CN113845399A - 邻芳基伯酰胺的制备方法 - Google Patents

邻芳基伯酰胺的制备方法 Download PDF

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CN113845399A
CN113845399A CN202111333166.1A CN202111333166A CN113845399A CN 113845399 A CN113845399 A CN 113845399A CN 202111333166 A CN202111333166 A CN 202111333166A CN 113845399 A CN113845399 A CN 113845399A
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陈晓蓓
罗凡
王佳瑞
张心予
钱彭飞
林慧玲
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East China University of Science and Technology
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Abstract

本发明涉及一种邻芳基伯酰胺的制备方法，包括：将α‑硅基腈和芳基亚砜混合在溶剂中，加入酸，搅拌，然后升温至40～80℃，搅拌，反应得到邻芳基伯酰胺；所述的α‑硅基腈的化学结构式为：
Figure DDA0003349544270000011
Si为选自三甲基硅基、叔丁基二甲基硅基、二甲基苯基硅基、三乙基硅基、三异丙基硅基、或叔丁基二苯基硅基的硅基基团；R1为取代或者未取代的烷基；所述的芳基亚砜的化学结构式为：
Figure DDA0003349544270000012
Ar为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环；R2为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环、取代或者未取代的烷基；所述的邻芳基伯酰胺的化学结构式为：
Figure DDA0003349544270000013

Description

邻芳基伯酰胺的制备方法
技术领域
本发明涉及有机合成领域，具体涉及一种邻芳基伯酰胺的制备方法。
背景技术
伯酰胺(RCONH2)是一种非常重要的有机官能团，不仅经常作为合成中间体，也广泛存在于多种天然产物、生物活性分子和药物中。
现有技术制备伯酰胺的方法之一是使用含腈基的化合物在强酸或者强碱条件下水解得到，此方法的缺点是不容易控制在酰胺的阶段，因为酰胺易于继续水解产生不易分离的羧酸，或者其它副产物杂质；而且很多官能团对强酸强碱不耐受，所以这类反应的官能团兼容性不高(Org.Process Res.Dev.,2019,23,1918-1925)。
另外，现有技术中一种广泛用于制备邻芳基叔酰胺
Figure BDA0003349544250000011
的方法是使用过渡金属催化的酰胺邻位芳化(J.Am.Chem.Soc.,2006,128,4976-4985)，但是这类技术只局限于氮上没有氢的叔酰胺底物，如果氮上含有氢，芳基化会优先发生在氮上(Org.Lett.,2000,2,1101-1104)。最近还有一种技术使用临时保护基策略制备邻芳基仲酰胺，但是此技术对于邻芳基伯酰胺无效(J.Am.Chem.Soc.,2019,141,11749-11753)。
因此，提供一种利用简单的试剂和操作选择性制备邻芳基伯酰胺的新方法具有重要意义。
发明内容
本发明的主要目的在于克服现存的上述缺点，而提供一种原料易于获取、反应操作简单、具有很好的原子经济性的邻芳基伯酰胺的制备方法。
为了实现上述目的，本发明采用的邻芳基伯酰胺的制备方法的技术方案如下：
包括：将α-硅基腈和芳基亚砜混合在溶剂中，加入酸，搅拌，然后升温至40～80℃，搅拌，反应得到邻芳基伯酰胺；
优选地，将α-硅基腈和芳基亚砜混合在溶剂中，0℃下缓慢滴加酸，滴加完成后，继续搅拌5～15min，然后升温至40～80℃，搅拌8～24小时，反应得到邻芳基伯酰胺。
所述的α-硅基腈的化学结构式为：
Figure BDA0003349544250000021
Si为选自三甲基硅基TMS、叔丁基二甲基硅基TBS、二甲基苯基硅基DMPS、三乙基硅基TES、三异丙基硅基TIPS、或叔丁基二苯基硅基TBDPS的硅基基团，优选TMS、DMPS和TES，更优选TMS；R1为取代或者未取代的烷基，取代指基团上的一个或多个氢原子被取代基取代，取代基独立的选自卤素、烯、炔、醚、羧酸酯、硼酸酯、或酰胺中的一种或几种；
所述的芳基亚砜的化学结构式为：
Figure BDA0003349544250000022
Ar为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环；R2为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环、取代或者未取代的烷基，取代指基团上的一个或多个氢原子被取代基取代，取代基独立的选自卤素、烷基、烷氧基、炔基、烯基、酯基、硼酸酯中的一种或几种，芳杂环中的杂原子选自O和/或S；
所述的邻芳基伯酰胺的化学结构式为：
Figure BDA0003349544250000023
较佳地，所述的溶剂选自1,2-二氯乙烷DCE、乙腈MeCN、三氟甲基苯PhCF3、甲苯、或正己烷，优选DCE和PhCF3，更优选DCE；
所述的酸选自三氟甲烷磺酸TfOH、双三氟甲基磺酰亚胺Tf2NH、甲烷磺酸MsOH、或三氟化硼乙醚BF3·Et2O，优选TfOH和Tf2NH，更优选TfOH。
作为其中的一个实施方案，反应可表示如下：
Figure BDA0003349544250000024
较佳地，加入酸具体为：在0℃下加入酸；升温至40～80℃具体为：升温至50℃；反应时间为6～48小时；反应时间为8～24小时，更优选12小时。
本发明提供的邻芳基伯酰胺的制备方法的有益效果在于：
1)比传统技术水解腈基制备伯酰胺的条件更加温和，酸的用量少，不需要很高的反应温度；
2)不会产生过度水解的羧酸副产物；
3)不会有氮上官能团化的产物；
4)官能团兼容性强，底物范围广；
5)产物中芳环上邻位含有硫醚，可以进行广泛的官能团转化。
附图说明
图1a～1b为化合物3a的核磁谱图。
图2为化合物3ac的x射线晶体学分析图。
图3为本发明的邻芳基伯酰胺产物可以进行的官能团转化示意图。
具体实施方式
为了能够更清楚地理解本发明的技术内容，特举以下实施例详细说明。
本发明提供的邻芳基伯酰胺的制备方法，以α-硅基腈和芳基亚砜为底物，在酸以及溶剂存在下，50℃发生[3,3]-Sigmatropic重排反应，得到产物邻芳基伯酰胺，解决了现有技术容易产生羧酸副产物、或者容易产生氮芳基化产物的问题。
本发明提供的制备方法，具有很高的化学选择性，不会产生难以分离的羧酸和氮芳基化副产物。制备得到的邻芳基伯酰胺化合物具有很大的应用价值，可以进一步进行广泛的转化，制备酮、酯、羧酸、胺、氮杂环等，在药物合成中具有重要意义。
本发明各实施例中涉及的原料或者为现有可市购产品，或者可根据现有方法制备。
实施例1
邻芳基伯酰胺的制备
将α-硅基腈1(0.75mmol)和芳基亚砜2(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(67μL,0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3。
不同反应底物α-硅基腈1和芳基亚砜2以及得到的对应产物芳基伯酰胺产品3如下所示：
Figure BDA0003349544250000041
Figure BDA0003349544250000042
上述收率为分离收率，反应完成的时间为12小时。
上述产物数据表征如下：
Figure BDA0003349544250000043
按照标准投料量，2a(0.5mmol)，收率82％。(2a结构式：
Figure BDA0003349544250000044
)
1H NMR(400MHz,CDCl3):δ7.66–7.59(m,1H),7.56–7.49(m,1H),7.46–7.39(m,1H),7.38–7.29(m,3H),7.29–7.21(m,3H),5.42(brs,1H),5.36(brs,1H),4.23(t,J＝7.4Hz,1H),2.22–2.08(m,1H),1.78–1.62(m,1H),1.42–1.28(m,1H),1.27–1.12(m,1H),0.91(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ175.6,142.8,137.1,135.2,132.9,129.6,129.5,129.2,128.4,128.0,126.7,48.0,35.3,20.9,14.0.HRMS(ESI-TOF):calculated for[C17H20NOS(M+H+)]:286.1266,found:286.1271.
Figure BDA0003349544250000051
1H NMR(400MHz,CDCl3):δ7.38–7.30(m,2H),7.09–7.05(m,4H),7.05–7.00(m,1H),5.44(s,1H),5.27(s,1H),4.14(dd,J＝7.7,7.1Hz,1H),2.34(s,3H),2.30(s,3H),2.15–2.01(m,1H),1.65–1.52(m,1H),1.36–1.20(m,1H),1.20–1.06(m,1H),0.84(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.8,142.7,139.6,136.5,135.1,133.9,130.1,129.8,129.1,128.91,128.86,47.9,35.3,21.4,21.1,20.9,14.1.HRMS(ESI-TOF):calculatedfor[C19H23NOSNa(M+Na)]+:336.1398,found:336.1398.
Figure BDA0003349544250000052
1H NMR(400MHz,CDCl3):δ7.85(d,J＝1.8Hz,1H),7.67–7.61(m,2H),7.60–7.52(m,5H),7.52–7.41(m,5H),7.41–7.29(m,4H),5.71(s,1H),5.45(s,1H),4.26(t,J＝7.3Hz,1H),2.27–2.14(m,1H),1.80–1.67(m,1H),1.42–1.28(m,1H),1.29–1.16(m,1H),0.89(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.5,143.1,142.2,140.1,140.0,139.7,135.9,135.3,131.8,129.6,129.0,128.9,128.1,127.9,127.7,127.2,127.01,126.95,126.6,48.2,35.4,21.0,14.0.HRMS(ESI-TOF):calculated for[C29H27NOSNa(M+Na)]+:460.1711,found:460.1710.
Figure BDA0003349544250000053
1H NMR(400MHz,CDCl3):δ7.44–7.37(m,1H),7.33–7.27(m,1H),7.18–7.07(m,2H),7.02–6.89(m,3H),5.97(brs,1H),5.38(brs,1H),4.11(t,J＝7.4Hz,1H),2.10–1.98(m,1H),1.63–1.50(m,1H),1.32–1.19(m,1H),1.19–1.07(m,1H),0.83(t,J＝7.3Hz,3H).13CNMR(151MHz,CDCl3):δ175.1(d,J＝2.6Hz),δ163.5(d,J＝242.5Hz),161.8(d,J＝240.0Hz),145.3(d,J＝8.2Hz),136.8(d,J＝8.2Hz),131.9(d,J＝3.2Hz),130.8(d,J＝8.0Hz),128.2(d,J＝2.7Hz),116.6(d,J＝21.9Hz),115.7(d,J＝22.4Hz),115.4(d,J＝22.0Hz),48.4,35.4,20.8,13.9.19F NMR(565MHz,CDCl3):δ-110.44(dd,J＝15.4,8.0Hz),-114.82–-114.90(m).HRMS(ESI-TOF):calculated for[C17H18F2NOS(M+H)]+:322.1077,found:322.1078.
Figure BDA0003349544250000061
1H NMR(400MHz,CDCl3):δ7.59(d,J＝2.3Hz,1H),7.37–7.32(m,1H),7.29–7.25(m,2H),7.25–7.20(m,1H),7.13–7.08(m,2H),5.69(s,1H),5.40(s,1H),4.09(dd,J＝7.9,6.9Hz,1H),2.16–2.02(m,1H),1.68–1.53(m,1H),1.37–1.25(m,1H),1.24–1.10(m,1H),0.87(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.7,144.3,135.92,135.86,134.9,133.0,131.0,130.4,129.7,128.8,128.5,48.3,35.4,20.9,14.0.HRMS(ESI-TOF):calculated for[C17H17Cl2NOSNa(M+Na)]+:376.0306,found:376.0307.
Figure BDA0003349544250000062
1H NMR(400MHz,CDCl3):δ7.72–7.68(m,1H),7.41–7.35(m,2H),7.35–7.30(m,1H),7.25–7.19(m,1H),7.05–6.98(m,2H),6.12(s,1H),5.45(s,1H),4.06–4.01(m,1H),2.10–1.97(m,1H),1.64–1.50(m,1H),1.35–1.21(m,1H),1.20–1.06(m,1H),0.83(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.9,144.4,136.0,135.4,132.5,131.63,131.57,131.3,130.7,123.90,120.89,48.2,35.4,20.9,13.9.HRMS(ESI-TOF):calculated for[C17H17Br2NOSNa(M+Na)]+:463.9295,found:463.9295.
Figure BDA0003349544250000063
1H NMR(400MHz,CDCl3):δ7.75–7.67(m,4H),7.38–7.28(m,5H),7.10–6.08(m,1H),6.94–6.88(m,2H),5.19(brs,1H),5.11(brs,1H),3.94(t,J＝7.4Hz,1H),2.45(brs,3H),2.45(brs,3H),1.91–1.76(m,1H),1.43–1.29(m,1H),1.21–1.07(m,1H),1.06–0.92(m,1H),0.79(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.3,150.3,148.4,145.83,145.80,144.2,135.9,135.3,132.3,132.1,131.5,130.4,130.00,129.96,128.6,128.5,123.6,122.6,122.4,48.2,35.3,29.8,21.8,20.7,13.9.HRMS(ESI-TOF):calculatedfor[C31H31NO7S3Na(M+Na)]+:648.1160,found:648.1157.
Figure BDA0003349544250000071
1H NMR(400MHz,CDCl3):δ7.46–7.38(m,1H),7.14–7.09(m,2H),7.09–7.05(m,1H),6.83–6.75(m,3H),5.20(brs,1H),5.14(brs,1H),4.19(t,J＝7.3Hz,1H),3.80(s,3H),3.77(s,3H),2.15–1.97(m,1H),1.65–1.52(m,1H),1.35–1.18(m,1H),1.21–1.07(m,1H),0.85(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.3,160.7,158.7,144.6,136.8,130.6,128.5,124.5,115.1,114.1,113.5,55.6,48.2,35.3,29.8,20.9,14.1.HRMS(ESI-TOF):calculated for[C21H23NO5SNa(M+Na)]+:424.1195,found:424.1194.
Figure BDA0003349544250000072
1H NMR(400MHz,CDCl3):δ7.51–7.44(m,1H),7.35–7.29(m,1H),7.22–7.15(m,2H),7.06–6.96(m,3H),5.24(brs,1H),5.15(brs,1H),4.08(dd,J＝7.9,6.8Hz,1H),2.28(s,3H),2.27(s,3H),2.14–1.95(m,1H),1.66–1.53(m,1H),1.35–1.22(m,1H),1.22–1.09(m,1H),0.85(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.7,169.5,169.2,151.7,149.6,144.4,136.1,134.4,130.4,129.9,122.9,122.0,121.6,48.2,35.8,21.3,21.2,20.9,14.0.HRMS(ESI-TOF):calculated for[C19H23NO3SNa(M+Na)]+:368.1296,found:424.368.1301.
Figure BDA0003349544250000073
1H NMR(400MHz,CDCl3):δ8.25–8.21(m,1H),7.97–7.91(m,2H),7.91–7.85(m,1H),7.47–7.42(m,1H),7.24–7.19(m,2H),5.38(brs,2H),4.11(t,J＝7.4Hz,1H),3.91(s,3H),3.90(s,3H),2.24–2.09(m,1H),1.75–1.66(m,1H),1.39–1.23(m,1H),1.24–1.09(m,1H),0.86(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.6,166.5,166.4,142.6,142.0,137.9,134.3,131.3,130.7,129.6,129.1,128.9,128.8,52.5,52.4,48.4,35.3,21.0,14.0.HRMS(ESI-TOF):calculated for[C21H23NO5SNa(M+Na)]+:424.1195,found:424.1196.
Figure BDA0003349544250000081
1H NMR(400MHz,CDCl3):δ8.55(t,J＝8.0Hz,1H),7.81–7.74(m,1H),7.67–7.55(m,1H),7.54–7.44(m,1H),5.66(brs,1H),5.59(brs,1H),4.00(t,J＝7.2Hz,1H),2.30–2.17(m,1H),1.93–1.81(m,1H),1.51–1.39(m,1H),1.39–1.30(m,1H),0.96(t,J＝7.3Hz,3H).13CNMR(101MHz,CDCl3):δ180.4,174.4,136.3,136.1,136.0,132.7,131.4,130.2,129.9,129.4,128.6,126.9,126.5,126.4,47.7,35.1,21.0,14.1.HRMS(ESI-TOF):calculatedfor[C18H18NO2S(M+H)]+:312.1058,found:312.1059.
Figure BDA0003349544250000082
1H NMR(400MHz,CDCl3):δ8.17–8.09(m,1H),8.10–8.01(m,1H),7.88–7.81(m,1H),7.52–7.41(m,4H),5.91(brs,1H),5.59(brs,1H),3.74(t,J＝7.5Hz,1H),2.32–2.19(m,1H),2.05–1.93(m,1H),1.47–1.22(m,2H),0.93(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ174.8,139.7,138.7,136.30,136.26,134.5,127.2,125.6,125.2,124.9122.9,122.0,120.7,51.6,34.1,21.0,14.1.HRMS(ESI-TOF):calculated for[C17H17NOSK(M+K)]+:322.0668,found:322.0665.
Figure BDA0003349544250000083
1H NMR(400MHz,CDCl3):δ8.53(t,J＝7.9Hz,1H),8.02(d,J＝8.5Hz,1H),7.89(t,J＝8.0Hz,1H),7.80(d,J＝8.6Hz,1H),7.68(t,J＝7.4Hz,1H),7.63–7.55(m,1H),7.55–7.44(m,1H),7.06(t,J＝7.7Hz,1H),6.46(d,J＝7.3Hz,1H),5.15(brs,2H),4.66(t,J＝7.2Hz,1H),2.23–2.10(m,1H),1.81–1.67(m,1H),1.25–1.17(m,1H),1.16–1.04(m,1H),0.80(t,J＝7.1Hz,1H).13C NMR(101MHz,CDCl3):δ175.2,145.1,135.7,135.6,134.0,133.7,131.5,130.6,128.9,128.6,127.9,127.2,127.0,126.8,126.7,126.6,125.9,125.8,125.7,123.9,123.3,49.5,35.4,20.9,14.1.HRMS(ESI-TOF):calculated for[C25H23NOSNa(M+Na)]+:408.1398,found:408.1392.
Figure BDA0003349544250000091
1H NMR(400MHz,CDCl3):δ7.37(d,J＝5.5Hz,1H),7.30(dd,J＝5.3,1.1Hz,1H),7.17(dd,J＝3.6,1.1Hz,1H),7.08(d,J＝5.5Hz,1H),6.94(dd,J＝5.3,3.6Hz,1H),5.55(brs,1H),5.28(brs,1H),4.04(t,J＝7.5Hz,1H),2.15–2.02(m,1H),1.71–1.59(m,1H),1.35–1.12(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.1,144.8,135.9,132.1,130.3,129.8,129.4,127.7,127.2,45.7,34.8,20.8,14.0.HRMS(ESI-TOF):calculated for[C16H15NOS3Na(M+Na)]+:320.0213,found:320.0215.
Figure BDA0003349544250000092
1H NMR(400MHz,CDCl3):δ7.39–7.34(m,1H),7.26–7.19(m,2H),7.19–7.12(m,1H),5.94(brs,1H),5.68(brs,1H),3.99(t,J＝7.4Hz,1H),2.46(s,3H),2.19–2.05(m,1H),1.79–1.67(m,1H),1.42–1.15(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.9,138.5,137.1,127.8,127.3,126.6,126.0,47.6,34.4,20.9,16.5,14.1.HRMS(ESI-TOF):calculated for[C12H17NOSNa(M+Na)]+:246.0929,found:246.0926.
Figure BDA0003349544250000093
1H NMR(400MHz,CDCl3):δ7.52–7.47(m,1H),7.42–7.37(m,1H),7.30–7.22(m,5H),7.22–7.17(m2H),5.25(brs,1H),5.11(brs,1H),4.09(s,2H),4.05(t,J＝7.4Hz,1H),2.14–2.00(m,1H),1.58–1.45(m,1H),1.37–1.22(m,1H),1.21–1.07(m,1H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.8,141.8,137.7,134.5,132.2,128.9128.7,128.0,127.6,127.6,127.4,47.9,40.6,34.9,20.9,14.1.HRMS(ESI-TOF):calculated for[C18H21NOSNa(M+Na)]+:322.1242,found:322.1236.
Figure BDA0003349544250000101
1H NMR(400MHz,CDCl3):δ7.46–7.40(m,2H),7.27–7.15(m,2H),5.72(brd,J＝20.8Hz,2H),4.26(t,J＝7.4Hz,1H),3.41–3.29(m,1H),2.24–2.10(m,1H),1.75–1.60(m,1H),1.40–1.28(m,7H),1.25–1.17(m,1H),0.91(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ176.0,141.9,134.6,132.9,127.9,127.8,127.5,47.9,39.3,34.7,23.3,23.2,21.0,14.2.HRMS(ESI-TOF):calculated for[C14H21NOSNa(M+Na)]+:274.1242,found:274.1236.
Figure BDA0003349544250000102
1H NMR(400MHz,CDCl3):δ7.59(d,J＝7.8Hz,1H),7.37(d,J＝7.6Hz,1H),7.28–7.22(m,1H),7.21–7.13(m,1H),5.60(brs,1H),5.35(brs,1H),3.84(t,J＝7.3Hz,1H),2.21–2.07(m,2H),1.81–1.67(m,1H),1.41–1.19(m,2H),1.17–1.04(m,2H),0.91(t,J＝7.3Hz,3H),0.78–0.66(m,2H).13C NMR(101MHz,CDCl3):δ175.6137.7,137.6,127.8,127.3,127.0,126.0,47.6,34.4,20.9,14.1,12.4,8.9,8.6.HRMS(ESI-TOF):calculated for[C14H19NOSNa(M+Na)]+:272.1085,found:272.1079.
Figure BDA0003349544250000103
1H NMR(400MHz,CDCl3):δ7.43–7.36(m,2H),7.25–7.17(m,2H),5.94–5.80(m,1H),5.62(brs,1H),5.44(brs,1H),5.15–5.01(m,2H),4.18(t,J＝7.4Hz,1H),3.54(d,J＝7.0Hz,2H),2.22–2.10(m,1H),1.76–1.64(m,1H),1.41–1.30(m,1H),1.29–1.18(m,1H),0.92(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.7,141.1,134.6,133.3,131.3,127.7,127.6,118.3,47.9,38.2,34.7,21.0,14.2.HRMS(ESI-TOF):calculated for[C14H19NOSNa(M+Na)]+:272.1085,found:272.1086.
Figure BDA0003349544250000111
1H NMR(400MHz,CDCl3):δ7.31–7.23(m,1H),7.15(dd,J＝9.9,2.8Hz,1H),6.97–6.89(m,1H),5.99(brs,1H),5.72(brs,1H),4.06(t,J＝7.0Hz,1H),2.43(s,3H),2.15–2.02(m,1H),1.75–1.61(m,1H),1.42–1.16(m,2H),0.91(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.3,δ161.9(d,J＝246.3Hz),141.8(d,J＝7.3Hz),131.9(d,J＝3.0Hz),130.2(d,J＝7.9Hz),115.0(d,J＝21.8Hz),114.8(d,J＝22.7Hz),47.9,34.7,20.9,18.0,14.0.19F NMR(376MHz,CDCl3):δ-115.1(s).HRMS(ESI-TOF):calculatedfor[C12H16FNOSNa(M+Na)]+:264.0834,found:264.0833.
Figure BDA0003349544250000112
1H NMR(400MHz,CDCl3):δ7.39(d,J＝2.1Hz,1H),7.23–7.13(m,2H),5.71(brd,J＝29.5Hz,2H),3.96(t,J＝7.3Hz,1H),2.46(s,3H),2.19–2.03(m,1H),1.77–1.63(m,1H),1.42–1.18(m,2H),0.92(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.0,140.3,135.6,132.2,128.1,128.0,127.6,47.6,34.6,20.9,16.9,14.0.HRMS(ESI-TOF):calculated for[C12H16ClNOSNa(M+Na)]+:280.0539,found:280.0543.
Figure BDA0003349544250000113
1H NMR(400MHz,CDCl3):δ7.51(d,J＝2.1Hz,1H),7.37–7.29(m,1H),7.12–7.04(m,1H),5.97(brs,1H),5.68(brs,1H),3.93(t,J＝7.4Hz,1H),2.45(s,3H),2.15–2.00(m,1H),1.74–1.61(m,1H),1.41–1.16(m,2H),0.91(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.1,140.5,136.3,130.8,130.3,128.1,120.0,47.6,34.6,20.9,16.6,14.0.HRMS(ESI-TOF):calculated for[C12H16BrNOSNa(M+Na)]+:324.0034,found:324.0038.
Figure BDA0003349544250000121
1H NMR(400MHz,CDCl3):δ7.36(d,J＝2.7Hz,1H),7.29–7.25(m,1H),7.17(dd,J＝8.8,2.7Hz,1H),5.92(brs,1H),5.70(brs,1H),3.97(t,J＝7.4Hz,1H),2.52(s,3H),2.17–2.05(m,1H),1.79–1.64(m,1H),1.44–1.19(m,2H),0.93(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.5,147.7,140.5,138.1,127.4,120.7,120.5,118.85(q,J＝320.9Hz),47.6,34.8,20.8,16.4,13.9.19F NMR(376MHz,CDCl3):δ-72.74(s).HRMS(ESI-TOF):calculatedfor[C13H16F3NO4S2Na(M+Na)]+:394.0371,found:394.0365.
Figure BDA0003349544250000122
1H NMR(400MHz,CDCl3):δ7.74(d,J＝0.9Hz,1H),7.64(dd,J＝7.9,1.1Hz,1H),7.20–1.14(m,1H),5.59(brs,2H),3.93(t,J＝7.3Hz,1H),2.48(s,3H),2.25–2.11(m,1H),1.84–1.72(m,1H),1.41–1.19(m,14H),0.91(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.6,141.3,137.1,134.1,133.4,124.5,83.9,47.7,34.2,24.99,24.95,21.0,15.8,14.1.HRMS(ESI-TOF):calculated for[C18H28BNO3SNa(M+Na)]+:372.1781,found:372.1778.
Figure BDA0003349544250000123
1H NMR(400MHz,CDCl3):δ7.56(d,J＝1.6Hz,1H),7.54–7.48(m,2H),7.42–7.38(m,1H),7.38–7.29(m,3H),7.21–7.16(m,1H),5.62(brs,1H),5.36(brs,1H),3.96(t,J＝7.4Hz,1H),2.52(s,3H),2.24–2.07(m,1H),1.85–1.71(m,1H),1.45–1.20(m,2H),0.94(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.1,138.1,138.0,131.7,130.9,130.4,128.5,128.4,125.6,123.3,120.7,90.1,89.1,47.5,34.5,20.9,16.1,14.1.HRMS(ESI-TOF):calculated for[C20H21NOSNa(M+Na)]+:346.1242,found:346.1233.
Figure BDA0003349544250000131
1H NMR(400MHz,CDCl3):δ8.21–8.08(m,1H),7.86–7.72(m,4H),7.73–7.66(m,2H),7.56–7.43(m,5H),7.38–7.30(m,1H),5.36(brs,1H),5.25–4.95(m,2H),2.64–2.52(m,1H),1.98–1.86(m,1H),1.51–1.36(m,1H),1.15–0.98(m,1H),0.83(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ176.0,138.7,134.1,133.9,133.8,133.4,132.3,132.0,130.5,129.3,129.01,128.98,128.88,127.9,127.8,127.4,127.1,127.0,126.6,126.5,125.7,48.5,33.7,21.7,14.3.HRMS(ESI-TOF):calculated for[C25H23NOSNa(M+Na)]+:408.1398,found:408.1393.
Figure BDA0003349544250000132
1H NMR(400MHz,CDCl3):δ7.99(d,J＝8.0Hz,1H),7.82–7.73(m,2H),7.52–7.39(m,3H),5.53(brs,1H),5.22(brs,1H),4.79(t,J＝8.0Hz,1H),2.58(s,3H),2.57–2.48(m,1H),1.98–1.85(m,1H),1.48–1.31(m,1H),1.15–0.99(m,1H),0.85(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ176.3,136.3,134.8,132.7,131.6,128.9,128.8,127.0,125.7,125.2,125.0,47.7,33.3,21.6,17.8,14.3.HRMS(ESI-TOF):calculated for[C16H19NOSNa(M+Na)]+:296.1085,found:296.1077.
Figure BDA0003349544250000133
1H NMR(400MHz,CDCl3):δ7.95–7.87(m,1H),7.70–7.64(m,1H),7.30–7.16(m,6H),7.14–7.09(m,1H),5.65(brs,1H),4.98(brs,1H),4.26(dd,J＝8.7,6.2Hz,1H),2.29–2.18(m,1H),1.84–1.70(m,1H),1.24–1.11(m,1H),1.07–0.92(m,1H),0.75(t,J＝7.3Hz,3H).13CNMR(101MHz,CDCl3):δ174.4,141.5,139.9,137.6,136.8,134.0,129.5,128.6,127.1,125.6,124.7,124.1,122.3,45.6,32.3,21.1,14.0.HRMS(ESI-TOF):calculated for[C19H19NOS2Na(M+Na)]+:364.0806,found:364.0797.
Figure BDA0003349544250000141
1H NMR(400MHz,CDCl3):δ7.54–7.50(m,1H),7.32–7.24(m,3H),7.21–7.13(m3H),5.34(brs,1H),5.20(brs,1H),3.90(t,J＝7.5Hz,1H),2.13–2.02(m,1H),1.77–1.59(m,1H),1.36–1.11(m,2H),0.87(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ175.1,147.0,138.3,130.7,129.3,127.7,126.8,126.3,126.2,45.8,34.9,20.8,14.0.HRMS(ESI-TOF):calculated for[C15H17NOS2Na(M+Na)]+:314.0649,found:314.0638.
Figure BDA0003349544250000142
1H NMR(400MHz,CDCl3):δ7.95–7.88(m,1H),7.71–7.62(m,1H),7.30–7.15(m,6H),7.15–7.06(m,1H),5.61(brs,1H),4.97(brs,1H),4.26(dd,J＝8.7,6.2Hz,1H),2.29–2.18(m,1H),1.84–1.72(m,1H),1.24–1.12(m,1H),1.06–0.93(m,1H),0.75(t,J＝7.3Hz,3H).13CNMR(101MHz,CDCl3):δ174.4,141.5,139.9,137.6,136.8,131.0,129.5,128.6,127.1,125.6,124.7,124.1,122.3,45.6,32.3,21.1,14.0.HRMS(ESI-TOF):calculated for[C19H19NOS2Na(M+Na)]+:364.0806,found:364.0799.
Figure BDA0003349544250000143
1H NMR(400MHz,CDCl3),mixture of two isomer:δ7.79(d,J＝7.8Hz,0.86H),7.54–7.45(m,1H),7.41–7.31(m,1H),7.30–7.14(m,6H),6.96(s,0.14H),5.78–5.62(m,1.06H),5.26(brs,0.94H),4.33(t,J＝7.4Hz,0.14H),3.94(dd,J＝9.1,6.3Hz,0.86H),2.30–2.10(m,1H),1.99–1.88(m,0.86H),1.78–1.67(m,0.14H),1.43–1.32(m,0.28H),1.28–1.14(m,1.92H),0.91(t,J＝7.4Hz,0.42H),0.85(t,J＝7.3Hz,2.58H).13C NMR(101MHz,CDCl3),mixture of two isomer:δ175.5,174.4,156.6,156.3,148.4,145.2,141.3,134.8,132.8,132.2,129.5,129.2,128.5,128.3,128.2,128.1,127.2,126.6,126.0,125.9,125.3,123.4,123.3,121.8,121.0,113.3,111.7,111.3,48.2,43.9,43.8,35.2,32.5,20.9,14.1,13.9.HRMS(ESI-TOF):calculated for[C19H19NO2SNa(M+Na)]+:348.1034,found:348.1034.
Figure BDA0003349544250000151
1H NMR(400MHz,CDCl3):δ7.60–7.55(m,1H),7.53–7.48(m,1H),7.42(t,J＝7.4Hz,1H),7.36–7.21(m,6H),5.82(brs,1H),5.36(brs,1H),4.35(q,J＝7.0Hz,1H),1.48(d,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ176.2,143.9,136.8,134.9,132.8,129.5,129.4,129.2,128.2,128.1,126.7,42.7,18.2.HRMS(ESI-TOF):calculated for[C15H15NOSNa(M+Na)]+:280.0772,found:280.0786.
Figure BDA0003349544250000152
1H NMR(400MHz,CDCl3):δ7.66–7.60(m,1H),7.56–7.51(m,1H),7.46–7.40(m,1H),7.37–7.29(m,3H),7.29–7.22(m,3H),5.55(brs,1H),5.35(brs,1H),4.21(t,J＝7.4Hz,1H),2.24–2.07(m,1H),1.78–1.65(m,1H),1.40–1.21(m,11H),1.21–1.07(m,1H),0.94(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3):δ175.6,142.9,137.1,135.2,132.9,129.6,129.4,129.1,128.4,128.0,126.6,48.3,33.2,32.0,29.5,29.5,29.3,27.7,22.8,14.2.HRMS(ESI-TOF):calculated for[C22H29NOSNa(M+Na)]+:378.1868,found:378.1875.
Figure BDA0003349544250000153
1H NMR(400MHz,CDCl3):δ7.77–7.71(m,1H),7.58–7.52(m,1H),7.49–7.39(m,1H),7.38–7.29(m,3H),7.29–7.22(m,3H),5.50(brs,1H),5.35(brs,1H),3.91(d,J＝10.6Hz,1H),2.58–2.44(m,1H),1.12(d,J＝6.2Hz,3H),0.70(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3):δ175.4,142.1,137.4,135.4,133.1,129.6,129.4,129.1,128.7,127.9,126.6,55.9,31.6,21.7,19.8.HRMS(ESI-TOF):calculated for[C17H19NOSNa(M+Na)]+:308.1085,found:308.1087.
Figure BDA0003349544250000161
1H NMR(400MHz,CDCl3):δ7.61–7.55(m,1H),7.52–7.46(m,1H),7.41–7.34(m,1H),7.29–7.14(m,7H),7.14–7.07(m,4H),5.35(brs,1H),5.21(brs,1H),4.17(t,J＝6.5Hz,1H),2.67–2.56(m,1H),2.52–2.35(m,2H),2.04–1.82(m,1H).13C NMR(101MHz,CDCl3):δ175.0,142.6,141.6,137.2135.4,132.9,129.7,129.4,129.3,128.6,128.5,128.4,128.2,126.7,126.0,47.7,34.8,33.9.HRMS(ESI-TOF):calculated for[C22H21NOSNa(M+Na)]+:370.1242,found:370.1247.
Figure BDA0003349544250000162
1H NMR(400MHz,CDCl3):δ7.75–7.67(m,1H),7.49–7.44(m,1H),7.40(t,J＝7.4Hz,1H),7.29–7.23(m,3H),7.22–7.13(m,4H),7.12–7.07(m,2H),7.07–7.02(m,2H),5.39(brs,1H),5.26(brs,1H),4.45(dd,J＝8.4,5.8Hz,1H),3.47(dd,J＝13.1,9.4Hz,1H),2.86(dd,J＝13.4,5.2Hz,1H).13C NMR(101MHz,CDCl3):δ174.5,142.3,139.5,137.2,135.4,132.6,129.6,129.4,129.2,128.8,128.6,128.4,128.3,126.6,126.3,50.5,39.2.HRMS(ESI-TOF):calculated for[C21H19NOSNa(M+Na)]+:356.1085,found:356.1090.
Figure BDA0003349544250000163
1H NMR(400MHz,CDCl3):δ7.59–7.52(m,1H),7.51–7.44(m,1H),7.37(t,J＝7.4Hz,1H),7.31–7.23(m,3H),7.23–7.15(m,3H),5.71–5.58(m,1H),5.29(brs,2H),5.02–4.88(m,2H),4.25(t,J＝7.4Hz,1H),2.92–2.78(m,1H),2.46–2.33(m,1H).13C NMR(151MHz,CDCl3):δ174.8,142.0,137.0,135.5,135.3,133.0,129.6,129.5,129.2,128.6,128.2,126.8,117.1,48.2,37.1.HRMS(ESI-TOF):calculated for[C17H17NOSNa(M+Na)]+:306.0929,found:306.0939.
Figure BDA0003349544250000171
1H NMR(400MHz,CDCl3):δ7.59–7.55(m,1H),7.49–7.45(m,1H),7.40–7.31(m,3H),7.28–7.24(m,4H),7.24–7.20(m,2H),7.19–7.14(m,3H),5.37(brs,1H),5.24(brs,1H),4.49(t,J＝7.0Hz,1H),2.48–2.35(m,3H),2.02–1.93(m,1H).13C NMR(101MHz,CDCl3):δ174.8,142.0,137.0,135.2,133.3,131.7,129.6,129.5,129.4,128.5,128.32,128.27,127.7,126.8,124.0,89.2,81.6,47.0,32.1,17.8.HRMS(ESI-TOF):calculated for[C24H21NOSNa(M+Na)]+:394.1242,found:394.1249.
Figure BDA0003349544250000172
1H NMR(400MHz,CDCl3):δ7.64–7.59(m,1H),7.58–7.54(m,1H),7.48–7.43(m,1H),7.39–7.32(m,3H),7.32–7.24(m,3H),5.69(brs,1H),5.36(brs,1H),4.25(t,J＝7.3Hz,1H),3.57–3.45(m,2H),2.35–2.23(m,1H),1.95–1.85(m,1H),1.85–1.75(m,1H),1.70–1.57(m,1H).13C NMR(151MHz,CDCl3):δ175.0,142.1,136.8,135.3,133.0,129.7,129.5,129.2,128.31,128.28,126.9,47.5,44.7,30.6,30.4.HRMS(ESI-TOF):calculated for[C17H18ClNOSNa(M+Na)]+:342.0695,found:342.0692.
Figure BDA0003349544250000173
1H NMR(400MHz,CDCl3):δ7.57(d,J＝7.6Hz,1H),7.48(d,J＝7.6Hz,1H),7.38(t,J＝7.3Hz,1H),7.29–7.23(m,3H),7.22–7.14(m,5H),6.74(d,J＝8.6Hz,2H),5.80(brs,1H),5.36(brs,1H),4.24(t,J＝7.2Hz,1H),3.87–3.78(m,2H),2.33–2.21(m,1H),1.91–1.80(m,1H),1.78–1.68(m,1H),1.67–1.54(m,1H).13C NMR(151MHz,CDCl3):δ175.2,157.6,142.4,136.9,135.3,132.9,129.7,129.5,129.3,129.1,128.3,128.2,126.7,125.4,115.8,67.9,47.8,29.6,27.2.HRMS(ESI-TOF):calculated for[C22H23ClNO2SNa(M+Na)]+:434.0957,found:434.0955.
Figure BDA0003349544250000181
1H NMR(400MHz,CDCl3):δ7.63(d,J＝7.7Hz,1H),7.50(d,J＝7.7Hz,1H),7.41(t,J＝7.4Hz,1H),7.37–7.30(m,3H),7.30–7.22(m,4H),5.82(brs,1H),5.43(brs,1H),4.23(t,J＝7.2Hz,1H),2.25–2.10(m,1H),1.83–1.67(m,1H),1.52–1.41(m,1H),1.30(brs,13H),0.92–0.74(m,2H).13C NMR(151MHz,CDCl3):δ175.6,142.7,137.0,134.9,132.9,129.33,129.29,129.17,128.4,127.9,126.6,83.0,75.0,48.2,35.9,24.9,22.1.HRMS(ESI-TOF):calculated for[C23H31BNO3S(M+H)]+:412.2118,found:418.2124.
Figure BDA0003349544250000182
1H NMR(400MHz,CDCl3):δ7.70(d,J＝8.2Hz,2H),7.47–7.37(m,2H),7.32–7.25(m,3H),7.23–7.17(m,3H),7.16–7.07(m,3H),5.63(brs,1H),5.27(brs,1H),4.04(t,J＝7.3Hz,1H),3.87(dd,J＝6.4,5.5Hz,2H),2.38(s,3H),2.03–1.91(m,1H),1.58–1.41(m,3H),1.25–1.04(m,3H),1.03–0.91(m,1H).13C NMR(151MHz,CDCl3):δ175.3,144.7,142.5,136.9,135.2,133.2,132.8,129.9,129.5,129.4,129.1,128.2,128.0,127.9,126.7,70.6,48.0,32.8,28.6,26.9,25.2,21.7.HRMS(ESI-TOF):calculated for[C26H30NO4S2(M+H)]+:484.1616,found:484.1626.
Figure BDA0003349544250000183
1H NMR(400MHz,CDCl3):δ8.08–8.01(m,2H),7.59–7.54(m,2H),7.51–7.42(m,3H),7.41–7.36(m,1H),7.31–7.23(m,3H),7.22–7.16(m,3H),5.70(brs,1H),5.36(brs,1H),4.26(t,J＝6.6Hz,2H),4.19(t,J＝7.3Hz,1H),2.21–2.10(m,1H),1.75–1.64(m,3H),1.46–1.30(m,1H),1.25–1.12(m,1H).13C NMR(101MHz,CDCl3):δ175.5,166.7,142.7,137.0,135.3,132.9,132.8,130.5,129.6,129.4,129.1,128.4,128.3,128.0,126.7,65.0,48.1,33.0,28.6,27.3,25.9.HRMS(ESI-TOF):calculated for[C26H28NO3S(M+H)]+:434.1790,found:434.1786.
Figure BDA0003349544250000191
1H NMR(600MHz,CDCl3):δ7.62(d,J＝7.7Hz,1H),7.54(d,J＝7.7Hz,1H),7.43(t,J＝7.5Hz,1H),7.38–7.30(m,3H),7.30–7.23(m,3H),6.46(d,J＝17.3Hz,1H),6.17(dd,J＝17.3,10.4Hz,1H),5.92(brs,1H),5.88(d,J＝10.4Hz,1H),5.42(brs,1H),4.22(t,J＝7.3Hz,1H),4.15(t,J＝6.6Hz,2H),2.24–2.13(m,1H),1.78–1.60(m,3H),1.44–1.28(m,3H),1.27–1.12(m,1H).13C NMR(151MHz,CDCl3):δ175.5,166.3,142.7,137.0,135.2,132.8,130.5,129.5,129.4,129.1,128.7,128.3,128.0,126.6,64.6,48.1,33.0,28.4,27.2,25.8.HRMS(ESI-TOF):calculated for[C22H25NO3SNa(M+Na)]+:406.1453,found:406.1445.
Figure BDA0003349544250000192
1H NMR(400MHz,CDCl3):δ7.66–7.61(m,1H),7.50–7.45(m,1H),7.39–7.33(m,1H),7.29–7.22(m,3H),7.21–7.13(m,3H),5.33(brs,1H),5.18(brs,1H),3.97–3.90(m,2H),3.84–3.77(m,1H),3.41(t,J＝11.2Hz,1H),3.30–3.22(m,1H),2.40–2.28(m,1H),1.87–1.79(m,1H),1.40–1.26(m,1H),1.11–1.01(m,2H).13C NMR(101MHz,CDCl3):δ174.4,140.6,137.2,135.6,133.5,129.7,129.5,129.2,128.7,128.1,126.8,68.1,67.7,54.0,38.2,32.0,29.8.HRMS(ESI-TOF):calculated for[C19H21NO2SNa(M+Na)]+:350.1191,found:350.1194.
Figure BDA0003349544250000193
1H NMR(400MHz,CDCl3):δ7.65(d,J＝7.8Hz,1H),7.43(d,J＝7.7Hz,1H),7.36(t,J＝7.6Hz,1H),7.27–7.22(m,3H),7.21–7.14(m,1H),7.12–7.07(m,4H),7.02–6.97(m,2H),5.48(brs,1H),5.33(brs,1H),4.39(dd,J＝9.1,5.5Hz,1H),3.90–3.40(m,3H),2.80(dd,J＝13.5,5.4Hz,1H),1,59–0.98(m,12H).13C NMR(151MHz,CDCl3):δ174.3,171.1,142.2,140.1,137.0,136.8,135.4,132.5,129.6,129.5,129.1,128.8,128.5,128.2,126.6,125.7,50.2,38.9,20.8,20.8.HRMS(ESI-TOF):calculated for[C28H33N2O2S(M+H)]+:461.2263,found:461.2260.
Figure BDA0003349544250000201
1H NMR(400MHz,CDCl3):δ7.55–7.50(m,1H),7.39–7.35(m,1H),7.34–7.28(m,1H),7.27–7.14(m,6H),5.41(brs,1H),5.26(brs,1H),1.67(s,6H).13C NMR(101MHz,CDCl3):δ180.1,146.2,137.6,136.0,135.5,129.8,129.1,128.3,128.2,126.9,126.5,48.8,27.5.HRMS(ESI-TOF):calculated for[C16H17NOSNa(M+Na)]+:294.0929,found:294.0922.
本发明的实施例1中各反应底物可常规市购，也可根据常规方法制备，比如：
Figure BDA0003349544250000202
把(i-Pr)2NH(3.08mL,22mmol)在THF(10mL)中的溶液冷至-78℃，缓慢滴加n-BuLi(8.8mL,2.5M in hexane)，搅拌十分钟，再慢慢滴加腈(20mmol)在THF(14mL)的溶液。-78℃下搅拌20分钟后，滴加TMSCl(2.8mL,22mmol)在THF(12mL)的溶液。在-78℃反应1.5小时后，让体系慢慢升至室温，在室温搅拌5小时。旋蒸除去溶剂，残留物用石油醚稀释，过滤，滤液浓缩，硅胶粉柱层析，石油醚/乙酸乙酯体系洗脱，得到产物α-硅基腈。
Figure BDA0003349544250000203
1H NMR(400MHz,CDCl3):δ1.81–1.70(m,1H),1.58–1.39(m,3H),1.37–1.17(m,11H),0.87(t,J＝6.9Hz,3H),0.18(s,9H).13C NMR(101MHz,CDCl3):δ122.5,31.9,30.1,29.44,29.35,29.1,26.8,22.8,19.0,14.2,-3.1.MS(EI-TOF):calculated for[C12H24NSi(M–CH3)]+:210.2,found:210.2.
Figure BDA0003349544250000204
1H NMR(400MHz,CDCl3):δ2.05–1.89(m,1H),1.77(d,J＝4.3Hz,1H),1.08(dd,J＝9.2,6.9Hz,6H),0.19(s,9H).13C NMR(101MHz,CDCl3):δ120.9,27.7,26.9,24.4,21.0,-2.0.HRMS(EI-TOF):calculated for[C7H14NSi(M–CH3)]+:140.0896,found:140.0898.
Figure BDA0003349544250000211
1H NMR(400MHz,CDCl3):δ7.36–7.29(m,2H),7.28–7.19(m,3H),3.12–2.96(m,1H),2.82–2.63(m,1H),1.98–1.82(m,1H),1.83–1.70(m,2H),0.19(s,9H).13C NMR(101MHz,CDCl3):δ140.4,128.7,128.6,126.4,122.0,35.8,28.7,18.3,-3.2.HRMS(EI-TOF):calculated for[C12H16NSi(M–CH3)]+:202.1052,found:202.1053.
Figure BDA0003349544250000212
1H NMR(400MHz,CDCl3):δ7.36–7.28(m,2H),7.28–7.21(m,3H),2.90–2.71(m,2H),2.09–1.98(m,1H),0.22(s,9H).13C NMR(101MHz,CDCl3):δ139.5,128.8,128.4,127.0,121.9,32.9,21.8,-3.1.HRMS(EI-TOF):calculated for[C11H14NSi(M–CH3)]+:188.0896,found:188.0891.
Figure BDA0003349544250000213
1H NMR(400MHz,CDCl3):δ3.59(t,J＝6.1Hz,2H),2.21–2.05(m,1H),1.97–1.84(m,1H),1.83–1.70(m,2H),1.71–1.58(m,1H),0.20(s,9H).13C NMR(101MHz,CDCl3):δ121.8,44.0,32.3,23.9,18.2,-3.1.
如图3所示，本发明的邻芳基伯酰胺产物可以进行广泛的官能团转化，合成其它重要的结构。
具体如下：
Figure BDA0003349544250000214
把干燥的25mL反应瓶中放置3a(142.7mg,0.5mmol)，(HCHO)n(75.0mg,1.5mmol)，HCOOH(0.3mL)和无水CH3CN(2.0mL)，氮气保护下在85℃搅拌24小时。反应完成后，冷至室温，减压除去溶剂，残余物柱层析纯化，得到无色油状物7(118.3mg,88％yield)(Rf＝0.21,eluent:PE/EtOAc＝50/1)。
1H NMR(400MHz,CDCl3):δ7.65(dd,J＝7.7,1.2Hz,1H),7.47–7.39(m,2H),7.35–7.28(m,3H),7.27–7.16(m,3H),4.54(dd,J＝9.4,5.3Hz,1H),1.92–1.80(m,1H),1.80–1.68(m,1H),1.66–1.55(m,1H),1.55–1.41(m,1H),0.94(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ138.7,135.9,135.0,132.6,129.5,129.4,129.3,129.0,128.5,126.9,121.1,37.4,34.8,20.6,13.4.The 1H NMR and 13C NMR of 7are consistent with thereported spectra.
Figure BDA0003349544250000221
把3a(142.7mg,0.5mmol)溶于EtOH(10mL)，加入3M的KOH水溶液(7.7mL)，在90℃加热24小时。反应完成后，冷至室温，减压除去一半溶剂，残余物用浓盐酸酸化到pH＝1，用乙酸乙酯(2x10mL)提取。合并有机提取物，用硫酸钠干燥，硅胶柱层析纯化，得到无色油状物8(108.8mg,76％yield)(Rf＝0.63,eluent:DCM/MeOH＝10/1)。
1H NMR(400MHz,CDCl3):δ7.52–7.45(m,2H),7.40–7.34(m,1H),7.32–7.23(m,5H),7.23–7.18(m,1H),4.49(t,J＝7.5Hz,1H),2.15–2.02(m,1H),1.80–1.66(m,1H),1.42–1.19(m,2H),0.91(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ180.2,141.3,137.0,134.9,134.3,129.6,129.2,128.8,128.3,128.2,126.5,47.7,35.4,20.8,14.0.HRMS(ESI-TOF):calculated for[C17H18O2SNa(M+Na)]+:309.0925,found:309.0926.
Figure BDA0003349544250000222
把3a(142.7mg,0.5mmol)溶于EtOH(2.5mL)，室温下加入浓H2SO4(98％,0.63mL)，然后加热回流12小时。反应完成后冷至室温，加水(5mL)稀释，用二氯甲烷(5mL×3)提取。合并提取液，用水洗(10mL)、盐水洗(10mL)、硫酸钠干燥，减压浓缩，硅胶柱层析纯化，得到无色油状物9(129.7mg,82％yield)(Rf＝0.32,eluent:PE/EtOAc＝8/1)。
1H NMR(400MHz,CDCl3):δ7.51–7.41(m,2H),7.37–7.31(m,1H),7.29–7.15(m,6H),4.42(t,J＝7.5Hz,1H),4.15–3.96(m,1H),2.14–1.97(m,1H),1.73–1.62(m,1H),1.39–1.18(m,2H),1.15(t,J＝7.1Hz,3H),0.88(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3):δ174.2,142.4,137.4,135.1,133.8,129.3,129.1,128.9,128.3,127.9,126.3,60.8,47.8,36.0,20.9,14.2,14.0.HRMS(ESI-TOF):calculated for[C19H22O2SNa(M+Na)]+:337.1238,found:337.1244.
Figure BDA0003349544250000231
把3a(142.7mg,0.5mmol)溶于无水THF(5mL)，冰浴至0℃，缓慢滴加格氏试剂CH3MgBr(1.0M in cyclopentyl methyl ether,3.25mL,3.25mmol)，滴加完毕，在0℃搅拌1小时，然年暖至室温继续搅拌12小时。反应完毕，冷至0℃，往反应液中慢慢滴加稀盐酸(1M,5mL)，然后用乙酸乙酯提取(5mL×3)，合并有机提取层，分别用水洗(10mL)、盐水洗(10mL)、硫酸钠干燥，减压浓缩，硅胶柱层析纯化，得到无色油状物10(89.7mg,63％yield)(Rf＝0.27,eluent:PE/EA＝50/1)。
1H NMR(400MHz,CDCl3):δ7.41–7.37(m,1H),7.27–7.21(m,3H),7.21–7.15(m,5H),4.44(t,J＝7.2Hz,1H),2.02–1.92(m,1H),1.91(s,3H),1.54–1.42(m,1H),1.26–1.13(m,1H),1.11–1.00(m,1H),0.79(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ208.5,141.5,136.7,134.7,134.4,129.8,129.4,128.9,128.3,128.0,126.8,55.3,34.5,29.8,20.8,14.2.HRMS(ESI-TOF):calculated for[C18H21OS(M+H)]+:285.1313,found:285.1303.
Figure BDA0003349544250000232
把3a(142.7mg,0.5mmol)溶于无水THF(2mL)，室温下缓慢滴加硼烷二甲硫醚复合物(1.0M in THF,2.5mL,2.5mmol)，滴加完毕，在65℃搅拌24小时。反应完毕，冷至0℃，加入甲醇(1.0mL)终止反应，加入氢氧化钠溶液((1M,5mL))，然后用乙酸乙酯提取(10mL×5)，合并有机提取层，硫酸钠干燥，减压浓缩，硅胶柱层析纯化，得到无色油状物11(97.6mg,72％yield)(Rf＝0.45,eluent:DCM/MeOH＝10/1)。
1H NMR(600MHz,CDCl3):δ7.35(dd,J＝7.8,1.3Hz,1H),7.33–7.29(m,1H),7.28–7.24(m,3H),7.23–7.13(m,4H),3.50–3.44(m,1H),2.92(dd,J＝12.9,5.5Hz,1H),2.83–2.75(m,1H),1.74(brs,2H),1.67–1.58(m,1H),1.57–1.48(m,1H),1.23–1.10(m,2H),0.82(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ145.5,137.2,135.2,134.2,130.0,129.2,128.6,127.1,126.5,47.9,44.8,36.1,20.6,14.3.The 1H NMR and 13C NMR of 11areconsistent with the reported spectra.
Figure BDA0003349544250000241
把3a(142.7mg,0.5mmol)溶于DCM(2mL)，室温下缓慢滴加m-CPBA(2.5equiv)在DCM(3mL)中的溶液，滴加完毕，在室温搅拌3小时。反应完毕，加入饱和碳酸氢钠溶液(5mL)终止反应，然后用DCM(5mL×3)提取，合并有机提取层，硫酸钠干燥，减压浓缩，残余固体溶于MeCN(2.5mL)和水(2.5mL)，氮气保护下加入[Bis(trifluoroacetoxy)iodo]benzene(PIFA,322.5mg,0.75mmol)，室温搅拌36小时。反应完成后，加入稀盐酸(1M,4mL)，形成两相混合物，用石油醚(10mL×3)洗涤，水溶液加氢氧化钠溶液(2M,4mL)碱化，用EtOAc((10mL×5)提取，合并提取液，硫酸钠干燥，减压除去溶剂，硅胶柱层析纯化，得到白色固体12(120.2mg,83％yield)(Rf＝0.39,eluent:DCM/MeOH＝10/1)。
1H NMR(400MHz,CDCl3):δ8.19(d,J＝7.9Hz,1H),7.88–7.78(m,2H),7.66–7.54(m,3H),7.53–7.46(m,2H),7.46–7.39(m,1H),4.60(t,J＝6.9Hz,1H),1.94(brs,2H),1.59–1.45(m,1H),1.44–1.30(m,1H),1.15–1.01(m,1H),0.98–0.86(m,1H),0.69(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ146.9,142.3,138.1,134.4,133.2,129.3,129.3,128.2,127.3,127.2,50.1,40.1,19.7,14.0.HRMS(ESI-TOF):calculated for[C16H20NO2S(M+H)]+:290.1215,found:290.1216.
Figure BDA0003349544250000242
把3a(142.7mg,0.5mmol)溶于甲苯(2.5mL)，室温下加入N,N-dimethyl formamidedimethyl acetal(DMF-DMA,1.5mL)，滴加完毕，在90℃搅拌2小时。反应完毕，减压除去溶剂，得到黄色油状物，溶于甲苯(2.5mL)，加入N2H4-H2O(98％purity,50μL,0.6mmol)和AcOH(1.5mL)，90℃搅拌12小时。减压除去溶剂，残余物用EtOAc(20ml)溶解，依次用饱和碳酸氢钠溶液(20mL)和盐水(20mL)洗涤，硫酸钠干燥，减压浓缩，硅胶柱层析纯化，得到白色固体13(143.9mg,93％yield)(Rf＝0.39,eluent:PE/EA＝1/1)。
1H NMR(400MHz,CDCl3):δ10.68(brs,1H),7.89(s,1H),7.55–7.51(m,1H),7.47–7.42(m,1H),7.35–7.30(m,1H),7.29–7.13(m,7H),4.88(t,J＝7.6Hz,1H),2.30–2.19(m,1H),2.01–1.90(m,1H),1.34–1.12(m,2H),0.86(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ143.4,137.0,136.9,134.90,134.86,133.3,129.6,129.4,129.3,128.8,128.0,126.8,40.0,37.3,20.8,13.9.HRMS(ESI-TOF):calculated for[C18H20N3S(M+H)]+:310.1378,found:310.1382.
Figure BDA0003349544250000251
把3a(142.7mg,0.5mmol)溶于THF(10mL)，加入过量的Raney 2800Ni(使用前用THF洗涤五次；注意：干燥的Raney Ni易于着火)。反应物在常压氢气下室温剧烈搅拌48小时。反应完成后，用乙酸乙酯稀释，经硅藻土过滤，乙酸乙酯洗涤，滤液浓缩，硅胶柱层析纯化，得到白色固体14(76.4mg,86％yield)(Rf＝0.28,eluent:PE/EA＝2/1)。
1H NMR(400MHz,CDCl3):δ7.39–7.22(m,5H),5.77(brs,1H),5.43(brs,1H),3.39(t,J＝7.6Hz,1H),2.20–2.01(m,1H),1.82–1.67(m,1H),1.36–1.16(m,2H),0.90(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ176.4,140.1,129.0,128.1,127.4,52.7,35.1,20.9,14.0.HRMS(ESI-TOF):calculated for[C11H16NO(M+H)]+:178.1232,found:178.1239.
实施例2
Figure BDA0003349544250000252
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加Tf2NH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率65％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至40℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率80％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至60℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率75％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于乙腈(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率60％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于正己烷(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率70％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于硝基甲烷(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率<5％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌6小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率75％。
实施例3
Figure BDA0003349544250000271
将α-硅基腈1a3(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率60％。
Figure BDA0003349544250000272
将α-硅基腈1a4(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TfOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌12小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率25％。
实施例4
Figure BDA0003349544250000273
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加AcOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃～80℃搅拌48小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率0％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加TFA(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃～80℃搅拌48小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率0％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加MsOH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃～80℃搅拌48小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率45％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加BBI(双苯磺酰亚胺，0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃～80℃搅拌48小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率0％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加BF3·Et2O(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃～80℃搅拌48小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率40％。
将α-硅基腈1a(0.75mmol)和芳基亚砜2a(0.5mmol)溶于DCE(3.3mL)，0℃下缓慢滴加Tf2NH(0.75mmol)，滴完后继续搅拌10分钟，随后升温至50℃搅拌24小时。恢复至室温后，向反应液中加入饱和碳酸氢钠溶液(5mL)终止反应，混合物用DCM(5mL×3)提取，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到芳基伯酰胺产品3a，分离收率65％。
本发明利用α-硅基腈和芳基亚砜的反应，可以在短时间内成功合成丰富多样的芳基伯酰胺产物，方法的官能团耐受性好，结果令人满意。
上述所有的产品都通过一系列的核磁共振技术进行结构表征，其中提供的图1～2为代表性的化合物3a的核磁谱图；且图2为化合物3ac的单晶结构通过x射线晶体学分析确认。
本发明使用α-硅基腈和芳基亚砜，在酸催化下发生[3,3]-Sigmatropic重排，具有很好的区域选择性，没有相应的羧酸和氮芳基化副产物产生。该方案操作十分简便，只需要在酸作用下，50℃搅拌12小时即可；原料易于制备，官能团耐受性好，产物可以进行广泛的官能团转化，得到多种重要的结构。本发明为芳基伯酰胺结构的合成提供了一种优秀方案，对未来的药物合成发展具有重大意义。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (6)

1.一种邻芳基伯酰胺的制备方法，其特征在于，包括：将α-硅基腈和芳基亚砜混合在溶剂中，加入酸，搅拌，然后升温至40～80℃，搅拌，反应得到邻芳基伯酰胺；
所述的α-硅基腈的化学结构式为：
Figure FDA0003349544240000011
Si为选自三甲基硅基、叔丁基二甲基硅基、二甲基苯基硅基、三乙基硅基、三异丙基硅基、或叔丁基二苯基硅基的硅基基团；R1为取代或者未取代的烷基，取代基独立的选自卤素、烯、炔、醚、羧酸酯、硼酸酯、或酰胺中的一种或几种；
所述的芳基亚砜的化学结构式为：
Figure FDA0003349544240000012
Ar为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环；R2为取代或者未取代的苯基、取代或者未取代的萘基、取代或者未取代的芳杂环、取代或者未取代的烷基，取代基独立的选自卤素、烷基、烷氧基、炔基、烯基、酯基、硼酸酯中的一种或几种，芳杂环中的杂原子选自O和/或S；
所述的邻芳基伯酰胺的化学结构式为：
Figure FDA0003349544240000013
2.根据权利要求1所述的制备方法，其特征在于，Si为选自三甲基硅基、二甲基苯基硅基、或三乙基硅基的硅基基团。
3.根据权利要求1所述的制备方法，其特征在于，所述的溶剂选自1,2-二氯乙烷、乙腈、三氟甲基苯、甲苯、或正己烷；
所述的酸选自三氟甲烷磺酸、双三氟甲基磺酰亚胺、甲烷磺酸、或三氟化硼乙醚。
4.根据权利要求1所述的制备方法，其特征在于，
加入酸具体为：在0℃下加入酸；
升温至40～80℃具体为：升温至50℃；
反应时间为6～48小时。
5.根据权利要求4所述的制备方法，其特征在于，反应时间为8～24小时。
6.根据权利要求1所述的制备方法，其特征在于，所述的制备方法具体为：
将α-硅基腈和芳基亚砜混合在溶剂中，0℃下缓慢滴加酸，滴加完成后，继续搅拌5～15min，然后升温至40～80℃，搅拌8～24小时，反应得到邻芳基伯酰胺。
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