涉及碳-碳键断裂的克莱森-施密特缩合反应

引用本文: 杨永青, 朱孟楠, 陆征, 陈立婷, 苏静. 涉及碳-碳键断裂的克莱森-施密特缩合反应[J]. 有机化学, 2016, 36(5): 1073-1079. doi: 10.6023/cjoc201509040 shu

Citation: Yang Yong-Qing, Zhu Meng-Nan, Lu Zheng, Chen Li-Ting, Su Jing. Claisen-Schmidt Condensation Involved with C—C Bond Cleavage[J]. Chinese Journal of Organic Chemistry, 2016, 36(5): 1073-1079. doi: 10.6023/cjoc201509040 shu

涉及碳-碳键断裂的克莱森-施密特缩合反应

1.
江苏大学药学院镇江 212013

通讯作者: 杨永青,E-mail: yqy@ujs.edu.cn

基金项目:
国家自然科学基金 No.21572118

江苏高校优势学科建设工程 PAPD

和江苏大学高级人才启动基金 Nos.10JDG042,14JDG018

摘要: 研究了BaOH₂促进的β-二酮与芳香醛的克莱森-施密特反应,反应产物可能为单烯烃或双烯烃化合物.单烯烃的生成涉及碳-碳键的断裂,双烯烃产物是姜黄素的三元环类似物.

关键词:

English

我们尝试发展一种路线简洁、操作简便的合成姜黄素类化合物的方法(Scheme 1),在其中关键的克莱森-施密特反应一步中,我们没有得到预期的结果,却意外发现了通过克莱森-施密特反应和碳-碳键断裂一锅法生成α,β-不饱和酮的方法.

图图式1 计划的姜黄素类化合物的合成路线

Figure 图式1. Planned synthetic route to curcumin and its analogues

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图1 姜黄素(1)与FLLL32 (2)的结构

Figure 1. The structures for curcumin (1) and FLLL32 (2)

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α,β-不饱和酮是一类引起有机化学家广泛兴趣的化合物. 它们具有广泛的化学反应性质^[1]和生理活性^[2]. 合成这类化合物的方法研究一直是有机化学的热点. 目前已经有多种高效合成这类化合物的方法——叶立德反应^[3]、缩合反应^[4]以及金属参与的反应^[5]等. 叶立德反应可以高效地生成多种不饱和羰基化合物,不过反应中产生大量含磷副产物影响了这类反应的广泛应用. 金属参与的反应拓展了不饱和酮的合成方法,但由于反应中使用催化剂或是底物不易制备,故其应用受到限制. 醛酮的缩合反应是制备α,β-不饱和酮的重要手段,克莱森-施密特反应虽然早在19世纪就已被发现^[6],但是至今仍然有着广泛的用途^[7]. 姜黄素(1)是一种对多种生物靶点具有活性的化合物^[8],Li等^[9]发现它的类似物FLLL32 (2)也具有相当吸引人的生物活性.

1 结果与讨论

化合物5a对所有使用的醛来说都是好的反应底物,它与苯甲醛以及对溴苯甲醛反应都得到了优秀的产率(表 3,Entry 2,94%; Entry 3,96%). 使用对二甲氨基苯甲醛时,反应收率42% (Entry 5),说明二甲氨基导致醛的反应活性降低. 化合物5c和苯甲醛的反应没有生成脱除酰基的化合物8,而是3,3-三亚甲基-6-苯基-2,4-己二酮-5-烯(9). 化合物5d可以和许多醛反应,不过与供电子醛反应时产率很低(Entries 10,12),显示供电子醛与这个底物的反应性能不匹配.

底物混合物中加入碱时,生成烯醇盐即受到芳香醛猝灭而后脱酰生成化合物8,生成双烯醇盐M2的可能性较低,因而不易生成化合物7. 不过也有反应同时生成化合物7和8(表 3,Entries 10,12),表明两种可能都是存在的. 二酮底物5a,5b和5c可能是因为酸性较低,不能形成双烯醇盐,因而无法得到双烯烃化合物7.

因为我们使用的底物5没有裸露的活性亚甲基,反应无需保护,通过我们的缩合反应可以由简单操作合成3,5-二氧代-1,7-二芳基-4,4-二亚甲基-1,6-庚二烯类化合物7db,收率(90%)高于通过复杂反应得到3,5-二氧代- 1,7-二芳基-1,6-庚二烯类化合物的反应(1,7-二苯基-5-羟基-1,4,6-庚三烯-3-酮,50%)^[11]. 我们从乙酰丙酮合成化合物7da的总收率为40%,文献中得来FLLL32的收率为28%^[9b,11],两种方法都能适用,但我们的方法更有优势(比较我们使用的缩合反应和文献中的Pabon缩合反应收率).

在若干反应(表 3,Entries 3,10,12,13)中,除了化合物8以外,还分离了对应的肉桂酸(10)^[12]. 我们分别将化合物5d与二烯烃化合物7dd置于甲醇-氢氧化钡溶液中搅拌1 d,以高于90%的收率回收这些化合物,显示化合物5d和7dd在反应条件下都很稳定. 基于这些发现,我们认为这个反应的机理可能是这样的: β-二酮化合物5d和氢氧化钡反应,生成单烯醇盐M1,它可以进一步和氢氧化钡反应生成双烯醇盐M2,随后与醛反应两次,经过单烯烃-烯醇中间体M3得到双烯烃产物7. 单烯烃-烯醇中间体M3也可以异构化成为中间体M4,M4的烯酮羰基接受氢氧根的亲核进攻生成中间体M5,该中间体可发生C—C键的断裂反应生成中间体M6,M6和醛反应可以得到单烯烃8,过程中还会生成肉桂酸化合物10.

表1 多亚甲基戊二酮与芳香醛缩合生成双烯烃^a Table1. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare dialkene

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Entry	n (5)	Ar (6)	Yield^b/% (7)
1	4 (5a)	3,4-diMeOC₆H₃ (6a)	0
2	4 (5a)	Ph (6b)	0
3	3 (5b)	Ph (6b)	0
4	2 (5c)	Ph (6b)	0
5	1 (5d)	3,4-diMeOC₆H₃ (6a)	57 (7da)
6	1 (5d)	Ph (6b)	90 (7db)
7	1 (5d)	4-MeOC₆H₄ (6c)	78 (7dc)
8	1 (5d)	4-BrC₆H₄ (6d)	32 (7dd)^c
9	1 (5d)	4-NO₂C₆H₄ (6e)	47 (7de)^d
^aDiketone was added into suspension of barium hydroxide octahydrate in methanol. Aldehyde was added 10 min later. ^b Isolated yield. ^c Compound 5 (25%) is recovered after acidic work-up. ^d Compound 5 (15%) is recovered after acidic work-up.

表1 多亚甲基戊二酮与芳香醛缩合生成双烯烃^a
Table1. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare dialkene

表2 多亚甲基戊二酮与芳香醛缩合生成单烯烃的条件筛选 Table2. Condition screening for condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene

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Entry	Base	Concentration/(mol•L^-1)	Yield^a/%
1	Ba(OH)₂^b	0.05	＜5
2	Ba(OH)₂^c	0.05	65
3	Ba(OH)₂^d	0.05	35
4	Ba(OH)₂	0.5	86
5	NaOH	0.5	39
6	DBU	0.5	72 ^e
7	TEA	0.5	0 ^f
^a Isolated yield; ^b Diketone was added into suspension of barium hydroxide octahydrate in methanol. 2.2 equiv. of aldehyde were added 10 min. later; ^c Base was added into mixture of substrates; ^d Only 1.2 equiv. of aldehyde were used in the order in method b; ^e The reaction course was 53 d; ^f No product was detected in 4 d.

表2 多亚甲基戊二酮与芳香醛缩合生成单烯烃的条件筛选
Table2. Condition screening for condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene

得到这些结果以后,我们就开始研究反应的底物适应性,结果在表 3中列出.

令人失望的是,这个条件下并没有生成FLLL32 (表 1,Entry 1). 除了回收的二甲氧基苯甲醛(6a),还得到了一种只有一个羰基的化合物. 使用苯甲醛(6b)作为亲电试剂(表 1,Entry 2)也没有得到期待的产物. 使用含有较少亚甲基的二酮化合物作为反应底物与苯甲醛反应,只有三元环化合物在和苯甲醛反应时得到了预期的双烯烃产物(表 1,Entry 6). 有较大环的二酮都没能生成我们期待的产物(表 1,Entries 2～4). 为了研究苯甲醛上取代基对反应的影响,用3,3-双亚甲基-3,5-戊二酮(5d)和各种取代苯甲醛进行反应(表 1,Enties 5,7～ 9). 虽然反应产率不一,但是反应都能顺利发生. 各种取代苯甲醛的反应产率(32%～78%)都低于苯甲醛(90%). 供电子基(4-MeO,Entry 7)比其它取代基好一些,强吸电子取代基(4-NO₂,Entry 9)和弱吸电子取代基(4-Br,Entry 8)的收率更低. 在苯甲醛上引入第二个供电子取代基(Entry 5)会导致反应收率的进一步下降.

生成双烯烃产物7的途径是两次克莱森-施密特缩合,生成单烯烃的途径中则多了C—C键的断裂. 因为分离到了化合物9,我们认为很可能存在中间体M4. C—C键断裂时中间体M4的两个羰基都可能接受进攻,成为断裂的那部分. 虽然文献报道的逆克莱森反应断裂的基团都是简单的羧酸^[13],不过检测时都发现了超过产物8产率一半的肉桂酸产物10,我们认为羟基进攻烯酮羰基,生成中间体M6后再次发生缩合得到化合物8是生成化合物8的主要途径.

表3 多亚甲基戊二酮与芳香醛缩合生成单烯烃 Table3. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene

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Entry^a	n (5)	Ar (6)	Yield^b/% (8)
1	4 (5a)	3,4-(MeO)₂C₆H₃ (6a)	86 (8aa)
2	4 (5a)	Ph (6b)	94 (8ab)
3	4 (5a)	4-BrC₆H₄ (6d)	96 (8ad)
4	4 (5a)	4-NO₂C₆H₄ (6e)	81 (8ae)
5	4 (5a)	4-Me₂NC₆H₄ (6f)	42 (8af)^c
6	3 (5b)	3,4-(MeO)₂C₆H₃ (6a)	80 (8ba)
7	3 (5b)	Ph (6b)	40 (8bb)^c
8	3 (5b)	4-BrC₆H₄ (6d)	78 (8bd)
9^d	2 (5c)	Ph (6b)	40 (9) ^c
10 ^e	1 (5d)	3,4-(MeO)₂C₆H₃ (6a)	12 (8da)
11	1 (5d)	Ph (6b)	83 (8db)
12 ^f	1 (5d)	4-MeOC₆H₄ (6c)	26 (8dc)
13	1 (5d)	4-BrC₆H₄ (6d)	70 (8dd)
14	1 (5d)	4-NO₂C₆H₄ (6e)	64 (8de)
15	1 (5d)	4-Pyridyl (6g)	75 (8dg)
^a To a mixture of diketone (1.0 mmol) and benzaldehyde (2.2 mmol) in methanol (2 mL) was added barium hydroxide octahydrate (2.2 mmol) at r.t. The reaction was monitored by TLC until diketone was consumed. ^b Isolated yield. ^c The only isolated product from complex midture. ^d 3,3-Trimethylene-6- phenyl-2,4-hexadione-5-ene (9) was isolated as the product. ^e Compound 7da was isolated (yield 11%) too. ^f Compound 7dc was isolated (yield 20%) too.

表3 多亚甲基戊二酮与芳香醛缩合生成单烯烃
Table3. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene

化合物5d在氢氧化钡作用下和芳香醛的反应与含有大一些环的化合物(5a～5c)完全不同,这引起我们很大的兴趣. 在化合物5a与化合物6a的反应中,虽然未能得到预期的双烯烃化合物,但是分离到一个产物,通过氢谱、碳谱、红外和质谱鉴定该化合物是1-环己基- 3-(3,4-二甲氧基苯基)丙烯酮(8aa)(＜5%)(表 2,Entry 1). 在筛选条件时发现改变加料顺序,即从把醛加入二酮与碱的混合液中改成把碱加入醛和二酮的混合物中,化合物8aa的收率提高到了65% (Entry 2),如果提高反应液浓度则反应产率进一步提高到86% (Entry 4). 因为反应产物中只有一个苯基,所以我们尝试降低醛的用量(从2.2 equiv. 降到1.2 equiv.,Entry 3 vs. Entry 2),结果反应收率降低到35%. 我们也对反应中使用的碱作了筛选,使用氢氧化钠作碱,反应速度有所提升(10 h vs. 13 h,Entry 5 & Entry 4),但反应收率降低到39%. 使用有机碱则导致反应速度大幅降低,以DBU为碱时反应53 d后原料5a消失,得到了产物8aa (产率72%,Entry 6),而以三乙胺作碱反应4 d没有观察到反应的发生(Entry 7).

对生成化合物7和8的选择问题,我们认为三元环底物5d与氢氧化钡反应一段时间后可以形成双烯醇盐M2,这个中间体可以与两分子醛反应生成产物7,而向

虽然没有在文献中见到3,3-多亚甲基-2,4-戊二酮与芳香醛的缩合反应,不过3,3-二甲基-2,4-戊二酮与芳香醛的缩合反应已有报道^[10]. 我们希望3,3-多亚甲基-2,4-戊二酮(5)可以在相同的条件下发生反应,产生对称的双烯烃化合物7. 我们首先尝试的底物是3,3-五亚甲基-2,4-戊二酮(5a)和3,4-二甲氧基苯甲醛(6a),如果反应如我们所期望的发生,得到的产物就是FLLL32.

2 结论

氢氧化钡可以促进3,3-多亚甲基-2,4-戊二酮与芳香醛的反应,生成双烯烃或单烯烃产物. 碱与底物加入反应体系的顺序可能导致不同产物的生成,这种现象迄今尚未见诸文献报道. 分析反应中得到的各种化合物,我们提出了这种调控反应可能的机理. 除了生成的两类烯酮化合物以外,这个反应也可能提供一种在温和条件下生成肉桂酸类化合物的办法.

3 实验部分

3.1 仪器与试剂

图4 可能的反应机理

Figure 4. Possible reaction mechanism

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熔点测定使用上海精密科学仪器有限公司WRS-1B数字熔点仪; 红外使用Thermo Nicolet Avatar 370 DTGS红外谱仪; 核磁共振使用Bruker AV500或DRX 400; 质谱使用Thermo LXQ线型离子阱质谱仪. 化合物5a,5b^[14],5c,5d^[15]依照文献方法以乙酰丙酮和二溴烷烃在碱性条件下合成,产率分别为60%,63%,73%和70%.

3.2 实验方法

3.2.2 缩合反应制备单烯烃化合物

3-(4-溴苯基)丙烯酸(10d)^[22]: 白色固体,收率42%. m.p. 254.0～256.0 ℃; ¹H NMR (400 MHz,DMSO-d₆) δ: 6.57 (d,J=16.0 Hz,1H),7.56 (d,J=16.0 Hz,1H),7.60 (d,J=8.4 Hz,2H),7.65 (d,J=8.8 Hz,2H),12.48 (s,1H); FT-IR (KBr) v: 2833,1685,1626,1585 cm^-1; EI-MS m/z: 228 (M+2)⁺,226 (M⁺,100),227 (M+1)⁺,225 (M-1)⁺.

1-环丙基-3-(4-硝基基苯基)丙烯酮(8de): 浅黄色固体,收率64%. m.p. 109.3～109.9 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.02～1.07 (m,2H),1.19～1.23 (m,2H),2.24～2.30 (m,1H),6.99 (d,J=16.0 Hz,1H),7.62 (d,J=16.0 Hz,1H),7.72 (d,J=8.8 Hz,2H),8.26 (d,J=8.8 Hz,2H); FT-IR (KBr) v: 2926,1676,1616,1515 cm^-1; EI- HRMS calcd for C₁₂H₁₁NO₃ ([M]⁺): 260.1281,found 217.0734.

向盛有3,3-五亚甲基-2,4-戊二酮(124 mg,0.74 mmol)和3,4-二甲氧基苯甲醛(267 mg,1.61 mmol)的甲醇(1.5 mL)溶液的反应瓶中加入八水合氢氧化钡(514 mg,1.63 mmol). 室温下搅拌直到TLC显示二酮底物消失. 以盐酸(5%,10 mL)淬灭反应,乙酸乙酯(15 mL×3)萃取. 有机相依次以水(15 mL)、碳酸氢钠饱和溶液(15 mL)和饱和食盐水(15 mL)洗,硫酸钠干燥后浓缩至干. 残余物以硅胶柱层析[V(乙酸乙酯):V(石油醚)=1:5]得到1-环己基-3-(3,4-二甲氧基苯基)丙烯酮(8aa),黄色油状液体176 mg,产率86%. ¹H NMR (400 MHz,CDCl₃) δ: 1.14～1.43 (m,5H),1.66 (d,J=12.0 Hz,1H),1.76～1.86 (m,4H),2.62 (tt,J=11.2,3.2 Hz,1H),3.86 (s,3H),3.87 (s,3H),6.64 (d,J=16.0 Hz,1H),6.82 (d,J=8.4 Hz,1H),7.04 (d,J=1.6 Hz,1H),7.09 (dd,J=8.4,1.6 Hz,1H),7.49 (d,J=16.0 Hz,1H); ¹³C NMR (100 MHz,CDCl₃) δ: 25.8,25.9,28.8,49.1,55.8,55.9,109.6,111.0,122.7,123.0,127.6,142.3,149.1,151.1,203.2; FT-IR (film) v: 21,1670,1592 cm^-1; ESI-HRMS calcd for C₁₇H₂₃O₃ ([M+H]⁺): 275.1642,found 275.1642.

1-环己基-3-(4-硝基基苯基)丙烯酮(8ae): 浅黄色固体,收率81%. m.p. 133.0～133.3 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.24～1.49 (m,5H),1.71～1.74 (m,1H),1.83～1.94 (m,4H),2.66 (tt,J=11.2,3.2 Hz,1H),6.94 (d,J=16.0 Hz,1H),7.61 (d,J=16.0 Hz,1H),7.72 (d,J=8.8 Hz,2H),8.25 (d,J=8.8 Hz,2H); ¹³C NMR (100 MHz,CDCl₃) δ: 25.8,25.9,28.6,49.9,124.2,128.2,128.9,139.2,141.1,148.5,202.5; FT-IR (KBr) v: 2928,1683,1612 cm^-1; ESI-HRMS calcd for C₁₅H₁₈NO₃ ([M+H]⁺): 260.1281,found 260.1282.

1-环己基-3-苯基丙烯酮(8ab)^[16]: 黄色油状液体,收率94%. ¹H NMR (400 MHz,CDCl₃) δ: 1.22～1.45 (m,5H),1.71 (d,J=12.4 Hz,1H),1.81～1.92 (m,4H),2.66 (tt,J=11.2,3.2 Hz,1H),6.81 (d,J=16.0 Hz,1H),7.37～7.39 (m,3H),7.55～7.61 (m,3H); FT-IR (film) v: 2927,1685,1609 cm^-1; EI-MS m/z: 241 (M⁺),131 (100).

环戊基-3-(3,4-二甲氧基苯基)丙烯酮(8ba): 浅黄色油状液体,收率80%. ¹H NMR (400 MHz,CDCl₃) δ: 1.63～1.72 (m,4H),1.84～1.89 (m,4H),3.17～3.25 (m,1H),3.92 (s,3H),3.93 (s,3H),6.67 (d,J=16.0 Hz,1H),6.88 (d,J=8.0 Hz,1H),7.08 (s,1H),7.14 (dd,J=8.2,1.8 Hz,1H),7.54 (d,J=16.0 Hz,1H); ¹³C NMR (100 MHz,CDCl₃) δ: 26.3,29.6,49.6,56.0,56.1,109.8,111.1,123.0,124.0,127.8,142.4,149.3,151.2,202.7; FT-IR (film) v: 2954,1687,1659,1611 cm^-1; ESI-HRMS calcd for C₁₆H₂₁NO₃ ([M+H]⁺): 261.1485,found 261.1486.

1-环丙基-3-(4-吡啶基)丙烯酮(8dg): 浅黄色油状液体,收率75%. ¹H NMR (400 MHz,CDCl₃) δ: 0.99～1.04 (m,2H),1.18 (quint,J=3.8 Hz,2H),2.24 (tt,J=7.8,4.6 Hz,1H),6.99 (d,J=16.0 Hz,1H),7.40 (d,J=6.0 Hz,2H),7.48 (d,J=16.0 Hz,1H),8.65 (d,J=6.0 Hz,2H); ¹³C NMR (100 MHz,CDCl₃) δ: 12.1,20.2,122.1,130.3,138.8,142.3,150.5,199.7; FT-IR (film) v: 2924,1682,1595 cm^-1; ESI-HRMS calcd for C₁₁H₁₂NO ([M+H]⁺): 174.0913,found 174.0912.

3-(3,4-二甲氧基苯基)丙烯酸(10a)^[18]: 浅黄色固体,收率10%. m.p. 183.3～183.6 ℃; ¹H NMR (400 MHz,DMSO-d₆) δ: 3.79 (s,3H),3.80 (s,3H),6.44 (d,J=16.0 Hz,1H),6.97 (d,J=8.4 Hz,1H),7.20 (dd,J=7.6,2.0 Hz,1H),7.31 (d,J=1.6 Hz,1H),7.52 (d,J=16.0 Hz,1H),12.20 (brs,1H); FT-IR (KBr) v: 2939,2841,1681,1625,1596 cm^-1; ESI-MS m/z: 209.1 (M+1)⁺.

1-环丙基-3-苯基丙烯酮(8db)^[19]: 浅黄色油状液体,收率83%. ¹H NMR (400 MHz,CDCl₃) δ: 0.96 (td,J=7.6,4.0 Hz,2H),1.16 (quint,J=3.8 Hz,2H),2.24 (tt,J=16.0,4.4 Hz,1H),6.87 (d,J=16.8 Hz,1H),7.37～7.38 (m,3H),7.54～7.56 (m,2H),7.61 (d,J=16.4 Hz,1H); FT-IR (film) v: 3008,1678,1645,1611 cm^-1; EI-MS m/z: 172 (M⁺),171 (100).

3-(4-甲氧基苯基)丙烯酸(10c)^[21]: 浅黄色固体,收率20%. m.p. 172.5～174.0 ℃; ¹H NMR (400 MHz,CD₃OD) δ: 3.83 (s,3H),6.34 (d,J=16.0 Hz,1H),6.96 (d,J=8.8 Hz,2H),7.54 (d,J=8.8 Hz,2H),7.62 (d,J=16.0 Hz,1H); FT-IR (KBr) v: 2936,2842,2560,1676,1622,1598 cm^-1; ESI-MS m/z: 179.1 (M+1)⁺.

1-环戊基-3-(4-硝基基苯基)丙烯酮(8be): 灰白色固体,收率78%. m.p. 82.6～83.9 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.61～1.72 (m,4H),1.82～1.90 (m,4H),3.17 (quint,J=8.0 Hz,1H),6.78 (d,J=16.0 Hz,1H),7.41 (d,J=8.4 Hz,2H),7.49～7.53 (m,3H); ¹³C NMR (100 MHz,CDCl₃) δ: 26.3,29.3,50.0,124.6,126.2,129.7,132.2,133.7,140.9,202.3; FT-IR (KBr) v: 2954,1687,1611 cm^-1; ESI-HRMS calcd for C₁₄H₁₆OBr ([M+H]⁺): 279.0379,found 279.0375.

1-环丙基-3-(4-溴苯基)丙烯酮(8dd)^[20]: 灰白色固体,收率70%. m.p. 72.1～72.4 ℃; ¹H NMR (400 MHz,CD₃Cl) δ: 0.97 (td,J=7.4,3.6 Hz,2H),1.15 (quint,J=3.6 Hz,2H),2.18～2.25 (m,1H),6.85 (d,J=16.0 Hz,1H),7.41 (d,J=8.4 Hz,2H),7.50～7.54 (m,3H); FT-IR (KBr) v: 2924,1671,1642,1602 cm^-1; EI-MS m/z: 252 (M+2),250 (M⁺),211,209,171 (100).

1-环己基-3-(4-溴苯基)丙烯酮(8ad): 灰白色固体,收率96%. m.p. 83.8～84.2 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.22～1.47 (m,5H),1.70～1.73 (m,1H),1.88～1.91 (m,4H),2.63 (tt,J=12.0,4.0 Hz,1H),6.80 (d,J=16.0 Hz,1H),7.42 (d,J=8.0 Hz,2H),7.50～7.54 (m,3H); ¹³C NMR (100 MHz,CDCl₃) δ: 25.9,26.0,28.8,49.7,124.6,125.3,129.7,132.2,133.8,140.9,203.0; FT-IR (KBr) v: 2924,1684,1613 cm^-1; ESI-HRMS calcd for C₁₅H₁₈OBr ([M+H]⁺): 293.0536,found 293.0532.

辅助材料(Supporting Information) 化合物7,8,9,10的¹H NMR,¹³C NMR 和MS图谱. 这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.

1-环丙基-3-(4-甲氧基苯基)丙烯酮(8dc)^[20]: 白色固体,收率26%. m.p. 63.1～63.4 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 0.95 (td,J=7.4,3.6 Hz,2H),1.14 (quint,J=3.8 Hz,2H),2.33 (tt,J=7.8,4.6 Hz,1H),3.84 (s,3H),6.77 (d,J=16.0 Hz,1H),6.91 (d,J=8.8 Hz,2H),7.52 (d,J=8.8 Hz,2H),7.58 (d,J=16.0 Hz,1H); FT-IR (KBr) v: 2922,1671,1599 cm^-1; EI-MS m/z: 202 (M⁺),161 (100).

1-环丙基-3-(3,4-二甲氧基苯基)丙烯酮(8da): 浅黄色油状液体,收率12%. ¹H NMR (400 MHz,CDCl₃) δ: 1.48～1.52 (m,4H),2.30 (s,3H),3.93 (s,6H),6.76 (d,J=16.0 Hz,1H),6.88 (d,J=8.4 Hz,1H),7.06 (d,J=1.2 Hz,1H),7.16 (dd,J=8.2,1.8 Hz,1H),7.59 (d,J=16.0 Hz,1H); ¹³C NMR (100 MHz,CDCl₃) δ: 17.2,28.7,56.06,56.11,110.0,111.2,122.2,123.5,127.2,144.5,149.4,151.7,204.5; FT-IR (film) v: 2921,1685,1592,1511 cm^-1; EI-HRMS calcd for C₁₄H₁₆O₃([M]⁺): 232.1094,found 232.1095.

1-环戊基-3-苯基丙烯酮(8bb)^[17]: 浅黄色油状液体,收率40%. ¹H NMR (400 MHz,CDCl₃) δ: 1.61～1.73 (m,4H),1.84～1.91 (m,4H),3.20 (quint,J=8.0 Hz,1H),6.80 (d,J=16.4 Hz,1H),7.37～7.40 (m,3H),7.55～7.61 (m,3H); FT-IR (film) v: 2954,1687,1659,1611 cm^-1; EI-MS m/z: 200 (M⁺),131 (100).

1-环己基-3-(4-二甲氨基苯基)丙烯酮(8af): 浅黄色固体,收率42%. m.p. 109.7～110.0 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.22～1.48 (m,5H),1.68～1.72 (m,1H),1.80～1.89 (m,4H),2.64 (tt,J=11.4,3.2 Hz,1H),3.01 (s,6H),6.61 (d,J=16.0 Hz,1H),6.65 (d,J=8.8 Hz,1H),7.45 (d,J=8.8 Hz,1H),7.55 (d,J=16.0 Hz,1H); ¹³C NMR (100 MHz,CDCl₃) δ: 26.0,26.1,29.1,40.2,49.2,111.9,119.9,122.4,130.1,143.1,151.9,203.4; FT-IR (KBr) v: 2927,1673,1584 cm^-1; ESI-HRMS calcd for C₁₇H₂₄NO ([M+H]⁺): 258.1852,found 258.1852.

3,3-三亚甲基-6-苯基-2,4-二氧代-5-己烯(9): 无色油状液体,收率40%. ¹H NMR (400 MHz,CDCl₃) δ: 1.92 (quint,J=5.4 Hz,2H),2.22 (s,3H),2.48 (t,J=6.0 Hz,2H),4.08 (t,J=5.0 Hz,2H),7.08 (d,J=15.6 Hz,1H),7.37～7.38 (m,3H),7.55～7.60 (m,3H); ¹³C NMR (100 MHz,CDCl₃) δ: 21.2,22.0,22.4,66.8,111.1,125.6,128.2,129.0,130.0,135.5,141.6,164.2,192.0; FT-IR (film) v: 2923,1662,1609 cm^-1; EI-HRMS calcd for C₁₅H₁₆O₂ ([M]⁺): 2 28.1145,found 228.1148.

3.2.1 缩合反应制备双烯烃化合物

3,5-二氧代-1,7-二(4-甲氧基苯基)-4,4-二亚甲基- 1,6-庚二烯(7dc): 黄色油状物,收率78%. ¹H NMR (400 MHz,CDCl₃) δ: 1.55 (s,4H),3.82 (s,6H),6.78 (d,J=16.0 Hz,2H),6.87 (d,J=8.0 Hz,4H),7.47 (d,J=8.0 Hz,4H),7.63 (d,J=16.0 Hz,2H); ¹³C NMR (100 MHz,CDCl₃) δ: 17.2,42.4,55.4,114.4,122.3,127.0,130.4,143.7,161.9,195.4; FT-IR (film) v: 2933,1663,1595 cm^-1; ESI-HRMS calcd for C₂₃H₂₂NaO₄ ([M+Na]⁺): 385.1410,found 385.1414.

3,5-二氧代-1,7-二(4-硝基苯基)-4,4-二亚甲基-1,6-庚二烯(7de): 黄色固体,收率47%. m.p. 181.0～181.4 ℃; ¹H NMR (400 MHz,DMSO-d₆) δ: 1.71 (s,4H),7.26 (d,J=16.0 Hz,2H),7.67 (d,J=16.0 Hz,2H),9.01 (d,J=8.8 Hz,4H),8.23 (d,J=8.8 Hz,4H); ¹³C NMR (100 MHz,DMSO-d₆) δ: 16.2,42.7,123.9,127.0,129.7,139.7,140.8,148.1,195.1; FT-IR (KBr) v: 3076,1674,1611 cm^-1; EI-HRMS calcd for C₂₁H₁₆N₂O₂ ([M]⁺): 392.1005,found 392.1010.

在敞口圆底烧瓶中加入八水合氢氧化钡(979 mg,3.10 mmol)和甲醇(13 mL),在搅拌下向烧瓶中加入3,3-二亚甲基-2,4-戊二酮(175 mg,1.39 mmol)的甲醇(5 mL)溶液. 该混合物在室温下搅拌10 min后成为澄清溶液,随后加入苯甲醛(325 mg,3.07mmol)的甲醇(10 mL)溶液. 室温搅拌直到薄层色谱(TLC)显示二酮底物消耗. 反应混合物以水(20 mL)稀释后二氯甲烷萃取(20 mL×3). 有机相分别依次以水(20 mL)和饱和食盐水(20 mL)洗涤. 硫酸钠干燥后浓缩至干,硅胶柱层析[V(乙酸乙酯):V(石油醚)=1:5]得到3,5-二氧代-4,4-二亚甲基-1,7-二苯基- 1,6-庚二烯(7db) 379 mg,收率90%,无色油状液体. ¹H NMR (400 MHz,CDCl₃) δ: 1.60 (s,4H),6.92 (d,J=16.0 Hz,2H),7.35～7.38 (m,6H),7.51～7.53 (m,4H),7.68 (d,J=16.0 Hz,2H); ¹³C NMR (100 MHz,CDCl₃) δ: 17.5,42.6,124.4,128.6,129.0,130.9,134.4,144.1,195.4; FT-IR (film) v: 3060,1671,1597 cm^-1; ESI-HRMS calcd for ([M+H]⁺): 303.1380,found 303.1377.

3,5-二氧代-1,7-二(3,4-二甲氧基苯基)-4,4-二亚甲基-1,6-庚二烯(7da): 收率57%. 黄色固体,m.p. 117.8～118.5 ℃; ¹H NMR (500 MHz,CDCl₃) δ: 1.57 (s,4H),3.85 (s,6H),3.90 (s,6H),6.79 (d,J=16.0 Hz,2H),6.84 (d,J=8.5 Hz,2H),7.00 (d,J=1.5 Hz,2H),7.12 (dd,J=8.0,2.0 Hz,2H),7.62 (d,J=16.0 Hz,2H); ¹³C NMR (125 MHz,CDCl₃) δ: 17.2,42.4,55.9,56.0,110.0,111.1,122.6,123.4,127.2,144.0,149.2,151.6,195.2; FT-IR (KBr) v: 2933,1660,1593 cm^-1; ESI-HRMS calcd for C₂₂H₂₆NaO₆ ([M+Na]⁺): 445.1622,found 445.1631.

3,5-二氧代-1,7-二(4-溴苯基)-4,4-二亚甲基-1,6-庚二烯(7dd): 黄色固体,收率32%. m.p. 104.4～104.6 ℃; ¹H NMR (400 MHz,CDCl₃) δ: 1.60 (s,4H),6.86 (d,J=15.6 Hz,2H),7.37 (d,J=8.4 Hz,4H),7.49 (d,J=8.4 Hz,4H),7.59 (d,J=15.6 Hz,2H); ¹³C NMR (100 MHz,CDCl₃) δ: 17.5,42.5,124.5,125.2,129.8,132.2,133.1,142.7,194.9; FT-IR (KBr) v: 3050,1667,1563 cm^-1; ESI-HRMS calcd for C₂₁H₁₇Br₂O₂ ([M+H]⁺): 458.9590,found 458.9584.

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图 1 姜黄素(1)与FLLL32 (2)的结构

Figure 1 The structures for curcumin (1) and FLLL32 (2)

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图式1 计划的姜黄素类化合物的合成路线

Scheme 1 Planned synthetic route to curcumin and its analogues

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图 4 可能的反应机理

Figure 4 Possible reaction mechanism

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表 1 多亚甲基戊二酮与芳香醛缩合生成双烯烃^a

Table 1. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare dialkene


Entry	n (5)	Ar (6)	Yield^b/% (7)
1	4 (5a)	3,4-diMeOC₆H₃ (6a)	0
2	4 (5a)	Ph (6b)	0
3	3 (5b)	Ph (6b)	0
4	2 (5c)	Ph (6b)	0
5	1 (5d)	3,4-diMeOC₆H₃ (6a)	57 (7da)
6	1 (5d)	Ph (6b)	90 (7db)
7	1 (5d)	4-MeOC₆H₄ (6c)	78 (7dc)
8	1 (5d)	4-BrC₆H₄ (6d)	32 (7dd)^c
9	1 (5d)	4-NO₂C₆H₄ (6e)	47 (7de)^d
^aDiketone was added into suspension of barium hydroxide octahydrate in methanol. Aldehyde was added 10 min later. ^b Isolated yield. ^c Compound 5 (25%) is recovered after acidic work-up. ^d Compound 5 (15%) is recovered after acidic work-up.

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表 2 多亚甲基戊二酮与芳香醛缩合生成单烯烃的条件筛选

Table 2. Condition screening for condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene


Entry	Base	Concentration/(mol•L^-1)	Yield^a/%
1	Ba(OH)₂^b	0.05	＜5
2	Ba(OH)₂^c	0.05	65
3	Ba(OH)₂^d	0.05	35
4	Ba(OH)₂	0.5	86
5	NaOH	0.5	39
6	DBU	0.5	72 ^e
7	TEA	0.5	0 ^f
^a Isolated yield; ^b Diketone was added into suspension of barium hydroxide octahydrate in methanol. 2.2 equiv. of aldehyde were added 10 min. later; ^c Base was added into mixture of substrates; ^d Only 1.2 equiv. of aldehyde were used in the order in method b; ^e The reaction course was 53 d; ^f No product was detected in 4 d.

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表 3 多亚甲基戊二酮与芳香醛缩合生成单烯烃

Table 3. Condensation of polymethyleneacetoacetone with arylaldehyde to prepare monoalkene


Entry^a	n (5)	Ar (6)	Yield^b/% (8)
1	4 (5a)	3,4-(MeO)₂C₆H₃ (6a)	86 (8aa)
2	4 (5a)	Ph (6b)	94 (8ab)
3	4 (5a)	4-BrC₆H₄ (6d)	96 (8ad)
4	4 (5a)	4-NO₂C₆H₄ (6e)	81 (8ae)
5	4 (5a)	4-Me₂NC₆H₄ (6f)	42 (8af)^c
6	3 (5b)	3,4-(MeO)₂C₆H₃ (6a)	80 (8ba)
7	3 (5b)	Ph (6b)	40 (8bb)^c
8	3 (5b)	4-BrC₆H₄ (6d)	78 (8bd)
9^d	2 (5c)	Ph (6b)	40 (9) ^c
10 ^e	1 (5d)	3,4-(MeO)₂C₆H₃ (6a)	12 (8da)
11	1 (5d)	Ph (6b)	83 (8db)
12 ^f	1 (5d)	4-MeOC₆H₄ (6c)	26 (8dc)
13	1 (5d)	4-BrC₆H₄ (6d)	70 (8dd)
14	1 (5d)	4-NO₂C₆H₄ (6e)	64 (8de)
15	1 (5d)	4-Pyridyl (6g)	75 (8dg)
^a To a mixture of diketone (1.0 mmol) and benzaldehyde (2.2 mmol) in methanol (2 mL) was added barium hydroxide octahydrate (2.2 mmol) at r.t. The reaction was monitored by TLC until diketone was consumed. ^b Isolated yield. ^c The only isolated product from complex midture. ^d 3,3-Trimethylene-6- phenyl-2,4-hexadione-5-ene (9) was isolated as the product. ^e Compound 7da was isolated (yield 11%) too. ^f Compound 7dc was isolated (yield 20%) too.

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