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• 吡唑类化合物具有多种生物活性, 例如除草、杀虫和杀菌、抗癌、抗菌、抗氧化和IRK4抑制等作用^[1], 含有吡唑及其衍生结构的化合物已被广泛应用于农药和医药开发中.具有螺环结构的吡唑类化合物是一类重要的吡唑衍生物, 含有这种结构单元的化合物已被证实具有抗癌^[2]、酶抑制^[3]、除草^[4]和抗结核分岐杆菌^[5]等作用, 因此, 它们的合成研究受到了广泛关注. 1960年, Huisgen课题组^[6]通过氰基亚胺和偶氮次甲基亚胺的[3+2]热环化反应构建了一系列的螺环吡唑类化合物. 1993年, Belletire课题组^[7]报道了一种通过自由基机理合成螺环吡唑类化合物的方法. 2014年, 施敏课题组^[8]通过钯催化反应, 合成了一种氮杂环状1, 3-偶极子, 并用这种偶极子合成了一系列具有螺环结构的吡唑类衍生物, 为实现螺环吡唑类化合物的合成提供了新的途径.

  环加成反应在杂环化合物合成中扮演着重要角色.截至目前, 已有多种1, 3-偶极子被用于环加成反应中, 例如硝酮、偶氮次甲基亚胺、亚甲胺叶立德、羰基叶立德、氰基叶立德、氰基亚胺、氰基氧化物、重氮化合物和叠氮化合物等^[9].其中, 氰基亚胺作为一种重要的1, 3-偶极子, 经常被用于含氮杂环化合物的合成^{[10, 11]}.在碱的存在下, N-芳基芳羰基亚肼酰氯脱去一分子氯化氢, 形成氰基亚胺中间体(Scheme 1), 再与亲偶极体如亚胺、烯烃、炔烃和烯胺等发生环加成反应, 得到杂环化合物. 1962年, Huisgen课题组^[12]报道了氰基亚胺与亚胺的[3+2]环加成反应, 合成三氮唑类化合物. 1979年, Tsuge课题组^[13]报道了氰基亚胺与氮杂环丙烷的[3+3]环加成反应, 实现1, 2, 4-三嗪类衍生物的合成.同年, Gandolfi课题组^[14]报道了氰基亚胺与环庚三烯亚胺[8+3]环化反应, 完成了环庚三烯并1, 2, 4-三嗪类化合物的合成. 2018年, 本课题组与王治永课题组^[15]相继报道了氰基亚胺与氮杂邻亚甲基苯醌的[4+3]环化反应, 实现^{[1, 2, 4]}三氮杂䓬衍生物的合成.最近, 本组^[16]报道了氰基亚胺与香豆灵酸甲酯或吡喃酮的[3+2]环加成反应, 以较高至优秀的产率和优秀的非对映选择性合成二氢吡喃并吡唑酮衍生物.基于我们之前的工作^[15~17], 本工作采用氰基亚胺与具有环外双键的二氢苯并呋喃二酮进行环加成反应, 高产率高立体选择性地合成了螺吡唑类化合物(Scheme 1).

  图式 1

  

  图式 1.  氰基亚胺与具有环外双键的二氢苯并呋喃二酮的环加成反应

  Scheme 1.  Cycloaddition reactions between methylenedihydrobenzofurandione and nitrilimines

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  1.   结果与讨论

  最初使用三乙烯二胺(DABCO)为碱, 探索了二氢苯并呋喃二酮类化合物1a和N-芳基芳羰基亚肼酰氯2a的[3+2]环加成反应, 以二氯甲烷(DCM)为溶剂, 在室温下反应24 h, 以72%的产率得到所期望的产物3aa(表 1, Entry 1).接下来, 分别筛选了1, 8-二氮杂二环十一碳-7-烯(DBU)、三乙胺(Et₃N)和二异丙基乙基胺(i-Pr₂- NEt)三种有机碱(Entries 2~4), 分别以69%、86%和75%的产率得到目标产物.作为对比, 使用碳酸铯和碳酸钾这两种无机碱分别得到了60%和78%的产率(Entries 5, 6).从上述结果可以看出, 所有碱均能以较高产率得到目标产物.相比于无机碱, 有机碱的效果更好, 产率相对较高.在所有测试的碱中, 采用三乙胺可以得到最高的产率, 因此, 选定三乙胺作为碱, 对溶剂和两种反应物的比例进行了筛选(Entries 7~13).根据筛选结果, 以三氯甲烷作为溶剂、三乙胺作为碱, 使用1.2 equiv.的N-芳基芳羰基亚肼酰氯(2a)时得到了最高产率(93%).通过X射线单晶衍射确定了产物3aa (CCDC: 1937319)的相对构型.

  表 1

  

  表 1  环加成反应条件筛选^a

  Table 1.  Screening of the reaction conditions

  下载: 导出CSV

  Entry	Base	Solvent	Yieldb/%
  1	DABCO	DCM	72
  2	DBU	DCM	69
  3	Et3N	DCM	86
  4	i-Pr2NEt	DCM	75
  5	K2CO3	DCM	60
  6	Cs2CO3	DCM	78
  7	Et3N	DCE	81
  8	Et3N	Toluene	67
  9	Et3N	CH3CN	75
  10	Et3N	THF	58
  11	Et3N	MeOH	78
  12	Et3N	CHCl3	89
  13c	Et3N	CHCl3	93
  a Reaction conditions: 1a (0.1 mmol)、2a (0.1 mmol), base (0.12 mmol), room temperature, 24 h; b Isolated yields, dr(3)＞20:1; c 2a (0.12 mmol), 12 h.

  在确立了最优条件之后, 对苯环上不同取代基的N-芳基芳羰基亚肼酰氯进行了探索, 测试反应底物的适用性, 结果如表 2所示.芳香基R¹上为卤素取代基时, [3+2]环加成反应以良好到优秀产率得到对应产物3ab~3ah (Entries 2~7, 产率83%~94%). R¹上的取代基为给电子基团时, 反应仍可高效进行(Entry 8, 产率91%).当R¹为2-萘基时, 以78%的产率得到螺环产物(Entry 9).芳香基R²为卤素或甲基取代基时, 氰基亚胺底物均兼容该反应, 以良好到优秀产率及优秀的非对映选择性得到目标产物(Entries 10~15, 产率80%~94%, dr＞20:1).除产物3ac外, 所有螺环产物的非对映异构体的比例均大于20:1.

  表 2

  

  表 2  N-芳基芳羰基亚肼酰氯2的范围^a

  Table 2.  Substrate scope of the arylcarbohydrazonoyl chlorides 2

  下载: 导出CSV

  Entry	R1	R2	t/h	3	Yieldb/%
  1	Ph	Ph	12	3aa	93
  2	2-FC6H4	Ph	12	3ab	93
  3c	3-FC6H4	Ph	12	3ac	83
  4	4-FC6H4	Ph	14	3ad	84
  8	3-ClC6H4	Ph	14	3ae	94
  5	2-BrC6H4	Ph	14	3af	93
  6	3-BrC6H4	Ph	14	3ag	88
  7	4-BrC6H4	Ph	24	3ah	91
  8	2-MeC6H4	Ph	24	3ai	91
  9	2-Naphthyl	Ph	12	3aj	78
  10	Ph	2-FC6H4	24	3ak	85
  11	Ph	2-ClC6H4	24	3al	80
  12	Ph	3-ClC6H4	24	3am	90
  13	Ph	3-BrC6H4	24	3an	94
  14	Ph	2-MeC6H4	48	3ao	85
  15	Ph	4-MeC6H4	14	3ap	89
  a Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), Et3N (0.12 mmol), room temperature. b Isolated yields. c dr=16:1.

  在完成了对N-芳基芳羰基亚肼酰氯底物的范围调查后, 又对二氢苯并呋喃二酮底物进行了探索(Scheme 2).在R位引入乙基或苯基时, 分别以78%和85%的产率以及大于20:1 dr值得到产物3ba和3ca.这表明在R位引入新的官能团并不影响反应的产率和立体选择性, 证明了该反应具有较好的底物兼容性.

  图式 2

  

  图式 2.  亚甲基二氢苯并呋喃二酮1的范围

  Scheme 2.  Substrate scope of methylenedihydrobenzofurandiones 1

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  2.   结论

  通过二氢苯并呋喃二酮化合物和氰基亚胺的[3+2]环加成反应, 在温和条件下高产率高非对映选择性地构建了一系列具有潜在生物活性的螺吡唑类化合物.这些螺环化合物的生物活性目前正在测试中.

  3.   实验部分

  3.1   仪器与试剂

  ¹H NMR和¹³C NMR数据通过Bruker 300核磁仪测定, 内标为TMS. HRMS数据通过ESI-MS技术测得.所有反应用磁力搅拌器搅拌, 在烘干的玻璃仪器中氩气保护下进行.

  所有试剂均通过商业购买, 无需进一步纯化.所有溶剂经无水无氧处理.有机溶剂通过减压旋转蒸发及油泵除去.反应通过薄层色谱(TLC)检测, 通过硅胶柱色谱分离纯化, 硅胶使用青岛海洋硅胶(中性, 200~300目).

  3.2   实验方法

  3.2.1   底物合成方法

  二氢苯并呋喃二酮类化合物1a~1c合成方法参考文献[18], N-芳基芳羰基亚肼酰氯的合成方法参考文献[19].

  3.2.2   螺环吡唑化合物3的合成

  氩气保护下向反应管中依次加入0.1 mmol的二氢苯并呋喃二酮(1)、0.12 mmol的N-芳基芳羰基亚肼酰氯(2)、0.12 mmol的Et₃N和1 mL的三氯甲烷, 在25 ℃水浴下反应, TLC跟踪反应, 待反应物1完全消耗, 直接经柱层析(石油醚/乙酸乙酯, V:V=4:1)纯化得化合物3.

  7a-甲基-2', 5'-二苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3aa):淡黄色固体, 34.6 mg, 产率93%. m.p. 125~127 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.66~7.56 (m, 2H), 7.44~7.30 (m, 5H), 7.16 (dd, J=8.7, 1.0 Hz, 2H), 7.01 (t, J=7.3 Hz, 1H), 6.83 (dd, J=10.4, 1.6 Hz, 1H), 6.19 (d, J=10.4 Hz, 1H), 3.60~3.31 (m, 3H), 2.65 (d, J=4.5 Hz, 2H), 1.74 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.1, 174.0, 147.3, 145.7, 141.5, 130.7, 129.11, 129.07, 129.0, 128.4, 125. 6, 121.5, 116.5, 78.6, 73.2, 42.4, 40.9, 33.2, 25.6; HRMS (ESI) calcd for C₂₃H₂₁N₂O₃[M+H]⁺ 373.1547, found 373.1551.

  5'-(2-氟苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ab):淡黄色固体, 36.5 mg, 产率93%. m.p. 188~190 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.92 (td, J=7.8, 1.8 Hz, 1H), 7.32 (ddd, J=7.4, 6.9, 1.9 Hz, 3H), 7.22~7.11 (m, 3H), 7.11~6.96 (m, 2H), 6.82 (dd, J=10.4, 1.7 Hz, 1H), 6.17 (d, J=10.4 Hz, 1H), 3.66~3.48 (m, 3H), 2.65 (d, J=4.5 Hz, 2H), 1.73 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 193.7, 174.0, 160.0 (d, J=251.2 Hz), 147.2, 142.1 (d, J=2.3 Hz), 141.2, 130.6 (d, J=8.5 Hz), 129.14, 129.09, 128.1 (d, J=3.2 Hz), 124.1 (d, J=3.0 Hz), 121.7, 118.7 (d, J=11.1 Hz), 116.5, 116.1 (d, J=22.2 Hz), 78.7, 73.2, 42.9 (d, J=9.0 Hz), 42.4, 33.0, 25.7; HRMS (ESI) calcd for C₂₃H₂₀FN₂O₃ [M+H]⁺ 391.1452, found 391.1449.

  5'-(3-氟苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ac):白色固体, 32.4 mg, 产率83%. m.p. 185~187 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.34 (qdd, J=11.8, 5.8, 4.4 Hz, 5H), 7.15 (dd, J=8.7, 1.0 Hz, 2H), 7.05 (ddd, J=14.7, 6.3, 4.3 Hz, 2H), 6.83 (dd, J=10.4, 1.6 Hz, 1H), 6.19 (d, J=10.4 Hz, 1H), 3.62~3.24 (m, 3H), 2.76~2.53 (m, 2H), 1.74 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.1, 173.8, 162.6 (d, J=246.3 Hz), 147.2, 144.5 (d, J=3.0 Hz), 141.1, 132.8 (d, J=8.3 Hz), 130.0 (d, J=8.3 Hz), 129.2, 129.0, 121.9, 121.2 (d, J=2.8 Hz), 116.6, 116.0 (d, J=21.5 Hz), 112.2 (d, J=23.0 Hz), 78.7, 73.4, 42.4, 40.7, 33.2, 30.6, 25.6; HRMS (ESI) calcd for C₂₃H₂₀FN₂O₃ [M+H]⁺ 391.1452, found 391.1458.

  5'-(4-氟苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ad):淡黄色固体, 32.6 mg, 产率84%. m.p. 191~193 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.64~7.53 (m, 2H), 7.33 (dd, J=8.6, 7.4 Hz, 2H), 7.19~6.96 (m, 5H), 6.82 (dd, J=10.4, 1.6 Hz, 1H), 6.18 (d, J=10.4 Hz, 1H), 3.53~3.30 (m, 3H), 2.76~2.53 (m, 2H), 1.73 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.2, 173.9, 163.1 (d, J=250.1 Hz), 147.3, 144.8, 141.4, 129.1, 129.0, 127.4 (d, J=8.4 Hz), 127.0 (d, J=3.2 Hz), 121.6, 116.5, 115.5 (d, J=22.0 Hz), 78.7, 73.4, 42.3, 41.0, 33.3, 25.6; HRMS (ESI) calcd for C₂₃H₂₀FN₂O₃[M+H]⁺ 391.1452, found 391.1451.

  5'-(3-氯苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ae):白色固体, 38.1 mg, 产率94%. m.p. 209~211 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.64 (d, J=2.0 Hz, 1H), 7.45~7.30 (m, 5H), 7.16 (dd, J=8.7, 1.0 Hz, 2H), 7.03 (t, J=7.3 Hz, 1H), 6.84 (dd, J=10.4, 1.6 Hz, 1H), 6.20 (d, J=10.4 Hz, 1H), 3.72~3.58 (m, 2H), 3.54~3.51 (m, 1H), 2.78~2.53 (m, 2H), 1.74 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ: 194.0, 173.6, 147.1, 144.1, 141.0, 134.4, 132.3, 129.5, 129.0, 128.9, 128.8, 125.2, 123.4, 121.8, 116.5, 78.6, 73.3, 42.3, 40.5, 33.1, 30.5, 25.5; HRMS (ESI) calcd for C₂₃H₂₀ClN₂O₃[M+H]⁺ 407.1157, found 407.1160.

  5'-(2-溴苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3af):淡黄色固体, 42.0 mg, 产率93%. m.p. 129~131 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.59 (ddd, J=11.2, 7.9, 1.3 Hz, 2H), 7.34 (dd, J=11.1, 4.7 Hz, 3H), 7.19 (ddd, J=14.0, 9.9, 4.8 Hz, 3H), 7.01 (t, J=7.3 Hz, 1H), 6.81 (dd, J=10.4, 1.6 Hz, 1H), 6.15 (d, J=10.4 Hz, 1H), 3.74~3.57 (m, 2H), 3.56~3.49 (m, 1H), 2.83~2.61 (m, 2H), 1.73 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 193.6, 173.9, 147.2, 145.4, 141.2, 133.8, 131.9, 130.3, 130.0, 129.2, 129.1, 127.2, 121.8, 120.9, 116.6, 78.6, 73.6, 43.4, 42.4, 33.1, 25.7; HRMS (ESI) calcd for C₂₃H₂₀BrN₂O₃ [M+H]⁺ 453.0634, found 451.0586, 453.0631.

  5'-(3-溴苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ag):淡黄色固体, 39.7 mg, 产率88%. m.p. 216~218 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.80 (t, J=1.7 Hz, 1H), 7.50~7.43 (m, 2H), 7.35 (dd, J=8.5, 7.5 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.16 (dd, J=8.7, 0.9 Hz, 2H), 7.03 (t, J=7.3 Hz, 1H), 6.84 (dd, J=10.4, 1.6 Hz, 1H), 6.20 (d, J=10.4 Hz, 1H), 3.61~3.30 (m, 3H), 2.76~2.55 (m, 2H), 1.75 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 207.3, 194.5, 174.2, 147.7, 144.5, 141.4, 133.1, 132.3, 130.3, 129.6, 128.7, 124.4, 123.0, 122.3, 117.0, 79.2, 73.8, 42.8, 41.0, 33.6, 31.0, 26.0; HRMS (ESI) calcd for C₂₃H₂₀BrN₂O₃[M+H]⁺ 453.0634, found 451.0614, 453.0637.

  5'-(4-溴苯基)-7a-甲基-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ah):白色固体, 41.1 mg, 产率91%. m.p. 199~201 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.55~7.41 (m, 4H), 7.34 (tt, J=4.1, 2.1 Hz, 2H), 7.18~7.09 (m, 2H), 7.07~6.96 (m, 1H), 6.83 (dd, J=10.4, 1.7 Hz, 1H), 6.18 (d, J=10.4 Hz, 1H), 3.53~3.30 (m, 3H), 2.77~2.51 (m, 2H), 1.73 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.1, 173.8, 147.3, 144.6, 141.2, 131.6, 129.6, 129.2, 129.0, 126.9, 123.2, 121.8, 116.6, 78.7, 73.5, 42.4, 40.7, 33.3, 25.6; HRMS (ESI) calcd for C₂₃H₂₀BrN₂O₃[M+H]⁺ 453.0634, found 451.0633, 453.0638.

  7a-甲基-2'-苯基-5'-(邻甲基苯基)-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ai):淡黄色固体, 35.3 mg, 产率91%. m.p. 162~164 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.57 (dt, J=4.5, 2.6 Hz, 2H), 7.40~7.30 (m, 3H), 7.28 (s, 1H), 7.25~7.12 (m, 3H), 6.79 (dd, J=10.4, 1.7 Hz, 1H), 6.16 (d, J=10.4 Hz, 1H), 3.28 (q, J=16.8 Hz, 2H), 3.01 (d, J=6.8 Hz, 1H), 2.85~2.60 (m, 2H), 2.35 (s, 3H), 1.58 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.2, 173.8, 147.5, 145.5, 140.2, 135.2, 131.5, 131.2, 128.9, 128.7, 128.2, 126.5, 126.3, 125.3, 125.1, 78.3, 74.9, 43.3, 40.1, 33.5, 25.8, 19.2; HRMS (ESI) calcd for C₂₄H₂₃N₂O₃[M+H]⁺ 387.1703, found 387.1669.

  7a-甲基-5'-(萘-2-基)-2'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3aj):白色固体, 33.1 mg, 产率78%. m.p. 187~189 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.00 (dd, J=8.7, 1.6 Hz, 1H), 7.90~7.78 (m, 3H), 7.72 (s, 1H), 7.55~7.44 (m, 2H), 7.36 (t, J=8.0 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 7.02 (t, J=7.3 Hz, 1H), 6.85 (dd, J=10.4, 1.5 Hz, 1H), 6.23 (d, J=10.4 Hz, 1H), 3.76~3.37 (m, 3H), 2.67 (d, J=4.8 Hz, 2H), 1.75 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.2, 174.0, 147.3, 145.8, 141.4, 133.4, 132.8, 129.2, 129.1, 128.3, 128.2, 128.0, 127.5, 126.5, 126.3, 125.1, 123.0, 121.6, 116.5, 78.7, 73.3, 42.4, 40.9, 33.2, 25.6; HRMS (ESI) calcd for C₂₇H₂₃N₂O₃[M+H]⁺ 445.1523, found 445.1525.

  2'-(2-氟苯基)-7a-甲基-5'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ak):白色固体, 33.3 mg, 产率85%. m.p. 222~224 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.64 (ddd, J=9.8, 6.9, 4.6 Hz, 3H), 7.38 (dd, J=5.1, 1.8 Hz, 3H), 7.22~7.06 (m, 3H), 6.83 (dd, J=10.4, 1.6 Hz, 1H), 6.19 (d, J=10.4 Hz, 1H), 6.15~6.14 (m, 1H), 3.41 (dd, J=38.7, 17.3 Hz, 2H), 3.24 (dd, J=2.6 Hz, 1.8 Hz, 1H), 2.70 (d, J=4.4 Hz, 2H), 1.69 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ: 207.0, 194.6, 173.9, 153.2 (d, J=242.1 Hz), 148.0, 147.8, 130.9, 130.1 (d, J=8.6 Hz), 129.7, 129.3, 128.8, 126.1, 125.4, 125.23, 125.17, 124.9, 116.2 (d, J=21.0 Hz), 78.5, 74.7, 44.1, 41.6, 33.4, 31.0, 26.4; HRMS (ESI) calcd for C₂₃H₂₀FN₂O₃[M+H]⁺ 391.1452, found 391.1453.

  2'-(2-氯苯基)-7a-甲基-5'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3al):白色固体, 32.5 mg, 产率80%, m.p. 138~140 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.65~7.52 (m, 3H), 7.45 (dd, J=7.8, 1.7 Hz, 1H), 7.38~7.27 (m, 4H), 7.23 (dd, J=7.5, 1.7 Hz, 1H), 6.78 (dd, J=10.4, 1.7 Hz, 1H), 6.16 (d, J=10.4 Hz, 1H), 3.29 (q, J=16.8 Hz, 2H), 3.03 (dd, J=55.1, 13.0 Hz, 2H), 2.70 (dd, J=19.0, 7.1 Hz, 1H), 1.60 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.4, 173.0, 148.3, 147.4, 139.5, 131.4, 130.9, 129.94, 129.84, 129.1, 129.0, 128.3, 128.1, 127.7, 125.6, 78.3, 75.7, 43.6, 40.4, 33.5, 30.6, 25.9; HRMS (ESI) calcd for C₂₃H₁₉ClN₂O₃Na[M+Na]⁺ 429.0976, found 429.0973.

  2'-(3-氯苯基)-7a-甲基-5'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3am):白色固体, 36.7 mg, 产率90%. m.p. 200~202 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.60 (dd, J=6.5, 3.2 Hz, 2H), 7.39 (dd, J=5.0, 1.8 Hz, 4H), 7.22 (d, J=8.1 Hz, 1H), 6.96~6.81 (m, 3H), 6.20 (d, J=10.4 Hz, 1H), 3.57~3.35 (m, 3H), 2.69~2.56 (m, 2H), 1.79 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 193.9, 173.6, 147.2, 146.5, 142.4, 135.1, 130.2, 130.0, 129.4, 129.1, 128.5, 125.7, 121.0, 116.2, 113.2, 78.8, 72.9, 42.4, 41.1, 33.2, 25.7; HRMS (ESI) calcd for C₂₃H₂₀ClN₂O₃[M+H]⁺ 407.1157, found 407.1151.

  2'-(3-溴苯基)-7a-甲基-5'-苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3an):白色固体, 42.2 mg, 产率94%. m.p. 216~218 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.63~7.56 (m, 2H), 7.42~7.36 (m, 4H), 7.20~7.06 (m, 2H), 6.95 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 6.84 (dd, J=10.4, 1.7 Hz, 1H), 6.20 (d, J=10.9 Hz, 1H), 3.56~3.34 (m, 3H), 2.66 (dd, J=7.2, 4.2 Hz, 2H), 1.79 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 193.9, 173.5, 147.2, 146.5, 142.5, 130.2, 129.5, 129.1, 128.5, 125.7, 123.9, 123.2, 119.0, 113.6, 78.8, 72.8, 42.3, 41.1, 33.2, 25.6; HRMS (ESI) calcd for C₂₃H₂₀BrN₂O₃[M+H]⁺ 453.0634, found 451.0584, 453.0636.

  7a-甲基-5'-苯基-2'-(邻甲基苯基)-2', 3a, 4', 7a-四氢- 2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ao):白色固体, 32.8 mg, 产率85%. m.p. 184~186 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.61~7.52 (m, 2H), 7.34 (dd, J=4.8, 2.5 Hz, 3H), 7.23~7.13 (m, 3H), 6.79 (dd, J=10.4, 1.7 Hz, 1H), 6.17 (d, J=10.3 Hz, 1H), 3.28 (q, J=16.9 Hz, 2H), 3.04~2.98 (m, 1H), 2.83~2.55 (m, 2H), 2.36 (s, 3H), 1.58 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.2, 173.8, 147.5, 145.6, 140.2, 135.2, 131.5, 131.2, 128.9, 128.7, 128.2, 126.5, 126.3, 125.3, 125.1, 78.3, 74.9, 43.3, 40.1, 33.5, 25.8, 19.2; HRMS (ESI) calcd for C₂₄H₂₃N₂O₃ [M+H]⁺ 387.1703, found 387.1705.

  7a-甲基-5'-苯基-2'-(对甲基苯基)-2', 3a, 4', 7a-四氢- 2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ap):白色固体, 34.4 mg, 产率89%. m.p. 192~194 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.63~7.53 (m, 2H), 7.39~7.32 (m, 3H), 7.09 (t, J=11.7 Hz, 4H), 6.81 (dd, J=10.4, 1.6 Hz, 1H), 6.17 (d, J=10.4 Hz, 1H), 3.61~3.17 (m, 3H), 2.63 (d, J=4.6 Hz, 2H), 2.32 (s, 3H), 1.70 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.2, 174.1, 147.3, 145.5, 139.3, 131.5, 130.8, 129.7, 129.0, 128.9, 128.4, 125.5, 117.3, 78.5, 73.7, 42.4, 40.8, 33.2, 25.6, 20.3; HRMS (ESI) calcd for C₂₄H₂₃N₂O₃[M+H]⁺ 387.1703, found 387.1704.

  7a-乙基-2', 5'-二苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ba):白色固体, 30.0 mg, 产率78%. m.p. 134~136 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.89~7.81 (m, 1H), 7.67~7.54 (m, 2H), 7.46~7.29 (m, 5H), 7.22~7.13 (m, 2H), 7.06~6.97 (m, 1H), 6.89~6.81 (m, 1H), 6.26 (d, J=10.5 Hz, 1H), 3.62~3.30 (m, 3H), 2.18~1.85 (m, 2H), 1.08 (t, J=7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.4, 174.2, 146.7, 145.7, 141.5, 130.62, 130.56, 129.9, 129.1, 128.4, 125.5, 121.7, 116.9, 115.0, 81.0, 73.5, 41.2, 40.2, 33.6, 32.2, 7.5; HRMS (ESI) calcd for C₂₄H₂₂N₂O₃Na[M+Na]⁺ 409.1523, found 409.1520.

  2', 5', 7a-三苯基-2', 3a, 4', 7a-四氢-2H-螺[苯并呋喃-3, 3'-吡唑]-2, 5(4H)-二酮(3ca):淡黄色固体, 37.1 mg, 产率85%. m.p. 168~170 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 7.72~7.56 (m, 2H), 7.54~7.35 (m, 8H), 7.34~7.27 (m, 2H), 7.25~7.15 (m, 2H), 7.02~6.94 (m, 1H), 6.91 (dd, J=10.4, 1.7 Hz, 1H), 6.54~6.39 (m, 1H), 3.71~3.44 (m, 3H), 2.77~2.55 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ: 194.5, 174.1, 145.8, 145.3, 141.4, 137.7, 130.6, 130.3, 129.2, 129.1, 128.4, 125.6, 124.0, 121.9, 117.1, 81.5, 73.7, 44.4, 41.2, 32.8; HRMS (ESI) calcd for C₂₈H₂₂N₂O₃Na [M+Na]⁺ 457.1523, found 457.1540.

  辅助材料(Supporting Information)  化合物3aa~3aq的¹H NMR和¹³C NMR谱图以及化合物3aa的X射线单晶衍射结构.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

  
  
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  图式 1  氰基亚胺与具有环外双键的二氢苯并呋喃二酮的环加成反应

  Scheme 1  Cycloaddition reactions between methylenedihydrobenzofurandione and nitrilimines

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  图式 2  亚甲基二氢苯并呋喃二酮1的范围

  Scheme 2  Substrate scope of methylenedihydrobenzofurandiones 1

  下载: 全尺寸图片 幻灯片

  表 1  环加成反应条件筛选^a

  Table 1.  Screening of the reaction conditions

  Entry	Base	Solvent	Yieldb/%
  1	DABCO	DCM	72
  2	DBU	DCM	69
  3	Et3N	DCM	86
  4	i-Pr2NEt	DCM	75
  5	K2CO3	DCM	60
  6	Cs2CO3	DCM	78
  7	Et3N	DCE	81
  8	Et3N	Toluene	67
  9	Et3N	CH3CN	75
  10	Et3N	THF	58
  11	Et3N	MeOH	78
  12	Et3N	CHCl3	89
  13c	Et3N	CHCl3	93
  a Reaction conditions: 1a (0.1 mmol)、2a (0.1 mmol), base (0.12 mmol), room temperature, 24 h; b Isolated yields, dr(3)＞20:1; c 2a (0.12 mmol), 12 h.

  下载: 导出CSV

  表 2  N-芳基芳羰基亚肼酰氯2的范围^a

  Table 2.  Substrate scope of the arylcarbohydrazonoyl chlorides 2

  Entry	R1	R2	t/h	3	Yieldb/%
  1	Ph	Ph	12	3aa	93
  2	2-FC6H4	Ph	12	3ab	93
  3c	3-FC6H4	Ph	12	3ac	83
  4	4-FC6H4	Ph	14	3ad	84
  8	3-ClC6H4	Ph	14	3ae	94
  5	2-BrC6H4	Ph	14	3af	93
  6	3-BrC6H4	Ph	14	3ag	88
  7	4-BrC6H4	Ph	24	3ah	91
  8	2-MeC6H4	Ph	24	3ai	91
  9	2-Naphthyl	Ph	12	3aj	78
  10	Ph	2-FC6H4	24	3ak	85
  11	Ph	2-ClC6H4	24	3al	80
  12	Ph	3-ClC6H4	24	3am	90
  13	Ph	3-BrC6H4	24	3an	94
  14	Ph	2-MeC6H4	48	3ao	85
  15	Ph	4-MeC6H4	14	3ap	89
  a Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), Et3N (0.12 mmol), room temperature. b Isolated yields. c dr=16:1.

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