English

• 吡喃并[2, 3-c]吡唑类杂环化合物是构成天然产物的重要结构单元，具有重要的生物活性和药理活性，已广泛应用于合成医药和可生物降解农药^[1-13]。因此该类化合物的合成一直受到化学工作者的关注。一般可以通过两组分或三组分反应制备吡喃并[2, 3-c]吡唑，近年来，催化乙酰乙酸乙酯、水合肼、醛和丙二腈为原料的四组分反应合成这类化合物逐渐成为研究热点^[13-14]。已经发展了多种催化体系，催化剂主要包括十六烷基三甲基氯化铵^[15]、[Dsim]AlCl₄^[16]、尿素^[17]、NaOH^[18]、椰油酰胺丙基甜菜碱^[19]、[Ni(L)(mimi)]^[20]、NaOAc^[21-22]、二氧化硫脲^[23]、1-(羧甲基)碘化吡啶鎓^[24]、牛血清白蛋白^[25]、柠檬汁^[26]、吗啉三氟甲磺酸酯^[14]、三苯甲基碳阳离子^[5]和[DMDBSI]·2HSO₄^[27]等。此外，超声波^[28-29]、研磨法^[30]和电化学^[31]等方法也可以合成吡喃并[2, 3-c]吡唑衍生物。上述方案均有各自的优点，然而，寻求更有效、可行的绿色方法来合成这类化合物仍然是有机化学研究的热点^{[23, 27, 30-32]}。

  磷酸氢盐是化学品市场上最常见的化学药剂，广泛用于化肥和食品添加剂等方面^[33-35]。它们具有绿色环保、价格低廉、水溶性好和分离方便等优点^[36-39]，作为催化剂已经应用于许多有机化学反应中，例如合成多氢喹啉^[40]和3, 4-二氢吡喃并[c]色烯^[41]。发展以磷酸氢盐作为催化剂的绿色有机合成方法和“一锅法”多组分反应制备各种杂环化合物是我们实验室的重要研究方向之一^[42-44]。另外，使用环保的试剂、催化剂和溶剂是绿色化学的基础^[45-46]。水^[47-49]和聚乙二醇(PEG)^[50-53]均为现代有机合成反应中常用的绿色溶剂和有效的反应促进剂^[54-57]。亦有报道用水和PEG的混合液作为绿色反应介质，其中PEG作为共溶剂、相转移催化剂或无机盐的配位溶剂使用从而提高负离子与有机反应物的反应活性^[58-59]。因此，本文在我们实验室前期工作的基础上重点研究在水和PEG的混合溶液中，磷酸盐作为催化剂促进醛、丙二腈、乙酰乙酸乙酯和水合肼的四组分“一锅法”反应，合成吡喃并[2, 3-c]吡唑衍生物(Scheme 1)。

  Scheme 1

  

  Scheme 1.  Synthesis of pyranopyrazole derivatives

  下载: 全尺寸图片 幻灯片

  1.   实验部分

  1.1   仪器和试剂

  X-5型数字熔点仪(温度未经校正) (北京泰克仪器有限公司)；Bruker TENSOR 27型傅里叶变换红外光谱仪(FT-IR，德国Bruker公司)，KBr压片；Bruker Avance 500 MHz型核磁共振波谱仪(NMR，德国Bruker公司)，氘代二甲亚砜(DMSO-d₆)为溶剂，四甲基硅烷(TMS)为内标。

  实验中使用的芳香醛均为分析纯试剂，购自于阿拉丁试剂有限公司(上海)或萨恩化学技术有限公司(上海)；丙二腈(≥99%)和水合肼(≥98%)均购自于上海阿拉丁试剂有限公司；乙酰乙酸乙酯购自于天津大茂化学试剂厂。PEG-200/400均为分析纯试剂，购自于科密欧化学试剂有限公司(天津)。

  1.2   实验方法

  目标化合物5的合成：向10 mL耐压管中加入20%K₂HPO₄·3H₂O、乙酰乙酸乙酯(0.5 mmol)、水合肼(0.5 mmol)、水和PEG的混合溶液(体积比1:1)1 mL，50 ℃下搅拌20 min。紧接着，将丙二腈(0.5 mmol)和苯甲醛(0.5 mmol)或取代的芳族醛(0.55 mmol)加入混合物中，并在50 ℃下继续搅拌1.5 h。反应完成后直接向体系中加入1.5 mL 50%乙醇，剧烈搅拌10 min以除去杂质、催化剂和PEG-200。将混合物在冰浴中冷却后抽滤，滤饼用冷的25%乙醇溶液洗涤。产物不需要再进一步提纯就可以得到纯净的化合物，且产物均通过IR光谱、¹H NMR和¹³C NMR进行表征。

  2.   结果与讨论

  2.1   反应条件的筛选

  根据实验设想，我们以乙酰乙酸乙酯、水合肼、丙二腈和苯甲醛(摩尔比1:1:1:1)作为模型底物，优化反应条件，结果见表 1。首先，分别考察KH₂PO₄、K₂HPO₄·3H₂O和K₃PO₄·3H₂O这3种磷酸盐对反应的催化效果(表 1，Entries 1~3)。如表 1所示，在50 ℃的PEG-400水溶液中反应1.5 h后，碱性较强的K₃PO₄催化的反应产率最低，弱碱性的K₂HPO₄·3H₂O催化的反应产率较高。我们继续筛选其他碱性的盐如NaHCO₃和K₂CO₃，趋势与之前相同、效果均不如K₂HPO₄·3H₂O(表 1, Entries 4~5)。反应现象与文献报道一致，弱酸性条件有利于活化醛羰基、弱碱性条件有利于活化亲核试剂、碱性过强可能引发副反应。随后，我们考察了溶剂对反应的影响。当用PEG-200代替PEG-400作为溶剂与水混合时产率有小幅度的上升(表 1, entry 6)。作为对照，在1 mL水或1 mL PEG-200中进行反应得到的产率较低(表 1, Entries 8~9)，并且改变混合溶液中水和PEG-200的体积或比例产率并没有升高，水和PEG-200的体积比是1:1，总量1 mL时效果最好(表 1, Entries 10~13)。接下来继续考察了温度和时间对反应的影响。结果表明，最佳反应温度为50 ℃，升高或降低反应温度产率均有一定程度的下降；最佳反应时间为1.5 h，缩短反应时间会使产率降低。最后，考察催化剂的用量发现，增加催化剂用量产率不变，降低催化剂用量到15%时，产率降低到91%(表 1, Entry 16)。

  表 1

  

  表 1  反应条件的优化

  Table 1.  Optimization of reaction conditions

  下载: 导出CSV

  Entrya	Catalyst	Solvent	V/mL	Temperature/℃	Yieldb/%
  1	KH2PO4	PEG-400:H2O	0.5/0.5	50	92
  2	K3PO4·3H2O	PEG-400:H2O	0.5/0.5	50	90
  3	K2HPO4·3H2O	PEG-400:H2O	0.5/0.5	50	95
  4	NaHCO3	PEG-400:H2O	0.5/0.5	50	91
  5	K2CO3	PEG-400:H2O	0.5/0.5	50	88
  6	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	98
  7	K2HPO4·3H2O	EtOH:H2O	0.5/0.5	50	94
  8	K2HPO4·3H2O	PEG-200	1.0	50	85
  9	K2HPO4·3H2O	H2O	1.0	50	68
  10	K2HPO4·3H2O	PEG-200:H2O	0.35/0.65	50	96
  11	K2HPO4·3H2O	PEG-200:H2O	0.65/0.35	50	95
  12	K2HPO4·3H2O	PEG-200:H2O	0.25/0.25	50	92
  13	K2HPO4·3H2O	PEG-200:H2O	0.75/0.75	50	98
  14	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	40	90
  15	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	60	93
  16c	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	91
  17d	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	98
  a.Reaction condition: 0.5 mmol substrate, mole fraction 20% catalyst; b.isolated yield; c.mole fraction 15% catalyst; d.mole fraction 25% catalyst.

  2.2   反应对不同底物的普适性

  在确定的最佳反应条件下，系统地考察了不同的醛与水合肼、乙酰乙酸乙酯和丙二腈的四组分“一锅法”反应。因为部分取代的苯甲醛受电子效应和空间效应的影响反应活性降低，所以统一增加芳香醛的物质的量到0.55 mol。如表 2所示，大多数芳香醛均能顺利地参与四组分反应，并以良好的产率得到相应的目标产物，但均略低于苯甲醛的反应结果。由表可以很明显地看出，芳香醛的反应活性受到取代基电子效应和空间效应的影响。弱吸电子基团取代的苯甲醛反应效果优于给电子和强吸电子基团(表 2, Entries 2~7)，而且邻位取代的结果最好。当在苯环上引入强吸电子基团时不利于反应的进行，例如硝基和氟，仅得到88%~91%的产率(表 2, Entries 8, 10~11)。但间硝基底物却得到了相对较高的产率，达到95%(表 2, Entry 9)。这种现象表明，苯环上和羰基上的电子云密度降低太多会导致产率下降。换句话说，苯甲醛的羰基被过度活化并不利于反应进行。体积较大的溴能够阻碍羰基与苯环的共轭，在间位的硝基对羰基的吸电子作用会弱很多，这可能是两种底物产率略高的原因。对于含有供电子基团的苯甲醛，邻位底物的产率略低于对位和间位底物，主要是受空间位阻影响。

  表 2

  

  表 2  化合物5的底物扩展

  Table 2.  Scope of substrate for the synthesis of compound 5

  下载: 导出CSV

  Entrya	Products	Ar	Yieldb/%
  1	5a	C6H5	98
  2	5b	2-BrC6H4	98
  3	5c	3-BrC6H4	93
  4	5d	4-BrC6H4	92
  5	5e	2-ClC6H4	96
  6	5f	3-ClC6H4	92
  7	5g	4-ClC6H4	90
  8	5h	2-NO2C6H4	88
  9	5i	3-NO2C6H4	95
  10	5j	4-NO2C6H4	91
  11	5k	4-FC6H4	88
  12	5l	2-CH3C6H4	92
  13	5m	3-CH3C6H4	92
  14	5n	4-CH3C6H4	95
  15	5o	2-OCH3C6H4	91
  16	5p	3-OCH3C6H4	93
  17	5q	4-OCH3C6H4	93
  a.Reacted at 50 ℃ for 1.5 h with 1.1 equiv. of aldehyde; b.isolated yield.

  3.   结论

  本文在K₂HPO₄·3H₂O催化下，高产率地实现了乙酰乙酸乙酯、水合肼、芳香醛与丙二腈进行4组分“一锅法”反应，合成了一系列1, 4-二氢吡喃并[2, 3-c]吡唑衍生物。此方法最突出的优点是绿色环保、反应条件温和、催化剂廉价易得、后处理和提纯简单。

  辅助材料(Supporting Information)[化合物5a~5q的IR、¹H NMR、¹³C NMR数据及谱图]可以免费从本刊网站(http://yyhx.ciac.jl.cn/)下载。

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  Scheme 1  Synthesis of pyranopyrazole derivatives

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  表 1  反应条件的优化

  Table 1.  Optimization of reaction conditions

  Entrya	Catalyst	Solvent	V/mL	Temperature/℃	Yieldb/%
  1	KH2PO4	PEG-400:H2O	0.5/0.5	50	92
  2	K3PO4·3H2O	PEG-400:H2O	0.5/0.5	50	90
  3	K2HPO4·3H2O	PEG-400:H2O	0.5/0.5	50	95
  4	NaHCO3	PEG-400:H2O	0.5/0.5	50	91
  5	K2CO3	PEG-400:H2O	0.5/0.5	50	88
  6	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	98
  7	K2HPO4·3H2O	EtOH:H2O	0.5/0.5	50	94
  8	K2HPO4·3H2O	PEG-200	1.0	50	85
  9	K2HPO4·3H2O	H2O	1.0	50	68
  10	K2HPO4·3H2O	PEG-200:H2O	0.35/0.65	50	96
  11	K2HPO4·3H2O	PEG-200:H2O	0.65/0.35	50	95
  12	K2HPO4·3H2O	PEG-200:H2O	0.25/0.25	50	92
  13	K2HPO4·3H2O	PEG-200:H2O	0.75/0.75	50	98
  14	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	40	90
  15	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	60	93
  16c	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	91
  17d	K2HPO4·3H2O	PEG-200:H2O	0.5/0.5	50	98
  a.Reaction condition: 0.5 mmol substrate, mole fraction 20% catalyst; b.isolated yield; c.mole fraction 15% catalyst; d.mole fraction 25% catalyst.

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  表 2  化合物5的底物扩展

  Table 2.  Scope of substrate for the synthesis of compound 5

  Entrya	Products	Ar	Yieldb/%
  1	5a	C6H5	98
  2	5b	2-BrC6H4	98
  3	5c	3-BrC6H4	93
  4	5d	4-BrC6H4	92
  5	5e	2-ClC6H4	96
  6	5f	3-ClC6H4	92
  7	5g	4-ClC6H4	90
  8	5h	2-NO2C6H4	88
  9	5i	3-NO2C6H4	95
  10	5j	4-NO2C6H4	91
  11	5k	4-FC6H4	88
  12	5l	2-CH3C6H4	92
  13	5m	3-CH3C6H4	92
  14	5n	4-CH3C6H4	95
  15	5o	2-OCH3C6H4	91
  16	5p	3-OCH3C6H4	93
  17	5q	4-OCH3C6H4	93
  a.Reacted at 50 ℃ for 1.5 h with 1.1 equiv. of aldehyde; b.isolated yield.

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