叔膦介导的叠氮化合物与不饱和酮的连续Staudinger/Aza-Michael加成反应合成<i>β</i>-氨基取代酮类化合物

引用本文: 丛甜甜, 王华敏, 刘媛媛, 吴海虹, 张俊良. 叔膦介导的叠氮化合物与不饱和酮的连续Staudinger/Aza-Michael加成反应合成β-氨基取代酮类化合物[J]. 有机化学, 2019, 39(8): 2157-2165. doi: 10.6023/cjoc201906005 shu

Citation: Cong Tiantian, Wang Huamin, Liu Yuanyuan, Wu Haihong, Zhang Junliang. Phosphine-Mediated Sequential Staudinger/Aza-Michael Addition of Azides with Unsaturated Ketones to Synthesize β-Amino Substituted Ketones[J]. Chinese Journal of Organic Chemistry, 2019, 39(8): 2157-2165. doi: 10.6023/cjoc201906005 shu

叔膦介导的叠氮化合物与不饱和酮的连续Staudinger/Aza-Michael加成反应合成β-氨基取代酮类化合物

丛甜甜 ^a, ,
王华敏 ^a, ,
刘媛媛 ^{a,
,} ,
吴海虹 ^{a,
,} ,
张俊良 ^{a,b,
,}

a.
华东师范大学化学与分子工程学院上海市绿色化学与化工过程绿色化重点实验室上海 200062
b.
复旦大学化学系上海 200438

通讯作者: 刘媛媛, yyliu@chem.ecnu.edu.cn; 吴海虹, hhwu@chem.ecnu.edu.cn; 张俊良, junliangzhang@fudan.edu.cn

基金项目:

国家自然科学基金（No.21871088）、上海市教育发展基金会和上海市教育委员会“晨光计划”（No.16CG22）、中央高校基本科研业务费专项资金（No.21871088）资助项目

摘要: 以叔膦为介导，水为添加剂，在1，2-二氯乙烷溶剂中，叠氮化合物与三氟甲基取代α，β-不饱和酮为原料，发生连续Staudinger/Aza-Michael加成反应.所开发反应可以中等到优秀的收率（最高96%）获得氢胺化产物，并且能够实现克级规模制备目标产物.此方法有广泛的底物范围（30个底物）.核磁共振磷谱监测实验验证了反应的启动步骤是叠氮与叔膦的Staudinger反应.

关键词:

English

Phosphine-Mediated Sequential Staudinger/Aza-Michael Addition of Azides with Unsaturated Ketones to Synthesize β-Amino Substituted Ketones

a.
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062
b.
Department of Chemistry, Fudan University, Shanghai 200438

Corresponding author: Liu, Yuanyuan, E-mail: yyliu@chem.ecnu.edu.cn; Wu, Haihong, E-mail: hhwu@chem.ecnu.edu.cn; Zhang, Junliang, E-mail: junliangzhang@fudan.edu.cn

Received Date: 06 June 2019
Revised Date: 09 July 2019
Available Online: 25 August 2019
Fund Project:

Project supported by the National Natural Science Foundation of China (No. 21871088), the Chenguang Program supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission (No. 16CG22), and the Fundamental Research Funds for the Central Universities (No. 21871088)

Abstract: A phosphine-mediated Staudinger/Aza-Michael addition of azides with trifluoromethyl substituted α, β-unsaturated ketones was developed, giving hydroamination products in medium to good yields (up to 96%). The hydroamination products could be prepared on gram scale and a wide range of substrates are tolerated under the optimized reaction conditions (30 examples). ³¹P NMR experiments indicate that this reaction was initiated by Staudinger reaction of azide with phosphine.

Key words:

叠氮化合物是有机合成中重要的合成子, 是构建含氮化合物的关键中间体^[1].叠氮化合物可以参与多种化学反应^[1], 例如Huisgen环加成^[2]、Curtius重排^[3]、Schmidt重排^[4]、Staudinger反应^[5].其中, Staudinger反应普适性广, 反应迅速, 可合成多种含氮化合物, 因而受到化学家们的广泛关注.叠氮化合物与叔膦作用, 释放一分子氮气, 生成氮杂叶立德的反应被称为Staudinger反应(Scheme 1a)^[5]. Staudinger反应中产生的氮杂叶立德是一种多功能中间体, 例如, 其可以被还原为伯胺, 还可作为亲核试剂进攻羰基化合物(酰卤、羧基等), 进而转化为酰胺、亚胺^[5f~5g].

图式 1

图式 1. Staudinger反应

Scheme 1. Staudinger reaction

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2018年, 我们小组^[6]报道了通过叔膦催化, 以三氟甲基取代的α, β-不饱和酮和TMSN₃为原料合成β-氨基-α-重氮羰基化合物的反应研究(Scheme 1b).在此反应中, 叠氮与叔膦作用产生叠氮膦, 经由三唑五元环中间体, 得到最终产物β-氨基-α-重氮羰基化合物.在此过程中作者猜测, 由于TMS基团的位阻原因, 导致产生膦亚胺的过程发生缓慢.基于以上的工作, 我们猜想可以采用一种小位阻的叠氮乙酸甲酯与三氟甲基取代的α, β-不饱和酮发生反应, 经由Scheme 1c过程得到环状化合物.

首先, 叠氮化合物与叔膦作用产生膦亚胺中间体, 膦亚胺中间体与酮发生氮杂Wittig反应生成亚胺.与此同时, 叔膦与丙烯酸甲酯作用得到两性离子中间体.两性离子中间体作为布朗斯特碱催化亚胺发生分子内Michael加成反应得到五元环状化合物.但令人遗憾的是, 反应没有按照我们的预想发生, 丙烯酸甲酯没有参与到反应中, 而是膦亚胺优先发生水解, 经由甘氨酸甲酯, 通过氮杂Michael加成得到了氢胺化产物.我们认为该氢胺化反应以叠氮化合物为胺源, 避免了分步的将叠氮化合物还原后分离, 再应用于Michael加成, 在适当的合成应用中可能会具有较好的反应步骤经济性, 如无商业可得的胺源而需要由卤代烃来制备胺时, 可以制备叠氮化合物, 然后以叔膦为还原剂直接进行氢胺化反应.基于这些考虑, 我们对该反应进行了研究.

1. 结果与讨论

1.1 反应条件的筛选

我们以三氟甲基取代的α, β-不饱和酮1h与叠氮乙酸甲酯2为模板底物进行了条件筛选(表 1).首先, 以甲苯为溶剂, 丙烯酸甲酯为添加剂对反应进行了尝试, 当使用二苯基甲基膦作为膦试剂时, 可以46%的产率获得氢胺化产物(Entry 1), 而未观察到环状产物.鉴于得到氢胺化产物的过程无需加入丙烯酸甲酯, 下面的条件筛选过程中未添加丙烯酸甲酯.以甲苯为溶剂考察了一系列叔膦对反应的影响(Entries 2~10).使用芳基烷基膦时, 均能以中等的核磁产率得到目标产物(Entries 2~4).改变叔膦为(ⁿBu)₃P或(^tBu)₃P, 反应不能顺利发生(Entries 5, 6).而采用三苯基膦作膦试剂时, 可以顺利得到目标产物, 较之二苯基甲基膦为膦试剂时, 产率略低(Entry 7).接着考察了几种双膦试剂对反应的影响, 当使用双膦之间存在一个亚甲基的双(二苯基膦)甲烷(DPPM)时, 只得到痕量产物(Entry 8), 而采用其它两种双膦试剂1, 3-双(二苯基膦基)丙烷(DPPP)及1, 4-双(二苯基膦)丁烷(DPPB)时, 可以中等的产率得到氮杂Michael加成产物(Entries 9, 10).随后, 选择二苯基甲基膦为膦试剂, 通过筛选不同类型的溶剂对反应做进一步优化, 发现以1, 2-二氯乙烷(DCE)为最优的反应溶剂(Entries 11~22).考虑到在Staudinger反应中水可以促进氮杂叶立德的还原, 我们在反应中加入水作为混合溶剂, 很遗憾, 未得到更好的结果(Entry 23).但令人高兴的是, 将加入水的量降至等物质的量时, 反应的产率有明显提高(Entry 24), 与此同时, 将叔膦的量增至1.2 equiv.时, 最终产物可以核磁收率90%, 分离收率78%得到(Entry 25).因此确定最优条件为: 1.2 equiv.二苯基甲基膦介导, 1.0 equiv.水为添加剂, DCE为溶剂, 室温搅拌.

表 1

表 1 反应条件的优化^a

Table 1. Optimization of the reaction conditions

下载: 导出CSV


Entry	Phosphine	Solvent	Yield^b/%
1^c	Ph₂PMe	Toluene	46
2	Ph₂PMe	Toluene	69
3	Ph₂PEt	Toluene	44
4	PhPMe₂	Toluene	64
5	(ⁿBu)₃P	Toluene	Trace
6	(^tBu)₃P	Toluene	n. r.
7	Ph₃P	Toluene	65
8	DPPM	Toluene	Trace
9	DPPP	Toluene	68
10	DPPB	Toluene	65
11	Ph₂PMe	DCM	50
12	Ph₂PMe	DCE	75 (50)^f
13	Ph₂PMe	THF	62
14	Ph₂PMe	MeOH	20
15	Ph₂PMe	CH₃CN	43
16	Ph₂PMe	Acetone	41
17	Ph₂PMe	Dioxane	41
18	Ph₂PMe	CHCl₃	54
19	Ph₂PMe	PhCl	49
20	Ph₂PMe	o-Xylene	53
21	Ph₂PMe	p-Xylene	44
22	Ph₂PMe	m-Xylene	58
23	Ph₂PMe	H₂O/DCE	53
24^d	Ph₂PMe	DCE	86
25^e	Ph₂PMe	DCE	90 (78^f)
^a Reaction conditions: 1h (0.1 mmol), 2 (0.12 mmol), and phosphine (0.1 mmol) in the solvent specified (1 mL) at room temperature for 12 h. ^b ¹⁹F NMR yield with PhCF₃ as an internal standard. ^c Methyl acrylate (0.1 mmol) was added. ^d H₂O (0.1 mmol) was added. ^e H₂O (0.1 mmol) was added, Ph₂PMe (1.2 equiv.) was used. ^f Isolated yield. DPPM＝Bis(diphenylphosphino)methane. DPPP＝Bis(1, 3-diphenylphosphino)propane. DPPB＝1, 4-bis(diphenylphosphanyl) butane

1.2 底物普适性考察

在上述最优的条件下, 我们对三氟甲基取代的α, β-不饱和酮与叠氮乙酸甲酯的Staudinger/aza-Michael加成反应进行了底物的普适性考察(表 2).首先, 对α, β-不饱和酮苯环上的取代基进行考察.当苯环的对位引入给电子基(甲基、甲氧基、异丁基、苯基、甲巯基)时, 能以良好到优秀的产率得到目标产物(Entries 2~6).而苯基的对位引入吸电子基(氟、氯、溴、三氟甲氧基、三氟甲基、硝基、氰基、甲氧羰基、甲氧磺酰基)时, 反应效果略差(Entries 7~15).苯环上的取代基的位置对反应的收率没有明显的影响(Entries 16~20).而当苯环上有双吸电子基取代时, 反应也可发生, 但产率较低(Entries 21, 22).萘环和杂芳环(噻吩基、呋喃基、吡啶基)取代的α, β-不饱和酮也可以良好到优秀的产率得到3w~3z (Entries 23~26).令人高兴的是, 烷基(环己基)取代的α, β-不饱和酮也能顺利地发生反应, 以90%的产率得到Michael加成产物(Entry 27).在此反应条件下, 五氟乙基和七氟丙基取代的α, β-不饱和酮同样可以顺利地参与连续Staudinger/Michael加成反应(Entries 28, 29).除此之外, 苄基叠氮也可应用于此反应, 并表现出较好的反应活性(Entry 30).

表 2

表 2 底物范围^a

Table 2. Substrate scope

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Entry	1	R	R_f	3	Yield^b/%
1	1a	Ph	CF₃	3a	85
2	1b	4-MeC₆H₄	CF₃	3b	96
3	1c	4-iso-Butylphenyl	CF₃	3c	86
4	1d	4-MeOC₆H₄	CF₃	3d	85
5	1e	4-PhC₆H₄	CF₃	3e	81
6	1f	4-MeSC₆H₄	CF₃	3f	86
7	1g	4-FC₆H₄	CF₃	3g	75
8	1h	4-ClC₆H₄	CF₃	3h	78
9	1i	4-BrC₆H₄	CF₃	3i	71
10	1j	4-CF₃OC₆H₄	CF₃	3j	73
11	1k	4-CF₃C₆H₄	CF₃	3k	70
12	1l	4-O₂NC₆H₄	CF₃	3l	66
13	1m	4-NCC₆H₄	CF₃	3m	78
14	1n	4-MeO₂CC₆H₄	CF₃	3n	80
15	1o	4-MeO₂SC₆H₄	CF₃	3o	52
16	1p	2-NO₂C₆H₄	CF₃	3p	72
17	1q	3-NO₂C₆H₄	CF₃	3q	65
18	1r	2-BrC₆H₄	CF₃	3r	73
19	1s	3-BrC₆H₄	CF₃	3s	80
20	1t	2-MeOC₆H₄	CF₃	3t	75
21	1u	3, 4-Cl₂C₆H₃	CF₃	3u	68
22	1v	3, 5-(CF₃)₂C₆H₃	CF₃	3v	50
23	1w	2-Naphthyl	CF₃	3w	95
24	1x	2-Furyl	CF₃	3x	65
25	1y	2-Thienyl	CF₃	3y	92
26	1z	2-Pyridyl	CF₃	3z	80
27	1aa	Cyclohexyl	CF₃	3aa	90
28	1ba	Ph	C₂F₅	3ba	65
29	1ca	Ph	C₃F₇	3ca	62
30^c	1h	4-ClC₆H₄	CF₃	3da	72
^a Reactions were performed with 1 (0.3 mmol), 2 (0.36 mmol), and Ph₂PMe (0.36 mmol) in DCE (3.0 mL) at room temperature for 12 h. ^b Yield of isolated product. DCE＝1, 2-Dichloroethane. ^c BnN₃ was used instead of 2.

为了验证此合成方法的实用性和可靠性, 我们进行了克级规模制备实验(Scheme 2).我们以1a与叠氮乙酸甲酯为底物, 以80%的产率获得1.15 g目标产物, 与小量规模的反应收率相当.

图式 2

图式 2. 克级规模制备

Scheme 2. Gram-scale reaction

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1.3 控制实验

为了初步探究反应过程, 我们进行了一系列控制实验研究(Scheme 3).在DCE作溶剂, 碳酸钾作碱的条件下, 甘氨酸甲酯盐酸盐与α, β-不饱和酮发生反应, 以87%的核磁收率得到目标产物.由此控制实验结果可推测, 反应可能经历了叠氮化合物转化为氨基化合物的过程(Scheme 3A).

图式 3

图式 3. 控制实验

Scheme 3. Control experiments

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随后我们尝试了不同的氮杂叶立德与α, β-不饱和酮1h的反应, 当使用二苯基甲基膦与三苯基膦衍生的氮杂叶立德时, 反应可以顺利发生, 以优秀的产率得到目标产物(Schemes 3B, 3C).而三丁基膦衍生的氮杂叶立德参与反应时, 仅以5%的产率得到目标产物(Scheme 3D).这一实验结果与我们条件筛选所得结果一致.

1.4 ³¹P NMR监测实验

为了进一步了解此反应的过程, 我们进行了³¹P NMR监测实验.首先, 对二苯基甲基膦进行核磁共振磷谱测定(图 1a).然后, 将α, β-不饱和酮1h与二苯基甲基膦混合, 进行核磁共振磷谱监测(图 1b).最后, 将叠氮乙酸甲酯与二苯基甲基膦混合, 进行核磁共振磷谱监测(图 1c).通过对比, 我们发现叔膦与α, β-不饱和酮混合没有新的磷谱信号峰出现.而叠氮与叔膦混合时有新的信号峰出现.基于以上实验结果我们得出, 此反应的启动步骤是叠氮乙酸甲酯与叔膦的Staudinger反应.

图 1

图 1. (a) 二苯基甲基磷的核磁共振磷谱; (b) α, β-不饱和酮1h与二苯基甲基膦的核磁共振磷谱; (c)叠氮乙酸甲酯与二苯基甲基膦的核磁共振磷谱

Figure 1. ³¹P NMR spectra of Ph₂PMe (a), Ph₂PMe containing trifluoromethyl substituted α, β-unsaturated ketone (b), and Ph₂PMe containing methyl 2-azidoacetate (c)

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基于³¹P NMR监测实验, 控制实验与以往的工作^{[5, 6]}, 我们提出了两种可能的反应机理(Scheme 4).一种机理为叠氮化合物与叔膦发生Staudinger反应生成氮杂叶立德, 随后氮杂叶立德被还原为氨基, 最后发生氮杂Michael加成反应得到氢胺化产物(path A).另一种可能的机理为氮杂叶立德先对不饱和酮中的烯烃进行加成, 然后发生水解, 得到最终产物(path B).

图式 4

图式 4. 可能的反应机理

Scheme 4. Proposed reaction mechanisms

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2. 结论

报道了一种以叠氮为胺源的氢胺化反应, 实现了以三氟甲基取代的α, β-不饱和酮与叠氮化合物为反应物, 叔膦为媒介(还原剂)的连续Staudinger/Aza-Mi- chael加成反应, 以中等到优秀的产率得到氢胺化产物.同时, 此反应可实现克级规模制备, 仍能以良好的收率得到氢胺化产物.核磁共振磷谱实验说明了叠氮与叔膦的Staudinger反应是此氢胺化反应的启动步骤.

3. 实验部分

3.1 仪器与试剂

所有实验均在空气氛围中进行; 制备反应所需的原料与溶剂均为商品化的化学纯和分析纯试剂; 实验过程中利用薄层色谱对反应进行检测, 采用柱层析分离化合物; 所使用的柱层析硅胶来源于青岛海洋化工.实验过程中所有化合物的核磁共振谱图数据(¹H NMR, ¹³C NMR, ¹⁹F NMR和³¹P NMR)表征来自于Bruker AM-400或者Bruker AM-500型核磁共振波谱仪; 高分辨质谱数据来自于Waters GCT Premier.

3.2 实验方法

空气氛围下, 在20 mL Schlenk反应管中将α, β-不饱和酮1 (0.3 mmol)、叠氮化合物2 (0.3 mmol)、水(0.3 mmol)溶于1, 2-二氯乙烷中, 搅拌下向反应混合物中加入二苯基甲基膦.反应12 h后减压除去溶剂, 经柱层析纯化得到目标化合物.

N-[2-(1, 1, 1-三氟-4-氧代-4-苯基丁基)]-甘氨酸甲酯(3a):白色液体, 产率85%. ¹H NMR (500 MHz, CDCl₃) δ: 7.95 (d, J＝7.7 Hz, 2H), 7.60 (s, 1H), 7.48 (t, J＝7.6 Hz, 2H), 3.90~3.86 (m, 1H), 3.67 (s, 3H), 3.63 (d, J＝9.2 Hz, 2H), 3.30~3.28 (m, 2H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (125 MHz, CDCl₃) δ: 195.7, 172.0, 136.2, 133.7, 128.8, 128.3, 128.1, 126.6 (q, J＝282.4 Hz), 55.7 (q, J＝28.8 Hz), 51.9, 49.8, 38.6; HRMS (ESI) calcd for C₁₃H₁₄F₃NNaO₃ (M+Na⁺): 312.0818, found 312.0826.

N-(2-(1, 1, 1-三氟-4-(4-甲基苯基)-4-氧代丁基))甘氨酸甲酯(3b):黄色固体, 产率96%. m.p. 37~38 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (d, J＝8.2 Hz, 2H), 7.41~7.06 (m, 2H), 3.98~3.77 (m, 1H), 3.67 (s, 3H), 3.63 (d, J＝5.2 Hz, 2H), 3.27 (dd, J＝6.0, 3.1 Hz, 2H), 2.42 (s, 3H), 1.93 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 195.3, 172.1, 144.7, 133.8, 129.5, 128.3, 126.6 (q, J＝282.3 Hz), 55.7 (q, J＝28.7 Hz), 52.0, 51.9, 49.8, 38.4, 21.7, 21.7; HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₃ (M+Na⁺): 326.0974, found 326.0976.

N-(2-(1, 1, 1-三氟-4-(4-异丁基苯基)-4-氧代丁基))甘氨酸甲酯(3c):白色液体, 产率86%. ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (d, J＝8.1 Hz, 2H), 7.26 (t, J＝7.4 Hz, 2H), 3.88 (s, 1H), 3.67 (s, 3H), 3.64 (d, J＝4.8 Hz, 2H), 3.29~3.27 (m, 2H), 2.54 (d, J＝7.2 Hz, 2H), 2.01~1.80 (m, 2H), 0.91 (d, J＝6.6 Hz, 6H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 195.3, 172.1, 148.4, 134.0, 129.5, 128.2, 126.6 (q, J＝282.2 Hz), 55.7 (q, J＝28.7 Hz), 51.9, 49.9, 45.4, 38.4, 30.1, 22.3; HRMS (ESI) calcd for C₁₇H₂₂F₃NNaO₃ (M+Na⁺): 368.1444, found 368.1448.

N-(2-(1, 1, 1-三氟-4-(4-甲氧基苯基)-4-氧代丁基))甘氨酸甲酯(3d):黄色固体, 产率85%. m.p. 81~82 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.95~7.92 (m, 2H), 6.97~6.93 (m, 2H), 3.87 (d, J＝7.1 Hz, 4H), 3.68 (s, 3H), 3.62 (d, J＝5.9 Hz, 2H), 3.24 (dd, J＝6.0, 4.5 Hz, 2H), 1.94 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 194.1, 172.1 164.0, 130.5, 129.3, 127.9, 126.6 (q, J＝282.3 Hz). 113.9, 56.2, 55.9, 55.7, 55.5, 55.5, 55.4, 51.9, 51.9, 49.9, 38.1; HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₄ (M+Na⁺): 342.0924, found 342.0927.

N-(2-(1, 1, 1-三氟-4-(4-[1, 1'-联苯基])-4-氧代丁基))甘氨酸甲酯(3e):黄色固体, 产率81%. m.p. 110~111 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.01 (d, J＝8.2 Hz, 2H), 7.69 (d, J＝8.2 Hz, 2H), 7.62 (d, J＝7.4 Hz, 2H), 7.48~7.38 (m, 3H), 3.90 (s, 1H), 3.68 (s, 3H), 3.65 (d, J＝4.8 Hz, 2H), 3.33~3.31 (m, 2H), 1.97 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (100 MHz, CDCl₃) δ: 195.3, 172.1, 146.4, 139.6, 134.9, 129.1, 128.8, 128.5, 127.4, 127.3, 126.6 (q, J＝282.3 Hz), 55.7 (q, J＝28.8 Hz), 52.0, 49.9, 38.6; HRMS (ESI) calcd for C₁₉H₁₈F₃NNaO₃ (M+Na⁺): 388.1131, found 388.1135.

N-(2-(1, 1, 1-三氟-4-(4-甲硫基苯基)-4-氧代丁基))甘氨酸甲酯(3f):白色液体, 产率86%. ¹H NMR (500 MHz, CDCl₃) δ: 7.85 (d, J＝8.5 Hz, 2H), 7.28~7.26 (m, 2H), 3.88~3.85 (m, 1H), 3.68 (s, 3H), 3.62 (q, J＝17.6 Hz, 2H), 3.29~3.19 (m, 2H), 2.52 (s, 3H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (125 MHz, CDCl₃) δ: 194.6, 172.0, 146.9, 132.4, 128.5, 126.6 (q, J＝282.4 Hz), 125.0, 55.7 (q, J＝28.8 Hz), 52.0, 49.8, 38.3, 14.7. HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₃S (M+Na⁺): 358.0695, found 358.0701.

N-(2-(1, 1, 1-三氟-4-(4-氟苯基)-4-氧代丁基))甘氨酸甲酯(3g):黄色液体, 产率75%. ¹H NMR (400 MHz, CDCl₃) δ: 7.99 (dd, J＝8.4, 5.5 Hz, 2H), 7.16 (t, J＝8.5 Hz, 2H), 3.87 (s, 1H), 3.69 (s, 3H), 3.63 (d, J＝6.9 Hz, 2H), 3.27 (d, J＝5.2 Hz, 2H), 1.93 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3, -104.0; ¹³C NMR (100 MHz, CDCl₃) δ: 194.1, 172.1, 166.1 (d, J＝255.9 Hz), 132.7 (d, J＝3.0 Hz), 130.9 (d, J＝9.5 Hz), 126.5 (q, J＝282.5 Hz), 116.0 (d, J＝22.0 Hz), 55.7 (q, J＝28.7 Hz), 52.0, 52.0, 49.0, 38.5; HRMS (ESI) calcd for C₁₃H₁₃F₄NNaO₃ (M+Na⁺): 330.0724, found 330.0728.

N-(2-(1, 1, 1-三氟-4-(4-氯苯基)-4-氧代丁基))甘氨酸甲酯(3h):黄色液体, 产率78%. ¹H NMR (400 MHz, CDCl₃) δ: 7.90 (d, J＝8.2 Hz, 2H), 7.46 (d, J＝8.1 Hz, 2H), 3.87 (s, 1H), 3.69 (s, 3H), 3.62 (t, J＝12.9 Hz, 2H), 3.27 (d, J＝5.9 Hz, 2H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 194.5, 172.1, 140.3, 134.5, 129.6, 129.1, 126.5 (q, J＝282.6 Hz), 55.6 (q, J＝28.8 Hz), 52.0, 49.8, 38.6; HRMS (ESI) calcd for C₁₃H₁₃F₃ClNNaO₃ (M+Na⁺): 346.0428, found 346.0433.

N-(2-(1, 1, 1-三氟-4-(4-溴苯基)-4-氧代丁基))甘氨酸甲酯(3i):黄色液体, 产率71%. ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (d, J＝8.5 Hz, 2H), 7.63 (d, J＝8.4 Hz, 2H), 3.86 (dd, J＝7.6, 4.7 Hz, 1H), 3.69 (s, 3H), 3.61 (t, J＝13.1 Hz, 2H), 3.26 (d, J＝5.7 Hz, 2H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 194.8, 172.1, 134.9, 132.1, 129.7, 129.0, 126.5 (q, J＝282.5 Hz), 56.1, 55.8, 55.6 (q, J＝28.8 Hz), 55.5, 55.2, 52.0, 49.8, 38.6. HRMS (ESI) calcd for C₁₃H₁₃BrF₃-NNaO₃ (M+Na⁺): 389.9923, found 389.9927.

N-(2-(1, 1, 1-三氟-4-(4-三氟甲氧基苯基)-4-氧代丁基))甘氨酸甲酯(3j):黄色液体, 产率73%. ¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J＝8.1 Hz, 2H), 7.75 (d, J＝8.2 Hz, 2H), 3.88 (dd, J＝13.5, 6.3 Hz, 1H), 3.68 (s, 3H), 3.61 (t, J＝15.7 Hz, 2H), 3.31 (d, J＝6.0 Hz, 2H), 1.89 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -63.2, -75.3; ¹³C NMR (125 MHz, CDCl₃) δ: 194.9, 194.9, 172.1, 138.9, 134.9 (q, J＝32.8 Hz), 128.5, 126.4 (q, J＝282.6 Hz), 125.9 (q, J＝3.7 Hz), 123.5 (q, J＝272.8 Hz), 55.6 (q, J＝28.9 Hz), 52.0, 49.7, 39.1, 39.0. HRMS (ESI) calcd for C₁₄H₁₃F₆NNaO₃ (M+Na⁺): 380.0692, found 380.0691.

N-(2-(1, 1, 1-三氟-4-(4-三氟甲基苯基)-4-氧代丁基))甘氨酸甲酯(3k):黄色固体, 产率70%. m.p. 45~46 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J＝8.1 Hz, 2H), 7.75 (d, J＝8.2 Hz, 2H), 3.88 (dd, J＝13.5, 6.3 Hz, 1H), 3.68 (s, 3H), 3.61 (t, J＝15.7 Hz, 2H), 3.31 (d, J＝6.0 Hz, 2H), 1.89 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -63.24, -75.29; ¹³C NMR (126 MHz, CDCl₃) δ: 194.92, 194.87, 172.10, 138.87, 134.94 (q, J＝32.8 Hz), 128.50, 126.40 (q, J＝282.6 Hz), 125.87 (q, J＝3.7 Hz), 123.45 (q, J＝272.8 Hz), 55.64 (q, J＝28.9 Hz), 51.98, 49.72, 39.05, 39.04. HRMS (ESI) calcd for C₁₄H₁₃F₆NNaO₃ (M+Na⁺): 380.0692, found 380.0691.

N-(2-(1, 1, 1-三氟-4-(4-硝基苯基)-4-氧代丁基))甘氨酸甲酯(3l):黄色液体, 产率66%. ¹H NMR (500 MHz, CDCl₃) δ: 8.34 (d, J＝8.7 Hz, 2H), 8.13 (d, J＝8.7 Hz, 2H), 3.90 (dd, J＝12.9, 6.9 Hz, 1H), 3.69 (s, 3H), 3.66~3.59 (m, 2H), 3.35 (d, J＝5.7 Hz, 2H), 1.91 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ:-75.2; ¹³C NMR (126 MHz, CDCl₃) δ: 194.4, 172.1, 150.6, 140.6, 129.2, 126.3 (q, J＝282.8 Hz), 124.0, 55.6 (q, J＝29.0 Hz), 52.0, 49.7, 39.4. HRMS (ESI) calcd for C₁₃H₁₃F₃N₂NaO₅ (M+Na⁺): 357.0669, found 357.0670.

N-(2-(1, 1, 1-三氟-4-(4-氰基苯基)-4-氧代丁基))甘氨酸甲酯(3m):黄色液体, 产率78%. ¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d, J＝8.2 Hz, 2H), 7.80 (d, J＝8.2 Hz, 2H), 3.89~3.86 (m, 1H), 3.69 (s, 3H), 3.65~3.58 (m, 2H), 3.30 (d, J＝6.0 Hz, 2H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (125 MHz, CDCl₃) δ: 194.6, 172.1, 139.1, 132.7, 130.9, 128.6, 126.3 (q, J＝282.7 Hz), 117.7, 117.0, 55.6 (q, J＝29.0 Hz), 52.0, 49.7, 39.1. HRMS (ESI) calcd for C₁₄H₁₃F₃N₂NaO₃ (M+Na⁺): 337.0770, found 337.0773.

N-(2-(1, 1, 1-三氟-4-(4-甲酸甲酯苯基)-4-氧代丁基))甘氨酸甲酯(3n):黄色固体, 产率80%. m.p. 89~90 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.14 (d, J＝8.3 Hz, 2H), 8.01 (d, J＝8.4 Hz, 2H), 3.96 (s, 3H), 3.89 (dd, J＝13.4, 6.7 Hz, 1H), 3.68 (s, 3H), 3.62 (t, J＝12.9 Hz, 2H), 3.32 (d, J＝6.1 Hz, 2H), 1.93 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 195.3, 172.1, 166.0, 139.4, 134.4, 130.0, 128.1, 126.5 (q, J＝282.6 Hz), 55.7 (q, J＝28.8 Hz), 52.5, 52.5, 52.0, 49.7, 39.1. HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₄ (M+Na⁺): 342.0924, found 342.0927.

N-(2-(1, 1, 1-三氟-4-(4-甲基磺酰基苯基)-4-氧代丁基))甘氨酸甲酯(3o):白色液体, 产率52%. ¹H NMR (500 MHz, CDCl₃) δ: 8.10 (dd, J＝32.0, 8.4 Hz, 4H), 3.92~3.87 (m, 1H), 3.70 (s, 3H), 3.66~3.59 (m, 2H), 3.35~3.34 (m, 2H), 3.10 (s, 3H), 1.93 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (125 MHz, CDCl₃) δ: 194.7, 172.1, 144.7 140.1, 129.7, 129.0, 128.1, 128.0, 126.4 (q, J＝282.7 Hz), 55.6 (q, J＝29.0 Hz), 52.0, 49.7, 44.3, 39.3. HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₅S (M+Na⁺): 390.0593, found 390.0599.

N-(2-(1, 1, 1-三氟-4-(2-硝基苯基)-4-氧代丁基))甘氨酸甲酯(3p):白色液体, 产率72%. ¹H NMR (500 MHz, CDCl₃) δ: 8.16 (d, J＝8.2 Hz, 1H), 7.78 (t, J＝7.4 Hz, 1H), 7.66 (dd, J＝11.5, 4.1 Hz, 1H), 7.52 (d, J＝7.5 Hz, 1H), 3.88-3.84 (m, 1H), 3.75 (s, 3H), 3.66 (q, J＝17.4 Hz, 2H), 3.22 (dd, J＝17.5, 3.1 Hz, 1H), 3.08 (dd, J＝17.5, 9.4 Hz, 1H), 2.03 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ:-75.3; ¹³C NMR (125 MHz, CDCl₃) δ: 198.4, 172.0, 145.4, 137.2, 134.6, 131.0, 127.6, 126.2 (q, J＝282.9 Hz), 124.5, 55.7 (q, J＝29.1 Hz), 52.0, 49.7, 42.7, 42.7. HRMS (ESI) calcd for C₁₃H₁₃F₃N₂NaO₅ (M+Na⁺): 357.0669, found 357.0675.

N-(2-(1, 1, 1-三氟-4-(3-硝基苯基)-4-氧代丁基))甘氨酸甲酯(3q):白色液体, 产率65%. ¹H NMR (500 MHz, CDCl₃) δ: 8.78 (s, 1H), 8.47 (d, J＝8.1 Hz, 1H), 8.29 (d, J＝7.7 Hz, 1H), 7.73 (t, J＝8.0 Hz, 1H), 3.94~3.89 (m, 1H), 3.70 (s, 3H), 3.66~3.60 (m, 2H), 3.41~3.32 (m, 2H), 1.93 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (125 MHz, CDCl₃) δ: 193.8, 172.1, 148.5, 137.5, 133.6, 130.1, 127.9, 126.3 (q, J＝282.7 Hz), 123.1, 55.6 (q, J＝29.0 Hz), 52.0, 49.7, 39.1. HRMS (ESI) calcd for C₁₃H₁₃F₃N₂NaO₅ (M+Na⁺): 357.0669, found 357.0673.

N-(2-(1, 1, 1-三氟-4-(2-溴苯基)-4-氧代丁基))甘氨酸甲酯(3r):黄色液体, 产率73%. ¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, J＝7.9 Hz, 1H), 7.46 (dd, J＝7.6, 1.6 Hz, 1H), 7.42~7.38 (m, 1H), 7.35~7.31 (m, 1H), 3.83 (s, 1H), 3.73 (s, 3H), 3.62 (q, J＝17.3 Hz, 2H), 3.34~3.19 (m, 2H), 1.96 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (100 MHz, CDCl₃) δ: 199.6, 172.0, 140.6, 133.8, 132.2, 129.0, 127.6, 126.3 (q, J＝283.0 Hz), 118.7, 100.0, 55.9 (q, J＝29.0 Hz), 52.0, 52.0, 49.6, 42.6. HRMS (ESI) calcd for C₁₄H₁₃F₃N₂NaO₃ (M+Na⁺): 337.0770, found 337.0773. HRMS (ESI) calcd for C₁₃H₁₃BrF₃NNaO₃ (M+Na⁺): 389.9923, found 389.9934.

N-(2-(1, 1, 1-三氟-4-(3-溴苯基)-4-氧代丁基))甘氨酸甲酯(3s):黄色液体, 产率80%. ¹H NMR (400 MHz, CDCl₃) δ: 8.08 (s, 1H), 7.87 (d, J＝7.8 Hz, 1H), 7.73 (d, J＝7.9 Hz, 1H), 7.37 (t, J＝7.9 Hz, 1H), 3.87 (dd, J＝13.3, 6.6 Hz, 1H), 3.69 (s, 3H), 3.61 (t, J＝13.2 Hz, 2H), 3.27 (d, J＝6.0 Hz, 2H), 1.91 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (100 MHz, CDCl₃) δ: 194.4, 172.1, 137.9, 136.6, 131.2, 130.4, 126.7, 126.5 (q, J＝282.6 Hz), 123.2, 55.6 (q, J＝28.5 Hz), 52.0, 52.0, 49.8, 38.8. HRMS (ESI) calcd for C₁₃H₁₃BrF₃NNaO₃ (M+Na⁺): 389.9923, found 389.9934.

N-(2-(1, 1, 1-三氟-4-(2-甲氧基苯基)-4-氧代丁基))甘氨酸甲酯(3t):白色液体, 产率75%. ¹H NMR (500 MHz, CDCl₃) δ: 7.75 (dd, J＝7.7, 1.7 Hz, 1H), 7.52~7.48 (m, 1H), 7.03~6.98 (m, 2H), 3.93 (s, 3H), 3.85~3.81 (m, 1H), 3.68 (s, 3H), 3.59 (q, J＝17.3 Hz, 2H), 3.36 (dd, J＝17.4, 3.2 Hz, 1H), 3.25 (dd, J＝17.4, 9.3 Hz, 1H), 1.98 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.5; ¹³C NMR (125 MHz, CDCl₃) δ: 197.7, 172.0, 158.8, 134.3, 130.7, 127.1, 126.6 (q, J＝282.4 Hz), 120.8, 111.6, 55.9 (q, J＝28.7 Hz), 55.5, 51.9, 49.8, 43.4, 43.4. HRMS (ESI) calcd for C₁₄H₁₆F₃NNaO₄ (M+Na⁺): 342.0924, found 342.0927.

N-(2-(1, 1, 1-三氟-4-(3, 4-二氯苯基)-4-氧代丁基))甘氨酸甲酯(3u):黄色液体, 产率68%. ¹H NMR (500 MHz, CDCl₃) δ: 8.03 (d, J＝2.0 Hz, 1H), 7.77 (dd, J＝8.4, 2.0 Hz, 1H), 7.57 (d, J＝8.4 Hz, 1H), 3.87 (dd, J＝13.4, 6.5 Hz, 1H), 3.69 (s, 3H), 3.62 (q, J＝17.5 Hz, 2H), 3.25 (d, J＝6.0 Hz, 2H), 1.90 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.3; ¹³C NMR (125 MHz, CDCl₃) δ: 193.6, 172.1, 138.4, 135.8, 133.6, 130.9, 130.1, 127.1, 126.4 (q, J＝282.7 Hz), 55.6 (q, J＝28.9 Hz), 52.0, 49.7, 38.8. HRMS (ESI) calcd for C₁₃H₁₂Cl₂F₃NNaO₃ (M+Na⁺): 380.0039, found 380.0041.

N-(2-(1, 1, 1-三氟-4-(3, 5-二三氟甲基苯基)-4-氧代丁基))甘氨酸甲酯(3v):黄色液体, 产率50%. ¹H NMR (500 MHz, CDCl₃) δ: 8.91~7.99 (m, 3H), 4.57~3.03 (m, 8H), 1.92 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -63.0, -75.2; ¹³C NMR (125 MHz, CDCl₃) δ: 193.2, 172.2, 137.7, 133.4-132.0 (m), 128.2, 126.8, 127.6-119.3 (m), 55.6 (q, J＝29.5 Hz), 52.0, 49.7, 39.2. HRMS (ESI) calcd for C₁₅H₁₃F₉NNaO₃ (M+H⁺): 426.0746, found 426.0750.

N-(2-(1, 1, 1-三氟-4-(2-萘基)-4-氧代丁基))甘氨酸甲酯(3w):白色固体, 产率95%. m.p. 90~91 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.45 (s, 1H), 8.02~7.95 (m, 2H), 7.90~7.86 (m, 2H), 7.64~7.55 (m, 2H), 3.96~3.93 (m, 1H), 3.67~3.62 (m, 5H), 3.43 (d, J＝5.7 Hz, 2H), 1.98 (d, J＝4.5 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.2; ¹³C NMR (100 MHz, CDCl₃) δ: 195.6, 172.1, 135.8, 133.6, 132.4, 130.1, 129.7, 128.9, 128.7, 127.8, 127.0, 126.6 (q, J＝282.3 Hz), 126.5, 124.1, 123.6, 56.3~55.7 (m), 52.0, 52.0, 49.9, 38.6. HRMS (ESI) calcd for C₁₇H₁₆F₃NNaO₃ (M+Na⁺): 362.0974, found 362.0976.

N-(2-(1, 1, 1-三氟-4-(2-呋喃基)-4-氧代丁基))甘氨酸甲酯(3x):白色固体, 产率65%. m.p. 38~39 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.63 (d, J＝1.0 Hz, 1H), 7.29~7.26 (m, 1H), 6.58 (dd, J＝3.6, 1.7 Hz, 1H), 3.87~3.81 (m, 1H), 3.69 (s, 3H), 3.61 (q, J＝17.5 Hz, 2H), 3.16 (d, J＝6.3 Hz, 2H), 1.94 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.5; ¹³C NMR (100 MHz, CDCl₃) δ: 184.7, 172.0, 152.3, 146.9, 126.4 (q, J＝282.7 Hz), 117.9, 112.6, 55.5 (q, J＝29.3 Hz), 52.0, 51.9, 49.6, 38.2. HRMS (ESI) calcd for C₁₁H₁₂F₃NNaO₄ (M+Na⁺): 302.0611, found 302.0611.

N-(2-(1, 1, 1-三氟-4-(2-噻吩基)-4-氧代丁基))甘氨酸甲酯(3y):黄色固体, 产率92%. m.p. 52~53 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.75 (dd, J＝3.8, 0.9 Hz, 1H), 7.70 (dd, J＝4.9, 0.9 Hz, 1H), 7.16 (dd, J＝4.8, 3.9 Hz, 1H), 3.86 (d, J＝5.6 Hz, 1H), 3.68 (s, 3H), 3.61 (d, J＝8.8 Hz, 2H), 3.23 (dd, J＝6.1, 4.6 Hz, 2H), 1.97 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.4; ¹³C NMR (100 MHz, CDCl₃) δ: 188.5, 172.0, 143.5, 134.7, 132.6, 126.4 (q, J＝282.6 Hz), 128.4, 77.4, 55.8 (q, J＝28.8 Hz), 52.0, 51.9, 49.7, 39.1, 39.1. HRMS (ESI) calcd for C₁₁H₁₂F₃NNaO₃S (M+Na⁺): 318.0382, found 318.0383.

N-(2-(1, 1, 1-三氟-4-(2-吡啶基)-4-氧代丁基))甘氨酸甲酯(3z):白色液体, 产率80%. ¹H NMR (500 MHz, CDCl₃) δ: 8.69 (d, J＝4.5 Hz, 1H), 8.07 (d, J＝7.8 Hz, 1H), 7.88~7.84 (m, 1H), 7.52~7.50 (m, 1H), 3.98~3.84 (m, 1H), 3.68~3.55 (m, 6H), 3.45 (dd, J＝17.2, 3.3 Hz, 1H), 2.06 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.4; ¹³C NMR (125 MHz, CDCl₃) δ: 197.7, 172.0, 152.7, 149.1, 137.0, 127.6, 126.6 (q, J＝282.8 Hz), 122.0, 55.9 (q, J＝28.9 Hz), 51.8, 49.5, 37.6, 37.6. HRMS (ESI) calcd for C₁₂H₁₃F₃N₂NaO₃ (M+Na⁺): 313.0770, found 313.0776.

N-(2-(1, 1, 1-三氟-4-环己基-4-氧代丁基))甘氨酸甲酯(3aa):白色液体, 产率90%. ¹H NMR (400 MHz, CDCl₃) δ: 3.72 (s, 3H), 3.69~3.51 (m, 3H), 2.83~2.68 (m, 2H), 2.39~2.33 (m, 1H), 1.88~1.81 (m, 5H), 1.68 (d, J＝11.1 Hz, 1H), 1.39~1.18 (m, 5H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -75.4; ¹³C NMR (100 MHz, CDCl₃) δ: 209.6, 172.1, 126.5 (q, J＝282.4 Hz), 55.4 (q, J＝28.9 Hz), 52.0, 51.9, 51.1, 49.7, 40.4, 28.2, 28.1, 25.7, 25.5, 25.5. HRMS (ESI) calcd for C₁₃H₂₀F₃NNaO₃ (M+Na⁺): 318.1287, found 318.1289.

N-(2-(1, 1, 1, 2, 2-五氟-5-苯基-5-氧代戊基))甘氨酸甲酯(3ba):黄色固体, 产率65%. m.p. 42~43 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J＝7.5 Hz, 2H), 7.61 (t, J＝7.4 Hz, 1H), 7.49 (t, J＝7.6 Hz, 2H), 4.06 (d, J＝9.3 Hz, 1H), 3.61 (d, J＝14.1 Hz, 5H), 3.36 (d, J＝5.8 Hz, 2H), 1.78 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -80.8 (s), -117.4 (d, J＝274.1 Hz), -124.8 (d, J＝274.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ: 195.9, 172.3, 136.3, 133.7, 128.8, 128.1, 120.7 (t, J＝36.2 Hz), 118.1~117.5 (m), 115.4 (d, J＝35.5 Hz), 54.9~54.4 (m), 52.0, 51.9, 49.6, 38.2. HRMS (ESI) calcd for C₁₄H₁₄F₅NNaO₃ (M+Na⁺): 362.0786, found 362.0793.

N-(2-(1, 1, 1, 2, 2, 3, 3-七氟-6-苯基-6-氧代己基))甘氨酸甲酯(3ca):黄色固体, 产率62%. m.p. 45~46 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J＝7.4 Hz, 2H), 7.62~7.47 (m, 3H), 4.15~4.11 (m, 1H), 3.61 (d, J＝8.6 Hz, 5H), 3.37 (d, J＝5.1 Hz, 2H), 1.76 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -80.9 (dd, J＝11.3, 9.1 Hz), -114.8~-115.6 (m), -121.1~121.9 (m), -123.6~125.9 (m); ¹³C NMR (125 MHz, CDCl₃) δ: 195.9, 172.4, 136.3, 133.7, 128.8, 128.1, 121.2 (d, J＝34.3 Hz), 119.1 (dd, J＝49.0, 19.3 Hz), 116.8 (dd, J＝62.0, 31.7 Hz), 114.8 (dd, J＝59.9, 29.2 Hz), 111.8 (dd, J＝73.3, 37.5 Hz), 109.7 (dd, J＝74.2, 36.7 Hz), 107.6 (dd, J＝73.6, 37.6 Hz), 55.0 (dd, J＝25.3, 21.5 Hz), 51.9, 49.6, 38.4. HRMS (ESI) calcd for C₁₅H₁₄F₇NNaO₃ (M+Na⁺): 412.0754, found 412.0760.

3-(苄基氨基)-4, 4, 4-三氟-1-(4-氯苯基)丁-1-酮(3da):白色液体, 产率72%. ¹H NMR (400 MHz, CDCl₃) δ: 7.87~7.84 (m, 2H), 7.45~7.42 (m, 2H), 7.27~7.20 (m, 5H), 4.01~3.88 (m, 3H), 3.26~3.13 (m, 2H), 1.58 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ: -74.4; ¹³C NMR (100 MHz, CDCl₃) δ: 194.9, 140.2, 139.4, 134.8, 129.6, 129.1, 128.4, 128.3, 127.3, 126.8 (q, J＝283.7 Hz), 55.7 (q, J＝28.5 Hz), 52.5, 38.5. HRMS (ESI) calcd for C₁₇H₁₅ClF₃NNaO (M+Na⁺): 364.0686, found 364.0688.

辅助材料(Supporting Information) 产物的¹H NMR、¹³C NMR、¹⁹F NMR核磁表征谱图与产物1d的单晶数据.这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

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  CCDC 1920161包含化合物3d的晶体学数据.这些数据可以从"The Cambridge Crystallographic Data Centre"免费获得.

图式 1 Staudinger反应

Scheme 1 Staudinger reaction

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图式 2 克级规模制备

Scheme 2 Gram-scale reaction

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图式 3 控制实验

Scheme 3 Control experiments

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图 1 (a) 二苯基甲基磷的核磁共振磷谱; (b) α, β-不饱和酮1h与二苯基甲基膦的核磁共振磷谱; (c)叠氮乙酸甲酯与二苯基甲基膦的核磁共振磷谱

Figure 1 ³¹P NMR spectra of Ph₂PMe (a), Ph₂PMe containing trifluoromethyl substituted α, β-unsaturated ketone (b), and Ph₂PMe containing methyl 2-azidoacetate (c)

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图式 4 可能的反应机理

Scheme 4 Proposed reaction mechanisms

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表 1 反应条件的优化^a

Table 1. Optimization of the reaction conditions


Entry	Phosphine	Solvent	Yield^b/%
1^c	Ph₂PMe	Toluene	46
2	Ph₂PMe	Toluene	69
3	Ph₂PEt	Toluene	44
4	PhPMe₂	Toluene	64
5	(ⁿBu)₃P	Toluene	Trace
6	(^tBu)₃P	Toluene	n. r.
7	Ph₃P	Toluene	65
8	DPPM	Toluene	Trace
9	DPPP	Toluene	68
10	DPPB	Toluene	65
11	Ph₂PMe	DCM	50
12	Ph₂PMe	DCE	75 (50)^f
13	Ph₂PMe	THF	62
14	Ph₂PMe	MeOH	20
15	Ph₂PMe	CH₃CN	43
16	Ph₂PMe	Acetone	41
17	Ph₂PMe	Dioxane	41
18	Ph₂PMe	CHCl₃	54
19	Ph₂PMe	PhCl	49
20	Ph₂PMe	o-Xylene	53
21	Ph₂PMe	p-Xylene	44
22	Ph₂PMe	m-Xylene	58
23	Ph₂PMe	H₂O/DCE	53
24^d	Ph₂PMe	DCE	86
25^e	Ph₂PMe	DCE	90 (78^f)
^a Reaction conditions: 1h (0.1 mmol), 2 (0.12 mmol), and phosphine (0.1 mmol) in the solvent specified (1 mL) at room temperature for 12 h. ^b ¹⁹F NMR yield with PhCF₃ as an internal standard. ^c Methyl acrylate (0.1 mmol) was added. ^d H₂O (0.1 mmol) was added. ^e H₂O (0.1 mmol) was added, Ph₂PMe (1.2 equiv.) was used. ^f Isolated yield. DPPM＝Bis(diphenylphosphino)methane. DPPP＝Bis(1, 3-diphenylphosphino)propane. DPPB＝1, 4-bis(diphenylphosphanyl) butane

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表 2 底物范围^a

Table 2. Substrate scope


Entry	1	R	R_f	3	Yield^b/%
1	1a	Ph	CF₃	3a	85
2	1b	4-MeC₆H₄	CF₃	3b	96
3	1c	4-iso-Butylphenyl	CF₃	3c	86
4	1d	4-MeOC₆H₄	CF₃	3d	85
5	1e	4-PhC₆H₄	CF₃	3e	81
6	1f	4-MeSC₆H₄	CF₃	3f	86
7	1g	4-FC₆H₄	CF₃	3g	75
8	1h	4-ClC₆H₄	CF₃	3h	78
9	1i	4-BrC₆H₄	CF₃	3i	71
10	1j	4-CF₃OC₆H₄	CF₃	3j	73
11	1k	4-CF₃C₆H₄	CF₃	3k	70
12	1l	4-O₂NC₆H₄	CF₃	3l	66
13	1m	4-NCC₆H₄	CF₃	3m	78
14	1n	4-MeO₂CC₆H₄	CF₃	3n	80
15	1o	4-MeO₂SC₆H₄	CF₃	3o	52
16	1p	2-NO₂C₆H₄	CF₃	3p	72
17	1q	3-NO₂C₆H₄	CF₃	3q	65
18	1r	2-BrC₆H₄	CF₃	3r	73
19	1s	3-BrC₆H₄	CF₃	3s	80
20	1t	2-MeOC₆H₄	CF₃	3t	75
21	1u	3, 4-Cl₂C₆H₃	CF₃	3u	68
22	1v	3, 5-(CF₃)₂C₆H₃	CF₃	3v	50
23	1w	2-Naphthyl	CF₃	3w	95
24	1x	2-Furyl	CF₃	3x	65
25	1y	2-Thienyl	CF₃	3y	92
26	1z	2-Pyridyl	CF₃	3z	80
27	1aa	Cyclohexyl	CF₃	3aa	90
28	1ba	Ph	C₂F₅	3ba	65
29	1ca	Ph	C₃F₇	3ca	62
30^c	1h	4-ClC₆H₄	CF₃	3da	72
^a Reactions were performed with 1 (0.3 mmol), 2 (0.36 mmol), and Ph₂PMe (0.36 mmol) in DCE (3.0 mL) at room temperature for 12 h. ^b Yield of isolated product. DCE＝1, 2-Dichloroethane. ^c BnN₃ was used instead of 2.

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沈阳化工大学材料科学与工程学院沈阳 110142