CN104744394B - 一种不对称合成含三氟甲基手性季碳化合物的方法 - Google Patents

一种不对称合成含三氟甲基手性季碳化合物的方法 Download PDF

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CN104744394B
CN104744394B CN201510085018.0A CN201510085018A CN104744394B CN 104744394 B CN104744394 B CN 104744394B CN 201510085018 A CN201510085018 A CN 201510085018A CN 104744394 B CN104744394 B CN 104744394B
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傅滨
侯绪和
麻红利
张振华
覃兆海
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Abstract

本发明属于有机合成方法技术领域，特别涉及一种不对称合成含三氟甲基手性季碳化合物的方法。本发明方法采用不对成催化Michael加成反应，在有机溶剂中，在双噁唑啉手性配体和镍催化剂的催化下，三氟甲基硝基烯与2‑乙酰基氮杂芳香化合物反应不对称合成(R)‑3‑三氟甲基‑3‑硝基甲基‑1‑(氮杂芳香环‑2‑基)‑丁‑1‑酮。本发明方法反应产率高，光学纯度高。本发明方法可作为提供三氟甲基季碳手性中心化合物的制备工具。

Description

一种不对称合成含三氟甲基手性季碳化合物的方法
技术领域
本发明属于有机合成方法技术领域，特别涉及一种不对称合成含三氟甲基手性季碳化合物的方法。
背景技术
含三氟甲基的化合物在医药，农药和材料等方面具有广泛而重要的应用(Nature,2011,473,470-477；Chem.Rev.2008,108,1–43；J.Med.Chem.2014,57,2989-3004；J.Med.Chem.2014,57,9522-9538)由于季碳中心位阻大，通常反应活性差，收率低甚至不反应，因此制备含三氟甲基季碳化合物是氟化学的一大挑战。目前合成含三氟甲基季碳手性中心化合物的方法主要有:一、硝基甲烷对含三氟甲基的β，β-二取代烯酮的Michael加成反应得到含三氟甲基季碳手性中心化合物(Norio Shibata*，Angew.Chem.Int.Ed.2013,52,5575–5579；Piotr Kwiatkowski,*Org.Lett.2014,16,5930-5933)；二、使用(β-三氟甲基-二取代硝基烯与吲哚化合物进行傅-克反应得到含三氟甲基季碳手性中心化合物(Yi-XiaJia等，J.Am.Chem.Soc.2013,135,2983-2986.)。
鉴于含三氟甲基化合物具有的广泛而优异的生物活性，在医药、农药和材料领域具有重要的应用，所以探索含三氟甲基化合物的制备新方法具有重要的意义，特别是高产率高光学活性的合成是目前有机合成领域的热点。
发明内容
针对现有技术不足，本发明提供了一种不对称合成含三氟甲基手性季碳化合物的方法。
一种不对称合成含三氟甲基手性季碳化合物的方法，采用不对称催化Michael加成反应，在有机溶剂中，在双噁唑啉手性配体和镍催化剂的催化下，三氟甲基硝基烯与2-乙酰基氮杂芳香化合物反应不对称合成(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳香环-2-基)-丁-1-酮，反应式如下：
所述不对称催化Michael加成反应所用的双噁唑啉手性配体取代基R为苯基、苄基、异丙基或叔丁基，优选取代基R为苯基的双噁唑啉手性配体。
所述不对称催化Michael加成反应所用的镍催化剂为NiCl2、Ni(ClO4)2、NiBr2、Ni(OAc)2或Ni(AcAc)2，优选镍催化剂为Ni(AcAc)2。
所述不对称催化Michael加成反应所用的有机溶剂为甲醇、乙醇、异丙醇、异丁醇、四氢呋喃、甲苯、二氯甲烷、三氯甲烷或乙醚，优选有机溶剂为异丙醇。
所述不对称催化Michael加成反应所用的三氟甲基硝基烯的取代基R1为芳基或烷基。
所述不对称催化Michael加成反应所用的2-乙酰基氮杂芳环化合物中取代基Ar(氮杂芳环)为噻唑、噁唑、N-甲基咪唑、苯并噻唑、吡啶、吡嗪、嘧啶、喹唑或喹啉等含氮芳香杂环。
所述不对称催化Michael加成反应温度范围为-50℃～50℃，优选反应温度为0℃。
所述不对称催化Michael加成反应双噁唑啉手性配体与镍催化剂的摩尔当量比为1.1:1。
所述不对称催化Michael加成反应中三氟硝基烯与2-乙酰基氮杂芳环化合物的摩尔当量比为1.5:1。
所述不对称催化Michael加成反应所用的镍催化剂与2-乙酰基氮杂芳香化合物的摩尔当量比为1％～10％，优选镍催化剂当量为10％。
本发明的有益效果为：
本发明方法反应产率高，光学纯度高。本发明方法可作为提供三氟甲基季碳手性中心化合物的制备工具。
具体实施方式
本发明提供了一种不对称合成含三氟甲基手性季碳化合物的方法，下面结合具体实施方式对本发明做进一步说明。
通过使用β-三氟甲基-二取代硝基烯与2-乙酰基氮杂芳香化合物的催化反应，在有机溶剂中，双噁唑啉和镍催化剂的催化作用下，一步得到含有季碳手性中心的(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳环-2-基)-丁-1-酮。其反应产率比较高(59～99％)，光学纯度高(93～99％)。本发明不对称合成(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳环-2-基)-丁-1-酮的方法参见式II。
不对称合成(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳环-2-基)-丁-1-酮的方法包括如下步骤：
在氮气保护下，在镍催化剂和双噁唑啉手性配体的混合溶液中加入2-乙酰基氮杂芳香化合物，室温搅拌后30分钟后用冰浴冷却，加入三氟硝基烯试剂，继续搅拌反应。反应完毕后除去溶剂，硅胶色谱纯化，制得(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳环-2-基)-丁-1-酮。
下表为利用不对称Michael加成反应合成含三氟甲基手性季碳化合物的示例(表1)。
表1不对称催化Michael加成反应合成含三氟甲基手性季碳化合物数据表
上述反应在醇溶剂中进行，反应温度为0℃，反应使用的镍源为Ni(AcAc)2，使用的双噁唑啉配体结构式优选为式III。
实施例1
合成2-三氟甲基-2-苯基-1硝基乙烯：
向干燥的100mL单口瓶中加入三氟乙酸锂(3g，25mmol)、镁屑(0.6g，25mmol)，加盖翻口塞置换N2三次，冰浴下加入THF(四氢呋喃20mL)，搅拌5min后滴加溴苯(4.71g，30mmol)，待溴苯滴加完毕，撤冰浴室温搅拌3h。反应完毕后，向反应瓶中加入浓度为1mol/L的HCl水溶液10mL，搅拌5min后抽滤，所得滤液加水后用乙酸乙酯3×50mL萃取，合并有机相并用浓盐水洗涤，无水硫酸钠干燥，脱溶剂后得到粗产品，经过硅胶柱分离(体积比乙酸乙酯：石油醚＝1:50)得到黄色液体三氟甲基苯基酮(0.87g，20％yield)。
向100mL单口瓶中加入三氟甲基苯基酮(1.25g，7.18mmol)，后再加入硝基甲烷(15mL，0.5mol/L)、三乙胺(1.09g，10.77mmol)，室温反应过夜。反应完毕后向反应液中加入10mL浓度为1mol/L的HCl水溶液，有机相用乙酸乙酯稀释后一次后用水、浓盐水洗涤，无水硫酸钠干燥，脱溶后粗产品用硅胶柱层析提纯(体积比乙酸乙酯：石油醚＝1:10)，得到无色液体2-硝基-1-三氟甲基-1-苯基-1-乙醇(1.6g，95％yield)。
向200mL单口瓶中加入2-硝基-1-三氟甲基-1-苯基-1-乙醇(1.6g，6.8mmol)，再加入甲苯(27mL，0.25mol/L)、吡啶(1.08g，13.6mmol)，冰浴下滴加二氯亚砜(1.21g，10.2mmol)，滴加完毕后撤除冰浴，室温反应过夜。次日，反应液用乙酸乙酯稀释后依次用饱和碳酸氢钠溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，脱溶后粗产品用硅胶层析柱提纯(体积比乙酸乙酯：石油醚＝1:50)，得到黄色液体(Z)-2-三氟甲基-2-苯基-1-硝基乙烯。
实施例2
合成(R)-3-三氟甲基-4-硝基-3-苯基-1-(2-噻唑)-1-丁酮：
向干燥的10mL圆底烧瓶中加入双噁唑啉配体9.2mg(0.0275mmol)，Ni(AcAc)2(6.5mg，0.0254mmol)，氮气保护下加入异丙醇1mL，室温下搅拌30min，再加入0.2mL异丙醇溶解的2-乙酰基噻唑(32.4mg,0.25mmol)，0℃下搅拌30min后，加入0.3mL异丙醇溶解的2-三氟甲基-2-苯基-1-硝基乙烯。加样完毕后，0℃下反应24h。待反应完毕，反应混合物减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:10，体积比)，得到白色固体3-三氟甲基-4-硝基-3-苯基-1-(2-噻唑)-1-丁酮81.8mg(99％yield)。
m.p.:168-170℃；[α]＝–13.07(c＝0.53,CH2Cl2)；99％ee,determined by HPLCanalysis[Daicel Chiralcel OD-H column,正己烷/异丙醇＝90:10,0.80mL/min,254nm；tR(major)＝21.13min,tR(minor)＝32.48min]；1H NMR(300MHz,CDCl3)δ8.07(d,J＝3.0Hz,1H),7.74(d,J＝3.0Hz,1H),7.39(s,5H),5.64(s,2H),4.41(q,J＝19.0Hz,2H)ppm.13C NMR(75MHz,CDCl3)δ188.74,165.92,144.71,132.83,128.95,128.89,126.90,126.43,125.43(q,J＝283.5Hz),74.34,49.76(q,J＝25.6Hz),36.19(d,J＝1.5Hz)ppm；19F NMR(282MHz,CDCl3)δ-72.80(s,3F)ppm；ESI-HRMS Calcd.for C14H12F3N2O3S([M+H]+):345.0515,Found345.0514.实施例3
(R)-3-三氟甲基-3-苯基-4-硝基-1-(2-吡啶)-1-丁酮：
向干燥的10mL圆底烧瓶中加入双噁唑啉配体9.2mg(0.0275mmol)、Ni(AcAc)2(6.5mg，0.0254mmol)，加入异丙醇1mL，氮气保护下室温搅拌30分钟，再加入0.2mL异丙醇溶解的2-乙酰基吡啶(30.25mg，0.25mmol)，0℃下搅拌30分钟，加入0.3mL异丙醇溶解的2-三氟甲基-2-苯基-1硝基乙烯(81.4mg，0.375mmol)。加样完毕后，0℃下反应24h。待反应完毕，反应混合物减压脱溶后直接通过硅胶层析柱分离提纯(乙酸乙酯：石油醚＝1:4，体积比)，得到白色固体3-三氟甲基-4-硝基-3-苯基-1-(2-吡啶)-1-丁酮80.3mg(95％yield)。
m.p.:148-149℃；[α]＝–16.24(c＝0.46,CH2Cl2)；92％ee,determined by HPLCanalysis[Daicel Chiralcel AS-H column,n-hexane/i-PrOH＝90:10,0.80mL/min,254nm；tR(minor)＝14.39min,tR(major)＝15.01min]；1H NMR(300MHz,CDCl3)δ8.80–8.67(m,1H),7.98(dd,J＝7.8,0.9Hz,1H),7.84(td,J＝7.7,1.7Hz,1H),7.53(ddd,J＝7.5,4.8,1.2Hz,1H),7.37(d,J＝4.9Hz,5H),5.67(dd,J＝33.5,12.3Hz,2H),4.49(dd,J＝89.1,19.5Hz,2H)ppm.13C NMR(75MHz,CDCl3)δ196.81,152.58,148.86,136.85,133.27,128.76,127.57,126.55,125.67(q,J＝283.5Hz),121.65,74.59,49.85(q,J＝25.5Hz),35.26ppm.19F NMR(282MHz,CDCl3)δ-72.84ppm.ESI-HRMS Calcd.for C16H14F3N2O3([M+H]+):339.0951,Found339.0953.
实施例4
(R)-3-三氟甲基-3-辛基-4-硝基-1-(2-噻唑)-1-丁酮：
向干燥的10mL圆底烧瓶中加入双噁唑啉配体9.2mg(0.0275mmol)，Ni(AcAc)2(6.5mg，0.0254mmol)，加入异丙醇1mL，氮气保护下室温搅拌30分钟，再加入0.20mL异丙醇溶解的2-乙酰基噻唑(32.4mg，0.255mmol)，0℃下搅拌30分钟，加入0.30mL异丙醇溶解的2-三氟甲基-2-辛基-1-硝基乙烯(94.9mg，0.375mmol)。加样完毕后，0℃下反应24小时。待反应完毕，反应混合物减压除去溶剂后直接通过硅胶层析柱分离提纯(体积比乙酸乙酯：石油醚＝1:10)，得到无色油状物76.6mg(79％yield)。
[α]＝-1.06(c＝0.56,CH2Cl2)；96％ee,Determined by HPLC analysis[DaicelChiralcel OJ-H column,n-hexane/i-PrOH＝90:10,0.80mL/min,254nm；tR(major)＝9.41min,tR(minor)＝10.98min]；1H NMR(300MHz,CDCl3)δ8.02(d,J＝3.0Hz,1H),7.73(d,J＝3.0Hz,1H),4.99(dd,J＝72.5,12.6Hz,2H),3.76(dd,J＝85.1,18.7Hz,2H),1.85(t,J＝7.7Hz,2H),1.45–1.17(m,12H),0.85(t,J＝6.7Hz,3H)ppm.13C NMR(75MHz,CDCl3)δ189.55,166.02,144.70,126.82,126.54(q,J＝283.5Hz),74.63,46.87(q,J＝24.6Hz),35.71,31.63,31.47,29.61,28.81,23.24,22.33,13.76ppm.19F NMR(282MHz,CDCl3)δ-72.72ppm；ESI-HRMS Calcd.for C16H24F3N2O3S([M+H]+):381.1454,Found 381.1458.

Claims (5)

1.一种不对称合成含三氟甲基手性季碳化合物的方法，其特征在于，采用不对称催化Michael加成反应，在有机溶剂中，在双噁唑啉手性配体和镍催化剂的催化下，三氟甲基硝基烯与2-乙酰基氮杂芳香化合物反应不对称合成(R)-3-三氟甲基-3-硝基甲基-1-(氮杂芳香环-2-基)-丁-1-酮，反应式如下：
其中，不对称催化Michael加成反应所用的双噁唑啉手性配体中取代基R为苯基、苄基、异丙基或叔丁基；取代基R1为芳基或烷基；取代基Ar为噻唑、噁唑、N-甲基咪唑、苯并噻唑、吡啶、吡嗪、嘧啶、喹唑或喹啉，所述镍催化剂与2-乙酰基氮杂芳香化合物的摩尔当量比为1％～10％，所述镍催化剂为Ni(AcAc)2。
2.根据权利要求1所述的一种不对称合成含三氟甲基手性季碳化合物的方法，其特征在于，所述不对称催化Michael加成反应所用的有机溶剂为甲醇、乙醇、异丙醇、异丁醇、四氢呋喃、甲苯、二氯甲烷、三氯甲烷或乙醚。
3.根据权利要求1所述的一种不对称合成含三氟甲基手性季碳化合物的方法，其特征在于，所述不对称催化Michael加成反应温度范围为-50℃～50℃。
4.根据权利要求1所述的一种不对称合成含三氟甲基手性季碳化合物的方法，其特征在于，所述不对称催化Michael加成反应所述双噁唑啉手性配体与镍催化剂的摩尔当量比为1.1:1。
5.根据权利要求1所述的一种不对称合成含三氟甲基手性季碳化合物的方法，其特征在于，所述不对称催化Michael加成反应中所述三氟甲基硝基烯与2-乙酰基氮杂芳环化合物的摩尔当量比为1.5:1。
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