A method for iron-catalyzed selective difunctionalization of non-activated alkenes

Abstract

The application discloses a method for iron-catalyzed selective difunctionalization of non-activated alkenes, and belongs to the technical field of catalytic synthesis. In the method, halogenated fluorinated alkanes and beta-halogenated aryl ethylene are used as electrophilic reagents, an iron-containing reagent is used as a catalyst, a boron-containing reagent is used as a reducing reagent, and under the action of a base and a ligand, the non-activated alkenes can be subjected to regioselective difunctionalization, two carbon-carbon bonds can be constructed at the same time, and the product has excellent E / Z selectivity (E:Z>20:1). The whole method is simple, easy to operate and safe, and the product of the coupling of the non-activated alkenes and the halogenated product is directly obtained in one step. Under the optimized reaction condition, the yield of the target product can be up to 95% after separation, and the deficiency that a guiding group needs to be introduced in the traditional transition metal-catalyzed multi-component coupling reaction is solved.

Description

Technical Field

[0001] This invention belongs to the field of catalytic synthesis technology, specifically relating to a method for selective bifunctionalization of non-activated olefins catalyzed by iron. Background Technology

[0002] Organic tandem reactions and multicomponent reactions are important synthetic strategies in organic chemistry, enabling the economical and efficient one-step synthesis of multi-site reaction products. These strategies have seen widespread development and application in drug synthesis, functional material preparation, and organic molecular framework construction. In the field of olefin bifunctionalization, traditional transition metal-catalyzed reactions can synthesize complex molecules by simultaneously constructing two adjacent carbon-carbon bonds. However, the regioselectivity of the newly formed carbon-carbon bonds is often unsatisfactory, hindering the application of bifunctionalization strategies in organic synthesis. This deficiency can be attributed to the weak resonance effect of in-situ generated alkyl radicals, which result in extremely high reactivity and trigger various side reactions. Transition metal-catalyzed three-component olefin reactions often rely on directed-group strategies to achieve good regioselectivity; however, the introduction of directed groups and their removal or transformation affect the step economy and atom economy. Furthermore, currently developed multicomponent reactions mainly use transition metal catalysts such as nickel, palladium, and copper. These catalysts are either expensive or biotoxic, affecting the later modification of drugs. Therefore, it is of great significance to develop environmentally friendly and effective methods for the bifunctionalization of unactivated olefins without the assistance of directing groups, especially by using cost-effective, green and non-toxic iron as a catalyst. Summary of the Invention

[0003] The technical problem to be solved by this invention is to provide a method for selective bifunctionalization of non-activated olefins catalyzed by iron, so as to solve the technical problems of insufficient selection and the need to introduce directing groups in traditional transition metal catalyzed multi-component coupling reactions.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for selective difunctionalization of unactivated olefins catalyzed by iron is provided, comprising the following steps: In an organic solvent, using halogenated fluoroalkanes and β-halogenated arylethylenes as electrophiles, an iron-containing reagent as a catalyst, and a boron-containing reagent as a reducing agent, the unactivated olefins are reacted under the action of a base and ligands to selectively undergo difunctionalization. The general reaction formula is as follows:

[0005]

[0006] In the formula: R f -X indicates a halofluoroalkanes; R1, R2, and R3 represent substituents on alkenes, and R4 represents a substituent on an aromatic ring.

[0007] The beneficial effects of the above-mentioned technical solution in this invention are as follows: Using transition metal iron as a catalyst offers advantages such as non-toxicity, low cost, and environmental friendliness. Utilizing dipinalloboryl ester as a reducing agent enables regioselective bifunctionalization of inactive olefins, simultaneously constructing two carbon-carbon bonds, and the product exhibits excellent E / Z selectivity (E:Z > 20:1). The raw materials used (inactive olefins, β-bromostyrene derivatives, and fluorinated bromoalkanes) are inexpensive and readily available. Furthermore, inactive olefins, β-bromostyrene derivatives, and fluorinated bromoalkanes are highly favored as important building blocks in organic synthesis, making this reaction highly promising. Due to the variable and difficult-to-control valence states of iron, coupling reactions using iron as a catalyst are currently relatively rare, and the reaction types are quite limited. In addition, the properties of fluorinated alkyl radicals differ from ordinary alkyl radicals; introducing fluorine atoms into drug molecules can modify the properties of the drugs, helping to improve their physicochemical characteristics.

[0008] Based on the above technical solution, the present invention can be further improved as follows:

[0009] Furthermore, R f X represents fluoroalkanes, and X represents halogens.

[0010] Furthermore, R1, R2, and R3 represent substituents on the olefin, and each substituent on the olefin is independently and arbitrarily selected from hydrogen, C1-C6, C2-C4, C3 ... 20 Alkyl, C1-C 20 Halogenated alkyl or C1-C 20 Alkyl aryl groups.

[0011] Furthermore, R4 represents a substituent on the aromatic ring, which can be arbitrarily selected from C1-C1. 20 Alkyl, halogen atoms, carbonyl, silyl ether or cyano groups.

[0012] Furthermore, the organic solvent is methyl tert-butyl ether, the halogenated fluoroalkane is 1-bromoperfluorohexane, the β-halogenated aryl ethylene is (E)-4-methylthio-β-bromostyrene, the iron-containing reagent is ferrous chloride, the boron-containing reagent is dipinacol diboronate, the base is lithium tert-butoxide, the ligand is 1,2-bis(diphenylphosphine)ethane, and the non-activated olefin is 4-phenyl-1-butene, allyltrimethylsilane, or 1-[(trans,trans)-4'-(3-butenyl)[1,1'-bicyclohexane]-4-yl]-4-methylbenzene.

[0013] Furthermore, the molar ratio of halofluoroalkanes, β-haloarylethylenes, iron-containing reagents, boron-containing reagents, bases, ligands, and non-activated alkenes is 2-4:1:0.05-0.2:2-3.5:2-3.5:0.05-0.2:2-3.

[0014] Furthermore, the molar ratio of halofluoroalkanes, β-haloarylethylenes, iron-containing reagents, boron-containing reagents, bases, ligands, and non-activated alkenes is 3:1:0.1:2.5:2.5:0.1:2.5.

[0015] Furthermore, methyl tert-butyl ether requires pre-drying with sodium before use.

[0016] Furthermore, the reaction temperature is 75-85℃, and the reaction time is 10-14h.

[0017] Furthermore, the reaction temperature was 80℃ and the reaction time was 12h.

[0018] The beneficial effects of this invention are as follows:

[0019] (1) The cross-reduction coupling reaction of olefins catalyzed by inexpensive metal iron provided by this invention does not require the introduction of directing groups into the olefins, simplifies the raw material preparation steps, expands the applicable range of substrates, enriches the reaction types of multi-component reactions, and solves the problem of regioselectivity control in the reaction process. Under standard reaction conditions, the yield of the target product after separation can be as high as 95%, and the E / Z selectivity is >20:1. It is a general, efficient, economical and environmentally friendly method for rapid construction of carbon-carbon bonds.

[0020] (2) In this invention, the environmentally friendly organic reagent, bis-pinacol diboronic acid ester, is used as a reducing agent, which can avoid environmental pollution caused by metal reducing agents such as zinc and manganese.

[0021] (3) The method of the present invention can modify a variety of natural products and drug molecule derivatives in the later stage, and plays an important role in drug modification and research and development. It can be widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals. Attached Figure Description

[0022] Figure 1 The proton NMR spectrum of product 1 ( 1 H-NMR);

[0023] Figure 2 The carbon NMR spectrum of product 1 ( 13 C-NMR);

[0024] Figure 3 The nuclear magnetic resonance fluorine spectrum of product 1 ( 19 F-NMR);

[0025] Figure 4 The proton NMR spectrum of product 2 ( 1 H-NMR);

[0026] Figure 5 The carbon NMR spectrum of product 2 ( 13 C-NMR);

[0027] Figure 6 The nuclear magnetic resonance fluorine spectrum of product 2 ( 19 F-NMR);

[0028] Figure 7 The proton NMR spectrum of product 3 ( 1 H-NMR);

[0029] Figure 8 The carbon NMR spectrum of product 3 ( 13 C-NMR);

[0030] Figure 9 The NMR fluorine spectrum of product 3 ( 19 F-NMR). Detailed Implementation

[0031] The specific embodiments of the present invention are described below to facilitate understanding of the invention by those skilled in the art. Unless otherwise specified, specific conditions are applied according to conventional conditions or the manufacturer's recommendations. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various modifications are obvious as long as they fall within the spirit and scope of the invention as defined and determined by the appended claims. All inventions utilizing the concept of this invention are protected.

[0032] The following tests used a nuclear magnetic resonance spectrometer (400MHz) manufactured by Agilent Technologies, model 400MRDD2.

[0033] Example 1

[0034] A method for selective difunctionalization of inactive olefins catalyzed by iron, the reaction equation of which is as follows:

[0035]

[0036] The specific steps are as follows:

[0037] (1) Cut 3g of metallic sodium into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of methyl tert-butyl ether and then reflux at 100℃ for 3h. Collect the distilled methyl tert-butyl ether and seal it for storage.

[0038] (2) Place an 8mL glass bottle with a magnetic stir bar in a glove box, weigh 46mg (1 equivalent) of (E)-4-methylthio-β-bromostyrene, 2.5mg (0.1 equivalent) of ferrous chloride, 153mg (3 equivalent) of dipinacol diboronic acid ester, 48mg (3 equivalent) of lithium tert-butoxide and 8mg (0.1 equivalent) of 1,2-bis(diphenylphosphine)ethane, add 75μL (2.5 equivalent) of 4-phenyl-1-butene and 128μL (3 equivalent) of 1-bromoperfluorohexane using a microsyringe, and then add 1mL of methyl tert-butyl ether with a syringe and mix well;

[0039] (3) Take the glass bottle out of the glove box and put it into an 80℃ constant temperature stirrer to react for 12 hours;

[0040] (4) Remove the glass bottle from the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration of 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases and dry with anhydrous sodium sulfate. Finally, concentrate under vacuum and elute with petroleum ether:ethyl acetate = 100:2 (v:v) by rapid column chromatography to obtain 102 mg of clear colorless oil (product 1), with a yield of 85%.

[0041] The structure of product 1 was characterized, and the results are as follows: Figure 1-3 As shown, specifically: 1 H NMR (400MHz, CDCl3) δ7.33-7.28(m,4H),7.25-7.18(m,5H),6.43(d,J=16Hz,1H),6.01(dd,J=16Hz,J=9.2Hz,1H ),2.80-2.70(m,2H),2.67-2.57(m,1H),2.50(s,3H),2.32-2.17(m,2H),1.99-1.91(m,1H),1.83-1.74(m,1H). 13 C NMR (100MHz, CDCl3) δ141.5,137.6,134.1,131.3,130.8,128.4,128.3,126.9,126.6,126.0,37.2,36.1,36.0(t,J=20Hz),33.2,15.9. 19F NMR(376MHz, CDCl3)δ-80.80(t,J=9.8Hz,3F),-110.87--113.33(m,2F),-121.70--121.81(m,2F) ,-122.77--122.89(m,2F),-123.50--123.62(m,2F),-126.06--126.19(m,2F).HRMS(ESI):calcd for C 25 H 20 F 13 S[MH] - :599.1083,found:599.1082.

[0042] Example 2

[0043] A method for selective difunctionalization of inactive olefins catalyzed by iron, the reaction equation of which is as follows:

[0044]

[0045] The specific steps are as follows:

[0046] (1) Cut 3g of metallic sodium into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of methyl tert-butyl ether and then reflux at 100℃ for 3h. Collect the distilled methyl tert-butyl ether and seal it for storage.

[0047] (2) Place an 8 mL glass bottle with a magnetic stir bar in a glove box and weigh 1 equivalent of (E)-4-methylthio-β-bromostyrene, 0.1 equivalent of ferrous chloride, 3 equivalents of dipinacol diboronic acid ester, 3 equivalents of lithium tert-butoxide, 0.1 equivalent of 1,2-bis(diphenylphosphine)ethane, 2.5 equivalents of allyltrimethylsilane and 3 equivalents of 1-bromoperfluorohexane. Then add 1 mL of methyl tert-butyl ether with a syringe and mix well.

[0048] (3) Take the glass bottle out of the glove box and put it into an 80℃ constant temperature stirrer to react for 14 hours;

[0049] (4) Remove the glass bottle from the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration of 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time. Combine the organic phases and dry with anhydrous sodium sulfate. Finally, concentrate under vacuum and elute with petroleum ether:ethyl acetate = 100:2 (v:v) by rapid column chromatography to obtain 101.9 mg of clear colorless oil (product 2), with a yield of 95%.

[0050] The structure of product 2 was characterized, and the results are as follows: Figure 4-6 As shown, specifically: 1H NMR (400MHz, CDCl3) δ7.38-7.23(m,5H),6.45(d,J=16Hz,1H),6.02(dd,J=16,9. 2Hz,1H),2.98-2.89(m,1H),2.29-2.17(m,2H),0.95-0.81(m,2H),0.05(s,9H). 13 C NMR (100MHz, CDCl3) δ137.2, 134.2, 129.6, 128.5, 127.3, 126.1, 39.1 (t, J = 20Hz), 33.2, 24.4, -0.9. 19 F NMR(376MHz, CDCl3)δ-80.89--80.97(m,3F),-111.21--113.71(m,2F),-121.77--121.87(m,2 F),-122.88--122.94(m,2F),-123.74--123.83(m,2F),-126.17--126.25(m,2F).HRMS(EI):C 20 H 21 F 13 Si[M] + :536.1205,found:536.1200.

[0051] Example 3

[0052] A method for selective difunctionalization of inactive olefins catalyzed by iron, the reaction equation of which is as follows:

[0053]

[0054] The specific steps are as follows:

[0055] (1) Cut 3g of metallic sodium into small pieces (50mg / piece) and place them in a 1L flask. Add 500mL of methyl tert-butyl ether and then reflux at 100℃ for 3h. Collect the distilled methyl tert-butyl ether and seal it for storage.

[0056] (2) Place an 8 mL glass bottle with a magnetic stir bar in a glove box and weigh 1 equivalent of (E)-4-methylthio-β-bromostyrene, 0.1 equivalent of ferrous chloride, 3 equivalents of dipinacol diboronic acid ester, 3 equivalents of lithium tert-butoxide, 0.1 equivalent of 1,2-bis(diphenylphosphine)ethane, 2.5 equivalents of 1-[(trans,trans)-4'-(3-butenyl)[1,1'-bicyclohexane]-4-yl]-4-methylbenzene and 3 equivalents of 1-bromoperfluorohexane. Then add 1 mL of methyl tert-butyl ether with a syringe and mix well.

[0057] (3) Take the glass bottle out of the glove box and put it into an 80℃ constant temperature stirrer to react for 10 hours;

[0058] (4) Remove the glass bottle from the constant temperature stirrer, add 1 mL of saturated ammonium chloride solution (concentration of 6.95 mol / L) to quench, then extract with ethyl acetate 3 times, 10 mL each time, combine the organic phases and dry with anhydrous sodium sulfate, finally concentrate under vacuum, and use petroleum ether:ethyl acetate = 100:2 (v:v) as eluent, elute by rapid column chromatography to obtain 123.6 mg of colorless transparent liquid (product 3), with a yield of 81%.

[0059] The structure of product 3 was characterized, and the results are as follows: Figure 7-9 As shown, specifically: 1 H NMR (400MHz, CDCl3) δ7.32(d,J=8.8Hz,2H),7.12(s,4H),6.88(d,J=8.8Hz,2H),6.38(d,J=16Hz, 1H),5.87(dd,J=15.6,9.2Hz,1H),3.82(s,3H),2.70-2.61(m,1H),2.49-2.39(m,1H),2.34(s,3H) ),2.27-2.13(m,2H),1.95-1.91(m,4H),1.86-1.84(m,2H),1.81-1.76(m,4H),1.65-1.57(m,1H) ,1.48-1.42(m,2H),1.33-1.24(m,2H),1.20-1.16(m,4H),1.06-1.01(m,2H),0.96-0.87(m,2H). 13 C NMR (100MHz, CDCl3) δ159.0,144.9,135.1,130.5,130.1,130.0,128.9,127.3,126.6,114.0,55.3,4 4.2, 43.4, 42.9, 38.0, 36.6, 36.0 (t, J = 21Hz), 34.7, 34.6, 33.7, 33.4, 33.2, 30.4, 30.0, 30.0, 20.9. 19 FNMR(376MHz, CDCl3)δ-80.82(t,J=9.4Hz,3F),-111.00–-113.42(m,2F),-121.70–-121.82(m,2F) ),-122.77–-122.89(m,2F),-123.52–-123.61(m,2F),-126.07–-126.18(m,2F).HRMS(EI):calcd for C 38 H43 F 13 O[M] + :762.3106,found:762.3146.

[0060] Comparative Example 1

[0061] Replace 1,2-bis(diphenylphosphine)ethane with 2,2'-bipyridine, and keep the other conditions the same as in Example 1.

[0062] Comparative Example 2

[0063] Replace ferrous chloride with NiBr2, and keep the other conditions the same as in Example 1.

[0064] Comparative Example 3

[0065] Replace ferrous chloride with CuCl2, and keep the other conditions the same as in Example 1.

[0066] Comparative Example 4

[0067] Ferrous chloride was omitted, and the remaining conditions were the same as in Example 1.

[0068] Comparative Example 5

[0069] Lithium tert-butoxide was replaced with sodium tert-butoxide, and the other conditions were the same as in Example 1.

[0070] Comparative Example 6

[0071] Lithium tert-butoxide was replaced with potassium methoxide, and the other conditions were the same as in Example 1.

[0072] Comparative Example 7

[0073] Lithium tert-butoxide was omitted, and the remaining conditions were the same as in Example 1.

[0074] Comparative Example 8

[0075] The dipinacol diboronic acid ester was omitted, and the other conditions were the same as in Example 1.

[0076] The yield data for comparative examples 1-8 are shown in Table 1.

[0077] Table 1. Yield comparison of Comparative Examples 1-8

[0078] Serial Number catalyst reducing agent alkali ligands Yield Comparative Example 1 <![CDATA[FeCl2]]> <![CDATA[B2pin2]]> t-BuOLi 2,2'-Bipyridine 48％ Comparative Example 2 <![CDATA[NiBr2]]> <![CDATA[B2pin2]]> t-BuOLi dppe 17％ Comparative Example 3 <![CDATA[CuCl2]]> <![CDATA[B2pin2]]> t-BuOLi dppe nd Comparative Example 4 / <![CDATA[B2pin2]]> t-BuOLi dppe nd Comparative Example 5 <![CDATA[FeCl2]]> <![CDATA[B2pin2]]> t-BuONa dppe 19％ Comparative Example 6 <![CDATA[FeCl2]]> <![CDATA[B2pin2]]> Potassium methoxide dppe 50％ Comparative Example 7 <![CDATA[FeCl2]]> <![CDATA[B2pin2]]> / dppe nd Comparative Example 8 <![CDATA[FeCl2]]> / t-BuOLi dppe nd

[0079] Wherein: B2pin2 is dipinazoline borate, t-BuOLi is lithium tert-butoxide, t-BuONa is sodium tert-butoxide, dppe is 1,2-bis(diphenylphosphine)ethane, and nd indicates that the product was not detected.

[0080] Results Analysis: In Comparative Example 1, replacing the bisphosphine ligand dppe with the dinitrogen ligand 2,2'-bipyridine led to a decrease in yield. Comparative Examples 2 and 3 showed that using nickel or copper catalysts instead of iron catalysts resulted in a significant decrease in yield, or even prevented the reaction from occurring. Comparative Example 4 showed that the reaction could not proceed without the addition of an iron catalyst. Comparative Examples 5 and 6 showed that replacing lithium tert-butoxide with sodium tert-butoxide or potassium methoxide resulted in a significant decrease in yield. Comparative Examples 7 and 8 showed that the reaction could not proceed without the addition of the base lithium tert-butoxide or the reducing agent B2pin2. In conclusion, the selection of standard reaction conditions is superior.

Claims

1. A method for selective difunctionalization of non-activated olefins catalyzed by iron, characterized in that, The reaction includes the following steps: In an organic solvent, using halofluoroalkanes and β-haloarylethylenes as electrophiles, an iron-containing reagent as a catalyst, and a boron-containing reagent as a reducing agent, a non-activated olefin is reacted under the action of a base and ligands to selectively undergo a bifunctionalization reaction. The general reaction formula is as follows: ， In the formula: R f -X indicates a halofluoroalkanes; R1, R2, and R3 represent substituents on alkenes, and R4 represents a substituent on an aromatic ring. The organic solvent is methyl tert-butyl ether, the halogenated fluoroalkane is 1-bromoperfluorohexane, the β-halogenated aryl ethylene is (E)-4-methylthio-β-bromostyrene, the iron-containing reagent is ferrous chloride, the boron-containing reagent is dipinacol diboronate, the base is lithium tert-butoxide, the ligand is 1,2-bis(diphenylphosphine)ethane, and the non-activated olefin is 4-phenyl-1-butene, allyltrimethylsilane, or 1-[(trans,trans)-4'-(3-butenyl)[1,1'-bicyclohexane]-4-yl]-4-methylbenzene.

2. The method for selective difunctionalization of non-activated olefins catalyzed by iron according to claim 1, characterized in that: The molar ratio of the halofluoroalkanes, β-haloarylethylenes, iron-containing reagents, boron-containing reagents, bases, ligands, and non-activated alkenes is 2-4:1:0.05-0.2:2-3.5:2-3.5:0.05-0.2:2-3.

3. The method for selective difunctionalization of non-activated olefins catalyzed according to claim 2, characterized in that: The molar ratio of the halofluoroalkanes, β-haloarylethylenes, iron-containing reagents, boron-containing reagents, bases, ligands, and non-activated alkenes is 3:1:0.1:2.5:2.5:0.1:2.

5.

4. The method for selective difunctionalization of non-activated olefins catalyzed according to claim 1, characterized in that: The methyl tert-butyl ether needs to be pre-dried with sodium before use.

5. The method for selective difunctionalization of non-activated olefins catalyzed according to claim 1, characterized in that: The reaction temperature is 75-85℃, and the reaction time is 10-14h.

6. The method for selective difunctionalization of non-activated olefins catalyzed according to claim 5, characterized in that: The reaction temperature is 80℃ and the reaction time is 12h.

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