CN114426510B - 一种全取代β-内酰胺的合成方法 - Google Patents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/568—Four-membered rings
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Abstract
本发明属于有机化工医药领域,涉及一种全取代β‑内酰胺的合成方法。本发明以羟基苯胺衍生物、芳基或乙烯基重氮化合物、取代环丁烯酮为原料,铑盐作为催化剂,再加入适量的溶剂,密封充氩气反应,先在室温附近搅拌反应一段时间,再升温反应一段时间,反应结束后减压蒸去溶剂,产物经硅胶柱层析或重结晶分离得到目标产物;实现了三组分串联一锅法合成全取代β‑内酰胺类化合物。本方法优点有:原料易得、底物适应性广、反应操作简单、效率高、原子经济和非对映选择性性高。副产物仅为N2和H2O,较为符合绿色化学的要求。
Description
技术领域
本发明属于有机化工医药领域,涉及一种金属铑盐催化三组分串联反应合成高非対映选择性的全取代β-内酰胺的方法。
背景技术
β-内酰胺类化合物是一类具有良好生物活性的化合物,广泛被用于抗生素,同时也是重要的有机合成前体化合物,在医药、有机合成中也发挥着重要的作用[Alcaide,B.,et al.Chem.Rev.2007,107,4437;Pitts,C.R.,et al.Chem.Rev.2014,114,7930;Saidjalolov,S.et al.Chem.Eur.J.2021,27,7687.]
因此,β-内酰胺的合成方法研究较为广泛,主要可以分为分子内环化和分子间环化。分子内环化反应合成β-内酰胺往往是多步反应过程,操作繁琐,分子间环化是更高效的方法[Pitts,C.R.,et al.Chem.Rev.2014,114,7930;Szostak,M.,et al.Chem.Rev.2013,113,5701;Pedroni,J.,et al.Angew.Chem.,Int.Ed.2014,53,9064.Xu,X.,etal.Chem.Sci.2015,6,2196l;Shu,T.,et al.Angew.Chem.,Int.Ed.2018,57,10985]。其中最有效的方法之一是利用Staudinger反应,即烯酮与亚胺反正[2+2]环加成反应得到β-内酰胺[Staudinger,H.,et al.Liebigs Ann.Chem.1907,40,1145;Staudinger,H.,etal.Liebigs Ann.Chem.1907,40,1149.]。特别是在合成具有光学活性的全取代β-内酰胺中,该方法非常有效[Cossio,F.P.,et al.Acc.Chem.Res.2008,41,925.]。由于烯酮不是很稳定,所以目前多先用酰氯在强碱条件下或者用易爆的重氮化合物经过Wolff重排合成不稳定的烯酮再和亚胺环加成。不仅操作复杂,而且大大限制了全取代β-内酰胺的结构多样性,不利于β-内酰胺类药物的合成研发。多组分串联合成全取代β-内酰胺是非常重要的绿色合成法[Mandler,M.D.,et al.Org.Lett.2014,16,740]。最近我们组实现了铑催化羟基苯胺与重氮化合物原位生成亚胺,并进一步与重氮化合物或者烯炔酮原位生成的烯酮反应得到丰富的全取代β-内酰胺[Chen,L.,et al.Org.Lett.2019,21,3804;Chen,L.,etal.Org.Lett.2019,21,4124.]。虽然使用烯基重氮也可以引入烯基,但是烯基重氮合成相对难,稳定性差,特别是最优条件必须使用到1.8个当量,反应时间长,对于放大工业生产非常不利。而使用烯炔酮得到的β-内酰胺无法3-位引入更容易后继衍生的烯基。
为了可以在β-内酰胺的3-位更方便地引入更容易后继衍生的烯基,丰富全取代β-内酰胺的结构,并使用更稳定的烯酮前体—环丁烯酮,我们实现了用铑盐为催化剂,使用廉价易得的羟基苯胺和易合成的重氮化合物和更加稳定的环丁烯酮为原料,高效方便的一锅三组分合成具有丰富结构的全取代β-内酰胺的新方法,该方法具有原子经济性高,一锅法操作简便、非对映选择性高等特点。
发明内容
本发明属于有机化工医药领域,涉及一种铑金属催化三组分串联反应合成高非対映选择性的全取代β-内酰胺的方法。
本发明以一锅法合成全取代β-内酰胺类化合物,反应首先加入羟基苯胺衍生物,重氮化合物以及铑催化剂,再加入适量的溶剂并用氩气保护,在25~35℃下搅拌反应一定时间,反应结束后加入环丁烯酮衍生物升温至50℃~110℃反应1~3小时,待反应结束后减压蒸去溶剂,以硅胶吸附,通过柱层析或混合溶剂重结晶分离得到目标产物;实现了以羟基苯胺衍生物、重氮化合物、环丁烯酮衍生物为原料,通过简单的一锅投料法合成全取代的β-内酰胺。所有产物其结构经1H NMR、13C NMR、HRMS和熔点确证,4daa结构经X射线单晶衍射确定。该反应投料的方式简便,底物适应性较广。
反应后用柱色谱分离方法提纯,以石油醚与乙酸乙酯的混合溶剂为洗脱剂或者以乙酸乙酯/石油醚体系为重结晶溶剂,对产物进行提纯以得到纯净的全取代的β-内酰胺产物。
全取代β-内酰胺产物合成方法为:
所用的铑催化剂包括:Rh2(OAc)4、Rh2(cap)4、Rh2(TFA)4、Rh2(esp)2、Rh2(OPiv)4,其用量为羟基苯胺化合物摩尔数的0.5~2%,其中最佳催化剂为Rh2(esp)2,用量为羟基苯胺化合物摩尔数的1%。
羟基苯胺衍生物为下述结构:
重氮化合物包括下述结构:
环丁烯酮衍生物为下述结构:
芳基或者烯基重氮化合物的用量为羟基苯胺类化合物用量的1~2当量,取代环丁烯酮的用量为羟基苯胺化合物用量的1~2当量。最优当量比为:羟基苯胺衍生物:重氮化合物:取代环丁烯酮摩尔比为=1:1.2:1.1。
先加入重氮化合物以及铑催化剂,再加入适量的溶剂,在25~35℃下搅拌反应一定时间,密封充氩气保护,反应结束后加入环丁烯酮衍生物升温至50℃~110℃反应1~3h左右,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到产物,或者用乙酸乙酯/石油醚混合溶剂体系进行重结晶提纯。
所述反应溶剂为有机溶剂。具体的有机溶剂为N,N-二甲基甲酰胺、乙腈、甲苯、二甲苯、四氢呋喃、1,4-二氧六环、1,2-二氯乙烷,乙腈、二氯甲烷、三氯甲烷中的一种。最优溶剂为1,2-二氯乙烷。
羟基苯胺在溶剂中的浓度为0.025~0.2mol/L,最佳浓度为0.05mol/L。
本发明合成了全取代β-内酰胺。
有益效果:
1).反应原料易得,容易制备。
2).反应操作简单,中间产物无需分离即可进行下一步反应,可以实现三组分串联反应。
3).反应条件较为温和,特别是反应时间较短,效率高。
4).原子经济性较高,生成的副产物仅为N2和H2O,较符合绿色化学的要求。
5).底物适应性广,产率中等至较高,具有很高的非对映选择性,并且在生成的β-内酰胺中引入了烯基,以方便的进行延伸,有益于后继高效药物筛选提供分子库。
附图说明:
图1为实施例1得到的4aaa的1H-NMR(核磁氢谱);
图2为实施例1得到的4aaa的13C-NMR(核磁碳谱);
图3为实施例1得到的4aaa的HRMS(高分辨质谱);
图4为实施例24得到的4daa的单晶结构图。
具体实施方式
下面结合实施例对本发明做进一步描述,但不限于此。
实施例1
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE(1,2-二氯乙烷)。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 32.2mg,收率84%。(非对映选择性dr>20:1),m.p.88.6–91.9℃;1H NMR(300MHz,CDCl3)δ7.58–7.52(m,2H),7.38–7.33(m,5H),7.32–7.26(m,5H),7.26–7.21(m,2H),7.11–7.04(m,1H),5.70(s,1H),5.56(s,1H),4.62(d,J=0.6Hz,1H),3.61(s,3H).13C NMR(75MHz,CDCl3)δ168.4,164.6,140.0,139.1,137.0,135.3,128.9,128.8,128.4,128.2,126.8,126.3,124.4,118.2,117.7,71.9,69.6,52.4.HRMS(ESI)m/z:[M+H]+Calcd.for C25H22NO3 +384.1594,Found 384.1590.
实施例2
放大反应:向带回流冷凝装置的100mL反应瓶中依次加入羟基苯胺1a392.4mg(3.6mmol),苯基重氮甲酯2a 760.6mg(4.32mmol),3-苯基环丁烯酮3a 570.5mg(3.96mmol)随后加入催化剂Rh2(esp)2 28.8mg(0.036mmol),30mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 1.13g,收率82%。放大反应效果较好,拥有一定的工业生产价值。
实施例3
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(OAc)4 0.4mg(0.001mmol),2mL DCM(二氯甲烷)。密封充氩气反应。反应先在35℃下反应1h,随后升温至50℃反应3h,反应结束后减压蒸去溶剂,收率<5%。
实施例4
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(cap)4 0.6mg(0.001mmol),2mL DCM。密封充氩气反应。反应先在35℃下反应1h,随后升温至50℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 11.5mg,收率30%。
实施例5
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(TFA)4 0.6mg(0.001mmol),2mL DCM。密封充氩气反应。反应先在35℃下反应1h,随后升温至50℃反应3h,反应结束后减压蒸去溶剂,收率<5%。
实施例6
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCM。密封充氩气反应。反应先在35℃下反应1h,随后升温至50℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 26.8mg,收率70%。
实施例7
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(OPiv)4 0.6mg(0.001mmol),2mL DCM。密封充氩气反应。反应先在35℃下反应1h,随后升温至50℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 21.8mg,收率57%。
实施例8
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL CHCl3密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 19.5mg,收率51%。
实施例9
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL THF,密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,收率<5%。
实施例10
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 29.9mg,收率78%。
实施例11
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL甲苯,密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 29.5mg,收率77%。
实施例12
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL MeCN,密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,收率<5%。
实施例13
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DMF,密封充氩气反应。反应先在35℃下反应1h,随后升温至80℃反应3h,反应结束后减压蒸去溶剂,收率<5%。
实施例14
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应1h,随后升温至60℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 56.69mg,收率74%。
实施例15
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应1h,随后升温至90℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 31.0mg,收率81%。
实施例16
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应1h,随后升温至110℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 30.6mg,收率80%。
实施例17
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应2h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 31.8mg,收率83%。
实施例18
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮甲酯2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)2 0.76mg(0.001mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应40min,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 29.1mg,收率76%。
实施例19
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)20.76mg(0.001mmol),4mL DCE,密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 28.7mg,收率75%。
实施例20
向反应管中依次加入羟基苯胺1a 43.6mg(0.4mmol),苯基重氮2a 84.4mg(0.48mmol),3-苯基环丁烯酮3a 63.2mg(0.44mmol)随后加入催化剂Rh2(esp)2 3.04mg(0.004mmol),2mL DCE,密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 124.1mg,收率81%。
实施例21
向反应管中依次加入羟基苯胺1a 10.9mg(0.1mmol),苯基重氮2a 21.1mg(0.12mmol),3-苯基环丁烯酮3a 15.8mg(0.11mmol)随后加入催化剂Rh2(esp)20.76mg(0.001mmol),2mL THF,密封充氩气反应。反应先在35℃下反应1h,随后升温至90℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aaa 28.0mg,收率73%。
实施例22
向反应管中依次加入N-(对甲苯基)羟胺1b 36.9mg(0.3mmol),苯基重氮甲酯2a63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4baa 65mg,收率54%(非对映选择性dr>20:1),m.p.99.8–103.7℃;1H NMR(400MHz,CDCl3)δ7.59–7.54(m,2H),7.39–7.36(m,3H),7.32–7.26(m,7H),7.08(d,J=8.3Hz,2H),5.72(s,1H),5.59(s,1H),4.64(s,1H),3.63(s,3H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ168.5,164.3,140.0,139.2,135.4,134.6,134.0,129.3,128.9,128.7,128.4,128.1,126.8,126.3,118.1,117.6,71.8,69.5,52.3,20.9.HRMS(ESI)m/z:[M+H]+Calcd.for C26H26NO3 +398.1751,Found 398.1744.
实施例23
向反应管中依次加入N-(间甲苯基)羟胺1c 36.9mg(0.3mmol),苯基重氮甲酯2a63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4caa 73mg,收率61%(非对映选择性dr>20:1),m.p.129.8–132.5℃;1H NMR(400MHz,CDCl3)δ7.56–7.51(m,2H),7.41(s,1H),7.37–7.33(m,3H),7.29–7.28(m,3H),7.26–7.23(m,2H),77.09(t,J=7.8Hz,1H),6.90(t,J=8.0Hz,2H),5.69(s,1H),5.56(s,1H),4.60(s,1H),3.61(s,3H),2.29(s,3H).13C NMR(100MHz,CDCl3)δ168.4,164.5,139.9,139.5,138.9,137.0,135.4,128.8,128.7,128.5,128.4,128.2,126.8,126.3,125.2,119.0,117.7,115.0,71.8,69.5,52.4,21.6.HRMS(ESI)m/z:[M+H]+Calcd.for C26H24NO3 +398.1751,Found 398.1749.
实施例24
向反应管中依次加入N-(2,6-二甲基苯基)羟胺1d 41.1mg(0.3mmol),苯基重氮甲酯苯基重氮甲酯2a 63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4daa 97mg,收率78%(非对映选择性dr>20:1),m.p.188.2–192.0℃;1H NMR(400MHz,CDCl3)δ7.53(d,J=7.2Hz,2H),7.45–7.31(m,6H),7.29–7.27(m,2H),7.17–7.13(m,2H),6.86(s,1H),5.81(s,1H),5.73(s,1H),5.36(s,1H),3.41(s,3H),2.72(s,3H),1.25(s,3H).
13C NMR(100MHz,CDCl3)δ170.1,167.1,141.3,140.4,139.7,138.7,135.2,132.0,129.2,129.0,128.9,128.5,128.0,127.5,126.5,118.8,77.1,59.8,52.0,20.2,18.6.HRMS(ESI)m/z:[M+H]+Calcd.for C27H26NO3 +412.1907,Found 412.1909.
实施例25
向反应管中依次加入N-(对甲氧基苯基)羟胺1e 41.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4eaa 76mg,收率61%(非对映选择性dr>20:1),m.p.194.7–197.6℃;1H NMR(400MHz,CDCl3)δ7.59–7.53(m,2H),7.41–7.36(m,3H),7.39–7.27(m,7H),6.84–6.77(m,2H),5.73(s,1H),5.58(s,1H),4.65(s,1H),3.77(s,3H),3.63(s,3H).13C NMR(75MHz,CDCl3)δ168.6,164.1,156.4,140.1,139.2,135.4,130.4,128.9,128.8,128.3,128.1,126.8,126.3,120.0,117.6,114.0,72.2,69.3,55.4,52.3.HRMS(ESI)m/z:[M+Na]+Calcd.for C26H23NNaO4 +436.1519,Found 436.1524.
实施例26
向反应管中依次加入N-(4-氯苯基)羟胺1f 42.9mg(0.3mmol),苯基重氮甲酯2a63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4faa 95mg,收率76%(非对映选择性dr>20:1),m.p.133.6–135.7℃;1H NMR(400MHz,CDCl3)δ7.55–7.50(m,2H),7.40–7.35(m,3H),7.33–7.23(m,7H),7.23–7.16(m,2H),5.70(s,1H),5.53(s,1H),4.64(s,1H),3.61(s,3H).13C NMR(100MHz,CDCl3)δ168.2,164.5,139.9,139.0,135.5,134.9,129.5,129.1,129.0,128.9,128.4,128.2,126.7,126.2,119.5,117.6,72.2,69.8,52.4.
HRMS(ESI)m/z:[M+H]+Calcd.for C25H21 35ClNO3 +418.1204,Found 418.1216.
实施例27
向反应管中依次加入N-(4-溴苯基)羟胺1g 56.1mg(0.3mmol),苯基重氮甲酯2a63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4gaa 92mg,收率66%(非对映选择性dr>20:1),m.p.138.2–139.7℃;1H NMR(400MHz,CDCl3)δ7.60–7.53(m,2H),7.42–7.37(m,5H),7.33–7.25(m,7H),5.74(s,1H),5.57(s,1H),4.68(s,1H),3.64(s,3H).13C NMR(100MHz,CDCl3)δ168.2,164.5,139.9,139.0,136.0,134.9,131.9,129.1,128.4,128.3,126.7,126.2,119.8,117.6,117.2,72.2,69.9,52.5.HRMS(ESI)m/z:[M+H]+Calcd.for C25H21 79BrNO3 +462.0699,Found462.0690;[M+H]+Calcd.for C25H21 81BrNO3 +464.0679,Found 464.0680.
实施例28
向反应管中依次加入N-(4-氟苯基)羟胺1h 38.1mg(0.3mmol),苯基重氮甲酯2a63.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4haa 86mg,收率71%(非对映选择性dr>20:1),m.p.115.6–117.2℃;1H NMR(300MHz,CDCl3)δ7.56–7.50(m,2H),7.38–7.32(m,5H),7.30–7.22(m,7H),5.70(s,1H),5.53(d,J=0.5Hz,1H),4.63(d,J=0.6Hz,1H),3.61(s,3H).13C NMR(75MHz,CDCl3)δ168.3,164.3,161.0(d,C-F,1JC-F=247Hz),139.7,139.0,136.9,131.2(d,C-F,4JC-F=3.3Hz),128.9,128.87(d,C-F,3JC-F=8.9Hz),128.4,128.3,126.2,124.5,118.0,117.9,115.8(d,C-F,2JC-F=21.5Hz),71.1,69.8,52.5.19F NMR(282MHz,CDCl3)δ-112.68.
HRMS(ESI)m/z:[M+H]+Calcd.for C25H21FNO3 +402.1500,Found 402.1508.
实施例29
向反应管中依次加入N-(4-三氟甲基苯基)羟胺1i 53.1mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-苯基3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4iaa 105mg,收率77%(非对映选择性dr>20:1),m.p.131.5–133.2℃;1H NMR(400MHz,CDCl3)δ7.64–7.56(m,2H),7.54(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),7.46–7.37(m,3H),7.35–7.26(m,5H),5.76(s,1H),5.57(s,1H),4.71(s,1H),3.66(s,3H).13C NMR(101MHz,CDCl3)δ168.0,164.9,139.8,139.8,138.9,134.8,129.2,128.5,128.3,126.6,126.2,126.1(q,C-F,3JC-F=3.7Hz),122.0(q,C-F,1JC-F=273Hz),118.0,117.7,72.3,70.1,52.6.19F NMR(282MHz,CDCl3)δ-62.13(s).HRMS(ESI)m/z:[M+H]+Calcd.for C26H21F3NO3 +452.1468,Found 452.1464.
实施例30
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),4-甲氧基苯基重氮甲酯2b74.2mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aba 76mg,收率61%(非对映选择性dr>20:1),m.p.123.3–125.2℃;1H NMR(300MHz,CDCl3)δ7.53–7.45(m,2H),7.37–7.33(m,2H),7.29–7.20(m,7H),7.09–7.03(m,1H),6.90–6.84(m,2H),5.70(s,1H),5.54(s,1H),4.59(s,1H),3.80(s,3H),3.59(s,3H).13C NMR(101MHz,CDCl3)δ168.6,164.7,159.7,140.0,139.2,137.0,128.8,128.4,128.2,128.1,127.0,126.2,124.3,118.2,117.4,114.2,71.8,69.8,55.3,52.3.HRMS(ESI)m/z:[M+Na]+Calcd.for C26H23NNaO4 +436.1519,Found 436.1513.
实施例31
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),4-氯苯基重氮甲酯2c75.6mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aca 100mg,收率80%(非对映选择性dr>20:1),m.p.128.1–130.2℃;1H NMR(300MHz,CDCl3)δ7.50–7.44(m,2H),7.35–7.30(m,4H),7.29(d,J=2.8Hz,3H),7.27–7.20(m,4H),7.11–7.05(m,1H),5.68(s,1H),5.58(s,1H),4.57(s,1H),3.60(s,3H).13C NMR(100MHz,CDCl3)δ168.2,164.2,139.6,138.9,136.8,134.8,133.9,129.0,129.0,128.4,128.4,126.2,124.5,117.99,117.96,71.0,69.7,52.6.HRMS(ESI)m/z:[M+H]+Calcd.for C25H21 35ClNO3 +418.1204,Found 418.1198.
实施例32
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),4-溴苯基重氮甲酯2d91.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4ada 98mg,收率71%(非对映选择性dr>20:1),m.p.117.3–119.8℃;1H NMR(300MHz,CDCl3)δ7.50(d,J=6.6Hz,2H),7.43(d,J=6.6Hz,2H),7.35–7.23(m,9H),7.12(t,J=5.4Hz,1H),5.70(s,1H),5.60(s,1H),4.59(s,1H),3.63(s,3H).13C NMR(75MHz,CDCl3)δ168.1,164.2,139.6,138.9,136.8,134.5,132.0,129.0,128.6,128.5,128.3,126.2,124.5,123.1,118.0,117.9,71.0,69.6,52.6.HRMS(ESI)m/z:[M+H]+Calcd.forC25H21 79BrNO3 +462.0699,Found 462.0682;[M+H]+Calcd.for C25H21 81BrNO3 +464.0679,Found464.0682.
实施例33
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),2-氟苯基重氮甲酯2e69.8mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aea 84mg,收率70%(非对映选择性dr>20:1),m.p.122.8–124.0℃;1H NMR(400MHz,CDCl3)δ7.67(td,J=7.9,1.3Hz,1H),7.45(d,J=7.9Hz,1H),7.42–7.36(m,1H),7.35–7.21(m,8H),7.12–7.08(m,2H),5.81(s,1H),5.57(s,1H),5.15(s,1H),3.63(s,3H).13C NMR(101MHz,CDCl3)δ168.4,164.6,161.0(d,C-F,1JC-F=251Hz),158.7,139.7(d,C-F,2JC-F=32Hz),136.6,131.5(d,C-F,3JC-F=9.3Hz),129.3(d,C-F,4JC-F=2.6Hz),128.9,128.4,127.9,126.1,124.9,124.8(d,C-F,4JC-F=3.4Hz),122.2(d,C-F,3JC-F=9.9Hz),118.8,118.4,117.3(d,C-F,2JC-F=23Hz),70.95,70.93,65.90,65.87,52.4.19FNMR(282MHz,CDCl3)δ-109.87(s).HRMS(ESI)m/z:[M+H]+Calcd.for C25H21FNO3 +402.1500,Found 402.1508.
实施例34
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),2,4-二氯苯基重氮甲酯2f87.8mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到无色油状液体4afa 91mg,收率67%(非对映选择性dr>20:1);1H NMR(400MHz,CDCl3)δ7.70(d,J=8.6Hz,1H),7.44–7.33(m,4H),7.30–7.26(m,7H),7.16–7.11(m,1H),5.81(s,1H),5.60(s,1H),5.25(s,1H),3.64(s,3H).13C NMR(100MHz,CDCl3)δ168.0,164.8,139.9,139.8,136.7,135.9,134.4,132.2,131.4,130.3,128.9,128.4,128.0,127.6,126.1,125.3,119.3,119.0,73.2,65.7,52.5.HRMS(ESI)m/z:[M+H]+Calcd.for C25H20 35Cl2NO3 +452.0815,Found 452.0817.
实施例35
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),2-碘苯基重氮甲酯2g108.7mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aga 76mg,收率50%(非对映选择性dr>20:1),m.p.162.8–164.1℃;1H NMR(300MHz,CDCl3)δ8.00(dd,J=7.9,1.3Hz,1H),7.71(dd,J=8.1,1.5Hz,1H),7.47–7.40(m,1H),7.35–7.30(m,2H),7.25–7.18(m,7H),7.13–7.01(m,2H),5.80(s,1H),5.57(s,1H),5.35(s,1H),3.61(s,3H).13C NMR(100MHz,CDCl3)δ168.3,165.3,144.2,140.0,139.6,137.1,134.6,131.2,130.7,128.7,128.4,128.3,127.9,126.0,124.9,119.2,118.3,93.6,75.1,66.1,52.3.
HRMS(ESI)m/z:[M+H]+Calcd.for C25H21INO3 +510.0561,Found 510.0570.
实施例36
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),2-萘基重氮甲酯2h81.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aha 69mg,收率53%(非对映选择性dr>20:1),m.p.176.8–178.2℃;1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.92–7.80(m,3H),7.64–7.58(m,1H),7.57–7.52(m,2H),7.44(d,J=7.9Hz,2H),7.36–7.25(m,7H),7.10(t,J=7.4Hz,1H),5.78(s,1H),5.65(s,1H),4.77(s,1H),3.70(s,3H).13C NMR(100MHz,CDCl3)δ168.4,164.6,140.0,139.1,137.1,133.1,132.9,132.7,129.0,128.9,128.6,128.4,128.2,127.4,127.0,126.7,126.68,126.3,124.4,123.8,118.1,117.6,72.1,69.7,52.5.HRMS(ESI)m/z:calculatedfor C29H24NO3 +[M+H]+:434.1751,Found 434.1737.
实施例37
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),2-胡椒环重氮甲酯2i79.2mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aia 82mg,收率64%(非对映选择性dr>20:1),m.p.144.4–145.7℃;1H NMR(300MHz,CDCl3)δ7.36(d,J=8.3Hz,2H),7.33–7.20(m,7H),7.10–7.03m,3H),6.76(d,J=8.2Hz,1H),5.96(s,2H),5.69(s,1H),5.53(s,1H),4.58(s,1H),3.58(s,3H).13C NMR(100MHz,CDCl3)δ168.4,164.5,148.3,148.0,139.9,139.1,136.9,128.8,128.4,128.2,126.2,124.4,120.7,118.2,117.5,108.4,107.4,101.5,71.9,69.9,52.4.HRMS(ESI)m/z:calculated for C26H22NO5 +[M+H]+:428.1492,Found 428.1502.
实施例38
向反应管中依次加入羟基苯胺衍生物1a 32.7mg(0.3mmol),3-噻吩基重氮甲酯2j65.5mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aja 83mg,收率71%(非对映选择性dr>20:1),m.p.117.1–118.3℃;1H NMR(400MHz,CDCl3)δ7.64(dd,J=3.0,1.3Hz,1H),7.41–7.34(m,3H),7.33–7.26(m,7H),7.16(dd,J=5.1,1.3Hz,1H),7.11(t,J=7.4Hz,1H),5.75(s,1H),5.60(s,1H),4.62(s,1H),3.62(s,3H).13C NMR(75MHz,CDCl3)δ168.4,164.2,139.4,138.9,136.9,136.4,128.9,128.4,128.2,126.9,126.4,126.1,124.4,124.38,117.9,117.7,69.4,69.2,52.5.HRMS(ESI)m/z:calculated for C23H20NO3S+[M+H]+:390.1158,Found 390.1151.
实施例39
向反应管中依次加入羟基苯胺衍生物1a 32.7mg(0.3mmol),苯基重氮磷酸二甲酯2k 81.4mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aka94mg,收率72%(非对映选择性dr>20:1),m.p.151.5–153.2℃;1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.58–7.55(m,2H),7.45–7.36(m,3H),7.35–7.26(m,3H),7.26–7.20(m,4H),7.13(t,J=7.4Hz,1H),5.94(s,1H),5.79(s,1H),4.58(d,J=7.8Hz,1H),3.56(dd,J=10.9,2.4Hz,6H).13C NMR(100MHz,CDCl3)δ165.4(d,C-P,3JC-P=4.7Hz),139.3,138.6(d,C-P,4JC-P=1.4Hz),137.5,136.4(d,C-P,2JC-P=10.5Hz),129.0,128.8,128.7,128.1,127.8,126.2(d,C-P,3JC-P=5.4Hz),125.8,124.5,118.9,118.5,70.5(d,C-P,1JC-P=168Hz),69.4,54.1(d,C-P,2JC-P=7.1Hz),552.3(d,C-P,2JC-P=7.7Hz).31P NMR(202MHz,CDCl3)δ21.44(s).HRMS(ESI)m/z:calculated for C25H25NO4P+[M+H]+:434.1516,Found 434.1512.
实施例40
向反应管中依次加入羟基苯胺衍生物1a 32.7mg(0.3mmol),乙烯基-2-萘基重氮甲酯2l 90.8mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mgRh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4ala103mg,收率75%(非对映选择性dr>20:1),m.p.149.1–150.9℃;1H NMR(300MHz,CDCl3)δ7.85–7.74(m,3H),7.69(s,1H),7.63(dd,J=6.9,1.5Hz,1H),7.50–7.44(m,4H),7.40–7.29(m 7H),7.15–7.06(m,2H),6.87(d,J=16.3Hz,1H),5.72(s,1H),5.62(s,1H),4.60(s,1H),3.56(s,3H).13C NMR(100MHz,CDCl3)δ168.7,164.1,139.1,138.7,136.7,133.4,133.37,133.0,132.8,129.1,128.6,128.5,128.3,128.2,127.7,127.6,126.6,126.5,125.9,124.4,123.5,123.4,118.0,117.8,69.9,69.8,52.7.HRMS(ESI)m/z:calculated for C31H25NO3 +[M+H]+:460.1907,Found 460.1896.
实施例41
向反应管中依次加入羟基苯胺衍生物1a 32.7mg(0.3mmol),2-(4-氯苯基)乙烯基重氮甲酯2m 85mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应3h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4ama 69mg,收率52%(非对映选择性dr>20:1),m.p.132.4–134.1℃;1H NMR(400MHz,CDCl3)δ7.46(d,J=7.7Hz,2H),7.43–7.30(m,11H),7.14(t,J=7.4Hz,1H),6.98(d,J=16.3Hz,1H),6.68(d,J=16.3Hz,1H),5.74(s,1H),5.64(s,1H),4.58(s,1H),3.57(s,3H).13C NMR(100MHz,CDCl3)δ168.5,164.0,139.0,138.6,136.6,134.4,134.0,131.4,129.1,129.0,128.6,128.4,128.2,125.9,124.4,124.0,118.2,117.8,69.6,69.6,52.7.HRMS(ESI)m/z:calculated for C27H23 35ClNO3 +[M+H]+:444.1361,Found 444.1364.
实施例42
向反应管中依次加入羟基苯胺衍生物1a 32.7mg(0.3mmol),对甲苯基重氮甲基2n52.6mg(0.36mmol),3-苯基环丁烯酮3a 47.5mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4ana 33mg,收率31%(非对映选择性dr>20:1),m.p.167.6–168.5℃;1H NMR(400MHz,CDCl3)δ7.40–7.33(m,2H),7.28–7.08(m,6H),7.04(t,J=7.4Hz,1H),6.90–6.79(m,6H),5.47(s,1H),5.23(s,1H),4.59(s,1H),2.26(s,3H),2.07(s,3H).13C NMR(100MHz,CDCl3)δ165.3,140.0,137.1,134.3,129.0,128.3,127.9,127.5,126.9,125.7,123.8,118.0,116.7,66.8,65.9,23.8,21.0.HRMS(ESI)m/z:calculated for C25H24NO+[M+H]+:354.1852,Found 354.1846.
实施例43
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-(3-甲基苯基)环丁烯酮3b 52.2mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aab 89mg,收率75%(非对映选择性dr>20:1),m.p.130.6–132.3℃;1H NMR(400MHz,CDCl3)δ7.64–7.58(m,2H),7.42–7.37(m,5H),7.31–7.26(m,2H),7.23–7.19(m,1H),7.15–7.09(m,4H),5.73(s,1H),5.60(s,1H),4.65(s,1H),3.64(s,3H),2.32(s,3H).13C NMR(75MHz,CDCl3)δ168.4,164.6,139.9,139.0,137.9,137.1,135.4,129.0,128.9,128.86,128.8,128.3,127.1,126.9,124.3,123.4,118.1,117.3,71.7,69.7,52.4,21.4.HRMS(ESI)m/z:calculated for C26H24NO3 +[M+H]+:398.1751,Found 398.1746.
实施例44
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-(4-溴苯基)环丁烯酮3c 73.2mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aac 61mg,收率44%(非对映选择性dr>20:1),m.p.144.6–146.7℃;1H NMR(400MHz,CDCl3)δ7.61–7.58(m,2H),7.46–7.34(m,7H),7.30–7.25(m,2H),7.15(d,J=6.3Hz,2H),7.11(5,J=5.7Hz,1H),5.73(s,1H),5.60(s,1H),4.58(s,1H),3.64(s,3H).13C NMR(100MHz,CDCl3)δ168.3,164.2,139.0,138.0,136.9,135.1,131.5,129.1,129.0,128.9,127.9,126.7,124.5,122.3,118.2,118.1,72.0,69.5,52.4.HRMS(ESI)m/z:calculated for C25H21 79BrNO3 +[M+H]+:462.0699,Found 462.0692;calculated forC25H21 81BrNO3 +[M+H]+:464.0699,Found 464.0677.
实施例45
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),4-氯-3-苯基环丁烯酮3d 58.7mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aad 75mg,收率60%(非对映选择性dr>20:1),m.p.147.8–149.1℃;1H NMR(300MHz,CDCl3)δ7.40–7.31(m,5H),7.30–7.17(m,9H),7.13–7.07(m,1H),6.73(d,J=1.3Hz,1H),4.46(d,J=1.3Hz,1H),3.72(s,3H).
13C NMR(75MHz,CDCl3)δ168.5,163.4,137.1,135.2,135.1,133.4,129.0,128.8,128.6,128.56,128.5,128.4,126.8,124.6,120.8,117.9,70.7,70.4,52.9.HRMS(ESI)m/z:calculated for C25H21 35ClNO3 +[M+H]+:418.1204,Found 418.1198.
实施例46
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-丁基环丁烯酮3e 40.9mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色粘状固体4aae 88mg,收率81%(非对映选择性dr>20:1),m.p.63.6–65.1℃;1H NMR(400MHz,CDCl3)δ7.68(dd,J=8.0,1.4Hz,2H),7.44–7.33(m,5H),7.27(t,J=7.9Hz,2H),7.09(t,J=7.4Hz,1H),5.24(s,1H),5.16(s,1H),4.07(s,1H),3.75(s,3H),2.25–1.99(m,2H),1.51–1.26(m,4H),0.92(t,J=7.1Hz,3H).13C NMR(75MHz,CDCl3)δ168.9,164.8,140.9,137.2,135.8,128.9,128.8,128.6,126.5,124.2,118.1,114.9,71.5,70.7,52.4,35.4,29.4,22.3,14.0.HRMS(ESI)m/z:calculated for C23H26NO3 +[M+H]+:364.1907,Found 364.1915.
实施例47
向反应管中依次加入羟基苯胺1a 32.7mg(0.3mmol),苯基重氮甲酯2a 63.4mg(0.36mmol),3-对联苯基环丁烯酮3f 72.6mg(0.33mmol)随后加入催化剂2.3mg Rh2(esp)2(0.003mmol),6mL DCE。密封充氩气反应。反应先在35℃下反应1h,随后升温至100℃反应1.5h,反应结束后减压蒸去溶剂,产物经硅胶柱层析[洗脱剂:V(乙酸乙酯)/V(石油醚)=1/20]纯化得到白色固体4aaf 107mg,收率71%(非对映选择性dr>20:1),m.p.;1H NMR(400MHz,CDCl3)δ7.69–7.60(m,4H),7.57(d,J=8.4Hz,2H),7.51–7.35(m,10H),7.34–7.28(m,2H),7.13(t,J=7.4Hz,1H),5.82(s,1H),5.65(s,1H),4.72(s,1H),3.68(s,3H).13C NMR(100MHz,CDCl3)δ168.5,164.6,140.9,140.4,139.6,138.0,137.1,135.4,129.0,128.9,128.89,127.6,127.1,127.0,126.9,126.7,124.4,118.2,117.6,72.1,69.7,52.4.HRMS(ESI)m/z:calculated for C31H26NO3 +[M+H]+:60.1907,Found 460.1904.
Claims (8)
1.一种三组分合成全取代的β-内酰胺的方法,其特征在于:反应首先加入羟基苯胺衍生物1,重氮化合物2以及铑催化剂,再加入溶剂,并用氩气保护,在25~35℃下搅拌反应一定时间,反应结束后加入环丁烯酮衍生物3升温至50℃~110℃,继续反应一段时间,待反应结束后减压蒸去溶剂,以硅胶吸附,通过柱层析或重结晶分离得到目标产物:
反应式如下:
其中,R1为4-甲基、4-氢、4-甲氧基、3-甲基、4-氟、4-氯、4-溴、4-三氟甲基或3,5-二甲基;R2为甲基、甲氧羰基或磷酸二甲酯基;R3为2,4-二氯苯基、苯基、4-甲基苯基、4-溴苯基、4-联苯基或正丁基;R4为氯或氢;芳基Ar为4-甲基苯基、4-甲氧基苯基、2-碘苯基、萘-2-基、2-氟苯基、2,4-二氯苯基、4-溴苯基或噻吩-3-基;取代乙烯基Vinyl为2-(4-氯苯基)乙烯基或萘-2-乙烯基;
所述铑催化剂为Rh2(cap)4、Rh2(esp)2、Rh2(OPiv)4中的一种或两种或多种混合;所述溶剂为甲苯、1,2-二氯乙烷、二氯甲烷、三氯甲烷中的一种。
2.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:所述的羟基苯胺衍生物的结构式如下:
3.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:所述的重氮化合物的结构式如下:
4.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:所述的环丁烯酮衍生物的结构式如下:
5.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:重氮化合物的用量为羟基苯胺衍生物用量的1~2当量,环丁烯酮衍生物的用量为羟基苯胺衍生物用量的1~2当量。
6.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:所述铑催化剂用量为羟基苯胺衍生物摩尔数的0.5~2%。
7.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:羟基苯胺在溶剂中的浓度为0.025~0.2mol/L。
8.如权利要求1所述的三组分合成全取代的β-内酰胺的方法,其特征在于:所述具体反应温度为先25~35℃搅拌反应40min~2h,再升温至50℃~110℃反应1~3h。
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