Electrochemical Synthesis of Pyrazoline and Pyrazole

Abstract

The present invention relates to an electrochemical method for the synthesis of pyrazolines and pyrazoles of formula (I). This method can be used in particular for the synthesis of mefenpyr-diethyl, a phytotoxicity reducer for herbicides.

Description

Technical Field

[0001] The present invention relates to an electrochemical method for the synthesis of pyrazoline and pyrazole. This method can be used in particular for the synthesis of mefenpyr - diethyl, a herbicide phytotoxicity reducer.

Background Art

[0002] Pyrazoline and pyrazole are essential components of complex agrochemical or pharmaceutical compounds and thus have high relevance for industrial applications.

[0003] Various methods for synthesizing pyrazoline and pyrazole are described in the prior art. For example, its preparation by [3 + 2] cycloaddition starting from the corresponding hydrazonoyl halide using a base is known. However, the hydrazonoyl halide required for this must sometimes be prepared in a complex manner using toxic and expensive halogenating reagents (WO2010 / 127855). Furthermore, α,β - unsaturated ketones can be reacted organocatalytically with hydrazine to obtain the corresponding pyrazoline, but this reaction must be carried out in the absence of water and under the use of a complex catalyst system and a toxic halogenated solvent. Furthermore, several methods are known that enable the enantioselective preparation of pyrazoline from alkyne components. These use expensive transition metal catalysts based on palladium, titanium, copper, and iridium, some of which have complex ligand systems.

[0004] Known methods are generally characterized as disadvantageous by the use of expensive transition metals, stoichiometric excesses of (auxiliary) reagents, the use of complex substrate syntheses or multi - step synthesis sequences, and the use of chemical halogenating agents as a normal excess component. The increase in material input and the use of toxic solvents result in an increase in reagent waste, which must be disposed of in a complex and expensive manner and is a barrier to the economic efficiency of the method.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, there is a need for a method for synthesizing pyrazole and pyrazoline that is not more costly, not more material-intensive, and not more time-consuming. Therefore, an object of the present invention is to provide a novel synthesis method that does not have the above-mentioned drawbacks.

Means for Solving the Problems

[0007] This object is achieved by the general formula (I)

Chemical Formula

Chemical formula

Chemical formula

[0008] Here,[[]]END]] TIFF2025522000000007.tif14162 represents the cis or trans isomer in the compound of formula (III), that is, R 3 and R 5 may be in cis or trans configuration with respect to each other, or R 4 and R 5 may be in cis or trans configuration with respect to each other.

[0009] In particular, the present invention relates to general formula (I-a) [Chemical formula] [wherein,[[]]END]] R 1 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl, or heterocyclyl, and in each case, is substituted or unsubstituted; R 2 is alkyl, -C(O)O-alkyl, cycloalkyl, aryl, or heterocyclyl, and in each case, is 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, and in each case, is substituted or unsubstituted, or is H; R 4 is alkyl, -C(O)O-alkyl, -C(O)O-aryl, cycloalkyl, aryl, or heterocyclyl, and in each case, is substituted or unsubstituted, or is H; Or R 3 and R 4 are R 3 and R 4Combined with a carbon atom in the compound of formula (I), it forms a substituted or unsubstituted cycloalkyl or heterocyclyl; 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 in the compound of formula (I) together with the carbon atom connecting R 4 and R 5 form a substituted or unsubstituted cycloalkyl or heterocyclyl; or R 1 and R 5 is R 1 and R 5 together with the carbon atom in the compound of formula (I) connecting R to form a substituted or unsubstituted cycloalkyl or heterocyclyl) A process for preparing a compound of

Chemical formula

Chemical formula

[0010] R 1 ~R 5 The alkyl, -C(O)O-alkyl, -C(O)N-(alkyl)2, -C(O)O-aryl, cycloalkyl, aryl, or heterocyclyl groups may each independently be substituted with different substituents.

[0011] The present invention provides an electrochemical method for directly synthesizing pyrazolines and pyrazoles from hydrazones and alkenes or alkynes. The substrates required for the reaction can be assembled from commercially available chemicals by simple condensation reactions, creating an added-value chain that allows the omission of environmentally harmful transition metals and halogenating agents as well as toxic solvents.

[0012] In this method, an iodide source is efficiently used with a dual function as a conductive salt and a mediator, resulting in little generation of costly reagent waste. The products can be easily purified, and the reagents used in superstoichiometric amounts can be reused, which further contributes to the economic efficiency and sustainability of this method. Therefore, the present invention enables simple, efficient, and sustainable electrochemical access to libraries of synthetically relevant pyrazolines and pyrazoles.

[0013] Preferably, alone or in combination, 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, or unsubstituted or substituted naphthyl.

[0014] Preferably, alone or in combination, 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, or unsubstituted or substituted phenyl.

[0015] Preferably, alone or in combination, 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.

[0016] Preferably, when TIFF2025522000000011.tif11163 is a single bond, alone or in combination, 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.

[0017] Alternatively, R 3 and R 4 are, together with the carbon atom in the compound of formula (I) connecting R 3 and R 4 preferably form a substituted C3-C 12 -cycloalkyl or heterocyclyl.

[0018] Preferably, alone or in combination, R 5 is H, unsubstituted or substituted C1-C6-alkyl, unsubstituted or substituted -C(O)O(C1-8 -alkyl), C3-C 12 -cycloalkyl, unsubstituted or substituted phenyl.

[0019] Alternatively, R 1 and R 5 are, with the C atom in the compound of formula (I) connecting R 3 and R 5 preferably substituted C3-C 12 -cycloalkyl or heterocyclyl may be formed.

[0020] Alternatively, R 4 and R 5 are, together with the carbon atom connecting each other R 4 and R 5 preferably form C3-C 12 cycloalkyl or heterocyclyl.

[0021] R 1 and R 5 when forming a ring system, preferably, R 3 and R 4 do not form a ring system, and vice versa.

[0022] More preferably, alone or in combination, R 1 is C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or polysubstituted by C1-C4-alkyl, phenyl mono- or polysubstituted by halogen, phenyl mono- or polysubstituted by nitro, phenyl mono- or polysubstituted by cyano, phenyl mono- or polysubstituted by -C(O)O(C 1-4 -alkyl), or naphthyl.

[0023] In particular, R 1 may be -C(O)OCH2CH3.

[0024] More preferably, alone or in combination, R 2 is C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or polysubstituted by C1-C4-alkyl, phenyl mono- or polysubstituted by halogen, phenyl mono- or polysubstituted by nitro, phenyl mono- or polysubstituted by cyano, phenyl mono- or polysubstituted by -C(O)O(C 1-4 -alkyl), mono- or polysubstituted phenyl, or naphthyl.

[0025] In particular, R 2 can be dichlorophenyl.

[0026] More preferably, alone or in combination, R 3 is C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C8-cycloalkyl, phenyl, phenyl mono- or polysubstituted by C1-C4-alkyl, phenyl mono- or polysubstituted by halogen, phenyl mono- or polysubstituted by nitro, phenyl mono- or polysubstituted by cyano, phenyl mono- or polysubstituted by -C(O)O(C 1-4 -alkyl), mono- or polysubstituted phenyl, or naphthyl.

[0027] In particular, R 3 can be CH3.

[0028] More preferably, when TIFF2025522000000012.tif11163 is a single bond, alone or in combination, R 4 is H, C1-C4-alkyl, -C(O)O(C 1-4-alkyl), -C(O)O-benzyl mono- or polysubstituted by C1-C4-alkyl, C(O)O-phenyl mono- or polysubstituted by C1-C4-alkyl, C3-C8-cycloalkyl, phenyl, phenyl mono- or polysubstituted by C1-C4-alkyl, phenyl mono- or polysubstituted by halogen, phenyl mono- or polysubstituted by nitro, phenyl mono- or polysubstituted by cyano, or phenyl mono- or polysubstituted by -C(O)O(C 1-4 -alkyl).

[0029] In particular, R 4 is -C(O)O(C 1-4 -alkyl), -C(O)O-benzyl mono- or polysubstituted by C1-C4-alkyl, or C(O)O-phenyl mono- or polysubstituted by C1-C4-alkyl.

[0030] More preferably, R 4 can be -C(O)OCH2CH3.

[0031] Even more preferably, alone or in combination,[[]] R 5 is H, C1-C4-alkyl, -C(O)O(C 1-4 -alkyl), C3-C 10 -cycloalkyl, phenyl, phenyl mono- or polysubstituted by C1-C4-alkyl, phenyl mono- or polysubstituted by halogen, phenyl mono- or polysubstituted by nitro, phenyl mono- or polysubstituted by cyano, or phenyl mono- or polysubstituted by -C(O)O(C 1-4 -alkyl).

[0032] In particular, R 5 can be H.

[0033] The iodide source is preferably used in the form of sodium iodide, lithium iodide, potassium iodide or a mixture thereof.

[0034] By using sodium iodide, lithium iodide, or potassium iodide for the dual roles of mediator and conductive salt, resources are conserved and efficient and simple recycling becomes possible. In contrast, the electrochemical methods known in the prior art require more material input due to the separate roles of the electrochemical mediator and the conductive salt, which is a barrier to the economic efficiency of the known methods.

[0035] Particularly preferred is sodium iodide.

[0036] The iodide source may be in an aqueous solution, an organic solvent, a solvent mixture of two or more organic solvents, or a two-phase mixture of an aqueous solution and an organic solvent or a solvent mixture of two or more organic solvents.

[0037] In one embodiment of the present invention, the iodide source is present in a two-phase 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 at a concentration of 0.2 to 2.0 M, more preferably at a concentration of 0.5 to 1.4 M, particularly at a concentration of 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. As the organic solvent, ethyl acetate and / or tert-butyl methyl ether are particularly preferred.

[0038] In another embodiment, the iodide source is in an aqueous solution without the addition of an organic solvent. Here, the iodide source is used at a concentration of 0.2 to 2.0 M, more preferably at a concentration of 0.5 to 1.4 M, particularly at a concentration of 0.8 to 1.4 M based on the aqueous solution.

[0039] In a further alternative embodiment, the iodide source is present in an organic solvent or a solvent mixture of two or more organic solvents without the addition of water. Here, the iodide source is used at a concentration of 0.2 to 4.0 M, more preferably at a concentration of 0.5 to 3.5 M, and particularly preferably at a concentration of 0.8 to 3.0 M, based on the organic solvent or the solvent mixture. The organic solvent is preferably selected from ethanol, acetonitrile, ethyl acetate, tert-butyl methyl ether, dichloromethane, chlorobenzene, 1,2-dichloroethane, or mixtures thereof. A mixture of ethanol and acetonitrile is particularly preferred as the organic solvent mixture, preferably at a mixing ratio of 1:10 to 10:1, more preferably 1:5 to 5:1, and particularly preferably 1:2 to 2:1 (volume / volume).

[0040] Compound (III) or (IV) is preferably used in an amount of 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.

[0041] The reaction is preferably carried out in an undivided electrolysis cell.

[0042] Graphite electrodes are preferably used as the anode and the cathode.

[0043] Therefore, the method according to the present invention is cost-effective with respect to the electrode materials and structures in a simple cell.

[0044] It is preferred to use isotropic graphite.

[0045] This method is preferably carried out at a current density of 20 to 50 mA / cm2, preferably 30 to 40 mA / cm2.

[0046] This method is preferably carried out until an applied charge amount of 1 to 10 F, preferably 2 to 6 F, is reached.

[0047] The reaction is preferably carried out at a temperature of 10 to 50 °C, preferably 20 to 40 °C.

[0048] These reaction conditions improve the yield of pyrazole or pyrazoline.

[0049] Preferably, when an aqueous phase is used, it is then separated and lyophilized to recover the iodide source. Alternatively, the aqueous phase can be separated and used without further treatment for further reaction steps or processes according to the present invention.

[0050] Recycling of the iodide source or the aqueous phase enables the production of the compound in a particularly environmentally friendly manner.

[0051] Compound (I) or (I-a) is preferably diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (mephenpyr-diethyl), compound (II) is ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate, and compound (III) is ethyl methacrylate, where R 1 is -C(O)O-ethyl; R 2 is 2,4-dichlorophenyl; R 3 is CH3; R 4 is -C(O)O-ethyl; R 5 is H.

[0052] The compound of formula (II) generally exists as a racemate or as the (E) or (Z) isomer, i.e.,

Chemical formula

[0053] One of the isomers can preferably be reacted in the process according to the invention. In this regard, in a further configuration of the invention, the yield of the synthesis can be increased by using one of the possible isomers of general formula (II-a).

[0054] Compound (I) or (I-a) is particularly preferably diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (mephenpyr-diethyl), compound (II) is (Z)-ethyl glyoxylate 2,5-dichlorophenylhydrazone, and compound (III) is ethyl methacrylate, where R 1 is -C(O)O-ethyl; R 2 is 2,4-dichlorophenyl; R 3 is CH3; R 4 is -C(O)O-ethyl; R 5 is H.

Mode for Carrying Out the Invention

[0055] Detailed Description of the Invention The method according to the invention enables the reaction to proceed efficiently in a two-phase solvent system consisting of water and an organic solvent. Here, the iodide source, preferably sodium iodide, is used on the one hand as a conductive salt and on the other hand as an electrochemical mediator.

[0056] Performing the reaction in an undivided electrolysis cell under galvanostatic operation with a simple cell structure (two-electrode configuration) enables scalable reaction conditions. The possibility of recycling the mediator and unreacted excess bipolar hydrophilic substances contributes to the sustainability and economic viability of the method.

[0057] In particular, a high yield of 73% of the herbicide phytotoxicity reducer mefenpyr - diethyl could be achieved using the method according to the present invention.

[0058] The terms used in this specification are known to those skilled in the art. Otherwise, the following definitions are used: Regarding the present invention, the term "alkyl" encompasses a saturated hydrocarbon group which may be branched or straight - chained, unsubstituted or at least monosubstituted. Examples of suitable alkyl groups which may be unsubstituted or mono - 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.

[0059] The term "cycloalkyl" preferably means a optionally substituted carbocyclic saturated ring system having 3 to 12, more preferably 3 to 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In the case of optionally substituted cycloalkyl, cyclic systems having substituents are included, and substituents having a double bond on the cycloalkyl group, such as alkylidene groups such as methylidene, are also included. In the case of optionally substituted cycloalkyl, polycyclic aliphatic systems are also included, such as bicyclo[1.1.0]butan - 1 - yl, bicyclo[1.1.0]butan - 2 - yl, bicyclo[2.1.0]pentan - 1 - yl, bicyclo[2.1.0]pentan - 2 - yl, bicyclo[2.1.0]pentan - 5 - yl, bicyclo[2.2.1]hept - 2 - yl (norbornyl), bicyclo[2.2.2]octan - 2 - yl, adamantan - 1 - yl and adamantan - 2 - yl.

[0060] In the case of a cycloalkyl that has been replaced, a spirocyclic aliphatic system is also included, for example, spiro[2.2]pentan-1-yl, spiro[2.3]hexan-1-yl, spiro[2.3]hexan-4-yl, 3-spiro[2.3]hexan-5-yl.

[0061] For the present invention, the term "aryl" means a monocyclic or polycyclic, preferably monocyclic or bicyclic, aromatic hydrocarbon group having preferably 6, 10 or 14 carbon atoms. The aryl group may be unsubstituted or may be mono- or polysubstituted by the same or different substituents. Examples of suitable aryl groups are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl.

[0062] For the present invention, the term "heterocyclyl" means a monocyclic or polycyclic system containing carbon atoms and 1, 2, 3, 4 or 5 heteroatoms, particularly nitrogen, oxygen and / or sulfur, having 3 to 20 ring atoms, preferably 3 to 14 ring atoms, particularly preferably 3 to 10 ring atoms, where the heteroatoms may be the same or different. The cyclic system may be saturated or mono- or poly-unsaturated. The term "heterocyclyl" also includes aliphatic and aromatic ring systems (heteroaryl) and combinations thereof, i.e., systems in which the aromatic ring is part of a bicyclic or polycyclic saturated, partially unsaturated and / or aromatic system.

[0063] Examples of suitable heterocycles are pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl, dihydropyranyl.

[0064] Examples of suitable heteroaryl groups include indolizinyl, benzimidazolyl, tetrazolyl, triazinyl, isoxazolyl, phthalazinyl, carbazolyl, carbolinyl, diazanaphthyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[d]thiazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinazolinyl, quinolinyl, naphthridinyl and isoquinolinyl.

[0065] Examples of aryl groups that are fused to a monocyclic or bicyclic ring system and are also convertible by the terms "heterocyclic" or "heterocyclyl" include (2,3)-dihydrobenzo[b]thiophenyl, (2,3)-dihydro-1H-indenyl, indolinyl, (2,3)-dihydrobenzofuranyl, (2,3)-dihydrobenzo[d]oxazolyl, benzo[d][1,3]dioxolyl, benzo[d][1,3]oxathiolyl, isoindolinyl, (1,3)-dihydroisobenzofuranyl, (1,3)-dihydrobenzo[c]thiophenyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, chromanyl, thiochromanyl, (1,2,3,4)-tetrahydroisoquinolinyl, (1,2,3,4)-tetrahydroquinoxalinyl, (3,4)-dihydro-2H-benzo[b][1,4]oxazinyl, (3,4)-dihydro-2H-benzo[b][1,4]thiazinyl, (2,3)-dihydrobenzo[b][1,4]dioxinyl, (2,3)-dihydrobenzo[b][1,4]oxathiinyl, (6,7,8,9)-tetrahydro-5H-benzo[7]annulenyl, (2,3,4,5)-tetrahydro-1H-benzo[b]azepinyl and (2,3,4,5)-tetrahydro-1H-benzo[c]azepinyl.

[0066] When one of the aforementioned groups is mono- or poly-substituted, suitable substituents are those well-known to those skilled in the art, preferably 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)-O-C 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)-O-C 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) are each independently selected from the group consisting of.

Examples

[0067] The following examples illustrate the present invention but do not limit the present invention.

[0068] Starting materials and protocols: Analytical grade chemicals were procured from common suppliers such as TCI, Aldrich and Acros and used.

[0069] The hydrazones used in the electro-synthesis were prepared from the corresponding aldehydes and hydrazine or hydrazine hydrochloride according to synthetic procedures known from the literature (P.G. Baraldi, S. Baraldi, G. Saponaro, M. Aghazadeh Tabrizi, R. Romagnoli, E. Ruggiero, F. Vincenzi, P.A. 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).

[0070] Isotropic graphite (Cgr, Sigrafine™ V2100, SGL Carbon, Bonn, Germany) was used as the electrode material. Before any tests were carried out, these were treated with sandpaper (grain size 1000 + 1200, Bosch, Stuttgart, Germany) and then the surface was washed with a paper towel.

[0071] Liquid chromatography was carried out as described above on silica gel 60M (40-63 μM, Machery-Nagel GmbH & Co., Dueren, Germany) using a Buechi Sepacore system and Buechi control unit C620, Buechi UV photometer C635, Buechi fraction collector C660 and two Buechi pump modules C605 (Buechi-Labortechnik GmbH, Germany), or using a PURIFLASH C18-HP 30 UM F0080 packed silica column (Interchim, Montlucon Cedex, France).

[0072] High-performance liquid chromatography was performed using a Shimadzu HPLC-MS equipped 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 100-5 C18 column (150x4 mm, Knauer, Berlin). Mobile phase: acetonitrile / water or acetonitrile / water / formic acid (1% by volume).

[0073] NMR spectroscopic measurements of 1H-NMR, 13C-NMR, 15N-NMR, 19F-NMR and 31P-NMR spectra, as well as all 2D NMR spectra, were recorded at 25 °C in CDCl3, DMSO-d6, CD2Cl2, CD3CN, (CD3)2CO or CD3OD using a Bruker Avance II HD 300 or Bruker Avance III HD 400 (400 MHz, 5 mm BBFO head with z-gradient and ATM, SampleXPress 60 sample changer, Analytische Messtechnik, Karlsruhe, Germany). 1H- and 13C-NMR spectra were referenced to the residual solvent signals.

[0074] Electrospray ionization (ESI+ / -) or atmospheric pressure chemical ionization (APCI+ / -) mass spectrometry was performed using an Agilant 6545 QTOF-MS (Agilant, Santa Clara (CA), USA).

[0075] Electrolysis was carried out using a cross stirrer in a temperature-controllable double-jacketed glass cell (SynLectro™, Merck KGaA, Darmstadt, Germany). Upscaling experiments were performed in a 300 ml double-jacketed glass cell. A constant current from a TDK-Lambda Z+ series (TDK-Lambda UK Limited, Devon, UK) was used as the current source.

[0076] Using two synthetic methods according to the present invention, Variant A and B, these are described below: Variant A of the synthesis method The hydrazone (3 mmol, 1 equivalent) and a suitable alkene or alkyne (8.1 mmol, 2.7 equivalents) were first charged into a 50 ml beaker electrolysis cell equipped with a temperature-controlled jacket and a cross-shaped magnetic stir bar. Ethyl acetate (5 ml) and 1 M aqueous sodium iodide solution (20 ml) were added. Constant current electrolysis at 35 mA / cm 2 was carried out with respect to an isotropic graphite (60×20×3 mm, immersion depth 2.7 cm, active electrode area 5.4 cm 2 ) as the anode and cathode at 25 °C and a stirring speed of 1000 rpm until an applied charge of 5 F (1447 C) was reached. The biphasic mixture was then transferred to a separatory funnel and the phases were separated. 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 carried out by column chromatography.

[0077] Variant B of the synthesis method The hydrazone (3.2 mmol, 1 equivalent) and a suitable alkene or alkyne (12.5 mmol, 3.9 equivalents) were first charged into a 50 ml beaker electrolysis cell equipped with a temperature-controlled jacket and a cross-shaped magnetic stir bar. Tert-butyl methyl ether (5 ml) and 1 M aqueous sodium iodide solution (20 ml) were added. Constant current electrolysis at 32.1 mA / cm 2 was carried out with respect to an isotropic graphite (60×20×3 mm, immersion depth 2.7 cm, active electrode area 5.4 cm 2 ) as the anode and cathode at 32 °C and a stirring speed of 1000 rpm until an applied charge of 2.58 F (797 C) was reached. The biphasic mixture was then transferred to a separatory funnel and the phases were separated. 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 carried out by column chromatography.

[0078] Synthesis product According to Variant A of the synthesis method according to the present invention, the herbicide phytotoxicity reducing agent mefenpyr - diethyl, which is agrichemically relevant, was successfully produced in a very good yield of 73% (Scheme 1).

Chemical formula

[0079] Also, according to Variant A of the synthesis method according to the present invention, ethyl glyoxalate phenylhydrazone was reacted with various alkenes and alkynes to obtain the corresponding pyrazoline or pyrazole (see Scheme 2). In particular, polymerization - sensitive alkenes such as styrene (2), acrylates (12, 13, 14), acrylonitrile (15), and acrylamide (16) can be used in the method according to the present invention. Also, alkenes having a silyl group (27) and vinyl phosphonate (11), as well as various alicyclic compounds (22 - 25) can be successfully reacted. The resistance to halogen could also be demonstrated by derivative 29. The results are summarized in Scheme 2.

[0080] Similarly, various benzaldehyde - based hydrazones and derivatives of aliphatic aldehydes were converted to the corresponding pyrazoles and pyrazolines by Variant B of the synthesis method according to the present invention (Scheme 3). In particular, benzaldehyde derivatives with relatively electron - deficient properties could be obtained in good yields. The p - nitro derivative (44) could also be prepared in a yield of 53%. The intramolecular cyclization of relatively electron - rich derivatives was also achieved in a good yield of 53%. In addition to various aromatic aldehydes, aliphatic aldehydes can also be converted. The corresponding pyrazolines were obtained in yields of 23 - 38%. The results are summarized in Scheme 3.

[0081] Furthermore, the applicability of the reactions according to variant methods A and B of the synthesis method according to the present invention was tested for hydrazones derived from various hydrazines using styrene as the parent dipole (Scheme 4). Here, both electron-deficient hydrazones and electron-rich hydrazones could be converted in yields up to 93% (Example 54). The results are summarized in Scheme 4.

[0082]

Chem.

[0083]

Chem.

[0084]

Chem.

[0085] The individual syntheses of Schemes 1 to 4 are described in detail below.

[0086] Example 1: Diethyl 1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate (mephenpyr-diethyl)

Chem.

[0087] Synthesis according to variant method A using ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (3 mmol, 783 mg, 1 equivalent) and ethyl methacrylate (8.1 mmol, 925 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 4% EtOAc), the pyrazoline was obtained as an orange oil (2.28 mmol, 820 mg, 73%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.41 (d, J = 2.1 Hz, 1H, H-3’), 7.25 - 7.19 (m, 2H, H-5’, H-6’), 4.33 (qd, J = 7.2, 1.7 Hz, 2H, H-2’’), 4.19 (q, J = 7.2 Hz, 2H, H-2’’’), 3.73 (d, J = 17.7 Hz, 1H, (H-4)’), 3.12 (d, J = 17.7 Hz, 1H, (H-4)’’), 1.46 (s, 3H, H-1’’’’), 1.35 (t, J = 7.1 Hz, 3H, H-3’’), 1.24 (t, J = 7.1 Hz, 3H, H-3’’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 18 35 Cl2N2O4 + H] + calculated value 373.0716, measured value 373.0718; [C 16 H 18 35 Cl 37 ClN2O4 + H] + calculated value 375.0690, measured value 375.0692; [C 16 H 18 37 Cl2N2O4 + H] + calculated value 377.0669, measured value 377.0674.

[0088] Example 2: Ethyl 1,5-diphenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0089] Synthesis according to Modified Method A using ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 equiv) and styrene (10.5 mmol, 1097 mg, 2.7 equiv). A charge of 5.4 F (2032 C) was applied. After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (3.02 mmol, 890 mg, 77%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.35 - 7.16 (m, 7H, H-3‘, H-2‘‘‘, H-3‘‘‘, H-4‘‘‘), 7.10 (dt, J = 7.9, 1.3 Hz, 2H, H-2’), 6.87 (tt, J = 7.2, 1.2 Hz, 1H, H-4‘), 5.42 (dd, J = 13.3, 7.0 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’‘), 3.72 (dd, J = 18.0, 13.3 Hz, 1H, (H-4)’), 3.05 (dd, J = 18.0, 7.0 Hz, 1H, (H-4)’’), 1.37 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 H 18 N2O2 + H] + Calculated value for 295.1441, found 295.1447.

[0090] Recycling of sodium iodide: Synthesis according to Variant A using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). Sodium iodide recovered from the reaction mixture for the synthesis of pyrazoline 32 was used by lyophilizing the aqueous phase. After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a yellow solid (2.40 mmol, 707 mg, 80%).

[0091] Scale-up (47 mmol): Similar to Variant A of the synthesis method, ethyl 2-(2-phenylhydrazono)acetate (46.8 mmol, 9.0 g, 1 equivalent) and styrene (126.3 mmol, 13.16 g, 2.7 equivalents) were initially charged into a 300 ml beaker cell equipped with a magnetic stir bar having a temperature control jacket and a stabilizing ring. Ethyl acetate (60 ml) and 1 M aqueous sodium iodide solution (240 ml) were added. Constant current electrolysis at 35 mA / cm 2 was carried out at 25 °C with a stirring speed of 750 rpm on a bipolar electrode stack consisting of four isotropic graphite electrodes (each 100×50×5 mm, immersion depth 7 cm, total active electrode area 105 cm 2 ) until the applied charge reached 5.4 F (24 488 C). The two-phase mixture was transferred to a separatory funnel, the phases were separated, 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 using cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a yellow solid (36.0 mmol, 10.6 g, 77%).

[0092] Example 3: Ethyl 5-(4-(tert-butyl)phenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0093] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 4-tert-butylstyrene (8.1 mmol, 1298 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (2.10 mmol, 735 mg, 70%). 1 1H-NMR (400 MHz, 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, 1.3 Hz, 1H, H-4’), 5.40 (dd, J = 13.2, 6.9 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.70 (dd,, J = 18.0, 13.3 Hz, 1H, (H-4)’), 3.05 (dd, J = 18.0, 6.9 Hz, 1H, (H-4)’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’), 1.30 (s, 9H, H-6’’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 22 H 26 N2O2 + H] + Calculated value 351.2067, measured value 351.2058.

[0094] Example 4: Ethyl 5-(naphthalen-2-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0095] Synthesis according to Variant A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 2-vinylnaphthalene (8.1 mmol, 1249 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow solid (1.34 mmol, 462 mg, 45%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.87 - 7.75 (m, 3H, H-3''', H-6''', H-7'''), 7.70 (d, J = 1.7 Hz, 1H, H-2'''), 7.51 - 7.45 (m, 2H, H-4''', H-5'''), 7.34 (dd, J = 8.5, 1.8 Hz, 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, 7.1 Hz, 1H, H-5), 4.35 (q, J = 7.1 Hz, 2H, H-2''), 3.79 (dd, J = 18.0, 13.3 Hz 1H, (H-4)'), 3.12 (dd, J = 18.1, 7.1 Hz 1H, (H-4)''), 1.38 (t, J = 7.1 Hz, 3H, H-3''). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 22 H 20 N2O2 + H] + Calculated value for 345.1598, measured value 345.1598.

[0096] Example 5: Ethyl 5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0097] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 4-methoxystyrene (8.1 mmol, 1087 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow solid (1.34 mmol, 433 mg, 45%). 1 1H-NMR (400 MHz, 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, 7.0 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.77 (s, 3H, H-5’’’), 3.69 (dd, J = 13.2, 7.0 Hz, 1H, (H-4)’), 3.02 (dd, J = 18.0, 7.0 Hz, 1H, (H-4)’’), 1.37 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 19 H 20 N2O3 + H] + Calculated value 325.1547, measured value 325.1544.

[0098] Example 6: Ethyl 5-(2,6-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate [Chemical formula]

[0099] Synthesis by modified method A of the synthetic method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 2,6-dichlorostyrene (8.1 mmol, 1402 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (1.77 mmol, 643 mg, 59%). 1 H-NMR (400 MHz, CDCl3), δ / ppm: 7.38 (dd, J = 8.0, 1.4 Hz, 1H, H-3‘‘‘), 7.24 (dd, J = 8.1, 1.4 Hz, 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, 1.0 Hz, 1H, H-4‘), 6.22 (dd, J = 14.6, 10.3 Hz, 1H, H-5), 4.37 (qd, J = 7.1, 3.0 Hz, 2H, H-2‘‘), 3.66 (dd, J = 18.1, 14.6 Hz, 1H, (H-4)‘), 3.20 (dd, J = 18.1, 10.3 Hz, 1H, (H-4)‘‘), 1.39 (t, J = 7.1 Hz, 3H, H-3‘‘). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C18 H 16 35 Cl2N2O2 + Na] + Calculated value 385.0481, measured value 385.0486; [C 18 H 16 35 Cl 37 ClN2O2 + Na] + Calculated value 387.0455, measured value 387.0460; [C 18 H 16 37 Cl2N2O2 + Na] + Calculated value 389.0434, measured value 389.0454.

[0100] Example 7: Ethyl 1,5,5-triphenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0101] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 1,1-diphenylethene (8.1 mmol, 1460 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow oil (0.87 mmol, 323 mg, 29%). 1 H-NMR (400 MHz, 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 = 7.1 Hz, 2H, H-2’’), 3.94 (s, 2H, H-4), 1.37 (t, J = 7.1 Hz, 3H, H-3’’). 1313C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 24 H 22 N2O2 + H] + Calculated value for [C19H15N2O2 + H] is 371.1754, found 371.1753.

[0102] Example 8: Ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate

Chemical Structure

[0103] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 equivalent) and phenylacetylene (10.5 mmol, 1070 mg, 2.7 equivalents). A charge of 5.4 F was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a yellow oil (0.99 mmol, 288 mg, 25%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.36 - 7.28 (m, 8H, H-2’, H-3’, H-2’’’, H-3’’’), 7.23 - 7.20 (m, 2H, H-4’, H-4’’’), 7.05 (s, 1H, H-4), 4.46 (q, J = 7.1 Hz, 2H, H-2’’), 1.43 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 H 16 N2O2 + H] + Calculated value 293.1285, measured value 293.1290.

[0104] Example 9: Ethyl 1-phenyl-1H-pyrazole-3-carboxylate

Chemical Structure

[0105] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and vinyl acetate (8.1 mmol, 697 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 10% EtOAc), the pyrazole was obtained as a yellow solid (0.96 mmol, 208 mg, 32%).

[0106] In this case, the initially formed acetylated pyrazole spontaneously deacetylates to give the compound ethyl 1-phenyl-1H-pyrazole-3-carboxylate. 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.93 (d, J = 2.5 Hz, 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 = 2.5 Hz, 1H, H-4), 4.44 (q, J = 7.1 Hz, 2H, H-2’’), 1.42 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, CDCl3), δ / ppm: 162.4, 145.4, 139.8, 129.6, 128.5, 127.8, 120.3, 110.5, 61.3, 14.5. HRMS (APCI+), m / z: [C 12H 12 N2O2 + H] + Calculated value: 217.0972, measured value: 217.0986.

[0107] Example 10: Ethyl 5-butyl-1-phenyl-1H-pyrazole-3-carboxylate

Chemical Structure

[0108] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 1-hexyne (8.1 mmol, 665 mg, 2.7 equivalents). Electrolysis was carried out at 50 °C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a dark yellow oil (0.26 mmol, 71 mg, 9%). 1 1H-NMR (400 MHz, 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 = 7.1 Hz, 2H, H-2’’), 2.60 (t, J = 7.7 Hz, 2H, H-1’’’), 1.56 (tt, J = 7.6, 7.6 Hz, 2H, H-2’’’), 1.39 (t, J = 7.1 Hz, 3H, H-3’’), 1.30 (qt, J = 7.4, 7.4 Hz, 2H, H-3’’’), 0.85 (t, J = 7.3 Hz, 3H, H-4’’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 20 N2O2 + H] +Calculated value: 273.1598, measured value: 273.1598.

[0109] Example 11: Ethyl 5-(diethoxyphosphoryl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0110] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and diethyl vinylphosphonate (8.1 mmol, 1330 mg, 2.7 equivalents). The pyrazoline was obtained as a yellow oil (1.32 mmol, 469 mg, 44%) by flash column chromatography on silica using cyclohexane / ethyl acetate (5% → 30% EtOAc) and reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (25% → 60% acetonitrile). 1 H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 4.69 (dd, J = 13.7, 7.2 Hz, 1H, H-5), 4.34 (qd, J = 7.1, 0.7 Hz, 2H, H-2’’), 4.19 - 3.95 (m, 4H, H-1’’’), 3.67 - 3.39 (m, 2H, H-4), 1.37 (t, J = 7.1 Hz, 3H, H-3’’), 1.24 (dt, J = 9.8, 7.1 Hz, 6H, H-2‘‘‘). 1313C-NMR (101 MHz, CDCl3), δ / ppm: 162.3, 143.4, 140.3 (d, J = 5.5 Hz), 129.0, 122.2, 115.9, 63.5 (d, J = 7.3 Hz), 63.0 (d, J = 7.0 Hz), 61.5, 58.3 (d, J = 164.0 Hz), 35.4 (d, J = 3.3 Hz), 16.6 (d, J = 5.5 Hz), 16.5 (d, J = 5.5 Hz), 14.5. 31 31P-NMR (162 MHz, CDCl3), δ / ppm: 19.69. HRMS (ESI+), m / z: [C 16 H 23 N2O5P + H] + Calculated value for 355.1417, measured value 355.1421.

[0111] Example 12: 3-Ethyl 5-methyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

Chemical Structure

[0112] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 equivalent) and methyl acrylate (10.5 mmol, 904 mg, 2.7 equivalents). A charge of 5.4 F was applied. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline was obtained as a yellow oil (3.46 mmol, 957 mg, 89%). 11H-NMR (400 MHz, CDCl3), δ / ppm: 7.32 - 7.25 (m, 2H, H-3’), 7.13 (dt, J = 7.9, 1.1 Hz, 2H, H-2’), 6.97 (tt, J = 7.3, 1.1 Hz, 1H, H-4’), 4.94 (dd, J = 13.6, 6.6 Hz, 1H, H-5), 4.34 (qd, J = 7.1, 0.7 Hz, 2H, H-2’’), 3.74 (s, 3H, H-2’’’), 3.55 (dd, J = 18.1, 13.5 Hz, 1H, (H-4)’), 3.32 (dd, J = 18.2, 6.6 Hz, 1H, (H-4)’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 14 H 16 N2O4 + H] + Calculated value 277.1183, measured value 277.1192.

[0113] Example 13: 3-Ethyl 5,5-dimethyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate [Chemical formula]

[0114] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and methyl methacrylate (8.1 mmol, 811 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a yellow oil (2.44 mmol, 709 mg, 81%). 11H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 4.30 (q, J = 7.1 Hz, 2H, H-2’’), 3.76 (s, 3H, H-2’’’), 3.54 (d, J = 17.8 Hz, 1H, (H-4)’), 3.18 (d, J = 17.8 Hz, 1H, (H-4)’’), 1.64 (s, 3H, H-1’’’’), 1.35 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 15 H 18 N2O4+ H] + Calculated value for [C17H21N2O4 + H] is 291.1339, found 291.1344.

[0115] Example 14: 3-Ethyl 5-methyl 5-(2-methoxy-2-oxoethyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

Chemical Structure

[0116] Synthesis according to modified method A of the synthesis method, using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and dimethyl itaconate (8.1 mmol, 1281 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→8% EtOAc), the pyrazoline was obtained as a yellow oil (2.73 mmol, 950 mg, 91%). 11H-NMR (400 MHz, 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 = 7.1 Hz, 2H, H-2’’), 3.72 (d, J = 18.4 Hz, 1H, (H-1’’’’)’), 3.70 (s, 3H, H-3’’’’), 3.65 (d, J = 18.4 Hz, 1H, (H-1’’’’)’’), 3.59 (s, 3H, H-2’’’), 3.25 (d, J = 16.6 Hz, 1H, (H-4)’), 2.87 (d, J = 16.6 Hz, 1H, (H-4)’’), 1.33 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 17 H 20 N2O6 + H] + Calculated value for 349.1394, measured value 349.1395.

[0117] Example 15: Ethyl 5-cyano-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0118] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and acrylonitrile (8.1 mmol, 430 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (2.68 mmol, 653 mg, 90%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.39 - 7.33 (m, 2H, H-3’), 7.24 (dt, J = 8.8, 1.0 Hz, 2H, H-2’), 7.10 - 7.04 (m, 1H, H-4’), 5.07 (ddd, J = 10.6, 8.2, 0.6 Hz, 1H, H-5), 4.35 (q, J = 7.1 Hz, 2H, H-2’’), 3.61 - 3.50 (m, 2H, H-4), 1.38 (td, J = 7.1, 0.7 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 13 H 13 N3O2+ Na] + The calculated value is 266.0900, the measured value is 266.0896.

[0119] Example 16: Ethyl 5-(dimethylcarbamoyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0120] Synthesis according to modified method A of the synthesis method, using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and N,N-dimethylacrylamide (8.1 mmol, 803 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow solid (1.73 mmol, 501 mg, 58%). 1 1H-NMR (400 MHz, 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, 7.9 Hz, 1H, H-5), 4.32 (qd, J = 7.1, 1.7 Hz, 2H, H-2’’), 3.54 (dd, J = 17.8, 14.0 Hz, 1H, (H-4)’), 3.12 (dd, J = 17.9, 7.9 Hz, 1H, (H-4)’’), 3.06 (s, 3H, H-2’’’), 2.97 (s, 3H, H-3’’’), 1.35 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 15 H 19 N3O3 + H] + Calculated value for 290.1499, measured value 290.1491.

[0121] Example 17: 3-Ethyl 4,5-dimethyl 1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate

Chemical formula

[0122] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and dimethyl maleate (8.1 mmol, 1167 mg, 2.7 equivalents). After flash column chromatography on silica using 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- and 4,5-trans-substituted pyrazolines ( 1 determined by 1H NMR).

[0123] Analysis data of 3-ethyl 4,5-dimethyl 4,5-cis-1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate: 1 1H-NMR (400 MHz, CD3CN), δ / ppm: 7.37 - 7.29 (m, 2H, H-3’), 7.06 (dt, J = 7.8, 1.1 Hz, 2H, H-2’), 7.02 (tt, J = 7.2, 1.1 Hz, 1H, H-4’), 5.41 (d, J = 13.8 Hz, 1H, H-5), 4.70 (d, J = 13.8 Hz, 1H, H-4), 4.26 (dddd, J = 17.9, 10.8, 7.1, 3.7 Hz, 2H, H-2’’), 3.71 (s, 3H, H-2’’’’), 3.66 (s, 3H, H-2’’’), 1.29 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 18 N2O6 + H] + calculated value 335.1238, measured value 335.1241.

[0124] Example 18: 3-Ethyl 4,5-dimethyl 4,5-trans-1-phenyl-4,5-dihydro-1H-pyrazole-3,4,5-tricarboxylate

Chemical formula

[0125] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and dimethyl fumarate (8.1 mmol, 1167 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→10% EtOAc), the pyrazoline was obtained as a yellow oil (2.10 mmol, 701 mg, 70%). 1 1H-NMR (400 MHz, 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 = 5.8 Hz, 1H, H-5), 4.39 (d, J = 5.8 Hz, 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 = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 18 N2O6+ Na] + Calculated value 357.1057, measured value 357.1057.

[0126] Example 19: Ethyl 3a,8b-cis-1-phenyl-1,3a,4,8b-tetrahydroindeno[1,2-c]pyrazole-3-carboxylate [Chemical formula]

[0127] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and indene (8.1 mmol, 941 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a pale yellow solid (1.60 mmol, 491 mg, 52%). 1 H-NMR (400 MHz, 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, 1.5 Hz, 1H, H-4’), 6.12 (d, J = 10.6 Hz, 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 = 7.1 Hz, 3H, H-3’’). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 19 H 18 N2O2 + H] + Calculated value for 307.1441, measured value 307.1434.

[0128] Example 20: Ethyl 4,5-trans-5-(4-methoxyphenyl)-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0129] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and trans-anethole (8.1 mmol, 1200 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline was obtained as a yellow oil (0.43 mmol, 165 mg, 16%). 1 1H-NMR (400 MHz, 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 = 5.8 Hz, 1H, H-5), 4.34 (qd, J = 7.1, 2.8 Hz, 2H, H-2’’), 3.77 (s, 3H, H-5’’’’), 3.27 (qd, J = 7.1, 5.7 Hz, 1H, H-4), 1.44 (d, J = 7.1 Hz, 3H, H-1’’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 20 H 22 N2O3+ H] + Calculated value 339.1703, measured value 339.1695.

[0130] Example 21: Ethyl 4,5-trans-1,4,5-triphenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (21)

Chemical formula

[0131] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 equivalent) and trans-stilbene (10.5 mmol, 1893 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as an orange solid (0.37 mmol, 137 mg, 9%). 1 H-NMR (400 MHz, 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, 1.5 Hz, 1H, H-4’), 5.29 (d, J = 5.2 Hz, 1H, H-5), 4.32 (d, J = 5.2 Hz, 1H, H-4), 4.28 - 4.10 (m, 2H, H-2’’), 1.21 (t, J = 7.1 Hz, 3H, H-3’’). 13 C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 24 H 22 N2O2 + H] + Calculated value 371.1754, measured value 371.1760.

[0132] Example 22: Ethyl 3a,7a-cis-1-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoindazole-3-carboxylate

Chemical formula

[0133] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3.9 mmol, 750 mg, 1 equivalent) and norbornene (10.5 mmol, 998 mg, 2.7 equivalents). A charge of 5.4 F (2032 C) was applied. After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), pyrazoline was obtained as a yellow solid (3.55 mmol, 1010 mg, 91%). 1 1H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 4.39 - 4.26 (m, 2H, H-2’’), 4.23 (d, J = 10.0 Hz, 1H, H-7a), 3.42 (d, J = 9.9 Hz, 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)’), 1.46 - 1.29 (m, 3H, (H-5)’’, (H-6)’’, (H-8)’), 1.37 (t, J = 7.1 Hz, 3H, H-3’’), 1.27 - 1.18 (m, 1H, (H-8)’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 17 H 20 N2O2 + H] + Calculated value 285.1598, measured value 285.1599.

[0134] Example 23: Ethyl 3a,9a-cis-5,8-bisacetoxy-1-phenyl-3a,4,9,9a-tetrahydro-1H-4,9-methanobenzo[f]indazole-3-carboxylate

Chemical Structure

[0135] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 5,8-bisacetoxybenzene[e]norbornene (8.1 mmol, 2092 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 5% EtOAc), pyrazoline was obtained as a yellow solid (2.43 mmol, 1089 mg, 81%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.32 (m, 4H, H-2’, H-3’), 6.98 (m, 1H, H-4’), 6.89 (d, J = 8.8 Hz, 1H, H-6), 6.86 (d, J = 8.8 Hz, 1H, H-7), 4.80 (d, J = 9.9 Hz, 1H, H-9a), 4.45 - 4.26 (m, 2H, H-2’’), 3.88 (d, J = 9.9 Hz, 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 = 7.1 Hz, 3H, H-3’’). 1313C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 25 H 24 N2O6 + H] + Calculated value for 449.1707, measured value 449.1696.

[0136] Example 24: Ethyl 3a,9a-cis-1-phenyl-3a,4,5,6,7,8,9,9a-octahydro-1H-cyclooct[c]pyrazole-3-carboxylate

Chemical Structure

[0137] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and cis-cyclooctene (8.1 mmol, 893 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow oil (1.02 mmol, 306 mg, 34%). 11H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 4.44 - 4.25 (m, 3H, H-9a, H-2’’), 3.46 (ddd, J = 12.6, 11.0, 1.6 Hz, 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 = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 18 H 24 N2O2 + H] + Calculated value for [C21H26N2O2 + H]+ 301.1911, found 301.1910.

[0138] Example 25: Ethyl 3a,7a-cis-1-phenyl-6,6,7a-trimethyl-3a,4,5,6,7,7a-hexahydro-1H-5,7-methanoindazole-3-carboxylate

Chemical Structure

[0139] Synthesis according to modified method A of the synthetic method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and (-)-α-pinene (8.1 mmol, 1103 mg, 2.7 equivalents). After purification by flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc) and preparative HPLC (water (+1 volume% formic acid) / acetonitrile 70%→100% MeCN), the pyrazoline was obtained as a yellow solid (0.11 mmol, 36 mg, 4%). 1 1H-NMR (400 MHz, 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, 5.0 Hz, 1H, H-3a), 2.57 (dd, J = 6.2, 4.6 Hz, 1H, H-7), 2.46 (dddd, J = 13.8, 10.8, 3.1, 2.1 Hz, 1H, (H-4)’), 2.25 (dddd, J = 10.6, 6.3, 6.3, 2.1 Hz, 1H, (H-8)’), 1.96 (dddd, J = 7.8, 3.1, 3.1, 3.0 Hz, 1H, H-5), 1.75 (ddd, J = 13.8, 5.0, 3.0 Hz, 1H, (H-4)’’), 1.40 (s, 3H, H-1‘‘‘), 1.38 (t, J = 7.1 Hz, 3H, H-3’’), 1.32 (s, 3H, H-6’), 1.04 (s, 3H, H-6’’), 0.96 (dd, J = 9.4, 4.8 Hz, 1H, (H-8)’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C20 H 26 N2O2 + H] + Calculated value: 327.2067, measured value: 327.2069.

[0140] Example 26: Ethyl (1R,5S)-6,6-dimethyl-2'-phenyl-1',2'-dihydrospiro[bicyclo[3.1.1]heptane-2,3'-pyrazole]-5'-carboxylate

Chemical Structure

[0141] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and (-)-β-pinene (8.1 mmol, 1103 mg, 2.7 equivalents). After purification by flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc) and preparative HPLC (70% water / acetonitrile → 100% MeCN), the pyrazoline was obtained as a yellow solid (0.21 mmol, 68 mg, 7%). 11H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’’), 5.46 - 5.41 (m, 1H, H-4’), 4.31 (q, J = 7.1 Hz, 2H, H-2’’’), 3.50 (dq, J = 16.5, 2.4 Hz, 1H, (H-3)’), 3.27 (dq, J = 16.4, 1.9 Hz, 1H, (H-3)’’), 2.38 (dt, J = 8.8, 5.6 Hz, 1H, (H-7)’), 2.31 (dp, J = 18.0, 3.0 Hz, 1H, (H-4)’), 2.23 (dp, J = 17.9, 2.6 Hz, 1H, (H-4)’’), 2.11 (ttd, J = 5.6, 2.7, 1.2 Hz, 1H, H-5), 2.04 (td, J = 5.6, 1.6 Hz, 1H, H-1), 1.38 (t, J = 7.1 Hz, 3H, 3’’’), 1.27 (s, 3H, H-6’), 1.13 (d, J = 8.8 Hz, 1H, (H-7)’’), 0.86 (s, 3H, H-6’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 20 H 26 N2O2 + H] + Calculated value for [C21H28N2O2 + H] is 327.2067, found 327.2054.

[0142] Example 27: Ethyl 1-phenyl-5-((trimethylsilyl)methyl)-4,5-dihydro-1H-pyrazole-3-carboxylate [Chemical formula]

[0143] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and allyltrimethylsilane (8.1 mmol, 926 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow oil (1.03 mmol, 315 mg, 34%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 7.29 (tt, J = 7.3, 2.0 Hz, 2H, H-3’), 7.18 - 7.12 (m, 2H, H-2’), 6.94 (tt, J = 7.3, 1.2 Hz, 1H, H-4’), 4.60 (dddd, J = 11.8, 11.8, 5.2, 1.8 Hz, 1H, H-5), 4.34 (qd, J = 7.1, 2.2 Hz, 2H, H-2’’), 3.29 (dd, J = 17.4, 11.7 Hz, 1H, (H-4)’), 2.78 (dd, J = 17.4, 5.1 Hz, 1H, (H-4)’’), 1.38 (t, J = 7.1 Hz, 3H H-3’’), 1.24 (dd, J = 14.6, 1.8 Hz, 1H, (H-1’’’)’), 0.90 (dd, J = 14.6, 11.8 Hz, 1H, (H-1’’’)’’), 0.11 (s, 9H, H-2’’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 24 N2O2Si + H] + Calculated value 305.1680, measured value 305.1684.

[0144] Example 28: Ethyl 5-butyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0145] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 1-hexene (8.1 mmol, 682 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow oil (0.95 mmol, 261 mg, 32%). 1 1H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 4.51 (dddd, J = 12.1, 9.3, 5.2, 2.6 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.28 (dd, J = 17.6, 12.2 Hz, 1H, (H-4)’), 2.93 (dd, J = 17.7, 5.2 Hz, 1H, (H-4)’’), 1.87 - 1.72 (m, 1H, (H-1’’’)’), 1.61 - 1.46 (m, 1H, (H-1’’’)’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’), 1.35 - 1.21 (m, 4H, H-2’’’, H-3’’’), 0.99 - 0.79 (m, 3H, H-4’’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 16 H 22 N2O2 + H] + Calculated value: 275.1754, measured value: 275.1758.

[0146] Example 29: Ethyl 5-(4-bromobutyl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0147] Synthesis according to modified method A of the synthesis method, using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and 6-bromo-1-hexene (8.1 mmol, 1321 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow oil (0.99 mmol, 348 mg, 33%). 11H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 4.53 (dddd, J = 11.9, 8.9, 5.2, 2.6 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.37 (td, J = 6.7, 2.4 Hz, 2H, H-4’’’), 3.30 (dd, J = 17.8, 12.3 Hz, 1H, (H-4)’), 2.94 (dd, J = 17.7, 5.2 Hz, 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, 6.1 Hz, 2H, H-2’’’), 1.37 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 21 79 BrN2O2 + H] + calculated value 353.0859, measured value 353.0864; [C 16 H 21 81 BrN2O2 + H] + calculated value 355.0839, measured value 355.0845.

[0148] Example 30: Ethyl 5-cyclohexyl-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0149] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and vinylcyclohexane (8.1 mmol, 893 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as an orange solid (0.85 mmol, 254 mg, 28%). 1 H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 4.50 (ddd, J = 12.1, 6.7, 3.5 Hz, 1H, H-5), 4.33 (q, J = 7.1 Hz, 2H, H-2’’), 3.10 (dd, J = 18.0, 12.1 Hz, 1H, (H-4)’), 3.05 (dd, J = 18.1, 6.6 Hz, 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 = 7.1 Hz, 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 )‘‘). 1313C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 18 H 24 N2O2 + H] + Calculated value for 301.1911, measured value 301.1906.

[0150] Example 31: Ethyl 5-(9H-carbazol-9-yl)-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0151] Synthesis by modified method A of the synthesis method using ethyl 2-(2-phenylhydrazono)acetate (3 mmol, 577 mg, 1 equivalent) and N-vinylcarbazole (8.1 mmol, 1565 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as an orange solid (1.68 mmol, 643 mg, 56%). 11H-NMR (400 MHz, DMSO-d6), δ / ppm: 8.18 (d, J = 7.6 Hz, 1H, H-4'''), 8.15 (d, J = 7.7 Hz, 1H, H-5'''), 8.07 (d, J = 8.3 Hz, 1H, H-1'''), 7.66 - 7.55 (m, 2H, H-5, H-2'''), 7.36 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H, H-7'''), 7.34 - 7.30 (m, 1H, H-3'''), 7.19 (ddd, J = 7.9, 7.3, 0.9 Hz, 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, 0.9 Hz, 1H, H-8'''), 6.78 (tt, J = 7.1, 1.3 Hz, 1H, H-4'), 4.34 (q, J = 7.1 Hz, 2H, H-2''), 3.85 (dd, J = 19.4, 12.9 Hz, 1H, (H-4)'), 3.19 (dd, J = 19.4, 5.9 Hz, 1H, (H-4)''), 1.32 (t, J = 7.1 Hz, 3H, H-3'') 13 13C-NMR (101 MHz, DMSO-d6), δ / ppm: 161.6, 141.2, 139.6, 139.5, 136.4, 129.2, 126.5, 126.4, 123.8, 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. HRMS (APCI+), m / z: [C 24 H 21 N3O2 + H] + Calculated value for [C21H17N3O2 + H] is 384.1707, measured value is 384.1703.

[0152] Example 32: 1,3,5-Triphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0153] Synthesis by modified method B of the synthesis method using benzaldehyde phenylhydrazone (3.2 mmol, 625 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (65% → 72% acetonitrile), pyrazoline was obtained as a yellow solid (2.36 mmol, 704 mg, 74%). 1 H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 5.28 (dd, J = 12.4, 7.3 Hz, 1H, H-5), 3.85 (dd, J = 17.1, 12.4 Hz, 1H, (H-4)’), 3.15 (dd, J = 17.0, 7.3 Hz, 1H, (H-4)’’). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 21 H 18 N2+ H] + Calculated value for 299.1543, measured value 299.1542.

[0154] Upscaling (38 mmol): Similar to Variant Method B of the synthesis method, benzaldehyde phenylhydrazone (38.2 mmol, 7.5 g, 1 equivalent) and styrene (149 mmol, 15.52 g, 3.9 equivalents) were first charged into a 300 ml beaker cell equipped with a temperature-controlled jacket and a magnetic stir bar with a stabilizing ring. tert-Butyl methyl ether (60 ml) and 1 M aqueous sodium iodide solution (240 ml) were added. Constant current electrolysis at 32 mA / cm 2 was carried out on a bipolar electrode stack consisting of four isotropic graphite (each 100×50×5 mm, immersion depth 7 cm, total active electrode area 105 cm 2 ) at 32 °C and a stirring speed of 750 rpm until the applied charge reached 2.6 F (9587 C). The two-phase mixture was transferred to a separatory funnel, the phases were separated, 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. Unreacted styrene (8.0 g, 76.8 mmol, 2 equivalents) was recovered by vacuum distillation. After recrystallization from isopropanol, pyrazoline was obtained as a yellow solid (26.4 mmol, 7.89 g, 69%). The sodium iodide used was recovered by lyophilizing the separated aqueous phase (36.3 g, 242 mmol, quantitative). An aliquot (3.0 g, 20 mmol) was reused for the synthesis of pyrazoline 1 (see above).

[0155] Example 33: 3-(4-Methylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0156] Synthesis according to Variant Method B of the synthesis method, using 4-methylbenzaldehyde phenylhydrazone (3.2 mmol, 673 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (50%→80% acetonitrile), pyrazoline was obtained as a yellow solid (2.15 mmol, 672 mg, 67%). 1 1H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 5.44 (dd, J = 12.2, 6.4 Hz, 1H, H-5), 3.89 (dd, J = 17.4, 12.2 Hz, 1H, (H-4)’), 3.07 (dd, J = 17.4, 6.4 Hz, 1H, (H-4)’’), 2.33 (s, 3H, H-5’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 22 H 20 N2+H] + Calculated value for [C22H21N2+H] is 313.1699, measured value is 313.1701.

[0157] Example 34: 3-(4-tert-Butylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0158] Synthesis according to variant B of the synthesis method using 4-tert-butylbenzaldehyde phenylhydrazone (3.2 mmol, 808 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (75% → 85% acetonitrile), the pyrazoline was obtained as a yellow solid (0.80 mmol, 285 mg, 25%). 1 H-NMR (400 MHz, 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, 3.0 Hz, 1H, H-4’’’), 7.12 (tt, J = 7.3, 2.1 Hz, 2H, H-3’), 7.05 - 6.98 (m, 2H, H-2’), 6.71 (tt, J = 7.3, 1.2 Hz, 1H, H-4’), 5.20 (dd, J = 12.3, 7.1 Hz, 1H, H-5), 3.78 (dd, J = 17.0, 12.3 Hz, 1H, (H-4)’), 3.08 (dd, J = 17.0, 7.1 Hz, 1H, (H-4)’’), 1.28 (s, 9H, H-6’’). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 25 H 26 N2+ H] + Calculated value for 355.2169, found 355.2175.

[0159] Example 35: 3-(4-Phenylphenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole [Chemical]

[0160] Synthesis according to modified method B of the synthesis method using 4-phenylbenzaldehyde phenylhydrazone (3.2 mmol, 872 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (70% → 100% acetonitrile), the pyrazoline was obtained as a pale yellow solid (0.65 mmol, 244 mg, 20%). 1 H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 5.51 (dd, J = 12.2, 6.3 Hz, 1H, H-5), 3.96 (dd, J = 17.5, 12.2 Hz, 1H, (H-4)’), 3.15 (dd, J = 17.5, 6.3 Hz, 1H, (H-4)’’). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 27 H 22 N2 + H] + Calculated value 375.1856, measured value 375.1848.

[0161] Example 36: 3-(Naphthalen-2-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical formula

[0162] Synthesis by modified method B of the synthesis method using 2-formylnaphthalenephenylhydrazone (3.2 mmol, 788 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (0.79 mmol, 275 mg, 25%). 1 H-NMR (400 MHz, CDCl3), δ / ppm: 8.18 (dd, J = 8.6, 1.7 Hz, 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, 1.2 Hz, 1H, H-4’), 5.34 (dd, J = 12.4, 7.2 Hz, 1H, H-5), 3.97 (dd, J = 16.9, 12.4 Hz, 1H, (H-4)’), 3.28 (dd, J = 16.9, 7.2 Hz, 1H, (H-4)’’). 1313C-NMR (101 MHz, CDCl3), δ / ppm: 146.9, 144.9, 142.7, 133.6, 133.5, 130.6, 129.3, 129.1, 128.3, 128.2, 128.0, 127.7, 126.6, 126.5, 126.0, 125.2, 123.6, 119.3, 113.6, 64.7, 43.7. HRMS (ESI+), m / z: [C 25 H 20 N2 + H] + Calculated value for 349.1699, measured value 349.1707.

[0163] Example 37: 3-(4-Fluorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0164] Synthesis by modified method B of the synthetic method using 4-fluorobenzaldehyde phenylhydrazone (3.2 mmol, 686 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 2% EtOAc), the pyrazoline was obtained as an orange solid (2.44 mmol, 772 mg, 76%). 11H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 5.31 (dd, J = 12.3, 7.3 Hz, 1H, H-5), 3.85 (dd, J = 17.1, 12.3 Hz, 1H, (H-4)’), 3.12 (dd, J = 17.1, 7.1 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, 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. 19 19F-NMR (376 MHz, CD3CN), δ / ppm: -115.4. HRMS (APCI+), m / z: [C 21 H 17 FN2+H] + calculated value 317.1449, measured value 317.1446.

[0165] Example 38: 3-(4-Chlorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0166] Synthesis by Variant Method B of the synthesis method using 4-chlorobenzaldehyde phenylhydrazone (3.2 mmol, 738 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a colorless solid (2.25 mmol, 749 mg, 70%). 1 1H-NMR (400 MHz, (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, 1.3 Hz, 1H, H-4’), 5.47 (dd, J = 12.4, 6.8 Hz, 1H, H-5), 3.96 (dd, J = 17.4, 12.4 Hz, 1H, (H-4)’), 3.13 (dd, J = 17.4, 6.8 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, (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. HRMS (ESI+), m / z: [C 21 H 17 35 ClN2+H] + calculated value 333.1153, measured value 333.1151; [C 21 H 17 37 ClN2+H] + calculated value 335.1131, measured value 335.1133.

[0167] Example 39: 3-(4-Bromophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0168] Synthesis according to modified method B of the synthesis method using 4-bromobenzaldehyde phenylhydrazone (3.2 mmol, 880 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→2% EtOAc), the pyrazoline was obtained as a yellow solid (1.95 mmol, 737 mg, 61%). 1 H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 5.50 (dd, J = 12.3, 6.4 Hz, 1H, H-5), 3.91 (dd, J = 17.5, 12.4 Hz, 1H, (H-4)’), 3.10 (dd, J = 17.5, 6.4 Hz, 1H, (H-4)’’). 13 C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 21 H 17 79 BrN2+H] + Calculated value 377.0648, measured value 377.0650; [C21 H 17 81 BrN2+ H] + Calculated value: 379.0630, measured value: 379.0632.

[0169] Example 40: 3-(2,6-dichlorophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical formula

[0170] Synthesis by modified method B of the synthesis method using 2,6-dichlorobenzaldehyde phenylhydrazone (3.2 mmol, 848 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (50% → 80% acetonitrile), pyrazoline was obtained as a yellow oil (2.60 mmol, 955 mg, 81%). 1 H-NMR (400 MHz, DMSO-d6), δ / ppm: 7.60 - 7.56 (m, 2H, H-3’’), 7.48 (dd, J = 8.9, 7.2 Hz, 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, 1.1 Hz, 1H, H-4’), 5.53 (dd, J = 12.4, 6.8 Hz, 1H, H-5), 3.85 (dd, J = 17.9, 12.4 Hz, 1H, (H-4)’), 2.97 (dd, J = 17.9, 6.9 Hz, 1H, (H-4)’’). 1313C-NMR (101 MHz, 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. HRMS (ESI+), m / z: calculated for [C 21 H 16 35 Cl2N2+ H] + 367.0763, found 367.0758; calculated for [C 21 H 16 35 Cl 37 ClN2+ H] + 369.0738, found 369.0735; calculated for [C 21 H 16 37 Cl2N2+ H] + 371.0718, found 371.0725.

[0171] Example 41: 1,5-Diphenyl-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole

Chemical formula

[0172] Synthesis by modified method B of the synthetic method using 4-trifluoromethylbenzaldehyde phenylhydrazone (3.2 mmol, 846 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 2% EtOAc), the pyrazoline was obtained as a yellow solid (1.21 mmol, 445 mg, 38%). 11H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 5.39 (dd, J = 12.5, 6.9 Hz, 1H, H-5), 3.88 (dd, J = 17.2, 12.5 Hz, 1H, (H-4)’), 3.16 (dd, J = 17.2, 7.0 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, CD2Cl2), δ / ppm: 145.6, 144.6, 142.7, 136.8, 123.0 (q, J = 32.5 Hz), 129.5, 129.3, 128.8, 126.3, 126.1, 125.8 (q, J = 3.9 Hz), 124.7 (q, J = 271.9 Hz), 119.9, 113.9, 64.9, 43.5. 19 19F-NMR (376 MHz, CD2Cl2), δ / ppm: -64.0. HRMS (APCI+), m / z: [C 22 H 17 F3N2+H] + Calculated value for [C

[0173] Example 42: 3-(4-Cyanophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical Structure

[0174] Synthesis according to modified method B of the synthesis method using 4-cyanobenzaldehyde phenylhydrazone (3.2 mmol, 708 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 2% EtOAc), the pyrazoline was obtained as a pale yellow solid (1.79 mmol, 579 mg, 56%). 1 1H-NMR (400 MHz, DMSO-d6), δ / ppm: 7.89 (d, J = 8.6 Hz, 2H, H-2’’), 7.85 (d, J = 8.6 Hz, 2H, H-3’’), 7.34 (dd, J = 8.0, 6.8 Hz, 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, 6.3 Hz, 1H, H-5), 3.93 (dd, J = 17.6, 12.5 Hz, 1H, (H-4)’), 3.15 (dd, J = 17.6, 6.3 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 22 H 17 N3 + H] + Calculated value 324.1495, measured value 324.1487.

[0175] Example 43: Methyl 4-(1,5-diphenyl-4,5-dihydro-1H-pyrazol-3-yl)benzoate

Chemical formula

[0176] Synthesis according to variant B of the synthesis method using methyl phenylhydrazone 4-formylbenzoate (3.2 mmol, 814 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a pale yellow solid (2.32 mmol, 826 mg, 72%). 1 1H-NMR (400 MHz, 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, 1.2 Hz, 1H, H-4’), 5.58 (dd, J = 12.4, 6.2 Hz, 1H, H-5), 3.95 (dd, J = 17.5, 12.5 Hz, 1H, (H-4)’), 3.86 (s, 3H, H-6’’), 3.15 (dd, J = 17.5, 6.3 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 23 H 20 N2O2 + H] + Calculated value 357.1598, measured value 357.1597.

[0177] Example 44: 3-(4-Nitrophenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole [Chemical Formula]

[0178] Synthesis by Modified Method B of the synthesis method using 4-nitrobenzaldehyde phenylhydrazone (3.2 mmol, 772 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→5% EtOAc), the pyrazoline was obtained as a red solid (1.70 mmol, 588 mg, 53%). Recrystallization from methanol gave red needles. 1 1H-NMR (400 MHz, DMSO-d6), δ / ppm: 8.29 - 8.23 (m, 2H, H-3’’), 7.99 - 7.93 (m, 2H, H-2’’), 7.35 (dd, J = 8.0, 6.8 Hz, 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, 1.2 Hz, 1H, H-4’), 5.65 (dd, J = 12.6, 6.2 Hz, 1H, H-5), 3.97 (dd, J = 17.6, 12.6 Hz, 1H, (H-4)’), 3.19 (dd, J = 17.6, 6.2 Hz, 1H, (H-4)’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 21 H 17 N3O2 + H]+ Calculated value: 344.1394, measured value: 344.1388.

[0179] Example 45: 2-Phenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole (45)

Chemical formula

[0180] Synthesis by modified method B of the synthesis method using 2-allyloxybenzaldehyde phenylhydrazone (3.2 mmol, 807 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (50% → 80% acetonitrile), pyrazoline was obtained as an orange oil (1.79 mmol, 447 mg, 56%). 1 H-NMR (400 MHz, CD3CN), δ / ppm: 7.78 (dd, J = 7.7, 1.7 Hz, 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, 1.1 Hz, 1H, H-8), 6.93 (dd, J = 8.3, 1.1 Hz, 1H, H-3), 6.85 (tt, J = 7.3, 1.2 Hz, 1H, H-4’), 4.72 (dd, J = 10.3, 5.8 Hz, 1H, (H-4)’), 4.24 (dd, J = 10.6, 9.7 Hz, 1H, (H-3)’), 4.11 (dd, J = 12.3, 10.3 Hz, 1H, (H-4)’’), 3.81 (dddd, J = 13.3, 12.4, 10.6, 5.8 Hz, 1H, H-3a), 3.28 (dd, J = 13.2, 9.7 Hz, 1H, (H-3)’). 1313C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 16 H 14 N2O + H] + calculated value for 251.1179, measured value 251.1178.

[0181] Example 46: 3-Methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical formula

[0182] Synthesis by modified method B of the synthetic method using acetaldehyde phenylhydrazone (3 mmol, 403 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). Electrolysis under an argon atmosphere. After reverse-phase flash column chromatography on C-18 silica using acetonitrile / water (50%→60% acetonitrile), the pyrazoline was obtained as a dark red solid (1.15 mmol, 273 mg, 38%). 11H-NMR (400 MHz, CD3CN), δ / ppm: 7.33 (tt, J = 6.8, 1.0 Hz, 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, 1.1 Hz, 1H, H-4'), 5.11 (dd, J = 11.9, 7.3 Hz, 1H, H-5), 3.48 (ddd, J = 17.7, 11.9, 1.3 Hz, 1H, (H-4)'), 2.63 (ddd, J = 17.6, 7.3, 1.2 Hz, 1H, (H-4)''), 2.00 (dd, J = 1.2, 1.1 Hz, 3H, H-1''). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 16 H 16 N2 + H] + calculated value 237.1386, measured value 237.1388.

[0183] Examples 47 and 48: 3-Cyclopropyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole (47) and 3-cyclopropyl-1,5-diphenyl-1H-pyrazole (48)

Chemical Structure

[0184] Synthesis according to modified method A of the synthetic method using formylcyclopropanephenylhydrazone (3 mmol, 479 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). A charge of 2F (579C) was applied. After purification by flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc) and preparative HPLC (water (+1 volume % formic acid) / acetonitrile 70% → 100% MeCN), pyrazoline 47 was obtained as an orange oil (0.69 mmol, 180 mg, 23%). Pyrazole 48 was obtained as a by-product as a yellow oil (0.23 mmol, 61 mg, 8%).

[0185] Analysis data of 3-cyclopropyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole 47: 1 1H-NMR (400 MHz, 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, 1.1 Hz, 1H, H-4’), 5.06 (dd, J = 11.7, 7.3 Hz, 1H, H-5), 3.31 (ddd, J = 17.4, 11.7, 0.6 Hz, 1H, (H-4)’), 2.51 (dd, J = 17.3, 7.3 Hz, 1H, (H-4)’’), 1.82 (tt, J = 8.4, 5.1 Hz, 1H, H-1’’), 0.86 - 0.81 (m, 2H, (H-2’’)’), 0.81 - 0.68 (m, 2H, (H-2’’)’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 H 18N2+ H] + Calculated value: 263.1543, measured value: 263.1540.

[0186] Analysis data of 3-cyclopropyl-1,5-diphenyl-1H-pyrazole 48: 1 H-NMR (400 MHz, 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 = 1.3 Hz, 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’’)’’). 13 C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 H 16 N2+ H] + Calculated value: 261.1386, measured value: 261.1387.

[0187] 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)

Chemical Structure

[0188] Synthesis according to modified method B of the synthetic method using 2-allyloxybenzaldehyde phenylhydrazone (3.2 mmol, 769 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). Electrolysis at 25 °C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 2% EtOAc), pyrazoline 49 was obtained as an orange solid (0.77 mmol, 264 mg, 24%). Pyrazoline 50 was obtained as a by-product as a dark yellow solid (0.54 mmol, 129 mg, 17%).

[0189] Analysis data of 3-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole 49: 11H-NMR (400 MHz, CDCl3), δ / ppm: 7.36 - 7.21 (m, 5H, H-2''', H-3''', H-4'''), 7.14 (ddd, J = 9.2, 7.2, 2.0 Hz, 2H, H-3'), 7.01 - 6.95 (m, 2H, H-2'), 6.74 (tt, J = 7.2, 1.2 Hz, 1H, H-4'), 5.65 (qt, J = 3.5, 1.4 Hz, 1H, H-2''), 5.12 (ddd, J = 12.1, 7.8 Hz, 1H, H-5), 3.61 (ddd, J = 16.5, 12.2, 3.9 Hz, 1H, (H-4)'), 3.20 (qd, J = 6.0, 1.5 Hz, 1H, H-4''), 2.90 (ddd, J = 16.7, 7.4, 4.8 Hz, 1H, (H-4)''), 2.52 (dtd, J = 8.6, 5.7, 2.8 Hz, 1H, (H-3'')'), 2.44 (ddd, J = 19.1, 3.3, 2.4 Hz, 1H, (H-7'')'), 2.38 (dt, J = 19.2, 3.1 Hz, 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''''). A mixture of inseparable 5R / S-diastereomers. 13 13C-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. A mixture of inseparable 5R / S-diastereomers. HRMS (APCI+), m / z: [C 24 H 26N2+ H] + Calculated value: 343.2169, measured value: 343.2155.

[0190] Analysis data of (4R,6R)-5,5-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,6-methanoindazole 50: 1 H-NMR (400 MHz, CDCl3), δ / ppm: 7.62 - 7.56 (m, 2H, H-2’), 7.40 - 7.33 (m, 2H, H-3’), 7.32 (d, J = 0.6 Hz, 1H, H-4), 7.20 (tq, J = 7.7, 1.0 Hz, 1H, H-4’), 3.03 (dd, J = 16.4, 3.1 Hz, 1H, (H-8)’), 2.92 (dd, J = 16.4, 2.7 Hz, 1H, (H-8)’’), 2.70 (t, J = 5.4 Hz, 1H, H-4), 2.62 (dt, J = 9.3, 5.7 Hz, 1H, (H-7)’), 2.28 (tt, J = 5.8, 2.9 Hz, 1H, H-6), 1.33 (s, 3H, H-5’), 1.29 (d, J = 9.3 Hz, 1H, (H-7)’’), 0.62 (s, 3H, H-5’’). 13 C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 16 H 18 N2+ H] + Calculated value: 239.1543, measured value: 239.1545.

[0191] Example 51: Ethyl 1-(4-methylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0192] Synthesis by modified method A of the synthetic method using ethyl 2-(2-(4-methylphenyl)hydrazono)acetate (3 mmol, 619 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (1.69 mmol, 522 mg, 56%). 1 1H-NMR (400 MHz, 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 = 8.8 Hz, 2H, H-3’), 6.98 (d, J = 8.9 Hz, 2H, H-2’), 5.40 (dd, J = 13.3, 7.2 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.71 (dd, J = 17.9, 13.3 Hz, 1H, (H-4)’), 3.04 (dd, J = 17.9, 7.2 Hz, 1H, (H-4)’’), 2.23 (s, 3H, H-5’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 19 H 20 N2O2 + H] + Calculated value for 309.1598, measured value 309.1595.

[0193] Example 52: Ethyl 1-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0194] Synthesis according to modified method A of the synthesis method using ethyl 2-(2-(4-fluorophenyl)hydrazono)acetate (3 mmol, 631 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (2.58 mmol, 793 mg, 86%). 1 1H-NMR (400 MHz, 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, 7.4 Hz, 1H, H-5), 4.33 (q, J = 7.1 Hz, 2H, H-2''), 3.72 (dd, J = 18.0, 13.2 Hz, 1H, (H-4)'), 3.05 (dd, J = 18.0, 7.4 Hz, 1H, (H-4)''), 1.37 (t, J = 7.1 Hz, 3H, H-3''). 13 13C-NMR (101 MHz, 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. 19 19F-NMR (376 MHz, CDCl3), δ / ppm: -124.08 (tt, J = 8.7, 4.7 Hz). HRMS (ESI+), m / z: [C 18 H 17 FN2O2 + Na] + Calculated value 335.1166, measured value 335.1168.

[0195] Example 53: Ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0196] Synthesis according to modified method A of the synthesis method, using ethyl 2-(2-(4-chlorophenyl)hydrazono)acetate (3 mmol, 680 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow solid (2.65 mmol, 872 mg, 88%). 1 1H-NMR (400 MHz, 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, 7.0 Hz, 1H, H-5), 4.31 (q, J = 7.1 Hz, 2H, H-2''), 3.70 (dd, J = 18.1, 13.2 Hz, 1H, (H-4)'), 3.03 (dd, J = 18.1, 7.0 Hz, 1H, (H-4)''), 1.34 (t, J = 7.1 Hz, 3H, H-3''). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 H 17 35ClN2O2+ H] + Calculated value 329.1051, measured value 329.1044; [C 18 H 17 37 ClN2O2+ H] + Calculated value 331.1028, measured value 331.1027.

[0197] Example 54: Ethyl 1-(4-bromophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0198] Synthesis by modified method A of the synthesis method using ethyl 2-(2-(4-bromophenyl)hydrazono)acetate (3 mmol, 813 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline was obtained as an orange solid (2.80 mmol, 1044 mg, 93%). 1 H-NMR (400 MHz, 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, 7.0 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2’’), 3.72 (dd, J = 18.2, 13.2 Hz, 1H, (H-4)’), 3.05 (dd, J = 18.1, 7.0 Hz, 1H, (H-4)’’), 1.37 (t, J = 7.1 Hz, 3H, H-3’’). 1313C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 18 H 17 79 BrN2O2 + H] + Calculated value for 373.0547, measured value 373.0546; [C 18 H 17 81 BrN2O2 + H] + Calculated value for 375.0526, measured value 375.0530.

[0199] Example 55: Ethyl 1-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0200] Synthesis by modified method A of the synthetic method using ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)acetate (3 mmol, 783 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a yellow solid (2.51 mmol, 913 mg, 84%). 11H-NMR (400 MHz, CDCl3), δ / ppm: 7.31 (d, J = 8.8 Hz, 1H, H-6’), 7.29 - 7.16 (m, 4H, H-3’, H-3’’’, H-4’’’), 7.16 (dd, J = 7.7, 1.9 Hz, 2H, H-2’’’), 7.07 (dd, J = 8.7, 2.4 Hz, 1H, H-5’), 5.90 (dd, J = 12.5, 6.0 Hz, 1H, H-5), 4.41 (qd, J = 7.1, 1.4 Hz, 2H, H-2’’), 3.73 (dd, J = 18.0, 12.6 Hz, 1H, (H-4)’), 3.35 (dd, J = 18.0, 6.0 Hz, 1H, (H-4)’’), 1.42 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: calculated for [C 18 H 16 35 Cl2N2O2 + H] + 363.0662, found 363.0658; calculated for [C 18 H 16 35 Cl 37 ClN2O2 + H] + 365.0635, found 365.0634; calculated for [C 18 H 16 37 Cl2N2O2 + H] + 367.0614, found 367.0613.

[0201] Example 56: Ethyl 1-(perfluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical formula

[0202] Synthesis by modified method A of the synthesis method using ethyl 2-(2-perfluorophenyl)hydrazono)acetate (3 mmol, 847 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as a brown oil (0.75 mmol, 288 mg, 25%). 1 H-NMR (400 MHz, CDCl3), δ / ppm: 7.31 - 7.21 (m, 5H, H-2''', H-3''', H-4'''), 5.42 (dd, J = 12.5, 9.5 Hz, 1H, H-5), 4.35 (q, J = 7.1 Hz, 2H, H-2''), 3.65 (dd, J = 18.1, 12.5 Hz, 1H, (H-4)'), 3.23 (dd, J = 18.1, 9.5 Hz, 1H, (H-4)''), 1.35 (t, J = 7.1 Hz, 3H, H-3''). 13 C-NMR (101 MHz, 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. 19 F-NMR (376 MHz, CDCl3), δ / ppm: -147.66 - -148.00 (m, F-3'), -158.85 (t, J = 21.7 Hz, F-4'), -163.46 - -163.63 (m, F-2'). HRMS (APCI+), m / z: [C 18H 13 F5N2O2 + H] + Calculated value 385.0970, measured value 385.0967.

[0203] Example 57: Ethyl 1-(4-cyanophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (57)

Chemical formula

[0204] Synthesis by modified method A of the synthesis method using ethyl 2-(2-(4-cyanophenyl)hydrazono)acetate (3 mmol, 652 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), the pyrazoline was obtained as a yellow solid (2.71 mmol, 866 mg, 90%). 1 1H-NMR (400 MHz, 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, 6.4 Hz, 1H, H-5), 4.35 (q, J = 7.1 Hz, 2H, H-2’’), 3.77 (dd, J = 18.4, 13.0 Hz, 1H, (H-4)’), 3.11 (dd, J = 18.4, 6.4 Hz, 1H, (H-4)’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (ESI+), m / z: [C 19 H 17 N3O2+ H] + Calculated value: 320.1394, measured value: 320.1393.

[0205] Example 58: 4-(3,5-Diphenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonic acid

Chemical Structure

[0206] Synthesis according to modified method B of the synthesis method using 4-(2-(2-ethoxy-2-oxoethylidene)hydrazinyl)benzenesulfonic acid (3.2 mmol, 884 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After reverse-phase flash column chromatography on C-18 silica using water / acetonitrile (50%→80% MeCN), a trace amount of pyrazoline was obtained. HRMS (ESI-), m / z: [C 21 H 18 N2O3S - H] - Calculated value: 377.0965, measured value: 377.0953.

[0207] Example 59: Ethyl 1-(2,4-dinitrophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate

Chemical Structure

[0208] Synthesis according to variant A of the synthesis method using ethyl 2-(2-(2,4-dinitrophenyl)hydrazono)acetate (2 mmol, 564 mg, 1 equivalent) and styrene (5.4 mmol, 562 mg, 2.7 equivalents). Dichloromethane was used as the organic solvent. Electrolysis was carried out at 35 °C. After flash column chromatography on silica with cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline was obtained as an orange solid (0.57 mmol, 221 mg, 29%). 1 1H-NMR (400 MHz, CDCl3), δ / ppm: 8.46 (d, J = 2.6 Hz, 1H, H-3’), 8.13 (dd, J = 9.3, 2.6 Hz, 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 (dd, J = 12.3, 7.4 Hz, 1H, H-5), 4.35 (qd, J = 7.2, 1.0 Hz, 2H, H-2’’), 3.81 (dd, J = 18.7, 12.3 Hz, 1H, (H-4)’), 3.20 (dd, J = 18.7, 7.5 Hz, 1H, (H-4)’’), 1.38 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 18 17 16 H14N4O6 + NH4] + The calculated value of 402.1408, the measured value 402.1406.

[0209] Example 60: Ethyl 1-(4-methoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate [Chemical formula]

[0210] Synthesis by modified method A of the synthesis method using ethyl 2-(2-(4-methoxyphenyl)hydrazono)acetate (3 mmol, 667 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica using cyclohexane / ethyl acetate (0%→3% EtOAc), pyrazoline was obtained as a yellow solid (1.58 mmol, 511 mg, 53%). 1 1H-NMR (400 MHz, 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, 7.6 Hz, 1H, H-5), 4.33 (q, J = 7.1 Hz, 2H, H-2''), 3.71 (s, 3H, H-5'), 3.70 (dd, J = 17.9, 13.4 Hz, 1H, (H-4)'), 3.03 (dd, J = 17.9, 7.6 Hz, 1H, (H-4)'), 1.36 (t, J = 7.1 Hz, 3H, H-3''). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 19 H 20 N2O3 + H] + Calculated value 325.1547, measured value 325.1542.

[0211] Example 61: Ethyl 1-(4-trifluoromethoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate [Chemical formula]

[0212] Synthesis by modified method A of the synthesis method using ethyl 2-(2-(4-trifluoromethoxyphenyl)hydrazono)acetate (3 mmol, 829 mg, 1 equivalent) and styrene (8.1 mmol, 844 mg, 2.7 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 3% EtOAc), the pyrazoline was obtained as an orange solid (0.98 mmol, 371 mg, 33%). 1 1H-NMR (400 MHz, 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, 7.2 Hz, 1H, H-5), 4.34 (q, J = 7.1 Hz, 2H, H-2''), 3.74 (dd, J = 18.1, 13.2 Hz, 1H, (H-4)'), 3.06 (dd, J = 18.1, 7.2 Hz, 1H, (H-4)''), 1.37 (t, J = 7.1 Hz, 3H, H-3''). 13 13C-NMR (101 MHz, 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. 19 19F-NMR (376 MHz, CDCl3), δ / ppm: -59.4. HRMS (ESI+), m / z: [C 19 H 17 F3N2O3 + H] + Calculated value 379.1264, measured value 379.1264.

[0213] Example 62: 1-Methyl-3,5-diphenyl-4,5-dihydro-1H-pyrazole

Chemical formula

[0214] Synthesis by modified method B of the synthesis method using benzaldehyde methylhydrazone (3.2 mmol, 429 mg, 1 equivalent) and styrene (12.5 mmol, 1302 mg, 3.9 equivalents). After flash column chromatography on silica with cyclohexane / ethyl acetate (0% → 2% EtOAc), pyrazoline was obtained as a yellow oil (0.76 mmol, 179 mg, 24%). 1 1H-NMR (400 MHz, 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’’’), 4.13 (dd, J = 14.4, 10.0 Hz, 1H, H-5), 3.49 (dd, J = 16.1, 10.0 Hz, 1H, (H-4)’), 3.01 (dd, J = 16.1, 14.4 Hz, 1H, H-(H-4)’’), 2.86 (s, 3H, H-1’). 13 13C-NMR (101 MHz, 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. HRMS (APCI+), m / z: [C 16 H 16 N2 + H] +Calculated value: 237.1386, measured value: 237.1386.

[0215] Example 63: Another synthetic route to obtain mefenpyr - diethyl from 2,5 - dichlorophenylhydrazine hydrochloride via (Z) - ethyl glyoxylate 2,5 - dichlorophenylhydrazone or (E) - ethyl glyoxylate 2,5 - dichlorophenylhydrazone

[0216] (a) (Z) - ethyl glyoxylate 2,5 - dichlorophenylhydrazone (2) [Chemical formula]

[0217] In a 250 ml round - bottom flask, 2,5 - dichlorophenylhydrazine hydrochloride (1a, 46.8 mmol, 10.0 g, 1.0 equivalent) was dissolved in THF (75 ml) and cooled to 0 °C. Triethylamine (56.2 mmol, 5.68 g, 1.2 equivalents) was added dropwise, and the mixture was stirred for 15 minutes, filtered, and the residue was washed with THF (25 ml). To the filtrate, ethyl glyoxylate (1b, 46.8 mol, 4.78 g, 1.0 equivalent) in toluene (1:1 w / w) at 0 °C was added dropwise. Then, the mixture was 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 (2:1 v / v) to obtain the product as a pale yellow solid (2, 37.6 mmol, 9.82 g, 80%).

[0218] [Chemical formula]

[0219] 11H NMR (400 MHz, CDCl3), δ / ppm: 8.68 (s, 1H, H-1), 7.57 (d, J = 8.9 Hz, 1H, H-3’), 7.30 - 7.22 (m, 2H, H-3, 6’), 7.20 (dd, J = 8.9, 2.4 Hz, 1H, H-5’), 4.31 (q, J = 7.1 Hz, 2H, H-2’’), 1.35 (t, J = 7.1 Hz, 3H, H-3’’). 13 13C NMR (101 MHz, CDCl3), δ / ppm: 163.6, 137.6, 129.1, 128.9, 128.3, 126.9, 118.5, 116.4, 61.3, 14.3. HRMS (ESI+), m / z: C 10 H 10 35 Cl2N2O2 + H + Calculated value for 261.0192 [M+H] + , found 261.0192; C 10 H 10 35 Cl 37 ClN2O2 + H + Calculated value for 263.0164 [M+H] + , found 263.0164; C 10 H 10 37 Cl2N2O2 + H + Calculated value for 265.0138 [M+H] + , found 265.0137. LC-MS analysis: Water + 0.1 vol% formic acid / MeCN (50 → 100% MeCN over 10 min, 100% MeCN for 10 min) R t = 9.910 min

[0220] (b) (E)-Ethyl glyoxylate 2,5-dichlorophenylhydrazone (3) [Chemical Structure Diagram]

[0221] In a 2 L round-bottom flask, ethyl glyoxylate (1b, 0.79 mol, 80.7 g, 1.05 equiv) was dissolved in toluene (1:1 w / w), and 2,5-dichlorophenylhydrazine hydrochloride (1a, 0.75 mol, 160.1 g, 1.0 equiv) was dissolved in ethanol (750 mL). Glacial acetic acid (0.75 mol, 45.0 g, 1.0 equiv) was added, and the mixture was heated under reflux overnight. After crystallizing the product at -30 °C, the product was filtered off and the residue was washed with water. The product was obtained as orange needles (3, 0.67 mol, 174.5 g, 89%) without further purification.

[0222]

Chemical Structure

[0223] 1 H NMR (400 MHz, CDCl3), δ / ppm: 12.58 (s, 1H, H-1), 7.54 (d, J = 8.9 Hz, 1H, H-6’), 7.33 (d, J = 2.3 Hz, 1H, H-3’), 7.22 (dd, J = 8.9, 2.3 Hz, 1H, H-5’), 6.75 (s, 1H, H-3), 4.29 (q, J = 7.1 Hz, 2H, H-2’’), 1.36 (t, J = 7.1 Hz, 3H, H-3’’). 13 C NMR (101 MHz, CDCl3), δ / ppm: 163.5, 138.5, 129.1, 128.2, 127.0, 121.6, 119.6, 115.4, 61.0, 14.3. LC-MS analysis: water + 0.1% by volume formic acid / MeCN (50 → 100% MeCN over 10 min, 100% MeCN for 10 min) R t = 14,049 min

[0224] (c) Mephenpyr-diethyl (4) from (Z)-ethyl glyoxylate 2,5-dichlorophenylhydrazone [Chem.]

[0225] In a 50 mL beaker cell with a jacket, (Z)-ethyl glyoxylate 2,5-dichlorophenylhydrazone (2, 19.1 mmol, 5.0 g, 1.0 equiv) and ethyl methacrylate (61.5 mmol, 7.02 g, 3.21 equiv) were dispersed in an aqueous solution of 1 M sodium iodide (20 mL). As the anode and cathode, isotropic graphite plates with an immersion depth of 2.7 cm and a related anode area of 5.4 cm 2 were used (dimensions: 60×20×3 mm). Constant current electrolysis was carried out at 33 °C, 1000 rpm, and a current density of 27.9 mA cm -2 until the applied charge reached 5.4 F. The two-phase mixture was transferred to a separatory funnel for separation. The aqueous layer was further extracted with ethyl acetate (1×30 mL), and the combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. After flash column chromatography on silica with cyclohexane / EtOAc (0%→4% EtOAc), mefenpyr-diethyl was obtained as an orange oil (4, 16.4 mmol, 6.13 g, 86%). 1 1H NMR (400 MHz, CDCl3), δ / ppm: 7.41 (d, J = 2.1 Hz, 1H, H-3’), 7.25 - 7.19 (m, 2H, H-5’, H-6’), 4.33 (qd, J = 7.2, 1.7 Hz, 2H, H-2’’), 4.19 (q, J = 7.2 Hz, 2H, H-2’’’), 3.73 (d, J = 17.7 Hz, 1H, (H-4)’), 3.12 (d, J = 17.7 Hz, 1H, (H-4)’’), 1.46 (s, 3H, H-1’’’’), 1.35 (t, J = 7.1 Hz, 3H, H-3’’), 1.24 (t, J = 7.1 Hz, 3H, H-3’’’). 1313C NMR (101 MHz, 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. HRMS (ESI+), m / z: C 16 H 18 35 Cl2N2O4+ H + Calculated value of 373.0716 [M+H] + , found 373.0718; C 16 H 18 35 Cl 37 ClN2O4+ H + Calculated value of 375.0690 [M+H] + , found 375.0692; C 16 H 18 37 Cl2N2O4+ H + Calculated value of 377.0669 [M+H] + , found 377.0674.

[0226] (d) Mephenpyr-diethyl (4) from (E)-ethyl glyoxylate 2,5-dichlorophenylhydrazone [Chemical formula]

[0227] In a 5 ml PTFE cell, the hydrazone 3 and ethyl methacrylate were dissolved in an organic solvent, and an aqueous sodium halide solution was added. As the anode and cathode, the immersion depths were 1.7 cm and the related anode areas were 1.7 cm 2An isotropic graphite plate (dimensions: 70×10×3 mm) was used. The mixture was subjected to constant current electrolysis at 33 °C with vigorous stirring (setting the magnetic stirrer at approximately 1000 rpm) until the applied charge reached 5.4 F. The mixture was transferred to a separatory funnel and the cell was rinsed with ethyl acetate. As an internal standard, 1 ml of a solution of 1,3,5-trimethoxybenzene (3.000 g / 100 ml ethyl acetate) was added. The mixture was shaken briefly and the layers were separated. The organic fraction was dried over anhydrous magnesium sulfate and filtered. An aliquot was filtered through silica gel and analyzed by GC to quantify the amount of pyrazoline.

[0228] (Z)-Hydrazone 2 was used under the conditions optimized for (E)-hydrazone 3. Since the conversion rate and yield were poor, a second screening was carried out. First, the solvent and the halide source were investigated. As a result, tert-butyl methyl ether and sodium iodide were obtained as the preferred conditions (Table 1).

[0229] Table 1: Solvent screening for the conversion of (E)-ethyl glyoxylate 2,5-dichlorophenylhydrazone

[0230]

Table 1

[0231] The preferred conditions for (E)-hydrazone are as follows:

Chemical formula

[0232] Alternatively, (E)-hydrazone can preferably be converted in a mixture of ethanol and acetonitrile (especially 1:1 volume / volume), and the yield is up to 73% (optimized conditions: 3.79 equivalents of methacrylate, 2.79 equivalents of NaI, 5 mA / cm2, 4.0 F, room temperature):

Chem.

Claims

1. General formula (I) 【Chemical Formula 1】 wherein 【Chem.】 is a single bond or a double bond; R １ is alkyl, -C(O)O-alkyl, cycloalkyl, aryl, or heterocyclyl, each optionally substituted or unsubstituted; R ２ is alkyl, -C(O)O-alkyl, cycloalkyl, aryl, or heterocyclyl, each optionally 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 is cycloalkyl, aryl, or heterocyclyl, and in each case is substituted or unsubstituted or H; R ４ is 【Chem.】 which exists when is a single bond, and R ４ is alkyl, -C(O)O-alkyl, C(O)O-aryl, cycloalkyl, aryl, or heterocyclyl, and in each case is substituted or unsubstituted or is H; or R ３ and R ４ is R ３ and R ４ together with the carbon atoms in the compound of formula (I) that link R and R form a substituted or unsubstituted cycloalkyl or heterocyclyl; R ５ is alkyl, —C(O)O-alkyl, cycloalkyl, aryl, or heterocyclyl, each optionally substituted or unsubstituted, or H; or R ４ and R ５ is R ４ and R ５ together with the carbon atoms in the compound that links R and R form a cycloalkyl or heterocyclyl, and in each case is substituted or unsubstituted; or R １ and R ５ is R １ and R ５ together with the carbon atoms in the compound of formula (I) that link R and R, form a cycloalkyl or heterocyclyl, in each case being substituted or unsubstituted A method for producing a compound of General formula (II) [Chemical Formula 2] [wherein, R １ and R ２ have the same definitions as in general formula (I)] is reacted in the presence of an iodide source with a compound of formula (III) or (IV) [Chemical Formula 3] [wherein, R ３ , R ４ and R ５ have the same meaning as general formula (I)] is electrochemically reacted with a compound. A production method characterized by this.

2. R １ is unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted -C(O)O(C １－８ -alkyl), unsubstituted or substituted C ３ -C １２ -cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl; and / or R ２ is unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted -C(O)O(C １－８ -alkyl), unsubstituted or substituted C ３ -C １２ -cycloalkyl, unsubstituted or substituted phenyl; and / or R ３ is H, unsubstituted or substituted C １ -C ６ -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 C ３ -C １２ -cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl; and / or R ４ is is a single bond, and R ４ is H, unsubstituted or substituted C １ -C ６ -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 C ３ -C １２ -cycloalkyl, unsubstituted or substituted phenyl; or R ３ and R ４ are, together with the carbon atoms in the compound of formula (I) that link R ３ and R ４ form an unsubstituted or substituted C ３ -C １２ -cycloalkyl; and / or R ５ is H, unsubstituted or substituted C １ -C ６ -alkyl, unsubstituted or substituted C(O)O(C １－８ -alkyl), unsubstituted or substituted C ３ -C １２ -cycloalkyl, unsubstituted or substituted phenyl; or R ４ and R ５ are, together with the carbon atom connecting R ４ and R ５ in the compound of formula (I), unsubstituted or substituted C ３ -C １２ -cycloalkyl or heterocyclyl to form; or R １ and R ５ wherein R １ and R ５ together with the carbon atoms in the compound of formula (I) that link R ３ -C １２ -cycloalkyl or heterocyclyl, which is unsubstituted or substituted, to form The method according to claim 1.

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 the presence of an iodide source in an aqueous solution.

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

6. The method according to any one of claims 1 to 5, wherein the reaction is carried out in the presence of an iodide source in a two-phase mixture of an aqueous solution and an organic solvent, and 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 compound (III) or (IV) is used in an amount of 1.0 to 6.0 equivalents, preferably 2.0 to 5.0 equivalents based on the amount of the compound of formula (II) used.

8. The method 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 the anode and the cathode.

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

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

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

13. The method 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. The method according to any one of claims 1 to 13, wherein the aqueous phase is subsequently separated and then optionally lyophilized to recover the iodide source.

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

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

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