CN102775367B - 一种3,4,5-三取代噁唑-2-酮的合成方法 - Google Patents
一种3,4,5-三取代噁唑-2-酮的合成方法 Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 22
- -1 3,4,5-tri-substituted oxazole-2-one Chemical class 0.000 title claims abstract description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 7
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
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- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000005755 formation reaction Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005504 styryl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
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- 0 CC(C)(C)OC(N(*)C#CC)=O Chemical compound CC(C)(C)OC(N(*)C#CC)=O 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
- IOUNQDKNJZEDEP-UHFFFAOYSA-N phosalone Chemical compound C1=C(Cl)C=C2OC(=O)N(CSP(=S)(OCC)OCC)C2=C1 IOUNQDKNJZEDEP-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
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- OIRHKGBNGGSCGS-UHFFFAOYSA-N 1-bromo-2-iodobenzene Chemical compound BrC1=CC=CC=C1I OIRHKGBNGGSCGS-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical group CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical group CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 1
- MPPOHAUSNPTFAJ-UHFFFAOYSA-N 2-[4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy]propanoic acid Chemical compound C1=CC(OC(C)C(O)=O)=CC=C1OC1=NC2=CC=C(Cl)C=C2O1 MPPOHAUSNPTFAJ-UHFFFAOYSA-N 0.000 description 1
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- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明公开了一种3,4,5-三取代噁唑-2-酮的合成方法,包括步骤:将钯催化剂、三叔丁基膦和碱溶解在有机溶剂中,加入N-乙炔基氨基甲酸叔丁酯与卤代烃形成反应体系,在25℃-70℃反应完全,制得3,4,5-三取代噁唑2-酮。该合成方法步骤短、只需一步,操作简单,反应收率高,底物适用性广、可以顺利地在3-位、4-位和5-位引入各种取代基,为低温反应、条件温和、实用性强,具有较大的实施价值和社会经济效益。
Description
技术领域
本发明涉及化学合成领域,具体涉及一种3,4,5-三取代噁唑-2-酮的合成方法。
背景技术
噁唑-2-酮,是一种含有氮、氧杂原子的不饱和五元杂环化合物,是一类重要的有机合成中间体,可用于氨基酸、氨基醇、二肽等化合物的合成。噁唑-2-酮在材料科学、农药和医药等领域也有着广泛的应用潜力和开发价值。噁唑-2-酮的结构式如下:
噁唑-2-酮类抗菌药是继磺胺类和氟喹诺酮类之后的一类新型化学合成抗菌药物,具有抑制多重耐药革兰氏阳性菌的作用。随着临床上耐药菌株的不断增加,噁唑-2-酮正成为一类极有发展前景的新型合成抗菌药物,例如:除草剂噁唑禾草灵(fenoxaprop)、杀虫剂伏杀硫磷(phosalone)、杀菌剂3-乙酰基-5,6,7-三氯苯并噁唑酮等。2000年美国食品与药品管理局批准linezolid(利萘唑胺)用于治疗耐药革兰氏阳性菌引起的感染性疾病。
多取代的噁唑-2-酮类化合物可以为含有噁唑-2-酮环结构单元的天然产物和医药中间体的合成提供有效途径。因此,多取代的噁唑-2-酮类化合物的合成成了国内外研究的热点。
目前,合成多取代噁唑-2-酮主要有以下几种方法:
1、利用α-羟基酮与异氰酸酯反应合成3-取代-4,5-二甲基-噁唑-2-酮的方法(Martínez R.et.al,Tetrahedron,2000,56,3857)。该方法的缺点是会有其它异构体的生成,很难进行分离纯化,且该方法仅适用于合成4位和5位上为短链烷基的多取代噁唑-2-酮。另一方面,异氰酸酯属于剧毒危险化学品,且化学性质活泼,对水分敏感,容易发生水解,显然,该方法实用性较差。该方法具体如下:
2、利用α-氨基酮和光气合成3-叔丁基-4-甲基-5-间氯苯基-噁唑-2-酮的方法(Hamad M.O.et.al,Bioorg.Med.Chem.2006,14,7051)。该方法用光气实现碳基的引入,但是光气剧毒,难以在工业生产上进行应用。该方法具体如下:
3、临界态二氧化碳法。姜焕峰等人报道了丙炔醇与伯胺在临界态二氧化碳(scCO2)和铜的存在下合成4-甲基-3,5-二取代噁唑-2-酮的方法(JiangH.et.al,Synthesis,2008,763),尽管该反应能够一步合成三取代噁唑-2-酮,但是临界态二氧化碳的使用需要在很苛刻的条件下才能将通常气态的二氧化碳转变成液态的二氧化碳,一般很难达到,实际操作困难,且该方法仅适用于合成4-位上为甲基的多取代噁唑-2-酮。该方法具体如下,其中,R为烷基、芳香族烃基或氢:
4、α-羟基酮与氨基甲酸乙酯反应的方法。例如,安息香和氨基甲酯乙酯在高温(150℃)下反应可以得到4,5-二苯基噁唑-2-酮(Whitney S.E.et.al,J.Org.Chem.1991,56,3058)。显然,该法只能合成4,5-二取代的噁唑-2-酮,而且条件剧烈,产率较低(52%),成本较高(氨基甲酯乙酯288元/5g,安奈吉试剂)。该方法具体如下:
5、金催化的炔基胺化合物的环化反应方法(Istrate F.M.et.al,Org.Lett.2008,10,925)。该方法可以高效地合成3,5-二取代的噁唑-2-酮化合物(R=芳基,R′=烷基),但是所用的金催化剂[PPh3Au(MeCN)]SbF6非常昂贵,更重要的是,它对于合成3,4,5-三取代的噁唑-2-酮还无能为力。
综上所述,尽管已经有一些多取代噁唑-2-酮的合成方法被报道,但是都存在着反应条件苛刻、采用剧毒或昂贵的化学试剂、产率较低、底物兼容性差等缺点。到目前为止,简单、高效、经济地合成3,4,5-三取代噁唑-2-酮的方法还非常少见。因此,有必要研究3,4,5-三取代噁唑-2-酮的新的合成方法。
发明内容
本发明提供了一种温和、高效、方便的3,4,5-三取代噁唑-2-酮的合成方法。
本发明发现:钯催化N-炔基氨基甲酸叔丁酯(如结构式II所示的化合物)与卤代烃(如结构式III所示的化合物)的偶联反应可以为3,4,5-三取代噁唑-2-酮提供有效途径。
一种3,4,5-三取代噁唑-2-酮的合成方法,包括步骤:
将钯催化剂、三叔丁基膦和碱溶解在有机溶剂中,加入结构式II所示的化合物和结构式III所示的化合物形成反应体系,在25℃-70℃反应完全,制得3,4,5-三取代噁唑2-酮;
R3X III
结构式II中,R1为苯基(Ph)、对甲基苯基、对氟苯基、对氯苯基、对溴苯基、对甲氧基苯基、3,4-二甲氧基苯基、2-萘基、叔丁基二苯基硅氧乙基(TBDPSO)、烷基或含杂原子的烷基;R2为苄基(Bn)、苯基、对氯苯基、烷基或含杂原子的烷基;Boc为叔丁氧羰基;
结构式III中,R3为苯基、苄基、苯乙烯基、单取代苯基、多取代苯基或芳香杂环基;X为Cl、Br或I。
所述的单取代苯基优选为邻甲基苯基、对氟苯基、对氯苯基、对溴苯基、对甲酰基苯基、对甲酸乙酯基苯基、对乙酰基苯基或间氰基苯基。
所述的芳香杂环基优选为吡啶基或噻吩基。
所述的烷基优选为C1-C10的烷基。
所述的含杂原子的烷基优选为碳链中插入O、S、NH的C1-C10的烷基。
所述的三叔丁基膦(t-Bu3P),作为配体,可采用市售产品。
结构式II所示的化合物采用现有技术制备,如可依据文献(Istrate F.M.et.al,Org.Lett.2008,10,925)中的方法合成。
结构式III所示的化合物采用市售产品。
本发明合成路线如下:
通过研究,本发明实现了制备3,4,5-三取代噁唑2-酮的优化反应条件,具体如下:
所述的钯催化剂优选醋酸钯(Pd(OAc)2)。
所述的碱优选碳酸钾(K2CO3)。
所述的有机溶剂优选N,N-二甲基甲酰胺(DMF)。
所述的钯催化剂(如醋酸钯)、三叔丁基膦、碱(如碳酸钾)、结构式III所示的化合物与结构式II所示的化合物的摩尔比为0.02-0.05∶0.1∶1.2∶1.12∶1,进一步优选为0.05∶0.1∶1.2∶1.12∶1。
所述的反应温度优选为50℃。
在以上优化反应条件下,原料转化完全,反应产率最高。
本发明中的反应,其反应时间没有严格的限制,通过定时取样,用现有分析方法如薄层色谱法(TLC)进行跟踪分析,当其中一种原料或多种原料都反应完毕,视为反应的终点即可。经过试验,为了使反应进行完全,所述的反应时间一般为5-24小时,优选为5-8小时,进一步优选为8小时。
优选条件的反应路线如下:
所述的反应在反应完全后采用萃取,萃取有机相经洗涤、干燥和柱层析分离等技术进行后处理,以得到高纯度的产物。所述的萃取可采用乙酸乙酯作为萃取剂。所述的洗涤可采用碳酸氢钠水溶液洗和饱和食盐水洗。所述的柱层析分离的条件为:硅胶300-400目,洗脱液:石油醚/乙酸乙酯的体积比为11/1。
采用本发明合成方法制备的3,4,5-三取代噁唑-2-酮,为结构式I所示的化合物:
结构式I中的R1、R2分别与结构式II中的R1、R2具有相同的含义,结构式I中的R3与结构式III中的R3具有相同的含义。
本发明采用钯催化剂催化N-炔基氨基甲酸叔丁酯与卤代烃的偶联反应合成3,4,5-三取代噁唑-2-酮,一步就能顺利地制备3,4,5-三取代的噁唑-2-酮,官能团兼容性很好。比较而言,传统的3,4,5-三取代噁唑-2-酮的合成需要多步化学反应过程,而且官能团兼容性较差。显然,本发明与现有技术相比,其有益效果主要体现在:1、步骤短、只需一步,操作简单;2、反应收率高;3、底物适用性广、可以顺利地在3-位、4-位和5-位引入各种取代基;4、低温反应、条件温和、实用性强。故本发明有较大的实施价值和社会经济效益。
具体实施方式
原料制备例1 原料化合物II的合成
结构式II所示的化合物依据文献(Istrate F.M.et.al,Org.Lett.2008,10,925)方法合成,以化合物1a为例,反应方程式及操作步骤如下:
在10mL的圆底烧瓶中加入苯乙炔溴(90mg,0.5mmol),N-苄基氨基甲酸叔丁酯(124mg,0.6mmol),磷酸钾(212mg,1.0mmol),五水硫酸铜(25mg,0.1mmol)和1,10-菲罗啉(36mg,0.2mmol),加入2mL甲苯溶解,得到反应体系。反应体系在80℃反应8小时后加10mL水淬灭,乙酸乙酯(10mL)萃取三次。有机相合并后用碳酸氢钠水溶液洗和饱和食盐水洗,得到的有机层经无水硫酸钠干燥,再旋转蒸发除去溶剂,然后用硅胶(300-400目)柱层析分离(洗脱液:石油醚/乙酸乙酯=15/1,体积比)得到100mg(产率:65%)N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a,为黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ1.58(s,9H),4.72(s,2H),7.47-7.24(m,10H);13C-NMR(CDCl3,100MHz):δ26.9,52.0,69.9,81.5,83.0,122.6,126.0,126.8,127.1,127.2,127.4,129.5,135.3,152.7;HRMS(EI)calcdfor C20H21NO2(M+)307.1572,Found 307.1567。表明黄色液体为结构式1a所示的N-苄基-N-苯乙炔基氨基甲酸叔丁酯。
其余结构式II所示的化合物合成方法同上。
实施例1:
将醋酸钯(2.8mg,0.0125mmol)、三叔丁基膦(5.0mg,0.025mmol)和碳酸钾(41mg,0.30mmol)加入1mL N,N-二甲基甲酰胺(DMF)溶解,置于10mL的圆底烧瓶中,加入N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a(77mg,0.25mmol),接着加入碘苯2a(56mg,0.28mmol),得到反应体系。反应体系在50℃下反应8小时后加10mL水淬灭,乙酸乙酯(10mL)萃取三次。有机相合并后用碳酸氢钠水溶液洗和饱和食盐水洗后得到的有机层经无水硫酸钠干燥,再旋转蒸发除去溶剂,然后用硅胶(300-400目)柱层析分离(洗脱液:石油醚/乙酸乙酯=11/1,体积比)得到75mg(产率:92%)3,4,5-三取代噁唑-2-酮,为黄色固体。
黄色固体的1H-NMR(CDCl3,400MHz):δ4.68(s,2H),6.95-7.10(m,2H),7.16-7.32(m,10H),7.40-7.50(m,3H);13C-NMR(CDCl3,100MHz):δ45.6,123.3,124.2,126.9,127.5,127.59,127.64,127.7,128.4,128.5,129.2,130.0,130.5,134.5,136.0,154.8;MS(EI,m/z):327(M+,11),283(1),194(100),165(20);mp:96-98℃;HRMS(EI)calcd for C22H17NO2(M+)327.1259,Found327.1262。表明黄色固体为结构式4a所示的3-苄基-4,5-二苯基噁唑-2-酮。
实施例2:
除用邻甲基碘苯2b代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率82%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ1.84(s,3H),4.52(d,J=15.2Hz,1H),4.65(d,J=15.2Hz,1H),6.87-6.98(m,2H),7.10-7.25(m,9H),7.27-7.39(m,2H),7.41-7.50(m,1H);13C-NMR(CDCl3,100MHz):δ19.0,45.7,122.0,123.5,126.4,126.6,127.4,127.8,127.9,128.0,128.4,128.5,130.4,130.7,131.1,134.3,135.9,139.1,154.9;MS(EI,m/z):341(M+,8),327(1),250(15),222(25),179(21);HRMS(EI)calcd for C23H19NO2(M+),341.1416,Found341.1411。表明黄色液体为结构式4b所示的3-苄基-4-邻甲基苯基-5-苯基-噁唑-2-酮。
实施例3:
除用对氟碘苯2c代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率84%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.67(s,2H),6.95-7.05(m,2H),7.12(t,J=8.4Hz,2H),7.20-7.42(m,10H);19F-NMR(CDCl3,282MHz):δ-110.0;13C-NMR(CDCl3,100MHz):δ45.6,116.5(d,J=22.6Hz),122.1,123.0(d,J=3.0Hz),124.2,127.4,127.5,127.8(d,J=4.6Hz),128.5,128.6,132.6,132.7,134.8,135.9,154.7,163.5(d,J=250.0Hz);MS(EI,m/z):345(M+,6),332(1),254(7),226(7),183(6);HRMS(EI)calcd for C22H16FNO2(M+),345.1165,Found 345.1169;mp:104-106℃。表明白色固体为结构式4c所示的3-苄基-4-对氟苯基-5-苯基-噁唑-2-酮。
实施例4:
除用对氯碘苯2d代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率91%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.68(s,2H),6.90-7.01(m,2H),7.14(d,J=7.2Hz,2H),7.21-7.32(m,8H),7.40(d,J=7.6Hz,2H);13C-NMR(CDCl3,100MHz):δ45.7,122.0,124.3,125.4,127.3,127.5,127.8,127.9,128.5,128.6,129.6,131.9,134.8,135.8,136.2,154.7;MS(EI,m/z):363(1),361(M+,3),270(5),272(1),235(3);HRMS(EI)calcd for C22H16C1NO2(M+),361.0870,Found 361.0867;mp:159-161℃。表明白色固体为结构式4d所示的3-苄基-4-对氯苯基-5-苯基-噁唑-2-酮。
实施例5:
除用对溴碘苯2e代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率90%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.67(s,2H),6.99-7.10(m,4H),7.15-7.30(m,8H),7.56(d,J=8.0Hz,2H);13C-NMR(CDCl3,100MHz):δ45.7,122.0,124.3,124.5,125.9,127.3,127.8,127.9,128.5,128.6,132.1,132.5,134.8,135.9,154.7;MS(EI,m/z):407(8),405(M+,10),316(6),314(8),235(12);HRMS(EI)calcd for C22H16BrNO2(M+),405.0364,Found 405.0363;mp:166-168℃。表明白色固体为结构式4e所示的3-苄基-4-对溴苯基-5-苯基-噁唑-2-酮。
实施例6:
除用对碘苯甲醛2f代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率81%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.71(s,2H),6.91-7.02(m,2H),7.09-7.25(m,8H),7.39(d,J=8.0Hz,2H),7.91(d,J=8.0Hz,2H),10.08(s,1H);13C-NMR(CDCl3,100MHz):δ45.9,122.0,124.6,127.1,127.3,127.9,128.2,128.5,128.6,130.2,131.2,133.1,135.2,135.7,136.9,154.8,191.2;MS(EI,m/z):355(M+,5),326(1),264(2),208(5),165(6);HRMS(EI)calcd forC23H17NO3(M+),355.1208,Found 355.1208;mp:165-167℃。表明白色固体为结构式4f所示的3-苄基-4-对甲酰基苯基-5-苯基-噁唑-2-酮。
实施例7:
除用对碘苯甲酸乙酯2g代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率84%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ1.43(t,J=7.2Hz,3H),4.42(q,J=7.2Hz,2H),4.69(s,2H),6.95-7.02(m,2H),7.10-7.25(m,8H),7.30(d,J=8.0Hz,2H),8.09(d,J=8.0Hz,2H);13C-NMR(CDCl3,100MHz):δ14.2,45.8,61.4,122.3,124.5,127.3,127.4,127.9,128.0,128.5,128.6,130.2,130.6,131.5,131.8,134.9,135.8,154.8,165.7;MS(EI,m/z):399(M+,2),326(1),308(1),235(12),105(100);HRMS(EI)calcd for C25H21NO4(M+),399.1471,Found399.1477;mp:117-119℃。表明白色固体为结构式4g所示的3-苄基-4-对甲酸乙酯基苯基-5-苯基-噁唑-2-酮。
实施例8:
除用对碘苯乙酮2h代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率81%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ2.66(s,3H),4.69(s,2H),6.92-7.08(m,2H),7.12-7.25(m,8H),7.32(d,J=8.4Hz,2H),7.99(d,J=8.4Hz,2H);13C-NMR(CDCl3,100MHz):δ26.7,45.8,122.1,124.5,127.2,127.3,127.9,128.1,128.5,128.6,129.0,130.8,131.7,135.0,135.7,137.9,154.8,197.2;MS(EI,m/z):369(M+,4),278(5),250(1),207(4);HRMS(EI)calcd forC24H19NO3(M+),369.1365,Found 369.1364;mp:148-150℃。表明白色固体为结构式4h所示的3-苄基-4-对乙酰基苯基-5-苯基-噁唑-2-酮。
实施例9:
除用溴苯3a代替实施例1中碘苯2a外,其余操作步骤同实施例1,得到3-苄基-4,5-二苯基噁唑-2-酮,产率84%,产物表征数据同实施例1。
实施例10:
除用邻甲基溴苯3b代替实施例1中碘苯2a外,其余操作步骤同实施例1,得到3-苄基-4-邻甲基苯基-5-苯基-噁唑-2-酮,产率78%,产物表征数据同实施例2。
实施例11:
除用对氟溴苯3c代替实施例1中碘苯2a外,其余操作步骤同实施例1,得到3-苄基-4-对氟苯基-5-苯基-噁唑-2-酮,产率77%,产物表征数据同实施例3。
实施例12:
除用对氯溴苯3d代替实施例1中碘苯2a外,其余操作步骤同实施例1,得到3-苄基-4-对氯苯基-5-苯基-噁唑-2-酮,产率80%,产物表征数据同实施例4。
实施例13:
除用对溴苯甲醛3e代替实施例1中碘苯2a外,其余操作步骤同实施例1,得到3-苄基-4-对甲酰基苯基-5-苯基-噁唑-2-酮,产率81%,产物表征数据同实施例6。
实施例14:
除用间氰基溴苯3f代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率93%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ4.68(s,2H),6.90-7.02(m,2H),7.15-7.30(m,8H),7.39(s,1H),7.41-7.50(m,1H),7.55-7.61(m,1H),7.75(d,J=7.6Hz,1H);13C-NMR(CDCl3,100MHz):δ45.9,113.5,117.4,120.7,124.4,126.8,127.2,128.0,128.3,128.6,128.7,130.1,133.3,134.1,134.9,135.3,135.5,154.5;MS(EI,m/z):352(M+,12),222(1),261(1),190(7),128(4);HRMS(EI)calcd for C23H16N2O2(M+),352.1212,Found 352.1213。表明黄色液体为结构式4i所示的3-苄基-4-(间氰基苯基)-5-苯基-噁唑-2-酮。
实施例15:
除用2-溴吡啶3g代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率70%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ5.03(s,2H),6.90-7.03(m,2H),7.12-7.41(m,10H),7.50-7.64(m,1H),8.78-8.85(m,1H);13C-NMR(CDCl3,100MHz):δ45.7,122.1,123.8,125.4,125.9,127.3,127.6,128.4,128.45,128.48,136.2,136.3,136.8,147.4,150.2,154.8;MS(EI,m/z):328(20),237(59),223(3),209(15),167(40);HRMS(EI)calcd for C21H16N2O2(M+),328.1212,Found 328.1210。表明黄色液体为结构式4j所示的3-苄基-4-(2-吡啶基)-5-苯基-噁唑-2-酮。
实施例16:
除用2-溴噻吩3h代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率85%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.73(s,2H),6.99(d,J=3.6Hz,1H),7.02-7.15(m,3H),7.17-7.30(m,6H),7.35-7.42(m,2H),7.55(d,J=5.2Hz,1H);13C-NMR(CDCl3,100MHz):δ45.6,115.9,124.6,126.3,127.3,127.4,127.8,127.9,128.1,128.4,128.5,129.8,131.5,136.0,136.9,154.4;MS(EI,m/z):333(M+,10),275(1),242(29),214(2),176(2);HRMS(EI)calcd forC20H15NO2S(M+),333.0823,Found 333.0822;mp:122-124℃。表明白色固体为结构式4k所示的3-苄基-4-(2-噻吩基)-5-苯基-噁唑-2-酮。
实施例17:
除用3-溴噻吩3i代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率77%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ4.70(s,2H),6.85-6.95(m,1H),7.02-7.11(m,2H),7.20-7.37(m,9H),7.39-7.51(m,1H);13C-NMR(CDCl3,100MHz):δ45.7,118.4,124.3126.7,127.28,127.3,127.7,127.8,128.0,128.47,128.5,128.6,135.3,136.2,154.8;MS(EI,m/z):333(M+,6),242(12),214(2),171(3);HRMS(EI)calcd for C20H15NO2S(M+),333.0823,Found333.0820。表明其为结构式41所示的3-苄基-4-(3-噻吩基)-5-苯基-噁唑-2-酮。
实施例18:
除用α-溴苯乙烯3j代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率71%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ4.53(s,2H),5.47(s,1H),6.02(s,1H),7.07-7.20(m,2H),7.21-7.42(m,11H),7.55-7.65(m,2H);13C-NMR(CDCl3,100MHz):δ45.8,122.4,122.5,124.4,126.1,127.5,127.6,127.7,127.8,128.4,128.5,129.0,129.1,135.4,135.5,136.0,136.3,154.9;MS(EI,m/z):353(M+,38),262(30),219(24),191(59),156(14);HRMS(EI)calcd for C24H19NO2(M+),353.1416,Found 353.1421。表明黄色液体为结构式4m所示的3-苄基-4-(α-苯乙烯基)-5-苯基-噁唑-2-酮。
实施例19:
除用苄溴3k代替实施例1中碘苯2a外,其余操作步骤同实施例1,产率81%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ3.91(s,2H),4.61(s,2H),7.18(d,J=6.8Hz,4H),7.27-7.42(m,9H),7.48-7.60(m,2H);13C-NMR(CDCl3,100MHz):δ29.3,45.4,120.7,125.0,126.9,127.3,127.6,127.8,127.9,128.1,128.8,129.2,135.4,136.0,136.2,155.4;MS(EI,m/z):341(M+,4),250(1),207(2),178(2),144(3);HRMS(EI)calcd for C23H19NO2(M+),341.1416,Found341.1414;mp:147-149℃。表明白色固体为结构式4n所示的3,4-二苄基-5-苯基-噁唑-2-酮。
实施例20:
除用N-苄基-N-对甲基苯乙炔基氨基甲酸叔丁酯1b(已有化合物,合成方法参见1a的合成)代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率84%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ2.28(s,3H),4.67(s,2H),7.01(d,J=8.4Hz,4H),7.15-7.30(m,7H),7.39-7.51(m,3H);13C-NMR(CDCl3,100MHz):δ21.1,45.6,122.5,124.3,124.9,127.1,127.5,127.7,128.5,129.0,129.1,129.8,130.6,134.7,136.1,137.6,154.9;MS(EI,m/z):341(M+,6),250(19),234(7),173(13);mp:112-114℃;HRMS(EI)calcd for C23H19NO2(M+),341.1416,Found 341.1410。表明白色固体为结构式4o所示的3-苄基-4-苯基-5-对甲基苯基-噁唑-2-酮。
实施例21:
除用N-苄基-N-对氟苯乙炔基氨基甲酸叔丁酯1c(已有化合物,合成方法参见1a的合成)代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率93%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.67(s,2H),6.89(t,J=8.8Hz,2H),6.95-7.10(m,2H),7.17-7.25(m,7H),7.38-7.47(m,2H),7.49-7.60(m,1H);19F-NMR(CDCl3,282MHz):δ-113.3;13C-NMR(CDCl3,100MHz):δ45.7,115.5(d,J=21.2Hz),122.9,123.96(d,J=2.9Hz),126.2(d,J=7.6Hz),126.8,127.5,127.8,128.5,129.3,130.1,130.6,133.8,136.0,154.7,163.2(d,J=247.0Hz);MS(EI,m/z):345(M+,2),297(1),254(2),226(4),183(4);HRMS(EI)calcd for C22H16FNO2(M+),345.1165,Found 345.1166;mp:80-82℃。表明白色固体为结构式4p所示的3-苄基-4-苯基-5-对氟苯基-噁唑-2-酮。
实施例22:
除用N-苄基-N-对氯苯乙炔基氨基甲酸叔丁酯1d(已有化合物,合成方法参见1a的合成)代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率83%,产物:黄色固体。
黄色固体的1H-NMR(CDCl3,400MHz):δ4.67(s,2H),6.90-7.02(m,2H),7.17(s,4H),7.19-7.25(m,5H),7.44(t,J=7.6Hz,2H),7.60-7.70(m,1H);13C-NMR(CDCl3,100MHz):δ45.7,123.8,125.4,126.2,126.7,127.5,127.8,128.5,128.7,129.4,130.2,130.5,133.3,133.6,135.9,154.6;MS(EI,m/z):363(3),361(M+,10),272(3),270(9),165(2);HRMS(EI)calcd for C22H16ClNO2(M+),361.0870,Found 361.0864;mp:156-158℃。表明黄色固体为结构式4q所示的3-苄基-4-苯基-5-对氯苯基-噁唑-2-酮。
实施例23:
除用N-苄基-N-对溴苯乙炔基氨基甲酸叔丁酯1e(已有化合物,合成方法参见1a的合成)代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率71%,产物:黄色固体。
黄色固体的1H-NMR(CDCl3,400MHz):δ4.67(s,2H),6.81-6.97(m,2H),6.99-7.10(m,2H),7.12-7.25(m,5H),7.27-7.38(m,2H),7.41-7.50(m,2H),7.51-7.61(m,1H);13C-NMR(CDCl3,100MHz):δ45.7,121.5,123.9,125.7,126.6,126.7,127.5,127.8,128.5,129.4,130.2,130.4,131.6,133.6,135.9,154.6;MS(EI,m/z):407(11),405(M+,14),316(9),314(11),235(12);HRMS(EI)calcd for C22H16BrNO2(M+),405.0364,Found 405.0361;mp:130-132℃。表明黄色固体为结构式4r所示的3-苄基-4-苯基-5-对溴苯基-噁唑-2-酮。
实施例24:
除用N-苄基-N-对甲氧基苯乙炔基氨基甲酸叔丁酯1f(已有化合物,合成方法参见1a的合成)代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率95%,产物:黄色固体。
黄色固体的1H-NMR(CDCl3,400MHz):δ3.74(s,3H),4.67(s,2H),6.69-6.80(m,2H),6.97-7.09(m,2H),7.15-7.25(m,7H),7.41(t,J=7.6Hz,2H),7.48-7.51(m,1H);13C-NMR(CDCl3,100MHz):δ45.5,55.1,113.8,120.3,121.5,125.8,127.1,127.4,127.6,128.4,129.1,129.8,130.6,134.6,136.1,154.9,159.0;MS(EI,m/z):357(M+,3),327(10),266(2),135(100);mp:156-158℃;HRMS(EI)calcd for C23H19NO3(M+),357.1365,Found 357.1360。表明黄色固体为结构式4s所示的3-苄基-4-苯基-5-对甲氧基苯基-噁唑-2-酮。
实施例25:
除用N-苄基-N-(3,4-二甲氧基苯乙炔基)氨基甲酸叔丁酯1g代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率90%,产物:黄色液体。黄色液体的1H-NMR(CDCl3,400MHz):δ3.57(s,3H),3.80(s,3H),4.66(s,2H),6.69(d,J=8.4Hz,1H),6.73-6.80(m,1H),6.86-6.90(m,1H),6.98-7.10(m,2H),7.14-7.25(m,5H),7.37-7.50(m,3H);13C-NMR(CDCl3,100MHz):δ45.6,55.3,55.7,107.4,110.9,117.0,120.5,121.7,127.2,127.4,127.6,128.4,129.1,129.8,130.7,134.5,136.0,148.5,148.6,154.8;HRMS(ESI)calcd for C24H21NO4(M+)387.1471,Found 387.1465。表明黄色液体为结构式4t所示的3-苄基-4-苯基-5-(3,4-二甲氧基苯基)-噁唑-2-酮。
实施例26:
除用N-苄基-N-(2-萘基乙炔基)氨基甲酸叔丁酯1h代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率85%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ4.72(s,2H),6.96-7.07(m,2H),7.12-7.20(m,1H),7.22-7.34(m,5H),7.38-7.62(m,6H),7.66-7.75(m,2H),7.91(s,1H);13C-NMR(CDCl3,100MHz):δ45.7,121.9,123.4,123.7,125.0,126.2,126.4,127.0,127.5,127.7,128.0,128.1,128.5,129.2,130.1,130.7,132.4,133.0,134.6,136.0,154.8;MS(EI,m/z):377(M+,2),286(1),215(4),155(100),127(43);HRMS(EI)calcd for C26H19NO2(M+),377.1416,Found 377.1412;mp:129-131℃。表明白色固体为结构式4u所示的3-苄基-4-苯基-5-(2-萘基)-噁唑-2-酮。
实施例27:
除用N-苯基-N-苯乙炔基氨基甲酸叔丁酯1i代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率92%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ7.09-7.20(m,2H),7.24-7.41(m,13H);13C-NMR(CDCl3,100MHz):δ123.5,125.0,126.8,127.0,127.5,127.8,128.0,128.4,128.9,129.5,130.2,133.5,135.0,153.5;MS(EI,m/z):313(M+,13),254(1),180(100),165(28),127(5);mp:191-193℃;HRMS(ESI)calcd for C21H15NO2(M+)313.1103,Found 313.1109。表明白色固体为结构式4v所示的3,4,5-三苯基-噁唑-2-酮。
实施例28:
除用N-对氯苯基-N-苯乙炔基氨基甲酸叔丁酯1j代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率85%,产物:白色固体。
白色固体的1H-NMR(CDCl3,400MHz):δ7.08(d,J=8.4Hz,2H),7.20-7.32(m,7H),7.34-7.43(m,5H);13C-NMR(CDCl3,100MHz):δ123.1,125.0,126.7,127.3,128.0,128.2,128.5,129.2,129.7,130.2,132.1,133.6,135.3,153.3;MS(EI,m/z):349(5),347(M+,15),270(1),216(32),214(100);mp:218-220℃。表明白色固体为结构式4w所示的3-对氯苯基-4,5-二苯基-噁唑-2-酮。
实施例29:
除用N-苯基-N-(4-叔丁基二苯基硅氧基-1-丁炔基)氨基甲酸叔丁酯1k代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率72%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ1.09(s,9H),2.83(t,J=6.0Hz,2H),4.01(t,J=6.0Hz,2H),7.05-7.20(m,4H),7.22-7.35(m,6H)7.36-7.50(m,6H),7.60-7.72(m,4H);13C-NMR(CDCl3,100MHz):δ19.3,26.9,28.6,61.2,125.0,126.4,126.6,127.4,127.8,128.5,128.6,129.0,129.1,129.8,133.4,134.3,135.3,135.5,154.3;HRMS(ESI)calcd for C33H33NO3Si(M+)519.2230,Found519.2227。表明黄色液体为结构式4x所示的3,4-二苯基-5-叔丁基二苯基硅氧乙基-噁唑-2-酮。
实施例30:
除用N-苯基-N-(1-葵炔)基氨基甲酸叔丁酯11代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率71%,产物:黄色液体。
黄色液体的1H-NMR(CDCl3,400MHz):δ0.88(t,J=7.2Hz,3H),1.20-1.40(m,10H),1.61-1.72(m,2H),2.44(t,J=7.6Hz,2H),6.97-7.08(m,2H),7.12-7.20(m,2H)7.22-7.25(m,1H),7.28-7.40(m,5H);13C-NMR(CDCl3,100MHz):δ14.0,22.6,24.8,27.5,28.9,29.0,29.1,31.7,123.0,126.2,126.9,127.2,128.4,128.5,128.8,129.0,134.2,138.3,154.3;MS(EI,m/z):349(M+,20),276(1),250(100),204(5),180(21);HRMS(EI)calcd for C23H27NO2(M+),349.2042,Found 349.2040。表明黄色液体为结构式4y所示的3,4-二苯基-5-辛烷基-噁唑-2-酮。
实施例31:
除用N-甲基-N-苯乙炔基氨基甲酸叔丁酯1m代替实施例1中N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a外,其余操作步骤同实施例1,产率76%,产物:黄色固体。
黄色固体的1H-NMR(CDCl3,400MHz):δ3.08(s,3H),7.18-7.55(m,10H);13C-NMR(CDCl3,100MHz):δ31.2,122.7,124.4,126.9,127.3,127.5,128.3,128.6,130.0,135.7,136.6,154.7;mp:93-95℃;HRMS(EI)calcd forC16H13NO2(M+)251.0946,Found 251.0951。表明黄色固体为结构式4z所示的3-甲基-4,5-二苯基噁唑-2-酮。
实施例32:
除了醋酸钯、三叔丁基膦、碳酸钾、碘苯和N-苄基-N-苯乙炔基氨基甲酸叔丁酯1a的摩尔比为0.02∶0.1∶1.2∶1.12∶1,反应温度为70℃,反应时间为5小时,其余操作步骤同实施例1,得到3-苄基-4,5-二苯基噁唑-2-酮,产率89%,产物表征数据同实施例1。
实施例33:
除了反应温度为25℃,反应时间为24小时,其余操作步骤同实施例1,得到3-苄基-4,5-二苯基噁唑-2-酮,产率68%,产物表征数据同实施例1。
Claims (6)
1.一种3,4,5-三取代噁唑-2-酮的合成方法,包括步骤:
将钯催化剂、三叔丁基膦和碱溶解在有机溶剂中,加入结构式II所示的化合物和结构式III所示的化合物形成反应体系,在25℃-70℃反应完全,制得3,4,5-三取代噁唑2-酮;
结构式II中,R1为对甲基苯基、对氟苯基、对氯苯基、对溴苯基、对甲氧基苯基、3,4-二甲氧基苯基、2-萘基、叔丁基二苯基硅氧乙基、烷基或含杂原子的烷基;
R2为对氯苯基、烷基或含杂原子的烷基;Boc为叔丁氧羰基;
所述的烷基为C1-C10的烷基;所述的含杂原子的烷基为碳链中插入O、S、NH的C1-C10的烷基;
结构式III中,R3为苯乙烯基、单取代苯基、多取代苯基或芳香杂环基;X为Cl、Br或I;
所述的单取代苯基为邻甲基苯基、对氟苯基、对氯苯基、对溴苯基、对甲酰基苯基、对甲酸乙酯基苯基、对乙酰基苯基或间氰基苯基;
所述的芳香杂环基为吡啶基或噻吩基。
2.根据权利要求1所述的合成方法,其特征在于,所述的钯催化剂为醋酸钯;所述的碱为碳酸钾。
3.根据权利要求1所述的合成方法,其特征在于,所述的有机溶剂为N,N-二甲基甲酰胺。
4.根据权利要求1所述的合成方法,其特征在于,所述的钯催化剂、三叔丁基膦、碱、结构式III所示的化合物与结构式II所示的化合物的摩尔比为0.02-0.05:0.1:1.2:1.12:1。
5.根据权利要求1所述的合成方法,其特征在于,在50℃反应完全。
6.根据权利要求1所述的合成方法,其特征在于,所述的反应时间为5小时-8小时。
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