CN101066945A - 一种合成3-位取代内酰胺类化合物的方法 - Google Patents
一种合成3-位取代内酰胺类化合物的方法 Download PDFInfo
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Abstract
本发明提供了一种合成3-取代内酰胺化合物的方法,是一种有效的以氮杂环卡宾作为催化剂,由醛基取代的小环胺类化合物高效率的合成3-取代内酰胺化合物的方法。与现有方法相比,该方法可适底物范围广,催化剂方便易得,反应条件温和,操作简便,而且反应效率高。另外,当底物中存在手性季碳中心时,该反应可以将其手性传递到产物中,可用来合成高对应选择性的含季碳中心的内酰胺类化合物。而且该方法无需加入任何金属盐类化合物,从而有利于药物的生产和处理。
Description
技术领域
本发明涉及一种合成3-位取代内酰胺类化合物的方法,尤其涉及一种通过底物中季碳手性中心手性保留来合成光学活性的螺环内酰胺化合物的方法。该方法是由氮杂环卡宾的前体盐与碱作用现场生成的氮杂环卡宾催化醛基取代的小环胺类化合物扩环的反应,也可以直接由氮杂环卡宾催化醛基取代的小环胺类化合物扩环的反应,该反应可以高效地合成3-位取代内酰胺类化合物。
背景技术
近年来,有机小分子催化由于其合成容易,结构修饰方便,无重金属残留等优点在全世界范围内引起了学术界和工业界的广泛关注[(a)Seayad,J.;List,B.Org.Biomol.Chem.2005,3,719-724.(b)Dalko,P.I.;Moisan,L.Angew.Chem.Int.Ed.2004,43,5138-5175.],其中由氮杂环卡宾为催化剂催化的有机反应在近年来更是取得了迅速的发展[a)H.Stetter,Angew.Chem.1976,88,695-704;Angew.Chem.Int.Ed.1976,15,639-647;b)M.S.Kerr,J.Read de Alaniz,T.Rovis,J.Am.Chem.Soc.2002,124,10298-10299;c)A.E.Mattson,A.R.Bharadwaj,K.A.Scheidt,J.Am.Chem.Soc.2004,126,2314-2315;d)M.S.Kerr,T.Rovis,J.Am.Chem.Soc.2004,126,8876-8877;e)J.Read de Alaniz,T.Rovis,J.Am.Chem.Soc.2005,127,6284-6289;f)Q.Liu,T.Rovis,J.Am.Chem.Soc.2006,128,2552-2553;g)Y.Hachisu,J.W.Bode,K.Suzuki,J.Am.Chem.Soc.2003,125,8432-8433;h)D.Enders,O.Niemeier,T.Balensiefer,Angew.Chem.2006,118,1491-1495;Angew.Chem.Int.Ed.2006,45,1463-1467;i)H.Takikawa,Y.Hachisu,J.W.Bode,K.Suzuki,Angew.Chem.2006,118,3572-3574;Angew.Chem.Int.Ed.2006,45,3492-3494;j)M.He,G.J.Uc,J.W.Bode,J.Am.Chem.Soc.2006,128,15088-15089;k)G.-Q.Li,L.-X.Dai,S.-L.You,Chem.Commun.2007,852-854],在这一领域中,我们最近发展了由氮杂环卡宾催化醛基取代的小环胺类化合物的扩环反应,该反应可以高效率地合成3-位取代内酰胺类化合物,而这一类化合物存在于大量的具有生物活性的天然和非天然产物中[a)N.C.Warshakoon;S.Wu;A.Boyer;R.Kawamoto;J.Sheville;S.Renock;K.Xu;M.Pokross;A.G.Evdokimov;R.Walter;M.Mekel.Bioorg.Med.Chem.Lett.2006,16,5598-5601;b)J.Uddin;K.Ueda;E.Siwu;M.Kita;D.Uemura Biorg.Med.Chem.,2006,14,6954-6961;c)H.Ishikawa;G.I.Elliott;J.Velcicky;Y.Choi;D.Boger J.Am.Chem.Soc.,2006,128,10596-10612;d)Hamlyn,Richard John;Rigoreau,Laurent Jean Martin;Raynham,Tony Michael;Priestley,Rachael Elizabeth;Soudy,Christelle Nicole Marguerite;Lyko,Frank;Bruckner,Bodo;Kern,Oliver Thomas.PCT Int.Appl.2007,71;e)Jacyno,John M.;Lin,Nan-Horng;Holladay,Mark W.;Sullivan,James P.CurrentTopics in Plant Physiology(1995),15(Phytochemicals and Health),294-6.f)J.A.Ferrendelli;H.J.Kupferberg Advances in Neurology 1980,27,587-96.]目前文献中对3-位取代的内酰胺化合物的合成报道很多,但其中大多都有金属参与反应或者反应条件较苛刻,反应时间很长等缺点,因而发展一种操作方便,条件温和,而且效率高的合成3-位取代内酰胺类化合物的方法是这方面的重点和难点。本发明人发展的利用氮杂环卡宾前体盐与碱作用,现场生成氮杂环卡宾或者直接用氮杂环卡宾这一有机小分子催化剂,通过对醛基取代小环内酰胺这一方便易得的底物扩环来实现3-位取代的内酰胺化合物的合成,对此类化合物的合成有着重要的意义。
发明内容
本发明目的是要提供一种高效的合成3-位取代内酰胺类化合物的方法。尤其是在底物中含有季碳手性中心时,反应可以将手性保留到产物中,可用来高效率高对映选择性地合成光学活性的3-位取代内酰胺类化合物。
本发明的方法是一种高效的由醛基取代四元环胺类化合物合成3-位取代内酰胺化合物的方法。该方法是由氮杂环卡宾前体盐与碱作用现场生成氮杂环卡宾作为催化剂,也可以直接用氮杂环卡宾作为催化剂。
式中:R1或R2任意选自H、含C1-C16的烷基、氨基、烷氧基或卤素原子等;
本发明的3-位取代的内酰胺化合物是以醛基取代的小环胺类化合物为原料,在有机溶剂的存在下,以氮杂环卡宾前体盐与碱的作用生成的氮杂环卡宾催化反应制得,也可以直接用氮杂环卡宾催化反应制得,可用下式表示:
醛基取代的小环胺类化合物的结构式为:
其中R1或R2任意选自H、含C1-C16的烷基、氨基、烷氧基或者卤素原子等;R3任意选自酰基、取代的芳基或者C1-C16的烷基的等;X为羰基或
n=0、1或2;当用氮杂环卡宾前体盐与碱作用现场生成氮杂环卡宾作为催化剂时,氮杂环卡宾的前体盐的结构式可以是任意光学纯的或其对映体或消旋体的如下结构式,但不受图示所限:
当直接用氮杂环卡宾作为催化剂时,氮杂环卡宾的结构式可以是任意光学纯的或其对映体或消旋体的如下结构式,但不受图示所限:
其中,R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16或R17为H、C1-C16的烷基、芳基、取代芳基;所述取代的芳基上的取代基为烷基、烷氧基或取代的胺基,上述各取代基可单独成键或者相互之间成键形成C5-C7的环烷基、芳基、取代芳基、含N、O、S的杂芳基或杂环烷基;A1,A2,A3,A4为Cl-、Br-、BF4 -或ClO4 -。
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、碳酸铯、磷酸钾、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、叔丁醇钾、叔丁醇钠或二异丙基乙基胺;
所述的醛基取代小环胺类化合物、氮杂环卡宾前体盐或氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0-0.2。
当用氮杂环卡宾前体盐与碱作用,现场生成氮杂环卡宾催化该反应时,所述的醛基取代的小环胺类化合物、氮杂环卡宾前体盐和碱的的摩尔比1∶0.01-0.2∶0.01-0.2。推荐摩尔比为1∶0.2∶0.2。尤其推荐反应的摩尔比为∶醛基取代小环胺类化合物∶氮杂环卡宾前体盐∶碱=1∶0.01∶0.01。
当直接用氮杂环卡宾催化该反应时,所述的醛基取代的小环胺类化合物、氮杂环卡宾和碱的的摩尔比1∶0.01-0.2∶0。尤其推荐反应的摩尔比为∶醛基取代小环胺类化合物∶氮杂环卡宾∶碱=1∶0.01∶0。
反应温度推荐为0℃至120℃,进一步推荐反应温度为:25℃至110℃。反应时间推荐为5小时-48小时。
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16和R17同前所述。
本发明中所提到的烷基、烃氧基、酰基等,除非另外说明,均推荐碳数为1~18的基团,进一步推荐碳数为1~10的,尤其推荐碳数为1~5的。本发明中所提到的环烷基,除非另外说明,均指碳数为3~18的基团,进一步推荐碳数为3~10的,尤其推荐碳数为3~7的。本发明中所提到的芳基,除非另外说明,均指苯基、C5~C10的含N、O或S的杂环基,推荐为苯基。本发明中提到的杂芳基,推荐C5~C10的含N、O和S的杂环基。
本发明方法中,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、二甲基乙酰胺、***、二氯甲烷、三氯甲烷、甲苯、二甲苯、环己烷、正己烷、正庚烷、二氧六环或乙腈等。
采用本发明方法所得产物可以经过重结晶,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—正己烷或异丙醇—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。推荐溶剂可为异丙醇—石油醚、乙酸乙酯—石油醚、乙酸乙酯—正己烷或异丙醇—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:乙酸乙酯∶石油醚=1∶0.1-50,异丙醇∶石油醚=1∶0.1-500。
本发明提供了一些新的3-位取代内酰胺化合物
其中例如R1为H;R2为甲基或苯基;R3为苯基、对甲基苯基、苄基、烷基。该类化合物可以经常规的反应将R3脱除以及将酰胺还原为氨基并上氨基保护基如苄氧羰基,从而具有广泛的应用。
本发明提供了一种有效的由氮杂环卡宾前体盐与碱作用,现场生成的氮杂环卡宾或者直接用氮杂环卡宾作为催化剂,由醛基取代的小环胺类化合物高效率的合成3-位取代内酰胺化合物的方法。与现有方法相比,该方法可适用于多种不同类型的醛基取代小环胺类化合物,反应条件温和,操作简便。另外,反应中无需加入任何金属盐类化合物,从而有利于药物的生产和处理。且反应的产率也较好,一般为78%-99%。
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:噻唑类氮杂环卡宾前体盐的制备
室温氩气保护下,在一干燥的反应管中将4,5-二甲基噻唑或者4-甲基-5-羟乙基噻唑(1.0mmol)溶于10mL干燥的乙腈中,在快速搅拌的条件下,将(1.0mmol)的溴化苄或者苄氯缓慢的滴加到体系中,回流3个小时。待反应结束,自然冷却至室温,在快速搅拌下,向体系中缓慢滴加乙酸乙酯30mL,体系有大量白色固体析出,静置。过滤,得白色固体,即为噻唑类卡宾的前体盐。
C1:溴化(3-苄基-4,5-二甲基噻唑)
3-Benzyl-4,5-dimethylthiazolium bromide
固体,91%产率。′H NMR(300MHZ,DMSO)67.492-7.324(m,5H),5.809(s,2H),2.499(s,3H),2.327(s,3H);MS(CI)m/z(relative intensity)204(M,13.6),171(8),142(10.4),114(72.81),91(100).
C2:溴化[3-苄基-4-甲基-5-(β-羟基乙基)噻唑]
3-Benzyl-5-(β-ethoxyethyl)-4-methy thiazolium Bromide
白色固体,82%产率;’H NMR(300MHz,CDCl3)11.51(s,1H),7.35(m,5H),6.12(d,2H,J=5.2Hz),3.49-3.65(m,4H),3.01(t,2H,J=5.4Hz),2.42(s,3H),1.19(t,3H,J=7.0Hz).
C3:2-Phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium chloride
总产率C3(15.778g 62%).Rf(丙酮)=0.09;1H NMR(300MHz,D2O)δ7.61-7.79(m,2H),7.50-7.59(m,3H),4.38(dd,2H,J=7.3,7.3Hz),3.13(dd,2H,J=7.3,7.3Hz),2.77(ddd,2H,J=15.0,7.7,7.7Hz);13C NMR(100MHz,D2O)δ163.9,135.5,131.0,130.3,121.3,47.5,26.7,21.5;IR(NaCl,压片)1586,1513,1426,1382,967cm-1;m.p.180-184℃;HRMS(快原子轰击),C11H12N3,计算值186.1031.实测值186.1038.
C4:1,3,4-triphenyl-4H-1,2,4-triazol-1-ium perchlorate
MS(m/z,rel.intensity)397(M+,100),398(22),399(32)
C5:1,3-二(2,6-二异丙基苯基)咪唑盐酸盐
1,3-Bis(2,6-diisopropylphenyl)imidzaolium chloride
MS(m/z,rel.intensity)397(M+,100),398(22),399(32).
C6:1,3-二(均三甲基苯基)咪唑盐酸盐
1,3-Bis(2,4,6-trimethylphenyl)imidazolium chicride
MS(m/z,相对强度)340(M+,100),341(23),342(32).
C7:
2-phenyl-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza-2-azoniacyclopenta[c]fluor--ene tetrafluoroborate
消旋或者手性化合物
MS(m/z,相对强度)337(M+,100),336(24),338(20).
C8:
2-Pentafluorophenyl-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza-2-azoniacyclopenta[c]fluorene tetrafluoroborate
MS(m/z,相对强度)380(M+,100),381(20),382(2).
C9:2-(2,4,6-trimethylphenyl)-6,10b-dihydro-4H,5aH-5-oxa-3,10cdiaza--2-azoniacyclopenta[c]fluorene tetrafluoroborate
消旋体或者手性化合物
MS(m/z,相对强度)419(M+,100),418(25),420(24)。
实施例2:氮杂环卡宾催化醛基取代内酰胺化合物的扩环反应
在氩气保护下,向一干燥的反应管中依次加入氮杂环卡宾前体盐化合物(0.01mmol),碱(0.01mmol),醛基取代小环胺类化合物(1.00mmol),二氯甲烷4.0mL,回流。反应结束,减压除去溶剂,将残留物柱层析分离得产物。未加特别说明,反应均以二氯甲烷为溶剂,反应温度回流。
P1:N-(对甲氧基苯基)-3-苯基琥珀酰亚胺
N-(4-methoxyphenyl)-3-phenylpyrrolidine-2,5-dione
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/4,v/v;白色固体,99%产率;1HNMR(CDCl3,300MHz)δ2.97(dd,1H,J1=4.8Hz,J2=18.3Hz),3.35(dd,1H,J1=9.9Hz,J2=18.6Hz),3.82(s,3H),4.16(dd,1H,J1=4.8Hz,J2=9.9Hz),6.98(d,2H,J=9.0Hz),7.23(d,2H,J=9.0Hz),7.29-7.42(m,5H);13C NMR(75MHz,CDCl3):δ37.2,45.9,55.4,114.5,124.4,127.3,127.6,128.0,129.2,137.2,159.5,175.4,176.9;IR(薄膜):νmax(cm-1)=3007,2953,2834,1705,1513,1250,1198,777,703,670;MS(电子轰击,相对强度)293(M+,50),161(100);元素分析C17H15NO3:计算值:C,72.58;H,5.37;N,4.98;实测值:C,72.42;H,5.26;N,4.83;m.p.161-162℃.
P2:N-(对甲氧基苯基)-3-(对甲氧基苯基)琥珀酰亚胺
N-(4-methoxyphenyl)-3-4-(methoxyphenyl)pyrrolidine-2,5-dione
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/3,v/v;白色固体,98%产率;1HNMR(CDCl3,300MHz)δ2.94(dd,1H,J1=4.8Hz,J2=18.3Hz),3.34(dd,1H,J1=9.6Hz,J2=18.6Hz),3.81(s,3H),3.82(s,3H),4.12(dd,1H,J1=4.8Hz,J2=9.6Hz),6.92(d,2H,J=8.7Hz),6.98(d,2H,J=9.0Hz)7.21-7.26(m,4H);13CNMR(75MHz,CDCl3):δ37.2,45.1,55.3,55.4,114.4,114.6,124.4,127.6,128.4,129.1,159.2,159.5,175.5,177.2;IR(薄膜):νmax(cm-1)=2960,2839,1705,1516,1251,1200,1181,1033,833,670;MS(电子轰击,相对强度)311(M+,43),134(100);元素分析C18H17NO4:计算值:C,69.44;H,5.50;N,4.50;实测值:C,69.30;H,5.79;N,4.32;m.p.172-173℃.
P3:N-(对甲氧基苯基)-3-(对氯苯基)琥珀酰亚胺
3-(4-chlorophenyl)-N-(4-methoxyphenyl)pyrrolidine-2,5-dione
催化剂为C6(1mol%);反应溶剂为1,4-二氧六环,回流;乙酸乙酯/石油醚=1/4,v/v;白色固体,93%产率;1H NMR(CDCl3,300MHz)δ2.95(dd,1H,J1=5.1Hz,J2=18.6Hz),3.37(dd,1H,J1=9.6Hz,J2=18.3Hz),3.83(s,3H),4.17(dd,1H,J1=4.8Hz,J2=9.6Hz),6.99(d,2H,J=9.0Hz),7.21-7.27(m,4H),7.38(d,2H,J=8.4Hz);13C NMR(75MHz,CDCl3):δ36.9,45.2,55.5,114.5,124.3,127.6,128.8,129.4,134.0,135.4,159.6,175.0,176.4;IR(压片):νmax(cm-1)=3472,3072,3012,2837,1783,1706,1513,1251,1205,1167,1029,832,670;MS(电子轰击,m/z,相对强度)315(M+,37),149(100);元素分析C17H14ClNO3:计算值:C,64.67;H,4.47;N,4.44;实测值:C,64.63;H,4.66;N,4.39;m.p.197-198℃.
P4:N-(对甲氧基苯基)-3-(2-噻吩基)琥珀酰亚胺
N-(4-methoxyphenyl)-3-(thiophen-2-yl)pyrrolidine-2,5-dione
催化剂为C6(1mol%);反应溶剂为1,4-二氧六环;乙酸乙酯/石油醚=1/4,v/v;白色固体,85%产率;1H NMR(CDCl3,300MHz)δ3.06(dd,1H,J1=5.4Hz,J2=18.3Hz),3.37(dd,1H,J1=9.6Hz,J2=18.6Hz),3.80(s,3H),4.39(dd,1H,J1=5.4Hz,J2=9.6Hz),6.94-7.06(m,4H),7.17-7.29(m,3H);13C NMR(75MHz,CDCl3):δ37.1,41.0,55.4,114.4,124.2,125.3,125.5,127.1,127.5,138.3,159.5,174.5,175.5;IR(压片):νmax(cm-1)=3105,3004,2833,1902,1779,1709,1704,1516,1405,1250,1199,1175,1030,667;MS(电子轰击,m/z,相对强度)287(M+,3),110(100);HRMS(电子轰击)C15H13NO3S(M+):计算值287.0616实测值:287.0619;m.p.122-124℃.
P5:N-(对甲氧基苯基)-3-甲基琥珀酰亚胺
N-(4-methoxyphenyl)-3-methylpyrrolidine-2,5-dione
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,91%产率;1HNMR(CDCl3,300MHz)δ1.45(d,3H,J=7.2Hz),2.49(dd,1H,J1=3.6Hz,J2=16.8Hz),3.00-3.13(m,2H),3.82(s,3H),6.98(d,2H,J=9.3Hz),7.19(d,2H,J=8.7Hz);13C NMR(75MHz,CDCl3):δ16.8,34.7,36.5,55.4,114.4,124.5,127.6,159.4,175.7,179.8;IR(压片):νmax(cm-1)=3005,2943,2846,1773,1704,1511,1396,1245,1182,1166,1031,836,668;MS(电子轰击,m/z,相对强度)219(M+,100);HRMS(电子轰击)C12H13NO3(M+):计算值:219.0895;实测值:219.0900;m.p.91-93℃.
P6:N-(对甲氧基苯基)-3-正戊基琥珀酰亚胺
N-(4-methoxyphenyl)-3-pentylpyrrolidine-2,5-dione
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,99%产率;1HNMR(CDCl3,300MHz)δ0.91(brs,3H),1.33-1.44(m,6H),1.55-1.68(m,1H),1.93-2.04(m,1H),2.53(m,1H),2.88-3.03(m,2H),3.81(s,3H),6.97(d,2H,J=9.0Hz),7.18(d,2H,J=9.0Hz);13C NMR(75MHz,CDCl3):δ14.0,22.4,26.3,31.4,31.4,34.5,40.0,55.4,114.4,124.5,127.6,159.4,176.0,179.3;IR(thin film):νmax(cm-1)=3074,2957,2932,2856,1776,1706,1519,1394,1255,1174,1027,822,769;MS(EI,m/z,rel.intensity)275(M+,53),205(100);HRMS(EI)C16H21NO3(M+):计算值275.1521;实测值:275.1521;m.p.67-68℃.
P7:N-(对甲氧基苯基)-3-异丙基琥珀酰亚胺
3-isopropyl-N-(4-methoxyphenyl)pyrrolidine-2,5-dione
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,93%产率;1HNMR(CDCl3,300MHz)δ0.96(d,3H,J=6.9Hz),1.04(d,3H,J=7.2Hz),2.39(m,1H),2.58(dd,1H,J1=4.2Hz,J2=18.3Hz),2.82(dd,1H,J1=9.3Hz,J2=18.3Hz),2.93(m,1H),3.80(s,3H),6.96(d,2H,J=8.7Hz),7.15(d,2H,J=9.0Hz);13C NMR(75MHz,CDCl3):δ17.1,19.8,29.0,30.3,45.5,55.3,114.3,124.4,127.6,159.3,176.1,178.6;IR(压片):νmax(cm-1)=2963,2935,1709,1513,1399,1255,1200,1035,831,771,672;MS(电子轰击,m/z,相对强度)247(M+,100);HRMS(电子轰击)C14H17NO3(M+):计算值:247.1208;实测值:247.1208;m.p.112-114℃.
P8:N-(对甲氧基苯基)-3,3-二甲基琥珀酰亚胺
N-(4-methoxyphenyl)-3,3-dimethylpyrrolidine-2,5-dione
催化剂为C6(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,97%产率;1HNMR(CDCl3,300MHz)δ1.42(s,6H),2.71(s,2H),3.83(s,3H),6.98(d,2H,J=9.0Hz),7.20(d,2H,J=9.0Hz);13C NMR(75MHz,CDCl3):δ25.7,25.7,40.0,43.7,55.4,114.4,124.6,127.6,159.4,175.1,182.4;IR(压片):νmax(cm-1)=2936,2843,1775,1710,1511,1397,1248,1148,1033,834,788;MS(电子轰击,m/z,相对强度)233(M+,87),83(100);HRMS(电子轰击)C13H15NO3(M+):计算值:233.1052;实测值:233.1051;
P9:N-(对甲氧基苯基)-3-乙基-3-苯基琥珀酰亚胺
3-ethyl-N-(4-methoxyphenyl)-3-phenylpyrrolidine-2,5-dione
催化剂为C6(5mol%);反应溶剂为1,4-二氧六环,回流,乙酸乙酯/石油醚=1/5,v/v;白色固体,97%产率;1H NMR(CDCl3,300MHz)δ0.97(t,3H,J=7.2Hz),2.17(dq,2H,J1=5.1Hz,J2=7.2Hz),3.06(AB,1H,JAB=18.3Hz),3.25(AB,1H,JBA=18.0Hz),3.80(s,3H),6.97(d,2H,J=8.7Hz),7.19(d,2H,J=8.7Hz),7.27-7.51(m,5H);13C NMR(75MHz,CDCl3):δ9.0,32.7,41.1,52.1,55.4,114.4,124.4,126.1,127.5,127.7,128.8,140.6,159.4,174.9,179.3;IR(压片):νmax(cm-1)=3474,3059,2970,2939,1779,1712,1515,1388,1253,1033,823,736,701;MS(电子轰击,m/z,相对强度)309(M+,66),149(100);HRMS(电子轰击)C19H19NO3(M+):计算值:309.1365;实测值:309.1371.
P10:N-(均三甲基)-3-苯基琥珀酰亚胺
N-mesityl-3-phenylpyrrolidine-2,5-dione
催化剂为C6(5mol%);乙酸乙酯/石油醚=1/5,v/v;白色固体,78%产率;1HNMR(300MHz,CDCl3)δ2.09(s,3H),2.11(s,3H),2.30(s,3H),3.05(dd,1H,J1=5.1Hz,J2=18.6Hz),3.43(dd,1H,J1=9.9Hz,J2=18.6Hz),4.24(dd,1H,J1=5.1Hz,J2=9.9Hz),6.97(d,2H,J=4.5Hz),7.31-7.44(m,5H);13C NMR(75MHz,CDCl3)δ17.6,17.8,21.0,37.2,46.2,127.3,127.4,127.9,129.1,129.3,129.3,135.1,135.2,137.0,139.3,175.1,176.4;IR(压片):νmax(cm-1)=3466,3028,2919,1773,1712,1488,1372,1184,863,785,667;MS(电子轰击,m/z,相对强度)293(M+,30),161(100);HRMS(电子轰击)C19H19NO2(M+):计算值:293.1416实测值:293.1412;m.p.137-138℃.
P11:
催化剂为C6(1mol%);乙酸乙酯/石油醚=1/3,v/v;白色泡沫状固体,92%产率99.9%ee,[手性柱AD-H,己烷/异丙醇=70/30,1.0ml·min-1,λ=220nm,t(最大保留时间)=19.67分钟,t(最小保留时间)=15.12分钟];[α]D 20=-46.5(c1.0,CHCl3).1H NMR和13C NMR显示体系存在旋转异构体,其物质的量比为2∶1。.1H NMR(300MHz,CDCl3)δ1.90-2.18(m,2H),2.78(AB,1H,JAB=17.7Hz),3.12,3.27(AB,1H,JBA=18.0Hz),3.60-3.71(m,2H),3.77,3.79(s,3H),5.06-5.18(m,2H),6.62,6.96(d,2H,J=9.0Hz),6.79,7.26(d,2H,J=9.0Hz),7.24-7.34(m,5H);13C NMR(75Hz,CDCl3)δ:23.1,23.9,38.2,40.0,41.4,42.4,47.4,48.3,55.3,55.3,64.2,65.1,67.2,68.1,114.1,114.3,123.9,124.5,127.3,127.8,127.8,128.0,128.4,128.5,128.6,128.7,135.1,135.9,153.0,154.1,159.2,159.4,173.1,173.6,177.4,177.7;IR(压片):νmax(cm-1)=2957,2883,2840,1718,1696,1514,1417,1253,1213,1166;MS(电子轰击,m/z,相对强度)394(M+,27),91(100);HRMS(电子轰击)计算值:C22H22N2O5(M+):394.1529实测值:394.1535;m.p.107-108℃.
P12:N-(对甲氧基苯基)-4-苯基吡咯烷酮
N-(4-methoxyphenyl)-4-phenylpyrrolidin-2-one
MS(m/z,相对强度)267(M+,100),268(19),269(2).
P13:N-(对甲氧基苯基)-4-甲基吡咯烷酮
N-(4-methoxyphenyl)-4-methylpyrrolidin-2-one
MS(m/z,相对强度)205(M+,100),206(13)
P14:N-(对甲氧基苯基)-4-正戊基吡咯烷酮
N-(4-methoxyphenyl)-4-penthylpyrrolidin-2-one
MS(m/z,相对强度)261(M+,100),262(18),263(2).
实施例3:产物中酰胺的还原(应用实例)
在氩气保护下,向干燥体系中加P11(0.5mmol,182.0mg)和四氢呋喃5mL。将体系置于冰水浴中冷却到0℃后,向体系中缓慢分批加入LiAlH4(2.5mmol,101.3mg),搅拌30分钟,撤去冰水浴,自然恢复室温,搅拌。反应完毕后(TLC跟踪反应),将体系冷却至0℃后,缓慢滴加蒸馏水0.18mL,搅拌30分钟后,过滤。用乙酸乙酯洗涤固体,合并有机相,干燥后柱层析。石油醚/乙酸乙酯=3/1,3‰三乙胺),得相应还原产物,产率86%。
White solid.99.7%ee,[手性柱OD-H(15cm),己烷/异丙醇=98/2,0.7ml·min-1,λ=230nm,t(最大保留时间)=15.71分钟,t(最小保留时间)=13.29分钟];[α]D 20=-18.4(c 0.82,CHCl3).1H NMR(300MHz,CDCl3)δ1.68-1.94(m,5H),2.13-2.20(m,1H),2.37(s,3H),2.76-2.83(m,2H),2.97(d,1H,J=9.3Hz),3.21-3.29(m,1H),3.35-3.44(m,2H),3.76(s,3H),6.52(d,2H,J=9.0Hz),6.85(d,2H,J=9.6Hz);13C NMR(75MHz,CDCl3)δ20.8,30.2,34.8,38.3,47.3,53.4,54.4,55.9,69.6,112.3,114.9,142.9,150.8;IR(压片):νmax(cm-1)=2979,2951,2828,2781,1516,1241,1042,814;MS(电子轰击,m/z,相对强度)246(M+,42),150(100).HRMS(电子轰击)C15H22NO(M+):计算值:246.1732实测值:246.1736;m.p.46-48℃.
Claims (7)
1.一种合成3-位取代内酰胺类化合物的方法,其特征是在有机溶剂的存在下和0℃~120℃下,以醛基取代小环胺类化合物为原料,以氮杂环卡宾前体盐或氮杂环卡宾与碱作用生成的氮杂环卡宾作为催化剂,反应2-36小时制得3-位取代的内酰胺化合物;
所述的醛基取代小环胺类化合物、氮杂环卡宾前体盐或氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0-0.2;
所述的氮杂环卡宾的前体盐具有如下结构式:
所述的氮杂环卡宾具有如下结构式:
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、碳酸铯、磷酸钾、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、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺;
其中R1,R2任意选自H,C1-C16的烷基、C3-C16的环烷基、氨基或取代的胺基、烷氧基或者卤素原子;R1,R2可以单独成键或者相互成键;R3任意选自酰基、C5~C10的含N、O或S的杂环基或者杂芳基、取代的芳基或者C1-C16的烷基;X为羰基或者
n=0,1,2;
R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16或R17为H、C1-C16的烷基、C5~C10的含N、O或S的杂环基、芳基或取代芳基;各取代基可单独成键或者相互成键形成C5-C7的环烷基、芳基、取代芳基、含N、O、S的杂芳基或杂环烷基;
所述取代的芳基上的取代基为烷基、烷氧基碳数为1~18;取代的胺基上的取代基为C1-C16的烷基、芳基、取代芳基或者C5~C10的含N、O或S的杂环芳基或者杂环烷基;A1、A2、A3或、A4任意为Cl-、Br-、BF4 -或ClO4 -;所述的烷基、烃氧基或酰基的碳数为1~18;所述的芳基是苯基、C5~C10的含N、O或S的杂环基或C5~C10的含N、O和S的杂芳基。
2.根据权利要求1所述的合成3-位取代内酰胺类化合物的方法,其特征是所述的醛基取代小环胺类化合物、氮杂环卡宾前体盐、碱的摩尔比为1∶0.01-0.2∶0.01-0.2。
3.根据权利要求1所述的合成3-位取代内酰胺类化合物的方法,其特征是所述的醛基取代小环胺类化合物、氮杂环卡宾、碱的摩尔比为1∶0.01-0.2∶0。
6.如权利要求1所述的合成3-位取代内酰胺化合物的方法,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、二甲基乙酰胺、***、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。
7.如权利要求1所述的合成3-位取代内酰胺化合物的方法,其特征是所得产物经过重结晶,薄层层析或柱层析减压蒸馏加以分离。
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