Method for synthesizing alpha-substituted allyl sulfone through reaction of cobalt-catalyzed sulfuryl allene and organic boric acid

Abstract

The invention provides a method for synthesizing alpha-substituted allyl sulfone by cobalt-catalyzed reaction of sulfuryl allene and organic boric acid, which comprises the following steps: taking sulfuryl allene as shown in a formula I and organic boric acid as shown in a formula II as raw materials, taking a cobalt complex as a catalyst and an organic ligand, and reacting in the presence of an additive to prepare the alpha-substituted allyl sulfone as shown in a formula III. The invention aims to realize hydroarylation and hydroalkenylation of sulfuryl allene and organic boric acid by adopting an economical and effective means, a cheap cobalt catalysis system is used in the reaction process, and a new way is provided for synthesis of allyl sulfone compounds with highly specific 1, 2-regioselectivity.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis. Specifically, this invention relates to a method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid. Background Technology

[0002] Sulfone-containing chiral compounds possess excellent biological activity and are important intermediates in the synthesis of natural products and biopharmaceuticals. Chiral allyl sulfones, as a common type of chiral sulfone, can be used in the synthesis of important chemicals such as antibacterial agents, anticancer agents, and herbicides. Therefore, developing synthetic strategies for chiral allyl sulfone compounds has significant practical implications.

[0003] Organoboron compounds possess advantages such as low toxicity and high stability, making them among the most important cross-coupling reagents. They can be widely used in many key fields such as organic semiconductors and fluorescent probes. Carbon-boron bonds can be selectively converted into carbon-carbon, carbon-nitrogen, carbon-oxygen, and carbon-halogen bonds, thereby achieving diversified construction of molecular skeletons. In research on carbon-boron bond construction strategies, borylation reactions under catalytic systems such as ruthenium, rhodium, iridium, and platinum have been extensively reported.

[0004] Hydroarylation is an effective way to convert carbon-boron bonds into carbon-carbon bonds. Arylboronic acids, as inexpensive and readily available coupling reagents, can be used in the hydroarylation of unsaturated hydrocarbons such as alkenes, alkynes, 1,3-dienes, and allenes. Currently, some research progress has been made in the hydroarylation of allenyl compounds with arylboronic acids, achieving diverse site selectivity to yield corresponding vinyl or allyl compounds under catalytic systems such as palladium, rhodium, platinum, and nickel.

[0005] In 2008, Professor Cheng Jianhong's research group first reported the hydroarylation reaction of alkynes with arylboronic acids under a cobalt catalytic system. Under the Co(acac)₂ / DPPE catalytic system, they successfully obtained a series of vinyl compounds with excellent regioselectivity. In their study, the authors pointed out that the appearance of a small number of trans-selective products in this reaction was due to the formation of a five-membered heterocyclic transition state.

[0006]

[0007] In 2023, Meng Fanke's research group reported a cobalt-catalyzed hydroarylation reaction of cyclopropenes with arylboronic acids. This reaction exhibits broad substrate universality, yielding a series of chiral cyclopropane compounds with excellent diastereoselectivity and enantioselectivity. Furthermore, through the ingenious use of deuteration experiments, the authors successfully demonstrated that arylboronic acids are the proton source for this reaction.

[0008]

[0009] The hydroarylation of sulfonyl allenes with arylboronic acids was reported by Professor Akira Aso's group in 2007. This reaction, under palladium catalysis, yielded a series of addition products with predominantly 2,3-selectivity. To date, no hydroarylation reactions of sulfonyl allenes with arylboronic acids exhibiting 1,2-site selectivity have been reported. Summary of the Invention

[0010] The purpose of this invention is to achieve the hydrogen arylation and hydrogen alkenylation of sulfone allenes and organoboronic acids using an economical and efficient method. The reaction process uses an inexpensive cobalt catalytic system, providing a new route for the synthesis of allyl sulfone compounds with highly specific 1,2-regioselectivity.

[0011] Surprisingly, we discovered that α-substituted allyl sulfone has certain anti-cancer effects, and we hope it can be applied to the field of anti-cancer drugs.

[0012] The technical solution adopted in this invention is:

[0013] A method for synthesizing α-substituted allyl sulfones by reacting cobalt-catalyzed sulfone allenes with organoboronic acids, the method comprising the following steps:

[0014] Using sulfone-based allenes as shown in Formula I and organoboronic acid as shown in Formula II as raw materials, cobalt complex as catalyst and organic ligand, α-substituted allyl sulfone as shown in Formula III was prepared by reaction in the presence of additives.

[0015] Formula I: In formula I, R 1 R 2 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 alkyl groups. 16 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl;

[0016] Formula II: R 3 -B(OH)2, R in formula II 3 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 alkyl groups. 16 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C4-C12 heteroaryl;

[0017] The substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, and phenyl;

[0018] Formula III:

[0019] The reaction formula is as follows:

[0020]

[0021] Furthermore, the R 1 R 2 Further selected from substituted or unsubstituted C6-C12 aryl groups, and substituted or unsubstituted C6-C12 heteroaryl groups; the R 3 Further selected from substituted or unsubstituted C6-C12 aryl groups and substituted or unsubstituted C6-C12 heteroaryl groups; the substituents are selected from: C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen groups, cyano groups, nitro groups, carboxyl groups, carboxylic acid ester groups, and phenyl groups.

[0022] Furthermore, according to claim 1, the method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid is characterized in that the R 1 R 2 Further selected from substituted or unsubstituted C6-12 aryl groups; the substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, phenyl.

[0023] Furthermore, the R 3 Further selected from substituted or unsubstituted C6-C12 aryl groups; the substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, phenyl.

[0024] In this specification, C1-C6 alkyl groups are used, more preferably alkyl groups with 1 to 4 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, and octyl.

[0025] In this specification, C3-C 16 The cycloalkyl group, more preferably an alkyl group with 3 to 8 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptane, 1-adamantyl and 2-adamantyl.

[0026] In this specification, aryl groups of C6-C12 are used, more preferably C6 aryl groups. Specific examples include phenyl, naphthyl, indene, biphenyl, terphenyl, fluorenyl, phenanthrene, and benzo[a]phenanthrene.

[0027] In this specification, C4-C12 heteroaryl groups are used. Specific examples include pyridyl, pyrimidinyl, triazinyl, furanyl, thiopheneyl, pyrroleyl, imidazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiopheneyl, benzofuranyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, dibenzofuranyl, benzodibenzofuranyl, dibenzothiopheneyl, benzodibenzothiapheneyl, carbazoleyl, benzocarbazoleyl, acridineyl, 9,10-dihydroacridyl, phenoxazinyl, phenthiazinyl, phenoxthiazyl, etc., but are not limited to these. The aforementioned heteroaryl groups are preferably pyridyl, pyrimidinyl, thiophene, furanyl, benzothiophene, benzofuranyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, dibenzofuranyl, dibenzothiophene, benzodibenzothiophene, benzodibenzofuranyl, carbazolyl, acridinel, phenoxazinyl, phenthiazinyl, and phenoxthialyl.

[0028] In this specification, the halogens are selected from: F, Cl, Br, I.

[0029] In this specification, the carboxylic acid ester group is selected from: methyl carboxylic acid ester, ethyl carboxylic acid ester, and propyl carboxylic acid ester;

[0030] Furthermore, the cobalt complex is selected from: Co(acac)2, Co(CO)8, CpCo(CO)2, (Ph3P)3CoCl.

[0031] Furthermore, the organic ligand is selected from:

[0032]

[0033] Furthermore, the additive is selected from alcohol compounds.

[0034] The alcohols are selected from methanol, ethanol, propanol, and butanol.

[0035] Furthermore, it also includes an alkali; the alkali is selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0036] Furthermore, the reaction temperature is 40-100℃, even further selected from 60-80℃; and even further selected from 70℃, 80℃, and 90℃.

[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0038] 1. The hydrogen arylation and hydrogen alkenylation of sulfone allenes with organoboronic acids use an inexpensive cobalt catalytic system to obtain highly specific allyl sulfone compounds, which are economical and can be used on a large scale.

[0039] 2. α-substituted allyl sulfone compounds have certain anticancer effects and are expected to be applied in the field of anticancer drugs. Attached Figure Description

[0040] Figure 1 The 1H NMR spectrum of the 3aa prepared in Example 1;

[0041] Figure 2 The 1H NMR spectrum of 3ba prepared in Example 2;

[0042] Figure 3 The 1H NMR spectrum of the 3ga prepared in Example 4;

[0043] Figure 4 The hydrogen spectrum of the 3ha sample prepared in Example 5. Detailed Implementation

[0044] The present invention will be further described below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise stated, the raw materials and reagents used in the embodiments of the present invention are conventionally purchased raw materials and reagents.

[0045] The technical solution of the present invention will be further explained below with reference to implementation examples.

[0046] Example 1

[0047] A 38 mL Schlenk sealing tube was used. After leak testing, Co(acac)₂ (7.1 mg, 10 mol%), 2,2′-bipyridine (3.7 mg, 12 mol%), sulfone allene 1a (0.2 mmol), and arylboronic acid 2a (0.4 mmol) were added sequentially to the tube. Nitrogen was then used to purge the system, and methanol (33 μL, 0.8 mmol) and acetonitrile (2 mL) were added under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 12 hours and then cooled to room temperature. After TLC analysis, the reaction solution was diluted with 30 mL of ethyl acetate and transferred to a flask. The reaction solution was concentrated to obtain the crude product. This crude product was then purified by column chromatography to obtain the target product 3aa.

[0048] 67.4mg, 93% yield, colorless oil. 1 H NMR (400MHz, CDCl3) δ7.57(d,J=8.3Hz,2H),7.43-7.41(m,2H),7.35-7.28(m,3H),7.20(d,J =8.1Hz,2H),7.03(br,4H),6.30(s,1H),5.73(s,1H),5.18(s,1H),2.39(s,3H),2.28(s,3H). 13 C{ 1H}NMR (101MHz, CDCl3) δ144.5,141.0,139.1,137.8,135.6,131.8,130.5,129.4 ,129.2,129.1,128.9,128.6,126.2,119.1,74.5,21.7,21.1.HRMS(ESI-MS)m / z calcd.forC 23 H 22 NaO2S[M+Na] + :385.1233,found:385.1236.

[0050]

[0051] Example 2

[0052] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 1b.

[0053] The target product 3ba was prepared.

[0054] 71.6mg, 94% yield, pale yellow oil. 1 H NMR(400MHz, CDCl3) δ7.59(d,J=8.2Hz,2H),7.40(dd,J=8.8,5.3Hz,2H),7.22(d,J=8.1Hz ,2H),7.04-6.97(m,6H),6.27(s,1H),5.72(s,1H),5.17(s,1H),2.40(s,3H),2.28(s,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ163.2(d,J=249.8Hz),144.7,141.1,138.8,137.9,135.5,132.3(d,J=8.4Hz ),129.5,129.22,129.19,127.5(d,J=3.1Hz),126.2,119.1,115.6(d,J=21.7Hz),73.6,21.7,21.1. 19 FNMR(376MHz,CDCl3)δ-112.4.HRMS(ESI-MS)m / z calcd.forC 23 H 21 FNaO2S[M+Na] + :403.1139,found:403.1134.

[0055] Example 3

[0056] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 1f.

[0057] The target product 3fa was prepared.

[0058] 71.5mg, 83% yield, yellow oil. 1 H NMR (400MHz, CDCl3)δ

[0059] 7.61(d,J=8.2Hz,2H),7.57(br,4H),7.23(d,J=8.2Hz,2H),7.02(d,J=8.1Hz,2H),6. 96(d,J=8.2Hz,2H),6.28(s,1H),5.74(s,1H),5.24(s,1H),2.41(s,3H),2.28(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ145.0,140.7,138.5,138.1,135.8,135.3,130.9,1 29.7,129.29,129.28,126.2,125.6(q,J=3.8Hz),119.7,74.0,21.7,21.2. 19 F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI-MS)m / zcalcd.for C 24 H 21 F3NaO2S[M+Na] + :453.1107,found:453.1109.

[0060] Example 4

[0061] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 1g. The target 3ga was prepared

[0062] 49.1mg, 60% yield, yellow oil. 1H NMR (400MHz, CDCl3) δ8.15(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),7.25(d,J=8.2Hz,2H),7.02(d,J= 8.1Hz,2H),6.95(d,J=8.2Hz,2H),6.28(s,1H),5.76(s,1H),5.30(s,1H),2.41(s,3H),2.27(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ148.1,145.3,140.5,139.1,138.3,138.1,135.1,131.5 ,129.8,129.3,129.2,126.2,123.7,119.9,73.7,21.7,21.1.HRMS(ESI-MS)m / z calcd.forC 23 H 21 NNaO4S[M+Na] + :430.1084,found:430.1082.

[0063] Example 5

[0064] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 1h.

[0065] The target product 3ha was prepared.

[0066] 52.8mg, 63% yield, white solid, mp113-114℃. 1 HNMR (400MHz, CDCl3) δ7.95(d,J=8.4Hz,2H),7.56(d,J=8.3Hz,2H),7.48(d,J=8.4Hz,2H),7.20(d,J=8.0Hz,2H),7.02 (d,J=8.5Hz,2H),6.99(d,J=8.6Hz,2H),6.28(s,1H),5.74(s,1H),5.22(s,1H),3.90(s,3H),2.39(s,3H),2.27(s,3H). 13 C{ 1H}NMR (101MHz, CDCl3) δ166.7,144.9,140.6,138.6,138.0,136.9,135.3,130. 5,129.8,129.6,129.2,126.2,119.5,74.2,52.3,21.7,21.1.HRMS(ESI-MS)m / z calcd.for C 25 H 24 KO4S[M+K] + :459.1027,found:459.1026.

[0067] Example 6

[0068] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 1k.

[0069] The target product 3ka was prepared.

[0070] 74.6 mg, 95% yield, white solid, mp100-101℃. 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 8.2Hz, 2H), 7.22-7.18 (m, 3H), 7.03 (br, 4H), 6.99-6.97 (m, 2H), 6.87 (dd,J=8.4,1.4Hz,1H),6.29(s,1H),5.73(s,1H),5.16(s,1H),3.74(s,3H),2.39(s,3H),2.28(s,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ159.6,144.5,140.9,139.0,137.7,135.6,133.1,129.5,129.4,129.2, 129.1,126.2,123.0,119.1,115.9,114.6,74.4,55.2,21.7,21.1.HRMS(ESI-MS)m / zcalcd.for C 24 H 24 NaO3S[M+Na] + :415.1338,found:415.1339.

[0071] Example 7

[0072] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 5a.

[0073] The target product 5aa was prepared.

[0074] 68.2mg, 93% yield, yellow oil. 1 H NMR (400MHz, CDCl3) δ7.68 (dd, J=8.8, 5.1Hz, 2H), 7.41 (dd, J=7.5, 1.6Hz, 2H), 7.34-7.29 (m, 3H),7.08(t,J=8.5Hz,2H),7.03(br,4H),6.29(s,1H),5.74(s,1H),5.16(s,1H),2.28(s,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ165.8(d,J=257.3Hz),140.8,138.9,138.0,134.6(d,J=3.1Hz),132.1(d ,J=9.7Hz),131.5,130.5,129.24,129.18,128.8,126.2,119.3,116.1(d,J=22.7Hz),74.7,21.2. 19 FNMR(376MHz,CDCl3)δ-103.5.HRMS(ESI-MS)m / zcalcd.for C 22 H 19 FNaO2S[M+Na] + :389.0982,found:389.0980.

[0075] Example 8

[0076] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with [missing information - likely a specific ingredient].

[0077] 5c The target product was prepared.

[0078] 5ca 71.0mg, 94% yield, orange oil. 1H NMR (400MHz, CDCl3) δ7.60 (d, J=8.8Hz, 2H), 7.43-7.41 (m, 2H), 7.35-7.28 (m, 3H), 7.06 (d, J=8.5Hz, 2H), 7. 03(d,J=8.6Hz,2H),6.86(d,J=8.8Hz,2H),6.31(s,1H),5.74(s,1H),5.17(s,1H),3.82(s,3H),2.28(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ163.6,141.1,139.0,137.7,131.9,131.4,130.5,130.0,129 .1,128.9,128.6,126.6,118.9,113.9,74.7,55.7,21.1.HRMS(ESI-MS)m / zcalcd.for C 23 H 22 NaO3S[M+Na] + :401.1182,found:401.1185.

[0079] Example 9

[0080] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with [missing information - likely a specific ingredient].

[0081] 5e The target product was prepared.

[0082] 5ea 74.0mg, 95% yield, pale yellow oil. 1 H NMR (400MHz, CDCl3) δ7.46-7.41(m,4H),7.33-7.29(m,3H),7.07(d,J=8.2Hz,2H),7.03(d,J=8.3Hz,2H),6.73(dd ,J=7.7,1.2Hz,1H),6.29(s,1H),5.74(s,1H),5.16(s,1H),4.62(t,J=8.8Hz,2H),3.21-2.99(m,2H),2.28(s,1H). 13 C{ 1H}NMR (101MHz, CDCl3) δ164.5,141.1,139.0,137.7,132.1,130.9,130.5,129.9,129.1,128.8, 128.5,128.0,126.4,126.2,118.9,109.2,74.7,72.4,28.8,21.1.HRMS(ESI-MS)m / zcalcd.for C 24 H 22 NaO3S[M+Na] + :413.1182,found:413.1182.

[0083] Example 10

[0084] The preparation steps are the same as in Example 1, except that sulfone allene 1a is replaced with 5h. The target product of 5 ha was prepared. 54.4mg, 75% yield, pale yellow oil. 1 HNMR (400MHz, CDCl3) δ7.62(d,J=5.6Hz,2H),7.46-7.40(m,3H),7.22(d,J=7.7Hz,2H),7.12(d,J=7.6Hz,2H),6.21(s,1H ),5.81(s,1H),5.19(s,1H),3.07-2.95(m,2H),2.33(s,3H),1.90-1.67(m,2H),1.43-1.34(m,2H),0.89(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(101MHz, CDCl3)δ141.0,138.6,138.2,131.1,130.3,129.4,129.2,129.0,126.2,119.0,71.0,51.6,24.0,21.8,21.2,13.6.HRMS(ESI-MS)m / z calcd.for C 20 H 24 NaO2S[M+Na] + :351.1389,found:351.1389.

[0085] Example 11

[0086] The preparation steps are the same as in Example 1, except that arylboronic acid 2a is replaced with 3c. The target product 3ac was prepared. 62.1mg, 81% yield, yellow oil. 1 HNMR(400MHz, CDCl3)δ7.55(d,J=8.3Hz,2H),7.41-7.38(m,2H),7.34-7.28(m,3H),7.14(t,J=7.5Hz,1H) ,7.06(t,J=1.6Hz,1H),7.01(dt,J=7.5,1.4Hz,1H),6.35(s,1H),5.75(s,1H),5.10(s,1H),2.39(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ144.8,143.7,140.2,135.3,134.3,131.5,130.4,129.8,12 9.5,129.2,129.1,128.7,128.0,126.7,124.6,121.0,74.3,21.7.HRMS(ESI-MS)m / z calcd.for C 22 H 19 ClKO2S[M+K] + :421.0426,found:421.0427.

[0087] Example 12

[0088] The preparation steps are the same as in Example 1, except that arylboronic acid 2a is replaced with 3e. The target product 3ae was prepared. 58.2mg, 78% yield, paleellow oil. 1 HNMR (400MHz, CDCl3) δ7.52 (d, J = 8.2Hz, 2H), 7.50-7.48 (m, 1H), 7.40-7.38 (m, 1H), 7.36-7.33 (m, 4H),7.32-7.27(m,3H),7.20(d,J=8.1Hz,2H),6.38(s,1H),5.76(s,1H),5.06(s,1H),2.39(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ145.0,143.0,139.5,135.0,131.4,131.2,131.0,130.2,130 .1,129.5,129.24,129.16,128.8,122.1,118.5,112.6,74.2,21.7.HRMS(ESI-MS)m / z calcd.for C23 H 19 NNaO2S[M+Na] + :396.1029,found:396.1030.

[0089] Example 13

[0090] The preparation steps are the same as in Example 1, except that arylboronic acid 2a is replaced with 3f. The target product 3af was prepared. 67.0mg, 83% yield, yellow oil. 1 HNMR(400MHz, CDCl3)δ7.87(d,J=8.4Hz,2H),7.53(d,J=8.3Hz,2H),7.39-7.36(m,2H),7.32-7.28(m,3H),7. 20(d,J=3.2Hz,2H),7.18(d,J=2.8Hz,2H),6.40(s,1H),5.81(s,1H),5.14(s,1H),3.87(s,3H),2.37(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ166.7,146.3,144.8,140.6,135.3,131.5,130.4,129.8 ,129.5,129.2,129.1,128.7,126.5,121.4,74.2,52.2,21.7.HRMS(ESI-MS)m / z calcd.for C 24 H 22 NaO4S[M+Na] + :429.1131,found:429.1132.

[0091] Example 14

[0092] The preparation steps are the same as in Example 1, except that arylboronic acid 2a is replaced with [missing information - likely a different ingredient].

[0093] 3h The target product was prepared.

[0094] 3ah 54.9mg, 65% yield, white solid, mp143-144℃. 1H NMR (400MHz, CDCl3) δ7.58(d,J=8.2Hz,2H),7.52(d,J=7.4Hz,2H),7.46-7.40(m,6H),7. 35-7.29(m,4H),7.22-7.20(m,4H),6.36(s,1H),5.82(s,1H),5.21(s,1H),2.40(s,3H). 13 C{ 1 H}NMR(101MHz,CDCl3)δ144.6,140.8,140.4,135.6,131.7,130.5,129.5,129.3,129.0,1 28.9,128.7,127.5,127.2,127.0,126.8,119.8,74.4,21.7.HRMS(ESI-MS)m / zcalcd.for C 28 H 24 NaO2S[M+Na] + :447.1389,found:447.1384.

[0095] Example 15

[0096] The preparation steps are the same as in Example 1, except that arylboronic acid 2a is replaced with 3i. The target product 3ai was prepared. 69.3mg, 87% yield, yellow oil. 1 H NMR (400MHz, CDCl3) δ7.77-7.74(m,1H),7.69(d,J=8.0Hz,2H),7.58(d,J=8.2Hz,2H),7.52(d,J=1.1Hz,1H),7.47-7.42( m,4H),7.35-7.32(m,3H),7.28-7.26(m,1H),7.19(d,J=8.0Hz,2H),6.42(s,1H),5.87(s,1H),5.29(s,1H),2.37(s,3H). 13 C{ 1 H}NMR (101MHz, CDCl3) δ144.6,141.3,139.2,135.6,133.1,132.8,131.8,130.5,129.4,129.3,129.0,12 8.7,128.19,128.16,127.6,126.4,126.3,125.4,124.5,120.3,74.5,21.6.HRMS(ESI-MS)m / zcalcd.for C 26 H22 KO2S[M+K] + :437.0972,found:437.0972.

[0097] Comparative Examples 1-4

[0098] Parallel experiments were conducted, with preparation steps similar to those in Example 1, except for the catalyst, coupling agent, and additives used, to prepare the target product 3aa.

[0099]

[0100]

[0101] 1a (0.2mmol), 2a (0.4mmol), Co(acac)2 (10mol%), bpy (12mol%), ROH (0.8mmol), MeCN (2mL), 12h.

[0102] The irreplaceable nature of the cobalt catalytic system was further confirmed by comparing Examples 1-4. In the absence of a catalyst, there was a surplus of feedstock and no reaction occurred. When Pd(OAc)₂ was used as a catalyst, a large amount of feedstock remained, and the target product was obtained in only a 13% yield. When [RhOH(cod)₂]₂ was used as a catalyst, a large amount of feedstock remained, and no product was formed. When Ni(acac)₂ was used as a catalyst, the feedstock reacted almost completely, and the target product was obtained in a 74% yield. All of these results are inferior to the reaction performance when Co(acac)₂ was used as a catalyst, which fully demonstrates the irreplaceable nature of the cobalt catalytic system.

[0103] Comparative Examples 5-7

[0104] Parallel experiments were conducted, with preparation steps similar to those in Example 1, except for different types of Co catalysts and a reaction temperature of 80°C, to obtain the target product 3aa.

[0105]

[0106]

[0107]

[0108] 1a (0.2mmol), 2a (0.4mmol), [Co] (10mol%), BINAP (12mol%), K2CO3 (0.4mmol), MeOH (0.8mmol), MeCN (2mL), 12h

[0109] Further investigation using Comparative Examples 5-7 revealed the influence of different types of Co catalysts. When Co(CO)8, CpCo(CO)2, and (Ph3P)3CoCl were used as catalyst precursors, a large amount of raw material remained in the reaction system. Therefore, Co(acac)2 was determined to be the optimal catalyst precursor.

[0110] Comparative Examples 8-13

[0111] The parallel experiment followed similar preparation steps as in Example 1, except for the ligand and coupling agent, and the target product 3aa was obtained.

[0112]

[0113]

[0114] 1a (0.2mmol), 2 (0.4mmol), Co(acac)2 (10mol%), L (12mol%), K2CO3 (0.4mmol), MeOH (0.8mmol), MeCN (2mL), 80°C, 12h.

[0115]

[0116] Further investigation using Comparative Examples 5-13 revealed the influence of coupling agents and ligands. When the coupling agent was phenylboronic anhydride, the use of ligands L1 and L3 resulted in significant residue of raw materials and no product formation. However, the use of ligands L2 or L4 yielded moderate yields (47%-77%). With L4 as the ligand, reactions using phenylboronic acid or p-methylphenylboronic acid as coupling agents yielded the corresponding hydroarylated products in yields of 63% and 65%, respectively. Compared to arylboronic anhydride, arylboronic acid is readily available and inexpensive, making it the initial substrate choice.

[0117] Comparative Examples 14-16

[0118] Parallel experiments were conducted, with preparation steps similar to those in Example 1, except that no alkali or additives were used and the reaction temperature was 80°C, resulting in the preparation of the target product 3aa.

[0119]

[0120]

[0121] 1a (0.2mmol), 2a (0.4mmol), Co(acac)2 (10mol%), bpy (12mol%), ROH (0.8mmol), MeCN (2mL), 12h.

[0122] The reaction effect under alkali-free conditions was further investigated using Comparative Examples 14-16. Under alkali-free conditions, the product yield increased to 78% (Comparative Example 14). The effects of additives were investigated under alkali-free conditions. When the additive was acetic acid (Comparative Example 15), a large amount of raw material remained, and no product was found to be formed. When there was no additive (Comparative Example 16), the yield decreased to 70%.

[0123] Effect Example

[0124] Antitumor activity was tested based on the 3aa compound prepared in Example 1.

[0125] The in vitro growth inhibitory activity of the 3aa compound against human cervical cancer cells (HeLa), human liver cancer cells (HuH-7), human non-small cell lung cancer cells (A549), and human lung adenocarcinoma cells (H1975) was detected by the MTT assay.

[0126] The compound was prepared into a 5.0 mg / mL solution using dimethyl sulfoxide (DMSO), and then diluted with RPMI-1640 medium to concentrations of 5, 10, 25, 50, and 100 μg / mL. HeLa cell suspensions in the exponential growth phase were added to 96-well plates (cell concentration 50,000 cells / mL, 100 μL / well) and incubated at 37°C with 5% CO2 for 12–18 h to allow cell adhesion. The supernatant was removed, and 100 μL of the compound at different concentrations was added to each well (four replicates per concentration). The plates were incubated for 24 h, the supernatant was discarded, and 60 μL of 2.0 mg / mL MTT solution was added to each well. The plates were incubated for another 3 h, and after removing the supernatant, 150 μL of dimethyl sulfoxide was added to each well. The plates were shaken slowly for 10 min to dissolve the deep blue crystals. The absorbance was measured at 490 nm using a microplate reader. The inhibition rate of each group against cancer cells was calculated using the following formula: Inhibition rate (%) = (OD value of control group - OD value of test group) / OD value of control group × 100%. Each experiment was repeated three times, and the average value was taken. A linear regression was performed between the logarithm of the sample concentration and the cell inhibition rate. The half-maximal inhibitory concentration (IC50) of the sample against cells was calculated using SPSS 17.0 software. The activity data are shown in Table 1. As can be seen from Table 1, the 3aa compound prepared in this invention exhibits good anticancer activity against human cervical cancer cells, human liver cancer cells, human lung cancer cells, and human lung adenocarcinoma cells.

[0127] Table 1 shows the in vitro activity test data:

[0128] Human cervical cancer cells Human liver cancer cells Human non-small cell lung cancer cells Human lung adenocarcinoma cells cell lines Hela HuH-7 A549 H1975 Sample IC50μM 35.58±2.82 0.45±2.21 0.96±1.24 8.26±4.22 Cisplatin IC50μM 56.12±7.82 3.61±1.10 2.41±0.81 15.98±8.95

[0129] As can be seen from the table, the compounds of the present invention show good anticancer activity against human cervical cancer cells, human liver cancer cells, human lung cancer cells, and human lung adenocarcinoma cells, and can be used to prepare anti-cervical cancer drugs, anti-liver cancer drugs, and anti-lung cancer drugs.

[0130] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allenes with organoboronic acids, characterized in that, The method includes the following steps: Using sulfone-based allenes as shown in Formula I and organoboronic acid as shown in Formula II as raw materials, cobalt complex as catalyst and organic ligand, α-substituted allyl sulfone as shown in Formula III was prepared by reaction in the presence of additives. Formula I: In formula I, R 1 R 2 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 alkyl groups. 16 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C4-C12 heteroaryl; Formula II: R 3 -B(OH)2, R in formula II 3 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C6 alkyl groups. 16 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C4-C12 heteroaryl; The substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, and phenyl; Formula III: The reaction formula is as follows:

2. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 1, characterized in that, The R 1 R 2 Further selected from substituted or unsubstituted C6-C12 aryl groups, and substituted or unsubstituted C6-C12 heteroaryl groups; the R 3 Further selected from substituted or unsubstituted C6-C12 aryl groups and substituted or unsubstituted C4-C12 heteroaryl groups; the substituents are selected from: C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen groups, cyano groups, nitro groups, carboxyl groups, carboxylic acid ester groups, and phenyl groups.

3. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 2, characterized in that, The R 1 R 2 Further selected from substituted or unsubstituted C6-12 aryl groups; the substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, phenyl.

4. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 2, characterized in that, The R 3 Further selected from substituted or unsubstituted C6-C12 aryl groups; the substituents are selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro, carboxyl, carboxylic acid ester, phenyl.

5. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 1, characterized in that, The cobalt complex is selected from: Co(acac)2, Co(CO)8, CpCo(CO)2, and (Ph3P)3CoCl.

6. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 1, characterized in that, The organic ligands are selected from:

7. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 1, characterized in that, The additives are selected from alcohol compounds.

8. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 5, characterized in that, The cobalt complex is selected from Co(acac)2.

9. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 6, characterized in that, The organic ligand is selected from: 2,2′-bipyridine ligand.

10. The method for synthesizing α-substituted allyl sulfone by reacting cobalt-catalyzed sulfone allene with organoboronic acid according to claim 7, characterized in that, The additive is selected from methanol.

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