阅读说明：本技术 一种二芳甲基烃基砜的合成方法 (A kind of synthetic method of two arylmethyls alkyl sulfone ) 是由 曾庆乐 库楚酷拉·拉纳卡·雷德 郑文婷 于 2019-09-25 设计创作，主要内容包括：砜是重要的药物和生物活性化合物。现在广受欢迎的除草剂甲基磺草酮和生物活性化合物(例如γ-分泌酶抑制剂)属于砜类化合物。此外,砜类的药物可以预防阿尔茨海默氏病。砜类化合物还被广泛用作有机合成的中间体。在砜类化合物中,二芳甲基烃基砜是合成三芳基甲烷的重要起始原料,作为无色染料、光致变色剂、生成树枝状聚合物的结构单元以及用于理论和生物学研究的底物,它受到了广泛的关注。本专利开发了一种可回收的离子交换树脂催化剂Amberlyst-15催化的三组分反应,以良好的收率和优异的收率在广泛的底物范围内合成二芳甲基烃基砜。以容易获得的芳基/烷基醛,芳基/烷基亚磺酸钠和多甲氧基苯为原料一锅法合成二芳甲基烃基砜,通过C-C和C-S键的形成制备二芳甲基烃基砜。该合成工艺具有反应条件特别温和,操作简单,产率普遍较高,和底物范围广等优点。(Sulfone is important drug and bioactive compound.Now very popular herbicide mesotrione and bioactive compound (such as inhibitors of gamma-secretase) belongs to sulfone compound.In addition, the drug of sulfone class can prevent Alzheimer's disease.Sulfone compound is also widely used as the intermediate of organic synthesis.In sulfone compound, two arylmethyl alkyl sulfones are the important starting materials for synthesizing triarylmethane, as leuco dye, photochromic agent, the structural unit for generating dendritic and for theoretical and biological study substrate, it is had received widespread attention.This patent develops a kind of three component reactions of recyclable ion-exchange resin catalyst Amberlyst-15 catalysis, and two arylmethyl alkyl sulfones are synthesized in extensive substrate spectrum with good yield and excellent yield.With the aryl groups per alkyl group aldehyde being easy to get, aryl groups per alkyl group sulfinic acid sodium and Polymethoxylated benzene are two arylmethyl alkyl sulfone of raw material one pot process, prepare two arylmethyl alkyl sulfones by the formation of C-C and C-S key.The advantages that synthesis technology has reaction condition especially mild, easy to operate, and yield is generally higher and substrate spectrum is wide.)

一种二芳甲基烃基砜的合成方法

技术领域

该专利涉及有机合成、药物合成、有机化工的研究领域，具体的方法就是烃基亚磺酸钠、芳基/烷基醛和多甲氧基苯进行三组分反应一步合成二芳甲基烃基砜类化合物。

背景技术

砜是重要的药物和生物活性化合物。现在广受欢迎的除草剂甲基磺草酮和生物活性化合物 (例如γ-分泌酶抑制剂)属于砜类化合物(D.Cornes,Patent:WO 2002/100173.R.A.Wichert and T.H.Beckett,WO 2002/019823.)。此外，砜类的药物可以预防阿尔茨海默氏病(I.Churcher,D. Beher,J.D.Best,J.L.Castro,E.E.Clarke,A.Gentry,T.Harrison,L.Hitzel,E.Kay,S.Kerrad,H. D.Lewis,P.M.Gutierrez,R.M.Smith,P.J.Oakley,M.Reilly,D.E.Shaw,M.S.Shearman,M.R. Teall,S.Williams andJ.D.J.Wrigley,Bioorg.Med.Chem.Lett.,2006,16,280.)。

它们也被广泛用作有机合成中的重要中间体(M.Nambo,Z.T.Ariki,D.C.Gonzalez,D.D. Beattie and C.M.Crudden,Org.Lett.,2016,18,2339.)。其中二芳基砜作为无色染料(R.Muthyala, in:Chemistry and Applications of Leuco Dyes(Eds.:A.R.Katrizky,G.J.Sabongi),Plenum,New York,1997.)，光致变色剂(D.F.Duxbury,Chem.Rev.,1993,93,381；R.Aldag,in:Photochroism: Molecules and Systems(Eds.:H.Dürr,H.Bouas-Laurent),Elsevier,London,1990.)，生成树枝状聚合物的结构单元(L.A.Baker,L.Sun and R.M.Crooks,Bull.Korean Chem.Soc.,2002,23,647.)以及用于理论(M.S.Baptista and G.L.Indig,J.Phys.Chem.B 1998,102,4678；F.Terrier,T.Boubaker,L.Xiao and P.G.Farrell,J.Org.Chem.,1992,57,3924.)和生物学研究(M.R.Detty,S.L. Gibson and S.J.Wagner,J.Med.Chem.,2004,47,3897；M.Wainwright,D.Phoenix,A.S.M. Burrow and J.Waring,J.Chemother.,1999,11,61；R.A.Al-Qawasmeh,Y.Lee,M.-Y.Cao,X.Gu, A.Vassilakos,J.A.Wright and A.Young,Bioorg.Med.Chem.Lett.,2004,14,347.)的底物，它受到了广泛的关注。

关于二芳甲基烃基砜的报道很少，主要有以下几种：(1)在FeCl₃存在下，通过α-酰胺基砜的芳基化反应合成二芳甲基烃基砜(P.Thirupathi and S.S.Kim,Eur.J.Org.Chem.,2010,2010, 1798.)。(2)在钯催化剂的存在下，通过甲基苯砜的芳基化制得二芳甲基烃基砜(M.Nambo and C.M.Crudden,Angew.Chem.Int.Ed.,2014,53,742.)。(3)在铁(III)酞菁-氯化铁存在下由磺酰腙合成砜(J.L.Zhao,S.H.Guo,J.Qiu,X.F.Gou,C.W.Hua and B.Chen,Tetrahedron Lett., 2016,57,2375.)。(4)通过对醌甲基化物与磺酰肼的1,6-共轭加成/芳构化/磺酰化反应制备二芳甲基烃基砜(T.Liu,J.Liu,S.Xia,J.Meng,X.Shen,X.Zhu,W.Chen,C.Sun and F.Cheng,ACS Omega,2018,3,1409.)。然而，在所有先前的报道中，都涉及两个步骤的反应来合成二芳甲基烃基砜，即芳基醛首先将其转化为相应的中间体，然后在第二步中将其进一步转化为二芳甲基烃基砜。

因此，为避免使用金属催化剂，有机溶剂和多步反应，我们开发了一种二芳甲基烃基砜的绿色合成方法，即在水中，可循环利用的催化剂Amberlyst-15催化芳基/烷基醛、烃基亚磺酸钠和多甲氧基苯的三组分反应合成二芳甲基烃基砜。

尽我们所知，未见与本申请相同的文献报道。

发明内容

本发明提供一种二芳甲基烃基砜的合成方法。

本发明公开的二芳甲基烃基砜的合成方法均一步完成，即在水中，Amberlyst-15催化芳基 /烷基醛、烃基亚磺酸钠和多甲氧基苯发生三组分反应，一步合成二芳甲基烃基砜，反应通式如下。其中，芳基/烷基醛为烷基醛、芳基醛和杂芳基醛。多甲氧基苯为二甲氧基苯和三甲氧基苯。烃基亚磺酸钠为芳基亚磺酸钠和烷基亚磺酸钠。

结合下面的实施例,更详细地阐述本发明，但并不认为它们是对本发明范围的限制。

具体实施方式

实施例一

往烘干带磁力搅拌子的磨口试管里加入苯甲醛(1.5毫摩尔)、苯基亚磺酸钠(1.0毫摩尔)、 1,3,5-三甲氧基苯(1.0毫摩尔)、Amberlyst-15(相对于1,3,5-三甲氧基苯质量的50％)、水(1毫升)，最后用橡皮塞密封磨口试管。把该试管置于60℃油浴锅中搅拌反应6小时。然后向反应混合物中加入水(10mL)，将离子交换树脂过滤并用乙酸乙酯(5mL)洗涤3次。将滤液用乙酸乙酯(10mL)萃取3次，并将合并的有机层用无水MgSO₄干燥，然后在旋转蒸发仪上在减压下吸附在一些硅胶上。将吸附了样品的硅胶转移到硅胶柱上。用硅胶柱色谱法(石油醚：乙酸乙酯＝5∶1作为洗脱剂)纯化后，得到白色固体1,3,5-三甲氧基-2-(苯基(苯基磺酰基) 甲基)苯产率为88％。反应方程式如下所示。

产物1,3,5-三甲氧基-2-(苯基(苯基磺酰基)甲基)苯的结构表征数据如下：

¹H NMR(400MHz,CDCl₃):δ＝7.69-7.63(m,2H),7.61-7.49(m,3H),7.45-7.24(m,5H),6.21 (s,1H),6.06(s,2H),3.80(s,3H),3.66(s,6H).

¹³C NMR(101MHz,CDCl₃)δ161.72,141.02,134.19,132.64,130.18,128.67,128.15,127.91, 127.64,104.12,91.00,67.77,55.59,55.30.

HRMS(ESI):calculated for C₂₂H₂₂O₅SNa[M+Na]⁺＝421.1086,found C₂₂H₂₂O₅SNa[M+ Na]⁺＝421.1079.

Melting point:106-107℃.

实施例二

4-氟苯甲醛代替实施例一中的苯甲醛，得到白色固体2-((4-氟苯基)(苯基磺酰基)甲基) -1,3,5-三甲氧基苯的产率为90％。

¹H NMR(400MHz,DMSO-d₆):δ7.70–7.60(m,1H),7.59–7.45(m,6H),7.20–7.08(m,2H),6.18(s,2H),6.09(s,1H),3.76(s,3H),3.62(s,6H)；

¹³C NMR(400MHz,DMSO-d6):δ167.99,166.74,165.56,145.29,138.48,137.31,137.23, 135.31,135.28,133.86,133.23,120.07,119.85,108.10,96.41,71.66,60.88,60.50.

HRMS(ESI):calculated for C₂₂H₂₁FO₅SNa[M+Na]⁺＝439.0991,found C₂₂H₂₁FO₅SNa[M+ Na]⁺＝439.0992.

Melting point:87-88℃.

实施例三

4-氯苯甲醛代替实施例一中的苯甲醛，得到白色固体2-((4-氯苯基)(苯基磺酰基)甲基) -1,3,5-三甲氧基苯的产率为91％。

¹H NMR(400MHz,CDCl₃):δ＝7.71-7.62(m,2H),7.59-7.49(m,3H),7.46-7.22(m,4H),6.14 (s,1H),6.05(s,2H),3.80(s,3H),3.64(s,6H).

¹³C NMR(101MHz,CDCl₃)δ161.91,140.66,133.51,132.81,131.54,128.64,128.26,128.03, 103.50,91.00,66.83,55.59,55.31.

HRMS(ESI):calculated for C₂₂H₂₁ClO₅SNa[M+Na]⁺＝455.0696,foundC₂₂H₂₁ClO₅SNa[M +Na]⁺＝455.0696.

Melting point:118-119℃.

实施例四

4-硝基苯甲醛代替实施例一中的苯甲醛，得到白色固体1,3,5-三甲氧基-2-((4-硝基苯基) (苯基磺酰基)甲基)苯的产率为90％。

¹H NMR(400MHz,CDCl₃):δ8.06(d,J＝8.9Hz,2H),7.71(d,J＝8.7Hz,2H),7.59(d,J＝ 7.2Hz,2H),7.48(t,J＝7.4Hz,1H),7.34(t,J＝7.8Hz,2H),6.14(s,1H),5.93(s,2H),3.71(s,3H), 3.51(s,6H).

¹³C NMR(101MHz,CDCl₃):δ162.34,146.96,142.16,140.09,133.15,130.79,128.72,128.35, 122.91,102.55,90.89,66.33,55.56,55.34.

HRMS(ESI):calculated for C₂₂H₂₁NO₇SNa[M+Na]⁺＝466.0936,found C₂₂H₂₁NO₇SNa[M+ Na]⁺＝466.0911.

Melting point:130-131℃.

实施例五

2-甲氧基苯甲醛代替实施例一中的苯甲醛，得到白色固体1,3,5-三甲氧基-2-((2-甲氧基苯基)(苯基磺酰基)甲基)苯的产率为70％。

¹H NMR(400MHz,CDCl₃):δ8.22(dd,J＝7.8,1.7Hz,1H),7.71–7.62(m,2H),7.53–7.44(m,1H),7.41–7.32(m,2H),7.20(ddd,J＝8.2,7.4,1.7Hz,1H),6.96(td,J＝7.6,1.2Hz,1H), 6.70(dd,J＝8.3,1.2Hz,1H),6.62(s,1H),6.01(s,2H),3.76(s,3H),3.60(s,6H),3.46(s,3H)；

¹³C NMR(101MHz,CDCl₃):161.50,156.88,141.53,132.36,132.32,128.75,128.73,127.98, 122.59,119.99,110.25,104.01,91.22,59.89,55.72,55.36,55.22.

HRMS(ESI):calculated for C₂₃H₂₄O₆SNa[M+Na]⁺＝451.1191,found C₂₃H₂₄O₆SNa[M+ Na]⁺＝451.1193.

Melting point:150-151℃.

实施例六

2-羟基苯甲醛代替实施例一中的苯甲醛，得到白色固体2-((苯基磺酰基)(2,4,6-三甲氧基苯基)甲基)苯酚的产率为75％。

¹H NMR(400MHz,DMSO-d₆)δ9.3(bs,1H),8.06(d,J＝7.9Hz,1H),7.55(td,J＝21.3,19.1, 7.4Hz,4H),7.32(d,J＝6.2Hz,1H),7.05(t,J＝7.7Hz,1H),6.77(t,J＝7.6Hz,1H),6.67(d,J＝ 8.0Hz,1H),6.53(s,1H),6.11(s,2H),3.73(s,3H),3.52(s,6H)；

¹³C NMR(101MHz,DMSO)δ161.70,155.61,148.72,141.20,133.42,132.66,128.90,128.90, 128.86,128.60,128.11,125.94,120.57,118.23,115.05,103.40,91.75,59.70,56.10,55.71.

HRMS(ESI):calculated for C₂₃H₂₄O₆SNa[M+Na]⁺m/z＝437.1035,foundC₂₃H₂₄O₆SNa[M +Na]⁺m/z＝437.1036.

Melting point:116-117℃.

实施例七

2-吡啶甲醛代替实施例一中的苯甲醛，得到白色固体-((苯基磺酰基)(2,4,6-三甲氧基苯基)甲基)吡啶的产率为75％。

¹H NMR(400MHz,CDCl₃):δ8.46(ddd,J＝4.9,1.9,0.9Hz,1H),8.07(dt,J＝8.0,1.1Hz, 1H),7.75–7.62(m,3H),7.56–7.46(m,1H),7.38(dd,J＝8.4,7.2Hz,2H),7.14(ddd,J＝7.6,4.9, 1.1Hz,1H),6.35(s,1H),5.98(s,2H),3.75(s,3H),3.50(s,6H).

¹³C NMR(101MHz,CDCl₃):δ162.09,154.76,148.64,140.75,135.73,132.81,128.97,128.11, 125.09,122.18,102.75,90.98,68.64,55.54,55.27.

HRMS(ESI):calculated for C₂₁H₂₁NO₅SNa[M+Na]⁺＝422.1038,found C₂₁H₂₁NO₅SNa[M+ Na]⁺＝422.1039.

Melting point:130-131℃.

实施例八

苯乙醛代替实施例一中的苯甲醛，得到浅色固体1,3,5-三甲氧基-2-(2-苯基-1-(苯基磺酰基)乙基)苯的产率为70％。

¹H NMR(400MHz,CDCl₃):δ7.78–7.66(m,2H),7.54(t,J＝7.6Hz,1H),7.42(t,J＝7.6 Hz,2H),7.20–7.01(m,5H),6.00(d,J＝2.3Hz,1H),5.81(d,J＝2.3Hz,1H),5.27(dd,J＝11.6, 4.7Hz,1H),3.89(dd,J＝13.6,11.6Hz,1H),3.74(s,3H),3.67(s,4H),3.38(s,3H).

¹³C NMR(101MHz,CDCl₃)δ161.59,160.78,159.85,139.83,138.45,132.71,128.93,128.67, 128.11,128.03,126.06,100.92,91.02,90.34,63.97,55.74,55.26,55.14,31.65.

HRMS(ESI):calculated for C₂₃H₂₄O₅SNa[M+Na]⁺＝435.1242,found C₂₂H₂₁FO₅SNa[M+ Na]⁺＝435.1242.

实施例九

甲醛代替实施例一中的苯甲醛，得到浅色固体1,3,5-三甲氧基-2-((苯基磺酰基)甲基) 苯的产率为82％。

¹H NMR(400MHz,CDCl₃):δ7.73–7.63(m,2H),7.59–7.47(m,1H),7.46–7.36(m,2H),5.96(s,2H),4.48(s,2H),3.76(s,3H),3.46(s,6H).

¹³C NMR(101MHz,CDCl₃)δ161.88,159.58,140.16,132.80,128.63,128.19,98.11,90.16, 55.38,55.29,51.65.

HRMS(ESI):calculated for C₁₆H₁₈O₅SNa[M+Na]⁺＝345.0773,found C₁₆H₁₈O₅SNa[M+ Na]⁺＝345.0772.

实施例十

乙醛代替实施例一中的苯甲醛，得到浅色固体1,3,5-三甲氧基-2-(1-(苯基磺酰基)乙基) 苯的产率为79％。

¹H NMR(400MHz,CDCl₃)δ7.78–7.64(m,2H),7.62–7.48(m,1H),7.48–7.36(m,2H),6.00(dd,J＝36.1,2.3Hz,2H),5.06(q,J＝7.3Hz,1H),3.80(s,3H),3.55(d,J＝15.4Hz,6H),1.84 (d,J＝7.3Hz,3H).

¹³C NMR(101MHz,CDCl₃)δ161.54,161.15,159.23,139.50,132.62,129.06,128.04,103.04, 91.08,90.17,57.86,55.62,55.24,12.81.

HRMS(ESI):calculated for C₁₇H₂₀O₅SNa[M+Na]⁺＝359.0929,found C₁₇H₂₀O₅SNa[M+ Na]⁺＝359.0921.

Melt point:123-124℃；

实施例十一

4-氯苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-(((4-氯苯基)磺酰基) (苯基)甲基)-1,3,5-三甲氧基苯的产率为90％。

¹H NMR(400MHz,CDCl₃):δ7.52–7.43(m,4H),7.31–7.25(m,2H),7.24–7.16(m,3H),6.08(s,1H),5.98(s,2H),3.72(s,3H),3.58(s,6H).

¹³C NMR(101MHz,CDCl₃):δ161.85,139.54,139.21,133.89,130.19,130.15,128.38,128.00, 127.79,103.82,92.88,91.02,68.04,55.57,55.31.

HRMS(ESI):calculated for C₂₂H₂₁ClO₅SNa[M+Na]⁺＝455.0696,foundC₂₂H₂₁ClO₅SNa [M+Na]⁺＝455.0695.

Melting point:125-126℃.

实施例十二

4-溴苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-(((4-溴苯基)磺酰基) (苯基)甲基)-1,3,5-三甲氧基苯的产率为80％。

¹H NMR(400MHz,CDCl₃)δ7.62–7.50(m,4H),7.53–7.45(m,2H),7.35–7.24(m,3H),6.17(s,1H),6.08(s,2H),3.81(s,3H),3.67(s,6H).

¹³C NMR(101MHz,CDCl₃):δ161.90,159.63,140.10,134.49,131.42,130.34,130.19,129.76, 129.02,128.06,127.86,103.80,92.91,91.05,68.08,55.61,55.36.

HRMS(ESI):calculated for C₂₂H₂₁BrO₅SNa[M+Na]⁺＝499.0191,foundC₂₂H₂₁BrO₅SNa[M +Na]⁺＝499.0149.

Melting point:127-128℃.

实施例十三

4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到1,3,5-三甲氧基-2-(苯基(对甲苯磺酰基)甲基)苯的产率为79％。

¹H NMR(400MHz,CDCl₃):δ7.61–7.50(m,4H),7.33–7.25(m,3H),7.20(dd,J＝7.4,1.3 Hz,2H),6.18(s,1H),6.08(s,2H),3.80(s,3H),3.67(s,6H),2.40(s,3H).

¹³C NMR(101MHz,CDCl₃):δ161.64,143.35,138.21,134.40,130.21,128.80,128.68,127.88, 127.58,104.34,91.05,67.80,55.61,55.30,21.51.

HRMS(ESI):calculated for C₂₃H₂₄O₅SNa[M+Na]⁺＝435.1242,found C₂₃H₂₄O₅SNa[M+ Na]⁺＝435.1228.

实施例十四

4-甲氧基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体1,3,5-三甲氧基-2-(((4- 甲氧基苯基)磺酰基)(苯基)甲基)苯的产率为75％。

¹H NMR(400MHz,CDCl₃):δ7.65–7.53(m,4H),7.33–7.22(m,3H),6.90–6.83(m,2H),6.17(s,1H),6.08(s,2H),3.83(d,J＝18.2Hz,6H),3.68(s,6H).

¹³C NMR(101MHz,CDCl₃):δ162.95,161.65,161.53,134.52,134.50,132.84,130.83,130.23, 129.76,129.02,127.91,127.58,113.36,104.48,92.91,91.09,67.94,55.68,55.57,55.33.

HRMS(ESI):calculated for C₂₃H₂₄O₆SNa[M+Na]⁺＝451.1191,found C₂₃H₂₄O₆SNa[M+ Na]⁺＝451.1187.

Melting point:120-121℃.

实施例十五

4-叔丁基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到黄色固体2-(((4-(叔丁基)苯基)磺酰基)(苯基)甲基)-1,3,5-三甲氧基苯的产率为76％。

¹H NMR(400MHz,CDCl₃):δ7.58(ddt,J＝9.0,4.3,2.7Hz,4H),7.44–7.37(m,2H),7.35– 7.23(m,3H),6.19(s,1H),6.05(s,2H),3.80(s,3H),3.63(s,6H),1.34(s,9H).

¹³C NMR(101MHz,CDCl₃):δ161.71,156.38,138.10,134.50,134.44,130.17,129.76,129.01, 128.55,128.45,127.87,127.53,125.59,125.15,104.34,92.91,91.02,67.59,55.60,55.34,55.32, 35.11,31.12,29.71.

HRMS(ESI):calculated for C₂₆H₃₀O₅SNa[M+Na]⁺＝477.1712,found C₂₆H₃₀O₅SNa[M+ Na]⁺＝477.1705.

Melting point:115-116℃.

实施例十六

叔丁基亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-((叔丁基磺酰基)(苯基)甲基)-1,3,5-三甲氧基苯的产率为75％。

¹H NMR(400MHz,CDCl₃):δ7.78–7.70(m,2H),7.26–7.11(m,3H),6.30(s,1H),6.05(t,J ＝1.9Hz,2H),3.83(s,3H),3.81(s,3H),3.70(s,3H),1.29(s,9H).

¹³C NMR(101MHz,CDCl₃):δ161.35,160.29,157.84,137.12,130.36,128.02,127.51,105.97, 91.71,91.07,62.36,57.62,56.18,55.77,55.31,24.18.

HRMS(ESI):calculated for C₂₀H₂₆O₅SNa[M+Na]⁺＝401.1399,found C₂₀H₂₆O₅SNa[M+ Na]⁺＝401.1383.

Melting point:112-113℃.

实施例十七

1,2,4-三甲氧基苯代替实施例一中的1,3,5-三甲氧基苯，得到1,2,4-三甲氧基-5-(苯基(苯基磺酰基)甲基)苯的产率为80％。

¹H NMR(400MHz,CDCl₃):δ7.70–7.57(m,5H),7.56–7.50(m,1H),7.42–7.29(m,5H),6.32(s,1H),6.03(s,1H),3.94(s,3H),3.85(s,3H),3.51(s,3H)；

¹³C NMR(101MHz,CDCl₃):δ151.64,149.97,143.14,138.84,133.34,133.16,129.99,128.86, 128.61,128.34,128.33,113.25,112.74,96.78,66.32,56.61,56.33,55.95.

HRMS(ESI):calculated for C₂₂H₂₂O₅SNa[M+Na]⁺＝421.1086,found C₂₂H₂₂O₅SNa[M+ Na]⁺＝421.1091.

实施例十八

1,3-二甲氧基苯代替实施例一中的1,3,5-三甲氧基苯，得到白色固体2,4-二甲氧基-1-(苯基(苯基磺酰基)甲基)苯的产率为69％。

¹H NMR(400MHz,CDCl₃):δ7.86(d,J＝8.7Hz,1H),7.59–7.52(m,2H),7.53–7.47(m,2H),7.47–7.40(m,1H),7.34–7.21(m,4H),7.19(s,1H),6.49(dd,J＝8.7,2.5Hz,1H),6.17(d,J ＝2.5Hz,1H),5.90(s,1H),3.71(s,3H),3.41(s,3H).

¹³C NMR(101MHz,CDCl₃)δ160.95,157.86,138.92,133.45,133.09,130.88,130.10,128.94, 128.53,128.27,128.25,114.13,109.99,104.67,98.24,66.32,55.37,55.34.

Melting point:111-112℃.

实施例十九

4-氯苯甲醛代替实施例一中的苯甲醛，4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-((4-氯苯基)(对甲苯磺酰基)甲基)-1,3,5-三甲氧基苯的产率为81％。

¹H NMR(400MHz,CDCl₃):δ7.61–7.47(m,4H),7.31–7.17(m,4H),6.11(s,1H),6.06(s, 2H),3.81(s,3H),3.76–3.54(s,6H),2.41(s,3H).

¹³C NMR(101MHz,CDCl₃):δ161.81,143.59,137.87,133.46,133.01,131.55,128.90,128.66, 128.01,103.76,91.02,66.86,55.61,55.31,21.52.

HRMS(ESI):calculated for C₂₃H₂₃ClO₅SNa[M+Na]⁺＝469.0852,foundC₂₃H₂₃ClO₅SNa [M+Na]⁺＝469.0830.

Melting point:108-109℃.

实施例二十

4-硝基苯甲醛代替实施例一中的苯甲醛，4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体1,3,5-三甲氧基-2-((4-硝基苯基)(对甲苯磺酰基)甲基)苯的产率为86％。

¹H NMR(400MHz,CDCl₃):δ8.09–8.01(m,2H),7.76–7.65(m,2H),7.50–7.40(m,2H),7.13(d,J＝8.0Hz,2H),6.11(s,1H),5.94(s,2H),3.71(s,3H),3.52(s,6H),2.32(s,3H).

¹³C NMR(101MHz,CDCl₃):δ162.25,146.93,144.03,142.37,137.25,130.83,128.99,128.72, 122.88,102.76,90.95,66.39,55.58,55.35,21.54.

HRMS(ESI):calculated for C₂₃H₂₃NO₇SNa[M+Na]⁺＝480.1093,found C₂₃H₂₃NO₇SNa[M +Na]⁺＝469.1061.

Melting point:133-134℃.

实施例二十一

2-吡啶甲醛代替实施例一中的苯甲醛，4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-(甲苯磺酰基(2,4,6-三甲氧基苯基)甲基)吡啶的产率为72％。

¹H NMR(400MHz,CDCl₃):δ8.44(ddd,J＝4.9,1.9,1.0Hz,1H),8.08(dt,J＝8.1,1.1Hz, 1H),7.66(td,J＝7.8,1.9Hz,1H),7.61–7.54(m,2H),7.20–7.16(m,2H),7.13(ddd,J＝7.5,4.9, 1.1Hz,1H),6.32(s,1H),5.99(s,2H),3.76(s,3H),3.52(s,6H),2.37(s,3H).

¹³C NMR(101MHz,CDCl₃):δ162.00,154.92,148.60,143.55,137.92,135.72,128.97,128.76, 125.15,122.14,102.97,91.02,68.71,55.55,55.28,21.51.

HRMS(ESI):calculated for C₂₂H₂₃NO₅SNa[M+Na]⁺＝436.1195,found C₂₂H₂₃NO₅SNa[M +Na]⁺＝436.1194.

Melting point:131-132℃.

实施例二十二

4-氯苯甲醛代替实施例一中的苯甲醛，4-氯苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-((4-氯苯基)((4-氯苯基)磺酰基)甲基)-1,3,5-三甲氧基苯的产率为93％。

¹H NMR(400MHz,CDCl₃):δ7.52–7.40(m,4H),7.33–7.25(m,2H),7.21–7.14(m,2H),6.01(s,1H),5.96(s,2H),3.71(s,3H),3.56(s,6H).

¹³C NMR(101MHz,CDCl₃)δ162.03,139.47,139.15,133.70,132.48,131.48,130.16,129.32, 128.50,128.13,127.19,103.18,90.97,67.04,55.58,55.34.

HRMS(ESI):calculated for C₂₂H₂₀Cl₂O₅SNa[M+Na]⁺m/z＝489.0306,foundC₂₂H₂₀Cl₂O₅SNa[M+Na]⁺m/z＝489.0322.

Melting point:133-134℃.

实施例二十三

2-溴-5-甲氧基苯甲醛代替实施例一中的苯甲醛，4-氯苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-((2-溴-5-甲氧基苯基)((4-氯苯基)磺酰基)甲基)-1,3,5-三甲氧基苯的产率为71％。

¹H NMR(400MHz,CDCl₃):δ8.02(d,J＝3.1Hz,1H),7.61–7.45(m,2H),7.39–7.28(m,2H),7.28–7.14(m,1H),6.64(dd,J＝8.8,3.1Hz,1H),6.27(s,1H),5.96(s,2H),3.78(s,3H),3.72 (s,3H),3.56(s,6H).

¹³C NMR(101MHz,CDCl₃)δ162.06,158.11,139.59,139.04,134.64,132.83,130.49,128.59, 118.51,115.97,115.54,102.34,91.05,66.20,55.57,55.47,55.28.

HRMS(ESI):calculated for C₂₃H₂₂BrClO₆SNa[M+Na]⁺m/z＝562.9907,foundC₂₂H₂₀Cl₂O₅SNa[M+Na]⁺m/z＝562.9906.

Melting point:161-162℃.

实施例二十四

4-氯苯甲醛代替实施例一中的苯甲醛，乙基亚磺酸钠代替实施例一中的苯亚磺酸钠，得到白色固体2-((4-氯苯基)(乙基磺酰基)甲基)-1,3,5-三甲氧基苯的产率为75％。

¹H NMR(400MHz,CDCl₃):δ7.54–7.45(m,2H),7.24–7.17(m,2H),6.10(s,2H),6.05(s, 1H),3.75(s,3H),3.73(s,6H),2.88(ddq,J＝45.8,13.7,7.5Hz,2H),1.22(t,J＝7.5Hz,3H).

¹³C NMR(101MHz,CDCl₃)δ161.91,133.80,132.53,131.11,128.37,103.49,91.36,65.15, 55.78,55.36,46.70,6.14.

HRMS(ESI):calculated for C₁₈H₂₁ClO₅SNa[M+Na]⁺＝407.0696,foundC₁₈H₂₁ClO₅SNa[M+Na]⁺＝407.0676.

Melting point:88-89℃.

实施例二十五

1,2,4-三甲氧基苯代替实施例一中的1,3,5-三甲氧基苯，4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到1,2,4-三甲氧基-5-(苯基(对甲苯磺酰基)甲基)苯的产率为80％。

¹H NMR(400MHz,CDCl₃):δ7.63–7.54(m,3H),7.54–7.48(m,2H),7.36–7.28(m,3H),7.16(d,J＝7.9Hz,2H),6.33(s,1H),5.98(s,1H),3.92(s,3H),3.84(s,3H),3.52(s,3H),2.37(s, 3H).

¹³C NMR(101MHz,CDCl₃):δ151.66,149.89,144.00,143.18,135.98,133.54,130.01,128.97, 128.88,128.54,128.25,113.26,97.03,66.40,56.61,56.44,55.97,21.54.

HRMS(ESI):calculated for C₂₃H₂₄O₅SNa[M+Na]⁺＝435.1242,found C₂₃H₂₄O₅SNa[M+ Na]⁺＝435.1225.

实施例二十六

1,2,4-三甲氧基苯代替实施例一中的1,3,5-三甲氧基苯，4-硝基苯甲醛代替实施例一中的苯甲醛，得到白色固体1,2,4-三甲氧基-5-((4-硝基苯基)(苯基磺酰基)甲基)苯的产率为89％。

¹H NMR(400MHz,CDCl₃):δ8.20–8.12(m,2H),7.83–7.71(m,2H),7.68–7.58(m,2H),7.59–7.49(m,1H),7.43(s,1H),7.37(t,J＝7.8Hz,2H),6.27(s,1H),6.08(s,1H),3.88(s,3H), 3.81(s,3H),3.45(s,3H).

¹³C NMR(101MHz,CDCl₃):δ151.66,150.53,147.60,143.32,140.85,138.28,133.65,130.88, 128.82,128.58,123.64,112.94,111.31,96.64,65.69,56.72,56.15,55.98.

HRMS(ESI):calculated for C₂₂H₂₀NO₇S[M-H]⁺＝442.0955,found C₂₂H₂₀NO₇S[M-H]⁺＝442.0951.

Melting point:160-161℃.

实施例二十七

1,2,4-三甲氧基苯代替实施例一中的1,3,5-三甲氧基苯，4-硝基苯甲醛代替实施例一中的苯甲醛，4-甲基苯亚磺酸钠代替实施例一中的苯亚磺酸钠，得到产物1,2,4-三甲氧基-5-((4- 硝基苯基)(对甲苯磺酰基)甲基)苯的产率为80％。

¹H NMR(400MHz,CDCl₃):δ8.21–8.09(m,2H),7.74(d,J＝8.8Hz,2H),7.53–7.48(m,2H),7.47(s,1H),7.21–7.13(m,2H),6.30(s,1H),6.04(s,1H),3.89(s,3H),3.82(s,3H),3.49(s, 3H),2.36(s,3H).

¹³C NMR(101MHz,CDCl₃)δ151.67,150.42,147.57,144.68,143.33,141.06,135.39,130.89, 129.24,128.84,123.60,112.87,111.63,96.81,65.79,56.70,56.25,55.99,21.59.

HRMS(ESI):calculated for C₂₃H₂₂NO₇S[M-H]⁺＝456.1111,found C₂₂H₂₀NO₇S[M-H]⁺＝456.1114。