CN104592006A - 一种苯丙酸类化合物的合成方法 - Google Patents
一种苯丙酸类化合物的合成方法 Download PDFInfo
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- -1 phenylpropionic acid compound Chemical class 0.000 title claims abstract description 70
- 238000001308 synthesis method Methods 0.000 title 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000012298 atmosphere Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000006254 arylation reaction Methods 0.000 claims abstract description 9
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims abstract description 6
- 238000004440 column chromatography Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000000605 extraction Methods 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 5
- 238000004809 thin layer chromatography Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 abstract 2
- ZJSVWUVAXVULRP-UHFFFAOYSA-N 1-(3-amino-1-oxidopyridin-1-ium-2-yl)propan-1-one Chemical compound C(CC)(=O)C1=[N+](C=CC=C1N)[O-] ZJSVWUVAXVULRP-UHFFFAOYSA-N 0.000 abstract 1
- LVRDGDMGDMEQCF-UHFFFAOYSA-N C(CC)(=O)NC1=[N+](C=CC=C1)[O-] Chemical compound C(CC)(=O)NC1=[N+](C=CC=C1)[O-] LVRDGDMGDMEQCF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000013375 chromatographic separation Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 abstract 1
- 235000019797 dipotassium phosphate Nutrition 0.000 abstract 1
- 229910001679 gibbsite Inorganic materials 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 15
- 239000000758 substrate Substances 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FEIQOMCWGDNMHM-UHFFFAOYSA-N 5-phenylpenta-2,4-dienoic acid Chemical class OC(=O)C=CC=CC1=CC=CC=C1 FEIQOMCWGDNMHM-UHFFFAOYSA-N 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- CYVVFWBKWGJMNQ-UHFFFAOYSA-N 2-benzylbutanoic acid Chemical compound CCC(C(O)=O)CC1=CC=CC=C1 CYVVFWBKWGJMNQ-UHFFFAOYSA-N 0.000 description 3
- MCIIDRLDHRQKPH-UHFFFAOYSA-N 2-methyl-3-phenylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=CC=C1 MCIIDRLDHRQKPH-UHFFFAOYSA-N 0.000 description 3
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- BQHWATVEWGHHHF-UHFFFAOYSA-N 2,2-dimethyl-3-phenylpropanoic acid Chemical class OC(=O)C(C)(C)CC1=CC=CC=C1 BQHWATVEWGHHHF-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- FIUFLISGGHNPSM-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanoic acid Chemical compound COC1=CC=C(CCC(O)=O)C=C1 FIUFLISGGHNPSM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种苯在N,O-双齿导向基作用下以醋酸钯作为催化剂直接实现羰基β位sp3C-H键的直接芳基化反应来合成苯丙酸类化合物的方法:在空气氛围中,向史莱克管中依次加入2-丙酰胺基-吡啶-1-氧化物、醋酸钯、三水磷酸氢二钾、芳基碘代化合物和二甲亚砜,反应20~30小时,反应结束后,冷却至室温,萃取、干燥、浓缩、色谱分离得到芳基化的产物;将得到的芳基化产物溶于NaOH的乙醇溶液中反应20~30小时,反应结束后中和、萃取、干燥、浓缩、柱层析得苯丙酸类化合物。本发明反应条件温和,不需要外加添加剂,官能团容忍性好;2-丙酰氨基吡啶-1-氧化物中羰基β位sp3C-H键可直接芳基化。
Description
技术领域
本发明涉及一种活化酰胺类化合物羰基β位sp3C-H键来合成苯丙酸类化合物的方法。该方法是以脂肪族羧酸为起始原料引入N,O-双齿导向基,在醋酸钯的催化下高选择性的实现了羰基β位的芳基化反应,最后再将导向基移除得到苯丙酸类化合物。
背景技术
苯丙酸及其衍生物普遍存在于医药、农药和石油化工行业中,而且苯丙酸中的羧基本身是一个活性基团,可以作为中间体和其他化合物反应,从而合成许多在燃料、液晶材料、医药等方面有重要作用的化合物。比如,以苯丙酸类物质作为母体合成的酸性物质能有效的促进血纤维蛋白酶的自发溶解作用,快速抑制血清中毒;对甲氧基苯丙酸及其钠盐、钾盐、酰苯胺盐和铵盐是一类高效的农用杀虫剂。因此,苯丙酸类化合物的合成引起了人们的广泛关注。以往文献报道的苯丙酸类化合物苯基的引入主要是通过乌尔曼 (Ullmann) 反应。由于C-H键的直接官能团化不需要经过预活化,合成步骤简短而得到了快速的发展。近年来,陆续有文献报道通过C-H键的直接官能团化来合成苯的衍生物 (Angew. Chem. Int. Ed. 2007, 46, 3135 –3138.;J. Am. Chem. Soc. 2005, 127 , 5936-5945.),但大多数是集中在比较活泼的sp2C-H键,由于饱和C-H键的键能较高,因此sp3C-H键的直接芳基化反应报道较少 (Acc. Chem. Res. 2003,36, 234-245;J. Am. Chem. Soc. 2010, 132, 3965–3972),使得反应的应用范围有很强的局限性。因此发展一种以廉价金属为催化剂,没有外加配体,在较为温和的条件下通过sp3C-H键的直接芳基化来合成苯丙酸类化合物有广阔的应用前景。
发明内容
本发明的目的是提供一种利用N,O-双齿导向基在醋酸钯的催化下实现酰胺类化合物羰基β位sp3C-H键的直接芳基化来合成苯丙酸类化合物的方法。
为实现上述目的,本发明采用以下技术方案:一种苯丙酸类化合物的合成方法,步骤如下:
(1)在空气氛围中,向史莱克管中依次加入2-丙酰胺基-吡啶-1-氧化物、醋酸钯、三水磷酸氢二钾、芳基碘代化合物和二甲亚砜,115~125 oC条件下反应20~30小时,反应结束后,冷却至室温,萃取、干燥、浓缩、薄层色谱分离得到芳基化的产物;其中2-丙酰胺基-吡啶-1-氧化物的结构式为: ;芳基碘代化合物的结构式为:;
R1,R2为氢原子、直连烷基、支链烷基或苄基,R3为氢原子、烷氧基、甲基、氟、氯或溴,R3在苯环C2-C4位;
(2)将得到的芳基化产物溶于NaOH的乙醇溶液中,85~95 oC下反应20~30小时,反应结束后中和、萃取、干燥、浓缩、柱层析得苯丙酸类化合物;
反应式如下:
R1,R2为氢原子、直连烷基、支链烷基或苄基,R3为氢原子、烷氧基、甲基、氟、氯或溴,R3在苯环C2-C4位。
所述步骤(1)中2-丙酰胺基-吡啶-1-氧化物、醋酸钯、三水磷酸氢二钾和芳基碘代化合物的物质的量之比为0.1~0.3:0.01~0.03:0.4~0.6:1.0~1.4,其中以1 mmol 2-丙酰胺基-吡啶-1-氧化物为基准,所需二甲亚砜的体积为5~7.5mL。
所述步骤(2)中所述步骤(2)中氢氧化钠的乙醇溶液的用量以芳香酰氨基吡啶-1-氧化物为基准,1mmol2-丙酰胺基-吡啶-1-氧化物所需NaOH的乙醇溶液为7~8mL。
所述步骤(2)中NaOH的乙醇溶液的浓度为1.5~2.5mol/L。
所述步骤(1)中的萃取采用乙酸乙酯萃取,用无水硫酸钠干燥,真空浓缩。
所述步骤(1)中的薄层色谱采用的展开剂为二氯甲烷和丙酮按照体积比为6:1混合。
所述步骤(2)中加入稀盐酸溶液中和,用二氯甲烷萃取,用无水硫酸钠干燥,减压蒸馏进行浓缩。
所述稀盐酸溶液的浓度为1~2mol/L。
所述步骤(2)中柱层析所用的淋洗剂为二氯甲烷和甲醇按照体积比为1:10混合。
本发明的有益效果:本发明提供了一种在新型的N,O-双齿导向基作用下以醋酸钯作为催化剂直接实现了羰基β位sp3C-H键的直接芳基化反应来合成苯丙酸类化合物的方法。本发明克服了传统方法的弊端,具有以下优点:(1)反应条件温和,不需要外加添加剂,官能团容忍性好;(2) 2-丙酰氨基吡啶-1-氧化物中羰基β位sp3C-H键的直接芳基化;(3) 导向基可以很容易的引入和移除;(4)本方法所得的相应的苯丙酸类化合物的产率可达83%。
具体实施方式
为了使本发明的目得、技术方案及优点更加清楚明白,本发明用以下具体实例进行说明。显然,本发明不限于以上的实施例,还可以有许多变形,本领域的普通技术人员能从本发明公开内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
实施例1
本实施例的苯丙酸的制备方法如下:
(1)2-丙酰胺基吡啶-1-氧化物的制备
惰性气体保护下,称取丙酸 (6 mmol),2-氨基吡啶氮氧化物 (660 mg, 6 mmol),DMAP (73.3 mg, 0.6 mmol) 置于100 mL的三口瓶中,加入30 mL无水二氯甲烷。冰水浴条件下滴加30 mL含EDCI (1.14 g, 7.2 mmol) 的无水二氯甲烷溶液。滴加完成后,撤去冰水浴,室温搅拌8小时。反应结束后,向反应液中加入50 mL无水二氯甲烷稀释,分别用15 mL (3×5 mL) 1mol/L的稀盐酸溶液、15 (3×5 mL) mL的饱和碳酸氢钠溶液、35 mL (3×10 mL)的饱和食盐水洗涤,合并有机相,用无水硫酸钠干燥过夜。过滤,减压蒸馏除去有机相的溶剂,所得的粗产品经柱色谱分离提纯(淋洗剂为二氯甲烷:丙酮),得到2-丙酰胺基吡啶-1-氧化物的纯品0.65 g,产率65%;
熔点 92-93 oC. 1 H NMR (400 MHz, CDCl3) δ 10.04 (s, NH, 1H), 8.46 (dd, J = 8.5, 1.8 Hz, 1H, Ar-H), 8.25 (dd, J = 6.5, 1.1 Hz, 1H, Ar-H), 7.37-7.32 (m, 1H, Ar-H), 7.01-6.97 (m, 1H, Ar-H), 2.57 (q, J =7.5 Hz, 2H, CH 2CH3), 1.28 (t, J = 7.5 Hz, 3H, CH2CH 3). 13 C NMR (100 MHz, CDCl3) δ 172.7, 144.2, 137.0, 128.2, 118.4, 114.7, 31.0, 9.1. HRMS (positive ESI) Calcd for C8H11N2O2 (M+H) 167.0815, Found 167.0815;
(2)2-(3-苄基丙酰胺基)-吡啶-1-氧化物的制备
空气氛围下,称取底物2-丙酰胺基吡啶-1-氧化物 (0.2 mmol), 醋酸钯 (4.5 mg, 0.02 mmol),三水磷酸氢二钾 (115 mg, 0.5 mmol),碘苯 (1.2 mmol, 115 uL)置于10 mL的史莱克管中,加入1 mL的二甲亚砜,在120 oC下反应26 h。反应结束后,冷却至室温,加入10 mL的蒸馏水,混匀后用乙酸乙酯 (3×10 mL) 萃取。合并有机相,用饱和食盐水 (3×10 mL) 洗,有机相用无水硫酸钠干燥。真空浓缩有机相,用二氯甲烷/丙酮作为展开剂(体积比为6:1),薄层色谱分离得2-(3-苯丙酰胺基)-吡啶-1-氧化物31.9 mg,产率66%;
熔点103-104 oC. 1 H NMR(400 MHz, CDCl3) δ 10.05 (s, NH, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H, Ar-H), 8.21 (dd, J = 6.5, 1.1 Hz, 1H, Ar-H), 7.35-7.32 (m, 1H, Ar-H), 7.31-7.19 (m, 5H, Ph-H), 6.99-6.95 (m, 1H, Ar-H), 3.07 (t, J =7.4 Hz, 2H, CH 2CH3), 2.85 (t, J = 8.1 Hz, 3H, CH2CH 3). 13 C NMR(100 MHz, CDCl3) δ 171.0, 144.1, 140.0, 137.1, 128.7, 128.3, 128.2, 126.5, 118.6, 114.8, 39.3, 30.9. HRMS (positive ESI) Calcd for C14H15N2O2 (M+H) 243.1128, Found 243.1129;
(3)苯丙酸的制备
空气氛围下,称取2-(3-苯基丙酰胺基)吡啶1-氧化物48.4 mg (0.2 mmol),氢氧化钠120 mg (3 mmol)置于10 mL的史莱克管中,加入1 mL的无水乙醇,在90 oC下反应24 h。反应结束后,冷却至室温,加入30 mL1mol/L的稀盐酸溶液,再加入30 mL (3×10 mL)的二氯甲烷萃取。合并有机相,用无水硫酸钠干燥,过滤,减压蒸馏除去溶剂,所得的物质经柱色谱分离提纯 (淋洗剂为二氯甲烷:甲醇 = 1:10),得到苯丙酸的纯品23.8 mg, 80%;
1 H NMR (400 MHz, CDCl3) δ 7.29 (q, J = 1.4 Hz, 2H, Ph-H), 7.21 (t, J = 4.8 Hz, 3H, Ph-H), 2.96 (t, J =7.5 Hz, 2H, CH 2CH2), 2.68 (t, J = 8.0 Hz, 2H, CH2CH 2). 13 C NMR (100 MHz, CDCl3) δ 179.6, 140.2, 128.6, 128.3, 126.4, 35.7, 30.6。
实施例2
本实施例的2-甲基-3-苯丙酸的制备方法如下:
(1) 2-(2-甲基-3-苄基丙酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-甲基丙酰胺基)吡啶-1-氧化物 (0.2 mmol, 36 mg),PhI (1.2 mmol,135 μL),Pd(OAc)2 (10 mol%, 4.5 mg),K2HPO4·3H2O (0. 5 mmol, 115mg),DMSO 1 mL 空气氛围中120 oC下反应26 小时,得2-(2-甲基-3-苄基丙酰胺基)吡啶-1-氧化物21.7 mg, 产率42%;
熔点 86-88 oC. 1 H NMR(400 MHz, CDCl3) δ 10.01 (s, NH, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H, Ar-H), 8.21 (dd, J = 6.5, 1 Hz, 1H, Ar-H), 7.33 (t, J = 1.24 Hz, 1H, Ar-H), 7.30-7.18 (m, 5H, Ph-H), 6.98-6.94 (m, 1H, Ar-H), 3.14 (q, J = 7.0 Hz, 1H, CH3(CH2)CH), 2.89-2.82 (m,1H, CH3(CHH)CH), 2.76 (q,J = 7.5 Hz, 1H, CH3(CHH)CH), 1.29 (d,J = 6.8 Hz, 1H, CH3CHHCHCH2), 1.67-1.62 (m,1H, CH3CHHCHCH2), 0.99-0.95 (m,3H, CH 3(CH2)CH). 13 C NMR(100 MHz, CDCl3) δ 174.9, 144.1, 138.8, 137.0, 129.0, 128.5, 128.1, 126.6, 118.6, 114.8, 44.6, 39.8, 17.5. HRMS (positive ESI) Calcd for C15H17N2O2(M+H) 257.1285, Found 257.1286;
(2)2-甲基-3-苯丙酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-甲基-3-苄基丙酰胺基)吡啶-1-氧化物 (0.2 mmol, 52.0 mg), NaOH (3 mmol, 120 mg), EtOH 1.5 mL, 温度 90℃下反应24 h, HCl (2N)酸化得 2-甲基-3-苯丙酸。
实施例3
本实施例的2,2-二甲基-3-苯丙酸的制备方法如下:
(1)2-(2,2-二甲基-3-苄基丙酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2,2-二甲基丙酰胺基)吡啶-1-氧化物 (0.2 mmol, 38.8 mg),PhI (1.2 mmol,135 μL),Pd(OAc)2 (10 mol%, 4.5 mg),K2HPO4·3H2O (0. 5 mmol, 115mg),DMSO 1 mL 空气氛围中120 oC下反应26 小时,得2-(2,2-二甲基-3-苄基丙酰胺基)吡啶-1-氧化物23.4 mg, 产率43%;
1 H NMR (400 MHz, CDCl3) δ 10.35 (s, NH, 1H), 8.49 (d, J = 6.8 Hz, 1H, Ar-H), 8.22 (d, J = 6.5 Hz, 1H, Ar-H), 7.34 (t, J = 8.0 Hz, 1H, Ar-H), 7.25-7.19 (m, 3H, Ph-H), 7.13 (d, J = 6.7 Hz, 2H, Ph-H), 6.99-6.95 (t, J = 7.3 Hz, 1H, Ar-H), 2.97 (s, 2H, CH 2C(CH3)2), 1.35 (s,6H, CH2C(CH 3)2). 13 C NMR (100 MHz, CDCl3) δ 176.6, 144.3, 137.2, 137.0, 130.2, 128.1, 126.7, 118.5, 114.5, 46.5, 45.2, 24.9. HRMS (positive ESI) Calcd for C16H19N2O2 (M+H) 271.1441, Found 271.1443;
(2)2,2-二甲基-3-苯丙酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2,2-二甲基-3-苄基丙酰胺基)吡啶-1-氧化物 (0.2 mmol, 54.0 mg), NaOH (3 mmol, 120 mg), EtOH 1.5 mL, 温度 90℃下反应24 h, HCl (1.5N)酸化得 2,2-二甲基-3-苯丙酸。
实施例4
本实施例的2-苄基丁酸的制备方法如下:
(1)2-(2-苄基丁酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-甲基丁酰胺基)吡啶-1-氧化物 (0.2 mmol,38.8 mg),PhI (1.2 mmol,135 μL),Pd(OAc)2 (10 mol%, 4.5 mg),K2HPO4·3H2O (0. 5 mmol, 115mg),DMSO 1 mL 空气氛围中120 oC下反应26 小时,得2-(2-苄基丁酰胺基)吡啶-1-氧化物41.7 mg, 产率77%;
1 H NMR (400 MHz, CDCl3) δ 9.97 (s, NH, 1H), 8.46 (d, J = 8.5 Hz, 1H, Ar-H), 8.18 (d, J = 6.4 Hz, 1H, Ar-H), 7.31-7.29 (m, 1H, Ar-H), 7.25-7.18 (m, 5H, Ph-H), 6.95-6.91 (m, 1H, Ar-H), 3.06 (q, J = 8.3 Hz, 1H, CH3CH2CHCH3), 2.86-2.81 (m,1H, CH3CH2CHCHH), 2.73-2.66 (m,1H, CH3CH2CHCHH), 1.83-1.75 (m,1H, CH3CHHCHCH2), 1.67-1.62 (m,1H, CH3CHHCHCH2), 0.99-0.95 (m,3H, CH 3CH2CHCH3). 13 C NMR (100 MHz, CDCl3) δ 174.3, 143.9, 139.0, 137.0, 128.8, 128.5, 128.1, 126.5, 118.5, 114.7, 52.3, 38.4, 25.6, 11.8. HRMS (positive ESI) Calcd for C16H19N2O2 (M+H) 271.1441, Found 271.1444;
(2)2-苄基丁酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-苄基丁酰胺基)吡啶-1-氧化物 (0.2 mmol, 54.0 mg), NaOH (3 mmol, 120 mg), EtOH 1.5 mL, 温度 90℃下反应24 h, HCl (2N)酸化得 2-苄基丁酸。
实施例5
本实施例的2-苄基己酸的制备方法如下:
(1) 2-(2-苄基己酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-甲基己酰胺基)吡啶-1-氧化物 (0.2 mmol, 44.4 mg),PhI (1.2 mmol,135 μL),Pd(OAc)2 (10 mol%, 4.5 mg),K2HPO4·3H2O (0. 5 mmol, 115mg),DMSO 1 mL 空气氛围中120 oC下反应26 小时,得2-(2-苄基己酰胺基)吡啶-1-氧化物50.0 mg, 产率83%;
1 H NMR (400 MHz, CDCl3) δ 9.91 (s, NH, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H, Ar-H), 8.19 (dd, J = 6.5, 1.1 Hz, 1H, Ar-H), 7.33-7.28 (m, 1H, Ar-H), 7.25-7.16 (m, 5H, Ph-H), 6.97-6.93 (m, 1H, Ar-H), 3.05 (q, J = 8.4 Hz, 1H, CH3CH2CH2CH2CH(CH2)), 2.83 (q, J = 6.4 Hz, 1H, CH3CH2CH2CH2CH(CHH)), 2.76-2.71 (m,1H, CH3CH2CH2CH2CH(CHH)), 1.80-1.73 (m,1H, CH3CH2CH2CHHCH(CH2)), 1.62-1.55 (m,1H, CH3CH2CH2CHHCH(CH2)), 1.33-1.32 (m,4H, CH3CH2CHHCH2CH(CH2)), 0.86 (t, J = 6.9 Hz, 3H, CH 3CH2CH2CH2CH(CH2)). 13 C NMR (100 MHz, CDCl3) δ 174.5, 143.9, 139.0, 137.0, 128.8, 128.5, 128.1, 126.5, 118.5, 114.7, 51.1, 38.8, 32.3, 29.5, 22.7, 13.9 . HRMS (positive ESI) Calcd for C18H23N2O2 (M+H) 299.1754, Found 299.1758;
(2)2-苄基己酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-苄基己酰胺基)吡啶-1-氧化物 (0.2 mmol, 60.0 mg), NaOH (3 mmol, 120 mg), EtOH 1.5 mL, 温度 90℃下反应24 h, HCl (2N)酸化得 2-苄基己酸。
实施例6
本实施例的2-苄基环丙酸的制备方法如下:
(1)2-(2-苄基环丙基甲酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-环丙基甲酰胺基)吡啶-1-氧化物 (0.2 mmol, 35.6 mg),PhI (1.2 mmol,135 μL),Pd(OAc)2 (10 mol%, 4.5 mg),K2HPO4·3H2O (0. 5 mmol, 115mg),DMSO 1 mL 空气氛围中120 oC下反应26 小时,得2-(2-苄基环丙基甲酰胺基)吡啶-1-氧化物13.2 mg, 产率26%;
熔点147-148 oC. 1 H NMR(400 MHz, CDCl3) δ 10.15 (s, NH, 1H), 8.20 (dd, J = 3.6, 1.8 Hz, 1H, Ar-H), 8.18 (m, 1H, Ar-H), 7.31-7.17 (m, 6H, Ar-H), 6.92-6.88 (m, 1H, Ar-H), 2.71 (q, J = 16.9, 8.6 Hz, 1H, CHCHCH2), 2.29-2.23 (m,1H, CHCHCH2), 1.92-1.87 (m,1H, CHCHCHH), 1.49-1.44 (m,1H, CHCHCHH). 13 C NMR(100 MHz, CDCl3) δ 168.4, 144.1, 136.9, 135.8, 129.2, 128.15, 128.08, 126.8, 118.1, 114.6, 27.0, 25.0, 11.4. HRMS (positive ESI) Calcd for C15H15N2O2 (M+H) 255.1128, Found 255.1130;
(2)2-苄基环丙酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-苄基环丙基甲酰胺基)吡啶-1-氧化物 (0.2 mmol, 51.0 mg), NaOH (3 mmol, 120 mg), EtOH 1.5 mL, 温度 90℃下反应24 h, HCl (2N)酸化得 2-苄基环丙酸。
实施例7
本实施例的2-(4-氟苄基)己酸的制备方法如下:
(1) 2-(2-(4-氟苄基)己酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-甲基己酰胺基)吡啶-1-氧化物 (0.1 mmol, 22.2 mg),4-FC6H4I (1.0 mmol,137μL),Pd(OAc)2 (0.01mol, 2.25mg),K2HPO4·3H2O (0. 4 mmol, 92mg),DMSO 0.5mL 空气氛围中115 oC下反应30 小时,得2-(2-(4-氟苄基)己酰胺基)吡啶-1-氧化物28.1mg, 产率89%;
1 H NMR(400 MHz, CDCl3) δ 9.95 (s, NH, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H, Ar-H), 8.20 (dd, J = 6.5, 1.8 Hz, 1H, Ar-H), 7.34-7.29 (m, 1H, Ar-H), 7.16-7.13 (m, 2H, Ph-H), 6.99-6.91 (m, 3H, Ar-H), 6.86-6.80 (m, 2H, Ph-H), 3.02 (q,J = 8.6 Hz, 1H, CH3CH2CH2CH2CH(CHH)), 2.81(q,J = 6.2 Hz, 1H, CH3CH2CH2CH2CH(CHH)), 2.73-2.66 (m,1H, CH3CH2CH2CH2CH(CHH)), 1.81-1.72 (m,1H, CH3CH2CH2CHHCH(CH2)), 1.63-1.56 (m,1H, CH3CH2CHHCH2CH(CH2)), 1.38-1.32 (m,4H, CH3CH 2CH 2CH2CH(CH2)), 0.87 (t, J = 7.0 Hz, 3H, CH 3CH2CH2CH2CH(CH2)). 13 C NMR(100 MHz, CDCl3) δ 174.3, 161.6 (d, J F-C = 242.9 Hz), 143.9, 137.0, 134.6 (d, J F-C = 3.1 Hz), 130.3 (J F-C = 7.9 Hz), 128.1, 118.6, 115.3 (d, J F-C = 21.1 Hz), 114.7. 51.1, 37.9, 32.4, 29.5, 22.6, 13.9. 19F NMR (376 MHz, CDCl3) δ -116.51. HRMS (positive ESI) Calcd for C18H22FN2O2 (M+H) 317.1660, Found 317.1664;
(2)2-(4-氟苄基)己酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-(4-氟苄基)己酰胺基)吡啶-1-氧化物 (0.2 mmol, 64.0 mg), NaOH (2.1 mmol, 84mg), EtOH 1.4mL, 温度 85℃下反应30 h, HCl (2N)酸化得 2-(4-氟苄基)己酸。
实施例8
本实施例的2-(2-甲基苄基)己酸的制备方法如下:
(1)2-(2-(2-甲基苄基)己酰胺基)吡啶-1-氧化物的制备
按实施例1步骤(2)所述的方法,不同的是所用底物和试剂为:2-(2-甲基己酰胺基)吡啶-1-氧化物 (0.3 mmol, 66.6 mg),2-MeC6H4I (1.4 mmol,158 μL),Pd(OAc)2 (0.03 mmol, 6.75 mg),K2HPO4·3H2O (0. 6 mmol, 138mg),DMSO 2.25 mL 空气氛围中125 oC下反应20 小时,得2-(2-(2-甲基苄基)己酰胺基)吡啶-1-氧化物81.4 mg, 产率87%;
1 H NMR(400 MHz, CDCl3) δ 9.88 (s, NH, 1H), 8.46 (dd, J = 8.5, 1.7 Hz, 1H, Ar-H), 8.19 (dd, J = 6.5, 1.1 Hz, 1H, Ar-H), 7.34-7.29 (m, 1H, Ar-H), 7.14-7.06 (m, 4H, Ph-H), 6.98-6.94 (m, 1H, Ar-H), 3.05 (q, J = 8.4 Hz, 1H, CH3CH2CH2CH2CH(CH2)), 2.85 (q,J = 6.5 Hz, 1H, CH3CH2CH2CH2CH(CHH)), 2.73-2.66 (m,1H, CH3CH2CH2CH2CH(CHH)), 2.35 (s, 3H, CH 3), 1.84-1.76 (m,1H, CH3CH2CH2CHHCH(CH2)), 1.65-1.62 (m,1H, CH3CH2CHHCH2CH(CH2)), 1.38-1.28 (m,4H, CH3CH 2CH 2CH2CH(CH2)), 0.87 (t, J = 7.0 Hz, 3H, CH 3CH2CH2CH2CH(CH2)). 13 C NMR(100 MHz, CDCl3) δ174.6, 144.0, 137.2, 137.0, 136.0, 130.5, 129.5, 128.1, 126.7, 126.0, 118.5, 114.7, 49.8, 36.0, 32.5, 29.6, 22.7, 19.6, 13.9. HRMS (positive ESI) Calcd for C19H25N2O2 (M+H) 313.1911, Found 313.1911;
(2)2-(2-甲基苄基)己酸的制备
按实施例1步骤(3)所述的方法,不同的是所用底物和试剂为:2-(2-(2-甲基苄基)己酰胺基)吡啶-1-氧化物 (0.2 mmol, 63.0 mg), NaOH (4mmol, 160 mg), EtOH 1.6 mL, 温度 95℃下反应20 h, HCl (2N)酸化得 2-(2-甲基苄基)己酸。
Claims (9)
1.一种苯丙酸类化合物的合成方法,其特征在于步骤如下:
(1)在空气氛围中,向史莱克管中依次加入2-丙酰胺基-吡啶-1-氧化物、醋酸钯、三水磷酸氢二钾、芳基碘代化合物和二甲亚砜,115~125 oC条件下反应20~30小时,反应结束后,冷却至室温,萃取、干燥、浓缩、薄层色谱分离得到芳基化的产物;其中2-丙酰胺基-吡啶-1-氧化物的结构式为: ;芳基碘代化合物的结构式为:;
R1,R2为氢原子、直连烷基、支链烷基或苄基,R3为氢原子、烷氧基、甲基、氟、氯或溴,R3在苯环C2-C4位;
(2)将得到的芳基化产物溶于NaOH的乙醇溶液中,85~95 oC下反应20~30小时,反应结束后中和、萃取、干燥、浓缩、柱层析得苯丙酸类化合物。
2.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(1)中2-丙酰胺基-吡啶-1-氧化物、醋酸钯、三水磷酸氢二钾和芳基碘代化合物的物质的量之比为0.1~0.3:0.01~0.03:0.4~0.6:1.0~1.4,其中以1 mmol 2-丙酰胺基-吡啶-1-氧化物为基准,所需二甲亚砜的体积为5~7.5mL。
3.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(2)中所述步骤(2)中氢氧化钠的乙醇溶液的用量以芳香酰氨基吡啶-1-氧化物为基准,1mmol 2-丙酰胺基-吡啶-1-氧化物所需NaOH的乙醇溶液为7~8mL。
4.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(2)中NaOH的乙醇溶液的浓度为1.5~2.5mol/L。
5.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(1)中的萃取采用乙酸乙酯萃取,用无水硫酸钠干燥,真空浓缩。
6.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(1)中的薄层色谱采用的展开剂为二氯甲烷和丙酮按照体积比为6:1混合。
7.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(2)中加入稀盐酸溶液中和,用二氯甲烷萃取,用无水硫酸钠干燥,减压蒸馏进行浓缩。
8.根据权利要求7所述的苯丙酸类化合物的合成方法,其特征在于:所述稀盐酸溶液的浓度为1~2mol/L。
9.根据权利要求1所述的苯丙酸类化合物的合成方法,其特征在于:所述步骤(2)中柱层析所用的淋洗剂为二氯甲烷和甲醇按照体积比为1:10混合。
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CN112851579A (zh) * | 2019-11-27 | 2021-05-28 | 衡阳师范学院 | 用于铜催化卤代芳烃偶联反应的配体化合物、催化体系和偶联反应 |
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