CN107298640B - 一种亚甲基酮化合物的制备方法及其应用 - Google Patents

一种亚甲基酮化合物的制备方法及其应用 Download PDF

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CN107298640B
CN107298640B CN201710589595.2A CN201710589595A CN107298640B CN 107298640 B CN107298640 B CN 107298640B CN 201710589595 A CN201710589595 A CN 201710589595A CN 107298640 B CN107298640 B CN 107298640B
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曹子平
朱洪波
孟新
尤进茂
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Qufu Normal University
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Abstract

本发明公开了一种亚甲基酮化合物的制备方法及其应用，涉及有机合成领域，工艺包括：1)在三价金盐催化剂存在下，将芳酮化合物和卤亚甲基三烷基铵盐溶于溶剂中，2)80～130℃反应1‑4小时，分离纯化得到α‑亚甲基芳酮化合物，反应环境污染小，底物适用范围广。

Description

一种亚甲基酮化合物的制备方法及其应用
技术领域
本发明涉及有机合成领域，具体涉及一种亚甲基芳香酮或亚甲基杂环芳酮化合物的制备方法及其应用。
背景技术
1,2-二取代丙烯酮，也称亚甲基酮，是一类重要的有机结构单元，其衍生物广泛存在于天然产物和药物活性分子中。例如，利尿酸具有高效的利尿作用。同时，丙烯酮衍生物是重要的有机中间体，是合成复杂分子的重要有机原料。因此，该衍生物的合成具有重要的意义。
现有的合成路线如式①所示，主要有酮类化合物与甲醛(或多聚甲醛)在酸或碱性条件下发生羟醛缩合反应得到亚甲基酮(Bugarin,A.；Jones,K.D.and Connell,B.T.Efficient,direct a-methylenation of carbonyls mediated bydiisopropylammonium trifluoroacetate,Chem.Commun.,2010,46,1715-1717)。
Figure GDA0001369844810000011
使用醛类(如甲醛或多聚甲醛)通过羟醛缩合反应来制备α-亚甲基酮，原料具有较强的毒性。尤其在反应中，醛类化合物需要过量使用，严重污染环境。同时，该反应用到酸或碱性条件，官能团兼容性较差，底物具有较大的局限性。例如，对于酸碱敏感的底物不能兼容，易于水解的底物不能兼容，体系的适用范围受限。因此，尽管这类方法能够提供亚甲基酮的合成方案，但其反应条件苛刻，适用范围面窄，发展新的酮的α-亚甲基化反应很有必要。
发明内容
针对上述现有技术的问题，本发明的目的在于提供一种亚甲基酮化合物的制备方法，反应环境污染小，底物适用范围广。本发明目的还在于提供一种上述制备方法在药物中间体及天然产物合成中的应用，底物毒性小，分离纯化难度低。
提供一种亚甲基酮化合物的制备方法，工艺包括：1)在三价金盐催化剂存在下，将芳酮化合物和卤亚甲基三烷基铵盐溶于溶剂中，2)80～130℃反应1-4小时，分离纯化得到α-亚甲基芳酮化合物；
其中，芳酮化合物为苯基芳香酮或杂环芳酮化合物。
优选的，反应结束后于反应物中加入水将反应猝灭。通过本发明高价金盐催化体系，结合水猝灭终止工艺，能够降低末期副反应，并进一步降低反应体系毒性及纯化难度，提高收率。
优选的，所述芳酮化合物、卤亚甲基三烷基铵盐和三价金盐的物质的量比为1:(1-3):(0.02-0.2)。
优选的，在所述芳酮化合物和卤亚甲基三烷基铵盐添加过程中或添加前，将所述三价金盐加入溶剂当中，使反应在三价金盐溶液环境中进行。
优选的，所述三价金盐为三氯化金、水合氯金酸钠和氯金酸钾中的至少一种。
优选的，所述苯基芳香酮包括苯乙酮、苯丙酮、苯戊酮、取代的苯丙酮、苯甲酰乙酸酯、4-氧代-4-苯基丁酸、5-氧代-5-苯基戊酸、二芳基乙酮、茚酮、茚酮衍生物、1-四氢萘酮、1-四氢萘酮衍生物或苯并环庚酮。
优选的，所述杂环芳酮化合物为四氢咔唑酮。
所述卤亚甲基三烷基铵盐优选为氯亚甲基三烷基铵盐。优选的，所述氯亚甲基三烷基铵盐为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(简称selectfluor)、四氟硼酸化的1-(氯甲基)-1,4-二氮杂二环[2.2.2]辛烷盐，以及氯化的1-(氯甲基)-1,4-二氮杂二环[2.2.2]辛烷盐中的至少一种。上述三种氯亚甲基三烷基铵盐结构依次如式②所示。
Figure GDA0001369844810000021
本发明通过采用高价金盐作为催化剂，避免了酸碱的催化体系，扩大了官能团兼容范围。其使用氯化的铵盐代替醛类化合物，显著降低了体系毒性。
所述溶剂优选包括二甲基亚砜、N，N-二甲基甲酰铵、二氧六环、甲苯和氯仿，更优选采用二甲基亚砜。
进一步提供一种上述制备方法在药物中间体及天然产物中间体合成中的应用。
本发明所带来的综合效果包括：
该方法所用的氯亚甲基三烷基铵盐易于制备，避免了有毒醛类的使用；无酸无碱反应体系对反应底物具有更好的兼容性，扩大了底物的范围；本发明方法在药物中间体、天然产物等的合成中有很大的应用潜力。
具体实施方式
下面结合具体实施例对本发明做进一步解释说明，但应理解，本发明的范围不限于此。
实施例1-21
亚甲基酮化合物制备方法的工艺步骤包括：在单口烧瓶中，加入1.0mmol芳酮化合物、1.2mmol selectfluor和0.05mmol二水合氯金酸钠，溶于4毫升二甲基亚砜中；100摄氏度下反应2小时；停止反应，向体系中加入水淬灭反应，再分三次各加入7毫升乙酸乙酯萃取，合并有机相，每次用5毫升水洗三次，无水硫酸钠干燥；柱层析提纯得α-亚甲基芳酮。芳酮化合物为苯基芳香酮或杂环芳酮化合物。
所述苯基芳香酮包括苯乙酮、苯丙酮、苯戊酮、取代的苯丙酮、苯甲酰乙酸酯、4-氧代-4-苯基丁酸、5-氧代-5-苯基戊酸、二芳基乙酮、茚酮、茚酮衍生物、1-四氢萘酮、1-四氢萘酮衍生物或苯并环庚酮。
所述杂环芳酮化合物为四氢咔唑酮。
本发明制备方法反应机理如式③所示。具体地，以实施例1中1-四氢萘酮为例，金活化羰基形成络合物A，失去质子，形成烯醇负离子B，作为亲核试剂，与铵盐发生SN2(即双分子亲核取代反应)取代反应(相近的胺离去)，得到中间体C，最终消除一分子HCl得到亚甲基酮产品。
Figure GDA0001369844810000031
将上述制备方法用于药物中间体及天然产物中间体的合成。
本发明实施例中芳酮化合物(表中简称芳香酮)、相应产物及其分离产率如表1所示。从表中可以看出，本发明方法适用于多官能团体系的芳酮亚甲基化反应，反应底物兼容性好，并且分离产率除反应物苯乙酮外均在75％以上，最高达97％。并且苯乙酮也高达38％。因此本发明不仅适用范围广，在天然产物等有机中间体合成中，还能获得优异的分离产率，获得了满意的技术效果。
表1亚甲基芳酮反应物、产物及其分离产率
Figure GDA0001369844810000041
通过本发明制备方法制得各亚甲基酮化合物核磁共振谱图数据如下：
实施例1
2-Methylene-3,4-dihydronaphthalen-1(2H)-one.Colorless oil；yield142.0mg,90％；Rf＝0.77(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ8.12(d,J＝7.8Hz,1H),7.48(dd,J＝7.5,7.4Hz,1H),7.35(dd,J＝7.7,7.5Hz,1H),7.25(d,J＝7.8Hz,1H),6.23(d,J＝1.6Hz,1H),5.45(d,J＝1.6Hz,1H),3.00(t,J＝6.7Hz,2H),2.86(t,J＝6.7Hz,2H)；13C NMR(125.8MHz,CDCl3):δ187.6,144.1,143.4,133.4,133.1,128.5,128.2,127.0,121.7,31.7,29.7.
实施例2
6-Methoxy-2-methylene-3,4-dihydronaphthalen-1(2H)-one.Colorless oil；yield 148.2mg,79％；Rf＝0.68(hexanes/EtOAc＝5/1)；1H NMR(500MHz,CDCl3):δ8.07(d,J＝8.7Hz,1H),6.84(dd,J＝8.7,2.5Hz,1H),6.68(d,J＝2.5Hz,1H),6.17(d,J＝1.5Hz,1H),5.39(dd,J＝3.3,1.6Hz,1H),3.85(s,3H),2.95(t,J＝6.1Hz,2H),2.82(t,J＝6.1Hz,2H)；13C NMR(125.8MHz,CDCl3):δ186.4,163.6,146.6,143.4,130.6,126.6,120.9,113.3,112.4,55.4,31.7,30.0.
实施例3
3-Methylene-2,3-dihydro-1H-carbazol-4(9H)-one.White solid,m.p.172-173℃；yield 163.5mg,83％；Rf＝0.68(hexanes/EtOAc＝1/1)；1H NMR(500MHz,DMSO-d6):δ12.0(s,1H),8.03(d,J＝6.9Hz,1H),7.42(d,J＝7.0Hz,1H),7.24-7.14(m,2H),5.91(s,1H),5.39(s,1H),3.06(t,J＝6.5Hz,2H),2.90(t,J＝6.3Hz,2H)；13C NMR(125.8MHz,CDCl3):δ182.7,152.9,145.0,136.9,125.4,123.3,122.2,120.9,118.3,112.9,112.2,31.2,23.5.
实施例4
2-Methylene-2,3-dihydro-1H-inden-1-one.Yellow oil；yield 114.9mg,80％；Rf＝0.33(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.86(d,J＝7.7Hz,1H),7.59(ddd,J＝7.6,7.3,0.9Hz,1H),7.48(d,J＝7.7Hz,1H),7.39(dd,J＝7.6,7.4Hz,1H),6.37-6.34(m,1H),5.64-5.61(m,1H),3.75(s,2H)；13C NMR(125.8MHz,CDCl3):δ193.4,149.8,143.3,138.2,134.8,127.5,126.3,124.6,119.2,31.7.
实施例5
5,6-Dimethoxy-2-methylene-2,3-dihydro-1H-inden-1-one.White solid,m.p.92-94℃；yield 177.0mg,87％；Rf＝0.54(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ7.28(s,1H),6.89(s,1H),6.28-6.25(m,1H),5.55-5.52(m,1H),3.97(s,3H),3.92(s,3H),3.64(s,2H)；13C NMR(125.8MHz,CDCl3):δ192.1,155.6,149.6,145.2,
143.8,131.3,117.6,107.2,105.1,56.2,56.1,31.5.
实施例6
6-Methylene-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one.White solid,m.p.95-96C；yield 138.9mg,81％；Rf＝0.68(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.73(dd,J＝7.7,1.2Hz,1H),7.45(ddd,J＝7.5,7.5,1.4Hz,1H),7.33(ddd,J＝7.5,7.5,1.0Hz,1H),7.17(d,J＝7.5Hz,1H),6.24(d,J＝2.0Hz,1H),5.44-5.41(m,1H),2.81(t,J＝7.0Hz,2H),2.37(t,J＝6.8Hz,2H),1.96-1.89(m,2H)；13C NMR(125.8MHz,CDCl3):δ197.4,146.1,139.9,138.2,132.5,129.0,128.9,126.9,123.4,30.9,29.2,26.8.
实施例7
1-Phenylprop-2-en-1-one.Light yellow oil；yield 50.1mg,38％；Rf＝0.76(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.97-7.93(m,2H),7.58(ddd,J＝7.4,7.4,1.2Hz,1H),7.51-7.46(m,2H),7.16(dd,J＝17.2,10.6Hz,1H),6.44(dd,J＝17.2,1.7Hz,1H),5.94(dd,J＝10.6,1.7Hz,1H)；13C NMR(125.8MHz,CDCl3):δ191.1,137.3,133.0,132.4,130.2,128.7,128.6.
实施例8
2-Methyl-1-phenylprop-2-en-1-one.Colorless oil；yield 113.5mg,78％；Rf＝0.76(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.23(d,J＝7.5Hz,2H),7.52(dd,J＝7.5,7.3Hz,1H),7.42(dd,J＝7.5,7.5Hz,2H),5.90(s,1H),5.62(s,1H),2.07(s,3H)；13CNMR(125.8MHz,CDCl3):δ198.3,143.7,137.7,131.9,129.3,128.1,127.0,18.6.
实施例9
2-Methylene-1-phenylpentan-1-one.Colorless oil；yield 142.3mg,82％；Rf＝0.81(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.76(dd,J＝8.4,1.4Hz,2H),7.53(dd,J＝7.5,7.4Hz,1H),7.43(dd,J＝7.8,7.5Hz,2H),5.81(d,J＝1.0Hz,1H),5.58(s,1H),2.45(t,J＝7.6Hz,2H),1.59-1.49(m,2H),0.97(t,J＝7.4Hz,3H)；13C NMR(125.8MHz,CDCl3):δ198.4,148.2,137.9,132.1,129.5,128.1,125.2,34.3,21.3,13.8.
实施例10
2-Methyl-1-(p-tolyl)prop-2-en-1-one.Light yellow oil；yield 137.5mg,86％；Rf＝0.76(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.66(d,J＝8.2Hz,2H),7.23(d,J＝8.0Hz,2H),5.87-5.84(m,1H),5.59-5.57(m,1H),2.40(s,3H),2.06(dd,J＝1.2,1.1Hz,3H)；13C NMR(125.8MHz,CDCl3):δ198.1,143.8,142.7,134.9,129.6,128.8,126.0,21.5,18.8.
HRMS(ESI)m/zcalcd for C11H13O(M+H)+161.0961,found 161.0960.
实施例11
1-(4-Hydroxyphenyl)-2-methylprop-2-en-1-one.Colorless oil；yield131.2mg,81％；Rf＝0.7(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ7.75(ddd,J＝8.8,2.6,1.9Hz,2H),7.35(b,1H),6.90(ddd,J＝8.7,2.6,1.9Hz,2H),5.84-5.83(m,1H),5.57-5.55(m,1H),2.07(s,3H)；13C NMR(125.8MHz,CDCl3):δ198.5,160.6,143.7,132.4,129.4,125.5,115.3,19.1.
实施例12
1-(4-Fluorophenyl)-2-methylprop-2-en-1-one.Colorless oil；yield139.0mg,85％；Rf＝0.76(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.78(dd,J＝8.8,5.5Hz,2H),7.11(dd,J＝8.7,8.6Hz,2H),5.91-5.88(m,1H),5.58(s,1H),2.07(s,3H)；13C NMR(125.8MHz,CDCl3):δ196.8,165.2(d,J＝253.3Hz),143.7,133.8(d,J＝3.3Hz),132.0(d,J＝9.1Hz),126.5,115.3(d,J＝21.8Hz),18.7.
实施例13
1-(4-Chlorophenyl)-2-methylprop-2-en-1-one.Colorless oil；yield169.5mg,94％；Rf＝0.76(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.67(ddd,J＝8.5,2.3,1.9Hz,2H),7.40(ddd,J＝8.5,2.3,1.9Hz,2H),5.92-5.89(m,1H),5.60-5.57(m,1H),2.05(s,3H)；13C NMR(125.8MHz,CDCl3):δ197.0,143.6,138.4,135.9,130.8,128.4,127.0,18.6.
实施例14
1-(2-Hydroxyphenyl)-2-methylprop-2-en-1-one.Colorless oil；yield145.8mg,90％；Rf＝0.83(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ11.9(s,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.48(ddd,J＝7.8,7.8,1.7Hz,1H),7.01(dd,J＝8.4,0.8Hz,1H),6.87(ddd,J＝7.7,7.6,1.1Hz,1H),5.75-5.70(m,1H),5.43(s,1H),2.09(dd,J＝1.2,1.1Hz,3H)；13C NMR(125.8MHz,CDCl3):δ203.4,163.1,142.6,136.3,132.7,123.0,118.5,118.4,118.3,19.4.
HRMS(ESI)m/zcalcd for C10H11O2(M+H)+163.0754,found 163.0752.
实施例15
Ethyl 2-benzoylacrylate.Colorless oil；yield 153.2mg,75％；Rf＝0.42(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ7.86(dd,J＝8.0,1.3Hz,2H),7.59(ddd,J＝7.5,7.4,1.2Hz,1H),7.46(dd,J＝8.0,7.5Hz,2H),6.69(d,J＝0.6Hz,1H),6.06(d,J＝0.6Hz,1H),4.22(q,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H)；13C NMR(125.8MHz,CDCl3):δ193.2,164.3,141.5,136.3,133.5,131.3,129.4,128.5,61.5,13.9.
实施例16
3-Benzoylbut-3-enoic acid.Colorless oil；yield 163.4mg,86％；Rf＝0.31(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ7.78(dd,J＝8.4,1.4Hz,2H),7.56(ddd,J＝7.4,1.2,1.2Hz,1H),7.44(dd,J＝7.8,7.6Hz,2H),6.05(s,1H),5.83(s,1H),3.57(s,2H)；13C NMR(125.8MHz,CDCl3):δ197.2,175.9,140.5,136.9,132.5,129.9,129.7,128.3,37.9.
实施例17
4-Benzoylpent-4-enoic acid.Colorless oil；yield 159mg,78％；Rf＝0.43(hexanes/EtOAc＝1/1)；1H NMR(500MHz,CDCl3):δ10.2(b,1H),7.72(dd,J＝8.4,1.2Hz,2H),7.54(dd,J＝7.4,7.4Hz,1H),7.43(dd,J＝7.8,7.6Hz,2H),5.94(s,1H),5.69(s,1H),2.81(t,J＝7.4Hz,2H),2.63(dd,J＝7.4Hz,2H)；13C NMR(125.8MHz,CDCl3):δ197.8,178.9,146.0,137.6,132.3,129.5,128.2,127.2,32.6,27.3.HRMS(ESI)m/zcalcd for C12H13O3(M+H)+205.0859,found 205.0864.
实施例18
1,2-Diphenylprop-2-en-1-one.Yellow oil；yield 183.3mg,88％；Rf＝0.61(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.92(d,J＝7.4Hz,2H),7.56(dd,J＝7.4,7.4Hz,1H),7.47-7.42(m,4H),7.39-7.31(m,3H),6.08(s,1H),5.65(s,1H)；13C NMR(125.8MHz,CDCl3):δ197.5,148.3,137.1,137.0,133.1,130.0,128.6,128.4,128.3,127.0,120.9.
实施例19
1-(4-Methoxyphenyl)-2-phenylprop-2-en-1-one.Yellow oil；yield 201.7mg,85％；Rf＝0.32(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.92(ddd,J＝8.8,2.8,1.9Hz,2H),7.45-7.41(m,2H),7.37-7.28(m,3H),6.91(ddd,J＝8.8,2.8,1.9Hz,2H),6.00(s,1H),5.56(s,1H),3.86(s,3H)；13C NMR(125.8MHz,CDCl3):δ196.3,163.7,148.5,137.1,132.4,129.8,128.6,128.3,126.8,118.9,113.7,55.5.
实施例20
1-(4-Chlorophenyl)-2-phenylprop-2-en-1-one.Yellow oil；yield 234.5mg,97％；Rf＝0.71(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.84(ddd,J＝8.6,2.3,1.9Hz,2H),7.43-7.38(m,4H),7.38-7.32(m,3H),6.07(s,1H),5.65(s,1H)；13C NMR(125.8MHz,CDCl3):δ196.2,148.0,139.6,136.7,135.4,131.4,128.8,128.7,128.6,127.0,121.1.
实施例21
2-(4-Chlorophenyl)-1-phenylprop-2-en-1-one.Yellow oil；yield 228.0mg,94％；Rf＝0.69(hexanes/EtOAc＝20/1)；1H NMR(500MHz,CDCl3):δ7.89(d,J＝7.4Hz,2H),7.57(dd,J＝7.5,7.3Hz,1H),7.45(dd,J＝7.7,7.7Hz,2H),7.37(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,2H),6.08(s,1H),5.68(s,1H)；13C NMR(125.8MHz,CDCl3):δ197.1,147.0,136.9,135.4,134.4,133.2,129.9,128.8,128.5,128.4,121.8.
虽然本发明已作了详细描述，但对本领域技术人员来说，在本发明精神和范围内的修改将是显而易见的。此外，应当理解的是，本发明记载的各方面、不同具体实施方式的各部分、和列举的各种特征可被组合或全部或部分互换。在上述的各个具体实施方式中，那些参考另一个具体实施方式的实施方式可适当地与其它实施方式组合，这是将由本领域技术人员所能理解的。此外，本领域技术人员将会理解，前面的描述仅是示例的方式，并不旨在限制本发明。

Claims (7)

1.一种亚甲基酮化合物的制备方法，其特征在于，工艺包括：1)在三价金盐催化剂存在下，将芳酮化合物和卤亚甲基三烷基铵盐溶于溶剂中，2)80～130℃反应1-4小时，分离纯化得到α-亚甲基芳酮化合物；
其中，芳酮化合物为苯基芳香酮或杂环芳酮化合物；所述卤亚甲基三烷基铵盐为1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐；所述三价金盐为二水合氯金酸钠。
2.根据权利要求1所述的制备方法，其特征在于，反应结束后于反应物中加入水将反应猝灭。
3.根据权利要求1所述的制备方法，其特征在于，所述芳酮化合物、卤亚甲基三烷基铵盐和三价金盐的物质的量比为1:(1-3):(0.02-0.2)。
4.根据权利要求1所述的制备方法，其特征在于，在所述芳酮化合物和卤亚甲基三烷基铵盐添加过程中或添加前，将所述三价金盐加入溶剂当中，使反应在三价金盐溶液环境中进行。
5.根据权利要求1所述的制备方法，其特征在于，所述苯基芳香酮包括苯乙酮、苯丙酮、苯戊酮、取代的苯丙酮、苯甲酰乙酸酯、4-氧代-4-苯基丁酸、5-氧代-5-苯基戊酸、二芳基乙酮、茚酮、茚酮衍生物、1-四氢萘酮、1-四氢萘酮衍生物或苯并环庚酮；和或
所述杂环芳酮化合物为四氢咔唑酮。
6.根据权利要求1所述的制备方法，其特征在于，所述溶剂为二甲基亚砜、N，N-二甲基甲酰铵、二氧六环、甲苯和氯仿中的至少一种。
7.一种如权利要求1-6中任一项所述制备方法在药物中间体及天然产物中间体合成中的应用。
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