CN114716288A - 一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法 - Google Patents
一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
本发明公开了一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法,将含氨基酸衍生物1、炔基溴化物2、溶剂、光催化剂和碱添加剂的均相溶液于设有光源的微流场反应装置中进行反应,收集流出液,即得含式3所示的氨基酸脱羧炔基化的化合物的反应液。本发明所提供的方法具有反应条件温和,无需金属催化剂,且使用的炔基化试剂可通过廉价易得的原料简单合成得到,反应易于放大合成等优势,为规模化生产的应用奠定了基础。
Description
技术领域
本发明属于化学合成领域,具体涉及一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法。
背景技术
氨基酸作为蛋白质的基本组成单位,是一种具有重要价值且广泛存在的有机化合物。氨基酸作为重要的有机合成砌块,其绿色无毒的性质近年来在有机合成的应用中得到了广泛关注。氨基酸分子由于存在自由的氨基(-NH2)和羧基(-COOH)官能团,通过脱羧脱氨等方式可以高效地制备不同类型的化合物。脱羧偶联的反应方式可以选择性地脱除氨基酸分子的羧基官能团,成为有机合成构建新的C-C键的重要手段。可见光是绿色清洁的可再生能源,在有机合成中领域的应用受到了极大的青睐。可见光催化的有机合成反应具有反应条件温和、官能团兼容性好、操作简便等优点。随着众多新型高效光催化剂的开发,基于可见光催化的α-氨基酸功能化修饰的路线越来越受到人们的重视。
目前,利用光催化技术实现氨基酸脱羧炔基化的方法已有许多文献报道。Chen课题组在2015年利用Ru(bpy)3(PF6)2作为光催化剂同时添加氧化剂,实现了α-酮酸与乙炔基苯并异戊烷的脱羧炔基化(Angew.Chem.,Int.Ed.2015,54,7872)。不久之后,Waser课题组报道了使用铱配合物作为替代光催化剂的方法,直接实现了脱羧炔基化反应,无需外部的助氧化剂。同时也发现底物的范围也可以拓展到各种羧酸,包括脂肪族、α-酮基、α-氨基酸(Angew.Chem.,Int.Ed.2015,54,11200)。传统的氨基酸脱羧炔基化的方法往往伴随着光催化剂难获取、反应条件苛刻、底物范围较窄、对环境不友好等诸多缺点,这些缺点极大程度的限制了其在大规模工业生产中的投入使用。因此开发一种条件温和,原材料获取简单,绿色环保的氨基酸脱羧炔基化的方法是非常有必要的。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法。
为了解决上述技术问题,本发明公开了一种利用微流场可见光催化技术实现氨基酸脱羧炔基化的方法,其特征在于,将氨基酸衍生物1、炔基溴化物2溶于溶剂中,依次加入光催化剂和碱添加剂,配置成均相溶液,所述均相溶液泵入设有光源的微流场反应装置中进行反应,收集流出液,即得含式3所示的氨基酸脱羧炔基化的化合物的反应液;
其中,
R1选自-Ac,-Boc,-Cbz,-Ts,或氨基酸及其衍生物;优选地,R1选自-Boc、-Cbz;
R2为氨基酸上的取代基;
R3选自烷基、烷氧基、芳基、芳基衍生物、杂环、或杂环衍生物;优选地,R3选自取代或非取代苯基、联苯基或吡啶基;所述取代为烷基取代,优选为异丁烷基取代。
优选地,氨基酸衍生物1为下述结构中的任意一种:
优选地,炔基溴化物2为下述结构中的任意一种:
优选地,式3所示的氨基酸脱羧炔基化的化合物为下述结构中的任意一种:
其中,所述溶剂为乙腈(MeCN)、甲醇(MeOH)、乙酸乙酯(EA)、二氯甲烷(DCM)、四氢呋喃(THF)、1,4-二氧六环(Dioxane)、二甲基亚砜(DMSO)、N,N-二甲基甲酰胺(N,N-Dimethylformamide)、N,N-二甲基乙酰胺(N,N-Dimethylacetamide)、氯仿和丙酮中的任意一种或多种组合;优选地,所述溶剂为二甲基亚砜。
其中,所述光催化剂为三(2-(4-氟苯基)吡啶)合铱(Ir(p-F-ppy)3)、(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐([Ir(dtbbpy)(ppy)2][PF6])、三(2-苯基吡啶)合铱(fac-Ir(ppy)3)、石墨相碳化氮(g-C3N4)、10-甲基-9-均三甲苯基吖啶高氯酸盐(9-Mesityl-10-MethylacridiniuM Perchlorate)、三(2,2'-联吡啶)二氯化钌([Ru(phen)3]Cl2)、三(2,2'-联吡啶)钌二(六氟磷酸)盐(Ru(bpy)3(PF6)2)和2,4,5,6-四(9-咔唑基)-间苯二腈(4CzIPN)中的任意一种或多种组合;优选地,所述光催化剂为2,4,5,6-四(9-咔唑基)-间苯二腈(4CzIPN)。
其中,所述碱添加剂为三乙胺(Et3N)、4-二甲氨基吡啶(DMAP)、1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(DBU)、N,N-二异丙基乙胺(DIPEA)、N,N,N',N'-四甲基乙二胺(TEMED)和2,6-二甲基吡啶(2,6-LUTIDINE)中的任意一种或多种组合;优选地,所述碱添加剂为1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(DBU)。
其中,所述氨基酸衍生物1和炔基溴化物2的摩尔比为1:1~5,优选为1:2。
其中,所述氨基酸衍生物1的浓度为0.05~1mmol/mL,优选为0.1~0.5mmol/mL。
其中,所述氨基酸衍生物1、光催化剂和碱添加剂的摩尔比为1:0.01~0.03:1~2,优选为1:0.02:1.5。
其中,所述微流场反应装置包括进料泵、微流场反应器、光源和接收器;其中,进料泵依次与微流场反应器、接收器通过管道串联,微流场反应器置于光源的照射下,见图1、图2。
其中,所述微流场反应装置中微流场反应器为孔道结构,孔道数量根据需要增加或减少,其材质为全氟烷氧基烷烃(PFA);所述微流场反应器的尺寸内径为0.5~2.0mm,优选为0.5~1.0mm,进一步优选0.6mm,长度为5~20m;所述微流场反应器的体积为1~15.7mL,优选为1.0mL。
其中,所述均相溶液的泵入速率为0.1~2.0mL/min。
其中,所述反应的温度为20~30℃,优选为室温。
其中,所述反应的停留时间为30s~2.6h,优选为30s~60min,更优选30s~30min,最优选10min。
其中,所述光源为灯带或灯泡,优选为蓝色LED光源。
其中,所述光源的功率为5~60W,优选为40~60W,优选为50W。
其中,所述光源的波长为435~577nm,优选为450~470nm,进一步优选455nm。
有益效果:与现有技术相比,本发明的优势体现在:
(1)本发明是一个新颖的基于微流场可见光催化反应技术实现氨基酸脱羧炔基化的方法,通过将氨基酸衍生物和炔基溴化物用适当的溶剂溶解后,加入光催化剂2,4,5,6-四(9-咔唑基)-间苯二腈(4CzIPN)和碱1,8-二氮杂二环十一碳-7-烯(DBU),在可见光的照射条件下可以实现氨基酸的脱羧与炔基功能化反应。
(2)本发明设计的体系中无固体不溶物,不会造成微流场管路堵塞的问题,具有操作简便、安全性高、提升了表观反应速率的同时提高产物的选择性,利于规模化连续生产。
(3)本发明无需使用价格昂贵的过渡金属催化剂,大大降低了反应成本的同时解决了后处理带来的环境污染问题。
(4)本发明使用的光源为可见光,是一种可持续的能源,符合绿色化学的发展理念。
(5)本发明除了可实现单个氨基酸衍生物的脱羧炔基化修饰之外,还可以进一步衍生至多肽衍生物的炔基化修饰。
(6)本发明所使用的炔基化试剂可通过廉价易得的原料通过简单步骤进行合成,避免了原有方法所使用的复杂的炔基化试剂。
(7)本发明的产率可达73%~97%。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1本发明反应流程示意图。
图2光催化微流场反应装置。
图3为化合物2-(苯乙炔基)吡咯烷-1-羧酸叔丁酯的氢谱图。
图4为化合物2-(苯乙炔基)吡咯烷-1-羧酸叔丁酯的碳谱图。
图5为化合物2-(苯乙炔基)吡咯烷-1-羧酸苄酯的氢谱图。
图6为化合物2-(苯乙炔基)吡咯烷-1-羧酸苄酯的碳谱图。
图7为化合物(1-(4-羟基苯基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯的氢谱图。
图8为化合物(1-(4-羟基苯基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯的碳谱图。
图9为化合物(4-甲基-1-苯基-1-炔-3-基)氨基甲酸叔丁酯的氢谱图。
图10为化合物(4-甲基-1-苯基-1-炔-3-基)氨基甲酸叔丁酯的碳谱图。
图11为化合物(1-(1氢-吲哚-2-基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯的氢谱图。
图12为化合物(1-(1氢-吲哚-2-基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯的碳谱图。
图13为化合物(2-氧代-2-(2-(苯乙炔基)吡咯烷-1-基)乙基)氨基甲酸叔丁酯的氢谱图。
图14为化合物(2-氧代-2-(2-(苯乙炔基)吡咯烷-1-基)乙基)氨基甲酸叔丁酯的碳谱图。
图15为化合物2-([1,1'-联苯]-4-基乙炔基)吡咯烷-1-羧酸叔丁酯的氢谱图。
图16为化合物2-([1,1'-联苯]-4-基乙炔基)吡咯烷-1-羧酸叔丁酯的碳谱图。
图17为化合物2-((4-(叔丁基)苯基)乙炔基)吡咯烷-1-羧酸叔丁酯的氢谱图。
图18为化合物2-((4-(叔丁基)苯基)乙炔基)吡咯烷-1-羧酸叔丁酯的碳谱图。
图19为化合物2-(吡啶-3-基乙炔基)吡咯烷-1-羧酸叔丁酯的氢谱图。
图20为化合物2-(吡啶-3-基乙炔基)吡咯烷-1-羧酸叔丁酯的碳谱图。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1
先后称取(叔丁氧羰基)-L-脯氨酸43.0mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过注射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-(苯乙炔基)吡咯烷-1-羧酸叔丁酯52.1mg,产率为96%。表征数据如下(图3、4):1HNMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.31–7.24(m,3H),4.85–4.53(m,1H),3.43(d,J=62.1Hz,2H),2.16–1.87(m,4H),1.50(s,9H).13C NMR(100MHz,Chloroform-d)δ154.2,131.6,128.2,128.0,123.3,81.5,79.6,48.8,45.6,33.8,28.5,23.8.HRMS(ESI)m/z:calcd for C17H21NO2Na[M+Na]+:294.1465,found:294.1477.
实施例2
先后称取(叔丁氧羰基)-L-脯氨酸1.08g(5mmol,1.0equiv),(溴乙炔)苯1.81g(10mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯2.28g(15mmol,1.5equiv),2,4,5,6-四(9-咔唑基)-间苯二腈0.0789g(0.1mmol,2.0mmol%),加入10mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过注射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-(苯乙炔基)吡咯烷-1-羧酸叔丁酯1.19g,产率为88%。
实施例3
先后称取(苄氧羰基)-L-脯氨酸49.9mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过折射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-(苯乙炔基)吡咯烷-1-羧酸苄酯49.5mg,产率为81%。表征数据如下(图5、6):1H NMR(400MHz,Chloroform-d)δ7.49–7.23(m,10H),5.37–5.05(m,2H),4.89–4.69(m,1H),3.65–3.35(m,2H),2.22–1.89(m,4H).13CNMR(100MHz,Chloroform-d)δ154.5,137.0,131.9,131.7,128.4,128.2(3),128.1(8),128.0,127.7,127.6,123.0,89.5,66.9,48.7,46.3,34.0,23.8.HRMS(ESI)m/z:calcd for C20H19NO2Na[M+Na]+:328.1308,found:328.1309.
实施例4
先后称取叔丁氧碳基-酪氨酸56.3mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过折射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物(1-(4-羟基苯基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯58.0mg,产率为86%。表征数据如下(图7、8):1H NMR(400MHz,Chloroform-d)δ7.38–7.33(m,2H),7.32–7.26(m,3H),7.15(d,J=8.1Hz,2H),6.81–6.76(m,2H),4.84(s,2H),3.02–2.90(m,2H),1.45(s,9H).13C NMR(100MHz,Chloroform-d)δ155.0,131.6,131.0,128.3(4),128.2(8),122.7,115.2,88.2,84.2,80.2,44.9,41.4,28.4.HRMS(ESI)m/z:calcd for C21H23NO3Na[M+Na]+:360.1570,found:360.1572.
实施例5
先后称取叔丁氧碳基-缬氨酸43.5mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过折射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物((4-甲基-1-苯基-1-炔-3-基)氨基甲酸叔丁酯39.9mg,产率为73%。表征数据如下(图9、10):1HNMR(400MHz,Chloroform-d)δ7.43-7.38(m,2H),7.32–7.27(m,3H),4.94–4.73(m,1H),4.54(s,1H),2.03–1.94(m,1H),1.47(s,9H),1.05(s,3H),1.03(s,3H).13C NMR(100MHz,Chloroform-d)δ155.0,131.7,128.3,128.2,122.9,87.5,83.8,79.7,49.3,33.5,28.4,18.9,17.7.HRMS(ESI)m/z:calcd for C17H23NO2Na[M+Na]+:296.1621,found:296.1621.
实施例6
先后称取叔丁氧碳基-色氨酸60.9mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过折射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物((1-(1氢-吲哚-2-基)-4-苯基丁-3-炔-2-基)氨基甲酸叔丁酯52.6mg,产率为73%。表征数据如下(图11、12):1H NMR(400MHz,Chloroform-d)δ8.23(s,1H),7.72(d,J=7.8Hz,1H),7.37–7.23(m,6H),7.18(t,J=7.5Hz,1H),7.14–7.06(m,2H),5.11–4.76(m,2H),3.22(d,J=5.4Hz,2H),1.44(s,9H).13CNMR(100MHz,Chloroform-d)δ154.9,136.1,131.7,128.2,123.4,122.9,122.0,119.5,119.3 111.1,110.9,89.2,83.4,79.9,60.5,44.6,31.9,28.4,21.1,14.2.HRMS(ESI)m/z:calcd for C23H24N2O2Na[M+Na]+:383.1730,found:383.1733.
实施例7
先后称取叔丁氧碳基-甘氨酰-脯氨酸54.5mg(0.2mmol,1.0equiv),(溴乙炔)苯72.4mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过折射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物(2-氧代-2-(2-(苯乙炔基)吡咯烷-1-基)乙基)氨基甲酸叔丁酯55.2mg,产率为84%。表征数据如下(图13、14):1H NMR(400MHz,Chloroform-d)δ7.43–7.37(m,2H),7.33–7.26(m,3H),5.50(d,J=19.0Hz,1H),5.05–4.67(m,1H),4.22–4.12(m,1H),3.98–3.83(m,1H),3.72–3.35(m,2H),2.27–1.94(m,4H),1.45(s,9H).13C NMR(100MHz,Chloroform-d)δ167.2(d,J=86.3Hz,1C),155.9(d,J=2.1Hz,1C),131.8(d,J=9.0Hz,1C),128.4(d,J=45.0Hz,1C),128.2(d,J=18.6Hz,1C),87.6(d,J=125.7Hz,1C),83.3(d,J=210.1Hz,1C),79.6(d,J=6.4Hz,1C),48.4(d,J=23.4Hz,1C),45.6(d,J=92.7Hz,1C),43.2(d,J=2.9Hz,1C),33.5(d,J=206.3Hz,1C),28.4,23.8(d,J=190.0Hz,1C).HRMS(ESI)m/z:calcd forC19H24N2O3Na[M+Na]+:351.1679,found:351.1681.
实施例8
先后称取(叔丁氧羰基)-L-脯氨酸43.0mg(0.2mmol,1.0equiv),4-(2-溴炔基)-1,1'-联苯103mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过注射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-([1,1'-联苯]-4-基乙炔基)吡咯烷-1-羧酸叔丁酯60.5mg,产率为87%。表征数据如下(图15、16):1H NMR(400MHz,Chloroform-d)δ7.60–7.49(m,4H),7.49–7.38(m,4H),7.37–7.30(m,1H),4.91–4.53(m,1H),3.45(d,J=63.0Hz,2H),2.22–1.88(m,4H),1.51(s,9H).13C NMR(100MHz,Chloroform-d)δ154.2,140.7,140.4,132.0,128.9,127.6,127.0,126.9,122.2,90.7,81.4,79.7,48.8,45.7,33.8,28.6,23.9.HRMS(ESI)m/z:calcd forC23H25NO2Na[M+Na]+:370.1778,found:370.1777.
实施例9
先后称取(叔丁氧羰基)-L-脯氨酸43.0mg(0.2mmol,1.0equiv),4-叔丁基-(溴乙炔)苯94.9mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过注射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-((4-(叔丁基)苯基)乙炔基)吡咯烷-1-羧酸叔丁酯62.9mg,产率为96%。表征数据如下(图17、18):1H NMR(400MHz,Chloroform-d)δ7.32(t,J=5.8Hz,4H),4.82–4.53(m,1H),3.43(d,J=62.2Hz,2H),2.16–1.86(m,4H),1.50(s,9H),1.30(s,9H).13C NMR(100MHz,Chloroform-d)δ154.2,151.2,131.3,125.2,120.3,89.2,81.5,79.6,48.8,45.6,34.7,33.9,31.2,28.6,23.8.HRMS(ESI)m/z:calcd for C21H29NO2Na[M+Na]+:350.2091,found:350.2090.
实施例10
先后称取(叔丁氧羰基)-L-脯氨酸43.0mg(0.2mmol,1.0equiv),2-(苯基溴乙炔)吡啶72.8mg(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯45.7mg(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈3.16mg(0.004mmol,2.0mmol%),加入2mL的二甲基亚砜溶解后用注射器抽取并置于注射泵上待用。将反应液通过注射泵泵入微流场反应器中(盘管内径为0.6mm,体积为1mL)进行反应,设置泵入流速为0.1mL/min。用蓝色LED光源(50W,455nm)进行照射,在室温下进行反应,停留时间10min,TLC检测反应进行并收集反应液。待反应完全结束后淬灭反应并通过柱层析的方式(洗脱剂为石油醚:乙酸乙酯)分离得到最终产物2-(吡啶-3-基乙炔基)吡咯烷-1-羧酸叔丁酯45.2mg,产率为83%。表征数据如下(图19、20):1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),8.51(s,1H),7.68(d,J=6.0Hz,1H),7.23(s,1H),4.88–4.52(m,1H),3.45(d,J=51.9Hz,2H),2.16–1.91(m,4H),1.49(s,9H).13C NMR(100MHz,Chloroform-d)δ154.1,152.2,148.3,138.5,123.0,120.4,93.5,79.8,78.3,48.7,45.7,33.7,28.5,23.8.HRMS(ESI)m/z:calcd for C16H20N2O2Na[M+Na]+:295.1417,found:295.1421.
表1
[a]反应条件:称取氨基酸衍生物(0.2mmol,1.0equiv),加入到干燥的Schlenk反应管中,置换氩气三次;炔基溴化物(0.4mmol,2.0equiv),1,8-二氮杂二环十一碳-7-烯(0.3mmol,1.5equiv)2,4,5,6-四(9-咔唑基)-间苯二腈(0.004mmol,2.0mmol%)用2mL二甲基亚砜溶解,注射器注入到Schlenk反应管中。用蓝色LED光源(50W,455nm)进行照射,室温下进行反应,反应时间12h。反应结束后进行TLC检测,通过柱层析得到产物。
[b]反应条件:分别称取氨基酸衍生物(0.2mmol,1.0equiv)、炔基溴化物(0.4mmol,2.0equiv),用2mL二甲基亚砜溶解,待完全溶解后装载在注射器中。反应液泵入盘管内径为0.6mm的反应器中,体积为1mL,微流场反应器流速为0.1mL/min,用蓝色LED光源(50W,455nm)进行照射,室温下进行反应,停留时间10min。反应结束后进行TLC检测,通过柱层析得到产物。
本发明提供了一种利用光催化微通道制备氨基酸炔基化物的方法的思路及方法,具体实现该技术方案的方法和途径很多,以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (10)
2.根据权利要求1所述方法,其特征在于,所述溶剂为乙腈、甲醇、乙酸乙酯、二氯甲烷、四氢呋喃、1,4-二氧六环、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、氯仿和丙酮中的任意一种或多种组合。
3.根据权利要求1所述方法,其特征在于,所述光催化剂为三(2-(4-氟苯基)吡啶)合铱、(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐、三(2-苯基吡啶)合铱、石墨相碳化氮、10-甲基-9-均三甲苯基吖啶高氯酸盐、三(2,2'-联吡啶)二氯化钌、三(2,2'-联吡啶)钌二(六氟磷酸)盐和2,4,5,6-四(9-咔唑基)-间苯二腈中的任意一种或多种组合。
4.根据权利要求1所述方法,其特征在于,所述的碱添加剂为三乙胺、4-二甲氨基吡啶、1,8-二偶氮杂双螺环[5.4.0]十一-7-烯、N,N-二异丙基乙胺、N,N,N',N'-四甲基乙二胺和2,6-二甲基吡啶中的任意一种或多种组合。
5.根据权利要求1所述方法,其特征在于,所述氨基酸衍生物1和炔基溴化物2的摩尔比为1:1~5。
6.根据权利要求1所述方法,其特征在于,所述氨基酸衍生物1的浓度为0.05~1mmol/mL。
7.根据权利要求1所述方法,其特征在于,所述氨基酸衍生物1、光催化剂和碱添加剂的摩尔比为1:0.01~0.03:1~2。
8.根据权利要求1所述方法,其特征在于,所述微流场反应装置中微流场反应器为孔道结构,其材质为全氟烷氧基烷烃;所述微流场反应器的尺寸内径为0.5~2.0mm,长度为5~20m。
9.根据权利要求1所述方法,其特征在于,所述反应的温度为20~30℃;所述反应的停留时间为30s~2.6h。
10.根据权利要求1所述方法,其特征在于,所述光源为灯带或灯泡;所述光源的功率为5~60W;所述光源的波长为435~577nm。
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