可见光诱导的共轭磺酰胺串联脱砜/环化反应

引用本文: 李增增, 袁莉, 王良能, 王硕文, 余健, 夏绿露, 邓佑林, 唐石. 可见光诱导的共轭磺酰胺串联脱砜/环化反应[J]. 应用化学, 2017, 34(11): 1287-1294. doi: 10.11944/j.issn.1000-0518.2017.11.170054 shu

Citation: LI Zengzeng, YUAN Li, WANG Liangneng, WANG Shuowen, YU Jian, XIA Lyulu, DENG Youlin, TANG Shi. Visible Light Induced Desulfonylative Annulation Cascade of N-Sulfonylmethacrylamides[J]. Chinese Journal of Applied Chemistry, 2017, 34(11): 1287-1294. doi: 10.11944/j.issn.1000-0518.2017.11.170054 shu

可见光诱导的共轭磺酰胺串联脱砜/环化反应

吉首大学化学化工学院, 武陵山地区民族药解析与创制湖南省工程实验室湖南吉首 416000

通讯作者: 唐石, 副教授; Tel/Fax:0743-8563911;E-mail:stang@jsu.edu.cn; 研究方向:有机催化与合成

基金项目:
国家自然基金资助项目（21462017，21662013），吉首大学研究生科研创新项目资助（JGY201636），吉首大学科技处研究生科研项目（Jdy16018）

摘要: 发展了一种可见光诱导的共轭磺酰胺串联脱砜/环化，合成全氟烷基化吲哚酮或α-芳基酰胺的方法。此反应以多氟烷基碘或溴为氟源，在发光二极管蓝光灯照射下，利用面式-三（2-苯基吡啶）合铱催化N-烷基-N-甲基丙烯酰基苯磺酰胺经过串联自由基加成/β-芳基迁移/脱砜环化过程，一步构筑两重碳-碳键，以41%~78%的产率合成了一系列含氟吲哚酮或α-芳基酰胺。此方法底物适用范围广，反应条件温和（室温），催化体系绿色，为具有潜在生理活性的含氟吲哚酮及α-芳基酰胺的合成提供了一条高效、快捷的新途径。

关键词:

English

Visible Light Induced Desulfonylative Annulation Cascade of N-Sulfonylmethacrylamides

Hu'nan Engineering Laboratory for Analyse and Drugs Development of Ethnomedicine in Wuling Mountains, Collge of Chemistry and Chemical Engineering, Jishou Unversity, Jishou, Hu'nan 416000, China

Corresponding author: TANG Shi, associate professor; Tel/Fax:0743-8563911; E-mail:stang@jsu.edu.cn; Research interests:organic catalysis and synthesis

Received Date: 01 March 2017
Accepted Date: 08 May 2017
Revised Date: 10 April 2017
Available Online: 10 November 2017
Fund Project:
Supported by the National Natural Science Foundation of China(No.21462017, No.21662013), the Research Innovation Program for Graduates of Jishou University(No.JGY201636), the Research Program for Graduates of Science and Technology Department of Jishou University(No.JDY16018)

Abstract: A visible light induced desulfonylative cyclization cascade of N-sulfonylmethacrylamides toward perfluoroalkylated oxindoles and α-arylamides was developed. Under light-emitting diode(LED) irradiation, in the presence of fac-tris-2-phenylpyridine iridium(Ⅲ)(fac-Ir(ppy)₃) and perfluoroalkyl iodides or bromides, N-butyl-N-(tolylsulfonyl)methacrylamides underwent tandem radical addition/β-arylmigration/desulfonylation to construct two-fold of C-C bonds in single step, leading to a series of perfluoroalkylated oxindoles and α-aryl-β-perfluoroalkyl amide in 41%~78% yield. This mild catalytic protocol exhibits a broad substrate scope and therefore, provides a green and efficient approach to fluorinated oxindoles with potential biological activities.

Key words:

含氟有机分子广泛存在于很多药物和有机农药化学品中^[1]。在复杂的分子骨架中引入含氟基团已经被广泛地用于医药化学中^[2]。值得注意的是，利用各种氟试剂(例如, Umemoto试剂、Togni试剂和CF₃SO₂Cl等)进行烯烃双官能团化，一步引入两个新的官能基团，作为有效的有机氟化合物制备途径在过去的几年中得到许多有机化学家的关注^[3-5]。2013年，Nevado课题组^[6]报道了芳基磺酰胺三氟甲基化合成α-芳基-β-三氟甲基酰胺。2015年，Xia课题组^[7]也报道了一例类似反应，他们利用CF₃SO₂Cl作为三氟甲基自由基源，在钌光催化剂的催化作用下，实现芳基磺酰胺自由基串联加成/环化反应。但是，这些方法只限于在分子骨架中引入简单的氟代甲基基团(例如二氟甲基或三氟甲基)。因此，在利用苯磺酰胺串联脱磺/环合合成含氟吲哚酮反应中，增加引入的含氟基团的多样性(如引入各种全氟烷基化基团)，目前仍然具有重要的合成意义。由于其具有方便、绿色、安全等优点，可见光催化在过去的几年中，已经发展成为一种强大的合成工具被用于现代有机合成中^[8]。全氟碘/溴代烷基试剂是有机氟化学常用的试剂，相对于其它常见烷基试剂(例如, R_fSO₂Cl(R_f为全氟烷基基团)和Togni试剂)来说比较便宜，通过商业渠道也容易得到^[9-14]。基于以上研究背景，以及我们对可见光诱导全氟烷基化研究的兴趣^[15]，我们拟以全氟碘/溴代烷基试剂作为全氟烷基自由源，通过可见光诱导苯磺酰胺脱磺全氟烷基化，在温和的反应条件下合成各种全氟烷基化吲哚酮及α-芳基酰胺类化合物，快速引入CF₃、n-C₃F₇、i-C₃F₇、n-C₄F₉、n-C₆F₁₃、n-C₈F₁₇、n-C₁₀F₂₁和CF₂CO₂Et(Et：乙基)等一系列含氟基团(Scheme 1)。

Scheme1. Synthesis of perfluorinated oxindoles or α-aryl-β-perfluorobutyl amides

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1 实验部分

1.1 仪器和试剂

实验中所用的芳基磺酰氯、草酰氯、全氟碘/溴代烷基试剂和面式-三(2-苯基吡啶)合铱(fac-Ir(ppy)₃)等均购自阿拉丁试剂公司或百灵威试剂公司，其它试剂(购自安耐吉试剂公司)除标明外均为分析纯。实验中所需的原料芳基磺酰胺1a~1m参照相关文献[6]报道方法合成得到。

AVANCE 400 MHz型超导傅里叶数字化核磁共振仪(瑞士Bruker公司)；GC-MS-QP2010型质谱仪(日本岛津公司)；XT5A型显微熔点仪(北京市科仪电光学仪器厂)；RE-52AA型旋转蒸发仪(上海亚荣生化仪器厂)。

1.2 目标产物3的合成

以目标产物3a的合成为例，取原料N-正丁基-N-甲基丙烯酰基-4-甲基苯磺酰胺1a(88.5 mg, 0.3 mmol)溶于2.0 mL二氧六环中，加入fac-Ir(ppy)₃(3.6 mg, 2.0%摩尔分数)和K₃PO₄(127.2 mg, 0.6 mmol)，再加入C₄F₉I(207.5 mg, 0.6 mmol)，并使用N₂气保护，在5 W蓝色发光二极管(LED)灯照射下，搅拌反应24 h。经TLC检验反应完全后，经柱层析分离，石油醚-乙酸乙酯(体积比7:1)梯度洗脱，得到目标产物3a, 为一种油状液体，产率为78%。

1.3 产物的表征数据

产物3a:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.18~7.13(m, 1H), 6.89(d, J=7.6 Hz, 1H), 6.71(s, 1H), 3.76(dt, J=14.4, 7.2 Hz, 1H), 3.70~3.61(m, 1H), 2.86(dd, J=35.4, 15.1 Hz, 1H), 2.61~2.49(m, 1H), 2.40(s, 3H), 1.69~1.61(m, 2H), 1.43~1.38(m, 5H), 0.96(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.7, 142.3, 138.5, 128.5, 123.4, 122.8, 121.3~110.1(m), 109.7, 43.9, 39.7, 36.8(d, J=20.5 Hz), 29.3, 26.2, 21.9, 20.1, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.0(t, J=8.0 Hz, 3F), -108.8(A-B, J_F-F=268 Hz, 1F), -114.9(A-B, J_F-F=273 Hz, 1F), -124.6(br, 2F), -125.2~ -126.3(m, 2F); HRMS m/z(ESI-TOF)计算值C₁₉H₂₁F₉NO [M+H]⁺ 450.1474, 实测值:450.1476。

产物3b:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.15(d, J=7.8 Hz, 1H), 6.88(d, J=5.0 Hz, 1H), 4.62(dt, J=14.0, 7.0 Hz, 1H), 2.87(dd, J=35.3, 16.2 Hz, 1H), 2.62~2.49(m, 1H), 2.39(s, 3H), 1.48(dd, J=7.0, 5.0 Hz, 6H), 1.38(s, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.6, 141.6, 138.2, 128.8, 123.5, 122.6, 122.1-111.9(m), 111.1, 43.9, 37.0(t, J=20.3 Hz), 26.3, 22.0, 19.2, 19.0;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.1(t, J=8.0 Hz, 3F), -108.7(A-B, J_F-F=268 Hz, 1F), -114.9(A-B, J_F-F=273 Hz, 1F), -124.6(br, 2F), -125.2~ -126.2(m, 2F); HRMS m/z(ESI)计算值C₁₈H₁₉F₉NO [M+H]⁺ 436.1318, 实测值:436.1320。

产物3c:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.17(d, J=8.2 Hz, 1H), 6.58(dd, J=8.2, 2.2 Hz, 1H), 6.48(d, J=2.2 Hz, 1H), 3.84(s, 3H), 3.79~3.70(m, 1H), 3.68~3.60(m, 1H), 2.84(dd, J=35.2, 15.2 Hz, 1H), 2.64~2.48(m, 1H), 1.65(tdd, J=10.4, 7.6, 2.9 Hz, 2H), 1.42~1.35(m, 5H), 0.95(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:179.1, 160.2, 143.5, 124.3, 123.4, 120.8~110.2(m), 105.9, 96.9, 55.4, 43.7, 39.9, 36.9(t, J=20.1 Hz), 29.2, 26.2, 20.0, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.1(t, J=9.8 Hz, 3F), -108.8(A-B, J_F-F=262.6 Hz, 1F), -113.7(A-B, J_F-F=269.3 Hz, 1F), -124.7(br, 2F), -125.1~ -126.8(m, 2F); HRMS m/z(ESI)计算值C₁₉H₂₁F₉NO₂ [M+H]⁺ 466.1424, 实测值:466.1426。

产物3d:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.40~7.33(m, 2H), 7.09(s, 1H), 3.81(dt, J=14.4, 7.3 Hz, 1H), 3.76~3.65(m, 1H), 2.94(dd, J=35.1, 15.4 Hz, 1H), 2.74~2.51(m, 1H), 1.71~1.61(m, 2H), 1.44(s, 3H), 1.42~1.37(m, 2H), 0.97(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.1, 142.9, 135.3, 130.9(q, J=32.6 Hz), 124.3(q, J=272.8 Hz), 122.6, 119.4(q, J=4.1 Hz), 119.3~108.5(m), 105.4(q, J=3.8 Hz), 44.1(d, J=1.9 Hz), 36.8(t, J=20.5 Hz), 29.1, 26.1, 20.1, 13.6;¹⁹F NMR(376 MHz, CDCl₃), δ:-63.5(s, 3F), -81.2(t, J=9.8 Hz, 3F), -107.3(A-B, J_F-F=273.3 Hz, 1F), -112.7(A-B, J_F-F=273.0 Hz, 1F), -124.9(br, 2F), -125.1~ -126.7(m, 2F); HRMS m/z(ESI)计算值C₁₉H₁₈F₁₂NO [M+H]⁺ 504.1192, 实测值:504.1194。

产物3e:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.69(dd, J=8.4, 1.1 Hz, 1H), 7.47(d, J=7.4 Hz, 1H), 7.17(dd, J=8.3, 7.5 Hz, 1H), 3.96(ddd, J=15.0, 8.7, 6.5 Hz, 1H), 3.82~3.74(m, 1H), 2.99(dd, J=34.7, 15.4 Hz, 1H), 2.74~2.52(m, 1H), 1.48(s, 3H), 1.42~1.36(m, 2H), 1.33~1.26(m, 2H), 0.90(t, J=7.2 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.9, 136.2, 135.1, 127.3, 124.6, 122.1, 121.2~103.1(m), 43.0, 42.2, 37.2(t, J=20.3 Hz), 29.5, 26.5, 19.7, 13.6;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.2(t, J=9.9 Hz, 3F), -108.0(A-B, J_F-F=273.6 Hz, 1F), -112.8(A-B, J_F-F=274.3 Hz, 1F), -124.9(br, 2F), -125.1~ -126.9(m, 2F); HRMS m/z(ESI)计算值C₁₈H₁₈F₉N₂O₃ [M+H]⁺ 481.1169, 实测值:481.1171。

产物3f:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.40~7.33(m, 2H), 7.09(s, 1H), 3.81(dt, J=14.5, 7.3 Hz, 1H), 3.75~3.65(m, 1H), 2.93(dd, J=35.1, 15.4 Hz, 1H), 2.73~2.51(m, 1H), 1.70~1.62(m, 2H), 1.44(s, 3H), 1.43~1.37(m, 2H), 0.97(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.1, 142.9, 135.2, 130.9(q, J=32.5 Hz), 124.5(q, J=273.0 Hz), 123.9, 119.4(q, J=4.2 Hz), 119.1~107.3(m), 105.4(q, J=3.7 Hz), 44.0, 40.1, 36.6(t, J=20.9 Hz), 29.1, 26.0, 20.0, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-63.5(s, 3F), -81.0(t, J=10.0 Hz, 3F), -109.5~-112.4(m, 2F), -127.8~-129.1(m, 2F); HRMS m/z(ESI)计算值C₁₈H₁₈F₁₀NO₂ [M+H]⁺ 454.1224, 实测值:454.1226。

产物3g:黄色固体; mp 86.0~86.7 ℃; ¹H NMR (400 MHz, CDCl₃), δ:7.34(s, 2H), 7.06(s, 1H), 3.79(dt, J=14.5, 7.4 Hz, 1H), 3.73~3.63(m, 1H), 2.93(t, J=16.3 Hz, 1H), 2.69(t, J=15.2 Hz, 1H), 1.69~1.60(m, 2H), 1.43(s, 3H), 1.39(dd, J=14.5, 7.3 Hz, 2H), 0.98(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:177.4, 142.9, 135.1, 130.9(d, J=32.6 Hz), 123.9, 122.6, 119.2(q, J=4.1 Hz), 118.1-109.2(m), 105.2(q, J=3.9 Hz), 45.4(d, J=4.1 Hz), 40.1, 33.7, 33.5, 29.1, 27.9, 20.1, 13.6;¹⁹F NMR(376 MHz, CDCl₃), δ:-62.6(s, 3F), -76.46~-78.02(m, 6F), -184.0~-188.0(m, 1F); HRMS m/z(ESI)计算值C₁₈H₁₈F₁₀NO [M+H]⁺ 454.1224, 实测值:454.1226。

产物3h:黄色固体; mp 45.3~46.1 ℃; ¹H NMR(400 MHz, CDCl₃), δ:7.15(d, J=7.6 Hz, 1H), 6.89(dd, J=7.6, 0.5 Hz, 1H), 6.71(s, 1H), 3.80~3.71(m, 1H), 3.70~3.60(m, 1H), 2.86(dd, J=35.4, 15.2 Hz, 1H), 2.71~2.50(m, 1H), 2.40(s, 3H), 1.70~1.60(m, 2H), 1.43~1.38(m, 5H), 0.96(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.8, 142.3, 138.5, 128.5, 123.4, 122.9, 120.1~110.5(m), 109.7, 43.9, 39.9, 36.8(d, J=20.5 Hz), 29.3, 26.2, 21.9, 20.1, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.0(t, J=8.1 Hz, 3F), -108.6(A-B, J_F-F=267 Hz, 1F), -114.8(A-B, J_F-F=263 Hz, 1F), -121.9(br, 2F), -122.8(br, 2F), -123.6(br, 2F), -125.2~-126.8(m, 2F); HRMS m/z(ESI)计算值C₂₁H₂₁F₁₃NO [M+H]⁺ 550.1411, 实测值:550.1413。

产物3i:黄色固体; mp 76.4~77.3 ℃; ¹H NMR(400 MHz, CDCl₃), δ:7.15(d, J=7.6 Hz, 1H), 6.88(d, J=7.4 Hz, 1H), 6.71(s, 1H), 3.76(dt, J=14.5, 7.1 Hz, 1H), 3.70~3.60(m, 1H), 2.86(dd, J=35.2, 15.2 Hz, 1H), 2.63~2.48(m, 1H), 2.40(s, 3H), 1.65(ddd, J=10.4, 7.7, 2.8 Hz, 2H), 1.44~1.34(m, 5H), 0.96(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.8, 142.3, 138.5, 128.5, 123.4, 122.9, 120.7~110.5(m), 109.7, 43.9, 39.9, 36.9(t, J=20.2 Hz), 29.3, 26.2, 21.9, 20.1, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-80.9(t, J=8.0 Hz, 3F), -108.9(A-B, J_F-F=269 Hz, 1F), -114.0(A-B, J_F-F=270 Hz, 1F), -121.8(br, 2F), -122.1(br, 4F), -122.9(br, 2F), -123.8(br, 2F), -126.1~-126.8(m, 2F); HRMS m/z(ESI)计算值C₂₃H₂₁F₁₇NO [M+H]⁺ 650.1347, 实测值:650.1349。

产物3j:黄色固体; mp 71.5~72.5 ℃.¹H NMR(400 MHz, CDCl₃), δ:7.15(d, J=7.6 Hz, 1H), 6.88(d, J=7.6 Hz, 1H), 6.71(s, 1H), 3.76(dt, J=14.4, 7.2 Hz, 1H), 3.71~3.61(m, 1H), 2.86(dd, J=35.2, 15.2 Hz, 1H), 2.61~2.48(m, 1H), 2.40(s, 3H), 1.68~1.62(m, 2H), 1.43~1.36(m, 5H), 0.96(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.8, 142.3, 138.5, 128.5, 123.4, 122.9, 120.8-110.4(m), 109.7, 43.9, 39.9, 36.9(t, J=20.0 Hz), 29.3, 26.2, 21.9, 20.1, 13.7;¹⁹F NMR(376 MHz, CDCl₃), δ:-80.8(t, J=12.7 Hz, 3F), -107.5(d, J_F-F=341.0 Hz, 1F), -112.3(d, J_F-F=341.5 Hz, 1F), -121.8(br, 10F), -122.7(br, 2F), -123.9(br, 2F), -126.2(br, 2F); HRMS m/z(ESI)计算值C₂₅H₂₁F₂₁NO [M+H]⁺ 750.1283, 实测值:750.1285。

产物3k:¹H NMR(400 MHz, CDCl₃), δ:7.07(d, J=7.5 Hz, 1H), 6.85(d, J=7.5 Hz, 1H), 6.70(s, 1H), 4.10~3.87(m, 2H), 3.71 (ddt, J=61.0, 14.5, 7.4 Hz, 2H), 2.90~2.67(m, 2H), 2.40(s, 3H), 1.73~1.60(m, 2H), 1.48~1.33(m, 5H), 1.20(t, J=7.1 Hz, 3H), 0.99(t, J=7.3 Hz, 3H); ¹³C NMR(126 MHz, CDCl₃), δ:179.0, 163.6(t, J=32.3 Hz), 143.0, 138.5, 128.0, 123.7, 122.4, 116.7, 114.7(t, J=252.6 Hz), 109.5, 62.8, 44.1(t, J=22.7 Hz), 39.9, 29.3, 25.8, 21.8, 20.1, 13.8, 13.6;¹⁹F NMR(376 MHz, CDCl₃), δ:-100.8(d, J_F-F=266.5 Hz, 1F), -103.6(d, J_F-F=266.6 Hz, 1F); HRMS m/z(ESI)计算值C₁₉H₂₆F₂NO₃ [M+H]⁺ 354.1876, 实测值:354.1878。

产物3l:¹H NMR(400 MHz, CDCl₃), δ:7.33(s, 2H), 7.08(s, 1H), 4.25~3.92(m, 2H), 3.89~3.61(m, 2H), 2.96~2.73(m, 2H), 1.75~1.59(m, 2H), 1.50~1.36(m, 5H), 1.22(t, J=7.2 Hz, 3H), 1.00(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.4, 163.5, 143.47, 134.9, 130.9(q, J=32.4 Hz), 127.4, 125.0(q, J =278.2 Hz), 118.3, 114.9(t, J=256.7 Hz), 104.9, 63.1, 41.2(t, J=24.8 Hz), 40.1, 31.3, 29.1, 25.7, 20.1, 13.7, 13.6;¹⁹F NMR(376 MHz, CDCl₃), δ:-62.4(s, 3F), -100.8(d, J_F-F=266.5 Hz, 1F), -103.6(d, J_F-F=266.6 Hz, 1F); HRMS m/z(ESI)计算值C₁₉H₂₃F₅NO₃ [M+H]⁺ 408.1593, 实测值:408.1595。

产物3m:¹H NMR(400 MHz, CDCl₃), δ:7.38(s, 2H), 7.10(s, 1H), 3.90~3.65(m, 2H), 2.99~2.61(m, 2H), 1.72~1.64(m, 2H), 1.49~1.37(m, 5H), 0.99(t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:178.1, 143.2, 135.1, 131.1(q, J=32.5 Hz), 125.4(q, J=278.4 Hz), 124.1, 124.0(q, J=272.2 Hz), 119.6, 105.5, 44.3, 41.0(q, J=28.5 Hz), 40.3, 29.4, 25.5, 20.2, 13.7;HRMS m/z(ESI)计算值C₁₆H₁₈F₆NO [M+H]⁺354.1288, 实测值:354.1290。

1.4 目标产物5的合成

以目标产物5a的合成为例，取原料N-苯甲基-N-甲基丙烯酰基-4-甲基苯磺酰胺88.5 mg(0.3 mmol)溶于2.0 mL二氧六环中，加入fac-Ir(ppy)₃ 3.6 mg(2.0%(摩尔分数)和K₃PO₄ 127.2 mg(0.6 mmol)，再加入C₄F₉I 207.5 mg(0.6 mmol)，并使用N₂气保护，在5 W蓝色LED灯照射下反应24 h。经TLC检验反应完全后，经柱层析分离，石油醚-乙酸乙酯梯度洗脱，得到目标产物5a，淡黄色油状液体，产率为50%。

1.5 产物的表征数据

产物5a:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.36~7.30(m, 4H), 7.30~7.21(m, 4H), 7.09(dd, J=10.2, 4.3 Hz, 1H), 6.85(s, 1H), 3.21(ddd, J=28.5, 15.7, 12.7 Hz, 1H), 2.89~2.71(m, 1H), 2.37(s, 3H), 1.92(s, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:173.5, 138.0, 137.9, 137.4, 129.9, 129.0, 126.6, 124.6, 120.0, 48.9, 38.1(t, J=19.2 Hz), 23.1, 21.0;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.0(t, J=9.9 Hz, 3F), -109.5~-110.3(m, 2F), -120.7~-128.3(m, 4F); HRMS m/z(ESI)计算值C₂₁H₁₉F₉NO [M+H]⁺ 472.1317, 实测值:472.1314。

产物5b:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ:7.33(d, J=8.2 Hz, 2H), 7.23(dd, J=13.3, 5.9 Hz, 4H), 6.79(dd, J=12.7, 10.8 Hz, 3H), 3.76(s, 3H), 3.29~3.13(m, 1H), 2.87~2.71(m, 1H), 2.37(s, 3H), 1.91(s, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:173.5, 156.7, 138.2, 137.9, 130.5, 129.8, 126.6, 121.9, 114.1, 55.5, 48.7, 38.1(t, J=19.5 Hz), 23.1, 21.0;¹⁹F NMR(376 MHz, CDCl₃), δ:-80.9(t, J=9.9 Hz, 3F), -109.6~-110.3(m, 2F), -120.7~-128.5(m, 4F); HRMS m/z(ESI)计算值C₂₂H₂₁F₉NO₂ [M+H]⁺ 502.1424, 实测值:502.1423。

产物5c:[7]:黄色油状物; ¹H NMR(400 MHz, CDCl₃), δ: 7.33(d, J=8.2 Hz, 2H), 7.21(s, 2H), 6.84~6.75(m, 4H), 3.76(s, 3H), 3.31~3.11(m, 1H), 2.87~2.67(m, 1H), 2.37(s, 3H), 1.91(s, 3H); ¹³C NMR(101 MHz, CDCl₃), δ:173.5, 156.7, 138.3, 137.9, 130.5, 129.8, 126.6, 122.0, 114.1, 55.5, 48.7, 38.1(t, J=19.5 Hz), 23.1, 21.0;¹⁹F NMR(376 MHz, CDCl₃), δ:-81.1(t, J=10.0 Hz, 3F), -109.5~-110.4(m, 2F), -120.7~-128.4(m, 4F); HRMS m/z(ESI)计算值C₂₁H₁₉F₉NO₂ [M+H]⁺ 488.1267, 实测值:488.1268。

2 结果与讨论

2.1 反应条件探索

以N-正丁基-N-甲基丙烯酰基-4-甲基苯磺酰胺(1a)与全氟碘代丁烷(2a)的环化反应为模板反应探索最佳反应条件(表 1)。首先，对催化剂进行了摸索，令人高兴的是，当使用fac-Ir(ppy)₃作为催化剂，在5 W蓝色LED灯照射下，通过串联多氟烷基化/芳基迁移/脱砜化环合反应以78%的产率得到目标产物3a(Entry 1)。接着，考察了其它常见光催化剂(如Ru(bpy)₃Cl₂，bpy:联吡啶)等，结果发现其催化效果均不如fac-Ir(ppy)₃(Entries 2~4)。同时，还对碱进行了筛选，结果表明，K₃PO₄的效果最好，产率达到51%，而其它无机碱(如K₂CO₃, Cs₂CO₃, Na₂CO₃, KOAc)的效果均不如K₃PO₄(Entries 5~8)。对溶剂的进一步考察发现二氧六环是最好的溶剂选择，使用其它溶剂(如N, N-二甲基甲酰胺DMF等)产率将会不同程度降低(Entries 9~12)。在接下来的两个控制实验中，我们发现在不使用光催化剂fac-Ir(ppy)₃或者在黑暗条件下时无目标产物生成(Entries 13~14)，这表明催化剂fac-Ir(ppy)₃和光照条件对此反应的进行是必备的。

表 1 优化反应条件筛选 Table 1. Screening of optimal reaction conditions

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Entry	Initiator	Oxidant	Solvent	Yield of 3a/%^b
1	fac-Ir(ppy)₃	K₃PO₄	dioxane	78
2^c	Ru(bpy)₃Cl₂	K₃PO₄	dioxane	39
3^c	Ru(bpy)₃Cl₂·6H₂O	K₃PO₄	dioxane	32
4^c	Eosin Y	K₃PO₄	dioxane	trace
5	fac-Ir(ppy)₃	K₂CO₃	dioxane	54
6	fac-Ir(ppy)₃	Cs₂CO₃	dioxane	34
7	fac-Ir(ppy)₃	Na₂CO₃	dioxane	15
8	fac-Ir(ppy)₃	KOAc	dioxane	21
9	fac-Ir(ppy)₃	K₃PO₄	DMF	61
10	fac-Ir(ppy)₃	K₃PO₄	DMSO	19
11	fac-Ir(ppy)₃	K₃PO₄	CH₃CN	24
12	fac-Ir(ppy)₃	K₃PO₄	CH₂Cl₂	trace
13	none	K₃PO₄	dioxane	trace
14^d	fac-Ir(ppy)₃	K₃PO₄	dioxane	trace
a.Reaction conditions:1a(0.3 mmol), C₄F₉I(2 stoichiometric number), photocatalyst(2% mole fraction), base(2 stoichiometric number), and solvent(2 mL) were irradiated with a 5 W blue LED at room temperature for 24 h under N₂. DMF=N, N-dimethyl formamide, DMSO=dimethyl sulfoxide, Eosin Y=2′, 4′, 5′, 7′-tetrabromofluorescein; b.yield of the isolated product; c.using 5% molar fraction of photocatalyst; d.under darkness.

综上所述，最佳反应条件为：N-正丁基-N-甲基丙烯酰基苯磺酰胺1a(0.3 mmol)，K₃PO₄(2倍化学计量)，全氟碘代丁烷2a(2倍化学计量)，fac-Ir(ppy)₃(2.0%摩尔分数)为光催化剂，二氧六环为溶剂，5 W蓝LED灯为光源，N₂气保护，室温下反应24 h。

2.2 反应底物范围

得到最佳反应条件后，我们对反应底物的适用范围进行了考察。实验结果表明，N-烷基苯磺酰胺的N原子上带各种烷基取代基团(如，Bu:丁基, i-Pr:异丙基)时，最佳反应条件对其都表现较好的兼容性。接下来，我们还探究了苯环上取代基对环化反应的影响，令人欣喜的是，在苯环对位上连上各种取代基团时，不论推电子基团或拉电子基团(甲氧基(MeO)、CF₃、NO₂)，均表现有较好的反应活性。接着，我们还对多氟烷基试剂的范围进行了研究，正如我们期待的一样，多种全氟烷基试剂(如C₃F₇I、C₄F₉I、C₆F₁₃I、C₈F₁₇I和C₁₀F₂₁I等)对此脱磺酰环合反应均有较高的活性，能以较好的产率得到相应的全氟烷基化吲哚酮目标产物。此外，CF₃I这种氟化试剂也可作为有效氟源用于此反应中，从而在骨架中引入重要三氟甲基基团，只是产率稍微有所降低。芳基磺酰胺的这种串联去磺酰化/全氟烷基化反应，可以将含有各种长度碳链的全氟烷基基团高效地引入有机分子骨架中，这可望成为一种快速、可控的途径去合成各种亲脂的含氟吲哚酮及酰胺，以用于含氟生物活性化合物的筛选。

表 2 环化反应的底物范围^a Table 2. Scope of substrates in cyclization^a

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Entry	Substrate	Product	Yield of 3/%
1	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3a	78
2	R₁=Me, R₂=i-Pr, R₃=Me, R_f=n-C₄F₉	3b	60
3	R₁=MeO, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3c	63
4	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3d	45
5	R₁=NO₂, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3e	41
6	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=n-C₃F₇	3f	64
7	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=i-C₃F₇	3g	52
8	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₆F₁₃	3h	54
9	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₈F₁₇	3i	47
10	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₁₀F₂₁	3j	42
11_b	R₁=Me, R₂=n-Bu, R₃=Me, R_f=CF₂CO₂Et	3k	73
12	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f= CF₂CO₂Et	3l	56
13	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=CF₃	3m	45
a.Reaction conditions:1(0.3 mmol), R_f-I(2 equiv), Ir(ppy)₃(2% molar fraction), K₃PO₄(2 equiv), and dioxane(2 mL) were irradiated with a 5 W blue LEDs at room temperature for 24 h; b.using BrCF₂CO₂Et as the fluorine source.

接下来，我们还探究了其它类型可见光诱导下的芳基酰胺的串联脱磺酰/烷基化反应(Scheme 2)。当共轭芳基磺酰胺的N上烷基基团替换为芳基基团时，反应结果发生了较大的变化。此结果与Nevado的报道^[6]较为相似，在全氟烷基碘试剂存在下，反应可能是经历了一个自由基串联加成/1, 4芳基迁移/去磺化过程，以中等产率得到α-芳基-β-2-氟/全氟烷基酰胺(5a~5c)。

Scheme2. Scope of N-(arylsulfonyl)methacrylamides in the cyclization leading to α-aryl-β-perfluorobutyl amides Reaction conditions:1(0.3 mmol), C₄F₉-I(2 equiv), Ir(ppy)₃(2% molar fraction), K₃PO₄(2 equiv), and dioxane(2 mL) were irradiated with a 5 W blue LED at room temperature for 24 h

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2.3 反应机理

根据以上实验结果及文献报道^[3-7]，我们提出了可能的反应机理过程(Scheme 3)。首先，在紫外可见光的激发下，光催化剂fac-Ir(kⅢ)(ppy)₃在LED蓝光灯照射下转化为其激发态[fac-Ir(Ⅲ)(bpy)₃]^*，其被全氟碘代丁烷氧化，生成[fac-Ir(Ⅳ)(ppy)₃]⁺以及R_f·自由基A, 接着自由基R_f·对芳基磺酰苯胺(1或4)的C＝C双键进行加成，生成中间体B。紧接着B发生分子内自由基环化得到自由基C，然后中间体C发生脱磺酰化得到自由基中间体D^[6]。当N原子上取代基为烷基基团时，芳环上的酰基自由基发生分子内环化得到吲哚酮3。然而，当N原子上取代基换成芳基基团时(R=aryl)，可能是由于连有芳基基团的N自由基较稳定性的特点^[7]，自由基D将直接从溶剂夺取氢，从而发生氢化得到产物α-芳基-β-2-氟/全氟烷基酰胺5。

Scheme3. Proposed mechanism for desulfonylative annulation cascade of N-arylsulfonyl methacrylamides

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3 结论

本文发展了一种可见光诱导下，共轭苯磺酰胺脱砜环化合成含氟吲哚酮和α-芳基酰胺的方法。此反应以全氟碘代烷烃为氟源，面式-三(2-苯基吡啶)合铱催化N-烷基-N-甲基丙烯酰基苯磺酰胺或N-芳基基-N-甲基丙烯酰基苯磺酰胺发生自由基加成/β-芳基迁移/脱砜环化，快速合成多种含多氟烷基基团的吲哚酮或α-芳基-β-氟烷基酰胺。此方法具有底物适应范围广、反应条件温和(室温)，操作简单等特点，为制备全氟吲哚酮和α-芳基酰胺提供了一种途径。

辅助材料(Supporting Information)[目标产物NMR表征图]可以免费从本刊网站(http://yyhx.ciac.jl.cn/)下载。

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Scheme 1 Synthesis of perfluorinated oxindoles or α-aryl-β-perfluorobutyl amides

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Scheme 2 Scope of N-(arylsulfonyl)methacrylamides in the cyclization leading to α-aryl-β-perfluorobutyl amides Reaction conditions:1(0.3 mmol), C₄F₉-I(2 equiv), Ir(ppy)₃(2% molar fraction), K₃PO₄(2 equiv), and dioxane(2 mL) were irradiated with a 5 W blue LED at room temperature for 24 h

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Scheme 3 Proposed mechanism for desulfonylative annulation cascade of N-arylsulfonyl methacrylamides

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表 1 优化反应条件筛选

Table 1. Screening of optimal reaction conditions


Entry	Initiator	Oxidant	Solvent	Yield of 3a/%^b
1	fac-Ir(ppy)₃	K₃PO₄	dioxane	78
2^c	Ru(bpy)₃Cl₂	K₃PO₄	dioxane	39
3^c	Ru(bpy)₃Cl₂·6H₂O	K₃PO₄	dioxane	32
4^c	Eosin Y	K₃PO₄	dioxane	trace
5	fac-Ir(ppy)₃	K₂CO₃	dioxane	54
6	fac-Ir(ppy)₃	Cs₂CO₃	dioxane	34
7	fac-Ir(ppy)₃	Na₂CO₃	dioxane	15
8	fac-Ir(ppy)₃	KOAc	dioxane	21
9	fac-Ir(ppy)₃	K₃PO₄	DMF	61
10	fac-Ir(ppy)₃	K₃PO₄	DMSO	19
11	fac-Ir(ppy)₃	K₃PO₄	CH₃CN	24
12	fac-Ir(ppy)₃	K₃PO₄	CH₂Cl₂	trace
13	none	K₃PO₄	dioxane	trace
14^d	fac-Ir(ppy)₃	K₃PO₄	dioxane	trace
a.Reaction conditions:1a(0.3 mmol), C₄F₉I(2 stoichiometric number), photocatalyst(2% mole fraction), base(2 stoichiometric number), and solvent(2 mL) were irradiated with a 5 W blue LED at room temperature for 24 h under N₂. DMF=N, N-dimethyl formamide, DMSO=dimethyl sulfoxide, Eosin Y=2′, 4′, 5′, 7′-tetrabromofluorescein; b.yield of the isolated product; c.using 5% molar fraction of photocatalyst; d.under darkness.

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表 2 环化反应的底物范围^a

Table 2. Scope of substrates in cyclization^a


Entry	Substrate	Product	Yield of 3/%
1	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3a	78
2	R₁=Me, R₂=i-Pr, R₃=Me, R_f=n-C₄F₉	3b	60
3	R₁=MeO, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3c	63
4	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3d	45
5	R₁=NO₂, R₂=n-Bu, R₃=Me, R_f=n-C₄F₉	3e	41
6	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=n-C₃F₇	3f	64
7	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=i-C₃F₇	3g	52
8	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₆F₁₃	3h	54
9	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₈F₁₇	3i	47
10	R₁=Me, R₂=n-Bu, R₃=Me, R_f=n-C₁₀F₂₁	3j	42
11_b	R₁=Me, R₂=n-Bu, R₃=Me, R_f=CF₂CO₂Et	3k	73
12	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f= CF₂CO₂Et	3l	56
13	R₁=CF₃, R₂=n-Bu, R₃=Me, R_f=CF₃	3m	45
a.Reaction conditions:1(0.3 mmol), R_f-I(2 equiv), Ir(ppy)₃(2% molar fraction), K₃PO₄(2 equiv), and dioxane(2 mL) were irradiated with a 5 W blue LEDs at room temperature for 24 h; b.using BrCF₂CO₂Et as the fluorine source.

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