CN111559976A - 一种杂芳基硫醚的合成方法 - Google Patents

一种杂芳基硫醚的合成方法 Download PDF

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CN111559976A
CN111559976A CN202010477913.8A CN202010477913A CN111559976A CN 111559976 A CN111559976 A CN 111559976A CN 202010477913 A CN202010477913 A CN 202010477913A CN 111559976 A CN111559976 A CN 111559976A
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CN111559976B (zh
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徐清
王�琦
章小兰
赵霖昱
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Yangzhou University
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    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

本发明公开了一种杂芳基硫醚的合成方法，其步骤为：在无催化剂、无溶剂、无添加剂等条件下，不使用常规有机硫化物如硫醇或硫酚，直接以卤代芳烃/2‑溴吡啶、硫脲和取代苄基溴为原料一步选择性合成非对称杂芳基硫醚。该方法避免了毒性大、臭味重的有机硫化物如硫醇或硫酚的使用，缩短了合成步骤，从而提高了合成效率，且反应具有很好的选择性，可以优先得到非对称硫醚。

Description

一种杂芳基硫醚的合成方法
技术领域
本发明涉及一种杂芳基硫醚的合成方法，属于有机硫化合物合成技术领域。
背景技术
有机硫化合物是一类非常重要的化合物，作为有机和药物合成的重要中间体，在催化、高分子材料和天然产物以及农药等领域有重要的用途。此外,各种硫醚结构广泛存在于具有各种生物和药物活性的分子中，比如治疗发炎、抗抑郁、人体免疫缺陷病毒，哮喘和老年痴呆等疾病。
然而，在前期工作中，反应体系中需要加入催化剂，助剂，或者添加剂等，产生较多废弃物。因此，寻找新的绿色简洁方法利用稳定低毒的原料一步合成非对称杂芳基硫醚化合物对有机合成、生化和药物化学家而言都是非常有意义的。
发明内容
本发明旨在提供一种无任何外加催化剂条件下，使用廉价易得的苄溴为烷基化试剂，使用常见的硫脲为硫源，与2-溴吡啶直接反应制备杂芳基硫醚的方法。
本发明技术方案是：一种杂芳基硫醚的合成方法，包括以卤代芳烃或2-溴吡啶、硫脲(也可以是硒脲)和取代苄基溴作为反应原料，选择性合成非对称杂芳基硫醚的步骤，
Method A
Figure BDA0002516431420000011
Method B
Figure BDA0002516431420000012
其中，FG是指卤代芳烃的取代官能团，优选甲基、氯；取代苄基溴中的R是指苯基、对甲基苯基、对硝基苯基、对氯苯基、肉桂基、萘基、环戊基、环己基以及环庚基等官能团。
较佳的，反应时间为2～24小时，反应温度为80～170℃。
较佳的，卤代芳烃或2-溴吡啶、硫脲和取代苄基溴三者的摩尔比为1:1.2:1.2。
较佳的，反应在有溶剂或无溶剂条件下进行。
较佳的，反应在惰性气体保护下或在空气下进行。
与现有技术相比，本发明的优点是：本方法避免了毒性大、臭味重的有机硫化物如硫醇或硫酚的使用，缩短了合成步骤，从而提高了合成效率，且反应具有很好的选择性，可以优先得到非对称硫醚，同时该反应无需任何外加催化剂、助剂、或添加剂。
下面结合具体实施方式对本发明做进一步介绍。
具体实施方式
下面的实施例对本发明进行更详细的阐述，而不是对本发明的进一步限定。
以2-溴吡啶、硫脲和苄溴为原料一步选择性合成非对称杂芳基硫醚的方法。该方法避免了毒性大、臭味重的有机硫化物如硫醇或硫酚的使用，缩短了合成步骤，从而提高了合成效率，且反应具有很好的选择性，可以优先得到非对称硫醚。该方法反应条件简单、无需惰性气体保护、无需溶剂、易于操作，对反应条件的要求较低。反应时间为2～24 小时，反应温度为80～170℃。
实施例1
2-溴吡啶、硫脲和苄溴制备2-吡啶基苯甲硫醚
Figure BDA0002516431420000021
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol,1.2equiv.)直接在空气下密封、无溶剂条件下加热80℃反应1h,然后加入苄溴(205.2mg,1.20mmol,1.2equiv.)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率76％。1H NMR(400MHz,CDCl3):δ8.47(d，J＝4.3Hz，1H),7.47-7.41 (m,3H),7.31(t,J＝7.4Hz，2H)，7.28-7.25(m,1H),7.15(d,J＝8.1Hz,1H)，6.99-6.94(m， 1H)，4.46(s，2H).13C NMR(100MHz，CDCl3):δ158.4，149.3，135.9，128.9，128.4,127.1, 122.0,119.5,34.4.MS(EI):m/z(％)201(48),168(100),154(2),124(10),121(4),91(58), 65(24),51(8).This compound was known:Jia X,Yu L,Liu J,Xu Q,Sickert M,Chen L,Lautens M,Green Chem,2014,16:3444-3449.
实施例2
2-溴吡啶、硫脲和4-甲基苄溴制备2-吡啶基(4-甲基)-苯甲硫醚
Figure BDA0002516431420000031
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入4-甲基苄溴在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率63％。1H NMR(400MHz,CDCl3):δ8.46(d,J＝4.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.31(d,J＝7.7 Hz,2H),7.13(dd,J＝14.9,7.9Hz,3H),6.99-6.95(m,1H),4.42(s,2H),2.33(s,3H).13C NMR(100MHz,CDCl3):δ159.0,149.3,135.9,134.7,129.1,128.8,122.0,119.5,34.2,21.1. MS(EI):m/z(％)215(68),182(85),167(30),105(100),79(45),51(15).This compound was known:Pathak AK,Pathak V,Seitz LE,Suling WJ,Reynolds RC,J Med Chem,2004,47: 273-276.
实施例3
2-溴吡啶、硫脲和3-甲基苄溴制备2-吡啶基(3-甲基)-苯甲硫醚
Figure BDA0002516431420000032
高压封管中依次加入硫脲(91.3mg,1.2mmol,1.2equiv.)和3-甲基苄溴(222.1mg,1.20mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入2-溴吡啶在170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率72％。1H NMR(400MHz,CDCl3):δ8.46(d,J＝4.6Hz,1H),7.48-7.44(m,1H), 7.24-7.13(m,4H),7.05(d,J＝6.7Hz,1H),7.01-6.95(m,1H),4.41(s,2H),2.32(s,3H).13C NMR(100MHz,CDCl3):δ158.9,149.3,138.1,137.6,135.9,129.6,128.3,127.8,125.9, 122.0,119.5,34.4,21.3.MS(EI):m/z(％)215(30),181(68),167(23),105(100),79(68),51 (32).Thiscompound was known:Pathak AK,Pathak V,Seitz LE,Suling WJ,Reynolds RC， J MedChem，2004,47:273-276.
实施例4
2-溴吡啶、硫脲和2-甲基苄溴制备2-吡啶基(2-甲基)-苯甲硫醚
Figure BDA0002516431420000041
高压封管中依次加入2-溴吡啶(158.0mg，1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封，无溶剂条件下加热80℃反应1h,然后加入2-甲基苄溴(222.1mg,1.20mmol,1.2equiv.)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率75％。1H NMR(400MHz,CDCl3):δ8.50(d,J＝4.8Hz,1H),7.46(t, J＝7.7Hz,1H),7.41(d,J＝7.1Hz,1H),7.21-7.14(m,4H),7.02-6.96(m,1H),4.49(s,2H), 2.45(s,3H).13C NMR(100MHz,CDCl3):δ159.1,149.4,136.9,135.9,135.4,130.4,129.9, 127.4,126.1,122.1,119.5,32.6,19.3.MS(EI):m/z(％)215(91),182(100),167(70),105 (100),79(71),51(22).This compound was known:Pathak AK,Pathak V,Seitz LE,Suling WJ,Reynolds RC,J Med Chem,2004,47:273-276.
实施例5
2-溴吡啶、硫脲和3-甲氧基苄溴制备2-吡啶基(3-甲氧基)-苯甲硫醚
Figure BDA0002516431420000042
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(152.4mg,2.0mmol,2.0equiv.)直接在空气下密封,无溶剂条件下80℃反应1h，然后加入4-甲氧基苄溴在140 ℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率46％。1H NMR(400MHz,CDCl3):δ8.45(d,J＝4.8Hz,1H),7.44(t,J＝7.7Hz,1H),7.18(t,J＝ 8.2Hz,1H),7.14(d,J＝8.0Hz,1H),6.99-6.95(m,3H),6.77(d,J＝8.3Hz,1H),4.42(s, 2H),3.76(s,3H).13C NMR(100MHz,CDCl3):δ159.2,158.7,149.3,139.5,135.9,129.4, 122.0,121.2,119.5,114.4,112.7,55.1,34.4.MS(EI):m/z(％)231(30),198(100),183(31), 121(68),91(58),78(75),65(32),51(34).This compound was known:Han X,Wu J,Org Lett,2010,12:5780-5782.
实施例6
2-溴吡啶、硫脲和4-硝基苄溴制备2-吡啶基(4-硝基)-苯甲硫醚
Figure BDA0002516431420000051
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入4-硝基苄溴在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率43％。1H NMR(400MHz,CDCl3):δ8.44(d,J＝4.1Hz,1H),8.12(d,J＝8.5Hz,2H),7.57(d,J＝8.4 Hz,2H),7.49(t,J＝7.3Hz，1H),7.16(d，J＝8.0Hz,1H),7.05-6.97(m,1H),4.51(s,2H). 13C NMR(100MHz,CDCl3):δ157.1，149.3，146.5，136.1，129.7，123.5，122.3，119.9，33.2. Calcd forC12H11N2O2S(M+H):247.0541；found:247.0529.This compound was known:Seto M,Miyamoto N,Aikawa K，Aramaki Y,Kanzaki N，Iizawa Y,Babab M,Shiraishia M, BioorgMed Chem,2005,13:363-386.
实施例7
2-溴吡啶、硫脲和4-氯苄溴制备2-吡啶基(4-氯)-苯甲硫醚
Figure BDA0002516431420000061
高压封管中依次加入硫脲(91.3mg,1.2mmol,1.2equiv.)和4-氯苄溴(246.6mg,1.20 mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入2-溴吡啶在 140℃继续反应29h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率71％。1HNMR(400MHz,CDCl3):δ8.43(d,J＝4.0Hz,1H),7.44(t,J＝7.7Hz,1H),7.33(d,J＝ 8.0Hz,2H),7.23(d,J＝8.2Hz,2H),7.13(d,J＝8.1Hz,1H),6.97(t,J＝6.1Hz,1H),4.39 (s,2H).13C NMR(100MHz,CDCl3):δ158.1,149.3,136.8,135.9,132.7,130.2,128.5,122.1,119.7,33.5.HRMS(ESI)for C12H11NSCl(M+H)Calcd:236.0301；found:236.0315.Thiscompound was known:Ma X,Yu L,Su C,Yang Y,Li H,Xu Q,Adv Synth Catal,2017,359:1-8.
实施例8
2-溴吡啶、硫脲和4-氯苄溴制备2-吡啶基-1-萘甲硫醚
Figure BDA0002516431420000062
高压封管中依次加入硫脲(91.3mg,1.2mmol,1.2equiv.)和1-溴甲基萘(265.3mg,1.20mmol,1.2equiv.),以及2equiv.H2O直接在空气下密封,无溶剂条件下80℃反应1h, 然后加入2-溴吡啶在140℃继续反应29h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率66％。1H NMR(400MHz,CDCl3):δ8.57-8.52(m,1H),8.19(d,J＝8.2 Hz,1H),7.87(d,J＝7.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.62(d,J＝6.9Hz,1H),7.57-7.49 (m,2H),7.47-7.36(m,2H),7.16(d,J＝8.0Hz,1H),7.02-6.99(t,J＝6.4Hz,1H),4.96(s, 2H).13C NMR(100MHz,CDCl3):δ159.0,149.4,135.9,133.2,131.7,128.7,128.1,127.5, 126.2,125.8,125.4,123.9,122.2,119.5,32.2.HRMS(ESI)for C16H14NS(M+H)Calcd: 252.0847；found:252.0862.This compound was known:Ma X,Yu L,Su C,Yang Y,Li H, Xu Q,Adv SynthCatal,2017,359:1-8.
实施例9
2-溴吡啶、硫脲和肉桂基溴制备2-吡啶基肉桂硫醚
Figure BDA0002516431420000071
高压封管中依次加入硫脲(152.4mg,2.0mmol,2.0equiv.)和肉桂基溴(265.3mg,1.20 mmol,1.2equiv.),以及2equiv H2O直接在空气下密封,无溶剂条件下80℃反应1h,然后加入2-溴吡啶(316.0mg,2.0mmol)在100℃继续反应29h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率61％。1H NMR(400MHz,CDCl3):δ8.46(d,J＝4.1Hz, 1H),7.46(m,1H),7.35-7.19(t,J＝8.0Hz,6H),7.01-6.96(m,1H),6.62(d,J＝6.0Hz,1H), 6.39-6.30(m,1H),4.02(dt,J＝7.2Hz,2H).13C NMR(100MHz,CDCl3):δ158.8,149.8, 137.2,136.3,133.0,128.8,127.8,126.7,125.7,122.7,119.9,33.0.MS(EI):m/z(％)227(56), 212(38),194(92),167(4),136(32),115(100),91(35),65(8),51(8).This compound wasknown:Santos SD,Quignard F,Sinou D，Choplin A,Top Catal，2000，13:311-318.
实施例10
2-溴吡啶、硫脲和正溴辛烷制备2-吡啶基苯乙硫醚
Figure BDA0002516431420000072
高压封管中依次加入2-溴吡啶(158.0mg，1.0mmol),硫脲(91.3mg,1.2mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入beta-溴代苯乙烷(222.1mg,1.2mmol)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率53％。1H NMR(400MHz,CDCl3):δ8.48(d,J＝4.6Hz,1H),7.46(t,J＝7.7Hz,1H),7.37-7.15(m,6H),7.00-6.95(m,1H),3.48-3.43(t,J＝7.8Hz,2H),3.05(t,J＝ 7.8Hz,2H).13C NMR(100MHz,CDCl3):δ158.9,149.5,140.5,135.8,128.6,128.4,126.3, 122.3,119.3,35.8,31.4.MS(EI):m/z(％)215(6),124(100),111(100),91(48),78(100),67(52),51(38).This compound was known:Ma X,Yu L,Su C,Yang Y,Li H,Xu Q,Adv SynthCatal,2017,359:1-8.
实施例11
2-溴吡啶、硫脲和(1-溴乙基)苯制备2-((1-苯基乙基)硫基)吡啶
Figure BDA0002516431420000081
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入(1-溴乙基)苯(164.4mg,1.2equiv.)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率48％。1H NMR(400MHz,CDCl3):δ8.45(d,J＝4.2Hz,1H),7.43(dd,J ＝22.0,7.8Hz,3H),7.31(t,J＝7.5Hz,2H),7.23(d,J＝7.0Hz,1H),7.10(d,J＝8.0Hz,1H), 6.97-6.93(m,1H),5.12(q,J＝7.0Hz,1H),1.76(d,J＝7.5Hz,3H).13C NMR(100MHz, CDCl3):δ158.8,149.4,143.2,135.9,128.4,127.3,122.7,119.6,43.5,22.6.MS(EI):m/z(％) 215(23),182(18),105(100),77(36),51(16).This compound was known:Qiao Z,Wei J,Jiang X，Org Lett,2014，16:1212-1215.
实施例12
2-溴吡啶、硫脲和1-溴丁烷制备2-吡啶基-1-丁硫醚
Figure BDA0002516431420000091
高压封管中依次加入硫脲(91.3mg,1.2mmol,1.2equiv.)和1-溴丁烷(164.4mg,1.20 mmol,1.2equiv.)直接在空气下密封,无溶剂条件下80℃反应1h,然后加入2-溴吡啶在 170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率61％。1HNMR(400MHz,CDCl3):δ8.39(d,J＝4.3Hz,1H),7.43(t,J＝7.7Hz,1H),7.13(d,J＝ 8.1Hz,1H),6.93(t,J＝6.1Hz,1H),3.14(t,J＝7.3Hz,2H),1.66(q,J＝7.3Hz,2H),1.45 (q,J＝7.3Hz,2H),0.92(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3):δ159.6,149.3, 135.7,122.0,119.0,31.4,29.8,22.0,13.6.MS(EI):m/z(％)167(21),138(64),125(100), 111(74),78(88),67(66),51(32).This compound was known:Guo F,Sun J,Xu Z,Kühn FE, Zang S,Zhou M,Catal Commun,2017,96:11-14.
实施例13
2-溴吡啶、硫脲和1-溴己烷制备2-吡啶基-1-己硫醚
Figure BDA0002516431420000092
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入1-溴己烷(198.1 mg,1.2equiv)在170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率58％。1H NMR(400MHz,CDCl3):δ8.39(d,J＝4.6Hz,1H),7.42(t,J＝7.7Hz, 1H),7.13(d,J＝8.0Hz,1H),6.95-6.89(t,J＝6.2Hz,1H),3.13(t,J＝7.4Hz,2H),1.71-1.65 (m,2H),1.47-1.22(m,8H),0.87(m,3H).13C NMR(100MHz,CDCl3):δ159.5,149.3,135.7, 122.0,119.0,31.3,30.1,29.2,28.6,22.5,14.0.MS(EI):m/z(％)195(40),138(94),125 (100),111(100),78(58),67(42),51(14).This compound was known:Du B，Quan Z,Da Y, Zhang Y,Wang X,Adv Synth Catal,2015,357:1270-1276.
实施例14
2-溴吡啶、硫脲和正溴辛烷制备2-吡啶基-1-辛硫醚
Figure BDA0002516431420000101
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg，1.2mmol，1.2equiv.)直接在空气下密封，无溶剂条件下加热80℃反应1h，然后加入1-溴辛烷(231.8mg,1.2equiv)在170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率63％。1H NMR(400MHz,CDCl3):δ8.38(d,J＝4.0Hz,1H),7.41(t,J＝7.6Hz, 1H),7.12(d,J＝8.1Hz,1H),6.91(t,J＝6.1Hz,1H),3.13(t,J＝7.3Hz,2H),1.67(q,J＝ 7.5Hz,2H),1.44-1.20(m,13H),0.85(t,J＝6.1Hz,3H).13C NMR(100MHz,CDCl3):δ 159.6,149.3,135.6,122.0,119.0,31.7,30.1,29.3,29.1,28.9,22.6,14.0.MS(EI):m/z(％) 223(26),190(10),176(13),138(58),125(95),111(100),106(18),78(31),67(22),55(7). Thiscompound was known:Duan Z,Ranjit S，Zhang P,Liu X,Chem Eur J，2009,15: 3666-3669.
实施例15
2-溴吡啶、硫脲和1-溴癸烷制备2-吡啶基-1-癸硫醚
Figure BDA0002516431420000102
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封，无溶剂条件下加热80℃反应1h，然后加入1-溴癸烷(265.4mg，1.2equiv)在170℃继续反应23h。经TLC监测反应完全后，产物用柱色谱分离提纯。分离收率69％。1H NMR(400MHz,CDCl3):δ8.37(d,J＝3.6Hz,1H),7.39(t，J＝15.4Hz， 1H),7.10(d，J＝8.1Hz，1H),6.89(t,J＝6.1Hz,1H),3.12(t,J＝7.4Hz,2H),1.67(p,2H)， 1.44-1.36(m,2H),1.23(s,12H),0.84(t,J＝6.2Hz,3H).13C NMR(100MHz,CDCl3):δ 159.6,149.3,135.6,122.0,119.0,31.8,30.0,29.5,29.4,29.3,29.2,29.1,28.9,22.6,14.0.MS (EI):m/z(％)251(6),218(4),204(6),190(4),138(54),125(94),111(100),78(46),67(26), 55(18).This compound was known:Brussaard Y,Olbrich F,Schaumann E,Inorg Chem,2013,52:13160-13166.
实施例16
2-溴吡啶、硫脲和溴代环庚烷制备2-吡啶基环庚基硫醚
Figure BDA0002516431420000111
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入溴代环庚烷(212.5mg,1.2equiv)在170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率42％。1H NMR(400MHz,CDCl3):δ8.39(d,J＝4.6Hz,1H),7.43-7.39 (m,1H),7.10(d,J＝8.1Hz,1H),6.92-6.89(m,1H),3.97-3.90(m,1H),2.08-2.01(m,2H), 1.70-1.54(m,10H).13C NMR(100MHz,CDCl3):δ159.6,149.4,135.7,122.7,119.1,44.5, 34.8,28.3,25.9.Calcd for C12H18NS(M+H):208.1160；found:208.1155.
实施例17
2-溴吡啶、硫脲和溴代环己烷制备2-吡啶基环己基硫醚
Figure BDA0002516431420000112
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入溴代环己烷(195.7mg,1.2equiv)在170℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率37％。1H NMR(400MHz,CDCl3):δ8.44-8.39(d,J＝3.2Hz,1H),7.45(t, J＝6.9Hz,1H),7.15(d,J＝8.0Hz,1H),6.98-6.93(m,1H),3.86-3.77(m,1H),2.07-2.05(m,2H),1.82-1.39(m,8H).13C NMR(100MHz,CDCl3):δ149.4,135.8,122.8,119.2,42.9,33.2,25.9.MS(EI):m/z(％)193(4),160(22),138(20),111(100),78(52),67(88),55(56), 51(48),41(82).This compound was known:Zhao J,Fang H,Han J,Pan Y,Li G，Adv SynthCatal,2014,356:2719-2724.
实施例18
2-溴吡啶、硫脲和溴代环戊烷制备2-吡啶基环戊基硫醚
Figure BDA0002516431420000121
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入溴代环戊烷(178.8mg，1.2equiv)在170℃继续反应23h。经TLC监测反应完全后，产物用柱色谱分离提纯。分离收率61％。1H NMR(400MHz,CDCl3):δ8.43-8.39(m，1H)，7.45(t，J＝7.2Hz， 1H)，7.15(d,J＝7.9Hz，1H),6.97-6.92(m,1H),4.02(q,J＝6.4Hz,1H),2.18-2.10(m,2H),1.79-1.59(m,6H).13C NMR(100MHz,CDCl3):δ160.4,149.4,135.7,122.1,119.0,42.9,33.4,24.8.Calcd for C10H14NS(M+H):180.0847；found:180.0866.
实施例19
2-溴吡啶、硫脲和2-溴乙基乙基醚制备2-吡啶基(2-乙氧基)乙基硫醚
Figure BDA0002516431420000122
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入2-溴乙基乙基醚(183.6mg,1.2equiv)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率16％。1H NMR(400MHz,CDCl3):δ8.38(d,J＝4.0Hz,1H),7.43(t,J ＝7.7Hz,1H),7.15(d,J＝8.0Hz,1H),6.93(t,J＝6.0Hz,1H),3.67(t,J＝6.6Hz,2H), 3.54-3.50(m,2H),3.37(t,J＝6.6Hz,2H),1.19(t,J＝6.9Hz,3H).13C NMR(100MHz， CDCl3):δ158.5，149.3,135.7，122.2，119.3，69.3,66.2,29.3,15.1.Calcd for C9H14NOS (M+H):184.0796；found:184.0799.This compound was known:Ma X,Yu L,Su C，Yang Y, Li H,Xu Q,AdvSynth Catal,2017,359:1-8.
实施例20
2-溴吡啶、硫脲和溴甲基环已烷制备2-吡啶基环己基甲基硫醚
Figure BDA0002516431420000131
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入溴甲基环己烷(212.5mg,1.2equiv)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率42％。1H NMR(400MHz,CDCl3):δ8.38(d,J＝4.3Hz,1H),7.42(t,J＝ 7.7Hz,1H),7.14(d,J＝8.1Hz,1H),6.94(t,J＝6.4Hz,1H),3.06(d,J＝6.8Hz,2H),1.88 (d,J＝12.8Hz,2H),1.72-1.59(m,4H),1.19(dq,J＝21.6,11.8Hz,4H),1.00(q,J＝12.1Hz, 2H).13C NMR(100MHz,CDCl3):δ159.8,149.2,135.7,122.0,119.0,37.7,37.0,32.7,26.3,26.0.MS(EI):m/z(％)207(10),174(22),160(21),125(86),111(100),78(25),67(26),55(20).This compound was known:Ma X,Yu L,Su C,Yang Y,Li H,Xu Q,Adv Synth Catal,2017,359:1-8.
实施例21
2-溴吡啶、硫脲和溴代叔丁烷制备2-吡啶基叔丁基硫醚
Figure BDA0002516431420000141
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol)，硫脲(91.3mg，1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入溴代叔丁烷(164.4mg,1.2equiv)在140℃继续反应23h。经TLC监测反应完全后，产物用柱色谱分离提纯。分离收率43％。1H NMR(400MHz，CDCl3):δ8.45(d,J＝4.2Hz,1H),7.43(dd,J ＝22.0,7.8Hz，3H)，7.31(t,J＝7.5Hz,2H),7.23(d,J＝7.0Hz,1H),7.10(d,J＝8.0Hz,1H), 6.97-6.93(m,1H),5.12(q,J＝7.0Hz,1H),1.76(d,J＝7.5Hz,3H).13C NMR(100MHz, CDCl3):δ158.8,149.4,143.2,135.9，128.4,127.3,122.7,119.6，43.5，22.6.MS(EI):m/z(％) 215(23),182(18),105(100),77(36),51(16).This compound was known:Qiao Z,Wei J,Jiang X,Org Lett,2014,16:1212-1215.
实施例22
2-溴-5-甲基吡啶、硫脲和苄溴制备2-(5-甲基)吡啶基苯甲硫醚
Figure BDA0002516431420000142
高压封管中依次加入2-溴-5-甲基吡啶(172.0mg,1.0mmol),硫脲(91.3mg,1.2mmol，1.2equiv.)直接在空气下密封,无溶剂条件下加热120℃反应1h,然后加入苄溴(205.2mg,1.2equiv)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率82％。1H NMR(400MHz,CDCl3):δ8.30(s,1H),7.40(d,J＝7.6Hz,2H), 7.25(dd,J＝19.0,7.1Hz,4H),7.06(d,J＝8.1Hz,1H),4.42(s,2H),2.26(s,3H).13C NMR (100MHz,CDCl3):δ155.2,149.6,138.1,136.9,128.9,128.4,127.0,121.7,34.7,17.8.MS (EI):m/z(％)215(100),182(100),167(28),138(46),91(100),65(74),53(14).This compound wasknown:Ma X,Yu L,Su C,Yang Y，Li H,Xu Q,Adv Synth Catal，2017，359: 1-8.
实施例23
2-溴-4-甲基吡啶、硫脲和苄溴制备2-(4-甲基)吡啶基苯甲硫醚
Figure BDA0002516431420000151
高压封管中依次加入2-溴-4-甲基吡啶(172.0mg,1.0mmol),硫脲(91.3mg,1.2mmol, 1.2equiv.)直接在空气下密封,无溶剂条件下加热120℃反应1h,然后加入苄溴(205.2 mg,1.2equiv)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率62％。1H NMR(400MHz,CDCl3):δ8.32(d,J＝5.1Hz,1H),7.40(d,J＝7.4Hz,2H),7.29(t,J＝7.4Hz,2H),7.23(d,J＝7.2Hz,1H),6.99(s,1H),6.81(d,J＝4.9Hz,1H),4.44(s,2H),2.25(s,3H).13C NMR(100MHz,CDCl3):δ158.4,148.9,147.1,138.0,128.9,128.4,127.0,122.5,121.0,34.4,20.8.MS(EI):m/z(％)215(82),182(100),181(5),154(3), 138(5),91(60),65(44)，53(5).This compound was known:Nishida H，Arikawa Y，Fujimori I,Bioorg Med Chem,2017,25:3447-3460.
实施例24
2-溴-5-氯吡啶、硫脲和苄溴制备5-氯吡啶基苯甲硫醚
Figure BDA0002516431420000152
高压封管中依次加入硫脲(91.3mg,1.2mmol，1.2equiv.)和苄溴(205.2mg,1.20mmol,1.2equiv.),直接在空气下密封,无溶剂条件下80℃反应1h,然后加入2-溴-5-氯吡啶(192.4mg,1.0mmol)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率77％。1H NMR(400MHz,CDCl3):δ8.42(s,1H),7.40(t,J＝7.9Hz, 3H),7.31(t,J＝7.2Hz,2H),7.25(d,J＝6.5Hz,1H),7.09(d,J＝8.5Hz,1H),4.41(s,2H). 13C NMR(100MHz,CDCl3):δ156.9,148.0,137.6,135.8,128.9,128.5,127.2,122.6,34.6. MS(EI):m/z(％)235(35),202(58),167(7),144(3),113(3),91(100),65(26),51(4).This compound wasknown:Nishida H,Arikawa Y,Fujimori I,Bioorg Med Chem,2017,25: 3447-3460.
实施例25
2-溴吡啶、硒脲和苄溴制备2-吡啶基苯甲硒醚
Figure BDA0002516431420000161
高压封管中依次加入2-溴吡啶(158.0mg,1.0mmol),硒脲(147.6mg,1.2mmol,1.2equiv.)直接在空气下密封,无溶剂条件下加热80℃反应1h,然后加入苄溴(205.2 mg,1.20mmol,1.2equiv.)在140℃继续反应23h。经TLC监测反应完全后,产物用柱色谱分离提纯。分离收率23％。1H NMR(400MHz,CDCl3):δ8.50(d,J＝4.3Hz,1H), 7.45-7.37(m,3H),7.27(t,J＝8.9Hz,3H),7.20(t,J＝7.2Hz,1H),7.05-7.01(t,J＝6.0Hz, 1H),4.47(s,2H).13C NMR(100MHz,CDCl3):δ155.6,150.0,139.0,135.9,129.0,128.5, 126.8,125.4,120.4,29.3.MS(EI):m/z(％)249(18),168(100),91(100),65(54),51(18). Thiscompound was known:Thurow S,Webber R,Perin G,
Figure BDA0002516431420000162
EJ,Alves D, TetrahedronLett,2013,54:3215-3218。

Claims (5)

1.一种杂芳基硫醚的合成方法，其特征在于，包括以卤代芳烃/2-溴吡啶、硫脲和取代苄基溴作为反应原料，选择性合成非对称杂芳基硫醚的步骤，
Method A
Figure FDA0002516431410000011
Method B
Figure FDA0002516431410000012
其中，FG为甲基、氯；R为苯基、对甲基苯基、对硝基苯基、对氯苯基、肉桂基、萘基、环戊基、环己基或环庚基。
2.如权利要求1所述的方法，其特征在于，反应时间为2～24小时，反应温度为80～170℃。
3.如权利要求1所述的方法，其特征在于，卤代芳烃/2-溴吡啶、硫脲和取代苄基溴三者的摩尔比为1:1.2:1.2。
4.如权利要求1所述的方法，其特征在于，反应在有溶剂或无溶剂条件下进行。
5.如权利要求1所述的方法，其特征在于，反应在惰性气体保护下或在空气下进行。
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