CN115322128B - 一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用 - Google Patents

一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用 Download PDF

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CN115322128B
CN115322128B CN202210938986.1A CN202210938986A CN115322128B CN 115322128 B CN115322128 B CN 115322128B CN 202210938986 A CN202210938986 A CN 202210938986A CN 115322128 B CN115322128 B CN 115322128B
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陈良安
裴盼
赵旻
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Nanjing Normal University
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Abstract

本发明公开了一种基于烷基卤代物合成C(sp3)‑S键的有机硫化合物及其制备方法与应用。在有机溶剂中，以甲酸硫酯为硫源、廉价金属单质为催化剂，与非活化的卤代烷烃偶联构建C(sp3)‑S键的硫化合物。本发明开发了一种低毒廉价、稳定且原子经济性高的硫源试剂，使用催化量的廉价金属作为催化剂，该金属催化剂廉价易得、催化效率高、成本低廉，适合开展大规模的生产应用；反应条件温和，选择性高；底物官能团兼容性好且适用范围广、天然产物及药物分子也可以兼容，在合成药物和工业领域上都具有重要的实际应用价值；在优化条件之下，C(sp3)‑S键的有机硫化合物的产率高达90%。

Description

一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制 备方法与应用
技术领域
本发明属于催化合成技术和均相金属催化偶联合成领域，具体涉及一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用。
背景技术
C(sp3)-S键是有机化学中的基本结构单元，它广泛存在于天然产物、药物分子和先进材料中，具有很高的应用价值。例如：从灰色链霉菌中分离出的Griseoviridin是Streptogramin抗生素的代表性成员；Viracept与其它成分一起被用作抗人类免疫缺陷病毒药物；Penicillin V(抗生素)、Nelfinavir(抗病毒药物)、Cimetidine(消化***药物)与Celesticetin(天然产物)等等，因此，构建C(sp3)-S键是有机合成领域的研究热点。
早期C-S键的合成往往局限于金属硫代盐和有机卤化物之间的缩合反应，其中烷基卤代物与硫醇的亲核取代反应是形成C(sp3)-S键的最经典方法，但是此类反应需要高温、强碱；底物大多仅限于伯卤代物；产率低；硫醇气味难闻且具有高毒性等缺点。除此之外，在构建C-S键的领域中，硫源主要是硫醇、二硫化物、磺酰氯、磺酰肼、硫化钠/钾、硫代磺酸盐等硫试剂。尽管这些硫源试剂都已经得到了很好的应用，但目前为止，报道过的这些有机/无机硫源试剂大多数都存在着活性低、刺激性气味、毒性大以及官能团兼容性差等问题。所以，寻找一种反应活性高、廉价易得且操作简便的硫源试剂被认为是构建C(sp3)-S键的重点发展方向之一。
甲酸硫酯作为通用的甲酰化试剂，在过渡金属催化反应中构建C-C键具有广泛的应用，最突出的优点是，可以从多种廉价易得的工业起始原料中制得，易于处理，稳定性高，原子经济性高。但是目前，在过渡金属催化的交叉偶联反应中，甲酸硫酯作为构建C(sp3)-S键的硫源试剂未见报道。因此，将其开发为环境友好，廉价易得和操作简便的硫源试剂来合成在药物和工业上用途广泛的硫化合物具有重要的实际应用价值。
通过文献调研，发现在诸多构建C-S键的策略中，光催化反应和过渡金属催化反应已然成为主流，主要是发展构建C(sp2)-S键的反应，但是，由于大多数的反应均需使用对水和空气敏感的有机金属试剂，会导致β-氢化物的消除和均二聚，使得C(sp3)-S键的构建十分困难；同时也存在着反应条件苛刻、还原剂使用过量、金属催化剂成本过高等问题。除此之外，在当量廉价金属反应中，CO2、异氰酸酯和酰氯等亲电试剂已经成功地与烷基卤化物偶联得到C(sp2)-S键的硫化合物，然而关于通过廉价金属催化的偶联反应形成C(sp3)-S键的报道少之又少。
发明内容
针对现有技术的不足，本发明提供了一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用，打破过去当量金属的使用，首次提出以催化量的廉价金属作为催化剂，该类廉价金属催化剂将非活化的伯/仲卤代烃与另一个新开发硫源试剂偶联构建C(sp3)-S键。解决了现有C(sp3)-S键的硫化合物的合成反应条件苛刻、反应产率较低、官能团相容性差；硫源试剂具有高毒性和刺激性气味、贵金属催化剂的使用；不环保、不安全、不经济的问题。实现了一种成本低廉、催化效率高的合成方法，同时也为现有C(sp3)-S键的有机硫化合物的合成提供一种很好的补充方法。
为解决现有技术问题，本发明采取的技术方案为
一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，包括如下步骤：在N2氛围下，以甲酸硫酯为硫源、廉价金属单质为金属催化剂，非活化卤代烷烃/>为亲电试剂，在有机溶剂中，在温度为30-100℃下反应8-24小时，反应结束后，依次经过淬灭，萃取，减压蒸馏，分离纯化，合成得到C(sp3)-S键的硫化合物，其中，R任意选自C1-C20的直链烷基，C3-C20环烷基，取代或非取代的苯基、联苯基、荼基、蔥基或菲基。
反应通式表示如下：1°and2°alkyl halides
作为优选的是，当非活化的卤代烷烃为作为亲电试剂时，所述非活化卤代烷烃、甲酸硫酯与金属催化剂的摩尔比为1:(1-2):(0.1-0.9)。
作为优选的是，所述的有机溶剂的浓度为0.2-1M。
作为优选的是，所述反应的温度为60-100℃。
作为改进的是，所述的非活化卤代烷烃中的R1选自氢；R2和R3可以相同也可以不相同，当R2与R3相同时，R2和R3可以独立任意选自C1-C20直链烷基、C1-C20卤取代烷基，C1-C20硼酸烷基，C1-C20烷基羰基、硝基、羟基、酯基、羧基或氰基，C1-C20烷氨基羰基，C3-C20的含杂原子环烷基、类固醇基、糖基或者核苷基，其中，所述杂原子为N、O或S；当R2与R3不相同时，R2选自氢、R3任意选自C1-C20直链烷基，C1-C20卤取代烷基，C1-C20硼酸烷基，C1-C20烷基羰基、硝基、羟基、酯基、羧基或者氰基，C1-C20烷氨基羰基；X为Cl，Br或I。
作为优选的是，所述金属催化剂选自锰粉、锌粉、铁粉、铜粉或双-(1,5-环辛二烯)镍中一种。
作为优选的是，所述有机溶剂选二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N-二甲酰胺、N,N-二乙酰胺、乙酸乙酯、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、环戊基二甲醚、1,3-二甲基-2-咪唑啉酮中一种。
上述任一种方法制备得到的C(sp3)-S键的有机硫化合物。
上述任一种C(sp3)-S键的有机硫化合物在制备新兴药物，或修饰生物活性分子及天然产物上的应用。
有益效果：
与现有技术相比，本发明一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物及其制备方法与应用，首次提出使用催化量的廉价金属催化剂，具有催化效率高、环境友好、成本低廉等特点，这种金属催化剂可使甲酸硫酯的C-S键的区域选择性断裂产生硫自由基，再与非活化卤代烷烃发生偶联反应，合成C(sp3)-S键的有机硫化物。具有如下优点：
(1)本发明只需一步反应，在优化的反应条件之下，目标产品分离后产率可高达90％以上，且打破了以往烷基卤化物与硫醇的取代反应仅限于伯卤代物的缺陷，底物官能团兼容性好，且可适用于复杂药物分子的修饰；
(2)本发明打破了过去当量金属的使用，首次提出以催化量的廉价金属作为催化剂实现了C(sp3)-S键的构建，是一种更加高效且经济的合成有机硫化物的方法；
(3)本发明提供的甲酸硫酯可以从多种廉价易得的起始试剂中制得，来源广泛，易于处理，稳定性高且原子经济性高。迄今为止，在过渡金属催化的交叉偶联反应中，甲酸硫酯作为构建C(sp3)-S键的硫源试剂未见报道。本发明通过选择性断裂C-S键，首次将其开发为一种廉价易得、环境友好的新型硫源试剂，为现有的C(sp3)-S键的构建提供了一种很好的补充方法；
(4)本发明的方法合成的C(sp3)-S键的有机硫化物为重要的有机中间体，广泛应用于医药中间体和生物领域。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实施例所描述的内容仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径或通过现有技术简单制备获得。
实施例1
氮气保护下，10mL反应瓶中依次加入锰粉(0.15mmol)，仲卤代烷烃1a(0.3mmol)，甲酸芳基硫酯2a(0.36mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应16h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物1，1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),7.32–7.27(m,2H),7.25–7.15(m,3H),6.91–6.84(m,2H),3.81(s,3H),3.12–3.03(m,2H),2.91–2.84(m,2H).13C NMR(100MHz,CDCl3):δ159.06,140.50,133.40,128.64,128.59,126.47,126.41,114.72,55.48,37.38,36.04.其产率94％。
实施例2
氮气保护下，10mL反应瓶中依次加入锌粉(0.15mmol)，伯卤代烷烃1b(0.3mmol)，甲酸芳基硫酯2a(0.38mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在65℃下反应12h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物2，1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),7.32–7.27(m,2H),7.25–7.15(m,3H),6.91–6.84(m,2H),3.81(s,3H),3.12–3.03(m,2H),2.91–2.84(m,2H).13C NMR(100MHz,CDCl3):δ159.06,140.50,133.40,128.64,128.59,126.47,126.41,114.72,55.48,37.38,36.04.其产率90％。
实施例3
氮气保护下，10mL反应瓶中依次加入铜粉(0.15mmol)，伯卤代烷烃1c(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和N,N-二乙酰胺(0.9mL)。室温下混合均匀后，反应混合物在80℃下反应13h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝300:1)，得到相应的产物3，1H NMR(400MHz,CDCl3):δ7.40–7.33(m,2H),7.28(dd,J＝7.3,6.1Hz,2H),6.94(s,1H),6.90–6.81(m,4H),4.05(t,J＝6.1Hz,2H),3.79(s,3H),3.01(t,J＝7.1Hz,2H),2.09–2.00(m,2H).13C NMR(100MHz,CDCl3):δ159.05,158.93,133.37,129.56,126.24,120.82,114.72,114.60,66.02,55.47,32.49,29.17.其产率89％。
实施例4
氮气保护下，10mL反应瓶中依次加入锰粉(0.18mmol)，伯卤代烷烃1d(0.3mmol)，甲酸芳基硫酯2a(0.38mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应16h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物4，1H NMR(400MHz,CDCl3):δ7.38–7.31(m,2H),6.88–6.81(m,2H),4.48(t,J＝6.1Hz,1H),4.36(t,J＝6.0Hz,1H),3.80(s,3H),2.87–2.78(m,2H),1.75–1.64(m,2H),1.63–1.56(m,2H),1.56–1.47(m,2H).13C NMR(100MHz,CDCl3):δ158.96,133.27,126.65,114.65,84.86,83.22,55.47,35.81,30.20,30.00,29.04,24.45,24.39.19F NMR(376MHz,CDCl3):δ-218.33.其产率85％。
实施例5
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，伯卤代烷烃1e(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和二甲亚砜(0.9mL)。室温下混合均匀后，反应混合物在100℃下反应18h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物5，1H NMR(400MHz,CDCl3):δ7.37–7.29(m,2H),6.87–6.80(m,2H),4.11(q,J＝7.1Hz,2H),3.79(s,3H),2.85–2.78(m,2H),2.27(t,J＝7.5Hz,2H),1.66–1.60(m,2H),1.59–1.54(m,2H),1.49–1.38(m,2H),1.25(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3):δ173.77,158.94,133.24,126.75,114.65,60.38,55.47,35.78,34.33,29.10,28.26,24.66,14.39.其产率90％。
实施例6
氮气保护下，10mL反应瓶中依次加入锌粉(0.18mmol)，伯卤代烷烃1f(0.3mmol)，甲酸芳基硫酯2a(0.35mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应18h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物6，1H NMR(400MHz,CDCl3):δ7.38–7.30(m,2H),6.88–6.81(m,2H),3.79(s,3H),2.83(t,J＝6.8Hz,2H),2.33(t,J＝6.9Hz,2H),1.83–1.67(m,4H).13C NMR(100MHz,CDCl3):δ159.21,133.66,125.81,119.50,114.75,77.48,77.16,76.84,55.44,35.13,28.18,24.22,16.90.其产率63％。
实施例7
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，伯卤代烷烃1g(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在80℃下反应13h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物7，1H NMR(400MHz,CDCl3):δ8.11(d,J＝2.3Hz,1H),7.89(dd,J＝7.7,1.2Hz,1H),7.56(td,J＝7.4,1.4Hz,1H),7.50–7.40(m,2H),7.39–7.29(m,3H),7.02(t,J＝7.7Hz,1H),6.86–6.81(m,2H),5.18(s,2H),4.08(t,J＝6.7Hz,2H),3.79(s,3H),3.63(s,2H),2.82–2.76(m,2H),1.65–1.59(m,2H),1.58–1.52(m,2H),1.44–1.36(m,2H),1.35–1.27(m,2H).13C NMR(100MHz,CDCl3):δ191.00,171.63,160.58,158.88,140.59,136.48,135.67,133.13,132.91,132.56,129.61,129.41,128.06,127.95,126.85,125.23,121.16,114.63,73.77,65.11,55.47,40.42,35.81,29.31,28.57,28.36,25.60.其产率70％。
实施例8
氮气保护下，10mL反应瓶中依次加入双-(1,5-环辛二烯)镍(0.24mmol)，伯卤代烷烃1h(0.3mmol)，甲酸芳基硫酯2a(0.38mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应13h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝10:1)，得到相应的产物8，1H NMR(400MHz,CDCl3):δ7.38–7.30(m,2H),6.88–6.81(m,2H),3.79(s,3H),2.83(t,J＝6.8Hz,2H),2.33(t,J＝6.9Hz,2H),1.83–1.67(m,4H).13C NMR(100MHz,CDCl3):δ159.21,133.66,125.81,119.50,114.75,77.48,77.16,76.84,55.44,35.13,28.18,24.22,16.90.其产率40％。
实施例9
氮气保护下，10mL反应瓶中依次加入锌粉(0.18mmol)，伯卤代烷烃1i(0.3mmol)，甲酸芳基硫酯2a(0.3mmol)和N-甲基吡咯烷酮(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应13h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物9，1H NMR(400MHz,CDCl3):δ7.37–7.29(m,2H),6.88–6.79(m,2H),3.79(s,3H),3.61(t,J＝6.4Hz,2H),2.85–2.79(m,2H),1.63–1.52(m,4H),1.51–1.42(m,3H).13CNMR(100MHz,CDCl3):δ158.89,133.14,126.76,114.63,62.84,55.44,35.86,32.35,29.18,24.92.其产率85％。
实施例10
氮气保护下，10mL反应瓶中依次加入双-(1,5-环辛二烯)镍(0.20mmol)，仲卤代烷烃1j(0.3mmol)，甲酸芳基硫酯2a(0.30mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在60℃下反应15h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝200:1)，得到相应的产物10，1H NMR(400MHz,CDCl3):δ7.39–7.34(m,2H),7.31–7.25(m,2H),7.21–7.14(m,3H),6.85–6.79(m,2H),3.80(s,3H),2.99–2.88(m,1H),2.82(dt,J＝8.8,4.2Hz,1H),2.72(ddd,J＝13.7,9.9,6.6Hz,1H),1.98–1.87(m,2H),1.81–1.69(m,1H),1.01(d,J＝6.8Hz,3H),0.95(d,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3):δ159.10,142.24,134.84,128.60,128.47,126.99,125.93,114.56,57.86,55.45,33.89,33.41,31.63,19.56,19.20.其产率60％。
实施例11
氮气保护下，10mL反应瓶中依次加入锰粉(0.27mmol)，仲卤代烷烃1k(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应15h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物11，1H NMR(400MHz,CDCl3):δ7.40–7.34(m,2H),7.30–7.24(m,2H),7.21–7.14(m,3H),6.86–6.82(m,2H),3.81(s,3H),2.92–2.76(m,3H),1.86–1.77(m,2H),1.56–1.46(m,4H),0.89(t,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3):δ159.44,142.19,135.79,128.58,128.47,125.91,125.03,114.48,55.44,49.57,36.78,36.14,33.05,20.13,14.10.其产率65％。
实施例12
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，伯卤代烷烃1l(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应13h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物12，1H NMR(400MHz,CDCl3):δ7.41–7.34(m,2H),7.30–7.25(m,2H),7.21–7.14(m,3H),6.87–6.79(m,2H),3.81(s,3H),2.91–2.73(m,3H),1.86–1.76(m,2H),1.58–1.51(m,2H),1.50–1.39(m,2H),1.34–1.23(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3):δ159.43,142.19,135.80,128.58,128.47,125.91,125.02,114.47,55.45,49.82,36.11,34.23,33.06,29.08,22.74,14.21.其产率85％。
实施例13
氮气保护下，10mL反应瓶中依次加入锰粉(0.15mmol)，仲卤代烷烃1m(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应18h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物13，1H NMR(400MHz,CDCl3):δ7.39–7.34(m,2H),7.29–7.26(m,1H),7.25–7.21(m,3H),7.21–7.13(m,2H),7.13–7.05(m,4H),6.87–6.81(m,2H),3.81(s,3H),3.19–3.10(m,1H),3.01–2.86(m,2H),2.81–2.70(m,2H),1.93–1.81(m,1H),1.79–1.67(m,1H).13C NMR(100MHz,CDCl3):δ159.56,141.86,139.50,135.84,129.32,128.56,128.44,128.43,126.43,125.94,124.88,114.59,55.47,51.06,41.66,34.88,32.97.其产率85％。
实施例14
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1n(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应15h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝200:1)，得到相应的产物14，1H NMR(400MHz,CDCl3):δ7.41–7.34(m,2H),7.30–7.25(m,2H),7.21–7.14(m,3H),6.87–6.79(m,2H),3.81(s,3H),2.91–2.73(m,3H),1.86–1.76(m,2H),1.58–1.51(m,2H),1.50–1.39(m,2H),1.34–1.23(m,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3):δ159.43,142.19,135.80,128.58,128.47,125.91,125.02,114.47,55.45,49.82,36.11,34.23,33.06,29.08,22.74,14.21.其产率80％。
实施例15
氮气保护下，10mL反应瓶中依次加入锌粉(0.20mmol)，仲卤代烷烃1o(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在100℃下反应9h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物15，1H NMR(400MHz,CDCl3):δ7.42–7.35(m,2H),6.88–6.80(m,2H),3.80(s,3H),2.98–2.82(m,1H),1.98–1.86(m,2H),1.80–1.72(m,2H),1.63–1.57(m,1H),1.38–1.14(m,6H).13C NMR(100MHz,CDCl3):δ159.42,135.73,125.09,114.40,55.44,48.06,33.51,26.27,25.91.其产率10％。
实施例16
氮气保护下，10mL反应瓶中依次加入锰粉(0.15mmol)，仲卤代烷烃1p(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应17h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物16，1H NMR(400MHz,CDCl3):δ7.40–7.34(m,2H),6.87–6.80(m,2H),3.80(s,3H),3.49–3.37(m,1H),2.03–1.88(m,2H),1.83–1.67(m,2H),1.62–1.54(m,4H).13C NMR(100MHz,CDCl3):δ159.08,134.26,127.06,114.48,55.45,48.10,33.52,24.77.其产率40％。
实施例17
氮气保护下，10mL反应瓶中依次加入锌粉(0.15mmol)，仲卤代烷烃1q(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和二甲亚砜(0.9mL)。室温下混合均匀后，反应混合物在100℃下反应17h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物17，1HNMR(400MHz,CDCl3):δ7.43–7.37(m,2H),6.88–6.83(m,2H),3.95(dt,J＝11.7,3.7Hz,2H),3.80(s,3H),3.38(td,J＝11.4,2.3Hz,2H),3.11–3.01(m,1H),1.84(dd,J＝12.2,1.5Hz,2H),1.65(dd,J＝10.9,4.3Hz,1H),1.59(dd,J＝10.2,3.5Hz,1H).13C NMR(100MHz,CDCl3):δ159.83,136.28,123.71,114.57,67.56,55.47,44.69,33.31.其产率30％。
实施例18
氮气保护下，10mL反应瓶中依次加入锌粉(0.20mmol)，仲卤代烷烃1r(0.3mmol)，甲酸芳基硫酯2a(0.36mmol)和二甲亚砜(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应17h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物18，1H NMR(400MHz,CDCl3):δ7.38(d,J＝8.5Hz,2H),6.84(d,J＝8.6Hz,2H),3.96(d,J＝6.1Hz,2H),3.79(s,3H),3.04–2.95(m,1H),2.84(t,J＝11.4Hz,2H),1.85(dd,J＝13.1,2.9Hz,2H),1.43(s,9H).13C NMR(100MHz,CDCl3):δ159.79,154.77,136.22,123.79,114.56,79.62,55.41,45.73,32.21,28.52.其产率30％。
实施例19
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1s(0.3mmol)，甲酸芳基硫酯2a(0.36mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在100℃下反应8h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝50:1)，得到相应的产物19，1H NMR(400MHz,CDCl3):δ8.22(d,J＝8.6Hz,1H),7.78(d,J＝8.7Hz,2H),7.57(ddd,J＝8.4,6.9,1.1Hz,1H),7.43–7.36(m,3H),7.22(d,J＝9.0Hz,1H),6.81–6.72(m,2H),4.37(dt,J＝9.4,6.3Hz,1H),4.30(dt,J＝9.4,5.8Hz,1H),3.71(s,3H),3.55–3.45(m,1H),2.13–2.03(m,2H),1.36(t,J＝6.4Hz,3H).13C NMR(100MHz,CDCl3):δ159.47,153.21,135.63,133.25,130.00,128.98,128.17,127.80,126.31,124.60,124.48,115.14,114.49,109.54,67.64,55.35,41.36,36.54,21.66.其产率70％。
实施例20
氮气保护下，10mL反应瓶中依次加入锌粉(0.18mmol)，仲卤代烷烃1t(0.3mmol)，甲酸芳基硫酯2a(0.30mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应20h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚)，得到相应的产物20，1H NMR(400MHz,CDCl3):δ7.41–7.35(m,2H),6.86–6.81(m,2H),3.80(s,3H),2.92–2.81(m,1H),1.99–1.90(m,1H),1.84–0.91(m,31H),0.91–0.78(m,11H),0.75(s,3H),0.66–0.56(m,4H).13C NMR(100MHz,CDCl3):δ159.38,135.70,125.07,114.39,56.62,56.38,55.44,54.51,48.22,47.16,42.71,40.14,39.65,38.97,36.30,35.93,35.86,35.58,32.16,29.36,28.81,28.38,28.16,24.32,23.96,22.98,22.71,21.16,18.80,12.43,12.20.其产率50％。
实施例21
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1u(0.3mmol)，甲酸芳基硫酯2a(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应17h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝1:1)，得到相应的产物21，1H NMR(400MHz,CDCl3):δ7.50–7.43(m,2H),6.86(t,J＝5.9Hz,2H),5.39(d,J＝2.8Hz,1H),5.17(t,J＝9.9Hz,1H),5.02(dd,J＝10.0,3.3Hz,1H),4.56(d,J＝9.9Hz,1H),4.18(dd,J＝11.3,6.8Hz,1H),4.09(dd,J＝11.3,6.5Hz,1H),3.88(t,J＝6.6Hz,1H),3.81(s,3H),2.10(d,J＝7.9Hz,6H),2.04(s,3H),1.97(s,3H).13C NMR(100MHz,CDCl3):δ170.54,170.35,170.25,169.59,160.35,136.03,122.13,114.46,87.12,74.39,72.18,67.39,67.31,61.64,55.47,21.05,20.84,20.78,20.75.其产率55％。
实施例22
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2a(0.36mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应17h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物22，1H NMR(400MHz,CDCl3):δ7.39(d,J＝8.4Hz,2H),6.84(t,J＝7.0Hz,2H),3.79(s,3H),3.67–3.42(m,3H),3.39–3.19(m,2H),2.18–2.05(m,1H),1.90–1.75(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ159.86,154.46,135.71,135.61,124.43,124.32,114.72,79.45,55.44,51.73,51.64,46.74,46.05,45.01,44.60,31.98,31.42,28.60.其产率90％。
实施例23
氮气保护下，10mL反应瓶中依次加入锰粉(0.21mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2b(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应16h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物23，1H NMR(400MHz,CDCl3):δ7.32(d,J＝8.1Hz,2H),7.12(t,J＝7.3Hz,2H),3.74–3.44(m,3H),3.42–3.23(m,2H),2.33(s,3H),2.23–2.11(m,1H),1.95–1.81(m,1H),1.45(s,9H).13C NMR(100MHz,CDCl3):δ154.47,137.72,132.81,132.66,130.75,130.60,129.94,79.53,77.48,77.16,76.84,51.90,51.78,45.90,45.23,45.00,44.63,32.11,31.55,28.62,21.23.其产率90％。
实施例24
氮气保护下，10mL反应瓶中依次加入锌粉(0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2c(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应11h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物24，1H NMR(400MHz,CDCl3):δ7.34(d,J＝8.2Hz,2H),7.16(t,J＝7.4Hz,2H),3.76–3.44(m,3H),3.44–3.24(m,2H),2.97–2.80(m,1H),2.25–2.11(m,1H),1.96–1.81(m,1H),1.44(d,J＝7.6Hz,9H),1.24(d,J＝5.6Hz,6H).13C NMR(100MHz,CDCl3):δ154.36,148.46,132.62,132.40,131.08,130.89,127.22,79.37,51.84,51.79,45.69,45.03,44.93,44.52,33.78,32.02,31.53,29.72,28.52,23.91.其产率88％。
实施例25
氮气保护下，10mL反应瓶中依次加入双-(1,5-环辛二烯)镍(0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2c(0.4mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在90℃下反应12h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝15:1)，得到相应的产物25，1H NMR(400MHz,CDCl3):δ7.38–7.28(m,4H),3.75–3.46(m,3H),3.45–3.23(m,2H),2.26–2.12(m,1H),1.96–1.82(m,1H),1.44(s,9H),1.30(s,9H).13C NMR(100MHz,CDCl3):δ154.41,150.70,132.24,131.98,130.95,130.73,126.17,79.42,51.92,51.88,45.61,44.97,44.58,34.62,32.08,31.61,31.33,28.58.其产率90％。
实施例26
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2d(0.4mmol)和N-甲基吡咯烷酮(0.9mL)。室温下混合均匀后，反应混合物在60℃下反应11h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝15:1)，得到相应的产物26，1H NMR(400MHz,CDCl3):δ7.47–7.35(m,2H),6.99(d,J＝6.4Hz,2H),3.76–3.43(m,3H),3.43–3.21(m,2H),2.16(dt,J＝12.5,6.2Hz,1H),1.85(dt,J＝12.4,6.1Hz,1H),1.43(s,9H).13C NMR(100MHz,CDCl3):δ163.83,161.36,154.39,135.08,134.99,134.88,129.38,129.28,116.38,116.16,79.54,51.74,51.67,46.33,45.63,44.91,44.53,32.00,31.44,28.57.19F NMR(376MHz,CDCl3):δ-113.65.其产率90％。
实施例27
氮气保护下，10mL反应瓶中依次加入锰粉0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2e(0.4mmol)和N-甲基吡咯烷酮(0.9mL)。室温下混合均匀后，反应混合物在80℃下反应12h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝10:1)，得到相应的产物27，1H NMR(400MHz,CDCl3):δ7.36–7.29(m,2H),7.29–7.23(m,2H),3.74–3.43(m,3H),3.43–3.20(m,2H),2.26–2.13(m,1H),1.92–1.81(m,1H),1.44(s,9H).13C NMR(101MHz,CDCl3):δ154.39,133.51,133.17,133.05,129.32,79.63,51.84,51.73,45.61,44.91,44.56,32.09,31.50,28.60.其产率90％。
实施例28
氮气保护下，10mL反应瓶中依次加入锰粉(0.27mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2f(0.36mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应12h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物28，1H NMR(400MHz,CDCl3):δ7.40(d,J＝5.2Hz,2H),7.27–7.22(m,2H),3.74–3.43(m,3H),3.43–3.21(m,2H),2.29–2.13(m,1H),1.95–1.82(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ154.38,133.98,133.24,133.11,132.25,121.41,79.63,51.85,51.73,45.43,44.89,44.75,44.56,32.09,31.50,28.60.其产率80％。
实施例29
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2g(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应11h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物29，1H NMR(400MHz,CDCl3):δ7.35(dd,J＝7.6,1.1Hz,1H),7.29–7.21(m,1H),6.90(dt,J＝13.2,7.4Hz,2H),3.89(s,3H),3.87–3.77(m,1H),3.74–3.47(m,2H),3.43–3.23(m,2H),2.27–2.13(m,1H),1.95–1.82(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ158.47,154.48,132.84,132.78,128.82,122.59,121.16,110.88,79.47,55.91,52.06,51.88,44.99,44.60,43.50,42.76,32.06,31.49,28.63.其产率85％。
实施例30
氮气保护下，10mL反应瓶中依次加入锰粉0.20mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2h(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在60℃下反应11h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物30，1H NMR(400MHz,CDCl3):δ7.42(t,J＝7.4Hz,1H),7.27(d,J＝5.1Hz,1H),7.09(d,J＝6.7Hz,2H),3.83–3.74(m,1H),3.71–3.46(m,2H),3.43–3.23(m,2H),2.27–2.09(m,1H),1.92–1.78(m,1H),1.44(s,9H).13C NMR(100MHz,CDCl3):δ163.56,161.11,154.43,134.83,129.91,124.69,124.65,121.22,116.16,115.93,79.56,77.48,77.16,76.84,51.90,51.79,44.87,44.47,44.04,32.11,31.56,28.59.19F NMR(376MHz,CDCl3):δ-107.76.其产率70％。
实施例31
氮气保护下，10mL反应瓶中依次加入锌粉(0.24mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2i(0.4mmol)和N,N-二乙酰胺(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应11h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物31，1H NMR(400MHz,CDCl3):δ7.12(t,J＝11.9Hz,3H),3.66–3.30(m,4H),3.28–3.16(m,1H),2.52(s,6H),2.18–2.04(m,1H),1.92–1.78(m,1H),1.44(s,9H).13C NMR(101MHz,CDCl3):δ154.44,143.50,143.44,132.29,132.18,128.68,128.29,79.39,51.63,51.53,45.80,45.01,44.60,32.38,31.68,28.58,22.23.其产率80％。
实施例32
氮气保护下，10mL反应瓶中依次加入双-(1,5-环辛二烯)镍(0.21mmol)，仲卤代烷烃1v(0.3mmol)，甲酸芳基硫酯2j(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应15h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝20:1)，得到相应的产物31，1H NMR(400MHz,CDCl3):δ7.19(t,J＝11.6Hz,3H),7.06(s,1H),3.70(dt,J＝14.5,9.8Hz,2H),3.62–3.45(m,1H),3.45–3.23(m,2H),2.33(d,J＝4.1Hz,3H),2.20(dd,J＝11.7,5.9Hz,1H),1.89(dd,J＝12.3,6.3Hz,1H),1.45(s,9H).13CNMR(100MHz,CDCl3):δ154.35,138.87,134.35,134.20,132.33,132.24,128.89,128.71,128.56,128.07,79.45,51.88,51.82,45.24,44.90,44.54,32.07,31.53,28.52,21.34.其产率80％。
实施例33
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，仲卤代烷烃1w(0.3mmol)，甲酸烷基硫酯2k(0.4mmol)和1,3-二甲基-2-咪唑啉酮(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应18h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物33，1H NMR(400MHz,CDCl3):δ7.73–7.64(m,3H),7.41(dd,J＝8.5,1.5Hz,1H),7.30(t,J＝7.4Hz,2H),7.21(dd,J＝12.9,7.2Hz,3H),7.16–7.09(m,2H),4.07(t,J＝6.4Hz,2H),3.90(s,3H),3.84(q,J＝7.1Hz,1H),2.84(dd,J＝9.1,6.5Hz,2H),2.70(dd,J＝9.2,6.4Hz,2H),2.39(t,J＝7.3Hz,2H),1.59–1.54(m,5H),1.54–1.46(m,2H),1.34–1.26(m,2H).13C NMR(100MHz,CDCl3):δ174.84,157.72,140.75,135.91,133.77,129.39,129.02,128.59,127.22,126.45,126.38,126.06,119.10,105.66,64.70,55.43,45.64,36.46,33.76,32.13,29.23,28.30,25.22,18.59.其产率45％。
实施例34
氮气保护下，10mL反应瓶中依次加入锰粉(0.18mmol)，伯卤代烷烃1w(0.3mmol)，甲酸烷基硫酯2l(0.4mmol)和N,N-二甲酰胺(0.9mL)。室温下混合均匀后，反应混合物在80℃下反应18h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝10:1)，得到相应的产物34，1H NMR(400MHz,CDCl3):δ7.75–7.67(m,3H),7.43(dd,J＝8.5,1.5Hz,1H),7.19–7.11(m,2H),4.09(t,J＝6.6Hz,2H),3.94(s,3H),3.86(q,J＝7.1Hz,1H),2.64–2.55(m,1H),2.42(t,J＝7.4Hz,2H),1.99–1.89(m,2H),1.82-1.72(d,J＝22.2Hz,2H),1.62–1.58(m,5H),1.51(dd,J＝15.1,7.5Hz,2H),1.38–1.22(m,8H).13C NMR(100MHz,CDCl3):δ174.85,157.71,135.91,133.77,129.39,129.03,127.22,126.39,126.05,119.08,105.66,64.76,55.44,45.64,43.60,33.85,29.98,29.68,28.32,26.27,26.00,25.38,18.60.其产率55％。
实施例35
氮气保护下，10mL反应瓶中依次加入锰粉(0.20mmol)，伯卤代烷烃1w(0.3mmol)，甲酸烷基硫酯2a(0.4mmol)和N,N-二甲基丙烯基脲(0.9mL)。室温下混合均匀后，反应混合物在70℃下反应19h。反应结束后，加水(6mL)淬灭，乙酸乙酯(3×5mL)萃取，合并有机相，盐水(3×5mL)洗涤，过滤，无水硫酸钠干燥，减压浓缩后经硅胶板分离(石油醚/乙酸乙酯＝100:1)，得到相应的产物35，1H NMR(400MHz,CDCl3):δ7.70(dd,J＝12.3,5.3Hz,3H),7.41(dd,J＝8.5,1.3Hz,1H),7.23–7.08(m,4H),6.84(d,J＝8.5Hz,2H),4.09–4.03(m,2H),3.91(s,3H),3.85(q,J＝7.1Hz,1H),3.79(s,3H),3.60(s,2H),2.29(t,J＝7.3Hz,2H),1.58–1.43(m,6H),1.33–1.24(m,3H).13C NMR(100MHz,CDCl3):δ174.84,158.63,157.71,135.89,133.77,130.60,129.96,129.38,129.02,127.22,126.37,126.04,119.09,113.95,105.66,64.70,55.43,55.40,45.62,35.73,31.13,28.85,28.27,25.20,18.60.其产率40％。
实施例36
按照实施例1的步骤完成，不同的是改变催化剂，选用锌粉为催化剂，得到1产率为70％。
实施例37
按照实施例1的步骤完成，不同的是改变溶剂，选用二甲亚砜作为溶剂，得到1产率为74％。
实施例38
利用实施例1制备的有机硫化合物的应用(克级反应)：
按照实施例1的步骤完成，不同的是改变了1v的摩尔量，将其由0.3mmol scale扩大至4.5mmol scale，得到大于1g(1.21g,产率为92％)的含硫化合物23。
注：实施例7、20、21、33、34和35的伯/仲卤代物均由药物分子出发合成，再按相应步骤完成，得到含硫药物分子。
本发明廉价金属催化剂与非活化卤代烷烃进行氧化加成形成高活性的金属物种，也可以使各种取代的甲酸硫酯的C-S键区域选择性断裂产生硫自由基，进而作为有效的硫源试剂，进一步地有利于反应的顺利进行；利用的是过渡金属催化交叉偶联反应得到产物。其中对于甲酸硫酯和非活化卤代烷烃上的各种取代基影响的是整体的电子云密度大小以及反应时的空间位阻大小，即取代基的修饰只是一定程度上影响反应，不对反应的发生起决定作用。

Claims (5)

1.一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，在N2氛围下，以甲酸硫酯为硫源、双-(1,5-环辛二烯)镍或廉价金属单质为金属催化剂，非活化卤代烷烃/>为亲电试剂，在有机溶剂中，在温度为30-100℃下反应8-24小时，反应结束后，依次经过淬灭，萃取，减压蒸馏，分离纯化，合成得到C(sp3)-S键的硫化合物其中，R任意选自C1-C20的直链烷基，C3-C20环烷基，取代或非取代的苯基、联苯基、萘基、蔥基或菲基，其中，所述廉价金属单质选自锰粉、锌粉、铁粉、铜粉或中一种廉价金属单质；所述的非活化卤代烷烃/>中的R1选自氢；R2和R3可以相同也可以不相同，
当R2与R3相同时，R2和R3可以独立任意选自C3-C20的含杂原子环烷基或糖基，其中，所述杂原子为N、O或S；
当R2与R3不相同时，R2选自氢、R3任意选自C1-C20直链烷基，C1-C20卤取代烷基，C1-C20硼酸烷基，C1-C20烷基羰基、硝基、羟基、酯基、羧基或者氰基，C1-C20烷氨基羰基；X为Cl，Br或I。
2.根据权利要求1所述的一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，当非活化的卤代烷烃为作为亲电试剂时，所述非活化卤代烷烃、甲酸硫酯与金属催化剂的摩尔比为1:(1-2):(0.1-0.9)。
3.根据权利要求1所述的一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，所述的有机溶剂的浓度为0.2-1M。
4.根据权利要求1所述的一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，所述反应的温度为60-100℃。
5.根据权利要求1所述的一种基于烷基卤代物合成C(sp3)-S键的有机硫化合物的方法，其特征在于，所述有机溶剂选二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N-二甲酰胺、N,N-二乙酰胺、乙酸乙酯、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、环戊基二甲醚、1,3-二甲基-2-咪唑啉酮中一种。
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