Method for synthesizing aryl butanone by ligand-regulated nickel-catalyzed ring-opening hydrogenation of aryl cyclopropyl ketone

Abstract

The invention discloses a method for synthesizing aryl butanone by using aryl cyclopropyl ketone as a reaction substrate, ethylene glycol dimethyl ether nickel bromide as a pre-catalyst, 4, 5-bis (diphenylphosphino)-9, 9-dimethyl xanthene as a ligand, trifluoroethanol as a hydrogen donor and zinc powder as a reducing agent through ligand regulation and nickel catalysis, and the method comprises the following steps: synthesizing the aryl butanone by using the aryl cyclopropyl ketone as the reaction substrate, ethylene glycol dimethyl ether nickel bromide as a pre-catalyst, 4, 5-bis (diphenylphosphino)-9, 9-dimethyl xanthene as the ligand, trifluoroethanol as a hydrogen donor and zinc powder as a reducing agent; the aryl butanone is synthesized through efficient and selective ring opening hydrogenation. The method has the advantages that the reaction system is cheap and easy to obtain, the substrate range is wide, the reaction condition is mild, the yield of the target product is high, and the method has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of methodologies for activating and breaking carbon-carbon σ bonds, and specifically uses 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (ligand) to regulate ethylene glycol dimethyl ether nickel bromide (nickel catalyst) to in-situ generate catalytic active species, combines zinc powder as a reducing agent, and trifluoroethanol as a hydrogen donor to achieve efficient ring opening of a three-membered ring structure in an aromatic cyclopropyl ketone, and hydrogenates the 1,3 positions to a saturated three-carbon structure to obtain an aromatic butanone. Background Art

[0002] The basic skeleton of organic compounds is composed of carbon-carbon bonds, and their breaking process is widely present in industrial development and life systems. The activation reaction of carbon-carbon σ bonds can discover abundant and economical raw materials in nature. However, compared with the widely studied carbon-carbon bond formation methodology, the research on carbon-carbon bond breaking is still relatively backward.

[0003] The cyclopropane structure is one of the most important skeletons in organic chemistry. It is widely found in drugs and agricultural chemicals. Due to its small ring strain, cyclopropane can be used as an effective substrate for studying carbon-carbon bond breaking. According to the degree of activation of cyclopropane, it can be divided into three categories: the most studied donor-acceptor cyclopropane (DA cyclopropane), the extremely challenging inert unactivated cyclopropane, and the single activated cyclopropane with an activity between the two. The reaction of single activated cyclopropane is generally cross-coupling with another substrate, or functionalization after ring opening. These reactions require the introduction of a second molecular fragment in the ring opening step, and there are relatively few reports on the ring opening hydrogenation of single activated cyclopropane, that is, the direct ring opening to obtain the product.

[0004] In the ring-opening hydrogenation reaction of cyclopropane, the currently applicable substrates are limited to highly activated donor acceptor cyclopropane (DA cyclopropane). The reaction usually uses an equivalent or far-exceeding stoichiometric amount of metal reducing reagents, or uses hydrogen for direct hydrogenation. The above traditional methods of ring-opening hydrogenation reactions have harsh reaction conditions and may have potential safety issues. A research group proposed to use Ir photocatalysts, N,N-diisopropylethylamine and water as hydrogen donors under blue light irradiation, and react for 15 to 36 hours under blue light irradiation to achieve a more gentle way to hydrogenate the donor acceptor cyclopropane, but it cannot avoid the problems of expensive photocatalysts and long reaction time in photocatalysis. There are fewer studies on single-activated cyclopropane. Some research groups have proposed the ring-opening hydrogenation of single-activated cyclopropane at 200°C using noble metal Rh complexes as catalysts and deuterated benzene as solvents. The reaction conditions are relatively harsh. In order to solve the current problems in the cyclopropane ring-opening hydrogenation reaction, such as limited substrate types and harsh reaction conditions, it is necessary to develop a milder and more efficient catalytic system. Summary of the invention

[0005] The invention aims to overcome the shortcomings of the existing cyclopropane compounds that the ring opening and subsequent reactions require high substrate activation and harsh reaction conditions, and to provide a ligand-regulated nickel-catalyzed method for synthesizing aryl butanone by ring opening and hydrogenation of aryl cyclopropyl ketone. The method starts from a single activated cyclopropane, and the catalytic system for carbon-carbon σ bond cleavage and ring opening and hydrogenation is cheap and readily available, with mild reaction conditions and safe and efficient steps.

[0006] To achieve the above purpose, the scheme adopted by the present invention is: under the protection of inert gas, the aromatic cyclopropyl ketone shown in formula I, ethylene glycol dimethyl ether nickel bromide, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, trifluoroethanol and zinc powder are added to an organic solvent, reacted at 70-100° C., and separated and purified after the reaction is completed to obtain the aromatic butanone shown in formula II.

[0007]

[0008] In the formula, Ar represents any one of aryl, heterocyclic aryl, substituted aryl, and substituted heterocyclic aryl, such as phenyl, naphthyl, thienyl, benzothienyl, etc., or phenyl substituted by 1 to 3 of the following: C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, phenoxy, trifluoromethyl substituted phenyl, and benzyloxy substituted phenyl.

[0009] In the above synthesis method, the amount of ethylene glycol dimethyl ether nickel bromide added is preferably 10% to 20% of the molar amount of the aryl cyclopropyl ketone.

[0010] In the above synthesis method, preferably, the amount of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene added is 5% to 10% of the molar amount of the aryl cyclopropyl ketone.

[0011] In the above synthesis method, the amount of zinc powder added is preferably 2 to 3 times the molar amount of the aryl cyclopropyl ketone.

[0012] In the above synthesis method, the amount of trifluoroethanol added is preferably 1 to 2 times the molar amount of the aryl cyclopropyl ketone.

[0013] In the above synthesis method, the organic solvent is preferably selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol and 1,4-dioxane.

[0014] In the above-mentioned synthesis method, the reaction is preferably carried out at 70 to 100° C. for 6 to 12 hours.

[0015] The beneficial effects of the present invention are as follows:

[0016] The present invention uses ethylene glycol dimethyl ether nickel bromide as a precatalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene as a ligand, trifluoroethanol as a hydrogen donor, and zinc powder as a reducing agent to carry out a ring-opening hydrogenation reaction of aryl cyclopropyl ketone to obtain aryl butanone. The present invention has the advantages of a cheap and readily available reaction system and a wide range of substrates, mild reaction conditions, a high yield of a target product, and broad application prospects. DETAILED DESCRIPTION

[0017] The present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments.

[0018] Example 1

[0019] Synthesize phenyl butanone with the following structural formula

[0020]

[0021] In a glove box, 0.0093g (0.03mmol) of ethylene glycol dimethyl ether nickel bromide, 0.0086g (0.015mmol) of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 0.0392g (0.6mmol) of zinc powder, 29μL (0.4mmol) of trifluoroethanol, 28μL (0.2mmol) of phenylcyclopropyl ketone, and 1mL of tetrahydrofuran were added to a Shrek tube, and the Shrek tube mouth glass stopper was sealed with vacuum grease, and it was removed from the glove box and stirred at 70°C for 12 hours. After the reaction was completed, the reaction mixture was filtered through a silica gel pad and purified by rapid column chromatography, using petroleum ether and ethyl acetate as eluents to obtain phenylbutyrophenone with a yield of 90%. The product spectrum data is: 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J=7.2Hz,2H),7.55(t,J=7.3Hz,1H),7.45(t ,J=7.6Hz,2H),2.95(t,J=7.3Hz,2H),1.77(h,J=7.4Hz,2H),1.01(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.6,137.2,133.0,128.7,128.2,41.2,17.9,14.0.

[0022] Example 2

[0023] Synthesize 4-(Fluorophenyl)-1-butanone with the following structural formula

[0024]

[0025] In this example, cyclopropyl (4-fluorophenyl) ketone was used to replace the phenyl cyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 4-(fluorophenyl)-1-butanone with a yield of 68%. The spectral data of the product were as follows: 1 H NMR (400MHz, Chloroform-d) δ7.98(dd,J=8.7,5.6Hz,2H),7.12(t,J=8.6Hz,2H),2.92(t,J=7.3Hz,2H),1.76(h,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ199.0,167.0,164.5,133.6,130.8,130.7,115.9,115.6,40.6,17.9,14.0; 19 F NMR (376MHz, Chloroform-d) δ-105.64.

[0026] Example 3

[0027] Synthesize 1-(naphthalene-1-yl)-1-butanone with the following structural formula

[0028]

[0029] In this example, cyclopropyl (naphthalene-1-yl) ketone was substituted with an equal molar amount of phenylcyclopropyl ketone used in Example 1, and the other steps were the same as in Example 1 to obtain 1-(naphthalene-1-yl)-1-butanone with a yield of 71%. The spectral data of the product were as follows: 1 H NMR (400MHz, Chloroform-d) δ8.55(d,J=9.3Hz,1H),7.97(d,J=8.2Hz,1H),7.86(dd,J=14.9,8. 2Hz,2H),7.60–7.47(m,3H),3.04(t,J=7.3Hz,2H),1.83(h,J=7.4Hz,2H),1.04(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ205.2,136.5,134.1,132.4,130.2,128.5,127.9,127.3,126.5,125.9,124.5,44.3,18.3,14.0.

[0030] Example 4

[0031] Synthesize 1-(3-methoxyphenyl)-1-butanone with the following structural formula

[0032]

[0033] In this example, cyclopropyl (3-methoxyphenyl) ketone was used to replace the phenyl cyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(3-methoxyphenyl)-1-butanone with a yield of 82%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=7.6Hz,1H),7.50–7.45(m,1H),7.35(t,J=7.9Hz,1H),7.08(d d,J=7.7,2.2Hz,1H),3.84(s,3H),2.92(t,J=7.3Hz,2H),1.76(q,J=7.4Hz,2H),0.99(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.4,159.9,138.6,129.6,120.8,119.4,112.4,55.5,40.7,17.9,14.0.

[0034] Example 5

[0035] Synthesize 1-(2-naphthyl)-1-butanone with the following structural formula

[0036]

[0037] In this example, cyclopropyl-2-naphthyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(2-naphthyl)-1-butanone with a yield of 79%. The spectral data of the product were as follows: 1 HNMR (400MHz, Chloroform-d) δ8.47(s,1H),8.07–7.84(m,4H),7.63–7.51(m,2H),3.08(t,J=7.3Hz,2H),1.90–1.77(m,2H),1.05(t,J=7.3Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.6,135.6,134.5,132.7,129.7,129.6,128.5,128.5,127.9,126.8,124.1,40.7,18.1,14.1.

[0038] Example 6

[0039] Synthesize 1-(4-methylphenyl)-1-butanone with the following structural formula

[0040]

[0041] In this example, cyclopropyl (4-methylphenyl) ketone was used to replace the phenyl cyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(4-methylphenyl)-1-butanone with a yield of 57%. The spectral data of the product were as follows: 1 H NMR (400MHz, Chloroform-d) δ7.97(d,J=8.0Hz,2H),7.36(d,J=7.9Hz,2H),3.03(t,J=7.3Hz,2H),2.51(s,3H),1.87(h,J=7.4Hz,2H),1.11(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.3,143.7,134.8,129.4,128.3,40.6,21.7,18.0,14.0.

[0042] Example 7

[0043] Synthesize 1-(3-phenoxyphenyl)-1-butanone with the following structural formula

[0044]

[0045] In this example, cyclopropyl (3-phenoxyphenyl) ketone was used to replace the phenyl cyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(3-phenoxyphenyl)-1-butanone with a yield of 74%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ7.69(d,J=7.7Hz,1H),7.63–7.55(m,1H),7.42(t,J=7.9Hz,1H),7.36(t,J=8.0Hz,2 H),7.22–7.10(m,2H),7.02(d,J=7.6Hz,2H),2.91(t,J=7.3Hz,2H),1.76(p,J=7.3Hz,2H),0.99(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ199.9,157.8,156.8,139.0,130.1,123.9,123.2,122.9,119.2,118.1,40.8,17.8,14.0.

[0046] Example 8

[0047] Synthesize 1-[1,1′-biphenyl]-4-yl-1-butanone having the following structural formula

[0048]

[0049] In this example, phenylcyclopropyl ketone used in Example 1 was replaced with an equal molar amount of [1,1′-biphenyl]-4-ylcyclopropyl ketone, and the other steps were the same as in Example 1 to obtain 1-[1,1′-biphenyl]-4-yl-1-butanone with a yield of 81%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ8.04(d,J=8.4Hz,2H),7.63(d,J=7.0Hz,2H),7.47(t,J=7.4Hz,2H),7.47(t ,J=7.4Hz,2H),7.40(t,J=7.3Hz,1H),2.98(t,J=7.3Hz,2H),1.81(h,J=7.4Hz,2H),1.03(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.2,145.7,140.1,135.9,129.1,128.8,128.3,127.4,127.3,40.7,18.0,14.0.

[0050] Example 9

[0051] Synthesize 1-(4-phenoxyphenyl)-1-butanone with the following structural formula

[0052]

[0053] In this example, cyclopropyl (4-phenoxyphenyl) ketone was used to replace the phenyl cyclopropyl ketone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(4-phenoxyphenyl)-1-butanone with a yield of 94%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.9Hz,2H),7.44–7.35(m,2H),7.19(t,J=7.4Hz,1H),7.07(d,J =7.5Hz,2H),7.00(d,J=8.9Hz,2H),2.90(t,J=7.3Hz,2H),1.77(p,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H); 13C NMR (101MHz, Chloroform-d) δ199.2,161.9,155.7,131.9,130.4,130.1,124.7,120.2,117.4,40.4,18.0,14.0.

[0054] Example 10

[0055] Synthesize 1-(3-thienyl)-1-butanone with the following structural formula

[0056]

[0057] In this example, cyclopropyl-3-thienylmethanone was used to replace the phenylcyclopropylmethanone used in Example 1 in an equal amount, and the other steps were the same as in Example 1 to obtain 1-(3-thienyl)-1-butanone with a yield of 67%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ8.03(d,J=3.3Hz,1H),7.54(d,J=5.1Hz,1H),7.29(dd,J =5.1,2.9Hz,1H),2.84(t,J=7.3Hz,2H),1.74(p,J=7.4Hz,2H),0.98(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ194.9,142.6,131.8,127.1,126.3,41.9,17.9,14.0.

[0058] Embodiment 11

[0059] Synthesize 1-[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-1-butanone having the following structural formula

[0060]

[0061] In this example, 1-[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]cyclopropyl ketone was used to replace the phenylcyclopropyl ketone used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain 1-[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-1-butanone with a yield of 70%. The spectral data of the product were as follows: 1 H NMR (400MHz, Chloroform-d) δ8.06(d,J=8.0Hz,2H),7.75–7.65(m,6H),2.99(t,J=7.3Hz,2H),1.81(p,J=7.4Hz,2H),1.03(t,J=7.4Hz,3H); 13C NMR (101MHz, Chloroform-d) δ200.0,144.0,143.6,136.7,128.9,127.7,127.6,126.0,126.0,40.7,17.9,14.0; 19 F NMR (376MHz, Chloroform-d) delta-62.42.

[0062] Example 12

[0063] Synthesize 1-[3-(phenylmethoxy)phenyl]-1-butanone with the following structural formula

[0064]

[0065] In this example, cyclopropyl[3-(phenylmethoxy)phenyl]butanone was used to replace the phenylcyclopropyl ketone used in Example 1 in an equal molar amount, and the other steps were the same as in Example 1 to obtain 1-[3-(phenylmethoxy)phenyl]-1-butanone with a yield of 73%. The spectral data of the product were as follows: 1 H NMR(400MHz,Chloroform-d)δ7.61–7.54(m,2H),7.45(d,J=7.1Hz,2H),7.42–7.32(m,4H),7.21 –7.15(m,1H),5.12(s,2H),2.93(t,J=7.3Hz,2H),1.77(h,J=7.4Hz,2H),1.01(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ200.3,159.1,138.6,136.7,129.7,128.8,128.2,127.7,121.0,120.1,113.7,70.3,40.8,17.9,14.0.

[0066] In Example 1, no pre-catalyst ethylene glycol dimethyl ether nickel bromide, ligand 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, hydrogen donor trifluoroethanol, or reducing agent zinc powder was added, and the other steps were the same as in Example 1. No target product phenylbutanone was produced, which indicates that the above conditions are necessary for the ring-opening hydrogenation of aromatic cyclopropyl ketones.

Claims

1. A method for synthesizing aryl butanone by ring-opening hydrogenation of aryl cyclopropyl ketone catalyzed by ligand-regulated nickel, characterized in that: Under the protection of inert gas, the aromatic cyclopropyl ketone shown in formula I, ethylene glycol dimethyl ether nickel bromide, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, trifluoroethanol and zinc powder are added to an organic solvent, reacted at 70-100° C., and separated and purified after the reaction is completed to obtain the aromatic butanone shown in formula II; In the formula, Ar represents any one of an aryl group, a heterocyclic aryl group, a substituted aryl group, and a substituted heterocyclic aryl group.

2. The method for synthesizing aryl butanone by ring-opening hydrogenation of aryl cyclopropyl ketone catalyzed by ligand-regulated nickel according to claim 1, characterized in that: The Ar represents any one of phenyl, naphthyl, thienyl, benzothienyl, or phenyl substituted by 1 to 3 of the following: C1-C4 alkyl, C1-C4 alkoxy, halogen, phenyl, phenoxy, trifluoromethyl substituted phenyl, benzyloxy substituted phenyl.

3. The method for synthesizing aromatic butanone by ligand-regulated nickel-catalyzed ring-opening hydrogenation of aromatic cyclopropyl ketone according to claim 1 or 2, characterized in that: The added amount of ethylene glycol dimethyl ether nickel bromide is 10% to 20% of the molar amount of the aryl cyclopropyl ketone.

4. The method for synthesizing aromatic butanone by ligand-regulated nickel-catalyzed ring-opening hydrogenation of aromatic cyclopropyl ketone according to claim 1 or 2, characterized in that: The added amount of the 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene is 5% to 10% of the molar amount of the aromatic cyclopropyl ketone.

5. The method for synthesizing aromatic butanone by ring-opening hydrogenation of aromatic cyclopropyl ketone catalyzed by ligand-regulated nickel according to claim 1 or 2, characterized in that: The added amount of the zinc powder is 2 to 3 times the molar amount of the aryl cyclopropyl ketone.

6. The method for synthesizing aromatic butanone by ring-opening hydrogenation of aromatic cyclopropyl ketone catalyzed by ligand-regulated nickel according to claim 1 or 2, characterized in that: The amount of trifluoroethanol added is 1 to 2 times the molar amount of the aryl cyclopropyl ketone.

7. The method for synthesizing aromatic butanone by ring-opening hydrogenation of aromatic cyclopropyl ketone catalyzed by ligand-regulated nickel according to claim 1 or 2, characterized in that: The organic solvent is selected from any one of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol and 1,4-dioxane.

8. The method for synthesizing aryl butanone by ring-opening hydrogenation of aryl cyclopropyl ketone catalyzed by ligand-regulated nickel according to claim 1 or 2, characterized in that: The reaction is carried out at 70-100°C for 6-12 hours.

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