全氟烷基取代的芴基炔膦酸二乙酯化合物的一锅法合成

引用本文: 孙小莉, 孙振华, 韩敏敏, 韩靖, 何伟民, 陈杰, 邓红梅, 邵敏, 张慧, 曹卫国. 全氟烷基取代的芴基炔膦酸二乙酯化合物的一锅法合成[J]. 有机化学, 2019, 39(1): 192-199. doi: 10.6023/cjoc201808028 shu

Citation: Sun Xiaoli, Sun Zhenhua, Han Minmin, Han Jing, He Weimin, Chen Jie, Deng Hongmei, Shao Min, Zhang Hui, Cao Weiguo. Synthesis of Perfluoroalkylated Fluorenes with Phosphonate Group via One-Pot Synthesis Process[J]. Chinese Journal of Organic Chemistry, 2019, 39(1): 192-199. doi: 10.6023/cjoc201808028 shu

全氟烷基取代的芴基炔膦酸二乙酯化合物的一锅法合成

孙小莉 ^a, ,
孙振华 ^a, ,
韩敏敏 ^b, ,
韩靖 ^a, ,
何伟民 ^a, ,
陈杰 ^a, ,
邓红梅 ^c, ,
邵敏 ^c, ,
张慧 ^{a,c,
,} ,
曹卫国 ^{a,d,e,
,}

a.
上海大学化学系上海 200444
b.
上海大学钱伟长学院上海 200444
c.
上海大学微结构重点实验室分析测试中心上海 200444
d.
中国科学院上海有机化学研究所有机金属化学国家重点实验室上海 200032
e.
中国科学院上海有机化学研究所有机氟化学重点实验室上海 200032

通讯作者: 张慧, wgcao@staff.shu.edu.cn; 曹卫国, wgcao@staff.shu.edu.cn

基金项目:

国家自然科学基金（No.21672138）资助项目

摘要: 报道了一种以茚酮、丙二腈、全氟烷基炔膦酸二乙酯为原料合成全氟烷基取代的芴基炔膦酸二乙酯类化合物的新方法.采用一锅合成法，可将不同基团取代的茚酮直接转化为一系列相应的全氟烷基取代的芴基炔膦酸二乙酯衍生物.整个反应过程无需金属催化，具备反应条件温和、区域选择性好、产率较高、操作简便等优点.

关键词:

English

Synthesis of Perfluoroalkylated Fluorenes with Phosphonate Group via One-Pot Synthesis Process

Sun Xiaoli ^a, ,
Sun Zhenhua ^a, ,
Han Minmin ^b, ,
Han Jing ^a, ,
He Weimin ^a, ,
Chen Jie ^a, ,
Deng Hongmei ^c, ,
Shao Min ^c, ,
Zhang Hui ^{a,c,
,} ,
Cao Weiguo ^{a,d,e,
,}

a.
Department of Chemistry, Shanghai University, Shanghai 200444
b.
Qianweichang College, Shanghai University, Shanghai 200444
c.
Laboratory for Microstructures, Instrumental Analysis and Research Center of Shanghai University, Shanghai 200444
d.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
e.
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032

Corresponding author: Zhang, Hui, E-mail: yehao7171@shu.edu.cn; Cao, Weiguo, E-mail: wgcao@staff.shu.edu.cn

Received Date: 24 August 2018
Revised Date: 13 September 2018
Available Online: 25 January 2019
Fund Project:

Project supported by the National Natural Science Foundation of China (No. 21672138)

Abstract: A simple and versatile metal-free protocol for the synthesis of perfluoroalkyated fluorene derivatives bearing phosphonate group is achieved. The reactions proceeded via one-pot three-component condensation of indenones, fluorinated alkynylphosphonates and malononitrile under mild conditions. This protocol is highly regioselective, operationally facile and applicable to a variety of indenones in good to excellent yields.

Key words:

芴类衍生物在生物医药和光电材料领域所具备的重要性使化学家对这类化合物产生了浓厚的兴趣^{[1, 2]}.近些年来芴在有机电致发光材料领域中得到了广泛的研究与开发, 通过对芴类单元的修饰可以改变最高占有分子轨道(HOMO)与最低未占分子轨道(LUMO)之间的能隙差, 从而改变发光波长, 制作不同的发光器件^[3](图 1).苯芴醇, 作为一种合成的芴乙醇类化合物, 具有较强的灭无性体作用, 用于治疗恶性疟, 具有疗效较高而毒副反应较小的特点^[4](图 1).此外, 芴类化合物在有机金属化学中可以作为有效配体和金属络合形成新的配位体系, 在肽合成化学中则可以作为独特的保护基团而得到广泛应用^[5].

图 1

图 1. 芴类的发光材料与苯芴醇

Figure 1. Light-emitting material of fluorene and lumefantrine

下载: 全尺寸图片幻灯片

基于此类化合物的重要性, 发展实用有效的合成种类繁多的多官能团取代的芴类化合物的方法就成为有机化学家需要迫切解决的一个重要问题.传统构建芴环的方法包括Friedel-Crafts型反应^[6]、过渡金属催化的环合反应^[7]、自由基介入的环合反应^[8]和其他反应^[9]等.

传统方法虽然提供了合成芴类化合物的多种途径, 但是它们存在的一些缺点, 如原料难得、反应区域选择性差、能进行反应的底物范围比较狭窄、反应条件苛刻、多步骤合成等, 使得发展新的高效、底物范围广、反应条件温和的合成方法成为有机化学家必须解决的难题.

多组分反应(MCRs)基于它们在有机合成中体现出来的原子经济高效的特点, 现在已成为有机化学、药物化学和组合化学领域中构建化合物环骨架的一个强有力的工具^[10].

我们课题组^[11]已经证实, 采用茚酮、丙二腈和含氟炔酸酯三组分一锅串联反应可以直接构建芴环, 得到全氟烷基取代的芴衍生物.第二步环合反应无需金属催化, 80 ℃, 在碳酸钾存在下通过区域选择性Michael加成/环合等串联反应以较高产率得到目标产物.

研究证实, 当向生物活性分子中引入含氟基团或膦酯基团后, 新形成的分子通常都会在脂溶性和酶的结合性等物理化学性质方面产生显著变化^[12].由此我们设想如果将含氟基团和膦酯基团一起引入生物活性分子, 所合成的这类新化合物对于发现新生物活性分子一定具有重要意义.于是我们尝试将孙振华等的方法做了拓展, 用含氟炔膦酸二乙酯取代含氟炔酸酯, 一锅两步三组分合成了全氟烷基取代的芴基炔膦酸二乙酯类化合物, 反应同样无需金属催化, 环合反应在室温即可进行, 收率良好; 卤素原子、甲氧基和甲基等基团不受反应条件影响, 从而使底物范围得到一定拓展.

1. 结果与讨论

首先, 选定茚酮(1a)、丙二腈(2)与4, 4, 4-三氟-2-炔膦酸二乙酯(3a)的反应作为模板反应对反应条件进行优化.反应以一锅两步的方式进行. 1a和2通过Knoevenagel缩合反应得到中间体2-(2, 3-二氢-1H-茚-1-亚基)丙二腈(5a), 后者与全氟烷基-2-炔膦酸二乙酯(3a)及NaOH在25 ℃条件下继续反应6 h, 得到所需的芴产物4a, 产率61%(表 1, Entry 1).为了提高收率, 我们对影响第二步反应的几个要素包括碱、溶剂、碱量、反应温度和反应时间等进行了进一步筛选(表 1).对碱筛选的结果表明NaOH最适合本反应, 而且, 第二步反应如果没有碱存在, 得不到目标产物(表 1, Entry 8).和甲苯相比, 反应在其他溶剂如乙腈(MeCN)、二氯甲烷(DCM)、四氢呋喃(THF)和无水乙醇(EtOH)中进行时, 所得产物收率略低(表 1, Entry 1 vs. Entries 9~12).将NaOH的量从0.5 equiv.增加到1.5 equiv., 产率提高到69%(表 1, Entry 14), 但是进一步增加碱的用量, 收率反而降低了(表 1, Entry 15).将反应置于0 ℃或者50 ℃进行, 导致反应收率下降明显(表 1, Entries 16和17).将第二步反应时间由6 h延长到16 h后, 得到82%收率的4a(表 1, Entry 19), 进一步延长反应时间, 收率则再没有显著提升(表 1, Entry 20).

表 1

表 1 反应条件的优化^a

Table 1. Optimization of reaction conditions

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Entry	Solvent	Base (equiv.)	T^b/℃	Time^c/h	Yield^d/%
1	Toluene	NaOH (0.5)	r.t.	6	61
2	Toluene	KOH (0.5)	r.t.	6	57
3	Toluene	K₂CO₃ (0.5)	r.t.	6	49
4	Toluene	Piperidine (0.5)	r.t.	6	—
5	Toluene	CsCO₃ (0.5)	r.t.	6	45
6	Toluene	CsF (0.5)	r.t.	6	Trace
7	Toluene	Et₃N (0.5)	r.t.	6	Trace
8	Toluene	NaOH (0)	r.t.	6	—
9	MeCN	NaOH (0.5)	r.t.	6	52
10	DCM	NaOH (0.5)	r.t.	6	55
11	THF	NaOH (0.5)	r.t.	6	53
12	EtOH	NaOH (0.5)	r.t.	6	53
13	Toluene	NaOH (1.0)	r.t.	6	65
14	Toluene	NaOH (1.5)	r.t.	6	69
15	Toluene	NaOH (2.0)	r.t.	6	59
16	Toluene	NaOH (1.5)	0	6	29
17	Toluene	NaOH (1.5)	50	6	41
18	Toluene	NaOH (1.5)	r.t.	12	73
19	Toluene	NaOH (1.5)	r.t.	16	82
20	Toluene	NaOH (1.5)	r.t.	24	81
^a Reaction conditions: 1a (1.0 mmol), 2a (1.0 equiv.), AcOH (0.1 equiv.) and NH₄OAc (0.2 equiv.) were mixed and stirred in refluxing toluene (5.0 mL) for 12 h. After cooling to the confined temperature, 3a (1.2 equiv.) and base were added and continued to be stirred for the referred time. ^b Reaction temperature for the second step. ^c Reaction time for the second step. ^d Isolated yields for two steps in one pot.

利用得到的最优化反应条件(表 1, Entry 19), 我们对茚酮上取代基R的性质和位置对反应的影响做了探索.如表 2所示, R为给电子基团或吸电子基团取代的茚酮都适用于该反应, 均能以好的收率得到所需的全氟烷基芴基炔膦酸二乙酯衍生物.在同一个取代位置上, 取代基的吸电子能力越强, 收率降低越明显(表 2, Entry 5 vs. Entries 4和6), 总的来说, 未取代茚酮和给电子取代基能得到更高收率(表 2, Entry 1和Entries 7~11).用氟、氯和溴等卤素原子取代的芴酮, 均以良好的产率得到目标产物, 从而可以利用取代反应或者金属催化偶联反应实现目标产物进一步的衍生官能化.取代基在不同的取代位置例如甲基在芴酮的4、5或6位取代时, 也可以以良好的收率得到所需的芴基炔膦酸二乙酯衍生物(表 2, Entries 8~10), 说明取代基取代位置对反应影响不大.用碳链更长的五氟乙基或七氟正丙基替代三氟甲基取代的炔膦酸二乙酯, 反应一样可以顺利进行, 并得到满意收率, 虽然因为位阻缘故, 收率相比2a有所降低(表 2, Entry 1 vs. Entries 12和15).

表 2

表 2 全氟烷基芴基炔膦酸二乙酯的合成^a

Table 2. Scope of the synthesis of perfluoroalkylated fluorenes with phosphonate group

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Entry	R	R_F	Product 4	Yield^b/%
1	H	CF₃	4a	82
2	6-Br	CF₃	4b	57
3	4-Br	CF₃	4c	50
4	5-Cl	CF₃	4d	62
5	5-F	CF₃	4e	48
6	5-Br	CF₃	4f	68
7	5-MeO	CF₃	4g	70
8	4-Me	CF₃	4h	74
9	5-Me	CF₃	4i	70
10	6-Me	CF₃	4j	75
11	6-MeO	CF₃	4k	78
12	H	C₂F₅	4l	74
13	5-Me	C₂F₅	4m	60
14	6-MeO	C₂F₅	4n	67
15	H	n-C₃F₇	4o	58
16	5-Me	n-C₃F₇	4p	51
17	6-MeO	n-C₃F₇	4q	49
^a Reaction conditions: 1 (1.0 mmol), 2 (1.0 equiv.), AcOH (0.1 equiv.) and NH₄OAc (0.2 equiv.) were stirred in refluxing toluene (5.0 mL) for 12 h After cooling to the room temperature, 3 (1.2 equiv.) and NaOH (1.5 equiv.) were added and continued to be stirred for 16 h at the same temperature. ^b Isolated yields for two steps in one pot.

4a的结构由单晶X射线分析结果确定(图 2)^[13].其他产物的结构通过与4a的¹H NMR, ¹³C NMR, ¹⁹F NMR, IR和MS, HRMS等进行比较后得到确认.

图 2

图 2. 4a的X射线晶体结构

Figure 2. X-ray crystal structure of 4a

下载: 全尺寸图片幻灯片

根据实验结果和以前相关的文献报道^{[11, 14]}, 该反应的反应历程如Scheme 1所示.首先茚酮1和丙二腈(2)通过Knoevenagel缩合反应得到中间体2-(2, 3-二氢-1H-茚-1-亚基)丙二腈(5)^[15], 然后中间体5先是在碱NaOH的作用下发生去质子化, 得到碳负离子中间体6, 中间体6高区域选择性地进攻全氟烷基-2-炔膦酸二乙酯3中构建炔键的两个碳中亲核性更强的2位碳原子, 通过分子间Michael加成反应形成新的碳负离子7, 后者通过对氰基进行分子内亲核加成以实现成环得到中间体8, 8随之发生芳构化得到目标产物4.

图式 1

图式 1. 可能的反应路径

Scheme 1. Possible reaction pathway

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2. 结论

发展了一种简单高效的合成全氟烷基芴基炔膦酸二乙酯类化合物的新方法.该方法通过一锅两步方式, 经过Knoevenagel缩合反应/Michael加成反应/环化的一系列过程将含氟基团和炔膦酸二乙酯基团一并引入到芴分子中.该反应的起始原料容易获得, 实验操作简便, 不需要专门分离出第一步中间体, 反应时间短, 底物范围广, 具有被用来设计新药物和有机光电材料的良好应用前景.

3. 实验部分

3.1 仪器与试剂

熔点在上海物理光学仪器公司生产的WRS-1数字熔点仪上测得, 未经校正. ¹H, ¹⁹F NMR和¹³C NMR光谱在Bruker AVANCE Ⅲ HD-600 MHz, Bruker DRX-500 MHz和JNM-ECZ400S/L-400 MHz光谱仪上测得, ¹H NMR和¹³C NMR光谱以TMS为内标, ¹⁹F NMR以C₆F₆为内标, CDCl₃为溶剂. IR光谱在AVATAR370 FTIR光谱仪上测得.低分辨率质谱(LR-MS)和高分辨率质谱(HR-MS)分别在Agilent 6230, Thermo Fisher Scientic LTQ FTICR-MS或Agilent 1100 LC/MSD SL仪器上测得. X射线单晶结构测定分析在Bruker Smart Apex2 CCD光谱仪上进行.文中报道的产率是指经柱层析分离得到的化合物的产率, 其纯度通过¹H NMR测定.实验中所用试剂未经标明的, 均为直接购买的分析纯试剂, 使用前未做进一步纯化.全氟烷基-2-炔膦酸二乙酯根据参考文献[16]制备.

3.2 实验方法

茚酮1 (1.0 mmol)、丙二腈2 (1.0 equiv.)、冰醋酸(0.1 equiv.)和醋酸铵(0.2 equiv.)的混合物在甲苯(5.0 mL)中回流12 h后, 将反应体系冷却至室温, 加入全氟烷基-2-炔膦酸二乙酯3 (1.2 equiv.)和氢氧化钠(1.5 equiv.), 在室温下继续搅拌16 h.循环水泵真空下除去溶剂, 残留物经硅胶柱层析纯化, 用石油醚/乙酸乙酯(V:V, 15:1~10:1)洗脱, 得到所需产物4.

3-氨基-4-氰基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4a):黄色固体. m.p. 142.2~142.7 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.3 Hz, 6H), 4.07 (s, 2H), 4.11~4.27 (m, 4H), 7.15 (brs, 2H), 7.47~7.52 (m, 2H), 7.58~7.59 (m, 1H), 8.49~8.50 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.0 Hz), 37.5, 63.0 (d, ²J_C-P＝6.0 Hz), 93.8 (d, ³J_C-P＝16.3 Hz), 103.6 (d, ¹J_C-P＝183.0 Hz), 116.0, 122.9, 123.6 (qd, ³J_C-P＝5.3 Hz, ¹J_C-F＝275.1 Hz, CF₃), 124.7, 127.6, 130.3~130.4 (m), 130.5, 134.0 (qd, ²J_C-P＝5.1 Hz, ²J_C-F＝32.4 Hz), 136.7, 145.5, 149.2, 155.7 (d, ²J_C-P＝10.0 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3289, 2923, 2853, 2209, 1622, 1397, 1284, 1177, 1127, 1047, 1022, 766 cm^－1; MS (ESI) m/z (%): 411 [(M+H)]⁺; HRMS (DART) calcd for C₁₉H₁₉F₃N₂O₃P (M+H)⁺ 411.1080, found 411.1079.

氨基-6-溴-4-氰基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4b):黄色固体. m.p. 143.5~143.8 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.0 Hz, 6H), 4.00 (s, 2H), 4.11~4.30 (m, 4H), 7.17 (brs, 2H), 7.42~7.44 (m, 1H), 7.58~7.60 (m, 1H), 8.54~8.55 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.0 Hz), 37.3, 63.2 (d, ²J_C-P＝5.6 Hz), 93.9 (d, ³J_C-P＝16.3 Hz), 104.8 (d, ¹J_C-P＝182.4 Hz), 115.7, 121.7, 123.5 (qd, ³J_C-P＝5.2 Hz, ¹J_C-F＝275.6 Hz, CF₃), 125.9, 126.2, 130.6 (m), 133.5, 134.4 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.5 Hz), 138.8, 144.2, 147.7, 155.8 (d, ²J_C-P＝10.5 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －55.0 (s, CF₃); IR (KBr) δ: 3264, 2919, 2851, 2209, 1619, 1394, 1284, 1164, 1129, 1047, 1011, 776 cm^－1; MS (ESI) m/z: 489 (M+H)⁺; HRMS (ESI) calcd for C₁₉H₁₈- BrF₃N₂O₃P (M+H)⁺ 489.0192, found 489.0187.

3-氨基-8-溴-4-氰基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4c):黄色固体. m.p. 182.5~182.8 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.0 Hz, 6H), 4.00 (s, 2H), 4.11~4.30 (m, 4H), 7.18 (brs, 2H), 7.35~7.38 (m, 1H), 7.63~7.64 (m, 1H), 8.40~8.42 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.0 Hz), 39.3, 63.2 (d, ²J_C-P＝5.6 Hz), 94.2 (d, ³J_C-P＝16.0 Hz), 104.9 (d, ¹J_C-P＝182.2 Hz), 115.8, 119.8, 121.9, 123.5 (qd, ³J_C-P＝5.2 Hz, ¹J_C-F＝275.6 Hz, CF₃), 129.5, 129.6 (m), 133.4, 134.5 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.4 Hz), 138.2, 145.5, 148.6, 155.8 (d, ²J_C-P＝10.3 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3276, 2909, 2854, 2210, 1622, 1394, 1284, 1170, 1135, 1038, 1016, 763 cm^－1; MS (ESI) m/z: 489 [(M+H)]⁺; HRMS (ESI) calcd for C₁₉H₁₈- BrF₃N₂O₃P (M+H)⁺ 489.0192, found 489.0188.

3-氨基-4-氰基-8-甲氧基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4d):黄色固体. m.p. 145.6~146.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 1.34 (t, J＝7.2 Hz, 6H), 3.88 (s, 3H), 3.98 (s, 2H), 4.07~4.26 (m, 4H), 6.97~7.00 (m, 1H), 7.05~7.06 (m, 1H), 7.08 (brs, 2H), 8.33~8.35 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.6 Hz), 37.4, 55.7, 62.9 (d, ²J_C-P＝5.6 Hz), 92.7 (d, ³J_C-P＝16.4 Hz), 101.7 (d, ¹J_C-P＝183.9 Hz), 109.6, 114.3, 116.3, 123.7 (qd, ³J_C-P＝5.0 Hz, ¹J_C-F＝275.5 Hz, CF₃), 124.3, 129.7, 130.1~130.2 (m), 133.6 (qd, ²J_C-P＝5.2 Hz, ²J_C-F＝32.5 Hz), 148.1, 149.5, 155.8 (d, ²J_C-P＝10.1 Hz), 162.1; ¹⁹F NMR (470 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3297, 3218, 2909, 2963, 2835, 2210, 1606, 1402, 1284, 1167, 1118, 1042, 1017, 782 cm^－1; MS (ESI) m/z: 441 [(M+H)]⁺; HRMS (ESI) calcd for C₂₀H₂₁F₃N₂O₄P (M+H)⁺ 441.1195, found 441.1189.

3-氨基-7-氯-4-氰基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4e):黄色固体. m.p. 155.9~156.4 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.0 Hz, 6H), 4.01 (s, 2H), 4.11~4.30 (m, 4H), 7.16 (brs, 2H), 7.41~7.43 (m, 1H), 7.52~7.53 (m, 1H), 8.34~8.35 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.8 Hz), 37.3, 63.1 (d, ²J_C-P＝5.9 Hz), 93.7 (d, ³J_C-P＝16.2 Hz), 104.2 (d, ¹J_C-P＝181.8 Hz), 115.9, 123.6 (qd, ³J_C-P＝5.4 Hz, ¹J_C-F＝275.3 Hz, CF₃), 123.9, 125.1, 128.2, 130.0~130.1 (m), 134.3 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.8 Hz), 135.3, 136.8, 147.2, 148.1, 155.8 (d, ²J_C-P＝10.1 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: -55.0 (s, CF₃); IR (KBr) ν: 3257, 2911, 2209, 1616, 1400, 1287, 1170, 1043, 1017, 768 cm^－1; MS (ESI) m/z: 445 (M+H)⁺; HRMS (ESI) calcd for C₁₉H₁₈ClF₃- N₂O₃P (M+H)⁺ 445.0695, found 445.0690.

3-氨基-4-氰基-7-氟-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4f):黄色固体. m.p. 179.8~180.2 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 1.35 (t, J＝6.9 Hz, 6H), 4.04 (s, 2H), 4.11~4.26 (m, 4H), 7.16 (brs, 2H), 7.17~7.19 (m, 1H), 7.25 (s, 1H), 8.42~8.44 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.9 Hz), 37.5, 63.1 (d, ²J_C-P＝5.9 Hz), 93.5 (d, ³J_C-P＝16.2 Hz), 103.5 (d, ¹J_C-P＝182.8 Hz), 112.1 (d, ²J_C-F＝22.9 Hz, Ar-F), 115.4 (d, ²J_C-F＝23.1 Hz, Ar-F), 116.0, 123.6 (qd, ³J_C-P＝5.2 Hz, ¹J_C-F＝275.4 Hz, CF₃), 124.6, 124.7 (d, ³J_C-F＝9.5 Hz, Ar-F), 130.1~130.2 (m), 133.0, 134.1 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.3 Hz), 148.2, 148.3, 155.8 (d, ²J_C-P＝10.1 Hz), 164.4 (d, ¹J_C-F＝250.4 Hz, Ar-F); ¹⁹F NMR (564 MHz, CDCl₃) δ: －108.5 (s, ArF), －55.0 (s, CF₃); IR (KBr) ν: 3302, 3228, 2906, 2208, 1611, 1405, 1284, 1175, 1047, 1022, 764 cm^－1; MS (ESI) m/z: 429 (M+H)⁺; HRMS (ESI) calcd for C₁₉H₁₈F₄N₂O₃P (M+H)⁺ 429.0993, found 429.0988.

3-氨基-7-溴-4-氰基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4g):黄色固体. m.p. 166.2~166.5 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.0 Hz, 6H), 4.03 (s, 2H), 4.10~4.27 (m, 4H), 7.16 (brs, 2H), 7.59~7.61 (m, 1H), 7.72 (s, 1H), 8.31~8.32 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.1 Hz), 37.3, 63.2 (d, ²J_C-P＝6.1 Hz), 93.8 (d, ³J_C-P＝16.3 Hz), 104.4 (d, ¹J_C-P＝182.4 Hz), 115.9, 123.6 (qd, ³J_C-P＝5.1 Hz, ¹J_C-F＝275.3 Hz, CF₃), 124.2, 125.2, 128.1, 129.9~130.0 (m), 131.0, 134.4 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.3 Hz), 135.8, 147.3, 147.4, 148.2, 155.8 (d, ²J_C-P＝10.4 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3293, 3197, 2914, 2848, 2211, 1612, 1401, 1283, 1188, 1044, 1021, 771 cm^－1; MS (ESI) m/z: 489 (M+H)⁺; HRMS (ESI) calcd for C₁₉H₁₈Br- F₃N₂O₃P (M+H)⁺ 489.0192, found 489.0190.

3-氨基-4-氰基-8-甲基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4h):黄色固体. m.p. 189.9~190.4 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.3 Hz, 6H), 2.43 (s, 3H), 3.91 (s, 2H), 4.11~4.27 (m, 4H), 7.13 (brs, 2H), 7.30~7.31 (m, 1H), 7.38~7.41 (m, 1H), 8.30~8.32 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.0 Hz), 18.8, 36.4, 63.0 (d, ²J_C-P＝5.9 Hz), 93.9 (d, ³J_C-P＝16.2 Hz), 103.5 (d, ¹J_C-P＝183.0 Hz), 116.1, 120.5, 123.7 (qd, ³J_C-P＝5.3 Hz, ¹J_C-F＝275.3 Hz, CF₃), 128.0, 130.4~130.5 (m), 131.5, 134.1 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.3 Hz), 136.4, 144.3, 149.7, 155.7 (d, ²J_C-P＝10.5 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －55.5 (s, CF₃); IR (KBr) ν: 3301, 3199, 2911, 2851, 2210, 1629, 1397, 1286, 1163, 1121, 1020, 762 cm^－1; MS (ESI) m/z: 425 (M+H)⁺; HRMS (ESI) calcd for C₂₀H₂₁F₃N₂O₃P (M+H)⁺ 425.1236, found 425.1238.

3-氨基-4-氰基-7-甲基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4i):黄色固体. m.p. 172.3~172.8 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.36 (t, J＝7.0 Hz, 6H), 2.46 (s, 3H), 3.98 (s, 2H), 4.10~4.27 (m, 4H), 7.11 (brs, 2H), 7.26~7.27 (m, 1H), 7.36 (s, 1H), 8.31~8.32 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.5 Hz), 22.0, 37.3, 63.0 (d, ²J_C-P＝5.6 Hz), 93.4 (d, ³J_C-P＝16.4 Hz), 102.8 (d, ¹J_C-P＝183.0 Hz), 116.2, 122.7, 123.7 (qd, ³J_C-P＝5.2 Hz, ¹J_C-F＝275.3 Hz, CF₃), 125.3, 128.7, 130.4~130.5 (m), 134.2, 133.9 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.4 Hz), 141.3, 145.9, 149.5, 155.7 (d, ²J_C-P＝10.4 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3391, 3217, 2911, 2212, 1638, 1400, 1286, 1165, 1147, 1043, 1016, 773 cm^－1; MS (ESI) m/z: 425 (M+H)⁺; HRMS (DART) calcd for C₂₀H₂₁F₃N₂O₃P (M+H)⁺ 425.1236, found 425.1237.

3-氨基-4-氰基-6-甲基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4j):黄色固体. m.p. 126.2~126.8 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.38 (t, J＝7.3 Hz, 6H), 2.51 (s, 3H), 4.03 (s, 2H), 4.13~4.30 (m, 4H), 7.16 (brs, 2H), 7.33~7.34 (m, 1H), 7.47~7.48 (m, 1H), 8.30 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.6 Hz), 21.7, 37.1, 63.0 (d, ²J_C-P＝5.6 Hz), 93.7 (d, ³J_C-P＝16.3 Hz), 103.4 (d, ¹J_C-P＝183.0 Hz), 116.2, 123.3, 123.7 (qd, ³J_C-P＝5.0 Hz, ¹J_C-F＝275.4 Hz, CF₃), 124.5, 130.9~131.0 (m), 131.8, 134.1 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.5 Hz), 136.9, 137.6, 142.9, 149.4, 155.7 (d, ²J_C-P＝10.1 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －54.9 (s, CF₃); IR (KBr) ν: 3306, 3194, 2911, 2217, 1628, 1396, 1282, 1159, 1124, 1046, 1019, 765 cm^－1; MS (ESI) m/z: 425 [(M+H)]⁺; HRMS (ESI) calcd for C₂₀H₂₁F₃N₂O₃P (M+H)⁺ 425.1236, found 425.1241.

3-氨基-4-氰基-6-甲氧基-1-(三氟甲基)-9H-芴-2-炔膦酸二乙酯(4k):黄色固体. m.p. 160.8~161.3 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 1.35 (t, J＝7.0 Hz, 6H), 3.90 (s, 3H), 3.96 (s, 2H), 4.08~4.27 (m, 4H), 7.05~7.07 (m, 1H), 7.12 (brs, 2H), 7.43~7.45 (m, 1H), 7.98~7.99 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝7.0 Hz), 36.8, 55.7, 63.0 (d, ²J_C-P＝5.8 Hz), 93.7 (d, ³J_C-P＝16.3 Hz), 103.6 (d, ¹J_C-P＝183.0 Hz), 106.4, 116.1, 118.6, 123.7 (dq, ³J_C-P＝5.0 Hz, ¹J_C-F＝275.4 Hz, CF₃), 125.4, 131.5~131.6 (m), 134.0 (qd, ²J_C-P＝5.0 Hz, ²J_C-F＝32.2 Hz), 137.9, 138.0, 149.3, 155.7 (d, ²J_C-P＝10.3 Hz), 160.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: －54.8 (s, CF₃); IR (KBr) ν: 3292, 3215, 2995, 2914, 2218, 1610, 1396, 1287, 1169, 1046, 1015, 794 cm^－1; MS (ESI) m/z: 441 (M+H)⁺; HRMS (ESI) calcd for C₂₀H₂₁F₃N₂O₄P [(M+H)]⁺ 441.1195, found 441.1188.

3-氨基-4-氰基-1-(五氟乙基)-9H-芴-2-炔膦酸二乙酯(4l): 黄色固体. m.p. 168.6~169.1 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 1.34 (t, J＝7.0 Hz, 6H), 4.07 (s, 2H), 4.10~4.28 (m, 4H), 7.30 (brs, 2H), 7.45~7.51 (m, 2H), 7.55~7.57 (m, 1H), 8.48~8.50 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.1 (d, ³J_C-P＝6.4 Hz), 37.6, 62.9 (d, ²J_C-P＝6.1 Hz), 94.2 (d, ³J_C-P＝16.8 Hz), 104.8 (d, ¹J_C-P＝185.4 Hz), 112.2~117.3 (m, CF₂), 116.0, 119.6 (qt, ¹J_C-F＝287.4 Hz, ²J_C-F＝37.4 Hz, CF₃), 122.9, 124.5, 127.5, 130.5, 131.4~131.5 (m), 132.8~133.2 (m), 136.3, 145.5~145.6 (m), 149.1, 155.6 (d, ²J_C-P＝10.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －78.1 (s, CF₃), －101.3 (s, CF₂); IR (KBr) ν: 3389, 3215, 2924, 2851, 2214, 1638, 1395, 1271, 1178, 1039, 1016, 761 cm^－1; MS (ESI) m/z: 461 (M+H)⁺; HRMS (ESI) calcd. for C₂₀H₁₉F₅N₂O₃P (M+H)⁺ 461.1060, found 461.1052.

3-氨基-4-氰基-7-甲基-1-(五氟乙基)-9H-芴-2-炔膦酸二乙酯(4m):黄色固体. m.p. 178.1~178.8 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 1.34 (t, J＝7.2 Hz, 6H), 2.45 (s, 3H), 4.01 (s, 2H), 4.08~4.28 (m, 4H), 7.26 (s, 1H), 7.28 (brs, 2H), 7.36 (s, 1H), 8.33~8.35 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.4 Hz), 22.0, 37.5, 63.0 (d, ²J_C-P＝6.0 Hz), 93.9 (d, ³J_C-P＝16.8 Hz), 104.1 (d, ¹J_C-P＝185.9 Hz), 112.6~117.1 (m, CF₂), 116.3, 119.8 (qt, ¹J_C-F＝287.4 Hz, ²J_C-F＝37.5 Hz, CF₃), 122.9, 125.2, 128.6, 131.5~131.7 (m), 132.7~133.1 (m), 133.9, 141.4, 146.1, 149.5, 155.7 (d, ²J_C-P＝10.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －78.2 (s, CF₃), －101.3 (s, CF₂); IR (KBr) ν: 3280, 3212, 2909, 2213, 1628, 1394, 1275, 1205, 1047, 1016, 768 cm^－1; MS (ESI) m/z: 475 (M+H)⁺; HRMS (ESI) calcd. for C₂₁H₂₁F₅N₂O₃P (M+H)⁺ 475.1212, found 475.1206.

3-氨基-4-氰基-6-甲氧基-1-(五氟乙基)-9H-芴-2-炔膦酸二乙酯(4n):黄色固体. m.p. 133.8~134.1 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.35 (t, J＝7.0 Hz, 6H), 3.92 (s, 3H), 4.00 (s, 2H), 4.10~4.28 (m, 4H), 7.07~7.09 (m, 1H), 7.30 (brs, 2H), 7.43~7.45 (m, 1H), 8.02 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.2 (d, ³J_C-P＝6.5 Hz), 37.0, 55.7, 63.0 (d, ²J_C-P＝6.1 Hz), 94.1 (d, ³J_C-P＝16.8 Hz), 104.8 (d, ¹J_C-P＝185.4 Hz), 106.5, 112.3~117.4 (m, CF₂), 116.3, 118.8, 119.7 (qt, ¹J_C-F＝287.5 Hz, ²J_C-F＝37.3 Hz, CF₃), 125.3, 132.6~132.7 (m), 132.9~133.3 (m), 137.6, 138.1~138.2 (m), 149.3, 155.7 (d, ²J_C-P＝10.9 Hz), 159.6; ¹⁹F NMR (376 MHz, CDCl₃) δ: －78.0 (s, CF₃), －101.2 (s, CF₂); IR (KBr) ν: 3279, 3213, 2924, 2215, 1610, 1388, 1281, 1204, 1043, 1015, 794 cm^－1; MS (ESI) m/z: 491 (M+H)⁺; HRMS (ESI) calcd for C₂₁H₂₁F₅N₂O₄P (M+H)⁺ 491.1162, found 491.1156.

3-氨基-4-氰基-1-(七氟正丙基)-9H-芴-2-炔膦酸二乙酯(4o):黄色固体; m.p. 172.1~172.5 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.34 (t, J＝7.3 Hz, 6H), 4.09 (s, 2H), 4.10~4.28 (m, 4H), 7.37 (brs, 2H), 7.47~7.52 (m, 2H), 7.56~7.57 (m, 1H), 8.51~8.52 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.3 (d, ³J_C-P＝5.9 Hz), 38.2, 63.0 (d, ²J_C-P＝6.0 Hz), 94.5 (d, ³J_C-P＝16.9 Hz), 105.3 (d, ¹J_C-P＝185.3 Hz), 107.4~112.5 (m, CF₂), 114.4~116.8 (m, CF₂), 116.3, 116.8~121.6 (m, CF₃), 123.1, 124.6, 127.6, 130.7, 132.2~132.4 (m), 132.5~132.6 (m), 136.4, 145.8~145.9 (m), 149.3, 155.8 (d, ²J_C-P＝10.9 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －80.0 (t, J＝10.6 Hz, CF₃), －100.7 (s, CF₂), －120.7 (s, CF₂); IR (KBr) ν: 3295, 3199, 2911, 2213, 1612, 1391, 1268, 1222, 1196, 1046, 1009, 743 cm^－1; MS (ESI) m/z: 511 (M+H)⁺; HRMS (ESI) calcd for C₂₁H₁₉F₇N₂O₃P (M+H)⁺ 511.1025, found 511.1020.

3-氨基-4-氰基-7-甲基-1-(七氟正丙基)-9H-芴-2-炔膦酸二乙酯(4p):黄色固体. m.p. 178.2~178.6 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 1.34 (t, J＝7.0 Hz, 6H), 2.47 (s, 3H), 4.06 (s, 2H), 4.08~4.27 (m, 4H), 7.27 (s, 1H), 7.28 (brs, 2H), 7.36 (s, 1H), 8.35~8.37 (m, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.1 (d, ³J_C-P＝6.1 Hz), 21.8, 37.8, 62.8 (d, ²J_C-P＝6.3 Hz), 94.0 (d, ³J_C-P＝16.8 Hz), 104.3 (d, ¹J_C-P＝185.6 Hz), 107.3~112.4 (m, CF₂), 114.3~116.7 (m, CF₂), 116.2, 116.9~121.8 (m, CF₃), 122.7, 125.0, 128.5, 132.0~132.1 (m), 132.2, 133.7, 141.3, 146.1, 149.4, 155.6 (d, ²J_C-P＝10.9 Hz); ¹⁹F NMR (470 MHz, CDCl₃) δ: －80.0 (t, J＝10.3 Hz, CF₃), －100.7 (s, CF₂), －120.8 (s, CF₂); IR (KBr) ν: 3270, 3191, 2903, 2210, 1618, 1393, 1220, 1205, 1046, 1021, 760 cm^－1; MS (ESI) m/z: 525 (M+H)⁺; HRMS (ESI) calcd for C₂₂H₂₁F₇N₂O₃P (M+H)⁺ 525.1184, found 525.1178.

3-氨基-4-氰基-6-甲氧基-1-(七氟正丙基)-9H-芴-2-炔膦酸二乙酯(4q):黄色固体; m.p. 154.9~155.2 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 1.33 (t, J＝7.0 Hz, 6H), 3.91 (s, 3H), 4.02 (s, 2H), 4.06~4.27 (m, 4H), 7.05~7.08 (m, 1H), 7.35 (brs, 2H), 7.42~7.44 (m, 1H), 8.02 (s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 16.3 (d, ³J_C-P＝5.9 Hz), 37.4, 55.7, 63.0 (d, ²J_C-P＝6.0 Hz), 94.4 (d, ³J_C-P＝16.8 Hz), 105.1 (d, ¹J_C-P＝185.3 Hz), 106.4, 107.0~112.5 (m, CF₂), 115.8 (m, CF₂), 116.3, 116.8~121.9 (m, CF₃), 118.8, 125.2, 132.2~132.6 (m), 133.2~133.3 (m), 137.5, 138.2, 149.3, 155.7 (d, ²J_C-P＝10.9 Hz), 159.5; ¹⁹F NMR (376 MHz, CDCl₃) δ: －80.0 (t, J＝11.5 Hz, CF₃), －100.6 (s, CF₂), －120.6 (s, CF₂); IR (KBr) ν: 3275, 3191, 2923, 2212, 1610, 1386, 1276, 1210, 1195, 1042, 1017, 746 cm^－1; MS (ESI) m/z: 541 [(M+H)]⁺; HRMS (ESI) calcd for C₂₂H₂₁F₇N₂O₄P (M+H)⁺ 541.1132, found 541.1127.

辅助材料(Supporting Information) 全氟烷基取代的芴基膦酸酯4a~4q的核磁共振谱图.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 芴类的发光材料与苯芴醇

Figure 1 Light-emitting material of fluorene and lumefantrine

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图 2 4a的X射线晶体结构

Figure 2 X-ray crystal structure of 4a

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图式 1 可能的反应路径

Scheme 1 Possible reaction pathway

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表 1 反应条件的优化^a

Table 1. Optimization of reaction conditions


Entry	Solvent	Base (equiv.)	T^b/℃	Time^c/h	Yield^d/%
1	Toluene	NaOH (0.5)	r.t.	6	61
2	Toluene	KOH (0.5)	r.t.	6	57
3	Toluene	K₂CO₃ (0.5)	r.t.	6	49
4	Toluene	Piperidine (0.5)	r.t.	6	—
5	Toluene	CsCO₃ (0.5)	r.t.	6	45
6	Toluene	CsF (0.5)	r.t.	6	Trace
7	Toluene	Et₃N (0.5)	r.t.	6	Trace
8	Toluene	NaOH (0)	r.t.	6	—
9	MeCN	NaOH (0.5)	r.t.	6	52
10	DCM	NaOH (0.5)	r.t.	6	55
11	THF	NaOH (0.5)	r.t.	6	53
12	EtOH	NaOH (0.5)	r.t.	6	53
13	Toluene	NaOH (1.0)	r.t.	6	65
14	Toluene	NaOH (1.5)	r.t.	6	69
15	Toluene	NaOH (2.0)	r.t.	6	59
16	Toluene	NaOH (1.5)	0	6	29
17	Toluene	NaOH (1.5)	50	6	41
18	Toluene	NaOH (1.5)	r.t.	12	73
19	Toluene	NaOH (1.5)	r.t.	16	82
20	Toluene	NaOH (1.5)	r.t.	24	81
^a Reaction conditions: 1a (1.0 mmol), 2a (1.0 equiv.), AcOH (0.1 equiv.) and NH₄OAc (0.2 equiv.) were mixed and stirred in refluxing toluene (5.0 mL) for 12 h. After cooling to the confined temperature, 3a (1.2 equiv.) and base were added and continued to be stirred for the referred time. ^b Reaction temperature for the second step. ^c Reaction time for the second step. ^d Isolated yields for two steps in one pot.

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表 2 全氟烷基芴基炔膦酸二乙酯的合成^a

Table 2. Scope of the synthesis of perfluoroalkylated fluorenes with phosphonate group


Entry	R	R_F	Product 4	Yield^b/%
1	H	CF₃	4a	82
2	6-Br	CF₃	4b	57
3	4-Br	CF₃	4c	50
4	5-Cl	CF₃	4d	62
5	5-F	CF₃	4e	48
6	5-Br	CF₃	4f	68
7	5-MeO	CF₃	4g	70
8	4-Me	CF₃	4h	74
9	5-Me	CF₃	4i	70
10	6-Me	CF₃	4j	75
11	6-MeO	CF₃	4k	78
12	H	C₂F₅	4l	74
13	5-Me	C₂F₅	4m	60
14	6-MeO	C₂F₅	4n	67
15	H	n-C₃F₇	4o	58
16	5-Me	n-C₃F₇	4p	51
17	6-MeO	n-C₃F₇	4q	49
^a Reaction conditions: 1 (1.0 mmol), 2 (1.0 equiv.), AcOH (0.1 equiv.) and NH₄OAc (0.2 equiv.) were stirred in refluxing toluene (5.0 mL) for 12 h After cooling to the room temperature, 3 (1.2 equiv.) and NaOH (1.5 equiv.) were added and continued to be stirred for 16 h at the same temperature. ^b Isolated yields for two steps in one pot.

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