CN113214179B - 一种Cu催化的杂原子α位C-H活化方法 - Google Patents

一种Cu催化的杂原子α位C-H活化方法 Download PDF

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CN113214179B
CN113214179B CN202110533808.6A CN202110533808A CN113214179B CN 113214179 B CN113214179 B CN 113214179B CN 202110533808 A CN202110533808 A CN 202110533808A CN 113214179 B CN113214179 B CN 113214179B
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赵德鹏
常喆
黄佳林
王思
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Sun Yat Sen University
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Abstract

本发明涉及有机合成技术领域，尤其涉及一种Cu催化的杂原子α位C‑H活化方法。本发明公开了一种Cu催化的杂原子α位C‑H活化方法，该活化方法以铜作为催化剂，N‑F键的氟试剂作为氧化剂，将杂环化合物中杂原子α位的C‑H键氧化活化得到半缩醛或者缩胺类结构，该结构可以在酸性或者F‑存在的条件下发生消除反正得到亚胺盐中间体，并于亲核试剂进行反应达到进一步对杂环α位的C‑H键活化的目的。该活化方法可以对多种杂环统一活化，且活化方法操作简单。

Description

一种Cu催化的杂原子α位C-H活化方法
技术领域
本发明涉及有机合成技术领域，尤其涉及一种Cu催化的杂原子α位C-H活化方法。
背景技术
通过对候选药物引入不同的官能团可以改变其亲和力、溶解性和代谢，从而显著地提高其生物活性。一些研究报道表明，有超过2000个的先导化合物引入甲基这一官能团后，不仅效力被增强，并能够对其生物过程进行研究。在药物研发的过程中，从头合成药物分子，成为了其发展的限速步骤并且损害了原子经济性。因此研发出一种通用的方法可以对复杂分子进行后期的官能团化是至关重要的。含N,O杂原子的化合物广泛存在于药物及天然活性化合物中。因此对其α位的C-H键进行官能团化的研究至关重要。现有的活化方法多局限在单一杂环的活化，或者较为苛刻的反应条件(例如：文献En Route toIntermolecular Cross-Dehydrogenative Coupling Reactions的活化方法，如下述反应路线)
Figure BDA0003067352190000011
发明内容
有鉴于此，本发明提供了一种Cu催化的杂原子α位C-H活化方法，该活化方法可以对多种杂环统一活化，且活化方法操作简单。
其具体技术方案如下：
本发明提供了一种Cu催化的杂原子α位C-H活化方法，包括以下步骤：
在氮气或惰性气体的保护下，将含α位C-H键的含杂环化合物、铜催化剂、氟试剂和R1-OH在溶剂体系中进行反应；得到杂环氧化物；
R1为氢、取代或非取代的烃基；
所述烃基可以为烷烃基，其中，所述饱和烷烃基的碳原子数优选为1～5，优选为1～4，所述饱和烷烃基优选为伯烷基或叔烷基；所述不饱和烷烃基优选为烯烃基。
所述烃基还可以为芳烃基，所述芳烃基优选为苄基。
所述取代的烃基包括上述烃基的卤素原子取代、烷基取代或杂环基取代。
R1最优选为氢、甲基、乙基、异丙基、正丙基、正丁基、已烯基、对氯苯基、苄基、邻甲基苄基、间甲基苄基、
Figure BDA0003067352190000021
本发明中，所述氧化剂为含N-F键的氟试剂。
本发明以铜作为催化剂，N-F键的氟试剂作为氧化剂，将杂环化合物中杂原子α位的C-H键氧化活化得到半缩醛或者缩胺类结构。
本发明中，所述含α位C-H键的含杂环化合物如式(Ⅰ)所示结构，所述杂环氧化物如式(Ⅱ)所示结构；
Figure BDA0003067352190000022
其中，X为取代杂原子或非取代杂原子，所述杂原子优选为O或N，所述杂原子上的取代基优选为2-硝基苯磺酰基、4-硝基苯磺酰基、叔丁氧羰基、苄氧基羰基、三氟乙酸基、甲基、乙基、乙烯基或取代的芳基，进一步优选为：
Figure BDA0003067352190000031
Figure BDA0003067352190000032
2-硝基苯磺酰基或对硝基苯磺酰基。
Y为取代或非取代的碳原子，所述碳原子数量优选为1～3，所述碳原子的数量优选为1或2。
Z为取代或非取代的杂原子、取代或非取代的碳原子，所述杂原子优选为O、N或S，所述碳原子数量为1～3个，优选为1或2；所述取代的碳原子中的取代基优选为甲基、乙基或苯基。
当Z为取代或非取代的碳原子时，Y与Z可以互相键合形成取代芳环或非取代芳环，或互相键合形成双键；所述芳环优选为苯环，所述取代的芳环的取代基优选为卤素、烷氧基、取代烷基或非取代烷基，更优选为卤素、甲氧基或甲基。
R2选自氢、取代或非取代烃基、酮基或酯基；所述烃基优选为烷烃基或芳烃基；所述烷烃的碳原子数优选为1～3，更优选为甲基；所述烷烃的取代基优选为乙酰氧基；所述芳烃基优选为苯基；所述芳烃基的取代基优选为卤素；所述酯基优选为甲酸甲酯基。
本发明Cu催化的杂原子α位C-H活化方法中，所述铜催化剂为二价铜催化剂或一价铜盐与配体配位形成的一价铜催化剂；所述二价铜催化剂为Cu(acac)2；所述一价铜盐为Cu(OAc)，述配体选自以下结构的化合物：
Figure BDA0003067352190000033
其中，R3选自Ph、Bn、i-Pr或t-Bu，R4选自Bn或t-Bu；
所述含N-F键的氟试剂优选为NFSI或SelectflourII；
所述溶剂体系为乙腈；
所述α位C-H键的含杂环化合物、铜催化剂、氧化剂与R1-OH的摩尔比为1：(0.08～0.12)：(1～5)：(1～5)，优选为1：0.1：3：1.5；
所述反应的温度为20-35℃，时间为18-24h，优选为60℃下反应24h；
本发明提供的Cu催化的杂原子α位C-H活化方法还包括以下步骤：
在氮气或惰性气体的保护下，将上述杂环氧化物与氟试剂或酸性试剂在溶剂体系中进行消除反应，再加入亲核试剂进行亲核反应。
本发明所述亲核反应得到的杂原子α位C-H活化的产物如式(Ⅲ)所示；
Figure BDA0003067352190000041
其中，Nu为亲核试剂。
本发明杂环氧化物的半缩醛或者缩胺类结构可以在酸性或者F-存在的条件下发生消除反正得到亚胺盐中间体，并于亲核试剂进行反应达到进一步对杂环α位的C-H键活化的目的。
在本发明中，所述氟试剂为二乙氨基三氟化硫；
所述酸性试剂为路易斯酸，优选为三氟化硼乙醚或三氟甲基磺酸三甲基硅酯；
所述亲核试剂为本领域任意一种亲核试剂，优选为格式试剂，甲基铝，二乙基锌，锡试剂，硅试剂、芳香性亲核试剂；所述芳香性亲核试剂优选为吲哚或苯酚。
所述杂环氧化物与氟试剂/酸性试剂的摩尔比为1：(1～3)，其中，杂环氧化物与氟试剂的摩尔比为1：1，杂环氧化物与酸性试剂的摩尔比为1：3；
所述杂环氧化物与亲核试剂的摩尔比为1：(1～5)，优选为1：3；
所述消除反应的温度为-78℃，时间为1～3h，优选在-78℃的条件下反应1h；
所述亲核反应具体为：在-78℃的条件下反应0.5～2h，再在常温下反应2～4h，优选在-78℃的条件下反应1h，再转常温下反应2h；
本发明中的消除反应和亲核反应均在溶剂体系中进行，所述溶剂优选为二氯甲烷。
本发明中，常温为25±5℃。
从以上技术方案可以看出，本发明具有以下优点：
本发明提供了一种Cu催化的杂原子α位C-H活化方法，该活化方法以铜作为催化剂，N-F键的氟试剂作为氧化剂，将杂环化合物中杂原子α位的C-H键氧化活化得到半缩醛或者缩胺类结构，该结构可以在酸性或者F-存在的条件下发生消除反正得到亚胺盐中间体，并于亲核试剂进行反应达到进一步对杂环α位的C-H键活化的目的。该活化方法可以对多种杂环统一活化，且该活化方法中使用的催化剂商业可得，活化方法操作简单。
具体实施方式
为使得本发明的发明目的、特征、优点能够更加的明显和易懂，下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，下面所描述的实施例仅是本发明一部分实施例，而非全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
本发明实施例4中，制备杂环氧化物2pa、2qa、2ra、2sa、2ua、2va和2ta是为了鉴定2p的核磁，因此未提供收率。
实施例1
在氮气保护下将表1所示杂环(1mmol)，催化剂(0.1mmol)，NFSI(3mmol)与水(1.5mmol)加入1mL乙腈中，35℃搅拌反应24h，加入饱和碳酸氢钠后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到杂环氧化物(如表1所示)。
Figure BDA0003067352190000051
2a:白色固体；产率89％.
1H NMR(400MHz,Acetone)δ8.03–7.87(m,2H),7.87–7.66(m,2H),6.19(d,J＝8.5Hz,1H),6.14–6.03(m,1H),4.66(dd,J＝9.8,6.0Hz,1H),4.29(dd,J＝9.8,1.6Hz,1H).
13C NMR(101MHz,Acetone)δ154.8,142.5,133.7,120.6,119.2,107.8,80.6,71.3.
HRMS(ESI+,m/z)calculated for C10H8N2O3[M+H]+:205.0608；found:205.0607.
Figure BDA0003067352190000061
2b:无色油状；产率77％.
1H NMR(500MHz,DMSO)δ8.05–7.95(m,2H),7.68–7.60(m,2H),7.09(d,J＝8.2Hz,1H),5.94(t,J＝7.0Hz,1H),4.56(dd,J＝9.0,6.7Hz,1H),4.16(d,J＝9.7Hz,1H).
13C NMR(126MHz,DMSO)δ154.2,137.9,130.3,127.9,124.9,123.0,118.5,111.8,79.4,70.4.
HRMS(ESI+,m/z)calculated for C10H8N2O3[M+H]+:205.0608；found:205.0610.
Figure BDA0003067352190000062
2ha:白色固体；2h产率92％，2ha产率86％.
1H NMR(400MHz,DMSO)δ8.09(d,J＝8.8Hz,2H),7.92(d,J＝8.8Hz,2H),7.82(d,J＝7.5Hz,1H),7.79–7.71(m,2H),7.64(t,J＝7.3Hz,1H),7.03(d,J＝10.3Hz,1H),6.65(d,J＝10.2Hz,1H).
13C NMR(101MHz,DMSO)δ166.0,144.2,141.8,133.4,133.0,130.6,129.9,123.8,123.2,120.9,119.0,105.9,81.7.
HRMS(ESI+,m/z)calculated for C15H10N2O2[M+H]+:251.0815；found:251.0815.
实施例2
在氮气保护下将表1所示杂环(1mmol)，催化剂(0.1mmol)，NFSI(3mmol)与水(1.5mmol)加入1mL乙腈中，25℃搅拌反应24h，加入饱和碳酸氢钠后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到杂环氧化物(如表1所示)。
Figure BDA0003067352190000071
2l:淡黄色晶体；产率92％.
1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.7Hz,2H),7.58(d,J＝8.7Hz,2H),5.69(t,J＝6.4Hz,1H),4.16(d,J＝8.1Hz,1H),2.82-2.72(m,1H),2.58–2.29(m,2H),2.12–1.98(m,1H).
13C NMR(101MHz,CDCl3)δ174.9,141.5,132.7,121.7,118.5,107.8,84.5,29.9,28.1.
HRMS(ESI+,m/z)calculated for C11H10N2O2[M+Na]+:225.0634；found:225.0639.
Figure BDA0003067352190000072
2m:淡黄色油状；产率72％.
1H NMR(400MHz,DMSO)δ7.96–7.88(m,2H),7.87–7.79(m,2H),6.44(d,J＝7.9Hz,1H),5.70–5.61(m,1H),2.98–2.86(m,1H),2.16(dd,J＝13.0,8.3Hz,1H),1.93(ddd,J＝13.0,10.5,6.0Hz,1H),1.14(d,J＝7.1Hz,3H).
13C NMR(101MHz,DMSO)δ176.9,142.5,132.9,120.6,118.9,106.1,81.4,36.7,35.0,15.59.HRMS(ESI+,m/z)calculated for C12H12N2O2[M+H]+:217.0972；found:217.0976.
Figure BDA0003067352190000073
2n:白色固体；产率66％.
1H NMR(400MHz,DMSO)δ7.94(d,J＝8.9Hz,2H),7.84(d,J＝8.9Hz,2H),6.96(t,J＝1.8Hz,1H),6.58(d,J＝9.9Hz,1H),6.05(d,J＝9.4Hz,1H),1.86(s,3H).
13C NMR(126MHz,DMSO)δ169.3,141.6,141.2,134.5,133.0,119.3,119.0,105.1,81.0,10.5.
HRMS(ESI+,m/z)calculated for C12H10N2O2[M+H]+:215.0815；found:215.0814.
Figure BDA0003067352190000081
2o:白色固体；产率59％.
1H NMR(400MHz,DMSO)δ7.97–7.90(m,2H),7.86–7.76(m,2H),6.60(d,J＝10.0Hz,1H),5.83(d,J＝10.0Hz,1H),2.27-2.21(m,2H),1.99(s,3H),1.03(t,J＝7.5Hz,3H).
13C NMR(101MHz,DMSO)δ169.2,150.8,141.8,133.0,132.9,119.1,119.0,104.7,82.8,16.1,12.8,11.2.
HRMS(ESI+,m/z)calculated for C14H14N2O2[M+H]+:243.1128；found:243.1127.
实施例3
在氮气保护下将表1所示杂环(1mmol)，催化剂(0.1mmol)，NFSI(3mmol)与甲醇(1.5mmol)加入1mL乙腈中，35℃搅拌反应24h，加入饱和碳酸氢钠后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到杂环氧化物(如表1所示)。
Figure BDA0003067352190000082
2aa:白色固体；产率95％.
1H NMR(400MHz,CDCl3)δ7.85–7.79(m,2H),7.71–7.65(m,2H),5.71(dd,J＝6.0,1.7Hz,1H),4.49(dd,J＝10.5,5.9Hz,1H),4.42(dd,J＝10.5,1.7Hz,1H),3.32(s,3H).
13C NMR(126MHz,CDCl3)δ154.0,140.8,133.2,119.7,118.5,108.3,85.4,66.2,50.7.
HRMS(ESI+,m/z)calculated for C11H10N2O3[M+H]+:219.0764；found:219.0764.
Figure BDA0003067352190000091
2c:无色油状；产率56％.
1H NMR(400MHz,CDCl3)δ7.61–7.53(m,2H),7.38–7.31(m,2H),5.60(dd,J＝6.1,1.6Hz,1H),4.46(dd,J＝10.4,6.1Hz,1H),4.37(dd,J＝10.4,1.6Hz,1H),3.30(s,3H).
13C NMR(101MHz,CDCl3)δ154.7,135.3,131.1,129.3,122.2,86.2,66.5,51.3.
HRMS(ESI+,m/z)calculated for C10H10NO3Cl[M+H]+:228.0422；found:228.0427.
Figure BDA0003067352190000092
2d:白色固体；产率97％.
1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.77–7.71(m,2H),7.44–7.38(m,3H),5.60(dd,J＝6.5,2.2Hz,1H),4.49(dd,J＝10.3,6.6Hz,1H),4.30(dd,J＝10.4,2.2Hz,1H),3.46(s,3H).
13C NMR(101MHz,CDCl3)δ153.0,149.8,134.0,130.6,128.7,127.5,85.4,66.7,53.5.
HRMS(ESI+,m/z)calculated for C11H12N2O3[M+Na]+:243.0740；found:243.0747.
Figure BDA0003067352190000101
2e:无色油状；产率95％.
1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.66(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),5.58(dd,J＝6.5,2.2Hz,1H),4.46(dd,J＝10.4,6.6Hz,1H),4.26(dd,J＝10.4,2.2Hz,1H),3.82(s,3H),3.42(s,3H).
13C NMR(101MHz,CDCl3)δ161.5,153.1,149.5,129.1,126.6,114.0,85.2,66.5,55.3,53.1.
HRMS(ESI+,m/z)calculated for C12H14N2O4[M+H]+:251.1026；found:251.1028.
Figure BDA0003067352190000102
2f:白色固体；产率92％.
1H NMR(400MHz,CDCl3)δ8.69(s,1H),7.63(d,J＝8.1Hz,2H),7.21(d,J＝8.0Hz,2H),5.60(dd,J＝6.5,2.1Hz,1H),4.47(dd,J＝10.4,6.5Hz,1H),4.28(dd,J＝10.4,2.1Hz,1H),3.44(s,3H),2.38(s,3H).
13C NMR(101MHz,CDCl3)δ153.2,149.8,141.1,131.3,129.5,127.6,85.3,66.6,53.3,21.5.
HRMS(ESI+,m/z)calculated for C12H14N2O3[M+H]+:235.1077；found:235.1079.
Figure BDA0003067352190000111
2g:白色固体；产率85％.
1H NMR(400MHz,CDCl3)δ8.73(s,1H),7.65(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),5.58(dd,J＝6.5,2.1Hz,1H),4.49(dd,J＝10.4,6.5Hz,1H),4.29(dd,J＝10.4,2.1Hz,1H),3.44(s,3H).
13C NMR(101MHz,CDCl3)δ152.9,148.2,136.5,132.5,128.9,128.6,85.3,66.6,53.4.
HRMS(ESI+,m/z)calculated for C11H11N2O3Cl[M+H]+:255.0531；found:255.0530.
Figure BDA0003067352190000112
2h:白色固体；产率80％.
1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.9Hz,2H),7.93(d,J＝8.9Hz,1H),7.73-7.69(m,3H),7.64-7.60(m,2H),6.52(s,1H),2.88(s,3H).
13C NMR(101MHz,CDCl3)δ166.8,141.6,139.2,133.6,133.1,132.2,130.7,124.2,123.5,1201,118.8,107.6,86.8,48.9.
HRMS(ESI+,m/z)calculated for C16H12N2O2[M+H]+:265.0972；found:265.0971.
Figure BDA0003067352190000113
2i:无色油状；产率82％.
1H NMR(500MHz,CDCl3)δ8.10(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.66–7.57(m,2H),7.41(t,J＝8.4Hz,1H),6.51(s,1H),2.89(s,3H).
13C NMR(126MHz,CDCl3)δ165.6(d,J＝3.4Hz),164.2(d,J＝252.0Hz),141.3,134.7(d,J＝2.6Hz),134.5(d,J＝8.9Hz),133.2,125.4(d,J＝8.6Hz),121.1(d,J＝22.7Hz),120.2,118.7,111.2(d,J＝23.94Hz),108.0,86.4,48.9.
19F NMR(471MHz,CDCl3)δ-108.51(td,J＝8.0,4.5Hz).
HRMS(ESI+,m/z)calculated for C16H11N2O2F[M+H]+:283.0877；found:283.0879.
Figure BDA0003067352190000121
2j:无色油状；产率85％.
1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.8Hz,2H),7.87(d,J＝8.0Hz,1H),7.72(d,J＝8.8Hz,2H),7.64–7.58(m,2H),6.49(s,1H),2.91(s,3H).
13C NMR(101MHz,CDCl3)δ165.7,141.3,141.0,140.2,133.2,131.3,130.6,125.5,124.0,120.1,118.7,108.0,86.2,49.1.
HRMS(ESI+,m/z)calculated for C16H11N2O2Cl[M+H]+:299.0582；found:299.0581.
Figure BDA0003067352190000122
2k:无色油状；产率92％.
1H NMR(500MHz,CDCl3)δ7.98(d,J＝7.9Hz,2H),7.58(d,J＝7.9Hz,2H),7.38(d,J＝7.9Hz,1H),7.14–7.10(m,1H),6.34(s,1H),3.78(s,3H),2.74(s,3H).
13C NMR(101MHz,CDCl3)δ166.8,161.8,141.6,133.8,133.1,131.2,124.6,121.6,120.1,118.8,107.56,106.9,86.6,55.8,48.7.
HRMS(ESI+,m/z)calculated for C17H14N2O3[M+H]+:295.1077；found:295.1077.
实施例4
氮气保护下将表1所示的杂环1p(1mmol)，催化剂(0.1mmol)，SelectflourII(3mmol)与水(1.5mmol)加入1mL乙腈中，20℃搅拌反应24h，加入饱和碳酸氢钠后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到杂环氧化物(如表1所示)。
Figure BDA0003067352190000131
2pa:无色油状；2p产率73％.
1H NMR(400 MHz,CDCl3)δ8.14–8.03(m,1H),7.73–7.60(m,3H),5.23(d,J＝4.8Hz,1H),3.52(td,J＝8.9,2.6 Hz,1H),3.35(s,3H),3.29-3.22(m,1H),2.18-2.08(m,1H),2.02–1.89(m,2H),1.89-1.78(m,1H).
13C NMR(101 MHz,CDCl3)δ148.4,133.6,132.4,131.6,131.3,124.1,92.3,55.5,46.9,32.4,23.2.
HRMS(ESI+,m/z)calculated for C11H14N2O5S[M+Na]+:309.0516；found:309.0515.
Figure BDA0003067352190000132
2qa:无色油状；2q产率51％.
1H NMR(400 MHz,CDCl3)δ8.15–8.11(m,1H),7.74–7.70(m,2H),7.63–7.58(m,1H),5.31(d,J＝4.6 Hz,1H),4.34(t,J＝8.3 Hz,1H),3.74(d,J＝2.8Hz,3H),3.42(s,3H),2.38–2.23(m,2H),2.04-1.96(m,1H),1.80–1.68(m,1H).
13C NMR(101MHz,CDCl3)δ171.9,148.2,134.1,131.8,131.6,124.1,92.9,60.3,55.3,52.6,32.4,28.6.
HRMS(ESI+,m/z)calculated for C13H16N2O7S[M+Na]+:367.0570；found:367.0571.
Figure BDA0003067352190000141
2ra:无色油状；2r产率63％.
1H NMR(400MHz,CDCl3)δ8.38–8.33(m,2H),8.09–7.98(m,2H),5.11(d,J＝4.9Hz,1H),3.63-3.58(m,1H),3.43(s,3H),2.01-1.94(m,1H),1.90–1.81(m,1H),1.81–1.70(m,1H),1.36(d,J＝6.2Hz,3H),1.29–1.20(m,1H).
13C NMR(126MHz,CDCl3)δ150.0,145.2,128.4,124.3,92.7,57.3,55.0,32.0,31.9,23.2.
HRMS(ESI+,m/z)calculated for C12H16N2O5S[M+Na]+:323.0672；found:323.0671.
Figure BDA0003067352190000142
2sa:无色油状；2s产率60％.
1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.8Hz,1H),7.72(t,J＝7.5Hz,1H),7.65–7.60(m,2H),7.31–7.25(m,4H),5.40(d,J＝4.5Hz,1H),4.57(t,J＝8.3Hz,1H),3.58(s,3H),2.46–2.31(m,1H),2.23-2.15(m,1H),2.13–2.04(m,1H),1.91-1.82(m,1H).
13C NMR(101MHz,CDCl3)δ148.4,140.3,134.0,133.3,131.9,131.3,131.2,128.6,128.4,124.0,93.5,64.0,55.6,35.1,32.4.
HRMS(ESI+,m/z)calculated for C16H15N2O4SCl[M+H]+:367.0514；found:367.0513.
Figure BDA0003067352190000151
2ua:无色油状；2u产率52％.
1H NMR(400MHz,Acetone)δ8.33(d,J＝8.7Hz,2H),8.12(d,J＝8.7Hz,2H),7.41–7.34(m,1H),7.25–7.18(m,2H),7.08–6.99(m,1H),5.99(s,1H),3.92-3.86(m,1H),3.62–3.51(m,1H),2.77–2.69(m,1H),2.67–2.59(m,1H).
13C NMR(126MHz,Acetone)δ151.0,147.3,134.5,134.0,129.5,129.5,129.4,129.3,127.1,125.2,85.6,55.7,39.9,27.5.
HRMS(ESI+,m/z)calculated for C16H16N2O5S[M+Na]+:371.0672；found:371.0671.
Figure BDA0003067352190000152
2va:无色油状；2v产率65％.
1H NMR(500MHz,Acetone)δ8.17(d,J＝8.0Hz,1H),7.92–7.86(m,1H),7.86–7.80(m,2H),7.43(d,J＝8.3Hz,1H),7.38(d,J＝8.2Hz,1H),7.29(s,1H),5.91(s,1H),3.95(dd,J＝13.9,5.4Hz,1H),3.68–3.56(m,1H),3.41(s,3H),2.81–2.73(m,1H),2.69–2.55(m,1H).
13C NMR(101MHz,Acetone)δ148.8,137.3,135.5,133.9,133.8,133.2,132.1,131.6,131.6,130.2,125.3,122.6,85.4,55.9,39.1,27.6.
HRMS(ESI+,m/z)calculated for C16H15N2O5S Br[M+Na]+:448.9777；found:448.9775.
Figure BDA0003067352190000161
2ta:无色油状；2t产率41％.
1H NMR(400MHz,CDCl3)δ8.12–8.08(m,1H),7.75–7.64(m,3H),5.13(s,1H),4.52(dd,J＝10.8,8.7Hz,1H),4.28(dd,J＝10.8,6.3Hz,1H),4.05–4.00(m,1H),3.42(s,3H),2.08(s,3H),1.95-1.80(m,2H),1.72-1.66(m,2H),1.44–1.31(m,2H).
13C NMR(126MHz,CDCl3)δ170.8,147.7,133.6,133.6,131.9,131.3,124.5,84.9,63.8,55.6,51.1,29.9,24.5,21.0,13.1.
实施例5
在氮气保护下将表1所示的杂环1d(1mmol)，催化剂(0.1mmol)，NFSI(3mmol)与醇(1.5mmol)加入1mL乙腈中，35℃搅拌反应24h，加入饱和碳酸氢钠后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到杂环氧化物2da-2dh。
Figure BDA0003067352190000162
2da:白色固体；产率85％.
1H NMR(500MHz,CDCl3)δ8.85(s,1H),7.76–7.71(m,2H),7.42-7.41(m,3H),5.62(dd,J＝6.6,2.3Hz,1H),4.50(dd,J＝10.2,6.6Hz,1H),4.29(dd,J＝10.2,2.3Hz,1H),3.85(dq,J＝9.2,7.0Hz,1H),3.62(dq,J＝9.3,7.0Hz,1H),1.24(t,J＝7.0Hz,3H).
13C NMR(126MHz,CDCl3)δ152.9,150.1,134.2,130.6,128.7,127.5,85.1,67.3,62.5,15.2.
HRMS(ESI+,m/z)calculated for C12H14N2O3[M+H]+:235.1078；found:235.1077；.
Figure BDA0003067352190000171
2db:无色油状；产率70％.
1H NMR(500MHz,CDCl3)δ8.96(s,1H),7.76–7.64(m,2H),7.48–7.37(m,3H),5.59(dd,J＝6.3,2.0Hz,1H),4.50(dd,J＝9.8,6.5Hz,1H),4.23(dd,J＝9.8,2.0Hz,1H),4.16(dt,J＝12.2,6.1Hz,1H),1.23(dd,J＝11.3,6.2Hz,6H).
13C NMR(126MHz,CDCl3)δ152.8,150.7,134.3,130.5,128.7,127.4,84.4,70.8,68.4,23.2,22.5.
HRMS(ESI+,m/z)calculated for C13H16N2O3[M+H]+:229.1236；found:249.1234；.
Figure BDA0003067352190000172
2dc:无色油状；产率81％.
1H NMR(500MHz,CDCl3)δ8.77(s,1H),7.76–7.71(m,2H),7.42–7.40(m,3H),5.64(dd,J＝6.5,1.6Hz,1H),4.51–4.44(m,1H),4.32–4.25(m,1H),3.75(dt,J＝8.8,6.4Hz,1H),3.52(dt,J＝8.9,6.5Hz,1H),1.60–1.54(m,2H),1.41–1.32(m,2H),0.89(dd,J＝7.7,7.1Hz,3H).
13C NMR(126MHz,CDCl3)δ153.0,149.7,134.1,130.6,128.7,127.5,84.7,67.1,66.2,31.5,19.2,13.7.
HRMS(ESI+,m/z)calculated for C14H18N2O3[M+H]+:263.1392；found:263.1390；.
Figure BDA0003067352190000173
2dd:白色固体；产率84％.
1H NMR(400MHz,CDCl3)δ8.89(s,1H),7.75–7.69(m,2H),7.45–7.39(m,3H),7.37–7.30(m,5H),5.70(dd,J＝6.5,2.2Hz,1H),4.86(d,J＝11.6Hz,1H),4.74–4.69(m,1H),4.50(dd,J＝10.2,6.5Hz,1H),4.34(dd,J＝10.2,2.2Hz,1H).
13C NMR(126MHz,CDCl3)δ152.9,150.5,136.6,134.1,130.6,128.7,128.6,128.2,128.0,127.5,84.8,69.4,67.4.
HRMS(ESI+,m/z)calculated for C17H16N2O3[M+H]+:297.1234；found:297.1234；.
Figure BDA0003067352190000181
2de:无色油状；产率77％.
1H NMR(500MHz,CDCl3)δ8.89(s,1H),7.65–7.62(m,2H),7.38–7.33(m,3H),7.25–7.22(m,2H),7.20(d,J＝9.2Hz,2H),5.60(dd,J＝6.5,2.2Hz,1H),4.77(d,J＝11.8Hz,1H),4.61(d,J＝11.8Hz,1H),4.44(dd,J＝10.2,6.5Hz,1H),4.26(dd,J＝10.2,2.2Hz,1H).
13C NMR(126MHz,CDCl3)δ152.8,151.0,135.2,134.0,134.0,130.7,129.2,128.8,127.5,85.3,68.8,67.4.
HRMS(ESI+,m/z)calculated for C17H15N2O3Cl[M+H]+:331.0844；found:331.0843；.
Figure BDA0003067352190000182
2df:无色油状；产率76％.
1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.74–7.72(m,2H),7.43–7.40(m,3H),5.75(ddt,J＝16.9,10.2,6.7Hz,1H),5.63(dd,J＝6.5,2.1Hz,1H),5.00–4.89(m,2H),4.49(dd,J＝10.2,6.5Hz,1H),4.29(dd,J＝10.2,2.2Hz,1H),3.76(dt,J＝9.2,6.4Hz,1H),3.53(dt,J＝9.2,6.4Hz,1H),2.04(dd,J＝14.2,7.2Hz,2H),1.64–1.57(m,2H),1.49–1.40(m,2H).
13C NMR(126MHz,CDCl3)δ153.0,149.8,138.3,134.1,130.6,128.7,127.5,114.7,84.8,67.1,66.3,33.3,28.9,25.2.
HRMS(ESI+,m/z)calculated for C16H20N2O3[M+H]+:289.1546；found:289.1547；.
Figure BDA0003067352190000191
2dg:无色油状；产率85％.
1H NMR(400MHz,CDCl3)δ8.70(s,1H),7.75(dd,J＝6.5,2.9Hz,2H),7.38(dd,J＝6.8,3.6Hz,3H),5.74(dd,J＝6.3,1.9Hz,1H),5.53(d,J＝5.0Hz,1H),4.58(dd,J＝7.9,2.3Hz,1H),4.48(dd,J＝10.3,6.4Hz,1H),4.39(dd,J＝10.4,2.0Hz,1H),4.31(dd,J＝5.0,2.4Hz,1H),4.19(dd,J＝7.9,1.7Hz,1H),3.98(t,J＝6.3Hz,1H),3.83(dd,J＝10.2,7.1Hz,1H),3.71(dd,J＝10.2,5.5Hz,1H),1.46(s,3H),1.40(s,3H),1.31(s,3H),1.27(s,3H).
13C NMR(126MHz,CDCl3)δ153.0,149.3,134.0,130.5,128.6,127.6,109.4,108.7,96.3,84.4,70.7,70.5,70.4,66.9,66.4,64.7,26.0,25.9,24.8,24.3.
HRMS(ESI+,m/z)calculated for C22H28N2O8[M+Na]+:471.1738；found:471.1740；.
Figure BDA0003067352190000192
2dh:无色油状；产率83％.
1H NMR(400MHz,CDCl3)δ8.98(d,J＝14.6Hz,1H),7.71(dt,J＝7.3,2.1Hz,2H),7.48–7.33(m,3H),5.61(ddd,J＝6.6,4.6,2.2Hz,1H),4.95(d,J＝2.9Hz,1H),4.64(dd,J＝17.1,5.9Hz,1H),4.58–4.46(m,2H),4.37–4.26(m,2H),3.89(ddd,J＝10.0,7.3,5.4Hz,1H),3.66(ddd,J＝17.2,9.8,6.8Hz,1H),3.29(d,J＝10.3Hz,3H),1.46(d,J＝3.1Hz,3H),1.27(d,J＝6.4Hz,3H).
13C NMR(126MHz,CDCl3)δ152.7,152.6,150.8,150.7,134.1,134.0,130.7,128.7,127.5,127.5,112.5,112.5,109.6,109.3,85.9,85.9,85.1,85.0,84.9,84.9,81.8,81.7,68.6,68.4,67.3,67.1,55.0,54.9,26.4,26.4,24.8.
实施例6
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后加入吲哚(3mmol)，继续反应3小时后，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3o。
Figure BDA0003067352190000201
3o:黄色固体；yield产率59％.
1H NMR(400MHz,CDCl3)δ7.32–7.24(m,1H),7.22–7.16(m,1H),7.09–7.03(m,1H),7.02–6.97(m,1H),6.97–6.91(m,1H),6.90–6.85(m,1H),6.79–6.66(m,2H),5.23–5.16(m,1H),4.20–4.12(m,1H),4.02–3.92(m,1H),3.58(s,3H),2.42(s,3H),2.41–2.26(m,2H),2.24–2.15(m,1H),2.15–2.02(m,1H).
13C NMR(126MHz,CDCl3)δ146.7,136.5,135.0,133.6,131.5,129.7,129.5,125.5,122.9,120.6,118.9,118.5,109.0,108.3,57.4,49.9,34.2,29.3,25.7,10.1.
HRMS(ESI+,m/z)calculated for C20H21N3O4S[M+H]+:400.1326；found:400.1327；.
实施例7
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后滴加三甲基铝(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3p。
Figure BDA0003067352190000211
3p:黄色固体；产率90％.
1H NMR(400MHz,CDCl3)δ8.09–7.94(m,1H),7.71–7.63(m,2H),7.62–7.53(m,1H),4.14–3.95(m,1H),3.55–3.33(m,2H),2.04–1.88(m,2H),1.86–1.71(m,1H),1.64–1.54(m,1H),1.24(d,J＝6.4Hz,3H).
13C NMR(126MHz,CDCl3)δ148.3,133.4,132.5,131.4,130.5,123.8,56.5,48.8,33.7,24.0,22.0.
HRMS(ESI+,m/z)calculated for C11H14N2O4S[M+H]+:271.0747；found:271.0748；.
实施例8
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后滴加二乙基锌(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3q。
Figure BDA0003067352190000212
3q:黄色液体；产率78％.
1H NMR(400MHz,CDCl3)δ8.04–7.96(m,1H),7.73–7.62(m,2H),7.62–7.54(m,1H),3.90–3.81(m,1H),3.51–3.37(m,2H),1.96–1.83(m,2H),1.83–1.64(m,3H),1.52–1.39(m,1H),0.87(t,J＝7.4Hz,3H).
13C NMR(126MHz,CDCl3)δ148.4,133.4,132.4,131.3,130.6,123.8,62.2,48.9,30.3,28.4,24.2,10.2.
HRMS(ESI+,m/z)calculated for C12H16N2O4S[M+H]+:285.0904；found:285.0909；.
实施例9
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后滴加萘酚(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3r。
Figure BDA0003067352190000221
3r:黄色固体；产率71％.
1H NMR(400MHz,DMSO)δ9.83(s,1H),8.00(d,J＝8.8Hz,1H),7.72(dd,J＝16.8,8.0Hz,2H),7.64(d,J＝8.8Hz,1H),7.59(t,J＝7.8Hz,1H),7.38–7.13(m,3H),7.03(dd,J＝14.4,8.4Hz,2H),5.82(t,J＝8.6Hz,1H),3.86(dd,J＝10.2,4.1Hz,2H),2.35–2.19(m,2H),2.17–2.07(m,1H),1.96–1.81(m,1H).
13C NMR(101MHz,DMSO)δ153.3,147.2,133.5,132.1,131.4,131.0,129.4,129.2,128.4,128.2,125.9,123.6,122.4,122.1,118.1,116.2,56.9,49.5,32.5,25.7.
HRMS(ESI+,m/z)calculated for C20H18N2O6S[M+H]+:437.0778；found:437.0777；.
实施例10
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后滴加三丁基烯丙基锡(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3s。
Figure BDA0003067352190000231
3s:黄色液体；产率85％.
1H NMR(400MHz,CDCl3)δ8.06–7.96(m,1H),7.73–7.63(m,2H),7.63–7.55(m,1H),5.79–5.67(m,1H),5.14–4.98(m,2H),4.05–3.96(m,1H),3.45(t,J＝6.4Hz,2H),2.56–2.46(m,1H),2.31–2.19(m,1H),1.98–1.83(m,2H),1.82–1.72(m,2H).
13C NMR(126MHz,CDCl3)δ148.4,134.0,133.5,132.2,131.4,130.7,123.9,117.9,60.0,49.1,40.0,30.3,24.0.
HRMS(ESI+,m/z)calculated for C13H16N2O4S[M+H]+:297.0904；found:297.0908；.
实施例11
氮气保护下，零下78度的条件将杂环氧化产物2p(1mmol)与三氟化硼乙醚(3mmol)加入二氯甲烷中，后滴加叠氮基三甲基硅烷(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物3t。
Figure BDA0003067352190000232
3t:黄色液体；产率76％.
1H NMR(400MHz,CDCl3)δ8.19–8.05(m,1H),7.78–7.69(m,2H),7.69–7.64(m,1H),5.63–5.51(m,1H),3.65(td,J＝8.8,8.1,2.6Hz,1H),3.32(td,J＝8.9,8.4,5.3Hz,1H),2.18–1.95(m,4H).
13C NMR(101MHz,CDCl3)δ148.2,134.0,132.1,131.8,131.3,124.3,77.0,47.7,33.4,23.4.
HRMS(ESI+,m/z)calculated for C10H11N5O4S[M+Na]+:320.0424；found:320.0434；.
实施例12
氮气保护下，零下78度的条件将杂环氧化产物2l(1mmol)与二乙氨基三氟化硫(DAST)(1mmol)加入二氯甲烷中，反应1小时后滴加格式试剂(3mmol)，继续反应1小时后转常温反应2h，加入水淬灭后用二氯甲烷萃取，饱和食盐水洗，无水Na2SO4干燥，色谱柱分离，得到产物(如表2所示)。
Figure BDA0003067352190000241
3h:无色油状；产率93％.
1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.7Hz,2H),7.59(d,J＝8.7Hz,2H),4.32(dt,J＝8.5,4.2Hz,1H),2.69–2.47(m,2H),2.18–2.11(m,1H),2.11–2.01(m,1H),1.98–1.88(m,1H),0.94(d,J＝7.0Hz,3H),0.72(d,J＝6.8Hz,3H).
13C NMR(126MHz,CDCl3)δ174.8,141.8,132.9,123.4,118.6,108.3,63.2,31.7,28.3,18.4,17.4,14.2.
HRMS(ESI+,m/z)calculated for C14H16N2O[M+H]+:229.1335；found:229.1333；.
Figure BDA0003067352190000242
3j:无色油状；产率78％.
1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.7Hz,2H),7.51(d,J＝8.8Hz,2H),7.36–7.27(m,3H),7.19–7.17(m,2H),5.28(dd,J＝6.9,3.9Hz,1H),2.81–2.73(m,1H),2.72–2.58(m,2H),2.09–2.00(m,1H).
13C NMR(126MHz,CDCl3)δ175.2,142.2,140.2,132.7,129.3,128.1,125.5,121.1,118.7,107.4,63.3,31.1,29.0.
HRMS(ESI+,m/z)calculated for C17H14N2O[M+H]+:263.1179；found:263.1179；.
Figure BDA0003067352190000251
3k:无色油状；产率88％.
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.8Hz,2H),7.51(d,J＝8.8Hz,2H),7.16(dd,J＝8.4,5.2Hz,2H),7.01(t,J＝8.5Hz,2H),5.32–5.22(m,1H),2.79–2.58(m,3H),2.04–1.96(m,1H).
13C NMR(126MHz,CDCl3)δ175.0,162.2(d,J＝248.2Hz),141.9,135.9(d,J＝3.2Hz),132.6,127.20(d,J＝8.2Hz),121.2,118.6,116.2(d,J＝21.4Hz),107.4,62.5,31.0,29.0.
19F NMR(376MHz,CDCl3)δ-113.52(ddd,J＝13.6,8.4,5.0Hz).
HRMS(ESI+,m/z)calculated for C17H13FN2O[M+H]+:281.1085；found:281.1086；.
Figure BDA0003067352190000252
3m:无色油状；产率57％.
1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.8Hz,2H),7.51(d,J＝8.8Hz,2H),7.13(d,J＝7.9Hz,2H),7.06(d,J＝8.0Hz,2H),5.25–5.22(m,1H),2.81–2.57(m,3H),2.05–1.99(m,1H).
13C NMR(101MHz,CDCl3)δ175.3,142.3,137.9,137.2,132.7,129.9,125.4,121.2,118.7,107.3,63.2,31.2,29.2,21.0.
HRMS(ESI+,m/z)calculated for C18H16N2O[M+H]+:277.1335；found:277.1335；.
表1
Figure BDA0003067352190000253
Figure BDA0003067352190000261
Figure BDA0003067352190000271
Figure BDA0003067352190000281
Figure BDA0003067352190000291
表2
Figure BDA0003067352190000292
Figure BDA0003067352190000301
以上所述，以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。

Claims (6)

1.一种Cu催化的杂原子α位C-H活化方法，其特征在于，包括以下步骤：
在惰性气体的保护下，将含α位C-H键的杂环化合物、铜催化剂、氧化剂和R1-OH在溶剂体系中进行反应，将所述杂环化合物的α位C-H键氧化，得到杂环氧化物；
其中，R1为氢、取代或非取代的烃基；所述氧化剂为含N-F键的氟试剂；
所述铜催化剂为二价铜催化剂或一价铜盐与配体配位形成的一价铜催化剂；
所述二价铜催化剂为Cu(acac)2或Cu(OTf)2；
所述一价铜盐为Cu(OAc)、Cu(CH3CN)4PF6或Cu(CH3CN)4BF4；
所述配体选自以下结构的化合物：
Figure FDA0003920308900000011
其中，R3选自Ph、Bn或t-Bu，R4选自Bn或t-Bu；
所述溶剂体系为乙腈；
所述含α位C-H键的含杂环化合物如式(Ⅰ)所示结构，所述杂环氧化物如式(Ⅱ)所示结构；
Figure FDA0003920308900000012
其中，X为取代杂原子或非取代杂原子；
Y为取代或非取代的碳原子，所述碳原子个数为1～3；
Z为取代或非取代的杂原子、取代或非取代的碳原子，所述碳原子个数为1～3；
若Z为取代或非取代的碳原子，Z与Y可以互相键合形成取代或非取代芳环，或互相键合形成双键；
R1为氢、取代或非取代烃基；
R2选自氢、取代或非取代烃基、酮基或酯基。
2.根据权利要求1所述的Cu催化的杂原子α位C-H活化方法，其特征在于，所述α位C-H键的含杂环化合物、铜催化剂、氧化剂与R1-OH的摩尔比为1：(0.08～0.12)：(1～5)：(1～5)；
所述反应的温度为20-35℃，时间为18-24h。
3.一种制备方法，其特征在于，采用权利要求1-2任意一项所述的方法制备得到杂环氧化物，在惰性气体的保护下，将所述的杂环氧化物与氟试剂或酸性试剂在溶剂体系中进行消除反应，再加入亲核试剂进行亲核反应；
所述氟试剂为Dast；
所述酸性试剂为路易斯酸。
4.根据权利要求3所述的方法，其特征在于，所述消除反应的温度为-78℃，时间为1～3h；
所述亲核反应具体为：在-78℃的条件下反应0.5～2h，再在常温下反应2～4h。
5.根据权利要求3所述的方法，其特征在于，所述亲核试剂为格式试剂，甲基铝，二乙基锌，锡试剂，硅试剂或芳香性亲核试剂。
6.根据权利要求3所述的方法，其特征在于，所述杂环氧化物与氟试剂/酸性试剂的摩尔比为1：(1～3)；
所述杂环氧化物与亲核试剂的摩尔比为1：(1～5)。
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* Cited by examiner, † Cited by third party
Title
Copper catalyzed late-stage C(SP3)-H functionlization of nitrogen heterocycles;Zhe Chang et al.;《Nature Communications》;20210715;第12卷(第1期);第4342页 *
Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed redical relay;Wen Zhang et al.;《Science》;20160902;第353卷(第6303期);第1014-1018页 *
Late-stage oxidative C(sp3)-H methylation;Kaibo Feng et al.;《Nature》;20200316;第580卷;第621-627页 *
Site-Selective Copper-Catalyzed Azidation of Benzylic C-H Bonds;Sung-Eun Suh et al.;《Journal of the American Chemical Society》;20200615;第142卷(第26期);第11388-11393页 *

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