CN109053800B - 季鏻盐支载手性氨基-硫脲及其制备方法和用途 - Google Patents
季鏻盐支载手性氨基-硫脲及其制备方法和用途 Download PDFInfo
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- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 150000004714 phosphonium salts Chemical group 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 7
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- RYSJPPKSWNQIIO-UHFFFAOYSA-N 4-amino-2,6-bis(trifluoromethyl)phenol Chemical compound NC1=CC(C(F)(F)F)=C(O)C(C(F)(F)F)=C1 RYSJPPKSWNQIIO-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000010523 cascade reaction Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 8
- 230000003287 optical effect Effects 0.000 abstract description 4
- 229920000642 polymer Polymers 0.000 abstract description 4
- 238000004064 recycling Methods 0.000 abstract description 4
- 150000001450 anions Chemical class 0.000 abstract description 2
- 150000001768 cations Chemical class 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- -1 polarity Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 8
- 238000006555 catalytic reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011345 viscous material Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005337 ground glass Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
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- B01J31/0255—Phosphorus containing compounds
- B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
- B01J31/0268—Phosphonium compounds, i.e. phosphine with an additional hydrogen or carbon atom bonded to phosphorous so as to result in a formal positive charge on phosphorous
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Abstract
本发明涉及一种手性催化剂季鏻盐支载手性氨基‑硫脲,其结构如下:
Description
技术领域
本发明涉及一种手性催化剂季鏻盐支载手性氨基-硫脲及其制备方法和用途。
背景技术
利用手性催化剂进行不对称合成,是获取手性化合物的最有效的方法之一。手性氨基-硫脲是一类典型的双官能有机小分子催化剂,该类催化剂在过去十年中已取得长足的发展,被广泛应用于催化不对称Michael加成、Mannich、Michael-adol串联等有机反应。但小分子手性催化剂价格昂贵、难以回收和重复使用,一直是不对称催化反应难以实现大规模工业应用的障碍。
解决该问题的传统方法之一是将手性催化剂支载在不溶性聚合物或无机物载体上,以简化产物与催化剂的分离纯化。催化剂的支载化虽然取得了很大的成功,但多数支载催化剂由于无规载体影响了催化活性单元的自由度,甚至破坏了催化活性中心周围的立体微环境,而且存在传质困难等缺点,因此,传统的支载催化剂在解决催化剂的分离回收的同时往往牺牲了催化剂的高选择性和催化活性等优点。
发明内容
本发明所要解决的问题是提供高产率高立体选择性催化Michael-aldol串联反应且能够回收循环使用的手性催化剂季鏻盐支载手性氨基-硫脲及其制备方法,本发明原料及试剂廉价易得,路线可行,反应后处理简单。
本发明提供的技术方案是,季鏻盐支载手性氨基-硫脲,其结构如下式1所示:
本发明还提供了上述季鏻盐支载手性氨基-硫脲1的制备方法,该方法包括下述步骤:
(1)在有机溶剂中,在三苯基膦和偶氮二甲酸二乙酯(DEAD)存在下,化合物2 与3,5-二(三氟甲基)-4-羟基苯胺反应得到化合物3,反应温度为0~25℃,反应时间为6~12 h,上述化合物的摩尔比为化合物2:3,5-二(三氟甲基)-4-羟基苯胺:三苯基膦:DEAD= 1:1~1.5:1~1.5:1~1.5;
(2)在有机溶剂中,二环己基碳酰亚胺(DCC)存在下,化合物3与二硫化碳(CS2)反应得到化合物4, 反应温度为-10~25℃,反应时间为12~24 h,上述化合物的摩尔比为化合物3:CS2:DCC = 1:3~6:1~1.5;
(3)在有机溶剂中,化合物4与(R)-(+)-1,1'-联-2-萘胺反应得到季鏻盐支载手性氨基-硫脲1,反应温度为0~40℃,反应时间为6~12 h,上述化合物的摩尔比为化合物4:(R)-(+)-1,1'-联-2-萘胺= 1:1~1.5;
上述化合物2,3,4具有如下结构式:
所述有机溶剂为二氯甲烷、三氯甲烷、N, N-二甲基甲酰胺、四氢呋喃、丙酮或乙酸乙酯,步骤(1)-(3)的有机溶剂均可任意独立地选取其中之一。
上述反应过程由如下反应式表示:
本发明提供的季鏻盐支载手性氨基-硫脲的用途,是作为手性催化剂用于催化Michael-aldol串联反应,由如下反应式表示:
其中:
Ar1为烷基、芳基、杂环基;
Ar2为烷基、芳基、杂环基。
本发明提出了一种手性催化剂季鏻盐支载手性氨基-硫脲及其制备方法。以季鏻盐为可溶性载体,该载体对比聚合物载体最大的优点是分子量低,其支载量至少是传统聚合物载体的10倍。更为重要的是,它们的极性、溶解度、酸碱度等理化性质可以通过选择不同的阴、阳离子,取代基大小和烷基链长短等来设计,满足具体反应和分离过程的要求。本发明制得季鏻盐支载手性氨基-硫脲催化剂,作为手性催化剂催化不对称反应为均相反应,反应快,便于在线检测。该手性催化试剂不仅保留了手性氨基-硫脲催化不对称反应的高收率以及高立体选择性,得到高光学纯度的手性化合物,同时实现了手性催化剂的回收循环使用。反应路线简单可行,后处理简单,所合成的高光学纯度的手性化合物作为医药、农药的中间体或终产物,具有重要的应用价值。
具体实施方式
通过以下实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1-3:季鏻盐支载手性氨基-硫脲的制备方法。
实施例1
将化合物2(参照文献[Catalysis Communications 35 (2013) 1-5]方法制备得到)(2.57 g, 5 mmol)、3,5-二(三氟甲基)-4-羟基苯胺(1.84 g, 7.5 mmol)及三苯基膦(1.96 g, 7.5 mmol)溶解在无水二氯甲烷(50 mL)中,0℃搅拌15 min,然后缓慢滴加偶氮二甲酸二乙酯(DEAD)(1.5 mL, 7.5 mmol)的无水二氯甲烷(10 mL)混合溶液,氮气保护反应15 h。反应完毕,减压蒸馏除去溶剂得黄色粘稠物,用少量二氯甲烷(2 mL)溶解,加入冰乙醚(50 mL),析出白色固体,抽滤,滤饼用冰乙醚洗涤得化合物3(3.41 g,产率92%)。1H-NMR(600 MHz, CDCl3) δ=7.88-7.85 (m, 3H, ArH), 7.82-7.80 (m, 2H, ArH), 7.75-7.72 (m, 6H, ArH), 7.64–7.61 (m, 8H, ArH), 7.18-7.16 (d, J=7.8 Hz, 2H, ArH),5.35 (s, 2H, NH2), 5.21 (s, 2H, CH 2 O). 13C-NMR (150 MHz, CDCl3): δ=141.5,140.3, 136.7, 135.5, 134.0, 130.5, 128.2, 125.3, 117.9, 116.6, 72.2.
参照上述步骤,采用三氯甲烷、N, N-二甲基甲酰胺、四氢呋喃、丙酮或乙酸乙酯代替实施例1中的二氯甲烷作为溶剂,可得到类似的结果。
实施例2
化合物3(2.97 g, 4 mmol)溶解在无水四氢呋喃(50 mL)中,-10℃缓慢滴加CS2 (1.45 mL,24 mmol),滴毕,迅速加入二环己基碳酰亚胺(DCC)(0.82 g, 4 mmol),在-10℃反应24 h。反应完毕,减压蒸馏除去溶剂得棕黄色粘稠物,用少量二氯甲烷(2 mL)溶解,加入冰乙醚(50 mL),析出淡黄色固体,抽滤,滤饼用冰乙醚洗涤得化合物4(2.29 g,产率73%)。1H-NMR(600 MHz, CDCl3) δ=7.89-7.85 (m, 3H, ArH), 7.81-7.80 (m, 2H, ArH),7.75-7.72 (m, 6H, ArH), 7.67–7.62 (m, 8H, ArH), 7.39-7.37 (d, J=7.8 Hz, 2H,ArH), 5.21 (s, 2H, CH 2 O). 13C-NMR (150 MHz, CDCl3): δ=149.2, 136.9, 136.6,135.4, 133.8, 130.5, 128.0, 124.3, 123.8, 117.8, 116.8, 71.9.
参照上述步骤,采用二氯甲烷、三氯甲烷、N, N-二甲基甲酰胺、丙酮或乙酸乙酯代替实施例2中的四氢呋喃作为溶剂,可得到类似的结果。
实施例3
化合物4 (1.57 g, 2 mmol)溶解在四氢呋喃(20 mL)中,加入(R)-(+)-1,1'-联-2-萘胺 (0.57 g, 2 mmol),于25℃反应6 h。反应完毕,减压蒸馏除去溶剂得黄色粘稠物,用少量二氯甲烷(2 mL)溶解,加入冰乙醚(50 mL),析出淡黄色固体,抽滤,滤饼用冰乙醚洗涤得季鏻盐支载手性氨基-硫脲1(1.60 g,产率75%)。1H-NMR(600 MHz, CDCl3) δ=8.92 (d,J=7.8 Hz, 2H, ArH), 8.05-7.92 (m, 6H, ArH), 7.89-7.85 (m, 5H, ArH), 7.82-7.80(m, 2H, ArH), 7.75-7.72 (m, 6H, ArH), 7.67–7.62 (m, 8H, ArH), 7.42-7.35 (m,4H, ArH), 5.22 (s, 2H, CH 2 O). 13C-NMR (150 MHz, CDCl3): δ=180.2, 147.0, 144.5,141.8, 136.9, 136.7, 135.4, 133.9, 130.4, 128.1, 127.5, 126.2, 125.0, 124.3,123.8, 121.6, 117.8, 117.2, 116.8, 115.3, 71.9.
参照上述步骤,采用二氯甲烷、三氯甲烷、N, N-二甲基甲酰胺、丙酮或乙酸乙酯代替实施例2中的四氢呋喃作为溶剂,可得到类似的结果。
实施例4:季鏻盐支载手性氨基-硫脲1作为手性催化剂在催化Michael-aldol串联反应中的用途。
实施例 4
在带有磨口玻璃塞的反应管中依次加入化合物5( 0.5 mmol)、化合物6 (1.0mmol)、催化剂1(0.05 mmol)和乙醇(2 mL ),25℃下反应72~120 h。过滤,并用冰乙醇洗涤(1 mL×3),真空干燥得到化合物7。滤液减压蒸馏除去溶剂,用少量二氯甲烷(1 mL)溶解,加入冰乙醚(20 mL)得淡黄色固体,抽滤,回收手性催化剂1。催化反应结果如表1所示。
表1.季鏻盐支载手性氨基-硫脲催化多米诺 Michael-aldol反应
(a粗产物产率; b根据粗产物的 1H-NMR 图谱得到; c 根据HPLC手性柱测得。)
实施例5:季鏻盐支载手性氨基-硫脲催化剂1的回收循环使用。
季鏻盐支载氨基-硫脲催化剂1催化(E)-4-苯基-3-丁烯-2-酮与苯甲酰乙酸乙酯的Michael-aldol串联反应后,过滤,去溶剂,加入少量二氯甲烷并用冰乙醚沉淀,回收催化剂并真空干燥,其回收率为90%。用回收的催化剂再次催化(E)-4-苯基-3-丁烯-2-酮与苯甲酰乙酸乙酯的Michael-aldol串联反应,其重复催化效果见表2。从表2可知,季鏻盐支载手性氨基-硫脲催化剂1使用5次后,催化剂活性没有显著降低。
表2. 季鏻盐支载氨基-硫脲催化剂1的回收使用
(a粗产物产率; b通过粗产物的1H-NMR计算; c 根据HPLC手性柱测定。)。
Claims (4)
2.一种制备权利要求1所述的季鏻盐支载手性氨基-硫脲的方法,包括下述步骤:
(1)在有机溶剂中,在三苯基膦和偶氮二甲酸二乙酯存在下,化合物2 与3,5-二(三氟甲基)-4-羟基苯胺反应得到化合物3,反应温度为0~25℃,反应时间为6~12 h,上述化合物的摩尔比为化合物2:3,5-二(三氟甲基)-4-羟基苯胺:三苯基膦:偶氮二甲酸二乙酯= 1:1~1.5:1~1.5:1~1.5;
(2)在有机溶剂中,二环己基碳酰亚胺存在下,化合物3与二硫化碳反应得到化合物4,反应温度为-10~25℃,反应时间为12~24 h,上述化合物的摩尔比为化合物3:二硫化碳:二环己基碳酰亚胺= 1:3~6:1~1.5;
(3)在有机溶剂中,化合物4与(R)-(+)-1,1'-联-2-萘胺反应得到季鏻盐支载手性氨基-硫脲1,反应温度为0~40℃,反应时间为6~12 h,上述化合物的摩尔比为化合物4:(R)-(+)-1,1'-联-2-萘胺= 1:1~1.5;
上述化合物2,3,4具有如下结构式:
3.如权利要求2所述的方法,其特征是:所述有机溶剂为二氯甲烷、三氯甲烷、N, N-二甲基甲酰胺、四氢呋喃、丙酮或乙酸乙酯,步骤(1)-(3)的有机溶剂均可任意独立地选取其中之一。
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