CN113816999B - 咖啡因衍生的氮杂环卡宾钯配合物及其合成方法与催化应用 - Google Patents
咖啡因衍生的氮杂环卡宾钯配合物及其合成方法与催化应用 Download PDFInfo
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- CN113816999B CN113816999B CN202111254198.2A CN202111254198A CN113816999B CN 113816999 B CN113816999 B CN 113816999B CN 202111254198 A CN202111254198 A CN 202111254198A CN 113816999 B CN113816999 B CN 113816999B
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Classifications
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/006—Palladium compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
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Abstract
本发明属于化学合成与金属有机催化技术领域，具体涉及一类咖啡因衍生的氮杂环卡宾钯配合物及其合成方法与催化应用。涉及顺式螯合配位的双卡宾配合物和季铵盐修饰的内盐型单卡宾配合物。双卡宾配合物以茶碱、1,3‑二溴丙烷和氮杂环为原料，经桥连二唑、二价季铵盐等中间体再与醋酸钯反应生成。在不对称二价季铵盐的去质子化与配位过程中，因咖啡因季铵盐骨架具有更好的酸性，其卡宾优先生成并与钯配位，生成了由苯并咪唑、咪唑、吡唑季铵盐修饰的内盐型单咖啡因卡宾配合物。上述配合物的制备不仅拓展了咖啡因衍生氮杂环卡宾的配位化学，更为高活性过渡金属催化剂和高活性金属药物提供了潜在的候选配合物。
Description
技术领域
本发明属于化学合成与金属有机催化技术领域，具体涉及一类咖啡因衍生的氮杂环卡宾钯配合物及其合成方法与催化应用。
背景技术
氮杂环卡宾(NHC)是金属有机化学中最先进的配体之一，它使金属中心在催化、光电材料、药物等方面表现出优异的性能。另外，NHC还具有成本低、制备简单、毒性小、稳定性高等优点，在一定程度上代替了叔膦配体被广泛应用于各类催化反应中。
咖啡因(Caffeine)是黄嘌呤、茶碱衍生的一种生物碱，广泛存在于咖啡、可可和茶叶等植物的浆果、种子和叶片中，在人类和动物的代谢中间体中也有发现，表现出兴奋中枢神经等生理作用。咖啡因结构中含有一个咪唑环，被当作构建NHC的前驱体，经烷基化、脱质子化即可实现C8与过渡金属的配位。Picquet和Casini等[Inorg.Chem.2014,53,2296-2303]发现咖啡因衍生的bisNHC-Au配合物对卵巢癌细胞A2780/R具有良好的细胞毒性，其半抑制浓度(IC50)值为15.6μM，是顺铂(IC50＝35μM)的二分之一，更重要的，这类NHC金属药物对健康细胞(HEK-293T)的毒性很弱，因此是克服顺铂类药物毒副作用的潜在金属药物。Philiips和Willans等[Dalton.Trans.2015,44,7563-7569]合成了一系列咖啡因衍生的NHC-Ag配合物，具有广谱抗癌活性，对恶性黑色素瘤(A375)、结肠直肠癌(HCT116)、结肠直肠腺癌(HT-29)、宫颈鳞状细胞癌(SiHa)、和胶质母细胞瘤(U-87MG和U-251)等均表现出一定的抑制作用。
由此可知，咖啡因是制备具有生理活性的NHC配合物的有效前体，然而，由于其骨架上存在两个吸电子的羰基，N9的季铵化常常遇到困难，因而咖啡因的结构多样性比经典NHC要少得多。目前为止，大多数咖啡因衍生的NHC仅作为一种未修饰的单齿配体进行配位，参与螯合配位或由功能基团修饰的咖啡因衍生物则鲜见报道。此外，鉴于其生物学性质，咖啡因的研究主要集中在药物活性的探索上，催化活性的研究仍相对较少。
发明内容
为了拓展咖啡因衍生氮杂环卡宾配合物的结构多样性，本发明旨在设计合成咖啡因衍生NHC参与的顺式螯合双卡宾-钯配合物，其合成路线为首先制备烷基桥连的二价咖啡因前体季铵盐，再经去质子化、金属配位生成目标配合物。在金属化过程中，由不对称二价盐参与的反应意外分离到了内盐型的、由季铵盐修饰的单咖啡因衍生NHC钯配合物。所得配合物在芳基卤化物的氰基化反应中均表现出一定的催化转化作用，其中，内盐型配合物更是由于其季铵盐修饰基团带来的额外相转移催化作用，催化表现更为突出。
本发明二价季铵盐的合成方法为：以茶碱和1,3-二溴丙烷为原料，在碱存在的条件下，加热(60℃)反应12小时，当茶碱与1,3-二溴丙烷的比例为2:1时，分离到对称的丙基双茶碱(1)，添加过量的1,3-二溴丙烷则生成了溴丙基茶碱(2)。溴丙基茶碱(2)和其他氮杂环在钠化氢存在下混合搅拌，合成了不对称的N^N二唑前体(3-5)，再经与碘甲烷反应制得卡宾前体季铵盐(6-9)。合成路线如下：
以二甲基亚砜为溶剂，醋酸钯为碱性金属前体，120℃反应2h，80℃反应12h后，对称的二价前体季铵盐6和咖啡因-苯并咪唑前体盐7均主要生成了顺式-双卡宾钯配合物10和11；咖啡因-咪唑前体盐8同时生成了双卡宾螯合配合物13与内盐型单卡宾配合物14；咖啡因-吡唑二价盐9则只生成了内盐型单卡宾配合物16。经反应条件进一步优化，通过降低反应温度至室温，缩短反应时间至15分钟，苯并咪唑季铵功能化的咖啡因卡宾钯配合物12中间体得以顺利生成；通过添加碳酸铯，咖啡因-吡唑螯合配位的双卡宾-钯配合物15最终得以成功制备。
在成功获得并对上述配合物进行完全表征后，这些配合物被用于催化卤代芳烃的氰化反应转化。
本发明的优点和技术效果：
通过合成桥连的二价前体季铵盐及后续与金属配位，本发明首次成功合成了4例咖啡因衍生的顺式螯合双氮杂环卡宾钯金属配合物(10,11,13,15)和3例季铵盐修饰的内盐型咖啡因单卡宾配合物(12,14,16)，借此拓展了咖啡因卡宾的配位化学，并为高活性过渡金属催化剂和高活性金属药物提供了潜在的候选配合物。在本发明中，上述配合物被成功应用于芳基卤化物的氰基化反应，其中，季铵盐修饰的内盐型咖啡因单卡宾配合物更表现出了额外的相转移催化作用，使底物的转化速率进一步提高。
附图说明：
图1为化合物6·2HI3，10，13，16的单晶结构图。
图2为配合物催化对溴苯乙酮底物的时间-产率曲线。
具体实施方式
下面结合实施例对本发明作进一步详述说明。
实施例1
(1)1,3-亚丙基桥连二茶碱1的合成
100mL的圆底烧瓶中加入茶碱(360mg,2.00mmol)和二甲基甲酰胺(20mL)，加热至茶碱完全溶解，待反应液冷却至室温后加入K2CO3粉末(415mg,3.00mmol)和二溴丙烷(102μL,1.00mmol)，在60℃下搅拌24小时。减压蒸馏除去二甲基甲酰胺溶剂得到粗产物，经蒸馏水(10mL×3)和乙醚(10mL×3)洗涤得到白色粉末状固体产物1。
1：白色固体，产率50％。1H NMR(300MHz,DMSO-d6):δ7.98(s,2H,NCHN),4.28(t,4H,3J＝7Hz,NCH2),3.38(s,6H,NCH3),3.17(s,6H,NCH3),2.47-2.38(m,2H,CH2)；13C{1H}NMR(125MHz,DMSO-d6):δ154.2,150.9(C＝O),148.3(Ar-C),142.5(NCHN),105.9(Ar-C),43.9(NCH2),30.3(CH2),29.4,27.5(NCH3).Anal.Calcd.for C17H20N8O4:C 51.00,H 5.03,N27.99,found:C 51.32,H 4.98,N 27.69.MS(ESI):m/z 401[M+H]+.
(2)对称咖啡因二价盐6的合成
25mL密封管中加入化合物1(0.50mmol)，碘甲烷(3mL,48.00mmol)，80℃封反应3天，真空旋蒸除去溶剂，制得粗品。
6·2HI3：粗产品用二氯甲烷(10mL×5)洗涤，在二氯甲烷/甲醇中重结晶，得到黑色固体，产率27％。经乙腈和水的饱和溶液缓慢挥发得到单晶。1H NMR(300MHz,DMSO-d6):δ9.45(s,2H,NCHN),4.54(t,4H,3J＝7Hz,NCH2),4.19(s,6H,NCH3),3.78(s,6H,NCH3),3.27(s,6H,NCH3),2.48-2.43(m,2H,CH2)；13C{1H}NMR(75MHz,DMSO-d6):δ153.1,150.1(C＝O),139.7(NCHN),139.6,107.3(Ar-C),45.4,37.2,31.5,29.3,28.6(NCH2,NCH3&CH2).Anal.Calcd.for C19H26I6N8O4:C 19.15,H 2.20,N 9.40,found:C 19.47,H 2.52,N9.88.MS(ESI):m/z 215[M–2I3]2+.
6·2HBF4：6·2HI3(428mg,0.36mmol)和四氟硼酸银(240mg,1.23mmol)溶解在乙腈(5ml)中，搅拌2小时，过滤，除去溶剂，得无色油状物。向油状物中加入大量乙醚，有沉淀析出，沉淀物经乙醚洗涤后得到白色固体产物(187mg,0.31mmol,86％)。1H NMR(400MHz,CD3CN):δ8.61(s,2H,NCHN),4.54(t,4H,3J＝7Hz,NCH2),4.09(s,6H,NCH3),3.73(s,6H,NCH3),3.30(s,6H,NCH3),2.55-2.47(m,2H,CH2)；13C{1H}NMR(125MHz,CD3CN):δ154.6,151.4(C＝O),141.1(NCHN),139.8,109.0(Ar-C),46.8,38.2,32.3,30.8,29.2(NCH2,NCH3&CH2).Anal.Calcd.for C19H26B2F8N8O4:C 37.78,H 4.34,N 18.55,found:C 38.13,H 4.39,N19.00.MS(ESI):m/z 215[M–2BF4]2+.
(3)cis-[PdI2(di-Caf)]配合物10的合成
将化合物6·2HBF4(185mg,0.31mmol)、醋酸钯(69mg,0.31mmol)和碘化钾(515mg,3.10mmol)溶于乙腈(10mL)中，在80℃下搅拌过夜，减压蒸除溶剂，再用二氯甲烷(30mL)溶解产品，收集二氯甲烷相，蒸除溶剂得近白色固体，产率39％。经乙腈饱和溶液缓慢挥发得到单晶。由于溶解度有限，在核磁共振(DMSO-d6)中只观察到甲基峰。Anal.Calcd.forC19H24I2N8O4Pd:C 28.94,H 3.07,N 14.21found:C 29.13,H 3.46,N 14.28.MS(ESI):m/z661[M–I]+.
实施例2
(1)溴丙基茶碱2的合成
100mL的圆底烧瓶中加入茶碱(1802mg,10.00mmol)和DMF(30mL)，适当加热至茶碱完全溶解，待反应液冷却至室温后加入K2CO3粉末(2.07g,15.00mmol)和二溴丙烷(3mL,30.00mmol)，在60℃下搅拌12小时。减压蒸馏除去溶剂，向反应瓶中加入二氯甲烷(60mL)，水(30mL×3)萃取，收集有机相，无水硫酸钠干燥过滤旋干后得到粗产物，经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/80，V/V)纯化，得到淡黄色固体产物2。
2：淡黄色固体，产率50％。1H NMR(300MHz,CDCl3):δ7.63(s,1H,NCHN),4.46(t,2H,3J＝6Hz,NCH2),3.58(s,3H,NCH3),3.39(s,3H,NCH3),3.32(t,2H,3J＝6Hz,CH2Br),2.48-2.40(m,2H,CH2).13C{1H}NMR(75MHz,CDCl3):δ155.7,152.2(C＝O),149.8(Ar-C),142.1(NCHN),107.3(Ar-C),45.8(NCH2),33.1(BrCH2),30.4(CH2),30.1,28.6(NCH3).Anal.Calcd.for C10H13BrN4O2:C 39.88,H 4.35,N 18.61,found:C 39.99,H 4.52,N18.78.MS(ESI):m/z 301[M+H]+.
(2)1,3-亚丙基桥连茶碱-苯并咪唑3的合成
在50mL的圆底烧瓶中加入苯并咪唑(3.00mmol)和四氢呋喃(20mL)，超声使其完全溶解，加入氢化钠(40mg,3.00mmol)，反应1小时后加入2(301mg,1.00mmol)，搅拌12小时。反应结束后减压蒸除溶剂，向反应瓶中加入饱和氢氧化钠水溶液(30mL)，充分搅拌至溶解，二氯甲烷(20mL×3)萃取，有机相用无水硫酸钠干燥浓缩后得到白色粉末状固体产物3。
3：白色固体，产率91％。1H NMR(300MHz,CDCl3):δ7.91(s,1H,NCHN),7.83-7.80(m,1H,Ar-H),7.43(s,1H,NCHN),7.38-7.29(m,3H,Ar-H),4.31-4.26(m,4H,NCH2),3.58(s,3H,NCH3),3.41(s,3H,NCH3),2.62-2.52(m,2H,CH2)；13C{1H}NMR(75MHz,CDCl3):δ155.8,152.2(C＝O),149.9(Ar-C),144.6(benz-NCHN),143.2(Ar-C),141.5(theo-NCHN),134.1,124.0,123.2,121.4,110.1,107.6(Ar-C),45.2,42.7(NCH2),31.5(CH2),30.5,28.8(NCH3).Anal.Calcd.for C17H18N6O2:C 60.34,H 5.36,N 24.84,found:C 60.55,H 4.96,N24.96.MS(ESI):m/z 339[M+H]+.
(3)咖啡因-苯并咪唑二价盐7的合成
25mL密封管中加入化合物3(0.50mmol)，碘甲烷(3mL,48.00mmol)，80℃密封反应3天，真空旋蒸除去溶剂，制得粗品。
7·2HI3：从二氯甲烷/甲醇中结晶得到，黑色固体，产率38％。1H NMR(300MHz,DMSO-d6):δ9.73(s,1H,NCHN),9.35(s,1H,NCHN),8.08-8.04(m,2H,Ar-H),7.74-7.71(m,2H,Ar-H),4.63-4.54(m,4H,NCH2),4.16(s,3H,NCH3),4.10(s,3H,NCH3),3.76(s,3H,NCH3),3.24(s,3H,NCH3),2.58-2.49(m,2H,CH2).MS(ESI):m/z 184[M–2I3]2+.
7·2HI：经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/80-1/10，V/V)对7·2HI3纯化得到淡黄色固体，产率35％。1H NMR(300MHz,DMSO-d6):δ9.75(s,1H,NCHN),9.38(s,1H,NCHN),8.09-8.05(m,2H,Ar-H),7.75-7.69(m,2H,Ar-H),4.64-4.55(m,4H,NCH2),4.16(s,3H,NCH3),4.10(s,3H,NCH3),3.76(s,3H,NCH3),3.23(s,3H,NCH3),2.58-2.54(m,2H,CH2).13C{1H}NMR(75MHz,DMSO-d6):δ153.1,150.1(C＝O),142.9(benz-NCHN),139.6(theo-NCHN),131.9,130.9,126.6,126.6,113.7,113.5,107.3(Ar-C,two are coincident),45.7,43.4,37.2,33.4,31.5,28.7,28.5(NCH2,NCH3&CH2).Anal.Calcd.for C19H24I2N6O2:C36.67,H 3.89,N 13.51,found:C 37.02,H 3.78,N 13.88.MS(ESI):m/z 184[M–2I]2+.
(4)卡宾钯金属配合物11、12的合成
将化合物7·2HI(149mg,0.24mmol)和醋酸钯(54mg,0.24mmol)溶解于二甲基亚砜(2mL)中，反应15分钟，加水形成棕色悬浮液，收集沉淀并进行硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/100-1/50，V/V)，得到化合物11，黄色固体，产率34％；硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/20，V/V)，得到化合物12，棕色固体，产率12％。化合物11也可以通过另一种方法制备，将化合物7·2HI(62mg,0.10mmol)和醋酸钯(23mg,0.10mmol)溶解于二甲基亚砜(6mL)中，先120℃下反应2小时，再80℃下反应12小时，真空蒸馏除去溶剂，用水(5ml×3)洗涤残渣，产品收率为89％。
11：黄色固体，产率34％。1H NMR(300MHz,DMSO-d6):δ7.76-7.72(m,1H,Ar-H),7.68-7.65(m,1H,Ar-H),7.36-7.33(m,2H,Ar-H),5.16-4.99(m,3H,NCH2),4.82-4.81(m,1H,NCH2),4.38(s,3H,NCH3),4.12(s,3H,NCH3),3.65(s,3H,NCH3),3.13(s,3H,NCH3),2.59-2.50(m,1H,CH2),1.99-1.85(m,1H,CH2)；13C{1H}NMR(100MHz,DMSO-d6):δ175.4(caf-Ccarbene),171.6(benz-Ccarbene),152.4,150.0(C＝O),140.5,134.3,133.8,123.5,123.3,111.1,110.5,108.5(Ar-C),50.4,48.6,35.2,31.4,29.2,28.1(NCH2,NCH3&CH2,two arecoincident).Anal.Calcd.for C19H22I2N6O2Pd:C 31.41,H 3.05,N 11.57,found:C 31.57,H 3.39,N 11.82.MS(ESI):m/z 640[M–I+CH3CN]+.
12：棕色固体，产率12％。1H NMR(400MHz,DMSO-d6):δ9.86(s,1H,NCHN),8.13-8.11(m,1H,Ar-H),8.03-8.01(m,1H,Ar-H),7.71-7.66(m,2H,Ar-H),4.72(t,3J＝6Hz,4H,NCH2),4.29(s,3H,NCH3),4.12(s,3H,NCH3),3.70(s,3H,NCH3),3.14(s,3H,NCH3),2.73(br-s,2H,CH2)；13C{1H}NMR(100MHz,DMSO-d6):δ174.2(caf-Ccarbene),152.1,150.0(C＝O),142.7(benz-NCHN),140.5,131.9,131.2,129.6,126.5,113.7,113.6,109.0(Ar-C),46.7,43.8,33.4,31.5,29.1,29.0,28.1(NCH2,NCH3&CH2).Anal.Calcd.for C19H23I3N6O2Pd:C 26.70,H2.71,N 9.83,found:C 26.85,H 2.88,N 10.03.MS(ESI):m/z 726[M–I]+.
实施例3
(1)1,3-亚丙基桥连茶碱-咪唑4的合成
合成方法与实施例2中1,3-亚丙基桥连茶碱-苯并咪唑3相同。
4：白色粉末，产率90％。1H NMR(400MHz,CDCl3):δ7.49(s,1H,NCHN),7.45(s,1H,NCHN),7.10(s,1H,NCH),6.95(s,1H,NCH),4.24(t,2H,3J＝7Hz,NCH2),4.02(t,2H,3J＝7Hz,NCH2),3.59(s,3H,NCH3),3.42(s,3H,NCH3),2.48-2.41(m,2H,CH2)；13C{1H}NMR(125MHz,CDCl3):δ155.8,152.3(C＝O),150.0(Ar-C),141.6(theo-NCHN),137.7(imi-NCHN),130.9,119.2,107.6(Ar-C),45.0,44.4(NCH2),32.5(CH2),30.5,28.8(NCH3).Anal.Calcd.forC13H16N6O2:C 54.16,H 5.59,N 29.15,found:C 54.15,H 5.61,N 29.38.MS(ESI):m/z 289[M+H]+.
(2)咖啡因-咪唑二价盐8的合成
合成方法与实施例2中咖啡因-苯并咪唑二价盐7相同。
8·2HI：经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/80-1/10，V/V)对粗产物进行纯化，得到古黄色固体，产率74％。1H NMR(300MHz,DMSO-d6):δ9.41(s,1H,NCHN),9.15(s,1H,NCHN),7.80(s,1H,NCH),7.76(s,1H,NCH),4.49(t,2H,3J＝6Hz,NCH2),4.30(t,2H,3J＝6Hz,NCH2),4.17(s,3H,NCH3),3.87(s,3H,NCH3),3.76(s,3H,NCH3),3.27(s,3H,NCH3),2.44-2.40(m,2H,CH2)；13C{1H}NMR(75MHz,DMSO-d6):δ153.2,150.1(C＝O),139.7(theo-NCHN),139.5(Ar-C),136.8(imi-NCHN),123.7,122.2,107.4(Ar-C),45.5,37.3,35.9,31.5,29.5,28.6(NCH2,NCH3&CH2,two are coincident).Anal.Calcd.for C15H22I2N6O2:C 31.49,H3.88,N 14.69,found:C 31.25,H 3.54,N 14.57.MS(ESI):m/z 159[M–2I]2+.
(3)卡宾钯金属配合物13、14的合成
将化合物8·2HI(228.8mg,0.40mmol)和醋酸钯(89.8mg,0.40mmol)溶解于二甲基亚砜(10mL)中，先120℃下反应2小时，再80℃下反应12小时，减压蒸馏除去溶剂得粗产物，粗产物经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/30，V/V)纯化，得到化合物13。经乙腈饱和溶液缓慢挥发得到单晶。粗产物经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/20，V/V)纯化，得到化合物14。
13：黄色固体，产率47％。1H NMR(500MHz,DMSO-d6):δ7.35(s,1H,NCH),7.33(s,1H,NCH),5.07-4.94(m,2H,NCH2),4.78(t,1H,2J＝14Hz,NCHH),4.37(m,4H,NCHH+NCH3),3.84(s,3H,NCH3),3.69(s,3H,NCH3),3.18(s,3H,NCH3),2.45-2.40(m,1H,CH2),1.88-1.81(m,1H,CH2)；13C{1H}NMR(125MHz,DMSO-d6):δ172.4(caf-Ccarbene),161.3(imi-Ccarbene),152.4,150.1(C＝O),140.4,123.4,123.3,108.3(Ar-C),51.5,50.1,37.8,31.3,30.2,28.1(NCH2,NCH3&CH2,two are coincident).Anal.Calcd.for C15H20I2N6O2Pd:C 26.63,H 2.98,N12.42,found:C 26.97,H 2.76,N 12.06.MS(ESI):m/z 549[M–I]+.
14：橙红色固体，产率12％。1H NMR(500MHz,DMSO-d6):δ9.19(s,1H,NCHN),7.82(s,NCH),7.72(s,NCH),4.62(t,2H,3J＝7Hz,NCH2),4.38(t,2H,3J＝7Hz,NCH2),4.30(s,3H,NCH3),3.89(s,3H,NCH3),3.72(s,3H,NCH3),3.20(s,3H,NCH3),2.63-2.62(m,2H,CH2).13C{1H}NMR(100MHz,DMSO-d6):δ174.5(caf-Ccarbene),152.2,150.0(C＝O),140.6(Ar-C),136.8(imi-NCHN),123.8,122.5,109.2(Ar-C),46.4,46.1,36.1,31.6,29.0,28.7,28.2(NCH2,NCH3&CH2).Anal.Calcd.for C15H21I3N6O2Pd:C 22.39,H 2.63,N 10.45,found:C 22.67,H2.61,N 10.77.MS(ESI):m/z 677[M–I]+.
实施例4
(1)1,3-亚丙基桥连茶碱-吡唑5的合成
合成方法与实施例2中1,3-亚丙基桥连茶碱-苯并咪唑3相同。
5：白色粉末，产率91％。1H NMR(300MHz,CDCl3):δ7.65(s,1H,NCHN),7.53(d,1H,3J＝2Hz,pyr-H),7.39(d,1H,3J＝2Hz,pyr-H),6.28(t,1H,3J＝2Hz,pyr-H),4.28(t,2H,3J＝6Hz,NCH2),4.13(t,2H,3J＝6Hz,NCH2),3.59(s,3H,NCH3),3.41(s,3H,NCH3),2.50-2.42(m,2H,CH2)；13C{1H}NMR(75MHz,CDCl3):δ155.8,152.3(C＝O),149.9(Ar-C),142.6(theo-NCHN),140.3,129.9,107.4,106.6(Ar-C),48.8,45.0(NCH2),31.9(CH2),30.5,28.7(NCH3).Anal.Calcd.for C13H16N6O2:C 54.16,H 5.59,N 29.15,found:C 54.85,H 5.68,N29.33.MS(ESI):m/z 289[M+H]+.
(2)咖啡因-吡唑二价盐9的合成
合成方法与实施例2中咖啡因-苯并咪唑二价盐7相同。
经硅胶柱层析(洗脱剂：甲醇/二氯甲烷＝1/80-1/10，V/V)对粗产物进行纯化，得到化合物9。
9·2HI：淡黄色固体，产率85％。1H NMR(300MHz,DMSO-d6):δ9.51(s,1H,NCHN),8.65(d,1H,3J＝2Hz,pyr-H),8.58(d,1H,3J＝2Hz,pyr-H),6.92(t,1H,3J＝2Hz,pyr-H),4.66(t,2H,3J＝7Hz,NCH2),4.54(t,2H,3J＝7Hz,NCH2),4.19(s,3H,NCH3),4.18(s,3H,NCH3),3.76(s,3H,NCH3),3.26(s,3H,NCH3),2.53-2.46(m,2H,CH2)；13C{1H}NMR(75MHz,DMSO-d6):δ153.2,150.1(C＝O),139.6(theo-NCHN),139.5,138.4,136.9,107.5,107.3(Ar-C),46.4,45.4,37.4,37.2,31.5,28.6,27.9(NCH2,NCH3&CH2).Anal.Calcd.forC15H22I2N6O2:C 31.49,H 3.88,N 14.69,found:C 31.78,H 3.64,N 14.78.MS(ESI):m/z445[M–I]2+.
(3)卡宾钯金属配合物15、16的合成
将化合物9·2HI(114mg,0.20mmol)和醋酸钯(45mg,0.20mmol)溶解于二甲基亚砜(5mL)中，先120℃下反应2小时，再80℃下反应12小时，真空蒸馏除去溶剂，用水(5ml×3)洗涤残渣，产品16在乙腈中溶解，过滤后收集乙腈相，减压旋蒸除去乙腈，得化合物16。经二氯甲烷/甲醇饱和溶液缓慢蒸发得到单晶。
向上述产物16的二甲基亚砜溶液加入碳酸铯(261mg,0.80mmol)，60℃反应过夜。减压蒸除溶剂，残留物经水洗涤三次。加入二氯甲烷以溶解产物，过滤，旋蒸得化合物15。
15：棕色固体，产率28％。1H NMR(300MHz,DMSO-d6):δ7.91(d,1H,3J＝3Hz,py-H),6.32(d,1H,3J＝3Hz,py-H),5.20-4.97(m,2H,NCH2),4.79-4.73(m,1H,NCH2),4.31(s,4H,NCH3&NCH2),3.91(s,3H,NCH3),3.65(s,3H,NCH3),3.17(s,3H,NCH3),2.40-2.36(m,1H,CH2),2.06-1.94(m,1H,CH2)；13C{1H}NMR(100MHz,DMSO-d6):δ152.4,150.0(C＝O),140.5,136.2,113.0,108.7(Ar-C),51.9,50.2,38.6,36.8,31.9,28.9,28.6(NCH2,NCH3&CH2),卡宾位移经2D HMBC确定位于174.8(caf-Ccarbene)和163.0(pyr-Ccarbene)处。Anal.Calcd.forC15H20I2N6O2Pd:C 26.63,H 2.98,N 12.42,found:C 26.90,H 2.55,N 12.31.MS(ESI):m/z549[M–I]+.
16：棕色固体，产率69％。1H NMR(300MHz,DMSO-d6):δ8.72(d,1H,3J＝2Hz,py-H),8.54(d,1H,3J＝2Hz,py-H),6.91(t,1H,3J＝2Hz,py-H),4.72(t,2H,3J＝7Hz,NCH2),4.66(t,2H,3J＝7Hz,NCH2),4.30(s,3H,NCH3),4.20(s,3H,NCH3),3.72(s,3H,NCH3),3.20(s,3H,NCH3),2.67-2.62(m,2H,CH2)；13C{1H}NMR(100MHz,DMSO-d6):δ174.5(caf-Ccarbene),152.3,150.0(C＝O),140.6,138.6,137.1,109.1,107.3(Ar-C),46.7,46.3,37.1,31.5,29.0,28.2,26.8(NCH2,NCH3&CH2).Anal.Calcd.for C15H21I3N6O2Pd:C 22.39,H 2.63,N 10.45,found:C 22.65,H 2.56,N 10.34.MS(ESI):m/z 677[M–I]+.
实施例5本发明配合物的催化应用
(1)时间-产率曲线
在空气氛围下，将4-溴苯乙酮(5.00mmol)、三水合亚铁氰化钾(1.25mmol)、钯催化剂(0.05mmol)、碳酸钾(5.00mmol)、DMA(5mL)溶剂和内标十二烷(5.00mmol)加入到Schlenk反应管中，120℃下进行反应。特定时间后，吸取一滴反应液加乙酸乙酯稀释至1mL,气相色谱法进行定量分析。
结果表明所有由咖啡因配位的杂双卡宾配合物(11、13、15)及单卡宾配合物(12、14、16)在9小时以后的催化产率均大于80％，而对称[PdI2(di-Caf)]配合物10的催化产率仅为29％。申请人认为该配合物的低活性源于其超低溶解度，甚至在反应介质DMA中也很难溶解。
对化合物11和12，13和14，15和16的催化效果进行进一步比较的结果表明，内盐型配合物的催化速度总是快于双卡宾螯合的配合物，这可能归功于内盐型配合物的特殊结构，其季铵盐修饰基团起到了瞬时相转移催化的作用，可以将K4[Fe(CN)6]·3H2O带入到有机相，从而进一步反应。而随着反应的进行，在碱性催化条件下，内盐中间体逐渐被转化为相应的顺式螯合双卡宾钯配合物，因此其最终催化产率与双卡宾钯配合物的类似。
(2)底物拓展
在空气氛围下，将芳基卤化物(1.00mmol)、三水合亚铁氰化钾(0.25mmol)、钯催化剂(15/16，0.01mmol)、碳酸钾(1.00mmol)和DMA(1mL)溶剂加入到Schlenk反应管中，将该混合物在120℃下反应一段时间后，减压蒸馏除去溶剂，用硅胶柱层析对残留物进行纯化，得到相应产物。
表1
上表中的底物拓展结果表明，卤代芳烃上的吸电子基团对氰化反应起促进作用，推电子基团则使之活性降低。在当前催化条件下，氯苯类似物的转化率仍然不理想，有待进一步提高。
Claims (6)
1.一类咖啡因衍生的氮杂环卡宾钯配合物，其特征在于：所述咖啡因衍生的氮杂环卡宾钯配合物包括顺式螯合配位的双卡宾配合物(10,11,13,15)和季铵盐修饰的内盐型单卡宾配合物(12,14,16)；所述双卡宾钯配合物(10,11,13,15)含有两个或一个咖啡因衍生的氮杂环卡宾配体，以及一个苯并咪唑、咪唑或吡唑衍生的氮杂环卡宾，两个卡宾配体由亚丙基桥连并呈顺式配位；季铵盐修饰的内盐型单卡宾配合物(12,14,16)为苯并咪唑、咪唑、吡唑季铵盐修饰的单咖啡因卡宾配位的钯配合物；
所述双卡宾钯配合物(10,11,13,15)具体结构如下：
所述季铵盐修饰的内盐型单卡宾配合物(12,14,16)具体结构式如下：
2.根据权利要求1所述的咖啡因衍生的氮杂环卡宾钯配合物的合成方法，其特征在于：所述合成方法为：
(1)合成二唑前体；
(2)合成二价季铵盐前体；
(3)合成咖啡因衍生的氮杂环卡宾钯配合物。
3.根据权利要求2所述的咖啡因衍生的氮杂环卡宾钯配合物的合成方法，其特征在于：步骤(1)所述二唑前体的合成方法为：以茶碱、1,3-二溴丙烷为原料，碳酸钾为碱，再与不同氮杂环和氢化钠反应合成二唑前体。
4.根据权利要求2所述的咖啡因衍生的氮杂环卡宾钯配合物的合成方法，其特征在于：步骤(2)所述二价季铵盐前体的合成方法为：二唑和碘甲烷在80℃密封反应3天，二氯甲烷/甲醇或丙酮重结晶除去一价盐，柱层析脱除I2，合成二价季铵盐前体。
5.根据权利要求2所述的咖啡因衍生的氮杂环卡宾钯配合物的合成方法，其特征在于：步骤(3)以二甲基亚砜为溶剂，二价季铵盐前体与醋酸钯反应，得产物咖啡因衍生的氮杂环卡宾钯配合物。
6.据权利要求1所述的咖啡因衍生的氮杂环卡宾钯配合物的应用，其特征在于，所述配合物用于催化卤代芳烃的氰化反应。
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