CN116905020A - Method for synthesizing 1, 3-fluoroamine product by electrochemical mode - Google Patents
Method for synthesizing 1, 3-fluoroamine product by electrochemical mode Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- -1 aryl cyclopropane Chemical group 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- 239000000047 product Substances 0.000 claims abstract description 39
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims abstract description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 239000006260 foam Substances 0.000 claims description 13
- 229910002804 graphite Inorganic materials 0.000 claims description 13
- 239000010439 graphite Substances 0.000 claims description 13
- 229910052759 nickel Inorganic materials 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 150000002148 esters Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000012038 nucleophile Substances 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000007142 ring opening reaction Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000012544 monitoring process Methods 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 108
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 81
- 238000001228 spectrum Methods 0.000 description 14
- NSCRQBOAESPNCL-UHFFFAOYSA-N 1-(2,2-dimethylcyclopropyl)-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C1C(C)(C)C1 NSCRQBOAESPNCL-UHFFFAOYSA-N 0.000 description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- 239000003792 electrolyte Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 150000003217 pyrazoles Chemical class 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- HMYZHKQXXQAFLN-UHFFFAOYSA-N CC(C)(C1)C1C(C=C1)=CC(OC)=C1OC Chemical compound CC(C)(C1)C1C(C=C1)=CC(OC)=C1OC HMYZHKQXXQAFLN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- WVGCPEDBFHEHEZ-UHFFFAOYSA-N 4-bromo-1h-pyrazole Chemical compound BrC=1C=NNC=1 WVGCPEDBFHEHEZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000001942 cyclopropanes Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B11/00—Electrodes; Manufacture thereof not otherwise provided for
- C25B11/04—Electrodes; Manufacture thereof not otherwise provided for characterised by the material
- C25B11/051—Electrodes formed of electrocatalysts on a substrate or carrier
- C25B11/055—Electrodes formed of electrocatalysts on a substrate or carrier characterised by the substrate or carrier material
- C25B11/057—Electrodes formed of electrocatalysts on a substrate or carrier characterised by the substrate or carrier material consisting of a single element or compound
- C25B11/061—Metal or alloy
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/05—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/07—Oxygen containing compounds
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/09—Nitrogen containing compounds
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/11—Halogen containing compounds
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
Abstract
The invention relates to a method for electrochemically promoting synthesis of aryl cyclopropane ring-opening 1, 3-fluoroamine products, which comprises the steps of reacting aryl cyclopropane compound with pyrazole through electrocatalytic reaction. Step one: adding aryl cyclopropane, pyrazole and tetraethylammonium tetrafluoroborate into a single-port reaction bottle with magnetons; slowly adding ultra-dry 1, 2-dichloroethane under nitrogen atmosphere, stirring at room temperature for reaction, monitoring the reaction by TLC, and stopping the reaction when the aryl cyclopropane is completely reacted; and thirdly, transferring the mixture obtained in the second step into a reaction bottle, concentrating the solvent by using a rotary evaporator, and separating and purifying the obtained crude product by using a silica gel column to obtain a corresponding 1, 3-fluoroamine product. The following advantages are achieved over the conventional method for synthesizing 1, 3-difunctional products: synthesizing to obtain a 1, 3-fluoroamine product with a single configuration; the reaction yield is higher; the method has wide application range, and can obtain a series of 1, 3-fluoroamine derivatives.
Description
Technical Field
The invention belongs to the field of organic chemistry, and in particular relates to a method for preparing a 1, 3-fluoroamine product.
Background
The 1, 3-fluoroamine compound widely exists in nature, and has wide application prospects in various fields such as biomedicine, organic chemical synthesis and the like. There are two main approaches to the ring-opening synthesis of 1, 3-difunctional products of non-activated cyclopropanes, one is oxidation addition depending on transition metals, but these reactions are limited to ring-opening rearrangement or cycloaddition reactions, requiring specific directing groups for regioselective ring-opening functionalization; another relies on electrophilic activation of lewis acidic species and most transformations are limited to electrophilic addition reactions only. In summary, these methods for synthesizing 1, 3-difunctional products have certain disadvantages, such as harsh reaction conditions, low product yields, long reaction times, use of toxic reagents, low regioselectivity, and the like.
Disclosure of Invention
The invention aims to provide an effective method for synthesizing a 1, 3-fluoroamine product, which solves the defects that a transition metal catalyst or Lewis acid is required to be added in the reaction process, the yield of the product is low, the chemical selectivity is low and the like in the traditional synthesis method through an electrocatalytic mode. According to the method, aryl cyclopropane and alcohols are used as raw materials through electrocatalysis, the 1, 3-fluoroamine compound with a single structure is effectively synthesized, the stability of the used reagent is high, no additional catalyst or oxidant is needed in the reaction process, the reaction time is shortened by 2-4 hours, the reaction yield is high, the reaction application range is wide, and the like.
In order to solve the technical problems of the invention, the technical proposal is as follows: a method for electrochemically synthesizing a 1, 3-fluoroamine product comprising the steps of:
step one: arylcyclopropane derivative (formula one), pyrazole and its derivative (formula two) and tetraethylammonium tetrafluoroborate are added into a drying bottle with magnetons, and a graphite positive electrode and a foam nickel negative electrode are added;
slowly adding ultra-dry 1, 2-dichloroethane under nitrogen atmosphere, introducing a direct current power supply at room temperature, stirring for reaction, and stopping the reaction when the aryl cyclopropane derivative (formula I) is completely reacted;
transferring the mixture obtained in the step two into a reaction bottle, spin-drying the solvent by using a rotary evaporator, and finally separating and purifying the obtained crude product by using a silica gel column to obtain a 1, 3-fluoroamine derivative (formula III);
the specific reaction route is as follows:
wherein R is 1 The method comprises the following steps: alkyl, halogen or ester groups; r is R 2 The method comprises the following steps: methyl, halogen, phenyl or ester groups.
Preferably, the cyclopropane derivative (formula one) is selected from various aromatic cyclopropanes.
Preferably, the pyrazoles and derivatives thereof are amine nucleophiles.
Preferably, the temperature of the reaction is 25 ℃; the reaction time is 2-4h.
Preferably, the reaction molar ratio is an arylcyclopropane derivative: pyrazole and derivatives thereof: tetraethylammonium tetrafluoroborate = 1:2:2.
preferably, the electrodes are graphite positive electrodes and nickel foam negative electrodes.
Preferably, in the second step, a direct current power supply of 5mA is supplied at room temperature and the reaction is stirred.
Preferably, the specific reaction route is as follows:
wherein R is 1 Alkyl, halogen, methoxy; r is R 2 Phenyl, halogen;
the structural formula of the target product is as follows:
preferably, the specific reaction route is as follows:
wherein R is methyl, phenyl, halogen or ester;
the specific structure of the target product is as follows:
the preparation scheme for electrocatalytic synthesis of the 1, 3-fluoroamine compound is as follows:
step one: arylcyclopropane derivatives of formula 1 (1 equiv,0.2 mmol), pyrazoles and their derivatives of formula 2 bis (2 equiv,0.4 mmol) and ammonium tetraethyltetrafluoroborate (2 equiv,0.4 mmol) were added to a dry 25ml single-necked flask with a magnet and graphite positive electrode and nickel foam negative electrode were added.
Step two: 5ml of ultra-dry organic solvent 1, 2-dichloroethane was slowly added under nitrogen atmosphere, graphite was used as anode, foam nickel was used as cathode, the reaction was stirred at 25 ℃ for 5mA under power, and monitored by TLC plate until the aryl cyclopropane derivative was completely reacted, and the reaction was stopped.
Transferring the mixture obtained in the step two into an eggplant type bottle, concentrating the solvent under low pressure by using a rotary evaporator, and finally separating and purifying the obtained crude product by using a silica gel column to obtain a corresponding 1, 3-fluoroamine product as shown in a figure III.
Formula I, formula III R 1 The method comprises the following steps: an alkyl group, a hydroxyl group,methoxy, halogen.
Formula II, formula III R 2 The method comprises the following steps: halogen, phenyl, ester group.
In the second step, the TLC plate monitors the reaction, and the reaction time is 2-4h.
The 1, 3-fluoroamine product obtained in the third step is a product with a single configuration.
Compared with the prior art, the invention has the beneficial effects that:
1. the reaction system of the invention is simple, only electrolyte tetraethyl ammonium tetrafluoroborate is needed to be added in the reaction to be used as nucleophilic fluorine source, the selected substrate is stable and easy to obtain, and the preparation cost is low.
2. The reaction system is clean, the conversion rate is higher, and the products are easy to separate.
3. The method has wide applicability, most common pyrazole derivatives are suitable for the method, the applicability of the substrate is wide, and a series of 1, 3-fluoroamine compounds can be prepared according to the method.
4. The electrolyte tetraethylammonium tetrafluoroborate used in the present invention is an electrolyte capable of providing fluoride ion. The electrolyte tetraethylammonium tetrafluoroborate used in the invention is an electrolyte which is obtained after a large amount of screening and has better capability of providing fluoride ions. The electrolyte tetraethyl ammonium tetrafluoroborate is selected to have high selectivity, can synthesize a single product of 1, 3-fluoro-oxygenated compounds, and has high yield.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows nuclear magnetic resonance of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole provided in example 1 of the present invention 1 H spectrogram;
FIG. 2 shows nuclear magnetic resonance of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole provided in example 1 of the present invention 19 F, spectrogram;
FIG. 3 is a schematic illustration of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methyl) provided in example 1 of the present inventionNuclear magnetic resonance of phenylbutyl) -1-hydro-pyrazole 13 C, spectrogram;
FIG. 4 shows nuclear magnetic resonance of ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate provided in example 1 of the present invention 1 H spectrogram;
FIG. 5 shows nuclear magnetic resonance of ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate provided in example 1 of the present invention 19 F, spectrogram;
FIG. 6 shows nuclear magnetic resonance of ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate provided in example 1 of the present invention 13 C, spectrogram;
FIG. 7 is a nuclear magnetic resonance of example 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole of the present invention 1 H spectrogram;
FIG. 8 is a nuclear magnetic resonance of example 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole of the present invention 19 F, spectrogram;
FIG. 9 is a nuclear magnetic resonance of example 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole of the present invention 13 C spectrogram.
FIG. 10 shows nuclear magnetic resonance of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1H-pyrazole provided in example 1 of the present invention 1 H spectrogram;
FIG. 11 shows nuclear magnetic resonance of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1H-pyrazole provided in example 1 of the present invention 19 F, spectrogram;
FIG. 12 shows nuclear magnetic resonance of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1H-pyrazole provided in example 1 of the present invention 13 C, spectrogram;
FIG. 13 shows nuclear magnetic resonance of 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl) -1H-pyrazole provided in example 1 of the present invention 1 H spectrogram;
FIG. 14 shows nuclear magnetic resonance of 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl) -1H-pyrazole provided in example 1 of the present invention 19 F, spectrogram;
FIG. 15 is a schematic illustration of a 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) provided in example 1 of the present invention) Nuclear magnetic resonance of (E) -3-methylbutyl) -1H-pyrazole 13 C, spectrogram;
FIG. 16 shows nuclear magnetic resonance of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole provided in example 1 of the present invention 1 H spectrogram;
FIG. 17 shows nuclear magnetic resonance of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole provided in example 1 of the present invention 19 F, spectrogram;
FIG. 18 shows nuclear magnetic resonance of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole provided in example 1 of the present invention 13 C, spectrogram;
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
According to the method, various types of 1, 3-fluoroamine compounds can be synthesized through the same mechanism according to different reaction substrate structures.
(1) The utility of the process is discussed using different classes of arylcyclopropane compounds with pyrazoles as template substrates. The specific reaction equation is as follows:
wherein R is 1 Is alkyl, halogen, methoxy. R is R 2 Phenyl, halogen;
the structural formula of the target product is as follows:
(2) The utility of the process is discussed using different classes of pyrazoles and derivatives thereof with 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene as a template substrate. The specific reaction equation is as follows:
wherein R is methyl, phenyl, halogen or ester.
The specific structure of the target product is as follows:
(3aN1).. 1 H NMR(400MHz,Chloroform-d):δ7.54(d,J＝1.8Hz,1H),7.43(d,J＝2.3Hz,1H),7.24(d,J＝8.8Hz,2H),6.84(d,J＝8.7Hz,2H),6.24–6.22(m,1H),5.54(dd,J＝9.2,4.2Hz,1H),3.77(s,3H),3.09–2.92(m,1H),2.42(td,J＝14.6,4.2Hz,1H),1.29(d,J＝21.7Hz,3H),1.12(d,J＝21.8Hz,3H). 19 F NMR(376MHz,Chloroform-d):δ-137.46–-137.93(m,1F). 13 C NMR(101MHz,Chloroform-d):δ159.05,139.08,133.76,128.69,127.82,113.97,105.66,94.74(d,J＝166.8Hz),61.15(d,J＝5.0 Hz),55.22,45.92(d,J＝22.8 Hz),28.09(d,J＝24.2 Hz),25.38(d,J＝24.8Hz).HRMS(ESI,m/z):calcd for C 15 H 20 FN 2 O,[M+H] + :263.1560,found:263.1564.
(3aN2). 1 H NMR(401 MHz,Chloroform-d):δ7.48(s,1H),7.43(d,J＝0.7 Hz,1H),7.23(d,J＝8.9 Hz,2H),6.85(d,J＝8.8 Hz,2H),5.48(dd,J＝8.8,4.5 Hz,1H),3.78(s,3H),3.04–2.88(m,1H),2.39(td,J＝15.0,4.5 Hz,1H),1.29(d,J＝21.6 Hz,3H),1.16(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.94–-138.41(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.31,139.59,132.87,128.88,127.91,114.10,94.50(d,J＝166.9 Hz),93.17,61.96,55.25,45.47(d,J＝23.0Hz),27.99(d,J＝24.6 Hz),25.74(d,J＝24.7 Hz).HRMS(ESI,m/z):calcd forC 15 H 19 BrFN 2 O,[M+H] + :341.0665,found:341.0662.
(3aN3). 1 H NMR(401 MHz,Chloroform-d):δ7.55(d,J＝1.3 Hz,1H),7.29(d,J＝8.7 Hz,2H),6.83(d,J＝8.8 Hz,2H),6.28(d,J＝1.9 Hz,1H),5.78(dd,J＝9.6,3.2Hz,1H),3.77(s,3H),3.24–3.07(m,1H),2.37(td,J＝14.7,3.3 Hz,1H),1.31(d,J＝21.5 Hz,3H),1.10(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.54–-137.94(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.06,139.96,133.19,128.01,113.96,112.76,108.63,94.60(d,J＝166.1 Hz),58.01(d,J＝4.6 Hz),55.22,45.89(d,J＝22.8 Hz),28.10(d,J＝24.3 Hz),25.34(d,J＝24.7 Hz).HRMS(ESI,m/z):calcd for C 15 H 19 BrFN 2 O,[M+H] + :341.0665,found:341.0659.
(3aN4). 1 H NMR(400 MHz,Chloroform-d):δ7.33(s,1H),7.24–7.21(m,2H),7.20–7.18(m,1H),6.83(d,J＝8.7 Hz,2H),5.44(dd,J＝9.1,4.2 Hz,1H),3.77(s,3H),3.06–2.89(m,1H),2.38(td,J＝14.5,4.2 Hz,1H),2.03(s,3H),1.28(d,J＝21.7Hz,3H),1.14(d,J＝21.8 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.24–-137.60(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ158.99,139.42,134.05,127.76,127.49,116.22,113.94,94.84(d,J＝166.1 Hz),60.95(d,J＝5.2 Hz),55.23,45.79(d,J＝23.0 Hz),28.09(d,J＝24.4 Hz),25.43(d,J＝24.9 Hz),8.89.HRMS(ESI,m/z):calcd for C 16 H 22 FN 2 O,[M+H] + :277.1716,found:277.1718.
(3aN5). 1 H NMR(401 MHz,Chloroform-d):δ7.93(s,2H),7.29–7.24(m,2H),6.86(d,J＝8.7 Hz,2H),5.53(dd,J＝8.7,4.6 Hz,1H),3.79(s,3H),3.78(s,3H),3.05–2.89(m,1H),2.42(td,J＝15.3,4.6 Hz,1H),1.30(d,J＝21.6 Hz,3H),1.16(d,J＝21.6 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.36–-138.75(m,1F). 13 CNMR(101 MHz,Chloroform-d):δ163.38,159.44,140.87,132.41,132.13,128.05,114.77,114.19,94.37(d,J＝167.3 Hz),62.02(d,J＝4.7 Hz),55.27,51.31,45.56(d,J＝22.7 Hz),27.92(d,J＝24.4 Hz),25.88(d,J＝24.7 Hz).HRMS(ESI,m/z):calcdfor C 17 H 22 FN 2 O 3 ,[M+H] + :321.1614,found:321.1612.
(3aN6). 1 H NMR(401 MHz,Chloroform-d):δ7.93(d,J＝1.5 Hz,2H),7.33–7.22(m,2H),6.85(d,J＝8.8 Hz,2H),5.53(dd,J＝8.8,4.5 Hz,1H),4.26(q,J＝7.1Hz,2H),3.77(s,3H),3.06–2.89(m,1H),2.42(td,J＝15.2,4.6 Hz,1H),1.31(t,J＝6.3 Hz,3H),1.30(d,J＝21.5 Hz,3H),1.15(d,J＝21.6 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.33–-138.71(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ162.98,159.39,140.84,132.50,132.06,128.00,115.16,114.15,94.38(d,J＝167.4Hz),61.96(d,J＝4.7 Hz),60.13,55.25,45.54(d,J＝22.6 Hz),27.93(d,J＝24.4 Hz),25.82(d,J＝24.6 Hz),14.33.HRMS(ESI,m/z):calcd for C 18 H 24 FN 2 O 3 ,[M+H] + :335.1771,found:335.1776.
(3aN7).0.2 mmol scale,2 h. 1 H NMR(401 MHz,Chloroform-d):δ7.98(s,1H),7.73(d,J＝8.8 Hz,1H),7.60(d,J＝8.4 Hz,1H),7.34(d,J＝8.7 Hz,2H),7.28–7.24(m,1H),7.09–7.01(m,1H),6.84(d,J＝8.8 Hz,2H),5.82(dd,J＝8.6,4.6 Hz,1H),3.76(s,3H),3.28–3.12(m,1H),2.58(td,J＝14.8,4.6 Hz,1H),1.31(d,J＝21.6 Hz,3H),1.11(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.77–-138.11(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.30,148.48,133.01,128.12,125.76,122.25,121.76,121.65,120.17,117.71,114.05,94.75(d,J＝167.0Hz),62.95(d,J＝4.8 Hz),55.25,45.98(d,J＝22.6 Hz),28.11(d,J＝24.2 Hz),25.55(d,J＝24.6 Hz).HRMS(ESI,m/z):calcd for C 19 H 22 FN 2 O,[M+H] + :313.1716,found:313.1714.
(3aN8).0.2 mmol scale,2 h. 1 H NMR(401 MHz,Chloroform-d):δ7.98(s,1H),7.74(d,J＝8.8 Hz,1H),7.60(dd,J＝8.4,1.1 Hz,1H),7.29–7.23(m,2H),7.09–7.01(m,1H),6.84(d,J＝7.6 Hz,1H),5.82(dd,J＝8.6,4.6 Hz,2H),3.76(s,3H),2.58(td,J＝14.7,4.6 Hz,1H),1.30(d,J＝21.6 Hz,3H),1.11(d,J＝21.7 Hz,3H). 19 FNMR(376 MHz,Chloroform-d):δ-137.71–-138.07(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.30,148.48,133.02,128.13,125.76,122.26,121.77,121.66,120.17,117.71,114.05,94.75(d,J＝167.6 Hz),62.93,55.25,45.98(d,J＝22.4 Hz),28.11(d,J＝24.2 Hz),25.55(d,J＝24.5 Hz).HRMS(ESI,m/z):calcd forC 19 H 22 FN 2 O,[M+H] + :313.1716,found:313.1717.
(3aN9). 1 H NMR(400 MHz,Chloroform-d):δ7.87(s,1H),7.64(d,J＝8.9 Hz,1H),7.34(s,1H),7.31(d,J＝8.7 Hz,2H),7.11(d,J＝7.3 Hz,1H),6.83(d,J＝8.7Hz,2H),5.80(dd,J＝8.8,4.4 Hz,1H),3.76(s,3H),3.27–3.11(m,1H),2.56(td,J＝14.6,4.4 Hz,1H),2.39(s,3H),1.30(d,J＝21.6 Hz,3H),1.10(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.47–-137.84(m,1F). 13 C NMR(101MHz,Chloroform-d):δ159.22,147.37,133.22,130.96,128.63,128.01,122.07,121.39,118.24,117.38,114.00,94.77(d,J＝167.1 Hz),62.78(d,J＝4.7 Hz),55.23,45.98(d,J＝22.7 Hz),28.14(d,J＝24.2 Hz),25.41(d,J＝24.6 Hz),21.67.HRMS(ESI,m/z):calcd for C 20 H 24 FN 2 O,[M+H] + :327.1873,found:327.1873.
(3aN10). 1 H NMR(400 MHz,Chloroform-d):δ7.93(s,1H),7.67(d,J＝8.4 Hz,1H),7.57(d,J＝1.9 Hz,1H),7.34(d,J＝8.8 Hz,2H),7.19(dd,J＝9.1,2.0 Hz,1H),6.85(d,J＝8.7 Hz,2H),5.80(dd,J＝8.6,4.6 Hz,1H),3.76(s,3H),3.26–3.09(m,1H),2.57(td,J＝15.0,4.6 Hz,1H),1.31(d,J＝21.6 Hz,3H),1.10(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.07–-138.54(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.36,146.77,132.61,128.10,127.28,127.10,122.09,121.92,119.23,118.86,114.08,94.60(d,J＝167.2 Hz),63.12(d,J＝4.5 Hz),55.22,45.86(d,J＝22.5 Hz),28.01(d,J＝24.4 Hz),25.59(d,J＝24.6 Hz).HRMS(ESI,m/z):calcd for C 19 H 21 ClFN 2 O,[M+H] + :347.1326,found:347.1328.
(3aN11). 1 H NMR(401 MHz,Chloroform-d):δ8.45(s,1H),8.13(s,1H),7.88(dd,J＝9.1,1.6 Hz,1H),7.72(d,J＝9.1 Hz,1H),7.37(d,J＝8.8 Hz,2H),6.86(d,J＝8.8 Hz,2H),5.83(dd,J＝8.4,4.8 Hz,1H),3.91(s,3H),3.76(s,3H),3.27–3.10(m,1H),2.59(td,J＝15.2,4.9 Hz,1H),1.31(d,J＝21.5 Hz,3H),1.11(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.31–-138.71(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ167.47,159.48,149.77,132.39,128.25,125.65,124.91,124.73,123.72,121.06,117.53,114.15,94.55(d,J＝167.4 Hz),63.38(d,J＝4.6 Hz),55.24,52.00,45.89(d,J＝22.6 Hz),27.99(d,J＝24.3 Hz),25.73(d,J＝24.6 Hz).HRMS(ESI,m/z):calcd for C 21 H 24 FN 2 O 3 ,[M+H] + :371.1771,found:371.1774.
(3aN12). 1 H NMR(401 MHz,Chloroform-d):δ7.71(d,J＝8.8 Hz,1H),7.49(d,J＝8.5 Hz,1H),7.39(d,J＝8.8 Hz,2H),7.34–7.27(m,1H),7.14–7.06(m,1H),6.83(d,J＝8.8 Hz,2H),6.13(dd,J＝9.2,3.4 Hz,1H),3.75(s,3H),3.48–3.31(m,1H),2.54(td,J＝14.8,3.4 Hz,1H),1.33(d,J＝21.4 Hz,3H),1.04(d,J＝21.8 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.85–-138.26(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ159.20,148.14,132.60,128.31,126.71,122.36,121.93,119.38,118.16,113.98,105.84,94.68(d,J＝166.9 Hz),59.57(d,J＝4.3 Hz),55.21,46.01(d,J＝22.6 Hz),28.15(d,J＝24.2 Hz),25.41(d,J＝24.7 Hz).HRMS(ESI,m/z):calcd for C 19 H 21 BrFN 2 O,[M+H] + :391.0821,found:391.0817.
(3bN1). 1 H NMR(400 MHz,Chloroform-d):δ7.55(d,J＝1.9 Hz,1H),7.44(d,J＝2.3 Hz,1H),7.10–6.98(m,2H),6.88(t,J＝8.5 Hz,1H),6.26(t,J＝2.1 Hz,1H),5.52(dd,J＝9.3,3.9 Hz,1H),3.85(s,3H),3.06–2.91(m,1H),2.44–2.32(m,1H),1.30(d,J＝21.6 Hz,3H),1.10(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-134.03–-134.11(m,1F),-138.04–-138.39(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ153.39,150.94,139.34,134.71(d,J＝5.8 Hz),128.85,122.31,114.52(d,J＝19.4 Hz),113.25,105.88,94.62(d,J＝166.6 Hz),60.71,56.21,45.84(d,J＝22.7 Hz),28.21(d,J＝24.3 Hz),25.21(d,J＝24.9 Hz).HRMS(ESI,m/z):calcd for C 15 H 19 F 2 N 2 O,[M+H] + :281.1465,found:281.1466.
(3cN1). 1 H NMR(400 MHz,Chloroform-d):δ7.55(s,1H),7.44(d,J＝2.3 Hz,1H),7.34(d,J＝2.3 Hz,1H),7.17(dd,J＝8.5,2.3 Hz,1H),6.85(d,J＝8.5 Hz,1H),6.25(s,1H),5.51(dd,J＝9.3,3.9 Hz,1H),3.86(s,3H),3.09–2.91(m,1H),2.44–2.31(m,1H),1.30(d,J＝21.6 Hz,3H),1.10(d,J＝21.7 Hz,3H). 19 F NMR(376MHz,Chloroform-d):δ-138.07–-138.44(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ154.60,139.53,135.01,129.00,128.69,126.14,122.63,112.14,106.06,94.78(d,J＝167.0 Hz),60.82,56.29,45.98(d,J＝22.6 Hz),28.40(d,J＝24.4 Hz),25.36(d,J＝24.7 Hz).HRMS(ESI,m/z):calcd for C 15 H 19 ClFN 2 O,[M+H] + :297.1170,found:297.1169.
(3dN1). 1 H NMR(400 MHz,Chloroform-d):δ7.55(d,J＝1.9 Hz,1H),7.51(d,J＝2.3 Hz,1H),7.44(d,J＝3.0 Hz,1H),7.22(dd,J＝8.5,2.3 Hz,1H),6.82(d,J＝8.5Hz,1H),6.25(t,J＝2.1 Hz,1H),5.51(dd,J＝9.4,3.9 Hz,1H),3.85(s,3H),3.09–2.91(m,1H),2.44–2.31(m,1H),1.30(d,J＝21.6 Hz,3H),1.09(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.08–-138.44(m,1F). 13 C NMR(101MHz,Chloroform-d)δ155.35,139.37,135.31,131.58,128.83,126.77,111.85,111.70,105.90,94.60(d,J＝167.2 Hz),60.56(d,J＝5.0 Hz),56.24,45.87(d,J＝22.7 Hz),28.24(d,J＝24.4 Hz),25.21(d,J＝24.7 Hz).HRMS(ESI,m/z):calcd forC 15 H 19 BrFN 2 O,[M+H] + :341.0665,found:341.0663.
(3eN1). 1 H NMR(400 MHz,Chloroform-d):δ7.47(d,J＝17.3 Hz,2H),6.87–6.83(m,2H),6.81–6.78(m,1H),5.46(dd,J＝9.0,4.3 Hz,1H),3.85(d,J＝1.5 Hz,6H),3.07–2.90(m,1H),2.38(td,J＝14.9,4.3 Hz,1H),1.30(d,J＝21.5 Hz,3H),1.15(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-138.08–-138.45(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ149.08,148.77,139.58,133.40,129.02,118.77,110.96,109.78,94.52(d,J＝166.8 Hz),93.25,62.18,55.86,45.49(d,J＝22.9 Hz),28.02(d,J＝24.3 Hz),25.65(d,J＝24.8 Hz).HRMS(ESI,m/z):calcdfor C 16 H 21 BrFN 2 O 2 ,[M+H] + :371.0770,found:371.0071.
(3fN1). 1 H NMR(401 MHz,Chloroform-d):δ7.53(d,J＝1.9 Hz,1H),7.43(d,J＝2.3 Hz,1H),7.13–7.07(m,2H),6.75(d,J＝9.0 Hz,1H),6.23(t,J＝2.1 Hz,1H),5.51(dd,J＝9.2,4.1 Hz,1H),3.79(s,3H),3.09–2.92(m,1H),2.41(td,J＝14.6,4.2Hz,1H),2.18(s,3H),1.28(d,J＝21.7 Hz,3H),1.12(d,J＝21.8 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.32–-137.72(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ157.27,139.02,133.26,129.03,128.64,126.88,125.01,109.81,105.61,94.80(d,J＝165.6 Hz),61.26(d,J＝5.2 Hz),55.30,45.93(d,J＝23.0 Hz),28.08(d,J＝24.4 Hz),25.41(d,J＝24.7 Hz),16.31.HRMS(ESI,m/z):calcd forC 16 H 22 FN 2 O,[M+H] + :277.1716,found:277.1715.
(3fN2). 1 H NMR(400 MHz,Chloroform-d):δ7.42(d,J＝15.5 Hz,2H),7.09(d,J＝6.7 Hz,2H),6.76(d,J＝9.1 Hz,1H),5.41(dd,J＝8.9,4.4 Hz,1H),3.80(s,3H),3.04–2.87(m,1H),2.38(td,J＝15.0,4.4 Hz,1H),2.19(s,3H),1.30(d,J＝21.6 Hz,3H),1.16(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.81–-138.19(m,1F). 13 C NMR(101 MHz,Chloroform-d):δ157.51,137.39,132.37,129.03,127.09,126.69,125.08,109.97,109.84,94.57(d,J＝166.9 Hz),62.07(d,J＝4.8 Hz),55.31,45.41(d,J＝22.8 Hz),27.97(d,J＝24.2 Hz),25.74(d,J＝24.6 Hz),16.33.HRMS(ESI,m/z):calcd for C 16 H 21 ClFN 2 O,[M+H] + :311.1326,found:311.1329.
(3fN3). 1 H NMR(400 MHz,Chloroform-d):δ7.45(d,J＝17.8 Hz,2H),7.11–7.08(m,2H),6.77–6.73(m,1H),5.44(dd,J＝8.8,4.6 Hz,1H),3.80(s,3H),3.04–2.87(m,1H),2.46–2.32(m,1H),2.19(s,3H),1.29(d,J＝21.6 Hz,3H),1.16(d,J＝21.7 Hz,3H). 19 F NMR(376 MHz,Chloroform-d):δ-137.83–-138.19(m,1F). 13 CNMR(101 MHz,Chloroform-d):δ157.52,139.52,132.33,129.06,128.83,127.09,125.11,109.84,94.56(d,J＝167.1Hz),93.11,62.05(d,J＝4.8Hz),55.31,45.44(d,J＝22.8Hz),27.97(d,J＝24.3Hz),25.75(d,J＝24.6Hz),16.33.HRMS(ESI,m/z):calcd for C 16 H 21 BrFN 2 O,[M+H] + :355.0821,found:355.0821.
(3fN4). 1 H NMR(400MHz,Chloroform-d):δ7.98(s,1H),7.74(d,J＝8.6Hz,1H),7.60(d,J＝7.2Hz,1H),7.30–7.18(m,3H),7.09–7.01(m,1H),6.75(d,J＝9.1Hz,1H),5.79(dd,J＝8.7,4.6Hz,1H),3.78(s,3H),3.28–3.11(m,1H),2.58(td,J＝14.8,4.6Hz,1H),2.18(s,3H),1.30(d,J＝21.6Hz,3H),1.11(d,J＝21.7Hz,3H). 19 F NMR(376MHz,Chloroform-d):δ-137.52–-137.88(m,1F). 13 C NMR(101MHz,Chloroform-d):δ157.50,148.43,132.45,129.26,126.99,125.68,125.34,122.18,121.77,121.59,120.17,117.72,109.80,94.79(d,J＝167.1Hz),63.07,55.30,45.93(d,J＝22.5Hz),28.08(d,J＝24.3Hz),25.56(d,J＝24.6Hz),16.30.HRMS(ESI,m/z):calcd for C 20 H 24 FN 2 O,[M+H] + :327.1873,found:327.1871.
(3uN1). 1 H NMR(400MHz,Chloroform-d):δ7.46(d,J＝22.1Hz,2H),7.29(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,2H),5.43(dd,J＝8.6,5.4Hz,1H),3.78(s,3H),3.07–2.90(m,1H),2.59–2.41(m,1H),2.28–1.99(m,3H),1.94–1.70(m,3H). 19 FNMR(376MHz,Chloroform-d):δ-134.82–-135.11(m,1F). 13 C NMR(101MHz,Chloroform-d):δ159.40,139.81,132.16,129.35,128.23,114.04,96.28(d,J＝210.1Hz),92.82,61.57(d,J＝3.8Hz),55.26,41.90(d,J＝22.0Hz),34.23(d,J＝21.6Hz),32.64(d,J＝21.8Hz),12.14(d,J＝11.8Hz).HRMS(ESI,m/z):calcd for C 16 H 19 BrFN 2 O,[M+H] + :353.0665,found:353.0664.
example 1
This example is directed to the preparation of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole. The specific operation is as follows:
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under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -3, 4-dimethoxybenzene (0.2 mmol), 4-bromopyrazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were added to a single-port reaction flask equipped with a magnet in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -3, 4-dimethoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (2% ea/PE) to give the desired product 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole as a colourless oil in 38% yield.
Determination of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole nuclear magnetic resonance hydrogen spectrum gave the following results: 1 H NMR(400MHz,Chloroform-d):δ7.47(d,J＝17.3Hz,2H),6.87–6.83(m,2H),6.81–6.78(m,1H),5.46(dd,J＝9.0,4.3Hz,1H),3.85(d,J＝1.5Hz,6H),3.07–2.90(m,1H),2.38(td,J＝14.9,4.3Hz,1H),1.30(d,J＝21.5Hz,3H),1.15(d,J＝21.7Hz,3H).
determination of the nuclear magnetic resonance fluorine spectrum of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole gave the following results: 19 F NMR(376MHz,Chloroform-d):δ-138.08–-138.45(m,1F).
determination of the nuclear magnetic resonance carbon spectrum of 4-bromo-1- (1- (3, 4-dimethoxyphenyl) -3-fluoro-3-methylbutyl) -1-hydro-pyrazole gave the following results: 13 C NMR(101MHz,Chloroform-d):δ149.08,148.77,139.58,133.40,129.02,118.77,110.96,109.78,94.52(d,J＝166.8Hz),93.25,62.18,55.86,45.49(d,J＝22.9Hz),28.02(d,J＝24.3Hz),25.65(d,J＝24.8Hz).
example 2
This example is directed to the preparation of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylic acid ethyl ester. The specific operation is as follows:
under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene (0.2 mmol), ethyl 4-pyrazolecarboxylate (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were added to a single-port reaction flask equipped with a magnet in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (1% ea/PE) to give the desired product ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate as colorless oily liquid in 76% yield.
Determination of nuclear magnetic resonance hydrogen spectrum of ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate gave the following results: 1 H NMR(400MHz,Chloroform-d):δ7.93(d,J＝1.5Hz,2H),7.33–7.22(m,2H),6.85(d,J＝8.8Hz,2H),5.53(dd,J＝8.8,4.5Hz,1H),4.26(q,J＝7.1Hz,2H),3.77(s,3H),3.06–2.89(m,1H),2.42(td,J＝15.2,4.6Hz,1H),1.31(t,J＝6.3Hz,3H),1.30(d,J＝21.5Hz,3H),1.15(d,J＝21.6Hz,3H).
the nuclear magnetic resonance fluorine spectrum of the ethyl 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylate is determined as follows: 19 F NMR(376MHz,Chloroform-d):δ-138.33–-138.71(m,1F).
the nuclear magnetic resonance carbon spectrum of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-pyrazole-4-carboxylic acid ethyl ester is measured, and the result is that: 13 C NMR(101MHz,Chloroform-d):δ162.98,159.39,140.84,132.50,132.06,128.00,115.16,114.15,94.38(d,J＝167.4Hz),61.96(d,J＝4.7Hz),60.13,55.25,45.54(d,J＝22.6Hz),27.93(d,J＝24.4Hz),25.82(d,J＝24.6Hz),14.33.
example 3
This example proceeds to the preparation of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole. The specific operation is as follows:
under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene (0.2 mmol), indazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were added to a single-port reaction flask equipped with a magneton in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (2% ea/PE) to give the desired product 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole as a colourless oily liquid in 40% yield.
Determination of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole nuclear magnetic resonance hydrogen spectrum gave the following results: 1 H NMR(400MHz,Chloroform-d):δ7.98(s,1H),7.74(d,J＝8.8Hz,1H),7.60(dd,J＝8.4,1.1Hz,1H),7.29–7.23(m,2H),7.09–7.01(m,1H),6.84(d,J＝7.6Hz,1H),5.82(dd,J＝8.6,4.6Hz,2H),3.76(s,3H),2.58(td,J＝14.7,4.6Hz,1H),1.30(d,J＝21.6Hz,3H),1.11(d,J＝21.7Hz,3H).
determination of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole nuclear magnetic resonance fluorine spectrum gave the following results: 19 F NMR(376MHz,Chloroform-d):δ-137.71–-138.07(m,1F).
determination of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydro-indazole nuclear magnetic resonance carbon spectrum gave the following results: 13 C NMR(101MHz,Chloroform-d):δ159.30,148.48,133.02,128.13,125.76,122.26,121.77,121.66,120.17,117.71,114.05,94.75(d,J＝167.6Hz),62.93,55.25,45.98(d,J＝22.4Hz),28.11(d,J＝24.2Hz),25.55(d,J＝24.5Hz).
example 4
Under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene (0.2 mmol), pyrazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were added to a single-port reaction flask equipped with a magneton in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (2% ea/PE) to give the desired product 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 h-pyrazole as a colourless oily liquid in 57% yield.
The nuclear magnetic resonance hydrogen spectrum of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 1 H NMR(400MHz,Chloroform-d):δ7.54(d,J＝1.8Hz,1H),7.43(d,J＝2.3Hz,1H),7.24(d,J＝8.8Hz,2H),6.84(d,J＝8.7Hz,2H),6.24–6.22(m,1H),5.54(dd,J＝9.2,4.2Hz,1H),3.77(s,3H),3.09–2.92(m,1H),2.42(td,J＝14.6,4.2Hz,1H),1.29(d,J＝21.7Hz,3H),1.12(d,J＝21.8Hz,3H).
the nuclear magnetic resonance fluorine spectrum of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydrogen-pyrazole was measured, and the result is: 19 F NMR(376MHz,Chloroform-d):δ-137.46–-137.93(m,1F).
the nuclear magnetic resonance spectrum of 1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1-hydrogen-pyrazole was measured, and the result is: 13 C NMR(101MHz,Chloroform-d):δ159.05,139.08,133.76,128.69,127.82,113.97,105.66,94.74(d,J＝166.8Hz),61.15(d,J＝5.0Hz),55.22,45.92(d,J＝22.8Hz),28.09(d,J＝24.2Hz),25.38(d,J＝24.8Hz).
example 5
Under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -3-methyl-4-methoxybenzene (0.2 mmol), pyrazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were charged into a single-port reaction flask equipped with a magneton in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -3-methyl-4-methoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (2% ea/PE) to give the desired product 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl) -1 h-pyrazole as a colourless oily liquid in 60% yield.
Para-1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl)Determination of the hydrogen nuclear magnetic resonance spectrum of the radical) -1 hydrogen-pyrazole, the result is as follows: 1 H NMR(400MHz,Chloroform-d):δ7.53(d,J＝1.9Hz,1H),7.43(d,J＝2.3Hz,1H),7.13–7.07(m,2H),6.75(d,J＝9.0Hz,1H),6.23(t,J＝2.1Hz,1H),5.51(dd,J＝9.2,4.1Hz,1H),3.79(s,3H),3.09–2.92(m,1H),2.41(td,J＝14.6,4.2Hz,1H),2.18(s,3H),1.28(d,J＝21.7Hz,3H),1.12(d,J＝21.8Hz,3H).
the nuclear magnetic resonance fluorine spectrum of 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 19 F NMR(376MHz,Chloroform-d):δ-137.32–-137.72(m,1F).
the nuclear magnetic resonance spectrum of 1- (3-fluoro-1- (4-methoxy-3-methylphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 13 C NMR(101MHz,Chloroform-d):δ157.27,139.02,133.26,129.03,128.64,126.88,125.01,109.81,105.61,94.80(d,J＝165.6Hz),61.26(d,J＝5.2Hz),55.30,45.93(d,J＝23.0Hz),28.08(d,J＝24.4Hz),25.41(d,J＝24.7Hz),16.31.
example 6
Under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene (0.2 mmol), pyrazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry 1, 2-dichloroethane (5 ml) were added to a single-port reaction flask equipped with a magneton in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates until complete reaction of 1- (2, 2-dimethylcyclopropyl) -4-methoxybenzene. The reaction solvent was transferred to a reaction flask, and the solvent was concentrated using a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (2% ea/PE) to give the desired product 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 h-pyrazole as a colourless oily liquid in 59% yield.
The nuclear magnetic resonance hydrogen spectrum of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 1 H NMR(400MHz,Chloroform-d):δ7.55(d,J＝1.3Hz,1H),7.29(d,J＝8.7Hz,2H),6.83(d,J＝8.8Hz,2H),6.28(d,J＝1.9Hz,1H),5.78(dd,J＝9.6,3.2Hz,1H),3.77(s,3H),3.24–3.07(m,1H),2.37(td,J＝14.7,3.3Hz,1H),1.31(d,J＝21.5Hz,3H),1.10(d,J＝21.7Hz,3H).
the nuclear magnetic resonance fluorine spectrum of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 19 F NMR(376MHz,Chloroform-d):δ-137.54–-137.94(m,1F).
the nuclear magnetic resonance spectrum of 3-bromo-1- (3-fluoro-1- (4-methoxyphenyl) -3-methylbutyl) -1 hydrogen-pyrazole was measured, and the result is: 13 C NMR(101MHz,Chloroform-d):δ59.06,139.96,133.19,128.01,113.96,112.76,108.63,94.60(d,J＝166.1Hz),58.01(d,J＝4.6Hz),55.22,45.89(d,J＝22.8Hz),28.10(d,J＝24.3Hz),25.34(d,J＝24.7Hz).
comparative example 1
This comparative example is compared with the preparation of 1- (3-fluoro-1-methoxy-3-methylbutyl) -4-methoxybenzene according to the following procedure:
under nitrogen atmosphere, 1- (2, 2-dimethylcyclopropyl) -3, 4-dimethoxybenzene (0.2 mmol), 4-bromopyrazole (0.4 mmol), tetraethylammonium tetrafluoroborate (0.4 mmol) and ultra-dry tetrahydrofuran (5 ml) were added to a single-port reaction flask equipped with a magnet in an IKA electrochemical apparatus using graphite as anode and nickel foam as cathode. The reaction was carried out at room temperature by applying 5 mA. The reaction was monitored using TLC plates and no formation of the target product was observed.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (9)
1. A method for electrochemically synthesizing a 1, 3-fluoroamine product, comprising the steps of:
step one: arylcyclopropane derivative (formula one), pyrazole and its derivative (formula two) and tetraethylammonium tetrafluoroborate are added into a drying bottle with magnetons, and a graphite positive electrode and a foam nickel negative electrode are added;
slowly adding ultra-dry 1, 2-dichloroethane under nitrogen atmosphere, introducing a direct current power supply at room temperature, stirring for reaction, and stopping the reaction when the aryl cyclopropane derivative (formula I) is completely reacted;
transferring the mixture obtained in the step two into a reaction bottle, spin-drying the solvent by using a rotary evaporator, and finally separating and purifying the obtained crude product by using a silica gel column to obtain a 1, 3-fluoroamine derivative (formula III);
the specific reaction route is as follows:
wherein R is 1 The method comprises the following steps: alkyl, halogen or ester groups; r is R 2 The method comprises the following steps: methyl, halogen, phenyl or ester groups.
2. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the cyclopropane derivative (formula one) is selected from a variety of aromatic cyclopropanes.
3. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the pyrazole and derivatives thereof are amine nucleophiles.
4. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the temperature of the reaction is 25 ℃; the reaction time is 2-4h.
5. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the reaction molar ratio is an arylcyclopropane derivative: pyrazole and derivatives thereof: tetraethylammonium tetrafluoroborate = 1:2:2.
6. the method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the electrodes are a graphite positive electrode and a nickel foam negative electrode.
7. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein in step two, a 5mA dc power source is applied at room temperature and the reaction is stirred.
8. The method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein the specific reaction scheme is as follows:
wherein R is 1 Alkyl, halogen, methoxy; r is R 2 Phenyl, halogen;
the structural formula of the target product is as follows:
9. the method for electrochemically synthesizing a 1, 3-fluoroamine product of claim 1, wherein: the specific reaction route is as follows:
wherein R is methyl, phenyl, halogen or ester;
the specific structure of the target product is as follows:
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