CN116969820A - Method for realizing visible light-induced intramolecular alkynyl migration of 1, 4-eneyne compound and realizing unactivated olefin difunctional - Google Patents

Abstract

A method for visible light-induced intramolecular migration of alkynyl groups in 1,4-enyne compounds and achieving difunctionalization of unactivated alkenes. It involves the migration of alkynyl groups of alkenes. It is a method to solve the existing direct selective functionalization method catalysts. Technical problems include expensiveness, harsh reaction conditions and poor regioselectivity. The method of the present invention: add 1,4-enyne compound, trifluoromethyl source, photocatalyst, alkali and solvent into a transparent reactor, use blue LEDs to illuminate the reaction in a nitrogen atmosphere, and then purify to obtain the alkene A product in which the alkynyl group migrates within the alkyne molecule and achieves difunctionalization of unactivated alkenes; the structural formula of this product is: Where R is hydrogen or alkyl. This method achieves bifunctionalization of alkenes through intramolecular migration strategies, constructs alkynone structures and introduces trifluoromethyl groups. It can be used for screening drug lead compounds or for biological activity testing, and can also be used for organic methodology mechanism research. field.

Description

Visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and non-activation Methods for difunctionalization of olefins

Technical field

The invention relates to a preparation method for olefin alkynyl group migration, and belongs to the field of organic synthesis.

Background technique

In the past few years, radical-mediated olefin difunctionalization has attracted widespread attention as it provides an effective tool for rational regulation of olefins. Mechanistically speaking, free radicals add to double bonds in alkene molecules to generate secondary alkyl or tertiary alkyl free radicals, which can be intercepted by external free radical capture reagents to obtain bifunctional products; or can be further combined with molecules The unsaturated bonds within the polymer are cyclized to produce cyclized products; specific groups (such as aryl groups, alkynyl groups) can also be rearranged to produce products with different group migrations. Alkyne group is a very important functional group in organic chemistry. Alkyne compounds are widely used in multidisciplinary fields such as organic chemistry, medicinal chemistry and chemical biology. A typical drug is the highly effective anti-tumor antibiotic Calicheamicin. It can be seen that it is particularly important to develop an efficient alkynylation method. At the same time, fluorine-containing compounds are becoming more and more widely used. In recent years, intramolecular functional group migration reactions initiated by free radicals have received widespread attention.

Therefore, it is particularly important to develop a new method to achieve alkynylation of alkenes under mild conditions, especially visible light-induced trifluoromethylation of alkenes while simultaneously transferring intramolecular alkynyl groups. Trifluoromethyl compounds are an important class of compounds, and about 50 types of trifluoromethyl compounds have been tested for biological activity. Whether it is aliphatic compounds with anesthetic effects, phenothiazine sedatives and antiemetics, benzothiadiazine diuretics, and some antihistamines, antiasthmatics, and antimalarials that have not been clinically evaluated , anti-Staphylococcus aureus and other compounds, all contain trifluoromethyl groups. Acetylenones are very attractive precursors for the synthesis of heterocyclic compounds, such as pyrrole, furan, furanone, pyrazole, isoxazole, pyrimidine, quinolone, flavonoid, etc., which can be used as templates in the synthesis process. It is also a useful synthetic intermediate for the preparation of furans, 1,4-dicarbonyl compounds, pyrrole and bicyclic structural compounds. These compounds are key skeletons or intermediates for many drugs, spices or pesticides and have a wide range of application scenarios.

In recent years, great progress has been made in the study of intramolecular functional group migration promoted by trifluoromethyl, which mainly includes intramolecular 1,4-migration, 1,5-migration and 1,2-migration. In general, for There have been relatively few studies on 1,2-alkynyl migration. Although many migration types have been developed, current research still has many limitations and requires further improvement and development: (1) Most reactions still use transition metal catalysis, and experimental conditions need to be further improved to develop milder reaction systems. It is more in line with the development requirements of green chemistry; (2) Most of the free radical sources currently used are relatively expensive, such as the trifluoromethyl source Umemoto's reagent, Togni's reagent and Langloi's reagent. Therefore, relatively cheap and easily available free radical sources should be developed. Reduce the cost of reaction.

Contents of the invention

The present invention is to solve the technical problems of expensive catalysts, harsh reaction conditions and poor regional selectivity of the existing direct selective functionalization method, and provides light-induced intramolecular alkynyl migration of 1,4-enyne compounds and Methods to achieve difunctionalization of unactivated olefins.

The method of visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and realizing difunctionalization of unactivated olefins according to the present invention is carried out according to the following steps:

1. At room temperature, add the 1,4-enyne compound, trifluoromethyl source, photocatalyst, and alkali into a transparent reactor and seal it; then replace the gas in the reactor with nitrogen to form a nitrogen atmosphere, and then inject the solvent. Mix evenly; illuminate the reactor with blue LEDs for reaction;

2. After the reaction is completed, the solvent is removed by rotary evaporation, and then separated and purified by prefabricated silica gel column chromatography to obtain a product in which the alkynyl group migrates within the alkyne molecule and achieves difunctionalization of unactivated alkene;

The structural formula of the 1,4-enyne compound described in step 1 is: where R is hydrogen or alkyl;

The structural formula of the trifluoromethyl source described in step one is:

The photocatalyst described in step one is fac-Ir(ppy) ₃ , and its structural formula is:

The structural formula of the product in which the alkynyl group migrates within the alkyne molecule and achieves difunctionalization of unactivated olefins as described in step 2 is: Where R is hydrogen or alkyl.

Furthermore, the base described in step one is potassium bicarbonate.

Furthermore, the solvent described in step one is methanol or acetonitrile.

Furthermore, in step one, the molar ratio of the 1,4-enyne compound and the trifluoromethyl source is 1:(1-3).

Furthermore, in step one, the molar ratio of the 1,4-enyne compound to the base is 1:(1-2).

Furthermore, in step one, the ratio of the amount of the 1,4-enyne compound to the volume of the solvent is 1 mmol: (1-10) mL.

Furthermore, in step one, the molar ratio of the 1,4-enyne compound to the photocatalyst is 1:(1-4).

Furthermore, the LEDs lamp described in step one is 5 to 30 watts, and the irradiation reaction time is 1 to 4 days.

Furthermore, the solvent used in the silica gel column chromatography separation and purification described in step one is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of (10-1):1.

The synthesis process of the preparation method of the present invention is expressed by the following reaction formula:

The present invention adopts a simple and efficient one-step method of 1,4-enyne intramolecular alkynyl migration compound, in which fac-Ir(ppy) ₃ is used as a catalyst to cause the visible light-promoted and initiated reaction between the alkenyl compound and the trifluoromethyl reagent. In the photochemical reaction, in the reaction system of the present invention, the trifluoromethyl group has excellent free radical reactivity, electrophilicity and nucleophilicity, allowing the reaction to proceed smoothly and enabling selective migration of alkenes. The abundant visible light in nature as the driving force has the advantages of being renewable, green, and pollution-free, with mild preparation conditions, safe catalysts, simple operation, and low energy consumption.

This method achieves difunctionalization of alkenes through intramolecular migration strategies, constructs alkynone structures and introduces trifluoromethyl groups, which greatly improves the atom economy of the reaction and has important synthetic value and research significance. The 1,4-enyne intramolecular alkynyl group-migrating trifluoromethyl compound prepared by the present invention has good biomedical potential and can further improve its application value.

Description of the drawings

Figure 1 is a ¹ H NMR spectrum of the trifluoromethyl compound with intramolecular alkynyl migration of 1,4-enyne obtained in Example 1.

Figure 2 is a ¹³ C NMR spectrum of the trifluoromethyl compound with intramolecular alkynyl migration of 1,4-enyne obtained in Example 1.

Detailed ways

The following examples are used to verify the beneficial effects of the present invention:

Example 1: In this example, the visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and the method of achieving difunctionalization of unactivated olefins are carried out according to the following steps:

1. At room temperature, mix 37mg (0.2mmol) 2,3-dimethyl-5-phenylpent-1-en-4-yn-3-ol and 86.9mg (0.2mmol) S-trifluoromethylthianiol. Add anthracene triflate, 1.31mg (0.002mmol) fac-Ir(ppy) ₃ and 40mg (0.4mmol) potassium bicarbonate into a 10mL penicillin bottle, seal it with a rubber stopper and a sealing film; then use a needle to connect the penicillin bottle and air pump, extract the air from the penicillin bottle, backfill it with nitrogen, repeat three times, form a nitrogen atmosphere in the penicillin bottle, then inject 1mL methanol as the solvent, and mix evenly; at room temperature, illuminate the reactor with 30W blue LEDs Carry out the reaction and monitor the reaction progress with TLC. The reaction is completed after 1 day of reaction;

2. After the reaction is completed, the solvent is removed by concentrating on a rotary evaporator, and then a mixed solution of petroleum ether:ethyl acetate with a volume ratio of 5:1 is used as a developing agent to perform silica gel column chromatography, purification and separation to complete visible light induction. The intramolecular alkynyl group of the 1,4-enyne compound is migrated and the unactivated olefin is difunctionalized to obtain a trifluoromethyl compound with the intramolecular alkynyl group of the 1,4-enyne compound.

The reaction formula of this embodiment is:

The product was a yellow liquid with a purity of 99% and a yield of 70%.

The ¹ H NMR spectrum of the product in this example is shown in Figure 1. The nuclear magnetic data is: ¹ H NMR (400MHz, Chloroform-d) δ7.47–7.39 (m, 2H), 7.32 (dd, J = 5.2, 2.0Hz ,3H),2.93-2.81(m,1H),2.68–2.36(m,4H),1.53(s,3H).

The ¹³ C NMR spectrum of the product of this example is shown in Figure 2. ¹³ C NMR (101MHz, Chloroform-d) δ205.58, 131.51, 128.55, 128.32, 125.61 (q, J = 273.9Hz), 122.43, 88.14, 85.87, 44.36 (d, J＝2.3Hz), 41.25 (q, J＝27.9Hz), 26.20, 25.60.

It can be seen from the ¹ H NMR spectrum and the ¹³ C NMR spectrum that the structural formula of the product prepared in this example is:

In this embodiment, the bifunctionalization of alkenes is achieved through an intramolecular migration strategy, an acetylenone structure is constructed, and a trifluoromethyl group is introduced.

Example 2: In this example, the visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and the method of achieving difunctionalization of unactivated olefins are carried out according to the following steps:

1. At room temperature, 40.1mg (0.2mmol) 2,3-dimethyl-5-(p-toluene)pent-1-en-4-yn-3-ol, 86.9mg (0.2mmol) S-trifluoromethyl Add thianthrone trifluoromethanesulfonate, 1.31 mg (0.002 mmol) fac-Ir(ppy) ₃ and 40 mg (0.4 mmol) potassium bicarbonate into a 10 mL penicillin bottle, seal it with a rubber stopper and a sealing film; then use a needle Connect the penicillin bottle and the air pump, extract the air from the penicillin bottle, backfill it with nitrogen, repeat three times, form a nitrogen atmosphere in the penicillin bottle, then inject 1mL methanol as the solvent, and mix evenly; at room temperature, use 30W blue LEDs in the reactor The reaction was carried out under light illumination, and TLC was used to monitor the reaction progress. The reaction was completed after 1 day of reaction;

2. After the reaction is completed, the solvent is removed by concentrating on a rotary evaporator, and then a mixed solution of petroleum ether:ethyl acetate with a volume ratio of 5:1 is used as a developing agent to perform silica gel column chromatography, purification and separation to complete visible light induction. The intramolecular alkynyl group of the 1,4-enyne compound is migrated and the unactivated olefin is difunctionalized to obtain a trifluoromethyl compound with the intramolecular alkynyl group of the 1,4-enyne compound.

The reaction formula of this embodiment is:

The product in this example is a yellow liquid with a purity of 99% and a yield of 55%.

The NMR data of the products in this example are:

¹ H NMR (400MHz, CDCl ₃ ) δ7.35 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 2.89 (dq, J = 15.1, 10.7 Hz, 1H), 2.64 –2.42(m,4H),2.38(s,3H),1.55(s,3H);

¹³ C NMR (151MHz, CDCl ₃ ) δ205.83, 138.75, 131.44, 129.10, 125.67 (q, J = 279Hz), 119.42, 87.46, 86.00, 44.42, 41.33 (q, J = 27.9Hz), 26.24, 25.66, 21.43 .

It can be seen from the ¹ H NMR spectrum and the ¹³ C NMR spectrum that the structural formula of the trifluoromethyl compound with intramolecular alkynyl migration of 1,4-enyne in this example is:

In this embodiment, the bifunctionalization of alkenes is achieved through an intramolecular migration strategy, an acetylenone structure is constructed, and a trifluoromethyl group is introduced.

Example 3: In this example, the visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and the method of achieving difunctionalization of unactivated olefins are carried out according to the following steps:

1. At room temperature, 48.5mg (0.2mmol) 5-(4-(tert-butyl)phenyl)-2,3-dimethylpent-1-en-4-yn-3-ol, 86.9mg (0.2 mmol)S-trifluoromethylthianthrene trifluoromethanesulfonate, 1.31mg (0.002mmol) fac-Ir(ppy) ₃ and 40mg (0.4mmol) potassium bicarbonate were added to the 10mL penicillin bottle and sealed with a rubber stopper. Seal with parafilm; then use a needle to connect the penicillin bottle and the air pump, extract the air in the penicillin bottle, use nitrogen to backfill, repeat three times, form a nitrogen atmosphere in the penicillin bottle, then inject 1mL of methanol as the solvent, and mix evenly; at room temperature, The reactor was illuminated with 30W blue LEDs for reaction, and TLC was used to monitor the reaction progress. The reaction was completed after 1 day of reaction;

2. After the reaction is completed, concentrate and spin to dryness using a rotary evaporator to remove the solvent, and then use a mixed solution of petroleum ether:ethyl acetate with a volume ratio of 3:1 as a developing agent to perform silica gel column chromatography, purification and separation to complete visible light induction. The intramolecular alkynyl group of the 1,4-enyne compound is migrated and the unactivated olefin is difunctionalized to obtain a trifluoromethyl compound with the intramolecular alkynyl group of the 1,4-enyne compound.

The reaction formula of this embodiment is:

The product in this example is a white solid with a purity of 99% and a yield of 40%.

The NMR data of the products in this example are:

¹ H NMR (400MHz, CDCl ₃ ) δ7.41(d,J＝8.8Hz,2H),7.38(d,J＝8.8Hz,2H).2.90(dq,J＝14.9,10.7Hz,1H),2.66 –2.45(m,4H),1.56(s,3H),1.34(s,9H);

¹³ C NMR (151MHz, CDCl ₃ ) δ205.83, 151.92, 131.28, 125.63 (q, J = 279Hz) 125.33, 119.44, 87.50, 85.95, 44.38 (d, J = 2.02Hz), 41.33 (q, J = 27.9Hz) ,34.75,31.11,26.23,25.67.

From the ¹ H NMR spectrum and the ¹³ C NMR spectrum, it can be seen that the structure of the product in this example is:

In this embodiment, the bifunctionalization of alkenes is achieved through an intramolecular migration strategy, an acetylenone structure is constructed, and a trifluoromethyl group is introduced.

Example 4: In this example, the visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and the method for achieving difunctionalization of unactivated olefins are carried out according to the following steps:

1. At room temperature, 45.7mg (0.2mmol) 2,3-dimethyl-5-(4-propylphenyl)pent-1-en-4-yn-3-ol, 86.9mg (0.2mmol) S -Trifluoromethylthianthrene trifluoromethanesulfonate, 1.31mg (0.002mmol) fac-Ir(ppy) ₃ and 40mg (0.4mmol) potassium bicarbonate were added to a 10mL penicillin bottle and sealed with a rubber stopper and sealing film ; Then use a needle to connect the penicillin bottle and the air pump, extract the air in the penicillin bottle, use nitrogen to backfill, repeat three times, form a nitrogen atmosphere in the penicillin bottle, then inject 1mL methanol as the solvent, mix evenly; at room temperature, use the reactor 5W blue LEDs were used to illuminate the reaction, and TLC was used to monitor the reaction progress. The reaction was completed after 4 days of reaction;

2. After the reaction is completed, concentrate and spin to dryness using a rotary evaporator to remove the solvent, and then use a mixed solution of petroleum ether: ethyl acetate with a volume ratio of 1:1 as a developing agent to perform silica gel column chromatography, purification and separation to complete visible light induction. The intramolecular alkynyl group of the 1,4-enyne compound is migrated and the unactivated olefin is difunctionalized to obtain a trifluoromethyl compound with the intramolecular alkynyl group of the 1,4-enyne compound.

The reaction formula of this embodiment is:

The product in this example is a yellow liquid with a purity of 99% and a yield of 46%.

The nuclear magnetic data of the product in this example are: ¹ H NMR (400MHz, CDCl ₃ ) δ7.37 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 2.87 (dt, J ＝14.8,10.7Hz,1H),2.71–2.40(m,6H),1.82–1.59(m,2H),1.55(s,3H),0.95(t,J＝7.3Hz,3H);

¹³ C NMR (151MHz, CDCl ₃ ) δ205.89, 143.52, 131.43, 128.69 (q, J = 279Hz), 128.51, 119.62, 87.47, 86.03, 42.20 (q, J = 27.3Hz), 37.92, 29.69, 26.27, 25.69 , 24.33,13.69.

From the ¹ H NMR spectrum and the ¹³ C NMR spectrum, it can be seen that the structure of the product of this example is:

In this embodiment, the bifunctionalization of alkenes is achieved through an intramolecular migration strategy, an acetylenone structure is constructed, and a trifluoromethyl group is introduced.

Example 5: In this example, the visible light-induced intramolecular alkynyl migration of 1,4-enyne compounds and the method for achieving difunctionalization of unactivated olefins are carried out according to the following steps:

1. At room temperature, 45.7mg (0.2mmol) 2,3-dimethyl-5-(3-methylphenyl)pent-1-en-4-yn-3-ol, 86.9mg (0.2mmol) S -Trifluoromethylthianthrene trifluoromethanesulfonate, 1.31mg (0.002mmol) fac-Ir(ppy) ₃ and 40mg (0.4mmol) potassium bicarbonate were added to a 10mL penicillin bottle and sealed with a rubber stopper and sealing film ; Then use a needle to connect the penicillin bottle and the air pump, extract the air in the penicillin bottle, use nitrogen to backfill, repeat three times, form a nitrogen atmosphere in the penicillin bottle, then inject 1mL methanol as the solvent, mix evenly; at room temperature, use the reactor 5W blue LEDs were used to illuminate the reaction, and TLC was used to monitor the reaction progress. The reaction was completed after 4 days of reaction;

2. After the reaction is completed, concentrate and spin to dryness using a rotary evaporator to remove the solvent, and then use a mixed solution of petroleum ether: ethyl acetate with a volume ratio of 1:1 as a developing agent to perform silica gel column chromatography, purification and separation to complete visible light induction. The intramolecular alkynyl group of the 1,4-enyne compound is migrated and the unactivated olefin is difunctionalized to obtain a trifluoromethyl compound with the intramolecular alkynyl group of the 1,4-enyne compound.

The reaction formula of this embodiment is:

The product in this example is a yellow liquid with a purity of 99% and a yield of 55%.

The nuclear magnetic data of the product in this example are: ¹ H NMR (400MHz, Chloroform-d) δ7.33–7.19 (m, 3H), 7.15 (d, J = 7.2Hz, 1H), 2.87 (dq, J = 15.1 ,10.8Hz,1H),2.49(s,4H),2.33(s,3H),1.53(s,3H);

¹³ C NMR (101MHz, Chloroform-d) δ205.78,138.09,132.10,129.46,128.61,128.24,128.30(q,J＝279Hz),122.25,87.76,86.06,44.39,41.31(q,J＝27.9Hz),2 6.28 ,25.67,21.15.

From the ¹ H NMR spectrum and the ¹³ C NMR spectrum, it can be seen that the structure of the product of this example is:

In this embodiment, the bifunctionalization of alkenes is achieved through an intramolecular migration strategy, an acetylenone structure is constructed, and a trifluoromethyl group is introduced.

Claims (9)

1. A method for visible light induced intramolecular alkyne migration of a 1, 4-eneyne compound and realization of dual functional groups of an unactivated alkene, characterized in that the method comprises the following steps:

1. at room temperature, adding a 1, 4-eneyne compound, a trifluoromethyl source, a photocatalyst and alkali into a transparent reactor, and sealing; then using nitrogen to replace the gas in the reactor to form nitrogen atmosphere, then injecting solvent, and uniformly mixing; the reactor is irradiated with blue LEDs to react;

2. after the reaction is finished, removing the solvent by rotary evaporation, and separating and purifying by prefabricated silica gel column chromatography to complete visible light-induced 1, 4-eneyne compound intramolecular alkyne migration and realize unactivated olefin difunctional, so as to obtain an eneyne intramolecular alkyne migration and realize unactivated olefin difunctional product;

wherein the structural formula of the 1, 4-eneyne compound in the first step is as follows:wherein R is hydrogen or alkyl;

the structural formula of the trifluoromethyl source in the first step is as follows:

the photocatalyst in the first step is fac-Ir (ppy) ₃ The structural formula is as follows:

the structural formula of the product for realizing the difunctional group of the unactivated olefin by the migration of the alkynyl in the eneyne molecule in the second step is as follows:wherein R is hydrogen or alkyl.

2. The method for visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound according to claim 1, wherein said base in step one is potassium bicarbonate.

3. The method for visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound according to claim 1 or 2, wherein said solvent in step one is methanol or acetonitrile.

4. The method for the visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound and the realization of the dual functional group of an unactivated olefin according to claim 1 or 2, wherein in the first step, the molar ratio of the 1, 4-eneyne compound to the trifluoromethyl source is 1 (1-3).

5. The method for the visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound according to claim 1 or 2, wherein in the step one, the molar ratio of the 1, 4-eneyne compound to the base is 1 (1-2).

6. The method for visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound according to claim 1 or 2, wherein the ratio of the amount of the substance of the 1, 4-eneyne compound to the volume of the solvent in step one is 1mmol: (1-10) mL.

7. The method for the visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound and the realization of the dual-functional group of an unactivated olefin according to claim 1 or 2, wherein in the first step, the molar ratio of the 1, 4-eneyne compound to the photocatalyst is 1 (1-4).

8. The method for the visible light-induced intramolecular alkyne migration of a 1, 4-eneyne compound according to claim 1 or 2, wherein said LEDs in step one are operated at 5 to 30 watts for a reaction time of 1 to 4 days.

9. The method for realizing the difunctional group of the unactivated olefin by the intramolecular alkynyl migration of the 1, 4-eneyne compound induced by the visible light according to claim 1 or 2, wherein the solvent used in the separation and purification of the silica gel column chromatography in the step one is a mixed solvent of petroleum ether and ethyl acetate according to the volume ratio of (10-1): 1.