CN115417738B - Photo-induced alpha-hydrofluorination method for diazoaryl ester compound - Google Patents

Photo-induced alpha-hydrofluorination method for diazoaryl ester compound Download PDF

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CN115417738B
CN115417738B CN202211123173.3A CN202211123173A CN115417738B CN 115417738 B CN115417738 B CN 115417738B CN 202211123173 A CN202211123173 A CN 202211123173A CN 115417738 B CN115417738 B CN 115417738B
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ester compound
alpha
diazoaryl
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ester
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CN115417738A (en
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杨超
李斌
郭林
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Shenzhen Graduate School Harbin Institute of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms

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Abstract

The invention relates to a photoinduction alpha-position hydrofluorination method of a diazo aryl ester compound, belongs to the technical field of photoinduction synthesis, and particularly relates to a method for realizing direct alpha-position hydrofluorination of the diazo aryl ester compound by photoinduction under the condition of no external photocatalyst. The invention aims to solve the technical problem of difficulty in constructing a C-F bond in organic synthesis. The method comprises the following steps: adding diazoaryl ester compound, fluoridation reagent and acid salt into solvent, mixing, and irradiating with light source at room temperature under inert gas atmosphere to obtain alpha-fluoroaryl ester compound. The method has the advantages of simple operation, commercially available raw materials, high-yield synthesis of the reaction by using blue light irradiation, high atomic economy and wide substrate universality. The invention is applied to the field of organic synthesis.

Description

Photo-induced alpha-hydrofluorination method for diazoaryl ester compound
Technical Field
The invention belongs to the technical field of photoinduction synthesis, and particularly relates to a method for realizing direct hydrofluorination of alpha-position of diazoaryl ester compounds by photoinduction under the condition of no external photocatalyst.
Background
In recent years, photochemical carbene transfer reactions have attracted interest to organic chemists as a metal-free route to obtain the carbene activity of aryl diazoacetic acid esters in cycloaddition, rearrangement, X-H bond insertion or olefination reactions. The alpha-diazocarbonyl compound can generate a reaction intermediate with high electrophilicity after being treated by Bronsted acid or Lewis acid, can react with various nucleophiles, and can be inserted into hydrocarbon, carbon heteroatom and heteroatom hydrogen bonds.
The insertion of H-F bonds is an important study in organic synthesis, namely the construction of C-F bonds as well as C-H bonds. The construction of C-F bonds is one step of high practical value in chemical synthesis, and thus researchers have been working to develop efficient, selective and convenient methods to accomplish the construction of C-F bonds. So far, there are many constructions for achieving C-F bonds based on transition metal catalysis and thermal reactions. In most cases, however, high temperature heating, the use of hazardous chemicals, or the addition of heavy metal catalysts are required to achieve this type of reaction. The construction of C-F bonds for photoinduction remains a challenging area. Therefore, the construction of C-F bond by a mild, efficient and green method is one of the very significant and challenging research subjects, and the research on the C-F bond is also in progress with the development of organic chemistry.
Disclosure of Invention
The invention aims to solve the technical problem of difficulty in constructing a C-F bond in organic synthesis, and provides a photoinduction alpha-position hydrofluorination method of a diazoaryl ester compound.
A method for alpha-hydrofluorination of a photoinduction diazoaryl ester compound, which comprises the following steps:
1. adding a diazoaryl ester compound, a fluorination reagent and an acid salt into a solvent, and uniformly mixing to obtain a mixed solution;
2. and (3) irradiating the mixed solution obtained in the step (I) by adopting LEDs with the wavelength of 450-470 nm under the nitrogen atmosphere and the room temperature, removing the solvent by rotary evaporation, and then separating and purifying by adopting a thin layer chromatography to obtain the product, namely the alpha-fluoroaryl ester compound.
Further, in the step one, the ratio of the diazoaryl ester compound to the solvent is 0.2-0.3 mmol:2mL;
the ratio of the fluorinating agent to the solvent is 0.4-0.6 mmol:2mL;
KH 2 PO 4 the ratio of the solvent to the solvent is 0.3-0.45 mmol:2mL.
Further, in the second step, the power of the LED light source is 10W.
Further, the irradiation time is controlled to be 2-12 hours in the second step.
The reaction formula of the invention is:
wherein R is 1 F, cl, br, CF of a shape of F, cl, br, CF 3 、NO 2 、COOCH 3 Or Ph; r is R 2 Is allyl or isopropoxyethyl.
The invention aims to explore a diazoaryl ester compound and bis (2-methoxyethyl) amino sulfur trifluoride, and complete the construction of a C-F bond under the condition of no additional metal catalyst. Under the condition of blue light induction, alpha position of the diazoaryl ester compound forms a singlet state carbene to react with a fluorination reagent, no catalyst is needed to participate, the reaction cycle only comprises diazoaryl ester and the fluorination reagent, and potassium dihydrogen phosphate is additionally added as a reaction promoter to replace the traditional metal catalyst, and the reaction is simpler, more green, milder and more efficient by changing the pH value of the system instead of participating in the reaction cycle.
The diazophenylacetic acid methyl ester compound takes 2- (4-chlorophenyl) -2-diazoacetic acid methyl ester as an example, and the reaction mechanism is as follows:
initially, under 10w 460nm blue light irradiation, the diazocarbonyl group in the α -diazocarbonyl compound decomposes to form a singlet carbene having a pair of unbound electrons and an empty orbital, participating in a small amount of moisture will provide hydrogen ions, attack the singlet carbene, and further form the exact center of the carbocation, leaving an empty orbital, BAST will provide fluoride anions, attack the empty orbital to form a C-F bond, thereby obtaining methyl 2- (4-chlorophenyl) -2-fluoroacetate.
Compared with the prior art, the method for constructing the alpha-fluoroaryl ester compound by using the method has the advantages of convenience, greenness, mildness and high efficiency, and mainly has the following advantages:
(1) Under the condition of no external metal catalyst, alpha-position hydrofluorination of the diazoaryl ester compound is realized.
(2) The synthesis of the alpha-fluoroaryl ester compound can be realized by illumination at room temperature, and the reaction condition is green and mild.
(3) Compared with photocatalysis, the reaction principle is essentially different, the invention has the advantages that the light is only an induction effect, the reaction system can automatically generate, the reaction cycle only relates to diazoaryl ester and bis (2-methoxyethyl) amino sulfur trifluoride, no catalyst or acid-base salt is needed to participate, the monopotassium phosphate is used as a reaction accelerator to replace the traditional metal catalyst, the reaction is efficiently carried out by changing the pH value of the system instead of participating in the reaction cycle, and the reaction efficiency is obviously improved without other substances participating in the reaction due to the reduction of substances participating in the reaction cycle, and the purity of the substances is higher.
(4) The diazonium aryl ester compound, the fluorination reagent, the acid salt and the solvent used in the reaction system are all cheap and easily available commercial chemicals, so that the whole reaction system is economical and has high efficiency.
(5) The reaction system has good substrate universality, is suitable for some substrates containing sensitive functional groups, has high atom economy, and can obtain higher yield through optimizing reaction conditions.
(6) The formation of C-F bond can be induced by using light, and fluorine atoms are introduced, so that the method has quite great potential application value in the aspect of medicinal chemistry.
The method is applied to the field of organic synthesis and is used for preparing the alpha-fluoroaryl ester compound.
Drawings
FIG. 1 is a block diagram of an α -fluoroaryl ester compound-1 obtained in example one 1 H NMR spectrum;
FIG. 2 is a block diagram of the α -fluoroaryl ester compound-1 obtained in example one 19 F NMR spectrum;
FIG. 3 is a block diagram of an α -fluoroaryl ester compound-1 obtained in example one 13 C NMR spectrum.
Detailed Description
The present invention is not limited to the above embodiments, and the object of the invention can be achieved by one or a combination of several embodiments.
The first embodiment is as follows: the method for alpha-hydrofluorination of the photoinduction diazoaryl ester compound comprises the following steps:
1. adding a diazoaryl ester compound, a fluorination reagent and an acid salt into a solvent, and uniformly mixing to obtain a mixed solution;
2. and (3) irradiating the mixed solution obtained in the step (I) by adopting LEDs with the wavelength of 450-470 nm under the nitrogen atmosphere and the room temperature, removing the solvent by rotary evaporation, and then separating and purifying by adopting a thin layer chromatography to obtain the product, namely the alpha-fluoroaryl ester compound.
According to the invention, under the condition of blue light irradiation and no additional catalyst, the insertion of H-F bonds is completed, so that the simplicity and convenience of the reaction are reflected; the reaction can be realized at room temperature, and the reaction mildness is reflected; and the cheap monopotassium phosphate is used for replacing a high heavy metal catalyst, so that the reaction is economical and environment-friendly. The method principle of the invention only occurs under the photoinduction condition, is essentially different from the photocatalysis principle that other catalysts participate in the light circulation, does not involve other substances to participate in the reaction principle process, only comprises diazoaryl ester and bis (2-methoxyethyl) amino sulfur trifluoride, and additionally, potassium dihydrogen phosphate is added to replace the traditional metal catalyst and is used as a reaction accelerator, and the reaction process is promoted by changing the pH value of the system instead of participating in the reaction circulation, so that the reaction process is more efficient and convenient.
The second embodiment is as follows: the present embodiment is different from the specific embodiment in that: step one, wherein the diazoaryl ester compound is 2- (2-bromophenyl) -2-diazoacetic acid methyl ester, 2- (4-chlorophenyl) -2-diazoacetic acid methyl ester, 4- (1-diazo-2-methoxy-2-oxyethyl) benzoic acid methyl ester, 2-diazo-2- (3, 4-dichlorophenyl) acetic acid methyl ester, 2-diazo-2- (naphthalene-2-yl) acetic acid methyl ester, 2-diazo-2-phenylacetic acid allyl ester or 2-diazo-2-phenylacetic acid ethyl ester. The other is the same as in the first embodiment.
And a third specific embodiment: this embodiment differs from the implementation of one or two in that: step one the fluorinating agent is bis (2-methoxyethyl) aminotrifluoride. The other is the same as the first or second embodiment.
The specific embodiment IV is as follows: the present embodiment differs from the implementation of one to three in that: step one the acid salt is KH 2 PO 4 . The others are the same as one of the three or nine embodiments.
Fifth embodiment: the present embodiment differs from the implementation by one to four in that: in the first step, the solvent is anhydrous diethyl ether. The others are the same as in one to one fourth embodiments.
Specific embodiment six: the present embodiment differs from the implementation of one to five in that: the ratio of the diazoaryl ester compound to the solvent is 0.2-0.3 mmol:2mL;
the ratio of the fluorinating agent to the solvent is 0.4-0.6 mmol:2mL;
KH 2 PO 4 the ratio of the solvent to the solvent is 0.3-0.45 mmol:2mL. The others are the same as in one of the first to fifth embodiments.
Seventh embodiment: the present embodiment differs from the implementation of one to six in that: and step two, the power of the LED light source is 10W. The others are the same as in one of the first to sixth embodiments.
Eighth embodiment: the present embodiment differs from the implementation of one of the first to seventh embodiments in that: and step two, controlling the irradiation time to be 2-12 hours. The other is the same as in one of the first to seventh embodiments.
Detailed description nine: this embodiment differs from the implementation of one to eight in that: and step two, the solvent used for separating and purifying by the thin layer chromatography is a mixture of petroleum ether and ethyl acetate. The others are the same as in one to eight embodiments.
Detailed description ten: this embodiment differs from one of the implementations one to nine in that: the volume ratio of petroleum ether to ethyl acetate is 100:1. The others are the same as in one of the embodiments one to nine.
Embodiment one:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2- (4-chlorophenyl) -2-diazonium methyl acetate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 2h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2- (4-chlorophenyl) -2-diazonium methyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to methyl p-chlorophenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol) MeCN (15 mL); the reaction mixture was stirred overnight for 12h, and consumption of starting material was confirmed by TLC with NH 4 A saturated solution of Cl (5 mL) quenched the reaction mixture; extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and dried over MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2- (4-chlorophenyl) -2-diazonoacetate as a dark orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-1 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 82%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.47–7.36(m,4H),5.80(d,J＝47.2Hz,1H),3.80(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.67(d,J＝27.7Hz),135.76(d,J＝2.6Hz),132.70(d,J＝21.0Hz),129.12,128.06(d,J＝6.2Hz),88.65(d,J＝186.2Hz),52.81. 19 F NMR(376MHz,CDCl 3 )δppm＝-180.89(d,J＝47.4Hz,1F).
embodiment two:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2- (2-bromophenyl) -2-diazonium methyl acetate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 2h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2- (2-bromophenyl) -2-diazonium methyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to methyl o-bromophenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol) MeCN (15 mL); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2- (2-bromophenyl) -2-diazonoacetate as a dark orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-2 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 69%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.68–7.30(m,4H),6.26(d,J＝46.4Hz,1H),3.83(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.53(d,J＝27.8Hz),133.30,131.29(d,J＝2.5Hz),128.83(d,J＝6.2Hz),128.02,123.36(d,J＝4.6Hz),88.37(d,J＝184.6Hz),52.85. 19 F NMR(376MHz,CDCl 3 )δppm＝-181.38(d,J＝47.3Hz,1F).
embodiment III:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of methyl 4- (1-diazonium-2-methoxy-2-oxyethyl) benzoate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 1h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 4- (1-diazonium-2-methoxy-2-oxyethyl) methyl benzoate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to MeCN (15 mL) of methyl 4- (2-ethoxy-2-oxoethyl) benzoate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 The reaction mixture was quenched with a saturated solution of Cl (5 mL), extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in vacuo 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) givesTo yellow powdered methyl 4- (1-diazonium-2-methoxy-2-oxoethyl) benzoate.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-3 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 80%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝8.09(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),5.88(d,J＝47.4Hz,1H),3.93(s,3H),3.79(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.41(d,J＝27.0Hz),166.43,138.75(d,J＝20.5Hz),131.28(d,J＝1.8Hz),130.05,126.38(d,J＝6.5Hz),88.80(d,J＝187.0Hz),52.88,52.34. 19 F NMR(376MHz,CDCl 3 )δppm＝-183.82(d,J＝47.2Hz).
embodiment four:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2-diazonium-2- (3, 4-dichlorophenyl) acetic acid methyl ester, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 6h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2-diazonium-2- (3, 4-dichlorophenyl) acetic acid methyl ester comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to methyl 3, 4-dichlorophenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol) MeCN (15 mL);the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 The reaction mixture was quenched with a saturated solution of Cl (5 mL), extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in vacuo 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2-diazonium-2- (3, 4-dichlorophenyl) acetate as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-4 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 58%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.60(s,1H),7.52(d,J＝8.3Hz,1H),7.33(d,J＝8.5Hz,1H),5.78(d,J＝47.1Hz,1H),3.83(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.16(d,J＝27.2Hz),134.58–133.75(m),133.21,130.93,128.52(d,J＝6.9Hz),125.73(d,J＝6.4Hz),87.96(d,J＝188.1Hz),53.02. 19 F NMR(376MHz,CDCl 3 )δppm＝-182.76(d,J＝47.1Hz,1F).
fifth embodiment:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2-diazonium-2- (naphthalene-2-yl) methyl acetate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 2h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
Wherein, the preparation method of the 2-diazonium-2- (naphthalene-2-yl) methyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to methyl 2-naphthylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol) MeCN (15 mL); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2-diazonium-2- (naphthalen-2-yl) acetate as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-5 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 82%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝8.23(d,J＝8.4Hz,1H),7.95(t,J＝8.7Hz,2H),7.68–7.60(m,2H),7.60–7.51(m,2H),6.42(d,J＝46.9Hz,1H),3.80(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝169.44(d,J＝27.9Hz),133.91,130.71,130.07(d,J＝18.9Hz),128.89,128.12(d,J＝8.7Hz),127.18,126.99(d,J＝7.9Hz),126.30,125.70(d,J＝30.9Hz),125.14,123.70,88.70(d,J＝185.1Hz),52.80,39.10. 19 F NMR(376MHz,CDCl 3 )δppm＝-177.81(d,J＝46.9Hz,1F).
example six:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL anhydrous diethyl ether solvent, adding 0.2mmol of 2-diazonium-2-phenylacetic acid allyl ester, and mixing to obtainTo a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 12h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2-diazonium-2-phenyl allyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to MeCN (15 mL) of allyl phenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol); the reaction mixture was stirred overnight for 12h, the consumption of starting material was confirmed by TLC and in doing so NH was used 4 The reaction mixture was quenched with a saturated solution of Cl (5 mL), extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in vacuo 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded allyl 2-diazonium-2-phenylacetate as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-6 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 68%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.55–7.32(m,5H),5.98–5.89(m,1H),5.36–5.19(m,2H),4.72(t,J＝5.6Hz,1H),4.64(d,J＝7.1Hz,1H),3.70(s,1H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.32(d,J＝27.5Hz),134.22(d,J＝20.5Hz),132.08,131.17,129.74(d,J＝2.3Hz),129.35,128.76(d,J＝22.0Hz),127.19,126.74(d,J＝6.0Hz),119.11,118.32,89.39(d,J＝185.8Hz),65.86(d,J＝65.9Hz),41.39. 19 F NMR(376MHz,CDCl 3 )δppm＝-179.87(d,J＝47.4Hz,1F).
embodiment seven:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2-isopropoxyethyl 2-diazonium-2-phenylacetic acid, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 12h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2-isopropoxyethyl 2-diazonium-2-phenylacetic acid comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to 2-isopropoxyethylphenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol) MeCN (15 mL); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded 2-isopropoxyethyl 2-diazonium-2-phenylacetic acid as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-7 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 65%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.54–7.40(m,5H),5.82(d,J＝47.6Hz,1H),4.26(t,J＝5.3Hz,2H),3.52(t,J＝6.2Hz,2H),2.04–1.61(m,6H),1.30(s,1H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.62(d,J＝27.7Hz),134.26(d,J＝20.5Hz),129.75(d,J＝2.4Hz),128.89,126.64(d,J＝6.1Hz),89.36(d,J＝185.8Hz),64.92,44.27,28.85,25.89. 19 F NMR(376MHz,CDCl 3 )δppm＝-180.29(1F).
example eight:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2- (4- (tert-butyl) phenyl) -2-diazonium methyl acetate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 3h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
Wherein, the preparation method of the 2- (4- (tertiary butyl) phenyl) -2-diazonium methyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to MeCN (15 mL) of methyl p-tert-butylphenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2- (4- (tert-butyl) phenyl) -2-diazonium acetate as an orange solid.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-8 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 83%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.45(q,J＝8.3Hz,4H),5.81(d,J＝47.7Hz,1H),3.82(s,3H),1.36(s,9H). 13 C NMR(101MHz,CDCl 3 )δppm＝169.41(d,J＝28.0Hz),153.10(d,J＝2.5Hz),150.15,131.82–130.62(m),129.09,126.78(d,J＝5.7Hz),126.00,125.74,89.48(d,J＝184.7Hz),52.50(d,J＝59.0Hz),40.86,34.79(d,J＝28.5Hz),31.47(d,J＝10.8Hz),1.22. 19 F NMR(376MHz,CDCl 3 )δppm＝-178.03(d,J＝48.0Hz,1F).
example nine:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2-diazonium-2- (3-nitrophenyl) methyl acetate, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 2h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
The preparation method of the 2-diazonium-2- (3-nitrophenyl) methyl acetate comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to MeCN (15 mL) of methyl m-nitrophenylacetate (10.0 mmol), p-toluenesulfonyl azide (15.0 mol); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; by passing throughPurification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2-diazonium-2- (3-nitrophenyl) acetate as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-9 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and the structural formula is as follows:
purity 99%, yield 78%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝8.40–8.23(m,2H),7.85(d,J＝7.6Hz,1H),7.65(t,J＝8.0Hz,1H),5.95(d,J＝46.9Hz,1H),3.84(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝167.92(d,J＝26.9Hz),148.43,136.17(d,J＝21.5Hz),132.24(d,J＝6.4Hz),130.06,124.49,121.56(d,J＝7.5Hz),88.08(d,J＝188.7Hz),53.15. 19 F NMR(376MHz,CDCl 3 )δppm＝-184.31(d,J＝47.0Hz).
example ten:
the alpha-hydrofluorination method of the photoinduction diazoaryl ester compound comprises the following steps:
1. 0.4mmol of bis (2-methoxyethyl) aminotrifluorosulfur and 0.3mmol of acid salt KH 2 PO 4 Dissolving in 2mL of anhydrous diethyl ether solvent, then adding 0.2mmol of 2-diazonium-2- (3- (trifluoromethyl) phenyl) acetic acid methyl ester, and uniformly mixing to obtain a mixed solution;
2. introducing nitrogen for 5min, magnetically stirring at room temperature, simultaneously irradiating the mixed solution obtained in the step I by adopting a 10W light source with the wavelength of 460nm plus or minus 10nm, controlling the irradiation time to be 9h, controlling the stirring speed to be 620rpm, and monitoring the reaction progress by adopting TLC; then the solvent is removed by reduced pressure distillation, and then the thin layer chromatography is adopted for separation and purification, and the obtained product is the alpha-fluoroaryl ester compound.
Wherein, the preparation method of the 2-diazonium-2- (3- (trifluoromethyl) phenyl) acetic acid methyl ester comprises the following steps: 1, 8-diazabicyclo [5.4.0]Undec-7-ene (15.0 mmol) was added to methyl m-trifluoromethyl phenylacetate (10.0 m)mol), p-toluenesulfonyl azide (15.0 mol) in MeCN (15 mL); the reaction mixture was stirred overnight for 12h, and TLC was used to confirm consumption of starting material while NH was used 4 A saturated solution of Cl (5 mL) quenched the reaction mixture, extracted with DCM (3X 30 mL), washed with brine (3X 10 mL), and concentrated in MgSO 4 Drying and then concentrating the mixture under pressure to a crude product; purification by column chromatography (1:100 ethyl acetate/petroleum ether) afforded methyl 2-diazonium-2- (3- (trifluoromethyl) phenyl) acetate as an orange oil.
The alpha-fluoroaryl ester compound prepared in the embodiment is identified as alpha-fluoroaryl ester compound-10 by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, and has the structural formula:
purity 99%, yield 56%; the nuclear magnetic data analysis is as follows: 1 H NMR(400MHz,CDCl 3 )δppm＝7.77(s,1H),7.71(d,J＝7.8Hz,2H),7.59(t,J＝7.8Hz,1H),5.90(d,J＝47.2Hz,1H),3.84(s,3H). 13 C NMR(101MHz,CDCl 3 )δppm＝168.34(d,J＝27.0Hz),135.18(d,J＝21.0Hz),130.07–129.10(m),126.48,123.38(t,J＝5.2Hz),88.58(d,J＝187.5Hz),52.97. 19 F NMR(376MHz,CDCl 3 )δppm＝-62.78(3F),-183.15(d,J＝47.1Hz,1F).

Claims (6)

1. a photo-induced alpha-hydrofluorination method of diazoaryl ester compounds is characterized by comprising the following steps:
1. adding a diazoaryl ester compound, a fluorination reagent and an acid salt into a solvent, and uniformly mixing to obtain a mixed solution;
2. irradiating the mixed solution obtained in the first step by adopting LEDs with the wavelength of 450-470 nm under the nitrogen atmosphere and the room temperature condition, removing the solvent by rotary evaporation, and then separating and purifying by adopting a thin layer chromatography to obtain an alpha-fluoroaryl ester compound;
step one, wherein the diazoaryl ester compound is 2- (2-bromophenyl) -2-diazoacetic acid methyl ester, 2- (4-chlorophenyl) -2-diazoacetic acid methyl ester, 4- (1-diazo-2-methoxy-2-oxyethyl) benzoic acid methyl ester, 2-diazo-2- (3, 4-dichlorophenyl) acetic acid methyl ester, 2-diazo-2- (naphthalene-2-yl) acetic acid methyl ester, 2-diazo-2-phenylacetic acid allyl ester or 2-diazo-2-phenylacetic acid ethyl ester;
step one, the fluorinating agent is bis (2-methoxyethyl) amino sulfur trifluoride;
step one the acid salt is KH 2 PO 4 ；
In the first step, the solvent is anhydrous diethyl ether.
2. The method for alpha-hydrofluorination of a photoinduction diazoaryl ester compound according to claim 1, wherein the ratio of the diazoaryl ester compound to the solvent in the step one is 0.2-0.3 mmol:2mL;
the ratio of the fluorinating agent to the solvent is 0.4-0.6 mmol:2mL;
KH 2 PO 4 the ratio of the solvent to the solvent is 0.3-0.45 mmol:2mL.
3. The method of claim 1, wherein the LEDs in step two have a light source power of 10W.
4. The method for alpha-hydrofluorination of a photoinduction diazoaryl ester compound according to claim 1, wherein the irradiation time is controlled to be 2-12 hours in the second step.
5. The method for alpha-hydrofluorination of photoinduction diazoaryl ester compounds according to claim 1, wherein the solvent used for separation and purification by thin layer chromatography in the second step is a mixture of petroleum ether and ethyl acetate.
6. The method for alpha-hydrofluorination of photoinduction diazoaryl ester compounds according to claim 5, wherein the volume ratio of petroleum ether to ethyl acetate is 100:1.
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* Cited by examiner, † Cited by third party
Title
（日）石川延男主编.《含氟生理活性物质的开发和应用》.华东理工大学出版社,2000,(第1版),第67-70页. *
Munaretto, Laieli S. et al..H-F bond insertions into α-diazo carbonyl compounds.《Organic & Biomolecular Chemistry》.2022,第20卷(第31期),第6178-6182页. *
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