铟粉促进下“一锅法”合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物

引用本文: 李军, 黄丹凤, 张怀远, 张兴虎, 王娟娟, 王克虎, 苏瀛鹏, 胡雨来. 铟粉促进下“一锅法”合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物[J]. 有机化学, 2017, 37(11): 2985-2992. doi: 10.6023/cjoc201703050 shu

Citation: Li Jun, Huang Danfeng, Zhang Huaiyuan, Zhang Xinghu, Wang Juanjuan, Wang Ke-Hu, Su Yingpeng, Hu Yulai. Indium-Promoted Preparation of α-Methylene-γ-trifluoromethyl-γ-lactams via One-Pot Reaction[J]. Chinese Journal of Organic Chemistry, 2017, 37(11): 2985-2992. doi: 10.6023/cjoc201703050 shu

铟粉促进下“一锅法”合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物

西北师范大学化学化工学院兰州 730070

通讯作者: 黄丹凤, huangdf@nwnu.edu.cn; 胡雨来, huyl@nwnu.edu.cn

基金项目:

国家自然科学基金（Nos.21662030，21462037）资助项目

摘要: 探索了铟粉促进下，三氟乙醛甲基半缩醛或三氟苯乙酮与酰肼、2-（溴甲基）丙烯酸乙酯的"一锅法"反应，得到了一系列α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物.该方法使用价廉易得的三氟乙醛甲基半缩醛或三氟苯乙酮作为三氟甲基合成砌块，反应条件温和、产率高、操作简单，为合成含三氟甲基的α-亚甲基-γ-丁内酰胺化合物提供了一种新方法.

关键词:

English

Indium-Promoted Preparation of α-Methylene-γ-trifluoromethyl-γ-lactams via One-Pot Reaction

College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070

Corresponding author: Huang Danfeng, E-mail: huangdf@nwnu.edu.cn; Hu Yulai, huyl@nwnu.edu.cn

Received Date: 30 March 2017
Revised Date: 03 July 2017
Available Online: 25 November 2017
Fund Project:

Project supported by the National Natural Science Foundation of China (Nos. 21662030, 21462037)

Abstract: An one-pot reaction of trifluoroacetaldehyde methyl hemiacetal or trifluoroketones, acylhydrazines and ethyl 2-(bromomethyl)acrylate promoted by indium powder has been investigated and a series of α-methylene-γ-trifluoromethyl-γ-lactams were obtained with high yieds. The features of this process include readily available starting materials as trifluoromethyl source, mild conditions and easy operation. The reaction provides a new method for the snythesis of trifluoromethylated α-methylene-γ-lactams.

Key words:

one-pot
/ indium powder
/ trifluoroacetaldehyde methyl hemiacetal
/ trifluoroketone
/ 2-(bromomethyl) acrylate
/ arylacylhydrazine
/ α-methylene-γ-trifluoromethyl-γ-lactams

α-亚甲基-γ-丁内酰胺及其衍生物广泛存在于具有生物活性的天然产物及药物的结构之中^[1~3].它和α-亚甲基-γ-丁内酯在抗菌、抗炎和抗过敏方面具有相似的性质^[2], 但是其毒副作用比后者小, 更适用于抗癌、抗肿瘤以及消炎药物的合成与临床应用.因此, 如何获得α-亚甲基-γ-丁内酰胺化合物备受化学家和药物学家的青睐.目前, 除了从天然产物分离得到这类物质外, 人们已发展了各种合成α-亚甲基-γ-丁内酰胺的方法^[3], 如分子内的Baylis-Hillman反应^{[1a, 4]}、Baylis-Hillman醇及其衍生物作为前体参与的反应^{[2a, 5]}、Wittig或Horner-Wadsworth-Emmons反应^[6]、过渡金属试剂对亚胺的加成^[7]以及自由基反应^[8]等.其中, 烯丙基有机金属试剂对亚胺的加成是合成α-亚甲基-γ-丁内酰胺的一种颇具吸引力的方法.例如, 金属锌^{[5e, 9]}、铟^[10]和锡^[11]促进的烯丙基化反应和有机硼试剂^[12]与亚胺的反应都已成功得到了α-亚甲基-γ-丁内酰胺化合物.

另外, 向有机物分子中引入强吸电子的三氟甲基团可以极大地改变有机化合物的理化性质及生理活性^[13].例如, 含三氟甲基的药物分子往往具有好的亲油性和抗新陈代谢氧化的稳定性, 增强了其生物利用度, 因此在药物或潜在的药物分子中引入三氟甲基基团具有重要意义.通常, 向有机分子中引入三氟甲基的方法主要有两种:三氟甲基试剂法和三氟甲基合成砌块法^[13~15].本小组^[16]致力于使用价廉易得的三氟甲基试剂或三氟甲基砌块作为氟源, 构建了一系列三氟甲基化合物.在我们^[17]探索铟粉促进下“一锅法”合成三氟甲基高烯丙基酰肼化合物的工作基础上, 在铟粉促进下, 以三氟乙醛甲基半缩醛或三氟苯乙酮为三氟甲基合成砌块, 通过它与酰肼、2-(溴甲基)丙烯酸乙酯的“一锅法”环化反应, 提供了一种制备含三氟甲基的α-亚甲基-γ-丁内酰胺化合物的新方法, 特别是通过该反应构筑了一个含三氟甲基的叔碳中心, 为进一步探索催化不对称合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物奠定了基础.

1 结果与讨论

1.1 铟粉促进下以三氟乙醛甲基半缩醛为三氟甲基合成砌块的“一锅法”反应

在铟粉促进下, 由三氟乙醛甲基半缩醛、苯甲酰肼和烯丙基溴的“一锅法”反应^[17]制备三氟甲基高烯丙基酰肼化合物的工作基础上, 我们用2-(溴甲基)丙烯酸乙酯代替烯丙基溴, 尝试了铟粉促进下三氟乙醛甲基半缩醛1、苯甲酰肼(2a)和2-(溴甲基)丙烯酸乙酯(3)的“一锅法”反应.结果发现, 在四氢呋喃溶剂中回流条件下, 得到了预期产物4a, 产率为68%.当反应在乙醇^[18]溶剂中进行时, 4a的产率可达81%(表 1, Entry 1).然后, 在此条件下, 我们探索了其他酰肼对该反应的适用性(Eq. 1), 结果见表 1.

表 1 酰肼的适用范围^a Table 1. Substrate scope of acylhydrazines

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Entry	R¹	Product	Isolated yield/%
1	C₆H₅	4a	81
2	o-MeC₆H₄	4b	Trace
3	m-MeC₆H₄	4c	51
4	p-MeC₆H₄	4d	84
5	p-MeOC₆H₄	4e	89
6	p-FC₆H₄	4f	71
7	p-ClC₆H₄	4g	73
8	p-CF₃C₆H₄	4h	86
9	m-BrC₆H₄	4i	75
10	2-Furyl	4j	81
11	2-Naphthyl	4k	72
12	Me	—	0
13	n-C₁₇H₃₅	—	0
^aA mixture of 1 (0.3 mmol), acylhydrazine (0.2 mmol) in EtOH (4.0 mL) was stirred at reflux for 3 h, then 3 (0.5 mmol) and in powder (0.3 mmol) were added and stirred at reflux for another 21 h.

由表 1可知, 无论芳香酰肼还是杂环酰肼, 都能与三氟乙醛甲基半缩醛、2-(溴甲基)丙烯酸乙酯和铟粉发生“一锅法”反应, 得到相应的α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物.对于芳香酰肼, 苯环上的取代基的电子性质对反应影响不大, 不管取代基是吸电子的还是供电子的, 所得产物的产率都在71%以上(Entries 1~9).然而, 取代基在苯环上的位置对反应有较大影响.例如, p-甲基苯甲酰肼作为底物反应时4d产率为84%, m-甲基苯甲酰肼反应时4c产率降为51%, 而o-甲基苯甲酰肼反应时仅有痕量的4b产生(Entries 2~4).对于2-呋喃酰肼和2-萘酰肼参与的反应, 也能以高产率得到目标产物(Entries 10, 11).对于链状的脂肪族酰肼, 不管碳链是长链还是短链, 反应都没有发生(Entries 12, 13).这可能是由于脂肪族酰肼形成的酰腙不如芳香酰肼形成的酰腙稳定, 因此不利于下一步烯丙基化/环化反应的进行.

1.2 铟粉促进下以三氟苯乙酮为三氟甲基合成砌块的“一锅法”反应

在铟粉促进下, 三氟苯乙酮、苯甲酰肼和烯丙基溴“一锅法”反应^[17]的基础上, 我们使用2-(溴甲基)丙烯酸乙酯代替烯丙基溴进行上述反应(Eq. 2).结果发现, 该“一锅法”反应在乙醇溶剂中, 对甲苯磺酸(PTSA)催化下能够顺利进行, 并且以47%的产率得到环化产物6a(表 2, Entry 1);在PTSA和Ni(ClO)₄·6H₂O的双催化^[17]下, 环化产物6a的产率仅为52%(表 2, Entry 2), 没有明显提高.然后我们对反应的物料比重新进行了筛选(表 2, Entries 3~6).最终发现在PTSA作为催化剂, 三氟苯乙酮(5a)、苯甲酰肼(2a)、2-(溴甲基)丙烯酸乙酯(3)和铟粉的物质的量之比为1: 1.2: 3.5: 2.5时, 6a的产率达到了80%.

表 2 合成化合物6a反应条件优化^a Table 2. Optimization of reaction condition for the synthesis of compound 6a

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Entry	Molar ratio of 5a/2a/3/In	Catalyst/mol%	Isolated yield/%
1	1/1.2/2.5/1.5	PTSA (20)	47
2	1/1.2/2.5/1.5	PTSA (20) Ni(ClO)₄·6H₂O (10)	52
3	1/1.2/3/1.5	PTSA (20)	54
4	1/1.2/3/2	PTSA (20)	56
5	1/1.2/3.5/2	PTSA (20)	72
6	1/1.2/3.5/2.5	PTSA (20)	80
^a A mixture of 5a (0.2 mmol), 2a (0.24 mmol), catalyst (20 mol%, 0.04 mmol) in EtOH (3.0 mL) was stirred at reflux for 5 h, then 3(0.5~0.7 mmol). In powder (0.3~0.5 mmol) were added and stirred at reflux for another 19 h.

在上述最优的反应条件下, 我们探索了不同的三氟甲基酮和不同的酰肼与2-(溴甲基)丙烯酸乙酯和铟粉的“一锅法”反应(Eq. 3).由表 3可知, 对于芳香酰肼和三氟苯乙酮, 不管苯环上连有供电子基还是吸电子基, 反应都能顺利进行并且以较好的产率得到相应环化产物(Entries 1~6, 8~14).但是, 对于苯环上连有强吸电子基CF₃的酰肼和三氟苯乙酮, 反应不能发生(Entries 7, 15).研究结果还发现, 取代基在苯环上的位置对反应有较大影响.例如, p-甲基苯甲酰肼反应时6c产率为82%, m-甲基苯甲酰肼反应时6d产率降为74%, o-甲基苯甲酰肼反应时6e产率仅为51% (Entries 3~5).对于氯代三氟苯乙酮, 当氯原子分别在苯环上的对位和间位时反应所得产物6j和6k的产率分别是78%和70%, 而o-氯代三氟苯乙酮的反应却不能发生(Entries 11~13).对于杂环酰肼, 如2-呋喃酰肼的反应产率也能达到80% (Entry 8).然而, 对于脂肪酰肼, 如乙酰肼, 反应却没有发生(Entry 16).这仍然是由于脂肪族酰肼的生成的酰腙不稳定, 导致烯丙基化/环化反应不能发生.

表 3 三氟甲基酮和酰肼的适用范围^a Table 3. Substrate scope of trifluoromethylketones and acylhydrazines

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Entry	R¹	R²	Product	Isolated yield/%
1	Ph	Ph	6a	80
2	p-MeOC₆H₄	Ph	6b	83
3	p-MeC₆H₄	Ph	6c	82
4	m-MeC₆H₄	Ph	6d	74
5	o-MeC₆H₄	Ph	6e	51
6	p-ClC₆H₄	Ph	6f	78
7	p-CF₃C₆H₄	Ph	—	0
8	2-Furyl	Ph	6g	80
9	Ph	p-MeOC₆H₄	6h	86
10	Ph	p-MeC₆H₄	6i	82
11	Ph	p-ClC₆H₄	6j	78
12	Ph	m-ClC₆H₄	6k	70
13	Ph	o-ClC₆H₄	—	Trace
14	Ph	m-BrC₆H₄	6l	72
15	Ph	p-CF₃C₆H₄	—	0
16	Me	Ph	—	0
^a A mixture of 5 (0.2 mmol), 2(0.24 mmol), PTSA (20 mol%, 0.04 mmol) in EtOH (3.0 mL) was stirred at reflux for 5 h, then 3(0.7 mmol). In powder (0.5 mmol) were added and stirred at reflux for another 19 h.

1.3 反应机理探讨

在文献[19]报道和实验结果基础上, 我们认为铟粉促进下“一锅法”合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺的反应机理可能如Scheme 1所示.以三氟乙醛甲基半缩醛为例说明:首先, 三氟乙醛甲基半缩醛1和酰肼2反应形成酰腙7; 然后, 7与金属铟和2-(溴甲基)丙烯酸乙酯(3)形成的烯丙基铟试剂8^[19b]发生亲核加成反应, 得到中间体9; 最后, 9发生环化和水解反应生成4.

图式 1 推测的反应机理 Scheme1. Proposed mechanism

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2 结论

综上所述, 本文报道了铟粉促进下, 通过三氟乙醛甲基半缩醛或三氟苯乙酮与酰肼和2-(溴甲基)丙烯酸乙酯的“一锅法”反应, 合成α-亚甲基-γ-三氟甲基-γ-丁内酰胺化合物的方法.该方法使用价廉易得的三氟乙醛甲基半缩醛或三氟苯乙酮作为三氟甲基合成砌块, 具有反应条件温和、产率高、操作简单等优点.特别是, 当三氟苯乙酮作为氟源时, 通过该反应生成的α-亚甲基-γ-丁内酰胺化合物具有一个含三氟甲基的叔碳中心, 为进一步合成该类具有重要药理活性的化合物提供了一种有效的方法.

3 实验部分

3.1 仪器与试剂

核磁共振谱用BRUKER PT jxf790425AM 400 MHz或Agilent DD2 600 MHz型核磁共振仪测定, 以氘代氯仿作为溶剂, TMS为内标; 高分辨质谱用Bruker APEX Ⅱ傅里叶变换离子回旋共振质谱仪测定, ESI源; 熔点测定用显微熔点测定仪测定, 温度未校正.化合物2b~2m按照文献[20]方法自制, 其它试剂均为国产分析纯级.

3.2 实验方法

3.2.1 化合物4a的合成

在50 mL的圆底烧瓶中, 依次加入三氟乙醛甲基半缩醛(1) (0.039 g, 0.30 mmol)、苯甲酰肼(2a) (0.027 g, 0.20 mmol)和4 mL乙醇, 将此混合液在回流条件下搅拌.薄层色谱(TLC)检测反应, 3 h后有酰腙大量生成.此时加入2-(溴甲基)丙烯酸乙酯(3) (0.096 g, 0.50 mmol)和铟粉(0.034 g, 0.30 mmol), 继续回流此反应混合物, TLC检测21 h反应完全.然后向反应混合物中加入3 mL饱和氯化铵溶液, 搅拌10 min, 用乙酸乙酯(5 mL×3)萃取, 分出有机相, 用无水硫酸镁干燥, 蒸去溶剂后, 进行柱层析[V(石油醚): V(乙酸乙酯)=5: 1]分离得产物4a (44 mg).化合物4b~4k制备方法同4a.

N-苯甲酰胺基-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4a):白色固体; 46.0 mg, 产率81%. m.p. 177~178 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.01 (br, 1H, NH), 7.78 (d, J=8.4 Hz, 2H, ArH), 7.42 (s, 1H, ArH), 7.29 (t, J=7.8 Hz, 2H, ArH), 6.23 (s, 1H, =CH₂), 5.59 (s, 1H, =CH₂), 4.50~4.48 (m, 1H, CF₃CH), 3.25~3.20 (m, 1H, CH₂), 2.89 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.0, 165.5, 132.9, 132.4, 130.5, 128.5, 127.5, 124.6 (q, J_C-F=280.1 Hz), 120.6, 56.7 (q, J_C-F=31.8 Hz), 24.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.4 Hz); HRMS (ESI) calcd for C₁₃H₁₂F₃N₂O₂[M+H]⁺ 285.0845, found 285.0842.

N-(3-甲基苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4c):白色固体; 30.1 mg, 产率51%. m.p. 141~143 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.80 (s, 1H, NH), 7.61 (d, J=6.0 Hz, 2H, ArH), 7.23 (d, J=7.8 Hz, 1H, ArH), 7.18 (t, J=7.8 Hz, 1H, ArH), 6.22 (t, J=2.4 Hz, 1H, =CH₂), 5.58 (t, J=2.4 Hz, 1H, =CH₂), 4.52~4.48 (m, 1H, CF₃CH), 3.25~3.20 (m, 1H, CH₂), 2.91~2.87 (m, 1H, CH₂), 2.27 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 167.9, 165.6, 138.3, 133.1, 133.0, 130.5, 128.4, 128.1, 124.6 (q, J_C-F=280.1 Hz), 124.5, 120.4, 56.7 (q, J_C-F=31.7 Hz), 24.8, 21.1;¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.4 Hz); HRMS (ESI) calcd for C₁₄H₁₃F₃N₂O₂Na[M+Na]⁺ 321.0821, found 321.0826.

N-(4-甲基苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4d):白色固体; 50.1 mg, 产率84%. m.p. 140~142 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.92 (s, 1H, NH), 7.67 (d, J=7.8 Hz, 2H, ArH), 7.06 (d, J=7.8 Hz, 2H, ArH), 6.20 (s, 1H, =CH₂), 5.56 (s, 1H, =CH₂, ), 4.47 (s, 1H, CF₃CH), 3.22~3.18 (m, 1H, CH₂), 2.87 (d, J=17.4 Hz, 1H, CH₂), 2.31 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 168.0, 165.5, 143.0, 133.0, 129.1, 127.8, 127.5, 124.6 (q, J_C-F=280.1 Hz), 120.4, 56.8 (q, J_C-F=31.7 Hz), 24.8, 21.4;¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.0 Hz); HRMS (ESI) calcd for C₁₄H₁₃F₃N₂O₂Na[M+Na]⁺ 321.0821, found 321.0828.

N-(4-甲氧基苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4e):白色固体; 55.9 mg, 产率89%. m.p. 158~160 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.94 (br, 1H, NH), 7.77 (d, J=8.4 Hz, 2H, ArH), 6.76~6.75 (m, 2H, ArH), 6.22 (s, 1H, =CH₂), 5.58 (s, 1H, =CH₂), 4.47 (s, 1H, CF₃CH), 3.79 (s, 3H, OCH₃), 3.24~3.20 (m, 1H, CH₂), 2.88 (d, J=17.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.1, 165.1, 162.9, 133.0, 129.5, 124.6 (q, J_C-F=279.9 Hz), 122.9, 120.4, 113.7, 56.9 (q, J_C-F=31.7 Hz), 55.3, 24.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.4 Hz); HRMS (ESI) calcd for C₁₄H₁₃F₃N₂O₃Na[M+Na]⁺ 337.0770, found 337.0778.

N-(4-氟苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4f):白色固体; 42.9 mg, 产率71%. m.p. 154~156 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.19 (s, 1H, NH), 7.82~7.79 (m, 2H, ArH), 6.96 (t, J=8.4 Hz, 2H, ArH), 6.24 (s, 1H, =CH₂), 5.61 (s, 1H, =CH₂), 4.46 (CF₃CH, s, 1H), 3.25~3.21 (m, 1H, CH₂), 2.90 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.3, 165.2 (d, J=252.5 Hz), 164.2, 132.8, 130.0 (d, J=9.2 Hz), 126.6 (d, J=2.8 Hz), 124.5 (q, J_C-F=280.1 Hz), 120.8, 115.6 (d, J=22.0 Hz), 56.8 (q, J_C-F=32.0 Hz), 24.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: －77.0 (d, J_F-H=6.4 Hz), 106.5; HRMS (ESI) calcd for C₁₃H₁₀F₄N₂O₂Na[M+Na]⁺ 325.0571, found 325.0577.

N-(4-氯苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4g):白色固体; 46.4 mg, 产率73%. m.p. 160~162 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.25 (s, 1H, NH), 7.68 (d, J=8.4 Hz, 2H, ArH), 7.23 (d, J=8.4 Hz, 2H, ArH), 6.22 (s, 1H, =CH₂), 5.60 (s, 1H, =CH₂), 4.45~4.42 (m, 1H, CF₃CH), 3.23~3.19 (m, 1H, CH₂), 2.90~2.86 (m, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.3, 164.3, 138.9, 132.7, 128.8, 128.7, 128.6, 124.4 (q, J_C-F=280.1 Hz), 120.9, 56.8 (q, J_C-F=31.8 Hz), 24.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: －77.0 (d, J_F-H=6.4 Hz); HRMS (ESI) calcd for C₁₃H₁₄ClF₃N₃O₂[M+NH₄]⁺ 336.0721, found 336.0723.

N-(4-三氟甲基苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4h):白色固体; 60.5 mg, 产率86%. m.p. 137~138 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.16 (s, 1H, NH), 7.84 (d, J=8.4 Hz, 2H, ArH), 7.53 (d, J=8.4 Hz, 2H, ArH), 6.27 (t, J=2.4 Hz, 1H, =CH₂), 5.64 (s, 1H, =CH₂), 4.49~4.46 (m, 1H, CF₃CH), 3.28~3.23 (m, 1H, CH₂), 2.93 (dd, J=17.4, 2.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.1, 163.9, 134.0 (q, J_C-F=32.4 Hz), 133.5, 132.5, 127.8, 125.6 (q, J=3.6 Hz), 124.4 (q, J_C-F=280.0 Hz), 123.4 (q, J_C-F=270.7 Hz), 121.1, 56.9 (q, J_C-F=32.0 Hz), 24.9; ¹⁹F NMR (376 MHz, CDCl₃) δ: －67.8, －81.0 (d, J_F-H=6.0 Hz); HRMS (ESI) calcd for C₁₄H₁₀F₆N₂O₂Na[M+Na]⁺ 375.0539, found 375.0544.

N-(3-溴苯甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4i):白色固体; 54.3 mg, 产率75%. m.p. 122~124 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 10.03 (s, 1H, NH), 7.89 (s, 1H, ArH), 7.71 (d, J=7.8 Hz, 1H, ArH), 7.58 (d, J=7.8 Hz, 1H, ArH), 7.19~7.16 (m, 1H, ArH), 6.23 (t, J=2.4 Hz, 1H, =CH₂), 5.60 (s, 1H, =CH₂), 4.47~4.44 (m, 1H, CF₃CH), 3.25~3.20 (m, 1H, CH₂), 2.90 (dd, J=17.4, 2.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 168.0, 163.9, 135.5, 132.7, 132.2, 130.9, 130.1, 125.6, 124.4 (q, J_C—F=280.2 Hz), 122.8, 120.9, 56.8 (q, J_C—F=31.6 Hz), 24.8;¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.0 Hz); HRMS (ESI) calcd for C₁₃H₁₀BrF₃N₂O₂Na[M+Na]⁺ 384.9770, found 384.9777.

N-(2-呋喃甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4j):白色固体; 44.4 mg, 产率81%. m.p. 154~155 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.59 (br, 1H, NH), 7.42 (d, J=1.6 Hz, 1H, C₄H₃O), 7.14 (d, J=3.2 Hz, 1H, C₄H₃O), 6.42 (dd, J=4.0, 2.0 Hz, 1H, C₄H₃O), 6.23 (t, J=2.4 Hz, 1H, =CH₂), 5.59 (t, J=2.4 Hz, 1H, =CH₂), 4.50~4.44 (m, 1H, CF₃CH), 3.23 (dd, J=17.6, 9.2 Hz, 1H, CH₂), 2.93~2.88 (m, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 167.3, 156.5, 145.4, 145.2, 132.8, 124.6 (q, J_C—F=280.1 Hz), 120.5, 116.4, 112.0, 56.9 (q, J_C—F=31.8 Hz), 24.8 (d, J=1.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ: －76.9 (d, J_F-H=6.4 Hz); HRMS (ESI) calcd for C₁₁H₉F₃N₂O₃Na[M+Na]⁺ 297.0457, found 297.0461.

N-(2-萘甲酰胺基)-α-亚甲基-γ-三氟甲基-γ-丁内酰胺(4k):白色固体; 48.1 mg, 产率72%. m.p. 187~189 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.60 (s, 1H, NH), 8.35 (d, J=7.8 Hz, 1H, ArH), 7.90 (d, J=8.4 Hz, 1H, ArH), 7.83 (d, J=7.8 Hz, 1H, ArH), 7.68 (d, J=6.6 Hz, 1H, ArH), 7.55~7.50 (m, 2H, ArH), 7.36~7.34 (m, 1H, ArH), 6.18 (d, J=1.8 Hz, 1H, =CH₂), 5.55 (d, J=1.2 Hz, 1H, =CH₂), 4.59 (s, 1H, CF₃CH), 3.21 (CH₂, dd, J=16.2, 9.6 Hz, 1H), 2.88 (CH₂, d, J=17.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.8, 167.2, 133.5, 132.7, 131.9, 130.2, 129.9, 128.3, 127.6, 126.6, 126.1, 125.1, 124.7 (q, J_C-F=279.6 Hz), 124.5, 120.6, 56.7 (q, J_C-F=31.6 Hz), 24.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: －76.7 (d, J_F-H=6.0 Hz); HRMS (ESI) calcd for C₁₇H₁₃F₃N₂O₂Na[M+Na]⁺ 357.0821, found 357.0826.

3.2.2 化合物6a的合成

在50 mL的圆底烧瓶中, 依次加入三氟苯乙酮(5a) (0.034 g, 0.20 mmol)、苯甲酰肼(2a) (0.033 g, 0.24 mmol)、对甲苯磺酸(0.007 g, 0.04 mmol)和EtOH (3 mL), 将混合物在回流条件下搅拌. TLC检测反应, 5 h后有酰腙大量的生成.此时加入2-(溴甲基)丙烯酸乙酯(3) (0.135 g, 0.70 mmol)、铟粉(0.057 g, 0.50 mmol), 继续搅拌回流此反应混合物, TLC检测19 h后反应完全.然后向反应混合物中加入3 mL饱和氯化铵溶液, 搅拌10 min, 用乙酸乙酯(5 mL×3)萃取, 分出有机相, 用无水硫酸镁干燥, 蒸去溶剂后, 进行柱层析[V(石油醚): V(乙酸乙酯)=5: 1]分离得产物6a (58 mg).化合物6b~6l制备方法同6a.

N-苯甲酰胺基-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6a):白色固体; 57.6 mg, 产率80%. m.p. 66~67 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.60 (NH, br, 1H), 7.61 (d, J=7.2 Hz, 2H, ArH), 7.54 (d, J=7.8 Hz, 1H, ArH), 7.39~7.30 (m, 4H, ArH), 7.25~7.22 (m, 2H), 6.28 (s, 1H, =CH₂), 5.59 (s, 1H, =CH₂), 3.46 (d, J=18.0 Hz, 1H, CH₂), 3.22 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (100 MHz, CDCl₃) δ: 166.4, 165.5, 133.9, 133.0, 132.0, 130.9, 129.1, 128.6, 128.3, 127.5, 127.1, 125.7 (q, J_C-F=286.3 Hz), 119.8, 68.8 (q, J_C-F=27.5 Hz), 37.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.4. HRMS (ESI) calcd for C₁₉H₁₆F₃N₂O₂[M+H]⁺ 361.1158, found 361.1155.

N-(4-甲氧基苯甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6b):白色固体; 64.7 mg, 产率83%. m.p. 128~130 ℃; ¹H NMR (600 MHz, CDCl₃)δ: 8.90 (br, 1H, NH), 7.53 (d, J=7.8 Hz, 4H, ArH), 7.35 (t, J=7.2 Hz, 1H, ArH), 7.20 (t, J=7.2 Hz, 2H, ArH), 6.83 (d, J=8.4 Hz, 2H, ArH), 6.25 (s, 1H, =CH₂), 5.57 (s, 1H, =CH₂), 3.72 (s, 3H, OCH₃), 3.42 (d, J=18.0 Hz, 1H, CH₂), 3.21 (d, J=17.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.4, 165.4, 159.7, 133.3, 131.9, 130.9, 128.7, 128.2, 127.5, 125.8 (q, J_C-F=286.5 Hz), 125.4, 119.5, 113.8, 68.5 (q, J_C-F=27.0 Hz), 55.1, 36.9; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.9; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₃[M+H]⁺ 391.1264, found 391.1261.

N-(4-甲基苯甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6c):白色固体; 61.4 mg, 产率82%. m.p. 102~104 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.57 (br, 1H, NH), 7.62 (d, J=7.2 Hz, 2H, ArH), 7.44 (d, J=8.4 Hz, 2H, ArH), 7.35~7.29 (m, 3H, ArH), 7.02 (d, J=8.4 Hz, 2H, ArH), 6.28 (s, 1H, =CH₂), 5.58 (s, 1H, =CH₂), 3.46 (d, J=18.0 Hz, 1H, CH₂), 3.22 (d, J=18.0 Hz, 1H, CH₂), 2.30 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 166.4, 165.4, 142.5, 134.1, 133.1, 129.0, 128.8, 128.5, 128.1, 127.5, 127.1, 125.8 (q, J_C-F=285.0 Hz), 119.6, 68.8 (q, J_C-F=27.0 Hz), 36.9, 21.4; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.4; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₂[M+H]⁺ 375.1315, found 375.1310.

N-(3-甲基苯甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6d):白色固体; 55.5 mg, 产率74%. m.p. 134~136 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.86 (NH, br, 1H), 7.62 (d, J=7.2 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.38~7.33 (m, ArH, 4H), 7.25~7.17 (m, 2H, ArH), 6.29 (s, 1H, =CH₂), 5.58 (s, 1H, =CH₂), 3.48 (d, J=18.6 Hz, 1H, CH₂), 3.21 (d, J=17.4 Hz, 1H, CH₂), 2.29 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 165.9, 165.8, 138.4, 134.2, 133.0, 132.9, 131.3, 129.1, 128.7, 128.3, 128.2, 127.0, 125.8 (q, J_C-F=285.8 Hz), 124.3, 119.8, 68.7 (q, J_C-F=28.5 Hz), 37.0, 21.2; ¹⁹F NMR (564MHz, CDCl₃) δ: －71.9; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₂ [M+H]⁺ 375.1315, found 375.1311.

N-(2-甲基苯甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6e):白色固体; 38.2 mg, 产率51%. m.p. 53~55 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J=7.2 Hz, 2H, NH), 7.44~7.36 (m, 3H, ArH), 7.30~7.20 (m, 3H, ArH), 7.15~7.08 (m, 2H, ArH), 6.28 (s, 1H, =CH₂), 5.57 (s, 1H, =CH₂), 3.48 (d, J=18.0 Hz, 1H, CH₂), 3.22 (d, J=17.6 Hz, 1H, CH₂), 2.24 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 167.7, 165.3, 137.1, 134.2, 132.9, 131.0, 130.7, 129.2, 128.8, 127.0, 125.8 (q, J_C-F=285.5 Hz), 125.6, 119.9, 116.0, 68.5 (q, J_C-F=27.6 Hz), 37.0, 19.2; ¹⁹F NMR (376 MHz, CDCl₃)δ: －72.3; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₂[M+H]⁺ 375.1315, found 375.1309.

N-(4-氯苯甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6f):白色固体; 61.5 mg, 产率78%. m.p. 66~67 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 9.08 (s, 1H, NH), 7.60 (d, J=6.6 Hz, 2H, ArH), 7.47 (d, J=8.4 Hz, 2H, ArH), 7.35~7.30 (m, 3H, ArH), 7.16 (d, J=8.4 Hz, 2H, ArH), 6.30 (s, 1H, =CH₂), 5.63 (s, 1H, =CH₂), 3.46 (d, J=18.0 Hz, 1H, CH₂), 3.25 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.7, 164.2, 138.4, 133.6, 133.0, 129.2, 129.0, 128.8, 128.5, 128.4, 127.2, 125.7 (q, J_C-F=286.1 Hz), 120.1, 68.9 (q, J_C-F=27.2 Hz), 37.0; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.7; HRMS (ESI) calcd for C₁₉H₁₆ClF₃N₂O₂[M+H]⁺ 395.0769, found 395.0766.

N-(2-呋喃甲酰胺基)-α-亚甲基-γ-苯基-γ-三氟甲基-γ-丁内酰胺(6g):白色固体; 56.2 mg, 产率80%. m.p. 74~76 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.11 (s, 1H, NH), 7.62 (d, J=7.8 Hz, 2H, ArH), 7.40 (t, J=7.2 Hz, 2H, ArH), 7.37~7.34 (m, 2H, ArH, C₄H₃O, ), 7.10 (d, J=3.6 Hz, 1H, C₄H₃O), 6.41 (dd, J=3.6, 1.8 Hz, 1H, C₄H₃O), 6.31 (s, 1H, =CH₂), 5.59 (s, 1H, =CH₂), 3.49 (d, J=18.0 Hz, 1H, CH₂), 3.19 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 165.6, 156.2, 145.4, 144.8, 134.2, 132.8, 129.1, 128.8, 126.9, 125.7 (q, J_C-F=285.5 Hz), 119.9, 116.6, 112.1, 68.6 (q, J_C-F=28.5 Hz), 37.1; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.1; HRMS (ESI) calcd for C₁₇H₁₄F₃N₂O₃ [M+H]⁺ 351.0951, found 351.0948.

N-苯甲酰胺基-α-亚甲基-γ-(4-甲氧基苯基)-γ-三氟甲基-γ-丁内酰胺(6h):白色固体; 67.1 mg, 产率86%. m.p. 124~126 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.89 (br, NH, 1H), 7.53 (d, J=7.8 Hz, 4H, ArH), 7.35 (t, J=7.2 Hz, 1H, ArH), 7.20 (t, J=7.2 Hz, 2H, ArH), 6.83 (d, J=8.4 Hz, 2H, ArH), 6.25 (s, 1H, =CH₂), 5.57 (s, 1H, =CH₂), 3.72 (OCH₃, s, 3H), 3.42 (d, J=18.0 Hz, 1H, CH₂), 3.21 (d, J=17.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.4, 165.4, 159.7, 133.3, 131.9, 130.9, 128.7, 128.2, 127.5, 125.8 (q, J_C-F=286.5 Hz), 125.4, 124.8, 119.5, 113.8, 68.5 (q, J_C-F=27.0 Hz), 55.1, 36.9; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.9; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₃ [M+H]⁺ 391.1264, found 391.1261.

N-苯甲酰胺基-α-亚甲基-γ-(4-甲基苯基)-γ-三氟甲基-γ-丁内酰胺(6i):白色固体; 61.5 mg, 产率82%. m.p. 98~100 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.12 (br, 1H, NH), 7.59 (d, J=7.2 Hz, 2H, ArH), 7.49 (d, J=7.8 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.33~7.29 (m, 2H, ArH), 7.17 (d, J=7.2 Hz, 2H, ArH), 6.29 (s, 1H, =CH₂), 5.58 (s, 1H, =CH₂), 3.46 (d, J=18.0 Hz, 1H, CH₂), 3.20 (d, J=17.4 Hz, 1H, CH₂), 2.31 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 166.5, 165.3, 139.1, 133.1, 132.2, 131.3, 131.1, 129.4, 128.5, 127.5, 126.9, 125.8 (q, J_C-F=285.0 Hz), 119.7, 68.6 (q, J_C-F=28.5 Hz), 37.0, 21.0; ¹⁹F NMR (564MHz, CDCl₃) δ: －72.2; HRMS (ESI) calcd for C₂₀H₁₈F₃N₂O₂ [M+H]⁺ 375.1315, found 375.1317.

N-苯甲酰胺基-α-亚甲基-γ-(4-氯苯基)-γ-三氟甲基-γ-丁内酰胺(6j):白色固体; 61.6 mg, 产率78%. m.p. 74~76 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.68 (s, 1H, NH), 7.58 (d, J=8.4 Hz, 2H, ArH), 7.55 (d, J=7.8 Hz, 2H, ArH), 7.40 (t, J=7.2 Hz, 1H, ArH, ), 7.31 (d, J=9.0 Hz, 2H, ArH), 7.25 (ArH, t, J=6.6 Hz, 2H), 6.29 (s, 1H, =CH₂), 5.61 (s, 1H, =CH₂), 3.45 (d, J=18.0 Hz, 1H, CH₂), 3.18 (d, J=17.4 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.4, 165.4, 142.5, 134.0, 133.1, 128.9, 128.8, 128.5, 128.0, 127.5, 127.1, 125.7 (q, J_C-F=285.0 Hz), 119.6, 68.8 (q, J_C-F=28.5 Hz), 36.9;¹⁹F NMR (376 MHz, CDCl₃) δ: －72.5; HRMS (ESI) calcd for C₁₉H₁₅ClF₃N₂O₂[M+H]⁺ 395.0769, found 395.0762.

N-苯甲酰胺基-α-亚甲基-γ-(3-氯苯基)-γ-三氟甲基-γ-丁内酰胺(6k):白色固体; 55.3 mg, 产率70%. m.p. 62~64 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.82 (br, 1H, NH), 7.64 (s, 1H, ArH), 7.56~7.54 (m, 3H, ArH), 7.39 (t, J=7.6 Hz, 1H, ArH), 7.29~7.20 (m, 4H, ArH), 6.30 (s, 1H, =CH₂), 5.61 (s, 1H, =CH₂), 3.45 (d, J=18.0 Hz, 1H, CH₂), 3.19 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.3, 165.5, 135.9, 134.4, 132.5, 132.1, 130.7, 129.9, 129.4, 128.3, 127.5, 127.4, 125.6, 125.4 (q, J_C-F=285.0 Hz), 120.2, 68.5 (q, J_C-F=28.5 Hz), 36.7; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.5; HRMS (ESI) calcd for C₁₉H₁₅ClF₃N₂O₂[M+H]⁺ 395.0769, found 395.0764.

N-苯甲酰胺基-α-亚甲基-γ-(3-溴苯基)-γ-三氟甲基-γ-丁内酰胺(6l):白色固体; 63.1 mg, 产率72%. m.p. 88~90 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.58 (s, 1H, NH), 7.78 (s, 1H, ArH), 7.61~7.55 (m, 3H, ArH), 7.46~7.38 (m, 2H, ArH), 7.27~7.20 (m, 3H, ArH), 6.30 (s, 1H, =CH₂), 5.61 (s, 1H, =CH₂), 3.45 (d, J=18.0 Hz, 1H, CH₂), 3.18 (d, J=18.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, CDCl₃) δ: 166.1, 165.6, 136.2, 132.5, 132.3, 132.2, 130.9, 130.3, 130.2, 128.4, 127.5, 126.0, 125.5 (q, J_C-F=286.5 Hz), 122.5, 120.3, 68.4 (q, J_C-F=27.0 Hz), 36.8; ¹⁹F NMR (376 MHz, CDCl₃) δ: －72.5; HRMS (ESI) cacld for C₁₉H₁₅BrF₃N₂O₂ [M+H]⁺ 438.0264, found 439.0258.

辅助材料(Supporting Information) 合成产物的核磁共振氢谱、碳谱和氟谱以及高分辨质谱.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 推测的反应机理

Scheme 1 Proposed mechanism

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表 1 酰肼的适用范围^a

Table 1. Substrate scope of acylhydrazines

Entry	R¹	Product	Isolated yield/%
1	C₆H₅	4a	81
2	o-MeC₆H₄	4b	Trace
3	m-MeC₆H₄	4c	51
4	p-MeC₆H₄	4d	84
5	p-MeOC₆H₄	4e	89
6	p-FC₆H₄	4f	71
7	p-ClC₆H₄	4g	73
8	p-CF₃C₆H₄	4h	86
9	m-BrC₆H₄	4i	75
10	2-Furyl	4j	81
11	2-Naphthyl	4k	72
12	Me	—	0
13	n-C₁₇H₃₅	—	0
^aA mixture of 1 (0.3 mmol), acylhydrazine (0.2 mmol) in EtOH (4.0 mL) was stirred at reflux for 3 h, then 3 (0.5 mmol) and in powder (0.3 mmol) were added and stirred at reflux for another 21 h.

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表 2 合成化合物6a反应条件优化^a

Table 2. Optimization of reaction condition for the synthesis of compound 6a

Entry	Molar ratio of 5a/2a/3/In	Catalyst/mol%	Isolated yield/%
1	1/1.2/2.5/1.5	PTSA (20)	47
2	1/1.2/2.5/1.5	PTSA (20) Ni(ClO)₄·6H₂O (10)	52
3	1/1.2/3/1.5	PTSA (20)	54
4	1/1.2/3/2	PTSA (20)	56
5	1/1.2/3.5/2	PTSA (20)	72
6	1/1.2/3.5/2.5	PTSA (20)	80
^a A mixture of 5a (0.2 mmol), 2a (0.24 mmol), catalyst (20 mol%, 0.04 mmol) in EtOH (3.0 mL) was stirred at reflux for 5 h, then 3(0.5~0.7 mmol). In powder (0.3~0.5 mmol) were added and stirred at reflux for another 19 h.

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表 3 三氟甲基酮和酰肼的适用范围^a

Table 3. Substrate scope of trifluoromethylketones and acylhydrazines

Entry	R¹	R²	Product	Isolated yield/%
1	Ph	Ph	6a	80
2	p-MeOC₆H₄	Ph	6b	83
3	p-MeC₆H₄	Ph	6c	82
4	m-MeC₆H₄	Ph	6d	74
5	o-MeC₆H₄	Ph	6e	51
6	p-ClC₆H₄	Ph	6f	78
7	p-CF₃C₆H₄	Ph	—	0
8	2-Furyl	Ph	6g	80
9	Ph	p-MeOC₆H₄	6h	86
10	Ph	p-MeC₆H₄	6i	82
11	Ph	p-ClC₆H₄	6j	78
12	Ph	m-ClC₆H₄	6k	70
13	Ph	o-ClC₆H₄	—	Trace
14	Ph	m-BrC₆H₄	6l	72
15	Ph	p-CF₃C₆H₄	—	0
16	Me	Ph	—	0
^a A mixture of 5 (0.2 mmol), 2(0.24 mmol), PTSA (20 mol%, 0.04 mmol) in EtOH (3.0 mL) was stirred at reflux for 5 h, then 3(0.7 mmol). In powder (0.5 mmol) were added and stirred at reflux for another 19 h.

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沈阳化工大学材料科学与工程学院沈阳 110142