CN112794821B - 一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应 - Google Patents

一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应 Download PDF

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CN112794821B
CN112794821B CN202110002559.8A CN202110002559A CN112794821B CN 112794821 B CN112794821 B CN 112794821B CN 202110002559 A CN202110002559 A CN 202110002559A CN 112794821 B CN112794821 B CN 112794821B
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欧阳旋慧
黄静
宋仁杰
李金恒
唐梓亮
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Nanchang Hangkong University
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Abstract

本发明公开了一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)‑N交叉偶联反应方法。该方法使用新颖的二酰基过氧化物作为烷基化试剂，在铜催化下对各种不同的含氮亲核试剂引入不同的烷基，反应条件温和简单、经济便宜、产率优异，反应底物适应性好。

Description

一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C (sp3)-N交叉偶联反应
技术领域
本申请属于有机合成技术领域，具体涉及一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应方法。
背景技术
在过去的几十年中，由于C-N键在药物、天然产物和农药中的重要作用， C-N键的构建一直是有机合成的重点领域，其中，C(sp3)-N键的形成引起了广泛关注。因此，许多形成C(sp3)-N键的策略包括将氮亲核试剂与烷基亲电试剂(例如脂肪族卤化物，醇等)偶联，还原胺化，烯烃的加氢胺化和烯烃的碳氨化。虽然已经取得了巨大的成就，但是这种可用的方法仍然受限于使用强碱，窄的反应底物范围和工艺所产生的大量的废物。
脂肪族羧酸及其衍生物价格便宜，稳定，低毒且易于获得，并且在天然产物和药物中广泛发现，从而使自由基脱羧烷基化反应成为快速构建C(sp3)-X(X ＝C，N，O，S等)键的有效途径。在2017年，Fu,Peters课题组发展了一种 N-羟基邻苯二甲酰亚胺烷基酯的脱羧C(sp3)-N交叉偶联反应，通过光照料条件下铜络中物的单电子还原过程，制备烷基邻苯二甲酰亚胺(参见J.Am.Chem. Soc.2017,139,12153.)。在2018年，Macmillan课题组(参见Nature.2018,559, 83.)和Hu课题组(Nat Catal.2018,1,120.)独立地报道了双重铜催化和光氧化还原催化脱羧C(sp3)-N交叉偶联反应，分别使用烷基NHP酯和碘代均三甲基苯二羧酸酯作为烷基前体。根据这些结果，烷基羧酸前体化合物例如N-羟基邻苯二甲酰亚胺烷基酯和碘代均三甲基苯二羧酸酯在光氧化还原或过渡金属催化下经过单电子还原形成烷基自由基中间体，烷基自由基中间体容易地与 LnCunX-氮亲核性配合物A反应。
尽管在脱羧C(sp3)-N偶联方面取得了巨大的成就，但受限于烷基化底物的来源及适应范围，本领域仍然非常需要用一种新型的烷基化试剂来实现 C(sp3)-N键的构建。二酰基过氧化物是一类氧化还原活性酯，可以很容易地从脂肪族羧酸制备，并且在廉价的过渡金属催化和加热下易于脱羧以提供烷基。受这些开创性工作的启发，我们假设如果氧化性二酰基过氧化物可以在光氧化还原催化或铜催化下生成烷基自由基，该烷基自由基物种可以进一步与 LnCunX-氮亲核性配合物A反应以建立C(sp3)-N键。在这里，我们开发了一种新的二酰基过氧化物与氮亲核试剂的脱羧C(sp3)-N交叉偶联，提供了各种烷基化的氮亲核试剂，包括吲唑、三唑、吲哚、嘌呤、咔唑、苯胺、磺酰胺和其他氮亲核试剂。
发明内容
本发明的目的在于克服现有技术的不足，提供一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应方法。该方法使用新颖的二酰基过氧化物作为烷基化试剂，对各种不同的含氮亲核试剂引入不同的烷基，反应条件温和简单、经济便宜、产率优异，反应底物适应性好。
根据本发明提供的一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应方法，包括如下步骤：
向反应器加入式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体和有机溶剂，随后将反应器内气氛用惰性气氛置换，将反应器置于一定温度下搅拌反应，反应完全后经后处理得到式3所示的目标产物。反应式如下：
Figure BDA0002881852200000031
上述反应式中，R1,R2彼此独立地选自氢、取代或未取代的C1-20烷基、取代或未取代的C3-20环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-20杂芳基、取代或未取代的C6-20芳基磺酰基；或者R1,R2彼此连接，并与连接 R1,R2的氮原子一起形成含或不含其它杂原子的C2-20的杂环结构，所述杂环结构任选地被取代基所取代。其中，R1,R2不同时选自氢。
R3选自取代或未取代的C1-20烷基。
优选地，R1,R2彼此独立地选自氢、甲基、取代或未取代的苯基、取代或未取代的苯基磺酰基；或者R1,R2彼此连接，并与连接R1,R2的氮原子一起形成含或不含其它杂原子的C2-12的杂环结构，所述杂环结构任选地被取代基所取代。其中，R1,R2不同时选自氢。
R3选自取代或未取代的C1-20伯烷基。
在本文的任意部分中，所述“取代或未取代的”中的取代基及前述杂环结构的取代基选自卤素、-CN、-NO2、C1-6烷基、C1-6烷氧基、-CHO、苯基、卤代苯基、C1-6烷基取代的苯基、C1-6烷氧基取代的苯基、2-甲氨基羰基-4-吡啶氧基、C3-8环烷基、C2-12炔基、C2-12烯基、苯甲酰基、C1-6烷氧基羰基。
最优选地，式1所示的含氮亲核试剂选自具有如下结构的化合物：
Figure BDA0002881852200000041
式2所示的二酰基过氧化物选自具有如下结构的化合物：
Figure BDA0002881852200000042
根据本发明前述的方法，其中，所述的铜催化剂选自CuBr、Cu(OTf)2、 Cu(MeCN)4PF6、Cu(MeCN)4BF4、CuTc、CuI、CuCl、Cu(OAc)2、CuBr2、CuCl2、 Cu(acac)2中的任意一种或几种；最优选地，所述的铜催化剂选自CuBr。
根据本发明前述的方法，其中，所述的含氮或含磷有机配体选自如下：
Figure BDA0002881852200000051
最优选地，所述的配体选自
Figure BDA0002881852200000052
根据本发明的制备方法，其中，所述的有机溶剂选自1,4-二氧六环、甲醇、乙醇、乙腈、甲苯、DMSO、DMF中的任意一种或几种的混合溶剂。优选地，所述的有机溶剂选自1,4-二氧六环。
根据本发明前述的方法，其中，所述的惰性气氛为氩气气氛或氮气氛，优选为氩气气氛。
根据本发明前述的方法，其中，所述一定温度下搅拌反应的反应温度为室温至100℃，优选为60-80℃，最优选为60℃；反应时间为4-48h，优选为12-24h，最优选为12h。
根据本发明前述的方法，其中，式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体的摩尔比为1:(1-3):(0.05～0.3): (0.05～0.5)；优选地，式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体的摩尔比为1:1.5:0.2:0.3。
根据本发明前述的方法，其中，所述的后处理操作如下：
将反应液浓缩得到残余物，将残余物经硅胶柱层析分离得到式3所示的目标产物，其中硅胶柱层析洗脱液为石油醚/乙酸乙酯的混合溶剂。
较之现有技术，本发明的方法取得了如下的有益效果：
本发明首次报道一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧 C(sp3)-N交叉偶联反应方法。该方法使用新颖的二酰基过氧化物作为烷基化试剂，对各种不同的含氮亲核试剂引入不同的烷基，反应条件温和简单、经济便宜、产率优异，反应底物适应性好。
具体实施方式
以下结合具体实施例，对本发明作进一步地详述。在下文中，如无特殊说明，所采用的方法均为本领域的常规方法，所使用的原料及试剂均可以由常规商业途径购买获得和/或借鉴现有的已知方法制备获得，例如本发明中使用的各种二酰基过氧化物通过使用相应的烷基羧酸类化合物，在 DMAP/DCC/H2O2/DCM条件下反应制备获得(Angew.Chem.Int.Ed.2017,56, 3650；Chem.Sci.,2017,8,2081；Chem.Sci.2019,10,3632；J.Am.Chem.Soc. 2019,141,548)。
实施例1-18反应条件优化试验
以式1a的吲唑、式2a所示的二正十二烷酰基过氧化物为模板底物，探讨了不同反应条件下对式3aa目标产物产率的影响，代表性试验结果见表1。
反应式如下：
Figure BDA0002881852200000071
表1：
实施例 变量 产率(％)<sup>b</sup>
1 无 96
2 不加入CuBr trace
3 不加入Phen trace
4 Cu(OTf)<sub>2</sub>代替CuBr 86
5 Cu(MeCN)<sub>4</sub>PF<sub>6</sub>代替CuBr 88
6 CuTc代替CuBr 93
7 CuI代替CuBr 89
8 L2代替L1 90
9 L3代替L1 50
10 L4代替L1 42
11 L5代替L1 32
12 PPh<sub>3</sub>代替L1 21
13 MeOH代替1,4-dioxane 85
14 MeCN代替1,4-dioxane 79
15 PhMe代替1,4-dioxane 64
16 DMSO代替1,4-dioxane 37
17 反应温度为室温 75
18 反应温度为80℃ 91
b表示分离产率。
其中实施例1操作如下：
向Schlenk封管反应器中，加入1a的吲唑(0.2mmol)、式2a所示的二正十二烷酰基过氧化物(2equiv,0.4mmol),CuBr(20mol％,0.04mmol),1,10-Phen(30 mol％,0.06mmol，L1)和1,4-二氧六环(2mL)，将反应器内气氛用氩气置换，随后将反应器置于60℃条件下搅拌反应直至经TLC和/或GC-MS监测原料消耗完全，反应完全后(12h)，减压浓缩得到残余物，将残余物经硅胶柱层析分离 (石油醚/乙酸乙酯)得到目标产物。棕色油状液体(52.2mg,产率96％,Rf＝0.8(PE/EA＝20:1))；1H NMR(500MHz,CDCl3)δ7.97(s,1H),7.69(d,J＝8.0 Hz,1H),7.40-7.30(m,2H),7.10(t,J＝7.5Hz,1H),4.34(t,J＝7.0Hz,2H), 1.94-1.87(m,2H),1.30-1.20(m,16H),0.87(t,J＝7.0Hz,3H)；13C NMR(126 MHz,CDCl3)δ139.4,132.6,126.0,124.0,121.1,120.3,109.0,48.9,31.9,29.9, 29.6,29.6,29.5,29.4,29.3,26.9,22.7,14.2；LRMS(EI,70eV)m/z(％):272(M+, 29),173(30),131(100),118(50)；HRMS m/z(ESI)calcd for C18H28N2([M+H]+) 273.2325,found 273.2328。
实施例2-18除了表1中所列变量之外，其余操作及参数选择同实施例1。
实施例19-40反应底物拓展试验之一
以实施例1为最佳反应条件，在该相同的参数和操作条件下，仅仅替换含氮亲核试剂的种类，探究了不同含氮亲核试剂的在最佳反应条件下的适应性，结果如下：
Figure BDA0002881852200000091
产物结构表征：
化合物3ba:黄色油状液体；1H NMR(500MHz,CDCl3)δ7.71-7.66(m,1H), 7.27(m,3H),4.15(t,J＝7.5Hz,2H),1.84-1.78(m,2H),1.32-1.25(m,16H),0.88 (t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ141.8,140.5,135.0,123.0, 122.5,119.4,109.5,44.5,31.9,29.5,29.5,29.4,29.3,29.3,29.2,26.7,22.7,14.1； LRMS(EI,70eV)m/z(％):306(M+,5),277(6),271(100),165(16)；HRMS m/z (ESI)calcd for C18H27ClN2([M+H]+)307.1936,found 307.1941。
化合物3ca:黄色固体；m.p.194.2-194.8℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ8.72(d,J＝2.0Hz,1H),8.32-8.16(m,2H),7.47(d,J＝9.0Hz, 1H),4.42(t,J＝7.0Hz,2H),2.00-1.87(m,2H),1.31-1.23(m,16H),0.87(t,J＝ 7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ142.2,141.1,135.6,123.0,121.3, 119.0,109.3,49.5,31.9,29.8,29.5,29.5,29.4,29.3,29.1,26.8,22.7,14.1；LRMS (EI,70eV)m/z(％):317(M+,11),274(3),218(29),176(100),130(19)；HRMS m/z(ESI)calcd for C18H27N3O2([M+H]+)318.2176,found 318.2176。
化合物3da:白色固体；m.p.80.0-81.4℃(uncorrected))；1H NMR(500MHz, CDCl3)δ8.04-7.96(m,1H),7.45(m,1H),7.35-7.26(m,1H),4.60(m,2H), 2.02-1.97(m,2H),1.28-1.21(m,16H),0.87(t,J＝7.0Hz,3H)；13C NMR(126 MHz,CDCl3)δ146.6,144.6,133.6,131.7,129.7,128.1,125.0,121.0,119.4,110.3, 109.2,48.4,31.9,29.7,29.6,29.5,29.3,29.3,29.0,26.7,22.7,14.1；LRMS(EI,70 eV)m/z(％):307(M+,25),208(22),180(53),166(84)；HRMS m/z(ESI)calcd for C17H26ClN3([M+H]+)308.1888,found 308.1892。
化合物3ea:白色固体；m.p.101.3-101.9℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ7.81(s,1H),7.80-7.76(m,2H),7.42(t,J＝7.5Hz,2H),7.33(t,J ＝7.5Hz,1H),4.44(t,J＝7.0Hz,2H),2.02-1.96(m,2H),1.33-1.25(m,16H), 0.87(t,J＝7.0Hz,3H)；13CNMR(126MHz,CDCl3)δ147.5,130.6,128.8,128.3, 125.9,55.1,31.9,29.8,29.6,29.5,29.4,29.3,29.1,26.5,22.7,14.1；LRMS(EI,70 eV)m/z(％):299(M+,25),270(4),256(4),228(10),172(20),158(22),145(22)； HRMS m/z(ESI)calcd for C19H29N3([M+H]+)300.2434,found 300.2437。
化合物3fa:黄色液体；1H NMR(500MHz,CDCl3)δ7.72(s,1H),7.54(s, 1H),7.48(d,J＝8.0Hz,1H),7.23(t,J＝8.0Hz,1H),7.07(d,J＝7.5Hz,1H), 4.36(t,J＝7.0Hz,2H),2.32(s,3H),1.94-1.86(m,2H),1.21-1.16(m,16H),0.79 (t,J＝5.5Hz,3H)；13C NMR(126MHz,CDCl3)δ147.6,138.5,130.6,130.5, 129.1,128.7,126.5,123.0,55.1,31.9,29.8,29.6,29.5,29.4,29.3,29.1,26.5,22.7, 21.4,14.1；LRMS(EI,70eV)m/z(％):313(M+,37),270(6),242(12),200(7), 186(25),172(24),159(32)；HRMS m/z(ESI)calcd forC20H31N3([M+H]+) 314.2591,found 314.2595。
化合物3ga：白色固体；m.p.98.1-99.8℃(uncorrected))；1H NMR(500MHz, CDCl3)δ7.79(s,1H),7.71(d,J＝8.5Hz,2H),7.39(d,J＝8.5Hz,2H),4.43(t,J ＝7.0Hz,2H),2.02-1.94(m,2H),1.33-1.25(m,16H),0.87(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ146.4,134.0,130.6,129.1,129.0,127.1,55.2,31.9, 29.8,29.6,29.5,29.4,29.3,29.0,26.5,22.7,14.1；LRMS(EI,70eV)m/z(％):333 (M+,32),290(5),262(11),248(9),206(24),192(23),179(34)；HRMS m/z(ESI) calcd for C19H28ClN3([M+H]+)334.2045,found334.2048。
化合物3ha:黄色液体；1H NMR(500MHz,CDCl3)δ8.39(d,J＝5.0Hz,1H), 7.44(d,J＝3.0Hz,1H),7.31(d,J＝5.0Hz,1H),6.67(d,J＝3.0Hz,1H),4.32(t, J＝7.0Hz,2H),1.87(s,2H),1.31-1.24(m,16H),0.87(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ147.5,142.1,131.2,120.8,118.1,116.7,110.7,98.4, 45.0,31.9,30.3,29.5,29.5,29.4,29.3,29.1,26.8,22.7,14.1；LRMS(EI,70eV) m/z(％):297(M+,79),268(7),240(11),212(18),198(75),156(100),143(74)； HRMS m/z(ESI)calcd for C19H27N3([M+H]+)298.2278,found298.2279。
化合物3ia:棕色液体；1H NMR(500MHz,CDCl3)δ8.12(d,J＝8.0Hz,1H), 7.66(d,J＝8.0Hz,1H),7.35(d,J＝3.0Hz,1H),7.28-7.22(m,2H),4.18(t,J＝ 7.0Hz,2H),1.87-1.81(m,2H),1.26-1.24(m,16H),0.87(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ140.5,138.2,132.3,122.7,120.2,117.3,116.2,101.7, 46.9,31.9,30.3,29.5,29.5,29.4,29.3,29.2,26.9,22.7,14.1；LRMS(EI,70eV) m/z(％):316(M+,100),203(53),175(95),129(63)；HRMS m/z(ESI)calcd for C18H28N2O2([M+H]+)317.2224,found 317.2227。
化合物3ja:黄色液体；1H NMR(500MHz,CDCl3)δ7.10(t,J＝4.5Hz,2H), 7.05(d,J＝3.0Hz,1H),6.78-6.73(m,1H),6.56(d,J＝3.0Hz,1H),4.09(t,J＝ 7.0Hz,2H),1.84-1.79(m,2H),1.29-1.24(m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ127.7,121.8,121.7,105.6,105.5,104.0,103.8,97.0, 46.8,31.9,30.2,29.6,29.6,29.6,29.3,29.2,27.0,22.7,14.1；19F NMR(471MHz, CDCl3)δ-122.10–-122.28(m)；LRMS(EI,70eV)m/z(％):289(M+,66),260(4), 246(5),204(3),190(13),176(20),148(100)；HRMS m/z(ESI)calcd for C19H28FN([M+H]+)290.2279,found 290.2284。
化合物3ka:黄色液体；1H NMR(500MHz,CDCl3)δ9.99(s,1H),8.31(m, 1H),7.70(s,1H),7.38-7.29(m,3H),4.16(t,J＝7.0Hz,2H),1.92-1.85(m,2H), 1.25(m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ184.5, 138.3,137.2,125.5,123.9,122.9,122.1,118.0,110.1,47.3,31.9,29.8,29.5,29.5, 29.4,29.3,29.1,26.9,22.7,14.1；LRMS(EI,70eV)m/z(％):299(M+,100),270 (37),200(17),172(23),158(86)；HRMS m/z(ESI)calcdfor C20H29NO([M+H]+) 300,2322,found 300.2326。
化合物3la:黄色液体；1H NMR(500MHz,CDCl3)δ9.08(s,1H),8.93(s,1H), 8.04(s,1H),4.23(t,J＝7.0Hz,2H),1.86(m,2H),1.20-1.16(m,16H),0.80(t,J＝ 7.0Hz,3H)；13CNMR(126MHz,CDCl3)δ152.5,148.5,145.3,134.0,130.9,60.4, 43.9,31.9,29.9,29.5,29.5,29.4,29.3,26.7,22.6,14.1；LRMS(EI,70eV)m/z(％): 274(M+,83),231(18),203(25),189(29),175(66),161(41),147(49),133(65), 120(49)；HRMS m/z(ESI)calcd forC16H26N4([M+H]+)275.2230,found 275.2228。
化合物3ma:白色固体；m.p.222.8-223.1℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ8.00(d,J＝2.0Hz,2H),7.43(d,J＝9.0,2H),7.16-7.12(m,2H), 4.08(t,J＝7.0Hz,2H),1.73-1.66(m,2H),1.20-1.11(m,16H),0.79(t,J＝7.0Hz, 3H)；13C NMR(126MHz,CDCl3)δ139.3,129.0,123.4,123.2,111.9,110.4,43.3, 31.9,29.6,29.6,29.5,29.4,29.3,28.8,27.2,22.7,14.2；LRMS(EI,70eV)m/z(％): 479(M+,1),383(100),369(11),341(11),327(14),313(32),207(71)；HRMS m/z (ESI)calcd for C23H29Br2N([M+H]+)478.0740,found 478.0741。
化合物3na:棕色固体；m.p.190.4-191.9℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ8.17-8.10(m,1H),7.90-7.84(m,1H),7.79-7.72(m,2H),5.28 (s,1H),3.11-3.07(m,2H),1.55-1.47(m,2H),1.45-1.22(m,16H),0.88(t,J＝ 7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ148.1,133.8,133.6,132.8,131.1, 125.4,43.9,31.9,29.6,29.5,29.5,29.4,29.3,29.0,26.5,22.7,14.1；LRMS(EI, 70eV)m/z(％):356(M+,1),239(2),215(20),170(49)；HRMS m/z(ESI) calcd for C17H28N2O4S([M+H]+)357.1843,found 357.1844.
化合物3oa:黄色液体；1H NMR(500MHz,CDCl3)δ7.09(t,J＝8.0Hz,2H), 6.60(t,J＝7.0Hz,1H),6.52(d,J＝8.0Hz,2H),3.02(t,J＝7.0Hz,2H),1.55-1.51 (m,2H),1.45-1.21(m,16H),0.81(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3) δ148.6,129.2,117.1,112.7,44.0,31.9,29.6,29.6,29.6,29.5,29.37,29.3,27.2, 22.7,14.1；LRMS(EI,70eV)m/z(％):247(M+,12),106(100)；HRMS m/z(ESI) calcd for C17H29N([M+H]+)248.2373,found 248.2376。
化合物3pa:棕色液体；1H NMR(500MHz,CDCl3)δ6.86(t,J＝7.5Hz,1H), 6.75(d,J＝8.0Hz,1H),6.66-6.56(m,2H),3.83(s,3H),3.10(t,J＝7.0Hz,2H), 1.66-1.61(m,2H),1.47-1.26(m,16H),0.88(t,J＝6.0Hz,3H)；13C NMR(126 MHz,CDCl3)δ146.8,138.6,121.3,116.1,109.8,109.4,55.4,43.8,31.9,29.7, 29.6,29.6,29.5,29.4,27.3,22.7,14.1；LRMS(EI,70eV)m/z(％):277(M+,25), 136(100)；HRMS m/z(ESI)calcd for C18H31NO([M+H]+)278.2478,found 278.2479。
化合物3qa:黄色液体；1H NMR(500MHz,CDCl3)δ7.64(d,J＝8.0,1H), 7.19-7.17(m,1H),6.54(d,J＝8.0,1H),6.41(m,1H),4.12(s,1H),3.15-3.11(m, 2H),1.69-1.63(m,2H),1.41-1.27(m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR (126MHz,CDCl3)δ147.4,139.0,129.4,118.3,110.5,85.4,44.2,32.0,29.7,29.7, 29.6,29.4,29.4,29.2,27.2,22.7,14.2；LRMS(EI,70eV)m/z(％):373(M+,40), 232(100),219(6)；HRMS m/z(ESI)calcd forC17H28IN([M+H]+)374.1339,found 374.1337。
化合物3ra:黄色液体；1H NMR(500MHz,CDCl3)δ7.10(d,J＝9.0Hz,2H), 6.50(d,J＝9.0Hz,2H),3.05(t,J＝7.0Hz,2H),1.61-1.57(m,2H),1.47-1.26(m, 16H),0.89(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ147.1,129.0,121.5, 113.7,44.1,31.9,29.7,29.6,29.6,29.6,29.4,29.3,27.1,22.7,14.1；LRMS(EI,70 eV)m/z(％):281(M+,17),140(100)；HRMS m/z(ESI)calcd for C17H28ClN ([M+H]+)282.1983,found 282.1987。
化合物3sa:棕色液体；1H NMR(500MHz,CDCl3)δ7.08(d,J＝8.5Hz,2H), 6.57(d,J＝8.5Hz,2H),3.60(s,1H),3.08(t,J＝7.0Hz,2H),1.60-1.57(m,2H), 1.48-1.26(m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ148.3, 128.9,118.7,117.6,113.0,43.9,31.9,29.7,29.6,29.6,29.5,29.4,27.2,22.8,22.7, 14.1；HRMS m/z(ESI)calcd forC18H28N2([M+H]+)273.2325,found 273.2330。
化合物3ta:黄色固体；m.p.173.0-173.7℃(uncorrected))；1H NMR(500MHz,CDCl3)δ8.07(d,J＝9.0,2H),6.51(d,J＝9.0,2H),4.64(s,1H),3.20(s,2H), 1.67-1.62(m,2H),1.48-1.27(m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR(126 MHz,CDCl3)δ153.6,137.6,126.5,110.9,43.4,31.9,29.6,29.6,29.5,29.4,29.3, 29.1,27.0,22.7,14.1；LRMS(EI,70eV)m/z(％):292(M+,17),151(100)；HRMS m/z(ESI)calcd for C17H28N2O2([M+H]+)293.2224,found 293.2222。
化合物3ua:红色固体；1H NMR(500MHz,CDCl3)δ6.95(t,J＝8.0Hz,1H), 6.85(d,J＝7.0Hz,1H),6.48-6.44(m,2H),3.21-3.16(m,2H),3.16-3.12(m,2H), 2.67(t,J＝6.0Hz,2H),1.90-1.83(m,2H),1.51-1.47(m,2H),1.31-1.19(m,16H), 0.81(t,J＝7.0Hz,3H)；13CNMR(126MHz,CDCl3)δ145.4,129.1,127.0,122.1, 115.1,110.4,51.5,49.4,31.9,29.7,29.6,29.6 29.4,28.2,27.3,26.2,22.7,22.3, 14.1；LRMS(EI,70eV)m/z(％):287(M+,11),146(100)；HRMS m/z(ESI)calcd for C20H33N([M+H]+)288.2686,found 288.2688。
化合物3va:棕色液体；1H NMR(500MHz,CDCl3)δ7.22(t,J＝8.0Hz,2H), 6.67(m,3H),3.31-3.26(m,2H),2.91(s,3H),1.57(d,J＝6.5Hz,2H),1.31-1.25 (m,16H),0.88(t,J＝7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ149.4,129.1, 115.8,112.1,52.9,38.3,31.9,29.7,29.6,29.6,29.3,27.2,26.7,22.7,14.1；LRMS (EI,70eV)m/z(％):261(M+,11),176(11),120(100)；HRMS m/z(ESI)calcd for C18H31N([M+H]+)262.2529,found 262.2532.
化合物3wa:黄色液体；1H NMR(500MHz,CDCl3)δ8.31(d,J＝5.5Hz,1H), 8.05(d,J＝4.0Hz,1H),7.68(d,J＝2.0Hz,1H),6.89(d,J＝9.0Hz,3H),6.61(d, J＝8.5Hz,2H),3.10(t,J＝7.0Hz,2H),2.99(d,J＝5.0Hz,3H),1.59-1.53(m, 2H),1.30-1.24(m,16H),0.89(t,J＝6.5Hz,3H)；13C NMR(126MHz,CDCl3)δ 167.4,164.8,152.0,149.4,146.6,144.4,121.8,113.7,113.6,110.0,44.3,31.9, 29.6,29.5,29.5,29.3,29.3,29.1,27.2,26.1,22.7,14.1；HRMS m/z(ESI)calcd for C24H35N3O2([M+H]+)398.2802,found 398.2801。
实施例41-51反应底物拓展试验之二
以实施例1为最佳反应条件，在该相同的参数和操作条件下，仅仅替换二烷酰基过氧化物的种类，探究了不同的二烷酰基过氧化物在最佳反应条件下的适应性，结果如下：
Figure BDA0002881852200000161
其中化合物3ac、3ad、3ah和3al的制备过程中，反应温度为100℃，其余参数均同实施例1。
产物表征数据如下：
化合物3ab:黄色液体；1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.71(d,J＝ 8.0Hz,1H),7.44-7.32(m,2H),7.15-7.08(m,1H),4.41-4.35(m,2H),1.96-1.91 (m,2H),1.81-1.72(m,3H),1.62-1.59(m,2H),1.52-1.49(m,2H),1.16-1.14(m, 2H)；13C NMR(126MHz,CDCl3)δ139.3,132.6,126.0,124.0,121.1,120.3,109.0, 48.3,37.4,36.1,32.5,25.2；LRMS(EI,70eV)m/z(％):214(M+,30),186(25), 145(47),131(100)；HRMS m/z(ESI)calcdfor C14H18N2([M+H]+)215.1543, found 215.1539。
化合物3ac:白色固体；m.p.50.2-51.7℃(uncorrected))；1H NMR(500MHz, CDCl3)δ8.01(s,1H),7.71(d,J＝8.0Hz,1H),7.32-7.27(m,1H),7.26-7.18(m, 5H),7.13(d,J＝8.0Hz,2H),4.59(t,J＝7.5Hz,2H),3.21(t,J＝7.5Hz,2H)；13C NMR(126MHz,CDCl3)δ139.5,138.4,133.1,128.8,128.6,126.6,126.1,123.9, 121.1,120.4,108.9,50.5,36.4；LRMS(EI,70eV)m/z(％):222(M+,30),131 (100),118(50)；HRMS m/z(ESI)calcd for C15H14N2([M+H]+)223.1230,found 223.1232。
化合物3ad:黄色液体；1H NMR(500MHz,CDCl3)δ8.00(s,1H),7.71(d,J＝8.0Hz,1H),7.33-7.25(m,2H),7.11(t,J＝7.5Hz,1H),7.05(q,J＝8.0Hz,4H), 4.60-4.53(m,2H),3.21-3.12(m,2H),2.30(s,3H)；13C NMR(126MHz,CDCl3)δ 139.4,136.2,135.3,133.0,129.3,128.6,126.1,123.9,121.1,120.4,108.9,50.6, 35.9,21.0；LRMS(EI,70eV)m/z(％):236(M+,25),131(100),118(40)；HRMS m/z(ESI)calcd for C16H16N2([M+H]+)237.1386,found 237.1388。
化合物3ae:黄色固体；m.p.278.2-279.1℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ8.00(s,1H),7.72(d,J＝8.0Hz,1H),7.38-7.30(m,2H),7.13(m, 1H),7.07(q,J＝8.0Hz,4H),4.37(t,J＝7.0Hz,2H),2.62-2.57(m,2H),2.31(s, 3H),2.28-2.22(m,2H)；13CNMR(126MHz,CDCl3)δ139.5,137.9,135.5,132.9, 129.1,128.3,126.1,124.0,121.1,120.4,109.0,48.1,32.5,31.3,21.0；LRMS(EI, 70eV)m/z(％):250(M+,26),145(1),131(100)；HRMS m/z(ESI)calcd for C17H18N2([M+H]+)251.1546,found 251.1546。
化合物3af:黄色液体；1H NMR(500MHz,CDCl3)δ7.92(s,1H),7.64(d,J＝ 8.0Hz,1H),7.40(d,J＝8.5Hz,1H),7.33-7.27(m,1H),7.06(t,J＝7.5Hz,1H), 4.44(t,J＝6.0Hz,2H),2.12-2.06(m,4H),1.96(d,J＝2.5Hz,1H)；13C NMR(126 MHz,CDCl3)δ139.7,133.2,126.2,123.9,121.1,120.5,109.0,83.2,69.4,47.1, 28.6,15.9；LRMS(EI,70eV)m/z(％):184(M+,30),131(100)；HRMS m/z(ESI) calcd for C12H12N2([M+H]+)185.1073,found185.1075。
化合物3ag:黄色液体；1H NMR(500MHz,CDCl3)δ7.92(d,J＝1.0Hz,1H), 7.65-7.63(m,1H),7.29(d,J＝8.5Hz,2H),7.23-7.22(m,1H),7.16(s,1H), 7.06-7.01(m,1H),6.93(d,J＝8.5Hz,2H),4.28(t,J＝7.0Hz,2H),2.53-2.42(m, 2H),2.21-2.10(m,2H)；13C NMR(126MHz,CDCl3)δ140.0,139.5,133.0,131.5, 130.2,126.2,124.0,121.2,120.5,119.8,108.9,47.9,32.3,31.0；LRMS(EI,70eV) m/z(％):314(M+,17),131(100)；HRMS m/z(ESI)calcd for C16H15BrN2([M+H]+) 315.0491,found 315.0493。
化合物3ah:黄色液体；1H NMR(500MHz,CDCl3)δ7.91(s,1H),7.81-7.75 (m,2H),7.64(d,J＝8.0Hz,1H),7.44(t,J＝7.5Hz,1H),7.38-7.31(m,3H),7.27 (t,J＝7.5Hz,1H),7.05(t,J＝7.5Hz,1H),4.44(t,J＝7.0Hz,2H),2.89(t,J＝7.0 Hz,2H),2.32-2.27(m,J＝7.0Hz,2H)；13C NMR(126MHz,CDCl3)δ199.3, 139.5,136.7,133.1,133.0,128.6,128.0,126.3,124.0,121.1,120.6,109.1,47.9, 35.1,24.1；LRMS(EI,70eV)m/z(％):264(M+,6),144(68),131(100)；HRMS m/z(ESI)calcd for C17H16N2O([M+H]+)265.1335,found265.1338。
化合物3ai:黄色液体；1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.72(d,J＝ 8.0Hz,1H),7.41-7.34(m,2H),7.13(t,J＝7.0Hz,1H),4.40(t,J＝7.0Hz,2H), 4.12-4.07(m,2H),2.31(t,J＝7.5Hz,2H),2.00-1.94(m,2H),1.66(m,2H), 1.23-1.20(t,J＝7.0Hz,3H)；13CNMR(126MHz,CDCl3)δ173.2,139.4,132.9, 126.2,124.0,121.1,120.4,108.9,60.3,48.4,33.7,29.2,22.2,14.2；LRMS(EI,70 eV)m/z(％):246(M+,15),217(30),173(27),118(100)；HRMS m/z(ESI)calcd for C14H18N2O2([M+H]+)247.1441,found 247.1445。
化合物3aj:黄色液体；1H NMR(500MHz,CDCl3)δ7.99(s,1H),7.73(d,J＝ 8.01Hz,1H),7.42-7.35(m,2H),7.15-7.13(m,1H),4.39(t,J＝7.0Hz,2H),3.35 (t,J＝7.0Hz,2H),1.99-1.93(m,2H),1.91-1.85(m,2H),1.50-1.43(m,2H)；13C NMR(126MHz,CDCl3)δ139.4,132.9,126.2,124.0,121.2,120.5,108.9,48.6, 33.4,32.3,29.0,25.5；LRMS(EI,70eV)m/z(％):266(M+,10),187(20),131 (100)；HRMS m/z(ESI)calcd for C12H15BrN2([M+H]+)267.0491,found 267.0496。
化合物3ak:白色固体；m.p.298.2-298.7℃(uncorrected))；1H NMR(500 MHz,CDCl3)δ7.98(s,1H),7.72(d,J＝8.0Hz,1H),7.42-7.34(m,2H),7.13(m, 1H),4.37(t,J＝7.0Hz,2H),1.95-1.88(m,2H),1.41-1.24(m,28H),0.88(t,J＝ 7.0Hz,3H)；13C NMR(126MHz,CDCl3)δ139.4,132.6,126.0,124.0,121.1, 120.3,109.0,48.9,32.0,29.9,29.7,29.7,29.7,29.7,29.7,29.7,29.6,29.6,29.5, 29.4,29.2,26.9,22.7,14.1；LRMS(EI,70eV)m/z(％):356(M+,7),327(2),313 (1),243(1),201(2),173(18)；HRMS m/z(ESI)calcd for C24H40N2([M+H]+) 357.3264,found 357.3266。
化合物3al:黄色液体；1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.72(d,J＝ 8.0Hz,1H),7.40(d,J＝8.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.12(t,J＝7.0Hz, 1H),5.34(m,2H),4.36(t,J＝7.0Hz,2H),1.99-1.92(m,6H),1.41-1.26(m,20H), 0.88(t,J＝6.0Hz,3H)；13CNMR(126MHz,CDCl3)δ139.4,132.7,130.0,129.7, 126.0,124.0,121.1,120.3,109.0,48.9,31.9,29.9,29.8,29.7,29.5,29.3,29.2,29.2, 29.1,27.2,27.2,26.9,22.7,14.2；LRMS(EI,70 eV)m/z(％):354(M+,11),269(5), 255(6),241(5),201(5),173(6),131(100)；HRMS m/z(ESI)calcd for C24H38N2 ([M+H]+)355.3108,found 355.3112。

Claims (14)

1.一种自由基介导的二酰基过氧化物与含氮亲核试剂的脱羧C(sp3)-N交叉偶联反应方法，包括如下步骤：
向反应器加入式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体和有机溶剂，随后将反应器内气氛用惰性气氛置换，将反应器置于一定温度下搅拌反应，反应完全后经后处理得到式3所示的目标产物；反应式如下：
Figure FDA0003590897890000011
上述反应式中，R1,R2彼此独立地选自氢、取代或未取代的C1-20烷基、取代或未取代的C3-20环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-20杂芳基、取代或未取代的C6-20芳基磺酰基；或者R1,R2彼此连接，并与连接R1,R2的氮原子一起形成含或不含其它杂原子的C2-20的杂环结构，所述杂环结构任选地被取代基所取代；并且其中，R1,R2不同时选自氢；
R3选自取代或未取代的C1-20烷基；
所述“取代或未取代的”中的取代基及前述杂环结构的取代基选自卤素、-CN、-NO2、C1-6烷基、C1-6烷氧基、-CHO、苯基、卤代苯基、C1-6烷基取代的苯基、C1-6烷氧基取代的苯基、2-甲氨基羰基-4-吡啶氧基、C3-8环烷基、C2-12炔基、C2-12烯基、苯甲酰基、C1-6烷氧基羰基；
所述的铜催化剂选自CuBr、Cu(OTf)2、Cu(MeCN)4PF6、Cu(MeCN)4BF4、CuTc、CuI、CuCl、Cu(OAc)2、CuBr2、CuCl2、Cu(acac)2中的任意一种或几种；
所述的含氮或含磷有机配体选自如下L1～L11中的一种或几种：
Figure FDA0003590897890000021
2.根据权利要求1所述的方法，其特征在于，R1,R2彼此独立地选自氢、甲基、取代或未取代的苯基、取代或未取代的苯基磺酰基；或者R1,R2彼此连接，并与连接R1,R2的氮原子一起形成含或不含其它杂原子的C2-12的杂环结构，所述杂环结构任选地被取代基所取代；并且
其中，R1,R2不同时选自氢；
R3选自取代或未取代的C1-20伯烷基；
其中，所述“取代或未取代的”中的取代基及前述杂环结构的取代基选自卤素、-CN、-NO2、C1-6烷基、C1-6烷氧基、-CHO、苯基、卤代苯基、C1-6烷基取代的苯基、C1-6烷氧基取代的苯基、2-甲氨基羰基-4-吡啶氧基、C3-8环烷基、C2-12炔基、C2-12烯基、苯甲酰基、C1-6烷氧基羰基。
3.根据权利要求1所述的方法，其特征在于，式1所示的含氮亲核试剂选自具有如下结构的化合物：
Figure FDA0003590897890000031
式2所示的二酰基过氧化物选自具有如下结构的化合物：
Figure FDA0003590897890000032
Figure FDA0003590897890000042
4.根据权利要求1所述的方法，其特征在于，所述的铜催化剂选自CuBr；所述的含氮或含磷有机配体选自
Figure FDA0003590897890000041
5.根据权利要求1所述的方法，其特征在于，所述的有机溶剂选自1,4-二氧六环、甲醇、乙醇、乙腈、甲苯、DMSO、DMF中的任意一种或几种的混合溶剂。
6.根据权利要求5所述的方法，其特征在于，所述的有机溶剂选自1,4-二氧六环。
7.根据权利要求1所述的方法，其特征在于，所述的惰性气氛为氩气气氛或氮气气氛。
8.根据权利要求7所述的方法，其特征在于，所述的惰性气氛为氩气气氛。
9.根据权利要求1所述的方法，其特征在于，所述一定温度下搅拌反应的反应温度为室温至100℃；反应时间为4-48h。
10.根据权利要求9所述的方法，其特征在于，所述一定温度下搅拌反应的反应温度为60-80℃，反应时间为12-24h。
11.根据权利要求10所述的方法，其特征在于，所述一定温度下搅拌反应的反应温度为60℃，反应时间为12h。
12.根据权利要求1所述的方法，其特征在于，式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体的摩尔比为1:(1-3):(0.05～0.3):(0.05～0.5)。
13.根据权利要求12所述的方法，其特征在于，式1所示的含氮亲核试剂、式2所示的二酰基过氧化物、铜催化剂、含氮或含磷有机配体的摩尔比为1:1.5:0.2:0.3。
14.根据权利要求1所述的方法，其特征在于，所述的后处理操作如下：将反应液浓缩得到残余物，将残余物经硅胶柱层析分离得到式3所示的目标产物，其中硅胶柱层析洗脱液为石油醚/乙酸乙酯的混合溶剂。
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