氮杂环卡宾催化氰基乙酸酯与二烯酮双Michael反应:非对映选择性合成多取代环己酮和茚

引用本文: 张阳, 邢芬, 冯泽男, 杜广芬, 顾承志, 何林. 氮杂环卡宾催化氰基乙酸酯与二烯酮双Michael反应:非对映选择性合成多取代环己酮和茚[J]. 有机化学, 2020, 40(6): 1608-1617. doi: 10.6023/cjoc202002012 shu

Citation: Zhang Yang, Xing Fen, Feng Zenan, Du Guangfen, Gu Chengzhi, He Lin. N-Heterocyclic Carbene-Catalyzed Double Michael Addition of Cyano Acetates and Dienones: Diastereoselective Synthesis of Multisubstituted Cyclohexanones and Indanes[J]. Chinese Journal of Organic Chemistry, 2020, 40(6): 1608-1617. doi: 10.6023/cjoc202002012 shu

氮杂环卡宾催化氰基乙酸酯与二烯酮双Michael反应:非对映选择性合成多取代环己酮和茚

石河子大学化学化工学院新疆石河子 832000

通讯作者: 杜广芬, duguangfen@shzu.edu.cn; 何林, helin@shzu.edu.cn

基金项目:

国家自然科学基金(No.21662029)资助项目

摘要: 利用氮杂环卡宾(NHC)独特的Brønsted碱性催化二烯酮与氰基乙酸酯的双Michael加成反应.在10 mol% NHC催化下，二乙烯酮可以与氰基乙酸酯反应，以60%~89%的产率和5：1~>20：1的dr值得到多取代环己酮.在相同反应条件下，邻苯二烯酮与氰基乙酸酯和丙二腈等反应，以77%~98%的产率和>20：1的dr值得到多取代茚产物.

关键词:

English

N-Heterocyclic Carbene-Catalyzed Double Michael Addition of Cyano Acetates and Dienones: Diastereoselective Synthesis of Multisubstituted Cyclohexanones and Indanes

School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832000

Corresponding author: Du, Guangfen, E-mail: duguangfen@shzu.edu.cn; He, Lin, E-mail: helin@shzu.edu.cn

Received Date: 11 February 2020
Revised Date: 14 March 2020
Available Online: 25 June 2020
Fund Project:

Project supported by the National Natural Science Foundation of China (No. 21662029)

Abstract: The unique Brønsted basic character of N-heterocyclic carbenes (NHCs) has been used to catalyze the double Michael addition between dienones and cyanoacetates. In the presence of 10 mol% NHC, divinyl ketones reacted with cyano acetates to produce multisubstituted cyclohexanones in 60%~89% yields with 5:1~>20:1 dr. Under the same conditions, benzenedi(enones) underwent double Michael addition with cyano acetates or malononitrile to construct multisubstituted indanes in 77%~98% yields and >20:1 dr.

Key words:

氮杂环卡宾(NHCs)作为一类重要的有机小分子催化剂, 在有机合成化学中有着广泛应用^[1].由于邻位氮原子的供电子作用, NHC中心碳原子带有部分负电荷, 因而具有极强的亲核性, 可以与多种不同的亲电试剂发生亲核加成形成共价键, 催化相应的化学转化.除了经典的安息香缩合^[2]和Stetter反应^[3]外, Glorius和Bode等^[4]发展了α, β-不饱和烯醛延伸极性反转反应, Rovis等^[5]发展了官能团化醛的极性反转, 扩展了NHCs在极性反转领域的应用.基于NHCs的强亲核性, 叶松课题组^[6]和Chi小组^[7]分别在烯酮(ketenes)活化和酯的活化方面做了大量开创性工作, 发展了一系列手性杂环的合成新方法.但以上这些反应均是建立在NHCs强的Lewis碱性基础上的.另一方面, NHCs具有独特的Brønsted碱性.利用这一性质, 2009年, Coquerel等^[8]首次利用NHCs催化了活泼烯烃分子内的Michael加成反应, 合成了螺环内酯.接着, Scheidt等^[9]利用NHCs对醇羟基的活化, 研究了醇与α, β-不饱和烯酮的oxo-Michael加成, 并尝试了不对称反应.在以上两例报道中, NHC通过与亲核试剂中的活泼氢形成氢键来活化亲核试剂, 表现出优良的Brønsted碱性.随后, Zhang等^[10]发展了胺与烯酮的aza-Michael加成反应.我们课题组发展了NHCs催化的Vinylogous-Michael加成^[11a]、Sulfa-Michael加成^{[11b, 11c]}和双Michael加成等^{[11d, 11e]}反应.更有意义的是, Huang小组^[12]首次实现了手性氮杂环卡宾催化下, 活泼烯烃的分子间不对称Michael加成、Aza-Michael加成、Sulfa-Michael加成和氢转移反应, 这些优秀的工作极大地促进了对NHCs Brønsted碱性的研究.

官能团化的多取代环己酮和多取代茚是两类重要的有机化合物, 在有机合成中有着广泛应用^[13].二乙烯基酮的双Michael加成反应为多取代环己酮的合成提供了有效方法^[14], 而有机催化的串联反应则可高效构筑茚类化合物^[15].负载型固体碱KF/Al₂O₃在超声辐射下可高效催化二烯酮与活泼亚甲基化合物的双Michael加成反应, 几分钟内即可高产率地得到多取代环己酮^[16a]. 1, 2-环己二胺可以通过活化二烯酮的羰基, 催化二烯酮与丙二腈等活泼亚甲基化合物的双Michael加成反应, 以较高的收率得到反式结构为主的多取代环己酮^[16b]. n-Bu₃P可以作为Lewis碱通过对二烯酮的碳碳双键的亲核进攻, 催化与活泼亚甲基的双Michael加成, 以良好的产率得到环己酮产物^[16c].天然生物碱类有机伯胺催化剂, 如奎宁和辛可宁等可催化二烯酮的不对称双Michael加成或者串联反应, 以优秀的ee值得到手性环己酮衍生物^[16d~16f].最近, 我们对NHCs的Brønsted碱催化性能开展了持续研究^[11].基于我们的研究工作, 认为可以利用NHCs的Brønsted碱性, 催化氰基乙酸酯与二烯酮发生双Michael加成, 合成多取代环己酮和茚, 由于氰基和酯基均易于衍生化, 这为进一步制备多样化的环己酮和茚提供了机会.

1. 结果与讨论

首先以二烯酮1a与氰基乙酸甲酯(2a)作为模型反应, 对反应条件进行优化.在无水N, N-二甲基甲酰胺(DMF)中, 以稳定的NHC A为催化剂, 室温反应12 h, 即可以87%的收率和＞20:1的dr值得到多取代环己酮产物3a(表 1, Entry 1).在此基础上, 对其他几种NHCs催化剂进行了考察.用NHC A的前体盐IPr•HCl和^tBuOK反应现场生成NHC A来催化该反应, 可以71%的产率和＞20:1的dr值得到目标产物(表 1, Entry 1).咪唑型NHC B可以催化反应进行, 以53%的产率和优秀的dr值得到目标产物(表 1, Entry 2).饱和咪唑盐型NHC C可有效催化反应进行, 以75%的产率和＞20:1的dr值得到3a(表 1, Entry 3).而噻唑型NHC D和三唑型NHC E, 由于其Brønsted碱性较弱, 催化效率较低, 只以较低产率得到3a(表 1, Entries 4, 5), 但产物的dr值仍然可以达到＞20:1.接下来, 以NHC A为催化剂, 对反应溶剂进行了筛选.以四氢呋喃为溶剂, 可以83%的产率和11:1的dr值得到3a(表 1, Entry 6).以二氯甲烷为溶剂时, 虽然可以获得85%的产率, 但反应的dr值降为3:1(表 1, Entry 7).该反应在甲苯中反应时, 可以66%的收率和8:1的dr值得到环己酮产物3a(表 1, Entry 8).在极性溶剂或质子溶剂中, 该双Michael加成反应可以顺利进行, 以较高的产率得到目标产物, 但dr值下降明显(表 1, Entries 9~11).当降低催化剂用量时, 反应需要更长的时间, 且产率下降为79%(表 1, Entry 12).综上所述, 反应最优条件为: 10 mol%的NHC A为催化剂, DMF为溶剂, 1.5 equiv.的2a, 室温反应12 h(表 1, Entry 1).

表 1

表 1 反应条件的优化^a

Table 1. Optimization of reaction conditions

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Entry	Catalyst	Base	Solvent	Yield^b/%	dr^c
1	A	—	DMF	87 (71)^d	＞20:1
2	B	^tBuOK	DMF	53	＞20:1
3	C	^tBuOK	DMF	75	＞20:1
4	D	^tBuOK	DMF	55	＞20:1
5	E	^tBuOK	DMF	79	＞20:1
6	A	—	THF	83	11:1
7	A	—	DCM	85	3:1
8	A	—	Toluene	66	8:1
9	A	—	CH₃CN	75	3:1
10	A	—	DMSO	72	6:1
11	A	—	MeOH	85	5:1
12^e	A	—	DMF	79	＞20:1
^a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), base (10 mol%), solvent 1.0 mL; ^b Isolated total yield of two diastereomers; ^c dr was determined by ¹H NMR analysis of the crude reaction mixture. ^d 12 mol% NHC precursor IPr•HCl, 10 mol% ^tBuOK. ^e Using 5 mmol% NHC A.

在确定了最优反应条件后, 对反应的普适性进行了研究(表 2).苯基对位连有给电子基或拉电子基的二乙烯基酮, 均可顺利地与氰基乙酸甲酯发生双Michael加成, 以较好的收率和优秀的dr值得到相应的产物(表 2, Entries 2~5).其中, 连有拉电子取代基的二烯酮取得了更高的产率.当苯基对位连有强拉电子的氟原子时, 以85%的产率得到环己酮3f, 但dr值降为5:1(表 2, Entry 6).间位或邻位等不同位置取代的二烯酮可有效参加反应, 以较高的产率和dr值给出相应产物(表 2, Entries 7~10).但当邻甲基苯取代的二烯酮1k与氰基乙酸甲酯反应时, 产物的dr值降为5:1(表 2, Entry 11). β-萘基取代的二烯酮可顺利反应, 以85%的产率和＞20:1的dr值得到多取代环己酮3l(表 2, Entry 12).芳杂环取代的二烯酮同样适于该串联反应, 以85%的产率和10:1的dr值生成相应的目标产物3m(表 2, Entry 13).更有意思的是, 当把不对称的二烯酮1n用于该双Michael加成反应时, 仍然可以9:1的dr值得到目标产物3n(表 2, Entry 14).同样的, 氰基乙酸乙酯可以与二烯酮顺利反应, 以74%的收率和优秀的dr值得到相应产物3o(表 2, Entry 15).

表 2

表 2 反应底物普适性研究^a

Table 2. Evaluation of substrate scope

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Entry	Ar¹	Ar²	R	dr^b	3	Yield^c/%
1	C₆H₅	C₆H₅	Me	＞20:1	3a	87
2	4-CH₃C₆H₄	4-CH₃C₆H₄	Me	＞20:1	3b	60
3	4-MeOC₆H₄	4-MeOC₆H₄	Me	＞20:1	3c	70
4	4-BrC₆H₄	4-BrC₆H₄	Me	＞20:1	3d	84
5	4-ClC₆H₄	4-ClC₆H₄	Me	＞20:1	3e	85
6	4-FC₆H₄	4-FC₆H₄	Me	5:1	3f	85
7	3-BrC₆H₄	3-BrC₆H₄	Me	＞20:1	3g	88
8	3-ClC₆H₄	3-ClC₆H₄	Me	＞20:1	3h	89
9	2-ClC₆H₄	2-ClC₆H₄	Me	＞20:1	3i	81
10	2-CH₃OC₆H₄	2-CH₃OC₆H₄	Me	11:1	3j	85
11	2-CH₃C₆H₄	2-CH₃C₆H₄	Me	5:1	3k	70
12	β-Naphthyl	β-Naphthyl	Me	＞20:1	3l	85
13	2-Thienyl	2-Thienyl	Me	10:1	3m	85
14	4-CH₃OC₆H₄	4-CH₃C₆H₄	Me	9:1	3n	71
15^c	C₆H₅	C₆H₅	Et	＞20:1	3o	74
^a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), solvent 1.0 mL; ^b dr was determined by ¹H NMR analysis of the crude reaction mixture. ^cIsolated total yield of two diastereomers

通过对产物3n的X单晶衍射分析, 确定了这一类多取代环己酮的分子结构和相对构型(图 1).

图 1

图 1. 3n的X射线晶体结构

Figure 1. Single crystal X-ray structure of 3n

下载: 全尺寸图片幻灯片

接下来, 对邻苯二烯酮与活泼亚甲基的双Michael加成环化反应进行了研究.在前述最优反应条件下, 邻苯二烯酮4a可以与氰基乙酸甲酯顺利反应, 以优秀的产率和非对映选择性生成多取代茚产物5a(表 3, Entry 1).在随后对底物适应性的考察中, 发现无论二烯酮α-苯基的对位上带有拉电子基还是供电子基, 均可顺利环化, 高产率、高dr值地生成相应的多取代茚产物, 且取代基的电性和不同的取代基位置(对、间、邻位)对反应产率和非对映选择性无明显影响(表 3, Entries 2~8). β-萘基衍生的邻苯二烯酮可顺利进行双Michael加成反应, 以86%的产率和＞20:1的dr值生成产物5i(表 3, Entry 9).更有意思的是, α-烷基取代的双Michael受体4j可高效发生环加成, 以优秀的产率和dr值得到多取代茚5j(表 3, Entry 10).由于亲电活性下降, 邻苯二烯酯4k难以发生此类双Michael加成反应, 以97%的回收率对4k进行了回收(表 3, Entry 11).不对称的邻苯二烯酮可有效与氰基乙酸甲酯发生加成反应, 以较高的收率和优秀的dr值生成相应的多取代茚产物(表 3, Entries 12~15).另外, 氰基乙酸乙酯和丙二腈的活泼亚甲基也可以与邻苯二烯酮加成环化, 以优秀的产率和dr值得到对应的产物(表 3, Entries 16~17).

表 3

表 3 反应底物普适性研究^a

Table 3. Evaluation of substrate scope

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Entry	R¹	R²	EWG	dr^b	5	Yield^c/%
1	C₆H₅	C₆H₅	CO₂Me	＞20:1	5a	97
2	4-FC₆H₄	4-FC₆H₄	CO₂Me	＞20:1	5b	94
3	4-ClC₆H₄	4-ClC₆H₄	CO₂Me	＞20:1	5c	92
4	4-BrC₆H₄	4-BrC₆H₄	CO₂Me	＞20:1	5d	97
5	4-MeOC₆H₄	4-MeOC₆H₄	CO₂Me	＞20:1	5e	84
6	4-CH₃C₆H₄	4-CH₃C₆H₄	CO₂Me	＞20:1	5f	95
7	3-ClC₆H₄	3-ClC₆H₄	CO₂Me	＞20:1	5g	95
8	2-ClC₆H₄	2-ClC₆H₄	CO₂Me	＞20:1	5h	87
9	β-Naphthyl	β-Naphthyl	CO₂Me	＞20:1	5i	86
10	CH₃	CH₃	CO₂Me	＞20:1	5j	97
11	OEt	OEt	CO₂Me	—	5k	Trace
12	4-BrC₆H₄	4-ClC₆H₄	CO₂Me	＞20:1	5l	93
13	4-FC₆H₄	C₆H₅	CO₂Me	＞20:1	5m	80
14	4-CH₃C₆H₄	4-CH₃OC₆H₄	CO₂Me	＞20:1	5n	71
15	4-CH₃C₆H₄	C₆H₅	CO₂Me	＞20:1	5o	92
16	C₆H₅	C₆H₅	CO₂Et	＞20:1	5p	98
17	C₆H₅	C₆H₅	CN	＞20:1	5q	89
^a Reaction conditions: 4 (0.2 mmol), 2 (0.3 mmol), solvent 1.0 mL; ^b dr was determined by ¹H NMR analysis of the crude reaction mixture; ^c Isolated total yield of two diastereomers.

这类多取代茚的结构和相对构型通过化合物5d的X单晶衍射分析得以确定(图 2).

图 2

图 2. 5d的X射线晶体结构

Figure 2. Single crystal X-ray structure of 5d

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对于该反应, 我们提出的可能催化机理如Scheme 1所示. NHC作为Brønsted碱与氰基乙酸酯亚甲基上弱酸性的氢原子通过氢键作用, 形成中间体I, 该中间体与二烯酮的一端首先发生分子间Michael加成得到烯醇负离子II.通质子交换, 中间体II进一步转化为烯醇中间体III, 随后经互变异构生成中间体IV. NHC与该中间体的活泼氢质子通过氢键作用生成中间体V, 进一步通过分子内Michael加成环化得到烯醇负离子中间体VI, 最后经质子化和互变异构, 得到最终目标产物并释放出游离的NHC, 完成催化循环.

图式 1

图式 1. 氮杂环卡宾催化氰基酯的Michael反应机理

Scheme 1. N-Heterocyclic carbene catalyzes Michael reaction of cyanoester

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2. 结论

通过二烯酮与氰基乙酸酯和丙二腈等含活泼亚甲基化合物的分子间Michael加成—分子内Michael加成串联反应, 发展了一种有机催化合成多取代环己酮和多取代茚的有效方法. NHCs在该反应中表现出了优异的Brønsted碱催化活性.该方法具有条件温和、无需过渡金属、反应产率和dr值高及底物适应性较广等优点.

3. 实验部分

3.1 仪器与试剂

¹H NMR以TMS为内标, CDCl₃为溶剂, 用Bruker- DMX 400型核磁共振仪测试; HRMS用Thermo Scientific LTQ Orbitrap XL高分辨质谱仪测试; IR用Thermo Fisher Nicolet iS10红外光谱仪测试; 单晶结构由Bruker D8 VENTURE photon II单晶衍射仪测定.薄层色谱板是青岛海洋化工厂GF₂₅₄硅胶板, 柱层析硅胶是青岛海洋化工厂生产(200~300目); 溶剂经过干燥处理; 其他化学试剂均为分析纯, 购买于阿拉丁化学试剂公司.

3.2 实验方法

3.2.1 原料的合成

1, 5-二苯基-1, 4-二烯-3-酮1a~1o参考文献[17]合成, 3, 3'-(1, 2-亚苯基)二(1-苯基-2-烯-1-酮)4a~4q参考文献[18]合成.

3.2.2 多取代环己酮产物的合成方法

将25 mL的反应管放入红外干燥箱干燥20 min, 抽真空冷却到室温后, 换入氮气, 然后加入10 mol%的IPr, 以及46.8 mg (0.2 mol)烯酮化合物1a置于该反应管中, 抽真空20 min, 再换氮气, 如此反复三次, 再在氮气的保护下加入1.0 mL无水DMF, 搅拌溶解后, 用微量注射器加入29.7 mg (0.3 mmol)氰基乙酸甲酯, 在室温下搅拌反应10 h, 薄层色谱(TLC)跟踪监测, 反应结束后, 加入一定量的水, 再加入乙酸乙酯(5 mL×3)萃取, 用无水Na₂SO₄干燥, 浓缩有机相通过硅胶柱层析分离得到28.9 mg纯净的白色固体3a [V(石油醚):V(乙酸乙酯)＝10:1], 产率为87%.以相同方法合成化合物3b~3o.

2, 6-二苯基环己烷-1-氰基-4-氧代-1-甲酸甲酯(3a)^[19]:白色固体, 产率87%. m.p. 159.3~159.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.39~7.28 (m, 8H), 7.19~7.13 (m, 2H), 4.00~3.94 (m, 2H), 3.40 (s, 3H), 3.22~3.14 (m, 2H), 3.08~3.02 (m, 1H), 2.85~2.79 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 137.3, 136.6, 128.85, 128.77, 128.7, 128.5, 128.42, 128.41, 118.3, 55.7, 53.8, 48.2, 42.9, 42.4, 41.7.

2, 6-二对甲苯基环己烷-1-氰基-4-氧代-1-甲酸甲酯(3b):白色固体, 产率60%. m.p. 167.2~169.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.24 (d, J＝8.2 Hz, 2H), 7.19~7.12 (m, 4H), 7.04 (d, J＝8.2 Hz, 2H), 3.98~3.89 (m, 2H), 3.46 (s, 3H), 3.21~3.02 (m, 3H), 2.84~2.79 (m, 1H), 2.35 (d, J＝8.5 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 207.4, 166.7, 138.6, 138.2, 134.4, 133.7, 129.5, 128.4, 128.3, 118.5, 99.9, 55.7, 53.1, 47.9, 43.2, 42.0, 41.9, 21.2; IR (KBr) ν: 2956, 1751, 1682, 1582, 1389, 1223, 1029, 882, 755, 675, 611 cm^－1; HRMS (ESI) calcd for C₂₃H₂₄NO₃ (M+H)⁺ 362.17507, found 362.17507.

2, 6-双-(4-甲氧基苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3c):白色固体, 产率70%. m.p. 159.3~159.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.27 (dd, J＝8.8, 2.2 Hz, 2H), 7.11~7.06 (m, 2H), 6.91~6.84 (m, 4H), 3.96~3.88 (m, 2H), 3.81 (d, J＝6.2 Hz, 6H), 3.47 (s, 3H), 3.19~3.09 (m, 2H), 3.06~3.00 (m, 1H), 2.82~2.77 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 207.4, 166.8, 159.4, 129.6, 129.5, 128.6, 114.1, 55.9, 55.3, 55.2, 53.2, 47.5, 43.1, 42.0, 41.6; IR (KBr) ν: 2953, 1730, 1611, 1590, 1337, 1250, 1075, 822, 741, 660, 628 cm^－1; HRMS (ESI) calcd for C₂₃H₂₄NO₅ (M+H)⁺ 394.16490, found 394.16534.

2, 6-双-(4-溴苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3d):白色固体, 产率84%. m.p. 185.6~190.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.54~7.45 (m, 4H), 7.25~7.19 (m, 2H), 7.07~7.01 (m, 2H), 3.99~3.85 (m, 2H), 3.49 (s, 3H), 3.19~3.00 (m, 3H), 2.82~2.77 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 206.1, 166.3, 136.0, 132.1, 132.0, 130.2, 130.0, 123.1, 122.7, 55.2, 53.5, 47.5, 42.6, 41.9, 41.5. IR (KBr) ν: 2923, 2246, 1729, 1491, 1410, 1242, 1079, 1005, 824, 718, 628 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈Br₂NO₃ (M+H)⁺ 489.96480, found 489.96653.

2, 6-双-(4-氯苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3e):白色固体, 产率85%. m.p. 185.0~186.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.39~7.24 (m, 6H), 7.10 (d, J＝8.5 Hz, 2H), 3.99~3.89 (m, 2H), 3.48 (s, 3H), 3.20~3.00 (m, 3H), 2.83~2.78 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 206.2, 166.3, 135.5, 134.9, 134.5, 129.9, 129.7, 129.13, 129.05, 117.8, 55.3, 53.5, 47.5, 42.7, 41.9, 41.5; IR (KBr) ν: 3057, 1715, 1515, 1242, 1014, 819, 716, 660 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈Cl₂NO₃ (M+H)⁺ 402.06583, found 402.06540.

2, 6-双-(4-氟苯基)-1-氰基--4-氧代环己烷-1-甲酸甲酯(3f):白色固体, 产率85%. m.p. 172.5~174.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.36~7.30 (m, 2H), 7.19~7.13 (m, 2H), 7.11~7.02 (m, 4H), 4.00~3.92 (m, 2H), 3.47 (s, 3H), 3.21~3.11 (m, 2H), 3.07~3.01 (m, 1H), 2.84~2.79 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 206.5, 166.5, 161.4, 132.88, 132.85, 132.3, 130.3, 130.2, 130.2, 130.1, 118.0, 116.0, 115.9, 115.8, 115.7, 55.7, 53.4, 47.3, 42.8, 41.8, 41.6; IR (KBr) ν: 2954, 1715, 1494, 1407, 1257, 1076, 1012, 827, 666 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈F₂NO₃ (M+H)⁺ 370.12493, found 370.12543.

2, 6-双-(3-溴苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3g):白色固体, 产率88%. m.p. 184.7~186.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.50 (t, J＝8.7 Hz, 4H), 7.26~7.20 (m, 2H), 7.04 (d, J＝8.4 Hz, 2H), 3.97~3.87 (m, 2H), 3.49 (s, 3H), 3.19~3.09 (m, 2H), 3.07~3.01 (m, 1H), 2.84~2.76 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.3, 136.0, 135.4, 132.1, 132.0, 130.2, 130.0, 123.1, 55.1, 53.5, 47.5, 42.6, 41.97, 41.96, 41.5; IR (KBr) ν: 2958, 2242, 1754, 1688, 1596, 1451, 1365, 1240, 1045, 996, 752, 689 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈- Br₂NO₃ (M+H)⁺ 489.96480, found 489.96890.

2, 6-双-(3-氯苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3h):白色固体, 产率89%; m.p. 178.2~190.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (dd, J＝7.8, 1.5 Hz, 1H), 7.38 (td, J＝7.8, 1.6 Hz, 1H), 7.36~7.27 (m, 4H), 7.23~7.18 (m, 2H), 4.76~4.73 (m, 1H), 4.58~4.54 (m, 1H), 3.50 (s, 3H), 3.36~3.30 (m, 1H), 3.03~2.86 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 165.7, 135.5, 135.1, 134.9, 134.3, 130.2, 130.0, 129.9, 129.4, 129.3, 127.7, 127.3, 127.0, 53.5, 52.9, 44.5, 43.4, 43.3, 37.6; IR (KBr) ν: 2953, 1752, 1722, 1477, 1436, 1251, 1090, 1037, 920, 758, 607, 497 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈Cl₂NO₃ (M+H)⁺ 402.06583, found 402.06540.

2, 6-双-(2-氯苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3i):白色固体, 产率81%. m.p. 177.8~190.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (dd, J＝7.9, 1.4 Hz, 1H), 7.44~7.29 (m, 5H), 7.25~7.20 (m, 2H), 3.07~3.01 (m, 1H), 3.53 (s, 3H), 3.36~3.30 (m, 1H), , 3.06~2.89 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 205.7, 165.7, 135.5, 134.9, 134.3, 130.2, 129.94, 129.88, 129.4, 129.3, 127.7, 127.3, 127.0, 53.5, 52.8, 44.5, 43.4, 43.3, 37.6; IR (KBr) ν: 2953, 2230, 1749, 1722, 1479, 1435, 1090, 1251, 1090, 1035, 920, 755, 607 cm^－1; HRMS (ESI) calcd for C₂₁H₁₈Cl₂NO₃ (M+H)⁺ 402.06583, found 402.06540.

2, 6-双-(2-甲氧基苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3j):白色固体, 产率85%; m.p. 157.1~158.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.74 (dd, J＝7.8, 1.6 Hz, 2H), 7.32~7.27 (m, 2H), 3.07~3.01 (m, 1H), 3.84 (s, 6H), 3.34 (s, 3H), 3.17~3.07 (m, 2H), 2.77~2.72 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.5, 129.2, 127.2, 125.8, 120.9, 117.7, 110.7, 56.1, 55.5, 52.8, 44.4, 41.2; IR (KBr) ν: 2839, 1716, 1587, 1492, 1462, 1242, 1119, 1024, 750, 652 cm^－1; HRMS (ESI) calcd for C₂₃H₂₄NO₅ (M+ H)⁺ 394.16490, found 394.16531.

2, 6-双-(2-甲苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3k):白色固体, 产率70%. m.p. 167.7~169.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.71 (dd, J＝7.7, 1.0 Hz, 1H), 7.27~7.08 (m, 7H), 4.47~4.28 (m, 2H), 3.46 (s, 3H), 3.23~3.17 (m, 1H), 3.11~3.00 (m, 2H), 2.95~2.86 (m, 1H), 2.27 (s, 3H), 2.24 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 207.0, 166.8, 136.9, 136.6, 135.8, 131.2, 128.4, 127.9, 127.5, 126.8, 126.4, 126.2, 118.8, 53.6, 53.2, 44.6, 43.4, 37.4, 19.60, 19.57; IR (KBr) ν: 2956, 1751, 1682, 1582, 1389, 1223, 1029, 882, 755, 675, 611 cm^－1; HRMS (ESI) calcd for C₂₃H₂₄NO₃ (M+H)⁺ 362.17507, found 362.17507.

2, 6-二(萘-2-基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3l):白色固体, 产率85%. m.p. 164.7~166.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (dd, J＝7.9, 1.6 Hz, 2H), 7.45~7.34 (m, 4H), 7.28 (td, J＝7.9, 1.6 Hz, 2H), 4.54~4.50 (m, 2H), 3.43 (s, 3H), 3.16~3.05 (m, 2H), 2.87~2.78 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 203.3, 134.5, 133.8, 130.3, 129.6, 127.8, 127.7, 56.4, 53.3, 44.5, 44.1; IR (KBr) ν: 2975, 1747, 1719, 1575, 1294, 1243, 1051, 882, 666, 609 cm^－1; HRMS (ESI) calcd for C₂₉H₂₄NO₃ (M+H)⁺ 434.17507, not found.

2, 6-二(噻吩-2-基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3m):白色固体, 产率85%. m.p. 159.3~159.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.36~7.27 (m, 3H), 7.13~7.08 (m, 2H), 6.87 (dd, J＝5.0, 1.4 Hz, 1H), 4.13 (t, J＝5.8 Hz, 1H), 3.07~3.01 (m, 1H), 3.63~3.55 (m, 3H), 3.22~2.97 (m, 3H), 2.89~2.81 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 206.5, 166.4, 138.2, 137.1, 127.5, 127.2, 126.5, 125.9, 124.0, 123.8, 123.4, 118.1, 54.9, 43.89, 43.87, 42.6, 38.4; IR (KBr) ν: 3105, 2954, 2242, 1741, 1431, 1332, 1260, 1026, 918, 783, 680 cm^－1; HRMS (ESI) calcd for C₁₇H₁₆NO₃S₂ (M+H)⁺ 346.05661, found 346.05624.

2-(4-甲氧基苯基)-6-(对甲苯基)-1-氰基-4-氧代环己烷-1-甲酸甲酯(3n):白色固体, 产率71%. m.p. 159.3~159.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.28~7.21 (m, 2H), 7.16 (t, J＝7.5 Hz, 2H), 7.11~7.02 (m, 2H), 6.91~6.84 (m, 2H), 3.97~3.89 (m, 2H), 3.81 (d, J＝6.7 Hz, 3H), 3.46 (d, J＝1.8 Hz, 3H), 3.20~3.00 (m, 3H), 2.85~2.76 (m, 1H), 2.35 (d, J＝7.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 207.5, 166.7, 159.7, 159.4, 133.7, 129.7, 129.53, 129.50, 129.4, 129.3, 128.31, 128.25, 114.1, 114.0, 55.8, 55.7, 55.3, 55.2, 53.20, 53.15, 47.8, 47.5, 43.3, 43.0, 42.0, 41.9; IR (KBr) ν: 2839, 1716, 1587, 1492, 1462, 1242, 1119, 1024, 750, 652 cm^－1; HRMS (ESI) calcd for C₂₃H₂₄NO₄ (M+H)⁺ 378.16998, found 378.17001.

2, 6-二苯基环己烷-1-氰基-4-氧代-1-甲酸乙酯(3o):白色固体, 产率74%. m.p. 86~87 ℃ (lit.^[20c] 86~87 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.25 (q, J＝7.5, 6.9 Hz, 6H), 7.18~7.12 (m, 4H), 4.39~4.35 (m, 2H), 4.02~3.93 (m, 2H), 3.57~3.48 (m, 2H), 3.12~3.05 (m, 2H), 2.93~2.88 (m, 2H), 0.89~0.86 (m, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 210.1, 169.7, 139.9, 128.6, 128.1, 127.4, 63.8, 61.2, 43.7, 42.4, 13.4.

3.2.3 多取代茚产物的合成方法

将25 mL的反应管放入红外干燥箱干燥20 min, 抽真空冷却到室温后, 换入氮气, 然后加入10 mol%的IPr, 以及67.6 mg (0.2 mol)邻苯二烯酮化合物4a, 抽真空20 min, 再换氮气, 如此反复三次, 再在氮气的保护下加入1.0 mL无水DMF, 搅拌溶解后, 用微量注射器加入29.7 mg (0.3 mmol)氰基乙酸甲酯, 在室温下搅拌反应10 h, 薄层色谱(TLC)跟踪监测, 反应结束后, 加入一定量的水, 再加入乙酸乙酯(5 mL×3)萃取, 用无水Na₂SO₄干燥, 浓缩有机相通过硅胶柱层析分离得到42.4 mg纯净的白色固体5a [V(石油醚):V(乙酸乙酯)＝10:1], 产率为97%.以相同方法合成化合物5b~5q.

1, 3-双-(2-氧-2-苯基乙基)-2-氰基-2, 3-二氢-1H-茚- 2-羧酸甲酯(5a):白色固体, 产率97%. m.p. 124.0~125.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.11~8.07 (m, 4H), 7.67~7.61 (m, 2H), 7.56~7.49 (m, 4H), 7.33~7.27 (m, 2H), 7.20~7.14 (m, 2H), 4.67 (t, J＝6.7 Hz, 2H), 3.95 (s, 3H), 3.86~3.80 (m, 2H), 3.71~3.64 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 197.2, 140.7, 136.3, 133.6, 128.7, 128.3, 128.2, 123.4, 116.90, 53.7, 47.3, 40.6; IR (KBr) ν: 2908, 2237, 1756, 1600, 1451, 1366, 1048, 1000, 753, 685 cm^－1; HRMS (ESI) calcd for C₂₈H₂₄NO₄ (M+ H)⁺ 438.16998, found 438.17014.

1, 3-双-(2-(4-氟苯基)-2-氧乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5b):白色固体, 产率94%. m.p. 166.5~167.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.11~8.06 (m, 4H), 7.29 (dd, J＝3.28, 5.56 Hz, 2H), 7.19~7.11 (m, 6H), 4.62 (t, J＝6.96 Hz, 2H), 3.92 (s, 3H), 3.81~3.75 (m, 2H), 3.67~3.60 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.6, 168.7, 164.8, 140.6, 132.7, 130.9, 130.2, 128.4, 123.4, 116.8, 115.8, 62.2, 53.8, 40.54; IR (KBr) ν: 2914, 1747, 1684, 1594, 1361, 1228, 1205, 1150, 837, 624 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂F₂NO₄ (M+H)⁺ 474.15114, found 474.15173.

1, 3-双-(2-(4-氯苯基)-2-氧乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5c):白色固体, 产率92%. m.p. 178.5~179.5 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.01~7.97 (m, 4H), 7.79~7.46 (m, 4H), 7.29 (dd, J＝3.42, 5.72 Hz, 2H), 7.12~7.10 (m, 2H), 4.62 (t, J＝6.8 Hz, 2H), 3.91 (s, 3H), 3.80~3.74 (m, 2H), 3.66~3.59 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 168.6, 140.5, 140.2, 134.6, 129.6, 129.1, 128.5, 123.4, 62.5, 47.3, 40.6; IR (KBr) ν: 2915, 1733, 1681, 1587, 1399, 1355, 1255, 1008, 804, 657 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂Cl₂NO₄ (M+H)⁺ 506.0920, found 506.0920.

1, 3-双-(2-(4-溴苯基)-2-氧代乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5d):白色固体, 产率97%. m.p. 191.3~192.4 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95~7.89 (m, 4H), 7.66~7.62 (m, 4H), 7.29 (dd, J＝3.12, 5.6 Hz, 2H), 7.12~7.10 (m, 2H), 4.61 (t, J＝6.8 Hz, 2H), 3.91 (s, 3H), 3.80~3.74(m, 2H), 3.65~3.59 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.2, 168.6, 140.5, 134.9, 132.1, 129.7, 128.9, 128.5, 123.4, 53.8, 47.3, 40.6; IR (KBr) ν: 2916, 1759, 1478, 1359, 1243, 1068, 1002, 960, 767, 553 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂Br₂NO₄ (M+H)⁺ 593.9910, found 593.9910.

1, 3-双-(2-(4-甲氧基苯基)-2-氧乙基)-2-氰基-2, 3-二氢-1H-茚-2-羧酸甲酯(5e):白色固体, 产率84%. m.p. 200.0~202.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.06~8.02 (m, 4H), 7.27~7.25 (m, 2H), 7.13~7.10 (m, 2H), 6.98~6.95 (m, 4H), 4.65 (t, J＝6.7 Hz, 2H), 3.885 (d, J＝4.6 Hz, 9H), 3.79~3.73 (m, 2H), 3.63~3.57 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.6, 163.9, 130.6, 129.5, 128.3, 123.4, 113.9, 62.4, 55.5, 53.7, 47.4, 40.2; IR (KBr) ν: 2839, 1716, 1587, 1492, 1462, 1242, 1119, 1024, 750, 652 cm^－1; HRMS (ESI) calcd for C₃₀H₂₈NO₆ (M+H)⁺ 498.19111, found 498.19122.

1, 3-双-(2-(4-甲苯基)-2-氧乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5f):白色固体, 产率95%. m.p. 145.6~146.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J＝8.28 Hz, 4H), 7.30~7.24 (m, 6H), 7.12~7.10 (m, 2H), 4.63 (t, J＝6.64 Hz, 2H), 3.90 (s, 3H), 3.82~3.76 (m, 2H), 3.66~3.59 (m, 2H), 2.43 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.8, 144.5, 140.8, 133.9, 129.4, 128.4, 128.3, 123.4, 62.3, 53.6, 47.4, 40.5, 21.6; IR (KBr) ν: 2839, 1716, 1587, 1492, 1462, 1242, 1119, 1024, 750, 652 cm^－1; HRMS (ESI) calcd for C₃₀H₂₈NO₄ (M+H)⁺ 466.2013, found 466.2013.

1, 3-双-(2-(3-氯苯基)-2-氧乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5g):白色固体, 产率95%. m.p. 179.6~181.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.01 (t, J＝1.8 Hz, 2H), 7.95~7.91 (m, 2H), 7.59~7.57 (m, 2H), 7.45 (t, J＝7.9 Hz, 2H), 7.30~7.27 (m, 2H), 7.13~7.11 (m, 2H), 4.61 (t, J＝6.7 Hz, 2H), 3.94 (s, 3H), 3.82~3.76 (m, 2H), 3.67~3.60 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.9, 140.4, 137.8, 135.2, 133.6, 130.2, 128.5, 128.3, 126.4, 123.4, 62.1, 53.8, 47.3, 40.8; IR (KBr) ν: 2918, 1750, 1683, 1582, 1375, 1233, 1165, 1029, 822, 676 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂Cl₂NO₄ (M+H)⁺ 506.0920, found 506.0924.

1, 3-双-(2-(2-氯苯基)-2-氧乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5h):白色固体, 产率87%. m.p. 113.5~114.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.66~7.64 (m, 2H), 7.50~7.43 (m, 4H), 7.41~7.37 (m, 2H), 7.34~7.31 (m, 2H), 7.21~7.19 (m, 2H), 4.65~4.61 (m, 2H), 4.01 (s, 3H), 3.88~3.82 (m, 2H), 3.66~3.59 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 200.2, 140.3, 132.2, 131.0, 130.7, 129.3, 128.5, 127.2, 123.4, 116.7, 62.1, 53.9, 47.6, 45.0; IR (KBr) ν: 2915, 1741, 1695, 1588, 1431, 1359, 1236, 1071, 864, 747 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂Cl₂NO₄ (M+H)⁺ 506.09204, found 506.09235.

1, 3-双-(2-(萘-2-基)-2-氧代乙基)-2-氰基-2, 3-二氢- 1H-茚-2-羧酸甲酯(5i):白色固体, 产率86%. m.p. 168.2~169.9 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.63 (s, 2H), 8.15 (dd, J＝8.6, 1.8 Hz, 2H), 8.03 (dd, J＝8.1, 1.3 Hz, 2H), 8.00~7.91 (m, 4H), 7.68~7.59 (m, 4H), 7.35~7.30 (m, 2H), 7.25~7.19 (m, 2H), 4.76 (t, J＝6.7 Hz, 2H), 4.02~3.95 (m, 5H), 3.86~3.79 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 197.1, 168.7, 140.8, 135.8, 133.6, 132.5, 130.2, 129.7, 128.8, 128.7, 128.4, 127.8, 126.9, 62.4, 53.8, 47.4, 40.6; IR (KBr) ν: 2839, 1716, 1587, 1492, 1462, 1242, 1119, 1024, 750, 652 cm^－1; HRMS (ESI) calcd for C₃₆H₂₈NO₄ (M+H)⁺ 538.2013, found 538.2014.

1, 3-双-(2-氧丙基)-2-氰基-2, 3-二氢-1H-茚-2-羧酸甲酯(5j):白色固体, 产率97%. m.p. 107.7~108.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.27~7.25 (m, 2H), 7.05~7.02 (m, 2H), 4.35~4.32 (m, 2H), 3.91 (s, 3H), 3.29~3.23 (m, 2H), 3.13~3.06 (m, 2H), 2.29 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 205.7, 140.4, 128.3, 123.1, 116.6, 61.7, 53.7, 47.1, 45.3, 30.2; IR (KBr) ν: 2920, 1751, 1683, 1458, 1353, 1254, 1029, 882, 760, 676 cm^－1; HRMS (ESI) calcd for C₁₈H₂₀NO₄ (M+H)⁺ 314.1387, found 314.1393.

1-(2-(4-溴苯基)-2-氧乙基)-3-(2-(4-氯苯基)-2-氧乙基)-2-氰基-2, 3-二氢-1H-茚-2-羧酸甲酯(5l):白色固体, 产率93%. m.p. 176.1~178.0 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.00~7.97 (m, 2H), 7.92~7.89 (m, 2H), 7.64 (d, J＝8.5 Hz, 2H), 7.47 (d, J＝8.5 Hz, 2H), 7.30~7.27 (m, 2H), 7.13~7.10 (m, 2H), 4.61 (t, J＝6.7 Hz, 2H), 3.91 (s, 3H), 3.78~3.71 (m, 2H), 3.63~3.56 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.2, 168.6, 140.5, 134.9, 134.6, 129.7, 129.1, 128.9, 128.5, 123.4, 62.2, 53.8, 47.3, 40.6; IR (KBr) ν: 2929, 1715, 1634, 1455, 1380, 1309, 1178, 1092, 882, 668 cm^－1; HRMS (ESI) calcd for C₂₈H₂₂BrClNO₄ (M+H)⁺ 550.04152, found 550.0415.

1-(2-(4-氟苯基)-2-氧代乙基)-3-(2-氧代-2-苯基乙基)-2-异氰基-2, 3-二氢-1H-茚-2-羧酸甲酯(5m):白色固体, 产率80%. m.p. 179.3~189.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.10~8.04 (m, 4H), 7.63~7.59 (m, 1H), 7.53~7.48 (m, 2H), 7.28 (dd, J＝3.16, 5.48 Hz, 2H), 7.19~7.11 (m, 4H), 4.65~4.61 (m, 2H), 3.91 (s, 3H), 3.79~3.73 (m, 2H), 3.67~3.57 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 195.6, 168.7, 140.7, 136.3, 133.7, 132.8, 132.7, 131.0, 130.9, 128.8, 128.4, 128.3, 123.5, 123.4, 116.9, 116.0, 115.8, 62.3, 53.7, 47.4, 47.3, 40.63, 40.56; IR (KBr) ν: 2919, 1745, 1682, 1582, 1458, 1390, 1202, 1029, 819, 675 cm^－1; HRMS (ESI) calcd for C₂₈H₂₃FNO₄ (M+H)⁺ 456.1606, found 456.1607.

1-(2-(4-甲氧基苯基)-2-氧代乙基)-3-(2-氧代-2-(对甲苯基)乙基)-2, 3-二氢-1H-茚-2-羧酸甲酯(5n):白色固体, 产率71%. m.p. 172.1~173.6 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.05~8.02 (m, 2H), 7.95 (d, J＝8.2 Hz, 2H), 7.30~7.25 (m, 4H), 7.13~7.10 (m, 2H), 6.98~6.94 (m, 2H), 4.62 (t, J＝8.12 Hz, 2H), 3.89 (m, 6H), 3.79~3.70 (m, 2H), 3.62~3.54 (m, 2H), 2.43 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.8, 163.9, 144.5, 140.8, 133.9, 130.6, 128.4, 128.3, 123.43, 123.40, 116.9, 113.9, 62.4, 55.5, 53.7, 47.4, 47.3, 40.4, 40.2, 21.7; IR (KBr) ν: 2911, 1732, 1677, 1606, 1480, 1362, 1180, 1042, 749, 686 cm^－1; HRMS (ESI) calcd for C₃₀H₂₈NO₅ (M+H)⁺ 482.1962, found 482.1963.

1-(2-氧代-2-(对甲苯基乙基)-3-(2-氧代-2-苯乙基)-2-异氰基-2, 3-二氢-1H-茚-2-羧酸甲酯(5o):白色固体, 产率92%. m.p. 168.3~169.7 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.11~8.06 (m, 2H), 7.99 (d, J＝8.3 Hz, 2H), 7.67~7.61 (m, 1H), 7.57~7.50 (m, 2H), 7.35~7.26 (m, 4H), 7.19~7.12 (m, 2H), 4.66 (t, J＝6.7 Hz, 2H), 3.97~3.92 (m, 3H), 3.86~3.77 (m, 2H), 3.71~3.59 (m, 2H), 2.46 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 197.2, 168.7, 144.5, 140.8, 136.3, 133.9, 133.6, 129.4, 128.8, 128.4, 128.3, 123.5, 123.4, 62.3, 53.7, 47.4, 47.3, 40.6, 40.5, 21.7; IR (KBr) ν: 2954, 1732, 1677, 1606, 1480, 1362, 1180, 1042, 749, 686 cm^－1; HRMS (ESI) calcd for C₂₉H₂₆NO₄ (M+H)⁺ 452.1856, found 452.1856.

1, 3-双-(2-氧代-2-苯乙基)-2-氰基-2, 3-二氢-1H-茚-2-羧酸乙酯(5p):白色固体, 产率98%. m.p. 140.1~140.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.07~8.04 (m, 4H), 7.62~7.58 (m, 2H), 7.51~7.47 (m, 4H), 7.27~7.24 (m, 2H), 7.13~7.11 (m, 2H), 4.64 (t, J＝6.6 Hz, 2H), 4.44~4.39 (m, 2H), 3.85~3.79 (m, 2H), 3.71~3.65 (m, 2H), 1.29 (t, J＝7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 197.1, 140.8, 136.3, 128.7, 128.3, 128.2, 123.4, 117.0, 63.1, 62.4, 47.2, 40.6, 13.96; IR (KBr) ν: 2239, 1743, 1679, 1594, 1449, 1364, 1288, 1243, 1049, 1000, 856, 759, 689 cm^－1; HRMS (ESI) calcd for C₂₉H₂₆NO₄ (M+H)⁺ 452.18563, found 452.18524.

2-异氰基-1, 3-双-(2-氧代-2-苯乙基)-2, 3-二氢-1H-茚-2-腈(5q):白色固体, 产率89%. m.p. 140.1~140.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.13 (d, J＝7.5 Hz, 2H), 8.05 (d, J＝7.6 Hz, 2H), 7.70~7.63 (m, 2H), 7.59~7.51 (m, 4H), 7.31~7.28 (m, 2H), 7.25~7.23 (m, 1H), 7.12~7.10 (m, 1H), 4.77~4.73 (m, 1H), 4.65~4.62 (m, 1H), 3.88~3.69 (m, 3H), 3.65~3.59 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 196.0, 195.9, 139.5, 139.3, 136.0, 134.1, 133.9, 129.2, 129.0, 128.9, 128.4, 128.3, 124.9, 123.0, 48.4, 48.1, 45.1, 40.7, 40.2; IR (KBr) ν: 2895, 1687, 1580, 1449, 1355, 1235, 1000, 947, 749, 693 cm^－1; HRMS (ESI) calcd for C₂₇H₂₁N₂O₂ (M+H)⁺ 405.15975, found 405.15955.

辅助材料(Supporting Information) 化合物3n和5d的单晶数据、所有化合物的¹H NMR和¹³C NMR谱图以及催化剂A的合成方法.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 1 3n的X射线晶体结构

Figure 1 Single crystal X-ray structure of 3n

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图 2 5d的X射线晶体结构

Figure 2 Single crystal X-ray structure of 5d

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图式 1 氮杂环卡宾催化氰基酯的Michael反应机理

Scheme 1 N-Heterocyclic carbene catalyzes Michael reaction of cyanoester

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表 1 反应条件的优化^a

Table 1. Optimization of reaction conditions


Entry	Catalyst	Base	Solvent	Yield^b/%	dr^c
1	A	—	DMF	87 (71)^d	＞20:1
2	B	^tBuOK	DMF	53	＞20:1
3	C	^tBuOK	DMF	75	＞20:1
4	D	^tBuOK	DMF	55	＞20:1
5	E	^tBuOK	DMF	79	＞20:1
6	A	—	THF	83	11:1
7	A	—	DCM	85	3:1
8	A	—	Toluene	66	8:1
9	A	—	CH₃CN	75	3:1
10	A	—	DMSO	72	6:1
11	A	—	MeOH	85	5:1
12^e	A	—	DMF	79	＞20:1
^a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), base (10 mol%), solvent 1.0 mL; ^b Isolated total yield of two diastereomers; ^c dr was determined by ¹H NMR analysis of the crude reaction mixture. ^d 12 mol% NHC precursor IPr•HCl, 10 mol% ^tBuOK. ^e Using 5 mmol% NHC A.

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表 2 反应底物普适性研究^a

Table 2. Evaluation of substrate scope


Entry	Ar¹	Ar²	R	dr^b	3	Yield^c/%
1	C₆H₅	C₆H₅	Me	＞20:1	3a	87
2	4-CH₃C₆H₄	4-CH₃C₆H₄	Me	＞20:1	3b	60
3	4-MeOC₆H₄	4-MeOC₆H₄	Me	＞20:1	3c	70
4	4-BrC₆H₄	4-BrC₆H₄	Me	＞20:1	3d	84
5	4-ClC₆H₄	4-ClC₆H₄	Me	＞20:1	3e	85
6	4-FC₆H₄	4-FC₆H₄	Me	5:1	3f	85
7	3-BrC₆H₄	3-BrC₆H₄	Me	＞20:1	3g	88
8	3-ClC₆H₄	3-ClC₆H₄	Me	＞20:1	3h	89
9	2-ClC₆H₄	2-ClC₆H₄	Me	＞20:1	3i	81
10	2-CH₃OC₆H₄	2-CH₃OC₆H₄	Me	11:1	3j	85
11	2-CH₃C₆H₄	2-CH₃C₆H₄	Me	5:1	3k	70
12	β-Naphthyl	β-Naphthyl	Me	＞20:1	3l	85
13	2-Thienyl	2-Thienyl	Me	10:1	3m	85
14	4-CH₃OC₆H₄	4-CH₃C₆H₄	Me	9:1	3n	71
15^c	C₆H₅	C₆H₅	Et	＞20:1	3o	74
^a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), solvent 1.0 mL; ^b dr was determined by ¹H NMR analysis of the crude reaction mixture. ^cIsolated total yield of two diastereomers

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表 3 反应底物普适性研究^a

Table 3. Evaluation of substrate scope


Entry	R¹	R²	EWG	dr^b	5	Yield^c/%
1	C₆H₅	C₆H₅	CO₂Me	＞20:1	5a	97
2	4-FC₆H₄	4-FC₆H₄	CO₂Me	＞20:1	5b	94
3	4-ClC₆H₄	4-ClC₆H₄	CO₂Me	＞20:1	5c	92
4	4-BrC₆H₄	4-BrC₆H₄	CO₂Me	＞20:1	5d	97
5	4-MeOC₆H₄	4-MeOC₆H₄	CO₂Me	＞20:1	5e	84
6	4-CH₃C₆H₄	4-CH₃C₆H₄	CO₂Me	＞20:1	5f	95
7	3-ClC₆H₄	3-ClC₆H₄	CO₂Me	＞20:1	5g	95
8	2-ClC₆H₄	2-ClC₆H₄	CO₂Me	＞20:1	5h	87
9	β-Naphthyl	β-Naphthyl	CO₂Me	＞20:1	5i	86
10	CH₃	CH₃	CO₂Me	＞20:1	5j	97
11	OEt	OEt	CO₂Me	—	5k	Trace
12	4-BrC₆H₄	4-ClC₆H₄	CO₂Me	＞20:1	5l	93
13	4-FC₆H₄	C₆H₅	CO₂Me	＞20:1	5m	80
14	4-CH₃C₆H₄	4-CH₃OC₆H₄	CO₂Me	＞20:1	5n	71
15	4-CH₃C₆H₄	C₆H₅	CO₂Me	＞20:1	5o	92
16	C₆H₅	C₆H₅	CO₂Et	＞20:1	5p	98
17	C₆H₅	C₆H₅	CN	＞20:1	5q	89
^a Reaction conditions: 4 (0.2 mmol), 2 (0.3 mmol), solvent 1.0 mL; ^b dr was determined by ¹H NMR analysis of the crude reaction mixture; ^c Isolated total yield of two diastereomers.

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