 carbon atoms. The aryl group may be unsubstituted or monosubstituted or polysubstituted by the same or different substituents. Suitable aryl groups are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl.

[0117] In the context of the present invention, the term "heterocyclyl" refers to a monocyclic or polycyclic ring system having 3 to 20 ring atoms, preferably 3 to 14 ring atoms, particularly preferably 3 to 10 ring atoms, comprising carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur, wherein the heteroatoms may be identical or different. The ring system may be saturated or mono- or polyunsaturated. The term "heterocyclyl" includes aliphatic and aromatic ring systems (heteroaryl) and combinations thereof, i.e. also those systems in which the aromatic ring is part of a bicyclic or polycyclic saturated, partially unsaturated and / or aromatic system.

[0118] Examples of suitable heterocycles are pyrrolidinyl, thiopyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuranyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl, dihydropyranyl.

[0119] Examples of suitable heteroaryl groups include indolizinyl, benzimidazolyl, tetrazolyl, triazinyl, isoxazolyl, phthalazinyl, carbazolyl, carbolyl, naphthazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thienyl, benzo[d]thiazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinazolinyl, quinolinyl, naphthyridinyl and isoquinolinyl.

[0120] Examples of aryl groups which are fused to a monocyclic or bicyclic ring system and which also fall within the scope of the term "heterocycle" or "heterocyclyl" include (2,3)-dihydrobenzo[b]thienyl, (2,3)-dihydro-1H-indenyl, dihydroindolinyl, (2,3)-dihydrobenzofuranyl, (2,3)-dihydrobenzo[d]oxazolyl, benzo[d][1,3]dioxolyl, benzo[d][1,3]oxathiolanyl, isoindolyl, (1,3)-dihydroisobenzofuranyl, (1,3)-dihydrobenzo[c]thienyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, chromanyl, thiobenzo[d]oxazolyl, benzo[d][1,3]dioxolyl, benzo[d][1,3]oxathiolanyl, isoindolyl, (1,3)-dihydroisobenzofuranyl, (1,3)-dihydrobenzo[c]thienyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, chromanyl, thiobenzo[d]oxazolyl, benzo[d][1,3]dihydrobenzo[d]oxazolyl, benzo[d][1,3]oxathiolanyl, isoindolyl, 4]oxathiinyl, (2,3)-dihydrobenzo[b][1,4]dioxinyl, (2,3)-dihydrobenzo[b][1,4]oxathiinyl, (6,7,8,9)-tetrahydro-5H-benzo[7]annulyl, (2,3,4,5)-tetrahydro-1H-benzo[b]azepine, and (2,3,4,5)-tetrahydro-1H-benzo[c]azepine.

[0121] If one of the abovementioned radicals is monosubstituted or polysubstituted, suitable substituents are all substituents familiar to the person skilled in the art, preferably each independently selected from the following radicals: F, Cl, Br, I, -NO2, -CN, -OH, -SH, -NH2, -O-alkyl, -phenyl, -benzyl, alkyl-substituted phenyl or benzyl, -N(C 1-5 -alkyl)2, -N(C 1-5 -alkyl)(phenyl), -N(C 1-5 -alkyl)(CH2-phenyl), -N(C 1-5 -alkyl)(CH2-CH2-phenyl), -NH-C(=O)-OC 1-5 -alkyl, -C(=O)-H, -C(=O)-C 1-5 -alkyl, -C(=O)-phenyl, -C(=S)-C 1-5 -alkyl, -C(=S)-phenyl, -C(=O)-OH, -C(=O)-OC 1-5 -alkyl, -C(=O)-O-phenyl, -C(=O)-NH2, -C(=O)-NH-C 1-5 -alkyl, -C(=O)-N(C 1-5 -alkyl)2, -S(=O)-C 1-5 -alkyl, -S(=O)-phenyl, -S(=O)2-C 1-5-alkyl, -S(=O)2-phenyl, -S(=O)2-NH2, -SO3H and -Si(C 1-5 -alkyl).

[0122] Example

[0123] The following examples illustrate the invention without limiting it.

[0124] Raw materials and solutions

[0125] Analytical grade chemicals were purchased and used from common suppliers such as TCI, Aldrich, and Acros.

[0126] The hydrazone used in the electrosynthesis is prepared from the corresponding aldehyde and hydrazine or hydrazine hydrochloride according to the synthesis methods known in the literature (PG Baraldi, S. Baraldi, G. Saponaro, M. Aghazadeh Tabrizi, R. Romagnoli, E. Ruggiero, F. Vincenzi, PA Borea, K Varani, Journal of Medicinal Chemistry 2015, 58, 5355-5360, W. Wu, X. Yuan, J. Hu, X. Wu, Y. Wei, Z. Liu, J. Lu, J. Ye, Organic Letters 2013, 15, 4524-4527).

[0127] Use isostatic graphite (Cgr, Sigrafine TM V2100, SGL Carbon, Bonn, Germany) was used as electrode material. Before any experiments, these were treated with sandpaper (grit 1000+1200, Bosch, Stuttgart, Germany) and the surface was then cleaned with a paper towel.

[0128] Liquid chromatography was performed on silica gel 60M (40-63 μm, Machery-Nagel GmbH & Co., Düren, Germany) using a Büchi chromatograph system with a Büchi control unit C 620, a Büchi UV photometer C 635, a Büchi fraction collector C 660 and two Büchi pump modules C 605 (Büchi-Labortechnik GmbH, Essen, Germany) or using a PURIFLASH C18-HP 30UM F0080 packed silica gel column (Interchim, Cedex, France), with the above-mentioned Büchi chromatography system.

[0129] High performance liquid chromatography was performed using a Shimadzu HPLC-MS with a SIL 20A HT autosampler, a CTO-20AC column oven, two LC-20AD pump modules for setting the eluent gradient, a diode array detector SPD-M20A, a CBM-20A system controller, and a Eurospher II 100-5C18 column (150×4 mm, Knauer, Berlin). Mobile phase: acetonitrile / water or acetonitrile / water / formic acid (1 vol%).

[0130] NMR spectroscopy for 1H-NMR, 13C-NMR, 15N-NMR, 19F-NMR and 31P-NMR spectra and all 2D NMR spectra were recorded at 25° C. using a Bruker Avance II HD 300 or Bruker Avance III HD 400 (400 MHz, 5 mm BBFO probe with z-gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany) in CDCl3, DMSO-d6, CD2Cl2, CD3CN, (CD3)2CO or CD3OD. 1H-NMR and 13C-NMR spectra were referenced to the residual solvent signal.

[0131] Electrospray ionization (ESI+ / -) or atmospheric pressure chemical ionization (APCI+ / -) mass spectrometry was performed using an Agilant 6545 QTOF-MS (Agilant, Santa Clara (CA), USA).

[0132] The electrolysis was carried out in a temperature-controlled double-jacketed glass electrolytic cell (SynLectro TM , Merck KGaA, Darmstadt, Germany) with a cross-shaped stirrer. The scale-up experiments were performed in a 300 mL double-jacketed glass electrolytic cell. A galvanostat from the TDK-Lambda Z+ series (TDK-Lambda UK Limited, Devon, UK) was used as a current source.

[0133] Two synthetic methods of the invention were used, variants A and B, which are described below:

[0134] Synthesis Method Variant A

[0135] To a 50 mL beaker electrolytic cell with a temperature control jacket and a cross-shaped magnetic stirrer, first add hydrazone (3 mmol, 1 equivalent) and appropriate olefin or alkyne (8.1 mmol, 2.7 equivalents). Add ethyl acetate (5 mL) and 1 M sodium iodide aqueous solution (20 mL). Use isostatically pressed graphite (60×20×3 mm, immersion depth 2.7 cm, active electrode area 5.4 cm 2 ) as anode and cathode, at 25 ° C and a stirring speed of 1000 rpm at 35 mA / cm 2 The mixture was electrolyzed at a constant current until an applied charge of 5F (1447C) was reached. The biphasic mixture was then transferred to a separatory funnel to separate the phases. The aqueous phase was extracted with ethyl acetate (1×30 mL), the combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. Further purification was performed by column chromatography.

[0136] Synthesis Method Variant B

[0137] To a 50 mL beaker electrolytic cell with a temperature control jacket and a cross-shaped magnetic stirrer, first add hydrazone (3.2 mmol, 1 equivalent) and appropriate olefin or alkyne (12.5 mmol, 3.9 equivalents). Add tert-butyl methyl ether (5 mL) and 1 M sodium iodide aqueous solution (20 mL). Use isostatically pressed graphite (60×20×3 mm, immersion depth 2.7 cm, active electrode area 5.4 cm 2 ) as anode and cathode, at 32°C and a stirring speed of 1000 rpm, at 32.1 mA / cm 2 The mixture was electrolyzed at a constant current until an applied charge of 2.58 F (797 C) was reached. The biphasic mixture was then transferred to a separatory funnel to separate the phases. The aqueous phase was extracted with ethyl acetate (1×30 mL), the combined organic phases were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. Further purification was performed by column chromatography.

[0138] Synthetic products

[0139] According to the synthetic method variant A of the present invention, an agrochemically relevant herbicide safener mefenpyr-butyl was successfully produced with a productivity of 73% (Scheme 1).

[0140]

[0141] Scheme 1: Preparation of pyraclostrobin

[0142] Likewise according to the synthetic method variant A of the present invention, ethyl glyoxylate phenylhydrazone is reacted with various olefins and alkynes to provide the corresponding pyrazoline or pyrazole (see Scheme 2). In particular, polymerization-sensitive olefins such as styrene (2), acrylates (12, 13, 14), acrylonitrile (15) and acrylamide (16) can be used in the method of the present invention. In addition, olefins (27) and vinylphosphonates (11) with silicon groups as well as various alicyclic compounds (22-25) can also be successfully reacted. Tolerance to halogens can also be demonstrated by the derivative 29. The results are summarized in Scheme 2.

[0143] Similarly, various benzaldehyde hydrazones and aliphatic aldehyde derivatives were converted into the corresponding pyrazoles and pyrazolines by the synthetic process variant B according to the invention (Scheme 3). In particular, relatively electron-deficient benzaldehyde derivatives can be obtained in good yields. The p-nitro derivative (44) can also be prepared in a yield of 53%. The intramolecular cyclization of a relatively electron-rich derivative was also achieved in a good yield of 53%. In addition to various aromatic aldehydes, aliphatic aldehydes can also be converted. The corresponding pyrazolines are obtained in yields of 23 to 38%. The results are summarized in Scheme 3.

[0144] In addition, the reaction of the synthetic method variants A and B according to the invention was tested for the use of hydrazones derived from various hydrazines with styrene as a dipolephile. Here, both electron-deficient and electron-rich hydrazones were converted in yields of up to 93% (Example 54). The results are summarized in Scheme 4.

[0145]

[0146] Scheme 2: Reaction of various dipolephiles with ethyl glyoxylate phenylhydrazone.

[0147]

[0148] Scheme 3: Product range of various benzaldehyde-pyrazolines.

[0149]

[0150] Scheme 4: Product scope of various hydrazine derivatives.

[0151] The syntheses of each of Schemes 1 to 4 are described in detail below.

[0152] Example 1: 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (pyrazoline-butyl)

[0153]

[0154] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (3 mmol, 783 mg, 1 eq.) and ethyl methacrylate (8.1 mmol, 925 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→4% EtOAc), the pyrazoline (2.28 mmol, 820 mg, 73%) was obtained as an orange oil.

[0155] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.41 (d, J=2.1Hz, 1H, H-3'), 7.25-7.19 (m, 2H, H-5', H-6'), 4.33 (qd, J=7.2, 1.7Hz, 2H, H-2”), 4.19 (q, J=7.2Hz, 2H, H- 2"'),3.73(d,J=17.7Hz,1H,(H-4)'),3.12(d,J=17.7Hz,1H,(H-4)"),1.4 6(s,3H,H-1””), 1.35(t,J=7.1Hz,3H,H-3”), 1.24(t,J=7.1Hz,3H,H-3”’).

[0156] 13 C-NMR (101MHz, CDCl3), δ / ppm: 171.5, 162.3, 140.1, 138.0, 133.6, 133.4, 130.5, 130.2, 127.5, 73.6, 62.3, 61.5, 45.1, 22.1, 14.5, 14.1.

[0157] HRMS (ESI+), m / z: calculated [C 16 H 18 35 Cl2N2O4+H] + 373.0716, measured 373.0718; calculated [C 16 H 18 35 Cl 37 ClN2O4+H] + 375.0690, measured 375.0692; calculated [C 16 H 18 37 Cl2N2O4+H] + 377.0669, measured 377.0674.

[0158] Example 2: 1,5-Diphenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0159]

[0160] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 eq.) and styrene (10.5 mmol, 1097 mg, 2.7 eq.). A charge of 5.4F (2032C) was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (3.02 mmol, 890 mg, 77%) was obtained as a yellow solid.

[0161] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.35-7.16(m,7H,H-3',H-2″',H-3″’,H-4″’),7 .10(dt,J=7.9,1.3Hz,2H,H-2'),6.87(tt,J=7.2,1.2Hz,1H,H-4'),5.42(dd,J= 13.3,7.0Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2''),3.72(dd,J=18.0,13.3Hz, 1H, (H-4)'), 3.05 (dd, J=18.0, 7.0Hz, 1H, (H-4)”), 1.37 (t, J=7.1Hz, 3H, H-3”).

[0162] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.9, 142.7, 141.3, 138.3, 129.4, 129.1, 128.1, 125.8, 121.4, 114.7, 65.5, 61.4, 42.4, 14.5.

[0163] HRMS (APCI+), m / z: calculated [C 18 H 18 N2O2+H] + 295.1441, measured 295.1447.

[0164] Recycling of sodium iodide:

[0165] The synthesis according to the synthetic method variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). Sodium iodide recovered from the reaction mixture of the synthesis of pyrazoline 32 by freeze drying the aqueous phase was used. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.40 mmol, 707 mg, 80%) was obtained as a yellow solid.

[0166] Scale-up experiment (47mmol):

[0167] Analogously to the synthetic method variant A, a 300 mL beaker electrolytic cell with a temperature-controlled jacket and a magnetic stirrer with a stabilizing ring was first charged with ethyl 2-(2-phenylhydrazono)acetate (46.8 mmol, 9.0 g, 1 equivalent) and styrene (126.3 mmol, 13.16 g, 2.7 equivalents). Ethyl acetate (60 mL) and a 1 M aqueous sodium iodide solution (240 mL) were added. At 25° C. and a stirring speed of 750 rpm, a precipitate consisting of four pieces of isostatically pressed graphite (each 100×50×5 mm, immersion depth 7 cm, total active electrode area 105 cm 2 ) composed of a bipolar electrode stack at 35 mA / cm 2 The mixture was electrolyzed at a constant current until an applied charge of 5.4 F was reached (24 488C). The biphasic mixture was transferred to a separatory funnel to separate the phases, and the aqueous phase was extracted with ethyl acetate (1×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline (36.0 mmol, 10.6 mg, 77%) was obtained as a yellow solid.

[0168] Example 3: 5-(4-(tert-butyl)phenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0169]

[0170] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 4-tert-butylstyrene (8.1 mmol, 1298 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.10 mmol, 735 mg, 70%) was obtained as a yellow solid.

[0171] 1H-NMR (400MHz, CDCl3), δ / ppm:7.36-7.33(m,2H,H-2"'),7.21-7.12(m,6H,H-2' ,H-3',H-3"'),6.88(tt,J=7.1,1.3Hz,1H,H-4'),5.40(dd,J=13.2,6.9Hz,1H,H -5),4.34(q,J=7.1Hz,2H,H-2”),3.70(dd,,J=18.0,13.3Hz,1H,(H-4)'),3.05( dd, J=18.0, 6.9Hz, 1H, (H-4)”), 1.38 (t, J=7.1Hz, 3H, H-3”), 1.30 (s, 9H, H-6”’).

[0172] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.8, 150.9, 142.7, 138.2, 138.2, 129.0, 126.2, 125.3, 121.2, 114.6, 65.1, 61.2, 42.3, 34.6, 31.4, 14.5.

[0173] HRMS (APCI+), m / z: calculated [C 22 H 26 N2O2+H] + 351.2067, measured 351.2058.

[0174] Example 4: 5-(Naphthalen-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0175]

[0176] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 2-vinylnaphthalene (8.1 mmol, 1249 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.34 mmol, 462 mg, 45%) was obtained as a yellow solid.

[0177] 1H-NMR(400MHz, CDCl3), δ / ppm:7.87-7.75(m,3H,H-3"',H-6"',H-7"'),7.70(d ,J=1.7Hz,1H,H-2”'),7.51-7.45(m,2H,H-4”’,H-5”’),7.34(dd,J=8.5,1.8Hz ,1H,H-8"'),7.18-7.14(m,4H,H-2',H-3'),6.88-6.84(m,1H,H-4'),5.58(dd, J=13.2,7.1Hz,1H,H-5),4.35(q,J=7.1Hz,2H,H-2”),3.79(dd,J=18.0,13.3Hz 1H, (H-4)'), 3.12 (dd, J = 18.1, 7.1Hz 1H, (H-4)”), 1.38 (t, J = 7.1Hz, 3H, H-3”).

[0178] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.8,142.7,138.7,138.3,133.5,133.1,129.7,129 .1,128.1,127.9,126.7,126.4,124.7,123.5,121.4,114.7,65.7,61.4,42.4,14.5.

[0179] HRMS (ESI+), m / z: calculated [C 22 H 20 N2O2+H] + 345.1598, measured 345.1598.

[0180] Example 5: 5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0181]

[0182] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 4-methoxystyrene (8.1 mmol, 1087 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.34 mmol, 433 mg, 45%) was obtained as a yellow solid.

[0183] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.20-7.08 (m, 6H, H-2', H-3', H-2"'), 6.90-6.82 (m, 3H, H-4', H-3"'), 5.37 (dd, J=13.2, 7.0Hz, 1H, H-5), 4.34 (q, J=7.1Hz,2H,H-2”),3.77(s,3H,H-5”’),3.69(dd,J=13.2,7.0Hz,1H,(H-4)’),3.02(dd,J=18.0,7.0Hz,1H,(H-4)”),1.37(t,J=7.1Hz,3H,H-3”).

[0184] 13C-NMR (101MHz, CDCl3), δ / ppm: 162.9, 159.3, 142.7, 138.2, 133.4, 129.0, 127.0, 121.3, 114.7, 114.7, 65.0, 61.3, 55.4, 42.4, 14.5.

[0185] HRMS (ESI+), m / z: calculated [C 19 H 20 N2O3+H] + 325.1547, measured 325.1544.

[0186] Example 6: 5-(2,6-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0187]

[0188] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 2,6-dichlorostyrene (8.1 mmol, 1402 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.77 mmol, 643 mg, 59%) was obtained as a yellow solid.

[0189] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.38 (dd, J=8.0, 1.4Hz, 1H, H-3"'), 7.24 (dd, J=8.1, 1.4Hz, 1H ,H-5"'),7.20-7.14(m,3H,H-3',H-4"'),7.06-7.02(m,2H,H-2'),6.87(tt,J=7.3,1.0Hz,1H ,H-4'),6.22(dd,J=14.6,10.3Hz,1H,H-5),4.37(qd,J=7.1,3.0Hz,2H,H-2″),3.66(dd,J=18 .1,14.6Hz,1H,(H-4)'),3.20(dd,J=18.1,10.3Hz,1H,(H-4)“),1.39(t,J=7.1Hz,3H,H-3“).

[0190] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.8, 142.3, 138.1, 135.1, 135.0, 134.6, 130.9, 129.8, 129.1, 128.6, 121.6, 114.6, 61.3, 61.0, 38.7, 14.5.

[0191] HRMS (ESI+), m / z: calculated [C 18 H 16 35 Cl2N2O2+Na] + 385.0481, measured 385.0486; calculated [C 18 H 16 35 Cl 37 ClN2O2+Na] + 387.0455, measured 387.0460; calculated [C 18 H 16 37 Cl2N2O2+Na] + 389.0434, measured 389.0454.

[0192] Example 7: 1,5,5-Triphenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0193]

[0194] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 1,1-stilbene (8.1 mmol, 1460 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.87 mmol, 323 mg, 29%) was obtained as a yellow oil.

[0195] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.46-7.41(m,4H,H-2”'),7.41-7.23(m,6H,H-3”’,H-4”’),7.06-6.98(m,4H,H- 2',H-3'),6.82-6.76(m,1H,H-4'),4.34(q,J=7.1Hz,2H,H-2”),3.94(s,2H,H-4),1.37(t,J=7.1Hz,3H,H-3”).

[0196] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.9, 142.3, 142.2, 137.2, 128.6, 128.3, 128.2, 127.8, 121.5, 117.0, 79.1, 61.3, 56.2, 14.5.

[0197] HRMS (ESI+), m / z: calculated [C 24 H 22 N2O2+H] + 371.1754, measured 371.1753.

[0198] Example 8: Ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate

[0199]

[0200] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 eq.) and phenylacetylene (10.5 mmol, 1070 mg, 2.7 eq.). A charge of 5.4 F was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.99 mmol, 288 mg, 25%) was obtained as a yellow oil.

[0201] 1H-NMR(400MHz, CDCl3), δ / ppm:7,36-7,28(m,8H,H-2',H-3',H-2"',H-3"'),7,23-7,20(m,2 H, H-4', H-4"'), 7.05 (s, 1H, H-4), 4.46 (q, J = 7.1Hz, 2H, H-2"), 1.43 (t, J = 7.1Hz, 3H, H-3").

[0202] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.6, 144.8, 144.5, 139.7, 129.7, 129.1, 128.9, 128.8, 128.7, 128.5, 125.9, 110.1, 61.3, 14.6.

[0203] HRMS (APCI+), m / z: calculated [C 18 H 16 N2O2+H] + 293.1285, measured 293.1290.

[0204] Example 9: Ethyl 1-phenyl-1H-pyrazole-3-carboxylate

[0205]

[0206] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and vinyl acetate (8.1 mmol, 697 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→10% EtOAc), the pyrazole (0.96 mmol, 208 mg, 32%) was obtained as a yellow solid.

[0207] In this case, the initially formed acetylated pyrazole spontaneously deacetylated to give the compound ethyl 1-phenyl-1H-pyrazole-3-carboxylate.

[0208] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.93 (d, J=2.5Hz, 1H, H-5), 7.78-7.70 (m, 2H, H-2'), 7.53-7.42 (m, 2H, H-3'), 7.40-7.30(m,1H,H-4'),6.99(d,J=2.5Hz,1H,H-4),4.44(q,J=7.1Hz,2H,H-2”),1.42(t,J=7.1Hz,3H,H-3”).

[0209] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.4, 145.4, 139.8, 129.6, 128.5, 127.8, 120.3, 110.5, 61.3, 14.5.

[0210] HRMS (APCI+), m / z: calculated [C 12 H 12 N2O2+H] + 217.0972, measured 217.0986.

[0211] Example 10: 5-Butyl-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

[0212]

[0213] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 1-hexyne (8.1 mmol, 665 mg, 2.7 eq.). Electrolysis was performed at 50° C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline (0.26 mmol, 71 mg, 9%) was obtained as a dark yellow oil.

[0214] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.51-7.37(m,5H,H-2',H-3',H-4'),6.75(s,1H,H-4),4.40(q,J=7.1Hz,2H,H-2”),2.60(t,J=7.7Hz,2H,H -1"'), 1.56(tt,J=7.6,7.6Hz,2H,H-2"'), 1.39(t,J=7.1Hz,3H,H-3"), 1.30(qt,J=7.4,7.4Hz,2H,H-3"'), 0.85(t,J=7.3Hz,3H,H-4"').

[0215] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.8, 145.8, 144.0, 139.4, 129.2, 128.8, 126.1, 107.9, 61.0, 30.8, 25.9, 22.2, 14.5, 13.8.

[0216] HRMS (ESI+), m / z: calculated [C 16 H 20 N2O2+H] +273.1598, measured 273.1598.

[0217] Example 11: 5-(diethoxyphosphoryl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0218]

[0219] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and diethyl vinylphosphonate (8.1 mmol, 1330 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (5%→30% EtOAc) and reverse phase flash column chromatography on C-18 silica with acetonitrile / water (25%→60% acetonitrile), pyrazoline (1.32 mmol, 469 mg, 44%) was obtained as a yellow oil.

[0220] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.44-7.36 (m, 2H, H-2'), 7.32-7.27 (m, 2H, H-3'), 6.98 (tt, J=7.3, 1.1Hz, 1H, H-4'), 4.69 (dd, J=13.7, 7.2Hz, 1H, H-5) ,4.34(qd,J=7.1,0.7Hz,2H,H-2”),4.19-3.95(m,4H,H-1”’),3.67-3.39(m ,2H,H-4),1.37(t,J=7.1Hz,3H,H-3″),1.24(dt,J=9.8,7.1Hz,6H,H-2″’).

[0221] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.3, 143.4, 140.3 (d, J = 5.5Hz), 129.0, 122.2, 115.9, 63.5 (d, J = 7.3Hz), 6 3.0 (d, J = 7.0Hz), 61.5, 58.3 (d, J = 164.0Hz), 35.4 (d, J = 3.3Hz), 16.6 (d, J = 5.5Hz), 16.5 (d, J = 5.5Hz), 14.5.

[0222] 31 P-NMR (162MHz, CDCl3), δ / ppm: 19.69.

[0223] HRMS (ESI+), m / z: calculated [C 16 H 23 N2O5P+H]+ 355.1417, measured 355.1421.

[0224] Example 12: 3-ethyl 5-methyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

[0225]

[0226] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 eq.) and methyl acrylate (10.5 mmol, 904 mg, 2.7 eq.). A charge of 5.4 F was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline (3.46 mmol, 957 mg, 89%) was obtained as a yellow oil.

[0227] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.32-7.25 (m, 2H, H-3'), 7.13 (dt, J=7.9, 1.1Hz, 2H,H-2'),6.97(tt,J=7.3,1.1Hz,1H,H-4'),4.94(dd,J=13.6,6.6Hz,1H,H-5),4 .34(qd,J=7.1,0.7Hz,2H,H-2”),3.74(s,3H,H-2”’),3.55(dd,J=18.1,13.5Hz, 1H, (H-4)'), 3.32 (dd,, J=18.2, 6.6Hz, 1H, (H-4)”), 1.38 (t, J=7.1Hz, 3H, H-3”).

[0228] 13 C-NMR (101MHz, CDCl3), δ / ppm: 170.8, 162.2, 142.5, 138.6, 129.4, 121.9, 114.0, 62.3, 61.6, 53.1, 37.4, 14.5.

[0229] HRMS (APCI+), m / z: calculated [C 14 H 16 N2O4+H] + 277.1183, measured 277.1192.

[0230] Example 13: 3-ethyl 5,5-dimethyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

[0231]

[0232] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and methyl methacrylate (8.1 mmol, 811 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.44 mmol, 709 mg, 81%) was obtained as a yellow oil.

[0233] 1 H-NMR (400MHz, CD2Cl2), δ / ppm: 7.31-7.25 (m, 2H, H-3'), 7.10-7.06 (m, 2H, H-2'), 6.98 (tt, J=7.3, 1.1Hz, 1H, H-4'), 4.30 (q, J=7.1Hz, 2H, H -2”), 3.76 (s, 3H, H-2”’), 3.54 (d, J = 17.8Hz, 1H, (H-4)’), 3.18 (d, J = 17.8Hz, 1H, (H-4)”), 1.64 (s, 3H, H-1””), 1.35 (t, J = 7.1Hz, 3H, H-3”).

[0234] 13 C-NMR (101MHz, CD2Cl2), δ / ppm: 173.2, 162.5, 141.9, 137.5, 129.5, 122.3, 115.8, 70.8, 61.5, 53.4, 47.4, 21.6, 14.5.

[0235] HRMS (ESI+), m / z: calculated [C 15 H 18 N2O4+H] + 291.1339, measured 291.1344.

[0236] Example 14: 3-ethyl 5-methyl 5-(2-methoxy-2-oxoethyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

[0237]

[0238] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and dimethyl itaconate (8.1 mmol, 1281 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→8% EtOAc), the pyrazoline (2.73 mmol, 950 mg, 91%) was obtained as a yellow oil.

[0239] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.26-7.18(m,2H,H-3'),7.12--7.07(m,2H,H-2'),7. 01-6.95(m,1H,H-4'),4.30(q,J=7.1Hz,2H,H-2”),3.72(d,J=18.4Hz,1H,(H-1””)’) ,3.70(s,3H,H-3””),3.65(d,J=18.4Hz,1H,(H-1””)”),3.59(s,3H,H-2”’),3.25(d, J=16.6Hz, 1H, (H-4)'), 2.87 (d, J=16.6Hz, 1H, (H-4)”), 1.33 (t, J=7.1Hz, 3H, H-3”).

[0240] 13 C-NMR (101MHz, CDCl3), δ / ppm: 171.4, 169.7, 162.0, 141.5, 138.9, 129.2, 123.1, 116.9, 71.3, 61.3, 53.3, 51.9, 44.7, 37.8, 14.3.

[0241] HRMS (ESI+), m / z: calculated [C 17 H 20 N2O6+H] + 349.1394, measured 349.1395.

[0242] Example 15: 5-Cyano-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0243]

[0244] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and acrylonitrile (8.1 mmol, 430 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.68 mmol, 653 mg, 90%) was obtained as a yellow solid.

[0245] 1H-NMR(400MHz, CDCl3), δ / ppm:7.39-7.33(m,2H,H-3'),7.24(dt,J=8.8,1.0Hz,2H,H-2'),7.10-7.04(m,1H,H-4'),5.07( ddd,J=10.6,8.2,0.6Hz,1H,H-5),4.35(q,J=7.1Hz,2H,H-2”),3.61-3.50(m,2H,H-4),1.38(td,J=7.1,0.7Hz,3H,H-3”).

[0246] 13 C-NMR (101MHz, CDCl3), δ / ppm: 161.3, 141.5, 140.0, 129.6, 123.2, 116.2, 115.0, 61.9, 50.4, 37.9, 14.3.

[0247] HRMS (ESI+), m / z: calculated [C 13 H 13 N3O2+Na] + 266.0900, measured 266.0896.

[0248] Example 16: 5-(Dimethylcarbamoyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0249]

[0250] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and N,N-dimethylacrylamide (8.1 mmol, 803 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.73 mmol, 501 mg, 58%) was obtained as a yellow solid.

[0251] 1H-NMR(400MHz, CDCl3), δ / ppm:7.29-7.22(m,2H,H-3'),7.08-7.03(m,2H,H-2') ,6.96-6.90(m,1H,H-4'),5.13(dd,J=14.0,7.9Hz,1H,H-5),4.32(qd,J=7.1,1.7 Hz,2H,H-2”),3.54(dd,J=17.8,14.0Hz,1H,(H-4)'),3.12(dd,J=17.9,7.9Hz,1 H, (H-4)”), 3.06 (s, 3H, H-2”’), 2.97 (s, 3H, H-3”’), 1.35 (t, J = 7.1Hz, 3H, H-3”).

[0252] 13 C-NMR (101MHz, CDCl3), δ / ppm: 168.9, 162.3, 142.6, 137.6, 129.3, 121.7, 114.0, 61.9, 61.3, 36.9, 36.9, 36.4, 14.4.

[0253] HRMS (APCI+), m / z: calculated [C 15 H 19 N3O3+H] + 290.1499, measured 290.1491.

[0254] Example 17: 3-ethyl 4,5-dimethyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate

[0255]

[0256] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and dimethyl maleate (8.1 mmol, 1167 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→12% EtOAc), the product was obtained as an orange oil (2.00 mmol, 669 mg, 66%) as a 1.9:1 mixture of 4,5-cis-substituted and 4,5-trans-substituted pyrazoline (via 1 H NMR determination).

[0257] Analysis of 3-ethyl 4,5-dimethyl 4,5-cis-1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate data:

[0258] 1H-NMR (400MHz, CD3CN), δ / ppm: 7.37-7.29 (m, 2H, H-3'), 7.06 (dt, J = 7.8, 1. 1Hz,2H,H-2'),7.02(tt,J=7.2,1.1Hz,1H,H-4'),5.41(d,J=13.8Hz,1H,H- 5),4.70(d,J=13.8Hz,1H,H-4),4.26(dddd,J=17.9,10.8,7.1,3.7Hz,2H,H -2”), 3.71 (s, 3H, H-2””), 3.66 (s, 3H, H-2”’), 1.29 (t, J = 7.1Hz, 3H, H-3”).

[0259] 13 C-NMR (101MHz, CD3CN), δ / ppm: 169.6, 168.5, 161.9, 143.0, 137.7, 130.3, 123.0, 115.0, 66.2, 62.2, 54.7, 53.6, 14.4.

[0260] HRMS (ESI+), m / z: calculated [C 16 H 18 N2O6+H] + 335.1238, measured 335.1241.

[0261] Example 18: 3-ethyl 4,5-dimethyl 4,5-trans-1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate

[0262]

[0263] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and dimethyl fumarate (8.1 mmol, 1167 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→10% EtOAc), the pyrazoline (2.10 mmol, 701 mg, 70%) was obtained as a yellow oil.

[0264] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.33-7.28 (m, 2H, H-3'), 7.18-7.13 (m, 2H, H-2'), 7.04-6.98 (m, 1H, H-4'), 5.17 (d, J=5.8Hz, 1H, H-5), 4.39 (d, J = 5.8Hz, 1H, H-4), 4.44-4.25 (m, 2H, H-2”), 3.79 (s, 3H, H-2”’), 3.76 (s, 3H, H-2””), 1.36 (t, J = 7.1Hz, 3H, H-3”).

[0265] 13 C-NMR (101MHz, CDCl3), δ / ppm: 169.1, 169.0, 161.4, 141.8, 135.6, 129.4, 122.5, 114.5, 66.5, 61.7, 54.3, 53.4, 14.4.

[0266] HRMS (ESI+), m / z: calculated [C 16 H 18 N2O6+Na] + 357.1057, measured 357.1057.

[0267] Example 19: 3a,8b-cis-1-phenyl-1,3a,4,8b-tetrahydroindeno[1,2-c]pyrazole-3-carboxylic acid ethyl ester

[0268]

[0269] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and indene (8.1 mmol, 941 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.60 mmol, 491 mg, 52%) was obtained as a light yellow solid.

[0270] 1H-NMR (400MHz, CD2Cl2), δ / ppm: 7.45-7.35 (m, 5H, H-2', H-3', H-8), 7.32-7.23 (m, 2H, H-6, H-7), 7.14-7.08 (m, 1H, H-5), 7.02 (tt, J=7 .0,1.5Hz,1H,H-4'),6.12(d,J=10.6Hz,1H,H-8b),4.39-4.25(m,3H,H-3a,H-2”),3.53-3.41(m,2H,H-4),1.36(t,J=7.1Hz,3H,H-3”).

[0271] 13 C-NMR (101MHz, CD2Cl2), δ / ppm: 162.9, 143.0, 142.7, 142.0, 140.2, 129.7, 129.2, 127.5, 125.7, 125.4, 121.9, 115.5, 70.1, 61.2, 48.9, 36.4, 14.6.

[0272] HRMS (ESI+), m / z: calculated [C 19 H 18 N2O2+H] + 307.1441, measured 307.1434.

[0273] Example 20: 4,5-trans-5-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0274]

[0275] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and trans-anethole (8.1 mmol, 1200 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline (0.43 mmol, 165 mg, 16%) was obtained as a yellow oil.

[0276] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.22-7.16 (m, 2H, H-3'), 7.15-7.09 (m, 4H, H-2', H-2””), 6.90-6.81 (m, 3H, H-4’, H-3””), 4.86 (d, J=5.8Hz, 1H, H-5) ,4.34(qd,J=7.1,2.8Hz,2H,H-2”),3.77(s,3H,H-5””),3.27(qd,J=7.1,5 .7Hz,1H,H-4),1.44(d,J=7.1Hz,3H,H-1”'),1.38(t,J=7.1Hz,3H,H-3”).

[0277] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.7, 159.4, 142.6, 142.3, 132.6, 129.0, 126.7, 121.3, 114.7, 73.2, 61.1, 55.4, 50.3, 19.2, 14.4.

[0278] HRMS (APCI+), m / z: calculated [C 20 H 22 N2O3+H] + 339.1703, measured 339.1695.

[0279] Example 21: 4,5-trans-1,4,5-triphenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (21)

[0280]

[0281] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 eq.) and trans-stilbene (10.5 mmol, 1893 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.37 mmol, 137 mg, 9%) was obtained as an orange solid.

[0282] 1H-NMR (400MHz, CDCl3), δ / ppm: 7,40-7,14(m,14H,H-2',H-3',H-2"',H-3"',H-4"',H-2"",H-3"",H-4""),6,91(tt,J=7,0,1 ,5Hz,1H,H-4'),5,29(d,J=5,2Hz,1H,H-5),4,32(d,J=5.2Hz,1H,H-4),4,28-4,10(m,2H,H-2”),1,21(t,J=7,1Hz,3H,H-3”).

[0283] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.3, 142.2, 141.0, 140.7, 140.3, 129.6, 129 .3,129.2,128.3,127.8,127.3,125.4,121.6,114.8,74.9,61.1,61.0,14.2.

[0284] HRMS (APCI+), m / z: calculated [C 24 H 22 N2O2+H] + 371.1754, measured 371.1760.

[0285] Example 22: 3a,7a-cis-1-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindazole-3-carboxylic acid ethyl ester

[0286]

[0287] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 eq.) and norbornene (10.5 mmol, 998 mg, 2.7 eq.). A charge of 5.4 F (2032 C) was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (3.55 mmol, 1010 mg, 91%) was obtained as a yellow solid.

[0288] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.32-7.27 (m, 2H, H-3'), 7.23-7.18 (m, 2H, H-2'), 6.93 (tt, J = 7. 3,1.2Hz,1H,H-4'),4.39-4.26(m,2H,H-2”),4.23(d,J=10.0Hz,1H,H-7a),3.42(d,J=9.9Hz,1H ,H-3a),2.82-2.77(m,1H,H-7),2.71-2.66(m,1H,H-4),1.67-1.54(m,2H,(H-5)',(H-6)'),1.4 6-1.29(m,3H,(H-5)”,(H-6)”,(H-8)’),1.37(t,J=7.1Hz,3H,H-3”),1.27-1.18(m,1H,(H-8)”).

[0289] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.1, 142.4, 141.1, 129.2, 121.0, 114.0, 69.2, 61.0, 54.3, 41.6, 40.9, 33.2, 27.7, 24.7, 14.5.

[0290] HRMS (ESI+), m / z: calculated [C 17 H 20 N2O2+H] + 285.1598, measured 285.1599.

[0291] Example 23: 3a,9a-cis-5,8-diacetoxy-1-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-methanobenzo[f]indazole-3-carboxylic acid ethyl ester

[0292]

[0293] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 5,8-diacetoxybenzo[e]norbornene (8.1 mmol, 2092 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline (2.43 mmol, 1089 mg, 81%) was obtained as a yellow solid.

[0294] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.32 (m, 4H, H-2', H-3'), 6.98 (m, 1H, H-4'), 6.89 (d, J=8.8Hz, 1H, H-6), 6.86 (d ,J=8.8Hz,1H,H-7),4.80(d,J=9.9Hz,1H,H-9a),4.45-4.26(m,2H,H-2”),3.88(d,J=9.9Hz,1H,H-3a),3.84(br s,1H,H-4),3.83(br s,1H,H-9),2.42(s,3H,H-2”’),2.38(s,3H,H-2””),1.83(s,2H,H-10),1.41(t,J=7.1Hz,3H,H-3”).

[0295] 13 C-NMR (101MHz, CDCl3), δ / ppm:169.6,169.2,162.7,142.8,142.6,142.0,141.0,138.9,137 .8,129.3,121.6,121.5,120.8,114.4,68.6,61.1,54.1,47.3,46.2,43.5,20.9,20.9,14.6.

[0296] HRMS (APCI+), m / z: calculated [C 25 H 24 N2O6+H] + 449.1707, measured 449.1696.

[0297] Example 24: 3a,9a-cis-1-phenyl-3a,4,5,6,7,8,9,9a-octahydro-1H-cyclooctane[c]pyrazole-3-carboxylic acid ethyl ester

[0298]

[0299] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and cis-cyclooctene (8.1 mmol, 893 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.02 mmol, 306 mg, 34%) was obtained as a yellow oil.

[0300] 1H-NMR(400MHz, CDCl3), δ / ppm:7.34-7.27(m,2H,H-3'),7.16-7.11(m,2H, H-2'),6.95(tt,J=7.3,1.1Hz,1H,H-4'),4.44-4.25(m,3H,H-9a,H-2”),3. 46(ddd,J=12.6,11.0,1.6Hz,1H,H-3a),2.37-2.26(m,1H,(H-4)'),1.92- 1.40(m,11H,(H-4)”,H-5,H-6,H-7,H-8,H-9),1.37(t,J=7.1Hz,3H,H-3”).

[0301] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.2, 142.7, 142.2, 129.1, 121.6, 115.8, 65.6, 61.0, 48.5, 29.3, 27.8, 25.7, 25.5, 24.5, 23.5, 14.5.

[0302] HRMS (ESI+), m / z: calculated [C 18 H 24 N2O2+H] + 301.1911, measured 301.1910.

[0303] Example 25: 3a,7a-cis-1-phenyl-6,6,7a-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-5,7-methanoindazole-3-carboxylic acid ethyl ester

[0304]

[0305] The synthesis according to the synthetic method variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and (-)-α-pinene (8.1 mmol, 1103 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc) and purification by preparative HPLC (water (+1% by volume of formic acid) / acetonitrile 70%→100% MeCN), the pyrazoline (0.11 mmol, 36 mg, 4%) was obtained as a yellow solid.

[0306] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.28-7.23 (m, 4H, H-2', H-3'), 7.03-6.97 (m, 1H, H-4'), 4.42-4.27 (m, 2H, H-2”), 3.39 (dd, J= 10.7,5.0Hz,1H,H-3a),2.57(dd,J=6.2,4.6Hz,1H,H-7),2.46(dddd,J=13.8,10.8,3.1,2.1Hz,1H,(H-4)'),2.25(dddd,J=1 0.6,6.3,6.3,2.1Hz,1H,(H-8)'),1.96(dddd,J=7.8,3.1,3.1,3.0Hz,1H,H-5),1.75(dddd,J=13.8,5.0,3.0Hz,1H,(H-4)”), 1.40(s,3H,H-1″'), 1.38(t,J=7.1Hz,3H,H-3″), 1.32(s,3H,H-6′), 1.04(s,3H,H-6″), 0.96(dd,J=9.4,4.8Hz,1H,(H-8)″).

[0307] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.4, 142.3, 141.9, 128.9, 122.8, 118.7, 76.3, 60.9, 49.7, 46.3, 38.5, 38.1, 33.4, 28.5, 27.9, 26.1, 23.7, 14.6.

[0308] HRMS (APCI+), m / z: calculated [C 20 H 26 N2O2+H] + 327.2067, measured 327.2069.

[0309] Example 26: (1R,5S)-6,6-dimethyl-2'-phenyl-1',2'-dihydrospiro[bicyclo[3.1.1]heptane-2,3'-pyrazole]-5'-carboxylic acid ethyl ester

[0310]

[0311] The synthesis according to the synthetic method variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and (-)-β-pinene (8.1 mmol, 1103 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc) and purification by preparative HPLC (water / acetonitrile 70%→100% MeCN), the pyrazoline (0.21 mmol, 68 mg, 7%) was obtained as a yellow solid.

[0312] 1 H-NMR (400MHz, CDCl3), δ / ppm: 8.41 (s, 1H, H-1'), 7.33-7.24 (m, 2H, H-3”), 7.15-7.10 (m, 2H, H-2”), 6.96 (tt, J=7.4, 1.2Hz, 1H, H-4”), 5. 46-5.41(m,1H,H-4'),4.31(q,J=7.1Hz,2H,H-2"'),3.50(dq,J=16.5,2.4Hz,1H,(H-3)'),3.27(dq,J=16.4,1.9Hz,1H,(H-3)"),2.38(dt ,J=8.8,5.6Hz,1H,(H-7)'),2.31(dp,J=18.0,3.0Hz,1H,(H-4)'),2.23(dp,J=17.9,2.6Hz,1H,(H-4)”),2.11(ttd,J=5.6,2.7,1.2Hz,1H ,H-5),2.04(td,J=5.6,1.6Hz,1H,H-1),1.38(t,J=7.1Hz,3H,3"'),1.27(s,3H,H-6'),1.13(d,J=8.8Hz,1H,(H-7)"),0.86(s,3H,H-6").

[0313] 13 C-NMR (101MHz, CDCl3), δ / ppm: 165.5, 143.3, 142.6, 133.2, 129.4, 122.1, 119.4, 113.9, 61.4, 45.6, 40.7, 38.2, 33.2, 31.8, 31.6, 26.2, 21.1, 14.5.

[0314] HRMS (APCI+), m / z: calculated [C 20 H 26 N2O2+H] + 327.2067, measured 327.2054.

[0315] Example 27: 1-phenyl-5-((trimethylsilyl)methyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0316]

[0317] Synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and allyltrimethylsilane (8.1 mmol, 926 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.03 mmol, 315 mg, 34%) was obtained as a yellow oil.

[0318] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.29 (tt, J=7.3, 2.0Hz, 2H, H-3'), 7.18-7.12 (m,2H,H-2'),6.94(tt,J=7.3,1.2Hz,1H,H-4'),4.60(dddd,J=11.8,11.8,5 .2,1.8Hz,1H,H-5),4.34(qd,J=7.1,2.2Hz,2H,H-2”),3.29(dd,J=17.4,11. 7Hz,1H,(H-4)'),2.78(dd,J=17.4,5.1Hz,1H,(H-4)”),1.38(t,J=7.1Hz,3H H-3”), 1.24(dd,J=14.6,1.8Hz,1H,(H-1”’)’), 0.90(dd,J=14.6,11.8Hz,1H,(H-1”’)”), 0.11(s,9H,H-2”’).

[0319] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.4, 141.9, 138.4, 129.3, 121.3, 115.1, 61.2, 58.8, 39.0, 21.2, 14.6, -0.8.

[0320] HRMS (ESI+), m / z: calculated [C 16 H 24 N2O2Si+H] + 305.1680, measured 305.1684.

[0321] Example 28: 5-Butyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0322]

[0323] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 1-hexene (8.1 mmol, 682 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.95 mmol, 261 mg, 32%) was obtained as a yellow oil.

[0324] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.32-7.27(m,2H,H-3'),7.21-7.17(m,2H,H-2'),6.94(tt,J=7.3,1.2Hz ,1H,H-4'),4.51(dddd,J=12.1,9.3,5.2,2.6Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2”),3.28(dd,J=17.6 ,12.2Hz,1H,(H-4)'),2.93(dd,J=17.7,5.2Hz,1H,(H-4)”),1.87-1.72(m,1H,(H-1”’)’),1.61-1.46(m ,1H,(H-1”')”),1.38(t,J=7.1Hz,3H,H-3”),1.35-1.21(m,4H,H-2”’,H-3”’),0.99-0.79(m,3H,H-4”’).

[0325] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.3, 142.2, 138.5, 129.3, 121.3, 114.8, 61.2, 61.2, 36.8, 31.7, 26.7, 22.6, 14.5, 14.1.

[0326] HRMS (APCI+), m / z: calculated [C 16 H 22 N2O2+H] + 275.1754, measured 275.1758.

[0327] Example 29: 5-(4-bromobutyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0328]

[0329] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and 6-bromo-1-hexene (8.1 mmol, 1321 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.99 mmol, 348 mg, 33%) was obtained as a yellow oil.

[0330] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.33-7.27 (m, 2H, H-3'), 7.20-7.16 (m, 2H, H-2'), 6.94 (tt, J=7.3, 1.1Hz, 1H, H -4'),4.53(dddd,J=11.9,8.9,5.2,2.6Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2”),3.37(td,J=6.7,2.4Hz,2H,H- 4"'),3.30(dd,J=17.8,12.3Hz,1H,(H-4)'),2.94(dd,J=17.7,5.2Hz,1H,(H-4)"),1.89-1.72(m,3H,(H-1"')' ,H-3"'),1.62-1.51(m,1H,(H-1"')"),1.46(dtd,J=12.1,9.3,6.1Hz,2H,H-2"'),1.37(t,J=7.1Hz,3H,H-3").

[0331] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.1, 142.1, 138.6, 129.3, 121.4, 114.8, 61.2, 60.9, 36.8, 33.3, 32.3, 31.0, 23.2, 14.5.

[0332] HRMS (ESI+), m / z: calculated [C 16 H 21 79 BrN2O2+H] + 353.0859, measured 353.0864; calculated [C 16 H 21 81 BrN2O2+H] + 355.0839, measured 355.0845.

[0333] Example 30: Ethyl 5-cyclohexyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

[0334]

[0335] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and vinylcyclohexane (8.1 mmol, 893 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.85 mmol, 254 mg, 28%) was obtained as an orange solid.

[0336] 1 H-NMR (400MHz, CDCl3), δ / ppm:7.34-7.24(m,2H,H-3'),7.25--7.17(m,2H,H -2'),6.94(tt,J=7.2,1.2Hz,1H,H-4'),4.50(ddd,J=12.1,6.7,3.5Hz,1H,H- 5),4.33(q,J=7.1Hz,2H,H-2”),3.10(dd,J=18.0,12.1Hz,1H,(H-4)'),3.05( dd,J=18.1,6.6Hz,1H,(H-4)"),2.01(m,1H,H-1"'),1.83-1.75(m,1H,(H-3"' b )'),1.70-1.61(m,2H,(H-2“' b )'),(H-3“' a )'),1.60-1.55(m,1H,(H-4"')'),1.37(t,J=7.1Hz,3H,H-3"),1.43-1.31(m,1H,(H-2"' a )'),1.30-1.18(m,1H,(H-3“' b ) "), 1.15-1.00 (m, 3H, (H-2 "' b )“,(H-3”' a )")(H-4"')"),1.00-0.86(m,1H,(2"' a )“).

[0337] 13 C-NMR (101MHz, CDCl3), δ / ppm: 163.1, 142.4, 138.7, 129.2, 121.2, 115.1, 65.6, 61.1, 38.3, 32.4, 28.6, 26.4, 26.2, 25.6, 24.7, 14.5.

[0338] HRMS (ESI+), m / z: calculated [C 18 H24 N2O2+H] + 301.1911, measured 301.1906.

[0339] Example 31: 5-(9H-carbazol-9-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0340]

[0341] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 eq.) and N-vinylcarbazole (8.1 mmol, 1565 mg, 2.7 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.68 mmol, 643 mg, 56%) was obtained as an orange solid.

[0342] 1 H-NMR (400MHz, DMSO-d6), δ / ppm: 8.18 (d, J=7.6Hz, 1H, H-4"'), 8.15 (d, J=7.7Hz, 1H, H-5"'), 8.07 (d, J=8.3Hz, 1H, H-1"'), 7.66- 7.55(m,2H,H-5,H-2"'),7.36(ddd,J=8.4,7.2,1.3Hz,1H,H-7"'),7.34-7.30(m,1H,H-3"'),7.19(ddd,J=7.9,7.3,0.9Hz,1H,H-6 "'),7.12-7.03(m,2H,H-3'),7.07-6.99(m,2H,H-2'),6.98(dd,J=8.3,0.9Hz,1H,H-8"'),6.78(tt,J=7.1,1.3Hz,1H,H-4'),4.34 (q,J=7.1Hz,2H,H-2”), 3.85(dd,J=19.4,12.9Hz,1H,(H-4)’), 3.19(dd,J=19.4,5.9Hz,1H,(H-4)”), 1.32(t,J=7.1Hz,3H,H-3”).

[0343] 13C-NMR (101MHz, DMSO-d6), δ / ppm:161.6,141.2,139.6,139.5,136.4,129.2,126.5,126.4,12 3.8,122.5,121.7,120.8,120.6,120.2,120.1,113.9,109.8,109.2,69.5,60.9,37.4,14.2.

[0344] HRMS (APCI+), m / z: calculated [C 24 H 21 N3O2+H] + 384.1707, measured 384.1703.

[0345] Example 32: 1,3,5-Triphenyl-4,5-dihydro-1H-pyrazole

[0346]

[0347] The synthesis according to Synthesis Method Variant B used benzaldehyde phenylhydrazone (3.2 mmol, 625 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (65%→72% acetonitrile), pyrazoline (2.36 mmol, 704 mg, 74%) was obtained as a yellow solid.

[0348] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.76-7.70(m,2H,H-2”),7.42-7.37(m,2H,H-3”),7.37 -7.30(m,5H,H-4”,H-2”’,H-3”’),7.30-7.24(m,1H,H-4”’),7.23-7.16(m,2H,H-3’), 7.11-7.06(m,2H,H-2'),6.79(tt,J=7.2,1.2Hz,1H,H-4'),5.28(dd,J=12.4,7.3Hz,1 H,H-5),3.85(dd,J=17.1,12.4Hz,1H,(H-4)'),3.15(dd,J=17.0,7.3Hz,1H,(H-4)”).

[0349] 13C-NMR (101MHz, CDCl3), δ / ppm: 146.8, 145.0, 142.7, 132.9, 129.3, 129.0, 128.7, 128.7, 127.7, 126.0, 125.9, 119.2, 113.5, 64.6, 43.7.

[0350] HRMS (ESI+), m / z: calculated [C 21 H 18 N2+H] + 299.1543, measured 299.1542.

[0351] Scale-up (38 mmol):

[0352] Analogously to the synthetic method variant B, a 300 mL beaker electrolytic cell with a temperature-controlled jacket and a magnetic stirrer with a stabilizing ring was first charged with benzaldehyde phenylhydrazone (38.2 mmol, 7.5 g, 1 equivalent) and styrene (149 mmol, 15.52 g, 3.9 equivalents). Tert-butyl methyl ether (60 mL) and a 1 M aqueous sodium iodide solution (240 mL) were added. At 32° C. and a stirring speed of 750 rpm, a 4-well plate consisting of four pieces of isostatically pressed graphite (each 100×50×5 mm, immersion depth 7 cm, total active electrode area 105 cm 2 ) composed of a bipolar electrode stack at 35 mA / cm 2 The mixture was electrolyzed at a constant current until an applied charge of 2.6 F (9587C) was reached. The biphasic mixture was transferred to a separatory funnel to separate the phases, and the aqueous phase was extracted with ethyl acetate (1×100 mL). The combined organic phase was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Unreacted styrene (8.0 g, 76.8 mmol, 2 equivalents) was recovered by vacuum distillation. After recrystallization from isopropanol, pyrazoline (26.4 mmol, 7.89 g, 69%) was obtained as a yellow solid. The aqueous phase separated by freeze drying was used to recover the sodium iodide (36.3 g, 242 mmol, quantitative). A sample (3.0 g, 20 mmol) was repeatedly used for the synthesis of pyrazoline 1 (see above).

[0353] Example 33: 3-(4-methylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0354]

[0355] The synthesis according to Synthesis Method Variant B used 4-methylbenzaldehyde phenylhydrazone (3.2 mmol, 673 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (50%→72% acetonitrile), pyrazoline (2.15 mmol, 672 mg, 67%) was obtained as a yellow solid.

[0356] 1 H-NMR(400MHz,DMSO-d6),δ / ppm:7.66-7.61(m,2H,H-2”),7.36-7.31(m,2H,H-3”’), 7.30-7.21(m,5H,H-3”,H-2”’,H-4”’),7.17-7.11(m,2H,H-3’),7.01-6.96(m,2H,H- 2'),6.70(tt,J=7.2,1.1Hz,1H,H-4'),5.44(dd,J=12.2,6.4Hz,1H,H-5),3.89(dd,J =17.4,12.2Hz,1H,(H-4)'),3.07(dd,J=17.4,6.4Hz,1H,(H-4)”),2.33(s,3H,H-5”).

[0357] 13 C-NMR (101MHz, DMSO-d6), δ / ppm: 147.3, 144.4, 142.6, 138.3, 129.5, 129.2, 129.0, 128.8, 127.4, 125.8, 125.7, 118.4, 112.9, 63.1, 43.1, 21.0.

[0358] HRMS (ESI+), m / z: calculated [C 22 H 20 N2+H] + 313.1699, measured 313.1701.

[0359] Example 34: 3-(4-tert-Butylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0360]

[0361] The synthesis according to Synthesis Method Variant B used 4-tert-butylbenzaldehyde phenylhydrazone (3.2 mmol, 808 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (75%→85% acetonitrile), pyrazoline (0.80 mmol, 285 mg, 25%) was obtained as a yellow solid.

[0362] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.63-7.59(m,2H,H-2”),7.38-7.33(m,2H,H-3”),7.31-7.22( m,4H,H-2"',H-3"'),7.20(td,J=5.3,3.0Hz,1H,H-4"'),7.12(tt,J=7.3,2.1Hz,2H,H-3'),7. 05-6.98(m,2H,H-2'),6.71(tt,J=7.3,1.2Hz,1H,H-4'),5.20(dd,J=12.3,7.1Hz,1H,H-5),3. 78(dd,J=17.0,12.3Hz,1H,(H-4)'), 3.08(dd,J=17.0,7.1Hz,1H,(H-4)”), 1.28(s,9H,H-6”).

[0363] 13 C-NMR (101MHz, CDCl3), δ / ppm: 152.0, 146.9, 145.1, 142.8, 130.1, 129.2, 129.0, 127.6, 126.0, 125.7, 125.6, 119.0, 113.4, 64.5, 43.8, 34.9, 31.4.

[0364] HRMS (ESI+), m / z: calculated [C 25 H 26 N2+H] + 355.2169, measured 355.2175.

[0365] Example 35: 3-(4-phenylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0366]

[0367] The synthesis according to Synthesis Method Variant B used 4-phenylbenzaldehyde phenylhydrazone (3.2 mmol, 872 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (70%→100% acetonitrile), pyrazoline (0.65 mmol, 244 mg, 20%) was obtained as a dark yellow solid.

[0368] 1 H-NMR(400MHz,DMSO-d6),δ / ppm:7.86-7.81(m,2H,H-2”),7.76-7.70(m,4H,H-3”,H- 6”),7.53-7.21(m,8H,H-7”,H-8”,H-2”’,H-3”’,H-4”’),7.20-7.12(m,2H,H-3’),7. 08-6.97(m,2H,H-2'),6.72(tt,J=7.3,1.2Hz,1H,H-4'),5.51(dd,J=12.2,6.3Hz,1H ,H-5),3.96(dd,J=17.5,12.2Hz,1H,(H-4)'),3.15(dd,J=17.5,6.3Hz,1H,(H-4)”).

[0369] 13 C-NMR(101MHz,DMSO-d6),δ / ppm:146.9,144.1,142.6,140.1,131.4,129.0,128 .9,128.5,127.4,126.8,126.5,126.3,125.9,125.3,118.7,113.0,63.2,43.0.

[0370] HRMS (ESI+), m / z: calculated [C 27 H 22 N2+H] + 375.1856, measured 375.1848.

[0371] Example 36: 3-(Naphthalen-2-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0372]

[0373] The synthesis according to Synthesis Method Variant B used 2-formylnaphthophenylhydrazone (3.2 mmol, 788 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.79 mmol, 275 mg, 25%) was obtained as a yellow solid.

[0374] 1 H-NMR (400MHz, CDCl3), δ / ppm: 8.18 (dd, J=8.6, 1.7Hz, 1H, H-8”), 7.88-7.77 (m, 4H, H-2”, H-3”, H-6 ”,H-7”),7.50-7.45(m,2H,H-4”,H-5”),7.37-7.32(m,4H,H-2”’,H-3”’),7.30-7.24(m,1H,H-4”’) ,7.24-7.17(m,2H,H-3'),7.15-7.10(m,2H,H-2'),6.80(tt,J=7.2,1.2Hz,1H,H-4'),5.34(dd,J=1 2.4, 7.2Hz, 1H, H-5), 3.97 (dd, J=16.9, 12.4Hz, 1H, (H-4)'), 3.28 (dd, J=16.9, 7.2Hz, 1H, (H-4)").

[0375] 13 C-NMR (101MHz, CDCl3), δ / ppm:146.9,144.9,142.7,133.6,133.5,130.6,129.3,129.1,1 28.3,128.2,128.0,127.7,126.6,126.5,126.0,125.2,123.6,119.3,113.6,64.7,43.7.

[0376] HRMS (ESI+), m / z: calculated [C 25 H 20 N2+H] + 349.1699, measured 349.1707.

[0377] Example 37: 3-(4-Fluorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0378]

[0379] The synthesis according to Synthesis Method Variant B used 4-fluorobenzaldehyde phenylhydrazone (3.2 mmol, 686 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline (2.44 mmol, 772 mg, 76%) was obtained as an orange solid.

[0380] 1 H-NMR (400MHz, CD2Cl2), δ / ppm:7.77-7.67(m,2H,H-2”),7.39-7.24(m,5H,H-2” ',H-3”',H-4”’),7.19-7.14(m,2H,H-3’),7.13-7.07(m,2H,H-3”),7.07-7.02( m,2H,H-2'),6.76(tt,J=7.3,1.2Hz,1H,H-4'),5.31(dd,J=12.3,7.3Hz,1H,H-5 ), 3.85(dd,J=17.1,12.3Hz,1H,(H-4)'), 3.12(dd,J=17.1,7.1Hz,1H,(H-4)”).

[0381] 13 C-NMR (101MHz, CD2Cl2), δ / ppm: 164.6, 162.1, 146.4, 145.2, 143.0, 129.5, 129.2,128.0,127.9,127.8,126.3,119.4,116.0,115.8,113.6,64.8,44.0.

[0382] 19 F-NMR (376MHz, CD3CN), δ / ppm: -115.4.

[0383] HRMS (APCI+), m / z: calculated [C 21 H 17 FN2+H] + 317.1449, measured 317.1446.

[0384] Example 38: 3-(4-chlorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0385]

[0386] The synthesis according to Synthesis Method Variant B used 4-chlorobenzaldehyde phenylhydrazone (3.2 mmol, 738 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.25 mmol, 749 mg, 70%) was obtained as a colorless solid.

[0387] 1 H-NMR(400MHz, (CD3)2CO), δ / ppm:7.82-7.74(m,2H,H-2”),7.47-7.37(m,2H,H-3”), 7.39-7.29(m,4H,H-2"',H-3"'),7.32-7.20(m,1H,H-4"'),7.19-7.09(m,2H,H-3'),7 .10-7.03(m,2H,H-2'),6.73(tt,J=7.2,1.3Hz,1H,H-4'),5.47(dd,J=12.4,6.8Hz,1 H,H-5), 3.96(dd,J=17.4,12.4Hz,1H,(H-4)'), 3.13(dd,J=17.4,6.8Hz,1H,(H-4)”).

[0388] 13 C-NMR (101MHz, (CD3)2CO), δ / ppm: 206.3, 146.8, 145.5, 143.7, 134.5, 132.7, 129.9, 129.6, 129.5, 128.4, 128.1, 126.8, 119.8, 114.2, 65.0, 43.9.

[0389] HRMS (ESI+), m / z: calculated [C 21 H 17 35 ClN2+H] + 333.1153, measured 333.1151; calculated [C 21 H 17 37 ClN2+H] + 335.1131, measured 335.1133.

[0390] Example 39: 3-(4-bromophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0391]

[0392] The synthesis according to Synthesis Method Variant B used 4-bromobenzaldehyde phenylhydrazone (3.2 mmol, 880 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline (1.95 mmol, 737 mg, 61%) was obtained as a yellow solid.

[0393] 1 H-NMR (400MHz, DMSO-d6), δ / ppm:7.73-7.64(m,2H,H-2”),7.64-7.58(m,2H,H-3 ”),7.38-7.21(m,5H,H-2”’,H-3”’,H-4”’),7.19-7.10(m,2H,H-3’),7.07-6.96 (m,2H,H-2'),6.72(tt,J=7.3,1.1Hz,1H,H-4'),5.50(dd,J=12.3,6.4Hz,1H,H- 5), 3.91(dd,J=17.5,12.4Hz,1H,(H-4)'), 3.10(dd,J=17.5,6.4Hz,1H,(H-4)”).

[0394] 13 C-NMR (101MHz, DMSO-d6), δ / ppm: 146.2, 144.0, 142.4, 131.6, 131.5, 129.0, 128.9, 127.6, 127.5, 125.8, 121.7, 118.8, 113.0, 63.3, 42.7.

[0395] HRMS (ESI+), m / z: calculated [C 21 H 17 79 BrN2+H] + 377.0648, measured 377.0650; calculated [C 21 H 17 81 BrN2+H] + 379.0630, measured 379.0632.

[0396] Example 40: 3-(2,6-dichlorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0397]

[0398] The synthesis according to Synthesis Method Variant B used 2,6-dichlorobenzaldehyde phenylhydrazone (3.2 mmol, 848 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (50%→80% acetonitrile), pyrazoline (2.60 mmol, 955 mg, 81%) was obtained as a yellow oil.

[0399] 1 H-NMR (400MHz, DMSO-d6), δ / ppm: 7.60-7.56 (m, 2H, H-3”), 7.48 (dd, J=8.9, 7.2Hz, 1H, H -4”),7.42-7.33(m,4H,H-2”’,H-3”’),7.30-7.24(m,1H,H-4”’),7.17-7.08(m,2H,H-3 '),6.96-6.89(m,2H,H-2'),6.72(tt,J=7.2,1.1Hz,1H,H-4'),5.53(dd,J=12.4,6.8Hz ,1H,H-5),3.85(dd,J=17.9,12.4Hz,1H,(H-4)'),2.97(dd,J=17.9,6.9Hz,1H,(H-4)”).

[0400] 13 C-NMR (101MHz, DMSO-d6), δ / ppm: 144.4, 144.3, 142.3, 134.5, 131.5, 131.1, 128.9, 128.9, 128.5, 127.5, 126.1, 119.0, 113.0, 63.3, 45.9.

[0401] HRMS (ESI+), m / z: calculated [C 21 H 16 35 Cl2N2+H] + 367.0763, measured 367.0758; calculated [C 21 H 16 35 Cl 37 ClN2+H] + 369.0738, measured 369.0735; calculated [C 21 H 16 37 Cl2N2+H] + 371.0718, measured 371.0725.

[0402] Example 41: 1,5-diphenyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole

[0403]

[0404] The synthesis according to Synthesis Method Variant B used 4-trifluoromethylbenzaldehyde phenylhydrazone (3.2 mmol, 846 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline (1.21 mmol, 445 mg, 38%) was obtained as a yellow solid.

[0405] 1 H-NMR (400MHz, CD2Cl2), δ / ppm:7.88-7.79(m,2H,H-2”),7.68-7.62(m,2H,H-3” ),7.39-7.25(m,5H,H-2"',H-3"',H-4"'),7.22-7.14(m,2H,H-3'),7.11-7.05( m,2H,H-2'),6.80(tt,J=7.2,1.2Hz,1H,H-4'),5.39(dd,J=12.5,6.9Hz,1H,H-5 ), 3.88(dd,J=17.2,12.5Hz,1H,(H-4)'), 3.16(dd,J=17.2,7.0Hz,1H,(H-4)”).

[0406] 13 C-NMR (101MHz, CD2Cl2), δ / ppm: 145.6, 144.6, 142.7, 136.8, 123.0 (q, J = 32.5Hz), 129.5, 129 .3,128.8,126.3,126.1,125.8(q,J=3.9Hz),124.7(q,J=271.9Hz),119.9,113.9,64.9,43.5.

[0407] 19 F-NMR (376MHz, CD2Cl2), δ / ppm: -64.0.

[0408] HRMS (APCI+), m / z: calculated [C 22 H 17 F3N2+H] + 367.1417, measured 367.1411.

[0409] Example 42: 3-(4-cyanophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0410]

[0411] The synthesis according to Synthesis Method Variant B used 4-cyanobenzaldehyde phenylhydrazone (3.2 mmol, 708 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline (1.79 mmol, 579 mg, 56%) was obtained as a bright yellow solid.

[0412] 1 H-NMR (400MHz, DMSO-d6), δ / ppm: 7.89 (d, J=8.6Hz, 2H, H-2”), 7.85 (d, J=8.6Hz, 2H, H- 3"),7.34(dd,J=8.0,6.8Hz,2H,H-3"'),7.32-7.21(m,3H,H-2"',H-4"'),7.22-7.13(m ,2H,H-3'),7.09-7.01(m,2H,H-2'),6.81-6.72(m,1H,H-4'),5.60(dd,J=12.5,6.3Hz, 1H,H-5), 3.93(dd,J=17.6,12.5Hz,1H,(H-4)'), 3.15(dd,J=17.6,6.3Hz,1H,(H-4)”).

[0413] 13 C-NMR (101MHz, DMSO-d6), δ / ppm: 145.4, 143.4, 142.1, 136.7, 132.5, 129.1, 129.0, 127.6, 126.1, 125.8, 119.4, 118.9, 113.3, 110.1, 63.5, 42.3.

[0414] HRMS (APCI+), m / z: calculated [C 22 H 17 N3+H] + 324.1495, measured 324.1487.

[0415] Example 43: Methyl 4-(1,5-diphenyl-4,5-dihydro-1H-pyrazol-3-yl)benzoate

[0416]

[0417] The synthesis according to Synthesis Method Variant B used methyl 4-formylbenzoate phenylhydrazone (3.2 mmol, 814 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.32 mmol, 826 mg, 72%) was obtained as a bright yellow solid.

[0418] 1 H-NMR(400MHz,DMSO-d6),δ / ppm:8.02-7.95(m,2H,H-3”),7.89-7.83(m,2H,H-2”),7.39- 7.31(m,2H,H-3"'),7.31-7.21(m,3H,H-2"',H-4"'),7.21-7.14(m,2H,H-3'),7.08-7.01 (m,2H,H-2'),6.75(tt,J=7.1,1.2Hz,1H,H-4'),5.58(dd,J=12.4,6.2Hz,1H,H-5),3.95( dd,J=17.5,12.5Hz,1H,(H-4)'),3.86(s,3H,H-6”),3.15(dd,J=17.5,6.3Hz,1H,(H-4)”).

[0419] 13 C-NMR(101MHz,DMSO-d6),δ / ppm:165.9,146.0,143.6,142.2,136.7,129.5 ,129.1,128.9,128.9,127.5,125.8,125.7,119.2,113.2,63.3,52.2,42.6.

[0420] HRMS (APCI+), m / z: calculated [C 23 H 20 N2O2+H] + 357.1598, measured 357.1597.

[0421] Example 44: 3-(4-nitrophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0422]

[0423] The synthesis according to Synthesis Method Variant B used 4-nitrobenzaldehyde phenylhydrazone (3.2 mmol, 772 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), pyrazoline (1.70 mmol, 588 mg, 53%) was obtained as a red solid. Recrystallization from methanol gave red needles.

[0424] 1 H-NMR(400MHz,DMSO-d6),δ / ppm:8.29-8.23(m,2H,H-3”),7.99-7.93(m,2H,H-2”),7.3 5(dd,J=8.0,6.8Hz,2H,H-3”'),7.31-7.23(m,3H,H-2”’,H-4”’),7.22-7.16(m,2H,H-3 '),7.11-7.05(m,2H,H-2'),6.78(tt,J=7.2,1.2Hz,1H,H-4'),5.65(dd,J=12.6,6.2Hz ,1H,H-5),3.97(dd,J=17.6,12.6Hz,1H,(H-4)'),3.19(dd,J=17.6,6.2Hz,1H,(H-4)”).

[0425] 13 C-NMR (101MHz, DMSO-d6), δ / ppm: 146.5, 145.1, 143.2, 142.0, 138.7, 129.1, 129.0, 127.6, 126.3, 125.8, 124.0, 119.7, 113.4, 63.6, 42.3.

[0426] HRMS (APCI+), m / z: calculated [C 21 H 17 N3O2+H] + 344.1394, measured 344.1388.

[0427] Example 45: 2-Phenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole (45)

[0428]

[0429] The synthesis according to Synthesis Method Variant B used 2-allyloxybenzaldehyde phenylhydrazone (3.2 mmol, 807 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (50%→80% acetonitrile), pyrazoline (1.79 mmol, 447 mg, 56%) was obtained as an orange oil.

[0430] 1 H-NMR (400MHz, CD3CN), δ / ppm: 7.78 (dd, J=7.7, 1.7Hz, 1H, H-9), 7.32-7.24 (m, 3H, H-7, H-3'), 7.14-7.09 ( m,2H,H-2'),7.00(td,J=7.5,1.1Hz,1H,H-8),6.93(dd,J=8.3,1.1Hz,1H,H-3),6.85(tt,J=7.3,1.2Hz,1H ,H-4'),4.72(dd,J=10.3,5.8Hz,1H,(H-4)'),4.24(dd,J=10.6,9.7Hz,1H,(H-3)'),4.11(dd,J=12.3,10. 3Hz, 1H, (H-4)”), 3.81 (dddd, J=13.3, 12.4, 10.6, 5.8Hz, 1H, H-3a), 3.28 (dd, J=13.2, 9.7Hz, 1H, (H-3)’).

[0431] 13 C-NMR (101MHz, CD3CN), δ / ppm: 156.9, 147.8, 147.7, 131.8, 130.1, 125.0, 122.5, 120.3, 118.3, 118.2, 117.6, 114.2, 70.5, 52.3, 43.2.

[0432] HRMS (APCI+), m / z: calculated [C 16 H 14 N2O+H] + 251.1179, measured 251.1178.

[0433] Example 46: 3-Methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole

[0434]

[0435] Synthesis according to Synthesis Method Variant B used acetaldehyde phenylhydrazone (3 mmol, 403 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). Electrolysis was performed under an argon atmosphere. After reverse phase flash column chromatography on C-18 silica with acetonitrile / water (50%→60% acetonitrile), pyrazoline (1.15 mmol, 273 mg, 38%) was obtained as a dark red solid.

[0436] 1 H-NMR (400MHz, CD3CN), δ / ppm: 7.33 (tt, J=6.8, 1.0Hz, 2H, H-3”'), 7.29-7.20 (m, 3H, H -2"',H-4"'),7.11-7.04(m,2H,H-3'),6.86-6.79(m,2H,H-2'),6.63(tt,J=7.2,1.1H z,1H,H-4'),5.11(dd,J=11.9,7.3Hz,1H,H-5),3.48(ddd,J=17.7,11.9,1.3Hz,1H,(H -4)'), 2.63(ddd,J=17.6,7.3,1.2Hz,1H,(H-4)”), 2.00(dd,J=1.2,1.1Hz,3H,H-1”).

[0437] 13 C-NMR (101MHz, CD3CN), δ / ppm: 149.1, 145.6, 143.1, 128.9, 128.7, 127.2, 125.9, 117.8, 112.5, 63.3, 47.3, 15.5.

[0438] HRMS (ESI+), m / z: calculated [C 16 H 16 N2+H] + 237.1386, measured 237.1388.

[0439] Examples 47 and 48: 3-Cyclopropyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole (47) and 3-Cyclopropyl-1,5-diphenyl-1H-pyrazole (48)

[0440]

[0441] The synthesis according to the synthetic method variant A uses formylcyclopropanephenylhydrazone (3mmol, 479mg, 1 equivalent) and styrene (8.1mmol, 844mg, 2.7 equivalents). The charge of 2F (579C) is applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc) and purification by preparative HPLC (water (+1% by volume of formic acid) / acetonitrile 70%→100% MeCN), pyrazoline 47 (0.69mmol, 180mg, 23%) is obtained as an orange oil. The byproduct pyrazole 48 (0.23mmol, 61mg, 8%) is obtained as a yellow oil.

[0442] Analytical data of 3-cyclopropyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole 47:

[0443] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.36-7.29(m,2H,H-3”'),7.28-7.21(m,3H,H-2”’,H-4”’),7.12 -7.06(m,2H,H-3'),6.89-6.84(m,2H,H-2'),6.66(tt,J=7.3,1.1Hz,1H,H-4'),5.06(dd,J=11.7 ,7.3Hz,1H,H-5),3.31(ddd,J=17.4,11.7,0.6Hz,1H,(H-4)'),2.51(dd,J=17.3,7.3Hz,1H,(H-4 )"),1.82(tt,J=8.4,5.1Hz,1H,H-1"),0.86-0.81(m,2H,(H-2")'),0.81-0.68(m,2H,(H-2")').

[0444] 13 C-NMR (101MHz, CDCl3), δ / ppm: 155.0, 146.9, 144.1, 129.9, 129.7, 128.3, 126.9, 119.0, 118.3, 113.8, 64.6, 44.4, 12.0, 6.3, 6.1.

[0445] HRMS (APCI+), m / z: calculated [C 18 H 18 N2+H] + 263.1543, measured 263.1540.

[0446] Analytical data of 3-cyclopropyl-1,5-diphenyl-1H-pyrazole 48:

[0447] 1H-NMR(400MHz,CD3CN),δ / ppm:7.31-7.20(m,6H,H-3',H-4',H-3"',H-4"'),7.19-7.11(m,4H,H-2',H-2"'), 6.20(d,J=1.3Hz,1H,H-4),1.96-1.86(m,1H,H-1”),0.93-0.85(m,2H,(H-2”)’),0.76-0.68(m,2H,(H-2”)”).

[0448] 13 C-NMR (101MHz, CD3CN), δ / ppm: 156.6, 144.5, 141.3, 131.8, 129.8, 129.6, 129.4, 129.1, 128.1, 126.1, 118.3, 105.3, 9.8, 8.6.

[0449] HRMS (APCI+), m / z: calculated [C 18 H 16 N2+H] + 261.1386, measured 261.1387.

[0450] Examples 49 and 50: 3-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole (49) and (4R,6R)-5,5-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,6-methanoindazole (50)

[0451]

[0452] Synthesis according to Synthesis Method Variant B used 2-allyloxybenzaldehyde phenylhydrazone (3.2 mmol, 769 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.). Electrolysis was performed at 25°C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), pyrazoline 49 (0.77 mmol, 264 mg, 24%) was obtained as an orange solid. The byproduct pyrazoline 50 (0.54 mmol, 129 mg, 17%) was obtained as a dark yellow solid.

[0453] 3-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-diphenyl-4,5-dihydro-1H- Analytical data of pyrazole 49:

[0454] 1H-NMR(400MHz, CDCl3), δ / ppm:7.36-7.21(m,5H,H-2"',H-3"',H-4"'),7.14(dd d,J=9.2,7.2,2.0Hz,2H,H-3'),7.01-6.95(m,2H,H-2'),6.74(tt,J=7.2,1.2Hz ,1H,H-4'),5.65(qt,J=3.5,1.4Hz,1H,H-2”),5.12(ddd,J=12.1,7.8Hz,1H,H-5 ),3.61(ddd,J=16.5,12.2,3.9Hz,1H,(H-4)'),3.20(qd,J=6.0,1.5Hz,1H,H-4” ),2.90(ddd,J=16.7,7.4,4.8Hz,1H,(H-4)”),2.52(dtd,J=8.6,5.7,2.8Hz,1H, (H-3”)'),2.44(ddd,J=19.1,3.3,2.4Hz,1H,(H-7”)'),2.38(dt,J=19.2,3.1Hz , 1H, (H-7")")), 2.16 (dddt, J = 5.8, 4.3, 2.9, 1.5 Hz, 1H, H-6")), 1.40 (d, J = 4.3 Hz, 3H, H-5")'), 1.22 (dd, J = 8.9, 7.6 Hz, 1H, (H-3")")), 0.85 (d, J = 4.1 Hz, 3H, H-5")). Inseparable mixture of 5R / S-diastereomers.

[0455] 13 C-NMR (101 MHz, CDCl3), δ / ppm: 148.4, 145.2, 143.0, 142.3, 129.2, 128.9, 127.5, 126.0, 124.7, 118.8, 113.4, 64.5, 42.9, 42.0, 40.8, 37.9, 32.4, 31.5, 26.4, 21.1. Inseparable mixture of 5R / S-diastereomers.

[0456] HRMS (APCI+), m / z: calculated [C 24 H 26 N2+H] + 343.2169, measured 343.2155.

[0457] Analytical data of (4R,6R)-5,5-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,6-methanoindazole 50 according to:

[0458] 1H-NMR (400MHz, CDCl3), δ / ppm:7.62-7.56(m,2H,H-2'),7.40-7.33(m,2H,H-3'),7.32(d,J=0.6H z,1H,H-4),7.20(tq,J=7.7,1.0Hz,1H,H-4'),3.03(dd,J=16.4,3.1Hz,1H,(H-8)'),2.92(dd,J= 16.4,2.7Hz,1H,(H-8)"),2.70(t,J=5.4Hz,1H,H-4),2.62(dt,J=9.3,5.7Hz,1H,(H-7)'),2.28( tt,J=5.8,2.9Hz,1H,H-6),1.33(s,3H,H-5'),1.29(d,J=9.3Hz,1H,(H-7)”),0.62(s,3H,H-5”).

[0459] 13 C-NMR (101MHz, CDCl3), δ / ppm: 140.6, 136.4, 136.3, 129.2, 129.0, 126.2, 121.1, 41.4, 41.3, 39.3, 33.8, 29.1, 26.4, 21.3.

[0460] HRMS (APCI+), m / z: calculated [C 16 H 18 N2+H] + 239.1543, measured 239.1545.

[0461] Example 51: 1-(4-Methylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0462]

[0463] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-methylphenyl)hydrazono)acetate (3 mmol, 679 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.69 mmol, 522 mg, 56%) was obtained as a yellow solid.

[0464] 1H-NMR(400MHz, CDCl3), δ / ppm:7.35-7.30(m,2H,H-3"'),7.31-7.19(m,3H,H-2"',H -4"'),7.02(d,J=8.8Hz,2H,H-3'),6.98(d,J=8.9Hz,2H,H-2'),5.40(dd,J=13.3,7. 2Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2”),3.71(dd,J=17.9,13.3Hz,1H,(H-4)'),3 .04(dd,J=17.9,7.2Hz,1H,(H-4)”),2.23(s,3H,H-5’),1.38(t,J=7.1Hz,3H,H-3”).

[0465] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.9, 141.4, 140.4, 137.5, 130.7, 129.6, 129.3, 127.9, 125.7, 114.7, 65.6, 61.2, 42.2, 20.7, 14.5.

[0466] HRMS (APCI+), m / z: calculated [C 19 H 20 N2O2+H] + 309.1598, measured 309.1595.

[0467] Example 52: 1-(4-Fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0468]

[0469] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-fluorophenyl)hydrazono)acetate (3 mmol, 631 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.58 mmol, 793 mg, 86%) was obtained as a yellow solid.

[0470] 1H-NMR(400MHz, CDCl3), δ / ppm:7.36-7.30(m,2H,H-3"'),7.30-7.24(m,1H,H-4"') ,7.24-7.19(m,2H,H-2”'),7.07-7.00(m,2H,H-2'),6.91-6.83(m,2H,H-3'),5.36 (dd,J=13.2,7.4Hz,1H,H-5),4.33(q,J=7.1Hz,2H,H-2”),3.72(dd,J=18.0,13.2H z,1H,(H-4)'),3.05(dd,J=18.0,7.4Hz,1H,(H-4)”),1.37(t,J=7.1Hz,3H,H-3”).

[0471] 13 C-NMR (101MHz, CDCl3), δ / ppm:162.7,159.2,156.8,141.0,139.1,139.1,138 .3,129.4,128.1,125.8,115.9,115.8,115.8,115.5,65.9,61.3,42.5,14.4.

[0472] 19 F-NMR (376MHz, CDCl3), δ / ppm: -124.08 (tt, J=8.7, 4.7Hz).

[0473] HRMS (ESI+), m / z: calculated [C 18 H 17 FN2O2+Na] + 335.1166, measured 335.1168.

[0474] Example 53: 1-(4-Chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0475]

[0476] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-chlorophenyl)hydrazono)acetate (3 mmol, 680 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.65 mmol, 872 mg, 88%) was obtained as a yellow solid.

[0477] 1H-NMR(400MHz, CDCl3), δ / ppm:7.34-7.28(m,2H,H-3"'),7.30-7.20(m,1H,H-4"') ,7.19-7.15(m,2H,H-2”'),7.12-7.06(m,2H,H-3'),7.02-6.97(m,2H,H-2'),5.35 (dd,J=13.2,7.0Hz,1H,H-5),4.31(q,J=7.1Hz,2H,H-2”),3.70(dd,J=18.1,13.2H z,1H,(H-4)'),3.03(dd,J=18.1,7.0Hz,1H,(H-4)”),1.34(t,J=7.1Hz,3H,H-3”).

[0478] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.6, 141.3, 140.8, 139.0, 129.5, 129.0, 128.2, 126.3, 125.7, 115.8, 65.5, 61.5, 42.5, 14.5.

[0479] HRMS (APCI+), m / z: calculated [C 18 H 17 35 ClN2O2+H] + 329.1051, measured 329.1044; calculated [C 18 H 17 37 ClN2O2+H] + 331.1028, measured 331.1027.

[0480] Example 54: 1-(4-bromophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0481]

[0482] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-bromophenyl)hydrazono)acetate (3 mmol, 813 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.80 mmol, 1044 mg, 93%) was obtained as an orange solid.

[0483] 1H-NMR (400MHz, CDCl3), δ / ppm:7.36-7.31(m,2H,H-3”'),7.30-7.23(m,3H,H- 3',H-4"'),7.22-7.17(m,2H,H-2"'),6.99-6.94(m,2H,H-2'),5.37(dd,J=13 .2,7.0Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2”),3.72(dd,J=18.2,13.2Hz,1H ,(H-4)'),3.05(dd,J=18.1,7.0Hz,1H,(H-4)”),1.37(t,J=7.1Hz,3H,H-3”).

[0484] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.6, 141.7, 140.8, 139.1, 131.9, 129.5, 128.3, 125.7, 116.2, 113.8, 65.4, 61.5, 42.6, 14.5.

[0485] HRMS (ESI+), m / z: calculated [C 18 H 17 79 BrN2O2+H] + 373.0547, measured 373.0546; calculated [C 18 H 17 81 BrN2O2+H] + 375.0526, measured 375.0530.

[0486] Example 55: 1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0487]

[0488] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (3 mmol, 783 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.51 mmol, 913 mg, 84%) was obtained as a yellow solid.

[0489] 1H-NMR (400MHz, CDCl3), δ / ppm: 7.31 (d, J=8.8Hz, 1H, H-6'), 7.29-7.16 (m, 4H, H-3', H- 3"',H-4"'),7.16(dd,J=7.7,1.9Hz,2H,H-2"'),7.07(dd,J=8.7,2.4Hz,1H,H-5'),5. 90(dd,J=12.5,6.0Hz,1H,H-5),4.41(qd,J=7.1,1.4Hz,2H,H-2”),3.73(dd,J=18.0,1 2.6Hz, 1H, (H-4)'), 3.35 (dd, J=18.0, 6.0Hz, 1H, (H-4)"), 1.42 (t, J=7.1Hz, 3H, H-3").

[0490] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.5, 141.6, 139.7, 139.4, 130.5, 130.0, 128.9, 128.5, 127.4, 126.7, 126.5, 126.2, 67.8, 61.5, 41.4, 14.5.

[0491] HRMS (APCI+), m / z: calculated [C 18 H 16 35 Cl2N2O2+H] + 363.0662, measured 363.0658; calculated [C 18 H 16 35 Cl 37 ClN2O2+H] + 365.0635, measured 365.0634; calculated [C 18 H 16 37 Cl2N2O2+H] + 367.0614, measured 367.0613.

[0492] Example 56: 1-(Perfluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0493]

[0494] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-perfluorophenyl)hydrazono)acetate (3 mmol, 847 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.75 mmol, 288 mg, 25%) was obtained as a brown oil.

[0495] 1 H-NMR (400MHz, CDCl3), δ / ppm: 7.31-7.21 (m, 5H, H-2"', H-3"', H-4"'), 5.42 (dd, J=12.5, 9.5Hz, 1H, H-5), 4.35 (q, J=7.1 Hz,2H,H-2”), 3.65(dd,J=18.1,12.5Hz,1H,(H-4)’), 3.23(dd,J=18.1,9.5Hz,1H,(H-4)”), 1.35(t,J=7.1Hz,3H,H-3”).

[0496] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.2, 144.5, 142.5, 142.0, 139.1, 136.6, 129.2, 129.0, 128.8, 128.5, 126.8, 125.8, 118.3, 69.3, 61.8, 41.7, 14.4.

[0497] 19 F-NMR (376MHz, CDCl3), δ / ppm: -147.66--148.00(m,F-3'),-158.85(t,J=21.7Hz,F-4'),-163.46--163.63(m,F-2').

[0498] HRMS (APCI+), m / z: calculated [C 18 H 13 F5N2O2+H] + 385.0970, measured 385.0967.

[0499] Example 57: 1-(4-Cyanophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (57)

[0500]

[0501] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-cyanophenyl)hydrazono)acetate (3 mmol, 652 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (2.71 mmol, 2866 mg, 90%) was obtained as a yellow solid.

[0502] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.46-7.41(m,2H,H-3'),7.38-7.33(m,2H,H-3"'), 7.33-7.28(m,1H,H-4"'),7.20-7.16(m,2H,H-2"'),7.14-7.09(m,2H,H-2'),5.43 (dd,J=13.0,6.4Hz,1H,H-5),4.35(q,J=7.1Hz,2H,H-2”),3.77(dd,J=18.4,13.0H z,1H,(H-4)'),3.11(dd,J=18.4,6.4Hz,1H,(H-4)”),1.38(t,J=7.1Hz,3H,H-3”).

[0503] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.2, 145.7, 141.7, 140.1, 133.4, 129.7, 128.6, 125.5, 119.6, 114.5, 103.5, 64.9, 61.8, 42.8, 14.4.

[0504] HRMS (ESI+), m / z: calculated [C 19 H 17 N3O2+H] + 320.1394, measured 320.1393.

[0505] Example 58: 4-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonic acid

[0506]

[0507] Synthesis according to Synthesis Method Variant B used 4-(2-(2-ethoxy-2-oxoethylidene)hydrazino)benzenesulfonic acid (3.2 mmol, 884 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After reverse phase flash column chromatography on C-18 silica with water / acetonitrile (50%→80% acetonitrile), trace amounts of pyrazoline were obtained.

[0508] HRMS (ESI-), m / z: calculated [C 21 H 18 N2O3S-H] - 377.0965, measured 377.0953.

[0509] Example 59: 1-(2,4-dinitrophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0510]

[0511] The synthesis according to the synthetic method variant A used ethyl 2-(2-(2,4-dinitrophenyl)hydrazono)acetate (2 mmol, 564 mg, 1 eq.) and styrene (5.4 mmol, 562 mg, 2.7 eq.). Dichloromethane was used as the organic solvent. The electrolysis was carried out at 35° C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline (0.57 mmol, 221 mg, 29%) was obtained as an orange solid.

[0512] 1 H-NMR (400MHz, CDCl3), δ / ppm: 8.46 (d, J=2.6Hz, 1H, H-3'), 8.13 (dd, J=9.3, 2.6Hz, 1H,H-5'),7.37-7.28(m,3H,H-3"',H-4"'),7.22-7.15(m,3H,H-6',H-2"'),5.58(d d,J=12.3,7.4Hz,1H,H-5),4.35(qd,J=7.2,1.0Hz,2H,H-2”),3.81(dd,J=18.7,12. 3Hz, 1H, (H-4)'), 3.20 (dd, J=18.7, 7.5Hz, 1H, (H-4)"), 1.38 (t, J=7.1Hz, 3H, H-3").

[0513] 13 C-NMR (101MHz, CDCl3), δ / ppm: 161.4, 145.9, 140.3, 140.2, 138.6, 138.3, 129.9, 129.2, 127.2, 126.3, 122.2, 118.5, 66.2, 62.3, 43.2, 14.3.

[0514] HRMS (APCI+), m / z: calculated [C 18 H 16 N4O6+NH4] + 402.1408, measured 402.1406.

[0515] Example 60: 1-(4-methoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0516]

[0517] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-methoxyphenyl)hydrazono)acetate (3 mmol, 667 mg, 1 eq.) and styrene (8.1 mmol, 844 mg, 2.7 eq.). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (1.58 mmol, 511 mg, 53%) was obtained as a yellow solid.

[0518] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.35-7.30(m,2H,H-3"'),7.31-7.19(m,3H,H-2"', H-4"'),7.06-7.01(m,2H,H-2'),6.77-6.71(m,2H,H-3'),5.36(dd,J=13.3,7.6Hz ,1H,H-5),4.33(q,J=7.1Hz,2H,H-2”),3.71(s,3H,H-5’),3.70(dd,J=17.9,13.4H z, 1H, (H-4)'), 3.03 (dd, J = 17.9, 7.6Hz, 1H, (H-4)'), 1.36 (t, J = 7.1Hz, 3H, H-3”).

[0519] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.9, 154.7, 141.4, 137.1, 136.7, 129.3, 128.0, 125.9, 116.1, 114.4, 66.2, 61.2, 55.6, 42.3, 14.5.

[0520] HRMS (APCI+), m / z: calculated [C 19 H 20 N2O3+H] + 325.1547, measured 325.1542.

[0521] Example 61: 1-(4-trifluoromethoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester

[0522]

[0523] The synthesis according to Synthesis Method Variant A used ethyl 2-(2-(4-trifluoromethoxyphenyl)hydrazono)acetate (3 mmol, 829 mg, 1 eq) and styrene (8.1 mmol, 844 mg, 2.7 eq). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline (0.98 mmol, 371 mg, 33%) was obtained as an orange solid.

[0524] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.38-7.32(m,2H,H-3"'),7.31-7.26(m,1H,H-4"') ,7.24-7.20(m,2H,H-2”'),7.10-7.06(m,2H,H-3'),7.04-7.00(m,2H,H-2'),5.37 (dd,J=13.2,7.2Hz,1H,H-5),4.34(q,J=7.1Hz,2H,H-2”),3.74(dd,J=18.1,13.2H z,1H,(H-4)'),3.06(dd,J=18.1,7.2Hz,1H,(H-4)”),1.37(t,J=7.1Hz,3H,H-3”).

[0525] 13 C-NMR (101MHz, CDCl3), δ / ppm: 162.6, 143.3, 141.5, 140.8, 139.3, 129.5, 128.3, 125.7, 122.0, 121.9, 119.4, 115.3, 65.6, 61.4, 42.7, 14.4.

[0526] 19 F-NMR (376MHz, CDCl3), δ / ppm: -59.4.

[0527] HRMS (ESI+), m / z: calculated [C 19 H 17 F3N2O3+H] + 379.1264, measured 379.1264.

[0528] Example 62: 1-Methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole

[0529]

[0530] The synthesis according to Synthesis Method Variant B used benzaldehyde methylhydrazone (3.2 mmol, 429 mg, 1 eq.) and styrene (12.5 mmol, 1302 mg, 3.9 eq.) After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline (0.76 mmol, 179 mg, 24%) was obtained as a yellow oil.

[0531] 1 H-NMR(400MHz, CDCl3), δ / ppm:7.69-7.64(m,2H,H-2”),7.51-7.47(m,2H,H-2”’),7.44-7.30(m,6H,H-3”,H-4”,H-3”’,H-4”’),4.1 3(dd,J=14.4,10.0Hz,1H,H-5), 3.49(dd,J=16.1,10.0Hz,1H,(H-4)'), 3.01(dd,J=16.1,14.4Hz,1H,H-(H-4)”), 2.86(s,3H,H-1′).

[0532] 13 C-NMR (101MHz, CDCl3), δ / ppm: 149.8, 140.5, 133.0, 128.8, 128.7, 128.6, 127.9, 127.6, 125.9, 73.7, 43.4, 41.7.

[0533] HRMS (APCI+), m / z: calculated [C 16 H 16 N2+H] + 237.1386, measured 237.1386.

[0534] Example 63: Alternative synthetic route to pyraclostrobin starting from 2,5-dichlorophenylhydrazine hydrochloride via (Z)-ethylglyoxylate 2,5-dichlorophenylhydrazone or (E)-ethylglyoxylate 2,5-dichlorophenylhydrazone

[0535] (a) (Z)-Ethyl glyoxylate 2,5-dichlorophenylhydrazone (2)

[0536]

[0537] In a 250mL round-bottom flask, 2,5-dichlorophenylhydrazine hydrochloride (1a, 46.8mmol, 10.0g, 1.0 equivalent) was dissolved in THF (75mL) and cooled to 0°C. Triethylamine (56.2mmol, 5.68g, 1.2 equivalent) was added dropwise, the mixture was stirred for 15min and then filtered, and the residue was washed with THF (25mL). At 0°C, ethyl glyoxylate (1b, 46.8mol, 4.78g, 1.0 equivalent) in toluene (1:1w / w) was added dropwise to the filtrate. The mixture was then stirred for 5 hours, during which the mixture reached room temperature. The solvent was removed under reduced pressure, and the residue was recrystallized from cyclohexane / ethyl acetate (2:1v / v) to give the product (2,37.6mmol, 9.82g, 80%) as a pale yellow solid.

[0538] 1 H NMR (400MHz, CDCl3), δ / ppm: 8.68 (s, 1H, H-1), 7.57 (d, J = 8.9Hz, 1H, H-3'), 7.30-7.22 (m, 2H, H-3 ,6'),7.20(dd,J=8.9,2.4Hz,1H,H-5'),4.31(q,J=7.1Hz,2H,H-2”),1.35(t,J=7.1Hz,3H,H-3”).

[0539] 13 C NMR (101MHz, CDCl3), δ / ppm: 163.6, 137.6, 129.1, 128.9, 128.3, 126.9, 118.5, 116.4, 61.3, 14.3.

[0540] HRMS (ESI+), m / z: calculated C 10 H 10 35 Cl2N2O2+H + 261.0192[M+H] + , measured 261.0192; calculated C 10 H 10 35 Cl 37 ClN2O2+H + 263.0164[M+H] + , measured 263.0164; calculated C 10 H 10 37 Cl2N2O2+H + 265.0138[M+H] + , measured 265.0137

[0541] LC-MS analysis: water + 0.1 vol% formic acid / MeCN (50→100% MeCN over 10 min, 10 min at 100% MeCN)

[0542] R t =9.910min

[0543] (b) (E)-Ethyl glyoxylate 2,5-dichlorophenylhydrazone (3)

[0544]

[0545] In a 2L round-bottom flask, ethyl glyoxylate (1b, 0.79 mol, 80.7 g, 1.05 eq) was dissolved in toluene (1:1 w / w), and 2,5-dichlorophenylhydrazine hydrochloride (1a, 0.75 mol, 160.1 g, 1.0 eq) was dissolved in ethanol (750 mL). Glacial acetic acid (0.75 mol, 45.0 g, 1.0 eq) was added, and the mixture was heated under reflux overnight. After crystallization of the product at -30 °C, the product was filtered off and the residue was washed with water. The resulting product was obtained without further purification as an orange needle (3, 0.67 mol, 174.5 g, 89%).

[0546] 1 H NMR (400MHz, CDCl3), δ / ppm: 12.58 (s, 1H, H-1), 7.54 (d, J = 8.9Hz, 1H, H-6'), 7.33 (d, J = 2.3Hz, 1H, H-3'), 7. 22(dd,J=8.9,2.3Hz,1H,H-5'), 6.75(s,1H,H-3), 4.29(q,J=7.1Hz,2H,H-2”), 1.36(t,J=7.1Hz,3H,H-3”).

[0547] 13 C NMR (101MHz, CDCl3), δ / ppm: 163.5, 138.5, 129.1, 128.2, 127.0, 121.6, 119.6, 115.4, 61.0, 14.3.

[0548] LC-MS analysis: water + 0.1 vol% formic acid / MeCN (50→100% MeCN over 10 min, 10 min at 100% MeCN)

[0549] R t =14,049min

[0550] (c)(Z)-Ethyl glyoxylate 2,5-dichlorophenylhydrazone to pyraclostrobin (4)

[0551]

[0552] In a 50 mL jacketed beaker electrolytic cell, (Z)-ethylglyoxylate 2,5-dichlorophenylhydrazone (2,19.1 mmol, 5.0 g, 1.0 eq.) and ethyl methacrylate (61.5 mmol, 7.02 g, 3.21 eq.) were dispersed in a 1 M sodium iodide aqueous solution (20 mL). As anode and cathode, an isostatically pressed graphite plate (size: 60 × 20 × 3 mm) was used with an immersion depth of 2.7 cm and a relevant anode area of ​​5.4 cm. 2 The reaction was carried out at 33 °C and 1000 rpm at 27.9 mA cm -2 The mixture was electrolyzed at a constant current until a charge of 5.4 F was applied. The biphasic mixture was transferred to a separatory funnel for separation. The aqueous layer was extracted with ethyl acetate (1×30 mL), the combined organic portion was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed under reduced pressure to obtain a crude product. After flash column chromatography on silica with cyclohexane / EtOAc (0%→4% EtOAc), pyraclostrobin (4, 16.4 mmol, 6.13 mg, 86%) was obtained as an orange oil.

[0553] 1 H NMR (400MHz, CDCl3), δ / ppm: 7.41 (d, J=2.1Hz, 1H, H-3'), 7.25-7.19 (m, 2H, H-5', H-6'), 4.33 (qd, J=7.2, 1.7Hz, 2H, H-2”), 4.19 (q, J=7.2Hz, 2H, H-2 ”'),3.73(d,J=17.7Hz,1H,(H-4)'),3.12(d,J=17.7Hz,1H,(H-4)”),1.46 (s, 3H, H-1””), 1.35 (t, J = 7.1Hz, 3H, H-3”), 1.24 (t, J = 7.1Hz, 3H, H-3”’).

[0554] 13 C NMR (101MHz, CDCl3), δ / ppm: 171.5, 162.3, 140.1, 138.0, 133.6, 133.4, 130.5, 130.2, 127.5, 73.6, 62.3, 61.5, 45.1, 22.1, 14.5, 14.1.

[0555] HRMS (ESI+), m / z: calculated C 16 H 18 35 Cl2N2O4+H + 373.0716[M+H] +, measured 373.0718; calculated C 16 H 18 35 Cl 37 ClN2O4+H + 375.0690[M+H] + , measured 375.0692; calculated C 16 H 18 37 Cl2N2O4+H + 377.0669[M+H] + , measured value is 377.0674.

[0556] (d)(E)-Ethyl glyoxylate 2,5-dichlorophenylhydrazone to pyraclostrobin (4)

[0557]

[0558] In a 5 mL PTFE electrolytic cell, hydrazone 3 and ethyl methacrylate were dissolved in an organic solvent and an aqueous sodium halide solution was added. As anode and cathode, an isostatically pressed graphite plate (size: 70 × 10 × 3 mm) was used with an immersion depth of 1.7 cm and a relevant anode area of ​​1.7 cm. 2 . The mixture was electrolyzed at a constant current at 33°C with vigorous stirring (magnetic stir bar set at about 1000 rpm) until a charge of 5.4 F was applied. The mixture was transferred to a separatory funnel and the electrolytic cell was rinsed with ethyl acetate. As an internal standard, 1 mL of 1,3,5-trimethoxybenzene solution (3.000 g / 100 mL ethyl acetate) was added. The mixture was shaken slightly to separate the layers. The organic portion was dried over anhydrous magnesium sulfate and filtered. A sample was filtered through silica gel and analyzed by gas chromatography to determine the content of pyrazoline.

[0559] Due to the low conversion and yield when using (E)-hydrazone 3 under the conditions optimized for (Z)-hydrazone 2, a second round of screening was performed. First, the solvent and halide source were investigated. This resulted in tert-butyl methyl ether and sodium iodide being the preferred conditions (Table 1).

[0560] Table 1: Solvent screening for the transformation of (E)-ethylglyoxylate to 2,5-dichlorophenylhydrazone

[0561] Organic solvents NaX (X = halogen) <![CDATA[Yield 4 (GC) a > <![CDATA[CH2Cl2]]> NaCl 4％ <![CDATA[CH2Cl2]]> NaBr n / d PhCl NaI 15％ No organic solvents NaI 25％ <![CDATA[MeO t This]]> NaI 60％ PhMe NaI 28％

[0562] 5mL PTFE beaker test tube, 1mL organic solvent, 4mL 1M aq.NaX, 3.52mmol hydrazone 3, 3.21 equivalents of ethyl methacrylate, 33℃, isostatic graphite electrode, 27.9mA cm -2 , 5.4F.

[0563] a The determination was performed after external calibration using 1,3,5-trimethoxybenzene as the internal standard.

[0564] Preferred conditions for (E)-hydrazone are as follows:

[0565]

[0566] 5mL PTFE beaker test tube, 1mL MeO t Bu, 4 mL 1M aq. NaI, 0.60 mmol of hydrazone 3.

[0567] Alternatively, (E)-hydrazone can be preferably converted in a mixture of ethanol and acetonitrile (especially 1:1 vol / vol) with a yield of up to 73% (optimized conditions: 3.79 equivalents of methacrylate, 2.79 equivalents of NaI, 5 mA / cm 2 , 4.0F, room temperature):

[0568]

Claims

1. Method for preparing the compound of general formula (I) in is a single bond or a double bond; R 1 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted; R 2 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted; R 3 is alkyl, -C(O)O-alkyl, -C(O)O-aryl, -C(O)N-(alkyl)2, -CN, -P(O)(O-alkyl)2, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H; R 4 if is a single bond, and R 4 is alkyl, -C(O)O-alkyl, C(O)O-aryl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H; or R 3 and R 4 Connected to R in the compound of formula (I) 3 and R 4 The carbon atoms of the alkylene group and the alkylene group are taken together to form a substituted or unsubstituted cycloalkyl group or heterocyclic group; R 5 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl or heterocyclyl, in each case substituted or unsubstituted, or H; or R 4 and R 5 Connected to R in the compound of formula (I) 4 and R 5 The carbon atoms of the alkylene radicals are taken together to form a cycloalkyl or heterocyclyl radical, which may be substituted or unsubstituted in each case; or R 1 and R 5 Connected to R in the compound of formula (I) 1 and R 5 The carbon atoms of the alkylene radicals are taken together to form a cycloalkyl or heterocyclyl radical, which may be substituted or unsubstituted in each case; It is characterized in that Compounds of formula (II) Where R 1 and R 2 The definition is the same as that of general formula (I), and an electrochemical reaction occurs with a compound of formula (III) or (IV) in the presence of an iodide source. Where R 3 , R 4 and R 5 The definition of is the same as in the general formula (I).

2. The method according to claim 1, wherein R 1 is unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl; and / or R 2 is unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl; and / or R 3 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted -C(O)O-phenyl, unsubstituted or substituted -C(O)O-benzyl, unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl; and / or R 4 if is a single bond, and R 4 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted -C(O)O-phenyl, unsubstituted or substituted -C(O)O-benzyl, unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl; or R 3 and R 4 Connected to R in the compound of formula (I) 3 and R 4 The carbon atoms of 12 - cycloalkyl; and / or R 5 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C 1-8 -alkyl), unsubstituted or substituted C3-C 12 - cycloalkyl, unsubstituted or substituted phenyl; or R 4 and R 5 Connected to R in the compound of formula (I) 4 and R 5 The carbon atoms of 12 - cycloalkyl or heterocyclyl; or R 1 and R 5 Connected to R in the compound of formula (I) 1 and R 5 The carbon atoms of 12 - a cycloalkyl group or a heterocyclic group.

3. The method according to claim 1 or 2, wherein the iodide source is used in the form of sodium iodide, lithium iodide, potassium iodide or a mixture thereof.

4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in aqueous solution in the presence of an iodide source.

5. The method according to claim 4, wherein the iodide source is used in a concentration of 0.2 to 2.0 M, based on the aqueous solution, preferably 0.5 to 1.4 M, based on the aqueous solution.

6. The process according to any one of claims 1 to 5, wherein the reaction is carried out in a biphasic mixture of an aqueous solution and an organic solvent in the presence of an iodide source, wherein the organic solvent is preferably selected from ethyl acetate, tert-butyl methyl ether, dichloromethane, chlorobenzene, 1,2-dichloroethane or a mixture thereof.

7. The method according to any one of claims 1 to 6, wherein the amount of compound (III) or (IV) used is 1.0 to 6.0 equivalents, based on the amount of substance of the compound of formula (II) used, preferably 2.0 to 5.0 equivalents.

8. The process according to any one of claims 1 to 7, wherein the reaction is carried out in an undivided electrolytic cell.

9. The method according to any one of claims 1 to 8, wherein graphite electrodes are used as anode and cathode.

10. The method according to claim 9, wherein isostatically pressed graphite is used.

11. The method according to any one of claims 1 to 10, wherein the method is carried out at 20 to 50 mA / cm 2 The current density is preferably 30 to 40 mA / cm 2 .

12. The method according to any one of claims 1 to 11, wherein the method is carried out until the amount of applied charge reaches 1 to 10 F, preferably 2 to 6 F.

13. The process according to any one of claims 1 to 12, wherein the reaction is carried out at a temperature of 10 to 50°C, preferably 20 to 40°C.

14. A process according to any one of claims 1 to 13, wherein the aqueous phase is subsequently separated and optionally subsequently freeze-dried to recover the iodide source.

15. The method according to any one of claims 1 to 14, wherein is a single bond, and the compound of the general formula (II) reacts with the compound of the general formula (III).

16. The method according to any one of claims 1 to 15, wherein the compound (I) is diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate, the compound (II) is ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate; and the compound (III) is ethyl methacrylate.

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