CN111116510B - 一类2-取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法和应用 - Google Patents
一类2-取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一类2‑取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法,以式(1)所示的N‑烷基/N‑芳基硫代酰胺衍生物为原料,在氧化剂,催化剂的存在下,在有机溶剂中,在温和的反应条件下,发生分子内的烯硫醇互变进而串联发生C‑S偶联去氢偶联反应,得到所述的2‑取代亚甲基二氢苯并[d]噻唑类衍生物。本发明2‑取代亚甲基二氢苯并[d]噻唑类衍生物的合成方法通过条件控制,具有条件温和、原子步骤经济、收率高等优点,且具有高化学选择性和高区域选择性,具有广泛的应用前景。本发明还公开了所述2‑取代亚甲基二氢苯并[d]噻唑类衍生物在医药和材料科学中的应用。
Description
技术领域
本发明属于合成医药、化工领域,主要涉及一类2-取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法和应用。
背景技术
苯并杂环类双环化合物广泛存在于自然界中,尤其是含N、O、S等元素的杂环结构更是普遍存在于天然产物和生物活性分子中。苯并噻唑和二氢苯并噻唑均为特殊的同时含N、S两种元素的双环杂环类物质,在医药和材料科学中均有广泛的应用。目前,通过分子内C-S偶联来构建具有芳香性的苯并噻唑类化合物的报道很多,而合成所述的无芳香性的二氢苯并噻唑类化合物的方法却鲜有报道。
发明内容
本发明的目的是针对现有技术的不足而提供的一类2-取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法,该合成方法采用了便宜易得的催化剂和氧化剂,在温和的条件下以良好至优秀的收率合成了2-取代亚甲基二氢苯并[d]噻唑类衍生物。该方法操作简单,原子经济、步骤经济,具有很高的化学选择性和位置选择性,底物适用范围较广,收率高。
本发明提出了2-取代亚甲基二氢苯并[d]噻唑类衍生物及其合成方法。
本发明提出的一类2-取代亚甲基二氢苯并[d]噻唑类衍生物,具下式(2)结构:
其中,R1为氢、烷基、苯基、酯基、酰基、卤素、烷氧基、磺酰胺基等;
R2为烷基、有取代的烷基等;
R3,R4独自为烷基或苄基等。
优选地,
R1为氢、甲基、甲氧基、磺酰胺基、卤素、甲酸乙酯基、乙酰基、苯基等;
R2为甲基、乙基、异丙基、正己基、苯乙基、3-甲氧基丙基等;
R3、R4独自为甲基、乙基、异丙基、苄基等。
本发明提出的一种2-取代亚甲基二氢苯并[d]噻唑类衍生物的合成方法,包括:在有机溶剂中,在室温条件下,式(1)所示的N-烷基/N-芳基硫代酰胺衍生物和氧化剂、催化剂发生分子内的烯硫醇互变进而串联发生C-S偶联去氢偶联反应,得到如式(2)所示的2-取代亚甲基二氢苯并[d]噻唑类衍生物。
所述反应过程如反应式(Ⅰ)所示:
其中,R1为氢、烷基、苯基、酯基、酰基、卤素、烷氧基、磺酰胺基等;
R2为烷基、有取代的烷基等;
R3,R4独自为烷基或苄基等。
优选地,
R1为氢、甲基、甲氧基、磺酰胺基、卤素、甲酸乙酯基、乙酰基、苯基等;
R2为甲基、乙基、异丙基、正己基、苯乙基、3-甲氧基丙基等;
R3、R4独自为甲基、乙基、异丙基、苄基等。
其中,所述式(1)所示的N-烷基/N-芳基硫代酰胺衍生物与氧化剂的摩尔比为1:(1-2);优选地,为1:2、1:1.5、1:1;进一步优选地为1:2;式(1)所示的N-烷基/N-芳基硫代酰胺衍生物与催化剂的摩尔比为1:(0.05-0.1);优选地,为1:0.1、1:0.05;进一步优选地为1:0.1。
其中,所述的催化剂为无水溴化钴、无水氯化钴、无水三溴化铁、无水溴化镍、无水溴化铜、无水溴化锌、无水三氯化铝、三氟化硼***;优选地为无水溴化钴。
其中,所述的氧化剂为DDQ、过硫酸钾、过硫酸钠、TBHP、DTBP、氧气;优选地为DDQ。
其中,所述有机溶剂为无水乙腈、无水甲苯、无水四氢呋喃、无水二氯甲烷、无水1,4-二氧六环、无水N,N-二甲基甲酰胺、无水二甲亚砜;优选地为无水乙腈。
其中,所述反应的时间为4~20小时。
其中,本发明所述方法还包括后处理和柱色谱分离纯化步骤;其中,所述分离纯化是用乙酸乙酯/石油醚混合溶剂为洗脱剂进行柱层析分离,乙酸乙酯:石油醚混合溶剂的体积比为1:3~1:10。
在一个具体实施方式中,本发明所述方法包括:将式(1)所示的N-烷基/N-芳基硫代酰胺衍生物和氧化剂、催化剂于有机溶剂中在室温下发生分子内的烯硫醇互变,进而串联发生C-S偶联去氢偶联反应,TLC监测至原料反应完,反应用饱和硫代硫酸钠溶液淬灭,二氯甲烷萃取混合物,用饱和碳酸氢钠溶液洗涤有机相,用无水硫酸钠干燥,过滤。滤液在减压下浓缩,残余物采用石油醚/乙酸乙酯的混合溶剂进行柱色谱分离,得到如式(2)所示的2-取代亚甲基二氢苯并[d]噻唑类衍生物。
本发明提出的合成2-取代亚甲基二氢苯并[d]噻唑类衍生物的方法,是以式(1)所示的N-烷基/N-芳基硫代酰胺衍生物为原料,在催化剂,氧化剂的存在下,在有机溶剂中,在温和的反应条件下,发生分子内的烯硫醇互变进而串联发生C-S偶联去氢偶联反应,经过后处理和柱色谱分离纯化,得到纯化的2-取代亚甲基二氢苯并[d]噻唑类衍生物。
本发明采用了易于制备的原料,通过分子内的去氢偶联反应,在温和的反应条件下,高效构建了2-取代亚甲基二氢苯并[d]噻唑类衍生物。该方法操作简单,原子经济、步骤经济,具有很高的化学选择性和位置选择性,底物适用范围较广,收率最高可至99%。本发明合成的该类2-取代亚甲基二氢苯并[d]噻唑类衍生物均为新化合物,是首次合成,可以应用在医药和材料科学中。
附图说明
图1-32分别为本发明实施例1-32合成的2-取代亚甲基二氢苯并[d]噻唑类衍生物的核磁共振1HNMR、13C NMR图谱。
具体实施方式
以下结合具体实施例及附图,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
实施例1
将2-(甲基(苯基)氨基甲酰基)丙二酸二甲酯(56.2mg,0.2mmol),无水溴化钴(4.4mg,0.02mmol),DDQ(90.8mg,0.4mmol)加入到反应瓶中,加入无水乙腈4mL,至于室温下反应4小时,TLC检测原料完全消耗,加入饱和硫代硫酸钠溶液(4mL)淬灭反应,有机相用二氯甲烷萃取,再用饱和碳酸氢钠溶液洗涤有机相2次,有机相在减压下浓缩,残余物通过硅胶柱色谱分离,得到纯产物55.1mg,其结构如式(2-1)所示,产率99%。核磁共振1H NMR、13CNMR图谱如图1所示,产物:1HNMR(500MHz,CDCl3)δ7.60(dd,J=7.8,0.5Hz,1H),7.41–7.37(m,1H),7.23(ddd,J=13.8,10.4,4.5Hz,2H),3.84(s,6H),3.50(s,3H).13C NMR(126MHz,CDCl3)δ167.38,166.90,141.55,127.36,126.55,123.71,121.72,111.32,87.82,51.84,37.21.
HRMS(EI)m/z calculated for C13H13NO4S[M]+279.0565,found 279.0569.
实施例2
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-甲氧基苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间5小时,所得到的产物如结构式(2-2)所示。产率为91%。核磁共振1H NMR、13C NMR图谱如图2所示,产物:1HNMR(500MHz,CDCl3)δ7.39(s,1H),7.18(dd,J=8.3,0.7Hz,1H),7.09(d,J=8.3Hz,1H),3.83(s,6H),3.48(s,3H),2.41(s,3H).13C NMR(126MHz,CDCl3)δ167.42,167.10,139.54,133.85,127.55,127.42,121.80,111.09,87.14,51.76,37.30,21.04.
HRMS(EI)m/z calculated for C14H15NO5S[M]+309.0671,found 309.0673.
实施例3
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(对甲苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间4小时,所得到的产物如结构式(2-3)所示。产率为87%。核磁共振1H NMR、13C NMR图谱如图3所示,产物:1H NMR(500MHz,CDCl3)δ7.31(s,1H),7.10(d,J=8.3Hz,1H),7.01(d,J=8.3Hz,1H),3.75(s,6H),3.39(s,3H),2.33(s,3H).13C NMR(126MHz,CDCl3)δ167.40,167.06,139.52,133.83,127.54,127.40,121.78,111.08,87.14,51.75,37.29,21.03.
HRMS(EI)m/z calculated for C14H15NO4S[M]+293.0722,found 293.0724.
实施例4
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-(N,4-二甲基苯基磺酰胺基)苯基)(甲基)氨基甲硫酰基)二甲基丙二酸酯,室温下反应时间5小时,所得到的产物如结构式(2-4)所示。产率为89%。核磁共振1H NMR、13C NMR图谱如图4所示,产物:1H NMR(500MHz,CDCl3)δ7.41(d,J=8.2Hz,2H),7.25(d,J=8.1Hz,2H),7.20(dd,J=8.7,2.0Hz,1H),7.17(d,J=1.9Hz,1H),7.12(d,J=8.7Hz,1H),3.84(s,6H),3.48(s,3H),3.18(s,3H),2.43(s,3H).13C NMR(126MHz,CDCl3)δ167.21,166.46,143.97,140.52,137.49,132.95,129.51,127.88,127.72,126.00,119.52,111.20,88.76,51.97,38.44,37.22,21.58.
HRMS(EI)m/z calculated for C21H22N2O6S2[M]+462.0919,found 462.0916.
实施例5
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-氟苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间4小时,所得到的产物如结构式(2-5)所示。产率为88%。核磁共振1H NMR、13C NMR图谱如图5所示,产物:1HNMR(500MHz,CDCl3)δ7.32(dd,J=7.6,2.4Hz,1H),7.16–7.06(m,2H),3.84(s,6H),3.48(s,3H).13C NMR(126MHz,CDCl3)δ167.22,166.75,160.22,158.28,137.96,128.90,128.83,114.05,113.85,112.03,111.96,108.87,108.66,88.26,51.90,37.47.
HRMS(EI)m/z calculated for C13H12NO4SF[M]+297.0471,found 297.0467.
实施例6
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-氯苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间4小时,所得到的产物如结构式(2-6)所示。产率为64%。核磁共振1H NMR、13C NMR图谱如图6所示,产物:1H NMR(500MHz,CDCl3)δ7.55(d,J=1.9Hz,1H),7.32(dd,J=8.7,1.9Hz,1H),7.08(d,J=8.7Hz,1H),3.84(s,6H),3.46(s,3H).13C NMR(126MHz,CDCl3)δ167.20,166.04,140.27,129.17,128.93,126.74,121.45,111.91,88.78,51.98,37.21.
HRMS(EI)m/z calculated for C13H12NO4SCl[M]+313.0176,found 313.0181.
实施例7
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-溴苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间4小时,所得到的产物如结构式(2-7)所示。产率为73%。核磁共振1H NMR、13C NMR图谱如图7所示,产物:1H NMR(500MHz,CDCl3)δ7.69(d,J=1.8Hz,1H),7.46(dd,J=8.7,1.8Hz,1H),7.03(d,J=8.7Hz,1H),3.84(s,6H),3.46(s,3H).13C NMR(126MHz,CDCl3)δ167.19,165.87,140.71,129.53,129.33,124.24,116.33,112.29,88.83,52.00,37.16.
HRMS(EI)m/z calculated for C13H12NO4SBr[M]+356.9670,found 356.9668.
实施例8
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-碘苯基)(甲基)氨基甲硫酰基)丙二酸二甲酯,室温下反应时间7小时,所得到的产物如结构式(2-8)所示。产率为82%。核磁共振1H NMR、13C NMR图谱如图8所示,产物:1H NMR(600MHz,CDCl3)δ7.77(s,1H),7.55(d,J=8.5Hz,1H),6.83(d,J=8.6Hz,1H),3.76(s,6H),3.37(s,3H).13C NMR(151MHz,CDCl3)δ167.18,165.50,141.34,135.29,129.90,129.64,112.69,88.86,86.11,51.99,37.01.
HRMS(EI)m/z calculated for C13H12INO4S[M]+404.9532,found404.9534.
实施例9
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-(乙氧基羰基)苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间12小时,所得到的产物如结构式(2-9)所示。产率为82%。核磁共振1H NMR、13C NMR图谱如图9所示,产物:1H NMR(500MHz,CDCl3)δ8.24(d,J=1.3Hz,1H),8.07(dd,J=8.6,1.4Hz,1H),7.18(d,J=8.6Hz,1H),4.40(q,J=7.1Hz,2H),3.85(s,6H),3.52(s,3H),1.42(t,J=7.1Hz,3H).13C NMR(126MHz,CDCl3)δ167.13,166.01,165.52,144.69,128.41,127.31,125.85,123.17,110.51,89.97,61.29,52.06,36.96,14.35.
HRMS(EI)m/z calculated for C16H17NO6S[M]+351.0777,found 351.0776.
实施例10
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((4-乙酰基苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的产物如结构式(2-10)所示。产率为85%。核磁共振1H NMR、13C NMR图谱如图10所示,产物:1H NMR(500MHz,CDCl3)δ8.15(d,J=1.4Hz,1H),7.99(dd,J=8.6,1.5Hz,1H),7.20(d,J=8.6Hz,1H),3.85(s,6H),3.52(s,3H),2.63(s,3H).13C NMR(126MHz,CDCl3)δ196.07,167.10,165.76,144.82,132.66,127.63,127.40,122.09,110.60,90.36,52.12,36.89,26.58.
HRMS(EI)m/z calculated for C15H15NO5S[M]+321.0671,found 321.0675.
实施例11
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((2-甲氧基苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间5小时,所得到的产物如结构式(2-11)所示。产率为87%。核磁共振1H NMR、13C NMR图谱如图11所示,产物:1HNMR(500MHz,CDCl3)δ7.21–7.13(m,2H),6.87(dd,J=7.0,2.1Hz,1H),3.92(s,3H),3.84(s,6H),3.70(s,3H).13C NMR(126MHz,CDCl3)δ169.08,167.38,147.61,130.89,129.41,124.82,113.94,109.14,87.27,56.02,51.69,42.24.
HRMS(EI)m/z calculated for C14H15NO5S[M]+309.0671,found 309.0674.
实施例12
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(邻甲苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间10小时,所得到的产物如结构式(2-12)所示。产率为89%。核磁共振1HNMR、13C NMR图谱如图12所示,产物:1H NMR(500MHz,CDCl3)δ7.43(t,J=4.5Hz,1H),7.13(d,J=4.8Hz,2H),3.85(s,6H),3.63(s,3H),2.67(s,3H).13C NMR(126MHz,CDCl3)δ170.29,167.33,141.26,130.29,128.18,124.04,123.29,119.53,88.49,51.78,43.28,20.50.
HRMS(EI)m/z calculated for C14H15NO4S[M]+293.0722,found 293.0720.
实施例13
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(间甲苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间12小时,所得到的产物为混合物,如结构式(2-13-a)和(2-13-b)所示。总产率为83%(比例为a:b=3.7:1)。核磁共振1H NMR、13CNMR图谱如图13所示,产物:1H NMR(500MHz,CDCl3)δ7.47(d,J=7.9Hz,1H),7.30(t,J=7.8Hz,1H),7.07(d,J=8.1Hz,1H),7.05(d,J=3.3Hz,1H),7.03(s,1H),3.85(s,2H),3.84(s,6H),3.50(s,1H),3.48(s,3H),2.47(s,1H),2.46(s,3H).13C NMR(126MHz,CDCl3)δ167.53,167.45,167.38,141.78,136.93,126.74,124.89,124.48,124.30,121.34,111.92,108.93,87.47,51.80,51.78,37.42,37.26,21.67,19.51.
HRMS(EI)m/z calculated for C14H15NO4S[M]+293.0722,found 293.0718.
实施例14
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3-甲氧基苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间20小时,所得到的产物为混合物,如结构式(2-14-a)和(2-14-b)所示。总产率为70%(比例为a:b=1.4:1)。核磁共振1HNMR、13C NMR图谱如图14所示,产物:1H NMR(500MHz,CDCl3)δ7.70(s,1H),7.46(d,J=8.6Hz,1H),6.83(dd,J=8.6,2.2Hz,1H),6.73(d,J=2.1Hz,1H),6.68(s,1H),3.96(s,2H),3.87(s,3H),3.84(s,4H),3.84(s,6H),3.48(s,2H),3.47(s,3H).13C NMR(126MHz,CDCl3)δ168.22,167.43,167.33,167.19,159.42,155.41,142.83,142.01,125.39,122.19,119.97,118.96,110.45,107.15,97.71,95.69,88.58,87.80,56.76,55.86,51.94,51.81,37.52,37.38.
HRMS(EI)m/z calculated for C14H15NO5S[M]+309.0671,found 309.0669.
实施例15
本实施例实验方法基本与实施例2-1相同,本实施例中所采用的原料为2-([1,1'-联苯]-3-基(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的两个产物如结构式(2-15-a)和(2-15-b)所示。总产率为97%(比例为a:b=1.25:1)。产物a的核磁共振1H NMR、13C NMR图谱如图15-a所示,产物a:1H NMR(500MHz,CDCl3)δ7.63(d,J=8.1Hz,1H),7.59(d,J=7.5Hz,2H),7.50–7.43(m,3H),7.39(t,J=7.3Hz,1H),7.35(s,1H),3.85(s,6H),3.54(s,3H).13C NMR(126MHz,CDCl3)δ167.34,167.16,142.26,140.46,140.36,129.00,127.85,127.29,126.40,123.06,121.89,109.94,88.19,51.88,37.30.
HRMS(EI)m/z calculated for C19H17NO4S[M]+355.0878,found 355.0876.
产物b的核磁共振1H NMR、13C NMR图谱如图15-b所示,产物b:1H NMR(500MHz,CDCl3)δ7.59(d,J=7.3Hz,2H),7.47(dd,J=14.1,7.5Hz,3H),7.40(t,J=7.4Hz,1H),7.27(d,J=8.0Hz,1H),7.18(d,J=8.1Hz,1H),3.83(s,6H),3.53(s,3H).13C NMR(126MHz,CDCl3)δ167.40,167.34,142.17,138.71,136.74,129.09,128.40,128.04,127.86,127.16,126.27,125.80,123.98,110.12,87.65,51.83,37.53.
HRMS(EI)m/z calculated for C19H17NO4S[M]+355.0878,found 355.0881.
实施例16
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3-氟苯基)(甲基)氨基甲硫酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的产物为混合物,如结构式(2-16-a)和(2-16-b)所示。总产率为87%(比例为a:b=12.5:1)。核磁共振1HNMR、13C NMR图谱如图16所示,产物:1H NMR(500MHz,CDCl3)δ7.42(dd,J=8.5,5.1Hz,1H),7.25(td,J=8.1,5.5Hz,1H),6.87(ddd,J=25.3,12.6,5.5Hz,2H),3.76(s,6H),3.41(s,1H),3.38(s,3H).13C NMR(126MHz,CDCl3)δ167.35,167.17,163.08,161.13,142.76,142.67,122.59,122.51,122.47,122.45,111.18,110.99,99.40,99.18,88.98,52.01,51.96,37.41,37.19,1.02.
HRMS(EI)m/z calculated for C13H12FNO4S[M]+297.0471,found297.0474.
实施例17
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3-氯苯基)(甲基)氨基甲酰基)丙二酸二甲酯,室温下反应时间6小时,所得到的两个产物如结构式(2-17-a)和(2-17-b)所示。总产率为86%(比例为a:b=2.7:1)。产物a的核磁共振1H NMR、13C NMR图谱如图17-a所示,产物a:1H NMR(500MHz,CDCl3)δ7.48(d,J=8.2Hz,1H),7.22–7.15(m,2H),3.84(s,6H),3.46(s,3H).13C NMR(126MHz,CDCl3)δ167.16,166.47,142.61,132.63,125.73,123.72,122.41,111.50,89.11,52.00,37.09.
HRMS(EI)m/z calculated for C13H12NO4SCl[M]+313.0176,found 313.0177.
产物b的核磁共振1H NMR、13C NMR图谱如图17-b所示,产物b:1H NMR(500MHz,CDCl3)δ7.32(t,J=8.0Hz,1H),7.20(d,J=7.9Hz,1H),7.07(d,J=8.2Hz,1H),3.85(s,6H),3.48(s,3H).13C NMR(126MHz,CDCl3)δ167.22,165.87,142.58,127.74,127.55,126.89,123.49,109.24,89.10,52.02,37.34.
HRMS(EI)m/z calculated for C13H12NO4SCl[M]+313.0176,found 313.0179.
实施例18
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3,5-二甲氧基苯基)(甲基)氨基甲硫酰基)丙二酸二甲酯,室温下反应时间5小时,所得到的产物如结构式(2-18)所示。产率为89%。核磁共振1H NMR、13C NMR图谱如图18所示,产物:1H NMR(500MHz,CDCl3)δ6.28(d,J=5.1Hz,2H),3.84(s,3H),3.79(s,3H),3.76(s,6H),3.38(s,3H).13C NMR(126MHz,CDCl3)δ168.65,167.33,160.92,154.62,143.29,107.58,94.34,89.40,87.28,56.01,55.91,51.71,37.61.
HRMS(EI)m/z calculated for C15H17NO6S[M]+339.0777,found339.0781.
实施例19
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3,5-二氟苯基)(甲基)氨基甲硫酰基)二甲基丙二酸酯,室温下反应时间16小时,所得到的产物如结构式(2-19)所示。产率为71%。核磁共振1H NMR、13C NMR图谱如图19所示,产物:1H NMR(500MHz,CDCl3)δ6.72–6.62(m,2H),3.77(s,6H),3.37(s,3H).13C NMR(126MHz,CDCl3)δ167.01,166.06,163.27,163.18,161.31,161.22,157.58,157.47,155.60,155.49,144.28,144.21,144.18,144.10,110.06,110.04,109.88,109.86,99.27,99.08,99.05,98.86,95.51,95.48,95.28,95.25,90.07,52.13,37.28.
HRMS(EI)m/z calculated for C13H11F2NO4S[M]+315.0377,found315.0382.
实施例20
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(萘-1-基)氨基甲酰基)丙二酸二甲酯,室温下反应时间12小时,所得到的产物如结构式(2-20)所示。产率为79%。核磁共振1HNMR、13C NMR图谱如图20所示,产物:1HNMR(500MHz,CDCl3)δ8.33(d,J=8.6Hz,1H),7.93(d,J=8.3Hz,1H),7.71(d,J=8.5Hz,1H),7.63(d,J=8.5Hz,1H),7.57(t,J=7.7Hz,1H),7.52(t,J=7.4Hz,1H),3.92(s,3H),3.89(s,6H).13C NMR(126MHz,CDCl3)δ170.95,167.34,137.17,133.29,129.55,126.69,125.80,125.62,124.93,122.13,121.69,118.80,88.49,51.83,45.19.
HRMS(EI)m/z calculated for C17H15NO4S[M]+329.0722,found 329.0719.
实施例21
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(萘-2-基)氨基甲酰基)丙二酸二甲酯,室温下反应时间10小时,所得到的产物如结构式(2-21)所示。产率为70%。核磁共振1HNMR、13C NMR图谱如图21所示,产物:1H NMR(500MHz,CDCl3)δ7.86(t,J=7.6Hz,2H),7.80(d,J=8.9Hz,1H),7.58(t,J=7.7Hz,1H),7.48(t,J=7.5Hz,1H),7.34(d,J=8.9Hz,1H),3.87(s,6H),3.57(s,3H).13C NMR(126MHz,CDCl3)δ167.43,167.20,138.71,129.99,128.84,127.86,127.83,127.26,125.71,123.06,122.91,111.15,86.99,51.80,37.74.
HRMS(EI)m/z calculated for C17H15NO4S[M]+329.0722,found 329.0721.
实施例22
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(噻吩-2-基)氨基甲酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的产物如结构式(2-22)所示。产率为46%。核磁共振1HNMR、13C NMR图谱如图22所示,产物:1H NMR(500MHz,CDCl3)δ7.38(d,J=5.3Hz,1H),6.96(d,J=5.3Hz,1H),3.83(s,6H),3.55(s,3H).13C NMR(126MHz,CDCl3)δ172.99,167.08,146.50,128.67,121.75,112.20,86.14,51.68,39.33.
HRMS(EI)m/z calculated for C11H11NO4S2[M]+285.0130,found 285.0134.
实施例23
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(苯基)氨基甲酰基)丙二酸二乙酯,室温下反应时间10小时,所得到的产物如结构式(2-23)所示。产率为88%。核磁共振1HNMR、13C NMR图谱如图23所示,产物:1HNMR(500MHz,CDCl3)δ7.57(d,J=7.8Hz,1H),7.39–7.33(m,1H),7.23–7.15(m,2H),4.30(q,J=7.1Hz,4H),3.50(s,3H),1.35(t,J=7.1Hz,6H).13C NMR(126MHz,CDCl3)δ167.11,165.77,141.57,127.31,126.39,123.45,121.63,111.08,88.92,60.61,37.00,14.41.
HRMS(EI)m/z calculated for C15H17NO4S[M]+307.0878,found 307.0876.
实施例24
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(苯基)氨基甲酰基)丙二酸二异丙酯,室温下反应时间12小时,所得到的产物如结构式(2-24)所示。产率为86%。核磁共振1HNMR、13C NMR图谱如图24所示,产物:1H NMR(500MHz,CDCl3)δ7.55(d,J=7.7Hz,1H),7.36–7.32(m,1H),7.19(t,J=7.6Hz,1H),7.14(d,J=8.2Hz,1H),5.18(hept,J=6.2Hz,2H),3.49(s,3H),1.34(d,J=6.3Hz,12H).13C NMR(126MHz,CDCl3)δ166.78,164.60,141.60,127.27,126.27,123.21,121.59,110.81,90.21,67.98,36.65,22.06.
HRMS(EI)m/z calculated for C17H21NO4S[M]+335.1191,found 335.1187.
实施例25
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(甲基(苯基)氨基甲酰基)丙二酸二苄基酯,室温下反应时间4小时,所得到的产物如结构式(2-25)所示。产率为81%。核磁共振1HNMR、13C NMR图谱如图25所示,产物:1HNMR(500MHz,CDCl3)δ7.55(d,J=7.8Hz,1H),7.31(dt,J=29.5,13.9Hz,11H),7.20(t,J=7.6Hz,1H),7.13(d,J=8.2Hz,1H),5.27(s,4H),3.39(s,3H).13C NMR(126MHz,CDCl3)δ166.81,141.56,136.46,128.45,128.15,127.92,127.37,126.53,123.69,121.71,111.34,88.27,66.50,37.36.
HRMS(EI)m/z calculated for C25H21NO4S[M]+431.1191,found431.1189.
实施例26
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为1-苄基3-甲基-2-(甲基(苯基)氨基甲酰基)丙二酸酯,室温下反应时间6小时,所得到的产物如结构式(2-26)所示。产率为85%。核磁共振1HNMR、13C NMR图谱如图26所示,产物:1H NMR(500MHz,CDCl3)δ7.57(d,J=7.8Hz,1H),7.43(d,J=7.4Hz,2H),7.36(t,J=7.6Hz,3H),7.30(t,J=7.3Hz,1H),7.22(t,J=7.6Hz,1H),7.16(d,J=8.2Hz,1H),5.31(s,2H),3.82(s,3H),3.43(s,3H).13C NMR(126MHz,CDCl3)δ167.43,166.77,166.74,141.55,136.55,128.44,127.92,127.34,126.53,123.69,121.70,111.32,88.06,66.34,51.80,37.28.
HRMS(EI)m/z calculated for C19H17NO4S[M]+355.0878,found 355.0883.
实施例27
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(乙基(苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间6小时,所得到的产物如结构式(2-27)所示。产率为92%。核磁共振1HNMR、13C NMR图谱如图27所示,产物:1H NMR(500MHz,CDCl3)δ7.55(d,J=7.7Hz,1H),7.37–7.31(m,1H),7.22–7.13(m,2H),4.02(q,J=7.2Hz,2H),3.83(s,6H),1.35(t,J=7.2Hz,3H).13C NMR(126MHz,CDCl3)δ167.74,162.40,140.46,127.27,126.30,123.21,121.73,110.91,88.19,52.11,42.86,12.36.
HRMS(EI)m/z calculated for C14H15NO4S[M]+293.0722,found 293.0726.
实施例28
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(异丙基(苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的产物如结构式(2-28)所示。产率为79%。核磁共振1HNMR、13C NMR图谱如图28所示,产物:1H NMR(500MHz,CDCl3)δ7.59(d,J=7.8Hz,1H),7.50(d,J=8.4Hz,1H),7.34–7.29(m,1H),7.20(t,J=7.6Hz,1H),4.41(hept,J=6.9Hz,1H),3.82(s,6H),1.60(d,J=6.9Hz,6H).13C NMR(126MHz,CDCl3)δ167.73,167.55,139.13,128.87,125.61,123.33,122.05,114.39,87.76,55.79,51.95,20.07.
HRMS(EI)m/z calculated for C15H17NO4S[M]+307.0878,found 307.0881.
实施例29
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(己基(苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间10小时,所得到的产物如结构式(2-29)所示。产率为91%。核磁共振1HNMR、13C NMR图谱如图29所示,产物:1H NMR(500MHz,CDCl3)δ7.56(d,J=7.7Hz,1H),7.34(t,J=7.8Hz,1H),7.19(t,J=7.6Hz,1H),7.13(d,J=8.2Hz,1H),3.96–3.91(m,2H),3.83(s,6H),1.77–1.67(m,2H),1.27(d,J=16.1Hz,6H),0.88(t,J=6.4Hz,3H).13C NMR(126MHz,CDCl3)δ167.71,162.99,140.73,127.29,126.24,123.20,121.73,111.18,88.31,52.08,48.06,31.32,26.80,26.37,22.49,13.92.
HRMS(EI)m/z calculated for C18H23NO4S[M]+349.1348,found 349.1345.
实施例30
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-(苯乙基(苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间8小时,所得到的产物如结构式(2-30)所示。产率为94%。核磁共振1HNMR、13C NMR图谱如图30所示,产物:1HNMR(500MHz,CDCl3)δ7.55(d,J=7.7Hz,1H),7.36–7.27(m,3H),7.19(ddd,J=19.7,12.3,6.6Hz,5H),4.17–4.11(m,2H),3.82(s,6H),3.04–2.99(m,2H).13C NMR(126MHz,CDCl3)δ167.74,162.54,140.58,137.14,128.79,128.66,127.20,127.00,126.34,123.30,121.79,110.98,88.79,52.18,48.95,32.79.
HRMS(EI)m/z calculated for C20H19NO4S[M]+369.1035,found 369.1033.
实施例31
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为2-((3-甲氧基丙基)(苯基)氨基甲酰基)丙二酸二甲酯,室温下反应时间6小时,所得到的产物如结构式(2-31)所示。产率为83%。核磁共振1H NMR、13C NMR图谱如图31所示,产物:1H NMR(500MHz,CDCl3)δ7.55(d,J=7.7Hz,1H),7.34(t,J=7.7Hz,1H),7.23(d,J=8.2Hz,1H),7.19(t,J=7.4Hz,1H),4.10(t,J=7.3Hz,2H),3.83(s,6H),3.31(t,J=5.1Hz,2H),3.28(s,3H),2.04–1.96(m,2H).13C NMR(126MHz,CDCl3)δ167.71,162.67,140.89,127.02,126.27,123.21,121.60,111.33,88.46,69.28,58.72,52.11,45.05,27.13.
HRMS(EI)m/z calculated for C16H19NO5S[M]+337.0984,found 337.0986.
实施例32
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为四甲基2,2'-((((羰基双(4,1-亚苯基))双(甲基氮杂二基))双(羰硫基))二丙二酸酯(117.6mg,0.2mmol),无水溴化钴(8.8mg,0.04mmol)和DDQ(181.6mg,0.8mmol),室温下反应时间6小时,所得到的产物如结构式(2-32)所示。产率为89%。核磁共振1H NMR、13C NMR图谱如图32所示,产物:1H NMR(600MHz,CDCl3)δ7.95(d,J=1.0Hz,2H),7.75(dd,J=8.5,1.2Hz,2H),7.21–7.16(m,3H),3.79(s,12H),3.48(s,6H).13C NMR(151MHz,CDCl3)δ193.11,167.13,165.74,144.66,132.83,129.12,127.75,123.67,110.51,90.47,52.17,36.97.
HRMS(EI)m/z calculated for C27H24N2O9S2[M]+584.0923,found584.0919。
Claims (6)
2.根据权利要求1所述的合成方法,其特征在于,所述式(1)所示的N-烷基硫代酰胺衍生物与氧化剂的摩尔比为1:(1-2);所述式(1)所示的N-烷基硫代酰胺衍生物与催化剂的摩尔比为1:(0.05-0.1)。
3.根据权利要求1所述的合成方法,其特征在于,所述的有机溶剂为乙腈、甲苯、四氢呋喃、二氯甲烷、1,4-二氧六环、N,N-二甲基甲酰胺、二甲亚砜。
4.根据权利要求1所述的合成方法,其特征在于,所述反应的时间为4~20小时。
5.根据权利要求1所述的合成方法,其特征在于,所述方法还包括后处理和柱色谱分离纯化步骤;其中,所述分离纯化是用乙酸乙酯/石油醚混合溶剂为洗脱剂进行柱层析分离,乙酸乙酯:石油醚混合溶剂的体积比为1:3~1:10。
6.根据权利要求1所述的合成方法,其特征在于,所述方法具体包括:将式(1)所示的N-烷基硫代酰胺衍生物和氧化剂、催化剂于有机溶剂中在室温下发生分子内的烯硫醇互变进而串联发生C-S偶联去氢偶联反应,TLC监测至原料反应完,反应用饱和硫代硫酸钠溶液淬灭,二氯甲烷萃取混合物,用饱和碳酸氢钠溶液洗涤有机相,用无水硫酸钠干燥,过滤;滤液在减压下浓缩,残余物采用石油醚/乙酸乙酯的混合溶剂进行柱色谱分离,得到如式(2)所示的2-取代亚甲基二氢苯并[d]噻唑类衍生物。
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