An electrochemical synthesis method for precise regioselective olefin arylation

Abstract

The present invention discloses an electrochemical synthesis method for the precise regioselective olefin arylation, which uses benzyltrimethylammonium chloride, terephthalonitrile, olefin and iodobenzene as raw materials, and electrochemically reacts for 3 to 4 hours at room temperature and constant current conditions of 9.0 mA. The organic layer in the product is concentrated and chromatographed to obtain an arylethane compound. The molar ratio of benzyltrimethylammonium chloride, terephthalonitrile, olefin and iodobenzene is 5:1:5:2. The present invention develops an electrochemical transition metal-free, non-directing group-assisted three-component double arylation strategy for olefins, which avoids the use of transition metal catalysts, oxidants and organometallic reagents, has a high yield of the target product, does not require pre-prepared raw materials, improves the economy of the synthesis process, greatly reduces the preparation cost of arylethane compounds, and provides a simple and modular electrochemical method for industrial production, realizing the precise synthesis of arylethane compounds with high regioselectivity.

Description

Technical Field

[0001] The present invention relates to an electrochemical synthesis method for accurate regioselective olefin arylation, and specifically belongs to the technical field of organic synthesis. Background Art

[0002] 1,1,2-Triarylethane and 1,2-diarylethane are very important compounds, which are widely found in organic functional materials, drugs and active molecules, as shown in (a) below. In recent years, the synthesis of diarylethane molecular skeletons has aroused great interest among chemists. The traditional synthesis strategy is the cross-coupling of benzyl electrophilic reagents and aromatic coupling reagents under transition metal catalysis. Although this method is very mature, from the perspective of retrosynthesis, the modular synthesis of diaryl alkanes and triaryl alkanes through three components is a strategy with higher freedom and more attractive. Attracted by this concept, chemists have made many attempts on the strategy of three-component assembly of 1,2-diaryl alkanes, and the transition metal-catalyzed 1,2-diarylation of olefins has achieved good results. However, these methods usually require the use of precious metal catalysts such as palladium and nickel, and use the steric hindrance of directing groups or olefin substrates to regulate the regioselectivity of the reaction. At the same time, transition metal-catalyzed strategies usually require the participation of a molecule of an organic metal reagent (organomagnesium reagent, organic zinc reagent, etc.), and are accompanied by the coupling of the two components to obtain biaryl hydrocarbons and Heck by-products, as shown in (b).

[0003]

[0004] In recent years, the free radical-involved three-component 1,2-diarylation of olefins often requires the participation of catalysts FeCl2, Fe(OTf)2 and an equivalent amount of oxidant, and the target product yield is moderate (Org. Lett. 2015, 17, 2174-2177, 40% to 73%; Chin. J. Org. Chem. 2017, 37, 1160, 35% to 74%), and usually obtains 1,2-diaryl alkane compounds with the same aryl substitution at the 1,2 positions, which is difficult to meet the requirements of synthetic chemistry for the synthesis of diverse molecules. Therefore, the development of a three-component-involved transition metal-free, non-directing group-assisted diarylation strategy for aryl / alkyl olefins, achieving high regioselective control of olefins, and synthesizing polyaryl ethane compounds with high added value and biological activity has become a problem that chemists are eager to solve. Summary of the invention

[0005] The purpose of the present invention is to develop an electrochemical three-component diarylation strategy for olefins without transition metal catalysis and the assistance of directing groups, avoiding the use of transition metal catalysts, oxidants, and organometallic reagents, and synthesizing the target product in high yield, providing a simple and modular electrochemical method for the precise synthesis of aromatic ethane compounds with high regioselectivity.

[0006] The present invention discloses an electrochemical synthesis method for precise regioselective olefin arylation, which is characterized in that: the electrochemical synthesis method is to add benzyltrimethylammonium chloride and terephthalonitrile into a three-necked flask with a zinc electrode as an anode and an RVC (netted glassy carbon) electrode as a cathode, and then slowly add olefin and 0.06mmol / mL iodobenzene acetonitrile solution under nitrogen atmosphere and stirring, maintain room temperature and constant current conditions of 9.0mA, and perform electrochemical reaction for 3 to 4h; the organic layer in the product is concentrated and subjected to column chromatography to obtain an arylethane compound.

[0007] The molar ratio of benzyltrimethylammonium chloride, terephthalonitrile, olefin and iodobenzene is 5:1:5:2.

[0008] The arylethane compound is a 1,1,2-triarylethane compound or a 1,2-diarylethane compound.

[0009] The possible mechanisms are as follows:

[0010]

[0011] Cyclic voltammetry experiments show that the reduction potential of terephthalonitrile is E = -1.75V (vs Ag / AgCl), and the reduction potential of iodobenzene is E = -2.5V (vs Ag / AgCl). Terephthalonitrile is preferentially reduced, and the obtained radical anion intermediate can further reduce iodobenzene, thereby achieving high regioselective control of olefins. Compared with the existing preparation methods, the present invention does not require the addition of transition metal catalysts, ligands, and the assistance of chelating directing groups.

[0012] The general reaction formula is as follows:

[0013]

[0014] Where: EWG represents an electron-withdrawing group, such as cyano, ester, sulfone, etc., X represents a halogen (iodine, bromine, chlorine), R 1 represents various electron-donating groups (amino, ether, thioether, methyl, phenyl) or electron-withdrawing groups (ester, fluorine, chlorine, etc.), R 2 , R 3 , R 4 represents an alkyl group, an aryl group or hydrogen.

[0015] Beneficial effects of the present invention: The present invention develops an electrochemical three-component diarylation strategy for olefins without transition metal catalysis and the assistance of directing groups, avoiding the use of transition metal catalysts, oxidants, and organometallic reagents. The yield of the synthesized target product is high (50-81%), and no pre-prepared raw materials are required, which improves the economy of the synthesis process and greatly reduces the preparation cost of aromatic ethane compounds. It provides a simple and modular electrochemical method for industrial production, realizes the precise synthesis of aromatic ethane compounds with high regioselectivity, thereby obtaining polyaryl substituted alkane compounds with potential physiological activity, which can better realize their potential application value. DETAILED DESCRIPTION

[0016] Example 1

[0017] synthesis

[0018]

[0019] 1) In a 25mL three-necked flask equipped with a stirrer, add 1.5mmol benzyltrimethylammonium chloride and 0.3mmol terephthalonitrile, a zinc electrode (15mm×15mm×1mm) as the anode, and an RVC electrode (12mm×12mm×0.3mm) as the cathode, and then use a double-row tube to pump 3 times. In a nitrogen atmosphere, slowly add a solution of 1.5mmol p-methylstyrene and 0.6mmol iodobenzene dissolved in 10mL acetonitrile, and at room temperature, use constant current conditions (9.0mA), electrolyze the reaction solution for 3h, and detect with TLC spot plate.

[0020] 2) After the reaction is completed, the organic layer of the product is concentrated and subjected to column chromatography to obtain the above-mentioned 1,1,2-triarylethane compound as a colorless oil with a yield of 70%.

[0021] 1 H NMR (400MHz, CDCl3) δ7.49(d,J=8.4Hz,2H),7.24(d,J=8.8Hz,2H),7.20–7.12(m,3H),7.11–7.02(m,4H),6.97( d,J=6.4Hz,2H),4.25(t,J=8.0Hz,1H),3.38(dd,J=13.6,6.8Hz,1H),3.27(dd,J=13.6,8.8Hz,1H),2.30(s,3H); 13 C NMR (100MHz, CDCl3) δ150.4,140.1,139.5,136.6,132.3,129.5,129.1,129.0,128.4,127.9,126.4,119.1,110.2,52.9,41.9,21.1; HRMS (ESI +):calcd.for C 22 H 20 N(M+H + ):298.1590.Found:298.1596.

[0022] Example 2

[0023] synthesis

[0024]

[0025] 1) In a 25mL three-necked flask reaction tube equipped with a stirrer, add 1.5mmol benzyltrimethylammonium chloride and 0.3mmol terephthalonitrile, use a zinc electrode (15mm×15mm×1mm) as the anode, and an RVC electrode (12mm×12mm×0.3mm) as the cathode, and then use a double-row tube to pump 3 times. Under a nitrogen atmosphere, 1.5mmol p-3-vinylbenzothiazole and 0.6mmol iodobenzene are dissolved in 10mL acetonitrile and slowly added. At room temperature, use constant current conditions (9.0mA), electrolyze the reaction solution for 4h, and detect with TLC spot plate.

[0026] 2) After the reaction, the organic layer was concentrated and subjected to column chromatography to obtain the above-mentioned 1,1,2-triarylethane compound as a white solid with Mp.: 91-93° C. and a yield of 65%.

[0027] 1 H NMR (400MHz, CDCl3) δ7.83(d,J=8.0Hz,1H),7.44(d,J=8.4Hz,3H),7.38(s,1H),7.29(t,J=7.2Hz,1H),7.24(d,J=5.2Hz,2H),7. 19–7.13(m,4H),6.96(d,J=7.6Hz,2H),4.58(dd,J=9.6,5.6Hz,1H),3.60(dd,J=13.6,5.6Hz,1H),3.24(dd,J=13.6,9.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ148.5,140.7,138.9,138.2,137.6,132.3,129.1,129.0,128 .5,126.6,124.7,124.2,123.1,122.5,122.0,118.9,110.5,47.5,42.2; HRMS(ESI + ):calcd.for C 23 H 18 NS(M+H + ):340.1154.Found:340.1161.

[0028] Example 3

[0029] synthesis:

[0030]

[0031] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Under nitrogen atmosphere, 1.5mmol p-2-vinylfluorene and 0.6mmol iodobenzene were dissolved in 10mL acetonitrile and slowly added. At room temperature, the reaction solution was electrolyzed for 4h under constant current conditions (9.0mA) and detected by TLC spot plate.

[0032] 2) After the reaction, the organic layer was concentrated and subjected to column chromatography to obtain the pure 1,1,2-triarylethane compound as a white solid with Mp.: 186-187° C. and a yield of 81%.

[0033] 1 H NMR (400MHz, CDCl3) δ7.75(d,J=7.2Hz,1H),7.66(d,J=8.0Hz,1H),7.52(d,J=8.0Hz,3H),7.36(t,J=7.2Hz,1H),7.31–7.25(m,4H),7.11( t,J=7.2Hz,2H),7.05(t,J=7.2Hz,2H),6.59(d,J=7.2Hz,2H),3.82(s,2H),3.49(d,J=12.4Hz,1H),3.42(d,J=12.4Hz,1H).,1.60(s,3H); 13 C NMR (100MHz, CDCl3) δ155.4,146.8,143.5,143.3,141.4,140.1,137.2,131.8,130.8,128.8,127.6,12 6.9,126.8,126.6,126.4,125.2,124.4,120.0,120.0,119.1,109.8,48.0,47.7,37.1,27.1; HRMS(ESI + ):calcd.for C 28 H 22 N(M+H + ):386.1903.Found:386.1897.

[0034] Example 4

[0035] synthesis:

[0036]

[0037] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Under a nitrogen atmosphere, 1.5mmol p-2-ethyl-1-butene and 0.6mmol iodobenzene were dissolved in 10mL acetonitrile and slowly added. At room temperature, the reaction solution was electrolyzed for 3h under constant current conditions (9.0mA) and detected by TLC spot plate.

[0038] 2) After the reaction is completed, the organic layer is concentrated and subjected to column chromatography to obtain the pure 1,2-diarylethane compound as a white solid with Mp.: 119-121° C. and a yield of 50%.

[0039] 1 H NMR(400MHz, CDCl3)δ7.56(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),7.15–7.06(m, 3H),6.66(d,J=8.0Hz,2H),2.89(s,2H),1.78–1.68(m,4H),0.81(t,J=7.2Hz,6H); 13 CNMR (100MHz, CDCl3) δ152.7,137.7,131.8,130.2,128.2,127.8,126.3,119.3,109.5,46.0,44.5,27.8,8.3; HRMS (ESI + ):calcd.for C 19 H 22 N(M+H + ):264.1747.Found:264.1746.

[0040] Example 5

[0041] synthesis:

[0042]

[0043] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Dissolve 1.5mmol p-methylstyrene and 0.6mmol p-iodobenzyl alcohol in 10mL acetonitrile and add slowly under nitrogen atmosphere. Electrolyze the reaction solution for 4h at room temperature under constant current conditions (9.0mA) and detect with TLC spot plate.

[0044] 2) After the reaction, the organic layer was concentrated and subjected to column chromatography to obtain the pure 1,1,2-triarylethane compound as a colorless oil with a yield of 72%.

[0045] 1 H NMR (400MHz, CDCl3) δ7.49(d,J=8.0Hz,2H),7.25(d,J=7.6Hz,2H),7.17(d,J=8.0Hz,2H),7.07(d,J=8.4Hz,4H),6.98(d,J=8.0H z,2H),4.60(s,2H),4.24(t,J=8.0Hz,1H),3.38(dd,J=13.6,7.2Hz,1H),3.28(dd,J=13.6,8.4Hz,1H),2.29(s,3H),1.71(s,1H); 13 C NMR (100MHz, CDCl3) δ150.3,140.0,138.9,136.6,132.3,129.5,129.3,129.0,127.9,127.1,119.1,110.2,65.2,52.8,41.5,21.1; HRMS (ESI + ):calcd.for C 23 H 21 NONa(M+Na + ):350.1515.Found:350.1520.

[0046] Example 6

[0047] synthesis:

[0048]

[0049] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Under a nitrogen atmosphere, 1.5mmol p-methylstyrene and 0.6mmol 3,4-dimethyliodobenzene were dissolved in 10mL acetonitrile and slowly added. At room temperature, the reaction solution was electrolyzed for 3h under constant current conditions (9.0mA) and detected by TLC spot plate.

[0050] 2) After the reaction, the organic layer was concentrated and subjected to column chromatography to obtain the pure 1,1,2-triarylethane compound as a colorless oil with a yield of 70%.

[0051] 1 H NMR (400MHz, CDCl3) δ7.40(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),7.05–6.95(m,4H),6.83(d,J=7.6Hz,1H),6.69(s,1H),6.60(d,J= 7.6Hz,1H),4.15(t,J=7.6Hz,1H),3.21(dd,J=14.0,6.8Hz,1H),3.14(d,J=14.0,8.8Hz,1H),2.21(s,3H),2.08(s,3H),2.07(s,3H); 13 C NMR (100MHz, CDCl3) δ150.5,140.4136.8,136.4,134.4,132.2,130.4,129.6,12 9.4,129.0,127.9,126.4,119.1,110.0,52.8,41.4,21.1,19.8,19.4; HRMS(ESI + ):calcd.for C 24 H 24 N(M+H + ):326.1903.Found:326.1911.

[0052] Example 7

[0053] synthesis:

[0054]

[0055] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Dissolve 1.5mmol p-methylstyrene and 0.6mmol p-iodophenyl β-D-glucose pentaacetate in 10mL acetonitrile and add slowly under nitrogen atmosphere. At room temperature, use constant current conditions (9.0mA) to electrolyze the reaction solution for 3h, and detect with TLC spot plate.

[0056] 2) After the reaction is completed, the organic layer is concentrated and subjected to column chromatography to obtain the pure glycosyl-substituted 1,1,2-triarylethane compound as a yellow oil with a yield of 50%.

[0057] 1 H NMR(400MHz, CDCl3)δ7.52(t,J=8.4Hz,2H),7.27–7.23(m,2H),7.12–7.03(m,4H),6.89 (d,J=8.4Hz,2H),6.80(d,J=8.8Hz,2H),5.30–5.20(m,2H),5.15(t,J=9.2Hz,1H),5.01( d,J=7.2Hz,1H),4.28(dd,J=12.4,5.2Hz,1H),4.22–4.12(m,2H),3.87–3.80(m,1H),3. 37–3.29(m,1H),3.28–3.19(m,1H),2.31(d,J=7.2Hz,3H),2.04(dd,J=7.2,4.8Hz,12H); 13 C NMR (100MHz, CDCl3) δ170.6,170.3,169.5,169.4,155.4,150.3,139.9,136.6,134.5,132.3,130.1,129.5,128.9,127 .9,117.0,117.0,110.2,99.3,72.8,72.1,71.3,68.5,62.1,53.0,53.0,41.0,21.1,20.7,20.7,20.7,20.7; HRMS(ESI + ):calcd.forC 36 H 37 NO 10 Na(M+Na + ):642.2698.Found:642.2702.

[0058] Example 8

[0059] synthesis:

[0060]

[0061] 1) Add 1.5mmol benzyltrimethylammonium chloride, 0.3mmol terephthalonitrile, zinc electrode (15mm×15mm×1mm) as anode, RVC electrode (12mm×12mm×0.3mm) as cathode to a clean 25mL three-necked flask reaction tube equipped with a stirrer, and then use a double-row tube to pump 3 times. Under nitrogen atmosphere, 1.5mmol p-methylstyrene and 0.6mmol 4-(4-(4-iodophenylethane)-3-methoxyphenyl)butane-2-one (Vanillylacetone derivative) were dissolved in 10mL acetonitrile and slowly added. At room temperature, the reaction solution was electrolyzed for 3h under constant current conditions (9.0mA) and detected by TLC spot plate.

[0062] 2) After the reaction is completed, the organic layer is concentrated and subjected to column chromatography to obtain the pure 1,1,2-triarylethane compound substituted with the above-mentioned biologically active molecule in the form of yellow oil with a yield of 72%.

[0063] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 8.4Hz, 2H), 7.25–7.19 (m, 4H), 7.09–7.04 (m, 4H), 6.96(d,J=8.0Hz,2H),6.77–6.71(m,2H),6.64(dd,J=8.0,2.0Hz,1H),5.01(s,2H) ,4.23(t,J=8.0Hz,1H),3.84(s,3H),3.36(dd,J=13.6,7.2Hz,1H),3.26(dd,J=13. 6,8.8Hz,1H),2.85–2.80(m,2H),2.72(t,J=7.2Hz,2H),2.28(s,3H),2.12(s,3H); 13 C NMR(100 MHz, CDCl3)δ208.0,150.2,149.8,146.6,139.9,139.0,132.2,129.4,129.1,128.9,127.8,127 .4,120.1,119.0,114.6,112.4,110.0,71.1,56.0,52.7,45.3,41.4,30.1,29.4,21.0; HRMS(ESI + ):calcd.for C 34 H 34 NO3(M+H +):504.2533.Found:504.2541。

Claims

1. An electrochemical synthesis method for precise regioselective olefin arylation, characterized in that: The electrochemical synthesis method is to add benzyltrimethylammonium chloride and terephthalonitrile into a three-necked flask with a zinc electrode as an anode and an RVC electrode as a cathode, then slowly add olefins and 0.06mmol / mL iodobenzene acetonitrile solution under nitrogen atmosphere and stirring, maintain room temperature and 9.0 mA constant current conditions, and perform electrochemical reaction for 3 to 4 hours; the organic layer in the product is concentrated and column chromatographed to obtain an arylethane compound.

2. The electrochemical synthesis method for precise regioselective olefin arylation according to claim 1, characterized in that: The molar ratio of benzyltrimethylammonium chloride, terephthalonitrile, olefin and iodobenzene is 5:1:5:

2.

3. The electrochemical synthesis method for precise regioselective olefin arylation according to claim 1, characterized in that: The arylethane compound is a 1,1,2-triarylethane compound or a 1,2-diarylethane compound.

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