CN102924459B - 吡咯稠环3-吲哚酮类化合物的合成方法 - Google Patents
吡咯稠环3-吲哚酮类化合物的合成方法 Download PDFInfo
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Abstract
本发明公开了一种吡咯稠环3-吲哚酮类化合物合成方法,是在反应溶剂中,氮气保护下,以稠环靛红类化合物和双取代乙炔类化合物为原料,在钯金属催化、氧化剂作用下,反应得到吡咯稠环3-吲哚酮类化合物。本发明原料简单易得,原子经济型高、合成方法路线简便,效能优越。
Description
技术领域
本发明具体涉及一种吡咯稠环3-吲哚酮类化合物的合成方法,属于有机化合物工艺应用技术领域。
背景技术
近年来,化学家们一直在寻找更绿色的有机合成方法,C-H键活化凭借其在环境友好性、可持续性方面的优良特性而受到诸多化学工作者的关注,其中通过多位点活化,一次性构造复杂分子骨架更是化学家们共同追求的目标,本发明实现了Pd催化C-H/N-H键断裂,完成对炔类化合物的氧化环加成以构建含氮杂环化合物,此类方法原子经济性高、步骤简短。
吡咯吲哚并环类骨架广泛存在于一系列天然产物中,是自然界内不可或缺的一类分子模块,如式(A)中所示三种天然代表性的天然产物均含有此类结构单元,这更突显了高效完成此类结构的重要性,同时敦促了化学工作者寻求相关创新性方法学以填补该领域的空缺,实现该领域的多元化发展。
式(A);现有技术中,吡咯吲哚酮类化合物的主要方面如式(II)所示:a,以邻碘苯吡咯化合物为原料在催化剂作用下发生插羰化反应;b,以邻氨基苯甲酸类化合物与2,5-二甲氧基呋喃为原料,串联反应构建吡咯吲哚酮;c,以邻吡咯苯甲酸化合物为原料发生傅克酰基化反应。以上反应中均存在原料构建困难,反应步骤多,原子经济性差等不足;另外路线a中用到了潜在危险性较大的一氧化碳气体,路线b中用到了稳定性较差的2,5-二甲氧基呋喃,路线c采用傅克反应的方法,后处理较繁琐,甚至可能影响产率。
式(II);
本发明以廉价易得的商品为原料,在催化剂作用下,一步法实现C-H/N-H活化,构建了多取代吡咯稠环3-吲哚酮类化合物,条件相对温和,后处理方便,工业前景良好。本发明为构建吡咯稠环3-吲哚酮类化合物提供了简便高效的创新性方法学,为此类骨架的药物化学研究以及复杂天然产物的全合成提供了巨大的帮助。
发明内容
本发明的目的在于提供一种吡咯稠环3-吲哚酮类化合物的合成方法,在反应溶剂中,氮气保护下,以稠环靛红类化合物和双取代乙炔类化合物为原料,在钯金属催化、氧化剂作用下,反应得到吡咯稠环3-吲哚酮类化合物。反应过程如式(I)所示:
式(I);
其中,R1、R2、R3为氢原子、烷基、环烷基、含杂原子烷基、芳基、杂芳基或卤素;R4为烷基、环烷基、含杂原子烷基、芳基、杂芳基或卤素;R1、R2、R3、R4之间成环或不成环;R5、R6为氢原子、烷基、环烷基、芳基或杂芳基;R5、R6之间成环或不成环。
本发明中,R1、R2、R3、R4、R5、R6包括但不仅仅局限于上述基团。
本发明中,在反应瓶内,惰性气体保护下,将化合物1(X mmol)、炔类化合物2(Y mmol)溶于乙腈/1,4-二氧六环(Z mL)(v/v=1∶1)中,加入钯金属(U mmol),氧化剂(V mmol),T ℃条件下反应W小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3(吡咯稠环3-吲哚酮类)。
本发明所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述钯金属为零价钯或二价钯,包括Pd(OAc)2、Pd(OTf)2、Pd(TFA)2、PdCl2、PdCl2(dppe)2、PdCl2(dppe)、PdCl2(dppb)2、PdCl2(dppb)、PdCl2(dppf)2、PdCl2(dppf)或Pd(PPh3)4。
其中,所述钯金属用量为稠环靛红类化合物的0.01-0.30当量。
其中,所述氧化剂为金属银类、金属铜类化合物,芳基过氧化物,烷基过氧化物,双氧水,臭氧或氧气,包括Ag2O、AgOTf、AgNO3、AgOAc、Ag2CO3、Ag2SO4、AgCO3CF3、Cu(OAc)2、Cu(OAc)2,Cu(TFA)2、Cu(OTf)2、CuSO4、CuCO3、CuBr2、CuCl2、CuO、CuBr2、CuI、CuBr、CuCl、Cu2O、Cu、m-CPBA、过氧苯甲酰、过氧叔丁醇、双氧水、臭氧或氧气。
其中,所述氧化剂用量为0.20当量-5.00当量。
其中,所述反应溶剂为脂肪烃类、芳烃类、卤代烷类、醇类、酯类、酮类、亚砜类、酰胺类、腈类、杂环类溶剂等,其中包括N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲醇、异丙醇、四氢呋喃、1,4-二氧六环、甲苯、乙腈、二氯乙烷、氯仿、丙酮、二甲亚砜之任意一种或任意组合。
其中,所述稠环靛红类化合物浓度为0.05mmol/L-5.00mmol/L,所述双取代乙炔类化合物浓度为0.05mmol/L-5.00mmol/L。
其中,所述双取代乙炔类化合物当量数为2.00当量-8.00当量。
其中所述反应在25-180℃温度下进行。
本发明中的优点在于,本发明合成方法中所使用的各原料简单易得,均为工业化商品,来源广泛,价格低廉,并且性质稳定,保存条件不苛刻;其次,此合成方法路线简短,利用C-H/N-H键活化,一步构建吡咯稠环3-吲哚酮类化合物,原子经济性高、效能优越,实现了该体系化学合成的突破性进展,并且将促进该体系相关药物化学研究的深层次扩展。本发明应用价值较高,为药物研发、小分子药物的高通量筛选、以及复杂天然产物的全合成提供了实用、高效的新方法。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
实施例1
惰性气体保护下,将稠环靛红类化合物1(0.20mmol)、炔类化合物2a(1.00mmol)溶于乙腈/1,4-二氧六环(2.00mL)(v/v=1∶1)中,加入醋酸钯(0.02mmol),醋酸银(0.40mmol),100℃条件下反应体系搅拌12小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3a,产率63%yield(recovered yield85%)。1H NMR(500MHz,CDCl3):δ=7.76(t,J=8.0Hz,2H),7.63(d,J=8.0Hz,1H),7.56-7.54(m,2H),7.46(t,J=8.5Hz,1H),7.38-7.30(m,8H),7.20-7.17(m,3H),7.02(dd,J=7.0,2.0Hz,2H),6.81-6.77(t,J=8.0Hz,,1H),6.67(d,J=8.5Hz,1H);13C NMR(125MHz,CDCl3):δ=179.85,144.00,138.77,136.91,134.11,132.69,132.23,131.73,131.56,131.28,130.24,129.92,129.72,129.49,129.29,128.76,128.49,128.31,128.10,127.22,127.08,126.20,125.58,121.40,120.06;HRMS(ESI)计算值C33H22NO[M+H]+448.1696,实际值448.1698.。
实施例2
操作步骤同实施例1,产率62%(原料回收后产率(recovered yield)为91%)。1H NMR(500MHz,CDCl3):δ=7.76-7.72(m,2H),7.62(d,J=8.5Hz,1H),7.54(dd,J=7.0,2.0Hz,2H),7.26(d,J=1.5Hz,1H),7.25(d,J=1.5Hz,2H),6.93(d d,J=7.0,2.0Hz,2H),6.89(t,J=2.0Hz,2H),6.84(dd,J=7.0,2.5Hz,2H),6.77(d,J=8.5Hz,1H),6.76-6.74(m,1H),3.85(s,3H),3.81(s,3H),3.78(s,3H);13C NMR(125MHz,CDCl3):δ=179.59,160.77,160.07,158.79,143.87,138.71,137.21,133.01,132.63,132.42,131.70,129.38,129.28,129.02,127.96,126.76,126.72,126.13,125.75,125.07,124.34,121.47,120.11,114.97,114.06,113.77,55.88,55.67,55.59;HRMS(ESI)计算值C36H27NNaO4[M+Na]+560.1832,实际值560.1837.。
实施例3
操作步骤同实施例1,产率52%(原料回收后产率为79%)。1H NMR(500MHz,CDCl3):δ=7.78(d,J=8.5Hz,1H),7.73(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H),7.45-7.42(m,2H),7.39-7.36(m,3H),7.30-7.26(m,4H),7.22-7.20(m,2H),6.93-6.89(m,3H),6.72(d,J=8.5Hz,1H);13C NMR(125MHz,CDCl3):δ=179.78,143.82,138.92,136.33,135.39,134.87,133.70,132.98,132.44,132.11,131.47,130.73,130.59,130.01,129.64,129.57,129.19,128.82,128.66,128.61,128.47,127.57,126.47,125.20,121.25,120.15;HRMS(ESI)计算值C33H19Cl3NNaO[M+Na]+572.0346,实际值572.0353.。
实施例4
操作步骤同实施例1,产率71%(原料回收后产率为94%)。1H NMR(500MHz,CDCl3):δ=8.15(s,1H),7.83-7.72(m,4H),7.67-7.55(m,3H),7.49-7.12(m,14H),7.05(dd,J=8.0,2.0Hz,1H),6.83-6.77(m,1H),6.69(dd,J=8.5,4.0Hz,1H);13C NMR(125MHz,CDCl3):δ=179.87,144.04,144.02,138.81,137.02,134.17,133.68,133.63,133.54,132.73,132.69,132.63,132.37,132.26,131.77,131.53,131.35,130.29,130.23,130.13,130.04,129.97,129.77,129.65,129.59,129.54,129.37,129.33,129.15,129.07,128.85,128.82,128.58,128.39,128.13,128.06,128.01,127.98,127.88,127.64,127.31,127.14,126.79,126.33,126.29,126.24,125.62,121.46,120.10;HRMS(ESI)计算值C41H25NNaO[M+Na]+570.1828,实际值560.1837.。
实施例5
操作步骤同实施例1,产率48%(原料回收后产率为87%)。1H NMR(500MHz,CDCl3):δ7.78(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.68-7.60(m,3H),7.59-7.56(m,4H),7.52-7.49(m,4H),7.39-7.36(m,1H),7.09(t,J=8.0Hz,2H),6.82-6.79(m,1H),6.50(d,J=8.5Hz,1H);13C NMR(125MHz,CDCl3):δ=179.86,143.82,139.06,137.10,135.76,134.87,134.49,132.52,132.21,131.39,130.68,130.62,130.41,129.88,129.70,128.72,128.48,128.04,126.78,126.75,126.59,125.99,125.96,125.64,125.61,124.83,123.44,121.15,120.22;HRMS(ESI)计算值C36H18F9NO[M+H]+652.1322,实际值652.1316.。
实施例6
惰性气体保护下,将稠环靛红类化合物1a(0.20mmol)、炔类化合物2a(1.00mmol)溶于DMF(2.00mL)中,加入醋酸钯(0.02mmol),醋酸银(0.40mmol),120℃条件下反应体系搅拌12小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3a,收率60%。
实施例7
惰性气体保护下,将稠环靛红类化合物1a(0.20mmol)、炔类化合物2a(0.30mmol)溶于DMF(2.00mL)中,加入醋酸钯(0.02mmol),醋酸银(0.40mmol),120℃条件下反应体系搅拌12小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3a,收率45%。
实施例8
惰性气体保护下,将稠环靛红类化合物1a(0.20mmol)、炔类化合物2a(1.00mmol)溶于DMF(2.00mL)中,加入醋酸钯(0.02mmol),醋酸铜(0.40mmol),120℃条件下反应体系搅拌12小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3a,收率40%。
实施例9
惰性气体保护下,将稠环靛红类化合物1a(0.20mmol)、炔类化合物2a(1.00mmol)溶于乙腈/1,4-二氧六环(2.00mL)(v/v=1:1)中,加入醋酸钯(0.02mmol),醋酸银(0.40mmol),140℃条件下反应体系搅拌12小时,TLC检测,反应完毕后,降至室温,二氯甲烷萃取数次,合并有机相,干燥,旋转去除溶剂得粗品,快速柱层析得产物3a,收率65%。
Claims (8)
1.一种吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,在反应溶剂中,氮气保护下,以稠环靛红类化合物和双取代乙炔类化合物为原料,在钯金属催化、氧化剂作用下,反应得到吡咯稠环3-吲哚酮类类化合物;反应过程如式(I)所示:
其中,R1、R2、R3为氢原子、烷基、环烷基、含杂原子烷基、芳基、杂芳基或卤素;R4为烷基、环烷基、含杂原子烷基、芳基、杂芳基或卤素;R1、R2、R3、R4之间成环或不成环;R5、R6为氢原子、烷基、环烷基、芳基或杂芳基;
其中,所述钯金属是Pd(OAc)2,所述氧化剂是AgOAc或Cu(OAc)2。
2.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述钯金属用量为所述稠环靛红类化合物的0.01-0.30当量。
3.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述氧化剂用量为0.20当量-5.00当量。
4.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述反应溶剂为脂肪烃类、芳烃类、卤代烷类、醇类、酯类、酮类、亚砜类、酰胺类、腈类或杂环类溶剂。
5.如权利要求4所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述反应溶剂是N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲醇、异丙醇、四氢呋喃、1,4-二氧六环、甲苯、乙腈、二氯乙烷、氯仿、丙酮、二甲亚砜之任意一种或任意组合。
6.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述稠环靛红类化合物浓度为0.05mmol/L-5.00mmol/L,所述双取代乙炔类化合物浓度为0.05mmol/L-5.00mmol/L。
7.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述双取代乙炔类化合物当量数为2.00当量-8.00当量。
8.如权利要求1所述吡咯稠环3-吲哚酮类化合物的合成方法,其特征在于,所述反应在25-180℃温度下进行。
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