超声辐射下合成含苯并噻喃片段的新颖螺吲哚类化合物及其抗真菌活性

引用本文: 周冠, 梁国超, 钟一凡, 韩晓燕, 陈国锋, 宋亚丽. 超声辐射下合成含苯并噻喃片段的新颖螺吲哚类化合物及其抗真菌活性[J]. 有机化学, 2015, 36(1): 143-150. doi: 10.6023/cjoc201508007 shu

Citation: Zhou Guan, Liang Guochao, Zhong Yifan, Han Xiaoyan, Chen Guofeng, Song Yali. Ultrasound Promoted Synthesis of Novel Substituted Spirooxindole Compounds Containing Thiochroman Moiety with Antifungal Activity[J]. Chinese Journal of Organic Chemistry, 2015, 36(1): 143-150. doi: 10.6023/cjoc201508007 shu

超声辐射下合成含苯并噻喃片段的新颖螺吲哚类化合物及其抗真菌活性

a.
河北大学药学院河北省药品质量控制重点实验室保定071002
b.
河北大学教育部药物化学与分子诊断重点实验室保定 071002
c.
河北大学化学与环境科学学院保定 071002

通讯作者: 宋亚丽, E-mail: yalisong@hbu.edu.cn

基金项目:
河北省药物质量分析控制重点实验室开放基金、“重大新药创制”国家科技重大专项资助项目 2012ZX09103-101-057

摘要: 探索了一种快速、高效的超声合成方法, 通过三组分一锅法合成了20个2'-氨基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈类结构新颖的螺吲哚化合物.所得到的化合物均由¹H NMR, ¹³C NMR和HRMS确证.研究了超声对产率和反应时间的影响.采用微量稀释法对所合成的化合物进行了抗真菌活性的测定.其中, 化合物4f对新生隐球菌、絮状表皮癣菌和总状毛霉的抑制活性均优于阳性对照药物氟康唑.

关键词:

English

Ultrasound Promoted Synthesis of Novel Substituted Spirooxindole Compounds Containing Thiochroman Moiety with Antifungal Activity

a.
Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences, Hebei University, Baoding 071002
b.
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei University, Baoding 071002
c.
College of Chemistry and Environmental Science, Hebei University, Baoding 071002

Corresponding author: Song Yali, yalisong@hbu.edu.cn

Received Date: 06 August 2015
Revised Date: 23 September 2015
Fund Project:
the Open Project Program of Key Laboratory of Pharmaceutical Quality Control of Hebei Province, the National Major Scientific and Technological Special Project for 'Significant New Drugs Development'

Abstract: A rapid and efficient ultrasound-promoted one-pot synthesis of 2'-amino-2-oxo-5'H-spiro[indoline-3, 4'-thiochromeno[4, 3-b]pyran]-3'-carbonitrile compounds by one-pot three-component reaction had been developed. Structures of all products were characterized by ¹H NMR, ¹³C NMR and HRMS. The effect of ultrasound on yield and reaction time had been studied to understand the role of ultrasound in the reaction. The antifungal activity was determined by micro dilution method. Compound 4f exhibited inhibitory activity to Cryptococcus neoformans, Epidermophyton floccosum and Mucor racemosus better than the positive control drug fluconazole.

Key words:

吡喃及其衍生物是一类重要的杂环化合物, 其结构是多种天然产物的核心骨架^[1].它们表现出广泛的生物活性, 如抗癌^[2]、抗菌^[3]、和抗增殖^[4]等活性.吲哚环是一个众所周知的杂环, 它广泛存在于多种天然产物和药物中^[5].含吲哚基团的化合物表现出抗菌和抗真菌等活性^[6].此外, 已经报道, C-3螺吲哚衍生物能显著提高生物活性^[7].螺吲哚片段是许多药物和天然生物碱中的核心结构^[8].由于螺吲哚结构的重要生物活性, 引起了学者对该结构合成的兴趣, 并且有大量文献报道了螺吲哚杂环化合物的合成^[9].

硫色满酮是一类重要的含硫杂环化合物, 人们对此类化合物的合成和生物活性方面已经做了大量研究, 合成了多种硫色满酮的衍生物, 已报道的有3位Mannich碱取代^[10]、3位次苄基取代^[11]、3位烃基取代^[12]、2-烷基取代^[13]、4位双吲哚^[14]等化合物, 它们中大部分都有很好的抗癌或抗真菌活性.而含硫色满酮片段的螺吲哚结构还未见报道.

20世纪80年代以来, 随着声化学的发展, 超声波在有机合成中的应用研究蓬勃发展.与传统的有机合成方法比较, 超声辐射可缩短反应时间、提高反应产率, 已广泛用于有机合成^[15].文献中也有关于超声波促进一锅法合成反应的报道^[16].于是我们利用在超声辐射的条件下, 通过硫色满酮、丙二腈与靛红三组分一锅法合成含硫色满酮片段的螺吲哚类化合物4^[17] (Eq.1), 并测定了它们的体外抗真菌活性.

1 结果与讨论

1.1 反应条件的优化

我们以6-氯硫色满酮(1 mmol)、丙二腈(1 mmol)与靛红(1 mmol)三组分一锅法合成化合物4a为例, 探讨了催化剂、超声频率和反应温度对反应收率的影响.结果见表 1.

表1 反应条件的影响 Table1. Effect of reaction condition

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Entry	Catalyst (mol%)	Frequency/kHz	Temperature/℃	Time/min	Yield/%
1	NaOH (20)	40	r.t	60	0
2	NaHCO₃(20)	40	r.t	60	0
3	Triethylamine (20)	40	r.t	60	0
4	L-proline (20)	40	r.t	60	0
5	Piperidine (10)	40	r.t	15	85
6	Piperidine (20)	40	r.t	15	91
7	Piperidine (30)	40	r.t	15	90
8	Piperidine (20)	40	40	15	85
9	Piperidine (20)	40	50	15	84
10	Piperidine (20)	25	r.t	15	75

表1 反应条件的影响
Table1. Effect of reaction condition

我们首先考察了催化剂对反应的影响, 由表 1的数据(表 1, Entries 1～4)可以看出, NaOH、NaHCO₃、三乙胺和L-脯氨酸作为催化剂时, 反应60 min后, 并未见产物生成.使用哌啶作为催化剂, 反应可顺利发生, 15 min后反应即可完成.随后, 考察了哌啶的用量(表 1, Entries 5～7), 发现当哌啶的用量为20 mol%时, 产率最高, 可达到91%.随着催化剂用量的增加, 产率没有显著提升.当升高反应温度时(表 1, Entries 8, 9), 产率不但没有提高, 反而降低到84%.

我们也考察了超声频率对反应的影响.如表 1所示, 在其他条件均相同的情况下, 以频率为25 kHz的超声辐射, 4a的产率为75% (表 1, Entry 10), 明显低于以频率为40 kHz超声辐射时的产率91% (表 1, Entry 6).可见, 超声频率对产率有较大影响.

鉴于以上影响反应的因素, 我们选择的反应条件为:硫色满酮(1 mmol)、丙二腈(1 mmol)、靛红(1 mmol)、哌啶(0.2 mmol)、乙醇(5 mL)、超声辐射频率为40 kHz、室温反应.

在选定条件下利用超声辐射合成了一系列螺吲哚化合物, 结果见表 2.与此同时, 还进行了仅搅拌无超声辐射的试验, 结果也列于表 2中.由表 2中的数据可以看出, 在超声辐射和哌啶的存在下, 绝大部分化合物的产率都在80%以上, 而且反应能在30 min内完成.与仅搅拌无超声辐射条件下的反应相比, 反应时间明显缩短, 收率也有所提高.如4b的合成, 在超声辐射下仅反应9 min产率可达到92%, 若仅用搅拌, 反应90 min产率才达到86%.显然, 超声辐射能够加速此类反应, 缩短反应时间, 使收率进一步提高.

表2 在超声辐射和普通条件下4a～4t的合成 Table2. Synthesis of 4a～4t under both ultrasonic irradiation and conventional method

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Compd.	R¹	R²	R³	R⁴	R⁵	Ultrasonic irradiation		Conventional
Compd.	R¹	R²	R³	R⁴	R⁵	Time/min	Yield/%	Time/min	Yield/%
4a	H	H	Cl	H	H	15	91	100	89
4b	H	H	Cl	CH₃	H	9	92	90	86
4c	H	H	F	H	H	15	88	90	81
4d	H	H	F	CH₃	H	9	94	90	80
4e	H	F	CH₃	H	H	25	80	90	76
4f	H	F	CH₃	CH₃	H	19	84	60	79
4g	F	H	H	H	H	12	94	45	91
4h	F	H	H	CH₃	H	12	96	45	87
4i	H	H	CH₃	H	H	22	88	120	83
4j	H	H	CH₃	CH₃	H	17	93	120	80
4k	H	Cl	Cl	H	H	8	91	45	90
4l	H	Cl	Cl	CH₃	H	8	91	45	86
4m	CH₃	H	H	H	H	26	83	120	81
4n	CH₃	H	H	CH₃	H	22	87	90	70
4o	Cl	H	H	H	H	18	80	90	65
4p	Cl	H	H	CH₃	H	14	85	90	72
4q	H	H	Cl	H	Cl	22	82	120	80
4r	H	H	Cl	NO₂	H	35	60	210	55
4s	H	H	CH₃	H	Cl	45	72	240	65
4t	H	H	CH₃	NO₂	H	60	41	360	35

表2 在超声辐射和普通条件下4a～4t的合成
Table2. Synthesis of 4a～4t under both ultrasonic irradiation and conventional method

1.2 反应机理

Scheme 1提出了螺吲哚化合物生成的可能机理.首先, 丙二腈2与靛红3发生克脑文格尔缩合反应生成中间5, 硫色满酮1与哌啶形成烯胺结构6.烯胺结构6与克脑文格尔缩合中间体5加成生成中间体7.消除哌啶后, 形成中间体9, 发生了分子内环合生成中间体10.最后一步中间体10发生互变异构生成产物4.

图图式1 螺吲哚化合物生成的可能机理

Figure 图式1. Proposed mechanism for the synthesis of spirooxindole compounds

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1.3 体外抗真菌活性

为了探索所合成化合物的体外抗真菌活性, 本实验分别测定了新生隐球菌(Cryptococcus neoformans, C.n.), 白色念珠菌(Canidia albicans, C.a.), 絮状表皮癣菌(Epidermophyton floccosum, E.f.), 总状毛霉(Mucor racemosus, M.r.)和石膏样小孢子菌(Microsporum gypseum, M.g.)等5种真菌的抗菌活性(表 3).受试真菌均来自于中国医学科学院菌种保藏中心.

表3 目标化合物的最小抑菌浓度^a Table3. Minimum inhibitory concentrations of target compounds

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Compd.	MIC/(μg•mL^-1)
Compd.	C.n.	C.a.	E.f.	M.r.	M.g.
4a	64	128	64	32	32
4b	32	> 128	64	16	128
4c	64	> 128	32	64	64
4d	32	128	32	64	128
4e	64	> 128	16	16	64
4f	16	> 128	8	16	64
4g	64	64	64	64	128
4h	32	128	64	128	64
4i	128	128	128	64	128
4j	64	> 128	64	64	64
4k	64	> 128	64	64	64
4l	64	128	64	128	128
4m	128	> 128	128	> 128	64
4n	128	> 128	128	128	64
4o	64	128	64	64	128
4p	128	128	64	64	64
4q	64	64	32	128	128
4r	32	128	64	64	64
4s	128	128	128	64	128
4t	128	128	64	32	64
F	32	16	32	32	16
B	4	2	2	4	2
^aF:氟康唑(Fluconazole); B:两性霉素B (Amphotericin B).

表3 目标化合物的最小抑菌浓度^a
Table3. Minimum inhibitory concentrations of target compounds

本实验采用微量稀释法对5种受试真菌进行活性测试, 20个目标化合物先用适量二甲基亚砜溶解, 再用无菌蒸馏水稀释, 然后加入到已灭过菌的1%的葡萄糖蛋白胨琼脂培养基中, 样品浓度分别为128、64、32、16、8、4、2 μg•mL^-1.之后接种供试菌(每种菌同时作一空白对照), 置恒温烘箱中培养5～7 d.以两性霉素B (Amphotericin B)和氟康唑(Fluconazole)为阳性对照, 以无菌生长的最低浓度为最小抑菌浓度(MIC值).

从表 3可看出目标化合物对C.a.和M.g.表现出较弱的抑制作用, 但是部分化合物对C.n.、E.f.和M.r.有良好的抑制作用.其中, 化合物4f对C.n.的抑制活性优于阳性对照药物氟康唑, 最小抑菌浓度可达到16 μg•mL^-1; 化合物4b、4d、4h和4r对C.n.的最小抑菌浓度为32 μg•mL^-1, 抑制活性与阳性对照药物氟康唑相当.当苯并噻喃部分的苯环上带有吸电子取代基时(如F或Cl), 且R⁴有取代基时, 化合物表现出较好的抑制活性.如: 4b (R³＝Cl, R⁴＝CH₃; MIC＝32 μg•mL^-1) > 4a (R³＝Cl, R⁴＝H; MIC＝64 μg•mL^-1).

化合物4e和4f对E.f.的抑制活性优于氟康唑, 最小抑菌浓度分别为16和8 μg•mL^-1; 4c、4d和4q的最小抑菌浓度为32 μg•mL^-1, 对E.f.的抑制活性与氟康唑相当.当R²、R³中一个取代基为F原子或R³和R⁵均为Cl原子时, 化合物表现出较好活性.如: 4c (R³＝F; MIC＝32 μg•mL^-1) > 4i (R³＝CH₃; MIC＝128 μg•mL^-1); 4q (R³, R⁵＝Cl; MIC＝32 μg•mL^-1) > 4a (R³＝Cl; MIC＝64 μg•mL^-1).

化合物4b、4e和4f对M.r.的抑制活性优于对照药物氟康唑, 最小抑菌浓度为16 μg•mL^-1; 4a和4t的最小抑菌浓度为32 μg•mL^-1, 对E.f.的抑制活性与氟康唑相当.当苯并噻喃部分的苯环上含吸电子取代基时(R²＝F或R³＝Cl), 化合物表现出较好的抑制活性.如: 4b(R³＝Cl, R⁴＝CH₃; MIC＝32 μg•mL^-1) > 4j (R³＝CH₃, R⁴＝CH₃; MIC＝64 μg•mL^-1).

2 结论

在超声辐射和哌啶存在下, 硫色满酮、丙二腈和靛红的反应可采用一锅法完成, 反应条件温和, 反应时间短, 收率高, 为此类化合物的合成提供了一种简便有效的方法.采用微量稀释法对所合成的20个化合物进行体外抗真菌活性的测定.其中, 化合物4f对C.n.、E.f.和M.r.的抑制活性均优于阳性对照药物氟康唑.

3 实验部分

3.1 仪器与试剂

¹H NMR, ¹³C NMR由Bruker Advance Ш 600 MHz型核磁共振波谱仪测定, TMS作为内标物, DMSO-d₆作为溶剂; 熔点由SGWX-4型显微熔点仪测定; 高分辨质谱由Bruker apex ultra 7.0 T傅里叶变换离子回旋质谱仪测定; 集热式恒温加热磁力搅拌器(DF-101S)来自巩义市予华科技有限公司.BUG25-06(功率250 W, 频率25 kHz)和BUG40-06(功率250 W, 频率40 kHz)超声波清洗器来自上海必能信超声有限公司.硫色满酮^[18]和靛红^[19]按照文献报道合成, 试剂均为国产分析纯.

3.2 实验方法

将硫色满酮(1 mmol)、丙二腈(1 mmol)、靛红(1 mmol)、哌啶(0.2 mmol)加到含有5 mL乙醇的25 mL圆底烧瓶中, 将反应瓶置于超声清洗器中, 使反应瓶中液面略低于超声清洗器中水面, 用TLC监测跟踪反应情况, 反应完毕后抽滤, 得到沉淀, 用乙醇重结晶得纯产品(表 2).所合成的20个化合物未见文献报道, 所有结构均由¹H NMR, ¹³C NMR和HRMS确证.

2'-氨基-9'-氯-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4a):淡粉色粉末, 收率91%.m.p.312～314 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.73 (s, 1H, NH), 7.72 (d, J＝2.4 Hz, 1H, ArH), 7.35 (dd, J＝8.4, 2.4 Hz, 1H, ArH), 7.33～7.30 (m, 3H, ArH and NH₂), 7.28 (dd, J＝7.8, 1.2 Hz, 1H, ArH), 7.25 (d, J＝7.2 Hz, 1H, ArH), 7.06 (t, J＝7.2 Hz, 1H, ArH), 6.91 (d, J＝7.2 Hz, 1H, ArH), 3.06 (d, J＝15.6 Hz, 1H, CH₂), 2.89 (d, J＝15.6 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.57, 160.98, 142.43, 142.39, 131.91, 131.85, 130.82, 130.04, 129.60, 128.96, 128.85, 125.40, 123.76, 123.25, 118.53, 110.53, 106.34, 55.02, 52.63, 24.29.HRMS (ESI) calcd for C₂₀H₁₃ClN₃O₂S[M+H]⁺ 394.0412, found 394.0412.

2'-氨基-9'-氯-5-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4b):淡粉色粉末, 收率92%.m.p.311～313 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.63 (s, 1H, NH), 7.72 (d, J＝2.4 Hz, 1H, ArH), 7.35 (dd, J＝8.4, 2.4 Hz, 1H, ArH), 7.33～7.27 (m, 3H, ArH and NH₂), 7.08 (d, J＝8.4 Hz, 2H, ArH), 6.80 (d, J＝7.8 Hz, 1H, ArH), 3.06 (d, J＝15.0 Hz, 1H, CH₂), 2.89 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.50, 160.92, 142.28, 139.94, 132.24, 132.02, 131.85, 130.82, 130.36, 129.57, 128.94, 128.85, 125.82, 123.73, 118.59, 110.26, 106.46, 55.20, 52.71, 24.32, 21.08.HRMS (ESI) calcd for C₂₁H₁₅Cl-N₃O₂S [M+H]⁺ 408.0568, found 408.0573.

2'-氨基-9'-氟-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4c):白色粉末, 收率88%.m.p.303～305 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.72 (s, 1H, NH), 7.51 (dd, J＝10.2, 2.4 Hz, 1H), 7.32 (dd, J＝8.4, 5.4 Hz, 1H, ArH), 7.29 (dd, J＝7.8, 0.6 Hz, 1H, ArH), 7.28 (s, 2H, NH₂), 7.26 (d, J＝7.2 Hz, 1H, ArH), 7.18 (td, J＝8.4, 3.0 Hz, 1H, ArH), 7.05 (td, J＝7.8, 0.6 Hz, 1H, ArH), 6.91 (d, J＝7.8 Hz, 1H, ArH), 3.05 (d, J＝15.0 Hz, 1H, CH₂), 2.87 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.59, 161.69, 160.99, 160.08, 142.63, 142.61, 142.43, 131.88, 130.04, 129.11, 129.06, 129.02, 128.97, 128.24, 128.22, 125.40, 123.25, 118.54, 117.04, 116.89, 111.32, 111.15, 110.53, 106.44, 55.03, 52.60, 24.40.HRMS (ESI) calcd for C₂₀H₁₃FN₃O₂S [M+H]⁺ 378.0707, found 378.0712.

2'-氨基-9'-氟-5-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4d):白色粉末, 收率94%.m.p.296～298 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.62 (s, 1H, NH), 7.50 (dd, J＝10.2, 2.4 Hz, 1H, ArH), 7.32 (dd, J＝8.4, 5.4 Hz, 1H, ArH), 7.26 (s, 2H, NH₂), 7.18 (td, J＝8.4, 3.0 Hz, 1H, ArH), 7.08 (d, J＝7.8 Hz, 2H, ArH), 6.80 (d, J＝7.8 Hz, 1H, ArH), 3.05 (d, J＝15.0 Hz, 1H, CH₂), 2.87 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.51, 161.69, 160.92, 160.08, 142.51, 142.50, 139.94, 132.24, 132.05, 130.35, 129.09, 129.03, 128.97, 128.92, 128.19, 128.17, 125.82, 118.60, 117.01, 116.86, 111.28, 111.12, 110.25, 106.57, 55.20, 52.68, 24.43, 21.08.HRMS (ESI) calcd for C₂₁H₁₅FN₃O₂S[M+H]⁺ 392.0864, found 392.0865.

2'-氨基-8'-氟-9'-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4e):白色粉末, 收率80%.m.p.300～302 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.71 (s, 1H, NH), 7.44 (d, J＝10.2 Hz, 1H, ArH), 7.28 (td, J＝7.8, 1.2 Hz, 1H, ArH), 7.25 (s, 2H, NH₂), 7.24～7.19 (m, 2H, ArH), 7.05 (td, J＝7.8, 0.6 Hz, 1H, ArH), 6.90 (d, J＝7.8 Hz, 1H, ArH), 3.03 (d, J＝15.0 Hz, 1H, CH₂), 2.84 (d, J＝15.0 Hz, 1H, CH₂), 2.21 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.68, 161.00, 160.17, 158.57, 142.68, 142.67, 142.42, 131.96, 130.04, 130.01, 129.98, 127.75, 127.73, 126.75, 126.59, 126.54, 125.35, 123.24, 118.58, 110.91, 110.74, 110.50, 105.25, 55.04, 52.55, 24.47, 14.38, 14.36.HRMS (ESI) calcd for C₂₁H₁₅FN₃O₂S [M+H]⁺ 392.0864, found 392.0867.

2'-氨基-8'-氟-5, 9'-二甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4f):白色粉末, 收率84%.m.p.301～303 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.61 (s, 1H, NH), 7.44 (d, J＝10.8 Hz, 1H, ArH), 7.24 (s, 2H, NH₂), 7.21 (d, J＝7.2 Hz, 1H, ArH), 7.11～7.05 (m, 2H, ArH), 6.79 (d, J＝7.8 Hz, 1H, ArH), 3.03 (d, J＝15.0 Hz, 1H, CH₂), 2.85 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃), 2.21 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.61, 160.94, 160.17, 158.58, 142.57, 142.56, 139.92, 132.22, 132.14, 130.31, 130.01, 129.98, 127.69, 127.67, 126.72, 126.59, 126.54, 125.78, 118.66, 110.88, 110.71, 110.24, 105.36, 55.22, 52.63, 24.49, 21.07, 14.38, 14.36.HRMS (ESI) calcd for C₂₂H₁₆FN₃O₂SNa [M+ Na]⁺ 428.0840, found 428.0843.

2'-氨基-7'-氟-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4g):白色粉末, 收率94%.m.p.284～286 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.73 (s, 1H, NH), 7.53 (dd, J＝7.8, 0.6 Hz, 1H, ArH), 7.35～7.24 (m, 6H, ArH and NH₂), 7.06 (td, J＝7.8, 0.6 Hz, 1H, ArH), 6.92 (d, J＝7.8 Hz, 1H, ArH), 3.09 (d, J＝15.0 Hz, 1H, CH₂), 2.90 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.62, 161.00, 158.92, 157.33, 142.79, 142.76, 142.45, 131.92, 130.04, 129.24, 129.22, 126.94, 126.88, 125.39, 123.26, 120.66, 120.53, 120.10, 120.09, 118.57, 116.79, 116.65, 110.54, 105.68, 55.03, 52.62, 23.67.HRMS (ESI) calcd for C₂₀H₁₃FN₃O₂S [M+H]⁺ 378.0707, found 378.0710.

2'-氨基-7'-氟-5-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4h):白色粉末, 收率96%.m.p.273～276 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.63 (s, 1H, NH), 7.53 (d, J＝7.8 Hz, 1H, ArH), 7.36～7.30 (m, 1H, ArH), 7.30～7.25 (m, 3H, ArH and NH₂), 7.09 (d, J＝7.2 Hz, 2H, ArH), 6.80 (d, J＝8.4 Hz, 1H, ArH), 3.08 (d, J＝15.0 Hz, 1H, CH₂), 2.91 (d, J＝15.0 Hz, 1H, CH₂), 2.27 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.56, 160.94, 158.93, 157.34, 142.69, 142.66, 139.95, 132.25, 132.09, 130.37, 129.23, 129.21, 126.92, 126.86, 125.82, 120.61, 120.48, 120.07, 120.06, 118.64, 116.75, 116.61, 110.27, 105.79, 55.23, 52.70, 23.70, 21.08.HRMS (ESI) calcd for C₂₁H₁₄FN₃O₂SNa [M+Na]⁺ 414.0683, found 414.0686.

2'-氨基-9'-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4i):白色粉末, 收率88%.m.p.302～304 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.69 (s, 1H, NH), 7.52 (s, 1H, ArH), 7.28 (t, J＝7.8 Hz, 1H, ArH), 7.23 (d, J＝5.4 Hz, 3H, ArH and NH₂), 7.16 (d, J＝7.8 Hz, 1H, ArH), 7.11 (dd, J＝7.8, 1.2 Hz, 1H, ArH), 7.05 (t, J＝7.8 Hz, 1H, ArH), 6.90 (d, J＝7.8 Hz, 1H, ArH), 2.99 (d, J＝15.0 Hz, 1H, CH₂), 2.78 (d, J＝15.0 Hz, 1H, CH₂), 2.31 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.81, 161.13, 143.34, 142.41, 135.53, 132.20, 130.58, 129.93, 129.39, 127.25, 127.18, 125.31, 124.64, 123.21, 118.70, 110.46, 105.13, 55.02, 52.64, 24.42, 21.23.HRMS (ESI) calcd for C₂₁H₁₆N₃O₂S[M+H]⁺ 374.0958, found 374.0961.

2'-氨基-5, 9'-二甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4j):白色粉末, 收率93%.m.p.306～308 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.59 (s, 1H, NH), 7.52 (s, 1H, ArH), 7.23 (s, 2H, NH₂), 7.16 (d, J＝7.8 Hz, 1H, ArH), 7.11 (d, J＝7.8 Hz, 1H, ArH), 7.08 (d, J＝7.8 Hz, 1H, ArH), 7.06 (s, 1H, ArH), 6.79 (d, J＝7.8 Hz, 1H, ArH), 2.99 (d, J＝15.0 Hz, 1H, CH₂), 2.79 (d, J＝15.0 Hz, 1H, CH₂), 2.32 (s, 3H, CH₃), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.75, 161.08, 143.24, 139.92, 135.51, 132.37, 132.18, 130.55, 130.25, 129.34, 127.24, 127.18, 125.74, 124.61, 118.78, 110.20, 105.25, 55.19, 52.72, 24.45, 21.24, 21.08.HRMS (ESI) calcd for C₂₂H₁₈N₃O₂S[M+H]⁺ 388.1114, found 388.1119.

2'-氨基-8', 9'-二氯-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4k):白色粉末, 收率91%.m.p.310～312 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.74 (s, 1H, NH), 7.86 (s, 1H, ArH), 7.63 (s, 1H, ArH), 7.32 (s, 2H, NH₂), 7.31～7.27 (m, 1H, ArH), 7.25 (d, J＝7.2 Hz, 1H, ArH), 7.06 (t, J＝7.8 Hz, 1H, ArH), 6.91 (d, J＝7.8 Hz, 1H, ArH), 3.09 (d, J＝15.0 Hz, 1H, CH₂), 2.94 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.46, 160.91, 142.44, 141.90, 133.98, 132.16, 131.68, 130.08, 128.72, 128.63, 127.49, 125.41, 123.26, 118.45, 110.57, 106.60, 55.05, 52.62, 24.37.HRMS (ESI) calcd for C₂₀H₁₂Cl₂N₃O₂S[M+H]⁺ 428.0022, found 428.0028.

2'-氨基-8', 9'-二氯-5-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4l):白色粉末, 收率91%.m.p.315～317 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.64 (s, 1H, NH), 7.85 (s, 1H, ArH), 7.63 (s, 1H, ArH), 7.30 (s, 2H, NH₂), 7.11～7.06 (m, 2H, ArH), 6.80 (t, J＝7.8 Hz, 1H, ArH), 3.09 (d, J＝15.0 Hz, 1H, CH₂), 2.95 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.38, 160.84, 141.79, 139.95, 133.92, 132.25, 132.15, 131.86, 130.40, 128.72, 128.60, 127.49, 125.83, 125.38, 118.52, 110.30, 106.73, 55.23, 52.70, 24.41, 21.08.HRMS (ESI) calcd for C₂₁H₁₃Cl₂-N₃O₂SNa[M+Na]⁺ 463.9998, found 464.0003.

2'-氨基-7'-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4m):白色粉末, 收率83%.m.p.282～284 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.71 (s, 1H, NH), 7.56 (d, J＝7.8 Hz, 1H, ArH), 7.29 (t, J＝7.8 Hz, 1H, ArH), 7.25 (d, J＝3.6 Hz, 3H, ArH and NH₂), 7.22 (d, J＝7.2 Hz, 1H, ArH), 7.18 (t, J＝7.8 Hz, 1H, ArH), 7.06 (t, J＝7.8 Hz, 1H, ArH), 6.91 (d, J＝7.8 Hz, 1H, ArH), 3.04 (d, J＝15.0 Hz, 1H, CH₂), 2.81 (d, J＝15.0 Hz, 1H, CH₂), 2.20 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.82, 161.20, 143.58, 142.43, 135.08, 132.81, 132.24, 131.31, 129.93, 127.14, 125.31, 125.10, 123.21, 121.81, 118.73, 110.47, 104.21, 55.04, 52.64, 24.02, 20.28.HRMS (ESI) calcd for C₂₁H₁₆N₃O₂S[M+H]⁺ 374.0958, found 374.0961.

2'-氨基-5, 7'-二甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4n):白色粉末, 收率87%.m.p.236～238 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.61 (s, 1H, NH), 7.56 (d, J＝7.8 Hz, 1H, ArH), 7.23 (s, 2H, NH₂), 7.21 (d, J＝7.2 Hz, 1H, ArH), 7.18 (t, J＝7.8 Hz, 1H, ArH), 7.09 (d, J＝7.8 Hz, 1H, ArH), 7.07 (s, 1H, ArH), 6.81 (d, J＝7.8 Hz, 1H, ArH), 3.04 (d, J＝15.0 Hz, 1H, CH₂), 2.81 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃), 2.20 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.76, 161.14, 143.45, 139.94, 135.08, 132.74, 132.43, 132.20, 131.29, 130.26, 127.13, 125.74, 125.09, 121.77, 118.81, 110.21, 104.34, 55.19, 52.71, 24.03, 21.08, 20.28.HRMS (ESI) calcd for C₂₂H₁₇N₃O₂SNa[M+Na]⁺ 410.0934, found 410.0940.

2'-氨基-7'-氯-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4o):白色粉末, 收率80%.m.p.288～290 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.74 (s, 1H, NH), 7.66 (dd, J＝7.8, 1.2 Hz, 1H, ArH), 7.48 (dd, J＝8.4, 1.2 Hz, 1H, ArH), 7.33～7.27 (m, 4H, ArH and NH₂), 7.26 (d, J＝7.8 Hz, 1H, ArH), 7.06 (t, J＝7.2 Hz, 1H, ArH), 6.92 (d, J＝7.8 Hz, 1H, ArH), 3.11 (d, J＝15.0 Hz, 1H, CH₂), 2.93 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.62, 161.05, 143.01, 142.45, 133.02, 131.89, 130.64, 130.46, 130.05, 129.07, 126.60, 125.39, 123.26, 122.71, 118.57, 110.56, 105.20, 55.07, 52.65, 24.17.HRMS (ESI) calcd for C₂₀H₁₂ClN₃O₂SNa [M+Na]⁺ 416.0231, found 416.0237.

2'-氨基-7'-氯-5-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4p):白色粉末, 收率85%.m.p.277～279 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 10.63 (s, 1H, NH), 7.66 (dd, J＝7.8, 1.2 Hz, 1H, ArH), 7.47 (dd, J＝7.8, 1.2 Hz, 1H, ArH), 7.30 (t, J＝7.8 Hz, 1H, ArH), 7.27 (s, 2H, NH₂), 7.09 (d, J＝9.0 Hz, 2H, ArH), 6.80 (d, J＝7.8 Hz, 1H, ArH), 3.11 (d, J＝15.0 Hz, 1H, CH₂), 2.93 (d, J＝15.0 Hz, 1H, CH₂), 2.26 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 177.54, 160.98, 142.88, 139.95, 132.96, 132.26, 132.08, 130.64, 130.43, 130.37, 129.06, 126.58, 125.82, 122.68, 118.64, 110.27, 105.32, 55.22, 52.72, 24.18, 21.08.HRMS (ESI) calcd for C₂₁H₁₄ClN₃O₂SNa[M+Na]⁺ 430.0388, found 430.0393.

2'-氨基-7, 9'-二氯-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4q):白色粉末, 收率82%.m.p.314～316 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.22 (s, 1H, NH), 7.74 (d, J＝2.4 Hz, 1H, ArH), 7.41 (s, 2H, NH₂), 7.39～7.33 (m, 2H, ArH), 7.31 (d, J＝8.4 Hz, 1H, ArH), 7.26 (d, J＝7.2 Hz, 1H, ArH), 7.12～7.08 (m, 1H, ArH), 3.10 (d, J＝15.0 Hz, 1H, CH₂), 2.96 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.67, 161.00, 142.63, 140.24, 133.62, 132.07, 130.84, 130.09, 129.69, 128.96, 128.73, 124.52, 124.13, 123.86, 118.42, 114.86, 105.64, 54.67, 53.54, 24.29.HRMS (ESI) calcd for C₂₀H₁₂Cl₂N₃O₂S[M+H]⁺ 428.0022, found 428.0025.

2'-氨基-9'-氯-5-硝基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4r):白色粉末, 收率60%.m.p.278～280 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.46 (s, 1H, NH), 8.28～8.27 (m, 1H, ArH), 8.19 (d, J＝2.4 Hz, 1H, ArH), 7.75 (d, J＝2.4 Hz, 1H, ArH), 7.49 (s, 2H, NH₂), 7.37 (dd, J＝8.4, 2.4 Hz, 1H, ArH), 7.32 (d, J＝8.4 Hz, 1H, ArH), 7.14 (d, J＝9.0 Hz, 1H, ArH), 3.11 (d, J＝15.0 Hz, 1H, CH₂), 3.03 (d, J＝15.0 Hz, 1H, CH₂); ¹³C NMR (150 MHz, DMSO-d₆)δ: 178.26, 161.18, 148.85, 144.36, 143.09, 132.72, 132.12, 130.81, 129.75, 128.98, 128.78, 127.27, 123.98, 121.29, 118.29, 111.05, 104.77, 53.93, 52.84, 24.16.HRMS (ESI) calcd for C₂₀H₁₂-ClN₄O₄S [M+H]⁺ 439.0267, found 439.0272.

2'-氨基-7-氯-9'-甲基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4s):白色粉末, 收率72%.m.p.308～310 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.18 (s, 1H, NH), 7.54 (s, 1H, ArH), 7.38～7.33 (m, 3H, ArH and NH₂), 7.23 (d, J＝7.2 Hz, 1H, ArH), 7.16 (d, J＝7.8 Hz, 1H, ArH), 7.13～7.07 (m, 2H, ArH), 3.02 (d, J＝15.0 Hz, 1H, CH₂), 2.85 (d, J＝15.0 Hz, 1H, CH₂), 2.32 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆)δ: 177.90, 161.16, 143.58, 140.21, 135.54, 133.98, 130.70, 129.99, 129.57, 127.27, 127.07, 124.72, 124.49, 124.06, 118.57, 114.80, 104.46, 54.68, 53.57, 24.42, 21.24.HRMS (ESI) calcd for C₂₁H₁₅ClN₃O₂S [M+H]⁺ 408.0568, found 408.0571.

2'-氨基-9'-甲基-5-硝基-2-氧代-5'H-螺[吲哚啉-3, 4'-苯并噻喃[4, 3-b]吡喃]-3'-甲腈(4t):白色粉末, 收率41%.m.p.280～282 ℃; ¹H NMR (600 MHz, DMSO-d₆) δ: 11.45 (s, 1H, NH), 8.28 (d, J＝2.4 Hz, 1H, ArH), 8.15 (d, J＝2.4 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.44 (s, 2H, NH₂), 7.20～7.12 (m, 3H, ArH), 3.03～2.96 (m, 2H, CH₂), 2.33 (s, 3H, CH₃); ¹³C NMR (150 MHz, DMSO-d₆) δ: 178.46, 161.34, 148.85, 144.34, 144.04, 135.54, 133.11, 130.76, 129.63, 127.28, 127.18, 127.06, 124.83, 121.07, 118.43, 111.00, 103.61, 53.91, 52.88, 24.29, 21.22.HRMS (ESI) calcd for C₂₁H₁₅N₄O₄S[M+H]⁺ 419.0814, found 419.0819.

辅助材料(Supporting Information) 化合物4a～4t的¹H NMR和¹³H NMR图谱.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 螺吲哚化合物生成的可能机理

Scheme 1 Proposed mechanism for the synthesis of spirooxindole compounds

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表 1 反应条件的影响

Table 1. Effect of reaction condition

Entry	Catalyst (mol%)	Frequency/kHz	Temperature/℃	Time/min	Yield/%
1	NaOH (20)	40	r.t	60	0
2	NaHCO₃(20)	40	r.t	60	0
3	Triethylamine (20)	40	r.t	60	0
4	L-proline (20)	40	r.t	60	0
5	Piperidine (10)	40	r.t	15	85
6	Piperidine (20)	40	r.t	15	91
7	Piperidine (30)	40	r.t	15	90
8	Piperidine (20)	40	40	15	85
9	Piperidine (20)	40	50	15	84
10	Piperidine (20)	25	r.t	15	75

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表 2 在超声辐射和普通条件下4a～4t的合成

Table 2. Synthesis of 4a～4t under both ultrasonic irradiation and conventional method

Compd.	R¹	R²	R³	R⁴	R⁵	Ultrasonic irradiation		Conventional
Compd.	R¹	R²	R³	R⁴	R⁵	Time/min	Yield/%	Time/min	Yield/%
4a	H	H	Cl	H	H	15	91	100	89
4b	H	H	Cl	CH₃	H	9	92	90	86
4c	H	H	F	H	H	15	88	90	81
4d	H	H	F	CH₃	H	9	94	90	80
4e	H	F	CH₃	H	H	25	80	90	76
4f	H	F	CH₃	CH₃	H	19	84	60	79
4g	F	H	H	H	H	12	94	45	91
4h	F	H	H	CH₃	H	12	96	45	87
4i	H	H	CH₃	H	H	22	88	120	83
4j	H	H	CH₃	CH₃	H	17	93	120	80
4k	H	Cl	Cl	H	H	8	91	45	90
4l	H	Cl	Cl	CH₃	H	8	91	45	86
4m	CH₃	H	H	H	H	26	83	120	81
4n	CH₃	H	H	CH₃	H	22	87	90	70
4o	Cl	H	H	H	H	18	80	90	65
4p	Cl	H	H	CH₃	H	14	85	90	72
4q	H	H	Cl	H	Cl	22	82	120	80
4r	H	H	Cl	NO₂	H	35	60	210	55
4s	H	H	CH₃	H	Cl	45	72	240	65
4t	H	H	CH₃	NO₂	H	60	41	360	35

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表 3 目标化合物的最小抑菌浓度^a

Table 3. Minimum inhibitory concentrations of target compounds

Compd.	MIC/(μg•mL^-1)
Compd.	C.n.	C.a.	E.f.	M.r.	M.g.
4a	64	128	64	32	32
4b	32	> 128	64	16	128
4c	64	> 128	32	64	64
4d	32	128	32	64	128
4e	64	> 128	16	16	64
4f	16	> 128	8	16	64
4g	64	64	64	64	128
4h	32	128	64	128	64
4i	128	128	128	64	128
4j	64	> 128	64	64	64
4k	64	> 128	64	64	64
4l	64	128	64	128	128
4m	128	> 128	128	> 128	64
4n	128	> 128	128	128	64
4o	64	128	64	64	128
4p	128	128	64	64	64
4q	64	64	32	128	128
4r	32	128	64	64	64
4s	128	128	128	64	128
4t	128	128	64	32	64
F	32	16	32	32	16
B	4	2	2	4	2
^aF:氟康唑(Fluconazole); B:两性霉素B (Amphotericin B).

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