CN113135870B - 一种制备手性α-芳基羰基化合物的方法及产品 - Google Patents
一种制备手性α-芳基羰基化合物的方法及产品 Download PDFInfo
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Abstract
本发明公开了一种制备手性α‑芳基羰基化合物的方法,包括:R2取代二醋酸碘苯化合物经过路易斯酸活化,然后与R3立体取代噁唑啉化合物在碱存在下反应得到所述手性α‑芳基羰基化合物;所述R1选自H、一个或多个烷基、一个或多个卤代烷基、烷氧羰基、卤素或者上述原子组合形成的多取代;R2选自H、烷基、取代烷基,其中取代基选自环烷基、卤素、烷氧基、杂环烷基、取代杂环烷基、芳基、氰基、芳氧基、羰基;R3选自烷基、取代烷基、芳基。该方法反应条件温和、立体选择性好、产物易分离、操作简单。
Description
技术领域
本发明属于有机化学合成领域,特别涉及一种制备手性α-芳基羰基化合物的新方法及产品。
背景技术
由于α-芳基化合物的重要性,被广泛的研究,手性α-芳基羰基化合物就是其中的一种。目前是许多药物活性分子合成的重要中间体。手性α-芳基羰基化合物主要用于医药领域;
手性α-芳基羰基化合物在医药领域中具有重要的药物活性和生理活性。(J.Med.Chem.,1970,13:203;Curr.Drug Metab.2001,2:37.)。
到目前为止,一些手性α-芳基羰基化合物的合成方法已经被相继报道。
过渡金属钯在手性配体作用下催化偶联体系已经报道被用来制备手性α-芳基羰基化合物(J.Mol.Catal.1992,72:L11.J.Am.Chem.Soc.1998,120:1918)。可是该类反应所制得的手性α-芳基羰基化合物的立体选择性较差。
二芳基碘鎓盐可以作为芳基源来实现手性α-芳基羰基化合物的合成(J.Am.Chem.Soc.2011,133:4260;J.Am.Chem.Soc.2011,133:13782)。可是该类方法反应体系中存在碱性物质,很容易导致产物的外消旋化。
钾试剂例如KHMDS也可用于手性α-芳基羰基化合物的合成(Nature,2018,562:105;Org.Lett.2017,19:352)。但该类方法使用了强碱,反应条件苛刻,易发生副反应,官能团兼容性差。
锂试剂例如正丁基锂也可用于手性α-芳基羰基化合物的合成(Chem.Commun.,2005,4453)。但是该类方法使用了强碱,步骤繁琐,并且原料不易得。
发明内容
为了克服现有技术中存在的缺陷,本发明提供了一种制备手性α-芳基羰基化合物的新方法,具有反应条件温和、立体选择性好、产物易分离、操作简单等优点。
一种制备手性α-芳基羰基化合物的新方法,包括:R1取代二醋酸碘苯化合物(II)经过路易斯酸活化,然后与R3立体取代噁唑啉化合物(III)在碱存在下反应得到所述手性α-芳基羰基化合物(I);
所述R1选自H、一个或多个烷基、一个或多个卤代烷基、烷氧羰基、卤素或者上述原子组合形成的多取代;R2选自H、烷基、取代烷基,其中取代基选自环烷基、卤素、烷氧基、杂环烷基、取代杂环烷基、芳基、氰基、芳氧基、羰基;R3选自烷基、取代烷基、芳基。
本发明提供了的制备手性α-芳基羰基化合物的新方法,其采用在有机溶剂存在下通过二醋酸碘苯和噁唑啉的[3,3]迁移重排反应合成手性α-芳基羰基化合物。
作为优选,所述R1选自H、一个或多个C1~C3烷基、一个或多个卤代C1~C3烷基、C1~C3烷氧羰基、卤素或者上述原子组合形成的多取代;R2选自H、C1~C10烷基、取代C1~C10烷基,其中取代基选自环己基、卤素、C1~C3烷氧基、哌啶基、取代哌啶基、苯基、卤素取代苯基、氰基、苯氧基、卤素取代苯氧基、苯乙烯取代羰基、噻吩取代羰基;R3选自C1~C4烷基、苯取代C1~C3烷基、芳基。
作为进一步优选,所述R1选自H、甲基、多个甲基多取代、卤代甲基、多个卤代甲基多取代、甲氧羰基、卤素或者卤素与一个或多个甲基组成的多取代;多取代时,可以是间位取代、对位取代等。
作为进一步优选,所述R2选自H、正丁基、甲基、异丙基取代乙基(1位或2位取代)、环己基甲基、氯代丙基(1位、2位、3位取代)、溴代正己基(可以任意的为1~6位取代)、甲氧基取代正己基(可以任意的为1~6位取代)、N位取代的哌啶-6-基(比如N-对甲苯磺酰基取代)乙基、2-对溴苯基乙基、氰基取代的戊基、4-对氯甲基氧基正丁基等。R3选自正丁基、异丙基、叔丁基、苄基、苯基、甲基等。
作为一种方案,所述手性α-芳基羰基化合物经过进一步水解得到对应的羧酸化合物:
该化合物可以用于合成多种现有或者新的化合物。R1、R2取代情况如上述内容所述。
所述水解可以在硫酸等无机酸溶液中进行,反应溶剂可以采用1,4-二氧六环、甲苯等,反应温度可以为80~120℃。
利用上述羧酸化合物可以进一步还原得到对应的醇化合物,也可以与醇化合物或者氨化合物反应得到对应的酯化合物和酰胺化合物等。羧酸化合物上碘取代位置,可以与烯烃化合物(比如苯乙烯)或者炔烃化合物(苯乙炔)反应,得到对应的苯代烯烃化合物(苯乙烯取代苯羧酸化合物)或苯代炔烃化合物(苯乙炔取代苯羧酸化合物);或者与苯基硼酸反应,联苯基取代的羧酸化合物。或者以上反应类型的组合等。
作为优选,所述的路易斯酸为三氟甲磺酸三甲基硅酯、三氟甲磺酸三乙基硅酯、三氟甲磺酸三异丙基硅酯中的一种或多种。
作为优选,反应温度为:-50℃~30℃;进一步优选为:-40℃~25℃。
反应在有机溶剂中进行,所述有机溶剂为二氯甲烷、乙腈中的一种或者混合物。
作为优选,所用到的碱为2-甲基吡啶、三乙烯二胺、三乙胺、二异丙基乙基胺和1,8-二氮杂二环十一碳-7-烯中的一种或多种。
作为优选,所述二R2取代醋酸碘苯化合物与R3立体取代噁唑啉化合物的摩尔比为1:(1~3);所述R2取代二醋酸碘苯化合物与路易斯酸的摩尔比为1:(1~3);所述R2取代二醋酸碘苯化合物与碱的摩尔比为1:(1~3)。也就是说,所述方法中各物质的当量为:R2取代二醋酸碘苯1.0equiv,R3立体取代噁唑啉1.0至3.0equiv,路易斯酸1.0至3.0equiv,碱1.0至3.0equiv。
本发明方法的具体工艺包括以下步骤:-40℃下在100mL反应瓶内称取二醋酸碘苯,将溶剂加入到其中,然后加入路易斯酸,搅拌均匀,适当时间后加入噁唑啉,适当时间后加入碱,用薄层色谱法跟踪反应进程,展开剂为石油醚/乙酸乙酯的体积比为10/1。反应结束后,将反应物料减压浓缩,柱层析法分离,得到手性α-芳基羰基化合物。
一种化合物,结构如下式所示:
所述R1选自H、一个或多个烷基、一个或多个卤代烷基、烷氧羰基、卤素或者上述原子组合形成的多取代;R2选自烷基、取代烷基,其中取代基选自环烷基、卤素、烷氧基、杂环烷基、取代杂环烷基、芳基、氰基、芳氧基、羰基;R3选自烷基、取代烷基、芳基。
常见的结构如下:
一种化合物,结构如下式所示:
所述R1选自H、一个或多个烷基、一个或多个卤代烷基、烷氧羰基、卤素或者上述原子组合形成的多取代;R2选自H、烷基、取代烷基,其中取代基选自环烷基、卤素、烷氧基、杂环烷基、取代杂环烷基、芳基、氰基、芳氧基、羰基。
参见图1,本发明利用(4)位取代噁唑啉化合物(III)的(4)位取代基特定构型的导向作用,可以得到高纯的具有两个手性中心手性产物,进一步可以得到高纯度的手性羧酸化合物。
本发明中二醋酸碘苯化合物与(4)位取代噁唑啉化合物可以直接市购,也可以自行制备得到。
与现有方法相比,本方法通过二醋酸碘苯和噁唑啉的[3,3]迁移重排反应合成手性α-芳基羰基化合物,其优势在于:
本方法反应条件温和、立体选择性好,产物易分离、操作简单;
本方法所用原料价廉易得,避免了传统方法中用到的很难制备和购买的催化剂,反应条件苛刻;
对二醋酸碘苯和噁唑啉的[3,3]迁移重排反应,能够制备化学稳定的手性α-芳基羰基化合物,为这一类化合物的合成提供了新的反应策略。
附图说明
图1为本发明的反应原理示意图;
图2为实施例得到的酰胺化合物的单晶检测图。
具体实施方式
以下介绍本发明提供的制备手性α-芳基羰基化合物的新方法的具体实施实例,提供了多个具体实施实例。应当指出的是,本发明的实施不局限于以下实施实例。
实施例中原料(II)采用市购产品,原料(III)部分来源于市购,其中部分化合物的制备方法为:
(S)-4-异丁基-2-戊基-4,5-二氢噁唑(6a):
0℃向(S)-2-氨基-3-甲基丁基-1-基醇(2.48g,24mmol)和Et3N(3.3mL,24mmol)的DCM(67mL)溶液中,滴加己酰氯(2.8mL,20mmol)。混合物升温至室温,搅拌3h,加入DCM(33mL)和Et3N(13.9mL,100mmol)。0℃加入MsCl(1.9mL,24mmol),相同温度下搅拌过夜。水淬灭反应,DCM萃取,Na2SO4干燥,浓缩,残留物经过柱层析纯化得到浅黄色油状物6a((S)-4-异丁基-2-戊基-4,5-二氢噁唑)2.86g,收率78%。(Rf=0.28,eluent:PE/EtOAc=10/1):1HNMR(600MHz,CDCl3):δ4.19–4.14(m,1H),3.92–3.82(m,2H),2.29–2.22(m,2H),1.76–1.67(m,1H),1.64–1.56(m,2H),1.33–1.26(m,4H),0.92(d,J=6.8Hz,3H),0.89–0.83(m,6H)。
(S)-4-(叔丁基)-2-乙基-4,5-二氢噁唑(6b’):按照化合物(6a)的方法,利用20mmol对应的酰氯得到前黄色油状物1.86g,收率60%.(Rf=0.23,eluent:PE/EtOAc=10/1):1H NMR(600MHz,CDCl3):δ4.14–4.09(m,1H),4.02–3.98(m,1H),3.82–3.77(m,1H),2.33–2.22(m,2H),1.15(t,J=7.6Hz,3H),0.85(s,9H)。
(S)-4-异丙基-2-(4-甲基戊基)-4,5-二氢噁唑(6c):
-78℃,向(S)-4-异丙基-2-甲基-4,5-二氢噁唑(1.91g,15mmol)的THF(50mL)溶液中加入n-BuLi(2.5M,6.6mL)。搅拌3h,-78℃滴加1-Br-3-甲基丁烷(2.27g,15mmol)的THF(10.5mL)溶液,搅拌1h,t升温至室温搅拌过夜,加入水,DCM萃取。合并有机层,Na2SO4干燥,浓缩。浓缩物经过柱层析纯化得到浅黄色液体化合物6c,1.83g,收率62%.(Rf=0.25,eluent:PE/EtOAc=10/1)。1H NMR(600MHz,CDCl3):δ4.22–4.17(m,1H),3.94–3.84(m,2H),2.30–2.20(m,2H),1.78–1.68(m,1H),1.66–1.49(m,3H),1.24–1.17(m,2H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.7Hz,9H)。
(S)-4-异丙基-2-(7-甲氧基庚基)-4,5-二氢噁唑(6g):按照化合物6c相似的方法,利用12mmol对应的酰氯得到化合物6g,1.91g,收率66%。(Rf=0.30,eluent:PE/EtOAc=3/1):1H NMR(600MHz,CDCl3):δ4.19–4.14(m,1H),3.91–3.82(m,2H),3.33(t,J=6.6Hz,2H),3.30(s,3H),2.28–2.18(m,2H),1.76–1.66(m,1H),1.62–1.50(m,4H),1.36–1.24(m,6H),0.92(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H)。
(S)-5-异丙基-2-(2-(1-Ts-哌啶-4-基)乙基)-4,5-二氢噁唑(6h):按照化合物6c相似的方法,利用10mmol对应的酰氯得到化合物6h,1.14g,收率30%.(Rf=0.20,eluent:PE/EtOAc=1/1):1H NMR(600MHz,CDCl3):δ7.58(d,J=8.2Hz,2H),7.27(d,J=7.7Hz,2H),4.14–4.10(m,1H),3.84(t,J=8.0Hz,1H),3.82–3.76(m,1H),3.70(d,J=11.6Hz,2H),2.38(s,3H),2.21–2.13(m,4H),1.72–1.60(m,3H),1.55–1.45(m,2H),1.30–1.20(m,2H),1.19–1.11(m,1H),0.87(d,J=6.8Hz,3H),0.79(d,J=6.8Hz,3H)。
(S)-4-丁基-2-戊基-4,5-二氢噁唑:按照化合物6a相似的方法,利用20mmol对应的酰氯得到(S)-4-丁基-2-戊基-4,5-二氢噁唑1.97g,收率50%。(Rf=0.31,eluent:PE/EtOAc=10/1)。1H NMR(600MHz,CDCl3):δ4.28–4.23(m,1H),4.06–3.98(m,1H),3.80(t,J=8.0Hz,1H),2.24(t,J=7.7Hz,2H),1.66–1.55(m,3H),1.46–1.39(m,1H),1.37–1.25(m,8H),0.92–0.84(m,6H)。
化合物(I)制备方法:
在100毫升的反应瓶内进行抽真空,抽换氮气三次,在氮气保护下加入二醋酸碘苯化合物(II,1.0mmol,1.0eq)和无水的DCM(10mL,0.1M)并置于-40℃,然后加入三氟甲磺酸三甲基硅酯(2.0mmol,2.0eq.),反应10分钟后加入(4)(S)-取代-噁唑啉衍生物(III,2.0mmol,2.0eq.),再过10分钟后,加入2-甲基吡啶(2.0mmol,2.0eq.)。48小时后用薄层色谱法跟踪反应进程,展开剂为石油醚/乙酸乙酯的体积比为10/1,监测到反应结束,将反应液通过减压浓缩,柱层析法分离得到化合物I。
实施例1
R1为H,R2为正丁基,R3为异丙基,通过上述方法得到238.9mg黄色液体化合物1,收率是62%(>20/1dr)。1H NMR(600MHz,CDCl3):δ7.85–7.81(m,1H),7.44–7.40(m,1H),7.33–7.27(m,1H),6.95–6.89(m,1H),4.21–4.16(m,1H),4.02(t,J=7.6Hz,1H),3.98–3.93(m,1H),3.89(t,J=7.9Hz,1H),2.07–1.96(m,1H),1.85–1.79(m,2H),1.37–1.30(m,3H),1.24–1.18(m,1H),0.93(d,J=6.8Hz,3H),0.88–0.83(m,6H).
13C NMR(151MHz,CDCl3):δ167.9,143.5,139.7,128.7,128.6,128.0,102.0,71.9,69.5,49.0,34.2,32.4,29.6,22.7,19.1,17.8,14.1.
IR(neat):2955,2928,2870,1661,1465,1435,1106,745.
HRMS(ESI-TOF):calculated for[C17H25INO(M+H+)]:386.0975,found:386.0976.
实施例2
R1为H,R2为异戊基,R3为异丙基,通过同样的方法可以得到231.6mg黄色液体化合物2(>20/1dr),收率是58%。1H NMR(400MHz,CDCl3):δ7.85–7.80(m,1H),7.44–7.40(m,1H),7.32–7.27(m,1H),6.94–6.88(m,1H),4.21–4.16(m,1H),4.00(t,J=7.6Hz,1H),3.98–3.93(m,1H),3.90(t,J=7.9Hz,1H),2.04–1.96(m,1H),1.87–1.78(m,2H),1.60–1.51(m,1H),1.30–1.22(m,1H),1.15–1.05(m,1H),0.93(d,J=6.8Hz,3H),0.88–0.82(m,9H).
13C NMR(101MHz,CDCl3):δ168.0,143.4,139.7,128.7,128.6,128.0,102.0,71.7,69.5,49.2,36.4,32.27,32.25,28.0,22.7,22.6,19.1,17.7.
IR(neat):2953,2899,2869,1662,1465,1384,1365,1170,1010,742.
HRMS(ESI-TOF):calculated for[C18H27INO((M+H+)]:400.1132,found:400.1129.
实施例3
R1为H,R2为环己基甲基,R3为异丙基,通过同样的方法可以得到229.7mg白色固体化合物3,收率是54%(>20/1dr)。1H NMR(600MHz,CDCl3):δ7.84–7.80(m,1H),7.49–7.43(m,1H),7.31–7.27(m,1H),6.93–6.87(m,1H),4.20–4.13(m,2H),3.97–3.92(m,1H),3.92–3.88(m,1H),1.93–1.86(m,1H),1.86–1.75(m,3H),1.70–1.63(m,3H),1.62–1.57(m,1H),1.25–1.10(m,4H),1.01–0.89(m,5H),0.83(d,J=6.8Hz,3H).
13C NMR(151MHz,CDCl3):δ167.9,143.7,139.7,128.7,128.6,128.1,101.6,71.7,69.3,46.4,42.0,35.3,33.6,33.2,32.2,26.6,26.3,26.2,19.0,17.6.
IR(neat):2914,2845,1659,1460,1438,1230,770.
HRMS(ESI-TOF):calculated for[C20H29INO(M+H+)]:426.1288,found:426.1284.
实施例4
R1为H,R2为3-氯-正丙基,R3为异丙基,通过同样的方法可以得到275.9mg黄色液体化合物4,收率是68%(>20/1dr)。1H NMR(600MHz,CDCl3):δ7.85–7.81(m,1H),7.41–7.37(m,1H),7.33–7.28(m,1H),6.95–6.90(m,1H),4.23–4.17(m,1H),4.04(t,J=7.4Hz,1H),3.98–3.92(m,1H),3.89(t,J=8.0Hz,1H),3.52(t,J=6.7Hz,2H),2.20–2.11(m,1H),2.00–1.93(m,1H),1.92–1.77(m,2H),1.76–1.67(m,1H),0.93(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H).
13C NMR(151MHz,CDCl3):167.4,142.6,139.8,129.0,128.8,127.9,101.8,71.8,69.7,48.3,44.8,32.3,31.6,30.4,19.1,17.8.
IR(neat):2956,2870,1661,1584,1562,1465,1010,970,730.
HRMS(ESI-TOF):calculated for[C16H22ClINO(M+H+)]:406.0429,found:406.0427.
实施例5
R1为H,R2为6-甲氧基正己基,R3为异丙基,通过同样的方法可以得到270.5mg黄色液体化合物5,收率是61%(>20/1dr)。1H NMR(600MHz,CDCl3):δ7.84–7.80(m,1H),7.43–7.38(m,1H),7.31–7.27(m,1H),6.93–6.88(m,1H),4.21–4.15(m,1H),4.02(t,J=7.5Hz,1H),3.98–3.92(m,1H),3.89(t,J=7.9Hz,1H),3.32(t,J=6.6Hz,2H),3.30(s,3H),2.06–1.96(m,1H),1.86–1.77(m,2H),1.56–1.48(m,2H),1.38–1.28(m,5H),1.26–1.19(m,1H),0.92(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H).
13C NMR(151MHz,CDCl3):δ168.0,143.3,139.7,128.8,128.6,128.0,101.9,73.0,71.7,69.5,58.6,49.0,34.3,32.3,29.6,29.4,27.3,26.0,19.1,17.8.
IR(neat):2927,2856,1662,1464,1384,1365,1116,1010,738.
HRMS(ESI-TOF):calculated for[C20H31INO2(M+H+)]:444.1394,found:444.1386.
实施例6
R1为H,R2为N-对甲苯磺酰基-哌啶-5-基甲基,R3为异丙基,通过同样的方法可以得到296.1mg黄色液体化合物6,收率是51%(>20/1dr)。1H NMR(400MHz,CDCl3):δ7.80–7.75(m,1H),7.61–7.57(m,2H),7.38–7.33(m,1H),7.30–7.24(m,3H),6.91–6.86(m,1H),4.16–4.11(m,1H),4.04(t,J=7.6Hz,1H),3.91–3.85(m,1H),3.82(t,J=8.0Hz,1H),3.74–3.68(m,2H),2.39(s,3H),2.18–2.11(m,2H),1.96–1.89(m,1H),1.88–1.83(m,1H),1.78–1.66(m,3H),1.40–1.26(m,2H),1.19–1.11(m,1H),0.87(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).
13C NMR(151MHz,CDCl3):δ167.4,143.4,142.9,139.7,133.1,129.6,128.9,128.7,127.8,127.7,101.5,71.7,69.5,46.3,46.2,46.1,40.5,32.7,32.2,31.6,31.4,21.6,18.9,17.7.
IR(neat):2917,2847,1661,1597,1465,1161,1093,931,815,724.
HRMS(ESI-TOF):calculated for[C26H34IN2O3S(M+H+)]:581.1329,found:581.1332.
实施例7
R1为甲基(与I为对位取代),R2为n-Bu,R3为异丙基,通过同样的方法可以得到231.6mg黄色液体化合物7,收率是58%(>20/1dr)。1H NMR(600MHz,CDCl3:δ7.70–7.66(m,1H),7.25–7.22(m,1H),6.76–6.72(m,1H),4.21–4.15(m,1H),4.00–3.94(m,2H),3.89(t,J=8.0Hz,1H),2.26(s,3H),2.05–1.96(m,1H),1.91–1.75(m,2H),1.39–1.28(m,3H),1.26–1.17(m,1H),0.93(d,J=6.9Hz,3H),0.89–0.83(m,6H).
13C NMR(151MHz,CDCl3):δ168.1,143.1,139.3,138.5,129.8,128.8,97.8,71.7,69.3,48.7,34.3,32.2,29.6,22.7,21.1,19.0,17.6,14.1.
IR(neat):2956,1660,1462,1374,1186,1166,1010,813.
HRMS(ESI-TOF):calculated for[C18H27INO(M+H+)]:400.1132,found:400.1123.
实施例8
R1为甲氧羰基(与I为对位取代),R2为n-Bu,R3为异丙基,通过同样的方法可以得到190.6mg黄色液体化合物8,收率是43%(>20/1dr)。1H NMR(600MHz,CDCl3:δ8.09–8.07(m,1H),7.92(d,J=8.2Hz,1H),7.57–7.52(m,1H),4.21–4.16(m,1H),4.03(t,J=7.5Hz,1H),4.00–3.94(m,1H),3.92–3.86(m,4H),2.07–1.99(m,1H),1.87–1.77(m,2H),1.38–1.28(m,3H),1.25–1.18(m,1H),0.93(d,J=6.8Hz,3H),0.88–0.84(m,6H).
13C NMR(151MHz,CDCl3):δ167.4,166.6,144.1,140.0,130.7,129.3,128.9,108.0,71.8,69.5,52.3,48.9,34.1,32.3,29.6,22.7,18.9,17.7,14.1.
IR(neat):2954,2928,2871,1725,1662,1590,1464,1435,1193,1111,837,807.
HRMS(ESI-TOF):calculated for[C19H27INO3(M+H+)]:444.1030,found:444.1029.
实施例9
R1为H,R2为n-Bu,R3为t-Bu,通过同样的方法可以得到黄色液体化合物9,收率是47%,dr值大于20/1(通过反应液体系核磁磁确定)。1H NMR(600MHz,CDCl3):δ7.85–7.80(m,1H),7.48–7.42(m,1H),7.32–7.27(m,1H),6.93–6.88(m,1H),4.17–4.12(m,1H),4.02(t,J=7.6Hz,1H),3.96(t,J=8.3Hz,1H),3.88–3.83(m,1H),2.05–1.97(m,1H),1.87–1.79(m,1H),1.37–1.29(m,3H),1.25–1.19(m,1H),0.90–0.84(m,12H).
13C NMR(151MHz,CDCl3):δ167.9,143.6,139.7,128.7,128.5,128.2,101.9,75.7,68.5,49.0,34.3,33.9,29.5,26.1,22.7,14.1.
IR(neat):2953,2868,1663,1584,1562,1476,1464,1392,1362,1174,1010,744.
HRMS(ESI-TOF):calculated for[C18H27INO(M+H+)]:400.1132,found:400.1127.
实施例10
R1为H,R2为n-Bu,R3为Bn,通过同样的方法可以得到221.0mg黄色液体化合物10,收率是51%,dr值大于20/1(通过反应液体系核磁磁确定)。1H NMR(600MHz,CDCl3):δ7.85(d,J=7.9Hz,1H),7.32–7.27(m,4H),7.25–7.21(m,1H),7.21–7.17(m,2H),6.96–6.91(m,1H),4.46–4.38(m,1H),4.14(t,J=9.0Hz,1H),4.02(t,J=7.4Hz,1H),3.96–3.91(m,1H),3.20–3.13(m,1H),2.71–2.59(m,1H),2.08–1.98(m,1H),1.87–1.75(m,1H),1.42–1.29(m,3H),1.28–1.17(m,1H),0.89(t,J=7.2Hz,3H).
13C NMR(151MHz,CDCl3):δ168.7,143.2,139.7,137.8,129.5,128.8,128.7,128.6,127.9,126.6,101.9,71.5,67.2,48.9,41.4,34.1,29.5,22.7,14.1.
IR(neat):3025,2953,2926,2856,1658,1583,1495,1460,1010,737,699.
HRMS(ESI-TOF):calculated for[C21H25INO(M+H+)]:434.0975,found:434.0971.
实施例11
R1为H,R2为甲基,R3为t-Bu,通过同样的方法可以得到214.3mg黄色液体化合物11,产率是60%(>20/1dr)。
1H NMR(600MHz,CDCl3:δ7.85–7.81(m,1H),7.38–7.34(m,1H),7.32–7.28(m,1H),6.95–6.89(m,1H),4.20–4.15(m,1H),4.13–4.06(m,1H),3.97(t,J=8.4Hz,1H),3.91–3.86(m,1H),1.49(d,J=7.1Hz,3H),0.91(s,9H).
13C NMR(151MHz,CDCl3):δ168.5,144.7,139.7,128.74,128.69,127.6,101.0,75.7,68.8,43.9,33.9,26.1,19.6.
IR(neat):2953,2901,2868,1664,1584,1467,1392,1374,1187,1117,745.
HRMS(ESI-TOF):calculated for[C15H21INO(M+H+)]:358.0662,found:358.0662.
羧酸化合物的制备:
将化合物1~11按照如下方法即可得到对应的羧酸化合物:
向25mL反应管中加入化合物I(1.0mmol),4M的H2SO4(2.0mL)和1,4-二氧六环(2.0mL),然后在100℃下反应15h。反应结束后冷却至室温,并向其中加入2M的NaOH至碱性,然后减压浓缩。剩余物用1M的HCl酸化并用二氯甲烷萃取,有机相用无水Na2SO4干燥,减压浓缩后得到产物,产物不需要进一步纯化。
1H NMR(600MHz,CDCl3):δ7.88–7.84(m,1H),7.38–7.35(m,1H),7.34–7.30(m,1H),6.99–6.92(m,1H),4.09(t,J=7.5Hz,1H),2.10–2.00(m,1H),1.82–1.72(m,1H),1.39–1.31(m,3H),1.28–1.22(m,1H),0.91–0.86(m,3H).
13C NMR(151MHz,CDCl3):δ179.8,141.7,139.9,129.1,128.8,128.1,102.1,55.0,33.2,29.5,22.7,14.0.
IR(neat):2954,2927,2858,1700,1464,1435,1239,1120,740.
HRMS(ESI-TOF):calculated for[C12H14IO2(M–H-)]:317.0044,found:317.0042.
以化合物(IV-1)为原料可以实现各种中间体的合成,比如:
1H NMR(600MHz,CDCl3):δ7.62–7.58(m,1H),7.58–7.49(m,3H),7.43–7.37(m,3H),7.34–7.27(m,3H),6.98(d,J=16.0Hz,1H),4.04(t,J=7.5Hz,1H),2.22–2.11(m,1H),1.87–1.76(m,1H),1.38–1.23(m,4H),0.92–0.84(m,3H).
1H NMR(600MHz,CDCl3):δ7.88–7.84(m,1H),7.35–7.30(m,1H),7.21–7.16(m,1H),6.95–6.89(m,1H),3.75–3.68(m,2H),3.30–3.23(m,1H),1.79–1.72(m,1H),1.64–1.56(m,1H),1.53(s,1H),1.37–1.22(m,3H),1.21–1.12(m,1H),0.86(t,J=7.2Hz,3H).
1H NMR(600MHz,CDCl3):δ7.54–7.50(m,1H),7.47–7.43(m,2H),7.42–7.36(m,4H),7.35–7.31(m,1H),7.30–7.27(m,1H),3.82(t,J=7.6Hz,1H),2.04–1.95(m,1H),1.77–1.68(m,1H),1.19–1.10(m,2H),1.10–1.00(m,2H),0.78(t,J=7.3Hz,3H).
构型确定:
对化合物I构型的确定时,本发明通过将化合物I转为羧酸,然后做成酰胺,最后通过单晶确定,以化合物(IV-1)为例,过程如下:
将羧酸化合物(IV-1)(636.4mg,2.0mmol)溶解在二氯甲烷中,然后向其中加入对溴苯胺(516.0mg,3.0mmol),1-羟基苯并三唑(HOBT,405.4mg,3.0mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCl,557.2mg,3.0mmol)。反应30分钟后,向反应体系加入饱和碳酸氢钠水溶液,然后用二氯甲烷萃取,无水硫酸钠干燥并减压浓缩。剩余物通过柱层析纯化可得到相应的白色固体(熔点:95–97℃)酰胺(689.4mg,73%)。
1H NMR(600MHz,CDCl3:δ7.87–7.83(m,1H),7.49–7.46(m,1H),7.45–7.41(s,1H),7.40–7.31(m,5H),6.99–6.94(m,1H),3.94–3.89(m,1H),2.26–2.14(m,1H),1.85–1.78(m,1H),1.40–1.30(m,3H),1.28–1.20(m,1H),0.93–0.85(m,3H).
13C NMR(151MHz,CDCl3):δ171.0,142.3,139.8,137.0,131.9,129.33,129.31,128.2,121.5,116.9,102.1,57.3,32.9,29.8,22.7,14.1.
IR(neat):3293,2952,2924,1662,1526,1485,1394,1047,748,540.
HRMS(ESI-TOF):calculated for[C18H19BrINO(M+Na+)]:493.9587,found:493.9579.
将得到的酰胺溶解在乙醚中,得到的乙醚溶液在-20℃的冰箱中通过缓慢挥发生长得到单晶,单晶图如图2所示,结果如下:
该化合物的晶体学数据(不包括结构因素)已经保存在剑桥晶体学数据中心,CCDC号为:1922210。
Claims (6)
3.根据权利要求1所述的制备手性α-芳基羰基化合物的方法,其特征在于,所述的路易斯酸为三氟甲磺酸三甲基硅酯、三氟甲磺酸三乙基硅酯、三氟甲磺酸三异丙基硅酯中的一种或多种。
4.根据权利要求1所述的制备手性α-芳基羰基化合物的方法,其特征在于,反应温度为:-50℃~30℃;反应在有机溶剂中进行,所述有机溶剂为二氯甲烷、乙腈中的一种或者混合物。
5.根据权利要求1所述的制备手性α-芳基羰基化合物的方法,其特征在于,所用到的碱为2-甲基吡啶、三乙烯二胺、三乙胺、二异丙基乙基胺和1,8-二氮杂二环十一碳-7-烯中的一种或多种。
6.根据权利要求1所述的制备手性α-芳基羰基化合物的方法,其特征在于,所述R1取代二醋酸碘苯化合物与R3立体取代噁唑啉化合物的摩尔比为1:(1~3);所述二醋酸碘苯化合物与路易斯酸的摩尔比为1:(1~3);所述二醋酸碘苯化合物与碱的摩尔比为1:(1~3)。
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Asymmetric Iodonio-[3,3]-Sigmatropic Rearrangement to Access Chiral α‑Aryl Carbonyl Compounds;Tian Junsong et al.;《J. Am. Chem. Soc.》;20200313;第142卷;第6884-6890页 * |
Enantioselective α-Arylation of Carbonyls via Cu(I)-Bisoxazoline Catalysis;James S. Harvey et al.;《J. Am. Chem. Soc.》;20110817;第133卷;第13782-13785页 * |
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