CN112939835A - 一种β-内酰胺类化合物的合成方法 - Google Patents
一种β-内酰胺类化合物的合成方法 Download PDFInfo
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Abstract
本发明提供了一种β‑内酰胺类化合物的合成方法,包括:在催化剂、配体和添加剂的作用下,式1所示烯烃、式2所示亚胺及CO反应,形成式3所示β‑内酰胺类化合物。本发明以式1所示烯烃、式2所示亚胺及CO为原料,在催化剂、膦配体和添加剂的作用下,一步直接合成β‑内酰胺类化合物,原料稳定易得、成本低,且产品产率高,环境污染小。
Description
技术领域
本发明涉及有机合成领域,特别涉及一种β-内酰胺类化合物的合成方法。
背景技术
β-内酰胺四元环是一种重要的结构基元,在很多常见的药物如青霉素、头孢菌素、碳青霉烯和甲氧苄啶类抗生素中都存在,该类结构也是这些药物的重要药效团。同时,β-内酰胺类化合物在抗病毒、抗肿瘤、抗HIV等方面均表现出良好的生物活性。除此之外,β-内酰胺类化合物还是一种重要的合成子,常被用于合成一些非天然氨基酸、寡肽、拟肽、杂环化合物和具有生物活性的天然产物。由于该类化合物的特殊用途,目前已有多种方法合成β-内酰胺类化合物,常见的方法如下:
方法一:Staudinger反应(Tetrahedron 2008,64,10465-10496)。该反应最开始是利用烯酮和亚胺作原料合成β-内酰胺类化合物,由于烯酮的反应活性普遍很高,难以分离和保存,随后人们便发展了利用酰氯在碱的作用下原位生成烯酮,然后与亚胺反应生成产物β-内酰胺。然而酰氯是一种毒性较大且活泼的化合物,不易保存,往往需要利用酸与当量的活化试剂现场制备。无论是利用活化试剂原位制备烯酮还是利用酰氯合成β-内酰胺类化合物,都会生成酸或其他副产物,对环境不友好。
方法二:Kinugasa反应(Angew.Chem.Int.Ed.2004,43,2198–2200)。该方法是利用硝酮与炔作原料,在过渡金属催化剂的作用下合成β-内酰胺类化合物。在手性配体的作用下利用该方法可以以较高的对映选择性得到手性β-内酰胺类化合物,然而该方法的底物较特殊,限制了其大规模应用。
除了上述两种方法外,还有一些方法利用锌试剂(Chem.Rev.1989,89,1447–1465.)、重氮化合物(Curr.Org.Chem.2016,20,29–40.)、β-氨基酸(TetrahedronLett.1988,29,2203–2205.)、氮杂环丙烷(Eur.J.Org.Chem.2017,5943–5960.)、大位阻的二级胺(Science2016,354,851–857.)、烯丙基卤化物(Tetrahedron2004,60,6895–6900.)、烯丙基磷酸酯(Tetrahedron Lett.1993,34,6553–6556.)或苄基卤化物(TetrahedronLetters2012,53,1613–1616.)等作为原料。这些方法虽然各有优点,但反应原料普遍较为特殊,难以制备,且原子经济性不高,对环境有一定的污染。
发明内容
有鉴于此,本发明的目的在于提供一种β-内酰胺类化合物的合成方法。本发明提供的合成方法能够高效制备β-内酰胺类化合物,且原料易得,有利于规模化生产。
本发明提供了一种β-内酰胺类化合物的合成方法,包括:
在催化剂、配体和添加剂的作用下,式1所示烯烃、式2所示亚胺及CO反应,形成式3所示β-内酰胺类化合物;
其中:
式1所示烯烃为链状烯烃;
R1、R2独立的选自:氢、C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基;
n=1~2;
或
式1所示烯烃为环状烯烃;
R1与R2连接形成环状烯烃,所述环状烯烃为C4~C16的单烯烃或二烯烃;
式2中,R3、R4独立的选自:C1~C40的脂肪烃基、C4~C60的芳香基团、酯基或磺酰基;
式3中:
R5为:氢或甲基;
或
R5与R6连接形成环状烯烃或环状烷烃,其中的环状烯烃为C4~C16的单烯烃,环状烷烃为C4~C16的环状烷烃。
优选的,所述式1所示烯烃选自式1a~式1m所示化合物中的一种或几种:
优选的,所述式2所示亚胺选自式2a~2o所示化合物中的一种或几种:
优选的,所述催化剂选自钯基催化剂、镍基催化剂、钴基催化剂和铑基催化剂中的一种或几种;
所述催化剂的摩尔量为式2所示亚胺摩尔量的0.01%~10%。
优选的,所述钯基催化剂选自氯化钯、溴化钯、碘化钯、醋酸钯、三氟乙酸钯、四氟硼酸钯、三氟甲磺酸钯、六氟锑酸钯,三叔丁基膦钯、四三苯基膦钯、三苯基膦氯化钯、双乙腈氯化钯和烯丙基氯化钯中的一种或几种;
所述镍基催化剂选自氯化镍、溴化镍、醋酸镍、三氟乙酸氟化镍、四氟硼酸镍、三氟甲磺酸镍和六氟锑酸镍中的一种或几种;
所述钴基催化剂选自八羰基二钴、醋酸钴和氯化钴中的一种或几种;
所述铑基催化剂选自醋酸铑和氯化铑中的一种或几种。
优选的,所述配体为有机膦配体;
所述配体的摩尔量为式2所示亚胺摩尔量的0.02%~20%。
优选的,所述配体选自(±)-2,2'-双-(二苯膦基)-1,1'-联萘、(±)-2,2'-双-(二苯膦基)-6,6'-二甲氧基-1,1'-联苯、1,1'-双(二苯基膦)二茂铁、双(2-二苯基膦苯基)醚、4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,2-双(二苯基膦)乙烷、1,2-双(二苯基膦)丙烷、1,2-双(二苯基膦)丁烷、三苯基膦、正丁基二(1-金刚烷基)膦、苄基二金刚烷基膦、2-二环己基膦基-2'-(N,N-二甲氨基)联苯、2-双环已基膦-2',6'-二异丙氧基联苯和2-双环已基膦-2',6'-二甲氧基联苯中的一种或几种。
优选的,所述添加剂选自三乙胺盐酸盐、N-甲基吡咯烷酮盐酸盐、氨基酸酯盐酸盐、吡啶盐酸盐、醋酸、三氟甲磺酸、对甲苯磺酸、三氟乙酸、吡啶、4-二甲氨基吡啶、含取代基的吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、喹啉、含取代基的喹啉、三乙烯二胺、四乙基碘化铵、四丁基碘化铵、四丁基溴化铵、四丁基氯化铵、四丁基乙酸铵、三苯基氯硅烷、叔丁基二甲基氯硅烷、三甲基氯硅烷、三甲基氯硅烷络合物、氯化锌、氯化铈、氯化铝和氯化铁中的一种或几种;
所述添加剂的摩尔量为式2所示亚胺摩尔量的0.01%~100%。
优选的,所述CO的气压为1~60atm;所述反应的温度为50~180℃。
优选的,所述反应在溶剂介质中进行;
所述溶剂选自苯、氯苯、氟苯、甲苯、三氟甲苯、二甲苯、均三甲苯、1,4-二氧六环、四氢呋喃、苯甲醚、乙腈、苯腈、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙二醇二甲醚、甲基叔丁基醚、甲基环戊基醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和二甲基亚砜中的一种或几种。
本发明提供的制备方法以式1所示烯烃、式2所示亚胺及CO为原料,在催化剂、膦配体和添加剂的作用下,一步直接合成β-内酰胺类化合物,原料稳定易得、成本低,且产品产率高,环境污染小。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据提供的附图获得其他的附图。
图1为实施例27所得产物trans-3ck的核磁共振氢谱图;
图2为实施例27所得产物trans-3ck的核磁共振碳谱图;
图3为实施例27所得产物trans-3ck的核磁共振氟谱图;
图4为实施例27所得产物cis-3ck的核磁共振氢谱图;
图5为实施例27所得产物cis-3ck的核磁共振碳谱图;
图6为实施例27所得产物cis-3ck的核磁共振氟谱图。
具体实施方式
本发明提供了一种β-内酰胺类化合物的合成方法,包括:
在催化剂、配体和添加剂的作用下,式1所示烯烃、式2所示亚胺及CO反应,形成式3所示β-内酰胺类化合物;
其中:
式1所示烯烃为链状烯烃;
R1、R2独立的选自:氢、C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基;
n=1~2;
或
式1所示烯烃为环状烯烃;
R1与R2连接形成环状烯烃,所述环状烯烃为C4~C16的单烯烃或二烯烃;
式2中,R3、R4独立的选自:C1~C40的脂肪烃基、C4~C60的芳香基团、酯基或磺酰基;
式3中:
R5为:氢或甲基;
或
R5与R6连接形成环状烯烃或环状烷烃,其中的环状烯烃为C4~C16的单烯烃,环状烷烃为C4~C16的环状烷烃。
本发明提供的制备方法以式1所示烯烃、式2所示亚胺及CO为原料,在催化剂、膦配体和添加剂的作用下,一步直接合成β-内酰胺类化合物,原料稳定易得、成本低,且产品产率高,环境污染小。
按照本发明,采用式1所示烯烃、式2所示亚胺及CO作为反应原料。三者的反应路线如下:
本发明中,采用的烯烃为式1所示烯烃:
对于式1所示烯烃为链状烯烃时:
R1、R2独立的选自:氢、C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基。其中,所述C1~C40的脂肪烃基为取代或非取代的脂肪烃基,所述C4~C60的芳香基团为取代或非取代的芳香基团。n为1~2。
其中,R1、R2优选为一个为氢、一个不为氢;即为R1氢,R2选自C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基,或者,R2为氢,R1选自C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基。
对于式1所示烯烃为环状烯烃时:
R1与R2连接形成环状烯烃,所述环状烯烃为C4~C16的单烯烃或二烯烃,即n=1~2。在本发明的一些实施例中,所述环状烯烃为C6的二烯烃。
优选的,所述式1所示烯烃选自式1a~式1m所示化合物中的一种或几种:
本发明中,采用的亚胺为式2所示亚胺:
R3、R4独立的选自:C1~C40的脂肪烃基、C4~C60的芳香基团、酯基或磺酰基。其中,所述C1~C40的脂肪烃基为取代或非取代的脂肪烃基,所述C4~C60的芳香基团为取代或非取代的芳香基团。
优选的,所述式2所示亚胺选自式2a~2o所示化合物中的一种或几种:
本发明对式1所示烯烃与式2所示亚胺的来源没有特殊限制,为一般市售品或按照本领域技术人员熟知的常规制备方式制得即可。本发明中,所述式1所示烯烃与式2所示亚胺的摩尔比优选为1∶(0.1~2)。
本发明中,反应原料还包括CO。本发明中,CO气体在反应体系中的气压优选为1~60atm,更优选为40atm。
本发明中,上述三种原料反应生成式3所示β-内酰胺类化合物:
其中,R3、R4与上述技术方案中所述一致,在此不再一一赘述。
式1为链状烯烃时,对应的式3中:
R5为:氢或甲基;
R6为:其中,R7选自:氢、C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基;其中,所述C1~C40的脂肪烃基为取代或非取代的脂肪烃基,所述C4~C60的芳香基团为取代或非取代的芳香基团。n与式1中n相同。
式1为环状烯烃时,对应的式3中:
R5与R6连接形成环状烯烃或环状烷烃,其中的环状烯烃为C4~C16的单烯烃,环状烷烃为C4~C16的环状烷烃。
优选的,所得式3所示β-内酰胺类化合物优选自以下结构:
按照本发明,上述三种原料在催化剂、配体和添加剂的作用下进行反应。
本发明中,所述催化剂优选为钯基催化剂、镍基催化剂、钴基催化剂和铑基催化剂中的一种或几种。
其中:
所述钯基催化剂选自氯化钯、溴化钯、碘化钯、醋酸钯、三氟乙酸钯、四氟硼酸钯、三氟甲磺酸钯、六氟锑酸钯,三叔丁基膦钯、四三苯基膦钯、三苯基膦氯化钯、双乙腈氯化钯和烯丙基氯化钯中的一种或几种;
所述镍基催化剂选自氯化镍、溴化镍、醋酸镍、三氟乙酸氟化镍、四氟硼酸镍、三氟甲磺酸镍和六氟锑酸镍中的一种或几种;
所述钴基催化剂选自八羰基二钴、醋酸钴和氯化钴中的一种或几种;
所述铑基催化剂选自醋酸铑和氯化铑中的一种或几种。
本发明中,所述催化剂的摩尔量与式2所示亚胺的摩尔量之比优选为0.01%~10%。
本发明中,所述配体优选为有机膦配体;更优选为(±)-2,2'-双-(二苯膦基)-1,1'-联萘(BINAP)、(±)-2,2'-双-(二苯膦基)-6,6'-二甲氧基-1,1'-联苯(MeO-BIPHEP)、1,1'-双(二苯基膦)二茂铁(DPPF)、双(2-二苯基膦苯基)醚(DPE-phos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、1,2-双(二苯基膦)乙烷(DPPE)、1,2-双(二苯基膦)丙烷(DPPP)、1,2-双(二苯基膦)丁烷(DPPB)、三苯基膦、正丁基二(1-金刚烷基)膦、苄基二金刚烷基膦、2-二环己基膦基-2'-(N,N-二甲氨基)联苯(Davephos)、2-双环已基膦-2',6'-二异丙氧基联苯(Ruphos)和2-双环已基膦-2',6'-二甲氧基联苯(S-Phos)中的一种或几种。本发明采用有机膦配体能够调节催化剂的电子云密度及空间位阻,同时还起到稳定催化剂的作用,配体本身不参与化学反应。
本发明中,所述配体的摩尔量与式2所示亚胺的摩尔量之比优选为0.02%~20%。
本发明中,所述添加剂优选为三乙胺盐酸盐、N-甲基吡咯烷酮盐酸盐、氨基酸酯盐酸盐、吡啶盐酸盐、醋酸、三氟甲磺酸、对甲苯磺酸、三氟乙酸、吡啶、4-二甲氨基吡啶(DMAP)、含取代基的吡啶、三乙胺、N,N-二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、喹啉、含取代基的喹啉、三乙烯二胺(DABCO)、四乙基碘化铵、四丁基碘化铵、四丁基溴化铵、四丁基氯化铵、四丁基乙酸铵、三苯基氯硅烷、叔丁基二甲基氯硅烷、三甲基氯硅烷、三甲基氯硅烷络合物、氯化锌、氯化铈、氯化铝和氯化铁中的一种或几种。本发明采用添加剂,能够活化生成的烯酮中间体,有利于亚胺对烯酮亲核进攻,促进反应的进行。
本发明中,所述添加剂的摩尔量与式2所示亚胺的摩尔量之比优选为0.01%~100%。
本发明中,原料的反应优选在溶剂介质中进行。所述溶剂优选为苯、氯苯、氟苯、甲苯、三氟甲苯、二甲苯、均三甲苯、1,4-二氧六环、四氢呋喃、苯甲醚、乙腈、苯腈、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙二醇二甲醚、甲基叔丁基醚、甲基环戊基醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和二甲基亚砜中的一种或几种。本发明中,所述溶剂与式1所示烯烃的用量比优选为(1~5)mL∶1mmol。
本发明中,所述反应的温度优选为50~180℃,更优选为60~160℃,进一步优选为120℃。所述反应的时间优选为2~48h。
本发明中,上述制备方法的操作过程具有优选为:向反应釜中加入催化剂、配体、式2所示亚胺、溶剂、式1所示烯烃和添加剂,然后用CO气体置换反应釜中的气体,充入一定压力的CO,在反应温度下搅拌反应。反应完成后将反应体系降至室温,放出CO,再将所得反应物经柱层析,得到式3所示β-内酰胺类化合物。
本发明提供的制备方法中,以式1所示烯烃、式2所示亚胺及CO为原料,在催化剂、膦配体和添加剂的作用下,一步直接合成β-内酰胺类化合物,原料稳定易得、成本低,且产品产率高,无任何副产物生成(即原子利用率达100%)、环境污染小,且产物结构新颖,容易进一步衍生化得到一系列新型β-内酰胺类化合物,在新药研发和合成中具有重要价值。
与现有技术相比,本发明提供的制备方法具有以下有益效果:
1、本发明以烯烃作为主要反应物,原料简单、易得、稳定,一步即可高效制备β-内酰胺化合物。
2、原子利用率高达100%,无任何副产物生成,对环境污染小。
3、反应效率高,具有良好的底物适应性,可以制备具有多种结构和含有不同官能团的β-内酰胺化合物。
为了进一步理解本发明,下面结合实施例对本发明优选实施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特征和优点,而不是对本发明权利要求的限制。
实施例1:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(CH3CN)2Cl2(0.025mmol,6.5mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),三乙胺盐酸盐(0.025mmol),三乙胺(0.1mmol),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120℃下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3aa,收率73%,纯度98%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例2:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(CH3CN)2Cl2(0.025mmol,6.5mg),2-二环己膦基-2'-(N,N-二甲胺)-联苯(0.05mmol,19.7mg),三乙胺盐酸盐(0.025mmol),三乙胺(0.1mmol),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120℃下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.0:1)。将反应体系柱层析即可得到产物3aa,收率76%,纯度97%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例3:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),PdCl2(0.025mmol,4.4mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120℃下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.3:1)。将反应体系柱层析即可得到产物3aa,收率66%,纯度98%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例4:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),NiBr2(0.025mmol,5.5mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120℃下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.3:1)。将反应体系柱层析即可得到产物3aa,收率56%,纯度96%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例5:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Co2(CO)8(0.025mmol,8.6mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120℃下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.3:1)。将反应体系柱层析即可得到产物3aa,收率66%,纯度96%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例6:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(CH3CN)2Cl2(0.025mmol,6.5mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),吡啶盐酸盐(0.025mmol,2.9mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.3:1)。将反应体系柱层析即可得到产物3aa,收率61%,纯度98%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例7:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(t-Bu3P)2(0.025mmol,12.8mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),四丁基碘化铵(0.1mmol,36.9mg),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应体系通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3aa,收率45%,纯度97%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例8:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(t-Bu3P)2(0.025mmol,12.8mg),2-二环己基膦-2′,6′-二甲氧基-联苯(0.05mmol,20.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),氯化铁(0.1mmol,16.2mg),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3aa,收率32%,纯度96%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例9:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(t-Bu3P)2(0.025mmol,12.8mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),甲苯(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3aa,收率48%,纯度97%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例10:β-内酰胺3aa的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2a(0.5mmol,97.7mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3aa,收率93%,纯度98%。
1H NMR(500MHz,CDCl3)δ7.42–7.33(m,2H),7.33–7.22(m,6H),7.22–7.09(m,6H),7.06–6.98(m,1H),6.69(d,J=16.2Hz,0.57H),6.64(d,J=16.1Hz,0.38H),6.33(d,J=16.1Hz,0.38H),5.52(d,J=16.2Hz,0.59H),5.00(d,J=14.9Hz,0.43H),4.95(d,J=14.9Hz,0.6H),4.47(s,0.41H),4.26(s,0.6H),3.96(d,J=14.9Hz,0.39H),3.88(d,J=14.9Hz,0.61H),1.54(s,1.75H),1.02(s,1.15H).13C NMR(126MHz,CDCl3)δ171.7,171.5,137.0,136.7,135.7,135.6,135.3,135.3,131.2,130.4,129.3,128.9,128.8,128.6,128.5,128.5,128.5,128.4,128.3,128.2,127.8,127.8,127.8,127.5,127.5,127.4,127.1,126.8,126.5,126.3,66.8,65.7,62.3,61.9,44.5,44.2,21.0,16.1.HRMS(ESI)calcd.for C25H24O+[M+H]+:354.1852,found:354.1860.
实施例11:β-内酰胺3ab的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2b(0.5mmol,114.9mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.6:1)。将反应体系柱层析即可得到产物3ab,收率83%,纯度96%。
1H NMR(400MHz,CDCl3)δ7.44–7.35(m,2H),7.35–7.29(m,2H),7.28–7.24(m,2H),7.24–7.11(m,6H),7.13–7.01(m,2H),6.68(d,J=16.1Hz,0.63H),6.66(d,J=16.1Hz,0.35H),6.35(d,J=16.1Hz,0.35H),5.52(d,J=16.1Hz,0.65H),4.97(d,J=15.2Hz,0.37H),4.91(d,J=15.0Hz,0.63H),4.49(s,0.35H),4.29(s,0.67H),3.94(d,J=15.2Hz,0.37H),3.88(d,J=15.1Hz,0.63H),1.57(s,1.96H),1.03(s,1.05H).13C NMR(101MHz,CDCl3)δ171.9,171.6,137.8,137.8,137.0,136.6,135.1,135.0,134.8,134.7,131.4,130.6,130.3,129.2,128.9,128.8,128.7,128.7,128.6,128.6,128.5,128.5,128.5,128.1,128.1,127.9,127.6,127.6,127.2,126.7,126.6,126.6,126.6,126.4,67.1,66.0,62.6,62.3,43.9,43.7,21.2,16.2.HRMS(ESI)calcd.for C25H22NOClNa+[M+Na]+:410.1282,found:410.1278.
实施例12:β-内酰胺3ac的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2c(0.5mmol,131.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.0:1)。将反应体系柱层析即可得到产物3ac,收率75%,纯度96%。
1H NMR(400MHz,CDCl3)δ7.59–7.56(m,2H),7.43–7.26(m,7H),7.21–7.12(m,4H),7.08–7.02(m,1H),6.69(d,J=16.1Hz,0.6H),6.65(d,J=15.9Hz,0.42H),6.35(d,J=16.1Hz,0.39H),5.52(d,J=16.2Hz,0.62H),5.02(d,J=15.2Hz,0.41H),4.96(d,J=15.1Hz,0.61H),4.49(s,0.38H),4.28(s,0.611H),4.06(d,J=15.2Hz,0.41H),3.99(d,J=15.1Hz,0.61H),1.57(s,1.86H),1.04(s,1.19H).13C NMR(101MHz,CDCl3)δ171.9,171.6,139.8,139.8,137.0,136.6,135.0,135.0,131.5,130.6,130.2(JC-F=32.3Hz),129.1,129.0,128.9,128.8,128.8,128.8,128.6,128.5,128.5,128.0,127.6,127.6,127.2126.6,126.5,126.4,126.0(JC-F=2.0Hz),124.1(JC-F=273.7Hz),67.3,66.2,62.7,62.4,44.1,43.9,21.3,16.3.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.for C26H23 F3ON+[M+H]+:422.1726,found:422.1730.
实施例13:β-内酰胺3ad的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2d(0.5mmol,113.0mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.0:1)。将反应体系柱层析即可得到产物3ad,收率63%,纯度96%。
1H NMR(500MHz,CDCl3)δ7.44–7.26(m,5H),7.24–7.07(m,6H),7.07–7.00(m,1H),6.88–6.77(m,2H),6.67(d,J=16.2Hz,0.62H),6.62(d,J=16.1Hz,0.38H),6.32(d,J=16.1Hz,0.39H),5.52(d,J=16.2Hz,0.62H),4.96(d,J=14.8Hz,0.41H),4.91(d,J=14.8Hz,0.61H),4.44(s,0.40H),4.23(s,0.62H),3.91(d,J=14.8Hz,0.42H),3.83(d,J=14.8Hz,0.66H),3.80(s,1.89H),3.77(s,1.20H),1.53(s,1.87H),1.01(s,1.20H).13C NMR(126MHz,CDCl3)δ171.8,171.5,159.3,159.3,137.1,136.8,135.5,135.5,131.2,130.4,130.0,129.9,129.4,128.8,128.7,128.5,128.4,128.3,127.9,127.8,127.8,127.7,127.6,127.5,127.2,126.9,126.5,126.4,114.3,114.3,66.7,65.5,62.2,61.9,55.4,55.4,44.0,43.7,21.0,16.2.HRMS(ESI)calcd.for C26H26O2N+[M+H]+:384.1958,found:384.1965.
实施例14:β-内酰胺3ae的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2e(0.5mmol,106.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3ae,收率68%,纯度98%。
1H NMR(400MHz,CDCl3)δ7.45–7.24(m,5H),7.25–7.10(m,6H),7.10–6.91(m,4H),6.68(d,J=16.2Hz,0.67H),6.63(d,J=16.4Hz,0.33H),6.32(d,J=16.1Hz,0.32H),5.52(d,J=16.2Hz,0.67H),4.95(d,J=14.9Hz,0.35H),4.90(d,J=14.9Hz,0.67H),4.45(s,0.33H),4.24(s,0.66H),3.96(d,J=14.9Hz,0.33H),3.89(d,J=14.9Hz,0.67H),1.54(s,2.06H),1.02(s,0.99H).13C NMR(101MHz,CDCl3)δ171.8,171.5,162.4(JC-F=247.5Hz),137.0,136.7,135.2,135.2,131.6(JC-F=3.0Hz),131.5(JC-F=4.0Hz),131.3,130.5,130.4,130.3,130.3,129.2,129.1,128.9,128.7,128.7,128.6,128.5,128.5,128.4,127.9,127.6,127.2,126.,126.6,126.5,126.4,115.97,115.9(JC-F=22.2Hz),115.8(JC-F=21.2Hz),67.0,65.8,62.4,62.1,43.8,43.6,21.1,16.2.19F NMR(376MHz,CDCl3)δ-114.3.HRMS(ESI)calcd.for C25H23FNO+[M+H]+:372.1758,found:372.1767.
实施例15:β-内酰胺3af的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2f(0.5mmol,104.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.1:1)。将反应体系柱层析即可得到产物3af,收率69%,纯度97%。
1H NMR(400MHz,CDCl3)δ7.44–7.27(m,4H),7.25(s,0H),7.23–7.00(m,10H),6.67(d,J=16.2Hz,0.68H),6.62(d,J=16.4Hz,0.32H),6.33(d,J=16.1Hz,0.31H),5.52(d,J=16.1Hz,0.73H),4.99(d,J=14.9Hz,0.33H),4.94(d,J=14.8Hz,0.69H),4.45(s,0.33H),4.25(s,0.74H),3.92(d,J=14.9Hz,0.32H),3.84(d,J=14.8Hz,0.69H),2.33(s,2.14H),2.31(s,0.99H),1.54(s,2.10H),1.02(s,0.92H).13C NMR(101MHz,CDCl3)δ171.8,171.6,137.6,137.6,137.1,136.8,135.5,135.4,132.7,132.6,131.3,130.4,129.6,129.4,128.8,128.7,128.6,128.5,128.5,128.3,128.3,127.8,127.6,127.5,127.2,126.9,126.5,126.4,66.7,65.6,62.3,61.9,44.2,44.0,21.3,21.2,21.0,16.2.HRMS(ESI)calcd.for C26H26NO+[M+H]+:368.2009,found:368.2013.
实施例16:β-内酰胺3ag的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2g(0.5mmol,104.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=84:80:30:1)。将反应体系柱层析即可得到产物3ag,收率74%,纯度95%。
1H NMR(400MHz,CDCl3)δ7.42–7.23(m,10H),7.25–7.07(m,4H),7.11–7.00(m,1H),6.70(d,J=16.1Hz,0.40H),6.68(d,J=16.1Hz,0.12H),6.62(d,J=16.0Hz,0.05H),6.50(d,J=16.1Hz,0.43H),6.33(d,J=16.1Hz,0.05H),6.22(d,J=16.1Hz,0.42H),5.52(d,J=16.2Hz,0.15H),5.49(d,J=16.1Hz,0.40H),5.12(q,J=7.2Hz,0.41H),5.04(q,J=7.2Hz,0.43H),4.45–4.25(m,0.73H),4.22(s,0.12H),4.10(s,0.43H),1.93(d,J=7.2Hz,0.14H),1.90(d,J=7.2Hz,0.35H),1.54(d,J=7.3Hz,1.24H),1.53(s,0.36H),1.43(d,J=7.2Hz,1.25H),1.41(s,1.27H),1.00(s,1.40H).13C NMR(101MHz,CDCl3)δ172.4,172.1,171.8,141.9,140.6,140.2,137.1,136.9,136.8,136.7,131.1,130.2,129.3,129.0,128.9,128.8,128.7,128.7,128.6,128.5,128.4,128.3,128.3,128.1,127.9,127.8,127.7,127.7,127.6,127.5,127.4,127.3,127.2,127.1,126.9,126.5,126.4,67.2,67.0,66.6,61.3,61.2,60.9,54.7,53.1,52.3,21.1,21.1,20.5,19.7,19.2,16.2.HRMS(ESI)calcd.for C26H26NO+[M+H]+:368.2009,found:368.2012.
实施例17:β-内酰胺3ah的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2h(0.5mmol,106.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.4:1)。将反应体系柱层析即可得到产物3ah,收率95%,纯度96%。
1H NMR(400MHz,CDCl3)δ7.37–7.35(m,1H),7.34–7.27(m,4H),7.27–7.24(m,1H),7.24–7.18(m,3H),7.18–7.13(m,2H),7.13–7.07(m,1H),7.07–6.99(m,2H),6.71(d,J=16.1Hz,0.41H),6.63(d,J=16.1Hz,0.59H),6.37(d,J=16.1Hz,0.39H),5.59(d,J=16.1Hz,0.61H),5.02(d,J=16.0Hz,0.42H),5.00(d,J=16.1Hz,0.59H),4.77(s,0.40H),4.60(s,0.60H),4.01(d,J=15.0Hz,0.41H),3.97(d,J=14.9Hz,0.59H),1.59(s,1.85H),1.05(s,1.22H).13C NMR(101MHz,CDCl3)δ171.9,171.8,161.0(JC-F=247.5Hz),160.9(JC-F=247.5Hz),136.2(JC-F=141.4Hz),136.1(JC-F=138.4Hz),131.8,130.5,129.7(JC-F=8.1Hz),129.6(JC-F=8.1Hz),129.0,129.0,128.8,128.7,128.6,128.5,128.5,128.0,128.0,128.0,128.0,127.9,127.9,127.8,127.6,126.6,126.4,126.2,124.4(JC-F=3.0Hz),124.3(JC-F=3.0Hz),123.5,123.4,123.3,115.8(JC-F=21.2Hz),115.5(JC-F=21.2Hz),62.3,62.0,60.6,60.5,59.8,59.8,45.0,44.9,20.4,16.6.19F NMR(376MHz,CDCl3)δ-117.5,-118.6.HRMS(ESI)calcd.for C25H23NOF+[M+H]+:372.1758,found:372.1759.
实施例18:β-内酰胺3ai的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2i(0.5mmol,104.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.2:1)。将反应体系柱层析即可得到产物3ai,收率79%,纯度98%。
1H NMR(400MHz,CDCl3)δ7.40–7.28(m,5H),7.25–7.19(m,4H),7.19–7.11(m,4H),7.02–6.95(m,1H),6.64(d,J=16.1Hz,0.36H),6.59(d,J=16.1Hz,0.64H),6.36(d,J=16.1Hz,0.33H),5.54(d,J=16.1Hz,0.70H),5.09(d,J=14.9,0.34H),5.06(d,J=16.0,0.65H),4.60(s,0.33H),4.48(s,0.67H),4.01(d,J=14.9Hz,0.35H),3.97(d,J=14.8Hz,0.67H),2.13(s,2.09H),2.11(s,1.13H),1.62(s,2.05H),1.00(s,1.00H).13C NMR(101MHz,CDCl3)δ172.0,171.8,137.0,136.8,136.2,135.8,135.7,134.1,134.0,131.5,130.8,130.7,130.7,129.4,129.0,128.9,128.7,128.7,128.6,128.5,128.4,128.0,127.9,127.9,127.8,127.8,127.5,126.6,126.4,126.3,126.2,126.2,126.2,126.0,63.7,63.0,61.8,61.6,44.9,44.8,20.7,19.7,19.6,15.4.HRMS(ESI)calcd.for C25H26NO+[M+H]+:368.2009,found:368.2016.
实施例19:β-内酰胺3aj的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2j(0.5mmol,114.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.6:1)。将反应体系柱层析即可得到产物3aj,收率81%,纯度98%。
1H NMR(400MHz,CDCl3)δ7.39–7.34(m,1H),7.33–7.27(m,5H),7.26–7.23(m,1H),7.23–7.12(m,5H),7.09–7.01(m,2H),6.69(d,J=16.2Hz,0.57H),6.63(d,J=16.1Hz,0.43H),6.30(d,J=16.1Hz,0.43H),5.50(d,J=16.1Hz,0.58H),4.98(d,J=15.6Hz,0.45H),4.93(d,J=16.0Hz,0.57H),4.42(s,0.44H),4.21(s,0.57H),3.98(d,J=14.9Hz,0.46H),3.89(d,J=14.9Hz,0.58H),1.55(s,1.71H),1.04(s,1.29H).13C NMR(101MHz,CDCl3)δ171.6,171.3,137.8,137.7,136.8,136.6,135.5,135.4,135.0,134.7,131.8,130.8,130.2,123.0,129.0,128.8,128.7,128.7,128.6,128.6,128.6,128.5,128.5,128.1,128.0,128.0,127.8,127.7,127.2,126.6,126.4,126.3,125.6,125.3,66.3,65.2,62.7,62.3,44.8,44.5,21.1,16.3.HRMS(ESI)calcd.for C25H22NOClNa+[M+Na]+:410.1282,found:410.1278.
实施例20:β-内酰胺3ak的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.6:1)。将反应体系柱层析即可得到产物3ak,收率91%,纯度97%。
(trans-3ak):1H NMR(400MHz,CDCl3)δ7.66(d,J=8.1Hz,2H),7.40–7.26(m,10H),7.22–7.17(m,2H),6.64(d,J=16.1Hz,1H),6.32(d,J=16.2Hz,1H),5.01(d,J=14.9Hz,1H),4.50(s,1H),3.98(d,J=14.9Hz,1H),1.02(s,3H).13C NMR(101MHz,CDCl3)δ171.6,139.7,136.5,135.3,130.9,130.6(JC-F=32.3Hz),129.1,128.8,128.7,128.6,128.1,128.1,127.5,126.6,125.9(JC-F=3.8Hz),124.1(JC-F=273.7Hz),65.3,62.3,44.9,16.3.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C26H23ON2 +[M+H]+:422.1726,found:422.1727.(cis-3ak):1H NMR(400MHz,CDCl3)δ7.59(d,J=8.1Hz,2H),7.36–7.29(m,3H),7.28–7.25(m,2H),7.23–7.13(m,5H),7.08–6.98(m,2H),6.70(d,J=16.1Hz,1H),5.45(d,J=16.1Hz,1H),4.96(d,J=14.9Hz,1H),4.29(s,1H),3.89(d,J=14.9Hz,1H),1.57(s,3H).13C NMR(101MHz,CDCl3)δ171.2,139.7,136.6,135.2,131.8,130.6(JC-F=32.3Hz),128.9,128.6,128.5,128.0,127.8,127.7,126.3,126.0,125.6(JC-F=3.8Hz),124.1(JC-F=273.7Hz),66.3,62.8,44.5,21.0.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.forC26H23ON2 +[M+H]+:422.1726,found:422.1727.
实施例21:β-内酰胺3al的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2l(0.5mmol,110.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.8:1)。将反应体系柱层析即可得到产物3al,收率70%,纯度98%。
(trans-3al):1H NMR(400MHz,CDCl3)δ7.73–7.65(m,2H),7.41–7.27(m,10H),7.23–7.15(m,2H),6.63(d,J=16.1Hz,1H),6.30(d,J=16.1Hz,1H),4.99(d,J=14.8Hz,1H),4.49(s,1H),4.00(d,J=14.9Hz,1H),1.01(s,3H).13C NMR(101MHz,CDCl3)δ171.4,141.2,136.3,135.1,132.7,131.1,129.1,128.8,128.6,128.3,128.2,128.1,127.8,126.6,118.5,112.2,65.3,62.6,45.0,16.3.HRMS(ESI)calcd.for C26H23ON2 +[M+H]+:379.1805,found:379.1812.(cis-3al):1H NMR(500MHz,CDCl3)δ7.64–7.59(m,2H),7.36–7.28(m,3H),7.26–7.18(m,5H),7.17–7.14(m,2H),7.06–7.01(m,2H),6.69(d,J=16.1Hz,1H),5.41(d,J=16.1Hz,1H),4.94(d,J=14.8Hz,1H),4.28(s,1H),3.91(d,J=14.8Hz,1H),1.57(s,3H).13C NMR(126MHz,CDCl3)δ171.1,141.3,136.4,135.2,132.5,132.2,129.1,128.7,128.2,128.2,128.0,126.3,125.6,118.6,112.2,66.4,63.3,44.8,21.2.HRMS(ESI)calcd.for C26H23ON2 +[M+H]+:379.1805,found:379.1812.
实施例22:β-内酰胺3am的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2m(0.5mmol,104.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.0:1)。将反应体系柱层析即可得到产物3am,收率68%,纯度97%。
1H NMR(400MHz,CDCl3)δ7.43–7.24(m,6H),7.26–7.09(m,6H),7.10–6.99(m,3H),6.62(d,J=16.1Hz,0.71H),6.50(d,J=16.1Hz,0.29H),6.19(d,J=16.1Hz,0.29H),5.45(d,J=16.1Hz,0.74H),4.38(s,0.30H),4.19(s,0.72H),4.10–3.84(m,1H),3.20–3.13(m,1H),3.01–2.83(m,2H),1.46(s,2.16H),0.94(s,0.92H).13C NMR(101MHz,CDCl3)δ171.8,171.6,138.4,138.3,137.1,136.8,135.6,135.6,131.2,130.3,129.7,129.0,128.9,128.8,128.7,128.7,128.7,128.4,128.4,128.3,127.8,127.5,127.5,127.1,126.9,126.8,126.8,126.6,126.3,68.2,66.7,62.0,61.7,41.5,41.3,34.1,34.0,21.3,15.8.HRMS(ESI)calcd.for C26H26NO+[M+H]+:368.2009,found:368.2012.
实施例23:β-内酰胺3an的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2n(0.5mmol,90.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=2.0:1)。将反应体系柱层析即可得到产物3an,收率67%,纯度97%。
(trans-3an):1H NMR(500MHz,CDCl3)δ7.45–7.40(m,2H),7.40–7.35(m,4H),7.34–7.31(m,3H),7.30–7.26(m,2H),7.25–7.21(m,3H),7.12–7.04(m,1H),6.73(d,J=16.1Hz,1H),6.50(d,J=16.1Hz,1H),5.10(s,1H),1.08(s,3H).13C NMR(126MHz,CDCl3)δ169.0,137.8,136.5,134.8,130.9,129.2,129.1,128.9,128.7,128.4,128.0,126.9,126.6,124.1,117.5,66.1,61.3,16.3.HRMS(ESI)calcd.for C24H22ON+[M+H]+:340.1696,found:340.1700.(cis-3an):1H NMR(500MHz,CDCl3)δ7.39–7.29(m,5H),7.29–7.25(m,2H),7.25–7.22(m,2H),7.21–7.13(m,3H),7.10–7.01(m,3H),6.72(d,J=16.2Hz,1H),5.55(d,J=16.2Hz,1H),4.93(s,1H),1.73(s,3H).13C NMR(126MHz,CDCl3)δ169.0,137.8,136.9,135.1,131.6,129.2,128.9,128.5,128.5,127.6,127.1,126.4,126.4,124.1,117.5,67.6,61.4,21.6.HRMS(ESI)calcd.for C24H22ON+[M+H]+:340.1696,found:340.1703.
实施例24:β-内酰胺3ao的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2o(0.5mmol,98.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.5:1)。将反应体系柱层析即可得到产物3ao,收率91%,纯度98%。
(trans-3ao):1H NMR(400MHz,CDCl3)δ8.60(dd,J=4.8,1.7Hz,1H),8.47(d,J=2.3Hz,1H),7.51(dt,J=7.8,2.0Hz,1H),7.41–7.33(m,3H),7.33–7.23(m,6H),7.22–7.17(m,2H),6.65(d,J=16.1Hz,1H),6.32(d,J=16.1Hz,1H),4.98(d,J=14.8Hz,1H),4.48(s,1H),3.99(d,J=14.9Hz,1H),1.06(s,3H).13C NMR(101MHz,CDCl3)δ171.5,149.8,148.9,136.5,135.2,134.7,131.2,131.0,129.1,128.7,128.6,128.5,128.1,128.1,126.6,123.6,63.7,62.2,44.8,16.6.HRMS(ESI)calcd.for C24H23ON2 +[M+H]+:355.1805,found:355.1808.(cis-3ao):1H NMR(400MHz,CDCl3)δ8.49(d,J=49.5Hz,2H),7.46–7.43(m,1H),7.38–7.25(m,3H),7.27–7.12(m,6H),7.11–7.03(m,2H),6.73(d,J=16.2Hz,1H),5.49(d,J=16.1Hz,1H),4.93(d,J=14.9Hz,1H),4.28(s,1H),3.89(d,J=14.8Hz,1H),1.58(s,3H).13C NMR(101MHz,CDCl3)δ171.2,149.9,149.3,136.5,135.2,135.1,132.1,131.2,129.0,128.6,128.5,128.1,127.8,126.3,126.0,123.4,64.6,62.9,44.5,21.1.HRMS(ESI)calcd.for C24H23ON2 +[M+H]+:355.1805,found:355.1808.
实施例25:β-内酰胺3ap的制备
将烯烃1a(0.6mmol,78.1mg),亚胺2p(0.5mmol,122.6mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.3:1)。将反应体系柱层析即可得到产物3ap,收率86%,纯度97%。
1H NMR(400MHz,CDCl3)δ7.90–7.73(m,3H),7.65–7.62(m,1H),7.56–7.44(m,2H),7.43–7.35(m,1H),7.37–7.22(m,5H),7.25–7.15(m,2H),7.19–7.04(m,2H),7.05–6.94(m,1H),6.76(d,J=16.2Hz,0.55H),6.67(d,J=16.1Hz,0.45H),6.39(d,J=16.1Hz,0.45H),5.58(d,J=16.2Hz,0.55H),5.05(d,J=14.9Hz,0.46H),4.99(d,J=14.8Hz,0.55H),4.63(s,0.46H),4.42(s,0.55H),4.08(d,J=14.9Hz,0.47H),3.94(d,J=14.9Hz,0.56H),1.60(s,1.65H),1.05(s,1.37H).13C NMR(101MHz,CDCl3)δ171.9,171.6,136.9,136.7,135.7,133.3,133.3,133.3,133.0,133.0,131.5,130.5,129.3,129.0,128.9,128.7,128.7,128.6,128.4,128.4,128.0,128.0,127.9,127.9,127.9,127.5,127.2,126.7,126.7,126.5,126.5,126.4,126.4,126.4,126.3,125.0,124.9,67.1,66.0,62.5,62.3,44.8,44.4,21.3,16.2.HRMS(ESI)calcd.for C29H26ON+[M+H]+:404.2009found:404.2004.
实施例26:β-内酰胺3bk的制备
将烯烃1b(0.6mmol,93.0mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.0:1)。将反应体系柱层析即可得到产物3bk,收率88%,纯度98%。
1H NMR(500MHz,CDCl3)δ7.67(d,J=8.1Hz,1H),7.63–7.60(m,2H),7.59–7.49(m,1H),7.42–7.26(m,6H),7.27–7.19(m,2H),7.20–7.06(s,1H),6.98(d,J=16.0Hz,0.53H),6.91(d,J=16.1Hz,0.44H),6.57(d,J=16.0Hz,0.53H),5.77(d,J=16.1Hz,0.48H),5.01(d,J=14.9,0.54H),4.99(d,J=10.0,0.45H),4.60(s,0.55H),4.38(s,0.47H),4.03(d,J=14.9Hz,0.54H),3.95(d,J=14.8Hz,0.46H),1.64(s,1.40H),1.08(s,1.60H).13C NMR(126MHz,CDCl3)δ170.6,170.4,139.7,139.6,139.6,139.2,135.1,135.1,134.1,133.1,133.0,132.8,132.7,131.3,130.6(JC-F=31.5Hz),130.5(JC-F=32.8Hz),129.1,129.0,128.5,128.5,128.5,128.1,127.9,127.7,127.5,127.0,126.1,126.0,125.9(JC-F=3.8Hz),125.8(JC-F=3.8Hz),124.0(JC-F=273.4Hz),124.0(JC-F=272.2Hz),117.7,117.6,111.2,110.9,66.4,64.7,62.9,62.4,44.9,44.8,20.3,15.9.19F NMR(376MHz,CDCl3)δ-62.6,-62.6.HRMS(ESI)calcd.for C27H22F3N2O+[M+H]+:447.1679,found:447.1692.
实施例27:β-内酰胺3ck的制备
将烯烃1c(0.6mmol,98.4mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.4:1)。将反应体系柱层析即可得到产物3ck,收率76%,纯度97%。
(trans-3ck):1H NMR(400MHz,CDCl3)δ7.66(d,J=8.1Hz,2H),7.40–7.28(m,6H),7.26–7.16(m,5H),6.58(d,J=16.1Hz,1H),6.33(d,J=16.1Hz,1H),5.01(d,J=14.8Hz,1H),4.49(s,1H),3.99(d,J=14.9Hz,1H),1.01(s,3H).13C NMR(101MHz,CDCl3)δ171.2,139.5,138.4,135.3,134.7,130.6(JC-F=33.3Hz),130.2,130.0,129.6,129.1,128.6,128.2,128.0,127.5,126.4,125.9(JC-F=1.1Hz),124.9,124.0(JC-F=272.7Hz),65.1,62.2,44.9,16.2.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C26H22ONF3Cl+[M+H]+:456.1337,found:456.1347.(cis-3ck):1H NMR(400MHz,CDCl3)δ7.60(d,J=8.0Hz,2H),7.37–7.27(m,3H),7.27(s,1H),7.25(s,1H),7.22–7.13(m,2H),7.17–7.08(m,2H),6.99(d,J=1.9Hz,1H),6.95–6.85(m,1H),6.64(d,J=16.1Hz,1H),5.45(d,J=16.1Hz,1H),4.96(d,J=14.8Hz,1H),4.30(s,1H),3.90(d,J=14.9Hz,1H),1.56(s,3H).13C NMR(101MHz,CDCl3)δ171.0,139.6,138.5,135.3,134.5,130.7(JC-F=33.3Hz),130.7,129.8,129.1,128.7,128.1,127.9,127.8,127.7,126.4,125.8(JC-F=4.0Hz),124.6,124.0(JC-F=272.7Hz),66.3,62.9,44.6,21.1.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.forC26H22ONF3Cl+[M+H]+:456.1337,found:456.1342.
所得产物的分子结构表征图参见图1-5所示,图1为实施例27所得产物trans-3ck的核磁共振氢谱图,图2为实施例27所得产物trans-3ck的核磁共振碳谱图,图3为实施例27所得产物trans-3ck的核磁共振氟谱图,图4为实施例27所得产物cis-3ck的核磁共振氢谱图,图5为实施例27所得产物cis-3ck的核磁共振碳谱图,图6为实施例27所得产物cis-3ck的核磁共振氟谱图。
实施例28:β-内酰胺3dk的制备
将烯烃1d(0.6mmol,86.5mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.3:1)。将反应体系柱层析即可得到产物3dk,收率87%,纯度97%。
(trans-3dk):1H NMR(400MHz,CDCl3)δ7.65(d,J=8.0Hz,2H),7.33–7.26(m,7H),7.21–7.17(m,2H),7.13(d,J=7.9Hz,2H),6.60(d,J=16.1Hz,1H),6.26(d,J=16.1Hz,1H),5.01(d,J=14.9Hz,1H),4.49(s,1H),3.98(d,J=14.8Hz,1H),2.34(s,3H),1.01(s,3H).13C NMR(101MHz,CDCl3)δ171.7,139.8,137.9,135.4,133.7,130.8,130.5(JC-F=32.3Hz),129.5,129.1,128.6,128.1,127.6,127.5,126.5,125.9(JC-F=4.0Hz),124.1(JC-F=273.7Hz),65.3,62.4,44.9,21.3,16.3.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C27H25ONF3 +[M+H]+:436.1883,found:436.1888.(cis-3dk):1H NMR(500MHz,CDCl3)δ7.58(d,J=8.0Hz,2H),7.34–7.29(m,3H),7.27–7.22(m,2H),7.20–7.14(m,2H),7.01(d,J=7.9Hz,2H),6.93(d,J=8.2Hz,2H),6.66(d,J=16.1Hz,1H),5.39(d,J=16.1Hz,1H),4.96(d,J=14.8Hz,1H),4.28(s,1H),3.89(d,J=14.9Hz,1H),2.27(s,3H),1.56(s,3H).13C NMR(126MHz,CDCl3)δ171.4,139.8,137.7,135.4,133.9,131.8,130.5(JC-F=32.8Hz),129.3,129.1,128.7,128.1,128.0,126.9,126.3,125.7(JC-F=3.8Hz),125.0,124.1(JC-F=272.2Hz),66.4,63.0,44.6,21.3,21.2.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C27H25ONF3 +[M+H]+:436.1883,found:436.1886.
实施例29:β-内酰胺3ek的制备
将烯烃1e(0.6mmol,94.9mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.5:1)。将反应体系柱层析即可得到产物3ek,收率82%,纯度98%。
(trans-3ek):1H NMR(500MHz,CDCl3)δ7.66(d,J=8.0Hz,2H),7.35–7.27(m,5H),7.26–7.22(m,1H),7.22–7.17(m,2H),7.13–7.03(m,2H),6.96(d,J=15.9Hz,1H),6.10(d,J=15.8Hz,1H),5.05(d,J=14.9Hz,1H),4.49(s,1H),3.95(d,J=14.9Hz,1H),2.29(s,3H),2.21(s,3H),1.03(s,3H).13C NMR(126MHz,CDCl3)δ171.6,139.8,137.0,136.2,135.4,134.2,130.6,130.4(JC-F=32.8Hz),129.8,129.6,129.1,128.5,128.1,127.4,125.9(JC-F=3.8Hz),125.7,124.1,124.1(JC-F=272.2Hz),65.4,62.6,44.7,20.7,16.5,15.6.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C28H26ONF3Na+[M+Na]+:472.1859,found:472.1876.(cis-3ek):1H NMR(500MHz,CDCl3)δ7.59(d,J=8.0Hz,2H),7.35–7.29(m,3H),7.29–7.24(m,2H),7.21–7.14(m,2H),6.99(d,J=7.5Hz,1H),6.91(d,J=16.0Hz,1H),6.87(t,J=7.7Hz,1H),6.48(d,J=7.8Hz,1H),5.24(d,J=15.9Hz,1H),4.97(d,J=14.8Hz,1H),4.31(s,1H),3.92(d,J=14.9Hz,1H),2.22(s,3H),2.12(s,3H),1.58(s,3H).13C NMR(126MHz,CDCl3)δ171.4,140.0,136.8,136.5,135.4,134.3,131.3,130.6(JC-F=32.8Hz),129.4,129.1,128.7,128.1,128.1,127.9,125.8(JC-F=3.8Hz),125.5,124.3,124.1(JC-F=273.4Hz),66.5,63.3,44.6,21.3,20.6,15.6.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C28H26ONF3Na+[M+Na]+:472.1859,found:472.1876.
实施例30:β-内酰胺3fk的制备
将烯烃1f(0.6mmol,108.1mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.4:1)。将反应体系柱层析即可得到产物3fk,收率78%,纯度96%。
(trans-3fk):1H NMR(400MHz,CDCl3)δ7.81–7.78(m,3H),7.73(d,J=1.7Hz,1H),7.65(d,J=8.0Hz,2H),7.58(dd,J=8.8,1.7Hz,1H),7.51–7.39(m,2H),7.36–7.23(m,5H),7.23–7.21(m,2H),6.80(d,J=16.1Hz,1H),6.45(dd,J=16.1,1.0Hz,1H),5.02(d,J=14.9Hz,1H),4.55(s,1H),4.00(d,J=14.8Hz,1H),1.06(d,J=1.0Hz,3H).13C NMR(101MHz,CDCl3)δ171.6,139.7,135.4,133.9,133.7,133.2,131.0,130.6(JC-F=32.3Hz),129.1,129.0,128.6,128.4,128.1,127.8,127.5,126.8,126.5,126.2,125.9(JC-F=4.0Hz),124.1(JC-F=272.7Hz),123.5,65.3,62.5,44.9,16.3.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C30H24ONF3Na+[M+Na]+:494.1702,found:494.1704.(cis-3fk):1H NMR(400MHz,CDCl3)δ7.71(ddd,J=8.7,7.0,2.4Hz,2H),7.63(d,J=8.6Hz,1H),7.58(d,J=8.1Hz,2H),7.50–7.46(m,1H),7.44–7.36(m,2H),7.35–7.25(m,5H),7.18(dd,J=7.6,1.9Hz,2H),7.14(dd,J=8.6,1.8Hz,1H),6.86(d,J=16.1Hz,1H),5.56(d,J=16.1Hz,1H),4.98(d,J=14.8Hz,1H),4.32(s,1H),3.91(d,J=14.9Hz,1H),1.60(s,3H).13C NMR(101MHz,CDCl3)δ171.3,139.8,135.4,134.1,133.5,133.1,132.0,130.6(JC-F=32.3Hz),129.1,128.7,128.2,128.1,128.1,128.0,127.7,126.5,126.5,126.4,126.0,125.7(JC-F=4.0Hz),124.1(JC-F=272.7Hz),123.4,66.4,63.1,44.6,21.1.19F NMR(376MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C30H24ONF3Na+[M+Na]+:494.1702,found:494.1704.
实施例31:β-内酰胺3gk的制备
将烯烃1g(0.6mmol,81.6mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.5:1)。将反应体系柱层析即可得到产物3gk,收率88%,纯度98%。
(trans-3gk):1H NMR(500MHz,CDCl3)δ7.65(d,J=8.0Hz,2H),7.35–7.27(m,5H),7.18(ddd,J=11.1,6.3,2.5Hz,3H),7.00–6.94(m,2H),6.77(d,J=15.9Hz,1H),6.14(d,J=15.9Hz,1H),4.99(d,J=14.9Hz,1H),4.48(s,1H),3.99(d,J=14.9Hz,1H),0.99(s,3H).13C NMR(126MHz,CDCl3)δ171.3,141.6,139.6,135.3,130.6(JC-F=32.8Hz),129.1,128.6,128.2,128.0,127.6,127.5,126.5,125.9(JC-F=3.8Hz),124.7,124.3,124.1(JC-F=272.2Hz),65.3,62.2,44.9,16.3.19F NMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.forC24H20ONF3SNa+[M+Na]+:450.1110,found:450.1118.(cis-3gk):1H NMR(500MHz,CDCl3)δ7.59(d,J=8.0Hz,2H),7.34–7.27(m,3H),7.26–7.24(m,2H),7.19–7.13(m,2H),7.04(dt,J=5.1,0.9Hz,1H),6.87(dd,J=5.1,3.5Hz,1H),6.82(d,J=10.3Hz,1H),6.80(dd,J=2.3,0.9Hz,1H),5.30(d,J=15.9Hz,1H),4.95(d,J=14.9Hz,1H),4.28(s,1H),3.88(d,J=14.9Hz,1H),1.55(s,3H).13C NMR(126MHz,CDCl3)δ171.0,141.7,139.6,135.3,130.6(JC-F=32.8Hz),129.1,128.7,128.1,127.9,127.4,126.1,125.7(JC-F=3.8Hz),125.5,125.1,124.5,124.1(JC-F=272.7Hz),66.3,62.8,44.6,21.0.19F NMR(376MHz,CDCl3)δ-62.6.19FNMR(471MHz,CDCl3)δ-62.5.HRMS(ESI)calcd.for C24H20ONF3SNa+[M+Na]+:450.1110,found:450.1118.
实施例32:β-内酰胺3hk的制备
将烯烃1h(溶解在NMP溶剂中,1mmol),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=3.5:1)。将反应体系柱层析即可得到产物3hk,收率68%,纯度98%。
(trans-3hk):1H NMR(400MHz,CDCl3)δ7.62(dd,J=8.2,4.4Hz,2H),7.39–7.25(m,5H),7.20–7.07(m,2H),5.83–5.63(m,1H),5.62–5.44(m,1H),4.86(dd,J=15.0,2.3Hz,1H),4.19(d,J=2.2Hz,0.80H),4.17(d,J=2.2Hz,0.20H),3.93(d,J=9.1Hz,0.22H),3.83(dd,J=14.9,3.5Hz,1H),3.59(dd,J=8.3,2.4Hz,0.79H),1.74–1.68(m,2.45H),1.55(dd,J=6.9,1.7Hz,0.59H).13C NMR(101MHz,CDCl3)δ168.8,168.7,141.9,141.8,135.3,135.3,131.5,130.8(JC-F=36.4Hz),130.8(JC-F=36.4Hz),129.0,128.6,128.0,126.9,126.9,126.1(JC-F=4.4Hz),124.1(JC-F=289.9Hz),124.0(JC-F=288.9Hz),123.4,64.0,61.0,60.8,59.4,45.0,44.9,18.2,13.8.19F NMR(376MHz,CDCl3)δ-62.6,-62.6.HRMS(ESI)calcd.for C20H18ONF3Na+[M+Na]+:368.1233,found:368.1229.(cis-3hk):1H NMR(400MHz,CDCl3)δ7.66–7.57(m,2H),7.34–7.28(m,4H),7.27–7.25(m,1H),7.19–7.12(m,2H),5.72(dqd,J=15.4,6.5,1.2Hz,0.63H),5.52(dqd,J=10.8,6.9,1.5Hz,0.37H),5.06–4.79(m,2H),4.71(d,J=5.6Hz,0.35H),4.65(d,J=5.5Hz,0.71H),4.44(ddd,J=9.4,5.5,1.4Hz,0.34H),4.12(ddt,J=7.9,5.6,1.1Hz,0.64H),3.91(dd,J=14.9,4.3Hz,1H),1.58(dd,J=7.0,1.8Hz,1.13H),1.51(ddd,J=6.5,1.7,0.9Hz,1.93H).13C NMR(101MHz,CDCl3)δ169.0,168.8,140.0,139.9,135.2,132.5,131.0,130.5(JC-F=32.3Hz),130.4(JC-F=32.3Hz),129.0,129.0,128.7,128.7,128.1,128.0,127.9,127.8,125.7(JC-F=4.0Hz),124.1(JC-F=272.7Hz),121.3,120.2,59.0,58.4,58.3,54.1,45.1,44.9,18.1,13.7.19F NMR(376MHz,CDCl3)δ-62.5,-62.6.HRMS(ESI)calcd.for C20H18ONF3Na+[M+Na]+:368.1233,found:368.1229.
实施例33:β-内酰胺3ik的制备
将烯烃1i(0.6mmol,48.0mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.8:1)。将反应体系柱层析即可得到产物3ik,收率61%,纯度97%。
1H NMR(400MHz,CDCl3)δ7.62(dd,J=8.4,2.6Hz,2H),7.35–7.26(m,5H),7.22–7.12(m,2H),5.99(dt,J=9.9,3.8Hz,0.56H),5.74(dt,J=10.1,3.6Hz,0.45H),5.67(dt,J=9.9,2.1Hz,0.55H),5.17(dt,J=10.1,2.0Hz,0.44H),4.99(d,J=16.0Hz,0.44H),4.96(d,J=13.4Hz,0.56H),4.32(s,0.56H),4.25(s,0.44H),3.92(d,J=3.9Hz,0.53H),3.89(d,J=3.9Hz,0.46H),2.16–1.81(m,3.38H),1.76–1.51(m,1.94H),1.36–1.18(m,0.80H),1.14–1.07(m,0.56H).13C NMR(101MHz,CDCl3)δ172.7,172.5,140.6,139.6,139.6,135.6,135.4,133.3,132.8,130.5(JC-F=32.3Hz),130.2(JC-F=32.3Hz),129.0,128.6,128.5,128.0,128.0,127.6,127.3,125.8(JC-F=3.03Hz),125.7(JC-F=3.03Hz),125.4,124.1(JC-F=273.7Hz),124.1(JC-F=272.7Hz),122.0,66.9,65.5,61.8,61.5,44.8,44.6,30.0,25.1,24.7,24.5,20.0,19.3.19F NMR(376MHz,CDCl3)δ-62.5,-62.5.HRMS(ESI)calcd.forC22H21ONF3 +[M+H]+:372.1570,found:372.1562.
实施例34:β-内酰胺3jk的制备
将烯烃1j(0.6mmol,75.6mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.5:1)。将反应体系柱层析即可得到产物3jk,收率34%,纯度96%。
(trans-3jk):1H NMR(400MHz,CDCl3)δ7.66(d,J=8.1Hz,2H),7.36–7.27(m,5H),7.19–7.12(m,2H),7.03(d,J=15.8Hz,1H),6.06(d,J=15.8Hz,1H),4.97(d,J=14.8Hz,1H),4.48(s,1H),4.22(q,J=7.1Hz,2H),3.97(d,J=14.8Hz,1H),1.31(t,J=7.1Hz,3H),0.97(s,3H).13C NMR(101MHz,CDCl3)δ169.6,166.1,145.6,138.9,134.9,130.9(JC-F=33.3Hz),129.2,128.6,128.3,127.5,126.0(JC-F=4.0Hz),124.0(JC-F=273.7Hz),122.4,64.0,61.9,60.9,45.0,15.3,14.3.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.forC23H23F3NO3 +[M+H]+:418.1625,found:418.1628.(cis-3jk):1H NMR(400MHz,CDCl3)δ7.65–7.58(m,2H),7.36–7.28(m,3H),7.26–7.20(m,2H),7.18–7.10(m,2H),6.27(d,J=15.8Hz,1H),6.09(d,J=15.8Hz,1H),4.93(d,J=14.8Hz,1H),4.30(s,1H),4.08(qd,J=7.1,2.2Hz,2H),3.88(d,J=14.8Hz,1H),1.53(s,3H),1.18(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ169.7,165.6,142.9,138.9,135.0,131.0(J=32.3Hz),129.1,128.6,128.2,127.7,126.0(J=3.0Hz),124.0(J=273.7Hz),123.5,66.0,62.3,60.5,44.7,20.4,14.1.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.for C23H23F3NO3 +[M+H]+:418.1625,found:418.1628.
实施例35:β-内酰胺3kk的制备
将烯烃1k(0.6mmol,60mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.2:1)。将反应体系柱层析即可得到产物3jk,收率82%,纯度96%。
(trans-3kk):1H NMR(400MHz,CDCl3)δ7.66(d,J=8.0Hz,5H),7.34–7.29(m,5H),7.23(dd,J=7.4,2.2Hz,2H),5.04(d,J=15.1Hz,1H),4.86(s,1H),4.25(q,J=7.1Hz,2H),3.97(d,J=15.1Hz,1H),1.30(t,J=7.1Hz,3H),1.05(s,3H).13C NMR(101MHz,CDCl3)δ171.0,169.1,137.6,134.3,130.9,128.9,128.2,128.1,127.6,126.1,125.3,66.7,61.9,50.3,20.2,14.0.19F NMR(376MHz,CDCl3)δ-62.6.HRMS(ESI)calcd.for C21H21F3NO3 +[M+H]+:392.1468,found:392.1476.(cis-3kk):1H NMR(400MHz,CDCl3)δ7.60(d,J=8.0Hz,2H),7.38–7.28(m,5H),7.16(dd,J=7.3,2.3Hz,2H),5.01(d,J=14.9Hz,1H),4.26(s,1H),3.94(d,J=14.9Hz,1H),3.83–3.65(m,2),1.64(s,3H),0.88(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.1,168.3,137.9,135.3,131.9,129.1,128.2,128.1,127.6,126.1,124.8,66.8,61.2,50.1,20.5,14.9.19F NMR(376MHz,CDCl3)δ-62.7.HRMS(ESI)calcd.forC21H21F3NO3 +[M+H]+:392.1468,found:392.1476.
实施例36:β-内酰胺3lk的制备
将烯烃1l(0.6mmol,104.4mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=1.4:1)。将反应体系柱层析即可得到产物3lk,收率64%,纯度97%。
(trans-3lk):1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.62(d,J=8.1Hz,2H),7.50(d,J=8.1Hz,2H),7.39(d,J=8.0Hz,2H),7.26(t,J=3.1Hz,3H),7.11(dd,J=6.6,2.9Hz,2H),5.02(d,J=14.9Hz,1H),4.61(s,1H),3.99(d,J=14.8Hz,1H),1.20(s,3H).13C NMR(125MHz,CDCl3)δ172.3,141.3,137.5,136.8,131.1,128.9,128.6,128.3,127.9,127.2,126.6,125.8,123.1,69.5,58.2,49.9,20.1.19F NMR(376MHz,CDCl3)δ-62.7,-62.8.HRMS(ESI)calcd.for C25H20F6NO+[M+H]+:464.1444,found:464.1452.(cis-3lk):1HNMR(400MHz,CDCl3)δ7.42–7.29(m,7H),7.21–7.08(m,4H),6.98(d,J=8.0Hz,2H),4.98(d,J=14.8Hz,1H),4.46(s,1H),3.81(d,J=14.8Hz,1H),1.75(s,3H).13C NMR(125MHz,CDCl3)δ172.1,141.5,137.2,135.8,132.1,129.4,128.6,128.3,127.9,127.1,126.4,125.8,123.1,68.5,58.2,49.7,21.1.19F NMR(376MHz,CDCl3)δ-62.7,-62.8.HRMS(ESI)calcd.for C25H20F6NO+[M+H]+:464.1444,found:464.1452.
实施例37:β-内酰胺3mk的制备
将烯烃1m(0.6mmol,31.8mg),亚胺2k(0.5mmol,131.5mg),Pd(t-Bu3P)2(0.025mmol,6.5mg),NMP·HCl(0.025mmol,3.4mg),吡啶(0.1mmol,8uL),三甲基氯硅烷(0.1mmol),N-甲基吡咯烷酮(1mL)加入到高压釜中,一氧化碳置换3次,充入40atm一氧化碳,在120摄氏度下搅拌12小时。反应结束后将反应釜冷却至室温,放出一氧化碳,取少量反应物通过气相色谱和气相色谱质谱联用仪测定产物的立体选择性(d.r.=12.1:1)。将反应体系柱层析即可得到产物3mk,收率94%,纯度98%。
(trans-3mk):1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.51–7.28(m,5H),7.17(dd,J=7.0,2.6Hz,2H),5.13–4.65(m,2H),4.04(d,J=15.0Hz,1H),1.19(s,3H).13CNMR(125MHz,CDCl3)δ172.4,140.3,135.6,131.9,129.2,128.1,127.9,127.8,126.5,123.1,115.3,64.9,50.4,45.6,20.1.19F NMR(376MHz,CDCl3)δ-62.7.HRMS(ESI)calcd.forC19H16F3N2O+[M+H]+:345.1209,found:345.1201.(cis-3mk):1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),7.33(q,J=2.6,2.1Hz,3H),7.11(q,J=3.0Hz,2H),4.88(d,J=14.7Hz,1H),4.28(s,1H),3.88(dd,J=14.9,1.9Hz,1H),1.73(d,J=1.9Hz,3H).13C NMR(125MHz,CDCl3)δ172.1,141.3,135.2,131.4,129.5,128.1,127.9,127.6,126.5,123.1,114.3,64.6,51.4,45.6,21.1.19F NMR(376MHz,CDCl3)δ-62.7.HRMS(ESI)calcd.for C19H16F3N2O+[M+H]+:345.1209,found:345.1201.
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下,在其它实施例中实现。因此,本发明将不会被限制于本文所示的这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (10)
1.一种β-内酰胺类化合物的合成方法,其特征在于,包括:
在催化剂、配体和添加剂的作用下,式1所示烯烃、式2所示亚胺及CO反应,形成式3所示β-内酰胺类化合物;
其中:
式1所示烯烃为链状烯烃;
R1、R2独立的选自:氢、C1~C40的脂肪烃基、C4~C60的芳香基团、酯基、醛基、酰胺基、磷酸酯基、氰基、砜基或亚砜基;
n=1~2;
或
式1所示烯烃为环状烯烃;
R1与R2连接形成环状烯烃,所述环状烯烃为C4~C16的单烯烃或二烯烃;
式2中,R3、R4独立的选自:C1~C40的脂肪烃基、C4~C60的芳香基团、酯基或磺酰基;
式3中:
R5为:氢或甲基;
或
R5与R6连接形成环状烯烃或环状烷烃,其中的环状烯烃为C4~C16的单烯烃,环状烷烃为C4~C16的环状烷烃。
4.根据权利要求1所述的合成方法,其特征在于,所述催化剂选自钯基催化剂、镍基催化剂、钴基催化剂和铑基催化剂中的一种或几种;
所述催化剂的摩尔量为式2所示亚胺摩尔量的0.01%~10%。
5.根据权利要求4所述的合成方法,其特征在于,所述钯基催化剂选自氯化钯、溴化钯、碘化钯、醋酸钯、三氟乙酸钯、四氟硼酸钯、三氟甲磺酸钯、六氟锑酸钯,三叔丁基膦钯、四三苯基膦钯、三苯基膦氯化钯、双乙腈氯化钯和烯丙基氯化钯中的一种或几种;
所述镍基催化剂选自氯化镍、溴化镍、醋酸镍、三氟乙酸氟化镍、四氟硼酸镍、三氟甲磺酸镍和六氟锑酸镍中的一种或几种;
所述钴基催化剂选自八羰基二钴、醋酸钴和氯化钴中的一种或几种;
所述铑基催化剂选自醋酸铑和氯化铑中的一种或几种。
6.根据权利要求1所述的合成方法,其特征在于,所述配体为有机膦配体;
所述配体的摩尔量为式2所示亚胺摩尔量的0.02%~20%。
7.根据权利要求1或6所述的合成方法,其特征在于,所述配体选自(±)-2,2'-双-(二苯膦基)-1,1'-联萘、(±)-2,2'-双-(二苯膦基)-6,6'-二甲氧基-1,1'-联苯、1,1'-双(二苯基膦)二茂铁、双(2-二苯基膦苯基)醚、4,5-双二苯基膦-9,9-二甲基氧杂蒽、1,2-双(二苯基膦)乙烷、1,2-双(二苯基膦)丙烷、1,2-双(二苯基膦)丁烷、三苯基膦、正丁基二(1-金刚烷基)膦、苄基二金刚烷基膦、2-二环己基膦基-2'-(N,N-二甲氨基)联苯、2-双环已基膦-2',6'-二异丙氧基联苯和2-双环已基膦-2',6'-二甲氧基联苯中的一种或几种。
8.根据权利要求1所述的合成方法,其特征在于,所述添加剂选自三乙胺盐酸盐、N-甲基吡咯烷酮盐酸盐、氨基酸酯盐酸盐、吡啶盐酸盐、醋酸、三氟甲磺酸、对甲苯磺酸、三氟乙酸、吡啶、4-二甲氨基吡啶、含取代基的吡啶、三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环十一碳-7-烯、喹啉、含取代基的喹啉、三乙烯二胺、四乙基碘化铵、四丁基碘化铵、四丁基溴化铵、四丁基氯化铵、四丁基乙酸铵、三苯基氯硅烷、叔丁基二甲基氯硅烷、三甲基氯硅烷、三甲基氯硅烷络合物、氯化锌、氯化铈、氯化铝和氯化铁中的一种或几种;
所述添加剂的摩尔量为式2所示亚胺摩尔量的0.01%~100%。
9.根据权利要求1所述的合成方法,其特征在于,所述CO的气压为1~60atm;
所述反应的温度为50~180℃。
10.根据权利要求1所述的合成方法,其特征在于,所述反应在溶剂介质中进行;
所述溶剂选自苯、氯苯、氟苯、甲苯、三氟甲苯、二甲苯、均三甲苯、1,4-二氧六环、四氢呋喃、苯甲醚、乙腈、苯腈、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、乙二醇二甲醚、甲基叔丁基醚、甲基环戊基醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮和二甲基亚砜中的一种或几种。
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