CN101921252A - 1-氧杂苯并杂环类化合物、合成方法和用途 - Google Patents
1-氧杂苯并杂环类化合物、合成方法和用途 Download PDFInfo
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Abstract
本发明提供了一种1-氧杂苯并杂环类化合物,以铱络合物作为催化剂,由烯丙基碳酸酯和苯酚类化合物高对映选择性地合成光学活性1-氧杂苯并杂环类化合物。该方法的原料易得、催化活性高、反应条件温和、底物适用范围广、产物对映选择性高等优点。本发明所合成的1-氧杂苯并杂环类化合物,容易通过化学途径合成广泛存在天然产物和药物中间体中的苯并二氢吡喃类衍生物片段。
Description
技术领域
本发明涉及一种1-氧杂苯并杂环类化合物、合成方法和用途。系由由金属依络合物催化的苯酚类化合物和烯丙基碳酸酯的烯丙基醚化反应和RCM反应结合,高效率、高对映选择性地合成1-氧杂苯并杂环类化合物。本发明涉及把1-氧杂苯并杂环类化合物经过简单氢化即可方便合成广泛存在天然产物和药物中间体中的苯并二氢吡喃类衍生物片段。
背景技术
苯并吡喃类化合物是一类非常重要的杂环化合物[(a)Hodgetts,K.J.Tetrahedron 2005,61,6860.(b)Choi,E.T.;Lee,M.H.;Kim,Y.;Park,Y.S.Tetrahedron 2008,64,1515.(c)Valla,C.;Baeza,A.;Menges,F.;Pfaltz,A.Synlett2008,3167.(d)Lecea,M.;Hernandez-Torres,G.;Urbano,A.;Carreno,M.C.;Colobert,F.Org.Lett.,2010,12,580.],这类骨架广泛存在与许多天然产物中,具有非常特殊的生理活性[(a)Shi,Y.-L.;Shi,M.Org.Biomol.Chem.2007,1499.(b)Torregroza,I.;Evans,T.;Das,B.C.Chem.Bio.lDrug.Des.2009,73,339.]。例如,calanolide A具有很好的抗艾滋病毒效果;rubustic acid是一种蛋白激酶抑制剂;mallotochromene是一种HIV-1逆转录抑制剂;tephrosine是一种抗肿瘤试剂;BW683C是一种非常有效的体外鼻病毒复制抑制剂。真是由于这类化合物具有这么多重要的生理活性,因此,这类化合物的合成受到了人们的高度重视。在过去的几十年内,许多有效合成苯并吡喃类化合物的方法被报道出来[For reviews:(a)Schweizer,E.E.;Meeder-Nycz,O.in Chromenes,Chromanes,Chromones(Eds.:Ellis,G.P.),Wiley-Interscience,New York,1977.(b)Keay,B.A.in Comprehensive Heterocyclic Chemistry II,Vol.2(Eds.:Katritzky,A.R.;Rees,C.W.;Scriven,E.F.V.),Pergamon,Oxford,1996,p.395.(c)Nicolaou,K.C.;Pfefferkorn,J.A.;Roecker,A.J.;Cao,G.-Q.;Barluenga,S.;Mitchell,H.J.J.Am. Chem.Soc.2000,122,9939.]。近年来,一锅法合成由于不需要对中间体的分离纯化,使反应变的更为简便高效,受到化学家们的高度关注。2005年,上海有机所的施敏研究员报道了DABCO催化的一锅法合成高官能团化的Chromene类化合物,能以非常高的收率得到目标产物[Shi,Y.-L.;Shi,M.Org.Lett.2005,7,3057.]。2009年,南开大学的黄有教授小组报道了PPh3催化的一锅法合成Chroman类化合物,能以较高的收率非常好的顺反比得到目标产物[Meng,X.;Huang,Y.;Zhao,H.;Xie,P.;Ma,J.;Chen,R.Org.Lett.2009,11,991.]。最近,美国新墨西哥大学的王伟教授小组报道了一例二级胺催化的一锅法合成4H-Chromene类化合物的方法[Zhang,X.;Zhang,S.;Wang,W.Angew.Chem.,Int.Ed.2010,48,1481.]。尽管合成苯并吡喃类化合物的方法很多,但是到目前为止,使用不对称催化的方法来合成这类化合物的报道并不是很多[Nishikata,T.;Yamamoto,Y.;Miyaura,N.Adv.Synth.Catal.2007,349,1759.]。因此,发展一类高效的不对称催化合成苯并吡喃类化合物的方法,具有着重要的意义。
发明内容
本发明的目的是提供一种1-氧杂苯并杂环类化合物,尤其是涉及一种光学活性1-氧杂苯并杂环类化合物。
本发明的目的是提供一种有效的合成1-氧杂苯并杂环类化合物的方法。
本发明的方法是一种有效的由苯酚类化合物和烯丙基碳酸酯类化合物合成1-氧杂苯并杂环类化合物的方法。
本发明的方法是一种有效的以铱络合物作为催化剂,由苯酚类化合物和烯丙基碳酸酯类化合物合成1-氧杂苯并杂环类化合物方法。
本发明的方法是一种有效的由手性铱络合物作为催化剂,由苯酚类化合物和烯丙基碳酸酯类化合物合成光学活性1-氧杂苯并杂环类化合物的方法。
本发明所合成的手性1-氧杂苯并杂环类化合物经过简单氢化即可方便合成广泛存在天然产物和药物中间体中的苯并二氢吡喃类衍生物片段。
其中*为手性碳原子,R1任意选自C1-C16的烷基、C3-C16的环烷基;C4-C10的含N、O或S的杂环基、芳基、R取代的芳基;R为C1-C4的烷基、C1-C4的全氟烷基、卤素或C1-C4的烷氧基;R2任意选自C1-C16的烷基、C3-C16的环烷基;C4-C10的含N、O或S的杂环基、芳基;所述的芳基是苯基或取代苯基;n为0或者1。
本发明的1-氧杂苯并杂环类化合物是以苯酚类化合物和烯丙基碳酸酯类化合物为原料,在有机溶剂的存在下,以[Ir(COD)Cl]2与手性配体作用生成的铱络合物作为催化剂,在碱的作用下反应制得,可用下式表示:
其中L为手性配体,Base为上文提到的各种碱及碱和添加剂的组合,Solv.为各种有机溶剂。Ru为烯烃复分解催化剂。
R1任意选自C1-C16的烷基、C3-C16的环烷基;C4-C10的含N、O或S的杂环基、芳基、R取代的芳基;R为C1-C4的烷基、C1-C4的全氟烷基、卤素或C1-C4的烷氧基;R2任意选自C1-C16的烷基、C3-C16的环烷基;C4-C10的含N、O或S的杂环基、芳基;所述的芳基是苯基或取代苯基;n为0或者1。
所述的配体结构式(为任意光学纯的结构,不受下列结构式显示所限)为:
其中,R3、R4或者R5任意选自C3-C16的环烷基、苯基、萘基、C1-C4的烷氧基取代的苯基、或C1-C4的烷氧基取代的萘基、异丙基或叔丁基。
所述的碱是三乙胺、1,8-二氮杂二环[5,4,0]十一碳-7-烯、1,5-二氮杂二环[4,3,0]壬-5-烯、N,O-双(三甲基硅基)乙酰胺、碳酸铯、碳酸钾,磷酸钾、醋酸钾、磷酸钾、氢化钠、正丁基锂、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、甲醇钠、质子海绵、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺以及碱和三氟磺酸银、氯化锂、分子筛等添加剂的组合。
所述的苯酚类化合物、烯丙基碳酸酯类化合物、[Ir(COD)Cl]2、配体、碱、Ru催化剂的摩尔比为1∶1∶0.01-0.1∶0.02-0.2∶0-1∶0.01-0.1,推荐反应的摩尔比为:苯酚类化合物、烯丙基碳酸酯类化合物、[Ir(COD)Cl]2、配体、碱、Ru催化剂的摩尔比为1∶1∶0.02-0.05∶0.04-0.1∶1∶0.05。反应在温度为0℃至120℃,推荐反应温度为:40℃至80℃。反应时间第一步醚化反应为4小时-24小时,第二步关环反应为1小时-12小时。
本发明方法中,所述水为蒸馏水。所述有机溶剂可以是极性或非极性溶剂。如苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环、乙腈等。
采用本发明方法所得产物1-氧杂苯并杂环类化合物可以经过重结晶,薄层层析,柱层析减压蒸馏等方法加以分离。如用重结晶的方法,推荐溶剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为二氯甲烷-正己烷,异丙醇-石油醚,乙酸乙酯-石油醚,乙酸乙酯-正己烷,异丙醇-乙酸乙酯-石油醚等混合溶剂。用薄层层析和柱层析方法,所用的展开剂为极性溶剂与非极性溶剂的混合溶剂。推荐溶剂可为乙醚-石油醚,乙酸乙酯-石油醚,乙酸乙酯-正己烷,异丙醇-乙酸乙酯-石油醚等混合溶剂,其体积比可以分别是:极性溶剂∶非极性溶剂=1∶0.1-500。例如:乙醚∶石油醚=1∶0.1-50,异丙醇∶石油醚=1∶0.1-500。
本发明提供了一种有效的由铱络合物作为催化剂,由苯酚类化合物和烯丙 基碳酸酯类化合物高对映选择性地合成1-氧杂苯并杂环类化合物的方法;提供了制备多种1-氧杂苯并杂环类化合物的方法。与现有方法相比,该方法可适用于多种不同类型的苯酚类化合物和烯丙基碳酸酯类化合物,反应条件温和,操作简便。另外,反应中除碱外无需加入任何添加剂。且反应的产率也较好(一般为29%-82%),对映选择性高(一般为86%-96%)。
本发明合成手性1-氧杂苯并杂环类化合物的经过简单氢化即可方便合成广泛存在天然产物和药物中间体中的苯并二氢吡喃类衍生物片段。
具体实施方式
通过下述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:苯酚类化合物在铱络合物催化下发生烯丙基醚化反应的碱和添加剂的研究:
其中,mol指摩尔,base指碱,THF指四氢呋喃。
序号 | 添加剂 | 碱 | 产率(%) | 3ae/3ae’ | ee(%) |
1 | - | K3PO4 | 68 | 91/9 | 95 |
2 | - | DABCO | 48 | 80/20 | 94 |
3 | - | Cs2CO3 | 60 | 85/15 | 96 |
4 | - | DBU | 10 | 53/47 | 95 |
5 | - | LiHMDS | 36 | 95/5 | 94 |
6 | - | NaHMDS | 62 | 82/18 | 89 |
7 | - | Et3N | n.r. | - | - |
8 | - | BSA | trace | - | - |
9 | - | DIEA | n.r. | - | - |
10 | CuI(1equiv) | Cs2CO3 | 46 | 89/11 | 93 |
11 | LiI(1equiv) | Cs2CO3 | <5 | - | - |
其中n.r.为不反应,trace为痕量产物。
其中DABCO是三乙烯二胺,DBU是1,8-二氮杂二环[5,4,0]十一碳-7-烯,LiHMDS是六甲基二硅基胺基锂,NaHMDS是六甲基二硅基胺基钠,BSA是N,O-双(三甲基硅烷)乙酰胺,DIEA是N,N-二异丙基乙胺,Cs2CO3是碳酸铯。实施例2:苯酚类化合物在铱络合物催化下发生烯丙基醚化反应的配体和离去基团的研究:
序号 | LG | 配体 | 产率(%) | 3ai/3ai | ee(%) |
1 | OCO2Me | L1 | 63 | 92/8 | 93 |
2 | OAc | L1 | n.r. | - | - |
3 | OBoc | L1 | trace | - | - |
4 | OPO(OEt)2 | L1 | 87 | 98/2 | 58 |
5 | OPO(OEt)2 | L1 | 87 | 98/2 | 58 |
6 | OPO(OEt)2 | L4 | 62 | 92/8 | -62 |
7 | OPO(OEt)2 | L5 | 86 | 80/20 | 30 |
8 | OPO(OEt)2 | L6 | 77 | 67/33 | 35 |
9 | OPO(OEt)2 | L7 | 81 | 64/36 | -59 |
其中Ph是苯基,Naphthyl是萘基,MeO是甲氧基,n.r.为不反应,trace为痕量产物。
实施例3:苯酚类化合物在铱络合物催化下发生烯丙基醚化反应的配体的研究:
序号 | 配体 | 碱 | 产率 | 3ae/3ae’ | ee(%) |
1 | L1 | Cs2CO3 | 60 | 85/15 | 96 |
2 | L1 | K3PO4 | 68 | 86/14 | 95 |
3 | L2 | Cs2CO3 | 71 | 93/7 | 95 |
4 | L2 | K3PO4 | 69 | 89/11 | 95 |
5 | L3 | Cs2CO3 | 57 | 72/28 | 97 |
6 | L3 | K3PO4 | 60 | 72/28 | 92 |
实施例4:苯酚类化合物在铱络合物催化下发生烯丙基醚化反应和RCM反应结合制备1-氧杂苯并杂环类化合物
在一干燥的反应管中依次加入[Ir(COD)Cl]2(0.004mmol)、手性配体(0.008mmol)、正丙胺(0.5mL)和THF(0.5mL),60℃下反应20分钟,然后自然冷至室温后油泵抽干。再依次向反应管中加入苯酚类衍生物(0.4mmol)、碳酸铯(0.2mmol)、烯丙基碳酸酯(0.2mmol)、THF(2mL),加热到50℃反应12小时。反应结束后,减压除去溶剂后过一硅胶短柱(乙醚/石油醚=1/100-1/150,v/v)。把得到的醚化产物溶于二氯甲烷(3mL),在向体系中加入Zhan-1B催化剂(0.2 mmol),在室温下反应4小时。反应结束后,减压除去溶剂后残留物柱层析分离得产物(乙酸乙酯/石油醚=1/100-1/30,v/v)。
P1:(S)-2-(4-甲氧基苯基)-2-氢-苯并吡喃
(S)-2-(4-methoxyphenyl)-2H-chromene
无色液体,产率:41%,86%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(minor)=28.80min,t(major)=35.26min];[α]D20=-126.5°(c=0.40,CH2Cl2).1H NMR(300MHz,CDCl3)δ3.80(s,3H),5.78(dd,J=9.9,3.3Hz,1H),5.86-5.87(m,1H),6.54(dd,J=9.9,1.5Hz,1H),6.75(d,J=8.1Hz,1H),6.83-6.90(m,3H),7.01(d,J=7.5Hz,1H),7.09(t,J=7.8Hz,1H),7.38(d,J=8.4Hz,2H).
P2:(S)-2-(4-甲基苯基)-2-氢-苯并吡喃
(S)-2-p-tolyl-2H-chromene
无色液体,产率:43%,94%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-l,λ=230nm,t(minor)=18.72min,t(major)=32.50min];[α]D20=-192.0°(c=0.89,CH2Cl2).1H NMR(300MHz,CDCl3)δ2.34(s,3H),5.78(dd,J=9.9,3.6Hz,1H),5.87-5.88(m,1H),6.53(d,J=9.9Hz,1H),6.76(d,J=7.8Hz,1H),6.85(t,J=7.5Hz,1H),7.01(d,J=7.5Hz,1H),7.09(t,J=7.8Hz,1H),7.17(d,J=7.8Hz,2H),7.34(d,J=8.1Hz,2H).
P3:(S)-2-(4-溴苯基)-2-氢-苯并吡喃
(S)-2-(4-bromophenyl)-2H-chromene
无色液体,产率:73%,94%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=99/1,v=1.0ml·min-1,λ=254nm,t(minor)=17.68min,t(major)=20.12min];[α]D20=-215.3°(c=1.00,CHCl3).1H NMR(400MHz,CDCl3)δ5.75(dd,J=10.0,3.2Hz,1H),5.85-5.86(m,1H),6.53(dd,J=10.0,2.0Hz,1H),6.77(d,J=8.4Hz,1H),6.86(t,J=7.2Hz,1H),7.00(dd,J=7.2,2.0Hz,1H),7.10(t,J=8.0Hz,1H),7.31(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H).13C NMR(100MHz,CDCl3)δ76.2,116.0,121.1,121.3,122.3,124.1,124.4,126.6,128.7,129.6,131.7,139.7,152.8.IR(thin film):vmax(cm-1)=3044,2926,1738,1630,1604,1589,1263,1228,1205,1114,1011,958,824,798,753;MS(EI,m/z,rel.intensity)285(M+,1),116(100);HRMS(EI)计算值(calcd for)C15H11OBr(M+):285.9993实测值(Found):285.9995.
P4:(S)-2-(3-甲氧基苯基)-2-氢-苯并吡喃
(S)-2-(3-methoxyphenyl)-2H-chromene
无色液体,产率:61%,93%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(minor)=5.04min,t(major)=5.57min];[α]D20=-154.6°(c=1.50,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.79(s,3H),5.78(dd,J=10.0,3.2Hz,1H),5.88-5.89(m,1H),6.50-6.53(m,1H),6.79(d,J=8.0Hz,1H),6.84-6.88(m,2H),6.99-7.30(m,5H).13C NMR(100MHz,CDCl3)δ55.2,112.5,113.8,116.0,119.2,121.2,121.3,124.0,124.8,126.6,129.4,129.7,142.4,153.1,159.8.IR(thin film):vmax(cm-1)=3041,2937,2834,1733,1601,1487,1455,1272,1040,778,753,699;MS(EI,m/z,rel.intensity)238(M+);HRMS(EI)计算值(calcd for)C16H14O2(M+):238.0994实测值(Found):238.0998.
P5:(S)-2-(3-氯苯基)-2-氢-苯并吡喃
(S-2-(3-chlorophenyl)-2H-chromene
无色液体,产率:62%,90%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(minor)=4.37min,t(major)=4.86min];[α]D20=-222.2°(c=1.30,CH2Cl2).1H NMR(400MHz,CDCl3)δ5.77(dd,J=10.0,3.6Hz,1H),5.88-5.90(m,1H),6.55(d,J=9.6Hz,11H),6.80(d,J=8.4Hz,1H),6.88(t,J=7.6Hz,1H),7.01(d,J=7.6Hz,1H),7.12(t,J=9.6Hz,1H),7.29-7.45(m,4H).13C NMR(100MHz,CDCl3)δ76.3,116.0,121.1,121.4,124.0,124.4,125.1,126.7,127.2,128.4,129.6,129.9,134.5,142.8,152.8.IR(thin film):vmax(cm-1)=2959,1738,1693,1485,1350,1229,1113,1078,775;MS(EI,m/z,rel.intensity)242(M+);HRMS(EI)计算值(calcd for)C15H11OCl(M+):242.0498实测值(Found):242.0500.
P6:(S)-2-苯基-2-氢-苯并吡喃
(S)-2-phenyl-2H-chromene
无色液体,产率:68%,94%ee[手性柱OJ-H (Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=0.6ml·min-1,λ=230nm,t(minor)=29.13min,t(major)=32.45min];[α]D20=-144.2°(c=0.66,CH2Cl2).1H NMR(300MHz,CDCl3)δ5.80(dd,J=9.6Hz,1H),5.91-5.93(m,1H),6.53(dd,J=9.6,1.2Hz,1H),6.89(d,J=8.1Hz,1H),6.86(t,J=8.1Hz,1H),7.01(d,J=7.8Hz,1H),7.11(t,J=7.8Hz,1H),7.32-7.47(m,5H).
P7:(R)-2-丙基-2-氢-苯并吡喃
(R)-2-propyl-2H-chromene
无色液体,产率:52%,93%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=99/1,v=1.0ml·min-1,λ=230nm,t(minor)=5.67min,t(major)=6.65min];[α]D20=-176.2°(c=0.85,CH2Cl2).1H NMR(400MHz,CDCl3)δ0.95(t,J=7.6Hz,3H),1.43-1.85(m,4H),4.84-4.86(m,1H),5.87(dd,J=4.8,2.4Hz,1H),6.38(d,J=7.5Hz,1H),6.77(d,J=6.0Hz,1H),6.83(t,J=5.4Hz,1H),6.95(d,J=5.7Hz,1H),7.09(t,J=6.9Hz,1H).
P8:(S)-6-甲氧基-2-苯基-2-氢-苯并吡喃
(S)-6-methoxy-2-phenyl-2H-chromene
无色液体,产率:29%,90%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=70/30,v=1.0ml·min-1,λ=254nm,t(minor)=32.62min,t(major)=44.26min];[α]D20=-224.8°(c=0.70,CH2Cl2).1H NMR(300MHz,CDCl3)δ3.76(s,3H),5.83-5.88(m,2H),6.49-6.75(m,4H),7.26-7.46(m,5H).
P9:(S)-6-溴-2-苯基-2-氢-苯并吡喃
(S)-6-bromo-2-phenyl-2H-chromene
无色液体,产率:50%,92%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=70/30,v=1.0ml·min-1,λ=230nm,t(minor)=16.55min,t(major)=19.48min];[α]D20=-151.4°(c=1.30,CH2Cl2).1H NMR(400MHz,CDCl3)δ5.84(dd,J=10.0,3.6Hz,1H),5.90-5.92(m,1H),6.47(dd,J=9.6,1.6Hz,1H),6.66(d,J=8.0Hz,1H),7.12(d,J=2.4Hz,1H),7.18(dd,J=8.8,2.8Hz,1H),7.33-7.43(m,5H).
P10:(S)-6-氯-2-苯基-2-氢-苯并吡喃
(S)-6-chloro-2-phenyl-2H-chromene
无色液体,产率:42%,92%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=97/3,v=1.0ml·min-1,λ=230nm,t(minor)=20.75min,t(major)=23.18min];[α]D20=-243.1°(c=1.00,CH2Cl2).1H NMR(300MHz,CDCl3)δ5.83-5.92(m,2H),6.48(d,J=9.9Hz,1H),6.71(d,J=9.0Hz,1H),6.99(d,J=2.7Hz,1H),7.04(dd,J=8.4,2.4Hz,1H),7.33-7.44(m,5H).
P11:(S)-6-氯-2-(4-氯苯基)-2-氢-苯并吡喃
(S)-6-chloro-2-(4-chlorophenyl)-2H-chromene
无色液体,产率:39%,92%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=70/30,v=1.0ml·min-1,λ=230nm,t(minor)=8.03min,t(major)=10.55min];[α]D20=-145.2°(c=1.00,CH2Cl2).1H NMR(300MHz,CDCl3)δ5.80-5.88(m,2H),6.49(d,J=9.9Hz,1H),6.70(d,J=8.4Hz,1H),6.99-7.35(m,6H).
P12:(S)-2-(4-甲氧基苯基)-2,5-二氢-1-苯并噁
(S)-2-(4-methoxyphenyl)-2,5-dihydrobenzo[b]oxepine
无色液体,产率:67%,95%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/ 异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(major)=26.40min,t(minor)=40.10min];[α]D20=-110.4°(c=0.85,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.33(dd,J=16.8,6.4Hz,1H),3.76-3.80(m,1H),3.80(s,3H),5.50-5.55(m,2H),5.97-6.03(m,1H),6.84-6.89(m,3H),6.99(t,J=7.6Hz,1H),7.08-7.11(m,2H),7.32(d,J=8.4Hz,2H).13C NMR(100MHz,CDCl3)δ31.4,55.3,82.0,113.7,122.7,123.9,126.2,127.6,128.4,129.2,130.4,132.5,136.5,156.8,159.5.IR(thin film):vmax(cm-1)=3400,2933,2836,1610,1512,1248,1175,1055,801,776;MS(EI,m/z,rel.intensity)252(M+);HRMS(EI)计算值(calcd for)C17H16O2(M+):252.1150实测值(Found):252.1154;Anal.计算值(calcd for)C17H16O2:C,80.93;H,6.39;实测值(Found):C,80.90;H,6.35.
P13:(S)-2-(4-甲基苯基)-2,5-二氢-1-苯并噁
(S)-2-p-tolyl-2,5-dihydrobenzo[b]oxepine
无色液体,产率:63%,94%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=85/15,v=1.0ml·min-1,λ=230nm,t(major)=11.76min,t(minor)=24.53min];[α]D20=-128.6°(c=0.86,CH2Cl2).1H NMR(400MHz,CDCl3)δ2.35(s,3H),3.29(dd,J=16.8,6.8Hz,1H),3.81-3.86(m,lH),5.48-5.56(m,2H),5.96-6.02(m,1H),6.87-6.90(m,1H),7.00(t,J=8.8Hz,1H),7.11(t,J=7.2Hz,2H),7.17(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H).13C NMR(100MHz,CDCl3)δ21.2,31.4,82.3,122.6,123.9,126.1,127.6,127.7,128.4,129.1,130.5,136.5,137.4,137.9,157.0.IR(thin film):vmax(cm-1)=3407,3023,2921,1605,1514,1488,1232,968,799;MS(EI,m/z,rel.intensity)236(M+);HRMS(EI)计算值(calcd for)C17H16O(M+):236.1201实测值(Found):236.1206.
P14:(S)-2-(4-溴苯基)-2,5-二氢-1-苯并噁
(S)-2-(4-bromophenyl)-2,5-dihydrobenzo[b]oxepine
无色液体,产率:82%,96%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=95/5,v=1.0ml·min-1,λ=230nm,t(major)=11.22min,t(minor)=19.52min];[α]D20=-77.3°(c=2.20,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.32(dd,J=16.8,6.8Hz,1H),3.80(dd,J=16.8,4.0Hz,1H),5.47-5.52(m,2H),5.98-6.04(m,1H),6.85(d,J=9.2Hz,1H),7.01(t,J=8.4Hz,1H),7.11(t,J=8.0Hz,2H),7.27(t,J=8.8Hz,2H),7.47-7.50(m,2H).13C NMR(75MHz,CDCl3)δ31.4,81.6,122.1,122.5,124.1,126.7,127.7,128.5,129.4,129.7,131.5,136.2,139.3,156.6.IR(thin film):vmax(cm-1)=3022,1585,1488,1453,1425,1263,1231,1102,1011,965,789;MS(EI,m/z,rel.intensity)300(M+);HRMS(EI)计算值(calcd for)C16H13OBr(M+):300.0150实测值(Found):300.0149;Anal.计算值(calcd for)C16H13OBr:C,63.81;H,4.35;实测值(Found):C,63.92;H,4.65.
P15:(S)-2-(3-甲氧基苯基)-2,5-二氢-1-苯并噁
(S)-2-(3-methoxyphenyl)-2,5-dihydrobenzo[b]oxepine
无色液体,产率:74%,95%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(major)=22.31min,t(minor)=32.57min];[α]D20=-131.9°(c=1.00,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.27(dd,J=16.8,6.8Hz,1H),3.80(S,3H),3.83-3.89(m,1H),5.47-5.57(m,2H),5.96-6.02(m,1H),6.87(dd,8.0,2.8Hz,1H),6.92(d,J=8.0Hz,1H),6.98-7.03(m,3H),7.10-7.14(m,2H),7.24-7.30(m,1H).13C NMR(100MHz,CDCl3)δ31.4,55.2, 82.3,113.0,113.8,119.9,122.5,124.0,126.2,127.7,128.4,129.4,130.4,136.3,142.0,157.0,159.7.IR(thin film):vmax(cm-1)=3395,2936,2834,1600,1488,1454,1266,1232,1197,1048,886,767;MS(EI,m/z,rel.intensity)252(M+);HRMS(EI)计算值(calcd for)C17H16O2(M+):252.1150实测值(Found):252.1155.
P16:(S)-2-(3-氯苯基)-2,5-二氢-1-苯并噁
(S)-2-(3-chlorophenyl)-2,5-dihydrobenzo[b]oxepine
无色液体,产率:61%,96%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(major)=10.27min,t(minor)=11.24min];[α]D20=-126.2°(c=0.94,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.26(dd,J=16.8,6.8Hz,1H),3.82-3.89(m,1H),5.46-5.53(m,2H),5.98-6.04(m,1H),6.91(d,J=7.6Hz,1H),7.02(t,J=8.0HZ,1H),7.11-7.15(m,2H),7.28-7.29(m,3H),7.44(s,1H).13C NMR(100MHz,CDCl3)δ31.4,81.7,122.4,124.2,125.7,126.8,127.8,128.2,128.6,129.6,129.7,134.3,136.2,142.4,156.8.IR(thin film):vmax(cm-1)=3023,1598,1488,1298,1232,1078,946,785,692;MS(EI,m/z,rel.intensity)256(M+);HRMS(EI)计算值(calcd for)C16H13OCl(M+):256.0655实测值(Found):256.0653;Anal.计算值(calcd for)C16H13OCl:C,74.85;H,5.10;实测值(Found):C,74.87;H,5.06.
P17:(S)-2-苯基-2,5-二氢-1-苯并噁
(S)-2-phenyl-2,5-dihydrobenzo[b]o×epine
无色液体,产率:81%,94%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(minor)=17.72min,t(major)=19.32min];[α]D20=-102.6°(c=1.02,CH2Cl2).1H NMR(400MHz,CDCl3)δ3.28(dd,J=16.8,6.8Hz,1H),3.86(d,J=16.8Hz,1H),5.52-5.57(m,2H),5.97-6.02(m,1H),6.89(d,J=8.0Hz,1H),7.01(d,J=7.2Hz,1H),7.09-7.13(m,2H),7.29-7.43(m,5H).13C NMR(100MHz,CDCl3)δ31.4,82.4,122.5,124.0,126.2,127.7,128.1,128.3,128.4,130.4,136.4,140.4,157.0.IR(thin film):vmax(cm-1)=3023,1598,1488,1298,1232,1078,946,785,692;MS(EI,m/z,rel.intensity)222(M+);HRMS(EI)计算值(calcd for)C16H14O(M+):222.1045实测值(Found):222.1039;Anal.计算值(calcd for)C16H14O:C,86.45;H,6.35;实测值(Found):C,86.25;H,6.46.
P18:(S)-2-正丙基-2,5-二氢-1-苯并噁
(R)-2-propyl-2,5-dihydrobenzo[b]oxepine
无色液体,产率:70%,94%ee[手性柱OJ-H (Daicel Chiralcel OJ-H),正己烷/异丙醇=90/10,v=0.6ml·min-1,λ=220nm,t(minor)=7.70min,t(major)=8.71min];[α]D20=+4.4°(c=0.82,CH2Cl2).1H NMR(400MHz,CDCl3)δ0.99(t,J=7.2Hz,3H),1.56-1.81(m,4H),3.10(dd,J=16.8,7.2Hz,1H),3.78(d,J=19.2Hz,1H),4.41-4.42(m,1H),5.40(d,J=11.2Hz,1H),5.80-5.85(m,1H),6.97-7.18(m,4H). 13C NMR(100MHz,CDCl3)δ13.9,18.8,31.6,38.1,80.1,121.9,123.6,125.7,127.7,128.6,131.5,136.0,157.7.IR(thin film):vmax(cm-1)=3390,2958,2930,1645,1487,1452,1253,1233,1109,980;MS(EI,m/z,rel.intensity)188(M+);HRMS(EI)计算值(calcd for)C13H16O(M+):188.1201实测值(Found):188.1205.
P19:(S)-2-甲基-2,5-二氢-1-苯并噁
(R)-2-methyl-2,5-dihydrobenzo[b]oxepine
无色液体,产率:49%,95%ee[手性柱IC(Daicel Chiralpak IC),正己烷/异丙醇=99/1,v=0.6ml·min-1,λ=220nm,t(major)=7.51min,t(minor)=8.00min];[α]D20=-12.6°(c=0.60,CH2Cl2).1H NMR(400MHz,CDCl3)δ1.41(d,J=6.8Hz,3H),3.18(dd,J=16.8,6.8Hz,1H),3.71(dd,J=16.8,6.4Hz,1H),4.60-4.63(m,1H),5.37-5.41(m,1H),5.78-5.84(m,1H),6.98-7.19(m,4H).13C NMR(100MHz,CDCl3)δ22.0,31.4,76.3,122.2,123.7,125.2,127.6,128.6,132.3,136.1,157.2.IR(thin film):vmax(cm-1)=2962,1454,1412,1260,1094,802;MS(EI,m/z,rel.intensity)160(M+);HRMS(EI)计算值(calcd for)C11H12O(M+):160.0888实测值(Found):160.0886.
P20:(S)-7-甲氧基2-苯基-2,5-二氢-1-苯并噁
(S)-7-methoxy-2-phenyl-2,5-dihydrobenzo[b]oxepine
无色液体,产率:70%,95%ee[手性柱IC(Daicel Chiralpak IC),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(major)=5.29min,t(minor)=6.17min];[α]D20=-120.1°(c=0.73,CH2Cl2).1H NMR(300MHz,CDCl3)δ3.22(dd,J=16.5,6.9Hz,1H),3.76(s,3H),3.84(d,J=16.5Hz,1H),5.46-5.56(m,2H),5.95-6.03(m,1H),6.60-6.67(m,2H),6.82(d,J=8.4Hz,1H),7.32-7.43(m,5H).13C NMR(100MHz,CDCl3)δ31.5,55.5,82.7,111.7,114.0,122.9,125.9,127.7,128.1,128.4,130.5,137.5,140.4,150.6,155.7.IR(thin film):vmax(cm-1)=2962,1454,1412,1260,1094,802;MS(EI,m/z,rel.intensity)252(M+);HRMS(EI)计算值(calcd for)C17H16O2(M+):252.1150实测值(Found):252.1154.
P21:(S)-7-氯2-苯基-2,5-二氢-1-苯并噁
(S)-7-chloro-2-phenyl-2,5-dihydrobenzo[b]oxepine
无色液体,产率:69%,93%ee[手性柱OD-H(Daicel Chiralcel OD-H),正己烷/异丙醇=90/10,v=1.0ml·min-1,λ=230nm,t(major)=4.57min,t(minor)=4.86min];[α]D20=-124.0°(c=0.67,CH2Cl2).1H NMR(300MHz,CDCl3)δ3.29(dd,J=16.5,6.0Hz,1H),3.77(d,J=18.9Hz,1H),5.51-5.58(m,2H),5.95-6.03(m,1H),6.77(d,J=8.1Hz,1H),7.04-7.11(m,2H),7.35-7.39(m,5H).13C NMR(100MHz,CDCl3)δ31.0,82.4,123.8,125.6,127.4,127.8,128.3,128.5,128.8,130.3,138.1,139.7,155.3.IR(thin film):vmax(cm-1)=3028,2927,2852,1655,1482,1452,1426,1239,1173,1056,1027,1002,879,821;MS(EI,m/z,rel.intensity)256(M+);HRMS(EI)计算值(calcd for)C16H13OCl(M+):256.0655实测值(Found):256.0653.
实例5:2-氢-苯并吡喃类化合物物经过简单的化学途经衍生化成有用的中间体。
取底物(27.6mg,0.10mmol)、PtO2(2.7mg)和乙酸乙酯(2mL)于一25mL反应管中,在1atm的H2下在室温反应4小时,TLC检测反应完全,过一硅藻土短柱,滤液浓缩后,柱层析(石油醚/乙醚=100/1)得到无色液体产物。
P22:(S)-6-氯-2-(4-氯苯基)--苯并二氢吡喃
该化合物是一种高效的体外鼻病毒复制抑制剂(BW683C)[(a)Bauer,D.J.;Selway,J.W.T.;Batchelor,J.F.;Tisdale,M.;Caldwell,I.C.;Young,D.A.Nature 1981,292,369.(b)Batchelor,J.F.;Bauer,D.J.;Hodson,H.F.;Selway,J.W.T.;Young,D.A.B.U.S.Patent,US 4461907,1984.]。无色液体,产率:95%,90%ee[手性柱OJ-H(Daicel Chiralcel OJ-H),正己烷/异丙醇=70/30,v=1.0ml·min-1,λ=230nm,t(minor)=6.87min,t(major)=10.78min];[α]D20=°(c=0.,CHCl3). 1H NMR(300MHz,CDCl3)δ1.98-2.07(m,1H),2.14-2.23(m,1H),2.71-2.79(m,1H),2.90-3.01(m,1H),5.01(dd,J=9.9,2.4Hz,1H),6.81-6.91(m,3H),7.31-7.40(m,4H).
P23:(S)-2-(4-溴苯基)--苯并二氢吡喃
黄色固体,产率:78%,94%ee[手性柱AS-H(Daicel Chiralcel AS-H),正己烷/异丙醇=99.75/0.25,v=0.6ml·min-1,λ=254nm,t(minor)=12.46min,t(major)=13.33min];[α]D20=-18.7°(c=0.50,CHCl3).1H NMR(300MHz,CDCl3)δ2.02-2.25(m,2H),2.79(dt,J=16.2,4.8Hz,1H),3.00(ddd,J=16.8,10.5,5.4Hz,1H),5.06(dd,J=9.9,2.4Hz,1H),6.85-6.93(m,2H),7.08-7.15(m,2H),7.29-7.44(m,4H);13C NMR(100MHz,CDCl3)δ25.1,29.9,77.7,116.9,120.3,121.8,126.0,127.3,127.8,128.5,129.5,141.7,155.1.m.p.:62-64℃.
Claims (6)
2.一种合成如权利要求1所述的光学活性1-氧杂苯并杂环类化合物的方法,其特征是在有机溶剂中,0℃~120℃下,以烯丙基碳酸酯类化合物和苯酚类衍生物为原料,以[Ir(COD)Cl]2与配体作用生成的铱络合物作为催化剂,在碱的作用下反应4-24小时后,经硅胶短柱纯化后,再在金属Ru催化剂下进行关环1-12小时反应,制得1-氧杂苯并杂环类化合物;
上述的烯丙基碳酸酯类化合物、苯酚类化合物、[Ir(COD)Cl]2、配体、碱、Ru催化剂的摩尔比为1∶1∶0.01-0.1∶0.02-0.2∶0-1∶0.01-0.1;
所述的配体是具有如下结构式的光学纯的配体:
所述的碱是三乙胺、1,8~二氮杂二环[5,4,0]十一碳~7~烯、1,5-二氮杂二环[4,3,0]壬~5~烯、三乙烯二胺、N,O-双(三甲基硅基)乙酰胺、碳酸铯、碳酸钾,磷酸钾、醋酸钾、磷酸钾、氢化钠、正丁基锂、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、甲醇钠、质子海绵、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺;或者加入三氟磺酸银、氯化锂或分子筛作为添加剂;
其中R1、R2如权利要求1所述;
R3、R4或者R5任意选自C3-C16的环烷基、苯基、萘基、C1-C4的烷氧基取代的苯基、或C1-C4的烷氧基取代的萘基、异丙基或叔丁基;LG是离去基团,为碳酸甲酯或、碳酸乙酯、磷酸酯或者碳酸叔丁基酯。
3.如权利要求2所述的合成光学活性1-氧杂苯并杂环类化合物的方法,其特征是所述的烯丙基碳酸酯类化合物、苯酚类化合物、[Ir(COD)Cl]2、配体、碱和Ru催化剂的摩尔比为1∶1∶0.02-0.05∶0.04-0.1∶1∶0.05。
4.一种如权利要求2所述合成光学活性1-氧杂苯并杂环类化合物的方法,其特征是所述有机溶剂是苯、四氯化碳、石油醚、四氢呋喃、二甲基甲酰胺、乙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环或乙腈。
5.一种如权利要求2所述合成光学活性1-氧杂苯并杂环类化合物的方法,其特征是所得产物经过重结晶、薄层层析、柱层析或减压蒸馏的分离。
6.一种如权利要求1所述的1-氧杂苯并杂环类化合物用途,其特征是用于制备广泛存在天然产物和药物中间体中的苯并二氢吡喃类衍生物片段。
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CN105218502B (zh) * | 2015-10-26 | 2017-12-15 | 浙江工业大学 | 一种手性苯并二氢吡喃类化合物的不对称合成方法 |
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